JPH0856672A - Gene of type c hepatitis virus - Google Patents

Abstract

PURPOSE: To obtain a type C hepatitis virus gene having a specific base sequence, coding for a type C hepatitis virus protein, expressing the protein in a host by integrating into an expression vector and producing a protein useful for diagnosis, treatment, etc., of type C hepatitis infecting through blood transfusion, etc., CONSTITUTION: This is a new type C hepatitis virus gene having a base sequence containing the base sequence of the formula, containing an RNA coding for a type C hepatitis virus protein and capable of producing a type C hepatitis virus protein useful as a diagnostic of type C hepatitis by the detection or classification of a type C hepatitis virus by means of antigen-antibody reaction, a vaccine for treating type C hepatitis, etc., by gene technology. The gene is prepared as follows: a type C hepatitis virus genome RNA is extracted from a serum of a type C hepatitis patient; a cDNA is synthesized with a reverse transcriptase using the genome RNA as a template; the cDNA is digested with an appropriate restriction enzyme, the obtained fragments are transduced into a plasmid, and the gene is integrated into a host cell; and the obtained recombinant DNAs are cloned and the objective gene is recovered from a positive clone.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel hepatitis C virus gene, hepatitis C virus protein and a method for producing the same.
And its use.

[0002]

2. Description of the Related Art Hepatitis C virus is RNA that is a causative virus of hepatitis that is transmitted by blood transfusion and other causes.
It is a virus and is known to exist in the blood of hepatitis C patients. It is known that there are various subtypes of the hepatitis C virus due to the high probability of mutation of its gene, and this virus is classified into several subtypes based on the sequence homology of the gene. It is possible.

However, the known viral subtypes and their nucleotide sequences are K1, K2a,
Only four kinds of K2b and Pt have been reported (Choo, QL., Kuo, G., Weiner, AJ., Et al., Science, 1
989,244: 359-361; Kato, N., Hijikata, M., Ootsuyama, Y.,
et al., Proc. Nat. Acad. Sci., 1990,87: 9524-9528; Okamo
to, H., Okada, S., Sugiyama, Y., et al., J.Gen.Virol., 199
1,72: 2697-2704; Okamoto, H., Kurai, K., Okada, S., et a
L., Virology, 1992, 188: 331-341).

On the other hand, by elucidating the structures of various virus subtypes, the development of diagnostic agents, therapeutic agents and the like for hepatitis C caused by these viruses can be expected.

[0005]

An object of the present invention is to provide a novel hepatitis C virus subtype gene, a hepatitis C virus protein, a method for producing the same, a method for classifying the same, and uses thereof.

[0006]

Means for Solving the Problems As a result of intensive research based on the above problems, the present inventors have found a hepatitis C virus having a novel subtype in the sera of hepatitis C patients, and found it. The separation was successful, and the present invention was completed. That is, the present invention comprises the hepatitis C virus genomic RNA characterized by having the base sequence represented by SEQ ID NO: 1 and the hepatitis C virus characterized by having the base sequence represented by SEQ ID NO: 2. Hepatitis C virus DNA containing DNA complementary or homologous to genomic RNA, or DNA encoding the amino acid sequence represented by SEQ ID NO: 4.

Further, the present invention is a hepatitis C virus protein consisting of a polypeptide containing the amino acid sequence represented by SEQ ID NO: 4. Furthermore, the present invention is a recombinant DNA incorporating a DNA complementary to the hepatitis C virus genomic RNA. Furthermore, the present invention provides the recombinant D
It is a transformant transformed with NA.

Furthermore, the present invention is a method for producing a hepatitis C virus protein, which comprises culturing the above transformant and separating the hepatitis C virus protein from the resulting culture. Furthermore, the present invention uses at least one of the primers represented by the nucleotide sequences of SEQ ID NOs: 5 to 11 to amplify a DNA complementary to the hepatitis C virus RNA, and the obtained amplified DNA fragment is subjected to electrophoresis. A method for detecting a DNA complementary to the hepatitis C virus genomic RNA, which comprises staining and detecting the DNA, or an antigen-antibody complex obtained by performing an antigen-antibody reaction using at least a part of the protein as an antigen A method for detecting hepatitis C virus, which comprises detecting hepatitis C virus from an object.

Furthermore, the present invention is characterized in that hepatitis C virus is classified into its subtypes using the DNA complementary to the hepatitis C virus RNA or the protein described above. Is the way. Furthermore, the present invention is a hepatitis C diagnostic agent comprising at least a part of the protein as an active ingredient.

Further, the present invention is a hepatitis C vaccine containing at least a part of the above protein as an active ingredient.
Here, "D homologous to hepatitis C virus genomic RNA
“NA” means that all of the nucleotide sequences represented by SEQ ID NO: 1 are the same sequences except that uracil (U) is replaced with thymine (T).

The present invention will be described in detail below. In the present invention, hepatitis C virus genomic RNA is extracted from the serum of a hepatitis C patient, and a single-stranded cDNA (complementary to hepatitis C virus genomic RNA is complementary to the template using, for example, reverse transcriptase and primers. Synthetic DNA),
If necessary, the cDNA is amplified, digested with an appropriate restriction enzyme and introduced into a plasmid, which is then incorporated into, for example, Escherichia coli or the like, and the resulting recombinant is cultured to produce cDN.
By isolating the A-containing plasmid, the DNA encoding the hepatitis C virus protein can be cloned.

Examples of the method for extracting the hepatitis C virus genomic RNA of the present invention include the guanidine method,
It can be extracted as follows. That is, a guanidine solution in an amount of about 5 times the volume of a small amount of serum is added, mixed and then phenol extracted, and the extracted RNA is precipitated with ethanol.

Using the thus obtained viral genomic RNA as a template, cDNA is synthesized using, for example, a reverse transcriptase and a primer. Examples of the reverse transcriptase include M
Examples thereof include MLV reverse transcriptase, AMV reverse transcriptase, Tth DNA polymerase and the like. Examples of the primer include a random primer and an antisense primer.

The cDNA thus obtained is subjected to polymerase chain reaction (hereinafter referred to as “PCR”) using a primer set in a region highly conserved among known virus subtypes.
The fragment can be amplified. Here, the “highly conserved region” means a region having extremely high nucleotide sequence homology even between hepatitis C viruses having different subtypes such as 5 ′ untranslated region.

The DNA fragment obtained by PCR can be purified by, for example, agarose gel electrophoresis, polyacrylamide electrophoresis or the like. Then, the purified DNA is treated with an appropriate restriction enzyme (for example, Eco
RI, BamHI, HindIII, etc.), and then inserted into a cloning vector cut out with the same restriction enzyme, and introduced into a transformable host to transform the vector, and then transformed into tetracycline resistance or ampicillin resistance. Recombinant DNA can be cloned.

As the vector DNA used here, a phage vector, a plasmid vector or the like is used. The phage vector is preferably M13 phage vector, and the plasmid vector is pUC18,
pUC19 and the like are preferable. Examples of the host include Escherichia coli and yeast.

The nucleotide sequence can be determined from the recombinant DNA thus cloned. That is,
From the tetracycline-resistant or ampicillin-resistant transformants already obtained, the desired clone is subjected to secondary screening by colony hybridization. The nucleotide sequence of a clone showing a positive result by this colony hybridization can be determined by a usual nucleotide sequencing method, for example, Sanger method, Maxam-Gilbert method, or the like.

However, when it is difficult to determine the entire nucleotide sequence because the sequence of the virus subtype greatly differs from the sequence of the previously reported virus subtype, the RACE method (Fr
Oman, et al., PNAS, 85, 8998-9002) is preferably used. The "RACE method" is a method in which an appropriate oligonucleotide is added to the end of an unknown region, and an unknown region is amplified by PCR using a primer complementary to the added sequence and a known primer. Is.

Sequence of hepatitis C virus DNA (genome R
Once the DNA complementary to NA is determined, the corresponding viral genomic RNA and the sequence of the DNA homologous to the genomic RNA can be determined. In addition, genome R
For confirmation and detection of DNA complementary to NA, an appropriate primer based on a DNA sequence homologous to the DNA or genomic RNA, for example, a primer represented by the nucleotide sequences of SEQ ID NOs: 5 to 11 [Pt type (SEQ ID NO: 5), K1 type (SEQ ID NO: 6), K2a type (SEQ ID NO: 7), K2b type (SEQ ID NO: 8), Ta type (SEQ ID NO: 9), Tr type (SEQ ID NO: 10) and all subtypes At least one of the common type (SEQ ID NO: 11)], and whether or not the gene is amplified can be examined. The above-mentioned primer is, for example, Applied Biosystems (ABI).
It can be synthesized using an automatic DNA synthesizer manufactured by the company.

For the detection of the obtained gene, PCR is used.
The latter gene fragment can be subjected to a commonly used electrophoresis, for example, agarose gel electrophoresis, and staining with ethidium bromide. When amplification is performed using each primer, the position of the band that appears as a result of electrophoresis changes depending on the difference in the primer used, and this makes it possible to determine the subtype of the virus used in the sample.

Next, all or part of the gene encoding the hepatitis C virus protein is excised from the obtained clone, ligated to the downstream of an appropriate promoter, enhancer, etc., and then introduced into an appropriate host. Perform transformation.
Examples of the promoter include LacZ, Ptac, LacI and the like,
Examples of the host include XL1-Blue, TB1, JM107 and the like, but XL1-Blue is preferable.

To obtain the hepatitis C virus protein of the present invention, the transformant may be cultured in a commonly used medium and purified by a commonly used method. Examples of the medium include LB medium containing ampicillin, TB
Examples of the medium include 2XYT medium. Furthermore, in order to improve the gene expression efficiently, isopropyl-1-thio-β-D-galactoside (IPT
G), glucose, etc. can also be added.

Culturing is usually carried out at 37 ° C. for 6 to 7 hours, and if necessary, aeration and stirring can be carried out. After culturing, the bacterial cells are collected, suspended in a buffer solution, frozen, thawed, boiled, etc., and then centrifuged to obtain a supernatant. Separation and purification of the hepatitis C virus protein from the obtained supernatant may be carried out according to commonly known protein purification methods. For example, salting out, centrifugation, various chromatographies, electrophoresis and the like are appropriately combined for purification.

Examples of various chromatographies include gel filtration, ion exchange chromatography, reverse phase chromatography, affinity chromatography and the like. The purity and the approximate molecular weight of the purified product are confirmed by SDS (sodium lauryl sulfate) polyacrylamide gel electrophoresis, Western blotting and the like.

The analysis of the amino acid sequence of the purified protein can also be carried out by an automatic Edman degradation method using a gas phase protein sequencer. Since the hepatitis C virus protein of the present invention produced by the above method has a high antibody titer and is easy to detect an antigen, it can be used as a diagnostic agent for hepatitis C, and can be used for hepatitis C virus vaccine and the like. .

The detection of hepatitis C virus antibody using the hepatitis C virus protein of the present invention is carried out as follows. That is, hepatitis C virus protein is solid-phased on a microtiter plate, test serum is added thereto and reacted, washed with a buffer, and antibodies bound to hepatitis C virus protein are treated with alkaline phosphatase or peroxidase. Labeled anti-human immunoglobulin (Ig
G) The antibody can be detected by reacting with the antibody, washing with a buffer solution, adding a chromogenic substrate, and detecting a change in absorbance with a densitometer.

When the hepatitis C virus protein of the present invention is administered as a hepatitis C vaccine, it is usually administered by injection (subcutaneous or intramuscular). In addition, the dose varies depending on whether it is an animal or a human, age, route of administration, and frequency of administration, and can be widely varied. In this case, the effective amount of the hepatitis C vaccine of the present invention and an effective amount administered as a composition of a suitable diluent and pharmacologically usable carrier are 0.01 to 0.1 μg / kg body weight / day, and 1 It is administered once to several times a day.

In addition, the hepatitis C vaccine of the present invention contains additives such as a stabilizer, a buffer, a preservative and an isotonicity agent,
It is usually provided in a unit dose ampoule or multi-dose container or tube. The composition may be in powder form for reconstitution with a suitable carrier, eg, pyrogen-free, sterile water, when used.

[0029]

EXAMPLES The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to these examples.

[Example 1] Hepatitis C virus genome R
Separation of NA To 100 μL of hepatitis C patient serum, 425 μL of 4.2 M guanidine thiocyanate, 0.1 M Tris-HCl (pH 7.5), 0.5% N-lauryl sarcosyl solution and 4 μL of 2-mercaptoethanol were added. Mix by inversion for 30 minutes.

Then, the mixture was extracted 3 times with a 4: 1 mixed phenol-chloroform solution and once with chloroform to remove proteins, followed by ethanol precipitation. 70 of the precipitate
% And 100% ethanol respectively, and the resulting pellets were used as purified hepatitis C virus genomic RNA.

Example 2 Cloning of Hepatitis C Virus Gene, Determination of Nucleotide Sequence, and Detection of Gene and Confirmation of Expression (1) Cloning of Hepatitis C Virus Gene In the genomic RNA obtained in Example 1, 50 mM Tris-HCl (p
H8.3), 75 mM KCl, 10 mM DTT, 3 mM MgCl ₂ , 1 mM dN
TPs mix (4 types of deoxynucleoside triphosphates consisting of dATP, dCTP, dGTP, dTTP; TOYOBO), 60 μg / ml random primer (TAKARA), 10U / ml M-MLV reverse transcriptase (GIBCO BRL) ) Each solution is added to a total volume of 20 μL
I made it. Then, the obtained solution was subjected to reverse transcription reaction at 42 ° C. for 30 minutes to obtain cDNA.

Next, using this cDNA as a template, amplification was carried out by a PCR reaction using primers specific to the hepatitis C virus genome. The reaction is 1 to above cDNA solution
5 mM 10 mM Tris-HCl (pH 8.0), 50 mM KCl, 1.5
_{mM MgCl 2, 0.1% Triton X} -100,0.2mM dNTP, each 4 [mu] g / ml the sense side and antisense end primer, and, 30 U / ml Taq DNA polymerase (Perkin Elmer Cetus) was added, performed in a total volume 25μL It was This sample was cycled at 94 ° C for 4 minutes for 1 cycle, 94 ° C for 30 seconds, 53 ° C for 1
And 1 minute at 72 ° C. as one cycle, 40 cycles were performed, and 7 minutes at 72 ° C. as one cycle.

The PCR product was electrophoresed on a 1-3% agarose gel, the band visualized under ultraviolet light was cut out by staining with ethidium bromide, and QIAEX, gel extraction kit (QIAEX) was used.
DNA was recovered using GEN). Next, the ends of the DNA were aligned (treated with restriction enzymes EcoRI and BamHI),
It was inserted into the M13 phage vector to obtain a recombinant plasmid. Escherichia coli JM109 was transformed with this recombinant and cultured for 12 to 16 hours to form plaques, whereby phages incorporating the hepatitis C virus cDNA fragment were obtained.

(2) Determination of nucleotide sequence Escherichia coli JM105 was infected with the phage obtained by the above method, and after sufficiently proliferating, the bacterial cells were separated and the phage was recovered using polyethylene glycol. Then, it was mixed with phenol and chloroform at a ratio of 4: 1 to 2
Single-stranded DNA of the phage was recovered by extracting once with chloroform and once with chloroform. Using this, the nucleotide sequence of DNA was determined by the dideoxy method of Sangar et al.

