EP1268856A2 - Detection de polymorphismes du nucleotide simple et de methylation de cytosine - Google Patents

Detection de polymorphismes du nucleotide simple et de methylation de cytosine

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Publication number
EP1268856A2
EP1268856A2 EP01923891A EP01923891A EP1268856A2 EP 1268856 A2 EP1268856 A2 EP 1268856A2 EP 01923891 A EP01923891 A EP 01923891A EP 01923891 A EP01923891 A EP 01923891A EP 1268856 A2 EP1268856 A2 EP 1268856A2
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EP
European Patent Office
Prior art keywords
single nucleotide
nucleotide polymorphisms
oligonucleotides
genomic dna
detection
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01923891A
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German (de)
English (en)
Inventor
Alexander Olek
Christian Piepenbrock
Kurt Berlin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Epigenomics AG
Original Assignee
Epigenomics AG
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Filing date
Publication date
Application filed by Epigenomics AG filed Critical Epigenomics AG
Publication of EP1268856A2 publication Critical patent/EP1268856A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/82—Translation products from oncogenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity
    • C07K14/4703—Inhibitors; Suppressors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6834—Enzymatic or biochemical coupling of nucleic acids to a solid phase
    • C12Q1/6837—Enzymatic or biochemical coupling of nucleic acids to a solid phase using probe arrays or probe chips
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6844—Nucleic acid amplification reactions
    • C12Q1/6853—Nucleic acid amplification reactions using modified primers or templates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/154—Methylation markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention describes a representative set of oligonucleotides or PNA (peptide nucleic acid) oligomers which are particularly suitable for simultaneously detecting SNPs (single nucleotide polymorphisms) and cytosine methylations in genomic DNA samples to distinguish cell types. and a method used.
  • SNPs single nucleotide polymorphisms
  • cytosine methylations in genomic DNA samples to distinguish cell types.
  • the human genome project the first sequencing of the human genome, will be completed in the next few years. This project will make it possible to identify all of the approximately 100,000 genes. Sequence information opens up undreamt-of possibilities for elucidating gene functions. This in turn opens up the possibility of doing pharmacogenetics and pharmacogenomics.
  • Pharmacogenetics and pharmacogenomics target the use of drugs depending on a genotype. The aim is to increase the effectiveness of medication.
  • the necessary intermediate step is the determination of the position lymorphisms and genotypes associated with a particular response. Therefore, increasingly efficient genotyping methods are required.
  • Microsatellites are highly polymorphic, i.e. they have a variety of alleles. They are characterized in that a repetitive sequence element with a different number of repetitions for different alleles is franked by conserved sequences. There is an average of one microsatellite marker per million bases. A map of 5,000 positioned microsatellite markers has been published by CEPH. Microsatellites are genotyped by determining the size of a PCR product with primers of the conserved, flanking sequence. The fluorescence-labeled PCR products are separated on gels.
  • SNP markers There are comparatively few described SNP markers. A card with 300,000 SNP markers is currently being developed by the SNP consortium and will be publicly available. Once the SNP markers have been identified, they can be assigned to genomic positions. The goal is to map 150,000 SNP markers by 2001 (Mashall, E. (1999); Science, 284, 406-407). There are a handful of genotyping methods for SNPS. Some are based on the separation of products on gels, such as the oligonucleotide ligase assay (OLA). It is therefore more suitable for medium throughput. Others rely on pure hybridization, which, however, does not have the same stringency. DNA arrays (DNA chips) are suitable for the analysis of a large number of SNPs in a limited number of individuals.
  • OVA oligonucleotide ligase assay
  • MALDI Matrix-assisted laser desorption / ionization time-of-flight mass spectrometry
  • MALDI has revolutionized the analysis of biomolecules (Karas, M. & Hillenkamp, F. Anal. Che. 60, 2299-2301 (1988)).
  • MALDI has been used in various variants for the analysis of DNA. The variants range from primer extension to sequencing (Liu, Y.-H., et al. Rapid Comraun. Mass Spectrom. 9, 735-743 (1,995); Ch'ang, L.-Y., et al. Rapid Commun. Mass Spectrom. 9, 772-774 (1995); Little, DP, et al. J. Mol. Med.
