CN112220937A - Application of over-expressed Dicerl in preparation of medicine for treating early and medium-term Alzheimer disease - Google Patents

Abstract

The invention provides application of adenoviruses expressing Dicer1 in preparation of medicaments for treating early and middle-stage Alzheimer's disease by hippocampal gyrus injection. Specifically, the invention discovers that the toxicity of A beta oligomer to neurons can be remarkably reversed by synthesizing the adenovirus over-expressing Dicer1 through in vitro packaging and expressing the virus in primary cultured neurons; compared with the injection of control virus, the virus vector containing the Dicer1 gene is injected into a CA3 hippocampal gyrus of mice to remarkably improve the cognitive function of APPswe/PSEN1dE9 mice, which indicates that the method of injecting adenovirus expressing the Dicer1 in a stereotaxic way in vitro or increasing the expression of the Dicer1 in the hippocampal gyrus in other ways can be used for treating early and middle-term Alzheimer disease.

Description

Application of over-expressed Dicerl in preparation of medicine for treating early and medium-term Alzheimer disease

Technical Field

The invention relates to the technical field of neurobiology, in particular to application of an over-expression Dicer1 vector in preparation of a medicament for treating early and middle-stage Alzheimer disease.

Background

Alzheimer's Disease (AD) is the first neurodegenerative disease with an initial occult, progressive development, clinically manifested as a gradual decline in memory and cognitive function. The pathological manifestations are central nervous system amyloid deposits, hyperphosphorylated tau deposits within neurons, neuronal synaptic loss and neuronal death. Currently there is no effective treatment regimen and drug for AD.

Dicer enzyme belongs to endoribonuclease-III (RNase-III) family members, and was first found in Drosophila. The Dicer family of drosophila includes both Dicer1 and Dicer2 genes, whereas nematodes and humans only function with Dicer 1. Dicer1 enzyme is a key enzyme for synthesis and maturation of miRNAs, and if the function of Dicer1 enzyme is deficient, the function of the enzyme can affect the maturation of miRNAs in cells, thereby affecting the expression of downstream target genes. Thus, Dicer1 is likely to play a very important role in the development of tumors. However, no studies have shown that the expression of Dicer1 is associated with alzheimer's disease.

Disclosure of Invention

The invention aims to provide a new application of Dicer1 gene aiming at the defects of the prior art, in particular to an application of Dicer1 gene in preparing a medicament for treating early and middle-term Alzheimer disease.

The purpose of the invention is realized by the following technical scheme:

firstly, the expression quantity of Dicer1 in wild type and AD mouse hippocampal gyrus tissues is analyzed by a quantitative PCR technology, and the result shows that the levels of Dicer1 protein and mRNA in the AD mouse hippocampal gyrus tissues are obviously lower than those of wild type mice.

Secondly, in the invention, Abeta 42 is used for treating primary cultured mouse hippocampal gyrus neurons, and in a parallel experiment, a control virus (Ad-EGFP) or a virus (AD-Dicer 1-T2A: EGFP) which expresses Dicer1 is infected at the same time of treatment, neurites are photographed in each treatment group and control group, and the neurite length is statistically analyzed. The results show that neurite length was significantly reduced after Α β 42 treatment compared to the control group; in a β 42-treated neurons infected with Dicer 1-overexpressing virus groups significantly increased neurite length compared to the control group virus groups. Suggesting the protective effect of over-expressing Dicer1 gene on neurons.

Further, the present invention uses 3.5-4 month old wild-type or AD mice, injected with control virus (Ad-EGFP) or over-expressed Dicer1 virus (Ad-Dicer 1-T2A: EGFP) in CA3 hippocampal gyrus, stained the mice with slices around the hippocampal gyrus, and separated the homogenate of CA3 region of hippocampal gyrus, analyzed the expression of Dicer1 and caspase3, and the results show that the content of Dicer1 is higher than that of wild-type and the level of activated caspase3 is equivalent to that of wild-type and is significantly lower than that of the group injected with control virus in AD mice injected with over-expressed Dicer1 virus. This suggests that injection of an adenovirus vector overexpressing Dicer1 inhibited neuronal apoptosis in hippocampal gyrus of AD mice.

Furthermore, for further behavioral verification, after the wild-type or AD mouse CA3 hippocampal gyrus is injected with the Dicer1 virus or the control virus, the water maze test is carried out, and the result shows that the time of the AD mouse over-expressing the Dicer1 to reach the platform is obviously shorter than that of the control AD group on the 5 th day and the 6 th day after the injection, the retention time of the AD mouse in the quadrant to which the platform belongs is prolonged, the frequency of crossing the platform is increased, and the fact that the space memory capacity of the AD mouse is improved by over-expressing the Dicer1 in the CA3 hippocampal gyrus is suggested.

In conclusion, Dicer1 gene is of great significance in treating alzheimer's disease.

The nucleotide sequence of the Dicer1 gene is shown in SEQ ID NO. 1.

Further, the present invention provides a viral vector comprising Dicer1 gene.

Further, the viral vector is adenovirus

The sequence is shown in SEQ ID NO. 2.

Compared with the prior art, the invention has the beneficial effects that: provides a new application of Dicer1 gene, in particular to an application of Dicer1 gene in preparing medicaments for treating early and middle-term Alzheimer disease. The method of increasing the expression of Dicer1 in the hippocampus by stereotactic injection of an adenovirus expressing Dicer1 or otherwise may be used for the treatment of early and mid-stage Alzheimer's disease.

Drawings

FIG. 1A is a plasmid vector incorporating Dicer1, and FIG. 1B is a control plasmid vector

FIG. 2 is a graph of the results of Dicer1 expression in hippocampal gyral tissues of wild type and AD mice, where A is Dicer1, caspase3, activated caspase3, GAPDH immunoblot, at 4 or 11 months of age, B and C are Dicer1 and activated caspase3 protein versus GAPDH levels, and D is Dicer1 mRNA relative levels.

FIG. 3 is a graph of the effect of Dicer1 overexpression in primary cultured mouse hippocampal neurons, where A is a photograph of an immunoblot of Dicer1, caspase3, activated caspase3, β III-tubulin after A β 42 treatment infected control virus or virus overexpressing Dicer1, B and C are photographs of a quantitative analysis of the treatment group Dicer1 and activated caspase3 in A, D is a photograph of the cell viability of primary cultured mouse hippocampal neurons after A β 42 treatment infected control virus or virus overexpressing Dicer1, E is a photograph of the above groups of neurons, and F is a length analysis of neurites in each group.

FIG. 4 is a graph showing that injection of adenovirus overexpressing Dicer1 inhibited apoptosis of neurons in hippocampal gyrus of APPswe/PSEN1dE9 AD mice. Wherein A/B is Dicer 1/activated caspase3 hippocampal slice staining pattern, C is Dicer1, caspase3, activated caspase3 and GAPDH immunoblotting pattern of hippocampal gyrus CA3 region, and D and E are quantitative analysis for protein expression of Dicer1 and activated caspase3 in group C respectively.

FIG. 5 is a graph showing the effect of overexpression of Dicer1 in hippocampal gyrus of CA3 on spatial memory capacity in AD mice. Wherein A is the incubation time of the wild type and AD mice injected with control virus and the AD mice injected with Dicer1 virus to reach the platform, B is the quadrant time distribution proportion of the mice in each group, C is the frequency of the mice in each group passing through the platform, and D and E are the swimming distance and swimming speed comparison.

The specific implementation mode is as follows:

the present invention will be further illustrated by the following specific examples, but the present invention is not limited to the following examples

The materials used in the present invention can be obtained commercially or by conventional methods in the art. For example, wild-type mouse C57BL/6J mouse was purchased from Wenzhou university of medicine Laboratory animal center, APPSwe/PSEN1dE9 (APP/PS 1) mouse was purchased from Jackson Laboratory, RNA isolation kit was purchased from Beijing Tiangen Biotech, Inc., and over-expression Dicer1 vector preparation and virus packaging were accomplished by Cyagen Biosciences Inc. (Guingzhou, China).

Example 1 Dicer1 immunoblotting and quantitative PCR analysis in mouse hippocampal gyrus tissue

WT at 4 or 11 months of age, AD mice hippocampal gyrus tissue homogenate, and immunoblot examination of Dicer1, caspase3, activated caspase3, GAPDH was used as internal reference. Each group consisted of 6 mice, three males, and three females. Mice were fasted overnight, the next day, under deep anesthesia with isoflurane, 4^oC phosphate buffer solution cardiac perfusion. Hippocampal gyrus tissues were isolated and frozen in liquid nitrogen. Tissue or cells were homogenized in RIPA buffer, consisting of: 460 mM Tris-HCl, pH7.4, 138 mM NaCl, 1mM EDTA, 2.5 mM NaF, 2.5 mM Na₃VO₄1mM phenylmethanesulfonyl fluoride (phenylmethanesulfonyl fluoride), 1mM Dithiothreitol (DTT), supplemented with 0.1% Nonidet P-40, and 1X protease/1X phosphatase inhibitor cocktail (Sigma, St. Louis, Mo.). Proteins were separated by electrophoresis on a 12% SDS-PAGE gel (Bio-Rad) and subsequently transferred to nitrocellulose (ThermoFisher). After membrane transfer, blocking of non-specific antigens with blocking solution (Beyotime Biotechnology) and primary antibody at 4^oC was incubated overnight, washed, and incubated with secondary antibody for 1 hour at room temperature and developed using chemiluminescent substrate (ThermoFisher). Protein quantification was performed using Image J software (National Institutes of Health, Bethesda, Md., USA). The results of using immunoblotting to quantify Dicer1 in hippocampal gyrus tissues of wild type and AD mice are shown in fig. 2A-C.

After isolation, the mouse hippocampal gyrus tissue was stored in liquid nitrogen, and RNA was extracted from the hippocampal gyrus tissue, and genomic DNA contamination was removed using an RNA isolation kit (beijing tiangen biotechnology limited). Then 200 ng of RNA was taken to synthesize cDNA (Vazyme, Nanjing, China), and the primer sequences were as follows:mDicer1sense strand primer, 5'-GTCAGCCGTCAGAACTCACTC-3', antisense strand primer, 5'-ACAGTCAAGGCGACATAGCAA-3';18s rRNA,

mRNA was amplified using 50 ng of cDNA as a template. The primer sequences are as follows:

sense strand, 5'-TTCGTATTGCGCCGCTAGA-3', antisense strand, 5' -CTTTCGCTCTGGTCCGTCTT-3'. SYBR^TM Green (Invitrogen) was used as a dye for quantitative PCR.

First step of amplification reaction, 50^oC, 2 min; second step, 95^oC, 10 min; third step 40 cycles of PCR reaction (95)^o C，10 s； 60 ^oC, 1 min). Reaction specificity is shown in the dissociation curve, the amplification curve shows as a single peak. 2^-△△CtThe method was used for quantification and calibration to control groups. The results of using quantitative PCR to quantify Dicer1 in hippocampal gyrus tissues of wild type and AD mice are shown in figure 2D.

Example 2 Effect of overexpression of Dicer1 on A β 42 neurotoxicity in Primary cultured mouse hippocampal gyrus neurons

Abeta 42 oligomer formulation

Solid form of A β 42 (GenScript, Nanjing, China) was dissolved in 1,1,1,3,3,3-Hexafluoro-2-propanol (Sigma-Aldrich) solvent, the insolubles were removed, and the dissolved A β 42 was placed at 4 ℃ for 30 minutes, followed by drying at room temperature and then dissolving in DMSO (Sigma-Aldrich) to prepare a 1mM solution. The solubilized polypeptide was diluted to 500 nM in a phenol red-free F12 solution, and after 24 hours at 4 ℃, the solution was centrifuged at 14,000 Xg for 30 minutes at 4 ℃, and the supernatant was collected as an A β 42 oligomer solution at a concentration of 100 nM.

Mouse primary neuron culture

Neonatal mice were used to culture cortical or hippocampal gyrus neurons. Minced mouse cerebral cortex or hippocampal gyrus tissue was isolated blunt, treated with 0.25% trypsin and 0.1% DNaseI, and incubated at 37 ℃ for 15 minutes in a carbon dioxide incubator. DMEM/F12 containing 10% calf serum was added, centrifuged at 120 Xg for 3 minutes by a centrifuge, the supernatant was collected, and the pellet was removed. The supernatant was added to a poly-D-lysine coated petri dish, and neurobasal/2% B27 culture medium was added, and 10. mu.M of cytarabine (mitosine arabinoside) which is a mitotic inhibitor was added to inhibit the growth of glial cells. After 24 hours, the culture medium was changed to the new formulation neurobasal/2% B27, and after 3 days of in vitro culture, the medium was used for the experiment.

