RU2812852C2 - Non-viral dna vectors and options for their use for expression of therapeutic agent based on factor viii (fviii) - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: following is described: a group of inventions including a capsid-free vector based on closed-ended DNA (ceDNA) for the expression of factor VIII (FVIII) protein, a method of expressing the FVIII protein in a cell, a pharmaceutical composition for gene therapy, a method of treating a subject suffering from hemophilia A, a cell for producing the protein FVIII, a ceDNA vector delivery composition and a ceDNA vector delivery kit. In one embodiment, the capsidless vector comprises at least one nucleic acid sequence located between flanking inverted terminal repeats (ITRs), wherein the at least one nucleic acid sequence encodes at least one factor VIII (FVIII) protein and is codon optimized for expression in the cell.

EFFECT: invention expands the range of agents for expressing factor VIII (FVIII) protein.

53 cl, 16 dwg, 15 tbl, 14 ex

Description

RELATED APPLICATIONS

[0001] This application claims benefit to US Provisional Application No. 62/817904, filed March 13, 2019, and US Provisional Application No. 62/856432, filed June 3, 2019, the contents of each of which are incorporated herein by reference in their entirety. .

LIST OF SEQUENCES

[0002] This application includes a sequence listing that has been filed electronically in ASCII format, as well as the sequences in Tables 1-9 herein, each of which is incorporated herein by reference in its entirety. The listed ASCII copy, created on March 11, 2020, is named 131698-06020_SL.txt and is 116781 bytes in size.

TECHNICAL FIELD

[0003] The present invention relates to the field of gene therapy, including non-viral vectors for expression of a transgene or isolated polynucleotides in a subject or cell. The present disclosure also relates to nucleic acid constructs, promoters, vectors and host cells, including polynucleotides, as well as methods for delivering exogenous DNA sequences to a target cell, tissue, organ or organism. For example, the present disclosure provides methods of using non-viral cccDNA vectors to express factor VIII (FVIII) from a cell, for example, expressing a therapeutic FVIII protein for treating a subject suffering from hemophilia A. The methods and compositions can be used, for example, to treat a disease by expressing FVIII in cell or tissue of the subject in need.

BACKGROUND OF THE ART

[0004] The goal of gene therapy is to improve clinical outcomes in patients suffering from either genetic mutations or acquired diseases caused by aberrations in the gene expression profile. Gene therapy involves the treatment or prevention of medical conditions caused by defective genes or abnormal regulation or expression, such as underexpression or overexpression, which can lead to a disorder, disease, malignancy, etc. For example, a disease or disorder caused by a defective gene may be treated, prevented, or ameliorated by delivering corrective genetic material to a patient, or may be treated, prevented, or ameliorated by modifying or suppressing a defective gene in a patient, for example, by providing corrective genetic material resulting in a therapeutic effect. expression of genetic material in the patient’s body.

[0005] The basis of gene therapy is the provision of a transcription cassette with an active gene product (sometimes called a transgene), for example, which can lead to a positive gain-of-function effect, a negative loss-of-function effect, or other outcome. Such outcomes may be attributed to the expression of a therapeutic protein, such as an antibody, functional enzyme, or fusion protein. Gene therapy can also be used to treat a disease or malignancy caused by other factors. Monogenic disorders in humans can be treated by delivering a normal gene to target cells and expressing it in them. Delivery and expression of the corrective gene in target cells of a patient can be achieved using numerous methods, including the use of engineered viruses and viral vectors for gene delivery. Among the numerous viral vectors available (eg, recombinant retrovirus, recombinant lentivirus, recombinant adenovirus, etc.), recombinant adeno-associated virus (rAAV) is gaining increasing popularity in gene therapy as a multi-purpose vector.

[0006] Adeno-associated viruses (AAVs) belong to the family Parvoviridae and, more specifically, constitute the genus Dependopareoviridae. AAV-derived vectors (i.e., recombinant AAV (rAAV) or AAV vectors) are an attractive method of delivering genetic material because (i) they are capable of infecting (transducing) a wide range of nondividing and dividing cell types, including myocytes and neurons ; (ii) they lack viral structural genes, which reduces host cell responses to viral infection, such as interferon-mediated responses; (iii) wild-type viruses are considered non-pathological in humans; (iv) unlike wild-type AAVs, which are capable of integrating into the host cell genome, replication-defective AAV vectors lack the rep gene and usually persist as episomes, which limits the risk of insertional mutagenesis or genotoxicity; and (ν) compared to other vector systems, AAV vectors are generally considered to be relatively weak immunogens and therefore do not elicit a significant immune response (see ii), thus allowing vector DNA persistence and potentially long-term expression of therapeutic transgenes.

[0007] However, the use of AAV particles as a vector for gene delivery has several serious disadvantages. One of the major disadvantages associated with rAAV is the limited viral packaging capacity of approximately 4.5 kb. heterologous DNA (Dong et al, 1996; Athanasopoulos et al, 2004; Lai et al, 2010), therefore the use of AAV vectors is limited by their ability to encode proteins smaller than 150,000 Da. A second disadvantage is that, as a result of the prevalence of wild-type AAV infection in the population, candidates for gene therapy using rAAV must be screened for the presence of neutralizing antibodies that eliminate the vector from the patient. A third disadvantage relates to the immunogenicity of the capsid, which precludes re-administration in patients who have not been withdrawn from initial treatment. The patient's immune system may respond to the vector, which essentially acts as a "booster" shot, stimulating the immune system to produce high titers of anti-AAV antibodies, which preclude future treatment. Some recent reports have raised concerns regarding immunogenicity in situations involving high doses. Another notable disadvantage is the relatively slow onset of AAV-mediated gene expression, given that single-stranded AAV DNA must be converted to double-stranded DNA before expression of the heterologous gene.

[0008] In addition, conventional AAV capsid virions are produced by introducing a plasmid or plasmids containing the AAV genome, rep genes and cap genes (Grimm et al., 1998). However, such capsidized AAV viral vectors have been found to ineffectively transduce certain types of cells and tissues, and capsids also induce an immune response.

[0009] Accordingly, the use of adeno-associated virus (AAV) vectors for gene therapy is limited due to single administration to patients (due to the patient's immune response), a limited range of transgenic genetic material suitable for delivery in AAV vectors due to the minimal capacity of the viral packaging ( about 4.5 kb), and slow AAV-mediated gene expression.

[0010] There is a large unmet need for disease-modifying therapies for hemophilia A. Current therapies are cumbersome and require intravenous (IV) administrations. First, these injectable factor VIII preparations do not provide continuous factor delivery, with minimal levels allowing bleeding episodes. Second, there are no approved gene therapies for hemophilia A, and AAV-based therapies cannot be used in 25% to 40% of patients due to pre-existing antibodies. AAV may only be administered once, and the resulting levels of factor VIII may not be high enough to be effective or may be higher than normal dose levels that cannot be titrated. Third, many patients with hemophilia A are unable to use these therapies due to the production of neutralizing antibodies to these exogenous, man-made clotting factors.

[0011] Accordingly, there is a need in the art for technology that enables expression of a therapeutic FVIII protein in a cell, tissue, or body of a subject for the treatment of hemophilia A.

SHORT DESCRIPTION

[0012] The technology described herein relates to methods and compositions for treating hemophilia A by expressing factor VIII (FVIII) protein from a capsidless (e.g., non-viral) DNA vector with covalently closed ends (referred to herein as a “DNA vector closed ends" or "ccDNA vector"), wherein said cccDNA vector contains a FVIII nucleic acid sequence or codon optimized variants thereof. This cccDNA vector can be used to produce FVIII proteins for treatment, monitoring and diagnosis. The use of cccDNA vectors expressing FVIII in a subject for the treatment of hemophilia A is suitable for: (i) providing disease-modifying levels of the FVIII enzyme, (ii) minimally invasive delivery, (iii) repeatability and dosing until effect is achieved, (iv) rapid onset of therapeutic effect, (v) sustained expression of the corrective FVIII enzyme in the liver, (vi) restoration of urea cycle function, and/or (vii) titration to achieve appropriate pharmacological levels of the defective enzyme.

[0013] In some embodiments, a cccDNA vector expressing FVIII is optionally present in liposomal nanoparticles (LNPs) for the treatment of hemophilia A. The cccDNA vectors described herein may provide one or more benefits, including, but not limited to, the following: , providing disease-modifying levels of factor VIII, minimal invasiveness in delivery, repeatability and dosing until effect is achieved, ensuring rapid onset of therapeutic effect within days of therapeutic intervention, sustained expression of corrective levels of factor VIII in the bloodstream, ability to titrate to achieve appropriate pharmacological levels of the defective coagulation factor and/or providing treatments for another type of hemophilia, including, but not limited to, factor VIII deficiency.

[0014] Accordingly, the present invention described herein relates to a capsid-free (e.g., non-viral) covalently closed-end DNA vector (referred to herein as a “closed-end DNA vector” or “ccDNA vector”) comprising a heterogeneous gene encoding FVIII to allow expression of the therapeutic FVIII protein in the cell. In accordance with one aspect, the present disclosure provides a capsidless closed-end DNA (ccDNA) vector comprising at least one heterologous nucleotide sequence between flanking inverted terminal repeats (ITRs), wherein at least one heterologous nucleotide sequence encodes at least one FVIII protein, wherein the at least one heterologous nucleotide sequence that encodes the at least one FVIII protein is selected from any of the sequences in Table 1. In accordance with some embodiments, the ccDNA vector comprises a nucleic acid sequence selected from any of the sequences in Table 9. In accordance with some embodiments, the cccDNA vector contains a nucleic acid sequence selected from the group consisting of SEQ ID NO: 207, SEQ ID NO: 210, SEQ ID NO: 212, SEQ ID NO: 199, SEQ ID NO: 208, SEQ ID NO: 211, and SEQ ID NO: 214. In accordance with some embodiments, the cccDNA vector contains a nucleic acid sequence that is at least 85% identical to SEQ ID NO: 210. In accordance in some embodiments, the cccDNA vector contains a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 210. In some embodiments, the cccDNA vector contains a nucleic acid sequence that is at least 95% identical to SEQ ID NO: 210. In accordance with some embodiments, the ccDNA vector contains a nucleic acid sequence that is at least 96% identical to SEQ ID NO: 210. In accordance with some embodiments, the ccDNA vector contains a nucleic acid sequence that is at least is 97% identical to SEQ ID NO: 210. In accordance with some embodiments, the cccDNA vector contains a nucleic acid sequence that is at least 98% identical to SEQ ID NO: 210. In accordance with some embodiments, the cccDNA vector contains a nucleic acid sequence acid that is at least 99% identical to SEQ ID NO: 210. In accordance with some embodiments, the cccDNA vector contains a nucleic acid sequence that is at least 85% identical to SEQ ID NO: 214. In accordance with some embodiments The cccDNA vector contains a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 214. In accordance with some embodiments, the cccDNA vector contains a nucleic acid sequence that is at least 95% identical to SEQ ID NO: 214. In accordance with some embodiments, the cccDNA vector contains a nucleic acid sequence that is at least 96% identical to SEQ ID NO: 214. In accordance with some embodiments, the cccDNA vector contains a nucleic acid sequence that is at least 97% identical to SEQ ID NO: 214. In accordance with some embodiments, the ccDNA vector contains a nucleic acid sequence that is at least 98% identical to SEQ ID NO: 214. In accordance with some embodiments, the ccDNA vector contains a nucleic acid sequence that is at least 99% identical to SEQ ID NO: 214.

[0015] In one embodiment, disclosed herein is a capsidless closed-end DNA (ccDNA) vector comprising at least one heterologous nucleotide sequence between flanking inverted terminal repeats (ITRs), wherein the at least one heterologous nucleotide sequence encodes at least one FVIII protein, wherein the at least one heterologous nucleotide sequence that encodes the at least one FVIII protein is selected from a sequence having at least 85% identity with any sequence in Table 1. In one embodiment, the specified at least one heterologous nucleotide sequence that encodes at least one FVIII protein is selected from a sequence having at least 90% identity with any sequence in Table 1. In one embodiment, the at least one heterologous nucleotide sequence that encodes at least one FVIII protein is selected from a sequence having at least 91% identity with any sequence in Table 1. In one embodiment, the at least one heterologous nucleotide sequence that encodes at least one FVIII protein is selected from a sequence, having at least 92% identity with any sequence in Table 1. In one embodiment, the at least one heterologous nucleotide sequence that encodes at least one FVIII protein is selected from a sequence having at least 93% identity with any sequence in Table 1. In one embodiment, said at least one heterologous nucleotide sequence that encodes at least one FVIII protein is selected from a sequence having at least 94% identity with any sequence in Table 1. In one embodiment, said at least one heterologous nucleotide sequence that encodes at least one FVIII protein is selected from a sequence having at least 95% identity with any sequence in Table 1. In one embodiment, the at least one heterologous nucleotide sequence that encodes at least one FVIII protein is selected from a sequence having at least 96% identity with any sequence in Table 1. In one embodiment, the at least one heterologous nucleotide sequence that encodes at least one FVIII protein is selected from a sequence, having at least 97% identity with any sequence in Table 1. In one embodiment, the at least one heterologous nucleotide sequence that encodes at least one FVIII protein is selected from a sequence having at least 98% identity with any sequence in Table 1. In one embodiment, said at least one heterologous nucleotide sequence that encodes at least one FVIII protein is selected from a sequence having at least 99% identity with any sequence in Table 1. In one embodiment, said at least one heterologous nucleotide sequence that encodes at least one FVIII protein is selected from a sequence comprising any sequence in Table 1. In one embodiment, the at least one heterologous nucleotide sequence that encodes at least one FVIII protein is selected from a sequence containing any sequence in Table 1.

[0016] In one embodiment, the sequence in Table 1 is selected from the group consisting of SEQ ID NO: 380, SEQ ID NO: 381, SEQ ID NO: 382, SEQ ID NO: 383, SEQ ID NO: 384, SEQ ID NO : 385, SEQ ID NO: 386, SEQ ID NO: 387, SEQ ID NO: 388, SEQ ID NO: 389, SEQ ID NO: 390, SEQ ID NO: 391, SEQ ID NO: 392, SEQ ID NO: 393 , SEQ ID NO: 394, SEQ ID NO: 395, SEQ ID NO: 396, and SEQ ID NO: 397. In one embodiment, the sequence is SEQ ID NO: 380. In one embodiment, the sequence is SEQ ID NO: 381 In one embodiment, the sequence is SEQ ID NO: 382. In one embodiment, the sequence is SEQ ID NO: 383. In one embodiment, the sequence is SEQ ID NO: 384. In one embodiment, the sequence is SEQ ID NO: : 385. In one embodiment, the sequence is SEQ ID NO: 386. In one embodiment, the sequence is SEQ ID NO: 387. In one embodiment, the sequence is SEQ ID NO: 388. In one embodiment, the sequence is SEQ ID NO: 389. In one embodiment, the sequence is SEQ ID NO: 390. In one embodiment, the sequence is SEQ ID NO: 391. In one embodiment, the sequence is SEQ ID NO: 392. In one embodiment, the sequence is is SEQ ID NO: 393. In one embodiment, the sequence is SEQ ID NO: 394. In one embodiment, the sequence is SEQ ID NO: 395. In one embodiment, the sequence is SEQ ID NO: 396. In one embodiment, the sequence is SEQ ID NO: 397.

[0017] In one embodiment, the ccDNA vector comprises a nucleic acid sequence selected from a sequence having at least 85% identity to any sequence in Table 9. In one embodiment, the ccDNA vector comprises a nucleic acid sequence selected from a sequence having at least 90% identity to any sequence in Table 9. In one embodiment, the cccDNA vector comprises a nucleic acid sequence selected from a sequence having at least 91% identity to any sequence in Table 9. In one embodiment, the cccDNA vector contains a nucleic acid sequence selected from a sequence having at least 92% identity with any sequence in Table 9. In one embodiment, the cccDNA vector contains a nucleic acid sequence selected from a sequence having at least 93% identity with any sequence in Table 9. In one embodiment, the cccDNA vector contains a nucleic acid sequence selected from a sequence having at least 94% identity with any sequence in Table 9. In one embodiment, the ccDNA vector contains a nucleic acid sequence selected from a sequence having at least 95% identity to any sequence in Table 9. In one embodiment, the cccDNA vector comprises a nucleic acid sequence selected from a sequence having at least 96% identity to any sequence in Table 9. In one embodiment, the cccDNA vector comprises a nucleic acid sequence selected from a sequence having at least 97% identity to any sequence in Table 9. In one embodiment, the cccDNA vector comprises a nucleic acid sequence selected from a sequence having at least 98% identity to any sequence in Table 9. In one embodiment, the cccDNA vector comprises a nucleic acid sequence selected from a sequence having at least 99% identity to any sequence in Table 9. In one embodiment, the ccDNA vector comprises a nucleic acid sequence comprising a sequence in Table 9 In one embodiment, the cccDNA vector contains a nucleic acid sequence consisting of the sequence in Table 9.

[0018] In one embodiment, the sequence in Table 9 is selected from the group consisting of SEQ ID NO: 197, SEQ ID NO: 198, SEQ ID NO: 199, SEQ ID NO: 200, SEQ ID NO: 201, SEQ ID NO : 202, SEQ ID NO: 203, SEQ ID NO: 204, SEQ ID NO: 205, SEQ ID NO: 206, SEQ ID NO: 207, SEQ ID NO: 208, SEQ ID NO: 209, SEQ ID NO: 210 , SEQ ID NO: 211, SEQ ID NO: 212, SEQ ID NO: 213, SEQ ID NO: 214, SEQ ID NO: 215, SEQ ID NO: 216, and SEQ ID NO: 217. In one embodiment, the sequence in the Table 9 represents SEQ ID NO: 197. In one embodiment, the sequence in Table 9 is SEQ ID NO: 198. In one embodiment, the sequence in Table 9 is SEQ ID NO: 199. In one embodiment, the sequence in Table 9 represents is 200. In one embodiment, the sequence in Table 9 is 201. In one embodiment, the sequence in Table 9 is 202. In one embodiment, the sequence in Table 9 is 203. In one embodiment, the sequence in Table 9 is 204 According to one implementation, the sequence in Table 9 is 205. According to one implementation, the sequence in Table 9 is 206. According to one implementation, the sequence in Table 9 is 207. According to one implementation, the sequence in Table 9 is 208. According to In one embodiment, the sequence in Table 9 is 209. In one embodiment, the sequence in Table 9 is 210. In one embodiment, the sequence in Table 9 is 211. In one embodiment, the sequence in Table 9 is 212. In one embodiment According to one implementation, the sequence in Table 9 is 213. In one implementation, the sequence in Table 9 is 214. In one implementation, the sequence in Table 9 is 215. In one implementation, the sequence in Table 9 is 216. In one implementation, the sequence in Table 9 is 217.

[0019] In one embodiment, the cccDNA vector comprises a nucleic acid sequence having at least 85% identity to SEQ ID NO: 210. In one embodiment, the ccDNA vector contains a nucleic acid sequence having at least 90% identity to SEQ ID NO: 210. In one embodiment, the ccDNA vector contains a nucleic acid sequence having at least 91% identity to SEQ ID NO: 210. In one embodiment, the ccDNA vector contains a nucleic acid sequence having at least 92% identity with SEQ ID NO: 210. In one embodiment, the ccDNA vector contains a nucleic acid sequence having at least 93% identity with SEQ ID NO: 210. In one embodiment, the ccDNA vector contains a nucleic acid sequence having at least 94 % identity to SEQ ID NO: 210. In one embodiment, the cccDNA vector contains a nucleic acid sequence having at least 95% identity to SEQ ID NO: 210. In one embodiment, the ccDNA vector contains a nucleic acid sequence having at least at least 96% identity with SEQ ID NO: 210. In one embodiment, the cccDNA vector contains a nucleic acid sequence having at least 97% identity with SEQ ID NO: 210. In one embodiment, the ccDNA vector contains a nucleic acid sequence having at least 98% identity to SEQ ID NO: 210. In one embodiment, the cccDNA vector comprises a nucleic acid sequence having at least 99% identity to SEQ ID NO: 210. In one embodiment, the cccDNA vector comprises a nucleic acid sequence comprising SEQ ID NO: 210. In one embodiment, the ccDNA vector contains a nucleic acid sequence consisting of SEQ ID NO: 210.

[0020] In one embodiment, the cccDNA vector comprises a nucleic acid sequence having at least 85% identity to SEQ ID NO: 214. In one embodiment, the ccDNA vector contains a nucleic acid sequence having at least 90% identity to SEQ ID NO: 214. In one embodiment, the ccDNA vector contains a nucleic acid sequence having at least 91% identity to SEQ ID NO: 214. In one embodiment, the ccDNA vector contains a nucleic acid sequence having at least 92% identity with SEQ ID NO: 214. In one embodiment, the ccDNA vector contains a nucleic acid sequence having at least 93% identity with SEQ ID NO: 214. In one embodiment, the ccDNA vector contains a nucleic acid sequence having at least 94 % identity to SEQ ID NO: 214. In one embodiment, the ccDNA vector contains a nucleic acid sequence having at least 95% identity to SEQ ID NO: 214. In one embodiment, the ccDNA vector contains a nucleic acid sequence having at least at least 96% identity with SEQ ID NO: 214. In one embodiment, the cccDNA vector contains a nucleic acid sequence having at least 97% identity with SEQ ID NO: 214. In one embodiment, the ccDNA vector contains a nucleic acid sequence having at least 98% identity to SEQ ID NO: 214. In one embodiment, the cccDNA vector comprises a nucleic acid sequence having at least 99% identity to SEQ ID NO: 214. In one embodiment, the cccDNA vector comprises a nucleic acid sequence comprising SEQ ID NO: 214. In one embodiment, the ccDNA vector comprises a nucleic acid sequence consisting of SEQ ID NO: 214.

[0021] The cccDNA vectors for expression of FVIII protein production described herein are non-capsidated linear duplex DNA molecules formed from a continuous strand of complementary DNA with covalently closed ends (linear, continuous and unencapsidated structure) that contain a 5' inverted sequence terminal repeat (ITR) and a 3'-ITR sequence, wherein said 5-ITR and 3'-ITR may have the same symmetrical three-dimensional organization with respect to each other (i.e., symmetrical or substantially symmetrical) or, alternatively, 5' -ITR and 3'-ITR may have different three-dimensional organization relative to each other (i.e., asymmetric ITRs). In addition, ITRs may originate from the same or different serotypes. In some embodiments, the cccDNA vector may contain ITR sequences that have a symmetrical three-dimensional spatial organization such that their structure has the same shape in geometric space, or have the same A, C-C', and B-B' loops in three-dimensional space (i.e. i.e. they are the same or are mirror images of each other). In some embodiments, one ITR may be derived from one AAV serotype, and the other ITR may be derived from a different AAV serotype.

[0022] Accordingly, certain aspects of the technology described herein relate to a cccDNA vector for improved expression and/or protein production of the FVIII protein described above, which contains ITR sequences flanking a heterologous nucleic acid sequence containing any FVIII nucleic acid sequence, disclosed in Tables 5, wherein said ITR sequences are selected from any of: (i) at least one wild-type (WT) ITR and at least one modified AAV inverted terminal repeat (mod-ITR) (e.g., asymmetric modified ITRs) ; (ii) two modified ITRs, wherein the mod-ITR pair has a different three-dimensional spatial organization relative to each other (e.g., asymmetric modified ITRs), or (iii) pairs of symmetric or substantially symmetric WT-WT ITRs, each WT-ITR has the same three-dimensional spatial organization, or (iv) pairs of symmetric or substantially symmetric modified ITRs, each mod-ITR having the same three-dimensional spatial organization. The cccDNA vectors disclosed herein can be produced in eukaryotic cells and are therefore free from prokaryotic DNA modifications and bacterial endotoxin contamination in insect cells.

[0023] The methods and compositions described herein relate in part to the discovery of non-viral non-capsid DNA vectors with covalently closed ends (ccDNA vectors) that can be used to express at least one FVIII protein or more than one FVIII protein from a cell , including, but not limited to, liver cells.

[0024] Accordingly, this document provides in one aspect DNA vectors (e.g., cccDNA vectors) comprising at least one heterologous nucleic acid sequence encoding at least one transgene encoding FVIII proteins operably linked to a promoter located between two different AAV inverted terminal repeat (ITR) sequences, wherein one of the ITRs contains a functional AAV end resolution site and a Rep binding site, and one of the ITRs contains a deletion, insertion or substitution relative to the other ITR; wherein said transgene encodes the FVIII protein; and wherein said DNA, when digested by a restriction enzyme having one recognition site on the DNA vector, is distinguished by the presence of characteristic bands of linear and continuous DNA compared to control linear and discontinuous DNA when analyzed on a non-denaturing gel. Other aspects include delivery of FVIII protein by expressing it in vivo from a cccDNA vector described herein, and further, treatment of hemophilia A using cccDNA vectors encoding FVIII. Also provided herein are cells containing a cccDNA vector encoding FVIII described herein. In some embodiments, the ccDNA vector is selected from the group consisting of ccDNA FVIII vector 16, ccDNA FVIII vector 19, ccDNA FVIII vector 21, ccDNA FVIII vector 8, ccDNA FVIII vector 17, ccDNA FVIII vector 20, and ccDNA FVIII vector 2 3. In some embodiments, the ccDNA vector is ccDNAFVIII vector 19 or ccDNA FVIII vector 23.

[0025] Aspects of the present invention relate to methods for producing cDNA vectors that can be used to express FVIII protein in a cell, as described herein. Other embodiments relate to a cccDNA vector obtained using the method proposed herein. In one embodiment, a capsid-free (e.g., non-viral) DNA vector (ccDNA vector) for producing FVIII protein is derived from a plasmid (referred to herein as a “ccDNA plasmid”) containing a polynucleotide expression construct template comprising, in this order: first 5'-inverted terminal repeat (eg, AAB ITR); heterologous nucleic acid sequence; and 3'-ITR (e.g., AAB ITR), wherein said 5'-ITR and 3'-ITR may be asymmetric to each other or symmetric (e.g., WT-ITR or modified symmetric ITR) as defined herein . In some embodiments, the ccDNA vector is selected from the group consisting of ccDNA FVIII vector 16, ccDNA FVIII vector 19, ccDNA FVIII vector 21, ccDNA FVIII vector 8, ccDNA FVIII vector 17, ccDNA FVIII vector 20, and ccDNA FVIII vector 2 3. In some embodiments, the ccDNA vector is ccDNAFVIII vector 19 or ccDNA FVIII vector 23.

[0026] The cDNA FVIII protein expression vector disclosed herein can be produced by a number of means that will be known to one of ordinary skill in the art upon reading this disclosure. For example, the polynucleotide expression construct template used to produce the ccDNA vectors of the present invention may be a ccDNA plasmid, a ccDNA bacmid, and/or a ccDNA baculovirus. In one embodiment, the cccDNA plasmid contains a restriction cloning site (e.g., SEQ ID NO: 123 and/or 124) operably located between the ITR, into which an expression cassette can be inserted, containing, for example, a promoter operably linked to the transgene, e.g. , a nucleic acid encoding FVIII. In some embodiments, cccDNA vectors for FVIII protein expression are derived from a polynucleotide template (eg, ccDNA plasmid, ccDNA bacmid, ccDNA baculovirus) containing symmetric or asymmetric ITRs (modified ITRs or WT ITRs).

[0027] In a permissive host cell, in the presence of, for example, Rep, a polynucleotide template having at least two ITRs is replicated to produce cccDNA vectors expressing the FVIII protein. Obtaining a cDNA vector takes place in two stages: first, excision (“extraction”) of the template from the matrix backbone (for example, the genome of a cDNA plasmid, ccDNA bacmid, ccDNA baculovirus, etc.) through Rep proteins, and, second, Rep-mediated replication of the excised cccDNA vector. The Rep proteins and Rep binding sites of various AAV serotypes are well known to those of ordinary skill in the art. One of ordinary skill in the art will appreciate the need to select a Rep protein from a serotype that binds to and replicates a nucleic acid sequence based on at least one functional ITR. For example, if a replication competent ITR is from AAB serotype 2, the corresponding Rep will be from an AAB serotype that works with that serotype, such as the AAB2 ITR with Rep AAB2 or AAB4, but not Rep AAB5, which does not work. After replication, the cccDNA vector with covalently closed ends continues to accumulate in permissive cells, and the cccDNA vector is preferably sufficiently stable over time in the presence of the Rep protein under standard replication conditions, for example, to accumulate at an amount of at least 1 pg/cell , preferably at least 2 pg/cell, preferably at least 3 pg/cell, more preferably at least 4 pg/cell, even more preferably at least 5 pg/cell.

[0028] Accordingly, one aspect of the present invention relates to a method of producing a cccDNA vector for the expression of such FVIII proteins, comprising the steps of: a) incubating a population of host cells (e.g., insect cells) bearing a polynucleotide expression construct template (e.g., a ccDNA plasmid , cccDNA bacmid and/or ccDNA baculovirus) lacking sequences encoding the viral capsid, in the presence of the Rep protein, under conditions effective to induce the production of said ccDNA vector in host cells and for a period of time sufficient to do so, wherein said host cells do not contain sequences encoding the viral capsid; and b) collecting and isolating the cDNA vector from the host cells. The presence of the Rep protein induces replication of the ITR-modified vector polynucleotide to produce a cccDNA vector for expression of the FVIII protein in the host cell. However, viral particles (eg, AAV virions) are not expressed. Thus, there is no size limitation imposed by virions. In some embodiments, the ccDNA vector is selected from the group consisting of ccDNA FVIII vector 16, ccDNA FVIII vector 19, ccDNA FVIII vector 21, ccDNA FVIII vector 8, ccDNA FVIII vector 17, ccDNA FVIII vector 20, and ccDNA FVIII vector 2 3. In some embodiments, the ccDNA vector is ccDNAFVIII vector 19 or ccDNA FVIII vector 23.

[0029] The presence of a cDNA vector isolated from host cells suitable for expression of the FVIII protein can be confirmed by digesting DNA isolated from the host cell with a restriction enzyme having a single recognition site on the cDNA vector and analyzing the digested DNA material for denaturing and non-denaturing gels to confirm the presence of characteristic bands of linear and continuous DNA compared to linear and discontinuous DNA.

[0030] Also provided herein are methods for expressing FVIII protein that has therapeutic use using a cccDNA vector in a cell or subject. Such FVIII proteins can be used to treat hemophilia A. Accordingly, provided herein are methods of treating hemophilia A comprising administering a cccDNA vector encoding a therapeutic FVIII protein to a subject in need thereof. In accordance with some embodiments, the cccDNA vector encoding the therapeutic FVIII protein is selected from the group consisting of ccDNA FVIII vector 16, ccDNA FVIII vector 19, ccDNA FVIII vector 21, ccDNA FVIII vector 8, ccDNA FVIII vector 17, ccDNA FVIII vector 20 and cccDNAFVIII vector 23. In some embodiments, the cccDNA vector is cccDNAFVIII vector 19 or ccDNAFVIII vector 23. In some embodiments, serum FVIII levels in the subject are increased in subjects administered the cccDNA vector compared to with control. In some embodiments, the increase in FVIII levels is greater than about 40% compared to control. In some embodiments, the increase in FVIII levels is greater than about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% compared to control.

[0031] In some embodiments, one aspect of the technology described herein relates to a non-viral, capsid-free, covalently closed-end DNA vector (ccDNA vector), wherein the cccDNA vector contains at least one heterologous nucleotide sequence operably located between two inverted terminal repeat sequences, wherein said ITR sequences may be asymmetric or symmetric or substantially symmetric as those terms are defined herein, wherein at least one of the ITRs comprises a functional end resolution site and a Rep binding site, and optionally, said heterologous nucleic acid sequence encodes a transgene (eg, FVIII protein), and wherein said vector is not located in a viral capsid.

[0032] These and other aspects of the present invention are described in more detail below.

DESCRIPTION OF DRAWINGS

[0033] The embodiments of the present disclosure summarized briefly above and discussed in more detail below will be understood with reference to the illustrative embodiments of the disclosure shown in the accompanying drawings. However, the accompanying drawings illustrate only exemplary embodiments of the present disclosure and therefore should not be construed as limiting the scope, since the disclosure may permit other equally effective embodiments.

[0034] FIG. 1A illustrates an exemplary structure of a cccDNA vector for expression of the FVIII protein disclosed herein containing asymmetric ITRs. In this embodiment, an exemplary cccDNA vector contains an expression cassette containing a CAG promoter, WPRE, and BGHpA. An open reading frame (ORF) encoding the FVIII transgene can be inserted into the cloning site (R3/R4) between the CAG promoter and the WPRE. The expression cassette is flanked by two inverted terminal repeats (ITRs) - the wild-type AAB2 ITR on the left (at the 5' end) and the modified ITR on the right (at the 3' end) of the expression cassette, therefore the two ITRs flanking the expression cassette are asymmetric with respect to each other to friend.

[0035] FIG. 1B illustrates the exemplary structure of a cccDNA expression vector for FVIII disclosed herein containing asymmetric ITRs with an expression cassette containing a CAG promoter, WPRE and BGHpA. An open reading frame (ORF) encoding the FVIII transgene can be inserted into the cloning site between the CAG promoter and the WPRE. The expression cassette is flanked by two inverted terminal repeats (ITRs) - a modified ITR on the left (at the 5' end) and a wild-type ITR on the right (at the 3' end) of the expression cassette.

[0036] FIG. 1C illustrates an exemplary structure of a cccDNA FVIII expression vector disclosed herein containing asymmetric ITRs, with an expression cassette containing an enhancer/promoter, an FVIII transgene, a post-transcriptional element (WPRE), and a poly(A) signal. The open reading frame (ORF) allows the FVIII transgene to be inserted into the cloning site between the CAG promoter and the WPRE. The expression cassette is flanked by two inverted terminal repeats (ITRs) that are asymmetrical to each other; a modified ITR to the left (5' end) and a modified ITR to the right (3 end) of the expression cassette, wherein the 5' ITR and 3' ITR are both modified ITRs but have different modifications (i.e. they do not have the same modifications).

[0037] FIG. 1D illustrates an exemplary structure of a cccDNA expression vector for FVIII disclosed herein containing symmetrical modified ITRs or substantially symmetrical modified ITRs as defined herein, with an expression cassette containing a CAG promoter, WPRE and BGHpA. The open reading frame (ORF) encoding the FVIII transgene is inserted into the cloning site between the CAG promoter and the WPRE. The expression cassette is flanked by two modified inverted terminal repeats (ITRs), with the 849849949 5' modified ITR and 3' modified ITR being symmetrical or substantially symmetrical.

[0038] FIG. 1E illustrates an exemplary structure of a cccDNA expression vector for FVIII disclosed herein containing symmetrical modified ITRs or substantially symmetrical modified ITRs as defined herein, with an expression cassette comprising an enhancer/promoter, a transgene, a post-transcriptional element (WPRE), and poly(A) signal. The open reading frame (ORF) allows the insertion of a transgene (eg FVIII) into the cloning site between the CAG promoter and the WPRE. The expression cassette is flanked by two modified inverted terminal repeats (ITRs), wherein the 5' modified ITR and the 3' modified ITR are symmetrical or substantially symmetrical.

[0039] FIG. 1F illustrates an exemplary structure of a cccDNA expression vector for FVIII disclosed herein containing symmetrical WT-ITRs or substantially symmetrical WT-ITRs as defined herein, with an expression cassette containing a CAG promoter, WPRE and BGHpA. An open reading frame (ORF) encoding a transgene (eg, FVIII) is inserted into the cloning site between the CAG promoter and the WPRE. The expression cassette is flanked by two wild-type inverted terminal repeats (WT-ITRs), the 5' WT-ITR and 3' WT-ITR being symmetrical or substantially symmetrical.

[0040] FIG. 1G illustrates an exemplary structure of a cccDNA expression vector for FVIII disclosed herein, containing symmetrical modified ITRs or substantially symmetrical modified ITRs as defined herein, with an expression cassette containing an enhancer/promoter, transgene (e.g., FVIII), post-transcriptional element (WPRE) and poly(A) signal. The open reading frame (ORF) allows the insertion of a transgene (eg FVIII) into the cloning site between the CAG promoter and the WPRE. The expression cassette is flanked by two wild-type inverted terminal repeats (WT-ITRs), the 5' WT-ITR and 3' WT-ITR being symmetrical or substantially symmetrical.

[0041] FIG. 2A shows a T-shaped stem-loop structure of the left ITR of wild type AAB2 (SEQ ID NO: 52) identifying arm A-A', arm B-B', arm C-C', two Rep binding sites (RBE and RBE' ), and also shows the terminal resolution site (TRS). RBE contains a group of 4 duplex tetramers that are believed to interact with either Rep 78 or Rep 68. In addition, RBE' is also believed to interact with the Rep complex assembled on a wild-type ITR or a mutated ITR in the construct. Regions D and D' contain transcription factor binding sites and other conserved structure. FIG. 2B shows putative Rep-catalyzed nicking and ligation activity in the wild-type left ITR (SEQ ID NO: 53), including the T-shaped stem-loop structure of the AAB2 wild-type left ITR with identification of arm A-A', arm B-B' , the C-C' arm, two Rep binding sites (RBE and RBE), and also shows a terminal resolution site (TRS) and a region D and D' containing several transcription factor binding sites and other conserved structure.

[0042] FIG. 3A shows the primary structure (polynucleotide sequence) (left) and secondary structure (right) of the RBE-containing portions of the A-A' arm, as well as the C-C' and B-B' arms of the left wild-type AAB2 ITR (SEQ ID NO: 54 ). FIG. 3B shows an example sequence of a mutated ITR (also called a modified ITR) for the left ITR. Shown is the primary structure (left) and predicted secondary structure (right) of the RBE portion of the A-A' arm, C arm, and B-B' arm of the exemplary mutated left ITR (ITR-1, left) (SEQ ID NO: 113). FIG. 3C shows the primary structure (left) and secondary structure (right) of the RBE-containing portion of the A-A' loop and arms B-B' and C-C' of the right wild-type AAB2 ITR (SEQ ID NO: 55). FIG. 3D shows an example right modified ITR. Shown is the primary structure (left) and predicted secondary structure (right) of the RBE-containing portion of the A-A', B-B' and C arms of the exemplary mutant right ITR (ITR-1, right) (SEQ ID NO: 114). Any combination of left and right ITRs (eg, AAB2 or other viral serotype ITRs or synthetic ITRs) can be used as described herein. Each of the polynucleotide sequences in FIG. 3A-3D refers to the sequence used in the genome of the plasmid or bacmid/baculovirus used to produce cccDNA as described herein. Also in each of FIGS. 3A-3D show the corresponding cccDNA secondary structures deduced from the configurations of the cccDNA vector in the plasmid or bacmid/baculovirus genome and predicted Gibbs free energy values.

[0043] FIG. 4A is a diagram illustrating a preparatory method for producing baculovirus-infected insect cells (BICs) that can be used to produce the cDNA expression vector for FVIII disclosed herein in the method described in the diagram of FIG. 4B. FIG. 4B is a diagram of an exemplary method for producing cccDNA, and FIG. 4C illustrates the biochemical method and method for confirming the production of the cccDNA vector. FIG. 4D and FIG. 4E are schematic illustrations describing a method for identifying the presence of cccDNA in DNA collected from cell pellets obtained during the ccDNA production methods of FIG. 4B. FIG. 4D schematically shows the expected bands of exemplary cccDNA left uncut or digested with a restriction endonuclease and then electrophoresed on either a native gel or a denaturing gel. The leftmost diagram is a native gel and shows several bands indicating that in duplex and uncut form, ccDNA exists in at least monomeric and dimeric states, observed as a faster migrating monomer of smaller size and a slower migrating dimer that is twice the size exceeds the size of the monomer. The second diagram from the left shows that when cccDNA is cut with a restriction endonuclease, the initial bands disappear and faster migrating (i.e., smaller) bands appear, corresponding to the expected sizes of fragments remaining after cleavage. Under denaturing conditions, the original duplex DNA is single-stranded and migrates as a molecule twice the size observed on a native gel because the complementary strands are covalently linked. Thus, in the second diagram on the right, digested ccDNA shows a band distribution similar to that observed on the native gel, but the bands migrate as fragments that are twice the size of their counterparts on the native gel. The rightmost diagram shows that uncut cccDNA under denaturing conditions migrates as a single-stranded open ring, so the size of the observed bands is twice the size of the bands observed under native conditions in which the ring is not opened. In this figure, “kb.” used to indicate the relative size of nucleotide molecules based on, depending on the context, either the length of the nucleotide chain (for example, for single-stranded molecules observed under denaturing conditions) or the number of base pairs (for example, for double-stranded molecules observed under native conditions). FIG. 4E shows DNA having a discontinuous structure. CCDNA can be cut with a restriction endonuclease having one recognition site in the CCDNA vector to produce two DNA fragments of different sizes (1 kb and 2 kb) under both neutral and denaturing conditions . FIG. 4E also shows cccDNA having a linear and continuous structure. The cDNA vector can be cut with a restriction endonuclease to produce two DNA fragments that migrate as 1 kb. and 2 thousand p.o. under neutral conditions, but under denaturing conditions the chains remain connected and form single chains that migrate as 2 kb. and 4 thousand p.o.

[0044] FIG. 5 is an exemplary denaturing gel analysis of example cccDNA vectors with (+) or without (-) endonuclease digestion (EcoRI for cccDNA constructs 1 and 2; BamH1 for cccDNA constructs 3 and 4; SpeI for cccDNA constructs 5 and 6; and XhoI for cccDNA constructs 7 and 8). Structures 1-8 are described in Example 1 of PCT International Application PCT/US18/49996, which is incorporated herein by reference in its entirety. The dimensions of the stripes highlighted with an asterisk were determined and indicated at the bottom of the figure.

[0045] FIG. 6 displays the results of the experiments described in Example 7 and specifically shows IVIS images obtained from mice treated with LNP-poly(C) control (far left mouse) and four mice treated with LNP-cDNA luciferase (all except far left mice). Four mice treated with cccDNA showed significant fluorescence in the mouse liver region.

[0046] FIG. 7 shows the results of the experiment described in Example 8. Dark dots indicate the presence of protein resulting from expression of the cccDNA transgene and demonstrate the association of the introduced LNP-ccDNA with hepatocytes.

[0047] FIG. 8A and 8B depict the results of the eye studies described in Example 9. FIG. 8A shows representative IVIS images from rat eyes injected with ^JetPEI®- ccDNA-luciferase (top left), compared to an uninjected eye of the same rat (top right) or a rat eye injected with luciferase DNA plasmid (bottom left). , and the uninjected eye of the same rat (bottom right). FIG. 8B shows a plot of the average luminosity observed in the treated eyes or the corresponding untreated eyes in each of the treatment groups. Rats treated with cccDNA exhibited prolonged significant fluorescence (and hence luciferase transgene expression) for 99 days, which was significantly different from rats treated with the luciferase plasmid, which showed minimal relative fluorescence (and therefore luciferase transgene expression).

[0048] FIG. 9A and 9B depict the results of the cccDNA stability and repeat dosing study in Rag2 mice described in Example 10. FIG. 9A shows a plot of total flux versus time observed in LNP-ccDNA-Luc-treated wild-type c57bl/6 mice or Rag2 mice. FIG. 9B is a graph showing the effect of repeated dosing on luciferase transgene expression levels in Rag2 mice, with increased stable expression observed after repeated dosing (arrow indicates time of repeated dosing).

[0049] FIG. 10 presents data from the cDNA luciferase expression study in treated mice described in Example 11, showing total flux in each group of mice throughout the study. High levels of unmethylated CpG correlated with lower total flux observed in mice over time, while liver-specific promoter usage correlated with prolonged stable expression of the cccDNA vector transgene for at least 77 days.

[0050] FIG. 11A and 11B show hydrodynamic delivery of a cDNA vector expressing FVIII. FIG. 11A shows FVIII expression levels in day 3 and day 7 serum samples from mice following hydrodynamic injection of three different cccDNA vectors expressing FVIII (LPS1-F8-v1; LPS1-F8-v2; LPS1-F8-v3) or a control ccDNA vector (ccDNA expressing luciferase only) (shown as Vehicle). Two of the three cccDNA vectors expressing FVIII showed FVIII expression. FIG. 11B is a dose response plot of FVIII expression levels in serum samples over a 30-day period from mice following hydrodynamic injection of small or large amounts of three different cccDNA vectors expressing FVIII (LPS1-F8-v1; LPS1-F8-v2 ; LPS1-F8-v3) or small amounts of cDNA vector as a vehicle control (expressing luciferase only).

[0051] FIG. 12 is a graph depicting plasma FVIII concentration (IU/mL) 3 days after hydrodynamic delivery of various cccDNA vectors expressing FVIII (ccDNA FVIII vector 4, ccDNA FVIII vector 6, ccDNA FVIII vector 12, ccDNA FVIII vector 14 , cDNAFVIII-vector 16, ccDNAFVIII-vector 18, ccDNAFVIII-vector 19, ccDNAFVIII-vector 21, ccDNAFVIII-vector 22). CccDNAFVIII-vector 16, ccDNAFVIII-vector 19, and ccDNAFVIII-vector 21 showed the highest concentration of factor VIII in plasma after 3 days. Vehicle alone was used as a control.

[0052] FIG. 13 is a graph showing plasma FVIII concentration (IU/mL) 3 days after hydrodynamic delivery of various cDNA FVIII-expressing vectors (ccDNA FVIII-vector 1, ccDNA FVIII-vector 2, ccDNA FVIII-vector 3, ccDNA FVIII-vector 5 , cDNAFVIII-vector 7, ccDNAFVIII-vector 8, ccDNAFVIII-vector 12, ccDNAFVIII-vector 13, ccDNAFVIII-vector 15). CctDNAFVIII vector 8 showed the highest concentration of factor VIII in plasma after 3 days. Vehicle alone was used as a control.

[0053] FIG. 14 is a graph showing plasma FVIII concentration (IU/mL) 3 days after hydrodynamic delivery of various cDNA FVIII-expressing vectors (ccDNA FVIII vector 9, ccDNA FVIII vector 10, ccDNA FVIII vector 11, ccDNA FVIII vector 12 , cDNAFVIII-vector 17, ccDNAFVIII-vector 20, ccDNAFVIII-vector 24, ccDNAFVIII-vector 25, ccDNAFVIII-vector 26). CccDNAFVIII-vector 17 and ccDNAFVIII-vector 20 showed the highest concentration of factor VIII in plasma after 3 days. Vehicle alone was used as a control.

[0054] FIG. 15 is a graph that depicts plasma FVIII concentration (IU/ml) 1 day after hydrodynamic delivery of increasing doses of cDNAFVIII vector 23 (0.005 μg-50 μg). As shown in FIG. 15, FVIII in plasma increased in a dose-dependent manner with increasing dosage of cDNAFVIII vector 23. Vehicle alone was used as a control.

[0055] FIG. 16 is a graph that displays plasma FVIII concentration (MP/ml) 7 days after hydrodynamic delivery of the LNP:ccDNAFVIII-vector 23 study drug.

DETAILED DESCRIPTION OF THE INVENTION

[0056] Provided herein is a method of treating hemophilia A using a cccDNA vector containing one or more nucleic acids that encode a therapeutic FVIII protein or fragment thereof. Also provided herein are cccDNA vectors for expression of the FVIII protein described herein containing one or more heterologous nucleic acids that encode the FVIII protein. In some embodiments, expression of the FVIII protein may involve secretion of the therapeutic protein from the cell in which it is expressed. Alternatively, in some embodiments, the expressed FVIII protein may act or function (eg, exert its effect) within the cell in which it is expressed. In some embodiments, the cccDNA vector expresses the FVIII protein in the liver, muscle (eg, skeletal muscle) of the subject, or other part of the body that can function as a depot for production and secretion of the therapeutic FVIII protein into multiple systemic compartments.

I. Definitions

[0057] Unless otherwise defined herein, scientific and technical terms used in connection with this application shall have the meanings commonly known to those of ordinary skill in the art to which this disclosure pertains. It should be understood that the present invention is not limited to the specific methodology, protocols and reagents, etc. described herein and is therefore subject to variations. The terminology used herein is intended solely to describe specific embodiments and is not intended to limit the scope of the present invention, which is defined solely by the claims. Definitions of common terms in immunology and molecular biology can be found in The Merck Manual of Diagnosis and Therapy, 19th ed., published by Merck Sharp & Dohme Corp., 2011 (ISBN 978-0-911910-19-3); Robert S. Porter et al. (ed.), Fields Virology, 6th ed., published by Lippincott Williams & Wilkins, Philadelphia, PA, USA (2013), Knipe, D.M. and Howley, P.M. (ed.), The Encyclopedia of Molecular Cell Biology and Molecular Medicine, published by Blackwell Science Ltd., 1999-2012 (ISBN 9783527600908); and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8); Immunology, Werner Luttmann, published by Elsevier, 2006; Janeway's Immunobiology, Kenneth Murphy, Allan Mowat, Casey Weaver (eds.), Taylor & Francis Limited, 2014 (ISBN 0815345305, 9780815345305); Lewin's Genes XI, published by Jones & Bartlett Publishers, 2014 (ISBN-1449659055); Michael Richard Green and Joseph Sambrook, Molecular Cloning: A Laboratory Manual, 4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., USA (2012) (ISBN 1936113414); Davis et al, Basic Methods in Molecular Biology, Elsevier Science Publishing, Inc., New York, USA (2012) (ISBN 044460149X); Laboratory Methods in Enzymology: DNA, Jon Lorsch (ed.) Elsevier, 2013 (ISBN 0124199542); Current Protocols in Molecular Biology (CPMB), Frederick M. Ausubel (ed.), John Wiley and Sons, 2014 (ISBN047150338X, 9780471503385), Current Protocols in Protein Science (CPPS), John E. Coligan (ed.), John Wiley and Sons, Inc., 2005; and Current Protocols in Immunology (CPI) (John E. Coligan, ADA Μ Kruisbeek, David Η Margulies, Ethan Μ Shevach, Warren Strobe, (eds.) John Wiley and Sons, Inc., 2003 (ISBN 0471142735, 9780471142737), contents which are incorporated herein by reference in their entirety).

[0058] As used herein, the terms “administration,” “administered,” and variations thereof refer to the administration to a subject of a composition or agent (e.g., a therapeutic nucleic acid or immunosuppressant described herein) and include simultaneous and sequential administration of one or more compositions or agents . “Administration” may refer to, for example, therapeutic, pharmacokinetic, diagnostic, research, placebo, and experimental methods. "Introduction" also includes in vitro and ex vivo treatment methods. Administration of the composition or agent to a subject is accomplished by any suitable route, including orally, pulmonaryly, intranasally, parenterally (intravenous, intramuscular, intraperitoneal, or subcutaneous), rectal, lymphatic, intratumoral, or topical. Administration of the composition or agent to the subject is accomplished by electroporation. Administration includes self-administration and administration by another person. Administration may be accomplished by any suitable route. A suitable route of administration allows the composition or agent to perform its intended function. For example, if the appropriate route is intravenous, the composition is administered by administering said composition or agent into a vein of the subject.

[0059] As used herein, the terms “nucleic acid therapeutic,” “therapeutic nucleic acid,” and “TNA” are used interchangeably and refer to any therapeutic option using nucleic acids as the active component of a therapeutic agent for treating a disease or disorder. As used herein, these expressions refer to RNA-based therapeutics and DNA-based therapeutics. Non-limiting examples of RNA therapeutics include mRNA, antisense RNA and oligonucleotides, ribozymes, aptamers, RNA interfering (RNAi), Dicer dsRNA substrate, short hairpin RNA (shRNA), asymmetric interfering RNA (aiRNA), microRNA (miRNA). Non-limiting examples of DNA-based therapeutics include minicircle DNA, minigene, viral DNA (eg, lentivirus or AAV genome) or non-viral synthetic DNA vectors, closed-end linear duplex DNA (ccDNA/CELiD), plasmids, bacmids, doggybone DNA vectors (dbDNA™), minimalist vector for immunologically defined gene expression (MIDGE), non-viral minimal strand DNA vector (linear covalently closed DNA vector), or dumbbell minimal DNA vector (“dumbbell DNA”).

[0060] As used herein, an "effective amount" or a "therapeutically effective amount" of a therapeutic agent, such as a therapeutic FVIII protein or fragment thereof, is an amount sufficient to produce the intended effect, such as treating or preventing hemophilia A. Suitable Assays for Measuring expression of a target gene or target sequence include, for example, examination of protein or RNA levels using techniques known to those skilled in the art, such as dot blot, Northern blot, in situ hybridization, ELISA, immunoprecipitation, functional enzyme assay, as well as phenotypic assays known to those skilled in the art. However, dosage levels are based on various factors, including the type of injury, age, body weight, gender, medical condition of the patient, severity of the condition, route of administration, and the specific active agent used. Accordingly, the dosage regimen may vary significantly, but can be determined in the usual way by the attending physician using standard methods. In addition, the terms “therapeutic amount”, “therapeutically effective amount” and “pharmaceutically effective amount” include prophylactic or prophylactic amounts of compositions according to the described invention. In prophylactic or prophylactic applications of the described invention, pharmaceutical compositions or drugs are administered to a patient susceptible to or otherwise at risk of developing a disease, disorder or condition, in an amount sufficient to eliminate or reduce the risk, reduce the severity or delay the onset of said disease, disorders or conditions, including biochemical, histological and/or behavioral symptoms of the specified disease, disorder or condition, its complications, and intermediate pathological phenotypes that occur during the development of the specified disease, disorder or condition. It is usually preferable to use the maximum dose, i.e. the highest safe dose according to some medical opinion. In some embodiments, the disease, disorder, or condition is hemophilia A. The terms “dose” and “dosage” are used interchangeably herein.

[0061] As used herein, the term “therapeutic effect” refers to the consequences of treatment, the results of which are assessed as targeted and beneficial. The therapeutic effect may include, directly or indirectly, stopping, reducing or eliminating the manifestation of the disease. The therapeutic effect may also include, directly or indirectly, stopping, reducing or eliminating the progression of disease manifestations.

[0062] For any therapeutic agent described herein, a therapeutically effective amount may initially be determined based on preliminary in vitro studies and/or animal models. The therapeutically effective dose can also be determined based on human data. The dose used may be adjusted based on the relative bioavailability and potency of the compound administered. Dosage adjustments to achieve maximum effectiveness based on the methods described above and other well known methods are within the capabilities of one of ordinary skill in the art. The general principles for determining therapeutic efficacy, which can be found in Chapter 1 of Goodman and Oilman, The Pharmacological Basis of Therapeutics, 10th ed., McGraw-Hill (New York) (2001), incorporated herein by reference, are summarized below.

[0063] Pharmacokinetic principles provide a basis for modifying dosing regimens to achieve the target degree of therapeutic efficacy with a minimum of unacceptable adverse events. Additional recommendations for dosage modification may be obtained in situations where plasma drug concentrations can be measured and related to the therapeutic window.

[0064] As used herein, the terms “heterologous nucleotide sequence” and “transgene” are used interchangeably and refer to a nucleic acid of interest (other than a nucleic acid encoding a capsid polypeptide) that is inserted into a cccDNA vector and can be delivered and expressed by a cccDNA vector. vector disclosed herein.

[0065] As used herein, the terms "expression cassette" and "transcription cassette" are used interchangeably and refer to a linear stretch of nucleic acids that includes a transgene operably linked to one or more promoters or other regulatory sequences sufficient to direct transcription of the transgene, but which does not contain capsid coding sequences, other vector sequences or inverted terminal repeat regions. The expression cassette may further comprise one or more cis-acting sequences (eg, promoters, enhancers, or repressors), one or more introns, and one or more post-transcriptional regulatory elements.

[0066] The terms "polynucleotide" and "nucleic acid", used interchangeably herein, refer to the polymeric form of nucleotides of any length, whether ribonucleotides or deoxyribonucleotides. Thus, the term includes single-, double- or multi-stranded DNA or RNA, genomic DNA, cDNA, DNA-RNA hybrids, or a polymer comprising purine and pyrimidine bases or other natural, chemically or biochemically modified, non-natural or derivatized nucleotide bases. "Oligonucleotide" generally refers to polynucleotides containing from about 5 to about 100 nucleotides of single- or double-stranded DNA. However, for purposes of the present disclosure, there is no upper limit on the length of the oligonucleotide. Oligonucleotides are also known as "oligomers" or "oligos" and can be isolated from genes or chemically synthesized using methods known in the art. The terms “polynucleotide” and “nucleic acid” should be understood to include, for the purposes of the described embodiments, single-stranded (such as sense or antisense) and double-stranded polynucleotides. The DNA may be in the form of, for example, antisense molecules, plasmid DNA, DNA-DNA duplexes, pre-condensed DNA, PCR products, vectors (P1, PAC, BAC, ΥAC, artificial chromosomes), expression cassettes, chimeric sequences, chromosomal DNA or derivatives and combinations of these groups. The DNA may be in the form of a minicircle, plasmid, bacmid, minigene, minimal strand DNA (linear covalently closed DNA vector), closed end linear duplex DNA (CELiD or cccDNA), doggybone DNA (dbDNA™), dumbbell DNA, minimalistic vector for immunologically defined gene expression (MIDGE), viral vector or non-viral vectors. The RNA may be in the form of short interfering RNA (siRNA), Dicer substrate dsRNA, short hairpin RNA (shRNA), asymmetric interfering RNA (aiRNA), microRNA (miRNA), mRNA, rRNA, tRNA, viral RNA (vRNA), and combinations thereof . Nucleic acids include nucleic acids containing known nucleotide analogues or modified backbone residues or linkages, which are synthetic, natural or non-natural, and which have binding properties similar to those of the reference nucleic acid. Examples of such analogues and/or modified residues include, but are not limited to, phosphorothioates, phosphodiamidate-morpholine oligomer (morpholino), phosphoamidates, methylphosphonates, chiral methylphosphonates, 2'-O-methylribonucleotides, locked nucleic acid (LNA™) and peptide nucleic acids (PNAs). ). Except as specifically stated, the term includes nucleic acids containing known analogues of natural nucleotides that have binding properties similar to those of the reference nucleic acid. Unless otherwise indicated, a particular nucleic acid sequence is also intended to include conservatively modified variants thereof (eg, degenerate codon substitutions), alleles, orthologs, single nucleotide polymorphisms (SNPs), and complementary sequences, as well as explicitly stated sequence.

[0067] "Nucleotides" contain the sugar deoxyribose (DNA) or ribose (RNA), a base, and a phosphate group. Nucleotides are connected to each other through phosphate groups.

[0068] "Bases" include purines and pyrimidines, which include, but are not limited to, the natural compounds adenine, thymine, guanine, cytosine, uracil, inosine and natural analogues, as well as synthetic derivatives of purines and pyrimidines, which include, but are not limited to, modifications that introduce new reactive groups such as, but not limited to, amines, alcohols, thiols, carboxylates and alkyl halides.

[0069] As used herein, the term “interfering RNA” or “RNAi” or “interfering RNA sequence” includes single-stranded RNA (e.g., mature siRNA, ssRNAi oligonucleotides, ssDNAi oligonucleotides), double-stranded RNA (i.e., duplex RNA such as siRNA, dsRNA-Dicer substrate, shRNA, aiRNA or pre-miRNA), DNA-RNA hybrid (see, for example, PCT Publication No. WO 2004/078941) or DNA-DNA hybrid (see, for example, PCT Publication No. WO 2004 /104199) that is capable of reducing or inhibiting the expression of a target gene or sequence (for example, by mediating the destruction or inhibiting the translation of mRNAs that are complementary to an interfering RNA sequence) when the interfering RNA is in the same cell as the target gene or sequence. Thus, interfering RNA refers to single-stranded RNA that is complementary to the target mRNA sequence, or double-stranded RNA formed by two complementary strands or one self-complementary strand. The interfering RNA may have substantial or complete identity with the target gene or sequence or may contain a region of mismatch (ie, a mismatch motif). The interfering RNA sequence may correspond to the full-length target gene or a subsequence thereof. Preferably, interfering RNA molecules are synthesized chemically. The disclosures of each of the patent documents mentioned above are incorporated herein by reference in their entirety for all purposes.

[0070] Interfering RNA includes "short interfering RNA" or "siRNA", for example, interfering RNA of about 15-60, 15-50 or 15-40 (duplex) nucleotides in length, more typically about 15-30, 15-25 or 19-25 (duplex) nucleotides in length and is preferably about 20-24, 21-22 or 21-23 (duplex) nucleotides in length (e.g., each complementary sequence of a double-stranded siRNA is 15-60, 15-50, 15- 40, 15-30, 15-25 or 19-25 nucleotides in length, preferably about 20-24, 21-22 or 21-23 nucleotides in length, and double-stranded siRNA is about 15-60, 15-50, 15-40 , 15-30, 15-25 or 19-25 base pairs in length, preferably about 18-22, 19-20 or 19-21 base pairs in length). siRNA duplexes may contain 3'-overhangs having from about 1 to about 4 nucleotides or from about 2 to about 3 nucleotides, and 5-phosphate ends. Examples of siRNA include, but are not limited to, a double-stranded polynucleotide molecule assembled from two single-stranded molecules, one strand being the sense strand and the other being the complementary antisense strand; a double-stranded polynucleotide molecule assembled from a single-stranded molecule in which the sense and antisense regions are connected by a nucleic acid-based or non-nucleic acid-based linker; a double-stranded polynucleotide molecule with a hairpin secondary structure having self-complementary sense and antisense regions; and a circular single-stranded polynucleotide molecule with two or more loop structures and a stem having self-complementary sense and antisense regions, wherein the circular polynucleotide can be processed in vivo or in vitro to produce an active double-stranded siRNA molecule. As used herein, the term “siRNA” includes RNA-RNA duplexes as well as DNA-RNA hybrids (see, for example, PCT Publication No. WO 2004/078941).

[0071] As used herein, the term “nucleic acid construct” refers to a nucleic acid molecule, whether single-stranded or double-stranded, that is isolated from a naturally occurring gene or that is modified to contain segments of nucleic acids in a manner that is not otherwise would exist in nature, or is synthetic. The term “nucleic acid construct” is synonymous with the term “expression cassette” when the nucleic acid construct contains control sequences necessary for the expression of a coding sequence according to the present disclosure. An "expression cassette" includes a DNA coding sequence operably linked to a promoter.

[0072] By "hybridizable" or "complementary" or "substantially complementary" is meant that the nucleic acid (eg, RNA) includes a nucleotide sequence that allows it to bind non-covalently, i.e. form Watson-Crick base pairs and/or G/U base pairs, "renature" or "hybridize" with another nucleic acid in a sequence-specific, antiparallel manner (i.e., the nucleic acid specifically binds to a complementary nucleic acid) under appropriate conditions temperature and ionic strength of the solution in vitro and/or in vivo. As is known in the art, standard Watson-Crick base pairing includes: adenine (A) pairing with thymidine (T), adenine (A) pairing with uracil (U), and guanine (G) pairing with cytosine (C). In addition, it is also known in the art that when two RNA molecules (eg, dsRNA) are hybridized, a guanine (G) base is paired with a uracil (U). For example, G/U base pairing is partly responsible for the degeneracy (i.e., redundancy) of the genetic code in the case of base pairing of tRNA anti-codons with codons in mRNA. For purposes of the present disclosure, the guanine (G) protein-binding segment (dsRNA duplex) of the DNA-targeting RNA molecule of the present invention is considered to be complementary to uracil (U), and vice versa. Thus, when a G/U base pair can be obtained at a specific nucleotide position of the protein binding segment (dsRNA duplex) of a DNA-targeting RNA molecule according to the present invention, that position is not considered to be non-complementary, but instead is considered to be complementary.

[0073] The terms "peptide", "polypeptide" and "protein" are used interchangeably herein and refer to the polymeric form of amino acids of any length, which may include encoded and non-encoded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides having modified peptide backbones.

[0074] A DNA sequence that “codes” for a particular FVIII protein is a DNA nucleic acid sequence that is transcribed into a particular RNA and/or protein. A DNA polynucleotide may encode RNA (mRNA) that is translated into a protein, or a DNA polynucleotide may encode RNA that is not translated into a protein (eg, tRNA, rRNA, or DNA-targeting RNA; also called “non-coding” RNA or “ncRNA”).

[0001] As used herein, the term “fusion protein” refers to a polypeptide that contains protein domains from at least two different proteins. For example, the fusion protein may comprise (i) FVIII or a fragment thereof and (ii) at least one non-GOI protein. Fusion proteins covered herein include, but are not limited to, an antibody or Fc or antigen binding fragment of an antibody fused to an FVIII protein, such as a receptor extracellular domain, ligand, enzyme, or peptide. The FVIII protein or fragment thereof that is part of the fusion protein may be a monospecific antibody or a bispecific or multispecific antibody.

[0075] As used herein, the term “genomic safe harbor gene” or “safe harbor gene” refers to a gene or loci into which a nucleic acid sequence can be inserted such that the sequence can integrate and function in a predictable manner (e.g., to express a protein representing interest) without significant negative consequences for endogenous gene activity or cancer stimulation. In some embodiments, a safe harbor gene also represents loci or a gene at which the inserted nucleic acid sequence can be expressed more efficiently and at higher levels than at a non-safe harbor site.

[0076] As used herein, the term “gene delivery” refers to the method by which foreign DNA is transferred into host cells for gene therapy applications.

[0077] As used herein, the term “terminal repeat” or “TR” includes any viral terminal repeat or synthetic sequence that contains at least one minimum required origin of replication and a region containing a palindromic hairpin structure. The Rep binding sequence (“RBS”) (also called the RBE (Rep binding element)) and the terminal resolution site (“TRS”) together constitute the “minimum required origin of replication” and, accordingly, the TR contains at least one RBS and at least at least one TRS. Each of the TRs that are inversely complementary to each other within a specific region of a polynucleotide sequence is generally referred to as an “inverted terminal repeat” or “ITR.” In the context of a virus, ITRs mediate viral replication, packaging, integration, and proviral release. Surprisingly, according to the present invention, TRs that are not reverse complementary along their entire length can still perform the normal functions of ITRs and thus, as used herein, the term ITR refers to a TR in a cccDNA genome or a cccDNA vector that is capable of mediate replication of the cDNA vector. One of ordinary skill in the art will appreciate that cccDNA vectors of complex configuration may contain more than two pairs of ITRs or asymmetric ITRs. The ITR may be an AAB ITR or a non-AAB ITR, or may be derived from an AAB ITR or a non-AAB ITR. For example, the ITR may be from the Parvoviridae family, which includes parvoviruses and dependoviruses (eg, canine parvovirus, bovine parvovirus, murine parvovirus, porcine parvovirus, human parvovirus B-19), or the SV40 hairpin, which serves as the SV40 origin of replication, may be used in as an ITR, which may be further modified by truncation, substitution, deletion, insertion and/or addition. Viruses of the Parvoviridae family consist of two subfamilies: Parvovirinae, which infect vertebrates, and Densovirinae, which infect invertebrates. Dependoparvoviruses comprise the adeno-associated virus (AAV) family of viruses that are capable of replication in vertebrate hosts, including, but not limited to, human, primate, bovine, canine, equine and ovine species. For convenience, herein the ITR located in the 5-direction (to the left) of the expression cassette in the cDNA vector is referred to as the “5'-ITR” or “left ITR”, and the ITR located in the 3-direction (to the right) of the expression cassette in a cccDNA vector, is called the “3'-ITR” or “right-hand ITR”.

[0078] “Wild-type ITR” or “WT-ITR” refers to a naturally occurring ITR sequence in an AAV or other dependovirus that retains, for example, Rep binding activity and Rep nicking ability. The nucleotide sequence of the WT-ITR from any AAV serotype may differ slightly from the canonical natural sequence due to degeneracy of the genetic code or drift, and thus the WT-ITR sequences provided for use herein include WT-ITR sequences generated in as a result of natural changes occurring during the production process (for example, replication errors).

[0079] As used herein, the term “substantially symmetrical WT-ITRs” or “a pair of essentially symmetrical WT-ITRs” refers to a pair of WT-ITRs in a single ccDNA genome or ccDNA vector that are both wild-type ITRs that have reverse complementary sequences along their entire length. For example, an ITR may be considered a wild-type sequence even if it contains one or more nucleotides that differ from the canonical natural sequence, provided that these changes do not affect the properties and overall three-dimensional structure of the sequence. In some aspects, the differing nucleotides represent conserved sequence changes. As one non-limiting example, a sequence having at least 95%, 96%, 97%, 98%, or 99% sequence identity with a canonical sequence (measured, for example, using BLAST at default settings) also has symmetric three-dimensional spatial organization with a different WT-ITR sequence such that their three-dimensional structures have the same shape in geometric space. An essentially symmetrical WT-ITR contains identical loops A, C-C' and B-B' in three-dimensional space. That an essentially symmetrical WT-ITR is WT can be functionally confirmed by determining whether it contains a functional Rep binding site (RBE or RBE') and a terminal resolution site (TRS) that pairs with the corresponding Rep protein. Other functions may be tested, including expression of the transgene under permissive conditions, but are not required.

[0080] As used herein, the expressions “modified ITR” or “mod-ITR” or “mutant ITR” are used interchangeably herein and refer to an ITR that contains a mutation in at least one or more nucleotides compared to the WT-ITR from the same serotype. The mutation may result in a change in one or more of regions A, C, C', B, B' in the ITR and may result in a change in three-dimensional spatial organization (i.e., its three-dimensional structure in geometric space) compared to three-dimensional spatial organization by the WT-ITR organization from the same serotype.

[0081] As used herein, the term “asymmetric ITRs,” also referred to as “asymmetric ITR pairs,” refers to a pair of ITRs in the same ccDNA genome or ccDNA vector that are not inversely complementary in their full length. As one non-limiting example, an asymmetric ITR in a pair does not have a symmetrical three-dimensional spatial organization with its cognate ITR such that their three-dimensional structures have different shapes in geometric space. In other words, asymmetric ITRs in a pair have different overall geometric structures, i.e. they have different organizations of their A, C-C' and B-B' loops in three-dimensional space (e.g., a single ITR may have a short C-C' arm and/or a short B-B' arm compared to a cognate ITR). The sequence difference between two ITRs may be due to the addition, deletion, truncation, or point mutation of one or more nucleotides. In one embodiment, one ITR of a pair of asymmetric ITRs may be a wild-type AAB ITR sequence, and the other ITR is a modified ITR as defined herein (eg, a non-wild-type ITR sequence or a synthetic sequence). In another embodiment, neither ITR of a pair of asymmetric ITRs is a wild-type AAV sequence, and the two ITRs are modified ITRs that have different shapes in geometric space (ie, a different overall geometric structure). In some embodiments, one mod-ITR of a pair of asymmetric ITRs may have a short C-C' arm, and the other ITR may have a different modification (e.g., a single arm or a short B-B' arm, etc.) such that they have a different three-dimensional spatial organization compared to cognate asymmetric mod-ITR.

[0082] As used herein, the term “symmetrical ITRs” refers to a pair of ITRs in a single cccDNA genome or cccDNA vector that are wild-type or mutated (e.g., modified relative to wild-type) dependoviral ITR sequences and are reverse complementary throughout. length In one non-limiting example, both ITRs are wild-type ITR sequences from AAB2. In another example, none of the ITRs are the sequence of the wild-type AAB2 ITR (i.e., they are modified ITRs, also called mutant ITRs) and may differ in sequence from the wild-type ITR due to addition, deletion, substitution, truncation, or point mutation nucleotide. For convenience, herein the ITR located in the 5' direction (to the left) relative to the expression cassette in the cDNA vector is referred to as the "5' ITR" or "left ITR", and the ITR located in the 3' direction (to the right) relative to expression cassette in the cccDNA vector is called the “3'-ITR” or “right ITR”.

[0083] As used herein, the term “substantially symmetric modified ITRs” or “substantially symmetric mod-ITR pair” refers to a pair of modified ITRs in a single ccDNA genome or ccDNA vector that both have reverse complementary sequences throughout their entire length. For example, a modified ITR may be considered substantially symmetrical even if it has some nucleotide sequences that differ from the reverse complementary sequence, provided that these changes do not affect the properties and overall shape. As one non-limiting example, a sequence is provided that has at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with the canonical sequence (measured by BLAST at default settings), and also has a symmetrical three-dimensional spatial organization with respect to its cognate modified ITR such that their three-dimensional structures have the same shape in geometric space. In other words, a pair of essentially symmetrical modified ITRs have loops A, C-C' and B-B' identically organized in three-dimensional space. In some embodiments, ITRs from a mod-ITR pair may have different reverse complementary nucleotide sequences, but still have the same symmetrical three-dimensional spatial organization, i.e. both ITRs contain mutations that result in the same overall three-dimensional shape. For example, one ITR (e.g., 5'-ITR) in a mod-ITR pair may be from one serotype, and the other ITR (e.g., 3'-ITR) may be from a different serotype, but both may have the same corresponding mutation (e.g., if a 5'-ITR has a deletion in region C, then a cognate modified 3'-ITR from another serotype has a deletion at the corresponding position in region C') such that the pair of modified ITRs has the same symmetrical three-dimensional spatial organization. In such embodiments, each ITR in a modified ITR pair may be from a different serotype (e.g., AAB1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12), such as a combination of AAB2 and AAB6, whereby a modification in one ITR is mapped to a corresponding position in a cognate ITR from another serotype. In one embodiment, a pair of substantially symmetrical modified ITRs is referred to as a modified ITR (mod-ITR) pair, provided that the difference in nucleotide sequences between said ITRs does not affect properties or overall shape and they have substantially the same shape in three-dimensional space. By way of non-limiting example, a mod-ITR is provided that has at least 95%, 96%, 97%, 98%, or 99% sequence identity with the canonical mod-ITR, as determined using standard methods well known in the art, such as BLAST (Basic Local Alignment Search Tool) or BLASTN, at default settings, and also have a symmetrical three-dimensional spatial organization so that their three-dimensional structure has the same shape in geometric space. A pair of essentially symmetric mod-ITRs have identical loops A, C-C' and B-B' in three-dimensional space, for example, if a modified ITR in a pair of essentially symmetric mod-ITRs has a deletion of the C-C' arm, then the cognate mod- The ITR has a corresponding deletion of the C-C' loop and also has a similar three-dimensional structure of the remaining A and B-B' loops of the same shape in geometric space with its cognate mod-ITR.

[0084] The term “flanking” refers to the relative position of one nucleic acid sequence with respect to another nucleic acid sequence. Typically in an ABC sequence, A and C flank B. The same is true for the arrangement of AxBxC. Accordingly, the flanking sequence precedes or follows the flanking sequence, but need not be adjacent to or immediately adjacent to the flanking sequence. In one embodiment, the term “flanking” refers to the terminal repeats at each end of a linear duplex ccDNA vector.

[0085] As used herein, the terms “treat,” “treat,” and/or “treatment” include suppressing, substantially inhibiting, slowing, or reversing the progression of a condition, substantially alleviating clinical symptoms of a condition, or substantially preventing the onset of clinical symptoms of a condition, obtaining favorable or targeted clinical outcomes. In accordance with some embodiments, the condition is hemophilia A. Treatment also refers to achieving one or more of the following: (a) reducing the severity of the disorder; (b) limiting the development of symptoms characteristic of the disorder(s) being treated; (c) limiting the worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting the recurrence of the disorder(s) in patients who previously had the disorder(s); and (f) limiting the recurrence of symptoms in patients who have not previously had symptoms of the specified disorder(s). Beneficial or targeted clinical outcomes, such as pharmacological and/or physiological effects, include, but are not limited to, preventing the onset of a disease, disorder or condition in a subject who may be predisposed to the disease, disorder or condition but is not yet experiencing symptoms or does not yet exhibit symptoms of the specified disease (preventative treatment), relief of symptoms of the specified disease, disorder or condition, reduction in the intensity of the disease, disorder or condition, stabilization (i.e., no worsening) of the specified disease, disorder or condition, prevention of the spread of the specified diseases, disorders or conditions, delaying or slowing the progression of said diseases, disorders or conditions, alleviating or temporarily alleviating said diseases, disorders or conditions, and combinations thereof, and increasing the duration of survival compared to expected survival without treatment.

[0086] As used herein, the term “increase,” “enhancement,” “enhancement” (and similar terms) generally refers to the act of increasing, directly or indirectly, a concentration, level, function, activity, or behavior relative to the natural, expected, or average, or relative to the control condition.

[0087] As used herein, the term “minimize,” “reduce,” “reduce,” and/or “inhibit” (and similar terms) generally refers to the act of reducing, directly or indirectly, the concentration, level, function, activity, behavior relative to natural , expected, average, or relative to the control condition.

[0088] As used herein, the term “ccDNA genome” refers to an expression cassette that further includes at least one inverted terminal repeat region. The cDNA genome may further comprise one or more spacer regions. In some embodiments, the cccDNA genome is included as an intermolecular duplex DNA polynucleotide in a plasmid or viral genome.

[0089] As used herein, the term “cccDNA spacer region” refers to an intervening sequence that separates functional elements in a cccDNA vector or ccDNA genome. In some embodiments, cccDNA spacer regions hold two functional elements at a target distance for optimal functionality. In some embodiments, the cDNA spacer regions provide or increase the genetic stability of the cDNA genome, for example, in a plasmid or baculovirus. In some embodiments, cccDNA spacer regions facilitate prepared genetic manipulation of the cccDNA genome by providing convenient locations for cloning sites and the like. For example, in certain aspects, an oligonucleotide "polylinker" containing multiple restriction endonuclease sites, or a non-open reading frame sequence designed to lack known protein (e.g., transcription factor) binding sites, can be placed in the cccDNA genome to separating cis-acting factors, for example, using a 6-member, 12-member, 18-member, 24-member, 48-member, 86-member, 176-member insertion, etc. between the end resolution site and the 5-direction transcriptional regulatory element. Likewise, a spacer can be inserted between the polyadenylation signal sequence and the 3' end resolution site.

[0090] As used herein, the terms “Rep binding site,” “Rep binding element,” “RBE,” and “RBS” are used interchangeably and refer to the binding site of a Rep protein (e.g., Rep 78 AAB or Rep 68 AAB) that, upon binding by the Rep protein allows the Rep protein to perform its site-specific endonuclease activity on a sequence including the RBS. The RBS sequence and its reverse complementary sequence together form one RBS. RBS sequences are known in the art and include, for example, 5'-GCGCGCTCGCTCGCTC-3' (SEQ ID NO: 60), which is the RBS sequence identified in AAB2. In embodiments of the present invention, any known RBS sequence can be used, including other known AAB RBS sequences and other known natural or synthetic RBS sequences. Without being limited to any theory, it is believed that the nuclease domain of the Rep protein binds to the duplex nucleotide sequence GCTC and, accordingly, direct binding and stable assembly of two known Rep proteins of AAB on the duplex oligonucleotide 5'-(GCGC)(GCTC)(GCTC) occurs. (GCTC)-3' (SEQ ID NO: 60). In addition, soluble aggregated conformers (i.e., an indefinite number of interconnected Rep proteins) dissociate and bind to oligonucleotides that contain Rep binding sites. Each Rep protein interacts with both nitrogenous bases and the phosphodiester backbone on each chain. Interactions with nitrogenous bases provide sequence specificity, while interactions with the phosphodiester backbone are nonspecific or less sequence specific and stabilize the protein-DNA complex.

[0091] As used herein, the terms "terminal resolution site" and "TRS" are used interchangeably herein and refer to the region in which Rep forms a tyrosine phosphodiester bond with a 5'-thymidine to form a 3'-OH, which serves as a substrate for DNA elongation using a cellular DNA polymerase, for example DNA polymerase delta or DNA polymerase epsilon. Alternatively, the Rep-thymidine complex may participate in a coordinated ligation reaction. In some embodiments, the TRS includes at least an unpaired thymidine. In some embodiments, the nicking efficiency of the TRS can be controlled at least in part by the distance between it and the RBS within a single molecule. If the acceptor substrate is a complementary ITR, then the resulting product is an intramolecular duplex. TRS sequences are known in the art and include, for example, 5'-GGTTGA-3' (SEQ ID NO: 61), which is a hexanucleotide sequence identified in AAB2. In embodiments of the present invention, any known TRS sequence can be used, including other known AAB TRS sequences and other known natural or synthetic TRS sequences, such as AGTT (SEQ ID NO: 62), GGTTGG (SEQ ID NO: 63), AGTTGG (SEQ ID NO: 64), AGTTGA (SEQ ID NO: 65), and other motifs such as RRTTRR (SEQ ID NO: 66).

[0092] As used herein, the term “ccDNA plasmid” refers to a plasmid that contains the cccDNA genome as an intermolecular duplex.

[0093] As used herein, the term “ccDNA bacmid” refers to an infectious baculovirus genome containing the cccDNA genome as an intermolecular duplex that is capable of propagation in E. coli as a plasmid and, accordingly, can serve as a shuttle vector for the baculovirus.

[0094] As used herein, the term “ccDNA baculovirus” refers to a baculovirus that contains the cccDNA genome as an intermolecular duplex within the baculovirus genome.

[0095] As used herein, the terms “ccDNA-baculovirus-infected insect cell” and “ccDNA-IPV” are used interchangeably and refer to an invertebrate host cell (including, but not limited to, an insect cell (e.g., an Sf9 cell)) infected cDNA baculovirus.

[0096] As used herein, the term “ccDNA” refers to capsid-free linear double-stranded (ds) duplex DNA with closed ends for non-viral gene transfer, synthetic or otherwise. A detailed description of cccDNA is provided in International Application PCT/US 2017/020828, filed March 3, 2017, the contents of which are expressly incorporated herein by reference in their entirety. Some methods for producing cccDNA containing various sequences and inverted terminal repeat (ITR) configurations using cellular methods are described in Example 1 of international application PCT/US 18/49996, filed September 7, 2018, and PCT/US 2018/064242, filed December 6, 2018, each of which is incorporated herein by reference in its entirety. Some methods for producing synthetic cccDNA vectors containing various ITR sequences and configurations are described, for example, in international application PCT/US 2019/14122, filed January 18, 2019, the contents of which are incorporated herein by reference in their entirety.

[0097] As used herein, the term “closed-end DNA vector” refers to a capsid-free DNA vector with at least one covalently closed end, wherein at least a portion of the vector has an intramolecular duplex structure.

[0098] As used herein, the terms “ccDNA vector” and “ccDNA” are used interchangeably and refer to a closed-ended DNA vector containing at least one terminal palindrome. In some embodiments, the cccDNA contains two covalently closed ends.

[0099] As used herein, the term "nzDNA" or "nicked cccDNA" refers to DNA with closed ends containing a single-strand break or gap of 1-100 base pairs in the "stem" or spacer region located in the 5' direction relative to the open reading frame (eg, promoter and transgene to be expressed).

[00100] As used herein, the terms “gap” and “single-strand break” are used interchangeably and refer to the interrupted portion of the synthetic DNA vector of the present invention, creating a portion of a single-stranded DNA portion of an otherwise double-stranded ccDNA. The gap can range from 1 base pair to 100 base pairs in length on a single strand of duplex DNA. Typical gaps designed and created using the methods described herein, and synthetic vectors obtained using these methods, may have, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 pairs bases in length. Exemplary gaps in the present disclosure may be from 1 base pair to 10 base pairs in length, from 1 to 20 base pairs in length, from 1 to 30 base pairs in length.

[00101] As defined herein, “reporters” refer to proteins that can be used to provide detectable indicators. Reporters typically generate a measurable signal such as fluorescence, color, or luminescence. Sequences encoding reporter proteins encode proteins whose presence in a cell or organism can be easily observed. For example, fluorescent proteins cause a cell to fluoresce when excited by light of a specific wavelength, luciferases cause a cell to catalyze a reaction that generates light, and enzymes such as β-galactosidase convert a substrate into a colored product. Exemplary reporter polypeptides that may be used for experimental or diagnostic purposes include, but are not limited to, β-lactamase, β-galactosidase (LacZ), alkaline phosphatase (AP), thymidine kinase (TK), green fluorescent protein (GFP), and others fluorescent proteins, chloramphenicol acetyltransferase (CAT), luciferase and others well known in the art.

[00102] As used herein, the terms “sense” and “antisense” refer to the orientation of a structural element on a polynucleotide. The sense and antisense variants of the element are inversely complementary to each other.

[00103] As used herein, the term “synthetic AAV vector” and “synthetic production of AAV vector” refers to the AAV vector and synthetic methods for its production in a completely cell-free environment.

[00104] As used herein, “reporters” refer to proteins that can be used to provide detectable performance. Reporters typically generate a measurable signal such as fluorescence, color, or luminescence. Sequences encoding reporter proteins encode proteins whose presence in a cell or organism can be easily observed. For example, fluorescent proteins cause a cell to fluoresce when excited by light of a specific wavelength, luciferases cause a cell to catalyze a reaction that generates light, and enzymes such as β-galactosidase convert a substrate into a colored product. Exemplary reporter polypeptides that may be used for experimental or diagnostic purposes include, but are not limited to, β-lactamase, β-galactosidase (LacZ), alkaline phosphatase (AP), thymidine kinase (TK), green fluorescent protein (GFP), and others fluorescent proteins, chloramphenicol acetyltransferase (CAT), luciferase and others well known in the art.

[00105] As used herein, the term "effector protein" refers to a polypeptide that provides a detectable indicator, either, for example, as a reporter polypeptide, or, more preferably, as a cell killing polypeptide, such as a toxin, or an agent that sensitizes the cell to destruction by the selected agent or in its absence. Effector proteins include any protein or peptide that directly targets or damages the DNA and/or RNA of a host cell. For example, effector proteins may include, but are not limited to, a restriction endonuclease that targets a host cell DNA sequence (whether genomic or extrachromosomal element), a protease that cleaves a target polypeptide essential for cell survival, a DNA gyrase inhibitor, and ribonuclease type toxin. In some embodiments, effector protein expression controlled by a synthetic biological circuit described herein can participate as a factor in another synthetic biological circuit, thereby expanding the range and complexity of the responsiveness of the biological circuit system.

[00106] Transcriptional regulators refer to transcriptional activators and repressors that either activate or repress the transcription of a gene of interest, such as FVIII. Promoters are regions of nucleic acid that initiate transcription of a particular gene. Transcription activators typically bind in the vicinity of transcriptional promoters and recruit RNA polymerase to directly initiate transcription. Repressors bind to transcriptional promoters and sterically hinder the initiation of transcription by RNA polymerase. Other transcriptional regulators can serve as either activators or repressors depending on their site of binding and cellular and environmental conditions. Non-limiting examples of classes of transcriptional regulators include, but are not limited to, homeodomain proteins, zinc finger proteins, Forkhead proteins, and leucine zipper proteins.

[00107] As used herein, a “repressor protein” or “inducer protein” is a protein that binds to a regulatory sequence element and represses or activates, respectively, the transcription of sequences operably associated with said regulatory sequence element. Preferred repressor and inducer proteins described herein are sensitive to the presence or absence of at least one introduced agent or environmental factor. Preferred proteins described herein are modular in form and contain, for example, separable DNA binding and input binding agents or responsive elements or domains.

[00108] As used herein, the term “carrier” includes any and all possible solvents, dispersion media, bases, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption retarding agents, buffers, carrier solutions, suspensions, colloids, and the like . The use of such media and agents for pharmaceutically active substances is well known in the art. Additional active ingredients may also be included in the compositions. The expression "pharmaceutically acceptable" refers to molecular particles and compositions that do not cause a toxic, allergic or similar adverse reaction when administered to a host.

[00109] As used herein, the term “administrative agent-responsive domain” is a transcription factor domain that binds or otherwise responds to a condition or administered agent in a manner that renders the DNA-binding fusion domain attached thereto responsive to the presence of the condition or administered agent. In one embodiment, the presence of the condition or administration agent results in a conformational change in the input response domain, or in the protein to which it is fused, that modifies the transcription modulating activity of the transcription factor.

[00110] The term "in vivo" refers to assays or methods that are performed on or in an organism, such as a multicellular animal. In some aspects described herein, the method or use is considered to be performed "in vivo" if a single cell organism, such as a bacterium, is used. The term "ex vivo" refers to methods and applications that are performed using a living cell with an intact membrane located outside the body of a multicellular animal or plant, for example, explants, cultured cells, including primary cells and cell lines, transformed cell lines, and extracted tissues or cells, including but not limited to blood cells. The term "in vitro" refers to assays and methods that do not require the presence of a cell with an intact membrane, such as cell extracts, and may refer to the introduction of a programmable synthetic biological circuit in a cell-free system, such as an environment containing no cells or cellular systems such as cell extracts.

[00111] As used herein, the term “promoter” refers to any nucleic acid sequence that regulates the expression of another nucleic acid sequence by driving the transcription of said nucleic acid sequence, which may be a heterologous target gene encoding a protein or RNA. Promoters may be constitutive, inducible, repressible, tissue specific, or any combination of these. A promoter is a control region of a nucleic acid sequence that controls the initiation and rate of transcription of the rest of the nucleic acid sequence. A promoter may also contain genetic elements to which regulatory proteins and molecules, such as RNA polymerase and other transcription factors, can bind. In some embodiments of the aspects described herein, a promoter may drive the expression of a transcription factor that regulates the expression of the promoter itself. The promoter sequence may contain a transcription initiation site, as well as protein-binding domains responsible for binding RNA polymerase. Eukaryotic promoters will often, but not always, contain "TATA" boxes and "CAT" boxes. Various promoters, including inducible promoters, can be used to drive the expression of transgenes in the cDNA vectors disclosed herein. The promoter sequence may be limited at its 3' end by the transcription initiation site and extends upstream (in the 5' direction), including the minimum number of bases or elements necessary to initiate transcription at levels detected above background.

[00112] As used herein, the term “enhancer” refers to a cis-acting regulatory sequence (e.g., 50-1500 base pairs) that binds one or more proteins (e.g., activator proteins or transcription factor) to enhance transcriptional activation of a nucleic acid sequence . Enhancers can be located up to 1,000,000 base pairs upstream of the start site of the gene or downstream of the start site of the gene they regulate. The enhancer may be located within an intronic region or within an exonic region of an unrelated gene.

[00113] A promoter can be said to drive the expression or direct transcription of the nucleic acid sequence that it regulates. The expressions "operably linked", "operably located", "operably linked", "under control" and "under transcriptional control" indicate that the promoter is in the correct functional position and/or orientation relative to the nucleic acid sequence it regulates to control the initiation of transcription and/or expression of said sequence. As used herein, “inverted promoter” refers to a promoter in which the nucleic acid sequence is arranged in reverse orientation such that a strand that was a sense strand becomes a non-coding strand and vice versa. Inverted promoter sequences can be used in various embodiments to regulate the state of the switch. Additionally, in various embodiments, a promoter may be used in combination with an enhancer.

[00114] A promoter can be a promoter that is naturally associated with a gene or sequence, and can also be obtained by isolating 5' non-coding sequences located in the 5' direction relative to the coding segment and/or exon of a particular gene or sequence. Such a promoter may be called "endogenous". Likewise, in some embodiments, the enhancer may be an enhancer that is naturally associated with a nucleic acid sequence and is located either 3' or 5' of the sequence.

[00115] In some embodiments, the encoding nucleic acid segment is located under the control of a “recombinant promoter” or a “heterologous promoter,” both of which terms refer to a promoter that is not typically associated with the encoded nucleic acid sequence to which the promoter is operably linked in its natural environment. A recombinant or heterologous enhancer refers to an enhancer not normally associated with a particular nucleic acid sequence in its natural environment. Such promoters or enhancers may include promoters or enhancers of other genes; promoters or enhancers isolated from any other prokaryotic, viral or eukaryotic cell; and synthetic promoters or enhancers that are not “natural”, e.g. contain various elements of different transcriptional regulatory regions and/or expression-altering mutations introduced using genetic engineering methods known in the art. In addition to obtaining promoter and enhancer nucleic acid sequences synthetically, promoter sequences can be obtained using recombinant cloning and/or nucleic acid amplification technology, including PCR, in relation to the synthetic biological circuits and modules disclosed herein (see, for example, US Patent No. 4,683,202, US Pat. No. 5,928,906, each of which is incorporated herein by reference). In addition, it is also possible to use control sequences that direct transcription and/or expression of sequences in non-nuclear organelles such as mitochondria, chloroplasts, and the like.

[00116] As described herein, an “inducible promoter” is a promoter that is characterized by initiation or enhancement of transcriptional activity in the presence of, under the influence of, or upon contact with an inducer or inducing agent. An "inducer" or "inducing agent" as defined herein can be endogenous or typically is an exogenous compound or protein that is administered so as to have the activity of inducing the transcriptional activity of an inducible promoter. In some embodiments, the inducer or inducing agent, i.e. chemical, compound or protein may itself be produced by transcription or expression of a nucleic acid sequence (ie, the inducer may be an inducer protein expressed by another component or module), which may itself be under the control of an inducible promoter. In some embodiments, the inducible promoter is induced in the absence of certain agents, such as a repressor. Examples of inducible promoters include, but are not limited to, tetracycline-sensitive, metallothioneine, ecdysone-sensitive promoters, mammalian viral promoters (eg, adenovirus late promoter; and murine mammary tumor virus long terminal repeat (MMTV-LTR) promoter), and other steroid-responsive promoters. promoters, rapamycin-sensitive promoters, etc.

[00117] The terms "DNA regulatory sequences", "control elements" and "regulatory elements", used interchangeably herein, refer to transcriptional and translational control sequences such as promoters, enhancers, polyadenylation signals, terminators, protein degradation signals, etc. .p. that mediate and/or regulate transcription of a non-coding sequence (eg, DNA-targeting RNA) or coding sequence (eg, site-directed modifying polypeptide or Cas9/Csn1 polypeptide) and/or regulate translation of the encoded polypeptide.

[00118] "Operably coupled" refers to placement in close proximity such that the components so described are in a relationship that allows them to function in the manner intended for them. For example, a promoter is operably linked to a coding sequence if said promoter affects its transcription or expression. An "expression cassette" includes a heterogeneous DNA sequence that is operably linked to a promoter or other regulatory sequence sufficient to control transcription of the transgene in the cDNA vector. Suitable promoters include, for example, tissue-specific promoters. Promoters can also be derived from AAV.

[00119] As used herein, the term “subject” refers to a human or animal receiving treatment, including prophylactic treatment, using a cccDNA vector in accordance with the present invention. Typically the animal is a vertebrate such as, but not limited to, a primate, rodent, pet or game animal. Primates include, but are not limited to, chimpanzees, cynomolgus macaques, coatats, and macaques such as rhesus monkeys. Rodents include mice, rats, marmots, ferrets, rabbits and hamsters. Domestic and game animals include, but are not limited to, cows, horses, pigs, deer, bison, buffalo, felid species such as the domestic cat, canid species such as the dog, fox, wolf, bird species such as chicken, emu , ostrich, and fish such as trout, catfish and salmon. In certain embodiments of the aspects described herein, the subject is a mammal, such as a primate or a human. The subject may be male or female. Additionally, the subject may be an infant or child. In some embodiments, the subject may be a newborn or unborn subject, such as an in utero subject. Preferably the subject is a mammal. The mammal may be a human, non-human primate, mouse, rat, dog, cat, horse or cow, but these examples are not limiting. Non-human mammals may be advantageously used as subjects in animal models of diseases and disorders. In addition, the methods and compositions described herein can be used for domesticated animals and/or pets. The human subject may be of any age, gender, race or ethnicity, such as Caucasian (White), Asian, African, Black, African American, Afro-European, Hispanic, Middle Eastern, etc. In some embodiments, the subject may be a patient or other subject in a clinical setting. In some embodiments, the subject is already undergoing treatment. In some embodiments, the subject is an embryo, fetus, newborn, infant, child, adolescent, or adult. In some embodiments, the subject is a human fetus, a newborn human, a human infant, a human child, a human adolescent, or an adult. In some embodiments, the subject is an animal embryo or a non-human embryo or a non-human primate embryo. In some embodiments, the subject is a human embryo.

[00120] As used herein, the term “host cell” includes any type of cell that is susceptible to transformation, transfection, transduction, or the like. using a nucleic acid construct or cDNA expression vector according to the present invention. By way of non-limiting examples, the host cell may be an isolated primary cell, pluripotent stem cells, CD34 ⁺ cells, induced pluripotent stem cells, or any of a number of immortalized cell lines (eg, HepG2 cells). Alternatively, the host cell may be an in situ or in vivo cell in a tissue, organ or organism.

[00121] The term "exogenous" refers to a substance present in a cell other than its natural source. As used herein, the term “exogenous” may refer to a nucleic acid (e.g., a nucleic acid encoding a polypeptide) or polypeptide that has been introduced through a process involving human activity into a biological system, such as a cell or organism, in which it is not normally present. are detected and introduction of the nucleic acid or polypeptide into such a cell or organism is desired. Alternatively, "exogenous" may refer to a nucleic acid or polypeptide that has been introduced through a process involving human activity into a biological system, such as a cell or organism, in which it is found in relatively low quantities, and an increase in the amount of the nucleic acid or polypeptide in a cell or organism is desired, for example, to obtain ectopic expression or levels. In contrast, the term "endogenous" refers to a substance that is native to a biological system or cell.

[00122] The term "sequence identity" refers to the affinity between two nucleotide sequences. For the purposes of this disclosure, the degree of sequence identity between two deoxyribonucleotide sequences is determined using the Needleman-Wunsch algorithm (Needleman and Wunsch, 1970, supra), implemented in the Needle program of the EMBOSS package (EMBOSS: The European Molecular Biology Open Software Suite, Rice et at, 2000 , above), preferably version 3.0.0 or later. The optional parameters used are a pass opening penalty of 10, a pass extension penalty of 0.5, and a substitution matrix of EDNAFULL (EMBOSS NCBI version NUC4.4). The Needle output called "longest identical fragment length" (obtained using the -nobrief option) is used as the percent identity and is calculated as follows: (Identical deoxyribonucleotides x 100)/(Alignment length - Total number of gaps in alignment). The length of the alignment is preferably at least 10 nucleotides, preferably at least 25 nucleotides, more preferably at least 50 nucleotides, and most preferably at least 100 nucleotides.

[00123] As used herein, the term “homology” or “homologous” is defined as the percentage of nucleotide residues that are identical to nucleotide residues in the corresponding sequence on the target chromosome after sequence alignment and the introduction of gaps, if necessary, to achieve the maximum percentage of sequence identity. Alignment to determine percent homology of a nucleotide sequence can be achieved in various ways known in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, ClustalW2 or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for sequence alignment, including any algorithms necessary to achieve maximum alignment over the entire length of the sequences being compared. In some embodiments, a nucleic acid sequence (e.g., a DNA sequence), such as a homologous arm, is considered “homologous” when the sequence is at least 70%, at least 75%, at least 80%, at least by 85%, by at least 90%, by at least 91%, by at least 92%, by at least 93%, by at least 94%, by at least 95%, by at least 96%, at least 97%, at least 98%, at least 99% or more identical to the corresponding native or unedited nucleic acid sequence (eg, genomic sequence) of the host cell.

[00124] As used herein, the term “heterologous” means a nucleotide or polypeptide sequence that is not found in the native nucleic acid or protein, respectively. A heterologous nucleic acid sequence can be linked to a naturally occurring nucleic acid sequence (or variant thereof) (eg, by genetic engineering) to produce a chimeric nucleotide sequence encoding a chimeric polypeptide. A heterologous nucleic acid sequence can be joined to a polypeptide variant (eg, by genetic engineering) to produce a nucleotide sequence encoding a polypeptide fusion variant.

[00125] A "vector" or "expression vector" is a replicon, such as a plasmid, bacmid, phage, virus, virion or cosmid, to which another DNA segment can be attached, i.e. "insertion" to cause the attached segment to replicate in the cell. A vector may be a nucleic acid construct designed for delivery into a host cell or for transfer between different host cells. As used herein, a vector may be viral or non-viral in origin and/or final form, however, for the purpose of this disclosure, “vector” generally refers to a cccDNA vector as that term is used herein. The term "vector" includes any genetic element that is capable of replication when associated with appropriate control elements and that can transfer gene sequences into cells. In some embodiments, the vector may be an expression vector or a recombinant vector.

[00126] As used herein, the term “expression vector” refers to a vector that directs the expression of RNA or polypeptide from sequences linked to transcriptional control sequences on the vector. The sequences expressed will often, but not necessarily, be heterogeneous with respect to the cell. The expression vector may contain additional elements, for example, the expression vector may have two replication systems, allowing it to be maintained in two organisms, for example, human cells for expression and a prokaryotic host for cloning and amplification. The term "expression" refers to cellular processes involved in the production of RNA and proteins and, where appropriate, the secretion of proteins, including, where applicable, but not limited to, for example, transcription, transcript processing, translation and folding, modification and processing squirrel. "Expression products" include RNA transcribed from a gene and polypeptides produced by translation of mRNA transcribed from the gene. The term "gene" means a nucleic acid sequence that is transcribed (DNA) into RNA in vitro or in vivo when operably linked to appropriate regulatory sequences. The gene may optionally include regions preceding and following the coding region, for example, 5'-untranslated (5'-UTR) or "leader" sequences and 3'-UTR or "trailer" sequences, as well as intermediate sequences (introns) between individual coding segments (exons).

[00127] By “recombinant vector” is meant a vector that includes a heterologous nucleic acid sequence or “transgene” that is capable of expression in vivo. It should be understood that the vectors described herein, in some embodiments, can be combined with other suitable compositions and therapies. In some embodiments, the vector is episomal. The use of a suitable episomal vector provides a means of maintaining the nucleotide of interest in a subject in multicopy extrachromosomal DNA, thereby eliminating the potential effects of chromosomal integration.

[00128] As used herein, the expression “genetic disease” refers to a disease, in part or in whole, directly or indirectly, caused by one or more abnormalities in the genome, in particular, a condition present from birth. The abnormality may be a mutation, insertion, or deletion. The abnormality may affect the coding sequence of a gene or its regulatory sequence. The genetic disorder may include, but is not limited to, Duchenne muscular dystrophy (DMD), hemophilia, cystic fibrosis, Huntington's chorea, familial hypercholesterolemia (LDL receptor defect), hepatoblastoma, Wilson's disease, congenital hepatic porphyria, inherited liver metabolic disorders, Lesch syndrome. Nihana, sickle cell anemia, thalassemia, xeroderma pigmentosum, Fanconi anemia, retinitis pigmentosa, ataxia telangiectasia, Bloom's syndrome, retinoblastoma and Tay-Sachs disease.

[00129] As used herein, the term “inhibitory polynucleotide” refers to a DNA or RNA molecule that reduces or prevents the expression (transcription or translation) of a second (target) polynucleotide. Inhibitory polynucleotides include antisense polynucleotides, ribozymes and external guide sequences. The term "inhibitory polynucleotide" further includes DNA and RNA molecules, such as RNAi, that encode existing inhibitory molecules, such as DNA molecules that encode ribozymes.

[00130] As used herein, “gene silencing” or “silenced gene”, with respect to the activity of an RNAi molecule, such as siRNA or siRNA, refers to a decrease in the level of mRNA of a target gene in a cell.

[00131] As used herein, the term “RNAi” refers to any type of interfering RNA, including, but not limited to, siRNA, shRNAi, endogenous miRNA, and artificial miRNA. For example, it includes sequences previously identified as siRNAs, regardless of the mechanism of subsequent RNA processing (i.e., although siRNAs are believed to have a specific mode of processing in vivo resulting in mRNA cleavage, such sequences may be included into vectors between the flanking sequences described herein). The term "RNAi" can include both RNAi molecules that silence a gene and effector RNAi molecules that activate gene expression.

[00132] As used herein, the term “comprising” or “comprises” is used to refer to compositions, methods and their respective component(s) that are essential to the specified method or composition, but allow the inclusion of unspecified elements, whether essential or not.

[00133] As used herein, the term “consisting essentially of” refers to elements required for a particular implementation. The term allows for elements that do not materially affect the core and novel or functional characteristic(s) of the specified embodiment. The use of the term “comprising” indicates inclusion rather than limitation.

[00134] The term “consisting of” refers to the compositions, methods and their respective components described herein, which do not include any elements not listed in the specified embodiment description.

[00135] As used herein, the term “consisting essentially of” refers to elements required for a particular implementation. The term allows for the presence of additional elements that do not significantly affect the basic and novel or functional characteristic(s) of the specified embodiment of the present invention.

[00136] In the present specification and the accompanying claims, the singular terms (respectively "a", "an" and "the" in the original English text) include their plural equivalents unless the context clearly indicates otherwise . Accordingly, for example, reference to “method” includes one or more methods and/or steps of the type described herein and/or those that will be apparent to those skilled in the art upon reading the present disclosure, and the like. Likewise, the term “or” is provided to include “and” unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present disclosure, suitable methods and materials are described below. As used herein, “for example” (the abbreviation “e.g.” in the English source text, derived from the Latin expression “exempli gratia”) indicates a non-limiting example. Accordingly, “for example” is synonymous with the term “for example”.

[00137] The groups of alternative elements or embodiments of the present invention disclosed herein are not to be construed as limitations. Each group member may be referred to and stated individually or in any combination with other group members or other elements presented herein. One or more members of the group may be included or excluded from the group for reasons of convenience and/or patentability. Upon any such inclusion or deletion herein, the specification is deemed to contain the group modified so as to satisfy the condition of a written description of all Markush groups used in the appended claims.

[00138] In some embodiments of any aspect, the disclosure described herein does not address a method for cloning humans, methods for modifying the genetic identity of a human germline, applications for industrial or commercial uses of human embryos, or methods for modifying the genetic identity of animals that may cause them suffering without any significant medical benefit to the person or animal, as well as animals obtained through such methods.

[00139] Definitions of other terms are provided herein in the description of various aspects of the present invention.

[00140] All patents and other publications; including literary references, issued patents, published patent applications, and patent applications pending contemporaneously with this application; mentioned herein are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, methodologies described in such publications that may be used in connection with the technology described herein. These publications are presented solely by reason of their disclosure prior to the filing date of this application. Nothing in this regard should be construed as an admission that the inventors have no rights in an earlier invention with respect to such disclosure by reason of prior invention or for any other reason. All statements regarding dates or representations regarding the contents of these documents are based on information available to the applicants and do not constitute an admission in any way as to the correctness of the dates or contents of these documents.

[00141] The description of embodiments of the present disclosure is not to be construed as exhaustive or limiting of the present invention to the precise form disclosed. Although specific embodiments and examples of the disclosure have been described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as will be appreciated by those skilled in the relevant art. For example, although the steps or functions of a method are presented in the specified order, in alternative embodiments the functions may be performed in a different order, or the functions may be performed substantially simultaneously. The principles of this disclosure provided herein may be applied to other procedures or methods as appropriate. Various implementations described herein may be combined to provide additional implementations. Aspects of the present disclosure may be modified, as necessary, to apply the compositions, functions and concepts of the above references and applications to provide additional embodiments of the present disclosure. In addition, for reasons of biological functional equivalence, some changes in protein structure may be made without affecting the biological or chemical action in a qualitative or quantitative sense. These and other changes may be made to the disclosure in light of the detailed description. All such modifications are intended to be included within the scope of the appended claims.

[00142] Specific elements of any of the above embodiments may be combined or replaced with elements of other embodiments. In addition, although the benefits associated with some embodiments of the present disclosure have been described in the context of those embodiments, other embodiments may also exhibit such benefits, and not all embodiments must necessarily demonstrate such benefits to fall within the scope of the disclosure.

[00143] The technology described herein is further illustrated by the following examples, which should in no way be construed as further limitations. It should be understood that the present invention is not limited to the specific methodology, protocols and reagents, etc. described herein and is therefore subject to variations. The terminology used herein is intended solely to describe specific embodiments and is not intended to limit the scope of the present invention, which is defined solely by the claims.

II. Expression of FVIII protein from cccDNA vector

[00144] The technology described herein is generally directed to the expression and/or production of FVIII protein in a cell from a non-viral DNA vector, such as the ccDNA vector described herein. CccDNA vectors for expression of the FVIII protein are described herein in the section entitled “ccDNA vectors in general.” In particular, cccDNA vectors for FVIII protein expression contain a pair of ITRs (e.g., symmetric or asymmetric, as described herein), and between the pair of ITRs, a nucleic acid encoding the FVIII protein, as described herein, operably linked to a promoter or regulatory sequence. A distinctive advantage of cccDNA vectors for FVIII protein expression compared to conventional AAV vectors and even lentiviral vectors is the absence of size restrictions for heterologous nucleic acid sequences encoding the target protein. Thus, even the full-length FVIII protein of 6.8 kb. can be expressed from a single cDNA vector. Thus, the cccDNA vectors described herein can be used to express a therapeutic FVIII protein in a subject in need thereof, for example, a subject suffering from hemophilia A.

[00145] As will be appreciated, the cccDNA vector technologies described herein can be adapted to any level of complexity or can be applied in a modular manner where the expression of different FVIII protein components can be controlled independently. For example, it is specifically contemplated that the cccDNA vector technologies developed herein may be as simple as using a single cccDNA vector to express a single heterologous gene sequence (e.g., FVIII protein), or may be as complex as using multiple cccDNA vectors , where each vector expresses multiple FVIII proteins or associated cofactors or accessory proteins, each independently controlled by different promoters. The embodiments below are specifically provided for herein and may be adapted by one skilled in the art as necessary.

[00146] In one embodiment, a single cDNA vector can be used to express one FVIII protein component. Alternatively, a single cccDNA vector can be used to express multiple components (e.g., at least 2) of the FVIII protein under the control of a single promoter (e.g., a strong promoter), optionally using IRES sequence(s) to ensure proper expression of each components, such as cofactors or accessory proteins.

[00147] Also provided herein, in another embodiment, is a single cDNA vector containing at least two inserts (eg, expressing a heavy chain or a light chain), the expression of each insert being under the control of its own promoter. Promoters may include multiple copies of the same promoter, multiple different promoters, or any combination thereof. One skilled in the art will appreciate that it is often desirable to express FVIII protein components at different expression levels, allowing the stoichiometry of the individual expressed components to be controlled to ensure efficient folding and combination of the FVIII protein in the cell.

[00148] Additional variations of cDNA vector technologies may be contemplated by one skilled in the art or adapted from protein production methods using standard vectors.

A. Nucleic acids

[00149] This document proposes the characterization and development of nucleic acid molecules for potential therapeutic applications. In some embodiments, the nucleic acids for therapeutic use encode the FVIII protein. In some embodiments, where appropriate, chemical modification of oligonucleotides is described to alter and improve in vivo properties (delivery, stability, lifetime, folding, target specificity) as well as their biological function and mechanism that directly correlate with therapeutic application.

[00150] Exemplary therapeutic nucleic acids according to the present disclosure that may be immunostimulatory and require the use of immunosuppressive agents disclosed herein may include, but are not limited to, minigenes, plasmids, minicircles, short interfering RNA (siRNA), microRNA (miRNA) , antisense oligonucleotides (ASO), ribozymes, closed-end double-stranded DNA (e.g., cccDNA, CELiD, linear covalently closed DNA (“minimal strand”), doggybone (dbDNA™), closed-end protelomeric DNA, or dumbbell-shaped linear DNA), Dicer dsRNA substrate, short hairpin RNA (shRNA), asymmetric interfering RNA (aiRNA), microRNA (miRNA), mRNA, tRNA, rRNA and viral DNA vectors, viral RNA vector; and any combination thereof.

[00151] siRNAs or miRNAs that can negatively regulate intracellular levels of specific proteins through a process called RNA interference (RNAi) are also contemplated by the present invention as nucleic acid therapeutics. Once the siRNA or miRNA is introduced into the cytoplasm of the host cell, these double-stranded RNA constructs bind to a protein called RISC. The RISC complex removes the sense strand of siRNA or siRNA. The RISC complex, in combination with complementary mRNA, cleaves the mRNA and releases the cut strands. RNAi is carried out by inducing specific destruction of mRNA, which leads to negative regulation of the corresponding protein.

[00152] Antisense oligonucleotides (ASOs) and ribozymes that inhibit translation of mRNA into protein may be nucleic acid-based therapeutics. In the case of antisense constructs, these single-stranded deoxynucleic acids have a sequence complementary to the mRNA sequence of the target protein and are capable of binding to the mRNA through Watson-Crick base pairing. This binding prevents translation of the target mRNA and/or triggers the destruction of the mRNA transcript by RNase H. As a result, the antisense oligonucleotide has increased specificity of action (ie, negative regulation of a specific protein associated with the disease).

[00153] In any of the methods provided herein, the therapeutic nucleic acid may be therapeutic RNA. The therapeutic RNA may be an mRNA translation inhibitor, an RNA interference (RNAi) agent, a catalytically active RNA molecule (ribozyme), transfer RNA (tRNA), or RNA that binds an mRNA transcript (ASO), protein, or other molecular ligand (aptamer). In any of the methods provided herein, the RNAi agent may be double-stranded RNA, single-stranded RNA, microRNA, short interfering RNA, short hairpin RNA, or triplex oligonucleotide.

[00154] In some embodiments, the therapeutic nucleic acid is double-stranded DNA with closed ends, such as cccDNA. In some embodiments, expression and/or production of the therapeutic protein in the cell occurs from a non-viral DNA vector, such as a cccDNA vector. A distinctive advantage of cccDNA vectors for therapeutic protein expression compared to conventional AAV vectors and even lentiviral vectors is the absence of size restrictions for heterologous nucleic acid sequences encoding the target protein. Thus, even a large therapeutic protein can be expressed from a single cccDNA vector. Thus, cccDNA vectors can be used to express a therapeutic protein in a subject in need thereof.

[00155] In general, the cccDNA vector for expression of a therapeutic protein disclosed herein contains, in the 5' to 3' direction: the first inverted terminal repeat (ITR) of an adeno-associated virus (AAV), a nucleotide sequence of interest (e.g. , an expression cassette described herein), and a second AAV ITR. The ITR sequences are selected from any of: (i) at least one WT-ITR and at least one modified AAB inverted terminal repeat (mod-ITR) (eg, asymmetric modified ITRs); (ii) two modified ITRs, wherein the mod-ITR pair has a different three-dimensional spatial organization in relation to each other (e.g., asymmetric modified ITRs), or (iii) a pair of symmetric or substantially symmetric WT-WT-ITRs, each WT-ITR has the same three-dimensional spatial organization, or (iv) pairs of symmetric or substantially symmetric modified ITRs, each mod-ITR having the same three-dimensional spatial organization.

[00156] In some embodiments, the transgene encoding the FVIII protein may also encode a secretory sequence such that the FVIII protein is targeted to the Golgi apparatus and endoplasmic reticulum (ER), where the FVIII protein will be folded into the correct conformation by chaperone molecules as it passes through ER and release from the cell. Exemplary secretory sequences include, but are not limited to, VH-02 (SEQ ID NO: 88) and VK-A26 (SEQ ID NO: 89) and the IgK signal sequence (SEQ ID NO: 126), as well as the Glue secretory signal providing secretion of the tagged protein from the cytosol (SEQ ID NO: 188), the secretory sequence TMD-ST, which directs the tagged protein to the Golgi apparatus (SEQ ID NO: 189).

[00157] Regulatory switches can also be used to fine-tune the expression of the FVIII protein so that the FVIII protein is expressed in the intended manner, including, but not limited to, expressing the FVIII protein at a target expression level or amount, or, alternatively, in the presence of or in the absence of a specific signal, including a cellular signaling event. For example, as described herein, expression of the FVIII protein from a cccDNA vector can be turned on or off when a particular condition occurs, as described in the section herein entitled “Regulatory Switches.”

[00158] For example, and for purposes of illustration only, FVIII proteins can be used to turn off an undesirable response, such as too high a level of FVIII protein production. The FVIII gene may contain a signal peptide marker for delivery of the FVIII protein to the target cell. However, in any situation it may be desirable to regulate FVIII protein expression. CccDNA vectors are easily adaptable to the use of regulatory switches.

[00159] A distinctive advantage of cccDNA vectors compared to conventional AAV vectors and even lentiviral vectors is that there is no size limitation for heterologous nucleic acid sequences encoding the FVIII protein. Thus, even full-length FVIII, and optionally any cofactors or accessory proteins, can be expressed from a single cccDNA vector. In addition, depending on the desired stoichiometry, multiple segments of the same FVIII protein can be expressed and the same or different promoters can be used, and regulatory switches can be used to fine-tune the expression of each region. For example, as shown in the Examples, a cccDNA vector can be used that contains a dual promoter system such that a different promoter is used for each domain of the FVIII protein. The use of a cccDNA plasmid to produce FVIII protein can include a unique combination of promoters for the expression of FVIII protein domains, resulting in the correct ratios of each domain to produce a functional FVIII protein. Accordingly, in some embodiments, the cDNA vector can be used to express different regions of the FVIII protein separately (eg, under the control of a different promoter).

[00160] In another embodiment, the FVIII protein expressed from the cccDNA vectors further comprises additional functionality, such as fluorescence, enzymatic activity, a secretion signal, or an immune cell activator.

[00161] In some embodiments, the cccDNA encoding the FVIII protein may further comprise a linker domain, for example. As used herein, “linker domain” refers to an oligo- or polypeptide region from about 2 to 100 amino acids in length that links any domains/regions of the FVIII protein described herein. In some embodiments, linkers may include or be composed of flexible residues, such as glycine and serine, such that adjacent protein domains can move freely relative to each other. Longer linkers can be used when it is desirable to ensure that two adjacent domains do not sterically interfere with each other. Linkers can be cleavable or non-cleavable. Examples of cleavable linkers include 2A linkers (eg, T2A), 2A-like linkers or functional equivalents thereof, and combinations thereof. The linker may be a T2A linker region derived from Thosea asigna virus.

[00162] One skilled in the art can take a known and/or publicly available protein sequence, such as FVIII, etc., and reverse engineer a cDNA sequence to encode such a protein. The cDNA can then be codon optimized to match the intended host cell and inserted into a cDNA vector as described herein.

B. cccDNA vectors expressing FVIII protein

[00163] A cDNA FVIII protein expression vector having one or more sequences encoding a target FVIII may contain regulatory sequences such as promoters, secretion signals, poly(A) regions, and enhancers. At least the cDNA vector contains one or more heterologous sequences encoding the FVIII protein.

[00164] To achieve highly efficient and accurate assembly of the FVIII protein, some embodiments specifically provide that the FVIII protein contains an endoplasmic reticulum (ER) leader sequence to direct it to the ER where protein folding occurs. For example, a sequence that directs the expressed protein(s) to the ER for folding.

[00165] In some embodiments, a cellular or extracellular localization signal (e.g., a secretory signal, a nuclear localization signal, a mitochondrial localization signal, etc.) is contained in a cccDNA vector to direct secretion or targeted subcellular localization of FVIII such that the FVIII protein may bind to intracellular target(s) (eg, within the body) or extracellular target(s).

[00166] In some embodiments, the cDNA FVIII protein expression vector described herein allows for the assembly and expression of any target FVIII protein in a modular manner. As used herein, the term “modular” refers to elements in the cDNA expression plasmid that can be easily removed from the construct. For example, modular elements in a cDNA-generating plasmid contain unique pairs of restriction sites flanking each element in the construct, allowing for exclusive manipulation of individual elements (see, for example, FIGS. 1A-1G). Thus, the cccDNA vector platform can support the expression and assembly of any desired FVIII protein configuration. Provided herein in various embodiments are plasmid cccDNA vectors that can reduce and/or minimize the number of manipulations required to assemble a target ccDNA vector encoding an FVIII protein.

C. Exemplary FVIII proteins expressed by cccDNA vectors

[00167] In particular, the cDNA FVIII protein expression vector disclosed herein may encode, for example, but not limited to, FVIII proteins, as well as variants and/or active fragments thereof, for use in treatment, prevention and/or alleviating one or more symptoms of hemophilia A. In one aspect, hemophilia A is human hemophilia A.

(i) Therapeutic FVIII proteins and fragments thereof

[00168] Essentially any variant of a therapeutic FVIII protein or fragment thereof (eg, a functional fragment) can be encoded and expressed from a cccDNA vector as described herein. One skilled in the art will understand that a therapeutic FVIII protein includes all splice variants and orthologs of the FVIII protein. The therapeutic FVIII protein includes intact molecules as well as fragments (eg, functional ones).

[00169] Factor VIII

[00170] Factor VIII is a nonenzymatic cofactor of activated coagulation factor IX (FIXa) that, upon proteolytic activation, interacts with FLXa to form a strong, noncovalent complex that binds to and activates factor X (FX).

[00171] The factor VIII gene or protein may also be referred to as F8, coagulation factor VIII, procoagulant component, antihemophilic factor, F8C, AHF, DXS1253E, FVIII, HEMA, or F8B. Expression of the factor VIII gene is tissue specific and is mainly observed in liver cells. The highest levels of factor VIII mRNA and protein were detected in liver sinusoidal cells; significant amounts of factor VIII are also present in hepatocytes and Kupffer cells (resident macrophages of the liver sinusoids). Moderate levels of factor VIII protein are detected in serum and plasma. Factor VIII protein is expressed at low to moderate levels in the fetal brain, retina, kidney, and testis.

[00172] Factor VIII mRNA is expressed in many tissues of the body, including bone marrow, whole blood, white blood cells, lymph nodes, thymus, brain, cerebral cortex, cerebellum, retina, spinal cord, tibial nerve, heart, artery, smooth muscle, skeletal muscle, small intestine, colon, adipocytes, kidney, liver, lung, spleen, stomach, esophagus, bladder, pancreas, thyroid gland, salivary gland, adrenal gland, pituitary gland, mammary gland, skin, ovary, uterus, placenta, prostate and testis. The FVIII gene, located on the long arm of the X chromosome, occupies a region approximately 186 thousand bp long. and consists of 26 exons (69-3106 bp) and introns (from 207 bp to 32.4 thousand bp). The total length of the coding sequence of this gene is 9 thousand bp.