  • 5-methylcytosine The most frequently covalently modified base in the DNA of eukaryotic cells is 5-methylcytosine. For example, it plays a role in the regulation of transcription, in genetic imprinting and in tumorigenesis. The identification of 5-methylcytosine as a component of genetic information is therefore of considerable interest. However, 5-methylcytosine positions cannot be identified by sequencing since 5-methylcytosine has the same base pairing behavior as cytosine. In addition, in the case of PCR amplification, the epigenetic information which the 5-methylcytosines carry is completely lost.
  • the state of the art in terms of sensitivity is defined by a method which includes the DNA to be examined in an agarose matrix, thereby preventing the diffusion and renaturation of the DNA (bisulfite only reacts on single-stranded DNA) and all precipitation and purification steps replaced by rapid dialysis (Olek, A. et al., Nucl. Acids. Res. 1996, 24, 5064-5066).
  • This method individual cells can be examined, which illustrates the potential of the method.
  • only individual regions up to approximately 3000 base pairs in length have so far been investigated; global examination of cells for thousands of possible methylation analyzes is not possible.
  • this method too, cannot reliably analyze very small fragments from small sample quantities. Despite the diffusion protection, these are lost through the matrix.
  • Fluorescent-labeled probes have been used in many cases for scanning an immobilized DNA array.
  • the simple attachment of Cy3 and Cy5 dyes to the 5 'OH of the respective probe is particularly suitable for fluorescent labels.
  • the fluorescence of the hybridized probes is detected, for example, using a confocal microscope.
  • the dyes Cy3 and Cy5, among many others, are commercially available. task
  • the present invention is intended to provide a set of oligonucleotides or PNA oligomers and a method which are particularly suitable for the simultaneous detection of SNPs (single nucleotide polymorphisms) and cytosine methylations in genomic DNA samples.
  • SNPs single nucleotide polymorphisms
  • cytosine methylations in genomic DNA samples.
  • the task is therefore solved by a set of oligonucleotides or PNA (peptide nucleic acid) oligomers for the detection of single nucleotide polymorphisms (SNPs, single nucleotide polymorphisms) and for the detection of the cytosine methylation state in chemically pretreated genomic DNA, the base sequences being selected are from SEQ-ID: 1 to SEQ-ID: 382046.
  • SNPs single nucleotide polymorphisms
  • the set according to the invention includes both the base sequences with the SEQ-ID: 1 to SEQ-ID: 382046 itself and / or those by extending, shortening or changing the sequences mentioned with the SEQ-ID: 1 to SEQ-ID : 382046 contains.
  • the sentence according to the invention can thus be composed according to the invention from unchanged sequences and / or sequences modified in the manner according to the invention.
  • the present invention describes a set of oligomer probes (oligonucleotides and / or PNA oligomers) for the detection of single nucleotide polymorphisms and / or the cytosine methylation state in chemically pretreated genomic DNA, which is particularly preferably at least 10 of the listed oligonucleotide or PNA
  • the set of oligomer probes for the detection of single nucleotide polymorphisms and / or the cytosine methylation state in chemically pretreated genomic DNA comprises at least 100
  • Oligonucleotide or PNA sequences selected from the sequences SEQ-ID: 1 to SEQ-ID: 382046, or at least 100 PNA oligomers or oligonucleotide sequences, which in turn comprise the sequences listed there, namely the sequences SEQ-ID: 1 to SEQ ID: 382046.
  • the set of oligonucleotides for the detection of single nucleotide polymorphisms and the cytosine methylation state in the chemically pretreated genomic DNA is particularly preferably characterized in that the majority of the base sequences at the 5 'end and / or at the 3' end are each extended by a further base, the bases can be A, T or C.
  • the set of oligonucleotides for the detection of single nucleotide polymorphisms and the cytosine methylation state in the chemically pretreated genomic DNA is particularly preferably once again characterized in that the base sequences at the 5 'end and / or at the 3' end are in each case extended by a further base , where the bases can be A, T or G.
  • the set of oligonucleotides for the detection of single nucleotide polymorphisms and the cytosine methylation state in the chemically pretreated genomic DNA is preferably characterized in that the base sequence sequences at the 5 'end and / or at the 3' end are in each case extended by at least two further bases, where the bases can be A, T or C.
  • the set of oligonucleotides for the detection of individual nucleotide polymorphisms and the cytosine methylation state in the chemically pretreated genomic DNA is preferably characterized in that the majority of the base sequences at the 5 'end and / or at the 3' end are each extended by at least two further bases are present, wherein the bases can be A, T or G.
  • the set of PNA (peptide nucleic acid) oligomers for the detection of single nucleotide polymorphisms and the cytosine methylation state in the chemically pretreated genomic DNA is particularly preferably characterized in that at the 5 'end and / or at the 3' end of the oligomer a nucleobase is omitted.
