CN115074369B

CN115074369B - Adeno-associated virus vector expressing full-length ABCA4 gene and application thereof

Info

Publication number: CN115074369B
Application number: CN202210721461.2A
Authority: CN
Inventors: 杨阳; 魏于全; 王青楠
Original assignee: Chengdu Jinweike Biological Technology Co ltd
Current assignee: Chengdu Jinweike Biological Technology Co ltd
Priority date: 2022-06-24
Filing date: 2022-06-24
Publication date: 2023-10-20
Anticipated expiration: 2042-06-24
Also published as: CN115074369A

Abstract

The invention discloses an adeno-associated virus vector expressing a full-length ABCA4 gene and application thereof. The gene fragment of ABCA4 encodes any fragment obtained by breaking the full-length protein of ABCA4 by taking p1150Cys as a cleavage site. A recombinant adeno-associated virus is prepared from carrier containing coding gene of human ABCA4-N or ABCA4-C protein fragment containing intein fragment, rep and Cap protein expression plasmid of AAV, and helper plasmid cotransfection HEK293 cell. The recombinant adeno-associated virus can be used for efficiently transducing retina photoreceptor cells in an STGDI disease model, and can efficiently express full-length ABCA4 protein, thereby realizing the aim of disease treatment.

Description

Adeno-associated virus vector expressing full-length ABCA4 gene and application thereof

Technical Field

The invention belongs to the field of biological medicine, and relates to an adeno-associated virus vector expressing a full-length ABCA4 gene and application thereof.

Background

STARGARDT disease (STGDI), known as yellow spot disease of the fundus, is the most common macular dystrophy disease in adolescents, and can result in severe, irreversible bilateral vision impairment with a prevalence of about 1/10000 to 1/8000. The clinical characteristics of the eye drop are that the eye drop is caused in teenagers (10-20 years old), progressive binocular central vision is accompanied by different degrees of macular area and peripheral retinal pigment epithelium layer (retinal pigment epithelium, RPE) and nerve epithelium layer atrophy, the most large area lipofuscin is deposited in the macular area after fundus examination, the eye drop is typical 'gold foil-like' reflection, early stage can only be represented as 'siltation-like' or yellow white spots limited to the fovea and parachloroea, late stage lipofuscin is distributed in the RPE layer, fluorescein fundus angiography (fluorescein fundus angiography, FFA) is in the form of 'choroidal inundation sign', and coherent light tomography (OCT) shows that the retinal choroid is thin and becomes thin with high reflection particles deposited. The genetic mode of STGDI is autosomal recessive inheritance, and the only pathogenic gene is ABCA4 (ATP-Binding Cassette, subfamilies A, membrane 4) gene, which is located on chromosome 1p22.1, consists of 50 exons, has the total length of about 8kb, encodes 2235 amino acids and is called Rim transmembrane protein, and the protein belongs to subfamily of ATP-Binding Cassette transport superfamily genes, is mainly located on outer sections of photoreceptors and is a transport protein necessary for visual cycle. It has been found that pathogenic mutations of over 900 ABCA4 genes (The Human Gene Mutation Database, HGDM; http:// www.hgmd.cf.ac.uk/ac/index. Php), in addition to STGDI, can also lead to autosomal recessive cone cell dystrophy and retinitis pigmentosa. In STGDI patients, ABCA4 gene mutation can hinder transportation and recycling of retinoids, causing retinoids to accumulate and accumulate, ultimately leading to the formation of toxic retinoid dimers (N-retinyl-N-view Huang Chunan, A2E), thereby denaturing retinal pigment epithelium and photoreceptor cells, and losing vision in patients.

For the treatment of the normal gene dysfunction disease, the most direct method is to introduce the normal gene into the body of a patient by using a vector to realize the treatment effect. In recent years, clinical researches on gene therapy are continuously emerging, and important breakthroughs are made in the fields of some genetic diseases and malignant tumors, so that new hopes are brought for patients with diseases which are invalid, easy to relapse or difficult to treat in the traditional therapies. In 2008, kong et al packaged the full-length ABCA4 coding sequence into a equine infectious anemia virus (Equine infectious anaemia virus, EIAV) -engineered lentiviral vector and delivered to post-natal day 5 ABCA4 knockout mice by subretinal injection [1]. ABCA4 protein expression lasted more than 12 months, reducing accumulation of A2E. In 2011, the company Oxford Biomedica in the united kingdom developed a phase I/II clinical test (NCT 01367444) of EIAV-based lentiviral vector gene therapy, which terminated in 2019 and had an unsatisfactory therapeutic effect. Although lentiviruses have strong gene packaging capacity, their size and viral structure limit the transduction capacity of lentiviral vectors in the retina. Due to the lack of clinical efficacy data, the industry is currently seldom encouraged to continue STGDI gene therapy using lentiviral vectors. In the field of gene therapy, adeno-associated viral vectors (Adeno associated virus, AAV) have been widely used in clinical trials for therapeutic transgene delivery and retinal disease, showing good safety and fewer adverse events. Luxturna (voretigene neparvovec) of Spark Therapeutics was the first AAV gene therapy approved by the FDA in 2017 for the treatment of hereditary retinopathy caused by the RPE65 gene mutation. However, the ABCA4 gene coding sequence is approximately 6.8kb, which is difficult to deliver using AAV vectors because of the optimal packaging capacity of AAV, which is approximately 4.7kb. In early STGDI gene therapy studies, allocca et al attempted to construct a single "oversized" AAV comprising the complete 6.8kb ABCA4 coding sequence. Studies have found that "oversized" AAV is indeed capable of producing the full-length ABCA4 protein in vivo and in vitro [2]. However, the clinical application of this approach is difficult due to the inability to reliably produce homogeneous AAV formulations containing defined transgenes. In 2014, trapani et al developed dual AAV vector gene therapy strategies based on trans-splicing, overlapping (hybrid), and the like for delivering large gene segments [3]. In the Trapani et al study, it was found that the "overlay" double AAV vector strategy was not effective in expressing full-length genes of interest in photoreceptor cells. Thus, in subsequent studies, researchers have focused on trans-splicing (trans-splicing) and hybrid dual AAV vector delivery technologies. In 2019, dyka et al found that 18% of eyes expressed full-length ABCA4 protein after injection of trans-splicing (trans-splicing) double AAV vectors in ABCA4 knockout mice; whereas 50% of the eyes expressed full length ABCA4 protein after injection of the hybrid double AAV vector. Furthermore, eyes of trans-shear (trans-splicing) and hybrid (hybrid) double AAV vector treated groups showed a significant reduction in lipofuscin particles compared to untreated eyes [4]. Due to the various restriction steps required for efficient transduction of dual AAV vectors, including: proper DNA concatemer formation, stability of heterogeneous mRNA, and splicing efficiency across vector junctions, transgene expression efficiency achieved using dual AAV vectors in photoreceptors is far lower than that achieved using a single AAV vector [5].

The Split inteins (Split inteins) are a genetic element found in unicellular organisms such as archaea, cyanobacteria, etc., which are expressed as two separate polypeptides at the end of the host protein and catalyze their trans-splicing to form a larger protein, which is not catalyzed to produce carryover in the final protein product [6,7]. The split inteins are widely used for protein purification, protein labeling steps, recombination of CRISPR/Cas9 gene editing nucleases, and the like. In 2019, tornabene et al found that the split intein successfully spliced two green fluorescent protein fragments into a complete green fluorescent protein, and the splicing efficiency was high, without significant difference in protein level from the single AAV vector expression. These experimental results demonstrate that multiple AAV vector-delivered polypeptide fragments can be successfully spliced into a complete and functional protein by cleavage of the intein splicing action [5].

Since AAV-mediated gene therapy has now become an approved treatment for hereditary retinal degeneration, the ability to increase AAV transgene size would greatly widen the range of therapeutic indications. STGDI is inherited by autosomal recessive inheritance, the only causative gene is the ABCA4 gene, the coding sequence is about 6.8kb, and the optimal packaging capacity of single AAV is exceeded (< 4.7 kb). The most critical of the split intein double AAV vector strategy is the intein sequence and cleavage site, as this will greatly affect the cleavage efficiency of the protein of interest, as well as the tertiary structure and post-translational modification of the protein of interest, and thus the protein function. In addition, double AAV vectors express the N-and C-termini of ABCA4 proteins, respectively, due to split intein. Therefore, the N-terminal and C-terminal byproducts that are not efficiently spliced have potential safety risks.

Disclosure of Invention

The object of the present invention is to address the above-mentioned deficiencies of the prior art and to provide an ABCA4-N or ABCA4-C terminal protein expression cassette.

It is a second object of the present invention to provide vectors and vector systems comprising said expression cassette.

It is a third object of the present invention to provide recombinant adeno-associated viruses expressing ABCA4 protein and compositions thereof.

The fourth object of the invention is to provide the application of the protein expression frame, the vector and the recombinant adeno-associated virus.

The aim of the invention can be achieved by the following technical scheme:

the gene fragment of ABCA4 encodes any fragment obtained by breaking the full-length protein of ABCA4 by taking p1150Cys as a cleavage site.

As a preferred aspect of the present invention, one end of the ABCA4 gene fragment contains an intein fragment; the inteins were selected from Synechocystis sp.strain PCC6803 DnaB (Ssp intein, SEQ ID NO. 2), rhodothermus marinus DnaB (Rma intein, SEQ ID NO. 3), nostoc punctiforme PCC73102 DnaE (Npu intein, SEQ ID NO. 4) and Consensu DnaE (Cfa intein, SEQ ID NO. 5).

The intein is selected from Rma intein shown in SEQ ID NO.3 or Npu intein shown in SEQ ID NO. 4.

Preferably, the ABCA4 gene fragment according to the present invention is selected from any one of the following:

(1) The coding gene of the human ABCA4-N protein fragment containing the intein fragment shown in SEQ ID NO.8,

(2) The coding gene of the human ABCA4-C protein fragment containing the intein fragment is shown as SEQ ID NO. 9.

An ABCA4-N or ABCA4-C terminal protein expression frame, which consists of an enhancer-promoter-intron-target gene sequence-polyA signal, wherein the enhancer is selected from human 214bp interphotoreceptor retinoid-binding protein (IRBP) enhancer sequence (PMID: 9723991 or US 20140275231), and the promoter is selected from human RS1 (Retinoschisin 1) promoter specific to retina photoreceptor cells, human Rho (Rhodopsin) promoter, human RK (rhodopsin kinase) promoter or mouse CAR (Cone arrestin) promoter; the intron is selected from the SV40 intron; the target gene is selected from coding genes of human ABCA4-N or ABCA4-C protein fragments containing intein fragments; the polyA signal sequence is selected from SV40 PolyA, bGH polyA, hGH polyA or rBG polyA sequences; the enhancer, the promoter, the intron, the target gene sequence and the polyA are connected through a bond or a nucleotide connecting sequence; the human ABCA4-N and ABCA4-C protein fragments are obtained by breaking the full-length protein of ABCA4 by taking p1150Cys as a cleavage site.

As a preferred aspect of the present invention, the intein is selected from Rma intein shown in SEQ ID NO.3 or Npu intein shown in SEQ ID NO. 4; preferably Rma intein shown in SEQ ID No. 3.

As a further preferred aspect of the invention, the amino acid sequence of the human ABCA4-N end containing the intein fragment is shown as SEQ ID NO.6, and the amino acid sequence of the human ABCA4-C end containing the intein fragment is shown as SEQ ID NO. 7. The nucleotide sequence of the coding gene of the human ABCA4-N protein fragment containing the intein fragment is shown as SEQ ID NO.8, and the nucleotide sequence of the coding gene of the human ABCA4-C protein fragment containing the intein fragment is shown as SEQ ID NO. 9.

As a preferred aspect of the invention, the promoter is selected from RK promoters, and the sequence of the promoter is shown as SEQ ID NO. 10; the intron sequence is selected from SV40 intron, and the sequence is shown as 4863bp-4959bp of a nucleotide sequence disclosed by GenBank accession number MK 225672.1; the polyA is selected from bGH ployA, and the sequence is shown as 957bp-1181bp of a nucleotide sequence disclosed in GenBank accession number MT 267334.1.

As a further preferred aspect of the invention, the nucleotide sequence of the ABCA4-N terminal protein expression frame is shown as SEQ ID NO.11; the nucleotide sequence of the ABCA4-C end protein expression frame is shown as SEQ ID NO.12.

A vector comprising the ABCA4 gene fragment of the present invention or the ABCA4-N or ABCA4-C terminal protein expression cassette of the present invention.

As a preferred aspect of the invention, the vector is selected from any one of the following recombinant adeno-associated viral vector serotypes: AAV1, AAV2, AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAVrh10, AAV-LK03 or AAVAnc80d, preferably AAV2, AAV5, AAV8 or AAV9.

A plasmid composition comprising a vector comprising said ABCA 4-N-terminal protein expression cassette of the present invention and a vector comprising said ABCA 4-C-terminal protein expression cassette; preferably comprises the vector, a Rep and Cap protein expression plasmid of AAV, and a helper plasmid; further preferred are the vectors, the Rep and Cap protein expression plasmids pAAV2/8 of AAV and the helper plasmid pAdΔF6.

The recombinant adeno-associated virus is prepared by packaging the vector, the Rep and Cap protein expression plasmid of AAV and the helper plasmid cotransfected HEK293 cells.

As one preferable choice of the invention, the recombinant adeno-associated virus is prepared by co-transfecting HEK293 cells with the vector containing the ABCA4-N protein expression frame, the Rep and Cap protein expression plasmid of AAV and the auxiliary plasmid.

As a preferable mode, the recombinant adeno-associated virus is prepared by co-transfecting HEK293 cells with the vector containing the ABCA4-C protein expression frame, the Rep and Cap protein expression plasmid of AAV and the auxiliary plasmid.

A recombinant adeno-associated virus composition comprises a vector containing an ABCA4-N protein expression frame, a Rep and Cap protein expression plasmid of AAV and an auxiliary plasmid cotransfected HEK293 cell, and is packaged to obtain the recombinant adeno-associated virus; and the recombinant adeno-associated virus is prepared by co-transfecting HEK293 cells with the vector containing the ABCA4-C protein expression frame, the Rep and Cap protein expression plasmid of AAV and the auxiliary plasmid.

The ABCA4 gene fragment, the ABCA4-N or ABCA4-C end protein expression frame, the vector, the plasmid composition, the recombinant adeno-associated virus and the application of the recombinant adeno-associated virus composition in preparing medicines for treating STGDI diseases are disclosed.

The beneficial effects are that:

the invention provides a novel recombinant adeno-associated virus which is designed efficiently and specifically expresses ABCA4 protein in a tissue mode and application of the recombinant adeno-associated virus in treatment of STGDI. According to the invention, firstly, the ABCA4 gene is subjected to password optimization, so that the expression level of the ABCA4 protein is improved. No systematic screening of cleavage sites and intein sequences for the target proteins is seen in the prior art. For the split intein mediated dual AAV vector technology, it would be crucial to determine the optimal sequence and split point of the target protein, since this would greatly affect its intracellular protein cleavage efficiency, as well as the tertiary structure and post-translational modification of the target proteinThereby affecting protein function. In the present invention, we systematically screened intein for cleavage sites and intein sequences for the protein of interest based on protein structure and optimized ABCA4 gene sequence. In the present invention, we also found that the use of the Rma intein in vitro and in vivo enabled the trans-splicing of two polypeptides formed by cleavage of the p1150Cys site of ABCA4 protein to form a full-length protein with little detectable by-products, showing very good safety. Finally, constructing AAV8 intein virus vector of high-efficiency tissue specific expression full-length ABCA4, preparing AAV8.RK. ABCA4-N and AAV8.RK. ABCA4-C virus, and using for gene therapy research of STGDI disease. In the STGDI (ABCA 4-KO) disease model, low doses (1X 10) ⁸ GC/. Mu.l AAV8.RK. ABCA4-N was mixed with AAV8.RK. ABCA4-C virus in equal volumes, 1. Mu.l for each eye, medium dose (1X 10) ⁹ GC/. Mu.l AAV8.RK. ABCA4-N was mixed with AAV8.RK. ABCA4-C virus in equal volumes, 1. Mu.l for each eye) and high doses (1X 10 ¹⁰ GC/. Mu.l AAV8.RK. ABCA4-N was mixed with AAV8.RK. ABCA4-C virus in equal volumes, 1. Mu.l of recombinant adeno-associated virus combination was injected into each eye and passed through the subretinal space, respectively, and the efficacy of gene therapy was evaluated after injection into the ocular fundus of the disease mice. Fundus autofluorescence intensities were significantly lower in the low, medium and high dose treated groups at month 3 and 6 post-dose than in the untreated group of STGDI disease mice (ABCA 4-KO), similar to wild-type mice; six months after administration, the b wave amplitude of mice in the treatment group is higher than that of mice in the untreated group through Electroretinogram (ERG) detection, and the retinal function is obviously improved; high Performance Liquid Chromatography (HPLC) detection found that AAV8 intein gene therapy was reduced to normal levels for 3 months, toxic retinoid dimer A2E, and full-length ABCA4 protein expression was restored to normal levels in retinal photoreceptor cells at 22% (low dose treatment group), 24% (medium dose treatment group) and 30% (high dose treatment group). The results show that the novel design of the optimized ABCA4 protein coding sequence, the design of intein cleavage sites and intein sequences and the design of an ABCA4 protein AAV8 intein expression frame can efficiently transduce retinal photoreceptor cells in an STGDI disease model and efficiently express the full-length ABCA4 protein to realize disease treatmentIs a target of (2).

Drawings

FIG. 1 pAAV.CBh.ABCA4wt.bGH (Panel A) and plasmid spectra of pAAV. CBh. ABCA4co. BGH (Panel B) expression vectors

FIG. 2 in vitro expression level verification of ABCA4 protein expression vector

FIG. 3 design, vector construction and verification of the cleavage site of the intein in the ABCA4 target gene sequence

Design of cleavage site of intein of ABCA4 target gene sequence

B is a schematic diagram of four broken intein systems

C is comparison of expression levels of full-length ABCA4 protein and byproducts of the vectors of 12 experimental groups and control group by Western blotting in example 3

Statistical graph with D as C

FIG. 4 pAAV.RK.ABCA4.RmaintN.bGH and plasmid maps of pAAV. RK. Rmail C. ABCA4.BGH two vectors

FIG. 5 schematic structural diagrams of recombinant adeno-associated virus AAV8.RK. ABCA4-N and recombinant adeno-associated virus AAV8.RK. ABCA4-C

FIG. 6B-wave amplitude statistics for low dose, medium dose, high dose, untreated, wild type mice one month (Panel A) and six months (Panel B) after viral administration

FIG. 7 expression of ABCA4 protein in retinal cells following AAV8 intein Gene therapy

A is ABCA4 protein immunofluorescence detection. Detecting the expression of ABCA4 protein in eye tissues of all groups of mice by immunofluorescence 3 months after gene therapy, scale = 50 μm;

b is in vivo ABCA4 protein expression level detection. WB detection ABCA4 and GAPDH in retinal tissue of mice 3 months after gene therapy;

c is the in vivo ABCA4 protein expression level WB detection gray value statistics. Image J was used to analyze the graph (A) for statistical relative gray values.

FIG. 8 accumulation results of lipofuscin in fundus of mice in each group

FIG. 9 results of detection of fundus autofluorescence intensity of mice in each group by FAF module of Heidelberg laser ophthalmic diagnostic instrument

Detailed Description

Example 1: ABCA4 protein target gene sequence optimization and expression vector construction

The amino acid sequence of the ABCA4 protein is shown as Genbank database NP 000341.2, and wild type ABCA4 gene (ABCA 4wt, genbank database NM-000350.3 (104 bp-6925 bp)) and codon optimized ABCA4 gene (ABCA 4co, SEQ ID NO. 1) are synthesized through enzyme digestion connection to construct pAAV.CBh.ABCA4wt.bGH (FIG. 1A, SEQ ID NO. 15) and pAAV.CBh.ABCA4co.bGH (FIG. 1B, SEQ ID NO. 16) expression vectors respectively.

Example 2: in vitro expression level verification of ABCA4 protein expression vector

The expression levels of ABCA4 protein were compared by Western blotting (Western blot) using paav.cbh.abca4wt.bgh and paav.cbh.abca4wt.bgh in example 1 at the same plasmid amount (250 ng) by transfecting HEK293 cells cultured in 24 well plates with PEImax transfection reagent, extracting the protein after 72 h. The results show that the codon optimization can significantly improve the expression level of the protein (figure 2A), and the expression level of the ABCA4 protein is improved by 4.7 times after the codon optimization by comparing the gray values of protein bands (figure 2B).

Example 3: design, vector construction and verification of ABCA4 target gene sequence intein cleavage site

The inteins were used to trans-splice at the p1150Cys, p1140Cys, p1177Cys sites of the ABCA4 protein, respectively, with cysteines from position 1 to 1150, from position 1 to 1140, or from position 1 to 1177 as the nitrogen terminal sequence (ABCA 4-N), with cysteines from 1151 to 2235, or from 1141 to 2235, or from 1178 to 2235 as the carbon terminal sequence (ABCA 4-C) (fig. 3A). Ssp inteins (Ssp) ^intein SEQ ID NO. 2), npu intein (Npu ^intein SEQ ID No. 3), rma intein (Rma ^intein SEQ ID No. 4) and Cfa intein (Cfa ^intein SEQ ID No. 5) four split intein systems (FIG. 3B), split intein ABCA4 expression vectors were constructed, HEK293 cells were co-transfected, and the expression efficiency of full-length ABCA4 protein was examined.

According to Ssp ^intein 、Npu ^intein 、Rma ^intein 、Cfa ^intein Four types of intein system and three types of intein cleavage sites of p1150cys, p1140cys and p1177cys of ABCA4 protein are provided with 12 groups of experimental groups, a full-length ABCA4 target gene and eGFP are used as a control group, HEK293 cells cultured in 24 pore plates are transfected, the proteins are extracted after 72 hours, and the expression level of the full-length ABCA4 proteins of each group of vectors is compared by using a western blotting method. Results show use of Rma ^intein Trans-splicing was performed at the p1150Cys site of ABCA4 protein, and the by-products were barely detectable, with the highest expression efficiency of the full-length ABCA4 protein (fig. 3c, d).

Example 4: gene therapy candidate vector design construction

Construction of Rma for further evaluation ^intein Expression in vivo after trans-splicing at the p1150Cys site of ABCA4 protein, therapeutic efficacy and safety of gene therapy. We synthesized the retinal photoreceptor cell specific RK promoter (SEQ ID NO. 10) and constructed viral packaging cis plasmid vectors pAAV. RK. ABCA4.Rmain N.bGH (FIG. 4A, SEQ ID NO. 17) and pAAV. RK. Rmain C.ABCA4.bGH two vectors (FIG. 4B, SEQ ID NO. 18) by T4 ligation subcloning, comprising the ABCA4-N terminal protein expression cassette (SEQ ID NO. 11) and ABCA4-C terminal protein expression cassette (SEQ ID NO. 12) according to the invention, respectively.