Effect of overexpression of Dicer1 on A β 42 neurotoxicity

On the third day after the primary culture, after the replacement of the primary cultured mouse hippocampal gyrus neurons with a fresh neurobasal/2% B27 solution, Abeta 42 (100 nM) was treated for 48 hours; in parallel experiments, after fluid changes, Abeta 42 (100 nM) treatment was performed simultaneously with infection with control virus (Ad-EGFP) or virus overexpressing Dicer1 (AD-Dicer 1-T2A: EGFP), and after 48 hours, proteins were collected and analyzed by immunoblot analysis for Dicer1, caspase3 expression, and beta III-tubulin as an internal reference (see FIGS. 3A-C). Primary cultured mouse hippocampal gyrus neurons, 48 hours of Α β 42 (100 nM) treatment on the third day after culture; in parallel experiments, after fluid changes, Abeta 42 (100 nM) treatment was accompanied by infection with control virus (Ad-EGFP) or with virus overexpressing Dicer1 (AD-Dicer 1-T2A: EGFP), and 48 hours later cytotoxicity assays were performed (see FIG. 3D). Neurons in each treatment group, including neurites, were photographed and analyzed statistically for neurite length (see fig. 3E), with a β 42 treatment for 48 hours in neurons infected with control virus, with a significant decrease in neurite length compared to the control group, p =0.025, and with a β 42-treated neurons, with infection of over-expressed Dicer1 virus, with a significant increase in neurite length compared to the control group, p =0.047 (see fig. 3F). The above experiments show that overexpression of Dicer1 significantly reduced the neurotoxicity of Α β 42 in primary cultured mouse hippocampal gyral neurons.

Example 3 Effect of overexpression of Dicer1 on Primary cultured mouse hippocampal gyrus neurons

3.5-4 month old wild-type or APPswe/PSEN1dE9 AD mice injected with either control virus (Ad-EGFP) or over-expressed Dicer1 virus (Ad-Dicer 1-T2A: EGFP) in the CA3 hippocampal gyrus (1.2X 10)⁹Viral particles/mL). After 17 days of injection, cardiac perfusion was performed, each mouse was sectioned around the hippocampus, 60 sections each 10 μm thick, and one section was selected for staining every 6 sections (see fig. 4A-B). Separating hippocampal gyrus CA3 area, homogenizing, and analyzing the expression of Dicer1 and caspase3; GAPDH was used as an internal control for quantitative analysis (see FIGS. 4C-E). The results show that injection of adenovirus overexpressing Dicer1 inhibited apoptosis of neurons in hippocampal gyrus of APPswe/PSEN1dE9 mice.

Example 4 Effect of overexpression of Dicer1 on cognitive function in AD mice

Water maze experiment: a water maze (diameter is 1.2 m) is filled with a proper amount of water (24 ℃), nontoxic white pigment is added into the water, the water maze consists of black curtains with intervals of 80 cm, and three visual markers are respectively stuck on the black curtains. When the mouse starts to train, the mouse is respectively put into water from four quadrants of the water maze, and the training mouse explores and searches for an underwater platform (the diameter is 1 cm and 10 cm underwater) for 60 seconds at most. Training was performed 4 times a day with 10 minutes intervals between each training and 6 days. The time it took to find the underwater platform was tested on day 7 (60 seconds maximum). The spatial memory ability of the mice was examined by the above experiment. The SLY-WMS Morris Water size System (Beijing Sunny Instruments Co. Ltd.) was used to examine the mouse swimming pattern, distance, speed, and time distribution in each quadrant.

Effect of overexpression of Dicer1 in CA3 hippocampal gyrus on spatial memory capacity of AD mice: mice were divided into the following three groups: hippocampal gyrus was injected with wild type mice of control virus (Ad-EGFP, n =16), APPswe/PSEN1dE9 mice of control virus (Jackson Laboratories) (APP/PS1 Ad-EGFP, n =15), and APPswe/PSEN1dE9 mice overexpressing Dicer1 virus (Ad-Dicer 1-T2A: EGFP) (APP/PS1 Ad-Dicer1-T2A: EGFP, n = 14). Time to arrival at plateau for each group of mice was tested for daily and treatment status using a repeated two-way ANOVA test, p_day =0.00001, p_treatment=0.0241, p_interaction=0.0148. Tukey's post hoctest is used for correction. AD mice were injected with control virus and over-expressed Dicer1 virus, and were analyzed for plateau time contrast, day 5, p =0.008, day 6, p =0.00001 (see figure 5A). Injecting Dicer 1-overexpressing virus into CA3 hippocampus of AD mouse, prolonging the retention time of the virus in the quadrant where the platform belongs, repeating two-way ANOVA test to analyze and compare the quadrant and each group, and p_quadrant =0.1122, p_type=1, p_interaction=0.0046。Tukey's post hoctest is used for correction. APP/PS1 Ad-Dicer 1-T2A: EGFP vs. APP/PS1 Ad-EGFP, **p=0.0087; APP/PS1 Ad-EGFP vsWT Ad-EGFP (n =16),/p =0.0023 (see fig. 5B). Injection of Dicer1 virus increased the frequency of crossing the platform, Tukey' spost hoctest for correction, APP/PS1 Ad-Dicer1-T2A EGFPvs. APP/PS1 Ad-EGFP ; *p=0.043; APP/PS1 Ad-EGFP vsWT Ad-EGFP,/p =0.039 (see fig. 5C). Swim distance and E, swim speed did not change between groups (see FIGS. 5D-E). From the above experiments, it is known that overexpression of Dicer1 in the hippocampal gyrus of CA3 can improve the spatial memory of AD mice.

The above embodiments are intended to illustrate rather than to limit the invention, and any modifications and variations of the present invention are within the spirit of the invention and the scope of the claims.

Sequence listing

Application of <120> over-expressed Dicer1 in preparation of medicine for treating early and middle-stage Alzheimer disease

<160> 2

<170> SIPOSequenceListing 1.0

<210> 1

<211> 5721

<212> DNA/RNA

<213> Artificial Sequence (Artificial Sequence)

<400> 1

atggcaggcc tgcagctcat gacccctgct tcctcaccaa tgggtccttt ctttggactg 60

ccatggcaac aagaagcaat tcatgataac atttatacgc caagaaaata ccaggttgag 120

ctgctggaag cagctctgga ccataacaca attgtgtgct tgaacactgg ctcagggaag 180

acgttcatcg cggtcctgct caccaaagag ctggcccatc agatcagggg cgacctcaac 240

ccgcatgcaa aaaggaccgt gttcctcgtc aactctgcaa accaggttgc tcaacaagtg 300

tcagccgtca gaactcactc ggatctcaag gttggagagt actcagacct agaagtaaat 360

gcatcttgga caaaagagag atggagccaa gagtttacta agcaccaggt tctcattatg 420

acttgctatg tcgccttgac tgttttgaaa aatggttact tatcactgtc agacattaac 480

cttttggtgt ttgatgagtg tcatcttgcg attctagacc acccctatcg tgaaattatg 540

aagctctgtg agagttgtcc atcatgccct cgaattttgg gactaactgc ttccatttta 600

aatgggaaat gtgatccaga ggaattggaa gagaagattc agaaactgga gcgaattctc 660

aggagtgacg ctgagacggc gactgacttg gtggtcctgg acagatacac ttctcagcct 720

tgtgagattg tggtagactg tggaccgttt actgacagaa gtgggctgta tgagagattg 780

ctgatggagt tagaagcagc acttgatttt atcaatgatt gtaatgtagc tgtacattca 840

aaggaaagag attctacttt gatttccaaa caaatcctct cagactgccg tgcagtgttg 900

gttgttctgg gaccctggtg tgcagataaa gtagctggga tgatggtaag agaacttcag 960

aagtacatca aacatgagca agaggagcta cacaggaagt tcctattgtt tacagacacc 1020

ttgttaagga aaatacacgc cctgtgtgaa gagtacttct cacctgcctc acttgacctg 1080

aagtatgtaa ctcccaaagt catgaaactg ctcgagatcc tgcgcaaata caagccctat 1140

gagcgacagc agtttgaaag tgttgagtgg tacaataaca ggaatcagga taattacgtg 1200

tcctggagtg attccgagga tgacgatgat gacgaagaaa ttgaagaaaa agaaaagcca 1260

gagacaaatt ttccttctcc gtttaccaat attttatgtg ggattatttt tgtggaaaga 1320

agatacacag cagttgtcct aaacagattg ataaaggaag ctggcaaaca agatccagag 1380

ctggcttata tcagcagcaa ctttataact ggacacggca ttggaaagaa ccagcctcgc 1440

agcaaacaga tggaggcgga gttcagaaag caggaggagg tacttaggaa atttcgagct 1500

catgagacca acctgctcat tgcaacaagt gttgtagaag agggtgtgga tattcccaag 1560

tgcaatttgg tggttcgttt tgatttgcct acagagtatc gatcatatgt ccagtctaaa 1620

ggacgggcac gagcgccgat ctctaattac gtaatgttag cagatacaga caagataaag 1680

agctttgaag aagacctcaa gacctacaaa gctattgaaa agatcttaag gaacaagtgt 1740

tcgaagtcag cggatggtgc tgaggcggac gtccatgctg gtgtagatga tgaggatgct 1800

ttcccgccat atgtgctgag gcctgatgat gggggtcctc gagtcacaat caacactgcc 1860

attggacaca tcaacagata ttgtgctcga ttaccaagtg atccgtttac gcatctagct 1920

cccaaatgta gaacccgaga attgcctgat ggtacatttt attcaactct ttatcttccg 1980

attaactcac ctcttcgagc ctccattgtt ggtccaccga tggacagtgt acggttggct 2040

gaaagagtgg tagctctcat ttgctgtgaa aaactgcaca aaattggtga actggatgaa 2100

cacttgatgc cagttgggaa agagactgtt aaatatgaag aagagctgga cttacatgac 2160

gaggaggaga ccagtgttcc cgggagacca gggtccacaa aacgacggca gtgctacccc 2220

aaagcaattc cagagtgctt gagggagagt taccccaaac ccgaccagcc ttgttacctg 2280

tatgtgatag gaatggtctt aactaccccc ctccctgatg aactcaactt caggcggcgg 2340

aagctctacc cacctgagga caccacaaga tgctttggga tcctgacagc caaacccata 2400

cctcagattc ctcactttcc tgtgtataca cgctctggag aggtcaccat atccatcgag 2460

ctgaagaagt ctggtttcac attgtctcaa caaatgctcg agctgattac aagattgcac 2520

cagtacatat tctcacatat tctccggctt gagaagcctg ccctggagtt taaacctaca 2580

ggcgcggagt cagcctactg tgttctacct cttaatgttg ttaatgactc cggcactttg 2640

gacattgact ttaaattcat ggaggatatt gagaagtcgg aagctcggat aggcattcct 2700

agcaccaagt attcaaagga aacaccgttt gtctttaagt tagaagatta ccaagatgca 2760

gtgatcattc caagataccg caattttgat cagcctcatc gattttatgt agctgatgta 2820

tatacggatc ttaccccact cagtaaattt ccttcccctg aatatgaaac ttttgcagaa 2880

tattataaaa caaagtataa ccttgacctg accaatctca accagccact gctggatgtt 2940

gaccacacat cttccagact gaaccttttg acacctcggc atttgaatca gaaggggaaa 3000

gcacttcctc taagcagtgc tgagaagagg aaggccaaat gggaaagtct gcagaacaaa 3060

cagatcctgg ttccggaact ctgtgctata catccaatcc cagcatcact gtggagaaaa 3120

gcggtttgtc tccccagcat actgtatcgc cttcactgcc ttctgactgc agaggaacta 3180

agagctcaga cagccagcga tgctggtgtg ggtgtcagat cacttcccgt ggattttaga 3240

taccctaact tagacttcgg gtggaaaaaa tctattgata gcaagtcttt catctcaagc 3300

tgtaactcct cgttggctga gagtgataat tactgtaagc acagcacaac tgtagtccct 3360

gaacatgctg cacatcaagg tgctactaga ccctccttag aaaaccatga ccaaatgtct 3420

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cccagcaatg aatgtcctct actgagtaat acgtaccttg atgggaacgc taacacatct 3720