  • Detection of individual nucleotide polymorphisms and the cytosine methylation state in the chemically pretreated genomic DNA is preferably characterized in that at least two nucleobases are omitted at the 5 'end and / or at the 3' end of the oligomer.
  • a representative set of oligonucleotides and / or PNA oligomers comprising oligomers and / or oligonucleotides according to the sequences SEQ-ID: 1 to SEQ-ID: 382046, is intended for the detection of cytosine methylations and single nucleotide polymorphisms in genomic DNA to differentiate between Cell types or tissues or used to study cell differentiation.
  • the following procedural steps are carried out one after the other:
  • a genomic DNA sample is chemically treated in such a way that at the 5 'position, unmethylated cytosine bases in uracil, Thy or another base which is similar to the cytosine in terms of hybridization behavior are converted.
  • the genomic DNA to be analyzed is preferably obtained from conventional sources for DNA, such as. B. cell lines, blood, sputum, stool, urine, brain spinal fluid, paraffin-embedded tissue, histological slides and all possible combinations thereof.
  • the amplification is carried out by means of the polymerase chain reaction (PCR), a thermostable DNA polymerase being used.
  • PCR polymerase chain reaction
  • a second process step more than ten different fragments are amplified from the chemically pretreated genomic DNA, each of which is less than 2000 base pairs long, using synthetic oligonucleotides as primers.
  • the oligonucleotides or PNA oligomers are bound to a solid phase at defined locations.
  • oligonucleotides and / or PNA- Oligomer sequences arranged on a flat solid phase in the form of a rectangular or hexagonal grid.
  • the solid phase surface preferably consists of silicon, glass, polystyrene, aluminum, steel, iron, copper, nickel, silver or gold.
  • the amplicates are hybridized to a set of oligonucleotides or PNA oligomers which comprise at least 10 of the above-mentioned sequences, namely the sequences SEQ-ID: 1 to SEQ-ID: 382046.
  • the amplification of several DNA sections is carried out in one reaction vessel.
  • the base sequences of the set of oligonucleotides according to the invention are mostly at the 5 'end and / or at the 3' end in each case by a further one Base extends forward, whereby the bases can be either A, T or G.
  • the base sequences of the set of oligonucleotides according to the invention are mostly at the 5 'end and / or at the 3' end each extended by at least two further bases, where the bases can be either A, T or C.
  • the base sequences of the set of oligonucleotides according to the invention for the detection of individual nucleotide polymorphisms and of the cytosine methylation state are mostly at the 5 'end and / or at the 3' end in each case by at least two further bases extended, whereby the bases can be either A, T or G.
  • a set of PNA oligomers from the above-mentioned base sequences is used, a nucleobase being omitted at the 5 'end and / or at the 3' end of the oligomer.
  • a set of PNA oligomers from the above-mentioned base sequences is used, at least two nucleobases being omitted at the 5 'end and / or at the 3' end of the oligomer.
  • At least 10 of the above-mentioned oligonucleotide or PNA sequences are used to detect the cytosine methylation state, or at least 10 PNA oligomers or oligonucleotide sequences which in turn comprise the sequences mentioned above, namely the sequences SEQ-ID: 1 to SEQ-ID: 382046.
  • At least 100 of the above-mentioned oligonucleotide or PNA sequences are used to detect the cytosine methylation state, or at least 100 PNA oligomer or oligonucleotide sequences which in turn comprise the sequences mentioned above, namely the sequences SEQ-ID: 1 to SEQ-ID: 382046.
  • At least one primer is bound to a solid phase.
  • different amplificates are arranged on the solid phase in the form of a rectangular or hexagonal grid.
  • the solid phase surface preferably consists of silicon, glass, polystyrene aluminum, steel, iron, copper, nickel, silver or gold.
  • the hybridized amplificates are detected.
  • the labels attached to the amplificates can be identified at any position on the solid phase at which an oligonucleotide sequence is located.
  • the labels of the amplified products are fluorescent labels.
  • the labels of the amplificates are radionuclides.
  • the amplificates carry removable mass markings which are detected in a mass spectrometer.
  • the amplified products, fragments of the amplified products or probes complementary to the amplified products are detected in the mass spectrometer.
  • the fragments generated have a single positive or negative net charge in the mass spectrometer for better detectability.
  • the set of oligonucleotides and / or PNA oligomers according to the invention is preferably used for diagnosis and / or Predict adverse events for patients or individuals.