Example 5: AAV virus production and purification

Method for packaging and purifying recombinant AAV virus by referring to Martin Lock et al (8)]AAV Rep and Cap protein expression plasmids (pAAV 2/8), helper plasmids (pAdΔF6) and AAV packaging cis plasmids (pAAV.RK.RmaintC.ABCA4.bGH, SEQ ID No.18; pAAV.RK.ABCA4.RmaintN.bGH, SEQ ID No. 17) were co-transfected with PEI, respectively, into HEK293 cell packaging to prepare viruses AAV8.RK. ABCA4-N (FIG. 5A, SEQ ID No. 13) and AAV8.RK. ABCA4-C viruses (FIG. 5B, SEQ ID No. 14), after 48h transfection, the cells and culture supernatants were harvested, AAV virus was purified by ultracentrifugation using iodixanol ultracentrifugation gradient, and virus titer AAV8.RK. ABCA4-N virus titer was determined to be 7.38X10 by digital quantitative PCR (ddPCR) method ¹³ GC/mL, AAV8.RK. ABCA4-C viral titre of 2.77×10 ¹³ GC/mL。

Example 6: AAV8 intein gene therapy for improving ERG function of STGDI disease mice

STGDI-disease mice (ABCA 4-KO,4 weeks old, n=10) were co-injected through the subretinal space using an equal proportion mix of AAV8.Rk. ABCA4-N and AAV8.Rk. ABCA4-C viruses prepared in example 5 (AAV 8 intein for short). Treatment groups with low doses (1X 10) were divided according to the virus injection dose ⁸ GC AAV8 intein), medium dose treatment group (1×10 ⁹ GC AAV8 intein, high dose treatment group (1X 10) ¹⁰ GC AAV8 intein). One month and six months after virus administration, b-wave amplitudes were measured by ERG for each treated, untreated, and wild-type mice at different stimulation intensities. The results showed that no statistical differences occurred in b-wave amplitudes for the low, medium, high, untreated, wild-type mice one month after viral administration (fig. 6A); six months after virus dosing, the treated mice had higher B-wave amplitudes than the untreated mice, and the statistical differences between the low, medium and untreated mice were most pronounced (fig. 6B, ×p<0.05，**p<0.01，***p<0.001 Shows that AAV8 intein treatment can significantly improve the eye retina electrophysiological function of STGDI disease mice.

Example 7: restoration of ABCA4 protein expression in retinal cells following AAV8 intein gene therapy

At 3 months post injection we collected eye tissues from mice and examined the expression of ABCA4 protein in retinal tissues by frozen sections and immunofluorescent staining. The results show that ABCA4 expression in ocular tissues of mice was restored to normal levels in all treated groups (low dose group n=4, medium dose group n=4, high dose group n=4) and wild type mice (n=4) as compared to untreated groups (n=6), distributed predominantly in the retinal photoreceptor cell layer (fig. 7A). Meanwhile, retina tissues of eyeballs are collected for protein cleavage, and the expression of the ABCA4 full-length protein is further detected and analyzed by a western blotting method. The results showed that ABCA4 protein was expressed efficiently in ocular tissues of both the treated group (low dose group n=6, medium dose group n=6, high dose group n=6) and wild type (n=6) mice compared to untreated group (n=6) (fig. 7B). Low dose therapeutic group1×10 ⁸ GC AAV8 intein), medium dose treatment group (1×10 ⁹ GC AAV8 intein, high dose treatment group (1X 10) ¹⁰ GC AAV8 intein) ABCA4 protein levels reached 22%,24% and 30% of normal mice, respectively. And in all WB-detected treatment group samples, full length ABCA4 protein was detected and none of the truncated by-product proteins was detected.

Example 8: AAV8 intein gene therapy to reduce STGDI mouse toxic retinoid dimer (N-retinyl-N-View Huang Chunan, A2E) accumulation

3 months after injection, we collected eye tissues of mice, performed intra-tissue pigment extraction and high performance liquid chromatography detection, and detected the accumulation of toxic retinoid dimers (N-retinyl-N-view Huang Chunan, A2E) in eye tissues of mice. The results showed that the A2E content in the wild-type, low-dose and medium-dose treated mice was 0 in the group 3 months after injection, and 7.03X10 in the untreated mice of the same age ^-6 mol/l, 6.21X10 in mice in the high dose treatment group ^- ⁶ mol/l, indicating a significant reduction in accumulation of fundus lipofuscin in both the low and medium dose treatment groups (figure 8).

Example 9: AAV8 intein gene therapy to reduce fundus autofluorescence in STGDI mouse model

The FAF module of the Heidelberg laser ophthalmic diagnostic instrument is used for detecting the autofluorescence intensity of the fundus of the mouse 3 months and 6 months after injection. The results showed that the autofluorescence intensity of the treated mice was much closer to that of the wild-type mice, significantly weaker than that of the untreated mice, indicating that AAV8 intein treatment could significantly improve ocular pigmentation in the disease mice (fig. 9).

Reference to the literature

1.Kong J,Kim SR,Binley K,Pata I,Doi K,Mannik J,Zernant-Rajang J,Kan O,Iqball S,Naylor S et al:Correction of the disease phenotype in the mouse model of Stargardt disease by lentiviral gene therapy.Gene Ther 2008,15(19):1311-1320.

2.Allocca M,Doria M,Petrillo M,Colella P,Garcia-Hoyos M,Gibbs D,Kim SR,Maguire A,Rex TS,Di Vicino U et al:Serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery in mice.J Clin Invest 2008,118(5):1955-1964.

3.Trapani I,Colella P,Sommella A,Iodice C,Cesi G,de Simone S,Marrocco E,Rossi S,Giunti M,Palfi A et al:Effective delivery of large genes to the retina by dual AAV vectors.EMBO Mol Med 2014,6(2):194-211.

4.Dyka FM,Molday LL,Chiodo VA,Molday RS,Hauswirth WW:Dual ABCA4-AAV Vector Treatment Reduces Pathogenic Retinal A2E Accumulation in a Mouse Model of Autosomal Recessive Stargardt Disease.Hum Gene Ther 2019,30(11):1361-1370.

5.Tornabene P,Trapani I,Minopoli R,Centrulo M,Lupo M,de Simone S,Tiberi P,Dell’Aquila F,Marrocco E,Iodice C et al:Intein-mediated protein trans-splicing expands adeno-associated virus transfer capacity in the retina.Science Translational Medicine 2019,11(492):eaav4523.

6.Novikova O,Topilina N,Belfort M:Enigmatic distribution,evolution,and function of inteins.J Biol Chem 2014,289(21):14490-14497.

7.Mills KV,Johnson MA,Perler FB:Protein splicing:how inteins escape from precursor proteins.J Biol Chem 2014,289(21):14498-14505.

8.Lock M,Alvira M,Vandenberghe LH,Samanta A,Toelen J,Debyser Z,Wilson JM:Rapid,simple,and versatile manufacturing of recombinant adeno-associated viral vectors at scale.Human gene therapy 2010,21(10):1259-1271.

Sequence listing

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<120> adeno-associated virus vector expressing full-length ABCA4 gene and application thereof

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tgctttcaga gccccacacc tggcgaaagc cctggcatcg tgtccaacta caacaacagc 300

atcctggcca gagtgtaccg ggacttccaa gagctgctga tgaacgcccc tgagtctcag 360

cacctgggca gaatctggac cgagctgcac atcctgagcc agttcatgga caccctgaga 420

acacaccccg agagaatcgc cggcaggggc atcagaatcc gggacatcct gaaggacgag 480

gaaaccctga cactgttcct catcaagaac atcggcctga gcgacagcgt ggtgtacctg 540

ctgatcaaca gccaagtgcg gcccgagcag tttgctcatg gcgtgccaga tctcgccctg 600

aaggatatcg cctgttctga ggccctgctg gaacggttca tcatcttcag ccagcggaga 660

ggcgccaaga ccgtcagata tgccctgtgc agtctgagcc agggaaccct gcagtggatc 720

gaggataccc tgtacgccaa cgtggacttc ttcaagctgt tccgggtgct gcccacactg 780

ctggattcta gatcccaggg catcaacctg agaagctggg gcggcatcct gtccgacatg 840

agcccaagaa tccaagagtt catccaccgg cctagcatgc aggacctgct gtgggttacc 900

agacctctga tgcagaacgg cggacccgag acattcacca agctgatggg aattctgagc 960

gatctgctgt gcggctaccc tgaaggcgga ggatctagag tgctgagctt caattggtac 1020

gaggacaaca actacaaggc cttcctgggc atcgactcca ccagaaagga ccccatctac 1080

agctacgacc ggcggacaac cagcttctgc aatgccctga tccagagcct ggaaagcaac 1140

cctctgacca agatcgcttg gagggccgcc aaacctctgc tgatgggaaa gatcctgtac 1200

acccctgaca gccctgccgc cagaagaatc ctgaagaacg ccaacagcac cttcgaggaa 1260

ctggaacacg tgcgcaagct ggtcaaggcc tgggaagaag tgggacctca gatctggtac 1320

ttcttcgaca atagcaccca gatgaacatg atcagagaca ccctgggcaa ccctaccgtg 1380

aaggacttcc tgaacagaca gctgggcgaa gagggcatta ccgccgaggc catcctgaac 1440

tttctgtaca agggccccag agagtcccag gccgacgaca tggccaactt cgattggcgg 1500

gacatcttca acatcaccga cagaaccctg cggctggtca accagtacct ggaatgcctg 1560

gtgctggaca agttcgagag ctacaacgac gagacacagc tgacccagag agccctgtct 1620

ctgctggaag agaatatgtt ctgggctggc gtggtgttcc ccgacatgta cccttggaca 1680

agcagcctgc ctcctcacgt gaagtacaag atccggatgg acatcgacgt ggtcgaaaag 1740

accaacaaga tcaaggatcg gtactgggac agcggcccta gagctgatcc cgtggaagat 1800

tttcggtaca tctggggcgg attcgcatac ctgcaggaca tggtggaaca gggaatcaca 1860

cggtcccagg tgcaggctga agctcctgtg ggaatctacc tgcagcagat gccttatcct 1920

tgcttcgtgg acgacagctt catgatcatc ctgaatcggt gcttccccat cttcatggtg 1980

ctggcctgga tctactccgt gtctatgacc gtgaagtcca tcgtgctgga aaaagagctg 2040

cggctgaaag agacactgaa gaaccagggc gtgtccaatg ccgtgatctg gtgcacctgg 2100

tttctggaca gcttctccat tatgagcatg agcatctttc tgctgacgat cttcatcatg 2160

cacggccgga tcctgcacta cagcgacccc tttatcctct tcctgttcct gctggccttc 2220

agcaccgcta caatcatgct gtgttttctg ctgtccacct tcttcagcaa ggcctctctg 2280

gccgctgctt gtagcggcgt gatctacttc accctgtacc tgcctcacat cctgtgcttc 2340

gcatggcagg acagaatgac cgccgagctg aagaaagctg tgtccctgct gagccctgtg 2400

gcctttggct ttggcaccga gtacctcgtc agatttgagg aacaaggact gggactgcag 2460

tggtccaaca tcggcaatag ccctacagag ggcgacgagt tcagcttcct gctgtctatg 2520

cagatgatgc tgctggacgc cgccgtgtat ggactgctgg cttggtatct ggaccaggtg 2580

ttcccaggcg attacggcac tcctctgcct tggtatttcc tgctgcaaga gagctactgg 2640

ctcggcggcg agggatgtag caccagagaa gaaagagccc tggaaaagac cgagcctctg 2700

accgaggaaa cagaggaccc tgaacaccca gagggcatcc acgatagctt tttcgagaga 2760

gaacaccccg gctgggtgcc aggcgtgtgt gtgaagaatc tggtcaagat cttcgagccc 2820

tgcggcagac ctgccgtgga cagactgaac atcaccttct acgagaacca gattaccgcc 2880

tttctgggcc acaacggcgc tggcaagaca accacactga gcatcctcac aggcctgctg 2940

cctccaacaa gcggcacagt tctcgttggc ggcagagaca tcgagacaag cctggatgcc 3000

gtcagacagt ccctgggcat gtgccctcag cacaacatcc tgtttcacca cctgaccgtg 3060

gccgagcaca tgctgtttta tgcccagctg aagggcaaga gccaagaaga ggctcagctg 3120

gaaatggaag ccatgctcga ggacaccggc ctgcaccaca agagaaatga ggaagcccag 3180

gatctgagcg gcggcatgca gagaaaactg agcgtggcca ttgccttcgt gggcgacgcc 3240

aaggttgtga tcctggatga gcctacaagc ggcgtggacc cttacagcag aagatccatc 3300

tgggatctgc tgctgaagta cagaagcggc cggaccatca tcatgagcac ccaccacatg 3360

gacgaggccg atctgctcgg agacagaatc gccatcattg ctcagggcag actgtactgc 3420

agcggcaccc cactgtttct gaagaactgt tttggcaccg gcctgtacct gacactcgtg 3480

cggaagatga agaacatcca gagccagcgg aagggcagcg agggcacatg tagctgtagc 3540

agcaagggct tcagcaccac ctgtcctgct cacgtggacg atctgacccc tgaacaggtg 3600

ctggatggcg acgtgaacga gctgatggac gtggtgctgc accacgtgcc tgaggccaag 3660

ctggtggaat gcatcggcca agagctgatc ttcctgctgc ctaacaagaa cttcaagcac 3720

cgggcctacg ccagcctgtt cagagagctg gaagagacac tggccgatct gggcctgagc 3780

agctttggca tcagcgacac ccctctggaa gaaatcttcc tgaaagtgac cgaggacagc 3840

gacagcggcc cactttttgc tggcggagca cagcagaaac gcgagaacgt gaaccctaga 3900

cacccctgtc tgggccctag agagaaagcc ggacagaccc ctcaggacag caatgtgtgc 3960

tctcctggtg ctcctgccgc tcaccctgaa ggacaacctc cacctgagcc tgagtgtcct 4020

ggacctcagc tgaataccgg cacacagctg gttctgcagc acgtgcaagc cctgctggtc 4080

aagagattcc agcacaccat cagaagccac aaggactttc tggcccagat tgtgctgccc 4140

gccaccttcg tttttctggc tctgatgctg agcatcgtga tccctccatt cggcgagtac 4200

cccgctctga cactgcaccc ttggatctac ggccagcagt acaccttctt cagcatggac 4260

gagcctggca gcgagcagtt tacagtgctg gctgatgtgc tgctgaacaa gcccggcttc 4320

ggcaaccgct gtctgaaaga aggatggctg cctgagtacc cctgcggcaa tagcacccct 4380

tggaaaaccc ctagcgtgtc ccctaacatc acccagctgt tccagaaaca gaaatggacc 4440

caagtgaacc cctctccatc ctgccggtgc tccaccagag aaaagctgac catgctgccc 4500

gagtgtccag aaggtgcagg cggacttcct ccacctcaga gaacccagag aagcaccgag 4560

attctgcagg acctgaccga ccggaatatc agcgacttcc tggttaagac ataccccgca 4620

ctgatccggt ccagcctgaa gtccaagttc tgggtcaacg agcagagata cggcggcatc 4680

tctatcggcg gaaagctgcc tgtggtgcct atcacaggcg aagccctcgt gggctttctg 4740

tctgacctgg gcagaatcat gaacgtgtcc ggcggaccca tcaccagaga ggccagcaaa 4800

gagatccccg atttcctgaa gcacctggaa accgaggata acatcaaagt gtggttcaac 4860

aacaaaggct ggcacgccct ggtgtccttt ctgaacgtgg cccacaacgc catcctgaga 4920

gccagcctgc ctaaggacag aagccctgag gaatacggca tcaccgtgat ctcccagcca 4980

ctgaacctga ccaaagagca gctgagcgag atcaccgtgc tgaccacatc tgtggatgcc 5040

gtggtggcca tctgcgtgat cttctccatg agcttcgtgc ctgcctcctt cgtgctgtat 5100

ctgatccaag agagagtgaa caagagcaag cacctccagt ttatcagcgg agtgtcccca 5160

accacctact gggtcaccaa ctttctgtgg gacatcatga actactccgt gtctgccggc 5220

ctggtcgtgg gcatcttcat cggctttcag aagaaggcct acacaagccc cgagaacctg 5280

cctgctctgg ttgctctgct gctgctgtat ggctgggccg tgattcccat gatgtacccc 5340

gccagcttcc tgttcgatgt gcctagcaca gcctacgtgg ccctgagctg cgccaatctg 5400

ttcatcggca tcaacagcag cgccatcacc ttcatcctgg aactgttcga gaacaacaga 5460

accctgctgc ggttcaacgc cgtgctgaga aagctgctga tcgtgttccc tcacttctgc 5520

ctcggcagag gcctgattga tctggccctg tctcaggccg tgaccgacgt gtacgctaga 5580

tttggcgagg aacacagcgc caatcctttc cactgggacc tgatcggcaa gaacctgttc 5640

gccatggtgg tggaaggcgt ggtgtatttc ctgctgactc tgctggtgca gcggcacttc 5700

tttctgtccc aatggatcgc cgagcctacc aaagaaccca tcgtggacga ggacgacgac 5760

gtggccgaag agagacagag aatcatcacc ggcggcaaca agaccgacat cctgaggctg 5820

cacgagctga ccaagatcta ccctggcaca tctagccctg ccgtggacag actgtgtgtg 5880

ggagttagac ctggcgagtg ctttggcctg ctgggagtta atggcgccgg aaagaccacc 5940

accttcaaga tgctgaccgg cgacaccaca gtgaccagcg gagatgctac tgtggccggc 6000

aagagcatcc tgaccaacat cagcgaggtg caccagaaca tgggctactg ccctcagttc 6060

gacgccatcg acgaactgct gacaggcaga gagcacctgt atctgtacgc cagactgaga 6120

ggcgtgcccg ccgaagaaat tgagaaggtg gccaactggt ccatcaagag cctgggactg 6180

accgtgtacg ccgattgtct ggccggcaca tatagcggcg gaaacaagcg gaagctgagc 6240

accgccattg ctctgatcgg atgccctcct ctggtcctgc tggatgagcc tacaaccggc 6300

atggatcccc aggctagacg gatgctgtgg aacgtgatcg tgtccatcat ccgcgaaggc 6360

agagccgtgg tcctgacaag ccacagcatg gaagagtgcg aggccctgtg taccagactg 6420

gccatcatgg tcaagggcgc cttcagatgc atgggcacca ttcagcacct gaaaagcaag 6480

ttcggcgacg gctacatcgt gaccatgaag atcaagtccc caaaggacga cctgctgcca 6540

gatctgaacc ccgtggaaca gttcttccag ggcaacttcc ctggctccgt gcagcgggaa 6600

agacactaca acatgctgca gtttcaggtg tccagcagct ccctggccag aatctttcag 6660

ctgctgctct cccacaagga tagcctgctg attgaagagt acagcgtgac ccagaccaca 6720

ctggaccagg tgttcgtgaa cttcgccaag cagcagaccg agagccacga cttgcctctg 6780

caccctagag ctgccggcgc ttctagacag gcccaggatt aa 6822

<210> 2

<211> 154

<212> PRT

<213> Synechocystis sp. Strain PCC6803

<400> 2

Cys Ile Ser Gly Asp Ser Leu Ile Ser Leu Ala Ser Thr Gly Lys Arg

1 5 10 15

Val Pro Ile Lys Asp Leu Leu Gly Glu Lys Asp Phe Glu Ile Trp Ala

20 25 30

Ile Asn Glu Gln Thr Met Lys Leu Glu Ser Ala Lys Val Ser Arg Val

35 40 45

Phe Cys Thr Gly Lys Lys Leu Val Tyr Thr Leu Lys Thr Arg Leu Gly

50 55 60

Arg Thr Ile Lys Ala Thr Ala Asn His Arg Phe Leu Thr Ile Asp Gly

65 70 75 80

Trp Lys Arg Leu Asp Glu Leu Ser Leu Lys Glu His Ile Ala Leu Pro

85 90 95

Arg Lys Leu Glu Ser Ser Ser Leu Gln Leu Ala Pro Glu Ile Glu Lys

100 105 110

Leu Pro Gln Ser Asp Ile Tyr Trp Asp Pro Ile Val Ser Ile Thr Glu

115 120 125

Thr Gly Val Glu Glu Val Phe Asp Leu Thr Val Pro Gly Leu Arg Asn

130 135 140

Phe Val Ala Asn Asp Ile Ile Val His Asn

145 150

<210> 3

<211> 153

<212> PRT

<213> Marine thermophilic halophilic bacteria (Rhodothermus marinus)

<400> 3

Cys Leu Ala Gly Asp Thr Leu Ile Thr Leu Ala Asp Gly Arg Arg Val

1 5 10 15

Pro Ile Arg Glu Leu Val Ser Gln Gln Asn Phe Ser Val Trp Ala Leu

20 25 30

Asn Pro Gln Thr Tyr Arg Leu Glu Arg Ala Arg Val Ser Arg Ala Phe

35 40 45

Cys Thr Gly Ile Lys Pro Val Tyr Arg Leu Thr Thr Arg Leu Gly Arg

50 55 60

Ser Ile Arg Ala Thr Ala Asn His Arg Phe Leu Thr Pro Gln Gly Trp

65 70 75 80

Lys Arg Val Asp Glu Leu Gln Pro Gly Asp Tyr Leu Ala Leu Pro Arg

85 90 95

Arg Ile Pro Thr Ala Ser Ala Ala Ala Cys Pro Glu Leu Arg Gln Leu

100 105 110

Ala Gln Ser Asp Val Tyr Trp Asp Pro Ile Val Ser Ile Glu Pro Asp

115 120 125

Gly Val Glu Glu Val Phe Asp Leu Thr Val Pro Gly Pro His Asn Phe

130 135 140

Val Ala Asn Asp Ile Ile Ala His Asn

145 150

<210> 4

<211> 137

<212> PRT

<213> nostoc (Nostoc punctiforme)