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ggccccaatc cgggactgat tctccaggct ttgacactgt caaatgccag tgatgggttt 3900

aacctggagc ggcttgagat gcttggcgac tcctttttaa agcatgctat caccacatat 3960

ctgttttgca cgtaccctga tgctcatgaa ggccgccttt catatatgag aagcaaaaag 4020

gtcagcaact gtaacctgta tcgccttggc aagaagaagg gactgcccag ccgcatggtg 4080

gtgtcgatat tcgatcctcc tgtgaattgg cttcctcctg gttatgtggt aaaccaagac 4140

aaaagtaact cagagaagtg ggaaaaggat gaaatgacaa aagactgctt gctggctaat 4200

ggcaaactgg gtgaggcctg tgaggaggag gaggacctga cgtggagggc ccccaaggag 4260

gaggccgagg atgaggacga cttcctggag tatgaccagg agcatatcca gtttatagac 4320

agcatgctca tgggctcggg cgccttcgtg aggaaaatct ctctgtcgcc cttctcagcc 4380

tccgactctg catacgaatg gaagatgccc aagaaggcct ccttgggcag tatgccgttt 4440

gcctcgggcc ttgaggattt tgattacagc tcttgggatg cgatgtgcta tctggatcct 4500

agcaaagccg ttgaagagga tgactttgtg gtaggtttct ggaatccatc agaagagaac 4560

tgtggcgtcg acacagggaa gcagtccatt tcttacgact tgcacacgga gcagtgcatt 4620

gctgacaaga gcatagcgga ctgtgtggag gccctgctgg gctgctactt aaccagctgc 4680

ggcgagaggg ctgctcagct cttcctctgt tcgctggggc tgaaggtgct cccagtaatc 4740

aaaaggacca gccgggagaa ggccttggac cctgctcagg agaacggaag cagccaacaa 4800

aagagccttt cagggagctg tgcctctcca gttggcccac gctcctctgc agggaaagac 4860

ttggagtacg gctgcctgaa gatcccaccg aggtgcatgt ttgaccatcc agacgcagag 4920

aaaaccctca accacctgat atctgggttt gaaacttttg agaagaaaat taactataga 4980

ttcaagaata aggcttatct tctgcaggct tttacacacg cctcctacca ctacaacact 5040

atcactgatt gttaccagcg cttagaattc ctgggagatg cgattttgga ctacctcata 5100

accaagcacc tttatgaaga cccacggcag cattctccag gggtcttgac tgacttgcgc 5160

tctgcccttg tcaataacac catctttgca tcattggctg tgaagtatga ctaccacaag 5220

tactttaaag ctgtctctcc tgagctcttt catgttattg atgactttgt gaagtttcag 5280

cttgagaaga acgaaatgca aggaatggac tctgagctta ggagatccga ggaggatgag 5340

gagaaagaag aggatatcga agtccccaag gccatggggg acatttttga gtctcttgct 5400

ggtgccattt atatggacag tgggatgtct ctggaggtgg tctggcaggt gtactatccg 5460

atgatgcagc ctctaataga aaagttttct gcaaatgtgc ctcgttctcc agtgagagaa 5520

ttgctcgaga tggaaccaga aactgccaag tttagcccag cggagagaac ttatgatgga 5580

aaggtcagag tcaccgtgga agtggtggga aaggggaaat ttaaaggtgt tggccggagc 5640

tacaggatcg ccaagtctgc tgcagcacga agggccctcc gcagcctcaa agctaaccag 5700

cctcaggttc ctaacagctg a 5721

<210> 2

<211> 40978

<212> DNA/RNA

<213> Artificial Sequence (Artificial Sequence)