  • the set of oligonucleotides and / or PNA oligomers according to the invention is preferably used for the diagnosis and / or prognosis of adverse events for patients or individuals, these adverse events belonging to at least one of the following categories: adverse drug effects; Cancers; CNS malfunction, damage or illness; aggressive symptoms or behavioral disorders; clinical, psychological and social consequences of brain injuries; psychotic disorders and personality disorders; Dementia and / or associated syndromes; cardiovascular disease, malfunction and damage; Malfunction, damage or disease of the gastrointestinal tract; Malfunction, damage or disease of the respiratory system; Injury, inflammation, infection, immunity and / or convalescence; Malfunction, damage or illness of the body as a deviation in the development process; Malfunction, damage or disease of the skin, muscles, connective tissue or bones; endocrine and metabolic dysfunction, injury or illness; Headache or sexual malfunction.
  • the set of oligonucleotides and / or PNA oligomers according to the invention is preferably used to differentiate between cell types or tissues or to investigate cell differentiation.
  • the invention furthermore relates to a kit which contains at least 10 oligonucleotides or PNA oligomers and primers for the preparation of the amplificates and instructions for carrying out the method.
  • Preferred according to the invention is a set of oligonucleotides for the detection of single nucleotide polymorphisms (SNPs, single nucleotide polymorphisms) and the cytosine methylation state in chemically pretreated genomic DNA, where the base sequences are mostly at the 5 'end and / or at the 3' end another base is extended, the bases can be either A, T or C.
  • a set of oligonucleotides is preferred for the detection of single nucleotide polymorphisms (SNPs, single nucleotide polymorphisms) and the cytosine methylation state in chemically pretreated genomic DNA, where the base sequences are mostly one more at the 5 'end and / or at the 3' end
  • the base is extended, and the bases can be either A, T or G.
  • a set of oligonucleotides for the detection of single nucleotide polymorphisms is preferred according to the invention
  • SNPs single nucleotide polymorphisms
  • cytosine methylation state in chemically pretreated genomic DNA, where the majority of the base sequences at the 5 'end and / or at the 3' end are each extended by at least two additional bases, the bases being either A, Can be T or C.
  • Preferred according to the invention is a set of oligonucleotides for the detection of single nucleotide polymorphisms (SNPs, single nucleotide polymorphisms) and the cytosine methylation state in chemically pretreated genomic DNA, where the base sequences are mostly at the 5 'end and / or at the 3' end in each case by at least two further bases are present in an extended manner, whereby the bases can be either A, T or G.
  • SNPs single nucleotide polymorphisms
  • cytosine methylation state in chemically pretreated genomic DNA
  • Oligomers for the detection of single nucleotide polymorphisms (SNPs, single nucleotide polymorphisms) and the cytosine methylation state in chemically pretreated genomic DNA, where a nucleobase is omitted at the 5 'end and / or at the 3' end of the oligomer.
  • SNPs single nucleotide polymorphisms
  • cytosine methylation state in chemically pretreated genomic DNA, where a nucleobase is omitted at the 5 'end and / or at the 3' end of the oligomer.
  • Preferred according to the invention is a set of PNA (peptide nucleic acid) oligomers for the detection of single nucleotide polymorphisms (SNPs, single nucleotide polymorphisms) and the cytosine methylation state in chemically pretreated genomic DNA, where in each case at the 5 'and / or at the 3' end of the Oligomers at least two nucleobases are omitted.
  • SNPs single nucleotide polymorphisms
  • a set of oligomer probes for detecting the cytosine methylation state and / or single nucleotide polymorphisms in chemically pretreated genomic DNA, comprising at least 10 of the above-mentioned oligonucleotide or PNA sequences, is preferred.
  • Preferred according to the invention is a set of oligomer probes (oligonucleotides and / or PNA oligomers) for the detection of the cytosine methylation state and / or of single nucleotide polymorphisms in chemically pretreated genomic DNA, comprising at least 100 of the above-mentioned oligonucleotide or PNA sequences.
  • the present invention also relates to a method for analyzing a representative set of cytosine methylations and single nucleotide polymorphisms in genomic DNA samples to distinguish cell types.
  • a method for analyzing a representative set of cytosine methylations and single nucleotide polymorphisms in genomic DNA samples to distinguish cell types.
  • chemical treatment at the 5-position unmethylated cytosine bases is converted into uracil, thymidine or another base which is not similar to cytosine in terms of hybridization behavior.
  • the amplificates are hybridized to a set of oligonucleotides or PNA oligomers, comprising at least 10 of the above
  • the non-hybridized amplificates are removed.
  • the hybridized amplificates are detected.
  • the chemical treatment is carried out by means of a solution of a bisulfite, bisulfite or disulfite.