<400> 4

Cys Leu Ser Tyr Glu Thr Glu Ile Leu Thr Val Glu Tyr Gly Leu Leu

1 5 10 15

Pro Ile Gly Lys Ile Val Glu Lys Arg Ile Glu Cys Thr Val Tyr Ser

20 25 30

Val Asp Asn Asn Gly Asn Ile Tyr Thr Gln Pro Val Ala Gln Trp His

35 40 45

Asp Arg Gly Glu Gln Glu Val Phe Glu Tyr Cys Leu Glu Asp Gly Ser

50 55 60

Leu Ile Arg Ala Thr Lys Asp His Lys Phe Met Thr Val Asp Gly Gln

65 70 75 80

Met Leu Pro Ile Asp Glu Ile Phe Glu Arg Glu Leu Asp Leu Met Arg

85 90 95

Val Asp Asn Leu Pro Asn Ile Lys Ile Ala Thr Arg Lys Tyr Leu Gly

100 105 110

Lys Gln Asn Val Tyr Asp Ile Gly Val Glu Arg Asp His Asn Phe Ala

115 120 125

Leu Lys Asn Gly Phe Ile Ala Ser Asn

130 135

<210> 5

<211> 136

<212> PRT

<213> Consensus

<400> 5

Cys Leu Ser Tyr Asp Thr Glu Ile Leu Thr Val Glu Tyr Gly Phe Leu

1 5 10 15

Pro Ile Gly Lys Ile Val Glu Glu Arg Ile Glu Cys Thr Val Tyr Thr

20 25 30

Val Asp Lys Asn Gly Phe Val Tyr Thr Gln Pro Ile Ala Gln Trp His

35 40 45

Asn Arg Gly Glu Gln Glu Val Phe Glu Tyr Cys Leu Glu Asp Gly Ser

50 55 60

Ile Ile Arg Ala Thr Lys Asp His Lys Phe Met Thr Thr Asp Gly Gln

65 70 75 80

Met Leu Pro Ile Asp Glu Ile Phe Glu Arg Gly Leu Asp Leu Lys Gln

85 90 95

Val Asp Gly Leu Pro Val Lys Ile Ile Ser Arg Lys Ser Leu Gly Thr

100 105 110

Gln Asn Val Tyr Asp Ile Gly Val Glu Lys Asp His Asn Phe Leu Leu

115 120 125

Lys Asn Gly Leu Val Ala Ser Asn

130 135

<210> 6

<211> 1251

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<400> 6

Met Gly Phe Val Arg Gln Ile Gln Leu Leu Leu Trp Lys Asn Trp Thr

1 5 10 15

Leu Arg Lys Arg Gln Lys Ile Arg Phe Val Val Glu Leu Val Trp Pro

20 25 30

Leu Ser Leu Phe Leu Val Leu Ile Trp Leu Arg Asn Ala Asn Pro Leu

35 40 45

Tyr Ser His His Glu Cys His Phe Pro Asn Lys Ala Met Pro Ser Ala

50 55 60

Gly Met Leu Pro Trp Leu Gln Gly Ile Phe Cys Asn Val Asn Asn Pro

65 70 75 80

Cys Phe Gln Ser Pro Thr Pro Gly Glu Ser Pro Gly Ile Val Ser Asn

85 90 95

Tyr Asn Asn Ser Ile Leu Ala Arg Val Tyr Arg Asp Phe Gln Glu Leu

100 105 110

Leu Met Asn Ala Pro Glu Ser Gln His Leu Gly Arg Ile Trp Thr Glu

115 120 125

Leu His Ile Leu Ser Gln Phe Met Asp Thr Leu Arg Thr His Pro Glu

130 135 140

Arg Ile Ala Gly Arg Gly Ile Arg Ile Arg Asp Ile Leu Lys Asp Glu

145 150 155 160

Glu Thr Leu Thr Leu Phe Leu Ile Lys Asn Ile Gly Leu Ser Asp Ser

165 170 175

Val Val Tyr Leu Leu Ile Asn Ser Gln Val Arg Pro Glu Gln Phe Ala

180 185 190

His Gly Val Pro Asp Leu Ala Leu Lys Asp Ile Ala Cys Ser Glu Ala

195 200 205

Leu Leu Glu Arg Phe Ile Ile Phe Ser Gln Arg Arg Gly Ala Lys Thr

210 215 220

Val Arg Tyr Ala Leu Cys Ser Leu Ser Gln Gly Thr Leu Gln Trp Ile

225 230 235 240

Glu Asp Thr Leu Tyr Ala Asn Val Asp Phe Phe Lys Leu Phe Arg Val

245 250 255

Leu Pro Thr Leu Leu Asp Ser Arg Ser Gln Gly Ile Asn Leu Arg Ser

260 265 270

Trp Gly Gly Ile Leu Ser Asp Met Ser Pro Arg Ile Gln Glu Phe Ile

275 280 285

His Arg Pro Ser Met Gln Asp Leu Leu Trp Val Thr Arg Pro Leu Met

290 295 300

Gln Asn Gly Gly Pro Glu Thr Phe Thr Lys Leu Met Gly Ile Leu Ser

305 310 315 320

Asp Leu Leu Cys Gly Tyr Pro Glu Gly Gly Gly Ser Arg Val Leu Ser

325 330 335

Phe Asn Trp Tyr Glu Asp Asn Asn Tyr Lys Ala Phe Leu Gly Ile Asp

340 345 350

Ser Thr Arg Lys Asp Pro Ile Tyr Ser Tyr Asp Arg Arg Thr Thr Ser

355 360 365

Phe Cys Asn Ala Leu Ile Gln Ser Leu Glu Ser Asn Pro Leu Thr Lys

370 375 380

Ile Ala Trp Arg Ala Ala Lys Pro Leu Leu Met Gly Lys Ile Leu Tyr

385 390 395 400

Thr Pro Asp Ser Pro Ala Ala Arg Arg Ile Leu Lys Asn Ala Asn Ser

405 410 415

Thr Phe Glu Glu Leu Glu His Val Arg Lys Leu Val Lys Ala Trp Glu

420 425 430

Glu Val Gly Pro Gln Ile Trp Tyr Phe Phe Asp Asn Ser Thr Gln Met

435 440 445

Asn Met Ile Arg Asp Thr Leu Gly Asn Pro Thr Val Lys Asp Phe Leu

450 455 460

Asn Arg Gln Leu Gly Glu Glu Gly Ile Thr Ala Glu Ala Ile Leu Asn

465 470 475 480

Phe Leu Tyr Lys Gly Pro Arg Glu Ser Gln Ala Asp Asp Met Ala Asn

485 490 495

Phe Asp Trp Arg Asp Ile Phe Asn Ile Thr Asp Arg Thr Leu Arg Leu

500 505 510

Val Asn Gln Tyr Leu Glu Cys Leu Val Leu Asp Lys Phe Glu Ser Tyr

515 520 525

Asn Asp Glu Thr Gln Leu Thr Gln Arg Ala Leu Ser Leu Leu Glu Glu

530 535 540

Asn Met Phe Trp Ala Gly Val Val Phe Pro Asp Met Tyr Pro Trp Thr

545 550 555 560

Ser Ser Leu Pro Pro His Val Lys Tyr Lys Ile Arg Met Asp Ile Asp

565 570 575

Val Val Glu Lys Thr Asn Lys Ile Lys Asp Arg Tyr Trp Asp Ser Gly

580 585 590

Pro Arg Ala Asp Pro Val Glu Asp Phe Arg Tyr Ile Trp Gly Gly Phe

595 600 605

Ala Tyr Leu Gln Asp Met Val Glu Gln Gly Ile Thr Arg Ser Gln Val

610 615 620

Gln Ala Glu Ala Pro Val Gly Ile Tyr Leu Gln Gln Met Pro Tyr Pro

625 630 635 640

Cys Phe Val Asp Asp Ser Phe Met Ile Ile Leu Asn Arg Cys Phe Pro

645 650 655

Ile Phe Met Val Leu Ala Trp Ile Tyr Ser Val Ser Met Thr Val Lys

660 665 670

Ser Ile Val Leu Glu Lys Glu Leu Arg Leu Lys Glu Thr Leu Lys Asn

675 680 685

Gln Gly Val Ser Asn Ala Val Ile Trp Cys Thr Trp Phe Leu Asp Ser

690 695 700

Phe Ser Ile Met Ser Met Ser Ile Phe Leu Leu Thr Ile Phe Ile Met

705 710 715 720

His Gly Arg Ile Leu His Tyr Ser Asp Pro Phe Ile Leu Phe Leu Phe

725 730 735

Leu Leu Ala Phe Ser Thr Ala Thr Ile Met Leu Cys Phe Leu Leu Ser

740 745 750

Thr Phe Phe Ser Lys Ala Ser Leu Ala Ala Ala Cys Ser Gly Val Ile

755 760 765

Tyr Phe Thr Leu Tyr Leu Pro His Ile Leu Cys Phe Ala Trp Gln Asp

770 775 780

Arg Met Thr Ala Glu Leu Lys Lys Ala Val Ser Leu Leu Ser Pro Val

785 790 795 800

Ala Phe Gly Phe Gly Thr Glu Tyr Leu Val Arg Phe Glu Glu Gln Gly

805 810 815

Leu Gly Leu Gln Trp Ser Asn Ile Gly Asn Ser Pro Thr Glu Gly Asp

820 825 830

Glu Phe Ser Phe Leu Leu Ser Met Gln Met Met Leu Leu Asp Ala Ala

835 840 845

Val Tyr Gly Leu Leu Ala Trp Tyr Leu Asp Gln Val Phe Pro Gly Asp

850 855 860

Tyr Gly Thr Pro Leu Pro Trp Tyr Phe Leu Leu Gln Glu Ser Tyr Trp

865 870 875 880

Leu Gly Gly Glu Gly Cys Ser Thr Arg Glu Glu Arg Ala Leu Glu Lys

885 890 895

Thr Glu Pro Leu Thr Glu Glu Thr Glu Asp Pro Glu His Pro Glu Gly

900 905 910

Ile His Asp Ser Phe Phe Glu Arg Glu His Pro Gly Trp Val Pro Gly

915 920 925

Val Cys Val Lys Asn Leu Val Lys Ile Phe Glu Pro Cys Gly Arg Pro

930 935 940

Ala Val Asp Arg Leu Asn Ile Thr Phe Tyr Glu Asn Gln Ile Thr Ala

945 950 955 960

Phe Leu Gly His Asn Gly Ala Gly Lys Thr Thr Thr Leu Ser Ile Leu

965 970 975

Thr Gly Leu Leu Pro Pro Thr Ser Gly Thr Val Leu Val Gly Gly Arg

980 985 990

Asp Ile Glu Thr Ser Leu Asp Ala Val Arg Gln Ser Leu Gly Met Cys

995 1000 1005

Pro Gln His Asn Ile Leu Phe His His Leu Thr Val Ala Glu His Met

1010 1015 1020

Leu Phe Tyr Ala Gln Leu Lys Gly Lys Ser Gln Glu Glu Ala Gln Leu

1025 1030 1035 1040

Glu Met Glu Ala Met Leu Glu Asp Thr Gly Leu His His Lys Arg Asn

1045 1050 1055

Glu Glu Ala Gln Asp Leu Ser Gly Gly Met Gln Arg Lys Leu Ser Val

1060 1065 1070

Ala Ile Ala Phe Val Gly Asp Ala Lys Val Val Ile Leu Asp Glu Pro

1075 1080 1085

Thr Ser Gly Val Asp Pro Tyr Ser Arg Arg Ser Ile Trp Asp Leu Leu

1090 1095 1100

Leu Lys Tyr Arg Ser Gly Arg Thr Ile Ile Met Ser Thr His His Met

1105 1110 1115 1120

Asp Glu Ala Asp Leu Leu Gly Asp Arg Ile Ala Ile Ile Ala Gln Gly

1125 1130 1135

Arg Leu Tyr Cys Ser Gly Thr Pro Leu Phe Leu Lys Asn Cys Leu Ala

1140 1145 1150

Gly Asp Thr Leu Ile Thr Leu Ala Asp Gly Arg Arg Val Pro Ile Arg

1155 1160 1165

Glu Leu Val Ser Gln Gln Asn Phe Ser Val Trp Ala Leu Asn Pro Gln

1170 1175 1180

Thr Tyr Arg Leu Glu Arg Ala Arg Val Ser Arg Ala Phe Cys Thr Gly

1185 1190 1195 1200

Ile Lys Pro Val Tyr Arg Leu Thr Thr Arg Leu Gly Arg Ser Ile Arg

1205 1210 1215

Ala Thr Ala Asn His Arg Phe Leu Thr Pro Gln Gly Trp Lys Arg Val

1220 1225 1230

Asp Glu Leu Gln Pro Gly Asp Tyr Leu Ala Leu Pro Arg Arg Ile Pro

1235 1240 1245

Thr Ala Ser

1250

<210> 7

<211> 1176

<212> PRT

<213> Artificial sequence (Artificial Sequence)

<400> 7

Met Ala Ala Ala Cys Pro Glu Leu Arg Gln Leu Ala Gln Ser Asp Val

1 5 10 15

Tyr Trp Asp Pro Ile Val Ser Ile Glu Pro Asp Gly Val Glu Glu Val

20 25 30

Phe Asp Leu Thr Val Pro Gly Pro His Asn Phe Val Ala Asn Asp Ile

35 40 45

Ile Ala His Asn Cys Phe Gly Thr Gly Leu Tyr Leu Thr Leu Val Arg

50 55 60

Lys Met Lys Asn Ile Gln Ser Gln Arg Lys Gly Ser Glu Gly Thr Cys

65 70 75 80

Ser Cys Ser Ser Lys Gly Phe Ser Thr Thr Cys Pro Ala His Val Asp

85 90 95

Asp Leu Thr Pro Glu Gln Val Leu Asp Gly Asp Val Asn Glu Leu Met

100 105 110

Asp Val Val Leu His His Val Pro Glu Ala Lys Leu Val Glu Cys Ile

115 120 125

Gly Gln Glu Leu Ile Phe Leu Leu Pro Asn Lys Asn Phe Lys His Arg

130 135 140

Ala Tyr Ala Ser Leu Phe Arg Glu Leu Glu Glu Thr Leu Ala Asp Leu

145 150 155 160

Gly Leu Ser Ser Phe Gly Ile Ser Asp Thr Pro Leu Glu Glu Ile Phe

165 170 175

Leu Lys Val Thr Glu Asp Ser Asp Ser Gly Pro Leu Phe Ala Gly Gly

180 185 190

Ala Gln Gln Lys Arg Glu Asn Val Asn Pro Arg His Pro Cys Leu Gly

195 200 205

Pro Arg Glu Lys Ala Gly Gln Thr Pro Gln Asp Ser Asn Val Cys Ser

210 215 220

Pro Gly Ala Pro Ala Ala His Pro Glu Gly Gln Pro Pro Pro Glu Pro

225 230 235 240

Glu Cys Pro Gly Pro Gln Leu Asn Thr Gly Thr Gln Leu Val Leu Gln

245 250 255

His Val Gln Ala Leu Leu Val Lys Arg Phe Gln His Thr Ile Arg Ser

260 265 270

His Lys Asp Phe Leu Ala Gln Ile Val Leu Pro Ala Thr Phe Val Phe

275 280 285

Leu Ala Leu Met Leu Ser Ile Val Ile Pro Pro Phe Gly Glu Tyr Pro

290 295 300

Ala Leu Thr Leu His Pro Trp Ile Tyr Gly Gln Gln Tyr Thr Phe Phe

305 310 315 320

Ser Met Asp Glu Pro Gly Ser Glu Gln Phe Thr Val Leu Ala Asp Val

325 330 335

Leu Leu Asn Lys Pro Gly Phe Gly Asn Arg Cys Leu Lys Glu Gly Trp

340 345 350

Leu Pro Glu Tyr Pro Cys Gly Asn Ser Thr Pro Trp Lys Thr Pro Ser

355 360 365

Val Ser Pro Asn Ile Thr Gln Leu Phe Gln Lys Gln Lys Trp Thr Gln

370 375 380

Val Asn Pro Ser Pro Ser Cys Arg Cys Ser Thr Arg Glu Lys Leu Thr

385 390 395 400

Met Leu Pro Glu Cys Pro Glu Gly Ala Gly Gly Leu Pro Pro Pro Gln

405 410 415

Arg Thr Gln Arg Ser Thr Glu Ile Leu Gln Asp Leu Thr Asp Arg Asn

420 425 430

Ile Ser Asp Phe Leu Val Lys Thr Tyr Pro Ala Leu Ile Arg Ser Ser

435 440 445

Leu Lys Ser Lys Phe Trp Val Asn Glu Gln Arg Tyr Gly Gly Ile Ser

450 455 460

Ile Gly Gly Lys Leu Pro Val Val Pro Ile Thr Gly Glu Ala Leu Val

465 470 475 480

Gly Phe Leu Ser Asp Leu Gly Arg Ile Met Asn Val Ser Gly Gly Pro

485 490 495

Ile Thr Arg Glu Ala Ser Lys Glu Ile Pro Asp Phe Leu Lys His Leu

500 505 510

Glu Thr Glu Asp Asn Ile Lys Val Trp Phe Asn Asn Lys Gly Trp His

515 520 525

Ala Leu Val Ser Phe Leu Asn Val Ala His Asn Ala Ile Leu Arg Ala

530 535 540

Ser Leu Pro Lys Asp Arg Ser Pro Glu Glu Tyr Gly Ile Thr Val Ile

545 550 555 560

Ser Gln Pro Leu Asn Leu Thr Lys Glu Gln Leu Ser Glu Ile Thr Val

565 570 575

Leu Thr Thr Ser Val Asp Ala Val Val Ala Ile Cys Val Ile Phe Ser

580 585 590

Met Ser Phe Val Pro Ala Ser Phe Val Leu Tyr Leu Ile Gln Glu Arg

595 600 605

Val Asn Lys Ser Lys His Leu Gln Phe Ile Ser Gly Val Ser Pro Thr

610 615 620

Thr Tyr Trp Val Thr Asn Phe Leu Trp Asp Ile Met Asn Tyr Ser Val

625 630 635 640

Ser Ala Gly Leu Val Val Gly Ile Phe Ile Gly Phe Gln Lys Lys Ala

645 650 655

Tyr Thr Ser Pro Glu Asn Leu Pro Ala Leu Val Ala Leu Leu Leu Leu

660 665 670

Tyr Gly Trp Ala Val Ile Pro Met Met Tyr Pro Ala Ser Phe Leu Phe

675 680 685

Asp Val Pro Ser Thr Ala Tyr Val Ala Leu Ser Cys Ala Asn Leu Phe

690 695 700

Ile Gly Ile Asn Ser Ser Ala Ile Thr Phe Ile Leu Glu Leu Phe Glu

705 710 715 720

Asn Asn Arg Thr Leu Leu Arg Phe Asn Ala Val Leu Arg Lys Leu Leu

725 730 735

Ile Val Phe Pro His Phe Cys Leu Gly Arg Gly Leu Ile Asp Leu Ala

740 745 750

Leu Ser Gln Ala Val Thr Asp Val Tyr Ala Arg Phe Gly Glu Glu His

755 760 765

Ser Ala Asn Pro Phe His Trp Asp Leu Ile Gly Lys Asn Leu Phe Ala

770 775 780

Met Val Val Glu Gly Val Val Tyr Phe Leu Leu Thr Leu Leu Val Gln

785 790 795 800

Arg His Phe Phe Leu Ser Gln Trp Ile Ala Glu Pro Thr Lys Glu Pro

805 810 815

Ile Val Asp Glu Asp Asp Asp Val Ala Glu Glu Arg Gln Arg Ile Ile

820 825 830

Thr Gly Gly Asn Lys Thr Asp Ile Leu Arg Leu His Glu Leu Thr Lys

835 840 845

Ile Tyr Pro Gly Thr Ser Ser Pro Ala Val Asp Arg Leu Cys Val Gly

850 855 860

Val Arg Pro Gly Glu Cys Phe Gly Leu Leu Gly Val Asn Gly Ala Gly

865 870 875 880

Lys Thr Thr Thr Phe Lys Met Leu Thr Gly Asp Thr Thr Val Thr Ser

885 890 895

Gly Asp Ala Thr Val Ala Gly Lys Ser Ile Leu Thr Asn Ile Ser Glu

900 905 910

Val His Gln Asn Met Gly Tyr Cys Pro Gln Phe Asp Ala Ile Asp Glu

915 920 925

Leu Leu Thr Gly Arg Glu His Leu Tyr Leu Tyr Ala Arg Leu Arg Gly

930 935 940

Val Pro Ala Glu Glu Ile Glu Lys Val Ala Asn Trp Ser Ile Lys Ser

945 950 955 960

Leu Gly Leu Thr Val Tyr Ala Asp Cys Leu Ala Gly Thr Tyr Ser Gly

965 970 975

Gly Asn Lys Arg Lys Leu Ser Thr Ala Ile Ala Leu Ile Gly Cys Pro

980 985 990

Pro Leu Val Leu Leu Asp Glu Pro Thr Thr Gly Met Asp Pro Gln Ala

995 1000 1005

Arg Arg Met Leu Trp Asn Val Ile Val Ser Ile Ile Arg Glu Gly Arg

1010 1015 1020

Ala Val Val Leu Thr Ser His Ser Met Glu Glu Cys Glu Ala Leu Cys

1025 1030 1035 1040

Thr Arg Leu Ala Ile Met Val Lys Gly Ala Phe Arg Cys Met Gly Thr

1045 1050 1055

Ile Gln His Leu Lys Ser Lys Phe Gly Asp Gly Tyr Ile Val Thr Met

1060 1065 1070

Lys Ile Lys Ser Pro Lys Asp Asp Leu Leu Pro Asp Leu Asn Pro Val

1075 1080 1085

Glu Gln Phe Phe Gln Gly Asn Phe Pro Gly Ser Val Gln Arg Glu Arg

1090 1095 1100

His Tyr Asn Met Leu Gln Phe Gln Val Ser Ser Ser Ser Leu Ala Arg

1105 1110 1115 1120

Ile Phe Gln Leu Leu Leu Ser His Lys Asp Ser Leu Leu Ile Glu Glu

1125 1130 1135

Tyr Ser Val Thr Gln Thr Thr Leu Asp Gln Val Phe Val Asn Phe Ala

1140 1145 1150

Lys Gln Gln Thr Glu Ser His Asp Leu Pro Leu His Pro Arg Ala Ala

1155 1160 1165

Gly Ala Ser Arg Gln Ala Gln Asp

1170 1175

<210> 8

<211> 3756

<212> DNA

<213> Artificial sequence (Artificial Sequence)