The results are shown in SEQ ID NO: 2. Sequence number 2
From this, the sequence of the hepatitis C virus genomic RNA of the present invention can be determined, and the result is shown in SEQ ID NO: 1. Further, from SEQ ID NO: 1, the nucleotide sequence of DNA homologous to hepatitis C virus genomic RNA can be determined, and the result is shown in SEQ ID NO: 3. Furthermore, the deduced amino acid sequence encoding the hepatitis C virus protein can be determined from SEQ ID NO: 2. In this case, the part that is considered to encode the hepatitis C virus protein is considered to be the 339 to 9408th 9069 nucleotide sequence in the nucleotide sequence of SEQ ID NO: 2, and is deduced from the nucleotide sequence. The amino acid sequence of this is shown in SEQ ID NO: 4.

(3) Detection of Gene and Confirmation of Expression The DNA amplified by the PCR method was subjected to electrophoresis on an agarose gel of 1 to 3% depending on the size, and the gene was detected by staining with ethidium bromide. . As a result, a DNA fragment having the expected mobility was detected.

[Example 3] Purification of protein and confirmation of expression (1) Purification of protein Induction of expression of hepatitis C virus capsid gene fragment cloned into pMAL-C2 in host strain XL1-Blue using IPTG Then, after culturing at 37 ° C for 3 to 4 hours, the cells were transferred to a centrifuge tube and centrifuged at 12000 rpm for 30 seconds (4 ° C) to collect the cells from the E. coli culture solution, and 50 mM Tris-HCl (pH 7.
After washing with 4), dissolve in 1 × Column buffer (including 10 mM sodium phosphate, 0.5 M sodium chloride, 1 mM sodium azide, 10 mM β-mercaptoethanol and 1 mM EGTA), freeze (-20 ° C), thaw Was repeated twice and then heated at 100 ° C. for 5 minutes to obtain an expressed protein.

Amylose resin was packed in a 2.5 × 10 cm column and washed with 8 times the amount of 1 × Column buffer.
Inject crude extract of expressed protein at a rate of 1 ml / min. After washing with 8 times more 1 × Column buffer,
A protein containing 10 mM maltose was poured into the column buffer to extract the protein. If you collect 3 ml each, the protein will start to flow out within the first 5 runs, so collect 10 to 20 fractions. Measure OD with UV of 280 nm and use Ami
Concentrate to about 1 mg / ml with con Centricon. Furthermore, in some cases, 1 mg of factor Xa is added to 100 mg of the obtained protein, and the target hepatitis C virus core protein is separated from the maltose-binding protein by leaving it at room temperature or 4 ° C for 3 hours to several days. You can also The reaction was performed with the same amount of 2 × SDS-PAGE sample.
It is stopped by adding buffer, and after boiling for 5 minutes, it is subjected to SDS-PAGE.

(2) Confirmation of protein expression Next, the protein obtained in (1) was subjected to SDS-polyacrylamide gel electrophoresis, and the protein was separated on the nylon membrane by Western blotting after separating by molecular weight. It was transcribed. The expressed protein was detected using the antiserum of the same patient as the primary antibody and the anti-human IgG antibody labeled with alkaline phosphatase as the secondary antibody.

The results are shown in FIG. In FIG. 1, M
Is a molecular weight marker, lane 1 is a fusion protein obtained from the serum of a patient, lane 2 is a protein obtained by treating the serum of a patient with factor Xa, lane 3 is a protein not induced by IPTG, and lane 4 is a protein of the env region. The expressed lanes and lane 5 are samples of sera of healthy individuals. From FIG. 1, a 22-kilodalton band considered to be a capsid protein was detected (lane 2).

[Example 4] Detection and classification of hepatitis C virus subtypes. The following PCR reaction was performed using 1 μL of 20 μL of cDNA obtained from 100 μL of serum from a hepatitis C patient. Six types of sense primers, Pt (SEQ ID NO: 5), K1 specific to each type of virus, were used as primers.
(SEQ ID NO: 6), K2a (SEQ ID NO: 7), K2b (SEQ ID NO: 8), Ta (SEQ ID NO: 9) and Tr (SEQ ID NO: 10)
Was synthesized and used.

The reaction solution was 10 × PCR buffer [500 mM
KCL, 100mM Tris-HCl (pH8.8), 15mMMgCl ₂ , 1% Triton
X-100] 2.5 μL, DNA Taq polymerase (5000 units
(/ ml; manufactured by Wako) 14 μL of sterile distilled water was added to 0.15 μL
Use 16.65 μL of solution A. On the other hand, each of the 6 types of sense primers (SEQ ID NOS: 5 to 10; 0.1 μg / μL in each) was 1 μL, and an antisense primer common to all types (SEQ ID NO: 11; 0.1 μg / μL) was 1 μL, and further, 10 mM dNTP
Solution B is a total of 7.5 μL of a solution obtained by adding 0.5 μL of (N = A, C, T, G).

Solution A, cDNA and 1-2 drops of liquid paraffin were added to the reaction tube and set in a thermal cycler heated to 70 ° C. After leaving it for about 15 seconds or longer, add solution B and start the cycle. PCR cycle is 94 ℃
After 4 minutes, 94 ℃ 1 minute, 61 ℃ 1 minute, 72 ℃ 1 minute 10 cycles, 90 ℃ 30 seconds, 59 ℃ 1 minute, 72 ℃
30 cycles were performed for 1 minute, and finally, incubation was performed at 70 ° C. for 7 minutes to obtain a PCR product.

The hepatitis C virus subtypes can be classified by the position of the band when ethidium bromide staining is performed after electrophoresis on a 3% agarose gel. That is, PCR containing the 7 types of primers (6 types of primers and antisense primer)
The position where the band appears when the product is used differs depending on the reacted primer, and is as shown in FIG. In FIG. 2, M is a sample obtained by cleaving φX174 DNA with HaeIII, which is an index of the size of the PCR product, and lanes 1 to 6 show the bands when Pt, K1, K2a, K2b, Ta, and Tr were used, respectively. Represent In this case, for example, if the test sample is Pt-type, the sample reacts with the Pt-type sense primer contained in the solution B and is amplified, so that the Pt-type position (lane 1) in FIG. A band should appear.

Therefore, it was examined at what position the sample used in this example appeared as a band. As a result, in the sample used in this example, a band appeared at the position of lane 6 in FIG. 2 (the position of “←” in FIG. 2). Therefore, it was found that the virus subtype used in this example was classified into Tr type.

[0047]

INDUSTRIAL APPLICABILITY According to the present invention, hepatitis C virus genomic RNA, DNA complementary to the RNA or homologous DN.
A and hepatitis C virus proteins and methods for producing the same are provided. Hepatitis C virus genomic RNA of the present invention
Can be used for classification of hepatitis C virus subtypes, and the hepatitis C virus protein of the present invention can be used for classification of the above subtypes, while a diagnostic agent for hepatitis C, hepatitis C It is useful as a vaccine.

[0048]

[Sequence list]