<400> 2

catcatcaat aatatacctt attttggatt gaagccaata tgataatgag ggggtggagt 60

ttgtgacgtg gcgcggggcg tgggaacggg gcgggtgacg tagtagtgtg gcggaagtgt 120

gatgttgcaa gtgtggcgga acacatgtaa gcgacggatg tggcaaaagt gacgtttttg 180

gtgtgcgccg gtgtacacag gaagtgacaa ttttcgcgcg gttttaggcg gatgttgtag 240

taaatttggg cgtaaccgag taagatttgg ccattttcgc gggaaaactg aataagagga 300

agtgaaatct gaataatttt gtgttactca tagcgcgtaa tatttgtcta gggccgcggg 360

gactttgacc gtttacgtgg agactcgccc aggtgttttt ctcaggtgtt ttccgcgttc 420

cgggtcaaag ttggcgtttt attattatag tcagtcgaag cttggatccg gtacctctag 480

aattctcgag cggccgctag cgacatcgga tctcccgatc ccctatggtc gactctcagt 540

acaatctgct ctgatgccgc atagttaagc cagtatctgc tccctgcttg tgtgttggag 600

gtcgctgagt agtgcgcgag caaaatttaa gctacaacaa ggcaaggctt gaccgacaat 660

tgcatgaaga atctgcttag ggttaggcgt tttgcgctgc ttcgcgatgt acgggccaga 720

tatacgcgtt gacattgatt attgactagt tattaatagt aatcaattac ggggtcatta 780

gttcatagcc catatatgga gttccgcgtt acataactta cggtaaatgg cccgcctggc 840

tgaccgccca acgacccccg cccattgacg tcaataatga cgtatgttcc catagtaacg 900

ccaataggga ctttccattg acgtcaatgg gtggactatt tacggtaaac tgcccacttg 960

gcagtacatc aagtgtatca tatgccaagt acgcccccta ttgacgtcaa tgacggtaaa 1020

tggcccgcct ggcattatgc ccagtacatg accttatggg actttcctac ttggcagtac 1080

atctacgtat tagtcatcgc tattaccatg gtgatgcggt tttggcagta catcaatggg 1140

cgtggatagc ggtttgactc acggggattt ccaagtctcc accccattga cgtcaatggg 1200

agtttgtttt ggcaccaaaa tcaacgggac tttccaaaat gtcgtaacaa ctccgcccca 1260

ttgacgcaaa tgggcggtag gcgtgtacgg tgggaggtct atataagcag agctctctgg 1320

ctaactagag aacccactgc ttactggctt atcgaaatta atacgactca ctatagggag 1380

acccaagctg gctagttaag ctatcaacaa gtttgtacaa aaaagcaggc tgccaccatg 1440

gcaggcctgc agctcatgac ccctgcttcc tcaccaatgg gtcctttctt tggactgcca 1500

tggcaacaag aagcaattca tgataacatt tatacgccaa gaaaatacca ggttgagctg 1560

ctggaagcag ctctggacca taacacaatt gtgtgcttga acactggctc agggaagacg 1620

ttcatcgcgg tcctgctcac caaagagctg gcccatcaga tcaggggcga cctcaacccg 1680

catgcaaaaa ggaccgtgtt cctcgtcaac tctgcaaacc aggttgctca acaagtgtca 1740

gccgtcagaa ctcactcgga tctcaaggtt ggagagtact cagacctaga agtaaatgca 1800

tcttggacaa aagagagatg gagccaagag tttactaagc accaggttct cattatgact 1860

tgctatgtcg ccttgactgt tttgaaaaat ggttacttat cactgtcaga cattaacctt 1920

ttggtgtttg atgagtgtca tcttgcgatt ctagaccacc cctatcgtga aattatgaag 1980

ctctgtgaga gttgtccatc atgccctcga attttgggac taactgcttc cattttaaat 2040

gggaaatgtg atccagagga attggaagag aagattcaga aactggagcg aattctcagg 2100

agtgacgctg agacggcgac tgacttggtg gtcctggaca gatacacttc tcagccttgt 2160

gagattgtgg tagactgtgg accgtttact gacagaagtg ggctgtatga gagattgctg 2220

atggagttag aagcagcact tgattttatc aatgattgta atgtagctgt acattcaaag 2280

gaaagagatt ctactttgat ttccaaacaa atcctctcag actgccgtgc agtgttggtt 2340

gttctgggac cctggtgtgc agataaagta gctgggatga tggtaagaga acttcagaag 2400

tacatcaaac atgagcaaga ggagctacac aggaagttcc tattgtttac agacaccttg 2460

ttaaggaaaa tacacgccct gtgtgaagag tacttctcac ctgcctcact tgacctgaag 2520

tatgtaactc ccaaagtcat gaaactgctc gagatcctgc gcaaatacaa gccctatgag 2580

cgacagcagt ttgaaagtgt tgagtggtac aataacagga atcaggataa ttacgtgtcc 2640

tggagtgatt ccgaggatga cgatgatgac gaagaaattg aagaaaaaga aaagccagag 2700

acaaattttc cttctccgtt taccaatatt ttatgtggga ttatttttgt ggaaagaaga 2760

tacacagcag ttgtcctaaa cagattgata aaggaagctg gcaaacaaga tccagagctg 2820

gcttatatca gcagcaactt tataactgga cacggcattg gaaagaacca gcctcgcagc 2880

aaacagatgg aggcggagtt cagaaagcag gaggaggtac ttaggaaatt tcgagctcat 2940

gagaccaacc tgctcattgc aacaagtgtt gtagaagagg gtgtggatat tcccaagtgc 3000

aatttggtgg ttcgttttga tttgcctaca gagtatcgat catatgtcca gtctaaagga 3060

cgggcacgag cgccgatctc taattacgta atgttagcag atacagacaa gataaagagc 3120

tttgaagaag acctcaagac ctacaaagct attgaaaaga tcttaaggaa caagtgttcg 3180

aagtcagcgg atggtgctga ggcggacgtc catgctggtg tagatgatga ggatgctttc 3240

ccgccatatg tgctgaggcc tgatgatggg ggtcctcgag tcacaatcaa cactgccatt 3300

ggacacatca acagatattg tgctcgatta ccaagtgatc cgtttacgca tctagctccc 3360

aaatgtagaa cccgagaatt gcctgatggt acattttatt caactcttta tcttccgatt 3420

aactcacctc ttcgagcctc cattgttggt ccaccgatgg acagtgtacg gttggctgaa 3480

agagtggtag ctctcatttg ctgtgaaaaa ctgcacaaaa ttggtgaact ggatgaacac 3540

ttgatgccag ttgggaaaga gactgttaaa tatgaagaag agctggactt acatgacgag 3600

gaggagacca gtgttcccgg gagaccaggg tccacaaaac gacggcagtg ctaccccaaa 3660

gcaattccag agtgcttgag ggagagttac cccaaacccg accagccttg ttacctgtat 3720

gtgataggaa tggtcttaac tacccccctc cctgatgaac tcaacttcag gcggcggaag 3780

ctctacccac ctgaggacac cacaagatgc tttgggatcc tgacagccaa acccatacct 3840

cagattcctc actttcctgt gtatacacgc tctggagagg tcaccatatc catcgagctg 3900

aagaagtctg gtttcacatt gtctcaacaa atgctcgagc tgattacaag attgcaccag 3960

tacatattct cacatattct ccggcttgag aagcctgccc tggagtttaa acctacaggc 4020

gcggagtcag cctactgtgt tctacctctt aatgttgtta atgactccgg cactttggac 4080

attgacttta aattcatgga ggatattgag aagtcggaag ctcggatagg cattcctagc 4140

accaagtatt caaaggaaac accgtttgtc tttaagttag aagattacca agatgcagtg 4200

atcattccaa gataccgcaa ttttgatcag cctcatcgat tttatgtagc tgatgtatat 4260

acggatctta ccccactcag taaatttcct tcccctgaat atgaaacttt tgcagaatat 4320

tataaaacaa agtataacct tgacctgacc aatctcaacc agccactgct ggatgttgac 4380

cacacatctt ccagactgaa ccttttgaca cctcggcatt tgaatcagaa ggggaaagca 4440

cttcctctaa gcagtgctga gaagaggaag gccaaatggg aaagtctgca gaacaaacag 4500

atcctggttc cggaactctg tgctatacat ccaatcccag catcactgtg gagaaaagcg 4560

gtttgtctcc ccagcatact gtatcgcctt cactgccttc tgactgcaga ggaactaaga 4620

gctcagacag ccagcgatgc tggtgtgggt gtcagatcac ttcccgtgga ttttagatac 4680

cctaacttag acttcgggtg gaaaaaatct attgatagca agtctttcat ctcaagctgt 4740

aactcctcgt tggctgagag tgataattac tgtaagcaca gcacaactgt agtccctgaa 4800

catgctgcac atcaaggtgc tactagaccc tccttagaaa accatgacca aatgtctgtg 4860

aactgcaaaa ggttgcccgc tgagtcacct gctaagctcc aaagtgaggt ttcaacggat 4920

cttacagcaa ttaatggtct ttcttacaat aaaaaccttg ccaatggcag ttatgattta 4980

gttaacagag acttttgcca aggaaatcag ctgaattact tcaagcagga aatacctgta 5040

caaccaacta cctcatatcc cattcagaat ttgtacaatt atgagaacca gcccaagccc 5100

agcaatgaat gtcctctact gagtaatacg taccttgatg ggaacgctaa cacatctacc 5160

tcagatggaa gccccgcggt gtccacgatg cctgccatga tgaatgctgt taaagcactc 5220

aaggacagga tggactctga gcagagccct tctgttgggt actcctcaag gactcttggc 5280

cccaatccgg gactgattct ccaggctttg acactgtcaa atgccagtga tgggtttaac 5340

ctggagcggc ttgagatgct tggcgactcc tttttaaagc atgctatcac cacatatctg 5400

ttttgcacgt accctgatgc tcatgaaggc cgcctttcat atatgagaag caaaaaggtc 5460

agcaactgta acctgtatcg ccttggcaag aagaagggac tgcccagccg catggtggtg 5520

tcgatattcg atcctcctgt gaattggctt cctcctggtt atgtggtaaa ccaagacaaa 5580

agtaactcag agaagtggga aaaggatgaa atgacaaaag actgcttgct ggctaatggc 5640

aaactgggtg aggcctgtga ggaggaggag gacctgacgt ggagggcccc caaggaggag 5700

gccgaggatg aggacgactt cctggagtat gaccaggagc atatccagtt tatagacagc 5760

atgctcatgg gctcgggcgc cttcgtgagg aaaatctctc tgtcgccctt ctcagcctcc 5820

gactctgcat acgaatggaa gatgcccaag aaggcctcct tgggcagtat gccgtttgcc 5880

tcgggccttg aggattttga ttacagctct tgggatgcga tgtgctatct ggatcctagc 5940

aaagccgttg aagaggatga ctttgtggta ggtttctgga atccatcaga agagaactgt 6000

ggcgtcgaca cagggaagca gtccatttct tacgacttgc acacggagca gtgcattgct 6060

gacaagagca tagcggactg tgtggaggcc ctgctgggct gctacttaac cagctgcggc 6120

gagagggctg ctcagctctt cctctgttcg ctggggctga aggtgctccc agtaatcaaa 6180

aggaccagcc gggagaaggc cttggaccct gctcaggaga acggaagcag ccaacaaaag 6240

agcctttcag ggagctgtgc ctctccagtt ggcccacgct cctctgcagg gaaagacttg 6300

gagtacggct gcctgaagat cccaccgagg tgcatgtttg accatccaga cgcagagaaa 6360

accctcaacc acctgatatc tgggtttgaa acttttgaga agaaaattaa ctatagattc 6420

aagaataagg cttatcttct gcaggctttt acacacgcct cctaccacta caacactatc 6480

actgattgtt accagcgctt agaattcctg ggagatgcga ttttggacta cctcataacc 6540

aagcaccttt atgaagaccc acggcagcat tctccagggg tcttgactga cttgcgctct 6600

gcccttgtca ataacaccat ctttgcatca ttggctgtga agtatgacta ccacaagtac 6660

tttaaagctg tctctcctga gctctttcat gttattgatg actttgtgaa gtttcagctt 6720

gagaagaacg aaatgcaagg aatggactct gagcttagga gatccgagga ggatgaggag 6780

aaagaagagg atatcgaagt ccccaaggcc atgggggaca tttttgagtc tcttgctggt 6840

gccatttata tggacagtgg gatgtctctg gaggtggtct ggcaggtgta ctatccgatg 6900

atgcagcctc taatagaaaa gttttctgca aatgtgcctc gttctccagt gagagaattg 6960

ctcgagatgg aaccagaaac tgccaagttt agcccagcgg agagaactta tgatggaaag 7020

gtcagagtca ccgtggaagt ggtgggaaag gggaaattta aaggtgttgg ccggagctac 7080

aggatcgcca agtctgctgc agcacgaagg gccctccgca gcctcaaagc taaccagcct 7140

caggttccta acagcggaag cggagagggc aggggaagtc ttctaacatg cggggacgtg 7200

gaggaaaatc ccggccccat ggtgagcaag ggcgaggagc tgttcaccgg ggtggtgccc 7260

atcctggtcg agctggacgg cgacgtaaac ggccacaagt tcagcgtgtc cggcgagggc 7320

gagggcgatg ccacctacgg caagctgacc ctgaagttca tctgcaccac cggcaagctg 7380

cccgtgccct ggcccaccct cgtgaccacc ctgacctacg gcgtgcagtg cttcagccgc 7440

taccccgacc acatgaagca gcacgacttc ttcaagtccg ccatgcccga aggctacgtc 7500

caggagcgca ccatcttctt caaggacgac ggcaactaca agacccgcgc cgaggtgaag 7560

ttcgagggcg acaccctggt gaaccgcatc gagctgaagg gcatcgactt caaggaggac 7620

ggcaacatcc tggggcacaa gctggagtac aactacaaca gccacaacgt ctatatcatg 7680

gccgacaagc agaagaacgg catcaaggtg aacttcaaga tccgccacaa catcgaggac 7740

ggcagcgtgc agctcgccga ccactaccag cagaacaccc ccatcggcga cggccccgtg 7800

ctgctgcccg acaaccacta cctgagcacc cagtccgccc tgagcaaaga ccccaacgag 7860

aagcgcgatc acatggtcct gctggagttc gtgaccgccg ccgggatcac tctcggcatg 7920

gacgagctgt acaagtaaac ccagctttct tgtacaaagt ggttgatcta gagggcccgc 7980

ggttcgaagg taagcctatc cctaaccctc tcctcggtct cgattctacg cgtaccggtt 8040

agtaatgagt ttaaacgggg gaggctaact gaaacacgga aggagacaat accggaagga 8100

acccgcgcta tgacggcaat aaaaagacag aataaaacgc acgggtgttg ggtcgtttgt 8160

tcataaacgc ggggttcggt cccagggctg gcactctgtc gataccccac cgagacccca 8220

ttggggccaa tacgcccgcg tttcttcctt ttccccaccc caccccccaa gttcgggtga 8280

aggcccaggg ctcgcagcca acgtcggggc ggcaggccct gccatagcag atccgattcg 8340

acagatcact gaaatgtgtg ggcgtggctt aagggtggga aagaatatat aaggtggggg 8400