<400> 8

atgggctttg tgcgacagat tcagctgctg ctgtggaaga actggaccct gcggaagcgg 60

cagaaaatca gattcgtggt ggaactcgtg tggcccctga gcctgtttct ggtgctgatc 120

tggctgcgga acgccaatcc tctgtacagc caccacgagt gtcacttccc caacaaggcc 180

atgccttctg ccggaatgct gccttggctg cagggcatct tctgcaacgt gaacaacccc 240

tgctttcaga gccccacacc tggcgaaagc cctggcatcg tgtccaacta caacaacagc 300

atcctggcca gagtgtaccg ggacttccaa gagctgctga tgaacgcccc tgagtctcag 360

cacctgggca gaatctggac cgagctgcac atcctgagcc agttcatgga caccctgaga 420

acacaccccg agagaatcgc cggcaggggc atcagaatcc gggacatcct gaaggacgag 480

gaaaccctga cactgttcct catcaagaac atcggcctga gcgacagcgt ggtgtacctg 540

ctgatcaaca gccaagtgcg gcccgagcag tttgctcatg gcgtgccaga tctcgccctg 600

aaggatatcg cctgttctga ggccctgctg gaacggttca tcatcttcag ccagcggaga 660

ggcgccaaga ccgtcagata tgccctgtgc agtctgagcc agggaaccct gcagtggatc 720

gaggataccc tgtacgccaa cgtggacttc ttcaagctgt tccgggtgct gcccacactg 780

ctggattcta gatcccaggg catcaacctg agaagctggg gcggcatcct gtccgacatg 840

agcccaagaa tccaagagtt catccaccgg cctagcatgc aggacctgct gtgggttacc 900

agacctctga tgcagaacgg cggacccgag acattcacca agctgatggg aattctgagc 960

gatctgctgt gcggctaccc tgaaggcgga ggatctagag tgctgagctt caattggtac 1020

gaggacaaca actacaaggc cttcctgggc atcgactcca ccagaaagga ccccatctac 1080

agctacgacc ggcggacaac cagcttctgc aatgccctga tccagagcct ggaaagcaac 1140

cctctgacca agatcgcttg gagggccgcc aaacctctgc tgatgggaaa gatcctgtac 1200

acccctgaca gccctgccgc cagaagaatc ctgaagaacg ccaacagcac cttcgaggaa 1260

ctggaacacg tgcgcaagct ggtcaaggcc tgggaagaag tgggacctca gatctggtac 1320

ttcttcgaca atagcaccca gatgaacatg atcagagaca ccctgggcaa ccctaccgtg 1380

aaggacttcc tgaacagaca gctgggcgaa gagggcatta ccgccgaggc catcctgaac 1440

tttctgtaca agggccccag agagtcccag gccgacgaca tggccaactt cgattggcgg 1500

gacatcttca acatcaccga cagaaccctg cggctggtca accagtacct ggaatgcctg 1560

gtgctggaca agttcgagag ctacaacgac gagacacagc tgacccagag agccctgtct 1620

ctgctggaag agaatatgtt ctgggctggc gtggtgttcc ccgacatgta cccttggaca 1680

agcagcctgc ctcctcacgt gaagtacaag atccggatgg acatcgacgt ggtcgaaaag 1740

accaacaaga tcaaggatcg gtactgggac agcggcccta gagctgatcc cgtggaagat 1800

tttcggtaca tctggggcgg attcgcatac ctgcaggaca tggtggaaca gggaatcaca 1860

cggtcccagg tgcaggctga agctcctgtg ggaatctacc tgcagcagat gccttatcct 1920

tgcttcgtgg acgacagctt catgatcatc ctgaatcggt gcttccccat cttcatggtg 1980

ctggcctgga tctactccgt gtctatgacc gtgaagtcca tcgtgctgga aaaagagctg 2040

cggctgaaag agacactgaa gaaccagggc gtgtccaatg ccgtgatctg gtgcacctgg 2100

tttctggaca gcttctccat tatgagcatg agcatctttc tgctgacgat cttcatcatg 2160

cacggccgga tcctgcacta cagcgacccc tttatcctct tcctgttcct gctggccttc 2220

agcaccgcta caatcatgct gtgttttctg ctgtccacct tcttcagcaa ggcctctctg 2280

gccgctgctt gtagcggcgt gatctacttc accctgtacc tgcctcacat cctgtgcttc 2340

gcatggcagg acagaatgac cgccgagctg aagaaagctg tgtccctgct gagccctgtg 2400

gcctttggct ttggcaccga gtacctcgtc agatttgagg aacaaggact gggactgcag 2460

tggtccaaca tcggcaatag ccctacagag ggcgacgagt tcagcttcct gctgtctatg 2520

cagatgatgc tgctggacgc cgccgtgtat ggactgctgg cttggtatct ggaccaggtg 2580

ttcccaggcg attacggcac tcctctgcct tggtatttcc tgctgcaaga gagctactgg 2640

ctcggcggcg agggatgtag caccagagaa gaaagagccc tggaaaagac cgagcctctg 2700

accgaggaaa cagaggaccc tgaacaccca gagggcatcc acgatagctt tttcgagaga 2760

gaacaccccg gctgggtgcc aggcgtgtgt gtgaagaatc tggtcaagat cttcgagccc 2820

tgcggcagac ctgccgtgga cagactgaac atcaccttct acgagaacca gattaccgcc 2880

tttctgggcc acaacggcgc tggcaagaca accacactga gcatcctcac aggcctgctg 2940

cctccaacaa gcggcacagt tctcgttggc ggcagagaca tcgagacaag cctggatgcc 3000

gtcagacagt ccctgggcat gtgccctcag cacaacatcc tgtttcacca cctgaccgtg 3060

gccgagcaca tgctgtttta tgcccagctg aagggcaaga gccaagaaga ggctcagctg 3120

gaaatggaag ccatgctcga ggacaccggc ctgcaccaca agagaaatga ggaagcccag 3180

gatctgagcg gcggcatgca gagaaaactg agcgtggcca ttgccttcgt gggcgacgcc 3240

aaggttgtga tcctggatga gcctacaagc ggcgtggacc cttacagcag aagatccatc 3300

tgggatctgc tgctgaagta cagaagcggc cggaccatca tcatgagcac ccaccacatg 3360

gacgaggccg atctgctcgg agacagaatc gccatcattg ctcagggcag actgtactgc 3420

agcggcaccc cactgtttct gaagaactgt ctggctggcg atactctcat taccctggcc 3480

gatggacgac gagtgcctat tagagaactg gtgtcacagc agaatttttc cgtgtgggct 3540

ctgaatcctc agacttaccg cctggagagg gctagagtga gtagagcttt ctgtaccggc 3600

atcaaacctg tgtaccgcct caccactaga ctggggagat ccattagggc cactgccaac 3660

caccgatttc tcacacctca gggctggaaa cgagtcgatg aactccagcc tggagattac 3720

ctggctctgc ctaggagaat ccctactgcc tcctaa 3756

<210> 9

<211> 3531

<212> DNA

<213> Artificial sequence (Artificial Sequence)

<400> 9

atggcggcgg cgtgcccgga actgcgtcag ctggcgcaga gcgatgtgta ttgggatccg 60

attgtgagca ttgaaccgga tggcgtggaa gaagtgtttg atctgaccgt gccgggcccg 120

cataactttg tggcgaacga tattattgcg cataactgtt ttggcaccgg cctgtacctg 180

acactcgtgc ggaagatgaa gaacatccag agccagcgga agggcagcga gggcacatgt 240

agctgtagca gcaagggctt cagcaccacc tgtcctgctc acgtggacga tctgacccct 300

gaacaggtgc tggatggcga cgtgaacgag ctgatggacg tggtgctgca ccacgtgcct 360

gaggccaagc tggtggaatg catcggccaa gagctgatct tcctgctgcc taacaagaac 420

ttcaagcacc gggcctacgc cagcctgttc agagagctgg aagagacact ggccgatctg 480

ggcctgagca gctttggcat cagcgacacc cctctggaag aaatcttcct gaaagtgacc 540

gaggacagcg acagcggccc actttttgct ggcggagcac agcagaaacg cgagaacgtg 600

aaccctagac acccctgtct gggccctaga gagaaagccg gacagacccc tcaggacagc 660

aatgtgtgct ctcctggtgc tcctgccgct caccctgaag gacaacctcc acctgagcct 720

gagtgtcctg gacctcagct gaataccggc acacagctgg ttctgcagca cgtgcaagcc 780

ctgctggtca agagattcca gcacaccatc agaagccaca aggactttct ggcccagatt 840

gtgctgcccg ccaccttcgt ttttctggct ctgatgctga gcatcgtgat ccctccattc 900

ggcgagtacc ccgctctgac actgcaccct tggatctacg gccagcagta caccttcttc 960

agcatggacg agcctggcag cgagcagttt acagtgctgg ctgatgtgct gctgaacaag 1020

cccggcttcg gcaaccgctg tctgaaagaa ggatggctgc ctgagtaccc ctgcggcaat 1080

agcacccctt ggaaaacccc tagcgtgtcc cctaacatca cccagctgtt ccagaaacag 1140

aaatggaccc aagtgaaccc ctctccatcc tgccggtgct ccaccagaga aaagctgacc 1200

atgctgcccg agtgtccaga aggtgcaggc ggacttcctc cacctcagag aacccagaga 1260

agcaccgaga ttctgcagga cctgaccgac cggaatatca gcgacttcct ggttaagaca 1320

taccccgcac tgatccggtc cagcctgaag tccaagttct gggtcaacga gcagagatac 1380

ggcggcatct ctatcggcgg aaagctgcct gtggtgccta tcacaggcga agccctcgtg 1440

ggctttctgt ctgacctggg cagaatcatg aacgtgtccg gcggacccat caccagagag 1500

gccagcaaag agatccccga tttcctgaag cacctggaaa ccgaggataa catcaaagtg 1560

tggttcaaca acaaaggctg gcacgccctg gtgtcctttc tgaacgtggc ccacaacgcc 1620

atcctgagag ccagcctgcc taaggacaga agccctgagg aatacggcat caccgtgatc 1680

tcccagccac tgaacctgac caaagagcag ctgagcgaga tcaccgtgct gaccacatct 1740

gtggatgccg tggtggccat ctgcgtgatc ttctccatga gcttcgtgcc tgcctccttc 1800

gtgctgtatc tgatccaaga gagagtgaac aagagcaagc acctccagtt tatcagcgga 1860

gtgtccccaa ccacctactg ggtcaccaac tttctgtggg acatcatgaa ctactccgtg 1920

tctgccggcc tggtcgtggg catcttcatc ggctttcaga agaaggccta cacaagcccc 1980

gagaacctgc ctgctctggt tgctctgctg ctgctgtatg gctgggccgt gattcccatg 2040

atgtaccccg ccagcttcct gttcgatgtg cctagcacag cctacgtggc cctgagctgc 2100

gccaatctgt tcatcggcat caacagcagc gccatcacct tcatcctgga actgttcgag 2160

aacaacagaa ccctgctgcg gttcaacgcc gtgctgagaa agctgctgat cgtgttccct 2220

cacttctgcc tcggcagagg cctgattgat ctggccctgt ctcaggccgt gaccgacgtg 2280

tacgctagat ttggcgagga acacagcgcc aatcctttcc actgggacct gatcggcaag 2340

aacctgttcg ccatggtggt ggaaggcgtg gtgtatttcc tgctgactct gctggtgcag 2400

cggcacttct ttctgtccca atggatcgcc gagcctacca aagaacccat cgtggacgag 2460

gacgacgacg tggccgaaga gagacagaga atcatcaccg gcggcaacaa gaccgacatc 2520

ctgaggctgc acgagctgac caagatctac cctggcacat ctagccctgc cgtggacaga 2580

ctgtgtgtgg gagttagacc tggcgagtgc tttggcctgc tgggagttaa tggcgccgga 2640

aagaccacca ccttcaagat gctgaccggc gacaccacag tgaccagcgg agatgctact 2700

gtggccggca agagcatcct gaccaacatc agcgaggtgc accagaacat gggctactgc 2760

cctcagttcg acgccatcga cgaactgctg acaggcagag agcacctgta tctgtacgcc 2820

agactgagag gcgtgcccgc cgaagaaatt gagaaggtgg ccaactggtc catcaagagc 2880

ctgggactga ccgtgtacgc cgattgtctg gccggcacat atagcggcgg aaacaagcgg 2940

aagctgagca ccgccattgc tctgatcgga tgccctcctc tggtcctgct ggatgagcct 3000

acaaccggca tggatcccca ggctagacgg atgctgtgga acgtgatcgt gtccatcatc 3060

cgcgaaggca gagccgtggt cctgacaagc cacagcatgg aagagtgcga ggccctgtgt 3120

accagactgg ccatcatggt caagggcgcc ttcagatgca tgggcaccat tcagcacctg 3180

aaaagcaagt tcggcgacgg ctacatcgtg accatgaaga tcaagtcccc aaaggacgac 3240

ctgctgccag atctgaaccc cgtggaacag ttcttccagg gcaacttccc tggctccgtg 3300

cagcgggaaa gacactacaa catgctgcag tttcaggtgt ccagcagctc cctggccaga 3360

atctttcagc tgctgctctc ccacaaggat agcctgctga ttgaagagta cagcgtgacc 3420

cagaccacac tggaccaggt gttcgtgaac ttcgccaagc agcagaccga gagccacgac 3480

ttgcctctgc accctagagc tgccggcgct tctagacagg cccaggatta a 3531

<210> 10

<211> 296

<212> DNA

<213> human (homosapiens)

<400> 10

ggccccagaa gcctggtggt tgtttgtcct tctcagggga aaagtgaggc ggccccttgg 60

aggaaggggc cgggcagaat gatctaatcg gattccaagc agctcagggg attgtctttt 120

tctagcacct tcttgccact cctaagcgtc ctccgtgacc ccggctggga tttagcctgg 180

tgctgtgtca gccccggtct cccaggggct tcccagtggt ccccaggaac cctcgacagg 240

gcccggtctc tctcgtccag caagggcagg gacgggccac aggccaaggg cggtac 296

<210> 11

<211> 4495

<212> DNA

<213> Artificial sequence (Artificial Sequence)

<400> 11

ggccccagaa gcctggtggt tgtttgtcct tctcagggga aaagtgaggc ggccccttgg 60

aggaaggggc cgggcagaat gatctaatcg gattccaagc agctcagggg attgtctttt 120

tctagcacct tcttgccact cctaagcgtc ctccgtgacc ccggctggga tttagcctgg 180

tgctgtgtca gccccggtct cccaggggct tcccagtggt ccccaggaac cctcgacagg 240

gcccggtctc tctcgtccag caagggcagg gacgggccac aggccaaggg cggtactcta 300

gaggatccgg tactcgagga actgaaaaac cagaaagtta actggtaagt ttagtctttt 360

tgtcttttat ttcaggtccc ggatccggtg gtggtgcaaa tcaaagaact gctcctcagt 420

ggatgttgcc tttacttcta ggcctgtacg gaagtgttac ttctgctcta aaagctgcgg 480

aattgtaccc gcggccgcca ccatgggctt tgtgcgacag attcagctgc tgctgtggaa 540

gaactggacc ctgcggaagc ggcagaaaat cagattcgtg gtggaactcg tgtggcccct 600

gagcctgttt ctggtgctga tctggctgcg gaacgccaat cctctgtaca gccaccacga 660

gtgtcacttc cccaacaagg ccatgccttc tgccggaatg ctgccttggc tgcagggcat 720

cttctgcaac gtgaacaacc cctgctttca gagccccaca cctggcgaaa gccctggcat 780

cgtgtccaac tacaacaaca gcatcctggc cagagtgtac cgggacttcc aagagctgct 840

gatgaacgcc cctgagtctc agcacctggg cagaatctgg accgagctgc acatcctgag 900

ccagttcatg gacaccctga gaacacaccc cgagagaatc gccggcaggg gcatcagaat 960

ccgggacatc ctgaaggacg aggaaaccct gacactgttc ctcatcaaga acatcggcct 1020

gagcgacagc gtggtgtacc tgctgatcaa cagccaagtg cggcccgagc agtttgctca 1080

tggcgtgcca gatctcgccc tgaaggatat cgcctgttct gaggccctgc tggaacggtt 1140

catcatcttc agccagcgga gaggcgccaa gaccgtcaga tatgccctgt gcagtctgag 1200

ccagggaacc ctgcagtgga tcgaggatac cctgtacgcc aacgtggact tcttcaagct 1260

gttccgggtg ctgcccacac tgctggattc tagatcccag ggcatcaacc tgagaagctg 1320

gggcggcatc ctgtccgaca tgagcccaag aatccaagag ttcatccacc ggcctagcat 1380

gcaggacctg ctgtgggtta ccagacctct gatgcagaac ggcggacccg agacattcac 1440

caagctgatg ggaattctga gcgatctgct gtgcggctac cctgaaggcg gaggatctag 1500

agtgctgagc ttcaattggt acgaggacaa caactacaag gccttcctgg gcatcgactc 1560

caccagaaag gaccccatct acagctacga ccggcggaca accagcttct gcaatgccct 1620

gatccagagc ctggaaagca accctctgac caagatcgct tggagggccg ccaaacctct 1680

gctgatggga aagatcctgt acacccctga cagccctgcc gccagaagaa tcctgaagaa 1740

cgccaacagc accttcgagg aactggaaca cgtgcgcaag ctggtcaagg cctgggaaga 1800

agtgggacct cagatctggt acttcttcga caatagcacc cagatgaaca tgatcagaga 1860

caccctgggc aaccctaccg tgaaggactt cctgaacaga cagctgggcg aagagggcat 1920

taccgccgag gccatcctga actttctgta caagggcccc agagagtccc aggccgacga 1980

catggccaac ttcgattggc gggacatctt caacatcacc gacagaaccc tgcggctggt 2040

caaccagtac ctggaatgcc tggtgctgga caagttcgag agctacaacg acgagacaca 2100

gctgacccag agagccctgt ctctgctgga agagaatatg ttctgggctg gcgtggtgtt 2160

ccccgacatg tacccttgga caagcagcct gcctcctcac gtgaagtaca agatccggat 2220

ggacatcgac gtggtcgaaa agaccaacaa gatcaaggat cggtactggg acagcggccc 2280

tagagctgat cccgtggaag attttcggta catctggggc ggattcgcat acctgcagga 2340

catggtggaa cagggaatca cacggtccca ggtgcaggct gaagctcctg tgggaatcta 2400

cctgcagcag atgccttatc cttgcttcgt ggacgacagc ttcatgatca tcctgaatcg 2460

gtgcttcccc atcttcatgg tgctggcctg gatctactcc gtgtctatga ccgtgaagtc 2520

catcgtgctg gaaaaagagc tgcggctgaa agagacactg aagaaccagg gcgtgtccaa 2580

tgccgtgatc tggtgcacct ggtttctgga cagcttctcc attatgagca tgagcatctt 2640

tctgctgacg atcttcatca tgcacggccg gatcctgcac tacagcgacc cctttatcct 2700

cttcctgttc ctgctggcct tcagcaccgc tacaatcatg ctgtgttttc tgctgtccac 2760

cttcttcagc aaggcctctc tggccgctgc ttgtagcggc gtgatctact tcaccctgta 2820

cctgcctcac atcctgtgct tcgcatggca ggacagaatg accgccgagc tgaagaaagc 2880

tgtgtccctg ctgagccctg tggcctttgg ctttggcacc gagtacctcg tcagatttga 2940

ggaacaagga ctgggactgc agtggtccaa catcggcaat agccctacag agggcgacga 3000

gttcagcttc ctgctgtcta tgcagatgat gctgctggac gccgccgtgt atggactgct 3060

ggcttggtat ctggaccagg tgttcccagg cgattacggc actcctctgc cttggtattt 3120

cctgctgcaa gagagctact ggctcggcgg cgagggatgt agcaccagag aagaaagagc 3180

cctggaaaag accgagcctc tgaccgagga aacagaggac cctgaacacc cagagggcat 3240

ccacgatagc tttttcgaga gagaacaccc cggctgggtg ccaggcgtgt gtgtgaagaa 3300

tctggtcaag atcttcgagc cctgcggcag acctgccgtg gacagactga acatcacctt 3360

ctacgagaac cagattaccg cctttctggg ccacaacggc gctggcaaga caaccacact 3420

gagcatcctc acaggcctgc tgcctccaac aagcggcaca gttctcgttg gcggcagaga 3480

catcgagaca agcctggatg ccgtcagaca gtccctgggc atgtgccctc agcacaacat 3540

cctgtttcac cacctgaccg tggccgagca catgctgttt tatgcccagc tgaagggcaa 3600

gagccaagaa gaggctcagc tggaaatgga agccatgctc gaggacaccg gcctgcacca 3660

caagagaaat gaggaagccc aggatctgag cggcggcatg cagagaaaac tgagcgtggc 3720

cattgccttc gtgggcgacg ccaaggttgt gatcctggat gagcctacaa gcggcgtgga 3780

cccttacagc agaagatcca tctgggatct gctgctgaag tacagaagcg gccggaccat 3840

catcatgagc acccaccaca tggacgaggc cgatctgctc ggagacagaa tcgccatcat 3900

tgctcagggc agactgtact gcagcggcac cccactgttt ctgaagaact gtctggctgg 3960

cgatactctc attaccctgg ccgatggacg acgagtgcct attagagaac tggtgtcaca 4020

gcagaatttt tccgtgtggg ctctgaatcc tcagacttac cgcctggaga gggctagagt 4080

gagtagagct ttctgtaccg gcatcaaacc tgtgtaccgc ctcaccacta gactggggag 4140

atccattagg gccactgcca accaccgatt tctcacacct cagggctgga aacgagtcga 4200

tgaactccag cctggagatt acctggctct gcctaggaga atccctactg cctcctaaac 4260

gcgtcctcga ctgtgccttc tagttgccag ccatctgttg tttgcccctc ccccgtgcct 4320

tccttgaccc tggaaggtgc cactcccact gtcctttcct aataaaatga ggaaattgca 4380

tcgcattgtc tgagtaggtg tcattctatt ctggggggtg gggtggggca ggacagcaag 4440

ggggaggatt gggaagacaa tagcaggcat gctggggatg cggtgggctc tatgg 4495

<210> 12

<211> 4273

<212> DNA

<213> Artificial sequence (Artificial Sequence)