 SEQ ID NO: 1 Sequence length: 9444 Sequence type: Nucleic acid Number of strands: Single-stranded topology: Linear Sequence type: Genomic RNA Sequence: ACCUGCCUCU UUCGAGGCGA CACUCCACCA UGAAUCACUC CCCUGUGAGG AACUCUUGUC 60 UUCACGCGGA AAGCGUCUAG CCAUGGC GAGAGCCAUA GUGGUCUGCG GAACCGGUGA GUACACCGGA AUCGCCGGGA 180 UGACCGGGUC CUUUCUUGGA ACAACCCGCU CAAUGCCCGG AAAUUUGGGC GUGCCCCCGC 240 GAGAUCACUA GCCGAGUAGU GUUGGGUCGC GAAAGGCCUU GUGGUACUGC CUGAUAGGGU 300 GCUUGCGAGU GCCCCGGGAG GUCUCGUAGA CCGUGCAACA UGAGCACACU UCCUAAACCU 360 AAAAGACAAA CAAAAAGAAA CACACUCCGC CGCCCAAAGA ACGUUAAGUU CCCGGCUGGC 420 GGGCAGAUCG UUGGUGAAGU AUAUGUCCUG CCGCGUAGGG GCCCACAAUU GGGUGUGCGC 480 GAAGUACGUA AGACUUCCGA GCGAUCACAA CCUCGCGGAC GGCGUCAGCC UACCCCCAAG 540 GCACGCCCGC GCGAGGGCCG GUCCUGGGCC CAGCCCGGGU ACCCUUGGCC CCUCUACGGG 600 AAUGAGGGCU GUGGUUGGGC AGGAUGGCUC UUGCCCCCCC GCGGUUCUCG CCCCAGCUGG 660 GGCCAAAAUG ACCCCCGGCG UAGAUCCCGC AACUUGGGUA AGGUC AUCGA UACCCUAACG 720 UGCGGAUUUG CCGACCUCAU GGGGUACAUU CCGCUCAUCG GCGCCCCUGU AGGGGGCGUC 780 GCAAGAGCCC UCGCUCAUGG UGUGAGAGCA CUUGAGGACG GAGUGAACUA CGCAACAGGG 840 AAUCUUCCUG GUUGCUCCUU CUCUAUCUUC CUCCUCGCUC UCUUCUCCUG CUUGACUUGC 900 CCCGCGUCCA GUCUGGAGUA CAGGAAUGCG UCUGGCCUAU AUUUGCUUAC CAACGACUGC 960 UCCAACAGGA GCAUUGUGUA UGAGGCCGAC GACGUGAUCU UGCACUUACC CGGAUGCGUG 1020 CCCUGCGUCG AAACCGACAA CAACAACACA UCGUGCUGGA CACCGAUUUC ACCGACGGUG 1080 GCCGUCAAGC ACCCUGGUGU GACCACCGCG UCGAUCCGAA AUCAUGUGAA UAUGUUGGUG 1140 GCCCCGCCAA CGCUGUGCUC AGCACUAUAC GUCGAAGACG CCUUCGGGGC CGUGUCCCUU 1200 GUGGGACAAG CGUUCACCUU UAGACCUCGC CAACACAAGA CUGUGCAGAC GUGCAACUGC 1260 UCAAUAUACC CAGGUCAUGU CUCAGGACAU CGUAUGGCUU GGGAUAUGAU GAUGAACUGG 1320 UCCCCCGCAA UCGGGCUAGU GAUAUCACAC UUGAUGCGGU UGCCCCAAAC GUUCUUUGAC 1380 CUGGUCGUGG GGGCCCACUG GGGCGUGAUG GCAGGCCUCG CCUACUUUUC CAUGCAAGGC 1440 AAUUGGGCCA AGGUCGUCAU CGUGCUAAUC AUGUUUUCAG GAGUGGACGC GACAACACAC 1500 ACCACUGGUG GCAGCGCGGC CCAAGCCACU GCCGGGUUUA CAAGUUUUUU CACCC GAGGU 1560 CCAAGUCAGA AUUUGCAAUU GGUCAACUCA AAUGGGUCAU GGCACAUUAA CAGCACUGCC 1620 UUGAAUUGCA ACGAUUCCCU AAACACUGGC UUUAUAGCGG GCCUCUUCUA CUAUCACAAA 1680 UUCAACUCCU CGGGGUGCCC UGAGCGAAUG UCCAGCUGUA AGCCCAUCAC AUAUUUCAAU 1740 CAGGGGUGGG GCCCAUUGAC AGAUGCUAAC AUAAAUGGUC CCAGUGAGGA CAGACCAUAU 1800 UGCUGGCACU AUCCACCCAG ACCCUGUAAC AUAACCAAGC CGUUGAAUGU CUGUGGGCCC 1860 GUCUACUGCU UUACACCCUC ACCGGUGGUG GUGGGCACCA CUGAUAUUAA AGGCCUGCCA 1920 ACUUAUAGGU UUGGUGUGAA CGAGUCAGAU GUCUUCUUGU UGACCUCUUU GAGACCCCCC 1980 CAAGGCCGGU GGUUUGGAUG UGUGUGGAUG AACAGUACAG GGUUUGUAAA GACUUGUGGG 2040 GCUCCCCCUU GCAACAUCUA UGGGGGGAUG AAGGACAUUG AAGCAAAUCA AACCCACCUU 2100 AAAUGCCCUA CCGAUUGUUU CAGGAAGCAC CAUGAUGCCA CGUUUACCCG CUGCGGGUCC 2160 GGGCCCUGGC UUACGCCAAG GUGUCUGGUA GACUACCCGU ACCGACUGUG GCAUUAUCCU 2220 UGCACUGUGA ACUUCUCUAU AUUCAAGGUC AGAAUGUUCG UAGGAGGACA UGAACAUCGA 2280 UUCUCAGCCG CCUGCAACUG GACGAGGGGA GAGCGCUGUG AUCUUGAAGA UCGUGACCGC 2340 AGUGAGCAAC AACCACUGCU CCAUUCAACG ACUGACUCGC UAAUAUUGCC AUGCUCAUUU 2400 ACACCUAUGC GCCGCCUGUC AACAGGGCUC AUACACCUCC ACCAGAACAU CGUGGACGUG 2460 CAAUACCUCU AUGGUGUUGG UUCUGCCGUA GUGGGCUGGG CUCUCAAGUG GGAGUUCGUC 2520 GUCCUCGUCU UCCUCCUUCU GGCGGACGCA CGCGUGUGUG UGGCCCUCUG GAUGAUGUUA 2580 CUGAUUUCUC AGGCGGAAGC AGCAAUGGAG AACUUGGUGA UGCUGAACGC CCUCAGCGCA 2640 GCGGGACAAC AGGGUUACGU CUGGUACCUG GUUGCAUUCU GCGCCGCAUG GCACAUCCGG 2700 GGGAAGCUCG UUCCGCUGAU AACCUAUGGU UUGACAGGCC UGUGGCCCCU AGCCCUGCUC 2760 GACCUCCUGC UCCCUCAGCG UGCUUACGCU UGGACGGGAG AAGACGAUGC CACCAUCGGG 2820 GCCGGGGUGC UCCUGCUCCU CGGGUUCUUU ACCUUAUCAC CAUGGUAUAA GCACUGGAUU 2880 GGCCGUCUUA UCUGGUGGAA CCAGUAUGCC AUAUGCAGGG GUGAGGCCGC CUUGCAAGUA 2940 UGGGUCCCCC CCCUGCUUGU UCGAGGUAGU CGGGACAGUG UGAUUUUACU AGCAAGCCUA 3000 CUGUAUCCCU CUCUAAUCUU UGACAUCACA AAGCUGCUGA UAGCCGUCCU UGGGCCACUG 3060 UAUUUAAUAC AAGCCGCACU CACCAGCACC CCCUACUUUG UCCGCGCCCA CGUGUUGAUU 3120 CGUAUCUGCA UGUUGGUGCG CUCUGCAAUG GGAGGGAAGU ACGUCCAAAU GGCCGUGCUG 3180 ACGGUUGGCC GGUGGUUUAA CACCUAUCUG UAUGACCACC UGUCCCCCAU ACAGGACUGG 3240 G CUGCCGAGG GUCUCAAAGG ACUGGCGGUG GCCACGGAGC CCGUCAUCUU UAGUCCUAUG 3300 GAGAUUAAGG UUAUCACCUG GGGUGCAGAC ACAGCAGCCU GCGGAGACAU CUUGUGCGGG 3360 UUGCCCGUUU CGGCGCGGUU GGGCCGCGAG UUGUUGCUGG GUCCGGCUGA CGAUUACAAG 3420 AAGAUGGGAU GGCGCCUACU GUCCCCGAUC UCAGCAUACG CCCAGCAAAC UCGGGGACUA 3480 UUUGGAACUA UUGUCACCAG CCUGACAGGU AGGGAUAAGA ACGUGGUGAC UGGUGAGGUG 3540 CAGGUGCUGU CCACGGCCAC CCAGACCUUC UUGGGUACGA CAGUAGGGGG GGUCAUGUGG 3600 ACUGUUUACC AUGGUGCUGG GUCGCGGACU CUUGCUGGUA ACAAACGGCC CGCGCUUCAA 3660 AUGUACACCA AUGUGGACCA GGACCUGGUA GGUUGGCCAG CGCCUGCGGG GACCAAGUCC 3720 CUUGACCCCU GCACGUGCGG UUCUUCCGAC CUGUACCUGG UGACGCGUGA GGCCGACGUC 3780 CUCCCCGCCC GCCGUAGGGG AGACUCAACG GCGAGUUUAC UCAGUACCAG ACCACUGUCC 3840 UGCCUCAAAG GUUCUUCUGG GGGUCCUGUC AUGUGCCCUU CGGGGCACGU GGUGGGGAUC 3900 UUCAGGGCGG CAGUGUGCAC CAGAGGUGUC GCAAAAGCCC UGCAGUUCAU ACCAGUGGAA 3960 ACUCUGAGUA CGCAGGUCAG GUCUCCAUCU UUUAGUGACA AUUCCACCCC CCCUGCCGUC 4020 CCGGAGUCCU ACCAAGUAGG AUACCUUCAC GCCCCCACUG GAAGCGGCAA AAGCACCAAA 4080 GUCCCCG CCG CUUAUGUUGC ACAGGGAUAU UCUGUCCUAG UGCUAAAUCC AUCGGUAGCG 4140 GCUACCCUGG GUUUUGGCAC GUACAUGUCA AAAGCCUAUG GGAUUGACCC CAACAUCCGU 4200 ACGGGGACAC GCACCAUCAC AACCGGUGCC AAACUCACCU ACUCCACAUA CGGCAAGUUC 4260 CUCGCCGAUG GGGGUUGUUC UGGAGGCGCC UAUGACGUGA UCAUCUGCGA UGAAUGUCAC 4320 GCGCAAGACG CUACCUCCAU ACUGGGUAUA GGCACGGUGC UGGAUCAAGC AGAGACAGCC 4380 GGGGUGAGGC UGACGGUACU GGCAACCGCG ACCCCUCCCG GCAGCAUCAC GGUGCCGCAU 4440 CCUAAUAUCG AGGAGGUGGG CCUCACCAGU GACGGAGAAA UCCCCUUUUA UGGCAAAGCC 4500 CUCCCACUGG CAAUGAUCAA GGGAGGAAGA CACCUUGUAU UCUGCCAUUC AAAGGAAAAA 4560 UGUGACGAGC UGGCCAGCAA GCUCAGAGGG AUGGGGGUCA ACGCUGUAGC GUUUUAUAGA 4620 GGCCUCGACG UGUCCGUGAU ACCUGUAUCC GGAGACGUGG UAGUAUGUGC UACUGAUGCC 4680 CUCAUGACCG GAUAUACAGG GGAUUUUGAC ACCGUUAUAG ACUGUAACGU GGCUGUGGAG 4740 CAGUACGUCG ACUUCAGUCU AGACCCCACU UUCUCCAUUG AGACACGCAC GGUUCCCCAG 4800 GACGCGGUGU CCCGAAGUCA ACGCAGGGGC CGUACGGGCC GGGGUAGACC GGGAAUAUAC 4860 CGGUUUGUCA CUCCAGGGGA GCGGCCGUCC GGCAUGUUUG ACUCGGUGGU GCUAUGUGAG 4920 UGCUAUGACG CA GGUUGUUC CUGGUAUGAC CUACAACCUG CUGAGACCAC AGUGCGACUG 4980 AGAGCAUACC UGUCCACCCC GGGGCUACCU GUCUGCCAAG ACCACCUAGA CUUCUGGGAG 5040 AGAGUGUUUA CCGGACUGAC UCAUAUAGAU GCCCACUUCU UGUCACAGGC AAAACAGCAG 5100 GGCCUAAACU UUGCAUACUU GGUGGCAUAU CAAGCCACUG UCUGCGCUCG UGCAAAGGCG 5160 AGCCCACCAU GUUGGGAUGA GAUGUGGAAA UGUCUCAUAC GCCUGAAGCC GACUCUGCAA 5220 GGCCCUACUC CUCUCCUGUA UAGGUUAGGA GCAAUUCAAA AUGACAUCUG CAUGACACAC 5280 CCUAUUACCA AGUACAUCAU GGCUUGCAUG UCAGCUGACU UGGAAGUCAC CACGAGCGCC 5340 UGGGUGCUGG UUGGUGGUGU UCUAGCAGCC CUCGCAGCCU ACUGUUUAUC AGUAGGUUGU 5400 GUCGUCAUCG UGGGGCAUAU CGAGCUAGGA GGCAAACCUG CGCUCGUCCC UGACAGACAA 5460 GUACUGUACC AACAAUAUGA UGAGAUGGAA GAAUGUUCCC AGUCUGCUCC UUACAUCGAG 5520 CAAGCACAGG CUAUCGCUCA GCAAUUCAAG GACAAAGUCC UCGGCUUGCU GCAAAGGGCG 5580 AGCCAACAAG AAGCUGAAAU UCGACCCAUA GUGCAAUCAC AAUGGCAGAA AGCGGAGGCG 5640 UUCUGGCAAC AGCACAUGUG GAACUUUGUG AGCGGGAUCC AGUACCUGGC CGGUCUCUCC 5700 ACACUGCCAG GCAACCCUGC CGUGGCUUCC CUUAUGGCCU UCACCGCCUC UGUAACCAGC 5760 CCCCUCACAA CCAACCAG AC UAUGUUCUUU AACAUCCUUG GAGGUUGGGU AGCCACACAC 5820 CUAGCGGGAC CUGCAGCAUC UUCCGCGUUU GUGGUAAGCG GCUUGGCUGG CGCCGCUGUG 5880 GGAGGCAUAG GCAUUGGCAG GGUGUUGCUU GACGUGCUUG CCGGGUAUGG GGCUGGGGUC 5940 UCCGGCGCCC UAGUGGCCUU CAAAAUCAUG GGAGGAGAGC UCCCUACCAC AGAGGACAUG 6000 GUCAAUCUUC UGCCUGCCAU CUUAUCCCCU GGAGCGUUGG UUGUUGGCGU GAUAUGUGCU 6060 GCAGUGUUGC GCCGGCAUGU AGGCCCUGGG GAAGGAGCAG UGCAGUGGAU GAACAGACUC 6120 AUAGCGUUCG CAUCUCGGGG GAACCAUGUA UCACCAACAC ACUAUGUCCC CGAGAGCGAC 6180 GCGGCAGCAA AAGUAACAGC AUUGCUGAGC UCUCUAACCG UCACCCGAUU GCUUCGCCGG 6240 UUACACCAGU GGAUCAACGA GGACUAUCCU AGUCCCUGCA ACGGUGACUG GUUACAUGAC 6300 AUCUGGGACU GGGUCUGUAU CGUACUUAGU GACUUUAAGA CCUGGCUUUC GGCCAAGAUC 6360 AUGCCCAAGG UGCCAGGCAU ACCCUUUCUC UCAUGUCAAA AGGGGUACAA GGGAGUAUGG 6420 CGAGGGGAUG GGGUGAUGAC AACGCGUUGC CCUUGUGGGG AAGACUUUAC AGGACACGUA 6480 AGGAAUGGGU CCAUGAGGAU AGCAGGAUCA GGCCUCUGCG CUAACAUGUG GCAUGGCACC 6540 UUCCCCAUCA AUGAAUACAC CACUGGGCCG AGUACACCCG UCCCCGCGCA CAAUUACUCG 6600 CGUGCCCUGU GGCGCGUGAC CUC CGACAGU UAUGUCGAGG UGCGUAGGGU GGGGGAUACU 6660 CAUUACGUGG UGGGGGCCAC GAACGACGGC CUAAAAAUCC CAUGCCAGGU GCCAGCGCCA 6720 GAGUUCUUCA CCGAGUUAGA CGGAGUGAGG CUCCACCGCU AUGCUCCUCC UUGUAAGCCC 6780 CUUCUGAGGG ACGAGAUCAC CUUCAGUGUA GGAUUGCAUU CAUAUGCAAA UGGGUCCCAG 6840 CUUUCAUGCG AACCCGAGCC GGACGUCGCA GUGUUAACCU CGAUGUUGCG AGAUCCUGCU 6900 CACAUCACCG CCGCCACAGC GGCCCGGCGC CUUGCGCGCG GUUCACCUCC AUCGGAAGCU 6960 AGCUCCUCUG CCAGCCAGCU CUCAGCUCCG UCACUGAAAG CCACUUGUCA AACGCACAGG 7020 CCGCAUCCUG ACGCUGAGCU GAUAGACGCU AACCUUCUAU GGAGGCAAGA GAUGGGUAGC 7080 AAUAUCACUC GGGUAGAGUC CGAGACGAAG GUGGUGAUCC UUGACUCUUU CGAGCCCCUG 7140 AGGGCCGAAG AAGACGACAC AGAGCUCUCG AUACCGGCAG AGUGCUUCAA GAAACCGCCC 7200 AAGUACCCAC CGGCCCUUCC UAUCUGGGCC AGACCGGACU ACAACCCUCC UUUGCUCCCU 7260 UCAUGGAAGG ACCCAACCUA CGAGCCGCCC GCAGUUCACG GGUGUGCCUU GCCACCAACU 7320 CGUCCCGCAC CAGUGCCUCC CCCCCGCAGA AAGAGGACAA UCAAGCUCGA UGGGUCGAAU 7380 GUGUCCGCGG CACUCCUUGC CCUGGCAGAG AGAUCUUUCC CGUCGACGAA ACCGGAAGGG 7440 ACAGGCACAU CCUCCUCAGG AGUAGGUAC A GAAUCCACCG CUGAGUCCGG UGACUCGCCC 7500 GAAACUGGCG AAGAAUCGGA CGUGGAGUCA UAUUCGUCCA UGCCGCCCCU UGAGGGGGAA 7560 CCGGGUGACC CGGACCUGGA UGCUGACUCU UGGUCCACCG UCAGUGACUC CGAAGAGCAG 7620 AGCGUGGUUU GCUGUUCUAU GUCAUACUCC UGGACUGGCG CCAUAAUAAC ACCAUGCAGC 7680 GCCGAGGAGG AAAAACUACC UAUCAGUCCA CUCAGCAACU CGUUGCUGAG ACACCACAAU 7740 CUUGUCUACU CUACGUCAUC UCGAAGCGCC GCCGCACGUC AGAAGAAGGU UACCUUCGAC 7800 AGACUGCAAG UGCUCGAUGA CCAUUACAAA AAUGUACUCA AGGAGGUGAA GGAGCGAGCA 7860 UCUGGGGUGA AGGGUCGCCU GCUCUCUUUC GAGGAAGCAU GCUCUCUUGU CCCCCCCCAC 7920 UCCGGCCGGU CGAAGUACGG GUAUAGUGCA AAGGAUGUUC GUUCCUUGUC CAGCAAAGCC 7980 AUGAACCAGA UCCGUUCCGU CUGGGAGGAC UUGUUGGAGG ACAAUAGUAC CCCAAUUCCC 8040 ACCACCAUUA UGGCGAAGAA CGAGGUGUUU AGCGUGAACC CCGCGAAGGG GGGCCGCAAA 8100 CCUGCCCGUC UCAUCGUCUA UCCUGAUCUG GGGGUGCGGG UCUGUGAGAA ACGCGCCCUA 8160 UAUGACGUGA UACAGAAGUU GUCAAUUGCA ACGAUGGGGC CUGCCUACGG GUUCCAAUAC 8220 UCGCCCAAAC AGCGAGUGGA GCAUCUUCUU AAGAUGUGGA CGUCGAAGAA GACCCCCUUA 8280 GGGUUUUCAU ACGACACUCG UUGCUUUGAC UCUA CUGUCA CCGAACAUGA CAUCAGGACG 8340 GAGGAGGGGA UAUACCAAUG UUGUGACCUU GAACCAGAGG CUCGGAAGGC AAUCAGCGCU 8400 CUCACAGAGC GACUGUACAU CGGGGGUCCC AUGUAUAACA GCAAAGGACU CCAAUGCGGU 8460 UAUCGCCGCU GCCGCGCUAG CGGCGUCUUG CCUACCAGCU UUGGCAACAC AAUAACCUGU 8520 UACAUCAAGG CCACCGCAGC CAGCAGAGCU GCGGGUCUCA AAAACCCGUC UUUCCUUGUC 8580 UGUGGAGACG AUUUGGUGGU GAUAUCUGAG AGUUGCGGUG UCGAGGAAGA CAGAACAGCC 8640 CUGCGAGCCU UCACGGAGGC CAUGACCAGA UAUUCUGCUC CCCCUGGAGA CGCCCCACAG 8700 CCCACCUACG ACUUGGAGCU GAUUUCAUCU UGCUCCUCAA ACGUCUCCGU GGCAUGCGAC 8760 GGAGCGGGUA AGAGGUACUA UUACCUCACC CGGGACCCAG AGACUCCCUU AGCCCGUGCG 8820 GCUUGGGAGA CUGCUCGCCA CACUCCAGUU AACUCCUGGU UGGGAAAUAU CAUCAUGUUC 8880 GCCCCUACCA UUUGGGUCCG CAUGGUGUUG AUAACCCACU UCUUUUCCAU ACUGCAAGCC 8940 CAGGAGCAGC UUGAAAGAGC CCUAGACUUU GAAAUGUACG GGGCUACCUA CUCAGUCACU 9000 CCACUGGACU UACCAGCUAU CAUUGAAAGA CUCCAUGGUU UGAGCGCGUU CUCGCUUCAC 9060 GGUUACUCUC CAACUGAGCU CAACAGAGUG GCGGGGGCUC UCAGAAAGCU UGGGAUCCCC 9120 CCCCUACGAG CGUGGAGACA UCGGGCACGA GCAGUACGCG CCAAACUCAU UGCCCAAGGA 9180 GGAAAGGCCA GAAUAUGCGG UCUAUACCUC UUUAACUGGG CAGUGCGCAC CAAAACCAAA 9240 CUCACUCCAU UGCCGACUGC GGGCCAGCUA GAUCUUUCUA GUUGGUUUAC GGUCGGUGUC 9300 GGCGGGAACG ACAUUUAUCA CAGCGUGUCG CGUGCCCGAA CCCGCCAUUU GCUGCUUUGC 9360 CUACUCCUAC UUACCGUAGG GGUAGGCAUU UUCCUCCUAC CUGCUCGGUG AGCUGGUAGG 9420 UUAACACCCC AACCCUGUGU UUUU 9444