tcttatgtag ttttgtatct gttttgcagc agccgccgcc gccatgagca ccaactcgtt 8460

tgatggaagc attgtgagct catatttgac aacgcgcatg cccccatggg ccggggtgcg 8520

tcagaatgtg atgggctcca gcattgatgg tcgccccgtc ctgcccgcaa actctactac 8580

cttgacctac gagaccgtgt ctggaacgcc gttggagact gcagcctccg ccgccgcttc 8640

agccgctgca gccaccgccc gcgggattgt gactgacttt gctttcctga gcccgcttgc 8700

aagcagtgca gcttcccgtt catccgcccg cgatgacaag ttgacggctc ttttggcaca 8760

attggattct ttgacccggg aacttaatgt cgtttctcag cagctgttgg atctgcgcca 8820

gcaggtttct gccctgaagg cttcctcccc tcccaatgcg gtttaaaaca taaataaaaa 8880

accagactct gtttggattt ggatcaagca agtgtcttgc tgtctttatt taggggtttt 8940

gcgcgcgcgg taggcccggg accagcggtc tcggtcgttg agggtcctgt gtattttttc 9000

caggacgtgg taaaggtgac tctggatgtt cagatacatg ggcataagcc cgtctctggg 9060

gtggaggtag caccactgca gagcttcatg ctgcggggtg gtgttgtaga tgatccagtc 9120

gtagcaggag cgctgggcgt ggtgcctaaa aatgtctttc agtagcaagc tgattgccag 9180

gggcaggccc ttggtgtaag tgtttacaaa gcggttaagc tgggatgggt gcatacgtgg 9240

ggatatgaga tgcatcttgg actgtatttt taggttggct atgttcccag ccatatccct 9300

ccggggattc atgttgtgca gaaccaccag cacagtgtat ccggtgcact tgggaaattt 9360

gtcatgtagc ttagaaggaa atgcgtggaa gaacttggag acgcccttgt gacctccaag 9420

attttccatg cattcgtcca taatgatggc aatgggccca cgggcggcgg cctgggcgaa 9480

gatatttctg ggatcactaa cgtcatagtt gtgttccagg atgagatcgt cataggccat 9540

ttttacaaag cgcgggcgga gggtgccaga ctgcggtata atggttccat ccggcccagg 9600

ggcgtagtta ccctcacaga tttgcatttc ccacgctttg agttcagatg gggggatcat 9660

gtctacctgc ggggcgatga agaaaacggt ttccggggta ggggagatca gctgggaaga 9720

aagcaggttc ctgagcagct gcgacttacc gcagccggtg ggcccgtaaa tcacacctat 9780

taccgggtgc aactggtagt taagagagct gcagctgccg tcatccctga gcaggggggc 9840

cacttcgtta agcatgtccc tgactcgcat gttttccctg accaaatccg ccagaaggcg 9900

ctcgccgccc agcgatagca gttcttgcaa ggaagcaaag tttttcaacg gtttgagacc 9960

gtccgccgta ggcatgcttt tgagcgtttg accaagcagt tccaggcggt cccacagctc 10020

ggtcacctgc tctacggcat ctcgatccag catatctcct cgtttcgcgg gttggggcgg 10080

ctttcgctgt acggcagtag tcggtgctcg tccagacggg ccagggtcat gtctttccac 10140

gggcgcaggg tcctcgtcag cgtagtctgg gtcacggtga aggggtgcgc tccgggctgc 10200

gcgctggcca gggtgcgctt gaggctggtc ctgctggtgc tgaagcgctg ccggtcttcg 10260

ccctgcgcgt cggccaggta gcatttgacc atggtgtcat agtccagccc ctccgcggcg 10320

tggcccttgg cgcgcagctt gcccttggag gaggcgccgc acgaggggca gtgcagactt 10380

ttgagggcgt agagcttggg cgcgagaaat accgattccg gggagtaggc atccgcgccg 10440

caggccccgc agacggtctc gcattccacg agccaggtga gctctggccg ttcggggtca 10500

aaaaccaggt ttcccccatg ctttttgatg cgtttcttac ctctggtttc catgagccgg 10560

tgtccacgct cggtgacgaa aaggctgtcc gtgtccccgt atacagactt gagaggcctg 10620

tcctcgagcg gtgttccgcg gtcctcctcg tatagaaact cggaccactc tgagacaaag 10680

gctcgcgtcc aggccagcac gaaggaggct aagtgggagg ggtagcggtc gttgtccact 10740

agggggtcca ctcgctccag ggtgtgaaga cacatgtcgc cctcttcggc atcaaggaag 10800

gtgattggtt tgtaggtgta ggccacgtga ccgggtgttc ctgaaggggg gctataaaag 10860

ggggtggggg cgcgttcgtc ctcactctct tccgcatcgc tgtctgcgag ggccagctgt 10920

tggggtgagt actccctctg aaaagcgggc atgacttctg cgctaagatt gtcagtttcc 10980

aaaaacgagg aggatttgat attcacctgg cccgcggtga tgcctttgag ggtggccgca 11040

tccatctggt cagaaaagac aatctttttg ttgtcaagct tggtggcaaa cgacccgtag 11100

agggcgttgg acagcaactt ggcgatggag cgcagggttt ggtttttgtc gcgatcggcg 11160

cgctccttgg ccgcgatgtt tagctgcacg tattcgcgcg caacgcaccg ccattcggga 11220

aagacggtgg tgcgctcgtc gggcaccagg tgcacgcgcc aaccgcggtt gtgcagggtg 11280

acaaggtcaa cgctggtggc tacctctccg cgtaggcgct cgttggtcca gcagaggcgg 11340

ccgcccttgc gcgagcagaa tggcggtagg gggtctagct gcgtctcgtc cggggggtct 11400

gcgtccacgg taaagacccc gggcagcagg cgcgcgtcga agtagtctat cttgcatcct 11460

tgcaagtcta gcgcctgctg ccatgcgcgg gcggcaagcg cgcgctcgta tgggttgagt 11520

gggggacccc atggcatggg gtgggtgagc gcggaggcgt acatgccgca aatgtcgtaa 11580

acgtagaggg gctctctgag tattccaaga tatgtagggt agcatcttcc accgcggatg 11640

ctggcgcgca cgtaatcgta tagttcgtgc gagggagcga ggaggtcggg accgaggttg 11700

ctacgggcgg gctgctctgc tcggaagact atctgcctga agatggcatg tgagttggat 11760

gatatggttg gacgctggaa gacgttgaag ctggcgtctg tgagacctac cgcgtcacgc 11820

acgaaggagg cgtaggagtc gcgcagcttg ttgaccagct cggcggtgac ctgcacgtct 11880

agggcgcagt agtccagggt ttccttgatg atgtcatact tatcctgtcc cttttttttc 11940

cacagctcgc ggttgaggac aaactcttcg cggtctttcc agtactcttg gatcggaaac 12000

ccgtcggcct ccgaacggta agagcctagc atgtagaact ggttgacggc ctggtaggcg 12060

cagcatccct tttctacggg tagcgcgtat gcctgcgcgg ccttccggag cgaggtgtgg 12120

gtgagcgcaa aggtgtccct gaccatgact ttgaggtact ggtatttgaa gtcagtgtcg 12180

tcgcatccgc cctgctccca gagcaaaaag tccgtgcgct ttttggaacg cggatttggc 12240

agggcgaagg tgacatcgtt gaagagtatc tttcccgcgc gaggcataaa gttgcgtgtg 12300

atgcggaagg gtcccggcac ctcggaacgg ttgttaatta cctgggcggc gagcacgatc 12360

tcgtcaaagc cgttgatgtt gtggcccaca atgtaaagtt ccaagaagcg cgggatgccc 12420

ttgatggaag gcaatttttt aagttcctcg taggtgagct cttcagggga gctgagcccg 12480

tgctctgaaa gggcccagtc tgcaagatga gggttggaag cgacgaatga gctccacagg 12540

tcacgggcca ttagcatttg caggtggtcg cgaaaggtcc taaactggcg acctatggcc 12600

attttttctg gggtgatgca gtagaaggta agcgggtctt gttcccagcg gtcccatcca 12660

aggttcgcgg ctaggtctcg cgcggcagtc actagaggct catctccgcc gaacttcatg 12720

accagcatga agggcacgag ctgcttccca aaggccccca tccaagtata ggtctctaca 12780

tcgtaggtga caaagagacg ctcggtgcga ggatgcgagc cgatcgggaa gaactggatc 12840

tcccgccacc aattggagga gtggctattg atgtggtgaa agtagaagtc cctgcgacgg 12900

gccgaacact cgtgctggct tttgtaaaaa cgtgcgcagt actggcagcg gtgcacgggc 12960

tgtacatcct gcacgaggtt gacctgacga ccgcgcacaa ggaagcagag tgggaatttg 13020

agcccctcgc ctggcgggtt tggctggtgg tcttctactt cggctgcttg tccttgaccg 13080

tctggctgct cgaggggagt tacggtggat cggaccacca cgccgcgcga gcccaaagtc 13140

cagatgtccg cgcgcggcgg tcggagcttg atgacaacat cgcgcagatg ggagctgtcc 13200

atggtctgga gctcccgcgg cgtcaggtca ggcgggagct cctgcaggtt tacctcgcat 13260

agacgggtca gggcgcgggc tagatccagg tgatacctaa tttccagggg ctggttggtg 13320

gcggcgtcga tggcttgcaa gaggccgcat ccccgcggcg cgactacggt accgcgcggc 13380

gggcggtggg ccgcgggggt gtccttggat gatgcatcta aaagcggtga cgcgggcgag 13440

cccccggagg tagggggggc tccggacccg ccgggagagg gggcaggggc acgtcggcgc 13500

cgcgcgcggg caggagctgg tgctgcgcgc gtaggttgct ggcgaacgcg acgacgcggc 13560

ggttgatctc ctgaatctgg cgcctctgcg tgaagacgac gggcccggtg agcttgagcc 13620

tgaaagagag ttcgacagaa tcaatttcgg tgtcgttgac ggcggcctgg cgcaaaatct 13680

cctgcacgtc tcctgagttg tcttgatagg cgatctcggc catgaactgc tcgatctctt 13740

cctcctggag atctccgcgt ccggctcgct ccacggtggc ggcgaggtcg ttggaaatgc 13800

gggccatgag ctgcgagaag gcgttgaggc ctccctcgtt ccagacgcgg ctgtagacca 13860

cgcccccttc ggcatcgcgg gcgcgcatga ccacctgcgc gagattgagc tccacgtgcc 13920

gggcgaagac ggcgtagttt cgcaggcgct gaaagaggta gttgagggtg gtggcggtgt 13980

gttctgccac gaagaagtac ataacccagc gtcgcaacgt ggattcgttg atatccccca 14040

aggcctcaag gcgctccatg gcctcgtaga agtccacggc gaagttgaaa aactgggagt 14100

tgcgcgccga cacggttaac tcctcctcca gaagacggat gagctcggcg acagtgtcgc 14160

gcacctcgcg ctcaaaggct acaggggcct cttcttcttc ttcaatctcc tcttccataa 14220

gggcctcccc ttcttcttct tctggcggcg gtgggggagg ggggacacgg cggcgacgac 14280

ggcgcaccgg gaggcggtcg acaaagcgct cgatcatctc cccgcggcga cggcgcatgg 14340

tctcggtgac ggcgcggccg ttctcgcggg ggcgcagttg gaagacgccg cccgtcatgt 14400

cccggttatg ggttggcggg gggctgccat gcggcaggga tacggcgcta acgatgcatc 14460

tcaacaattg ttgtgtaggt actccgccgc cgagggacct gagcgagtcc gcatcgaccg 14520

gatcggaaaa cctctcgaga aaggcgtcta accagtcaca gtcgcaaggt aggctgagca 14580

ccgtggcggg cggcagcggg cggcggtcgg ggttgtttct ggcggaggtg ctgctgatga 14640

tgtaattaaa gtaggcggtc ttgagacggc ggatggtcga cagaagcacc atgtccttgg 14700

gtccggcctg ctgaatgcgc aggcggtcgg ccatgcccca ggcttcgttt tgacatcggc 14760

gcaggtcttt gtagtagtct tgcatgagcc tttctaccgg cacttcttct tctccttcct 14820

cttgtcctgc atctcttgca tctatcgctg cggcggcggc ggagtttggc cgtaggtggc 14880

gccctcttcc tcccatgcgt gtgaccccga agcccctcat cggctgaagc agggctaggt 14940

cggcgacaac gcgctcggct aatatggcct gctgcacctg cgtgagggta gactggaagt 15000

catccatgtc cacaaagcgg tggtatgcgc ccgtgttgat ggtgtaagtg cagttggcca 15060

taacggacca gttaacggtc tggtgacccg gctgcgagag ctcggtgtac ctgagacgcg 15120

agtaagccct cgagtcaaat acgtagtcgt tgcaagtccg caccaggtac tggtatccca 15180

ccaaaaagtg cggcggcggc tggcggtaga ggggccagcg tagggtggcc ggggctccgg 15240

gggcgagatc ttccaacata aggcgatgat atccgtagat gtacctggac atccaggtga 15300

tgccggcggc ggtggtggag gcgcgcggaa agtcgcggac gcggttccag atgttgcgca 15360

gcggcaaaaa gtgctccatg gtcgggacgc tctggccggt caggcgcgcg caatcgttga 15420

cgctctagac cgtgcaaaag gagagcctgt aagcgggcac tcttccgtgg tctggtggat 15480

aaattcgcaa gggtatcatg gcggacgacc ggggttcgag ccccgtatcc ggccgtccgc 15540

cgtgatccat gcggttaccg cccgcgtgtc gaacccaggt gtgcgacgtc agacaacggg 15600

ggagtgctcc ttttggcttc cttccaggcg cggcggctgc tgcgctagct tttttggcca 15660

ctggccgcgc gcagcgtaag cggttaggct ggaaagcgaa agcattaagt ggctcgctcc 15720

ctgtagccgg agggttattt tccaagggtt gagtcgcggg acccccggtt cgagtctcgg 15780

accggccgga ctgcggcgaa cgggggtttg cctccccgtc atgcaagacc ccgcttgcaa 15840

attcctccgg aaacagggac gagccccttt tttgcttttc ccagatgcat ccggtgctgc 15900

ggcagatgcg cccccctcct cagcagcggc aagagcaaga gcagcggcag acatgcaggg 15960

caccctcccc tcctcctacc gcgtcaggag gggcgacatc cgcggttgac gcggcagcag 16020

atggtgatta cgaacccccg cggcgccggg cccggcacta cctggacttg gaggagggcg 16080

agggcctggc gcggctagga gcgccctctc ctgagcggta cccaagggtg cagctgaagc 16140

gtgatacgcg tgaggcgtac gtgccgcggc agaacctgtt tcgcgaccgc gagggagagg 16200

agcccgagga gatgcgggat cgaaagttcc acgcagggcg cgagctgcgg catggcctga 16260

atcgcgagcg gttgctgcgc gaggaggact ttgagcccga cgcgcgaacc gggattagtc 16320

ccgcgcgcgc acacgtggcg gccgccgacc tggtaaccgc atacgagcag acggtgaacc 16380

aggagattaa ctttcaaaaa agctttaaca accacgtgcg tacgcttgtg gcgcgcgagg 16440

aggtggctat aggactgatg catctgtggg actttgtaag cgcgctggag caaaacccaa 16500

atagcaagcc gctcatggcg cagctgttcc ttatagtgca gcacagcagg gacaacgagg 16560

cattcaggga tgcgctgcta aacatagtag agcccgaggg ccgctggctg ctcgatttga 16620

taaacatcct gcagagcata gtggtgcagg agcgcagctt gagcctggct gacaaggtgg 16680

