CA2395240A1

CA2395240A1 - Biallelic markers derived from genomic regions carrying genes involved in central nervous system disorders

Info

Publication number: CA2395240A1
Application number: CA002395240A
Authority: CA
Inventors: Tom Chu; Marta Blumenfeld; Daniel Cohen
Original assignee: Genset S.A.; Tom Chu; Marta Blumenfeld; Daniel Cohen; Serono Genetics Institute S.A.
Current assignee: Merck Biodevelopment SAS
Priority date: 2000-01-13
Filing date: 2001-01-11
Publication date: 2001-07-19
Also published as: EP1285088A2; AU2699901A; WO2001051659A3; WO2001051659A2

Abstract

The invention provides polynucleotides including biallelic markers derived from genes involved in CNS disorders and from genomic regions flanking those genes. Primers hybridizing to regions flanking these biallelic markers are also provided. This invention also provides polynucleotides and methods suitable for genotyping a nucleic acid containing sample for one or more biallelic markers of the invention. Further, the invention provides methods to detect a statistical correlation between a biallelic marker allele and a phenotype and/or between a biallelic marker haplotype and a phenotype.

Description

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BIALLELIC MARKERS DERIVED FROM GENOMIC REGIONS CARRYING GENES
INVOLVED IN CENTRAL NERVOUS SYSTEM DISORDERS
FIELD OF THE INVENTION
The present invention is in the held of pharmacogenomics, and is primarily directed to biallelic markers that are located in or in the vicinity of genes that play a role in disorders of the brain and nervous system and to the uses of these markers. The present invention encompasses methods of establishing associations between these markers and central nervous system (CNS) disorders such as psychiatric disorders and neurodegenerative diseases as well as associations between these markers and treatment response to a variety of therapeutic agents. The present invention also provides means to determine the genetic predisposition of individuals to such diseases and means to predict responses to such drugs.
BACKGROUND OF THE INVENTION
Advances in the technological armamentarium available to basic and clinical investigators have enabled increasingly sophisticated studies of brain and nervous system function in health and disease. Numerous hypotheses both neurobiological and pharmacological have been advanced with respect to the neurochemical and genetic mechanisms involved in central nervous system (CNS) disorders, including psychiatric disorders and neurodegenerative diseases. However, CNS disorders have complex and poorly understood etiologies, as well as symptoms that are overlapping, poorly characterized, and difficult to measure.
As a result future treatment regimes and drug development efforts will be required to be more sophisticated and focused on multigenic causes, and will need new assays to segment disease populations, and provide more accurate diagnostic and prognostic information on patients suffering from CNS
disorders.
A, Neurological Basis of CNS Disorders Neurotransmitters serve as signal transmitters throughout the body; therefore, diseases that affect neurotransmission can have serious consequences. Far example, for over 30 years the leading theory to explain the biological basis of many psychiatric disorders such as depression has been the monoamine hypothesis. This hypothesis proposes that depression is partially due to a deficiency in one of the three major biogenic monoamines, namely dopamine, norepinephrine and serotonin, However, this hypothesis has been replaced by one that takes into account the overall function of the brain and no longer only considers a single neuronal system.
Dopamine Dopamine is synthesized via the hydroxylation of tyrosine to dihydroxyphenylalanine (DOPA), involving the enzyme tyrosine hydroxylase (TH) and catechol O-methyl transferase (see Table 2: TH and COMT). Tyrosine hydroxylase is the rate-limiting enzyme in the synthesis of catecholamines such as dopamine and norepinephrine. Dopamine and the enzymes involved in its biosynthesis and degradation are known to be involved in the pathophysiology of a depression, schizophrenia and Parkinson's disease. For example, it is believed tyrosine hydroxylase may be involved in the pathophysiology of psychiatric disorders and positive associations have been reported for tyrosine hydroxylase gene markers in mood disorders.
However, a recent study Was unable to conclude tyrosine hydroxylase variants are related with depressive symptomatology in subjects affected by mood disorder (Serretti A.
et al.; American Journal ofMedical Genetics 81(2):127-130, 1998).
Dopamine, released from the nerve terminals, is largely recaptured by a re-uptake mechanism involving dopamine transporter (DAT) (see Table 2: DAT). Following re-uptake, dopamine is metabolized by monoamine oxidases A and B (MAOA/B) (see Table 2:
MAOA and MAOB). Monoamine oxidase A and B are critical enzymes in deamination of biogenic amines and may be involved in the pathophysiology of rnaj or psychoses, including mood disorder, Parkinson's disease and schizophrenia. Recently, evidence for genetic association between the MAOA gene and bipolar mood disorder was demonstrated in a Caucasian population, but not seen in a Japanese population (Sasaki T. et al.; Biological Psychiatry 44(9):922-924, 1998).
Receptors for dopamine regulate dopaminergic neurotransmission. A plethora of dopamine receptors exist, including the presynaptic dopamine transporter and at least five pharmacologic subtypes (Dl -which is linked to the enzyme adenyl cyclase, DZ -not linked to adenyl cyclase, D3, D4, and DS). Classically, the most extensively investigated dopamine receptor is the DZ receptor, as it is stimulated by dopaminergic agonists for the treatment of Parkinson's disease and blocked by dopamine antagonist neuroleptics for the treatment of schizophrenia (see Table 2: DRD2). Recently, other dopamine receptors, particularly the D~
receptor, have become targets for new antipsychotics in the treatment of Parkinson's disease (see Table 2: DRD4). It appears the interaction of all or some of the dopamine receptors play a role in many CNS disorders. However, only a limited number of studies investigating the association of such disorders with genes of the dopaminergic pathway have been completed and often with conflicting results.
Norepinephrine The noradrenergic system is known to play a large role in the determination of mood, dysfunction of contributes to the "functional" disorders of depression, mania and anxiety. It is believed depressed patients are unable to produce sufficient norepinephrine in some parts of the brain for neuronal transmission, while mania may result from excessive activity or sensitivity of this system.
The amino acid tyrosine, having been actively taken up by adrenergic neurons, is converted to DOPA by means of tyrosine hydroxylase. DOPA is then converted to dopamine and later into norepinephrine in the synaptic vesicles. Conversion of norepinephrine to epinephrine occurs in the adrenal medulla and also in certain restricted parts of the brain.
Catecholamine degradation is enzymatically controlled by MAOAIB
intraneuronally, with the main norepinephrine metabolite being 3-methoxy-4-hydroxyphenylglycol.
The noradrenergic neuron is regulated by a multiplicity of receptors and for norepinephrine, these being designated a~, ocz, ail and (32. Postsynaptic norepinephrine receptors bind norepinephrine released from the presynaptic neuron and activate a molecular cascade in the postsynaptic neuron. Specifically, the activation of a2 receptors causes inhibition of norepinephrine, whereas activation of (31 receptors leads to increased release of norepinephrine from adrenergic terminals (see Table 2: ADRB1R). Systemically, the adrenoreceptor subtypes ocl, a2, (31 and (32 are functional in a variety of other ways ranging from vasodilatation to initiating smooth muscle relaxation. The action of norepinephrine is terminated by the norepinephrine transporter (NET), a membrane protein that serves as a reuptake pump for synaptic norepinephrine (see Table 2: NET). These receptors and transporter are the target of many therapeutic agents currently used to treat psychiatric disorders particularly depression.
Serotonin~5-hydroxytryptamine, SHT~
The serotoninergic system is an anatomically diverse system with pathways that follow closely those of the noradrenergic system, but are quite different from those of the dopaminergic distribution. The physiological functions in which the serotoninergic system is involved include sleep, appetite, nociception, diurnal rhythmicity, neuroendocrine regulation and mood. At the level of consciousness there is also the suggestion that rational thought processes arise, using previously stored information, with the aid of the serotoninergic system.
Serotoninergic projections innervating the hypothalamus influence the secretion of several anterior pituitary hormones. There is evidence that serotonin may serve as the final common pathway by which other neurotransmitters act in controlling secretion of many hormones.
Tryptophan is taken up by active transport into the neurons where it is hydroxylated by tryptophan hydroxylase to 5-hydroxytryptophan (SHTP). The latter is then decarboxylated to serotonin which, following release from the neurons, is recovered by a re-uptake mechanism:
Degradation of serotonin occurs by way of MAOAB and the majority of the metabolites are excreted in the urine.
Serotonin receptors come in 13 or more subtypes that can vary in their sensitivity to serotonin and in the effects they produce. An increasingly complex series of serotonin receptors is being identified. Presynaptic serotonin uptake sites and serotonin receptors designated SHTI
(and further subdivided into SHT,a, SHT,b, SHT,~), SHT2, SHT3, SHT4, and SHT6, have been identified by means of pharmacological studies (see Table 2: SHTT, SHT1A, SHTR2C, SHTR6, and 5HTR7). As a whole, communication between two neurons is complex and may be mediated by more than one neurotransmitter; for example, the serotonergic system may co-exist with other neurotransmitter in the same synapses.
Gamma aminobutyric acid (GABA) Gamma aminobutyric acid (GABA) is an important amino acid which functions as the most prevalent inhibitory neurotransmitter in the central nervous system.
Gamma aminobutyric acid works in partnership with a derivative of Vitamin B-6, pyridoxine, to cross from the axons to the dendrites through the synaptic cleft, in response to an electrical signal in the neuron and inhibits message transmission. This helps control the nerve cells from firing too fast, which would overload the system.
The gamma aminobutyric acid (a) receptor (see Table 2: GABRAS and GABRG2) appears to play a key role in modulating anxiety and could be involved in either the etiology or the pathogenesis of anxiety disorders (Crowe et al. Arn JPsyclZiatry 154:8). A
benzodiazepine binding site is located on this receptor, and ligands that bind to this site can either increase or .
decrease anxiety.
Growth associated protein ~GAP43) Growth associated protein (GAP43) is localized exclusively to nerve tissue and is known to play a role in synaptic transmission and membrane permeability. The expression of GAP43 is associated with mammalian peripheral nerve regeneration (Kosik et al. Neuron 1:127-132, 1988). A polymorphism in the 3'-untranslated region of GAP43 is found at slightly lower frequencies in Alzheimers and Parkinson's patients (Poduslo. Hufn Genet.
92:635-636, 1993).
Subreceptor Activity The activity of subreceptors has also been investigated in recent years for its role in a .
wide range of CNS disorders. When neurotransmitters bind to receptors on the membranes of postsynaptic neurons, they elicit a target response in the cell via a second or third messenger Several different messenger chemicals are known including cyclic adenosine monophosphate (AMP). G proteins serve as signal transduction subunits in the cyclic AMP
pathway (see Table

2: Gbeta3). G protein coupled receptors are thought to have seven membrane spanning domains and have been divided into 2 subclasses: those in which the binding site is in the extracellular domain for example receptors for glycoprotein hormones, such as thyroid stimulating hormone (TSH) and follicle stimulating hormone (FSH) and those in which the ligand binding site is likely to be in the plane of the 7 transmembrane domains for example rhodopsin and receptors for small neurotransmitters and hormones for example muscarinic acetylcholine receptor.
However, orphan G-protein coupled receptor (see Table 2: HM77) does not contain N-linked glycosylation .
sites near the N-terminus like other members of this protein family. .
There is evidence that various monoamine or monoaminergic receptors are able to alter cyclic AMP levels through the same G protein. Therefore, G proteins serve as an important cross-talk mechanism between transmitter systems in the CNS. An abnormality in a G protein or in the responsiveness of cyclic AMP to any of the receptors may result in an alteration in monoaminergic neurotransmission. For example, guanine nucleotide binding protein olfactory type (see Table 2: GOLF) is believed to play a role in signaling involving the cAMP mediated signaling pathway as well as the norepinephrine pathway.
B. Endocrine Basis of CNS Disorders Biological theories of many CNS disorders have long revolved around the main monoamine systems, namely dopamine, norepinephrine and serotonin. It is apparent, however, that these three systems do not completely explain the pathophysiology of many CNS disorders.
The hypothalamic-pituitary-adrenal (HPA) axis, including the effects of corticotrophin-releasing factor and glucocorticoids, plays an important role in the pathophysiology of CNS disorders.
The hypothalamus lies at the top of the hierarchy regulating hormone secretion via the hypothalamus-pituitary-adrenal (HPA) axis. It manufactures and releases peptides that act on the pituitary, thus stimulating or inhibiting the pituitary's release of various hormones into the blood.
These hormones, among them growth hormone, thyroid-stimulating hormone and adrenocorticotrophic hormone (ACTH), control the release of other hormones from target glands.
In addition to functioning outside the nervous system, the hormones released in response to pituitary hormones feed back to the pituitary and hypothalamus. There they deliver inhibitory signals that serve to limit excess hormone biosynthesis. .
Also included in the regulation of the HPA axis is vasopressin receptor 1A
(see Table 2:
AVPR1A). Vasopressin receptors are present in a number of tissues including the anterior pituitary, where they stimulate adrenocorticotrophic hormone (ACTH) release (Thibonnier et al.
Genomics 31: 327-334, 1996).
Dysregulation of the HPA axis appears to be an important feature of many psychiatric .
disorders and neurodegenerative diseases. When a threat to physical or psychological well-being is detected, the hypothalamus amplifies production of corticotrophin-releasing factor (CRF), which induces the pituitary to secrete ACTH (see Table 2: CRF, CRHBP, CRFR1 and CRFR2).
ACTH then instructs the adrenal glands to release cortisol. Therefore, it is believed chronic activation of the HPA axis may lay the ground for illness.
The increased HPA drive is primarily mediated by hypersecretion of corticotrophin-releasing factor. Patients with major depression show increased levels of lumbar cerebrospinal fluid (CSF) corticotrophin-releasing factor as compared to matched controls or patients with other neurologic illnesses (Plotsky, P.M., Psych. Clin. Of North Atyz., 21 (2):293-307, 1998).
Dysregulation of hypothalamic corticotrophin-releasing factor neurons, Whether intrinsic or extrinsic to these neurons, can result in corticotrophin-releasing factor hypersectretion leading to elevations in cortisol followed by adaptive down regulation of both pituitary and central glucocorticoid receptors and corticotrophic-releasing receptors.

The anxiolytic effects of corticotrophin-releasing factor appear to be mediated by the activation of the central noradrenergic system. A CRF-positive projection has been identified linking limbic structures to the noradrenergic locus ceruleus, stimulation of which plays an important role in emotional memory and increases tyrosine hydroxylase activity. Therefore, primary or secondary dysfunction of corticotrophin-releasing factor would be expected to initiate a cascade of maladaptations.
Glucocorticoids and mineralocorticoids are both classes of steroid hormones that play an important role in the HPA axis; and have therefore been implicated in the pathophysiology of various psychiatric disorders and neurodegenerative diseases (see Table 2: GRL
and MLR).
Glucocorticoids exert numerous effects on metabolism, reproduction, inflammation and immunity. In addition, glucocorticoids serve as the primary negative feedback mechanism that regulates the HPA axis. Mineralocorticoids maintain electrolyte balance by regulating salt and water retention in the kidneys.
Brain-derived neurotrophic factor (see Table 2: BDNF) is a member of a group of proteins that includes neurotrophin-31415 and nerve growth factor (NGF) and are believed to play a role in the etiology of a number of CNS-related disorders including schizophrenia and Parkinson's disease (Hawi et al. Psychiatry Research 81: 111-116, 1998 and Gasser et al. Annals ofNeurology 36(3)387-396, 1994). BDNF plays an important role in promoting growth and maintenance during normal development and differentiation of the vertebrate system (Hanson et al. Genornics 13: 1331-1333, 1992). Further, it is believed BDNF has an effect on the differentiation of dopaminergic and serotonergic neurons (Studer et al. Euro.
J. of Neuroscience 7: 223-233, 1995).
C. Examples of CNS Disorders Neurotransmitter and hormonal abnormalities are implicated in disorders of movement (e.g. Parkinson's disease, Huntington's disease, motor neuron disease, etc.), disorders of mood (e.g. unipolar depression, bipolar disorder, anxiety, etc.) and diseases involving the intellect (e.g.
Alzheimer's disease, Lewy body dementia, schizophrenia, etc.), In addition, Neurotransmitter and hormonal abnormalities have been implicated in a wide range of disorders, such as coma, head injury, cerebral infarction, epilepsy, alcoholism and the mental retardation statesvof metabolic origin seen particularly in childhood.
Schizophrenia In developed countries schizophrenia occurs in approximately one per cent of the adult population at some point during their lives. There are an estimated 45 million people with schizophrenia in the world, with more than 33 million of them in the developing countries.
Moreover, schizophrenia accounts for a fourth of all mental health costs and takes up one in three psychiatric hospital beds. Most schizophrenia patients are never able to work.
The cost of schizophrenia to society is enormous. In the United States, for example, the direct cost of treatment of schizophrenia has been estimated to be close to 0.5% of the gross national product.
Standardized mortality ratios (SMRs) for schizophrenic patients are estimated to be two to four times higher than the general population and their life expectancy overall is 20 % shorter than for the general population.
The most common cause of death among schizophrenic patients is suicide (in 10%
of patients) which represents a 20 times higher risk than for the general population. Deaths from heart disease and from diseases of the respiratory and digestive system are also increased among schizophrenic patients.
Schizophrenia comprises a group of psychoses with either'positive' or'negative' symptoms. Positive symptoms consist of hallucinations, delusions and disorders of thought;
negative symptoms include emotional flattening, lack of volition and a decrease in motor activity.
A number of biochemical abnormalities have been identified and, in consequence, several neurotransmitter-based hypotheses have been advanced over xecent years; the most popular one has been "the dopamine hypothesis," one variant of which states that there is over-activity of the mesolimbic dopamine pathways at the level of the Dz receptor.
However, researchers have been unable to consistently find an association between various receptors of the dopaminergic system and schizophrenia.
In addition to the hypotheses which are briefly presented here, and which attempt to draw together the neurochemical observations in schizophrenia, one should add that some abnormalities of cortical neuropeptides are well documented. These abnormalities include changes in the levels of somatostatin, substance P, cholecystokinin (CCK) and vasoactive intestinal peptide (VIP) found in association with negative symptom defect states in the temporal area of the brain (i.e. the hippocampus, amygdala and neocortex), in particular. ' Bipolar Disorder Bipolar disorders are relatively common, occurnng in about 1.3% of the population, and ' have been reported to constitute about half of the mood disorders seen in psychiatric clinics.
Bipolar disorders have been found to vary with gender depending of the type of disorder; for example, bipolar disorder I is found equally among men and women, while bipolar disorder II is reportedly more common in women. The age of onset of bipolar disorders is typically in the teenage years and diagnosis is typically made in the patient's early twenties.
Bipolar disorders also occur among the elderly, generally as a result of a neurological disorder or other medical conditions. In addition to the severe effects on patients' social development, suicide completion rates among bipolar patients are reported to be about 15%.
Bipolar disorders are characterized by phases of excitement and depression;
the excitement phases (mania) and depressive phases can alternate or occur in numerous admixtures with varying degrees of severity and duration. Because bipolar disorders can exist in different forms and display different symptoms, the classification ofbipolar disorder has been the subject of extensive studies resulting in the definition of bipolar disorder subtypes and widening of the overall concept to include patients previously thought to be suffering from different disorders.
Bipolar disorders often share certain clinical signs, symptoms, treatments and neurobiological features with psychotic illnesses in general and therefore present a challenge to the psychiatrist to make an accurate diagnosis. Furthermore, because the course of bipolar disorders and various mood and psychotic disorders can differ greatly, it is critical to characterize the illness as early as possible in order to offer means to manage the illness over a long term.
Diagnosis of bipolar disorder can be very challenging. One particularly troublesome difficulty is that some patients exhibit mixed states, simultaneously manic and dysphoric or depressive, but do not fall into the DSM-IV classification because not all required criteria for mania and major depression are met daily for at least one week. Other difficulties include classification of patients in the DSM-IV groups based on duration of phase since patients often cycle between excited and depressive episodes at different rates. In particular, it is reported that the use of antidepressants may alter the course of the disease for the worse by causing "rapid-cycling". Also making diagnosis more difficult is the fact that bipolar patients, particularly at what is known as Stage III mania, share symptoms of disorganized thinking and behavior with bipolar disorder patients. Furthermore, psychiatrists must distinguish between agitated depression and mixed mania; it is common that patients with major depression exhibit agitation, resulting in bipolar-like features.
For both schizophrenia and bipolar disorder, all the known molecules used for treatment have side effects and act only against the symptoms of the disease. There is a strong need for new molecules without associated side effects or reduced side effects which are directed against targets that are involved in the causal mechanisms of schizophrenia and bipolar disorder.
Therefore, tools facilitating the discovery and characterization of these targets are necessary and useful.
The aggregation of schizophrenia and bipolar disorder in families, the evidence from twin and adoption studies, and the lack of variation in incidence worldwide, indicate that schizophrenia and bipolar disorder are primarily genetic conditions, although environmental risk factors are also involved at some level as necessary, sufficient, or interactive causes. For example, schizophrenia occurs in 1% of the general population. However, if a subject has one grandparent with schizophrenia, the risk of getting the illness increases to about 3%, while one parent with Schizophrenia increases risk to about 10%. When both parents have schizophrenia, the risk rises to approximately 40%. Consequently, there is a strong need to identify genes involved in schizophrenia and bipolar disorder. The knowledge of these genes will allow researchers to understand the etiology of schizophrenia and bipolar disorder and could lead to drugs and medications which are directed against the cause of the diseases, not just against their symptoms.
There is also a great need for new methods to detect susceptibility to schizophrenia and bipolar disorder, as well as for preventing or following up the development of the disease.
Diagnostic tools could also prove extremely useful. Indeed, early identification of subjects at risk of developing schizophrenia would enable early and/or prophylactic treatment to be administered. Moreover, accurate assessments of the eventual efficacy of a medicament as well as the patent's eventual tolerance to it may enable clinicians to enhance the benefit/risk ratio of schizophrenia and bipolar disorder treatment regimes.
Depression Depression is a serious medical illness that affects 340 million people worldwide. In contrast to the normal emotional experiences of sadness, loss, or passing mood states, clinical depression is persistent and can interfere significantly with an individual's ability to function. As a result, depression is the leading cause of disability throughout the world with an estimated cost of $53 billion each year in the United States alone.
Symptoms of depression include depressed mood, diminished interest or pleasure in activities, change in appetite or weight, insomnia or hypersomnia, psycho-motor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive guilt, anxiety, inability to concentrate or act decisively, and recurrent thoughts of death or suicide. A diagnosis of unipolar major depression (or major depressive disorder) is made if a person has five or more of these symptoms and impairment in usual functioning nearly every day during the same two-week period. The onset of depression generally begins in late adolescence or early adult life;
however, recent evidence suggests depression may be occurring earlier in life in people born in the past thirty years.
The World Health Organization predicts that by the year 2020 depression will be the greatest burden of ill-health to people in the developing world, and that by then depression will be the second largest cause of death and disability. Beyond the almost unbearable misery it causes, the big risk in major depression is suicide. Within five years of suffering a major depression, an estimated 25% of sufferers try to kill themselves. In addition, depression is a frequent and serious complication of heart attack, stroke, diabetes, and cancer. According to one recent study that covered a 13 year period, individuals with a history of maj or depression were four times as likely to suffer a heart attack compared to people without such a history.
Depression may be a feature in up to 50% of patients with CNS disorders such as Parkinson's disease and Alzheimer's disease. The neuronal loss in the locus ceruleus, typical of Alzheimer's disease, is greatest in those patients who have depression; such patients also have lower norepinephrine levels than do those who lack depressive features.
Approximately 50% of patients with Alzheimer's disease have less norepinephrine than normal in the majority of cortical and subcortical areas of the brain that have been examined to date.
Many neurochemical findings are coming to light implicating a biological basis for the depression, at least for certain subtypes. Abnormalities of monoamine function have been xecognized in depression for many years involving norepinephrine, serotonin and dopamine.
Changes in adrenoceptor density and function as well as changes in adrenoceptors associated with the pituitary-adrenal axis function strongly implicate a disorder in central noxadrenergic transmission in depression. This dysfunction may be caused by changes in the activity of tyrosine hydroxylase. The effect of corticotrophin releasing factor in modulating the activity of noradrenergic neurons in the locus ceruleus may provide the link between environmental trigger factors and central noradrenergic dysfunction, along with dysfunction of the HPA axis.
Dysfunction of serotonin metabolism, as shown by decreased concentrations of the metabolite SHIAA in cerebrospinal fluid (CSF), is linked with depression;
nevertheless, it is not a feature in all patients with depression. Therefore, a subgroup entitled "serotonin depression"
has been proposed. Often included among those who suffer from serotonin depression are patients who also suffer a number of neurological diseases. A reduction in the number of serotonin-containing neurons in the median raphe in Parkinson's disease, Alzheimer's disease and, possibly, the elderly, is associated with the development of depression.
Low levels of the dopamine metabolite HVA are found in the CSF in patients with depression. In addition, dopamine agonists produce a therapeutic response in depression.
Presently, antidepressants are designed to address many of the symptoms of depression by increasing neurotransmitter concentration in aminergic synapses. Distinct pharmacologic mechanisms allow the antidepressants to be separated into seven different classes. The two classical mechanisms are those of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs): The most widely prescribed agents are the serotonin selective reuptake inhibitors (SSRIs). Three other classes of antidepressants, like the SSRIs, increase serotonergic neurotransmission, but they also have additional actions, namely dual serotonin and norepinephrine reuptake inhibition; serotonin-2 antagonism/reuptake inhibition; and a2 antagonism plus serotonin-2 and -3 antagonism. The selective norepinephrine and dopamine reuptake inhibitors define a novel class of antidepressant that has no direct actions on the serotonin system.
Recent findings suggest some re-appraisal and modifications of the monoamine hypothesis are necessary. The increased levels of monoamine transmitters at the synapses, although quickly produced in response to antidepressant therapy, are in contrast with the much slower clinical recovery of the patient from depression, which takes about two weeks to begin and may only reach maximal levels several weeks later. Moreover, should acute depletion of either norepinephrine and/or serotonin occur experimentally in a normal individual, then depression does not, in the short-term, occur. Not in keeping with the hypothesis, too, is the cerebral resistance generated in response to the pharmacological changes induced by antidepressant compounds. These counteractive changes comprise reduction in the number of post-synaptic (3-receptors, together with a lowered firing rate of noradrenergic neurons.
In addition, there are subsets of patients with differential responses to antidepressants.
Thus far, biochemical predictors of treatment response have failed to identify definite parameters that could correctly identify patients more likely to respond to particular classes of antidepressants (Schatzberg, Alan F., Journal of Clinical Psychiatry, 59:15-18, 1998). As a result, psychiatrists often must choose a treatment based on intuition or trail and error. However, probes such as biallelic markers could serve as an invaluable tool to successfully identify patients who might respond preferentially to existing and new antidepressants (Charney, Dennis S, Journal of Clinical Psychiatry, 59:11-14, 1998). In particular, markers from genes known to affect drug response such as transcription factors (see Table 2: SEF-1B) and drug metabolizing enzymes (see Table 2: CYP3A4) need to be investigated to determine "responders" and "non-responders" to medicaments.
While modulating monoamine activity as a therapeutic strategy continues to dominate research, an important new development has been the emergence of novel mechanisms of action, notably modulation of the activity of neuropeptides, namely through the neuropeptide receptor Y1, the tachykinin NK1 receptor and nicotinic receptors (see Table 2: NPY1R, TACRl and CHRNA7). Recent clinical trails showed that tachykinin NK1 receptor antagonists are effective in treating depression and chemotherapy-induced emesis. Therefore, it is well possible that such antagonists will be clinically useful for treatment of specific CNS disorders.
Nicotinic receptors are known to serve as important ligand-gated ion channels active in classical, excitatory neurotransmission and perhaps more novel forms of neurochemical signaling.
Their critical functional roles both centrally and peripherally make them ideal targets for regulation of the nervous system. Finally, new antidepressants that may render the HPA axis more sensitive to glucocorticoid feedback are being investigated as well.
In addition to monoamine dysfunction as a possible cause of depression, researchers have reported increased activity in the HPA axis in untreated depressed patients, as evinced by raised levels of cortisol in urine, blood and cerebrospinal fluid, as well as by other measures.
Numerous studies have confirmed that substantial numbers of depressed patients, particularly those most severely affected, display HPA axis hyperactivity. Patients with depression frequently have symptom clusters which point strongly to involvement of the HPA system as a relay station between neurocircuitries in the brain and peripheral hormone and autonomic nervous function. It has been proposed that this increased, state-dependent hyperactivity of the HPA system in depression is probably initiated and/or maintained by the combination of enhanced central production of corticotrophin-releasing factor and desensitization of the binary, glucocorticoid receptor binding system in the hippocampus, which is the central regulator of HPA system activity.
Deeper investigation of the phenomenon has now revealed alterations at each level of the HPA axis in depressed patients. For instance, both the adrenal gland and the pituitary are enlarged, and the adrenal gland hypersecretes cortisol. But many researchers, have become persuaded that aberrations in GRF-producing neurons of the hypothalamus and elsewhere bear most of the responsibility for HPA axis hyperactivity and the emergence of depressive symptoms.
Many studies have shown corticotrophin-releasing factor concentrations in cerebrospinal fluid to be elevated in depressed patients, compared with control subjects or individuals with other psychiatric disorders. This magnification of corticotrophin-releasing factor levels is reduced by treatment with antidepressants and by effective electroconvulsive therapy. Further, postmortem brain tissue studies have revealed a marked exaggeration both in the number of CRF-producing neurons in the hypothalamus and in the expression of the corticotrophin-releasing factor gene (resulting in elevated corticotrophin-releasing factor synthesis) in depressed patients as compared with controls. Moreover, delivery of corticotrophin-releasing factor to the brains of laboratory animals produces behavioral effects that are cardinal features of depression in humans, namely, insomnia, decreased appetite, decreased libido and anxiety.
Geneticists have provided some of the oldest proof of a biological component to depression in many people. Depression and manic-depression frequently run in families. Thus, close blood relatives of patients with severe depressive or bipolar disorder are much more likely to suffer from those or related conditions than are members of the general population. Studies of identical and fraternal twins also support an inherited component. Illness in both members of a pair is much higher for manic-depression in identical twins than in fraternal and is somewhat , elevated for depression alone.
In the past 20 years, genetic researchers have expended great effort trying to identify the genes which contribute to depression. So far, though, those genes have evaded discovery, perhaps because a predisposition to depression involves several genes, each of which makes only a small, hard-to-detect contribution. As a result, psychiatrists today have to choose antidepressant medications by intuition and trial and error; a situation that can put suicidal patients in jeopardy for weeks or months until the right compound is selected.
Therefore, there is a strong need to successfully identify genes involved in depression; thus allowing researchers to understand the etiology of depression and address its cause, rather than symptoms.
Alzheimer's Disease ~ Alzheimer's disease is characterized by the onset in middle age of a slowly progressive dementia; there is loss of memory for past events, inability to develop new memories and impairment of intellect, all leading to a lessened capacity for dealing with the tasks and problems of daily living. It is the most common cause of both presenile and senile dementia. Alzheimer's disease is not the non-specific degenerative disorder of the CNS that it was once thought to be, as neurochemical studies on postmortem material now reveal the degeneration to be selective for certain neuronal populations in the subcortical and cortical areas; other cell populations seem to be unaffected. Senile plaques and neurofibrillary tangles are the characteristic histological feature, found throughout the cerebral cortex and especially in certain regions of the limbic system (the amygdala and hippocampus), perhaps accounting for the memory loss so typical of the early phase of the disease. In addition, there is reduction of acetylcholine, norepinephrine, serotonin and somatostatin in the subcortical areas in Alzheimer's disease.
The activity of CAT, the enzyme involved in acetylcholine synthesis, is markedly decreased in Alzheimer's disease. This decrease does not occur in all areas of the brain, but does so particularly in the hippocampus and amygdala, which are some of the main sites where senile plaques and neurofibrillary tangles accumulate. The loss of such cortical cholinergic activity correlates well with he degree of dementia in patients with this disease. A
further finding is that ~ nerve growth factor (NGF) is now known to be involved in the maintenance of cholinergic neurons in the forebrain; also, nicotine, a cholinomimetic compound, is able to stimulate dopaminergic neurons via their nicotinic receptors; thus, seemingly, to provide smokers with some protection against degeneration of the dopaminergic neurons. The forebrain cholinergic system degenerates not only in Alzheimer's disease, but also in alcohol-induced dementia, Pick's , disease, Lewy body dementia, progressive supranuclear palsy and in Parkinson's disease.
In Alzheimer's disease there is a reduction of both serotonin and its receptor proteins in the temporal lobe of the brain, as revealed from studies on autopsy and biopsy material. The loss of serotonin is, however, less than in Parkinson's disease and it would be unlikely, therefore, that the severe memory loss of Alzheimer's disease could be accounted for on this basis alone, although in Parkinson's disease there is an important difference in that the SHT~ receptor is not decreased. Of interest in this context, but not necessarily related, is the bradyphrenia (characterized by difficulty in concentration, slowing of thought processes and inability to associate ideas) of Parkinson's disease where serotonin is low in most of the cortical regions. In the Lewy body type of senile dementia it is common for visual hallucinations to occur, and ~it is of great interest that in the temporal lobe the serotonergic activity is higher (as shown by the raised serotonergic:cholinergic ratio) in those patients who suffer from hallucinations compared with those who do not.
In addition to the involvement of serotonin in Alzheimer's disease, patients also suffer from decreased levels of norepinephrine and several neuropeptides. It is in those patients with Alzheimer's disease who also have depression that there is not only greatest reduction in the number of neurons within the locus ceruleus but also a markedly reduced norepinephrine content.
There is also associated reduction in cortical somatostatin and corticotrophin-releasing factor, and loss of the somatostatin content of neurons in the temporal cortex develops early in the condition.
There is no laiown definitive cure for Alzheimer's disease; therefore, treatment is aimed at relief of symptoms and protection from the effects of the deteriorating condition. Most treatments are still considered experimental or have had variable results.
Treatment is also aimed at underlying disorders that contribute to confusion such as heart failure, hypoxia, thyroid disorders, anemia, nutritional disorders, infections, and psychiatric conditions such as depression.
The correction of coexisting medical and psychiatric disorders often improves the patient's mental function.
Parkinson's Disease Parkinson's disease is, a disabling progressive neurodegenerative disorder characterized by tremor, rigidity, bradykinesia, and loss of postural reflexes. In the United States, about a million people are believed to suffer from Parkinson's disease, and about 50,000 new cases are reported every year. Because the symptoms typically appear later in life, these Tables are expected to grow as the average age of the population increases over the next several decades:
The disorder is most frequent among people in there 70s and 80s, and appears to be slightly more common in men than in women. Parkinson's disease is found all over the world.
The rates vary from country to country, but it is not clear whether this reflects true ethnic or geographic differences or simply variations in data collection.
The pathology is not completely understood, but there appears to be consistent changes in the melanin-containing nerve cells in the brainstem (substantia nigra, locus ceruleus), where there are varying degrees of nerve cell loss with reactive gliosis along with eosinophilic intracytoplasmic inclusions (Lewy bodies). As a result, the primary neurochemical defect in Parkinson's disease is the loss of dopaminergic projections to the striatum.
Moreover, the loss of these populations of neurons also leads to neurotransmitter deficits, but to a lesser~extent than that which accompanies the massive degeneration of dopaminergic neurons. For example, norepinephrine, serotonin and acetylcholine are variably decreased in Parkinson's disease dueao .
loss of neurons in the locus ceruleus, raphe nuclei and the nucleus basalis of Meynert. Thus, some of the secondary clinical features of Parkinson's disease have been ascribed to these neurotransmitter deficits.
The neurochemical defect associated with Parkinson's disease can be partially corrected by L-DOPA, which helps replace the brain's dopamine, but cannot reverse the progression of the disease. There is no specific biological test for the diagnosis of Parkinson's disease. Twin studies have shown variable results and suggest that the genetics of this disorder will prove to be ' complex. Despite the importance and severity of Parkinson's disease and many years of research, a cause has not been identified and there is neither means of preventing the disease nor a proven permanent cure.

Findings of considerable importance in this search would be the location of a genetic marker, determination of the probability of penetrance, determination of possible genetic heterogeneity, and evidence of multifactorial inheritance with environmental interaction. Genetic factors determining susceptibility to Parkinson's disease will enhance epidemiological studies and possibly lead to identification of susceptible groups and of significant risk factors.
HuntinQton's Disease Huntington's disease is a hereditary neurodegenerative disease that generally develops subtly in a person's thirties or forties; though it can begin any time between childhood and old age. In the United States alone, about 30,000 people have Huntington's disease, while at least 150,000 others have a 50 percent risk of developing the disease and thousands more of their relatives live with the possibility that they, too, might develop Huntington's disease.
Huntington's disease is characterized by difficulties in three areas: a movement disorder, dementia, and psychiatric disturbances. The movement disorder consists of two parts:
involuntary twitching movement which first tend to involve the fingers and toes and then progress to include the whole body, and difficulties with voluntary movements in the form of clumsiness, stiffness, or trouble with walking. Dementia refers to a gradual loss of intellectual abilities such as memory, concentration, problem solving, and judgment.
Psychiatric disturbances do not strike every person with Huntington's disease, but when they do, usually take the form of depression, irritability, and apathy. Depression and other psychiatric conditions in people with Huntington's disease, which seem to result from damage to the brain, can be debilitating.
Loss of neurotransmitter receptors, especially glutamate and dopamine receptors, is one of the pathologic hallmarks of patients with Huntington's disease (Cha J.H. et al.; Proc National Acad Sci USA rnay 26;95(11):6480-5, 1998). In addition, deficiency of GABA
permits excessive dopaminergic activity in the corpus striatum resulting in onset of Huntington's disease, on account of the imbalance generated between cholinergic and dopaminergic systems.
Researchers have identified a single gene product thought to be causal when mutated by a tri-nucleotide repeat expansion. However, there is at present no cure for Huntington's disease or even any direct treatments, although researchers are presently working on a number of treatments which may slow down the progression of the disease. In the early and middle stages of the disease, medications called neuroleptics, which are given in larger doses for psychiatric complaints, can be given in small doses to Huntington's disease patients to suppress the involuntary movements. Drugs that cause increased dopamine release in the brain and dopamine -receptor agonists are used, but both precipitate nausea and vomiting as side effects and dopamine antagonists are anti-emetic.
Pharmaco~enomics and CNS Disorders The vast majority of common diseases, such as all of the CNS disorders described above, are polygenic, meaning multiple genes cause them. In addition, these diseases are modulated by environmental factors such as pollutants, chemicals and diet. This is why many diseases are considered to be multifactorial; they result from a synergistic combination of factors, both genetic and environmental. Therapeutic management and drug development could be markedly improved by the identiftcation of specific genetic polymorphisms that determine and predict patient susceptibility to diseases or patient responses to drugs.
To assess the origins of individual variations in disease susceptibility or drug response, pharmacogenomics uses the genomic technologies to identify polymorphisms within genes which are part of biological pathways involved in disease susceptibility, etiology, and development, or more specifically in drug response pathways responsible for a drug's efficacy, tolerance or toxicity. Pharmacogenomics can also provide tools to refine the design of drug development by decreasing the incidence of adverse events in drug tolerance studies, by better ' defining patient subpopulations of responders and non-responders in efficacy studies and, by combining the results obtained therefrom, to further allow better enlightened individualizeddrug usage based on efficacy/tolerance prognosis. Pharmacogenomics can also provide tools to identify new targets for designing drugs and to optimize the use of already existing drugs, in order to either increase their response rate and/or exclude non-responders from corresponding treatment, or decrease their undesirable side effects andlor exclude from corresponding treatment patients with marked susceptibility to undesirable side effects. However, for pharmacogenomics to become clinically useful on a large scale, additional molecular tools and diagnostics tests must become available.
Genetic Analysis of Complex Traits Until recently, the identification of genes linked with detectable traits has relied mainly on a statistical approach called linkage analysis. Linkage analysis is based upon establishing a correlation between the transmission of genetic markers and that of a specific trait throughout generations within a family. Linkage analysis involves the study of families with multiple .
affected individuals and is useful in the detection of inherited-traits, which are caused by a single .
gene, or possibly a very small number of genes. Linkage analysis has been successfully applied to map simple genetic traits that show clear Mendelian inheritance patterns and which have. a high penetrance (the probability that a person with a given genotype will exhibit a trait). About 100 pathological trait-causing genes have been discovered using linkage analysis over the last 10 years. But, linkage studies have proven difficult when applied to complex genetic traits. Most traits of medical relevance do not follow simple Mendelian monogenic inheritance. However, complex diseases often aggregate in families, which suggests that there is a genetic component to be found. Such complex traits are often due to the combined action of multiple genes as well as environmental factors. Such complex trait, include susceptibilities to heart disease, hypertension, diabetes, cancer and inflammatory diseases. Drug efficacy, response and tolerance/toxicity can also be considered as multifactoral traits involving a genetic component in the same way as complex diseases. Linkage analysis cannot be applied to the study of such traits for which no large informative families are available. Moreover, because of their low penetrance, such complex traits do not segregate in a clear-cut Mendelian manner as they are passed from one generation to the next. Attempts to map such diseases have been plagued by inconclusive results, demonstrating the need for more sophisticated genetic tools.
Knowledge of genetic variation in the neuronal and endocrine systems is important for understanding why some people are more susceptible to disease or respond differently to treatments. Ways to identify genetic polymorphism and to analyze how they impact and predict disease susceptibility and response to treatment are needed.
Although the genes involved in the neuronal and endocrine systems represent major drug targets and are of high relevance to pharmaceutical research we. still have scant knowledge concerning the extent and nature of, sequence variation in these genes and their regulatory elements. In the case where polymorphisms have been identified the relevance of the variation is .
rarely understood. While polymorphisms hold promise for use as genetic markers in determining which genes contribute to multigenic or quantitative traits, suitable markers and suitable methods for exploiting those markers have not been found and brought to bare on the genes related to disorders of the brain and nervous system.
In the cases where polymorphisms have been identified, the relevance of the variation is rarely understood. While polymorphisms hold promise for use as genetic markers in determining which genes contribute to multigenic or quantitative traits, suitable markers and suitable methods for exploiting those markers have not been found and brought to bare on the genes related to central nervous system disorders.
SUMMARY OF THE INVENTION
The present invention is based on the discovery of a set of novel CNS disorder-related biallelic markers. 'See Table 7. These markers are located in the coding regions as well as non-coding regions adjacent to genes which express proteins associated with CNS
disorders. The position of these markers and knowledge of the surrounding sequence has been used to design polynucleotide compositions which are useful in determining the identity of nucleotides at the marker position, as well as more complex association and haplotyping studies which are useful in determining the genetic basis for disease states involving the neuronal and endocrine systems. In addition, the compositions and methods of the invention find use in the identification of the targets for the development of pharmaceutical agents and diagnostic methods, as well as the characterization of the differential efficacious responses to and side effects from pharmaceutical agents acting on CNS disorders. Further, the compositions and methods of the invention may be employed in a process for screening for antagonists and/or agonists for the polypeptides of the invention. Such molecules may prove useful as therapeutics in the diagnosis and/or treatment of CNS disorders, particularly depression.
A first embodiment of the invention encompasses polynucleotides consisting of, consisting essentially of, or comprising a contiguous span of nucleotides of a sequence selected as an individual or in any combination from the group consisting of SEQ ID N0:
1-542, the complements thereof, the sequences described in arty one or more of Tables 8, 9, 10, 1 l, 12, 13 and 14 and the complements thereof, wherein said contiguous span is at least 6, 8, 10, 12, 15, 20, 25, 30, 35, 40, 50, 75, 100, 200, 500 or 1000 nucleotides in length, to the extent that such a ' length is consistent with the lengths of the particular Sequence ID. The present invention also relates to polynucleotides hybridizing under stringent or intermediate conditions to a sequence selected from the group consisting of SEQ m NO: 1-542; and the complements thereof. In addition, the polynucleotides of the invention encompass polynucleotides with any further limitation described in this disclosure, or those following, specified alone or in any combination:
Said contiguous span may optionally include the CNS disorder-related biallelic marker in said sequence; Optionally either the original or the alternative allele of Table 9 may be specified as ,being.present at said CNS disorder-related biallelic marker; Optionally either the first or the.
second allele of Tables 8 or 10 may be specified as being present at said CNS
disorder-related biallelic marker; Optionally, said polynucleotide may consists of, or consist essentially of a .
contiguous span which ranges in length from 8, 10, 12, 15, 18 or 20 to 25, .35, 40, 50, 60, 70, or 80 nucleotides, or be specified as being 12, 15, 18, 20, 25, 35, 40, or 50 nucleotides in length and including a CNS disorder-related biallelic marker of said sequence, and optionally the original allele of Table 9 is present at said biallelic marker; Optionally, said biallelic marker may be within 6, 5, 4, 3, 2, or 1 nucleotides of the center of said polynucleotide or at the centex of said 2S polynucleotide; Optionally, the 3' end of said contiguous span may be present at. the 3' end of said polynucleotide; Optionally, biallelic marker may be present at the 3' end of said polynucleotide; Optionally, the 3' end of said polynucleotide may be located within or at least 2, ~4, 6, 8, 10, 12, 15, 18, 20, 25, 50, 100, 250, 500 or 1000 nucleotides upstream of a CNS disorder-related biallelic marker in said sequence, to the extent that such a distance is consistent with'the lengths of the particular Sequence >D; Optionally, the 3' end of said polynucleotide may be located 1 nucleotide upstream of a CNS disorder-related biallelic marker in said sequence; and -Optionally, said polynucleotide may further comprise a label. .
A second embodiment of the invention encompasses any polynucleotide of the invention attached to a solid support. In addition, the polynucleotides of the invention which are attached to a solid support encompass polynucleotides with any further limitation described in this disclosure, or those following, specified alone or in any combination:
Optionally, said polynucleotides may be specified as attached individually or in groups of at least 2, 5, 8, 10, 12, 15, 20, or 25 distinct polynucleotides of the inventions to a single solid support; Optionally, polynucleotides other than those of the invention may be attached to the same solid support as polynucleotides of the invention; Optionally, when multiple polynucleotides are attached to a solid support they may be attached at random locations, or in an ordered array; Optionally, said ordered array may be addressable.
A third embodiment of the invention encompasses the use of any polynucleotide for, or any polynucleotide for use in, determining the identity of one or more nucleotides at a CNS
disorder-related biallelic marker. Microsequencing primers are provided in Table 12. In addition, the polynucleotides of the invention for use in determining the identity of one or more nucleotides at a CNS disorder-related biallelic marker encompass polynucleotides with any further limitation described in this disclosure, or those following, specified alone or in any . combination. Optionally, said CNS disorder-related biallelic marker may be in a sequence selected individually or in any combination from the group consisting of SEQ m NO: 1-542; and the complements thereof; Optionally, said polynucleotide may comprise a sequence disclosed in the present specification; Optionally, said polynucleotide may consist of, or consist essentially of any polynucleotide described in the present specification; Optionally, said determining may be performed in a hybridization assay, sequencing assay, microsequencing assay, or an enzyme-based mismatch detection assay; Optionally, said polynucleotide may be attached to a solid support, array, or addressable array; Optionally, said polynucleotide may be labeled.
A fourth embodiment of the invention encompasses the use of any polynucleotide for, or any polynucleotide for use in, amplifying a segment of nucleotides comprising a CNS disorder-related biallelic marker. Amplification primers are provided in Table 13. Tn addition, he polynucleotides of the invention for use in amplifying a segment of nucleotides comprising a CNS disorder-related biallelic marker encompass polynucleotides with any further limitation .
described in this disclosure, or those following, specified alone or in any combination:
Optionally, said CNS disorder-related biallelic marker may be in a sequence selected individually or in any combination from the group consisting of SEQ )D 1-130; and the complements thereof;
Optionally, said CNS disorder-related biallelic marker may be selected individually or~in any combination from the biallelic markers described in Table 7; Optionally, said CNS disorder-related biallelic marker may be selected from the following biallelic markers:
99-27207-117, 99-28110-75, 99-28134-215, 99-32181-192, 99-28106-185, 99-30858-354, 18-20-174, 313, 18-31-178, 18-38-395, 99-30853-364, 19-56-140, 19-28-136, 99-28788-300, 99-32061-304, 99-32121-242, 19-14-241, 16-50-196, 8-19-372, 12-254-180, 10-214-279, 10-217-91, 18-194-130, 18-186-391, 18-198-252, 18-242-300, 20-205-302, 19-58-162, 19-9-45, 19-22-74, 19-88-185, 19-18-310, 19-19-174, 19-17-188, 19-16-127, 99-32148-315, 19-46-322, 99-32131-312, 99-32065-303, 19-44-251, 19-29-303, 18-355-67, 18-353-267, 18-338-305, 16-88-185, 24-243-346, 99-62531-351, 99-54279-152, 99-28171-458, 99-28173-395, 18-186-394, 8-15-126, 298, 99-28?22-90 and 99-32306-409; Optionally, said CNS disorder-related biallelic marker may be selected from the following biallelic markers: 99-28788-300, 99-32061-304, 99-32121-242, 19-14-241, 19-28-136, 16-50-196, 19-58-162, 19-9-45, 20-205-302, 24-243-346, 99-27207-117, 99-28110-75, 99-28134-215, 99-32181-192, 19-17-188 and 19-19-174;
Optionally, said polynucleotide may comprise a sequence disclosed in the present specification;
Optionally, said polynucleotide may consist of, or consist essentially of any polynucleotide described in the present specification; Optionally, said amplifying may be performed by a PCR
or LCR.
Optionally, said polynucleotide may be attached to a solid support, array, or addressable array.
Optionally, said polynucleotide may be labeled.
A fifth embodiment of the invention encompasses methods of genotyping a biological sample comprising determining the identity of a nucleotide at a CNS disorder-related biallelic marker. In addition, the genotyping methods of the invention encompass methods with any further limitation described in this disclosure, or those following, specified alone or in any combination: Optionally, said CNS disorder-related biallelic marker may be in a sequence selected individually or in any combination from the group consisting of SEQ m NO: 1-542, and the complements thereof; Optionally, said CNS disorder-related biallelic marker may be selected individually or in any combination from the biallelic markers described in Table 7; Optionally, said CNS disorder-related biallelic marker may be selected from the following biallelic markers:
99-27207-117, 99-28110-75, 99-28134-215, 99-32181-192, 99-28106-185, 99-30858-354, 18-.20 20-174, 99-32002-313, 18-31-178, 18-38-395, 99-30853-364, 19-56-140,-19-28-136, 99-28788-300, 99-32061-304, 99-32121-242, 19-14-241, 16-50-196, 8-19-372, 12-254-180, 10-214-279, 10-217-91, 18-194-130, 18-186-391, 18-198-252, 18-242-300, 20-205-302, 19-58-162, 19-9-45, 19-22-74, 19-88-185, 19-18-310, 19-19-174, 19-17-188, 19-16-127, 99-32148-315, 19-46-322;
99-32131-312, 99-32065-303, 19-44-251, 19-29-303, 18-355-67, 18-353-267, 18-338-305, 16-88-185, 24-243-346, 99-62531-351, 99-54279-152, 99-28171-458, 99-28173-395, 18-186-394, 8-15-126, 99-2409-298, 99-28722-90 and 99-32306-409; Optionally, said CNS
disorder-related biallelic marker may be selected from the following biallelic markers: 99-28788-300, 99-32061-304, 99-32121-242, 19-14-241, 19-28-136, 16-50-196, 19-58-162, 19-9-45, 20-205-302, 24-243-346, 99-27207-117, 99-28110-75, 99-28134-215, 99-32181-192, 19-17-188 and 19-19-174;
Optionally, said method further comprises determining the identity of a second nucleotide at said biallelic marker, wherein said first nucleotide and second nucleotide are not base paired (by Watson & Crick base pairing) to one another; Optionally, said biological sample is derived from a single individual or subject; Optionally, said method is performed in vitro;
Optionally, said biallelic marker is determined for both copies of said biallelic marker present in said individual's genome; Optionally, said biological sample is derived from multiple subjects or individuals;
Optionally, said method further comprises amplifying a portion of said sequence comprising the biallelic marker prior to said determining step; Optionally, wherein said amplifying is performed by PCR, LCR, or replication of a recombinant vector comprising an origin of replication and said portion in a host cell; Optionally, wherein said determining is performed by a hybridization assay, sequencing assay, microsequencing assay, or an enzyme based mismatch detection assay.
A sixth embodiment of the invention comprises methods of estimating the frequency of an allele in a population comprising genotyping individuals from said population for a CNS
disorder-related biallelic marker and determining the proportional representation of said biallelic marker in said population. In addition, the methods of estimating the frequency of an allele in a population of the invention encompass methods with any further limitation described in this disclosure, or those following, specified alone or in any combination:
Optionally, said CNS
disorder-related biallelic marker may be in a sequence selected individually or in any combination from the group consisting of SEQ NO: 1-542; and the complements thereof;
Optionally, said CNS disorder-related biallelic marker may be selected from the biallelic markers described in Table 7; Optionally, said CNS disorder-related biallelic marker may be selected from the following biallelic markers: 99-27207-117, 99-28110-75, 99-28134-215, 99-32181-192;
99-28106-185, 99-30858-354, 18-20-174, 99-32002-313, 18-31-178, 18-38-395, 99-30853-364, 19-56-140, 19-28-136, 99-28788-300, 99-32061-304, 99-32121-242, 19-14-241, 16-50-196, 8-19-372, 12-254-180, 10-214-279, 10-217-91, 18-194-130, 18-186-391, 18-198-252, 18-242-300, 20-205-302, 19-58-162, 19-9-45, 19-22-74, 19-88-185, 19-18-310, 19-19-174, 19-17-188, 19-16-127, 99-32148-315, 19-46-322, 99-32131-312, 99-32065-303, 19-44-251, 19-29-303; 18-355-67, v 18-353-267, 18-338-305, 16-88-185, 24-243-346, 99-62531-351, 99-54279-152, 99-28171-458, , 99-28173-395, 18-186-394, 8-15-126, 99-2409-298, 99-28722-90 and 99-32306-409;
Optionally, said CNS disorder-related biallelic marker may be selected from the following biallelic markers: 99-28788-300, 99-32061-304, 99-32121-242, 19-14-241, 19-28-136, 16-50-196, 19-58-162, 19-9-45, 20-205-302, 24-243-346, 99-27207-117, 99-28110-75, 99-28134-215, ' 99-32181-192, 19-17-188 and 19-19-174; Optionally, determining the frequency of a biallelic marker allele in a population may be accomplished by determining the identity of the nucleotides for both copies of said biallelic marker present in the genome of each individual in said population and calculating the proportional representation of said nucleotide at said CNS
disorder-related biallelic marker for the population; Optionally, determining the frequency of a biallelic marker allele in a population may be accomplished by performing a genotyping method on a pooled biological sample derived from a representative number of individuals, or each individual, in said population, and calculating the proportional amount of said nucleotide compared with the total.
A seventh embodiment of the invention comprises methods of detecting an association between an allele and a phenotype, comprising the steps of a) determining the frequency of at least one CNS disorder-related biallelic marker allele in a trait positive population, b) determining the frequency of said CNS disorder-related biallelic marker allele in a control population and; c) determining whether a statistically significant association exists between said genotype and said phenotype. In addition, the methods of detecting an association between an allele and a phenotype of the invention encompass methods with any further limitation described in this disclosure, or those following, specified alone or in any combination:
Optionally, said CNS disorder-related biallelic marker may be in a sequence selected individually or in any combination from the group consisting of SEQ )D NO: 1-542, and the complements thereof;
Optionally, said CNS disorder-related biallelic marker may be selected from the biallelic markers described in Table 7; Optionally, said control population may be a trait negative population, or a random population; Optionally, said phenotype is a CNS disorder, a response to an agent acting on a CNS disorder, or side effect to an agent acting on a CNS disorder;
Optionally, the identity of the nucleotides at the biallelic markers in everyone of the following sequences:'SEQ m NO:
1-542 is determined in steps a) and b).
An eighth embodiment of the present invention encompasses methods of estimating the frequency of a haplotype for a set of biallelic markers in a population, comprising the steps of a) genotyping each individual in said population for at least one CNS disorder-related biallelic marker, b) genotyping each individual in said population for a second biallelic marker by determining the identity of the nucleotides at said second biallelic marker for both copies of said second biallelic marker present in the genome; and c) applying a haplotype determination.method to the identities of the nucleotides determined in steps a) and b) to obtain an estimate of said frequency. In addition the methods of estimating the frequency of a haplotype of the invention encompass methods with any further limitation described in this disclosure, or those following, specified alone or in any combination: Optionally said haplotype determination method is selected from the group consisting of asymmetric PCR amplification, double PCR
amplification of specific alleles, the Clark method, or an expectation maximization algorithm; Optionally, said second biallelic marker is a CNS disorder-related biallelic marker in a sequence selected from the group consisting of the biallelic markers of SEQ )D NO: 1-542, and the complements thereof; .
Optionally, said CNS disorder-related biallelic markers may be selected individually or in any combination from the biallelic markers described in Table 7; Optionally, said CNS disorder-related biallelic marker may be selected from the following biallelic markers:
99-27207-117, 99-28110-75, 99-28134-215, 99-32181-192, 99-28106-185, 99-30858-354, 18-20-174, 313, 18-31-178, 18-38-395, 99-30853-364, 19-56-140, 19-28-136, 99-28788-300, 99-32061-304, 99-32121-242, 19-14-241, 16-50-196, 8-19-372, 12-254-180, 10-214-279, 10-217-91, 18-194-130, 18-186-391, 18-198-252, 18-242-300, 20-205-302, 19-58-162, 19-9-45, 19-22-74, 19-88-185, 19-18-310, 19-19-174, 19-17-188, 19-16-127, 99-32148-315, 19-46-322, 99-32131-312, 99-32065-303, 19-44-251, 19-29-303, 18-355-67, 18-353-267, 18-338-305, 16-88-185, 24-243-346, 99-62531-351, 99-54279-152, 99-28171-458, 99-28173-395, 18-186-394, 8-15-126, 298, 99-28722-90 and 99-32306-4097; Optionally, said CNS disorder-related biallelic marker may be selected from the following biallelic markers: 99-28788-300, 99-32061-304, 99-32121-242, 19-14-241, 19-28-136, 16-50-196, 19-58-162, 19-9-45, 20-205-302, 24-243-346, 99-27207-117, 99-28110-75, 99-28134-215, 99-32181-192, 19-17-188 and 19-19-174;
Optionally, the identity of the nucleotides at the biallelic markers in everyone of the sequences of SEQ >D NO:
1-542 is determined in steps a) and b).
A ninth embodiment of the present invention encompasses methods of detecting an association between a haplotype and a phenotype, comprising the steps of: a) estimating the frequency of at least one haplotype in a trait positive population according to a method of estimating the frequency of a haplotype of the invention; b) estimating the frequency of said haplotype in a control population according to the method of estimating the frequency of a haplotype of the invention; and c) determining Whether a statistically significant association exists between said haplotype and said phenotype. In addition, the methods of detecting an association between a haplatype and a phenotype of the invention encompass methods with any further limitation described in this disclosure, or those following, specified alone or in any combination: Optionally, said CNS disorder-related biallelic marker may be in a sequence selected individually or in any combination from the group consisting of SEQ
)17 NO: 1-542, and the complements thereof; Optionally, said CNS disorder-related biallelic markers may be selected individually or in any combination from the biallelic markers described in Table 7;
Optionally, said CNS disorder-related biallelic marker may be selected from the following biallelic markers: 99-27207-117, 99-28110-75, 99-28134-215, 99-32181-192, 99-28106-185, 99-30858-354, 18-20-174, 99-32002-313, 18-31-178, 18-38-395, 99-30853-364, 19-56-140, 19-28-136; 99-28788-300, 99-32061-304, 99-32121-242, 19-14-241, 16-50-196, 8-19-372;
12-254-180, 10-214-279, 10-217-91, 18-194-130, 18-186-391, 18-198-252, 18-242-300, 20-205-302, 1,9-58-162, 19-9-45, 19-22-74, 19-88-185, 19-18-310, 19-19-174, 19-17-188, 19-16-127, 99-32148-315, 19-46-322, 99-32131-312, 99-32065-303, 19-44-251, 19-29-303, 18-355-67, 18-353-267, 18-338-305, 16-88-185, 24-243-346, 99-62531-351, 99-54279-152, 99-28171-458, 99-28173-395, 18-186-394, 8-15-126, 99-2409-298, 99-28722-90 and 99-32306-409; Optionally, said CNS
disorder-related biallelic marker may be selected from the following biallelic markers: 99-28788-300, 99-32061-304, 99-32121-242, 19-14-241, 19-28-136, 16-50-196, 19-58-162, 19-9-45, 20-205-302, 24-243-346, 99-27207-117, 99-28110-75, 99-28134-215, 99-32181-192, 19-17-188 and 19-19-174; Optionally, said control population may be a trait negative population, or a random population; Optionally, said phenotype is a CNS disorder, a response to an agent acting on a CNS disorder, or side effect to an agent acting on a CNS disorder; Optionally, the identity of the nucleotides at the biallelic markers in everyone of the following sequences:
SEQ ID NO: 1-542 is included in the estimating steps a) and b).
A tenth embodiment of the present invention encompasses polypeptides encoded by SEQ
m NO: 543 or 544, as well as antisense analogs thereof and biologically active and diagnostically or therapeutically useful fragments and derivatives thereof.
The polypeptides of the present invention are of human origin. In accordance with a further aspect of the present invention, there is provided a method for producing such polypeptides by recombinant techniques which comprises culturing recombinant prokaryotic and/or eukaryotic host cells, containing a nucleic acid sequence encoding a polypeptide of the present invention, under conditions promoting expression of said protein and subsequent recovery of said protein. A
further embodiment of the present invention encompasses antibodies against such polypeptides.
An eleventh embodiment of the present invention is a method for using one or more of the polypeptides according to the invention to screen for polypeptide antagonists and/or agonists and/or receptor ligands. A further embodiment of the present invention is a method of using such agonists to activate the polypeptides of the present invention for the treatment of conditions related to the underexpression of the polypeptide of the present invention, preferably depression.
In accordance With another aspect of the present invention there is provided a method of using such antagonists for inhibiting the polypeptide of the present invention for treating conditions associated with overexpression of the polypeptides of the present invention.
A twelfth embodiment of the present invention encompasses non-naturally occurring synthetic, isolated and/or recombinant polypeptides which are fragments, consensus fragments and/or sequences having conservative amino acid substitutions, of at least one transmembrane domain, such that the polypeptides of the present invention may bind ligands, or which may also modulate, quantitatively or qualitatively, ligand binding to the polypeptides of the present invention. A further embodiment of the present invention encompasses synthetic or recombinant' polypeptides, conservative substitution derivatives thereof, antibodies, anti-idiotype antibodies, compositions and methods that can be useful as potential modulators of CNS-related protein function, by binding to ligands or modulating ligand binding, due to their expected biological properties, which may be used in diagnostic, therapeutic and/or research applications relating'to CNS disorders. In yet a further embodiment of the present invention, there is provided synthetic,' isolated or recombinant polypeptides which are designed to inhibit or mimic various polypeptides of the invention or fragments thereof, as receptor types and subtypes.
A thirteenth embodiment of the present invention encompasses a diagnostic assay for detecting a disease or susceptibility to a disease related to a mutation in a nucleic acid sequence encoding a polypeptide of the present invention. Preferably said disease is depression.
A fourteenth embodiment of the present invention is a method of administering a drug or a treatment comprising the steps of: a) .obtaining a nucleic acid sample from an individual; b) determining the identity of the polymorphic base of at least one CNS disorder-related biallelic marker which is associated with a positive response to the treatment or the drug; or at least one biallelic CNS disorder-related marker which is associated with a negative response to the treatment or the drug; and c) administering the treatment or the drug to the individual if the nucleic acid sample contains said biallelic marker associated with a positive response to the treatment or the drug or if the nucleic acid sample lacks said biallelic marker associated with a negative response to the treatment or the drug. In addition, the methods of the present invention for administering a drug or a treatment encompass methods with any further limitation described in this disclosure, or those following, specified alone or in any combination:
optionally, said CNS
disorder-related biallelic marker may be in a sequence selected individually or in any combination from the group consisting of SEQ. )D. NO: 1-542 and the complements thereof , or optionally, the administering step comprises administering the drug or the treatment to the individual if the nucleic acid sample contains said biallelic marker associated with a positive response to the treatment or the drug and the nucleic acid sample lacks said biallelic marker associated with a negative response to the treatment or the drug.
A fifteenth embodiment of the present invention is a method of selecting an individual for inclusion in a clinical trial of a treatment or drug comprising the steps of a) obtaining a nucleic acid sample from an individual; b) determining the identity of the polymorphic base of at least one CNS disorder-related biallelic marker which is associated with a positive response to the treatment or the drug, or at least one CNS disorder-related biallelic marker which is associated with a negative response to the treatment or the drug in the nucleic acid sample, and c) including the individual in the clinical trial if the nucleic acid sample contains said CNS disorder-related biallelic marker associated with a positive response to the treatment or the drug or if the nucleic acid sample lacks said biallelic marker associated with a negative response to the treatment or the drug. In addition, the methods of the present invention for selecting an individual for inclusion in a clinical trial of a treatment or drug encompass methods with any further limitation described in this disclosure, or those following, specified alone or in any combination: Optionally, said CNS disorder-related biallelic marker may be in a sequence selected individually or in any combination from the group consisting of SEQ.
ID. NO: 1-542 and the complements thereof, optionally, the including step comprises administering~the drug or the treatment to the individual if the nucleic acid sample contains said biallelic marker associated with a positive response to the treatment or the drug and the nucleic acid sample lacks said biallelic marker associated with a negative response to the treatment or the drug.
Additional embodiments are set forth in the Detailed Description of the Invention and in the Examples.
BRIEF DESCRIPTION OF THE TABLES
Tables 7A and 7C are charts containing a list of all of the CNS-related biallelic markers for each gene with an indication of the gene for which the marker is in closest physical proximity, an indication of whether the markers have been validated by microsequencing (with a Y indicating that the markers have been validated by microsequencing and an N
indicating that it has not), and an indication of the identity and frequency of the least common allele determined by genotyping (with a blank left to indicate that the frequency has not yet been reported for some markers).
Tables 7B and 7D contain all of the CNS-related biallelic markers provided in Tables 7A
and 7C; however, they are provided in shorter, easier to search sequences of 47 nucleotides.
Accordingly, Table 7A begins with SEQ U~ NO: 1 and ends with SEQ )D NO: 130, while corresponding Table 7B begins with SEQ ID NO: 131 and ends with SEQ 1Z7 NO:
260. Also Table 7C begins with SEQ ID NO: 261 and ends with SEQ )D NO: 401, while corresponding Table 7D begins with SEQ ID NO: 402 and ends with SEQ 117 NO: 542. Table 1 contains the first five markers listed in the sequence listing and their corresponding SEQ
m numbers in Tables 7A and 7C to illustrate the relationship between Tables 7A and 7B:
Table 1 BIALLELIC SEQ ID BIALLELIC SEQ ID BIALLELIC .
MARKER NO. MARKER NO. IN MARKER
ID IN TABLE POSITION IN TABLE POSITION IN

ID NO. ID NO.

99-28108-2335 ' 233 ~ 135 ~ 24 Tables 7B and 7D are the same as Tables 7A and 7C, respectively, in that they are a list of all of the CNS-related biallelic markers for each gene with an indication of the gene for which the marker is in closest physical proximity, an indication of whether the markers have been validated by microsequencing (with a Y indicating that the markers have been validated by microsequencing and an N indicating that it has not), and an indication of the identity and frequency of the least common allele determined by genotyping (with a blank left to indicate that the frequency has not yet been reported for some markers). However, the "Biallelic Marker Position in SEQ ID No." for all of the CNS-related biallelic markers provided in Tables 7B and 7D is position 24 (representing the midpoint of the 47mers that make up Tables 7B and 7D) Tables 8, 9, and 10 are charts containing lists of the CNS disorder-related biallelic markers. Each marker is described by indicating its SEQ m, the biallelic marker ID, and the two most common alleles. Table 8 is a chart containing a list of biallelic markers surrounded by preferred sequences. In the column labeled, "POSITION RANGE OF PREFERRED
SEQUENCE" of Table 8 regions of particularly preferred sequences are listed for each SEQ ID, which contain a CNS disorder-related biallelic marker, as well as particularly preferred regions of sequences that do not contain a CNS disorder-related biallelic marker but, which are in sufficiently close proximity to a CNS disorder-related biallelic marker to be useful as amplification or sequencing primers.
Table 11 is a chart listing particular sequences that are useful for designing some of the .
primers and probes of the invention. Each sequence is described by indicating its Sequence m and the positions of the first and last nucleotides (position range) of the particular sequence in the Sequence>D.
Table 12 is a chart listing microsequencing primers which have been used to genotype CNS disorder-related biallelic markers (indicated by an *) and other preferred microsequencing primers for use in genotyping CNS disorder-related biallelic markers. Each of the primers which falls within the strand of nucleotides included in the Sequence Listing are described by indicating their Sequence >D number and the positions of the first and last nucleotides (position range) of the primers in the Sequence m. Since the sequences in the Sequence Listing are single stranded and half the possible microsequencing primers are composed of nucleotide sequences from the complementary strand, the primers that are composed of nucleotides in the complementary strand are described by indicating their SEQ lD numbers and the positions of the first and last nucleotides to which they are complementary (complementary position range) in the Sequence DJ.
Table 13 is a chart listing amplification primers which have been used to amplify polynucleotides containing one or more CNS disorder-related biallelic markers.
Each of the .
primers which falls within the strand of nucleotides included in the Sequence Listing are ' described by indicating their Sequence m number and the positions of the first and last nucleotides (position range) of the primers in the Sequence )D. Since the sequences in the Sequence Listing are single stranded and half the possible amplification primers are composed of nucleotide sequences from the complementary strand, the primers that are composed of nucleotides in the complementary strand are defined by the SEQ ID numbers and the positions of the first and last nucleotides to which they are complementary (complementary position range) in the Sequence TD.
Table 14 is a chart listing preferred probes useful in genotyping CNS disorder-related biallelic markers by hybridization assays. The probes are 25-mers with a CNS
disorder-related biallelic markers in the center position, and described by indicating their Sequence m number and the positions of the first and last nucleotides (position range) of the probes in the Sequence m. The probes complementary to the sequences in each position range in each Sequence ID are also understood to be a part of this preferred list even though they are not specified separately:
Table 1 S is a table showing the results of single marker association tests between both biallelic marker alleles and genotypes of candidate genes and major depression.

Table 16 is a table showing the results of the LR rank of haplotypes using combinations of 2, 3 and 4 biallelic markers from each gene.
Table 17 is a table showing the rank of permutation tests for individual haplotypes confirming the statistical significance of the association between biallelic marker haplotypes from the candidate genes and major depression.
Table 18 is a table showing the results of single marker association tests between both biallelic marker alleles and genotypes of candidate genes and major depression using additional markers and a new population set as described in Example 4.
Table 19 is a table showing the results of the LR rank of haplotypes using combinations of 2, 3 and 4 biallelic markers from additional candidate genes and using data from a new population set as described in Example 4.
Table 20 is a table showing the rank of permutation tests for individual haplotypes from Table 19 confirming the statistical significance of the association between biallelic marker haplotypes from additional candidate genes and major depression.
DETAILED DESCRIPTION OF THE INVENTION .
I. Candidate Genes of the Present Invention Different approaches can be employed to perform association studies: genome-wide association studies, candidate region association studies and candidate gene association studies.
Genome-wide association studies rely on the screening of genetic markers evenly spaced and covering the entire genome. Candidate region association studies rely on the screening of genetic markers evenly spaced covering a region identified as linked to the trait of interest. The candidate gene approach is based on the study of genetic markers specifically derived from genes potentially involved in the pathophysiology of a disease. In the present invention; genes involved in the central nervous system and/or the endocrine system have been chosen as candidate genes. The candidate genes of the present invention are listed in Table 2.
Table 2 Candidate Gene Name Gene Symbol Description Serotonin receptor SHTR6 A postsynaptic serotonin receptor.