SEQ ID NO: 2 Sequence length: 9444 Sequence type: Nucleic acid Number of strands: Single-strand topology: Linear Sequence type: cDNA to Genomic RNA Sequence: AAAAACACAG GGTTGGGGTG TTAACCTACC AGCTCACCGA GCAGGTAGGA GGAAAATGCC 60 TACCCCTACGGTAAAGTAGGA CAGCAAATGG CGGGTTCGGG CACGCGACAC 120 GCTGTGATAA ATGTCGTTCC CGCCGACACC GACCGTAAAC CAACTAGAAA GATCTAGCTG 180 GCCCGCAGTC GGCAATGGAG TGAGTTTGGT TTTGGTGCGC ACTGCCCAGT TAAAGAGGTA 240 TAGACCGCAT ATTCTGGCCT TTCCTCCTTG GGCAATGAGT TTGGCGCGTA CTGCTCGTGC 300 CCGATGTCTC CACGCTCGTA GGGGGGGGAT CCCAAGCTTT CTGAGAGCCC CCGCCACTCT 360 GTTGAGCTCA GTTGGAGAGT AACCGTGAAG CGAGAACGCG CTCAAACCAT GGAGTCTTTC 420 AATGATAGCT GGTAAGTCCA GTGGAGTGAC TGAGTAGGTA GCCCCGTACA TTTCAAAGTC 480 TAGGGCTCTT TCAAGCTGCT CCTGGGCTTG CAGTATGGAA AAGAAGTGGG TTATCAACAC 540 CATGCGGACC CAAATGGTAG GGGCGAACAT GATGATATTT CCCAACCAGG AGTTAACTGG 600 AGTGTGTGGCGA GCAGTCTCCC AAGCCGCACG GGCTAAGGGA GTCTCTGGGT CCCGGGTGAG 660 GTAATAGTAC CTCTTACCCG CTCCGTCGCA TGCCACGGAG ACGTTTGAGG AGCAAGATGA 720 AATCAGCTCC AAGTCGTAGG TGGGCTGTGG GGCGTCTCCA GGGGGAGCAG AATATCTGGT 780 CATGGCCTCC GTGAAGGCTC GCAGGGCTGT TCTGTCTTCC TCGACACCGC AACTCTCAGA 840 TATCACCACC AAATCGTCTC CACAGACAAG GAAAGACGGG TTTTTGAGAC CCGCAGCTCT 900 GCTGGCTGCG GTGGCCTTGA TGTAACAGGT TATTGTGTTG CCAAAGCTGG TAGGCAAGAC 960 GCCGCTAGCG CGGCAGCGGC GATAACCGCA TTGGAGTCCT TTGCTGTTAT ACATGGGACC 1020 CCCGATGTAC AGTCGCTCTG TGAGAGCGCT GATTGCCTTC CGAGCCTCTG GTTCAAGGTC 1080 ACAACATTGG TATATCCCCT CCTCCGTCCT GATGTCATGT TCGGTGACAG TAGAGTCAAA 1140 GCAACGAGTG TCGTATGAAA ACCCTAAGGG GGTCTTCTTC GACGTCCACA TCTTAAGAAG 1200 ATGCTCCACT CGCTGTTTGG GCGAGTATTG GAACCCGTAG GCAGGCCCCA TCGTTGCAAT 1260 TGACAACTTC TGTATCACGT CATATAGGGC GCGTTTCTCA CAGACCCGCA CCCCCAGATC 1320 AGGATAGACG ATGAGACGGG CAGGTTTGCG GCCCCCCTTC GCGGGGTTCA CGCTAAACAC 1380 CTCGTTCTTC GCCATAATGG TGGTGGGAAT TGGGGTACTA TTGTCCTCCA ACAAGTCCTC 1440 CCAGACGGAA CGGATCTGGT TCATGGCTTT GCTGGACAAG GAACGAACAT CCTTTGCACT 1500 ATACCCGTAC TTCGACCGGC CGGAGTGGGG GGGGACAAGA GAGCATGCTT CCTCGAAAGA 1560 GAGCAGGCGA CCCTTCACCC CAGATGCTCG CTCCTTCACC TCCTTGAGTA CATTTTTGTA 1620 ATGGTCATCG AGCACTTGCA GTCTGTCGAA GGTAACCTTC TTCTGACGTG CGGCGGCGCT 1680 TCGAGATGAC GTAGAGTAGA CAAGATTGTG GTGTCTCAGC AACGAGTTGC TGAGTGGACT 1740 GATAGGTAGT TTTTCCTCCT CGGCGCTGCA TGGTGTTATT ATGGCGCCAG TCCAGGAGTA 1800 TGACATAGAA CAGCAAACCA CGCTCTGCTC TTCGGAGTCA CTGACGGTGG ACCAAGAGTC 1860 AGCATCCAGG TCCGGGTCAC CCGGTTCCCC CTCAAGGGGC GGCATGGACG AATATGACTC 1920 CACGTCCGAT TCTTCGCCAG TTTCGGGCGA GTCACCGGAC TCAGCGGTGG ATTCTGTACC 1980 TACTCCTGAG GAGGATGTGC CTGTCCCTTC CGGTTTCGTC GACGGGAAAG ATCTCTCTGC 2040 CAGGGCAAGG AGTGCCGCGG ACACATTCGA CCCATCGAGC TTGATTGTCC TCTTTCTGCG 2100 GGGGGGAGGC ACTGGTGCGG GACGAGTTGG TGGCAAGGCA CACCCGTGAA CTGCGGGCGG 2160 CTCGTAGGTT GGGTCCTTCC ATGAAGGGAG CAAAGGAGGG TTGTAGTCCG GTCTGGCCCA 2220 GATAGGAAGG GCCGGTGGGT ACTTGGGCGG TTTCTTGAAG CACTCTGCCG GTATCGAGAG 2280 CTCTGTGTCG TCTTCTTCGG CCCTCAGGGG CTCGAAAGAG TCAAGGATCA CCACCTTCGT 2340 CTCGGACTCT ACCCGAGTGA TATTGC TACC CATCTCTTGC CTCCATAGAA GGTTAGCGTC 2400 TATCAGCTCA GCGTCAGGAT GCGGCCTGTG CGTTTGACAA GTGGCTTTCA GTGACGGAGC 2460 TGAGAGCTGG CTGGCAGAGG AGCTAGCTTC CGATGGAGGT GAACCGCGCG CAAGGCGCCG 2520 GGCCGCTGTG GCGGCGGTGA TGTGAGCAGG ATCTCGCAAC ATCGAGGTTA ACACTGCGAC 2580 GTCCGGCTCG GGTTCGCATG AAAGCTGGGA CCCATTTGCA TATGAATGCA ATCCTACACT 2640 GAAGGTGATC TCGTCCCTCA GAAGGGGCTT ACAAGGAGGA GCATAGCGGT GGAGCCTCAC 2700 TCCGTCTAAC TCGGTGAAGA ACTCTGGCGC TGGCACCTGG CATGGGATTT TTAGGCCGTC 2760 GTTCGTGGCC CCCACCACGT AATGAGTATC CCCCACCCTA CGCACCTCGA CATAACTGTC 2820 GGAGGTCACG CGCCACAGGG CACGCGAGTA ATTGTGCGCG GGGACGGGTG TACTCGGCCC 2880 AGTGGTGTAT TCATTGATGG GGAAGGTGCC ATGCCACATG TTAGCGCAGA GGCCTGATCC 2940 TGCTATCCTC ATGGACCCAT TCCTTACGTG TCCTGTAAAG TCTTCCCCAC AAGGGCAACG 3000 CGTTGTCATC ACCCCATCCC CTCGCCATAC TCCCTTGTAC CCCTTTTGAC ATGAGAGAAA 3060 GGGTATGCCT GGCACCTTGG GCATGATCTT GGCCGAAAGC CAGGTCTTAA AGTCACTAAG 3120 TACGATACAG ACCCAGTCCC AGATGTCATG TAACCAGTCA CCGTTGCAGG GACTAGGATA 3180 GTCCTCGTTG ATCCACTGGT GTAACCGGCG A AGCAATCGG GTGACGGTTA GAGAGCTCAG 3240 CAATGCTGTT ACTTTTGCTG CCGCGTCGCT CTCGGGGACA TAGTGTGTTG GTGATACATG 3300 GTTCCCCCGA GATGCGAACG CTATGAGTCT GTTCATCCAC TGCACTGCTC CTTCCCCAGG 3360 GCCTACATGC CGGCGCAACA CTGCAGCACA TATCACGCCA ACAACCAACG CTCCAGGGGA 3420 TAAGATGGCA GGCAGAAGAT TGACCATGTC CTCTGTGGTA GGGAGCTCTC CTCCCATGAT 3480 TTTGAAGGCC ACTAGGGCGC CGGAGACCCC AGCCCCATAC CCGGCAAGCA CGTCAAGCAA 3540 CACCCTGCCA ATGCCTATGC CTCCCACAGC GGCGCCAGCC AAGCCGCTTA CCACAAACGC 3600 GGAAGATGCT GCAGGTCCCG CTAGGTGTGT GGCTACCCAA CCTCCAAGGA TGTTAAAGAA 3660 CATAGTCTGG TTGGTTGTGA GGGGGCTGGT TACAGAGGCG GTGAAGGCCA TAAGGGAAGC 3720 CACGGCAGGG TTGCCTGGCA GTGTGGAGAG ACCGGCCAGG TACTGGATCC CGCTCACAAA 3780 GTTCCACATG TGCTGTTGCC AGAACGCCTC CGCTTTCTGC CATTGTGATT GCACTATGGG 3840 TCGAATTTCA GCTTCTTGTT GGCTCGCCCT TTGCAGCAAG CCGAGGACTT TGTCCTTGAA 3900 TTGCTGAGCG ATAGCCTGTG CTTGCTCGAT GTAAGGAGCA GACTGGGAAC ATTCTTCCAT 3960 CTCATCATAT TGTTGGTACA GTACTTGTCT GTCAGGGACG AGCGCAGGTT TGCCTCCTAG 4020 CTCGATATGC CCCACGATGA CGACACAACC TACTGAT AAA CAGTAGGCTG CGAGGGCTGC 4080 TAGAACACCA CCAACCAGCA CCCAGGCGCT CGTGGTGACT TCCAAGTCAG CTGACATGCA 4140 AGCCATGATG TACTTGGTAA TAGGGTGTGT CATGCAGATG TCATTTTGAA TTGCTCCTAA 4200 CCTATACAGG AGAGGAGTAG GGCCTTGCAG AGTCGGCTTC AGGCGTATGA GACATTTCCA 4260 CATCTCATCC CAACATGGTG GGCTCGCCTT TGCACGAGCG CAGACAGTGG CTTGATATGC 4320 CACCAAGTAT GCAAAGTTTA GGCCCTGCTG TTTTGCCTGT GACAAGAAGT GGGCATCTAT 4380 ATGAGTCAGT CCGGTAAACA CTCTCTCCCA GAAGTCTAGG TGGTCTTGGC AGACAGGTAG 4440 CCCCGGGGTG GACAGGTATG CTCTCAGTCG CACTGTGGTC TCAGCAGGTT GTAGGTCATA 4500 CCAGGAACAA CCTGCGTCAT AGCACTCACA TAGCACCACC GAGTCAAACA TGCCGGACGG 4560 CCGCTCCCCT GGAGTGACAA ACCGGTATAT TCCCGGTCTA CCCCGGCCCG TACGGCCCCT 4620 GCGTTGACTT CGGGACACCG CGTCCTGGGG AACCGTGCGT GTCTCAATGG AGAAAGTGGG 4680 GTCTAGACTG AAGTCGACGT ACTGCTCCAC AGCCACGTTA CAGTCTATAA CGGTGTCAAA 4740 ATCCCCTGTA TATCCGGTCA TGAGGGCATC AGTAGCACAT ACTACCACGT CTCCGGATAC 4800 AGGTATCACG GACACGTCGA GGCCTCTATA AAACGCTACA GCGTTGACCC CCATCCCTCT 4860 GAGCTTGCTG GCCAGCTCGT CACATTTTTC CTTTGAATGG CA GAATACAA GGTGTCTTCC 4920 TCCCTTGATC ATTGCCAGTG GGAGGGCTTT GCCATAAAAG GGGATTTCTC CGTCACTGGT 4980 GAGGCCCACC TCCTCGATAT TAGGATGCGG CACCGTGATG CTGCCGGGAG GGGTCGCGGT 5040 TGCCAGTACC GTCAGCCTCA CCCCGGCTGT CTCTGCTTGA TCCAGCACCG TGCCTATACC 5100 CAGTATGGAG GTAGCGTCTT GCGCGTGACA TTCATCGCAG ATGATCACGT CATAGGCGCC 5160 TCCAGAACAA CCCCCATCGG CGAGGAACTT GCCGTATGTG GAGTAGGTGA GTTTGGCACC 5220 GGTTGTGATG GTGCGTGTCC CCGTACGGAT GTTGGGGTCA ATCCCATAGG CTTTTGACAT 5280 GTACGTGCCA AAACCCAGGG TAGCCGCTAC CGATGGATTT AGCACTAGGA CAGAATATCC 5340 CTGTGCAACA TAAGCGGCGG GGACTTTGGT GCTTTTGCCG CTTCCAGTGG GGGCGTGAAG 5400 GTATCCTACT TGGTAGGACT CCGGGACGGC AGGGGGGGTG GAATTGTCAC TAAAAGATGG 5460 AGACCTGACC TGCGTACTCA GAGTTTCCAC TGGTATGAAC TGCAGGGCTT TTGCGACACC 5520 TCTGGTGCAC ACTGCCGCCC TGAAGATCCC CACCACGTGC CCCGAAGGGC ACATGACAGG 5580 ACCCCCAGAA GAACCTTTGA GGCAGGACAG TGGTCTGGTA CTGAGTAAAC TCGCCGTTGA 5640 GTCTCCCCTA CGGCGGGCGG GGAGGACGTC GGCCTCACGC GTCACCAGGT ACAGGTCGGA 5700 AGAACCGCAC GTGCAGGGGT CAAGGGACTT GGTCCCCGCA GGCGCTGG CC AACCTACCAG 5760 GTCCTGGTCC ACATTGGTGT ACATTTGAAG CGCGGGCCGT TTGTTACCAG CAAGAGTCCG 5820 CGACCCAGCA CCATGGTAAA CAGTCCACAT GACCCCCCCT ACTGTCGTAC CCAAGAAGGT 5880 CTGGGTGGCC GTGGACAGCA CCTGCACCTC ACCAGTCACC ACGTTCTTAT CCCTACCTGT 5940 CAGGCTGGTG ACAATAGTTC CAAATAGTCC CCGAGTTTGC TGGGCGTATG CTGAGATCGG 6000 GGACAGTAGG CGCCATCCCA TCTTCTTGTA ATCGTCAGCC GGACCCAGCA ACAACTCGCG 6060 GCCCAACCGC GCCGAAACGG GCAACCCGCA CAAGATGTCT CCGCAGGCTG CTGTGTCTGC 6120 ACCCCAGGTG ATAACCTTAA TCTCCATAGG ACTAAAGATG ACGGGCTCCG TGGCCACCGC 6180 CAGTCCTTTG AGACCCTCGG CAGCCCAGTC CTGTATGGGG GACAGGTGGT CATACAGATA 6240 GGTGTTAAAC CACCGGCCAA CCGTCAGCAC GGCCATTTGG ACGTACTTCC CTCCCATTGC 6300 AGAGCGCACC AACATGCAGA TACGAATCAA CACGTGGGCG CGGACAAAGT AGGGGGTGCT 6360 GGTGAGTGCG GCTTGTATTA AATACAGTGG CCCAAGGACG GCTATCAGCA GCTTTGTGAT 6420 GTCAAAGATT AGAGAGGGAT ACAGTAGGCT TGCTAGTAAA ATCACACTGT CCCGACTACC 6480 TCGAACAAGC AGGGGGGGGA CCCATACTTG CAAGGCGGCC TCACCCCTGC ATATGGCATA 6540 CTGGTTCCAC CAGATAAGAC GGCCAATCCA GTGCTTATAC CATGGTGATA AGG TAAAGAA 6600 CCCGAGGAGC AGGAGCACCC CGGCCCCGAT GGTGGCATCG TCTTCTCCCG TCCAAGCGTA 6660 AGCACGCTGA GGGAGCAGGA GGTCGAGCAG GGCTAGGGGC CACAGGCCTG TCAAACCATA 6720 GGTTATCAGC GGAACGAGCT TCCCCCGGAT GTGCCATGCG GCGCAGAATG CAACCAGGTA 6780 CCAGACGTAA CCCTGTTGTC CCGCTGCGCT GAGGGCGTTC AGCATCACCA AGTTCTCCAT 6840 TGCTGCTTCC GCCTGAGAAA TCAGTAACAT CATCCAGAGG GCCACACACA CGCGTGCGTC 6900 CGCCAGAACG AGGATCACCT CCTGCAGCTT GTCCCACTTG AGAGCCCAGC GGAGATGGGC 6960 AGTTCCTTGT GGTTTCTCCT ATTGCACGTC CACGATGTAG AGCACGAGGT CAATCTCGGG 7020 AGAACTGAGG CGGCGCATAG GTGTAATTCT CGTTGGCATA ATATCGCTCT GTCAGCTTGA 7080 ATGGAGCAGT GGTTGAACGA GACTGCCCTC TGCTAGATGT TCTACACAGC GCTCTCCCCT 7140 CGAGGACAAG CAGGGCGCAC TCTTACCTAC TTCATGTCCT CCTACGAACA AAGTGTGCTT 7200 GATAATTCTC TTCAAGAGAG TGCAAGGATA ATGCCACACA CCCATCGGGT TCTCTAGGTC 7260 TGTGCTTGGC GTAAGCCAGG GCCCGGTGCC CGTGCGGGAT AACGACCGTA GTTGGTGCTT 7320 CCTGAAACAA TCGGATGCCG TTTTAACCTG CCTTACTTTT GCAACATACA GGAAGTAGCC 7380 CCCATAGATG TTGCAAGGCC GACGGCCACA TCTCAAATGT TTGCCTGTAC TGTTCATCC A 7440 CACACAAGCA AAGCACCGCG CTACCCCCCG AGAGTTAGAG GTCAACAAGA AGACATCTGA 7500 GTCGTTGTCA GGTTTGGATA TTCTTGGCAG GCCTTTAATA TCAGTGGTCC CCACGTCCTG 7560 GCCACTCCCA CTAAAGCAGT AGACGGGCCC ACAGACTTTC AAGCGCAACC AATACAATGA 7620 GGGTCTGGGT GGATAGTGCC AGCATTATGG AGTGAGGAGT GACCCTGCAT TTATGTTAGC 7680 ATCTGTCAAT GGCCCCCAGG CCACTAACTT TAAACAGATG GGCTTACAGC TGGACATTCG 7740 GTCAGGCGAC GGGCTCCTCA TCTTTTTGTG ATAGTAGAAG AGGCCCGCAA TAAACGCACA 7800 CAAATCCCAT TCGTTGCAAT TCAAGGCAGT GCTGTTTATG TGGGATCTGG GTAAACACTT 7860 GACCAATTGC AAATTCTGAC TTGGTCCTCG CCTGTTTTTT GAACATTACC CGGCAGTGGC 7920 TTGGGCCGCG CTCCCACCTC TGCACACACA ACTCGCGTCC ACTCCTGAAA ACATGATTAG 7980 GACGATCTCG TGGAACCGGG ATAAGCCTTG CATGGAAAAG TAGGCGAGCC CTGCGTTCTG 8040 CGGGGTCAGC CGCCCCACGA CCAGGTCAAA GAACGTATGG GGGTACGCGT AGTTCTCAGA 8100 TATCACTAGC CCGATTGCGG GGGAGCAGTT GTTCTAGTAT AGGGTTGCCA TACGATGTCC 8160 TGAGACATGA CCAGGGTAAT TTCTCGTCAA CGTGGTCTGC ACAGTCTTGT GTTGGCGAGG 8220 ACTAAACCTG TTGCGAACAG GGTGAAGGGA CACGGCCCCG AAGGCGTCAT CGACCAATTC 8280 ACGACTCGTG TCCGTTGGCG GGGCCACCAA CATATTGACA TGTATTGCCT AGCTGCGCCA 8340 GGTCACACCA GGGTGCTTGA CGGCGACCGT GCGTCTTTAG CCACAGCTGC ACGATGTGTT 8400 GTTGTTGTCG GTAACGACCG TCCCGTGCGT AGGCCCATTC ACGTTCTACA CGTCGTCGGC 8460 CTCATACACA ATGCTCCTGT TGGAGCAGTC GTTGGTAAGC ATTATATGGC CAGACGCATT 8520 CCTGTACTCC AGACTGGACG CGGGGCAAGT CAAGCAGGAG AAGAGAGCGA GGAGGAAGAT 8580 AGAGAAGGAG CAACCAGGAA GATTCCCTGT TGCGTAGTTC ACTCCGTCCT CAAGTGCTCT 8640 CACACCATGA GCGAGGGCTC TTGCGACGCC CCCTACAGGG GCGCCGATGA GCGGAATGTA 8700 CCCCATGAGG TCGGCAAATC CGCACGTTAG GGTATCGATG ACCTTACCCA AGTTGCGGGA 8760 TCTACGCCGG GGGTCATTTT GGCCCCAGCT GGGGCGAGAA CCGCGGGGGG GCAAGAGCCA 8820 TCCTGCCCAA CCACAGCCCT CATTCCCGTA GAGGGGCCAA GGGTACCCGG GCTGGGCCCA 8880 GGACCGGCCC TCGCGCGGGC GTGCCTTGGG GGTAGGCTGA CGCCGTCCGC GAGGTTGTGA 8940 TCGCTCGGAA GTCTTACGTA CTTCGCGCAC ACCCAATTGT GGGCCCCTAC GCGGCAGGAC 9000 ATATACTTCA CCAACGATCT GCCCGCCAGC CGGGAACTTA ACGTTCTTTG GGCGGCGGAG 9060 TGTGTTTCTT TTTGTTTGTC TTTTAGGTTT AGGAAGTGTG CTCATGTTGC ACGGTCTACG 9120 AGACC TCCCG GGGCACTCGC AAGCACCCTA TCAGGCAGTA CCACAAGGCC TTTCGCGACC 9180 CAACACTACT CGGCTAGTGA TCTCGCGGGG GCACGCCCAA ATTTCCGGGC ATTGAGCGGG 9240 TTGTTCCAAG AAAGGACCCG GTCATCCCGG CGATTCCGGT GTACTCACCG GTTCCGCAGA 9300 CCACTATGGC TCTCCCGGAA GGGGGGGGCC TGGAGGCTGC ACGACACTCG TACTAACGCC 9360 ATGGCTAGAC GCTTTCCGCG TGAAGACAGA AGTTCCTCAC AGGGGAGTGA TTCATGGTGG 9420 AGTGTCGCCT CGAAAGAGGC AGGT 9444