ccgccatcaa ctattccatg cttagcctgg gcaagtttta cgcccgcaag atataccata 16740

ccccttacgt tcccatagac aaggaggtaa agatcgaggg gttctacatg cgcatggcgc 16800

tgaaggtgct taccttgagc gacgacctgg gcgtttatcg caacgagcgc atccacaagg 16860

ccgtgagcgt gagccggcgg cgcgagctca gcgaccgcga gctgatgcac agcctgcaaa 16920

gggccctggc tggcacgggc agcggcgata gagaggccga gtcctacttt gacgcgggcg 16980

ctgacctgcg ctgggcccca agccgacgcg ccctggaggc agctggggcc ggacctgggc 17040

tggcggtggc acccgcgcgc gctggcaacg tcggcggcgt ggaggaatat gacgaggacg 17100

atgagtacga gccagaggac ggcgagtact aagcggtgat gtttctgatc agatgatgca 17160

agacgcaacg gacccggcgg tgcgggcggc gctgcagagc cagccgtccg gccttaactc 17220

cacggacgac tggcgccagg tcatggaccg catcatgtcg ctgactgcgc gcaatcctga 17280

cgcgttccgg cagcagccgc aggccaaccg gctctccgca attctggaag cggtggtccc 17340

ggcgcgcgca aaccccacgc acgagaaggt gctggcgatc gtaaacgcgc tggccgaaaa 17400

cagggccatc cggcccgacg aggccggcct ggtctacgac gcgctgcttc agcgcgtggc 17460

tcgttacaac agcggcaacg tgcagaccaa cctggaccgg ctggtggggg atgtgcgcga 17520

ggccgtggcg cagcgtgagc gcgcgcagca gcagggcaac ctgggctcca tggttgcact 17580

aaacgccttc ctgagtacac agcccgccaa cgtgccgcgg ggacaggagg actacaccaa 17640

ctttgtgagc gcactgcggc taatggtgac tgagacaccg caaagtgagg tgtaccagtc 17700

tgggccagac tattttttcc agaccagtag acaaggcctg cagaccgtaa acctgagcca 17760

ggctttcaaa aacttgcagg ggctgtgggg ggtgcgggct cccacaggcg accgcgcgac 17820

cgtgtctagc ttgctgacgc ccaactcgcg cctgttgctg ctgctaatag cgcccttcac 17880

ggacagtggc agcgtgtccc gggacacata cctaggtcac ttgctgacac tgtaccgcga 17940

ggccataggt caggcgcatg tggacgagca tactttccag gagattacaa gtgtcagccg 18000

cgcgctgggg caggaggaca cgggcagcct ggaggcaacc ctaaactacc tgctgaccaa 18060

ccggcggcag aagatcccct cgttgcacag tttaaacagc gaggaggagc gcattttgcg 18120

ctacgtgcag cagagcgtga gccttaacct gatgcgcgac ggggtaacgc ccagcgtggc 18180

gctggacatg accgcgcgca acatggaacc gggcatgtat gcctcaaacc ggccgtttat 18240

caaccgccta atggactact tgcatcgcgc ggccgccgtg aaccccgagt atttcaccaa 18300

tgccatcttg aacccgcact ggctaccgcc ccctggtttc tacaccgggg gattcgaggt 18360

gcccgagggt aacgatggat tcctctggga cgacatagac gacagcgtgt tttccccgca 18420

accgcagacc ctgctagagt tgcaacagcg cgagcaggca gaggcggcgc tgcgaaagga 18480

aagcttccgc aggccaagca gcttgtccga tctaggcgct gcggccccgc ggtcagatgc 18540

tagtagccca tttccaagct tgatagggtc tcttaccagc actcgcacca cccgcccgcg 18600

cctgctgggc gaggaggagt acctaaacaa ctcgctgctg cagccgcagc gcgaaaaaaa 18660

cctgcctccg gcatttccca acaacgggat agagagccta gtggacaaga tgagtagatg 18720

gaagacgtac gcgcaggagc acagggacgt gccaggcccg cgcccgccca cccgtcgtca 18780

aaggcacgac cgtcagcggg gtctggtgtg ggaggacgat gactcggcag acgacagcag 18840

cgtcctggat ttgggaggga gtggcaaccc gtttgcgcac cttcgcccca ggctggggag 18900

aatgttttaa aaaaaaaaaa gcatgatgca aaataaaaaa ctcaccaagg ccatggcacc 18960

gagcgttggt tttcttgtat tccccttagt atgcggcgcg cggcgatgta tgaggaaggt 19020

cctcctccct cctacgagag tgtggtgagc gcggcgccag tggcggcggc gctgggttct 19080

cccttcgatg ctcccctgga cccgccgttt gtgcctccgc ggtacctgcg gcctaccggg 19140

gggagaaaca gcatccgtta ctctgagttg gcacccctat tcgacaccac ccgtgtgtac 19200

ctggtggaca acaagtcaac ggatgtggca tccctgaact accagaacga ccacagcaac 19260

tttctgacca cggtcattca aaacaatgac tacagcccgg gggaggcaag cacacagacc 19320

atcaatcttg acgaccggtc gcactggggc ggcgacctga aaaccatcct gcataccaac 19380

atgccaaatg tgaacgagtt catgtttacc aataagttta aggcgcgggt gatggtgtcg 19440

cgcttgccta ctaaggacaa tcaggtggag ctgaaatacg agtgggtgga gttcacgctg 19500

cccgagggca actactccga gaccatgacc atagacctta tgaacaacgc gatcgtggag 19560

cactacttga aagtgggcag acagaacggg gttctggaaa gcgacatcgg ggtaaagttt 19620

gacacccgca acttcagact ggggtttgac cccgtcactg gtcttgtcat gcctggggta 19680

tatacaaacg aagccttcca tccagacatc attttgctgc caggatgcgg ggtggacttc 19740

acccacagcc gcctgagcaa cttgttgggc atccgcaagc ggcaaccctt ccaggagggc 19800

tttaggatca cctacgatga tctggagggt ggtaacattc ccgcactgtt ggatgtggac 19860

gcctaccagg cgagcttgaa agatgacacc gaacagggcg ggggtggcgc aggcggcagc 19920

aacagcagtg gcagcggcgc ggaagagaac tccaacgcgg cagccgcggc aatgcagccg 19980

gtggaggaca tgaacgatca tgccattcgc ggcgacacct ttgccacacg ggctgaggag 20040

aagcgcgctg aggccgaagc agcggccgaa gctgccgccc ccgctgcgca acccgaggtc 20100

gagaagcctc agaagaaacc ggtgatcaaa cccctgacag aggacagcaa gaaacgcagt 20160

tacaacctaa taagcaatga cagcaccttc acccagtacc gcagctggta ccttgcatac 20220

aactacggcg accctcagac cggaatccgc tcatggaccc tgctttgcac tcctgacgta 20280

acctgcggct cggagcaggt ctactggtcg ttgccagaca tgatgcaaga ccccgtgacc 20340

ttccgctcca cgcgccagat cagcaacttt ccggtggtgg gcgccgagct gttgcccgtg 20400

cactccaaga gcttctacaa cgaccaggcc gtctactccc aactcatccg ccagtttacc 20460

tctctgaccc acgtgttcaa tcgctttccc gagaaccaga ttttggcgcg cccgccagcc 20520

cccaccatca ccaccgtcag tgaaaacgtt cctgctctca cagatcacgg gacgctaccg 20580

ctgcgcaaca gcatcggagg agtccagcga gtgaccatta ctgacgccag acgccgcacc 20640

tgcccctacg tttacaaggc cctgggcata gtctcgccgc gcgtcctatc gagccgcact 20700

ttttgagcaa gcatgtccat ccttatatcg cccagcaata acacaggctg gggcctgcgc 20760

ttcccaagca agatgtttgg cggggccaag aagcgctccg accaacaccc agtgcgcgtg 20820

cgcgggcact accgcgcgcc ctggggcgcg cacaaacgcg gccgcactgg gcgcaccacc 20880

gtcgatgacg ccatcgacgc ggtggtggag gaggcgcgca actacacgcc cacgccgcca 20940

ccagtgtcca cagtggacgc ggccattcag accgtggtgc gcggagcccg gcgctatgct 21000

aaaatgaaga gacggcggag gcgcgtagca cgtcgccacc gccgccgacc cggcactgcc 21060

gcccaacgcg cggcggcggc cctgcttaac cgcgcacgtc gcaccggccg acgggcggcc 21120

atgcgggccg ctcgaaggct ggccgcgggt attgtcactg tgccccccag gtccaggcga 21180

cgagcggccg ccgcagcagc cgcggccatt agtgctatga ctcagggtcg caggggcaac 21240

gtgtattggg tgcgcgactc ggttagcggc ctgcgcgtgc ccgtgcgcac ccgccccccg 21300

cgcaactaga ttgcaagaaa aaactactta gactcgtact gttgtatgta tccagcggcg 21360

gcggcgcgca acgaagctat gtccaagcgc aaaatcaaag aagagatgct ccaggtcatc 21420

gcgccggaga tctatggccc cccgaagaag gaagagcagg attacaagcc ccgaaagcta 21480

aagcgggtca aaaagaaaaa gaaagatgat gatgatgaac ttgacgacga ggtggaactg 21540

ctgcacgcta ccgcgcccag gcgacgggta cagtggaaag gtcgacgcgt aaaacgtgtt 21600

ttgcgacccg gcaccaccgt agtctttacg cccggtgagc gctccacccg cacctacaag 21660

cgcgtgtatg atgaggtgta cggcgacgag gacctgcttg agcaggccaa cgagcgcctc 21720

ggggagtttg cctacggaaa gcggcataag gacatgctgg cgttgccgct ggacgagggc 21780

aacccaacac ctagcctaaa gcccgtaaca ctgcagcagg tgctgcccgc gcttgcaccg 21840

tccgaagaaa agcgcggcct aaagcgcgag tctggtgact tggcacccac cgtgcagctg 21900

atggtaccca agcgccagcg actggaagat gtcttggaaa aaatgaccgt ggaacctggg 21960

ctggagcccg aggtccgcgt gcggccaatc aagcaggtgg cgccgggact gggcgtgcag 22020

accgtggacg ttcagatacc cactaccagt agcaccagta ttgccaccgc cacagagggc 22080

atggagacac aaacgtcccc ggttgcctca gcggtggcgg atgccgcggt gcaggcggtc 22140

gctgcggccg cgtccaagac ctctacggag gtgcaaacgg acccgtggat gtttcgcgtt 22200

tcagcccccc ggcgcccgcg cggttcgagg aagtacggcg ccgccagcgc gctactgccc 22260

gaatatgccc tacatccttc cattgcgcct acccccggct atcgtggcta cacctaccgc 22320

cccagaagac gagcaactac ccgacgccga accaccactg gaacccgccg ccgccgtcgc 22380

cgtcgccagc ccgtgctggc cccgatttcc gtgcgcaggg tggctcgcga aggaggcagg 22440

accctggtgc tgccaacagc gcgctaccac cccagcatcg tttaaaagcc ggtctttgtg 22500

gttcttgcag atatggccct cacctgccgc ctccgtttcc cggtgccggg attccgagga 22560

agaatgcacc gtaggagggg catggccggc cacggcctga cgggcggcat gcgtcgtgcg 22620

caccaccggc ggcggcgcgc gtcgcaccgt cgcatgcgcg gcggtatcct gcccctcctt 22680

attccactga tcgccgcggc gattggcgcc gtgcccggaa ttgcatccgt ggccttgcag 22740

gcgcagagac actgattaaa aacaagttgc atgtggaaaa atcaaaataa aaagtctgga 22800

ctctcacgct cgcttggtcc tgtaactatt ttgtagaatg gaagacatca actttgcgtc 22860

tctggccccg cgacacggct cgcgcccgtt catgggaaac tggcaagata tcggcaccag 22920

caatatgagc ggtggcgcct tcagctgggg ctcgctgtgg agcggcatta aaaatttcgg 22980

ttccaccgtt aagaactatg gcagcaaggc ctggaacagc agcacaggcc agatgctgag 23040

ggataagttg aaagagcaaa atttccaaca aaaggtggta gatggcctgg cctctggcat 23100

tagcggggtg gtggacctgg ccaaccaggc agtgcaaaat aagattaaca gtaagcttga 23160

tccccgccct cccgtagagg agcctccacc ggccgtggag acagtgtctc cagaggggcg 23220

tggcgaaaag cgtccgcgcc ccgacaggga agaaactctg gtgacgcaaa tagacgagcc 23280

tccctcgtac gaggaggcac taaagcaagg cctgcccacc acccgtccca tcgcgcccat 23340

ggctaccgga gtgctgggcc agcacacacc cgtaacgctg gacctgcctc cccccgccga 23400

cacccagcag aaacctgtgc tgccaggccc gaccgccgtt gttgtaaccc gtcctagccg 23460

cgcgtccctg cgccgcgccg ccagcggtcc gcgatcgttg cggcccgtag ccagtggcaa 23520

ctggcaaagc acactgaaca gcatcgtggg tctgggggtg caatccctga agcgccgacg 23580

atgcttctga atagctaacg tgtcgtatgt gtgtcatgta tgcgtccatg tcgccgccag 23640

aggagctgct gagccgccgc gcgcccgctt tccaagatgg ctaccccttc gatgatgccg 23700

cagtggtctt acatgcacat ctcgggccag gacgcctcgg agtacctgag ccccgggctg 23760

gtgcagtttg cccgcgccac cgagacgtac ttcagcctga ataacaagtt tagaaacccc 23820

acggtggcgc ctacgcacga cgtgaccaca gaccggtccc agcgtttgac gctgcggttc 23880

atccctgtgg accgtgagga tactgcgtac tcgtacaagg cgcggttcac cctagctgtg 23940

ggtgataacc gtgtgctgga catggcttcc acgtactttg acatccgcgg cgtgctggac 24000

aggggcccta cttttaagcc ctactctggc actgcctaca acgccctggc tcccaagggt 24060

gccccaaatc cttgcgaatg ggatgaagct gctactgctc ttgaaataaa cctagaagaa 24120

gaggacgatg acaacgaaga cgaagtagac gagcaagctg agcagcaaaa aactcacgta 24180

tttgggcagg cgccttattc tggtataaat attacaaagg agggtattca aataggtgtc 24240

gaaggtcaaa cacctaaata tgccgataaa acatttcaac ctgaacctca aataggagaa 24300

tctcagtggt acgaaactga aattaatcat gcagctggga gagtccttaa aaagactacc 24360

ccaatgaaac catgttacgg ttcatatgca aaacccacaa atgaaaatgg agggcaaggc 24420

attcttgtaa agcaacaaaa tggaaagcta gaaagtcaag tggaaatgca atttttctca 24480

actactgagg cgaccgcagg caatggtgat aacttgactc ctaaagtggt attgtacagt 24540

gaagatgtag atatagaaac cccagacact catatttctt acatgcccac tattaaggaa 24600

ggtaactcac gagaactaat gggccaacaa tctatgccca acaggcctaa ttacattgct 24660

tttagggaca attttattgg tctaatgtat tacaacagca cgggtaatat gggtgttctg 24720

gcgggccaag catcgcagtt gaatgctgtt gtagatttgc aagacagaaa cacagagctt 24780

tcataccagc ttttgcttga ttccattggt gatagaacca ggtacttttc tatgtggaat 24840

caggctgttg acagctatga tccagatgtt agaattattg aaaatcatgg aactgaagat 24900