Serotonin receptor SHTR7 A postsynaptic serotonin receptor.
7 .

Neuronal nicotinic CHRNA7 An ion channel in the reward acid pathway..
receptor a7 Corticotrophin releasingCRFR1 A corticotrophin releasing factor factor receptor 1 receptor in the hypothalamus-pituitary-adrenal axis.

Mineralocorticoid MLR A mineralocorticoid receptor.
receptor Corticotrophin releasingCRFR2 A corticotrophin releasing factor receptor in factor receptor 2 the hypothalamus-pituitary-adrenal axis.

Glucocorticoid receptorGRL A glucocorticoid receptor in the hypothalamus-pituitary-adrenal axis.

Monoamine oxidase MAOA Key enzyme in catecholamine A metabolism.

Monoamine oxidase MAOB Key enzyme in catecholamine B metabolism.

Serotonin receptor 5HTR2c Postsynaptic receptor for serotonin.

Tyrosine hydroxylaseTH The rate-limiting enzyme in the synthesis of dopamine and norepinephrine.

Corticotrophin releasingCRF A hormone released by the hypothalamus that factor stimulates the release of corticotrophin by the anterior pituitary gland.

Dopamine receptor DRD4 A postsynaptic dopamine receptor.

Serotonin transporterSHTT A presynaptic membrane receptor that serves as a reuptake mechanism for serotonin.

Dopamine receptor DRD3 A postsynaptic dopamine receptor.

3 Cytochrome P450 3A4 CYP3A4 A principal drug metabolizing enzyme.

Norepinephrine transporterNET A membrane protein responsible for .

termination of the action of synaptic norepinephrine.

Neurokinin or tachykininNK1/TACR1 A receptor for the neuropeptideaubstance P.

receptor 1 Neuropeptide Yl receptorNPY1R A receptor for the neuropeptide Y1: Belongs to family of g-protein coupled receptors with it highest similarity to tachykinins receptors.

Dopamine receptor DRD2 G protein-coupled dopamine receptor.

Guanine nucleotide Gbeta3 An important component of CAMP
binding mediated protein, (33 signaling pathways.

Wolfram Syndrome WFS 1 A gene that plays a role in 1 gene the etiology of Wolfram syndrome.

Beta 1 adrenergic ADRB1R An important component of the receptor norepinephrine signaling pathway. Antidepressants are known to suppress expression.

Brain derived neurotrophicBDNF A protein known to affect the differentiation of factor dopaminergic and serotonergic neurons.

Increased by antidepressants and electro-convulsive therapy.

Orphan G-protein HM74 A putative chemokine receptor.
coupled receptor Vasopressin receptorAVPR1A A receptor that stimulates adrenocorticotrophic hormone (ACTH) release in the anterior pituitary.

Serotonin receptor SHT1A A receptor that is misregulated 1-A in depression, as well as anxiety and stress.

Growth associated GAP43 A protein known to play a role protein 43 in synaptic plasticity. Increased levels in suicide victims.

Guanine nucleotide GOLF (GNAL) A protein known to play a role binding in signaling:

protein, a, subunit, possibly in cAMP mediated signaling olfactory type pathways and norepinephrine-related pathways.

Clock protein CLOCK A protein associated with sleeping patterns in humans.

Corticotrophin hormoneCRHBP A protein capable of binding to corticotrophin binding protein releasing factor.

Dopamine transporterDAT (SLC6A3)A protein involved in the re-uptake of dopamine.

Phosphodiesterase PDE4b An enzyme believed to be involved type 4b in mediating central nervous system effects of therapeutic agents ranging from antidepressants to anti-inflammatory agents.

Catechol O-methyl COMT An enzyme that catalyzes the transfer of a transferase methyl group from s-adenosylmethionine to a catecholamine such as dopamine, epinephrine, or norepinephrine.

Melanin concentratingSLC1 A transmembrane protein that serves as the hormone receptor functional receptor of melanin concentrating hormone.

Transcription factorSEF2-1B A transcription factor that binds to the e-box (TCF4) present in the somatostatin receptor 2 initiator element (sstr2,-inr) to activate transcription (by similarity).

Heat shock protein HSP70 A protein believed to interact with polypeptides during a variety of assembly processes in such a way as to prevent the formation of nonfunctional structures.

GABA-A receptor subunitGABRG2 A receptor known to mediate inhibitory neurotransmission, complexing with DRDS

and promoting mutually inhibitory functional interactions between these receptor systems, putatively involved in the physiological dependence on alcohol, and in the maintenance of psychomotor disease states.

GABA-A receptor subunitGABRAS A receptor known to be part of the ligand-gated ionic channels protein family.
Associated with bipolar disorder.

Both the central nervous system and the endocrine system play an important role in the pathophysiology of CNS disorders, moreover, these systems contain important drug targets and genetic polymorphisms in these genes are highly relevant in the response to a number of drugs.
The candidate gene analysis clearly provides a short-cut approach to the identification of genes and gene polymorphisms related to a particular disease when some information concerning the pathophysiology of the disorder is available as is the case for many CNS
disorders. However, it should be noted that all of the biallelic markers disclosed in the instant application can be employed as part of genome-wide association studies or as part of candidate region association studies and such uses are specifically contemplated in the present invention and claims. All of the markers are known to be in close proximity to the genes with which they are listed in Table 7.
For a portion of the markers, the precise' position of the marker with respect to the various coding and non-coding elements of the genes has also been determined.
II. Definitions Before describing the invention in greater detail, the following definitions are set forth to illustrate and define the meaning and scope of the terms used to describe the invention herein.
As used interchangeably herein, the terms "nucleic acid molecule", "oligonucleotide", and "polynucleotide", unless specifically stated otherwise, include RNA or, DNA (either single or double stranded, coding, complementary or antisense), or RNA/DNA hybrid sequences of more than one nucleotide in either single chain or duplex form (although each of the above species may be particularly specified). The term "nucleotide" as used herein as an adjective to describe molecules comprising RNA, DNA, or RNA/DNA hybrid sequences of any length in single-stranded or duplex form. More precisely, the expression "nucleotide sequence"
encompasses the nucleic material itself and is thus not restricted to the sequence information (i.e.
the succession of letters chosen among the four base letters) that biochemically characterizes a specific DNA or RNA molecule. The term "nucleotide" is also used herein as a noun to refer to individual nucleotides or varieties of nucleotides, meaning a molecule, or individual unit in a larger nucleic acid molecule, comprising a purine or pyrimidine, a ribose or deoxyribose sugar moiety, and a phosphate group, or phosphodiester linkage in the case of nucleotides within an oligonucleotide or polynucleotide. Although the term "nucleotide" is also used herein to encompass "modified nucleotides" which comprise at least one modifications (a) an alternative .
linking group, (b) an analogous form of purine, (c) an analogous form of pyrimidine, or (d) an analogous sugar, for examples of analogous linking groups, purine,,pyrimidines, and sugars see for example PCT publication No. WO 95/04064. Preferred modifications of the present invention include, but are not limited to, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-earboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrauracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v) ybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic .
acid methylester, uracil-5.-oxyacetic acid, 5-methyl-2-thiouracil, 3-(3-amino-carbaxypropyl) uracil, and 2,6-diaminopurine. The polynucleotide sequences of the invention may be prepared by any known method, including synthetic, recombinant, ex vivo generation, ox a combination thereof, as well as utilizing any purification methods known in the art.
Methylenemethylimino linked oligonucleosides as well as mixed backbone compounds having, may be prepared as described in U.S. Pat. Nos. 5,3?8,825; 5,386,023;
5,489,677; 5,602,240; and 5,610,289. Formacetal and thioformacetal linked oligonucleosides may be prepared as described in U.S. Pat. Nos. 5,264,562 and 5,264,564. Ethylene oxide linked oligonucleosides may be prepared as described in U.S. Pat. No. 5,223,618. Phosphinate oligonucleotides maybe prepared as described in U.S. Pat. No. 5,508,270.. Alkyl phosphonate oligonucleotides may be prepared as described in U.S. Pat. No. 4,469,863. 3'-Deoxy-3'-methylene phosphonate oligonucleotides may be prepared as described in U.S. Pat. Nos. 5,610,289 or 5,625,050.
Phosphoramidite oligonucleotides may be prepared as described in U.S. Pat. No. 5,256,775 or U.S. Pat. No.
5,366,878. Alkylphosphonothioate oligonucleotides may be prepared as described in published PCT applications WO 94/17093 and WO 94/02499. 3'-Deoxy-3'-amino phosphoramidate oligonucleotides may be prepared as described in U.S. Pat. No. 5,476,925.
Phosphotriester oligonucleotides may be prepared as described in U.S. Pat. No. 5,023,243.
Borano phosphate oligonucleotides may be prepared as described in U.S. Pat. Nos. 5,130,302 and 5,177,198. The polynucleotide sequences of the invention may be prepared by any known method, including synthetic, recombinant, ex vivo generation, or a combination thereof, as well as utilizing any purification methods known in the art.
The term "isolated" further requires that the material be removed from its original environment (e.g., the natural environment if it is naturally occurring). For example, a naturally-occurring polynucleotide present in a living animal is not isolated, but the same polynucleotide, separated from some or all of the coexisting materials in the natural system, is isolated.
Specifically excluded from the definition of "isolated" are: naturally-occurring chromosomes (such as chromosome spreads), artificial chromosome libraries, genomic libraries, and cDNA
libraries that exist either as an in vitro nucleic acid molecule preparation or as a transfected/transformed host cell preparation, wherein the host cells are either an in vitro heterogeneous preparation or plated as a heterogeneous population of single colonies. Also specifically excluded are the above libraries wherein a specified polynucleotide of the present invention makes up less than 5% of the number of nucleic acid molecule inserts in the vector molecules: Further specifically excluded are whole cell-genomic DNA or whole cell~RNA or mRNA preparations (including said whole cell preparations which are mechanically sheared or enzymatically digested). Further specifically excluded are the above whole cell preparations as either an in vitro preparation or as a heterogeneous mixture separated by electrophoresis (including blot transfers of the same) wherein the polynucleotide of the invention has not further been separated from the heterologous polynucleotides in the electrophoresis medium (e.g., further separating by excising a single band from a heterogeneous band population in an agarose gel or nylon blot).
As used herein, the term "purified" does not require absolute purity; rather, it is intended as a relative definition. Individual 5' EST clones isolated from a cDNA library have been conventionally purified to electrophoretic homogeneity. The sequences obtained from these clones could not be obtained directly either from the library or from total human DNA. The cDNA clones are not naturally occurring as such, but rather are obtained via manipulation of a partially purified naturally occurring substance (messenger RNA). The conversion of mRNA into a cDNA library involves the creation of a synthetic substance (cDNA) and pure individual cDNA
clones can be isolated from the synthetic library by clonal selection. Thus, creating a cDNA
library from messenger RNA and subsequently isolating individual clones from that library results in an approximately 104-106 fold purification of the native message. Purification of starting material or natural material to at least one order of magnitude, preferably two or three orders, and more preferably four or five orders of magnitude is expressly contemplated.
Alternatively, purification may be expressed as "at least" a percent purity relative to heterologous polynucleotides (DNA, RNA

or both). As a preferred embodiment, the polynucleotides of the present invention are at least; 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 96%, 98%, 99%, or 100% pure relative to heterologous polynucleotides. As a further preferred embodiment the polynucleotides have an "at least" purity ranging from any number, to the thousandth position, between 90% and 100% (e.g., 5' EST at least 99.995% pure) relative to heterologous polynucleotides.
Additionally, purity of the polynucleotides may be expressed as a percentage (as described above) relative to all materials and compounds other than the carrier solution. Each number, to the thousandth position, may be claimed as individual species of purity.
The term "primer" denotes a specific oligoiiucleotide sequence which is complementary to a target nucleotide sequence and used to hybridize to the 'target nucleotide sequence. A primer serves as an initiation point for nucleotide polymerization catalyzed by DNA
polymerase, RNA
polymerase or reverse transcriptase.
The term "probe" denotes a defined nucleic acid segment (or nucleotide analog segment, e.g., polynucleotide as defined herein) which can be used to identify a specific polynucleotide sequence present in samples, said nucleic acid segment comprising a nucleotide sequence complementary of the specific polynucleotide sequence to be identified.
The term "CNS disorder" refers to any condition linked to dysfunction of the central . nervous system which is known in the art. A CNS disorder includes dysfunction of one or several physiological systems contributing to the function of the central nervous system, which includes the endocrine system and the peripheral nervous system. A CNS
disorder further refers to disorders in neurotransmitter synthesis and degradation, neurotransmitter function, neurotransmitter receptor function, weurotransmitter signal transduction, neurotransmitter transporter function, motor neuron function, hormone synthesis and degradation, hormone function, hormone receptor function and hormone signal transduction. "CNS
disorders" include mood disorders such as depression, bipolar disorder, anxiety, attention deficit disorder and schizophrenia. "CNS disorders" also include neurodegenerative disorders such as Parkinson's disease, Huntington's disease, Pick's disease, progressive supranuclear palsy, Lewy body dementia and Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy and deafness). "CNS disorders" also include disorders of movement such as motor neuron disease'as well as diseases involving the intellect such as Alzheimer's disease, Wernicke's encephalopathy and Jakob-Creutzfeldt disease. "CNS disorders" further include other disorders such as coma, head injury, cerebral infarction, epilepsy, alcoholism and states of mental retardation. All of the possible CNS disorders listed herein are included in, or may be excluded from, the present invention as individual species.
The term "depression" as used herein refers to both unipolar major depression (or major depressive disorder) and bipolar disorder.

An "agent acting on a CNS disorder" includes any drug or compound known in the art that addresses, reduces or alleviates one or more symptoms of a CNS disorder.
"Agents acting on a CNS disorder" includes any drug or a compound modulating the activity or concentration of an enzyme or regulatory molecule involved in a CNS disorder that is known in the art. An agent acting on a CNS disorder includes but is not limited to tyrosine hydroxylase, monoamine oxidase .
A/B, dopamine (3-hydroxylase, aldehyde dehydrogenase, phenylethanolamine N-methyltransferase, catechol o-methyltransferase, tryptophan hydroxylase, acetyl coenzyme A, proteinases, oestrogens, glucocorticoids, mineralocorticoids, nicotine, substance P and precursors to neurotransmitters such as tryptophan. "Agent acting on a CNS disorder"
further refers to compounds modulating the synthesis, degradation, reuptake and action of neurotransmitters and hormones such as tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), serotonin selective reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitor (NRI) such as reboxetine, dual serotonin and norepinephrine reuptake inhibitor (SNRI), serotonin-2 antagonist/reuptake inhibitors (SARIS), noradrenergic and specific serotonergic antidepressants (NaSSAs), drugs that cause increased dopamine release in the brain such as levodopa, dopamine receptor agonists such as bromocriptine, dopamine antagonists such as metoclopramide, neuroleptic drugs such as phenothiazines, adrenergic agonists such as clonidine, N-methyl-D-asparate antagonists such as phencyclidine, anticholinergic compounds, benzodiazepine drugs and anxiolytic compounds. Preferably, "agent acting on a CNS disorder" refers to the ' antidepressant drug Reboxetine.
The terms "response to an agent acting on a CNS disorder" refer to drug efficacy, including but not limited to the ability to metabolize a compound, the ability to convert a pro-drug to an active drug, and to the pharmacokinetics (absorption, distribution, elimination) and the pharmacodynamics (receptor-related) of a drug in an individual.
The terms "side effects to an agent acting on a CNS disorder" refer to adverse effects of therapy resulting from extensions of the principal pharmacological action of the drug or to idiosyncratic adverse reactions resulting from an interaction of the drug with unique host factors.
"Side effects to an agent acting on a CNS disorder" include, but are not limited to autonomic side effects such as orthostatic hypotension, blurred vision, dry mouth, nasal congestion and constipation. "Side effects to an agent acting on a CNS disorder" also include anxiety, sleep ' disturbances, sexual dysfunction, gastrointestinal disturbances, nausea, diarrhea, orthostasis, dizziness, sedation, hypertension and shock.
The terms "trait" and "phenotype" are used interchangeably herein and refer to any visible, detectable or otherwise measurable property of an organism such as symptoms of, or susceptibility to a disease for example. Typically the terms "trait" or "phenotype" are used herein to refer to symptoms of, or susceptibility to a CNS disorder; or to refer to an individual's response to an agent acting on a CNS disorder; or to refer to symptoms of, or susceptibility to side effects to an agent acting on a GNS disorder.
The term "allele" is used herein to refer to variants of a nucleotide sequence. A biallelic polymorphism has two forms. Typically the first identified allele is designated as the original allele whereas other alleles are designated as alternative alleles. Diploid organisms may be homozygous or heterozygous fox an allelic form.
The term "heterozygosity rate" is used herein to refer to the incidence of individuals in a population, which are heterozygous at a particular allele. In a biallelic system the heterozygosity rate is on average equal to 2Pa(1-Pa), where Pa is the frequency of the least common allele. In order to be useful.in genetic studies a genetic marker should have an adequate level of heterozygosity to allow a reasonable probability that a randomly selected person will be heterozygous.
The term "genotype" as used herein refers to the identity of the alleles present in an individual or a sample. In the context of the present invention a genotype preferably refers to the description of the biallelic marker alleles present in an individual or a sample. The term "genotyping" a sample or an individual for a biallelic marker consists of determining the specific allele or the specific nucleotide carried by an individual at a biallelic marker.
The term "mutation" as used herein refers to a difference in DNA sequence between or among different genomes or individuals which has a frequency below 1%.
The term "haplotype" refers to a combination of alleles present in an individual or a sample. In the context of the present invention a haplotype preferably refers to a combination of biallelic marker alleles found in.a given individual and which may be associated with a phenotype.
The term "polymorphism" as used herein refers to the occurrence of two or more alternative genomic sequences or alleles between or among different genomes or individuals.
"Polymorphic" refers to the condition in which two or more variants of a specific genomic sequence can be found in a population. A "polymorphic site" is the locus at which the variation occurs. A single nucleotide polymorphism is a single base pair change.
Typically a single nucleotide polymorphism is the replacement of one nucleotide by another nucleotide at~the polymorphic site. Deletion of a single nucleotide or insertion of a single nucleotide, also give rise to single nucleotide polymorphisms. In the context of the present invention "single nucleotide polymorphism" preferably refers to a single nucleotide substitution. Typically, between different genomes or between different individuals, the polymorphic site may be occupied by two different nucleotides.
The terms "biallelic polymorphism" and "biallelic marker" are used interchangeably herein to refer to a polymorphism having two alleles at a fairly high frequency in the population, preferably a single nucleotide polymorphism. A "biallelic marker allele"
refers to the nucleotide variants present at a biallelic marker site. Typically the frequency of the less common allele of the biallelic markers of the present invention has been validated to be greater than 1%, preferably the frequency is greater than 10%, more preferably the frequency is at least 20% (i.e.
heterozygosity rate of at least 0.32), even more preferably the frequency is at least 30% (i.e.
heterozygosity rate of at least 0.42). A biallelic marker wherein the frequency of the less common allele is 30% or more is termed a "high quality biallelic marker."
The location of nucleotides in a polynucleotide with respect to the center of the polynucleotide are described herein in the following manner. When a polynucleotide has an odd number of nucleotides, the nucleotide at an equal distance from the 3' and 5' ends of the polynucleotide is considered to be "at the center" of the polynucleotide, and any nucleotide immediately adjacent to the nucleotide at the center, or the nucleotide at the center itself is considered to be "within 1 nucleotide of the center." With an odd number of nucleotides in a polynucleotide any of the five nucleotide positions in the middle of the polynucleotide would be considered to be within 2 nucleotides of the center, and so on. When a polynucleotide has an even number of nucleotides, there would be a bond and not a nucleotide at the center. of the polynucleotide. Thus, either of the two central nucleotides would be considered to be "within 1 nucleotide'of the center" and any of the four nucleotides in the middle of the polynucleotide would be considered to be "within 2 nucleotides of the center", and so on. For polymorphisms which involve the substitution, insertion or deletion of 1 or more nucleotides, the polymorphism, allele or biallelic marker is "at the center" of a polynucleotide if the difference between the distance from the substituted, inserted, or deleted polynucleotides of the polymorphism and the 3' end of the polynucleotide, and the distance from the substituted, inserted, or deleted polynucleotides of the polymorphism and the 5' end of the polynucleotide is zero or one nucleotide. If this difference is 0 to 3, then the polymorphism is considered to be "within 1 nucleotide of the center." If the difference is 0 to 5, the polymorphism is considered to be "within 2 nucleotides of the center." If the difference is 0 to 7, the polymorphism is considered to be "within 3 nucleotides of the center," and so on. For polymorphisms which involve the substitution, insertion or deletion of 1 or more nucleotides, the polymorphism, allele or biallelic marker is "at the center" of a polynucleotide if the difference between the distance from the substituted, inserted, or deleted polynucleotides of the polymozphism and the 3' end of the polynucleotide, and the distance from the substituted, inserted, or deleted polynucleotides of the polymorphism and the 5' end of the polynucleotide is zero or one nucleotide.
If this difference is 0 to 3, then the polymorphism is considered to be "within 1 nucleotide of the center." If the difference is 0 to 5, the polymorphism is considered to be "within 2 nucleotides of the center." If the difference is 0 to 7, the polymorphism is considered to be "within 3 nucleotides of the center," and so on.

The term "upstream" is used herein to refer to a location which is toward the 5' end of the polynucleotide from a specific reference point.
The terms "base paired" and "Watson & Crick base paired" are used interchangeably herein to refer to nucleotides which can be hydrogen bonded to one another be virtue of their sequence identities in a manner like that found in double-helical DNA with thymine or uracil residues linked to adenine residues by two hydrogen bonds and cytosine and guanine residues linked by three hydrogen bonds (See Stryer, L., Biochernistiy, 4th edition, 1995).
The terms "complementary" or "complement thereof' are used herein to refer to the sequences of polynucleotides which is capable of forming Watson & Crick base pairing with another specified polynucleotide throughout the entirety of the complementary region. This term is applied to pairs of polynucleotides based solely upon their sequences and not any particular set of conditions under which the two polynucleotides would actually bind.
As used herein the term "CNS disorder-related biallelic marker" relates to a set of biallelic markers in linkage disequilibrium with genes disclosed in Tables 7(A-D) which express proteins that. are involved in the pathophysiology CNS disorders. The term CNS
disorder-related biallelic marker encompasses all of the biallelic markers disclosed in Tables 7(A-D). The preferred CNS disorder-related biallelic marker alleles of the present invention include each one of the alleles described in Tables 7, 8, 9, and 10 individually or in groups consisting of all the .
possible combinations of the alleles included in Tables 7, 8, 9, and 10. In addition, Table 7 may include Tables 7A-7D, or Tables 7A, 7B, 7C or 7D as individual embodiments of the present invention or in any combination of the four.
The term "sequence described in Table 8" is used herein to refer to the entire collection of nucleotide sequences or any individual sequence defined in Table 8. The SEQ
ID that contains each "sequence described in Table 8" is provided in the column labeled, "SEQ ID NO."
, The range of nucleotide positions within the Sequence ID of which each sequence consists is provided in the same row as the Sequence ID in a column labeled, "POSITION
RANGE OF
PREFERRED SEQUENCE". It should be noted that some of the Sequence ID numbers have multiple sequence ranges listed, because they contain multiple "sequences described in Table 8."
Unless otherwise noted the term "sequence described in Table 8" is to be construed as . encompassing sequences that contain either of the two alleles listed in the columns labeled, "1sT
ALLELE" and "2ND ALLELE" at the position identified in field <222> of the allele feature in the appended Sequence Listing for each Sequence ID number referenced in Table 8.
The term "sequence described in Table 9" is used herein to refer to the entire collection of nucleotide sequences or any individual sequence defined in Table 9. Unless otherwise noted, the "sequences described in Table 9" consist of the entire sequence of each Sequence >D
provided in the column labeled, "SEQ ID NO." Also unless otherwise noted the term "sequence described in Table 9" is to be construed as encompassing sequences that contain either of the two alleles listed in the columns labeled, "ORIGINAL ALLELE" and "ALTERNATIVE
ALLELE"
at the position identified in field <222> of the allele feature in the appended Sequence Listing for each Sequence ID number referenced in Table 9.
The term "sequence described in Table 10" is used herein to refer to the entire collection of nucleotide sequences or any individual sequence defined in Table 10. Unless otherwise noted, the "sequences described in Table 10" consist of the entire sequence of each Sequence )D
provided in the column labeled, "SEQ ID NO." Also unless otherwise noted the term "sequence described in Table 10" is to be construed as encompassing sequences that contain either of the two alleles listed in the columns labeled, "1 ST ALLELE" and "2ND ALLELE" at the position identified in field <222> of the allele feature in the appended Sequence Listing for each Sequence ID number referenced in Table 10:
The term "sequence described in Table 11" is used herein to refer to the entire collection of nucleotide sequences or any individual sequence defined in Table 11. The SEQ ID that contains each "sequence described in Table 11 " is provided in the column labeled, "SEQ ID
NO." The range of nucleotide positions within the Sequence ID of which each sequence consists is provided in the same row as the Sequence ID in a column labeled, "POSITION
RANGE OF .' PREFERRED SEQUENCE". It should be noted that some of the Sequence ID numbers have multiple sequence ranges listed, because they contain multiple "sequences described in Table 11."
The term "sequence described in Table 12" is used herein to refer to the entire collection of nucleotide sequences or any individual sequence defined in Table 12. The SEQ ID that contains each "sequence described in Table 12" is provided in the column labeled, "SEQ ID
NO." The range of nucleotide positions within the Sequence ID of which half of the sequences consists is provided in the same row as the Sequence ID in a column labeled, "POSITION
RANGE OF MICROSEQUENCING PRIMERS". The remaining half of the sequences described in Table 12 are complementary to the range of nucleotide positions within the Sequence ID provided in the same row as the Sequence ID in a column labeled, "COMPLEMENTARY POSITION RANGE OF MICROSEQUENCING PRIMERS".
The term "sequence described in Table 13" is used herein to refer to the entire collection of nucleotide sequences or any individual sequence defined in Table 13. The SEQ ID that contains each "sequence described in Table 13" is provided in the column labeled, "SEQ ID
NO." The range of nucleotide positions within the Sequence ID of which half of the sequences consists is provided in the same row as the Sequence ID in a column labeled, "POSITION
RANGE OF AMPLIFICATION PRIMERS". The remaining half of the sequences described .in Table 13 are complementary to the range of nucleotide positions within the Sequence ID
provided in the same row as the Sequence ID in a column labeled, "COMPLEMENTARY ' POSITION RANGE OF AMPLIFICATION PRIMERS".

The term "sequence described in Table 14" is used herein to refer to the entire collection of nucleotide sequences or any individual sequence defined in Table 14. The SEQ ID that contains each "sequence described in Table 14" is provided in the column labeled, "SEQ ID
NO.". The range of nucleotide positions within the Sequence ID of which each sequence consists is provided in the same row as the Sequence ID in a column labeled, "POSITION
RANGE OF
PROBES". The sequences which are complementary to the ranges listed in the column labeled, "POSITION RANGE OF PROBES" are also encompassed by the term, "sequence described in Table l4." Unless otherwise noted the term "sequence described in Table 14" is to be construed as encompassing sequences that contain either of the two alleles listed in the allele feature in the appended Sequence Listing for each Sequence ID number referenced in Table 14.
The terms "biallelic marker described in Table"'and "allele described in Table" are used herein to refer to any or all alleles which are listed in the allele feature in the appended Sequence Listing for each Sequence ID number referenced in the particular Table being mentioned.
The following abbreviations are used in this disclosure: serotonin receptor 6 gene is abbreviated SHTR6; serotonin receptor 7 gene is abbreviated SHTR7; neuronal nicotinic acid receptor a7 gene is abbreviated CHRNA7; corticotrophin releasing factor receptor lgene is abbreviated CRFRl; mineralocorticoid receptor gene is abbreviated MLR;
corticotrophin releasing factor receptor 2 gene is abbreviated CRFR2; glueocortieoid receptor gene is abbreviated GRL; monoamine oxidases A and B genes are abbreviated MAOA/B;
serotonin receptor 2C gene is abbreviated SHTR2c; tyrosine hydroxylase gene is abbreviated TH;
corticotrophin releasing factor gene is abbreviated CRF; dopamine receptor 4 gene is abbreviated DRD4; serotonin transporter gene is abbreviated SHTT; dopamine receptor 3 gene is abbreviated DRD3; cytochrome P450 3A4 gene is abbreviated CYP3A4; norepinephrine transporter gene is abbreviated NET; neurokinin or tachykinin receptor 1 gene is abbreviated NK11TACR1;
dopamine receptor 4 gene is abbreviated DRD2; guanine nucleotide binding protein, (33 gene is abbreviated Gbeta3; Wolfram Syndrome 1 gene is abbreviated WFS1; Beta 1 adrenergic receptor gene is abbreviated ADRB 1R; Brain derived neurotrophic factor gene is abbreviated BDNF; ' Orphan G-protein coupled receptor gene is abbreviated HM74; Vasopressin receptor 1A gene is abbreviated AVPR1A; Serotonin receptor 1-A gene is abbreviated SHT1A; Growth associated protien 43 gene is abbreviated GAP43; Guanine nucleotide binding protein, oc subunit,, olfactory type gene is abbreviated GOLF (GNAL); Clock protein gene is abbreviated CLOCK;
Corticotrophin hormone binding protein gene is abbreviated CRHBP; Dopamine transporter gene is abbreviated DAT (SLC6A3); Phosphodiesterase type 4b gene is abbreviated PDE4b; Catechol O-methyl transferase gene is abbreviated COMT; Melanin concentrating hormone receptor gene is abbreviated SLCI; Transcription factor gene is abbreviated SEF2-1B (TCF4);
Heat shock protein gene is abbreviated HSP70; GABA-A receptor subunit gene is abbreviated GABRG2;
and GABA-A receptor subunit 5 gene is abbreviated GABRAS.

III, Biallelic Markers and Polynucleotides Comprising Biallelic Markers A. Advantages of the Biallelic Markers of the Present Invention The CNS disorder-related biallelic markers of the present invention offer a number of important advantages over other genetic markers such as RFLP (Restriction fragment length polymorphism) and VNTR (Variable Number of Tandem Repeats) markers.
The first generation of markers, were RFLPs, which are variations that modify the length of a restriction fragment. But methods used to identify and to type RFLPs are relatively wasteful of materials, effort, and time. The second generation of genetic markers were VNTRs, which can be categorized as either minisatellites or microsatellites. Minisatellites are tandemly repeated DNA sequences present in units of 5-50 repeats which are distributed along regions of the human chromosomes ranging from 0.1 to 20 kilobases in length. Since they present many possible alleles, their informative content is very high. Minisatellites are scored by performing Southern blots to identify the number of tandem repeats present in a nucleic acid sample from the .
' individual being tested. However, there are only 104 potential VNTRs that can be typed by' Southern blotting. Moreover, both RFLP and VNTR markers are costly and time-consuming to develop and assay in large numbers.
Single nucleotide polymorphism or biallelic markers can be used in the same manner as RFLPs and VNTRs but offer several advantages. Single nucleotide polymorphisms are densely spaced in the human genome and represent the most frequent type of variation.
An estimated number of more than 10' sites are scattered along the 3x109 base pairs of the human genome.
Therefore, single nucleotide polymorphism occur at a greater frequency and with greater uniformity than RFLP or VNTR markers which means that there is a greater probability that such a marker will be found in close proximity to a genetic locus of interest.
Single nucleotide polymorphisms are less variable than VNTR markers but are mutationally more stable.
Also, the different forms of a characterized single nucleotide polymorphism, such as the biallelic markers of the present invention, are often easier to distinguish and can therefore be typed easily on a routine basis. Biallelic markers have single nucleotide based alleles and they have only two common alleles, which allows highly parallel detection and automated scoring.
The biallelic markers of the present invention offer the possibility of rapid, high-throughput genotyping of a large number of individuals.
Biallelic markers are densely spaced in the genome, sufficiently informative and can be assayed in large numbers. The combined effects of these advantages make biallelic markers extremely valuable in genetic studies. Biallelic markers can be used in linkage studies in families, in allele sharing methods, in linkage disequilibrium studies in populations, in association studies of case-control populations. An important aspect of the present invention is that biallelic markers allow association studies to be performed to identify genes involved in complex traits. Association studies examine the frequency of marker alleles in unrelated case-and control-populations and are generally employed in the detection of polygenic or sporadic traits. Association studies may be conducted within the general population and are not limited to studies performed on related individuals in affected families (linkage studies). Biallelic markers in different genes can be screened in parallel for direct association with disease or response to a treatment. This multiple gene approach is a powerful tool for a variety of human genetic studies as it provides the necessary statistical power to examine the synergistic effect of multiple genetic factors on a particular phenotype, drug response, sporadic trait, or disease state with a complex genetic etiology.
B. Polynucleotides of the Present Invention The present invention encompasses polynucleotides for use as primers and probes in the methods of the invention. These polynucleotides may consist of, consist essentially 'of, or comprise a contiguous span of nucleotides of a sequence from any sequence in the Sequence Listing as well as.sequences which are complementary thereto ("complements thereof'). The "contiguous span" may be at least 8, 10, 12, 15, 18, 20, 25, 35, 40, 50, 70, 80, 100, 250, 500, .
1000, 2000 or 3000 nucleotides in length, to the extent that a contiguous span of these lengths is consistent with the lengths of the particular Sequence ID. It should be noted that the polynucleotides of the present invention are not limited to having the exact flanking sequences surrounding the polymorphic bases which, are enumerated in the Sequence Listing. Rather, it , will be appreciated that the flanking sequences surrounding the biallelic markers, or any of the primers of probes of the invention which, are more distant from the markers, may be lengthened or shortened to any extent compatible with their intended use and the present invention specifically contemplates such sequences. It will be appreciated that the polynucleotides referred to in the Sequence Listing may be of any length compatible with their intended use. Also the flanking regions outside of the contiguous span need not be homologous to native flanking sequences which actually occur in human subjects. The addition of any nucleotide sequence, which is compatible with the nucleotides intended use is specifically contemplated. The contiguous span may optionally include the CNS disorder-related biallelic marker in said sequence. Biallelic markers generally consist of a polymorphism at one single base position.
Each biallelic marker therefore corresponds to two forms of a polynucleotide sequence which, when compared with one another, present a nucleotide modification at one position. Usually, the nucleotide modification involves the substitution of one nucleotide for another. Optionally either the original or the alternative allele of the biallelic markers disclosed in Table 9, or the first or second allele disclosed in Table 8 and 10 may be specified as being present at the CNS disorder-related biallelic marker.
The invention also relates to polynucleotides that hybridize, under conditions of high or intermediate stringency, to a polynucleotide of a sequence from any sequence in the Sequence Listing as well as sequences, which are complementary thereto. Preferably such polynucleotides are at least 20, 25, 35, 40, 50, 70, 80, 100, 250, 500, 1000, 2000 or 3000 nucleotides in length, to the extent that a polynucleotide of these lengths is consistent with the lengths of the particular Sequence m. Preferred polynucleotides comprise a CNS disorder-related biallelic marker.
Optionally either the original or the alternative allele of the biallelic markers disclosed in Table 9 may be specified as being present at the CNS disorder-related biallelic marker. Conditions of high and intermediate stringency are further described herein.
The preferred polynucleotides of the invention include the sequence ranges included in any one the sequence ranges of Tables 8 and 11 to 14 individually or in groups consisting of all the possible combinations of the ranges of included in Tables 8, and 11 to 14.
The preferred polynucleotides of the invention also include fragments of at least 8; 10, 12, 15, 18, 20, 25, 35, 40, 50, 70, 80, 100, 250, 500 or 1000 consecutive nucleotides of the sequence ranges included in any one of the sequence ranges of Tables 9, and 12 to 15'to the extent that fragments of these lengths are consistent with the lengths of the particular sequence range. The preferred , polynucleotides of the invention also include fragments of at least 8, 10, 12, 15, 18, 20, 25, 35, 40, 50, 70, 80, 100, 250, 500 or 1000 consecutive nucleotides of the sequence complementary to the sequence ranges included in any one of the sequence ranges of Tables 8 and 11 to 14 to.the extent that fragments of these lengths are consistent with the lengths of the particular sequence range.
. The primers of the present invention may be designed from the disclosed sequences for any method known in the art. A preferred set of primers is fashioned such that the 3' end of the contiguous span of identity with the sequences of the Sequence Listing is present at~the 3' end of the primer. Such a configuration allows the 3' end of the primer to hybridize to a selected nucleic acid sequence and dramatically increases the efficiency of the primer for amplification or ~ sequencing reactions. In a preferred set of primers the contiguous span is found in one of the sequences described in Table 11. Allele specific primers may be designed such that a biallelic marker is at the 3' end of the contiguous span and the contiguous span is present at the 3' end of the primer. Such allele specific primers tend to selectively prime an amplification or sequencing reaction so long as they are used with a nucleic acid sample that contains one of the two alleles present at a biallelic marker. The 3' end of primer of the invention may be located within or at least 2, 4, 6, 8, 10, 12, 15, 18, 20, 25, 50, 100, 250, 500, 1000, 2000 or 3000 to the extent that this distance is consistent with the particular Sequence ID, nucleotides upstream of a CNS disorder-related biallelic marker in said sequence or at any other location which is appropriate for their intended use in sequencing, amplification or the location of novel sequences or markers. A list of preferred amplification primers is disclosed in Table 13. Primers with their 3' ends located 1 nucleotide upstream of a CNS disorder-related biallelic marker have a special utility as microsequencing assays. Preferred microsequencing primers are described in Tables 12.

The probes of the present invention may be designed from the disclosed sequences for any method known in the art, particularly methods which allow for testing if a particular sequence or marker disclosed herein is present. A preferred set of probes may be designed for use in the hybridization assays of the invention in any manner known in the art such that they selectively bind to one allele of a biallelic marker, but not the other under any particular set of assay conditions. Preferred hybridization probes may consists of, consist essentially of, or comprise a contiguous span which ranges in length from 8, 10, 12, 15, 18 or 20 to 25, 35, 40, 50, 60, 70, or 80 nucleotides, or be specified as being 12, 15, 18, 20, 25, 35, 40, or 50 nucleotides in length and including a CNS disorder-related biallelic marker of said sequence.
Optionally the original allele or alternative allele disclosed in Table 9 and the first or second allele disclosed in Tables 8 and 10 may be specified as being present at the biallelic marker site. Optionally, .said biallelic marker may be within 6, 5, 4, 3, 2, or 1 nucleotides of the center of the hybridization probe or at the center of said probe. A particularly preferred set of hybridization probes is disclosed in Table 14 or a sequence complementary thereto.
Any of the polynucleotides of the present invention can be labeled, if desired, by incorporating a label detectable by spectroscopic, photochemical, biochemical, immunochemical, or chemical means. For example, useful labels include radioactive substances, fluorescent dyes.
or biotin. Preferably, polynucleotides are labeled at their 3' and 5' ends. A
label can also be used to capture the primer, so as to facilitate the immobilization of either the primer or a primer extension product, such as amplified DNA, on a solid support. A capture label is attached to the primers or probes and can be a specific binding member which forms a binding pair with the solid's phase reagent's specific binding member (e.g. biotin and streptavidin). Therefore depending upon the type of label carried by a polynucleotide or a probe, it may be employed to capture or to detect the target DNA. Further, it will be understood that the polynucleotides, - primers or probes provided herein, may, themselves, serve as the capture label. For example, in the case where a solid phase reagent's binding member is a nucleic acid sequence, it may be selected such that it binds a complementary portion of a primer or probe to thereby immobilize the primer or probe to the solid phase. In cases where a polynucleotide probe itself serves as the binding member, those skilled in the art will recognize that the probe will contain a sequence or "tail" that is not complementary to the target. In the case where a polynucleotide primer itself serves as the capture label, at least a portion of the primer will be free to hybridize with a nucleic acid on a solid phase. DNA Labeling techniques are well known to the skilled technician.
Any of the polynucleotides, primers and probes of the present invention can be conveniently immobilized on a solid support. Solid supports are known to those skilled in the art and include the walls of wells of a reaction tray, test tubes, polystyrene beads, magnetic beads, nitrocellulose strips, membranes, microparticles such as latex particles, sheep (or other animal) red blood cells, duracytes~ and others. The solid support is not critical and can be selected by one skilled in the art. Thus, latex particles, microparticles, magnetic or non-magnetic beads, membranes, plastic tubes, walls of microtiter wells, glass or silicon chips, sheep (or other suitable animal's) red blood cells and duracytes are all suitable examples. Suitable methods for immobilizing nucleic acids on solid phases include ionic, hydrophobic, covalent interactions and the like. A solid support, as used herein, refers to any material which is insoluble, or can be made insoluble by a subsequent reaction. The solid support can be chosen for its intrinsic ability to attract and immobilize the capture reagent. Alternatively, the solid phase can retain an additional receptor which has the ability to attract and immobilize the capture reagent. The additional receptor can include a charged substance that is oppositely charged With respect to the capture reagent itself or to a charged substance conjugated to the capture reagent. As yet another alternative, the receptor molecule can be any specific binding member which is immobilized upon (attached to) the solid support and which has the ability to immobilize the capture reagent through a specific binding reaction. The receptor molecule enables the indirect binding of the capture reagent to a solid support material before the performance of the assay or during the performance of the assay. The solid phase thus can be a plastic, derivatized plastic, magnetic or non-magnetic metal, glass or silicon surface of a test tube, microtiter well, sheet, bead, microparticle, chip, sheep (or other suitable animal's) red blood cells, duracytes~ and other configurations known to those of ordinary skill in the art. The polynucleotides of the invention can be attached to or immobilized on a solid support individually or in groups of at least 2, 5, 8, 10, 12, 15, 20, or 25 distinct polynucleotides of the inventions to a single solid support. In addition, polynucleotides other than those of the invention may be attached to the same solid support as one or more polynucleotides of the invention.
Any polynucleotide provided herein may be attached in overlapping areas or at random locations on the solid support. Alternatively the polynucleotides of the invention may be attached in an ordered array wherein each polynucleotide is attached to a distinct region of the solid support which does not overlap with the attachment site of any other polynucleotide.
Preferably, such an ordered array of polynucleotides is designed to be "addressable" where he distinct locations are recorded and can be accessed as part of an assay procedure. Addressable polynucleotide arrays typically comprise a plurality of different oligonucleotide probes that are coupled to a surface of a substrate in different known locations. The knowledge of the precise location of each polynucleotides location makes these "addressable" arrays particularly useful in hybridization assays. Any addressable array technology known in the art can be employed with the polynucleotides of the invention. One particular embodiment of these polynucleotide arrays is known as the GenechipsT"~, and has been generally described in US Patent 5,143,854; PCT
publications WO 90J15070 and 92110092. These arrays may generally be produced using mechanical synthesis methods or light directed synthesis methods, which incorporate a combination of photolithographic methods and solid phase oligonucleotide synthesis (Fodor et al., Science, 251:767-777, 1991). The immobilization of arrays of oligonucleotides on solid supports has been rendered possible by the development of a technology generally identified as "Very Large Scale Immobilized Polymer Synthesis" (VLSIPSTM) in which, typically, probes are immobilized in a high density array on a solid surface of a chip. Examples of VLSIPSTM
technologies are provided in US Patents 5,143,854 and 5,412,087 and in PCT
Publications WO
90115070, WO 92110092 and WO 95/11995, which describe methods for forming oligonucleotide arrays through techniques such as light-directed synthesis techniques. In designing strategies aimed at providing arrays of nucleotides immobilized on solid supports, further presentation strategies were developed to order and display the oligonucleotide arrays on the chips in an attempt to maximize hybridization patterns and sequence information. Examples of such presentation strategies are disclosed in PCT Publications WO 94/12305, WO 94/11530, WO 97129212 and WO 97/31256.
Oligonucleotide arrays may comprise at least one of the sequences selected from the group consisting of SEQ ID No. 1-130; and the sequences complementary thereto or a fragment thereof of at least 8, 10, 12, 15, 18, 20, 25, 35, 40, 50, 70, 80, 100, 250, 500, 1000, 2000 or 3000 consecutive nucleotides, to the extent that fragments of these lengths is consistent with the lengths of the particular Sequence ID, for determining whether a sample contains one or more alleles of the biallelic markers of the present invention. Oligonucleotide arrays may also comprise at least one of the sequences selected from the group consisting of SEQ )D No. 1-130;
and the sequences complementary thereto or a fragment thereof of at least 8, 10, 12, 15, 18, 20, 25, 35, 40, 50, 70, 80, 100, 250, 500, 1000, 2000 or 3000 consecutive nucleotides, to the extent that fragments of these lengths is consistent with the lengths of the particular Sequence m, for amplifying one or more alleles of the biallelic markers of Table 7. In other embodiments, arrays may also comprise at least one of the sequences selected from the group consisting of SEQ ID
No. 1-130; and the sequences complementary thereto or a fragment thereof of at least 8, 10, 12~
15, 18, 20, 25, 35, 40, 50, 70, 80, 100, 250, 500, 1000, 2000 or 3000 consecutive nucleotides, to the extent that fragments of these lengths is consistent with the lengths of the particular Sequence ID, for conducting microsequencing analyses to determine whether a sample contains one or more alleles of the biallelic markers of the invention. 1n still further embodiments, the oligonucleotide array may comprise at least one of the sequences selecting from the group consisting of SEQ ID No. 1-130; and the sequences complementary thereto or a fragment thereof of at least 8, 10, 12, 15, 18, 20, 25, 35, 40, 50, 70, 80, 100, 250, 500, 1000, 2000 or 3000 nucleotides in length, to the extent that fragments of these lengths is consistent with the lengths of the particular Sequence ID, for determining whether a sample contains one or more alleles of the biallelic markers of the present invention. In still further embodiments, the oligonucleotide array may comprise at least one of the novel sequences listed in the fifth column of Table 8 or the sequences complementary thereto or a fragment comprising at least 8, 10, 12, 15, 18, 20, 25, 35, 40, 50, 70, 80, 100, 250, 500 or 1000 consecutive nucleotides thereof to the extent that fragments of these lengths are consistent with the lengths of the particular novel sequences.
The present invention also encompasses diagnostic kits comprising one or more polynucleotides of the invention, optionally with a portion or all of the necessary reagents and instructions for genotyping a test subject by determining the identity of a nucleotide at a CNS
disorder-related biallelic marker. The determining of the identity may optionally be at a CNS
disorder-related biallelic marker that predicts the response of a therapeutic agent, preferably Reboxetine, when administered to a patient suffering from depression. The polynucleotides of a kit may optionally be attached to a solid support, or be part of an array or addressable array of polynucleotides. The kit may provide for the determination of the identity of the nucleotide at a marker position by any method known in the art including,.but not. limited to, a sequencing assay method, a microsequencing assay method, a hybridization assay method, or an allele specific amplification method. Optionally such a kit may include instructions for scoring the results of the determination with respect to the test subj ects' risk of contracting a CNS disorder, or likely response to an agent acting on CNS disorders, or chances of suffering from side effects to an agent acting on CNS disorders.
C. Polypeptides of the Invention The polynucleotides which encode the WFS1 and the NET polypeptide may include:
only the coding sequence for the mature polypeptide; the coding sequence for the polypeptide and additional coding sequence such as a leader or secretory sequence or a proprotein sequence;
the coding sequence for the polypeptide (and optionally additional coding sequence) and non-coding.sequence, such as introns or non-coding sequence 5' and/or 3' of the coding sequence for the mature polypeptide. , Thus, the term "polynucleotide encoding a polypeptide" encompasses a polynucleotide 25. which includes only coding sequence for the polypeptide as well as a polynucleotide which includes additional coding and/or non-coding sequence.
. As hereinabove indicated, the polynucleotides may have a coding sequence which is.a naturally occurring allelic variant of the coding sequence of SEQ >D NO: 543 or 544. As known in the art, an allelic variant is an alternate form of a polynucleotide sequence which may have a substitution, deletion or addition of one or more nucleotides, which does not substantially alter the function of the encoded polypeptide.
D. Host Cells Host cells are genetically engineered (transduced or transformed or transfected) with the vectors of this invention which may be, for example, a cloning vector or an expression vector:
The vector may be, for example, in the form of a plasmid, a viral particle, a phage, etc: The engineered host cells can be cultured in conventional nutrient media modified as appropriate for activating promoters, selecting transformants or amplifying the WFS 1 or NET
gene. The culture conditions, such as temperature, pH and the like, are those previously used with the host cell selected for expression, and will be apparent to the ordinarily skilled artisan.
The polynucleotides of the present invention may be employed for producing polypeptides by recombinant techniques. Thus, for example, the polynucleotide may be included in any one of a variety of expression vectors for expressing a polypeptide.
Such vectors include chromosomal, nonchromosomal and synthetic DNA sequences, e.g., derivatives of SV40;
bacterial plasmids; phage DNA; baculovirus; yeast plasmids; vectors derived from combinations of plasmids and phage DNA, viral DNA such as vaccinia, adenovirus, fowl pox virus, and pseudorabies. However, any other vector may be used as long as it is replicable and viable in the host.
The appropriate DNA sequence may be inserted into the vector by a variety of procedures. In general, the DNA sequence is inserted into an appropriate restriction endonuclease sites) by procedures known in the art. Such procedures and others:are deemed to be within the scope of those skilled in the art.
The DNA sequence in the expression vector is operatively linked to an appropriate expression control sequences) (promoter) to direct mRNA synthesis. As representative examples of such promoters, there may be mentioned: LTR or SV40 promoter, the E. coli.
lac or trp, the phage lambda P_L promoter and other promoters known to control expression of genes in prokaryotic or eukaryotic cells or their viruses. The expression vector also contains a ribosome binding site for translation initiation and a transcription terminator. The vector may also include appropriate sequences for amplifying expression.
In addition, the expression vectors preferably contain one or more selectable marker genes to provide a phenotypic trait for selection of transformed host cells such as dihydrofolate reductase or neomycin resistance for eukaryotic cell culture, or such as tetracycline or ampicillin resistance in E. coli.
The vector containing the appropriate DNA sequence as hereinabove described, as well as an appropriate promoter or control sequence, may be employed to transform an appropriate host to permit the host to express the protein.
As representative examples of appropriate hosts, there may be mentioned:
bacterial cells, such as E. coli, Streptomyces, Salmonella typhimurium; fungal cells, such as yeast; insect cells such as Drosophila S2 and Spodoptera Sf~; animal cells such as CHO, COS or Bowes .
melanoma; adenoviruses; plant cells, etc. The selection of an appropriate host is deemed to be within the scope of those skilled in the art from the teachings herein.
E. Screenin Assays The polynucleotides of the present invention may be employed for producing polypeptides by recombinant techniques. Thus, for example, the polynucleotide may be included in any one of a variety of expression vectors for expressing a polypeptide.
Such vectors include chromosomal, nonchromosomal and synthetic DNA sequences, e.g., derivatives of SV40;
bacterial plasmids; phage DNA; baculovirus; yeast plasmids; vectors derived from combinations of plasmids and phage DNA, viral DNA such as vaccinia, adenovirus, fowl pox virus, and pseudorabies. However, any other vector may be used as long as it is replicable and viable in the host.
The appropriate DNA sequence may be inserted into the vector by a variety of procedures. In general, the DNA sequence is inserted into an appropriate restriction endonuclease sites) by procedures known in the art. Such procedures and others are deemed to be within the scope of those skilled in the art.
The DNA sequence in the expression vector is operatively linked to an appropriate expression control sequences) (promoter) to direct mRNA synthesis. As representative examples of such promoters, there may be mentioned: LTR or SV40 promoter, the E, coli.
lac or trp, the phage lambda P_L promoter and other promoters known to control expression of genes in prokaryotic or eukaryotic cells or their viruses. The expression vector also contains a ribosome binding site for translation initiation and a transcription terminator. The vector may also include appropriate sequences for amplifying expression.
In addition, the expression vectors preferably contain one or more selectable marker genes to provide a phenotypic trait for selection of transformed host cells such as dihydrofolate reductase or neomycin resistance for eukaryotic cell culture, or such as tetracycline or ampicillin resistance in E. coli.
The vector containing the appropriate DNA sequence as hereinabove described, as well as an appropriate promoter or control sequence, may be employed to transform an appropriate host to permit the host to express the protein. .
As representative examples of appropriate hosts, there may be mentioned:
bacterial cells, such as E. coli, Streptomyces, Salmonella typhimurium; fungal cells, such as yeast; insect cells such as Drosophila S2 and Spodoptera Sf9; animal cells such as CHO, COS or Bowes:
melanoma; adenoviruses; plant cells, etc. The selection of an appropriate host is deemed to be within the scope of those skilled in the art from the teachings herein.
More particularly, the present invention also includes recombinant constructs comprising one or more of the sequences as broadly described above. The constructs comprise a vector, such as a plasmid or viral vector, into which. a sequence of the invention has been inserted, in a forward or reverse orientation. In a preferred aspect of this embodiment, the construct further comprises regulatory sequences, including, for example, a promoter, operably linked to the sequence. Large numbers of suitable vectors and promoters are known to those of skill in the art, and are commercially available. The following vectors are provided by way of example.
Bacterial: pQE70, pQE60, pQE-9 (Qiagen), pbs, pDlO, phagescript, psiX174, pbluescript SK, pbsks, pNHBA, pNHl6a, pNHl8A, pNH46A (Stratagene); ptrc99a, pKK223-3, pKK233-3, pDR540, pRITS (Pharmacia). Eukaryotic: pWLNEO, pSV2CAT, pOG44, pXTl, pSG
(Stratagene) pSVK3, pBPV, pMSG, PSVL (Pharmacia). However, any other plasmid or vector may be used as long as they are replicable and viable in the host.
Promoter regions can be selected from any desired gene using CAT
(chloramphenicol transferase) vectors or other vectors with selectable markers. Two appropriate vectors are PKK232-8 and PCM7. Particular named bacterial promoters include lacI, lacZ, T3, T7, gpt, lambda P_R, P_L and trp. Eukaryotic promoters include CMV immediate early, HSV
thymidine kinase, early and late SV40, LTRs from retrovirus, and mouse metallothionein-I.
Selection of the appropriate vector and promoter is well within the level of ordinary skill in the art.
In a further embodiment, the present invention relates to host cells containing the above-described constructs. The host cell can be a higher eukaryotic cell, such as a mammalian cell, or a lower eukaryotic cell, such as a yeast cell, or the host cell can be a prokaryotic cell, such as a bacterial cell. Introduction of the construct into the host cell can be effected by calcium phosphate transfection, DEAF-Dextran mediated transfection, or electroporation: (Davis, L., Dibner, M., Battey, L, Basic Methods in Molecular Biology, (1986)).
The constructs in host cells can be used in a conventional manner to produce the gene .
product encoded by the recombinant sequence. Alternatively, the polypeptides of the invention can be synthetically~produced by conventional peptide synthesizers.
Mature proteins can be expressed in mammalian cells, yeast, bacteria, or other cells under the control of appropriate promoters. Cell-free translation systems can also be employed to produce such proteins using RNAs derived from the DNA constructs of the present invention.
Appropriate cloning and expression vectors for use with prokaryotic and eukaryotic hosts are described by Sambrook, et al., Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor, N.Y:, (1989), the disclosure of which is hereby incorporated by reference:
Transcription of the DNA encoding the polypeptides of .the present invention by higher eukaryotes is increased. by inserting an enhancer sequence into the vector.
Enhancers are cis-acting elements of DNA, usually about from 10 to 300 by that act on a promoter to increase its transcription. Examples including the SV40 enhancer on the late side of the replication origin by 100 to 270, a cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers.
Generally, recombinant expression vectors will include origins of replication and selectable markers permitting transformation of the host cell, e.g., the ampicillin resistance gene of E. coli and S. cerevisiae TRP1 gene, and a promoter derived from a.highly-expressed gene to direct transcription of a downstream structural sequence. Such promoters can be derived from operons encoding glycolytic enzymes such as 3-phosphoglycerate kinase (PGK), .alpha.-factor, acid phosphatase, or heat shock proteins, among others. The heterologous structural sequence is assembled in appropriate phase with translation initiation and termination sequences, and preferably, a leader sequence capable of directing secretion of translated protein into the periplasmic space or extracellular medium. Optionally, the heterologous sequence can encode a fusion protein including an N-terminal identification peptide imparting desired characteristics, e.g., stabilization or simplified purification of expressed recombinant product.
Useful expression vectors for bacterial use are constructed by inserting a structural DNA
sequence encoding a desired protein together with suitable translation initiation and termination signals in operable reading phase with a functional promoter. The vector will comprise one or more phenotypic selectable markers and an origin of replication to ensure maintenance of the vector and to, if desirable, provide amplification within the host. Suitable prokaryotic hosts for transformation include E. coli, Bacillus subtilis, Salmonella typhimurium and various species within the genera Pseudomonas, Streptomyces, and Staphylococcus, although others may also be employed as a matter of choice.
As a representative but nonlimiting example, useful expression vectors for bacterial use can comprise a selectable marker and bacterial origin of replication derived from commercially available plasmids comprising genetic elements of the well known cloning vector pBR322 (ATCC 37017). Such commercial vectors include, for example, pKK223-3 (Pharmacia Fine Chemicals, Uppsala, Sweden) and GEMl (Promega Biotec, Madison, Wis., USA).
These pBR322 "backbone" sections are combined with an appropriate promoter and the structural '.
sequence to be expressed.
Following transformation of a suitable host strain and growth of the host strain to ari appropriate cell density, the selected promoter is induced by appropriate means (e.g., temperature shift or chemical induction) and cells are cultured for an additional period.
Cells are typically harvested by centrifugation, disrupted by physical or chemical means, and the resulting crude extract retained for further purification. Microbial cells employed in expression of proteins can be disrupted by any convenient method, including freeze-thaw cycling, sonication, mechanical disruption, or use of cell lysing agents, such methods are well know to those skilled in the art.
Various mammalian cell culture systems can also be employed to express recombinant.
protein. Examples of mammalian expression systems include the COS-7 lines of monkey kidney flbroblasts, described by Gluzman, Cell, 23:175 (1981), and other cell lines capable of expressing a compatible vector, for example, the C127, 3T3, CHO, HeLa and BHK cell lines.
Mammalian expression vectors will comprise an origin of replication, a suitable promoter and enhancer, and also any necessary xibosome binding sites, polyadenylation site, splice donor and acceptor sites, transcriptional termination sequences, and 5' flanking nontranscribed sequences. DNA sequences .
derived from the SV40 splice, and polyadenylation sites may be used to provide the required nontranscribed genetic elements.

The WFS 1 and NET polypeptides can be recovered and purified from recombinant cell cultures by methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Protein refolding steps can be used, as necessary, in completing configuration of the mature protein. Finally, high performance liquid chromatography (HPLC) can be employed for final purification steps.
The polypeptides of the present invention may be a naturally purified product, or a product of chemical synthetic procedures, or produced by recombinant techniques from a prokaryotic or eukaryotic host (for example, by bacterial, yeast, higher plant, insect and mammalian cells in culture). Depending upon the host employed in a recombinant production procedure, the polypeptides of the present invention rnay be glycosylated or may be non-glycosylated. Polypeptides of the invention may also include an initial methionine amino acid residue.
~ . F. Screening Assay The WFS 1 protein receptor of the present invention may be employed in a process for screening for antagonists andlor agonists for the receptor.
In general, such screening procedures involve providing appropriate cells which express the receptor on the surface thereof. In particular, a polynucleotide encoding the receptor of the present invention is employed to transfect cells to thereby express the WFS 1 receptor. Such transfection may be accomplished by procedures as hereinabove described.
One such screening procedure involves the use of the melanophores which are transfected to express the WFS 1 receptor of the present invention. Such a screening technique is. ' described in PCT WO 92101810 published Feb. 6, 1992.
Thus, for example, such assay may be employed for screening for a receptor antagonist .
by contacting the melanophore cells which encode the WFS 1 receptor with both the receptor ligand and a compound to be screened. Inhibition of he signal generated by the ligand indicates that a compound is a potential antagonist for the receptor, i.e., inhibits activation of the receptor.
The screen may be employed for determining an agonist by contacting such cells with compounds to be screened and determining whether such compound generates a signal; i.e., activates the receptor.
Other screening techniques include the use of cells which express WFS1 receptor (for example, transfected CHO cells) in a system which measures extracellular pH
changes caused by receptor activation, for example, as described in Science, volume 246, pages 181-29.6 (October 1989). For example, potential agonists or antagonists may be contacted with a cell which expresses the WFS 1 receptor and a second messenger response, e.g. signal transduction or pH
changes, may be measured to determine whether the potential agonist or antagonist is effective.

Another such screening technique involves introducing RNA encoding the WFS 1 receptor into xenopus oocytes to transiently express the receptor. The receptor oocytes may then be contacted in the case of antagonist screening with the receptor ligand and a compound to be screened, followed by detection of inhibition of a calcium signal.
Another screening technique involves expressing the WFSl receptor in which the receptor is linked to a phospholipase C or D. As representative examples of such cells, there may be mentioned endothelial cells, smooth muscle cells, embryonic kidney cells, etc. The screening for an antagonist or agonist may be accomplished as hereinabove described by detecting activation of the receptor or inhibition of activation of the receptor from the phospholipase second signal.
Another method involves screening for antagonists by determining inhibition of binding of labeled ligand to cells which have the receptor on the surface thereof..
Such a method involves transfecting a eukaryotic cell with DNA encoding the WFS1 receptor such that the cell expresses the receptor on its surface and contacting the cell with a potential antagonist in the presence of a labeled form of a known ligand. The ligand can be labeled, e.g., by radioactivity. The amount of labeled ligand bound to the receptors is measured, e.g., by measuring radioactivity of the receptors. If the potential antagonist binds to the receptor as determined by a reduction of labeled ligand which binds to the receptors, the binding of labeled ligand to the receptor is inhibited.
The present invention also provides a method for determining whether a ligand not known to be capable of binding to a WFS 1 receptor can bind to such receptor which comprises contacting a mammalian cell which expresses a WFS1 receptor with the ligand under conditions permitting binding of ligands to the WFS1 receptor, detecting the presence of a ligand which binds to the receptor and thereby determining whether the ligand binds to the WFS 1 receptor.
The systems hereinabove described for determining agonists and/or antagonists may also be employed for determining ligands which bind to the receptor.
In general, antagonists for WFS 1 receptors which are determined by screening procedures may be employed for a variety of therapeutic purposes. For example, such antagonists have been employed for treatment of hypertension, angina pectoris, myocardial infarction, ulcers, asthma, allergies, psychoses, depression, migraine, vomiting, stroke, eating disorders, migraine . headaches, cancer and benign prostatic hypertrophy.
Agonists for WFS 1 receptors are also useful for therapeutic purposes, such as the treatment of Wolfram syndrome and/or depression.
Examples of WFS 1 receptor antagonists include an antibody, or in some cases an oligonucleotide, which binds to the WFS 1 receptor but does not elicit a second messenger response such that the activity of the WFS1 receptor is prevented. Antibodies include anti-idiotypic antibodies which recognize unique determinants generally associated with the antigen-binding site of an antibody.

Potential antagonists also include proteins which are closely related to the ligand of the WFS 1 receptor, i.e. a fragment of the ligand, which have lost biological function and when binding to the WFS 1 receptor, elicit no response.
A potential antagonist also includes an antisense construct prepared through the use of antisense technology. Antisense technology can be used to control gene expression through triple-helix formation or antisense DNA or RNA, both of which methods are based on binding of a polynucleotide to DNA or RNA. For example, the 5' coding portion of the polynucleotide sequence, which encodes for the mature polypeptides of the present invention, is used to design an antisense RNA oligonucleotide of from about 10 to 40 base pairs in length.
A DNA
oligonucleotide is designed to be complementary to a region of the gene involved in transcription (triple helix -see Lee et al., Nucl. Acids Res., 6:3073 (.1979);
Cooney et al, Science, 241:456 (1988); and Dervan et al., Science, 251: 1360 (1991)), thereby preventing transcription and the production of WFS 1 receptor. The antisense RNA oligonucleotide hybridizes to the mRNA in vivo and blocks translation of the mRNA molecule into the WFS 1 receptor (antisense--Okano, J. Neurochem., 56:560 (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression, CRC Press, Boca Raton, Fla. (1988)). The oligonucleotides described above can also be delivered to cells such that the antisense RNA or DNA may be expressed in vivo to inhibit production of WFS 1 receptor.
Another potential antagonist is a small molecule which binds to the WFS1 receptor, making it inaccessible to ligands such that normal biological activity is prevented. Examples of small molecules include but 'are not limited to small peptides or peptide-like molecules.
Potential antagonists also include a soluble form of a WFS1 receptor, e.g. a fragment of the receptor, which binds to the ligand and prevents the ligand from interacting with membrane bound WFS 1 receptors.
The WFS 1 receptor and antagonists or agonists may be employed in combination with a suitable pharmaceutical Garner. Such compositions comprise a therapeutically effective amount of the polypeptide, and a pharmaceutically acceptable carrier or excipient.
Such a carrier includes but is not limited to saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. The formulation should suit the mode of administration.
G. Antibodies The polypeptides, their fragments or other derivatives, or analogs thereof, or cells expressing them can be used as an immunogen to produce antibodies thereto.
These antibodies can be, for example, polyclonal or monoclonal antibodies. The present invention also includes chimeric, single chain, and humanized antibodies, as well as Fab fragments, or the product of an Fab expression library. Various procedures known in the art may be used for the production of such antibodies and fragments.

Antibodies generated against the polypeptides corresponding to a sequence of the present invention can be obtained by direct injection of the polypeptides into an animal or by administering the polypeptides to an animal, preferably a nonhuman. The antibody so obtained will then bind the polypeptides itself. In this manner, even a sequence encoding only a fragment of the polypeptides can be used to generate antibodies binding the whole native polypeptides.
Such antibodies can then be used to isolate the polypeptide from tissue expressing that polypeptide.
IV. Methods for De Novo Identification of Biallelic Markers Large fragments of human DNA, carrying genes of interest involved in CNS
disorders;
were cloned, sequenced and screened for biallelic markers. Biallelic markers within the candidate genes themselves as well as markers located on the same genomic fragment were identified. It will be clear to one of skill in the art that large fragments of human genomic DNA
may be obtained from any appropriate source and may be cloned into a number of suitable vectors.
In a preferred embodiment of the invention, BAC (Bacterial Artificial Chromosomes) vectors were used to construct DNA libraries covering the entire human genome.
Specific amplification primers were designed for each candidate gene and'the BAC
library was screened by PCR until there was at least one positive BAC clone per candidate gene.
Genomic sequence, 20' screened for biallelic markers, was generated by sequencing ends of BAC
subclones. Details of a preferred embodiment are provided in Example 1. As a preferred alternative to sequencing the ends of an adequate number of BAC subclones, high throughput deletion-based sequencing vectors, which allow the generation of a high quality sequence information covering fragments of about 6kb, may be used. Having sequence fragments longer than 2.5 or 3kb enhances the chances of identifying biallelic markers therein. Methods of constructing and sequencing a nested set of deletions are disclosed in the related U.S. Patent Application entitled "High Throughput DNA Sequencing Vector" (Serial No. 09/058,746).
In another embodiment of the invention, genomic sequences of candidate genes were available in public databases allowing direct screening for biallelic markers.
Any of a variety of methods can be used to screen a genomic fragment for single nucleotide polymorphisms such as differential hybridization with oligonucleotide probes, detection of changes in the mobility measured by gel electrophoresis or direct sequencing of the amplified nucleic acid. A preferred method for identifying biallelic markers involves comparative sequencing of genomic DNA fragments from an appropriate number of unrelated individuals.
In a first embodiment, DNA samples from unrelated individuals are pooled together, following which the genomic DNA of interest is amplified and sequenced. The nucleotide sequences thus obtained are then analyzed to identify significant polymorphisms. One of the major advantages of this method resides in the fact that the pooling of the DNA samples substantially reduces the number of DNA amplification reactions and sequencing reactions, which must be carried out. Moreover, this method is sufficiently sensitive so that a biallelic marker obtained thereby usually demonstrates a sufficient frequency of its less common allele to be useful in conducting association studies. Usually, the frequency of the least common allele of a biallelic marker identified by this method is at least 10%.
In a second embodiment, the DNA samples are not pooled and are therefore amplified and sequenced individually. This method is usually preferred when biallelic markers need to be identified in order to perform association studies within candidate genes.
Preferably, highly relevant gene regions such as promoter regions or exon regions may be screened for biallelic markers. A biallelic marker obtained using this method may show a lower:
degree of informativeness for conducting association studies, e.g. if the frequency of its less frequent allele may be less than about 10%. Such a biallelic marker will .however be sufficiently informative to conduct association studies and it will further be appreciated that including less informative biallelic markers in the genetic analysis studies of the present invention, may allow in some cases the direct identification of causal mutations, which may, depending on their penetrance, be rare mutations.
The following is a description of the various parameters of a preferred method used by the inventors for the identification of the biallelic markers of the present invention..
A. Genomic DNA Samples The genomic DNA samples from which the biallelic markers of the present invention are generated are preferably obtained from unrelated individuals corresponding to a heterogeneous population of known ethnic background. The number of individuals from whom DNA
samples are obtained can vary substantially, preferably from about 10 to about 1000, more preferably from about 50 to about 200 individuals. Usually, DNA samples are collected from~at least about 100 individuals in order to have sufficient polymorphic diversity in a given.population to identify.
as many markers as possible and to generate statistically significant results.
As for the source of the genomic DNA to be subjected to analysis, any test sample can be foreseen without any particular limitation. These test samples include biological samples, which can be tested by the methods of the present invention described herein, and include human and animal body fluids such as whole blood, serum, plasma, cerebrospinal fluid, urine, lymph fluids, and various external secretions of the respiratory, intestinal and genitourinary tracts, tears, saliva, milk, white blood cells, myelomas and the like; biological fluids such as cell culture supernatants; fixed tissue specimens including tumor and non-tumor tissue and lymph node tissues; bone marrow aspirates and axed cell specimens. The preferred source of genomic DNA -used in the present invention is from peripheral venous blood of each donor.
Techniques to prepare genomic DNA from biological samples are well known to the skilled technician. Details of a preferred embodiment are provided in Example 1. The person skilled in the art can choose to amplify pooled or unpooled DNA samples.
B. DNA Amplification The identification of biallelic markers in a sample of genomic DNA may be facilitated through the use of DNA amplification methods. DNA samples can be pooled or unpooled fox the amplification step. DNA amplification techniques are well known to those skilled in the art.
Various methods to amplify DNA fragments carrying biallelic markers are further described herein. The PCR technology is the preferred amplification technique used to identify new biallelic markers.
In a first embodiment, biallelic markers are identified using genomic sequence information generated by the inventors. Genomic DNA fragments, such as the inserts of the BAC clones described above, are sequenced and. used to design primers for the amplification of 500 by fragments: These 500 by fragments are amplified from genomic DNA and are scanned for biallelic markers. Primers may be designed using the OSP software (Hillier L. and Green P., 1991). All primers may contain, upstream of the specific target bases, a common oligonucleotide tail that serves as a sequencing primer. Those skilled in the art are familiar with primer extensions, which can be used for these purposes.
In another embodiment of the invention, genomic sequences of candidate genes are available in public databases allowing direct screening for biallelic markers.
Preferred primers, useful for the amplification of genomic sequences encoding the candidate genes, focus on promoters, exons and splice sites of the genes. A biallelic marker present in these functional regions of the gene has a higher probability to be a causal mutation.
Preferred primers include those disclosed in Table 13.
C. Sequencing of Amplified Genomic DNA and Identification of Single Nucleotide Polymorphisms The amplification products generated as described above, are then sequenced using any method known and available to the skilled technician. Methods for sequencing DNAwsing either the dideoxy-mediated method (Sanger method) or the Maxam-Gilbert method are widely known ~ .' to those of ordinary skill in the art. Such methods are for example disclosed in Maniatis et al.
(Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press, Second Edition, 1989).
Alternative approaches include hybridization to high-density DNA probe arrays as described in Chee et al. (Science 274, 610, 1996).
Preferably, the amplified DNA is subjected to automated dideoxy terminator sequencing reactions using a dye primer cycle sequencing protocol. The products of the sequencing reactions are run on sequencing gels and the sequences are determined using gel image analysis.
The polymorphism search is based on the presence of superimposed peaks in the electrophoresis pattern resulting from different bases occurring at the same position. Because each dideoxy terminator is labeled with a different fluorescent molecule, the two peaks corresponding to a biallelic site present distinct colors corresponding to two different nucleotides at the same position on the sequence. However, the presence of two peaks can be an artifact due to background noise. To exclude such an artifact, the two DNA strands are sequenced and a comparison between the peaks is carried out. In order to be registered as a polymorphic sequence, the polymorphism has to be detected on both strands.
The above procedure permits those amplification products, which contain biallelic markers to be identified. The detection limit for the frequency of biallelic polymorphisms detected by sequencing pools of 100 individuals is approximately 0.1 for the minor allele, as verified by sequencing pools of known allelic frequencies. However, more than 90% of the biallelic polymorphisms detected by the pooling method have a frequency for the minor allele higher than 0.25. Therefore, the biallelic markers selected by this method have, a .frequency of at least 0.1 for the minor allele and less than 0.9 for the major allele.
Preferably at least 0.2 for the minor allele and less than 0.8 for the major allele, more preferably at least 0.3 for the minor allele' and less than 0.7 for the major allele, thus a heterozygosity rate higher than 0.18, preferably higher than 0.32, more preferably higher than 0.42.
In another embodiment, biallelic markers are detected by sequencing individual DNA
samples; the frequency of the minor allele of such a biallelic marker may be less than 0.1.
The markers carried by the same fragment of genomic DNA, such as the insert in a BAG.
clone, need not necessarily be ordered with respect to one another within the genomic fragment to conduct association studies. However, in some embodiments of the present invention, the order of biallelic markers carried by the same fragment of genomic DNA are determined.. .
D. Validation of the Biallelic Markers of the Present Invention The polymorphisms are evaluated for their usefulness as genetic markers by validating that both alleles are present in a population. Validation of the biallelic markers is accomplished by genotyping a group of individuals by a method of the invention and demonstrating that both alleles are present. Microsequencing is a preferred method of genotyping alleles." The validation by genotyping step may be performed on individual samples derived from, each individual in the group or by genotyping a pooled sample derived from more than one individual.
The group can be as small as one individual if that individual is heterozygous for the allele in question. .
Preferably the group contains at least three individuals, more preferably the group contains five or six individuals, so that a single validation test will be more likely to result in the validation of more of the biallelic markers that are being tested. It should be noted, however, that whem the validation test is performed on a small group it may result in a false negative result if as a result of sampling error none of the individuals tested carries one of the two alleles. Thus, the validation process is less useful in demonstrating that a particular initial result is an artifact, than it is at demonstrating that there is a bona fide biallelic marker at a particular position in a sequence. For an indication of whether a particular biallelic marker has been validated see Table 7. All of the genotyping, haplotyping, association, and interaction study methods of the invention may optionally be performed solely with validated biallelic markers.
E. Evaluation of the Frequency of the Biallelic Markers of the Present Invention The validated biallelic markers are further evaluated for their usefulness as genetic markers by determining the frequency of the least common allele at the biallelic marker site.
The determination of the least common allele is accomplished by genotyping a group of individuals by a method of the invention and demonstrating that both alleles are present. This determination of frequency by genotyping step may be performed on individual samples derived from each individual in the group or by genotyping a pooled sample derived from more than one individual. The group must be large enough to be representative of the population as a whole.
Preferably the group contains at least 20 individuals, more preferably the group contains at least 50 individuals, most preferably the group contains at least 100 individuals.
Of course the larger the group the greater the accuracy of the frequency determination because of reduced sampling error. For an indication of the frequency for the less common allele of a particular biallelic marker of the invention see Table 7. A biallelic marker wherein the frequency of the less common allele is 30% or more is termed a "high quality biallelic marker." All of the genotyping;
haplotyping, association, and interaction study methods of the invention may optionally be performed solely with high quality biallelic markers.
V. Methods of Genotypin~ an Individual for Biallelic Markers Methods are provided to genotype a biological sample for one or more biallelic markers of the present invention, all of which may be performed in vitf°o. Such methods of genotyping comprise determining the identity of a nucleotide at a CNS disorder-related biallelic marker by any method known in the art. These methods find use in genotyping case-control populations in association studies as well as individuals in the context of detection of alleles of biallelic markers which, are lrnown to be associated with a given trait, in which case both copies of the biallelic marker present in individual's genome are determined so that an individual may be classified as homozygous or heterozygous for a particular allele.
These genotyping methods can be performed nucleic acid samples derived from a single individual or pooled DNA samples.
Genotyping can be performed using similar methods as those described above for the identification of the biallelic markers, or using other genotyping methods such as those further described below. In preferred embodiments, the comparison of sequences of amplified genomic fragments from different individuals is used to identify new biallelic markers whereas microsequencing is used for genotyping known biallelic markers in diagnostic and association study applications.