SEQ ID NO: 3 Sequence length: 9444 Sequence type: Nucleic acid Number of strands: Single strand Topology: Linear Sequence type: Other nucleic acid (cDNA homologous to Genomic RNA) Sequence: ACCTGCCTCT TTCGAGGCGA CACTCCACCA TGAATCACTC CCCTGTGAGG AACTTCTGTC 60 TTCACGCGGA AAGCGTCTAG CCATGGCGTT AGTACGAGTG TCGTGCAGCC TCCAGGCCCC 120 CCCCTTCCGG GAGAGCCATA GTGGTCTGCG GAACCGGTGA GTACACCGGA ATCGCCGGGA 180 TGACCGGGTC CTTTCTTGGA ACAACCCGCT CAATGCCCGG AAATTTGGGC GTGCCCCCGC 240 GAGATCACTA GCCGAGTAGT GTTGGGTCGC GAAAGGCCTT GTGGTACTGC CTGATAGGGT 300 GCTTGCGAGT GCCCCGGGAG GTCTCGTAGA CCGTGCAACA TGAGCACACT TCCTAAACCT 360 AAAAGACAAA CAAAAAGAAA CACACTCCGC CGCCCAAAGA ACGTTAAGTT CCCGGCTGGC 420 GGGCAGATCG TTGGTGAAGT ATATGTCCTG CCGCGTAGGG GCCCACAATT GGGTGTGCGC 480 GAAGTACGTA AGACTTCCGA GCGATCACAA CCTCGCGGAC GGCGTCAGCC TACCCCCAAG 540 GCACGCCCGC GCGAGGGCCG GTCCTGGGCC CAGCCCGGGT ACCCTTGGCC CCTCTACGGG 600 AATGAGGGCT GTGGTTGGGC AGGATGCCTCCCTTCC AGCTGG 660 GGCCAAAATG ACCCCCGGCG TAGATCCCGC AACTTGGGTA AGGTCATCGA TACCCTAACG 720 TGCGGATTTG CCGACCTCAT GGGGTACATT CCGCTCATCG GCGCCCCTGT AGGGGGCGTC 780 GCAAGAGCCC TCGCTCATGG TGTGAGAGCA CTTGAGGACG GAGTGAACTA CGCAACAGGG 840 AATCTTCCTG GTTGCTCCTT CTCTATCTTC CTCCTCGCTC TCTTCTCCTG CTTGACTTGC 900 CCCGCGTCCA GTCTGGAGTA CAGGAATGCG TCTGGCCTAT ATTTGCTTAC CAACGACTGC 960 TCCAACAGGA GCATTGTGTA TGAGGCCGAC GACGTGATCT TGCACTTACC CGGATGCGTG 1020 CCCTGCGTCG AAACCGACAA CAACAACACA TCGTGCTGGA CACCGATTTC ACCGACGGTG 1080 GCCGTCAAGC ACCCTGGTGT GACCACCGCG TCGATCCGAA ATCATGTGAA TATGTTGGTG 1140 GCCCCGCCAA CGCTGTGCTC AGCACTATAC GTCGAAGACG CCTTCGGGGC CGTGTCCCTT 1200 GTGGGACAAG CGTTCACCTT TAGACCTCGC CAACACAAGA CTGTGCAGAC GTGCAACTGC 1260 TCAATATACC CAGGTCATGT CTCAGGACAT CGTATGGCTT GGGATATGAT GATGAACTGG 1320 TCCCCCGCAA TCGGGCTAGT GATATCACAC TTGATGCGGT TGCCCCAAAC GTTCTTTGAC 1380 CTGGTCGTGG GGGCCCACTG GGGCGTGATG GCAGGCCTCG CCTACTTTTC CATGCAAGGC 1440 AATTGGGCCA AGGTCGTCAT CGTGCTAATC ATGTTTTCAG GAGTGGACGC GACAACACAC 1500 ACCACTGGTG GCAGCGCGGC CCAAGCCACT GCCGGGTTTA CAAGTTTTTT CACCCGAGGT 1560 CCAAGTCAGA ATTTGCAATT GGTCAACTCA AATGGGTCAT GGCACATTAA CAGCACTGCC 1620 TTGAATTGCA ACGATTCCCT AAACACTGGC TTTATAGCGG GCCTCTTCTA CTATCACAAA 1680 TTCAACTCCT CGGGGTGCCC TGAGCGAATG TCCAGCTGTA AGCCCATCAC ATATTTCAAT 1740 CAGGGGTGGG GCCCATTGAC AGATGCTAAC ATAAATGGTC CCAGTGAGGA CAGACCATAT 1800 TGCTGGCACT ATCCACCCAG ACCCTGTAAC ATAACCAAGC CGTTGAATGT CTGTGGGCCC 1860 GTCTACTGCT TTACACCCTC ACCGGTGGTG GTGGGCACCA CTGATATTAA AGGCCTGCCA 1920 ACTTATAGGT TTGGTGTGAA CGAGTCAGAT GTCTTCTTGT TGACCTCTTT GAGACCCCCC 1980 CAAGGCCGGT GGTTTGGATG TGTGTGGATG AACAGTACAG GGTTTGTAAA GACTTGTGGG 2040 GCTCCCCCTT GCAACATCTA TGGGGGGATG AAGGACATTG AAGCAAATCA AACCCACCTT 2100 AAATGCCCTA CCGATTGTTT CAGGAAGCAC CATGATGCCA CGTTTACCCG CTGCGGGTCC 2160 GGGCCCTGGC TTACGCCAAG GTGTCTGGTA GACTACCCGT ACCGACTGTG GCATTATCCT 2220 TGCACTGTGA ACTTCTCTAT ATTCAAGGTC AGAATGTTCG TAGGAGGACA TGAACATCGA 2280 TTCTCAGCCG CCTGCAACTG GACGAGGGGA GAGCGCTGTG ATCTTGAAGA TCGTGACCGC 2340 AGTGAG CAAC AACCACTGCT CCATTCAACG ACTGACTCGC TAATATTGCC ATGCTCATTT 2400 ACACCTATGC GCCGCCTGTC AACAGGGCTC ATACACCTCC ACCAGAACAT CGTGGACGTG 2460 CAATACCTCT ATGGTGTTGG TTCTGCCGTA GTGGGCTGGG CTCTCAAGTG GGAGTTCGTC 2520 GTCCTCGTCT TCCTCCTTCT GGCGGACGCA CGCGTGTGTG TGGCCCTCTG GATGATGTTA 2580 CTGATTTCTC AGGCGGAAGC AGCAATGGAG AACTTGGTGA TGCTGAACGC CCTCAGCGCA 2640 GCGGGACAAC AGGGTTACGT CTGGTACCTG GTTGCATTCT GCGCCGCATG GCACATCCGG 2700 GGGAAGCTCG TTCCGCTGAT AACCTATGGT TTGACAGGCC TGTGGCCCCT AGCCCTGCTC 2760 GACCTCCTGC TCCCTCAGCG TGCTTACGCT TGGACGGGAG AAGACGATGC CACCATCGGG 2820 GCCGGGGTGC TCCTGCTCCT CGGGTTCTTT ACCTTATCAC CATGGTATAA GCACTGGATT 2880 GGCCGTCTTA TCTGGTGGAA CCAGTATGCC ATATGCAGGG GTGAGGCCGC CTTGCAAGTA 2940 TGGGTCCCCC CCCTGCTTGT TCGAGGTAGT CGGGACAGTG TGATTTTACT AGCAAGCCTA 3000 CTGTATCCCT CTCTAATCTT TGACATCACA AAGCTGCTGA TAGCCGTCCT TGGGCCACTG 3060 TATTTAATAC AAGCCGCACT CACCAGCACC CCCTACTTTG TCCGCGCCCA CGTGTTGATT 3120 CGTATCTGCA TGTTGGTGCG CTCTGCAATG GGAGGGAAGT ACGTCCAAAT GGCCGTGCTG 3180 ACGGTTGGCC G GTGGTTTAA CACCTATCTG TATGACCACC TGTCCCCCAT ACAGGACTGG 3240 GCTGCCGAGG GTCTCAAAGG ACTGGCGGTG GCCACGGAGC CCGTCATCTT TAGTCCTATG 3300 GAGATTAAGG TTATCACCTG GGGTGCAGAC ACAGCAGCCT GCGGAGACAT CTTGTGCGGG 3360 TTGCCCGTTT CGGCGCGGTT GGGCCGCGAG TTGTTGCTGG GTCCGGCTGA CGATTACAAG 3420 AAGATGGGAT GGCGCCTACT GTCCCCGATC TCAGCATACG CCCAGCAAAC TCGGGGACTA 3480 TTTGGAACTA TTGTCACCAG CCTGACAGGT AGGGATAAGA ACGTGGTGAC TGGTGAGGTG 3540 CAGGTGCTGT CCACGGCCAC CCAGACCTTC TTGGGTACGA CAGTAGGGGG GGTCATGTGG 3600 ACTGTTTACC ATGGTGCTGG GTCGCGGACT CTTGCTGGTA ACAAACGGCC CGCGCTTCAA 3660 ATGTACACCA ATGTGGACCA GGACCTGGTA GGTTGGCCAG CGCCTGCGGG GACCAAGTCC 3720 CTTGACCCCT GCACGTGCGG TTCTTCCGAC CTGTACCTGG TGACGCGTGA GGCCGACGTC 3780 CTCCCCGCCC GCCGTAGGGG AGACTCAACG GCGAGTTTAC TCAGTACCAG ACCACTGTCC 3840 TGCCTCAAAG GTTCTTCTGG GGGTCCTGTC ATGTGCCCTT CGGGGCACGT GGTGGGGATC 3900 TTCAGGGCGG CAGTGTGCAC CAGAGGTGTC GCAAAAGCCC TGCAGTTCAT ACCAGTGGAA 3960 ACTCTGAGTA CGCAGGTCAG GTCTCCATCT TTTAGTGACA ATTCCACCCC CCCTGCCGTC 4020 CCGGAGTCCT ACCAAGT AGG ATACCTTCAC GCCCCCACTG GAAGCGGCAA AAGCACCAAA 4080 GTCCCCGCCG CTTATGTTGC ACAGGGATAT TCTGTCCTAG TGCTAAATCC ATCGGTAGCG 4140 GCTACCCTGG GTTTTGGCAC GTACATGTCA AAAGCCTATG GGATTGACCC CAACATCCGT 4200 ACGGGGACAC GCACCATCAC AACCGGTGCC AAACTCACCT ACTCCACATA CGGCAAGTTC 4260 CTCGCCGATG GGGGTTGTTC TGGAGGCGCC TATGACGTGA TCATCTGCGA TGAATGTCAC 4320 GCGCAAGACG CTACCTCCAT ACTGGGTATA GGCACGGTGC TGGATCAAGC AGAGACAGCC 4380 GGGGTGAGGC TGACGGTACT GGCAACCGCG ACCCCTCCCG GCAGCATCAC GGTGCCGCAT 4440 CCTAATATCG AGGAGGTGGG CCTCACCAGT GACGGAGAAA TCCCCTTTTA TGGCAAAGCC 4500 CTCCCACTGG CAATGATCAA GGGAGGAAGA CACCTTGTAT TCTGCCATTC AAAGGAAAAA 4560 TGTGACGAGC TGGCCAGCAA GCTCAGAGGG ATGGGGGTCA ACGCTGTAGC GTTTTATAGA 4620 GGCCTCGACG TGTCCGTGAT ACCTGTATCC GGAGACGTGG TAGTATGTGC TACTGATGCC 4680 CTCATGACCG GATATACAGG GGATTTTGAC ACCGTTATAG ACTGTAACGT GGCTGTGGAG 4740 CAGTACGTCG ACTTCAGTCT AGACCCCACT TTCTCCATTG AGACACGCAC GGTTCCCCAG 4800 GACGCGGTGT CCCGAAGTCA ACGCAGGGGC CGTACGGGCC GGGGTAGACC GGGAATATAC 4860 CGGTTTGTCA CTCCAGGGGA GC GGCCGTCC GGCATGTTTG ACTCGGTGGT GCTATGTGAG 4920 TGCTATGACG CAGGTTGTTC CTGGTATGAC CTACAACCTG CTGAGACCAC AGTGCGACTG 4980 AGAGCATACC TGTCCACCCC GGGGCTACCT GTCTGCCAAG ACCACCTAGA CTTCTGGGAG 5040 AGAGTGTTTA CCGGACTGAC TCATATAGAT GCCCACTTCT TGTCACAGGC AAAACAGCAG 5100 GGCCTAAACT TTGCATACTT GGTGGCATAT CAAGCCACTG TCTGCGCTCG TGCAAAGGCG 5160 AGCCCACCAT GTTGGGATGA GATGTGGAAA TGTCTCATAC GCCTGAAGCC GACTCTGCAA 5220 GGCCCTACTC CTCTCCTGTA TAGGTTAGGA GCAATTCAAA ATGACATCTG CATGACACAC 5280 CCTATTACCA AGTACATCAT GGCTTGCATG TCAGCTGACT TGGAAGTCAC CACGAGCGCC 5340 TGGGTGCTGG TTGGTGGTGT TCTAGCAGCC CTCGCAGCCT ACTGTTTATC AGTAGGTTGT 5400 GTCGTCATCG TGGGGCATAT CGAGCTAGGA GGCAAACCTG CGCTCGTCCC TGACAGACAA 5460 GTACTGTACC AACAATATGA TGAGATGGAA GAATGTTCCC AGTCTGCTCC TTACATCGAG 5520 CAAGCACAGG CTATCGCTCA GCAATTCAAG GACAAAGTCC TCGGCTTGCT GCAAAGGGCG 5580 AGCCAACAAG AAGCTGAAAT TCGACCCATA GTGCAATCAC AATGGCAGAA AGCGGAGGCG 5640 TTCTGGCAAC AGCACATGTG GAACTTTGTG AGCGGGATCC AGTACCTGGC CGGTCTCTCC 5700 ACACTGCCAG GCAACCCTGC CGTGGCTT CC CTTATGGCCT TCACCGCCTC TGTAACCAGC 5760 CCCCTCACAA CCAACCAGAC TATGTTCTTT AACATCCTTG GAGGTTGGGT AGCCACACAC 5820 CTAGCGGGAC CTGCAGCATC TTCCGCGTTT GTGGTAAGCG GCTTGGCTGG CGCCGCTGTG 5880 GGAGGCATAG GCATTGGCAG GGTGTTGCTT GACGTGCTTG CCGGGTATGG GGCTGGGGTC 5940 TCCGGCGCCC TAGTGGCCTT CAAAATCATG GGAGGAGAGC TCCCTACCAC AGAGGACATG 6000 GTCAATCTTC TGCCTGCCAT CTTATCCCCT GGAGCGTTGG TTGTTGGCGT GATATGTGCT 6060 GCAGTGTTGC GCCGGCATGT AGGCCCTGGG GAAGGAGCAG TGCAGTGGAT GAACAGACTC 6120 ATAGCGTTCG CATCTCGGGG GAACCATGTA TCACCAACAC ACTATGTCCC CGAGAGCGAC 6180 GCGGCAGCAA AAGTAACAGC ATTGCTGAGC TCTCTAACCG TCACCCGATT GCTTCGCCGG 6240 TTACACCAGT GGATCAACGA GGACTATCCT AGTCCCTGCA ACGGTGACTG GTTACATGAC 6300 ATCTGGGACT GGGTCTGTAT CGTACTTAGT GACTTTAAGA CCTGGCTTTC GGCCAAGATC 6360 ATGCCCAAGG TGCCAGGCAT ACCCTTTCTC TCATGTCAAA AGGGGTACAA GGGAGTATGG 6420 CGAGGGGATG GGGTGATGAC AACGCGTTGC CCTTGTGGGG AAGACTTTAC AGGACACGTA 6480 AGGAATGGGT CCATGAGGAT AGCAGGATCA GGCCTCTGCG CTAACATGTG GCATGGCACC 6540 TTCCCCATCA ATGAATACAC CACTGGGCCG AGT ACACCCG TCCCCGCGCA CAATTACTCG 6600 CGTGCCCTGT GGCGCGTGAC CTCCGACAGT TATGTCGAGG TGCGTAGGGT GGGGGATACT 6660 CATTACGTGG TGGGGGCCAC GAACGACGGC CTAAAAATCC CATGCCAGGT GCCAGCGCCA 6720 GAGTTCTTCA CCGAGTTAGA CGGAGTGAGG CTCCACCGCT ATGCTCCTCC TTGTAAGCCC 6780 CTTCTGAGGG ACGAGATCAC CTTCAGTGTA GGATTGCATT CATATGCAAA TGGGTCCCAG 6840 CTTTCATGCG AACCCGAGCC GGACGTCGCA GTGTTAACCT CGATGTTGCG AGATCCTGCT 6900 CACATCACCG CCGCCACAGC GGCCCGGCGC CTTGCGCGCG GTTCACCTCC ATCGGAAGCT 6960 AGCTCCTCTG CCAGCCAGCT CTCAGCTCCG TCACTGAAAG CCACTTGTCA AACGCACAGG 7020 CCGCATCCTG ACGCTGAGCT GATAGACGCT AACCTTCTAT GGAGGCAAGA GATGGGTAGC 7080 AATATCACTC GGGTAGAGTC CGAGACGAAG GTGGTGATCC TTGACTCTTT CGAGCCCCTG 7140 AGGGCCGAAG AAGACGACAC AGAGCTCTCG ATACCGGCAG AGTGCTTCAA GAAACCGCCC 7200 AAGTACCCAC CGGCCCTTCC TATCTGGGCC AGACCGGACT ACAACCCTCC TTTGCTCCCT 7260 TCATGGAAGG ACCCAACCTA CGAGCCGCCC GCAGTTCACG GGTGTGCCTT GCCACCAACT 7320 CGTCCCGCAC CAGTGCCTCC CCCCCGCAGA AAGAGGACAA TCAAGCTCGA TGGGTCGAAT 7380 GTGTCCGCGG CACTCCTTGC CCTGGCAGAG AGATCTTTC C CGTCGACGAA ACCGGAAGGG 7440 ACAGGCACAT CCTCCTCAGG AGTAGGTACA GAATCCACCG CTGAGTCCGG TGACTCGCCC 7500 GAAACTGGCG AAGAATCGGA CGTGGAGTCA TATTCGTCCA TGCCGCCCCT TGAGGGGGAA 7560 CCGGGTGACC CGGACCTGGA TGCTGACTCT TGGTCCACCG TCAGTGACTC CGAAGAGCAG 7620 AGCGTGGTTT GCTGTTCTAT GTCATACTCC TGGACTGGCG CCATAATAAC ACCATGCAGC 7680 GCCGAGGAGG AAAAACTACC TATCAGTCCA CTCAGCAACT CGTTGCTGAG ACACCACAAT 7740 CTTGTCTACT CTACGTCATC TCGAAGCGCC GCCGCACGTC AGAAGAAGGT TACCTTCGAC 7800 AGACTGCAAG TGCTCGATGA CCATTACAAA AATGTACTCA AGGAGGTGAA GGAGCGAGCA 7860 TCTGGGGTGA AGGGTCGCCT GCTCTCTTTC GAGGAAGCAT GCTCTCTTGT CCCCCCCCAC 7920 TCCGGCCGGT CGAAGTACGG GTATAGTGCA AAGGATGTTC GTTCCTTGTC CAGCAAAGCC 7980 ATGAACCAGA TCCGTTCCGT CTGGGAGGAC TTGTTGGAGG ACAATAGTAC CCCAATTCCC 8040 ACCACCATTA TGGCGAAGAA CGAGGTGTTT AGCGTGAACC CCGCGAAGGG GGGCCGCAAA 8100 CCTGCCCGTC TCATCGTCTA TCCTGATCTG GGGGTGCGGG TCTGTGAGAA ACGCGCCCTA 8160 TATGACGTGA TACAGAAGTT GTCAATTGCA ACGATGGGGC CTGCCTACGG GTTCCAATAC 8220 TCGCCCAAAC AGCGAGTGGA GCATCTTCTT AAGATGTGGA CGTC GAAGAA GACCCCCTTA 8280 GGGTTTTCAT ACGACACTCG TTGCTTTGAC TCTACTGTCA CCGAACATGA CATCAGGACG 8340 GAGGAGGGGA TATACCAATG TTGTGACCTT GAACCAGAGG CTCGGAAGGC AATCAGCGCT 8400 CTCACAGAGC GACTGTACAT CGGGGGTCCC ATGTATAACA GCAAAGGACT CCAATGCGGT 8460 TATCGCCGCT GCCGCGCTAG CGGCGTCTTG CCTACCAGCT TTGGCAACAC AATAACCTGT 8520 TACATCAAGG CCACCGCAGC CAGCAGAGCT GCGGGTCTCA AAAACCCGTC TTTCCTTGTC 8580 TGTGGAGACG ATTTGGTGGT GATATCTGAG AGTTGCGGTG TCGAGGAAGA CAGAACAGCC 8640 CTGCGAGCCT TCACGGAGGC CATGACCAGA TATTCTGCTC CCCCTGGAGA CGCCCCACAG 8700 CCCACCTACG ACTTGGAGCT GATTTCATCT TGCTCCTCAA ACGTCTCCGT GGCATGCGAC 8760 GGAGCGGGTA AGAGGTACTA TTACCTCACC CGGGACCCAG AGACTCCCTT AGCCCGTGCG 8820 GCTTGGGAGA CTGCTCGCCA CACTCCAGTT AACTCCTGGT TGGGAAATAT CATCATGTTC 8880 GCCCCTACCA TTTGGGTCCG CATGGTGTTG ATAACCCACT TCTTTTCCAT ACTGCAAGCC 8940 CAGGAGCAGC TTGAAAGAGC CCTAGACTTT GAAATGTACG GGGCTACCTA CTCAGTCACT 9000 CCACTGGACT TACCAGCTAT CATTGAAAGA CTCCATGGTT TGAGCGCGTT CTCGCTTCAC 9060 GGTTACTCTC CAACTGAGCT CAACAGAGTG GCGGGGGCTC TCAGAAAGCT TGGGATCCCC 9120 CCCCTACGAG CGTGGAGACA TCGGGCACGA GCAGTACGCG CCAAACTCAT TGCCCAAGGA 9180 GGAAAGGCCA GAATATGCGG TCTATACCTC TTTAACTGGG CAGTGCGCAC CAAAACCAAA 9240 CTCACTCCAT TGCCGACTGC GGGCCAGCTA GATCTTTCTA GTTGGTTTAC GGTCGGTGTC 9300 GGCGGGAACG ACATTTATCA CAGCGTGTCG CGTGCCCGAA CCCGCCATTT GCTGCTTTGC 9360 CTACTCCTAC TTACCGTAGG GGTAGGCATT TTCCTCCTAC CTGCTCGGTG AGCTGGTAGG 9420 TTAACACCCC AACCCTGTGT TTTT 9444