<400> 12

ggccccagaa gcctggtggt tgtttgtcct tctcagggga aaagtgaggc ggccccttgg 60

aggaaggggc cgggcagaat gatctaatcg gattccaagc agctcagggg attgtctttt 120

tctagcacct tcttgccact cctaagcgtc ctccgtgacc ccggctggga tttagcctgg 180

tgctgtgtca gccccggtct cccaggggct tcccagtggt ccccaggaac cctcgacagg 240

gcccggtctc tctcgtccag caagggcagg gacgggccac aggccaaggg cggtactcta 300

gaggatccgg tactcgagga actgaaaaac cagaaagtta actggtaagt ttagtctttt 360

tgtcttttat ttcaggtccc ggatccggtg gtggtgcaaa tcaaagaact gctcctcagt 420

ggatgttgcc tttacttcta ggcctgtacg gaagtgttac ttctgctcta aaagctgcgg 480

aattgtaccc gcggccgcca ccatggcggc ggcgtgcccg gaactgcgtc agctggcgca 540

gagcgatgtg tattgggatc cgattgtgag cattgaaccg gatggcgtgg aagaagtgtt 600

tgatctgacc gtgccgggcc cgcataactt tgtggcgaac gatattattg cgcataactg 660

ttttggcacc ggcctgtacc tgacactcgt gcggaagatg aagaacatcc agagccagcg 720

gaagggcagc gagggcacat gtagctgtag cagcaagggc ttcagcacca cctgtcctgc 780

tcacgtggac gatctgaccc ctgaacaggt gctggatggc gacgtgaacg agctgatgga 840

cgtggtgctg caccacgtgc ctgaggccaa gctggtggaa tgcatcggcc aagagctgat 900

cttcctgctg cctaacaaga acttcaagca ccgggcctac gccagcctgt tcagagagct 960

ggaagagaca ctggccgatc tgggcctgag cagctttggc atcagcgaca cccctctgga 1020

agaaatcttc ctgaaagtga ccgaggacag cgacagcggc ccactttttg ctggcggagc 1080

acagcagaaa cgcgagaacg tgaaccctag acacccctgt ctgggcccta gagagaaagc 1140

cggacagacc cctcaggaca gcaatgtgtg ctctcctggt gctcctgccg ctcaccctga 1200

aggacaacct ccacctgagc ctgagtgtcc tggacctcag ctgaataccg gcacacagct 1260

ggttctgcag cacgtgcaag ccctgctggt caagagattc cagcacacca tcagaagcca 1320

caaggacttt ctggcccaga ttgtgctgcc cgccaccttc gtttttctgg ctctgatgct 1380

gagcatcgtg atccctccat tcggcgagta ccccgctctg acactgcacc cttggatcta 1440

cggccagcag tacaccttct tcagcatgga cgagcctggc agcgagcagt ttacagtgct 1500

ggctgatgtg ctgctgaaca agcccggctt cggcaaccgc tgtctgaaag aaggatggct 1560

gcctgagtac ccctgcggca atagcacccc ttggaaaacc cctagcgtgt cccctaacat 1620

cacccagctg ttccagaaac agaaatggac ccaagtgaac ccctctccat cctgccggtg 1680

ctccaccaga gaaaagctga ccatgctgcc cgagtgtcca gaaggtgcag gcggacttcc 1740

tccacctcag agaacccaga gaagcaccga gattctgcag gacctgaccg accggaatat 1800

cagcgacttc ctggttaaga cataccccgc actgatccgg tccagcctga agtccaagtt 1860

ctgggtcaac gagcagagat acggcggcat ctctatcggc ggaaagctgc ctgtggtgcc 1920

tatcacaggc gaagccctcg tgggctttct gtctgacctg ggcagaatca tgaacgtgtc 1980

cggcggaccc atcaccagag aggccagcaa agagatcccc gatttcctga agcacctgga 2040

aaccgaggat aacatcaaag tgtggttcaa caacaaaggc tggcacgccc tggtgtcctt 2100

tctgaacgtg gcccacaacg ccatcctgag agccagcctg cctaaggaca gaagccctga 2160

ggaatacggc atcaccgtga tctcccagcc actgaacctg accaaagagc agctgagcga 2220

gatcaccgtg ctgaccacat ctgtggatgc cgtggtggcc atctgcgtga tcttctccat 2280

gagcttcgtg cctgcctcct tcgtgctgta tctgatccaa gagagagtga acaagagcaa 2340

gcacctccag tttatcagcg gagtgtcccc aaccacctac tgggtcacca actttctgtg 2400

ggacatcatg aactactccg tgtctgccgg cctggtcgtg ggcatcttca tcggctttca 2460

gaagaaggcc tacacaagcc ccgagaacct gcctgctctg gttgctctgc tgctgctgta 2520

tggctgggcc gtgattccca tgatgtaccc cgccagcttc ctgttcgatg tgcctagcac 2580

agcctacgtg gccctgagct gcgccaatct gttcatcggc atcaacagca gcgccatcac 2640

cttcatcctg gaactgttcg agaacaacag aaccctgctg cggttcaacg ccgtgctgag 2700

aaagctgctg atcgtgttcc ctcacttctg cctcggcaga ggcctgattg atctggccct 2760

gtctcaggcc gtgaccgacg tgtacgctag atttggcgag gaacacagcg ccaatccttt 2820

ccactgggac ctgatcggca agaacctgtt cgccatggtg gtggaaggcg tggtgtattt 2880

cctgctgact ctgctggtgc agcggcactt ctttctgtcc caatggatcg ccgagcctac 2940

caaagaaccc atcgtggacg aggacgacga cgtggccgaa gagagacaga gaatcatcac 3000

cggcggcaac aagaccgaca tcctgaggct gcacgagctg accaagatct accctggcac 3060

atctagccct gccgtggaca gactgtgtgt gggagttaga cctggcgagt gctttggcct 3120

gctgggagtt aatggcgccg gaaagaccac caccttcaag atgctgaccg gcgacaccac 3180

agtgaccagc ggagatgcta ctgtggccgg caagagcatc ctgaccaaca tcagcgaggt 3240

gcaccagaac atgggctact gccctcagtt cgacgccatc gacgaactgc tgacaggcag 3300

agagcacctg tatctgtacg ccagactgag aggcgtgccc gccgaagaaa ttgagaaggt 3360

ggccaactgg tccatcaaga gcctgggact gaccgtgtac gccgattgtc tggccggcac 3420

atatagcggc ggaaacaagc ggaagctgag caccgccatt gctctgatcg gatgccctcc 3480

tctggtcctg ctggatgagc ctacaaccgg catggatccc caggctagac ggatgctgtg 3540

gaacgtgatc gtgtccatca tccgcgaagg cagagccgtg gtcctgacaa gccacagcat 3600

ggaagagtgc gaggccctgt gtaccagact ggccatcatg gtcaagggcg ccttcagatg 3660

catgggcacc attcagcacc tgaaaagcaa gttcggcgac ggctacatcg tgaccatgaa 3720

gatcaagtcc ccaaaggacg acctgctgcc agatctgaac cccgtggaac agttcttcca 3780

gggcaacttc cctggctccg tgcagcggga aagacactac aacatgctgc agtttcaggt 3840

gtccagcagc tccctggcca gaatctttca gctgctgctc tcccacaagg atagcctgct 3900

gattgaagag tacagcgtga cccagaccac actggaccag gtgttcgtga acttcgccaa 3960

gcagcagacc gagagccacg acttgcctct gcaccctaga gctgccggcg cttctagaca 4020

ggcccaggat taataaacgc gtcctcgact gtgccttcta gttgccagcc atctgttgtt 4080

tgcccctccc ccgtgccttc cttgaccctg gaaggtgcca ctcccactgt cctttcctaa 4140

taaaatgagg aaattgcatc gcattgtctg agtaggtgtc attctattct ggggggtggg 4200

gtggggcagg acagcaaggg ggaggattgg gaagacaata gcaggcatgc tggggatgcg 4260

gtgggctcta tgg 4273

<210> 13

<211> 4918

<212> DNA

<213> Artificial sequence (Artificial Sequence)

<400> 13

ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60

ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120

aggggttcct tgtagttaat gattaacccg ccatgctact tatctacgta gccatgctct 180

aggaagatcg gaattcgccc ttaagggccc cagaagcctg gtggttgttt gtccttctca 240

ggggaaaagt gaggcggccc cttggaggaa ggggccgggc agaatgatct aatcggattc 300

caagcagctc aggggattgt ctttttctag caccttcttg ccactcctaa gcgtcctccg 360

tgaccccggc tgggatttag cctggtgctg tgtcagcccc ggtctcccag gggcttccca 420

gtggtcccca ggaaccctcg acagggcccg gtctctctcg tccagcaagg gcagggacgg 480

gccacaggcc aagggcggta ctctagagga tccggtactc gaggaactga aaaaccagaa 540

agttaactgg taagtttagt ctttttgtct tttatttcag gtcccggatc cggtggtggt 600

gcaaatcaaa gaactgctcc tcagtggatg ttgcctttac ttctaggcct gtacggaagt 660

gttacttctg ctctaaaagc tgcggaattg tacccgcggc cgccaccatg ggctttgtgc 720

gacagattca gctgctgctg tggaagaact ggaccctgcg gaagcggcag aaaatcagat 780

tcgtggtgga actcgtgtgg cccctgagcc tgtttctggt gctgatctgg ctgcggaacg 840

ccaatcctct gtacagccac cacgagtgtc acttccccaa caaggccatg ccttctgccg 900

gaatgctgcc ttggctgcag ggcatcttct gcaacgtgaa caacccctgc tttcagagcc 960

ccacacctgg cgaaagccct ggcatcgtgt ccaactacaa caacagcatc ctggccagag 1020

tgtaccggga cttccaagag ctgctgatga acgcccctga gtctcagcac ctgggcagaa 1080

tctggaccga gctgcacatc ctgagccagt tcatggacac cctgagaaca caccccgaga 1140

gaatcgccgg caggggcatc agaatccggg acatcctgaa ggacgaggaa accctgacac 1200

tgttcctcat caagaacatc ggcctgagcg acagcgtggt gtacctgctg atcaacagcc 1260

aagtgcggcc cgagcagttt gctcatggcg tgccagatct cgccctgaag gatatcgcct 1320

gttctgaggc cctgctggaa cggttcatca tcttcagcca gcggagaggc gccaagaccg 1380

tcagatatgc cctgtgcagt ctgagccagg gaaccctgca gtggatcgag gataccctgt 1440

acgccaacgt ggacttcttc aagctgttcc gggtgctgcc cacactgctg gattctagat 1500

cccagggcat caacctgaga agctggggcg gcatcctgtc cgacatgagc ccaagaatcc 1560

aagagttcat ccaccggcct agcatgcagg acctgctgtg ggttaccaga cctctgatgc 1620

agaacggcgg acccgagaca ttcaccaagc tgatgggaat tctgagcgat ctgctgtgcg 1680

gctaccctga aggcggagga tctagagtgc tgagcttcaa ttggtacgag gacaacaact 1740

acaaggcctt cctgggcatc gactccacca gaaaggaccc catctacagc tacgaccggc 1800

ggacaaccag cttctgcaat gccctgatcc agagcctgga aagcaaccct ctgaccaaga 1860

tcgcttggag ggccgccaaa cctctgctga tgggaaagat cctgtacacc cctgacagcc 1920

ctgccgccag aagaatcctg aagaacgcca acagcacctt cgaggaactg gaacacgtgc 1980

gcaagctggt caaggcctgg gaagaagtgg gacctcagat ctggtacttc ttcgacaata 2040

gcacccagat gaacatgatc agagacaccc tgggcaaccc taccgtgaag gacttcctga 2100

acagacagct gggcgaagag ggcattaccg ccgaggccat cctgaacttt ctgtacaagg 2160

gccccagaga gtcccaggcc gacgacatgg ccaacttcga ttggcgggac atcttcaaca 2220

tcaccgacag aaccctgcgg ctggtcaacc agtacctgga atgcctggtg ctggacaagt 2280

tcgagagcta caacgacgag acacagctga cccagagagc cctgtctctg ctggaagaga 2340

atatgttctg ggctggcgtg gtgttccccg acatgtaccc ttggacaagc agcctgcctc 2400

ctcacgtgaa gtacaagatc cggatggaca tcgacgtggt cgaaaagacc aacaagatca 2460

aggatcggta ctgggacagc ggccctagag ctgatcccgt ggaagatttt cggtacatct 2520

ggggcggatt cgcatacctg caggacatgg tggaacaggg aatcacacgg tcccaggtgc 2580

aggctgaagc tcctgtggga atctacctgc agcagatgcc ttatccttgc ttcgtggacg 2640

acagcttcat gatcatcctg aatcggtgct tccccatctt catggtgctg gcctggatct 2700

actccgtgtc tatgaccgtg aagtccatcg tgctggaaaa agagctgcgg ctgaaagaga 2760

cactgaagaa ccagggcgtg tccaatgccg tgatctggtg cacctggttt ctggacagct 2820

tctccattat gagcatgagc atctttctgc tgacgatctt catcatgcac ggccggatcc 2880

tgcactacag cgaccccttt atcctcttcc tgttcctgct ggccttcagc accgctacaa 2940

tcatgctgtg ttttctgctg tccaccttct tcagcaaggc ctctctggcc gctgcttgta 3000

gcggcgtgat ctacttcacc ctgtacctgc ctcacatcct gtgcttcgca tggcaggaca 3060

gaatgaccgc cgagctgaag aaagctgtgt ccctgctgag ccctgtggcc tttggctttg 3120

gcaccgagta cctcgtcaga tttgaggaac aaggactggg actgcagtgg tccaacatcg 3180

gcaatagccc tacagagggc gacgagttca gcttcctgct gtctatgcag atgatgctgc 3240

tggacgccgc cgtgtatgga ctgctggctt ggtatctgga ccaggtgttc ccaggcgatt 3300

acggcactcc tctgccttgg tatttcctgc tgcaagagag ctactggctc ggcggcgagg 3360

gatgtagcac cagagaagaa agagccctgg aaaagaccga gcctctgacc gaggaaacag 3420

aggaccctga acacccagag ggcatccacg atagcttttt cgagagagaa caccccggct 3480

gggtgccagg cgtgtgtgtg aagaatctgg tcaagatctt cgagccctgc ggcagacctg 3540

ccgtggacag actgaacatc accttctacg agaaccagat taccgccttt ctgggccaca 3600

acggcgctgg caagacaacc acactgagca tcctcacagg cctgctgcct ccaacaagcg 3660

gcacagttct cgttggcggc agagacatcg agacaagcct ggatgccgtc agacagtccc 3720

tgggcatgtg ccctcagcac aacatcctgt ttcaccacct gaccgtggcc gagcacatgc 3780

tgttttatgc ccagctgaag ggcaagagcc aagaagaggc tcagctggaa atggaagcca 3840

tgctcgagga caccggcctg caccacaaga gaaatgagga agcccaggat ctgagcggcg 3900

gcatgcagag aaaactgagc gtggccattg ccttcgtggg cgacgccaag gttgtgatcc 3960

tggatgagcc tacaagcggc gtggaccctt acagcagaag atccatctgg gatctgctgc 4020

tgaagtacag aagcggccgg accatcatca tgagcaccca ccacatggac gaggccgatc 4080

tgctcggaga cagaatcgcc atcattgctc agggcagact gtactgcagc ggcaccccac 4140

tgtttctgaa gaactgtctg gctggcgata ctctcattac cctggccgat ggacgacgag 4200

tgcctattag agaactggtg tcacagcaga atttttccgt gtgggctctg aatcctcaga 4260

cttaccgcct ggagagggct agagtgagta gagctttctg taccggcatc aaacctgtgt 4320

accgcctcac cactagactg gggagatcca ttagggccac tgccaaccac cgatttctca 4380

cacctcaggg ctggaaacga gtcgatgaac tccagcctgg agattacctg gctctgccta 4440

ggagaatccc tactgcctcc taaacgcgtc ctcgactgtg ccttctagtt gccagccatc 4500

tgttgtttgc ccctcccccg tgccttcctt gaccctggaa ggtgccactc ccactgtcct 4560

ttcctaataa aatgaggaaa ttgcatcgca ttgtctgagt aggtgtcatt ctattctggg 4620

gggtggggtg gggcaggaca gcaaggggga ggattgggaa gacaatagca ggcatgctgg 4680

ggatgcggtg ggctctatgg cctcgagtta agggcgaatt cccgataagg atcttcctag 4740

agcatggcta cgtagataag tagcatggcg ggttaatcat taactacaag gaacccctag 4800

tgatggagtt ggccactccc tctctgcgcg ctcgctcgct cactgaggcc gggcgaccaa 4860

aggtcgcccg acgcccgggc tttgcccggg cggcctcagt gagcgagcga gcgcgcag 4918

<210> 14

<211> 4696

<212> DNA

<213> Artificial sequence (Artificial Sequence)

<400> 14

ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60

ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120

aggggttcct tgtagttaat gattaacccg ccatgctact tatctacgta gccatgctct 180

aggaagatcg gaattcgccc ttaagggccc cagaagcctg gtggttgttt gtccttctca 240

ggggaaaagt gaggcggccc cttggaggaa ggggccgggc agaatgatct aatcggattc 300

caagcagctc aggggattgt ctttttctag caccttcttg ccactcctaa gcgtcctccg 360

tgaccccggc tgggatttag cctggtgctg tgtcagcccc ggtctcccag gggcttccca 420

gtggtcccca ggaaccctcg acagggcccg gtctctctcg tccagcaagg gcagggacgg 480

gccacaggcc aagggcggta ctctagagga tccggtactc gaggaactga aaaaccagaa 540

agttaactgg taagtttagt ctttttgtct tttatttcag gtcccggatc cggtggtggt 600

gcaaatcaaa gaactgctcc tcagtggatg ttgcctttac ttctaggcct gtacggaagt 660

gttacttctg ctctaaaagc tgcggaattg tacccgcggc cgccaccatg gcggcggcgt 720

gcccggaact gcgtcagctg gcgcagagcg atgtgtattg ggatccgatt gtgagcattg 780

aaccggatgg cgtggaagaa gtgtttgatc tgaccgtgcc gggcccgcat aactttgtgg 840

cgaacgatat tattgcgcat aactgttttg gcaccggcct gtacctgaca ctcgtgcgga 900

agatgaagaa catccagagc cagcggaagg gcagcgaggg cacatgtagc tgtagcagca 960

agggcttcag caccacctgt cctgctcacg tggacgatct gacccctgaa caggtgctgg 1020

atggcgacgt gaacgagctg atggacgtgg tgctgcacca cgtgcctgag gccaagctgg 1080

tggaatgcat cggccaagag ctgatcttcc tgctgcctaa caagaacttc aagcaccggg 1140

cctacgccag cctgttcaga gagctggaag agacactggc cgatctgggc ctgagcagct 1200

ttggcatcag cgacacccct ctggaagaaa tcttcctgaa agtgaccgag gacagcgaca 1260

gcggcccact ttttgctggc ggagcacagc agaaacgcga gaacgtgaac cctagacacc 1320

cctgtctggg ccctagagag aaagccggac agacccctca ggacagcaat gtgtgctctc 1380

ctggtgctcc tgccgctcac cctgaaggac aacctccacc tgagcctgag tgtcctggac 1440

ctcagctgaa taccggcaca cagctggttc tgcagcacgt gcaagccctg ctggtcaaga 1500

gattccagca caccatcaga agccacaagg actttctggc ccagattgtg ctgcccgcca 1560

ccttcgtttt tctggctctg atgctgagca tcgtgatccc tccattcggc gagtaccccg 1620

ctctgacact gcacccttgg atctacggcc agcagtacac cttcttcagc atggacgagc 1680

ctggcagcga gcagtttaca gtgctggctg atgtgctgct gaacaagccc ggcttcggca 1740

accgctgtct gaaagaagga tggctgcctg agtacccctg cggcaatagc accccttgga 1800

aaacccctag cgtgtcccct aacatcaccc agctgttcca gaaacagaaa tggacccaag 1860

tgaacccctc tccatcctgc cggtgctcca ccagagaaaa gctgaccatg ctgcccgagt 1920

gtccagaagg tgcaggcgga cttcctccac ctcagagaac ccagagaagc accgagattc 1980

tgcaggacct gaccgaccgg aatatcagcg acttcctggt taagacatac cccgcactga 2040

tccggtccag cctgaagtcc aagttctggg tcaacgagca gagatacggc ggcatctcta 2100

tcggcggaaa gctgcctgtg gtgcctatca caggcgaagc cctcgtgggc tttctgtctg 2160

acctgggcag aatcatgaac gtgtccggcg gacccatcac cagagaggcc agcaaagaga 2220

tccccgattt cctgaagcac ctggaaaccg aggataacat caaagtgtgg ttcaacaaca 2280

aaggctggca cgccctggtg tcctttctga acgtggccca caacgccatc ctgagagcca 2340

gcctgcctaa ggacagaagc cctgaggaat acggcatcac cgtgatctcc cagccactga 2400

acctgaccaa agagcagctg agcgagatca ccgtgctgac cacatctgtg gatgccgtgg 2460

tggccatctg cgtgatcttc tccatgagct tcgtgcctgc ctccttcgtg ctgtatctga 2520

tccaagagag agtgaacaag agcaagcacc tccagtttat cagcggagtg tccccaacca 2580

cctactgggt caccaacttt ctgtgggaca tcatgaacta ctccgtgtct gccggcctgg 2640

tcgtgggcat cttcatcggc tttcagaaga aggcctacac aagccccgag aacctgcctg 2700

ctctggttgc tctgctgctg ctgtatggct gggccgtgat tcccatgatg taccccgcca 2760

gcttcctgtt cgatgtgcct agcacagcct acgtggccct gagctgcgcc aatctgttca 2820

tcggcatcaa cagcagcgcc atcaccttca tcctggaact gttcgagaac aacagaaccc 2880

tgctgcggtt caacgccgtg ctgagaaagc tgctgatcgt gttccctcac ttctgcctcg 2940

gcagaggcct gattgatctg gccctgtctc aggccgtgac cgacgtgtac gctagatttg 3000

gcgaggaaca cagcgccaat cctttccact gggacctgat cggcaagaac ctgttcgcca 3060

tggtggtgga aggcgtggtg tatttcctgc tgactctgct ggtgcagcgg cacttctttc 3120

tgtcccaatg gatcgccgag cctaccaaag aacccatcgt ggacgaggac gacgacgtgg 3180

ccgaagagag acagagaatc atcaccggcg gcaacaagac cgacatcctg aggctgcacg 3240

agctgaccaa gatctaccct ggcacatcta gccctgccgt ggacagactg tgtgtgggag 3300

ttagacctgg cgagtgcttt ggcctgctgg gagttaatgg cgccggaaag accaccacct 3360

tcaagatgct gaccggcgac accacagtga ccagcggaga tgctactgtg gccggcaaga 3420

gcatcctgac caacatcagc gaggtgcacc agaacatggg ctactgccct cagttcgacg 3480

ccatcgacga actgctgaca ggcagagagc acctgtatct gtacgccaga ctgagaggcg 3540

tgcccgccga agaaattgag aaggtggcca actggtccat caagagcctg ggactgaccg 3600

tgtacgccga ttgtctggcc ggcacatata gcggcggaaa caagcggaag ctgagcaccg 3660

ccattgctct gatcggatgc cctcctctgg tcctgctgga tgagcctaca accggcatgg 3720

atccccaggc tagacggatg ctgtggaacg tgatcgtgtc catcatccgc gaaggcagag 3780

ccgtggtcct gacaagccac agcatggaag agtgcgaggc cctgtgtacc agactggcca 3840

tcatggtcaa gggcgccttc agatgcatgg gcaccattca gcacctgaaa agcaagttcg 3900

gcgacggcta catcgtgacc atgaagatca agtccccaaa ggacgacctg ctgccagatc 3960

tgaaccccgt ggaacagttc ttccagggca acttccctgg ctccgtgcag cgggaaagac 4020

actacaacat gctgcagttt caggtgtcca gcagctccct ggccagaatc tttcagctgc 4080

tgctctccca caaggatagc ctgctgattg aagagtacag cgtgacccag accacactgg 4140

accaggtgtt cgtgaacttc gccaagcagc agaccgagag ccacgacttg cctctgcacc 4200

ctagagctgc cggcgcttct agacaggccc aggattaata aacgcgtcct cgactgtgcc 4260

ttctagttgc cagccatctg ttgtttgccc ctcccccgtg ccttccttga ccctggaagg 4320

tgccactccc actgtccttt cctaataaaa tgaggaaatt gcatcgcatt gtctgagtag 4380

gtgtcattct attctggggg gtggggtggg gcaggacagc aagggggagg attgggaaga 4440

caatagcagg catgctgggg atgcggtggg ctctatggcc tcgagttaag ggcgaattcc 4500

cgataaggat cttcctagag catggctacg tagataagta gcatggcggg ttaatcatta 4560

actacaagga acccctagtg atggagttgg ccactccctc tctgcgcgct cgctcgctca 4620

ctgaggccgg gcgaccaaag gtcgcccgac gcccgggctt tgcccgggcg gcctcagtga 4680

gcgagcgagc gcgcag 4696

<210> 15

<211> 11250

<212> DNA

<213> Artificial sequence (Artificial Sequence)