A. Source of DNA for Genotyping Any source of nucleic acids, in purified or non-purified form, can be utilized as the starting nucleic acid, provided it contains or is suspected of containing the specific nucleic acid sequence desired. DNA or RNA may be extracted from cells, tissues, body fluids and the like as described herein. While nucleic acids for use in the genotyping methods of the invention can be derived from any mammalian source, the test subjects and individuals from which nucleic acid samples are taken are generally understood to be human.
B. Amplification of DNA Fragments Comprising Biallelic Markers Methods and polynucleotides are provided to amplify a segment of nucleotides comprising one or more biallelic marker of the present invention. It will be appreciated that amplification of DNA fragments comprising biallelic markers may be used in various methods and for various purposes and is not restricted to genotyping. Nevertheless, many genotyping methods, although not all, require the previous amplification of the DNA
region carrying the biallelic marker of interest. Such methods specifically increase the concentration or total number of sequences that span the biallelic marker or include that site and sequences located either distal or proximal to it. Diagnostic assays may also rely on amplification of DNA
segments carrying a biallelic marker of the pxesent invention.
Amplification of DNA may be achieved by any method known in the art. The established PCR (polymerase chain reaction) method or by developments thereof or alternatives.
Amplification methods which can be utilized herein include but are not limited to Ligase Chain Reaction (LCR) as described in EP A 320 308 and EP A 439 182, Gap LCR
(Wolcott, M.J., Clin.
Microbiol. Rev. 5:370-386), the so-called "NASBA" or "3SR" technique described in Guatelli J.C. et al. (Proc. Natl. Acad. Sci. USA 87:1874-1878, 1990) and in Compton J.
(Nature 350:91-92, 1991), Q-beta amplification as described in European Patent Application no 4544610, strand displacement amplification as described in Walker et al. (Clip. Chem. 42:9-13, 1996) and.EP A
684 315 and, target mediated amplification as described in PCT Publication WO
9322461.
LCR and Gap LCR are exponential amplification techniques, both depend on DNA .
ligase to join adjacent primers annealed to a DNA molecule. In Ligase Chain Reaction (LCR);
probe pairs are used which include two primary (first and second) and two secondary (third and fourth) probes, all ,of which are employed in molar excess to target. The first probe hybridizes to a first segment of the target strand and the second probe hybridizes to a second segment of the target strand, the first and second segments being contiguous so that the primary probes abut one another in 5' phosphate-3'hydroxyl relationship, and so that a ligase can covalently fuse or ligate the two probes into a fused product. In addition, a third (secondary) probe can hybridize to a portion of the first probe and a fourth (secondary) probe can hybridize to a portion of the second probe in a similar abutting fashion. Of course, if the target is initially double stranded, the secondary probes also will hybridize to the target complement in the first instance. Once the ligated strand of primary probes is separated from the target strand, it will hybridize with the third and fourth probes Which can be ligated to form a complementary, secondary ligated product. It is important to realize that the ligated products are functionally equivalent to either the target or its complement. By repeated cycles of hybridization and ligation, amplification of the target sequence is achieved. A method for multiplex LCR has also been described (WO
9320227). Gap LCR (GLCR) is a version of LCR where the probes are not adjacent but are separated by 2 to 3 bases.
For amplification of mRNAs, it is within the scope of the present invention to reverse transcribe mRNA into cDNA followed by polymerise chain reaction (RT-PCR); or, to use a single enzyme for both steps as described in U.S. Patent No. 5,322,770 or, to use Asymmetric Gap LCR (RT-AGLCR) as described by Marshall R.L. et al. (PCR Methods and Applications

4:80-84, 1994). AGLCR is a modification of GLCR that allows the amplification of RNA.
Some of these amplification methods are particularly suited for the detection of single nucleotide polymorphisms and allow the simultaneous amplification of a target sequence and.the identification of the polymorphic nucleotide as it is further described herein.
The.PCR technology is the preferred amplification technique used in the present invention. A variety of PCR techniques are familiar to those skilled in the art. For a review of PCR
technology, see Molecular Cloning to Genetic Engineering White, B.A. Ed. in Methods in Molecular Biology 67: Humana Press, Totowa (1997) and the publication entitled "PCR Methods and Applications" (1991, Cold Spring Harbor Laboratory Press). In each of these PCR
procedures, PCR primers on either side of the nucleic acid sequences to be amplified are added to a suitably prepared nucleic acid sample along with dNTPs and a thermostable polymerise such as Taq polymerise, Pfu polymerise, or Vent polymerise. The nucleic acid in the sample is denatured and , the PCR primers are specifically hybridized to complementary nucleic acid sequences in the sample.
The hybridized primers are extended. Thereafter, another cycle of denaturation, hybridization, and extension is initiated. The cycles are repeated multiple times to produce an amplified fragment containing the nucleic acid sequence between the primer sites. PCR has further been. described in several patents including US Patents 4,683,195, 4,683,202 and 4,965,188.
The identification of biallelic markers as described above allows the design of appropriate oligonucleotides, which can be used as primers to amplify DNA
fragments comprising the biallelic markers of the present invention. Amplification can be performed using the primers initially used to discover new biallelic markers which are described herein or any set of primers allowing the amplification of a DNA fragment comprising a biallelic marker of the present invention. Primers can be prepared by any suitable method. As for example, direct chemical synthesis by a method such as the phosphodiester method of Narang S.A. et al.
(Methods Enzymol. 68:90-98, 1979), the phosphodiester method of Brown E.L. et al. (Methods Enzynol. 68:109-151, 1979), the diethylphosphoramidite method of Beaucage et al.
(Tetrahedf-on Lett. 22:1859-1862, 1981) and the solid support method described in EP 0 707 592.
In some embodiments the present invention provides primers for amplifying a DNA
fragment containing one or more biallelic markers of the present invention.
Preferred ampliEcation primers are listed in Table 13. It will be appreciated that the primers listed are merely exemplary and that any other set of primers which produce amplification products containing one or more biallelic markers of the present invention.
The primers are selected to be substantially complementary to the different strands of each specific sequence to be amplified. The length of the primers of the present invention can . range from 8 to 100 nucleotides, preferably from 8 to 50, 8 to 30 or more preferably 8 to 25 nucleotides. Shorter primers tend to lack specificity for a target nucleic acid sequence and generally require cooler temperatures to form sufficiently stable hybrid complexes with the template. Longer primers are expensive to produce and can sometimes self hybridize to form hairpin structures. The formation of stable hybrids depends on the melting temperature (Tm) of the DNA. The Tm depends on the length of the primer, the ionic strength of the solution and the G+C content. The higher the G+C content of the primer, the higher is the melting temperature because G:C pairs are held by three H bonds whereas A:T pairs have only two.
The G+C content of the ampliEcation primers of the present invention preferably ranges between 10 and 75 %, more preferably between 35 and 60 %, and most preferably between 40 and 55 %.
The appropriate length for primers under a particular set of assay conditions may be empirically determined by one of skill in the art.
The spacing of the primers determines the length of the segment to be amplified. In the context of the present invention amplified segments carrying biallelic markers can range in size from at least about 25 by to 35 kbp. Amplification fragments from 25-3000 by are typical, fragments from 50-1000 by are preferred and fragments from 100-600 by are highly preferred.. It will be appreciated that amplification primers for the biallelic markers may be any~sequence which allow the specific amplification of any DNA fragment carrying the markers.
Amplification primers may be labeled or immobilized on a solid support as described in I.
C. Methods of Genotypin~ DNA samples for Biallelic Markers Any method known in the art can be used to identify the nucleotide present at a biallelic marker site. Since the biallelic marker allele to be detected has been identified and specified in the present invention, detection will prove simple for one of ordinary skill in the art by employing any of a number of techniques. Many genotyping methods require the previous .
amplification of the DNA region carrying the biallelic marker of interest.
While the amplification of target or signal is often preferred at present, ultrasensitive detection methods which do not require amplification are also encompassed by the present genotyping methods.
Methods well-known to those skilled in the art that can be used to detect biallelic polymorphisms include methods such as, conventional dot blot analyzes, single strand conformational polymorphism analysis (SSCP) described by Orita et al. (Proc. Natl. Acad. Sci.
U.S.A 86:27776-2770, 1989), denaturing gradient gel electrophoresis (DGGE), heteroduplex analysis, mismatch cleavage detection, and other conventional techniques as described in Sheffield, V.C. et al. (P~°oc.
Natl. Acad. Sci. USA 49:699-706, 1991), White et al. (Genomics 12:301-306, 1992), Grompe, M.
et al. (Proc. Natl. Acad. Sci. USA 86:5855-5892, 1989) and Grompe, M. (Nature Genetics 5:111-117, 1993). Another method for determining the identity of the nucleotide present at a particular polymorphic site employs a specialized exonuclease-resistant nucleotide derivative as described in US patent 4,656,127.
Preferred methods involve directly determining the identity of the nucleotide present at a biallelic marker site by sequencing assay, enzyme-based mismatch detection assay, or hybridization assay. The following is a description of some preferred methods.
A,highly - .
preferred method is the microsequencing technique. The term "sequencing assay"
is used herein to refer to polymerase extension of duplex primeritemplate complexes and includes both traditional sequencing and microsequencing.
i) Sequencin assays The nucleotide present at a polymorphic site can be determined by sequencing methods.
In a preferred embodiment, DNA samples are subjected to PCR amplification before sequencing as described above. DNA sequencing methods are described herein. .
Preferably, the amplified DNA is subjected to automated dideoxy terminator sequencing reactions using a dye-primer cycle sequencing protocol. Sequence analysis allows the identification of the base present at the biallelic marker site.
ii) Microseguencin~ assay In microsequencing methods, a nucleotide at the polymorphic site that is unique to one of the alleles in a target DNA is detected by a single nucleotide primer extension reaction. This method involves appropriate microsequencing primers which, hybridize just upstream of a polymorphic base of interest in the target nucleic acid. A polymerase is used to specifically extend the 3' end of the primer with one single ddNTP (chain terminator) complementary to the selected nucleotide at the polymorphic site. Next the identity of the incorporated nucleotide is determined in any suitable way. ..
Typically, microsequencing reactions are carxied out using fluorescent ddNTPs and the extended microsequencing primers are analyzed by electrophoresis on ABI 377 sequencing machines to determine the identity of the incorporated nucleotide as described in EP 412 883.
Alternatively capillary electrophoresis can be used in order to process a higher number of assays simultaneously. An example of a typical microsequencing procedure that can be used in the context of the present invention is provided in Example 2.

Different approaches can be used to detect the nucleotide added to the microsequencing primer. A homogeneous phase detection method based on fluorescence resonance energy transfer has been described by Chen and I~wok (Nucleic Acids Researcla 25:347-353 1997) and Chen et al. (Proc. Natl. Acad. Sci. USA 94120 10756-10761,1997). In this method amplified genomic DNA fragments containing polymorphic sites are incubated with a 5'-fluorescein-labeled primer in the presence of allelic dye-labeled dideoxyribonucleoside triphosphates and a modified Taq polymerase. The dye-labeled primer is extended one base by the dye-terminator specific for the allele present on the template. At the end of the genotyping reaction, the fluorescence intensities of the two dyes in the reaction mixture are analyzed directly without separation or' purification.
All these steps can be performed in the same tube and the fluorescence changes can be monitored in real time. Alternatively, the extended primer may be analyzed by MALDI-TOF
Mass Spectrometry. The base at the polymorphic site is identified by the mass added onto the microsequencing primer (see Haff L.A. and Smirnov LP., Gen.ome Research, 7:378-388, 1997):
Microsequencing may be achieved by the established microsequencing method or by developments or derivatives thereof. Alternative methods include several solid-phase microsequencing techniques. The basic microsequencing protocol is the same as described previously, except that the method is conducted as a heterogenous phase assay, in which the primer or the target molecule is immobilized or captured onto a solid support.
To simplify the primer separation and the terminal nucleotide addition analysis, oligonucleotides are attached to solid supports or axe modified in such ways that permit affinity separation as well as polymerase extension. The 5' ends and internal nucleotides of synthetic oligonucleotides can be modified in a number of different ways to permit different affinity separation approaches, e.g., biotinylation. ~ If a single affinity group is used on the oligonucleotides, the oligonucleotides can be separated from the incorporated terminator reagent. This eliminates the need of physical or size separation.
More than one oligonucleotide can be separated from the terminator reagent and analyzed simultaneously if more than one affinity group is used. This permits the analysis of several nucleic acid species or more nucleic acid sequence information per extension reaction. The , affinity group need not be on the priming oligonucleotide but could alternatively be present on the template. For example, immobilization can be carried out via an interaction between biotinylated DNA and streptavidin-coated microtitration wells or avidin-coated polystyrene particles. In the same manner oligonucleotides or templates may be attached to a solid support,in a high-density format. In such solid phase microsequencing reactions, incorporated ddNTPs can be radiolabeled (Syvanen, Cliraica Chirnica Acta 226:225-236, 1994) or linked to fluorescein (Livak and Hainer, Hunzata Mutation 3:379-385,1994). The detection of radiolabeled ddNTPs can be achieved through scintillation-based techniques. The detection of fluorescein-linked ddNTPs can be based on the binding of antifluorescein antibody conjugated with alkaline phosphatase, followed by incubation with a chromogenic substrate (such as p-nitrophenyl phosphate). Other possible reporter-detection pairs include: ddNTP linked to dinitrophenyl (DNP) and anti-DNP alkaline phosphatase conjugate (Harju et al., Clin. Claena.
39/11 2282-2287, . 1993) or biotinylated ddNTP and horseradish peroxidase-conjugated streptavidin with o-phenylenediamine as a substrate (WO 92/15712). As yet another alternative solid-phase microsequencing procedure, Nyren et al. (Analytical Biochemistry 208:171-175, 1993) described a method relying on the detection of DNA polymerase activity by an enzymatic luminometric inorganic pyrophosphate detection assay (ELIDA).
Pastinen et al. (Genome research 7:606-614, 1997) describe a method for multiplex detection of single nucleotide polymorphism in which the solid phase minisequencing principle 10' is applied to an oligonucleotide array format. High-density arrays of DNA
probes attached to a solid support (DNA chips) are further described herein.
In one aspect the present invention provides polynucleotides and methods to genotype one or more biallelic markers of the present invention by performing a microsequencing assay.
Preferred microsequencing primers include those being featured in Table 12. It will be appreciated that the microsequencing primers listed in Table 12 are merely exemplary and that, any primer having a 3' end immediately adjacent to a polymorphic nucleotide may be used.
Similarly, it will be appreciated that microsequencing analysis may be performed for any biallelic marker or any combination of biallelic markers of the present invention. One aspect of the present invention is a solid support which includes one or more microsequencing primers listed in Table 12, or fragments comprising at least 8, at least 12, at least 15, or at least 20 . consecutive nucleotides thereof and having a 3' terminus immediately upstream of the corresponding biallelic marker, for determining the identity of a nucleotide at a biallelic marker site.
iii) Mismatch detection assays based on polymerises and 1i ases 25' In one aspect the present invention provides polynucleotides and methods to determine the allele of one or more biallelic markers of the present invention in a biological sample, by mismatch detection assays based on polymerises and/or ligases. These assays are based on the specificity of polymerises and ligases. Polymerization reactions places particularly stringent requirements on correct base pairing of the 3' end of the amplification primer and the joining of two oligonucleotides hybridized to a target DNA sequence is quite sensitive.
to mismatches close to the ligation site, especially at the 3' end. The terms "enzyme based mismatch detection assay"
are used herein to refer to any method of determining the allele of a biallelic marker based on the specificity of ligases and polymerises. Preferred methods are described below.
Methods, primers and various parameters to amplify DNA fragments comprising biallelic markers of the present invention are further described herein.
1. Allele specific amplification Discrimination between the two alleles of a biallelic marker can also be achieved by allele specific amplification, a selective strategy, whereby one of the alleles is amplified without amplification of the other allele. This is accomplished by placing a polymorphic base at the 3' end of one of the amplification primers. Because the extension forms from the 3'end of the primer, a mismatch at or near this position has an inhibitory effect on amplification. Therefore, under appropriate amplification conditions, these primers only direct amplification on their complementary allele. Designing the appropriate allele-specific primer and the corresponding assay conditions are well with the ordinary skill in the art.
2. Ligationlamplification based methods The "Oligonucleotide Ligation Assay" (OLA) uses two oligonucleotides which are designed to be capable of hybridizing to abutting sequences of a single .strand of target molecules. One of the oligonucleotides is biotinylated, and he other is.
detectably labeled. If the precise complementary sequence is found in a target molecule, the oligonucleotides will hybridize such that their termini abut, and create a ligation substrate that can be captured and . detected. OLA is capable of detecting biallelic markers and may be advantageously combined with PCR as described by Nickerson D.A. et al. (Proc. Natl. Acad.~ Sci. U.S.A.
87:8923-8927, 1990). In this method, PCR is used to achieve the exponential amplification of target DNA;
which is then detected using OLA.
Other methods which are particularly suited for the detection of biallelic markers include LCR (ligase chain reaction), Gap LCR (GLCR) which are described herein. As mentioned above LCR uses two pairs of probes to exponentially amplify a specific target. The sequences of each pair of oligonucleotides, is selected to permit the pair to hybridize to abutting sequences of the same strand of the target. Such hybridization forms a substrate for a template-dependant ligase.
In accordance with the present invention, LCR can be performed with oligonucleotides having the proximal and distal sequences of the same strand of a biallelic marker site. In one embodiment, either oligonucleotide will be designed to include the biallelic marker site. In such an embodiment, the reaction conditions are selected such that the oligonucleotides can be ligated together only if the target molecule either contains or lacks the specific nucleotide(s)~that is complementary to the biallelic marker on the oligonucleotide. In an alternative embodiment, the oligonucleotides will not include the biallelic marker, such that when they hybridize to the target molecule, a "gap" is created as described in WO 90101069. This gap is then "filled" with , complementary dNTPs (as mediated by DNA polymerase), or by an additional pair of oligonucleotides. Thus at the end of each cycle, each single strand has a complement capable of serving as a target during the next cycle and exponential allele-specific amplification of the desired sequence is obtained.
Ligase/Polymerase-mediated Genetic Bit AnalysisTM is another method for determining the identity of a nucleotide at a preselected site in a nucleic acid molecule (WO 95/21271). This method involves the incorporation of a nucleoside triphosphate that is complementary to the nucleotide present at the preselected site onto the terminus of a primer molecule, and their subsequent ligation to a second oligonucleotide. The reaction is monitored by detecting a specific label attached to the reaction's solid phase or by detection in solution.
iv) Hybridization assay methods A preferred method of determining the identity of the nucleotide present at a biallelic marker site involves nucleic acid hybridization. The hybridization probes, which can be conveniently used in such reactions, preferably include the probes defined herein. Any hybridization assay may be used including Southern hybridization, Northern hybridization, dot blot hybridization and solid-phase hybridization (see Sambrook et al., Molecular Cloning - A
Laboratory Manual, Second Edition, Cold Spring Harbor Press, N.Y., 1989).
Hybridization refers to the formation of a duplex structure by two single stranded nucleic acids due to complementary base pairing. Hybridization can occur between exactly complementary nucleic acid strands or between nucleic acid strands that contain minor regions of mismatch. Specific probes can be designed that hybridize to one form of a biallelic marker and .
not to the other and therefore are able to discriminate between different allelic forms. Allele-specific probes are often used in pairs, one member of a pair showing perfect match to a target sequence containing the original allele and the other showing a perfect match to the target sequence containing the alternative allele. Hybridization conditions should be sufficiently stringent that there is a significant difference in hybridization intensity between alleles, and preferably an essentially binary response, whereby a probe hybridizes to only one of the alleles.
Stringent, sequence specific hybridization conditions, under which a probe will hybridize only to the exactly complementary target sequence are well known in the art (Sambrook et al., Molecular Cloning - A Laboratory Manual, Second Edition, Cold Spring Harbor Press, N.Y., 1989).
Stringent conditions are sequence dependent and will be different in different circumstances.
Generally, stringent conditions are selected to be about 5°C lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH. By way of example and not limitation, procedures using conditions of high stringency are as follows:
Prehybridization of filters containing DNA is carried out for 8 h to overnight at 65°C in buffer composed of 6X SSC, 50 mM Tris-HCl (pH 7.5), 1 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA, and 500 ~.glml~
denatured salmon sperm DNA. Filters are hybridized for 48 h at 65°C, the preferred hybridization temperature, in prehybridization mixture containing 100 ~g/ml denatured salmon sperm DNA and 5-20 X 106 cpm of 32P-labeled probe. Alternatively, the hybridization step can be performed at 65°C in the presence of SSC buffer, 1 x SSC
corresponding to 0.15M NaCI and ' 0.05 M Sodium citrate. Subsequently, filter washes can be done at 37°C
for 1 h in a solution containing 2X SSC, 0.01% PVP, 0.01% Ficoll, and 0.01% BSA, followed by a wash in O.1X
SSC at 50°C for 45 min. Alternatively, filter washes can be performed in a solution containing 2 x SSC and 0.1% SDS, or 0.5 x SSC and 0.1% SDS, or 0.1 x SSC and 0.1% SDS at 68°C for 15 minute intervals. Following the wash steps, the hybridized probes are detectable by autoradiography. By way of example and not limitation, procedures using conditions of intermediate stringency are as follows: Filters containing DNA are prehybridized, and then hybridized at a temperature of 60°C in the presence of a 5 x SSC buffer and labeled probe.
Subsequently, filters washes are performed in a solution containing 2x SSC at 50°C and the hybridized probes are detectable by autoradiography. Other conditions of high and intermediate stringency which may be used are well known in the art and as cited in Sambrook et al.
(Molecular Cloning - A Laboratory Manual, Second Edition, Cold Spring Harbor Press, N.Y., 1989) and Ausubel et al. (Current Protocols in Molecular Biology, Green Publishing Associates and Wiley Interscience, N.Y., 1989).
Although such hybridizations can be performed in solution, it is preferred to employ a solid-phase hybridization assay. The target DNA comprising a biallelic marker of the present invention may be amplified prior to the hybridization reaction. The presence of a specific allele in the sample is determined by detecting the presence or the absence of stable hybrid duplexes formed between the probe and the target DNA. The detection of hybrid duplexes can.be carried out by a number of methods. Various detection assay formats are well known which utilize detectable labels bound to either the target or the probe to enable detection of the hybrid duplexes: Typically, hybridization duplexes are separated from unhybridized nucleic acids and the labels bound to the duplexes are then detected. Those skilled in the art will recognize that wash steps may be employed to wash away excess target DNA or probe. Standard heterogeneous assay formats are suitable for detecting the hybrids using the labels present on the primers and probes.
Two recentlydeveloped assays allow hybridization-based allele discrimination with no need for separations or washes (see Landegren U. et al., Geraonae Research, 8:769-776,1998)..
The TaqMan assay takes advantage of the 5' nuclease activity of Taq DNA
polymerase to digest a DNA probe annealed specifically to the accumulating amplification product.
TaqMan probes are labeled with a donor-acceptor dye pair that interacts via fluorescence energy transfer.
Cleavage of the TaqMan probe by the advancing polymerase during amplification dissociates the donor dye from the quenching acceptor dye, greatly increasing the.donor fluorescence. All reagents necessary to detect two allelic variants can be assembled at the beginning of the reaction and the results are monitored in real time (see Livak et al., Nature Genetics, 9:341-342, 1995).
In an alternative homogeneous hybridization-based procedure, molecular beacons are used for allele discriminations. Molecular beacons are hairpin-shaped oligonucleotide probes that report the presence of specific nucleic acids in homogeneous solutions. When they bind to their targets they undergo a conformational reorganization that restores the fluorescence of an internally quenched fluorophore (Tyagi et al., Nature Biotechnology, 16:49-53, 1998).

The polynucleotides provided herein can be used in hybridization assays for the detection of biallelic marker alleles in biological samples. These probes are characterized in that they preferably comprise between 8 and 50 nucleotides, and in that they are sufficiently complementary to a sequence comprising a biallelic marker of the present invention to hybridize thereto and preferably sufficiently specific to be able to discriminate the targeted sequence for only one nucleotide variation. The GC content in the probes of the invention usually ranges between 10 and 75 %, preferably between 35 and 60 %, and more preferably between 40 and 55 %. The length of these probes can range from 10, 15, 20, or 30 to at least 100 nucleotides,' preferably from 10 to 50, more preferably from 18 to 35 nucleotides. A
particularly preferred probe is 25 nucleotides in length. Preferably the biallelic marker is within 4 nucleotides of the center of the polynucleotide probe. In particularly preferred probes the biallelic marker is at the center of said polynucleotide. Shorter probes may lack specificity for a target nucleic acid sequence and generally require cooler temperatures to form sufficiently stable hybrid complexes with the template. Longer probes are expensive to produce and can sometimes self hybridize to form hairpin structures. Methods for the synthesis of oligonucleotide probes have been described above and can be applied to the probes of the present invention.
Preferably the probes of the present invention are labeled or immobilized on a solid support. Labels and solid supports are further described in I. Detection probes are generally nucleic acid sequences or uncharged nucleic acid analogs such as, for example peptide nucleic acids which are disclosed in International Patent Application WO 92120702;
morpholino analogs which are described in U.S. Patents Numbered 5,185,444; 5,034,506 and

5,142,047. The probe may have to be rendered "non-extendable" in that additional dNTPs cannot be added to the probe. In and of themselves analogs usually are non-extendable and nucleic acid probes can be rendered non-extendable by modifying the 3' end of the probe such that the hydroxyl group is no longer capable of participating in elongation. For example, the 3' end of the probe can be functionalized with the capture or detection label to thereby consume or otherwise block the hydroxyl group. Alternatively, the 3' hydroxyl group simply can be cleaved, replaced or modified, U.S. Patent Application Serial No. 07/049,061 filed April 19, 1993 describes modifications, which can be used to render a probe non-extendable.
The probes of the present invention are useful for a number of purposes. They can be used in Southern hybridization to genomic DNA or Northern hybridization to mRNA. The probes can also be used to detect PCR amplification products. ~By assaying the hybridization to an allele specific probe, one can detect the presence or absence of a biallelic marker allele in a given sample.
High-Throughput parallel hybridizations in array format are specifically encompassed within "hybridization assays" and are described below.
i. Hybridization to addressable arrays of oli~onucleotides Hybridization assays based on oligonucleotide arrays rely on the differences in hybridization stability of short oligonucleotides to perfectly matched and mismatched target sequence variants. Efficient access to polymorphism information is obtained through a basic structure comprising high-density arrays of oligonucleotide probes attached to a solid support (the chip) at selected positions. Each DNA chip can contain thousands to millions of individual synthetic DNA probes arranged in a grid-like pattern and miniaturized to the size of a dime.
The chip technology has already been applied with success in numerous cases.
For example, the screening of mutations has been undertaken in the BRCAl gene, in S. cerevisiae mutant strains, and in the protease gene of HIS-1 virus (Hacia et al., Nature Genetics, 14(4):441-447, 1996; Shoemaker et al., Nature Genetics, 14(4):450-456, 1996 ; Kozal et al., Nature Medicine, 2:753-759, 1996). Chips of various formats for use in detecting biallelic polymorphisms can be produced on a customized basis by Affymetrix (GeneChipT""), Hyseq (HyChip and HyGnostics), and Protogene Laboratories.
In general, these methods employ arrays of oligonucleotide probes that are complementary to target nucleic acid sequence segments from an individual which, target sequences include a polymorphic marker. EP785280 describes a tiling strategy for the detection of single nucleotide polymorphisms. Briefly, arrays may generally be "tiled"
for a large number of specific polymorphisms. By "tiling" is generally meant the synthesis of a defined set of oligonucleotide probes which is made up of a sequence complementary to the target sequence of interest, as well as preselected variations of that sequence, e.g., substitution of one or more given ' positions with one or more members of the basis set of monomers, i.e.
nucleotides. Tiling strategies are further described in PCT application No. WO 95/11995. In a particular aspect, arrays are tiled for a number of specific, identified biallelic marker sequences. In particular the array is tiled to include a number of detection blocks, each detection block being specific for a~
specific biallelic marker or a set of biallelic markers. For example, a detection block may be tiled to include a number of probes, which span the sequence segment that includes a specific polymorphism. To ensure probes that are complementary to each allele, the probes are synthesized in pairs differing at the biallelic marker. In addition to the probes differing at the polymorphic base, monosubstituted probes are also generally tiled within the detection block.
These monosubstituted probes have bases at and up to a certain number of bases in either direction from the polymorphism, substituted with the remaining nucleotides (selected from A, T, G, C and U). Typically the probes in a tiled detection block will include substitutions of the sequence positions up to and including those that are 5 bases away from the biallelic marker. The monosubstituted probes provide internal controls for the tiled array, to distinguish-actual hybridization from artefactual cross-hybridization. Upon completion of hybridization with the target sequence and washing of the array, the array is scanned to determine the position on the array to which the target sequence hybridizes. The hybridization data from the scanned array is then analyzed to identify which allele or alleles of the biallelic marker are present in the sample.
Hybridization and scanning may be carried out as described in PCT application No. WO
92!10092 and WO 95/11995 and US patent No. 5,424,186.
Thus, in some embodiments, the chips may comprise an array of nucleic acid sequences of fragments of about 15 nucleotides in length. In further embodiments, the chip may comprise an array including at least one of the sequences selected from the group consisting of SEQ ID
No. 1-130 and the sequences complementary thereto, or a fragment thereof at least about 8 consecutive nucleotides, preferably 10, 15, 20, more preferably 25, 30, 40, 47, or 50 consecutive nucleotides. In some embodiments, the chip may comprise an array of at least 2~ 3, 4, 5, 6, 7, 8 or more of these polynucleotides of the invention. Solid supports and polynucleotides of the present invention attached to solid supports are further described in I.
v Inte a~ ted systems Another technique, which may be used to analyze polymorphisms, includes multicomponent integrated systems, which miniaturize and compartmentalize processes such as PCR and capillary electrophoresis reactions in a single functional device. An example of such' technique is disclosed in US patent 5,589,136, which describes the integration of~PCR
amplification and capillary electrophoresis in chips. , .
Integrated systems can be envisaged mainly when microfluidic systems are used.
These systems comprise a pattern of microchannels designed onto a glass, silicon, quartz, or plastic wafer included on a microchip. The movements of the samples are controlled by electric, electroosmotic or hydrostatic forces applied across different areas of the microchip. For genotyping biallelic markers, the microfluidic system may integrate nucleic acid amplification, microsequencing, capillary electrophoresis and a detection method such as laser-induced fluorescence detection.
VI. Methods of Genetic Analysis Using the Biallelic Markers of the Present Invention Different methods are available for the genetic analysis of complex traits (see Lander and Schork, Science, 265, 2037-2048, 1994). The search for disease-susceptibility genes is conducted using two main methods: the linkage approach in which evidence is sought for cosegregation between a locus and a putative trait locus using family studies, and the association approach in which evidence is sought for a statistically significant association between an allele and a trait or a trait causing allele (I~houry J. et al., Furzdamentals of Genetic Epidezzziology, .
Oxford University Press, NY, 1993). In general, the biallelic markers of the present invention find use in any method known in the art to demonstrate a statistically significant correlation between a genotype and a phenotype. The biallelic markers may be used in parametric and non-parametric linkage analysis methods. Preferably, the biallelic markers of the present invention are used to identify genes associated with detectable traits using association studies, an approach which does not require the use of affected families and which permits the identification of genes associated with complex and sporadic traits.
The genetic analysis using the biallelic markers of the present invention may be conducted on any scale. The whole set of biallelic markers of the present invention or any subset of biallelic markers of the present invention may be used. In some embodiments a subset of biallelic maxkers corresponding to one or several candidate genes of the present invention may be used. In other embodiments a subset of biallelic markers corresponding to CNS
disorder candidate genes may be used. Alternatively, a subset of biallelic markers of the present invention localised on a specific chromosome segment may be used. Further, any set of genetic markers including a biallelic marker of the present invention may be used. A set of biallelic polymorphisms that, could be used as genetic markers in combination with the biallelic markers of the present invention, has been described in WO 98/20165. As mentioned above, it should be noted that the biallelic markers of the present invention may be included in any complete or~
partial genetic map of the human genome. These different uses are specifically contemplated in the present invention and claims.
A. Linka _~alysis Linkage analysis is based upon establishing a correlation between the transmission of genetic markers and that of a specific trait throughout generations within a family: Thus, the aim of linkage analysis is to detect marker loci that show cosegregation with a trait of interest in pedigrees.
i. Parametric methods . When data are available from successive generations there is the opportunity to study the degree of linkage between pairs of loci. 'Estimates of the recombination fraction enable loci to be , ordered and placed onto a genetic map. With loci that are genetic markers; a genetic map can be established, and then the strength of linkage between markers and traits can be calculated and used to indicate the relative positions of markers and genes affecting those traits (Weir, B.S.;
Genetic data Analysis Il.~ Methods for Discrete population genetic Data, Sinauer Assoc., I~ac., Sunderland, MA, USA, 1996). The classical method for linkage analysis is the logarithm of odds (lod) score method (see Morton N.E., Arn.J. Huna. Genet., 7:277-318, 1955; Ott J.~ Analysis of Hurnan Genetic Linkage, John Hopkins University Press, Baltirnore, 1991):
Calculation of lod scores requires specification of the mode of inheritance for the disease (parametric method).
Generally, the length of the candidate region identified using linkage analysis is between 2 and 20Mb. Once a candidate region is identified as described above, analysis of recombinant individuals using additional markers allows further delineation of the candidate region. Linkage analysis studies have generally relied on the use of a maximum of 5,000 microsatellite markers, thus limiting the maximum theoretical attainable resolution of linkage analysis to about 600 kb on average.

Linkage analysis has been successfully applied to map simple genetic traits that show clear Mendelian inheritance patterns and which have a high penetrance (i.e., the ratio between the number of trait positive carriers of allele a and the total number of a carriers in the population).
However, parametric linkage analysis suffers from a variety of drawbacks.
First, it is limited by its reliance on the choice of a genetic model suitable for each studied trait.
Furthermore, as already mentioned, the resolution attainable using linkage analysis is limited, and complementary studies are required to refine the analysis of the typical 2Mb to 20Mb regions initially identified through linkage analysis. In addition, parametric linkage analysis approaches have proven difficult when applied to complex genetic traits, such as those due to the combined action of multiple genes and/or environmental factors. It is very difficult to model these factors adequately in a lod score analysis. In such cases, too large an effort and cost are needed to recruit the adequate number of affected families required for applying linkage analysis to these situations, as recently discussed by Risch, N. and Merikangas, K. (Science, 273:1516-1517, 1996).
ii. Non-parametric methods The advantage of the so-called non-parametric methods for linkage analysis is that they do not require specification of the mode of inheritance for the disease, they tend to be more useful for the analysis of complex traits. In non-parametric methods, one tries to prove that the inheritance pattern of a chromosomal region is not consistent with random Mendelian segregation by showing that affected relatives inherit identical copies of the region more often than expected by chance. Affected relatives should show excess "allele sharing" even in the presence of incomplete penetrance and polygenic inheritance. In non-parametric:linkage analysis the degree of agreement at a marker locus in two individuals can be measured either by the number of alleles identical by state (IBS) or by the number of alleles identical by descent (IBD).
Affected sib pair analysis is a well-known special case and is the simplest form of these methods.
The biallelic markers of the present invention may be used in both parametric and non-parametric linkage analysis. Preferably biallelic markers may be used in non parametric methods which allow the mapping of genes involved in complex traits. The biallelic markers of the present invention may be used in both IBD- and IBS- methods to map genes affecting a complex trait. In such studies, taking advantage of the high density of biallelic markers, several adjacent biallelic marker loci may be pooled to achieve the efficiency attained by multi-allelic markers (Zhao et al., Arn. J. Hurra. Genet., 63:225-240, 1998).
However, both parametric and non-parametric linkage analysis methods analyse affected relatives, they tend to be of limited value in the genetic analysis of drug responses or in the analysis of side effects to treatments. This type of analysis is impractical in such cases due to the lack of availability of familial cases. In fact, the likelihood of having more than one individual in a family being exposed to the same drug at the same time is extremely low.
B. Population Association Studies The present invention comprises methods for identifying one or several genes among a set of candidate genes that are associated with a detectable trait using the biallelic markers of the present invention. In one embodiment the present invention comprises methods to detect an association between a biallelic marker allele or a biallelic marker haplotype and a trait. Further, the invention comprises methods to identify a trait causing allele in linkage disequilibrium with any biallelic marker allele of the present invention.
As described above, alternative approaches can be employed to perform association studies: genome-wide association studies, candidate region association studies and candidate gene association studies. In a preferred embodiment, the biallelic markers of the present invention are used to perform candidate gene association studies. The candidate gene analysis clearly provides a short-cut approach to the identification of genes and gene polymorphisms related to a particular trait when some information concerning the biology of the trait is available.
Further, the biallelic markers of the present invention may be incorporated in any map of genetic markers of the human genome in order to perform genome-wide association studies. Methods to generate a high-density map of biallelic markers has been described in US
Provisional Patent application serial number 60/02,614. The biallelic markers of the present invention may further be incorporated in any map of a specific candidate region of the genome (a specific chromosome or a specific chromosomal segment for example).
As mentioned above, association studies may be conducted within the general population and are not limited to studies performed on related individuals in affected families. Association studies are extremely valuable as they permit the analysis of sporadic or multifactor traits.
Moreover, association studies represent a powerful method for fme-scale mapping enabling much finer mapping of trait causing alleles than linkage studies. Studies based on pedigrees often only narrow the location of the trait causing allele. Association studies using the biallelic markers of the present invention can therefore be used to refine the location of a trait causing allele in a candidate region identified by Linkage Analysis methods. Moreover, once a chromosome segment of interest has been identified, the presence of a candidate gene such as a ;
candidate gene of.the present invention, in the region of interest can provide a shortcut to the identification of the trait causing allele. Biallelic markers of the present invention can be used to . .
demonstrate that a candidate gene is associated with a trait. Such uses are specifically contemplated in the present invention and claims.
i. Determining the frequency of a biallelic marker allele or of a biallelic marker haplotype in a population Association studies explore the relationships among frequencies for sets of alleles between loci.
l~Determinin~ the frequency of an allele in a population Allelic frequencies of the biallelic markers in a population can be determined using one of the methods described above under the heading "Methods for genotyping an individual for biallelic markers", or any genotyping procedure suitable for this intended purpose. Genotyping pooled samples or individual samples can determine the frequency of a biallelic marker allele in a population. One way to reduce the number of genotypings required is to use pooled samples.
A major obstacle in using pooled samples is in terms of accuracy and reproducibility for determining accurate DNA concentrations in setting up the pools. Genotyping individual samples provides higher sensitivity, reproducibility and accuracy and; is the preferred method used in the present invention. Preferably, each individual is genotyped separately and simple gene counting is applied to determine the frequency of an allele of a biallelic marker or of a genotype in a given population.
2) Determining the frequency of a haplotype in a population :The gametic phase of haplotypes is unknown when diploid individuals are heterozygous at more than one locus. Using genealogical information in families gametic phase can sometimes be inferred (Perlin et al., Ana. J. Hurn. Genet., 55:777-787, 1994). When no genealogical. .
information is available different strategies may be used. One possibility is that the multiple-site heterozygous diploids can be eliminated from the analysis, keeping only the homozygotes and the single-site heterozygote individuals, but this approach might lead to a possible bias in the sample composition and the underestimation of low-frequency haplotypes.
Another possibility is that single chromosomes can be studied independently, for example, by asymmetric PCR
amplification (see Newton et al., Nucleic Acids Res., 17:2503-2516, 1989; Wu et al., Proc. Natl.
Aced. Sci. USA, 86:2757, 1989) or by isolation of single chromosome by limit dilution followed by PCR amplification (see Ruano et al., Proc. Natl. Aced. Sci. USA, 87:6296-6300, 1990).
Further, a sample may be haplotyped for sufficiently close biallelic markers by double PCR
amplification of specific alleles (Sarkar, G, and Sommer S.S., Biotechniques, 1991). These' approaches are not entirely satisfying either because of their technical complexity, the additional cost they entail, their lack of generalisation at a large scale, or the possible biases they introduce.
To overcome these difficulties, an algorithm to infer the phase of PCR-amplified DNA genotypes introduced by Clark A.G. (Mol. Biol. Evol., 7:111-122, 1990) may be used.
Briefly, the principle is to start filling a preliminary list of haplotypes present in the sample by examining unambiguous individuals, that is, the complete homozygotes and the single-site heterozygotes.
Then other individuals in the same sample are screened for the possible occurrence of previously recognized haplotypes. For each positive identification, the complementary haplotype is added to the list of recognized haplotypes, until the phase information for all individuals is either resolved or identified as unresolved. This method assigns a single haplotype to each multiheterozygous individual, whereas several haplotypes are possible when there are more than one heterozygous site. Alternatively, one can use methods estimating haplotype frequencies in a population without assigning haplotypes to each individual. Preferably, a method based on an expectation-maximization (EM) algorithm (Dempster et al., J. R. Stat. Soc., 39B: 1-38, 1977) leading to maximum-likelihood estimates of haplotype frequencies under the assumption of Hardy-Weinberg proportions (random mating) is used (see Excoffier L. and Slatkin M., Mol. Biol. Evol., 12(5): 921-927, 1995). The EM algorithm is a generalized iterative maximum-likelihood approach to estimation that is useful when data are ambiguous and/or incomplete. The EM
algorithm is used to resolve heterozygotes into haplotypes. Haplotype estimations are further described below under the heading "Statistical methods". Any other method known in the art to determine or to estimate the frequency of a haplotype in a population may also be used.
. ii. Linkage disequilibrium analysis Linkage disequilibrium is the non-random association of alleles at two or more loci and represents a powerful tool for mapping genes involved in disease traits (see Ajioka R.S. et al., Am. J. Hum. Genet., 60:1439-1447, 1997). Biallelic markers, because they are densely spaced in the human genome and can be genotyped in more numerous numbers than other types of genetic markers (such as RFLP or VNTR markers), are particularly useful in genetic analysis based on linkage disequilibrium. The biallelic markers of the present invention may be used in any linkage disequilibrium analysis method known in the art.
Briefly, when a disease mutation is first introduced into a population (by a new mutation or,the immigration of a mutation carrier), it necessarily resides on a single chromosome and thus on a single "background" or "ancestral" haplotype of linked markers.
Consequently,. there is complete disequilibrium between these markers and the disease mutation: one finds the disease mutation only in the presence of a specific set of marker alleles. Through subsequent generations recombinations occur between the disease mutation and these marker polymorphisms, and the disequilibrium gradually dissipates. The pace of this dissipation is a function of the recombination frequency, so the markers closest to the disease gene will manifest higher levels of disequilibrium than those further away. When not broken up by recombination, "ancestral" .
haplotypes and linkage disequilibrium between marker alleles at different loci can be tracked not only through pedigrees but also through populations. Linkage disequilibrium is usually seen as an association between one specific allele at one locus and another specific allele at a second locus.
The pattern or curve of disequilibrium between disease and marker loci is expected to exhibit a maximum that occurs at the disease locus. Consequently, the amount of linkage disequilibrium between a disease allele and closely linked genetic markers may yield valuable information regarding the location of the disease gene. For fine-scale mapping of a disease locus, it is useful to have some knowledge of the patterns of linkage disequilibrium that exist between markers in the studied region. As mentioned above the mapping resolution achieved.
through the analysis of linkage disequilibrium is much higher than that of linkage studies. The high density of biallelic markers combined with linkage disequilibrium analysis provides powerful tools for fine-scale mapping. Different methods to calculate linkage disequilibrium are described below under the heading "Statistical Methods".
iii. Population-based case-control studies of trait-marker associations As mentioned above, the occurrence of pairs of specific alleles at different loci on the same chromosome is not random and the deviation from random is called linkage disequilibrium.
Association studies focus on population frequencies and rely on the phenomenon of linkage disequilibrium. If a specific allele in a given gene is directly involved in causing a particular trait, its frequency will be statistically increased in an affected (trait positive) population, when compared to the frequency in a trait negative population or in a random control population. As a consequence of the existence of linkage disequilibrium, the frequency of all other alleles present in the.haplotype carrying the trait-causing allele will also be increased in trait positive individuals compared to trait negative individuals or random controls. Therefore, association between the trait and any allele (specifically a biallelic marker allele) in linkage disequilibrium with the trait-causing allele will suffice to suggest the presence of a trait-related gene in that particular region.
Case-control populations can be genotyped for biallelic markers to identify associations that narrowly locate a trait causing allele. As any marker in linkage disequilibrium with one given marker associated with a trait will be associated with the trait. Linkage disequilibrium~ allows the relative frequencies .in case-control populations of a limited number of genetic polymorphisms (specifically biallelic markers) to be analyzed as an alternative to screening all possible functional polymorphisms in order to find trait-causing alleles. Association studies compare the frequency of marker alleles in unrelated case-control populations, and represent powerful tools for the dissection of complex traits.
1'~ Case-control populations Sinclusion criteria) Population-based association studies do not concern familial inheritance but compare the prevalence of a particular genetic marker, or a set of markers, in case-control populations. They are case-control studies based on comparison of unrelated case (affected or trait positive) individuals and unrelated control (unaffected or trait negative or random) individuals.
Preferably the control group is composed of unaffected or trait negative individuals. Further, the control group is ethnically matched to the case population. Moreover, the control group is preferably matched to the case=population for the main known confusion factor for the trait under study (for example age-matched for an age-dependent trait). Ideally, individuals in the two samples are paired in such a way that they are expected to differ only in their disease status. In the following "trait positive population", "case population" and "affected population" are used interchangeably.
An important step in the dissection of complex traits using association studies is the choice of case-control populations (see Lander and Schork, Science, 265, 2037-2048, 1994). A

major step in the choice of case-control populations is the clinical definition of a given trait or phenotype. Any genetic trait may be analyzed by the association method proposed here by carefully selecting the individuals to be included in the trait positive and trait negative phenotypic groups. Four criteria are often useful: clinical phenotype, age at onset, family history and severity. The selection procedure for continuous or quantitative traits (such as blood pressure for example) involves selecting individuals at opposite ends of the phenotype distribution of the trait under study, so as to include in these trait positive and trait negative populations individuals with non-overlapping phenotypes. Preferably, case-control populations consist of phenotypically homogeneous populations. Trait positive and trait negative populations consist of phenotypically uniform populations of individuals representing each between 1 and 98%, preferably between 1 and 80%, more preferably between 1 and 50%, and more preferably between 1 and 30%,.most preferably between 1 and 20% of the-total population under study, and selected among individuals exhibiting non-overlapping phenotypes. The clearer the difference between the two trait phenotypes, the greater the probability of detecting an association with biallelic markers. The selection of those drastically different but relatively unifoim phenotypes enables efficient comparisons in association studies and the possible detection of marked differences at the genetic level, provided that the sample sizes of the populations under study are significant enough.
In preferred embodiments, a first group of between 50 and 300 trait positive individuals, preferably about 100 individuals, are recruited according to their phenotypes.
A similar number of trait negative individuals are included in such studies.
In the present. invention, typical examples of inclusion criteria include a CNS disorder or the evaluation of the response to a drug acting on a CNS disorder or side effects to treatment with drugs acting on a CNS disorder.
Suitable examples of association studies using biallelic markers including the biallelic markers of the present invention, are studies involving the following populations:
a case population suffering from a CNS disorder and a healthy unaffected control population, or a case population treated with agents acting on a CNS disorder suffering from side-effects resulting from the treatment and a control population treated with the same agents showing no side-effects, or a case population treated with agents acting on a CNS disorder showing a beneficial response and a control population treated with same agents showing no beneficial response.
2) Association analysis The general strategy to perform association studies using biallelic markers derived from a region carrying a candidate gene is to scan two groups of individuals (case-control populations) in order to measure and statistically compare the allele frequencies of the biallelic markers of the present invention in both groups.
If a statistically significant association with a trait is identified for at least one or more of the analyzed biallelic markers, one can assume that: either the associated allele is directly responsible for causing the trait (the associated allele is the trait causing allele), or more likely the associated allele is in linkage disequilibrium with the trait causing allele. The specific characteristics of the associated allele With respect to the candidate gene function usually gives further insight into the relationship between the associated allele and the trait (causal or in linkage disequilibrium). If the evidence indicates that the associated allele within the candidate gene is most probably not the trait causing allele but is in linkage disequilibrium with the real trait causing allele, then the trait causing allele can be found by sequencing the vicinity of the associated marker.
Association studies are usually run in two successive steps. In a first phase, the frequencies of a reduced number of biallelic markers from one or several candidate genes are determined in the trait positive and trait negative populations. In a second phase of the analysis, the identity of the candidate gene and the position of the genetic loci responsible for the given trait is further refined using a higher density of markers from the relevant region. However, if the candidate gene under study is relatively small in length, as it is the case for many of the candidate genes analyzed included in the present invention, a single phase may be sufficient to establish significant associations.
3) Haplotype analysis As described above, when a chromosome carrying a disease allele first appears in a population as a result of either mutation or migration, the mutant allele necessarily resides on a chromosome having a set of linked markers: the ancestral haplotype. This haplotype can be tracked through populations and its statistical association with a given trait can be analyzed.
Complementing single point (allelic) association studies with multi-point association studies also called haplotype studies increases the statistical power of association studies. Thus, a haplotype association study allows one to define the frequency and the type of the ancestral carrier haplotype. A haplotype analysis is important in that it increases the statistical power of an analysis involving individual markers.
In a first stage of a haplotype frequency analysis, the frequency of the possible haplotypes based on various combinations of the identified biallelic markers of the invention is determined. The haplotype frequency is then compared for distinct populations of trait positive and control individuals. The number of trait positive individuals, which should be, subjected to this analysis to obtain statistically significant results usually ranges between 30 and 300, with a preferred number of individuals ranging between 50 and 150. The same considerations apply to the number of unaffected individuals (or random control) used in the study.
The results of this first analysis provide haplotype frequencies in case-control populations, for each evaluated haplotype frequency a p-value and an odd ratio are calculated. If a statistically significant association is found the relative risk for an individual carrying the given haplotype of being affected with the trait under study can be approximated.
4) Interaction analysis The biallelic markers of the present invention may also be used to identify patterns of biallelic markers associated with detectable traits resulting from polygenic interactions. The analysis of genetic interaction between alleles at unlinked loci requires individual genotyping using the techniques described herein. The analysis of allelic interaction among a selected set of biallelic markers with appropriate level of statistical significance can be considered as a haplotype analysis. Interaction analysis consists in stratifying the case-control populations with respect to a given haplotype for the first loci and performing a haplotype analysiswith the second loci with each subpopulation.
Statistical methods used in association studies are further described below in IV.C. ' iv. Testing for linkage in the presence of association The biallelic markers of the present invention may further be used in TDT
(transmission/disequilibrium test). TDT tests for both linkage and association and is not affected by population stratification. TDT requires data from affected individuals and their parents or data from unaffected sibs instead of from parents (see Spielmann S. et al., Azzz. J Huzn. Genet.;
52:506-516, 1993; Schaid D.J. et al., Genet. Epidemiol.,13:423-450, 1996;
Spielmann S. and Ewens W.J., Am. J. Hum. Genet., 62:450-458, 1998). Such combined tests generally reduce the false - positive errors produced by separate analyses.
C. Statistical Methods In general, any method known in the art to test whether a trait and a genotype show a statistically significant correlation may be used.
i. Methods in linkage analysis Statistical methods and computer programs useful for linkage analysis are well-known to those skilled in the art (see Terwilliger J.D. and Ott J., Handbook of Hunzan Genetic Linkage, John Hopkizzs University Press, London, 1994; Ott J., Analysis of Huzzzan Genetic Linkage, John -Hopkins University Press, Baltirnor°e, 1991).
ii. Methods to estimate haplotype frequencies in a population As described above, when genotypes are scored, it is often not possible to distinguish heterozygotes so that haplotype frequencies cannot be easily inferred. When the gametic phase is not known, haplotype frequencies can be estimated from the multilocus genotypic data. Any method known to person skilled in the art can be used to estimate haplotype frequencies (see Lange K., Matlaernatical azzd Statistical Methods for Genetic Analysis, Springer, New York, 1997;
Weir, B.S., Genetic data Analysis IL~ Methods for Discrete population gezzetic Data, Sizzauer Assoc., Inc., Sunderland, MA, USA, 1996). Preferably, maximum-likelihood haplotype frequencies are computed using an Expectation- Maximization (EM) algorithm (see Dempster et al., J. R. Stat. Soc., 39B:1-38, 1977; Excoffier L. and Slatkin M., Mol. Biol.
Evol., 12(5): 921-927, 1995). This procedure is an iterative process aiming at obtaining maximum-likelihood estimates of haplotype frequencies from multi-locus genotype data when the gametic phase is unknown. Haplotype estimations are usually performed by applying the EM
algorithm using for example the EM-HAPLO program (Hawley M.E. et al., Arza. J. Phys. Anthropol., 18:104, 1994) or the Arlequin program (Schneider et al., Arlequirz: a software for population genetics data analysis, University of Geneva, 1997). The EM algorithm is a generalized iterative maximum likelihood approach to estimation and is briefly described below.
In what follows, phenotypes will refer to multi-locus genotypes with unknown haplotypic phase. Genotypes will refer to mutli-locus genotypes with known haplotypic phase.
Suppose one has a sample of N unrelated individuals typed for K markers. The data observed are the unknown-phase K locus phenotypes that can be categorized with F different phenotypes. Further, suppose that we have H possible haplotypes (in the case of K biallelic markers, we have for the maximum number of possible haplotypes H-- 2 x ).
For phenotype j with c~ possible genotypes, we have:
P~ =,~P(genotype(i))=~P(lak,hz). Equation 1 a=m=i Here, P~ is the probability of the j~' phenotype, and P(h~,h~ is the probability of the ith genotype composed of haplotypes lzk and hz. Under random mating (i. e. Hardy-Weinberg Equilibrium), P(h~h~ is expressed as:
P(hh , hi ) = P(ltk )Z for hk = lzz , and P(hk , hl ) = 2P(lzk )P(lzz ) for h~ ~ hl . Equation 2 The E-M algorithm is composed of the following steps: First, the genotype frequencies are estimated from a set of initial values of haplotype frequencies. These haplotype frequencies are denoted Pl~o~, P2~o~, h3~o),..., hH~oJ. The initial values for the haplotype frequencies may be obtained from a random number generator or in some other way well known in the art: This step is referred to the Expectation step. The next step in the method, called the Maximization step, consists of using the estimates for the genotype frequencies to re-calculate the haplotype frequencies. The first iteration haplotype frequency estimates are denoted by P~~'~, P2~'~, P3~'~,. ~ ~, PH~'~. In general, the Expectation step at the st" iteration consists of calculating the probability of placing each phenotype into the different possible genotypes based on the haplotype frequencies of the previous iteration:

( )~S~ = h' P' (hk' hr )~S~
P hk , hr , Equation 3 N P~
where n~ is the number of individuals with the jth phenotype and P~ (hk , hr ) ~S~ is the probability of genotype hkhr in phenotype j. In the Maximization step, which is equivalent to the gene-counting method (Smith, Ann. Hurn. Genet., 21:254-276, 1957), the haplotype frequencies are re-estimated based on the genotype estimates:
°i P ~s+~> _ 1 ~ ~ S P (h h ) ~S~ .
r - 2 ra ,; x ~ r Equation 4 ,;=i r=i Here, St is an indicator variable which counts the number of occurrences that haplotype t is present in ith genotype; it takes on values 0, 1, and 2.
The E-M iterations cease when the following criterion has been reached. Using Maximum Likelihood Estimation (MLE) theory, one assumes that the phenotypes j are distributed multinomially. At each iteration s, one can compute the likelihood function L.
Convergence is achieved when the difference of the log-likehood between two consecutive iterations is less than some small number, preferably 10-x.
iii. Methods to calculate linkage disequilibrium between markers A number of methods can be used to calculate linkage disequilibrium between any two genetic positions, in practice linkage disequilibrium is measured by applying a statistical association test to haplotype data taken from a population.
Linkage disequilibrium between any pair of.biallelic markers comprising at least one of the biallelic markers of the present invention (M;, M~) having alleles (a;/b;) at marker M; and alleles (a~/b~) at marker M~ can be calculated for every allele combination (a;,a~ .
a;,b~. b;,a~ and b;,b~), according to the Piazza formula ~aiaj- ~e4 - ~ (84 + 83) (A4 +A2), where A4= - - = frequency of genotypes not having allele a; at M; and not having allele a~ at M~
83= - + = frequency of genotypes not having allele a; at M; and having allele a~ at M~
92= + - = frequency of genotypes having allele a; at M; and not having allele a~ at ~M~
Linkage disequilibrium (LD) between pairs of biallelic markers (M;, M~) can also be calculated for every allele combination (ai,aj; ai,bj ; b;,a~ andb;,b~), according to the maximum-likelihood estimate (MLE) for delta (the composite genotypic disequilibrium coefficient), as described by Weir (Weir B.S., Genetic Data Analysis, Sinauer-Ass. Eds, 1996). The MLE for the composite linkage disequilibrium is:
Da;a, (2y + n2 + n3 + n~/2)/N - 2(pr(a;).pr(a~)) Where n; = E phenotype (a;/a;, a~la~), n2 = ~ phenotype (a;la;, a~lb~), n3= E
phenotype (a;/b;, a~la~), n4= E phenotype (a;/b;, a~/b~) and N is the number of individuals in the sample.

This formula allows linkage disequilibrium between alleles to be estimated when only genotype, and not haplotype, data are available.
Another means of calculating the linkage disequilibrium between markers is as follows.
For a couple of biallelic markers, M; (allbl) and M~ (a~lb~), fitting the Hardy-Weinberg equilibrium, one can estimate the four possible haplotype frequencies in a given population according to the approach described above.
The estimation of gametic disequilibrium between ai and aj is simply:
Daia~ = pr(haplotype(ai , a~ )) - pr(ai ).pr(a j ).
Where pr(a~ is the probability of allele a; and pr(a~ is the probability of allele a~ and where pr(haplotype (a~, a~) is estimated as in Equation 3 above.
For a couple of biallelic marker only one measure of disequilibrium is necessary to describe the association between M; and M.
Then a normalised value of the above is calculated as follows:
D'aiaj - Daiaj / max (-pr(a;).pr(aj) , -pr(bi).pr(bj)) wlth Daiaj~~
D'aiaj - Daiaj / max (pr(bi).pr(aj) , pr(a;).pr(bj)) with Da;aj>0 The skilled person will readily appreciate that other LD calculation methods can be used without undue experimentation.
Linkage disequilibrium among a set of biallelic markers having an adequate heterozygosity rate can be determined by genotyping between 50 and 1000 unrelated individuals, preferably between 75 and 200, more preferably around 100.
iv. Testing for association Methods for determining the statistical significance of a correlation between a phenotype and a genotype, in this case an allele at a biallelic marker or a haplotype made up of such alleles, may be determined by any statistical test known .in the art and with any accepted threshold of statistical significance being required. The application of particular methods and thresholds of significance are well with in the skill of the ordinary practitioner of the art.
Testing for association is performed by determining the frequency of a biallelic marker allele in case and control populations and comparing these frequencies with a statistical test to determine if their is a statistically significant difference in frequency which would indicate a correlation between the trait and the biallelic marker allele under study.
Similarly, a haplotype analysis is performed by estimating the frequencies of all possible haplotypes for a given set of biallelic markers in case and control populations, and comparing these frequencies with a statistical test to determine if their is a statistically significant correlation between the haplotype and the phenotype (trait) under study. Any statistical tool useful to test for a statistically significant association between a genotype and a phenotype may be used.
Preferably the statistical test employed is a chi-square test with one degree of freedom. A p-value is then determined (the P-value is the probability that a statistic as large or larger than the observed one would occur by chance).
1) Statistical significance In preferred embodiments, significance for diagnostic purposes, either as a positive basis for further diagnostic tests or as a preliminary starting point for early preventive therapy, the p value related to a biallelic marker association is preferably about 1 x 10-2 or less, more preferably about 1 x 10-4 or less, for a single biallelic marker analysis and about 1 x 10-3 or less, still more preferably 1 x 10-6 or less and most preferably of about 1 x 10-8 or less, for a haplotype analysis involving several markers. These values are believed to be applicable to any association studies involving single or multiple marker combinations.
The skilled person can use the range of values set forth above as a starting point in order to carry out association studies with biallelic markers of the present invention. In doing so, significant associations between the biallelic markers of the present invention and CNS disorders can be revealed and used for diagnosis and drug screening purposes.
2 Phenotypic permutation In order to confirm the statistical significance of the first stage haplotype analysis described above, it might be suitable to perform further analyses in which genotyping data from case-control individuals are pooled and randomized with respect to the trait phenotype. Each individual genotyping data is randomly allocated to two groups, which contain the same number of individuals as the case-control populations used to compile the data obtained in the first stage.
A second stage haplotype analysis is preferably run on these artificial groups, preferably for the markers included in the haplotype of the first stage analysis showing the highest relative risk coefficient. This experiment is re-iterated preferably at least between 100 and 10000 times. The repeated iterations allow the determination of the percentage of obtained haplotypes with a significant p-value level.
3) Assessment of statistical association To address the problem of false positives similar analysis may be performed with the same case-control populations in random genomic regions. Results in random regions and the candidate region are compared as described in US Provisional Patent Application entitled "Methods, software and apparati for identifying genomic regions harbouring a gene associated with a detectable trait".
v. Evaluation of risk factors The association between a risk factor (in genetic epidemiology the risk factor is the presence or the absence of a certain allele or haplotype at marker loci) and a disease is measured by the odds ratio (OR) and by the relative risk (RR). If P(R~) is the probability of developing the disease for individuals with risk factor R and P(R-) is the probability for individuals without the risk factor, then the relative risk is simply the ratio of the two probabilities, that is:

RR= P(R+)/P(R_) In case-control studies, direct measures of the relative risk cannot be obtained because of the sampling design. However, the odds ratio allows a good approximation of the relative risk for low-incidence diseases and can be calculated:
F+ F-OR =
1-F+ (1-F-) OR = [F+1(1-F+)] / [F-/(1-F-)]
F+ is the frequency of the exposure to the risk factor in cases and F- is the frequency of the exposure to the risk factor in controls. F+ and F- are calculated using the allelic or haplotype frequencies of the study and further depend on the underlying genetic model (dominant, recessive, additive...).
One can further estimate the attributable risk (AR) which describes the proportion of individuals in a population exhibiting a trait due to a given risk factor.
This measure is important in quantitating the role of a specific factor in disease etiology and in terms of the public health impact of a risk factor. The public health relevance of this measure lies in estimating the proportion of cases of disease in the population that could be prevented if the exposure of interest ~ were absent. AR is determined as follows:
~ - Ps (~-1) / (Ps (~-1)+1) AR is the risk attributable to a biallelic marker allele or a biallelic marker haplotype. PE is the frequency of exposure to an allele or a haplotype within the population at large; and RR is the relative risk which is approximated with the odds ratio when the trait under study has a relatively low incidence in the general population.
D. Association of Biallelic Markers of the Invention with Ma'ot r Depression In the context of the present invention, an association between .biallelic marker alleles from candidate genes of the present invention and a CNS disorder was demonstrated. The considered CNS disorder was major depression.
~ Depression is a serious medical illness that affects 340 million people worldwide. In contrast to the normal emotional experiences of sadness, loss, or passing mood states, clinical depression is persistent and can interfere significantly with an individual's ability to function.
Many neurochemical findings are coming to light implicating a biological basis for the depression, at least for certain subtypes. Abnormalities of monoamine function as well as over stimulation of the HPA axis have been recognized in depression for many years.
Patterns of clustering and segregation in depressive families have suggested a genetic component to depression. However, the lack of a defined and specific depression phenotype and of suitable markers for genetic analysis is proving to be a major hurdle for reliably identifying genes associated with depression. As a result, psychiatrists today have to choose antidepressant medications by intuition and trial and error; a situation that can put suicidal patients in jeopardy for weeks or months until the right compound is selected. Clearly, there is a strong need to successfully identify genes involved in depression; thus allowing researchers to understand the etiology of depression and address its cause, rather than symptoms.
As mentioned above, both the nervous system and endocrine system play a major role in the etiology of depression. More specifically, the neurotransmitters dopamine, norepinephrine and serotonin as well as the hormones corticotrophin releasing factor, glucocorticoids, mineralocorticoids and various neuropeptides are thought to play a major role in the pathophysiology of depression.
In order to investigate and identify a genetic origin of depression, a candidate gene scan for depression was conducted. The rational of this approach was to: 1) select candidate genes potentially involved in the pathophysiology of interest, in this case major depression, 2) to identify biallelic markers in those genes and finally 3) to measure the frequency of biallelic marker alleles in order to determine if some alleles are more frequent in depressed populations than in non-affected populations. Results were further validated by haplotype studies.
Significant associations between biallelic marker alleles from the serotonin receptor 6 (SHTR6), serotonin 7 (SHTR7), serotonin transporter (SHTT), dopamine receptor 3 (DRD3), norepinephrine transporter (NET), guanine nucleotide binding protein, (33 (Gbeta3), glucocorticoid receptor (GRL), drug metabolizing enzyme cytochrome P450 3A4 (Chl.'3A4) and Wolfram Syndrome 1 (WFSI) genes and depression were demonstrated in the context of the present invention. Association studies are further described in Examples 3, 4 and 5. .
This information is extremely valuable. The lrnowledge of a potential genetic predisposition, even if this predisposition is not absolute, might contribute in a very significant manner to treatment efficacy of depressed patients and to the development of diagnostic tools.
E. Identification of Biallelic Markers in Linkage Disequilibrium with the Biallelic Markers of the Invention Once a first biallelic marker has been identified in a genomic region of interest, the practitioner of ordinary skill in the art, using the teachings of the present invention, can easily identify additional biallelic markers in linkage disequilibrium with this first marker. As mentioned before any marker in linkage disequilibrium with a first marker associated with a trait will be associated with the trait. Therefore, once an association has been demonstrated between a given biallelic marker and a trait, the discovery of additional biallelic markers associated with . .
this trait is of great interest in order to increase the density of biallelic markers in this particular region.. The causal gene or mutation will be found in the vicinity of the marker or set of markers showing the highest correlation with the trait.
Identification of additional markers in linkage disequilibrium with a given marker involves: (a) amplifying a genomic fragment comprising a first biallelic marker from a plurality of individuals; (b) identifying of second biallelic markers in the genomic region harboring said first biallelic marker; (c) conducting a linkage disequilibrium analysis between said first biallelic marker and second biallelic markers; and (d) selecting said second biallelic markers as being in linkage disequilibrium with said first marker. Subcombinations comprising steps (b) and (c) are also contemplated.
Methods to identify biallelic markers and to conduct linkage disequilibrium analysis are described herein and can be carried out by the skilled person without undue experimentation.
The present invention then also concerns biallelic markers which are in linkage disequilibrium , with the specific biallelic markers shown in Table 7 and which are expected to present similar characteristics in terms of their respective association with a given trait. .
F. Identification of Functional Mutations Once a positive association is confirmed with a biallelic marker of the present invention, the associated candidate gene can be scanned for mutations by comparing the sequences of a selected number of trait positive and trait negative individuals. In a preferred embodiment, functional regions such as exons and splice sites, promoters and other regulatory regions of the candidate gene are scanned for mutations. Preferably, trait positive individuals carry the haplotype shown to be associated with the trait and trait negative individuals do not carry the haplotype or allele associated with the trait. The mutation detection procedure is essentially similar to that used for biallelic site identification.
The method used to detect such mutations generally comprises the following steps: (a) amplification of a region of the candidate gene comprising a biallelic marker or a group of biallelic markers associated with the trait from DNA samples of trait positive patients and trait negative controls; (b) sequencing of the amplified region; (c) comparison of DNA sequences from trait-positive patients and trait-negative controls; and (d) determination of mutations specific to trait-positive patients. Subcombinations which comprise steps (b) and (c) are specifically contemplated.
It is preferred that candidate polymorphisms be then verified by screening a larger population of cases and controls by means of any genotyping procedure such as those described herein, preferably using a microsequencing technique in an individual test format. .
Polymorphisms are considered as candidate mutations when present in cases and controls at frequencies compatible with the expected association results.
VII. Biallelic Markers of the Invention in Methods of Genetic Diagnostics The biallelic markers of the present invention can also be used to develop diagnostics tests capable of identifying individuals who express a detectable trait as the result of a specific genotype or individuals whose genotype places them at risk of developing a detectable trait at a subsequent time. The trait analyzed using the present diagnostics may be any detectable trait, including a CNS disorder, a response to an agent acting on a CNS disorder or side effects to an agent acting on a CNS disorder.
The diagnostic techniques of the present invention may employ a variety of methodologies to determine whether a test subj ect has a biallelic marker pattern associated with an increased risk of developing a detectable trait or whether the individual suffers from a detectable trait as a result of a particular mutation, including methods which enable the analysis of individual chromosomes for haplotyping, such as family studies, single sperm DNA analysis or somatic hybrids.
The present invention provides diagnostic methods to determine whether an individual is at risk of developing a disease or suffers from a disease resulting from a mutation or a polymorphism in a candidate gene of the present invention. The present invention also provides methods to determine whether an individual is likely to respond positively to an agent acting on a CNS disorder or whether an individual is at risk of developing an adverse side effect to an agent acting on a CNS disorder.
These methods involve obtaining a nucleic acid sample from the individual and, determining, whether the nucleic acid sample contains at least one allele or at least one biallelic marker haplotype, indicative of a risk of developing the trait or indicative that the individual expresses the trait as a result of possessing a particular candidate gene polymorphism or mutation (trait-causing allele).
Preferably, in such diagnostic methods, a nucleic acid sample is obtained from the individual and this sample is genotyped using methods described herein. The diagnostics maybe based on a single biallelic marker or on a group of biallelic markers.
In each of these methods, a nucleic acid sample is obtained from the test subject and the biallelic marker pattern of one or more of the biallelic markers listed in Table 7 is.determined.
In one embodiment, PCR amplification is conducted on the nucleic acid sample to amplify regions in which polymorphisms associated with a detectable phenotype have been ' identified. The amplification products are sequenced to determine whether the individual possesses one or more polymorphisms associated with a detectable phenotype.
The primers used to generate amplification products may comprise the primers listed in Table 13. Alternatively, the nucleic acid sample is subjected to microsequencing reactions as described above to determine whether the individual possesses one or more polymorphisms associated with a detectable phenotype resulting from a mutation or a polymorphism in a candidate gene. The primers used in the microsequencing reactions may include the primers listed in Table 12. In another embodiment, the nucleic acid sample is contacted with one or more allele specific oligonucleotide probes which, specifically hybridize to one or more candidate gene alleles associated with a detectable phenotype. The probes used in the hybridization assay may include the probes listed in Table 14.