gaacttccaa attactgctt tccactggga ggtgtgatta atacagagac tcttaccaag 24960

gtaaaaccta aaacaggtca ggaaaatgga tgggaaaaag atgctacaga attttcagat 25020

aaaaatgaaa taagagttgg aaataatttt gccatggaaa tcaatctaaa tgccaacctg 25080

tggagaaatt tcctgtactc caacatagcg ctgtatttgc ccgacaagct aaagtacagt 25140

ccttccaacg taaaaatttc tgataaccca aacacctacg actacatgaa caagcgagtg 25200

gtggctcccg ggttagtgga ctgctacatt aaccttggag cacgctggtc ccttgactat 25260

atggacaacg tcaacccatt taaccaccac cgcaatgctg gcctgcgcta ccgctcaatg 25320

ttgctgggca atggtcgcta tgtgcccttc cacatccagg tgcctcagaa gttctttgcc 25380

attaaaaacc tccttctcct gccgggctca tacacctacg agtggaactt caggaaggat 25440

gttaacatgg ttctgcagag ctccctagga aatgacctaa gggttgacgg agccagcatt 25500

aagtttgata gcatttgcct ttacgccacc ttcttcccca tggcccacaa caccgcctcc 25560

acgcttgagg ccatgcttag aaacgacacc aacgaccagt cctttaacga ctatctctcc 25620

gccgccaaca tgctctaccc tatacccgcc aacgctacca acgtgcccat atccatcccc 25680

tcccgcaact gggcggcttt ccgcggctgg gccttcacgc gccttaagac taaggaaacc 25740

ccatcactgg gctcgggcta cgacccttat tacacctact ctggctctat accctaccta 25800

gatggaacct tttacctcaa ccacaccttt aagaaggtgg ccattacctt tgactcttct 25860

gtcagctggc ctggcaatga ccgcctgctt acccccaacg agtttgaaat taagcgctca 25920

gttgacgggg agggttacaa cgttgcccag tgtaacatga ccaaagactg gttcctggta 25980

caaatgctag ctaactacaa cattggctac cagggcttct atatcccaga gagctacaag 26040

gaccgcatgt actccttctt tagaaacttc cagcccatga gccgtcaggt ggtggatgat 26100

actaaataca aggactacca acaggtgggc atcctacacc aacacaacaa ctctggattt 26160

gttggctacc ttgcccccac catgcgcgaa ggacaggcct accctgctaa cttcccctat 26220

ccgcttatag gcaagaccgc agttgacagc attacccaga aaaagtttct ttgcgatcgc 26280

accctttggc gcatcccatt ctccagtaac tttatgtcca tgggcgcact cacagacctg 26340

ggccaaaacc ttctctacgc caactccgcc cacgcgctag acatgacttt tgaggtggat 26400

cccatggacg agcccaccct tctttatgtt ttgtttgaag tctttgacgt ggtccgtgtg 26460

caccggccgc accgcggcgt catcgaaacc gtgtacctgc gcacgccctt ctcggccggc 26520

aacgccacaa cataaagaag caagcaacat caacaacagc tgccgccatg ggctccagtg 26580

agcaggaact gaaagccatt gtcaaagatc ttggttgtgg gccatatttt ttgggcacct 26640

atgacaagcg ctttccaggc tttgtttctc cacacaagct cgcctgcgcc atagtcaata 26700

cggccggtcg cgagactggg ggcgtacact ggatggcctt tgcctggaac ccgcactcaa 26760

aaacatgcta cctctttgag ccctttggct tttctgacca gcgactcaag caggtttacc 26820

agtttgagta cgagtcactc ctgcgccgta gcgccattgc ttcttccccc gaccgctgta 26880

taacgctgga aaagtccacc caaagcgtac aggggcccaa ctcggccgcc tgtggactat 26940

tctgctgcat gtttctccac gcctttgcca actggcccca aactcccatg gatcacaacc 27000

ccaccatgaa ccttattacc ggggtaccca actccatgct caacagtccc caggtacagc 27060

ccaccctgcg tcgcaaccag gaacagctct acagcttcct ggagcgccac tcgccctact 27120

tccgcagcca cagtgcgcag attaggagcg ccacttcttt ttgtcacttg aaaaacatgt 27180

aaaaataatg tactagagac actttcaata aaggcaaatg cttttatttg tacactctcg 27240

ggtgattatt tacccccacc cttgccgtct gcgccgttta aaaatcaaag gggttctgcc 27300

gcgcatcgct atgcgccact ggcagggaca cgttgcgata ctggtgttta gtgctccact 27360

taaactcagg cacaaccatc cgcggcagct cggtgaagtt ttcactccac aggctgcgca 27420

ccatcaccaa cgcgtttagc aggtcgggcg ccgatatctt gaagtcgcag ttggggcctc 27480

cgccctgcgc gcgcgagttg cgatacacag ggttgcagca ctggaacact atcagcgccg 27540

ggtggtgcac gctggccagc acgctcttgt cggagatcag atccgcgtcc aggtcctccg 27600

cgttgctcag ggcgaacgga gtcaactttg gtagctgcct tcccaaaaag ggcgcgtgcc 27660

caggctttga gttgcactcg caccgtagtg gcatcaaaag gtgaccgtgc ccggtctggg 27720

cgttaggata cagcgcctgc ataaaagcct tgatctgctt aaaagccacc tgagcctttg 27780

cgccttcaga gaagaacatg ccgcaagact tgccggaaaa ctgattggcc ggacaggccg 27840

cgtcgtgcac gcagcacctt gcgtcggtgt tggagatctg caccacattt cggccccacc 27900

ggttcttcac gatcttggcc ttgctagact gctccttcag cgcgcgctgc ccgttttcgc 27960

tcgtcacatc catttcaatc acgtgctcct tatttatcat aatgcttccg tgtagacact 28020

taagctcgcc ttcgatctca gcgcagcggt gcagccacaa cgcgcagccc gtgggctcgt 28080

gatgcttgta ggtcacctct gcaaacgact gcaggtacgc ctgcaggaat cgccccatca 28140

tcgtcacaaa ggtcttgttg ctggtgaagg tcagctgcaa cccgcggtgc tcctcgttca 28200

gccaggtctt gcatacggcc gccagagctt ccacttggtc aggcagtagt ttgaagttcg 28260

cctttagatc gttatccacg tggtacttgt ccatcagcgc gcgcgcagcc tccatgccct 28320

tctcccacgc agacacgatc ggcacactca gcgggttcat caccgtaatt tcactttccg 28380

cttcgctggg ctcttcctct tcctcttgcg tccgcatacc acgcgccact gggtcgtctt 28440

cattcagccg ccgcactgtg cgcttacctc ctttgccatg cttgattagc accggtgggt 28500

tgctgaaacc caccatttgt agcgccacat cttctctttc ttcctcgctg tccacgatta 28560

cctctggtga tggcgggcgc tcgggcttgg gagaagggcg cttctttttc ttcttgggcg 28620

caatggccaa atccgccgcc gaggtcgatg gccgcgggct gggtgtgcgc ggcaccagcg 28680

cgtcttgtga tgagtcttcc tcgtcctcgg actcgatacg ccgcctcatc cgcttttttg 28740

ggggcgcccg gggaggcggc ggcgacgggg acggggacga cacgtcctcc atggttgggg 28800

gacgtcgcgc cgcaccgcgt ccgcgctcgg gggtggtttc gcgctgctcc tcttcccgac 28860

tggccatttc cttctcctat aggcagaaaa agatcatgga gtcagtcgag aagaaggaca 28920

gcctaaccgc cccctctgag ttcgccacca ccgcctccac cgatgccgcc aacgcgccta 28980

ccaccttccc cgtcgaggca cccccgcttg aggaggagga agtgattatc gagcaggacc 29040

caggttttgt aagcgaagac gacgaggacc gctcagtacc aacagaggat aaaaagcaag 29100

accaggacaa cgcagaggca aacgaggaac aagtcgggcg gggggacgaa aggcatggcg 29160

actacctaga tgtgggagac gacgtgctgt tgaagcatct gcagcgccag tgcgccatta 29220

tctgcgacgc gttgcaagag cgcagcgatg tgcccctcgc catagcggat gtcagccttg 29280

cctacgaacg ccacctattc tcaccgcgcg taccccccaa acgccaagaa aacggcacat 29340

gcgagcccaa cccgcgcctc aacttctacc ccgtatttgc cgtgccagag gtgcttgcca 29400

cctatcacat ctttttccaa aactgcaaga tacccctatc ctgccgtgcc aaccgcagcc 29460

gagcggacaa gcagctggcc ttgcggcagg gcgctgtcat acctgatatc gcctcgctca 29520

acgaagtgcc aaaaatcttt gagggtcttg gacgcgacga gaagcgcgcg gcaaacgctc 29580

tgcaacagga aaacagcgaa aatgaaagtc actctggagt gttggtggaa ctcgagggtg 29640

acaacgcgcg cctagccgta ctaaaacgca gcatcgaggt cacccacttt gcctacccgg 29700

cacttaacct accccccaag gtcatgagca cagtcatgag tgagctgatc gtgcgccgtg 29760

cgcagcccct ggagagggat gcaaatttgc aagaacaaac agaggagggc ctacccgcag 29820

ttggcgacga gcagctagcg cgctggcttc aaacgcgcga gcctgccgac ttggaggagc 29880

gacgcaaact aatgatggcc gcagtgctcg ttaccgtgga gcttgagtgc atgcagcggt 29940

tctttgctga cccggagatg cagcgcaagc tagaggaaac attgcactac acctttcgac 30000

agggctacgt acgccaggcc tgcaagatct ccaacgtgga gctctgcaac ctggtctcct 30060

accttggaat tttgcacgaa aaccgccttg ggcaaaacgt gcttcattcc acgctcaagg 30120

gcgaggcgcg ccgcgactac gtccgcgact gcgtttactt atttctatgc tacacctggc 30180

agacggccat gggcgtttgg cagcagtgct tggaggagtg caacctcaag gagctgcaga 30240

aactgctaaa gcaaaacttg aaggacctat ggacggcctt caacgagcgc tccgtggccg 30300

cgcacctggc ggacatcatt ttccccgaac gcctgcttaa aaccctgcaa cagggtctgc 30360

cagacttcac cagtcaaagc atgttgcaga actttaggaa ctttatccta gagcgctcag 30420

gaatcttgcc cgccacctgc tgtgcacttc ctagcgactt tgtgcccatt aagtaccgcg 30480

aatgccctcc gccgctttgg ggccactgct accttctgca gctagccaac taccttgcct 30540

accactctga cataatggaa gacgtgagcg gtgacggtct actggagtgt cactgtcgct 30600

gcaacctatg caccccgcac cgctccctgg tttgcaattc gcagctgctt aacgaaagtc 30660

aaattatcgg tacctttgag ctgcagggtc cctcgcctga cgaaaagtcc gcggctccgg 30720

ggttgaaact cactccgggg ctgtggacgt cggcttacct tcgcaaattt gtacctgagg 30780

actaccacgc ccacgagatt aggttctacg aagaccaatc ccgcccgcca aatgcggagc 30840

ttaccgcctg cgtcattacc cagggccaca ttcttggcca attgcaagcc atcaacaaag 30900

cccgccaaga gtttctgcta cgaaagggac ggggggttta cttggacccc cagtccggcg 30960

aggagctcaa cccaatcccc ccgccgccgc agccctatca gcagcagccg cgggcccttg 31020

cttcccagga tggcacccaa aaagaagctg cagctgccgc cgccacccac ggacgaggag 31080

gaatactggg acagtcaggc agaggaggtt ttggacgagg aggaggagga catgatggaa 31140

gactgggaga gcctagacga ggaagcttcc gaggtcgaag aggtgtcaga cgaaacaccg 31200

tcaccctcgg tcgcattccc ctcgccggcg ccccagaaat cggcaaccgg ttccagcatg 31260

gctacaacct ccgctcctca ggcgccgccg gcactgcccg ttcgccgacc caaccgtaga 31320

tgggacacca ctggaaccag ggccggtaag tccaagcagc cgccgccgtt agcccaagag 31380

caacaacagc gccaaggcta ccgctcatgg cgcgggcaca agaacgccat agttgcttgc 31440

ttgcaagact gtgggggcaa catctccttc gcccgccgct ttcttctcta ccatcacggc 31500

gtggccttcc cccgtaacat cctgcattac taccgtcatc tctacagccc atactgcacc 31560

ggcggcagcg gcagcggcag caacagcagc ggccacacag aagcaaaggc gaccggatag 31620

caagactctg acaaagccca agaaatccac agcggcggca gcagcaggag gaggagcgct 31680

gcgtctggcg cccaacgaac ccgtatcgac ccgcgagctt agaaacagga tttttcccac 31740

tctgtatgct atatttcaac agagcagggg ccaagaacaa gagctgaaaa taaaaaacag 31800

gtctctgcga tccctcaccc gcagctgcct gtatcacaaa agcgaagatc agcttcggcg 31860

cacgctggaa gacgcggagg ctctcttcag taaatactgc gcgctgactc ttaaggacta 31920

gtttcgcgcc ctttctcaaa tttaagcgcg aaaactacgt catctccagc ggccacaccc 31980

ggcgccagca cctgtcgtca gcgccattat gagcaaggaa attcccacgc cctacatgtg 32040

gagttaccag ccacaaatgg gacttgcggc tggagctgcc caagactact caacccgaat 32100

aaactacatg agcgcgggac cccacatgat atcccgggtc aacggaatcc gcgcccaccg 32160

aaaccgaatt ctcttggaac aggcggctat taccaccaca cctcgtaata accttaatcc 32220

ccgtagttgg cccgctgccc tggtgtacca ggaaagtccc gctcccacca ctgtggtact 32280

tcccagagac gcccaggccg aagttcagat gactaactca ggggcgcagc ttgcgggcgg 32340

ctttcgtcac agggtgcggt cgcccgggca gggtataact cacctgacaa tcagagggcg 32400

aggtattcag ctcaacgacg agtcggtgag ctcctcgctt ggtctccgtc cggacgggac 32460

atttcagatc ggcggcgccg gccgtccttc attcacgcct cgtcaggcaa tcctaactct 32520

gcagacctcg tcctctgagc cgcgctctgg aggcattgga actctgcaat ttattgagga 32580

gtttgtgcca tcggtctact ttaacccctt ctcgggacct cccggccact atccggatca 32640

atttattcct aactttgacg cggtaaagga ctcggcggac ggctacgact gaatgttaag 32700

tggagaggca gagcaactgc gcctgaaaca cctggtccac tgtcgccgcc acaagtgctt 32760

tgcccgcgac tccggtgagt tttgctactt tgaattgccc gaggatcata tcgagggccc 32820

ggcgcacggc gtccggctta ccgcccaggg agagcttgcc cgtagcctga ttcgggagtt 32880

tacccagcgc cccctgctag ttgagcggga caggggaccc tgtgttctca ctgtgatttg 32940

caactgtcct aaccttggat tacatcaaga tctttgttgc catctctgtg ctgagtataa 33000

taaatacaga aattaaaata tactggggct cctatcgcca tcctgtaaac gccaccgtct 33060

tcacccgccc aagcaaacca aggcgaacct tacctggtac ttttaacatc tctccctctg 33120

tgatttacaa cagtttcaac ccagacggag tgagtctacg agagaacctc tccgagctca 33180