SEQ ID NO: 4 Sequence length: 3023 Sequence type: Amino acid Number of chains: Single chain Topology: Linear Sequence type: Protein Sequence: Met Ser Thr Leu Pro Lys Pro Lys Arg Gln Thr Lys Arg Asn Thr Leu 5 10 15 Arg Arg Pro Lys Asn Val Lys Phe Pro Ala Gly Gly Gln Ile Val Gly 20 25 30 Glu Val Tyr Val Leu Pro Arg Arg Gly Pro Gln Leu Gly Val Arg Glu 35 40 45 Val Arg Lys Thr Ser Glu Arg Ser Gln Pro Arg Gly Arg Arg Gln Pro 50 55 60 Thr Pro Lys Ala Arg Pro Arg Glu Gly Arg Ser Trp Ala Gln Pro Gly 65 70 75 80 Tyr Pro Trp Pro Leu Tyr Gly Asn Glu Gly Cys Gly Trp Ala Gly Trp 85 90 95 Leu Leu Pro Pro Arg Gly Ser Arg Pro Ser Trp Gly Gln Asn Asp Pro 100 105 110 1Arg Arg Arg Ser Arg Asn Leu Gly Lys Val Ile Asp Thr Leu Thr Cys 115 120 125 Gly Phe Ala Asp Leu Met Gly Tyr Ile Pro Leu Ile Gly Ala Pro Val 130 135 140 Gly Gly Val Ala Arg Ala Leu Ala His Gly Val Arg Ala Leu Glu Asp 145 150 155 160 Gly Val Asn Tyr Ala Thr Gly Asn Leu Pro Gly Cys Ser Phe Ser I le 165 170 175 Phe Leu Leu Ala Leu Phe Ser Cys Leu Thr Cys Pro Ala Ser Ser Leu 180 185 190 Glu Tyr Arg Asn Ala Ser Gly Leu Tyr Leu Leu Thr Asn Asp Cys Ser 195 200 205 Asn Arg Ser Ile Val Tyr Glu Ala Asp Asp Val Ile Leu His Leu Pro 210 215 220 Gly Cys Val Pro Cys Val Glu Thr Asp Asn Asn Asn Thr Ser Cys Trp 225 230 235 240 Thr Pro Ile Ser Pro Thr Val Ala Val Lys His Pro Gly Val Thr Thr 245 250 255 Ala Ser Ile Arg Asn His Val Asn Met Leu Val Ala Pro Pro Thr Leu 260 265 270 Cys Ser Ala Leu Tyr Val Glu Asp Ala Phe Gly Ala Val Ser Leu Val 275 280 285 Gly Gln Ala Phe Thr Phe Arg Pro Arg Gln His Lys Thr Val Gln Thr 290 295 300 Cys Asn Cys Ser Ile Tyr Pro Gly His Val Ser Gly His Arg Met Ala 305 310 315 320 Trp Asp Met Met Met Asn Trp Ser Pro Ala Ile Gly Leu Val Ile Ser 325 330 335 His Leu Met Arg Leu Pro Gln Thr Phe Phe Asp Leu Val Val Gly Ala 340 345 350 His Trp Gly Val Met Ala Gly Leu Ala Tyr Phe Ser Met Gln Gly Asn 355 360 365 Trp Ala Lys Val Val Ile Val Leu Ile Met Phe Ser Gly Val Asp Ala370 375 380 Thr Thr His Thr Thr Gly Gly Ser Ala Ala Gln Ala Thr Ala Gly Phe 385 390 395 400 Thr Ser Phe Phe Thr Arg Gly Pro Ser Gln Asn Leu Gln Leu Val Asn 405 410 415 Ser Asn Gly Ser Trp His Ile Asn Ser Thr Ala Leu Asn Cys Asn Asp 420 425 430 Ser Leu Asn Thr Gly Phe Ile Ala Gly Leu Phe Tyr Tyr His Lys Phe 435 440 445 Asn Ser Ser Gly Cys Pro Glu Arg Met Ser Ser Cys Lys Pro Ile Thr 450 455 460 Tyr Phe Asn Gln Gly Trp Gly Pro Leu Thr Asp Ala Asn Ile Asn Gly 465 470 475 480 Pro Ser Glu Asp Arg Pro Tyr Cys Trp His Tyr Pro Pro Arg Pro Cys 485 490 495 Asn Ile Thr Lys Pro Leu Asn Val Cys Gly Pro Val Tyr Cys Phe Thr 500 505 510 Pro Ser Pro Val Val Val Gly Thr Thr Asp Ile Lys Gly Leu Pro Thr 515 520 525 Tyr Arg Phe Gly Val Asn Glu Ser Asp Val Phe Leu Leu Thr Ser Leu 530 535 540 Arg Pro Pro Gln Gly Arg Trp Phe Gly Cys Val Trp Met Asn Ser Thr 545 550 555 560 Gly Phe Val Lys Thr Cys Gly Ala Pro Pro Cys Asn Ile Tyr Gly Gly 565 570 575 Met Lys Asp Ile Glu Ala Asn Gln Thr His Leu Lys Cys Pro Thr Asp580 585 590 Cys Phe Arg Lys His His Asp Ala Thr Phe Thr Arg Cys Gly Ser Gly 595 600 605 Pro Trp Leu Thr Pro Arg Cys Leu Val Asp Tyr Pro Tyr Arg Leu Trp 610 615 620 His Tyr Pro Cys Thr Val Asn Phe Ser Ile Phe Lys Val Arg Met Phe 625 630 635 640 Val Gly Gly His Glu His Arg Phe Ser Ala Ala Cys Asn Trp Thr Arg 645 650 655 Gly Glu Arg Cys Asp Leu Glu Asp Arg Asp Arg Ser Glu Gln Gln Pro 660 665 670 Leu Leu His Ser Thr Thr Asp Ser Leu Ile Leu Pro Cys Ser Phe Thr 675 680 685 Pro Met Arg Arg Leu Ser Thr Gly Leu Ile His Leu His Gln Asn Ile 690 695 700 Val Asp Val Gln Tyr Leu Tyr Gly Val Gly Ser Ala Val Val Gly Trp 705 710 715 720 Ala Leu Lys Trp Glu Phe Val Val Leu Val Phe Leu Leu Leu Ala Asp 725 730 735 Ala Arg Val Cys Val Ala Leu Trp Met Met Leu Leu Ile Ser Gln Ala 740 745 750 Glu Ala Ala Met Glu Asn Leu Val Met Leu Asn Ala Leu Ser Ala Ala 755 760 765 Gly Gln Gln Gly Tyr Val Trp Tyr Leu Val Ala Phe Cys Ala Ala Trp 770 775 780 His Ile Arg Gly Lys Leu Val Pro Leu Ile Thr Tyr Gly Leu Thr Gly 785 790 795 800 Leu Trp Pro Leu Ala Leu Leu Asp Leu Leu Leu Pro Gln Arg Ala Tyr 805 810 815 Ala Trp Thr Gly Glu Asp Asp Ala Thr Ile Gly Ala Gly Val Leu Leu 820 825 830 Leu Leu Gly Phe Phe Thr Leu Ser Pro Trp Tyr Lys His Trp Ile Gly 835 840 845 Arg Leu Ile Trp Trp Asn Gln Tyr Ala Ile Cys Arg Gly Glu Ala Ala 850 855 860 Leu Gln Val Trp Val Pro Pro Leu Leu Val Arg Gly Ser Arg Asp Ser 865 870 875 880 Val Ile Leu Leu Ala Ser Leu Leu Tyr Pro Ser Leu Ile Phe Asp Ile 885 890 895 Thr Lys Leu Leu Ile Ala Val Leu Gly Pro Leu Tyr Leu Ile Gln Ala 900 905 910 Ala Leu Thr Ser Thr Pro Tyr Phe Val Arg Ala His Val Leu Ile Arg 915 920 925 Ile Cys Met Leu Val Arg Ser Ala Met Gly Gly Lys Tyr Val Gln Met 930 935 940 Ala Val Leu Thr Val Gly Arg Trp Phe Asn Thr Tyr Leu Tyr Asp His 945 950 955 960 Leu Ser Pro Ile Gln Asp Trp Ala Ala Glu Gly Leu Lys Gly Leu Ala 965 970 975 Val Ala Thr Glu Pro Val Ile Phe Ser Pro Met Glu Ile Lys Val Ile 980 985 990 Thr Trp Gly Ala Asp Thr Ala Ala Cys Gly Asp Ile Leu Cys Gly Leu 995 1000 1005 Pro Val Ser Ala Arg Leu Gly Arg Glu Leu Leu Leu Gly Pro Ala Asp 1010 1015 1020 Asp Tyr Lys Lys Met Gly Trp Arg Leu Leu Ser Pro Ile Ser Ala Tyr 1025 1030 1035 1040 Ala Gln Gln Thr Arg Gly Leu Phe Gly Thr Ile Val Thr Ser Leu Thr 1045 1050 1055 Gly Arg Asp Lys Asn Val Val Thr Gly Glu Val Gln Val Leu Ser Thr 1060 1065 1070 Ala Thr Gln Thr Phe Leu Gly Thr Thr Val Gly Gly Val Met Trp Thr 1075 1080 1085 Val Tyr His Gly Ala Gly Ser Arg Thr Leu Ala Gly Asn Lys Arg Pro 1090 1095 1100 Ala Leu Gln Met Tyr Thr Asn Val Asp Gln Asp Leu Val Gly Trp Pro 1105 1110 1115 1120 Ala Pro Ala Gly Thr Lys Ser Leu Asp Pro Cys Thr Cys Gly Ser Ser 1125 1130 1135 Asp Leu Tyr Leu Val Thr Arg Glu Ala Asp Val Leu Pro Ala Arg Arg 1140 1145 1150 Arg Gly Asp Ser Thr Ala Ser Leu Leu Ser Thr Arg Pro Leu Ser Cys 1155 1160 1165 Leu Lys Gly Ser Ser Gly Gly Pro Val Met Cys Pro Ser Gly His Val 1170 1175 1180 Val Gly Ile Phe Arg Ala Ala Val Cys Thr Arg Gly Val Ala Lys Ala 1185 1190 1195 1200 Leu Gln Phe Ile Pro Val G lu Thr Leu Ser Thr Gln Val Arg Ser Pro 1205 1210 1215 Ser Phe Ser Asp Asn Ser Thr Pro Pro Ala Val Pro Glu Ser Tyr Gln 1220 1225 1230 Val Gly Tyr Leu His Ala Pro Thr Gly Ser Gly Lys Ser Thr Lys Val 1235 1240 1245 Pro Ala Ala Tla Val Ala Gln Gly Tyr Ser Val Leu Val Leu Asn Pro 1250 1255 1260 Ser Val Ala Ala Thr Leu Gly Phe Gly Thr Tyr Met Ser Lys Ala Tyr 1265 1270 1275 1280 Gly Ile Asp Pro Asn Ile Arg Thr Gly Thr Arg Thr Ile Thr Thr Gly 1285 1290 1295 Ala Lys Leu Thr Tyr Ser Thr Tyr Gly Lys Phe Leu Ala Asp Gly Gly 1300 1305 1310 Cys Ser Gly Gly Ala Tyr Asp Val Ile Ile Cys Asp Glu Cys His Ala 1315 1320 1325 Gln Asp Ala Thr Ser Ile Leu Gly Ile Gly Thr Val Leu Asp Gln Ala 1330 1335 1340 Glu Thr Ala Gly Val Arg Leu Thr Val Leu Ala Thr Ala Thr Pro Pro 1345 1350 1355 1360 Gly Ser Ile Thr Val Pro His Pro Asn Ile Glu Glu Val Gly Leu Thr 1365 1370 1375 Ser Asp Gly Glu Ile Pro Phe Tyr Gly Lys Ala Leu Pro Leu Ala Met 1380 1385 1390 Ile Lys Gly Gly Arg His Leu Val Phe Cys His Ser Lys Glu Lys Cys 139 5 1400 1405 Asp Glu Leu Ala Ser Lys Leu Arg Gly Met Gly Val Asn Ala Val Ala 1410 1415 1420 Phe Tyr Arg Gly Leu Asp Val Ser Val Ile Pro Val Ser Gly Asp Val 1425 1430 1435 1440 Val Val Cys Ala Thr Asp Ala Leu Met Thr Gly Tyr Thr Gly Asp Phe 1445 1450 1455 Asp Thr Val Ile Asp Cys Asn Val Ala Val Glu Gln Tyr Val Asp Phe 1460 1465 1470 Ser Leu Asp Pro Thr Phe Ser Ile Glu Thr Arg Thr Val Pro Gln Asp 1475 1480 1485 Ala Val Ser Arg Ser Gln Arg Arg Gly Arg Thr Gly Arg Gly Arg Pro 1490 1495 1500 1505 1510 1515 1520 