In a preferred embodiment the identity of the nucleotide present at, at least one, SHTR6 related biallelic marker selected from the group consisting of 99-27207-117, 99-28110-75, and 99-28134-215, is determined and the detectable trait is depression.
In a preferred embodiment the identity of the nucleotide present at, at least one, SHTR7 related biallelic marker selected from the group consisting of 99-32181-192 and 99-28106-185, is determined and the detectable trait is depression.
In a preferred embodiment the identity of the nucleotide present at, at least one, GRL
related biallelic marker selected from the group consisting of 99-30858-354, 18-20-174,' 99-32002-313, 18-31-178, 18-38-395, and 99-30853-364, is determined and the detectable trait is depression.
In a preferred embodiment the identity of the nucleotide present at, at least one, NET
related biallelic marker selected from the group consisting of 19-56-140, 19-28-136, 99-28788-300, 99-32061-304, 99-32121-242, 19-14-241, and 16-50-196, is determined and the detectable trait is depression.
In a preferred embodiment the identity of the nucleotide present at, at least one, DRD3 related biallelic marker selected from the group consisting of 8-19-372, is determined and the detectable trait is depression.
In a preferred embodiment the identity of the nucleotide present at, at least one, CYP3A4 related biallelic marker selected from the group consisting of 12-254-180, 10-214-279, and 10-217-91, is determined and the detectable trait is depression.
In a preferred embodiment the identity of the nucleotide present at, at least one, SHTT
related biallelic marker selected from the group consisting of 18-194-130, 18-186-391, 18-198-252, and 18-242-300, is determined and the detectable trait is depression.
In a preferred embodiment the identity of the nucleotide present at, at least one, Gbeta3 related biallelic marker selected from the group consisting of 20-205-302, 19-58-162, 19-9-45, 19-22-74, and 19-88-185, is determined and the detectable trait is depression.
In a preferred embodiment the identity of the nucleotide present at, at least one, WFS 1 related biallelic marker selected from the group consisting of 19-18-310, 19-19-174, 19-17-188, and 19-16-127, is determined and the detectable trait is depression.
~ Diagnostic kits comprising polynucleotides of the present invention are further described in section I.
These diagnostic methods are extremely valuable as they can, in certain circumstances, be used to initiate preventive treatments or to allow an individual carrying a significant haplotype to foresee warning signs such as minor symptoms. In diseases in which attacks may be extremely violent and sometimes fatal if not treated on time, such as asthma, the knowledge of a potential predisposition, even if this predisposition is not absolute, might contribute in a very significant manner to treatment efficacy. Similarly, a diagnosed predisposition to a potential side effect could immediately direct the physician toward a treatment for which such side effects have not been observed during clinical trials.
Diagnostics, which analyze and predict response to a drug or side effects to a drug, may be used to determine whether an individual should be treated with a particular drug. For example, if the diagnostic indicates a likelihood that an individual will respond positively to treatment with a particular drug, the drug may be administered to the individual. Conversely, if the diagnostic indicates that an individual is likely to respond negatively to treatment with a particular drug, an alternative course of treatment may be prescribed. A
negative response may be defined as either the absence of an efficacious response or the presence of toxic side effects.
Clinical drug trials represent another application for the markers of the present invention.
One or more markers indicative of response to an agent acting on a CNS
disorder or to side effects to an agent acting on a CNS disorder may be identified using the methods described above. Thereafter, potential participants in clinical trials of such an agent may be screened to identify those individuals most likely to respond favorably to the drug and exclude those likely to experience side effects. In that way, the effectiveness of drug treatment may be measured in individuals who respond positively to the drug, without lowering the measurement as anesult of the inclusion of individuals who are unlikely to respond positively in the study and without risking undesirable safety problems.
VIII. DNA Typing Methods and Systems The present invention also encompasses a DNA typing system having a much higher discriminatory power than currently available typing systems. The systems and associated methods are particularly applicable in the identification of individuals for forensic science and paternity determinations. These applications have become increasingly important; in forensic science, for example, the identification of individuals by polymorphism analysis has become widely accepted by courts as evidence.
While forensic geneticists have developed many techniques to compare homologous segments of DNA to determine if the segments are identical or if they differ in one or more nucleotides, each technique still has certain disadvantages. In particular, the techniques vary widely in terms of expense of analysis, time required to carry out an analysis and statistical power.
RFLP analysis methods The best known and most widespread method in forensic DNA typing is the restriction fragment length polymorphism (RFLP) analysis. In RFLP testing, a repetitive DNA sequence referred to as a variable number tandem repeat (VNTR) which varies between individuals is analyzed. The core repeat is typically a sequence of about 15 base pairs in length; and highly polymorphic VNTR loci can have an average of about 20 alleles. DNA restriction sites located on either site of the VNTR are exploited to create DNA fragments from about O.SKb to less than l OKb which are then separated by electrophoresis, indicating the number of repeats found in the individual at the particular loci. RFLP methods generally consist of (1) extraction and isolation of DNA, (2) restriction endonuclease digestion; (3) separation of DNA
fragments by electrophoresis; (4) capillary transfer; (5) hybridization with radiolabelled probes; (6) autoradiography; and (7) interpretation of results (Lee, H.G. et al., Am. J.
Forensic. Med. Pathol.
15(4): 269-282 (1994)). RFLP methods generally combine analysis at about 5 loci and have much higher discriminate potential than other available test due the highly polymorphic nature of the VNTRs. However, autoradiography is costly and time consuming and an analysis generally takes weeks or months for turnaround. Additionally, a large amount of sample DNA is required, which is often not available at a crime scene. Furthermore, the reliability of the system and its credibility as evidence is decreased because the analysis of tightly spaced bands on electrophoresis results in a high rate of error.
PCR methods PCR based methods offer an alternative to RFLP methods. In a first method called AmpFLP, DNA fragments containing VNTRs are amplified and then separated electrophoretically, without the restriction step of RFLP method. While this method allows small quantities of sample DNA to be used, decreases analysis time by avoiding autoradiography, and retains high discriminatory potential, it nevertheless requires electrophoretic separation which takes substantial time and introduces an significant error rate. In another AmpFLP method, short tandem repeats (STRs) of 2 to 8 base pairs are analyzed. STRs are more suitable to analysis of degraded DNA samples since they require smaller amplified fragments but have the disadvantage of requiring separation of the amplified fragments. While STRs are far less informative than longer repeats, similar discriminatory potential can be achieved if enough STRs are used in a single analysis.
Other methods include sequencing of mitochondria) DNA, which is especially suitable for situations where sample DNA is very degraded or in small quantities.
However, only a small region of 1Kb of the mitochondria) DNA referred to as the D-Loop locus has been found useful for typing because of its polymorphic nature, resulting in lower discriminatory potential than with RFLP or AmpFLP methods. Furthermore, DNA sequencing is expensive to carry out on a large number of samples.
Further available methods include dot-blot methods, which involve using allele specific oligonucleotide probes which hybridize sequence specifically to one allele of a polymorphic site.
Systems include the HLA DQ-alpha kit developed by Cetus Corp. which has a discriminatory value of about 1 in 20, and a dot-blot strip referred to as the Polymarker strip combining five genetic loci for a discriminatory value of about one in a few thousand.
(Weedn, V., Clinics in Lab. Med. 16(1): 187-196 (1996)).

In addition to difficulties in analysis and time consuming laboratory procedures, it remains desirable for all DNA typing systems to have a higher discriminatory power. Several applications exist in which even the most discriminating tests need improvement in order to remove the considerable remaining doubt resulting from such analyses. Table 3 below lists characteristics of currently available forensic testing systems (Weedn, (1996)) and compares them with the method of the invention.
Table 3 Test type Technology TurnaroundDiscf~irninatorySensitivitySample time potential (amount DNA) RFLP VNTR Weeks long . Highly intact or (autoradiography)months 106 to 109 DNA

AmpFLP VNTR Days 100pg Moderate (PCR based) 103 to 106 degradation Dot blot Sequence specificDays lng Moderate (ex.

HLADQAl) oligonucleotide 101 to 103 degradation probes MitochondrialD-loop sequenceDays lpg Severe DNA (PCR based) 102 degradation Present Biallelic MarkersHours 6 100pg Moderate marker to 238 > >

set (set of 13, Days degradation set of 100, set of (throughput 200, set of 270) dependent) Applications As described above, an important application of DNA typing tests is to determine whether a DNA sample (e.g. from a crime scene) originated from an individual suspected of leaving said DNA sample.
There are several applications for DNA typing which require a particularly powerful genotyping system. In a first application, a high powered typing system is advantageous when for example a suspect is identified by searching a DNA profile database such as that maintained by the U.S. Federal Bureau of Investigation. Since databases may contain large numbers of data entries that are expected to increase consistently, currently used forensic systems can be expected to identify several matching DNA profiles due to their relative lack of power.
While database searches generally reinforce the evidence by excluding other possible suspects, low powered typing systems resulting in the identification of several individuals may often tend to diminish the overall case against a defendant.

In another application, a target population is systematically tested to identify an individual having the same DNA profile as that of a DNA sample. In such a situation, a defendant is chosen at random based on DNA profile from a large population of innocent individuals. Since the population tested can often be large enough that at least one positive match is identified, and it is usually not possible to exhaustively test a population, the usefulness of the evidence will depend on the level of significance of the forensic test.
In order to render such an application useful as a sole or primary source of evidence, DNA typing systenns of extremely high discriminatory potential are required.
In yet another application, it is desirable to be able to discriminate between related individuals. Because related individuals will be expected to share a large portion of alleles at polymorphic sites, a very high powered DNA typing assay would be required to discriminate between them. This can have important effects if a sample is found to match the.defendant's DNA profile and no evidence that the perpetrator is a relative can be found.
Accordingly, there a need in this art for a rapid, simple, inexpensive and accurate technique having a very high resolution value to determine relationships between individuals and differences in degree of relationships. Also, there is a need in the art for a very accurate genetic relationship test procedure which uses very small amounts of an original DNA
sample, yet . .
produces very accurate results.
The present invention thus involves methods for the identification of individuals comprising determining the identity of the nucleotides at set of genetic markers in a biological sample, wherein said set of genetic markers comprises at least one CNS
disorder-related marker.
The present invention provides an extensive set of biallelic markers allowing a higher discriminatory potential than the genetic markers used in current forensic typing systems. Also, biallelic markers can be genotyped in individuals with much higher efficiency and accuracy than the genetic markers used in current forensic typing systems. In preferred embodiments, the invention comprises determining the identity of a nucleotide at a CNS disorder-related marker by single nucleotide primer extension, Which does not require electrophoresis as in techniques described above and results in lower rate of experimental error. As shown in Table 3, above, in comparison with PCR based VNTR based methods which allow discriminatory potential of thousands to millions, and RFLP based methods which allow discriminatory potential of merely millions to billions under optimal assumptions, the biallelic marker based method of the present invention provides a radical increase in discriminatory potential.
Any suitable set of genetic markers and biallelic markers of the invention may be used, and may be selected according to the discriminatory power desired. Biallelic markers, sets of biallelic markers, probes, primers, and methods for determining the identity of said biallelic markers are further described herein.
Discriminatory potential of biallelic marker tyoing Calculating discriminatory potential The discriminatory potential of the forensic test can be determined in terms of the profile frequency, also referred to as the random match probability, by applying the product rule. The product rule involves multiplying the allelic frequencies of all the individual alleles tested, and multiplying by an additional factor of 2 for each heterozygous locus.
In one example discussed below, the discriminatory potential of biallelic marker typing can be considered in the context of forensic science. In order to determine the discriminatory potential with respect to the numbers of biallelic markers to be used in a genetic typing system, the formulas and calculations below assume that (1) the population under study is sufficiently large (so that we can assume no consanguinity); (2) all markers chosen are not correlated, so that the product rule (Lander and Budlowle (1992)) can be applied; and (3) the ceiling rule can be applied or that the allelic frequencies of markers in the population under study are known with sufficient accuracy.
As noted in Weir, B.S., Genetic data Ataalysis IL Methods for Discrete population .
genetic Data, Sinauer Assoc., Inc., Sundef-land, MA, USA, 1996, the example assumes a crime has been committed and a sample of DNA from the perpetrator (P) is available for analysis. The genotype of this DNA sample can be determined for several genetic markers, and the profile A of the perpetrator can thereby be determined.
In this example, one suspect (S) is available for typing. The same set of genetic markers, such as the biallelic markers of the invention, are typed and the same profile A is obtained for (S) and (P). Two hypotheses are thus presented as follows:
(1) either S is P (event C) (2) either S is not P (event E).
The ratio L of both probabilities can then be calculated using the following equation:
L = pr(S = A, P = A l C) pr(S=A,P=AlC) L can then further be calculated by the following equation:
L = 1 ( 1 ) Equation 1 pr(P=AlS=A,C) These probabilities as well as L can be calculated in several settings, notably for different kinship coefficients between P and S for a genetic marker (see Weir, (1996)).
Assuming that all genetic markers chosen are independent of each other, the global ratio L for a set of genetic markers will be the product over each genetic marker of all L.
It is further possible to estimate the mean number of biallelic markers or VNTRs required to have a ratio L equal to 10$ or 106 by calculating the expectancy of the random variable L using the following equation:

N
E(L) = Tj E(Li ) where N is the number of loci i=1 G; _ E(Li ) _ ~ pr(P = Aij l S = Aij , C).Lij, where Aij is the genotype j at the ith marker, j=1 Lij the ratio associated with such genotype, Gi being the number of genotypes at locus i.
From equation 1, it can easily be derived that the expectancy of L; is G;, the number of possible genotypes of this marker.
The general expectancy for a set of genetic markers can then be expressed by the following equation:
N
E(L) = jlGi (2) Equation 2 i=1 Biallelic marker-based DNA typing systems Using the equations described above, it is possible to select biallelic marker-based DNA
typing systems having a desired discriminatory potential.
Using biallelic markers, E(L) can thus be expressed as 3N. When using VNTR-based DNA typing systems, assuming the VNTRs have 10 alleles, E(L) can be expressed as 55~:
Based on these results, the number of biallelic markers or VNTRs needed to obtain, in mean, a ratio of at least 106 or 108 can calculated, and are set forth below in Table 4.
Table 4 Marker sets L=106 L=108 Biallelic 13 17 5-allele markers (e.g.5 7 VNTR) 10-allele markers 4 5 (e.g. VNTR) Thus, in a first embodiment, DNA typing systems and methods of the invention may comprise genotyping a set of at least 13 or at least 17 biallelic markers to obtain a ratio of at least 106 or 108, assuming a flat distribution of L across the biallelic markers. In preferred embodiments, a greater number of biallelic markers is genotyped to obtain a higher L value.
Preferably at least l, 2, 3, 4, 5, 10, 13, 15, 17, 20, 25, 30, 40, 50, 70, 85, 100, 150, 200, 250 or all of the CNS disorder-related markers are genotyped. Said DNA typing systems of the invention would result in L values as listed in Table 5 below as an indication of the discriminate potential of the systems of the invention.
Table 5 Number of biallelic L
markers 50 7.2 * 1023 100 5*1047 271 3~271 In situations where the distribution of L is not flat, such as in the worst case when the perpetrator is homozygous for the major allele at each genetic locus and L
thus takes the lowest value, a larger number of biallelic markers is required for the same discriminatory potential:
Therefore, in preferred embodiments, DNA typing systems and methods of the invention using a larger number of biallelic markers allow for uneven distributions of L across the biallelic markers. For example, assuming unrelated individuals, a set of independent markers having an allelic frequency of 0.1/0.9, and the genetic profile of a homozygote at each genetic loci for the major allele, 66 biallelic markers are required to obtain a ratio of 106, and 88 biallelic markers are required to obtain a ratio of 108. Thus, in preferred embodiments based on the use of markers having a maj or allele of sufficiently high frequency, this is a first estimation of the upper bound of markers required in a DNA typing system. .
In further embodiments, it is also desirable to have the ability to discriminate between relatives. Although unrelated individuals have a low probability of sharing genetic profiles, the probability is greatly increased for relatives. For example, the DNA profile of a suspect matches the DNA profile of a sample at a crime scene, and the probability of obtaining the same DNA
profile if left by an untyped relative is required. Table 6 below (Weir (1996)) lists probabilities for several different types of relationships, assuming alleles Ai and Aj, and population frequencies pi and pj, and lists likelihood ratios assuming genetic loci having allele frequencies of 0.1.
Table 6 Genotype Relationship Pr(p=ASS=A) L

Ai Aj Full brothers (1+pi+pj+2pi 3.3 pj)/4 Father and son (pi+pj)/2 10.0 Half brothers (pi+pj+4pi pj)/416.7 Uncle and nephew(1+pi+pj+2pi 16.7 pj)/4 First cousins (1+pi+pj+l2pi 25.0 pj)/8 Unrelated 2pi pj 50.0 Aj Aj I Full brothers I (1+pi)2/q, 3.3 Father and son pi 10.0 Half brothers pi (1+pi)/2 18.2 Uncle and nephewpi (1+pi)/2 18.2 First cousins pi (1+3pi)!4 30.8 Unrelated pit 100.0 In one example, where the suspect is the full brother of the perpetrator, the number of required biallelic markers will be 187 assuming the profile is that of a homozygote for the major allele at each biallelic marker.
In yet further embodiments, the DNA typing systems and methods of the present invention may further take into account effects of subpopulations on the discriminatory potential:
In embodiments described above for example, DNA typing systems consider close familial relationships, but do not take into account membership in the same population.
While population membership is'expected 'to have little effect, the invention may further comprise genotyping a larger set of biallelic markers to achieve higher discriminatory potential.
Alternatively, a larger set of biallelic markers may be optimized for typing selected populations;
alternatively, the ceiling principle may be used to study allele frequencies from individuals in various populations of interest, taking for any particular genotype the maximum allele frequency found among the populations.
The invention thus encompasses methods for genotyping comprising determining the identity of a nucleotide at least 13, 15, 17, 20, 25, 30, 40, 50, 66, 70, 85, 88, 100, 187, 200, or 250, 500, 700, 1000 or 2000 biallelic markers in a biological sample, wherein at least 1, 2, 3, 4, : ' 5, 10, 13, 17, 20, 25, 30, 40, 50, 70, 85, 100, 150, 200, 250 or all of said biallelic markers are CNS disorder-related markers selected from the group consisting of SEQ ID NOS:
1-271. .
Any markers known in the art may be used with the CNS disorder-related markers of the present invention in the DNA typing methods and systems described herein, for example in anyone of the following web sites offering collections of SNPs and information about those SNPs:
Tlae Genetic Annotation Initiative ~(http://c~ap.n~i.nih.~ovl, GAI/l. An NIH
run site which contains information on candidate SNPs thought to be related to cancer and tumorigenesis generally.
dbSNP Polymorplaisrn Repository (http://www.ncbi.nlmnih.~ov/~). A more comprehensive NIH-run database containing information on SNPs with broad applicability in biomedical research.
HUGO Mutatiofa Database haitiative (http://ariel.ucsa",;",Plb.edu.au:80/ -cottonlmdi.html. A database meant to provide systematic access to information about human mutations including SNPs. This site is maintained by the Human Genome Organisation (HUGO).
Human SNP Database (htt~:!/www genome.wi.mit.edu/SNP/human/index.htmll.
Managed by the Whitehead Institute for Biomedical Research Genome Institute, this site contains information about SNPs resulting from the many Whitehead research projects on mapping and sequencing.
SNPs in the Huznan-Gezzorne SNP database .(http://www.ibc.wustl.edulSNPI. This website provides access to SNPs that have been organized by chromosomes and cytogenetic location. The site is run by Washington University.
HGBase (http://hgb~gr.ki.se/). HGBASE is an attempt to summarize all known sequence variations in the human genome, to facilitate research into how genotypes affect common diseases, drug responses, and other complex phenotypes, and is run by the Karolinska Institute of Sweden.
The SNP Consortium Database (http:l/snp.cshl.org/db/snp/mapl. A collection of SNPs and related information resulting from the collaborative effort of a number of large pharmaceutical and information processing companies.
GeneSNPs ~http://www.genome.utah.edu/genes~t~s/). Run by the University of Utah, this site contains information about SNPs resulting from the U. S. National Institute of Environmental Health's initiative to understand the relationship between genetic variation and response to environmental stimuli and xenobiotics.
In addition, biallelic markers provided in the following patents and patent applications may also be used with the map-related biallelic markers of the invention in the DNA typing methods and systems described above: US Serial No. 60/206,615, filed 24 March 2000; US
Serial No. 60!216,745, fled 30 June 2000; WIPO Serial No. PCT/IB00/00184, filed 11 February.
2000; WIPO Serial No. PCT/IB98/01193, fled 17 July 1998; PCT Publication No.
WO
99/54500, filed 21 April 1999; and WIPO Serial No. PCT/IB00/00403, filed 24 March 2000.
Biallelic markers, sets of biallelic markers, probes, primers, and methods for determining the identity of a nucleotide at said biallelic markers are also encompassed and are further described herein, and may encompass any further limitation described in this disclosures alone or in any combination.
Forensic matching by microsequencing is further described in Example 6 below Throughout this application, various publications, patents, and published patent applications are cited. The disclosures of the publications, patents, and published patent specifications referenced in this application are hereby incorporated by reference into the present disclosure to more fully describe the state of the art to which this invention pertains.

EXAMPLES
Several of the methods of the present invention are described in the following examples, which are offered by way of illustration and not by way of limitation. Many other modifications and variations of the invention as herein set forth can be made without departing from the spirit and scope thereof and therefore only such limitations should be imposed as are indicated by the appended claims.
Example 1: De Novo Identification of Biallelic Markers The biallelic markers set forth in this application were isolated from human genomic sequences. To identify biallelic markers, genomic fragments were amplified, sequenced and compared in a plurality of individuals.
DNA samples Donors were unrelated and healthy. They represented a sufficient diversity for being representative of a French heterogeneous population. The DNA from 100 individuals was extracted and tested for the de novo identification of biallelic markers.
DNA samples were prepared peripheral venous blood as follows. 30 ml of peripheral venous blood were taken from each donor in the presence of EDTA. Cells (pellet) were collected after centrifugation for 10 minutes at 2000 rpm. Red cells were lysed in a lysis solution (50 ml final volume: 10 mM Tris pH7.6; 5 mM MgCl2; 10 mM NaCl). The solution was centrifuged (10 minutes, 2000 rpm) as many times as necessary to eliminate the residual red cells present in the supernatant, after resuspension of the pellet in the lysis solution. The pellet of white cells was lysed overnight at 42°C with 3.7 ml of lysis solution composed of: (a) 3 ml TE 10-2 (Tris-HCl 10 mM, EDTA 2 mM) / NaCI 0.4 M; (b) 200 ~l SDS 10%; and (c) 500 w1 proteinase K
(2 mg proteinase K in TE 10-2 / NaCI 0.4 M).
For the extraction of proteins, 1 ml saturated NaCI (6M) (1/3.5 v/v) was added. After vigorous agitation, the solution was centrifuged for 20 minutes at 10000 rpm.
For the precipitation of DNA, 2 to 3 volumes of 100% ethanol were added to the previous supernatant, and the solution was centrifuged for 30 minutes at 2000 rpm. The DNA solution was rinsed three times with 70% ethanol to eliminate salts, and centrifuged for 20 minutes at 2000 rpm. The pellet was dried at 37°C, and resuspended in 1 ml TE 10-1 or 1 ml water. The DNA
concentration was evaluated by measuring the optical density (OD) at 260 nm (1 unit OD = 50 p,g/ml DNA). To determine the presence of proteins in the DNA solution, the OD

ratio was determined. Only DNA preparations having a OD 260 / OD 280 ratio between 1.8 and 2 were used in the subsequent examples described below. DNA pools were constituted by mixing equivalent quantities of DNA from each individual.

Amplification of ~enomic DNA by PCR
Amplification of specific genomic sequences was carried out on pooled DNA
samples obtained as described above.
Amplification Timers The primers used for the amplification of human genomic DNA fragments were defined with the OSP software (Hillier & Green, 1991). Preferably, primers included, upstream of the specific bases targeted for amplification, a common oligonucleotide tail useful for sequencing.
Primers PU contain the following additional PU 5' sequence :
TGTAAAACGACGGCCAGT;
primers RP contain the following RP 5' sequence : CAGGAAACAGCTATGACC..Primers are listed in Table 12.
Amplification PCR assays were performed using the following protocol:
Final volume 25 ~1 DNA 2 ng/~l .
MgClz 2 mM
dNTP (each) 200 ~.M
primer (each) 2.9 ng/~.1 Ampli Taq Gold DNA polymerase 0.05 unit/pl PCR buffer (10x = 0.1 M TrisHCl pH8.3 O.SM KCl) lx DNA amplification was performed on a Genius II thermocycler. After heating at 94°C
for 10 min, 40 cycles were performed. Cycling times and temperatures were: 30 sec at 94°C, 55°C for 1 min and 30 sec at 72°C. Holding for 7 min at 72°C allowed final elongation. The quantities of the amplification products obtained were determined on 96-well microtiter plates, using a fluorometer and Picogreen as intercalant agent (Molecular Probes).
Sequencing of amplified genomic DNA and identification of biallelic~olymorphisms Sequencing of the amplified DNA was carried out on ABI 377 sequencers. The sequences of the amplification products were determined using automated dideoxy terminator sequencing reactions with a dye terminator cycle sequencing protocol. The products of the sequencing reactions were run on sequencing gels and the sequences were determined using gel image analysis (ABI Prism DNA Sequencing Analysis software 2.1.2 version).
The sequence data were further evaluated to detect the presence of biallelic markers within the amplified fragments. The polymorphism search was based on the presence of superimposed peaks in the electrophoresis pattern resulting from different bases occurring at the same position. However, the presence of two peaks can be an artifact due to background noise.

To exclude such an artifact, the two DNA strands were sequenced and a comparison between the two strands was carried out. In order to be registered as a polymorphic sequence, the polymorphism had to be detected on both strands. Further, some biallelic single nucleotide polymorphisms were conftrmed by microsequencing as described below.
Biallelic markers were identified in the analyzed fragments and are shown in Table 7.
Example 2: Genotype of Biallelic Markers The biallelic markers identified as described above were further confirmed and their respective frequencies were determined through microsequencing.
Microsequencing was carried out on individual DNA samples obtained as described herein.
Microsequencin~ primers Amplification of genomic DNA fragments from individual DNA samples was performed as described in Example 1 using the same set of PCR primers (Table 12).
Microsequencing was carried out on the amplified fragments using specifte primers. See Table 13.
The preferred .
primers used in microsequencing had about 19 nucleotides in length and hybridized just upstream of the considered polymorphic base.
The microsequencing reactions were performed as follows: 5 p1 of PCR products were added to 5 p,1 purification mix (2U SAP (Shrimp alkaline phosphate) (Amersham E70092X)); 2U
Exonuclease I (Amersham E70073Z); and 1 p,1 SAP buffer (200 mM Tris-HCl pHB, 100 mM
MgCl2) in a microtiter plate. The reaction mixture was incubated 30 minutes at 37°C~ and denatured 10 minutes at 94°C afterwards. To each well was then added 20 p,1 of microsequencing reaction mixture containing: 10 pmol microsequencing oligonucleotide (l9mers, GENSET, crude synthesis, 5 OD), 1 U Thermosequenase (Amersham E79000G), 1.25 p1 Thermosequenase buffer (260 mM Tris HCl pH 9.5, 65 mM MgClz), and the two appropriate fluorescent ddNTPs complementary to the nucleotides at the polymorphic site corresponding to both polymorphic bases (11.25 nM TAMRA-ddTTP ; 16.25 nM ROX-ddCTP ; 1.675 nM
REG-ddATP ; 1.25 nM RHO-ddGTP ; Perkin Elmer, Dye Terminator Set 401095). After 4 minutes at 94°C, 20 PCR cycles of 15 sec at 55°C, 5 sec at 72°C, and 10 sec at 94°C were carried out in a Tetrad PTC-225 thermocycler (MJ Research). The microtiter plate was centrifuged 10 sec at 1500 rpm. The unincorporated dye terminators were removed by precipitation with 19 ~.l MgCl2 2mM and 55 p1 100 % ethanol. After 15 minute incubation at room temperature, the microtiter .
plate was centrifuged at 3300 rpm 15 minutes at 4°C. After discarding the supernatants, the microplate was evaporated to dryness under reduced pressure (Speed Vac).
Samples were resuspended in 2.5 p1 formamide EDTA loading buffer and heated for 2 min at 95°C. 0.8 p1 microsequencing reaction were loaded on a 10 % (19:1) polyacrylamide sequencing gel. The data were collected by an ABI PRISM 377 DNA sequencer and processed using the GENESCAN software (Perkin Elmer).
Frequency of biallelic markers Frequencies are reported for the less common allele only and are shown in Table 7.
Example 3: Association Study Between Ma'oj r Depression and the Biallelic Markers of Candidate Genes Collection of DNA samples from affected and non-affected individuals The disease trait followed in this association study was major depression, a complex disorder believed to involve several neurotransmitter pathways including those utilizing norepinephrine and serotonin. The depressed patient population consists of 140 individuals that participated in a clinical study for the evaluation of the anti-depressant compound Reboxetine (Montgomery S.A. and Schatzberg A.F.; Journal Clin. Psychiatry 59(suppl 14): 3-7, 1998).
Approximately 90% of these individuals were from a Caucasian ethnic background. The control population consisted of 94 individuals from a Caucasian population that had been found not to have any personal or family evidence of psychiatric disease.
Geno ink of affected and control individuals The general strategy was to individually determine allele frequencies of biallelic markers in all individuals from each population described above. Allele frequencies of the biallelic markers were determined by performing microsequencing reactions on amplified DNA
fragments obtained from genomic PCR performed on DNA samples from each individual:
Genomic PCR and microsequencing were performed as detailed above in Examples 1 and 2 Frequency of the biallelic markers alleles and genotypes of candidate gene and association with maior depression Frequencies of biallelic marker alleles were compared in the case-control populations described above. The data in Table 15 show the p-value obtained for each marker typed for.each candidate gene for individual alleles and genotypes. Nine markers from 7 of 19 candidate genes were significant at the 5% level for allele frequency differences while seven markers from 6 of 19 candidate genes were significant at the 5% level for genotype frequency differences. In 4 cases, the same marker was significant at the 5% level for both allele and genotype frequency differences. This occurred for markers from the genes 5HTR6, 5HTR7, NET, and Gbeta3.
These genes all participate in the mechanism of either serotonin or norepinephrine neurotransmission.
Haplotype frequency anal sis The results of the haplotype analysis using combinations of 2, 3, and 4 biallelic markers from each gene are shown in Tables 17 and 18. Haplotype analyses for the candidate genes were performed by estimating the frequencies of all 2, 3, and 4 marker haplotypes in the depressed and control populations. Haplotype estimations were performed by applying the Expectation-s Maximization (EM) algorithm (Excoffier and Slatkin, Mol. Biol. Evol., 12:921-927, 1995).
Estimated haplotype frequencies in the depressed and control populations were compared by means of permutation tests based on individual haplotypes (Permutation test) as well as the distribution of frequencies from all possible haplotypes derived from a particular combination of given markers (Omnibus LR test).
The results of the Omnibus LR test are shown in Table 16. Listed are the top 10 marker combinations for each category of 4, 3, and 2 marker combinations and boxed in a double line border are the top 5% of each category (by p-value based on phenotypic reiteration of at least 1000 simulations). It is remarkable that several of the same genes identified by single marker association tests also appear in the top 5% of the Omnibus LR test. In particular, markers from the genes NET and Gbeta3 appear as top 5% in each category of combinations for the Omnibus LR test.
The, results of the Permutation test for individual haplotypes are shown in Table 17.
Listed are the top 20 haplotypes for each category of 4, 3, and 2 marker haplotypes and boxed in a double line border are the top 1% of each category (by p-value based on phenotypic reiteration of at least 1000 simulations). Again it is remarkable that several of the same genes identified by single marker association tests and Omnibus LR test also contribute haplotypes that appear in the top 1% of the Permutation test for individual haplotypes. Of all genes, only NET contributes to the top percentiles of each category of testing (individual markers for allele and genotype frequencies, Omnibus LR 4,3 and 2 marker combinations, and Permutation test for individual 4, .
3, and 2 marker haplotypes). However several other genes contribute to several testing categories including previously mentioned Gbeta3 and 5HTR7 as well as WFS1, GRL, SHTT
and DRD3.
Two preferred haplotypes can be constructed from markers derived from the NET
gene.
One consists of markers 99-28788/300, 99-32061/304, and 99-32121/242 each manifesting the G
allele. The GGG haplotype is present in only 1 % of depressed cases vs. 7% of controls. While this haplotype is low in overall frequency, the p-value by permutation test is 2 X 10-a and the p-value for this group of markers is 2 X 10-3 by Omnibus LR test suggesting that the result is highly significant. A second haplotype consists of markers 16-3/199, 16-28/93, and 16-50/196 manifesting alleles TCT respectively. The haplotype TCT is present in only 30%
of cases vs.
43% of controls. The p-value by permutation test is 9 X 10~ and the p-value for this group of markers is 8.9 X 10~ by Omnibus LR test, also indicating a high level of significance.

Another example of a preferred haplotype comes from markers 16-16/285, 16-17/121, and 16-106/364 which are derived from the gene Gbeta3. The haplotype TTC is present in 21 of cases vs. 35% of controls. The p-value by permutation test is 1 X 10-3 and the p-value for this group of markers is 1 X 10~ by Omnibus LR test, indicating a high level of significance.
Example 4: Association Study Between Major Depression and the Biallelic Markers of Candidate Genes The association analysis of Example 3 was repeated using a different population set as described below. In general, these estimates agreed with the frequencies observed in the first screening within a few percent. Statistical assessments of haplotype frequency differences between depressed cases and controls were made by Omnibus LR tests and individual haplotype tests.
For Omnibus analyses, WFS 1 marker combinations showed the most significant (p<0.01) differences between the depressed cases and controls for 2, 3, and 4 locus haplotypes.
Strongest among these associations were combinations of markers spanning the core exonic region of the WFS1 gene including 19-17/188, 19-19/174, and 24-243/346.
Several NET marker combinations showed significant associations (p<0.05) including those from the 5' flanking region and those from the exonic region. When compared to the distribution of Omnibus p-values observed in the 1St screening, 11 WFS1 marker combinations would have been among the top 5% of observed Omnibus p-values whereas 2 NET marker combinations would have been among the top 5%.
For individual haplotypes; haplotype GT from WFS1 markers 19-17/188 and 24-showed an 11% difference (37% cases vs. 26% controls, p<0.001). A similar difference was observed for haplotype GC from WFS l markers 19-17/188 and 19-19/174 and GCT
from all three markers (p<0.005). Several NET haplotypes showed >10% frequency differences between cases and controls (p<0.01). When compared to the distribution of individual haplotype p-values observed in the first screening, 6 WFS1 marker combinations would have been among the top 1% of observed individual haplotype p-values. ' Frequency of the biallelic markers alleles and enotypes of candidate ~ene.and association with major depression Frequencies of biallelic marker alleles were compared in the case-control populations described above. The data in Table 18 show the p-value obtained for each marker typed for each candidate gene for individual alleles and genotypes. Nine markers from 7 of 19 candidate genes were significant at the 5% level for allele frequency differences while seven markers from 6 of 19 candidate genes were significant at the 5% level for genotype frequency differences. In 4 cases, the same marker was significant at the 5% level for both allele and genotype frequency differences. This occurred for markers from the genes SHTR6, SHTR7, and WFS1.

Haplot'~pe frequency analysis The results of the haplotype analysis using combinations of 2, 3, and 4 biallelic markers from each gene are shown in Tables 19 and 20. Haplotype analyses for the candidate genes were performed by estimating the frequencies of all 2, 3, and 4 marker haplotypes in the depressed and control populations. Haplotype estimations were performed by applying the Expectation-Maximization (EM) algorithm (Excoffier and Slatkin, Mol. Biol. Evol., 12:921-927, 1995).
Estimated haplotype frequencies in the depressed and control populations were compared by means of permutation tests based on individual haplotypes (Permutation test) as well as the distribution of frequencies from all possible haplotypes derived from a particular combination of given markers (Omnibus LR test).
The results of the Omnibus LR test are shown in Table 19. Listed are the top 10 marker combinations for each category of 4, 3, and 2 marker combinations and boxed in a double line border are the top 5% of each category (by p-value based on phenotypic reiteration of at least 1000 simulations). It is remarkable that several of the same genes identified by single marker association tests also appear in the top 5% of the Omnibus LR test. In particular, markers from the gene WFS 1 appears as top 5% in each category of combinations for the Omnibus LR test.
The results of the Permutation test for individual haplotypes are shown in Table 20.
Listed are the top 20 haplotypes for each category of 4, 3, and 2 marker haplotypes and boxed in a double line border are the top 1% of each category (by p-value based on phenotypic reiteration of at least 1000 simulations). Again it is remarkable that several of the same genes identified by single marker association tests and Omnibus LR test also contribute haplotypes that appear in the top 1 % of the Permutation test for individual haplotypes. Of all genes, WFS 1 contributes to the top percentiles of nearly all categories of testing (individual markers for allele and genotype frequencies, Omnibus LR 4,3 and 2 marker combinations, and Permutation test for individual 3 and 2 marker haplotypes). However several other genes contribute to several testing categories including previously mentioned SHTR7 as well as NET, GRL, SHTT and DRD3.
A preferred haplotype can be constructed from markers derived from the WFS 1 gene.
This consists of markers 19-17/188, 19-19/174, and 24-243/176 manifesting alleles GCT
.respectively. The GCT haplotype is present in 34% of depressed cases vs. 24%
of controls.
While this haplotype is low in overall frequency, the p-value by permutation test is 3 X 10-3 and the p-value for this group of markers is 1 X 10-3 by Omnibus LR test suggesting that the result is highly significant.
Example 5: Response to Reboxetine in Depressed Patients Single point analyses were also performed on data from the candidate genes to determine Reboxetine response among depressed patients as compared to controls. Two markers from NET

(99-32061/304 and 99-32121/242) showed allelic and genotypic association (p<0.05). A single marker from Gbeta3 (18-355/67) showed allelic association with drug response (p=0.05).
Multipoint analyses on the data revealed Omnibus LR-based associations to be minimal for these genes with only two marker combinations from NET achieving a level of significance of p<0.05. At the individual haplotype level, a number of NET haplotypes achieved this level of significance with 10-15% responder/non-responder differences in haplotype frequencies. Also of note is the observation that a few individual haplotypes from Gbeta3 showed a remarkable level of significance (p<0.0005) corresponding to a nearly infinite relative risk (15-20% in non-responders vs. 0% in responders). This difference in estimated haplotype frequency is based largely on the observation that one particular haplotype cannot be unambiguously detected in the 204 responder haplotypes although there are at least 9 copies in 182 non-responder haplotypes.
In conclusion, modest association is present between NET and drug response. In addition, select individual haplotypes from Gbeta3 show a strong statistical association with drug response.
Example 6: Forensic Matching by Microsequencin DNA samples are isolated from forensic specimens of, for example, hair, semen, blood or skin cells by conventional methods. A panel of PCR primers based on a number of the sequences of SEQ ID NOS: 1 to 542 is then utilized according to the methods described herein to ' amplify DNA of approximately 500 bases in length from the forensic specimen.
The alleles present at each of the selected biallelic markers site according to biallelic markers SEQ ID NOS:
1 to 542 are then identified according Example 2. A simple database comparison of the analysis results determines the differences, if any, between the sequences from a subject individual or from a database and those from the forensic sample. In a preferred method, statistically significant differences between the suspect's DNA sequences and those from the sample conclusively prove a lack of identity. This lack of identity can be proven, for example, with only one sequence. Identity, on the other hand, should be demonstrated with a large number of sequences, all matching. Preferably, a minimum of 13, 17, 20, 25, 30, 40, 50, 66, 70, 85, 88, 100, 187, 200 or 250 biallelic markers are used to test identity between the suspect and the sample.
In accordance with the regulations relating to Sequence Listings, the following codes have been used in the Sequence Listing to indicate the locations of biallelic markers within the sequences and to identify each of the alleles present at the polymorphic base.
The code "r" in the sequences indicates that one allele of the polymorphic base is a guanine, while the other allele is an adenine. The code "y" in the sequences indicates that one allele of the polymorphic base is a thymine, while the other allele is a cytosine. The code "m" in the sequences indicates that one allele of the polymorphic base is an adenine, while the other allele is an cytosine. The code "k" in the sequences indicates that one allele of the polymorphic base is a guanine, while the other allele is a thymine. The code "s" in the sequences indicates that one allele of the polymorphic base is a guanine, while the other allele is a cytosine. The code "w" in the sequences indicates that one allele of the polymorphic base is an adenine, while the other allele is an thymine.

GENE BIALLELIC SEQ BIALLELIC VALIDATIONGENOTYPING
MARKER ID MARKER MICRO- LEAST
ID NO. POSITION SEQUENCINGCOMMON
IN ALLELE
SEQ ID NO. FREQUENCY

5HTR6 99-27199-2071 207 Y T 0.30 5HTR6 99-27207-1172 117 Y C 0.37 5HTR6 99-28110-757 74 Y T 0.48 5HTR6 99-28134-2159 215 Y T 0.37 5HTR7 99-28149-11812 118 Y C 0.31 5HTR7 _ 13 285 Y G 0.49 5HTR7 99-28171-45814 457 Y A 0.38 5HTR7 99-32181-19217 192 Y C 0.38 5HTR7 99-32193-25818 257 Y T 0.65 CHRNA7 99-28722-9019 90 Y C 0.32 CHRNA7 99-28730-35120 351 Y A 0.38 CHRNA7 99-32306-40921 407 Y G 0.33 CRFR1 99-27088-24622 246 Y A 0.38 CRFR1 99-27090-20323 204 Y G 0.22 CRFR1 99-27091-22024 221 Y A 0.49 CRFR1 99-27094-40626 406 Y T 0.21 CRFR1 99-27097-8328 83 Y T 0.47 CRFR1 99-27550-4830 48 Y A 0.26 CRFR1 .99-27561-10632 106 Y

MLR 16-31-738 34 738 Y G 0.47 MLR 99-27563-40036 400 Y A 0.44 MLR _ 37 443 Y

MLR 99-28732-13338 133 Y A 0.31 MLR 99-28735-5639 56 Y T 0.30 MLR 99-28738-31941 319 Y C 0.37 CRFR2 99-27875-18543 185 Y C 0.40 CRFR2 99-27880-17644 176 Y T 0.44 CRFR2 99-28747-37145 373 Y C 0.44 CRFR2 99-28753-35346 352 Y C 0.39 CRFR2 99-28755-20647 207 Y G 0.41 GRL 16-38-323 49 323 Y A 0.33 GRL 99-28484-17950 179 Y A 0.40 TABLE 7A (cont) GRL 99-30853-36451 364 Y G 0.42 GRL 99-28485-19852 198 Y G 0.20 GRL 99-30858-35453 354 Y T 0.16 GRL 99-32002-31354 311 Y A 0.48 GRL 18-20-174 56 174 Y G 0.27 GRL 18-31-178 57 178 Y C 0.35 GRL 18-38-395 58 395 Y T 0.37 MAOA 18-2-192 59 192 Y T 0.32.

MAOB 99-26921-21060 211 Y G 0.48 MAOA 16-215-80 61 250 Y T 0.33 ' MAOA-B 18-132-36862 368 Y C 0.34 MAOA 18-133-29363 292 Y A 0.27 5HTR2c 18-12-191 64 191 Y A 0.14 5HTR2c 18-11-137 65 138 Y G 0.27 5HTR2c 18-93-96 66 96 Y

TH 16-115-34367 343 Y C 0.24 TH 16-42-140 68 140 Y G 0.30 TH 18-251-17669 176 Y T 0.43 TH 18-269-44 70 44 Y A 0.38 5HTT 18-186-39179 391 Y T 0.47 5HTT 18-194-13080 130 Y T 0.48 ' 5HTT 18-198-25281 252 Y A 0.49.

5HTT 18-242-30082 299 Y G 0.46.

DRD3 8-15-126 83 1501 Y G ~ 0.30 ' DRD3 8-'19-372 84 1501 Y A 0.28 "' DRD3 99-2409-29885 428 Y A 0.40 DRD3 99-339-54 86 1501 Y G 0.46 .

CYP3A4-712-254-18087 311 Y G 0.46 .' CYP3A4-710-214-27988 1501 Y C 0.12 CYP3A4-710-217-91 89 1501 Y T 0.07 ';

N ET 99-28788-30091 300 Y A . 0.47 ' N ET 99-32121-24293 244 Y G 0.48 NET _ 95 304 Y A 0.39.

N ET 16-2-76 99 95 Y A 0.27 ' NET 16-28-93 100 120 Y C 0.44 NET 16-3-199 101 342 Y C 0.32 N ET 16-50-197 102 197 Y C 0.21, 'TACR1 99-28761-311105 311 Y A 0.22 TABLE 7A (cont) TACR1 99-28771-86106 86 Y T 0.48 TACR1 99-28791-291107 291 Y A 0.26 TACR1 99-32361-419111 420 Y T 0.48 DRD2 16-21-228 112 228 Y A 0.16 DRD2 16-22-156 113 156 Y C 0.45 DRD2 16-23-404 114 404 Y G 0.47 DRD2 16-24-175 115 175 Y A 0.16 DRD2 16-25-286 116 286 Y T 0.37 Gbeta3 16-106-364119 364 Y T 0.01, Gbeta3 16-16-285 120 285 Y T 0.38 Gbeta3 16-17-121 121 121 Y T _0.36 Gbeta3 16-84-185 122 185 Y C 0.40 Gbeta3 16-87-74 123 74 Y A 0.34 Gbeta3 16-91-333 124 333 Y A 0.43 WFS1 16-128-142125 142 Y C 0.27 W FS 16-133-205126 245 Y G 0.34 WFS1 16-135-181127 232 Y A 0.28 W FS 16-145-405128 455 Y C 0.11 W FS 16-177-320129 320 Y A 0.07 W FS 16-4-354 130 354 Y C 0.36 GENE BIALLELIC SEQ ID BIALLELIC VALIDATIONGENOTYPING
. MARKER NO. MARKER MICRO- LEAST
ID POSITION SEQUENCINGCOMMON
IN ALLELE
SEQ ID FREQUENCY
NO.

5HTR6 99-27199-207131 24 Y T ' .' 0.30 5HTR6 99-27207-117132 24 Y C 0.37.

5HTR6 99-28110-75137 24 Y T 0.48 5HTR6' 99-28125-81138 24 Y

5HTR6 99-28134-215139 24 Y T 0.37 5HTR7 99-28149-118142 24 Y C ~ 0.31 5HTR7 99-28160-285143 24 Y G 0.49 5HTR7 99-28171-458144 24 Y A 0.38 .

5HTR7 99-32181-192147 24 Y C 0.38 5HTR7 99-32193-258148 24 Y T 0.65 CHRNA7 99-28722-90149 24 Y C 0.32 CHRNA7 99-28730-351150 24 Y A 0.38 CHRNA7 99-32306-409151 24 Y G 0.33 CRFR1 99-27088-246152 24 Y A~ 0.38 CRFR1 99-27090-203~ 153 24 - Y G ~ 0.22 TABLE 7B (cont) CRFR1 99-27091-220154 24 Y A 0.49 CRFR1 99-27094-406156 24 Y T 0.21 CRFR1 99-27097-83158 24 Y T 0.47 CRFR1 99-27550-48160 24 Y A 0.26 MLR 16-31-738 164 24 Y G 0.47 MLR 99-27563-400166 24 Y A 0.44 MLR 99-28732-133168 24 Y A 0.31 MLR 99-28735-56169 24 Y T 0.30 MLR ~ 99-28736-399170 24 Y

MLR 99-28738-319171 24 Y C 0.37 MLR ' 99-28739-364172 24 Y

CRFR2 99-27875-185173 24 Y C ' 0.40 CRFR2 99-27880-176174 24 Y T _ 0.44 CRFR2 99-28747-371175 24 Y C ~ ' 0.44 CRFR2 99-28753-353176 24 Y C _ 0.39 CRFR2 99-28755-206177 24 Y G 0.41 G RL 16-38-323 179 24 Y A 0.33 GRL 99-28484-179180 24 Y A 0.40 GRL 99-30853-364181 24 Y G 0.42 GRL 99-28485-19. 182 24 Y G 0.20 GRL _ 183 24 Y T 0.16 GRL _ 184 24 Y A 0.48 GRL 18-20-174 186 24 Y G , ' 0.27 GRL 18-31-178 187 24 Y C 0.35 GRL 18-38-395 188 24 Y T 0.37 MAOA 18-2-192 189 24 Y T 0.32 MAOB 99-26921-210190 24 Y G 0.48 MAOA 16-215-80 191 24 Y T ' 0.33 MAOA-B 18-132-368192 24 Y C 0.34 MAOA 18-133-293193 24 Y A . ' 0.27 5HTR2c 18-12-191 194 24 Y A 0.14 5HTR2c 18-11-137 195 24 Y G 0.27 _ 5HTR2c 18-93-96 196 24 Y
, TH 16-115-343197 24 Y C ' 0.24 ~

TH 16-42-140 198 24 Y G 0.30 TH 18-251-176199 24 Y T 0.43 TH 18-269-44 200 24 Y A 0.38 DRD4 18-291-91 208 24 Y ~~

TABLE 7B (cont) 5HTT 18-186-391 209 24 Y T 0.47 5HTT 18-194-130 210 24 Y T 0.48 5HTT 18-198-252 211 24 Y A 0.49 5HTT 18-242-300 212 24 Y G 0.46 DRD3 8-15-126 213 24 Y G 0.30 DRD3 8-19-372 214 24 Y A 0.28 DRD3 99-2409-298215 24 Y A 0.40 DRD3 99-339-54 216 24 Y G 0.46 CYP3A4-712-254-180 217 24 Y G 0.46 CYP3A4-710-214-279 218 24 Y C 0.12 CYP3A4-710-217-91 219 24 Y T 0.07 NET 99-28788-300221 24 Y A 0.47 N ET 99-32121-242223 24 Y G ~ 0.48 NET 99-32061-304225 24 Y A . 0.39 N ET 99-32123-11_8227 24 Y

N ET 16-2-76 229 24 Y A ' 0.27 NET 16-28-93 230 24 Y C 0.44 NET 16-3-199 231 24 Y C 0.32 NET 16-50-197 232 24 Y C 0.21 TACR1 99-28761-311235 24 Y A 0.22 TACR1 99-28771-86236 24 Y T 0.48 TACR1 99-28791-291237 24 Y A 0.26 TACR1 99-32361-419241 24 Y T 0.48 DRD2 16-21-228 242 24 Y A 0.16 DRD2 16-22-156 243 24 Y C . 0.45 . DRD2 16-23-404 244 24 Y G ' 0.47 ' DRD2 16-24-175 245 24 Y A ;.' 0.16 DRD2 16-25-286 246 24 Y T 0.37 DRD2 16-25-279 247 24 Y .. , Gbeta3 16-106-364 249 24 Y T 0.01 Gbeta3 16-16-285 250 24 Y T 0.38 Gbeta3 16-17-121 251 24 Y T 0.36 Gbeta3 16-84-185 252 24 Y C 0.40 Gbeta3 16-87-74 253 24 Y A ' 0.3 Gbeta3 16-91-333 254 24 Y A _ 0.43 WFS1 16-128-142 255 24 Y C ' 0.27 WFS1 16-133-205 256 24 Y G ' 0.34 WFS1 16-135-181 257 24 Y A ~ 0.28 WFS1 16-145-405 258 24 Y C ~ ' 0.11 WFS1 16-177-320 259 24 Y A 0.07 WFS1 16-4-354 260 24 Y C 0.36 GENE BIALLELIC SEQ ID BIALLELIC VALIDATIONGENOTYPING
MARKER NO. MARKER MICRO- LEAST
ID POSITION SEQUENCINGCOMMON
IN ALLELE
SEQ ID FREQUENCY
NO.

MAO A/B 18-473-362261 362 Y C 0.43 MAO A/B 99-12361-88262 88 Y C 0.36 MAO A/B 99-12368-335263 335 Y C 0.36 MAO A/B 99-12370-67264 67 Y A 0.29 N ET 99-32148-315265 314 Y C 0.27 N ET 19-46-322 266 322 Y C 0.31 NET 19-47-315 267 315 Y T 0.14 NET 99-32052-262269 263 Y T 0.38 CYP3A4/710-213-292270 1501 Y G 0.11 5HTT 18-429 273 _ Y

5HTT _ 274 256 Y C 0.48 Gbeta3 18-355-67 275 68 Y C 0.49 Gbeta3 18-353-267276 266 Y T 0.27 Gbeta3 18-338-305277 306 Y G 0.3 WFS1 24-243-346278 1501 Y T 0.3 W FS1 99-62531-351279 1501 Y T 0.36 WFS1 99-54279-152280 1501 Y G 0.44 DRD2 _ 281 245 Y A 0.45 DRD2 __ 282 291 Y C ~ 0.37 DRD2 _ 283 346 Y T 0.45 DRD2 18-177-406284 406. Y T 0.37 HM74 18-298-338285 338 Y G 0.49 HM74 _ 287 104 Y

HM74 18-884-30 288 _ Y C 0.26 HM74 99-61513-139290 140 Y A 0.26 HM74 99-6151 291 179 Y G 0.27 HM74 _ 292 _ Y C 0.33 CRHBP 18-204-70 293 70 Y C 0.20 CRHBP 18-207-441294 442 Y C 0.41 CRHBP 18-212-200296 200 Y T 0.31.

CRHBP 18-229-334297 334 Y T ~ 0.33 CRHBP 18-230-332298 332 Y T ~ 0.32 AVPR1A 18-966-378299 378 Y C 0.41 AVPR1A 18-987-308300 307 Y A 0.35 AVPR1A 18-1172-138302 138 Y G 0.16 AVPR1A 18-1173-92303 92 Y T 0.32 AVPR1A 18-1174-387304 387 Y C ~ 0.21 _ ____ AVPR1 18-1175-416305 416 Y G 0.21 A

AVPR1A 18-542-146306 146 Y G 0.21 5HT1 8-42-211 307 1501 Y G 0.46 A

5HT1A 8-45-389 308 1501 Y G 0.01 5HT1A 18-994-270309 270 Y C 0.25 5HT1A 18-912-165310 165 Y T 0.46 5HT1A 18-991-124311 124 Y T 0.45 TABLE 7C (cont) 5HT1A 99-65963-368314' 368 Y

A

5HT1 99-5070-176318 175 Y T 0.02 A

GABRG2 18-523-352320 352 Y C 0.49 GABRG2 18-545-478321 480 Y G 0.45 GABRG2 18-522-194322 194 Y G 0.32 GABRG2 18-524-284323 284 Y C 0.36 ADRB1 18-626-52 324 52 Y G 0.36 R

ADRB1 18-629-189325 189 Y T 0.40 R

ADRB1 18-1131-71326 71 Y T 0.41 R

R

R -ADRB1 18-597-27 329 27 Y A 0.20 R

GABRA5 18-730-203330 203 Y G 0.48 GABRA5 18-734-89 331 89 Y C 0.48 GABRA5 18-895-321332 321 Y A 0.27 GOLF 18-590-216335 216 . Y G 0.42 GOLF 18-817-436336 433 Y T " 0.41 GOLF 18-829-85 337 85 Y G 0.39 GOLF 18-839-271340 271 Y C 0.40 GOLF 18-770-194_ 194 Y T 0.37 GOLF 18-771-302342 302 Y G 0.30 GOLF 18-827-53 343 53 Y G 0.34 GOLF 18-768-318344 318 Y G 0.31 GOLF 18-769-26 345 26 Y A ~ 0:17 SLC6A3 18-709-321346 320 Y C 0.46 SLC6A3 18-714-280347 281 Y T 0.17 SLC6A3 18-843-271348 271 Y C 0.37 SLC6A3 18-850-265349 265 Y T 0.34.

SLC6A3 18-853-296350 296 Y T 0.23 SLC6A3 18-867-331351 332 Y C 0.48 SLC6A3 18-856-85 353 85 Y C 0.42 SLC6A3 18-861-101354 101 Y T 0.33 PDE4b 18-635-323355 323 Y

PDE4b 18-636-205356 205 Y A 0.36 PDE4b 18-649-427357 427 Y C 0.46 PDE4b 18-1134-316358 316 Y G 0.38 PDE4b 18-633-316359 316 Y

COMT 18-492-212361 212 Y C 0.41 COMT 18-488-156362 156 Y T 0.45 COMT 18-491-266363 266 Y T 0.42 COMT 18-497-141364 141 Y T 0.43 COMT 18-503-174365 174 Y C 0.31 COMT 18-490-95 366 - 95 Y A 0.31 ~

TABLE 7C (cont) SLC1 18-562-418370 418 Y C 0.49 SLC1 18-564-204_ 204 Y C 0.50 _ SEF2-1 18-1032-262372 261 Y C 0.33 B

SEF2-1 18-1035-412373 412 Y C 0.50 B

SEF2-1 18-1036-293374 293 Y C 0.34 B

SEF2-1 18-1038-95375 95 Y T 0.34 B

SEF2-1 18-1040-361376 361 Y G 0.44 B

SEF2-1 18-748-356377 356 Y T 0.47 B .

BDNF 18-937-181378 179 Y A 0.26 BDNF 18-942-175379 175 Y T 0.29 BDNF 18-937-147381 145 Y ' BDNF 18-946-408382 407 Y C 0.20 GAP43 18-787-133383 133 Y A 0.39 .

GAP43 18-1149-239384 239 Y A 0.49 GAP43 18-1159-291385 291 Y 6 0.23 GAP43 18-1135-273386 273 Y T 0.43 GAP43 18-802-460390 459 Y A 0.32 CLOCK 18-1064-110391 109 Y C 0.36 CLOCK 18-1068-327392 327 Y T 0.32 CLOCK 18-1069-365393 365 Y A ' 0.23 CLOCK 18-1073-367394 367 Y A 0.35 CLOCK 18-1070-272395 272 Y T 0.36 CLOCK 18-1080-361399 363 Y C 0.18 HSP70 18-506-297400 297 Y ~
' HSP70 18-570-38 401 38 ~ ~ ~ ~
~

GENE BIALLELIC SEQ ID BIALLELIC VALIDATIONGENOTYPING ;
MARKER NO. MARKER MICRO- LEAST ' ID POSITION SEQUENCINGi IN COMMON , SEQ ID ALLELE
NO. FREQUENCY

MAO A/B 18-473-362402 24 Y C 0.43 MAO A/B 99-12361-88403 24 Y C 0.36 MAO A/B 99-12368-335404 24 Y C 0.36 MAO A/B 99-12370-67405 24 Y A 0.29 N ET 99-32148-315406 24 Y C 0.27 N ET 19-46-322 407 24 Y C ' 0.31 N ET 19-47-315 408 24 Y T 0.14 NET 99-32052-262410 24 Y T 0.38 CYP3A4/710-213-292411 24 Y G 0.11 5HTT 18-246-256415 24 Y C 0.48 TABLE 7D (cont) Gbeta3 18-355-67 416 24 Y C 0.49 Gbeta3 18-353-267417 24 Y T 0.27 Gbeta3 18-338-305418 24 Y G 0.3 WFS1 24-243-346419 24 Y T 0.3 W FS 99-62531-351420 24 Y T 0.36 W FS 99-54279-152421 24 Y G 0.44 DRD2 18-168-245422 24 Y A 0.45 DRD2 18-171-291423 24 Y C 0.37 DRD2 18-172-346424 24 Y T 0.45 DRD2 18-177-406425 24 Y T 0.37 HM74 18-298-338426 24 Y G 0.49 HM74 18-884-30 429 24 Y C 0.26 HM74 99-61513-139431 24 Y A 0.26 HM74 99-61514-179432 24 Y G 0.27 HM74 99-61516-323433 24 Y C 0.33 CRHBP 18-204-70 434 24 Y C 0.20 CRHBP 18-207-441435 24 Y C 0.41 CRHBP 18-212-200437 24 Y T 0.31 CRHBP 18-229-334438 24 Y T 0.33 CRHBP 18-230-332439 24 Y T 0.32 AVPR1A _ 440 24 Y C 0.41 AVPR1A 18-987-308441 24 Y A 0.35 AVPR1A 18-1172-138443 24 Y G ' 0.16 -AVPR1A 18-1173-92444 24 Y T 0.32 AVPR1A 18-1174-387445 24 Y C 0.21 AVPR1A 18-1175-416446 24 Y G 0.21 AVPR1A 18-542-146447 24 Y G 0.21 HT 8-42-211 448 24 Y G 0.46 5HT1A 8-45-389 449 24 Y G ' 0.01 5HT1A 18-994-270450 24 Y C 0.25 5HT1A 18-912-165451 24 Y T 0.46 5HT1A 18-991-124452 24 Y T 0.45 5HT1A _ 455 24 Y

A

5HT1A 99-5069-331458 24 ' Y

5HT1A 99-5070-176459 24 Y T 0.02 GABRG2 _ 461 24 Y C 0.49 18-523-352_ GABRG2 18-545-478462 24 Y G 0.45 GABRG2 18-52 463 24 Y G 0.32 GABRG2 _ 464 24 Y C 0.36 ADRB1R 18-626-52 465 24 Y G 0.36 ADRB1 18-629-189466 24 Y T 0.40 R

ADRB1 18-1131-71467 24 Y T 0.41 R .

R

R

ADRB1 18-597-27 470 24 Y A 0.20 R

TABLE 7D (cont) GABRA5 18-730-203471 24 Y G 0.48 GABRA5 18-734-89 472 24 Y C 0.48 GABRA5 18-895-321473 24 Y A 0.27 GOLF 18-590-216_ 24 Y G 0.42 _ GOLF 18-817-436477 24 Y T 0.41 GOLF 18-829-85 478 24 Y G 0.39 GOLF 18-839-271481 24 Y C 0.40.

GOLF 18-770-194482 24 Y T 0.37 GOLF 18-771-302483 24 Y G 0.30 GOLF 18-827-53 484 24 Y G 0.34 GOLF 18-768-318485 24 Y G 0.31 GOLF 18-769-26 486 24 Y A 0.17 SLC6A3 18-709-321487 24 Y C 0.46 SLC6A3 18-714-280488 24 Y T 0.17.

SLC6A3 18-843-271489 24 Y C 0.37 SLC6A3 18-850-265490 24 Y T 0.34 SLC6A3 18-853-296491 24 Y T 0.23 SLC6A3 18-867-331492 24 Y C 0.48 SLC6A3 18-856-85 494 24 Y C 0.42 SLC6A3 18-861-101495 24 Y T 0.33 PDE4b 18-635-323496 24 Y

PDE4b 18-636-205497 24 Y A 0.36 PDE4b 18-649-427498 24 Y C 0.46 PDE4b 18-1134-316499 24 Y G 0.38 PDE4b 18-633-316500 24 Y

COMT 18-492-212502 24 Y C 0.41 COMT 18-488-156503 24 Y T 0.45 COMT 18-491-26650 24 Y T 0.42 COMT 18-497-141_ 24 Y T 0.43 COMT 18-503-174506 24 Y C 0.31 COMT 18-490-95 507 24 Y A 0.31 , ~

NPY1 R 18-699-115508 24 Y .

SLC1 18-562-418511 24 Y C ' 0.49 SLC1 18-564-204512 24 Y C 0.496 SEF2-1 18-1032-262513 24 Y C 0.33 B

SEF2-1 18-1035-412514 24 Y C 0.50 B

SEF2-1 18-1036-293515 24 Y C 0.34 B .

SEF2-1 18-1038-95516 24 Y T 0.34 B

SEF2-1 18-1040-361517 24 Y G 0.44 B

SEF2-1 18-748-356518 24 Y T 0.47 B

BDNF 18-937-181519 24 Y A 0.26 BDNF 18-942-175520 24 Y T 0.29 BDNF 18-946-408523 24 Y C 0.20 GAP43 18-787-133524 24 Y A 0.39 GAP43 18-1149-239525 24 Y A 0.49 TABLE 7D (cont) GAP43 18-1159-291526 24 Y G 0.23 GAP43 18-1135-273527 24 Y T 0.43 GAP43 18-802-460531 24 Y A 0.32 CLOCK 18-1064-110532 24 Y C 0.36 CLOCK 18-1068-327533 24 Y T 0.32 CLOCK 18-1069-365534 24 Y A 0.23 CLOCK 18-1073-367535 24 Y A 0.35 CLOCK 18-1070-272536 24 Y T 0.36 CLOCK 18-1080-361540 24 Y C 0.18 ID MARKER ALLELE ALLELE SEQUENCE
NO. ID

12 99-28149-118C T [1-478]

13 99-28160-285A G [1-456]

14 99-28171-458A G [1-48],[141-514]

15 99-28173-395C T [1-550]

16 99-32177-113C T [1-466]

17 99-32181-192C T [1-449]

18 99-32193-258G T [1-458]

20 99-28730-351A G [1-452]

21 99-32306-409G C [1-455]

28 99-27097-83C T [1-273]

29 99-27098-162C T [226-421 ]

32 99-27561-106A G [1-465]

33 99-27562-366G T [1-470]

35 99-27110-301G C [1-455]

37 99-27573-443G T [1-513]

38 99-28732-133A G [1-411]

40 99-28736-399C T [1-453]

41 99-28738-319C T [1 _458]

42 99-28739-364C - T - [1 _509]

62 18-132-368C T [1-480]

64 18-12-191 A C [1-450]

65 18-11-137 A G [1-157],[348-390]

66 18-93-96 G T [1-454]

69 18-251-176C T [104-494]

72 18-393-330G C [1-93],[146-479]

73 18-394-402A C [1-21],[119-518]

75 18-284-139C T [146-450] ;

76 18-285-305A G [1-520]

77 18-289-239C T [1-486] ' 78 18-291-91 C T [1-453]

80 18-194-130C T [1-460]

81 18-198-252A G [1-316],[349-459]

82 18-242-300A G [224-476]

85 99-2409-298A G [117-127],[160-359],[395-71,1]

86 99-339-54 G C [1-247],[293-1514],[1544-2128],[2159-3001]

98 99-32148-315G C [1-24]

108 99-32077-66A G [37-63]

1110 ~99-32376-426A G ~[235-470] ~I

SEQ.IDBIALLELIC ORIGINAL ALTERNATIVE
NO. MARKER ID ALLELE ALLELE

6 99-28109-275G A

7 99-28110-75C T

8 99-28125-81A C

9 99-28134-215C T

60 _ G A

1129 16-177-320 A ~ G

ID MARKER ALLELE ALLELE
NO. ID

SEQ. POSITION RANGE OF PREFERRED
ID SEQUENCE
NO.