<400> 15

ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60

ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120

aggggttcct tgtagttaat gattaacccg ccatgctact tatctactta agcgttacat 180

aacttacggt aaatggcccg cctggctgac cgcccaacga cccccgccca ttgacgtcaa 240

tagtaacgcc aatagggact ttccattgac gtcaatgggt ggagtattta cggtaaactg 300

cccacttggc agtacatcaa gtgtatcata tgccaagtac gccccctatt gacgtcaatg 360

acggtaaatg gcccgcctgg cattgtgccc agtacatgac cttatgggac tttcctactt 420

ggcagtacat ctacgtatta gtcatcgcta ttaccatggt cgaggtgagc cccacgttct 480

gcttcactct ccccatctcc cccccctccc cacccccaat tttgtattta tttatttttt 540

aattattttg tgcagcgatg ggggcggggg gggggggggg gcggggcgag gggcggggcg 600

gggcgaggcg gagaggtgcg gcggcagcca atcagagcgg cgcgctccga aagtttcctt 660

ttatggcgag gcggcggcgg cggcggccct ataaaaagcg aagcgcgcgg cgggcgggag 720

tcgctgcgcg ctgccttcgc cccgtgcccc gctccgccgc cgcctcgcgc cgcccgcccc 780

ggctctgact gaccgcgtta ctcccacagg tgagcgggcg ggacggccct tctcctccgg 840

gctgtaatta gctgagcaag aggtaagggt ttaagggatg gttggttggt ggggtattaa 900

tgtttaatta cctggagcac ctgcctgaaa tcactttttt tcaggttgga ccggtgccac 960

catgggcttc gtgagacaga tacagctttt gctctggaag aactggaccc tgcggaaaag 1020

gcaaaagatt cgctttgtgg tggaactcgt gtggccttta tctttatttc tggtcttgat 1080

ctggttaagg aatgccaacc cactctacag ccatcatgaa tgccatttcc ccaacaaggc 1140

gatgccctca gcaggaatgc tgccgtggct ccaggggatc ttctgcaatg tgaacaatcc 1200

ctgttttcaa agccccaccc caggagaatc tcctggaatt gtgtcaaact ataacaactc 1260

catcttggca agggtatatc gagattttca agaactcctc atgaatgcac cagagagcca 1320

gcaccttggc cgtatttgga cagagctaca catcttgtcc caattcatgg acaccctccg 1380

gactcacccg gagagaattg caggaagagg aatacgaata agggatatct tgaaagatga 1440

agaaacactg acactatttc tcattaaaaa catcggcctg tctgactcag tggtctacct 1500

tctgatcaac tctcaagtcc gtccagagca gttcgctcat ggagtcccgg acctggcgct 1560

gaaggacatc gcctgcagcg aggccctcct ggagcgcttc atcatcttca gccagagacg 1620

cggggcaaag acggtgcgct atgccctgtg ctccctctcc cagggcaccc tacagtggat 1680

agaagacact ctgtatgcca acgtggactt cttcaagctc ttccgtgtgc ttcccacact 1740

cctagacagc cgttctcaag gtatcaatct gagatcttgg ggaggaatat tatctgatat 1800

gtcaccaaga attcaagagt ttatccatcg gccgagtatg caggacttgc tgtgggtgac 1860

caggcccctc atgcagaatg gtggtccaga gacctttaca aagctgatgg gcatcctgtc 1920

tgacctcctg tgtggctacc ccgagggagg tggctctcgg gtgctctcct tcaactggta 1980

tgaagacaat aactataagg cctttctggg gattgactcc acaaggaagg atcctatcta 2040

ttcttatgac agaagaacaa catccttttg taatgcattg atccagagcc tggagtcaaa 2100

tcctttaacc aaaatcgctt ggagggcggc aaagcctttg ctgatgggaa aaatcctgta 2160

cactcctgat tcacctgcag cacgaaggat actgaagaat gccaactcaa cttttgaaga 2220

actggaacac gttaggaagt tggtcaaagc ctgggaagaa gtagggcccc agatctggta 2280

cttctttgac aacagcacac agatgaacat gatcagagat accctgggga acccaacagt 2340

aaaagacttt ttgaataggc agcttggtga agaaggtatt actgctgaag ccatcctaaa 2400

cttcctctac aagggccctc gggaaagcca ggctgacgac atggccaact tcgactggag 2460

ggacatattt aacatcactg atcgcaccct ccgcctggtc aatcaatacc tggagtgctt 2520

ggtcctggat aagtttgaaa gctacaatga tgaaactcag ctcacccaac gtgccctctc 2580

tctactggag gaaaacatgt tctgggccgg agtggtattc cctgacatgt atccctggac 2640

cagctctcta ccaccccacg tgaagtataa gatccgaatg gacatagacg tggtggagaa 2700

aaccaataag attaaagaca ggtattggga ttctggtccc agagctgatc ccgtggaaga 2760

tttccggtac atctggggcg ggtttgccta tctgcaggac atggttgaac aggggatcac 2820

aaggagccag gtgcaggcgg aggctccagt tggaatctac ctccagcaga tgccctaccc 2880

ctgcttcgtg gacgattctt tcatgatcat cctgaaccgc tgtttcccta tcttcatggt 2940

gctggcatgg atctactctg tctccatgac tgtgaagagc atcgtcttgg agaaggagtt 3000

gcgactgaag gagaccttga aaaatcaggg tgtctccaat gcagtgattt ggtgtacctg 3060

gttcctggac agcttctcca tcatgtcgat gagcatcttc ctcctgacga tattcatcat 3120

gcatggaaga atcctacatt acagcgaccc attcatcctc ttcctgttct tgttggcttt 3180

ctccactgcc accatcatgc tgtgctttct gctcagcacc ttcttctcca aggccagtct 3240

ggcagcagcc tgtagtggtg tcatctattt caccctctac ctgccacaca tcctgtgctt 3300

cgcctggcag gaccgcatga ccgctgagct gaagaaggct gtgagcttac tgtctccggt 3360

ggcatttgga tttggcactg agtacctggt tcgctttgaa gagcaaggcc tggggctgca 3420

gtggagcaac atcgggaaca gtcccacgga aggggacgaa ttcagcttcc tgctgtccat 3480

gcagatgatg ctccttgatg ctgctgtcta tggcttactc gcttggtacc ttgatcaggt 3540

gtttccagga gactatggaa ccccacttcc ttggtacttt cttctacaag agtcgtattg 3600

gcttggcggt gaagggtgtt caaccagaga agaaagagcc ctggaaaaga ccgagcccct 3660

aacagaggaa acggaggatc cagagcaccc agaaggaata cacgactcct tctttgaacg 3720

tgagcatcca gggtgggttc ctggggtatg cgtgaagaat ctggtaaaga tttttgagcc 3780

ctgtggccgg ccagctgtgg accgtctgaa catcaccttc tacgagaacc agatcaccgc 3840

attcctgggc cacaatggag ctgggaaaac caccaccttg tccatcctga cgggtctgtt 3900

gccaccaacc tctgggactg tgctcgttgg gggaagggac attgaaacca gcctggatgc 3960

agtccggcag agccttggca tgtgtccaca gcacaacatc ctgttccacc acctcacggt 4020

ggctgagcac atgctgttct atgcccagct gaaaggaaag tcccaggagg aggcccagct 4080

ggagatggaa gccatgttgg aggacacagg cctccaccac aagcggaatg aagaggctca 4140

ggacctatca ggtggcatgc agagaaagct gtcggttgcc attgcctttg tgggagatgc 4200

caaggtggtg attctggacg aacccacctc tggggtggac ccttactcga gacgctcaat 4260

ctgggatctg ctcctgaagt atcgctcagg cagaaccatc atcatgtcca ctcaccacat 4320

ggacgaggcc gacctccttg gggaccgcat tgccatcatt gcccagggaa ggctctactg 4380

ctcaggcacc ccactcttcc tgaagaactg ctttggcaca ggcttgtact taaccttggt 4440

gcgcaagatg aaaaacatcc agagccaaag gaaaggcagt gaggggacct gcagctgctc 4500

gtctaagggt ttctccacca cgtgtccagc ccacgtcgat gacctaactc cagaacaagt 4560

cctggatggg gatgtaaatg agctgatgga tgtagttctc caccatgttc cagaggcaaa 4620

gctggtggag tgcattggtc aagaacttat cttccttctt ccaaataaga acttcaagca 4680

cagagcatat gccagccttt tcagagagct ggaggagacg ctggctgacc ttggtctcag 4740

cagttttgga atttctgaca ctcccctgga agagattttt ctgaaggtca cggaggattc 4800

tgattcagga cctctgtttg cgggtggcgc tcagcagaaa agagaaaacg tcaacccccg 4860

acacccctgc ttgggtccca gagagaaggc tggacagaca ccccaggact ccaatgtctg 4920

ctccccaggg gcgccggctg ctcacccaga gggccagcct cccccagagc cagagtgccc 4980

aggcccgcag ctcaacacgg ggacacagct ggtcctccag catgtgcagg cgctgctggt 5040

caagagattc caacacacca tccgcagcca caaggacttc ctggcgcaga tcgtgctccc 5100

ggctaccttt gtgtttttgg ctctgatgct ttctattgtt atccctcctt ttggcgaata 5160

ccccgctttg acccttcacc cctggatata tgggcagcag tacaccttct tcagcatgga 5220

tgaaccaggc agtgagcagt tcacggtact tgcagacgtc ctcctgaata agccaggctt 5280

tggcaaccgc tgcctgaagg aagggtggct tccggagtac ccctgtggca actcaacacc 5340

ctggaagact ccttctgtgt ccccaaacat cacccagctg ttccagaagc agaaatggac 5400

acaggtcaac ccttcaccat cctgcaggtg cagcaccagg gagaagctca ccatgctgcc 5460

agagtgcccc gagggtgccg ggggcctccc gcccccccag agaacacagc gcagcacgga 5520

aattctacaa gacctgacgg acaggaacat ctccgacttc ttggtaaaaa cgtatcctgc 5580

tcttataaga agcagcttaa agagcaaatt ctgggtcaat gaacagaggt atggaggaat 5640

ttccattgga ggaaagctcc cagtcgtccc catcacgggg gaagcacttg ttgggttttt 5700

aagcgacctt ggccggatca tgaatgtgag cgggggccct atcactagag aggcctctaa 5760

agaaatacct gatttcctta aacatctaga aactgaagac aacattaagg tgtggtttaa 5820

taacaaaggc tggcatgccc tggtcagctt tctcaatgtg gcccacaacg ccatcttacg 5880

ggccagcctg cctaaggaca ggagccccga ggagtatgga atcaccgtca ttagccaacc 5940

cctgaacctg accaaggagc agctctcaga gattacagtg ctgaccactt cagtggatgc 6000

tgtggttgcc atctgcgtga ttttctccat gtccttcgtc ccagccagct ttgtccttta 6060

tttgatccag gagcgggtga acaaatccaa gcacctccag tttatcagtg gagtgagccc 6120

caccacctac tgggtgacca acttcctctg ggacatcatg aattattccg tgagtgctgg 6180

gctggtggtg ggcatcttca tcgggtttca gaagaaagcc tacacttctc cagaaaacct 6240

tcctgccctt gtggcactgc tcctgctgta tggatgggcg gtcattccca tgatgtaccc 6300

agcatccttc ctgtttgatg tccccagcac agcctatgtg gctttatctt gtgctaatct 6360

gttcatcggc atcaacagca gtgctattac cttcatcttg gaattatttg agaataaccg 6420

gacgctgctc aggttcaacg ccgtgctgag gaagctgctc attgtcttcc cccacttctg 6480

cctgggccgg ggcctcattg accttgcact gagccaggct gtgacagatg tctatgcccg 6540

gtttggtgag gagcactctg caaatccgtt ccactgggac ctgattggga agaacctgtt 6600

tgccatggtg gtggaagggg tggtgtactt cctcctgacc ctgctggtcc agcgccactt 6660

cttcctctcc caatggattg ccgagcccac taaggagccc attgttgatg aagatgatga 6720

tgtggctgaa gaaagacaaa gaattattac tggtggaaat aaaactgaca tcttaaggct 6780

acatgaacta accaagattt atccaggcac ctccagccca gcagtggaca ggctgtgtgt 6840

cggagttcgc cctggagagt gctttggcct cctgggagtg aatggtgccg gcaaaacaac 6900

cacattcaag atgctcactg gggacaccac agtgacctca ggggatgcca ccgtagcagg 6960

caagagtatt ttaaccaata tttctgaagt ccatcaaaat atgggctact gtcctcagtt 7020

tgatgcaatt gatgagctgc tcacaggacg agaacatctt tacctttatg cccggcttcg 7080

aggtgtacca gcagaagaaa tcgaaaaggt tgcaaactgg agtattaaga gcctgggcct 7140

gactgtctac gccgactgcc tggctggcac gtacagtggg ggcaacaagc ggaaactctc 7200

cacagccatc gcactcattg gctgcccacc gctggtgctg ctggatgagc ccaccacagg 7260

gatggacccc caggcacgcc gcatgctgtg gaacgtcatc gtgagcatca tcagagaagg 7320

gagggctgtg gtcctcacat cccacagcat ggaagaatgt gaggcactgt gtacccggct 7380

ggccatcatg gtaaagggcg cctttcgatg tatgggcacc attcagcatc tcaagtccaa 7440

atttggagat ggctatatcg tcacaatgaa gatcaaatcc ccgaaggacg acctgcttcc 7500

tgacctgaac cctgtggagc agttcttcca ggggaacttc ccaggcagtg tgcagaggga 7560

gaggcactac aacatgctcc agttccaggt ctcctcctcc tccctggcga ggatcttcca 7620

gctcctcctc tcccacaagg acagcctgct catcgaggag tactcagtca cacagaccac 7680

actggaccag gtgtttgtaa attttgctaa acagcagact gaaagtcatg acctccctct 7740

gcaccctcga gctgctggag ccagtcgaca agcccaggac tgagcggccg cgataatcaa 7800

cctctggatt acaaaatttg tgaaagattg actggtattc ttaactatgt tgctcctttt 7860

acgctatgtg gatacgctgc tttaatgcct ttgtatcatg ctattgcttc ccgtatggct 7920

ttcattttct cctccttgta taaatcctgg ttagttcttg ccacggcgga actcatcgcc 7980

gcctgccttg cccgctgctg gacaggggct cggctgttgg gcactgacaa ttccgtggtg 8040

cgactgtgcc ttctagttgc cagccatctg ttgtttgccc ctcccccgtg ccttccttga 8100

ccctggaagg tgccactccc actgtccttt cctaataaaa tgaggaaatt gcatcgcatt 8160

gtctgagtag gtgtcattct attctggggg gtggggtggg gcaggacagc aagggggagg 8220

attgggaaga caatagcagg catgctgggg atgcggtggg ctctatggct cgagtagata 8280

agtagcatgg cgggttaatc attaactaca aggaacccct agtgatggag ttggccactc 8340

cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc cgacgcccgg 8400

gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag ccttaattaa cctaattcac 8460

tggccgtcgt tttacaacgt cgtgactggg aaaaccctgg cgttacccaa cttaatcgcc 8520

ttgcagcaca tccccctttc gccagctggc gtaatagcga agaggcccgc accgatcgcc 8580

cttcccaaca gttgcgcagc ctgaatggcg aatgggacgc gccctgtagc ggcgcattaa 8640

gcgcggcggg tgtggtggtt acgcgcagcg tgaccgctac acttgccagc gccctagcgc 8700

ccgctccttt cgctttcttc ccttcctttc tcgccacgtt cgccggcttt ccccgtcaag 8760

ctctaaatcg ggggctccct ttagggttcc gatttagtgc tttacggcac ctcgacccca 8820

aaaaacttga ttagggtgat ggttcacgta gtgggccatc gccctgatag acggtttttc 8880

gccctttgac gttggagtcc acgttcttta atagtggact cttgttccaa actggaacaa 8940

cactcaaccc tatctcggtc tattcttttg atttataagg gattttgccg atttcggcct 9000

attggttaaa aaatgagctg atttaacaaa aatttaacgc gaattttaac aaaatattaa 9060

cgcttacaat ttaggtggca cttttcgggg aaatgtgcgc ggaaccccta tttgtttatt 9120

tttctaaata cattcaaata tgtatccgct catgagacaa taaccctgat aaatgcttca 9180

ataatattga aaaaggaaga gtatgagtat tcaacatttc cgtgtcgccc ttattccctt 9240

ttttgcggca ttttgccttc ctgtttttgc tcacccagaa acgctggtga aagtaaaaga 9300

tgctgaagat cagttgggtg cacgagtggg ttacatcgaa ctggatctca acagcggtaa 9360

gatccttgag agttttcgcc ccgaagaacg ttttccaatg atgagcactt ttaaagttct 9420

gctatgtggc gcggtattat cccgtattga cgccgggcaa gagcaactcg gtcgccgcat 9480

acactattct cagaatgact tggttgagta ctcaccagtc acagaaaagc atcttacgga 9540

tggcatgaca gtaagagaat tatgcagtgc tgccataacc atgagtgata acactgcggc 9600

caacttactt ctgacaacga tcggaggacc gaaggagcta accgcttttt tgcacaacat 9660

gggggatcat gtaactcgcc ttgatcgttg ggaaccggag ctgaatgaag ccataccaaa 9720

cgacgagcgt gacaccacga tgcctgtagc aatggcaaca acgttgcgca aactattaac 9780

tggcgaacta cttactctag cttcccggca acaattaata gactggatgg aggcggataa 9840

agttgcagga ccacttctgc gctcggccct tccggctggc tggtttattg ctgataaatc 9900

tggagccggt gagcgtgggt ctcgcggtat cattgcagca ctggggccag atggtaagcc 9960

ctcccgtatc gtagttatct acacgacggg gagtcaggca actatggatg aacgaaatag 10020

acagatcgct gagataggtg cctcactgat taagcattgg taactgtcag accaagttta 10080

ctcatatata ctttagattg atttaaaact tcatttttaa tttaaaagga tctaggtgaa 10140

gatccttttt gataatctca tgaccaaaat cccttaacgt gagttttcgt tccactgagc 10200

gtcagacccc gtagaaaaga tcaaaggatc ttcttgagat cctttttttc tgcgcgtaat 10260

ctgctgcttg caaacaaaaa aaccaccgct accagcggtg gtttgtttgc cggatcaaga 10320

gctaccaact ctttttccga aggtaactgg cttcagcaga gcgcagatac caaatactgt 10380

tcttctagtg tagccgtagt taggccacca cttcaagaac tctgtagcac cgcctacata 10440

cctcgctctg ctaatcctgt taccagtggc tgctgccagt ggcgataagt cgtgtcttac 10500

cgggttggac tcaagacgat agttaccgga taaggcgcag cggtcgggct gaacgggggg 10560

ttcgtgcaca cagcccagct tggagcgaac gacctacacc gaactgagat acctacagcg 10620

tgagctatga gaaagcgcca cgcttcccga agggagaaag gcggacaggt atccggtaag 10680

cggcagggtc ggaacaggag agcgcacgag ggagcttcca gggggaaacg cctggtatct 10740

ttatagtcct gtcgggtttc gccacctctg acttgagcgt cgatttttgt gatgctcgtc 10800

aggggggcgg agcctatgga aaaacgccag caacgcggcc tttttacggt tcctggcctt 10860

ttgctggcct tttgctcaca tgttctttcc tgcgttatcc cctgattctg tggataaccg 10920

tattaccgcc tttgagtgag ctgataccgc tcgccgcagc cgaacgaccg agcgcagcga 10980

gtcagtgagc gaggaagcgg aagagcgccc aatacgcaaa ccgcctctcc ccgcgcgttg 11040

gccgattcat taatgcagct ggcacgacag gtttcccgac tggaaagcgg gcagtgagcg 11100

caacgcaatt aatgtgagtt agctcactca ttaggcaccc caggctttac actttatgct 11160

tccggctcgt atgttgtgtg gaattgtgag cggataacaa tttcacacag gaaacagcta 11220

tgaccatgat tacgccagat ttaattaagg 11250

<210> 16

<211> 11250

<212> DNA

<213> Artificial sequence (Artificial Sequence)