  • the amplification is carried out by means of the polymerase chain reaction (PCR). It is preferred according to the invention that the oligonucleotides or PNA oligomers are bound to a solid phase at defined locations.
  • PCR polymerase chain reaction
  • oligonucleotides and / or PNA oligomer sequences are arranged on a flat solid phase in the form of a rectangular or hexagonal grid.
  • markings attached to the amplifiers can be identified at any position of the solid phase at which an oligonucleotide sequence is located.
  • At least one primer is bound to a solid phase during the amplification.
  • different amplificates are arranged on the solid phase in the form of a rectangular or hexagonal grid.
  • the labels of the amplified products are fluorescent labels.
  • the labels of the amplificates are radionuclides.
  • the amplificates carry removable mass markings which are detected in a mass spectrometer.
  • the amplificates, fragments of the amplificates or probes complementary to the amplificates are detected in the mass spectrometer. It is preferred according to the invention that the fragments generated have a single positive or negative net charge for better detectability in the mass spectrometer.
  • the detection is carried out and visualized using matrix-assisted laser desorption / ionization mass spectrometry (MALDI) or using electrospray mass spectrometry (ESI).
  • MALDI matrix-assisted laser desorption / ionization mass spectrometry
  • ESI electrospray mass spectrometry
  • the polymerases are heat-resistant DNA polymerases.
  • the amplification of several DNA sections is carried out in one reaction vessel.
  • the solid phase surface consists of silicon, glass, polystyrene, aluminum, steel, iron, copper, nickel, silver or gold.
  • the genomic DNA was obtained from a DNA sample, sources of DNA e.g. B. cell lines, blood, sputu, stool, urine, brain spinal fluid, paraffin-embedded tissue, histological slides and all possible combinations thereof.
  • sources of DNA e.g. B. cell lines, blood, sputu, stool, urine, brain spinal fluid, paraffin-embedded tissue, histological slides and all possible combinations thereof.
  • the invention also relates to the use of a set of at least 10 of the above-mentioned oligonucleotides and / or PNA oligomers, selected from the sequences SEQ-ID: 1 to SEQ-ID: 382046, or of at least 10 oligomers or oligonucleotides which comprise the above sequences include, for the diagnosis and / or prognosis of adverse events for patients or individuals.
  • oligonucleotides and / or PNA oligomers selected from the sequences SEQ ID: 1 to SEQ ID: 382046, or else at least 10 oligomers or oligonucleotides which comprise the above sequences include, for the diagnosis and / or prognosis of adverse events for patients or individuals, these adverse events belonging to at least one of the following categories: adverse drug effects, cancer; CNS malfunction, damage or illness; aggressive symptoms or behavioral disorders; clinical, psychological and social consequences of brain injuries, psychotic disorders and personality disorders; Dementia and / or associated syndromes; cardiovascular disease, malfunction and
  • a set of at least 10 of the above-mentioned oligonucleotides and / or PNA oligomers selected from the sequences SEQ-ID: 1 to SEQ-ID: 382046, or of at least 10 oligomers or oligonucleotides which meet the above mentioned sequences include, to differentiate between cell types or tissues or to study cell differentiation.
  • the present invention also relates to a kit containing at least 10 of the above-mentioned oligonucleotides and / or PNA oligomers, selected from the sequences SEQ-ID: 1 to SEQ-ID: 382046, or of at least 10 oligomers or oligonucleotides which comprise the above sequences include, and primers for the preparation of the amplificates and instructions for performing the method according to the invention.
  • sequence listing with the sequences SEQ-ID: 1 to SEQ-ID: 382046 is enclosed with the international application in electronically readable form and is part of this application.

Abstract

L'invention concerne un ensemble d'oligonucléotides ou d'oligomères PNA et un procédé qui convient à la détection de méthylation de cytosine et du polymorphisme du nucléotide simple (SNP) dans des prélèvements d'ADN génomiques. Ce procédé sert au diagnostic et/ou au pronostic d'événements préjudiciables chez des patients ou des individus, tels que des maladies.
EP01923891A 2000-04-07 2001-04-06 Detection de polymorphismes du nucleotide simple et de methylation de cytosine Withdrawn EP1268856A2 (fr)

Applications Claiming Priority (3)

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DE10019173 2000-04-07
DE10019173 2000-04-07
PCT/IB2001/000713 WO2001077384A2 (fr) 2000-04-07 2001-04-06 Detection de polymorphismes du nucleotide simple et de methylation de cytosine

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EP (1) EP1268856A2 (fr)
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WO (1) WO2001077384A2 (fr)

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US20040241651A1 (en) 2004-12-02

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