1 [103-147]

7 [1-25]

8 [508-518]

9 [398-432]

[295-364]

11 [301-342]

23 [246-287]

25 [369-413]

30 [126-153],[182-468]

31 [271-313],(443-452], 34 [408-461 ]

39 [147-235],[438-457]

43 [498-549]

46 (432-448]

49 [263-320]

54 [472-489]

59 [280-321 ]

63 [486-505]

71 [258-437],[669-927]

74 [90-165]

79 [1-82],j150-191]

83 [1-16],[144-498],[620-800],[1300-1366], 1823-1908 , 2336-2365 , 2398-3001 88 [1-1297],[1998-2689],[2895-2965]

92 [255-348],[493-499]

93 [445-467]

94 [1-16],[396-438]

96 [246-288]

97 [1-91],[420-541]

111 [443-457]

121 [130-181 ]

122 [160-399]

123 [144-145],[351-435]

128 [283-551 ]

129 [375-458]

TABLE '12 SEQ POSITION RANGE COMPLEMENTARY
ID OF POSITION RANGE OF
NO. MICROSEQUENCING MICROSEQUENCING
PRIMERS PRIMERS

1 188-206* 208-227 2 98-116* 118-136*

3 34-52* 54-73 4 314-332* 334-353 214-232* 234-253 8 62-80* 82-101 9 196-214* 216-235 77-95* 97-116 12 98-117 119-137*

13 266-284* 286-305 14 438-456* 458-477 375-394 396-414*

16 93-112 114-132*

18 238-256* 258-277 19 71-89* 91-110 332-350* 352-370*

23 185-203* 205-224 26 387-405* 407-426 28-47 49-67*

31 316-334* 336-355 32 87-105* 107-126 34 715-737* 739-761*

281-299* 301-319*

36 381-399* 401-420 37 423-442 444-462*

38 114-132* 134-153 379-398 400-418*

41 299-318 320-338*

42 345-363* 365-384 43 ~ 165-184 186-204*

TABLE 12 (cont) 44 156-175 177-195*

45 353-372 374-392*

46 332-351 353-371*

47 187-206 208-226*

49 300-322* 324-346*

50 160-178* 180-199 51 345-363* 365-384 52 179-197* 199-217*

53 334-353 355-373*

54 292-310* 312-331 55 347-365* 367-385*

56 155-173* 175-194 57 158-177 179-197*

58 375-394 396-414*

60 192-210* 212-231 61 231-249* 251-270 62 348-367 369-387*

63 273-291* 293-311*

64 172-190* 192-210*

65 118-137 139-157*

66 77-95* 97-115*

67 320-342* 344-366*

68 121-139* 141-163*

69 157-175* 177-196 70 25-43* 45-64 71 601-623* 625-644 72 311-329* 331-349*

74 32-54* 56-74*

75 120-138* 140-159 76 286-304* 306-325 77 219-238 240-258*

78 71-90 92-110*

79 371-390 392-410*

80 110-129 131-149*

81 233-251 * 253-272 82 280-298* 300-319 83 1481-1500 1502-1520*

84 1481-1500 1502-1520*

85 408-427 429-447*

86 1482-1500* 1502-1521 87 292-310* 312-331 88 1482-1500* 1502-1521 89 1482-1500* 1502-1521 ~90 149-167* 169-187*

TABLE 12 (cont.) 91 281-299* 301-320 92 244-262* 264-282*

93 225-243* 245-264 95 285-303* 305-324 96 284-302* 304-322*

97 99-117* 119-138 98 294-313 315-333*

99 76-94* 96-114*

100 101-119* 121-143*

101 323-341* 343-361*

102 178-196* 198-216*

103 158-180* 182-200*

104 183-205* 207-225*

105 292-310* 312-331 106 67-85* 87-106 107 272-290* 292-311 108 47-65* 67-85*

109 448-466* 468-486*

110 407-425* 427-446 111 400-419 421-439*

112 205-227* 229-251*

113 133-155* 157-175*

114 381-403* 405-427*

115 156-174* 176-194*

116 267-285* 287-305* .

117 260-278* 280-298*

118 370-392* 394-416*

119 345-363* 365-383*

120 265-284 286-304*

121 102-120* 122-140*

122 162-184* 186-208*

123 51-73* 75-97*

124 310-332* 334-356*

125 123-141 * 143-161 126 222-244* 246-268*

127 209-231 * 233-251 128 436-454* 456-474*

129 297-319* 321-343*

130 335-353* 355-373*

261 343-361* 363-382 262 68-87 89-107*

263 316-334* 336-355 264 48-66* 68-87 TABLE 12 (cont.) 265 295-313* 315-333*

266 302-321 323-341*

267 296-314* 316-334*

268 327-345* 347-366 269 244-262* 264-282*

270 1482-1500* 1502-1521 271 115-134 136-154*

272 400-418* 420-439 273 271-289* 291-309*

274 237-255* 257-276 -275 48-67 69-87*

276 246-265 267-285*

277 287-305* 307-326 278 1482-1500* 1502-1521 279 1482-1500* 1502-1521 _ 1482-1500* 1502-1521 281 225-244 246-264*

282 271-290 292-310*

283 327-345* 347-366 _ 387-405* 407-426 '284 285 319-337* 339-357*

286 91-109* 111-130 1287 85-103* 105-124 288 12-30* 32-50*

289 323-341* 343-362 290 121-139* 141-160 291 160-178* 180-199 292 304-322* 324-343 293 50-69 71-89*

294 422-441 443-461*

295 46-64* 66-85 296 181-199* 201-220 297 314-333 335-353*

298 313-331* 333-352 299 358-377 379-397*

300 288-306* 308-327 301 99-117* 119-138 302 119-137* 139-158 304 368-386* 388-407 305 397-415* 417-436 306 127-145* 147-165*

307 1481-1500 1482-1500*

308 1481-1500 1502-1520*

309 250-269 271-289*

310 146-164* 166-184*

311 105-123* 125-144 312 199-218 220-238*

313 293-311 * 313-331 314 349-367* 369-388 315 206-224* 226-245 316 56-74* 76-95 317 1482-1500* 1502-1521 ia~

TABLE. '12 (cont.) 318 156-174* 176-194*

1319 328-347 349-367*

320 332-351 353-371*

321 461-479* 481-500 322 175-193* 195-214 323 265-283* 285-304 324 33-51 * 53-72 325 169-188 190-208*

326 51-70 72-90*

327 106-125 127-145*

328 40-58* 60-79 329 7-26 28-46*

330 184-202* 204-223 331 70-88* 90-108*

332 302-320* 322-341 333 50-68* 70-89 334 39-57* 59-77*

335 197-215* 217-236 336 414-432* 434-452*

337 66-84* 86-105 338 368-386* 388-407 339 239-258 260-278*

340 252-270* 272-291 341 175-193* 195-213*

342 283-301* 303-321*

343 33-52 54-72*

344 299-317* 319-338 345 6-25 27-45*

346 300-319 321-339*

347 262-280* 282-300*

348 252-270* 272-290*

349 246-264* 266-284*

350 277-295* 297-315*

351 313-331 * 333-352 352 54-72* 74-93 353 66-84* 86-104*

354 82-100* 102-120*

355 304-322* 324-343 356 186-204* 206-225 35 408-426* 428-447 _ 297-315* 317-336 359 297-315* 317-336 360 406-424* 426-445 361 193-211* 213-231*

362 137-155* 157-175*

363 247-265* 267-285*

364 122-140* 142-160*

365 155-173* 175-194 366 75-94 96-114*

367 95-113* 115-134 36_8 274-292* 294-312*

369 3-21 * 23-42 1370 ~ 399-417* 419-438 TABLE 12 (cont.) 371 185-203* 205-224 372 242-260* 262-281 373 393-411 * 413-431 *

374 274-292* 294-313 375 75-94 96-114*

376 342-360* 362-381 377 336-355 357-375*

378 160-178* 180-198*

379 158-174* 176-195 380 202-220* 222-241 381 126-144* 946-9 65 382 387-406 408-426*

383 113-132 134-152*

384 220-238* 240-259 385 272-290* 292-311 386 254-272* 274-293 387 89-107* 109-128 388 49-67* 69-88 389 276-294* 296-315 390 440-458* 460-479 391 89-108 110-128*

392 307-326 328-346*

393 345-364 366-384*

394 348-366* 368-387 395 253-271* 273-292 396 16-34* 36-54*

397 396-414* 416-435 398 146-164* 166-185 399 343-362 364-382*

_ 278-296* 298-317 1401 I 19-37* -. I - 3g_58 --SEQ POSITION RANGE COMPLEMENTARY
ID OF POSITION RANGE
NO. AMPLIFICATION OF
PRIMERS AMPLIFICATION
PRIMERS

1-18 _ 1-X8 434-454 -..

I~ 1-18 531-549 TABLE 13 (cont) TABLE 13 (cont) 92 1-18 - - 4.78-498 110 1-18 449-469 ~ , 125 1-20 308-327 ; , 261 1-21 482-502 , I~ ~ 1-18 478-498 ~ I

TABLE 13(cont.) , 314 1-19 _ TABLE 13 (cont.) _ 1-21 485-505 _ 1-18 570-589 TABLE 13 (cont.) SEQ POSITION RANGE
ID OF PROBES
NO.

j 2 105-129 _ 8 gg_93 ~~ 45 361-385 TABLE 14 (cont.) TABLE 14 (COnt.) 51 352-376 83 _ 102 _ TABLE 14 ~ 271 123-147 011t ~

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SEQUENCE LISTING
<110> GENSET
<120> BIALLELIC MARKERS DERIVED FROM GENOMIC REGIONS CARRYING
GENES INVOLVED IN CENTRAL NERVOUS SYSTEM DISORDERS.
<130> 10488-51 LAB
<150> 60/175,854 <151> 2000-01-13 <160> 544 <170> PatentIn version 2.0 <210> 1 <211> 450 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 207 <223> 99-27199-207 . polymorphic base C or T
<220>
<221> misc_binding <222> 188. 206 <223> 99-27199-207.mis1 <220>
<221> misc_binding <222> 208. 227 <223> 99-27199-207.mis2, potential complement <220>
<221> primer bind <222> 1..20 <223> upstream amplification primer <220>
<221> grimer bind <222> 431..450 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 195. 219 <223> 99-27199-207 potential probe <400> 1 tataagaggc ttgattcagg ttctggaact cagtaggtag aagcctccat gcctatccat 60 gcatgtttgc gtgtttgcat gtgtgtacat gcacatttgc acatgattgt ccacgttcac 120 gtgtgtgcat gtgtatgtgt gtgacattca tctcctccac tgctgttgga gtccctccca 180 gcacccaatg tggccaggga cactgayggc cttttctggg gtcttttgcc agattgccaa 240 ggaatcatcg aggacgtcat cctgctgggt gcgcctgtgg agggagaagc caagcattgg 300 gagcctttcc ggaaggtggt gtccgggagg atcatcaacg gctactgcag gtctgtccaa 360 acctcgtgcc agcggggaag tgacaatgct tacggagcac ttagtatgcc caggctctgt 420 gttggggaca catatttgag acctaatccc 450 <210> 2 <211> 452 is <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 117 <223> 99-27207-117 : polymorphic base C or T
<220>
<221> misc_binding <222> 98..116 <223> 99-27207-117.mis1 <220>
<221> misc_binding <222> 118. 136 <223> 99-27207-117.mis2, complement <220>
<221> primer bind <222> 1..21 <223> upstream amplification primer <220>
<221> primer bind <222> 432..452 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 105..129 <223> 99-27207-117 potential probe <400> 2 ccaaaaagaa atcacagcaa cgtgaaggtt aaggctaact tttcaaacat cagaatcctg 60 acaatggttg cagtagcttt caaggagaca tggtgtgtgg ccagcccctc cagggcygtg 120 tggacagctt tttgtgtatt ttcctgggtg actcacagca tcaaagggag aaaggaggta 180 gtaattgttc agcacttgac atgtgcttga acacttcgta atcgcaatct gtgecaggca 240 gtggcaccat ctcccctttt tagatgaaga aaccgaggca ccgagataaa aagtaacttg 300 ctcaaggcaa tttaggaagt tgtaaaacca accaacacat atggaatgtg tattatctgc 360 taggctcatt taatatctca tctgaccttc cagataccca tctgatgtag gtaccactcc 420 cagctccaat tgtgagattc agaggggaga as 452 <210> 3 <211> 464 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 53 <223> 99-27213-53 : polymorphic base A or G
<220>
<221> misc binding <222> 34..52 <223> 99-27213-53.mis1 <220>
<221> misc binding <222> 54..73 <223> 99-27213-53.mis2, potential complement <220>

<221> primer bind <222> 1..18 <223> upstream amplification primer <220>

<221> primer bind <222> 446..464 <223> downstream amplificationimer, pr complement <220>

<221> misc_binding <222> 41..65 <223> 99-27213-53 potential probe <400> 3 tatgtagact ctttccccag gaaaaggcttcacacatgtaattgtttatg carcgttagg60 gactctcaga ttctgtggtc tctggaaggatctgagacccagggaagcca tagcaactgt120 tcagccagga gacctggctc tcagtttgattctgctactaaccctctgtg tggccttggg180 cacgtgtctt tccctccctg gacaccagcacacattttctttttttacct atacaattaa240 gggattgaat gatacgtaaa tttctcttgactgtaaggttttgtgtttct gggaggtgag300 ttcatcactg ggccgaccaa ggtgactctttgcagctgaggtctagagtg tgacgtacca360 cccctctgct cctgggtccc tgtctgagccctaaggccacccggcttccc tcacttgttt420 agtgacttca cctctcctct ctgtgcctcatttcttcatctctc 464 <210> 4 <211> 546 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 333 <223> 99-27218-333 . polymorphicbase G T
or <220>

binding <221> misc _ <222> 314. 332 <223> 99-27218-333.mis1 <220>
<221> misc_binding <222> 334. 353 ' <223> 99-27218-333.mis2, potential complement <220>
<221> primer bind <222> 1..20 <223> upstream amplification primer <220>
<221> primer bind <222> 528..546 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 321..345 <223> 99-27218-333 potential probe <400> 4 gaagagtaga ggtaaaagag ttaaaatgat taacacattt accctgatct tggctattgt 60 gggtcgtagg tgggtcttat tgtgggtcgt ggctattgta ggtctgataa tcaatattca 120 tgtttatatatgtaatagtaatcattaatgtgtacttcttgaaacaatttagtaccaggt 180 attgtggtaagccttggcagggggtggcacacaggtgaataggcactggccctaccctcg 240 aggggcttactgccttgaggaatgtgaaaaggatgagggacatttgacccccattttgga 300 aaatatgcagatatttaataggtggaccaggtkggggagtgtgtttcactccttgaaggt 360 gtcccaaaggagagggatactttggttccttctgggaatgatgagaatgaccatcactta 420 ttgagcacttaaccgcatgccaggcacggtgctgagcatgttatattttacatcattatc 480 tcatatccttgtaagatatttctccatttttacaatggaagctcatggtggcagaatccc 540 tccttt 546 <210> 5 <211> 413 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 233 <223> 99-28108-233 : polymorphic base A or C
<220>
<221> mist binding <222> 214..232 <223> 99-28108-233.mis1 <220>

<221> misc binding <222> 234..253 <223> 99-28108-233.mis2, potential complement <220>

<221> primer bind -<222> 1..18 <223> upstream amplification primer <220>

<221> primer bind <222> 394..413 <223> downstream amplification primer, complement <220>

binding <221> misc _ <222> 221. 245 <223> 99-28208-233 potential probe <400> 5 catgcctgtt cttccatcca cactccaggg ctgcccaccagctgacaggc accatcaact60 ggcagcaaca gagcaggcgc aggtacaaag aaggcagctcactcctgctc ttaggagatc120 caatcagatc tgccctgtac agccatgtag gctgtgcgctgcataactcc agggacatga180 gtcacacaga cacaatgtga gtgtgctccc ccgtcatgcaacatctggac acmactaaca240 gagcatggtg aatacatgct gaattgcatt cagtatggctgtgaactagg cctggggaca300 agaatgaatt ttacatggaa agaatttcct gtagcaggaacagaggggat aacaacagca360 ataaataata ataagaagaa gctaccactt cttgagcatgtaccacatac caa 413 <210> 6 <211> 454 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 275 <223> 99-28109-275 : polymorphic baseG
A or <220>
<221> misc_binding <222> 255. 274 <223> 99-28109-275.misl, potential <220>
<221> mist binding <222> 276..295 <223> 99-28109-275.mis2, potential complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 434..454 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 263. 287 <223> 99-28109-275 potential probe <400> 6 caatgtcatc gacaacccct ggggggtgtg tctccatcga tcagcagagg ttggcaagca 60 cctggcccac atcctgctct cccggcagca ggtacctggg aatggctgtg tgggcgtggc 120 attgagcaag aggggaagtc aggtgctgac ttgttcacag atatcagcct tagaggcaag 180 gctacttgga gataactcaa tggttttggg ggtgtgggca gtccttgctg cctctccagt 240 tcaagtaatg aatgtgtcct aggatgaaca gtaaraatta tagactctgc agctctagca 300 ggtatttagg taaggactga ataacagggc atctgcaggt aggaacaagt ctgggggact 360 ctggcagaag caaaagtggc tcctatgtat cagctcttca ttcaagtgtt taggataatc 420 actgggctca tttgggtgat atttcagtgg aaac 454 <210> 7 <211> 549 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 74 <223> 99-28110-75 : polymorphic base C or T
<220>
<221> misc_binding <222> 54..73 <223> 99-28110-75.misl, potential <220>
<221> mist binding <222> 75..94 <223> 99-28110-75.mis2, potential complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 530..549 <223> downstream amplification primer, complement <220>

<221> misc binding <222> 62..86 <223> 99-28110-75 potential probe <400> 7 aaccacttct cactcacctctgtgcccacagccagccccg cacatcgtgg ggtttccgtg60 ggaaccagat cccygcaggtacaaatggggcccagccctt cctgtttcct gcctcaaaag120 acaccccaac ttacccaaacagaggctgccatcacccacc tccatctgcc ccagtgactc180 cttccaagcc catcaggcccctttgggttctttcacttct tggacctcaa tttcctcatg240 tataaaatga ggctaataaagagacctataccacgtgggc tggctgtgtg gctttgataa300 tacatgtaac aggcttattggcacagggttagaggccact accagaagct acagagatgt360 gtgaatgcag gcagtactgaagcagtggttaacagcccag gttcatccgg ctctaccact420 cacatgccgt ggcaccgcctgcagcctcagttttcacacc tgtacaacgg gttactacca480 ctatgcagga cctctatgaggatcaaatgacttaccccgt aaaacatgtg agttgttggc540 tactgcggt 549 <210> 8 <211> 518 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 81 <223> 99-28125-81 : polymorphic base A or C

<220>

<221> misc binding <222> 62..80 <223> 99-28125-8l.misl <220>

<221> misc binding <222> 82..101.

<223> 99-28125-8l.mis2, potential complement <220>

<221> primer bind <222> 1..18 <223> upstream amplification primer <220>

<221> primerbind <222> 500..518 <223> downstream amplification primer, complement <220>

<221> misc binding <222> 69..93 <223> 99-28125-81 potential probe <400> 8 ggggagtgtt gttaaaagta cagattcyta cagatctcct gcatgtggga60 agccctaccc ccgaggaagc tgtaattcca maagctctct tgttccctaa actctaagaa120 gggaccttga ccactgtccc gctgtgactg tcaagtctcc gttgctgttg ggctgtttca180 acatgaccct agttcatttg accttgggct ttaaaggtct ggaggaacag gtaccctgag240 ctccttgtga gctgaccctc agatctctga gctggaaagg accagctcct ttggtccttc300 acctctggat cggcaggatc caaaagtctg ggcctgggca atctgcacat ctatcaggag360 ctggactgga caatgggggg atgttgcagc acccattgat tttagaagga ggccgtgagg420 catgggctga aaggggtgca ggctggaagc atgggcgggc ggtgtgtggc tggaagacag480 ttcggggaga tgttctgcta gctcgtgccc tccttcccac ttcatggt 51B
<210> 9 <211> 472 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 215 <223> 99-28134-215 : polymorphic base C or T
<220>
<221> misc binding <222> 196..-214 <223> 99-28134-215.mis1 <220>

<221> misc binding _ <222> 216. 235 <223> 99-28134-2I5.mis2, potential complement <220>

<221> primer bind <222> 1..20 <223> upstream amplification primer <220>

<221> primer bind <222> 453..472 <223> downstream amplification primer, complement .

<220>

<221> misc binding _ <222> 203. 227 <223> 99-28134-215 potential probe <400> 9 tggatggatg gggcttctac tcaggccagt cttagagggctcagttttgg gtttaatctt' ccctcctgcc ccaaagtctg agtcacagct ttggctgaaaccccgcaggt cctccttctc120 aaaccccaaa gggttgcttc ctttctagcc ctgcagccgccagccttcac gggccccctc180 ctctggctgg agggtctgtc accctgtttg ggtayaggctcctgcacgct ggcggcctcc240 tgttctagca ccctgecctg tctccaaggc agcactcagaaagctcagcc taggcccctc300 cagcccctcc ctccaccacc aaagactaac acagaagcctctcagacctt gttcaaagac360 ctccctgtgg yccwatcttt gtttttcagt ctgtgtccactcgcccatgt cccttccccc420 agctccaacc agccaagccg ccccagcctc tcctgtcatcctgctgctct ca 472 <210> 10 <211> 546 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 96 <223> 99-28137-96 : polymorphic base A or G

<220>

<221> misc binding <222> 77..95 <223> 99-28137-96.mis1 <220>

WO 01/51659 PCT/IBO1l00116 <221> misc_binding <222> 97..116 <223> 99-28137-96.mis2, potential complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 529..546 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 84..108 <223> 99-28137-96 potential probe <400> 10 caggaatgct gctattacca ccgctggcca caaggggtcc cagccctgca ggcagccgca 60 ccaaggctcg aaaagcagtc ccagctctta gcaggrcaga ctctgccagg cagagaaggc 120 gccctgaatg gccggccccc agagaaagct gctgagctca tggttatccc tgggtccaca 180 accatttggc actgtaggag caacgataac ccgcatatga tcactgtgca cgttgttatt 240 gcagacagca gagagaaagg ccccagggac cagcagctct gcgtgcagtc tgcgttctgc 300 tcccaggctt attctcattg gctgtgtgac cttgggcaag ccccatcccc tctctgaccc 360 tgtttcctcg tcttccaagg gaaatcgcgt tgatctctaa gggccttttc agcaacagcc 420 ttgccaacaa caaaagcacc tgaagtagcc tttatgttgg agggatatct gagccatcct 480 tgctattcac cacaaactgt cagcttactg aagttttaaa ttcttctgcc agattgtcat- 540 tgtcct 546 <210> 11 <211> 401 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 305 <223> 99-32204-305 . polymorphic base A or G
<220>
<221> misc_binding <222> 285. 304 <223> 99-32204-305.misl, potential <220>
<221> misc binding <222> 306..325 <223> 99-32204-305.mis2, potential complement <220>
<221> primer bind <222> 1..20 <223> upstream amplification primer <220>
<221> primer bind <222> 384..401 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 293..317 <223> 99-32204-305 potential probe <400> 11 gtttggttta cttagccatc ccctccccaa atacatacct cattaccacc ccaaggtaat 60 cccagtaaat tgcagtgggg caaattataa tcactgtggt agcagtagct aacatttatc 120 cagggttcac tggtgccaga cagtgttacc atgccattta acctgcccaa ctcacctgtg 180 aggcaggtcc tgttattatc cacatgttat ctcagaggga aatgaagctg agaggtaaag 240 tgaggacaca aagccaattt ccaggggaac caggactccc ccaggtggtt ggacttcaga 300 gtccractct taaccccatc ctccactgcc tccctctgcc accttgtaaa tcaaaataac 360 gatactagct aacatcgttt ttagtctcat gtagttgagc c 401 <210> I2 <211> 478 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 118 <223> 99-28149-118 : polymorphic base C or T
<220>
<221> misc_binding <222> 98..117 <223> 99-28249-118.misl, potential <220>
<221> misc_binding <222> 119. 137 <223> 99-28149-118.mis2, complement <220>
<221> primer bind <222> 1..19 <223> upstream amplification primer <220>
<221> primer bind <222> 459..478 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 106..130 <223> 99-28149-118 potential probe <400> 12 cagcaaattg ctagtgaact tgcaactttt tcaccttttt cttcatctta atgaactagg 60 aaggtcattt tctagatggc tttgcctgaa taagcccaca tacgatactg tgaccttyga 120 tgggaggagc tagcatgtga tgttaaggcc aagtccatgg aatggacagc aatgcacaac 180 agataattcc tcatgtctca cgacagtggt aagattccca gtggctgctt tggtgagagc 240 ttttaattgg ggttcttagg aacttgtatt attatttaaa ccagagtgtg agctcctaga 300 gaacaccggc tgtcatggtc cttttttaag tactccacta tcttgcgtat aatgagtcct 360 ccttacagtt tgttgagtca ataagtacat gttgaactta gcatatcagg gtacagcata 420 ggggacctgg ccaaattctg ctcgttgtta gtcaccagct ggatgtccac attcatca 478 <2I0> I3 <211> 456 <2I2> DNA
<2I3> Homo Sapiens <220>

<221> allele <222> 285 .
<223> 99-28160-285 : polymorphic base A or G
<220>
<221> misc binding <222> 266..284 <223> 99-28160-285.mis1 <220>
<221> misc_binding <222> 286. 305 <223> 99-28160-285.mis2, potential complement <220>
<221> primer bind <222> 1..19 <223> upstream amplification primer <220>
<221> primer bind <222> 439..456 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 273. 297 <223> 99-28160-285 potential probe <400> 13 caaaagagtc aaagcagagg ccttgagaat tgcttgagaa tttatgctac tttcaggagc 60 tttttgtggt ataacaatgc agagcataga aggaggaagg aaatggtatt tgtttcaaag 120 gatcattatt tacttctggt ttcagtagtc agttagccag tagatatact gagaaactta 180 agaaagtccc catcatctct gttgaagaag gataagttgg tgcacgatga caatataaca 240 ttatattgca tcatagtgtt atggatcaag tgctagggga tcgcrataat gggagtaagt 300 agctggggtg gggtgcagat aggaaggacc ttacagtaga ggtgacactt gagcaaggtc 360 ttaagggata aataggagtt tgctaggcta tgaagtgggg actagaagtg cagacacttt 420 ctgtcttctc cactttggcc tgttactcta tttccc 456 <210> 14 <211> 514 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 457 <223> 99-28171-458 : polymorphic base A or G
<220>
<221> misc binding <222> 438..456 <223> 99-28171-458.mis1 <220>
<221> misc binding <222> 458..477 <223> 99-28171-458.mis2, potential complement <220>
<221> primer bind c222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 494..514 <223> downstream amplification primer, complement <220>
<221> mist binding <222> 445..469 <223> 99-28171-458 potential probe <400> 14 ggaaggttgg ggattgtgaa rgagggccca ggagctctat agcataccaa acactccatt 60 tgtgtacttt gcagctcttt tcccttttgt catcttcact gtatgcttag ggcaccataa 120 tttcaattat gcaatttcct ctaaaatctc ccacaaacct cttctggagt ctaagtaact 180 tgtcatcgca tttctgtcat gtgatagatg tgtttctaaa aaattggatt ccactccttt 240 tcttgaataa tcacatgact tcagattatt tagcatttta tgacataagc agtttgatac 300 ctgctttggc ccagcagttt tgggatgggg tagatgttaa ttatctccat atgcaggtaa 360 tacagtagaa tcttaggtag ttcatggttc acacagttaa atgactctct caaggggttg 420 acaagggatt tgtactcaag ctttgattcc aaatctrctg ttatttccta ctgggaaatg 480 ctttttaaag ttactttaca gcagaactct ttgt 514 <210> 15 <211> 550 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 395 <223> 99-28173-395 : polymorphic base C or T
<220>
<221> mist binding <222> 375.-.394 <223> 99-28173-395.misl, potential <220>
<221> mist binding <222> 396..414 <223> 99-28173-395.mis2, complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> S32..550 <223> downstream amplification primer, complement <220>
<221> mist binding <222> 383..407 <223> 99-28173-395 potential probe <400> 15 agagccaatg agatacacgt tcaactagga cagaaatact atcttaacaa atgtcattcc 60 cagaaataat caacacaggt gaaagaatta gagatgggga aaagtcaaaa aatgagagag 120 ggaaaggttg cagtgtggaa aatagcattt aaattctaac caaactagaa tcagacatat 180 aggaaaatct aaaataaaat ctgggagcct tgaagccgga ggaagaatta aggaaatctg 240 tgttcgggag ggaaaagcag aaggggcctt caagtacaac tgaattaaat caagatggac 300 tgccagttct agaaaaagac aagtttctcc attccccgta aatgctcagg agtaaacccc 360 agtagtcaca gctgggccag tcccaactta tactytgggc aatcgaaact catttgccaa 420 gcagagactt ggaccatact gcctagaaca tgcctaccat tctttcttta ttcttttgaa 480 agagtactgc cactcaagtg acttttgcaa ttgagagtct gattatcatc tctatgctga 540 aaatccttca 550 <210> 16 <211> 466 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 113 <223> 99-32177-I13 : polymorphic base C or T
<220>
<221> misc binding <222> 93..112 <223> 99-32177-113.misl, potential <220>
<221> misc_binding <222> 114. 132 <223> 99-32177-113.mis2, complement <220> , <221> primer bind <222> 1..19 <223> upstream amplification primer <220>
<221> primer bind <222> 446..466 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 101. 125 <223> 99-32177-113 potential probe <400> 16 cccagaaata gaaaccaact atcaggcaaa gccttcgtga ggcaatttgg ggttgtaaca 60 ctacattacc tacaaatcaa tggatatttt aggagaaatt aaaaagggat gaygtactct 120 gttcaaaaaa aaggtttgaa acccagcaga ttcctgtggg ctttgcatcc ccagccctag 180 gcatctctgt ttaaagaggc agcttagtga taagggagga ggagagaatt tctaagaagg 240 ggtagaagtg tagacttata tttatatata tttttaaaaa gtttttattg tttagcagct 300 tcagtaaggt ataatttcaa gatcataaaa ttacccaggg taagtgggta tagataagta 360 tataggtcat ttattttgag tgaattttta gagttttgta tctatcaaca caattcagtt 420 ttagaacatt ttttaatatc tcttacttca ttttgggttg ctgtaa 466 <210> 17 <211> 449 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 192 <223> 99-32181-192 : polymorphic base C or T
<220>
<221> misc binding <222>172..191 <223>99-32181-192.misl, potential <220>

<221>misc binding <222>193..212 <223>99-32181-192.mis2, potential complement <220>

<221>primer bind <222>1..18 <223>upstream amplification primer <220>

<221>primer bind <222>432..449 <223>downstream amplification primer, complement <220>

<221>misc binding <222>_ 180. 204 <223>99-32181-192 potential probe <400>17 gtcagacatt actcctaacc 60 cctcatggsc aaacctgata ccactccttt cttgctgtgt tctatcagcc gtgtgcccac 120 tccctgtcct catcacccag gagtaggggt gggggtgtga agagtggtca ccaacaatgg 180 tggggattaa atgagatgaa tcatgcatag cccttggcac gattgctact gctgacaccc 240 gycagttcct atgctcctct acttgggtat tgccttcatg atggctttct gtgaaaaaaa 300 ttctgggatg tgtggccttc atcaaaaatg tgtttattta aaaaaaggac ctccatagca 360 cctgagattt tcatttaatt ttgcctatgt tctcacactg cagcactgat cttcacatca 420 gatactaaaa agctaactcc tggatctaag ctgctaagac ctggcagttt 449 gctaatgtcg gtgttctgc <210>18 <211>458 <212>DNA

<213>Homo Sapiens <220>

<221>allele <222>257 <223>99-32193-258 : polymorphic base G or T

<220>

<221>misc binding <222>_ 238. 256 <223>99-32193-258.mis1 <220>

<221>misc binding <222>_ 258. 277 <223>99-32193-258.mis2, potential complement <220>

<221>primer bind <222>1..19 <223>upstream amplification primer <220>

<221>primer bind <222>438..458 <223>downstream amplification primer, complement <220>
<221> misc binding <222> 245..269 <223> 99-32193-258 potential probe <400> 18 gaaggagatg agattagaga agtgttgcaa attatattgg gattcagacc aggtaaagag 60 tttggacttt attctaagtg cggcagaacc actggagact ttgaaacata gggtgaaatg 120 gtctggcttt taattttaat ggttcattgt ggttactttg tggagaatga aatggaggag 180 ggtgagaatg aaaacttgga gaccaatggg aaggcttcta cgttagtcaa ggcaagaggt 240 aatcgtagct tggactkggt tggagtagtg gagacagaga caactggaga aattccggat 300 ctgtcttgga ggtgtatcgg caggccttgc tgatggactg gatgtaggcg ctgagggaga 360 caggcatgaa ggatgactct tgtgcttttg gctcaagcaa ttcagtagat ggtgatactg 420 tttaccaaga catgatggta gtagaattgg tggtaaaa 458 <210> 19 <211> 450 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 90 <223> 99-28722-90 : polymorphic base C or T
<220>
<221> misc_binding <222> 71..89 <223> 99-28722-90.mis1 <220>

<221> misc_binding <222> 91..110 <223> 99-28722-90.mis2, potentialcomplement <220>

<221> primer bind <222> 1..17 <223> upstream amplification primer <220>

<221> primer bind <222> 429..449 <223> downstream amplificationimer, ement pr compl <220>

<221> misc binding <222> 78..102 <223> 99-28722-90 potential probe <400> 19 atacgataca etctgccaag tccattttgaattccatggcctgaatcatt aactttcaaa60 gccaaagcat ttaaaagata aaattatccycttggcactcctcaaactgt gctcttgacc120 tcttctgtta ggctacagtt ttgtttctggctgtgcaaatgtcacataat gccactgcac180 ccggcagtat cttcttcata gcaacagatcataataaaagtccctcggag gctgtttgtg240 tttcacatac acatggaatg aaagaaaaatgcagtgtgctatataaagcg agagaaatgc300 ataagcttca tctttcattt gcagccaattggttttaataagcttttatg ctgagaggtg360 aataattagc atatgttctt aattaagattgttctagagcagtagagtgc tccaggtcgt420 taaaaatggt tttgtgtctc aatgtcttaa 450 <210> 20 <211> 452 <212> DNA

<213> Homo Sapiens <220>
<221> allele <222> 351 <223> 99-28730-351 : po3ymorphic base A or G
<220>
<221> misc_binding <222> 332. 350 <223> 99-28730-351.mis1 <220>
<221> misc binding <222> 352..370 <223> 99-28730-351.mis2, complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 435..451 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 339. 363 <223> 99-28730-351 potential probe <400> 20 attcttggta tcctacacga aatctattta tatccaacat aactaatgtt ctgaggaacc 60 cactttatga aacaggattt tgtactgcta ttagtggtga gtcacaataa gaagggaaag 120 atacccaagc tcgcattgtg agaggtcata cagagatggg tccaaatgga atcaggagtt. 180 gaaaggcata gagatgtccc tagaaactgg aggagaccac caagttgttc taaagccagg 240 agaagaatct aacattggcc tgaaagctaa agcctacctg tgggtacaaa ttggacaaag 300 gatactttgc tggacagtca gaaattcagc tgtggagcac caggctggca rtgagctctg 360 ccctcaggca cgccacatag gcagcaccag gactgaggac atctgaggct gagaacggat 420 gtaagaacca tcttggtgtt gtgagatgaa tt 452 <230> 22 <211> 455 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 407 <223> 99-32306-409 : polymorphic base G or C
<220>
<221> misc_binding <222> 387. 406 <223> 99-32306-409.misl, potential <220>
<221> misc_binding <222> 408..427 <223> 99-32306-409.mis2, potential complement <220>

<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 437..454 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 395. 419 <223> 99-32306-409 potential probe <220>
<221> misc_feature <222> 162 <223> n=a, g, c or t <400> 21 catttgcacc tgcactcccc tgaccttgca ctgtggtaga ccagttgctc tctaagtctg 60 ctgctcagtt gtcatctgag atagtccttt attgtcttga ggtggggcta tgtctccttt 120 tgtctaggat ttttattggt tttactgcag aatatcatca angatttatc tttttcactg 180 aagatgcata aagggtaaac attctgaggc ctaggatgac tgaaaatgtg tttatttggc 240 atcgacactc agtataattt ttttttacca ggtgtagaat tctaagttda waataatttc 300 ctctgtggac tttgaagtta ctgcctcatt gtttccagtg ttactaatga gaaatctsat~ 360 gcgagtttga ctgtgatttc tttacagatg ccctgttttg ttccttstct tctaaaacat 420 cacaatgatg catttagggg tgggtgattt tttta 455 <210> 22 <211> 527 <212> DNA
<2I3> Homo Sapiens~
<220>
<221> allele <222> 246 <223> 99-27088-246 : polymorphic base A or G
<220>
<221> mist binding <222> 226..245 <223> 99-27088-246.misl, potential <220>
<221> misc_binding <222> 247. 266 <223> 99-27088-246.mis2, potential complement <220>
<221> primer bind <222> 1..19 <223> upstream amplification primer <220>
<221> primer bind <222> 510..527 <223> downstream amplification primer, complement <220>
<221> miec binding <222> 234..258 <223> 99-27088-246 potential probe <400>

gtttttcttagcttgctggtgtttttaactcaataaaatgtcaattaact tcgtgagctt60 tcctttaactctatataatctttgcgtttgaatggctgccaatcaaacgc aaagatagat120 gttttctttgaatatgggccaatttccgtgtatgcaccttgttgtcagga tcagctagat180 tatggtgtagtaacaatgtcgatatctcaatggcttgacaaaagtttggt ttccgctcat240 gctacrtgttctgtgagatcagtggggagctcggagtttccacagttacc agcaaacgga300 gagaattctggagggcctcgaacaggcaagcaaatgatctagcccggaag tgatgtttgt360 cactttccttcacatctcattggtctgaactggtcacatgaccccaggca accccagagg420 gccaggaaattcgggctccttgtgcttgccaggaaaggagagtggccctg ttgaaaccgc480 ctgtgactgagacagtgaaagaaatttgacctaaccaactccatctt 527 <210>

<211>

<212>
DNA

<213> Sapiens Homo <220>

<221>
allele <222>

<223> base A
99-27090-203 or G
: polymorphic <220>

<221>
misc binding _ 203 <222>
185.

<223>
99-27090-203.mis1 <220>

<221> misc binding <222> 205..224 <223> 99-27090-203.mis2, potential complement <220>

<221> primer bind <222> 7...20 <223> upstream amplification primer <220>

<221> primer bind <222> 431..451 <223> downstream amplification primer, complement <220>

<221> misc binding .

<222> 192..

<223> 99-27090-203 potential probe <400> 23 gaactctcct ctaatagaac ttccaagttg gccccgcaggcactattttg gtgcagagga60 acccgtcaag cttgacttta aatctggetc tgccactaaatcacccaggg cctttcctct120 ttgggccccc gtttccctgt ctgtaaaatg agaggattgaacagggcagt ccctagagtc180 tgttcagaag ttctcagact gggrcttggg ttcttgcacttttcattttg tcactgttga240 tgtcatcaca cacacaccca cgcacagagt ggagtgaggatttcggctgc acagcaggat300 ggcccagatg ataggaggag gcagggggcg atcactggctgggaggatgg ctgggaaaag360 aggaggaagg ggaaaggcac gcgaggtcac aaatgcaccaaaaggcattt cctggcmtag420 ccctgtgcct cccttctaaa gagccatcac a 451 <210> 24 <211> 473 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 221 <223> 99-27091-220 : polymorphic base A or G
<220>
<221> misc_binding <222> 201. 220 <223> 99-27091-220.misl, potential <220>
<221> misc_binding <222> 222. 241 <223> 99-27091-220.mis2, potential complement <220>
<221> primer bind <222> 1..20 <223> upstream amplification primer <220>
<221> primer_,bind <222> 455..473 <2~3> downstream amplification primer, complement <220>
<221> misc binding <222> 209..233 <223> 99-27091-220 potential probe <400> 24 atcagcggat ggtgaagagg agatcagcgg atggtgggag gaaaaatgca ggaaatctct 60 ggacttttca tggaagtatg attcaggaat aaggcagaag ccctcacaaa ccttccacag 120 agcaagaggt ggcacaggca cagattctgc tacagagcag acctttccag agaggaaagg 180 ttggtttggg aattttaaga agcatttttc tttgcataac rcaacaccag tcctctgtgt 240 ttagaaaatg cctgtgtgaa ccatcacatt caagagaggg acacaagtgt cagggttcta 300 ggcagccaag ggaagactag ccctttgcct ggaatttggc ttcattttct gacgaatcaa 360 gatttgctct gctcctctgt gcacgccagg acattaagat gcgagaataa gaacttatag 420 cctgtatatt tgccatctaa ttagtgtctt gggtcctaag tgctttgtgc cga 473 <210> 25 <2II> 472 ' <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 145 <223> 99-27093-145 : polymorphic base C or T
<220>
<221> misc_binding <222> 125. 144 <223> 99-27093-145.misl, potential <220>
<221> misc binding <222> 146..165 <223> 99-27093-145.mis2, potential complement <220>
<221> primer bind <222> 1..20 <223> upstream amplification primer <220>

<221> primer bind <222> 453..472 <223> downstream amplification primer, complement <220> '' binding <221> misc _ <222> 133. 157 <223> 99-27093-145 potential probe <400> 25 aggctaggag atgaggagtg gggctgggctgcctctgcacatcatcaaag ccaacactca60 gtctaatcca aatcttgcta gagcatagaacataaggtagaatgagtctt taagcaactg120 ggagtcatct cgaggtaaac agaaytccaagagtaacgaaggcccagagt gaatttattt180 tgagagagtt tcctgttgga gtagcagacactctgcagtagtgtttttct ctctcctggg240 tgggactgcc ctgcctatat gcacttaaggcatagagtttcctgttcttg cctcttctca300 gagccttgca ttgaaactca aatgtattctcagaaatttctctccacaca atgacatatc360 gcctctgtgc ttttactctc tttgtctttctctttctctcaaccattgtt .ttccacccat420 cctctttttc ctaaacttct taagattgttggccatttccctttctccct cc 472 <210> 26.

<211> 455 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 406 <223> 99-27094-406 : polymorphicbase C T
or <220>

binding <221> misc _ <222> 387. 405 <223> 99-27094-406.mis1 <220>
<221> misc binding <222> 407..426 <223> 99-27094-406.mis2, potential complement <220>
<221> primer bind <222> 1..20 <223> upstream amplification primer <220>
<221> primer bind <222> 436..4-55 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 394. 418 <223> 99-27094-406 potential probe <400> 26 ttataggtcc caagaagcag ggcctagaaa ccaagagctt gacacgcagt caaactccaa 60 agcagtgtgt gagtgaagga aggaaagacg ggtgttgaaa agcaggtgac tttgagaagg 120 gaggggtccc tggcagcacc tcccttcctc cccgtttcta ggctctaggg tggggctgaa 180 tgatcatgag gcacaaaggt gggtgacatg caagtgctga gaagcactga gctcacaacg 240 gccctcatca tcttctcaga gccaccaagg agctactggc caccaaggag ctactccata 300 ggccttcctg ttggaattac agaacccact tgaaaccaga gatcaagtcc agccctatcc 360 accaggcatc ccaggagaag ccaagaccct atgcccagtt ccgccyggcc accaaggccc 420 ttctgaagga gcaccctcat tggggaacct ctcca 455 <210> 27 <211> 450 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 410 <223> 99-27096-410 : polymorphic base A or G
<220>
<221> misc_binding <222> 390. 409 <223> 99-27096-410.misl, potential <220>
<221> misc binding <222> 411..430 <223> 99-27096-410.mis2, potential complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 432..450 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 398. 422 <223> 99-2709.6-410 potential probe <400> 27 gagtggagag atttgtagct cagctgcaag ttttatttgg agccttgggg ctgccaggct 60 gtgcacggaa gtgaggcatt agccagtgag tgaacctcgt gctctgccag cttcagcttc 120 agtgccgttt tgattttctc tactagttgg aagatagtaa atcacatgaa gtcttgaaaa 180 cttggttctg aaaggagcgc cagtggctgg gactggtgat ggagtggagg agcaagaggc 240 atctgagaaa ggccaaaagc actttggttt gatttcagag aagatgacat gttcagttca 300 ccccatttac catatgcttc gactgtagtt cccactgttt cagggtgcta gttgttggtg 360 agaagtggag gaagccaaga accctccccg ggaaaatggt tttcatcacr cacaccaact 420 gcatttattt gcaaatcttc acactgcccg 450 <210> 28 <211> 504 <212> DNA , <213> Homo Sapiens <220>
<221> allele <222> 83 <223> 99-27097-83 : polymorphic base C or T
<220>
<221> misc_binding <222> 63..82 <223> 99-27097-83.misl, potential <220>
<221> misc_binding <222> 84..103 <223> 99-27097-83.mis2, potential complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 486..504 <223> downstream amplification primer, complement <220>
<221> mist binding <222> 71..95 <223> 99-27097-83 potential probe <220>
<221> misc_feature <222> 213 <223> n=a, g, c or t <400> 28 gttcttttca ctacctcctg cttaattttt aatttctaag attagaccct tcatctatcc 60 atgacacctg cctgtcatcc ccygaaaaaa ggtgaacgcc gttcagaaat ttttctagcc 120 tgagctcact cccagttcac ttatttttgc tttgtcatgg ctgcccagtc cccacttgta 180 gaccaggaat aggtcatggc tgcggggact acnacctgtc gctgctgcaa gggccggcct 240 ctgtttccgg ggctgagtgg gggccagacc tgccaggagc accatcttct gtgggtcctg 300 cctggatgtc acatcccggc cccaagaagt cactgcaaac cttcgtatta ttgagcttca 360 catcctagaa tttgctgtca ctgtggctgc tgcatgaagt tgtcctgaga gaaacgggca 420 ttgtcattaa cagggaaatt gatggtctgg gggaaaagtc atcctcattc tcttgcagat 480 ctatgggtga ttgagactgg ctga 504 <210> 29 <211> 421 <212> DNA
<213> Iiomo Sapiens <220>
<221> allele <222> 162 <223> 99-27098-162 : polymorphic base C or T
<220>
<221> misc_binding <222> 142. 161 <223> 99-27098-162.misl, potential <220>
<221> misc_binding <222> 163. 182 <223> 99-27098-162.mis2, potential complement <220>
<221> primer bind <222> 1..19 -<223> upstream amplification primer <220>
<221> primer bind <222> 404..421 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 150. 174 <223> 99-27098-162 potential probe <400>

acttctgcccagtttggtgcaggggagctgggtagttgccgacttttcctatcttgatcc 60 ctactcagtgtaacaatttatctgtacaactgattccatcaccaggatctttagacccct 120 ctggtcattcagccaatcacaagcactcatccacaggacacygccgatgatgccatttac 180 tgagcagttactatgtgcttggccctagtgagtaccgggttagcttgtgtgaaccccatg 240 gcaacccgtgagacaggtaccatcatactccaagttgtggatgacaaaaaactctccaag 300 cagctaaacaatatggcttaggtctcacagtgagcagggagctgggatttgtgcccagga 360 ggcccgatcagagcctacctccttaaccattaggccaaactgcctccacatgcagaacac 420 t 421 <210> 30 <211> 468 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 4B
<223> 99-27550-48 : polymorphic base A or G
<220>
<221> misc_binding <222> 28..47 <223> 99-27550-48.misl, potential <220>
<221> misc_binding <222> 49..67 <223> 99-27550-48.rnis2, complement <220>
<221> primer bind <222> 1..19 <223> upstream amplification primer <220>
<221> primer bind <222> 448..468 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 36..60 <223> 99-27550-48 potential probe <400> 30 tgtgtgtgtg gggtatgtgt gaacattttt catgcttgat gtgagccrga agaaaaatga 60 gcttctctat ttgataagtg tggacctgcc cacagcacta aatttggttc tgccgtcacc 120 ggcgccatga agcagcagcc tggtttagag gcttgccttt ggtttcaaat aatttctcca 180 ggctcatgtt acatatgacc cattcacaga ggctggaggg catggcttct ccagtcctta 240 gcactaaaga cgtgtctttt ggctcctgca cgactagcac aggcagtaga accagatggg 300 ggatgctctg aggttgcaga ggcaggaagg caagcgggag agagcttggg cctggacaga 360 gggatgagct ggctccctcc ccagctgtga aatctctgag tctcagtttg cttctctgca 420 aaatgaggat aataatcccc acctcgggac tgaggattaa cgaggcaa 468 <210> 31 <211> 452 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 335 <223> 99-27558-335 : polymorphic base C or T
<220>
<221> misc_binding <222> 316. 334 <223> 99-27558-335.mis1 <220>
<221> mist binding <222> 336..355 <223> 99-27558-335.mis2, potential complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 432..452 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 323. 347 <223> 99-27558-335 potential probe <400> 31 gtcaaatcaa cactcgtcta cattcaaatt tcacattttt ccccctctaa gataacagta 60 taattgagaa ctgacaggga cctaatgaca gtatggtccc ctcacactga atggtcacat 120 ttgcctaaat tgaaataacg tatgctagaa acaatcttaa gcagatctgt cattttaact 180 atatgtgatg tagagttgaa tgttcattcc agataattta gtcaatgtag gtaactaatg 240 gctcacacta attcaggcca agaaaatgca ttccctctct ttcttcctgt ccctttctct 300 tgctgaaaga gaaatctcat ggccgcatat gttayacaat catgcccact tatgtaggat 360 cacagaaggc agaatagcag agaagaaaga aaactggaga gttgggtcct gatcctagcc 420 atcttgtatg accttagaca attcattacc tt 452 <210> 32 <2I1> 465 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 106 <223> 99-27561-106 : polymorphic base A or G
<220>
<221> mist binding <222> 87..105 <223> 99-27561-106.mis1 <220>
<221> mist binding <222> 107..126 <223> 99-27561-106.mis2, potential complement <220>
<221> primer bind <222> 1..19 <223> upstream amplification primer <220>
<221> primer bind <222> 446..4'65 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 94..118 <223> 99-27561-106 potential probe <400> 32 cagtcactca aacaatgtca caaagaaccc tttgacagga atgtatcctg tgttgactct 60 actttgctct gagtagtctt tccccaggtg atgataaaaa tggtcrtcat cgccaggctt 120 gtgtcctgtt tagtaggaat atacaagaag agctcagtaa atgctggccc caccactaag 180 caaaaacaaa acttttgttg ttgttattgt tgttttaaat aacagcttag acctttcttc 240 tttccttgtt attctctttc atctgtaatc cagttttcta cttctgaagt atagaatgtt 300 ctgatgattt attcttcatt acccacaact tgcacatgtt tatttaaaaa tgccaggatt 360 gcctggccgt tgtgtgctgt taacctttgt ttgctgttag tggatccctg aagttcaggc 420 tcccagggga gcagataatg ggtatccagt tcctgcaata tccac 465 <210> 33 <211> 470 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 364 <223> 99-27562-366 : polymorphic base G or T
<220>
<221> misc_binding <222> 344. 363 <223> 99-27562-366.misl, potential <220>
<221> miac_binding <222> 365. 384 <223> 99-27562-366.mis2, potential complement <220>
<221> primer bind <222> 1..19 <223> upstream amplification primer <220>
<221> primer bind <222> 450..470 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 352..376 <223> 99-27562-366 potential probe <400> 33 ttcctccaccaccactttcctcatcaccgtgttcagagacccccaaagsc ccctyamamt60 cccagaaacacccccctggccactcctaacttgccatgcccaggagttag gtgcttccac120 tagtgacatggagctggcgtttggggggcacctcagcaggtgacgggaag agaagacccc180 agcctcaccagctgggctgcagcagggagaggagtcctcatgttccagca gggactctca240 gctgttttcctgtaaaaccatggttctcaactgggggccactgagatgtc tagagagatg300 tttttgttttcacaactcggggagggtgctactgacatcttgtgggtaga ggccaggaat360 gctkttaaacatcctacaaggaaggcacaggacagtctcctacatcaaaa tatgacccag420 ccccaatgtcaccactgctggggttgacactggcactgctatcttaatta 470 <210>

<21I>

<212>
DNA

<213> Sapiens Iiomo <220>

<221> le alle <222>

<223> 1-738 :
16-3 polymorphic base C
or G

<220>

<221> binding misc <222> .737 715.

<223> 1-738.mis1 <220>

<221> misc binding _ <222> 739. 761 <223> 16-31-738.mis2,complement <220>

<221> primer bind <222> 1..25 c223> upstream amplification primer <220>

c221> primer bind <222> 975..1003 c223> downstream amplification primer, complement c220>

c221> misc binding _ c222> 726. 750 <223> i6-31-738 potential probe <400> 34 ccactttgga taaatgccctctaactagcagcttttaactgcctttgcga tgggaggtct60 accacccttc ctttacccaaagatgaatttcggatcattttctgtacaat ttttaaagga120 cgtttgaata atatttctttctttatcattgcggacgctcccaaatctca gcggaggtgt180 agcgcataag ggcagttgaaggagatatagatcctatagatcctgtataa aagggggtct240 ggaattctgc atttcccgttcgctagcattcgcgaaactcttgagacagc gtacgcttcc300 tatggcatca gttggaatttaagggcaagggagaagggtgctcggcgtgc ggccgcggcg360 taccggagct gcactttgcagggagaagtggctgcgtaatccggagcaca gtcagtatgg420 tgctgtgtgc ttgttgttttgttttgttttccacttttctcccccttttc ccgccacacc480 actattttgg aaagtttggccactttggataaatgccctctaactagcag cttttaactg540 cctttgcgat gggaggtctaccacccttcctttacccaaagatgaatttc ggatcatttt600 ctgtacaatt tttaaaggacgtttgaataatatttctttctttatcattg cggacgctcc660 caaatctcag ccggaggtgtagcgcataagggcagttgaaggagatatag atcctaatag720 atcctgtata aaaggggstctggaaattcgtgcatttcccgttcgctagc attcgcgaaa780 ctcttgagac aggctacgcttcctatggcatcagttggaattttaagggc aagggagaag840 gggacgaagc ttcttttggtggcatccttactctgctactgaattttagg tgcgtggctt900 tgcctactca atttaaaaagaccaggtttaaataataatggtttatggca ccatcagttt960 taattattta ttatgacataggagttaggaaaacttttgatag 1003 <210> 35 <2I1> 455 <212> DNA
<213> Homo.Sapiens <220>
<221> allele <222> 300 <223> 99-27110-301 : polymorphic base G or C
<220>
<221> misc_binding <222> 281. 299 <223> 99-27110-301.mis1 <220>
<221> misc binding <222> 301..319 <223> 99-27110-301.mis2, complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 438..455 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 288..312 <223> 99-27110-301 potential probe <400> 35 ttcacattgg gtggcagctg gtcgaaacat tcctgtcagt gactgcagga cagtaacctt 60 cagacctcga atgcccccta attttctgaa atgaagttac agttcctttt ctgttcaact 120 agcaagctaa agttcagccc tcttacctga ttccacactg atcatctgga aggaaggtag 180 gattcaagga gaactctttg agtggaagag cagtcagaga tgtaattctg.cgcctgttct 240 cttacagcaa aaccaagaac ttttgctcta agagagtgga ctttgggagt gaactttgts 300 agatgattag atggtgatgt cctttcttgt taaaggagga aatccatgta ggagcctcag 360 gatcgcacag gctgaggact gagtgttaaa catggcaggc cttccttcat ggggcttgag 420 ggatttcctg cagtgccctt cctcctctcc ctgac 455 <210> 36 <211> 546 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 400 <223> 99-27563-400 : polymorphic base A or G
<220>
<221> misc binding <222> 381..399 <223> 99-27563-400.mis1 <220>
<221> misc binding <222> 401..420 ,, <223> 99-27563-400.mis2, potential complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 526..546 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 388. 412 <223> 99-27563-400 potential probe <400> 36 taaccacact gaaacctctt cggttgtctt gaaacctttc tactttttct gtactttttg 60 ttttgttctt ggtctcccgc ttggggcatt tgtgggactc cagcacgttt tctggcttct 120 gcttcatcct gctccatcgg ggaatgacac actgcggtgt ctgcagctcc tggaaggtgt 180 catttgacaa cacatgtggg agaggaggtc cttggagtgc tgcagctttg ggaaagctgc 240 ctcgtttccc ttttcctcta gaagcagaac cagctctacg agagtgagac tgggaacttg 300 atggctcaga gagcatcttt tcctcccatt ttagaaaatc agattttctc ctgtgggaaa 360 aaaaaattcc atgcactctc tctctgttaa agatcagctr ttcccttctg atcttggaaa 420 gaggttctgc actcctggaa ccggtcacag gaacgcacag atcatggcag gatgcgctgg 480 gacggcccat cttggcaagg ttcagtctga atggcatgga gaccgggaga tagaggggtt 540 ttagat 546 <210> 37 <211> 513 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 443 <223> 99-27573-443 : polymorphic base G or T
<220>
<221> misc binding .
<222> 423..442 <223> 99-27573-443.misl, potential <220>
<221> misc_binding <222> 444. 462 <223> 99-27573-443.mis2, complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 496..513 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 431..455 <223> 99-27573-443 potential probe <400>

gtctcgtttcattcagtgacattttgaacacacacgtgttccctgtctgc agcacccagg60 tgctcttcacctaagataccccgtcttctgctaaaccagtacaccagttt ccacgagcag120 tttcccgaggcttctgcactcctcagcatgctctcagattgtttcccctg ccggagaact180 agcaccgtgttcttcagtaccagcatggtctcctggccagcccctaggtg caatcctcca240 acacggtgacactcagcaacctagggccaagtttacccacttgtctccct atacacaatg300 ctcctgcacctgctcacctaccaggggccgtcccgccccagcagcctacc ctgtctgcca360 cagctctgcttcctggcattcccacctctgcctcaagctttgcctttcct ctcaagctcc420 ccgccctgctctaatcttgcccktccttggctcagctccagttccacctc ccccaatact480 ccccctgtggcctctctaacccatacaccttcc 513 <210>

<211>

<212>
DNA

<213> Sapiens Homo <220>

<221>
allele <222>

<223> base A
99-28732-133 or G
. polymorphic <220>

<221>
misc binding <222> _ 114. 132 <223> s1 99-28732-133.mi <220>
<221> misc_binding <222> 134. 153 <223> 99-28732-133.mis2, potential complement <220>
<221> primer bind <222> 1..19 -<223> upstream amplification primer <220>
<221> primer bind <222> 391..410 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 121. 145 <223> 99-28732-133 potential probe <400> 38 ctgttgttgt tcccccctca cacgcataaa ccagtgtacg tgaatcctaa cttgccaata 60 cctcagagat aggaaaatat attttgatgt acagacgctt tatgggcttg tgctggaagg 120 tcacgtgcct tartggtcat gagatcctgg tgcaaagtgg atagaaagtg cttctttgta 180 tgcagcgtcc tccccttcgt agatggccag ttcccccgaa tgtctttaat atctgaactt 240 gagaatgagg atgttgattt ctaattctag ccccaaccta gattgtctat ggctcttcag 300 ttatcctgga aaatcaaaat atattttact atcttgaagt attggcaagt taggattcat 360 aaacacttgg atgaccagcc acaaggcaat gtggcattgt ggttaagagg c 411 <210> 39 <211> 457 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 56 <223> 99-28735-56 : polymorphic base C or T
<220>
<221> misc_binding <222> 36..55 <223> 99-28735-56.misl, potential <220>
<221> misc_binding <222> 57..76 <223> 99-28735-56.mis2, potential complement <220>
<221> primer bind <222> 1..19 <223> upstream amplification primer <220>
<221> primer bind <222> 438..456 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 44..68 <223> 99-28735-56 potential probe <400> 39 ttgtcctgat taccatttct aagactaaag aatctttacg tggtgaaagt cctagycagc 60 catcattcgg cacaacagtg gcttgtcaaa agggtatgta gcaggtcata ccagcctcag 120 gagggtagag caaagcaaaa aaggaaatct tgccatgtca tgtttcaaag ctcttgtgaa 180 tcttgagatc tcattagaaa tctgtcacag ttttaataga gtcccaccaa gatgtgctct 240 gcctgctctt ttgcaggttg gtcaggatag gaagcagggc ctccccagtg ccagttcctc 300 ggggaacaat tcacgagaat ctaaggagtt gtctcccagc agtgccagga aagagtggct 360 gccaaaatgt tactagtaat taaggactag gcacctgagg gcagcaacta agcacatact 420 agttattata acatccagta gaacaaatga aactcct 457 <210> 40 <211> 453 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 399 <223> 99-28736-399 : polymorphic base C or T
<220>
<221> misc_binding <222> 379. 398 <223> 99-28736-399.misl, potential <220>
<221> mist binding <222> 400..418 <223> 99-28736-399.mis2, complement <220>
<221> primer bind <222> 1..20 <223> upstream amplification primer <220>
<221> primer bind <222> 434..452 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 387. 411 <223> 99-28736-399 potential probe <400> 40 gtttcttatt actgattctg aacatctgtc acaaagcaga ttttgttcag gacattatga 60 acaactgcat cattcattac cgggtgaaat aagtgtaaca ccaccaggcc actataccac 120 cagtgacatt catttcccac aaaacatcaa cactgaaaca tacactacac atgcacacaa 180 aatggcatga atacaatgat tattcaatgt atagtctaaa tatttcttat ccttttaatc ~ 240 cacttgtatg aaattccttt tctcaagata gatgaggggt aaaagtgaca ttttctaacc 300 ttctcctcta cttcgaaatt ctgtgaactt cctctaatca gaactaagta gcggtgcagt 360 ttctctttaa tgataaatga tttgttggtt ttttgtgtyc attgcttaga agcagtgagt 420 gttaaggaca acaccttaaa agtgttagct ccc 453 <210> 41 <211> 458 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 319 <223> 99-28738-319 : polymorphic base C or T
<220>
<221> misc_binding <222> 299. 318 <223> 99-28738-319.misl, potential <220>
<221> misc_binding <222> 320. 338 <223> 99-28738-319.mis2, complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 441..457 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 307. 331 <223> 99-28738-319 potential probe <400> 41 ggagagacac actgagacat tctcttctag tccagactat gagagcatgt aacacatata 60 acatgagacc cagcacctag caccgtgtca gacacatgat tatctgtgta atgactgagt 120 aagcaaattc agagatgtgc tctcaaagcg atctggcagc aagttacttc cttcatgcct 180 tcactgacct tgactctgac attgttcttc ataccaggat ttttagagac ttctcacttc 240 atccaaacac cccagctggc agtgctacta gtgtgcagcc accatcaggg aaaagctttg 300 gattctatgc aaaacaggyc ctcagggttg taacaatgtg ggJgcctgag tggcaagggg 360 cccagggctg aagtcagagc cctagaggag actcctggct acctagatgc atctgggaaa 420 ttaacccctg ggccttgctc gctgtwacct gcaatacg 458 <210> 42 <211> 509 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 364 <223> 99-28739-364 . polymorphic base C or T
<220>
<221> misc_binding <222> 345. 363 <223> 99-28739-364.mis1 <220>
<221> misc_binding <222> 365. 384 <223> 99-28739-364.mis2, potential complement <220>
<221> primer bind <222> 1..17 -<223> upstream amplification primer <220>
<221> primer bind <222> 489..508 <223> downstream amplification primer, complement <220>
<221> mist binding <222> 352..376 <223> 99-28739-364 potential probe <400> 42 ctcctcctcc aaaacacacg gagacactgg tatttgtgtg cacatgtgtg tacatatgta 60 caaatgtgtg actatgtatg tgtacgtgtg tacacgcaca ctttcttttt aggaagactc 120 caaatcatct cgggacttta gacctggaga acgtaagtct cctgggtcag acgcctacca 180 ggctgtcctc ttttatccaa actggcagat ctgcattggc tttaggcact gaccctcatt 240 cacatggctg tgtgcccaga gcaggtatcc tataccccgt gtgattctca ttggtctaaa 300 tccttgcaaa tgatggatgt agggtaagca tgtgactcag ttctgcatac tgggatgtga 360 ggaygggtaa actaggaaga aattcctgga aaagttttct cattcttaaa ggaacacaag 420 gatgagacac ctccttccgc cagagtgtgg ccatgataca tggaactgtg gtagtcatct 480 cgtcccgcca gggaaacaag acagaggcc 509 <210> 43 <211> 549 <212> DNA
<213> Homo Sapiens <220>
<221> allele ' <222> 185 <223> 99-27875-185 : polymorphic base C or T
<220>
<221> mist binding <222> 165..184 <223> 99-27875-185.misl, potential <220>
<221> misc binding <222> 186..204 <223> 99-27875-185.mis2, complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 531..549 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 173..197 <223> 99-27875-185 potential probe <400> 43 taagggtaaa ggagagagat ttaagattaa tatagtaaaa accctataaa cctaacttta 60 agttaactat taagtatcta tattaactca tgaaaagttt atcttttaaa aaatatcaac 120 ttcctagctc agatcactga caaggtttat aattagtgat caataccatc cccactaata 180 agtaycaagt accagggctc cttggagaaa tgtctgattc caagtctggg acaggaaatg 240 tataagatga gatggcaata tcttgtcata ttaaaggaag ttttcagaga ctacaagggc 300 tgtgtcaaaa ggactcagca gagaactcct agtcaccaaa gactggacaa tttaaccacc 360 aataagataa ctgcaactga ctgaatatca aatatttgaa tctaaagttc acaacagtag 420 gaggaaaaaa cgaaaaggca ggcaggaact cgtgcatttc tgaaggatgt tagggaacca 480 actaatggaa aacaggttta aaaagacaag gggtgggaga atggatgaag macttattct 540 cacctttct 549 <210> 44 <211> 462 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 176 <223> 99-27880-176 : polymorphic base C or T
<220>
<221> misc_binding <222> 156. 175 <223> 99-27880-176.misl, potential <220>
<221> misc binding <222> 177..195 <223> 99-27880-176.mis2, complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 444..4-62 <223> downstream amplification primer, complement <220>

<221>
misc binding <222>
164..188 <223>

potential probe <400>

gtagggtgaaagttgtggcaggaggattgttctagatatctagggcagacaacattgctg 60 aagttggggtgaggatgtatcagtaaccaactggagttctggaaacaacctccgtccagg 120 tatttggggggcctatatgacagaaaggccagcaagcaagcttaccctcatcactyactt 180 ggcctctattcaaatagcctacttttgtctgatctatccagggatgtgtgggaaggcata 240 ttggggctggtgagttctatatttctttagaaatttattatgactcagctgtttatgact 300 taagttttttgtgatttctatacgttattcctggtatcatctcttagagtaatacattcc 360 atataaaatacgaggtgtagctaaacataactttctaaggccccaaagtgttttcccagc 420 cccagcgcccacccatttcctgtcttctcttcttactcactg 462 <210> 45 <211> 497 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 373 <223> 99-28747-371 : polymorphic base C or T
<220>
<221> misc_binding <222> 353. 372 <223> 99-28747-371.misl, potential <220>
<221> misc_binding <222> 374. 392 <223> 99-28747-371.mis2, complement <220>
<221> primer bind <222> 1..19 <223> upstream amplification primer <220>
<221> primer bind <222> 478..496 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 361. 385 <223> 99-28747-371 potential probe <400> 45 agcaacactc agtgggctcg tcgccatgac gccagcctgt ggaggaaagt ggggagggga 60 ccaacacagg acccctgtgg cagaagctgc cttggaactg agaaacatca ctagaactca 120 tcaagccctc cacccacctg gtgcagatga actgaggtct gaagagggga gaccacctgc 180 ccaaagggag aaaagcagtc agtaggatgg ccgggattag atctggctct cagttcctag 240 ttcctatgaa gtaatgcagg gagaagacag ctggctggca ggatgccagc agcatccctc 300 caggggggca aggggctgcc tttctctaca ggcttttagg gaccagacct tctcaatcta 360 gatagacaga atyctccctc ccaggacatc cccagaagcc acagagttct gggggctctc 420 agagatagca ggagaccacc accccagaat gaggatagcc attcttggtg tgagcrggat 480 ttcccctacc caaggac 497 <210> 46 <211> 448 <212> DNA

<213> Homo Sapiens <220>
<221> allele <222> 352 <223> 99-28753-353 . polymorphic base C or T
<220>
<221> misc_binding <222> 332. 351 <223> 99-28753-353.misl, potential <220>
<221> misc_binding <222> 353. 371 <223> 99-28753-353.mis2, complement <220>
<221> primer bind <222> 1..20 <223> upstream amplification primer <220>
<221> primer bind <222> 427..447 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 340..364 <223> 99-28753-353 potential probe <400> 46 ccacagccct cgctattaac catggggcag tactccctcc acaagaggca ttcggtttgc 60 gaggagagct tagaggtttg gaaagaagac tcatacctcc ggcctggagg atcagggagg 120 acttagccct ctgagctgga cttctgggga caggttggat tttagcaggt gagtgtaata 180 ggcacaggag aggccctcta ggctgagggg actgagcaaa ggcaaggaga caggctgggc 240 tttgtgcctt gggaggagtg tgttgtatgg agaacaggga gtaggagaaa gaaacaatga 300 ggctggggag gggcatggag gtcaggtgat gcagggcatt ctacagggct tyaccatctg 360 gagagggagc ctgggtgagc ttgtgagcag agaagctcaa ttttgggagc acactgtcct 420 ctggaggaaa ggagaagtaa ggggattt <210> 47 <211> 471 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 207 <223> 99-28755-206 : polymorphic base A or G
<220>
<221> misc binding <222> 187..206 <223> 99-28?55-206.misl, potential <220>
<221> misc binding <222> 208..226 <223> 99-28755-206.mis2, complement <220>

<221> primer bind <222> 1..17 <223> upstream amplification primer <220>
<221> primer bind <222> 452..470 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 195..219 <223> 99-28755-206 potential probe <400> 47 tcttgaggga tatgaggcat tataaaaatt cctgggttgt gggagaatga gtacttatca 60 tcttctcctt~tgagttaaat ttttttgtgc ccaattttat agaaatcatg tggatccctt 120 ttgcaaatgg atgaatgctg ttagaagctg aacaggcaag gctgtatgtt tggagaagct 180 gggaccctat ccgctgcact cagagcrggg accatccgcc aagggagaca gggaagggtc 240 tgtgccacct gctggaggga gggcagagga aggcagggag aaggctatgg gtctgctgac 300 aaacccacgc tgcctctgag ggtgagggaa ggttgggctt tcctgaaggg aggggcctcc 360 atttcctgtc tgatgctggc atggcctgtg ctaggtgtcc ccgtgggctc tcattcagcc 420 ttcactgtga gcctccgagg tggacttaga tccattgcta aacagatgag g 471 <210> 48 <211> 541 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 366 <223> 99-32333-366 : polymorphic base C or T
<220>
<221> misc_binding <222> 346. 365 <223> 99-32333-366.misl, potential <220>
<221> misc_binding <222> 367. 386 <223> 99-32333-366.mis2, potential complement <220>
<221> primer bind <222> 1..20 <223> upstream amplification primer <220>
<221> primer bind <222> 520..5_40 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 354. 378 <223> 99-32333-366 potential probe <400> 48 acttagttca ttctttgagg ttaaatgtcc tagaaagaac yayacggttg atgtctaaca 60 ttacgtacac tcaagcttta gaatggccaa gtggatgacg ctgtttcttt caattaacct 120 gacatataca acctctcctt tctagccatt cttctggttg gctttcctag taatctgccc l80 aggagtgtaacttctgcaggcagaggtgaggtaaaaatggtgaagtaaggcaaggagata 240 aagaggaagaaggcaaggagcagtgattcagaagcatcagaccgaaaagaaaatttgtgg 300 gagctgatgaagacttcttataaacttctatcttcagcaatacttgaatgctaggaaagg 360 ctataycccagacaactattatcccatttatgatctgtcaagctttcacagtgaaatcac 420 tcaggattcttattttttttaaaaaaaccccagatccctgggtctcagacctagtgaatc 480 agcatctccagagtagaacctaggaattcacatctttaccccaaaagtaccccagacaat 540 t 541 <210> 49 <211> 4I6 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 323 <223> 16-38-323 . polymorphic base A or C
<220>
<221> mist binding <222> 300..322 <223> 16-3B-323.misl <220>
<221> misc_binding <222> 324. 346 <223> 16-38-323.mis2, complement <220>
<221> primer bind <222> 1..28 <223> upstream amplification primer <220>
<221> primer bind <222> 389..416 <223> downstream amplification primer, complement <220>
<221> mist binding <222> 311..335 <223> 16-38-323 potential probe <400> 49 agttgctctt ttatgttttg catcttacct ggtattgcct ttgcccattt cactgctgca 60 atcacttgcc gccctcctaa catgttgagc gtagtcatga tcctccaagt tgagtctgga 120 acagagctat catatcctgc atataacact tcaggttcaa taacctccaa cagtgacacc 180 agggtagggg tgagttgtgg taacgttgca ggaactattg ttttgttacc aggattttca 240 gaggtttctt gtgagactcc tgtagtggcc tgctgaattc cttttatttt tttctttgtt 300 tttcgagctg tgggtattta aamaaataca tagaaatgaa ctgtaatggg aaggtctgcg 360 ctacacagtt tattcaagaa~gtatttttac tttctaaaac tattaagatg ggagaa 416 <210> 50 <211> 506 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 179 <223> 99-28484-179 : polymorphic base A or T
<220>

<221> misc binding <222> 160..178 <223> 99-28484-179.mis1 c220>
<221> mist binding <222> 180..199 <223> 99-28484-179.mis2, potential complement <220>
<221> primer bind <222> 1..17 <223> upstream amplification primer <220>
<221> primer bind <222> 488..505 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 167..191 <223> 99-28484-179 potential probe <400> 50 gcggctacaa aatattctgg tactccatcc tagaccagag tttcaaggtt cgttatcatt 60 tgtagcatga tactggatcc tcacagtgct tgcctttcat tcaggtgcca ggaaacgtct 120 gcctgaatga atgggtgtaa tttacctgca cattttacat gcttctctag gtgtgtgawt 180 aactcataat ccatccatga ctttcaccca taatcctcct tgtagcaatt gctttgcttg 240 caacaaaact aagtagacat atctagcttt atgcatggtt ttctctctct gaactctaac 300 ataaactcag cctcaggaat tattcggttt ctactacatt tgccattctg attgggaacc 360 accagcattc aggtattcac ctggaacaag gcattttgtt ccaagggttc ctcacttaaa 420 agcaagcacc ctagcaatag ttcataatgg aacttcttaa cattctcaga atgtttggca 480 cagctgtgag tgaacacaca ttgagc 506 <210> 51 <211> 486 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 364 <223> 99-30853-364 . polymorphic base A or G
<220>
<221> misc binding <222> 345..363 <223> 99-30853-364.mis1 c220>
<221> misc binding <222> 365..384 <223> 99-30853-364.mis2, potential complement <220>
<221> primer bind <222> 1..17 -<223> upstream amplification primer <220>
<221> primer bind <222> 465..485 <223> downstream amplification primer, complement <220>

binding <221>
misc _ 376 <222>
352.