[00173] The mature factor VIII polypeptide contains the structural domains A1-A2-B-A3-C1-C2. Three acidic subdomains, designated a1-a3-A1(a1)-A2(a2)-B-(a3)A3-C1-C2, are localized at the boundaries of the A domains and play an important role in the interaction between FVIII and other proteins (in particular , with thrombin). Mutations in these subdomains reduce the level of factor VIII activation by thrombin.

[00174] Factor VIII protein (an isoform of coagulation factor VIII) is a [Homo sapiens] pre-protein; accession number: NP_000123.1 (2351 amk.) and has the following sequence:

[00176] A distinctive advantage of cccDNA vectors compared to conventional AAV vectors and even lentiviral vectors is that there is no size limitation for heterologous nucleic acid sequences encoding the target protein. Thus, multiple full-length therapeutic FVIII proteins can be expressed from a single cccDNA vector.

[00177] Expression of a therapeutic FVIII protein or fragment thereof from a cccDNA vector can be achieved both spatially and temporally using one or more inducible or repressible promoters known in the art or described herein, including regulatory switches, described in this document.

[00178] In one embodiment, a therapeutic FVIII protein is a “therapeutic protein variant,” which refers to a therapeutic FVIII protein having an altered amino acid sequence, composition, or structure compared to the corresponding native therapeutic FVIII protein. In one embodiment, FVIII is a functional variant (eg, wild type). Expression of a mutant variant of the FVIII protein, such as a point mutation or deletion mutation that results in hemophilia A, may also be suitable, for example, to establish an animal model of the disease and/or to evaluate drugs for the treatment of hemophilia A. Delivery of mutant or modified FVIII proteins into a cell-based or animal model system can be performed to create a disease model. Such a cell-based or animal model can be used for research and/or drug screening. The therapeutic FVIII protein expressed from cccDNA vectors may further contain a sequence/fragment that imparts additional functionality, such as fluorescence, enzymatic activity, or a secretion signal. In one embodiment, the FVIII therapeutic protein variant comprises a non-native identification tag sequence (eg, an immune tag) that allows it to be distinguished from the endogenous FVIII therapeutic protein in the recipient host cell.

[00179] One skilled in the art can take a known and/or publicly available protein sequence, such as a therapeutic FVIII protein, and reverse engineer a cDNA sequence to encode such a protein. The cDNA can then be codon optimized to match the intended host cell and inserted into a cDNA vector as described herein.

[00180] In one embodiment, the coding sequence for a therapeutic FVIII protein can be obtained from an existing host cell or cell line, for example, by reverse transcribing mRNA obtained from the host and amplifying the sequence using PCR.

(ii) cccDNA vectors expressing therapeutic FVIII protein

[00181] A cccDNA vector having one or more sequences encoding a target therapeutic FVIII protein may contain regulatory sequences such as promoters, secretion signals, poly(A) regions, and enhancers. At least the cccDNA vector contains one or more heterologous sequences encoding a therapeutic FVIII protein or a functional fragment thereof. Exemplary cassette inserts for producing cccDNA vectors encoding therapeutic FVIII proteins are shown in Figures 1A-1G. In one embodiment, the cccDNA vector contains the FVIII sequence listed in Table 1 herein.

(iii) Therapeutic FVIII proteins and their applications for the treatment of hemophilia A

[00182] The cccDNA vectors described herein can be used to deliver therapeutic FVIII proteins for the treatment of hemophilia A associated with nonphysiological FVIII protein expression and/or mutations in FVIII proteins.

[00183] The cDNA vectors described herein can be used to express any target therapeutic FVIII protein. Exemplary therapeutic FVIII proteins include, but are not limited to, any FVIII protein expressed by the sequences set forth in Table 1 herein.

[00184] In one embodiment, the expressed therapeutic FVIII protein is functional for treating hemophilia A. In some embodiments, the therapeutic FVIII protein does not elicit an immune system response.

[00185] In another embodiment, cccDNA vectors encoding a therapeutic FVIII protein or a fragment thereof (eg, a functional fragment) can be used to produce a chimeric protein. Thus, it is specifically provided herein that a cccDNA vector expressing the chimeric protein can be introduced, for example, into any one or more tissues selected from: liver, kidney, gallbladder, prostate, adrenal gland. In some embodiments, when a cccDNA vector expressing FVIII is administered to an infant or administered to a subject in utero, the cccDNA vector expressing FVIII can be administered to any one or more tissues selected from: liver, adrenal gland, heart, intestine, lung, and stomach, or into liver progenitor stem cells for the treatment of hemophilia A in vivo or ex vivo.

[00186] Hemophilia:

[00187] Hemophilia A is a genetic deficiency of clotting factor VIII that causes increased bleeding and usually affects males. In most cases, it is inherited as an X-linked recessive trait, although there are cases that arise as a result of spontaneous mutations. Symptoms of hemophilia A include episodes of internal or external bleeding. Individuals with more severe hemophilia experience heavier and more frequent bleeding, while others with mild hemophilia tend to have more minor symptoms except in cases of surgery or serious injury. Patients with moderate hemophilia have a variety of symptoms that range from severe to mild.

[00188] Current treatments for preventing bleeding in people with hemophilia A include a factor VIII drug. Most individuals with severe hemophilia require regular intravenous administration of recombinant factor VIII or its plasma concentrate. Recombinant coagulation factor VIII is one of the most difficult proteins to manufacture industrially due to the low efficiency of its gene transcription, significant intracellular loss of its proprotein during post-translational processing, and instability of the secreted protein. Patients with mild hemophilia can control their condition with desmopressin, a drug that releases factor VIII stored in blood vessel walls.

[00189] There are many complications associated with the treatment of hemophilia A. In children, an easily accessible intravenous port can be inserted to minimize frequent traumatic intravenous cannulation. However, these ports are associated with a high rate of infection and the risk of clots forming at the tip of the catheter, rendering it useless. Viral infections may be common in hemophilia patients due to frequent blood transfusions, which expose patients to blood-borne infections such as HIV, hepatitis B, and hepatitis C. Prion infections can also be transmitted through blood transfusions. Another therapeutic complication of hemophilia A is the development of inhibitory antibodies to factor VIII due to frequent infusions. They are produced when the body recognizes infused factor VIII as foreign because the body does not produce its own copy. In such individuals, activated factor VII, a precursor to factor VIII in the coagulation cascade, can be administered by infusion to treat hemorrhage in individuals with hemophilia and antibodies to replacement factor VIII.

[00190] Coagulation cascade

[00191] Coagulation, also known as coagulation, is the process by which blood changes from a liquid to a gel, forming a blood clot. This potentially leads to hemostasis, the cessation of blood loss from the damaged vessel, followed by recovery. The mechanism of coagulation involves platelet activation, adhesion and aggregation along with fibrin deposition and maturation. Coagulation disorders are pathological conditions that can lead to bleeding (hemorrhage or bruising) or obstructive clotting (thrombosis).

[00192] Coagulation begins almost immediately after injury to a blood vessel has damaged the endothelium lining the blood vessel. The effect of blood on the subendothelial space initiates two processes: changes in platelets and the effect of subendothelial tissue factor on plasma factor VII, which ultimately leads to the formation of fibrin. Platelets immediately form a plug at the site of injury; this is called primary hemostasis. At the same time, secondary hemostasis occurs: additional coagulation factors or clotting factors beyond factor VII (including factor VIII) respond in a complex cascade to form fibrin strands that strengthen the platelet plug.

[00193] The coagulation cascade of secondary hemostasis has two initial pathways that lead to the formation of fibrin. These include the contact activation pathway (also known as the intrinsic pathway) and the tissue factor pathway (also known as the extrinsic pathway), which both lead to the same fundamental reactions that produce fibrin. The primary pathway for initiating blood coagulation is the tissue factor (extrinsic) pathway. The pathways are a series of reactions in which the zymogen (inactive enzyme precursor) of the serine protease and its glycoprotein cofactor are activated to become the active components, which then catalyze the next reaction in the cascade, ultimately leading to the formation of cross-linked fibrin. Coagulation factors are usually designated by Roman numerals with an added lowercase "a" to indicate the active form.

[00194] Coagulation factors are typically serine proteases (enzymes) that act by breaking down downstream proteins. The exceptions are tissue factor, FV, FVIII, FXIII. Tissue factor, FV and FVIII are glycoproteins, and factor XIII is a transglutaminase. Coagulation factors circulate as inactive zymogens. Thus, the coagulation cascade is classically divided into three pathways. The tissue factor pathway and the contact activation pathway both activate the “final common pathway” of factor X, thrombin, and fibrin.

[00195] The primary role of the tissue factor (extrinsic) pathway is to create the "thrombin burst", a process by which the rapid release of thrombin, the most important component of the coagulation cascade in terms of its feedback activation functions, occurs. FVIIa circulates in greater quantities than any other activated coagulation factor. The process includes the following steps:

[00196] Step 1: Following blood vessel injury, FVII leaves the bloodstream and comes into contact with tissue factor (TF) expressed on tissue factor-bearing cells (stromal fibroblasts and leukocytes) to form an activated complex (TF-FVIIa).

[00197] Step 2: TF-FVIIa activates FIX and FX.

[00198] Step 3: FVII itself is activated by thrombin, FXIa, FXII and FXa.

[00199] Step 4: FX activation (to form FXa) of TF-FVIIa is almost immediately inhibited by tissue factor pathway inhibitor (TFPI).

[00200] Step 5: FXa and its cofactor FVa form a prothrombinase complex that activates prothrombin to thrombin.

[00201] Step 6: Thrombin then activates other components of the coagulation cascade, including FV and FVIII (which forms a complex with FIX), and activates and releases FVIII from its complex with von Willebrand factor (vWF).

[00202] Step 7: FVIIIa is a cofactor of FIXa, and together they form a “tenase” complex that activates FX; and thus the cycle continues.

[00203] The contact activation pathway (intrinsic) begins with the formation of a primary complex of high molecular weight kininogen (HMWK), prekallikrein and FXII (Hageman factor) on collagen. Prekallikrein becomes kallikrein, and FXII becomes FXIIa. FXIIa turns FXI into FXIa. Factor X1a activates FIX, which with its cofactor FVIIIa forms a tenase complex that activates FX to FXa. The minor role played by the contact activation pathway in initiating clot formation can be illustrated by the fact that patients with severe deficiencies of FXII, HMWK and prekallikrein do not have impaired hemostasis. Instead, the contact activation system is more involved in inflammation and innate immunity.

[00204] The final common pathway, which is common to the intrinsic and extrinsic coagulation pathways, involves the conversion of prothrombin to thrombin and fibrinogen to fibrin. Thrombin has many functions besides converting fibrinogen to fibrin, the building block of the hemostatic plug. In addition, it is the most important platelet activator, and in addition to this it activates factors VIII and V and their inhibitor, protein C (in the presence of thrombomodulin), and also activates factor XIII, which forms covalent bonds that cross-link the fibrin polymers that are formed from activated monomers.

[00205] Once activated through the contact factor or tissue factor pathways, the coagulation cascade is maintained in a prothrombotic state by continued activation of FVIII and FIX to form the tenase complex until it is suppressed by the anticoagulant pathways. The methods involve administering to a subject an effective amount of a composition comprising a cccDNA vector encoding a therapeutic FVIII protein or a fragment thereof (eg, a functional fragment) as described herein. As will be understood by a skilled practitioner, the term "effective amount" refers to the amount of the administered cccDNA composition that results in expression of the protein in a "therapeutically effective amount" for treating a disease or disorder.

[00206] Dosage ranges for a composition containing a cccDNA vector encoding a therapeutic FVIII protein or a fragment (e.g., a functional fragment) thereof depend on effectiveness (e.g., promoter effectiveness) and include amounts large enough to produce the desired effect, e.g., expression target therapeutic protein FVIII for the treatment of phenylketonuria (hemophilia A). The dosage should not be so high as to cause unacceptable unwanted side effects. Typically, dosage will vary depending on the specific characteristics of the cccDNA vector, expression efficiency, and the age, condition, and gender of the patient. The dosage can be determined by one skilled in the art and, unlike conventional AAV vectors, can also be adjusted by the individual physician in case of any complication, since cccDNA vectors do not contain immune system-activating capsid proteins that prevent repeated dosing.

[00207] Administration of the cccDNA compositions described herein can be repeated over a limited period of time. In some embodiments, doses are administered intermittently or by pulsing. In a preferred embodiment, the above doses are administered over several months. The duration of treatment depends on clinical progress and the patient's response to therapy. “Booster” treatments over time are also provided. In addition, the level of expression can be titrated as the subject grows.

[00208] The therapeutic FVIII protein may be expressed in the subject for at least 1 week, at least 2 weeks, at least 1 month, at least 2 months, at least 6 months, at least 12 months/one years, at least 2 years, at least 5 years, at least 10 years, at least 15 years, at least 20 years, at least 30 years, at least 40 years, at least 50 years or more. Long-term expression can be achieved by reintroducing the cccDNA vectors described herein at predetermined or desired intervals.

[00209] As used herein, the term “therapeutically effective amount” is an amount of expressed therapeutic FVIII protein or functional fragment thereof that is sufficient to produce a statistically significant, measurable change in the expression of a disease biomarker or a reduction in a specific disease symptom (see “Measurement of Effectiveness” below) . Such effective amounts can be calibrated in clinical studies as well as in animal studies for a particular cDNA composition.

[00210] The exact amounts of cccDNA vector required for administration depend on the judgment of the practitioner and are individual to each individual. Suitable dosing regimens are also variable, but typical is an initial administration followed by repeat doses at one or more intervals followed by an injection or other administration. Alternatively, a continuous intravenous infusion sufficient to maintain blood concentrations within the ranges indicated for in vivo therapies, particularly for the treatment of acute diseases/disorders, is provided.

[00211] Agents that can be used in the methods and compositions described herein can be administered topically, intravenously (by bolus or continuous infusion), by intracellular injection, interstitial injection, orally, by inhalation, intraperitoneally, intramuscularly, subcutaneously , into the cavity, and they can also be delivered by peristaltic means, if necessary, or other means known to those skilled in the art. If necessary, the agent can be administered systemically. It can also be administered in utero.

[00212] The effectiveness of a given treatment for hemophilia A can be determined by a qualified physician. However, treatment is considered "effective treatment", as that term is used herein, if any or all of the signs or symptoms of the disease or disorder are modified in a favorable manner, or if other clinically accepted symptoms or markers of the disease are improved or alleviated, e.g. by 10% after treatment with a cccDNA vector encoding FVIII or a functional fragment thereof. Effectiveness can also be measured by the individual's lack of deterioration, which is assessed by stabilization of the disease or need for medical intervention (ie, progression of the disease stops or at least slows down). Methods for measuring these indicators are known to those skilled in the art and/or are described herein. Treatment includes any treatment of a disease in an individual or animal (some non-limiting examples include a human or mammal) and includes: (1) inhibiting the disease, such as stopping or slowing the progression of the disease or disorder; or (2) alleviation of the disease, such as causing regression of symptoms; and (3) preventing or reducing the likelihood of developing a disease, or preventing secondary diseases/disorders associated with the disease, such as liver or kidney failure. An effective amount for treating a disease means an amount that, when administered to a mammal in need thereof, is sufficient to provide effective treatment, as that term is defined herein, of that disease.

[00213] The effectiveness of an agent can be determined by assessing physical indicators that are specific to hemophilia A. Standard methods for analyzing hemophilia A indicators are known in the art.

[00214] In some embodiments, the cDNA FVIII protein expression vector disclosed herein may also encode cofactors or other polypeptides, sense or antisense oligonucleotides, or RNA (coding or noncoding; e.g., siRNA, shRNA, micro-RNA, and the like antisense analogues (eg, antagoMiR)), which can be used in combination with the FVIII protein expressed from cccDNA. In addition, expression cassettes containing a sequence encoding the FVIII protein may also include an exogenous sequence that encodes a reporter protein to be used for experimental or diagnostic purposes, such as β-lactamase, β-galactosidase (LacZ), alkaline phosphatase, thymidine kinase , green fluorescent protein (GFP), chloramphenicol acetyltransferase (CAT), luciferase and others well known in the art.

[00215] In one embodiment, the cccDNA vector contains a nucleic acid sequence for expression of an FVIII protein that is functional for treating hemophilia A. In a preferred embodiment, the therapeutic FVIII protein does not cause an immune system response unless required.

III. General cccDNA vector for use in the production of therapeutic FVIII proteins

[00216] Embodiments of the present invention are based on methods and compositions containing linear closed-end duplex (ccDNA) vectors that can express an FVIII transgene. In some embodiments, the transgene is a sequence encoding an FVIII protein. The cDNA FVIII protein expression vectors described herein are not limited in size, allowing, for example, the expression of all components required for transgene expression from a single vector. The cccDNA vector for expression of the FVIII protein is preferably duplex, eg, self-complementary, in at least part of the molecule, such as an expression cassette (eg, the ccDNA is not a double-stranded circular molecule). The cDNA vector has covalently closed ends and is thus resistant to digestion by an exonuclease (eg, exonuclease I or exonuclease III), for example, for more than an hour at 37°C.

[00217] In general, the cDNA vector for expression of the FVIII protein disclosed herein contains, in the 5' to 3' direction: the first inverted terminal repeat (ITR) of an adeno-associated virus (AAV), a nucleotide sequence of interest (e.g. , an expression cassette described herein), and a second AAV ITR. The ITR sequences are selected from any of: (i) at least one WT-ITR and at least one modified AAB inverted terminal repeat (mod-ITR) (eg, asymmetric modified ITRs); (ii) two modified ITRs, wherein the mod-ITR pair has a different three-dimensional spatial organization in relation to each other (e.g., asymmetric modified ITRs), or (iii) a pair of symmetric or substantially symmetric WT-WT-ITRs, each WT-ITR has the same three-dimensional spatial organization, or (iv) pairs of symmetric or substantially symmetric modified ITRs, each mod-ITR having the same three-dimensional spatial organization.

[00218] Included herein are methods and compositions containing a cccDNA vector for production of FVIII protein, which may further include a delivery system, such as, but not limited to, a liposomal nanoparticle delivery system. Disclosed herein are non-limiting exemplary liposome nanoparticle systems contemplated for use. In accordance with some aspects of the present disclosure, a lipid nanoparticle is provided comprising cccDNA and an ionizable lipid. For example, the composition of lipid nanoparticles that are prepared and loaded with a cccDNA vector obtained by this method is disclosed in international application PCT/US2018/050042, filed September 7, 2018, which is incorporated herein in its entirety.

[00219] The cDNA FVIII protein expression vectors disclosed herein do not have packaging restrictions imposed by limited space within the viral capsid. CccDNA vectors provide a viable eukaryotic-produced alternative to plasmid DNA vectors produced by prokaryotes, as opposed to encapsulated AAV genomes. This allows the insertion of control elements, such as regulatory switches disclosed herein, large transgenes, multiple transgenes, etc.

[00220] FIG. 1A-1E schematically show non-limiting exemplary ccDNA vectors for FVIII protein expression or corresponding ccDNA plasmid sequence. CCDNA vectors for expression of the FVIII protein are capsidless and can be obtained from a plasmid encoding, in this order: a first ITR, an expression cassette containing the transgene, and a second ITR. An expression cassette may include one or more regulatory sequences that mediate and/or control expression of a transgene, for example, an expression cassette may contain one or more of the following elements in this order: enhancer/promoter, reporter (transgene) ORF, post-transcriptional regulatory element (e.g. , WPRE) and a polyadenylation and termination signal (eg, BGH poly(A)).

[00221] The expression cassette may also contain an internal ribosome entry site (IRES) and/or a 2A element. Cis-regulatory elements include, but are not limited to, a promoter, a riboswitch, an insulator, a mir-regulated element, a post-transcriptional regulatory element, a tissue- and cell type-specific promoter, and an enhancer. In some embodiments, the ITR may act as a promoter of a transgene, such as the FVIII protein. In some embodiments, the cccDNA vector contains additional components for regulating transgene expression, such as a regulatory switch, which are described herein in the section entitled "Regulatory Switches" for controlling and regulating FVIII protein expression, and may include, if necessary, a regulatory switch. switch, which is a “kill switch” to ensure controlled death of the cell containing the cccDNA vector.

[00222] The expression cassette may contain more than 4000 nucleotides, 5000 nucleotides, 10000 nucleotides or 20000 nucleotides, or 30000 nucleotides, or 40000 nucleotides, or 50000 nucleotides, or any range from about 4000 to 10000 nucleotides, or 10000-50000 nucleotides ov, or more 50,000 nucleotides. In some embodiments, the expression cassette may contain a transgene with a length ranging from 500 to 50,000 nucleotides. In some embodiments, the expression cassette may contain a transgene with a length ranging from 500 to 75,000 nucleotides. In some embodiments, the expression cassette may contain a transgene with a length ranging from 500 to 10,000 nucleotides. In some embodiments, the expression cassette may contain a transgene with a length ranging from 1,000 to 10,000 nucleotides. In some embodiments, the expression cassette may contain a transgene with a length ranging from 500 to 5000 nucleotides. There are no restrictions on the size of cccDNA vectors enclosed in a capsid, allowing delivery of a large expression cassette to ensure efficient transgene expression. In some embodiments, the cccDNA vector lacks prokaryote-specific methylation.

[00223] The cDNA expression cassette may include, for example, an exogenous expressed sequence (e.g., an open reading frame) or a transgene that encodes a protein that is either absent, inactive, or deficient in activity in the recipient subject, or a gene that encodes a protein that has a target biological or therapeutic effect. The transgene may encode a gene product, the function of which may be to correct the expression of a defective gene or transcript. In principle, an expression cassette can include any gene that encodes a protein, polypeptide or RNA that is either reduced or absent due to mutation, or that provides a therapeutic benefit when overexpressed, and is considered to be included within the scope of the present disclosure.

[00224] The expression cassette may contain any transgene (eg, encoding an FVIII protein), for example, an FVIII protein that can be used to treat hemophilia A in a subject, that is, a therapeutic FVIII protein. The cccDNA vector can be used to deliver and express any FVIII protein of interest in a subject, alone or in combination with polypeptide-encoding nucleic acids or non-coding nucleic acids (eg, RNAi, miR, etc.), as well as exogenous genes and nucleotide sequences, including viral sequences, in the genome of subjects, for example, HIV virus sequences and the like. Preferably, the cDNA vector disclosed herein is used for therapeutic purposes (eg, medical, diagnostic or veterinary purposes) or immunogenic polypeptides. In certain embodiments, the cccDNA vector can be used to express any gene of interest in a subject, which includes one or more polypeptides, peptides, ribozymes, peptide nucleic acids, siRNA, RNAi, antisense oligonucleotides, antisense polynucleotides, or RNAs (encoding or non-coding ; e.g., siRNA, shRNA, micro-RNA and their antisense analogues (e.g., antagoMiR)), antibodies, fusion proteins, or any combination thereof.

[00225] An expression cassette may also encode polypeptides, sense or antisense oligonucleotides, or RNA (coding or non-coding; e.g., miRNA, shRNA, micro-RNA, and antisense analogs thereof (e.g., antagoMiR)). Expression cassettes may include an exogenous sequence that encodes a reporter protein to be used for experimental or diagnostic purposes, such as β-lactamase, β-galactosidase (LacZ), alkaline phosphatase, thymidine kinase, green fluorescent protein (GFP), chloramphenicol acetyltransferase (CAT) , luciferase and others well known in the art.

[00226] The sequences provided in the expression cassette expression construct of the cDNA vector for expression of the FVIII protein described herein can be codon optimized for the target host cell. As used herein, the term “codon optimized” or “codon optimization” refers to the process of modifying a nucleic acid sequence to enhance expression in vertebrate cells of interest, such as a mouse or human, by replacing at least one or more than one or a significant number codons of a native sequence (e.g., a prokaryotic sequence) by the codons that are most or most frequently used in the genes of that vertebrate. Different species exhibit specific preferences for certain codons of a particular amino acid. Typically, codon optimization does not change the amino acid sequence of the original translated protein. Optimized codons can be determined using, for example, the Gene Forge ^® platform for codon optimization and custom gene synthesis from Aptagen (Aptagen, Inc., 2190 Fox Mill Rd. Suite 300, Herndon, VA, 20171) or other publicly available database. In some embodiments, the nucleic acid encoding the FVIII protein is optimized for expression in humans and/or is human FVIII or a functional fragment thereof, as known in the art.

[00227] The transgene expressed by the cDNA FVIII protein expression vector as described herein encodes the FVIII protein. CccDNA vectors for FVIII protein expression differ from plasmid-based expression vectors in many structural features. CccDNA vectors may have one or more of the following characteristics: absence of original (i.e., uninserted) bacterial DNA, absence of a prokaryotic origin of replication, self-sufficiency, i.e. they do not require any sequences other than the two ITRs, including the Rep binding site and the terminal resolution site (RBS and TRS), and exogenous sequence between the ITRs, the presence of ITR sequences that form hairpins, and the absence of bacterial-type DNA methylation or virtually any other methylation, which is considered abnormal in the mammalian host. In general, the vectors of the present invention preferably do not contain any prokaryotic DNA, but it is contemplated that some prokaryotic DNA may be inserted as an exogenous sequence, by way of non-limiting example, in a promoter or enhancer region. Another important feature that distinguishes cccDNA vectors from plasmid-based expression vectors is that cccDNA vectors are single-stranded linear DNA with closed ends, while plasmids are always double-stranded DNA.

[00228] CCDNA FVIII protein expression vectors produced using the methods provided herein preferably have a linear and continuous structure rather than a discontinuous structure, as determined by restriction enzyme digestion analysis (FIG. 4D). A linear and continuous structure is believed to be more resistant to attack by cellular endonucleases and is also less likely to recombine and cause mutagenesis. Thus, the cccDNA vector in the form of a linear and continuous structure is the preferred embodiment. A continuous, linear, single-stranded, intramolecular duplex cDNA vector may have covalently linked terminal regions without sequences encoding AAV capsid proteins. These cDNA vectors are structurally different from plasmids (including the cDNA plasmids described herein), which are circular duplex nucleic acid molecules of bacterial origin. The complementary strands of plasmids can be separated after denaturation to produce two nucleic acid molecules, while cccDNA vectors, which have complementary strands, constitute a single DNA molecule and therefore remain a single molecule even after denaturation. In some embodiments, the cDNA vectors described herein can be produced without methylation of prokaryotic DNA bases, unlike plasmids. Thus, cccDNA vectors and ccDNA plasmids differ both in structure (in particular, linear versus circular), and in terms of the methods used to obtain and purify these different entities (see below), as well as in terms of in terms of DNA methylation, which refers to the prokaryotic type for cDNA plasmids and the eukaryotic type for cDNA vectors.

[00229] There are several advantages to using a cccDNA vector for FVIII protein expression as described herein compared to plasmid-based expression vectors, such advantages include, but are not limited to: 1) plasmids contain bacterial DNA sequences and are methylated, prokaryotic-specific, for example, methylation of 6-methyladenosine and 5-methylcytosine, while the sequences of the capsid-free AAV vector are of eukaryotic origin and do not undergo prokaryotic-specific methylation; as a result, capsidless AAV vectors are less likely to induce inflammatory and immune responses compared to plasmids; 2) while plasmids require the presence of a resistance gene during the production method, cccDNA vectors do not; 3) while a circular plasmid is not delivered to the nucleus when introduced into a cell and requires excessive loading to overcome destruction by cellular nucleases, ccDNA vectors contain viral cis elements, i.e. ITRs, which confer nuclease resistance and can be engineered to target and deliver to the nucleus. The minimum defining elements required for ITR function are proposed to be the Rep binding site (RBS; 5'-GCGCGCTCGCTCGCTC-3' (SEQ ID NO: 60) for AAB2) and the terminal resolution site (TRS; 5'-AGTTGG-3' (SEQ ID NO: 64) for AAB2) plus a variable palindromic hairpin sequence; and 4) cccDNA vectors do not overrepresent CpG dinucleotides often found in plasmids of prokaryotic origin, which are reported to bind a member of the Toll-like receptor family, inducing a T cell-mediated immune response. In contrast, transduction with the capsidless AAV vectors described herein can effectively target cell and tissue types that are difficult to transduce with conventional AAV virions using different delivery reagents. IV. Inverted terminal repeats (ITRs)

[00230] As disclosed herein, cccDNA vectors for FVIII protein expression comprise a transgene or heterologous nucleic acid sequence located between two inverted terminal repeat (ITR) sequences, wherein said ITR sequences may be a pair of asymmetric ITRs or a pair of symmetric or cross-linked ITRs. essentially symmetrical ITRs, as those terms are defined herein. The cccDNA vector disclosed herein may contain ITR sequences that are selected from any of: (i) at least one WT ITR and at least one modified AAV inverted terminal repeat (mod-ITR) (e.g., asymmetric modified ITRs ); (ii) two modified ITRs, wherein the mod-ITR pair has a different three-dimensional spatial organization relative to each other (e.g., asymmetric modified ITRs), or (iii) pairs of symmetric or substantially symmetric WT-WT ITRs, each WT-ITR has the same three-dimensional spatial organization, or (iv) pairs of symmetrical or substantially symmetrical modified ITRs, each mod-ITR having the same three-dimensional spatial organization, which methods of the present disclosure may further include a delivery system such as, but not limited to , a delivery system based on liposomal nanoparticles.

[00231] In some embodiments, the ITR sequence may be derived from viruses of the Parvoviridae family, which includes two subfamilies: Parvovirinae, which infect vertebrates, and Densovirinae, which infect insects. The subfamily Parvovirinae (called parvoviruses) includes the genus Dependovirus, whose members, in most conditions, require coinfection with a helper virus such as an adenovirus or herpes virus for effective infection. The genus Dependovirus includes adeno-associated virus (AAV) that commonly infects humans (e.g., serotypes 2, 3A, 3B, 5, and 6) or primates (e.g., serotypes 1 and 4), as well as related viruses that infect other warm-blooded animals (e.g. , adeno-associated viruses of bovine, canine, equine and sheep). Parvoviruses and other members of the family Parvoviridae are described generally in Kenneth I. Berns, “Parvoviridae: The Viruses and Their Replication,” Chapter 69 in FIELDS VIROLOGY (3d Ed. 1996).

[00232] Although the ITRs exemplified in the specification and Examples herein are WT-ITR AAB2, one of ordinary skill in the art will appreciate that, as stated above, ITRs from any known parvovirus, for example, a dependovirus such as AAV (for example, from the genome of AAV1, AAV2, AAV3, AAV4, AAV5, AAV 5, AAV7, AAV8, AAV9, AAV10, AAV11, AAB12, AABrh8, AABrh10, AAB-DJ and AAB-DJ8 For example, NCBI: NC 002077; NC 001401; NC001729; NC001829; NC006152; NC 006260; NC 006261, chimeric ITRs or ITRs from any synthetic AAV. In some embodiments, AAV can infect warm-blooded animals, such as avian (PAAV), bovine (CAAV), canine, equine, and ovine adeno-associated viruses. In some embodiments, the ITR is derived from parvovirus B19 (GenBank accession no. NC 000883), small mouse virus (MVM) (GenBank accession no. NC 001510); goose parvovirus (GenBank accession no. NC 001510); GenBank accession NC 001701); snake parvovirus 1 (GenBank accession number NC 006148). In some embodiments, the 5' WT-ITR may be from one serotype and the 3' WT-ITR may be from a different serotype, as discussed herein.

[00233] One of ordinary skill in the art will recognize that ITR sequences have a general double-stranded Holliday junction structure, which is typically a T- or Y-hairpin structure (see, for example, FIG. 2A and FIG. 3A), where each WT-ITR formed by two palindromic arms or loops (B-B' and C-C) embedded in a larger palindromic arm (A-A'), and a single-stranded sequence D (with the order of these palindromic sequences determining the "flip" or "flop" orientation of the ITR ). See, for example, the structural analysis and comparison of ITR sequences from different AAV serotypes (AAV1-AAV6) described in Grimm et at, J. Virology, 2006; 80(1); 426-439; Yan et at, J. Virology, 2005; 364-379; Duan et ai, Virology 1999; 261; 8-14. One of ordinary skill in the art can readily determine WT-ITR sequences from any AAV serotype for use in a cccDNA vector or ccDNA plasmid based on the exemplary AAB2 ITR sequences provided herein. See, for example, the comparison of ITR sequences from different AAV serotypes (AAV1-AAV6, avian AAV (PAAV) and bovine AAV (BAAV)) described in Grimm et al., J. Virology, 2006; 80(1); 426-439; which shows the % identity of the left ITR of AAV2 with the left ITR from other serotypes: AAV-1 (84%), AAV-3 (86%), AAV-4 (79%), AAV-5 (58%), AAV-6 (left ITR) (100%) and AAV-6 (right ITR) (82%).

A. Pairs of symmetrical ITRs

[00234] In some embodiments, the cccDNA vector for expression of the FVIII protein described herein contains, in the 5' to 3' direction: the first inverted terminal repeat (ITR) of an adeno-associated virus (AAV), a nucleotide sequence of interest (eg , an expression cassette described herein) and a second ITR of AAB, wherein said first ITR (5' ITR) and second ITR (3' ITR) are symmetrical or substantially symmetrical with respect to each other, that is, the ccDNA vector may contain sequences ITRs that have a symmetrical three-dimensional spatial organization such that their structure has the same shape in geometric space, or have the same A, C-C and B-B' loops in three-dimensional space. In such an embodiment, the pair of symmetrical ITRs or the pair of substantially symmetrical ITRs may be modified ITRs (eg, mod-ITRs) that are not wild-type ITRs. A mod-ITR pair may have the same sequence that has one or more modifications relative to the wild-type ITR, and they are inversely complementary to each other (inverted). In alternative embodiments, a pair of modified ITRs is substantially symmetrical as defined herein, that is, a pair of modified ITRs may have different sequences but a corresponding or identical symmetrical three-dimensional shape.

(i) Wild type ITR

[00235] In some embodiments, symmetric ITRs or substantially symmetric ITRs are wild type (WT-ITR), as described herein. In other words, both ITRs have wild-type sequence but do not necessarily have to be WT-ITRs from the same AAV serotype. That is, in some embodiments, one WT-ITR may be derived from one serotype of AAV, and another WT-ITR may be derived from a different serotype of AAV. In such an embodiment, the WT-ITR pair is substantially symmetrical as defined herein, that is, they can have one or more conserved nucleotide modifications while maintaining a symmetrical three-dimensional spatial organization.

[00236] Accordingly, as disclosed herein, cccDNA vectors contain a transgene or heterologous nucleic acid sequence located between two flanking wild-type inverted terminal repeat (WT-ITR) sequences that are either reverse complementary (inverted) to each other to each other, or, alternatively, are substantially symmetrical with respect to each other, that is, the WT-ITR pair has a symmetrical three-dimensional spatial organization. In some embodiments, the wild-type ITR sequence (e.g., WT-ITR of AAB) contains a functional Rep binding site (RBS; e.g., 5'-GCGCGCTCGCTCGCTC-3' for AAB2, SEQ ID NO: 60) and a functional terminal resolution site (TRS; e.g. 5'-AGTT-3', SEQ ID NO: 62).

[00237] In one aspect, cccDNA vectors for FVIII protein expression can be derived from a vector polynucleotide that encodes a heterologous nucleic acid operably located between two WT inverted terminal repeat (WT-ITR) sequences (e.g., AAB WT-ITR) . In other words, both ITRs have wild-type sequence but do not necessarily have to be WT-ITRs from the same AAV serotype. That is, in some embodiments, one WT-ITR may be derived from one serotype of AAV, and another WT-ITR may be derived from a different serotype of AAV. In such an embodiment, the WT-ITR pair is substantially symmetrical as defined herein, that is, they can have one or more conserved nucleotide modifications while maintaining a symmetrical three-dimensional spatial organization. In some embodiments, the 5' WT-ITR is derived from one AAV serotype and the 3' WT-ITR is derived from the same or a different AAV serotype. In some embodiments, the 5' WT-ITR and 3' WT-ITR are mirror images of each other, that is, they are symmetrical. In some embodiments, the 5' WT-ITR and 3' WT-ITR are from the same serotype of AAV.

[00238] WT-ITRs are well known. In one embodiment, the two ITRs are from the same serotype AAB2. In some embodiments, WT from other serotypes can be used. There are a number of homologous serotypes, for example, AAV2, AAV4, AAV6, AAV8. In one embodiment, highly homologous ITRs (eg, ITRs with a similar loop structure) can be used. In another embodiment, a WT-ITR may be used for AABs that are more different, such as AAB2 and AAB5, and in yet another embodiment, an ITR may be used that is essentially a WT, that is, it has the basic loop structure of the WT, but some conservative nucleotide changes that do not change or affect properties. When using WT-ITR from the same viral serotype, one or more regulatory sequences can be additionally used. In certain embodiments, the regulatory sequence is a regulatory switch that allows modulation of the activity of the cccDNA, such as the expression of the encoded FVIII protein.

[00239] In some embodiments, one aspect of the technology described herein relates to a cccDNA vector for expression of an FVIII protein, wherein the cccDNA vector comprises at least one heterologous nucleotide sequence encoding an FVIII protein operably located between two inverted sequences. wild-type terminal repeats (WT-ITRs), wherein the WT-ITRs may be from the same serotype, different serotypes, or substantially symmetrical with respect to each other (i.e., they have a symmetrical three-dimensional spatial organization such that their structure has the same shape in geometric space, or have the same loops A, C-C' and B-B' in three-dimensional space). In some embodiments, symmetrical WT-ITRs contain a functional end resolution site and a Rep binding site. In some embodiments, the heterologous nucleic acid sequence encodes a transgene, and the vector is not contained within a viral capsid.

[00240] In some embodiments, the WT-ITRs are the same but inversely complementary to each other. For example, the sequence AACG in the 5' ITR may be a CGTT (ie reverse complementary sequence) in the 3' ITR at the corresponding site. In one example, the 5' sense strand of the WT-ITR contains the sequence ATCGATCG, and the corresponding 3' sense strand of the WT-ITR contains CGATCGAT (ie, the reverse complementary sequence of ATCGATCG). In some embodiments, the WT-ITR cccDNA further comprises an end resolution site and a replication protein binding site (RPS) (sometimes referred to as a replication protein binding site), such as a Rep binding site.

[00241] Exemplary WT-ITR sequences for use in cDNA FVIII protein expression vectors containing WT-ITR are presented in Table 3 herein, which shows WT-ITR pairs (5' WT-ITR and 3' WT-ITR ITR).

[00242] As an illustrative example, the present disclosure provides a cccDNA vector for expressing an FVIII protein comprising a promoter operably linked to a transgene (e.g., a heterologous nucleic acid sequence), with or without a regulatory switch, wherein the ccDNA is devoid of capsid proteins and: (a) is produced from a cccDNA plasmid (e.g., see FIGS. 1F-1G) that encodes a WT-ITR, with each WT-ITR having the same number of intramolecular duplex base pairs in its hairpin secondary configuration (preferably excluding deletion of any terminal AAA or TTT loops in this configuration compared to these reference sequences), and (b) identified as cccDNA using an assay to identify cccDNA using agarose gel electrophoresis on a native gel and under denaturing conditions in Example 1.

[00243] In some embodiments, the flanking WT-ITRs are substantially symmetrical to each other. In this embodiment, the 5' WT-ITR may be derived from one AAV serotype and the 3' WT-ITR may be derived from a different AAV serotype such that the WT-ITRs are not identical reverse complementary sequences. For example, the 5' WT-ITR may be derived from AAB2, and the 3' WT-ITR may be derived from a different serotype (eg, AAB1, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12). In some embodiments, the WT-ITR may be selected from two different parvoviruses selected from any of: AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, snake parvovirus (eg , royal python parvovirus), bovine parvovirus, goat parvovirus, avian parvovirus, equine parvovirus, shrimp parvovirus, porcine parvovirus or insect AAV. In some embodiments, such a WT ITR combination is a combination of the WT ITRs of AAB2 and AAB6. In one embodiment, WT-ITRs are substantially symmetrical when one ITR is inverted relative to another ITR that is at least 90% identical, at least 95% identical, at least 96%... 97%... 98%... 99%... 99.5%, including all intermediate values, and has the same symmetrical three-dimensional spatial organization. In some embodiments, a pair of WT-ITRs is substantially symmetrical because they have a symmetrical three-dimensional spatial organization, for example, having the same three-dimensional organization of arms A, C-C', B-B', and D. In one embodiment, a pair of substantially symmetrical WTs -ITRs are inverted with respect to each other and are at least 95% identical, at least 96%... 97%... 98%... 99%... 99.5% identical, including all intermediate values, with respect to each other, and one WT-ITR retains a Rep binding site (RBS) 5'-GCGCGCTCGCTCGCTC-3' (SEQ ID NO: 60) and a terminal resolution site (TRS). In some embodiments, a pair of substantially symmetrical WT-ITRs are inverted with respect to each other and are at least 95% identical, at least 96%... 97%... 98%... 99%... 99.5% identical, including everything in between values, relative to each other, and one WT-ITR retains a Rep binding site (RBS) 5'-GCGCGCTCGCTCGCTC-3' (SEQ ID NO: 60) and a terminal resolution site (TRS) and in addition to a variable palindromic sequence providing formation of a hairpin secondary structure. Homology can be determined using standard methods well known in the art, such as BLAST (“Basic Local Alignment Search Tool”), BLASTN with default settings.

[00244] In some embodiments, the ITR structural element can be any structural element that is involved in the functional interaction of the ITR with a large Rep protein (eg, Rep 78 or Rep 68). In certain embodiments, the structural element provides selectivity for the interaction of the ITR with the large Rep protein, i.e. determines, at least in part, which Rep protein functionally interacts with the ITR. In other embodiments, the structural element physically interacts with the large Rep protein when the Rep protein is bound to the ITR. Each structural element may be, for example, an ITR secondary structure, an ITR nucleotide sequence, a gap between two or more elements, or a combination of any of the above. In one embodiment, the structural elements are selected from the group consisting of arm A and A', arm B and B', arm C and C', arm D, a Rep binding site (RBE), and RBE' (i.e., the complementary sequence of the RBE ) and terminal resolution site (TRS).

[00245] By way of example only, Table 2 shows exemplary WT-ITR combinations.

[00246] tgcatgc 2: Exemplary combinations of WT-ITRs from the same serotype or different serotypes or different parvoviruses. The order shown does not indicate the position of the ITR, for example, “AAB1, AAB2” demonstrates that cccDNA can contain the WT AAB1 ITR at the 5' position and the WT AAB2 ITR at the 3' position, or vice versa, the WT AAB2 ITR at the 5' position, a WT ITR of AAB1 at the 3' position. Abbreviations: AAV serotype 1 (AAV1), AAV serotype 2 (AAV2), AAV serotype 3 (AAV3), AAV serotype 4 (AAV4), AAV serotype 5 (AAV5), AAV serotype 6 (AAV6), AAV serotype 7 (AAV7) , AAV serotype 8 (AAV8), AAV serotype 9 (AAV9), AAV serotype 10 (AAV10), AAV serotype 11 (AAV11) or AAV serotype 12 (AAV12); genome AABrh8, AABrh10, AAB-DJ and AAB-DJ8 (e.g. NCBI: NC 002077; NC 001401; NC 001729; NC 001829; NC 006152; NC 006260; NC 006261), ITR from warm-blooded animals (avian AAV (PAAV), bovine AAV (BAAV), canine, equine and ovine AAV), ITR from parvovirus B19 (GenBank accession number: NC 000883), small mouse virus (MVM) (GenBank accession number NC 001510); goose: goose parvovirus (GenBank accession number NC 001701); snake: snake parvovirus 1 (GenBank accession number NC 006148).

[00247] By way of example only, Table 3 provides sequences of exemplary WT-ITRs from several different AAV serotypes.

[00248] In some embodiments, the nucleotide sequence of a WT-ITR sequence may be modified (e.g., by modifying 1, 2, 3, 4, or 5 or more nucleotides or any range thereof), wherein said modification is a substitution with a complementary nucleotide, e.g. , G for C, and vice versa, and T for A, and vice versa.

[00249] In certain embodiments of the present invention, the cDNA vector for expression of the FVIII protein does not have a WT-ITR consisting of a nucleotide sequence selected from any of: SEQ ID NO: 1, 2, 5-14. According to alternative embodiments of the present invention, if the cccDNA vector has a WT-ITR containing a nucleotide sequence selected from any of: SEQ ID NO: 1, 2, 5-14, then the flanking ITR is also WT, and the cccDNA vector contains a control switch, for example, as disclosed herein and in international application PCT/US 18/49996 (for example, see Table 11 of PCT/US 18/49996). In some embodiments, the cccDNA vector for expression of the FVIII protein comprises a regulatory switch as disclosed herein and a selected WT-ITR having a nucleotide sequence selected from any of the group consisting of: SEQ ID NO: 1, 2, 5- 14.

[00250] The cDNA vector for expression of the FVIII protein described herein may include WT-ITR structures that retain the functional portions of RBE, TRS, and RBE'. FIG. 2A and FIG. 2B, using the wild-type ITR for illustrative purposes, shows one possible mechanism for the TRS site to function within part of the wild-type ITR structure of a ccDNA vector. In some embodiments, the cDNA vector for expressing the FVIII protein comprises one or more functional WT-ITR polynucleotide sequences that contain a Rep binding site (RBS; 5'-GCGCGCTCGCTCGCTC-3' (SEQ ID NO: 60) for AAB2) and a site end resolution (TRS; 5'-AGTT (SEQ ID NO: 62)). In some embodiments, the at least one WT-ITR is functional. In alternative embodiments, wherein the cccDNA vector for expressing the FVIII protein contains two WT-ITRs that are substantially symmetrical to each other, at least one WT-ITR is functional and at least one WT-ITR is non-functional.

B. Modified ITRs (mod-ITRs) in general for cccDNA vectors containing pairs of asymmetric ITRs or pairs of symmetric ITRs

[00251] As discussed herein, the cDNA vector for expression of the FVIII protein may contain a pair of symmetric ITRs or a pair of asymmetric ITRs. In both cases, one or both of the ITRs may be modified ITRs - the difference is that in the first case (i.e., symmetrical mod-ITRs), the mod-ITRs have the same three-dimensional spatial organization (i.e., have the same A-arm configurations -A', C-C' and B-B'), while in the second case (i.e. asymmetric mod-ITRs), mod-ITRs have different three-dimensional spatial organization (i.e. have different arm configurations A-A', C-C' and B-B').

[00252] In some embodiments, a modified ITR is an ITR that is modified by deletion, insertion, and/or substitution from the wild-type ITR sequence (eg, the AAB ITR). In some embodiments, at least one of the ITRs in the cccDNA vector contains a functional Rep binding site (RBS; e.g., 5'-GCGCGCTCGCTCGCTC-3' for AAB2, SEQ ID NO 60) and a functional terminal resolution site (TRS; e.g., 5 '-AGTT-3', SEQ ID NO: 62). In one embodiment, at least one of the ITRs is a non-functional ITR. In one embodiment, not each of the different or modified ITRs is a wild-type ITR from different serotypes.

[00253] Specific changes and mutations in the ITR are described in detail herein, but in the context of an ITR, “altered,” “mutated,” or “modified” indicates that nucleotides have been inserted, deleted, and/or replaced relative to the wild type, reference, or original ITR sequence. The altered or mutated ITR may be a modified ITR. In this document, “designed” refers to the aspect of human manipulation. For example, a polypeptide is considered to be “engineered” when at least one aspect of the polypeptide, such as its sequence, has been manipulated by humans to be different from the aspect that exists in nature.

[00254] In some embodiments, mod-ITR may be synthetic. In one embodiment, the synthetic ITR is based on ITR sequences from more than one AAV serotype. In another embodiment, the synthetic ITR does not include an AAV-based sequence. In yet another embodiment, the synthetic ITR retains the ITR structure described above, although it has only some or no AAV-derived sequence. In some aspects, the synthetic ITR may preferentially interact with wild-type Rep or Rep of a particular serotype, or in some cases will not be recognized by wild-type Rep and will only be recognized by the mutated Rep.

[00255] One of skill in the art can determine the corresponding sequence in other serotypes using known means. For example, determining whether the change occurs in region A, A', B, B', C, C' or D, and determining the corresponding region in another serotype. ^BLAST® (Basic Local Alignment Search Tool) or other homology alignment programs with default parameters can be used to determine the corresponding sequence. The present invention also provides populations and multiple cccDNA vectors containing mod-ITRs from a combination of different AAV serotypes, that is, one mod-ITR may be derived from one AAV serotype and another mod-ITR may be derived from a different serotype. Without being limited to any theory, in one embodiment, one ITR may be derived from or based on an AAB2 ITR sequence, and the other cDNA vector ITR may be derived from or based on any one or more ITR sequences of AAV serotype 1 (AAV1), AAV serotype 4 ( AAV4), AAV serotype 5 (AAV5), AAV serotype 6 (AAV6), AAV serotype 7 (AAV7), AAV serotype 8 (AAV8), AAV serotype 9 (AAV9), AAV serotype 10 (AAV10), AAV serotype 11 (AAV11 ) or AAV serotype 12 (AAV12).

[00256] Any parvovirus ITR can be used as an ITR or primary ITR for modification. Preferably, the parvovirus is a dependovirus. AAV is more preferable. The serotype selected may be based on the tissue tropism of the serotype. AAB2 has broad tissue tropism, AAB1 predominantly targets neurons and skeletal muscle, and AAV5 predominantly targets neurons, retinal pigment epithelium, and photoreceptors. AAV6 primarily targets skeletal muscle and lungs. AAB8 primarily targets the liver, skeletal muscle, heart, and pancreatic tissue. AAB9 predominantly targets liver, skeletal and lung tissue. In one embodiment, the modified ITR is based on the AAB2 ITR.

[00257] More specifically, the ability of a structural element to operably interact with a particular large Rep protein can be altered by modifying the structural element. For example, the nucleotide sequence of the structural element may be modified compared to the wild-type ITR sequence. In one embodiment, a structural element (e.g., arm A, arm A', arm B, arm B', arm C, arm C', arm D, RBE, RBE', and TRS) of the ITR can be removed and replaced with a wild-type structural element from another parvovirus. For example, the replacement structure may be derived from AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, snake parvovirus (eg, royal python parvovirus), bovine parvovirus, goat parvovirus, avian parvovirus parvovirus, canine parvovirus, equine parvovirus, shrimp parvovirus, porcine parvovirus or insect AAV. For example, the ITR may be an AAB2 ITR, and arm A or A' or the RBE may be replaced by a structural element from AAB5. In another example, the ITR may be an AAB5 ITR, and the C or C' arms, RBE, and TRS may be replaced by a building block from AAB2. In another example, the AAB ITR may be an AAB5 ITR in which arms B and B' are replaced by B and B' of the AAB2 ITR.

[00258] By way of example only, Table 4 sets forth exemplary modifications of at least one nucleotide (e.g., deletion, insertion, and/or substitution) in regions of the modified ITR, where X indicates modification of at least one nucleic acid (e.g., deletion , insertion and/or substitution) in this region relative to the corresponding wild-type ITR. In some embodiments, any modification of at least one nucleotide (e.g., deletion, insertion, and/or substitution) in any of regions C and/or C' and/or B and/or B' preserves three consecutive nucleotides T (t ie TTT) in at least one terminal loop. For example, if the modification results in any of: a single arm ITR (e.g., one arm C-C' or one arm B-B'), or a modified arm C-B' or an arm C'-B, or a two-arm ITR of at least with one truncated arm (e.g., a C-C' truncated arm and/or a B-B' truncated arm), at least one arm or at least one of two ITR arms (where one arm may be truncated) retains three consecutive nucleotides T (ie TTT) in at least one terminal loop. In some embodiments, the C-C' truncated arm and/or the B-B' truncated arm has three consecutive T nucleotides (ie, TTT) in the terminal loop.

[00259] Table 4: Exemplary combinations of modifications to at least one nucleotide (e.g., deletion, insertion, and/or substitution) in various regions or arms B-B' and C-C' of the ITR (X indicates a nucleotide modification, e.g., addition, deletion or substitution of at least one nucleotide in the region).

[00260] In some embodiments, a mod-ITR for use in a cccDNA protein expression vector, FVIII comprises a pair of asymmetric ITRs or a pair of symmetric mod-ITRs as disclosed herein, may contain any of the combinations of modifications presented in Table 4, and also modification of at least one nucleotide in any one or more regions selected from: between A' and C, between C and C', between C' and B, between B and B', and between B' and A. In some embodiments implementation, any modification of at least one nucleotide (eg, deletion, insertion and/or substitution) in regions C or C' or B or B' still retains the terminal loop of the stem-loop structure. In some embodiments, any modification of at least one nucleotide (e.g., deletion, insertion, and/or substitution) between C and C' and/or B and B' preserves three consecutive T nucleotides (i.e., TTT) in at least one end loop. In alternative embodiments, any modification of at least one nucleotide (e.g., deletion, insertion, and/or substitution) between C and C' and/or B and B' preserves three consecutive nucleotides A (i.e., AAA) in at least one end loop. In some embodiments, a modified ITR for use in the present invention may comprise any of the combinations of modifications presented in Table 4, as well as modification of at least one nucleotide (e.g., deletion, insertion, and/or substitution) in any one or more of the regions selected from: A', A and/or D. For example, in some embodiments, a modified ITR for use in the present invention may contain any of the combinations of modifications presented in Table 4, as well as a modification of at least one nucleotide (for example, a deletion , insertion, and/or substitution) in region A. In some embodiments, a modified ITR for use in the present invention may contain any of the combinations of modifications presented in Table 4, as well as modification of at least one nucleotide (e.g., deletion, insertion, and/or or replacement) in area A'. In some embodiments, a modified ITR for use in the present invention may comprise any of the combinations of modifications presented in Table 4, as well as modification of at least one nucleotide (e.g., deletion, insertion, and/or substitution) in the A and/or A' region . In some embodiments, a modified ITR for use in the present invention may contain any of the combinations of modifications presented in Table 4, as well as modification of at least one nucleotide (e.g., deletion, insertion, and/or substitution) in region D.

[00261] In one embodiment, the nucleotide sequence of the building block may be modified (e.g., by modifying 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19 or 20 or more nucleotides or any range thereof) to obtain a modified structural element. In one embodiment, specific modifications to the ITR are provided herein as examples (e.g., SEQ ID NOs: 3, 4, 15-47, 101-116, or 165-187, or shown in FIGS. 7A-7B from PCT/US 2018 /064242, filed December 6, 2018 (e.g., SEQ ID NO 97-98, 101-103, 105-108, 111-112, 117-134, 545-54 in PCT/US 2018/064242)). In some embodiments, the ITR may be modified (e.g., by modifying 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 or more nucleotides or any range thereof). In other embodiments, the ITR may be at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more sequence identity with one of the modified ITRs having SEQ ID NO: 3, 4, 15-47, 101-116 or 165-187, or the RBE-containing region of the A-A' arm and the C-C arms ' and B-B' having SEQ ID NO: 3, 4, 15-47, 101-116 or 165-187, or presented in Tables 2-9 (i.e. SEQ ID NO: 110-112, 115- 190, 200-468) of international application PCT/US 18/49996, which is incorporated herein by reference in its entirety.

[00262] In some embodiments, the modified ITR may, for example, comprise the removal or deletion of all or a portion of an arm A-A', or all or a portion of an arm B-B', or all or a portion of an arm C-C ', or alternatively, deleting 1, 2, 3, 4, 5, 6, 7, 8, 9 or more base pairs forming a stem loop, provided that the terminal loop capping the stem (e.g., one arm) is all still present (for example, see ITR-21 at FIG. 7A from PCT/US 2018/064242, filed December 6, 2018). In some embodiments, the modified ITR may comprise deletion of 1, 2, 3, 4, 5, 6, 7, 8, 9, or more base pairs from the B-B' arm. In some embodiments, the modified ITR may comprise deletion of 1, 2, 3, 4, 5, 6, 7, 8, 9, or more base pairs from the C-C' arm (see, for example, ITR-1 in FIG. 3B or ITR-45 at FIGURE 7A from PCT/US 2018/064242 filed December 6, 2018). In some embodiments, the modified ITR may comprise deleting 1, 2, 3, 4, 5, 6, 7, 8, 9, or more base pairs from the C-C' arm and deleting 1, 2, 3, 4, 5, 6, 7, 8, 9 or more base pairs from arm B-B'. Any combination of base pair deletions is possible, for example, 6 base pairs in the C-C' arm and 2 base pairs in the B-B' arm can be deleted. As an illustrative example, FIG. 3B shows an exemplary modified ITR with at least 7 base pairs removed from each of the C portion and the C' portion, a nucleotide substitution in the loop between the C and C' regions, and a deletion of at least one base pair from each of the B region and the B regions. ' such that the modified ITR contains two arms, of which at least one arm (eg, C-C') is truncated. In some embodiments, the modified ITR also contains a deletion of at least one base pair from each of the B region and the B' regions such that the B-B' arm is also truncated relative to the WT ITR.

[00263] In some embodiments, the modified ITR may have from 1 to 50 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50) nucleotide deletions relative to the full-length wild-type ITR sequence. In some embodiments, the modified ITR may have 1 to 30 nucleotide deletions relative to the full-length WT ITR sequence. In some embodiments, the modified ITR has 2 to 20 nucleotide deletions relative to the full-length wild-type ITR sequence.

[00264] In some embodiments, the modified ITR does not contain any nucleotide deletions in the RBE-containing portion of the A or A' regions so as not to interfere with DNA replication (eg, binding of the RBE by the Rep protein or formation of a single-strand break at the end resolution site). In some embodiments, a modified ITR provided for use herein has one or more deletions in the B, B', C, and/or C region as described herein.

[00265] In some embodiments, a cccDNA FVIII protein expression vector comprising a pair of symmetric ITRs or a pair of asymmetric ITRs comprises a regulatory switch as disclosed herein and at least one selected modified ITR having a nucleotide sequence selected from any from the group consisting of: SEQ ID NO: 3, 4, 15-47, 101-116 or 165-187.

[00266] According to another embodiment, the structure of the structural element may be modified. For example, a structural element has a change in stem height and/or number of nucleotides in a loop. For example, the stem height may be about 2, 3, 4, 5, 6, 7, 8 or 9 nucleotides or more, or any value within that range. In one embodiment, the stem may be from about 5 nucleotides to about 9 nucleotides in height and operably interacts with Rep. In another embodiment, the stem may be approximately 7 nucleotides in height and operably interacts with Rep. In another example, the loop may be 3, 4, 5, 6, 7, 8, 9 or 10 nucleotides or more, or any value within that range.

[00267] In another embodiment, the number of GAGY binding sites or GAGY-related binding sites in an RBE or extended RBE may be increased or decreased. In one example, an RBE or extended RBE may contain 1, 2, 3, 4, 5 or 6 or more GAGY binding sites or any value within the specified range. Each GAGY binding site may independently be the exact GAGY sequence or a sequence similar to GAGY, provided that the sequence is sufficient for binding of the Rep protein.

[00268] In another embodiment, the distance between two elements (such as, but not limited to, an RBE and a hairpin) can be changed (eg, increased or decreased) to change the functional interaction with the large Rep protein. For example, the distance may be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 nucleotides or more or any value within the specified range.

[00269] The cDNA FVIII protein expression vector described herein may include an ITR structure that is modified from the wild-type AAB2 ITR structure disclosed herein but still retains the functional portion of RBE, TRS, and RBE'. FIG. 2A and FIG. 2B shows one possible mechanism for the TRS site to function within the wild-type ITR portion of a ccDNA vector for FVIII protein expression. In some embodiments, the cccDNA vector for expression of the FVIII protein contains one or more functional ITR polynucleotide sequences that contain a Rep binding site (RBS; 5'-GCGCGCTCGCTCGCTC-3' (SEQ ID NO: 60) for AAB2) and an end resolution site ( TRS;5'-AGTT (SEQ ID NO: 62)). In some embodiments, at least one ITR (wt or modified ITR) is functional. In alternative embodiments, when the cccDNA vector for FVIII protein expression contains two modified ITRs that are different or asymmetrical with respect to each other, at least one modified ITR is functional and at least one modified ITR is non-functional.

[00270] In some embodiments, the modified ITR (eg, left or right ITR) of a cccDNA vector for FVIII protein expression, as described herein, has modifications in a loop arm, truncated arm, or spacer. Exemplary ITR sequences having modifications in the loop arm, truncated arm, or spacer are listed in Table 2 (ie, SEQ ID NO: 135-190, 200-233); Table 3 (eg SEQ ID NO: 234-263); Table 4 (eg SEQ ID NO: 264-293); Table 5 (eg, SEQ ID NO: 294-318 herein); Table 6 (eg SEQ ID NO: 319-468); and Table 7-9 (for example, SEQ ID NO: 101-110, 111-112, 115-134) or in Table 10A or 10B (for example, SEQ ID NO: 9, 100, 469-483, 484-499) international application PCT/US 18/49996, which is incorporated herein by reference in its entirety.

[00271] In some embodiments, the modified ITR for use in a cDNA FVIII protein expression vector containing an asymmetric ITR pair or a symmetric mod-ITR pair is selected from any or a combination of ITRs listed in Tables 2, 3, 4, 5. 6, 7, 8, 9 and 10A-10B of international application PCT/US 18/49996, which is incorporated herein by reference in its entirety.

[00272] Additional exemplary modified ITRs for use in a cccDNA FVIII protein expression vector containing an asymmetric ITR pair or a symmetric mod-ITR pair in each of the above classes are presented in Tables 5A and 5B. The predicted secondary structure of the right modified ITRs in Table 5A is shown in FIG. 7A of international application PCT/US 2018/064242, filed December 6, 2018, and the predicted secondary structure of the left modified ITRs in Table 5B is shown in FIG. 7B International Application PCT/US 2018/064242, filed December 6, 2018, which is incorporated herein by reference in its entirety.

[00273] Table 5A and Table 5B show exemplary right and left modified ITRs.

[00274] Table 5A: Example Modified Right ITRs. These exemplary modified right-hand ITRs may comprise the RBE GCGCGCTCGCTCGCTC-3' (SEQ ID NO: 60), the ACTGAGGC spacer (SEQ ID NO: 69), the complementary spacer sequence GCCTCAGT (SEQ ID NO: 70), and the RBE' (i.e., complementary RBE sequence) GAGCGAGCGAGCGCGC (SEQ ID NO: 71).

[00275] TABLE 5B: Example Modified Left ITRs. These exemplary modified left ITRs may comprise the RBE GCGCGCTCGCTCGCTC-3' (SEQ ID NO: 60), the spacer ACTGAGGC (SEQ ID NO: 69), the complementary spacer sequence GCCTCAGT (SEQ ID NO: 70), and the complementary sequence RBE (i.e. RBE) GAGCGAGCGAGCGCGC (SEQ ID NO: 71).

[00276] In one embodiment, the cDNA vector for expression of the FVIII protein contains, in the 5' to 3' direction: the first inverted terminal repeat (ITR) of an adeno-associated virus (AAV), a nucleotide sequence of interest (for example, an expression cassette described herein) and a second ITR of AAB, wherein said first ITR (5'-ITR) and second ITR (3'-ITR) are asymmetric with respect to each other, i.e. they have different three-dimensional spatial configurations in relation to each other. As an exemplary embodiment, the first ITR may be a wild-type ITR and the second ITR may be a mutated or modified ITR, or conversely, the first ITR may be a mutated or modified ITR and the second ITR may be a wild-type ITR. In some embodiments, the first ITR and the second ITR are both mod-ITRs, but have different sequences or different modifications and thus are not the same modified ITRs and have different three-dimensional spatial configurations. In other words, a cccDNA vector with asymmetric ITRs contains ITRs in which any changes in one ITR relative to the WT-ITR are not reflected in the other ITR; or, alternatively, if the asymmetric ITRs have a pair of modified asymmetric ITRs, they may have a different sequence and a different three-dimensional shape in relation to each other. Exemplary asymmetric ITRs in the cDNA vector for expression of the FVIII protein and for use in the preparation of the cDNA plasmid are presented in Tables 5A and 5B.

[00277] In an alternative embodiment, the cccDNA vector for expressing the FVIII protein contains two symmetrical mod-ITRs, that is, both ITRs have the same sequence but are inversely complementary to each other. In some embodiments, a pair of symmetric mod-ITRs comprises at least one or any combination of deletions, insertions, or substitutions relative to a wild-type ITR sequence from the same AAV serotype. Additions, deletions, or substitutions in symmetrical ITRs are the same but inversely complementary to each other. For example, an insertion of 3 nucleotides in the C 5' ITR region will be reflected in the insertion of 3 reverse complementary nucleotides in the corresponding region in the C' 3' ITR region. For purposes of illustration only, if the addition is an AACG at the 5' ITR, the addition is a CGTT at the 3' ITR at the corresponding site. For example, if the sense strand of the 5' ITR is ATCGATCG with the addition of AACG between G and A, this gives the sequence ATCGAACGATCG (SEQ ID NO: 51). The corresponding sense strand of the 3' ITR is CGATCGAT (reverse complementary sequence ATCGATCG) with the addition of CGTT (i.e. reverse complementary sequence AACG) between T and C, giving the sequence CGATCGTTCGAT (SEQ ID NO: 49) (reverse complementary sequence ATCGAACGATCG) (SEQ ID NO: 51).

[00278] In alternative embodiments, a pair of modified ITRs is substantially symmetrical as defined herein, that is, a pair of modified ITRs may have a different sequence but have a corresponding or identical symmetrical three-dimensional shape. For example, one modified ITR may be from one serotype and another modified ITR may be from a different serotype, but they have the same mutation (eg, insertion, deletion, or nucleotide substitution) in the same region. In other words, for illustrative purposes only, a 5'mod-ITR may be derived from AAB2 and have a deletion in the C region, and a 3' mod-ITR may be derived from AAB5 and have a corresponding deletion in the C' region, and provided that 5' mod-ITR and 3'mod-ITR have the same or symmetrical three-dimensional spatial organization and are intended for use in the present invention as a pair of modified ITRs.

[00279] In some embodiments, a pair of substantially symmetric mod-ITRs has the same A, C-C', and B-B' loops in three-dimensional space, for example, if a modified ITR in a pair of substantially symmetric mod-ITRs has a deletion of arm C- C', then the cognate mod-ITR has a corresponding deletion of the C-C' loop, and also has a similar three-dimensional structure of the remaining loops A and B-B' of the same shape in geometric space with its cognate mod-ITR. By way of example only, substantially symmetrical ITRs may have a symmetrical spatial organization such that their structure has the same shape in geometric space. This may occur, for example, when a GC pair is modified, for example, into a CG pair or vice versa, or when an A-T pair is modified into a T-A pair, or vice versa. Therefore, using the above illustrative example of a modified 5' ITR as ATCGAACGATCG (SEQ ID NO: 51) and a modified 3' ITR as CGATCGTTCGAT (SEQ ID NO: 49) (i.e., the reverse complementary sequence to ATCGAACGATCG (SEQ ID NO: 51) )), these modified ITRs would still be symmetric if, for example, the 5' ITR had the sequence ATCGAAC C ATCG (SEQ ID NO: 50), where the G in addition is modified to C, and the substantially symmetric 3' ITR has sequence CGATCGTTCGAT (SEQ ID NO: 49), without the corresponding T modification in addition to a. In some embodiments, such a pair of modified ITRs is substantially symmetrical because the pair of modified ITRs has symmetrical stereochemistry.

[00280] Table 6 shows exemplary pairs of symmetrical modified ITRs (ie, left-handed modified ITR and symmetrical right-handed modified ITR) for use in a cccDNA vector for expression of the FVIII protein. The bolded (red) sequence region identifies a portion of the ITR sequences (ie, loop sequences A-A', C-C', and B-B') also shown in FIG. 31A-46B. These exemplary modified ITRs may comprise the RBE GCGCGCTCGCTCGCTC-3' (SEQ ID NO: 60), the spacer ACTGAGGC (SEQ ID NO: 69), the complementary sequence of the spacer GCCTCAGT (SEQ ID NO: 70) and the RBE' (i.e., the complementary sequence RBE) GAGCGAGCGAGCGCGC (SEQ ID NO: 71).

[00281] In some embodiments, a cccDNA FVIII protein expression vector containing a pair of asymmetric ITRs may contain an ITR with a modification corresponding to any of the modifications in the ITR sequences or partial ITR sequences presented in any one or more of Tables 5A-5B in this document, or the sequences shown in FIGS. 7A-7B of international application PCT/US 2018/064242, filed December 6, 2018, which is incorporated herein in its entirety, or disclosed in Tables 2, 3, 4, 5, 6, 7, 8, 9 or 10A-10B of the international Application PCT/US 18/49996, filed September 7, 2018, which is incorporated herein by reference in its entirety.

V. Exemplary cDNA Vectors

[00282] As described above, the present disclosure relates to recombinant cccDNA expression vectors and cccDNA vectors that encode an FVIII protein containing any of: a pair of asymmetric ITRs, a pair of symmetric ITRs, or a pair of substantially symmetric ITRs as described above. In certain embodiments, the present disclosure provides recombinant cDNA FVIII protein expression vectors having ITR and transgene flanking sequences, wherein said ITR sequences are asymmetric, symmetric, or substantially symmetrical with respect to each other as defined herein, and the cccDNA further comprising a nucleotide sequence of interest (eg, an expression cassette containing a transgene nucleic acid) located between flanking ITRs, wherein said nucleic acid molecule lacks sequences encoding a viral capsid protein.

[00283] The cccDNA expression vector for expression of the FVIII protein can be any cccDNA vector that can be conveniently subjected to recombinant DNA techniques, including the nucleotide sequence(s) described herein, provided that at least one ITR is changed. The cDNA vectors for expression of the FVIII protein of the present disclosure are compatible with the host cell into which the cDNA vector is to be introduced. In certain embodiments, the cDNA vectors may be linear. In certain embodiments, cDNA vectors may exist as extrachromosomal entities. In certain embodiments, the cccDNA vectors of the present disclosure may contain element(s) that allow integration of a donor sequence into the genome of a host cell. As used herein, “transgene” and “heterogeneous nucleotide sequence” are synonymous and encode the FVIII protein as described herein.

[00284] In FIG. 1A-1G show diagrams of the functional components of two non-limiting plasmids that can be used to generate a cccDNA vector for expression of the FVIII protein. FIG. 1A, 1B, 1D, 1F show the construction of cccDNA vectors or corresponding ccDNA plasmid sequences for expression of the FVIII protein. CccDNA vectors do not have capsids and can be derived from a plasmid encoding, in this order: a first ITR, an expressed transgene cassette, and a second ITR, wherein the sequences of the first and second ITR are asymmetric, symmetrical, or substantially symmetrical to each other, as defined in this document. CccDNA vectors for FVIII protein expression do not have capsids and can be derived from a plasmid encoding, in this order: a first ITR, the transgene (protein or nucleic acid) to be expressed, and a second ITR, wherein the sequences of the first and second ITRs are asymmetric, symmetrical, or substantially symmetrical with respect to each other as defined herein. In some embodiments, the expressed transgene cassette includes, as appropriate, an enhancer/promoter, one or more homology arms, a donor sequence, a post-transcriptional regulatory element (e.g., WPRE, e.g., SEQ ID NO: 67), and a polyadenylation and termination signal (e.g. , BGH poly(A), for example, SEQ ID NO: 68).

[00285] FIG. 5 depicts a gel confirming the production of cccDNA from several plasmid constructs using the method described in the Examples. The cctDNA vector is confirmed by the characteristic banding profile in the gel, as discussed in relation to FIG. 4A above and in the Examples.

A. Regulatory elements

[00286] The cDNA FVIII protein expression vectors described herein containing an asymmetric ITR pair or a symmetric ITR pair as defined herein may further contain a particular combination of cis-regulatory elements. Cis-regulatory elements include, but are not limited to, a promoter, a riboswitch, an insulator, a mir-regulated element, a post-transcriptional regulatory element, a tissue- and cell type-specific promoter, and an enhancer. In some embodiments, the ITR may act as a promoter of a transgene, such as the FVIII protein. In some embodiments, the cccDNA FVIII protein expression vector described herein includes additional components for regulating transgene expression, such as regulatory switches described herein for regulating transgene expression or a kill switch that can kill the cell containing the cccDNA -vector encoding the FVIII protein. Regulatory elements, including regulatory switches, that can be used in the present invention are discussed in more detail in international application PCT/US 18/49996, which is incorporated herein by reference in its entirety.

[00287] In embodiments, the second nucleotide sequence includes a regulatory sequence and a nucleotide sequence encoding a nuclease. In certain embodiments, the gene regulatory sequence is operably linked to a nucleotide sequence encoding a nuclease. In certain embodiments, the regulatory sequence is useful for controlling the expression of a nuclease in a host cell. In certain embodiments, the regulatory sequence includes a suitable promoter sequence capable of directing transcription of a gene operably linked to the promoter sequence, such as a nucleotide sequence encoding a nuclease(s) of the present disclosure. In certain embodiments, the second nucleotide sequence includes an intronic sequence associated with the 5' end of the nucleotide sequence encoding the nuclease. In certain embodiments, the enhancer sequence is provided in the 5-direction relative to the promoter to improve promoter efficiency. In certain embodiments, the regulatory sequence includes an enhancer and a promoter, wherein the second nucleotide sequence includes an intronic sequence upstream of a nucleotide sequence encoding a nuclease, wherein the intron includes one or more nuclease cleavage sites, and wherein the promoter is operably linked to the nucleotide sequence, encoding a nuclease.

[00288] CCDNA vectors for FVIII protein expression, produced synthetically or using a cell-based production method as described herein in the Examples, may further contain a specific combination of cis-regulatory elements, such as a WHP post-transcriptional regulatory element (WPRE) (eg, SEQ ID NO: 67) and BGH poly(A) (SEQ ID NO: 68). Suitable expression cassettes for use in expression constructs do not have the packaging limitation imposed by the viral capsid.

(i) Promoters:

[00289] One of ordinary skill in the art will appreciate that the promoters used in cDNA vectors for expression of the FVIII protein, as described herein, must be tailored according to the particular sequences on which they exert promoter action. In some embodiments, the promoter is any promoter or promoter sequence described in International Application No. PCT/US 2020/021328, filed March 6, 2020, which is incorporated herein by reference in its entirety.

[00290] In some embodiments, the promoter is a VandenDriessche (VD) promoter. In accordance with some embodiments, the VD promoter comprises SEQ ID NO: 191, shown below:

[00291] In accordance with some embodiments, the promoter contains a nucleic acid sequence that is at least about 85% identical to SEQ ID NO: 191. In accordance with some embodiments, the promoter contains a nucleic acid sequence that is at least about 90% identical to SEQ ID NO: 191. is identical to SEQ ID NO: 191. In accordance with some embodiments, the promoter contains a nucleic acid sequence that is at least about 95% identical to SEQ ID NO: 191. In accordance with some embodiments, the promoter contains a nucleic acid sequence that is at least is about 96% identical to SEQ ID NO: 191. In accordance with some embodiments, the promoter contains a nucleic acid sequence that is at least about 97% identical to SEQ ID NO: 191. In accordance with some embodiments, the promoter contains a nucleic acid sequence that which is at least about 98% identical to SEQ ID NO: 191. In accordance with some embodiments, the promoter comprises a nucleic acid sequence that is at least about 99% identical to SEQ ID NO: 191. In accordance with some embodiments, the promoter consists from the nucleic acid sequence SEQ ID NO: 191.

[00292] The cDNA vector expression cassettes for FVIII protein expression may include a promoter that can influence overall expression levels as well as cell specificity. In the case of transgene expression, for example FVIII protein expression, they may include a highly active immediate early promoter of viral origin. Expression cassettes may contain tissue-specific eukaryotic promoters to restrict transgene expression to specific cell types and reduce toxic effects and immune responses caused by unregulated ectopic expression. In some embodiments, the expression cassette may comprise a promoter or a synthetic regulatory element, such as a CAG promoter (SEQ ID NO: 72). The CAG promoter contains (i) the cytomegalovirus (CMV) early enhancer element, (ii) the promoter, first exon, and first intron of the chicken beta-actin gene, and (iii) the splice acceptor of the rabbit beta-globin gene. Alternatively, the expression cassette may comprise an alpha-1 antitrypsin (AAT) promoter (SEQ ID NO: 73 or SEQ ID NO: 74), a liver-specific (LP1) promoter (SEQ ID NO: 75 or SEQ ID NO: 76 ) or human elongation factor-1-alpha (EF1a) promoter (e.g., SEQ ID NO: 77 or SEQ ID NO: 78). In some embodiments, the expression cassette includes one or more constitutive promoters, e.g., a Rous sarcoma virus (RSV) retroviral LTR promoter (optionally with an RSV enhancer) or a cytomegalovirus (CMV) immediate early promoter (optionally with a CMV enhancer, e.g., SEQ ID NO : 79). Alternatively, an inducible promoter, a transgene-native promoter, a tissue-specific promoter, or various promoters known in the art may be used.

[00293] Suitable promoters, including those described herein, may be derived from viruses and may thus be referred to as viral promoters, or they may be derived from any organism, including prokaryotic or eukaryotic organisms. Suitable promoters can be used to drive expression by any RNA polymerase (eg, pol I, pol II, pol III). Exemplary promoters include, but are not limited to, the SV40 early promoter, the mouse mammary tumor virus long terminal repeat (LTR) promoter; adenovirus large late promoter (Ad MLP); herpes simplex virus (HSV) promoter, cytomegalovirus (CMV) promoter such as the CMV immediate early (CMVIE) promoter region, Rous sarcoma virus (RSV) promoter, human small nuclear RNA U6 promoter (U6, e.g., SEQ ID NO: 80) (Miyagishi et al., Nature Biotechnology 20, 497-500 (2002)), improved U6 promoter (e.g., Xia et al., Nucleic Acids Res. 2003 Sep. 1; 31(17)), human H1 promoter (H1) (eg, SEQ ID NO: 81 or SEQ ID NO: 155), CAG promoter, human alpha-1 antitrypsin (HAAT) promoter (eg, SEQ ID NO: 82), etc. In certain embodiments, said promoters are modified at their intron-containing 3' end to include one or more nuclease cleavage sites. In certain embodiments, the DNA containing the nuclease cleavage site(s) is foreign to the promoter DNA.

[00294] In one embodiment, the promoter used is the native promoter of a gene encoding a therapeutic protein. The promoters and other regulatory sequences of the corresponding genes encoding therapeutic proteins are known and have been characterized. The promoter region used may further include one or more additional regulatory sequences (eg, native), such as enhancers (eg, SEQ ID NO: 79 and SEQ ID NO: 83), including the SV40 enhancer (SEQ ID NO: 126).

[00295] In some embodiments, the promoter may also be a promoter from a human gene, such as human ubiquitin C (hUbC), human actin, human myosin, human hemoglobin, human muscle creatine, or human metallothionein. The promoter may also be a tissue-specific promoter, such as a liver-specific promoter, for example human alpha-1 antitrypsin (HAAT), natural or synthetic. In one embodiment, delivery to the liver can be achieved using specific targeting of endogenous ApoE by a cccDNA vector-containing composition that is directed to hepatocytes by a low-density lipoprotein (LDL) receptor present on the surface of the hepatocyte.

[00296] Non-limiting examples of promoters suitable for use in accordance with the present invention include any of the promoters described herein or any of the following: CAG promoter, for example, (SEQ ID NO: 72), HAAT promoter (SEQ ID NO : 82), the human EF1-α promoter (SEQ ID NO: 77) or a fragment of the EF1a promoter (SEQ ID NO: 78), the IE2 promoter (e.g., SEQ ID NO: 84) and the rat EF1-α promoter (SEQ ID NO: 85), the mEF1 promoter (SEQ ID NO: 59) or a fragment of the 1E1 promoter (SEQ ID NO: 125).

(ii) Enhancers

[00297] In some embodiments, the cccDNA expressing FVIII contains one or more enhancers. In some embodiments, the enhancer sequence is located 5' to the promoter sequence. In some embodiments, the enhancer sequence is located 3' to the promoter sequence. In some embodiments, an enhancer is any enhancer or enhancer sequence described in International Application No. PCT/US 2020/021328, filed March 6, 2020, which is incorporated herein by reference in its entirety.

(iii) 5'UTR sequences and intronic sequences

[00298] In some embodiments, the cccDNA vector contains a 5′-UTR sequence and/or an intronic sequence that is located in the 3′ direction of the 5′-ITR sequence. In some embodiments, the 5'UTR is located upstream of the transgene, for example, the FVIII protein coding sequence. Exemplary 5'UTR sequences are listed in International Application No. PCT/US 2020/021328, for example in Table 9A, which is incorporated herein by reference in its entirety.

(iv) 3'-UTR sequences

[00299] In some embodiments, the cccDNA vector contains a 3'-UTR sequence that is located in the 5' direction relative to the 3'-ITR sequence. In some embodiments, the 3'UTR is located upstream of a transgene, for example, a sequence encoding an FVIII protein. Exemplary 3'UTR sequences are listed in International Application No. PCT/US 2020/021328, for example in Table 9B, which is incorporated herein by reference in its entirety.

Polyadenylation sequences:

[00300] A sequence encoding a polyadenylation sequence may be included in a cccDNA vector for expression of the FVIII protein to stabilize the mRNA expressed from the ccDNA vector and to promote nuclear export and translation. In one embodiment, the cDNA vector does not include a polyadenylation sequence. In other embodiments, the cccDNA vector for expression of the FVIII protein includes at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 40, at least 45, at least 50 or more adenine dinucleotides. In some embodiments, the polyadenylation sequence is about 43 nucleotides, about 40-50 nucleotides, about 40-55 nucleotides, about 45-50 nucleotides, about 35-50 nucleotides, or any range therebetween.

[00301] Expression cassettes may include any polyadenylation sequence known in the art, or a variant thereof. In some embodiments, the polyadenylation sequence (poly(A)) is selected from any of the sequences listed in International Application No. PCT/US 2020/021328, for example, Table 10, which is incorporated herein by reference in its entirety. Other poly(A) sequences commonly known in the art may also be used, such as, but not limited to, natural sequence isolated from bovine BGHpA (e.g., SEQ ID NO: 68) or SV40pA virus (e.g., SEQ ID NO: 68) NO: 86) or a synthetic sequence (SEQ ID NO: 87). Some expression cassettes may also include an SV40 5' late poly(A) signal enhancer (USE) sequence. In some embodiments, the USE sequence can be used in combination with SV40pA or a heterologous poly(A) signal. The poly(A) sequences are located in the 3-direction relative to the transgene encoding the FVIII protein.

Expression cassettes may also include a post-transcriptional element to enhance transgene expression. In some embodiments, a woodchuck hepatitis virus post-transcriptional regulatory element (WHP) (WPRE) (eg, SEQ ID NO: 67) is used to enhance transgene expression. Other post-transcriptional processing elements may be used, such as a post-transcriptional element from the herpes simplex virus or hepatitis B virus (HBV) thymidine kinase gene. Secretory sequences, such as VH-02 and VK-A26 sequences, such as SEQ ID NO: 88 and SEQ ID NO: 89, may be associated with the transgenes.

(vi) Nuclear localization sequences

[00302] In some embodiments, the cccDNA vector for expressing the FVIII protein contains one or more nuclear localization sequences (NLS), such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more NLS. In some embodiments, one or more NLSs are located at or near the amino terminus, at or near the carboxy terminus, or a combination thereof (e.g., one or more NLSs at the amino terminus and/or one or more NLSs at the carboxy-terminal). If more than one NLS is present, each may be selected independently of the others such that one NLS will be present in more than one copy and/or in combination with one or more other NLSs present in one or more copies. Non-limiting examples of NLS are given in Table 7.

B. Additional components of cDNA vectors

[00303] CCDNA vectors for FVIII protein expression according to the present disclosure may contain nucleotides that encode other components for gene expression. For example, to select targeting events for specific genes, a protective shRNA can be engineered into a microRNA and inserted into a recombinant cccDNA vector designed for site-specific integration at a highly active locus, such as the albumin locus. Such embodiments may provide a system for selecting and propagating genetically modified hepatocytes in vivo in any genetic environment, for example, as described in Nygaard et al., A universal system to select gene-modified hepatocytes in vivo, Gene Therapy, June 8, 2016. cctDNA -vectors according to the present disclosure may contain one or more selectable markers that allow selection of transformed, transfected, transduced or the like cells. A selectable marker is a gene whose product provides biocidal or viral resistance, resistance to heavy metals, prototrophy to auxotrophs, NeoR, etc. In certain embodiments, positive selection markers, such as NeoR, are included in the donor sequences. Negative selection markers may be included after the donor sequences, for example, an HSV-tk nucleic acid sequence encoding a negative selection marker may be included in the nucleic acid construct after the donor sequence.

C. Regulatory switches

[00304] A molecular regulatory switch is a switch that generates a measurable change of state in response to a signal. Such regulatory switches can be suitably combined with the cccDNA FVIII protein expression vectors described herein to control the output of FVIII protein expression from the cccDNA vector. In some embodiments, the cccDNA vector for expression of the FVIII protein contains a regulatory switch that serves to fine-tune the expression of the FVIII protein. For example, it may serve as a biocontainment function for the cDNA vector. In some embodiments, the switch is a two-position (“ON/OFF”) switch that is configured to start or stop (ie, stop) expression of the FVIII protein in the cccDNA vector in a controlled and regulated manner. In some embodiments, the switch may include a "kill switch" that may instruct a cell containing the cccDNA vector to initiate programmed cell death upon activation of the switch. Exemplary regulatory switches provided for use in a cccDNA vector for expression of the FVIII protein can be used to regulate transgene expression and are discussed in more detail in international application PCT/US 18/49996, which is incorporated herein by reference in its entirety.

(i) Binary control switches

[00305] In some embodiments, the cccDNA vector for expression of the FVIII protein contains a regulatory switch that can serve to controllably modulate the expression of the FVIII protein. For example, an expression cassette located between the ITR of a cccDNA vector may further comprise a regulatory region, for example, a promoter, a cis element, a repressor, an enhancer, etc., which is operably linked to a nucleic acid sequence encoding the FVIII protein, wherein said regulatory region the region is regulated by one or more cofactors or exogenous agents. As a non-limiting example, regulatory regions can be modulated by small molecule switches or inducible or repressible promoters. Non-limiting examples of inducible promoters are hormone inducible or metal inducible promoters. Other exemplary inducible promoter/enhancer elements include, but are not limited to, the RU486 inducible promoter, the ecdysone inducible promoter, the rapamycin inducible promoter, and the metallothionein promoter.

(ii) Small molecule regulatory switches

[00306] Various small molecule regulatory switches known in the art are known in the art and can be combined with the cccDNA FVIII protein expression vectors disclosed herein to produce a regulatory switch-controlled cccDNA vector. In some embodiments, the regulatory switch may be selected from any one or combination of the following: an orthogonal ligand/nuclear receptor pair, such as a retinoid receptor variant/LG335 and GRQCIMFI, together with an artificial promoter controlling expression of an operably linked transgene, as disclosed in Taylor et al. BMC Biotechnology 10 (2010): 15; engineered steroid receptors, such as a modified C-terminal truncated progesterone receptor that cannot bind progesterone but binds RU486 (mifepristone) (US Pat. No. 5,364,791); the Drosophila ecdysone receptor and its ecdysteroid ligands (Saez, et al., PNAS, 97(26)(2000), 14512-14517); or a switch controlled by the antibiotic trimethoprim (TMP) as described in Sando R 3 ^rd ; Nat Methods. 2013, 10(11): 1085-8. In some embodiments, the regulatory switch for controlling the transgene or expressed by the cccDNA vector is a prodrug activation switch, such as disclosed in US Pat. Nos. 8,771,679 and 6,339,070.

(iii) Control switches “with access code”

[00307] In some embodiments, the control switch may be a "passcode switch" or a "passcode circuit." Switches with an access code allow you to fine-tune the control of transgene expression from a cccDNA vector when specific conditions arise, i.e. For expression and/or repression of a transgene to occur, a combination of conditions must be present. For example, at least conditions A and B must occur for transgene expression to occur. The access code regulatory switch may be any number of conditions, such as at least 2 or at least 3 or at least 4 or at least 5, or at least 6, or at least 7 or more conditions, the presence of which is necessary for the expression of the transgene. In some embodiments, at least 2 conditions must occur (eg, conditions A, B), and in some embodiments, at least 3 conditions must occur (eg, A, B, and C or A, B, and D). By way of example only, the expression of a gene with cccDNA containing a regulatory switch with access code "ABC" requires the presence of conditions A, B and C. Conditions A, B and C may be as follows; condition A represents the presence of a condition or disease, condition B represents a hormonal response, and condition C represents a response to transgene expression. For example, if a transgene edits a defective EPO gene, then condition A is the presence of chronic kidney disease (CKD), condition B is the presence of hypoxic conditions in the subject's kidneys, condition C is the presence of impaired recruitment of erythropoietin-producing cells (EPC) to the kidneys; or, alternatively, impaired HIF-2 activation. When oxygen levels rise or a target EPO level is reached, the transgene turns off again until 3 conditions occur that turn it back on.

[00308] In some embodiments, a passcode regulatory switch or "passcode circuit" provided for use in a cccDNA vector comprises hybrid transcription factors (TFs) to expand the range and level of complexity of environmental signals used to determine biocontainment conditions . Unlike a deadman switch, which triggers cell death when a predetermined condition is met, a passcode circuit allows for cell survival or transgene expression given a specific passcode, and can be easily reprogrammed to allow expression transgene and/or cell survival only in the presence of a predetermined environmental condition or access code.

[00309] Any and all combinations of regulatory switches disclosed herein, e.g., small molecule switches, nucleic acid-based switches, small molecule-nucleic acid hybrid switches, post-transcriptional transgene regulatory switches, post-translational regulation, radiation-controlled switches, hypoxia-mediated switches switches and other control switches known to those skilled in the art disclosed herein may be used in a passcode control switch as disclosed herein. Regulatory switches provided for the application are also discussed in the review article by Kis et al., JR Soc Interface. 12: 20141000 (2015) and summarized in Table 1 of the Kis paper. In some embodiments, the control switch for use in the passcode system may be selected from any of the switches or combination thereof disclosed in Table 11 of International Patent Application PCT/US18/49996, which is incorporated herein by reference in its entirety.

(iv) Nucleic acid-based regulatory switches to control transgene expression

[00310] In some embodiments, the regulatory switch for controlling expression of the cccDNA FVIII protein is based on a nucleic acid-based control mechanism. Exemplary nucleic acid-based control mechanisms are known in the art and are contemplated for use. For example, such mechanisms include riboswitches such as those disclosed, for example, in US2009/0305253, US2008/0269258, US2017/0204477, WO2018026762A1, US patent 9222093 and European patent application EP288071, and disclosed in the review article by Villa JK et al. Microbiol Spectr. May 2018; 6(3). Also included are metabolite-sensitive transcriptional biosensors such as those disclosed in WO2018/075486 and WO2017/147585. Other mechanisms known in the art for use include transgene silencing using siRNA or RNAi molecules (eg, miR, shRNA). For example, the cccDNA vector may contain a regulatory switch encoding an RNAi molecule that is complementary to two parts of the transgene expressed by the cccDNA vector. When such RNAi is expressed, even if a transgene (for example, FVIII protein) is expressed by a cccDNA vector, it will be suppressed by a complementary RNAi molecule, and if RNAi is not expressed, when a transgene (for example, FVIII protein) is expressed by a cccDNA vector, the transgene will be suppressed does not occur under the influence of RNAi.

[00311] In some embodiments, the regulatory switch is a tissue-specific self-inactivating regulatory switch, such as disclosed in US2002/0022018, whereby the regulatory switch intentionally turns off a transgene (e.g., FVIII protein) at a site where expression of the transgene would otherwise be detrimental . In some embodiments, the regulatory switch is a recombinase-reversible gene expression system, such as those disclosed in US2014/0127162 and US Pat. No. 8,324,436.

(v) Post-transcriptional and post-translational regulatory switches.

[00312] In some embodiments, the regulatory switch for controlling expression of the FVIII protein by the cDNA vector is a post-transcriptional modification system. For example, such a regulatory switch may be a tetracycline- or theophylline-sensitive aptazyme riboswitch disclosed in US2018/0119156, GB201107768, WO2001/064956A3, EP 2707487 and Beilstein et al., ACS Synth. Biol., 2015, 4 (5), pp 526-534; Zhong et at., Elife. 2016 Nov 2;5. pii: e18858. In some embodiments, one of ordinary skill in the art can encode both the transgene and an inhibitory siRNA that contains a ligand-sensitive aptamer (negative switch), resulting in a positive ligand-sensitive switch.

(vi) Other exemplary control switches

[00313] Any known regulatory switch can be used in a cccDNA vector to control expression of the FVIII protein by the cccDNA vector, including switches triggered by environmental changes. Additional examples include, but are not limited to those listed; BOC method according to Suzuki et al., Scientific Reports 8; 10051 (2018); genetic code expansion and non-physiological amino acid; radiation controlled or ultrasonic controlled positive/negative (on/off) switches (see, for example, Scott S. et at, Gene Ther. 2000 Jul; 7(13): 1121-5; US patents 5612318; 5571797; 5770581; 5817636 ; and WO 1999/025385 Al. In some embodiments, the regulatory switch is controlled by an implantable system, for example, disclosed in US Pat. No. 7,840,263; US2007/0190028A1, in which gene expression is controlled by one or more forms of energy, including electromagnetic energy, that activates promoters that functionally associated with the transgene in the cDNA vector.

[00314] In some embodiments, the regulatory switch provided for use in the cccDNA vector is a hypoxia-mediated or stress-activated switch, such as those disclosed in WO1999060142A2, US Pat. No. 5,834,306; 6218179; 6709858; US2015/0322410; Greco et al., (2004) Targeted Cancer Therapies 9, S368, as well as FROG, TOAD, and NRSE elements and conditionally inducible suppressive elements, including hypoxia response elements (HRE), inflammatory response elements (IRE), and shear stress-activated elements (SSAE), for example, as disclosed in US Pat. No. 9,394,526. Such an embodiment can be used to “turn on” expression of a transgene from a cccDNA vector after ischemia or in ischemic tissues and/or tumors.

(vii) "Emergency switches"

[00315] Other embodiments described herein relate to the cDNA FVIII protein expression vector described herein comprising a kill switch. The "kill switch" disclosed herein allows the cell containing the specified cccDNA vector to be destroyed or subjected to programmed cell death as a method of permanently removing the introduced cccDNA vector from the subject's system. One of ordinary skill in the art will appreciate that the use of "kill switches" in cccDNA vectors for FVIII protein expression will typically involve targeting the cccDNA vector to a limited number of cells that the subject can tolerate losing, or to a cell type apoptosis of which is desired (for example, on cancer cells). In all aspects, the “kill switch” disclosed herein is designed to provide rapid and reliable killing of a cell containing the cccDNA vector in the absence of a survival input or other specified condition. In other words, the “safety switch” encoded by the cccDNA vector for expression of the FVIII protein described herein may limit the survival of the cell containing the ccDNA vector to an environment defined by specific input signals. Such “kill switches” serve to provide a biological containment function should the cDNA vector for FVIII protein expression be removed from a subject or ensure that it does not express the encoded FVIII protein.

[00316] Other “kill switches” known to one of ordinary skill in the art are provided for use in the cDNA FVIII protein expression vector disclosed herein, for example, as disclosed in US2010/0175141; US2013/0009799; US2011/0172826; US2013/0109568, as well as the “kill switches” disclosed in Jusiak et al., Reviews in Cell Biology and Molecular Medicine; 2014; 1-56; Kobayashi et al., PNAS, 2004; 101; 8419-9; Marchisio et al., Int. Journal of Biochem and Cell Biol., 2011; 43; 310-319; and in Reinshagen et al, Science Translational Medicine, 2018, 11.

[00317] Accordingly, in some embodiments, the cccDNA vector for expression of the FVIII protein may comprise a "kill switch" nucleic acid construct that contains a nucleic acid encoding an effector toxin or reporter protein, wherein expression of the effector toxin (e.g., death protein) or reporter The protein is controlled using a predefined condition. For example, a predetermined condition may be the presence of an environmental agent, such as, for example, an exogenous agent, without which the cell will by default express an effector toxin (eg, a death protein) and be killed. In alternative embodiments, the predetermined condition is the presence of two or more environmental agents, for example, the cell will survive only when supplied with two or more required exogenous agents, and without any of them, the cell containing the cccDNA vector is destroyed.

[00318] In some embodiments, the cccDNA FVIII protein expression vector is modified to include a "safety switch" to destroy cells containing the cccDNA vector to effectively stop in vivo expression of a transgene expressed by the cccDNA vector (e.g., FVIII protein expression ). Specifically, the cccDNA vector is further genetically engineered to express a switch protein that does not function in mammalian cells under normal physiological conditions. Cells expressing a switch protein will only be destroyed upon administration of a drug or exposure to an environmental condition that specifically targets said switch protein, stopping expression of the therapeutic protein or peptide. For example, it has been reported that cells expressing HSV thymidine kinase can be killed by administration of drugs such as ganciclovir and cytosine deaminase. See, for example, Dey and Evans, Suicide Gene Therapy by Herpes Simplex Virus-1 Thymidine Kinase (HSV-TK), in Targets in Gene Therapy, edited by You (2011); and Beltinger et al., Proc. Natl. Acad. Sci. USA 96(15):8699–8704 (1999). In some embodiments, the cccDNA vector may contain a siRNA-based “kill switch” called DISE (Death Induced by Survival Gene Elimination) (Murmann et al., Oncotarget. 2017;8:84643- 84658. Induction of DISE in ovarian cancer cells in vivo).

VI. Detailed description of the method for obtaining the cDNA vector

A. Receipt in general

[00319] Certain methods for producing a cccDNA vector for expressing an FVIII protein containing an asymmetric ITR pair or a symmetric ITR pair as defined herein are described in section IV of international application PCT/US18/49996, filed September 7, 2018, which is fully incorporated herein by reference. In some embodiments, the cDNA FVIII protein expression vector disclosed herein can be produced using insect cells as described herein. In alternative embodiments, the cDNA FVIII protein expression vector disclosed herein can be produced synthetically and, in some embodiments, cell-free, as disclosed in international application PCT/US19/14122, filed January 18, 2019. which is incorporated herein by reference in its entirety.

[00320] As described herein, in one embodiment, a cccDNA vector for expression of the FVIII protein can be produced, for example, by a method comprising the steps of: a) incubating a population of host cells (e.g., insect cells) carrying the polynucleotide an expression construct template (e.g., cccDNA plasmid, ccDNA bacmid, and/or ccDNA baculovirus) lacking viral capsid coding sequences in the presence of Rep protein under conditions effective to induce production of said ccDNA vector in atca agcacaacat and for a period time sufficient for this, while said host cells do not contain sequences encoding the viral capsid; and b) collecting and isolating the cDNA vector from the host cells. The presence of the Rep protein induces replication of the ITR-modified vector polynucleotide to produce a cccDNA vector in the host cell. However, viral particles (eg, AAV virions) are not expressed. Thus, there is no size limitation such as is present naturally in AAV vectors or other viral vectors.

[00321] The presence of a cDNA vector isolated from host cells can be confirmed by digesting DNA isolated from a host cell with a restriction enzyme having a single recognition site on the cDNA vector and analyzing the digested DNA material on a non-denaturing gel for confirmation the presence of characteristic bands of linear and continuous DNA compared to linear and discontinuous DNA.

[00322] According to another aspect of the present invention, the use of host cell lines having a polynucleotide template for expression of a DNA vector (ccDNA template) stably integrated into its genome in the production of a non-viral DNA vector, for example, as described in Lee, L et al. (2013) Plos One 8(8): e69879. Preferably, Rep is added to host cells at an MOI of about 3. When the host cell line is a mammalian cell line, such as HEK293 cells, the cell lines may have a stably integrated vector polynucleotide array, and a second vector, such as a herpes virus, may be used to introduce Rep protein into cells, allowing cctDNA to be excised and amplified in the presence of Rep and a helper virus.

[00323] In one embodiment, the host cells used to produce the cccDNA FVIII protein expression vectors described herein are insect cells, and to deliver both the polynucleotide that encodes the Rep protein and the polynucleotide template of the nonviral expression construct The DNA vector for cccDNA uses a baculovirus, for example, as described in FIG. 4A-4C and Example 1. In some embodiments, the host cell is engineered to express the Rep protein.

[00324] The cccDNA vector is then collected and isolated from the host cells. The timing of collection and recovery of the cccDNA vectors described herein from cells can be selected and optimized to achieve high yield production of said cccDNA vectors. For example, the collection time may be selected based on cell viability, cell morphology, cell proliferation, etc. In one embodiment, the cells are cultured under sufficient conditions and harvested sufficiently after infection with the baculovirus to produce cccDNA vectors, but before the majority of cells begin to die due to toxicity of the baculovirus. DNA vectors can be isolated using plasmid purification kits, such as endotoxin-free Plasmid Kits from Qiagen. Other methods developed for isolating plasmids can also be adapted for DNA vectors. Generally, any method for purifying nucleic acids can be used.

[00325] DNA vectors can be purified using any DNA purification methods known to those skilled in the art. In one embodiment, the cDNA vectors are purified as DNA molecules. In another embodiment, cccDNA vectors are purified as exosomes or microparticles.

[00326] The presence of a cccDNA vector for FVIII protein expression can be confirmed by digesting vector DNA isolated from cells with a restriction enzyme having a single recognition site on the DNA vector and analyzing both digested and undigested DNA material using a gel. electrophoresis to confirm the presence of characteristic bands of linear and continuous DNA compared to linear and discontinuous DNA. FIG. 4C and FIG. 4D illustrates one embodiment for identifying the presence of closed-end cccDNA vectors produced using the methods described herein.

B. cDNA plasmid

[00327] A cccDNA plasmid is a plasmid used to subsequently obtain a ccDNA vector for expression of the FVIII protein. In some embodiments, the cccDNA plasmid can be constructed using known techniques to provide at least the following elements as operably linked components in the direction of transcription: (1) a modified 5'-ITR sequence; (2) an expression cassette containing a cis-regulatory element, for example, a promoter, an inducible promoter, a regulatory switch, enhancers, and the like; and (3) a modified 3'-ITR sequence, wherein said 3'-ITR sequence is symmetrical with respect to the 5'-ITR sequence. In some embodiments, the ITR-flanked expression cassette contains a cloning site for introducing an exogenous sequence. The expression cassette replaces the rep and cap coding regions of the AAV genomes.

[00328] In one aspect, a cccDNA vector for expression of the FVIII protein is derived from a plasmid, referred to herein as a "ccDNA plasmid", encoding, in this order: the first inverted terminal repeat (ITR) of an adeno-associated virus (AAV), an expression cassette containing a transgene, and a mutated or modified AAV ITR, wherein said cDNA plasmid lacks sequences encoding the AAV capsid protein. In alternative embodiments, the cccDNA plasmid encodes, in that order: a first (or 5') modified or mutated AAV ITR, an expression cassette containing the transgene, and a second (or 3') modified AAV ITR, wherein said ccDNA plasmid lacks sequences encoding AAV capsid protein, and wherein said 5'- and 3'-ITRs are symmetrical with respect to each other. In alternative embodiments, ccDNA plasmid a encodes, in this order: a first (or 5') modified or mutated AAV ITR, an expression cassette containing a transgene, and a second (or 3') mutated or modified AAV ITR, wherein said ccDNA plasmid a is devoid of sequences encoding the AAV capsid protein, and wherein said modified 5' and 3' ITRs have the same modifications (ie, they are reverse complementary or symmetrical to each other).

[00329] In a further embodiment, the cDNA plasmid system is devoid of viral capsid protein coding sequences (i.e., devoid of AAV capsid genes as well as capsid genes of other viruses). In addition, in a particular embodiment, the cccDNA plasmid also lacks sequences encoding the AAV Rep protein. Accordingly, in a preferred embodiment, the ccDNA plasmid lacks the functional AAB cap and AAV rep genes, GG-3' for AAV2, and the variable palindromic sequence that provides hairpin formation.

[00330] The cDNA plasmid of the present invention can be obtained using natural nucleotide sequences from the genomes of any AAV serotypes well known in the art. In one embodiment, the cccDNA plasmid backbone is derived from the genome of AAB1, AAB2, AAB3, AAB4, AAB5, AAB5, AAB7, AAB8, AAB9, AAB10, AAB11, AAB12, AABrh8, AABrh10, AAB-DJ, and AAB-DJ8. For example, NCBI: NC 002077; NC001401; NC001729; NC001829; NC006152; NC 006260; NC 006261; from the Kotin and Smith virus index ("The Springer Index of Viruses"), available at a link maintained by Springer (web address: oesys.springer.de/viruses/database/mkchapter.asp?virID=42.04.) (note: links URL or database refers to the contents of the URL or database available from the link as of the actual filing date of this application). In a specific embodiment, the cDNA plasmid backbone is derived from the AAB2 genome. In another specific embodiment, the cDNA plasmid backbone is a synthetic backbone genetically engineered to include at its 5' and 3 ends ITRs derived from one of the AAV genomes.

[00331] The cccDNA plasmid may optionally include a selectable or selectable marker for use in creating a cell line that produces the ccDNA vector. In one embodiment, the selectable marker may be inserted after (ie, in the 3' direction) the 3' ITR sequence. In another embodiment, the selectable marker may be inserted upstream (ie, in the 5' direction) of the 5' ITR sequence. Suitable selectable markers include, for example, markers that confer drug resistance. Selectable markers may be, for example, resistance genes to blasticidin S, kanamycin, geneticin, and the like. In a preferred embodiment, the selectable marker for selecting for drug sensitivity is a blasticidin S resistance gene.

[00332] An exemplary cccDNA vector (eg, pAABO) for expression of the FVIII protein is derived from the pAAB plasmid. A method for producing a rAAV vector may include: (a) delivering the rAAV plasmid to a host cell as described above, wherein both the host cell and the plasmid are deprived of genes encoding the capsid protein, (b) culturing the host cell under conditions ensuring the production of the cDNA genome; and (c) collecting cells and isolating the AAV genome produced from said cells.

C. Exemplary Method for Producing cccDNA Vectors from ccDNA Plasmids

[00333] This document also provides methods for producing capsidless cccDNA vectors for expression of the FVIII protein, in particular a method with sufficiently high yield to provide sufficient quantities of vector for in vivo experiments.

[00334] In some embodiments, a method for producing a cccDNA vector for expressing an FVIII protein includes the following steps: (1) introducing a nucleic acid construct containing an expression cassette and two symmetrical ITR sequences into a host cell (e.g., Sf9 cells), (2 ) optionally creating a clonal cell line, for example, using a selectable marker present on a plasmid, (3) introducing a gene encoding Rep (either by transfection or infection with a baculovirus carrying said gene) into said insect cell; and (4) cell collection and cDNA vector purification. The nucleic acid construct containing the expression cassette and two ITR sequences described above to produce the cccDNA vector may be in the form of a ccDNA plasmid or bacmid or baculovirus produced using a ccDNA plasmid as described below. The nucleic acid construct can be introduced into a host cell by transfection, viral transduction, stable integration, or other methods known in the art.

D. Cell lines

[00335] The host cell lines used in the production of the cccDNA vector for expression of the FVIII protein may include insect cell lines derived from Spodoptera frugiperda, such as Sf9, Sf21 cells, or Trichoplusia ni cells, or cell lines of other invertebrate animals, vertebrates animals or other eukaryotes, including mammalian cells. Other cell lines known to one of ordinary skill in the art may also be used, such as HEK293, Huh-7, HeLa, HepG2, HeplA, 911, CHO, COS, MeWo, NIH3T3, A549, HT1 180, monocytes, as well as mature and immature dendritic cells. Host cell lines can be transfected to stably express the cccDNA plasmid to obtain a cccDNA vector with high yield.

[00336] CCDNA plasmids can be introduced into Sf9 cells by transient transfection using reagents (eg, liposomal, calcium phosphate) or physical means (eg, electroporation) known in the art. Alternatively, stable Sf9 cell lines can be generated with the cccDNA plasmid stably integrated into their genomes. Such stable cell lines can be created by incorporating a selectable marker into a cccDNA plasmid as described above. If the cccDNA plasmid used to transfect a cell line includes a selectable marker, for example, for an antibiotic, cells that have been transfected with the ccDNA plasmid and have integrated the ccDNA plasmid DNA into their genome can be selected by adding the antibiotic to the cell culture media. Stable cell clones can then be isolated using single cell dilution or colony transfer techniques and expanded.

E. Isolation and purification of cDNA vectors:

[00337] Examples of the method for preparing and isolating cccDNA vectors are described in FIG. 4A-4E and in specific examples below. The cDNA FVIII protein expression vectors disclosed herein can be derived from producer cells expressing the AAV Rep protein(s) further transformed with a ccDNA plasmid, a ccDNA bacmid, or a ccDNA baculovirus. Plasmids that can be used to generate cccDNA vectors include plasmids that encode the FVIII protein or plasmids that encode one or more REP proteins.

[00338] In one aspect, the polynucleotide encodes an AAV Rep protein (Rep 78 or 68) delivered to the producing cell on a plasmid (Rep-plasmid), bacmid (Rep-bacmid), or baculovirus (Rep-baculovirus). Rep plasmid, Rep bacmid and Rep baculovirus can be produced using the methods described above.

[00339] Described herein are methods for producing a cDNA vector for the expression of FVIII protein. The expression constructs used to produce the cccDNA vector for expression of the FVIII protein described herein may be a plasmid (e.g., ccDNA plasmids), bacmid (e.g., ccDNA-baculovirus), and/or a baculovirus (e.g., ccDNA-baculovirus). . As a non-limiting example, a cccDNA vector can be obtained from cells coinfected with a cccDNA baculovirus and a Rep baculovirus. Rep proteins produced from Rep baculovirus can replicate cccDNA baculovirus to produce cccDNA vectors. Alternatively, cccDNA vectors for expression of the FVIII protein can be obtained from cells stably transfected with a construct containing the AAV Rep protein coding sequence (Rep78/52) delivered in Rep plasmids, Rep bacmids or Rep baculovirus. The cccDNA baculovirus can be transiently transfected into cells, replicated using the Rep protein, and can produce cccDNA vectors.

[00340] A bacmid (e.g., cccDNA bacmid) can be transfected into permissive insect cells such as Sf9, Sf21, Tni (Trichoplusia ni), High Five cell, and generate a cccDNA baculovirus, which is a recombinant baculovirus including the sequences , containing symmetrical ITRs and an expression cassette. Insect cells can be reinfected with cDNA baculovirus to produce the next generation of recombinant baculovirus. Optionally, the step can be repeated one or more times to obtain more recombinant baculovirus.

[00341] The timing of collection and recovery of the cDNA FVIII protein expression vectors described herein from cells can be selected and optimized to achieve high yield production of said ccDNA vectors. For example, the collection time may be selected based on cell viability, cell morphology, cell proliferation, etc. Typically, cells can be collected a period of time after baculovirus infection sufficient to obtain cDNA vectors (e.g., cDNA vectors) but before most cells begin to die due to viral toxicity. CctDNA vectors can be isolated from Sf9 cells using plasmid purification kits such as the Qiagen ENDO-FREE PLASMID ^® kits. Other methods developed for plasmid isolation can also be adapted for cDNA vectors. Typically, any nucleic acid purification methods known in the art, as well as commercially available DNA extraction kits, can be used.

[00342] Alternatively, purification can be accomplished by alkaline lysis of the cell pellet, centrifuging the resulting lysate, and performing chromatographic separation. As one non-limiting example, this method can be performed by loading the supernatant onto an ion exchange column (eg, SARTOBIND ^Q® ) that retains nucleic acids, followed by elution (eg, 1.2 M NaCl solution) and further chromatographic purification on a column to gel filtration (for example, on 6 Fast Flow GE). The capsidless AAV vector is then isolated, for example, by precipitation.

[00343] In some embodiments, cccDNA vectors for FVIII protein expression may also be purified in the form of exosomes or microparticles. It is known in the art that many cell types release not only soluble proteins, but also complex protein/nucleic acid cargos by shedding membrane microvesicles (Cocucci et al, 2009; EP 10306226.1). Such vesicles include microvesicles (also called microparticles) and exosomes (also called nanovesicles), both of which contain proteins and RNA as cargo. Microvesicles are formed by direct budding of the plasma membrane, and exosomes are released into the extracellular environment upon fusion of multivesicular endosomes with the plasma membrane. Accordingly, cccDNA vector-containing microvesicles and/or exosomes can be isolated from cells transduced with a ccDNA plasmid or bacmid, or with a baculovirus produced using a ccDNA plasmid.

[00344] Microvesicles can be isolated by filtration or ultracentrifugation of the culture medium at 20,000×g, and exosomes at 100,000×g. The optimal duration of ultracentrifugation can be determined experimentally and depends on the specific cell type from which the vesicles are isolated. Preferably, the culture medium is first clarified by low-speed centrifugation (eg at 2000×g for 5-20 minutes) and subjected to centrifugal concentration using, for example, an ^AMICON® spin column (Millipore, Watford, UK). Microvesicles and exosomes can be further purified by FACS or MACS using specific antibodies that recognize specific surface antigens present on microvesicles and exosomes. Other methods for purifying microvesicles and exosomes include, but are not limited to, immunoprecipitation, affinity chromatography, filtration, and magnetic beads coated with specific antibodies or aptamers. After purification, the vesicles are washed, for example, with phosphate-buffered saline (PBS). One advantage of using microvesicles or exosomes to deliver cccDNA-containing vesicles is that such vesicles can be targeted to different cell types by incorporating proteins into their membrane that are recognized by specific receptors on the relevant cell types. (see also EP 10306226)

[00345] Another aspect of the present invention relates to methods for purifying cccDNA vectors from host cell lines that have stably integrated the cccDNA construct into their own genome. In one embodiment, the cDNA vectors are purified as DNA molecules. In another embodiment, cccDNA vectors are purified as exosomes or microparticles.

[00346] FIG. 5 of international application PCT/US18/49996 shows a gel confirming the production of cccDNA from several ccDNA plasmid constructs using the method described in the Examples. The cctDNA vector is confirmed by the characteristic banding profile in the gel, as discussed in relation to FIG. 4D in Examples.

VII. Pharmaceutical compositions

[00347] In another aspect, pharmaceutical compositions are provided. The pharmaceutical composition contains a cccDNA vector for expression of the FVIII protein described herein and a pharmaceutically acceptable carrier or diluent.

[00348] The cDNA FVIII protein expression vectors described herein can be included in pharmaceutical compositions suitable for administration to a subject for in vivo delivery to cells, tissues or organs of the subject. Typically, the pharmaceutical composition contains a cccDNA vector disclosed herein and a pharmaceutically acceptable carrier. For example, the cccDNA vectors for expression of the FVIII protein described herein can be included in a pharmaceutical composition suitable for the intended route of therapeutic administration (eg, parenteral administration). Passive tissue transduction by intravenous or intra-arterial high-pressure infusion, as well as intracellular injection such as intranuclear microinjection or intracytoplasmic injection, is also contemplated. Pharmaceutical compositions for therapeutic purposes can be formulated as a solution, microemulsion, dispersion, liposomes or other ordered structure suitable for high concentration of cccDNA vector. Sterile injection solutions can be prepared by incorporating the cccDNA vector compound in the required amount in an appropriate buffer with one or a combination of the ingredients listed above, if necessary, followed by sterilization by filtration, including the ccDNA vector that can be prepared to deliver the transgene to nucleic acid into recipient cells, which leads to therapeutic expression of a transgene or donor sequence in them. The composition may also include a pharmaceutically acceptable carrier.

[00349] Pharmaceutically active compositions containing a cccDNA vector for expression of the FVIII protein can be formulated to deliver the transgene for various purposes into a cell, for example, into the cells of a subject.

[00350] Pharmaceutical compositions for therapeutic purposes generally must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable for high concentration of cccDNA vector. Sterile injection solutions can be prepared by incorporating the cDNA vector compound in the required amount in an appropriate buffer with one or a combination of the ingredients listed above, if necessary, followed by sterilization by filtration.

[00351] The cDNA FVIII protein expression vector disclosed herein may be included in a pharmaceutical composition suitable for topical, systemic, intra-amniotic, intrathecal, intracranial, intra-arterial, intravenous, intralymphatic, intraperitoneal, subcutaneous, tracheal, interstitial (e.g. , intramuscular, intracardiac, intrahepatic, intrarenal, intracerebral), intrathecal, intravesical, conjunctival (eg, extraorbital, intraorbital, retroorbital, intraretinal, subretinal, choroidal, subchoroidal, intrastromal, intracameral and intravitreal), intracochlear and mucosal (eg, oral, rectal , nasal) administration. Passive tissue transduction by intravenous or intra-arterial high-pressure infusion, as well as intracellular injection such as intranuclear microinjection or intracytoplasmic injection, is also contemplated.

[00352] In some aspects, the methods provided herein include delivering one or more cDNA FVIII protein expression vectors disclosed herein into a host cell. Also provided herein are cells produced by such methods and organisms (such as animals, plants or fungi) containing or derived from such cells. Methods for delivering nucleic acids may include lipofection, nucleofection, microinjection, biolistics, liposomes, immunoliposomes, polycation or lipid:nucleic acid conjugates, bare DNA, and agent-enhanced DNA uptake. Lipofection is described, for example, in US Pat. Nos. 5,049,386, 4,946,787 and 4,897,355, and lipofection reagents are sold commercially (eg, Transfectam™ and Lipofectin™). Delivery may be to cells (eg, in vitro or ex vivo administration) or to target tissues (eg, in vivo administration).

[00353] Various techniques and methods for delivering nucleic acids into cells are known in the art. For example, nucleic acids, such as cccDNA for FVIII protein expression, can be formulated as lipid nanoparticles (LNPs), lipidoids, liposomes, lipid nanoparticles, lipoplexes, or core-shell nanoparticles. Typically, LNPs are composed of a nucleic acid molecule (e.g., cccDNA), one or more ionizable or cationic lipids (or salts thereof), one or more nonionic or neutral lipids (e.g., a phospholipid), a molecule that prevents aggregation (e.g., PEG or a PEG-lipid conjugate), and optionally a sterol (eg cholesterol).

[00354] Another method of delivering nucleic acids, such as cccDNA for FVIII protein expression, into a cell is by conjugating the nucleic acid to a ligand that is internalized by the cell. For example, a ligand can bind to a cell surface receptor and be internalized through endocytosis. A ligand may be covalently linked to a nucleotide in a nucleic acid. Exemplary conjugates for delivering nucleic acids into a cell are described, for example, in WO2015/006740, WO2014/025805, WO2012/037254, WO2009/082606, WO2009/073809, WO2009/018332, WO2006/112872, WO 2004/090108, WO2004/091515 and WO2017 /177326.

[00355] Nucleic acids, such as cDNA vectors for FVIII protein expression, can also be delivered into cells by transfection. Suitable transfection methods include, but are not limited to, lipid-mediated transfection, cationic polymer-mediated transfection, or calcium phosphate precipitation. Transfection reagents are well known in the art and include, but are not limited to, TurboFect Transfection Reagent (Thermo Fisher Scientific), Pro-Ject Reagent (Thermo Fisher Scientific), TRANSPASS™ P Protein Transfection Reagent (New England Biolabs), CHARIOT™ Protein Delivery Reagent (Active Motif), PROTEOJUICE™ Protein Transfection Reagent (EMD Millipore), 293fectin, LIPOFECTAMINE™ 2000, LIPOFECTAMINE™ 3000 (Thermo Fisher Scientific), LIPOFECTAMINE™ (Thermo Fisher Scientific), LIPOFECTIN™ (Thermo Fisher Scientific) Scientific), DMRIE-C, CELLFECTIN™ (Thermo Fisher Scientific), OLIGOFECTAMINE™ (Thermo Fisher Scientific), LIPOFECTACE™, FUGENE™ (Roche, Basel, Switzerland), FUGENE™ HD (Roche), TRANSFECTAM™ (transfectam, Promega, Madison, WI), TFX-10™ (Promega), TFX-20™ (Promega), TFX-50™ (Promega), TRANSFECTIN™ (BioRad, Hercules, CA), SILENTFECT™ (Bio-Rad), EfFectene™ ( Qiagen, Valencia, CA), DC-chol (Avanti Polar Lipids), GENEPORTER™ (Gene Therapy Systems, San Diego, CA), DHARMAFECT 1™ (Dharmacon, Lafayette, CO), DHARMAFECT 2™ (Dharmacon), DHARMAFECT 3 ™ (Dharmacon), DHARMAFECT 4™ (Dharmacon), ESCORT™ III (Sigma, St. Louis, MO), and ESCORT™ IV (Sigma Chemical Co.). Nucleic acids such as cctDNA can also be delivered into cells using microfluidic techniques known to those skilled in the art.

[00356] The cDNA FVIII protein expression vectors described herein can also be administered directly into the body to transduce cells in vivo. Administration is accomplished by any of the routes commonly used to bring the molecule into maximum contact with blood or tissue cells, including, but not limited to, injection, infusion, topical application, and electroporation. Suitable routes for administering such nucleic acids are available and well known to those skilled in the art, and although more than one route may be used to administer a particular composition, a particular route can often provide a faster and more efficient response than another route of administration.

[00357] Methods of administering a vector nucleic acid, such as the cDNA FVIII protein expression vector disclosed herein, may include delivery to hematopoietic stem cells, for example, using methods described, for example, in US Pat. No. 5,928,638.