gctactccat cagaaaaaac accaccctcc ttacctgccg ggaacgtacg agtgcgtcac 33240

cggccgctgc accacaccta ccgcctgacc gtaaaccaga ctttttccgg acagacctca 33300

ataactctgt ttaccagaac aggaggtgag cttagaaaac ccttagggta ttaggccaaa 33360

ggcgcagcta ctgtggggtt tatgaacaat tcaagcaact ctacgggcta ttctaattca 33420

ggtttctcta gaaatggacg gaattattac agagcagcgc ctgctagaaa gacgcagggc 33480

agcggccgag caacagcgca tgaatcaaga gctccaagac atggttaact tgcaccagtg 33540

caaaaggggt atcttttgtc tggtaaagca ggccaaagtc acctacgaca gtaataccac 33600

cggacaccgc cttagctaca agttgccaac caagcgtcag aaattggtgg tcatggtggg 33660

agaaaagccc attaccataa ctcagcactc ggtagaaacc gaaggctgca ttcactcacc 33720

ttgtcaagga cctgaggatc tctgcaccct tattaagacc ctgtgcggtc tcaaagatct 33780

tattcccttt aactaataaa aaaaaataat aaagcatcac ttacttaaaa tcagttagca 33840

aatttctgtc cagtttattc agcagcacct ccttgccctc ctcccagctc tggtattgca 33900

gcttcctcct ggctgcaaac tttctccaca atctaaatgg aatgtcagtt tcctcctgtt 33960

cctgtccatc cgcacccact atcttcatgt tgttgcagat gaagcgcgca agaccgtctg 34020

aagatacctt caaccccgtg tatccatatg acacggaaac cggtcctcca actgtgcctt 34080

ttcttactcc tccctttgta tcccccaatg ggtttcaaga gagtccccct ggggtactct 34140

ctttgcgcct atccgaacct ctagttacct ccaatggcat gcttgcgctc aaaatgggca 34200

acggcctctc tctggacgag gccggcaacc ttacctccca aaatgtaacc actgtgagcc 34260

cacctctcaa aaaaaccaag tcaaacataa acctggaaat atctgcaccc ctcacagtta 34320

cctcagaagc cctaactgtg gctgccgccg cacctctaat ggtcgcgggc aacacactca 34380

ccatgcaatc acaggccccg ctaaccgtgc acgactccaa acttagcatt gccacccaag 34440

gacccctcac agtgtcagaa ggaaagctag ccctgcaaac atcaggcccc ctcaccacca 34500

ccgatagcag tacccttact atcactgcct caccccctct aactactgcc actggtagct 34560

tgggcattga cttgaaagag cccatttata cacaaaatgg aaaactagga ctaaagtacg 34620

gggctccttt gcatgtaaca gacgacctaa acactttgac cgtagcaact ggtccaggtg 34680

tgactattaa taatacttcc ttgcaaacta aagttactgg agccttgggt tttgattcac 34740

aaggcaatat gcaacttaat gtagcaggag gactaaggat tgattctcaa aacagacgcc 34800

ttatacttga tgttagttat ccgtttgatg ctcaaaacca actaaatcta agactaggac 34860

agggccctct ttttataaac tcagcccaca acttggatat taactacaac aaaggccttt 34920

acttgtttac agcttcaaac aattccaaaa agcttgaggt taacctaagc actgccaagg 34980

ggttgatgtt tgacgctaca gccatagcca ttaatgcagg agatgggctt gaatttggtt 35040

cacctaatgc accaaacaca aatcccctca aaacaaaaat tggccatggc ctagaatttg 35100

attcaaacaa ggctatggtt cctaaactag gaactggcct tagttttgac agcacaggtg 35160

ccattacagt aggaaacaaa aataatgata agctaacttt gtggaccaca ccagctccat 35220

ctcctaactg tagactaaat gcagagaaag atgctaaact cactttggtc ttaacaaaat 35280

gtggcagtca aatacttgct acagtttcag ttttggctgt taaaggcagt ttggctccaa 35340

tatctggaac agttcaaagt gctcatctta ttataagatt tgacgaaaat ggagtgctac 35400

taaacaattc cttcctggac ccagaatatt ggaactttag aaatggagat cttactgaag 35460

gcacagccta tacaaacgct gttggattta tgcctaacct atcagcttat ccaaaatctc 35520

acggtaaaac tgccaaaagt aacattgtca gtcaagttta cttaaacgga gacaaaacta 35580

aacctgtaac actaaccatt acactaaacg gtacacagga aacaggagac acaactccaa 35640

gtgcatactc tatgtcattt tcatgggact ggtctggcca caactacatt aatgaaatat 35700

ttgccacatc ctcttacact ttttcataca ttgcccaaga ataaagaatc gtttgtgtta 35760

tgtttcaacg tgtttatttt tcaattgcag aaaatttcga atcatttttc attcagtagt 35820

atagccccac caccacatag cttatacaga tcaccgtacc ttaatcaaac tcacagaacc 35880

ctagtattca acctgccacc tccctcccaa cacacagagt acacagtcct ttctccccgg 35940

ctggccttaa aaagcatcat atcatgggta acagacatat tcttaggtgt tatattccac 36000

acggtttcct gtcgagccaa acgctcatca gtgatattaa taaactcccc gggcagctca 36060

cttaagttca tgtcgctgtc cagctgctga gccacaggct gctgtccaac ttgcggttgc 36120

ttaacgggcg gcgaaggaga agtccacgcc tacatggggg tagagtcata atcgtgcatc 36180

aggatagggc ggtggtgctg cagcagcgcg cgaataaact gctgccgccg ccgctccgtc 36240

ctgcaggaat acaacatggc agtggtctcc tcagcgatga ttcgcaccgc ccgcagcata 36300

aggcgccttg tcctccgggc acagcagcgc accctgatct cacttaaatc agcacagtaa 36360

ctgcagcaca gcaccacaat attgttcaaa atcccacagt gcaaggcgct gtatccaaag 36420

ctcatggcgg ggaccacaga acccacgtgg ccatcatacc acaagcgcag gtagattaag 36480

tggcgacccc tcataaacac gctggacata aacattacct cttttggcat gttgtaattc 36540

accacctccc ggtaccatat aaacctctga ttaaacatgg cgccatccac caccatccta 36600

aaccagctgg ccaaaacctg cccgccggct atacactgca gggaaccggg actggaacaa 36660

tgacagtgga gagcccagga ctcgtaacca tggatcatca tgctcgtcat gatatcaatg 36720

ttggcacaac acaggcacac gtgcatacac ttcctcagga ttacaagctc ctcccgcgtt 36780

agaaccatat cccagggaac aacccattcc tgaatcagcg taaatcccac actgcaggga 36840

agacctcgca cgtaactcac gttgtgcatt gtcaaagtgt tacattcggg cagcagcgga 36900

tgatcctcca gtatggtagc gcgggtttct gtctcaaaag gaggtagacg atccctactg 36960

tacggagtgc gccgagacaa ccgagatcgt gttggtcgta gtgtcatgcc aaatggaacg 37020

ccggacgtag tcatatttcc tgaagcaaaa ccaggtgcgg gcgtgacaaa cagatctgcg 37080

tctccggtct cgccgcttag atcgctctgt gtagtagttg tagtatatcc actctctcaa 37140

agcatccagg cgccccctgg cttcgggttc tatgtaaact ccttcatgcg ccgctgccct 37200

gataacatcc accaccgcag aataagccac acccagccaa cctacacatt cgttctgcga 37260

gtcacacacg ggaggagcgg gaagagctgg aagaaccatg tttttttttt tattccaaaa 37320

gattatccaa aacctcaaaa tgaagatcta ttaagtgaac gcgctcccct ccggtggcgt 37380

ggtcaaactc tacagccaaa gaacagataa tggcatttgt aagatgttgc acaatggctt 37440

ccaaaaggca aacggccctc acgtccaagt ggacgtaaag gctaaaccct tcagggtgaa 37500

tctcctctat aaacattcca gcaccttcaa ccatgcccaa ataattctca tctcgccacc 37560

ttctcaatat atctctaagc aaatcccgaa tattaagtcc ggccattgta aaaatctgct 37620

ccagagcgcc ctccaccttc agcctcaagc agcgaatcat gattgcaaaa attcaggttc 37680

ctcacagacc tgtataagat tcaaaagcgg aacattaaca aaaataccgc gatcccgtag 37740

gtcccttcgc agggccagct gaacataatc gtgcaggtct gcacggacca gcgcggccac 37800

ttccccgcca ggaaccttga caaaagaacc cacactgatt atgacacgca tactcggagc 37860

tatgctaacc agcgtagccc cgatgtaagc tttgttgcat gggcggcgat ataaaatgca 37920

aggtgctgct caaaaaatca ggcaaagcct cgcgcaaaaa agaaagcaca tcgtagtcat 37980

gctcatgcag ataaaggcag gtaagctccg gaaccaccac agaaaaagac accatttttc 38040

tctcaaacat gtctgcgggt ttctgcataa acacaaaata aaataacaaa aaaacattta 38100

aacattagaa gcctgtctta caacaggaaa aacaaccctt ataagcataa gacggactac 38160

ggccatgccg gcgtgaccgt aaaaaaactg gtcaccgtga ttaaaaagca ccaccgacag 38220

ctcctcggtc atgtccggag tcataatgta agactcggta aacacatcag gttgattcac 38280

atcggtcagt gctaaaaagc gaccgaaata gcccggggga atacataccc gcaggcgtag 38340

agacaacatt acagccccca taggaggtat aacaaaatta ataggagaga aaaacacata 38400

aacacctgaa aaaccctcct gcctaggcaa aatagcaccc tcccgctcca gaacaacata 38460

cagcgcttcc acagcggcag ccataacagt cagccttacc agtaaaaaag aaaacctatt 38520

aaaaaaacac cactcgacac ggcaccagct caatcagtca cagtgtaaaa aagggccaag 38580

tgcagagcga gtatatatag gactaaaaaa tgacgtaacg gttaaagtcc acaaaaaaca 38640

cccagaaaac cgcacgcgaa cctacgccca gaaacgaaag ccaaaaaacc cacaacttcc 38700

tcaaatcgtc acttccgttt tcccacgtta cgtcacttcc cattttaaga aaactacaat 38760

tcccaacaca tacaagttac tccgccctaa aacctacgtc acccgccccg ttcccacgcc 38820

ccgcgccacg tcacaaactc caccccctca ttatcatatt ggcttcaatc caaaataagg 38880

tatattattg atgatgttaa ttaatttaaa tccgcatgcg atatcgagct ctcccgggaa 38940

ttcggatctg cgacgcgagg ctggatggcc ttccccatta tgattcttct cgcttccggc 39000

ggcatcggga tgcccgcgtt gcaggccatg ctgtccaggc aggtagatga cgaccatcag 39060

ggacagcttc aaggccagca aaaggccagg aaccgtaaaa aggccgcgtt gctggcgttt 39120

ttccataggc tccgcccccc tgacgagcat cacaaaaatc gacgctcaag tcagaggtgg 39180

cgaaacccga caggactata aagataccag gcgtttcccc ctggaagctc cctcgtgcgc 39240

tctcctgttc cgaccctgcc gcttaccgga tacctgtccg cctttctccc ttcgggaagc 39300

gtggcgcttt ctcatagctc acgctgtagg tatctcagtt cggtgtaggt cgttcgctcc 39360

aagctgggct gtgtgcacga accccccgtt cagcccgacc gctgcgcctt atccggtaac 39420

tatcgtcttg agtccaaccc ggtaagacac gacttatcgc cactggcagc agccactggt 39480

aacaggatta gcagagcgag gtatgtaggc ggtgctacag agttcttgaa gtggtggcct 39540

aactacggct acactagaag gacagtattt ggtatctgcg ctctgctgaa gccagttacc 39600

ttcggaaaaa gagttggtag ctcttgatcc ggcaaacaaa ccaccgctgg tagcggtggt 39660

ttttttgttt gcaagcagca gattacgcgc agaaaaaaag gatctcaaga agatcctttg 39720

atcttttcta cggggtctga cgctcagtgg aacgaaaact cacgttaagg gattttggtc 39780

atgagattat caaaaaggat cttcacctag atccttttaa atcaatctaa agtatatatg 39840

agtaaacttg gtctgacagt taccaatgct taatcagtga ggcacctatc tcagcgatct 39900

gtctatttcg ttcatccata gttgcctgac tccccgtcgt gtagataact acgatacggg 39960

agggcttacc atctggcccc agtgctgcaa tgataccgcg agacccacgc tcaccggctc 40020

cagatttatc agcaataaac cagccagccg gaagggccga gcgcagaagt ggtcctgcaa 40080

ctttatccgc ctccatccag tctattaatt gttgccggga agctagagta agtagttcgc 40140

cagttaatag tttgcgcaac gttgttgcca ttgctgcagg catcgtggtg tcacgctcgt 40200

cgtttggtat ggcttcattc agctccggtt cccaacgatc aaggcgagtt acatgatccc 40260

ccatgttgtg caaaaaagcg gttagctcct tcggtcctcc gatcgttgtc agaagtaagt 40320

tggccgcagt gttatcactc atggttatgg cagcactgca taattctctt actgtcatgc 40380

catccgtaag atgcttttct gtgactggtg agtactcaac caagtcattc tgagaatagt 40440

gtatgcggcg accgagttgc tcttgcccgg cgtcaacacg ggataatacc gcgccacata 40500

gcagaacttt aaaagtgctc atcattggaa aacgttcttc ggggcgaaaa ctctcaagga 40560

tcttaccgct gttgagatcc agttcgatgt aacccactcg tgcacccaac tgatcttcag 40620

catcttttac tttcaccagc gtttctgggt gagcaaaaac aggaaggcaa aatgccgcaa 40680

aaaagggaat aagggcgaca cggaaatgtt gaatactcat actcttcctt tttcaatatt 40740

attgaagcat ttatcagggt tattgtctca tgagcggata catatttgaa tgtatttaga 40800

aaaataaaca aataggggtt ccgcgcacat ttccccgaaa agtgccacct gacgtctaag 40860

aaaccattat tatcatgaca ttaacctata aaaataggcg tatcacgagg ccctttcgtc 40920

ttcaaggatc cgaattcccg ggagagctcg atatcgcatg cggatttaaa ttaattaa 40978

Claims (4)

1. The Dicer1 gene or the product thereof is applied to the preparation of medicaments for treating early and middle-stage Alzheimer's disease, and the nucleotide sequence of the Dicer1 gene is shown as SEQ ID No. 1.

2. The use of claim 1, wherein said product is a viral vector comprising the Dicer1 gene.

3. The use of claim 2, wherein the viral vector is an adenoviral vector.

4. The use of claim 3, wherein the vector has the sequence shown in SEQ ID No. 2.

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