<223>

potential probe <400>

tgttctcaagcaaggtcggcaaactatgacctgcccgtcaaatccaacctgccacctgtc60 acctaacaattctgtaactgctcccacatacaacatggtcgtcatcataaatcctatagg120 tattgttgagagcaggaggaaagtttggttgagtgagtgagagaccttacccaagccttc180 ctgtggtctctaggagtcatggcagagttcgctgacactggtctgcttttaaccagcctt240 gccagtgacctttcaaattccctgaggagcaaaaggccaaattgaacctgaaagaaaaca300 cctctcagtgttgactgagttgcagtagaaaatggacctgacaaaacgttagtacacttt360 ctcrattgggttagctcaaaatatgttattaggtcttttttccagaggaaaatgcttaca420 cagaccctcttcctccccactccttcacctctacaggagaaaatgaggmwwyacagaaca480 ctatta 486 <210> 52 <211> 467 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 198 <223> 99-28485-198 : polymorphic base G or T
<220> .
<221> misc_binding <222> 279. 197 <223> 99-28485-198.mis1 <220>
<221> misc_binding <222> 199. 217 <223> 99-28485-198.mis2, complement <220>
<221> primer bind <222> 1..17 <223> upstream amplification primer <220>
<221> primer bind <222> 449..466 <223> downstream amplification primer, complement <220>
<221> mist binding <222> 186..210 <223> 99-28485-198 potential probe <400> 52 gcattataag gcaacacctg gatctgaatt cagctctgcc taattccaaa atctatgcac 60 ctcataacct tgtgactgtt gcctggcagg ggcctgcaga gtagcatcca ttaagcttga 120 cagagttttt taagattatg tgggtcactt aacagacagt cttaaggtaa ggttaaacat 180 caaagttaat ttctgttktc tatctatcct gccccttcta tccttcatat cacaatggag 240 cacaaattat aattaagaga tacaaaagca ttcagtcact tccatttttt tctttagata 300 cttactatat taagtcttaa atgaacatat tggcattcca aattattaag ataatgtcat 360 gctggtcatt gaaatgctaa attaacatga agactacatt tcaaaaatac aaaagtataa 420 ataggagtgt tttgtatatt cataccacga tttttgccct tagagga 467 <210> 53 <211> 474 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 354 <223> 99-30858-354 : polymorphic base C or T
<220>
<221> misc binding <222> 334..353 <223> 99-30858-354.misl, potential <220>
<221> misc_binding <222> 355. 373 <223> 99-30858-354.mis2, complement <220>
<221> primer bind <222> 1..17 <223> upstream amplification primer <220>
<221> primer bind <222> 456..473 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 342. 366 <223> 99-30858-354 potential probe <400> 53 aatctactgg gaaactgtcc atttcaacaa gagcacctca gacagtaact ggaaagagaa 60 atagctcata ttctcaggaa cgttagtcat cttgaagcag catgattcgt gatacctgga 120 aaatgcacat ggcagtcact aaaattgggt tctagggata cttttaataa gatttgagag 180 gagctggatc cattcattcc catggtacct aacacagcac cactacacag caggcctgtc 240 ccaaatttcc tttgctgctg gagaacatcc tcatggggga gcccccaagc tgcctaggaa 300 atgggttaac aggagggcac tcagggatct ccttcagttt ctccagccat cttygctgcc 360 acgcccaagc ccaggccacc ttcacctctc acctgggcgc ttccactggc cgcctgacac 420 atcttgtcac tggcttceac tcttgctccc agaacccctt cttcacatag cagc 474 <210> 54 <211> 489 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 311 <223> 99-32002-313 : polymorphic base A or G
<220>
<221> misc_binding <222> 292. 310 <223> 99-32002-313.mis1 <220>
<221> misc binding <222> 312..331 <223> 99-32002-313.mis2, potential complement <220>
<221> primer bind <222> 1..19 -<223> upstream amplification primer <220>
<221> primer bind <222> 472..488 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 299. 323 <223> 99-32002-313 potential probe <400> 54 aagaccacat ttcagcaagg actggctctg aatgacacct ggattctatg gcctttccct 60 ccactttggg aagctcttta gttagacagg tactgtaggc ggcaggagaa aaaaagctaa 120 ttattacttg ttggagtctt gtctcaggca tgctgtgggg ctgtgcaaga ttcgctgctc 180 tgctgctgtt gtcattttga tgctacaatt acagagaggc ggttcagcac ccagccgatc~ 240 ggtgtggctg ccaaacacat ttgagcatga caagataaat ttgttagaca ccagcacagg 300 gtgggtgaga rgacatcctg ctgactttat aaagtgatgt ggggcagggt tgtcgaggta 360 agtgatgatt gtcaagtttg ccagagatga tagataactc ctttggcaga acacctaggt 420 cattcctttt aaagtcaggt agctaagagg ctgtttggtt tctgcagcgc tgctacctac 480 ttggggaac 489 <210> 55 <211> 526 <212> DNA ' <213> Homo Sapiens <220>
<221> allele <222> 366 <223> 18-15-366 : polymorphic base C or T
<220>
<221> mist binding <222> 347..365 <223> 18-15-366.mis1 <220>
<221> misc_binding <222> 367. 385 <223> 18-I5-366.mis2, complement <220>
<221> primer bind <222> 1..20 <223> upstream amplification primer <220>
<221> primer bind <222> 507..5-25 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 354..378 <223> 18-15-366 potential probe <400>

atgaaattagaatgacctacatcaaagagctaggaaaagccattgtcaagagggaaggaa 60 actccagccagaactggcagcggttttatcaactgacaaaactcttggattctatgcatg 120 aagtaagtgtcaaacataaagccaaatataagagttttctgggacaaagtatgttttgat 180 tagtgaatataattatataccagcagcgcccccacccccgcccccagtttgtggatgttg 240 gtgatagcttgagttcaacttatgaacttcagttttgtagacatttttcctaaggccaat 300 tatgaaatatcctttcacctagtcatgtgtatataaaatcaccatgttattacagaattt 360 agtaayactgtttttaaaaagtatgattaatccattaaattagaataatgcacccttcat 420 atattatggtactacagtgattcatgaaataattctatataattctacatacaatcaaag 480 aaatataaaatgtgttttgtacggaagtgcttatttttcatctggg 526 <210>

<211>

<212>
DNA

<213> Sapiens Homo <220>

<221> le alle <222>

<223> 0-174 18-2 : polymorphic base A or G

<220>

<221> binding misc <222> _ 155. 173 <223> 0-174.mis1 <220>
<221> misc_binding <222> 175. 194 <223> 18-20-174.mis2, potential complement <220>
<221> primer bind <222> 1..17 <223> upstream amplification primer <220>
<221> grimer bind <222> 408..425 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 162. 186 <223> 18-20-174 potential probe <400> 56 ttctctcttc agtgttcatg aaccacagat aagttccttt cccacatttt cacagtcata 60 ggatccagta aggaaggccc gagtgatact tgctgggtca ctgagctggt gatgcctggg 120 ctcagctcca gacatgctgg gtcccaggcc tgagcttgtg tcttcaaact aggratacat 180 caattactta attattgctg gtacaaaaca gggtctaagg aaggccaggc tcaagagcac 240 agttaaaaaa gaaatcccct ccacagctgc ccttgccctg gttggggtgg aggccagcag 300 gcccctcatt gccaggtagg aagcattaga tacgcctgat gagctagaag ctttcttttt 360 tadacaatga agtagaggca aggtgttcta actccccgtc cagagaagag smaggaaagc 420 tagaac 426 <210> 57 <211> 458 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 178 <223> 18-31-178 : polymorphic base C or T
<220>
<221> misc binding <222> 158..177 <223> 18-31-178.misl, potential <220>
<221> misc binding <222> 179..197 <223> 18-31-178.mis2, complement <220>
<221> primer bind <222> 1..19 <223> upstream amplification primer <220>
<221> primer bind <222> 437..457 <223> downstream amplification primer, complement <220>
<22I> misc binding <222> 166..190 <223> 18-31-178 potential probe <400> 57 gtttttgtat gattcagtgt gaattaaatc ccacagtgta aaggacttta ctttcttaat 60 gtagattttc aaatacacaa ttactgatgt ttataagtag atttattaca ccaaagcacc 120 tagcaaattc ttgaatggat caggtcttat ttttcagtct tactttgcaa atttaagyca 180 aataattaag gatttgttaa atatttgtct taatatcaag cttttgcata tcggggccct 240 cttttataag ctttataagc aatcttttgt tttctctgct tgctcaaagt agctatgttt 300 gttgtatctg ttagtatttg ctctataaca aacatactgg gtgccttccc acttagattt 360 ggcaattatc actcctgtaa atgagatatt acataagata ggaaaaagaa cagtatcttt 420 ccaagaagaa tagtatcctt ccatattaac agtttaga 458 <210> 58 <211> 474 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 395 <223> 18-38-395 : polymorphic base A or T
<220>
<221> misc_binding <222> 375. 394 .
<223> 18-38-395.misl, potential <220>
<221> misc_binding <222> 396. 414 <223> 18-38-395.mis2, complement <220>
<221> primer bind <222> 1..19 -<223> upstream amplification primer <220>

<221> primer bind <222> 456..473 <223> downstream amplification primer, complement <220>

binding <221> misc _ <222> 383. 407 <223> 18-38-395 potential probe <400> 58 actgtaattg tatggtaaca tttaactgtacaggacttgg gaagttaggt ctagctgtga60 gtccaagaaa aggaaatgat tttgttcatcagccaacaat ttttgctata aaagcaaagc120 aatgtgagtg ggggccctaa aaatccccactgttttcgcc attctgacta ccacccactc180 cccaccaaag gtccctgggg cacaccctgcagaccttatt actttagggc acacattttg240 aaaagggctg actttgctaa tttgacttggcattttgatt aaagttactt tcatattttg300 attaaagtta taactgcatg atacaggcatactcttatca ccagtgcttt aagaacatga360 aacgggaagc tgatgacttc taaaccatttcacawtgagt ctaaattcac tgcttaataa420 taaataacaa tgataataat agtaacagatgtgtaccact cacatatacc acca 474 <210> 59 <211> 469 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 192 <223> 18-2-192 : polymorphic base G or T

<220>

binding <221> misc _ <222> 172. 191 <223> 18-2-192.misl, potential <220>

<221> misc binding -<222> 193..

<223> 18-2-192.mis2, complement <220>

<221> primer bind <222> 1..19 <223> upstream amplification primer <220>

<221> primer bind <222> 450..468 <223> downstream amplification primer, complement <220>

binding <221> misc _ <222> 180. 204 <223> 18-2-192 potential probe <400> 59 catcaaaata tcccaaaaga tgtttggaaaatatgttttt ataagaccta tagattgtga60 ttgagtaggt ttgaggtggg gcctgtgtatttgtattttt caacaagctt ttcaggtgat120 tatgataagc aaccagattt agaaaccagtgaataagttc aacgagatga tttgcacagt180 ggcctctttt aktcatcact taggttctgttatttttaga gccaaattaa tcaatcagtg240 cattgtttta acatccttgc cttacatatcttttccaaaa atttttaatt ttaaagggaa300 gaagggaaag ggaaagataa tttcctatgtttgtgtgaac acatccttgg ctcttctaat360 aatatgaaat acagtaaata atgacttgtaactattataa ttgtttttaa cattcatgaa420 tgaaaactaa ctacaatgtg ggttgattgg attccaggtt tcactctgc 469 <210> 60 <21I> 451 c212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 211 <223> 99-26921-210 : polymorphic base A or G
<220>
<221> mist binding <222> 192.'210 <223> 99-26921-210.mis1 <220>

<221> misc binding _ <222> 212. 231 <223> 99-26921-210.mis2, potential complement <220>

<221> primer bind <222> 1..21 <223> upstream amplification primer <220>

<221> primer bind <222> 431..451 <223> downstream amplification primer, complement <220>

<221> misc binding _ <222> 199. 223 <223> 99-26921-210 potential probe <400> 60 gaggaagatg ggttacttat ccatcaaatc cagactcatg gctgcttttc60 atgttagtca ggggggcatt agccccaccc gcactgctca tttgagccaa gaggagctcc120 cctgcctggg agtggccaga gaaagcctgc aggcaaaaac cagaggcctt aagttcatgt180 ttgcatcaga gtatgaaaat aagtgccaag gagatttggt caatgtctgc tacaaatgtc240 rggatccctg aagactcttg gctggaaacc tggccagaat ttcctgaaac cggaaacatt300 atggttccac ggtggccaaa gaagaaggag caggcaaagg gcaaaggaga ctggtggagc360 aagggagctg actagcgatt taggagggaa gcaggaaatt gggagtgatg agaagtgacg420 gtactatcat ttttagaatg cccakttaat acatagccca 451 a <210> 61 <211> 327 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 250 <223> 16-215-80 : polymorphic base C or T

<220>

<221> mist binding <222> 231..249 <223> 16-215-BO.misl <220>

<221> misc_binding <222> 251. 270 <223> 16-215-80.mis2, potential complement <220>
<221> primer bind <222> 171..188 <223> upstream amplification primer <220>
<221> primer bind <222> 284..3-03 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 238. 262 <223> 16-215-80 potential probe <220>
<22I> misc_feature <222> 29 <223> n=a, g, c or t <400> 61 ccctgcccac cttccaagta actctgtgna acctcttggt tcccttgaag ggtgattcgt 60 caacccgtgg gcaggatttt ctttgcgggc acagagactg ccacaaagtg gagcggctac 120 atggaagggg cagttgaggc tggagaacga gcagctaggg aggtaagcag gaaagcccag 180 gctctctccc tcccccatgg tgactttctt tcaggtctta aatggtctcg ggaaggtgac 240 cgagaaagay atctgggtac aagaacctga atcaaaggta agtttggtga ctctgggcac 300 tatctctcct tagaccaatc atggaac ~ 327 <210> 62 <211> 480 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 368 <223> 18-132-368 : polymorphic base C or T
<220>
<221> misc_binding <222> 348. 367 <223> 18-132-368.misl, potential <220>
<221> misc_binding <222> 369. 387 <223> 18-132-368.mis2, complement <220>
<221> primer bind <222> 1..18 -<223> upstream amplification primer <220>
<221> primer bind <222> 461..479 <223> downstream amplification primer, complement <220>

<221> mist binding <222> 356..380 <223> 18-132-368 potential probe <400> 62 ccccaactaa ttctcccctgttgttcagaatgaaattcag aatatagtgtcatggaaatt 60 gaactggcct ttttaactgtatcaaacatggtagaaagat tggtgagcatgagaaaacac 120 caaaagattt atcgaagtacacagtgtcctctggctgttg gcccctgtgccttgtctgca 180 gattggggaa tcaccccaggtcgggcaatgcttgctctcc attggcctcccatgtattcg 240 aattagcatt gagagcaagagagaggcaggaacgagaaac agggtcctggaaatttgttc 300 tcttggggca agtgcatggccactgatgcctgaagatttg gatgcagaccagacaacctc 360 ttggggtyct tttctgcattgaggtttgatttttattgag ttaaaatcttaacaataaag 420 atattttagg atggggccagactgcaaagtacataaaagt caggaaggagaacacaaaga 480 <210> 63 <211> 505 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 292 <223> 18-133-293 . polymorphic base A or C

<220>

<221> misc binding _ <222> 273. 291 <223> 18-133-293.mis1 <220>

<221> misc binding _ <222> 293. 311 <223> 18-7.33-293.mis2,complement <220>

<221> primer bind <222> 1..17 <223> upstream amplification primer <220>

<221>.primer bind <222> 487..504 <223> downstream amplification primer, complement <220>

<221> mist binding <222> 280..304 <223> 18-133-293 potential probe <400> 63 agatgtgaga agtgtggctagctgacagccccttgctgtg attttcttca ggatctgcct60 cagctttagt gttaacttcacaatattcttggggaaacac aagccaatga ctaaacaaaa120 cagtcttcat aggaaaacccgcagtgaatgactaagcaag gcagtggtat ggagctagac180 atttattcca gttgagtaactccgggcttctctgagaagt atctttcact gggaactccc240 acttggctgg cagagactttccagatctgcatctggatag ccctcttctg amgtttcctt300 tcagaaagag agataaagtttattttttgtttgtatgaag atgaatttct tttgccttca360 caattgaata acaacttaccttggtaaaggatttttggct caaaataact tttcctctga420 accgtttctc cccagtgcctaatattgagcaaatgtcaag cctagagaac agttaaaaga480 atatttgacc aacaccaacatagtc 505 <210> 64 <211> 450 <212> DNA

<213> Homo Sapiens <220>
<221> allele <222> 191 <223> 1B-12-191 : polymorphic base A or C
<220>
<221> misc binding <222> 172..190 <223> 18-12-191.mis1 <220>
<221> misc_binding <222> 192. 210 <223> 18-12-191.mis2, complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 431..449 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 179. 203 <223> 18-12-191 potential probe <400> 64 tttgcctagt tttgactgtt ggagcatcat attaaagttt tacatattaa aaaataaagt 60 caacaaggtt ggggaataca tgcaaaaaca aaacaaaatc cctaaatgtg aacaattggt 120 atcagaacca cagagaaaaa aaattcaaac taatcctagc attttgaaga caatgctttg 180 actatatgcc mttggtggaa aacattctaa agataaaatt gcaatgaaat tttaaacatt 240 gcatttcatt tattggtagt ggtatgggta tagaaattct gaaattaatt tcttgtatgg 300 taggatatag aaaatataaa taataaatat atcaatggtt tggggacaaa gttactcact 360 gtgagaaaaa tgaggaaaaa taaagaattg gaaagtagca agagtcctgt gttcgtgaat 420 tgggattaaa ggtattgata tataggagca 450 <210> 65 <211> 536 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 138 <223> 18-11-137 : polymorphic base A or G
<220>
<221> misc binding <222> 118..137 <223> 18-11-137.misl, potential <220>
<221> misc binding <222> 139..157 <223> 18-11-137.mis2, complement <220>

<221> primer bind <222> 1..18 <223> upstream amplification primer <220>

<221> primer bind <222> 516..535 <223> downstream amplification primer, complement <220>

binding <221> misc _ <222> 126. 150 <223> 18-11-137 potential probe <400> 65 tttctcaagt ggctctggca tctgttaaaatgccaaactcgtggtcctta acaccttgtg60 atgctggcac ctctctgcag acttttctcaatgtaacctcagaagttggg gaggactggg120 gagaagggag gtcctgcrgg gaggagaaaagggaaagtgggcaactccac tgaaggctgt180 cacacatttg ggggctgttc ccgacagttttaccttcctctttgggcccc tcctttctct240 tccctctcag tccccttgtc agatggttgatggggatcactgggagttgg ggtgactgtc300 aggaaggcag agagggggtt tgggcagcaggtgggaagtggggccaggtg gcctctcggg360 gttctcccac ctcacagttc tggggagttcagggttctgcaagcagagtg atccttaatt420 aataaacagc ggggcaggct cgggctccacgtcaggaaaactgcagtcag ccacgctggg480 ccacccgccc tctgcagagc acacgcaacagcgcagtcattaaagctgaa ctgagc 536 <210> 66 <211> 454 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 96 <223> 18-93-96 : polymorphic base G or T

<220>

<221> mi'sc_binding <222> 77..95 <223> 18-93-96.mis1 <220>
<221> misc binding <222> 97..115 <223> 18-93-96.mis2, complement <220>
<221> primer bind <222> 1..17 -<223> upstream amplification primer <220>
<221> primer bind <222> 436..453 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 84..108 <223> 18-93-96 potential probe <400> 66 caaatgccaa agggttcaca atgctgagat ttatcttact gttattttat aattttgagc 60 agcatttggt tttagtgggt tgtggcagaa attgtktctc tacagaatat tatcttaaga I20 gaacatattg aacataaagttaaaagttttccatcccttgaaattcacta gtggtaactt180 tgaacttcaa gaaaatgtcatttgagtttgataatgtctcaataaagcct ctctctgatg240 actaattctt agtcatctctcccttctcttacttcatatggcacttatta tagctttgtc300 acttgatcta gactactctgcattgctttttatttttttttctggaaaca tcaaggttag360 gaatcatgtg ttatggttctgtgtcactcgtacctggggcacctaagtgt acatatatat420 gtgtgtgtgt gcgctctgggctgtttaaccttat 454 <210> 67 <211> 553 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 343 <223> 16-115-343 : polymorphic base A or C

<220>

biriding <221> misc _ <222> 320. 342 <223> 16-115-343.mis1 <220>

<221> misc binding _ <222> 344. 366 <223> 16-115-343.mis2,complement <220>

<221> primer bind <222> 1..24 <223> upstream cation amplifi primer <220>

<221> primer bind <222> 533..553 <223> downstream amplification primer, complement <220>

<221> misc binding _ <222> 331. 355 <223> 16-115-343 potential probe <400> 67 caccgtcaca ataaaagaaactgtggtctctacacctgcc tggccccaca tctgtgccac60 agagacagac cctgggatcctcagactcccacacccccac cccagcctca ctcagaggtt120 tcgccctggc ctccttcctcctctgggagatggctggccg ccctggccag gcagctggcc180 cctccgggcc tggtttccccgctcaccctgaggccccgcc cagctctgag ccccaagcag240 ctccagaggc tcgggcaccctggccgagctgccccatctc cgtggggtgc cctcccaagg300 tggggagcca cgtgacagtgggagggcctctctcaggcct ggmagggagc aggggtcaca360 aactgtgctg gctgggggtggtctcagaggtgggcctgca ggcctaaccc tccctgctga420 cagggctccc agcccttgagagaaacagggatggaggaac agctgccctg atgccctcac480 ccacccggag caggccctgcgaaccaaggggaacctcagt gtggccccca gcatgtgtgc540 tgatggggag ggt 553 <210> 68 <211> 171 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 140 <223> 16-42-140 : polymorphic base A or G

<220>
<221> misc_binding <222> 121. 139 <223> 16-42-140.mis1 <220>
<221> misc_binding <222> 141. I63 <223> 16-42-140.mis2, complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 154..171 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 128..-152 <223> 16-42-140 potential probe <400> 68 cattgggcgc aggcagagcc tcatcgagga cgcccgcaag gagcgggagg cggcggtggc 60 agcagcggcc gctgcagtcc cctcggagcc cggggacccc ctggaggctg tggcctttga 120 ggagaaggag gggaaggccr tgctaaacct gctcttctcc ccgagggcca c 171 <210> 69 <211> 494 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 176 <223> 18-251-176 : polymorphic base C or T
<220>
<221> misc_binding <222> 157. 175 <223> 18-251-176.mis1 <220>
<221> misc binding <222> 177..196 <223> 18-251-176.mis2, potential complement <220>
<221> primer bind <222> 1..19 <223> upstream amplification primer <220>
<221> primer bind <222> 474..493 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 164..188 <223> 18-251-176 potential probe <400> 69 gaaaccccct cacacatcctggcctctactcgtacacaatattttctttt ttttaacttg60 gctgcagtga aaaagaatatttttagtaagctacttgttgtttacctaaa gcagccttaa120 gaagcccaga gcaggggatctgttaagtgaacgtagaagtggaagacaga tttgcytctc180 tcaggcacta gggcacttggctgtagaggggtgagtatggcaaacatcat gggaattatg240 agtagtgcgc ccacatccaaagctgcacgtgggttttcctgggcaaagaa actcaatgac300 tgtgcatcaa gagtgtacccagtctgacagcaggaaattgacagaaacga acagccccaa360 gccccagggc acatggaggcactcacctcaggcacracatttcagcagga gccaaaatca420 aaataaataa tattttattacaattttttaaaagacaggatctaacaggg ccagatgagg480 gtaaagcgag tgaa 494 <210> 70 <211> 478 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 44 <223> 18-269-44 : polymorphic base A or G

<220>

<221> misc_binding c222> 25..43 <223> 18-269-44.mis1 c220>

c221> misc binding c222> 45..64 c223> 18-269-44.mis2,potential complement <220>

c221> primer bind -<222> 1..17 <223> upstream amplification primer <220>

<221> primer bind <222> 457..477 <223> downstream amplification primer, complement <220>

<221> misc_binc3ing <222> 32..56 <223> 18-269-44 potential probe <400> 70 ctcatggtca gttgctcctggcttggcmagatggatggtcaggracttga aaggaacaca60 tttgggaaaa cggtagcaggaggtgtggggaagtgttgtgtggttagagg tctctgaaag120 ggcagagcgt gaagatcctcgcagcccatgtgacatttgccaaagggcaa ccgcctcagc180 cgaggagaag ctcagtgaccaggtagacaagatggccctttctttgggca tcagtcaggc240 tccttcccca gccaccctgtcattgtcagcaggctggtgaagatagagac tgtggtagca300 gggatggagg tcacacatgggatcggcacaggggctccactcaccaaggc ccatccacta360 agtgcccgcc tgccccagtgttgcaggggatctgccagcctccaggtgga gtggatgata420 tgagacagct gccggcatggaactggcaccgctgcgctttcaccaggata gaggcttg 478 <210> 71 <211> 927 <212> DNA

<213> Homo Sapiens <220>
<221> allele <222> 624 <223> 16-218-624 : polymorphic base C or G
<220>
<221> misc_binding <222> 601. 623 <223> 16-218-624.mis1 <220>
<221> misc_binding <222> 625. 644 <223> 16-218-624.mis2, potential complement <220>
<221> primer bind <222> 1..22 -<223> upstream amplification primer' <220>
<221> primer bind <222> 906..927 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 612..636 <223> 16-218-624 potential probe <400> 71 gaatcccttt caccctccat actgtatcca aagatcactt ttttcaaagg tcacctaggc 60 agaataatca aattaatgct tttaatttgg taatactgaa aagtaaattg caatgtatgc 120 acacacagat tgaaaatcag gtgccacaga catgagcatg cacagagaat ttctgcattc 180 tcatgcctta gtttatcaaa taaggaaaat gtataaaaag ctactccaca attggtgtgt 240 gaatatatta ctttatctaa atgcatcttc tcaggccagg catggtgatt gatgcctata 300 attccaactg ctcaggagtc tgaggatcgc ttgagtcctg gagttctagg ctgcagtgag 360 tatcacagtg ccttcagcct gggcaagaaa gtgagattct agctctaaaa tattttaaaa 420 ttcatctttt cacctcagtt tgtgtgcctc tgctggaaaa gaaagtccaa aggttattgt 480 tacattatgc aaataatatg ggcttgcaat caaaagagct ggttcctaat tctcacttta 540 ccactaactt gctgagtgac ttcaggtaag tcacttaact tctctggttc tcatttaaac 600 caagtgatct ctttaagtca tttstaatgt gaaaactgcg tgatttaatg agatatacat 660 tttggataat gatatggtta gattgtgtcc ccacccaaat ctcatcttga attgtagccc 720 ccataattcc cacgtgttgt gggagagacc tggtgggagg taactgaatc ataagggtgg 780 gttgttccca tgctgttctt gtgatagtaa ataagtctca tcagatctga tggttttaga 840 aaggggagtt ctctttcaca tgctctctct tgcctgccac catgtaagac gtgtctttgc 900 ttctccattg ccttctgcca tgattgt 927 <210> 72 <211> 479 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 330 <223> 18-393-330 : polymorphic base G or C
<220>
<221> misc binding <222> 311..329 <223> 18-393-330.mis1 <220>
<221> misc_binding <222> 331. 349 <223> 18-393-330.mis2, complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<22I> primer bind <222> 459..479 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 318. 342 <223> 18-393-330 potential probe <220>
<221> misc_feature <222> 457 <223> n=a, g, c or t <400> 72 agtgtacttc gtgattgggg caaactctgg gccagatctt gtggtctgaa attcagactc 60 tgcagtttac taactgtgtg attttgagtg actgcttaat ctctctgggc cccttttctt 120 catctgtaaa gtgggggtaa taatggcatc cacttcttag ggtagttgta accaataaat 180 gagttaatac aggaaaggcc ctttaataac tatgccataa tgtttttgct attattttta 240 ttcctgtaag aaaaggagcc aaagagtgga ataagatgag tttatattga gatcctaaaa 300 gacagaaagc tagtccctgt ttctcaatcs tccttctaaa gtcactttaa ccatcagctc 360 ccatctatgc agacagcaaa ctcagcaaca agaaagagcc cttaatactt catctcaagt 420 caccagaaac tcataggaag gcacagaaga ccaagtnaca aactactcct ttcattcct 479 <210> 73 <211> 518 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 402 <223> 18-394-402 : polymorphic base A or C
<220>
<221> misc_binding <222> 382. 401 <223> 18-394-402.misl, potential <220>
<221> misc binding <222> 403..421 <223> 18-394-402.mis2, complement <220>
<221> primer bind <222> 1..20 <223> upstream amplification primer <220>
<221> primer bind <222> 500..518 <223> downstream amplification primer, complement <220>
<221> mist binding <222> 390._.414 <223> 18-394-402 potential probe <400>

cttctgaggataacaaacaccmatgggaaaggcaacttattaaggtacatattacagtct 60 tctaatgtctaaagccagctagacatacatttaaatcccagcagaaattctctgaaaggt 120 ttgcctccaccctaggtcttccaacattagaagaacttcagagagaaagtaggacatttt 180 gtctctcttgggtatttgggaatcaaggtgcagacttggggtagcattgggggtcccatg 240 aagaattgaatacctaggcttatatcaaagccgcccctacctatacatgctccccagtgg 300 cccctgtggcccaatattccaagaatggctcggggaatggccagctcccccacagtcatt 360 tcagattggagcaggctccttagaagtccttggtgtccgagmcttagtcccacaatggat 420 gctggatatgggtcaacatcctggattcatggagagaggagggcatgtggcaaaatatag 480 ttaacttacattatttcttcctcattatcccctcaatt 518 <210> 74 <2I1> 587 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 55 <223> 16-217-55 : polymorphic base A or G
<220>
<222> mist binding <222> 32..54 <223> 16-217-55.mis1 <220>

<221> mist binding <222> 56..74 .

<223> 16-217-55.mis2,complement <220>

<221> primer bind <222> 1..20 ' <223> upstream amplification primer <220>

<221> primer bind <222> 568..587 <223> downstream amplification primer, complement <220>

<221> mist binding <222> 43..67 <223> 16-217-55 potential probe <400> 74 aacaggcgac tttgtcaagcccagtcccctccgtagctggatttcacctc caggrcagcc60 agctggacag acaggcagatgcaggctcagccccctggctgccgtgggac acacacacac120 acactgccac agccactgcccaccacacacacctagtgcagatgctggca cacccccaga180 aggaggctca cagctcgcaggggagacctgggctggacaaaacccagggg aggggagggt240 gtgtggggac caggcccctgctgagaaccctggggggaagcctgaggggg aattggggga300 tggagcccac actccacaccaggtctggccctcgagtgggtcggccttgg tgccagcccc360 tctgcggcca gagaaaagcagcttagggctgagctggagacgcggtgtcc ccgactgtgg420 gggaggggga ctcgaggtttccccttgatggacacagtgaatccaggcgg ctggggcaga480 gaccagcagc acgggacacg cgtgacctgt gctcctttcg agccgcagac gtcacagtga 540 cgacgtttaa gctcctaatc tccccaaatc ggcgggaagg attagag 587 <210> 75 <211> 450 <2I2> DNA
<213> Homo Sapiens <220>
<221> allele <222> 139 <223> 18-284-139 : polymorphic base C or T
<220>
<221> misc binding <222> 120..138 <223> 18-284-139.misl <220>
<221> misc binding <222> 140.159 <223> 18-284-139.mis2, potential complement <220>
<221> primer bind <222> 1..17 <223> upstream amplification primer <220>
<221> primer bind <222> 430..449 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 127. 151 <223> 18-284-139 potential probe <400> 75 gactcctagc ctcattgaag gatggttaga gaggcacggg gagctatcta gtggcaggcc 60 cacggtatat gtttgctgct ttctacaaat acgagatcaa aggaaaataa agcaggggtg 120 gttcctgtca gtgtggagyg agacccggga aagcatcctg gtggctgtca ggccttgctc 180 acggcccctt tctctttcag ggagaggatc ctccacagtg gtatcctgct gcgtgcccct 240 ccaggacagc acccagaggc ccgaattgct gctgcacaga gagcactcgg cctcacccca 300 cgttttccct aagttctgtc tagtaattcc actttggaga ggggggtgtt ccttgacaga 360 tttagagagt tgatgtaact tcctcggatc agttctgctg gctccatccc ctacctgctc 420 agccctgcac aaagtggcta agcacgccac 450 <210> 76 <211> 520 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 305 <223> 18-285-305 : polymorphic base A or G
<220>
<221> misc binding <222> 286..304 <223> 18-285-305.mis1 <220>
<221> misc_binding <222> 306. 325 <223> 18-285-305.mis2, potential complement <220>
<221> primer bind <222> 1..17 <223> upstream amplification primer <220>
<22I> primer-bind <222> 499..519 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 293. 317 <223> 18-285-305 potential probe <400> 76 gaggtgggag aaattacagc tgaggtagaa gctgcctcgg aaggccaggt gaagagccac 60 acctgtcaga tgggcttgtg gcctgcgttg ggcagggact cccagcaggc tgctgtccgg 120 ccacagttca gcctctgccy gaggcccggc cctgcctgtg ctccttatcc tatagctgca 180 gggccagctg aaagaagcaa ggcgtttccc tcccccatat cctgttctcg tagcatttat 240 ggtgcagtct cccacgcctg actgctgtct acttagaaaa ctgctgaaag ccagttgcat 300 ttcaratagt gtctgtgcca ccttcagagc ccttttgtga tcatgtttta tcagcttatt 360 ttatgtttta tgtgtgggct tcggcgatct ggggacatct ggtcaaccag ggcaggcaac 420 cttgtttcca agtggcagat gccagggtgg gtccagtctc cagaaaggga ttttccctgg~ 480 gaccattggc acctgttact tgtagtcttt tcagccttgg 520 <210> 77 <211> 486 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 239 <223> 18-289-239 : polymorphic base C or T
<220>
<221> misc_binding <222> 219. 238 <223> 18-289-239.misl, potential <220>
<221> misc_binding <222> 240. 258 <223> 18-289-239.mis2, complement <220>
<221> primer bind <222> 1..17 <223> upstream amplification primer <220>
<221> primer bind <222> 466..485 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 227..251 <223> 18-289-239 potential probe <220>
<221> misc_feature <222> 154,156 <223> n=a, g, c or t <400> 77 taaaaagcag ccgtgtccca cagcaaggct gccctgtgtc ccacagcaag gctgcctctc 60 cagctcaaaa aaaaatcctg gcgacagatc ttgagactct gctgctgtgg gactcttcct 120 gcacccacca cccagggcct caggaaggag ctgnancagg gtgttttaga aagaccttac 180 tctataaatg caaaaaccca gacttagtta acaaaagcct attacaaaga cattttctyc 240 tattgctacc tctccccatt taaatcctgt ctgtacaaaa aaataaaaac attagctggg 300 catggtggca cgtgcctgtg gtcccagcta cttgggaggc tgaggtgaga gcagtgcctg 360 agcctgggag gccgaggctg cagcgagccg ggatcctgac gccgccctcc agcccggcca 420 cagagaaaga cccacagagc ttskccgcag ccctcgtcca gcgcactgag atccctcacc 480 aaggac 486 <210> 78 <211> 453 <212> DNA
<2I3> Homo Sapiens <220>
<221> allele <222> 91 <223> 18-291-91 : polymorphic base C or T
<220>
<221> mist binding <222> 71..90 <223> 18-291-9l.misl, potential <220>
<221> misc_binding <222> 92..110 <223> 18-291-9l.mis2, complement <220>
<221> primer bind <222> 1..17 -<223> upstream amplification primer <220>
<221> primer bind <222> 432..452 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 79..103 <223> 18-291-91 potential probe <400> 78 cctccatgca ggaacagcct accctggact ggatccagct ctctcccagg cccaggttgt 60 gggagaaatg ggggacctcc gcctcccaat ygtgctggct ggaactttcc tgtgctgggg 120 attcggcgtt tgcagccagg gtggccagtc agggtgccag gctcccatct gaacactgac 180 agactgtggg ctgtgcagtc tacagcattg ggcacaacct cagcttgcta aaatactcag 240 tgcaggctgg gtgtggtggt cacgcctgta atcccagcta ctcgggaggc tgaggcagga 300 ggatccctta aagctaggga gtcaaagctg cagtgagccg agatcgtgcc actgcactcc 360 ggcctgggtg acggagaccc tgtctcaaaa aagaaaagaa aacgagtatt gggtggagag 420 aggaccaagc ccaattacta ctttagtgcg get 453 WO 01/51659 PCT/)BO1/00116 <210> 79 <21l> 460 <212> DNA
<213> Homo Sapiens <220>
<22l> allele <222> 391 <223> 18-186-391 : polymorphic base G or T
<220>
<221> misc_binding <222> 371. 390 <223> 18-186-391.misl, potential <220>
<221> misc_binding <222> 392. 410 <223> 18-186-391.mis2, complement <220>
<221> primer bind <222> 1..1B -<223> upstream amplification primer <220>
<221> primer bind <222> 442..4-59 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 3?9..403 <223> 18-186-391 potential probe <400> 79 taggggtcaa ataaatgcat actatgcgga cagacagaga ttttcgattt ttttttttta 60 gtttaataaa gtttgaaaac tttcaaagct cctgtacaat tccattaata ccagacttgg 120 caaaacgcta attctgtttg aaaaggtgtt tttttaaaag tagtatattt gaacaatgtc 180 taagtatgtg gggtggggag aatccatatc cgaatatctt cataaagcaa gttcttaaaa .240 tttgcaaagc tattaggtta gtgcaaaagt aatcatggtt tttcttttgc accaactaat 300 atttaccact gaacacgctg gcatttagat cacttccttc tttcagcatg ctagacagta 360 aagagaatgg gcatgaggtg gcaggaagaa kgaaagagtg aagataatgg agttaggtca 420 gtgagggata tttcctaaat tccccacttc ttttcctcta 460 <210> 80 <211> 460 <212> DNA
<2I3> Homo Sapiens <220>
<221> allele <222> 130 <223> 18-194-130 : polymorphic base C or T
<220>
<221> misc binding <222> 110..129 <223> 18-194-130.misl, potential <220>
<221> misc binding <222> 131..149 <223> 18-194-130.mis2, complement <220>
<221> primer bind <222> 1..17 <223> upstream amplification primer <220>
<221> primer bind <222> 439..459 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 118. 142 <223> 18-194-130 potential probe <400> 80 agctggaagc ctgtttggct tactattggt aagaaaaagt taaaatttta atctgtctga 60 acattatagt acatccaaat caataaaatg ttttagttgt ggtttttcat cagttttaat 120 cagataatgy cttacttctg tagatatagt ctagtatagt tcaaataaaa agacagttgt 180 acatagataa gacaaagcat attgtgaaaa tgttgggaaa tttaggttat tttaatgatg 240 gctgagaatt tgtgaacttt tctcatatgc tattaaactg aattactagt aaatttatgg 300 taccgagtat atcaaacagt gagggattta aagtaatttt gcaatttgct aaaatttcat 360 ccttaacata ctggctaaga gtgaaaaagc aagaagagag aaaaggaaaa ggatggaact 420 aagacaattc tattagaagt ggggagatgg caagaaaatt 460 <210> 81 <211> 459 ' <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 252 <223> 18-198-252 : polymorphic base A or G
<220>
<221> misc_binding <222> 233. 251 <223> 18-198-252.mis1 <220>
<221>.misc binding <222> 253. 272 <223> 18-198-252.mis2, potential complement <220>
<221> primer bind <222> 1..17 -<223> upstream amplification primer <220>
<221> primer bind <222> 438..458 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 240..264 <223> 18-198-252 potential probe <400>

ctgaaaaaagagctgacaaaattcaatccctaattaaaatgtttagcaac taaagttatt60 ggttaattttgagaattgatcctgtgttaacaaacatcaccaaagtctca aggettacaa120 tacaaaggtttatttctcgctcatgctacatgtccattgtggacggctgt ggctcctcac180 tgtcttcattctaggactgaagctgaaggcacagtacctatatgcaacat attgttcata240 tggcagaggggrgaaaagcaatgacttaatcaagcaatgactcctgaagt tttgctcaga300 tacagcatacatcacttccactggctaaagcaagcctcatggctaagcct gatatcaaga360 aggtaggaagtatactctctcacagggaggtgcacctggtagaaggactc tattatagag420 ataaactcagtagagaggattgccgaatagttgtaaata 459 <210>

<211>

<212>
DNA

<213> Sapiens Homo <220>

<221>
allele <222>

<223>

: polymorphic base A or G

<220>

<221> binding mist <222>
280..298 <223>
18-242-300.misl <220>

<221> mist binding <222> 300..319 <223> 18-242-300.mis2, potentialcomplement <220>

<221> primer bind <222> 1..I7 <223> upstream amplification primer <220>

<221> primer bind -<222> 455..4 <223> downstream amplification primer, complement <220>

<221> misc binding _ <222> 28?. 311 <223> 18-242-300 potential probe <400> 82 acctgacatt aagagacaag cagccgggatggctcctaaccagatcttct ttccctgttc60 ccaaaccatc tttcttcata gccggctctggggatgaggagcctgggtta ggaggaaggt120 ttgcaattga ccaggttcct gttttgaaggcttccacctagacttaagat agcaccgctc180 agaagatgga tgtgtgttta gcaatttcccattttattacctgcagacaa agaaaaaaaa240 agatataaat agatgtttaa ccacacaaataattcacattactgtcttct ttatgactrt300 gaaataataa aataaaatta aatcaacagcaataacaatttcggcacagt ggttactagg360 caaaatctgg aaaccaaatt gaaataagaaaactcataaactgggtgttg ggagcacact420 gtggaatttt tcttggtcaa aattctcacagagtgttcaagtgaaaggtg tattaa 476 <210> 83 <211> 3001 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 1501 <223> 8-15-126 : polymorphic base A or G
<220>
<221> misc binding <222> 1481..1500 <223> 8-15-126.misl, potential <220>
<221> misc binding <222> 1502..1520 <223> 8-15-126.mis2, complement <220>
<221> primer bind <222> 1376..1395 <223> upstream amplification primer <220>
<221> primer bind <222> 1792..1810 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 1489 .1513 <223> 8-15-126 potential probe <220>
<221> misc_feature <222> 15,619,631,646,2196,2462 <223> n=a, g, c or t <400>

ttggaaacaggctcntgagcagttgggtagagaattccctgagtgtggtctagacagggt60 tgtaaacttagtggaccttctccttggcactgtgggaggttacaacatcattctatagag120 gttagaggcataaccagtagagggtgccttagtccttttgggctgctatcacaaaatacc180 ataaactgagtagtttataaacaacagatatctatttttgacagttctgaaggctgggaa240 gtccaagatcaaggcaccagaagattcagtgtctggtgagggcctgctttctggttcata300 gatggctgtcttttcactatgtcttcccatggtgaaagagattagctagctctctgggtc360 tcttttataaaagcactaatcttattcatgagggctctgccctcataacctaatcacctc420 tcaaagacccccacctcctaataccatcatattgggaattaggatttctacatatgaatt480 tagggagacacaaacaccgagaccacagcagaagaccagagtggactcctctatagcacc540 tcctctagagcttggggcaagagtcacttttgcttgggtttcagggttactccctaagtc600 acaggccttatgtcttccncctagccttcangaactgtgagacaantaaatttctgctct660 ttataaattacccagactcaggtgttctgttatagcaacccaaaatggactaagatagat720 gggtttcattattcccacattttacatgggaagaatctggagctcagagaggtaaagtaa780 tatgcataaggtcccagagttaggaagcagcagagctgggattgtaatcctgcaacagct840 tcccatctcactcagagtccaagcatggtactttcaatagccctgcacaatctgtctacc900 tcacaccctcctattctactcctgcctcacttggctccagcctcaccagactccctccta960 tgacttctatgtgctagcccttcctgctggcccgtgttgttctcactgctcagactgcta1020 tcacatctgataactgcatggtctgcttcctgatctcctccaggtcaagactcaattgct1080 gatttctccatgaggagttcctgattatactcagatactcactcacatacgcacaatctt1140 cacccgttacttacctgcctctctgatttgtctccaatatacgtatcattattgaacaca1200 ccacatcttttatttatcttgtttattatctgtcttctcctctagaatgggagcttcaaa1260 gggaaggaattaaaattttatctgttttgttcattgctctatctccaactctcacaacag1320 tgcctactatatagaaaatgctcaataaatatttgctgatgcaataaataaaaaaatgta1380 actaagcaaccaagccccaaagagtctgattttattaatattgttttctgtctcctcaca1440 ggaagcccctggcatcacgt tgggctatggcatctctgagccagctgagt1500 cacctccctc rgccacctgaactacacctgtggggcagagaactccacaggtgccagccaggcccgccca1560 catgcctactatgccctctcctactgcgcgctcatcctggccatcgtettcggcaatggc1620 ctggtgtgcatggctgtgctgaaggagcgggccctgcagactaccaccaactacttagta1680 gtgagcctggctgtggcagacttgctggtggccaccttggtgatgccctgggtggtatac1740 ctggaggtgagtagacttcaggtgcatgttgtctctatgactgtgctagtacttgtcttc1800 cctgagttctggcctttggggctcaaaagactccccagacagtcaggaactgaggaagga1860 aggagagctctcattctccctgtaatgagagagttaaagctctggaaaacagtcaccatc1920 ctgtccctcatccacatcagaaccaaggagctgagaatgattctgttcatgggtctccag1980 tgttcaggtgactggatttgagtgacgggactcttcctaatatggcctagagtttattct2040 ctgtgccagacatgtctcaatgacatggtgggctgggtgaagcagtccagaagacctctt2100 caccagtgtttaatgtatatgagggtgagggtgtgcaggagggatgtgaggccaggagga2160 aaaaggaattatagaaaaaaaaaattagtgaatgtnaagggaagatagaaagaatgacca2220 ~cgaacagatcagacttctttcgatggctcagtccctctttgctctttcctcctgggtac2280 ~agttctccatagactctgctaccaaaggaacagacaaaaccctcaaatgtatattttcc2340 atgtgtccatgaatagtacagagcctttgccagagagatagtgcagcagatcctggtgaa2400 ttcttttggggagaaacatttattaaatttgaaagtattttcaattgggagtgcaaaaca2460 gnagccagggggtggtcaagacaaaacacccatttgctaacaaagaaatcagggtgacca2520 tatctgttcaagaaacagatattcttaccaggaaaacatgcaattacttaagatatgttt2580 ttttaaaaaaacctgagtatactattaatatttctcctctgcactgtgtgtcattttaaa2640 gaggtatccaatgaaggatcaaaatgatgctatgattaagagaaattaagattcatcaaa2700 ttaatatctcagttaatattgatagtaaaagtgacagttaattaagtatgacatatcacg2760 ggagagcaaaaaccttgtacatagactgcctgtgctaatacctttgttaaagaatggctg2820 ggaactaaaattagacttatgatctcaagggggagacataaagagagaaaaaaagaaaac2880 agagaaataaaaggaaaagaagaaaaacaactaggctgtgtagatctaaaggctaaggga2940 atacttgaggaaaaaatatgcatttattcttcccagttaggataatcctagttgggaggg3000 t 3001 <210> 84 <211> 2684 <212> DNA
<213> Homo Sapiens <220>
<221> allele .
<222> 1501 <223> 8-19-372 . polymorphic base A or G
<220>
<221> misc binding <222> 1481..1500 <223> 8-19-372.misl, potential <220>
<221> misc_binding <222> 1502 .1520 <223> 8-19-372.mis2, complement <220>
<221> primer bind <222> 1130..1148 <223> upstream amplification primer <220>
<221> primer bind <222> 1534..1552 <223> downstream amplification primer, complement c220>
c221> mist binding <222> 1489..1513 c223> 8-19-372 potential probe c220>
<221> misc_feature <222> 240 <223 > n=a, g, c or t <400> 84 aaggccaactttgaggttggagaatccccaaccctttatgaagactggccgggtgtacca 60 acagttgttgctcacagtgctggatgaagcacagatgttccatgtcacaatggtaaagag 120 ggatggggagttaaaattatagaaagaacattggcttgggcataaaactggctgcaagaa 180 catatttttcaggtgcagccttgggctacttactgaacctctctgagctttaatctgctn 240 catccgaaaagagagacagtaataatggcacctgtctcatataacgttgccataattatt 300 aggtgggataaggggtacaaagctcttggctcatcgcctggcagatattagtttgctttt 360 cttttctttttcaagatggggcacgtttcaggcccatcttgggccttggaggaatctcag 420 catctgctatgaagaaggcaaagctagagggacctcccaaggagaaatggcaggaacatt 480 tcaggatataaagcagggacaaggacccttctaagtgcacattctccatgtcacaatatc 540 attacctgcctttttcccatcccacctctgacaagtgctgggattccctgaaaaatcaaa 600 tctctgtcttgtattcagccgccatctgccctccatcccagattcaaaattggagaactg 660 gcattctcagcaaataaggcttcttcctttcattgcattcaaacaattctccaatgcctc 720 cgcaccagcaggcccttttctgagggctgcatccctcctgggagcctctgccctgttgcc 780 ctgtaatgctctccccagcctcccaggctgcatgtctctgtgtgacacttgtgacatcct 840 atgaaagggatcatctgtctatctagactgtttgctcccttgagagaagacatggtgtct 900 cattcatctttgtagccccagtgtctggcgtatgattgttggtaactttttattttaagc 960 aagctgtaagaaactcaaagatgaattagaccttctaccctcaaggacctgacagtatac 1020 gtatctgagactgcatccttcccaccccctgtgcagcagaaagtgcaggcaccacacgt,g1080 acatggagccgtgttttatgctccttactgagttctgatacttgctaactgctttacctt 1140 cccccttctcatccacaggggaccccactgtctgctccatctccaaccctgattttgtca 1200 tctactcttcagtggtgtccttctacctgccctttggagtgactgtccttgtctatgcca 1260 gaatctatgtggtgctgaaacaaaggagacggaaaaggatcctcactcgacagaacagtc 1320 agtgcaacagtgtcaggcctggcttcccccaacaagtaagtaccctggagggggtagagg 1380 gaagacaacacccaatctcctgacttcccagcctgtgtccagcagtgcatgattttgccg 1440 tttagctaaattggagacacaaatctgacaccgactttggaatctgctaattttggctgc 1500 rctttgaaggtaggaaatccaatctcaagaaaacattgatagttgcctctagagcctgcc 1560 ttacctggcaaagtgattggagagctcctgggcttgttctgcttcccttcaaagtctttc 1620 attttccccaaatgggcagcagctcagatgtcccacaggttttgaagtttaagtgcagca 1680 gttgtaccttgcactgctggtgggttcccagaactgactttttgtctaaaccactcatgc 1740 caagaatcactggggtccatcaaagccttttttccttactggatctgtccgtgtgtcaag 1800 gaactgacaagctggtgggatagggtgctgataaagcattttattggatctttctaggct 1860 , ctgaaaagaaatgtcattgcctctgcaatgatcttctaattgctagggctttaatttctc 1920 cttaccccattgcctggcacttagtagttttcccacgatgtacttgaagcatgaatggat 1980 atataccgatcacttgaaatctactagggaagggacagtggtaacattaaacagcatctg 2040 ccttcatggagcttagaatctagaaaagcaaataaagcacccctccactcaatgttaatg 2100 aagatcccagagctgaataggatgtttgccaaatgtgaggtgaagacaattaagcactca 2160 attatgaagtgctctggaggttatagaagagaaaacccaatatgctcagtgatatggttt 2220 ggctgtgtccccacccaaatctcatcttga'attgtagctcccacaattcccatgtgtcat 2280 gggagggacccagtgggaggtaactgaatgatgggggtgggtctttcccttgctgttctc 2340 atgatagtgaataagtctcacgagatctgatggttttatgagggggagtttccctgcaca 2400 aattttctcttgtctgctgccatgcaagacgtgcctttcaecttccaccatgattgtgag 2460 gcctccccagccacatggaactgtgaatccattaaacttctttttctttataaattaccc 2520 agtctcaggtatgtctttattagcagcatgaaaacaggctaatacactcaggaaagggct 2580 ccatagacagagtaagaattgagtttgatcttgaagacagatccaatttgggtgtctaga 2640 ttaatctttgatgacctagataatcttttttttttttttttttt 2684 <210> 85 <211> 711 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 428 <223> 99-2409-298 : polymorphic base A or G
<220>
<221> misc binding <222> 408..427 <223> 99-2409-298.misl, potential <220>
<221> misc binding WO 01/51659 PCT/iB01/00116 c222> 429..447 c223> 99-2409-298.mis2, complement <220>
<221> primer bind c222> 131..148 <223> upstream amplification primer <220>
<221> primer bind <222> 560..580 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 416. 440 <223> 99-2409-298 potential probe <220>
<221> misc_feature <222> 27,108,118 <223> n=a, g, c or t <400> 85 ctcaaagatg tcgttgacga aggagtncat gatccccatg gccttagagg agatgccggt 60 gtcagagtgg acctgcttca gcaccttgtg caagtacacg gagtagcntc ccttgcgntg 120 cgcttggttt cttgccgtac ttcttctgcg ccgtagtcac ccacctcttg gaagccctaa 180 ttgggatcag gagcggactt tgttggctct ggcatgtcga gggcgcacta caggtcgagg 240 tgaactaaca gcagctcgag aaaacgggaa ttaatttaat gtttgtcttt actaccaaac 300 tgtaagtttc gtgagattag gaccatattt gcatcattca ttattatgtc tctgggaccc 360 agcacaatgc ctagtacata ttaggacttc aataaacaaa tgcaaagtag cgcatggggc 420 tgcagccrca gatctcctgg gatctgggtc tgggagcagg cagtggcatc tgacacttca 480 tatcccttaa agaagacaaa atgtattcta tgacagatag ggaaccagag ccagggacta 540 gagtgtgact ccctgacttg ttagaggagg ttgggaaaaa tggccttgac tatcttccta 600 ggcagaggeg ggcaaactat gcaccccagc ccaaatccag ccctctgcct gttttggtaa 660 ataaagtttt attggaacac agttacatac tttttttttt tttttttttt t 711 c210> 86 <211> 3001 <212> DNA
<213> Homo Sapiens <220>
<221> allele c222> 1501 <223> 99-339-54 : polymorphic base G or C
<220>
<221> misc_binding <222> 1482 .1500 <223> 99-339-54.mis1 <220>
<221> misc_binding <222> 1502..1521 <223> 99-339-54.mis2, potential complement c220>
c221> primer bind c222> 1448..1467 <223> upstream amplification primer c220>

<221> primer bind <222> 1883..1902 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 1489..1513 <223> 99-339-54 potential probe <220>
<221> misc_feature <222> 120,890,929,2457 <223> n=a, g, c or t <400>

atactataaagattcagagactttccacattagtaaaatttttagaggtccagtaggctg60 gggaatgctgagacatgcacttcaaagtaaaggacaaattattgtaacttgcatttcccn120 ataactaagaaggaaacccagcaccaataagcgtcttctggttctgaaagcagcacattt180 cacactcagagacactactctagcacatacgccagctgaaacatgagtctaccagatttg240 gagagagcccagagcaggaaagggctctgcagcaggaccaggcagtagtgcaagctgctc300 tgtcatatgatgattttggtcacatgatgtggtagagcctacagtataggaggtatcatt360 gatagaaaaaggctgtgtacattttatggcaggcctcaataggcaaacacaaatagaccc420 ctaggattcagaagcaagacaagcaatttgcagcagagaactatacgtttagataaatat480 tcctggtgccctactggttcctagtaggaacacagcacccaactatgggatgccaagggt540 ccacacagcaaggactgcccattgcgaattctgacagacccccaaatcatgaaggcaggc600 aggcctaccaacaattgtaaggaaggaaatgatacgtttgggatcaggcattagcagagc660 cagagagcacaaataagttgcacgcatatgtggcccagactactagggtcatccatcaca720 tttgcactgatgcctcacccttagctcacacttacggcagcataaagtgagggcaaaagc780 tgagtttgatttatgtacgggtaagattggaatgtagtagcaagctaaaaatagactatt840 gctatataacaggaccacatccttagcgtgtcccagaaaattagggatgnagagaaattc. 900 ttcctaatggataaagcatcagatggtgncctttgtcgagagaaatactctgagataaga960 tatgtatcacttataggcagtagtgaattatttggacagttgactctatacaacctggga1020 agtagaatgtcttagccagttgatgtcagccagctcctatcagtgctggcacaataggca1080 cattaatggaccatgggtaaggaatggagacaccatcctaacaagactaattgactttat1140 ttttattttttttgagacggagtttcactcttgtcacccaggctggagtgcaatggtacc1200 atctcggctcactgcaacctctgcctcccaggttcaagtgattctcctctgtcagcctcc1260 caagtagctgggattacaggcacctgccaccaagccctgctaatttttgtatttttagta1320 gacatggggtttcaccatgttggccaggctggtctctaactcctgacctcaggtgatctg1380 ctggcctcggcctccaaaagtgctgggattacaggtgtgagccgcagtgactggcctaat1440 tgactttcttaatcaggagaagatagctcttctcttacatgatggcgacagaaaagaata1500 stcccttgcctaattttgatgataaatggataagtacaacaaccatgactgagaaacagt1560 ggtggtgatggaagctatttataggcccaacaacacgtgctctcacttgctaaggctgat1620 ctagttactgccactgctgaagatccagcctgacagcaacagataccatcactgagtctc1680 cagtatggctccatccctcaagaagaccaaccagcttcttaatggcaaattattcttctt1740 ' aatgacaaaatgggtcctttccaccatgtgattccaccctgtgattttgatacgaatgga1800 cacttatcctattcatacaacttcagctagacagtgcctatgtagcattt~gatccactga1860 aacaggatcctgccaaacattgcattggactaaagtaactgcttatgttaatggaagttt1920 aaccttaattacttccttataggccttaactccaaatacagtcacattgggggttataga1980 ttcaacatatgaattttggaaggctcttcttttcccagaattgtctttgctgaaaatcaa2040 ttgaccataaatataacgatttatttctggactgtcaattctgttccattggtctatatg2100 tcttcttactgcaaataccatactgttgataactgcagctttatagttagttttgaaatc2160 aaggattaaacattctccaactcctttcttcccacgcatggaaaatcactgatctctttt2220 ctgtctctacagatttacctattctaggtacttttctttttaaacagtgtcttttggcta2280 ttctaggtcttttgtacttctatgtaaattttacaatctgcttgtcagttcgtgatgaaa2340 aaggctggtggaattttgagagggattgtgttgtctatatatcaatttgtagaaagttgc2400 catcttaacatattgagttttcaaatctcagaacatagaatgttagaggtccctgtntct2460 tttttaattttaaatttcttttcataatttaaacattttttctattgaggtaaaattcat2520 atagataaaattaactattttaaagtgaacaattaagtggcatttattacattcacaata2580 tcgtacaacaactacctctatctagttccaaaatattttcatcaccacaaaagaaaactg2640 tgtacccatcaaacagttactcctetttcctttttctcccaacctcggacaccacagtct2700 tctttctgtctctatggatttacctgttactctgaatatttcatataaatgaagtcatac2760 aacatgtgacctttgtgtctgacttctttcgttagcacagtgagtgtcttcaaggttcat2820 tcacattgtagcatgtatcaacttcattccttttgatgaccaaatgatatcctattatat2880 gtatatacca cagtttgttt attcattgat gaatatttga attctttcta ccttttggct 2940 attgtgaata gtgcttctat gaatatttgt gtataagtac tcatttgaat acttttttta 3000 a 3001 <210> 87 <211> 1127 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 311 <223> 12-254-180 : polymorphic base A or G
<220>
<221> mist binding <222> 292..310 <223> 12-254-180.misl <220>

<221> mist binding <222> 312..331 <223> 12-254-180.mis2, potentialcomplement <220>

<221> primer bind <222> 132..152 <223> upstream amplification primer <220>

<221> primer bind <222> 586..603 <223> downstream amplification primer, complement <220>

<221> misc binding _ <222> 299. 323 <223> 12-254-180 potential probe <220>

<221> misc_feature <222> 952,958 <223> n=a, g, c or t <400> 87 ctgccacaat ctcctgagtccagacaatctagagcagaagggtagactga ggaaaatata60 cacagtataa aaaagtaacaaaatcaaaacctgaaacaaagatcaacatc caataaatgc120 ttctgaataa agggagagtagataagaactggattttaatcccaacactg ccatttacca180 gctggccaat actgagctagttactctaaagagttcagttttctcatttg tacaaatagg240 atttgtcttt ccatctcactgagttgtgatgagagtcatatgcaacagca tatgaagagg300 ctagcaaaag rtatttaacaagcgttcaacattctcatgatgacatgaat aacactgtac360 atacaacata ccaacttgataaatacacagcacagttaatagctgagggc agagttatgg420 ttgggaagag agagagtgcaacataggcagagtgaggggggattcccaca attttctaag480 acagaaaagt gggggaatcagtagttactggaaagaataggcaatgcctg actggataga540 aaaagattct atgcctttgtcaaatttcacaaaagtgacttaagcctata ctgcgggatg600 ttcacactac gtccctttagtgcagttacggtacttcaggctgcaagtaa ccaaatacaa660 ctaaaattgt cttatacaataagggcgtaattatctcatataacaagaag cttggcatga720 aggaaatttc aacaatttcacaacggcaacaaaaactctgtttcttctac ctttccacca780 ttcctgtgtt ctcagttccaatatggctgctaacatccatatgtcttccc cgcacatctc840 tttaaaagct acaaaaagatttcccaaaagcgtcttggaaaatttcctgt cccatctcca900 ttggccagac ccacctcccatgggactgcctcttgtgaagcacacaaagg gncagatncc960 aaacggtacc gttagggagacccagaagatggaccatccaggatagagac atgaagggca1020 gaagagggcc cagggatgtgtgtcectcagctggactacagggaaggagt tttggtcagg1080 ggaagaaaag cctcatttcc tatcagtcac tggtggaatg actaaag 1127 <210> 88 <211> 3001 <2l2> DNA
<213> Homo Sapiens <220>
<221> allele <222> 1501 <223> 10-214-279 : polymorphic base C or T
<220>
<221> misc_binding <222> 1482 .1500 <223> 10-214-279.mis1 <220>

<22I> _binding misc <222> ..1521 <223> potentialcomplement

10-214-279.mis2, <220>

<221>
primer bind <222> ..1244 <223>
upstream amplification primer <220>

<221>
primer bind <222> ..1764 <223>
downstream amplification primer, complement <220>

<221>
misc binding <222> ..1513 <223>

potential probe <220>

<221> feature misc <222> _ .2373 2368 .2369,2372.

<223> g, c or n=a, t <400>

aatcattgagttttgttctctatattttctctttatctaagaatgtcttc ccccctccat60 taacaatatcctctcattttattccatttaaaatatcccagtggtgcctt gcaagtgacc120 tcatctaactcaagcatttggtcatttggtaaatgtttaaggagtgatat gcagtcgatt180 ggtttgcatacaaatattaagttttttaatgtgaacatttagcaaatgac attcatgtat240 ttgcatgtgtgtgtgcttgcacatgtgcacatgcatgtctgtctgcaggg aaaatatatt300 catgccttttgaaaatttttaaataatgtgttatatttatagaaagattt ggaacctttt360 ctctgaagaagttaaagaacagatgtcattgattcatattaagcaagacc ctataaatct420 tatttctaggtctcatgtat-ttattaagcaactccacaccttaagcaggc tttctacata480 gaagaggaagaagatagagatggtttccatattattttcatattccacat tatttgtggc540 tttaggccagctatgtagctatcctgtatgtgtgctcagacaggagactc agccctgaga600 gaaggcggtcctctggcacacctaggatggggaaggtactcccttggaag tcccaagctg660 gcacttctggatctccatggcaattttcttgcccatcactccatggagat cagaatatca720 ctctattgtgtcccctcaacactgaaggagtgtctcaataagaaaagttg agtcaaaaca780 ctgtaggaattgagaggttccccacttgcactacccttgtaaaccaagag aagatgttaa840 aaaataaaacgataatgcttcctgaaggtgtcttcccatctttacactag atgggttcaa900 ttgagaggaattactggactgtggaagttgaagactgtccacataattaa aatgtacaat960 agctactcaggattaccttgcaagtttcaacatacacaaaattaacttca taagatggtt1020 taaaaagtttaccgttatacctaataatctggtttaaatttttaaaactc atccattttc1080 gttaaaatttaaatcaaaaaagaacacgggttcccatgaatttgtctcag gtcaaacctc1140 acacagaataggtgctccatgaatattttgttaaatgatagatgatgaat gttctcacta1200 tccaatcttcacacatcttatagagtaagtataacgaatccaagatttatagtgctgaaa1260 gtagtttttatatgtttacaaagcattattgtcagtaatttttttttactttgatgctat1320 actttctacttttgctttatttaatgcttctcaatatgctcgtttaactgttgcagatcc1380 ccctgaaattacgctttggaggacttcttctaacagaaaaacccattgttctaaaggctg1440 agtcaagggatgagaccgtaagtggagcctgatttccctaaggacttctggtttgctctt1500 yaagaaagctgtgccccagaacaccagagacctcaaattactttacaaatagaaccctga1560 aatgaagacgggcttcatccaatgtgctgcataaataatcagggattctgtacgtgcatt1620 gtgctctctcatggtctgtatagagtgttatacttggtaatatagaggagatgaccaaat1680 cagtgctggggaagtagatttggcttctctgcttctcataggactatctccaccaccccc1740 agttagcaccattaactcctcctgagctctgataacataattaacatttctcaataattt1800 caaccacaatcattaataaaaataggaattattttgatggctctaacagtgacatttata1860 tcatgtgttatatctgtagtattctatagtaagctttatattaagcaaatcaataaaaac1920 ctctttacaaaagtattattggatgtttcctgcacattaaggagaaatctatagaactga1980 atgactgagaaccaacaactaaatattttgatcattgtaatcactgttggtgtgggaact2040 ggagtgcagtggtgcaatcttggctcactgcgagctctgcctcccaggttcacgccattc2100 tcctgcctcaacctcctgagtagctgggattacaggtgcctgccaccacgcccggctaat2160 ttttctatttttagtacagacggagtttcactgtgttagccaggatgctctcgatctcct2220 gaccttatgatccacctgcctgggcctcccaaagtgctgggattacaggcatgagccacg2280 gtgcccagcccaatttgattattaacataggtgagagttaacccactatgactttgccca2340 ttgtttagaaagaatattcatagtttanntannacatttttgatgagaca~cagtggctca2400 cacctgtaatcccagcactttgggaggccaaggcaggcagatcatctgaggccaggagtt2460 caagaccagcctgaccaacatggtgaagccccctttctactaaaaatacaaaaattagct2520 aggtatggtggcacacgcctgtaatctcagctacccaggaggctgaggcaggggaattgc2580 ttgaacctgggaggtggaggctgcagtgagccaagatcatgccactgaactccagcctga2640 gtgacagagtgagactgcatctaaaaaataaaattatgcctttttgtagcacatatattt2700 tgtaacatacaactgaagccagtattatattattagttttcatttaatgttttcagccca2760 tctcccctgatatttctgggagacaggaaatatgttttcttacacctcttgcattccatc2820 ctcaactcccaactgtctaaatgcaatgaacatttaataaaaaaaacagttgattggtca2880 attgattggacaacaaggctgaaactactcatttcttttcttttcctatttcttccttta2940 ttttccctttctgaataatttagccctagagccattaggtgggtggcagccagatggtgg3000 c 3001 <210> 89 <211> 3001 <212> DNA
<213> Iiomo Sapiens <220>
<221> allele <222> 1501 <223> 10-217-91 : polymorphic base C or T
<220>
<221> misc binding <222> 1482..1500 <223> 10-217-9l.misl <220>
<221> misc binding <222> 1502-..1521 <223> 10-217-9l.mis2, potential complement <220>
<221> primer bind <222> 1414..1430 <223> upstream amplification primer <220>
<221> primer bind <222> 1759..1775 <223> downstream amplification primer, complement <220>

<221> misc binding <222> 1489..1513 <223> 10-217-91 potential probe <400> 89 gattgttggt acatagaaac atgcttggct tttgtttgtt gatcttgtat catagaacct 60 tgcagagctg acttagtatt tctagaagtc tttttgtata ttcttgagat tttatacatt 120 gacaattatg tcacttgaaa atagagacaa ttcttttatt tcctttccaa tctgtatgcc 180 ttttaattct ttttcccagt ataatgtcaa ataaatgtgt tgaatttttg aattgttcct 240 aatattagga aggaagcatt tggtctttca tcatcaagaa tgatttagat gaagtgggtt 300 tttttgtaga ttctctttat caaatggagg aattttctct ccctagtttg ctgaattttt 360 aacataaaag agtactgtaa gtactcatta taaaacaaaa tatggctgtg gaagatgaaa 420 gagagtttca agcatgctgg cttgataggc cagatccaag ctggcaaaaa taattatctc 480 tttcttcttt ttttctatcc atggaataaa aaattaagag gaaagaatgt taatagaatc ~ 540 gcattatttc ttcaaaatac gttgtgagtt ttaaaagtat tatctacctt ttttattata 600 ctttttttag ggtacatgtg cacaacgtgc aggtttgtta catatgtatg catgtgccat 660 gttggtgtgc tgtactcatt aactcatcat ttaacattag gtataactcc taatgctatc 720 cttcccccct ctccccaccc cacaacaggc cccagtgtgt gatgttcccc ttcctgtgtc 780 catgtgttct cattgtatat ttttttaaat ctaccacatc aaggcacctc tttttcatgt 840 tgcccatggt ttaggtgaac ataaagacag agctcgtctg aggcaacata cagtccaaca 900 aagccacctg cctctctgtc tccactctct ctctacactg cacgcgtgct aggtgttgat 960 cctgtctatt ccagtggaag aacaggttcc gtaccatgtg gagaatttgc atgtaaaagg 1020 agactgggat atacaggctg gagaccacat caggtggctg ggcatgtggg ataaatccta 1080 ttgagcatct gtcatagggc ctgtcactta gtagacagtc actaaatatt tgttaaatac 1140-atgatgcctg tttaacacat tttctacaac catggagacc tccacaactg atgtaggaca 1200 aaatctttct gctttgaact ctagcctttc gggccagtgg gatttatgaa aaatgccatc 1260 tctatagctg aggatgaaga atggaagaga atacgatcat tgctgtctcc aacattcacc 1320 agcggaaaac tcaaggaggt atgaaaataa cttgggtttt aattagaaac ttaaagaatg 1380 aatcaggtgg ggacaggtag aaagtaagat cagagttcct ttccgaggag tagtctgctg 1440 aatttgagct tcctaaaaat agtcttttta tgtacagaaa acacatcata aaattcatta 1500 yacaatgtca cttattgttc catgccaggc aaagtcatgt ccttctggga cttatgtctg 1560 cacatttaac tatgggtggt gttgtgtttt gtgcttagat ggtccctatc attgcccagt 1620 atggagatgt gttggtgaga aatctgaggc gggaagcaga gacaggcaag cctgtcacct 1680 tgaaacagta agtaggagca cagccatggg gttctgagct gtcatgagcc cctccagctg 1740 cctgctatgg agctgatact cccgctgttg ggttattcca gtgaccagac aaaaggaggg 1800 ctgtggtaat gcaacttcaa tgggtctccc aagatggggc agctccgatg aggaggtggg ~ 1860 gcagctggag gaaaaggatc ttctcccctg tgcacagagg tcagggttta catatctgtt 1920 aaattgtcac cttggatatt ctggaggact aaatacatcc tttaggggga aaagtgtgat 1980 tgtatcaaag ttttaagcat ggagtgtatg ggatggtgga aggggaaggc acttggtatc '2040 tgttggttgg cagtgagtag ggtgggaaag ttataatgga gaacttagaa taactttgat - 2100 catttcatgt tttttttctg agggtatcag tagaatacta aatattaaac attcccacca . 2160 tttctttttc ctccagtctc aaagagagag ggtggtaaaa acgctatagg tggggcaagc 2220 ctattatttg ctgtctacac ttatgcagga acaacaggtg taatctgagc ctgtcctggg ~ 2280 cagacagggg atatgtggtc actcactata gaagtttcca aatcaaattt tgagagtttt 2340 ttttaaccag gacatcattt gtcattatat tttacaaaaa taattctgcc atcagggcaa 2400 cctcagctca ccacagctgg ggatagtgga attttccaaa gcttgagcag ggagtataga 2460 gaataaggat gatatttcta ggagctcagg acatggtact gttgctttgt aaagtgctga 2520 agaggaatcg gctctgggca tagagtctgt agtcaggcaa tgtcacctgt cttgagcccc 2580 ttagaaagag tgaatttttc tactcttgtt ctgctgaagc acagtgctta cccatcttgt 2640 atcatccaca attaacacat gctactgcag ttgtctgata gtggatctct gtctttctat 2700 gactaggctc cttgacctca gaggtaagtc taactcagtt gagtgtctcc atcaccccca 2760 gcggagagcc agctgtgtca ctgacacctg ataatcacct tctgagggag tgtgatggga 2820 gatgctccag taaatagttc tgaaagtctg tggctgtttg tctgtcttga ctggacatgt 2880 ggatttcctg ctgcacgcat agaggaagga tggtaaagag gtgctgattt taattttcca 2940 catctttctc cactcagcgt ctttggggcc tacagcatgg atgtgatcac tagcacatca 3000 t <210> 90 <211> 410 <212> DNA
<213> Homo Sapiens <220>

<221> allele <222> 168 <223> 99-28779-168 : polymorphic base C or T
<220>
<221> misc_binding <222> 149. 167 <223> 99-28779-168.mis1 <220>
<221> misc binding <222> 169..187 <223> 99-28779-168.mis2, complement <220>
<221> primer bind <222> 1..17 -<223> upstream amplification primer <220>
<221> primer bind <222> 390..409 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 156. 180 <223> 99-28779-168 potential probe <400> 90 tgactgctta acagaccaag ttgcttgcat tttgtatgtt tagccctcct ttgccactgc 60 ttttagagcc ttggaaggct aagtgtgata gtaatgctag ctctaatgca tatttaaagg 120 agactgcctc gcttttagaa gacatctggt ctgctctctg catgaggyac agcagtaaag 180 ctctttgatt cccagaatca agaactctcc ccttcagact attaccgaat gcaaggtggt 240 taattgaagg ccactaattg atgctcaaat agaaggatat tgactatatt ggaacagatg 300 gagtctctac tacaaaagtc tttgggtatt tgtttcttac atagaaaatg ctaacatgaa 360 tagaaagata ctggtgcaag accattcccg ggaaagtaga catacttaca 410 <210> 91 <211> 479 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 300 <223> 99-28788-300 : polymorphic base A or G
<220>
<221> misc binding <222> 281..299 .
<223> 99-28788-300.mis1 <220>
<221> misc_binding <222> 301. 320 <223> 99-28788-300.mis2, potential complement <220>
<221> primer bind <222> 1..17 <223> upstream amplification primer <220>

<221> primer bind <222> 458..478 <223> downstream amplification primer, complement <220>

binding <221> misc _ <222> 288. 312 <223> 99-28788-300 potential probe <400> 91 tctacccatt ctgcttctctgatttttaatgcattgtctctatcccaggc tactttggag60 ggtcatcccg agtttgcagataaattcttccttcctctttggactcattt agaagaaagt120 tgtaactatg gaaatgatgtaactagcctgttaacatccctcagcttcct gttagaaatc,180 cccagtgaaa tgtggagaggttggcttttgacctttgtgttcaccatcat caccatcata240 caatatttat gaaacaccacacacatataattctgaactgagccaagcac agagatcacr300 tccactttcc tcaagggacttgtaatttaaccttggtctggtgtgctact tagaccaggt360 gtggttacat aagaaggaggctgctgccagcaaccacacattaataacaa-tctctctatt420 ttagaataag tccaggaatatgttaggcatggatgtagtaaagtagccaa gaaagggga479 <210> 92 <211> 499 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 263 <223> 99-32052-262polymorphicbase C T
: or <220>

<221> misc binding <222> 244..262 <223> 99-32052-262.mis1 <220>

binding <221> misc _ <222> 264. 282 <223> 99-32052-262.mis2, complement <220>

<221> primer bind <222> I..18 <223> upstream amplification primer <220>

<221> primer bind <222> 478..498 <223> downstream amplification primer, complement <220>

<221> mist binding -.275 <222> 251.