[00358] CCDNA vectors for expression of the FVIII protein in accordance with the present invention can be added to liposomes for delivery to a cell or target organ in a subject. Liposomes are vesicles that have at least one lipid bilayer. Liposomes are typically used as carriers for drug/therapeutic delivery in the context of pharmaceutical development. They work by fusing with the cell membrane and rearranging its lipid structure to deliver a drug or active pharmaceutical ingredient (API). Liposomal compositions for such delivery consist of phospholipids, in particular compounds containing a phosphatidylcholine group, however, these compositions may also include other lipids. Exemplary liposomes and liposome formulations, including, but not limited to, compounds containing polyethylene glycol (PEG) functional groups, are disclosed in International Application PCT/US2018/050042, filed September 7, 2018, and International Application PCT/US2018/064242. filed December 6, 2018, for example, see the section entitled “Pharmaceutical Formulations.”

[00359] Various delivery methods known in the art, or modifications thereof, can be used to deliver cccDNA vectors in vitro or in vivo. For example, in some embodiments, cccDNA vectors for FVIII protein expression are delivered by creating a transient hole in the cell membrane using mechanical, electrical, ultrasonic, hydrodynamic, or laser energy so as to facilitate entry of DNA into target cells. For example, the cccDNA vector can be delivered by transiently rupturing the cell membrane by forcing the cell through a channel of limited size or other methods known in the art. In some cases, the cccDNA vector individually is directly administered as unprotected DNA by injection into any of: any one or more tissues selected from: liver, kidney, gallbladder, prostate, adrenal gland, heart, intestine, lung and stomach, skin, thymus, cardiac muscle or skeletal muscle. In some cases, the cccDNA vector is delivered using a gene gun. Spherical gold or tungsten particles (1-3 μm in diameter) coated with capsidless AAV vectors can be accelerated to high speed using compressed gas to penetrate the cells of the target tissue.

[00360] Compositions comprising a cccDNA vector for expression of the FVIII protein and a pharmaceutically acceptable carrier are specifically provided herein. In some embodiments, the cccDNA vector is formulated with a lipid delivery system, such as liposomes, as described herein. In some embodiments, such compositions are administered by any route desired by a skilled practitioner. The compositions may be administered to a subject by various routes, including oral, parenteral, sublingual, transdermal, rectal, transmucosal, topical, inhalation, buccal, intrapleural, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intranasal, intrathecal and intraarticular, or combinations thereof. . For veterinary use, the composition may be administered in a reasonably acceptable formulation in accordance with normal veterinary practice. The veterinarian can easily determine the dosage schedule and route of administration that is most appropriate for a particular animal. The compositions can be administered using conventional syringes, needleless injection devices, "microparticle bombardment gene guns" or other physical methods such as electroporation ("EP"), hydrodynamic methods or the use of ultrasound.

[00361] In some cases, the cccDNA vector for FVIII protein expression is delivered by hydrodynamic injection, which provides a simple and highly effective method for direct intracellular delivery of any water-soluble compounds and particles to internal organs and skeletal muscle throughout the limb.

[00362] In some cases, cccDNA vectors for FVIII protein expression are delivered by ultrasound, creating nanoscopic pores in the membrane to facilitate intracellular delivery of DNA particles to internal organ or tumor cells, so the size and concentration of plasmid DNA is of great importance to the efficiency of the system. In some cases, cccDNA vectors are delivered by magnetofection, using magnetic fields to concentrate particles containing the nucleic acid into target cells.

[00363] In some cases, chemical delivery systems can be used, for example, using nanometer complexes that involve the compaction of negatively charged nucleic acid with polycationic nanometer particles, in the composition of a cationic liposome/micelle or cationic polymers. Cationic lipids used in this delivery method include, but are not limited to, monovalent cationic lipids, polyvalent cationic lipids, guanidine-containing compounds, cholesterol derivative compounds, cationic polymers (e.g., polyethylenimine, poly-L-lysine, protamine, other cationic polymers) and lipid-polymer hybrids.

A. Exosomes

[00364] In some embodiments, the cDNA FVIII protein expression vector disclosed herein is delivered packaged in an exosome. Exosomes are small membrane vesicles of endocytic origin that are released into the extracellular environment after the fusion of multivesicular bodies with the plasma membrane. Their surface consists of the lipid bilayer of the cell membrane of the donor cell, they contain cytosol from the cell that produced the exosome, and they expose membrane proteins of the parent cell on the surface. Exosomes are produced by various cell types, including epithelial cells, B and T lymphocytes, mast cells (MCs), and dendritic cells (DCs). In some embodiments, exosomes with a diameter of 10 nm to 1 μm, 20 nm to 500 nm, 30 nm to 250 nm, or 50 to 100 nm are provided for use. Exosomes can be isolated for delivery to target cells either by using their donor cells or by introducing specific nucleic acids into them. To obtain exosomes containing capsidless AAV vectors according to the present invention, various approaches known in the art can be used.

B. Microparticle/nanoparticles

[00365] In some embodiments, the cDNA FVIII protein expression vector disclosed herein is delivered via a lipid nanoparticle. Typically, lipid nanoparticles contain an ionizable aminolipid (e.g., heptatriakonta-6,9,28,31-tetraen-19-yl-4-(dimethylamino)butanoate, DLin-MC3-DMA, phosphatidylcholine (1,2-distearoyl-sn-glycero- 3-phosphocholine, DSPC), cholesterol and envelope lipid (polyethylene glycol dimyristoylglycerol, PEG-DMG), for example, as disclosed by Tam et al (2013). Advances in Lipid Nanoparticles for siRNA delivery. Pharmaceuticals 5(3): 498-507 .

[00366] In some embodiments, the lipid nanoparticle has an average diameter of from about 10 nm to about 1000 nm. In some embodiments, the lipid nanoparticle has a diameter of less than 300 nm. In some embodiments, the lipid nanoparticle has a diameter of from about 10 nm to about 300 nm. In some embodiments, the lipid nanoparticle has a diameter of less than 200 nm. In some embodiments, the lipid nanoparticle has a diameter of from about 25 nm to about 200 nm. In some embodiments, the lipid nanoparticle formulation (e.g., a composition containing a plurality of lipid nanoparticles) has a size distribution such that the average size (e.g., diameter) is from about 70 nm to about 200 nm, and more typically the average size is about 100 nm or less.

[00367] Various lipid nanoparticles known in the art can be used to deliver the FVIII protein expression DNA vector disclosed herein. For example, various delivery methods using lipid nanoparticles are described in US Patent Nos. 9404127, 9006417 and 9518272.

[00368] In some embodiments, the cDNA FVIII protein expression vector disclosed herein is delivered using a gold nanoparticle. Typically, the nucleic acid may be covalently associated with the gold nanoparticle or non-covalently associated with the gold nanoparticle (eg, associated by charge-charge interaction), for example, as described by Ding et al. (2014). Gold Nanoparticles for Nucleic Acid Delivery. Mol. Ther. 22(6); 1075-1083. In some embodiments, gold nanoparticle-nucleic acid conjugates are prepared using methods described, for example, in US Pat. No. 6,812,334.

C. Conjugates

[00369] In some embodiments, the cDNA FVIII protein expression vector disclosed herein is conjugated (eg, covalently linked) to an agent that enhances cellular uptake. A "cellular uptake enhancing agent" is a molecule that facilitates the transport of nucleic acid across a lipid membrane. For example, the nucleic acid may be conjugated to a lipophilic compound (e.g., cholesterol, tocopherol, etc.), cell penetrating peptide (CPP) (e.g., penetratin, TAT, Syn1B, etc.), and polyamines (e.g., spermine ). Additional examples of agents that increase cellular uptake are disclosed, for example, in Winkler (2013). Oligonucleotide conjugates for therapeutic applications. Ther. Deliv. 4(7); 791-809.

[00370] In some embodiments, the cDNA FVIII protein expression vector disclosed herein is conjugated to a polymer (eg, a polymer molecule) or a folate molecule (eg, a folic acid molecule). In general, delivery of nucleic acids conjugated to polymers is known in the art, for example, described in WO2000/34343 and WO2008/022309. In some embodiments, the cDNA FVIII protein expression vector disclosed herein is conjugated to a polyamide polymer, for example, as described in US Pat. No. 8,987,377. In some embodiments, the nucleic acid described in the present disclosure is conjugated to a folic acid molecule as described in US Pat. No. 8,507,455.

[00371] In some embodiments, the cDNA FVIII protein expression vector disclosed herein is conjugated to a carbohydrate, for example, as described in US Pat. No. 8,450,467.

D. Nanocapsule

[00372] Alternatively, nanocapsule formulations of the cDNA vector for expression of the FVIII protein disclosed herein may be used. Generally, nanocapsules can entrap substances in a stable and reproducible manner. To avoid side effects caused by intracellular polymer overload, such ultrafine particles (about 0.1 μm in size) must be constructed using polymers that can degrade in vivo. The use of biodegradable polyalkyl cyanoacrylate nanoparticles that meet such requirements is envisaged.

E. Liposomes

[00373] CCDNA vectors for expression of FVIII protein in accordance with the present invention can be added to liposomes for delivery to a cell or target organ in a subject. Liposomes are vesicles that have at least one lipid bilayer. Liposomes are typically used as carriers for drug/therapeutic delivery in the context of pharmaceutical development. They work by fusing with the cell membrane and rearranging its lipid structure to deliver a drug or active pharmaceutical ingredient (API). Liposomal compositions for such delivery consist of phospholipids, in particular compounds containing a phosphatidylcholine group, however, these compositions may also include other lipids.

[00374] The preparation and use of liposomes is generally known to those skilled in the art. Liposomes with improved serum stability and circulation half-life have been developed (US Patent No. 5,741,516). In addition, various methods for preparing liposomes and liposome-like preparations as potential drug carriers have been described (US Patent Nos. 5,567,434; 5,552,157; 5,565,213; 5,738,868 and 5,795,587).

F. Exemplary Compositions of Liposomes and Lipid Nanoparticles (LNPs)

[00375] CCDNA vectors for expression of the FVIII protein in accordance with the present invention can be added to liposomes for delivery into a cell, for example, into a cell in need of transgene expression. Liposomes are vesicles that have at least one lipid bilayer. Liposomes are typically used as carriers for drug/therapeutic delivery in the context of pharmaceutical development. They work by fusing with the cell membrane and rearranging its lipid structure to deliver a drug or active pharmaceutical ingredient (API). Liposomal compositions for such delivery consist of phospholipids, in particular compounds containing a phosphatidylcholine group, however, these compositions may also include other lipids.

[00376] Lipid nanoparticles (LNPs) containing cccDNA vectors are disclosed in International Application PCT/US2018/050042, filed September 7, 2018, and International Application PCT/US2018/064242, filed December 6, 2018, which are fully included herein, and are provided for use in the methods and compositions of cDNA vectors for expression of FVIII protein disclosed herein.

[00377] According to some aspects of the present disclosure, there is provided a liposomal formulation that includes one or more polyethylene glycol (PEG) functional compounds (so-called "PEGylated compounds") that can reduce immunogenicity/antigenicity, provide hydrophilicity and hydrophobicity, and reduce the incidence of dosing the compound(s). In other cases, the liposomal formulation simply includes the polymer polyethylene glycol (PEG) as an additional component. In such aspects, the molecular weight of the PEG or PEG functionality may range from 62 Da to about 5000 Da.

[00378] According to some aspects of the present disclosure, a liposomal formulation is provided that will deliver an API with a sustained or controlled release profile over a period of time ranging from several hours to weeks. In some related aspects, the liposomal formulation may contain aqueous chambers that are limited by lipid bilayers. In other related aspects, the liposomal formulation encapsulates the API with components that undergo a physical transition at elevated temperature that releases the API over a period of hours to weeks.

[00379] In some aspects, the liposomal composition contains sphingomyelin and one or more lipids disclosed herein. In some aspects, the liposomal composition contains optisomes.

[00380] According to some aspects of the present disclosure, there is provided a liposomal formulation that contains one or more lipids selected from: N-(carbonylmethoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt, (distearoyl-sn- glycerophosphoethanolamine), MPEG (methoxypolyethylene glycol)-conjugated lipid, HSPC (hydrogenated soy phosphatidylcholine); PEG (polyethylene glycol); DSPE (distearoyl-sn-glycerophosphoethanolamine); DSPC (distearoylphosphatidylcholine); DOPC (dioleoylphosphatidylcholine); DPPG (dipalmitoylphosphatidylglycerol); EPC (egg phosphatidylcholine); DOPS (dioleoylphosphatidylserine); POPC (palmitoyloleoylphosphatidylcholine); SM (sphingomyelin); MPEG (methoxy polyethylene glycol); DMPC (dimyristoylphosphatidylcholine); DMPG (dimyristoylphosphatidylglycerol); DSPG (distearoylphosphatidylglycerol); DEPC (dierucoylphosphatidylcholine); DOPE (dioleoyl-sn-glycerophosphoethanolamine); cholesterol sulfate (CS); dipalmitoylphosphatidylglycerol (DPPG); DOPC (dioleoyl-sn-glycerophosphatidylcholine) or any combination thereof.

[00381] According to some aspects of the present disclosure, there is provided a liposomal formulation comprising a phospholipid, cholesterol, and a PEGylated lipid in a molar ratio of 56:38:5. In some aspects, the total lipid content of the liposomal formulation is 2-16 mg/ml. According to some aspects of the present disclosure, there is provided a liposomal composition comprising a phosphatidylcholine-functional lipid, an ethanolamine-functional lipid, and a PEGylated lipid. According to some aspects of the present invention, there is provided a liposomal composition comprising a phosphatidylcholine-functional lipid, an ethanolamine-functional lipid, and a PEGylated lipid in a molar ratio of 3:0.015:2, respectively. According to some aspects of the present invention, there is provided a liposomal composition comprising a lipid containing a phosphatidylcholine functionality, cholesterol and a pegylated lipid. According to some aspects of the present invention, there is provided a liposomal composition comprising a phosphatidylcholine functional group-containing lipid and cholesterol. In some aspects, the PEGylated lipid is PEG-2000-DSPE. According to some aspects of the present disclosure, a liposomal formulation is provided comprising DPPG, soy PC, MPEG-DSPE lipid conjugate and cholesterol.

[00382] According to some aspects of the present disclosure, there is provided a liposomal formulation comprising one or more phosphatidylcholine functional group-containing lipids and one or more ethanolamine functional group-containing lipids. According to some aspects of the present disclosure, there is provided a liposomal composition comprising one or more of: phosphatidylcholine-functional lipids, ethanolamine-functional lipids, and sterols, such as cholesterol. In some aspects, the liposomal composition contains DOPC/DEPC; and DOPE.

[00383] According to some aspects of the present disclosure, a liposomal formulation is provided, further comprising one or more pharmaceutical excipients, for example, sucrose and/or glycine.

[00384] According to some aspects of the present disclosure, a liposomal formulation with a unilamellar or multilamellar structure is provided. In accordance with some aspects of the present disclosure, a liposomal formulation is provided that contains multivesicular particles and/or foam-based particles. In some aspects of the present disclosure, a liposomal formulation is provided that has a relative size greater than that of conventional nanoparticles, ranging from about 150 to 250 nm. In some aspects, the liposomal formulation is a lyophilized powder.

[00385] According to some aspects of the present disclosure, a liposomal formulation is provided that is prepared and loaded with cccDNA vectors disclosed or described herein by adding a weak base to a mixture containing isolated cccDNA outside a liposome. This addition increases the pH outside the liposomes to approximately 7.3 and stimulates the entry of the API into the liposome. In accordance with some aspects of the present disclosure, a liposomal formulation is provided having an acidic pH within the liposome. In such cases, the pH value within the liposomes may be 4-6.9, and more preferably pH 6.5. According to other aspects of the present disclosure, a liposomal formulation is provided using intraliposomal drug stabilization technology. In such cases, polymeric or non-polymeric highly charged anions and intraliposomal entrapment agents, such as polyphosphate or sucrose octasulfate, are used.

[00386] In accordance with some aspects of the present disclosure, a lipid nanoparticle is provided comprising cccDNA and an ionizable lipid. For example, a lipid nanoparticle formulation that is prepared and loaded with cccDNA obtained using the method disclosed in international application PCT/US2018/050042, filed September 7, 2018, which is incorporated herein. This can be done by intensively mixing ethanol solutions of lipids with an aqueous solution of ccDNA at a low pH, at which protonation of the ionizable lipid occurs and provides favorable energetic characteristics for ccDNA/lipid association and particle nucleation. The particles can be further stabilized by diluting with water and removing the organic solvent. Particles can be concentrated to a target level.

[00387] Typically, lipid particles are prepared at a ratio of total lipid to cccDNA (w/w) of about 10:1 to 30:1. In some embodiments, the lipid to cccDNA ratio (mass ratio; w/w ratio) may range from about 1:1 to about 25:1, from about 10:1 to about 14:1, from about 3:1 to about 15:1, from about 4:1 to about 10:1, from about 5:1 to about 9:1, or from about 6:1 to about 9:1. The amounts of lipids and cccDNA can be adjusted to provide a target N/P ratio, for example, an N/P ratio of 3, 4, 5, 6, 7, 8, 9, 10 or higher. Typically, the total lipid content of the lipid particles may range from about 5 mg/ml to about 30 mg/ml.

[00388] An ionizable lipid is typically used to condense a nucleic acid cargo, such as cccDNA, at low pH and to promote membrane association and fusogenicity. Typically, ionizable lipids are lipids containing at least one amino group that is positively charged or becomes protonated under acidic conditions, such as pH 6.5 or lower. In this document, ionizable lipids are also referred to as cationic lipids.

[00389] Exemplary ionizable lipids are described in international PCT patent publications WO 2015/095340, WO 2015/199952, WO 2018/011633, WO 2017/049245, WO 2015/061467, WO 2012/040184, WO 2012/ 000104, WO 2015/ 074085, WO 2016/081029, WO 2017/004143, WO 2017/075531, WO 2017/117528, WO 2011/022460, WO 2013/148541, WO 2013/116126, WO 2011/153 120, WO 2012/044638, WO 2012/ 054365, WO 2011/090965, WO 2013/016058, WO 2012/162210, WO 2008/042973, WO 2010/129709, WO 2010/144740, WO 2012/099755, WO 2013/049 328, WO 2013/086322, WO 2013/ 086373, WO 2011/071860, WO 2009/132131, WO 2010/048536, WO 2010/088537, WO 2010/054401, WO 2010/054406, WO 2010/054405, WO 2010/054 384, WO 2012/016184, WO 2009/ 086558, WO 2010/042877, WO 2011/000106, WO 2011/000107, WO 2005/120152, WO 2011/141705, WO 2013/126803, WO 2006/007712, WO 2011/038 160, WO 2005/121348, WO 2011/ 066651, WO 2009/127060, WO 2011/141704, WO 2006/069782, WO 2012/031043, WO 2013/006825, WO 2013/033563, WO 2013/089151, WO 2017/099 823, WO 2015/095346 and WO 2013/ 086354, and US patent publications US 2016/0311759, US 2015/0376115, US 2016/0151284, US 2017/0210697, US 2015/0140070, US 2013/0178541, US 2013/0303587, US 201 5/0141678, US 2015/0239926 , US 2016/0376224, US 2017/0119904, US 2012/0149894, US 2015/0057373, US 2013/0090372, US 2013/0274523, US 2013/0274504, US 2013/0274504, US 2009/0023673, US 2012/0128760 , US 2010/0324120, US 2014/0200257, US 2015/0203446, US 2018/0005363, US 2014/0308304, US 2013/0338210, US 2012/0101148, US 2012/0027796, US 2012/0058144, US 2013/0323269 , US 2011/0117125, US 2011/0256175, US 2012/0202871, US 2011/0076335, US 2006/0083780, US 2013/0123338, US 2015/0064242, US 2006/0051405, US 2013/0065939, US 2006/0008910 , US 2003/0022649, US 2010/0130588, US 2013/0116307, US 2010/0062967, US 2013/0202684, US 2014/0141070, US 2014/0255472, US 2014/0039032, US 2018/0028664, US 2016/0317458 and US 2013/0195920, the contents of which are incorporated herein by reference in their entirety.

[00390] In some embodiments, the ionizable lipid is MC3 (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl-4-(dimethylamino)butanoate (DLin-MC3-DMA or MRZ), having the following structure:

[00391] The DLin-MC3-DMA lipid is described in Jayaraman et al., Angew. Chem. Int. Ed Engl. (2012), 51(34): 8529-8533, the contents of which are incorporated herein by reference in their entirety.

[00392] In some embodiments, the ionizable lipid is lipid ATX-002, described in WO 2015/074085, the contents of which are incorporated herein by reference in their entirety.

[00393] In some embodiments, the ionizable lipid is (13Z,16Z)-N,N-dimethyl-3-nonyldocose-13,16-dien-1-amine (Compound 32), described in WO 2012/040184, the content of which is incorporated herein by reference in its entirety.

[00394] In some embodiments, the ionizable lipid is Compound 6 or Compound 22, described in WO 2015/199952, the contents of which are incorporated herein by reference in their entirety.

[00395] Without limitation, the ionizable lipid may comprise 20-90 mol% of the total lipids present in the lipid nanoparticle. For example, the molar content of the ionizable lipid may be 20-70 mol%, 30-60 mol%, or 40-50 mol% of the total lipids present in the lipid nanoparticle. In some embodiments, the ionizable lipid is from about 50 mol. % to about 90 mol. % of the total amount of lipids present in the lipid nanoparticle.

[00396] In some aspects, the lipid nanoparticle may further comprise a non-cationic lipid. Nonionic lipids include amphipathic lipids, neutral lipids and anionic lipids. Accordingly, the non-cationic lipid may be a neutral, uncharged, zwitterionic or anionic lipid. Non-cationic lipids are usually used to enhance fusogenicity.

[00397] Exemplary non-cationic lipids contemplated for use in the methods and compositions disclosed herein are described in international application PCT7US 2018/050042, filed September 7, 2018, and PCT/US 2018/064242, filed December 6, 2018. , which are included in this document in their entirety. Exemplary non-cationic lipids are described in International Application Publication WO 2017/099823 and US Patent Publication US 2018/0028664, the contents of which are incorporated herein by reference in their entirety.

[00398] The non-cationic lipid may comprise 0-30 mol% of the total lipids present in the lipid nanoparticle. For example, the content of non-cationic lipid is 5-20% (mol.) or 10-15% (mol.) of the total amount of lipids present in the lipid nanoparticle. In various embodiments, the molar ratio of ionizable lipid to neutral lipid ranges from about 2:1 to about 8:1.

[00399] In some embodiments, the lipid nanoparticles do not contain any phospholipids. In some aspects, the lipid nanoparticle may further comprise a component, such as a sterol, to provide membrane integrity.

[00400] One exemplary sterol that is suitable for use in a lipid nanoparticle is cholesterol and its derivatives. Exemplary cholesterol derivatives are described in international application WO 2009/127060 and US patent publication US 2010/0130588, the contents of which are incorporated herein by reference in their entirety.

[00401] The membrane integrity component, such as sterol, may comprise 0-50 mol% of the total lipids present in the lipid nanoparticle. In some embodiments, such a component constitutes 20-50 mol% and 30-40 mol% of the total lipid content of the lipid nanoparticle.

[00402] 1200

contain polyethylene glycol (PEG) or a conjugated lipid molecule. They are typically used to inhibit the aggregation of lipid nanoparticles and/or to provide steric stabilization. Exemplary conjugated lipids include, but are not limited to, PEG-lipid conjugates, polyoxazoline (PO7)-lipid conjugates, polyamide-lipid conjugates (such as ATTA-lipid conjugates), cationic polymer-lipid (CPL) conjugates; and mixtures thereof. In some embodiments, the conjugated lipid molecule is a PEG-lipid conjugate, such as a methoxy polyethylene glycol conjugated lipid. Exemplary PEG-lipid conjugates include, but are not limited to, PEG-diacylglycerol (DAT) (such as 1-(monomethoxypolyethylene glycol)-2,3-dimyristoylglycerol (PEG-DMG)), PEG-dialkyloxypropyl (DAA), PEG-phospholipid, PEG-ceramide (Cer), PEGylated phosphatidylethanolamine (PEG-PE), PEG-succinate diacylglycerol (PEGS-DAG) (such as 4-O-(2',3'-di(tetradecanoyloxy)propyl-1-O)-(w -methoxy(polyethoxy)ethyl)butanedioate (PEG-S-DMG)), PEG-dialkoxypropylcarbam, sodium salt of N-(carbonylmethoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine or a mixture thereof. Additional exemplary PEG-lipid conjugates are described, for example, in US5885613, US6287591, US2003/0077829, US2003/0077829, US2005/0175682, US2008/0020058, US2011/0117125, US2010/01305 88, US 2016/0376224 and US 2017/0119904, the contents of which are incorporated herein by reference in their entirety.

[00403] In some embodiments, the PEG lipid is a compound disclosed in US 2018/0028664, the contents of which are incorporated herein by reference in their entirety. In some embodiments, a PEG lipid is disclosed in US 20150376115 or US 2016/0376224, the contents of which are incorporated herein by reference in their entirety.

[00404] The PEG-DAA conjugate may be, for example, PEG-dilauryloxypropyl, PEG-dimyristyloxypropyl, PEG-dipalmityloxypropyl, or PEG-distearyloxypropyl. The PEG lipid may be one or more of PEG-DMG, PEG-dilaurylglycerol, PEG-dipalmitoylglycerol, PEG-disterylglycerol, PEG-dilaurylglycamide, PEG-dimyristylglycamide, PEG-dipalmitoylglycamide, PEG-disterylglycamide, PEG-cholesterol (1-[8 '-(cholest-5-en-3β-oxy)carboxamido-3',6'-dioxaoctanyl]carbamoyl-[omega]-methylpolyethylene glycol), PEG-DMB (3,4-ditetradecoxybenzyl-[omega]-methylpolyethylene glycol ether) and 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-K-[methoxypolyethylene glycol-2000]. In some examples, the PEG lipid may be selected from the group consisting of PEG-DMG, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxypolyethylene glycol-2000].

[00405] Lipids conjugated to a molecule other than PEG can also be used in place of PEG lipid. For example, polyoxazoline (POZ)-lipid conjugates, polyamide-lipid conjugates (such as ATTA-lipid conjugates), and cationic polymer-lipid (CPL) conjugates can be used instead of or in conjunction with PEG lipid. Exemplary conjugated lipids, i.e. PEG-lipids, (POZ)-lipid conjugates, ATTA-lipid conjugates and cationic polymer-lipids are described in international patent application publications WO1996/010392, WO1998/051278, WO 2002/087541, WO 2005/026372, WO 2008/147438 , WO 2009/086558, WO 2012/000104, WO 2017/117528, WO 2017/099823, WO 2015/199952, WO 2017/004143, WO 2015/095346, WO 2012/000104, WO 2012/000104 and WO 2010/006282 , publications of US patent applications US 2003/0077829, US 2005/0175682, US 2008/0020058, US 2011/0117125, US 2013/0303587, US 2018/0028664, US 2015/0376115, US 2016/0376 224, US 2016/0317458 , US 2013/0303587, US 2013/0303587 and US 20110123453, and US patents US 5885613, US 6287591, US 6320017 and US 6586559, the contents of which are incorporated herein by reference in their entirety.

[00406] In some embodiments, one or more additional compounds may be a therapeutic agent. The therapeutic agent may be selected from any class suitable for use for therapeutic purposes. In other words, the therapeutic agent may be selected from any class suitable for use for therapeutic purposes. In other words, the therapeutic agent may be selected according to the therapeutic purpose and the target biological effect. For example, if the cccDNA in the LNP can be used to treat hemophilia A, the additional compound may be an agent directed against hemophilia A (for example, a chemotherapeutic agent or other therapy for hemophilia A (including, but not limited to, a small molecule or antibody). According to another For example, if the LNP containing cccDNA can be used to treat an infection, the additional compound may be an antimicrobial agent (for example, an antibiotic or an antiviral compound).In yet another example, if the LNP containing cccDNA can be used to treat an immune disease or disorder, the additional compound may be a compound that modulates the immune response (e.g., an immunosuppressive compound, an immunostimulatory compound, or a compound that modulates one or more specific immune pathways).In some embodiments, other mixtures of various lipid nanoparticles containing other compounds, such as cDNA, encoding another protein or another compound, such as a therapeutic agent.

[00407] In some embodiments, the additional compound is an immunomodulatory agent. For example, the additional compound is an immunosuppressant. In some embodiments, the additional compound is an immunostimulating agent. Also provided herein is a pharmaceutical composition comprising a lipid nanoparticle-encapsulated insect cell-derived or synthetically produced cDNA FVIII protein expression vector disclosed herein and a pharmaceutically acceptable carrier or excipient.

[00408] According to some aspects of the present disclosure, a lipid nanoparticle formulation is provided, further comprising one or more pharmaceutical excipients. In some embodiments, the lipid nanoparticle formulation further comprises sucrose, tris, trehalose, and/or glycine.

[00409] The cDNA vector can form complexes with the lipid portion (portion) of the particle or can be encapsulated in the lipid portion (position) of the lipid nanoparticle. In some embodiments, the cccDNA may be completely encapsulated in the lipid portion of the lipid nanoparticle, thereby protecting it from degradation by a nuclease, for example, in an aqueous solution. In some embodiments, the cccDNA in the lipid nanoparticle is not significantly degraded after exposing the lipid nanoparticle to a nuclease at 37° C. for at least about 20, 30, 45, or 60 minutes. In some embodiments, the cccDNA in a lipid nanoparticle is not significantly degraded after the particle is incubated in serum at 37°C for at least about 30, 45, or 60 minutes, or at least about 2, 3, 4, 5, 6. 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34 or 36 hours.

[00410] In certain embodiments, the lipid nanoparticles are substantially non-toxic to a subject, such as a mammal such as a human. In some aspects, the lipid nanoparticle formulation is a lyophilized powder.

[00411] In some embodiments, lipid nanoparticles are solid core particles that have at least one lipid bilayer. In other embodiments, the lipid nanoparticles have a non-bilayer structure, i.e. have a non-lamellar (i.e. non-bilayer) morphology. Without limitation, non-bilayer morphologies may include, for example, three-dimensional tubes, rods, cubic particles, etc. For example, the morphology of lipid nanoparticles (lamellar versus non-lamellar) can be easily assessed and characterized using, for example, cryo-TEM (cryotransmission electron microscopy) analysis as described in US 2010/0130588, the contents of which are incorporated herein in their entirety via link.

[00412] In some other embodiments, lipid nanoparticles having a non-lamellar morphology are electron dense. In accordance with certain aspects of the present disclosure, a lipid nanoparticle is provided that is either single-layered or multilayered in structure. According to some aspects of the present disclosure, a lipid nanoparticle composition is provided that contains multivesicular particles and/or foam-based particles.

[00413] By controlling the composition and content of lipid components, it is possible to control the rate at which the lipid conjugate is released from the lipid particle and, in turn, the rate at which the lipid nanoparticle becomes fusogenic. In addition, other variables, including, for example, pH, temperature, or ionic strength, can be used to alter and/or control the rate at which the lipid nanoparticle becomes fusogenic. Other methods that can be used to control the rate at which a specified lipid nanoparticle becomes fusogenic will be apparent to those of ordinary skill in the art upon review of the disclosure. It will also be understood that the size of the lipid particles can be controlled by controlling the composition and concentration of the lipid conjugate.

[00414] The pKa of cationic lipids in formulations can be compared with the efficiency of LNPs for delivering nucleic acids (see Jayaraman et al., Angewandte Chemie, International Edition (2012), 51(34), 8529-8533; Semple et al., Nature Biotechnology 28, 172-176 (2010), both works are incorporated herein by reference in their entirety). The preferred pKa range is from ~5 to ~7. The pKa of a cationic lipid in lipid nanoparticles can be determined using an assay based on 2-(p-toluidino)-6-naphthalenesulfonic acid (TNS) fluorescence. VIII. Methods of application

[00415] The cDNA FVIII protein expression vector disclosed herein can also be used in a method of delivering a nucleotide sequence of interest (eg, encoding an FVIII protein) to a target cell (eg, a host cell). The method may be, in particular, a method of delivering FVIII protein to a cell of a subject in need thereof and treating hemophilia A. The present invention provides for in vivo expression of FVIII protein encoded in a cccDNA vector in a cell of a subject so that a therapeutic effect occurs FVIII protein expression. These results are observed both in vivo and in vitro delivery modes of the cDNA vector.

[00416] In addition, the present invention provides a method of delivering FVIII protein to a cell of a subject in need thereof, comprising repeated administrations of a cccDNA vector of the present invention encoding said FVIII protein. Since the cccDNA vector of the present invention does not induce an immune response similar to that typically observed against encapsidated viral vectors, such a multiple administration strategy is likely to be more successful in a cccDNA-based system. The cccDNA vector is administered in quantities sufficient to transfect cells of the target tissue and provide sufficient levels of gene transfer and FVIII protein expression without undue unwanted effects. Common and pharmaceutically acceptable routes of administration include, but are not limited to, intraretinal injection (eg, subretinal injection, suprachoroidal injection, or intravitreal injection), intravenous administration (eg, in a liposomal formulation), direct delivery to an organ of choice (eg, any one or more tissues selected from: liver, kidney, gallbladder, prostate, adrenal gland, heart, intestine, lung and stomach), intramuscular and other parenteral routes of administration. Routes of administration can be combined if required.

[00417] Delivery of the cccDNA vector for FVIII protein expression described herein is not limited to delivery of the FVIII protein to be expressed. For example, cccDNA vectors produced by a conventional method (e.g., using a cell-based production method (e.g., insect cell production methods)) or a synthetic method, as described herein, can be used in conjunction with other proposed delivery systems, to provide part of the gene therapy. One non-limiting example of a system that can be combined with cccDNA vectors in accordance with the present disclosure includes systems that separately deliver one or more cofactors or immune suppressors for efficient gene expression of a cccDNA vector expressing FVIII protein.

[00418] The present invention also provides a method of treating hemophilia A in a subject, comprising administering to a target cell in need thereof (particularly a muscle cell or tissue) of said subject a therapeutically effective amount of a cccDNA vector, optionally with a pharmaceutically acceptable carrier. Although the cDNA vector can be introduced in the presence of a carrier, such a carrier is not necessary. The selected cccDNA vector contains a nucleotide sequence encoding an FVIII protein that can be used to treat hemophilia A. In particular, the cccDNA vector may contain a target FVIII protein sequence operably linked to control elements capable of directing the transcription of the target FVIII protein encoded by the exogenous DNA sequence , when administered to a subject. The cccDNA vector can be introduced by any suitable route suggested above and elsewhere in this document.

[00419] The compositions and vectors provided herein can be used to deliver FVIII protein for a variety of purposes. In some embodiments, the transgene encodes an FVIII protein that is intended to be used for research purposes, for example, to create a somatic transgenic animal model carrying the transgene, for example, to study the function of the FVIII protein product. In another example, the transgene encodes the FVIII protein, which is intended for use in creating an animal model of hemophilia A. In some embodiments, the encoded FVIII protein can be used to treat or prevent hemophilia A conditions in a mammalian subject. The FVIII protein may be transferred into a patient (eg, expressed in the patient) in an amount sufficient to treat hemophilia A associated with decreased expression, absence of expression, or dysfunction of the gene.

[00420] In principle, an expression cassette may include a nucleic acid or any transgene that encodes an FVIII protein that is either reduced or absent due to mutation, or that provides a therapeutic benefit when overexpressed, and is considered to be included within the scope of the present invention. Preferably, uninserted bacterial DNA is not present, and preferably, bacterial DNA is not present in the cccDNA compositions provided herein.

[00421] The cccDNA vector is not limited to one ccDNA vector molecule. Thus, in another aspect, multiple cccDNA vectors expressing different proteins or the same FVIII protein but operably linked to different promoters or cis-regulatory elements can be delivered simultaneously or sequentially to a target cell, tissue, organ or organism subject. Thus, this strategy could enable simultaneous gene therapy or gene delivery of multiple proteins. It is also possible to place different parts of the FVIII protein in separate cccDNA vectors (e.g., different domains and/or cofactors required for the functionality of the FVIII protein), for example, which can be introduced simultaneously or at different times, and which can be adjusted separately by adding thereby providing an additional level of control over FVIII protein expression. Delivery can also be performed multiple times and, importantly for gene therapy in a clinical setting, followed by increasing or decreasing doses based on the lack of host immune response against the capsid due to the absence of the viral capsid. An anti-capsid response is not expected to occur due to the absence of a capsid.

[00422] The present invention also provides a method of treating a subject with hemophilia A, comprising administering to a target cell in need thereof (particularly a muscle cell or tissue) of said subject a therapeutically effective amount of a cccDNA vector disclosed herein, optionally with a pharmaceutical acceptable medium. Although the cDNA vector can be introduced in the presence of a carrier, such a carrier is not necessary. The implemented cDNA vector contains a nucleotide sequence of interest that can be used for the treatment of hemophilia A. In particular, the cDNA vector may contain a target exogenous DNA sequence operably linked to control elements capable of directing the transcription of the target polypeptide, protein or oligonucleotide encoded by the specified exogenous DNA sequence when administered to a subject. The cccDNA vector can be introduced by any suitable route suggested above and elsewhere in this document.

Methods for delivering cccDNA vectors for FVIII protein production

[00423] In some embodiments, the cDNA vector for expression of the FVIII protein can be delivered to the target cell in vitro or in vivo by various suitable methods. CctDNA vectors can be used or injected individually. DNA vectors can be delivered into a cell without the aid of a transfection reagent or other physical means. Alternatively, cDNA FVIII protein expression vectors can be delivered using any transfection reagent known in the art or other physical means known in the art that facilitate entry of DNA into the cell, such as liposomes, alcohols, compounds, polylysine-rich compounds, arginine-rich compounds, calcium phosphate, microvesicles, microinjection, electroporation, etc.

[00424] The cDNA FVIII protein expression vectors disclosed herein can be effectively targeted to cell and tissue types that are typically difficult to transduce with conventional AAV virions using various delivery reagents.

[00425] One aspect of the technology described herein relates to a method for delivering FVIII protein into a cell. In general, for in vivo and in vitro methods, the cDNA FVIII protein expression vector disclosed herein can be introduced into a cell using the methods disclosed herein as well as other methods known in the art. The cDNA FVIII protein expression vector disclosed herein is preferably introduced into the cell in a biologically effective amount. If a cccDNA vector is introduced into a cell in vivo (eg, a subject), a biologically effective amount of cccDNA vector is an amount sufficient to transduce and express FVIII protein in the target cell.

[00426] Exemplary methods of administering the cccDNA vector for expression of the FVIII protein disclosed herein include oral, rectal, transmucosal, intranasal, inhalation (e.g., aerosol), buccal (e.g., sublingual), vaginal, intrathecal, intraocular, transdermal, intraendothelial, in utero (or in ovo), parenteral (eg, intravenous, subcutaneous, intradermal, intracranial, intramuscular [including injection into skeletal, diaphragmatic and/or cardiac muscle], intrapleural, intracerebral, and intraarticular). Administration may be systemic or direct delivery to the liver or elsewhere (eg, any kidney, gall bladder, prostate, adrenal gland, heart, intestine, lung, and stomach).

[00427] Administration may be local (for example, to the surface of the skin and mucous membranes, including surfaces of the respiratory tract and transdermal administration), intralymphatic, etc., or by direct injection into a tissue or organ (for example, but not limited to, into the liver, as well as into the eye, muscles including skeletal muscle, cardiac muscle, diaphragmatic muscle, or brain).

[00428] The cccDNA vector can be introduced into any site in a subject, including, without limitation, a site selected from the group consisting of liver and/or also eyes, brain, skeletal muscle, smooth muscle, heart, diaphragm, respiratory epithelium tract, kidney, spleen, pancreas, skin.

[00429] The most appropriate route in any given case will depend on the nature and severity of the condition being treated, ameliorated and/or prevented, as well as the nature of the particular cccDNA vector used. In addition, cccDNA allows the introduction of more than one FVIII protein in one vector or in multiple cccDNA vectors (eg, a mixture of cccDNA).

A. Intramuscular injection of cDNA vector

[00430] In some embodiments, a method of treating a disease in a subject comprises administering to a target cell in need thereof (such as a muscle cell or tissue) of the subject a therapeutically effective amount of a cccDNA vector encoding an FVIII protein, optionally with a pharmaceutically acceptable carrier. In some embodiments, the cDNA vector for expressing the FVIII protein is introduced into muscle tissue of a subject.

[00431] In some embodiments, the cccDNA vector can be administered to any site in a subject, including, without limitation, a site selected from the group consisting of skeletal muscle, smooth muscle, heart, diaphragm, or ocular muscle.

[00432] Administration of the cccDNA vector for expression of the FVIII protein disclosed herein into skeletal muscle in accordance with the present invention includes, but is not limited to, administration into skeletal muscle in the extremities (e.g., upper arm, lower arm, upper parts of the leg and/or lower leg), back, neck, head (eg tongue), chest, abdomen, pelvis/perineum and/or fingers. The cctDNA vector disclosed herein can be delivered to skeletal muscle by intravenous administration, intra-arterial administration, intraperitoneal administration, limb perfusion (optionally isolated limb perfusion for the leg and/or arm; see, for example, Arruda et al., ( 2005) Blood 105: 3458-3464), and/or by direct intramuscular injection. In specific embodiments, the cccDNA vector disclosed herein is administered to the liver, eye, limb (arm and/or leg) of a subject (e.g., a subject with a muscular dystrophy such as DMD) by perfusion of the limb, optionally isolated perfusion of the limb (e.g. , by intravenous or intra-articular administration). In embodiments, the cDNA vector disclosed herein can be administered without the use of “hydrodynamic” techniques.

[00433] For example, tissue (eg, retinal) delivery of conventional viral vectors is often enhanced by hydrodynamic techniques (eg, high-volume intravenous/intravenous administration) that increase vasculature pressure and facilitate the ability of the viral vector to cross the endothelial cell barrier. In specific embodiments, the cccDNA vectors described herein can be administered without hydrodynamic techniques such as large volume infusions and/or increased intravascular pressure (e.g., greater than normal systolic pressure, e.g., an increase in intravascular pressure of less than or equal to 5% , 10%, 15%, 20%, 25% of normal systolic pressure). Such techniques may reduce or avoid side effects associated with hydrodynamic techniques, such as edema, nerve damage, and/or compartment syndrome.

[00434] In addition, a composition containing the cDNA FVIII protein expression vector disclosed herein that is administered to skeletal muscle may be administered to skeletal muscle in the extremities (e.g., upper arm, lower arm, upper arm). legs and/or lower leg), back, neck, head (e.g. tongue), chest, abdomen, pelvis/perineum and/or fingers. Suitable skeletal muscles include, but are not limited to, abductor digiti minimi (hand), abductor pollicis (foot), abductor pollicis, abductor pollicis 5, abductor pollicis brevis, abductor pollicis longus , adductor brevis, adductor hallucis, adductor longus, adductor magnus, adductor pollicis, anconeus, anterior scalene, articular knee, biceps brachii, biceps femoris, brachialis, brachioradialis muscle, buccal muscle, coracobrachialis muscle, corrugator brow muscle, deltoid muscle, depressor anguli oris muscle, depressor labii inferioris muscle, digastric muscle, dorsal interosseous muscles (hands), dorsal interosseous muscles (feet), extensor radialis brevis wrist, extensor carpi radialis longus, extensor carpi ulnaris, extensor of the little finger, extensor digitorum, extensor digitorum brevis, extensor digitorum longus, extensor hallucis brevis, extensor hallucis longus, extensor index finger, extensor pollicis brevis, long extensor pollicis, flexor carpi radialis, flexor carpi ulnaris, flexor digitorum brevis, flexor digitorum brevis, flexor digitorum brevis, flexor digitorum longus, flexor digitorum profundus, flexor digitorum superficialis, flexor hallucis brevis foot, flexor hallucis longus, flexor hallucis brevis, flexor hallucis longus, frontalis, gastrocnemius, geniohyoid, gluteus maximus, gluteus medius, gluteus minimus, gracilis, iliocostalis neck, iliocostalis lumborum, iliocostalis pectoralis, iliacus, inferior gemellus, inferior oblique, inferior rectus, infraspinatus, interspinous muscles, intertransverse muscles, lateral pterygoid, lateral rectus, latissimus dorsi, levator anguli oris, levator labii superioris, levator labii superioris and alae nasi, levator superior pallidum, levator scapulae, long rotator cuff, longissimus capitis, longissimus colli, longissimus thoracis, longus capitis muscle, longus colli muscle, lumbrical muscles (hands), lumbrical muscles (feet), masseter muscle, medial pterygoid muscle, medial rectus muscle, middle scalenus muscle, multifidus muscles, mylohyoid muscle, inferior oblique muscle capitis, superior oblique muscle capitis, obturator externus, obturator internus, occipital muscle, omohyoid muscle, opponus little finger muscle, opponus pollicis muscle, orbicularis oculi muscle, orbicularis oris muscle, palmar interosseous muscle, palmaris brevis, palmaris longus muscle, pectineus muscle, pectoralis major muscle, pectoralis minor muscle, peroneus brevis, peroneus longus muscle, peroneus 3 muscle, piriformis muscle, plantar interosseous muscles, plantaris muscle, subcutaneous neck muscle, popliteus muscle, posterior scalenus muscle, pronator quadratus muscle, pronator teres muscle muscle, psoas major, quadratus femoris, quadratus plantaris, rectus capitis anterior, rectus capitis lateralis, rectus capitis posterior major, rectus capitis posterior minor, rectus femoris, rhomboid major, rhomboid minor, laughter muscles, sartorius muscle, scalenus minor, semimembranosus, semispinalis capitis, semispinalis cervicis, semispinalis pectoralis, semitendinosus, serratus anterior, rotator brevis, soleus, spinalis capitis, spinalis cervicis, spinalis pectoralis, splenius muscle head, splenius neck muscle, sternocleidomastoid muscle, sternohyoid muscle, sternothyroid muscle, stylohyoid muscle, subclavian muscle, subscapularis muscle, superior gemellus muscle, superior oblique muscle, superior rectus muscle, supinator muscle, supraspinatus muscle , temporalis, tensor fasciae lata, teres major, teres minor, chest muscles, thyrohyoid, tibialis anterior, tibialis posterior, trapezius, triceps brachii, vastus intermedius, vastus lateralis , vastus medialis, zygomaticus major and zygomaticus minor, and any other suitable skeletal muscles known in the art.

[00435] Administration of the cccDNA vector for expression of the FVIII protein disclosed herein into the diaphragm muscle can be accomplished by any suitable route, including intravenous administration, intra-arterial administration, and/or intraperitoneal administration. In some embodiments, delivery of a transgene expressed from a cccDNA vector to a target tissue can also be achieved by delivering a synthetic depot containing the cccDNA vector, wherein the depot containing the cccDNA vector is implanted into skeletal, smooth muscle, cardiac, and/or diaphragmatic muscle tissue or the muscle tissue may be contacted with a film or other matrix containing the cDNA vector, as described herein. Such implantable matrices or substrates are described in US Pat. No. 7,201,898.

[00436] Administration of the cccDNA vector for expression of the FVIII protein disclosed herein into cardiac muscle includes administration into the left atrium, right atrium, left ventricle, right ventricle, and/or septum. The cccDNA vector described herein can be delivered to cardiac muscle by intravenous injection, intra-arterial injection such as intra-aortic injection, direct cardiac injection (eg, left atrium, right atrium, left ventricle, right ventricle), and/or coronary artery perfusion.

[00437] Administration of the cccDNA vector for expression of the FVIII protein disclosed herein into smooth muscle can be accomplished by any suitable route, including intravenous administration, intra-arterial administration, and/or intraperitoneal administration. In one embodiment, administration can be performed into, adjacent to, and/or on endothelial cells present in smooth muscle. Non-limiting examples of smooth muscle include the iris, bronchioles of the lung, muscles of the larynx (vocal cords), muscle layers of the stomach, esophagus, small and large intestines of the gastrointestinal tract, ureter, detrusor bladder, myometrium of the uterus, penis or prostate.

[00438] In some embodiments, the cDNA FVIII protein expression vector disclosed herein is introduced into skeletal muscle, diaphragmatic muscle, and/or cardiac muscle. In exemplary embodiments, the cccDNA vector of the present invention is used to treat and/or prevent skeletal, cardiac, and/or diaphragmatic muscle disorders.

[00439] In particular, it is contemplated that a composition comprising the cDNA FVIII protein expression vector disclosed herein can be delivered to one or more muscles of the eye (e.g., lateral rectus, medial rectus, superior rectus, inferior rectus muscle, superior oblique muscle, inferior oblique muscle), facial muscles (such as the occipitofrontal muscle, temporo-parietal muscle, prouder muscle, nasal muscle, depressor septum nasal muscle, orbicularis oculi muscle, corrugator muscle, muscle, depressor brow, auricular muscles, orbicularis oris muscle, depressor anguli oris muscle, laughter muscle, zygomatic major muscle, zygomatic minor muscle, levator labii superioris muscle, levator superior lip and ala nasi muscle, depressor inferior lip muscle, levator anguli oris muscle, buccal muscle, mentalis muscle) or muscles of the tongue (eg, genioglossus muscle, hyoglossus muscle, cartilaginous muscle, styloglossus muscle, palatoglossus muscle, superior longitudinal muscle, inferior longitudinal muscle, vertical muscle and transverse muscle).

(i) Intramuscular injection: In some embodiments, a composition comprising the cDNA FVIII protein expression vector disclosed herein can be administered by injection into one or more sites of a specific muscle, e.g., skeletal muscle (e.g., deltoid, vastus lateralis thigh muscle, ventrogluteal muscle, dorsal gluteus muscle, or anterolateral thigh muscle for infants), in the subject using a needle. The composition containing cccDNA can be introduced into other muscle cell subtypes. Non-limiting examples of muscle cell subtypes include skeletal muscle cells, cardiac muscle cells, smooth muscle cells and/or diaphragmatic muscle cells.

[00440] Methods for intramuscular injection are known to those skilled in the art and therefore are not described in detail herein. However, when performing an intramuscular injection, the appropriate needle size should be determined based on the age and size of the patient, the viscosity of the composition, and the injection site. Table 8 provides guidelines for approximate injection sites and appropriate needle size:

[00441] In certain embodiments, the cDNA FVIII protein expression vector disclosed herein is manufactured in a small volume, such as the approximate volume shown in Table 8, for a particular subject. In some embodiments, a general or local anesthetic may be administered to the subject prior to injection, as appropriate. This is especially desirable if multiple injections are required or if the injection is being given into a deeper muscle rather than the usual injection sites listed above.

[00442] In some embodiments, intramuscular injection can be combined with electroporation, pressure delivery, or the use of transfection reagents to enhance cellular uptake of the cccDNA vector.

(ii) Transfection Reagents: In some embodiments, the cDNA FVIII protein expression vector disclosed herein is formulated into compositions containing one or more transfection reagents to facilitate uptake of the vectors into myotubes or muscle tissue. Thus, in one embodiment, the nucleic acids described herein are introduced into a muscle cell, myotube, or muscle tissue by transfection using methods described elsewhere herein.

(iii) Electroporation: In certain embodiments, the cDNA FVIII protein expression vector disclosed herein is administered without a vehicle to facilitate entry of the ccDNA into cells or in a physiologically inert pharmaceutically acceptable vehicle (i.e., any vehicle that does not enhance or does not enhance the uptake of capsid-free nonviral vectors into myotubes). In such embodiments, uptake of the capsidless nonviral vector can be facilitated by electroporation of the cell or tissue.

[00443] Cell membranes are naturally resistant to the penetration of extracellular objects into the cell cytoplasm. One method of temporarily reducing this resistance is “electroporation,” where electric fields are used to create pores in cells without causing permanent cell damage. These pores are large enough to allow DNA vectors, pharmaceuticals, DNA and other polar compounds to enter the cell. Over time, the pores in the cell membrane close and the cell becomes impenetrable again.

[00444] Electroporation can be used in both in vitro and in vivo applications to introduce, for example, exogenous DNA into living cells. For in vitro applications, a sample of living cells is typically mixed with a composition containing, for example, DNA. The cells are then placed between electrodes, such as parallel plates, and an electric field is applied to the cell/composition mixture.

[00445] There are a number of in vivo electroporation methods; the electrodes may be provided in various configurations, such as, for example, a caliper that engages the epidermis overlying the area of cells to be treated. Alternatively, needle electrodes can be inserted into the tissue to access cells located deeper. In any case, after injecting a composition containing, for example, nucleic acids into the treatment area,

The electrodes apply an electric field to the area. In some electroporation applications, the electric field is a single rectangular pulse of the order of 100-500 V/cm with a duration of 10 to 60 ms. Such a pulse can be generated, for example, in the well-known Electro Square Porator T820 applications manufactured by BTX Division Genetronics, Inc.

[00446] Typically, successful uptake of, for example, nucleic acids occurs only if the muscle is electrically stimulated immediately or shortly after administration of the composition, for example, by injection into the muscle.

[00447] In certain embodiments, electroporation is achieved using pulsed electric fields or using low voltage/long pulse processing schemes (eg, using a square pulse electroporation system). Exemplary pulse generators capable of generating a pulsed electric field include, for example, the ECM600, which can generate an exponential waveform, and the ElectroSquarePorator (T820), which can generate a square waveform, both of which are available from BTX, a division of Genetronics, Inc. (San Diego, California). Square wave electroporation systems deliver controlled electrical pulses that rise rapidly to a set voltage, remain at that level for a set period of time (pulse duration), and then quickly fall to zero.

[00448] In some embodiments, a local anesthetic is administered, for example, by injection into a treatment site to reduce pain that may be associated with electroporation of tissue in the presence of a composition comprising a capsidless non-viral vector, as described herein. In addition, one skilled in the art will appreciate that a dose of the composition should be selected that minimizes and/or prevents excessive tissue damage leading to fibrosis, necrosis, or inflammation of the muscle.

(iv) Delivery Pressure: In some embodiments, delivery of the cDNA FVIII protein expression vector disclosed herein to muscle tissue is facilitated by delivery pressure that uses a combination of high volumes and rapid injection into an artery supplying a limb (e.g., iliac artery). This route of administration can be achieved by a variety of methods that involve infusing the vasculature of the limb with a composition containing the cccDNA vector, typically while isolating the muscle from the systemic circulation using a vascular clamp tourniquet. In one method, the composition is circulated through the vasculature of the limb to allow extravasation into cells. In another method, intravascular hydrodynamic pressure is increased to dilate vascular beds and increase uptake of the cccDNA vector into muscle cells or tissue. In one embodiment, the cccDNA composition is administered into an artery.

(v) Lipid Particulate Compositions: In some embodiments, the cDNA FVIII protein expression vector disclosed herein for intramuscular delivery is formulated as a composition containing a liposome, as described elsewhere herein.

(vi) Systemic administration of a cccDNA vector targeting muscle tissue: In some embodiments, the cccDNA vector for FVIII protein expression disclosed herein is formulated to target muscle through administration by indirect delivery, in which the cccDNA is transported into the muscle, and not to the liver. Accordingly, the technology described herein involves indirectly introducing compositions containing the cDNA FVIII protein expression vector disclosed herein into muscle tissue, for example, by systemic administration. Such compositions can be administered topically, intravenously (by bolus or continuous infusion), by intracellular injection, interstitial injection, orally, by inhalation, intraperitoneally, subcutaneously, intracavity, and they can be delivered by peristaltic means, if necessary, or with by other means known to those skilled in the art. If necessary, the agent can be administered systemically, for example, by intravenous infusion.

[00449] In some embodiments, uptake of a cccDNA FVIII protein expression vector disclosed herein into muscle cells/tissue is increased by the use of a targeting agent or moiety that preferentially targets the vector into muscle tissue. Thus, in some embodiments, the capsidless cccDNA vector may be concentrated in muscle tissue relative to the amount of capsidless cccDNA vectors present in other cells or tissues of the body.

[00450] In some embodiments, a composition comprising a cDNA FVIII protein expression vector disclosed herein further comprises a muscle cell targeting moiety. In other embodiments, the expressed gene product contains a targeting moiety specific to the tissue in which its action is desired. A targeting moiety may include any molecule or complex of molecules that is capable of targeting, interacting, connecting and/or binding to an intracellular, surface or extracellular biomarker of a cell or tissue. The biomarker may include, for example, a cellular protease, kinase, protein, cell surface receptor, lipid and/or aliphatic acid. Other examples of biomarkers that can be targeted, interacted with, coupled to and/or bind to targeting moieties include molecules associated with a particular disease. For example, biomarkers may include cell surface receptors involved in cancer development, such as epidermal growth factor receptor and transferrin receptor. Targeting moieties may include, but are not limited to, synthetic compounds, natural compounds or products, macromolecular entities, bioengineered molecules (e.g., polypeptides, lipids, polynucleotides, antibodies, antibody fragments), and small entities (e.g., small molecules, neurotransmitters, substrates, ligands, hormones and elemental compounds) that bind to molecules expressed in the target muscle tissue.

[00451] In certain embodiments, the targeting moiety may further comprise a receptor molecule, including, for example, receptors that naturally recognize a particular target cell molecule. Such receptor molecules include receptors that have been modified to increase their specificity of interaction with a target molecule, receptors that have been modified to interact with a target molecule not recognized by the receptor in vivo, and fragments of such receptors (see, for example, Skerra , 2000, J. Molecular Recognition, 13:167-187). A preferred receptor is a chemokine receptor. Exemplary chemokine receptors are described, for example, in Lapidot et al, 2002, Exp Hematol, 30:973-81 and Onuffer et al., 2002, Trends Pharmacol Sci, 23:459-67.

[00452] In other embodiments, the additional targeting moiety may comprise a ligand molecule, including, for example, ligands that naturally recognize a particular target cell receptor, such as a transferrin (Tf) ligand. Such ligand molecules include ligands that have been modified to increase their specificity for interaction with a target receptor, ligands that have been modified to interact with a target receptor that is not recognized by the ligand in natural conditions, and fragments of such ligands.

[00453] In other embodiments, the targeting moiety may comprise an aptamer. Aptamers are oligonucleotides selected to specifically bind to the target molecular structure of the target cell. Aptamers are typically the products of an affinity selection process similar to affinity selection in phage display (also known as in vitro molecular evolution). The method involves performing multiple tandem iterations of affinity separation, for example using a solid support to which the pathological immunogen is bound, followed by polymerase chain reaction (PCR) to amplify nucleic acids that have bound to the immunogens. Thus, each round of affinity separation enriches the nucleic acid population with molecules that successfully bind the target immunogen. In this way, a random pool of nucleic acids can be “trained” to produce aptamers that specifically bind target molecules. Aptamers are typically RNA, but may be DNA or analogs or derivatives thereof, such as, but not limited to, peptide nucleic acids (PNAs) and phosphorothioate nucleic acids.

[00454] In some embodiments, the targeting moiety may comprise a photodegradable ligand (i.e., a “locked” ligand) that is released, for example, by exposure to a focused beam of light such that the capsidless nonviral vectors or gene product are targeted to a specific tissue.

[00455] It is also provided herein that the compositions are delivered to multiple sites in one or more muscles of a subject. Thus, injections can be made in at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100 injection sites. Such sites may be distributed over the area of one muscle or may be distributed among several muscles.

B. Introduction of cccDNA vector for expression of FVIII protein in non-muscle sites

[00456] In another embodiment, a cccDNA vector for expressing FVIII protein is administered to the liver. The cDNA vector can also be injected into various areas of the eye, such as the cornea and/or optic nerve. The cDNA vector can also be injected into the spinal cord, brainstem (medulla oblongata, pons), midbrain (hypothalamus, thalamus, epithalamus, pituitary gland, substantia nigra, pineal gland), cerebellum, telencephalon (striatum, cerebral hemispheres, including the occipital , temporal, parietal and frontal lobes, cortex, basal ganglia, hippocampus and amygdala), limbic system, neocortex, striatum, cerebral hemispheres and inferior colliculus. The cctDNA vector can be delivered into the cerebrospinal fluid (eg, via lumbar puncture). A cccDNA vector for FVIII protein expression can be additionally Glu G1 intravascularly into the CNS in situations where the blood-brain barrier is disrupted (eg, brain tumor or cerebral infarction).

[00457] In some embodiments, the cDNA vector for expressing the FVIII protein can be administered to the target area(s) of the eye by any route known in the art, including, but not limited to, intrathecal, intraocular, intracerebral, intraocular, ophthalmic, intravenous (eg, in the presence of a sugar such as mannitol), intranasal, intraaural, intraocular (eg, intravitreal, subretinal, anterior chamber) and periocular (eg, sub-Tenon's region) delivery, and intramuscular delivery with retrograde delivery to motor neurons .

[00458] In some embodiments, the cccDNA vector for expression of the FVIII protein is administered in a liquid formulation by direct injection (eg, stereotactic injection) into a target area or compartment in the CNS. In other embodiments, the cccDNA vector may be provided by topical application to the target area or by intranasal administration of an aerosol formulation. Administration to the eye can be accomplished by topical application of liquid drops. As a further alternative, the cDNA vector can be administered as a slow release solid formulation (see, for example, US Pat. No. 7,201,898). In other additional embodiments, the cccDNA vector can be used for retrograde transport to treat, alleviate, and/or prevent diseases and disorders affecting motor neurons (e.g., amyotrophic lateral sclerosis (ALS); spinal muscular atrophy (SMA), etc.) . For example, the cccDNA vector can be delivered to muscle tissue, from which it can migrate into neurons.

C. Ex vivo treatment

[00459] In some embodiments, the cells are removed from the subject, the cDNA FVIII protein expression vector disclosed herein is introduced into the cells, and the cells are then returned to the subject. Methods for extracting cells from a subject for treatment ex vivo and then reintroducing them back into the subject are known in the art (see, for example, US Pat. No. 5,399,346; the contents of which are incorporated herein in their entirety). Alternatively, the cccDNA vector is introduced into cells obtained from another subject, into cultured cells, or into cells from any other suitable source, and the cells are administered to a subject in need thereof.

[00460] Cells transduced with the cDNA FVIII protein expression vector disclosed herein are preferably administered to a subject in a "therapeutically effective amount" in combination with a pharmaceutical carrier. Those skilled in the art will appreciate that therapeutic effects need not be complete or provide a cure, as long as they are beneficial to the subject in some way.

[00461] In some embodiments, the cccDNA FVIII protein expression vector disclosed herein may encode the FVIII protein described herein (sometimes referred to as a transgene or heterologous nucleotide sequence) that is to be produced in a cell in vitro, ex vivo, or in vivo. For example, in contrast to the use of cccDNA vectors described herein in a method of treatment discussed herein, in some embodiments, a cccDNA vector for expression of FVIII protein can be introduced into cultured cells and the expressed FVIII protein can be isolated from cells, for example to produce antibodies and fusion proteins. In some embodiments, cultured cells containing the cDNA FVIII protein expression vector disclosed herein can be used to commercially produce antibodies or fusion proteins, for example, as a source of cells for small-scale or large-scale biomanufacturing of antibodies or fusion proteins. In alternative embodiments, the cDNA FVIII protein expression vector disclosed herein is introduced into cells in a non-human host for the production of antibodies or fusion proteins in vivo, including small-scale production as well as commercial large-scale production of FVIII protein.

[00462] The cDNA FVIII protein expression vectors disclosed herein can be used in both veterinary and medical applications. Suitable subjects for the ex vivo gene delivery methods described above include both birds (e.g., chickens, ducks, geese, quail, turkeys, and pheasants) and mammals (e.g., human, bovine, ovine, goat, equine, feline, canine) and lagomorphs), with mammals being preferred. Human subjects are most preferred. Human subjects include newborns, infants, children and adolescents, and adults.

D. Dose Ranges

[00463] Provided herein are methods of treatment comprising administering to a subject an effective amount of a composition comprising a cccDNA vector encoding an FVIII protein as described herein. As will be appreciated by a skilled practitioner, the term "effective amount" refers to an administered amount of a cccDNA composition that results in the expression of FVIII protein in a "therapeutically effective amount" for the treatment of hemophilia A.

[00464] In vivo and/or in vitro assays may optionally be used to facilitate the determination of optimal dosage ranges for use. The exact dosage to be used in the formulation will also depend on the route of administration and the severity of the condition and should be determined in accordance with the judgment of one of ordinary skill in the art and the circumstances of each subject. Effective doses can be extrapolated from dose-response curves obtained from in vitro test systems or animal models.

[00465] for protein expression, the FVIIIs disclosed herein are administered in quantities sufficient to transfect cells of the target tissue and ensure sufficient levels of gene transfer and expression without undue adverse effects. Conventional and pharmaceutically acceptable routes of administration include, but are not limited to, those described above in the Introduction section, such as direct delivery to the target organ (eg, intraportal delivery to the liver), oral, inhalation (including intranasal and intratracheal delivery) , 1035 intratumoral and other initial routes of administration. Routes of administration can be combined if required.

[00466] The amount of cccDNA FVIII protein expression vectors disclosed herein required to achieve a given “therapeutic effect” will vary depending on several factors, including, but not limited to: route of nucleic acid administration, level of gene expression or RNA required to achieve a therapeutic effect, the particular disease or disorder being treated, and the stability of the gene(s), RNA product(s), or resulting expressed protein(s). One skilled in the art can readily determine a dosage range of a cccDNA vector for treating a patient suffering from a particular disease or disorder based on the above factors as well as other factors that are well known in the art.

[00467] The dosage schedule can be adjusted to ensure optimal therapeutic response. For example, the oligonucleotide can be administered repeatedly, for example, several doses can be administered daily or the dose can be proportionally reduced according to the requirements of the therapeutic situation. One of ordinary skill in the art will readily be able to determine appropriate dosages and administration schedules for the oligonucleotides in question, regardless of whether the oligonucleotides are to be administered to cells or subjects.

[00468] A "therapeutically effective dose" will be within a relatively wide range, which can be determined through clinical studies, and will depend on the specific application (nerve cells will require very small amounts, while systemic injection will require large amounts). For example, for direct in vivo injection into skeletal or cardiac muscle of a human subject, a therapeutically effective dose would be on the order of about 1 μg to 100 g of cccDNA vector. If exosomes or microparticles are used to deliver the cccDNA vector, the therapeutically effective dose can be determined experimentally but is expected to deliver between 1 μg and approximately 100 g of vector. Moreover, a therapeutically effective dose is an amount of cccDNA vector that expresses a sufficient amount of the transgene to produce an effect in a subject that results in a reduction in one or more symptoms of the disease, but does not result in significant off-target effects or significant unwanted side effects. In one embodiment, a “therapeutically effective amount” is an amount of expressed FVIII protein that is sufficient to produce a statistically significant, measurable change in the expression of a hemophilia A biomarker or reduction in a symptom of a particular disease. Such effective amounts can be calibrated in clinical studies as well as in animal studies for a particular cDNA vector composition.

[00469] The preparation of solutions of pharmaceutically acceptable excipients and carriers is well known to those skilled in the art, as is the development of suitable dosage and treatment regimens for use of the specific compositions described herein in various treatment regimens.

[00470] For in vitro transfection, an effective amount of cccDNA FVIII protein expression vectors disclosed herein for delivery into cells (1×10 ⁶ cells) will be on the order of 0.1 to 100 μg of ccDNA vector, preferably 1 to 20 µg and more preferably 1 to 15 µg or 8 to 10 µg. Larger cccDNA vectors will require higher doses. When using exosomes or microparticles, the effective in vitro dose can be determined experimentally, but will be designed to deliver essentially the same amount of cccDNA vector.

[00471] For the treatment of hemophilia A, the appropriate dosage of a cccDNA vector that expresses the FVIII protein disclosed herein will depend on the specific type of disease being treated, the type of FVIII protein, the severity and course of the hemophilia A disease, previous therapy, medical history patient and response to the antibody, as well as the decision of the attending physician. The cDNA vector encoding the FVIII protein is suitably administered to the patient at one time or over a series of treatments. Various dosing regimens are provided herein, including, but not limited to, single or multiple dosing at different times, bolus dosing, and pulse infusion.

[00472] Depending on the type and severity of the disease, the cccDNA vector is administered in an amount such that the encoded FVIII protein is expressed in the range of about 0.3 mg/kg to 100 mg/kg (e.g., 15 mg/kg to 100 mg /kg or any dosage within this range), by one or more separate administrations or continuous infusion. One typical daily dose of cccDNA vector is sufficient to result in expression of the encoded FVIII protein ranging from about 15 mg/kg to 100 mg/kg or more, depending on the factors mentioned above. One exemplary dose of cccDNA vector is an amount sufficient to result in expression of the encoded FVIII protein as disclosed herein, ranging from about 10 mg/kg to about 50 mg/kg. Thus, the patient may be administered one or more doses of the cccDNA vector in an amount sufficient to result in expression of the encoded FVIII protein at about 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 2. 0 mg/kg, 3 mg/kg, 4.0 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/ kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg or 100 mg/kg (or any combination thereof). In some embodiments, the cccDNA vector is in an amount sufficient to result in expression of the encoded FVIII protein for a total dose ranging from 50 mg to 2500 mg. An exemplary cDNA vector dose is an amount sufficient to result in total expression of the encoded FVIII protein of about 50 mg, about 100 mg, 200 mg, 300 mg, 400 mg, about 500 mg, about 600 mg, about 700 mg, about 720 mg, approximately 1000 mg, approximately 1050 mg, approximately 1100 mg, approximately 1200 mg, approximately 1300 mg, approximately 1400 mg, approximately 1500 mg, approximately 1600 mg, approximately 1700 mg, approximately 1800 mg, approximately 1900 mg, approximately 2000 mg , about 2050 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, or about 2500 mg (or any combination thereof). Since the expression of the FVIII protein from the cccDNA vector can be carefully controlled using regulatory switches herein or, alternatively, multiple doses of the cccDNA vector administered to the subject, the expression of the FVIII protein from the cccDNA vector can be controlled such that doses of the expressed FVIII protein can be administered with intermittently, for example every week, every two weeks, every three weeks, every four weeks, every month, every two months, every three months or every six months with the cccDNA vector. The progress of this therapy can be monitored using routine techniques and tests.

[00473] In certain embodiments, the cccDNA vector is administered in an amount sufficient to result in expression of the encoded FVIII protein at a dose of 15 mg/kg, 30 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg , 60 mg/kg or at a fixed dose, for example, 300 mg, 500 mg, 700 mg, 800 mg or higher. In some embodiments, expression of the FVIII protein from the cccDNA vector is controlled such that the FVIII protein is expressed every day, every other day, every week, every 2 weeks, or every 4 weeks for a period of time. In some embodiments, the expression of the FVIII protein from the cccDNA vector is controlled such that the FVIII protein is expressed every 2 weeks or every 4 weeks for a period of time. In certain embodiments, the time period is 6 months, one year, eighteen months, two years, five years, ten years, 15 years, 20 years, or the lifespan of the patient.

[00474] Treatment may include administration of a single dose or multiple doses. In some embodiments, more than one dose may be administered to a subject; in fact, multiple doses can be administered if necessary, since the cDNA vector does not induce a host immune response against the capsid due to the absence of a viral capsid. Thus, a person skilled in the art can easily determine the appropriate number of doses. The number of doses administered may be, for example, on the order of 1-100, preferably 2-20 doses.

[00475] Without being limited to any particular theory, the absence of the typical antiviral immune response caused by the administration of a cccDNA vector as described in the present disclosure (i.e., the absence of capsid components) allows the ccDNA vector to be administered to the host to express the FVIII protein multiple times. . In some embodiments, the number of times the heterologous nucleic acid is delivered to a subject ranges from 2 to 10 times (eg, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times). In some embodiments, the cDNA vector is delivered to a subject more than 10 times.

[00476] In some embodiments, a dose of the cDNA FVIII protein expression vector disclosed herein is administered to a subject no more than once per calendar day (eg, over a 24-hour period). In some embodiments, a dose of the cccDNA vector is administered to a subject no more than once every 2, 3, 4, 5, 6, or 7 calendar days. In some embodiments, a dose of the cDNA FVIII protein expression vector disclosed herein is administered to a subject no more than once per calendar week (eg, 7 calendar days). In some embodiments, a dose of the cccDNA vector is administered to a subject no more frequently than once every two weeks (eg, once every two calendar weeks). In some embodiments, a dose of the cccDNA vector is administered to a subject no more than once per calendar month (eg, once every 30 calendar days). In some embodiments, a dose of the cccDNA vector is administered to a subject no more than once every six calendar months. In some embodiments, a dose of the cccDNA vector is administered to a subject no more than once per calendar year (eg, 365 days or 366 days in a leap year).

[00477] In particular embodiments, more than one administration (e.g., two, three, four or more administrations) may be used to achieve a target level of gene expression over various periods of time, e.g., daily, weekly, monthly, annually, etc. ) cDNA vector for expression of the FVIII protein disclosed herein.

[00478] In some embodiments, a therapeutic FVIII protein encoded by a cccDNA vector disclosed herein can be regulated by a regulatory switch, an inducible or a repressible promoter such that it is expressed in a subject for at least 1 hour, for at least 1 hour 2 hours, at least 5 hours, at least 10 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 72 hours , at least 1 week, at least 2 weeks, at least 1 month, at least 2 months, at least 6 months, at least 12 months/one year, at least 2 years, at least 5 years, at least 10 years, at least 15 years, at least 20 years, at least 30 years, at least 40 years, at least 50 years or more. In one embodiment, expression can be achieved by reintroducing the cccDNA vectors described herein at predetermined or desired intervals. Alternatively, the cDNA FVIII protein expression vector disclosed herein may further contain gene editing system components (e.g., CRISPR/Cas, TALEN, zinc finger endonucleases, etc.) that allow the insertion of one or more sequences nucleic acids encoding the FVIII protein for a substantially permanent treatment or “cure” of a disease. Such cccDNA vectors containing gene editing components are disclosed in international application PCT/US18/64242 and may include 5' and 3' homology arms (for example, SEQ ID NO: 151-154, or sequences having at least 40% 50%, 60%, 70%, or 80% homology thereto) to insert a nucleic acid encoding the FVIII protein into a safe harbor region such as, but not including, the albumin gene or the CCR5 gene. As an example, a cccDNA vector expressing an FVIII protein may contain at least one genomic safe harbor (GSH)-specific homology arm for inserting an FVIII transgene into a genomic safe harbor, as disclosed in the international application patent PCT/US2019/020225, filed March 1, 2019, which is incorporated herein by reference in its entirety.

[00479] The duration of treatment depends on clinical progress and the patient's response to therapy. Continuous administration of relatively low maintenance doses after an initial higher therapeutic dose is provided.

E. Unit dosage forms

[00480] In some embodiments, pharmaceutical compositions containing the cDNA FVIII protein expression vector disclosed herein may be conveniently presented in a unit dosage form. The unit dosage form is typically adapted for one or more specific routes of administration of the pharmaceutical composition. In some embodiments, the unit dosage form is adapted for drops that will be administered directly into the eye. In some embodiments, the unit dosage form is adapted for administration by inhalation. In some embodiments, the unit dosage form is adapted for administration via a vaporizer. In some embodiments, the unit dosage form is adapted for administration via a nebulizer. In some embodiments, the unit dosage form is adapted for administration using an aerosol generator. In some embodiments, the unit dosage form is adapted for oral administration, for buccal administration, or for sublingual administration. In some embodiments, the unit dosage form is adapted for intravenous, intramuscular, or subcutaneous administration. In some embodiments, the unit dosage form is adapted for subretinal injection, suprachoroidal injection, or intravitreal injection.

[00481] In some embodiments, the unit dosage form is adapted for intrathecal or intracerebroventricular administration. In some embodiments, the pharmaceutical composition is formulated for topical administration. The amount of active ingredient that can be combined with the carrier material to form a unit dosage form will generally be the amount of compound that produces a therapeutic effect.

X. Treatment methods

[00482] The technology described herein also demonstrates methods for preparing, as well as methods for using, the disclosed cccDNA vectors for expression of FVIII protein in various ways, including, for example, ex vivo, ex situ, in vitro and in vivo applications, methodologies, diagnostic gene therapy procedures and/or regimens.

[00483] In one embodiment, the expressed therapeutic FVIII protein expressed from a cccDNA vector disclosed herein is functional for treating a disease. In a preferred embodiment, the FVIII therapeutic protein does not cause an immune system response unless required.

[00484] Provided herein is a method of treating hemophilia A in a subject, comprising administering to a target cell in need thereof (e.g., a muscle cell or tissue, or other type of affected cell) a therapeutically effective amount of a cccDNA expression vector of the subject. the FVIII protein disclosed herein, optionally with a pharmaceutically acceptable carrier. Although the cDNA vector can be introduced in the presence of a carrier, such a carrier is not necessary. The implemented cccDNA vector contains a nucleotide sequence encoding the FVIII protein as described herein, which can be used to treat a disease. In particular, a cccDNA vector for FVIII protein expression may comprise a target FVIII protein DNA sequence operably linked to control elements capable of directing transcription of the target FVIII protein encoded by the exogenous DNA sequence when introduced into a subject. The cDNA FVIII protein expression vector disclosed herein can be administered by any suitable route as described above and elsewhere herein.

[00485] Disclosed herein are compositions and formulations of cccDNA vectors for expression of FVIII protein as disclosed herein, which include one or more ccDNA vectors of the present invention along with one or more pharmaceutically acceptable buffers, diluents or excipients. Such compositions may be included in one or more diagnostic or therapeutic kits for diagnosing, preventing, treating, or alleviating one or more symptoms of hemophilia A. In one aspect, the disease, lesion, disorder, injury, or dysfunction is a disease, lesion, disorder, injury, or human dysfunction.

[00486] Another aspect of the technology described herein provides a method of providing to a subject in need thereof a diagnostically or therapeutically effective amount of a cDNA vector for expressing the FVIII protein disclosed herein, the method comprising providing in a cell, tissue or organ the subject in need thereof, the amount of cccDNA vector disclosed herein; and for a time effective to cause FVIII protein to be expressed from the cccDNA vector, thereby providing the subject with a diagnostically or therapeutically effective amount of FVIII protein expressed by the cccDNA vector. According to a further aspect, the subject is a human being.

[00487] Another aspect of the technology described herein provides a method for diagnosing, preventing, treating, or alleviating at least one or more hemophilia A symptoms, disorder, dysfunction, lesion, abnormal condition, or injury in a subject. Generally and generally, the method includes at least the step of administering to a subject in need thereof one or more of the disclosed cccDNA vectors for producing FVIII protein in an amount and for a time sufficient to diagnose, prevent, treat, or alleviate one or more more symptoms of disease, disorder, dysfunction, lesion, abnormal condition, or injury in the subject. In such an embodiment, the potency of the FVIII protein may be assessed in the subject, or alternatively, the FVIII protein or tissue location of the FVIII protein (including cellular and subcellular location) in the subject may be detected. Thus, the cDNA FVIII protein expression vector disclosed herein can be used as an in vivo diagnostic tool, for example, for detecting cancer or other indications. According to a further aspect, the subject is a human being.

[00488] Another aspect is the use of a cccDNA vector for expressing the FVIII protein disclosed herein as a tool for treating or reducing one or more hemophilia A symptoms or conditions. There are a number of inherited diseases in which defective genes are known, and they generally fall into two classes: deficiency conditions, usually of enzymes, which are usually inherited in a recessive manner, and imbalanced conditions, which may involve regulatory or structural proteins and which are typically , but not always, are inherited in a dominant manner. For unbalanced disease conditions, the cDNA FVIII protein expression vector disclosed herein can be used to create the hemophilia A condition in a model system, which can then be used in interventions to counteract the disease condition. Thus, the cccDNA vector for expression of FVIII protein disclosed herein allows the treatment of genetic diseases. Herein, the condition of hemophilia A is treated by partially or completely correcting the deficiency or imbalance that causes the disease or makes it more severe.

A. Host cells

[00489] In some embodiments, the cDNA FVIII protein expression vector disclosed herein delivers a FVIII protein transgene into a host cell of interest. In some embodiments, the cells are photoreceptor cells. In some embodiments, the cells are RPE cells. In some embodiments, the host cell in question is a human host cell, including, for example, blood cells, stem cells, hematopoietic cells, CD34 ⁺ cells, liver cells, cancer cells, vascular cells, muscle cells, pancreatic cells, nerve cells , eye cells or retinal cells, epithelial or endothelial cells, dendritic cells, fibroblasts or any other cells derived from a mammal, including, without limitation, liver cells (i.e. liver cells), lung cells, cardiac cells, pancreatic cells, intestinal cells, diaphragmatic cells, renal cells (ie, kidneys), nerve cells, blood cells, bone marrow cells, or any one or more selected tissues of the subject for which gene therapy is provided. In one aspect, the host cell in question is a human host cell.

[00490] The present disclosure also relates to recombinant host cells as mentioned above, including the cDNA FVIII protein expression vector disclosed herein. Thus, multiple host cells can be used depending on the purpose, as will be apparent to those skilled in the art. The FVIII protein expression construct or cDNA vector disclosed herein, including the donor sequence, is introduced into a host cell such that the donor sequence is maintained integrated into the chromosome as previously described. The term "host cell" includes any progeny of a parent cell that is not identical to the parent cell due to mutations occurring during replication. The choice of host cell will largely depend on the donor sequence and its source.

[00491] The host cell may also be a eukaryote, such as a mammalian, insect, plant or fungal cell. In one embodiment, the host cell is a human cell (eg, a primary cell, stem cell, or immortalized cell line). In some embodiments, a cDNA FVIII protein expression vector disclosed herein can be introduced into a host cell ex vivo and then delivered to the subject following a gene therapy event. The host cell may be any type of cell, such as a somatic cell or stem cell, an induced pluripotent stem cell, or a blood cell, such as a T cell or B cell, or a bone marrow cell. In certain embodiments, the host cell is an allogeneic cell. For example, T cell genome engineering can be used for various cancer immunotherapies, disease modulation such as HIV therapy (eg, receptor knockout such as CXCR4 and CCR5), and various immunodeficiency therapies. MHC receptors on B cells may be targets for immunotherapy. In some embodiments, genome-edited host cells, such as bone marrow stem cells, such as CD34 ⁺ cells, or induced pluripotent stem cells, can be transplanted back into the patient to express the therapeutic protein. B. Additional diseases for gene therapy:

[00492] In general, the cDNA FVIII protein expression vector disclosed herein can be used to deliver any FVIII protein as described above to treat, prevent, or alleviate symptoms associated with hemophilia A associated with impaired protein expression or gene expression in the subject.

[00493] In some embodiments, the cDNA FVIII protein expression vector disclosed herein can be used to deliver FVIII protein to skeletal, cardiac, or diaphragmatic muscle, to produce FVIII protein for secretion and circulation in the blood, or for systemic delivery to other tissues for the treatment, relief and/or prevention of hemophilia A.

[00494] The cDNA FVIII protein expression vector disclosed herein can be administered to the lungs of a subject by any suitable means, optionally by administering an aerosol suspension of respirable particles containing the cDNA vectors, which the subject inhales. Respirable particles can be liquid or solid. Aerosols of liquid particles containing cccDNA vectors can be produced using any suitable means, such as a pressurized aerosol nebulizer or an ultrasonic nebulizer, as known to those skilled in the art. See, for example, US Pat. No. 4,501,729. Particulate aerosols containing cccDNA vectors can be similarly generated using any particulate drug aerosol generator using techniques known in the pharmaceutical art.

[00495] In some embodiments, the cDNA FVIII protein expression vector disclosed herein can be administered to CNS tissues (eg, brain, eye).

[00496] Ocular disorders that may be treated, ameliorated, or prevented by the cccDNA FVIII protein expression vector disclosed herein include ophthalmic disorders affecting the retina, posterior tract, and optic nerve (e.g., retinitis pigmentosa, diabetic retinopathy, and others degenerative retinal diseases, uveitis, age-related macular degeneration, glaucoma). Many ophthalmic diseases and disorders are associated with one or more of three types of indications: (1) angiogenesis, (2) inflammation, and (3) degeneration. In some embodiments, the cccDNA vector disclosed herein can be used to deliver antiangiogenic factors; anti-inflammatory factors; factors that slow cell degeneration, promote cell preservation or promote cell growth, and combinations of the above. For example, diabetic retinopathy is characterized by angiogenesis. Diabetic retinopathy can be treated by delivering one or more antiangiogenic antibodies or fusion proteins intraocularly (eg, into the vitreous) or periocularly (eg, into the sub-Tenon's region). Additional ocular diseases that may be treated, ameliorated, or prevented by the cccDNA vectors of the present invention include geographic atrophy, vascular or wet macular degeneration, PKU, Leber congenital amaurosis (LCA), Usher syndrome, pseudoxanthoma elasticum (PXE), X-linked retinitis pigmentosa (XLRP), X-linked retinal separation (XLRS), choroideremia, Leber hereditary optic neuropathy (LHON), archomatopsia, rod-cone dystrophy, Fuchs' corneal endothelial dystrophy, diabetic macular edema, and ocular cancers or tumors.

[00497] In some embodiments, inflammatory ocular diseases or disorders (eg, uveitis) can be treated, ameliorated, or prevented using a cccDNA FVIII protein expression vector disclosed herein. One or more anti-inflammatory antibodies or fusion proteins can be expressed by intraocular (eg, vitreous or anterior chamber) administration of a cccDNA vector disclosed herein.

In some embodiments, the cDNA FVIII protein expression vector disclosed herein may encode an FVIII protein that is associated with a transgene encoding a reporter polypeptide (e.g., an enzyme such as green fluorescent protein or alkaline phosphatase). In some embodiments, the transgene that encodes a reporter protein suitable for experimental or diagnostic purposes is selected from any of: p-lactamase, p-galactosidase (LacZ), alkaline phosphatase, thymidine kinase, green fluorescent protein (GFP), chloramphenicol acetyltransferase (CAT) , luciferase and others well known in the art. In some aspects, cccDNA vectors expressing FVIII protein coupled to a reporter polypeptide can be used for diagnostic purposes, as well as to determine the efficacy of, or as markers of, the activity of the cccDNA vector in the subject to which they are administered.

C. Testing for successful gene expression using a cccDNA vector

[00498] To test the efficiency of delivery of the FVIII protein gene using a cccDNA vector, assays well known in the art can be used, which can be performed in both in vitro and in vivo models. Levels of FVIII protein expression by cccDNA can be assessed by one skilled in the art by measuring FVIII mRNA and protein levels (eg, reverse transcription HAZM, Western blot analysis, and enzyme-linked immunosorbent assay (ELISA)). In one embodiment, the cccDNA contains a reporter protein that can be used to assess FVIII protein expression, for example, by examining reporter protein expression using fluorescence microscopy or a luminescence plate reader. For in vivo applications, protein function assays can be used to test the functionality of a given FVIII protein to determine the success of gene expression. One skilled in the art will be able to determine the best test to measure the functionality of the FVIII protein expressed by the cccDNA vector, in vitro or in vivo.

[00499] It is provided herein that the effects of expression of the FVIII protein gene from a cccDNA vector in a cell or subject may last for at least 1 month, at least 2 months, at least 3 months, at least four months, at least 5 months, at least six months, at least 10 months, at least 12 months, at least 18 months, at least 2 years, at least 5 years, at least 10 years, at least 20 years or they can be permanent.

[00500] In some embodiments, the FVIII protein in an expression cassette, expression construct, or cccDNA vector described herein can be codon optimized for a host cell. As used herein, the term “codon optimized” or “codon optimization” refers to the process of modifying a nucleic acid sequence to enhance expression in vertebrate cells of interest, such as mouse or human (eg, humanization), by replacing at least one or more than one or a significant number of codons of a native sequence (eg, a prokaryotic sequence) by codons that are more frequently or most frequently used in the genes of that vertebrate. Different species exhibit specific preferences for certain codons of a particular amino acid. Typically, codon optimization does not change the amino acid sequence of the original translated protein. Optimized codons can be determined using, for example, the Gene Forge® platform for codon optimization and custom gene synthesis from Aptagen (Aptagen, Inc.) or other publicly available database.

D. Determination of Efficacy by Assessing FVIII Protein Expression from a cccDNA Vector

[00501] Essentially any method known in the art for determining protein expression can be used to analyze FVIII protein expression from a cccDNA vector. Non-limiting examples of such methods/assays include enzyme-linked immunosorbent assay (ELISA), affinity ELISA, ELISPOT, serial dilution, flow cytometry, surface plasmon resonance assay, kinetic exclusion assay, mass spectrometry, Western blotting, immunoprecipitation and PCR.

[00502] To assess FVIII protein expression in vivo, a biological sample may be obtained from a subject for analysis. Examples of biological samples include a biofluid sample, a physiological fluid sample, blood (including whole blood), serum, plasma, urine, saliva, biopsy and/or tissue sample, etc. A biological or tissue sample may also refer to a sample of tissue or fluid isolated from an individual, including, but not limited to, tumor biopsy, stool, cerebrospinal fluid, pleural fluid, nipple aspirates, lymph fluid, external sections of skin, respiratory, intestinal and genitourinary tract, tears, saliva, breast milk, cells (including, but not limited to, blood cells), tumors, organs, and samples of in vitro cell culture components. The term also includes a mixture of the samples mentioned above. The term "sample" also includes unprocessed or preprocessed (or preprocessed) biological samples. In some embodiments, the sample used for the assays and methods described herein includes a serum sample collected from the subject to be tested.

E. Determination of the effectiveness of expressed FVIII protein by clinical parameters

[00503] The effectiveness of a given FVIII protein expressed by a cccDNA vector for the treatment of hemophilia A (ie, functional expression) can be determined by a qualified clinician. However, treatment is considered “effective treatment,” as that term is used herein, if any or all of the signs or symptoms of hemophilia A are modified in a favorable manner, or if other clinically accepted symptoms or markers of the disease are improved or alleviated, for example by at least 10% after treatment with a cccDNA vector encoding the therapeutic FVIII protein as described herein. Effectiveness can also be measured by the individual's lack of deterioration, as measured by stabilization of hemophilia A or the need for medical intervention (ie, progression of the disease stops or at least slows). Methods for measuring these indicators are known to those skilled in the art and/or are described herein. Treatment includes any treatment of a disease in an individual or animal (some non-limiting examples include a human or mammal) and includes: (1) inhibiting hemophilia A, eg, stopping or slowing the progression of hemophilia A; or (2) alleviation of hemophilia A, such as causing regression of hemophilia A symptoms; and (3) preventing or reducing the likelihood of developing hemophilia A disease, or preventing secondary diseases/disorders associated with hemophilia A.

An effective amount for treating a disease means an amount that, when administered to a mammal in need thereof, is sufficient to result in effective treatment of that disease, as that term is defined herein. The effectiveness of an agent can be determined by assessing physical indicators that are specific to the disease hemophilia A. A physician may evaluate any one or more clinical symptoms of hemophilia A, which include: unexplained and excessive bleeding from cuts or injuries, or after surgery or dental procedures; many large or deep bruises; unusual bleeding after vaccinations; pain, swelling, or tightness in the joints; blood in urine or stool; nosebleeds without a known cause; in infants - inexplicable irritability.

XI. Various applications of cccDNA vectors expressing antibodies or fusion proteins

[00504] As disclosed herein, the FVIII protein expression compositions and cDNA vectors described herein can be used to express FVIII protein for a variety of purposes. In one embodiment, the cDNA vector expressing the FVIII protein can be used to create a somatic transgenic animal model carrying the transgene, for example, to study the function or progression of hemophilia A. In some embodiments, the cDNA vector expressing the FVIII protein can be used for the treatment, prevention or amelioration of hemophilia A conditions or disorders in a mammalian subject.

[00505] In some embodiments, the FVIII protein can be expressed from a cccDNA vector in a subject in an amount sufficient to treat a disease associated with increased expression, increased activity of the gene product, or nonphysiological upregulation of the gene.

[00506] In some embodiments, the FVIII protein can be expressed from a cccDNA vector in a subject in an amount sufficient to treat hemophilia A with reduced expression, no expression, or dysfunction of the protein.

[00507] One of ordinary skill in the art will understand that the transgene may not be the open reading frame of the gene that is itself transcribed; instead, it may be a promoter region or a repressor region of a target gene, and the cDNA vector may modify such a region, thereby modulating FVIII gene expression.

[00508] The FVIII protein expression compositions and cccDNA vectors disclosed herein can be used to deliver FVIII protein for various purposes, as described above.

[00509] In some embodiments, the transgene encodes one or more FVIII proteins that can be used to treat, alleviate, or prevent hemophilia A conditions in a mammalian subject. The FVIII protein expressed by the cccDNA vector is administered to a patient in an amount sufficient to treat hemophilia A associated with an abnormal gene sequence that can result in any one or more of the following: increased protein expression, overactive protein, decreased expression, no expression or dysfunction target gene or protein.

[00510] 1010 In some embodiments, the cDNA FVIII protein expression vectors disclosed herein are intended for use in diagnostic and screening methods whereby FVIII protein is transiently or stably expressed in a cell culture-based system or, alternatively, in a cell culture model. transgenic animal.

[00511] Another aspect of the technology described herein provides a method for transducing a population of mammalian cells with the cDNA FVIII protein expression vector disclosed herein. Generally and generally, the method includes at least the step of introducing into one or more cells of a population a composition that contains an effective amount of one or more of the cDNA FVIII protein expression vectors disclosed herein.

[00512] In addition, the present invention provides compositions, as well as therapeutic and/or diagnostic kits, that include one or more of the disclosed cccDNA vectors for expression of the FVIII protein as disclosed herein, or cccDNA compositions made with one or more additional ingredients or prepared in accordance with one or more instructions for use.

[00513] The cell into which the cccDNA vector for expression of the FVIII protein disclosed herein is to be introduced can be of any type, including, but not limited to, nerve cells (including cells of the peripheral and central nervous system, in particular cells brain), lung cells, retinal cells, epithelial cells (eg, intestinal and respiratory epithelial cells), muscle cells, dendritic cells, pancreatic cells (including islet cells), liver cells, myocardial cells, bone cells (eg, stem cells bone marrow), hematopoietic stem cells, spleen cells, keratinocytes, fibroblasts, endothelial cells, prostate cells, germ cells, etc. Alternatively, the cell may be any progenitor cell. As a further alternative, the cell may be a stem cell (eg, neural stem cell, liver stem cell). As yet another alternative, the cell may be a cancer or tumor cell. Moreover, the cells can be of any species origin, as indicated above.

A. Preparation and purification of cDNA vectors expressing FVIII

[00514] The cccDNA vectors disclosed herein should be used to produce FVIII protein both in vitro and in vivo. FVIII proteins produced in this manner can be isolated, tested for target function, and purified for further use in research or as therapeutic treatments. Each protein production system has its own advantages/disadvantages. While proteins produced in vitro can be easily purified and proteins produced in a short time, proteins produced in vivo may have post-translational modifications such as glycosylation.

[00515] Therapeutic FVIII protein produced using cDNA vectors can be purified using any method known to those skilled in the art, such as ion exchange chromatography, affinity chromatography, precipitation, or electrophoresis.

[00516] Therapeutic FVIII protein produced using the methods and compositions described herein can be tested to assess binding to the target protein.

EXAMPLES

[00517] The examples below are provided by way of illustration and not limitation. Those of ordinary skill in the art will appreciate that cccDNA vectors can be constructed from any of the wild-type ITRs or modified ITRs described herein, and that the exemplary methods below can be used to construct and evaluate the activity of such cccDNA vectors. Although the methods are exemplary for certain cDNA vectors, they are applicable to any cDNA vector as described.

EXAMPLE 1: Construction of cDNA vectors using an insect cell-based method

[00518] The preparation of cccDNA vectors using a polynucleotide template construct is described in Example 1 of PCT/US18/49996, which is incorporated herein by reference in its entirety. For example, the polynucleotide template construct used to produce the ccDNA vectors of the present invention may be a ccDNA plasmid, a ccDNA bacmid, and/or a ccDNA baculovirus. Without being limited to any theory, in a permissive host cell in the presence of, for example, Rep, a polynucleotide template construct containing two symmetrical ITRs and an expression construct where at least one of the ITRs is modified relative to the wild-type ITR sequence, is replicated to produce cccDNA vectors. Obtaining a cDNA vector takes place in two stages: first, cutting (“extracting”) the template from the template backbone (for example, the genome of a cDNA plasmid, ccDNA bacmid, ccDNA baculovirus, etc.) using Rep proteins, and , secondly, Rep-mediated replication of the excised cccDNA vector.

[00519] An exemplary method for producing cDNA vectors is from a cDNA plasmid, as described herein. In FIG. 1A and 1B, the polynucleotide template of each cDNA plasmid construct includes both a left modified ITR and a right modified ITR, with the following elements located between said ITRs: (i) an enhancer/promoter; (ii) cloning site for the transgene; (iii) a post-transcriptional response element (eg, woodchuck hepatitis virus post-transcriptional regulatory element (WPRE)); and (iv) a polyadenylation signal (eg, from the bovine growth hormone gene (BGHpA)). Unique restriction endonuclease recognition sites (R1-R6) (shown in FIG. 1A and FIG. 1B) were also introduced between each component to facilitate the introduction of new genetic components at specific sites in the constructs. R3 (PmeI) GTTTAAAC (SEQ ID NO: 123) and R4 (PacI) TTAATTAA (SEQ ID NO: 124) enzyme sites were engineered into the cloning site to introduce the open reading frame of the transgene. These sequences were cloned into the pFastBac HT B plasmid obtained from ThermoFisher Scientific.

[00520] Preparation of cccDNA-bacmid:

[00521] DHlOBac competent cells (MAX EFFICIENCY® DH10Bac™ competent cells, Thermo Fisher) were transformed with either test or control plasmids following the protocol according to the manufacturer's instructions. To obtain recombinant cccDNA bacmids, recombination between the plasmid and the baculovirus shuttle vector was induced in DHlOBac cells. Recombinant bacmids were selected by positive screening based on screening for blue-white staining of E. coli (marker Ф80dlacZΔM15 provides α-complementation of the β-galactosidase gene from the bacmid vector) on a bacterial agar plate containing X-gal and IPTG with antibiotics for selection of transformants and maintenance of bacmids and transposase-based plasmids. White colonies resulting from transposition that disrupts the β-galactosidase indicator gene were collected and cultured in 10 ml media.

[00522] Recombinant cccDNA bacmids were isolated from E. coli and transfected into Sf9 or Sf21 insect cells using FugeneHD to produce infectious baculovirus. Adherent Sf9 or Sf21 insect cells were cultured in 50 ml of media in T25 flasks at 25°C. After 4 days, the culture medium (containing P0 virus) was separated from the cells and filtered through a 0.45-μm filter to separate infectious baculovirus particles from cells or cellular debris.

[00523] Optionally, the first generation of baculovirus (P0) was amplified by infecting naïve Sf9 or Sf21 insect cells in 50-500 ml media. Cells were maintained in suspension cultures in an orbital shaker incubator at 130 rpm at 25°C, monitoring cell diameter and cell viability until cells reached a diameter of 18-19 nm (from a naïve cell diameter of 14-15 nm ) and density ~4.0×10 ⁶ cells/ml. At 3 to 8 days postinfection, baculovirus P1 particles in the medium were collected after centrifugation to remove cells and debris, followed by filtration through a 0.45-μm pore size filter.

[00524] The cDNA baculovirus containing the test constructs was collected and the infectivity or titer of the baculovirus was determined. In particular, four x20 ml cultures of Sf9 cells at 2.5 x 10 ⁶ cells/ml were treated with baculovirus P1 in the following dilutions: 1/1000, 1/10000, 1/50000, 1/100000 and incubated at 25-27°C. Infectivity was determined daily for 4-5 days by the increase in cell diameter and cell cycle arrest, as well as changes in cell viability.

[00525] The "Rep plasmid" disclosed in FIG. 8A from PCT/US18/49996, which is incorporated herein by reference in its entirety, was produced in the expression vector pFASTBAC™-Dual (ThermoFisher) containing both Rep78 (SEQ ID NO: 131 or 133) and Rep52 (SEQ ID NO: 132) or Rep68 (SEQ ID NO: 130) and Rep40 (SEQ ID NO: 129). The Rep plasmid was transformed into DH10Bac competent cells (MAX EFFICIENCY® DH10Bac™ competent cells (Thermo Fisher)) following the protocol provided by the manufacturer. To produce recombinant bacmids (“Rep bacmid”), recombination between the Rep plasmid and the baculovirus shuttle vector was induced in DH10Bac cells. Recombinant bacmids were selected by positive selection, which included screening for blue-white staining of E. coli (marker Ф80dlacZΔM15 provides α-complementation of the β-galactosidase gene from the bacmid vector) on a bacterial agar plate containing X-gal and IPTG. Single white colonies were collected and inoculated into 10 ml of selective media (kanamycin, gentamicin, tetracycline in LB broth). Recombinant bacmids (Rep bacmids) were isolated from E. coli, and Sf9 or Sf21 insect cells were transfected with the indicated Rep bacmids to produce infectious baculovirus.

[00526] Sf9 or Sf21 insect cells were cultured in 50 ml media for 4 days and infectious recombinant baculovirus (“Rep-baculovirus”) was isolated from the culture. Optionally, the first generation Rep baculovirus (P0) was amplified by infecting naïve insect cells with Sf9 or Sf21 and cultured in 50-500 ml media. 3-8 days after infection, baculovirus P1 particles in the medium were collected by separating the cells by centrifugation or filtration, or using another fractionation method. Rep-baculovirus was collected and the infectivity of the baculovirus was determined. Specifically, four x20 ml cultures of Sf9 cells at 2.5 x 10 ⁶ cells/ml were treated with baculovirus P1 at the following dilutions, 1/1000, 1/10000, 1/50000, 1/100000, and incubated. Infectivity was determined daily for 4-5 days by the increase in cell diameter and cell cycle arrest, as well as changes in cell viability.

[00527] Preparation and characterization of cccDNA vector

[00528] In FIG. 4The Sf9 insect cell culture medium containing (1) a sample containing cccDNA bacmid or cccDNA baculovirus and (2) Rep baculovirus described above was then added to a fresh Sf9 cell culture (2.5 x 10 ⁶ cells/ ml, 20 ml) at a ratio of 1:1000 and 1:10000, respectively. Cells were then cultured at 130 rpm at 25°C. Cell diameter and viability were detected 4-5 days after co-infection. When the cell diameter reached 18-20 nm with a viability of -70-80%, cell cultures were centrifuged, the medium was removed and cell pellets were collected. Cell pellets were first resuspended in a sufficient volume of aqueous medium, either water or buffer. The cccDNA vector was isolated and purified from cells using the Qiagen MIDI PLUS™ purification protocol (Qiagen, 0.2 mg cell pellet processed per column).

[00529] Yields of cccDNA vectors derived and purified from Sf9 insect cells were initially determined based on UV absorbance at 260 nm.

[00530] DNA vectors can be identified by agarose gel electrophoresis under native or denaturing conditions, as illustrated in FIG. 4D, where (a) the presence of characteristic bands migrating at twice the size on denaturing gels compared to native gels after restriction endonuclease digestion and analysis by gel electrophoresis, and (b) the presence of monomer and dimer bands (2x) on denaturing gels for undigested material is characterized by the presence of a cDNA vector.

[00531] The structures of the isolated cccDNA vectors were further analyzed by digesting DNA obtained from coinfected Sf9 cells (as described herein) with restriction endonucleases selected based on a) the presence of only one cut site in the ccDNA vectors, and b) obtaining fragments large enough to be clearly visible when fractionated on a 0.8% denaturing agarose gel (>800 bp). As illustrated in FIG. 4D and 4E, linear discontinuous DNA vectors and linear and continuous cccDNA vectors can be distinguished by the size of their reaction products—for example, a discontinuous DNA vector is expected to produce 1 kb fragments. and 2 kb, while a capsidless vector with a continuous structure is expected to produce fragments of 2 kb. and 4 thousand bp.

[00532] Thus, to qualitatively demonstrate that the isolated cccDNA vectors have covalently closed ends as required by their definition, samples were digested with a restriction endonuclease identified based on the specific sequence of the DNA vector as a single site restriction endonuclease, preferably resulting in two cleavage products of unequal size (for example, 1000 bp and 2000 bp). After digestion and electrophoresis on a denaturing gel (which separates two complementary DNA strands), linear, non-covalently closed DNA will be separated into 1000 bp fragments. and 2000 bp, while covalently closed DNA (i.e. cDNA vector) will be divided into fragments 2 times larger (2000 bp and 4000 bp), since two chains The DNA is linked, already unfolded, and twice as long (but single-stranded). In addition, when the monomeric, dimeric, and n-mer forms of DNA vectors are digested, they will all separate into fragments of equal sizes due to the interconnected ends of the multimeric DNA vectors (see FIG. 4D).

[00533] As used herein, the expression “assay for identifying DNA vectors by agarose gel electrophoresis on a native gel and under denaturing conditions” refers to an assay for assessing the presence of closed ends of cccDNA by performing restriction endonuclease digestion followed by electrophoretic assessment of the digestion products. The following is one such exemplary analysis, although one of ordinary skill in the art will appreciate that many variations of this example known in the art are possible. The restriction endonuclease is selected to be the enzyme that makes a single cut of the cDNA vector of interest to produce products that are approximately 1/3× and 2/3× the length of the DNA vector. This ensures band separation on both native and denaturing gels. It is important to remove the buffer from the sample before denaturation. Qiagen's PCR Product Purification Kit or desalting "spun columns", such as the GE HEALTHCARE ILUSTRA™ MICROSPIN™ G-25 columns, are some of the endonuclease digestion tools known in the art. The analysis involves, for example, i) digestion of DNA with appropriate restriction endonuclease(s), 2) addition, for example, to a Qiagen PCR purification kit, eluting with distilled water, iii) addition of a 10x denaturing solution (10x=0.5 M NaOH, 10 mM EDTA), adding 10x unbuffered dye, and performing analysis using DNA molecular weight markers prepared by adding a 10x denaturing solution to a 4x, 0.8-1.0% gel, preincubated with 1 mM EDTA and 200 mM NaOH to ensure the same concentration of NaOH in the gel and in the gel box, and analyze the gel in the presence of 1x denaturing solution (50 mM NaOH, 1 mM EDTA). One of ordinary skill in the art will understand what voltage to use for electrophoresis based on size and desired time to obtain results. After electrophoresis, the gels are drained, neutralized in 1x TBE or TAE and transferred to distilled water or 1x TBE/TAE with 1x SYBR Gold. The bands can then be visualized, for example, using Thermo Fisher's SYBR® Gold Nucleic Acid Gel Stain (10,000x concentrate in DMSO) and epifluorescent light (blue) or UV (312 nm).

[00534] The purity of the resulting cccDNA vector can be assessed using any method known in the art. As one exemplary and non-limiting method, the contribution of the cDNA plasmid to the total UV absorbance of the sample can be assessed by comparing the fluorescence intensity of the cDNA vector with a standard. For example, if based on UV absorbance it is determined that 4 μg of ccDNA vector is loaded on the gel, and the fluorescence intensity of the ccDNA vector is equivalent to a 2 kb band. with a known mass of 1 μg, then the mass of the ccDNA vector is 1 μg, and the ccDNA vector constitutes 25% of the total amount of UV absorbing material. Then plot the intensity of the band on the gel as a function of the calculated input amount to which the band corresponds. For example, if the total quantity of the cDNA vector corresponds to 8 kb, and the excised comparative band corresponds to 2 kb, then the intensity of the indicated band on the graph will correspond to 25% of the total amount administered, which in this case will be 0.25 mcg when 1.0 mcg is administered. Using titration of the cccDNA vector plasmid to construct a standard curve, the quantity for the cccDNA vector band is then calculated using the regression line equation, which can then be used to determine the percentage of the total input amount represented by the cccDNA vector, or the percentage purity.

[00535] For comparative purposes, Example 1 describes the preparation of cccDNA vectors using an insect cell-based method and polynucleotide template construct, and is also described in Example 1 of PCT/US18/49996, which is incorporated herein by reference in its entirety. For example, the polynucleotide template construct used to produce the ccDNA vectors of the present invention in accordance with Example 1 may be a ccDNA plasmid, a ccDNA bacmid, and/or a ccDNA baculovirus. Without being limited to any theory, in a permissive host cell in the presence of, for example, Rep, a polynucleotide template construct containing two symmetrical ITRs and an expression construct where at least one of the ITRs is modified relative to the wild-type ITR sequence is replicated to produce cccDNA vectors. Obtaining a cDNA vector takes place in two stages: first, cutting (“extracting”) the template from the template backbone (for example, the genome of a cDNA plasmid, ccDNA bacmid, ccDNA baculovirus, etc.) using Rep proteins, and , secondly, Rep-mediated replication of the excised cccDNA vector.

[00536] An exemplary method for producing cccDNA vectors in an insect cell method is preparation from a cccDNA plasmid as described herein. In FIG. 1A and 1B, the polynucleotide template construct of each cccDNA plasmid includes both a left modified ITR and a right modified ITR, with the following elements located between said ITRs: (i) an enhancer/promoter; (ii) cloning site for the transgene; (iii) a post-transcriptional response element (eg, woodchuck hepatitis virus post-transcriptional regulatory element (WPRE)); and (iv) a polyadenylation signal (eg, from the bovine growth hormone gene (BGHpA)). Unique restriction endonuclease recognition sites (R1-R6) (shown in FIG. 1A and FIG. 1B) were also introduced between each component to facilitate the introduction of new genetic components at specific sites in the constructs. R3 (PmeI) GTTTAAAC (SEQ ID NO: 123) and R4 (PacI) TTAATTAA (SEQ ID NO: 124) enzyme sites were engineered into the cloning site to introduce the open reading frame of the transgene. These sequences were cloned into the pFastBac HT B plasmid obtained from Thermo Fisher Scientific.

EXAMPLE 2: Synthetic production of cDNA by excision from a double-stranded DNA molecule

[00537] The synthetic production of cccDNA vectors is described in Examples 2-6 of International Application PCT/US19/14122, filed January 18, 2019, which is incorporated herein by reference in its entirety. One exemplary method of producing a cDNA vector using a synthetic method involves cutting out a double-stranded DNA molecule. In general, a cccDNA vector can be produced using a double-stranded DNA construct, for example, see FIG. 7A-8E from PCT/US19/14122. In some embodiments, the dsDNA construct is a cDNA plasmid, for example, see FIG. 6 in international patent application PCT/US2018/064242, filed December 6, 2018.

[00538] In some embodiments, the design for producing a cccDNA vector includes a regulatory switch described herein.

[00539] For illustrative purposes, Example 2 describes the preparation of cccDNA vectors as exemplary closed-end DNA vectors prepared using this method. However, although in this Example, cccDNA vectors are exemplified to illustrate synthetic in vitro production methods for producing a closed-end DNA vector by excision of a double-stranded polynucleotide containing an ITR and an expression cassette (e.g., a heterologous nucleic acid sequence), followed by ligation free 3' and 5' ends as described herein, one of ordinary skill in the art will know that, as illustrated above, a double-stranded DNA polynucleotide molecule can be modified to produce any target DNA vector with closed ends, including but not limited to but not limited to, doggybone DNA, dumbbell DNA, etc. Exemplary cccDNA vectors for the production of antibodies or fusion proteins that can be produced using the synthetic production method described in Example 2 are discussed in the sections entitled “III ccDNA Vectors in General.” Exemplary antibodies and fusion proteins expressed by cccDNA vectors are described in the section entitled “Exemplary Antibodies and Fusion Proteins Expressed by cccDNA Vectors.”

[00540] The method includes (i) excision of a sequence encoding an expression cassette from a double-stranded DNA construct, and (ii) formation of hairpin structures at one or more ITRs, and (iii) joining the free 5' and 3' ends by ligation, for example, using T4 DNA ligase.

[00541] The double-stranded DNA construct contains, in order from 5' to 3': a first restriction endonuclease site; left ITR; expression cassette; right ITR; and a second restriction endonuclease site. The double-stranded DNA construct is then contacted with one or more restriction endonucleases to create double-strand breaks at both restriction endonuclease sites. A single endonuclease may target both sites, or each site may be targeted by a different endonuclease, provided that restriction sites are not present in the cccDNA vector template. This allows the sequence between the restriction endonuclease sites to be excised from the rest of the double-stranded DNA construct (see FIG. 9 PCT/US19/14122). After ligation, a DNA vector with closed ends is formed.

[00542] One or both ITRs used in the method may be wild-type ITRs. Modified ITRs may also be used, which modification may include the deletion, insertion or substitution of one or more nucleotides from the wild-type ITR in the sequences forming arms B and B' and/or arms C and C' (see, for example, FIG. 6-8 and 10, FIG. 11B from PCT/US19/14122), and may have two or more hairpin loops (see, for example, FIG. 6-8, FIG. 11B from PCT/US 19/14122) or one hairpin loop (see, for example, FIGS. 10A-10B, FIG. 11B from PCT/US19/14122). A hairpin loop-modified ITR can be generated by genetic modification of an existing oligo or by biological and/or chemical de novo synthesis.

[00543] In a non-limiting example, ITR-6 left and right (SEQ ID NOs: 111 and 112) include 40 nucleotide deletions in arms B-B' and C-C' from the wild-type AAB2 ITR. The nucleotides remaining in the modified ITR are predicted to form a single hairpin structure. The Gibbs free energy of unfolding of the structure is approximately -54.4 kcal/mol. Other modifications may also be made to the ITR, including optional deletion of a functional Rep binding site or TRS site. EXAMPLE 3: obtaining cccDNA by designing oligonucleotides

[00544] Another exemplary method of producing a cccDNA vector using a synthetic method that involves the assembly of various oligonucleotides is presented in Example 3 of PCT/US19/14122, in which a ccDNA vector is prepared by synthesizing a 5' oligonucleotide and a 3' ITR oligonucleotide and ligating said ITR oligonucleotides into a double-stranded polynucleotide containing an expression cassette. In FIG. 11B of PCT/US19/14122 shows an exemplary method for ligating a 3' ITR oligonucleotide and a 3' ITR oligonucleotide into a double-stranded polynucleotide containing an expression cassette.

[00545] As disclosed herein, ITR oligonucleotides may comprise WT-ITR (eg, see FIG. 3A, FIG. 3C) or modified ITRs (eg, see FIG. 3B and FIG. 3D). (See also, for example, FIGS. 6A, 6B, 7A and 7B from PCT/US 19/14122, which is incorporated herein in its entirety). Exemplary ITR oligonucleotides include, but are not limited to, SEQ ID NO: 134-145 (eg, see Table 7 in PCT/US19/14122). Modified ITRs may include the deletion, insertion, or substitution of one or more nucleotides from the wild-type ITR in the sequences forming arms B and B' and/or arms C and C'. ITR oligonucleotides containing WT-ITR or mod-ITR described herein for use in cell-free synthesis can be obtained by genetic modification or biological and/or chemical synthesis. As discussed herein, the ITR oligonucleotides in Examples 2 and 3 may contain WT-ITRs or modified ITRs (mod-ITRs) in symmetric or asymmetric configurations, as discussed herein. EXAMPLE 4: obtaining cccDNA from a single-stranded DNA molecule

[00546] Another exemplary method for producing a cccDNA vector using a synthetic method, presented in Example 4 of PCT/US19/14122, uses single-stranded linear DNA containing two sense ITRs that flank the sense sequence of the expression cassette and are covalently attached to two antisense ITRs , which flank the antisense sequence of the expression cassette, and the ends of the specified single-stranded linear DNA are then ligated to form a single-stranded molecule with closed ends. One non-limiting example involves synthesizing and/or producing a single-stranded DNA molecule, renaturing portions of said molecule to form a single linear DNA molecule that contains one or more base-paired secondary structure regions, then ligating the free 5' and 3' ends together with the formation of a closed single-chain molecule.

[00547] An exemplary single-stranded DNA molecule for producing a cccDNA vector contains, from 5' to 3': a sense first ITR; semantic sequence of the expression cassette; semantic second ITR; antisense second ITR; antisense sequence of the expression cassette; and antisense first ITR.

[00548] The single-stranded DNA molecule for use in the exemplary method of Example 4 can be formed using any DNA synthesis methodology described herein, for example, by in vitro DNA synthesis, or provided by digestion of a DNA construct (e.g., plasmid) with nucleases and melting obtained dsDNA fragments to obtain ssDNA fragments.

[00549] Renaturation can be accomplished by lowering the temperature below the calculated melting temperatures of sense and antisense sequence pairs. The melting point depends on the content of the specific nucleotide bases and the characteristics of the solution used, for example, on the salt concentration. Melting points for any particular sequence and combination of solutions are readily calculated by one of ordinary skill in the art.

[00550] The free 5' and 3' ends of the renatured molecule can be ligated to each other or ligated to a hairpin molecule to form a cccDNA vector. Suitable exemplary ligation methodologies and hairpin molecules are described in Examples 2 and 3.

EXAMPLE 5: Purification and/or confirmation of ccDNA acquisition

[00551] Any of the DNA vector products produced by the methods described herein, for example, including the insect cell-based production methods described in Example 1 or the synthetic production methods described in Examples 2-4, can be purified , for example, to remove impurities, unused components or by-products using methods generally known to a qualified specialist; and/or can be analyzed to confirm that the resulting DNA vector (in this case the cDNA vector) is the target molecule. An exemplary method for purifying a DNA vector, such as cccDNA, is to use the Qiagen Midi Plus purification protocol (Qiagen) and/or gel purification.

[00552] The following is an exemplary method for confirming the identity of cccDNA vectors.

[00553] DNA vectors can be identified by agarose gel electrophoresis under native or denaturing conditions, as illustrated in FIG. 4D, where (a) the presence of characteristic bands migrating at twice the size on denaturing gels compared to native gels after restriction endonuclease digestion and analysis by gel electrophoresis, and (b) the presence of monomer and dimer bands (2x) on denaturing gels for undigested material is characterized by the presence of a cDNA vector.

[00554] The structures of the isolated cccDNA vectors were further analyzed by digesting the purified DNA with restriction endonucleases selected based on a) the presence of only one cutting site in the ccDNA vectors, and b) obtaining fragments large enough to be clearly visible when fractionated into 0.8% denaturing agarose gel (>800 bp). As illustrated in FIG. 4C and 4D, linear discontinuous DNA vectors and linear and continuous cccDNA vectors can be distinguished by the size of their reaction products—for example, a discontinuous DNA vector is expected to produce 1 kb fragments. and 2 kb, while a continuous cccDNA vector is expected to produce 2 kb fragments. and 4 thousand p.o.

[00555] Thus, to qualitatively demonstrate that the isolated cccDNA vectors have covalently closed ends as required by their definition, samples were digested with a restriction endonuclease identified based on the specific sequence of the DNA vector as a single site restriction endonuclease, preferably resulting in two cleavage products of unequal size (for example, 1000 bp and 2000 bp). After digestion and electrophoresis on a denaturing gel (which separates two complementary DNA strands), linear, non-covalently closed DNA will be separated into 1000 bp fragments. and 2000 bp, while covalently closed DNA (i.e. cDNA vector) will be divided into fragments 2 times larger (2000 bp and 4000 bp), since two chains The DNA is linked, already unfolded, and twice as long (but single-stranded). In addition, when the monomeric, dimeric and n-mer forms of DNA vectors are digested, they will all be separated into fragments of the same size due to the interconnected ends of the multimeric DNA vectors (see FIG. 4E).

[00556] As used herein, the expression “assay for identifying DNA vectors by agarose gel electrophoresis on a native gel and under denaturing conditions” refers to an assay for assessing the presence of closed ends of cccDNA by performing restriction endonuclease digestion followed by electrophoretic assessment of the digestion products. The following is one such exemplary analysis, although one of ordinary skill in the art will appreciate that many variations of this example known in the art are possible. The restriction endonuclease is selected to be the enzyme that makes a single cut of the cDNA vector of interest to produce products that are approximately 1/3× and 2/3× the length of the DNA vector. This ensures band separation on both native and denaturing gels. It is important to remove the buffer from the sample before denaturation. Qiagen's PCR Product Purification Kit or desalting "spun columns", such as the GE HEALTHCARE ILUSTRA™ MICROSPIN™ G-25 columns, are some of the endonuclease digestion tools known in the art. The analysis involves, for example, i) digestion of DNA with appropriate restriction endonuclease(s), 2) addition, for example, to a Qiagen PCR purification kit, eluting with distilled water, iii) addition of a 10x denaturing solution (10x=0.5 M NaOH, 10 mM EDTA), adding 10x unbuffered dye, and performing analysis using DNA molecular weight markers prepared by adding a 10x denaturing solution to a 4x, 0.8-1.0% gel, preincubated with 1 mM EDTA and 200 mM NaOH to ensure the same concentration of NaOH in the gel and in the gel box, and analyze the gel in the presence of 1x denaturing solution (50 mM NaOH, 1 mM EDTA). One of ordinary skill in the art will understand what voltage to use for electrophoresis based on size and desired time to obtain results. After electrophoresis, the gels are drained, neutralized in 1x TBE or TAE and transferred to distilled water or 1x TBE/TAE with lx SYBR Gold. The bands can then be visualized, for example, using Thermo Fisher's SYBR® Gold Nucleic Acid Gel Stain (10,000x concentrate in DMSO) and epifluorescent light (blue) or UV (312 nm). The above gel-based method can be adapted for purification purposes by isolating the cDNA vector from the gel band and allowing it to renature.