Asp Ser Val Val Leu Cys Glu Cys Tyr Asp Ala Gly Cys Ser Trp Tyr 1525 1530 1535 Asp Leu Gln Pro Ala Glu Thr Thr Val Arg Leu Arg Ala Tyr Leu Ser 1540 1545 1550 Thr Pro Gly Leu Pro Val Cys Gln Asp His Leu Asp Phe Trp Glu Arg 1555 1560 1565 Val Phe Thr Gly Leu Thr His Ile Asp Ala His Phe Leu Ser Gln Ala 1570 1575 1580 Lys Gln Gln Gly Leu Asn Phe Ala Tyr Leu Val Ala Tyr Gln Ala Thr 1585 1590 1595 1600 Val Cys Ala Arg Ala Lys Ala Ser Pro Pro Cys Trp Asp Glu Met Trp 1605 1610 1615 Lys Cys L eu Ile Arg Leu Lys Pro Thr Leu Gln Gly Pro Thr Pro Leu 1620 1625 1630 Leu Tyr Arg Leu Gly Ala Ile Gln Asn Asp Ile Cys Met Thr His Pro 1635 1640 1645 Ile Thr Lys Tyr Ile Met Ala Cys Met Ser Ala Asp Leu Glu Val Thr 1650 1655 1660 Thr Ser Ala Trp Val Leu Val Gly Gly Val Leu Ala Ala Leu Ala Ala 1665 1670 1675 1680 Tyr Cys Leu Ser Val Gly Cys Val Val Ile Val Gly His Ile Glu Leu 1685 1690 1695 Gly Gly Lys Pro Ala Leu Val Pro Asp Arg Gln Val Leu Tyr Gln Gln 1700 1705 1710 Tyr Asp Glu Met Glu Glu Cys Ser Gln Ser Ala Pro Tyr Ile Glu Gln 1715 1720 1725 Ala Gln Ala Ile Ala Gln Gln Phe Lys Asp Lys Val Leu Gly Leu Leu 1730 1735 1740 Gln Arg Ala Ser Gln Gln Glu Ala Glu Ile Arg Pro Ile Val Gln Ser 1745 1750 1755 1760 Gln Trp Gln Lys Ala Glu Ala Phe Trp Gln Gln His Met Trp Asn Phe 1765 1770 1775 Val Ser Gly Ile Gln Tyr Leu Ala Gly Leu Ser Thr Leu Pro Gly Asn 1780 1785 1790 Pro Ala Val Ala Ser Leu Met Ala Phe Thr Ala Ser Val Thr Ser Pro 1795 1800 1805 Leu Thr Thr Asn Gln Thr Met Phe Phe Asn Ile Leu Gly Gly Trp Val 1810 1815 1820 Ala Thr His Leu Ala Gly Pro Ala Ala Ser Ser Ala Phe Val Val Ser 1825 1830 1835 1840 Gly Leu Ala Gly Ala Ala Val Gly Gly Ile Gly Ile Gly Arg Val Leu 1845 1850 1855 Leu Asp Val Leu Ala Gly Tyr Gly Ala Gly Val Ser Gly Ala Leu Val 1860 1865 1870 Ala Phe Lys Ile Met Gly Gly Glu Leu Pro Thr Thr Glu Asp Met Val 1875 1880 1885 Asn Leu Leu Pro Ala Ile Leu Ser Pro Gly Ala Leu Val Val Gly Val 1890 1895 1900 Ile Cys Ala Ala Val Leu Arg Arg His Val Gly Pro Gly Glu Gly Ala 1905 1910 1915 1920 Val Gln Trp Met Asn Arg Leu Ile Ala Phe Ala Ser Arg Gly Asn His 1925 1930 1935 Val Ser Pro Thr His Tyr Val Pro Glu Ser Asp Ala Ala Ala Lys Val 1940 1945 1950 Thr Ala Leu Leu Ser Ser Leu Thr Val Thr Arg Leu Leu Arg Arg Leu 1955 1960 1965 His Gln Trp Ile Asn Glu Asp Tyr Pro Ser Pro Cys Asn Gly Asp Trp 1970 1975 1980 Leu His Asp Ile Trp Asp Trp Val Cys Ile Val Leu Ser Asp Phe Lys 1985 1990 1995 2000 Thr Trp Leu Ser Ala Lys Ile Met Pro Lys Val Pro Gly Ile Pro Phe 2005 2010 2015 Leu Ser C ys Gln Lys Gly Tyr Lys Gly Val Trp Arg Gly Asp Gly Val 2020 2025 2030 Met Thr Thr Arg Cys Pro Cys Gly Glu Asp Phe Thr Gly His Val Arg 2035 2040 2045 Asn Gly Ser Met Arg Ile Ala Gly Ser Gly Leu Cys Ala Asn Met Trp 2050 2055 2060 His Gly Thr Phe Pro Ile Asn Glu Tyr Thr Thr Gly Pro Ser Thr Pro 2065 2070 2075 2080 Val Pro Ala His Asn Tyr Ser Arg Ala Leu Trp Arg Val Thr Ser Asp 2085 2090 2095 Ser Tyr Val Glu Val Arg Arg Val Gly Asp Thr His Tyr Val Val Gly 2100 2105 2110 Ala Thr Asn Asp Gly Leu Lys Ile Pro Cys Gln Val Pro Ala Pro Glu 2115 2120 2125 Phe Phe Thr Glu Leu Asp Gly Val Arg Leu His Arg Tyr Ala Pro Pro 2130 2135 2140 Cys Lys Pro Leu Leu Arg Asp Glu Ile Thr Phe Ser Val Gly Leu His 2145 2150 2155 2160 Ser Tyr Ala Asn Gly Ser Gln Leu Ser Cys Glu Pro Glu Pro Asp Val 2165 2170 2175 Ala Val Leu Thr Ser Met Leu Arg Asp Pro Ala His Ile Thr Ala Ala 2180 2185 2190 Thr Ala Ala Arg Arg Leu Ala Arg Gly Ser Pro Pro Ser Glu Ala Ser 2195 2200 2205 Ser Ser Ala Ser Gln Leu Ser Ala Pro Ser Leu Lys Ala Thr Cys Gln 2210 2215 2220 Thr His Arg Pro His Pro Asp Ala Glu Leu Ile Asp Ala Asn Leu Leu 2225 2230 2235 2240 Trp Arg Gln Glu Met Gly Ser Asn Ile Thr Arg Val Glu Ser Glu Thr 2245 2250 2255 Lys Val Val Ile Leu Asp Ser Phe Glu Pro Leu Arg Ala Glu Glu Asp 2260 2265 2270 Asp Thr Glu Leu Ser Ile Pro Ala Glu Cys Phe Lys Lys Pro Pro Lys 2275 2280 2285 Tyr Pro Pro Ala Leu Pro Ile Trp Ala Arg Pro Asp Tyr Asn Pro Pro 2290 2295 2300 Leu Leu Pro Ser Trp Lys Asp Pro Thr Tyr Glu Pro Pro Ala Val His 2305 2310 2315 2320 Gly Cys Ala Leu Pro Pro Thr Arg Pro Ala Pro Val Pro Pro Pro Arg 2325 2330 2335 Arg Lys Arg Thr Ile Lys Leu Asp Gly Ser Asn Val Ser Ala Ala Leu 2340 2345 2350 Leu Ala Leu Ala Glu Arg Ser Phe Pro Ser Thr Lys Pro Glu Gly Thr 2355 2360 2365 Gly Thr Ser Ser Ser Gly Val Gly Thr Glu Ser Thr Ala Glu Ser Gly 2370 2375 2380 Asp Ser Pro Glu Thr Gly Glu Glu Ser Asp Val Glu Ser Tyr Ser Ser 2385 2390 2395 2400 Met Pro Pro Leu Glu Gly Glu Pro Gly Asp Pro Asp Leu Asp Ala Asp 2405 2410 2415 Ser Trp S er Thr Val Ser Asp Ser Glu Glu Gln Ser Val Val Cys Cys 2420 2425 2430 2435 2440 2445 Glu Glu Glu Lys Leu Pro Ile Ser Pro Leu Ser Asn Ser Leu Leu Arg 2450 2455 2460 His His Asn Leu Val Tyr Ser Thr Ser Ser Arg Ser Ala Ala Ala Arg 2465 2470 2475 2480 Gln Lys Lys Val Thr Phe Asp Arg Leu Gln Val Leu Asp Asp His Tyr 2485 2490 2495 Lys Asn Val Leu Lys Glu Val Lys Glu Arg Ala Ser Gly Val Lys Gly 2500 2505 2510 Arg Leu Leu Ser Phe Glu Glu Ala Cys Ser Leu Val Pro Pro His Ser 2515 2520 2525 Gly Arg Ser Lys Tyr Gly Tyr Ser Ala Lys Asp Val Arg Ser Leu Ser 2530 2535 2540 Ser Lys Ala Met Asn Gln Ile Arg Ser Val Trp Glu Asp Leu Leu Glu 2545 2550 2555 2560 Asp Asn Ser Thr Pro Ile Pro Thr Thr Ile Met Ala Lys Asn Glu Val 2565 2570 2575 Phe Ser Val Asn Pro Ala Lys Gly Gly Arg Lys Pro Ala Arg Leu Ile 2580 2585 2590 Val Tyr Pro Asp Leu Gly Val Arg Val Cys Glu Lys Arg Ala Leu Tyr 2595 2600 2605 Asp Val Ile Gln Lys Leu Ser Ile Ala Thr Met Gly Pro Ala Tyr Gly 2610 2615 2620 Phe Gln Tyr Ser Pro Lys Gln Arg Val Glu His Leu Leu Lys Met Trp 2625 2630 2635 2640 Thr Ser Lys Lys Thr Pro Leu Gly Phe Ser Tyr Asp Thr Arg Cys Phe 2645 2650 2655 Asp Ser Thr Val Thr Glu His Asp Ile Arg Thr Glu Glu Gly Ile Tyr 2660 2665 2670 Gln Cys Cys Asp Leu Glu Pro Glu Ala Arg Lys Ala Ile Ser Ala Leu 2675 2680 2685 Thr Glu Arg Leu Tyr Ile Gly Gly Pro Met Tyr Asn Ser Lys Gly Leu 2690 2695 2700 Gln Cys Gly Tyr Arg Arg Cys Arg Ala Ser Gly Val Leu Pro Thr Ser 2705 2710 2715 2720 Phe Gly Asn Thr Ile Thr Cys Tyr Ile Lys Ala Thr Ala Ala Ser Arg 2725 2730 2735 Ala Ala Gly Leu Lys Asn Pro Ser Phe Leu Val Cys Gly Asp Asp Leu 2740 2745 2750 Val Val Ile Ser Glu Ser Cys Gly Val Glu Glu Asp Arg Thr Ala Leu 2755 2760 2765 Arg Ala Phe Thr Glu Ala Met Thr Arg Tyr Ser Ala Pro Pro Gly Asp 2770 2775 2780 Ala Pro Gln Pro Thr Tyr Asp Leu Glu Leu Ile Ser Ser Cys Ser Ser 2785 2790 2795 2800 Asn Val Ser Val Ala Cys Asp Gly Ala Gly Lys Arg Tyr Tyr Tyr Leu 2805 2810 2815 Thr Arg Asp Pro Glu Thr Pro Leu Ala Arg Ala Ala Trp Glu Thr Ala 2820 282 5 2830 Arg His Thr Pro Val Asn Ser Trp Leu Gly Asn Ile Ile Met Phe Ala 2835 2840 2845 Pro Thr Ile Trp Val Arg Met Val Leu Ile Thr His Phe Phe Ser Ile 2850 2855 2860 Leu Gln Ala Gln Glu Gln Leu Glu Arg Ala Leu Asp Phe Glu Met Tyr 2865 2870 2875 2880 Gly Ala Thr Tyr Ser Val Thr Pro Leu Asp Leu Pro Ala Ile Ile Glu 2885 2890 2895 Arg Leu His Gly Leu Ser Ala Phe Ser Leu His Gly Tyr Ser Pro Thr 2900 2905 2910 Glu Leu Asn Arg Val Ala Gly Ala Leu Arg Lys Leu Gly Ile Pro Pro 2915 2920 2925 Leu Arg Ala Trp Arg His Arg Ala Arg Ala Val Arg Ala Lys Leu Ile 2930 2935 2940 Ala Gln Gly Gly Lys Ala Arg Ile Cys Gly Leu Tyr Leu Phe Asn Trp 2945 2950 2955 2960 Ala Val Arg Thr Lys Thr Lys Leu Thr Pro Leu Pro Thr Ala Gly Gln 2965 2970 2975 Leu Asp Leu Ser Ser Trp Phe Thr Val Gly Val Gly Gly Asn Asp Ile 2980 2985 2990 Tyr His Ser Val Ser Arg Ala Arg Thr Arg His Leu Leu Leu Cys Leu 2995 3000 3005 Leu Leu Leu Leu Thr Val Gly Val Gly Ile Phe Leu Leu Pro Ala Arg 3023 3010 3015 3020