<400> 16

ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60

ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120

aggggttcct tgtagttaat gattaacccg ccatgctact tatctactta agcgttacat 180

aacttacggt aaatggcccg cctggctgac cgcccaacga cccccgccca ttgacgtcaa 240

tagtaacgcc aatagggact ttccattgac gtcaatgggt ggagtattta cggtaaactg 300

cccacttggc agtacatcaa gtgtatcata tgccaagtac gccccctatt gacgtcaatg 360

acggtaaatg gcccgcctgg cattgtgccc agtacatgac cttatgggac tttcctactt 420

ggcagtacat ctacgtatta gtcatcgcta ttaccatggt cgaggtgagc cccacgttct 480

gcttcactct ccccatctcc cccccctccc cacccccaat tttgtattta tttatttttt 540

aattattttg tgcagcgatg ggggcggggg gggggggggg gcggggcgag gggcggggcg 600

gggcgaggcg gagaggtgcg gcggcagcca atcagagcgg cgcgctccga aagtttcctt 660

ttatggcgag gcggcggcgg cggcggccct ataaaaagcg aagcgcgcgg cgggcgggag 720

tcgctgcgcg ctgccttcgc cccgtgcccc gctccgccgc cgcctcgcgc cgcccgcccc 780

ggctctgact gaccgcgtta ctcccacagg tgagcgggcg ggacggccct tctcctccgg 840

gctgtaatta gctgagcaag aggtaagggt ttaagggatg gttggttggt ggggtattaa 900

tgtttaatta cctggagcac ctgcctgaaa tcactttttt tcaggttgga ccggtgccac 960

catgggcttt gtgcgacaga ttcagctgct gctgtggaag aactggaccc tgcggaagcg 1020

gcagaaaatc agattcgtgg tggaactcgt gtggcccctg agcctgtttc tggtgctgat 1080

ctggctgcgg aacgccaatc ctctgtacag ccaccacgag tgtcacttcc ccaacaaggc 1140

catgccttct gccggaatgc tgccttggct gcagggcatc ttctgcaacg tgaacaaccc 1200

ctgctttcag agccccacac ctggcgaaag ccctggcatc gtgtccaact acaacaacag 1260

catcctggcc agagtgtacc gggacttcca agagctgctg atgaacgccc ctgagtctca 1320

gcacctgggc agaatctgga ccgagctgca catcctgagc cagttcatgg acaccctgag 1380

aacacacccc gagagaatcg ccggcagggg catcagaatc cgggacatcc tgaaggacga 1440

ggaaaccctg acactgttcc tcatcaagaa catcggcctg agcgacagcg tggtgtacct 1500

gctgatcaac agccaagtgc ggcccgagca gtttgctcat ggcgtgccag atctcgccct 1560

gaaggatatc gcctgttctg aggccctgct ggaacggttc atcatcttca gccagcggag 1620

aggcgccaag accgtcagat atgccctgtg cagtctgagc cagggaaccc tgcagtggat 1680

cgaggatacc ctgtacgcca acgtggactt cttcaagctg ttccgggtgc tgcccacact 1740

gctggattct agatcccagg gcatcaacct gagaagctgg ggcggcatcc tgtccgacat 1800

gagcccaaga atccaagagt tcatccaccg gcctagcatg caggacctgc tgtgggttac 1860

cagacctctg atgcagaacg gcggacccga gacattcacc aagctgatgg gaattctgag 1920

cgatctgctg tgcggctacc ctgaaggcgg aggatctaga gtgctgagct tcaattggta 1980

cgaggacaac aactacaagg ccttcctggg catcgactcc accagaaagg accccatcta 2040

cagctacgac cggcggacaa ccagcttctg caatgccctg atccagagcc tggaaagcaa 2100

ccctctgacc aagatcgctt ggagggccgc caaacctctg ctgatgggaa agatcctgta 2160

cacccctgac agccctgccg ccagaagaat cctgaagaac gccaacagca ccttcgagga 2220

actggaacac gtgcgcaagc tggtcaaggc ctgggaagaa gtgggacctc agatctggta 2280

cttcttcgac aatagcaccc agatgaacat gatcagagac accctgggca accctaccgt 2340

gaaggacttc ctgaacagac agctgggcga agagggcatt accgccgagg ccatcctgaa 2400

ctttctgtac aagggcccca gagagtccca ggccgacgac atggccaact tcgattggcg 2460

ggacatcttc aacatcaccg acagaaccct gcggctggtc aaccagtacc tggaatgcct 2520

ggtgctggac aagttcgaga gctacaacga cgagacacag ctgacccaga gagccctgtc 2580

tctgctggaa gagaatatgt tctgggctgg cgtggtgttc cccgacatgt acccttggac 2640

aagcagcctg cctcctcacg tgaagtacaa gatccggatg gacatcgacg tggtcgaaaa 2700

gaccaacaag atcaaggatc ggtactggga cagcggccct agagctgatc ccgtggaaga 2760

ttttcggtac atctggggcg gattcgcata cctgcaggac atggtggaac agggaatcac 2820

acggtcccag gtgcaggctg aagctcctgt gggaatctac ctgcagcaga tgccttatcc 2880

ttgcttcgtg gacgacagct tcatgatcat cctgaatcgg tgcttcccca tcttcatggt 2940

gctggcctgg atctactccg tgtctatgac cgtgaagtcc atcgtgctgg aaaaagagct 3000

gcggctgaaa gagacactga agaaccaggg cgtgtccaat gccgtgatct ggtgcacctg 3060

gtttctggac agcttctcca ttatgagcat gagcatcttt ctgctgacga tcttcatcat 3120

gcacggccgg atcctgcact acagcgaccc ctttatcctc ttcctgttcc tgctggcctt 3180

cagcaccgct acaatcatgc tgtgttttct gctgtccacc ttcttcagca aggcctctct 3240

ggccgctgct tgtagcggcg tgatctactt caccctgtac ctgcctcaca tcctgtgctt 3300

cgcatggcag gacagaatga ccgccgagct gaagaaagct gtgtccctgc tgagccctgt 3360

ggcctttggc tttggcaccg agtacctcgt cagatttgag gaacaaggac tgggactgca 3420

gtggtccaac atcggcaata gccctacaga gggcgacgag ttcagcttcc tgctgtctat 3480

gcagatgatg ctgctggacg ccgccgtgta tggactgctg gcttggtatc tggaccaggt 3540

gttcccaggc gattacggca ctcctctgcc ttggtatttc ctgctgcaag agagctactg 3600

gctcggcggc gagggatgta gcaccagaga agaaagagcc ctggaaaaga ccgagcctct 3660

gaccgaggaa acagaggacc ctgaacaccc agagggcatc cacgatagct ttttcgagag 3720

agaacacccc ggctgggtgc caggcgtgtg tgtgaagaat ctggtcaaga tcttcgagcc 3780

ctgcggcaga cctgccgtgg acagactgaa catcaccttc tacgagaacc agattaccgc 3840

ctttctgggc cacaacggcg ctggcaagac aaccacactg agcatcctca caggcctgct 3900

gcctccaaca agcggcacag ttctcgttgg cggcagagac atcgagacaa gcctggatgc 3960

cgtcagacag tccctgggca tgtgccctca gcacaacatc ctgtttcacc acctgaccgt 4020

ggccgagcac atgctgtttt atgcccagct gaagggcaag agccaagaag aggctcagct 4080

ggaaatggaa gccatgctcg aggacaccgg cctgcaccac aagagaaatg aggaagccca 4140

ggatctgagc ggcggcatgc agagaaaact gagcgtggcc attgccttcg tgggcgacgc 4200

caaggttgtg atcctggatg agcctacaag cggcgtggac ccttacagca gaagatccat 4260

ctgggatctg ctgctgaagt acagaagcgg ccggaccatc atcatgagca cccaccacat 4320

ggacgaggcc gatctgctcg gagacagaat cgccatcatt gctcagggca gactgtactg 4380

cagcggcacc ccactgtttc tgaagaactg ttttggcacc ggcctgtacc tgacactcgt 4440

gcggaagatg aagaacatcc agagccagcg gaagggcagc gagggcacat gtagctgtag 4500

cagcaagggc ttcagcacca cctgtcctgc tcacgtggac gatctgaccc ctgaacaggt 4560

gctggatggc gacgtgaacg agctgatgga cgtggtgctg caccacgtgc ctgaggccaa 4620

gctggtggaa tgcatcggcc aagagctgat cttcctgctg cctaacaaga acttcaagca 4680

ccgggcctac gccagcctgt tcagagagct ggaagagaca ctggccgatc tgggcctgag 4740

cagctttggc atcagcgaca cccctctgga agaaatcttc ctgaaagtga ccgaggacag 4800

cgacagcggc ccactttttg ctggcggagc acagcagaaa cgcgagaacg tgaaccctag 4860

acacccctgt ctgggcccta gagagaaagc cggacagacc cctcaggaca gcaatgtgtg 4920

ctctcctggt gctcctgccg ctcaccctga aggacaacct ccacctgagc ctgagtgtcc 4980

tggacctcag ctgaataccg gcacacagct ggttctgcag cacgtgcaag ccctgctggt 5040

caagagattc cagcacacca tcagaagcca caaggacttt ctggcccaga ttgtgctgcc 5100

cgccaccttc gtttttctgg ctctgatgct gagcatcgtg atccctccat tcggcgagta 5160

ccccgctctg acactgcacc cttggatcta cggccagcag tacaccttct tcagcatgga 5220

cgagcctggc agcgagcagt ttacagtgct ggctgatgtg ctgctgaaca agcccggctt 5280

cggcaaccgc tgtctgaaag aaggatggct gcctgagtac ccctgcggca atagcacccc 5340

ttggaaaacc cctagcgtgt cccctaacat cacccagctg ttccagaaac agaaatggac 5400

ccaagtgaac ccctctccat cctgccggtg ctccaccaga gaaaagctga ccatgctgcc 5460

cgagtgtcca gaaggtgcag gcggacttcc tccacctcag agaacccaga gaagcaccga 5520

gattctgcag gacctgaccg accggaatat cagcgacttc ctggttaaga cataccccgc 5580

actgatccgg tccagcctga agtccaagtt ctgggtcaac gagcagagat acggcggcat 5640

ctctatcggc ggaaagctgc ctgtggtgcc tatcacaggc gaagccctcg tgggctttct 5700

gtctgacctg ggcagaatca tgaacgtgtc cggcggaccc atcaccagag aggccagcaa 5760

agagatcccc gatttcctga agcacctgga aaccgaggat aacatcaaag tgtggttcaa 5820

caacaaaggc tggcacgccc tggtgtcctt tctgaacgtg gcccacaacg ccatcctgag 5880

agccagcctg cctaaggaca gaagccctga ggaatacggc atcaccgtga tctcccagcc 5940

actgaacctg accaaagagc agctgagcga gatcaccgtg ctgaccacat ctgtggatgc 6000

cgtggtggcc atctgcgtga tcttctccat gagcttcgtg cctgcctcct tcgtgctgta 6060

tctgatccaa gagagagtga acaagagcaa gcacctccag tttatcagcg gagtgtcccc 6120

aaccacctac tgggtcacca actttctgtg ggacatcatg aactactccg tgtctgccgg 6180

cctggtcgtg ggcatcttca tcggctttca gaagaaggcc tacacaagcc ccgagaacct 6240

gcctgctctg gttgctctgc tgctgctgta tggctgggcc gtgattccca tgatgtaccc 6300

cgccagcttc ctgttcgatg tgcctagcac agcctacgtg gccctgagct gcgccaatct 6360

gttcatcggc atcaacagca gcgccatcac cttcatcctg gaactgttcg agaacaacag 6420

aaccctgctg cggttcaacg ccgtgctgag aaagctgctg atcgtgttcc ctcacttctg 6480

cctcggcaga ggcctgattg atctggccct gtctcaggcc gtgaccgacg tgtacgctag 6540

atttggcgag gaacacagcg ccaatccttt ccactgggac ctgatcggca agaacctgtt 6600

cgccatggtg gtggaaggcg tggtgtattt cctgctgact ctgctggtgc agcggcactt 6660

ctttctgtcc caatggatcg ccgagcctac caaagaaccc atcgtggacg aggacgacga 6720

cgtggccgaa gagagacaga gaatcatcac cggcggcaac aagaccgaca tcctgaggct 6780

gcacgagctg accaagatct accctggcac atctagccct gccgtggaca gactgtgtgt 6840

gggagttaga cctggcgagt gctttggcct gctgggagtt aatggcgccg gaaagaccac 6900

caccttcaag atgctgaccg gcgacaccac agtgaccagc ggagatgcta ctgtggccgg 6960

caagagcatc ctgaccaaca tcagcgaggt gcaccagaac atgggctact gccctcagtt 7020

cgacgccatc gacgaactgc tgacaggcag agagcacctg tatctgtacg ccagactgag 7080

aggcgtgccc gccgaagaaa ttgagaaggt ggccaactgg tccatcaaga gcctgggact 7140

gaccgtgtac gccgattgtc tggccggcac atatagcggc ggaaacaagc ggaagctgag 7200

caccgccatt gctctgatcg gatgccctcc tctggtcctg ctggatgagc ctacaaccgg 7260

catggatccc caggctagac ggatgctgtg gaacgtgatc gtgtccatca tccgcgaagg 7320

cagagccgtg gtcctgacaa gccacagcat ggaagagtgc gaggccctgt gtaccagact 7380

ggccatcatg gtcaagggcg ccttcagatg catgggcacc attcagcacc tgaaaagcaa 7440

gttcggcgac ggctacatcg tgaccatgaa gatcaagtcc ccaaaggacg acctgctgcc 7500

agatctgaac cccgtggaac agttcttcca gggcaacttc cctggctccg tgcagcggga 7560

aagacactac aacatgctgc agtttcaggt gtccagcagc tccctggcca gaatctttca 7620

gctgctgctc tcccacaagg atagcctgct gattgaagag tacagcgtga cccagaccac 7680

actggaccag gtgttcgtga acttcgccaa gcagcagacc gagagccacg acttgcctct 7740

gcaccctaga gctgccggcg cttctagaca ggcccaggat taagcggccg cgataatcaa 7800

cctctggatt acaaaatttg tgaaagattg actggtattc ttaactatgt tgctcctttt 7860

acgctatgtg gatacgctgc tttaatgcct ttgtatcatg ctattgcttc ccgtatggct 7920

ttcattttct cctccttgta taaatcctgg ttagttcttg ccacggcgga actcatcgcc 7980

gcctgccttg cccgctgctg gacaggggct cggctgttgg gcactgacaa ttccgtggtg 8040

cgactgtgcc ttctagttgc cagccatctg ttgtttgccc ctcccccgtg ccttccttga 8100

ccctggaagg tgccactccc actgtccttt cctaataaaa tgaggaaatt gcatcgcatt 8160

gtctgagtag gtgtcattct attctggggg gtggggtggg gcaggacagc aagggggagg 8220

attgggaaga caatagcagg catgctgggg atgcggtggg ctctatggct cgagtagata 8280

agtagcatgg cgggttaatc attaactaca aggaacccct agtgatggag ttggccactc 8340

cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc cgacgcccgg 8400

gctttgcccg ggcggcctca gtgagcgagc gagcgcgcag ccttaattaa cctaattcac 8460

tggccgtcgt tttacaacgt cgtgactggg aaaaccctgg cgttacccaa cttaatcgcc 8520

ttgcagcaca tccccctttc gccagctggc gtaatagcga agaggcccgc accgatcgcc 8580

cttcccaaca gttgcgcagc ctgaatggcg aatgggacgc gccctgtagc ggcgcattaa 8640

gcgcggcggg tgtggtggtt acgcgcagcg tgaccgctac acttgccagc gccctagcgc 8700

ccgctccttt cgctttcttc ccttcctttc tcgccacgtt cgccggcttt ccccgtcaag 8760

ctctaaatcg ggggctccct ttagggttcc gatttagtgc tttacggcac ctcgacccca 8820

aaaaacttga ttagggtgat ggttcacgta gtgggccatc gccctgatag acggtttttc 8880

gccctttgac gttggagtcc acgttcttta atagtggact cttgttccaa actggaacaa 8940

cactcaaccc tatctcggtc tattcttttg atttataagg gattttgccg atttcggcct 9000

attggttaaa aaatgagctg atttaacaaa aatttaacgc gaattttaac aaaatattaa 9060

cgcttacaat ttaggtggca cttttcgggg aaatgtgcgc ggaaccccta tttgtttatt 9120

tttctaaata cattcaaata tgtatccgct catgagacaa taaccctgat aaatgcttca 9180

ataatattga aaaaggaaga gtatgagtat tcaacatttc cgtgtcgccc ttattccctt 9240

ttttgcggca ttttgccttc ctgtttttgc tcacccagaa acgctggtga aagtaaaaga 9300

tgctgaagat cagttgggtg cacgagtggg ttacatcgaa ctggatctca acagcggtaa 9360

gatccttgag agttttcgcc ccgaagaacg ttttccaatg atgagcactt ttaaagttct 9420

gctatgtggc gcggtattat cccgtattga cgccgggcaa gagcaactcg gtcgccgcat 9480

acactattct cagaatgact tggttgagta ctcaccagtc acagaaaagc atcttacgga 9540

tggcatgaca gtaagagaat tatgcagtgc tgccataacc atgagtgata acactgcggc 9600

caacttactt ctgacaacga tcggaggacc gaaggagcta accgcttttt tgcacaacat 9660

gggggatcat gtaactcgcc ttgatcgttg ggaaccggag ctgaatgaag ccataccaaa 9720

cgacgagcgt gacaccacga tgcctgtagc aatggcaaca acgttgcgca aactattaac 9780

tggcgaacta cttactctag cttcccggca acaattaata gactggatgg aggcggataa 9840

agttgcagga ccacttctgc gctcggccct tccggctggc tggtttattg ctgataaatc 9900

tggagccggt gagcgtgggt ctcgcggtat cattgcagca ctggggccag atggtaagcc 9960

ctcccgtatc gtagttatct acacgacggg gagtcaggca actatggatg aacgaaatag 10020

acagatcgct gagataggtg cctcactgat taagcattgg taactgtcag accaagttta 10080

ctcatatata ctttagattg atttaaaact tcatttttaa tttaaaagga tctaggtgaa 10140

gatccttttt gataatctca tgaccaaaat cccttaacgt gagttttcgt tccactgagc 10200

gtcagacccc gtagaaaaga tcaaaggatc ttcttgagat cctttttttc tgcgcgtaat 10260

ctgctgcttg caaacaaaaa aaccaccgct accagcggtg gtttgtttgc cggatcaaga 10320

gctaccaact ctttttccga aggtaactgg cttcagcaga gcgcagatac caaatactgt 10380

tcttctagtg tagccgtagt taggccacca cttcaagaac tctgtagcac cgcctacata 10440

cctcgctctg ctaatcctgt taccagtggc tgctgccagt ggcgataagt cgtgtcttac 10500

cgggttggac tcaagacgat agttaccgga taaggcgcag cggtcgggct gaacgggggg 10560

ttcgtgcaca cagcccagct tggagcgaac gacctacacc gaactgagat acctacagcg 10620

tgagctatga gaaagcgcca cgcttcccga agggagaaag gcggacaggt atccggtaag 10680

cggcagggtc ggaacaggag agcgcacgag ggagcttcca gggggaaacg cctggtatct 10740

ttatagtcct gtcgggtttc gccacctctg acttgagcgt cgatttttgt gatgctcgtc 10800

aggggggcgg agcctatgga aaaacgccag caacgcggcc tttttacggt tcctggcctt 10860

ttgctggcct tttgctcaca tgttctttcc tgcgttatcc cctgattctg tggataaccg 10920

tattaccgcc tttgagtgag ctgataccgc tcgccgcagc cgaacgaccg agcgcagcga 10980

gtcagtgagc gaggaagcgg aagagcgccc aatacgcaaa ccgcctctcc ccgcgcgttg 11040

gccgattcat taatgcagct ggcacgacag gtttcccgac tggaaagcgg gcagtgagcg 11100

caacgcaatt aatgtgagtt agctcactca ttaggcaccc caggctttac actttatgct 11160

tccggctcgt atgttgtgtg gaattgtgag cggataacaa tttcacacag gaaacagcta 11220

tgaccatgat tacgccagat ttaattaagg 11250

<210> 17

<211> 7534

<212> DNA

<213> Artificial sequence (Artificial Sequence)