[00557] The purity of the resulting cccDNA vector can be assessed using any method known in the art. As one exemplary and non-limiting method, the contribution of the cDNA plasmid to the total UV absorbance of the sample can be assessed by comparing the fluorescence intensity of the cDNA vector with a standard. For example, if based on UV absorbance it is determined that 4 μg of ccDNA vector is loaded on the gel, and the fluorescence intensity of the ccDNA vector is equivalent to a 2 kb band. with a known mass of 1 μg, then the mass of the ccDNA vector is 1 μg, and the ccDNA vector constitutes 25% of the total amount of UV absorbing material. The intensity of the band on the gel is then plotted against the calculated input amount to which the band corresponds - for example, if the total amount of cDNA vector corresponds to 8 kb, and the excised comparative band corresponds to 2 kb, then the intensity of the indicated the bars on the graph will correspond to 25% of the total amount administered, which in this case would be 0.25 mcg when 1.0 mcg was administered. Using titration of the cccDNA vector plasmid to construct a standard curve, the quantity for the cccDNA vector band is then calculated using the regression line equation, which can then be used to determine the percentage of the total input amount represented by the cccDNA vector, or the percentage purity.

EXAMPLE 6: Controlled expression of a cccDNA transgene: Expression of a cccDNA vector transgene in vivo can be maintained and/or increased by repeated dosing.

[00558] The cccDNA vector was prepared in accordance with the methods described in Example 1 above, using a ccDNA plasmid containing the CAG promoter (SEQ ID NO: 72) and a luciferase transgene (SEQ ID NO: 56), as an example FVIII, flanked by asymmetric ITRs (eg, 5'-WT-ITR (SEQ ID NO: 2) and 3' mod-ITR (SEQ ID NO: 3)), and were evaluated in various in vivo treatment programs. This cDNA vector was used in all subsequent experiments described in Examples 6-10. In Example 6, the cccDNA vector was purified, formulated as a lipid nanoparticle (LNP-ccDNA) and administered by tail vein injection into each CD-I® IGS mouse. Liposomes were prepared using a suitable lipid mixture containing four components to form lipid nanoparticle (LNP) liposomes, including cationic lipids, auxiliary lipids, cholesterol, and PEG lipids.

[00559] To evaluate sustained in vivo transgene expression from a cccDNA vector over an extended period of time, LNP-ccDNA was administered in sterile PBS by intravenous tail vein injection into CD-I® IGS mice at approximately 5-7 weeks of age. Three groups were evaluated at different dosages: 0.1 mg/kg, 0.5 mg/kg and 1.0 mg/kg, ten mice per group (except for the 1.0 mg/kg group, which had 15 mice per group). Injections were administered on day 0. Five mice from each group received an injection of an additional identical dose on day 28. Luciferase expression was measured by IVIS imaging following intravenous administration of CD-I® IGS mice (Charles River Laboratories; wild-type (WT) mice). Luciferase expression was assessed by IVIS imaging after administration by intraperitoneal injection of 150 mg/kg luciferin substrate on days 3, 4, 7, 14, 21, 28, 31, 35, and 42 and regularly (eg, weekly, twice weekly, or every other every 10 days, or every 2 weeks) between days 42-110. Luciferase transgene expression, exemplified by FVIII, measured by IVIS imaging for at least 132 days after 3 different administration protocols (data not shown).

[00560] An extension study was performed to examine the effect of repeated dosing, eg, repeated administration of LNP-ccDNA expressing luciferase to subjects receiving LNP-ccDNA. In particular, the possibility of increasing expression levels by one or more additional injections of the cccDNA vector was assessed.

[00561] In this study, the biodistribution of cccDNA vector luciferase expression was assessed by IVIS in CD-1® IGS mice after an initial intravenous administration of 1.0 mg/kg (i.e., priming dose) on days 0 and 28 (Group A ). The second administration of cccDNA vector was by tail vein injection of 3 mg/kg (Group B) or 10 mg/kg (Group C) in 1.2 ml tail vein injection on day 84. Five (5) mice were used in this study. CD-1® in each of Groups A, B and C. IVIS imaging of luciferase expression in mice was performed before additional doses on days 49, 56, 63 and 70 as described above, and after repeated doses on day 84 and days 91, 98, 105, 112 and 132. Luciferase expression was assessed and detected in all three Groups A, B and C until at least day 110 (the longest period assessed).

[00562] The level of luciferase expression has been shown to be increased by repeated dosing (ie, repeated administration of a cccDNA composition) of LNP-ccDNA-Luc, as determined by assessing luciferase activity in the presence of luciferin. Luciferase transgene expression, as an example of FVIII, measured by IVIS imaging for at least 110 days after 3 different administration protocols (Groups A, B and C). Mice that did not receive any additional boost dose (priming dose of 1 mg/kg (i.e., Group A)) exhibited stable luciferase expression throughout the study. Mice in Group B that received a repeat dose of 3 mg/kg cccDNA vector showed approximately a sevenfold increase in observed luminosity compared to mice in Group C. Surprisingly, mice that received a repeat dose of 10 mg/kg cccDNA vector showed a 17-fold increase in observed luminosity. increase in observed luciferase luminosity compared to mice that did not receive any repeat dose (Group A).

[00563] Group A CD-1® IGS mice demonstrate luciferase expression following intravenous tail vein administration of 1 mg/kg cccDNA vector on days 0 and 28. Groups B and C CD-1® IGS mice demonstrate luciferase expression following 1 mg administration /kg of cccDNA vector at the first time point (day 0) and a repeat dose of ccDNA vector at the second time point on day 84. A second dose (i.e., boost) of ccDNA vector increased expression by at least 7-fold, and even up to 17 times.

[00564] A 3-fold increase in dose (i.e., amount) of cccDNA vector upon repeated dosing in Group B (i.e., upon repeated dosing of 3 mg/kg) resulted in a 7-fold increase in luciferase expression. Also unexpectedly, a 10-fold increase in the amount of cccDNA vector upon repeated dosing (i.e., a repeat dose of 10 mg/kg) in Group C resulted in a 17-fold increase in luciferase expression. Thus, a second administration (i.e., repeat dose) of cccDNA increased expression by at least 7-fold, and even up to 17-fold. This shows that the increase in transgene expression resulting from repeat dosing is greater than expected and dependent on the dose or amount of cccDNA vector at repeat dosing and appears to be synergistic with the initial transgene expression after the initial priming on day 0 Thus, the dose-dependent increase in transgene expression is not additive, rather, the level of transgene expression is dose-dependent and super-proportional to the total amount of cccDNA vector introduced at each time point.

[00565] Both Groups B and C showed a significant dose-dependent increase in luciferase expression compared to control mice (Group A) that did not receive a repeat dose of the cccDNA vector at the second time point. Taken together, these data indicate that expression of a cccDNA vector transgene can be increased in a dose-dependent manner by re-dosing (ie, reintroducing) the cccDNA vector at at least a second time point.

[00566] Taken together, these data demonstrate that the level of transgene expression, such as FVIII, from cccDNA vectors can be maintained at a steady state for at least 84 days and can be increased in vivo after a repeated dose of cccDNA vector administered at least at least at the second point in time. EXAMPLE 7: Stable expression of a transgene in vivo with cDNA vectors prepared as formulations with LNPs

[00567] The reproducibility of the results obtained in Example 6 with another lipid nanoparticle was assessed in vivo in mice. On day 0, mice were dosed with either a cccDNA vector containing a luciferase transgene driven by the CAG promoter that was encapsulated in an LNP different from that used in Example 6, or the same LNP containing poly(C) but without the ccDNA or luciferase gene. Specifically, male CD-1® mice, approximately 4 weeks old, were given a single injection of 0.5 mg/kg LNP-ccDNA-luciferase or control LNP-poly(C) administered intravenously via the lateral tail vein on day 0. On day 14 The animals were administered systemic luciferin at a dose of 150 mg/kg by intraperitoneal injection at 2.5 ml/kg. Approximately 15 minutes after luciferin administration, each animal was imaged using an in vivo imaging system (“IVIS”).

[00568] As shown in FIG. 7, significant fluorescence in the liver was observed in all four mice receiving cccDNA, with very little fluorescence observed in the animals except at the injection site, indicating that LNPs mediated liver-specific delivery of the cccDNA construct and that the delivered cccDNA vector was capable of controlled, sustained expression of its transgene for at least two weeks after administration. EXAMPLE 8: Sustained expression of a transgene in the liver in vivo after administration of a hCD NK vector

[00569] In a separate experiment, the localization of cccDNA delivered by LNP in the liver of experimental animals was assessed. The gccDNA vector containing the functional transgene of interest was encapsulated in the same LNPs as used in Example 7 and administered to mice in vivo at a dose level of 0.5 mg/kg by intravenous injection. After 6 hours, mice were sacrificed and liver samples were collected, formalin fixed, and paraffin embedded using standard protocols. RNAscope® in situ hybridization assays were performed to visualize cccDNA vectors in tissue using a probe specific for the ccDNA transgene and detection using a chromogenic reaction and hematoxylin staining (Advanced Cell Diagnostics). FIG. 8 shows results that indicate the presence of cccDNA in hepatocytes. EXAMPLE 9: Sustained expression of a cDNA transgene in the eye in vivo

[00570] The persistence of cccDNA vector transgene expression in tissues other than the liver was assessed to determine the tolerability and expression of the ccDNA vector following ocular administration in vivo. Although luciferase was used as an exemplary transgene in Example 9, one of ordinary skill in the art can readily replace the luciferase transgene with an FVIII sequence from any of the sequences listed in Table 1.

[00571] On day 0, male Sprague Dawley rats approximately 9 weeks old were treated by subretinal injection with 5 μl of either a cDNA vector containing a luciferase transgene formulated with jetPEI® transfection reagent (Polyplus) or plasmid DNA encoding luciferase, as a formulation with jetPEI®, in both cases at a concentration of 0.25 μg/μl. Four rats were tested in each group. Animals were sedated and study drug was administered to the right eye by subretinal injection using a 33-gauge needle. The left eye of each animal was left intact. Immediately after injection, eyes were examined by optical coherence tomography or fundus imaging to confirm the presence of a subretinal bleb. Rats received buprenorphine and topical antibiotic ointment according to standard procedures.

[00572] On days 7, 14, 21, 28 and 35, animals in both groups were systemically administered freshly prepared luciferin at a dose of 150 mg/kg by intraperitoneal injection at 2.5 ml/kg. 5-15 minutes after luciferin administration, all animals were imaged using IVIS under isoflurane anesthesia. Total flux [photon/s] and average flux (photon/s/sr/cm ² ) in the region of interest, including the eye, were obtained with an exposure of 5 minutes. The results are presented graphically as the average luminosity in the treated eye (“injected”) for each treatment group relative to the average luminosity in the untreated eye (“uninjected”) for each treatment group (FIG. 9B). Significant fluorescence was readily detected in eyes injected with the cDNA vector, but was much weaker in eyes injected with the plasmid (FIG. 9A). After 35 days, plasmid-injected rats were sacrificed, continuing the study for cccDNA-injected rats with luciferin injection and IVIS imaging on days 42, 49, 56, 63, 70, and 99. The results demonstrate that the cccDNA vector injected into the eye rats by a single injection, mediates transgene expression in vivo and that such expression was maintained at a high level for at least 99 days after injection.

EXAMPLE 10: Chronic dosing and repeated dosing of cccDNA vector in Rag2 mice.

[00573] In situations where one or more transgenes encoded in a cDNA vector gene expression cassette are expressed in a host environment (e.g., a cell or a subject) where the expressed protein is recognized as foreign, there is a possibility that the host an adaptive immune response will be generated that may lead to unwanted depletion of the expression product, which may be mistaken for lack of expression. In some cases, this may occur with a reporter molecule that is heterologous to the normal host environment. Accordingly, cccDNA vector transgene expression was assessed in vivo in the Rag2 mouse model, which lacks B and T cells and therefore does not mount an adaptive immune response to non-mouse-native proteins such as luciferase. In general, on day 0, gene-silenced c57b1/6 and Rag2 mice were treated by intravenous tail vein injection with 0.5 mg/kg LNP-encapsulated ccDNA vector expressing luciferase or poly(C) control, and on day 21 Some mice were given a repeat dose of the same LNP-encapsulated cccDNA vector at the same dose level. All tested groups consisted of 4 mice each. IVIS imaging was performed after luciferin injection as described in Example 9 at weekly intervals.

[00574] When comparing the total flux observed in IVIS assays, the fluorescence observed in wild-type mice (an indirect measure of the presence of expressed luciferase) injected with LNP-ccDNA-vector-Luc gradually decreased after day 21, while Rag2 mice , which were administered the same drug, exhibited relatively constant, robust luciferase expression throughout the 42 days of the experiment (FIG. 10A). The time point at approximately day 21 at which the mice showed a decline corresponds to the time window at which an adaptive immune response can be expected to emerge. Repeated administration of cccDNA vectored LNP to Rag2 mice resulted in a marked increase in expression that was sustained for at least the 21 days observed in this study (FIG. 10B). The results suggest that adaptive immunity may play a role in the expression of a non-native protein from a cccDNA vector in the host, and that the observed decrease in expression at a time period of 20+ days from initial administration may indicate an interfering adaptive immune response to the expressed molecule rather than to decrease expression (or in addition to it). It should be noted that this response is expected to be low when native proteins are expressed in the host, where presumably the host will correctly recognize the expressed molecules as self and will not mount such an immune response.

EXAMPLE 11: Effect of liver-specific expression and CpG modulation on sustained expression

[00575] As described in Example 10, an undesirable host immune response in some cases can artificially dampen what would otherwise be robust expression of one or more targeted transgenes from the introduced cccDNA vector. Two approaches were used to evaluate the effect of avoidance and/or attenuation of potential host immune responses on sustained expression from a cccDNA vector.

First, since the cDNA-Luc vector used in the previous examples was under the control of the constitutive CAG promoter, a similar construct was generated using the liver-specific promoter (hAAT) or another constitutive promoter (hEF-1) to determine whether Avoidance of prolonged exposure to myeloid cells or non-liver tissues will reduce any observed immune effects. Second, some cDNA-luciferase constructs have been engineered to have reduced CpG content, a known trigger of the host immune response. The expression of the luciferase gene encoded by cccDNA was measured when such modified cccDNA vectors with a replaced promoter were administered to mice.

[00576] Three different cDNA vectors were used, each encoding a luciferase transgene. The first ccDNA vector had a large number of unmethylated CpGs (~350) and contained a constitutive C AG promoter (“ccDNA CAG”); the second had a moderate amount of unmethylated CpG (~60) and contained the liver-specific hAAT promoter (“low-CpG hAAT ccDNA”); and the third was a methylated form of the second, lacking the unmethylated CpG, and also containing the hAAT promoter (“hAAT ccDNA without CpG”). Otherwise, the cccDNA vectors were identical. Vectors were prepared as described above.

[00577] Four groups of four male CD-1® mice, approximately 4 weeks old, received one of the LNP-encapsulated cccDNA vectors or a poly(C) control. On day 0, each mouse was given a single intravenous tail vein injection of 0.5 mg/kg cccDNA vector in a volume of 5 ml/kg. Body weight values were recorded on days -1, -, 1, 2, 3, 7 and weekly thereafter until the mice were sacrificed. Whole blood and serum samples were collected on days 0, 1, and 35. Intravital imaging was performed on days 7, 14, 21, 28, and 35, and weekly thereafter using an in vivo imaging system (IVIS). For imaging, each mouse was administered luciferin at 150 mg/kg by intraperitoneal injection at 2.5 ml/kg. After 15 minutes, each mouse was anesthetized and imaged. Mice were sacrificed on day 93 and terminal tissues, including liver and spleen, were collected. Cytokine measurements were performed 6 hours post-dose on day 0.

[00578] Although all cccDNA-treated mice showed significant fluorescence on days 7 and 14, in CAG cctDNA-treated mice, fluorescence decreased rapidly after day 14 and more gradually decreased throughout the remainder of the study. In contrast, in mice receiving low-CpG and no-CpG hAAT cccDNA, total flux remained at a consistently high level (Figure 11). This suggests that targeting the cccDNA vector specifically to the liver resulted in sustained and long-lasting transgene expression from the vector for at least 77 days after a single injection. Constructs with minimal or no CpG content had similar long-term sustained expression profiles, while the construct with a constitutive promoter and high CpG content showed decreased expression over time, suggesting that host immune activation upon introduction of the cccDNA vector may play a role in any decrease in expression observed when such a vector is administered to a subject. These results provide alternative methods for tailoring the duration of the response to the desired level by selecting a tissue-restricted promoter and/or changing the CpG content of the cccDNA vector when a potentially transgene-specific host immune response is observed.

EXAMPLE 12: Hydrodynamic delivery of cccDNA expressing FVIII

[00579] Hydrodynamic tail vein injection is a well-known method for introducing nucleic acid into the liver in rodents. In this system, pressurized injection of a large volume of unencapsulated nucleic acid results in a transient increase in cell permeability and delivery directly into tissues and cells. This provides an experimental mechanism to bypass many host immune systems, such as macrophage recruitment, allowing delivery and expression to be observed in the absence of such activity.

[00580] Three different cccDNA vectors, each with a wild-type left ITR and a truncated mutant right ITR and having a transgenic FVIII coding region, were prepared and purified as described above in Examples 1 and 5. Liver-specific ccDNA FVIII vectors promoter or PBS alone were injected into male C57bl/6J mice at approximately 6 weeks of age. Unprotected cccDNA vectors were administered at a dose of 0.005 mg per animal (4 animals per group) by hydrodynamic intravenous injection through the lateral tail vein in a volume of 1.2 ml administered over 5 seconds, or at a dose of 100 ml/kg administered over 5 -8 seconds. Body weight was measured on days 0, 1, 2, 3 and 7 and then weekly thereafter. Blood samples were collected from each treated animal on days 3, 7, 14, 21, and the final day 28. The presence of expressed FVIII in plasma samples was measured using a Human Total Factor VIII ELISA kit (Innovative Research) ).

[00581] As shown in FIG. 11A, FVIII was readily detected in plasma samples collected on days 3 and 7 from mice treated with two of the three cDNA FVIII vectors, but was not observed in mice treated with PBS. FIG. 11B shows that FVIII expression was dose volume dependent for the two vectors for which FVIII expression was observed and remained relatively constant throughout the 28-day study, with the exception of vector 3, which rapidly declined in expression after day 7. This experiment demonstrated that cccDNA vectors were able to express FVIII from the liver after hydrodynamic injection and that FVIII was rapidly and readily detected in serum after cccDNA injection.

[00582] EXAMPLE 13: Hydrodynamic delivery of FVIII-expressing cccDNA testing of various FVIII-expressing cccDNA vectors

[00583] The hydrodynamic delivery system described in Example 12 was used to test the effect of various cccDNA vectors expressing FVIII on serum FVIII levels, and detection of FVIII in serum indicated that the cccDNA vector was capable of expressing FVIII after injection.

[00584] The cccDNA vectors were prepared as described in Example 12. The cccDNA FVIII vectors (separately, without any encapsulation in LNP) and the control were each administered by hydrodynamic intravenous (IV) injection into C57BL/6 mice. CccDNA vectors were administered at a dose of 5 μg per animal (4 animals per group) by hydrodynamic intravenous injection through the lateral tail vein in a volume of 90-100 mg/ml. The end point was day 7. Vehicle alone was used as a control.

[00585] The following cDNA vectors were tested in three separate experiments. The sequences of the cccDNA vectors below are presented in Table 9. In Table 9, the open reading frame is indicated by underlining. The promoter is shown in bold.

(1) ccDNAFVIII-vector 4, ccDNAFVIII-vector 6, ccDNAFVIII-vector 12, ccDNAFVIII-vector 14, ccDNAFVIII-vector 16, ccDNAFVIII-vector 18, ccDNAFVIII-vector 19, ccDNAFVIII-vector 21, cc DNAFVIII vector 22;

(2) ccDNAFVIII-vector 1, ccDNAFVIII-vector 2, ccDNAFVIII-vector 3, ccDNAFVIII-vector 5, ccDNAFVIII-vector 7, ccDNAFVIII-vector 8, ccDNAFVIII-vector 12, ccDNAFVIII-vector 13, ccDNAFV III-vector 15;

(3) ccDNAFVIII-vector 9, ccDNAFVIII-vector 10, ccDNAFVIII-vector 11, ccDNAFVIII-vector 12, ccDNAFVIII-vector 17, ccDNAFVIII-vector 20, ccDNAFVIII-vector 24, ccDNAFVIII-vector 25, h cDNAFVIII-vector 26.

[00586] Study drugs were supplied as a concentrated stock solution and stored at a nominal temperature of 4°C. The compositions were not vortex mixed or centrifuged. The groups were housed in transparent polycarbonate cages with contact bedding on a ventilated rack in the treatment room. Feed and filtered tap water, acidified with 1 N. HCl to a target pH of 2.5-3.0 was provided to the animals ad libitum. Blood was collected at intermediate and final time points as shown below:

[00587] Blood sample collection was performed as follows:

[00588] Details of the study are described below:

[00589] Species (number, sex, age): C57BL/6 mice (JAX 000664) (N=40 and 4 spare, male, 6 weeks old on arrival) from Jackson Laboratories.

[00590] Compound class: ccDNA.

[00591] Cell Observations: Cell observations were performed daily.

[00592] Clinical Observations: Clinical observations were performed at 1, 5-6, and 24 hours post-dose on Day 0.

[00593] Body weight: Body weight of all animals was recorded on Days 0, 3 and 7, including before sacrifice.

[00594] Dosage form: Study drugs were supplied as a concentrated stock solution. The stock solution was diluted with PBS immediately before use. Prepared materials were stored at ~4°C (or on wet ice) unless dispensing was performed immediately.

[00595] Dosing: Test materials were administered on Day 0 by hydrodynamic IV injection at a prescribed volume per animal, 90-100 ml/kg (depending on the lightest animal in the group) via the lateral tail vein (dosing over 5 seconds).

[00596] Blood Collection: An interim blood sample was collected from the animals on Day 3 according to the table above. After each collection, the animals were subcutaneously injected with 0.5-1.0 ml of lactated Ringer's solution. Blood was collected from animals according to the blood collection tables above. For plasma collections, whole blood was collected into uncoated Eppendorf tubes. 120 μl was immediately withdrawn and placed in tubes containing 13.33 μl of 3.2% sodium citrate. The blood was gently mixed and maintained at ambient temperature until processed. Whole blood samples were centrifuged at 2000 g for 15 minutes under ambient conditions (20-25°C). Plasma samples were collected avoiding cell mass. One (1) aliquot was prepared and any clotting in the whole blood sample or hemolysis in the plasma was noted. All samples were stored at a nominal temperature of -70°C. All samples were stored at a nominal temperature of -70°C until shipment.

[00597] Recovery from anesthesia: Animals were monitored continuously while they were under anesthesia, during recovery, and until mobility was restored.

[00598] Killing and Terminal Blood Collection: On Day 7, animals were sacrificed by CO ₂ asphyxia followed by thoracotomy and exsanguination. The maximum available volume of blood was collected by cardiac puncture and processed for serum according to institutional SOPs and stored in two (2) aliquots. For plasma collections, whole blood was collected using a syringe, and 600 μL was immediately placed into tubes containing 66.66 μL of 3.2% sodium citrate. The blood was gently mixed and maintained at ambient temperature until processed. Whole blood samples were centrifuged at 2000 g for 15 minutes under ambient conditions (20-25°C). Plasma samples were collected, avoiding cell mass, and four (4) aliquots were made. Any clotting in the whole blood sample or hemolysis in the plasma was noted.

[00599] Results: The results shown in FIG. 12-15 show the effect of various cccDNA vectors expressing FVIII on serum FVIII levels, whereby detection of FVIII in serum indicated that the cccDNA vector was capable of expressing FVIII after injection. FIG. 12 is a graph depicting plasma FVIII concentration (IU/mL) 3 days after hydrodynamic delivery of various cccDNA vectors expressing FVIII (ccDNA FVIII vector 4, ccDNA FVIII vector 6, ccDNA FVIII vector 12, ccDNA FVIII vector 14 , cDNAFVIII-vector 16, ccDNAFVIII-vector 18, ccDNAFVIII-vector 19, ccDNAFVIII-vector 21, ccDNAFVIII-vector 22). CccDNAFVIII-vector 16, ccDNAFVIII-vector 19, and ccDNAFVIII-vector 21 showed the highest concentration of factor VIII in plasma after 3 days. Vehicle alone was used as a control. FIG. 13 is a graph showing plasma FVIII concentration (IU/mL) 3 days after hydrodynamic delivery of various cDNA FVIII-expressing vectors (ccDNA FVIII-vector 1, ccDNA FVIII-vector 2, ccDNA FVIII-vector 3, ccDNA FVIII-vector 5 , cDNAFVIII-vector 7, ccDNAFVIII-vector 8, ccDNAFVIII-vector 12, ccDNAFVIII-vector 13, ccDNAFVIII-vector 15). CctDNAFVIII vector 8 showed the highest concentration of factor VIII in plasma after 3 days. Vehicle alone was used as a control. FIG. 14 is a graph depicting plasma FVIII concentration (IU/mL) 3 days after hydrodynamic delivery of various cDNA FVIII-expressing vectors (ccDNA FVIII vector 9, ccDNA FVIII vector 10, ccDNA FVIII vector 11, ccDNA FVIII vector 12 , cDNAFVIII-vector 17, ccDNAFVIII-vector 20, ccDNAFVIII-vector 24, ccDNAFVIII-vector 25, ccDNAFVIII-vector 26). CccDNAFVIII-vector 17 and ccDNAFVIII-vector 20 showed the highest concentration of factor VIII in plasma after 3 days. Vehicle alone was used as a control. FIG. 15 is a graph that depicts plasma FVIII concentration (IU/ml) 1 day after hydrodynamic delivery of increasing doses of cccDNAFVIII vector 23 (0.005-50 μg). As shown in FIG. 15, FVIII in plasma increased in a dose-dependent manner with increasing dosage of cDNAFVIII vector 23. Vehicle alone was used as a control.

EXAMPLE 14: FVIII Expression Following Delivery of LNP:ccDNA in Combination with a Kinase Inhibitor in Male CD-1 Mice

[00600] LNP:ccDNA vectors were prepared as described in Example 6. The effect of cccDNA:lipid formulations was tested in male CD-1 mice. The carrier for dosing and preparing the inhibitor was 0.5% methylcellulose.

[00601] The LNP:ccDNA test material (“ccDNAFVIII-vector 23”) was introduced as follows:

[00602] Blood samples (interim and final) were collected as follows:

[00603] Tissue samples were collected as follows:

[00604] Details of the study are described below:

[00605] Species (number, sex, age): CD-1 mice (Ν=10+2 spare, male, 4 weeks old on arrival) from Charles River Laboratories.

[00606] Cell Observations: Cell observations were performed daily.

[00607] Clinical Observations: Clinical observations were performed approximately 1, 5-6, and 24 hours after dosing of study material on Day 0.

[00608] Body weight: Body weight of all animals was recorded on Days 0, 1, 2, 3 and 7, including before sacrifice.

[00609] Dosage form of the study material: The study drugs were supplied in the form of a concentrated stock solution. The stock solution was diluted with PBS immediately before use. Prepared materials were stored at ~4°C (or on wet ice) unless dispensing was performed immediately.

[00610] Dosing: Study drugs were administered at a dose of 5 ml/kg on Day 0 for Groups 1-2 by intravenous administration through the lateral tail vein.

[00611] Blood Collection: Interim blood samples were collected from all animals in Groups 1-2 on Day 3 according to the blood collection chart above. After each collection, the animals were subcutaneously injected with 0.5-1.0 ml of lactated Ringer's solution. For plasma collections, whole blood was collected into uncoated Eppendorf tubes by orbital sinus puncture under anesthesia according to institutional SOPs. 120 µl was immediately withdrawn and placed in tubes containing 13.33 pL of 3.2% sodium citrate. The blood was mixed gently and stored at ambient temperature until processed. Whole blood samples were centrifuged at 2000 g for 15 minutes under ambient conditions (20-25°C). Plasma samples were collected avoiding cell mass. One (1) aliquot was made and any clotting in the whole blood sample or hemolysis in the plasma will be noted.

[00612] Recovery from anesthesia: Animals were monitored continuously while they were under anesthesia, during recovery, and until mobility was restored.

[00613] Terminal Blood Collection: On Day 7, animals were sacrificed by CO ₂ asphyxia followed by thoracotomy and exsanguination. The maximum available volume of blood was collected by cardiac puncture and processed to obtain plasma. For plasma collections, whole blood was collected using a syringe and 600 μL was immediately placed into tubes containing 66.66 μL of 3.2% sodium citrate. The blood was mixed gently and stored at ambient temperature until processed. Whole blood samples were centrifuged at 2000 g for 15 minutes under ambient conditions (20-25°C). Plasma samples were collected, avoiding cell mass, and two (2) aliquots were made. Any clotting in the whole blood sample or hemolysis in the plasma was noted.

[00614] Perfusion: After exsanguination, all animals were subjected to cardiac perfusion with saline. In general terms, whole body intracardiac perfusion was performed by inserting a 23/21 gauge needle attached to a 10 mL syringe containing saline into the left ventricular lumen for perfusion. The right atrium was incised to provide drainage for the perfusate. Once the needle was placed into the heart, light and constant pressure was applied to the plunger to perfuse the animal. An adequate flow of rinsing solution was maintained until the exiting perfusate became clear (no visible blood), indicating that the rinsing solution had saturated the body and the procedure was complete.

[00615] Tissue Collection: Terminal tissues were collected from agonizing animals that were sacrificed before the planned time point. Whenever possible, tissues from animals that were found dead were collected and preserved.

[00616] After sacrifice and perfusion, the liver was harvested. Four (4) 25-50 mg sections were collected and weighed from the liver. Sections were flash frozen individually and stored at a nominal temperature of −70°C until shipment.

[00617] Results: FIG. 16 shows plasma FVIII concentration (IU/ml) 7 days after administration of the study drug LNP:ccDNAFVIII-vector 23. As shown in FIG. 16, FVIII was readily detected in plasma samples from mice treated with the test drug LNP:ccDNAFVIII vector 23 but was not observed in mice treated with vehicle alone.

LINKS

[00618] All publications and references, including, but not limited to, patents and patent applications set forth in this specification and in the Examples herein, are incorporated by reference in their entirety as if each individual publication or reference were specifically and separately incorporated herein by reference in its entirety. Any patent application to which this application claims priority is also incorporated herein by reference in the manner described above for publications and references.

--->

List of sequences

<110> GENERATION BIO CO.

<120> NON-VIRAL DNA VECTORS AND OPTIONS FOR THEIR APPLICATION FOR EXPRESSION

THERAPEUTIC DRUG BASED ON FACTOR VIII (FVIII)

<130> 131698-06020

<140> PCT/US2020/022738

<141> 2020-03-13

<150> 62/856,432

<151> 2019-06-03

<150> 62/817,904

<151> 2019-03-13

<160> 398

<170> Patent In version 3.5

<210> 1

<211> 141

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 1

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg

60

ccgggcgacc aaaggtcgcc cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc

120

gagcgcgcag ctgcctgcag g

141

<210> 2

<211> 141

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 2

cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcaaag cccgggcgtc

60

gggcgacctt tggtcgcccg gcctcagtga gcgagcgagc gcgcagagag ggagtggcca

120

actccatcac taggggttcc t

141

<210> 3

<211> 130

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 3

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg

60

ccgggcgacc aaaggtcgcc cgacgcccgg gcggcctcag tgagcgagcg agcgcgcagc

120

tgcctgcagg

130

<210> 4

<211> 130

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 4

cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcgtcg ggcgaccttt

60

ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact

120

aggggttcct

130

<210> 5

<211> 143

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 5

ttgcccactc cctctctgcg cgctcgctcg ctcggtgggg cctgcggacc aaaggtccgc

60

agacggcaga ggtctcctct gccggcccca ccgagcgagc gacgcgcgca gagagggagt

120

gggcaactcc atcactaggg taa

143

<210> 6

<211> 144

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 6

ttggccactc cctctatgcg cactcgctcg ctcggtgggg cctggcgacc aaaggtcgcc

60

agacggacgt gggtttccac gtccggcccc accgagcgag cgagtgcgca tagagggagt

120

ggccaactcc atcactagag gtat

144

<210> 7

<211> 127

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 7

ttggccactc cctctatgcg cgctcgctca ctcactcggc cctggagacc aaaggtctcc

60

agactgccgg cctctggccg gcagggccga gtgagtgagc gagcgcgcat agagggagtg

120

gccaact

127

<210> 8

<211> 166

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 8

tcccccctgt cgcgttcgct cgctcgctgg ctcgtttggg ggggcgacgg ccagaggggcc

60

gtcgtctggc agctctttga gctgccaccc ccccaaacga gccagcgagc gagcgaacgc

120

gacagggggg agagtgccac actctcaagc aagggggttt tgtaag

166

<210> 9

<211> 144

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 9

ttgcccactc cctctaatgc gcgctcgctc gctcggtggg gcctgcggac caaaggtccg

60

cagacggcag aggtctcctc tgccggcccc accgagcgag cgagcgcgca tagagggagt

120

gggcaactcc atcactaggg gtat

144

<210> 10

<211> 143

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 10

ttaccctagt gatggagttg cccactccct ctctgcgcgc gtcgctcgct cggtggggcc

60

ggcagaggag acctctgccg tctgcggacc tttggtccgc aggccccacc gagcgagcga

120

gcgcgcagag agggagtggg caa

143

<210> 11

<211> 144

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 11

atacctctag tgatggagtt ggccactccc tctatgcgca ctcgctcgct cggtggggcc

60

ggacgtggaa acccacgtcc gtctggcgac ctttggtcgc caggccccac cgagcgagcg

120

agtgcgcata gagggagtgg ccaa

144

<210> 12

<211> 127

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 12

agttggccac attagctatg cgcgctcgct cactcactcg gccctggaga ccaaaggtct

60

ccagactgcc ggcctctggc cggcagggcc gagtgagtga gcgagcgcgc atagagggag

120

tggccaa

127

<210> 13

<211> 166

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 13

cttacaaaac ccccttgctt gagagtgtgg cactctcccc cctgtcgcgt tcgctcgctc

60

gctggctcgt ttgggggggt ggcagctcaa agagctgcca gacgacggcc ctctggccgt

120

cgccccccca aacgagccag cgagcgagcg aacgcgacag ggggga

166

<210> 14

<211> 144

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 14

atacccctag tgatggagtt gcccactccc tctatgcgcg ctcgctcgct cggtggggcc

60

ggcagaggag acctctgccg tctgcggacc tttggtccgc aggccccacc gagcgagcga

120

gcgcgcatta gagggagtgg gcaa

144

<210> 15

<211> 120

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 15

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg

60

cgcacgcccg ggtttcccgg gcggcctcag tgagcgagcg agcgcgcagc tgcctgcagg

120

<210> 16

<211> 122

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 16

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg

60

ccgacgcccg ggctttgccc gggcggcctc agtgagcgag cgagcgcgca gctgcctgca

120

gg

122

<210> 17

<211> 129

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 17

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg

60

ccgggcgacc aaaggtcgcc cgacgcccgg gcgcctcagt gagcgagcga gcgcgcagct

120

gcctgcagg

129

<210> 18

<211> 101

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 18

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg

60

ctttgcctca gtgagcgagc gagcgcgcag ctgcctgcag g

101

<210> 19

<211> 139

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 19

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg

60

ccgggcgaca aagtcgcccg acgcccgggc tttgcccggg cggcctcagt gagcgagcga

120

gcgcgcagct gcctgcagg

139

<210> 20

<211> 137

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 20

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg

60

ccgggcgaaa atcgcccgac gcccgggctt tgcccgggcg gcctcagtga gcgagcgagc

120

gcgcagctgc ctgcagg

137

<210> 21

<211> 135

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 21

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg

60

ccgggcgaaa cgcccgacgc ccgggctttg cccgggcggc ctcagtgagc gagcgagcgc

120

gcagctgcct gcagg

135

<210> 22

<211> 133

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 22

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg

60

ccgggcaaag cccgacgccc gggctttgcc cgggcggcct cagtgagcga gcgagcgcgc

120

aggctgcctgc agg

133

<210> 23

<211> 139

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 23

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg

60

ccgggcgacc aaaggtcgcc cgacgcccgg gtttcccggg cggcctcagt gagcgagcga

120

gcgcgcagct gcctgcagg

139

<210> 24

<211> 137

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 24

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg

60

ccgggcgacc aaaggtcgcc cgacgcccgg tttccgggcg gcctcagtga gcgagcgagc

120

gcgcagctgc ctgcagg

137

<210> 25

<211> 135

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 25

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg

60

ccgggcgacc aaaggtcgcc cgacgcccgt ttcgggcggc ctcagtgagc gagcgagcgc

120

gcagctgcct gcagg

135

<210> 26

<211> 133

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 26

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg

60

ccgggcgacc aaaggtcgcc cgacgccctt tgggcggcct cagtgagcga gcgagcgcgc

120

aggctgcctgc agg

133

<210> 27

<211> 131

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 27

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg

60

ccgggcgacc aaaggtcgcc cgacgccttt ggcggcctca gtgagcgagc gagcgcgcag

120

ctgcctgcag g

131

<210> 28

<211> 129

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 28

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg

60

ccgggcgacc aaaggtcgcc cgacgctttg cggcctcagt gagcgagcga gcgcgcagct

120

gcctgcagg

129

<210> 29

<211> 127

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 29

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg

60

ccgggcgacc aaaggtcgcc cgacgtttcg gcctcagtga gcgagcgagc gcgcagctgc

120

ctgcagg

127

<210> 30

<211> 122

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 30

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg

60

ccgggcgacc aaaggtcgcc cgacggcctc agtgagcgag cgagcgcgca gctgcctgca

120

gg

122

<210> 31

<211> 130

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 31

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg

60

ccgggcgacc aaaggtcgcc cgacgcccgg gcggcctcag tgagcgagcg agcgcgcagc

120

tgcctgcagg

130

<210> 32

<211> 120

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 32

cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggaaacc cgggcgtgcg

60

cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact aggggttcct

120

<210> 33

<211> 122

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 33

cctgcaggca gctgcgcgct cgctcgctca ctgaggccgt cgggcgacct ttggtcgccc

60

ggcctcagtg agcgagcgag cgcgcagaga gggagtggcc aactccatca ctaggggttc

120

ct

122

<210> 34

<211> 122

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 34

cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcaaag cccgggcgtc

60

ggcctcagtg agcgagcgag cgcgcagaga gggagtggcc aactccatca ctaggggttc

120

ct

122

<210> 35

<211> 129

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 35

cctgcaggca gctgcgcgct cgctcgctca ctgaggcgcc cgggcgtcgg gcgacctttg

60

gtcgcccggc ctcagtgagc gagcgagcgc gcagagaggg agtggccaac tccatcacta

120

ggggttcct

129

<210> 36

<211> 101

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 36

cctgcaggca gctgcgcgct cgctcgctca ctgaggcaaa gcctcagtga gcgagcgagc

60

gcgcagagag ggagtggcca actccatcac taggggttcc t

101

<210> 37

<211> 139

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 37

cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcaaag cccgggcgtc

60

gggcgacttt gtcgcccggc ctcagtgagc gagcgagcgc gcagagaggg agtggccaac

120

tccatcacta ggggttcct

139

<210> 38

<211> 137

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 38

cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcaaag cccgggcgtc

60

gggcgatttt cgcccggcct cagtgagcga gcgagcgcgc agagagggag tggccaactc

120

catcactagg ggttcct

137

<210> 39

<211> 135

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 39

cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcaaag cccgggcgtc

60

gggcgtttcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg gccaactcca

120

tcactagggg ttcct

135

<210> 40

<211> 133

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 40

cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcaaag cccgggcgtc

60

gggctttgcc cggcctcagt gagcgagcga gcgcgcagag agggagtggc caactccatc

120

actaggggtt cct

133

<210> 41

<211> 139

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 41

cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggaaacc cgggcgtcgg

60

gcgacctttg gtcgcccggc ctcagtgagc gagcgagcgc gcagagaggg agtggccaac

120

tccatcacta ggggttcct

139

<210> 42

<211> 137

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 42

cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccggaaaccg ggcgtcgggc

60

gacctttggt cgcccggcct cagtgagcga gcgagcgcgc agagagggag tggccaactc

120

catcactagg ggttcct

137

<210> 43

<211> 135

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 43

cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgaaacggg cgtcgggcga

60

cctttggtcg cccggcctca gtgagcgagc gagcgcgcag agagggagtg gccaactcca

120

tcactagggg ttcct

135

<210> 44

<211> 133

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 44

cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccaaagggcg tcgggcgacc

60

tttggtcgcc cggcctcagt gagcgagcga gcgcgcagag agggagtggc caactccatc

120

actaggggtt cct

133

<210> 45

<211> 131

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 45

cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc caaaggcgtc gggcgacctt

60

tggtcgcccg gcctcagtga gcgagcgagc gcgcagagag ggagtggcca actccatcac

120

tagggggttcct

131

<210> 46

<211> 129

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 46

cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc aaagcgtcgg gcgacctttg

60

gtcgcccggc ctcagtgagc gagcgagcgc gcagagaggg agtggccaac tccatcacta

120

ggggttcct

129

<210> 47

<211> 127

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 47

cctgcaggca gctgcgcgct cgctcgctca ctgaggccga aacgtcgggc gacctttggt

60

cgcccggcct cagtgagcga gcgagcgcgc agagagggag tggccaactc catcactagg

120

ggttcct

127

<210> 48

<211> 122

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 48

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg

60

ccgggcgacc aaaggtcgcc cgacggcctc agtgagcgag cgagcgcgca gctgcctgca

120

gg

122

<210> 49

<211> 12

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 49

cgatcgttcg at

12

<210> 50

<211> 12

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 50

atcgaaccat cg

12

<210> 51

<211> 12

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 51

atcgaacgat cg

12

<210> 52

<211> 165

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 52

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg

60

ccgcccgggc aaagcccggg cgtcgggcga cctttggtcg cccggcctca gtgagcgagc

120

gagcgcgcag agagggagtg gccaactcca tcactagggg ttcct

165

<210> 53

<211> 140

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 53

cccctagtga tggagttggc cactccctct ctgcgcgctc gctcgctcac tgaggccgcc

60

cggggcaaagc ccgggcgtcg ggcgaccttt ggtcgcccgg cctcagtgag cgagcgagcg

120

cgcagagaga tcactagggg

140

<210> 54

<211> 91

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 54

gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgacctttgg

60

tcgcccggcc tcagtgagcg agcgagcgcg c

91

<210> 55

<211> 91

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 55

gcgcgctcgc tcgctcactg aggccgggcg accaaaggtc gcccgacgcc cgggctttgc

60

ccgggcggcc tcagtgagcg agcgagcgcg c

91

<210> 56

<211> 1662

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 56

gccgccacca tggaagacgc caaaaacata aagaaaggcc cggcgccatt ctatccgctg

60

gaagatggaa ccgctggaga gcaactgcat aaggctatga agagatacgc cctggttcct

120

ggaacaattg cttttacaga tgcacatatc gaggtggaca tcacttacgc tgagtacttc

180

gaaatgtccg ttcggttggc agaagctatg aaacgatatg ggctgaatac aaatcacaga

240

atcgtcgtat gcagtgaaaa ctctcttcaa ttctttatgc cggtgttggg cgcgttattt

300

atcggagttg cagttgcgcc cgcgaacgac atttataatg aacgtgaatt gctcaacagt

360

atgggcattt cgcagcctac cgtggtgttc gtttccaaaa aggggttgca aaaaattttg

420

aacgtgcaaa aaaagctccc aatcatccaa aaaattatta tcatggattc taaaacggat

480

taccagggat ttcagtcgat gtacacgttc gtcacatctc atctacctcc cggttttaat

540

gaatacgatt ttgtgccaga gtccttcgat agggacaaga caattgcact gatcatgaac

600

tcctctggat ctactggtct gcctaaaggt gtcgctctgc ctcatagaac tgcctgcgtg

660

agattctcgc atgccagaga tcctattttt ggcaatcaaa tcattccgga tactgcgatt

720

ttaagtgttg ttccattcca tcacggtttt ggaatgttta ctacactcgg atatttgata

780

tgtggatttc gagtcgtctt aatgtataga tttgaagaag agctgtttct gaggagcctt

840

caggattaca agattcaaag tgcgctgctg gtgccaaccc tattctcctt cttcgccaaa

900

agcactctga ttgacaaata cgatttatct aatttacacg aaattgcttc tggtggcgct

960

cccctctcta aggaagtcgg ggaagcggtt gccaagaggt tccatctgcc aggtatcagg

1020

caaggatatg ggctcactga gactacatca gctattctga ttacacccga gggggatgat

1080

aaaccgggcg cggtcggtaa agttgttcca ttttttgaag cgaaggttgt ggatctggat

1140

accgggaaaa cgctgggcgt taatcaaaga ggcgaactgt gtgtgagagg tcctatgatt

1200

atgtccggtt atgtaaacaa tccggaagcg accaacgcct tgattgacaa ggatggatgg

1260

ctacattctg gagacatagc ttactgggac gaagacgaac acttcttcat cgttgaccgc

1320

ctgaagtctc tgattaagta caaaggctat caggtggctc ccgctgaatt ggaatccatc

1380

ttgctccaac accccaacat cttcgacgca ggtgtcgcag gtcttcccga cgatgacgcc

1440

ggtgaacttc ccgccgccgt tgttgttttg gagcacggaa agacgatgac ggaaaaagag

1500

atcgtggatt acgtcgccag tcaagtaaca accgcgaaaa agttgcgcgg aggagttgtg

1560

tttgtggacg aagtaccgaa aggtcttacc ggaaaactcg acgcaagaaa aatcagagag

1620

atcctcataa aggccaagaa gggcggaaag atcgccgtgt aa

1662

<210> 57

<211> 453

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polypeptide

<220>

<221> MOD_RES

<222> (1)..(1)

<223> Any amino acid

<400> 57

Xaa Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Ser Tyr

20 25 30

Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Val Ile Trp Phe Asp Gly Thr Lys Lys Tyr Tyr Thr Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Thr Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Arg Gly Ile Gly Ala Arg Arg Gly Pro Tyr Tyr Met Asp