SEQ ID NO: 5 Sequence length: 26 Sequence type: Nucleic acid Number of strands: Single strand Topology: Linear Sequence type: Other nucleic acid (synthetic DNA) Sequence: CAGTCACTGA GAGCGACATC CGTACG 26

SEQ ID NO: 6 Sequence length: 28 Sequence type: Nucleic acid Number of strands: Single strand Topology: Linear Sequence type: Other nucleic acid (synthetic DNA) Sequence: AGGCCACTGC GGCCTGTCGA GCTGCGAA 28

SEQ ID NO: 7 Sequence length: 23 Sequence type: Nucleic acid Number of strands: Single strand Topology: Linear Sequence type: Other nucleic acid (synthetic DNA) Sequence: TATGTTCAAC AGCAAGGGCC AGA 23

SEQ ID NO: 8 Sequence length: 26 Sequence type: Nucleic acid Number of strands: Single strand Topology: Linear Sequence type: Other nucleic acid (synthetic DNA) Sequence: GGCTTGTTCC CTGCCTCAAG AGGCCA 26

SEQ ID NO: 9 Sequence length: 20 Sequence type: Nucleic acid Number of strands: Single strand Topology: Linear Sequence type: Other nucleic acid (synthetic DNA) Sequence: CTCCGGAACC CTGACTTTCT 20

SEQ ID NO: 10 Sequence length: 20 Sequence type: Nucleic acid Number of strands: Single strand Topology: Linear Sequence type: Other nucleic acid (synthetic DNA) Sequence: CCGCGCTAGC GGCGTCTTGC 20

SEQ ID NO: 11 Sequence length: 21 Sequence type: Nucleic acid Number of strands: Single strand Topology: Linear Sequence type: Other nucleic acid (synthetic DNA) Sequence: CCTGGTCATA GCCTCCGTGA A 21

[Brief description of drawings]

FIG. 1 is a diagram showing the results of Western blotting.

FIG. 2 is a schematic diagram of a result of performing agarose gel electrophoresis.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location C12P 21/02 C 9282-4B C12Q 1/68 A 9453-4B G01N 33/576 Z // (C12N 1/21 C12R 1:91) (C12P 21/02 C12R 1:91)

Claims (15)

[Claims] 1. A hepatitis C virus genomic RNA having the base sequence represented by SEQ ID NO: 1. 2. The DNA complementary to the hepatitis C virus genomic RNA according to claim 1, which has the nucleotide sequence represented by SEQ ID NO: 2. 3. The DNA homologous to the hepatitis C virus genomic RNA according to claim 1, which has the nucleotide sequence represented by SEQ ID NO: 3. 4. A hepatitis C virus protein consisting of a polypeptide containing the amino acid sequence represented by SEQ ID NO: 4. 5. A hepatitis C virus DNA containing a DNA encoding the amino acid sequence represented by SEQ ID NO: 4. 6. A recombinant DNA having the DNA according to claim 2 or 5 incorporated therein. 7. A transformant transformed with the recombinant DNA according to claim 6. 8. The method for producing a protein according to claim 4, which comprises culturing the transformant according to claim 7 and separating the protein according to claim 4 from the obtained culture. 9. The DN according to claim 2, wherein at least one of the primers represented by the nucleotide sequences of SEQ ID NOs: 5 to 11 is used.
3. The method for detecting DNA according to claim 2, wherein A is amplified, and the amplified DNA fragment obtained is subjected to electrophoresis and then stained to detect the DNA. 10. A method for detecting hepatitis C virus, which comprises performing an antigen-antibody reaction using at least a part of the protein according to claim 4 as an antigen, and detecting the hepatitis C virus from the resulting antigen-antibody complex. . 11. A method for classifying hepatitis C virus, which comprises classifying hepatitis C virus into its subtypes using the DNA according to claim 2. 12. A method for classifying hepatitis C virus, which comprises classifying hepatitis C virus into its subtypes using the protein according to claim 4. 13. The classification method according to claim 11, wherein the subtype is Tr type. 14. A hepatitis C diagnostic agent comprising at least a part of the protein according to claim 4 as an active ingredient. 15. A hepatitis C vaccine containing at least a part of the protein according to claim 4 as an active ingredient.