<223> 99-32052-262 potential probe <400> 92 cagagtgaca aataagtgct atggcttgat agaagtgaagctcttcacat atattcaaaa60 tacatatcac aaactttggt aaataggata gtaatctgaagaacttttgc cctttttacc120 ccatttactg taactcttgt ttctaggtaa tcgttctctctcaacaaact tctcaagcgt180 ctgtgtaaca agccacatgt tctaacaaat tgtctccatcgcacttcaac agccaggtcc240 ctatttttta taacgtatta acyttattat tttcttattattttaaaaga atctatgcac300 attagcaaaa tttaaaagat agagaaaaat ataaacagaaaaaattatgt ttacttctac360 caccctaaat caactattat caattttata catattttactccatctttt ttcaaagttt420 cttacatttt ccaatgtcat taaaattctc tgtgaatgta aattttaaaa actgtaccta 480 ctgttttttg gaatctgta 499 <210> 93 <211> 467 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 244 <223> 99-32121-242 : polymorphic base A or G
<220>
<221> misc_binding <222> 225. 243 <223> 99-32121-242.mis1 <220>

<221> misc binding <222> 245..264 <223> 99-32121-242.mis2, potential complement <220>

<221> primer bind <222> 1. .7.7 <223> upstream amplification primer <220>

<221> primer bind <222> 448..466 <223> downstream amplification primer, complement <220>

<221> misc binding <222> 232..256 <223> 99-32121-242 potential probe <220>

<221> misc_feature <222> 72 <223> n=a, g, c or t <400> 93 agcagtatga cagggaccat tctgggtctctgggaagttctcagctgcgg ggagctctgc60 aggccgcagt tnccagctaa atgaacaactttaccaaatgattgtccgcc ggtatgctaa120 tgaagatgga gatatggatt ttaacaatttcatcagctgcttggtccgcc tggatgccat180 gtttcgtgcc ttcaagtctc tggatagagatagagatggcctgattcaag tgtctatcaa240 agartggctg cagttgacca tgtattcctgaagtgggaactgagaagtca agatcctccc300 tggaggacag gactgaaaac cttgccaagctgtacacagttgctgatacc ctgtgcaaca360 gctctcattt cctggcaagc tctttcacaaccctacatatttctgatcat gtgctgcctt420 ttactgctga attaaaacag atattcacgaaaaatgttctgagtggt 467 <210> 94 <211> 469 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 169 <223> 99-32059-169 : polymorphicbase C T
or <220>
<221> misc binding <222> 149..168 <223> 99-32059-169.misl, potential <220>
<221> misc binding <222> 170..189 <223> 99-32059-169.mis2, potential complement <220>
<221> primer bind <222> 1..17 <223> upstream amplification primer <220>
<221> primer bind <222> 448..468 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 157. 181 <223> 99-32059-169 potential probe <400> 94 acaagaaccc acctaccttc cgggttaaga aatagaatat cccatacctg acaagcccac 60 atgcacccca cgccccctaa gcacattcac ccctgttccc tgctctaaaa taaacactat 120 cctgagtttg gcaaacacca cttctttgtt ttttctttat aatattacya tctatgaata 180 tatttctaaa caatacattg ttagtttatt cttcttcaaa ttttatgtaa aaggaatcac 240 actacagata ttgttctgtg acttatttgg cccaatatgt ttctgagatt catccttgct 300 gatggggttg gctgcagttc acttgttttc agtgttgttt atagtaattc tattgtatga 360 ataataacaa tttatttatt catccaactg tgaaggacat~ttggattgtt tccagttttt 420 ttttcttttt ggattttgaa caatgctgtc tataaacgct ttaggatgt 469 <210> 95 <211> 450 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 304 <223> 99-32061-304 . polymorphic base A or G
<220>
<221> misc_binding <222> 285. 303 <223> 99-32061-304.mis1 <220>
<221> misc binding <222> 305..324 <223> 99-32061-304.mis2, potential complement <220>
<221> primer bind <222> 1..19 <223> upstream amplification primer <220>
<221> primer bind <222> 430..449 <223> downstream amplification primer, complement <220>

<221> mist binding <222> 292..316 <223> 99-32061-304 potential probe <400> 95 cacaaaactc actattgccatagctgcaattaaaatttagataatctggc tgcttactaa60 agcaaatagc ttgataaaatgtaccccaaaacagataaaaattatacagc aaaatatact120 atttttttaa ttcttaaatgtcaaatcagtatcatgataagaattattgc acaatctttg180 gttcttttct ttaaaacctactgaggtccccaggaagaattataaactta ataaaaaaaa240 atccagactt gaagatatttcagggccacatttcaaaggagaccagctct ttggagggag300 gccrtaatcc ctccataacctgtcctaatctggagcccagagaagtccag agttagaact360 aaggagttac attgggtaagtacaaatagaaaagataatggtctcatgga aactccagac420 agtgggcccc atccctttcctggaagtcag 450 <210> 96 <211> 487 <212> DNA

<213> Homo Sapiens <220>

<22l> allele <222> 303 <223> 99-32065-303 base G
: polymorphic or T

<220>

<221> misc binding _ <222> 284. 302 <223> 99-32065-303.mis1 <220>

c221> mist binding c222> 304..322 <223> 99-32065-303.mis2, complement <220>

<221> primer bind -<222> 1..17 <223> upstream amplification primer <220>

<221> primer bind -<222> 469..4 <223> downstream amplification primer, complement <220>

<221> misc binding _ <222> 291. 315 <223> 99-32065-303 potential probe <400> 96 gcccaaatgc caactacatt atgataatcttctaaaagttataattgcct aatgttaaaa60 tattttgttt tctgagttat tgccaaatgcgatacatccctagttcggaa agatacccaa120 ctactatact tgaaaccact gaagctacaaaataccttgctctcagtttt cacatttgct180 tttctccctc tacagctttc tgcagtggcataagtggattagttatacta tttttattaa240 ttactttagt agtaatttct attaaaacaattattaataacaattattaa ccagtacagt300 ctkgttattt taaacattag catgaggcagaatggaactgcttttcaggc attatctaat360 taagatggta atagaggaga aactgatcatgagttgacaaagctactggt aaaagtttat420 tcttattgaa cagaaccaaa ttgttgtgatctgtatgccttaaaagtgca gcctcttatg480 tggactc <210> 97 <211> 541 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 118 <223> 99-32123-118 : polymorphic base A or G
<220>
<221> misc binding <222> 99..117 <223> 99-32123-118.mis1 <220>
<221> misc_binding <222> 119. 138 <223> 99-32123-118.mis2, potential complement <220>
<221> primer bind <222> 1..20 <223>,upstream amplification primer <220>
<221> primer bind <222> 520..540 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 106. 130 <223> 99-32123-118 potential probe <400> 97 cagtaaatga ateagtaaag tacaatataa cacaaaagaa aacgaaatat tgcttgattt 60 tttccaataa aagcaaggtt aataaaaaca tttttagtaa gaaaatctat catttttrtt 120 ttaaaaatct ttcaatttta aacatcatta ccaacacatt aaaagtatta tcaataagtg 180 cctttacaat ttcaagcaaa agctactgtg ttttccttat tggaaatact gctttcagtc 240 atcttttttg tctgaggtac tctcttcatg cttttcaggg ctgactttat tactggcggt 300 ggagggggtt gtctggactt ettttggtaa tgaaaacaca tggcacgtct ggaggtctag 360 gtatgttgta aatatcttag catattctgg atgctttaag gcaaaacttt taaattcctc 420 tagaagagaa agaaaaaaaa tccaataagt tggggtgaat cttcttttgg catgatgcag 480 attaataaat gactctaata atgcaattat tacaaaattc tactacccaa cacacaaaca 540 t 541 <210> 98 <211> 449 <212> DNA
<2I3> Homo Sapiens <220>
<221> allele <222> 314 <223> 99-32148-315 : polymorphic base G or C
<220>
<221> misc binding <222> 294..313 <223> 99-32148-315.misl, potential <220>

<221> misc binding <222> 315..333 <223> 99-32148-315.mis2, complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 428..448 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 302. 326 <223> 99-32148-315 potential probe <400> 98 tgagtgcatt tgatgtgggs cagcaaagct tcattcaggt ggaaacagat taagaagacc 60 aaagagtggt gaaatggcta agtaggaatg aaaaaacagc cagctacccg yggccagtgc 120 cttattctaa aagaggacag ctagcttgcc caaggactct tgcagaagga aacctgggag 180 agtttccttc tcctcttgca gaagtaaact cttcaggttg aagagtcagg aaggagctcc 240 agggatgagt gaagtcaact gaagttgcct cttttataaa cagctctgca gtggttctct 300 ggaaaccgag gctsgttgca aacccctaaa aagtactgct ctgcaaggct tgtaactgcc 360 atacttgtgt ggtcctgctc catctccatg tgtggcagtg ccagctgcaa ccagcctcac 420 acagggtccg agagtctcag aactgcaag 449 <210> 99 <211> 920 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 95 <223> 16-2-76 : polymorphic base A or G
<220>
<221> misc binding <222> 76..94 <223> 16-2-76.mis1 <220>
<221> misc binding <222> 96..114 <223> 16-2-76.mis2, complement <220>
<221> primer bind <222> 20..39 <223> upstream amplification primer <220>
<221> primer bind <222> 240..260 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 83..107 <223> 16-2-76 potential probe WO 01!51659 PCT/IBO1/00116 <400>

ctggggcctgagactgaggtccagggagaccctaattcct gcaccccacc cctcctggtt60 ccctccagatgggaggcatggaggctgtcatcacrggcct ggcagatgac ttccaggtcc120 tgaagcgacaccggaaactcttcacatttggcgtcacctt cagcactttc cttctcgccc180 tgttctgcataaccaaggtgagtaggggctgggctctggg tcacctgggg gcctctgagg240 ccgcatttcaataaagtcaaacattcctagccttagaact gggctgagct cagggagaac300 aatgcaggatccagcatcctcaattcagcggcctgaccca ctagggttag gcccagtagt360 cttcttccatctctgassctgaggattccattcagccctg ttaattgcct tattgacttg420 agggscagcaaaagtccctttggaacccatctaactcttt attggctgaa actgaggtga480 ctgtaacgtcaatacaacagcaccacagccctatgccctg ggttttcaaa tagagctccg540 agcaagtgggacagggggcaggtaagagttgacagacaca acaatcagtt cccacgtttg600 accaaagagggcctcttggcttcttctctccctgtgccag ggtggaattt acgtcttgac660 cctcctggacacctttgctgcgggcacctccatccttttt gctgtcctca tggaagccat720 cggagtttcctggttttatggtatgtgagtgtgtggaaaa gcctcagctc ccagtcctcc780 tagaatcctgcacctggaggtgtgcagggaggccttccat ttccaggaca gccacctaaa840 attccagagtccagcaagtcacttattgggaacaaatctc aatcctcggc tcatctttgg900 atgaacctgcccttaacagg 920 <210>
loo <211>

<212>
DNA

<213> Sapiens Homo <220>

<221>
allele <222>

<223>

. polymorphic base A or C

<220>

<221>
misc binding <222> _ 101. 119 <223>
16-28-93.mis1 <220>

<221> misc binding _ <222> 121. 143 <223> 16-28-93.mis2, complement <220>

<221> primer bind <222> 28..47 <223> upstream amplification primer <220>

<221> primer bind -<222> 354..3 <223> downstream amplification primer, complement <220>

<221> misc binding <222> 108..132 <223> 16-28-93 potential probe <400> 100 tctgttatct ctaaacctgt gttctgtccgcccacacatg acctaacaat tgggccccca60 gatactcccc tatcatgtgc agctcagaccaatggtttca gccattgatg aggtccttgm120 tgtttcttac aggagctggc ctagtgttcatcctgtatcc agaggccatt tctaccctgt180 ctggatctac attctgggct gttgtgtttttcgtcatgct cctggcgctg ggccttgaca240 gctcagtgag tgaccctgct taggatacctatcccccatc ccactgggcc tgaccccctt300 ccccaacaca cagtgctggg cctgaagttcccactattca aacaccaggt taacagttgt360 ttcccagaag gccctattta aattgcagacaaaaa 395 <210> lol <211> 922 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 342 <223> 16-3-199 : polymorphic base C or T
<220>
<221> misc_binding <222> 323. 341 <223> 16-3-199.mis1 <220>

<221> misc binding _ <222> 343. 361 <223> 16-3-199.mis2, complement <220>

<221> primer bind <222> 143..162 <223> upstream amplification primer <220>

<221> primer bind <222> 374..393 <223> downstream amplification primer, complement <220>

<221> misc binding <222> 330..354 <223> 16-3-199 potential probe <220>

<221> miac_feature <222> 565,643 <223> n=a, g, c or t <400> 101 agctcaagaa acagtgtctggatgagtgactcaatggacc agctccacaa acaaagctgg60 aggtgtcttg tacagaccccaaatgctatccatgtggggc tgcaggatca aatagcaggt120 ggccctcatc tgcaggtgcagccaggctgcragaagggtg tccctgggcc aagctgaggc180 ctcctcccct tctcttcctttcagagactggcctatggca tcacgccaga gaacgagcac240 cacctggtgg ctcagagggacatcagacagttccaggtgg gtgaagccta gacccctggg300 gtggagatta caagggcgggccctggctgttccctgctgt gyactgccca aggctagaca360 tcacatccag aaaacccagaaacccagtgtgagctgcctt ttccccttgg aaacatcggg420 atgggggaca gggaggctcaccttgagcccatggcctcag gcttgccctg tgactttggg480 gaggttctgc tgccctttctgggcctctgtgacaattagg gaatcaactt gcacgttccc540 tgaggtccgt gaaggaagggggtgnttttctgccttctct ctacctcctg ctgcccccgc600 cagctggccc ttgctcctttctgtccccaccatgtcatca agncctcgct gtctttctct660 gcagttgcaa cactggctggccatctgagcctgcctggag gagaaggagg aacccccatg720 ccaatgtcca ggtcacaggcatccgctgcgctcccacctc ggacaccatc ttgggattec780 tcccctggaa gttgtcctttctgatcctctcttcttttcc catttacaaa tgatttcgtg840 actgtagttt ttgttcaccttctgtgcatctggcctgggg gctgttagct cagaggagag900 gagcaaacag gaaaatgacttc 922 <210> 102 <211> 245 <212> DNA

<213> Homo Sapiens WO 01/51659 . PCT/1801/00116 <220>
<221> allele <222> 197 <223> 16-50-197 : polymorphic base C or T
<220>
<221> misc_binding <222> 178. 196 <223> 16-50-197.mis1 <220>

<221>misc binding <222>_ 198. 216 <223>16-50-197.mis2, complement <220>

<221>primer bind <222>1..20 <223>upstream amplification primer <220>

<221>primer bind <222>227..245 <223>downstream amplification primer, complement <220>

<221>misc binding <222>_ 185. 209 <223>16-50-197 potential probe <400>102 agaacctcat atcatggggg ccatggtaac aggcctgccc60 gggaggacct ggccctggct tgtgtgtgca aacgacatcc agcagatgat ggggttcagg120 caggagtgga caggttcagc ccgggtctat ttcgtcagtc ctgccttcct cctggtgtgt180 actggagact gtgctggaag agtgtctgca agggggctgt gtccaggatg gagctgggtg240 gggaagycct gcatgtgggg aggat 245 <210>103 <211>357 <212>DNA

<213>Homo Sapiens <220>

<22l>allele <222>181 <223>16-1-59 : polymorphic C or T
base <220>

<221>misc binding <222>_ 158. 180 <223>16-1-59.mis1 <220>
<22I> misc_binding <222> 182. 200 <223> 16-1-59.mis2, complement <220>
<221> primer bind <222> 123..142 <223> upstream amplification primer <220>

<221> primer bind <222> 290..309 <223> downstream amplification primer, complement <220>

<221> mist binding <222> 169..193 <223> 16-1-59 potential probe <400> 103 gttgccaggg ctgcccatct ctggttcagaccatgtttcctctggtctca gagcatcccc60 agggtttctc agcccttccg gaccagtgaggtgttccagtgttgtaggaa gcagaggctg120 atggcttttg tctgctggtt tcaggtatggattgatgccgcaactcagat atttttttcc1B0 ytgggggctg gatttggagt attgattgcatttgccagttacaacaaatt tgacaacaac240 tgttacaggt aagattcttc tcagaattctgagaagctctaaatcctggg gattgactct300 tgtggggtgg cagagagggc tctggtctggaagccaactctccctgggca agccaaa 357 <210> 104 <2I1> 920 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 206 <223> 16-2-187 : polymorphic base A or G

<220>

<221> mist binding <222> 7.83..205 <223> 16-2-187.mis1 <220>

<221> mist binding <222> 207..225 <223> 16-2-187.mis2,complement <220>

<221> primer bind <222> 20..39 . ' <223> upstream amplification primer <220>

<221> primer bind <222> 240..260 <223> downstream amplification primer, complement <220>

<221> misc binding _ <222> 194. 218 <223> 16-2-187 potential probe <400> 104 ctggggcctg agactgaggtccagggagaccctaattcct gcaccccacc cctcctggtt60 ccctccagat gggaggcatggaggctgtcatcacgggcct ggcagatgac ttccaggtcc120 tgaagcgaca ccggaaactcttcacatttggcgtcacctt cagcactttc cttctcgccc180 tgttctgcat aaccaaggtgagtagrggctgggctctggg tcacctgggg gcctctgagg240 ccgcatttca ataaagtcaaacattcctagccttagaact gggctgagct cagggagaac300 aatgcaggat ccagcatcctcaattcagcggcctgaccca ctagggttag gcccagtagt360 cttcttccat ctctgassctgaggattccattcagccctg ttaattgcct tattgacttg420 agggscagca aaagtccctttggaacccatctaactcttt attggctgaa actgaggtga480 ctgtaacgtc aatacaacagcaccacagccctatgccctg ggttttcaaa tagagctccg540 agcaagtggg acagggggcaggtaagagttgacagacaca acaatcagtt cccacgtttg600 accaaagagg gcctcttggcttcttctctccctgtgccag ggtggaattt acgtcttgac660 cctcctggac acctttgctgcgggcacctccatccttttt gctgtcctca tggaagccat720 cggagtttcc tggttttatggtatgtgagtgtgtggaaaa gcctcagctc ccagtcctcc780 tagaatcctg cacctggaggtgtgcagggaggccttccat ttccaggaca gccacctaaa840 attccagagt ccagcaagtcacttattgggaacaaatctc aatcctcggc tcatctttgg900 atgaacctgc ccttaacagg 920 <210> 105 <211> 466 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 311 <223> 99-28761-311 base A or G
: polymorphic <220>

<221> misc binding <222> 292..310 <223> 99-28761-311.mis1 <220>
<221> misc_binding <222> 312. 331 <223> 99-28761-311.mis2, potential complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 446..465 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 299. 323 <223> 99-28761-311 potential probe <400> 105 tttgtaactc taagaaggca tttttaaaaa gtaagtaggc aataaagaaa tggtacttct 60 atgtaagtag tgcatgtgta gtagtgagtt ttgtgatcaa tatacattgc tttgtatgtg 120 atttgctttt aagatgttgg aaatgagaat ctgatatatt agagaatttg acttacaaga 180 tttgcaattt taagtgtaac acctaggagg atttaatgaa ttaattttgt agtcaatgtt 240 tggatgctca ggagaacctg aatttatcag tttaattctc agcaggttga aatgctttaa 300 gagaatttgt rtgctaaatt tagaagtttt gatttattag tcttacaaga actaagtaag 360 tcctgagaaa gattttgttt cttctatttg taagtcttcc tgttagggat ttgaagattt 420 taacaaagcc agatgtatca aatttgtgag tatagtttga aatgct 466 <210> 106 <211> 462 c212> DNA
c213> Homo Sapiens c220>
<221> allele c222> 86 <223> 99-28771-86 : polymorphic base C or T
<220>

<221>~.misc binding <222> 67..85 <223> 99-28771-86.mis1 <220>
<221> misc_binding <222> 87..106 <223> 99-28771-86.mis2, potential complement <220>
<221> primer bind <222> 1..18 -<223> upstream amplification primer <220>
<221> primer bind <222> 444..461 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 74..98 <223> 99-28771-86 potential probe <400> 106 ttcagagtag taacttccaa aggctaatgg atgaatgtga gtatttccat tctcattgtg 60 gccaggaaag atagagataa tcatayagta cccagaaaat gactgcttca tatgatgagg 120 ctttaatttc cattttaatg gaaacatgtt catttaaaag aaagaaaagc agatttctga 180 actatgtctc ctctctccgt taacaacctg gatgtgcacc tagaattaat gagctacatt 240 tttatttcta ttttgctaaa gaggctgacc agggctgttg cattacctga tgtctaatct 300 ttccagtgct cctctcacgc ctcccctcac tgttttcccc cttctgaatg cgatgttagt 360 attttggctt tgtctcaaat aaacttacaa gtcgggtttt tatttctccc caacggagcc 420 tctcaaatcc cttatcttca gctcaacagg aaggagatta ct 462 <210> 107 <211> 452 <212> DNA
<213> Homo Sapiens <220>
<22I> allele <222> 291 <223> 99-28791-291 : polymorphic base A or G
<220>
<221> miac_binding <222> 272. 290 <223> 99-28791-291.mis1 <220>
<221> misc_binding.
<222> 292. 313 <223> 99-28791-291.mis2, potential complement <220>
<221> primer bind <222> 1..18 -<223> upstream amplification primer <220>
<221> primer bind <222> 432..451 <223> downstream amplification primer, complement <220>

<221> misc binding <222> 279..303 <223> 99-28791-291 potential probe <400> 107 taaaaaccca cactcaacatgggcagtcaagccaaagactgggacctttg gagagcctct60 ggaatgagag ttctctggggtacttccaaagggagctggcagtcagtcca ggggacctaa120 aggaatttgg ttgaacagtatcatctctgtgcatagtaagagggaatgtt gggtggtccg180 ggcagtttcc aatatggcaaagcatctgcttggacagtgccagcaagcct tcctctgacc240 cagtctccaa tgtccactaacttataaaaatgtcatcaactcccacatgt ragaaacacc300 atgatttgta ctgtgcatgggtcacattcttattctagaaatgcatcacc ctgtgtttat360 ccaagtgtgt ttacttggtgtaatgtccagtagtaatagaatatgaaata tcaaggaacc420 atctttgtta cgtgacttccaaaatgtgagat ~ 452 <210> 108 <211> 489 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 66 <223> 99-32077-66 base A
: polymorphic or G

<220>

<221> misc_binding <222> 47..65 <223> 99-32077-66.mis1 <220>

<221> misc binding <222> 67..85 <223> 99-32077-66.mis2, complement <220>

<221> primer bind <222> 1..38 ' <223> upstream amplification primer <220>

<221> primer bind ' <222> 471..488 <223> downstream amplification primer, complement <220>

<221> misc_binding <222> 54..78 <223> 99-32077-66 potential probe <400> 108 gctggaggtg agataaggca tcttcaccgctgcatttccagctttgtagg gggaaaacaa60 tttgcrtttg ggaaataatc caacaagcaatcctatggttttaatacaaa~.cactcaaaga120 ggttctggcc atgaccatct gggtccagcccttcactgaattggaaagac ggcaacgata180 atggttgaac aggcccacat gtgttggctctgattctgagtttcccctac ccaccgcacc240 ccatgattga agaggataca gggctccaccactgtcaggcatcaaggaag acacaggtct300 aggggagaaa tcaacacttc tcagggtccttttcaaggactaccccagag atggaaggtc360 atctagtcta tggtgtcctg gacctgccttggcagtagtcgtggccattt tggggtaacc420 taaagaaaac agacaatgtt tgatttgtaacatattgagagttgtttttg cccttttgat480 gacctgcag 489 <210> 109 <211> 489 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 467 <223> 99-32078-466 : polymorphic base C or T
<220>
<221> misc_binding <222> 448. 466 <223> 99-32078-466.mis1 <220>
<221> misc binding <222> 468..486 <223> 99-32078-466.mis2, complement <220>
<221> primer bind <222> 1..17 <223> upstream amplification primer <220>
<221> primer bind <222> 470..488 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 455. 479 <223> 99-32078-466 potential probe <400> 109 agcacccagt ttgttagagt aagactgggc caaagcatcc tgggatgcag tagtggtatg 60:
gtagactaac tgctgtaaca aatagacccc aaagcggatg gtagctcata cacaacagga 120 atttattctt gttctcatta cagtagtgga tatgggaata ataagcaggc tccaatctat 1B0 ctgggtcttt cagggaccca gaattgacaa ggctttgctt tcttcaacac ttggcttcaa 240 ggttatcctg gggttgcctt ctattctggc cagccagaag gaacaaaaaa catgatgtat 300 ttctatgcgg gaggctttta ggggcccagt ccacaaaagg cttacatcag ttccaccaac 360 tctccattgg ctggaacgca ggcacagggt ggcacctgac tgtgtgggaa atgtggtcca 420 tggctgctca gcacttccca gcatgatgct tggagcaagc aggccayctc tgtctgagag 480 aggatacag <210> 110 <211> 470 <212> DNA
<213> Iiomo Sapiens <220>
<221> allele <222> 426 <223> 99-32376-426 : polymorphic base A or G
<220>
<221> misc binding <222> 407..425 <223> 99-32376-426.mis1 <220>
<221> misc binding <222> 427_.446 <223> 99-32376-426.mis2, potential complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 449..469 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 414. 438 <223> 99-32376-426 potential probe <400> 110 ggggctgaga attactggca ttgagacttt tgatgctggt agctgcaact gatgcagttc 60 ctccttaaac ccagtgaaaa aacctgtggt cacgtagctt tcacacttta tcctatgtca 120 caaacaaacc tgaatctgca aacctcctgg gatggtcctg caaatgcaag gtgaccatga 180 acctgctgtt ccccagagcc ccctttgcat tgagggcttt tgaggccatc tctcatttga . 240 tacaagctga gcagcctcgt tcctcctgct cttcctcaaa tgtccttcag gctttctctc 300 cttctcacag catggtgcta gatgcttgac tttttacttc ctggaaaaaa aatttcaggt 360 ccatgtggct tcttgatagt aaaagaaagc aatactcatg tatttattgg ttcactcaca 420 tctggrtgtt agagccaaat tccaaagacc tttgaaagtt ctcttgcagg 470 <210> 111 <211> 457 <212> DNA
<213> Iiomo Sapiens <220>
<221> allele <222> 420 <223> 99-32361-419 : polymorphic base G or T
<220>
<221> misc_binding <222> 400..419 <223> 99-32361-419.misl, potential .
<220>
<221> misc_binding <222> 421. 439 <223> 99-32361-419.mis2, complement <220>
<221> primer bind <222> 1..18 -<223> upstream amplification primer <220>
<221> primer bind <222> 442..456 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 408..432 <223> 99-32361-419 potential probe <400> 111 $5 tctctaatct tctccatcatcattatctgttgaaattaaaatgcatcctg aggcatgctg60 cccagtggct ttatatcttgtctgcacaatgagattgtaagctccttgag gaaaaggacc120 aggttgtgtg tgaattatgcattccttgtggtgtctagaataatatcaag ttcagaagac180 tcaggtatca cttgagatgtctctttctggcccctccaatggtctgaata aatctgactc240 aaactcccag tttaacagtcttgatgaagcccaaagccctatccatgata cgtgagaatt300 cttattgttt ttcttttgatgggtcccattgtgactagttcaaaatactg gagactatgt360 cttttttcct tctcattaacatggttacaaaactctctcttttataaact tccataaaak420 ctggtgagtc tcttaagaactggtatttagagacctc 457 <210> 112 <211> 424 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 228 <223> 16-21-228 : polymorphic base A or G

<220>

binding <221> misc _ <222> 205. 227 <223> 16-21-228.mis1 <220>
<221> misc binding <222> 229..251 <223> 16-21-228.mis2, complement <220>
<221> primer bind <222> 1..25 -<223> upstream amplification primer <220>
<221> primer bind <222> 399..424 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 216. 240 <223> 16-21-228 potential probe , <400> 112 tagcaggcta agtcctcctt ctacttcatc ccagatgata cccacttcag gaagtctttc ccttctgtgg gatgagatgc ccattctgca gggctttcac tccctgcatc.ctgccaaacc 120 tcatcatctc ttacctggat tcctgctaca gcctcccagt tggtgtcccg cttccactct 1B0 gggcccctcc tctccgttct ccacagtgct gtcagaatca cctattcraa aggcgaatcc 240 gatcatgtgg ttcctgctgc ccttaggatc atgtataaac tcctagcatg acttttaagg 300 ccctctatga tcttgcctat tgcaacctcc ccagactcaa cccttgccag gtccctctgc 360 atcagctatc cagaatctct ttgaggccct ccacctgctg tctacctctc tacctctgtg 420 cttt 424 <210> 113 <211> 481 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 156 <223> 16-22-156 : polymorphic base C or T

<220>
<221> misc binding <222> 133..155 <223> 16-22-156.mis1 <220>

binding <221> misc _ <222> 157. 175 <223> 16-22-156.mis2,complement <220>

<221> primer bind <222> 1..24 <223> upstream amplification primer <220>

<221> primer bind <222> 458..481 <223> downstream amplification primer, complement <220> ' <221> misc binding _ <222> 144. 168 <223> 16-22-156 potential probe <400> 113 gcctgacaca tggtaagtccttagtattattacagttatt aggacttagc tgagccagct60 cagggcctgt actgcaggtctcagctttatgtgagcaaga gcattaagga atgatgcctg120 gatgcctggg ggtgtgaagaaaagagccttgggttygact agggaacctg gggccactcc180 ttcctctgct actaaatcaccaagtgatcttgttctgttt tcttctctga ccctccctag240 ttttgtccac ccttgaaataatcatctttccttttcacat ttcatgctta ccaagtactt300 gtcacctaat tatctcctctcttgataagctagatggtyc cttccagggc agcttagtag360 agagcatggg atgtgatgtttcagattccagctctgctgc acacctgcca ggtgaacttg420 gccacgttac atggcctctctgggcttcagttccctcacc tatgagtggg ataagcaagc480 c 481 <210> 114 <211> 478 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 404 <223> 16-23-404 : polymorphic base A or G
<220>
<221> misc_binding <222> 381. 403 <223> 16-23-404.mis1 <220>
<221> misc_binding <222> 405. 427 <223> 16-23-404.mis2, complement <220>
<221> primer bind <222> 1..26 -<223> upstream amplification primer <220>

cttttttcct tctcattaacatggttacaaaactctctcttttataaact tccataaaak420 ctggtgagtc tcttaagaactggtatttagagacctc <221> primer bind <222> 455..478 <223> downstream amplification primer, complement <220>

binding <221> misc _ <222> 392. 416 <223> 16-23-404 potential probe <400> 114 ctaagtggga ataacgctaaacatacttggattaatgcacaaggccctga gatagaggac60 aggcgtctgg tagacctagaagggcacgcaaacatatgaaacacatagga acacaagtga120 gttcaacaga cagagccaagttatcttgctgcaaacattaaaaggtggcc aacctctccc180 aatacacagg tcagactaaaaagatggtttactcttttaaaagttttctt gtgtcattct240 ttctggatac atcggcttcacttgttatgcccagacatggcaaaactaat gaccaagtaa300 tgagggaata gtaatggaaagacttgggagcagtccatcatcacagctta actttttgct360 cacaaccgtg tttttaatactctggtatctgctgtgcgtttgtrtatatc taagatgacc420 aggcagcctt aaacatctagttgcgttcatattctctgtaaaatcgctcc ttgttcct 478 <210> 115 <211> 428 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 175 <223> 16-24-175 : polymorphic base A or C

<220>

<221> misc binding <222> 156..174 <223> I6-24-175.mis1 <220>

<221> misc binding <222> 176..194 <223> 16-24-175.mis2,complement <220>

<22l> primer bind -<222> 1..22 <223> upstream amplification primer <220>

<221> primer bind -<222> 405..4 <223> downstream amplification primer, complement <220>

binding <221> misc _ <222> 163. 187 <223> 16-24-175 potential probe <400> 115 tcgaaccgat cttcagttgacagaagaggaaacaggctca gaaagattag gcaactcacc60 cgtctcaaga gttggtgacactaagcccagacctgtgtga ctctgaaatc cacacctgtg120 ttctttccac tgacatgagctgccttatggatgggcaggt tctggggtag gacgmgcaga180 gcagctgcgg ggactggtggcggassagtttgtgtacata gagccctcag gtgcggaagc240 mmagcagacc ccagcctctgccaggtggtagctgtaccaa catgcaagca gcaggcattc300 catcctccag agggatggagaacagggccagagaacccac agagggccgc atacaaaatc360 caggtctggt gtcctgccttcacctgcactgcaagggcag gactctaaga agctgtttat420 gaggcagg 428 <210> 116 <211> 433 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 286 <223> 16-25-286 : polymorphic base C or T
<220>
<221> misc_binding <222> 267. 285 <223> 16-25-286.mis1 <220>

binding <221> misc _ <222> 287. 305 <223> 16-25-286.mis2, complement <220>

<221> primer bind <222> 1..22 <223> upstream amplification primer <220>

<221> primer bind <222> 412..433 <223> downstream amplification primer, complement <220>

<221> misc binding <222> 274..298 <223> 16-25-286 potential probe <400> 116 ggtcccatgc ctcagtgaca tccttgcctccctggcaggg tgaccctgtg gtgtttgcag60 gagtcttcag agggtgaaag ggaggggccagtgagatggg tggctgatgc ctgggaactt120 gtccggcttt acccagagcc ctctgcctctggtgcaggag gctgcccggc gagcccagga180 gctggagatg gagatgctct ccagcaccagcccacccgag aggacccggt acagccccat240 cccacccagc caccaccagc tgactctccccgacccgtcc caccayggtc tccacagcac300 tccygacagc cccgccaaac cagagaagaatgggcatgcc aaagaccacc ccaagattgc360 caagatcttt gagatccaga ccatgcccaatggcaaarcc cggacctccc tcaagaccat420 gagccgtagg aag 433 <210> 117 <211> 433 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 279 <223> 16-25-279 : polymorphic base C or G

<220>

<221> misc binding <222> 260..278 <223> 16-25-279.mis1 <220>

<22I> misc binding WO 01!51659 PCT/IBO1/00116 <222> 280..298 <223> 16-25-279.mis2, complement <220>

<221> primer bind <222> 1..22 <223> upstream amplification primer <220>

<221> primer bind <222> 412..433 <223> downstream amplification primer, complement <220>

binding <221> misc _ <222> 267. 291 <223> 16-25-279 potential probe <400> 117 ggtcccatgc ctcagtgaca tccttgcctccctggcaggg tgaccctgtg gtgtttgcag60 gagtcttcag agggtgaaag ggaggggccagtgagatggg tggctgatgc ctgggaactt120 gtccggcttt acccagagcc ctctgcctctggtgcaggag gctgcccggc gagcccagga180 gctggagatg gagatgctct ccagcaccagcccacccgag aggacccggt acagccccat240 cccacccagc caccaccagc tgactctccccgacccgtsc caccayggtc tccacagcac300 tccygacagc cccgccaaac cagagaagaatgggcatgcc aaagaccacc ccaagattgc360 caagatcttt gagatccaga ccatgcccaatggcaaarcc cggacctccc tcaagaccat420 gagccgtagg nag 433 <210> !I8 <211> 478 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 393 <223> 16-23-393 : polymorphic base G or T

<220>

<221> misc binding <222> 370..392 <223> 16-23-393.mis1 <220>
<221> mist binding <222> 394..416 <223> 16-23-393.mis2, complement <220>
<221> primer bind <222> 1..26 -<223> upstream amplification primer <220>
<221> primer bind <222> 455..478 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 381..405 <223> 16-23-393 potential. probe <400>

ctaagtgggaataacgctaaacatacttggattaatgcacaaggccctgagatagaggac 60 aggcgtctggtagacctagaagggcacgcaaacatatgaaacacataggaacacaagtga 120 gttcaacagacagagccaagttatcttgctgcaaacattaaaaggtggccaacctctccc 180 aatacacaggtcagactaaaaagatggtttactcttttaaaagttttcttgtgtcattct 240 ttctggatacatcggcttcacttgttatgcccagacatggcaaaactaatgaccaagtaa 300 tgagggaatagtaatggaaagacttgggagcagtccatcatcacagcttaactttttgct 360 cacaaccgtgtttttaatactctggtatctgckgtgcgtttgtgtatatctaagatgacc 420 aggcagccttaaacatctagttgcgttcatattctctgtaaaatcgctccttgttcct 478 <210> 119 <211> 742 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 364 <223> 16-106-364 : polymorphic base C or T
<220>
<221> misc binding <222> 345..363 <223> 16-106-364.mis1 <220>

<221> misc binding <222> 365..383 <223> 16-106-364.mis2,complement <220>

<221> primer bind -<222> 1..22 <223> upstream amplification primer <220>

<221> primer bind <222> 723..742 <223> downstream imer, complement amplification pr <220>

<221> misc binding <222> 352..376 <223> 16-106-364 potential probe <400> 119 cccagatggg tgatctacaatgaccagaaagtgtgtgcct ccgagaagcc gcccaaggac60 ctgggctaca tctacttctaccagagagtggccagctaag agcctgcctc accccttacc120' aatgagggca ggggaagaccacctggcatgagggagaggg gctgagggat ggacttcagc180 ccctctgctc tgtaccctttttccttttgtccccggcagc agggaagaag ctggaggccg240 tgggagaatg gctgggcagagcagaggggcagcgatagac tctggggatg gagcaggacg300 gggacgggag gggccggccacctgtctgtaaggagacttt gttgcttccc ctgcccccgg360 aatycacagt gctctgcttctctgtgtcgccccgcccagc cccctggtgt ggagggaggg420 gtctcgtttg tgcgcgtgggtgtagctttgtgcatcctct cccagtggag cgatcacctg480 tgcctcccct ccccctttgtttgcccctgtgtggttggtc aaggagggat gtgagggaaa540 tagggacccc ccgacttgccctcctgcctcagtctttccc ccaccctgtc tcttccttgt600 ccttctctgg aaaatgccaaaatacacgatgtgaataaaa gtacaacggc taaattgtgt660 cctgtttgat accttgggggagaggcttaccttcctgggg ttagcaggag ggcgcttaag720 aaaactccta actctggccgcc 742 <210> I20 <211> 535 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 285 <223> 16-16-285 e C or T
: polymorphic bas <220>

<221> misc binding _ <222> 265. 284 <223> 16-16-285.misl,potential <220>

binding <221> misc _ <222> 286. 304 <223> 16-16-285.mis2,complement <220>

<221> primer bind -<222> 1..19 <223> upstream amplification primer <220>

<221> primer bind <222> 516..535 <223> downstream amplification primer, complement <220>

<221> misc binding <222> 273..297 <223> 16-16-285 potential probe <400> 120 gttggcaggg ctgcttctcaccccaaaccaagggagggac aggcagggag gctgagagca60 gcggcttgcc ctggagctgtcaggtgggaggcagagggcg ggagaggctg tgggctgccc120 aggtctgatc cctgacccacttgccacccgtgccctcagt tcttccccaa tggagaggcc180 atctgcacgg gctcggatgacgcttcctgccgcttgtttg acctgcgggc agaccaggag240 ctgatctgct tctcccacgagagcatcatctgcggcatca cgtcygtggc cttctccctc300 agtggccgcc tactattcgctggctacgacgacttcaact gcaatgtctg ggactccatg360 aagtctgagc gtgtgggtaagggccagccctggctgctgc ttcctcagct ggaaggaccc420 tccccagccc tccctccccattctgtaccccccatcagct cccatttcgg actctcttac480 tgctgtccct tgtcactgggtgactccacccctggaatcc agtacccctt ggttc 535 <210> 121 <211> 529 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 121 <223> 16-17-121 : polymorphic base C or T

<220>

<221> misc binding <222> 102..120 <223> 16-17-121.mis1 <220>

<221> misc binding <222> 122..140 <223> 16-17-121.mie2,complement <220>

<221> primer bind -<222> 1..19 <223> upstream amplification primer <220>

<221> primer bind <222> 508..529 <223> downstream amplification primer., complement <220>

<221> mist binding <222> 109..133 <223> 16-17-121 potential probe <400> 121 gcaggcccag cagacttgag tctgaggccccaggccctaggattcctccc ccagagccac60 tacctttgtc caggcctggg tggtatagggcgtttggccctgtgactatg gctctggcac120 yactagggtc ctggccctct tcttattcatgctttctcctttttctacct ttttttctct180 cctaagacac ctgcaataaa gtgtagcaccctggtacatctgtgatgttt gccttctact240 ctcttctgtt ccaaaaagac ccaggtcccatttaagggcagtaatgtgtt acaggtgctg300 tgataaaggc tgggtactgg atagcttgtgggcttatgggaggaggcctg agatgggtca360 gggggagaag gtattcagca ggtggctgggggactgtgtgcagcagttcg ctatggcctg420 cctgtggtgc ccatgtgttt gtacgggagggttagcttgagaaggaatca gattataaaa480 ggtcttgaat gtcaagccag agagtccagactttttcctaagggcaatg 529 <2I0> 122 <211> 540 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 185 <223> 16-84-185 : polymorphic base C or T

<220>

<221> mist binding <222> 162.184 <223> 16-84-185.mis1 <220>
<221> misc_binding <222> 186. 208 <223> 16-84-185.mis2, complement <220>
<221> primer bind <222> 1..22 <223> upstream amplification primer <220>
<221> primer bind <222> 525..540 <223> downstream amplification primer, complement <220>
<221> mist binding <222> 173..197 <223> 16-84-185 potential probe <400> 122 tagaatgcct ttaatgagca gtaaatctaa ttttattaaa tctcaaccct tgggtacggt 60 gtgtcatgaa atgggaagtagcacacagtactatatgctacagatgaagtacaatgctgt I20 caaatagggg tacttgtgttaattgttggagtcgcaagctgaactagcgttttcttttct 180 tttcytttct tttcttttcttttcttttcttttcttttcttcttttcaagacaggttctc 240 actctgtcac tcaggctagagtgcagtggtgcaatcacggttcactgcagcctcaacttc 300 ctgggctcaa gcgatcctcccacctcggcctcctaaaatgctgggattataggcatgagc 360 caccactccc agccccacttttttcagactggaaaacgcacactcacatgtgcatcttta 420 aatgatcact tgggctgtggtatggagaatggcgaccagtgaggaggcaggagctgttgt 480 ccgagcaagg gatgatattggcatcttggattggcatggtggcagtagtggtagtgcaga 540 <210> 123 <211> 525 < 212 ~> DNA

<213> Homo Sapiens <220>

<221> allele <222> 74 <223> 16-87-74 : A or G
polymorphic base <220>

<221> mist binding <222> 51..73 <223> 16-87-74.mis1 <220> _ <221> mist binding <222> 75..97 <223> 16-87-74.mis2,complement <220>

<221> primer bind <222> 1..22 <223> upstream ication amplif primer <220>

<221> primer bind <222> 504..525 <223> downstream amplification primer, complement <220>

<221> misc_binding <222> 62..86 <223> 16-87-74 potential probe <400> 123 gtccatttcc ctttgtccatgtgtccctcccaccctgcagccggctccct cacatccacc60 ctgggctgca ggcrtgctcggcaggctccccacagatcaaagcttgtcca gggtctgcat120 tgctgccaaa ggccaggaggactggtgtacagaccggaaggagctagagc ttagtggcag180 cctgagaggg gaagctgaaaaaggagaagaggcaaggggcattccagggg agcccgggag240 agccagcacg gcctcctggtatatgaggcaaagaggaagacagacacaga cacagggagc300 tgcaggctgg gggcataagctgggggctgggaagcatagatacagaaatg cacagatgtg360 agctgagaag caaggagggagagagagagacagaaagagagagagagacg tgccagggct420 tgagggacca gagagccctcccagcctctctcggagtgctggtatacagg atgctaccgt480 actagggtaa gacacctctggggacgctgagtatgggaatcaaag 525 <210> 124 <211> 665 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 333 <223> 16-91-333 . polymorphic base A or G
<220>
<221> mist binding <222> 310.._332 <223> 16-91-333.mis1 <220>
<221> misc_binding <222> 334. 356 <223> 16-91-333.mis2, complement <220>
<221> primer bind <222> 1..19 <223> upstream amplification primer <220>
<221> primer bind <222> 641..665 <223> downstream amplification primer, complement <220>
<221> mist binding <222> 321..345 <223> 16-91-333 potential probe <400> 124 geccatgctc agggtcagtt ggggaagggt ggaaacgggg agtgaagatt tgcctctgct 60 gctatcctga gctccatctc tctatccctc ccatctgtct ctggatttgt agtttcactg 120 tcagggctgc atgggaacca tcacttcaca aggactctaa tttgccctcc tttggcgcct ~ 180 gtgacaagct caggagatgg gcttccttct gccttgctgc ttctcacctt cctttatttt 240 cccccctctt gctcttcttt gaactctcca gctaaggtat gtttgcacca gtgtttgaaa 300 gaaccggcag ctgaacttgt ctgccagtgg gargggggct cttggagtta gctgtctggc 360 ctctggagac caccttctcc agcactgcct ctgccccaag gatcaatgtg ctctaagtat 420 tcatccccca acccctgacc ttgtcgctcc ctctccagtg ggcaatctgt cccaggctat 480 agaaaatgtc ctgagtgtcc tgctcttcta cccggaggat gaggctgcca agagggctct 540 gaaccagtac caggcccagc tgggagagcc gagacctggc ctcggaccca gagaggtaat 600.
cccctctcca cgctcacctg ggaggtagcc ccaaatcaaa caaatagacc tgagaagtaa 660 cctgg 665 <210> 125 <211> 327 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 142 <223> 16-128-142 . polymorphic base C or G
<220>
<221> mist binding <222> 123..141 <223> 16-128-142.mis1 <220>
<221> miec_binding <222> 143. 161 <223> 16-128-142.mis2, complement <220>
<221> primer bind <222> 1..20 <223> upstream amplification primer <220>
<221> primer bind <222> 308..327 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 130. 154 <223> 16-128-142 potential probe <400> 125 ctaggaacag tgcgccagtt tctggtgggc tgcagggcac gaggagatag tcaacttgtc 60 tgactgttaa tccaccctgt cccctgcaga tggaggggcg cagccaggcc ccgtgcccaa 120 gtccctgcag aagcagaggc gsatgctgga gcgcctggtc agcagcgagt gtgagtgcag 180 cccctgcccc gtctcaccca tgcctcccag cctgcacctg cagggcgacc tctccttcct 240 gtgcgactcc atcctggcct gccctatctc acccgtgcct cccagcctgc gcctgcaggg 300 cgacctctcc ttcctgtgcg accccat 327 <210> 126 <211> 551 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 245 <223> 16-133-205 : polymorphic base A or G
<220>
<221> misc binding <222> 222..244 <223> 16-133-205.mis1 <220> -<221> misc binding <222> 246..268 <223> 16-133-205.mis2, complement <220>
<221> primer bind <222> 41..59 <223> upstream amplification primer <220>
<221> primer bind <222> 472..4-90 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 233. 257 <223> 16-133-205 potential probe <400> 126 gttctcctgg cactttgctc acctctgttt cccctccagc tcttcctgga gtacctgtcc 60 tttgtgcaat acacctcctg gaactgtctt tccagtctct gctttttgtc ctgatgattt 120 tcatgtgctt ttcctctaca tcatgaagca tttactccac attatcttcc agtttgctca 180 tttgtcctca cctccactct tctctttctg aatttgcctg ttgctttttc agtctcttag 240 ctccrtggag tatgttcagt gttgctgtgt tctgatagag gctccttaag ccatcttgta 300 gattttttgt tgcacttcct ctcttccctt agacctccac aggaggaact tttcaatctg 360 tcctcttctc tctgcttaat gagcccctgc aaagggtttg ggaagtgctt cagcctctct 420 gtgattgtgt gttcacatta atatttatta ttttcttaaa tgtgcataaa tctcacaatg 480 tgaacagtga tcatctttga gtgatttttt ttctcctttc tacttttagt aattctccaa 540 attttctaca g 551 <210> 127 <211> 551 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 232 <223> 16-135-181 : polymorphic base A or T
<220>
<221> misc binding <222> 209..231 <223> 16-135-181.mis1 <220>
<221> misc binding <222> 233..251 <223> 16-135-181.mis2, complement <220>
<221> primer bind <222> 52..71 <223> upstream amplification primer <220>
<221> primer bind <222> 482..501 <223> downstream amplification primer, complement <220>
<22I> misc_binding <222> 220. 244 <223> 16-135-181 potential probe <400> 127 ttggttgtgg ggaccagaga cagagcaggc agggtctcac gttccccagg gcctctcaag 60 gatagaccct cgccctcatc tccaaaccac gcctcccaga caggaaccaa actcccagag 120 tctccaaact gcctgagcct tgcccactcc ctgggctaac acacacttta aaggaatccc 180 acagtcaccg tgtgaaaagc ttgctacact gcatttgatt ctgggcactg awagcagtac 240 ttggctgcag acactcgttt caaacaggcc ccatttttcc atctctgctg ctgttattag 300 gggagccctt agactctctt gcagcgccgg aataggcgct caagacgtgt gttaatattg 360 caacagcaaa tataatgaat ctgcagttgg ggacgctgag gccggagtgg tggatgaaag 420 gtggccggag ccttttccac gggtccaaac cacctgttac aggagaaggc gagcggcctc 480 gctaagcaac tggacgttcc gcgggcgggg cgggggcggg gccggggccc gagtccgctc 540 ggaaactttc g 551 <210> 128 <211> 551 .
<212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 455 <223> 16-145-405 : polymozphic base C or T
<220>

<221> misc binding <222> 436..454 <223> 16-145-405.mis1 <220>
<221> misc binding <222> 456..474 <223> 16-145-405.mis2, complement <220>
<221> primer bind <222> 51..69 <223> upstream amplification primer <220>
<221> primer bind <222> 523..540 <223> downstream amplification primer, complement <220>
<221> mist binding <222> 443.467 <223> 16-145-405 potential probe <400> 128 gtggaaaaaa ccatatggca ttgtcgcctt ctcagcctga cctggcatgc ac'tctcaccc. 60 tcatctgtca tgcctcetgc ttttccacct ggggggctga gaagtccggc catcgaaaec 120 ttggttcctg ccagccacgg gagtttggaa gctttatcag attcctgaag cctcgtttcc 180 tcatgggaac agtgcaggtg aaagcacctt cctctcggaa ccggggggaa gatgagagga 240 aattaaatag atgtatggcc ccgcagcagg actggcgctc tccattgtgt ctgaaattgg 300 caggttcttg gtctcactta cttcaagaat gaaaccacgg accctcgcgg tgactgttac 360 agttcttaaa ggcggcgtgt ctggagtttg ttccttctga tattcagatg tgttccgcgt 420 tttcctcctt ctggtgggtt cctcctctcg ctggytcagg agtgaagctg cagaccttca 480 cggcgagtgt cacagctcat aaacgcagta cagacccaaa gagtgagcag caattagatc. 540 tatcacaaag a 551 <210> 129 <211> 492 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 320 <223> 16-177-320 : polymorphic base A or G
<220>
<221> misc_binding -<222> 297. 319 <223> 16-177-320.mfs1 <220>
<221> misc binding <222> 321..343 <223> 16-177-320.mis2, complement <220>
<221> primer bind <222> 1..22 -<223> upstream amplification primer <220>
<221> primer bind <222> 472..492 <223> downstream fication ampli primer, complement <220>

binding <221> misc _ <222> 308. 332 <223> 16-177-320 potential probe <400> 129 gaccctatcc gataaatggtgcttcctcttcatgacaaagaaaatgaaca ctcattcact60 caaaatattc agcacctgctgtgtgcttcactcttcctggcacaggggat gcagaatgaa120 cagagagccc ctgccccactgggaggggtgtttgtggggagatggaccag gtaccagtca180 gtgaatatag cacaatggcaggtagagaaaagtgctacagtcatctaccg tgagcgctgt240 gatgctctgc ccagtttcaccacattaatggagcacccactatatgctgg acacatacca300 tgcattttct catcctagcrgctgttgcaaaatagacacgtccattgtga agactgcggg360 cggtagaatc gcagcccccaaaggtgtccaggtcctaatccccaaatcct gtttgtgtgt420 tcccttgcat ggcaggagggatgttgcagatgggattcagttaaagatct tgataccggg480 gagatgattc tg 492 <210> 130 <211> 759 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 354 <223> 16-4-354 : polymorphic base C or T

<220>

<221> mist binding <222> 335..353 <223> 16-4-354.mis1 <220>

<221> mist binding -<222> 355.
.373 <223> 16-4-354.mis2, complement <220>

<221> primer bind <222> 1..20 <223> upstream amplification primer <220>

<221> primer bind <222> 740..759 <223> downstream amplification primer, complement <220>

<221> misc binding _ <222> 342. 366 <223> 16-4-354 potential probe <400> 130 cctcgttccc acgtaccatc tttcccccaggtggtcaagtaccccctgca cgccatcatg60 gagatcaagg agtacctgat tgacatggcctccagggcaggcatgcactg gctgtccacc120 atcatcccca cgcaccacat caacgcgctcatcttcttcttcatcgtcag caacctcacc180 atcgacttct tcgccttctt catcccgctggtcatcttctacctgtcctt catctccatg240 gtgatctgca ccctcaaggt gttccaggacagcaaggcctgggagaactt ccgcaccctc300 accgacctgc tgctgcgctt cgagcccaacctggatgtggagcaggccga ggtyaacttc360 ggctggaacc acctggagcc ctatgcccatttcctgctctctgtcttctt cgtcatcttc420 tccttcccca tcgccagcaa ggactgcatcccctgctcggagctggctgt catcaccggc480 ttctttaccgtgaccagcta cctgagcctgagcacccatgcagagcccta cacgcgcagg540 gccctggccaccgaggtcac cgccggcctgctatcgctgctgccctccat gcccttgaat600 tggccctacctgaaggtcct tggccagaccttcatcaccgtgcctgtcgg ccacctggtc660 gtcctcaacgtcagcgtccc gtgcctgctctatgtctacctgctctatct cttcttccgc720 atggcacagctgaggaattt caagggcacctactgctac 759 <210>

<211>

<212>
DNA

<213> Sapiens Homo <220>

<221>
allele <222>

<223> base C
99-27199-207 or T
: polymorphic <400>

cccaatgtggccagggacac tgayggccttttctggggtcttttgcc 47 <210>

<211>

<212>
DNA

<213> Sapiens Homo <220>

<221>
allele <222>

<223> base C
99-27207-117 or T
: polymorphic <400>

tgtgtggccagcccctccag ggcygtgtggacagctttttgtgtatt 47 <210>

<211>

<212>
DNA

<213> Sapiens Homo <220>

<221>
allele <222>

<223>

: polymorphic base A or G

<400>

tcacacatgtaattgtttat gcarcgttagggactctcagattctgt 47 <210>

<211>

<212>
DNA

<213> Sapiens Homo <220>

<221>
allele <222>

<223> base G
99-27218-333 or T
. polymorphic <400>

gatatttaataggtggacca ggtkggggagtgtgtttcactccttga 47 <210>

<211>

<212>
DNA

<213> Sapiens Homo <220>

<221> allele <222> 24 <223> 99-28108-233 . polymorphicbase A or C

<400> 135 cccgtcatgc aacatctgga cacmactaacagagcatggt gaataca 47 <210> 136 <211> 47 <2I2> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28109-275 : polymorphicbase A or G

<400> 136 atgtgtccta ggatgaacag taaraattatagactctgca gctctag 47 <210> 137 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28110-75 : polymorphic base C or T

<400> 137 ggtttccgtg ggaaccagat cccygcaggtacaaatgggg cccagcc 47 <210> 138 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28125-81 : polymorphic base A or C

<400> 138 ggaccgagga agctgtaatt ccamaagctctctgggacct tgatgtt 47 <210> 139 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28134-215 : polymorphicbase C or T

<400> 139 gggtctgtca ccctgtttgg gtayaggctcctgcacgctg gcggcct 47 <210> 140 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28137-96 : polymorphic base A or G

<400> 140 aagcagtccc agctcttagc aggrcagactctgccaggca gagaagg 47 <210> 141 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-32204-305 : polymorphicbase A or G

<400> 141 caggtggttg gacttcagag tccractcttaaccccatcc tccactg 47 <210> 142 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28149-118 : polymorphicbase C or T

<400> 142 cccacatacg atactgtgac cttygatgggaggagctagc atgtgat 47 <210> 143 <211> 47 <212> DNA

<213 > Iiomo Sapiens .

<220>

<22I> allele <222> 24 <223> 99-28160-285 : polymorphicbase A or G

<400> 143 tggatcaagt gctaggggat cgcrataatgggagtaagta gctgggg 47 <210> 144 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28171-458 : polymorphicbase A or G

<400> 144 actcaagctt tgattccaaa tctrctgttatttcctactg ggaaatg 47 <210> 145 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28173-395 : polymorphicbase C or T

<400> 145 ctgggccagt cccaacttat actytgggcaatcgaaactc atttgcc 47 <2I0> 146 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-32177-113 : polymorphicbase C or T

<400> 146 taggagaaat taaaaaggga tgaygtactctgttcaaaaa aaaggtt 47 <210> 147 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-32181-192 : polymorphicbase C or T

<400> 147 acccaacaat gggattgcta ctgycagttcctatgctcct ctacttg 47 <210> 148 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-32193-258 : polymorphicbase G or T

<400> 148 aagaggtaat cgtagcttgg actkggttggagtagtggag acagaga 47 <210> 149 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28722-90 : polymorphicbase C or T

<400> 149 gcatttaaaa gataaaatta tccycttggcactcctcaaa ctgtgct 47 <210> 150 <211> 47 <2I2> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28730-351 : polymorphicbase A or G

<400> 150 agctgtggag caccaggctg gcartgagctctgccctcag gcacgcc 47 <210> 251 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-32306-409 : polymorphicbase G or C

<400> 151 acagatgccc tgttttgttc cttstcttctaaaacatcac aatgatg 47 <210> 152 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-27088-246 : polymorphicbase A or G

<400> 152 agtttggttt ccgctcatgc tacrtgttctgtgagatcag tggggag ~ 47 <210> 153 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-27090-203 : polymorphicbase A or G

<400> 153 tgttcagaag ttctcagact gggrcttgggttcttgcact tttcatt 47 <210> 154 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-27091-220 : polymorphicbase A or G

<400> 154 agaagcattt ttctttgcat aacrcaacaccagtcctctg tgtttag 47 <210> i55 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-27093-145 : polymorphicbase C or T

<400> 155 gagtcatctc gaggtaaaca gaaytccaagagtaacgaag gcccaga 47 <210> 156 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-27094-406 : polymorphicbase C or T

<400> 156 aagaccctat gcccagttcc gccyggccaccaaggccctt ctgaagg 47 <210> 157 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<22i> allele <222> 24 <223> 99-27096-410 : polymorphicbase A or G

<400> 157 cccgggaaaa tggttttcat cacrcacaccaactgcattt atttgca 47 <210> 158 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-27097-83 .: polymorphic base C or T

<400> 158 catgacacct gcctgtcatc cccygaaaaaaggtgaacgc cgttcag 47 <210> 159 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-27098-162 : polymorphic base C or T
<400> 159 acaagcactc atccacagga cacygccgatgatgccattt actgagc 47 <210> 160 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-27550-48 : polymorphic base A or G ' <400> 160 atttttcatg cttgatgtga gccrgaagaaaaatgagctt ctctatt 47 <210> 161 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-27558-335 . polymorphicbase C or T

<400> 161 aaatctcatg gccgcatatg ttayacaatcatgcccactt atgtagg 47 <210> 162 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-27561-106 : polymorphicbase A or G

<400> 162 cccaggtgat gataaaaatg gtcrtcatcgccaggcttgt gtcctgt 47 <210> 163 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-27562-366 : polymorphicbase G or T

<400> 163 tgtgggtaga ggccaggaat gctkttaaacatcctacaag gaaggca 47 <210> 164 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-31-738 : polymorphice C or G
bas <400> 164 taatagatcc tgtataaaag gggstctggaaattcgtgca tttcccg 47 <210> 165 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-27110-301 : polymorphicbase G or C

<400> 165 tggactttgg gagtgaactt tgtsagatgattagatggtg atgtcct 47 <210> 166 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-27563-400 : polymorphicbase A or G

<400> 166 tctctctctg ttaaagatca gctrttcccttctgatcttg gaaagag 47 <210> 167 <211> 47 <2I2> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-27573-443 : polymorphicbase G or T

<400> 167 cccgccctgc tctaatcttg cccktccttggctcagctcc agttcca 47 <210> 168 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28732-133 : polymorphicbase A or G

<400> 168 gtgctggaag gtcacgtgcc ttartggtcatgagatcctg gtgcaaa 47 <210> 169 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28735-56 : polymorphicase C or T
b <400> 169 tctttacgtg gtgaaagtcc tagycagccatcattcggca caacagt 47 <210> 170 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28736-399 : polymorphicbase C or T

<400> 170 aatgatttgt tggttttttg tgtycattgcttagaagcag tgagtgt 47 <210> 171 <211> 47 <2I2> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28738-319 : polymorphicbase C or T

<400> 171 ctttggattc tatgcaaaac aggycctcagggttgtaaca atgtggg 47 <210> 172 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28739-364 : polymorphicbase C or T

<400> 172 ttctgcatac tgggatgtga ggaygggtaaactaggaaga aattcct 47 <210> 173 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-27875-185 : polymorphicbase C or T

<400> 173 aataccatcc ccactaataa gtaycaagtaccagggctcc ttggaga 47 <210> 174 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-27880-176polymorphicbase C or T
:

<400> 174 caagcaagct cctctattca aatagcc 47 taccctcatc actyacttgg <210> 175 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28747-371: polymorphicbase C or T

<400> 175 ttctcaatct cccaggacat ccccaga 47 agatagacag aatyctccct <210> 176 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28753-353. polymorphicbase C or T

<400> 176 atgcagggca ttctacaggg cttyaccatc tggagaggga gcctggg 47 <210> 177 <211> 47 <2I2> DNA
<213> Homo Sapiens <220>
<221> allele <222> 24 <223> 99-28755-206 : polymorphic base A or G
<400> 177 accctatccg ctgcactcag agcrgggacc atccgccaag ggagaca 47 <210> 178 <211> 47 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 24 <223> 99-32333-366 : polymorphic base C or T
<400> 178 cttgaatgct aggaaaggct ataycccaga caactattat cccattt 47 <210> 179 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-38-323 : polymorphice A or C
bas <400> 179 ttttcgagct gtgggtattt aaamaaatacatagaaatga actgtaa 47 <210> 180 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28484-179 : polymorphicbase A or T

<400> 180 tacatgcttc tctaggtgtg tgawtaactcataatccatc catgact 47 <210> 181 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-30853-364 : polymorphicbase A or G

<400> 181 acaaaacgtt agtacacttt ctcrattgggttagctcaaa atatgtt 47 <210> 182 <211> 4?

<212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28485-198 : polymorphicbase G or T

<400> 182 aaacatcaaa gttaatttct gttktctatctatcctgccc cttctat 47 <210> 183 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-30858-354 : polymorphicbase C or T

<400> 183 ccttcagttt ctccagccat cttygctgcc acgcccaagc ccaggcc 47 <210> 184 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-32002-313 : polymorphic base A or G

<400> 184 acaccagcac agggtgggtg agargacatc ctgctgactttataaag 47 <210> 185 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 18-15-366 : polymorphic base C or T

<400> 185 catgttatta cagaatttag taayactgtt tttaaaaagtatgatta 47 <210> 186 <211> 47 <212> DNA ' <213> Homo Sapiens <220>

<221> allele <222> 24 <223> 18-20-174 : polymorphic base A or G

<400> 186 tgagcttgtg tcttcaaact aggratacat caattacttaattattg 47 <210> 187 <211> 47 <212> DNA

_ <213> Homo Sapiens <220>

<221> allele ' <222> 24 <223> 18-31-I78 : polymorphic base C or T

<400> 187 cagtcttact ttgcaaattt aagycaaata attaaggatttgttaaa 47 <210> 188 <211> 47 <212> DNA .