100 105 110

Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys

115 120 125

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

130 135 140

Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro

145 150 155 160

Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr

165 170 175

Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val

180 185 190

Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn

195 200 205

Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro

210 215 220

Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu

225 230 235 240

Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

245 250 255

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

260 265 270

Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly

275 280 285

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn

290 295 300

Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp

305 310 315 320

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro

325 330 335

Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu

340 345 350

Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn

355 360 365

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

370 375 380

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

385 390 395 400

Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

405 410 415

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

420 425 430

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

435 440 445

Ser Leu Ser Pro Gly

450

<210> 58

<211> 214

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polypeptide

<400> 58

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

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

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 59

<211> 1310

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 59

ggagccgaga gtaattcata caaaaggagg gatcgccttc gcaaggggag agcccaggga

60

ccgtccctaa attctcacag acccaaatcc ctgtagccgc cccacgacag cgcgaggagc

120

atgcgctcag ggctgagcgc ggggagagca gagcacacaa gctcatagac cctggtcgtg

180

ggggggagga ccggggagct ggcgcggggc aaactgggaa agcggtgtcg tgtgctggct

240

ccgccctctt cccgagggtg ggggagaacg gtatataagt gcggcagtcg ccttggacgt

300

tctttttcgc aacgggtttg ccgtcagaac gcaggtgagg ggcgggtgtg gcttccgcgg

360

gccgccgagc tggaggtcct gctccgagcg ggccggggccc cgctgtcgtc ggcggggatt

420

agctgcgagc attcccgctt cgagttgcgg gcggcgcggg aggcagagtg cgaggcctag

480

cggcaacccc gtagcctcgc ctcgtgtccg gcttgaggcc tagcgtggtg tccgcgccgc

540

cgccgcgtgc tactccggcc gcactctggt cttttttttt tttgttgttg ttgccctgct

600

gccttcgatt gccgttcagc aataggggct aacaaaggga gggtgcgggg cttgctcgcc

660

cggagcccgg agaggtcatg gttggggagg aatggaggga caggagtggc ggctggggcc

720

cgcccgcctt cggagcacat gtccgacgcc acctggatgg ggcgaggcct ggggtttttc

780

ccgaagcaac caggctgggg ttagcgtgcc gaggccatgt ggccccagca cccggcacga

840

tctggcttgg cggcgccgcg ttgccctgcc tccctaacta gggtgaggcc atcccgtccg

900

gcaccagttg cgtgcgtgga aagatggccg ctcccggggcc ctgttgcaag gagctcaaaa

960

tggaggacgc ggcagcccgg tggagcgggc gggtgagtca cccacacaaa ggaagagggc

1020

ctggtccctc accggctgct gcttcctgtg accccgtggt cctatcggcc gcaatagtca

1080

cctcgggctt ttgagcacgg ctagtcgcgg cggggggagg ggatgtaatg gcgttggagt

1140

ttgttcacat ttggtgggtg gagactagtc aggccagcct ggcgctggaa gtcatttttg

1200

gaatttgtcc ccttgagttt tgagcggagc taattctcgg gcttcttagc ggttcaaagg

1260

tatcttttaa accctttttt aggtgttgtg aaaaccaccg ctaattcaaa

1310

<210> 60

<211> 16

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 60

gcgcgctcgc tcgctc

16

<210> 61

<211> 6

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 61

ggttga

6

<210> 62

<211> 4

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 62

agtt

4

<210> 63

<211> 6

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 63

ggttgg

6

<210> 64

<211> 6

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 64

agttgg

6

<210> 65

<211> 6

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 65

agttga

6

<210> 66

<211> 6

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 66

rrttrr

6

<210> 67

<211> 581

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 67

gagcatctta ccgccattta ttcccatatt tgttctgttt ttcttgattt gggtatacat

60

ttaaatgtta ataaaacaaa atggtggggc aatcatttac atttttaggg atatgtaatt

120

actagttcag gtgtattgcc acaagacaaa catgttaaga aactttcccg ttatttacgc

180

tctgttcctg ttaatcaacc tctggattac aaaatttgtg aaagattgac tgatattctt

240

aactatgttg ctccttttac gctgtgtgga tatgctgctt tatagcctct gtatctagct

300

attgcttccc gtacggcttt cgttttctcc tccttgtata aatcctggtt gctgtctctt

360

ttagaggagt tgtggcccgt tgtccgtcaa cgtggcgtgg tgtgctctgt gtttgctgac

420

gcaaccccca ctggctgggg cattgccacc acctgtcaac tcctttctgg gactttcgct

480

ttccccctcc cgatcgccac ggcagaactc atcgccgcct gccttgcccg ctgctggaca

540

ggggctaggt tgctgggcac tgataattcc gtggtgttgt c

581

<210> 68

<211> 225

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 68

tgtgccttct agttgccagc catctgttgt ttgcccctcc cccgtgcctt ccttgaccct

60

ggaaggtgcc actcccactg tcctttccta ataaaatgag gaaattgcat cgcattgtct

120

gagtaggtgt cattctattc tggggggtgg ggtggggcag gacagcaagg gggaggattg

180

ggaagacaat agcaggcatg ctggggatgc ggtgggctct atggc

225

<210> 69

<211> 8

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 69

actgaggc

8

<210> 70

<211> 8

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 70

gcctcagt

8

<210> 71

<211> 16

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 71

gagcgagcga gcgcgc

16

<210> 72

<211> 1923

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 72

tcaatattgg ccattagcca tattattcat tggttatata gcataaatca atattggcta

60

ttggccattg catacgttgt atctatatca taatatgtac atttatattg gctcatgtcc

120

aatatgaccg ccatgttggc attgattatt gactagttat taatagtaat caattacggg

180

gtcattagtt catagcccat atatggagtt ccgcgttaca taacttacgg taaatggccc

240

gcctggctga ccgcccaacg acccccgccc attgacgtca ataatgacgt atgttcccat

300

agtaacgcca atagggactt tccattgacg tcaatgggtg gagtatttac ggtaaactgc

360

ccacttggca gtacatcaag tgtatcatat gccaagtccg ccccctattg acgtcaatga

420

cggtaaatgg cccgcctggc attatgccca gtacatgacc ttacgggact ttcctacttg

480

gcagtacatc tacgtattag tcatcgctat taccatggtc gaggtgagcc ccacgttctg

540

cttcactctc cccatctccc ccccctcccc acccccaatt ttgtatttat ttatttttta

600

attattttgt gcagcgatgg gggcgggggg gggggggggg cgcgcgccag gcggggcggg

660

gcggggcgag gggcggggcg gggcgaggcg gagaggtgcg gcggcagcca atcagagcgg

720

cgcgctccga aagtttcctt ttatggcgag gcggcggcgg cggcggccct ataaaaagcg

780

aagcgcgcgg cgggcgggag tcgctgcgac gctgccttcg ccccgtgccc cgctccgccg

840

ccgcctcgcg ccgcccgccc cggctctgac tgaccgcgtt actcccacag gtgagcgggc

900

gggacggccc ttctcctccg ggctgtaatt agcgcttggt ttaatgacgg cttgtttctt

960

ttctgtggct gcgtgaaagc cttgaggggc tccgggaggg ccctttgtgc gggggggagc

1020

ggctcggggg gtgcgtgcgt gtgtgtgtgc gtggggagcg ccgcgtgcgg cccgcgctgc

1080

ccggcggctg tgagcgctgc gggcgcggcg cggggctttg tgcgctccgc agtgtgcgcg

1140

aggggagcgc ggccgggggc ggtgccccgc ggtgcggggg gggctgcgag gggaacaaag

1200

gctgcgtgcg gggtgtgtgc gtgggggggt gagcaggggg tgtgggcgcg gcggtcgggc

1260

tgtaaccccc ccctgcaccc ccctccccga gttgctgagc acggcccggc ttcgggtgcg

1320

gggctccgta cggggcgtgg cgcggggctc gccgtgccgg gcggggggtg gcggcaggtg

1380

ggggtgccgg gcggggcggg gccgcctcgg gccggggagg gctcggggga ggggcgcggc

1440

ggcccccgga gcgccggcgg ctgtcgaggc gcggcgagcc gcagccattg ccttttatgg

1500

taatcgtgcg agagggcgca gggacttcct ttgtcccaaa tctgtgcgga gccgaaatct

1560

gggaggcgcc gccgcacccc ctctagcggg cgcggggcga agcggtgcgg cgccggcagg

1620

aaggaaatgg gcggggaggg ccttcgtgcg tcgccgcgcc gccgtcccct tctccctctc

1680

cagcctcggg gctgtccgcg gggggacggc tgccttcggg ggggacgggg cagggcgggg

1740

ttcggcttct ggcgtgtgac cggcggctct agagcctctg ctaaccatgt tttagccttc

1800

ttctttttcc tacagctcct gggcaacgtg ctggttattg tgctgtctca tcatttgtcg

1860

acagaattcc tcgaagatcc gaaggggttc aagcttggca ttccggtact gttggtaaag

1920

cca

1923

<210> 73

<211> 1272

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 73

aggctcagag gcacacagga gtttctgggc tcaccctgcc cccttccaac ccctcagttc

60

ccatcctcca gcagctgttt gtgtgctgcc tctgaagtcc acactgaaca aacttcagcc

120

tactcatgtc cctaaaatgg gcaaacattg caagcagcaa acagcaaaca cacagccctc

180

cctgcctgct gaccttggag ctggggcaga ggtcagagac ctctctgggc ccatgccacc

240

tccaacatcc actcgacccc ttggaatttc ggtggagagg agcagaggtt gtcctggcgt

300

ggtttaggta gtgtgagagg gtccgggttc aaaaccactt gctgggtggg gagtcgtcag

360

taagtggcta tgccccgacc ccgaagcctg tttccccatc tgtacaatgg aaatgataaa

420

gacgcccatc tgatagggtt tttgtggcaa ataaacattt ggtttttttg ttttgttttg

480

ttttgttttt tgagatggag gtttgctctg tcgcccaggc tggagtgcag tgacacaatc

540

tcatctcacc acaaccttcc cctgcctcag cctcccaagt agctgggatt acaagcatgt

600

gccaccacac ctggctaatt ttctattttt agtagagacg ggtttctcca tgttggtcag

660

cctcagcctc ccaagtaact gggattacag gcctgtgcca ccacacccgg ctaatttttt

720

ctatttttga cagggacggg gtttcaccat gttggtcagg ctggtctaga ggtaccggat

780

cttgctacca gtggaacagc cactaaggat tctgcagtga gagcagaggg ccagctaagt

840

ggtactctcc cagagactgt ctgactcacg ccaccccctc caccttggac acaggacgct

900

gtggtttctg agccaggtac aatgactcct ttcggtaagt gcagtggaag ctgtacactg

960

cccaggcaaa gcgtccgggc agcgtaggcg ggcgactcag atcccagcca gtggacttag

1020

cccctgtttg ctcctccgat aactggggtg accttggtta atattcacca gcagcctccc

1080

ccgttgcccc tctggatcca ctgcttaaat acggacgagg acagggccct gtctcctcag

1140

cttcaggcac caccactgac ctgggacagt gaatccggac tctaaggtaa atataaaatt

1200

tttaagtgta taatgtgtta aactactgat tctaattgtt tctctctttt agattccaac

1260

ctttggaact ga

1272

<210> 74

<211> 1177

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 74

ggctcagagg ctcagaggca cacaggagtt tctgggctca ccctgccccc ttccaacccc

60

tcagttccca tcctccagca gctgtttgtg tgctgcctct gaagtccaca ctgaacaaac

120

ttcagcctac tcatgtccct aaaatgggca aacattgcaa gcagcaaaca gcaaacacac

180

agccctccct gcctgctgac cttggagctg gggcagaggt cagagacctc tctgggccca

240

tgccacctcc aacatccact cgaccccttg gaatttcggt ggagaggagc agaggttgtc

300

ctggcgtggt ttaggtagtg tgagagggtc cgggttcaaa accacttgct gggtggggag

360

tcgtcagtaa gtggctatgc cccgaccccg aagcctgttt ccccatctgt acaatggaaa

420

tgataaagac gcccatctga tagggttttt gtggcaaata aacatttggt ttttttgttt

480

tgttttgttt tgttttttga gatggaggtt tgctctgtcg cccaggctgg agtgcagtga

540

cacaatctca tctcaccaca accttcccct gcctcagcct cccaagtagc tgggattaca

600

agcatgtgcc accacacctg gctaattttc tatttttagt agagacgggt ttctccatgt

660

tggtcagcct cagcctccca agtaactggg attacaggcc tgtgccacca cacccggcta

720

attttttcta tttttgacag ggacggggtt tcaccatgtt ggtcaggctg gtctagaggt

780

accggatctt gctaccagtg gaacagccac taaggattct gcagtgagag cagaggcca

840

gctaagtggt actctcccag agactgtctg actcacgcca ccccctccac cttggacaca

900

ggacgctgtg gtttctgagc caggtacaat gactcctttc ggtaagtgca gtggaagctg

960

tacactgccc aggcaaagcg tccgggcagc gtaggcgggc gactcagatc ccagccagtg

1020

gacttagccc ctgtttgctc ctccgataac tggggtgacc ttggttaata ttcaccagca

1080

gcctcccccg ttgcccctct ggatccactg cttaaatacg gacgaggaca gggccctgtc

1140

tcctcagctt caggcaccac cactgacctg ggacagt

1177

<210> 75

<211> 547

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 75

ccctaaaatg ggcaaacatt gcaagcagca aacagcaaac acacagccct ccctgcctgc

60

tgaccttgga gctggggcag aggtcagaga cctctctggg cccatgccac ctccaacatc

120

cactcgaccc cttggaattt ttcggtggag aggagcagag gttgtcctgg cgtggtttag

180

gtagtgtgag aggggaatga ctcctttcgg taagtgcagt ggaagctgta cactgcccag

240

gcaaagcgtc cgggcagcgt aggcgggcga ctcagatccc agccagtgga cttagcccct

300

gtttgctcct ccgataactg gggtgacctt ggttaatatt caccagcagc ctcccccgtt

360

gcccctctgg atccactgct taaatacgga cgaggacagg gccctgtctc ctcagcttca

420

ggcaccacca ctgacctggg acagtgaatc cggactctaa ggtaaatata aaatttttaa

480

gtgtataatg tgttaaacta ctgattctaa ttgtttctct cttttagatt ccaacctttg

540

gaactga

547

<210> 76

<211> 556

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 76

ccctaaaatg ggcaaacatt gcaagcagca aacagcaaac acacagccct ccctgcctgc

60

tgaccttgga gctggggcag aggtcagaga cctctctggg cccatgccac ctccaacatc

120

cactcgaccc cttggaattt cggtggagag gagcagaggt tgtcctggcg tggtttaggt

180

agtgtgagag gggaatgact cctttcggta agtgcagtgg aagctgtaca ctgcccaggc

240

aaagcgtccg ggcagcgtag gcgggcgact cagatcccag ccagtggact tagcccctgt

300

ttgctcctcc gataactggg gtgaccttgg ttaatattca ccagcagcct cccccgttgc

360

ccctctggat ccactgctta aatacggacg aggacactcg agggccctgt ctcctcagct

420

tcaggcacca ccactgacct gggacagtga atccggacat cgattctaag gtaaatataa

480

aatttttaag tgtataattt gttaaactac tgattctaat tgtttctctc ttttagattc

540

caacctttgg aactga

556

<210> 77

<211> 1179

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 77

ggctccggtg cccgtcagtg ggcagagcgc acatcgccca cagtccccga gaagttgggg

60

ggaggggtcg gcaattgaac cggtgcctag agaaggtggc gcggggtaaa ctgggaaagt

120

gatgtcgtgt actggctccg cctttttccc gagggtgggg gagaaccgta tataagtgca

180

gtagtcgccg tgaacgttct ttttcgcaac gggtttgccg ccagaacaca ggtaagtgcc

240

gtgtgtggtt cccgcgggcc tggcctcttt acgggttatg gcccttgcgt gccttgaatt

300

acttccacct ggctgcagta cgtgattctt gatcccgagc ttcgggttgg aagtgggtgg

360

gagagttcga ggccttgcgc ttaaggagcc ccttcgcctc gtgcttgagt tgaggcctgg

420

cctgggcgct ggggccgccg cgtgcgaatc tggtggcacc ttcgcgcctg tctcgctgct

480

ttcgataagt ctctagccat ttaaaatttt tgatgacctg ctgcgacgct ttttttctgg

540

caagatagtc ttgtaaatgc gggccaagat ctgcacactg gtatttcggt ttttggggcc

600

gcgggcggcg acggggcccg tgcgtcccag cgcacatgtt cggcgaggcg gggcctgcga

660

gcgcggccac cgagaatcgg acggggggtag tctcaagctg gccggcctgc tctggtgcct

720

ggtctcgcgc cgccgtgtat cgccccgccc tgggcggcaa ggctggcccg gtcggcacca

780

gttgcgtgag cggaaagatg gccgcttccc ggccctgctg cagggagctc aaaatggagg

840

acgcggcgct cgggagagcg ggcgggtgag tcacccacac aaaggaaaag ggcctttccg

900

tcctcagccg tcgcttcatg tgactccacg gagtaccggg cgccgtccag gcacctcgat

960

tagttctcga gcttttggag tacgtcgtct ttaggttggg gggaggggtt ttatgcgatg

1020

gagtttcccc acactgagtg ggtggagact gaagttaggc cagcttggca cttgatgtaa

1080

ttctccttgg aatttgccct ttttgagttt ggatcttggt tcattctcaa gcctcagaca

1140

gtggttcaaa gtttttttct tccatttcag gtgtcgtga

1179

<210> 78

<211> 141

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 78

aataaacgat aacgccgttg gtggcgtgag gcatgtaaaa ggttacatca ttatcttgtt

60

cgccatccgg ttggtataaa tagacgttca tgttggtttt tgtttcagtt gcaagttggc

120

tgcggcgcgc gcagcacctt t

141

<210> 79

<211> 317

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 79

ggtgtggaaa gtccccaggc tccccagcag gcagaagtat gcaaagcatg catctcaatt

60

agtcagcaac caggtgtgga aagtccccag gctccccagc aggcagaagt atgcaaagca

120

tgcatctcaa ttagtcagca accatagtcc cgcccctaac tccgcccatc ccgcccctaa

180

ctccgcccag ttccgcccat tctccgcccc atggctgact aatttttttt atttatgcag

240

aggccgaggc cgcctcggcc tctgagctat tccagaagta gtgaggaggc ttttttggag

300

gcctaggctt ttgcaaa

317

<210> 80

<211> 241

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 80

gagggcctat ttcccatgat tccttcatat ttgcatatac gatacaaggc tgttagagag

60

ataattggaa ttaatttgac tgtaaacaca aagatattag tacaaaatac gtgacgtaga

120

aagtaataat ttcttgggta gtttgcagtt ttaaaattat gttttaaaat ggactatcat

180

atgcttaccg taacttgaaa gtatttcgat ttcttggctt tatatatctt gtggaaagga

240

c

241

<210> 81

<211> 215

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 81

gaacgctgac gtcatcaacc cgctccaagg aatcgcgggc ccagtgtcac taggcgggaa

60

cacccagcgc gcgtgcgccc tggcaggaag atggctgtga gggacagggg agtggcgccc

120

tgcaatattt gcatgtcgct atgtgttctg ggaaatcacc ataaacgtga aatgtctttg

180

gatttgggaa tcgtataaga actgtatgag accac

215

<210> 82

<211> 546

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 82

ccctaaaatg ggcaaacatt gcaagcagca aacagcaaac acacagccct ccctgcctgc

60

tgaccttgga gctggggcag aggtcagaga cctctctggg cccatgccac ctccaacatc

120

cactcgaccc cttggaattt ttcggtggag aggagcagag gttgtcctgg cgtggtttag

180

gtagtgtgag aggggaatga ctcctttcgg taagtgcagt ggaagctgta cactgcccag

240

gcaaagcgtc cgggcagcgt aggcgggcga ctcagatccc agccagtgga cttagcccct

300

gtttgctcct ccgataactg gggtgacctt ggttaatatt caccagcagc ctcccccgtt

360

gcccctctgg atccactgct taaatacgga cgaggacagg gccctgtctc ctcagcttca

420

ggcaccacca ctgacctggg acagtgaatc cggactctaa ggtaaatata aaatttttaa

480

gtgtataatg tgttaaacta ctgattctaa ttgtttctct cttttagatt ccaacctttg

540

gaactg

546

<210> 83

<211> 576

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 83

tagtaatcaa ttacggggtc attagttcat agcccatata tggagttccg cgttacataa

60

cttacggtaa atggcccgcc tggctgaccg cccaacgacc cccgcccatt gacgtcaata

120

atgacgtatg ttcccatagt aacgccaata gggactttcc attgacgtca atgggtggag

180

tatttacggt aaactgccca cttggcagta catcaagtgt atcatatgcc aagtacgccc

240

cctattgacg tcaatgacgg taaatggccc gcctggcatt atgcccagta catgacctta

300

tgggactttc ctacttggca gtacatctac gtattagtca tcgctattac catggtgatg

360

cggttttggc agtacatcaa tgggcgtgga tagcggtttg actcacgggg atttccaagt

420

ctccacccca ttgacgtcaa tgggagtttg ttttggcacc aaaatcaacg ggactttcca

480

aaatgtcgta acaactccgc cccattgacg caaatgggcg gtaggcgtgt acggtgggag

540

gtctatataa gcagagctgg tttagtgaac cgtcag

576

<210> 84

<211> 150

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 84

ataaacgata acgccgttgg tggcgtgagg catgtaaaag gttacatcat tatcttgttc

60

gccatccggt tggtataaat agacgttcat gttggttttt gtttcagttg caagttggct

120

gcggcgcgcg cagcaccttt gcggccatct

150

<210> 85

<211> 1313

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 85

ggagccgaga gtaattcata caaaaggagg gatcgccttc gcaaggggag agcccaggga

60

ccgtccctaa attctcacag acccaaatcc ctgtagccgc cccacgacag cgcgaggagc

120

atgcgcccag ggctgagcgc gggtagatca gagcacacaa gctcacagtc cccggcggtg

180

gggggagggg cgcgctgagc gggggccagg gagctggcgc ggggcaaact gggaaagtgg

240

tgtcgtgtgc tggctccgcc ctcttcccga gggtggggga gaacggtata taagtgcggt

300

agtcgccttg gacgttcttt ttcgcaacgg gtttgccgtc agaacgcagg tgagtggcgg

360

gtgtggcttc cgcgggcccc ggagctggag ccctgctctg agcgggccgg gctgatatgc

420

gagtgtcgtc cgcagggttt agctgtgagc attcccactt cgagtggcgg gcggtgcggg

480

ggtgagagtg cgaggcctag cggcaacccc gtagcctcgc ctcgtgtccg gcttgaggcc

540

tagcgtggtg tccgccgccg cgtgccactc cggccgcact atgcgttttt tgtccttgct

600

gccctcgatt gccttccagc agcatgggct aacaaaggga gggtgtgggg ctcactctta

660

aggagcccat gaagcttacg ttggatagga atggaagggc aggaggggcg actggggccc

720

gcccgccttc ggagcacatg tccgacgcca cctggatggg gcgaggcctg tggctttccg

780

aagcaatcgg gcgtgagttt agcctacctg ggccatgtgg ccctagcact gggcacggtc

840

tggcctggcg gtgccgcgtt cccttgcctc ccaacaaggg tgaggccgtc ccgcccggca

900

ccagttgctt gcgcggaaag atggccgctc ccggggccct gttgcaagga gctcaaaatg

960

gaggacgcgg cagcccggtg gagcgggcgg gtgagtcacc cacacaaagg aagagggcct

1020

tgcccctcgc cggccgctgc ttcctgtgac cccgtggtct atcggccgca tagtcacctc

1080

gggcttctct tgagcaccgc tcgtcgcggc ggggggaggg gatctaatgg cgttggagtt

1140

tgttcacatt tggtgggtgg agactagtca ggccagcctg gcgctggaag tcattcttgg

1200

aatttgcccc tttgagtttg gagcgaggct aattctcaag cctcttagcg gttcaaaggt

1260

attttctaaa cccgtttcca ggtgttgtga aagccaccgc taattcaaag caa

1313

<210> 86

<211> 213

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 86

taagatacat tgatgagttt ggacaaacca caactagaat gcagtgaaaa aaatgcttta

60

tttgtgaaat ttgtgatgct attgctttat ttgtaaccat tataagctgc aataaacaag

120

ttaacaacaa caattgcatt cattttatgt ttcaggttca gggggaggtg tgggaggttt

180

tttaaagcaa gtaaaacctc tacaaatgtg gta

213

<210> 87

<211> 7

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic peptide

<400> 87

Pro Lys Lys Lys Arg Lys Val

15

<210> 88

<211> 19

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic peptide

<400> 88

Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly

1 5 10 15

Ala His Ser

<210> 89

<211> 19

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic peptide

<400> 89

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

1 5 10 15

Ser Arg Gly

<210> 90

<211> 7

<212> PROTEIN

<213> Monkey virus 40

<400> 90

Pro Lys Lys Lys Arg Lys Val

15

<210> 91

<211> 21

<212> DNA

<213> Monkey virus 40

<400> 91

cccaagaaga agaggaaggt g

21

<210> 92

<211> 16

<212> PROTEIN

<213> Unknown

<220>

<223> Description of unknown: two-component NLS sequence

nucleoplasmin

<400> 92

Lys Arg Pro Ala Ala Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys

1 5 10 15

<210> 93

<211> 9

<212> PROTEIN

<213> Unknown

<220>

<223> Description of the unknown: NLS sequence C-myc

<400> 93

Pro Ala Ala Lys Arg Val Lys Leu Asp

15

<210> 94

<211> 11

<212> PROTEIN

<213> Unknown

<220>

<223> Description of the unknown: NLS sequence C-myc

<400> 94

Arg Gln Arg Arg Asn Glu Leu Lys Arg Ser Pro

1 5 10

<210> 95

<211> 38

<212> PROTEIN

<213> Homo sapiens

<400> 95

Asn Gln Ser Ser Asn Phe Gly Pro Met Lys Gly Gly Asn Phe Gly Gly

1 5 10 15

Arg Ser Ser Gly Pro Tyr Gly Gly Gly Gly Gln Tyr Phe Ala Lys Pro

20 25 30

Arg Asn Gln Gly Gly Tyr

35

<210> 96

<211> 42

<212> PROTEIN

<213> Unknown

<220>

<223> Description of unknown: IBB domain from sequence

importin-alpha

<400> 96

Arg Met Arg Ile Glx Phe Lys Asn Lys Gly Lys Asp Thr Ala Glu Leu

1 5 10 15

Arg Arg Arg Arg Val Glu Val Ser Val Glu Leu Arg Lys Ala Lys Lys

20 25 30

Asp Glu Gln Ile Leu Lys Arg Arg Asn Val

35 40

<210> 97

<211> 8

<212> PROTEIN

<213> Unknown

<220>

<223> Description of the unknown: fibroid T protein sequence

<400> 97

Val Ser Arg Lys Arg Pro Arg Pro

15

<210> 98

<211> 8

<212> PROTEIN

<213> Unknown

<220>

<223> Description of the unknown: fibroid T protein sequence

<400> 98

Pro Pro Lys Lys Ala Arg Glu Asp

15

<210> 99

<211> 8

<212> PROTEIN

<213> Homo sapiens

<400> 99

Pro Gln Pro Lys Lys Lys Pro Leu

15

<210> 100

<211> 12

<212> PROTEIN

<213> Mus musculus

<400> 100

Ser Ala Leu Ile Lys Lys Lys Lys Lys Met Ala Pro

1 5 10

<210> 101

<211> 70

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 101

gcgcgctcgc tcgctcactg aggccgcccg ggaaacccgg gcgtgcgcct cagtgagcga

60

gcgagcgcgc

70

<210> 102

<211> 70

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 102

gcgcgctcgc tcgctcactg aggcgcacgc ccgggtttcc cgggcggcct cagtgagcga

60

gcgagcgcgc

70

<210> 103

<211> 72

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 103

gcgcgctcgc tcgctcactg aggccgtcgg gcgacctttg gtcgcccggc ctcagtgagc

60

gagcgagcgc gc

72

<210> 104

<211> 72

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 104

gcgcgctcgc tcgctcactg aggccgggcg accaaaggtc gcccgacggc ctcagtgagc

60

gagcgagcgc gc

72

<210> 105

<211> 72

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 105

gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggc ctcagtgagc

60

gagcgagcgc gc

72

<210> 106

<211> 72

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 106

gcgcgctcgc tcgctcactg aggccgacgc ccgggctttg cccgggcggc ctcagtgagc

60

gagcgagcgc gc

72

<210> 107

<211> 83

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 107

gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg ctttgcccgg

60

cctcagtgag cgagcgagcg cgc

83

<210> 108

<211> 83

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 108

gcgcgctcgc tcgctcactg aggccgggca aagcccgacg cccgggcttt gcccgggcgg

60

cctcagtgag cgagcgagcg cgc

83

<210> 109

<211> 77

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 109

gcgcgctcgc tcgctcactg aggccgaaac gtcgggcgac ctttggtcgc ccggcctcag

60

tgagcgagcg agcgcgc

77

<210> 110

<211> 77

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 110

gcgcgctcgc tcgctcactg aggccgggcg accaaaggtc gcccgacgtt tcggcctcag

60

tgagcgagcg agcgcgc

77

<210> 111

<211> 51

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 111

gcgcgctcgc tcgctcactg aggcaaagcc tcagtgagcg agcgagcgcg c

51

<210> 112

<211> 51

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 112

gcgcgctcgc tcgctcactg aggctttgcc tcagtgagcg agcgagcgcg c

51

<210> 113

<211> 80

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 113

gcgcgctcgc tcgctcactg aggccgcccg ggcgtcgggc gacctttggt cgcccggcct

60

cagtgagcga gcgagcgcgc

80

<210> 114

<211> 80

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 114

gcgcgctcgc tcgctcactg aggccgggcg accaaaggtc gcccgacgcc cgggcggcct

60

cagtgagcga gcgagcgcgc

80

<210> 115

<211> 79

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 115

gcgcgctcgc tcgctcactg aggcgcccgg gcgtcgggcg acctttggtc gcccggcctc

60

agtgagcgag cgagcgcgc

79

<210> 116

<211> 79

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 116

gcgcgctcgc tcgctcactg aggccgggcg accaaaggtc gcccgacgcc cgggcgcctc

60

agtgagcgag cgagcgcgc

79

<210> 117

<211> 5

<212> PROTEIN

<213> Influenza virus

<400> 117

Asp Arg Leu Arg Arg

15

<210> 118

<211> 7

<212> PROTEIN

<213> Influenza virus

<400> 118

Pro Lys Gln Lys Lys Arg Lys

15

<210> 119

<211> 10

<212> PROTEIN

<213> Hepatitis delta virus

<400> 119

Arg Lys Leu Lys Lys Lys Ile Lys Lys Leu

1 5 10

<210> 120

<211> 10

<212> PROTEIN

<213> Mus musculus

<400> 120

Arg Glu Lys Lys Lys Phe Leu Lys Arg Arg

1 5 10

<210> 121

<211> 20

<212> PROTEIN

<213> Homo sapiens

<400> 121

Lys Arg Lys Gly Asp Glu Val Asp Gly Val Asp Glu Val Ala Lys Lys

1 5 10 15

Lys Ser Lys Lys

20

<210> 122

<211> 17

<212> PROTEIN

<213> Homo sapiens

<400> 122

Arg Lys Cys Leu Gln Ala Gly Met Asn Leu Glu Ala Arg Lys Thr Lys

1 5 10 15

Lys

<210> 123

<211> 8

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 123

gtttaaac

8

<210> 124

<211> 8

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 124

ttaattaa

8

<210> 125

<211> 141

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 125

aataaacgat aacgccgttg gtggcgtgag gcatgtaaaa ggttacatca ttatcttgtt

60

cgccatccgg ttggtataaa tagacgttca tgttggtttt tgtttcagtt gcaagttggc

120

tgcggcgcgc gcagcacctt t

141

<210> 126

<211> 317

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 126

ggtgtggaaa gtccccaggc tccccagcag gcagaagtat gcaaagcatg catctcaatt

60

agtcagcaac caggtgtgga aagtccccag gctccccagc aggcagaagt atgcaaagca

120

tgcatctcaa ttagtcagca accatagtcc cgcccctaac tccgcccatc ccgcccctaa

180

ctccgcccag ttccgcccat tctccgcccc atggctgact aatttttttt atttatgcag

240

aggccgaggc cgcctcggcc tctgagctat tccagaagta gtgaggaggc ttttttggag

300

gcctaggctt ttgcaaa

317

<210> 127

<211> 72

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 127

gcgcgctcgc tcgctcactg aggccgggcg accaaaggtc gcccgacggc ctcagtgagc

60

gagcgagcgc gc

72

<210> 128

<211> 60

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 128

gagacagaca cactcctgct atgggtactg ctgctctggg ttccaggttc cactggtgac

60

<210> 129

<211> 1260

<212> DNA

<213> Adeno-associated virus - 2

<400> 129

atggagctgg tcgggtggct cgtggacaag gggattacct cggagaagca gtggatccag

60

gaggaccagg cctcatacat ctccttcaat gcggcctcca actcgcggtc ccaaatcaag

120

gctgccttgg acaatgcggg aaagattatg agcctgacta aaaccgcccc cgactacctg

180

gtgggccagc agcccgtgga ggacatttcc agcaatcgga tttataaaat tttggaacta

240

aacgggtacg atccccaata tgcggcttcc gtctttctgg gatgggccac gaaaaagttc

300

ggcaagagga acaccatctg gctgtttggg cctgcaacta ccgggaagac caacatcgcg

360

gaggccatag cccacactgt gcccttctac gggtgcgtaa actggaccaa tgagaacttt

420

cccttcaacg actgtgtcga caagatggtg atctggtggg aggaggggaa gatgaccgcc

480

aaggtcgtgg agtcggccaa agccattctc ggaggaagca aggtgcgcgt ggaccagaaa

540

tgcaagtcct cggcccagat agacccgact cccgtgatcg tcacctccaa caccaacatg

600

tgcgccgtga ttgacgggaa ctcaacgacc ttcgaacacc agcagccgtt gcaagaccgg

660

atgttcaaat ttgaactcac ccgccgtctg gatcatgact ttgggaaggt caccaagcag

720

gaagtcaaag actttttccg gtgggcaaag gatcacgtgg ttgaggtgga gcatgaattc

780

tacgtcaaaa agggtggagc caagaaaaga cccgccccca gtgacgcaga tataagtgag

840

cccaaacggg tgcgcgagtc agttgcgcag ccatcgacgt cagacgcgga agcttcgatc

900

aactacgcag acaggtacca aaacaaatgt tctcgtcacg tgggcatgaa tctgatgctg

960

tttccctgca gacaatgcga gagaatgaat cagaattcaa atatctgctt cactcacgga

1020

cagaaagact gtttagagtg ctttcccgtg tcagaatctc aacccgtttc tgtcgtcaaa

1080

aaggcgtatc agaaactgtg ctacattcat catatcatgg gaaaggtgcc agacgcttgc

1140

actgcctgcg atctggtcaa tgtggatttg gatgactgca tctttgaaca ataaatgatt

1200

taaatcaggt atggctgccg atggttatct tccagattgg ctcgaggaca ctctctctga

1260

<210> 130

<211> 1932

<212> DNA

<213> Adeno-associated virus - 2

<400> 130

atgccggggt tttacgagat tgtgattaag gtccccagcg accttgacga gcatctgccc

60

ggcatttctg acagctttgt gaactgggtg gccgagaagg aatgggagtt gccgccagat

120

tctgacatgg atctgaatct gattgagcag gcacccctga ccgtggccga gaagctgcag

180

cgcgactttc tgacggaatg gcgccgtgtg agtaaggccc cggaggccct tttctttgtg

240

caatttgaga agggagagag ctacttccac atgcacgtgc tcgtggaaac caccggggtg

300

aaatccatgg ttttgggacg tttcctgagt cagattcgcg aaaaactgat tcagagaatt

360

taccgcggga tcgagccgac tttgccaaac tggttcgcgg tcacaaagac cagaaatggc

420

gccggaggcg ggaacaaggt ggtggatgag tgctacatcc ccaattactt gctccccaaa

480

acccagcctg agctccagtg ggcgtggact aatatggaac agtatttaag cgcctgtttg

540

aatctcacgg agcgtaaacg gttggtggcg cagcatctga cgcacgtgtc gcagacgcag

600

gagcagaaca aagagaatca gaatcccaat tctgatgcgc cggtgatcag atcaaaaact

660

tcagccaggt acatggagct ggtcgggtgg ctcgtggaca aggggattac ctcggagaag

720

cagtggatcc aggaggacca ggcctcatac atctccttca atgcggcctc caactcgcgg

780

tcccaaatca aggctgcctt ggacaatgcg ggaaagatta tgagcctgac taaaaccgcc

840

cccgactacc tggtgggcca gcagcccgtg gaggacatt ccagcaatcg gatttataaa

900

attttggaac taaacgggta cgatccccaa tatgcggctt ccgtctttct gggatgggcc

960

acgaaaaagt tcggcaagag gaacaccatc tggctgtttg ggcctgcaac taccgggaag

1020

accaacatcg cggaggccat agcccacact gtgcccttct acgggtgcgt aaactggacc

1080

aatgagaact ttcccttcaa cgactgtgtc gacaagatgg tgatctggtg ggaggagggg

1140

aagatgaccg ccaaggtcgt ggagtcggcc aaagccattc tcggaggaag caaggtgcgc

1200

gtggaccaga aatgcaagtc ctcggcccag atagacccga ctcccgtgat cgtcacctcc

1260

aacaccaaca tgtgcgccgt gattgacggg aactcaacga ccttcgaaca ccagcagccg

1320

ttgcaagacc ggatgttcaa atttgaactc acccgccgtc tggatcatga ctttgggaag

1380

gtcaccaagc aggaagtcaa agactttttc cggtgggcaa aggatcacgt ggttgaggtg

1440

gagcatgaat tctacgtcaa aaagggtgga gccaagaaaa gacccgcccc cagtgacgca

1500

gatataagtg agcccaaacg ggtgcgcgag tcagttgcgc agccatcgac gtcagacgcg

1560

gaagcttcga tcaactacgc agacaggtac caaaacaaat gttctcgtca cgtgggcatg

1620

aatctgatgc tgtttccctg cagacaatgc gagagaatga atcagaattc aaatatctgc

1680

ttcactcacg gacagaaaga ctgtttagag tgctttcccg tgtcagaatc tcaacccgtt

1740

tctgtcgtca aaaaggcgta tcagaaactg tgctacattc atcatatcat gggaaaggtg

1800

cgacgctt gcactgcctg cgatctggtc aatgtggatt tggatgactg catctttgaa

1860

caataaatga tttaaatcag gtatggctgc cgatggttat cttccagatt ggctcgagga

1920

cactctctct ga

1932

<210> 131

<211> 1876

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 131

cgcagccacc atggcggggt tttacgagat tgtgattaag gtccccagcg accttgacgg

60

gcatctgccc ggcatttctg acagctttgt gaactgggtg gccgagaagg aatgggagtt

120

gccgccagat tctgacatgg atctgaatct gattgagcag gcacccctga ccgtggccga

180

gaagctgcag cgcgactttc tgacggaatg gcgccgtgtg agtaaggccc cggaggccct

240

tttctttgtg caatttgaga agggagagag ctacttccac atgcacgtgc tcgtggaaac

300

caccggggtg aaatccatgg ttttgggacg tttcctgagt cagattcgcg aaaaactgat

360

tcagagaatt taccgcggga tcgagccgac tttgccaaac tggttcgcgg tcacaaagac

420

cagaaatggc gccggaggcg ggaacaaggt ggtggatgag tgctacatcc ccaattactt

480

gctccccaaa acccagcctg agctccagtg ggcgtggact aatatggaac agtatttaag

540

cgcctgtttg aatctcacgg agcgtaaacg gttggtggcg cagcatctga cgcacgtgtc

600

gcagacgcag gagcagaaca aagagaatca gaatcccaat tctgatgcgc cggtgatcag

660

atcaaaaact tcagccaggt acatggagct ggtcgggtgg ctcgtggaca aggggattac

720

ctcggagaag cagtggatcc aggaggacca ggcctcatac atctccttca atgcggcctc

780

caactcgcgg tcccaaatca aggctgcctt ggacaatgcg ggaaagatta tgagcctgac

840

taaaaccgcc cccgactacc tggtgggcca gcagcccgtg gaggacatt ccagcaatcg

900

gatttataaa attttggaac taaacgggta cgatccccaa tatgcggctt ccgtctttct

960

gggatgggcc acgaaaaagt tcggcaagag gaacaccatc tggctgtttg ggcctgcaac

1020

taccgggaag accaacatcg cggaggccat agcccacact gtgcccttct acgggtgcgt

1080

aaactggacc aatgagaact ttcccttcaa cgactgtgtc gacaagatgg tgatctggtg

1140

ggaggagggg aagatgaccg ccaaggtcgt ggagtcggcc aaagccattc tcggaggaag

1200

caaggtgcgc gtggaccaga aatgcaagtc ctcggcccag atagacccga ctcccgtgat

1260

cgtcacctcc aacaccaaca tgtgcgccgt gattgacggg aactcaacga ccttcgaaca

1320

ccagcagccg ttgcaagacc ggatgttcaa atttgaactc acccgccgtc tggatcatga

1380

ctttgggaag gtcaccaagc aggaagtcaa agactttttc cggtgggcaa aggatcacgt

1440

ggttgaggtg gagcatgaat tctacgtcaa aaagggtgga gccaagaaaa gacccgcccc

1500

cagtgacgca gatataagtg agcccaaacg ggtgcgcgag tcagttgcgc agccatcgac

1560

gtcagacgcg gaagcttcga tcaactacgc agacaggtac caaaacaaat gttctcgtca

1620

cgtgggcatg aatctgatgc tgtttccctg cagacaatgc gagagaatga atcagaattc

1680

aaatatctgc ttcactcacg gacagaaaga ctgtttagag tgctttcccg tgtcagaatc

1740

tcaacccgtt tctgtcgtca aaaaggcgta tcagaaactg tgctacattc atcatatcat

1800

gggaaaggtg cgacgctt gcactgcctg cgatctggtc aatgtggatt tggatgactg

1860

catctttgaa caataa

1876

<210> 132

<211> 1194

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 132

atggagctgg tcgggtggct cgtggacaag gggattacct cggagaagca gtggatccag

60

gaggaccagg cctcatacat ctccttcaat gcggcctcca actcgcggtc ccaaatcaag

120

gctgccttgg acaatgcggg aaagattatg agcctgacta aaaccgcccc cgactacctg

180

gtgggccagc agcccgtgga ggacatttcc agcaatcgga tttataaaat tttggaacta

240

aacgggtacg atccccaata tgcggcttcc gtctttctgg gatgggccac gaaaaagttc

300

ggcaagagga acaccatctg gctgtttggg cctgcaacta ccgggaagac caacatcgcg

360

gaggccatag cccacactgt gcccttctac gggtgcgtaa actggaccaa tgagaacttt

420

cccttcaacg actgtgtcga caagatggtg atctggtggg aggaggggaa gatgaccgcc

480

aaggtcgtgg agtcggccaa agccattctc ggaggaagca aggtgcgcgt ggaccagaaa

540

tgcaagtcct cggcccagat agacccgact cccgtgatcg tcacctccaa caccaacatg

600

tgcgccgtga ttgacgggaa ctcaacgacc ttcgaacacc agcagccgtt gcaagaccgg

660

atgttcaaat ttgaactcac ccgccgtctg gatcatgact ttgggaaggt caccaagcag

720

gaagtcaaag actttttccg gtgggcaaag gatcacgtgg ttgaggtgga gcatgaattc

780

tacgtcaaaa agggtggagc caagaaaaga cccgccccca gtgacgcaga tataagtgag

840

cccaaacggg tgcgcgagtc agttgcgcag ccatcgacgt cagacgcgga agcttcgatc

900

aactacgcag accgctacca aaacaaatgt tctcgtcacg tgggcatgaa tctgatgctg

960

tttccctgca gacaatgcga gagaatgaat cagaattcaa atatctgctt cactcacgga

1020

cagaaagact gtttagagtg ctttcccgtg tcagaatctc aacccgtttc tgtcgtcaaa

1080

aaggcgtatc agaaactgtg ctacattcat catatcatgg gaaaggtgcc agacgcttgc

1140

actgcctgcg atctggtcaa tgtggatttg gatgactgca tctttgaaca ataa

1194

<210> 133

<211> 1876

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 133

cgcagccacc atggcggggt tttacgagat tgtgattaag gtccccagcg accttgacgg

60

gcatctgccc ggcatttctg acagctttgt gaactgggtg gccgagaagg aatgggagtt

120

gccgccagat tctgacatgg atctgaatct gattgagcag gcacccctga ccgtggccga

180

gaagctgcag cgcgactttc tgacggaatg gcgccgtgtg agtaaggccc cggaggccct

240

tttctttgtg caatttgaga agggagagag ctacttccac atgcacgtgc tcgtggaaac

300

caccggggtg aaatccatgg ttttgggacg tttcctgagt cagattcgcg aaaaactgat

360

tcagagaatt taccgcggga tcgagccgac tttgccaaac tggttcgcgg tcacaaagac

420

cagaaatggc gccggaggcg ggaacaaggt ggtggatgag tgctacatcc ccaattactt

480

gctccccaaa acccagcctg agctccagtg ggcgtggact aatatggaac agtatttaag

540

cgcctgtttg aatctcacgg agcgtaaacg gttggtggcg cagcatctga cgcacgtgtc

600

gcagacgcag gagcagaaca aagagaatca gaatcccaat tctgatgcgc cggtgatcag

660

atcaaaaact tcagccaggt acatggagct ggtcgggtgg ctcgtggaca aggggattac

720

ctcggagaag cagtggatcc aggaggacca ggcctcatac atctccttca atgcggcctc

780

caactcgcgg tcccaaatca aggctgcctt ggacaatgcg ggaaagatta tgagcctgac

840

taaaaccgcc cccgactacc tggtgggcca gcagcccgtg gaggacatt ccagcaatcg

900

gatttataaa attttggaac taaacgggta cgatccccaa tatgcggctt ccgtctttct

960

gggatgggcc acgaaaaagt tcggcaagag gaacaccatc tggctgtttg ggcctgcaac

1020

taccgggaag accaacatcg cggaggccat agcccacact gtgcccttct acgggtgcgt

1080

aaactggacc aatgagaact ttcccttcaa cgactgtgtc gacaagatgg tgatctggtg

1140

ggaggagggg aagatgaccg ccaaggtcgt ggagtcggcc aaagccattc tcggaggaag

1200

caaggtgcgc gtggaccaga aatgcaagtc ctcggcccag atagacccga ctcccgtgat

1260

cgtcacctcc aacaccaaca tgtgcgccgt gattgacggg aactcaacga ccttcgaaca

1320

ccagcagccg ttgcaagacc ggatgttcaa atttgaactc acccgccgtc tggatcatga

1380

ctttgggaag gtcaccaagc aggaagtcaa agactttttc cggtgggcaa aggatcacgt

1440

ggttgaggtg gagcatgaat tctacgtcaa aaagggtgga gccaagaaaa gacccgcccc

1500

cagtgacgca gatataagtg agcccaaacg ggtgcgcgag tcagttgcgc agccatcgac

1560

gtcagacgcg gaagcttcga tcaactacgc agacaggtac caaaacaaat gttctcgtca

1620

cgtgggcatg aatctgatgc tgtttccctg cagacaatgc gagagaatga atcagaattc

1680

aaatatctgc ttcactcacg gacagaaaga ctgtttagag tgctttcccg tgtcagaatc

1740

tcaacccgtt tctgtcgtca aaaaggcgta tcagaaactg tgctacattc atcatatcat

1800

gggaaaggtg cgacgctt gcactgcctg cgatctggtc aatgtggatt tggatgactg

1860

catctttgaa caataa

1876

<210> 134

<211> 51

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 134

ctaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt ggtcgcccgg c

51

<210> 135

<211> 65

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 135

ctaggactga ggccgcccgg gcaaagcccg ggcgtcgggc gacctttggt cgcccggcct

60

cagtc

65

<210> 136

<211> 67

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 136

ggactgaggc cgcccgggca aagcccgggc gtcgggcgac ctttggtcgc ccggcctcag

60

tcctgca

67

<210> 137

<211> 41

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 137

gtgcgggcga ccaaaggtcg cccgacgccc gggcgcactc a

41

<210> 138

<211> 56

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 138

ggactgaggc cgggcgacca aaggtcgccc gacgcccggg cggcctcagt cctgca

56

<210> 139

<211> 54

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 139

ctaggactga ggccgcccgg gcgtcgggcg acctttggtc gcccggcctc agtc

54

<210> 140

<211> 48

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 140

ggactgaggc cgggcgacca aaggtcgccc gacggcctca gtcctgca

48

<210> 141

<211> 46

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 141

ctaggactga ggccgtcggg cgacctttgg tcgcccggcc tcagtc

46

<210> 142

<211> 67

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 142

ggactgaggc ccgggcgacc aaaggtcgcc cgacgcccgg gctttgcccg ggcgcctcag

60

tcctgca

67

<210> 143

<211> 47

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 143

atacctaggc acgcgtgtta ctagttatta atagtaatca attacgg

47

<210> 144

<211> 29

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 144

atacctaggg gccgcacgcg tgttactag

29

<210> 145

<211> 42

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 145

atacactcag tgcctgcagg cacgtggtcc ggagatccag ac

42

<210> 146

<211> 3754

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 146

cctaggtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact aggggttcct

60

tgtagttaat gattaacccg ccatgctact tatcgcggcc gctcaatatt ggccattagc

120

catattattc attggttata tagcataaat caatattggc tattggccat tgcatacgtt

180

gtatctatat cataatatgt acatttatat tggctcatgt ccaatatgac cgccatgttg

240

gcattgatta ttgactagtt attaatagta atcaattacg gggtcattag ttcatagccc

300

atatatggag ttccgcgtta cataacttac ggtaaatggc ccgcctggct gaccgcccaa

360

cgacccccgc ccattgacgt caataatgac gtatgttccc atagtaacgc caatagggac

420

tttccattga cgtcaatggg tggagtattt acggtaaact gcccacttgg cagtacatca

480

agtgtatcat atgccaagtc cgccccctat tgacgtcaat gacggtaaat ggcccgcctg

540

gcattatgcc cagtacatga ccttacggga ctttcctact tggcagtaca tctacgtatt

600

agtcatcgct attaccatgg tcgaggtgag ccccacgttc tgcttcactc tccccatctc

660

ccccccctcc ccacccccaa ttttgtattt atttattttt taattatttt gtgcagcgat

720

gggggcgggg gggggggggg ggcgcgcgcc aggcggggcg gggcggggcg aggggcgggg

780

cggggcgagg cggagaggtg cggcggcagc caatcagagc ggcgcgctcc gaaagtttcc

840

ttttatggcg aggcggcggc ggcggcggcc ctataaaaag cgaagcgcgc ggcgggcggg

900

agtcgctgcg acgctgcctt cgccccgtgc cccgctccgc cgccgcctcg cgccgcccgc

960

cccggctctg actgaccgcg ttactcccac aggtgagcgg gcgggacggc ccttctcctc

1020

cgggctgtaa ttagcgcttg gtttaatgac ggcttgtttc ttttctgtgg ctgcgtgaaa

1080

gccttgaggg gctccgggag ggccctttgt gcggggggga gcggctcggg gggtgcgtgc

1140

gtgtgtgtgt gcgtggggag cgccgcgtgc ggcccgcgct gcccggcggc tgtgagcgct

1200

gcgggcgcgg cgcggggctt tgtgcgctcc gcagtgtgcg cgaggggagc gcggccgggg

1260

gcggtgcccc gcggtgcggg gggggctgcg aggggaacaa aggctgcgtg cggggtgtgt

1320

gcgtgggggg gtgagcaggg ggtgtgggcg cggcggtcgg gctgtaaccc ccccctgcac

1380

ccccctcccc gagttgctga gcacggcccg gcttcgggtg cggggctccg tacggggcgt

1440

ggcgcggggc tcgccgtgcc gggcgggggg tggcggcagg tgggggtgcc gggcggggcg

1500

gggccgcctc gggccgggga gggctcgggg gaggggcgcg gcggcccccg gagcgccggc

1560

ggctgtcgag gcgcggcgag ccgcagccat tgccttttat ggtaatcgtg cgagaggcg

1620

cagggacttc ctttgtccca aatctgtgcg gagccgaaat ctgggaggcg ccgccgcacc

1680

ccctctagcg ggcgcggggc gaagcggtgc ggcgccggca ggaaggaaat gggcggggag

1740

ggccttcgtg cgtcgccgcg ccgccgtccc cttctccctc tccagcctcg gggctgtccg

1800

cggggggacg gctgccttcg ggggggacgg ggcagggcgg ggttcggctt ctggcgtgtg

1860

accggcggct ctagagcctc tgctaaccat gttttagcct tcttcttttt cctacagctc

1920

ctgggcaacg tgctggttat tgtgctgtct catcatttgt cgacagaatt cctcgaagat

1980

ccgaaggggt tcaagcttgg cattccggta ctgttggtaa agccagttta aacgccgcca

2040

ccatggtgag caagggcgag gagctgttca ccggggtggt gcccatcctg gtcgagctgg

2100

acggcgacgt aaacggccac aagttcagcg tgtccggcga gggcgagggc gatgccacct

2160

acggcaagct gaccctgaag ttcatctgca ccaccggcaa gctgcccgtg ccctggccca

2220

ccctcgtgac caccctgacc tacggcgtgc agtgcttcag ccgctacccc gaccacatga

2280

agcagcacga cttcttcaag tccgccatgc ccgaaggcta cgtccaggag cgcaccatct

2340

tcttcaagga cgacggcaac tacaagaccc gcgccgaggt gaagttcgag ggcgacaccc

2400

tggtgaaccg catcgagctg aagggcatcg acttcaagga ggacggcaac atcctggggc

2460

acaagctgga gtacaactac aacagccaca acgtctatat catggccgac aagcagaaga

2520

acggcatcaa ggtgaacttc aagatccgcc acaacatcga ggacggcagc gtgcagctcg

2580

ccgaccacta ccagcagaac acccccatcg gcgacggccc cgtgctgctg cccgacaacc

2640

actacctgag cacccagtcc gccctgagca aagaccccaa cgagaagcgc gatcacatgg

2700

tcctgctgga gttcgtgacc gccgccggga tcactctcgg catggacgag ctgtacaagt

2760

aattaattaa gagcatctta ccgccatta ttcccatatt tgttctgttt ttcttgattt

2820

gggtatacat ttaaatgtta ataaaacaaa atggtggggc aatcatttac atttttaggg

2880

atatgtaatt actagttcag gtgtattgcc acaagacaaa catgttaaga aactttcccg

2940

ttatttacgc tctgttcctg ttaatcaacc tctggattac aaaatttgtg aaagattgac

3000

tgatattctt aactatgttg ctccttttac gctgtgtgga tatgctgctt tatagcctct

3060

gtatctagct attgcttccc gtacggcttt cgttttctcc tccttgtata aatcctggtt

3120

gctgtctctt ttagaggagt tgtggcccgt tgtccgtcaa cgtggcgtgg tgtgctctgt

3180

gtttgctgac gcaaccccca ctggctgggg cattgccacc acctgtcaac tcctttctgg

3240

gactttcgct ttccccctcc cgatcgccac ggcagaactc atcgccgcct gccttgcccg

3300

ctgctggaca ggggctaggt tgctgggcac tgataattcc gtggtgttgt ctgtgccttc

3360

tagttgccag ccatctgttg tttgcccctc ccccgtgcct tccttgaccc tggaaggtgc

3420

cactcccact gtcctttcct aataaaatga ggaaattgca tcgcattgtc tgagtaggtg

3480

tcattctatt ctggggggtg gggtggggca ggacagcaag ggggaggatt gggaagacaa

3540

tagcaggcat gctggggatg cggtgggctc tatggctcta gagcatggct acgtagataa

3600

gtagcatggc gggttaatca ttaactacac ctgcagcagg aacccctagt gatggagttg

3660

gccactccct ctctgcgcgc tcgctcgctc cctgcaggac tgaggccggg cgaccaaagg

3720

tcgcccgacg cccgggcggc ctcagtcctg cagg

3754

<210> 147

<211> 8418

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 147

ggcagctgcg cgctcgctcg ctcacctagg ccgcccgggc aaagcccggg cgtcgggcga

60

cctttggtcg cccggcctag gtgagcgagc gagcgcgcag agagggagtg gccaactcca

120

tcactagggg ttccttgtag ttaatgatta acccgccatg ctacttatcg cggccgctca

180

atattggcca ttagccatat tattcattgg ttatatagca taaatcaata ttggctattg

240

gccattgcat acgttgtatc tatatcataa tatgtacatt tatattggct catgtccaat

300

atgaccgcca tgttggcatt gattattgac tagttattaa tagtaatcaa ttacggggtc

360

attagttcat agcccatata tggagttccg cgttacataa cttacggtaa atggcccgcc

420

tggctgaccg cccaacgacc cccgcccatt gacgtcaata atgacgtatg ttcccatagt

480

aacgccaata gggactttcc attgacgtca atgggtggag tatttacggt aaactgccca

540

cttggcagta catcaagtgt atcatatgcc aagtccgccc cctattgacg tcaatgacgg

600

taaatggccc gcctggcatt atgcccagta catgacctta cgggactttc ctacttggca

660

gtacatctac gtattagtca tcgctattac catggtcgag gtgagcccca cgttctgctt

720

cactctcccc atctcccccc cctccccacc cccaattttg tatttattta ttttttaatt

780

attttgtgca gcgatggggg cggggggggg gggggggcgc gcgccaggcg gggcggggcg

840

gggcgagggg cggggcgggg cgaggcggag aggtgcggcg gcagccaatc agagcggcgc

900

gctccgaaag tttcctttta tggcgaggcg gcggcggcgg cggccctata aaaagcgaag

960

cgcgcggcgg gcgggagtcg ctgcgacgct gccttcgccc cgtgccccgc tccgccgccg

1020

cctcgcgccg cccgccccgg ctctgactga ccgcgttact cccacaggtg agcgggcggg

1080

acggcccttc tcctccgggc tgtaattagc gcttggttta atgacggctt gtttcttttc

1140

tgtggctgcg tgaaagcctt gaggggctcc gggagggccc tttgtgcggg ggggagcggc

1200

tcggggggtg cgtgcgtgtg tgtgtgcgtg gggagcgccg cgtgcggccc gcgctgcccg

1260

gcggctgtga gcgctgcggg cgcggcgcgg ggctttgtgc gctccgcagt gtgcgcgagg

1320

ggagcgcggc cgggggcggt gccccgcggt gcgggggggg ctgcgagggg aacaaaggct

1380

gcgtgcgggg tgtgtgcgtg ggggggtgag cagggggtgt gggcgcggcg gtcgggctgt

1440

aacccccccc tgcacccccc tccccgagtt gctgagcacg gcccggcttc gggtgcgggg

1500

ctccgtacgg ggcgtggcgc ggggctcgcc gtgccgggcg gggggtggcg gcaggtgggg

1560

gtgccgggcg gggcggggcc gcctcggggcc ggggagggct cgggggaggg gcgcggcggc

1620

ccccggagcg ccggcggctg tcgaggcgcg gcgagccgca gccattgcct tttatggtaa

1680

tcgtgcgaga gggcgcaggg acttcctttg tcccaaatct gtgcggagcc gaaatctggg

1740

aggcgccgcc gcaccccctc tagcgggcgc ggggcgaagc ggtgcggcgc cggcaggaag

1800

gaaatgggcg gggagggcct tcgtgcgtcg ccgcgccgcc gtccccttct ccctctccag

1860

cctcggggct gtccgcgggg ggacggctgc cttcgggggg gacggggcag ggcggggttc

1920

ggcttctggc gtgtgaccgg cggctctaga gcctctgcta accatgtttt agccttcttc

1980

tttttcctac agctcctggg caacgtgctg gttattgtgc tgtctcatca tttgtcgaca

2040

gaattcctcg aagatccgaa ggggttcaag cttggcattc cggtactgtt ggtaaagcca

2100

gtttaaacgc cgccaccatg gtgagcaagg gcgaggagct gttcaccggg gtggtgccca

2160

tcctggtcga gctggacggc gacgtaaacg gccacaagtt cagcgtgtcc ggcgaggcg

2220

agggcgatgc cacctacggc aagctgaccc tgaagttcat ctgcaccacc ggcaagctgc

2280

ccgtgccctg gcccaccctc gtgaccaccc tgacctacgg cgtgcagtgc ttcagccgct

2340

accccgacca catgaagcag cacgacttct tcaagtccgc catgcccgaa ggctacgtcc

2400

aggagcgcac catcttcttc aaggacgacg gcaactacaa gacccgcgcc gaggtgaagt

2460

tcgagggcga caccctggtg aaccgcatcg agctgaaggg catcgacttc aaggaggacg

2520

gcaacatcct ggggcacaag ctggagtaca actacaacag ccacaacgtc tatatcatgg

2580

ccgacaagca gaagaacggc atcaaggtga acttcaagat ccgccacaac atcgaggacg

2640

gcagcgtgca gctcgccgac cactaccagc agaacacccc catcggcgac ggccccgtgc

2700

tgctgcccga caaccactac ctgagcaccc agtccgccct gagcaaagac cccaacgaga

2760

agcgcgatca catggtcctg ctggagttcg tgaccgccgc cgggatcact ctcggcatgg

2820

acgagctgta caagtaatta attaagagca tcttaccgcc atttattccc atatttgttc

2880

tgtttttctt gatttgggta tacatttaaa tgttaataaa acaaaatggt ggggcaatca

2940

tttacatttt tagggatatg taattactag ttcaggtgta ttgccacaag acaaacatgt

3000

taagaaactt tcccgttatt tacgctctgt tcctgttaat caacctctgg attacaaaat

3060

ttgtgaaaga ttgactgata ttcttaacta tgttgctcct tttacgctgt gtggatatgc

3120

tgctttatag cctctgtatc tagctattgc ttcccgtacg gctttcgttt tctcctcctt

3180

gtataaatcc tggttgctgt ctcttttaga ggagttgtgg cccgttgtcc gtcaacgtgg

3240

cgtggtgtgc tctgtgtttg ctgacgcaac ccccactggc tggggcattg ccaccacctg

3300

tcaactcctt tctgggactt tcgctttccc cctcccgatc gccacggcag aactcatcgc

3360

cgcctgcctt gcccgctgct ggacaggggc taggttgctg ggcactgata attccgtggt

3420

gttgtctgtg ccttctagtt gccagccatc tgttgtttgc ccctcccccg tgccttcctt

3480

gaccctggaa ggtgccactc ccactgtcct ttcctaataa aatgaggaaa ttgcatcgca

3540

ttgtctgagt aggtgtcatt ctattctggg gggtggggtg gggcaggaca gcaaggggga

3600

ggattgggaa gacaatagca ggcatgctgg ggatgcggtg ggctctatgg ctctagagca

3660

tggctacgta gataagtagc atggcgggtt aatcattaac tacacctgca gcaggaaccc

3720

ctagtgatgg agttggccac tccctctctg cgcgctcgct cgctccctgc aggactgagg

3780

ccgggcgacc aaaggtcgcc cgacgcccgg gcggcctcag tcctgcaggg agcgagcgag

3840

cgcgcagctg cctgcacggg cgcgccggta ccgggagatg ggggaggcta actgaaacac

3900

ggaagggagac aataccggaa ggaacccgcg ctatgacggc aataaaaaga cagaataaaa

3960

cgcacgggtg ttgggtcgtt tgttcataaa cgcggggttc ggtcccaggg ctggcactct

4020

gtcgataccc caccgagacc ccattgggac caatacgccc gcgtttcttc cttttcccca

4080

ccccaacccc caagttcggg tgaaggccca gggctcgcag ccaacgtcgg ggcggcaagc

4140

cctgccatag ccactacggg tacgtaggcc aaccactaga actatagcta gagtcctggg

4200

cgaacaaacg atgctcgcct tccagaaaac cgaggatgcg aaccacttca tccggggtca

4260

gcaccaccgg caagcgccgc gacggccgag gtctaccgat ctcctgaagc cagggcagat

4320

ccgtgcacag caccttgccg tagaagaaca gcaaggccgc caatgcctga cgatgcgtgg

4380

agaccgaaac cttgcgctcg ttcgccagcc aggacagaaa tgcctcgact tcgctgctgc

4440

ccaaggttgc cgggtgacgc acaccgtgga aacggatgaa ggcacgaacc cagttgacat

4500

aagcctgttc ggttcgtaaa ctgtaatgca agtagcgtat gcgctcacgc aactggtcca

4560

gaaccttgac cgaacgcagc ggtggtaacg gcgcagtggc ggttttcatg gcttgttatg

4620

actgtttttt tgtacagtct atgcctcggg catccaagca gcaagcgcgt tacgccgtgg

4680

gtcgatgttt gatgttatgg agcagcaacg atgttacgca gcagcaacga tgttacgcag

4740

cagggcagtc gccctaaaac aaagttaggt ggctcaagta tgggcatcat tcgcacatgt

4800

aggctcggcc ctgaccaagt caaatccatg cgggctgctc ttgatctttt cggtcgtgag

4860

ttcggagacg tagccaccta ctcccaacat cagccggact ccgattacct cgggaacttg

4920

ctccgtagta agacattcat cgcgcttgct gccttcgacc aagaagcggt tgttggcgct

4980

ctcgcggctt acgttctgcc caggtttgag cagccgcgta gtgagatcta tatctatgat

5040

ctcgcagtct ccggcgagca ccggaggcag ggcattgcca ccgcgctcat caatctcctc

5100

aagcatgagg ccaacgcgct tggtgcttat gtgatctacg tgcaagcaga ttacggtgac

5160

gatcccgcag tggctctcta tacaaagttg ggcatacggg aagaagtgat gcactttgat

5220

atcgacccaa gtaccgccac ctaacaattc gttcaagccg agatcggctt cccggccgcg

5280

gagttgttcg gtaaattgtc acaacgccgc gaatatagtc tttaccatgc ccttggccac

5340

gcccctcttt aatacgacgg gcaatttgca cttcagaaaa tgaagagttt gctttagcca

5400

taacaaaagt ccagtatgct ttttcacagc ataactggac tgatttcagt ttacaactat

5460

tctgtctagt ttaagacttt attgtcatag tttagatcta ttttgttcag tttaagactt

5520

tattgtccgc ccacacccgc ttacgcaggg catccattta ttactcaacc gtaaccgatt

5580

ttgccaggtt acgcggctgg tctgcggtgt gaaataccgc acagatgcgt aaggagaaaa

5640

taccgcatca ggcgctcttc cgcttcctcg ctcactgact cgctgcgctc ggtcgttcgg

5700

ctgcggcgag cggtatcagc tcactcaaag gcggtaatac ggttatccac agaatcaggg

5760

gataacgcag gaaagaacat gtgagcaaaa ggccagcaaa aggccaggaa ccgtaaaaag

5820

gccgcgttgc tggcgttttt ccataggctc cgcccccctg acgagcatca caaaaatcga

5880

cgctcaagtc agaggtggcg aaacccgaca ggactataaa gataccaggc gtttccccct

5940

ggaagctccc tcgtgcgctc tcctgttccg accctgccgc ttaccggata cctgtccgcc

6000

tttctccctt cgggaagcgt ggcgctttct caatgctcac gctgtaggta tctcagttcg

6060

gtgtaggtcg ttcgctccaa gctgggctgt gtgcacgaac cccccgttca gcccgaccgc

6120

tgcgccttat ccggtaacta tcgtcttgag tccaacccgg taagacacga cttatcgcca

6180

ctggcagcag ccactggtaa caggattagc agagcgaggt atgtaggcgg tgctacagag

6240

ttcttgaagt ggtggcctaa ctacggctac actagaagga cagtatttgg tatctgcgct

6300

ctgctgaagc cagttacctt cggaaaaaga gttggtagct cttgatccgg caaacaaacc

6360

accgctggta gcggtggttt ttttgtttgc aagcagcaga ttacgcgcag aaaaaaagga

6420

tctcaagaag atcctttgat cttttctacg gggtctgacg ctcagtggaa cgaaaactca

6480

cgttaaggga ttttggtcat gagattatca aaaaggatct tcacctagat ccttttaaat

6540

taaaaatgaa gttttaaatc aatctaaagt atatatgagt aaacttggtc tgacagttac

6600

caatgcttaa tcagtgaggc acctatctca gcgatctgtc tatttcgttc atccatagtt

6660

gcctgactcc ccgtcgtgta gataactacg atacgggagg gcttaccatc tggccccagt

6720

gctgcaatga taccgcgaga cccacgctca ccggctccag atttatcagc aataaaccag

6780

ccagccggaa gggccgagcg cagaagtggt cctgcaactt tatccgcctc catccagtct

6840

attaattgtt gccgggaagc tagagtaagt agttcgccag ttaatagttt gcgcaacgtt

6900

gttgccattg ctacaggcat cgtggtgtca cgctcgtcgt ttggtatggc ttcattcagc

6960

tccggttccc aacgatcaag gcgagttaca tgatccccca tgttgtgcaa aaaagcggtt

7020

agctccttcg gtcctccgat cgttgtcaga agtaagttgg ccgcagtgtt atcactcatg

7080

gttatggcag cactgcataa ttctcttact gtcatgccat ccgtaagatg cttttctgtg

7140

actggtgagt actcaaccaa gtcattctga gaatagtgta tgcggcgacc gagttgctct

7200

tgcccggcgt caatacggga taataccgcg ccacatagca gaactttaaa agtgctcatc

7260

attggaaaac gttcttcggg gcgaaaactc tcaaggatct taccgctgtt gagatccagt

7320

tcgatgtaac ccactcgtgc acccaactga tcttcagcat cttttacttt caccagcgtt

7380

tctgggtgag caaaaacagg aaggcaaaat gccgcaaaaa agggaataag ggcgacacgg

7440

aaatgttgaa tactcatact cttccttttt caatattatt gaagcattta tcagggttat

7500

tgtctcatga gcggatacat atttgaatgt atttagaaaa ataaacaaat aggggttccg

7560

cgcacatttc cccgaaaagt gccacctgaa attgtaaacg ttaatatttt gttaaaattc

7620

gcgttaaatt tttgttaaat cagctcattt tttaaccaat aggccgaaat cggcaaaatc

7680

ccttataaat caaaagaata gaccgagata gggttgagtg ttgttccagt ttggaacaag

7740

agtccactat taaagaacgt ggactccaac gtcaaagggc gaaaaaccgt ctatcagggc

7800

gatggcccac tacgtgaacc atcaccctaa tcaagttttt tggggtcgag gtgccgtaaa

7860

gcactaaatc ggaaccctaa agggagcccc cgatttagag cttgacgggg aaagccggcg

7920

aacgtggcga gaaaggaagg gaagaaagcg aaaggagcgg gcgctagggc gctggcaagt

7980

gtagcggtca cgctgcgcgt aaccaccaca cccgccgcgc ttaatgcgcc gctacaggc

8040

gcgtcccatt cgccattcag gctgcaaata agcgttgata ttcagtcaat tacaaacatt

8100

aataacgaag agatgacaga aaaattttca ttctgtgaca gagaaaaagt agccgaagat

8160

gacggtttgt cacatggagt tggcaggatg tttgattaaa aacataacag gaagaaaaat

8220

gccccgctgt gggcggacaa aatagttggg aactgggagg ggtggaaatg gagtttttaa

8280

ggattattta gggaagagtg acaaaataga tgggaactgg gtgtagcgtc gtaagctaat

8340

acgaaaatta aaaatgacaa aatagtttgg aactagatt cacttatctg gttcggatct

8400

cctagtgagc tccctgca

8418

<210> 148

<211> 225

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 148

tgtgccttct agttgccagc catctgttgt ttgcccctcc cccgtgcctt ccttgaccct

60

ggaaggtgcc actcccactg tcctttccta ataaaatgag gaaattgcat cgcattgtct

120

gagtaggtgt cattctattc tggggggtgg ggtggggcag gacagcaagg gggaggattg

180

ggaagacaat agcaggcatg ctggggatgc ggtgggctct atggc

225

<210> 149

<211> 1177

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 149

ggctcagagg ctcagaggca cacaggagtt tctgggctca ccctgccccc ttccaacccc

60

tcagttccca tcctccagca gctgtttgtg tgctgcctct gaagtccaca ctgaacaaac

120

ttcagcctac tcatgtccct aaaatgggca aacattgcaa gcagcaaaca gcaaacacac

180

agccctccct gcctgctgac cttggagctg gggcagaggt cagagacctc tctgggccca

240

tgccacctcc aacatccact cgaccccttg gaatttcggt ggagaggagc agaggttgtc

300

ctggcgtggt ttaggtagtg tgagagggtc cgggttcaaa accacttgct gggtggggag

360

tcgtcagtaa gtggctatgc cccgaccccg aagcctgttt ccccatctgt acaatggaaa

420

tgataaagac gcccatctga tagggttttt gtggcaaata aacatttggt ttttttgttt

480

tgttttgttt tgttttttga gatggaggtt tgctctgtcg cccaggctgg agtgcagtga

540

cacaatctca tctcaccaca accttcccct gcctcagcct cccaagtagc tgggattaca

600

agcatgtgcc accacacctg gctaattttc tatttttagt agagacgggt ttctccatgt

660

tggtcagcct cagcctccca agtaactggg attacaggcc tgtgccacca cacccggcta

720

attttttcta tttttgacag ggacggggtt tcaccatgtt ggtcaggctg gtctagaggt

780

accggatctt gctaccagtg gaacagccac taaggattct gcagtgagag cagaggcca

840

gctaagtggt actctcccag agactgtctg actcacgcca ccccctccac cttggacaca

900

ggacgctgtg gtttctgagc caggtacaat gactcctttc ggtaagtgca gtggaagctg

960

tacactgccc aggcaaagcg tccgggcagc gtaggcgggc gactcagatc ccagccagtg

1020

gacttagccc ctgtttgctc ctccgataac tggggtgacc ttggttaata ttcaccagca

1080

gcctcccccg ttgcccctct ggatccactg cttaaatacg gacgaggaca gggccctgtc

1140

tcctcagctt caggcaccac cactgacctg ggacagt

1177

<210> 150

<211> 1326

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 150

ctgcagggcc cactagtgga gccgagagta attcatacaa aaggagggat cgccttcgca

60

aggggagagc cccaggaccg tccctaaatt ctcacagacc caaatccctg tagccgcccc

120

acgacagcgc gaggagcatg cgcccagggc tgagcgcggg tagatcagag cacacaagct

180

cacagtcccc ggcggtgggg ggaggggcgc gctgagcggg ggccagggag ctggcgcggg

240

gcaaactggg aaagtggtgt cgtgtgctgg ctccgccctc ttcccgaggg tggggggagaa

300

cggtatataa gtgcggtagt cgccttggac gttctttttc gcaacgggtt tgccgtcaga

360

acgcaggtga gtggcgggtg tggcttccgc gggccccgga gctggagccc tgctctgagc

420

gggccgggct gatatgcgag tgtcgtccgc agggtttagc tgtgagcatt cccacttcga

480

gtggcgggcg gtgcgggggt gagagtgcga ggcctagcgg caaccccgta gcctcgcctc

540

gtgtccggct tgaggcctag cgtggtgtcc gccgccgcgt gccactccgg ccgcactatg

600

cgttttttgt ccttgctgcc ctcgattgcc ttccagcagc atgggctaac aaagggaggg

660

tgtggggctc actcttaagg agcccatgaa gcttacgttg gataggaatg gaagggcagg

720

aggggcgact ggggcccgcc cgccttcgga gcacatgtcc gacgccacct ggatggggcg

780

aggcctgtgg ctttccgaag caatcgggcg tgagtttagc ctacctgggc catgtggccc

840

tagcactggg cacggtctgg cctggcggtg ccgcgttccc ttgcctccca acaagggtga

900

ggccgtcccg cccggcacca gttgcttgcg cggaaagatg gccgctcccg gggccctgtt

960

gcaaggagct caaaatggag gacgcggcag cccggtggag cgggcgggtg agtcaccac

1020

acaaaggaag agggccttgc ccctcgccgg ccgctgcttc ctgtgacccc gtggtctatc

1080

ggccgcatag tcacctcggg cttctcttga gcaccgctcg tcgcggcggg gggaggggat

1140

ctaatggcgt tggagtttgt tcacatttgg tgggtggaga ctagtcaggc cagcctggcg

1200

ctggaagtca ttcttggaat ttgccccttt gagtttggag cgaggctaat tctcaagcct

1260

cttagcggtt caaaggtatt ttctaaaccc gtttccaggt gttgtgaaag ccaccgctaa

1320

ttcaaa

1326

<210> 151

<211> 573

<212> DNA

<213> Mus musculus

<400> 151

gtaagagttt tatgtttttt catctctgct tgtatttttc tagtaatgga agcctggtat

60

tttaaaatag ttaaattttc ctttagtgct gatttctaga ttattattac tgttgttgtt

120

gttattattg tcattatttg catctgagaa cccttaggtg gttatattat tgatatattt

180

ttggtatctt tgatgacaat aatgggggat tttgaaagct tagctttaaa tttcttttaa

240

ttaaaaaaaa atgctaggca gaatgactca aattacgttg gatacagttg aatttattac

300

ggtctcatag ggcctgcctg ctcgaccatg ctatactaaa aattaaaagt gtgtgttact

360

aattttataa atggagtttc catttatatt tacctttatt tcttatttac cattgtctta

420

gtagatattt acaaacatga cagaaacact aaatcttgag tttgaatgca cagatataaa

480

cacttaacgg gttttaaaaa taataatgtt ggtgaaaaaa tataactttg agtgtagcag

540

agaggaacca ttgccacctt cagattttcc tgt

573

<210> 152

<211> 1993

<212> DNA

<213> Mus musculus

<400> 152

acgatcggga actggcatct tcagggagta gcttaggtca gtgaagagaa gaacaaaaag

60

cagcatatta cagttagttg tcttcatcaa tctttaaata tgttgtgtgg tttttctctc

120

cctgtttcca cagacaagag tgagatcgcc catcggtata atgatttggg agaacaacat

180

ttcaaaggcc tgtaagttat aatgctgaaa gcccacttaa tatttctggt agtattagtt

240

aaagttttaa aacacctttt tccaccttga gtgtgagaat tgtagagcag tgctgtccag

300

tagaaatgtg tgcattgaca gaaagactgt ggatctgtgc tgagcaatgt ggcagccaga

360

gatcacaagg ctatcaagca ctttgcacat ggcaagtgta actgagaagc acacattcaa

420

ataatagtta attttaattg aatgtatcta gccatgtgtg gctagtagct cctttcctgg

480

agagagaatc tggagcccac atctaacttg ttaagtctgg aatcttattt tttatttctg

540

gaaaggtcta tgaactatag ttttgggggc agctcactta ctaactttta atgcaataag

600

atctcatggt atcttgagaa cattattttg tctctttgta gtactgaaac cttatacatg

660

tgaagtaagg ggtctatact taagtcacat ctccaacctt agtaatgttt taatgtagta

720

aaaaaatgag taattaattt atttttagaa ggtcaatagt atcatgtatt ccaaataaca

780

gaggtatatg gttagaaaag aaacaattca aaggacttat ataatatcta gccttgacaa

840

tgaataaatt tagagagtag tttgcctgtt tgcctcatgt tcataaatct attgacacat

900

atgtgcatct gcacttcagc atggtagaag tccatattcc tttgcttgga aaggcaggtg

960

ttcccattac gcctcagaga atagctgacg ggaagaggct ttctagatag ttgtatgaaa

1020

gatatacaaa atctcgcagg tatacacagg catgatttgc tggttgggag agccacttgc

1080

ctcatactga ggtttttgtg tctgcttttc agagtcctga ttgccttttc ccagtatctc

1140

cagaaatgct catacgatga gcatgccaaa ttagtgcagg aagtaacaga ctttgcaaag

1200

acgtgtgttg ccgatgagtc tgccgccaac tgtgacaaat cccttgtgag taccttctga

1260

ttttgtggat ctactttcct gctttctgga actctgtttc aaagccaatc atgactccat

1320

cacttaaggc cccgggaaca ctgtggcaga gggcagcaga gagattgata aagccaggt

1380

gatgggaatt ttctgtggga ctccatttca tagtaattgc agaagctaca atacactcaa

1440

aaagtctcac cacatgactg cccaaatggg agcttgacag tgacagtgac agtagatatg

1500

ccaaagtgga tgagggaaag accacaagag ctaaaccctg taaaaagaac tgtaggcaac

1560

taaggaatgc agagagaaga agttgccttg gaagagcata ccaactgcct ctccaatacc

1620

aatggtcatc cctaaaacat acgtatgaat aacatgcaga ctaagcaggc tacatttagg

1680

aatatacatg tatttacata aatgtatatg catgtaacaa caatgaatga aaactgaggt

1740

catggatctg aaagagagca agggggctta catgagagg tttggaggga ggggttggag

1800

ggagggaggt attattcttt agttttacag ggaacgtagt aaaaacatag gcttctccca

1860

aaggagcaga gcccatgagg agctgtgcaa ggttccccag cttgatttta cctgctcctc

1920

aaattccctt gatttgtttt tattataatg actttactcc tagcttttag tgtcagatag

1980

aaaacatgga agg

1993

<210> 153

<211> 1350

<212> DNA

<213> Homo sapiens

<400> 153

taggaggctg aggcaggagg atcgcttgag cccaggagtt cgagaccagc ctgggcaaca

60

tagtgtgatc ttgtatctat aaaaataaac aaaattagct tggtgtggtg gcgcctgtag

120

tccccagcca cttggagggg tgaggtgaga ggattgcttg agcccgggat ggtccaggct

180

gcagtgagcc atgatcgtgc cactgcactc cagcctgggc gacagagtga gaccctgtct

240

cacaacaaca acaacaacaa caaaaaggct gagctgcacc atgcttgacc cagtttctta

300

aaattgttgt caaagcttca ttcactccat ggtgctatag agcacaagat tttatttggt

360

gagatggtgc tttcatgaat tcccccaaca gagccaagct ctccatctag tggacaggga

420

agctagcagc aaaccttccc ttcactacaa aacttcattg cttggccaaa aagagagtta

480

attcaatgta gacatctatg taggcaatta aaaacctatt gatgtataaa acagtttgca

540

ttcatggagg gcaactaaat acattctagg actttataaa agatcacttt ttatttatgc

600

acagggtgga acaagatgga ttatcaagtg tcaagtccaa tctatgacat caattattat

660

acatcggagc cctgccaaaa aatcaatgtg aagcaaatcg cagcccgcct cctgcctccg

720

ctctactcac tggtgttcat ctttggtttt gtgggcaaca tgctggtcat cctcatcctg

780

ataaactgca aaaggctgaa gagcatgact gacatctacc tgctcaacct ggccatctct

840

gacctgtttt tccttcttac tgtccccttc tgggctcact atgctgccgc ccagtgggac

900

tttggaaata caatgtgtca actcttgaca gggctctatt ttataggctt cttctctgga

960

atcttcttca tcatcctcct gacaatcgat aggtacctgg ctgtcgtcca tgctgtgttt

1020

gctttaaaag ccaggacggt cacctttggg gtggtgacaa gtgtgatcac ttgggtggtg

1080

gctgtgtttg cgtctctccc aggaatcatc tttaccagat ctcaaaaaga aggtcttcat

1140

tacacctgca gctctcattt tccatacagt cagtatcaat tctggaagaa tttccagaca

1200

ttaaagatag tcatcttggg gctggtcctg ccgctgcttg tcatggtcat ctgctactcg

1260

ggaatcctaa aaactctgct tcggtgtcga aatgagaaga agaggcacag ggctgtgagg

1320

cttatcttca ccatcatgat tgtttatttt

1350

<210> 154

<211> 1223

<212> DNA

<213> Homo sapiens

<400> 154

tgacagagac tcttgggatg acgcactgct gcatcaaccc catcatctat gcctttgtcg

60

gggagaagtt cagaaactac ctcttagtct tcttccaaaa gcacattgcc aaacgcttct

120

gcaaatgctg ttctattttc cagcaagagg ctcccgagcg agcaagctca gtttacaccc

180

gatccactgg ggagcaggaa atatctgtgg gcttgtgaca cggactcaag tgggctggtg

240

acccagtcag agttgtgcac atggcttagt tttcatacac agcctgggct gggggtgggg

300

tggggagaggt cttttttaaa aggaagttac tgttatagag ggtctaagat tcatccatt

360

atttggcatc tgtttaaagt agattagatc ttttaagccc atcaattata gaaagccaaa

420

tcaaaatatg ttgatgaaaa atagcaacct ttttatctcc ccttcacatg catcaagtta

480

ttgacaaact ctcccttcac tccgaaagtt ccttatgtat atttaaaaga aagcctcaga

540

gaattgctga ttcttgagtt tagtgatctg aacagaaata ccaaaattat ttcagaaatg

600

tacaactttt tacctagtac aaggcaacat ataggttgta aatgtgttta aaacaggtct

660

ttgtcttgct atggggagaa aagacatgaa tatgattagt aaagaaatga cacttttcat

720

gtgtgatttc ccctccaagg tatggttaat aagtttcact gacttagaac caggcgagag

780

acttgtggcc tgggagagct ggggaagctt cttaaatgag aaggaatttg agttggatca

840

tctattgctg gcaaagacag aagcctcact gcaagcactg catgggcaag cttggctgta

900

gaaggagaca gagctggttg ggaagacatg gggaggaagg acaaggctag atcatgaaga

960

accttgacgg cattgctccg tctaagtcat gagctgagca ggggagatcct ggttggtgtt

1020

gcagaaggtt tactctgtgg ccaaaggagg gtcaggaagg atgagcattt agggcaagga

1080

gaccaccaac agccctcagg tcagggtgag gatggcctct gctaagctca aggcgtgagg

1140

atgggaagga gggaggtatt cgtaaggatg ggaaggaggg aggtattcgt gcagcatatg

1200

aggatgcaga gtcagcagaa ctg

1223

<210> 155

<211> 215

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 155

gaacgctgac gtcatcaacc cgctccaagg aatcgcgggc ccagtgtcac taggcgggaa

60

cacccagcgc gcgtgcgccc tggcaggaag atggctgtga gggacagggg agtggcgccc

120

tgcaatattt gcatgtcgct atgtgttctg ggaaatcacc ataaacgtga aatgtctttg

180

gatttgggaa tcttataagt tctgtatgag accac

215

<210> 156

<211> 141

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 156

cctgcaggca gctgcgcgct cgctcgctca cctaggccgc ccgggcaaag cccgggcgtc

60

gggcgacctt tggtcgcccg gcctaggtga gcgagcgagc gcgcagagag ggagtggcca

120

actccatcac taggggttcc t

141

<210> 157

<211> 19

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 157

gcgcgctcgc tcgctcacc

19

<210> 158

<211> 22

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 158

ctaggtgagc gagcgagcgc gc

22

<210> 159

<211> 75

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 159

cctgcaggac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt ggtcgcccgg

60

cctcagtcct gcagg

75

<210> 160

<211> 130

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 160

aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagt

60

gcgggcgacc aaaggtcgcc cgacgcccgg gcgcactcag tgagcgagcg agcgcgcagc

120

tgcctgcagg

130

<210> 161

<211> 142

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 161

cctgcaggca gctgcgcgct cgctcgctcc ctaggactga ggccgcccgg gcgtcgggcg

60

acctttggtc gcccggcctc agtcctaggg agcgagcgag cgcgcagaga gggagtggcc

120

aactccatca ctaggggttc ct

142

<210> 162

<211> 80

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 162

gcgcgctcgc tcgctcactg agtgcgggcg accaaaggtc gcccgacgcc cgggcgcact

60

cagtgagcga gcgagcgcgc

80

<210> 163

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 163

gcgcgctcgc tcgctcactg a

21

<210> 164

<211> 18

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 164

gtgagcgagc gagcgcgc

18

<210> 165

<211> 89

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 165

gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgactttgtc

60

gcccggcctc agtgagcgag cgagcgcgc

89

<210> 166

<211> 89

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 166

gcgcgctcgc tcgctcactg aggccgggcg acaaagtcgc ccgacgcccg ggctttgccc

60

gggcggcctc agtgagcgag cgagcgcgc

89

<210> 167

<211> 87

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 167

gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgattttcgc

60

ccggcctcag tgagcgagcg agcgcgc

87

<210> 168

<211> 87

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 168

gcgcgctcgc tcgctcactg aggccgggcg aaaatcgccc gacgcccggg ctttgcccgg

60

gcggcctcag tgagcgagcg agcgcgc

87

<210> 169

<211> 85

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 169

gcgcgctcgc tcgctcactg aggccgcccg ggcaaagccc gggcgtcggg cgtttcgccc

60

ggcctcagtg agcgagcgag cgcgc

85

<210> 170

<211> 85

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 170

gcgcgctcgc tcgctcactg aggccgggcg aaacgcccga cgcccgggct ttgcccgggc

60

ggcctcagtg agcgagcgag cgcgc

85

<210> 171

<211> 89

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 171

gcgcgctcgc tcgctcactg aggccgcccg ggaaacccgg gcgtcgggcg acctttggtc

60

gcccggcctc agtgagcgag cgagcgcgc

89

<210> 172

<211> 89

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 172

gcgcgctcgc tcgctcactg aggccgggcg accaaaggtc gcccgacgcc cgggtttccc

60

gggcggcctc agtgagcgag cgagcgcgc

89

<210> 173

<211> 87

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 173

gcgcgctcgc tcgctcactg aggccgcccg gaaaccgggc gtcgggcgac ctttggtcgc

60

ccggcctcag tgagcgagcg agcgcgc

87

<210> 174

<211> 87

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 174

gcgcgctcgc tcgctcactg aggccgggcg accaaaggtc gcccgacgcc cggtttccgg

60

gcggcctcag tgagcgagcg agcgcgc

87

<210> 175

<211> 85

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 175

gcgcgctcgc tcgctcactg aggccgcccg aaacgggcgt cgggcgacct ttggtcgccc

60

ggcctcagtg agcgagcgag cgcgc

85

<210> 176

<211> 85

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 176

gcgcgctcgc tcgctcactg aggccgggcg accaaaggtc gcccgacgcc cgtttcgggc

60

ggcctcagtg agcgagcgag cgcgc

85

<210> 177

<211> 83

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 177

gcgcgctcgc tcgctcactg aggccgccca aagggcgtcg ggcgaccttt ggtcgcccgg

60

cctcagtgag cgagcgagcg cgc

83

<210> 178

<211> 83

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 178

gcgcgctcgc tcgctcactg aggccgggcg accaaaggtc gcccgacgcc ctttgggcgg

60

cctcagtgag cgagcgagcg cgc

83

<210> 179

<211> 81

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 179

gcgcgctcgc tcgctcactg aggccgccaa aggcgtcggg cgacctttgg tcgcccggcc

60

tcagtgagcg agcgagcgcg c

81

<210> 180

<211> 81

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 180

gcgcgctcgc tcgctcactg aggccgggcg accaaaggtc gcccgacgcc tttggcggcc

60

tcagtgagcg agcgagcgcg c

81

<210> 181

<211> 79

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 181

gcgcgctcgc tcgctcactg aggccgcaaa gcgtcgggcg acctttggtc gcccggcctc

60

agtgagcgag cgagcgcgc

79

<210> 182

<211> 79

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 182

gcgcgctcgc tcgctcactg aggccgggcg accaaaggtc gcccgacgct ttgcggcctc

60

agtgagcgag cgagcgcgc

79

<210> 183

<211> 81

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 183

ctgcgcgctc gctcgctcac tgaggccgaa acgtcgggcg acctttggtc gcccggcctc

60

agtgagcgag cgagcgcgca g

81

<210> 184

<211> 81

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 184

ctgcgcgctc gctcgctcac tgaggccggg cgaccaaagg tcgcccgacg tttcggcctc

60

agtgagcgag cgagcgcgca g

81

<210> 185

<211> 72

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 185

gcgcgctcgc tcgctcactg aggccgggcg accaaaggtc gcccgacggc ctcagtgagc

60

gagcgagcgc gc

72

<210> 186

<211> 80

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 186

gcgcgctcgc tcgctcactg aggccgggcg accaaaggtc gcccgacgcc cgggcggcct

60

cagtgagcga gcgagcgcgc

80

<210> 187

<211> 79

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 187

gcgcgctcgc tcgctcactg aggcgcccgg gcgtcgggcg acctttggtc gcccggcctc

60

agtgagcgag cgagcgcgc

79

<210> 188

<211> 48

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 188

ggagtcaaag ttctgtttgc cctgatctgc atcgctgtgg ccgaggcc

48

<210> 189

<211> 99

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

oligonucleotide

<400> 189

attcatacca acttgaagaa aaagttcagc ctcttcatcc tggtctttct cctgttcgca

60

gtcatctgtg tttggaagaa agggagcgac tatgaggcc

99

<210> 190

<211> 588

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 190

gcccctctcc ctcccccccc cctaacgtta ctggccgaag ccgcttggaa taaggccggt

60

gtgcgtttgt ctatatgtta ttttccacca tattgccgtc ttttggcaat gtgagggccc

120

ggaaacctgg ccctgtcttc ttgacgagca ttcctagggg tctttcccct ctcgccaaag

180

gaatgcaagg tctgttgaat gtcgtgaagg aagcagttcc tctggaagct tcttgaagac

240

aaacaacgtc tgtagcgacc ctttgcaggc agcggaaccc cccacctggc gacaggtgcc

300

tctgcggcca aaagccacgt gtataagata cacctgcaaa ggcggcacaa ccccagtgcc

360

acgttgtgag ttggatagtt gtggaaagag tcaaatggct ctcctcaagc gtattcaaca

420

aggggctgaa ggatgcccag aaggtacccc attgtatggg atctgatctg gggcctcggt

480

gcacatgctt tacatgtgtt tagtcgaggt taaaaaaacg tctaggcccc ccgaaccacg

540

gggacgtggt tttcctttga aaaacacgat gataatatgg ccacaacc

588

<210> 191

<211> 399

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 191

cgggggaggc tgctggtgaa tattaaccaa ggtcacccca gttatcggag gagcaaacag

60

gggctaagtc cacacgcgtg gtaccgtctg tctgcacatt tcgtagagcg agtgttccga

120

tactctaatc tccctaggca aggttcatat ttgtgtaggt tacttattct ccttttgttg

180

actaagtcaa taatcagaat cagcaggttt ggagtcagct tggcagggat cagcagcctg

240

ggttggaagg agggggtata aaagcccctt caccaggaga agccgtcaca cagatccaca

300

agctcctgaa gaggtaaggg tttaagggat ggttggttgg tggggtatta atgtttaatt

360

acctggagca cctgcctgaa atcacttttt ttcaggttg

399

<210> 192

<211> 14359

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 192

gacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg tggttacgcg cagcgtgacc

60

gctacacttg ccagcgccct agcgcccgct cctttcgctt tcttcccttc ctttctcgcc

120

acgttcgccg gctttccccg tcaagctcta aatcggggggc tccctttagg gttccgattt

180

agtgctttac ggcacctcga ccccaaaaaa cttgattagg gtgatggttc acgtagtggg

240

ccatcgccct gatagacggt ttttcgccct ttgacgttgg agtccacgtt ctttaatagt

300

ggactcttgt tccaaactgg aacaacactc aaccctatct cggtctattc ttttgattta

360

taagggattt tgccgatttc ggcctattgg ttaaaaaatg agctgattta acaaaaattt

420

aacgcgaatt ttaacaaaat attaacgttt acaatttcag gtggcacttt tcggggaaat

480

gtgcgcggaa cccctatttg tttatttttc taaatacatt caaatatgta tccgctcatg

540

agacaataac cctgataaat gcttcaataa tattgaaaaa ggaagagtat gagtattcaa

600

catttccgtg tcgcccttat tccctttttt gcggcatttt gccttcctgt ttttgctcac

660

ccagaaacgc tggtgaaagt aaaagatgct gaagatcagt tgggtgcacg agtgggttac

720

atcgaactgg atctcaacag cggtaagatc cttgagagtt ttcgccccga agaacgtttt

780

ccaatgatga gcacttttaa agttctgcta tgtggcgcgg tattatcccg tattgacgcc

840

gggcaagagc aactcggtcg ccgcatacac tattctcaga atgacttggt tgagtactca

900

ccagtcacag aaaagcatct tacggatggc atgacagtaa gagaattatg cagtgctgcc

960

ataaccatga gtgataacac tgcggccaac ttacttctga caacgatcgg aggaccgaag

1020

gagctaaccg cttttttgca caacatgggg gatcatgtaa ctcgccttga tcgttgggaa

1080

ccggagctga atgaagccat accaaacgac gagcgtgaca ccacgatgcc tgtagcaatg

1140

gcaacaacgt tgcgcaaact attaactggc gaactactta ctctagcttc ccggcaacaa

1200

ttaatagact ggatggaggc ggataaagtt gcaggaccac ttctgcgctc ggcccttccg

1260

gctggctggt ttattgctga taaatctgga gccggtgagc gtgggtctcg cggtatcatt

1320

gcagcactgg ggccagatgg taagccctcc cgtatcgtag ttatctacac gacggggagt

1380

caggcaacta tggatgaacg aaatagacag atcgctgaga taggtgcctc actgattaag

1440

cattggtaac tgtcagacca agtttactca tatatacttt agattgattt aaaacttcat

1500

ttttaattta aaaggatcta ggtgaagatc ctttttgata atctcatgac caaaatccct

1560

taacgtgagt tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa aggatcttct

1620

tgagatcctt tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc accgctacca

1680

gcggtggttt gtttgccgga tcaagagcta ccaactcttt ttccgaaggt aactggcttc

1740

agcagagcgc agataccaaa tactgtcctt ctagtgtagc cgtagttagg ccaccacttc

1800

aagaactctg tagcaccgcc tacatacctc gctctgctaa tcctgttacc agtggctgct

1860

gccagtggcg ataagtcgtg tcttaccggg ttggactcaa gacgatagtt accggataag

1920

gcgcagcggt cgggctgaac ggggggttcg tgcacacagc ccagcttgga gcgaacgacc

1980

tacaccgaac tgagatacct acagcgtgag cattgagaaa gcgccacgct tcccgaaggg

2040

agaaaggcgg acaggtatcc ggtaagcggc agggtcggaa caggagagcg cacgagggag

2100

cttccagggg gaaacgcctg gtatctttat agtcctgtcg ggtttcgcca cctctgactt

2160

gagcgtcgat ttttgtgatg ctcgtcaggg gggcggagcc tatggaaaaa cgccagcaac

2220

gcggcctttt tacggttcct ggccttttgc tggccttttg ctcacatgtt ctttcctgcg

2280

ttatcccctg attctgtgga taaccgtatt accgcctttg agtgagctga taccgctcgc

2340

cgcagccgaa cgaccgagcg cagcgagtca gtgagcgagg aagcggaaga gcgcctgatg

2400

cggtattttc tccttacgca tctgtgcggt atttcacacc gcagaccagc cgcgtaacct

2460

ggcaaaatcg gttacggttg agtaataaat ggatgccctg cgtaagcggg tgtgggcgga

2520

caataaagtc ttaaactgaa caaaatagat ctaaactatg acaataaagt cttaaactag

2580

acagaatagt tgtaaactga aatcagtcca gttatgctgt gaaaaagcat actggacttt

2640

tgttatggct aaagcaaact cttcattttc tgaagtgcaa attgcccgtc gtattaaaga

2700

ggggcgtggc caagggcatg gtaaagacta tattcgcggc gttgtgacaa tttaccgaac

2760

aactccgcgg ccgggaagcc gatctcggct tgaacgaatt gttaggtggc ggtacttggg

2820

tcgatatcaa agtgcatcac ttcttcccgt atgcccaact ttgtatagag agccactgcg

2880

ggatcgtcac cgtaatctgc ttgcacgtag atcacataag caccaagcgc gttggcctca

2940

tgcttgagga gattgatgag cgcggtggca atgccctgcc tccggtgctc gccggagact

3000

gcgagatcat agatatagat ctcactacgc ggctgctcaa acctgggcag aacgtaagcc

3060

gcgagagcgc caacaaccgc ttcttggtcg aaggcagcaa gcgcgatgaa tgtcttacta

3120

cggagcaagt tcccgaggta atcggagtcc ggctgatgtt gggagtaggt ggctacgtct

3180

ccgaactcac gaccgaaaag atcaagagca gcccgcatgg atttgacttg gtcagggccg

3240

agcctacatg tgcgaatgat gcccatactt gagccaccta actttgtttt agggcgactg

3300

ccctgctgcg taacatcgtt gctgctgcgt aacatcgttg ctgctccata acatcaaaca

3360

tcgacccacg gcgtaacgcg cttgctgctt ggatgcccga ggcatagact gtacaaaaaa

3420

acagtcataa caagccatga aaaccgccac tgcgccgtta ccaccgctgc gttcggtcaa

3480

ggttctggac cagttgcgtg agcgcatacg ctacttgcat tacagtttac gaaccgaaca

3540

ggcttatgtc aactgggttc gtgccttcat ccgtttccac ggtgtgcgtc acccggcaac

3600

cttgggcagc agcgaagtcg aggcatttct gtcctggctg gcgaacgagc gcaaggtttc

3660

ggtctccacg catcgtcagg cattggcggc cttgctgttc ttctacggca aggtgctgtg

3720

cacggatctg ccctggcttc aggagatcgg aagacctcgg ccgtcgcggc gcttgccggt

3780

ggtgctgacc ccggatgaag tggttcgcat cctcggtttt ctggaaggcg agcatcgttt

3840

gttcgcccag gactctagct atagttctag tggttggcta cgtatactcc ggaatattaa

3900

tagatcatgg agataattaa aatgataacc atctcgcaaa taaataagta ttttactgtt

3960

ttcgtaacag ttttgtaata aaaaaaccta taaatattcc ggattattca taccgtccca

4020

ccatcgggcg cggatctcgg tccgaaacca tgtcgtacta ccatcaccat caccatcacg

4080

attacgatat cccaacgacc gaaaacctgt attttcaggg cgccatggga tccggccggc

4140

ccctgcaggc agctgcgcgc tcgctcgctc actgaggccg cccgggcaaa gcccgggcgt

4200

cgggcgacct ttggtcgccc ggcctcagtg agcgagcgag cgcgcagaga gggagtggcc

4260

aactccatca ctaggggttc cttgtagtta atgattaacc cgccatgcta cttatctacg

4320

tagccatgct ctagagcggc cgcaggctca gaggcacaca ggagtttctg ggctcaccct

4380

gcccccttcc aacccctcag ttcccatcct ccagcagctg tttgtgtgct gcctctgaag

4440

tccacactga acaaacttca gcctactcat gtccctaaaa tgggcaaaca ttgcaagcag

4500

caaacagcaa acacacagcc ctccctgcct gctgaccttg gagctggggc agaggtcaga

4560

gacctctctg ggcccatgcc acctccaaca tccactcgac cccttggaat ttcggtggag

4620

aggagcagag gttgtcctgg cgtggtttag gtagtgtgag agggtccggg ttcaaaacca

4680

cttgctgggt ggggagtcgt cagtaagtgg ctatgccccg accccgaagc ctgtttcccc

4740

atctgtacaa tggaaatgat aaagacgccc atctgatagg gtttttgtgg caaataaaca

4800

tttggttttt ttgttttgtt ttgttttgtt ttttgagatg gaggtttgct ctgtcgccca

4860

ggctggagtg cagtgacaca atctcatctc accacaacct tcccctgcct cagcctccca

4920

agtagctggg attacaagca tgtgccacca cacctggcta attttctatt tttagtagag

4980

acgggtttct ccatgttggt cagcctcagc ctcccaagta actgggatta caggcctgtg

5040

ccaccacacc cggctaattt tttctatttt tgacagggac ggggtttcac catgttggtc

5100

aggctggtct agaggtaccg gatcttgcta ccagtggaac agccactaag gattctgcag

5160

tgagagcaga gggccagcta agtggtactc tcccagagac tgtctgactc acgccacccc

5220

ctccaccttg gacacaggac gctgtggttt ctgagccagg tacaatgact cctttcggta

5280

agtgcagtgg aagctgtaca ctgcccaggc aaagcgtccg ggcagcgtag gcgggcgact

5340

cagatcccag ccagtggact tagcccctgt ttgctcctcc gataactggg gtgaccttgg

5400

ttaatattca ccagcagcct cccccgttgc ccctctggat ccactgctta aatacggacg

5460

aggacagggc cctgtctcct cagcttcagg caccaccact gacctgggac agtgaatccg

5520

gactctaagg taaatataaa atttttaagt gtataatgtg ttaaactact gattctaatt

5580

gtttctctct tttagattcc aacctttgga actgagttta aaccgcagcc accatgcaga

5640

tcgagctgtc tacctgcttc ttcctgtgcc tgctgcggtt ctgcttcagc gccaccagaa

5700

gatattacct gggcgccgtg gaactgagct gggactacat gcagtctgac ctggggagagc

5760

tgcccgtgga cgctagattt cctccaagag tgcccaagag cttccccttc aacacctccg

5820

tggtgtacaa gaaaaccctg ttcgtggaat tcaccgacca cctgttcaat atcgccaagc

5880

ctcggcctcc ttggatggga ctgctgggac ctacaattca ggccgaggtg tacgacaccg

5940

tggtcatcac cctgaagaac atggccagcc atcctgtgtc tctgcacgcc gtgggagtgt

6000

cttattggaa ggcttctgag ggcgccgagt acgacgatca gacaagccag agagagaaag

6060

aggacgacaa ggttttccct ggcggcagcc acacctatgt ctggcaggtc ctgaaagaaa

6120

acggccctat ggcctccgat cctctgtgcc tgacatacag ctacctgagc cacgtggacc

6180

tggtcaagga cctgaattct ggcctgatcg gagccctgct cgtgtgtaga gaaggcagcc

6240

tggccaaaga gaaaacccag acactgcaca agttcatcct gctgttcgcc gtgttcgacg

6300

agggcaagag ctggcacagc gagacaaaga acagcctgat gcaggacagg gatgccgcct

6360

ctgctagagc ttggcctaag atgcacaccg tgaacggcta cgtgaacaga agcctgcctg

6420

gactgatcgg ctgccacaga aagtccgtgt actggcacgt gatcggcatg ggcacaacac

6480

ctgaggtgca cagcatcttt ctggaaggcc acaccttcct cgtgcggaac cacagacagg

6540

ccagcctgga aatcagccct atcaccttcc tgaccgctca gaccctgctg atggatctgg

6600

gccagtttct gctgttctgc cacatcagct cccaccagca cgatggcatg gaagcctacg

6660

tgaaggtgga cagctgcccc gaagaacccc agctgcggat gaagaacaac gaggaagccg

6720

aggactacga cgacgacctg accgactctg agatggacgt cgtcagattc gacgacgata

6780

acagccccag cttcatccag atcagaagcg tggccaagaa gcaccccaag acctgggtgc

6840

actatatcgc cgccgaggaa gaggactggg attacgctcc tctggtgctg gcccctgacg

6900

acagaagcta caagagccag tacctgaaca acggccctca gcggatcggc cggaagtata

6960

agaaagtgcg gttcatggcc tacaccgacg agacattcaa gaccagagag gccatccagc

7020

acgagagcgg aattctgggc cctctgctgt atggcgaagt gggcgataca ctgctgatca

7080

tcttcaagaa ccaggccagc agaccctaca acatctaccc tcacggcatc accgatgtgc

7140

ggcccctgta ttctagaagg ctgcccaagg gcgtgaagca cctgaaggac ttccctatcc

7200

tgcctggcga gattttcaag tacaagtgga ccgtgaccgt ggaagatggc cccaccaaga

7260

gcgaccctag atgtctgaca cggtactaca gcagcttcgt gaacatggaa cgcgacctgg

7320

ccagcggcct gattggacct ctgctgatct gctacaaaga aagcgtggac cagcggggca

7380

accagatcat gagcgacaag cggaacgtga tcctgtttag cgtgttcgat gagaaccggt

7440

cctggtatct gaccgagaac atccagcggt ttctgcccaa tcctgccggg gtgcaactgg

7500

aagatcctga gttccaggca agcaacatca tgcactccat caatggctat gtgttcgaca

7560

gcctgcagct gagcgtgtgc ctgcacgaag tggcctactg gtacatcctg agcattggcg

7620

cccagaccga cttcctgtcc gtgttcttta gcggctacac cttcaagcac aagatggtgt

7680

acgaggatac cctgacactg ttcccattca gcggcgagac agtgttcatg agcatggaaa

7740

accccggcct gtggattctg ggctgtcaca acagcgactt ccggaacaga ggcatgacag

7800

ccctgctgaa ggtgtccagc tgcgacaaga acaccggcga ctactacgag gacagctatg

7860

aggacatcag cgcctacctg ctgagcaaga acaatgccat cgagcccaga agcttcagcc

7920

agaatagcag acacccctcc acgacaga agcagttcaa cgccacaaca atccccgaga

7980

acgacatcga gaaaaccgat ccttggtttg cccacagaac ccctatgcct aagatccaga

8040

acgtgtcctc cagcgatctg ctgatgctcc tgagacagag ccctacacct cacggactga

8100

gcctgtccga tctgcaagag gccaaatacg aaaccttcag cgacgaccct tctcctggcg

8160

ccatcgacag caacaatagc ctgagcgaga tgacccactt cagaccacag ctgcaccaca

8220

gcggcgacat ggtgtttaca cctgagagcg gcctccagct gagactgaat gagaagctgg

8280

gaaccaccgc cgccaccgag ctgaagaaac tggacttcaa ggtgtcctct accagcaaca

8340

acctgatcag cacaatcccc tccgacaacc tggctgccgg caccgacaac acatcttctc

8400

tgggcccacc tagcatgccc gtgcactacg atagccagct ggataccaca ctgttcggca

8460

agaagtctag ccctctgaca gagtctggcg gccctctgtc tctgagcgag gaaaacaacg

8520

acagcaagct gctggaatcc ggcctgatga acagccaaga gtcctcctgg ggcaagaatg

8580

tgtccagcac cgagtccggc agactgttca agggaaagag agcccacgga cctgctctgc

8640

tgaccaagga taacgccctg ttcaaagtgt ccatcagcct gctcaagacc aacaagacct

8700

ccaacaactc cgccaccaac agaaagaccc acatcgacgg ccctagcctg ctgatcgaga

8760

atagccctag cgtctggcag aatatcctgg aaagcgacac cgagttcaag aaagtgaccc

8820

ctctgatcca cgaccggatg ctcatggaca agaacgccac cgctctgcgg ctgaaccaca

8880

tgagcaacaa gacaaccagc agcaagaata tggaaatggt gcagcagaag aaagaggggcc

8940

ccattcctcc agacgctcag aaccccgata tgagcttctt caagatgctc tttctgcccg

9000

agagcgcccg gtggattcag agaacacacg gcaagaactc cctgaactcc ggccagggac

9060

cttctccaaa gcagctggtt tccctgggac ctgagaagtc cgtggaagga cagaacttcc

9120

tgagcgaaaa gaacaaagtg gtcgtcggca agggcgagtt caccaaggat gtgggcctga

9180

aagagatggt ctttcccagc agccggaacc tgttcctgac caacctggac aacctgcacg

9240

agaacaacac ccacaatcaa gagaagaaga tccaagagga aatcgaaaag aaagagacac

9300

tcatccaaga gaacgtggtg ctgcctcaga tccacacagt gaccggcacc aagaacttta

9360

tgaagaatct gttcctgctg agtacccggc agaacgtgga aggcagctac gatggcgctt

9420

atgcccctgt gctgcaggac ttcagatccc tgaacgactc caccaatcgg acaaagaagc

9480

acacagccca cttctccaag aagggcgaag aagagaacct ggaaggactg ggcaatcaga

9540

ccaagcagat cgtcgagaag tacgcctgca ccaccagaat cagccccaac acaagccagc

9600

agaacttcgt gacccagcgg agcaaaagag ccctgaagca gtttcggctg cccctggaag

9660

aaaccgagct ggaaaagcgg atcatcgtgg acgacaccag cacacagtgg tccaagaaca

9720

tgaagcactt gacccctagc acactgaccc agatcgacta caacgagaaa gagaagggcg

9780

ctatcacaca gagcccactg agcgactgtc tgaccagaag ccacagcatc cctcaggcca

9840

acagatcccc tctgccaatc gccaaagtgt ctagcttccc cagcatcaga cccatctacc

9900

tgaccagagt gctgttccag gacaacagca gccatctgcc agccgccagc taccggaaga

9960

aagattctgg cgtgcaagag agcagccact ttctgcaggg cgctaagaag aacaatctga

10020

gcctggctat tctgaccctg gaaatgaccg gcgatcagag agaagtcggc tctctgggca

10080

ccagcgccac aaatagcgtg acctacaaaa aggtggaaaa caccgtgctg cctaagcctg

10140

acctgccaaa gacaagcggc aaggtggaac tgctgccaaa ggtgcacatc taccagaagg

10200

acctgtttcc taccgagaca agcaacggct ctcccggcca tctggatctg gtggaaggat

10260

ctctgctgca gggaaccgag ggcgccatca agtggaacga ggccaataga cctggcaagg

10320

tgcccttcct gagagtggcc acagagtcca gcgccaagac accctctaaa ctgctggacc

10380

ctctggcctg ggacaaccac tatggcactc agatccccaa agaggaatgg aagtcccaag

10440

agaagtcccc tgaaaagacc gccttcaaga agaaggacac cattctgtcc ctgaatgcct

10500

gcgagagcaa ccacgccatt gccgccatca atgagggcca gaacaagccc gagatcgaag

10560

tgacctgggc caagcaggga agaaccgaga gactgtgtag ccagaatcct cctgtgctga

10620

agcggcacca gagagaaatc acccggacca cactgcagag cgaccaagaa gagatcgatt

10680

acgacgatac catcagcgtc gagatgaaga aagaagattt cgacatctac gacgaggacg

10740

agaatcagag ccctcggagc ttccagaaga aaaccaggca ctactttatt gccgccgtcg

10800

agcggctgtg ggactacgga atgtctagct ctcctcacgt gctgcggaat agagcccagt

10860

ctggtagcgt gccccagttc aaaaaggtcg tgttccaaga gttcaccgac ggcagcttca

10920

cccagccact gtatagaggc gagctgaacg agcatctggg cctgctgggc ccttatatca

10980

gagccgaagt ggaagataac atcatggtca ccttccggaa tcaggctagc cggccttaca

11040

gcttctacag ctccctgatc tcctacgaag aggaccagag acagggcgca gagccccgga

11100

agaatttcgt gaagcccaac gagactaaga cctacttttg gaaggtgcag caccatatgg

11160

cccctacaaa ggacgagttc gactgcaaag cctgggccta cttctccgat gtggacctcg

11220

aaaaggacgt gcacagcgga ctcatcggcc cactgcttgt gtgccacacc aacacactga

11280

accccgctca cggcagacaa gtgacagtgc aagagttcgc cctgtttttc accatcttcg

11340

acgaaacgaa gtcctggtac ttcaccgaaa acatggaaag aaactgcagg gccccttgca

11400

acattcagat ggaagatccc accttcaaag agaactaccg gttccacgcc atcaacggct

11460

acatcatgga cacactgccc ggcctggtta tggcccagga tcagagaatc cggtggtatc

11520

tgctgtccat gggctccaac gagaatatcc actccatcca cttcagcggc cacgtgttca

11580

ccgtgcggaa aaaagaagag tacaaaatgg ccctgtacaa tctgtaccct ggggtgttcg

11640

aaaccgttga gatgctgcct agcaaggccg gaatttggag agtggaatgt ctgattggag

11700

agcacctcca cgccgggatg agcaccctgt ttctggtgta ctccaacaag tgtcagaccc

11760

ctctcggcat ggcctctggc cacattagag acttccagat caccgccagc ggacagtatg

11820

gacagtgggc ccctaaactg gccagactgc actactccgg cagcatcaat gcctggtcca

11880

ccaaagagcc tttcagctgg atcaaagtgg acctgctggc tcccatgatc atccacggaa

11940

tcaagaccca gggcgccaga caaaagttca gcagcctgta catcagccag ttcatcatca

12000

tgtacagcct ggacggaaag aagtggcaga cctaccgggg caatagcacc ggcacactga

12060

tggtgttctt cggcaacgtg gactccagcg gcattaagca caacatcttc aaccctccaa

12120

tcattgcccg gtacatccgg ctgcacccca cacactacag catcaggtct accctgagaa

12180

tggaactgat gggctgcgac ctgaacagct gctctatgcc cctcggaatg gaaagcaagg

12240

ccatcagcga cgcccagatc acagcctcta gctacttcac caacatgttc gccacttgga

12300

gcccctctaa ggcccggctt catctgcaag gcagaagcaa cgcttggagg ccccaagtga

12360

acaaccccaa agaatggctc caggtggact ttcagaaaac catgaaagtg acaggcgtga

12420

ccacacaggg cgtcaagtcc ctgctgacct ctatgtacgt gaaagagttt ctgatcagct

12480

ccagccagga cggccaccag tggaccctgt tcttccagaa cggcaaagtg aaagtgttcc

12540

agggaaatca ggacagcttc acacccgtgg tcaatagtct ggacccacca ctgctgaccc

12600

gctacctgcg aattcaccct cagtcttggg tgcaccagat tgccctgcgg atggaagtgc

12660

tgggctgtga agctcaggac ctctactagt taattaagag catcttaccg ccatttattc

12720

ccatatttgt tctgtttttc ttgatttggg tatacattta aatgttaata aaacaaaatg

12780

gtggggcaat catttacatt tttagggata tgtaattact agttcaggtg tattgccaca

12840

agacaaacat gttaagaaac tttcccgtta tttacgctct gttcctgtta atcaacctct

12900

ggattacaaa atttgtgaaa gattgactga tattcttaac tatgttgctc cttttacgct

12960

gtgtggatat gctgctttat agcctctgta tctagctatt gcttcccgta cggctttcgt

13020

tttctcctcc ttgtataaat cctggttgct gtctctttta gaggagttgt ggcccgttgt

13080

ccgtcaacgt ggcgtggtgt gctctgtgtt tgctgacgca acccccactg gctggggcat

13140

tgccaccacc tgtcaactcc tttctgggac tttcgctttc cccctcccga tcgccacggc

13200

agaactcatc gccgcctgcc ttgcccgctg ctggacaggg gctaggttgc tgggcactga

13260

taattccgtg gtgttgtctg tgccttctag ttgccagcca tctgttgttt gcccctcccc

13320

cgtgccttcc ttgaccctgg aaggtgccac tcccactgtc ctttcctaat aaaatgagga

13380

aattgcatcg cattgtctga gtaggtgtca ttctattctg gggggtgggg tggggcagga

13440

cagcaagggg gaggattggg aagacaatag caggcatgct ggggatgcgg tgggctctat

13500

ggctctagag catggctacg tagataagta gcatggcggg ttaatcatta actacacctg

13560

caggaggaac ccctagtgat ggagttggcc actccctctc tgcgcgctcg ctcgctcact

13620

gaggccgggc gaccaaaggt cgcccgacgc ccgggcggcc tcagtgagcg agcgagcgcg

13680

cagctgcctg caggggcgcg cctcgaggca tgcggtacca agcttgtcga gaagtactag

13740

aggatcataa tcagccatac cacatttgta gaggttttac ttgctttaaa aaacctccca

13800

cacctccccc tgaacctgaa acataaaatg aatgcaattg ttgttgttaa cttgtttatt

13860

gcagcttata atggttacaa ataaagcaat agcatcacaa atttcacaaa taaagcattt

13920

ttttcactgc attctagttg tggtttgtcc aaactcatca atgtatctta tcatgtctgg

13980

atctgatcac tgatatcgcc taggagatcc gaaccagata agtgaaatct agttccaaac

14040

tattttgtca tttttaattt tcgtattagc ttacgacgct acacccagtt cccatctatt

14100

ttgtcactct tccctaaata atccttaaaa actccatttc cacccctccc agttcccaac

14160

tattttgtcc gccccacagcg gggcattttt cttcctgtta tgtttttaat caaacatcct

14220

gccaactcca tgtgacaaac cgtcatcttc ggctactttt tctctgtcac agaatgaaaa

14280

tttttctgtc atctcttcgt tattaatgtt tgtaattgac tgaatatcaa cgcttatttg

14340

cagcctgaat ggcgaatgg

14359

<210> 193

<211> 11677

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 193

gacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg tggttacgcg cagcgtgacc

60

gctacacttg ccagcgccct agcgcccgct cctttcgctt tcttcccttc ctttctcgcc

120

acgttcgccg gctttccccg tcaagctcta aatcggggggc tccctttagg gttccgattt

180

agtgctttac ggcacctcga ccccaaaaaa cttgattagg gtgatggttc acgtagtggg

240

ccatcgccct gatagacggt ttttcgccct ttgacgttgg agtccacgtt ctttaatagt

300

ggactcttgt tccaaactgg aacaacactc aaccctatct cggtctattc ttttgattta

360

taagggattt tgccgatttc ggcctattgg ttaaaaaatg agctgattta acaaaaattt

420

aacgcgaatt ttaacaaaat attaacgttt acaatttcag gtggcacttt tcggggaaat

480

gtgcgcggaa cccctatttg tttatttttc taaatacatt caaatatgta tccgctcatg

540

agacaataac cctgataaat gcttcaataa tattgaaaaa ggaagagtat gagtattcaa

600

catttccgtg tcgcccttat tccctttttt gcggcatttt gccttcctgt ttttgctcac

660

ccagaaacgc tggtgaaagt aaaagatgct gaagatcagt tgggtgcacg agtgggttac

720

atcgaactgg atctcaacag cggtaagatc cttgagagtt ttcgccccga agaacgtttt

780

ccaatgatga gcacttttaa agttctgcta tgtggcgcgg tattatcccg tattgacgcc

840

gggcaagagc aactcggtcg ccgcatacac tattctcaga atgacttggt tgagtactca

900

ccagtcacag aaaagcatct tacggatggc atgacagtaa gagaattatg cagtgctgcc

960

ataaccatga gtgataacac tgcggccaac ttacttctga caacgatcgg aggaccgaag

1020

gagctaaccg cttttttgca caacatgggg gatcatgtaa ctcgccttga tcgttgggaa

1080

ccggagctga atgaagccat accaaacgac gagcgtgaca ccacgatgcc tgtagcaatg

1140

gcaacaacgt tgcgcaaact attaactggc gaactactta ctctagcttc ccggcaacaa

1200

ttaatagact ggatggaggc ggataaagtt gcaggaccac ttctgcgctc ggcccttccg

1260

gctggctggt ttattgctga taaatctgga gccggtgagc gtgggtctcg cggtatcatt

1320

gcagcactgg ggccagatgg taagccctcc cgtatcgtag ttatctacac gacggggagt

1380

caggcaacta tggatgaacg aaatagacag atcgctgaga taggtgcctc actgattaag

1440

cattggtaac tgtcagacca agtttactca tatatacttt agattgattt aaaacttcat

1500

ttttaattta aaaggatcta ggtgaagatc ctttttgata atctcatgac caaaatccct

1560

taacgtgagt tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa aggatcttct

1620

tgagatcctt tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc accgctacca

1680

gcggtggttt gtttgccgga tcaagagcta ccaactcttt ttccgaaggt aactggcttc

1740

agcagagcgc agataccaaa tactgtcctt ctagtgtagc cgtagttagg ccaccacttc

1800

aagaactctg tagcaccgcc tacatacctc gctctgctaa tcctgttacc agtggctgct

1860

gccagtggcg ataagtcgtg tcttaccggg ttggactcaa gacgatagtt accggataag

1920

gcgcagcggt cgggctgaac ggggggttcg tgcacacagc ccagcttgga gcgaacgacc

1980

tacaccgaac tgagatacct acagcgtgag cattgagaaa gcgccacgct tcccgaaggg

2040

agaaaggcgg acaggtatcc ggtaagcggc agggtcggaa caggagagcg cacgagggag

2100

cttccagggg gaaacgcctg gtatctttat agtcctgtcg ggtttcgcca cctctgactt

2160

gagcgtcgat ttttgtgatg ctcgtcaggg gggcggagcc tatggaaaaa cgccagcaac

2220

gcggcctttt tacggttcct ggccttttgc tggccttttg ctcacatgtt ctttcctgcg

2280

ttatcccctg attctgtgga taaccgtatt accgcctttg agtgagctga taccgctcgc

2340

cgcagccgaa cgaccgagcg cagcgagtca gtgagcgagg aagcggaaga gcgcctgatg

2400

cggtattttc tccttacgca tctgtgcggt atttcacacc gcagaccagc cgcgtaacct

2460

ggcaaaatcg gttacggttg agtaataaat ggatgccctg cgtaagcggg tgtgggcgga

2520

caataaagtc ttaaactgaa caaaatagat ctaaactatg acaataaagt cttaaactag

2580

acagaatagt tgtaaactga aatcagtcca gttatgctgt gaaaaagcat actggacttt

2640

tgttatggct aaagcaaact cttcattttc tgaagtgcaa attgcccgtc gtattaaaga

2700

ggggcgtggc caagggcatg gtaaagacta tattcgcggc gttgtgacaa tttaccgaac

2760

aactccgcgg ccgggaagcc gatctcggct tgaacgaatt gttaggtggc ggtacttggg

2820

tcgatatcaa agtgcatcac ttcttcccgt atgcccaact ttgtatagag agccactgcg

2880

ggatcgtcac cgtaatctgc ttgcacgtag atcacataag caccaagcgc gttggcctca

2940

tgcttgagga gattgatgag cgcggtggca atgccctgcc tccggtgctc gccggagact

3000

gcgagatcat agatatagat ctcactacgc ggctgctcaa acctgggcag aacgtaagcc

3060

gcgagagcgc caacaaccgc ttcttggtcg aaggcagcaa gcgcgatgaa tgtcttacta

3120

cggagcaagt tcccgaggta atcggagtcc ggctgatgtt gggagtaggt ggctacgtct

3180

ccgaactcac gaccgaaaag atcaagagca gcccgcatgg atttgacttg gtcagggccg

3240

agcctacatg tgcgaatgat gcccatactt gagccaccta actttgtttt agggcgactg

3300

ccctgctgcg taacatcgtt gctgctgcgt aacatcgttg ctgctccata acatcaaaca

3360

tcgacccacg gcgtaacgcg cttgctgctt ggatgcccga ggcatagact gtacaaaaaa

3420

acagtcataa caagccatga aaaccgccac tgcgccgtta ccaccgctgc gttcggtcaa

3480

ggttctggac cagttgcgtg agcgcatacg ctacttgcat tacagtttac gaaccgaaca

3540

ggcttatgtc aactgggttc gtgccttcat ccgtttccac ggtgtgcgtc acccggcaac

3600

cttgggcagc agcgaagtcg aggcatttct gtcctggctg gcgaacgagc gcaaggtttc

3660

ggtctccacg catcgtcagg cattggcggc cttgctgttc ttctacggca aggtgctgtg

3720

cacggatctg ccctggcttc aggagatcgg aagacctcgg ccgtcgcggc gcttgccggt

3780

ggtgctgacc ccggatgaag tggttcgcat cctcggtttt ctggaaggcg agcatcgttt

3840

gttcgcccag gactctagct atagttctag tggttggcta cgtatactcc ggaatattaa

3900

tagatcatgg agataattaa aatgataacc atctcgcaaa taaataagta ttttactgtt

3960

ttcgtaacag ttttgtaata aaaaaaccta taaatattcc ggattattca taccgtccca

4020

ccatcgggcg cggatctcgg tccgaaacca tgtcgtacta ccatcaccat caccatcacg

4080

attacgatat cccaacgacc gaaaacctgt attttcaggg cgccatggga tccggccggc

4140

ccctgcaggc agctgcgcgc tcgctcgctc actgaggccg cccgggcaaa gcccgggcgt

4200

cgggcgacct ttggtcgccc ggcctcagtg agcgagcgag cgcgcagaga gggagtggcc

4260

aactccatca ctaggggttc cttgtagtta atgattaacc cgccatgcta cttatctacg

4320

tagccatgct ctagagcggc cgcaggctca gaggcacaca ggagtttctg ggctcaccct

4380

gcccccttcc aacccctcag ttcccatcct ccagcagctg tttgtgtgct gcctctgaag

4440

tccacactga acaaacttca gcctactcat gtccctaaaa tgggcaaaca ttgcaagcag

4500

caaacagcaa acacacagcc ctccctgcct gctgaccttg gagctggggc agaggtcaga

4560

gacctctctg ggcccatgcc acctccaaca tccactcgac cccttggaat ttcggtggag

4620

aggagcagag gttgtcctgg cgtggtttag gtagtgtgag agggtccggg ttcaaaacca

4680

cttgctgggt ggggagtcgt cagtaagtgg ctatgccccg accccgaagc ctgtttcccc

4740

atctgtacaa tggaaatgat aaagacgccc atctgatagg gtttttgtgg caaataaaca

4800

tttggttttt ttgttttgtt ttgttttgtt ttttgagatg gaggtttgct ctgtcgccca

4860

ggctggagtg cagtgacaca atctcatctc accacaacct tcccctgcct cagcctccca

4920

agtagctggg attacaagca tgtgccacca cacctggcta attttctatt tttagtagag

4980

acgggtttct ccatgttggt cagcctcagc ctcccaagta actgggatta caggcctgtg

5040

ccaccacacc cggctaattt tttctatttt tgacagggac ggggtttcac catgttggtc

5100

aggctggtct agaggtaccg gatcttgcta ccagtggaac agccactaag gattctgcag

5160

tgagagcaga gggccagcta agtggtactc tcccagagac tgtctgactc acgccacccc

5220

ctccaccttg gacacaggac gctgtggttt ctgagccagg tacaatgact cctttcggta

5280

agtgcagtgg aagctgtaca ctgcccaggc aaagcgtccg ggcagcgtag gcgggcgact

5340

cagatcccag ccagtggact tagcccctgt ttgctcctcc gataactggg gtgaccttgg

5400

ttaatattca ccagcagcct cccccgttgc ccctctggat ccactgctta aatacggacg

5460

aggacagggc cctgtctcct cagcttcagg caccaccact gacctgggac agtgaatccg

5520

gactctaagg taaatataaa atttttaagt gtataatgtg ttaaactact gattctaatt

5580

gtttctctct tttagattcc aacctttgga actgagttta aaccgcagcc accatgcaga

5640

tcgagctgtc tacctgcttc ttcctgtgcc tgctgcggtt ctgcttcagc gccaccagaa

5700

gatattacct gggcgccgtg gaactgagct gggactacat gcagtctgac ctggggagagc

5760

tgcccgtgga cgctagattt cctccaagag tgcccaagag cttccccttc aacacctccg

5820

tggtgtacaa gaaaaccctg ttcgtggaat tcaccgacca cctgttcaat atcgccaagc

5880

ctcggcctcc ttggatggga ctgctgggac ctacaattca ggccgaggtg tacgacaccg

5940

tggtcatcac cctgaagaac atggccagcc atcctgtgtc tctgcacgcc gtgggagtgt

6000

cttattggaa ggcttctgag ggcgccgagt acgacgatca gacaagccag agagagaaag

6060

aggacgacaa ggttttccct ggcggcagcc acacctatgt ctggcaggtc ctgaaagaaa

6120

acggccctat ggcctccgat cctctgtgcc tgacatacag ctacctgagc cacgtggacc

6180

tggtcaagga cctgaattct ggcctgatcg gagccctgct cgtgtgtaga gaaggcagcc

6240

tggccaaaga gaaaacccag acactgcaca agttcatcct gctgttcgcc gtgttcgacg

6300

agggcaagag ctggcacagc gagacaaaga acagcctgat gcaggacagg gatgccgcct

6360

ctgctagagc ttggcctaag atgcacaccg tgaacggcta cgtgaacaga agcctgcctg

6420

gactgatcgg ctgccacaga aagtccgtgt actggcacgt gatcggcatg ggcacaacac

6480

ctgaggtgca cagcatcttt ctggaaggcc acaccttcct cgtgcggaac cacagacagg

6540

ccagcctgga aatcagccct atcaccttcc tgaccgctca gaccctgctg atggatctgg

6600

gccagtttct gctgttctgc cacatcagct cccaccagca cgatggcatg gaagcctacg

6660

tgaaggtgga cagctgcccc gaagaacccc agctgcggat gaagaacaac gaggaagccg

6720

aggactacga cgacgacctg accgactctg agatggacgt cgtcagattc gacgacgata

6780

acagccccag cttcatccag atcagaagcg tggccaagaa gcaccccaag acctgggtgc

6840

actatatcgc cgccgaggaa gaggactggg attacgctcc tctggtgctg gcccctgacg

6900

acagaagcta caagagccag tacctgaaca acggccctca gcggatcggc cggaagtata

6960

agaaagtgcg gttcatggcc tacaccgacg agacattcaa gaccagagag gccatccagc

7020

acgagagcgg aattctgggc cctctgctgt atggcgaagt gggcgataca ctgctgatca

7080