<400> 17

ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60

ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120

aggggttcct tgtagttaat gattaacccg ccatgctact tatctacgta gccatgctct 180

aggaagatcg gaattcgccc ttaagggccc cagaagcctg gtggttgttt gtccttctca 240

ggggaaaagt gaggcggccc cttggaggaa ggggccgggc agaatgatct aatcggattc 300

caagcagctc aggggattgt ctttttctag caccttcttg ccactcctaa gcgtcctccg 360

tgaccccggc tgggatttag cctggtgctg tgtcagcccc ggtctcccag gggcttccca 420

gtggtcccca ggaaccctcg acagggcccg gtctctctcg tccagcaagg gcagggacgg 480

gccacaggcc aagggcggta ctctagagga tccggtactc gaggaactga aaaaccagaa 540

agttaactgg taagtttagt ctttttgtct tttatttcag gtcccggatc cggtggtggt 600

gcaaatcaaa gaactgctcc tcagtggatg ttgcctttac ttctaggcct gtacggaagt 660

gttacttctg ctctaaaagc tgcggaattg tacccgcggc cgccaccatg ggctttgtgc 720

gacagattca gctgctgctg tggaagaact ggaccctgcg gaagcggcag aaaatcagat 780

tcgtggtgga actcgtgtgg cccctgagcc tgtttctggt gctgatctgg ctgcggaacg 840

ccaatcctct gtacagccac cacgagtgtc acttccccaa caaggccatg ccttctgccg 900

gaatgctgcc ttggctgcag ggcatcttct gcaacgtgaa caacccctgc tttcagagcc 960

ccacacctgg cgaaagccct ggcatcgtgt ccaactacaa caacagcatc ctggccagag 1020

tgtaccggga cttccaagag ctgctgatga acgcccctga gtctcagcac ctgggcagaa 1080

tctggaccga gctgcacatc ctgagccagt tcatggacac cctgagaaca caccccgaga 1140

gaatcgccgg caggggcatc agaatccggg acatcctgaa ggacgaggaa accctgacac 1200

tgttcctcat caagaacatc ggcctgagcg acagcgtggt gtacctgctg atcaacagcc 1260

aagtgcggcc cgagcagttt gctcatggcg tgccagatct cgccctgaag gatatcgcct 1320

gttctgaggc cctgctggaa cggttcatca tcttcagcca gcggagaggc gccaagaccg 1380

tcagatatgc cctgtgcagt ctgagccagg gaaccctgca gtggatcgag gataccctgt 1440

acgccaacgt ggacttcttc aagctgttcc gggtgctgcc cacactgctg gattctagat 1500

cccagggcat caacctgaga agctggggcg gcatcctgtc cgacatgagc ccaagaatcc 1560

aagagttcat ccaccggcct agcatgcagg acctgctgtg ggttaccaga cctctgatgc 1620

agaacggcgg acccgagaca ttcaccaagc tgatgggaat tctgagcgat ctgctgtgcg 1680

gctaccctga aggcggagga tctagagtgc tgagcttcaa ttggtacgag gacaacaact 1740

acaaggcctt cctgggcatc gactccacca gaaaggaccc catctacagc tacgaccggc 1800

ggacaaccag cttctgcaat gccctgatcc agagcctgga aagcaaccct ctgaccaaga 1860

tcgcttggag ggccgccaaa cctctgctga tgggaaagat cctgtacacc cctgacagcc 1920

ctgccgccag aagaatcctg aagaacgcca acagcacctt cgaggaactg gaacacgtgc 1980

gcaagctggt caaggcctgg gaagaagtgg gacctcagat ctggtacttc ttcgacaata 2040

gcacccagat gaacatgatc agagacaccc tgggcaaccc taccgtgaag gacttcctga 2100

acagacagct gggcgaagag ggcattaccg ccgaggccat cctgaacttt ctgtacaagg 2160

gccccagaga gtcccaggcc gacgacatgg ccaacttcga ttggcgggac atcttcaaca 2220

tcaccgacag aaccctgcgg ctggtcaacc agtacctgga atgcctggtg ctggacaagt 2280

tcgagagcta caacgacgag acacagctga cccagagagc cctgtctctg ctggaagaga 2340

atatgttctg ggctggcgtg gtgttccccg acatgtaccc ttggacaagc agcctgcctc 2400

ctcacgtgaa gtacaagatc cggatggaca tcgacgtggt cgaaaagacc aacaagatca 2460

aggatcggta ctgggacagc ggccctagag ctgatcccgt ggaagatttt cggtacatct 2520

ggggcggatt cgcatacctg caggacatgg tggaacaggg aatcacacgg tcccaggtgc 2580

aggctgaagc tcctgtggga atctacctgc agcagatgcc ttatccttgc ttcgtggacg 2640

acagcttcat gatcatcctg aatcggtgct tccccatctt catggtgctg gcctggatct 2700

actccgtgtc tatgaccgtg aagtccatcg tgctggaaaa agagctgcgg ctgaaagaga 2760

cactgaagaa ccagggcgtg tccaatgccg tgatctggtg cacctggttt ctggacagct 2820

tctccattat gagcatgagc atctttctgc tgacgatctt catcatgcac ggccggatcc 2880

tgcactacag cgaccccttt atcctcttcc tgttcctgct ggccttcagc accgctacaa 2940

tcatgctgtg ttttctgctg tccaccttct tcagcaaggc ctctctggcc gctgcttgta 3000

gcggcgtgat ctacttcacc ctgtacctgc ctcacatcct gtgcttcgca tggcaggaca 3060

gaatgaccgc cgagctgaag aaagctgtgt ccctgctgag ccctgtggcc tttggctttg 3120

gcaccgagta cctcgtcaga tttgaggaac aaggactggg actgcagtgg tccaacatcg 3180

gcaatagccc tacagagggc gacgagttca gcttcctgct gtctatgcag atgatgctgc 3240

tggacgccgc cgtgtatgga ctgctggctt ggtatctgga ccaggtgttc ccaggcgatt 3300

acggcactcc tctgccttgg tatttcctgc tgcaagagag ctactggctc ggcggcgagg 3360

gatgtagcac cagagaagaa agagccctgg aaaagaccga gcctctgacc gaggaaacag 3420

aggaccctga acacccagag ggcatccacg atagcttttt cgagagagaa caccccggct 3480

gggtgccagg cgtgtgtgtg aagaatctgg tcaagatctt cgagccctgc ggcagacctg 3540

ccgtggacag actgaacatc accttctacg agaaccagat taccgccttt ctgggccaca 3600

acggcgctgg caagacaacc acactgagca tcctcacagg cctgctgcct ccaacaagcg 3660

gcacagttct cgttggcggc agagacatcg agacaagcct ggatgccgtc agacagtccc 3720

tgggcatgtg ccctcagcac aacatcctgt ttcaccacct gaccgtggcc gagcacatgc 3780

tgttttatgc ccagctgaag ggcaagagcc aagaagaggc tcagctggaa atggaagcca 3840

tgctcgagga caccggcctg caccacaaga gaaatgagga agcccaggat ctgagcggcg 3900

gcatgcagag aaaactgagc gtggccattg ccttcgtggg cgacgccaag gttgtgatcc 3960

tggatgagcc tacaagcggc gtggaccctt acagcagaag atccatctgg gatctgctgc 4020

tgaagtacag aagcggccgg accatcatca tgagcaccca ccacatggac gaggccgatc 4080

tgctcggaga cagaatcgcc atcattgctc agggcagact gtactgcagc ggcaccccac 4140

tgtttctgaa gaactgtctg gctggcgata ctctcattac cctggccgat ggacgacgag 4200

tgcctattag agaactggtg tcacagcaga atttttccgt gtgggctctg aatcctcaga 4260

cttaccgcct ggagagggct agagtgagta gagctttctg taccggcatc aaacctgtgt 4320

accgcctcac cactagactg gggagatcca ttagggccac tgccaaccac cgatttctca 4380

cacctcaggg ctggaaacga gtcgatgaac tccagcctgg agattacctg gctctgccta 4440

ggagaatccc tactgcctcc taaacgcgtc ctcgactgtg ccttctagtt gccagccatc 4500

tgttgtttgc ccctcccccg tgccttcctt gaccctggaa ggtgccactc ccactgtcct 4560

ttcctaataa aatgaggaaa ttgcatcgca ttgtctgagt aggtgtcatt ctattctggg 4620

gggtggggtg gggcaggaca gcaaggggga ggattgggaa gacaatagca ggcatgctgg 4680

ggatgcggtg ggctctatgg cctcgagtta agggcgaatt cccgataagg atcttcctag 4740

agcatggcta cgtagataag tagcatggcg ggttaatcat taactacaag gaacccctag 4800

tgatggagtt ggccactccc tctctgcgcg ctcgctcgct cactgaggcc gggcgaccaa 4860

aggtcgcccg acgcccgggc tttgcccggg cggcctcagt gagcgagcga gcgcgcagcc 4920

ttaattaacc taattcactg gccgtcgttt tacaacgtcg tgactgggaa aaccctggcg 4980

ttacccaact taatcgcctt gcagcacatc cccctttcgc cagctgcatt aatgaatcgg 5040

ccaacgcgcg gggagaggcg gtttgcgtat tgggcgctct tccgcttcct cgctcactga 5100

ctcgctgcgc tcggtcgttc ggctgcggcg agcggtatca gctcactcaa aggcggtaat 5160

acggttatcc acagaatcag gggataacgc aggaaagaac atgtgagcaa aaggccagca 5220

aaaggccagg aaccgtaaaa aggccgcgtt gctggcgttt ttccataggc tccgcccccc 5280

tgacgagcat cacaaaaatc gacgctcaag tcagaggtgg cgaaacccga caggactata 5340

aagataccag gcgtttcccc ctggaagctc cctcgtgcgc tctcctgttc cgaccctgcc 5400

gcttaccgga tacctgtccg cctttctccc ttcgggaagc gtggcgcttt ctcatagctc 5460

acgctgtagg tatctcagtt cggtgtaggt cgttcgctcc aagctgggct gtgtgcacga 5520

accccccgtt cagcccgacc gctgcgcctt atccggtaac tatcgtcttg agtccaaccc 5580

ggtaagacac gacttatcgc cactggcagc agccactggt aacaggatta gcagagcgag 5640

gtatgtaggc ggtgctacag agttcttgaa gtggtggcct aactacggct acactagaag 5700

aacagtattt ggtatctgcg ctctgctgaa gccagttacc ttcggaaaaa gagttggtag 5760

ctcttgatcc ggcaaacaaa ccaccgctgg tagcggtggt ttttttgttt gcaagcagca 5820

gattacgcgc agaaaaaaag gatctcaaga agatcctttg atcttttcta cggggtctga 5880

cgctcagtgg aacgaaaact cacgttaagg gattttggtc atgagattat caaaaaggat 5940

cttcacctag atccttttaa attaaaaatg aagttttaaa tcaatctaaa gtatatatga 6000

gtaaacttgg tctgacagtt agaaaaactc atcgagcatc aaatgaaact gcaatttatt 6060

catatcagga ttatcaatac catatttttg aaaaagccgt ttctgtaatg aaggagaaaa 6120

ctcaccgagg cagttccata ggatggcaag atcctggtat cggtctgcga ttccgactcg 6180

tccaacatca atacaaccta ttaatttccc ctcgtcaaaa ataaggttat caagtgagaa 6240

atcaccatga gtgacgactg aatccggtga gaatggcaaa agtttatgca tttctttcca 6300

gacttgttca acaggccagc cattacgctc gtcatcaaaa tcactcgcat caaccaaacc 6360

gttattcatt cgtgattgcg cctgagcgag acgaaatacg cgatcgctgt taaaaggaca 6420

attacaaaca ggaatcgaat gcaaccggcg caggaacact gccagcgcat caacaatatt 6480

ttcacctgaa tcaggatatt cttctaatac ctggaatgct gttttcccag ggatcgcagt 6540

ggtgagtaac catgcatcat caggagtacg gataaaatgc ttgatggtcg gaagaggcat 6600

aaattccgtc agccagttta gtctgaccat ctcatctgta acatcattgg caacgctacc 6660

tttgccatgt ttcagaaaca actctggcgc atcgggcttc ccatacaatc gatagattgt 6720

cgcacctgat tgcccgacat tatcgcgagc ccatttatac ccatataaat cagcatccat 6780

gttggaattt aatcgcggcc tagagcaaga cgtttcccgt tgaatatggc tcatactctt 6840

cctttttcaa tattattgaa gcatttatca gggttattgt ctcatgagcg gatacatatt 6900

tgaatgtatt tagaaaaata aacaaatagg ggttccgcgc acatttcccc gaaaagtgcc 6960

acctgacgtc taagaaacca ttattatcat gacattaacc tataaaaata ggcgtatcac 7020

gaggcccttt cgtctcgcgc gtttcggtga tgacggtgaa aacctctgac acatgcagct 7080

cccggagacg gtcacagctt gtctgtaagc ggatgccggg agcagacaag cccgtcaggg 7140

cgcgtcagcg ggtgttggcg ggtgtcgggg ctggcttaac tatgcggcat cagagcagat 7200

tgtactgaga gtgcaccata tgcggtgtga aataccgcac agatgcgtaa ggagaaaata 7260

ccgcatcagg cgccattcgc cattcaggct gcgcaactgt tgggaagggc gatcggtgcg 7320

ggcctcttcg ctattacgcc agctggcacg acaggtttcc cgactggaaa gcgggcagtg 7380

agcgcaacgc aattaatgtg agttagctca ctcattaggc accccaggct ttacacttta 7440

tgcttccggc tcgtatgttg tgtggaattg tgagcggata acaatttcac acaggaaaca 7500

gctatgacca tgattacgcc agatttaatt aagg 7534

<210> 18

<211> 7312

<212> DNA

<213> Artificial sequence (Artificial Sequence)

<400> 18

ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60

ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120

aggggttcct tgtagttaat gattaacccg ccatgctact tatctacgta gccatgctct 180

aggaagatcg gaattcgccc ttaagggccc cagaagcctg gtggttgttt gtccttctca 240

ggggaaaagt gaggcggccc cttggaggaa ggggccgggc agaatgatct aatcggattc 300

caagcagctc aggggattgt ctttttctag caccttcttg ccactcctaa gcgtcctccg 360

tgaccccggc tgggatttag cctggtgctg tgtcagcccc ggtctcccag gggcttccca 420

gtggtcccca ggaaccctcg acagggcccg gtctctctcg tccagcaagg gcagggacgg 480

gccacaggcc aagggcggta ctctagagga tccggtactc gaggaactga aaaaccagaa 540

agttaactgg taagtttagt ctttttgtct tttatttcag gtcccggatc cggtggtggt 600

gcaaatcaaa gaactgctcc tcagtggatg ttgcctttac ttctaggcct gtacggaagt 660

gttacttctg ctctaaaagc tgcggaattg tacccgcggc cgccaccatg gcggcggcgt 720

gcccggaact gcgtcagctg gcgcagagcg atgtgtattg ggatccgatt gtgagcattg 780

aaccggatgg cgtggaagaa gtgtttgatc tgaccgtgcc gggcccgcat aactttgtgg 840

cgaacgatat tattgcgcat aactgttttg gcaccggcct gtacctgaca ctcgtgcgga 900

agatgaagaa catccagagc cagcggaagg gcagcgaggg cacatgtagc tgtagcagca 960

agggcttcag caccacctgt cctgctcacg tggacgatct gacccctgaa caggtgctgg 1020

atggcgacgt gaacgagctg atggacgtgg tgctgcacca cgtgcctgag gccaagctgg 1080

tggaatgcat cggccaagag ctgatcttcc tgctgcctaa caagaacttc aagcaccggg 1140

cctacgccag cctgttcaga gagctggaag agacactggc cgatctgggc ctgagcagct 1200

ttggcatcag cgacacccct ctggaagaaa tcttcctgaa agtgaccgag gacagcgaca 1260

gcggcccact ttttgctggc ggagcacagc agaaacgcga gaacgtgaac cctagacacc 1320

cctgtctggg ccctagagag aaagccggac agacccctca ggacagcaat gtgtgctctc 1380

ctggtgctcc tgccgctcac cctgaaggac aacctccacc tgagcctgag tgtcctggac 1440

ctcagctgaa taccggcaca cagctggttc tgcagcacgt gcaagccctg ctggtcaaga 1500

gattccagca caccatcaga agccacaagg actttctggc ccagattgtg ctgcccgcca 1560

ccttcgtttt tctggctctg atgctgagca tcgtgatccc tccattcggc gagtaccccg 1620

ctctgacact gcacccttgg atctacggcc agcagtacac cttcttcagc atggacgagc 1680

ctggcagcga gcagtttaca gtgctggctg atgtgctgct gaacaagccc ggcttcggca 1740

accgctgtct gaaagaagga tggctgcctg agtacccctg cggcaatagc accccttgga 1800

aaacccctag cgtgtcccct aacatcaccc agctgttcca gaaacagaaa tggacccaag 1860

tgaacccctc tccatcctgc cggtgctcca ccagagaaaa gctgaccatg ctgcccgagt 1920

gtccagaagg tgcaggcgga cttcctccac ctcagagaac ccagagaagc accgagattc 1980

tgcaggacct gaccgaccgg aatatcagcg acttcctggt taagacatac cccgcactga 2040

tccggtccag cctgaagtcc aagttctggg tcaacgagca gagatacggc ggcatctcta 2100

tcggcggaaa gctgcctgtg gtgcctatca caggcgaagc cctcgtgggc tttctgtctg 2160

acctgggcag aatcatgaac gtgtccggcg gacccatcac cagagaggcc agcaaagaga 2220

tccccgattt cctgaagcac ctggaaaccg aggataacat caaagtgtgg ttcaacaaca 2280

aaggctggca cgccctggtg tcctttctga acgtggccca caacgccatc ctgagagcca 2340

gcctgcctaa ggacagaagc cctgaggaat acggcatcac cgtgatctcc cagccactga 2400

acctgaccaa agagcagctg agcgagatca ccgtgctgac cacatctgtg gatgccgtgg 2460

tggccatctg cgtgatcttc tccatgagct tcgtgcctgc ctccttcgtg ctgtatctga 2520

tccaagagag agtgaacaag agcaagcacc tccagtttat cagcggagtg tccccaacca 2580

cctactgggt caccaacttt ctgtgggaca tcatgaacta ctccgtgtct gccggcctgg 2640

tcgtgggcat cttcatcggc tttcagaaga aggcctacac aagccccgag aacctgcctg 2700

ctctggttgc tctgctgctg ctgtatggct gggccgtgat tcccatgatg taccccgcca 2760

gcttcctgtt cgatgtgcct agcacagcct acgtggccct gagctgcgcc aatctgttca 2820

tcggcatcaa cagcagcgcc atcaccttca tcctggaact gttcgagaac aacagaaccc 2880

tgctgcggtt caacgccgtg ctgagaaagc tgctgatcgt gttccctcac ttctgcctcg 2940

gcagaggcct gattgatctg gccctgtctc aggccgtgac cgacgtgtac gctagatttg 3000

gcgaggaaca cagcgccaat cctttccact gggacctgat cggcaagaac ctgttcgcca 3060

tggtggtgga aggcgtggtg tatttcctgc tgactctgct ggtgcagcgg cacttctttc 3120

tgtcccaatg gatcgccgag cctaccaaag aacccatcgt ggacgaggac gacgacgtgg 3180

ccgaagagag acagagaatc atcaccggcg gcaacaagac cgacatcctg aggctgcacg 3240

agctgaccaa gatctaccct ggcacatcta gccctgccgt ggacagactg tgtgtgggag 3300

ttagacctgg cgagtgcttt ggcctgctgg gagttaatgg cgccggaaag accaccacct 3360

tcaagatgct gaccggcgac accacagtga ccagcggaga tgctactgtg gccggcaaga 3420

gcatcctgac caacatcagc gaggtgcacc agaacatggg ctactgccct cagttcgacg 3480

ccatcgacga actgctgaca ggcagagagc acctgtatct gtacgccaga ctgagaggcg 3540

tgcccgccga agaaattgag aaggtggcca actggtccat caagagcctg ggactgaccg 3600

tgtacgccga ttgtctggcc ggcacatata gcggcggaaa caagcggaag ctgagcaccg 3660

ccattgctct gatcggatgc cctcctctgg tcctgctgga tgagcctaca accggcatgg 3720

atccccaggc tagacggatg ctgtggaacg tgatcgtgtc catcatccgc gaaggcagag 3780

ccgtggtcct gacaagccac agcatggaag agtgcgaggc cctgtgtacc agactggcca 3840

tcatggtcaa gggcgccttc agatgcatgg gcaccattca gcacctgaaa agcaagttcg 3900

gcgacggcta catcgtgacc atgaagatca agtccccaaa ggacgacctg ctgccagatc 3960

tgaaccccgt ggaacagttc ttccagggca acttccctgg ctccgtgcag cgggaaagac 4020

actacaacat gctgcagttt caggtgtcca gcagctccct ggccagaatc tttcagctgc 4080

tgctctccca caaggatagc ctgctgattg aagagtacag cgtgacccag accacactgg 4140

accaggtgtt cgtgaacttc gccaagcagc agaccgagag ccacgacttg cctctgcacc 4200

ctagagctgc cggcgcttct agacaggccc aggattaata aacgcgtcct cgactgtgcc 4260

ttctagttgc cagccatctg ttgtttgccc ctcccccgtg ccttccttga ccctggaagg 4320

tgccactccc actgtccttt cctaataaaa tgaggaaatt gcatcgcatt gtctgagtag 4380

gtgtcattct attctggggg gtggggtggg gcaggacagc aagggggagg attgggaaga 4440

caatagcagg catgctgggg atgcggtggg ctctatggcc tcgagttaag ggcgaattcc 4500

cgataaggat cttcctagag catggctacg tagataagta gcatggcggg ttaatcatta 4560

actacaagga acccctagtg atggagttgg ccactccctc tctgcgcgct cgctcgctca 4620

ctgaggccgg gcgaccaaag gtcgcccgac gcccgggctt tgcccgggcg gcctcagtga 4680

gcgagcgagc gcgcagcctt aattaaccta attcactggc cgtcgtttta caacgtcgtg 4740

actgggaaaa ccctggcgtt acccaactta atcgccttgc agcacatccc cctttcgcca 4800

gctgcattaa tgaatcggcc aacgcgcggg gagaggcggt ttgcgtattg ggcgctcttc 4860

cgcttcctcg ctcactgact cgctgcgctc ggtcgttcgg ctgcggcgag cggtatcagc 4920

tcactcaaag gcggtaatac ggttatccac agaatcaggg gataacgcag gaaagaacat 4980

gtgagcaaaa ggccagcaaa aggccaggaa ccgtaaaaag gccgcgttgc tggcgttttt 5040

ccataggctc cgcccccctg acgagcatca caaaaatcga cgctcaagtc agaggtggcg 5100

aaacccgaca ggactataaa gataccaggc gtttccccct ggaagctccc tcgtgcgctc 5160

tcctgttccg accctgccgc ttaccggata cctgtccgcc tttctccctt cgggaagcgt 5220

ggcgctttct catagctcac gctgtaggta tctcagttcg gtgtaggtcg ttcgctccaa 5280

gctgggctgt gtgcacgaac cccccgttca gcccgaccgc tgcgccttat ccggtaacta 5340

tcgtcttgag tccaacccgg taagacacga cttatcgcca ctggcagcag ccactggtaa 5400

caggattagc agagcgaggt atgtaggcgg tgctacagag ttcttgaagt ggtggcctaa 5460

ctacggctac actagaagaa cagtatttgg tatctgcgct ctgctgaagc cagttacctt 5520

cggaaaaaga gttggtagct cttgatccgg caaacaaacc accgctggta gcggtggttt 5580

ttttgtttgc aagcagcaga ttacgcgcag aaaaaaagga tctcaagaag atcctttgat 5640

cttttctacg gggtctgacg ctcagtggaa cgaaaactca cgttaaggga ttttggtcat 5700

gagattatca aaaaggatct tcacctagat ccttttaaat taaaaatgaa gttttaaatc 5760

aatctaaagt atatatgagt aaacttggtc tgacagttag aaaaactcat cgagcatcaa 5820

atgaaactgc aatttattca tatcaggatt atcaatacca tatttttgaa aaagccgttt 5880

ctgtaatgaa ggagaaaact caccgaggca gttccatagg atggcaagat cctggtatcg 5940

gtctgcgatt ccgactcgtc caacatcaat acaacctatt aatttcccct cgtcaaaaat 6000

aaggttatca agtgagaaat caccatgagt gacgactgaa tccggtgaga atggcaaaag 6060

tttatgcatt tctttccaga cttgttcaac aggccagcca ttacgctcgt catcaaaatc 6120

actcgcatca accaaaccgt tattcattcg tgattgcgcc tgagcgagac gaaatacgcg 6180

atcgctgtta aaaggacaat tacaaacagg aatcgaatgc aaccggcgca ggaacactgc 6240

cagcgcatca acaatatttt cacctgaatc aggatattct tctaatacct ggaatgctgt 6300

tttcccaggg atcgcagtgg tgagtaacca tgcatcatca ggagtacgga taaaatgctt 6360

gatggtcgga agaggcataa attccgtcag ccagtttagt ctgaccatct catctgtaac 6420

atcattggca acgctacctt tgccatgttt cagaaacaac tctggcgcat cgggcttccc 6480

atacaatcga tagattgtcg cacctgattg cccgacatta tcgcgagccc atttataccc 6540

atataaatca gcatccatgt tggaatttaa tcgcggccta gagcaagacg tttcccgttg 6600

aatatggctc atactcttcc tttttcaata ttattgaagc atttatcagg gttattgtct 6660

catgagcgga tacatatttg aatgtattta gaaaaataaa caaatagggg ttccgcgcac 6720

atttccccga aaagtgccac ctgacgtcta agaaaccatt attatcatga cattaaccta 6780

taaaaatagg cgtatcacga ggccctttcg tctcgcgcgt ttcggtgatg acggtgaaaa 6840

cctctgacac atgcagctcc cggagacggt cacagcttgt ctgtaagcgg atgccgggag 6900

cagacaagcc cgtcagggcg cgtcagcggg tgttggcggg tgtcggggct ggcttaacta 6960

tgcggcatca gagcagattg tactgagagt gcaccatatg cggtgtgaaa taccgcacag 7020

atgcgtaagg agaaaatacc gcatcaggcg ccattcgcca ttcaggctgc gcaactgttg 7080

ggaagggcga tcggtgcggg cctcttcgct attacgccag ctggcacgac aggtttcccg 7140

actggaaagc gggcagtgag cgcaacgcaa ttaatgtgag ttagctcact cattaggcac 7200

cccaggcttt acactttatg cttccggctc gtatgttgtg tggaattgtg agcggataac 7260

aatttcacac aggaaacagc tatgaccatg attacgccag atttaattaa gg 7312

Claims

1. A plasmid composition comprising a vector comprising an ABCA 4-N-terminal protein expression cassette and a vector comprising an ABCA 4-C-terminal protein expression cassette; the ABCA4-N end protein expression frame consists of an enhancer-promoter-intron-intein fragment-containing coding gene sequence-polyA signal of a human ABCA4-N protein fragment, the ABCA4-C end protein expression frame consists of an enhancer-promoter-intron-intein fragment-containing coding gene-polyA signal of a human ABCA4-C protein fragment, the enhancer is selected from human 214bp interphotoreceptor retinoid-binding protein enhancer enhancer sequence, and the promoter is selected from retina photoreceptor cell specific human RS1 promoter, human Rho promoter, human RK promoter or mouse CAR promoter; the intron is selected from the SV40 intron; the coding gene sequence of the human ABCA4-N protein fragment containing the intein fragment is shown as SEQ ID NO.8, and the coding gene sequence of the human ABCA4-C protein fragment containing the intein fragment is shown as SEQ ID NO. 9; the polyA signal sequence is selected from SV40 PolyA, bGH polyA, hGH polyA or rBG polyA sequences; the enhancer, the promoter, the intron, the target gene sequence and the polyA are connected through a bond or a nucleotide connecting sequence.

2. The plasmid composition of claim 1, wherein the promoter is selected from the group consisting of the RK promoter, the sequence of which is shown in SEQ ID No. 10; the intron sequence is selected from SV40 intron, and the sequence is shown as 4863bp-4959bp of a nucleotide sequence disclosed by GenBank accession number MK 225672.1; the polyA is selected from bGH ployA, and the sequence is shown as 957bp-1181bp of a nucleotide sequence disclosed in GenBank accession number MT 267334.1.

3. The plasmid composition of any one of claims 1-2, wherein the ABCA4-N terminal protein expression cassette has a nucleotide sequence set forth in SEQ ID No.11; the nucleotide sequence of the ABCA4-C end protein expression frame is shown as SEQ ID NO.12.

4. The plasmid composition of any one of claims 1-2, wherein the vector is selected from any one of the recombinant adeno-associated viral vector serotypes selected from the group consisting of: AAV1, AAV2, AAV3B, AAV, AAV5, AAV6, AAV7, AAV8, AAV9, AAVrh10, AAV-LK03, or AAVAnc80d.

5. The plasmid composition of claim 4, wherein the vector is selected from the group consisting of any one of the recombinant adeno-associated viral vector serotypes: AAV2, AAV5, AAV8 or AAV9.

6. The plasmid composition according to claim 4, which comprises the vector according to claim 4, a Rep and Cap protein expression plasmid of AAV, and a helper plasmid.

7. The plasmid composition according to claim 6, which comprises the vector according to claim 4, the Rep and Cap protein expression plasmid pAAV2/8 of AAV, and the helper plasmid pAdΔF6.

8. A recombinant adeno-associated virus composition comprising two recombinant adeno-associated viruses:

i: recombinant adeno-associated virus prepared by co-transfecting HEK293 cell packaging with the vector containing ABCA4-N end protein expression frame, rep and Cap protein expression plasmid of AAV and auxiliary plasmid as described in claim 1 or 2;

II: recombinant adeno-associated virus prepared by co-transfecting HEK293 cell packaging with the vector containing ABCA4-C terminal protein expression frame, rep and Cap protein expression plasmid of AAV and auxiliary plasmid as described in claim 1 or 2.

9. The recombinant adeno-associated virus composition of claim 8, comprising two recombinant adeno-associated viruses:

i: recombinant adeno-associated virus prepared by co-transfecting HEK293 cell packaging of the vector containing ABCA4-N terminal protein expression frame, rep and Cap protein expression plasmid pAAV2/8 of AAV and auxiliary plasmid pAdΔF6 in claim 1 or 2;

II: recombinant adeno-associated virus prepared by co-transfecting HEK293 cell packaging with the vector containing ABCA4-C terminal protein expression frame, rep and Cap protein expression plasmid of AAV as claimed in claim 1 or 2.

10. Use of the plasmid composition of claim 1 or 2 in the manufacture of a medicament for the treatment of STGDI disease.

11. Use of the recombinant adeno-associated virus composition of claim 8 for the preparation of a medicament for the treatment of STGDI disease.