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 18-38-395 : polymorphic base A or T

<400> 188 gatgacttct aaaccatttc acawtgagtctaaattcactgcttaat 47 <210> 189 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 18-2-192 : polymorphicG or T
base <400> 189 gatttgcaca gtggcctctt ttaktcatcacttaggttctgttattt 47 <210> 190 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-26921-210 : polymorphicbase A
or G

<400> 190 aataagtgcc aaggagattt ggtrggatccctgcaatgtctgctaca 47 <210> 191 <211> 47 <212> DNA , <213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-215-80 : polymorphic base C or T

<400> 291 ctcgggaagg tgaccgagaa agayatctgggtacaagaacctgaatc 47 <210> 192 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> I8-132-368 : polymorphic base C or T

<400> 192 cagaccagac aacctcttgg ggtycttttctgcattgaggtttgatt 47 <210> 193 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 18-133-293 : polymorphic base A or C

<400> 193 gcatctggat agccctcttc tgamgtttcc tttcagaaagagagata 47 <210> 194 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 18-12-191 : polymorphic base A or C

<400> 194 agacaatgct ttgactatat gccmttggtg gaaaacattctaaagat 47 <210> 195 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 18-11-137 : polymorphic base A or G

<400> 195 actggggaga agggaggtcc tgcrgggagg agaaaagggaaagtggg 47 <210> 196 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 18-93-96 : polymorphic base G or T

<400> 196 tagtgggttg tggcagaaat tgtktctcta cagaatattatcttaag 47 <210> 197 <2l1> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-115-343 : polymorphic base A or C

<400> 197 gggagggcct ctctcaggcc tggmagggag caggggtcacaaactgt 47 <210> 198 <211> 47 <212> DNA

<213> Iiomo Sapiens <220> -c221> allele <222> 24 c223> 16-42-140 : polymorphic base A or G

c400> 198 ttgaggagaa ggaggggaag gccrtgctaa acctgctcttctccccg 47 <210> 199 <211> 47 <2I2> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 18-251-176 : polymorphic base C or T

<400> 199 gtagaagtgg aagacagatt tgcytctctc aggcactagggcacttg 47 <210> 200 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 18-269-44 : polymorphic base A or G

<400> 200 gcttggcmag atggatggtc aggracttga aaggaacacatttggga 47 <210> 201 <211> 47 <2I2> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-218-624 : polymorphic base C or G

<400> 201 caagtgatct ctttaagtca tttstaatgt gaaaactgcgtgattta 47 <210> 202 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 1B-393-330 : polymorphic base G or C

<400> 202 aagctagtcc ctgtttctca atcstccttc taaagtcactttaacca 47 <210> 203 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 18-394-402 . polymorphic base A or C

<400> 203 cttagaagtc cttggtgtcc gagmcttagt atgctgg 47 cccacaatgg <210> 204 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-217-55 : polymorphic base A or G

<400> 204 cgtagctgga tttcacctcc aggrcagcca caggcag 47 gctggacaga <210> 205 <21I> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 18-284-139 : polymorphic base C or T

<400> 205 gggtggttcc tgtcagtgtg gagygagacc tcctggt 47 cgggaaagca <210> 206 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 18-285-305 : polymorphic base A or G

<400> 206 tgctgaaagc cagttgcatt tcaratagtg cttcaga 47 tctgtgccac <210> 207 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 18-289-239 : polymorphic base C or T

<400> 207 agcctattac aaagacattt tctyctattg ccattta 47 ctacctctcc <210> 208 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 18-291-91 : polymorphic base C or T

<400> 208 atgggggacc tccgcctccc aatygtgctg gctggaactttcctgtg 47 <210> 209 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 18-186-391 : polymorphic base G or T

<400> 209 tgggcatgag gtggcaggaa gaakgaaaga gtgaagataatggagtt 47 <210> 210 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 18-194-130 : polymorphic base C or T

<400> 210 tcatcagttt taatcagata atgycttact tctgtagatatagtcta 47 <210> 211 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 18-198-252 : polymorphic base A or G

<400> 211 atattgttca tatggcagag gggrgaaaag caatgacttaatcaagc 47 <210> 212 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 18-242-300 : polymorphic base A or G

<400> 212 acattactgt cttctttatg actrtgaaat aataaaataaaattaaa 47 <210> 213 <211> 47 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 24 <223> 8-15-126 : polymorphic base A or G
<400> 213 tggcatctct gagccagctg agtrgccacc tgaactacac ctgtggg 47 <210> 214 <211> 47 <212> DNA
<213> Homo Sapiens <220>
<221> allele ' <222> 24 <223> 8-19-372 . polymorphic base A or G
<400> 214 tggaatctgc taattttggc tgcrctttga aggtaggaaa tccaatc 47 <210> 215 <211> 47 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 24 <223> 99-2409-298 : polymorphic base A or G
<400> 215 aagtagcgca tggggctgca gccrcagatc tcctgggctc tgggtct 47 <210> 216 <211> 47 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 24 <223> 99-339-54 : polymorphic base G or C
<400> 216 catgatggcg acagaaaaga atastccctt gcctaatttt gatgata 47 <210> 217 <211> 47 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 24 <223> 12-254-180 : polymorphic base A or G

<400> 217 gcatatgaag aggctagcaa aagrtattta acaagcgttc aacattc 47 <210> 218 <211> 47 <212> DNA
<213> Homo Sapiens .
<220>
<221> allele <222> 24 <223> 10-214-279 : polymorphic base C or T
<400> 218 ctaaggactt ctggtttgct cttyaagaaa gctgtgcccc agaacac 47 <210> 219 <211> 47 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 24 <223> 10-217-91 : polymorphic base C or T
<400> 219 aaaacacatc ataaaattca ttayacaatg tcacttattg ttccatg 47 <210> 220 <211> 47 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 24 <223> 99-28779-168 : polymorphic base C or T
<400> 220 tctggtctgc tctctgcatg aggyacagca gtaaagctct ttgattc 47 <210> 221 <211> 47 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 24 <223> 99-28788-300 : polymorphic base A or G
<400> 221 actgagccaa gcacagagat cacrtccact ttcctcaagg gacttgt 47 <210> 222 <211> 47 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 24 <223> 99-32052-262 : polymorphic base C or T
<400> 222 cctatttttt ataacgtatt aacyttattattttcttatt attttaa 47 <210> 223 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-32121-242 : polymorphicbase A or G

<400> 223 ctgattcaag tgtctatcaa agartggctgcagttgacca tgtattc 47 <210> 224 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-32059-169 : polymorphicbase C or T

<400> 224 ttgttttttc tttataatat tacyatctatgaatatattt ctaaaca 47 <210> 225 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-32061-304 : polymorphicbase A or G

<400> 225 gaccagctct ttggagggag gccrtaatccctccataacc tgtccta 47 <210> 226 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-32065-303 : polymorphicbase G or T

<400> 226 acaattatta accagtacag tctkgttattttaaacatta gcatgag 47 <210> 227 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-32123-118 : polymorphicbase A or G

<400> 227 tagtaagaaa atctatcatt tttrttttaaaaatctttca attttaa 47 <210> 228 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-32148-315 : polymorphicbase G or C

<400> 228 gtggttctct ggaaaccgag gctsgttgcaaacccctaaa aagtact 47 <210> 229 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-2-76 : polymorphic A or G
base <400> 229 ggaggcatgg aggctgtcat cacrggcctggcagatgact tccaggt 47 <210> 230 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-28-93 . polymorphic base A or C

<400> 230 ttcagccatt gatgaggtcc ttgmtgtttcttacaggagc tggccta 47 <210> 231 <211> 39 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 20 <223> 16-3-199 : polymorphice C or T
bas <400> 231 ctggctgttc cctgctgtgy actgcccaaggctagacat 39 <210> 232 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-50-197 : polymorphice C or bas T

<400> 232 ggtgtgtagt.gtctgcaggg aagycctgcatgtggggagggggctgt 47 <210> 233 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-1-59 : polymorphic C or T
base <400> 233 ccgcaactca gatatttttt tccytgggggctggatttggagtattg 47 <210> 234 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-2-187 : polymorphic base A or G

<400> 234 ttctgcataa ccaaggtgag tagrggctgggctctgggtcacctggg 47 <210> 235 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28761-311 : polymorphicbase A
or G

<400> 235 tgaaatgctt taagagaatt tgtrtgctaaatttagaagttttgatt 47 <210> 236 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28771-86 : polymorphicbase C
or T

<400> 236 caggaaagat agagataatc atayagtacccagaaaatgactgcttc 47 <210> 237 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-28791-291 : polymorphicbase A or G

<400> 237 aaatgtcatc aactcccaca tgtragaaacaccatgattt gtactgt 47 <210> 238 <211> 47 <212 > DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-32077-66 : polymorphic base A or G

<400> 238 tttgtagggg gaaaacaatt tgcrtttgggaaataatcca acaagca . 47 <210> 239 <211> 46 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-32078-466 : polymorphicbase C or T

<400> 239 tgatgcttgg agcaagcagg ccayctctgtctgagagagg atacag 46 <210> 240 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-32376-426 : polymorphicbase A or G

<400> 240 tttattggtt cactcacatc tggrtgttagagccaaattc caaagac 47 <210> 241 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 99-32361-419 : polymorphicbase G or T

<400> 241 ctcttttata aacttccata aaakctggtgagtctcttaa gaactgg 47 <210> 242 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-21-228 : polymorphic base A or G

<400> 242 agtgctgtca gaatcaccta ttcraaaggc gaatccgatcatgtggt 47 <210> 243 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-22-156 : polymorphic base C or T

<400> 243 tgtgaagaaa agagccttgg gttygactag ggaacctggggccactc 47 <210> 244 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-23-404 : polymorphic base A or G

<400> 244 tctggtatct gctgtgcgtt tgtrtatatc taagatgaccaggcagc 47 <210> 245 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-24-175 : polymorphic base A or C

<400> 245 tgggcaggtt ctggggtagg acgmgcagag cagctgcggggactggt 47 <210> 246 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-25-286 : polymorphic base C or T

<400> 246 actctccccg acccgtccca ccayggtctc cacagcactc cygacag 47 <210> 247 <211> 47 <2I2> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-25-279 : polymorphic base C or G

<400> 247 ccagctgact ctccccgacc cgtsccacca yggtctccacagcactc 47 <210> 248 <2I1> 47 <212 > DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-23-393 . polymorphic base G or T

<400> 248 gtttttaata ctctggtatc tgckgtgcgt ttgtgtatatctaagat 47 <210> 249 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> I6-106-364 : polymorphic base C or T

<400> 249 ' gttgcttccc ctgcccccgg aatycacagt gctctgcttctctgtgt 47 <210> 250 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-16-285 : polymorphic base C or T

<400> 250 agcatcatct gcggcatcac gtcygtggcc ttctccctcagtggccg 47 <210> 251 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-17-121 : polymorphic base C or T

<400> 251 ccctgtgact atggctctgg cacyactagg gtcctggccctcttctt 47 <210> 252 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele -<222> 24 <223> 16-84-185 : polymorphic base C
or T

<400> 252 aactagcgtt ttcttttctt ttcytttctt ttcttttcttttctttt 47 <210> 253 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-87-74 : polymorphic base A or G

<400> 253 cacatccacc ctgggctgca ggcrtgctcg gcaggctccccacagat 47 <210> 254 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-91-333 : polymorphic base A
or G

<400> 254 gctgaacttg tctgccagtg ggargggggc tcttggagttagctgtc 47 <210> 255 <211> 47 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 24 <223> 16-128-142 : polymorphic base C
or G

<400> 255 aagtccctgc agaagcagag gcgsatgctg gagcgcctgg tcagcag 47 <210> 256 <211> 47 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 24 <223> 16-133-205 : polymorphic base A or G

c400> 256 tgctttttca gtctcttagc tccrtggagt ttgctgt 47 atgttcagtg c210> 257 <211> 47 <212> DNA

<213> Homo Sapiens <220>

c221> allele ' c222> 24 c223> 16-135-181 : polymorphic base A or T

c400> 257 ctgcatttga ttctgggcac tgawagcagt agacact 47 acttggctgc c210> 258 c211> 47 <212> DNA

c213> Homo Sapiens c220>

<221> allele <222> 24 c223> 16-145-405 : polymorphic base C or T

<400> 258 tggtgggttc ctcctctcgc tggytcagga agacctt 47 gtgaagctgc c210> 259 c211> 47 <212> DNA

c213> Homo Sapiens <220>

<221> allele <222> 24 c223> 16-177-320 : polymorphic base A or G

<400> 259 accatgcatt ttctcatcct agcrgctgtt cacgtcc 47 gcaaaataga c210> 260 <211> 47 c212> DNA

<213> Homo Sapiens c220>

<221> allele <222> 24 c223> 16-4-354 . polymorphic base C or T

c400> 260 ctggatgtgg agcaggccga ggtyaacttc acctgga 47 ggctggaacc c210> 261 c211> 502 c212> DNA

<213> Homo Sapiens <220>
<221> allele <222> 362 <223> 18-473-362 : polymorphic base C or T
<220>
<221> misc_binding <222> 343. 361 <223> 18-473-362.mis1 <220>
<221> mist binding <222> 363..382 <223> 18-473-362.mis2, potential complement <220>
<221> primer bind <222> 1..21 <223> upstream amplification primer <220>
<221> primer bind <222> 482..502 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 350. 374 <223> 18-473-362 potential probe <400> 261 ggcattttag caagagatga ctaatcagag aggagttact agtggagaaa agtaatttga 60 gatgtatttt tgaagtagga atcatagtag accacaaaga gatcctttat ttctttaaag 120 ctatcattta ttgttagtac tgtaacaact tcacttatgt gatcctattg aatgctcaga 180 acaactgaac agctagctcc atttaacaga taagaaaatg catgttcaat accaagattc 240 aaacccaggc ctagccagct ccagaaacct gagcttttaa catttacgct ttcctacaaa 300 acagggtgac ttaacaaagt atctgtttct aaagacagtt cttagggcta agaaatcaga 360 aygtgccttt agaaataata agtattccta gttgtgtgtt aaaggtagga agctgaaacc 420 aacagacttt cctgtcccta agctaaacaa tactgaacca gtcaaaataa cttggctact 480 tgtcccagga aatacttgct cc 502 <210> 262 <211> 457 < 212 > DPTA
<213> Homo Sapiens <220>
<221> allele <222> 88 <223> 99-12361-88 : polymorphic base C or T
<220>
<221> misc_binding <222> 68..87 <223> 99-12361-88.misl, potential <220>
<221> misc_binding <222> 89..107 <223> 99-12361-88.mis2, complement <220>
<221> primer bind <222> 1..21 <223> upstream amplification primer <220>
<221> primer bind <222> 438..457 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 76..100 <223> 99-12361-88 potential probe <400> 262 caaggaacac aagagtttga ggscacttct ttagcctttg aactggttat tcatcctcat 60 tcttacctgg cattatttgg aatgcttyat ttcctctgta cctggccttc actcttggga 120 agtctagctt gtttgtgcag tttcctactg tttaaacaag agattgttta aactctagcc 180 actgatttcc acagctgttg ccagtgtttt tctttctcac tgaagccaaa catggagtgg 240 ctggagtctg gaaacatgcc ttgagaaatc aaagttccca tctgacattg cagcctactt 300 cctagagcta gtgtcactga ggaaggggtc atttactcat tctaatgtca ggattcccac 360 accaataacc acatcatttc tcaacaaata catcccttcc cctactccac ctcgggcaat 420 aactgtgggt ccggaggcta cagggctttg ggtgtgt 457 <210> 263 <211> 502 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 335 <223> 99-12368-335 : polymorphic base A or C
<220>
<221> mist binding <222> 316..334 <223> 99-12368-335.mis1 <220>
<221> mist binding <222> 336..355 <223> 99-12368-335.mis2, potential complement <220>
<221> primer bind <222> 1..20 <223> upstream amplification primer <220>
<221> primer bind <222> 482..502 <223> downstream amplification primer, complement <220>
<221> mist binding <222> 323.-.347 <223> 99-12368-335 potential probe <400> 263 gaacagaagg tattgaacag aaacaaagta ttttcaaaot ggtagaaaaa ggattagaaa 60 tcttggtctg tcaatttcct catatccttg gccacacata atgaccccaa gagcacttgt 120 tggcaatggg agggaagaag gagatcacat cagtcataag gccaccattg ccctgactcc 180 tggcatctgt cctgcttctt actttttatg agcagagtga ggtcaacagg caccatggaa 240 agagcactgc gttgaagtta cacattccgggacttcgcttgcttgctagc atcagtctgt300 agctgtaaag tggtgacagt aatacctaccactamggtgttgtgagaatt aaatgaggca360 ggatcttgga cttagaaagc tgcccagatatggtggctactgttgataag cattctggtt420 atactcatcg gattccctcc tcccacctcttccctggattgggtcattcc ctccaatgca480 gcccttctct ttcctcatgt at 502 <210> 264 <211> 461 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 67 <223> 99-12370-67 : polymorphicbase A
or G

<220>

<221> misc_binding , <222> 48..66 <223> 99-12370-67.mis1 <220>
<221> misc_binding <222> 68..87 <223> 99-12370-67.mis2, potential complement <220>
<221> primer bind <222> 1..19 <223> upstream amplification primer <220>
<222> primer bind <222> 441..461 <223> downstream amplification primer, complement <220> -<221> misc binding <222> 55..79 <223> 99-12370-67 potential probe <400> 264 attacgcaag cactacgcca attaatccaa gacctgtgcc aaatttaaaa ggaaaagcag 60 agttcartgc aaattctaga aatagttgtc aaaatcccca tttcttatgt cctagataat 120 acttgtatat ttctggatgt ccatagaaaa ataaggatgt cattacatag aacaatagct 180 gtcagcatac agaacaatag cagaacagtg gggaggattt cagatgtgaa cagtgcttgt 240 gagaatgaag caagctacag tgtcctccaa ggggacttcg tgagctcaac ttgacattta 300 gtctcacatg actgccttag gctccttggc accagtcaac acagaaggac attggatgtg 360 tttatccaac acttctgtct tgccaacaga gcagcatcag cagacagtcc tcttcagggg 420 aagagtcctc actgtataca gttgagatgt gaggaaatga c 461 <210> 265 <211> 449 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 314 <223> 99-32148-315 : polymorphic base G or C
<220>
<221> misc bindiag <222> 295..313 <223> 99-32148-315.mis1 <220>
<221> misc binding <222> 315..333 <223> 99-32148-315.mis2, complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 428..448 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 302..326 <223> 99-32148-315 potential probe <400> 265 tgagtgcatt tgatgtgggs cagcaaagct tcattcaggt ggaaacagat taagaagacc 60 aaagagtggt gaaatggcta agtaggaatg aaaaaacagc cagctacccg yggccagtgc 120 cttattctaa aagaggacag ctagcttgcc caaggactct tgcagaagga aacctgggag 180 agtttccttc tcctcttgca gaagtaaact cttcaggttg aagagtcagg aaggagctcc 240 agggatgagt gaagtcaact gaagttgcct cttttataaa cagctctgca gtggttctct 300 ggaaaccgag gctsgttgca aacccctaaa aagtactgct ctgcaaggct tgtaactgcc 360 atacttgtgt ggtcctgctc catctccatg tgtggcagtg ccagctgcaa ccagcctcac 420 acagggtccg agagtctcag aactgcaag 449 <210> 266 <211> 426 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 322 <223> 19-46-322 : polymorphic base C or T
<220>
<221> misc_binding <222> 302. 321 <223> 19-46-322.misl, potential <220>
<221> misc_binding <222> 323. 341 <223> 19-46-322.mis2, complement <220>
<221> primer bind <222> 1..19 - ' <223> upstream amplification primer <220>
<221> primer bind <222> 409..426 <223> downstream amplification primer, complement <220>

<221> misc binding _ <222> 310. 334 <223> 19-46-322 potential probe <400> 266 gatgagtgac tcaatggaccagctccacaaacaaagctgg aggtgtcttg tacagacccc60 aaatgctatc catgtggggctgcaggatcaaatagcaggt ggccctcatc tgggggtgca120 gccaggctgc cagaagggtgtccctgggccaagctgaggc ctcctcccct tctcttcctt180 tcagagactg gcctatggcatcacgccagagaacgagcac cacctggtgg ctcagaggga240 catcagacag ttccaggtgggtgaagcctagacccctggg gtggagatta caagggcggg300 ccctggctgt tccctgctgtgyactgcccaaggctagaca tcacatccag aaaacccaga360 aacccagtgt gagctgccttttccccttggaaacatcggg atgggggaca gggagcctca420 ccttga 426 <210> 267 <211> 422 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 315 <223> 19-47-315 : polymorphic base C or T

<220>

<221> misc binding _ <222> 296. 314 <223> 19-47-315.mis1 <220>

<221> misc binding _ <222> 316. 334 <223> 19-47-315.mis2,complement <220>

<221> primer bind <222> 1..19 <223> upstream amplification primer <220>

<221> primer bind <222> 403..422 <223> downstream amplification primer, complement <220>

<221> mist binding <222> 303..327 <223> 19-47-315 potential probe <220>

<221> misc feature .
~

<222> 103 <223> n=a, g, c or t <400> 267 tcctcgctgt ctttctctgcagttgcaacactggctggccatctgagcct gcctggagga60 gaaggaggaa cccccatgccaatgtccaggtcacaggcatycnctgcgct cccacctcgg120 acaccatctt gggattcctcccctggaagttgtcctttctgatcctctct tcttttccca180 tttacaaatg atttcgtgactgtagtttttgttcaccttctgtgcatctg gcctgggggc240 tgttagctca gaggagaggagcaaacaggaaaatgacttctgttctgtcc ccgctgtttt300 gggggaagtc tctcycactttgggatcctgctgaagctaggttcatgagg tcggaaatcc360 ccaccacatt tgcctagactttgggcacaggagttcttagtecaccaaat cagagagagg420 at 422 <210> 268 <211> 419 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 346 <223> 19-51-347 : polymorphic base A or G
<220>
<221> misc_binding <222> 327. 345 <223> 19-51-347.mis1 <220>
<221> misc_binding <222> 347. 366 <223> 19-51-347.mis2, potential complement <220>
<221> primer bind <222> 1..19 <223> upstream amplification primer <220>
<221> primer bind <222> 401..419 <223> downstream amplification primer, complement <220>
<221> miac_binding <222> 334. 358 <223> 19-51-347 potential probe <400> 268 atcaggtcaa gcccatgtgg tgcatggcag tggctagggt ccctgagtta ggggagagtg 60 gccaggtcct gtctccatca gcatgcattt gcagggactg gtctgtggtc acggcctctg 120 tcgtcctccc tgacgacatt taccctggtc ccctcccctc tcctctgggc aggcgtggtg 180 tcctgcacct tcacgagagc agcgggattc atgacatcgg cctgccccag tggcagctct 240 tgctctgtct gatggtcgtc gtcatcgtct tgtattttag cctctggaaa ggggtgaaga 300 catcaggaaa ggtaatatct ctgtgtttct ctttcactta cttggrtgat caaccttggg 360 gggtgtgatt atttctagca ataattatgt agctggtgga caaaaaagat ggagctgga 419 <210> 269 <211> 499 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 263 <223> 99-32052-262 : polymorphic base C or T
<220>
<221> misc_binding <222> 244. 262 <223> 99-32052-262.mis1 <220>
<221> misc binding <222> 264..282 <223> 99-32052-262.mis2, complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 478..498 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 251. 275 <223> 99-32052-262 potential probe <400> 269 cagagtgaca aataagtgct atggcttgat agaagtgaag ctcttcacat atattcaaaa 60 tacatatcac aaactttggt aaataggata gtaatctgaa gaacttttgc cctttttacc 120 ccatttactg taactcttgt ttctaggtaa tcgttctctc tcaacaaact tctcaagcgt 180 ctgtgtaaca agccacatgt tctaacaaat tgtctccatc gcacttcaac agccaggtcc 240 ctatttttta taacgtatta acyttattat tttcttatta ttttaaaaga atctatgcac 300 attagcaaaa tttaaaagat agagaaaaat ataaacagaa aaaattatgt ttacttctac 360 caccctaaat caactattat caattttata catattttac tccatctttt ttcaaagttt 420 cttacatttt ccaatgtcat taaaattctc tgtgaatgta aattttaaaa actgtaccta 480 ctgttttttg gaatctgta 499 <210> 270 <211> 3001 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 1501 <223> 10-213-292 : polymorphic base G or C
<220>
<221> misc_binding <222> 1482 .1500 <223> 10-213-292.mis1 <220>
<221> misc_binding <222> 1502..1521 <223> 10-213-292.mis2, potential complement <220>
<221> primer bind .
<222> 1211..1229 <223> upstream amplification primer <220>
<221> primer bind <222> 1588..1606 <223> downstream amplification primer, complement <220>
<221> misc bindiag <222> 1489..1513 <223> 10-213-292 potential probe <400> 270 gcagaagtataagatctttgtaaaacagtcctctccctggttcatctgctttctgttacc 60 acaataatgctaagtaaaaaaacatccaaaaacctccctggcatttaacaatatgcatat 120 tgctcacacgtcttgatagtgagctctgctgatattggcaggacttgctctggtctggct 180 gtgatctgatggagcctggccctgggtgcgctgtgcaggttgactcagctctgccccaca 240 tgtgtctcatgtttcagtcaggtaaccactggtgaagaagcaagctaggaaccagggtat 300 ctgacttctgagctaaactcttaaactctataatattgcctttcaaatataacactaagt 360 actaggtgcctatcaaccacactgttttcagacctctgccaaaacttggattctttgtgc 420 tatgaagagacatggcttttgggctggtctttgtgtggcagtgaggtgagcacaaaggga 480 tgttcttcagagattacagtccagccctgaagcaacaactaggagactgtttcagcaagt 540 gaggacagggctgtgtggggttctatccttttcataactttgcctggcactgaaatcaca 600 tgctctgataacatccaccagaactttcttttgtcatatttgggatagaaagggactagt 660 ttttcctcaaattattgatagagattttatataatatagtgtttctctccacattttatg 720 tatataacaaaagccctgcttttgtgtatatatgcatatatatatatatacacacacaca 780 cacacacatatatataatacaaatcctgctttgtaactgtttttgtttgtatatataaca 840 aaaagagttatgaaccagaagtttggccaataatccttgtcgcacagagaatttgctttt 900 tctatctgttttcactttcttggttacagacgtgtaacctcttttttgaatggtgacaat 960 cactttgtcatattttatttgatgctagtggtcatagcctattagtcatgtttgcttcca 1020 tgagaaagaaaaaccactacatggttatgctaaggatttcagtcattggggttagagcet 1080 tcccgaatgtctcctgctttcataactcctccacacatcttagtgggccattgagcacat 1140 caaagggcatgacagttattaaaatactttatgaatgctacaatcctttgccagtatgag 1200 ttgttctctggaacttctaacagttcaacagtactacatggactgagttaaaagttaatt 1260 caaaaatctcaatttatccaaatctgtttctttcttttcaggcaccacccacctatgata 1320 ctgtgctacagttggagtatcttgacatggtggtgaatgaaacactcagattattcccag 1380 ttgctatgagacttgagagggtctgcaaaaaagatgttgaaatcaatgggatgtttattc 1440 ccaaaggggtggtggtgatgattccaagctatgttcttcatcatgacccaaagtactgga 1500 sagagcctgagaagttcctccctgaaaggtaggaggcccctgggaagggagccctccctg 1560 aaccagcctggttcaagcatattctgcctctctacaggacagtctgggcttgtacaatca 1620 tttgcttgtctttttatgtttaaaaggttttttcaaatcatgaaattgatcattgtcaca 1680 ctttacaaaccacagactagataaaagaaaactatagccagtcacagtcccagcaactta 1740 agatgaaggtcctcaattatgtccttatgggtcataagtgtccaaaatgtaaggactctt 1800 ttaaaaacacatgatcacaatgctattattatgtcccacaaatgaatattttttcctgaa 1860 tataatcaaatcttcaggaatcaaatttgaataaaaaacatgcgtctaatcttcaaagaa 1920 tttataggttagtgcaacagatagacaaagaaagcagtgatgacactgctttccatcaat 1980 acagtagcatcatatgcctgtgtaaattatctgacttaaactattctatggaggtgtggg 2040 ggagaaagaaggagagatggagattagaagaaggaggagaaggaggagagaaggaggggt 2100 aagacaaggtagggaggagaaggaggagaattagaaaaacaagagacgagaggagaagga 2160 aagtgcaaaataacaattttgaagtagtgcaagacaatttcttctccttcctcatgacca 2220 acataagggtgacttgaggcaggaatctacttttctgtcagtcattctcatcacttatgt 2280 gccttttgtagtgtgaacacatcaccatcctgactataatttgagtgtttagaaataaat 2340 atactttgcaacagtatttatctcctctcaacaagactgaaagctcctataatgtaagga 2400 gagtagaaaggatctgtaccttacaattctcatagcaaaatatgcatagcaggatttcag 2460 tgactagcccacaaaagtatcctgtgtactgctagtagaggggtgggccctaagtaagaa 2520 accctaacatgtaactcttagaggtattatgtctttaacttttaaaatatctaccaatat 2580 ggaaccaggttcagtaaaaagaacaaggacaacatagatccttacatatacacacccttt 2640 ggaagtggacccagaaactgcattggcatgaggtttgctctcgtgaacatgaaacttgct 2700 ctagtcagagtccttcagaacttctccttcaaaccttgtaaagaaacacaggtcagtcaa 2760 ttttctgcattaataatgttttattaacaattattttaactgaatggtctatatatttaa 2820 aaaagaatacactcacttaatcttttaataatttgttctatgggccaaggaatctatttg 2880 gacccatctatgatctttaagggtgcttcagttctggagttcaaaagctgtagcattaaa 2940 aacatcatgcaatgtcaatgtagactagcatgacatgattatctacagtctccttgaact 3000 t 3001 <210> 271 <211> 465 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 135 <223> 18-419-135 : polymorphic base C or T

<220>
<221> misc binding <222> 115..134 <223> 18-419-135.misl, potential <220>
<221> misc binding <222> 136..154 <223> 18-419-135.mis2, complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 448..465 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 123. 147 <223> 18-419-135 potential probe <400> 271 ttccaaccct gttaagactc ttctacagtt gctttttgtg tagctgacca acataacaat 60 catgttcttt attctacatt ccttgataca tttcaaccct tccatactga tcacttccct 120 tctgttgggg caaaytcagt tttttttgtg aaaatgtttt ctattttacc cttgttcttg 180 aaagggtggc ccaatctcag taagataact tactgaccta ttctaaggct gggcccaaca 240 gagcctcact ccccaccctt gtagggaccc tggatctggg tagaacattt atgcggtagg 300 ggaacagtcc ttcttaaaca ggcgcttgga agccctttgc agatgccggt gagaatcggc 360 ggtctgggaa agagtacaca tcttgcagag aagctgaaga gggaagccct tttcctgttt 420 tttcactttc aagaacatga gccacctggc tgctttcttt tgtag 465 <210> 272 <211> 527 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 419 <223> 18-424-419 : polymorphic base G or C
<220>
<221> misc binding <222> 400.-.418 <223> 18-424-419.mis1 <220>
<221> misc_binding <222> 420. 439 <223> 18-424-419.mis2, potential complement <220>
<221> primer bind <222> 1..20 <223> upstream amplification primer <220>
<221> primer bind <222> 507..527 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 407..431 <223> 18-424-419 potential probe <220>
<221> misc feature <222> 47B
<223> n=a, g, c or t <400> 272 cgctttaatt tttagggttc caaaccaaaa gtggcaatca ccatggcata tgtgtacctg . 60 tgagcatgta gattcatgtg tgctgggggc attttatagc cagttctttc tcagagtccc 120 tttttctttt agccaatgga ttctggctag gaaaaacatt aaccgcacct tagtagacta 180 gttagaagac tgagaagaac caggtaggga agccagagaa gtgacattca gagatatttg 240 gaaacaaact tgagcataca ttttacccaa caggaattag ccaggcattt tatttttaaa 300 aaaagaaaga aaaagaaatt ttagcaactc tttgttgttg cccctctctg tgtttagaat 360 cgtgattttc cagctatgtt cctcacagcc gtaggatttc caagggtaaa aggtagagsa 420 gggggtgtgg aggtttggat atgagcatat gggacttcca tagctcctat ttgaaaanwt 480 gctgttttag aagagcctgt taagctgagt tttgaacttg acagcat 527 <210> 273 <211> 451 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 290 <223> 18-429-289 : polymorphic base A or C
<220>
<221> misc_binding <222> 271. 289 <223> 18-429-289.mis1 <220>
<221> misc_binding <222> 291. 309 <223> 18-429-289.mis2, complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 434..451 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 278..302 <223> 18-429-289 potential probe <220>
<221> misc_feature <222> 110 <223> n=a, g, c or t <400> 273 gtccagcttc tttagttccatgctgccagacagaccgtcagagcagaaca gataccttca60 ttttgtcata acttttttaaaaatggcaaaaaataatagccacatacagn tttgttagtg120 aggtgaaatt cctcatagaacaaagacaacaaagaatataaaatgtttct aatatgttaa180 aatatatttt atattctttgtattctttagtctgaaaggcttaaatctta catttctggt240 gggatttcag aaaaaaaagttttcttaggtaaagcgtcttttttcccttm aactagccca300 tttgaaactc ttctgtttctgaatgaatttcacctaacctgtctacagct atattcacag360 acactgtttt tccctttacagactgaccctaccctttctgttacaaaata cagaaacgtt420 gccagtgttt tttggttggttggttggtttg 451 <210> 274 <211> 487 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 256 <223> 18-246-256 : polymorphic base C or T

<220>

<221> misc binding <222> 237..255 <223> 18-246-256.mis1 <220>
<221> misc_binding <222> 257. 276 <223> 18-246-256.mis2, potential complement <220>
<221> primer bind <222> 1..17 <223> upstream amplification primer <220>
<221> primer bind <222> 466..486 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 244. 268 <223> 19-246-256 potential probe <400> 274 tcataggaag acgagagcaa atatttaatg tgttttgcct tcagttacat aggaaaaatg 60 tctaagaagg tgacattggg acttgtgttt aatgaaacag agaactgtgg gcagcgtcag 120 tgttgggttt ttaggagcgt agggagcaca cagctttgac tctttgtccc attacttgct 180 tctgtgtgaa gccactgagg ccccagggtt cgggttttcc tgccacgcac tctggggtgg 240 cagtgaccgt tccaayatgg atgagtgaga agcaggttct tatgaggttt gtgcaaattg 300 agcaagccac ttggggcatg ggtttttcct cttttctttc tttctttctt tttcccacta 360 aagaacagat tgaaagtgct tcacaattaa tcaaaagtcc cctcaacact ctggtgatcc 420 atctaagacc tctcagagat ataaccacca gcacagatat tcaaacccat ttttttcaat 480 ctccttg 487 <210> 275 <211> 453 <212> DNA
<213> Homo Sapiens <220>

<221> allele <222> 68 <223> 18-355-67 : polymorphic base C or T
<220>
<221> mist binding <222> 4s..s7 <223> 18-355-67.misl, potential <220>
<221> misc_binding <222> 69..87 <223> 18-355-67.mis2, complement <220>
<221> primer bind <222> 1..19 <223> upstream amplification primer <220>
<221> primer bind <222> 436..453 <223> downstream amplification primer, complement <220>
<221> mist binding <222> 56..80 <223> 18-355-67 potential probe <220>
<221> misc_feature <222> 32,51 <223> n=a, g, c or t <400> 275 tgccctgttt ctggttctgg tgctgggagg tnaggagtgg agaagactag ntcccctaga 60 gctgaggyct gtcttgaagg actcactggg gccctcatcc tcagggggct gattggcagc 120 cacccctcag tgtggtggac atggagaaag gaaaggctgg ggaaggtaag gatgctagag 180 gcccgagtct cctt'tggagg ccccaaagga ggaatgtcag ggagcttact ttctttgttg 240 cctcagctcc acacccctac caagttggca aatccactta ctcagggaca ctaacaccag 300 taagccaacc ctgatgatgt tctatgttgt acctctggac ctctaagcca ggccactgtg 360 gggagaccaa ggtcctaccc cagatcctgt cccctgggtg cttatgtgac ttaaggtaga 420 cataaggtag tgtgccagtt tagtgcatgt acg 453 <210> 276 <211> 471 <212> DNA
c213> Homo Sapiens c220>
<221> allele <222> 266 <223> 18-353-267 : polymorphic base C or T
<220>
<221> mist binding <222> 246..265 <223> 18-353-267.misl, potential <220>
<221> mist binding <222> 267..285 <223> 18-353-267.mis2, complement <220>

<221> primer bind <222> 1..18 <223> upstream amplification primer <220>

<221> primer bind -<222> 452..4 <223> downstream amplification primer, complement <220>

<221> misc binding _ <222> 254. 278 <223> 18-353-267 potential probe <400> 276 agttgcctac gtggctgggg aagcggggcgccggttgtactcacctcagc tcagggtcct60 agagacctgc gggttttgct ggtcgctgaggtctcccccacttccccacc tcacttaagc120 catcacttcc acctggtctc ccaaattgaggtcctgaagtcctgagaccc atgtcccacc180 caactccgac gtctttagat cccctttccctcggtgccagccttctgaga gtcccaacgt240 tctggcctct aggggatctg cagttygggcggtgggcggttctgattggc cagtcttcca300 tgaggctctg gggcacccag agtgtgtgtctggggtagggtggggaggct ggccaggggg360 cagaggtctg ccccccgtcc cagggctctgatgccctcctcccttcgcct cctcagttga420 agaagctgga tctggcagct gcggcassacacaccttctttgtagcaaac c . 471 <210> 277 <211> 468 <212> DNA

<213> Homo Sapiens <220>

<221> allele <222> 306 <223> 18-338-305 : polymorphic base A or G

<220>

<221> misc binding <222> 287..305 <223> 18-338-305.mis1 <220>
<221> misc_binding <222> 307. 326 <223> 18-338-305.mis2, potential complement <220>
<221> primer bind <222> 1..18 <223> upstream amplification primer <220>
<221> primer bind <222> 450..468 <223> downstream amplification primer, complement <220>
<221> misc binding <222> 294..318 <223> 18-338-305 potential probe <220>
<221> misc feature <222>

<223> g, c or n=a, t <400>

ttgtaggtccccaagatggtgggggtgcagggacagagagcttgctgttc tgctcctgat60 gtcacacaggggcttcctgbgcgncctggcatcaagatggccttccacaa gtcaagtggc120 cacatcctcaaggagctggctcagccactcacagctcctcccgaacccga ggtgcccttc180 cagtcttgtcttggaccctctggtgcctgcggctagggggctctggggaa gggtctttgc240 tgggcatttcttcctcttcctcttcctcctcctcctgtgactcctgcagc agttctttgg300 cttctrtccactcctggggttggggaggagagtgtggcccattccctgca cccaccttcc360 ctgggtcagctcagcccctgaccctcaccgactgtgagccttctcggggg ctccttgccc420 acccttcacgcaccaggagaaccacatcccttcctaacccgctcctta 468 <210>

<211>

<212>
DNA

<213> Sapiens Homo <220>

<221> le alle <222>

<223> 43-346 24-2 : polymorphic base C or T

<220>

<221> binding misc <222> _ 1482 .1500 <223> 43-346.mis1 <220>
<221> misc binding <222> 1502~..1521 <223> 24-243-346.mis2, potential complement <220>
<221> primer bind <222> 1156..1173 <223> upstream amplification primer <220>
<221> primer bind <222> 1652..1672 <223> downstream amplification primer, complement <220>
<221> misc_binding <222> 1489..1513 <223> 24-243-346 potential probe <220>
<221> misc_feature <222> 1556,2069,2084 <223> n=a, g, c or t <400> 278 agaatctctc tctctttttt attattattt tttgagacag agtttcactc tcatcgccca 60 ggctggaatg caatgacaaa atctcggctc gccacaacct ctgcctctcg ggttcaagcg 120 attcttctgc ctcagcctcc tgagtagctg ggaatacagg cggccgccac catgcccagc 180 taagtttttt tgtattttta gtagagacag ggtttcacca tgttggccag gctggtctcg 240 aacccctgac ctcaggtgat ctgctgcctc agcctcccaa agtgctggga ttacaggtct 300 gagccactgc gcccagccca gaatctcttt gagatggaca cacaccctct tcattattcc 360 agcttccata tggcagtggt gggctcgtcc tgcagaccag ttagctcagt ccatgaagta 420 ggagccttcg tgggctcaaa ggcaaatccc agcatgctca ctgctcagtg ccagaaagat 480 cacccccaga agccggctgc atcagtgtgg accaccaaga accatcaaac acacgtgttt 540 tctgtgtgctcgacctcCgttccttgctttttctgatgactgcaccttgatgtccctttt600 ggggaaccccgccactctcagtcctcatggtctgggtggcactgccccctcccctgcgct660 gcacagaaggcccgcacccccacctggccaatcagagttgccaggtcatctccctgacta720 cagcacctggttcagggatggacacagcccagcggagtttgtgctagaactgctgggaaa780 tgggctttcaccttctgctcatcttggcacgtggatgccagcttgaactgtggaaggtca840 ccctgtgggcagagcccctgagacacaggcagcacaggaaagcagagtggaatgggggcg900 ggggagtacttcctgatgacatcatctgagcccctggatccagccgtgcctgaagcaaac960 tactctaggctctacagatctatggactcatcaatcccttgcccctctacttttttggct1020 tgtgtcaatttatattgagattttgtcacttacaactaaaagggtcctgaatctaactca1080 ttctttgaaagtctgcctatcaatcacaaaatagcagtgtgatcagagctggataccatg1140 ggcaggtctccttccctctgtgaggttctatggagaacaccctacatctttttaattatt1200 tgtcatgcacgggccctatggatttgagagattcatggatgccacgtggaatcagtcaat1260 gaccctcactttctcaggcactacctagggcatcctccaggatgcgccccttcccggcac1320 agcccactgccatatcttgctggaacctgggtcatcgtccatcgtctatcacaggctccg1380 ccagccttcgtggatgccatctatgtccgtgggtctcacccgtctcgccaccagcttcca1440 ctacgacgctggacagtacacagggagcagacggggattccaggaggaagccactgcaaa1500 yagggcctgcagctgccctctctccttctgaaatcctagcatagtccaggacacangcac1560 ctccctggctgagcagctgaactgccaagctcaactccctgattgagcagatattctgca1620 gaaatagaaaaggatggagggaaggcttcttcccacacaatgaacatcaaacccacccaa1680 ggggcagtggctggggcctcccttcccaaacagctggctcaaaacatgcacaaaattttc1740 ccaaagtgggctgggagcagggcagctggcttccactttcatattactgatgcatccaga1800 catacttccatagtgtttaaaaatttttggatgtatgtcaaatgctcttaagagtgcgat1860 cttaggcatgtggtaaataaatatgatgtaatcctcccgtctccaagggtgctgctgccc1920 tctccctccctccctcactggtcctgggcaagcccttgacctccacgatctctctgcgcc1980 tctcgtgacgcccacaacaaggggctgtgccaaagggaaaggtagaaagaaaagaggatg2040 tgctgtgtgctgtcatcatccctgtgccnagagacagggcacangggtggtggccttgca2100 ccaccggcgcatcccccacatggggaagctggggtcaccctgcaccacaggcatcccatc2160 agcctctgtgacactgacaatgattctcgtgaatggacaggctgaatggtcctcagccct2220 ctctttctatgctggctgaactctgaggcgggaacaggacagacagtggctggaggccct2280 ggcagggagggcacccttctaacaggccctgcgtagccgagggcaccaaactgacaggca2340 ggacccctgagctcaccacggcctgccctgggccaggcaagaacgagcacgtccacccat2400 gagagttggggctgtgtaggtgactgtagacatcacccacagtgggagggttcctggagg2460 tgacgtccgaggcttggagcgcaaagtaggacaggcacactgccaagttcccagaagact2520 gagtgccaccagatcctgtggccagtcctcagtgtggtgtggggggctcagcaggagcac2580 atcagcaatcagatgggccaggtcaggataaagaacaggcgtgacagctgcttcctaaat2640 aatcaacggtgggtgccctgagtagcacctcctgctgtgcctgtccccagggcagcaggg2700 gctcagcgcactcccacatctgcatcagagccccagtccctcctgggcccccttgtaccc2760 tctaagactaagctcggaccccgccgggaaccacccccaggaccctacctcaggctgtgc2820 caccaccgtccacctggcagccccagccagaaacctggaggccaccctggctttctcccc2880 tccatgtctacctgtccctcagccttcttgtggcctggctactcctctctctgctccgcc2940 tcctggctggcctttaatgtaaacaatccatctaacagctgagccccactcacgacaatg3000 c 3001 <210> 279 <211> 3001 <212> DNA
<213> Homo Sapiens <220>
<221> allele <222> 1501 <223> 99-62531-351 : polymorphic base C or T
<220>
<221> misc binding <222> 1482-..1500 <223> 99-62531-351.mis1 <220>
<221> misc~binding <222> 1502..1521 <223> 99-62531-351.mis2, potential complement <220>
<221> primer bind <222> 1149..1166 <223> upstream amplification primer <220>
<221> primer bind <222> 1591..1608 <223> downstream <220>
amplification primer, complement <221> misc binding <222> 1489..1513 <223> 99-62531-351.potential probe <220>
<221> misc_feature <222> 755,890,893,1406,1412,2220,2222,2224,2232,2241 <223> n=a, g, c or t <400>

tgtggtttccctttccagggagtgatggctctgtaggctctgggattgctttttcatttg 60 tttgttgttttgggacagagttttactctgtcacccaggctagactgcagtggtaaatca 120 cagctcactgcagtctctgcctccccaggctcaggtgatcctcctgcctccccaggctca 180 ggtgatcctcctgcctcaacctcctgaatagctgggactacggtcatttttaattttttt 240 ttgtagaggtggagtctcgctatgttgtccaggctggtcttgaactcctaggctgaagca 300 atcctcccaccggggcctcccaaagtcctgggattatgggcgtgagcccccacacctggg 360 cttatttctcgagaaggggcttgtgctcctcctcacctgatgcctctccttctcccacca 420 gcgtcatcatgaccggggcctacaacaacttcttccgcatgttcgatcggaacaccaagc 480 gggacgtgaccctggaggcctcgagggaaagcagcaagccccgggctgtgctcaagccac 540 ggcgcgtgtgcgtggggggcaagcgccggcgtgatgacatcagtgtggacagcttggact tcaccaagaagatcctgcacacggcctggcacccggctgagaacatcattgccatcgccg 660 ccaccaacaacctgtacatcttccaggacaaggtaaactctgacatgcactaggtatgtg 720 cagttcccggcccctgccacccagcctcatgcaangtcatccccgacatgaccttcacga 780 ccgcaatgcaaggaggggaagaaagtcacagcactgatgaggacagctgcagaggtggca 840 gtgtgtggacacaggaagtttgggccccctccctgccccagctttcctanggnccagaat 900 tgtgtttggcagtaattgtctgtttaaaaaaataaaaaggaaaggaagcgttcaccgcca 960 caaatcataaaatggacatgactgtggagtcttacagttcagggttctttcattcacgtc 1020 ccttcctgtctcggtctgcggtctttaccacatcaataggactttttatgcgtccgggtt 1080 aatttttcactccagtgcgtcctgttgcagggaccggagctgatgggagctgcttctccc 1140 ccatgcctcactggtcccagatcagggctccagggacagatgatgagtctcaaacgagcc 1200 agccaggggttcttttggttataaatggggcaattcgccctgtctcagagctgatgacct 1260 caccgttgttttttggatggtgaattcatgctgagaatttgcagatgcaagctcctctcc 1320 taggtcttctgaatgtcttgaaacatcccaggtcccaggtctggtgcggtttcccgagag 1380 gagcggagtggggtttgtcttctgtngtgccntgtgtcctcatctgattcacctgccatt 1440 tgctgagcctctgctgtgtaccaggcgtggtgctcagccctagaggcagttgacttaccc 1500 yctgcagccctccctgccgcctcacccttcagcattcactgggcaccttcccggagcgga 1560 cactgactcccatgcacgattttttggaatcttcctcctgactgtgaggtgggtgttcat 1620 tcatttcctccataaacaccaacttctcgaagcgtgccaggctctgggctggatgctggg 1680 gataagcgggaacccttaggatcccctctgtccacgagaagaagctgaggctctgagcgg 1740 atgcacaggtcacccatggcaggtgccgtgcagtggtgtcaggaacccgtccgggtcttc 1800 acacaaggttctctccagtccatctcgtgggcggctcatgttagagcgacattcaaatgg 1860 aaggtttggaaaggaatgcctctgtcttgtgaagtaggacatggcagacttggcgacgac 1920 aagggtccaggagaactgagacgcaggatggaagacagagaagaccccccggagctcctc 1980 gctctgcttggtggcttcaggagtgtggccctccccaggactccacttcatcctgggctt 2040 gcaccctccttgagccaatgcactgaactgcctttgaaaggaaattgcatgttctgacca 2100 ttttaggatacctttactttaaggaccacacagtcccagaggacacatccctcgggaact 2160 ctgcccctctgacaatgagggccacagagaaggtggtgtttccatggtagatgctcctgn 2220 tntnggtgatanccaaacctngcccacccctctgagtcgtctttgctcatggacttgcag 2280 cagagccacgtagtttggcattttgattcagaaagtggggagcagagacccagccaaatc 2340 caaactttttttttggttttgttttgttttgttttttacaagatataacataacccagga 2400 aacagacccagctgaggttattctcagtggattacagtatacttttgtgtgtgtaaaagc 2460 acaaagtgcatgtgtactcacttctggccatataacatttacacagggaaatggatcatt 2520 gatttttttt taatcaacgtgaatgaagaatgtttgtttatatatcacta taaaatccag2580 ttgacctgga cagtattatatgtacatatctattctaattaaatttaaca atcaaaggat2640 tggattactt ttttcccccttgtaaagaggttcgagaatgtggtcaattg tatagatagc2700 gtgttaaagc caaaacccagctctgagggccttacccattacttggatat ttgctacgat2760 ccatctccct ttgtgagtcaaatgttaagagaagaaacttgtatttgcag ctagaggtta2820 ctgtcacatc atagatttaacatttaccatcttcaaagtacaaatcttac atgtccttca2880 aaaggaggtc ttaatacagttcctagttccttacttctgttttaaacttt gggtaccaaa2940 ccaaaaagaa gaaaaaagaaaggaaaagatcttctttgaagaaaagtatg tctctggatc3000 c 3001 <210> 280 <211> 3001 <2I2> DNA

<213> Homo Sapiens <220>

<221> allele <222> 1501 <223> 99-54279-152 base C
: polymorphic or G

<220>

<221> misc binding _ <222> 1502 .1521 <223> 99-54279-152.misl, potential complement <220>
<221> misc_binding <222> 1482 .1500 <223> 99-54279-152.mis2 <220>

<221> primer bind <222> 1635..1652 <223> upstream amplification primer, complement <220>

<221> primer bind <222> 1170..1187 <223> downstream amplification primer <220>

<221> misc binding <222> 1489..1513 <223> 99-54279-152 potential probe <220>

<221> misc_feature <222> 44,377,423,696,723,1501 <223> n=a, g, c or t <400> 280 .

ctaaagtgac agagttcagactttgagagtctgaatgaggcaanggtaag gattttcata60 gctctgagag agggttctcctgagaggggacagacatggcgtttgcacgg actcacacgc.

tgtggtatga gacacatgatcacactcactcatttctctcataaatcttc acttccttag180 aacctaccct cccgttagacactagctgtgtcttcttcagcctgacggtc ctctccggaa240 ggtgcgcgtc tgtctctcagcccaattcaaagaggtgggagaggcggcca cagcctctgt300 cggcctgctg ggcacctggggctatagaagagggaccgaggctcagcgag attaagtgac360 cacatcccac agctacntatggctgctgcaggatttgaatttaggacgat ctcgctgggc420 ccntactccc agcgagacaaattaacacaaagccccagggagacaaatta acccaaaccc480 ctggaagaat tttaaaagcagaagctcaagccccccaccccaacacagat tttgattccg540 ttggtctggg tgaggctacccagaaggccctgctgggtggcttgggggcc tgtgcagaag600 gccaggtgca ctgctccatgatggcaaaaccagcccagctccctgctctc ttgcaagggc660 tcagcatctg gtaccagagcaggagatgctcacaangtgagaatttctgt aggggtctac720 DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

~~ TTENANT LES PAGES 1 A 303 NOTE : Pour les tomes additionels, veuillez contacter 1e Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME
NOTE POUR LE TOME / VOLUME NOTE:

Claims

WHAT IS CLAIMED IS:

1. An isolated polynucleotide comprising a contiguous span of at least 12 nucleotides of a sequence selected from the group consisting of the sequences described in Table 7 and the complements thereof.

2. The polynucleotide according to claim 1, wherein said span includes a CNS
disorder-related biallelic marker in said sequence.

3. An isolated polynucleotide comprising a contiguous span of at least 12 nucleotides of a sequence selected from the group consisting of the sequences described in Table 9 and the complements thereof, wherein said span includes a CNS disorder-related biallelic marker in said sequence with the alternative allele present at said biallelic marker.

4. An isolated polynucleotide consisting essentially of a contiguous span of 8 to 50 nucleotides of a sequence selected from the group consisting of the sequences described in Table 9 and the complements thereof, wherein said span includes a CNS disorder-related biallelic marker in said sequence with the original allele present at said biallelic marker.

10. An isolated polynucleotide consisting essentially of a contiguous span of 8 to 50 nucleotides of a sequence selected from the group consisting of the sequences described in Table and the complements thereof, wherein said span includes a CNS disorder-related biallelic marker in said sequence.

6. The polynucleotide according to any one of claims 2 to 5, wherein said contiguous span is 18 to 35 nucleotides in length and said biallelic marker is within 4 nucleotides of the center of said polynucleotide.

7. The polynucleotide according to claim 6, wherein said polynucleotide consists of said contiguous span and said contiguous span is 25 nucleotides in length and said biallelic marker is at the center of said polynucleotide.

8. A polynucleotide for use in a hybridization assay for determining the identity of a nucleotide at a CNS disorder-related biallelic marker.

9. A polynucleotide for use in a sequencing assay for determining the identity of a nucleotide at a CNS disorder-related biallelic marker.

10. A polynucleotide for use in an allele specific amplification assay for determining the identity of a CNS disorder-related biallelic marker.

11 . A polynucleotide for use in amplifying a segment of nucleotides comprising a CNS disorder-related biallelic marker.

12. A use according to any one of claims 8 to 11, wherein said polynucleotide is selected from the sequences described in Table 7.

13. A method of genotyping an individual comprising: (a) obtaining a biological sample comprising a nucleic acid from said individual; (b) determining the identity of a polymorphic base at a biallelic marker from said nucleic acid; wherein said biallelic marker is selected from any one biallelic marker of Table 7; wherein the identity of the polymorphic base determines the genotype of the individual at said position.

14. A method according to claim 13, wherein said CNS disorder-related biallelic marker is selected from the biallelic markers described in Table 7.

15. The method according to claim 14, wherein said CNS disorder-related biallelic marker is selected from the group consisting of 99-27207-117, 99-28110-75, 99-28134-215, 99-32181-192, 99-28106-185, 99-30858-354, 18-20-174, 99-32002-313, 18-31-178, 18-38-395, 99-30853-364, 19-56-140, 19-28-136, 99-28788-300, 99-32061-304, 99-32121-242, 19-14-241, 16-50-196, 8-19-372, 12-254-180, 10-214-279, 10-217-91, 18-194-130, 18-186-391, 18-198-252, 18-242-300, 20-205-302, 19-58-162, 19-9-45, 19-22-74, 19-88-185, 19-18-310, 19-19-174, 19-17-188, 19-16-127, 99-32148-315, 19-46-322, 99-32131-312, 99-32065-303, 19-44-251,19-29-303, 18-355-67, 18-353-267, 18-338-305, 16-88-185, 24-243-346, 99-62531-351, 99-54279-152, 99-28171-458, 99-28173-395, 18-186-394, 8-15-126, 99-2409-298, 99-28722-90 and 409.

16. The method according to claim 14, wherein said CNS disorder-related biallelic marker is selected from the group consisting of 99-28788-300, 99-32061-304, 99-32121-242, 19-14-241, 19-28-136, 16-50-196, 19-58-162, 19-9-45, 20-205-302, 24-243-346, 99-27207-117, 99-28110-75, 99-28134-215, 99-32181-192, 19-17-188 and 19-19-174.

17. The method according to claim 13, wherein said biological sample is derived from a single subject.

18. The method according to claim 17, wherein the identity of the nucleotides at said biallelic marker is determined for both copies of said biallelic marker present in said subject's genome.

19. The method according claim 13, wherein said biological sample is derived from multiple subjects.

20. The method according to claim 13, further comprising amplifying a portion of said sequence comprising the biallelic marker prior to said determining step.

21. A method of determining the frequency in a population of an allele of a CNS
disorder-related biallelic marker, comprising:
a) genotyping individuals from said population for said biallelic marker according to the method of claim 13; and b) determining the proportional representation of said biallelic marker in said population.

22. The method according to claim 21, wherein said CNS disorder-related biallelic marker is selected from the biallelic markers described in Table 7.

23. The method according to claim 22, wherein said CNS disorder-related biallelic marker is selected from the group consisting of 99-27207-117, 99-28110-75, 99-28134-215, 99-32181-192, 99-28106-185, 99-30858-354, 18-20-174, 99-32002-313, 18-31-178, 18-38-395, 99-30853-364, 19-56-140, 19-28-136, 99-28788-300, 99-32061-304, 99-32121-242, 19-14-241, 16-50-196, 8-19-372, 12-254-180, 10-214-279, 10-217-91, 18-194-130, 18-186-391 18-198-252, 18-242-300, 20-205-302, 19-58-162, 19-9-45, 19-22-74, 19-88-185, 19-18-310, 19-19-174, 19-17-188, 19-16-127, 99-32148-315, 19-46-322, 99-32131-312, 99-32065-303, 19-44-251, 19-29-303, 18-355-67, 18-353-267, 18-338-305, 16-88-185, 24-243-346, 99-62531-351, 99-54279-152, 99-28171-458, 99-28173-395, 18-186-394, 8-15-126, 99-2409-298, 99-28722-90 and 409.

24. The method according to claim 22, wherein said CNS disorder-related biallelic marker is selected from the group consisting of 99-28788-300, 99-32061-304, 99-32121-242, 19-14-241, 19-28-136, 16-50-196, 19-58-162, 19-9-45, 20-205-302, 24-243-346, 99-27207-117, 99-28110-75, 99-28134-215, 99-32181-192, 19-17-188 and 19-19-174.

25. The method of detecting an association between an allele and a phenotype, comprising the steps of:
a) determining the frequency of at least one CNS disorder-related biallelic marker allele in a trait positive population according to the method of claim 21;
b) determining the frequency of said CNS disorder-related biallelic marker allele in a control population according to the method of claim 21; and c) determining whether a statistically significant association exists between said allele and said phenotype.

26. The method of estimating the frequency of a haplotype for a set of biallelic markers in a population, comprising:
a) genotyping each individual in said population for at least one CNS disorder-related biallelic marker according to claim 13;
b) genotyping each individual in said population for a second biallelic marker by determining the identity of the nucleotides at said second biallelic marker for both copies of said second biallelic marker present in the genome; and c) applying a haplotype determination method to the identities of the nucleotides determined in steps a) and b) to obtain an estimate of said frequency.

27. The method according to claim 26, wherein said haplotype determination method is selected from the group consisting of asymmetric PCR amplification, double PCR
amplification of specific alleles, the Clark method, or an expectation maximization algorithm.

28. The method according to claim 26, wherein said CNS disorder-related biallelic marker is selected from the biallelic markers described in Table 7.

29. The method according to claim 28, wherein said CNS disorder-related biallelic marker is selected from the group consisting of 99-27207-117, 99-28110-75, 99-28134-215, 99-32181-192, 99-28106-185, 99-30858-354, 18-20-174, 99-32002-313, 18-31-178, 18-38-395, 99-30853-364, 19-56-140, 19-28-136, 99-28788-300, 99-32061-304, 99-32121-242, 19-14-241, 16-50-196, 8-19-372, 12-254-180, 10-214-279, 10-217-91, 18-194-130, 18-186-391, 18-198-252, 18-242-300, 20-205-302, 19-58-162, 19-9-45, 19-22-74, 19-88-185, 19-18-310, 19-19-174, 19-17-188, 19-16-127, 99-32148-315, 19-46-322, 99-32131-312, 99-32065-303, 19-44-251, 19-29-303, 18-355-67, 18-353-267, 18-338-305, 16-88-185, 24-243-346, 99-62531-351, 99-54279-152, 99-28171-458, 99-28173-395, 18-186-394, 8-15-126, 99-2409-298, 99-28722-90 and 409.

30. The method according to claim 28, wherein said CNS disorder-related biallelic marker is selected from the group consisting of 99-28788-300, 99-32061-304, 99-32121-242, 19-14-241, 19-28-136, 16-50-196, 19-58-162, 19-9-45, 20-205-302, 24-243-346, 99-27207-117, 99-28110-75, 99-28134-215, 99-32181-192, 19-17-188 and 19-19-174.

31. The method according to claim 28, wherein said haplotype comprises one of the following sets of biallelic markers:
99-28106-185, and 99-32181-192;
18-20-174, 99-32002-313, 18-31-178, and 18-38-395;
18-20-174, 18-31-178, 18-38-395, and 99-30858-354;
18-20-174, 18-38-395, 99-30853-364, and 99-30858-354;
99-32002-313, 18-31-178, 18-38-395, and 99-30858-354;
18-20-174, 18-38-395, and 99-30858-354;
99-32002-313, 18-31-I78, and 99-30858-354;
18-31-178, 99-30853-364, and 99-30858-354;
19-56-140, 99-28788-300, 99-32061-304, and 99-32121-242;
19-28-136, 99-28788-300, 99-32061-304, and 99-32121-242;
19-14-241, 19-28-136, 99-32061-304, and 99-32121-242;
19-56-140, 19-28-136, 99-32061-304, and 99-32121-242;
19-14-241, 19-28-136, and 16-50-196;
19-28-136, 99-32061-304, and 99-32121-242;
99-28788-300, 99-32061-304, and 99-32121-242;
99-32061-304, and 99-32121-242;
19-56-140, 19-14-241, 19-28-136, and 16-50-196;
99-28788-300, 99-32061-304, and 99-32121-242;
16-50-196, 99-32061-304, and 99-32121-242;
19-14-241, 19-28-136, and 16-50-196;
19-14-241, 99-32061-304, and 99-32121-242;
19-14-241, and 19-28-136;
99-32061-304, and 99-32121-242;
8-15/126, and 99-2409/298;
12-254/180, 10-214/279, and 10-217/91;
18-186/391, 18-194/130, and 18-242/300;
18-186/394, 18-198/252, and 18-242/300;
19-58-162, 19-9-45, 19-22-74, and 20-205-302;
19-58-162, 19-9-45, 19-88-185, and 20-205-302;
19-58-162, 19-9-45, and 20-205-302;

19-58-162, 19-22-74, and 20-205-302;
19-58-162, and 20-205-302;
19-9-45, and 20-205-302;
19-22-74, and 20-205-302;
19-19-174, 19-17-188, and 19-18-310;
19-19-174, 19-16-127, and 19-17-188;
19-19-174, and 19-17-188; and 19-17-188, 19-19-174, 24-243-346, and 99-62531-351;
19-17-188, 19-19-174, 24-243-346, and 99-54279-152;
19-17-188, 19-19-174, 99-62531-351, and 99-54279-152;
99-32002-313, 18-31-178, 99-30853-364, and 99-30858-354;
99-32121-242, 99-32148-315, 19-46-322, and 99-32131-312;
99-28106-185, 99-28171-458, 99-28173-395, and 99-32181-192;
18-186-391, 18-194-130, 18-198-252, and 18-242-300.
19-17-188, 19-19-174, and 24-243-346;
19-17-188, 19-19-174, and 99-54279-152;
19-17-188, 24-243-346, and 99-54279-152;
19-17-188, 19-19-174, and 99-62531-351;
19-17-188, 24-243-346, and 99-62531-351;
99-32061-304, 19-28-136, and 99-32131-312;
12-254-180, 10-214-279, and 10-217-91;
18-186-391, 18-194-130, and 18-242-300;
18-186-394, 18-198-252, and 18-242-300;
8-15-126, 8-19-372, and 99-2409-298.
19-17-188, and 19-19-174;
19-17-188, and 24-243-346;
19-17-188, and 99-62531-351;
19-17-188, and 99-54279-152;
19-58-162, and 19-9-45;
8-15-126, and 99-2409-298;
18-31-178, and 99-30858-354;
18-186-394, and 18-242-300;
18-198-252, and 18-242-300; and 99-28722-90, and 99-32306-409.

32. The method according to claim 28, wherein said CNS disorder-related biallelic marker comprises one of the following sets of biallelic markers:

99-28788-300, 99-32061-304, and 99-32121-242;
19-14-241, 19-28-136, and 16-50-196;
19-17-188, 19-19-174, and 24-243-176; and 19-58-162, 19-9-45, and 20-205-302.

33. The method of detecting an association between a haplotype and a phenotype, comprising the steps of:
a) estimating the frequency of at least one haplotype in a trait positive population according to the method of claim 26;
b) estimating the frequency of said haplotype in a control population according to the method of claim 26; and c) determining whether a statistically significant association exists between said haplotype and said phenotype.

34. The method according to either claim 25 or 33, wherein said control population is a trait negative population.

35. The method according to either claim 25 or 33, wherein said case control population is a random population.

36. The method according to claim 56, wherein said CNS disorder-related biallelic marker is selected from the group consisting of 99-27207-117, 99-28110-75, 99-28134-215; 99-32181-192, 99-28106-185, 99-30858-354, 18-20-174, 99-32002-313, 18-31-178, 18-38-395, 99=
30853-364, 19-56-140, 19-28-136, 99-28788-300, 99-32061-304, 99-32121-242, 19-14-241, 16-50-196, 8-19-372, 12-254-180, 10-214-279, 10-217-91, 18-194-130, 18-186-391, 18-198-252, 18-242-300, 20-205-302, 19-58-162, 19-9-45, 19-22-74, 19-88-185, 19-18-310, 19-19-174, 19-17-188, and 19-16-127.

37. The method according to claim 33, wherein said CNS disorder-related biallelic marker is selected from the group consisting of 99-28788-300, 99-32061-304, 99-32121-242, 19-14-241, 19-28-136, 16-50-196, 19-58-162, 19-9-45, and 20-205-302.

38. The method according to claim 33, wherein said haplotype comprises one of the following sets of biallelic markers:
99-28106-185, and 99-32181-192;
18-20-174, 99-32002-313, 18-31-178, and 18-38-395;
18-20-174, 18-31-178, 18-38-395, and 99-30858-354;

18-20-174, 18-38-395, 99-30853-364, and 99-30858-354;
99-32002-313, 18-31-178, 18-38-395, and 99-30858-354;
18-20-174, 18-38-395, and 99-30858-354;
99-32002-313, 18-31-178, and 99-30858-354;
18-31-178, 99-30853-364, and 99-30858-354;
19-56-140, 99-28788-300, 99-32061-304, and 99-32121-242;
19-28-136, 99-28788-300, 99-32061-304, and 99-32121-242;
19-14-241, 19-28-136, 99-32061-304, and 99-32121-242;
19-56-140, 19-28-136, 99-32061-304, and 99-32121-242;
19-14-241, 19-28-136, and 16-50-196;
19-28-136, 99-32061-304, and 99-32121-242;
99-28788-300, 99-32061-304, and 99-32121-242;
99-32061-304, and 99-32121-242;
19-56-140, 19-14-241, 19-28-136, and 16-50-196;
99-28788-300, 99-32061-304, and 99-32121-242;
16-50-196, 99-32061-304, and 99-32121-242;
19-14-241, 19-28-136, and 16-50-196;
19-14-241, 99-32061-304, and 99-32121-242;
19-14-241, and 19-28-136;
99-32061-304, and 99-32121-242;
8-15/126, and 99-2409/298;
12-254/180, 10-214/279, and 10-217/91;
18-186/391, 18-194/130, and 18-242/300;
18-186/394, 18-198/252, and 18-242/300;
19-58-162, 19-9-45, 19-22-74, and 20-205-302;
19-58-162, 19-9-45, 19-88-185, and 20-205-302;
19-58-162, 19-9-45, and 20-205-302;
19-58-162, 19-22-74, and 20-205-302;
19-58-162, and 20-205-302;
19-9-45, and 20-205-302;
19-22-74, and 20-205-302;
19-19-174, 19-17-188, and 19-18-310;
19-19-174, 19-16-127, and 19-17-188;
19-19-174, and 19-17-188; and 19-17-188, 19-19-174, 24-243-346, and 99-62531-351;
19-17-188, 19-19-174, 24-243-346, and 99-54279-152;
19-17-188, 19-19-174, 99-62531-351, and 99-54279-152;

99-32002-313, 18-31-178, 99-30853-364, and 99-30858-354;
99-32121-242, 99-32148-315, 19-46-322, and 99-32131-312;
99-28106-185, 99-28171-458, 99-28173-395, and 99-32181-192;
18-186-391, 18-194-130, 18-198-252, and 18-242-300.
19-17-188, 19-19-174, and 24-243-346;
19-17-188, 19-19-174, and 99-54279-152;
19-17-188, 24-243-346, and 99-54279-152;
19-17-188, 19-19-174, and 99-62531-351;
19-17-188, 24-243-346, and 99-62531-351;
99-32061-304, 19-28-136, and 99-32131-312;
12-254-180, 10-214-279, and 10-217-91;
18-186-391, 18-194-130, and 18-242-300;
18-186-394, 18-198-252, and 18-242-300;
8-15-126, 8-19-372, and 99-2409-298.
19-17-188, and 19-19-174;
19-17-188, and 24-243-346;
19-17-188, and 99-62531-351;
19-17-188, and 99-54279-152;
19-58-162, and 19-9-45;
8-15-126, and 99-2409-298;
18-31-178, and 99-30858-354;
18-186-394, and 18-242-300;
18-198-252, and 18-242-300; and 99-28722-90, and 99-32306-409.

39. The method according to claim 33, wherein said haplotype comprises one of the following sets of biallelic markers:
99-28788-300, 99-32061-304, and 99-32121-242;
19-14-241, 19-28-136, and 16-50-196;
19-17-188, 19-19-174, and 24-243-176; and 19-58-162, 19-9-45, and 20-205-302.

40. The method according to either claim 25 or 33, wherein said phenotype is a CNS
disorder.

41. The method according to either claim 25 or 33, wherein said phenotype is a response to an agent acting on a CNS disorder.

42. The method according to either claim 25 or 33, wherein said phenotype is a side effect to an agent acting on a CNS disorder.

43. The method according to claim 25, wherein the identity of the nucleotides at all of the biallelic markers described in Table 7 is determined in steps a) and b).

44. The method of administering a drug or treatment comprising:
a) obtaining a nucleic acid sample from an individual;
b) determining the identity of the polymorphic base of at least one CNS
disorder-related biallelic marker according to the method of claim 13 which is associated with a positive response to said drug or treatment, or at least one CNS disorder-related marker which is associated with a negative response to said drug or treatment; and c) administering said drug or treatment to said individual if said nucleic acid sample contains at least one biallelic marker associated with a positive response to said drug or treatment, or if said nucleic acid sample lacks at least one bialleic marker associated with a negative response to said drug or treatment.

45. The method of selecting an individual for inclusion in a clinical trial of a drug or treatment comprising:
a) obtaining a nucleic acid sample from an individual;
b) determining the identity of the polymorphic base of at least one CNS
disorder-related biallelic marker according to the method of claim 13 which is associated with a positive response to said drug or treatment, or at least one biallelic marker associated with a negative response to said drug or treatment in said nucleic acid sample; and c) including said individual in said clinical trial if said nucleic acid sample contains at least one biallelic marker which is associated with a positive response to said drug or treatment, or if said nucleic acid sample lacks at least one biallelic marker associated with a negative response to said drug or treatment.

46. The diagnostic kit comprising a polynucleotide according to any one of claims 2, 3, 4 and 5.

47. The use of a polynucleotide in a hybridization assay for determining the identity of a nucleotide at a CNS disorder-related biallelic marker.

48. The use of a polynucleotide in a sequencing assay for determining the identity of a nucleotide at a CNS disorder-related biallelic marker.

49. The use of a polynucleotide in an allele specific amplification assay for determining the identity of a CNS disorder-related biallelic marker.

50. The use of a polynucleotide in amplifying a segment of nucleotides comprising a CNS disorder-related biallelic marker.