tcttcaagaa ccaggccagc agaccctaca acatctaccc tcacggcatc accgatgtgc

7140

ggcccctgta ttctagaagg ctgcccaagg gcgtgaagca cctgaaggac ttccctatcc

7200

tgcctggcga gattttcaag tacaagtgga ccgtgaccgt ggaagatggc cccaccaaga

7260

gcgaccctag atgtctgaca cggtactaca gcagcttcgt gaacatggaa cgcgacctgg

7320

ccagcggcct gattggacct ctgctgatct gctacaaaga aagcgtggac cagcggggca

7380

accagatcat gagcgacaag cggaacgtga tcctgtttag cgtgttcgat gagaaccggt

7440

cctggtatct gaccgagaac atccagcggt ttctgcccaa tcctgccggg gtgcaactgg

7500

aagatcctga gttccaggca agcaacatca tgcactccat caatggctat gtgttcgaca

7560

gcctgcagct gagcgtgtgc ctgcacgaag tggcctactg gtacatcctg agcattggcg

7620

cccagaccga cttcctgtcc gtgttcttta gcggctacac cttcaagcac aagatggtgt

7680

acgaggatac cctgacactg ttcccattca gcggcgagac agtgttcatg agcatggaaa

7740

accccggcct gtggattctg ggctgtcaca acagcgactt ccggaacaga ggcatgacag

7800

ccctgctgaa ggtgtccagc tgcgacaaga acaccggcga ctactacgag gacagctatg

7860

aggacatcag cgcctacctg ctgagcaaga acaatgccat cgagcctcgg agcttcagcc

7920

agaatcctcc tgtgctgaag cggcaccagc gcgagatcac cagaacaacc ctgcagagcg

7980

accaagagga aatcgattac gacgacacca tcagcgtcga gatgaagaaa gaagatttcg

8040

acatctacga cgaggacgag aatcagagcc ccagaagctt tcagaaaaag acccggcact

8100

acttcattgc cgccgtcgag agactgtggg actacggcat gtctagcagc cctcacgtgc

8160

tgagaaatag agcccagagc ggcagcgtgc cccagttcaa gaaagtggtg ttccaagagt

8220

tcaccgacgg cagcttcacc cagccactgt atagaggcga gctgaacgag catctgggcc

8280

tgctgggccc ttatatcaga gccgaagtgg aagataacat catggtcacc ttccggaatc

8340

aggctagccg gccttacagc ttctacagct ccctgatcag ctacgaagag gaccagagac

8400

agggcgctga gcccagaaag aacttcgtga agcccaacga gactaagacc tacttttgga

8460

aggtgcagca ccacatggcc cctacaaagg acgagttcga ctgcaaagcc tgggcctact

8520

tctccgatgt ggatctggaa aaggacgtgc acagcgggct catcggacca ctgcttgtgt

8580

gccacaccaa cacactgaac cccgctcacg gcagacaagt gacagtgcaa gagttcgccc

8640

tgttcttcac catcttcgac gaaacaaaga gctggtactt caccgagaat atggaacgga

8700

actgcagagc cccttgcaac atccagatgg aagatcccac cttcaaagag aactaccggt

8760

tccacgccat caacggctac atcatggaca cactgcccgg cctggttatg gcccaggatc

8820

agagaatccg gtggtatctg ctgtccatgg gctccaacga gaatatccac agcatccact

8880

tcagcggcca cgtgttcacc gtgcggaaaa aagaagagta caaaatggcc ctgtacaatc

8940

tgtaccctgg ggtgttcgaa accgtggaaa tgctgccttc caaggccggc atttggagag

9000

tggaatgtct gattggagag cacctccacg ccggaatgag caccctgttt ctggtgtaca

9060

gcaacaagtg tcagacccct ctcggcatgg cctctggaca catcagagac ttccagatca

9120

ccgcctctgg ccagtacgga cagtgggctc ctaaactggc tcggctgcac tacagcggca

9180

gcatcaatgc ctggtccacc aaagagccct tcagctggat caaggtggac ctgctggctc

9240

ccatgatcat ccacggaatc aagacccagg gcgccagaca gaagttcagc agcctgtaca

9300

tcagccagtt catcatcatg tacagcctgg acggcaagaa gtggcagacc tacagaggca

9360

acagcaccgg cacactcatg gtgttcttcg gcaacgtgga ctccagcggc attaagcaca

9420

acatcttcaa ccctccaatc attgcccggt acatccggct gcaccccaca cactacagca

9480

tccggtctac cctgagaatg gaactgatgg gctgcgacct gaacagctgc tctatgcccc

9540

tcggaatgga aagcaaggcc atcagcgacg cccagatcac agccagcagc tacttcacca

9600

acatgttcgc cacttggagc ccctccaagg ctagactgca tctgcagggc agaagcaacg

9660

cttggaggcc ccaagtgaac aaccccaaag agtggctgca ggttgacttt caaaagacca

9720

tgaaagtgac cggcgtgacc acacagggcg tcaagtctct gctgacctct atgtacgtga

9780

aagagttcct gatctccagc agccaggacg gccatcagtg gaccctgttt ttccagaacg

9840

gcaaagtgaa agtgttccag ggcaatcagg acagcttcac acccgtggtc aattctctgg

9900

accctccact gctgaccaga tacctgcgga ttcaccctca gtcttgggtg caccagatcg

9960

ctctgcggat ggaagtgctg ggctgtgaag ctcaggacct ctactagtta attaagagca

10020

tcttaccgcc atttattccc atatttgttc tgtttttctt gatttgggta tacatttaaa

10080

tgttaataaa acaaaatggt ggggcaatca tttacatttt tagggatatg taattactag

10140

ttcaggtgta ttgccacaag acaaacatgt taagaaactt tcccgttatt tacgctctgt

10200

tcctgttaat caacctctgg attacaaaat ttgtgaaaga ttgactgata ttcttaacta

10260

tgttgctcct tttacgctgt gtggatatgc tgctttatag cctctgtatc tagctattgc

10320

ttcccgtacg gctttcgttt tctcctcctt gtataaatcc tggttgctgt ctcttttaga

10380

ggagttgtgg cccgttgtcc gtcaacgtgg cgtggtgtgc tctgtgtttg ctgacgcaac

10440

ccccactggc tggggcattg ccaccacctg tcaactcctt tctgggactt tcgctttccc

10500

cctcccgatc gccacggcag aactcatcgc cgcctgcctt gcccgctgct ggacaggggc

10560

taggttgctg ggcactgata attccgtggt gttgtctgtg ccttctagtt gccagccatc

10620

tgttgtttgc ccctcccccg tgccttcctt gaccctggaa ggtgccactc ccactgtcct

10680

ttcctaataa aatgaggaaa ttgcatcgca ttgtctgagt aggtgtcatt ctattctggg

10740

gggtggggtg gggcaggaca gcaaggggga ggattgggaa gacaatagca ggcatgctgg

10800

ggatgcggtg ggctctatgg ctctagagca tggctacgta gataagtagc atggcgggtt

10860

aatcattaac tacacctgca ggaggaaccc ctagtgatgg agttggccac tccctctctg

10920

cgcgctcgct cgctcactga ggccgggcga ccaaaggtcg cccgacgccc gggcggcctc

10980

agtgagcgag cgagcgcgca gctgcctgca ggggcgcgcc tcgaggcatg cggtaccaag

11040

cttgtcgaga agtactagag gatcataatc agccatacca catttgtaga ggttttactt

11100

gctttaaaaa acctcccaca cctccccctg aacctgaaac ataaaatgaa tgcaattgtt

11160

gttgttaact tgtttattgc agcttataat ggttacaaat aaagcaatag catcacaaat

11220

ttcacaaata aagcattttt ttcactgcat tctagttgtg gtttgtccaa actcatcaat

11280

gtatcttatc atgtctggat ctgatcactg atatcgccta ggagatccga accagataag

11340

tgaaatctag ttccaaacta ttttgtcatt tttaattttc gtattagctt acgacgctac

11400

acccagttcc catctatttt gtcactcttc cctaaataat ccttaaaaac tccatttcca

11460

cccctcccag ttcccaacta ttttgtccgc ccacagcggg gcatttttct tcctgttatg

11520

tttttaatca aacatcctgc caactccatg tgacaaaccg tcatcttcgg ctactttttc

11580

tctgtcacag aatgaaaatt tttctgtcat ctcttcgtta ttaatgtttg taattgactg

11640

aatatcaacg cttatttgca gcctgaatgg cgaatgg

11677

<210> 194

<211> 13634

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 194

gacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg tggttacgcg cagcgtgacc

60

gctacacttg ccagcgccct agcgcccgct cctttcgctt tcttcccttc ctttctcgcc

120

acgttcgccg gctttccccg tcaagctcta aatcggggggc tccctttagg gttccgattt

180

agtgctttac ggcacctcga ccccaaaaaa cttgattagg gtgatggttc acgtagtggg

240

ccatcgccct gatagacggt ttttcgccct ttgacgttgg agtccacgtt ctttaatagt

300

ggactcttgt tccaaactgg aacaacactc aaccctatct cggtctattc ttttgattta

360

taagggattt tgccgatttc ggcctattgg ttaaaaaatg agctgattta acaaaaattt

420

aacgcgaatt ttaacaaaat attaacgttt acaatttcag gtggcacttt tcggggaaat

480

gtgcgcggaa cccctatttg tttatttttc taaatacatt caaatatgta tccgctcatg

540

agacaataac cctgataaat gcttcaataa tattgaaaaa ggaagagtat gagtattcaa

600

catttccgtg tcgcccttat tccctttttt gcggcatttt gccttcctgt ttttgctcac

660

ccagaaacgc tggtgaaagt aaaagatgct gaagatcagt tgggtgcacg agtgggttac

720

atcgaactgg atctcaacag cggtaagatc cttgagagtt ttcgccccga agaacgtttt

780

ccaatgatga gcacttttaa agttctgcta tgtggcgcgg tattatcccg tattgacgcc

840

gggcaagagc aactcggtcg ccgcatacac tattctcaga atgacttggt tgagtactca

900

ccagtcacag aaaagcatct tacggatggc atgacagtaa gagaattatg cagtgctgcc

960

ataaccatga gtgataacac tgcggccaac ttacttctga caacgatcgg aggaccgaag

1020

gagctaaccg cttttttgca caacatgggg gatcatgtaa ctcgccttga tcgttgggaa

1080

ccggagctga atgaagccat accaaacgac gagcgtgaca ccacgatgcc tgtagcaatg

1140

gcaacaacgt tgcgcaaact attaactggc gaactactta ctctagcttc ccggcaacaa

1200

ttaatagact ggatggaggc ggataaagtt gcaggaccac ttctgcgctc ggcccttccg

1260

gctggctggt ttattgctga taaatctgga gccggtgagc gtgggtctcg cggtatcatt

1320

gcagcactgg ggccagatgg taagccctcc cgtatcgtag ttatctacac gacggggagt

1380

caggcaacta tggatgaacg aaatagacag atcgctgaga taggtgcctc actgattaag

1440

cattggtaac tgtcagacca agtttactca tatatacttt agattgattt aaaacttcat

1500

ttttaattta aaaggatcta ggtgaagatc ctttttgata atctcatgac caaaatccct

1560

taacgtgagt tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa aggatcttct

1620

tgagatcctt tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc accgctacca

1680

gcggtggttt gtttgccgga tcaagagcta ccaactcttt ttccgaaggt aactggcttc

1740

agcagagcgc agataccaaa tactgtcctt ctagtgtagc cgtagttagg ccaccacttc

1800

aagaactctg tagcaccgcc tacatacctc gctctgctaa tcctgttacc agtggctgct

1860

gccagtggcg ataagtcgtg tcttaccggg ttggactcaa gacgatagtt accggataag

1920

gcgcagcggt cgggctgaac ggggggttcg tgcacacagc ccagcttgga gcgaacgacc

1980

tacaccgaac tgagatacct acagcgtgag cattgagaaa gcgccacgct tcccgaaggg

2040

agaaaggcgg acaggtatcc ggtaagcggc agggtcggaa caggagagcg cacgagggag

2100

cttccagggg gaaacgcctg gtatctttat agtcctgtcg ggtttcgcca cctctgactt

2160

gagcgtcgat ttttgtgatg ctcgtcaggg gggcggagcc tatggaaaaa cgccagcaac

2220

gcggcctttt tacggttcct ggccttttgc tggccttttg ctcacatgtt ctttcctgcg

2280

ttatcccctg attctgtgga taaccgtatt accgcctttg agtgagctga taccgctcgc

2340

cgcagccgaa cgaccgagcg cagcgagtca gtgagcgagg aagcggaaga gcgcctgatg

2400

cggtattttc tccttacgca tctgtgcggt atttcacacc gcagaccagc cgcgtaacct

2460

ggcaaaatcg gttacggttg agtaataaat ggatgccctg cgtaagcggg tgtgggcgga

2520

caataaagtc ttaaactgaa caaaatagat ctaaactatg acaataaagt cttaaactag

2580

acagaatagt tgtaaactga aatcagtcca gttatgctgt gaaaaagcat actggacttt

2640

tgttatggct aaagcaaact cttcattttc tgaagtgcaa attgcccgtc gtattaaaga

2700

ggggcgtggc caagggcatg gtaaagacta tattcgcggc gttgtgacaa tttaccgaac

2760

aactccgcgg ccgggaagcc gatctcggct tgaacgaatt gttaggtggc ggtacttggg

2820

tcgatatcaa agtgcatcac ttcttcccgt atgcccaact ttgtatagag agccactgcg

2880

ggatcgtcac cgtaatctgc ttgcacgtag atcacataag caccaagcgc gttggcctca

2940

tgcttgagga gattgatgag cgcggtggca atgccctgcc tccggtgctc gccggagact

3000

gcgagatcat agatatagat ctcactacgc ggctgctcaa acctgggcag aacgtaagcc

3060

gcgagagcgc caacaaccgc ttcttggtcg aaggcagcaa gcgcgatgaa tgtcttacta

3120

cggagcaagt tcccgaggta atcggagtcc ggctgatgtt gggagtaggt ggctacgtct

3180

ccgaactcac gaccgaaaag atcaagagca gcccgcatgg atttgacttg gtcagggccg

3240

agcctacatg tgcgaatgat gcccatactt gagccaccta actttgtttt agggcgactg

3300

ccctgctgcg taacatcgtt gctgctgcgt aacatcgttg ctgctccata acatcaaaca

3360

tcgacccacg gcgtaacgcg cttgctgctt ggatgcccga ggcatagact gtacaaaaaa

3420

acagtcataa caagccatga aaaccgccac tgcgccgtta ccaccgctgc gttcggtcaa

3480

ggttctggac cagttgcgtg agcgcatacg ctacttgcat tacagtttac gaaccgaaca

3540

ggcttatgtc aactgggttc gtgccttcat ccgtttccac ggtgtgcgtc acccggcaac

3600

cttgggcagc agcgaagtcg aggcatttct gtcctggctg gcgaacgagc gcaaggtttc

3660

ggtctccacg catcgtcagg cattggcggc cttgctgttc ttctacggca aggtgctgtg

3720

cacggatctg ccctggcttc aggagatcgg aagacctcgg ccgtcgcggc gcttgccggt

3780

ggtgctgacc ccggatgaag tggttcgcat cctcggtttt ctggaaggcg agcatcgttt

3840

gttcgcccag gactctagct atagttctag tggttggcta cgtatactcc ggaatattaa

3900

tagatcatgg agataattaa aatgataacc atctcgcaaa taaataagta ttttactgtt

3960

ttcgtaacag ttttgtaata aaaaaaccta taaatattcc ggattattca taccgtccca

4020

ccatcgggcg cggatctcgg tccgaaacca tgtcgtacta ccatcaccat caccatcacg

4080

attacgatat cccaacgacc gaaaacctgt attttcaggg cgccatggga tccggccggc

4140

ccctgcaggc agctgcgcgc tcgctcgctc actgaggccg cccgggcaaa gcccgggcgt

4200

cgggcgacct ttggtcgccc ggcctcagtg agcgagcgag cgcgcagaga gggagtggcc

4260

aactccatca ctaggggttc cttgtagtta atgattaacc cgccatgcta cttatctacg

4320

tagccatgct ctagagcggc cgcccctaaa atgggcaaac attgcaagca gcaaacagca

4380

aacacacagc cctccctgcc tgctgacctt ggagctgggg cagaggtcag agacctctct

4440

gggcccatgc cacctccaac atccactcga ccccttggaa tttttcggtg gagaggagca

4500

gaggttgtcc tggcgtggtt taggtagtgt gagaggggaa tgactccttt cggtaagtgc

4560

agtggaagct gtacactgcc caggcaaagc gtccggggcag cgtaggcggg cgactcagat

4620

cccagccagt ggacttagcc cctgtttgct cctccgataa ctggggtgac cttggttaat

4680

attcaccagc agcctccccc gttgcccctc tggatccact gcttaaatac ggacgaggac

4740

agggccctgt ctcctcagct tcaggcacca ccactgacct gggacagtga atccggactc

4800

taaggtaaat ataaaatttt taagtgtata atgtgttaaa ctactgattc taattgtttc

4860

tctcttttag attccaacct ttggaactga gtttaaaccg cagccaccat gcagatcgag

4920

ctgtctacct gcttcttcct gtgcctgctg cggttctgct tcagcgccac cagaagatat

4980

tacctgggcg ccgtggaact gagctgggac tacatgcagt ctgacctggg agagctgccc

5040

gtggacgcta gatttcctcc aagagtgccc aagagcttcc ccttcaacac ctccgtggtg

5100

tacaagaaaa ccctgttcgt ggaattcacc gaccacctgt tcaatatcgc caagcctcgg

5160

cctccttgga tgggactgct gggacctaca attcaggccg aggtgtacga caccgtggtc

5220

atcaccctga agaacatggc cagccatcct gtgtctctgc acgccgtggg agtgtcttat

5280

tggaaggctt ctgagggcgc cgagtacgac gatcagacaa gccagagaga gaaagaggac

5340

gacaaggttt tccctggcgg cagccacacc tatgtctggc aggtcctgaa agaaaacggc

5400

cctatggcct ccgatcctct gtgcctgaca tacagctacc tgagccacgt ggacctggtc

5460

aaggacctga attctggcct gatcggagcc ctgctcgtgt gtagagaagg cagcctggcc

5520

aaagagaaaa cccagacact gcacaagttc atcctgctgt tcgccgtgtt cgacgagggc

5580

aagagctggc acagcgagac aaagaacagc ctgatgcagg acagggatgc cgcctctgct

5640

agagcttggc ctaagatgca caccgtgaac ggctacgtga acagaagcct gcctggactg

5700

atcggctgcc acagaaagtc cgtgtactgg cacgtgatcg gcatgggcac aacacctgag

5760

gtgcacagca tctttctgga aggccacacc ttcctcgtgc ggaaccacag acaggccagc

5820

ctggaaatca gccctatcac cttcctgacc gctcagaccc tgctgatgga tctgggccag

5880

tttctgctgt tctgccacat cagctcccac cagcacgatg gcatggaagc ctacgtgaag

5940

gtggacagct gccccgaaga accccagctg cggatgaaga acaacgagga agccgaggac

6000

tacgacgacg acctgaccga ctctgagatg gacgtcgtca gattcgacga cgataacagc

6060

cccagcttca tccagatcag aagcgtggcc aagaagcacc ccaagacctg ggtgcactat

6120

atcgccgccg aggaagagga ctgggattac gctcctctgg tgctggcccc tgacgacaga

6180

agctacaaga gccagtacct gaacaacggc cctcagcgga tcggccggaa gtataagaaa

6240

gtgcggttca tggcctacac cgacgagaca ttcaagacca gagaggccat ccagcacgag

6300

agcggaattc tgggccctct gctgtatggc gaagtgggcg atacactgct gatcatcttc

6360

aagaaccagg ccagcagacc ctacaacatc taccctcacg gcatcaccga tgtgcggccc

6420

ctgtattcta gaaggctgcc caagggcgtg aagcacctga aggacttccc tatcctgcct

6480

ggcgagattt tcaagtacaa gtggaccgtg accgtggaag atggccccac caagagcgac

6540

cctagatgtc tgacacggta ctacagcagc ttcgtgaaca tggaacgcga cctggccagc

6600

ggcctgattg gacctctgct gatctgctac aaagaaagcg tggaccagcg gggcaaccag

6660

atcatgagcg acaagcggaa cgtgatcctg tttagcgtgt tcgatgagaa ccggtcctgg

6720

tatctgaccg agaacatcca gcggtttctg cccaatcctg ccggggtgca actggaagat

6780

cctgagttcc aggcaagcaa catcatgcac tccatcaatg gctatgtgtt cgacagcctg

6840

cagctgagcg tgtgcctgca cgaagtggcc tactggtaca tcctgagcat tggcgcccag

6900

accgacttcc tgtccgtgtt ctttagcggc tacaccttca agcacaagat ggtgtacgag

6960

gataccctga cactgttccc attcagcggc gagacagtgt tcatgagcat ggaaaacccc

7020

ggcctgtgga ttctgggctg tcacaacagc gacttccgga acagaggcat gacagccctg

7080

ctgaaggtgt ccagctgcga caagaacacc ggcgactact acgaggacag ctatgaggac

7140

atcagcgcct acctgctgag caagaacaat gccatcgagc ccagaagctt cagccagaat

7200

agcagacacc cctccaccag acagaagcag ttcaacgcca caacaatccc cgagaacgac

7260

atcgagaaaa ccgatccttg gtttgcccac agaaccccta tgcctaagat ccagaacgtg

7320

tcctccagcg atctgctgat gctcctgaga cagagcccta cacctcacgg actgagcctg

7380

tccgatctgc aagaggccaa atacgaaacc ttcagcgacg acccttctcc tggcgccatc

7440

gacagcaaca atagcctgag cgagatgacc cacttcagac cacagctgca ccacagcggc

7500

gacatggtgt ttacacctga gagcggcctc cagctgagac tgaatgagaa gctgggaacc

7560

accgccgcca ccgagctgaa gaaactggac ttcaaggtgt cctctaccag caacaacctg

7620

atcagcacaa tcccctccga caacctggct gccggcaccg acaacacatc ttctctgggc

7680

ccacctagca tgcccgtgca ctacgatagc cagctggata cccacactgtt cggcaagaag

7740

tctagccctc tgacagagtc tggcggccct ctgtctctga gcgaggaaaa caacgacagc

7800

aagctgctgg aatccggcct gatgaacagc caagagtcct cctggggcaa gaatgtgtcc

7860

agcaccgagt ccggcagact gttcaaggga aagagagccc acggacctgc tctgctgacc

7920

aaggataacg ccctgttcaa agtgtccatc agcctgctca agaccaacaa gacctccaac

7980

aactccgcca ccaacagaaa gacccacatc gacggcccta gcctgctgat cgagaatagc

8040

cctagcgtct ggcagaatat cctggaaagc gacaccgagt tcaagaaagt gacccctctg

8100

atccacgacc ggatgctcat ggacaagaac gccaccgctc tgcggctgaa ccacatgagc

8160

aacaagacaa ccagcagcaa gaatatggaa atggtgcagc agaagaaaga gggccccatt

8220

cctccagacg ctcagaaccc cgatatgagc ttcttcaaga tgctctttct gcccgagagc

8280

gcccggtgga ttcagagaac acacggcaag aactccctga actccggcca gggaccttct

8340

ccaaagcagc tggtttccct gggacctgag aagtccgtgg aaggacagaa cttcctgagc

8400

gaaaagaaca aagtggtcgt cggcaagggc gagttcacca aggatgtggg cctgaaagag

8460

atggtctttc ccagcagccg gaacctgttc ctgaccaacc tggacaacct gcacgagaac

8520

aacacccaca atcaagagaa gaagatccaa gaggaaatcg aaaagaaaga gacactcatc

8580

caagagaacg tggtgctgcc tcagatccac acagtgaccg gcaccaagaa ctttatgaag

8640

aatctgttcc tgctgagtac ccggcagaac gtggaaggca gctacgatgg cgcttatgcc

8700

cctgtgctgc aggacttcag atccctgaac gactccacca atcggacaaa gaagcacaca

8760

gcccacttct ccaagaaggg cgaagaagag aacctggaag gactgggcaa tcagaccaag

8820

cagatcgtcg agaagtacgc ctgcaccacc agaatcagcc ccaacacaag ccagcagaac

8880

ttcgtgaccc agcggagcaa aagagccctg aagcagtttc ggctgcccct ggaagaaacc

8940

gagctggaaa agcggatcat cgtggacgac accagcacac agtggtccaa gaacatgaag

9000

cacttgaccc ctagcacact gacccagatc gactacaacg agaaagagaa gggcgctatc

9060

acacagagcc cactgagcga ctgtctgacc agaagccaca gcatccctca ggccaacaga

9120

tcccctctgc caatcgccaa agtgtctagc ttccccagca tcagacccat ctacctgacc

9180

agagtgctgt tccaggacaa cagcagccat ctgccagccg ccagctaccg gaagaaagat

9240

tctggcgtgc aagagagcag ccactttctg cagggcgcta agaagaacaa tctgagcctg

9300

gctattctga ccctggaaat gaccggcgat cagagagaag tcggctctct gggcaccagc

9360

gccacaaata gcgtgaccta caaaaaggtg gaaaacaccg tgctgcctaa gcctgacctg

9420

ccaaagacaa gcggcaaggt ggaactgctg ccaaaggtgc acatctacca gaaggacctg

9480

tttcctaccg agacaagcaa cggctctccc ggccatctgg atctggtgga aggatctctg

9540

ctgcagggaa ccgagggcgc catcaagtgg aacgaggcca atagacctgg caaggtgccc

9600

ttcctgagag tggccacaga gtccagcgcc aagacaccct ctaaactgct ggaccctctg

9660

gcctgggaca accactatgg cactcagatc cccaaagagg aatggaagtc ccaagagaag

9720

tcccctgaaa agaccgcctt caagaagaag gacaccattc tgtccctgaa tgcctgcgag

9780

agcaaccacg ccattgccgc catcaatgag ggccagaaca agcccgagat cgaagtgacc

9840

tgggccaagc agggaagaac cgagagactg tgtagccaga atcctcctgt gctgaagcgg

9900

caccagagag aaatcacccg gaccacactg cagagcgacc aagaagagat cgattacgac

9960

gataccatca gcgtcgagat gaagaaagaa gatttcgaca tctacgacga ggacgagaat

10020

cagagccctc ggagcttcca gaagaaaacc aggcactact ttattgccgc cgtcgagcgg

10080

ctgtgggact acggaatgtc tagctctcct cacgtgctgc ggaatagagc ccagtctggt

10140

agcgtgcccc agttcaaaaa ggtcgtgttc caagagttca ccgacggcag cttcacccag

10200

ccactgtata gaggcgagct gaacgagcat ctgggcctgc tgggccctta tatcagagcc

10260

gaagtggaag ataacatcat ggtcaccttc cggaatcagg ctagccggcc ttacagcttc

10320

tacagctccc tgatctccta cgaagaggac cagagacagg gcgcagagcc ccggaagaat

10380

ttcgtgaagc ccaacgagac taagacctac ttttggaagg tgcagcacca tatggcccct

10440

acaaaggacg agttcgactg caaagcctgg gcctacttct ccgatgtgga cctcgaaaag

10500

gacgtgcaca gcggactcat cggcccactg cttgtgtgcc acaccaacac actgaacccc

10560

gctcacggca gacaagtgac agtgcaagag ttcgccctgt ttttcaccat cttcgacgaa

10620

acgaagtcct ggtacttcac cgaaaacatg gaaagaaact gcagggcccc ttgcaacatt

10680

cagatggaag atcccacctt caaagagaac taccggttcc acgccatcaa cggctacatc

10740

atggacacac tgcccggcct ggttatggcc caggatcaga gaatccggtg gtatctgctg

10800

tccatgggct ccaacgagaa tatccactcc atccacttca gcggccacgt gttcaccgtg

10860

cggaaaaaag aagagtacaa aatggccctg tacaatctgt accctggggt gttcgaaacc

10920

gttgagatgc tgcctagcaa ggccggaatt tggagagtgg aatgtctgat tggagagcac

10980

ctccacgccg ggatgagcac cctgtttctg gtgtactcca acaagtgtca gacccctctc

11040

ggcatggcct ctggccacat tagagacttc cagatcaccg ccagcggaca gtatggacag

11100

tgggccccta aactggccag actgcactac tccggcagca tcaatgcctg gtccaccaaa

11160

gagcctttca gctggatcaa agtggacctg ctggctccca tgatcatcca cggaatcaag

11220

acccagggcg ccagacaaaa gttcagcagc ctgtacatca gccagttcat catcatgtac

11280

agcctggacg gaaagaagtg gcagacctac cggggcaata gcaccggcac actgatggtg

11340

ttcttcggca acgtggactc cagcggcatt aagcacaaca tcttcaaccc tccaatcatt

11400

gcccggtaca tccggctgca ccccacacac tacagcatca ggtctaccct gagaatggaa

11460

ctgatgggct gcgacctgaa cagctgctct atgcccctcg gaatggaaag caaggccatc

11520

agcgacgccc agatcacagc ctctagctac ttcaccaaca tgttcgccac ttggagcccc

11580

tctaaggccc ggcttcatct gcaaggcaga agcaacgctt ggaggcccca agtgaacaac

11640

cccaaagaat ggctccaggt ggactttcag aaaaccatga aagtgacagg cgtgaccaca

11700

cagggcgtca agtccctgct gacctctatg tacgtgaaag agtttctgat cagctccagc

11760

caggacggcc accagtggac cctgttcttc cagaacggca aagtgaaagt gttccaggga

11820

aatcaggaca gcttcacacc cgtggtcaat agtctggacc caccactgct gacccgctac

11880

ctgcgaattc accctcagtc ttgggtgcac cagattgccc tgcggatgga agtgctgggc

11940

tgtgaagctc aggacctcta ctagttaatt aagagcatct taccgccatt tattcccata

12000

tttgttctgt ttttcttgat ttgggtatac atttaaatgt taataaaaca aaatggtggg

12060

gcaatcattt acatttttag ggatatgtaa ttactagttc aggtgtattg ccacaagaca

12120

aacatgttaa gaaactttcc cgttatttac gctctgttcc tgttaatcaa cctctggatt

12180

acaaaatttg tgaaagattg actgatattc ttaactatgt tgctcctttt acgctgtgtg

12240

gatatgctgc tttatagcct ctgtatctag ctattgcttc ccgtacggct ttcgttttct

12300

cctccttgta taaatcctgg ttgctgtctc ttttagagga gttgtggccc gttgtccgtc

12360

aacgtggcgt ggtgtgctct gtgtttgctg acgcaacccc cactggctgg ggcattgcca

12420

ccacctgtca actcctttct gggactttcg ctttccccct cccgatcgcc acggcagaac

12480

tcatcgccgc ctgccttgcc cgctgctgga caggggctag gttgctgggc actgataatt

12540

ccgtggtgtt gtctgtgcct tctagttgcc agccatctgt tgtttgcccc tcccccgtgc

12600

cttccttgac cctggaaggt gccactccca ctgtcctttc ctaataaaat gaggaaattg

12660

catcgcattg tctgagtagg tgtcattcta ttctgggggg tggggtgggg caggacagca

12720

agggggagga ttgggaagac aatagcaggc atgctgggga tgcggtgggc tctatggctc

12780

tagagcatgg ctacgtagat aagtagcatg gcgggttaat cattaactac acctgcagga

12840

ggaaccccta gtgatggagt tggccactcc ctctctgcgc gctcgctcgc tcactgaggc

12900

cgggcgacca aaggtcgccc gacgcccggg cggcctcagt gagcgagcga gcgcgcagct

12960

gcctgcaggg gcgcgcctcg aggcatgcgg taccaagctt gtcgagaagt actagaggat

13020

cataatcagc cataccacat ttgtagaggt tttacttgct ttaaaaaacc tcccacacct

13080

ccccctgaac ctgaaacata aaatgaatgc aattgttgtt gttaacttgt ttattgcagc

13140

ttataatggt tacaaataaa gcaatagcat cacaaatttc acaaataaag catttttttc

13200

actgcattct agttgtggtt tgtccaaact catcaatgta tcttatcatg tctggatctg

13260

atcactgata tcgcctagga gatccgaacc agataagtga aatctagttc caaactattt

13320

tgtcattttt aattttcgta ttagcttacg acgctacacc cagttcccat ctattttgtc

13380

actcttccct aaataatcct taaaaactcc atttccaccc ctcccagttc ccaactattt

13440

tgtccgccca cagcggggca tttttcttcc tgttatgttt ttaatcaaac atcctgccaa

13500

ctccatgtga caaaccgtca tcttcggcta ctttttctct gtcacagaat gaaaattttt

13560

ctgtcatctc ttcgttatta atgtttgtaa ttgactgaat atcaacgctt atttgcagcc

13620

tgaatggcga atgg

13634

<210> 195

<211> 10952

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 195

gacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg tggttacgcg cagcgtgacc

60

gctacacttg ccagcgccct agcgcccgct cctttcgctt tcttcccttc ctttctcgcc

120

acgttcgccg gctttccccg tcaagctcta aatcggggggc tccctttagg gttccgattt

180

agtgctttac ggcacctcga ccccaaaaaa cttgattagg gtgatggttc acgtagtggg

240

ccatcgccct gatagacggt ttttcgccct ttgacgttgg agtccacgtt ctttaatagt

300

ggactcttgt tccaaactgg aacaacactc aaccctatct cggtctattc ttttgattta

360

taagggattt tgccgatttc ggcctattgg ttaaaaaatg agctgattta acaaaaattt

420

aacgcgaatt ttaacaaaat attaacgttt acaatttcag gtggcacttt tcggggaaat

480

gtgcgcggaa cccctatttg tttatttttc taaatacatt caaatatgta tccgctcatg

540

agacaataac cctgataaat gcttcaataa tattgaaaaa ggaagagtat gagtattcaa

600

catttccgtg tcgcccttat tccctttttt gcggcatttt gccttcctgt ttttgctcac

660

ccagaaacgc tggtgaaagt aaaagatgct gaagatcagt tgggtgcacg agtgggttac

720

atcgaactgg atctcaacag cggtaagatc cttgagagtt ttcgccccga agaacgtttt

780

ccaatgatga gcacttttaa agttctgcta tgtggcgcgg tattatcccg tattgacgcc

840

gggcaagagc aactcggtcg ccgcatacac tattctcaga atgacttggt tgagtactca

900

ccagtcacag aaaagcatct tacggatggc atgacagtaa gagaattatg cagtgctgcc

960

ataaccatga gtgataacac tgcggccaac ttacttctga caacgatcgg aggaccgaag

1020

gagctaaccg cttttttgca caacatgggg gatcatgtaa ctcgccttga tcgttgggaa

1080

ccggagctga atgaagccat accaaacgac gagcgtgaca ccacgatgcc tgtagcaatg

1140

gcaacaacgt tgcgcaaact attaactggc gaactactta ctctagcttc ccggcaacaa

1200

ttaatagact ggatggaggc ggataaagtt gcaggaccac ttctgcgctc ggcccttccg

1260

gctggctggt ttattgctga taaatctgga gccggtgagc gtgggtctcg cggtatcatt

1320

gcagcactgg ggccagatgg taagccctcc cgtatcgtag ttatctacac gacggggagt

1380

caggcaacta tggatgaacg aaatagacag atcgctgaga taggtgcctc actgattaag

1440

cattggtaac tgtcagacca agtttactca tatatacttt agattgattt aaaacttcat

1500

ttttaattta aaaggatcta ggtgaagatc ctttttgata atctcatgac caaaatccct

1560

taacgtgagt tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa aggatcttct

1620

tgagatcctt tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc accgctacca

1680

gcggtggttt gtttgccgga tcaagagcta ccaactcttt ttccgaaggt aactggcttc

1740

agcagagcgc agataccaaa tactgtcctt ctagtgtagc cgtagttagg ccaccacttc

1800

aagaactctg tagcaccgcc tacatacctc gctctgctaa tcctgttacc agtggctgct

1860

gccagtggcg ataagtcgtg tcttaccggg ttggactcaa gacgatagtt accggataag

1920

gcgcagcggt cgggctgaac ggggggttcg tgcacacagc ccagcttgga gcgaacgacc

1980

tacaccgaac tgagatacct acagcgtgag cattgagaaa gcgccacgct tcccgaaggg

2040

agaaaggcgg acaggtatcc ggtaagcggc agggtcggaa caggagagcg cacgagggag

2100

cttccagggg gaaacgcctg gtatctttat agtcctgtcg ggtttcgcca cctctgactt

2160

gagcgtcgat ttttgtgatg ctcgtcaggg gggcggagcc tatggaaaaa cgccagcaac

2220

gcggcctttt tacggttcct ggccttttgc tggccttttg ctcacatgtt ctttcctgcg

2280

ttatcccctg attctgtgga taaccgtatt accgcctttg agtgagctga taccgctcgc

2340

cgcagccgaa cgaccgagcg cagcgagtca gtgagcgagg aagcggaaga gcgcctgatg

2400

cggtattttc tccttacgca tctgtgcggt atttcacacc gcagaccagc cgcgtaacct

2460

ggcaaaatcg gttacggttg agtaataaat ggatgccctg cgtaagcggg tgtgggcgga

2520

caataaagtc ttaaactgaa caaaatagat ctaaactatg acaataaagt cttaaactag

2580

acagaatagt tgtaaactga aatcagtcca gttatgctgt gaaaaagcat actggacttt

2640

tgttatggct aaagcaaact cttcattttc tgaagtgcaa attgcccgtc gtattaaaga

2700

ggggcgtggc caagggcatg gtaaagacta tattcgcggc gttgtgacaa tttaccgaac

2760

aactccgcgg ccgggaagcc gatctcggct tgaacgaatt gttaggtggc ggtacttggg

2820

tcgatatcaa agtgcatcac ttcttcccgt atgcccaact ttgtatagag agccactgcg

2880

ggatcgtcac cgtaatctgc ttgcacgtag atcacataag caccaagcgc gttggcctca

2940

tgcttgagga gattgatgag cgcggtggca atgccctgcc tccggtgctc gccggagact

3000

gcgagatcat agatatagat ctcactacgc ggctgctcaa acctgggcag aacgtaagcc

3060

gcgagagcgc caacaaccgc ttcttggtcg aaggcagcaa gcgcgatgaa tgtcttacta

3120

cggagcaagt tcccgaggta atcggagtcc ggctgatgtt gggagtaggt ggctacgtct

3180

ccgaactcac gaccgaaaag atcaagagca gcccgcatgg atttgacttg gtcagggccg

3240

agcctacatg tgcgaatgat gcccatactt gagccaccta actttgtttt agggcgactg

3300

ccctgctgcg taacatcgtt gctgctgcgt aacatcgttg ctgctccata acatcaaaca

3360

tcgacccacg gcgtaacgcg cttgctgctt ggatgcccga ggcatagact gtacaaaaaa

3420

acagtcataa caagccatga aaaccgccac tgcgccgtta ccaccgctgc gttcggtcaa

3480

ggttctggac cagttgcgtg agcgcatacg ctacttgcat tacagtttac gaaccgaaca

3540

ggcttatgtc aactgggttc gtgccttcat ccgtttccac ggtgtgcgtc acccggcaac

3600

cttgggcagc agcgaagtcg aggcatttct gtcctggctg gcgaacgagc gcaaggtttc

3660

ggtctccacg catcgtcagg cattggcggc cttgctgttc ttctacggca aggtgctgtg

3720

cacggatctg ccctggcttc aggagatcgg aagacctcgg ccgtcgcggc gcttgccggt

3780

ggtgctgacc ccggatgaag tggttcgcat cctcggtttt ctggaaggcg agcatcgttt

3840

gttcgcccag gactctagct atagttctag tggttggcta cgtatactcc ggaatattaa

3900

tagatcatgg agataattaa aatgataacc atctcgcaaa taaataagta ttttactgtt

3960

ttcgtaacag ttttgtaata aaaaaaccta taaatattcc ggattattca taccgtccca

4020

ccatcgggcg cggatctcgg tccgaaacca tgtcgtacta ccatcaccat caccatcacg

4080

attacgatat cccaacgacc gaaaacctgt attttcaggg cgccatggga tccggccggc

4140

ccctgcaggc agctgcgcgc tcgctcgctc actgaggccg cccgggcaaa gcccgggcgt

4200

cgggcgacct ttggtcgccc ggcctcagtg agcgagcgag cgcgcagaga gggagtggcc

4260

aactccatca ctaggggttc cttgtagtta atgattaacc cgccatgcta cttatctacg

4320

tagccatgct ctagagcggc cgcccctaaa atgggcaaac attgcaagca gcaaacagca

4380

aacacacagc cctccctgcc tgctgacctt ggagctgggg cagaggtcag agacctctct

4440

gggcccatgc cacctccaac atccactcga ccccttggaa tttttcggtg gagaggagca

4500

gaggttgtcc tggcgtggtt taggtagtgt gagaggggaa tgactccttt cggtaagtgc

4560

agtggaagct gtacactgcc caggcaaagc gtccggggcag cgtaggcggg cgactcagat

4620

cccagccagt ggacttagcc cctgtttgct cctccgataa ctggggtgac cttggttaat

4680

attcaccagc agcctccccc gttgcccctc tggatccact gcttaaatac ggacgaggac

4740

agggccctgt ctcctcagct tcaggcacca ccactgacct gggacagtga atccggactc

4800

taaggtaaat ataaaatttt taagtgtata atgtgttaaa ctactgattc taattgtttc

4860

tctcttttag attccaacct ttggaactga gtttaaaccg cagccaccat gcagatcgag

4920

ctgtctacct gcttcttcct gtgcctgctg cggttctgct tcagcgccac cagaagatat

4980

tacctgggcg ccgtggaact gagctgggac tacatgcagt ctgacctggg agagctgccc

5040

gtggacgcta gatttcctcc aagagtgccc aagagcttcc ccttcaacac ctccgtggtg

5100

tacaagaaaa ccctgttcgt ggaattcacc gaccacctgt tcaatatcgc caagcctcgg

5160

cctccttgga tgggactgct gggacctaca attcaggccg aggtgtacga caccgtggtc

5220

atcaccctga agaacatggc cagccatcct gtgtctctgc acgccgtggg agtgtcttat

5280

tggaaggctt ctgagggcgc cgagtacgac gatcagacaa gccagagaga gaaagaggac

5340

gacaaggttt tccctggcgg cagccacacc tatgtctggc aggtcctgaa agaaaacggc

5400

cctatggcct ccgatcctct gtgcctgaca tacagctacc tgagccacgt ggacctggtc

5460

aaggacctga attctggcct gatcggagcc ctgctcgtgt gtagagaagg cagcctggcc

5520

aaagagaaaa cccagacact gcacaagttc atcctgctgt tcgccgtgtt cgacgagggc

5580

aagagctggc acagcgagac aaagaacagc ctgatgcagg acagggatgc cgcctctgct

5640

agagcttggc ctaagatgca caccgtgaac ggctacgtga acagaagcct gcctggactg

5700

atcggctgcc acagaaagtc cgtgtactgg cacgtgatcg gcatgggcac aacacctgag

5760

gtgcacagca tctttctgga aggccacacc ttcctcgtgc ggaaccacag acaggccagc

5820

ctggaaatca gccctatcac cttcctgacc gctcagaccc tgctgatgga tctgggccag

5880

tttctgctgt tctgccacat cagctcccac cagcacgatg gcatggaagc ctacgtgaag

5940

gtggacagct gccccgaaga accccagctg cggatgaaga acaacgagga agccgaggac

6000

tacgacgacg acctgaccga ctctgagatg gacgtcgtca gattcgacga cgataacagc

6060

cccagcttca tccagatcag aagcgtggcc aagaagcacc ccaagacctg ggtgcactat

6120

atcgccgccg aggaagagga ctgggattac gctcctctgg tgctggcccc tgacgacaga

6180

agctacaaga gccagtacct gaacaacggc cctcagcgga tcggccggaa gtataagaaa

6240

gtgcggttca tggcctacac cgacgagaca ttcaagacca gagaggccat ccagcacgag

6300

agcggaattc tgggccctct gctgtatggc gaagtgggcg atacactgct gatcatcttc

6360

aagaaccagg ccagcagacc ctacaacatc taccctcacg gcatcaccga tgtgcggccc

6420

ctgtattcta gaaggctgcc caagggcgtg aagcacctga aggacttccc tatcctgcct

6480

ggcgagattt tcaagtacaa gtggaccgtg accgtggaag atggccccac caagagcgac

6540

cctagatgtc tgacacggta ctacagcagc ttcgtgaaca tggaacgcga cctggccagc

6600

ggcctgattg gacctctgct gatctgctac aaagaaagcg tggaccagcg gggcaaccag

6660

atcatgagcg acaagcggaa cgtgatcctg tttagcgtgt tcgatgagaa ccggtcctgg

6720

tatctgaccg agaacatcca gcggtttctg cccaatcctg ccggggtgca actggaagat

6780

cctgagttcc aggcaagcaa catcatgcac tccatcaatg gctatgtgtt cgacagcctg

6840

cagctgagcg tgtgcctgca cgaagtggcc tactggtaca tcctgagcat tggcgcccag

6900

accgacttcc tgtccgtgtt ctttagcggc tacaccttca agcacaagat ggtgtacgag

6960

gataccctga cactgttccc attcagcggc gagacagtgt tcatgagcat ggaaaacccc

7020

ggcctgtgga ttctgggctg tcacaacagc gacttccgga acagaggcat gacagccctg

7080

ctgaaggtgt ccagctgcga caagaacacc ggcgactact acgaggacag ctatgaggac

7140

atcagcgcct acctgctgag caagaacaat gccatcgagc ctcggagctt cagccagaat

7200

cctcctgtgc tgaagcggca ccagcgcgag atcaccagaa caaccctgca gagcgaccaa

7260

gaggaaatcg attacgacga caccatcagc gtcgagatga agaaagaaga tttcgacatc

7320

tacgacgagg acgagaatca gagccccaga agctttcaga aaaagacccg gcactacttc

7380

attgccgccg tcgagagact gtgggactac ggcatgtcta gcagccctca cgtgctgaga

7440

aatagagccc agagcggcag cgtgccccag ttcaagaaag tggtgttcca agagttcacc

7500

gacggcagct tcacccagcc actgtataga ggcgagctga acgagcatct gggcctgctg

7560

ggcccttata tcagagccga agtggaagat aacatcatgg tcaccttccg gaatcaggct

7620

agccggcctt acagcttcta cagctccctg atcagctacg aagaggacca gagacagggc

7680

gctgagccca gaaagaactt cgtgaagccc aacgagacta agacctactt ttggaaggtg

7740

cagcaccaca tggcccctac aaaggacgag ttcgactgca aagcctgggc ctacttctcc

7800

gatgtggatc tggaaaagga cgtgcacagc gggctcatcg gaccactgct tgtgtgccac

7860

accaacacac tgaaccccgc tcacggcaga caagtgacag tgcaagagtt cgccctgttc

7920

ttcaccatct tcgacgaaac aaagagctgg tacttcaccg agaatatgga acggaactgc

7980

agagcccctt gcaacatcca gatggaagat cccaccttca aagagaacta ccggttccac

8040

gccatcaacg gctacatcat ggacacactg cccggcctgg ttatggccca ggatcagaga

8100

atccggtggt atctgctgtc catgggctcc aacgagaata tccacagcat ccacttcagc

8160

ggccacgtgt tcaccgtgcg gaaaaaagaa gagtacaaaa tggccctgta caatctgtac

8220

cctggggtgt tcgaaaccgt ggaaatgctg ccttccaagg ccggcatttg gagagtggaa

8280

tgtctgattg gagagcacct ccacgccgga atgagcaccc tgtttctggt gtacagcaac

8340

aagtgtcaga cccctctcgg catggcctct ggacacatca gagacttcca gatcaccgcc

8400

tctggccagt acggacagtg ggctcctaaa ctggctcggc tgcactacag cggcagcatc

8460

aatgcctggt ccaccaaaga gcccttcagc tggatcaagg tggacctgct ggctcccatg

8520

atcatccacg gaatcaagac ccagggcgcc agacagaagt tcagcagcct gtacatcagc

8580

cagttcatca tcatgtacag cctggacggc aagaagtggc agacctacag aggcaacagc

8640

accggcacac tcatggtgtt cttcggcaac gtggactcca gcggcattaa gcacaacatc

8700

ttcaaccctc caatcattgc ccggtacatc cggctgcacc ccacacacta cagcatccgg

8760

tctaccctga gaatggaact gatgggctgc gacctgaaca gctgctctat gcccctcgga

8820

atggaaagca aggccatcag cgacgcccag atcacagcca gcagctactt caccaacatg

8880

ttcgccactt ggagcccctc caaggctaga ctgcatctgc agggcagaag caacgcttgg

8940

aggccccaag tgaacaaccc caaagagtgg ctgcaggttg actttcaaaa gaccatgaaa

9000

gtgaccggcg tgaccacaca gggcgtcaag tctctgctga cctctatgta cgtgaaagag

9060

ttcctgatct ccagcagcca ggacggccat cagtggaccc tgtttttcca gaacggcaaa

9120

gtgaaagtgt tccagggcaa tcaggacagc ttcacacccg tggtcaattc tctggaccct

9180

ccactgctga ccagatacct gcggattcac cctcagtctt gggtgcacca gatcgctctg

9240

cggatggaag tgctgggctg tgaagctcag gacctctact agttaattaa gagcatctta

9300

ccgccattta ttcccatatt tgttctgttt ttcttgattt gggtatacat ttaaatgtta

9360

ataaaacaaa atggtggggc aatcatttac atttttaggg atatgtaatt actagttcag

9420

gtgtattgcc acaagacaaa catgttaaga aactttcccg ttatttacgc tctgttcctg

9480

ttaatcaacc tctggattac aaaatttgtg aaagattgac tgatattctt aactatgttg

9540

ctccttttac gctgtgtgga tatgctgctt tatagcctct gtatctagct attgcttccc

9600

gtacggcttt cgttttctcc tccttgtata aatcctggtt gctgtctctt ttagaggagt

9660

tgtggcccgt tgtccgtcaa cgtggcgtgg tgtgctctgt gtttgctgac gcaaccccca

9720

ctggctgggg cattgccacc acctgtcaac tcctttctgg gactttcgct ttccccctcc

9780

cgatcgccac ggcagaactc atcgccgcct gccttgcccg ctgctggaca ggggctaggt

9840

tgctgggcac tgataattcc gtggtgttgt ctgtgccttc tagttgccag ccatctgttg

9900

tttgcccctc ccccgtgcct tccttgaccc tggaaggtgc cactcccact gtcctttcct

9960

aataaaatga ggaaattgca tcgcattgtc tgagtaggtg tcattctatt ctggggggtg

10020

gggtggggca ggacagcaag ggggaggatt gggaagacaa tagcaggcat gctggggatg

10080

cggtgggctc tatggctcta gagcatggct acgtagataa gtagcatggc gggttaatca

10140

ttaactacac ctgcaggagg aacccctagt gatggagttg gccactccct ctctgcgcgc

10200

tcgctcgctc actgaggccg ggcgaccaaa ggtcgcccga cgcccgggcg gcctcagtga

10260

gcgagcgagc gcgcagctgc ctgcaggggc gcgcctcgag gcatgcggta ccaagcttgt

10320

cgagaagtac tagaggatca taatcagcca taccacattt gtagaggttt tacttgcttt

10380

aaaaaacctc ccacacctcc ccctgaacct gaaacataaa atgaatgcaa ttgttgttgt

10440

taacttgttt attgcagctt ataatggtta caaataaagc aatagcatca caaatttcac

10500

aaataaagca tttttttcac tgcattctag ttgtggtttg tccaaactca tcaatgtatc

10560

ttatcatgtc tggatctgat cactgatatc gcctaggaga tccgaaccag ataagtgaaa

10620

tctagttcca aactattttg tcatttttaa ttttcgtatt agcttacgac gctacaccca

10680

gttcccatct attttgtcac tcttccctaa ataatcctta aaaactccat ttccacccct

10740

cccagttccc aactattttg tccgcccaca gcggggcatt tttcttcctg ttatgttttt

10800

aatcaaacat cctgccaact ccatgtgaca aaccgtcatc ttcggctact ttttctctgt

10860

cacagaatga aaatttttct gtcatctctt cgttattaat gtttgtaatt gactgaatat

10920

caacgcttat ttgcagcctg aatggcgaat gg

10952

<210> 196

<211> 14266

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 196

gacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg tggttacgcg cagcgtgacc

60

gctacacttg ccagcgccct agcgcccgct cctttcgctt tcttcccttc ctttctcgcc

120

acgttcgccg gctttccccg tcaagctcta aatcggggggc tccctttagg gttccgattt

180

agtgctttac ggcacctcga ccccaaaaaa cttgattagg gtgatggttc acgtagtggg

240

ccatcgccct gatagacggt ttttcgccct ttgacgttgg agtccacgtt ctttaatagt

300

ggactcttgt tccaaactgg aacaacactc aaccctatct cggtctattc ttttgattta

360

taagggattt tgccgatttc ggcctattgg ttaaaaaatg agctgattta acaaaaattt

420

aacgcgaatt ttaacaaaat attaacgttt acaatttcag gtggcacttt tcggggaaat

480

gtgcgcggaa cccctatttg tttatttttc taaatacatt caaatatgta tccgctcatg

540

agacaataac cctgataaat gcttcaataa tattgaaaaa ggaagagtat gagtattcaa

600

catttccgtg tcgcccttat tccctttttt gcggcatttt gccttcctgt ttttgctcac

660

ccagaaacgc tggtgaaagt aaaagatgct gaagatcagt tgggtgcacg agtgggttac

720

atcgaactgg atctcaacag cggtaagatc cttgagagtt ttcgccccga agaacgtttt

780

ccaatgatga gcacttttaa agttctgcta tgtggcgcgg tattatcccg tattgacgcc

840

gggcaagagc aactcggtcg ccgcatacac tattctcaga atgacttggt tgagtactca

900

ccagtcacag aaaagcatct tacggatggc atgacagtaa gagaattatg cagtgctgcc

960

ataaccatga gtgataacac tgcggccaac ttacttctga caacgatcgg aggaccgaag

1020

gagctaaccg cttttttgca caacatgggg gatcatgtaa ctcgccttga tcgttgggaa

1080

ccggagctga atgaagccat accaaacgac gagcgtgaca ccacgatgcc tgtagcaatg

1140

gcaacaacgt tgcgcaaact attaactggc gaactactta ctctagcttc ccggcaacaa

1200

ttaatagact ggatggaggc ggataaagtt gcaggaccac ttctgcgctc ggcccttccg

1260

gctggctggt ttattgctga taaatctgga gccggtgagc gtgggtctcg cggtatcatt

1320

gcagcactgg ggccagatgg taagccctcc cgtatcgtag ttatctacac gacggggagt

1380

caggcaacta tggatgaacg aaatagacag atcgctgaga taggtgcctc actgattaag

1440

cattggtaac tgtcagacca agtttactca tatatacttt agattgattt aaaacttcat

1500

ttttaattta aaaggatcta ggtgaagatc ctttttgata atctcatgac caaaatccct

1560

taacgtgagt tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa aggatcttct

1620

tgagatcctt tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc accgctacca

1680

gcggtggttt gtttgccgga tcaagagcta ccaactcttt ttccgaaggt aactggcttc

1740

agcagagcgc agataccaaa tactgtcctt ctagtgtagc cgtagttagg ccaccacttc

1800

aagaactctg tagcaccgcc tacatacctc gctctgctaa tcctgttacc agtggctgct

1860

gccagtggcg ataagtcgtg tcttaccggg ttggactcaa gacgatagtt accggataag

1920

gcgcagcggt cgggctgaac ggggggttcg tgcacacagc ccagcttgga gcgaacgacc

1980

tacaccgaac tgagatacct acagcgtgag cattgagaaa gcgccacgct tcccgaaggg

2040

agaaaggcgg acaggtatcc ggtaagcggc agggtcggaa caggagagcg cacgagggag

2100

cttccagggg gaaacgcctg gtatctttat agtcctgtcg ggtttcgcca cctctgactt

2160

gagcgtcgat ttttgtgatg ctcgtcaggg gggcggagcc tatggaaaaa cgccagcaac

2220

gcggcctttt tacggttcct ggccttttgc tggccttttg ctcacatgtt ctttcctgcg

2280

ttatcccctg attctgtgga taaccgtatt accgcctttg agtgagctga taccgctcgc

2340

cgcagccgaa cgaccgagcg cagcgagtca gtgagcgagg aagcggaaga gcgcctgatg

2400

cggtattttc tccttacgca tctgtgcggt atttcacacc gcagaccagc cgcgtaacct

2460

ggcaaaatcg gttacggttg agtaataaat ggatgccctg cgtaagcggg tgtgggcgga

2520

caataaagtc ttaaactgaa caaaatagat ctaaactatg acaataaagt cttaaactag

2580

acagaatagt tgtaaactga aatcagtcca gttatgctgt gaaaaagcat actggacttt

2640

tgttatggct aaagcaaact cttcattttc tgaagtgcaa attgcccgtc gtattaaaga

2700

ggggcgtggc caagggcatg gtaaagacta tattcgcggc gttgtgacaa tttaccgaac

2760

aactccgcgg ccgggaagcc gatctcggct tgaacgaatt gttaggtggc ggtacttggg

2820

tcgatatcaa agtgcatcac ttcttcccgt atgcccaact ttgtatagag agccactgcg

2880

ggatcgtcac cgtaatctgc ttgcacgtag atcacataag caccaagcgc gttggcctca

2940

tgcttgagga gattgatgag cgcggtggca atgccctgcc tccggtgctc gccggagact

3000

gcgagatcat agatatagat ctcactacgc ggctgctcaa acctgggcag aacgtaagcc

3060

gcgagagcgc caacaaccgc ttcttggtcg aaggcagcaa gcgcgatgaa tgtcttacta

3120

cggagcaagt tcccgaggta atcggagtcc ggctgatgtt gggagtaggt ggctacgtct

3180

ccgaactcac gaccgaaaag atcaagagca gcccgcatgg atttgacttg gtcagggccg

3240

agcctacatg tgcgaatgat gcccatactt gagccaccta actttgtttt agggcgactg

3300

ccctgctgcg taacatcgtt gctgctgcgt aacatcgttg ctgctccata acatcaaaca

3360

tcgacccacg gcgtaacgcg cttgctgctt ggatgcccga ggcatagact gtacaaaaaa

3420

acagtcataa caagccatga aaaccgccac tgcgccgtta ccaccgctgc gttcggtcaa

3480

ggttctggac cagttgcgtg agcgcatacg ctacttgcat tacagtttac gaaccgaaca

3540

ggcttatgtc aactgggttc gtgccttcat ccgtttccac ggtgtgcgtc acccggcaac

3600

cttgggcagc agcgaagtcg aggcatttct gtcctggctg gcgaacgagc gcaaggtttc

3660

ggtctccacg catcgtcagg cattggcggc cttgctgttc ttctacggca aggtgctgtg

3720

cacggatctg ccctggcttc aggagatcgg aagacctcgg ccgtcgcggc gcttgccggt

3780

ggtgctgacc ccggatgaag tggttcgcat cctcggtttt ctggaaggcg agcatcgttt

3840

gttcgcccag gactctagct atagttctag tggttggcta cgtatactcc ggaatattaa

3900

tagatcatgg agataattaa aatgataacc atctcgcaaa taaataagta ttttactgtt

3960

ttcgtaacag ttttgtaata aaaaaaccta taaatattcc ggattattca taccgtccca

4020

ccatcgggcg cggatctcgg tccgaaacca tgtcgtacta ccatcaccat caccatcacg

4080

attacgatat cccaacgacc gaaaacctgt attttcaggg cgccatggga tccggccggc

4140

ccctgcaggc agctgcgcgc tcgctcgctc actgaggccg cccgggcaaa gcccgggcgt

4200

cgggcgacct ttggtcgccc ggcctcagtg agcgagcgag cgcgcagaga gggagtggcc

4260

aactccatca ctaggggttc cttgtagtta atgattaacc cgccatgcta cttatctacg

4320

tagccatgct ctagagcggc cgcggctccg gtgcccgtca gtgggcagag cgcacatcgc

4380

ccacagtccc cgagaagttg gggggagggg tcggcaattg aaccggtgcc tagagaaggt

4440

ggcgcggggt aaactgggaa agtgatgtcg tgtactggct ccgccttttt cccgaggtg

4500

ggggagaacc gtatataagt gcagtagtcg ccgtgaacgt tctttttcgc aacgggtttg

4560

ccgccagaac acaggtaagt gccgtgtgtg gttcccgcgg gcctggcctc tttacgggtt

4620

atggcccttg cgtgccttga attacttcca cctggctgca gtacgtgatt cttgatcccg

4680

agcttcgggt tggaagtggg tgggagagtt cgaggccttg cgcttaagga gccccttcgc

4740

ctcgtgcttg agttgaggcc tggcctgggc gctggggccg ccgcgtgcga atctggtggc

4800

accttcgcgc ctgtctcgct gctttcgata agtctctagc catttaaaat ttttgatgac

4860

ctgctgcgac gctttttttc tggcaagata gtcttgtaaa tgcgggccaa gatctgcaca

4920

ctggtatttc ggtttttggg gccgcgggcg gcgacggggc ccgtgcgtcc cagcgcacat

4980

gttcggcgag gcggggcctg cgagcgcggc caccgagaat cggacggggg tagtctcaag

5040

ctggccggcc tgctctggtg cctggtctcg cgccgccgtg tatcgccccg ccctgggcgg

5100

caaggctggc ccggtcggca ccagttgcgt gagcggaaag atggccgctt cccggccctg

5160

ctgcagggag ctcaaaatgg aggacgcggc gctcgggaga gcgggcgggt gagtcaccca

5220

cacaaaggaa aagggccttt ccgtcctcag ccgtcgcttc atgtgactcc acggagtacc

5280

gggcgccgtc caggcacctc gattagttct cgagcttttg gagtacgtcg tctttaggtt

5340

ggggggaggg gttttatgcg atggagtttc cccacactga gtgggtggag actgaagtta

5400

ggccagcttg gcacttgatg taattctcct tggaatttgc cctttttgag tttggatctt

5460

ggttcattct caagcctcag acagtggttc aaagtttttt tcttccatt caggtgtcgt

5520

gagtttaaac cgcagccacc atgcagatcg agctgtctac ctgcttcttc ctgtgcctgc

5580

tgcggttctg cttcagcgcc accagaagat attacctggg cgccgtggaa ctgagctggg

5640

actacatgca gtctgacctg ggagagctgc ccgtggacgc tagatttcct ccaagagtgc

5700

ccaagagctt ccccttcaac acctccgtgg tgtacaagaa aaccctgttc gtggaattca

5760

ccgaccacct gttcaatatc gccaagcctc ggcctccttg gatgggactg ctgggaccta

5820

caattcaggc cgaggtgtac gacaccgtgg tcatcaccct gaagaacatg gccagccatc

5880

ctgtgtctct gcacgccgtg ggagtgtctt attggaaggc ttctgagggc gccgagtacg

5940

acgatcagac aagccagaga gagaaagagg acgacaaggt tttccctggc ggcagccaca

6000

cctatgtctg gcaggtcctg aaagaaaacg gccctatggc ctccgatcct ctgtgcctga

6060

catacagcta cctgagccac gtggacctgg tcaaggacct gaattctggc ctgatcggag

6120

ccctgctcgt gtgtagagaa ggcagcctgg ccaaagagaa aacccagaca ctgcacaagt

6180

tcatcctgct gttcgccgtg ttcgacgagg gcaagagctg gcacagcgag acaaagaaca

6240

gcctgatgca ggacagggat gccgcctctg ctagagcttg gcctaagatg cacaccgtga

6300

acggctacgt gaacagaagc ctgcctggac tgatcggctg cccagaaag tccgtgtact

6360

ggcacgtgat cggcatgggc acaacacctg aggtgcacag catctttctg gaaggccaca

6420

ccttcctcgt gcggaaccac agacaggcca gcctggaaat cagccctatc accttcctga

6480

ccgctcagac cctgctgatg gatctgggcc agtttctgct gttctgccac atcagctccc

6540

accagcacga tggcatggaa gcctacgtga aggtggacag ctgccccgaa gaaccccagc

6600

tgcggatgaa gaacaacgag gaagccgagg actacgacga cgacctgacc gactctgaga

6660

tggacgtcgt cagattcgac gacgataaca gccccagctt catccagatc agaagcgtgg

6720

ccaagaagca ccccaagacc tgggtgcact atatcgccgc cgaggaagag gactgggatt

6780

acgctcctct ggtgctggcc cctgacgaca gaagctacaa gagccagtac ctgaacaacg

6840

gccctcagcg gatcggccgg aagtataaga aagtgcggtt catggcctac accgacgaga

6900

cattcaagac cagagaggcc atccagcacg agagcggaat tctgggccct ctgctgtatg

6960

gcgaagtggg cgatacactg ctgatcatct tcaagaacca ggccagcaga ccctacaaca

7020

tctaccctca cggcatcacc gatgtgcggc ccctgtattc tagaaggctg cccaagggcg

7080

tgaagcacct gaaggacttc cctatcctgc ctggcgagat tttcaagtac aagtggaccg

7140

tgaccgtgga agatggcccc accaagagcg accctagatg tctgacacgg tactacagca

7200

gcttcgtgaa catggaacgc gacctggcca gcggcctgat tggacctctg ctgatctgct

7260

acaaagaaag cgtggaccag cggggcaacc agatcatgag cgacaagcgg aacgtgatcc

7320

tgtttagcgt gttcgatgag aaccggtcct ggtatctgac cgagaacatc cagcggtttc

7380

tgcccaatcc tgccggggtg caactggaag atcctgagtt ccaggcaagc aacatcatgc

7440

actccatcaa tggctatgtg ttcgacagcc tgcagctgag cgtgtgcctg cacgaagtgg

7500

cctactggta catcctgagc attggcgccc agaccgactt cctgtccgtg ttctttagcg

7560

gctacacctt caagcacaag atggtgtacg aggataccct gacactgttc ccattcagcg

7620

gcgagacagt gttcatgagc atggaaaacc ccggcctgtg gattctgggc tgtcacaaca

7680

gcgacttccg gaacagaggc atgacagccc tgctgaaggt gtccagctgc gacaagaaca

7740

ccggcgacta ctacgaggac agctatgagg acatcagcgc ctacctgctg agcaagaaca

7800

atgccatcga gcccagaagc ttcagccaga atagcagaca cccctccacc agacagaagc

7860

agttcaacgc cacaacaatc cccgagaacg acatcgagaa aaccgatcct tggtttgccc

7920

acagaacccc tatgcctaag atccagaacg tgtcctccag cgatctgctg atgctcctga

7980

gacagagccc tacacctcac ggactgagcc tgtccgatct gcaagaggcc aaatacgaaa

8040

ccttcagcga cgacccttct cctggcgcca tcgacagcaa caatagcctg agcgagatga

8100

cccacttcag accacagctg caccacagcg gcgacatggt gtttacacct gagagcggcc

8160

tccagctgag actgaatgag aagctgggaa ccaccgccgc caccgagctg aagaaactgg

8220

acttcaaggt gtcctctacc agcaacaacc tgatcagcac aatcccctcc gacaacctgg

8280

ctgccggcac cgacaacaca tcttctctgg gcccacctag catgcccgtg cactacgata

8340

gccagctgga taccacactg ttcggcaaga agtctagccc tctgacagag tctggcggcc

8400

ctctgtctct gagcgaggaa aacaacgaca gcaagctgct ggaatccggc ctgatgaaca

8460

gccaagagtc ctcctggggc aagaatgtgt ccagcaccga gtccggcaga ctgttcaagg

8520

gaaagagagc ccacggacct gctctgctga ccaaggataa cgccctgttc aaagtgtcca

8580

tcagcctgct caagaccaac aagacctcca acaactccgc caccaacaga aagacccaca

8640

tcgacggccc tagcctgctg atcgagaata gccctagcgt ctggcagaat atcctggaaa

8700

gcgacaccga gttcaagaaa gtgacccctc tgatccacga ccggatgctc atggacaaga

8760

acgccaccgc tctgcggctg aaccacatga gcaacaagac aaccagcagc aagaatatgg

8820

aaatggtgca gcagaagaaa gagggcccca ttcctccaga cgctcagaac cccgatatga

8880

gcttcttcaa gatgctcttt ctgcccgaga gcgcccggtg gattcagaga acacacggca

8940

agaactccct gaactccggc cagggacctt ctccaaagca gctggtttcc ctgggacctg

9000

agaagtccgt ggaaggacag aacttcctga gcgaaaagaa caaagtggtc gtcggcaagg

9060

gcgagttcac caaggatgtg ggcctgaaag agatggtctt tcccagcagc cggaacctgt

9120

tcctgaccaa cctggacaac ctgcacgaga acaacaccca caatcaagag aagaagatcc

9180

aagaggaaat cgaaaagaaa gagacactca tccaagagaa cgtggtgctg cctcagatcc

9240

acacagtgac cggcaccaag aactttatga agaatctgtt cctgctgagt acccggcaga

9300

acgtggaagg cagctacgat ggcgcttatg cccctgtgct gcaggacttc agatccctga

9360

acgactccac caatcggaca aagaagcaca cagcccactt ctccaagaag ggcgaagaag

9420

agaacctgga aggactgggc aatcagacca agcagatcgt cgagaagtac gcctgcacca

9480

ccagaatcag ccccaacaca agccagcaga acttcgtgac ccagcggagc aaaagagccc

9540

tgaagcagtt tcggctgccc ctggaagaaa ccgagctgga aaagcggatc atcgtggacg

9600

acaccagcac acagtggtcc aagaacatga agcacttgac ccctagcaca ctgacccaga

9660

tcgactacaa cgagaaagag aagggcgcta tcacacagag cccactgagc gactgtctga

9720

ccagaagcca cagcatccct caggccaaca gatcccctct gccaatcgcc aaagtgtcta

9780

gcttccccag catcagaccc atctacctga cgagtgct gttccaggac aacagcagcc

9840

atctgccagc cgccagctac cggaagaaag attctggcgt gcaagagagc agccactttc

9900

tgcagggcgc taagaagaac aatctgagcc tggctattct gaccctggaa atgaccggcg

9960

atcagagaga agtcggctct ctgggcacca gcgccacaaa tagcgtgacc tacaaaaagg

10020

tggaaaacac cgtgctgcct aagcctgacc tgccaaagac aagcggcaag gtggaactgc

10080

tgccaaaggt gcacatctac cagaaggacc tgtttcctac cgagacaagc aacggctctc

10140

ccggccatct ggatctggtg gaaggatctc tgctgcaggg aaccgagggc gccatcaagt

10200

ggaacgaggc caatagacct ggcaaggtgc ccttcctgag agtggccaca gagtccagcg

10260

ccaagacacc ctctaaactg ctggaccctc tggcctggga caaccactat ggcactcaga

10320

tccccaaaga ggaatggaag tcccaagaga agtcccctga aaagaccgcc ttcaagaaga

10380

aggacaccat tctgtccctg aatgcctgcg agagcaacca cgccattgcc gccatcaatg

10440

agggccagaa caagcccgag atcgaagtga cctgggccaa gcagggaaga accgagagac

10500

tgtgtagcca gaatcctcct gtgctgaagc ggcaccagag agaaatcacc cggaccacac

10560

tgcagagcga ccaagaagag atcgattacg acgataccat cagcgtcgag atgaagaaag

10620

aagatttcga catctacgac gaggacgaga atcagagccc tcggagcttc cagaagaaaa

10680

ccaggcacta ctttattgcc gccgtcgagc ggctgtggga ctacggaatg tctagctctc

10740

ctcacgtgct gcggaataga gcccagtctg gtagcgtgcc ccagttcaaa aaggtcgtgt

10800

tccaagagtt caccgacggc agcttcaccc agccactgta tagaggcgag ctgaacgagc

10860

atctgggcct gctgggccct tatatcagag ccgaagtgga agataacatc atggtcacct

10920

tccggaatca ggctagccgg ccttacagct tctacagctc cctgatctcc tacgaagagg

10980

accagagaca gggcgcagag ccccggaaga atttcgtgaa gcccaacgag actaagacct

11040

acttttggaa ggtgcagcac catatggccc ctacaaagga cgagttcgac tgcaaagcct

11100

gggcctactt ctccgatgtg gacctcgaaa aggacgtgca cagcggactc atcggcccac

11160

tgcttgtgtg ccacaccaac acactgaacc ccgctcacgg cagacaagtg acagtgcaag

11220

agttcgccct gtttttcacc atcttcgacg aaacgaagtc ctggtacttc accgaaaaca

11280

tggaaagaaa ctgcagggcc ccttgcaaca ttcagatgga agatcccacc ttcaaagaga

11340

actaccggtt ccacgccatc aacggctaca tcatggacac actgcccggc ctggttatgg

11400

cccaggatca gagaatccgg tggtatctgc tgtccatggg ctccaacgag aatatccact

11460

ccatccactt cagcggccac gtgttcaccg tgcggaaaaa agaagagtac aaaatggccc

11520

tgtacaatct gtaccctggg gtgttcgaaa ccgttgagat gctgcctagc aaggccggaa

11580

tttggagagt ggaatgtctg attggagagc acctccacgc cgggatgagc accctgtttc

11640

tggtgtactc caacaagtgt cagacccctc tcggcatggc ctctggccac attagagact

11700

tccagatcac cgccagcgga cagtatggac agtgggcccc taaactggcc agactgcact

11760

actccggcag catcaatgcc tggtccacca aagagccttt cagctggatc aaagtggacc

11820

tgctggctcc catgatcatc cacggaatca agacccaggg cgccagacaa aagttcagca

11880

gcctgtacat cagccagttc atcatcatgt acagcctgga cggaaagaag tggcagacct

11940

accggggcaa tagcaccggc acactgatgg tgttcttcgg caacgtggac tccagcggca

12000

ttaagcacaa catcttcaac cctccaatca ttgcccggta catccggctg caccccacac

12060

actacagcat caggtctacc ctgagaatgg aactgatggg ctgcgacctg aacagctgct

12120

ctatgcccct cggaatggaa agcaaggcca tcagcgacgc ccagatcaca gcctctagct

12180

acttcaccaa catgttcgcc acttggagcc cctctaaggc ccggcttcat ctgcaaggca

12240

gaagcaacgc ttggaggccc caagtgaaca accccaaaga atggctccag gtggactttc

12300

agaaaaccat gaaagtgaca ggcgtgacca cacagggcgt caagtccctg ctgacctcta

12360

tgtacgtgaa agagtttctg atcagctcca gccaggacgg ccaccagtgg accctgttct

12420

tccagaacgg caaagtgaaa gtgttccagg gaaatcagga cagcttcaca cccgtggtca

12480

atagtctgga cccaccactg ctgacccgct acctgcgaat tcaccctcag tcttgggtgc

12540

accagattgc cctgcggatg gaagtgctgg gctgtgaagc tcaggacctc tactagttaa

12600

ttaagagcat cttaccgcca tttattccca tatttgttct gtttttcttg atttgggtat

12660

acatttaaat gttaataaaa caaaatggtg gggcaatcat ttacattttt agggatatgt

12720

aattactagt tcaggtgtat tgccacaaga caaacatgtt aagaaacttt cccgttattt

12780

acgctctgtt cctgttaatc aacctctgga ttacaaaatt tgtgaaagat tgactgatat

12840

tcttaactat gttgctcctt ttacgctgtg tggatatgct gctttatagc ctctgtatct

12900

agctattgct tcccgtacgg ctttcgtttt ctcctccttg tataaatcct ggttgctgtc

12960

tcttttagag gagttgtggc ccgttgtccg tcaacgtggc gtggtgtgct ctgtgtttgc

13020

tgacgcaacc cccactggct ggggcattgc caccacctgt caactccttt ctgggacttt

13080

cgctttcccc ctcccgatcg ccacggcaga actcatcgcc gcctgccttg cccgctgctg

13140

gacaggggct aggttgctgg gcactgataa ttccgtggtg ttgtctgtgc cttctagttg

13200

ccagccatct gttgtttgcc cctcccccgt gccttccttg accctggaag gtgccactcc

13260

cactgtcctt tcctaataaa atgaggaaat tgcatcgcat tgtctgagta ggtgtcattc

13320

tattctgggg ggtggggtgg ggcaggacag caagggggag gattgggaag acaatagcag

13380

gcatgctggg gatgcggtgg gctctatggc tctagagcat ggctacgtag ataagtagca

13440

tggcgggtta atcattaact acacctgcag gaggaacccc tagtgatgga gttggccact

13500

ccctctctgc gcgctcgctc gctcactgag gccgggcgac caaaggtcgc ccgacgcccg

13560

ggcggcctca gtgagcgagc gagcgcgcag ctgcctgcag gggcgcgcct cgaggcatgc

13620

ggtaccaagc ttgtcgagaa gtactagagg atcataatca gccataccac atttgtagag

13680

gttttacttg ctttaaaaaa cctcccacac ctccccctga acctgaaaca taaaatgaat

13740

gcaattgttg ttgttaactt gtttattgca gcttataatg gttacaaata aagcaatagc

13800

atcacaaatt tcacaaataa agcatttttt tcactgcatt ctagttgtgg tttgtccaaa

13860

ctcatcaatg tatcttatca tgtctggatc tgatcactga tatcgcctag gagatccgaa

13920

cgataagt gaaatctagt tccaaactat tttgtcattt ttaattttcg tattagctta

13980

cgacgctaca cccagttccc atctattttg tcactcttcc ctaaataatc cttaaaaact

14040

ccatttccac ccctcccagt tcccaactat tttgtccgcc cacagcgggg catttttctt

14100

cctgttatgt ttttaatcaa acatcctgcc aactccatgt gacaaaccgt catcttcggc

14160

tactttttct ctgtcacaga atgaaaattt ttctgtcatc tcttcgttat taatgtttgt

14220

aattgactga atatcaacgc ttatttgcag cctgaatggc gaatgg

14266

<210> 197

<211> 11584

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 197

gacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg tggttacgcg cagcgtgacc

60

gctacacttg ccagcgccct agcgcccgct cctttcgctt tcttcccttc ctttctcgcc

120

acgttcgccg gctttccccg tcaagctcta aatcggggggc tccctttagg gttccgattt

180

agtgctttac ggcacctcga ccccaaaaaa cttgattagg gtgatggttc acgtagtggg

240

ccatcgccct gatagacggt ttttcgccct ttgacgttgg agtccacgtt ctttaatagt

300

ggactcttgt tccaaactgg aacaacactc aaccctatct cggtctattc ttttgattta

360

taagggattt tgccgatttc ggcctattgg ttaaaaaatg agctgattta acaaaaattt

420

aacgcgaatt ttaacaaaat attaacgttt acaatttcag gtggcacttt tcggggaaat

480

gtgcgcggaa cccctatttg tttatttttc taaatacatt caaatatgta tccgctcatg

540

agacaataac cctgataaat gcttcaataa tattgaaaaa ggaagagtat gagtattcaa

600

catttccgtg tcgcccttat tccctttttt gcggcatttt gccttcctgt ttttgctcac

660

ccagaaacgc tggtgaaagt aaaagatgct gaagatcagt tgggtgcacg agtgggttac

720

atcgaactgg atctcaacag cggtaagatc cttgagagtt ttcgccccga agaacgtttt

780

ccaatgatga gcacttttaa agttctgcta tgtggcgcgg tattatcccg tattgacgcc

840

gggcaagagc aactcggtcg ccgcatacac tattctcaga atgacttggt tgagtactca

900

ccagtcacag aaaagcatct tacggatggc atgacagtaa gagaattatg cagtgctgcc

960

ataaccatga gtgataacac tgcggccaac ttacttctga caacgatcgg aggaccgaag

1020

gagctaaccg cttttttgca caacatgggg gatcatgtaa ctcgccttga tcgttgggaa

1080

ccggagctga atgaagccat accaaacgac gagcgtgaca ccacgatgcc tgtagcaatg

1140

gcaacaacgt tgcgcaaact attaactggc gaactactta ctctagcttc ccggcaacaa

1200

ttaatagact ggatggaggc ggataaagtt gcaggaccac ttctgcgctc ggcccttccg

1260

gctggctggt ttattgctga taaatctgga gccggtgagc gtgggtctcg cggtatcatt

1320

gcagcactgg ggccagatgg taagccctcc cgtatcgtag ttatctacac gacggggagt

1380

caggcaacta tggatgaacg aaatagacag atcgctgaga taggtgcctc actgattaag

1440

cattggtaac tgtcagacca agtttactca tatatacttt agattgattt aaaacttcat

1500

ttttaattta aaaggatcta ggtgaagatc ctttttgata atctcatgac caaaatccct

1560

taacgtgagt tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa aggatcttct

1620

tgagatcctt tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc accgctacca

1680

gcggtggttt gtttgccgga tcaagagcta ccaactcttt ttccgaaggt aactggcttc

1740

agcagagcgc agataccaaa tactgtcctt ctagtgtagc cgtagttagg ccaccacttc

1800

aagaactctg tagcaccgcc tacatacctc gctctgctaa tcctgttacc agtggctgct

1860

gccagtggcg ataagtcgtg tcttaccggg ttggactcaa gacgatagtt accggataag

1920

gcgcagcggt cgggctgaac ggggggttcg tgcacacagc ccagcttgga gcgaacgacc

1980

tacaccgaac tgagatacct acagcgtgag cattgagaaa gcgccacgct tcccgaaggg

2040

agaaaggcgg acaggtatcc ggtaagcggc agggtcggaa caggagagcg cacgagggag

2100

cttccagggg gaaacgcctg gtatctttat agtcctgtcg ggtttcgcca cctctgactt

2160

gagcgtcgat ttttgtgatg ctcgtcaggg gggcggagcc tatggaaaaa cgccagcaac

2220

gcggcctttt tacggttcct ggccttttgc tggccttttg ctcacatgtt ctttcctgcg

2280

ttatcccctg attctgtgga taaccgtatt accgcctttg agtgagctga taccgctcgc

2340

cgcagccgaa cgaccgagcg cagcgagtca gtgagcgagg aagcggaaga gcgcctgatg

2400

cggtattttc tccttacgca tctgtgcggt atttcacacc gcagaccagc cgcgtaacct

2460

ggcaaaatcg gttacggttg agtaataaat ggatgccctg cgtaagcggg tgtgggcgga

2520

caataaagtc ttaaactgaa caaaatagat ctaaactatg acaataaagt cttaaactag

2580

acagaatagt tgtaaactga aatcagtcca gttatgctgt gaaaaagcat actggacttt

2640

tgttatggct aaagcaaact cttcattttc tgaagtgcaa attgcccgtc gtattaaaga

2700

ggggcgtggc caagggcatg gtaaagacta tattcgcggc gttgtgacaa tttaccgaac

2760

aactccgcgg ccgggaagcc gatctcggct tgaacgaatt gttaggtggc ggtacttggg

2820

tcgatatcaa agtgcatcac ttcttcccgt atgcccaact ttgtatagag agccactgcg

2880

ggatcgtcac cgtaatctgc ttgcacgtag atcacataag caccaagcgc gttggcctca

2940

tgcttgagga gattgatgag cgcggtggca atgccctgcc tccggtgctc gccggagact

3000

gcgagatcat agatatagat ctcactacgc ggctgctcaa acctgggcag aacgtaagcc

3060

gcgagagcgc caacaaccgc ttcttggtcg aaggcagcaa gcgcgatgaa tgtcttacta

3120

cggagcaagt tcccgaggta atcggagtcc ggctgatgtt gggagtaggt ggctacgtct

3180

ccgaactcac gaccgaaaag atcaagagca gcccgcatgg atttgacttg gtcagggccg

3240

agcctacatg tgcgaatgat gcccatactt gagccaccta actttgtttt agggcgactg

3300

ccctgctgcg taacatcgtt gctgctgcgt aacatcgttg ctgctccata acatcaaaca

3360

tcgacccacg gcgtaacgcg cttgctgctt ggatgcccga ggcatagact gtacaaaaaa

3420

acagtcataa caagccatga aaaccgccac tgcgccgtta ccaccgctgc gttcggtcaa

3480

ggttctggac cagttgcgtg agcgcatacg ctacttgcat tacagtttac gaaccgaaca

3540

ggcttatgtc aactgggttc gtgccttcat ccgtttccac ggtgtgcgtc acccggcaac

3600

cttgggcagc agcgaagtcg aggcatttct gtcctggctg gcgaacgagc gcaaggtttc

3660

ggtctccacg catcgtcagg cattggcggc cttgctgttc ttctacggca aggtgctgtg

3720

cacggatctg ccctggcttc aggagatcgg aagacctcgg ccgtcgcggc gcttgccggt

3780

ggtgctgacc ccggatgaag tggttcgcat cctcggtttt ctggaaggcg agcatcgttt

3840

gttcgcccag gactctagct atagttctag tggttggcta cgtatactcc ggaatattaa

3900

tagatcatgg agataattaa aatgataacc atctcgcaaa taaataagta ttttactgtt

3960

ttcgtaacag ttttgtaata aaaaaaccta taaatattcc ggattattca taccgtccca

4020

ccatcgggcg cggatctcgg tccgaaacca tgtcgtacta ccatcaccat caccatcacg

4080

attacgatat cccaacgacc gaaaacctgt attttcaggg cgccatggga tccggccggc

4140

ccctgcaggc agctgcgcgc tcgctcgctc actgaggccg cccgggcaaa gcccgggcgt

4200

cgggcgacct ttggtcgccc ggcctcagtg agcgagcgag cgcgcagaga gggagtggcc

4260

aactccatca ctaggggttc cttgtagtta atgattaacc cgccatgcta cttatctacg

4320

tagccatgct ctagagcggc cgcggctccg gtgcccgtca gtgggcagag cgcacatcgc

4380

ccacagtccc cgagaagttg gggggagggg tcggcaattg aaccggtgcc tagagaaggt

4440

ggcgcggggt aaactgggaa agtgatgtcg tgtactggct ccgccttttt cccgaggtg

4500

ggggagaacc gtatataagt gcagtagtcg ccgtgaacgt tctttttcgc aacgggtttg

4560

ccgccagaac acaggtaagt gccgtgtgtg gttcccgcgg gcctggcctc tttacgggtt

4620

atggcccttg cgtgccttga attacttcca cctggctgca gtacgtgatt cttgatcccg

4680

agcttcgggt tggaagtggg tgggagagtt cgaggccttg cgcttaagga gccccttcgc

4740

ctcgtgcttg agttgaggcc tggcctgggc gctggggccg ccgcgtgcga atctggtggc

4800

accttcgcgc ctgtctcgct gctttcgata agtctctagc catttaaaat ttttgatgac

4860

ctgctgcgac gctttttttc tggcaagata gtcttgtaaa tgcgggccaa gatctgcaca

4920

ctggtatttc ggtttttggg gccgcgggcg gcgacggggc ccgtgcgtcc cagcgcacat

4980

gttcggcgag gcggggcctg cgagcgcggc caccgagaat cggacggggg tagtctcaag

5040

ctggccggcc tgctctggtg cctggtctcg cgccgccgtg tatcgccccg ccctgggcgg

5100

caaggctggc ccggtcggca ccagttgcgt gagcggaaag atggccgctt cccggccctg

5160

ctgcagggag ctcaaaatgg aggacgcggc gctcgggaga gcgggcgggt gagtcaccca

5220

cacaaaggaa aagggccttt ccgtcctcag ccgtcgcttc atgtgactcc acggagtacc

5280

gggcgccgtc caggcacctc gattagttct cgagcttttg gagtacgtcg tctttaggtt

5340

ggggggaggg gttttatgcg atggagtttc cccacactga gtgggtggag actgaagtta

5400

ggccagcttg gcacttgatg taattctcct tggaatttgc cctttttgag tttggatctt

5460

ggttcattct caagcctcag acagtggttc aaagtttttt tcttccatt caggtgtcgt

5520

gagtttaaac cgcagccacc atgcagatcg agctgtctac ctgcttcttc ctgtgcctgc

5580

tgcggttctg cttcagcgcc accagaagat attacctggg cgccgtggaa ctgagctggg

5640

actacatgca gtctgacctg ggagagctgc ccgtggacgc tagatttcct ccaagagtgc

5700

ccaagagctt ccccttcaac acctccgtgg tgtacaagaa aaccctgttc gtggaattca

5760

ccgaccacct gttcaatatc gccaagcctc ggcctccttg gatgggactg ctgggaccta

5820

caattcaggc cgaggtgtac gacaccgtgg tcatcaccct gaagaacatg gccagccatc

5880

ctgtgtctct gcacgccgtg ggagtgtctt attggaaggc ttctgagggc gccgagtacg

5940

acgatcagac aagccagaga gagaaagagg acgacaaggt tttccctggc ggcagccaca

6000

cctatgtctg gcaggtcctg aaagaaaacg gccctatggc ctccgatcct ctgtgcctga

6060

catacagcta cctgagccac gtggacctgg tcaaggacct gaattctggc ctgatcggag

6120

ccctgctcgt gtgtagagaa ggcagcctgg ccaaagagaa aacccagaca ctgcacaagt

6180

tcatcctgct gttcgccgtg ttcgacgagg gcaagagctg gcacagcgag acaaagaaca

6240

gcctgatgca ggacagggat gccgcctctg ctagagcttg gcctaagatg cacaccgtga

6300

acggctacgt gaacagaagc ctgcctggac tgatcggctg cccagaaag tccgtgtact

6360

ggcacgtgat cggcatgggc acaacacctg aggtgcacag catctttctg gaaggccaca

6420

ccttcctcgt gcggaaccac agacaggcca gcctggaaat cagccctatc accttcctga

6480

ccgctcagac cctgctgatg gatctgggcc agtttctgct gttctgccac atcagctccc

6540

accagcacga tggcatggaa gcctacgtga aggtggacag ctgccccgaa gaaccccagc

6600

tgcggatgaa gaacaacgag gaagccgagg actacgacga cgacctgacc gactctgaga

6660

tggacgtcgt cagattcgac gacgataaca gccccagctt catccagatc agaagcgtgg

6720

ccaagaagca ccccaagacc tgggtgcact atatcgccgc cgaggaagag gactgggatt

6780

acgctcctct ggtgctggcc cctgacgaca gaagctacaa gagccagtac ctgaacaacg

6840

gccctcagcg gatcggccgg aagtataaga aagtgcggtt catggcctac accgacgaga

6900

cattcaagac cagagaggcc atccagcacg agagcggaat tctgggccct ctgctgtatg

6960

gcgaagtggg cgatacactg ctgatcatct tcaagaacca ggccagcaga ccctacaaca

7020

tctaccctca cggcatcacc gatgtgcggc ccctgtattc tagaaggctg cccaagggcg

7080

tgaagcacct gaaggacttc cctatcctgc ctggcgagat tttcaagtac aagtggaccg

7140

tgaccgtgga agatggcccc accaagagcg accctagatg tctgacacgg tactacagca

7200

gcttcgtgaa catggaacgc gacctggcca gcggcctgat tggacctctg ctgatctgct

7260

acaaagaaag cgtggaccag cggggcaacc agatcatgag cgacaagcgg aacgtgatcc

7320

tgtttagcgt gttcgatgag aaccggtcct ggtatctgac cgagaacatc cagcggtttc

7380

tgcccaatcc tgccggggtg caactggaag atcctgagtt ccaggcaagc aacatcatgc

7440

actccatcaa tggctatgtg ttcgacagcc tgcagctgag cgtgtgcctg cacgaagtgg

7500

cctactggta catcctgagc attggcgccc agaccgactt cctgtccgtg ttctttagcg

7560

gctacacctt caagcacaag atggtgtacg aggataccct gacactgttc ccattcagcg

7620

gcgagacagt gttcatgagc atggaaaacc ccggcctgtg gattctgggc tgtcacaaca

7680

gcgacttccg gaacagaggc atgacagccc tgctgaaggt gtccagctgc gacaagaaca

7740

ccggcgacta ctacgaggac agctatgagg acatcagcgc ctacctgctg agcaagaaca

7800

atgccatcga gcctcggagc ttcagccaga atcctcctgt gctgaagcgg caccagcgcg

7860

agatcaccag aacaaccctg cagagcgacc aagaggaaat cgattacgac gacaccatca

7920

gcgtcgagat gaagaaagaa gatttcgaca tctacgacga ggacgagaat cagagcccca

7980

gaagctttca gaaaaagacc cggcactact tcattgccgc cgtcgagaga ctgtgggact

8040

acggcatgtc tagcagccct cacgtgctga gaaatagagc ccagagcggc agcgtgcccc

8100

agttcaagaa agtggtgttc caagagttca ccgacggcag cttcacccag ccactgtata

8160

gaggcgagct gaacgagcat ctgggcctgc tgggccctta tatcagagcc gaagtggaag

8220

ataacatcat ggtcaccttc cggaatcagg ctagccggcc ttacagcttc tacagctccc

8280

tgatcagcta cgaagaggac cagagacagg gcgctgagcc cagaaagaac ttcgtgaagc

8340

ccaacgagac taagacctac ttttggaagg tgcagcacca catggcccct acaaaggacg

8400

agttcgactg caaagcctgg gcctacttct ccgatgtgga tctggaaaag gacgtgcaca

8460

gcgggctcat cggaccactg cttgtgtgcc acaccaacac actgaacccc gctcacggca

8520

gacaagtgac agtgcaagag ttcgccctgt tcttcaccat cttcgacgaa acaaagagct

8580

ggtacttcac cgagaatatg gaacggaact gcagagcccc ttgcaacatc cagatggaag

8640

atcccacctt caaagagaac taccggttcc acgccatcaa cggctacatc atggacacac

8700

tgcccggcct ggttatggcc caggatcaga gaatccggtg gtatctgctg tccatgggct

8760

ccaacgagaa tatccacagc atccacttca gcggccacgt gttcaccgtg cggaaaaaag

8820

aagagtacaa aatggccctg tacaatctgt accctggggt gttcgaaacc gtggaaatgc

8880

tgccttccaa ggccggcatt tggagagtgg aatgtctgat tggagagcac ctccacgccg

8940

gaatgagcac cctgtttctg gtgtacagca acaagtgtca gacccctctc ggcatggcct

9000

ctggacacat cagagacttc cagatcaccg cctctggcca gtacggacag tgggctccta

9060

aactggctcg gctgcactac agcggcagca tcaatgcctg gtccaccaaa gagcccttca

9120

gctggatcaa ggtggacctg ctggctccca tgatcatcca cggaatcaag acccaggcg

9180

cgacagaa gttcagcagc ctgtacatca gccagttcat catcatgtac agcctggacg

9240

gcaagaagtg gcagacctac agaggcaaca gcaccggcac actcatggtg ttcttcggca

9300

acgtggactc cagcggcatt aagcacaaca tcttcaaccc tccaatcatt gcccggtaca

9360

tccggctgca ccccacacac tacagcatcc ggtctaccct gagaatggaa ctgatgggct

9420

gcgacctgaa cagctgctct atgcccctcg gaatggaaag caaggccatc agcgacgccc

9480

agatcacagc cagcagctac ttcaccaaca tgttcgccac ttggagcccc tccaaggcta

9540

gactgcatct gcagggcaga agcaacgctt ggaggcccca agtgaacaac cccaaagagt

9600

ggctgcaggt tgactttcaa aagaccatga aagtgaccgg cgtgaccaca cagggcgtca

9660

agtctctgct gacctctatg tacgtgaaag agttcctgat ctccagcagc caggacggcc

9720

atcagtggac cctgtttttc cagaacggca aagtgaaagt gttccagggc aatcaggaca

9780

gcttcacacc cgtggtcaat tctctggacc ctccactgct gaccagatac ctgcggattc

9840

accctcagtc ttgggtgcac cagatcgctc tgcggatgga agtgctgggc tgtgaagctc

9900

aggacctcta ctagttaatt aagagcatct taccgccatt tattcccata tttgttctgt

9960

ttttcttgat ttgggtatac atttaaatgt taataaaaca aaatggtggg gcaatcattt

10020

acatttttag ggatatgtaa ttactagttc aggtgtattg ccacaagaca aacatgttaa

10080

gaaactttcc cgttatttac gctctgttcc tgttaatcaa cctctggatt acaaaatttg

10140

tgaaagattg actgatattc ttaactatgt tgctcctttt acgctgtgtg gatatgctgc

10200

tttatagcct ctgtatctag ctattgcttc ccgtacggct ttcgttttct cctccttgta

10260

taaatcctgg ttgctgtctc ttttagagga gttgtggccc gttgtccgtc aacgtggcgt

10320

ggtgtgctct gtgtttgctg acgcaacccc cactggctgg ggcattgcca ccacctgtca

10380

actcctttct gggactttcg ctttccccct cccgatcgcc acggcagaac tcatcgccgc

10440

ctgccttgcc cgctgctgga caggggctag gttgctgggc actgataatt ccgtggtgtt

10500

gtctgtgcct tctagttgcc agccatctgt tgtttgcccc tcccccgtgc cttccttgac

10560

cctggaaggt gccactccca ctgtcctttc ctaataaaat gaggaaattg catcgcattg

10620

tctgagtagg tgtcattcta ttctgggggg tggggtgggg caggacagca agggggagga

10680

ttgggaagac aatagcaggc atgctgggga tgcggtgggc tctatggctc tagagcatgg

10740

ctacgtagat aagtagcatg gcgggttaat cattaactac acctgcagga ggaaccccta

10800

gtgatggagt tggccactcc ctctctgcgc gctcgctcgc tcactgaggc cgggcgacca

10860

aaggtcgccc gacgcccggg cggcctcagt gagcgagcga gcgcgcagct gcctgcaggg

10920

gcgcgcctcg aggcatgcgg taccaagctt gtcgagaagt actagaggat cataatcagc

10980

cataccacat ttgtagaggt tttacttgct ttaaaaaacc tcccacacct ccccctgaac

11040

ctgaaacata aaatgaatgc aattgttgtt gttaacttgt ttattgcagc ttataatggt

11100

tacaaataaa gcaatagcat cacaaatttc acaaataaag catttttttc actgcattct

11160

agttgtggtt tgtccaaact catcaatgta tcttatcatg tctggatctg atcactgata

11220

tcgcctagga gatccgaacc agataagtga aatctagttc caaactattt tgtcattttt

11280

aattttcgta ttagcttacg acgctacacc cagttcccat ctattttgtc actcttccct

11340

aaataatcct taaaaactcc atttccaccc ctcccagttc ccaactattt tgtccgccca

11400

cagcggggca tttttcttcc tgttatgttt ttaatcaaac atcctgccaa ctccatgtga

11460

caaaccgtca tcttcggcta ctttttctct gtcacagaat gaaaattttt ctgtcatctc

11520

ttcgttatta atgtttgtaa ttgactgaat atcaacgctt atttgcagcc tgaatggcga

11580

atgg

11584

<210> 198

<211> 11558

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 198

gacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg tggttacgcg cagcgtgacc

60

gctacacttg ccagcgccct agcgcccgct cctttcgctt tcttcccttc ctttctcgcc

120

acgttcgccg gctttccccg tcaagctcta aatcggggggc tccctttagg gttccgattt

180

agtgctttac ggcacctcga ccccaaaaaa cttgattagg gtgatggttc acgtagtggg

240

ccatcgccct gatagacggt ttttcgccct ttgacgttgg agtccacgtt ctttaatagt

300

ggactcttgt tccaaactgg aacaacactc aaccctatct cggtctattc ttttgattta

360

taagggattt tgccgatttc ggcctattgg ttaaaaaatg agctgattta acaaaaattt

420

aacgcgaatt ttaacaaaat attaacgttt acaatttcag gtggcacttt tcggggaaat

480

gtgcgcggaa cccctatttg tttatttttc taaatacatt caaatatgta tccgctcatg

540

agacaataac cctgataaat gcttcaataa tattgaaaaa ggaagagtat gagtattcaa

600

catttccgtg tcgcccttat tccctttttt gcggcatttt gccttcctgt ttttgctcac

660

ccagaaacgc tggtgaaagt aaaagatgct gaagatcagt tgggtgcacg agtgggttac

720

atcgaactgg atctcaacag cggtaagatc cttgagagtt ttcgccccga agaacgtttt

780

ccaatgatga gcacttttaa agttctgcta tgtggcgcgg tattatcccg tattgacgcc

840

gggcaagagc aactcggtcg ccgcatacac tattctcaga atgacttggt tgagtactca

900

ccagtcacag aaaagcatct tacggatggc atgacagtaa gagaattatg cagtgctgcc

960

ataaccatga gtgataacac tgcggccaac ttacttctga caacgatcgg aggaccgaag

1020

gagctaaccg cttttttgca caacatgggg gatcatgtaa ctcgccttga tcgttgggaa

1080

ccggagctga atgaagccat accaaacgac gagcgtgaca ccacgatgcc tgtagcaatg

1140

gcaacaacgt tgcgcaaact attaactggc gaactactta ctctagcttc ccggcaacaa

1200

ttaatagact ggatggaggc ggataaagtt gcaggaccac ttctgcgctc ggcccttccg

1260

gctggctggt ttattgctga taaatctgga gccggtgagc gtgggtctcg cggtatcatt

1320

gcagcactgg ggccagatgg taagccctcc cgtatcgtag ttatctacac gacggggagt

1380

caggcaacta tggatgaacg aaatagacag atcgctgaga taggtgcctc actgattaag

1440

cattggtaac tgtcagacca agtttactca tatatacttt agattgattt aaaacttcat

1500

ttttaattta aaaggatcta ggtgaagatc ctttttgata atctcatgac caaaatccct

1560

taacgtgagt tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa aggatcttct

1620

tgagatcctt tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc accgctacca

1680

gcggtggttt gtttgccgga tcaagagcta ccaactcttt ttccgaaggt aactggcttc

1740

agcagagcgc agataccaaa tactgtcctt ctagtgtagc cgtagttagg ccaccacttc

1800

aagaactctg tagcaccgcc tacatacctc gctctgctaa tcctgttacc agtggctgct

1860

gccagtggcg ataagtcgtg tcttaccggg ttggactcaa gacgatagtt accggataag

1920

gcgcagcggt cgggctgaac ggggggttcg tgcacacagc ccagcttgga gcgaacgacc

1980

tacaccgaac tgagatacct acagcgtgag cattgagaaa gcgccacgct tcccgaaggg

2040

agaaaggcgg acaggtatcc ggtaagcggc agggtcggaa caggagagcg cacgagggag

2100

cttccagggg gaaacgcctg gtatctttat agtcctgtcg ggtttcgcca cctctgactt

2160

gagcgtcgat ttttgtgatg ctcgtcaggg gggcggagcc tatggaaaaa cgccagcaac

2220

gcggcctttt tacggttcct ggccttttgc tggccttttg ctcacatgtt ctttcctgcg

2280

ttatcccctg attctgtgga taaccgtatt accgcctttg agtgagctga taccgctcgc

2340

cgcagccgaa cgaccgagcg cagcgagtca gtgagcgagg aagcggaaga gcgcctgatg

2400

cggtattttc tccttacgca tctgtgcggt atttcacacc gcagaccagc cgcgtaacct

2460

ggcaaaatcg gttacggttg agtaataaat ggatgccctg cgtaagcggg tgtgggcgga

2520

caataaagtc ttaaactgaa caaaatagat ctaaactatg acaataaagt cttaaactag

2580

acagaatagt tgtaaactga aatcagtcca gttatgctgt gaaaaagcat actggacttt

2640

tgttatggct aaagcaaact cttcattttc tgaagtgcaa attgcccgtc gtattaaaga

2700

ggggcgtggc caagggcatg gtaaagacta tattcgcggc gttgtgacaa tttaccgaac

2760

aactccgcgg ccgggaagcc gatctcggct tgaacgaatt gttaggtggc ggtacttggg

2820

tcgatatcaa agtgcatcac ttcttcccgt atgcccaact ttgtatagag agccactgcg

2880

ggatcgtcac cgtaatctgc ttgcacgtag atcacataag caccaagcgc gttggcctca

2940

tgcttgagga gattgatgag cgcggtggca atgccctgcc tccggtgctc gccggagact

3000

gcgagatcat agatatagat ctcactacgc ggctgctcaa acctgggcag aacgtaagcc

3060

gcgagagcgc caacaaccgc ttcttggtcg aaggcagcaa gcgcgatgaa tgtcttacta

3120

cggagcaagt tcccgaggta atcggagtcc ggctgatgtt gggagtaggt ggctacgtct

3180

ccgaactcac gaccgaaaag atcaagagca gcccgcatgg atttgacttg gtcagggccg

3240

agcctacatg tgcgaatgat gcccatactt gagccaccta actttgtttt agggcgactg

3300

ccctgctgcg taacatcgtt gctgctgcgt aacatcgttg ctgctccata acatcaaaca

3360

tcgacccacg gcgtaacgcg cttgctgctt ggatgcccga ggcatagact gtacaaaaaa

3420

acagtcataa caagccatga aaaccgccac tgcgccgtta ccaccgctgc gttcggtcaa

3480

ggttctggac cagttgcgtg agcgcatacg ctacttgcat tacagtttac gaaccgaaca

3540

ggcttatgtc aactgggttc gtgccttcat ccgtttccac ggtgtgcgtc acccggcaac

3600

cttgggcagc agcgaagtcg aggcatttct gtcctggctg gcgaacgagc gcaaggtttc

3660

ggtctccacg catcgtcagg cattggcggc cttgctgttc ttctacggca aggtgctgtg

3720

cacggatctg ccctggcttc aggagatcgg aagacctcgg ccgtcgcggc gcttgccggt

3780

ggtgctgacc ccggatgaag tggttcgcat cctcggtttt ctggaaggcg agcatcgttt

3840

gttcgcccag gactctagct atagttctag tggttggcta cgtatactcc ggaatattaa

3900

tagatcatgg agataattaa aatgataacc atctcgcaaa taaataagta ttttactgtt

3960

ttcgtaacag ttttgtaata aaaaaaccta taaatattcc ggattattca taccgtccca

4020

ccatcgggcg cggatctcgg tccgaaacca tgtcgtacta ccatcaccat caccatcacg

4080

attacgatat cccaacgacc gaaaacctgt attttcaggg cgccatggga tccggccggc

4140

ccctgcaggc agctgcgcgc tcgctcgctc actgaggccg cccgggcaaa gcccgggcgt

4200

cgggcgacct ttggtcgccc ggcctcagtg agcgagcgag cgcgcagaga gggagtggcc

4260

aactccatca ctaggggttc cttgtagtta atgattaacc cgccatgcta cttatctacg

4320

tagccatgct ctagagcggc cgcccctaaa atgggcaaac attgcaagca gcaaacagca

4380

aacacacagc cctccctgcc tgctgacctt ggagctgggg cagaggtcag agacctctct

4440

gggcccatgc cacctccaac atccactcga ccccttggaa tttttcggtg gagaggagca

4500

gaggttgtcc tggcgtggtt taggtagtgt gagaggggaa tgactccttt cggtaagtgc

4560

agtggaagct gtacactgcc caggcaaagc gtccggggcag cgtaggcggg cgactcagat

4620

cccagccagt ggacttagcc cctgtttgct cctccgataa ctggggtgac cttggttaat

4680

attcaccagc agcctccccc gttgcccctc tggatccact gcttaaatac ggacgaggac

4740

agggccctgt ctcctcagct tcaggcacca ccactgacct gggacagtga atccggactc

4800

taaggtaaat ataaaatttt taagtgtata atgtgttaaa ctactgattc taattgtttc

4860

tctcttttag attccaacct ttggaactga gtttaaaccg cagccaccat gcagatcgag

4920

ctgtctacct gcttcttcct gtgcctgctg cggttctgct tcagcgccac cagaagatat

4980

tacctgggcg ccgtggaact gagctgggac tacatgcagt ctgacctggg agagctgccc

5040

gtggacgcta gatttcctcc aagagtgccc aagagcttcc ccttcaacac ctccgtggtg

5100

tacaagaaaa ccctgttcgt ggaattcacc gaccacctgt tcaatatcgc caagcctcgg

5160

cctccttgga tgggactgct gggacctaca attcaggccg aggtgtacga caccgtggtc

5220

atcaccctga agaacatggc cagccatcct gtgtctctgc acgccgtggg agtgtcttat

5280

tggaaggctt ctgagggcgc cgagtacgac gatcagacaa gccagagaga gaaagaggac

5340

gacaaggttt tccctggcgg cagccacacc tatgtctggc aggtcctgaa agaaaacggc

5400

cctatggcct ccgatcctct gtgcctgaca tacagctacc tgagccacgt ggacctggtc

5460

aaggacctga attctggcct gatcggagcc ctgctcgtgt gtagagaagg cagcctggcc

5520

aaagagaaaa cccagacact gcacaagttc atcctgctgt tcgccgtgtt cgacgagggc

5580

aagagctggc acagcgagac aaagaacagc ctgatgcagg acagggatgc cgcctctgct

5640

agagcttggc ctaagatgca caccgtgaac ggctacgtga acagaagcct gcctggactg

5700

atcggctgcc acagaaagtc cgtgtactgg cacgtgatcg gcatgggcac aacacctgag

5760

gtgcacagca tctttctgga aggccacacc ttcctcgtgc ggaaccacag acaggccagc

5820

ctggaaatca gccctatcac cttcctgacc gctcagaccc tgctgatgga tctgggccag

5880

tttctgctgt tctgccacat cagctcccac cagcacgatg gcatggaagc ctacgtgaag

5940

gtggacagct gccccgaaga accccagctg cggatgaaga acaacgagga agccgaggac

6000

tacgacgacg acctgaccga ctctgagatg gacgtcgtca gattcgacga cgataacagc

6060

cccagcttca tccagatcag aagcgtggcc aagaagcacc ccaagacctg ggtgcactat

6120

atcgccgccg aggaagagga ctgggattac gctcctctgg tgctggcccc tgacgacaga

6180

agctacaaga gccagtacct gaacaacggc cctcagcgga tcggccggaa gtataagaaa

6240

gtgcggttca tggcctacac cgacgagaca ttcaagacca gagaggccat ccagcacgag

6300

agcggaattc tgggccctct gctgtatggc gaagtgggcg atacactgct gatcatcttc

6360

aagaaccagg ccagcagacc ctacaacatc taccctcacg gcatcaccga tgtgcggccc

6420

ctgtattcta gaaggctgcc caagggcgtg aagcacctga aggacttccc tatcctgcct

6480

ggcgagattt tcaagtacaa gtggaccgtg accgtggaag atggccccac caagagcgac

6540

cctagatgtc tgacacggta ctacagcagc ttcgtgaaca tggaacgcga cctggccagc

6600

ggcctgattg gacctctgct gatctgctac aaagaaagcg tggaccagcg gggcaaccag

6660

atcatgagcg acaagcggaa cgtgatcctg tttagcgtgt tcgatgagaa ccggtcctgg

6720

tatctgaccg agaacatcca gcggtttctg cccaatcctg ccggggtgca actggaagat

6780

cctgagttcc aggcaagcaa catcatgcac tccatcaatg gctatgtgtt cgacagcctg

6840

cagctgagcg tgtgcctgca cgaagtggcc tactggtaca tcctgagcat tggcgcccag

6900

accgacttcc tgtccgtgtt ctttagcggc tacaccttca agcacaagat ggtgtacgag

6960

gataccctga cactgttccc attcagcggc gagacagtgt tcatgagcat ggaaaacccc

7020

ggcctgtgga ttctgggctg tcacaacagc gacttccgga acagaggcat gacagccctg

7080

ctgaaggtgt ccagctgcga caagaacacc ggcgactact acgaggacag ctatgaggac

7140

atcagcgcct acctgctgag caagaacaat gccatcgagc ccagaagctt cagccagaat

7200

agcagacacc cctccaccag acagaagcag ttcaacgcca caacaatccc cgagaacgac

7260

atcgagaaaa ccgatccttg gtttgcccac agaaccccta tgcctaagat ccagaacgtg

7320

tcctccagcg atctgctgat gctcctgaga cagagcccta cacctcacgg actgagcctg

7380

tccgatctgc aagaggccaa atacgaaacc ttcagcgacg acccttctcc tggcgccatc

7440

gacagcaaca atagcctgag cgagatgacc cacttcagac cacagctgca ccacagcggc

7500

gacatggtgt ttacacctga gagcggcctc cagctgagac tgaatgagaa gctgggaacc

7560

accgccgcca ccgagctgaa gaaactggac ttcaaggtgt cctctaccag caacaacctg

7620

atcagcacaa tcccctccga caacctggct gccggcaccg acaacacatc ttctctgggc

7680

ccacctagca tgcccgtgca ctacgatagc cagctggata cccacactgtt cggcaagaag

7740

tctagccctc tgacagagtc tggcggccct ctgtctctga gcgaggaaaa caacgacagc

7800

aagctgcctc ctgtgctgaa gcggcaccag cgggaaatca ccagaaccac actgcagagc

7860

gaccaagagg aaatcgatta cgacgacacc atcagcgtcg agatgaagaa agaagatttc

7920

gacatctacg acgaggacga gaatcagagc cccagatcct ttcagaaaaa gacccggcac

7980

tacttcattg ccgccgtcga gagactgtgg gactacggca tgtctagcag ccctcacgtg

8040

ctgagaaata gagcccagag cggcagcgtg ccccagttca agaaagtggt gttccaagag

8100

ttcaccgacg gcagcttcac ccagccactg tatagaggcg agctgaacga gcatctgggc

8160

ctgctgggcc cttatatcag agccgaagtg gaagataaca tcatggtcac cttccggaat

8220

caggctagcc ggccttacag cttctacagc tccctgatct cctacgaaga ggaccagaga

8280

cagggcgctg agccccggaa gaatttcgtg aagcccaacg agactaagac ctacttttgg

8340

aaggtgcagc accacatggc ccctacaaag gacgagttcg actgcaaagc ctgggcctac

8400

ttctccgatg tggatctgga aaaggacgtg cacagcgggc tcatcggacc actgcttgtg

8460

tgccacacca acacactgaa ccccgctcac ggcagacaag tgacagtgca agagttcgcc

8520

ctgttcttca ccatcttcga cgaaacaaag agctggtact tcaccgagaa tatggaacgg

8580

aactgcaggg ccccttgcaa catccagatg gaagatccca ccttcaaaga gaactaccgg

8640

ttccacgcca tcaacggcta catcatggac acactgcccg gcctggttat ggcccaggat

8700

cagagaatcc ggtggtatct gctgtccatg ggctccaacg agaatatcca cagcatccac

8760

ttcagcggcc acgtgttcac cgtgcggaaa aaagaagagt acaaaatggc cctgtacaat

8820

ctgtaccctg gggtgttcga aaccgtggaa atgctgcctt ccaaggccgg catttggaga

8880

gtggaatgtc tgattggaga gcacctccac gccggaatga gcaccctgtt tctggtgtac

8940

tccaacaagt gtcagacccc tctcggcatg gcctctggac acatcagaga cttccagatc

9000

accgcctctg gccagtacgg acagtgggct cctaaactgg ctcggctgca ctactccggc

9060

agcatcaatg cctggtccac caaagagccc ttcagctgga tcaaggtgga cctgctggct

9120

cccatgatca tccacggaat caagacccag ggcgcaagac agaagttcag cagcctgtac

9180

atcagccagt tcatcatcat gtacagcctg gacggaaaga agtggcagac ctaccggggc

9240

aatagcaccg gcacactcat ggtgttcttc ggcaacgtgg actccagcgg cattaagcac

9300

aacatcttca accctccaat cattgcccgg tacatccggc tgcaccccac acactacagc

9360

atccggtcta ccctgagaat ggaactgatg ggctgcgacc tgaacagctg ctctatgccc

9420

ctcggaatgg aaagcaaggc catcagcgac gccgatca cagccagcag ctacttcacc

9480

aacatgttcg ccacttggag cccctccaag gctagactgc atctgcaggg cagaagcaac

9540

gcttggaggc cccaagtgaa caaccccaaa gagtggctgc aggttgactt tcaaaagacc

9600

atgaaagtga ccggcgtgac cacacagggc gtcaagtctc tgctgacctc tatgtacgtg

9660

aaagagttcc tgattagcag cagccaggac ggccaccagt ggaccctgtt tttccagaac

9720

ggcaaagtga aagtgttcca gggcaatcag gacagcttca cacccgtggt caattctctg

9780

gaccctccac tgctgaccag atacctgcgg attcaccctc agtcttgggt gcaccagatc

9840

gctctgcgga tggaagtgct gggctgtgaa gctcaggacc tctactagtt aattaagagc

9900

atcttaccgc catttattcc catatttgtt ctgtttttct tgatttgggt atacatttaa

9960

atgttaataa aacaaaatgg tggggcaatc atttacattt ttagggatat gtaattacta

10020

gttcaggtgt attgccacaa gacaaacatg ttaagaaact ttcccgttat ttacgctctg

10080

ttcctgttaa tcaacctctg gattacaaaa tttgtgaaag attgactgat attcttaact

10140

atgttgctcc ttttacgctg tgtggatatg ctgctttata gcctctgtat ctagctattg

10200

cttcccgtac ggctttcgtt ttctcctcct tgtataaatc ctggttgctg tctcttttag

10260

aggagttgtg gcccgttgtc cgtcaacgtg gcgtggtgtg ctctgtgttt gctgacgcaa

10320

cccccactgg ctggggcatt gccaccacct gtcaactcct ttctgggact ttcgctttcc

10380

ccctcccgat cgccacggca gaactcatcg ccgcctgcct tgcccgctgc tggacaggg

10440

ctaggttgct gggcactgat aattccgtgg tgttgtctgt gccttctagt tgccagccat

10500

ctgttgtttg cccctccccc gtgccttcct tgaccctgga aggtgccact cccactgtcc

10560

tttcctaata aaatgaggaa attgcatcgc attgtctgag taggtgtcat tctattctgg

10620

ggggtggggt ggggcaggac agcaaggggg aggattggga agacaatagc aggcatgctg

10680

gggatgcggt gggctctatg gctctagagc atggctacgt agataagtag catggcgggt

10740

taatcattaa ctacacctgc aggaggaacc cctagtgatg gagttggcca ctccctctct

10800

gcgcgctcgc tcgctcactg aggccgggcg accaaaggtc gcccgacgcc cgggcggcct

10860

cagtgagcga gcgagcgcgc agctgcctgc aggggcgcgc ctcgaggcat gcggtaccaa

10920

gcttgtcgag aagtactaga ggatcataat cagccatacc acatttgtag aggttttact

10980

tgctttaaaa aacctcccac acctccccct gaacctgaaa cataaaatga atgcaattgt

11040

tgttgttaac ttgtttattg cagcttataa tggttacaaa taaagcaata gcatcacaaa

11100

tttcacaaat aaagcatttt tttcactgca ttctagttgt ggtttgtcca aactcatcaa

11160

tgtatcttat catgtctgga tctgatcact gatatcgcct aggagatccg aaccagataa

11220

gtgaaatcta gttccaaact attttgtcat ttttaatttt cgtattagct tacgacgcta

11280

cacccagttc ccatctattt tgtcactctt ccctaaataa tccttaaaaa ctccattcc

11340

acccctccca gttcccaact attttgtccg cccacagcgg ggcatttttc ttcctgttat

11400

gtttttaatc aaacatcctg ccaactccat gtgacaaacc gtcatcttcg gctacttttt

11460

ctctgtcaca gaatgaaaat ttttctgtca tctcttcgtt attaatgttt gtaattgact

11520

gaatatcaac gcttatttgc agcctgaatg gcgaatgg

11558

<210> 199

<211> 12190

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 199

gacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg tggttacgcg cagcgtgacc

60

gctacacttg ccagcgccct agcgcccgct cctttcgctt tcttcccttc ctttctcgcc

120

acgttcgccg gctttccccg tcaagctcta aatcggggggc tccctttagg gttccgattt

180

agtgctttac ggcacctcga ccccaaaaaa cttgattagg gtgatggttc acgtagtggg

240

ccatcgccct gatagacggt ttttcgccct ttgacgttgg agtccacgtt ctttaatagt

300

ggactcttgt tccaaactgg aacaacactc aaccctatct cggtctattc ttttgattta

360

taagggattt tgccgatttc ggcctattgg ttaaaaaatg agctgattta acaaaaattt

420

aacgcgaatt ttaacaaaat attaacgttt acaatttcag gtggcacttt tcggggaaat

480

gtgcgcggaa cccctatttg tttatttttc taaatacatt caaatatgta tccgctcatg

540

agacaataac cctgataaat gcttcaataa tattgaaaaa ggaagagtat gagtattcaa

600

catttccgtg tcgcccttat tccctttttt gcggcatttt gccttcctgt ttttgctcac

660

ccagaaacgc tggtgaaagt aaaagatgct gaagatcagt tgggtgcacg agtgggttac

720

atcgaactgg atctcaacag cggtaagatc cttgagagtt ttcgccccga agaacgtttt

780

ccaatgatga gcacttttaa agttctgcta tgtggcgcgg tattatcccg tattgacgcc

840

gggcaagagc aactcggtcg ccgcatacac tattctcaga atgacttggt tgagtactca

900

ccagtcacag aaaagcatct tacggatggc atgacagtaa gagaattatg cagtgctgcc

960

ataaccatga gtgataacac tgcggccaac ttacttctga caacgatcgg aggaccgaag

1020

gagctaaccg cttttttgca caacatgggg gatcatgtaa ctcgccttga tcgttgggaa

1080

ccggagctga atgaagccat accaaacgac gagcgtgaca ccacgatgcc tgtagcaatg

1140

gcaacaacgt tgcgcaaact attaactggc gaactactta ctctagcttc ccggcaacaa

1200

ttaatagact ggatggaggc ggataaagtt gcaggaccac ttctgcgctc ggcccttccg

1260

gctggctggt ttattgctga taaatctgga gccggtgagc gtgggtctcg cggtatcatt

1320

gcagcactgg ggccagatgg taagccctcc cgtatcgtag ttatctacac gacggggagt

1380

caggcaacta tggatgaacg aaatagacag atcgctgaga taggtgcctc actgattaag

1440

cattggtaac tgtcagacca agtttactca tatatacttt agattgattt aaaacttcat

1500

ttttaattta aaaggatcta ggtgaagatc ctttttgata atctcatgac caaaatccct

1560

taacgtgagt tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa aggatcttct

1620

tgagatcctt tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc accgctacca

1680

gcggtggttt gtttgccgga tcaagagcta ccaactcttt ttccgaaggt aactggcttc

1740

agcagagcgc agataccaaa tactgtcctt ctagtgtagc cgtagttagg ccaccacttc

1800

aagaactctg tagcaccgcc tacatacctc gctctgctaa tcctgttacc agtggctgct

1860

gccagtggcg ataagtcgtg tcttaccggg ttggactcaa gacgatagtt accggataag

1920

gcgcagcggt cgggctgaac ggggggttcg tgcacacagc ccagcttgga gcgaacgacc

1980

tacaccgaac tgagatacct acagcgtgag cattgagaaa gcgccacgct tcccgaaggg

2040

agaaaggcgg acaggtatcc ggtaagcggc agggtcggaa caggagagcg cacgagggag

2100

cttccagggg gaaacgcctg gtatctttat agtcctgtcg ggtttcgcca cctctgactt

2160

gagcgtcgat ttttgtgatg ctcgtcaggg gggcggagcc tatggaaaaa cgccagcaac

2220

gcggcctttt tacggttcct ggccttttgc tggccttttg ctcacatgtt ctttcctgcg

2280

ttatcccctg attctgtgga taaccgtatt accgcctttg agtgagctga taccgctcgc

2340

cgcagccgaa cgaccgagcg cagcgagtca gtgagcgagg aagcggaaga gcgcctgatg

2400

cggtattttc tccttacgca tctgtgcggt atttcacacc gcagaccagc cgcgtaacct

2460

ggcaaaatcg gttacggttg agtaataaat ggatgccctg cgtaagcggg tgtgggcgga

2520

caataaagtc ttaaactgaa caaaatagat ctaaactatg acaataaagt cttaaactag

2580

acagaatagt tgtaaactga aatcagtcca gttatgctgt gaaaaagcat actggacttt

2640

tgttatggct aaagcaaact cttcattttc tgaagtgcaa attgcccgtc gtattaaaga

2700

ggggcgtggc caagggcatg gtaaagacta tattcgcggc gttgtgacaa tttaccgaac

2760

aactccgcgg ccgggaagcc gatctcggct tgaacgaatt gttaggtggc ggtacttggg

2820

tcgatatcaa agtgcatcac ttcttcccgt atgcccaact ttgtatagag agccactgcg

2880

ggatcgtcac cgtaatctgc ttgcacgtag atcacataag caccaagcgc gttggcctca

2940

tgcttgagga gattgatgag cgcggtggca atgccctgcc tccggtgctc gccggagact

3000

gcgagatcat agatatagat ctcactacgc ggctgctcaa acctgggcag aacgtaagcc

3060

gcgagagcgc caacaaccgc ttcttggtcg aaggcagcaa gcgcgatgaa tgtcttacta

3120

cggagcaagt tcccgaggta atcggagtcc ggctgatgtt gggagtaggt ggctacgtct

3180

ccgaactcac gaccgaaaag atcaagagca gcccgcatgg atttgacttg gtcagggccg

3240

agcctacatg tgcgaatgat gcccatactt gagccaccta actttgtttt agggcgactg

3300

ccctgctgcg taacatcgtt gctgctgcgt aacatcgttg ctgctccata acatcaaaca

3360

tcgacccacg gcgtaacgcg cttgctgctt ggatgcccga ggcatagact gtacaaaaaa

3420

acagtcataa caagccatga aaaccgccac tgcgccgtta ccaccgctgc gttcggtcaa

3480

ggttctggac cagttgcgtg agcgcatacg ctacttgcat tacagtttac gaaccgaaca

3540

ggcttatgtc aactgggttc gtgccttcat ccgtttccac ggtgtgcgtc acccggcaac

3600

cttgggcagc agcgaagtcg aggcatttct gtcctggctg gcgaacgagc gcaaggtttc

3660

ggtctccacg catcgtcagg cattggcggc cttgctgttc ttctacggca aggtgctgtg

3720

cacggatctg ccctggcttc aggagatcgg aagacctcgg ccgtcgcggc gcttgccggt

3780

ggtgctgacc ccggatgaag tggttcgcat cctcggtttt ctggaaggcg agcatcgttt

3840

gttcgcccag gactctagct atagttctag tggttggcta cgtatactcc ggaatattaa

3900

tagatcatgg agataattaa aatgataacc atctcgcaaa taaataagta ttttactgtt

3960

ttcgtaacag ttttgtaata aaaaaaccta taaatattcc ggattattca taccgtccca

4020

ccatcgggcg cggatctcgg tccgaaacca tgtcgtacta ccatcaccat caccatcacg

4080

attacgatat cccaacgacc gaaaacctgt attttcaggg cgccatggga tccggccggc

4140

ccctgcaggc agctgcgcgc tcgctcgctc actgaggccg cccgggcaaa gcccgggcgt

4200

cgggcgacct ttggtcgccc ggcctcagtg agcgagcgag cgcgcagaga gggagtggcc

4260

aactccatca ctaggggttc cttgtagtta atgattaacc cgccatgcta cttatctacg

4320

tagccatgct ctagagcggc cgcggctccg gtgcccgtca gtgggcagag cgcacatcgc

4380

ccacagtccc cgagaagttg gggggagggg tcggcaattg aaccggtgcc tagagaaggt

4440

ggcgcggggt aaactgggaa agtgatgtcg tgtactggct ccgccttttt cccgaggtg

4500

ggggagaacc gtatataagt gcagtagtcg ccgtgaacgt tctttttcgc aacgggtttg

4560

ccgccagaac acaggtaagt gccgtgtgtg gttcccgcgg gcctggcctc tttacgggtt

4620

atggcccttg cgtgccttga attacttcca cctggctgca gtacgtgatt cttgatcccg

4680

agcttcgggt tggaagtggg tgggagagtt cgaggccttg cgcttaagga gccccttcgc

4740

ctcgtgcttg agttgaggcc tggcctgggc gctggggccg ccgcgtgcga atctggtggc

4800

accttcgcgc ctgtctcgct gctttcgata agtctctagc catttaaaat ttttgatgac

4860

ctgctgcgac gctttttttc tggcaagata gtcttgtaaa tgcgggccaa gatctgcaca

4920

ctggtatttc ggtttttggg gccgcgggcg gcgacggggc ccgtgcgtcc cagcgcacat

4980

gttcggcgag gcggggcctg cgagcgcggc caccgagaat cggacggggg tagtctcaag

5040

ctggccggcc tgctctggtg cctggtctcg cgccgccgtg tatcgccccg ccctgggcgg

5100

caaggctggc ccggtcggca ccagttgcgt gagcggaaag atggccgctt cccggccctg

5160

ctgcagggag ctcaaaatgg aggacgcggc gctcgggaga gcgggcgggt gagtcaccca

5220

cacaaaggaa aagggccttt ccgtcctcag ccgtcgcttc atgtgactcc acggagtacc

5280

gggcgccgtc caggcacctc gattagttct cgagcttttg gagtacgtcg tctttaggtt

5340

ggggggaggg gttttatgcg atggagtttc cccacactga gtgggtggag actgaagtta

5400

ggccagcttg gcacttgatg taattctcct tggaatttgc cctttttgag tttggatctt

5460

ggttcattct caagcctcag acagtggttc aaagtttttt tcttccatt caggtgtcgt

5520

gagtttaaac cgcagccacc atgcagatcg agctgtctac ctgcttcttc ctgtgcctgc

5580

tgcggttctg cttcagcgcc accagaagat attacctggg cgccgtggaa ctgagctggg

5640

actacatgca gtctgacctg ggagagctgc ccgtggacgc tagatttcct ccaagagtgc

5700

ccaagagctt ccccttcaac acctccgtgg tgtacaagaa aaccctgttc gtggaattca

5760

ccgaccacct gttcaatatc gccaagcctc ggcctccttg gatgggactg ctgggaccta

5820

caattcaggc cgaggtgtac gacaccgtgg tcatcaccct gaagaacatg gccagccatc

5880

ctgtgtctct gcacgccgtg ggagtgtctt attggaaggc ttctgagggc gccgagtacg

5940

acgatcagac aagccagaga gagaaagagg acgacaaggt tttccctggc ggcagccaca

6000

cctatgtctg gcaggtcctg aaagaaaacg gccctatggc ctccgatcct ctgtgcctga

6060

catacagcta cctgagccac gtggacctgg tcaaggacct gaattctggc ctgatcggag

6120

ccctgctcgt gtgtagagaa ggcagcctgg ccaaagagaa aacccagaca ctgcacaagt

6180

tcatcctgct gttcgccgtg ttcgacgagg gcaagagctg gcacagcgag acaaagaaca

6240

gcctgatgca ggacagggat gccgcctctg ctagagcttg gcctaagatg cacaccgtga

6300

acggctacgt gaacagaagc ctgcctggac tgatcggctg cccagaaag tccgtgtact

6360

ggcacgtgat cggcatgggc acaacacctg aggtgcacag catctttctg gaaggccaca

6420

ccttcctcgt gcggaaccac agacaggcca gcctggaaat cagccctatc accttcctga

6480

ccgctcagac cctgctgatg gatctgggcc agtttctgct gttctgccac atcagctccc

6540

accagcacga tggcatggaa gcctacgtga aggtggacag ctgccccgaa gaaccccagc

6600

tgcggatgaa gaacaacgag gaagccgagg actacgacga cgacctgacc gactctgaga

6660

tggacgtcgt cagattcgac gacgataaca gccccagctt catccagatc agaagcgtgg

6720

ccaagaagca ccccaagacc tgggtgcact atatcgccgc cgaggaagag gactgggatt

6780

acgctcctct ggtgctggcc cctgacgaca gaagctacaa gagccagtac ctgaacaacg

6840

gccctcagcg gatcggccgg aagtataaga aagtgcggtt catggcctac accgacgaga

6900

cattcaagac cagagaggcc atccagcacg agagcggaat tctgggccct ctgctgtatg

6960

gcgaagtggg cgatacactg ctgatcatct tcaagaacca ggccagcaga ccctacaaca

7020

tctaccctca cggcatcacc gatgtgcggc ccctgtattc tagaaggctg cccaagggcg

7080

tgaagcacct gaaggacttc cctatcctgc ctggcgagat tttcaagtac aagtggaccg

7140

tgaccgtgga agatggcccc accaagagcg accctagatg tctgacacgg tactacagca

7200

gcttcgtgaa catggaacgc gacctggcca gcggcctgat tggacctctg ctgatctgct

7260

acaaagaaag cgtggaccag cggggcaacc agatcatgag cgacaagcgg aacgtgatcc

7320

tgtttagcgt gttcgatgag aaccggtcct ggtatctgac cgagaacatc cagcggtttc

7380

tgcccaatcc tgccggggtg caactggaag atcctgagtt ccaggcaagc aacatcatgc

7440

actccatcaa tggctatgtg ttcgacagcc tgcagctgag cgtgtgcctg cacgaagtgg

7500

cctactggta catcctgagc attggcgccc agaccgactt cctgtccgtg ttctttagcg

7560

gctacacctt caagcacaag atggtgtacg aggataccct gacactgttc ccattcagcg

7620

gcgagacagt gttcatgagc atggaaaacc ccggcctgtg gattctgggc tgtcacaaca

7680

gcgacttccg gaacagaggc atgacagccc tgctgaaggt gtccagctgc gacaagaaca

7740

ccggcgacta ctacgaggac agctatgagg acatcagcgc ctacctgctg agcaagaaca

7800

atgccatcga gcccagaagc ttcagccaga atagcagaca cccctccacc agacagaagc

7860

agttcaacgc cacaacaatc cccgagaacg acatcgagaa aaccgatcct tggtttgccc

7920

acagaacccc tatgcctaag atccagaacg tgtcctccag cgatctgctg atgctcctga

7980

gacagagccc tacacctcac ggactgagcc tgtccgatct gcaagaggcc aaatacgaaa

8040

ccttcagcga cgacccttct cctggcgcca tcgacagcaa caatagcctg agcgagatga

8100

cccacttcag accacagctg caccacagcg gcgacatggt gtttacacct gagagcggcc

8160

tccagctgag actgaatgag aagctgggaa ccaccgccgc caccgagctg aagaaactgg

8220

acttcaaggt gtcctctacc agcaacaacc tgatcagcac aatcccctcc gacaacctgg

8280

ctgccggcac cgacaacaca tcttctctgg gcccacctag catgcccgtg cactacgata

8340

gccagctgga taccacactg ttcggcaaga agtctagccc tctgacagag tctggcggcc

8400

ctctgtctct gagcgaggaa aacaacgaca gcaagctgcc tcctgtgctg aagcggcacc

8460

agcgggaaat caccagaacc acactgcaga gcgaccaaga ggaaatcgat tacgacgaca

8520

ccatcagcgt cgagatgaag aaagaagatt tcgacatcta cgacgaggac gagaatcaga

8580

gccccagatc ctttcagaaa aagacccggc actacttcat tgccgccgtc gagagactgt

8640

gggactacgg catgtctagc agccctcacg tgctgagaaa tagagcccag agcggcagcg

8700

tgccccagtt caagaaagtg gtgttccaag agttcaccga cggcagcttc acccagccac

8760

tgtatagagg cgagctgaac gagcatctgg gcctgctggg cccttatatc agagccgaag

8820

tggaagataa catcatggtc accttccgga atcaggctag ccggccttac agcttctaca

8880

gctccctgat ctcctacgaa gaggaccaga gacagggcgc tgagccccgg aagaatttcg

8940

tgaagcccaa cgagactaag acctactttt ggaaggtgca gcaccacatg gcccctacaa

9000

aggacgagtt cgactgcaaa gcctgggcct acttctccga tgtggatctg gaaaaggacg

9060

tgcacagcgg gctcatcgga ccactgcttg tgtgccacac caacacactg aaccccgctc

9120

acggcagaca agtgacagtg caagagttcg ccctgttctt caccatcttc gacgaaacaa

9180

agagctggta cttcaccgag aatatggaac ggaactgcag ggccccttgc aacatccaga

9240

tggaagatcc caccttcaaa gagaactacc ggttccacgc catcaacggc tacatcatgg

9300

acacactgcc cggcctggtt atggcccagg atcagagaat ccggtggtat ctgctgtcca

9360

tgggctccaa cgagaatatc cacagcatcc acttcagcgg ccacgtgttc accgtgcgga

9420

aaaaagaaga gtacaaaatg gccctgtaca atctgtaccc tggggtgttc gaaaccgtgg

9480

aaatgctgcc ttccaaggcc ggcatttgga gagtggaatg tctgattgga gagcacctcc

9540

acgccggaat gagcaccctg tttctggtgt actccaacaa gtgtcagacc cctctcggca

9600

tggcctctgg acacatcaga gacttccaga tcaccgcctc tggccagtac ggacagtggg

9660

ctcctaaact ggctcggctg cactactccg gcagcatcaa tgcctggtcc accaaagagc

9720

ccttcagctg gatcaaggtg gacctgctgg ctcccatgat catccacgga atcaagaccc

9780

agggcgcaag acagaagttc agcagcctgt acatcagcca gttcatcatc atgtacagcc

9840

tggacggaaa gaagtggcag acctaccggg gcaatagcac cggcacactc atggtgttct

9900

tcggcaacgt ggactccagc ggcattaagc acaacatctt caaccctcca atcattgccc

9960

ggtacatccg gctgcacccc acaactaca gcatccggtc taccctgaga atggaactga

10020

tgggctgcga cctgaacagc tgctctatgc ccctcggaat ggaaagcaag gccatcagcg

10080

acgcccagat cacagccagc agctacttca ccaacatgtt cgccacttgg agcccctcca

10140

aggctagact gcatctgcag ggcagaagca acgcttggag gccccaagtg aacaacccca

10200

aagagtggct gcaggttgac tttcaaaaga ccatgaaagt gaccggcgtg accacacagg

10260

gcgtcaagtc tctgctgacc tctatgtacg tgaaagagtt cctgattagc agcagccagg

10320

acggccacca gtggaccctg tttttccaga acggcaaagt gaaagtgttc cagggcaatc

10380

aggacagctt cacacccgtg gtcaattctc tggaccctcc actgctgacc agatacctgc

10440

ggattcaccc tcagtcttgg gtgcaccaga tcgctctgcg gatggaagtg ctgggctgtg

10500

aagctcagga cctctactag ttaattaaga gcatcttacc gccatttatt cccatatttg

10560

ttctgttttt cttgatttgg gtatacattt aaatgttaat aaaacaaaat ggtggggcaa

10620

tcatttacat ttttagggat atgtaattac tagttcaggt gtattgccac aagacaaaca

10680

tgttaagaaa ctttcccgtt atttacgctc tgttcctgtt aatcaacctc tggattacaa

10740

aatttgtgaa agattgactg atattcttaa ctatgttgct ccttttacgc tgtgtggata

10800

tgctgcttta tagcctctgt atctagctat tgcttcccgt acggctttcg ttttctcctc

10860

cttgtataaa tcctggttgc tgtctctttt agaggagttg tggcccgttg tccgtcaacg

10920

tggcgtggtg tgctctgtgt ttgctgacgc aacccccact ggctggggca ttgccaccac

10980

ctgtcaactc ctttctggga ctttcgcttt ccccctcccg atcgccacgg cagaactcat

11040

cgccgcctgc cttgcccgct gctggacagg ggctaggttg ctgggcactg ataattccgt

11100

ggtgttgtct gtgccttcta gttgccagcc atctgttgtt tgcccctccc ccgtgccttc

11160

cttgaccctg gaaggtgcca ctcccactgt cctttcctaa taaaatgagg aaattgcatc

11220

gcattgtctg agtaggtgtc attctattct ggggggtggg gtggggcagg acagcaaggg

11280

ggaggattgg gaagacaata gcaggcatgc tggggatgcg gtgggctcta tggctctaga

11340

gcatggctac gtagataagt agcatggcgg gttaatcatt aactacacct gcaggaggaa

11400

cccctagtga tggagttggc cactccctct ctgcgcgctc gctcgctcac tgaggccggg

11460

cgaccaaagg tcgcccgacg cccgggcggc ctcagtgagc gagcgagcgc gcagctgcct

11520

gcaggggcgc gcctcgaggc atgcggtacc aagcttgtcg agaagtacta gaggatcata

11580

atcagccata ccacatttgt agaggtttta cttgctttaa aaaacctccc acacctcccc

11640

ctgaacctga aacataaaat gaatgcaatt gttgttgtta acttgtttat tgcagcttat

11700

aatggttaca aataaagcaa tagcatcaca aatttcacaa ataaagcatt tttttcactg

11760

cattctagtt gtggtttgtc caaactcatc aatgtatctt atcatgtctg gatctgatca

11820

ctgatatcgc ctaggagatc cgaaccagat aagtgaaatc tagttccaaa ctattttgtc

11880

atttttaatt ttcgtattag cttacgacgc tacacccagt tcccatctat tttgtcactc

11940

ttccctaaat aatccttaaa aactccattt ccacccctcc cagttcccaa ctattttgtc

12000

cgcccacagc ggggcatttt tcttcctgtt atgtttttaa tcaaacatcc tgccaactcc

12060

atgtgacaaa ccgtcatctt cggctacttt ttctctgtca cagaatgaaa atttttctgt

12120

catctcttcg ttattaatgt ttgtaattga ctgaatatca acgcttattt gcagcctgaa

12180

tggcgaatgg

12190

<210> 200

<211> 12165

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 200

aaagtagccg aagatgacgg tttgtcacat ggagttggca ggatgtttga ttaaaaacat

60

aacaggaaga aaaatgcccc gctgtgggcg gacaaaatag ttgggaactg ggaggggtgg

120

aaatggagtt tttaaggatt atttagggaa gagtgacaaa atagatggga actgggtgta

180

gcgtcgtaag ctaatacgaa aattaaaaat gacaaaatag tttggaacta gatttcactt

240

atctggttcg gatctcctag gcctgcaggc agctgcgcgc tcgctcgctc actgaggccg

300

cccgggcaaa gcccgggcgt cgggcgacct ttggtcgccc ggcctcagtg agcgagcgag

360

cgcgcagaga gggagtggcc aactccatca ctaggggttc cttgtagtta atgattaacc

420

cgccatgcta cttatcgcgg ccgctcaata ttggccatta gccatattat tcattggtta

480

tatagcataa atcaatattg gctattggcc attgcatacg ttgtatctat atcataatat

540

gtacatttat attggctcat gtccaatatg accgccatgt tggcattgat tattgactag

600

ttattaatag taatcaatta cggggtcatt agttcatagc ccatatatgg agttccgcgt

660

tacataactt acggtaaatg gcccgcctgg ctgaccgccc aacgaccccc gcccattgac

720

gtcaataatg acgtatgttc ccatagtaac gccaataggg actttccatt gacgtcaatg

780

ggtggagtat ttacggtaaa ctgcccactt ggcagtacat caagtgtatc atatgccaag

840

tccgccccct attgacgtca atgacggtaa atggcccgcc tggcattatg cccagtacat

900

gaccttacgg gactttccta cttggcagta catctacgta ttagtcatcg ctattaccat

960

ggtcgaggtg agccccacgt tctgcttcac tctccccatc tcccccccct ccccaccccc

1020

aattttgtat ttatttattt tttaattatt ttgtgcagcg atgggggcgg gggggggggg

1080

ggggcgcgcg ccaggcgggg cggggcgggg cgaggggcgg ggcggggcga ggcggagagg

1140

tgcggcggca gccaatcaga gcggcgcgct ccgaaagttt ccttttatgg cgaggcggcg

1200

gcggcggcgg ccctataaaa agcgaagcgc gcggcgggcg ggagtcgctg cgacgctgcc

1260

ttcgccccgt gccccgctcc gccgccgcct cgcgccgccc gccccggctc tgactgaccg

1320

cgttactccc acaggtgagc gggcgggacg gcccttctcc tccgggctgt aattagcgct

1380

tggtttaatg acggcttgtt tcttttctgt ggctgcgtga aagccttgag gggctccggg

1440

agggcccttt gtgcgggggg gagcggctcg gggggtgcgt gcgtgtgtgt gtgcgtgggg

1500

agcgccgcgt gcggcccgcg ctgcccggcg gctgtgagcg ctgcgggcgc ggcgcggggc

1560

tttgtgcgct ccgcagtgtg cgcgagggga gcgcggccgg gggcggtgcc ccgcggtgcg

1620

gggggggctg cgaggggaac aaaggctgcg tgcggggtgt gtgcgtgggg gggtgagcag

1680

ggggtgtggg cgcggcggtc gggctgtaac ccccccctgc acccccctcc ccgagttgct

1740

gagcacggcc cggcttcggg tgcggggctc cgtacggggc gtggcgcggg gctcgccgtg

1800

ccgggcgggg ggtggcggca ggtggggggtg ccgggcgggg cggggccgcc tcgggccggg

1860

gagggctcgg gggaggggcg cggcggcccc cggagcgccg gcggctgtcg aggcgcggcg

1920

agccgcagcc attgcctttt atggtaatcg tgcgagaggg cgcagggact tcctttgtcc

1980

caaatctgtg cggagccgaa atctgggagg cgccgccgca ccccctctag cgggcgcggg

2040

gcgaagcggt gcggcgccgg caggaaggaa atgggcgggg agggccttcg tgcgtcgccg

2100

cgccgccgtc cccttctccc tctccagcct cggggctgtc cgcgggggga cggctgcctt

2160

tcggggggga cggggcaggg cggggttcgg cttctggcgt gtgaccggcg gctctagagc

2220

ctctgctaac catgttttag cctttcttct ttttcctaca gctcctgggc aacgtgctgg

2280

ttattgtgct gtctcatcat ttgtcgacag aattcctcga agatccgaag gggttcaagc

2340

ttggcattcc ggtactgttg gtaaagccag tttaaaccgc agccaccatg cagatcgagc

2400

tgtctacctg cttcttcctg tgcctgctgc ggttctgctt cagcgccacc agaagatatt

2460

acctgggcgc cgtggaactg agctgggact acatgcagtc tgacctggga gagctgcccg

2520

tggacgctag atttcctcca agagtgccca agagcttccc cttcaacacc tccgtggtgt

2580

acaagaaaac cctgttcgtg gaattcaccg accacctgtt caatatcgcc aagcctcggc

2640

ctccttggat gggactgctg ggacctacaa ttcaggccga ggtgtacgac accgtggtca

2700

tcaccctgaa gaacatggcc agccatcctg tgtctctgca cgccgtggga gtgtcttatt

2760

ggaaggcttc tgagggcgcc gagtacgacg atcagacaag cccagagag aaagaggacg

2820

acaaggtttt ccctggcggc agccacacct atgtctggca ggtcctgaaa gaaaacggcc

2880

ctatggcctc cgatcctctg tgcctgacat acagctacct gagccacgtg gacctggtca

2940

aggacctgaa ttctggcctg atcggagccc tgctcgtgtg tagagaaggc agcctggcca

3000

aagagaaaac cgagacactg cacaagttca tcctgctgtt cgccgtgttc gacgagggca

3060

agagctggca cagcgagaca aagaacagcc tgatgcagga cagggatgcc gcctctgcta

3120

gagcttggcc taagatgcac accgtgaacg gctacgtgaa cagaagcctg cctggactga

3180

tcggctgcca cagaaagtcc gtgtactggc acgtgatcgg catgggcaca acacctgagg

3240

tgcacagcat ctttctggaa ggccacacct tcctcgtgcg gaaccacaga caggccagcc

3300

tggaaatcag ccctatcacc ttcctgaccg ctcagaccct gctgatggat ctgggccagt

3360

ttctgctgtt ctgccacatc agctcccacc agcacgatgg catggaagcc tacgtgaagg

3420

tggacagctg ccccgaagaa ccccagctgc ggatgaagaa caacgaggaa gccgaggact

3480

acgacgacga cctgaccgac tctgagatgg acgtcgtcag attcgacgac gataacagcc

3540

ccagcttcat ccagatcaga agcgtggcca agaagcaccc caagacctgg gtgcactata

3600

tcgccgccga ggaagaggac tgggattacg ctcctctggt gctggcccct gacgacagaa

3660

gctacaagag ccagtacctg aacaacggcc ctcagcggat cggccggaag tataagaaag

3720

tgcggttcat ggcctacacc gacgagacat tcaagaccag agaggccatc cagcacgaga

3780

gcggaattct gggccctctg ctgtatggcg aagtgggcga tacactgctg atcatcttca

3840

agaaccaggc cagcagaccc tacaacatct accctcacgg catcaccgat gtgcggcccc

3900

tgtattctag aaggctgccc aagggcgtga agcacctgaa ggacttccct atcctgcctg

3960

gcgagatttt caagtacaag tggaccgtga ccgtggaaga tggccccacc aagagcgacc

4020

ctagatgtct gacacggtac tacagcagct tcgtgaacat ggaacgcgac ctggccagcg

4080

gcctgattgg acctctgctg atctgctaca aagaaagcgt ggaccagcgg ggcaaccaga

4140

tcatgagcga caagcggaac gtgatcctgt ttagcgtgtt cgatgagaac cggtcctggt

4200

atctgaccga gaacatccag cggtttctgc ccaatcctgc cggggtgcaa ctggaagatc

4260

ctgagttcca ggcaagcaac atcatgcact ccatcaatgg ctatgtgttc gacagcctgc

4320

agctgagcgt gtgcctgcac gaagtggcct actggtacat cctgagcatt ggcgcccaga

4380

ccgacttcct gtccgtgttc tttagcggct acaccttcaa gcacaagatg gtgtacgagg

4440

ataccctgac actgttccca ttcagcggcg agacagtgtt catgagcatg gaaaaccccg

4500

gcctgtggat tctgggctgt cacaacagcg acttccggaa cagaggcatg acagccctgc

4560

tgaaggtgtc cagctgcgac aagaacaccg gcgactacta cgaggacagc tatgaggaca

4620

tcagcgccta cctgctgagc aagaacaatg ccatcgagcc tcggagcttc agccagaatc

4680

ctcctgtgct gaagcggcac cagcgcgaga tcaccagaac aaccctgcag agcgaccaag

4740

aggaaatcga ttacgacgac accatcagcg tcgagatgaa gaaagaagat ttcgacatct

4800

acgacgagga cgagaatcag agccccagaa gctttcagaa aaagacccgg cactacttca

4860

ttgccgccgt cgagagactg tgggactacg gcatgtctag cagccctcac gtgctgagaa

4920

atagagccca gagcggcagc gtgccccagt tcaagaaagt ggtgttccaa gagttcaccg

4980

acggcagctt cacccagcca ctgtatagag gcgagctgaa cgagcatctg ggcctgctgg

5040

gcccttatat cagagccgaa gtggaagata acatcatggt caccttccgg aatcaggcta

5100

gccggcctta cagcttctac agctccctga tcagctacga agaggaccag agacaggcg

5160

ctgagcccag aaagaacttc gtgaagccca acgagactaa gacctacttt tggaaggtgc

5220

agcaccacat ggcccctaca aaggacgagt tcgactgcaa agcctgggcc tacttctccg

5280

atgtggatct ggaaaaggac gtgcacagcg ggctcatcgg accactgctt gtgtgccaca

5340

ccaacacact gaaccccgct cacggcagac aagtgacagt gcaagagttc gccctgttct

5400

tcaccatctt cgacgaaaca aagagctggt acttcaccga gaatatggaa cggaactgca

5460

gagccccttg caacatccag atggaagatc ccaccttcaa agagaactac cggttccacg

5520

ccatcaacgg ctacatcatg gacacactgc ccggcctggt tatggcccag gatcagagaa

5580

tccggtggta tctgctgtcc atgggctcca acgagaatat ccacagcatc cacttcagcg

5640

gccacgtgtt caccgtgcgg aaaaaagaag agtacaaaat ggccctgtac aatctgtacc

5700

ctggggtgtt cgaaaccgtg gaaatgctgc cttccaaggc cggcatttgg agagtggaat

5760

gtctgattgg agagcacctc cacgccggaa tgagcaccct gtttctggtg tacagcaaca

5820

agtgtcagac ccctctcggc atggcctctg gacacatcag agacttccag atcaccgcct

5880

ctggccagta cggacagtgg gctcctaaac tggctcggct gcactacagc ggcagcatca

5940

atgcctggtc caccaaagag cccttcagct ggatcaaggt ggacctgctg gctcccatga

6000

tcatccacgg aatcaagacc cagggcgcca gacagaagtt cagcagcctg tacatcagcc

6060

agttcatcat catgtacagc ctggacggca agaagtggca gacctacaga ggcaacagca

6120

ccggcacact catggtgttc ttcggcaacg tggactccag cggcattaag cacaacatct

6180

tcaaccctcc aatcattgcc cggtacatcc ggctgcaccc cacacactac agcatccggt

6240

ctaccctgag aatggaactg atgggctgcg acctgaacag ctgctctatg cccctcggaa

6300

tggaaagcaa ggccatcagc gacgcccaga tcacagccag cagctacttc accaacatgt

6360

tcgccacttg gagcccctcc aaggctagac tgcatctgca gggcagaagc aacgcttgga

6420

ggccccaagt gaacaacccc aaagagtggc tgcaggttga ctttcaaaag accatgaaag

6480

tgaccggcgt gaccacacag ggcgtcaagt ctctgctgac ctctatgtac gtgaaagagt

6540

tcctgatctc cagcagccag gacggccatc agtggaccct gtttttccag aacggcaaag

6600

tgaaagtgtt cccaggcaat caggacagct tcacacccgt ggtcaattct ctggaccctc

6660

cactgctgac cagatacctg cggattcacc ctcagtcttg ggtgcaccag atcgctctgc

6720

ggatggaagt gctgggctgt gaagctcagg acctctacta gttaattaag agcatcttac

6780

cgccatttat tcccatattt gttctgtttt tcttgatttg ggtatacatt taaatgttaa

6840

taaaacaaaa tggtggggca atcatttaca tttttaggga tatgtaatta ctagttcagg

6900

tgtattgcca caagacaaac atgttaagaa actttcccgt tatttacgct ctgttcctgt

6960

taatcaacct ctggattaca aaatttgtga aagattgact gatattctta actatgttgc

7020

tccttttacg ctgtgtggat atgctgcttt atagcctctg tatctagcta ttgcttcccg

7080

tacggctttc gttttctcct ccttgtataa atcctggttg ctgtctcttt tagaggagtt

7140

gtggcccgtt gtccgtcaac gtggcgtggt gtgctctgtg tttgctgacg caacccccac

7200

tggctggggc attgccacca cctgtcaact cctttctggg actttcgctt tccccctccc

7260

gatcgccacg gcagaactca tcgccgcctg ccttgcccgc tgctggacag gggctaggtt

7320

gctgggcact gataattccg tggtgttgtc atcgattcca taaagtagga aacactacac

7380

gattccataa agtaggaaac actacatcac tccataaagt aggaaacact acagttaact

7440

gtgccttcta gttgccagcc atctgttgtt tgcccctccc ccgtgccttc cttgaccctg

7500

gaaggtgcca ctcccactgt cctttcctaa taaaatgagg aaattgcatc gcattgtctg

7560

agtaggtgtc attctattct ggggggtggg gtggggcagg acagcaaggg ggaggattgg

7620

gaagacaata gcaggcatgc tggggatgcg gtgggctcta tggcggcgcg ccgcatggct

7680

acgtagataa gtagcatggc gggttaatca ttaactacac ctgcaggagg aacccctagt

7740

gatggagttg gccactccct ctctgcgcgc tcgctcgctc actgaggccg ggcgaccaaa

7800

ggtcgcccga cgcccgggcg gcctcagtga gcgagcgagc gcgcagctgc ctgcaggtcg

7860

acgctagcag ctgatgcata gcatgcggta ccgggagatg ggggaggcta actgaaacac

7920

ggaagggagac aataccggaa ggaacccgcg ctatgacggc aataaaaaga cagaataaaa

7980

cgcacgggtg ttgggtcgtt tgttcataaa cgcggggttc ggtcccaggg ctggcactct

8040

gtcgataccc caccgagacc ccattgggac caatacgccc gcgtttcttc cttttcccca

8100

ccccaacccc caagttcggg tgaaggccca gggctcgcag ccaacgtcgg ggcggcaagc

8160

cctgccatag ccactacggg tacgtaggcc aaccactaga actatagcta gagtcctggg

8220

cgaacaaacg atgctcgcct tccagaaaac cgaggatgcg aaccacttca tccggggtca

8280

gcaccaccgg caagcgccgc gacggccgag gtctaccgat ctcctgaagc cagggcagat

8340

ccgtgcacag caccttgccg tagaagaaca gcaaggccgc caatgcctga cgatgcgtgg

8400

agaccgaaac cttgcgctcg ttcgccagcc aggacagaaa tgcctcgact tcgctgctgc

8460

ccaaggttgc cgggtgacgc acaccgtgga aacggatgaa ggcacgaacc cagttgacat

8520

aagcctgttc ggttcgtaaa ctgtaatgca agtagcgtat gcgctcacgc aactggtcca

8580

gaaccttgac cgaacgcagc ggtggtaacg gcgcagtggc ggttttcatg gcttgttatg

8640

actgtttttt tgtacagtct atgcctcggg catccaagca gcaagcgcgt tacgccgtgg

8700

gtcgatgttt gatgttatgg agcagcaacg atgttacgca gcagcaacga tgttacgcag

8760

cagggcagtc gccctaaaac aaagttaggt ggctcaagta tgggcatcat tcgcacatgt

8820

aggctcggcc ctgaccaagt caaatccatg cgggctgctc ttgatctttt cggtcgtgag

8880

ttcggagacg tagccaccta ctcccaacat cagccggact ccgattacct cgggaacttg

8940

ctccgtagta agacattcat cgcgcttgct gccttcgacc aagaagcggt tgttggcgct

9000

ctcgcggctt acgttctgcc caggtttgag cagccgcgta gtgagatcta tatctatgat

9060

ctcgcagtct ccggcgagca ccggaggcag ggcattgcca ccgcgctcat caatctcctc

9120

aagcatgagg ccaacgcgct tggtgcttat gtgatctacg tgcaagcaga ttacggtgac

9180

gatcccgcag tggctctcta tacaaagttg ggcatacggg aagaagtgat gcactttgat

9240

atcgacccaa gtaccgccac ctaacaattc gttcaagccg agatcggctt cccggccgcg

9300

gagttgttcg gtaaattgtc acaacgccgc gaatatagtc tttaccatgc ccttggccac

9360

gcccctcttt aatacgacgg gcaatttgca cttcagaaaa tgaagagttt gctttagcca

9420

taacaaaagt ccagtatgct ttttcacagc ataactggac tgatttcagt ttacaactat

9480

tctgtctagt ttaagacttt attgtcatag tttagatcta ttttgttcag tttaagactt

9540

tattgtccgc ccacacccgc ttacgcaggg catccattta ttactcaacc gtaaccgatt

9600

ttgccaggtt acgcggctgg tctgcggtgt gaaataccgc acagatgcgt aaggagaaaa

9660

taccgcatca ggcgctcttc cgcttcctcg ctcactgact cgctgcgctc ggtcgttcgg

9720

ctgcggcgag cggtatcagc tcactcaaag gcggtaatac ggttatccac agaatcaggg

9780

gataacgcag gaaagaacat gtgagcaaaa ggccagcaaa aggccaggaa ccgtaaaaag

9840

gccgcgttgc tggcgttttt ccataggctc cgcccccctg acgagcatca caaaaatcga

9900

cgctcaagtc agaggtggcg aaacccgaca ggactataaa gataccaggc gtttccccct

9960

ggaagctccc tcgtgcgctc tcctgttccg accctgccgc ttaccggata cctgtccgcc

10020

tttctccctt cgggaagcgt ggcgctttct caatgctcac gctgtaggta tctcagttcg

10080

gtgtaggtcg ttcgctccaa gctgggctgt gtgcacgaac cccccgttca gcccgaccgc

10140

tgcgccttat ccggtaacta tcgtcttgag tccaacccgg taagacacga cttatcgcca

10200

ctggcagcag ccactggtaa caggattagc agagcgaggt atgtaggcgg tgctacagag

10260

ttcttgaagt ggtggcctaa ctacggctac actagaagga cagtatttgg tatctgcgct

10320

ctgctgaagc cagttacctt cggaaaaaga gttggtagct cttgatccgg caaacaaacc

10380

accgctggta gcggtggttt ttttgtttgc aagcagcaga ttacgcgcag aaaaaaagga

10440

tctcaagaag atcctttgat cttttctacg gggtctgacg ctcagtggaa cgaaaactca

10500

cgttaaggga ttttggtcat gagattatca aaaaggatct tcacctagat ccttttaaat

10560

taaaaatgaa gttttaaatc aatctaaagt atatatgagt aaacttggtc tgacagttac

10620

caatgcttaa tcagtgaggc acctatctca gcgatctgtc tatttcgttc atccatagtt

10680

gcctgactcc ccgtcgtgta gataactacg atacgggagg gcttaccatc tggccccagt

10740

gctgcaatga taccgcgaga cccacgctca ccggctccag atttatcagc aataaaccag

10800

ccagccggaa gggccgagcg cagaagtggt cctgcaactt tatccgcctc catccagtct

10860

attaattgtt gccgggaagc tagagtaagt agttcgccag ttaatagttt gcgcaacgtt

10920

gttgccattg ctacaggcat cgtggtgtca cgctcgtcgt ttggtatggc ttcattcagc

10980

tccggttccc aacgatcaag gcgagttaca tgatccccca tgttgtgcaa aaaagcggtt

11040

agctccttcg gtcctccgat cgttgtcaga agtaagttgg ccgcagtgtt atcactcatg

11100

gttatggcag cactgcataa ttctcttact gtcatgccat ccgtaagatg cttttctgtg

11160

actggtgagt actcaaccaa gtcattctga gaatagtgta tgcggcgacc gagttgctct

11220

tgcccggcgt caatacggga taataccgcg ccacatagca gaactttaaa agtgctcatc

11280

attggaaaac gttcttcggg gcgaaaactc tcaaggatct taccgctgtt gagatccagt

11340

tcgatgtaac ccactcgtgc acccaactga tcttcagcat cttttacttt caccagcgtt

11400

tctgggtgag caaaaacagg aaggcaaaat gccgcaaaaa agggaataag ggcgacacgg

11460

aaatgttgaa tactcatact cttccttttt caatattatt gaagcattta tcagggttat

11520

tgtctcatga gcggatacat atttgaatgt atttagaaaa ataaacaaat aggggttccg

11580

cgcacatttc cccgaaaagt gccacctgaa attgtaaacg ttaatatttt gttaaaattc

11640

gcgttaaatt tttgttaaat cagctcattt tttaaccaat aggccgaaat cggcaaaatc

11700

ccttataaat caaaagaata gaccgagata gggttgagtg ttgttccagt ttggaacaag

11760

agtccactat taaagaacgt ggactccaac gtcaaagggc gaaaaaccgt ctatcagggc

11820

gatggcccac tacgtgaacc atcaccctaa tcaagttttt tggggtcgag gtgccgtaaa

11880

gcactaaatc ggaaccctaa agggagcccc cgatttagag cttgacgggg aaagccggcg

11940

aacgtggcga gaaaggaagg gaagaaagcg aaaggagcgg gcgctagggc gctggcaagt

12000

gtagcggtca cgctgcgcgt aaccaccaca cccgccgcgc ttaatgcgcc gctacaggc

12060

gcgtcccatt cgccattcag gctgcaaata agcgttgata ttcagtcaat tacaaacatt

12120

aataacgaag agatgacaga aaaattttca ttctgtgaca gagaa

12165

<210> 201

<211> 11512

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 201

aaagtagccg aagatgacgg tttgtcacat ggagttggca ggatgtttga ttaaaaacat

60

aacaggaaga aaaatgcccc gctgtgggcg gacaaaatag ttgggaactg ggaggggtgg

120

aaatggagtt tttaaggatt atttagggaa gagtgacaaa atagatggga actgggtgta

180

gcgtcgtaag ctaatacgaa aattaaaaat gacaaaatag tttggaacta gatttcactt

240

atctggttcg gatctcctag gcctgcaggc agctgcgcgc tcgctcgctc actgaggccg

300

cccgggcaaa gcccgggcgt cgggcgacct ttggtcgccc ggcctcagtg agcgagcgag

360

cgcgcagaga gggagtggcc aactccatca ctaggggttc cttgtagtta atgattaacc

420

cgccatgcta cttatcgcgg ccgcaggctc agaggcacac aggagtttct gggctcaccc

480

tgcccccttc caacccctca gttcccatcc tccagcagct gtttgtgtgc tgcctctgaa

540

gtccacactg aacaaacttc agcctactca tgtccctaaa atgggcaaac attgcaagca

600

gcaaacagca aacacacagc cctccctgcc tgctgacctt ggagctgggg cagaggtcag

660

agacctctct gggcccatgc cacctccaac atccactcga ccccttggaa tttcggtgga

720

gaggagcaga ggttgtcctg gcgtggttta ggtagtgtga gagggtccgg gttcaaaacc

780

acttgctggg tggggagtcg tcagtaagtg gctatgcccc gaccccgaag cctgtttccc

840

catctgtaca atggaaatga taaagacgcc catctgatag ggtttttgtg gcaaataaac

900

atttggtttt tttgttttgt tttgttttgt tttttgagat ggaggtttgc tctgtcgccc

960

aggctggagt gcagtgacac aatctcatct caccacaacc ttcccctgcc tcagcctccc

1020

aagtagctgg gattacaagc atgtgccacc acacctggct aattttctat ttttagtaga

1080

gacgggtttc tccatgttgg tcagcctcag cctcccaagt aactgggatt acaggcctgt

1140

gccaccacac ccggctaatt ttttctattt ttgacaggga cggggtttca ccatgttggt

1200

caggctggtc tagaggtacc ggatcttgct accagtggaa cagccactaa ggattctgca

1260

gtgagagcag agggccagct aagtggtact ctcccagaga ctgtctgact cacgccaccc

1320

cctccacctt ggacacagga cgctgtggtt tctgagccag gtacaatgac tcctttcggt

1380

aagtgcagtg gaagctgtac actgcccagg caaagcgtcc gggcagcgta ggcgggcgac

1440

tcagatccca gccagtggac ttagcccctg tttgctcctc cgataactgg ggtgaccttg

1500

gttaatattc accagcagcc tcccccgttg cccctctgga tccactgctt aaatacggac

1560

gaggacaggg ccctgtctcc tcagcttcag gcaccaccac tgacctggga cagtgaatcc

1620

ggactctaag gtaaatataa aatttttaag tgtataatgt gttaaactac tgattctaat

1680

tgtttctctc ttttagattc caacctttgg aactgagttt aaaccgcagc caccatgcag

1740

atcgagctgt ctacctgctt cttcctgtgc ctgctgcggt tctgcttcag cgccaccaga

1800

agatattacc tgggcgccgt ggaactgagc tgggactaca tgcagtctga cctggggagag

1860

ctgcccgtgg acgctagatt tcctccaaga gtgcccaaga gcttcccctt caacacctcc

1920

gtggtgtaca agaaaaccct gttcgtggaa ttcaccgacc acctgttcaa tatcgccaag

1980

cctcggcctc cttggatggg actgctggga cctacaattc aggccgaggt gtacgacacc

2040

gtggtcatca ccctgaagaa catggccagc catcctgtgt ctctgcacgc cgtgggagtg

2100

tcttattgga aggcttctga gggcgccgag tacgacgatc agacaagcca gagagagaaa

2160

gaggacgaca aggttttccc tggcggcagc cacacctatg tctggcaggt cctgaaagaa

2220

aacggcccta tggcctccga tcctctgtgc ctgacataca gctacctgag ccacgtggac

2280

ctggtcaagg acctgaattc tggcctgatc ggagccctgc tcgtgtgtag agaaggcagc

2340

ctggccaaag agaaaaccca gacactgcac aagttcatcc tgctgttcgc cgtgttcgac

2400

gagggcaaga gctggcacag cgagacaaag aacagcctga tgcaggacag ggatgccgcc

2460

tctgctagag cttggcctaa gatgcacacc gtgaacggct acgtgaacag aagcctgcct

2520

ggactgatcg gctgccacag aaagtccgtg tactggcacg tgatcggcat gggcacaaca

2580

cctgaggtgc acagcatctt tctggaaggc cacaccttcc tcgtgcggaa ccacagacag

2640

gccagcctgg aaatcagccc tatcaccttc ctgaccgctc agaccctgct gatggatctg

2700

ggccagtttc tgctgttctg ccacatcagc tcccaccagc acgatggcat ggaagcctac

2760

gtgaaggtgg acagctgccc cgaagaaccc cagctgcgga tgaagaacaa cgaggaagcc

2820

gaggactacg acgacgacct gaccgactct gagatggacg tcgtcagatt cgacgacgat

2880

aacagcccca gcttcatcca gatcagaagc gtggccaaga agcaccccaa gacctgggtg

2940

cactatatcg ccgccgagga agaggactgg gattacgctc ctctggtgct ggcccctgac

3000

gacagaagct acaagagcca gtacctgaac aacggccctc agcggatcgg ccggaagtat

3060

aagaaagtgc ggttcatggc ctacaccgac gagacattca agaccagaga ggccatccag

3120

cacgagagcg gaattctggg ccctctgctg tatggcgaag tgggcgatac actgctgatc

3180

atcttcaaga accaggccag cagaccctac aacatctacc ctcacggcat caccgatgtg

3240

cggcccctgt attctagaag gctgcccaag ggcgtgaagc acctgaagga cttccctatc

3300

ctgcctggcg agattttcaa gtacaagtgg accgtgaccg tggaagatgg ccccaccaag

3360

agcgacccta gatgtctgac acggtactac agcagcttcg tgaacatgga acgcgacctg

3420

gccagcggcc tgattggacc tctgctgatc tgctacaaag aaagcgtgga ccagcggggc

3480

aaccagatca tgagcgacaa gcggaacgtg atcctgttta gcgtgttcga tgagaaccgg

3540

tcctggtatc tgaccgagaa catccagcgg tttctgccca atcctgccgg ggtgcaactg

3600

gaagatcctg agttccaggc aagcaacatc atgcactcca tcaatggcta tgtgttcgac

3660

agcctgcagc tgagcgtgtg cctgcacgaa gtggcctact ggtacatcct gagcattggc

3720

gcccagaccg acttcctgtc cgtgttcttt agcggctaca ccttcaagca caagatggtg

3780

tacgaggata ccctgacact gttcccattc agcggcgaga cagtgttcat gagcatggaa

3840

aaccccggcc tgtggattct gggctgtcac aacagcgact tccggaacag aggcatgaca

3900

gccctgctga aggtgtccag ctgcgacaag aacaccggcg actactacga ggacagctat

3960

gaggacatca gcgcctacct gctgagcaag aacaatgcca tcgagcctcg gagcttcagc

4020

cagaatcctc ctgtgctgaa gcggcaccag cgcgagatca ccagaacaac cctgcagagc

4080

gaccaagagg aaatcgatta cgacgacacc atcagcgtcg agatgaagaa agaagatttc

4140

gacatctacg acgaggacga gaatcagagc cccagaagct ttcagaaaaa gacccggcac

4200

tacttcattg ccgccgtcga gagactgtgg gactacggca tgtctagcag ccctcacgtg

4260

ctgagaaata gagcccagag cggcagcgtg ccccagttca agaaagtggt gttccaagag

4320

ttcaccgacg gcagcttcac ccagccactg tatagaggcg agctgaacga gcatctgggc

4380

ctgctgggcc cttatatcag agccgaagtg gaagataaca tcatggtcac cttccggaat

4440

caggctagcc ggccttacag cttctacagc tccctgatca gctacgaaga ggaccagaga

4500

cagggcgctg agcccagaaa gaacttcgtg aagcccaacg agactaagac ctacttttgg

4560

aaggtgcagc accacatggc ccctacaaag gacgagttcg actgcaaagc ctgggcctac

4620

ttctccgatg tggatctgga aaaggacgtg cacagcgggc tcatcggacc actgcttgtg

4680

tgccacacca acacactgaa ccccgctcac ggcagacaag tgacagtgca agagttcgcc

4740

ctgttcttca ccatcttcga cgaaacaaag agctggtact tcaccgagaa tatggaacgg

4800

aactgcagag ccccttgcaa catccagatg gaagatccca ccttcaaaga gaactaccgg

4860

ttccacgcca tcaacggcta catcatggac acactgcccg gcctggttat ggcccaggat

4920

cagagaatcc ggtggtatct gctgtccatg ggctccaacg agaatatcca cagcatccac

4980

ttcagcggcc acgtgttcac cgtgcggaaa aaagaagagt acaaaatggc cctgtacaat

5040

ctgtaccctg gggtgttcga aaccgtggaa atgctgcctt ccaaggccgg catttggaga

5100

gtggaatgtc tgattggaga gcacctccac gccggaatga gcaccctgtt tctggtgtac

5160

agcaacaagt gtcagacccc tctcggcatg gcctctggac acatcagaga cttccagatc

5220

accgcctctg gccagtacgg acagtgggct cctaaactgg ctcggctgca ctacagcggc

5280

agcatcaatg cctggtccac caaagagccc ttcagctgga tcaaggtgga cctgctggct

5340

cccatgatca tccacggaat caagacccag ggcgccagac agaagttcag cagcctgtac

5400

atcagccagt tcatcatcat gtacagcctg gacggcaaga agtggcagac ctacagaggc

5460

aacagcaccg gcacactcat ggtgttcttc ggcaacgtgg actccagcgg cattaagcac

5520

aacatcttca accctccaat cattgcccgg tacatccggc tgcaccccac acactacagc

5580

atccggtcta ccctgagaat ggaactgatg ggctgcgacc tgaacagctg ctctatgccc

5640

ctcggaatgg aaagcaaggc catcagcgac gccgatca cagccagcag ctacttcacc

5700

aacatgttcg ccacttggag cccctccaag gctagactgc atctgcaggg cagaagcaac

5760

gcttggaggc cccaagtgaa caaccccaaa gagtggctgc aggttgactt tcaaaagacc

5820

atgaaagtga ccggcgtgac cacacagggc gtcaagtctc tgctgacctc tatgtacgtg

5880

aaagagttcc tgatctccag cagccaggac ggccatcagt ggaccctgtt tttccagaac

5940

ggcaaagtga aagtgttcca gggcaatcag gacagcttca cacccgtggt caattctctg

6000

gaccctccac tgctgaccag atacctgcgg attcaccctc agtcttgggt gcaccagatc

6060

gctctgcgga tggaagtgct gggctgtgaa gctcaggacc tctactagtt aattaagagc

6120

atcttaccgc catttattcc catatttgtt ctgtttttct tgatttgggt atacatttaa

6180

atgttaataa aacaaaatgg tggggcaatc atttacattt ttagggatat gtaattacta

6240

gttcaggtgt attgccacaa gacaaacatg ttaagaaact ttcccgttat ttacgctctg

6300

ttcctgttaa tcaacctctg gattacaaaa tttgtgaaag attgactgat attcttaact

6360

atgttgctcc ttttacgctg tgtggatatg ctgctttata gcctctgtat ctagctattg

6420

cttcccgtac ggctttcgtt ttctcctcct tgtataaatc ctggttgctg tctcttttag

6480

aggagttgtg gcccgttgtc cgtcaacgtg gcgtggtgtg ctctgtgttt gctgacgcaa

6540

cccccactgg ctggggcatt gccaccacct gtcaactcct ttctgggact ttcgctttcc

6600

ccctcccgat cgccacggca gaactcatcg ccgcctgcct tgcccgctgc tggacaggg

6660

ctaggttgct gggcactgat aattccgtgg tgttgtcatc gattccataa agtaggaaac

6720

actacacgat tccataaagt aggaaacact acatcactcc ataaagtagg aaacactaca

6780

gttaactgtg ccttctagtt gccagccatc tgttgtttgc ccctcccccg tgccttcctt

6840

gaccctggaa ggtgccactc ccactgtcct ttcctaataa aatgaggaaa ttgcatcgca

6900

ttgtctgagt aggtgtcatt ctattctggg gggtggggtg gggcaggaca gcaaggggga

6960

ggattgggaa gacaatagca ggcatgctgg ggatgcggtg ggctctatgg cggcgcgccg

7020

catggctacg tagataagta gcatggcggg ttaatcatta actacacctg caggaggaac

7080

ccctagtgat ggagttggcc actccctctc tgcgcgctcg ctcgctcact gaggccgggc

7140

gaccaaaggt cgcccgacgc ccgggcggcc tcagtgagcg agcgagcgcg cagctgcctg

7200

caggtcgacg ctagcagctg atgcatagca tgcggtaccg ggagatgggg gaggctaact

7260

gaaacacgga aggagacaat accggaagga acccgcgcta tgacggcaat aaaaagacag

7320

aataaaacgc acgggtgttg ggtcgtttgt tcataaacgc ggggttcggt cccagggctg

7380

gcactctgtc gataccccac cgagacccca ttgggaccaa tacgcccgcg tttcttcctt

7440

ttccccaccc caacccccaa gttcgggtga aggcccaggg ctcgcagcca acgtcggggc

7500

ggcaagccct gccatagcca ctacgggtac gtaggccaac cactagaact atagctagag

7560

tcctgggcga acaaacgatg ctcgccttcc agaaaaccga ggatgcgaac cacttcatcc

7620

ggggtcagca ccaccggcaa gcgccgcgac ggccgaggtc taccgatctc ctgaagccag

7680

ggcagatccg tgcacagcac cttgccgtag aagaacagca aggccgccaa tgcctgacga

7740

tgcgtggaga ccgaaacctt gcgctcgttc gccagccagg acagaaatgc ctcgacttcg

7800

ctgctgccca aggttgccgg gtgacgcaca ccgtggaaac ggatgaaggc acgaacccag

7860

ttgacataag cctgttcggt tcgtaaactg taatgcaagt agcgtatgcg ctcacgcaac

7920

tggtccagaa ccttgaccga acgcagcggt ggtaacggcg cagtggcggt tttcatggct

7980

tgttatgact gtttttttgt acagtctatg cctcgggcat ccaagcagca agcgcgttac

8040

gccgtgggtc gatgtttgat gttatggagc agcaacgatg ttacgcagca gcaacgatgt

8100

tacgcagcag ggcagtcgcc ctaaaacaaa gttaggtggc tcaagtatgg gcatcattcg

8160

cacatgtagg ctcggccctg accaagtcaa atccatgcgg gctgctcttg atcttttcgg

8220

tcgtgagttc ggagacgtag ccacctactc ccaacatcag ccggactccg attacctcgg

8280

gaacttgctc cgtagtaaga cattcatcgc gcttgctgcc ttcgaccaag aagcggttgt

8340

tggcgctctc gcggcttacg ttctgcccag gtttgagcag ccgcgtagtg agatctatat

8400

ctatgatctc gcagtctccg gcgagcaccg gaggcagggc attgccaccg cgctcatcaa

8460

tctcctcaag catgaggcca acgcgcttgg tgcttatgtg atctacgtgc aagcagatta

8520

cggtgacgat cccgcagtgg ctctctatac aaagttgggc atacgggaag aagtgatgca

8580

ctttgatatc gacccaagta ccgccaccta acaattcgtt caagccgaga tcggcttccc

8640

ggccgcggag ttgttcggta aattgtcaca acgccgcgaa tatagtcttt accatgccct

8700

tggccacgcc cctctttaat acgacgggca atttgcactt cagaaaatga agagtttgct

8760

ttagccataa caaaagtcca gtatgctttt tcacagcata actggactga tttcagttta

8820

caactattct gtctagttta agactttatt gtcatagttt agatctattt tgttcagttt

8880

aagactttat tgtccgccca cacccgctta cgcagggcat ccatttatta ctcaaccgta

8940

accgattttg ccaggttacg cggctggtct gcggtgtgaa ataccgcaca gatgcgtaag

9000

gagaaaatac cgcatcaggc gctcttccgc ttcctcgctc actgactcgc tgcgctcggt

9060

cgttcggctg cggcgagcgg tatcagctca ctcaaaggcg gtaatacggt tatccacaga

9120

atcaggggat aacgcaggaa agaacatgtg agcaaaaggc cagcaaaagg cccaggaaccg

9180

taaaaaggcc gcgttgctgg cgtttttcca taggctccgc ccccctgacg agcatcacaa

9240

aaatcgacgc tcaagtcaga ggtggcgaaa cccgacagga ctataaagat accaggcgtt

9300

tccccctgga agctccctcg tgcgctctcc tgttccgacc ctgccgctta ccggatacct

9360

gtccgccttt ctcccttcgg gaagcgtggc gctttctcaa tgctcacgct gtaggtatct

9420

cagttcggtg taggtcgttc gctccaagct gggctgtgtg cacgaacccc ccgttcagcc

9480

cgaccgctgc gccttatccg gtaactatcg tcttgagtcc aacccggtaa gacacgactt

9540

atcgccactg gcagcagcca ctggtaacag gattagcaga gcgaggtatg taggcggtgc

9600

tacagagttc ttgaagtggt ggcctaacta cggctacact agaaggacag tatttggtat

9660

ctgcgctctg ctgaagccag ttaccttcgg aaaaagagtt ggtagctctt gatccggcaa

9720

acaaaccacc gctggtagcg gtggtttttt tgtttgcaag cagcagatta cgcgcagaaa

9780

aaaaggatct caagaagatc ctttgatctt ttctacgggg tctgacgctc agtggaacga

9840

aaactcacgt taagggattt tggtcatgag attatcaaaa aggatcttca cctagatcct

9900

tttaaattaa aaatgaagtt ttaaatcaat ctaaagtata tatgagtaaa cttggtctga

9960

cagttaccaa tgcttaatca gtgaggcacc tatctcagcg atctgtctat ttcgttcatc

10020

catagttgcc tgactccccg tcgtgtagat aactacgata cgggagggct taccatctgg

10080

ccccagtgct gcaatgatac cgcgagaccc acgctcaccg gctccagatt tatcagcaat

10140

aaaccagcca gccggaaggg ccgagcgcag aagtggtcct gcaactttat ccgcctccat

10200

ccagtctatt aattgttgcc gggaagctag agtaagtagt tcgccagtta atagtttgcg

10260

caacgttgtt gccattgcta caggcatcgt ggtgtcacgc tcgtcgtttg gtatggcttc

10320

attcagctcc ggttcccaac gatcaaggcg agttacatga tcccccatgt tgtgcaaaaa

10380

agcggttagc tccttcggtc ctccgatcgt tgtcagaagt aagttggccg cagtgttatc

10440

actcatggtt atggcagcac tgcataattc tcttactgtc atgccatccg taagatgctt

10500

ttctgtgact ggtgagtact caaccaagtc attctgagaa tagtgtatgc ggcgaccgag

10560

ttgctcttgc ccggcgtcaa tacgggataa taccgcgcca catagcagaa ctttaaaagt

10620

gctcatcatt ggaaaacgtt cttcggggcg aaaactctca aggatcttac cgctgttgag

10680

atccagttcg atgtaaccca ctcgtgcacc caactgatct tcagcatctt ttactttcac

10740

cagcgtttct gggtgagcaa aaacaggaag gcaaaatgcc gcaaaaaagg gaataagggc

10800

gacacggaaa tgttgaatac tcatactctt cctttttcaa tattattgaa gcatttatca

10860

gggttattgt ctcatgagcg gatacatatt tgaatgtatt tagaaaaata aacaaatagg

10920

ggttccgcgc acatttcccc gaaaagtgcc acctgaaatt gtaaacgtta atattttgtt

10980

aaaattcgcg ttaaattttt gttaaatcag ctcatttttt aaccaatagg ccgaaatcgg

11040

caaaatccct tataaatcaa aagaatagac cgagataggg ttgagtgttg ttccagtttg

11100

gaacaagagt ccactattaa agaacgtgga ctccaacgtc aaagggcgaa aaaccgtcta

11160

tcagggcgat ggcccactac gtgaaccatc accctaatca agttttttgg ggtcgaggtg

11220

ccgtaaagca ctaaatcgga accctaaagg gagcccccga tttagagctt gacggggaaa

11280

gccggcgaac gtggcgagaa aggaagggaa gaaagcgaaa ggagcgggcg ctagggcgct

11340

ggcaagtgta gcggtcacgc tgcgcgtaac caccacaccc gccgcgctta atgcgccgct

11400

acagggcgcg tcccattcgc cattcaggct gcaaataagc gttgatattc agtcaattac

11460

aaacattaat aacgaagaga tgacagaaaa attttcattc tgtgacagag aa

11512

<210> 202

<211> 10563

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 202

aaagtagccg aagatgacgg tttgtcacat ggagttggca ggatgtttga ttaaaaacat

60

aacaggaaga aaaatgcccc gctgtgggcg gacaaaatag ttgggaactg ggaggggtgg

120

aaatggagtt tttaaggatt atttagggaa gagtgacaaa atagatggga actgggtgta

180

gcgtcgtaag ctaatacgaa aattaaaaat gacaaaatag tttggaacta gatttcactt

240

atctggttcg gatctcctag gcctgcaggc agctgcgcgc tcgctcgctc actgaggccg

300

cccgggcaaa gcccgggcgt cgggcgacct ttggtcgccc ggcctcagtg agcgagcgag

360

cgcgcagaga gggagtggcc aactccatca ctaggggttc cttgtagtta atgattaacc

420

cgccatgcta cttatcgcgg ccgccggggg aggctgctgg tgaatattaa ccaaggtcac

480

cccagttatc ggaggagcaa acaggggcta agtccacacg cgtggtaccg tctgtctgca

540

catttcgtag agcgagtgtt ccgatactct aatctcccta ggcaaggttc atatttgtgt

600

aggttactta ttctcctttt gttgactaag tcaataatca gaatcagcag gtttggagtc

660

agcttggcag ggatcagcag cctgggttgg aaggagggg tataaaagcc ccttcaccag

720

gagaagccgt cacacagatc cacaagctcc tgaagaggta agggtttaag ggatggttgg

780

ttggtggggt attaatgttt aattacctgg agcacctgcc tgaaatcact ttttttcagg

840

ttggtttaaa ccgcagccac catgcagatc gagctgtcta cctgcttctt cctgtgcctg

900

ctgcggttct gcttcagcgc caccagaaga tattacctgg gcgccgtgga actgagctgg

960

gactacatgc agtctgacct gggagagctg cccgtggacg ctagatttcc tccaagagtg

1020

cccaagagct tccccttcaa cacctccgtg gtgtacaaga aaaccctgtt cgtggaattc

1080

accgaccacc tgttcaatat cgccaagcct cggcctcctt ggatgggact gctgggacct

1140

acaattcagg ccgaggtgta cgacaccgtg gtcatcaccc tgaagaacat ggccagccat

1200

cctgtgtctc tgcacgccgt gggagtgtct tattggaagg cttctgaggg cgccgagtac

1260

gacgatcaga caagccagag agagaaagag gacgacaagg ttttccctgg cggcagccac

1320

acctatgtct ggcaggtcct gaaagaaaac ggccctatgg cctccgatcc tctgtgcctg

1380

acatacagct acctgagcca cgtggacctg gtcaaggacc tgaattctgg cctgatcgga

1440

gccctgctcg tgtgtagaga aggcagcctg gccaaagaga aaacccagac actgcacaag

1500

ttcatcctgc tgttcgccgt gttcgacgag ggcaagagct ggcacagcga gacaaagaac

1560

agcctgatgc aggacagga tgccgcctct gctagagctt ggcctaagat gcacaccgtg

1620

aacggctacg tgaacagaag cctgcctgga ctgatcggct gccacagaaa gtccgtgtac

1680

tggcacgtga tcggcatggg cacaacacct gaggtgcaca gcatctttct ggaaggccac

1740

accttcctcg tgcggaacca cagacaggcc agcctggaaa tcagccctat caccttcctg

1800

accgctcaga ccctgctgat ggatctgggc cagtttctgc tgttctgcca catcagctcc

1860

caccagcacg atggcatgga agcctacgtg aaggtggaca gctgccccga agaaccccag

1920

ctgcggatga agaacaacga ggaagccgag gactacgacg acgacctgac cgactctgag

1980

atggacgtcg tcagattcga cgacgataac agccccagct tcatccagat cagaagcgtg

2040

gccaagaagc accccaagac ctgggtgcac tatatcgccg ccgaggaaga ggactgggat

2100

tacgctcctc tggtgctggc ccctgacgac agaagctaca agagccagta cctgaacaac

2160

ggccctcagc ggatcggccg gaagtataag aaagtgcggt tcatggccta caccgacgag

2220

acattcaaga ccagagaggc catccagcac gagagcggaa ttctgggccc tctgctgtat

2280

ggcgaagtgg gcgatacact gctgatcatc ttcaagaacc aggccagcag accctacaac

2340

atctaccctc acggcatcac cgatgtgcgg cccctgtatt ctagaaggct gcccaagggc

2400

gtgaagcacc tgaaggactt ccctatcctg cctggcgaga ttttcaagta caagtggacc

2460

gtgaccgtgg aagatggccc caccaagagc gaccctagat gtctgacacg gtactacagc

2520

agcttcgtga acatggaacg cgacctggcc agcggcctga ttggacctct gctgatctgc

2580

tacaaagaaa gcgtggacca gcggggcaac cagatcatga gcgacaagcg gaacgtgatc

2640

ctgtttagcg tgttcgatga gaaccggtcc tggtatctga ccgagaacat ccagcggttt

2700

ctgcccaatc ctgccggggt gcaactggaa gatcctgagt tccaggcaag caacatcatg

2760

cactccatca atggctatgt gttcgacagc ctgcagctga gcgtgtgcct gcacgaagtg

2820

gcctactggt acatcctgag cattggcgcc cagaccgact tcctgtccgt gttctttagc

2880

ggctacacct tcaagcacaa gatggtgtac gaggataccc tgacactgtt cccattcagc

2940

ggcgagacag tgttcatgag catggaaaac cccggcctgt ggattctggg ctgtcacaac

3000

agcgacttcc ggaacagagg catgacagcc ctgctgaagg tgtccagctg cgacaagaac

3060

accggcgact actacgagga cagctatgag gacatcagcg cctacctgct gagcaagaac

3120

aatgccatcg agcctcggag cttcagccag aatcctcctg tgctgaagcg gcaccagcgc

3180

gagatcacca gaacaaccct gcagagcgac caagaggaaa tcgattacga cgacaccatc

3240

agcgtcgaga tgaagaaaga agatttcgac atctacgacg aggacgagaa tcagagcccc

3300

agaagctttc agaaaaagac ccggcactac ttcattgccg ccgtcgagag actgtgggac

3360

tacggcatgt ctagcagccc tcacgtgctg agaaatagag cccagagcgg cagcgtgccc

3420

cagttcaaga aagtggtgtt ccaagagttc accgacggca gcttcaccca gccactgtat

3480

agaggcgagc tgaacgagca tctgggcctg ctgggccctt atatcagagc cgaagtggaa

3540

gataacatca tggtcacctt ccggaatcag gctagccggc cttacagctt ctacagctcc

3600

ctgatcagct acgaagagga ccagagacag ggcgctgagc ccagaaagaa cttcgtgaag

3660

cccaacgaga ctaagaccta cttttggaag gtgcagcacc acatggcccc tacaaaggac

3720

gagttcgact gcaaagcctg ggcctacttc tccgatgtgg atctggaaaa ggacgtgcac

3780

agcgggctca tcggaccact gcttgtgtgc cacaccaaca cactgaaccc cgctcacggc

3840

agacaagtga cagtgcaaga gttcgccctg ttcttcacca tcttcgacga aacaaagagc

3900

tggtacttca ccgagaatat ggaacggaac tgcagagccc cttgcaacat ccagatggaa

3960

gatcccacct tcaaagagaa ctaccggttc cacgccatca acggctacat catggacaca

4020

ctgcccggcc tggttatggc ccaggatcag agaatccggt ggtatctgct gtccatgggc

4080

tccaacgaga atatccacag catccacttc agcggccacg tgttcaccgt gcggaaaaaa

4140

gaagagtaca aaatggccct gtacaatctg taccctgggg tgttcgaaac cgtggaaatg

4200

ctgccttcca aggccggcat ttggagagtg gaatgtctga ttggagagca cctccacgcc

4260

ggaatgagca ccctgtttct ggtgtacagc aacaagtgtc agacccctct cggcatggcc

4320

tctggacaca tcagagactt cgagatcacc gcctctggcc agtacggaca gtgggctcct

4380

aaactggctc ggctgcacta cagcggcagc atcaatgcct ggtccaccaa agagcccttc

4440

agctggatca aggtggacct gctggctccc atgatcatcc acggaatcaa gacccagggc

4500

gccagacaga agttcagcag cctgtacatc agccagttca tcatcatgta cagcctggac

4560

ggcaagaagt ggcagaccta cagaggcaac agcaccggca cactcatggt gttcttcggc

4620

aacgtggact ccagcggcat taagcacaac atcttcaacc ctccaatcat tgcccggtac

4680

atccggctgc accccacaca ctacagcatc cggtctaccc tgagaatgga actgatgggc

4740

tgcgacctga acagctgctc tatgcccctc ggaatggaaa gcaaggccat cagcgacgcc

4800

cagatcacag ccagcagcta cttcaccaac atgttcgcca cttggagccc ctccaaggct

4860

agactgcatc tgcagggcag aagcaacgct tggaggcccc aagtgaacaa ccccaaagag

4920

tggctgcagg ttgactttca aaagaccatg aaagtgaccg gcgtgaccac acagggcgtc

4980

aagtctctgc tgacctctat gtacgtgaaa gagttcctga tctccagcag ccaggacggc

5040

catcagtgga ccctgttttt ccagaacggc aaagtgaaag tgttccaggg caatcaggac

5100

agcttcacac ccgtggtcaa ttctctggac cctccactgc tgaccagata cctgcggatt

5160

caccctcagt cttgggtgca ccagatcgct ctgcggatgg aagtgctggg ctgtgaagct

5220

caggacctct actagttaat taagagcatc ttaccgccat ttattcccat atttgttctg

5280

tttttcttga tttgggtata catttaaatg ttaataaaac aaaatggtgg ggcaatcatt

5340

tacattttta gggatatgta attactagtt caggtgtatt gccacaagac aaacatgtta

5400

agaaactttc ccgttattta cgctctgttc ctgttaatca acctctggat tacaaaattt

5460

gtgaaagatt gactgatatt cttaactatg ttgctccttt tacgctgtgt ggatatgctg

5520

ctttatagcc tctgtatcta gctattgctt cccgtacggc tttcgttttc tcctccttgt

5580

ataaatcctg gttgctgtct cttttagagg agttgtggcc cgttgtccgt caacgtggcg

5640

tggtgtgctc tgtgtttgct gacgcaaccc ccactggctg gggcattgcc accacctgtc

5700

aactcctttc tgggactttc gctttccccc tcccgatcgc cacggcagaa ctcatcgccg

5760

cctgccttgc ccgctgctgg acaggggcta ggttgctggg cactgataat tccgtggtgt

5820

tgtctgtgcc ttctagttgc cagccatctg ttgtttgccc ctcccccgtg ccttccttga

5880

ccctggaagg tgccactccc actngtccttt cctaataaaa tgaggaaatt gcatcgcatt

5940

gtctgagtag gtgtcattct attctggggg gtggggtggg gcaggacagc aagggggagg

6000

attgggaaga caatagcagg catgctgggg atgcggtggg ctctatggct ctagagcatg

6060

gctacgtaga taagtagcat ggcgggttaa tcattaacta cacctgcagg aggaacccct

6120

agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg ccgggcgacc

6180

aaaggtcgcc cgacgcccgg gcggcctcag tgagcgagcg agcgcgcagc tgcctgcagg

6240

ggcgcgcctc gagccatggt gctagcagct gatgcatagc atgcggtacc gggagatggg

6300

ggaggctaac tgaaacacgg aaggagacaa taccggaagg aacccgcgct atgacggcaa

6360

taaaaagaca gaataaaacg cacgggtgtt gggtcgtttg ttcataaacg cggggttcgg

6420

tcccagggct ggcactctgt cgatacccca ccgagacccc attgggacca atacgcccgc

6480

gtttcttcct tttccccacc ccaaccccca agttcgggtg aaggcccagg gctcgcagcc

6540

aacgtcgggg cggcaagccc tgccatagcc actacgggta cgtaggccaa ccactagaac

6600

tatagctaga gtcctgggcg aacaaacgat gctcgccttc cagaaaaccg aggatgcgaa

6660

ccacttcatc cggggtcagc accaccggca agcgccgcga cggccgaggt ctaccgatct

6720

cctgaagcca gggcagatcc gtgcacagca ccttgccgta gaagaacagc aaggccgcca

6780

atgcctgacg atgcgtggag accgaaacct tgcgctcgtt cgccagccag gacagaaatg

6840

cctcgacttc gctgctgccc aaggttgccg ggtgacgcac accgtggaaa cggatgaagg

6900

cacgaaccca gttgacataa gcctgttcgg ttcgtaaact gtaatgcaag tagcgtatgc

6960

gctcacgcaa ctggtccaga accttgaccg aacgcagcgg tggtaacggc gcagtggcgg

7020

ttttcatggc ttgttatgac tgtttttttg tacagtctat gcctcgggca tccaagcagc

7080

aagcgcgtta cgccgtgggt cgatgtttga tgttatggag cagcaacgat gttacgcagc

7140

agcaacgatg ttacgcagca gggcagtcgc cctaaaacaa agttaggtgg ctcaagtatg

7200

ggcatcattc gcacatgtag gctcggccct gaccaagtca aatccatgcg ggctgctctt

7260

gatcttttcg gtcgtgagtt cggagacgta gccacctact cccaacatca gccggactcc

7320

gattacctcg ggaacttgct ccgtagtaag acattcatcg cgcttgctgc cttcgaccaa

7380

gaagcggttg ttggcgctct cgcggcttac gttctgccca ggtttgagca gccgcgtagt

7440

gagatctata tctatgatct cgcagtctcc ggcgagcacc ggaggcaggg cattgccacc

7500

gcgctcatca atctcctcaa gcatgaggcc aacgcgcttg gtgcttatgt gatctacgtg

7560

caagcagatt acggtgacga tcccgcagtg gctctctata caaagttggg catacgggaa

7620

gaagtgatgc actttgatat cgacccaagt accgccacct aacaattcgt tcaagccgag

7680

atcggcttcc cggccgcgga gttgttcggt aaattgtcac aacgccgcga atatagtctt

7740

taccatgccc ttggccacgc ccctctttaa tacgacgggc aatttgcact tcagaaaatg

7800

aagagtttgc tttagccata acaaaagtcc agtatgcttt ttcacagcat aactggactg

7860

atttcagttt acaactattc tgtctagttt aagactttat tgtcatagtt tagatctatt

7920

ttgttcagtt taagacttta ttgtccgccc acacccgctt acgcagggca tccatttatt

7980

actcaaccgt aaccgatttt gccaggttac gcggctggtc tgcggtgtga aataccgcac

8040

agatgcgtaa ggagaaaata ccgcatcagg cgctcttccg cttcctcgct cactgactcg

8100

ctgcgctcgg tcgttcggct gcggcgagcg gtatcagctc actcaaaggc ggtaatacgg

8160

ttatccacag aatcagggga taacgcagga aagaacatgt gagcaaaagg ccagcaaaag

8220

gccaggaacc gtaaaaaggc cgcgttgctg gcgtttttcc ataggctccg cccccctgac

8280

gagcatcaca aaaatcgacg ctcaagtcag aggtggcgaa acccgacagg actataaaga

8340

taccaggcgt ttccccctgg aagctccctc gtgcgctctc ctgttccgac cctgccgctt

8400

accggatacc tgtccgcctt tctcccttcg ggaagcgtgg cgctttctca atgctcacgc

8460

tgtaggtatc tcagttcggt gtaggtcgtt cgctccaagc tgggctgtgt gcacgaaccc

8520

cccgttcagc ccgaccgctg cgccttatcc ggtaactatc gtcttgagtc caacccggta

8580

agacacgact tatcgccact ggcagcagcc actggtaaca ggattagcag agcgaggtat

8640

gtaggcggtg ctacagagtt cttgaagtgg tggcctaact acggctacac tagaaggaca

8700

gtatttggta tctgcgctct gctgaagcca gttaccttcg gaaaaagagt tggtagctct

8760

tgatccggca aacaaaccac cgctggtagc ggtggttttt ttgtttgcaa gcagcagatt

8820

acgcgcagaa aaaaaggatc tcaagaagat cctttgatct tttctacggg gtctgacgct

8880

cagtggaacg aaaactcacg ttaagggatt ttggtcatga gattatcaaa aaggatcttc

8940

acctagatcc ttttaaatta aaaatgaagt tttaaatcaa tctaaagtat atatgagtaa

9000

acttggtctg acagttacca atgcttaatc agtgaggcac ctatctcagc gatctgtcta

9060

tttcgttcat ccatagttgc ctgactcccc gtcgtgtaga taactacgat acgggagggc

9120

ttaccatctg gccccagtgc tgcaatgata ccgcgagacc cacgctcacc ggctccagat

9180

ttatcagcaa taaaccagcc agccggaagg gccgagcgca gaagtggtcc tgcaacttta

9240

tccgcctcca tccagtctat taattgttgc cgggaagcta gagtaagtag ttcgccagtt

9300

aatagtttgc gcaacgttgt tgccattgct acaggcatcg tggtgtcacg ctcgtcgttt

9360

ggtatggctt cattcagctc cggttcccaa cgatcaaggc gagttacatg atcccccatg

9420

ttgtgcaaaa aagcggttag ctccttcggt cctccgatcg ttgtcagaag taagttggcc

9480

gcagtgttat cactcatggt tatggcagca ctgcataatt ctcttactgt catgccatcc

9540

gtaagatgct tttctgtgac tggtgagtac tcaaccaagt cattctgaga atagtgtatg

9600

cggcgaccga gttgctcttg cccggcgtca atacgggata ataccgcgcc acatagcaga

9660

actttaaaag tgctcatcat tggaaaacgt tcttcggggc gaaaactctc aaggatctta

9720

ccgctgttga gatccagttc gatgtaaccc actcgtgcac ccaactgatc ttcagcatct

9780

tttactttca ccagcgtttc tgggtgagca aaaacaggaa ggcaaaatgc cgcaaaaaag

9840

ggaataaggg cgacacggaa atgttgaata ctcatactct tcctttttca atattattga

9900

agcatttatc agggttattg tctcatgagc ggatacatat ttgaatgtat ttagaaaaat

9960

aaacaaatag gggttccgcg cacatttccc cgaaaagtgc cacctgaaat tgtaaacgtt

10020

aatattttgt taaaattcgc gttaaatttt tgttaaatca gctcattttt taaccaatag

10080

gccgaaatcg gcaaaatccc ttataaatca aaagaataga ccgagatagg gttgagtgtt

10140

gttccagttt ggaacaagag tccactatta aagaacgtgg actccaacgt caaagggcga

10200

aaaaccgtct atcagggcga tggcccacta cgtgaaccat caccctaatc aagttttttg

10260

gggtcgaggt gccgtaaagc actaaatcgg aaccctaaag ggagcccccg atttagagct

10320

tgacggggaa agccggcgaa cgtggcgaga aaggaaggga agaaagcgaa aggagcgggc

10380

gctagggcgc tggcaagtgt agcggtcacg ctgcgcgtaa ccaccacacc cgccgcgctt

10440

aatgcgccgc tacagggcgc gtcccattcg ccattcaggc tgcaaataag cgttgatatt

10500

cagtcaatta caaacattaa taacgaagag atgacagaaa aattttcatt ctgtgacaga

10560

gaa

10563

<210> 203

<211> 9871

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 203

ggccggcccc tgcaggcagc tgcgcgctcg ctcgctcact gaggccgccc gggcaaagcc

60

cgggcgtcgg gcgacctttg gtcgcccggc ctcagtgagc gagcgagcgc gcagagaggg

120

agtggccaac tccatcacta ggggttcctt gtagttaatg attaacccgc catgctactt

180

atctacgtag ccatgctcta gagtttgctg cttgcaatgt ttgcccattt tagggtggac

240

acaggacgct gtggtttctg agccagggg cgactcagat cccagccagt ggacttagcc

300

cctgtttgct cctccgataa ctggggtgac cttggttaat attcaccagc agcctccccc

360

gttgcccctc tggatccact gcttaaatac ggacgaggac agggccctgt ctcctcagct

420

tcaggcacca ccactgacct gggacagtga atcgccacca tgcagattga gctgagcacc

480

tgcttcttcc tgtgcctgct gaggttctgc ttctctgcca ccaggagata ctacctgggg

540

gctgtggagc tgagctggga ctacatgcag tctgacctgg gggagctgcc tgtggatgcc

600

aggttccccc ccagagtgcc caagagcttc cccttcaaca cctctgtggt gtacaagaag

660

accctgtttg tggagttcac tgaccacctg ttcaacattg ccaagcccag gcccccctgg

720

atgggcctgc tgggccccac catccaggct gaggtgtatg acactgtggt gatcaccctg

780

aagaacatgg ccagccaccc tgtgagcctg catgctgtgg gggtgagcta ctggaaggcc

840

tctgaggggg ctgagtatga tgaccagacc agccagaggg agaaggagga tgacaaggtg

900

ttccctgggg gcagccacac ctatgtgtgg caggtgctga aggagaatgg ccccatggcc

960

tctgaccccc tgtgcctgac ctacagctac ctgagccatg tggacctggt gaaggacctg

1020

aactctggcc tgattggggc cctgctggtg tgcagggagg gcagcctggc caaggagaag

1080

acccagaccc tgcacaagtt catcctgctg tttgctgtgt ttgatgaggg caagagctgg

1140

cactctgaaa ccaagaacag cctgatgcag gacagggatg ctgcctctgc cagggcctgg

1200

cccaagatgc acactgtgaa tggctatgtg aacaggagcc tgcctggcct gattggctgc

1260

cacaggaagt ctgtgtactg gcatgtgatt ggcatgggca ccacccctga ggtgcacagc

1320

atcttcctgg agggccacac cttcctggtc aggaaccaca ggcaggccag cctggagatc

1380

agccccatca ccttcctgac tgcccagacc ctgctgatgg acctgggcca gttcctgctg

1440

ttctgccaca tcagcagcca ccagcatgat ggcatggagg cctatgtgaa ggtggacagc

1500

tgccctgagg agccccagct gaggatgaag aacaatgagg aggctgagga ctatgatgat

1560

gacctgactg actctgagat ggatgtggtg aggtttgatg atgacaacag ccccagcttc

1620

atccagatca ggtctgtggc caagaagcac cccaagacct gggtgcacta cattgctgct

1680

gaggaggagg actgggacta tgcccccctg gtgctggccc ctgatgacag gagctacaag

1740

agccagtacc tgaacaatgg cccccagagg attggcagga agtacaagaa ggtcaggttc

1800

atggcctaca ctgatgaaac cttcaagacc agggaggcca tccagcatga gtctggcatc

1860

ctgggccccc tgctgtatgg ggaggtgggg gacaccctgc tgatcatctt caagaaccag

1920

gccagcaggc cctacaacat ctacccccat ggcatcactg atgtgaggcc cctgtacagc

1980

aggaggctgc ccaagggggt gaagcacctg aaggacttcc ccatcctgcc tggggagatc

2040

ttcaagtaca agtggactgt gactgtggag gatggcccca ccaagtctga ccccaggtgc

2100

ctgaccagat actacagcag ctttgtgaac atggagaggg acctggcctc tggcctgatt

2160

ggccccctgc tgatctgcta caaggagtct gtggaccaga ggggcaacca gatcatgtct

2220

gacaagagga atgtgatcct gttctctgtg tttgatgaga acaggagctg gtacctgact

2280

gagaacatcc agaggttcct gcccaaccct gctggggtgc agctggagga ccctgagttc

2340

caggccagca acatcatgca cagcatcaat ggctatgtgt ttgacagcct gcagctgtct

2400

gtgtgcctgc atgaggtggc ctactggtac atcctgagca ttggggccca gactgacttc

2460

ctgtctgtgt tcttctctgg ctacaccttc aagcacaaga tggtgtatga ggacaccctg

2520

accctgttcc ccttctctgg ggagactgtg ttcatgagca tggagaaccc tggcctgtgg

2580

attctgggct gccacaactc tgacttcagg aacaggggca tgactgccct gctgaaagtc

2640

tccagctgtg acaagaacac tggggactac tatgaggaca gctatgagga catctctgcc

2700

tacctgctga gcaagaacaa tgccattgag cccaggagct tcagccagaa ccccccagtg

2760

ctgaagaggc accagaggga gatcaccagg accaccctgc agtctgacca ggaggagatt

2820

gactatgatg acaccatctc tgtggagatg aagaaggagg actttgacat ctacgacgag

2880

gacgagaacc agagccccag gagcttccag aagaagacca ggcactactt cattgctgct

2940

gtggagaggc tgtgggacta tggcatgagc agcagccccc atgtgctgag gaacagggcc

3000

cagtctggct ctgtgcccca gttcaagaag gtggtgttcc aggagttcac tgatggcagc

3060

ttcacccagc ccctgtacag aggggagctg aatgagcacc tgggcctgct gggcccctac

3120

atcagggctg aggtggagga caacatcatg gtgaccttca ggaaccaggc cagcaggccc

3180

tacagcttct acagcagcct gatcagctat gaggaggacc agaggcaggg ggctgagccc

3240

aggaagaact ttgtgaagcc caatgaaacc aagacctact tctggaaggt gcagcaccac

3300

atggccccca ccaaggatga gtttgactgc aaggcctggg cctacttctc tgatgtggac

3360

ctggagaagg atgtgcactc tggcctgatt ggccccctgc tggtgtgcca caccaacacc

3420

ctgaaccctg cccatggcag gcaggtgact gtgcaggagt ttgccctgtt cttcaccatc

3480

tttgatgaaa ccaagagctg gtacttcact gagaacatgg agaggaactg cagggccccc

3540

tgcaacatcc agatggagga ccccaccttc aaggagaact acaggttcca tgccatcaat

3600

ggctacatca tggacaccct gcctggcctg gtgatggccc aggaccagag gatcaggtgg

3660

tacctgctga gcatgggcag caatgagaac atccacagca tccacttctc tggccatgtg

3720

ttcactgtga ggaagaagga ggagtacaag atggccctgt acaacctgta ccctggggtg

3780

tttgagactg tggagatgct gcccagcaag gctggcatct ggagggtgga gtgcctgatt

3840

ggggagcacc tgcatgctgg catgagcacc ctgttcctgg tgtacagcaa caagtgccag

3900

acccccctgg gcatggcctc tggccacatc agggacttcc agatcactgc ctctggccag

3960

tatggccagt gggcccccaa gctggccagg ctgcactact ctggcagcat caatgcctgg

4020

agcaccaagg agcccttcag ctggatcaag gtggacctgc tggcccccat gatcatccat

4080

ggcatcaaga cccagggggc caggcagaag ttcagcagcc tgtacatcag ccagttcatc

4140

atcatgtaca gcctggatgg caagaagtgg cagacctaca ggggcaacag cactggcacc

4200

ctgatggtgt tctttggcaa tgtggacagc tctggcatca agcacaacat cttcaacccc

4260

cccatcattg ccagatacat caggctgcac cccacccact acagcatcag gagcaccctg

4320

aggatggagc tgatgggctg tgacctgaac agctgcagca tgcccctggg catggagagc

4380

aaggccatct ctgatgccca gatcactgcc agcagctact tcaccaacat gtttgccacc

4440

tggagcccca gcaaggccag gctgcacctg cagggcagga gcaatgcctg gaggccccag

4500

gtcaacaacc ccaaggagtg gctgcaggtg gacttccaga agaccatgaa ggtgactggg

4560

gtgaccaccc aggggtgaa gagcctgctg accagcatgt atgtgaagga gttcctgatc

4620

agcagcagcc aggatggcca ccagtggacc ctgttcttcc agaatggcaa ggtgaaggtg

4680

ttccagggca accaggacag cttcacccct gtggtgaaca gcctggaccc ccccctgctg

4740

accagatacc tgaggattca cccccagagc tgggtgcacc agattgccct gaggatggag

4800

gtgctgggct gtgaggccca ggacctgtac tgaaataaaa gatctttatt ttcattagat

4860

ctgtgtgttg gttttttgtg tgtctagagc atggctacgt agataagtag catggcgggt

4920

taatcattaa ctacacctgc aggaggaacc cctagtgatg gagttggcca ctccctctct

4980

gcgcgctcgc tcgctcactg aggccgggcg accaaaggtc gcccgacgcc cgggcggcct

5040

cagtgagcga gcgagcgcgc agctgcctgc aggggcgcgc ctcgaggcat gcggtaccaa

5100

gcttgtcgag aagtactaga ggatcataat cagccatacc acatttgtag aggttttact

5160

tgctttaaaa aacctcccac acctccccct gaacctgaaa cataaaatga atgcaattgt

5220

tgttgttaac ttgtttattg cagcttataa tggttacaaa taaagcaata gcatcacaaa

5280

tttcacaaat aaagcatttt tttcactgca ttctagttgt ggtttgtcca aactcatcaa

5340

tgtatcttat catgtctgga tctgatcact gatatcgcct aggagatccg aaccagataa

5400

gtgaaatcta gttccaaact attttgtcat ttttaatttt cgtattagct tacgacgcta

5460

cacccagttc ccatctattt tgtcactctt ccctaaataa tccttaaaaa ctccattcc

5520

acccctccca gttcccaact attttgtccg cccacagcgg ggcatttttc ttcctgttat

5580

gtttttaatc aaacatcctg ccaactccat gtgacaaacc gtcatcttcg gctacttttt

5640

ctctgtcaca gaatgaaaat ttttctgtca tctcttcgtt attaatgttt gtaattgact

5700

gaatatcaac gcttatttgc agcctgaatg gcgaatggga cgcgccctgt agcggcgcat

5760

taagcgcggc gggtgtggtg gttacgcgca gcgtgaccgc tacacttgcc agcgccctag

5820

cgcccgctcc tttcgctttc ttcccttcct ttctcgccac gttcgccggc tttccccgtc

5880

aagctctaaa tcggggggctc cctttagggt tccgatttag tgctttacgg cacctcgacc

5940

ccaaaaaact tgattagggt gatggttcac gtagtgggcc atcgccctga tagacggttt

6000

ttcgcccttt gacgttggag tccacgttct ttaatagtgg actcttgttc caaactggaa

6060

caacactcaa ccctatctcg gtctattctt ttgatttata agggattttg ccgatttcgg

6120

cctattggtt aaaaaatgag ctgatttaac aaaaatttaa cgcgaatttt aacaaaatat

6180

taacgtttac aatttcaggt ggcacttttc ggggaaatgt gcgcggaacc cctatttgtt

6240

tatttttcta aatacattca aatatgtatc cgctcatgag acaataaccc tgataaatgc

6300

ttcaataata ttgaaaaagg aagagtatga gtattcaaca tttccgtgtc gcccttattc

6360

ccttttttgc ggcattttgc cttcctgttt ttgctcaccc agaaacgctg gtgaaagtaa

6420

aagatgctga agatcagttg ggtgcacgag tgggttacat cgaactggat ctcaacagcg

6480

gtaagatcct tgagagtttt cgccccgaag aacgttttcc aatgatgagc acttttaaag

6540

ttctgctatg tggcgcggta ttatcccgta ttgacgccgg gcaagagcaa ctcggtcgcc

6600

gcatacacta ttctcagaat gacttggttg agtactcacc agtcacagaa aagcatctta

6660

cggatggcat gacagtaaga gaattatgca gtgctgccat aaccatgagt gataacactg

6720

cggccaactt acttctgaca acgatcggag gaccgaagga gctaaccgct tttttgcaca

6780

acatggggga tcatgtaact cgccttgatc gttgggaacc ggagctgaat gaagccatac

6840

caaacgacga gcgtgacacc acgatgcctg tagcaatggc aacaacgttg cgcaaactat

6900

taactggcga actacttact ctagcttccc ggcaacaatt aatagactgg atggaggcgg

6960

ataaagttgc aggaccactt ctgcgctcgg cccttccggc tggctggttt attgctgata

7020

aatctggagc cggtgagcgt gggtctcgcg gtatcattgc agcactgggg ccagatggta

7080

agccctcccg tatcgtagtt atctacacga cggggagtca ggcaactatg gatgaacgaa

7140

atagacagat cgctgagata ggtgcctcac tgattaagca ttggtaactg tcagaccaag

7200

tttactcata tatactttag attgatttaa aacttcattt ttaatttaaa aggatctagg

7260

tgaagatcct ttttgataat ctcatgacca aaatccctta acgtgagttt tcgttccact

7320

gagcgtcaga ccccgtagaa aagatcaaag gatcttcttg agatcctttt tttctgcgcg

7380

taatctgctg cttgcaaaca aaaaaaccac cgctaccagc ggtggtttgt ttgccggatc

7440

aagagctacc aactcttttt ccgaaggtaa ctggcttcag cagagcgcag ataccaaata

7500

ctgtccttct agtgtagccg tagttaggcc accacttcaa gaactctgta gcaccgccta

7560

catacctcgc tctgctaatc ctgttaccag tggctgctgc cagtggcgat aagtcgtgtc

7620

ttaccgggtt ggactcaaga cgatagttac cggataaggc gcagcggtcg ggctgaacgg

7680

ggggttcgtg cacacagccc agcttggagc gaacgaccta caccgaactg agatacctac

7740

agcgtgagca ttgagaaagc gccacgcttc ccgaagggag aaaggcggac aggtatccgg

7800

taagcggcag ggtcggaaca ggagagcgca cgagggagct tccaggggga aacgcctggt

7860

atctttatag tcctgtcggg tttcgccacc tctgacttga gcgtcgattt ttgtgatgct

7920

cgtcaggggg gcggagccta tggaaaaacg ccagcaacgc ggccttttta cggttcctgg

7980

ccttttgctg gccttttgct cacatgttct ttcctgcgtt atcccctgat tctgtggata

8040

accgtattac cgcctttgag tgagctgata ccgctcgccg cagccgaacg accgagcgca

8100

gcgagtcagt gagcgaggaa gcggaagagc gcctgatgcg gtattttctc cttacgcatc

8160

tgtgcggtat ttcacaccgc agaccagccg cgtaacctgg caaaatcggt tacggttgag

8220

taataaatgg atgccctgcg taagcgggtg tgggcggaca ataaagtctt aaactgaaca

8280

aaatagatct aaactatgac aataaagtct taaactagac agaatagttg taaactgaaa

8340

tcagtccagt tatgctgtga aaaagcatac tggacttttg ttatggctaa agcaaactct

8400

tcattttctg aagtgcaaat tgcccgtcgt attaaagagg ggcgtggcca agggcatggt

8460

aaagactata ttcgcggcgt tgtgacaatt taccgaacaa ctccgcggcc gggaagccga

8520

tctcggcttg aacgaattgt taggtggcgg tacttgggtc gatatcaaag tgcatcactt

8580

cttcccgtat gcccaacttt gtatagagag ccactgcggg atcgtcaccg taatctgctt

8640

gcacgtagat cacataagca ccaagcgcgt tggcctcatg cttgaggaga ttgatgagcg

8700

cggtggcaat gccctgcctc cggtgctcgc cggagactgc gagatcatag atatagatct

8760

cactacgcgg ctgctcaaac ctgggcagaa cgtaagccgc gagagcgcca acaaccgctt

8820

cttggtcgaa ggcagcaagc gcgatgaatg tcttactacg gagcaagttc ccgaggtaat

8880

cggagtccgg ctgatgttgg gagtaggtgg ctacgtctcc gaactcacga ccgaaaagat

8940

caagagcagc ccgcatggat ttgacttggt cagggccgag cctacatgtg cgaatgatgc

9000

ccatacttga gccacctaac tttgttttag ggcgactgcc ctgctgcgta acatcgttgc

9060

tgctgcgtaa catcgttgct gctccataac atcaaacatc gacccacggc gtaacgcgct

9120

tgctgcttgg atgcccgagg catagactgt acaaaaaaac agtcataaca agccatgaaa

9180

accgccactg cgccgttacc accgctgcgt tcggtcaagg ttctggacca gttgcgtgag

9240

cgcatacgct acttgcatta cagtttacga accgaacagg cttatgtcaa ctgggttcgt

9300

gccttcatcc gtttccacgg tgtgcgtcac ccggcaacct tgggcagcag cgaagtcgag

9360

gcatttctgt cctggctggc gaacgagcgc aaggtttcgg tctccacgca tcgtcaggca

9420

ttggcggcct tgctgttctt ctacggcaag gtgctgtgca cggatctgcc ctggcttcag

9480

gagatcggaa gacctcggcc gtcgcggcgc ttgccggtgg tgctgacccc ggatgaagtg

9540

gttcgcatcc tcggttttct ggaaggcgag catcgtttgt tcgcccagga ctctagctat

9600

agttctagtg gttggctacg tatactccgg aatattaata gatcatggag ataattaaaa

9660

tgataaccat ctcgcaaata aataagtatt ttactgtttt cgtaacagtt ttgtaataaa

9720

aaaacctata aatattccgg attattcata ccgtcccacc atcgggcgcg gatctcggtc

9780

cgaaaccatg tcgtactacc atcaccatca ccatcacgat tacgatatcc caacgaccga

9840

aaacctgtat tttcagggcg ccatgggatc c

9871

<210> 204

<211> 9969

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 204

ggccggcccc tgcaggcagc tgcgcgctcg ctcgctcact gaggccgccc gggcaaagcc

60

cgggcgtcgg gcgacctttg gtcgcccggc ctcagtgagc gagcgagcgc gcagagaggg

120

agtggccaac tccatcacta ggggttcctt gtagttaatg attaacccgc catgctactt

180

atctacgtag ccatgctcta gagtctgtct gcacatttcg tagagcgagt gttccgatac

240

tctaatctcc ctaggcaagg ttcatattga cttaggttac ttattctcct tttgttgact

300

aagtcaataa tcagaatcag caggtttgga gtcagcttgg cagggatcag cagcctgggt

360

tggaaggagg gggtataaaa gccccttcac caggagaagc cgtcacacag atccacaagc

420

tcctgctagc aggtaagtgc cgtgtgtggt tcccgcgggc ctggcctctt tacgggttat

480

ggcccttgcg tgccttgaat tactgacact gacatccact ttttcttttt ctccacaggt

540

ttaaacgcca ccatgcagat tgagctgagc acctgcttct tcctgtgtct gctgaggttc

600

tgcttctctg ccaccaggag gtattacctg ggggctgtgg agctgagctg ggactatatg

660

cagtctgacc tgggggagct gcctgtggat gctaggttcc cccccagggt gcccaagagc

720

ttccccttta acacttctgt ggtgtacaag aagaccctgt ttgtggagtt cactgaccac

780

ctgttcaaca ttgccaagcc caggcccccc tggatggggc tgctggggcc caccatccag

840

gctgaggtgt atgacactgt ggtgatcacc ctgaagaaca tggccagcca ccctgtgagc

900

ctgcatgctg tgggggtgag ctactggaag gcttctgagg gggctgagta tgatgaccag

960

actagccaga gggagaagga ggatgacaag gtgtttcctg ggggcagcca tacctatgtg

1020

tggcaggtgc tgaaggagaa tggccccatg gcctctgacc ccctgtgcct gacctacagc

1080

tacctgtctc atgtggacct ggtgaaggac ctgaactctg gcctgattgg ggctctgctg

1140

gtgtgtaggg agggcagcct ggctaaggaa aagacccaga ccctgcataa gtttatcctg

1200

ctgtttgctg tgtttgatga gggcaagagc tggcactctg agaccaagaa cagcctgatg

1260

caggataggg atgctgcctc tgccagggct tggcctaaga tgcacactgt gaatgggtat

1320

gtgaatagga gcctgcctgg cctgattggc tgccacagga agtctgtgta ctggcatgtg

1380

attgggatgg gcaccacccc tgaggtccat agcatcttcc tggagggcca cactttcctg

1440

gtgaggaacc acagacaggc ctctctggag atctctccca tcaccttcct gactgctcag

1500

actctgctga tggacctggg ccagttcctg ctgttttgcc atattagcag ccaccagcat

1560

gatgggatgg aggcctatgt gaaggtggat agctgccctg aggagcctca gctgaggatg

1620

aagaacaatg aggaggctga agactatgat gatgacctga ctgattctga gatggatgtg

1680

gtgaggtttg atgatgacaa tagccccagc ttcattcaga tcaggtctgt ggccaagaaa

1740

caccccaaga cctgggtgca ctacattgct gctgaggaag aggactggga ctatgctccc

1800

ctggtgctgg cccctgatga taggtcttat aagagccagt acctgaacaa tgggccccag

1860

aggattggca ggaagtacaa gaaggtgagg ttcatggcct acactgatga aaccttcaaa

1920

accagggagg ccattcagca tgagtctggc atcctgggcc ctctgctgta tggggaggtg

1980

ggggacaccc tgctgatcat cttcaagaac caggccagca ggccctacaa catctatcct

2040

catggcatca ctgatgtgag gcccctgtac agcaggaggc tgcccaaggg ggtgaagcac

2100

ctgaaagact tccccatcct gcctggggag atctttaagt ataagtggac tgtgactgtg

2160

gaggatggcc ctaccaagtc tgaccccagg tgtctgacca ggtactattc tagctttgtg

2220

aacatggaga gggacctggc ctctggcctg attgggcccc tgctgatctg ctacaaggag

2280

tctgtggacc agaggggcaa ccagatcatg tctgacaaga ggaatgtgat cctgttttct

2340

gtgtttgatg agaataggag ctggtacctg actgagaaca tccagaggtt tctgcccaat

2400

cctgctgggg tgcagctgga ggatcctgag ttccaggcca gcaatatcat gcatagcatc

2460

aatggctatg tgtttgacag cctgcagctg tctgtgtgcc tgcatgaggt ggcctactgg

2520

tacatcctga gcattggggc ccagactgac tttctgtctg tgttcttttc tggctatacc

2580

ttcaagcaca agatggtgta tgaggatacc ctgaccctgt tccccttctc tggggagact

2640

gtgttcatga gcatggagaa tcctgggctg tggatcctgg ggtgccacaa ctctgatttt

2700

aggaacaggg ggatgactgc cctgctgaag gtgtctagct gtgataagaa cactggggac

2760

tactatgagg acagctatga ggacatttct gcttatctgc tgtctaagaa taatgccatt

2820

gagcccagaa gcttcagcca gaatccccct gtgctgaaga gacatcagag ggagatcacc

2880

agaactaccc tgcagtctga tcaggaggag attgactatg atgacactat ctctgtggag

2940

atgaagaagg aggactttga catctatgat gaggatgaga atcagtctcc caggagcttt

3000

cagaagaaga ccagacatta cttcattgct gctgtggaga ggctgtggga ctatggcatg

3060

agctctagcc ctcatgtgct gaggaacagg gcccagtctg gctctgtgcc ccagttcaag

3120

aaggtggtgt tccaggaatt cactgatggc agcttcaccc agcccctgta caggggggag

3180

ctgaatgagc acctggggcct gctggggcct tatatcaggg ctgaggtgga ggataatatt

3240

atggtgactt tcaggaacca ggccagcagg ccctactctt tctatagcag cctgatctct

3300

tatgaggagg atcagaggca gggggctgag cctaggaaga actttgtgaa gcccaatgag

3360

actaagacct acttctggaa ggtccagcac cacatggccc ctaccaagga tgagtttgac

3420

tgcaaggcct gggcctattt ctctgatgtg gatctggaga aggatgtcca ttctgggctg

3480

attggccccc tgctggtgtg ccacactaac actctgaatc ctgcccatgg caggcaggtg

3540

actgtccagg agtttgccct gttcttcact atctttgatg agaccaagag ctggtacttt

3600

actgagaaca tggagaggaa ctgcagagct ccttgcaata ttcagatgga ggaccccacc

3660

ttcaaggaga attacaggtt ccatgccatt aatgggtaca tcatggacac cctgcctggc

3720

ctggtgatgg ctcaggacca gaggatcagg tggtacctgc tgagcatggg ctctaatgag

3780

aatatccaca gcatccactt ctctgggcat gtgttcactg tgaggaagaa ggagggagtac

3840

aagatggctc tgtataatct gtaccctggg gtgtttgaaa ctgtggagat gctgccctct

3900

aaggctggca tctggagggt ggagtgcctg attggggagc acctgcatgc tggcatgagc

3960

accctgttcc tggtgtacag caacaagtgc cagacccccc tgggcatggc ctctggccac

4020

atcagggact tccagatcac tgcctctggc cagtatggcc agtgggcccc caagctggcc

4080

aggctgcact attctggcag catcaatgcc tggagcacca aggagccctt cagctggatc

4140

aaggtggacc tgctggcccc catgatcatt catggcatca agacccaggg ggccaggcag

4200

aagttcagct ctctgtacat ctctcagttc atcatcatgt actctctgga tgggaagaag

4260

tggcagacct acaggggcaa cagcactggc accctgatgg tgttctttgg gaatgtggac

4320

tcttctggca tcaagcacaa catcttcaat ccccccatca ttgctaggta tattaggctg

4380

catcccaccc actacagcat caggtctacc ctgaggatgg agctgatggg ctgtgacctg

4440

aactcttgca gcatgcccct gggcatggag tctaaggcca tctctgatgc ccagattact

4500

gccagcagct acttcaccaa catgtttgcc acctggagcc cctctaaggc caggctgcat

4560

ctgcagggga ggagcaatgc ctggaggcct caggtgaaca accccaagga gtggctgcag

4620

gtggatttcc agaagaccat gaaggtgact ggggtgacca cccagggggt caagagcctg

4680

ctgaccagca tgtatgtgaa ggagttcctg atcagcagca gccaggatgg ccaccagtgg

4740

actctgttct ttcagaatgg gaaggtgaag gtgtttcagg gcaatcagga ctctttcacc

4800

cctgtggtga acagcctgga cccccccctg ctgaccagat acctgaggat ccacccccag

4860

tcttgggtgc atcagattgc cctgaggatg gaggtgctgg gctgtgaggc tcaggatctg

4920

tactgagcgg ccgcaataaa agatcagagc tctagagatc tgtgtgttgg ttttttgtgt

4980

tctagagcat ggctacgtag ataagtagca tggcgggtta atcattaact acacctgcag

5040

gaggaacccc tagtgatgga gttggccact ccctctctgc gcgctcgctc gctcactgag

5100

gccgggcgac caaaggtcgc ccgacgcccg ggcggcctca gtgagcgagc gagcgcgcag

5160

ctgcctgcag gggcgcgcct cgaggcatgc ggtaccaagc ttgtcgagaa gtactagagg

5220

atcataatca gccataccac atttgtagag gttttacttg ctttaaaaaa cctcccacac

5280

ctccccctga acctgaaaca taaaatgaat gcaattgttg ttgttaactt gtttattgca

5340

gcttataatg gttacaaata aagcaatagc atcacaaatt tcacaaataa agcatttttt

5400

tcactgcatt ctagttgtgg tttgtccaaa ctcatcaatg tatcttatca tgtctggatc

5460

tgatcactga tatcgcctag gagatccgaa ccagataagt gaaatctagt tccaaactat

5520

tttgtcattt ttaattttcg tattagctta cgacgctaca cccagttccc atctattttg

5580

tcactcttcc ctaaataatc cttaaaaact ccatttccac ccctcccagt tcccaactat

5640

tttgtccgcc cacagcgggg catttttctt cctgttatgt ttttaatcaa acatcctgcc

5700

aactccatgt gacaaaccgt catcttcggc tactttttct ctgtcacaga atgaaaattt

5760

ttctgtcatc tcttcgttat taatgtttgt aattgactga atatcaacgc ttatttgcag

5820

cctgaatggc gaatgggacg cgccctgtag cggcgcatta agcgcggcgg gtgtggtggt

5880

tacgcgcagc gtgaccgcta cacttgccag cgccctagcg cccgctcctt tcgctttctt

5940

cccttccttt ctcgccacgt tcgccggctt tccccgtcaa gctctaaatc gggggctccc

6000

tttagggttc cgatttagtg ctttacggca cctcgacccc aaaaaacttg attagggtga

6060

tggttcacgt agtgggccat cgccctgata gacggttttt cgccctttga cgttggagtc

6120

cacgttcttt aatagtggac tcttgttcca aactggaaca acactcaacc ctatctcggt

6180

ctattctttt gatttataag ggattttgcc gatttcggcc tattggttaa aaaatgagct

6240

gatttaacaa aaatttaacg cgaattttaa caaaatatta acgtttacaa tttcaggtgg

6300

cacttttcgg ggaaatgtgc gcggaacccc tatttgttta tttttctaaa tacattcaaa

6360

tatgtatccg ctcatgagac aataaccctg ataaatgctt caataatatt gaaaaaggaa

6420

gagtatgagt attcaacatt tccgtgtcgc ccttattccc ttttttgcgg cattttgcct

6480

tcctgttttt gctcacccag aaacgctggt gaaagtaaaa gatgctgaag atcagttggg

6540

tgcacgagtg ggttacatcg aactggatct caacagcggt aagatccttg agagttttcg

6600

ccccgaagaa cgttttccaa tgatgagcac ttttaaagtt ctgctatgtg gcgcggtatt

6660

atcccgtatt gacgccgggc aagagcaact cggtcgccgc atacactatt ctcagaatga

6720

cttggttgag tactcaccag tcacagaaaa gcatcttacg gatggcatga cagtaagaga

6780

attatgcagt gctgccataa ccatgagtga taacactgcg gccaacttac ttctgacaac

6840

gatcggagga ccgaaggagc taaccgcttt tttgcacaac atgggggatc atgtaactcg

6900

ccttgatcgt tgggaaccgg agctgaatga agccatacca aacgacgagc gtgacaccac

6960

gatgcctgta gcaatggcaa caacgttgcg caaactatta actggcgaac tacttactct

7020

agcttcccgg caacaattaa tagactggat ggaggcggat aaagttgcag gaccacttct

7080

gcgctcggcc cttccggctg gctggtttat tgctgataaa tctggagccg gtgagcgtgg

7140

gtctcgcggt atcattgcag cactggggcc agatggtaag ccctcccgta tcgtagttat

7200

ctacacgacg gggagtcagg caactatgga tgaacgaaat agacagatcg ctgagatagg

7260

tgcctcactg attaagcatt ggtaactgtc agaccaagtt tactcatata tactttagat

7320

tgatttaaaa cttcattttt aatttaaaag gatctaggtg aagatccttt ttgataatct

7380

catgaccaaa atcccttaac gtgagttttc gttccactga gcgtcagacc ccgtagaaaa

7440

gatcaaagga tcttcttgag atcctttttt tctgcgcgta atctgctgct tgcaaacaaa

7500

aaaaccaccg ctaccagcgg tggtttgttt gccggatcaa gagctaccaa ctctttttcc

7560

gaaggtaact ggcttcagca gagcgcagat accaaatact gtccttctag tgtagccgta

7620

gttaggccac cacttcaaga actctgtagc accgcctaca tacctcgctc tgctaatcct

7680

gttaccagtg gctgctgcca gtggcgataa gtcgtgtctt accgggttgg actcaagacg

7740

atagttaccg gataaggcgc agcggtcggg ctgaacgggg ggttcgtgca cacagcccag

7800

cttggagcga acgacctaca ccgaactgag atacctacag cgtgagcatt gagaaagcgc

7860

cacgcttccc gaagggagaa aggcggacag gtatccggta agcggcaggg tcggaacagg

7920

agagcgcacg agggagcttc cagggggaaa cgcctggtat ctttatagtc ctgtcgggtt

7980

tcgccacctc tgacttgagc gtcgattttt gtgatgctcg tcaggggggc ggagcctatg

8040

gaaaaacgcc agcaacgcgg cctttttacg gttcctggcc ttttgctggc cttttgctca

8100

catgttcttt cctgcgttat cccctgattc tgtggataac cgtattaccg cctttgagtg

8160

agctgatacc gctcgccgca gccgaacgac cgagcgcagc gagtcagtga gcgaggaagc

8220

ggaagagcgc ctgatgcggt attttctcct tacgcatctg tgcggtattt cacaccgcag

8280

accagccgcg taacctggca aaatcggtta cggttgagta ataaatggat gccctgcgta

8340

agcgggtgtg ggcggacaat aaagtcttaa actgaacaaa atagatctaa actatgacaa

8400

taaagtctta aactagacag aatagttgta aactgaaatc agtccagtta tgctgtgaaa

8460

aagcatactg gacttttgtt atggctaaag caaactcttc attttctgaa gtgcaaattg

8520

cccgtcgtat taaagagggg cgtggccaag ggcatggtaa agactatatt cgcggcgttg

8580

tgacaattta ccgaacaact ccgcggccgg gaagccgatc tcggcttgaa cgaattgtta

8640

ggtggcggta cttgggtcga tatcaaagtg catcacttct tcccgtatgc ccaactttgt

8700

atagagagcc actgcgggat cgtcaccgta atctgcttgc acgtagatca cataagcacc

8760

aagcgcgttg gcctcatgct tgaggagatt gatgagcgcg gtggcaatgc cctgcctccg

8820

gtgctcgccg gagactgcga gatcatagat atagatctca ctacgcggct gctcaaacct

8880

gggcagaacg taagccgcga gagcgccaac aaccgcttct tggtcgaagg cagcaagcgc

8940

gatgaatgtc ttactacgga gcaagttccc gaggtaatcg gagtccggct gatgttggga

9000

gtaggtggct acgtctccga actcacgacc gaaaagatca agagcagccc gcatggattt

9060

gacttggtca gggccgagcc tacatgtgcg aatgatgccc atacttgagc cacctaactt

9120

tgttttaggg cgactgccct gctgcgtaac atcgttgctg ctgcgtaaca tcgttgctgc

9180

tccataacat caaacatcga cccacggcgt aacgcgcttg ctgcttggat gcccgaggca

9240

tagactgtac aaaaaaacag tcataacaag ccatgaaaac cgccactgcg ccgttaccac

9300

cgctgcgttc ggtcaaggtt ctggaccagt tgcgtgagcg catacgctac ttgcattaca

9360

gtttacgaac cgaacaggct tatgtcaact gggttcgtgc cttcatccgt ttccacggtg

9420

tgcgtcaccc ggcaaccttg ggcagcagcg aagtcgaggc atttctgtcc tggctggcga

9480

acgagcgcaa ggtttcggtc tccacgcatc gtcaggcatt ggcggccttg ctgttcttct

9540

acggcaaggt gctgtgcacg gatctgccct ggcttcagga gatcggaaga cctcggccgt

9600

cgcggcgctt gccggtggtg ctgaccccgg atgaagtggt tcgcatcctc ggttttctgg

9660

aaggcgagca tcgtttgttc gcccaggact ctagctatag ttctagtggt tggctacgta

9720

tactccggaa tattaataga tcatggagat aattaaaatg ataaccatct cgcaaataaa

9780

taagtatttt actgttttcg taacagtttt gtaataaaaa aacctataaa tattccggat

9840

tattcatacc gtcccaccat cgggcgcgga tctcggtccg aaaccatgtc gtactaccat

9900

caccatcacc atcacgatta cgatatccca acgaccgaaa acctgtattt tcagggcgcc

9960

atgggatcc

9969

<210> 205

<211> 10063

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 205

ggccggcccc tgcaggcagc tgcgcgctcg ctcgctcact gaggccgccc gggcaaagcc

60

cgggcgtcgg gcgacctttg gtcgcccggc ctcagtgagc gagcgagcgc gcagagaggg

120

agtggccaac tccatcacta ggggttcctt gtagttaatg attaacccgc catgctactt

180

atctacgtag ccatgctcta gaggaaccat tgccaccttc agggggaggc tgctggtgaa

240

tattaaccaa gatcacccca gttaccggag gagcaaacag ggactaagtt cacacgcgtg

300

gtaccgtctg tctgcacatt tcgtagagcg agtgttccga tactctaatc tccctaggca

360

aggttcatat ttgtgtaggt tacttattct ccttttgttg actaagtcaa taatcagaat

420

cagcaggttt ggagtcagct tggcagggat cagcagcctg ggttggaagg aggggtata

480

aaagcccctt caccaggaga agccgtcaca cagatccaca agctcctgaa gaggtaaggg

540

tttaagttat cgttagttcg tgcaccatta atgtttaatt acctggagca cctgcctgaa

600

atcatttttt tttcaggttg gctagtatgc agatcgagct ctccacctgc ttctttctgt

660

gcctgttgag attctgcttc agcgccacca ggagatacta cctggggggct gtggagctga

720

gctgggacta catgcagtct gacctggggg agctgcctgt ggatgccagg ttccccccca

780

gagtgcccaa gagcttcccc ttcaacacct ctgtggtgta caagaagacc ctgtttgtgg

840

agttcactga ccacctgttc aacattgcca agcccaggcc cccctggatg ggcctgctgg

900

gccccaccat ccaggctgag gtgtatgaca ctgtggtgat caccctgaag aacatggcca

960

gccaccctgt gagcctgcat gctgtggggg tgagctactg gaaggcctct gagggggctg

1020

agtatgatga ccagaccagc cagagggaga aggaggatga caaggtgttc cctgggggca

1080

gccacaccta tgtgtggcag gtgctgaagg agaatggccc catggcctct gaccccctgt

1140

gcctgaccta cagctacctg agccatgtgg acctggtgaa ggacctgaac tctggcctga

1200

ttggggccct gctggtgtgc agggagggca gcctggccaa ggagaagacc cagaccctgc

1260

acaagttcat cctgctgttt gctgtgtttg atgagggcaa gagctggcac tctgaaacca

1320

agaacagcct gatgcaggac agggatgctg cctctgccag ggcctggccc aagatgcaca

1380

ctgtgaatgg ctatgtgaac aggagcctgc ctggcctgat tggctgccac aggaagtctg

1440

tgtactggca tgtgattggc atgggcacca cccctgaggt gcacagcatc ttcctggagg

1500

gccacacctt cctggtcagg aaccacaggc aggccagcct ggagatcagc cccatcacct

1560

tcctgactgc ccagaccctg ctgatggacc tgggccagtt cctgctgttc tgccacatca

1620

gcagccacca gcatgatggc atggaggcct atgtgaaggt ggacagctgc cctgaggagc

1680

cccagctgag gatgaagaac aatgaggagg ctgaggacta tgatgatgac ctgactgact

1740

ctgagatgga tgtggtgagg tttgatgatg acaacagccc cagcttcatc cagatcaggt

1800

ctgtggccaa gaagcacccc aagacctggg tgcactacat tgctgctgag gaggaggact

1860

gggactatgc ccccctggtg ctggcccctg atgacaggag ctacaagagc cagtacctga

1920

acaatggccc ccagaggatt ggcaggaagt acaagaaggt caggttcatg gcctacactg

1980

atgaaacctt caagaccagg gaggccatcc agcatgagtc tggcatcctg ggccccctgc

2040

tgtatgggga ggtgggggac accctgctga tcatcttcaa gaaccaggcc agcaggccct

2100

acaacatcta cccccatggc atcactgatg tgaggcccct gtacagcagg aggctgccca

2160

aggggggtgaa gcacctgaag gacttcccca tcctgcctgg ggagatcttc aagtacaagt

2220

ggactgtgac tgtggaggat ggccccacca agtctgaccc caggtgcctg accagatact

2280

acagcagctt tgtgaacatg gagagggacc tggcctctgg cctgattggc cccctgctga

2340

tctgctacaa ggagtctgtg gaccagagg gcaaccagat catgtctgac aagaggaatg

2400

tgatcctgtt ctctgtgttt gatgagaaca ggagctggta cctgactgag aacatccaga

2460

ggttcctgcc caaccctgct ggggtgcagc tggaggaccc tgagttccag gccagcaaca

2520

tcatgcacag catcaatggc tatgtgtttg acagcctgca gctgtctgtg tgcctgcatg

2580

aggtggccta ctggtacatc ctgagcattg gggcccagac tgacttcctg tctgtgttct

2640

tctctggcta caccttcaag cacaagatgg tgtatgagga caccctgacc ctgttcccct

2700

tctctgggga gactgtgttc atgagcatgg agaaccctgg cctgtggatt ctgggctgcc

2760

acaactctga cttcaggaac aggggcatga ctgccctgct gaaagtctcc agctgtgaca

2820

agaacactgg ggactactat gaggacagct atgaggacat ctctgcctac ctgctgagca

2880

agaacaatgc cattgagccc aggagcttca gccagaatcc acccgtcctt aagcgccatc

2940

agcgcgagat caccaggacc accctgcagt ctgaccagga ggagattgac tatgatgaca

3000

ccatctctgt ggagatgaag aaggaggact ttgacatcta cgacgaggac gagaaccaga

3060

gccccaggag cttccagaag aagaccaggc actacttcat tgctgctgtg gagaggctgt

3120

gggactatgg catgagcagc agcccccatg tgctgaggaa cagggcccag tctggctctg

3180

tgccccagtt caagaaggtg gtgttccagg agttcactga tggcagcttc acccagcccc

3240

tgtacagagg ggagctgaat gagcacctgg gcctgctggg cccctacatc agggctgagg

3300

tggaggacaa catcatggtg accttcagga accaggccag caggccctac agcttctaca

3360

gcagcctgat cagctatgag gaggaccaga ggcagggggc tgagcccagg aagaactttg

3420

tgaagcccaa tgaaaccaag acctacttct ggaaggtgca gcaccacatg gcccccacca

3480

aggatgagtt tgactgcaag gcctgggcct acttctctga tgtggacctg gagaaggatg

3540

tgcactctgg cctgattggc cccctgctgg tgtgccacac caacaccctg aaccctgccc

3600

atggcaggca ggtgactgtg caggagtttg ccctgttctt caccatcttt gatgaaacca

3660

agagctggta cttcactgag aacatggaga ggaactgcag ggccccctgc aacatccaga

3720

tggaggaccc caccttcaag gagaactaca ggttccatgc catcaatggc tacatcatgg

3780

acaccctgcc tggcctggtg atggcccagg accagaggat caggtggtac ctgctgagca

3840

tgggcagcaa tgagaacatc cacagcatcc acttctctgg ccatgtgttc actgtgagga

3900

agaaggagga gtacaagatg gccctgtaca acctgtaccc tggggtgttt gagactgtgg

3960

agatgctgcc cagcaaggct ggcatctgga gggtggagtg cctgattggg gagcacctgc

4020

atgctggcat gagcaccctg ttcctggtgt acagcaacaa gtgccagacc cccctgggca

4080

tggcctctgg ccacatcagg gacttccaga tcactgcctc tggccagtat ggccagtggg

4140

cccccaagct ggccaggctg cactactctg gcagcatcaa tgcctggagc accaaggagc

4200

ccttcagctg gatcaaggtg gacctgctgg cccccatgat catccatggc atcaagaccc

4260

aggggggccag gcagaagttc agcagcctgt acatcagcca gttcatcatc atgtacagcc

4320

tggatggcaa gaagtggcag acctacaggg gcaacagcac tggcaccctg atggtgttct

4380

ttggcaatgt ggacagctct ggcatcaagc acaacatctt caaccccccc atcattgcca

4440

gatacatcag gctgcacccc acccactaca gcatcaggag caccctgagg atggagctga

4500

tgggctgtga cctgaacagc tgcagcatgc ccctgggcat ggagagcaag gccatctctg

4560

atgccgat cactgccagc agctacttca ccaacatgtt tgccacctgg agccccagca

4620

aggccaggct gcatctgcag ggcaggagca atgcctggag gccccaggtc aacaacccca

4680

aggagtggct gcaggtggac ttccagaaga ccatgaaggt gactggggtg accacccagg

4740

gggtgaagag cctgctgacc agcatgtatg tgaaggagtt cctgatcagc agcagccagg

4800

atggccacca gtggaccctg ttcttccaga atggcaaggt gaaggtgttc cagggcaacc

4860

aggacagctt cacccctgtg gtgaacagcc tggacccccc cctgctgacc agatacctga

4920

ggattcaccc ccagagctgg gtgcaccaga ttgccctgag gatggaggtg ctgggctgtg

4980

aggcccagga cctgtactga ggatccaata aaatatcttt attttcatta catctgtgtg

5040

ttggtttttt gtgtgttttc ctgtaacgat cgggtctaga gcatggctac gtagataagt

5100

agcatggcgg gttaatcatt aactacacct gcaggaggaa cccctagtga tggagttggc

5160

cactccctct ctgcgcgctc gctcgctcac tgaggccggg cgaccaaagg tcgcccgacg

5220

cccgggcggc ctcagtgagc gagcgagcgc gcagctgcct gcaggggcgc gcctcgaggc

5280

atgcggtacc aagcttgtcg agaagtacta gaggatcata atcagccata ccacatttgt

5340

agaggtttta cttgctttaa aaaacctccc acacctcccc ctgaacctga aacataaaat

5400

gaatgcaatt gttgttgtta acttgtttat tgcagcttat aatggttaca aataaagcaa

5460

tagcatcaca aatttcacaa ataaagcatt tttttcactg cattctagtt gtggtttgtc

5520

caaactcatc aatgtatctt atcatgtctg gatctgatca ctgatatcgc ctaggagatc

5580

cgaaccagat aagtgaaatc tagttccaaa ctattttgtc atttttaatt ttcgtattag

5640

cttacgacgc tacacccagt tcccatctat tttgtcactc ttccctaaat aatccttaaa

5700

aactccattt ccacccctcc cagttcccaa ctattttgtc cgcccacagc ggggcatttt

5760

tcttcctgtt atgtttttaa tcaaacatcc tgccaactcc atgtgacaaa ccgtcatctt

5820

cggctacttt ttctctgtca cagaatgaaa atttttctgt catctcttcg ttattaatgt

5880

ttgtaattga ctgaatatca acgcttattt gcagcctgaa tggcgaatgg gacgcgccct

5940

gtagcggcgc attaagcgcg gcgggtgtgg tggttacgcg cagcgtgacc gctacacttg

6000

ccagcgccct agcgcccgct cctttcgctt tcttcccttc ctttctcgcc acgttcgccg

6060

gctttccccg tcaagctcta aatcgggggc tccctttagg gttccgattt agtgctttac

6120

ggcacctcga ccccaaaaaa cttgattagg gtgatggttc acgtagtggg ccatcgccct

6180

gatagacggt ttttcgccct ttgacgttgg agtccacgtt ctttaatagt ggactcttgt

6240

tccaaactgg aacaacactc aaccctatct cggtctattc ttttgattta taagggattt

6300

tgccgatttc ggcctattgg ttaaaaaatg agctgattta acaaaaattt aacgcgaatt

6360

ttaacaaaat attaacgttt acaatttcag gtggcacttt tcggggaaat gtgcgcggaa

6420

cccctatttg tttatttttc taaatacatt caaatatgta tccgctcatg agacaataac

6480

cctgataaat gcttcaataa tattgaaaaa ggaagagtat gagtattcaa catttccgtg

6540

tcgcccttat tccctttttt gcggcatttt gccttcctgt ttttgctcac ccagaaacgc

6600

tggtgaaagt aaaagatgct gaagatcagt tgggtgcacg agtgggttac atcgaactgg

6660

atctcaacag cggtaagatc cttgagagtt ttcgccccga agaacgtttt ccaatgatga

6720

gcacttttaa agttctgcta tgtggcgcgg tattatcccg tattgacgcc gggcaagagc

6780

aactcggtcg ccgcatacac tattctcaga atgacttggt tgagtactca ccagtcacag

6840

aaaagcatct tacggatggc atgacagtaa gagaattatg cagtgctgcc ataaccatga

6900

gtgataacac tgcggccaac ttacttctga caacgatcgg aggaccgaag gagctaaccg

6960

cttttttgca caacatgggg gatcatgtaa ctcgccttga tcgttgggaa ccggagctga

7020

atgaagccat accaaacgac gagcgtgaca ccacgatgcc tgtagcaatg gcaacaacgt

7080

tgcgcaaact attaactggc gaactactta ctctagcttc ccggcaacaa ttaatagact

7140

ggatggaggc ggataaagtt gcaggaccac ttctgcgctc ggcccttccg gctggctggt

7200

ttattgctga taaatctgga gccggtgagc gtgggtctcg cggtatcatt gcagcactgg

7260

ggccagatgg taagccctcc cgtatcgtag ttatctacac gacggggagt caggcaacta

7320

tggatgaacg aaatagacag atcgctgaga taggtgcctc actgattaag cattggtaac

7380

tgtcagacca agtttactca tatatacttt agattgattt aaaacttcat ttttaattta

7440

aaaggatcta ggtgaagatc ctttttgata atctcatgac caaaatccct taacgtgagt

7500

tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa aggatcttct tgagatcctt

7560

tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc accgctacca gcggtggttt

7620

gtttgccgga tcaagagcta ccaactcttt ttccgaaggt aactggcttc agcagagcgc

7680

agataccaaa tactgtcctt ctagtgtagc cgtagttagg ccaccacttc aagaactctg

7740

tagcaccgcc tacatacctc gctctgctaa tcctgttacc agtggctgct gccagtggcg

7800

ataagtcgtg tcttaccggg ttggactcaa gacgatagtt accggataag gcgcagcggt

7860

cgggctgaac ggggggttcg tgcacacagc ccagcttgga gcgaacgacc tacaccgaac

7920

tgagatacct acagcgtgag cattgagaaa gcgccacgct tcccgaaggg agaaaggcgg

7980

acaggtatcc ggtaagcggc agggtcggaa caggagagcg cacgagggag cttccagggg

8040

gaaacgcctg gtatctttat agtcctgtcg ggtttcgcca cctctgactt gagcgtcgat

8100

ttttgtgatg ctcgtcaggg gggcggagcc tatggaaaaa cgccagcaac gcggcctttt

8160

tacggttcct ggccttttgc tggccttttg ctcacatgtt ctttcctgcg ttatcccctg

8220

attctgtgga taaccgtatt accgcctttg agtgagctga taccgctcgc cgcagccgaa

8280

cgaccgagcg cagcgagtca gtgagcgagg aagcggaaga gcgcctgatg cggtattttc

8340

tccttacgca tctgtgcggt atttcacacc gcagaccagc cgcgtaacct ggcaaaatcg

8400

gttacggttg agtaataaat ggatgccctg cgtaagcggg tgtgggcgga caataaagtc

8460

ttaaactgaa caaaatagat ctaaactatg acaataaagt cttaaactag acagaatagt

8520

tgtaaactga aatcagtcca gttatgctgt gaaaaagcat actggacttt tgttatggct

8580

aaagcaaact cttcattttc tgaagtgcaa attgcccgtc gtattaaaga ggggcgtggc

8640

caagggcatg gtaaagacta tattcgcggc gttgtgacaa tttaccgaac aactccgcgg

8700

ccgggaagcc gatctcggct tgaacgaatt gttaggtggc ggtacttggg tcgatatcaa

8760

agtgcatcac ttcttcccgt atgcccaact ttgtatagag agccactgcg ggatcgtcac

8820

cgtaatctgc ttgcacgtag atcacataag caccaagcgc gttggcctca tgcttgagga

8880

gattgatgag cgcggtggca atgccctgcc tccggtgctc gccggagact gcgagatcat

8940

agatatagat ctcactacgc ggctgctcaa acctgggcag aacgtaagcc gcgagagcgc

9000

caacaaccgc ttcttggtcg aaggcagcaa gcgcgatgaa tgtcttacta cggagcaagt

9060

tcccgaggta atcggagtcc ggctgatgtt gggagtaggt ggctacgtct ccgaactcac

9120

gaccgaaaag atcaagagca gcccgcatgg atttgacttg gtcagggccg agcctacatg

9180

tgcgaatgat gcccatactt gagccaccta actttgtttt agggcgactg ccctgctgcg

9240

taacatcgtt gctgctgcgt aacatcgttg ctgctccata acatcaaaca tcgacccacg

9300

gcgtaacgcg cttgctgctt ggatgcccga ggcatagact gtacaaaaaa acagtcataa

9360

caagccatga aaaccgccac tgcgccgtta ccaccgctgc gttcggtcaa ggttctggac

9420

cagttgcgtg agcgcatacg ctacttgcat tacagtttac gaaccgaaca ggcttatgtc

9480

aactgggttc gtgccttcat ccgtttccac ggtgtgcgtc acccggcaac cttgggcagc

9540

agcgaagtcg aggcatttct gtcctggctg gcgaacgagc gcaaggtttc ggtctccacg

9600

catcgtcagg cattggcggc cttgctgttc ttctacggca aggtgctgtg cacggatctg

9660

ccctggcttc aggagatcgg aagacctcgg ccgtcgcggc gcttgccggt ggtgctgacc

9720

ccggatgaag tggttcgcat cctcggtttt ctggaaggcg agcatcgttt gttcgcccag

9780

gactctagct atagttctag tggttggcta cgtatactcc ggaatattaa tagatcatgg

9840

agataattaa aatgataacc atctcgcaaa taaataagta ttttactgtt ttcgtaacag

9900

ttttgtaata aaaaaaccta taaatattcc ggattattca taccgtccca ccatcgggcg

9960

cggatctcgg tccgaaacca tgtcgtacta ccatcaccat caccatcacg attacgatat

10020

cccaacgacc gaaaacctgt attttcaggg cgccatggga tcc

10063

<210> 206

<211> 11668

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 206

ggccggcccc tgcaggcagc tgcgcgctcg ctcgctcact gaggccgccc gggcaaagcc

60

cgggcgtcgg gcgacctttg gtcgcccggc ctcagtgagc gagcgagcgc gcagagaggg

120

agtggccaac tccatcacta ggggttcctt gtagttaatg attaacccgc catgctactt

180

atctacgtag ccatgctcta gaaggctcag aggcacacag gagtttctgg gctcaccctg

240

cccccttcca acccctcagt tcccatcctc cagcagctgt ttgtgtgctg cctctgaagt

300

cccacactgaa caaacttcag cctactcatg tccctaaaat gggcaaacat tgcaagcagc

360

aaacagcaaa cacacagccc tccctgcctg ctgaccttgg agctggggca gaggtcagag

420

acctctctgg gcccatgcca cctccaacat ccactcgacc ccttggaatt tcggtggaga

480

ggagcagagg ttgtcctggc gtggtttagg tagtgtgaga gggtccgggt tcaaaaccac

540

ttgctgggtg gggagtcgtc agtaagtggc tatgccccga ccccgaagcc tgtttcccca

600

tctgtacaat ggaaatgata aagacgccca tctgataggg tttttgtggc aaataaacat

660

ttggtttttt tgttttgttt tgttttgttt tttgagatgg aggtttgctc tgtcgcccag

720

gctggagtgc agtgacacaa tctcatctca ccacaacctt cccctgcctc agcctcccaa

780

gtagctggga ttacaagcat gtgccaccac acctggctaa ttttctattt ttagtagaga

840

cgggtttctc catgttggtc agcctcagcc tcccaagtaa ctgggattac aggcctgtgc

900

caccacaccc ggctaatttt ttctattttt gacagggacg gggtttcacc atgttggtca

960

ggctggtcta gaggtaccgg atcttgctac cagtggaaca gccactaagg attctgcagt

1020

gagagcagag ggccagctaa gtggtactct cccagagact gtctgactca cgccaccccc

1080

tccaccttgg acacaggacg ctgtggtttc tgagccaggt acaatgactc ctttcggtaa

1140

gtgcagtgga agctgtacac tgcccaggca aagcgtccgg gcagcgtagg cgggcgactc

1200

agatcccagc cagtggactt agcccctgtt tgctcctccg ataactgggg tgaccttggt

1260

taatattcac cagcagcctc ccccgttgcc cctctggatc cactgcttaa atacggacga

1320

ggacagggcc ctgtctcctc agcttcaggc accaccactg acctgggaca gtgaatccgg

1380

actctaaggt aaatataaaa tttttaagtg tataatgtgt taaactactg attctaattg

1440

tttctctctt ttagattcca acctttggaa ctgagtttaa acgccgccac catgcagatc

1500

gagctgtcta cctgcttctt cctgtgcctg ctgcggttct gcttcagcgc caccagaaga

1560

tattacctgg gcgccgtgga actgagctgg gactacatgc agtctgacct gggagagctg

1620

cccgtggacg ctagatttcc tccaagagtg cccaagagct tccccttcaa cacctccgtg

1680

gtgtacaaga aaaccctgtt cgtggaattc accgaccacc tgttcaatat cgccaagcct

1740

cggcctcctt ggatgggact gctgggacct acaattcagg ccgaggtgta cgacaccgtg

1800

gtcatcaccc tgaagaacat ggccagccat cctgtgtctc tgcacgccgt gggagtgtct

1860

tattggaagg cttctgaggg cgccgagtac gacgatcaga caagccagag agagaaagag

1920

gacgacaagg ttttccctgg cggcagccac acctatgtct ggcaggtcct gaaagaaaac

1980

ggccctatgg cctccgatcc tctgtgcctg acatacagct acctgagcca cgtggacctg

2040

gtcaaggacc tgaattctgg cctgatcgga gccctgctcg tgtgtagaga aggcagcctg

2100

gccaaagaga aaacccagac actgcacaag ttcatcctgc tgttcgccgt gttcgacgag

2160

ggcaagagct ggcacagcga gacaaagaac agcctgatgc aggacagga tgccgcctct

2220

gctagagctt ggcctaagat gcacaccgtg aacggctacg tgaacagaag cctgcctgga

2280

ctgatcggct gccacagaaa gtccgtgtac tggcacgtga tcggcatggg cacaacacct

2340

gaggtgcaca gcatctttct ggaaggccac accttcctcg tgcggaacca cagacaggcc

2400

agcctggaaa tcagccctat caccttcctg accgctcaga ccctgctgat ggatctgggc

2460

cagtttctgc tgttctgcca catcagctcc caccagcacg atggcatgga agcctacgtg

2520

aaggtggaca gctgccccga agaaccccag ctgcggatga agaacaacga ggaagccgag

2580

gactacgacg acgacctgac cgactctgag atggacgtcg tcagattcga cgacgataac

2640

agccccagct tcatccagat cagaagcgtg gccaagaagc accccaagac ctgggtgcac

2700

tatatcgccg ccgaggaaga ggactgggat tacgctcctc tggtgctggc ccctgacgac

2760

agaagctaca agagccagta cctgaacaac ggccctcagc ggatcggccg gaagtataag

2820

aaagtgcggt tcatggccta caccgacgag acattcaaga ccagagaggc catccagcac

2880

gagagcggaa ttctgggccc tctgctgtat ggcgaagtgg gcgatacact gctgatcatc

2940

ttcaagaacc aggccagcag accctacaac atctaccctc acggcatcac cgatgtgcgg

3000

cccctgtatt ctagaaggct gcccaagggc gtgaagcacc tgaaggactt ccctatcctg

3060

cctggcgaga ttttcaagta caagtggacc gtgaccgtgg aagatggccc caccaagagc

3120

gaccctagat gtctgacacg gtactacagc agcttcgtga acatggaacg cgacctggcc

3180

agcggcctga ttggacctct gctgatctgc tacaaagaaa gcgtggacca gcggggcaac

3240

cagatcatga gcgacaagcg gaacgtgatc ctgtttagcg tgttcgatga gaaccggtcc

3300

tggtatctga ccgagaacat ccagcggttt ctgcccaatc ctgccggggt gcaactggaa

3360

gatcctgagt tccaggcaag caacatcatg cactccatca atggctatgt gttcgacagc

3420

ctgcagctga gcgtgtgcct gcacgaagtg gcctactggt acatcctgag cattggcgcc

3480

cagaccgact tcctgtccgt gttctttagc ggctacacct tcaagcacaa gatggtgtac

3540

gaggataccc tgacactgtt cccattcagc ggcgagacag tgttcatgag catggaaaac

3600

cccggcctgt ggattctggg ctgtcacaac agcgacttcc ggaacagagg catgacagcc

3660

ctgctgaagg tgtccagctg cgacaagaac accggcgact actacgagga cagctatgag

3720

gacatcagcg cctacctgct gagcaagaac aatgccatcg agcctcggag cttcagccag

3780

aatcctcctg tgctgaagcg gcaccagcgc gagatcacca gaacaaccct gcagagcgac

3840

caagaggaaa tcgattacga cgacaccatc agcgtcgaga tgaagaaaga agatttcgac

3900

atctacgacg aggacgagaa tcagagcccc agaagctttc agaaaaagac ccggcactac

3960

ttcattgccg ccgtcgagag actgtgggac tacggcatgt ctagcagccc tcacgtgctg

4020

agaaatagag cccagagcgg cagcgtgccc cagttcaaga aagtggtgtt ccaagagttc

4080

accgacggca gcttcaccca gccactgtat agaggcgagc tgaacgagca tctgggcctg

4140

ctgggccctt atatcagagc cgaagtggaa gataacatca tggtcacctt ccggaatcag

4200

gctagccggc cttacagctt ctacagctcc ctgatcagct acgaagagga ccagagacag

4260

ggcgctgagc ccagaaagaa cttcgtgaag cccaacgaga ctaagaccta cttttggaag

4320

gtgcagcacc acatggcccc tacaaaggac gagttcgact gcaaagcctg ggcctacttc

4380

tccgatgtgg atctggaaaa ggacgtgcac agcgggctca tcggaccact gcttgtgtgc

4440

cacaccaaca cactgaaccc cgctcacggc agacaagtga cagtgcaaga gttcgccctg

4500

ttcttcacca tcttcgacga aacaaagagc tggtacttca ccgagaatat ggaacggaac

4560

tgcagagccc cttgcaacat ccagatggaa gatcccacct tcaaagagaa ctaccggttc

4620

cacgccatca acggctacat catggacaca ctgcccggcc tggttatggc ccaggatcag

4680

agaatccggt ggtatctgct gtccatgggc tccaacgaga atatccacag catccacttc

4740

agcggccacg tgttcaccgt gcggaaaaaa gaagagtaca aaatggccct gtacaatctg

4800

taccctgggg tgttcgaaac cgtggaaatg ctgccttcca aggccggcat ttggagagtg

4860

gaatgtctga ttggagagca cctccacgcc ggaatgagca ccctgtttct ggtgtacagc

4920

aacaagtgtc agacccctct cggcatggcc tctggacaca tcagagactt cgagatcacc

4980

gcctctggcc agtacggaca gtgggctcct aaactggctc ggctgcacta cagcggcagc

5040

atcaatgcct ggtccaccaa agagcccttc agctggatca aggtggacct gctggctccc

5100

atgatcatcc acggaatcaa gacccagggc gccagacaga agttcagcag cctgtacatc

5160

agccagttca tcatcatgta cagcctggac ggcaagaagt ggcagaccta cagaggcaac

5220

agcaccggca cactcatggt gttcttcggc aacgtggact ccagcggcat taagcacaac

5280

atcttcaacc ctccaatcat tgcccggtac atccggctgc accccacaca ctacagcatc

5340

cggtctaccc tgagaatgga actgatgggc tgcgacctga acagctgctc tatgcccctc

5400

ggaatggaaa gcaaggccat cagcgacgcc cagatcacag ccagcagcta cttcaccaac

5460

atgttcgcca cttggagccc ctccaaggct agactgcatc tgcagggcag aagcaacgct

5520

tggaggcccc aagtgaacaa ccccaaagag tggctgcagg ttgactttca aaagaccatg

5580

aaagtgaccg gcgtgaccac acagggcgtc aagtctctgc tgacctctat gtacgtgaaa

5640

gagttcctga tctccagcag ccaggacggc catcagtgga ccctgttttt ccagaacggc

5700

aaagtgaaag tgttccaggg caatcaggac agcttcacac ccgtggtcaa ttctctggac

5760

cctccactgc tgaccagata cctgcggatt caccctcagt cttgggtgca ccagatcgct

5820

ctgcggatgg aagtgctggg ctgtgaagct caggacctct actagttaat taagagcatc

5880

ttaccgccat ttattcccat atttgttctg tttttcttga tttgggtata catttaaatg

5940

ttaataaaac aaaatggtgg ggcaatcatt tacattttta gggatatgta attactagtt

6000

caggtgtatt gccacaagac aaacatgtta agaaactttc ccgttattta cgctctgttc

6060

ctgttaatca acctctggat tacaaaattt gtgaaagatt gactgatatt cttaactatg

6120

ttgctccttt tacgctgtgt ggatatgctg ctttatagcc tctgtatcta gctattgctt

6180

cccgtacggc tttcgttttc tcctccttgt ataaatcctg gttgctgtct cttttagagg

6240

agttgtggcc cgttgtccgt caacgtggcg tggtgtgctc tgtgtttgct gacgcaaccc

6300

ccactggctg gggcattgcc accacctgtc aactcctttc tgggactttc gctttccccc

6360

tcccgatcgc cacggcagaa ctcatcgccg cctgccttgc ccgctgctgg acaggggcta

6420

ggttgctggg cactgataat tccgtggtgt tgtctgtgcc ttctagttgc cagccatctg

6480

ttgtttgccc ctcccccgtg ccttccttga ccctggaagg tgccactccc actgtccttt

6540

cctaataaaa tgaggaaatt gcatcgcatt gtctgagtag gtgtcattct attctggggg

6600

gtggggtggg gcaggacagc aagggggagg attgggaaga caatagcagg catgctgggg

6660

atgcggtggg ctctatggct ctagagcatg gctacgtaga taagtagcat ggcgggttaa

6720

tcattaacta cacctgcagg aggaacccct agtgatggag ttggccactc cctctctgcg

6780

cgctcgctcg ctcactgagg ccgggcgacc aaaggtcgcc cgacgcccgg gcggcctcag

6840

tgagcgagcg agcgcgcagc tgcctgcagg ggcgcgcctc gaggcatgcg gtaccaagct

6900

tgtcgagaag tactagagga tcataatcag ccataccaca tttgtagagg ttttacttgc

6960

tttaaaaaac ctcccacacc tccccctgaa cctgaaacat aaaatgaatg caattgttgt

7020

tgttaacttg tttattgcag cttataatgg ttacaaataa agcaatagca tcacaaattt

7080

cacaaataaa gcattttttt cactgcattc tagttgtggt ttgtccaaac tcatcaatgt

7140

atcttatcat gtctggatct gatcactgat atcgcctagg agatccgaac cagataagtg

7200

aaatctagtt ccaaactatt ttgtcatttt taattttcgt attagcttac gacgctacac

7260

ccagttccca tctattttgt cactcttccc taaataatcc ttaaaaactc catttccacc

7320

cctcccagtt cccaactatt ttgtccgccc acagcggggc atttttcttc ctgttatgtt

7380

tttaatcaaa catcctgcca actccatgtg acaaaccgtc atcttcggct actttttctc

7440

tgtcacagaa tgaaaatttt tctgtcatct cttcgttatt aatgtttgta attgactgaa

7500

tatcaacgct tatttgcagc ctgaatggcg aatgggacgc gccctgtagc ggcgcattaa

7560

gcgcggcggg tgtggtggtt acgcgcagcg tgaccgctac acttgccagc gccctagcgc

7620

ccgctccttt cgctttcttc ccttcctttc tcgccacgtt cgccggcttt ccccgtcaag

7680

ctctaaatcg ggggctccct ttagggttcc gatttagtgc tttacggcac ctcgacccca

7740

aaaaacttga ttagggtgat ggttcacgta gtgggccatc gccctgatag acggtttttc

7800

gccctttgac gttggagtcc acgttcttta atagtggact cttgttccaa actggaacaa

7860

cactcaaccc tatctcggtc tattcttttg atttataagg gattttgccg atttcggcct

7920

attggttaaa aaatgagctg atttaacaaa aatttaacgc gaattttaac aaaatattaa

7980

cgtttacaat ttcaggtggc acttttcggg gaaatgtgcg cggaacccct atttgtttat

8040

ttttctaaat acattcaaat atgtatccgc tcatgagaca ataaccctga taaatgcttc

8100

aataatattg aaaaaggaag agtatgagta ttcaacattt ccgtgtcgcc cttattccct

8160

tttttgcggc attttgcctt cctgtttttg ctcacccaga aacgctggtg aaagtaaaag

8220

atgctgaaga tcagttgggt gcacgagtgg gttacatcga actggatctc aacagcggta

8280

agatccttga gagttttcgc cccgaagaac gttttccaat gatgagcact tttaaagttc

8340

tgctatgtgg cgcggtatta tcccgtattg acgccgggca agagcaactc ggtcgccgca

8400

tacactattc tcagaatgac ttggttgagt actcaccagt cacagaaaag catcttacgg

8460

atggcatgac agtaagagaa ttatgcagtg ctgccataac catgagtgat aacactgcgg

8520

ccaacttact tctgacaacg atcggaggac cgaaggagct aaccgctttt ttgcacaaca

8580

tgggggatca tgtaactcgc cttgatcgtt gggaaccgga gctgaatgaa gccataccaa

8640

acgacgagcg tgacaccacg atgcctgtag caatggcaac aacgttgcgc aaactattaa

8700

ctggcgaact acttactcta gcttcccggc aacaattaat agactggatg gaggcggata

8760

aagttgcagg accacttctg cgctcggccc ttccggctgg ctggtttatt gctgataaat

8820

ctggagccgg tgagcgtggg tctcgcggta tcattgcagc actggggcca gatggtaagc

8880

cctcccgtat cgtagttatc tacacgacgg ggagtcaggc aactatggat gaacgaaata

8940

gacagatcgc tgagataggt gcctcactga ttaagcattg gtaactgtca gaccaagttt

9000

actcatatat actttagatt gatttaaaac ttcattttta atttaaaagg atctaggtga

9060

agatcctttt tgataatctc atgaccaaaa tcccttaacg tgagttttcg ttccactgag

9120

cgtcagaccc cgtagaaaag atcaaaggat cttcttgaga tccttttttt ctgcgcgtaa

9180

tctgctgctt gcaaacaaaa aaaccaccgc taccagcggt ggtttgtttg ccggatcaag

9240

agctaccaac tctttttccg aaggtaactg gcttcagcag agcgcagata ccaaatactg

9300

tccttctagt gtagccgtag ttaggccacc acttcaagaa ctctgtagca ccgcctacat

9360

acctcgctct gctaatcctg ttaccagtgg ctgctgccag tggcgataag tcgtgtctta

9420

ccgggttgga ctcaagacga tagttaccgg ataaggcgca gcggtcgggc tgaacggggg

9480

gttcgtgcac acagcccagc ttggagcgaa cgacctacac cgaactgaga tacctacagc

9540

gtgagcattg agaaagcgcc acgcttcccg aagggagaaa ggcggacagg tatccggtaa

9600

gcggcagggt cggaacagga gagcgcacga gggagcttcc agggggaaac gcctggtatc

9660

tttatagtcc tgtcgggttt cgccacctct gacttgagcg tcgatttttg tgatgctcgt

9720

caggggggcg gagcctatgg aaaaacgcca gcaacgcggc ctttttacgg ttcctggcct

9780

tttgctggcc ttttgctcac atgttctttc ctgcgttatc ccctgattct gtggataacc

9840

gtattaccgc ctttgagtga gctgataccg ctcgccgcag ccgaacgacc gagcgcagcg

9900

agtcagtgag cgaggaagcg gaagagcgcc tgatgcggta ttttctcctt acgcatctgt

9960

gcggtatttc acaccgcaga ccagccgcgt aacctggcaa aatcggttac ggttgagtaa

10020

taaatggatg ccctgcgtaa gcgggtgtgg gcggacaata aagtcttaaa ctgaacaaaa

10080

tagatctaaa ctatgacaat aaagtcttaa actagacaga atagttgtaa actgaaatca

10140

gtccagttat gctgtgaaaa agcatactgg acttttgtta tggctaaagc aaactcttca

10200

ttttctgaag tgcaaattgc ccgtcgtatt aaagaggggc gtggccaagg gcatggtaaa

10260

gactatattc gcggcgttgt gacaatttac cgaacaactc cgcggccggg aagccgatct

10320

cggcttgaac gaattgttag gtggcggtac ttgggtcgat atcaaagtgc atcacttctt

10380

cccgtatgcc caactttgta tagagagcca ctgcgggatc gtcaccgtaa tctgcttgca

10440

cgtagatcac ataagcacca agcgcgttgg cctcatgctt gaggagattg atgagcgcgg

10500

tggcaatgcc ctgcctccgg tgctcgccgg agactgcgag atcatagata tagatctcac

10560

tacgcggctg ctcaaacctg ggcagaacgt aagccgcgag agcgccaaca accgcttctt

10620

ggtcgaaggc agcaagcgcg atgaatgtct tactacggag caagttcccg aggtaatcgg

10680

agtccggctg atgttgggag taggtggcta cgtctccgaa ctcacgaccg aaaagatcaa

10740

gagcagcccg catggatttg acttggtcag ggccgagcct acatgtgcga atgatgccca

10800

tacttgagcc acctaacttt gttttagggc gactgccctg ctgcgtaaca tcgttgctgc

10860

tgcgtaacat cgttgctgct ccataacatc aaacatcgac ccacggcgta acgcgcttgc

10920

tgcttggatg cccgaggcat agactgtaca aaaaaacagt cataacaagc catgaaaacc

10980

gccactgcgc cgttaccacc gctgcgttcg gtcaaggttc tggaccagtt gcgtgagcgc

11040

atacgctact tgcattacag tttacgaacc gaacaggctt atgtcaactg ggttcgtgcc

11100

ttcatccgtt tccacggtgt gcgtcacccg gcaaccttgg gcagcagcga agtcgaggca

11160

tttctgtcct ggctggcgaa cgagcgcaag gtttcggtct ccacgcatcg tcaggcattg

11220

gcggccttgc tgttcttcta cggcaaggtg ctgtgcacgg atctgccctg gcttcaggag

11280

atcggaagac ctcggccgtc gcggcgcttg ccggtggtgc tgaccccgga tgaagtggtt

11340

cgcatcctcg gttttctgga aggcgagcat cgtttgttcg cccaggactc tagctatagt

11400

tctagtggtt ggctacgtat actccggaat attaatagat catggagata attaaaatga

11460

taaccatctc gcaaataaat aagtatttta ctgttttcgt aacagttttg taataaaaaa

11520

acctataaat attccggatt attcataccg tcccaccatc gggcgcggat ctcggtccga

11580

aaccatgtcg tactaccatc accatcacca tcacgattac gatatcccaa cgaccgaaaa

11640

cctgtatttt cagggcgcca tgggatcc

11668

<210> 207

<211> 11719

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 207

ggccggcccc tgcaggcagc tgcgcgctcg ctcgctcact gaggccgccc gggcaaagcc

60

cgggcgtcgg gcgacctttg gtcgcccggc ctcagtgagc gagcgagcgc gcagagaggg

120

agtggccaac tccatcacta ggggttcctt gtagttaatg attaacccgc catgctactt

180

atctacgtag ccatgctcta gaaggctcag aggcacacag gagtttctgg gctcaccctg

240

cccccttcca acccctcagt tcccatcctc cagcagctgt ttgtgtgctg cctctgaagt

300

cccacactgaa caaacttcag cctactcatg tccctaaaat gggcaaacat tgcaagcagc

360

aaacagcaaa cacacagccc tccctgcctg ctgaccttgg agctggggca gaggtcagag

420

acctctctgg gcccatgcca cctccaacat ccactcgacc ccttggaatt tcggtggaga

480

ggagcagagg ttgtcctggc gtggtttagg tagtgtgaga gggtccgggt tcaaaaccac

540

ttgctgggtg gggagtcgtc agtaagtggc tatgccccga ccccgaagcc tgtttcccca

600

tctgtacaat ggaaatgata aagacgccca tctgataggg tttttgtggc aaataaacat

660

ttggtttttt tgttttgttt tgttttgttt tttgagatgg aggtttgctc tgtcgcccag

720

gctggagtgc agtgacacaa tctcatctca ccacaacctt cccctgcctc agcctcccaa

780

gtagctggga ttacaagcat gtgccaccac acctggctaa ttttctattt ttagtagaga

840

cgggtttctc catgttggtc agcctcagcc tcccaagtaa ctgggattac aggcctgtgc

900

caccacaccc ggctaatttt ttctattttt gacagggacg gggtttcacc atgttggtca

960

ggctggtcta gaggtaccgg atcttgctac cagtggaaca gccactaagg attctgcagt

1020

gagagcagag ggccagctaa gtggtactct cccagagact gtctgactca cgccaccccc

1080

tccaccttgg acacaggacg ctgtggtttc tgagccaggt acaatgactc ctttcggtaa

1140

gtgcagtgga agctgtacac tgcccaggca aagcgtccgg gcagcgtagg cgggcgactc

1200

agatcccagc cagtggactt agcccctgtt tgctcctccg ataactgggg tgaccttggt

1260

taatattcac cagcagcctc ccccgttgcc cctctggatc cactgcttaa atacggacga

1320

ggacagggcc ctgtctcctc agcttcaggc accaccactg acctgggaca gtgaatccgg

1380

actctaaggt aaatataaaa tttttaagtg tataatgtgt taaactactg attctaattg

1440

tttctctctt ttagattcca acctttggaa ctgagtttaa acgccgccac catgcagatt

1500

gagctgagca cctgcttctt cctgtgcctg ctgaggttct gcttctctgc caccaggaga

1560

tactacctgg gggctgtgga gctgagctgg gactacatgc agtctgacct gggggagctg

1620

cctgtggatg ccaggttccc ccccagagtg cccaagagct tccccttcaa cacctctgtg

1680

gtgtacaaga agaccctgtt tgtggagttc actgaccacc tgttcaacat tgccaagccc

1740

aggcccccct ggatgggcct gctgggcccc accatccagg ctgaggtgta tgacactgtg

1800

gtgatcaccc tgaagaacat ggccagccac cctgtgagcc tgcatgctgt gggggtgagc

1860

tactggaagg cctctgaggg ggctgagtat gatgaccaga ccagccagag ggagaaggag

1920

gatgacaagg tgttccctgg gggcagccac acctatgtgt ggcaggtgct gaaggagaat

1980

ggccccatgg cctctgaccc cctgtgcctg acctacagct acctgagcca tgtggacctg

2040

gtgaaggacc tgaactctgg cctgattggg gccctgctgg tgtgcaggga gggcagcctg

2100

gccaaggaga agacccagac cctgcacaag ttcatcctgc tgtttgctgt gtttgatgag

2160

ggcaagagct ggcactctga aaccaagaac agcctgatgc aggacagga tgctgcctct

2220

gccagggcct ggcccaagat gcacactgtg aatggctatg tgaacaggag cctgcctggc

2280

ctgattggct gccacaggaa gtctgtgtac tggcatgtga ttggcatggg caccacccct

2340

gaggtgcaca gcatcttcct ggagggccac accttcctgg tcaggaacca caggcaggcc

2400

agcctggaga tcagccccat caccttcctg actgcccaga ccctgctgat ggacctgggc

2460

cagttcctgc tgttctgcca catcagcagc caccagcatg atggcatgga ggcctatgtg

2520

aaggtggaca gctgccctga ggagccccag ctgaggatga agaacaatga ggaggctgag

2580

gactatgatg atgacctgac tgactctgag atggatgtgg tgaggtttga tgatgacaac

2640

agccccagct tcatccagat caggtctgtg gccaagaagc accccaagac ctgggtgcac

2700

tacattgctg ctgaggagga ggactgggac tatgcccccc tggtgctggc ccctgatgac

2760

aggagctaca agagccagta cctgaacaat ggcccccaga ggattggcag gaagtacaag

2820

aaggtcaggt tcatggccta cactgatgaa accttcaaga ccagggaggc catccagcat

2880

gagtctggca tcctgggccc cctgctgtat ggggaggtgg gggacaccct gctgatcatc

2940

ttcaagaacc aggccagcag gccctacaac atctaccccc atggcatcac tgatgtgagg

3000

cccctgtaca gcaggaggct gcccaagggg gtgaagcacc tgaaggactt ccccatcctg

3060

cctggggaga tcttcaagta caagtggact gtgactgtgg aggatggccc caccaagtct

3120

gaccccaggt gcctgaccag atactacagc agctttgtga acatggagag ggacctggcc

3180

tctggcctga ttggccccct gctgatctgc tacaaggagt ctgtggacca gaggggcaac

3240

cagatcatgt ctgacaagag gaatgtgatc ctgttctctg tgtttgatga gaacaggagc

3300

tggtacctga ctgagaacat ccagaggttc ctgcccaacc ctgctggggt gcagctggag

3360

gaccctgagt tccaggccag caacatcatg cacagcatca atggctatgt gtttgacagc

3420

ctgcagctgt ctgtgtgcct gcatgaggtg gcctactggt acatcctgag cattggggcc

3480

cagactgact tcctgtctgt gttcttctct ggctacacct tcaagcacaa gatggtgtat

3540

gaggacaccc tgaccctgtt ccccttctct ggggagactg tgttcatgag catggagaac

3600

cctggcctgt ggattctggg ctgccacaac tctgacttca ggaacagggg catgactgcc

3660

ctgctgaaag tctccagctg tgacaagaac actggggact actatgagga cagctatgag

3720

gacatctctg cctacctgct gagcaagaac aatgccattg agcccaggag cttcagccag

3780

aatgccacta atgtgtctaa caacagcaac accagcaatg acagcaatgt gtctccccca

3840

gtgctgaaga ggcaccagag ggagatcacc aggaccaccc tgcagtctga cccaggagg

3900

attgactatg atgacaccat ctctgtggag atgaagaagg aggactttga catctacgac

3960

gaggacgaga accagagccc caggagcttc cagaagaaga ccaggcacta cttcattgct

4020

gctgtggaga ggctgtggga ctatggcatg agcagcagcc cccatgtgct gaggaacagg

4080

gcccagtctg gctctgtgcc ccagttcaag aaggtggtgt tccaggagtt cactgatggc

4140

agcttcaccc agcccctgta cagaggggag ctgaatgagc acctgggcct gctgggcccc

4200

tacatcaggg ctgaggtgga ggacaacatc atggtgacct tcaggaacca ggccagcagg

4260

ccctacagct tctacagcag cctgatcagc tatgaggagg accagaggca gggggctgag

4320

cccaggaaga actttgtgaa gcccaatgaa accaagacct acttctggaa ggtgcagcac

4380

cacatggccc ccaccaagga tgagtttgac tgcaaggcct gggcctactt ctctgatgtg

4440

gacctggaga aggatgtgca ctctggcctg attggccccc tgctggtgtg ccacaccaac

4500

accctgaacc ctgcccatgg caggcaggtg actngtgcagg agtttgccct gttcttcacc

4560

atctttgatg aaaccaagag ctggtacttc actgagaaca tggagaggaa ctgcagggcc

4620

ccctgcaaca tccagatgga ggaccccacc ttcaaggaga actacaggtt ccatgccatc

4680

aatggctaca tcatggacac cctgcctggc ctggtgatgg cccaggacca gaggatcagg

4740

tggtacctgc tgagcatggg cagcaatgag aacatccaca gcatccactt ctctggccat

4800

gtgttcactg tgaggaagaa ggaggagtac aagatggccc tgtacaacct gtaccctggg

4860

gtgtttgaga ctgtggagat gctgcccagc aaggctggca tctggagggt ggagtgcctg

4920

attggggagc acctgcatgc tggcatgagc accctgttcc tggtgtacag caacaagtgc

4980

cagacccccc tgggcatggc ctctggccac atcagggact tccagatcac tgcctctggc

5040

cagtatggcc agtgggcccc caagctggcc aggctgcact actctggcag catcaatgcc

5100

tggagcacca aggagccctt cagctggatc aaggtggacc tgctggcccc catgatcatc

5160

catggcatca agacccagg ggccaggcag aagttcagca gcctgtacat cagccagttc

5220

atcatcatgt acagcctgga tggcaagaag tggcagacct acaggggcaa cagcactggc

5280

accctgatgg tgttctttgg caatgtggac agctctggca tcaagcacaa catcttcaac

5340

ccccccatca ttgccagata catcaggctg caccccaccc actacagcat caggagcacc

5400

ctgaggatgg agctgatggg ctgtgacctg aacagctgca gcatgcccct gggcatggag

5460

agcaaggcca tctctgatgc ccagatcact gccagcagct acttcaccaa catgtttgcc

5520

acctggagcc ccagcaaggc caggctgcac ctgcagggca ggagcaatgc ctggaggccc

5580

caggtcaaca accccaagga gtggctgcag gtggacttcc agaagaccat gaaggtgact

5640

ggggtgacca cccagggggt gaagagcctg ctgaccagca tgtatgtgaa ggagttcctg

5700

atcagcagca gccaggatgg ccaccagtgg accctgttct tccagaatgg caaggtgaag

5760

gtgttccagg gcaaccagga cagcttcacc cctgtggtga acagcctgga cccccccctg

5820

ctgaccagat acctgaggat tcacccccag agctgggtgc accagattgc cctgaggatg

5880

gaggtgctgg gctgtgaggc ccaggacctg tactgattaa ttaagagcat cttaccgcca

5940

tttattccca tatttgttct gtttttcttg atttgggtat acatttaaat gttaataaaa

6000

caaaatggtg gggcaatcat ttacattttt agggatatgt aattactagt tcaggtgtat

6060

tgccacaaga caaacatgtt aagaaacttt cccgttattt acgctctgtt cctgttaatc

6120

aacctctgga ttacaaaatt tgtgaaagat tgactgatat tcttaactat gttgctcctt

6180

ttacgctgtg tggatatgct gctttatagc ctctgtatct agctattgct tcccgtacgg

6240

ctttcgtttt ctcctccttg tataaatcct ggttgctgtc tcttttagag gagttgtggc

6300

ccgttgtccg tcaacgtggc gtggtgtgct ctgtgtttgc tgacgcaacc cccactggct

6360

ggggcattgc caccacctgt caactccttt ctgggacttt cgctttcccc ctcccgatcg

6420

ccacggcaga actcatcgcc gcctgccttg cccgctgctg gacaggggct aggttgctgg

6480

gcactgataa ttccgtggtg ttgtctgtgc cttctagttg ccagccatct gttgtttgcc

6540

cctcccccgt gccttccttg accctggaag gtgccactcc cactgtcctt tcctaataaa

6600

atgaggaaat tgcatcgcat tgtctgagta ggtgtcattc tattctgggg ggtggggtgg

6660

ggcaggacag caagggggag gattgggaag acaatagcag gcatgctggg gatgcggtgg

6720

gctctatggc tctagagcat ggctacgtag ataagtagca tggcgggtta atcattaact

6780

acacctgcag gaggaacccc tagtgatgga gttggccact ccctctctgc gcgctcgctc

6840

gctcactgag gccgggcgac caaaggtcgc ccgacgcccg ggcggcctca gtgagcgagc

6900

gagcgcgcag ctgcctgcag gggcgcgcct cgaggcatgc ggtaccaagc ttgtcgagaa

6960

gtactagagg atcataatca gccataccac atttgtagag gttttacttg ctttaaaaaa

7020

cctcccacac ctccccctga acctgaaaca taaaatgaat gcaattgttg ttgttaactt

7080

gtttattgca gcttataatg gttacaaata aagcaatagc atcacaaatt tcacaaataa

7140

agcatttttt tcactgcatt ctagttgtgg tttgtccaaa ctcatcaatg tatcttatca

7200

tgtctggatc tgatcactga tatcgcctag gagatccgaa cgataagt gaaatctagt

7260

tccaaactat tttgtcattt ttaattttcg tattagctta cgacgctaca cccagttccc

7320

atctattttg tcactcttcc ctaaataatc cttaaaaact ccatttccac ccctcccagt

7380

tcccaactat tttgtccgcc cacagcgggg catttttctt cctgttatgt ttttaatcaa

7440

acatcctgcc aactccatgt gacaaaccgt catcttcggc tactttttct ctgtcacaga

7500

atgaaaattt ttctgtcatc tcttcgttat taatgtttgt aattgactga atatcaacgc

7560

ttatttgcag cctgaatggc gaatgggacg cgccctgtag cggcgcatta agcgcggcgg

7620

gtgtggtggt tacgcgcagc gtgaccgcta cacttgccag cgccctagcg cccgctcctt

7680

tcgctttctt cccttccttt ctcgccacgt tcgccggctt tccccgtcaa gctctaaatc

7740

gggggctccc tttagggttc cgatttagtg ctttacggca cctcgacccc aaaaaacttg

7800

attagggtga tggttcacgt agtggggccat cgccctgata gacggttttt cgccctttga

7860

cgttggagtc cacgttcttt aatagtggac tcttgttcca aactggaaca acactcaacc

7920

ctatctcggt ctattctttt gatttataag ggattttgcc gatttcggcc tattggttaa

7980

aaaatgagct gatttaacaa aaatttaacg cgaattttaa caaaatatta acgtttacaa

8040

tttcaggtgg cacttttcgg ggaaatgtgc gcggaacccc tatttgttta tttttctaaa

8100

tacattcaaa tatgtatccg ctcatgagac aataaccctg ataaatgctt caataatatt

8160

gaaaaaggaa gagtatgagt attcaacatt tccgtgtcgc ccttattccc ttttttgcgg

8220

cattttgcct tcctgttttt gctcacccag aaacgctggt gaaagtaaaa gatgctgaag

8280

atcagttggg tgcacgagtg ggttacatcg aactggatct caacagcggt aagatccttg

8340

agagttttcg ccccgaagaa cgttttccaa tgatgagcac ttttaaagtt ctgctatgtg

8400

gcgcggtatt atcccgtatt gacgccgggc aagagcaact cggtcgccgc atacactatt

8460

ctcagaatga cttggttgag tactcaccag tcacagaaaa gcatcttacg gatggcatga

8520

cagtaagaga attatgcagt gctgccataa ccatgagtga taacactgcg gccaacttac

8580

ttctgacaac gatcggagga ccgaaggagc taaccgcttt tttgcacaac atgggggatc

8640

atgtaactcg ccttgatcgt tgggaaccgg agctgaatga agccatacca aacgacgagc

8700

gtgacaccac gatgcctgta gcaatggcaa caacgttgcg caaactatta actggcgaac

8760

tacttactct agcttcccgg caacaattaa tagactggat ggaggcggat aaagttgcag

8820

gaccacttct gcgctcggcc cttccggctg gctggtttat tgctgataaa tctggagccg

8880

gtgagcgtgg gtctcgcggt atcattgcag cactggggcc agatggtaag ccctcccgta

8940

tcgtagttat ctacacgacg gggagtcagg caactatgga tgaacgaaat agacagatcg

9000

ctgagatagg tgcctcactg attaagcatt ggtaactgtc agaccaagtt tactcatata

9060

tactttagat tgatttaaaa cttcattttt aatttaaaag gatctaggtg aagatccttt

9120

ttgataatct catgaccaaa atcccttaac gtgagttttc gttccactga gcgtcagacc

9180

ccgtagaaaa gatcaaagga tcttcttgag atcctttttt tctgcgcgta atctgctgct

9240

tgcaaacaaa aaaaccaccg ctaccagcgg tggtttgttt gccggatcaa gagctaccaa

9300

ctctttttcc gaaggtaact ggcttcagca gagcgcagat accaaatact gtccttctag

9360

tgtagccgta gttaggccac cacttcaaga actctgtagc accgcctaca tacctcgctc

9420

tgctaatcct gttaccagtg gctgctgcca gtggcgataa gtcgtgtctt accgggttgg

9480

actcaagacg atagttaccg gataaggcgc agcggtcggg ctgaacgggg ggttcgtgca

9540

cacagcccag cttggagcga acgacctaca ccgaactgag atacctacag cgtgagcatt

9600

gagaaagcgc cacgcttccc gaagggagaa aggcggacag gtatccggta agcggcaggg

9660

tcggaacagg agagcgcacg agggagcttc cagggggaaa cgcctggtat ctttatagtc

9720

ctgtcgggtt tcgccacctc tgacttgagc gtcgattttt gtgatgctcg tcaggggggc

9780

ggagcctatg gaaaaacgcc agcaacgcgg cctttttacg gttcctggcc ttttgctggc

9840

cttttgctca catgttcttt cctgcgttat cccctgattc tgtggataac cgtattaccg

9900

cctttgagtg agctgatacc gctcgccgca gccgaacgac cgagcgcagc gagtcagtga

9960

gcgaggaagc ggaagagcgc ctgatgcggt attttctcct tacgcatctg tgcggtattt

10020

cacaccgcag accagccgcg taacctggca aaatcggtta cggttgagta ataaatggat

10080

gccctgcgta agcgggtgtg ggcggacaat aaagtcttaa actgaacaaa atagatctaa

10140

actatgacaa taaagtctta aactagacag aatagttgta aactgaaatc agtccagtta

10200

tgctgtgaaa aagcatactg gacttttgtt atggctaaag caaactcttc attttctgaa

10260

gtgcaaattg cccgtcgtat taaagagggg cgtggccaag ggcatggtaa agactatatt

10320

cgcggcgttg tgacaattta ccgaacaact ccgcggccgg gaagccgatc tcggcttgaa

10380

cgaattgtta ggtggcggta cttgggtcga tatcaaagtg catcacttct tcccgtatgc

10440

ccaactttgt atagagagcc actgcgggat cgtcaccgta atctgcttgc acgtagatca

10500

cataagcacc aagcgcgttg gcctcatgct tgaggagatt gatgagcgcg gtggcaatgc

10560

cctgcctccg gtgctcgccg gagactgcga gatcatagat atagatctca ctacgcggct

10620

gctcaaacct gggcagaacg taagccgcga gagcgccaac aaccgcttct tggtcgaagg

10680

cagcaagcgc gatgaatgtc ttactacgga gcaagttccc gaggtaatcg gagtccggct

10740

gatgttggga gtaggtggct acgtctccga actcacgacc gaaaagatca agagcagccc

10800

gcatggattt gacttggtca gggccgagcc tacatgtgcg aatgatgccc atacttgagc

10860

cacctaactt tgttttaggg cgactgccct gctgcgtaac atcgttgctg ctgcgtaaca

10920

tcgttgctgc tccataacat caaacatcga cccacggcgt aacgcgcttg ctgcttggat

10980

gcccgaggca tagactgtac aaaaaaacag tcataacaag ccatgaaaac cgccactgcg

11040

ccgttaccac cgctgcgttc ggtcaaggtt ctggaccagt tgcgtgagcg catacgctac

11100

ttgcattaca gtttacgaac cgaacaggct tatgtcaact gggttcgtgc cttcatccgt

11160

ttccacggtg tgcgtcaccc ggcaaccttg ggcagcagcg aagtcgaggc atttctgtcc

11220

tggctggcga acgagcgcaa ggtttcggtc tccacgcatc gtcaggcatt ggcggccttg

11280

ctgttcttct acggcaaggt gctgtgcacg gatctgccct ggcttcagga gatcggaaga

11340

cctcggccgt cgcggcgctt gccggtggtg ctgaccccgg atgaagtggt tcgcatcctc

11400

ggttttctgg aaggcgagca tcgtttgttc gcccaggact ctagctatag ttctagtggt

11460

tggctacgta tactccggaa tattaataga tcatggagat aattaaaatg ataaccatct

11520

cgcaaataaa taagtatttt actgttttcg taacagtttt gtaataaaaa aacctataaa

11580

tattccggat tattcatacc gtcccaccat cgggcgcgga tctcggtccg aaaccatgtc

11640

gtactaccat caccatcacc atcacgatta cgatatccca acgaccgaaa acctgtattt

11700

tcagggcgcc atgggatcc

11719

<210> 208

<211> 11796

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 208

ggccggcccc tgcaggcagc tgcgcgctcg ctcgctcact gaggccgccc gggcaaagcc

60

cgggcgtcgg gcgacctttg gtcgcccggc ctcagtgagc gagcgagcgc gcagagaggg

120

agtggccaac tccatcacta ggggttcctt gtagttaatg attaacccgc catgctactt

180

atctacgtag ccatgctcta gaaggctcag aggcacacag gagtttctgg gctcaccctg

240

cccccttcca acccctcagt tcccatcctc cagcagctgt ttgtgtgctg cctctgaagt

300

cccacactgaa caaacttcag cctactcatg tccctaaaat gggcaaacat tgcaagcagc

360

aaacagcaaa cacacagccc tccctgcctg ctgaccttgg agctggggca gaggtcagag

420

acctctctgg gcccatgcca cctccaacat ccactcgacc ccttggaatt tcggtggaga

480

ggagcagagg ttgtcctggc gtggtttagg tagtgtgaga gggtccgggt tcaaaaccac

540

ttgctgggtg gggagtcgtc agtaagtggc tatgccccga ccccgaagcc tgtttcccca

600

tctgtacaat ggaaatgata aagacgccca tctgataggg tttttgtggc aaataaacat

660

ttggtttttt tgttttgttt tgttttgttt tttgagatgg aggtttgctc tgtcgcccag

720

gctggagtgc agtgacacaa tctcatctca ccacaacctt cccctgcctc agcctcccaa

780

gtagctggga ttacaagcat gtgccaccac acctggctaa ttttctattt ttagtagaga

840

cgggtttctc catgttggtc agcctcagcc tcccaagtaa ctgggattac aggcctgtgc

900

caccacaccc ggctaatttt ttctattttt gacagggacg gggtttcacc atgttggtca

960

ggctggtcta gaggtaccgg atcttgctac cagtggaaca gccactaagg attctgcagt

1020

gagagcagag ggccagctaa gtggtactct cccagagact gtctgactca cgccaccccc

1080

tccaccttgg acacaggacg ctgtggtttc tgagccaggt acaatgactc ctttcggtaa

1140

gtgcagtgga agctgtacac tgcccaggca aagcgtccgg gcagcgtagg cgggcgactc

1200

agatcccagc cagtggactt agcccctgtt tgctcctccg ataactgggg tgaccttggt

1260

taatattcac cagcagcctc ccccgttgcc cctctggatc cactgcttaa atacggacga

1320

ggacagggcc ctgtctcctc agcttcaggc accaccactg acctgggaca gtgaatccgg

1380

actctaaggt aaatataaaa tttttaagtg tataatgtgt taaactactg attctaattg

1440

tttctctctt ttagattcca acctttggaa ctgagtttaa acgccgccac catgcagatt

1500

gagctgagca cctgcttctt cctgtgcctg ctgaggttct gcttctctgc caccaggaga

1560

tactacctgg gggctgtgga gctgagctgg gactacatgc agtctgacct gggggagctg

1620

cctgtggatg ccaggttccc ccccagagtg cccaagagct tccccttcaa cacctctgtg

1680

gtgtacaaga agaccctgtt tgtggagttc actgaccacc tgttcaacat tgccaagccc

1740

aggcccccct ggatgggcct gctgggcccc accatccagg ctgaggtgta tgacactgtg

1800

gtgatcaccc tgaagaacat ggccagccac cctgtgagcc tgcatgctgt gggggtgagc

1860

tactggaagg cctctgaggg ggctgagtat gatgaccaga ccagccagag ggagaaggag

1920

gatgacaagg tgttccctgg gggcagccac acctatgtgt ggcaggtgct gaaggagaat

1980

ggccccatgg cctctgaccc cctgtgcctg acctacagct acctgagcca tgtggacctg

2040

gtgaaggacc tgaactctgg cctgattggg gccctgctgg tgtgcaggga gggcagcctg

2100

gccaaggaga agacccagac cctgcacaag ttcatcctgc tgtttgctgt gtttgatgag

2160

ggcaagagct ggcactctga aaccaagaac agcctgatgc aggacagga tgctgcctct

2220

gccagggcct ggcccaagat gcacactgtg aatggctatg tgaacaggag cctgcctggc

2280

ctgattggct gccacaggaa gtctgtgtac tggcatgtga ttggcatggg caccacccct

2340

gaggtgcaca gcatcttcct ggagggccac accttcctgg tcaggaacca caggcaggcc

2400

agcctggaga tcagccccat caccttcctg actgcccaga ccctgctgat ggacctgggc

2460

cagttcctgc tgttctgcca catcagcagc caccagcatg atggcatgga ggcctatgtg

2520

aaggtggaca gctgccctga ggagccccag ctgaggatga agaacaatga ggaggctgag

2580

gactatgatg atgacctgac tgactctgag atggatgtgg tgaggtttga tgatgacaac

2640

agccccagct tcatccagat caggtctgtg gccaagaagc accccaagac ctgggtgcac

2700

tacattgctg ctgaggagga ggactgggac tatgcccccc tggtgctggc ccctgatgac

2760

aggagctaca agagccagta cctgaacaat ggcccccaga ggattggcag gaagtacaag

2820

aaggtcaggt tcatggccta cactgatgaa accttcaaga ccagggaggc catccagcat

2880

gagtctggca tcctgggccc cctgctgtat ggggaggtgg gggacaccct gctgatcatc

2940

ttcaagaacc aggccagcag gccctacaac atctaccccc atggcatcac tgatgtgagg

3000

cccctgtaca gcaggaggct gcccaagggg gtgaagcacc tgaaggactt ccccatcctg

3060

cctggggaga tcttcaagta caagtggact gtgactgtgg aggatggccc caccaagtct

3120

gaccccaggt gcctgaccag atactacagc agctttgtga acatggagag ggacctggcc

3180

tctggcctga ttggccccct gctgatctgc tacaaggagt ctgtggacca gaggggcaac

3240

cagatcatgt ctgacaagag gaatgtgatc ctgttctctg tgtttgatga gaacaggagc

3300

tggtacctga ctgagaacat ccagaggttc ctgcccaacc ctgctggggt gcagctggag

3360

gaccctgagt tccaggccag caacatcatg cacagcatca atggctatgt gtttgacagc

3420

ctgcagctgt ctgtgtgcct gcatgaggtg gcctactggt acatcctgag cattggggcc

3480

cagactgact tcctgtctgt gttcttctct ggctacacct tcaagcacaa gatggtgtat

3540

gaggacaccc tgaccctgtt ccccttctct ggggagactg tgttcatgag catggagaac

3600

cctggcctgt ggattctggg ctgccacaac tctgacttca ggaacagggg catgactgcc

3660

ctgctgaaag tctccagctg tgacaagaac actggggact actatgagga cagctatgag

3720

gacatctctg cctacctgct gagcaagaac aatgccattg agcccaggag cttcagccag

3780

aatgccacta atgtgtctaa caacagcaac accagcaatg acagcaatgt gtctccccca

3840

gtgctgaaga ggcaccagag ggagatcacc aggaccaccc tgcagtctga cccaggagg

3900

attgactatg atgacaccat ctctgtggag atgaagaagg aggactttga catctacgac

3960

gaggacgaga accagagccc caggagcttc cagaagaaga ccaggcacta cttcattgct

4020

gctgtggaga ggctgtggga ctatggcatg agcagcagcc cccatgtgct gaggaacagg

4080

gcccagtctg gctctgtgcc ccagttcaag aaggtggtgt tccaggagtt cactgatggc

4140

agcttcaccc agcccctgta cagaggggag ctgaatgagc acctgggcct gctgggcccc

4200

tacatcaggg ctgaggtgga ggacaacatc atggtgacct tcaggaacca ggccagcagg

4260

ccctacagct tctacagcag cctgatcagc tatgaggagg accagaggca gggggctgag

4320

cccaggaaga actttgtgaa gcccaatgaa accaagacct acttctggaa ggtgcagcac

4380

cacatggccc ccaccaagga tgagtttgac tgcaaggcct gggcctactt ctctgatgtg

4440

gacctggaga aggatgtgca ctctggcctg attggccccc tgctggtgtg ccacaccaac

4500

accctgaacc ctgcccatgg caggcaggtg actngtgcagg agtttgccct gttcttcacc

4560

atctttgatg aaaccaagag ctggtacttc actgagaaca tggagaggaa ctgcagggcc

4620

ccctgcaaca tccagatgga ggaccccacc ttcaaggaga actacaggtt ccatgccatc

4680

aatggctaca tcatggacac cctgcctggc ctggtgatgg cccaggacca gaggatcagg

4740

tggtacctgc tgagcatggg cagcaatgag aacatccaca gcatccactt ctctggccat

4800

gtgttcactg tgaggaagaa ggaggagtac aagatggccc tgtacaacct gtaccctggg

4860

gtgtttgaga ctgtggagat gctgcccagc aaggctggca tctggagggt ggagtgcctg

4920

attggggagc acctgcatgc tggcatgagc accctgttcc tggtgtacag caacaagtgc

4980

cagacccccc tgggcatggc ctctggccac atcagggact tccagatcac tgcctctggc

5040

cagtatggcc agtgggcccc caagctggcc aggctgcact actctggcag catcaatgcc

5100

tggagcacca aggagccctt cagctggatc aaggtggacc tgctggcccc catgatcatc

5160

catggcatca agacccagg ggccaggcag aagttcagca gcctgtacat cagccagttc

5220

atcatcatgt acagcctgga tggcaagaag tggcagacct acaggggcaa cagcactggc

5280

accctgatgg tgttctttgg caatgtggac agctctggca tcaagcacaa catcttcaac

5340

ccccccatca ttgccagata catcaggctg caccccaccc actacagcat caggagcacc

5400

ctgaggatgg agctgatggg ctgtgacctg aacagctgca gcatgcccct gggcatggag

5460

agcaaggcca tctctgatgc ccagatcact gccagcagct acttcaccaa catgtttgcc

5520

acctggagcc ccagcaaggc caggctgcac ctgcagggca ggagcaatgc ctggaggccc

5580

caggtcaaca accccaagga gtggctgcag gtggacttcc agaagaccat gaaggtgact

5640

ggggtgacca cccagggggt gaagagcctg ctgaccagca tgtatgtgaa ggagttcctg

5700

atcagcagca gccaggatgg ccaccagtgg accctgttct tccagaatgg caaggtgaag

5760

gtgttccagg gcaaccagga cagcttcacc cctgtggtga acagcctgga cccccccctg

5820

ctgaccagat acctgaggat tcacccccag agctgggtgc accagattgc cctgaggatg

5880

gaggtgctgg gctgtgaggc ccaggacctg tactgattaa ttaagagcat cttaccgcca

5940

tttattccca tatttgttct gtttttcttg atttgggtat acatttaaat gttaataaaa

6000

caaaatggtg gggcaatcat ttacattttt agggatatgt aattactagt tcaggtgtat

6060

tgccacaaga caaacatgtt aagaaacttt cccgttattt acgctctgtt cctgttaatc

6120

aacctctgga ttacaaaatt tgtgaaagat tgactgatat tcttaactat gttgctcctt

6180

ttacgctgtg tggatatgct gctttatagc ctctgtatct agctattgct tcccgtacgg

6240

ctttcgtttt ctcctccttg tataaatcct ggttgctgtc tcttttagag gagttgtggc

6300

ccgttgtccg tcaacgtggc gtggtgtgct ctgtgtttgc tgacgcaacc cccactggct

6360

ggggcattgc caccacctgt caactccttt ctgggacttt cgctttcccc ctcccgatcg

6420

ccacggcaga actcatcgcc gcctgccttg cccgctgctg gacaggggct aggttgctgg

6480

gcactgataa ttccgtggtg ttgtctccat aaagtaggaa acactacacg attccataaa

6540

gtaggaaaca ctacatcact ccataaagta ggaaacacta catgtgcctt ctagttgcca

6600

gccatctgtt gtttgcccct cccccgtgcc ttccttgacc ctggaaggtg ccactcccac

6660

tgtcctttcc taataaaatg aggaaattgc atcgcattgt ctgagtaggt gtcattctat

6720

tctggggggt ggggtggggc aggacagcaa gggggaggat tgggaagaca atagcaggca

6780

tgctggggat gcggtgggct ctatggctct agagcatggc tacgtagata agtagcatgg

6840

cgggttaatc attaactaca cctgcaggag gaacccctag tgatggagtt ggccactccc

6900

tctctgcgcg ctcgctcgct cactgaggcc gggcgaccaa aggtcgcccg acgcccgggc

6960

ggcctcagtg agcgagcgag cgcgcagctg cctgcagggg cgcgcctcga ggcatgcggt

7020

accaagcttg tcgagaagta ctagaggatc ataatcagcc ataccacatt tgtagaggtt

7080

ttacttgctt taaaaaacct cccacacctc cccctgaacc tgaaacataa aatgaatgca

7140

attgttgttg ttaacttgtt tattgcagct tataatggtt acaaataaag caatagcatc

7200

acaaatttca caaataaagc atttttttca ctgcattcta gttgtggttt gtccaaactc

7260

atcaatgtat cttatcatgt ctggatctga tcactgatat cgcctaggag atccgaacca

7320

gataagtgaa atctagttcc aaactatttt gtcattttta attttcgtat tagcttacga

7380

cgctacaccc agttcccatc tattttgtca ctcttcccta aataatcctt aaaaactcca

7440

tttccacccc tcccagttcc caactatttt gtccgcccac agcggggcat ttttcttcct

7500

gttatgtttt taatcaaaca tcctgccaac tccatgtgac aaaccgtcat cttcggctac

7560

tttttctctg tcacagaatg aaaatttttc tgtcatctct tcgttattaa tgtttgtaat

7620

tgactgaata tcaacgctta tttgcagcct gaatggcgaa tgggacgcgc cctgtagcgg

7680

cgcattaagc gcggcgggtg tggtggttac gcgcagcgtg accgctacac ttgccagcgc

7740

cctagcgccc gctcctttcg ctttcttccc ttcctttctc gccacgttcg ccggctttcc

7800

ccgtcaagct ctaaatcggg ggctcccttt agggttccga tttagtgctt tacggcacct

7860

cgaccccaaa aaacttgatt agggtgatgg ttcacgtagt gggccatcgc cctgatagac

7920

ggtttttcgc cctttgacgt tggagtccac gttctttaat agtggactct tgttccaaac

7980

tggaacaaca ctcaacccta tctcggtcta ttcttttgat ttataaggga ttttgccgat

8040

ttcggcctat tggttaaaaa atgagctgat ttaacaaaaa tttaacgcga attttaacaa

8100

aatattaacg tttacaattt caggtggcac ttttcgggga aatgtgcgcg gaacccctat

8160

ttgtttattt ttctaaatac attcaaatat gtatccgctc atgagacaat aaccctgata

8220

aatgcttcaa taatattgaa aaaggaagag tatgagtatt caacatttcc gtgtcgccct

8280

tattcccttt tttgcggcat tttgccttcc tgtttttgct cacccagaaa cgctggtgaa

8340

agtaaaagat gctgaagatc agttgggtgc acgagtgggt tacatcgaac tggatctcaa

8400

cagcggtaag atccttgaga gttttcgccc cgaagaacgt tttccaatga tgagcacttt

8460

taaagttctg ctatgtggcg cggtattatc ccgtattgac gccgggcaag agcaactcgg

8520

tcgccgcata cactattctc agaatgactt ggttgagtac tcaccagtca cagaaaagca

8580

tcttacggat ggcatgacag taagagaatt atgcagtgct gccataacca tgagtgataa

8640

cactgcggcc aacttacttc tgacaacgat cggaggaccg aaggagctaa ccgctttttt

8700

gcacaacatg ggggatcatg taactcgcct tgatcgttgg gaaccggagc tgaatgaagc

8760

cataccaaac gacgagcgtg acaccacgat gcctgtagca atggcaacaa cgttgcgcaa

8820

actattaact ggcgaactac ttactctagc ttcccggcaa caattaatag actggatgga

8880

ggcggataaa gttgcaggac cacttctgcg ctcggccctt ccggctggct ggtttattgc

8940

tgataaatct ggagccggtg agcgtgggtc tcgcggtatc attgcagcac tggggccaga

9000

tggtaagccc tcccgtatcg tagttatcta cacgacgggg agtcaggcaa ctatggatga

9060

acgaaataga cagatcgctg agataggtgc ctcactgatt aagcattggt aactgtcaga

9120

ccaagtttac tcatatatac tttagattga tttaaaactt catttttaat ttaaaaggat

9180

ctaggtgaag atcctttttg ataatctcat gaccaaaatc ccttaacgtg agttttcgtt

9240

ccactgagcg tcagaccccg tagaaaagat caaaggatct tcttgagatc ctttttttct

9300

gcgcgtaatc tgctgcttgc aaacaaaaaa accaccgcta ccagcggtgg tttgtttgcc

9360

ggatcaagag ctaccaactc tttttccgaa ggtaactggc ttcagcagag cgcagatacc

9420

aaatactgtc cttctagtgt agccgtagtt aggccaccac ttcaagaact ctgtagcacc

9480

gcctacatac ctcgctctgc taatcctgtt accagtggct gctgccagtg gcgataagtc

9540

gtgtcttacc gggttggact caagacgata gttaccggat aaggcgcagc ggtcgggctg

9600

aacggggggt tcgtgcacac agcccagctt ggagcgaacg acctacaccg aactgagata

9660

cctacagcgt gagcattgag aaagcgccac gcttcccgaa gggagaaagg cggacaggta

9720

tccggtaagc ggcagggtcg gaacaggaga gcgcacgagg gagcttccag ggggaaacgc

9780

ctggtatctt tatagtcctg tcgggtttcg ccacctctga cttgagcgtc gatttttgtg

9840

atgctcgtca ggggggcgga gcctatggaa aaacgccagc aacgcggcct ttttacggtt

9900

cctggccttt tgctggcctt ttgctcacat gttctttcct gcgttatccc ctgattctgt

9960

ggataaccgt attaccgcct ttgagtgagc tgataccgct cgccgcagcc gaacgaccga

10020

gcgcagcgag tcagtgagcg aggaagcgga agagcgcctg atgcggtatt ttctccttac

10080

gcatctgtgc ggtatttcac accgcagacc agccgcgtaa cctggcaaaa tcggttacgg

10140

ttgagtaata aatggatgcc ctgcgtaagc gggtgtgggc ggacaataaa gtcttaaact

10200

gaacaaaata gatctaaact atgacaataa agtcttaaac tagacagaat agttgtaaac

10260

tgaaatcagt ccagttatgc tgtgaaaaag catactggac ttttgttatg gctaaagcaa

10320

actcttcatt ttctgaagtg caaattgccc gtcgtattaa agaggggcgt ggccaagggc

10380

atggtaaaga ctatattcgc ggcgttgtga caatttaccg aacaactccg cggccgggaa

10440

gccgatctcg gcttgaacga attgttaggt ggcggtactt gggtcgatat caaagtgcat

10500

cacttcttcc cgtatgccca actttgtata gagagccact gcgggatcgt caccgtaatc

10560

tgcttgcacg tagatcacat aagcaccaag cgcgttggcc tcatgcttga ggagattgat

10620

gagcgcggtg gcaatgccct gcctccggtg ctcgccggag actgcgagat catagatata

10680

gatctcacta cgcggctgct caaacctggg cagaacgtaa gccgcgagag cgccaacaac

10740

cgcttcttgg tcgaaggcag caagcgcgat gaatgtctta ctacggagca agttcccgag

10800

gtaatcggag tccggctgat gttgggagta ggtggctacg tctccgaact cacgaccgaa

10860

aagatcaaga gcagcccgca tggatttgac ttggtcaggg ccgagcctac atgtgcgaat

10920

gatgcccata cttgagccac ctaactttgt tttagggcga ctgccctgct gcgtaacatc

10980

gttgctgctg cgtaacatcg ttgctgctcc ataacatcaa acatcgaccc acggcgtaac

11040

gcgcttgctg cttggatgcc cgaggcatag actgtacaaa aaaacagtca taacaagcca

11100

tgaaaaccgc cactgcgccg ttaccaccgc tgcgttcggt caaggttctg gaccagttgc

11160

gtgagcgcat acgctacttg cattacagtt tacgaaccga acaggcttat gtcaactggg

11220

ttcgtgcctt catccgtttc cacggtgtgc gtcacccggc aaccttgggc agcagcgaag

11280

tcgaggcatt tctgtcctgg ctggcgaacg agcgcaaggt ttcggtctcc acgcatcgtc

11340

aggcattggc ggccttgctg ttcttctacg gcaaggtgct gtgcacggat ctgccctggc

11400

ttcaggagat cggaagacct cggccgtcgc ggcgcttgcc ggtggtgctg accccggatg

11460

aagtggttcg catcctcggt tttctggaag gcgagcatcg tttgttcgcc caggactcta

11520

gctatagttc tagtggttgg ctacgtatac tccggaatat taatagatca tggagataat

11580

taaaatgata accatctcgc aaataaataa gtattttact gttttcgtaa cagttttgta

11640

ataaaaaaac ctataaatat tccggattat tcataccgtc cccacatcgg gcgcggatct

11700

cggtccgaaa ccatgtcgta ctaccatcac catcaccatc acgattacga tatcccaacg

11760

accgaaaacc tgtattttca gggcgccatg ggatcc

11796

<210> 209

<211> 10795

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 209

ggccggcccc tgcaggcagc tgcgcgctcg ctcgctcact gaggccgccc gggcaaagcc

60

cgggcgtcgg gcgacctttg gtcgcccggc ctcagtgagc gagcgagcgc gcagagaggg

120

agtggccaac tccatcacta ggggttcctt gtagttaatg attaacccgc catgctactt

180

atctacgtag ccatgctcta gacgggggag gctgctggtg aatattaacc aaggtcaccc

240

cagttatcgg aggagcaaac aggggctaag tccacacgcg tggtaccgtc tgtctgcaca

300

tttcgtagag cgagtgttcc gatactctaa tctccctagg caaggttcat atttgtgtag

360

gttacttatt ctccttttgt tgactaagtc aataatcaga atcagcaggt ttggagtcag

420

cttggcaggg atcagcagcc tgggttggaa ggagggggta taaaagcccc ttcaccagga

480

gaagccgtca cacagatcca caagctcctg aagaggtaag ggtttaaggg atggttggtt

540

ggtggggtat taatgtttaa ttacctggag cacctgcctg aaatcacttt ttttcaggtt

600

ggtttaaacg ccgccaccat gcagatcgag ctgtctacct gcttcttcct gtgcctgctg

660

cggttctgct tcagcgccac cagaagatat tacctgggcg ccgtggaact gagctgggac

720

tacatgcagt ctgacctggg agagctgccc gtggacgcta gatttcctcc aagagtgccc

780

aagagcttcc ccttcaacac ctccgtggtg tacaagaaaa ccctgttcgt ggaattcacc

840

gaccacctgt tcaatatcgc caagcctcgg cctccttgga tgggactgct gggacctaca

900

attcaggccg aggtgtacga caccgtggtc atcaccctga agaacatggc cagccatcct

960

gtgtctctgc acgccgtggg agtgtcttat tggaaggctt ctgagggcgc cgagtacgac

1020

gatcagacaa gccagagaga gaaagaggac gacaaggttt tccctggcgg cagccacacc

1080

tatgtctggc aggtcctgaa agaaaacggc cctatggcct ccgatcctct gtgcctgaca

1140

tacagctacc tgagccacgt ggacctggtc aaggacctga attctggcct gatcggagcc

1200

ctgctcgtgt gtagagaagg cagcctggcc aaagagaaaa cccagacact gcacaagttc

1260

atcctgctgt tcgccgtgtt cgacgagggc aagagctggc acagcgagac aaagaacagc

1320

ctgatgcagg acagggatgc cgcctctgct agagcttggc ctaagatgca caccgtgaac

1380

ggctacgtga acagaagcct gcctggactg atcggctgcc acagaaagtc cgtgtactgg

1440

cacgtgatcg gcatgggcac aacacctgag gtgcacagca tctttctgga aggccacacc

1500

ttcctcgtgc ggaaccacag acaggccagc ctggaaatca gccctatcac cttcctgacc

1560

gctcagaccc tgctgatgga tctgggccag tttctgctgt tctgccacat cagctcccac

1620

cagcacgatg gcatggaagc ctacgtgaag gtggacagct gccccgaaga accccagctg

1680

cggatgaaga acaacgagga agccgaggac tacgacgacg acctgaccga ctctgagatg

1740

gacgtcgtca gattcgacga cgataacagc cccagcttca tccagatcag aagcgtggcc

1800

aagaagcacc ccaagacctg ggtgcactat atcgccgccg aggaagagga ctgggattac

1860

gctcctctgg tgctggcccc tgacgacaga agctacaaga gccagtacct gaacaacggc

1920

cctcagcgga tcggccggaa gtataagaaa gtgcggttca tggcctacac cgacgagaca

1980

ttcaagacca gagaggccat ccagcacgag agcggaattc tgggccctct gctgtatggc

2040

gaagtgggcg atacactgct gatcatcttc aagaaccagg ccagcagacc ctacaacatc

2100

taccctcacg gcatcaccga tgtgcggccc ctgtattcta gaaggctgcc caagggcgtg

2160

aagcacctga aggacttccc tatcctgcct ggcgagattt tcaagtacaa gtggaccgtg

2220

accgtggaag atggccccac caagagcgac cctagatgtc tgacacggta ctacagcagc

2280

ttcgtgaaca tggaacgcga cctggccagc ggcctgattg gacctctgct gatctgctac

2340

aaagaaagcg tggaccagcg gggcaaccag atcatgagcg acaagcggaa cgtgatcctg

2400

tttagcgtgt tcgatgagaa ccggtcctgg tatctgaccg agaacatcca gcggtttctg

2460

cccaatcctg ccggggtgca actggaagat cctgagttcc aggcaagcaa catcatgcac

2520

tccatcaatg gctatgtgtt cgacagcctg cagctgagcg tgtgcctgca cgaagtggcc

2580

tactggtaca tcctgagcat tggcgcccag accgacttcc tgtccgtgtt ctttagcggc

2640

tacaccttca agcacaagat ggtgtacgag gataccctga cactgttccc attcagcggc

2700

gagacagtgt tcatgagcat ggaaaacccc ggcctgtgga ttctgggctg tcacaacagc

2760

gacttccgga acagaggcat gacagccctg ctgaaggtgt ccagctgcga caagaacacc

2820

ggcgactact acgaggacag ctatgaggac atcagcgcct acctgctgag caagaacaat

2880

gccatcgagc ctcggagctt cagccagaat cctcctgtgc tgaagcggca ccagcgcgag

2940

atcaccagaa caaccctgca gagcgaccaa gaggaaatcg attacgacga caccatcagc

3000

gtcgagatga agaaagaaga tttcgacatc tacgacgagg acgagaatca gagccccaga

3060

agctttcaga aaaagacccg gcactacttc attgccgccg tcgagagact gtgggactac

3120

ggcatgtcta gcagccctca cgtgctgaga aatagagccc agagcggcag cgtgccccag

3180

ttcaagaaag tggtgttcca agagttcacc gacggcagct tcacccagcc actgtataga

3240

ggcgagctga acgagcatct gggcctgctg ggcccttata tcagagccga agtggaagat

3300

aacatcatgg tcaccttccg gaatcaggct agccggcctt acagcttcta cagctccctg

3360

atcagctacg aagaggacca gagacagggc gctgagccca gaaagaactt cgtgaagccc

3420

aacgagacta agacctactt ttggaaggtg cagcaccaca tggcccctac aaaggacgag

3480

ttcgactgca aagcctgggc ctacttctcc gatgtggatc tggaaaagga cgtgcacagc

3540

gggctcatcg gaccactgct tgtgtgccac accaacacac tgaaccccgc tcacggcaga

3600

caagtgacag tgcaagagtt cgccctgttc ttcaccatct tcgacgaaac aaagagctgg

3660

tacttcaccg agaatatgga acggaactgc agagcccctt gcaacatcca gatggaagat

3720

cccaccttca aagagaacta ccggttccac gccatcaacg gctacatcat ggacacactg

3780

cccggcctgg ttatggccca ggatcagaga atccggtggt atctgctgtc catgggctcc

3840

aacgagaata tccacagcat ccacttcagc ggccacgtgt tcaccgtgcg gaaaaaagaa

3900

gagtacaaaa tggccctgta caatctgtac cctggggtgt tcgaaaccgt ggaaatgctg

3960

ccttccaagg ccggcatttg gagagtggaa tgtctgattg gagagcacct ccacgccgga

4020

atgagcaccc tgtttctggt gtacagcaac aagtgtcaga cccctctcgg catggcctct

4080

ggacacatca gagacttcca gatcaccgcc tctggccagt acggacagtg ggctcctaaa

4140

ctggctcggc tgcactacag cggcagcatc aatgcctggt ccaccaaaga gcccttcagc

4200

tggatcaagg tggacctgct ggctccatg atcatccacg gaatcaagac ccagggcgcc

4260

agacagaagt tcagcagcct gtacatcagc cagttcatca tcatgtacag cctggacggc

4320

aagaagtggc agacctacag aggcaacagc accggcacac tcatggtgtt cttcggcaac

4380

gtggactcca gcggcattaa gcacaacatc ttcaaccctc caatcattgc ccggtacatc

4440

cggctgcacc ccacacacta cagcatccgg tctaccctga gaatggaact gatgggctgc

4500

gacctgaaca gctgctctat gcccctcgga atggaaagca aggccatcag cgacgcccag

4560

atcacagcca gcagctactt caccaacatg ttcgccactt ggagcccctc caaggctaga

4620

ctgcatctgc agggcagaag caacgcttgg aggccccaag tgaacaaccc caaagagtgg

4680

ctgcaggttg actttcaaaa gaccatgaaa gtgaccggcg tgaccacaca gggcgtcaag

4740

tctctgctga cctctatgta cgtgaaagag ttcctgatct ccagcagcca ggacggccat

4800

cagtggaccc tgtttttcca gaacggcaaa gtgaaagtgt tccagggcaa tcaggacagc

4860

ttcacacccg tggtcaattc tctggaccct ccactgctga cgagatacct gcggattcac

4920

cctcagtctt gggtgcacca gatcgctctg cggatggaag tgctgggctg tgaagctcag

4980

gacctctact agttaattaa gagcatctta ccgccattta ttcccatatt tgttctgttt

5040

ttcttgattt gggtatacat ttaaatgtta ataaaacaaa atggtggggc aatcatttac

5100

atttttaggg atatgtaatt actagttcag gtgtattgcc acaagacaaa catgttaaga

5160

aactttcccg ttatttacgc tctgttcctg ttaatcaacc tctggattac aaaatttgtg

5220

aaagattgac tgatattctt aactatgttg ctccttttac gctgtgtgga tatgctgctt

5280

tatagcctct gtatctagct attgcttccc gtacggcttt cgttttctcc tccttgtata

5340

aatcctggtt gctgtctctt ttagaggagt tgtggcccgt tgtccgtcaa cgtggcgtgg

5400

tgtgctctgt gtttgctgac gcaaccccca ctggctgggg cattgccacc acctgtcaac

5460

tcctttctgg gactttcgct ttccccctcc cgatcgccac ggcagaactc atcgccgcct

5520

gccttgcccg ctgctggaca ggggctaggt tgctgggcac tgataattcc gtggtgttgt

5580

ctgtgccttc tagttgccag ccatctgttg tttgcccctc ccccgtgcct tccttgaccc

5640

tggaaggtgc cactcccact gtcctttcct aataaaatga ggaaattgca tcgcattgtc

5700

tgagtaggtg tcattctatt ctggggggtg gggtggggca ggacagcaag ggggaggatt

5760

gggaagacaa tagcaggcat gctggggatg cggtgggctc tatggctcta gagcatggct

5820

acgtagataa gtagcatggc gggttaatca ttaactacac ctgcaggagg aacccctagt

5880

gatggagttg gccactccct ctctgcgcgc tcgctcgctc actgaggccg ggcgaccaaa

5940

ggtcgcccga cgcccgggcg gcctcagtga gcgagcgagc gcgcagctgc ctgcaggggc

6000

gcgcctcgag gcatgcggta ccaagcttgt cgagaagtac tagaggatca taatcagcca

6060

taccacattt gtagaggttt tacttgcttt aaaaaacctc ccacacctcc ccctgaacct

6120

gaaacataaa atgaatgcaa ttgttgttgt taacttgttt attgcagctt ataatggtta

6180

caaataaagc aatagcatca caaatttcac aaataaagca tttttttcac tgcattctag

6240

ttgtggtttg tccaaactca tcaatgtatc ttatcatgtc tggatctgat cactgatatc

6300

gcctaggaga tccgaaccag ataagtgaaa tctagttcca aactattttg tcatttttaa

6360

ttttcgtatt agcttacgac gctacaccca gttcccatct attttgtcac tcttccctaa

6420

ataatcctta aaaactccat ttccacccct cccagttccc aactattttg tccgcccaca

6480

gcggggcatt tttcttcctg ttatgttttt aatcaaacat cctgccaact ccatgtgaca

6540

aaccgtcatc ttcggctact ttttctctgt cacagaatga aaatttttct gtcatctctt

6600

cgttattaat gtttgtaatt gactgaatat caacgcttat ttgcagcctg aatggcgaat

6660

gggacgcgcc ctgtagcggc gcattaagcg cggcgggtgt ggtggttacg cgcagcgtga

6720

ccgctacact tgccagcgcc ctagcgcccg ctcctttcgc tttcttccct tcctttctcg

6780

ccacgttcgc cggctttccc cgtcaagctc taaatcgggg gctcccttta gggttccgat

6840

ttagtgcttt acggcacctc gaccccaaaa aacttgatta gggtgatggt tcacgtagtg

6900

ggccatcgcc ctgatagacg gtttttcgcc ctttgacgtt ggagtccacg ttctttaata

6960

gtggactctt gttccaaact ggaacaacac tcaaccctat ctcggtctat tcttttgatt

7020

tataagggat tttgccgatt tcggcctatt ggttaaaaaa tgagctgatt taacaaaaat

7080

ttaacgcgaa ttttaacaaa atattaacgt ttacaatttc aggtggcact tttcggggaa

7140

atgtgcgcgg aacccctatt tgtttatttt tctaaataca ttcaaatatg tatccgctca

7200

tgagacaata accctgataa atgcttcaat aatattgaaa aaggaagagt atgagtattc

7260

aacatttccg tgtcgccctt attccctttt ttgcggcatt ttgccttcct gtttttgctc

7320

acccagaaac gctggtgaaa gtaaaagatg ctgaagatca gttgggtgca cgagtgggtt

7380

acatcgaact ggatctcaac agcggtaaga tccttgagag ttttcgcccc gaagaacgtt

7440

ttccaatgat gagcactttt aaagttctgc tatgtggcgc ggtattatcc cgtattgacg

7500

ccgggcaaga gcaactcggt cgccgcatac actattctca gaatgacttg gttgagtact

7560

caccagtcac agaaaagcat cttacggatg gcatgacagt aagagaatta tgcagtgctg

7620

ccataaccat gagtgataac actgcggcca acttacttct gacaacgatc ggaggaccga

7680

aggagctaac cgcttttttg cacaacatgg gggatcatgt aactcgcctt gatcgttggg

7740

aaccggagct gaatgaagcc ataccaaacg acgagcgtga caccacgatg cctgtagcaa

7800

tggcaacaac gttgcgcaaa ctattaactg gcgaactact tactctagct tcccggcaac

7860

aattaataga ctggatggag gcggataaag ttgcaggacc acttctgcgc tcggcccttc

7920

cggctggctg gtttattgct gataaatctg gagccggtga gcgtgggtct cgcggtatca

7980

ttgcagcact ggggccagat ggtaagccct cccgtatcgt agttatctac acgacgggga

8040

gtcaggcaac tatggatgaa cgaaatagac agatcgctga gataggtgcc tcactgatta

8100

agcattggta actgtcagac caagtttact catatatact ttagattgat ttaaaacttc

8160

atttttaatt taaaaggatc taggtgaaga tcctttttga taatctcatg accaaaatcc

8220

cttaacgtga gttttcgttc cactgagcgt cagaccccgt agaaaagatc aaaggatctt

8280

cttgagatcc tttttttctg cgcgtaatct gctgcttgca aacaaaaaaa ccaccgctac

8340

cagcggtggt ttgtttgccg gatcaagagc taccaactct ttttccgaag gtaactggct

8400

tcagcagagc gcagatacca aatactgtcc ttctagtgta gccgtagtta ggccaccact

8460

tcaagaactc tgtagcaccg cctacatacc tcgctctgct aatcctgtta ccagtggctg

8520

ctgccagtgg cgataagtcg tgtcttaccg ggttggactc aagacgatag ttaccggata

8580

aggcgcagcg gtcgggctga acggggggtt cgtgcacaca gcccagcttg gagcgaacga

8640

cctacaccga actgagatac ctacagcgtg agcattgaga aagcgccacg cttcccgaag

8700

ggagaaaggc ggacaggtat ccggtaagcg gcagggtcgg aacaggag cgcacgaggg

8760

agcttccagg gggaaacgcc tggtatcttt atagtcctgt cgggtttcgc cacctctgac

8820

ttgagcgtcg atttttgtga tgctcgtcag gggggcggag cctatggaaa aacgccagca

8880

acgcggcctt tttacggttc ctggcctttt gctggccttt tgctcacatg ttctttcctg

8940

cgttatcccc tgattctgtg gataaccgta ttaccgcctt tgagtgagct gataccgctc

9000

gccgcagccg aacgaccgag cgcagcgagt cagtgagcga ggaagcggaa gagcgcctga

9060

tgcggtattt tctccttacg catctgtgcg gtatttcaca ccgcagacca gccgcgtaac

9120

ctggcaaaat cggttacggt tgagtaataa atggatgccc tgcgtaagcg ggtgtgggcg

9180

gacaataaag tcttaaactg aacaaaatag atctaaacta tgacaataaa gtcttaaact

9240

agacagaata gttgtaaact gaaatcagtc cagttatgct gtgaaaaagc atactggact

9300

tttgttatgg ctaaagcaaa ctcttcattt tctgaagtgc aaattgcccg tcgtattaaa

9360

gaggggcgtg gccaagggca tggtaaagac tatattcgcg gcgttgtgac aatttaccga

9420

acaactccgc ggccgggaag ccgatctcgg cttgaacgaa ttgttaggtg gcggtacttg

9480

ggtcgatatc aaagtgcatc acttcttccc gtatgcccaa ctttgtatag agagccactg

9540

cgggatcgtc accgtaatct gcttgcacgt agatcacata agcaccaagc gcgttggcct

9600

catgcttgag gagattgatg agcgcggtgg caatgccctg cctccggtgc tcgccggaga

9660

ctgcgagatc atagatatag atctcactac gcggctgctc aaacctgggc agaacgtaag

9720

ccgcgagagc gccaacaacc gcttcttggt cgaaggcagc aagcgcgatg aatgtcttac

9780

tacggagcaa gttcccgagg taatcggagt ccggctgatg ttgggagtag gtggctacgt

9840

ctccgaactc acgaccgaaa agatcaagag cagcccgcat ggatttgact tggtcagggc

9900

cgagcctaca tgtgcgaatg atgcccatac ttgagccacc taactttgtt ttagggcgac

9960

tgccctgctg cgtaacatcg ttgctgctgc gtaacatcgt tgctgctcca taacatcaaa

10020

catcgaccca cggcgtaacg cgcttgctgc ttggatgccc gaggcataga ctgtacaaaa

10080

aaacagtcat aacaagccat gaaaaccgcc actgcgccgt taccaccgct gcgttcggtc

10140

aaggttctgg accagttgcg tgagcgcata cgctacttgc attacagttt acgaaccgaa

10200

caggcttatg tcaactgggt tcgtgccttc atccgtttcc acggtgtgcg tcacccggca

10260

accttgggca gcagcgaagt cgaggcattt ctgtcctggc tggcgaacga gcgcaaggtt

10320

tcggtctcca cgcatcgtca ggcattggcg gccttgctgt tcttctacgg caaggtgctg

10380

tgcacggatc tgccctggct tcaggagatc ggaagacctc ggccgtcgcg gcgcttgccg

10440

gtggtgctga ccccggatga agtggttcgc atcctcggtt ttctggaagg cgagcatcgt

10500

ttgttcgccc aggactctag ctatagttct agtggttggc tacgtatact ccggaatatt

10560

aatagatcat ggagataatt aaaatgataa ccatctcgca aataaataag tattttactg

10620

ttttcgtaac agttttgtaa taaaaaaacc tataaatatt ccggattatt cataccgtcc

10680

caccatcggg cgcggatctc ggtccgaaac catgtcgtac taccatcacc atcaccatca

10740

cgattacgat atcccaacga ccgaaaacct gtattttcag ggcgccatgg gatcc

10795

<210> 210

<211> 10846

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 210

ggccggcccc tgcaggcagc tgcgcgctcg ctcgctcact gaggccgccc gggcaaagcc

60

cgggcgtcgg gcgacctttg gtcgcccggc ctcagtgagc gagcgagcgc gcagagaggg

120

agtggccaac tccatcacta ggggttcctt gtagttaatg attaacccgc catgctactt

180

atctacgtag ccatgctcta gacgggggag gctgctggtg aatattaacc aaggtcaccc

240

cagttatcgg aggagcaaac aggggctaag tccacacgcg tggtaccgtc tgtctgcaca

300

tttcgtagag cgagtgttcc gatactctaa tctccctagg caaggttcat atttgtgtag

360

gttacttatt ctccttttgt tgactaagtc aataatcaga atcagcaggt ttggagtcag

420

cttggcaggg atcagcagcc tgggttggaa ggagggggta taaaagcccc ttcaccagga

480

gaagccgtca cacagatcca caagctcctg aagaggtaag ggtttaaggg atggttggtt

540

ggtggggtat taatgtttaa ttacctggag cacctgcctg aaatcacttt ttttcaggtt

600

ggtttaaacg ccgccaccat gcagattgag ctgagcacct gcttcttcct gtgcctgctg

660

aggttctgct tctctgccac caggagatac tacctggggg ctgtggagct gagctgggac

720

tacatgcagt ctgacctggg ggagctgcct gtggatgcca ggttcccccc cagagtgccc

780

aagagcttcc ccttcaacac ctctgtggtg tacaagaaga ccctgtttgt ggagttcact

840

gaccacctgt tcaacattgc caagcccagg cccccctgga tgggcctgct gggccccacc

900

atccaggctg aggtgtatga cactgtggtg atcaccctga agaacatggc cagccaccct

960

gtgagcctgc atgctgtggg ggtgagctac tggaaggcct ctgagggggc tgagtatgat

1020

gaccagacca gccagaggga gaaggaggat gacaaggtgt tccctggggg cagccacacc

1080

tatgtgtggc aggtgctgaa ggagaatggc cccatggcct ctgaccccct gtgcctgacc

1140

tacagctacc tgagccatgt ggacctggtg aaggacctga actctggcct gattggggcc

1200

ctgctggtgt gcagggaggg cagcctggcc aaggagaaga cccagaccct gcacaagttc

1260

atcctgctgt ttgctgtgtt tgatgagggc aagagctggc actctgaaac caagaacagc

1320

ctgatgcagg acagggatgc tgcctctgcc agggcctggc ccaagatgca cactgtgaat

1380

ggctatgtga acaggagcct gcctggcctg attggctgcc acaggaagtc tgtgtactgg

1440

catgtgattg gcatgggcac cacccctgag gtgcacagca tcttcctgga gggccacacc

1500

ttcctggtca ggaaccacag gcaggccagc ctggagatca gccccatcac cttcctgact

1560

gcccagaccc tgctgatgga cctgggccag ttcctgctgt tctgccacat cagcagccac

1620

cagcatgatg gcatggaggc ctatgtgaag gtggacagct gccctgagga gccccagctg

1680

aggatgaaga acaatgagga ggctgaggac tatgatgatg acctgactga ctctgagatg

1740

gatgtggtga ggtttgatga tgacaacagc cccagcttca tccagatcag gtctgtggcc

1800

aagaagcacc ccaagacctg ggtgcactac attgctgctg aggaggagga ctgggactat

1860

gcccccctgg tgctggcccc tgatgacagg agctacaaga gccagtacct gaacaatggc

1920

ccccagagga ttggcaggaa gtacaagaag gtcaggttca tggcctacac tgatgaaacc

1980

ttcaagacca gggaggccat ccagcatgag tctggcatcc tgggccccct gctgtatggg

2040

gaggtggggg acaccctgct gatcatcttc aagaaccagg ccagcaggcc ctacaacatc

2100

tacccccatg gcatcactga tgtgaggccc ctgtacagca ggaggctgcc caagggggtg

2160

aagcacctga aggacttccc catcctgcct ggggagatct tcaagtacaa gtggactgtg

2220

actgtggagg atggccccac caagtctgac cccaggtgcc tgaccagata ctacagcagc

2280

tttgtgaaca tggagaggga cctggcctct ggcctgattg gccccctgct gatctgctac

2340

aaggagtctg tggaccagag gggcaaccag atcatgtctg acaagaggaa tgtgatcctg

2400

ttctctgtgt ttgatgagaa caggagctgg tacctgactg agaacatcca gaggttcctg

2460

cccaaccctg ctggggtgca gctggaggac cctgagttcc aggccagcaa catcatgcac

2520

agcatcaatg gctatgtgtt tgacagcctg cagctgtctg tgtgcctgca tgaggtggcc

2580

tactggtaca tcctgagcat tggggcccag actgacttcc tgtctgtgtt cttctctggc

2640

tacaccttca agcacaagat ggtgtatgag gacaccctga ccctgttccc cttctctggg

2700

gagactgtgt tcatgagcat ggagaaccct ggcctgtgga ttctgggctg ccacaactct

2760

gacttcagga acaggggcat gactgccctg ctgaaagtct ccagctgtga caagaacact

2820

ggggactact atgaggacag ctatgaggac atctctgcct acctgctgag caagaacaat

2880

gccattgagc ccaggagctt cagccagaat gccactaatg tgtctaacaa cagcaacacc

2940

agcaatgaca gcaatgtgtc tcccccagtg ctgaagaggc accagaggga gatcaccagg

3000

accaccctgc agtctgacca ggaggagatt gactatgatg acaccatctc tgtggagatg

3060

aagaaggagg actttgacat ctacgacgag gacgagaacc agagccccag gagcttccag

3120

aagaagacca ggcactactt cattgctgct gtggagaggc tgtgggacta tggcatgagc

3180

agcagccccc atgtgctgag gaacagggcc cagtctggct ctgtgcccca gttcaagaag

3240

gtggtgttcc aggagttcac tgatggcagc ttcacccagc ccctgtacag aggggagctg

3300

aatgagcacc tgggcctgct gggcccctac atcagggctg aggtggagga caacatcatg

3360

gtgaccttca ggaaccaggc cagcaggccc tacagcttct acagcagcct gatcagctat

3420

gaggaggacc agaggcaggg ggctgagccc aggaagaact ttgtgaagcc caatgaaacc

3480

aagacctact tctggaaggt gcagcaccac atggccccca ccaaggatga gtttgactgc

3540

aaggcctggg cctacttctc tgatgtggac ctggagaagg atgtgcactc tggcctgatt

3600

ggccccctgc tggtgtgcca caccaacacc ctgaaccctg cccatggcag gcaggtgact

3660

gtgcaggagt ttgccctgtt cttcaccatc tttgatgaaa ccaagagctg gtacttcact

3720

gagaacatgg agaggaactg cagggccccc tgcaacatcc agatggagga ccccaccttc

3780

aaggagaact acaggttcca tgccatcaat ggctacatca tggacaccct gcctggcctg

3840

gtgatggccc aggaccagag gatcaggtgg tacctgctga gcatgggcag caatgagaac

3900

atccacagca tccacttctc tggccatgtg ttcactgtga ggaagaagga ggagtacaag

3960

atggccctgt acaacctgta ccctggggtg tttgagactg tggagatgct gcccagcaag

4020

gctggcatct ggagggtgga gtgcctgatt ggggagcacc tgcatgctgg catgagcacc

4080

ctgttcctgg tgtacagcaa caagtgccag acccccctgg gcatggcctc tggccacatc

4140

agggacttcc agatcactgc ctctggccag tatggccagt gggcccccaa gctggccagg

4200

ctgcactact ctggcagcat caatgcctgg agcaccaagg agcccttcag ctggatcaag

4260

gtggacctgc tggcccccat gatcatccat ggcatcaaga cccagggggc caggcagaag

4320

ttcagcagcc tgtacatcag ccagttcatc atcatgtaca gcctggatgg caagaagtgg

4380

cagacctaca ggggcaacag cactggcacc ctgatggtgt tctttggcaa tgtggacagc

4440

tctggcatca agcacaacat cttcaacccc cccatcattg ccagatacat caggctgcac

4500

cccacccact acagcatcag gagcaccctg aggatggagc tgatgggctg tgacctgaac

4560

agctgcagca tgcccctggg catggagagc aaggccatct ctgatgccca gatcactgcc

4620

agcagctact tcaccaacat gtttgccacc tggagcccca gcaaggccag gctgcacctg

4680

cagggcagga gcaatgcctg gaggccccag gtcaacaacc ccaaggagtg gctgcaggtg

4740

gacttccaga agaccatgaa ggtgactggg gtgaccaccc agggggtgaa gagcctgctg

4800

accagcatgt atgtgaagga gttcctgatc agcagcagcc aggatggcca ccagtggacc

4860

ctgttcttcc agaatggcaa ggtgaaggtg ttccagggca accaggacag cttcacccct

4920

gtggtgaaca gcctggaccc ccccctgctg accagatacc tgaggattca cccccagagc

4980

tgggtgcacc agattgccct gaggatggag gtgctgggct gtgaggccca ggacctgtac

5040

tgattaatta agagcatctt accgccatt attcccatat ttgttctgtt tttcttgatt

5100

tgggtataca tttaaatgtt aataaaacaa aatggtgggg caatcattta catttttagg

5160

gatatgtaat tactagttca ggtgtattgc cacaagacaa acatgttaag aaactttccc

5220

gttatttacg ctctgttcct gttaatcaac ctctggatta caaaatttgt gaaagattga

5280

ctgatattct taactatgtt gctcctttta cgctgtgtgg atatgctgct ttatagcctc

5340

tgtatctagc tattgcttcc cgtacggctt tcgttttctc ctccttgtat aaatcctggt

5400

tgctgtctct tttagaggag ttgtggcccg ttgtccgtca acgtggcgtg gtgtgctctg

5460

tgtttgctga cgcaaccccc actggctggg gcattgccac cacctgtcaa ctcctttctg

5520

ggactttcgc tttccccctc ccgatcgcca cggcagaact catcgccgcc tgccttgccc

5580

gctgctggac aggggctagg ttgctgggca ctgataattc cgtggtgttg tctgtgcctt

5640

ctagttgcca gccatctgtt gtttgcccct cccccgtgcc ttccttgacc ctggaaggtg

5700

ccactcccac tgtcctttcc taataaaatg aggaaattgc atcgcattgt ctgagtaggt

5760

gtcattctat tctggggggt ggggtggggc aggacagcaa gggggaggat tgggaagaca

5820

atagcaggca tgctggggat gcggtgggct ctatggctct agagcatggc tacgtagata

5880

agtagcatgg cgggttaatc attaactaca cctgcaggag gaacccctag tgatggagtt

5940

ggccactccc tctctgcgcg ctcgctcgct cactgaggcc gggcgaccaa aggtcgcccg

6000

acgcccgggc ggcctcagtg agcgagcgag cgcgcagctg cctgcagggg cgcgcctcga

6060

ggcatgcggt accaagcttg tcgagaagta ctagaggatc ataatcagcc ataccacatt

6120

tgtagaggtt ttacttgctt taaaaaacct cccacacctc cccctgaacc tgaaacataa

6180

aatgaatgca attgttgttg ttaacttgtt tattgcagct tataatggtt acaaataaag

6240

caatagcatc acaaatttca caaataaagc atttttttca ctgcattcta gttgtggttt

6300

gtccaaactc atcaatgtat cttatcatgt ctggatctga tcactgatat cgcctaggag

6360

atccgaacca gataagtgaa atctagttcc aaactatttt gtcattttta attttcgtat

6420

tagcttacga cgctacaccc agttcccatc tattttgtca ctcttcccta aataatcctt

6480

aaaaactcca tttccacccc tcccagttcc caactatttt gtccgcccac agcggggcat

6540

ttttcttcct gttatgtttt taatcaaaca tcctgccaac tccatgtgac aaaccgtcat

6600

cttcggctac tttttctctg tcacagaatg aaaatttttc tgtcatctct tcgttattaa

6660

tgtttgtaat tgactgaata tcaacgctta tttgcagcct gaatggcgaa tgggacgcgc

6720

cctgtagcgg cgcattaagc gcggcgggtg tggtggttac gcgcagcgtg accgctacac

6780

ttgccagcgc cctagcgccc gctcctttcg ctttcttccc ttcctttctc gccacgttcg

6840

ccggctttcc ccgtcaagct ctaaatcggg ggctcccttt agggttccga tttagtgctt

6900

tacggcacct cgaccccaaa aaacttgatt agggtgatgg ttcacgtagt gggccatcgc

6960

cctgatagac ggtttttcgc cctttgacgt tggagtccac gttctttaat agtggactct

7020

tgttccaaac tggaacaaca ctcaacccta tctcggtcta ttcttttgat ttataaggga

7080

ttttgccgat ttcggcctat tggttaaaaa atgagctgat ttaacaaaaa tttaacgcga

7140

attttaacaa aatattaacg tttacaattt caggtggcac ttttcgggga aatgtgcgcg

7200

gaacccctat ttgtttattt ttctaaatac attcaaatat gtatccgctc atgagacaat

7260

aaccctgata aatgcttcaa taatattgaa aaaggaagag tatgagtatt caacatttcc

7320

gtgtcgccct tattcccttt tttgcggcat tttgccttcc tgtttttgct cacccagaaa

7380

cgctggtgaa agtaaaagat gctgaagatc agttgggtgc acgagtgggt tacatcgaac

7440

tggatctcaa cagcggtaag atccttgaga gttttcgccc cgaagaacgt tttccaatga

7500

tgagcacttt taaagttctg ctatgtggcg cggtattatc ccgtattgac gccgggcaag

7560

agcaactcgg tcgccgcata cactattctc agaatgactt ggttgagtac tcaccagtca

7620

cagaaaagca tcttacggat ggcatgacag taagagaatt atgcagtgct gccataacca

7680

tgagtgataa cactgcggcc aacttacttc tgacaacgat cggaggaccg aaggagctaa

7740

ccgctttttt gcacaacatg ggggatcatg taactcgcct tgatcgttgg gaaccggagc

7800

tgaatgaagc cataccaaac gacgagcgtg acaccacgat gcctgtagca atggcaacaa

7860

cgttgcgcaa actattaact ggcgaactac ttactctagc ttcccggcaa caattaatag

7920

actggatgga ggcggataaa gttgcaggac cacttctgcg ctcggccctt ccggctggct

7980

ggtttattgc tgataaatct ggagccggtg agcgtgggtc tcgcggtatc attgcagcac

8040

tggggccaga tggtaagccc tcccgtatcg tagttatcta cacgacgggg agtcaggcaa

8100

ctatggatga acgaaataga cagatcgctg agataggtgc ctcactgatt aagcattggt

8160

aactgtcaga ccaagtttac tcatatatac tttagattga tttaaaactt catttttaat

8220

ttaaaaggat ctaggtgaag atcctttttg ataatctcat gaccaaaatc ccttaacgtg

8280

agttttcgtt ccactgagcg tcagaccccg tagaaaagat caaaggatct tcttgagatc

8340

ctttttttct gcgcgtaatc tgctgcttgc aaacaaaaaa accaccgcta ccagcggtgg

8400

tttgtttgcc ggatcaagag ctaccaactc tttttccgaa ggtaactggc ttcagcagag

8460

cgcagatacc aaatactgtc cttctagtgt agccgtagtt aggccaccac ttcaagaact

8520

ctgtagcacc gcctacatac ctcgctctgc taatcctgtt accagtggct gctgccagtg

8580

gcgataagtc gtgtcttacc gggttggact caagacgata gttaccggat aaggcgcagc

8640

ggtcgggctg aacggggggt tcgtgcacac agcccagctt ggagcgaacg acctacaccg

8700

aactgagata cctacagcgt gagcattgag aaagcgccac gcttcccgaa gggagaaagg

8760

cggacaggta tccggtaagc ggcagggtcg gaacaggaga gcgcacgagg gagcttccag

8820

ggggaaacgc ctggtatctt tatagtcctg tcgggtttcg ccacctctga cttgagcgtc

8880

gatttttgtg atgctcgtca ggggggcgga gcctatggaa aaacgccagc aacgcggcct

8940

ttttacggtt cctggccttt tgctggcctt ttgctcacat gttctttcct gcgttatccc

9000

ctgattctgt ggataaccgt attaccgcct ttgagtgagc tgataccgct cgccgcagcc

9060

gaacgaccga gcgcagcgag tcagtgagcg aggaagcgga agagcgcctg atgcggtatt

9120

ttctccttac gcatctgtgc ggtatttcac accgcagacc agccgcgtaa cctggcaaaa

9180

tcggttacgg ttgagtaata aatggatgcc ctgcgtaagc gggtgtgggc ggacaataaa

9240

gtcttaaact gaacaaaata gatctaaact atgacaataa agtcttaaac tagacagaat

9300

agttgtaaac tgaaatcagt ccagttatgc tgtgaaaaag catactggac ttttgttatg

9360

gctaaagcaa actcttcatt ttctgaagtg caaattgccc gtcgtattaa agaggggcgt

9420

ggccaagggc atggtaaaga ctatattcgc ggcgttgtga caatttaccg aacaactccg

9480

cggccgggaa gccgatctcg gcttgaacga attgttaggt ggcggtactt gggtcgatat

9540

caaagtgcat cacttcttcc cgtatgccca actttgtata gagagccact gcgggatcgt

9600

caccgtaatc tgcttgcacg tagatcacat aagcaccaag cgcgttggcc tcatgcttga

9660

ggagattgat gagcgcggtg gcaatgccct gcctccggtg ctcgccggag actgcgagat

9720

catagatata gatctcacta cgcggctgct caaacctggg cagaacgtaa gccgcgagag

9780

cgccaacaac cgcttcttgg tcgaaggcag caagcgcgat gaatgtctta ctacggagca

9840

agttcccgag gtaatcggag tccggctgat gttgggagta ggtggctacg tctccgaact

9900

cacgaccgaa aagatcaaga gcagcccgca tggatttgac ttggtcaggg ccgagcctac

9960

atgtgcgaat gatgcccata cttgagccac ctaactttgt tttagggcga ctgccctgct

10020

gcgtaacatc gttgctgctg cgtaacatcg ttgctgctcc ataacatcaa acatcgaccc

10080

acggcgtaac gcgcttgctg cttggatgcc cgaggcatag actgtacaaa aaaacagtca

10140

taacaagcca tgaaaaccgc cactgcgccg ttaccaccgc tgcgttcggt caaggttctg

10200

gaccagttgc gtgagcgcat acgctacttg cattacagtt tacgaaccga acaggcttat

10260

gtcaactggg ttcgtgcctt catccgtttc cacggtgtgc gtcacccggc aaccttgggc

10320

agcagcgaag tcgaggcatt tctgtcctgg ctggcgaacg agcgcaaggt ttcggtctcc

10380

acgcatcgtc aggcattggc ggccttgctg ttcttctacg gcaaggtgct gtgcacggat

10440

ctgccctggc ttcaggagat cggaagacct cggccgtcgc ggcgcttgcc ggtggtgctg

10500

accccggatg aagtggttcg catcctcggt tttctggaag gcgagcatcg tttgttcgcc

10560

caggactcta gctatagttc tagtggttgg ctacgtatac tccggaatat taatagatca

10620

tggagataat taaaatgata accatctcgc aaataaataa gtattttact gttttcgtaa

10680

cagttttgta ataaaaaaac ctataaatat tccggattat tcataccgtc caccatcgg

10740

gcgcggatct cggtccgaaa ccatgtcgta ctaccatcac catcaccatc acgattacga

10800

tatcccaacg accgaaaacc tgtattttca gggcgccatg ggatcc

10846

<210> 211

<211> 10923

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 211

ggccggcccc tgcaggcagc tgcgcgctcg ctcgctcact gaggccgccc gggcaaagcc

60

cgggcgtcgg gcgacctttg gtcgcccggc ctcagtgagc gagcgagcgc gcagagaggg

120

agtggccaac tccatcacta ggggttcctt gtagttaatg attaacccgc catgctactt

180

atctacgtag ccatgctcta gacgggggag gctgctggtg aatattaacc aaggtcaccc

240

cagttatcgg aggagcaaac aggggctaag tccacacgcg tggtaccgtc tgtctgcaca

300

tttcgtagag cgagtgttcc gatactctaa tctccctagg caaggttcat atttgtgtag

360

gttacttatt ctccttttgt tgactaagtc aataatcaga atcagcaggt ttggagtcag

420

cttggcaggg atcagcagcc tgggttggaa ggagggggta taaaagcccc ttcaccagga

480

gaagccgtca cacagatcca caagctcctg aagaggtaag ggtttaaggg atggttggtt

540

ggtggggtat taatgtttaa ttacctggag cacctgcctg aaatcacttt ttttcaggtt

600

ggtttaaacg ccgccaccat gcagattgag ctgagcacct gcttcttcct gtgcctgctg

660

aggttctgct tctctgccac caggagatac tacctggggg ctgtggagct gagctgggac

720

tacatgcagt ctgacctggg ggagctgcct gtggatgcca ggttcccccc cagagtgccc

780

aagagcttcc ccttcaacac ctctgtggtg tacaagaaga ccctgtttgt ggagttcact

840

gaccacctgt tcaacattgc caagcccagg cccccctgga tgggcctgct gggccccacc

900

atccaggctg aggtgtatga cactgtggtg atcaccctga agaacatggc cagccaccct

960

gtgagcctgc atgctgtggg ggtgagctac tggaaggcct ctgagggggc tgagtatgat

1020

gaccagacca gccagaggga gaaggaggat gacaaggtgt tccctggggg cagccacacc

1080

tatgtgtggc aggtgctgaa ggagaatggc cccatggcct ctgaccccct gtgcctgacc

1140

tacagctacc tgagccatgt ggacctggtg aaggacctga actctggcct gattggggcc

1200

ctgctggtgt gcagggaggg cagcctggcc aaggagaaga cccagaccct gcacaagttc

1260

atcctgctgt ttgctgtgtt tgatgagggc aagagctggc actctgaaac caagaacagc

1320

ctgatgcagg acagggatgc tgcctctgcc agggcctggc ccaagatgca cactgtgaat

1380

ggctatgtga acaggagcct gcctggcctg attggctgcc acaggaagtc tgtgtactgg

1440

catgtgattg gcatgggcac cacccctgag gtgcacagca tcttcctgga gggccacacc

1500

ttcctggtca ggaaccacag gcaggccagc ctggagatca gccccatcac cttcctgact

1560

gcccagaccc tgctgatgga cctgggccag ttcctgctgt tctgccacat cagcagccac

1620

cagcatgatg gcatggaggc ctatgtgaag gtggacagct gccctgagga gccccagctg

1680

aggatgaaga acaatgagga ggctgaggac tatgatgatg acctgactga ctctgagatg

1740

gatgtggtga ggtttgatga tgacaacagc cccagcttca tccagatcag gtctgtggcc

1800

aagaagcacc ccaagacctg ggtgcactac attgctgctg aggaggagga ctgggactat

1860

gcccccctgg tgctggcccc tgatgacagg agctacaaga gccagtacct gaacaatggc

1920

ccccagagga ttggcaggaa gtacaagaag gtcaggttca tggcctacac tgatgaaacc

1980

ttcaagacca gggaggccat ccagcatgag tctggcatcc tgggccccct gctgtatggg

2040

gaggtggggg acaccctgct gatcatcttc aagaaccagg ccagcaggcc ctacaacatc

2100

tacccccatg gcatcactga tgtgaggccc ctgtacagca ggaggctgcc caagggggtg

2160

aagcacctga aggacttccc catcctgcct ggggagatct tcaagtacaa gtggactgtg

2220

actgtggagg atggccccac caagtctgac cccaggtgcc tgaccagata ctacagcagc

2280

tttgtgaaca tggagaggga cctggcctct ggcctgattg gccccctgct gatctgctac

2340

aaggagtctg tggaccagag gggcaaccag atcatgtctg acaagaggaa tgtgatcctg

2400

ttctctgtgt ttgatgagaa caggagctgg tacctgactg agaacatcca gaggttcctg

2460

cccaaccctg ctggggtgca gctggaggac cctgagttcc aggccagcaa catcatgcac

2520

agcatcaatg gctatgtgtt tgacagcctg cagctgtctg tgtgcctgca tgaggtggcc

2580

tactggtaca tcctgagcat tggggcccag actgacttcc tgtctgtgtt cttctctggc

2640

tacaccttca agcacaagat ggtgtatgag gacaccctga ccctgttccc cttctctggg

2700

gagactgtgt tcatgagcat ggagaaccct ggcctgtgga ttctgggctg ccacaactct

2760

gacttcagga acaggggcat gactgccctg ctgaaagtct ccagctgtga caagaacact

2820

ggggactact atgaggacag ctatgaggac atctctgcct acctgctgag caagaacaat

2880

gccattgagc ccaggagctt cagccagaat gccactaatg tgtctaacaa cagcaacacc

2940

agcaatgaca gcaatgtgtc tcccccagtg ctgaagaggc accagaggga gatcaccagg

3000

accaccctgc agtctgacca ggaggagatt gactatgatg acaccatctc tgtggagatg

3060

aagaaggagg actttgacat ctacgacgag gacgagaacc agagccccag gagcttccag

3120

aagaagacca ggcactactt cattgctgct gtggagaggc tgtgggacta tggcatgagc

3180

agcagccccc atgtgctgag gaacagggcc cagtctggct ctgtgcccca gttcaagaag

3240

gtggtgttcc aggagttcac tgatggcagc ttcacccagc ccctgtacag aggggagctg

3300

aatgagcacc tgggcctgct gggcccctac atcagggctg aggtggagga caacatcatg

3360

gtgaccttca ggaaccaggc cagcaggccc tacagcttct acagcagcct gatcagctat

3420

gaggaggacc agaggcaggg ggctgagccc aggaagaact ttgtgaagcc caatgaaacc

3480

aagacctact tctggaaggt gcagcaccac atggccccca ccaaggatga gtttgactgc

3540

aaggcctggg cctacttctc tgatgtggac ctggagaagg atgtgcactc tggcctgatt

3600

ggccccctgc tggtgtgcca caccaacacc ctgaaccctg cccatggcag gcaggtgact

3660

gtgcaggagt ttgccctgtt cttcaccatc tttgatgaaa ccaagagctg gtacttcact

3720

gagaacatgg agaggaactg cagggccccc tgcaacatcc agatggagga ccccaccttc

3780

aaggagaact acaggttcca tgccatcaat ggctacatca tggacaccct gcctggcctg

3840

gtgatggccc aggaccagag gatcaggtgg tacctgctga gcatgggcag caatgagaac

3900

atccacagca tccacttctc tggccatgtg ttcactgtga ggaagaagga ggagtacaag

3960

atggccctgt acaacctgta ccctggggtg tttgagactg tggagatgct gcccagcaag

4020

gctggcatct ggagggtgga gtgcctgatt ggggagcacc tgcatgctgg catgagcacc

4080

ctgttcctgg tgtacagcaa caagtgccag acccccctgg gcatggcctc tggccacatc

4140

agggacttcc agatcactgc ctctggccag tatggccagt gggcccccaa gctggccagg

4200

ctgcactact ctggcagcat caatgcctgg agcaccaagg agcccttcag ctggatcaag

4260

gtggacctgc tggcccccat gatcatccat ggcatcaaga cccagggggc caggcagaag

4320

ttcagcagcc tgtacatcag ccagttcatc atcatgtaca gcctggatgg caagaagtgg

4380

cagacctaca ggggcaacag cactggcacc ctgatggtgt tctttggcaa tgtggacagc

4440

tctggcatca agcacaacat cttcaacccc cccatcattg ccagatacat caggctgcac

4500

cccacccact acagcatcag gagcaccctg aggatggagc tgatgggctg tgacctgaac

4560

agctgcagca tgcccctggg catggagagc aaggccatct ctgatgccca gatcactgcc

4620

agcagctact tcaccaacat gtttgccacc tggagcccca gcaaggccag gctgcacctg

4680

cagggcagga gcaatgcctg gaggccccag gtcaacaacc ccaaggagtg gctgcaggtg

4740

gacttccaga agaccatgaa ggtgactggg gtgaccaccc agggggtgaa gagcctgctg

4800

accagcatgt atgtgaagga gttcctgatc agcagcagcc aggatggcca ccagtggacc

4860

ctgttcttcc agaatggcaa ggtgaaggtg ttccagggca accaggacag cttcacccct

4920

gtggtgaaca gcctggaccc ccccctgctg accagatacc tgaggattca cccccagagc

4980

tgggtgcacc agattgccct gaggatggag gtgctgggct gtgaggccca ggacctgtac

5040

tgattaatta agagcatctt accgccatt attcccatat ttgttctgtt tttcttgatt

5100

tgggtataca tttaaatgtt aataaaacaa aatggtgggg caatcattta catttttagg

5160

gatatgtaat tactagttca ggtgtattgc cacaagacaa acatgttaag aaactttccc

5220

gttatttacg ctctgttcct gttaatcaac ctctggatta caaaatttgt gaaagattga

5280

ctgatattct taactatgtt gctcctttta cgctgtgtgg atatgctgct ttatagcctc

5340

tgtatctagc tattgcttcc cgtacggctt tcgttttctc ctccttgtat aaatcctggt

5400

tgctgtctct tttagaggag ttgtggcccg ttgtccgtca acgtggcgtg gtgtgctctg

5460

tgtttgctga cgcaaccccc actggctggg gcattgccac cacctgtcaa ctcctttctg

5520

ggactttcgc tttccccctc ccgatcgcca cggcagaact catcgccgcc tgccttgccc

5580

gctgctggac aggggctagg ttgctgggca ctgataattc cgtggtgttg tctccataaa

5640

gtaggaaaca ctacacgatt ccataaagta ggaaacacta catcactcca taaagtagga

5700

aacactacat gtgccttcta gttgccagcc atctgttgtt tgcccctccc ccgtgccttc

5760

cttgaccctg gaaggtgcca ctcccactgt cctttcctaa taaaatgagg aaattgcatc

5820

gcattgtctg agtaggtgtc attctattct ggggggtggg gtggggcagg acagcaaggg

5880

ggaggattgg gaagacaata gcaggcatgc tggggatgcg gtgggctcta tggctctaga

5940

gcatggctac gtagataagt agcatggcgg gttaatcatt aactacacct gcaggaggaa

6000

cccctagtga tggagttggc cactccctct ctgcgcgctc gctcgctcac tgaggccggg

6060

cgaccaaagg tcgcccgacg cccgggcggc ctcagtgagc gagcgagcgc gcagctgcct

6120

gcaggggcgc gcctcgaggc atgcggtacc aagcttgtcg agaagtacta gaggatcata

6180

atcagccata ccacatttgt agaggtttta cttgctttaa aaaacctccc acacctcccc

6240

ctgaacctga aacataaaat gaatgcaatt gttgttgtta acttgtttat tgcagcttat

6300

aatggttaca aataaagcaa tagcatcaca aatttcacaa ataaagcatt tttttcactg

6360

cattctagtt gtggtttgtc caaactcatc aatgtatctt atcatgtctg gatctgatca

6420

ctgatatcgc ctaggagatc cgaaccagat aagtgaaatc tagttccaaa ctattttgtc

6480

atttttaatt ttcgtattag cttacgacgc tacacccagt tcccatctat tttgtcactc

6540

ttccctaaat aatccttaaa aactccattt ccacccctcc cagttcccaa ctattttgtc

6600

cgcccacagc ggggcatttt tcttcctgtt atgtttttaa tcaaacatcc tgccaactcc

6660

atgtgacaaa ccgtcatctt cggctacttt ttctctgtca cagaatgaaa atttttctgt

6720

catctcttcg ttattaatgt ttgtaattga ctgaatatca acgcttattt gcagcctgaa

6780

tggcgaatgg gacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg tggttacgcg

6840

cagcgtgacc gctacacttg ccagcgccct agcgcccgct cctttcgctt tcttcccttc

6900

ctttctcgcc acgttcgccg gctttccccg tcaagctcta aatcgggggc tccctttagg

6960

gttccgattt agtgctttac ggcacctcga ccccaaaaaa cttgattagg gtgatggttc

7020

acgtagtggg ccatcgccct gatagacggt ttttcgccct ttgacgttgg agtccacgtt

7080

ctttaatagt ggactcttgt tccaaactgg aacaacactc aaccctatct cggtctattc

7140

ttttgattta taagggattt tgccgatttc ggcctattgg ttaaaaaatg agctgattta

7200

acaaaaattt aacgcgaatt ttaacaaaat attaacgttt acaatttcag gtggcacttt

7260

tcggggaaat gtgcgcggaa cccctatttg tttatttttc taaatacatt caaatatgta

7320

tccgctcatg agacaataac cctgataaat gcttcaataa tattgaaaaa ggaagagtat

7380

gagtattcaa catttccgtg tcgcccttat tccctttttt gcggcatttt gccttcctgt

7440

ttttgctcac ccagaaacgc tggtgaaagt aaaagatgct gaagatcagt tgggtgcacg

7500

agtgggttac atcgaactgg atctcaacag cggtaagatc cttgagagtt ttcgccccga

7560

agaacgtttt ccaatgatga gcacttttaa agttctgcta tgtggcgcgg tattatcccg

7620

tattgacgcc gggcaagagc aactcggtcg ccgcatacac tattctcaga atgacttggt

7680

tgagtactca ccagtcacag aaaagcatct tacggatggc atgacagtaa gagaattatg

7740

cagtgctgcc ataaccatga gtgataacac tgcggccaac ttacttctga caacgatcgg

7800

aggaccgaag gagctaaccg cttttttgca caacatgggg gatcatgtaa ctcgccttga

7860

tcgttgggaa ccggagctga atgaagccat accaaacgac gagcgtgaca ccacgatgcc

7920

tgtagcaatg gcaacaacgt tgcgcaaact attaactggc gaactactta ctctagcttc

7980

ccggcaacaa ttaatagact ggatggaggc ggataaagtt gcaggaccac ttctgcgctc

8040

ggcccttccg gctggctggt ttattgctga taaatctgga gccggtgagc gtgggtctcg

8100

cggtatcatt gcagcactgg ggccagatgg taagccctcc cgtatcgtag ttatctacac

8160

gacggggagt caggcaacta tggatgaacg aaatagacag atcgctgaga taggtgcctc

8220

actgattaag cattggtaac tgtcagacca agtttactca tatatacttt agattgattt

8280

aaaacttcat ttttaattta aaaggatcta ggtgaagatc ctttttgata atctcatgac

8340

caaaatccct taacgtgagt tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa

8400

aggatcttct tgagatcctt tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc

8460

accgctacca gcggtggttt gtttgccgga tcaagagcta ccaactcttt ttccgaaggt

8520

aactggcttc agcagagcgc agataccaaa tactgtcctt ctagtgtagc cgtagttagg

8580

ccaccacttc aagaactctg tagcaccgcc tacatacctc gctctgctaa tcctgttacc

8640

agtggctgct gccagtggcg ataagtcgtg tcttaccggg ttggactcaa gacgatagtt

8700

accggataag gcgcagcggt cgggctgaac ggggggttcg tgcacacagc ccagcttgga

8760

gcgaacgacc tacaccgaac tgagatacct acagcgtgag cattgagaaa gcgccacgct

8820

tcccgaaggg agaaaggcgg acaggtatcc ggtaagcggc agggtcggaa caggagagcg

8880

cacgagggag cttccagggg gaaacgcctg gtatctttat agtcctgtcg ggtttcgcca

8940

cctctgactt gagcgtcgat ttttgtgatg ctcgtcaggg gggcggagcc tatggaaaaa

9000

cgccagcaac gcggcctttt tacggttcct ggccttttgc tggccttttg ctcacatgtt

9060

ctttcctgcg ttatcccctg attctgtgga taaccgtatt accgcctttg agtgagctga

9120

taccgctcgc cgcagccgaa cgaccgagcg cagcgagtca gtgagcgagg aagcggaaga

9180

gcgcctgatg cggtattttc tccttacgca tctgtgcggt atttcacacc gcagaccagc

9240

cgcgtaacct ggcaaaatcg gttacggttg agtaataaat ggatgccctg cgtaagcggg

9300

tgtgggcgga caataaagtc ttaaactgaa caaaatagat ctaaactatg acaataaagt

9360

cttaaactag acagaatagt tgtaaactga aatcagtcca gttatgctgt gaaaaagcat

9420

actggacttt tgttatggct aaagcaaact cttcattttc tgaagtgcaa attgcccgtc

9480

gtattaaaga ggggcgtggc caagggcatg gtaaagacta tattcgcggc gttgtgacaa

9540

tttaccgaac aactccgcgg ccgggaagcc gatctcggct tgaacgaatt gttaggtggc

9600

ggtacttggg tcgatatcaa agtgcatcac ttcttcccgt atgcccaact ttgtatagag

9660

agccactgcg ggatcgtcac cgtaatctgc ttgcacgtag atcacataag caccaagcgc

9720

gttggcctca tgcttgagga gattgatgag cgcggtggca atgccctgcc tccggtgctc

9780

gccggagact gcgagatcat agatatagat ctcactacgc ggctgctcaa acctgggcag

9840

aacgtaagcc gcgagagcgc caacaaccgc ttcttggtcg aaggcagcaa gcgcgatgaa

9900

tgtcttacta cggagcaagt tcccgaggta atcggagtcc ggctgatgtt gggagtaggt

9960

ggctacgtct ccgaactcac gaccgaaaag atcaagagca gcccgcatgg atttgacttg

10020

gtcagggccg agcctacatg tgcgaatgat gcccatactt gagccaccta actttgtttt

10080

agggcgactg ccctgctgcg taacatcgtt gctgctgcgt aacatcgttg ctgctccata

10140

acatcaaaca tcgacccacg gcgtaacgcg cttgctgctt ggatgcccga ggcatagact

10200

gtacaaaaaa acagtcataa caagccatga aaaccgccac tgcgccgtta ccaccgctgc

10260

gttcggtcaa ggttctggac cagttgcgtg agcgcatacg ctacttgcat tacagtttac

10320

gaaccgaaca ggcttatgtc aactgggttc gtgccttcat ccgtttccac ggtgtgcgtc

10380

acccggcaac cttgggcagc agcgaagtcg aggcatttct gtcctggctg gcgaacgagc

10440

gcaaggtttc ggtctccacg catcgtcagg cattggcggc cttgctgttc ttctacggca

10500

aggtgctgtg cacggatctg ccctggcttc aggagatcgg aagacctcgg ccgtcgcggc

10560

gcttgccggt ggtgctgacc ccggatgaag tggttcgcat cctcggtttt ctggaaggcg

10620

agcatcgttt gttcgcccag gactctagct atagttctag tggttggcta cgtatactcc

10680

ggaatattaa tagatcatgg agataattaa aatgataacc atctcgcaaa taaataagta

10740

ttttactgtt ttcgtaacag ttttgtaata aaaaaaccta taaatattcc ggattattca

10800

taccgtccca ccatcggggcg cggatctcgg tccgaaacca tgtcgtacta ccatcaccat

10860

caccatcacg attacgatat cccaacgacc gaaaacctgt attttcaggg cgccatggga

10920

tcc

10923

<210> 212

<211> 12404

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 212

ggccggcccc tgcaggcagc tgcgcgctcg ctcgctcact gaggccgccc gggcaaagcc

60

cgggcgtcgg gcgacctttg gtcgcccggc ctcagtgagc gagcgagcgc gcagagaggg

120

agtggccaac tccatcacta ggggttcctt gtagttaatg attaacccgc catgctactt

180

atctacgtag ccatgctcta gagcggccgc tcaatattgg ccattagcca tattattcat

240

tggttatata gcataaatca atattggcta ttggccattg catacgttgt atctatatca

300

taatatgtac atttatattg gctcatgtcc aatatgaccg ccatgttggc attgattatt

360

gactagttat taatagtaat caattacggg gtcattagtt catagcccat atatggagtt

420

ccgcgttaca taacttacgg taaatggccc gcctggctga ccgcccaacg acccccgccc

480

attgacgtca ataatgacgt atgttcccat agtaacgcca atagggactt tccattgacg

540

tcaatgggtg gagtatttac ggtaaactgc ccacttggca gtacatcaag tgtatcatat

600

gccaagtccg ccccctattg acgtcaatga cggtaaatgg cccgcctggc attatgccca

660

gtacatgacc ttacgggact ttcctacttg gcagtacatc tacgtattag tcatcgctat

720

taccatggtc gaggtgagcc ccacgttctg cttcactctc cccatctccc ccccctcccc

780

acccccaatt ttgtatttat ttatttttta attattttgt gcagcgatgg gggcgggggg

840

gggggggggg cgcgcgccag gcggggcggg gcggggcgag gggcggggcg gggcgaggcg

900

gagaggtgcg gcggcagcca atcagagcgg cgcgctccga aagtttcctt ttatggcgag

960

gcggcggcgg cggcggccct ataaaaagcg aagcgcgcgg cgggcgggag tcgctgcgac

1020

gctgccttcg ccccgtgccc cgctccgccg ccgcctcgcg ccgcccgccc cggctctgac

1080

tgaccgcgtt actcccacag gtgagcgggc gggacggccc ttctcctccg ggctgtaatt

1140

agcgcttggt ttaatgacgg cttgtttctt ttctgtggct gcgtgaaagc cttgaggggc

1200

tccgggaggg ccctttgtgc gggggggagc ggctcggggg gtgcgtgcgt gtgtgtgtgc

1260

gtggggagcg ccgcgtgcgg cccgcgctgc ccggcggctg tgagcgctgc gggcgcggcg

1320

cggggctttg tgcgctccgc agtgtgcgcg aggggagcgc ggccgggggc ggtgccccgc

1380

ggtgcggggg gggctgcgag gggaacaaag gctgcgtgcg gggtgtgtgc gtggggggggt

1440

gagcagggg tgtgggcgcg gcggtcgggc tgtaaccccc ccctgcaccc ccctccccga

1500

gttgctgagc acggcccggc ttcgggtgcg gggctccgta cggggcgtgg cgcggggctc

1560

gccgtgccgg gcggggggtg gcggcaggtg ggggtgccgg gcggggcggg gccgcctcgg

1620

gccggggagg gctcggggga ggggcgcggc ggcccccgga gcgccggcgg ctgtcgaggc

1680

gcggcgagcc gcagccattg ccttttatgg taatcgtgcg agaggcgca gggacttcct

1740

ttgtcccaaa tctgtgcgga gccgaaatct gggaggcgcc gccgcacccc ctctagcggg

1800

cgcggggcga agcggtgcgg cgccggcagg aaggaaatgg gcggggaggg ccttcgtgcg

1860

tcgccgcgcc gccgtcccct tctccctctc cagcctcggg gctgtccgcg gggggacggc

1920

tgccttcggg ggggacgggg cagggcgggg ttcggcttct ggcgtgtgac cggcggctct

1980

agagcctctg ctaaccatgt tttagccttc ttctttttcc tacagctcct gggcaacgtg

2040

ctggttattg tgctgtctca tcatttgtcg acagaattcc tcgaagatcc gaaggggttc

2100

aagcttggca ttccggtact gttggtaaag ccagtttaaa cgccgccacc atgcagatcg

2160

agctgtctac ctgcttcttc ctgtgcctgc tgcggttctg cttcagcgcc accagagat

2220

attacctggg cgccgtggaa ctgagctggg actacatgca gtctgacctg ggagagctgc

2280

ccgtggacgc tagatttcct ccaagagtgc ccaagagctt ccccttcaac acctccgtgg

2340

tgtacaagaa aaccctgttc gtggaattca ccgaccacct gttcaatatc gccaagcctc

2400

ggcctccttg gatgggactg ctgggaccta caattcaggc cgaggtgtac gacaccgtgg

2460

tcatcaccct gaagaacatg gccagccatc ctgtgtctct gcacgccgtg ggagtgtctt

2520

attggaaggc ttctgagggc gccgagtacg acgatcagac aagccagaga gagaaagagg

2580

acgacaaggt tttccctggc ggcagccaca cctatgtctg gcaggtcctg aaagaaaacg

2640

gccctatggc ctccgatcct ctgtgcctga catacagcta cctgagccac gtggacctgg

2700

tcaaggacct gaattctggc ctgatcggag ccctgctcgt gtgtagagaa ggcagcctgg

2760

ccaaagagaa aacccagaca ctgcacaagt tcatcctgct gttcgccgtg ttcgacgagg

2820

gcaagagctg gcacagcgag acaaagaaca gcctgatgca ggacagggat gccgcctctg

2880

ctagagcttg gcctaagatg cacaccgtga acggctacgt gaacagaagc ctgcctggac

2940

tgatcggctg ccacagaaag tccgtgtact ggcacgtgat cggcatgggc acaacacctg

3000

aggtgcacag catctttctg gaaggccaca ccttcctcgt gcggaaccac agacaggcca

3060

gcctggaaat cagccctatc accttcctga ccgctcagac cctgctgatg gatctgggcc

3120

agtttctgct gttctgccac atcagctccc accagcacga tggcatggaa gcctacgtga

3180

aggtggacag ctgccccgaa gaaccccagc tgcggatgaa gaacaacgag gaagccgagg

3240

actacgacga cgacctgacc gactctgaga tggacgtcgt cagattcgac gacgataaca

3300

gccccagctt catccagatc agaagcgtgg ccaagaagca ccccaagacc tgggtgcact

3360

atatcgccgc cgaggaagag gactgggatt acgctcctct ggtgctggcc cctgacgaca

3420

gaagctacaa gagccagtac ctgaacaacg gccctcagcg gatcggccgg aagtataaga

3480

aagtgcggtt catggcctac accgacgaga cattcaagac cagagaggcc atccagcacg

3540

agagcggaat tctgggccct ctgctgtatg gcgaagtggg cgatacactg ctgatcatct

3600

tcaagaacca ggccagcaga ccctacaaca tctaccctca cggcatcacc gatgtgcggc

3660

ccctgtattc tagaaggctg cccaagggcg tgaagcacct gaaggacttc cctatcctgc

3720

ctggcgagat tttcaagtac aagtggaccg tgaccgtgga agatggcccc accaagagcg

3780

accctagatg tctgacacgg tactacagca gcttcgtgaa catggaacgc gacctggcca

3840

gcggcctgat tggacctctg ctgatctgct acaaagaaag cgtggaccag cggggcaacc

3900

agatcatgag cgacaagcgg aacgtgatcc tgtttagcgt gttcgatgag aaccggtcct

3960

ggtatctgac cgagaacatc cagcggtttc tgcccaatcc tgccggggtg caactggaag

4020

atcctgagtt ccaggcaagc aacatcatgc actccatcaa tggctatgtg ttcgacagcc

4080

tgcagctgag cgtgtgcctg cacgaagtgg cctactggta catcctgagc attggcgccc

4140

agaccgactt cctgtccgtg ttctttagcg gctacacctt caagcacaag atggtgtacg

4200

aggataccct gacactgttc ccattcagcg gcgagacagt gttcatgagc atggaaaacc

4260

ccggcctgtg gattctgggc tgtcacaaca gcgacttccg gaacagaggc atgacagccc

4320

tgctgaaggt gtccagctgc gacaagaaca ccggcgacta ctacgaggac agctatgagg

4380

acatcagcgc ctacctgctg agcaagaaca atgccatcga gcctcggagc ttcagccaga

4440

atcctcctgt gctgaagcgg caccagcgcg agatcaccag aacaaccctg cagagcgacc

4500

aagaggaaat cgattacgac gacaccatca gcgtcgagat gaagaaagaa gatttcgaca

4560

tctacgacga ggacgagaat cagagcccca gaagctttca gaaaaagacc cggcactact

4620

tcattgccgc cgtcgagaga ctgtgggact acggcatgtc tagcagccct cacgtgctga

4680

gaaatagagc ccagagcggc agcgtgcccc agttcaagaa agtggtgttc caagagttca

4740

ccgacggcag cttcacccag ccactgtata gaggcgagct gaacgagcat ctgggcctgc

4800

tgggccctta tatcagagcc gaagtggaag ataacatcat ggtcaccttc cggaatcagg

4860

ctagccggcc ttacagcttc tacagctccc tgatcagcta cgaagaggac cagagacagg

4920

gcgctgagcc cagaaagaac ttcgtgaagc ccaacgagac taagacctac ttttggaagg

4980

tgcagcacca catggcccct acaaaggacg agttcgactg caaagcctgg gcctacttct

5040

ccgatgtgga tctggaaaag gacgtgcaca gcgggctcat cggaccactg cttgtgtgcc

5100

acaccaacac actgaacccc gctcacggca gacaagtgac agtgcaagag ttcgccctgt

5160

tcttcaccat cttcgacgaa acaaagagct ggtacttcac cgagaatatg gaacggaact

5220

gcagagcccc ttgcaacatc cagatggaag atcccacctt caaagagaac taccggttcc

5280

acgccatcaa cggctacatc atggacacac tgcccggcct ggttatggcc caggatcaga

5340

gaatccggtg gtatctgctg tccatgggct ccaacgagaa tatccacagc atccacttca

5400

gcggccacgt gttcaccgtg cggaaaaaag aagagtacaa aatggccctg tacaatctgt

5460

accctggggt gttcgaaacc gtggaaatgc tgccttccaa ggccggcatt tggagagtgg

5520

aatgtctgat tggagagcac ctccacgccg gaatgagcac cctgtttctg gtgtacagca

5580

acaagtgtca gacccctctc ggcatggcct ctggacacat cagagacttc cagatcaccg

5640

cctctggcca gtacggacag tgggctccta aactggctcg gctgcactac agcggcagca

5700

tcaatgcctg gtccaccaaa gagcccttca gctggatcaa ggtggacctg ctggctccca

5760

tgatcatcca cggaatcaag acccagggcg cgacagaa gttcagcagc ctgtacatca

5820

gccagttcat catcatgtac agcctggacg gcaagaagtg gcagacctac agaggcaaca

5880

gcaccggcac actcatggtg ttcttcggca acgtggactc cagcggcatt aagcacaaca

5940

tcttcaaccc tccaatcatt gcccggtaca tccggctgca ccccacacac tacagcatcc

6000

ggtctaccct gagaatggaa ctgatgggct gcgacctgaa cagctgctct atgcccctcg

6060

gaatggaaag caaggccatc agcgacgccc agatcacagc cagcagctac ttcaccaaca

6120

tgttcgccac ttggagcccc tccaaggcta gactgcatct gcagggcaga agcaacgctt

6180

ggaggcccca agtgaacaac cccaaagagt ggctgcaggt tgactttcaa aagaccatga

6240

aagtgaccgg cgtgaccaca cagggcgtca agtctctgct gacctctatg tacgtgaaag

6300

agttcctgat ctccagcagc caggacggcc atcagtggac cctgtttttc cagaacggca

6360

aagtgaaagt gttccagggc aatcaggaca gcttcacacc cgtggtcaat tctctggacc

6420

ctccactgct gaccagatac ctgcggattc accctcagtc ttgggtgcac cagatcgctc

6480

tgcggatgga agtgctgggc tgtgaagctc aggacctcta ctagttaatt aagagcatct

6540

taccgccatt tattcccata tttgttctgt ttttcttgat ttgggtatac atttaaatgt

6600

taataaaaca aaatggtggg gcaatcattt acatttttag ggatatgtaa ttactagttc

6660

aggtgtattg ccacaagaca aacatgttaa gaaactttcc cgttatttac gctctgttcc

6720

tgttaatcaa cctctggatt acaaaatttg tgaaagattg actgatattc ttaactatgt

6780

tgctcctttt acgctgtgtg gatatgctgc tttatagcct ctgtatctag ctattgcttc

6840

ccgtacggct ttcgttttct cctccttgta taaatcctgg ttgctgtctc ttttagagga

6900

gttgtggccc gttgtccgtc aacgtggcgt ggtgtgctct gtgtttgctg acgcaacccc

6960

cactggctgg ggcattgcca ccacctgtca actcctttct gggactttcg ctttccccct

7020

cccgatcgcc acggcagaac tcatcgccgc ctgccttgcc cgctgctgga caggggctag

7080

gttgctgggc actgataatt ccgtggtgtt gtctccataa agtaggaaac actacacgat

7140

tccataaagt aggaaacact acatcactcc ataaagtagg aaacactaca tgtgccttct

7200

agttgccagc catctgttgt ttgcccctcc cccgtgcctt ccttgaccct ggaaggtgcc

7260

actcccactg tcctttccta ataaaatgag gaaattgcat cgcattgtct gagtaggtgt

7320

cattctattc tggggggtgg ggtggggcag gacagcaagg gggaggattg ggaagacaat

7380

agcaggcatg ctggggatgc ggtgggctct atggctctag agcatggcta cgtagataag

7440

tagcatggcg ggttaatcat taactacacc tgcaggagga acccctagtg atggagttgg

7500

ccactccctc tctgcgcgct cgctcgctca ctgaggccgg gcgaccaaag gtcgcccgac

7560

gcccgggcgg cctcagtgag cgagcgagcg cgcagctgcc tgcaggggcg cgcctcgagg

7620

catgcggtac caagcttgtc gagaagtact agaggatcat aatcagccat accacatttg

7680

tagaggtttt acttgcttta aaaaacctcc cacacctccc cctgaacctg aaacataaaa

7740

tgaatgcaat tgttgttgtt aacttgttta ttgcagctta taatggttac aaataaagca

7800

atagcatcac aaatttcaca aataaagcat ttttttcact gcattctagt tgtggtttgt

7860

ccaaactcat caatgtatct tatcatgtct ggatctgatc actgatatcg cctaggagat

7920

ccgaaccaga taagtgaaat ctagttccaa actattttgt catttttaat tttcgtatta

7980

gcttacgacg ctacacccag ttcccatcta ttttgtcact cttccctaaa taatccttaa

8040

aaactccatt tccacccctc ccagttccca actattttgt ccgcccacag cggggcattt

8100

ttcttcctgt tatgttttta atcaaacatc ctgccaactc catgtgacaa accgtcatct

8160

tcggctactt tttctctgtc acagaatgaa aatttttctg tcatctcttc gttattaatg

8220

tttgtaattg actgaatatc aacgcttatt tgcagcctga atggcgaatg ggacgcgccc

8280

tgtagcggcg cattaagcgc ggcgggtgtg gtggttacgc gcagcgtgac cgctacactt

8340

gccagcgccc tagcgcccgc tcctttcgct ttcttccctt cctttctcgc cacgttcgcc

8400

ggctttcccc gtcaagctct aaatcggggg ctccctttag ggttccgatt tagtgcttta

8460

cggcacctcg accccaaaaa acttgattag ggtgatggtt cacgtagtgg gccatcgccc

8520

tgatagacgg tttttcgccc tttgacgttg gagtccacgt tctttaatag tggactcttg

8580

ttccaaactg gaacaacact caaccctatc tcggtctatt cttttgattt ataagggatt

8640

ttgccgattt cggcctattg gttaaaaaat gagctgattt aacaaaaatt taacgcgaat

8700

tttaacaaaa tattaacgtt tacaatttca ggtggcactt ttcggggaaa tgtgcgcgga

8760

acccctattt gtttattttt ctaaatacat tcaaatatgt atccgctcat gagacaataa

8820

ccctgataaa tgcttcaata atattgaaaa aggaagagta tgagtattca acatttccgt

8880

gtcgccctta ttcccttttt tgcggcattt tgccttcctg tttttgctca cccagaaacg

8940

ctggtgaaag taaaagatgc tgaagatcag ttgggtgcac gagtgggtta catcgaactg

9000

gatctcaaca gcggtaagat ccttgagagt tttcgccccg aagaacgttt tccaatgatg

9060

agcactttta aagttctgct atgtggcgcg gtattatccc gtattgacgc cgggcaagag

9120

caactcggtc gccgcataca ctattctcag aatgacttgg ttgagtactc accagtcaca

9180

gaaaagcatc ttacggatgg catgacagta agagaattat gcagtgctgc cataaccatg

9240

agtgataaca ctgcggccaa cttacttctg acaacgatcg gaggaccgaa ggagctaacc

9300

gcttttttgc acaacatggg ggatcatgta actcgccttg atcgttggga accggagctg

9360

aatgaagcca taccaaacga cgagcgtgac accacgatgc ctgtagcaat ggcaacaacg

9420

ttgcgcaaac tattaactgg cgaactactt actctagctt cccggcaaca attaatagac

9480

tggatggagg cggataaagt tgcaggacca cttctgcgct cggcccttcc ggctggctgg

9540

tttattgctg ataaatctgg agccggtgag cgtgggtctc gcggtatcat tgcagcactg

9600

gggccagatg gtaagccctc ccgtatcgta gttatctaca cgacggggag tcaggcaact

9660

atggatgaac gaaatagaca gatcgctgag ataggtgcct cactgattaa gcattggtaa

9720

ctgtcagacc aagtttactc atatatactt tagattgatt taaaacttca tttttaattt

9780

aaaaggatct aggtgaagat cctttttgat aatctcatga ccaaaatccc ttaacgtgag

9840

ttttcgttcc actgagcgtc agaccccgta gaaaagatca aaggatcttc ttgagatcct

9900

ttttttctgc gcgtaatctg ctgcttgcaa acaaaaaaac caccgctacc agcggtggtt

9960

tgtttgccgg atcaagagct accaactctt tttccgaagg taactggctt cagcagagcg

10020

cagataccaa atactgtcct tctagtgtag ccgtagttag gccaccactt caagaactct

10080

gtagcaccgc ctacatacct cgctctgcta atcctgttac cagtggctgc tgccagtggc

10140

gataagtcgt gtcttaccgg gttggactca agacgatagt taccggataa ggcgcagcgg

10200

tcgggctgaa cggggggttc gtgcacacag cccagcttgg agcgaacgac ctacaccgaa

10260

ctgagatacc tacagcgtga gcattgagaa agcgccacgc ttcccgaagg gagaaaggcg

10320

gacaggtatc cggtaagcgg cagggtcgga acaggagagc gcacgaggga gcttccagga

10380

ggaaacgcct ggtatcttta tagtcctgtc gggtttcgcc acctctgact tgagcgtcga

10440

tttttgtgat gctcgtcagg ggggcggagc ctatggaaaa acgccagcaa cgcggccttt

10500

ttacggttcc tggccttttg ctggcctttt gctcacatgt tctttcctgc gttatcccct

10560

gattctgtgg ataaccgtat taccgccttt gagtgagctg ataccgctcg ccgcagccga

10620

acgaccgagc gcagcgagtc agtgagcgag gaagcggaag agcgcctgat gcggtatttt

10680

ctccttacgc atctgtgcgg tatttcacac cgcagaccag ccgcgtaacc tggcaaaatc

10740

ggttacggtt gagtaataaa tggatgccct gcgtaagcgg gtgtgggcgg acaataaagt

10800

cttaaactga acaaaataga tctaaactat gacaataaag tcttaaacta gacagaatag

10860

ttgtaaactg aaatcagtcc agttatgctg tgaaaaagca tactggactt ttgttatggc

10920

taaagcaaac tcttcatttt ctgaagtgca aattgcccgt cgtattaaag aggggcgtgg

10980

ccaagggcat ggtaaagact atattcgcgg cgttgtgaca atttaccgaa caactccgcg

11040

gccgggaagc cgatctcggc ttgaacgaat tgttaggtgg cggtacttgg gtcgatatca

11100

aagtgcatca cttcttcccg tatgcccaac tttgtataga gagccactgc gggatcgtca

11160

ccgtaatctg cttgcacgta gatcacataa gcaccaagcg cgttggcctc atgcttgagg

11220

agattgatga gcgcggtggc aatgccctgc ctccggtgct cgccggagac tgcgagatca

11280

tagatataga tctcactacg cggctgctca aacctgggca gaacgtaagc cgcgagagcg

11340

ccaacaaccg cttcttggtc gaaggcagca agcgcgatga atgtcttact acggagcaag

11400

ttcccgaggt aatcggagtc cggctgatgt tgggagtagg tggctacgtc tccgaactca

11460

cgaccgaaaa gatcaagagc agcccgcatg gatttgactt ggtcagggcc gagcctacat

11520

gtgcgaatga tgcccatact tgagccacct aactttgttt tagggcgact gccctgctgc

11580

gtaacatcgt tgctgctgcg taacatcgtt gctgctccat aacatcaaac atcgacccac

11640

ggcgtaacgc gcttgctgct tggatgcccg aggcatagac tgtacaaaaa aacagtcata

11700

acaagccatg aaaaccgcca ctgcgccgtt accaccgctg cgttcggtca aggttctgga

11760

ccagttgcgt gagcgcatac gctacttgca ttacagttta cgaaccgaac aggcttatgt

11820

caactgggtt cgtgccttca tccgtttcca cggtgtgcgt cacccggcaa ccttgggcag

11880

cagcgaagtc gaggcatttc tgtcctggct ggcgaacgag cgcaaggttt cggtctccac

11940

gcatcgtcag gcattggcgg ccttgctgtt cttctacggc aaggtgctgt gcacggatct

12000

gccctggctt caggagatcg gaagacctcg gccgtcgcgg cgcttgccgg tggtgctgac

12060

cccggatgaa gtggttcgca tcctcggttt tctggaaggc gagcatcgtt tgttcgccca

12120

ggactctagc tatagttcta gtggttggct acgtatactc cggaatatta atagatcatg

12180

gagataatta aaatgataac catctcgcaa ataaataagt attttactgt tttcgtaaca

12240

gttttgtaat aaaaaaacct ataaatattc cggattattc ataccgtccc accatcgggc

12300

gcggatctcg gtccgaaacc atgtcgtact accatcacca tcaccatcac gattacgata

12360

tcccaacgac cgaaaacctg tattttcagg gcgccatggg atcc

12404

<210> 213

<211> 11356

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 213

ggccggcccc tgcaggcagc tgcgcgctcg ctcgctcact gaggccgccc gggcaaagcc

60

cgggcgtcgg gcgacctttg gtcgcccggc ctcagtgagc gagcgagcgc gcagagaggg

120

agtggccaac tccatcacta ggggttcctt gtagttaatg attaacccgc catgctactt

180

atctacgtag ccatgctcta gagagtcaat gggaaaaacc cattggagcc aagtacactg

240

actcaatagg gactttccat tgggttttgc ccagtacata aggtcaatag ggggtgagtc

300

aacaggaaag tcccattgga gccaagtaca ttgagtcaat agggactttc caatgggttt

360

tgcccagtac ataaggtcaa tgggaggtaa gccaatgggt ttttcccatt actgacatgt

420

atactgagtc attagggact ttccaatggg ttttgcccag tacataaggt caataggggt

480

gaatcaacag gaaagtccca ttggagccaa gtacactgag tcaataggga ctttccatg

540

ggttttgccc agtacaaaag gtcaataggg ggtgagtcaa tgggtttttc ccattattgg

600

cacatacata aggtcaatag gggtgactag tggagaagag catgcttgag ggctgagtgc

660

ccctcagtgg gcagagagca catggcccac agtccctgag aagttggggg gaggggtggg

720

caattgaact ggtgcctaga gaaggtgggg cttgggtaaa ctgggaaagt gatgtggtgt

780

actggctcca cctttttccc cagggtgggg gagaaccata tataagtgca gtagtctctg

840

tgaacattca agcttctgcc ttctccctcc tgtgagtttg gtaagtcact gactgtctat

900

gcctgggaaa gggtggggcag gagatggggc agtgcaggaa aagtggcact atgaaccctg

960

cagccctaga caattgtact aaccttcttc tctttcctct cctgacaggt tggtgtacag

1020

tagcttccgt ttaaacgccg ccaccatgca gattgagctg agcacctgct tcttcctgtg

1080

cctgctgagg ttctgcttct ctgccaccag gagatactac ctggggggctg tggagctgag

1140

ctgggactac atgcagtctg acctggggga gctgcctgtg gatgccaggt tcccccccag

1200

agtgcccaag agcttcccct tcaacacctc tgtggtgtac aagaagaccc tgtttgtgga

1260

gttcactgac cacctgttca acattgccaa gcccaggccc ccctggatgg gcctgctggg

1320

ccccaccatc caggctgagg tgtatgacac tgtggtgatc accctgaaga acatggccag

1380

ccaccctgtg agcctgcatg ctgtgggggt gagctactgg aaggcctctg aggggctga

1440

gtatgatgac cagaccagcc agagggagaa ggaggatgac aaggtgttcc ctggggggcag

1500

cccacacctat gtgtggcagg tgctgaagga gaatggcccc atggcctctg accccctgtg

1560

cctgacctac agctacctga gccatgtgga cctggtgaag gacctgaact ctggcctgat

1620

tggggccctg ctggtgtgca gggagggcag cctggccaag gagaagaccc agaccctgca

1680

caagttcatc ctgctgtttg ctgtgtttga tgagggcaag agctggcact ctgaaaccaa

1740

gaacagcctg atgcaggaca gggatgctgc ctctgccagg gcctggccca agatgcacac

1800

tgtgaatggc tatgtgaaca ggagcctgcc tggcctgatt ggctgccaca ggaagtctgt

1860

gtactggcat gtgattggca tgggcaccac ccctgaggtg cacagcatct tcctggaggg

1920

cccacaccttc ctggtcagga accacaggca ggccagcctg gagatcagcc ccatcacctt

1980

cctgactgcc cagaccctgc tgatggacct gggccagttc ctgctgttct gccacatcag

2040

cagccaccag catgatggca tggaggccta tgtgaaggtg gacagctgcc ctgaggagcc

2100

ccagctgagg atgaagaaca atgaggaggc tgaggactat gatgatgacc tgactgactc

2160

tgagatggat gtggtgaggt ttgatgatga caacagcccc agcttcatcc agatcaggtc

2220

tgtggccaag aagcacccca agacctgggt gcactacatt gctgctgagg aggaggactg

2280

ggactatgcc cccctggtgc tggcccctga tgacaggagc tacaagagcc agtacctgaa

2340

caatggcccc cagaggattg gcaggaagta caagaaggtc aggttcatgg cctacactga

2400

tgaaaccttc aagaccaggg aggccatcca gcatgagtct ggcatcctgg gccccctgct

2460

gtatggggag gtgggggaca ccctgctgat catcttcaag aaccaggcca gcaggcccta

2520

caacatctac ccccatggca tcactgatgt gaggcccctg tacagcagga ggctgcccaa

2580

gggggtgaag cacctgaagg acttccccat cctgcctggg gagatcttca agtacaagtg

2640

gactgtgact gtggaggatg gccccaccaa gtctgacccc aggtgcctga ccagatacta

2700

cagcagcttt gtgaacatgg agagggacct ggcctctggc ctgattggcc ccctgctgat

2760

ctgctacaag gagtctgtgg accagagggg caaccagatc atgtctgaca agaggaatgt

2820

gatcctgttc tctgtgtttg atgagaacag gagctggtac ctgactgaga acatccagag

2880

gttcctgccc aaccctgctg gggtgcagct ggaggaccct gagttccagg ccagcaacat

2940

catgcacagc atcaatggct atgtgtttga cagcctgcag ctgtctgtgt gcctgcatga

3000

ggtggcctac tggtacatcc tgagcattgg ggcccagact gacttcctgt ctgtgttctt

3060

ctctggctac accttcaagc acaagatggt gtatgaggac accctgaccc tgttcccctt

3120

ctctggggag actgtgttca tgagcatgga gaaccctggc ctgtggattc tgggctgcca

3180

caactctgac ttcaggaaca ggggcatgac tgccctgctg aaagtctcca gctgtgacaa

3240

gaacactggg gactactatg aggacagcta tgaggacatc tctgcctacc tgctgagcaa

3300

gaacaatgcc attgagccca ggagcttcag ccagaatgcc actaatgtgt ctaacaacag

3360

caacaccagc aatgacagca atgtgtctcc cccagtgctg aagaggcacc agagggat

3420

caccaggacc accctgcagt ctgaccagga ggagattgac tatgatgaca ccatctctgt

3480

ggagatgaag aaggaggact ttgacatcta cgacgaggac gagaaccaga gccccaggag

3540

cttccagaag aagaccaggc actacttcat tgctgctgtg gagaggctgt gggactatgg

3600

catgagcagc agcccccatg tgctgaggaa cagggcccag tctggctctg tgccccagtt

3660

caagaaggtg gtgttccagg agttcactga tggcagcttc acccagcccc tgtacagagg

3720

ggagctgaat gagcacctgg gcctgctggg cccctacatc agggctgagg tggaggacaa

3780

catcatggtg accttcagga accaggccag caggccctac agcttctaca gcagcctgat

3840

cagctatgag gaggaccaga ggcagggggc tgagcccagg aagaactttg tgaagcccaa

3900

tgaaaccaag acctacttct ggaaggtgca gcaccacatg gcccccacca aggatgagtt

3960

tgactgcaag gcctgggcct acttctctga tgtggacctg gagaaggatg tgcactctgg

4020

cctgattggc cccctgctgg tgtgccacac caacaccctg aaccctgccc atggcaggca

4080

ggtgactgtg caggagtttg ccctgttctt caccatcttt gatgaaacca agagctggta

4140

cttcactgag aacatggaga ggaactgcag ggccccctgc aacatccaga tggaggaccc

4200

caccttcaag gagaactaca ggttccatgc catcaatggc tacatcatgg acaccctgcc

4260

tggcctggtg atggcccagg accagaggat caggtggtac ctgctgagca tgggcagcaa

4320

tgagaacatc cacagcatcc acttctctgg ccatgtgttc actgtgagga agaaggagga

4380

gtacaagatg gccctgtaca acctgtaccc tggggtgttt gagactgtgg agatgctgcc

4440

cagcaaggct ggcatctgga gggtggagtg cctgattggg gagcacctgc atgctggcat

4500

gagcaccctg ttcctggtgt acagcaacaa gtgccagacc cccctgggca tggcctctgg

4560

ccacatcagg gacttccaga tcactgcctc tggccagtat ggccagtggg cccccaagct

4620

ggccaggctg cactactctg gcagcatcaa tgcctggagc accaaggagc ccttcagctg

4680

gatcaaggtg gacctgctgg cccccatgat catccatggc atcaagaccc aggggggccag

4740

gcagaagttc agcagcctgt acatcagcca gttcatcatc atgtacagcc tggatggcaa

4800

gaagtggcag acctacaggg gcaacagcac tggcaccctg atggtgttct ttggcaatgt

4860

ggacagctct ggcatcaagc acaacatctt caaccccccc atcattgcca gatacatcag

4920

gctgcacccc accactaca gcatcaggag caccctgagg atggagctga tgggctgtga

4980

cctgaacagc tgcagcatgc ccctgggcat ggagagcaag gccatctctg atgcccagat

5040

cactgccagc agctacttca ccaacatgtt tgccacctgg agccccagca aggccaggct

5100

gcacctgcag ggcaggagca atgcctggag gccccaggtc aacaacccca aggagtggct

5160

gcaggtggac ttccagaaga ccatgaaggt gactggggtg accacccagg gggtgaagag

5220

cctgctgacc agcatgtatg tgaaggagtt cctgatcagc agcagccagg atggccacca

5280

gtggaccctg ttcttccaga atggcaaggt gaaggtgttc cagggcaacc aggacagctt

5340

cacccctgtg gtgaacagcc tggacccccc cctgctgacc agatacctga ggattcaccc

5400

ccagagctgg gtgcaccaga ttgccctgag gatggaggtg ctgggctgtg aggcccagga

5460

cctgtactga ttaattaaga gcatcttacc gccatttatt cccatatttg ttctgttttt

5520

cttgatttgg gtatacattt aaatgttaat aaaacaaaat ggtggggcaa tcatttacat

5580

ttttagggat atgtaattac tagttcaggt gtattgccac aagacaaaca tgttaagaaa

5640

ctttcccgtt atttacgctc tgttcctgtt aatcaacctc tggattacaa aatttgtgaa

5700

agattgactg atattcttaa ctatgttgct ccttttacgc tgtgtggata tgctgcttta

5760

tagcctctgt atctagctat tgcttcccgt acggctttcg ttttctcctc cttgtataaa

5820

tcctggttgc tgtctctttt agaggagttg tggcccgttg tccgtcaacg tggcgtggtg

5880

tgctctgtgt ttgctgacgc aacccccact ggctggggca ttgccaccac ctgtcaactc

5940

ctttctggga ctttcgcttt ccccctcccg atcgccacgg cagaactcat cgccgcctgc

6000

cttgcccgct gctggacagg ggctaggttg ctgggcactg ataattccgt ggtgttgtct

6060

ccataaagta ggaaacacta cacgattcca taaagtagga aacactacat cactccataa

6120

agtaggaaac actacatgtg ccttctagtt gccagccatc tgttgtttgc ccctcccccg

6180

tgccttcctt gaccctggaa ggtgccactc ccactgtcct ttcctaataa aatgaggaaa

6240

ttgcatcgca ttgtctgagt aggtgtcatt ctattctggg gggtggggtg gggcaggaca

6300

gcaaggggga ggattgggaa gacaatagca ggcatgctgg ggatgcggtg ggctctatgg

6360

ctctagatct agagcatggc tacgtagata agtagcatgg cgggttaatc attaactaca

6420

cctgcaggag gaacccctag tgatggagtt ggccactccc tctctgcgcg ctcgctcgct

6480

cactgaggcc gggcgaccaa aggtcgcccg acgcccgggc ggcctcagtg agcgagcgag

6540

cgcgcagctg cctgcagggg cgcgcctcga ggcatgcggt accaagcttg tcgagaagta

6600

ctagaggatc ataatcagcc ataccacatt tgtagaggtt ttacttgctt taaaaaacct

6660

cccacacctc cccctgaacc tgaaacataa aatgaatgca attgttgttg ttaacttgtt

6720

tattgcagct tataatggtt acaaataaag caatagcatc acaaatttca caaataaagc

6780

atttttttca ctgcattcta gttgtggttt gtccaaactc atcaatgtat cttatcatgt

6840

ctggatctga tcactgatat cgcctaggag atccgaacca gataagtgaa atctagttcc

6900

aaactatttt gtcattttta attttcgtat tagcttacga cgctacaccc agttcccatc

6960

tattttgtca ctcttcccta aataatcctt aaaaactcca tttccacccc tcccagttcc

7020

caactatttt gtccgcccac agcggggcat ttttcttcct gttatgtttt taatcaaaca

7080

tcctgccaac tccatgtgac aaaccgtcat cttcggctac tttttctctg tcacagaatg

7140

aaaatttttc tgtcatctct tcgttattaa tgtttgtaat tgactgaata tcaacgctta

7200

tttgcagcct gaatggcgaa tgggacgcgc cctgtagcgg cgcattaagc gcggcgggtg

7260

tggtggttac gcgcagcgtg accgctacac ttgccagcgc cctagcgccc gctcctttcg

7320

ctttcttccc ttcctttctc gccacgttcg ccggctttcc ccgtcaagct ctaaatcggg

7380

ggctcccttt agggttccga tttagtgctt tacggcacct cgaccccaaa aaacttgatt

7440

agggtgatgg ttcacgtagt gggccatcgc cctgatagac ggtttttcgc cctttgacgt

7500

tggagtccac gttctttaat agtggactct tgttccaaac tggaacaaca ctcaacccta

7560

tctcggtcta ttcttttgat ttataaggga ttttgccgat ttcggcctat tggttaaaaa

7620

atgagctgat ttaacaaaaa tttaacgcga attttaacaa aatattaacg tttacaattt

7680

caggtggcac ttttcgggga aatgtgcgcg gaacccctat ttgtttattt ttctaaatac

7740

attcaaatat gtatccgctc atgagacaat aaccctgata aatgcttcaa taatattgaa

7800

aaaggaagag tatgagtatt caacatttcc gtgtcgccct tattcccttt tttgcggcat

7860

tttgccttcc tgtttttgct cacccagaaa cgctggtgaa agtaaaagat gctgaagatc

7920

agttgggtgc acgagtgggt tacatcgaac tggatctcaa cagcggtaag atccttgaga

7980

gttttcgccc cgaagaacgt tttccaatga tgagcacttt taaagttctg ctatgtggcg

8040

cggtattatc ccgtattgac gccgggcaag agcaactcgg tcgccgcata cactattctc

8100

agaatgactt ggttgagtac tcaccagtca cagaaaagca tcttacggat ggcatgacag

8160

taagagaatt atgcagtgct gccataacca tgagtgataa cactgcggcc aacttacttc

8220

tgacaacgat cggaggaccg aaggagctaa ccgctttttt gcacaacatg ggggatcatg

8280

taactcgcct tgatcgttgg gaaccggagc tgaatgaagc cataccaaac gacgagcgtg

8340

acaccacgat gcctgtagca atggcaacaa cgttgcgcaa actattaact ggcgaactac

8400

ttactctagc ttcccggcaa caattaatag actggatgga ggcggataaa gttgcaggac

8460

cacttctgcg ctcggccctt ccggctggct ggtttattgc tgataaatct ggagccggtg

8520

agcgtgggtc tcgcggtatc attgcagcac tggggccaga tggtaagccc tcccgtatcg

8580

tagttatcta cacgacgggg agtcaggcaa ctatggatga acgaaataga cagatcgctg

8640

agataggtgc ctcactgatt aagcattggt aactgtcaga ccaagtttac tcatatatac

8700

tttagattga tttaaaactt catttttaat ttaaaaggat ctaggtgaag atcctttttg

8760

ataatctcat gaccaaaatc ccttaacgtg agttttcgtt ccactgagcg tcagaccccg

8820

tagaaaagat caaaggatct tcttgagatc ctttttttct gcgcgtaatc tgctgcttgc

8880

aaacaaaaaa accaccgcta ccagcggtgg tttgtttgcc ggatcaagag ctaccaactc

8940

tttttccgaa ggtaactggc ttcagcagag cgcagatacc aaatactgtc cttctagtgt

9000

agccgtagtt aggccaccac ttcaagaact ctgtagcacc gcctacatac ctcgctctgc

9060

taatcctgtt accagtggct gctgccagtg gcgataagtc gtgtcttacc gggttggact

9120

caagacgata gttaccggat aaggcgcagc ggtcgggctg aacggggggt tcgtgcacac

9180

agcccagctt ggagcgaacg acctacaccg aactgagata cctacagcgt gagcattgag

9240

aaagcgccac gcttcccgaa gggagaaagg cggacaggta tccggtaagc ggcagggtcg

9300

gaacaggaga gcgcacgagg gagcttccag ggggaaacgc ctggtatctt tatagtcctg

9360

tcgggtttcg ccacctctga cttgagcgtc gatttttgtg atgctcgtca ggggggcgga

9420

gcctatggaa aaacgccagc aacgcggcct ttttacggtt cctggccttt tgctggcctt

9480

ttgctcacat gttctttcct gcgttatccc ctgattctgt ggataaccgt attaccgcct

9540

ttgagtgagc tgataccgct cgccgcagcc gaacgaccga gcgcagcgag tcagtgagcg

9600

aggaagcgga agagcgcctg atgcggtatt ttctccttac gcatctgtgc ggtatttcac

9660

accgcagacc agccgcgtaa cctggcaaaa tcggttacgg ttgagtaata aatggatgcc

9720

ctgcgtaagc gggtgtgggc ggacaataaa gtcttaaact gaacaaaata gatctaaact

9780

atgacaataa agtcttaaac tagacagaat agttgtaaac tgaaatcagt ccagttatgc

9840

tgtgaaaaag catactggac ttttgttatg gctaaagcaa actcttcatt ttctgaagtg

9900

caaattgccc gtcgtattaa agaggggcgt ggccaagggc atggtaaaga ctatattcgc

9960

ggcgttgtga caatttaccg aacaactccg cggccgggaa gccgatctcg gcttgaacga

10020

attgttaggt ggcggtactt gggtcgatat caaagtgcat cacttcttcc cgtatgccca

10080

actttgtata gagagccact gcgggatcgt caccgtaatc tgcttgcacg tagatcacat

10140

aagcaccaag cgcgttggcc tcatgcttga ggagattgat gagcgcggtg gcaatgccct

10200

gcctccggtg ctcgccggag actgcgagat catagatata gatctcacta cgcggctgct

10260

caaacctggg cagaacgtaa gccgcgagag cgccaacaac cgcttcttgg tcgaaggcag

10320

caagcgcgat gaatgtctta ctacggagca agttcccgag gtaatcggag tccggctgat

10380

gttgggagta ggtggctacg tctccgaact cacgaccgaa aagatcaaga gcagcccgca

10440

tggatttgac ttggtcaggg ccgagcctac atgtgcgaat gatgcccata cttgagccac

10500

ctaactttgt tttagggcga ctgccctgct gcgtaacatc gttgctgctg cgtaacatcg

10560

ttgctgctcc ataacatcaa acatcgaccc acggcgtaac gcgcttgctg cttggatgcc

10620

cgaggcatag actgtacaaa aaaacagtca taacaagcca tgaaaaccgc cactgcgccg

10680

ttaccaccgc tgcgttcggt caaggttctg gaccagttgc gtgagcgcat acgctacttg

10740

cattacagtt tacgaaccga acaggcttat gtcaactggg ttcgtgcctt catccgtttc

10800

cacggtgtgc gtcacccggc aaccttgggc agcagcgaag tcgaggcatt tctgtcctgg

10860

ctggcgaacg agcgcaaggt ttcggtctcc acgcatcgtc aggcattggc ggccttgctg

10920

ttcttctacg gcaaggtgct gtgcacggat ctgccctggc ttcaggagat cggaagacct

10980

cggccgtcgc ggcgcttgcc ggtggtgctg accccggatg aagtggttcg catcctcggt

11040

tttctggaag gcgagcatcg tttgttcgcc caggactcta gctatagttc tagtggttgg

11100

ctacgtatac tccggaatat taatagatca tggagataat taaaatgata accatctcgc

11160

aaataaataa gtattttact gttttcgtaa cagttttgta ataaaaaaac ctataaatat

11220

tccggattat tcataccgtc cccacatcgg gcgcggatct cggtccgaaa ccatgtcgta

11280

ctaccatcac catcaccatc acgattacga tatcccaacg accgaaaacc tgtattttca

11340

gggcgccatg ggatcc

11356

<210> 214

<211> 11434

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 214

ggccggcccc tgcaggcagc tgcgcgctcg ctcgctcact gaggccgccc gggcaaagcc

60

cgggcgtcgg gcgacctttg gtcgcccggc ctcagtgagc gagcgagcgc gcagagaggg

120

agtggccaac tccatcacta ggggttcctt gtagttaatg attaacccgc catgctactt

180

atctacgtag ccatgctcta gacgggggag gctgctggtg aatattaacc aaggtcaccc

240

cagttatcgg aggagcaaac aggggctaag tccacacgcg tggtaccgtc tgtctgcaca

300

tttcgtagag cgagtgttcc gatactctaa tctccctagg caaggttcat atttgtgtag

360

gttacttatt ctccttttgt tgactaagtc aataatcaga atcagcaggt ttggagtcag

420

cttggcaggg atcagcagcc tgggttggaa ggagggggta taaaagcccc ttcaccagga

480

gaagccgtca cacagatcca caagctcctg aagaggtaag ggtttaaggg atggttggtt

540

ggtggggtat taatgtttaa ttacctggag cacctgcctg aaatcacttt ttttcaggtt

600

ggtttaaacg ccgccaccat gcaaattgag ttaagtacct gttttttcct gtgcctgttg

660

agattttgct tctctgctac cagaaggtat tacctgggag ctgtggagct gtcatgggac

720

tacatgcagt ctgacctggg agagctccct gttgatgcta ggtttccccc tagggtgcca

780

aagtcctttc cttttaacac ctcagtggtg tacaagaaga cactgtttgt ggagtttact

840

gaccacctct tcaatattgc taagccaaga cccccttgga tgggtctctt gggccctacc

900

atccaggctg aggtttatga tacagtggtg attaccctca agaatatggc ttctcatcct

960

gttagtctgc atgcagtagg ggtcagctat tggaaggcca gtgaaggagc tgagtatgat

1020

gaccagacca gccagagaga gaaagaggat gacaaggtgt tccctggggg atcacacacc

1080

tatgtgtggc aggtgttgaa ggaaaatgga cccatggcct ctgacccact ctgcctgact

1140

tactcctacc tgtctcatgt ggacctggtc aaagatctga actctggcct gattggggca

1200

ctgttggtgt gcagagaagg gtctcttgcc aaggagaaga ctcagaccct gcacaagttc

1260

atcctgctgt ttgctgtgtt tgatgaaggc aagtcttggc attctgagac taagaacagc

1320

ctgatgcaag atagagatgc tgcatctgcc agggcctggc ctaagatgca cactgtgaat

1380

ggatatgtga ataggtcctt gcctggcctg attggatgcc ataggaagtc tgtgtactgg

1440

catgtgattg gcatgggcac cacccctgag gttcactcta tttttctgga gggccatact

1500

ttccttgtga ggaatcatag acaggcctct ctggagatta gccctattac atttctgact

1560

gctcagaccc tcctcatgga cttggggcag tttctgttaa gctgccacat cagcagccat

1620

caacatgatg gtatggaagc ctatgtcaaa gtggatagct gccctgaaga accacagctt

1680

aggatgaaga acaatgagga ggcagaggac tatgatgatg atctgactga ttctgaaatg

1740

gatgtggtga gatttgatga tgataatagc ccttccttta tccagatcag gtcagtggcc

1800

aagaagcacc caaagacctg ggtgcattat attgctgctg aggagggagga ctgggactat

1860

gcccctctgg tgctggcccc tgatgataga agctataagt ctcaatactt gaataatggc

1920

ccacagagga ttgggagaaa gtacaaaaag gtgagattta tggcctacac tgatgagact

1980

ttcaagacca gagaggccat ccagcatgaa tcaggcattt tgggtcccct gctgtatgga

2040

gaggtggggg ataccctgct gatcatcttt aagaaccagg ccagcagacc ttacaacatt

2100

taccctcatg ggatcacaga tgtgaggcca ctctactcta ggagattgcc caagggagtc

2160

aagcatctta aggactttcc aatcctgcct ggggagatct tcaagtacaa atggacagtg

2220

acagttgagg atggacctac taagagtgac cccaggtgtc tgaccagata ttactctagc

2280

tttgtcaata tggaaagaga cctggcttca ggcttgatag gccctcttct catctgctac

2340

aaagagtctg tggaccagag aggaaatcag attatgtctg acaagagaaa tgttattctg

2400

ttttcagtct ttgatgagaa cagaagttgg tacttgacag agaacattca gagatttctg

2460

cctaaccctg caggagtgca gcttgaggac cctgagtttc aggcttccaa tatcatgcat

2520

tctatcaatg gctatgtgtt tgatagcctg cagctgtctg tgtgcctgca tgaggttgcc

2580

tattggtaca tcctgtctat tggggcccaa actgatttct tgtctgtgtt tttcagtgga

2640

tataccttta agcataagat ggtgtatgaa gataccttga cacttttccc tttctcagga

2700

gagactgtct tcatgtctat ggagaaccct ggactgtgga tcctgggatg ccacaactca

2760

gacttcagaa acaggggtat gacagctctg cttaaggtct cctcatgtga caaaaataca

2820

ggagactact atgaagattc ctatgaggac atctctgctt acctgctcag caaaaacaat

2880

gccattgagc ccagaagctt cagccagaat tccagacatc ccagtactag gcagaagcag

2940

tttaatgcca caccatccc agaaaatgac attgagaaga cagacccttg gtttgcccat

3000

agaaccccaa tgcccaagat tcagaatgtg agcagctcag acttgctgat gctgctgagg

3060

cagtctccta ctccccatgg cctgtccctc tcagatctgc aggaagccaa gtatgagaca

3120

ttttctgatg acccctcccc aggggctatt gacagtaaca acagcctgtc tgaaatgacc

3180

cacttcagac ctcagctcca ccacagtggg gatatggtgt ttaccccaga gtcaggcctg

3240

cagctgagac tgaatgagaa gctgggaacc acagctgcca cagaactgaa gaagctggat

3300

ttcaaggtga gctctacttc aaataatctg atttccacta tcccatctga caatttggca

3360

gctggcactg acaatacaag ctctctgggc ccacctagca tgccagtgca ttatgacagc

3420

cagttggaca ccactctttt tggaaagaaa tccagtcccc tgacagagtc aggaggaccc

3480

ctttctctgt ctgaggagaa caatgatagt aagcttctgg agtcaggctt gatgaactcc

3540

caggagagtt cttggggcaa gaatgtgagc tctagggaga tcaccagaac cactctgcag

3600

tctgaccaag aagagattga ttatgatgac actatctctg ttgagatgaa gaaggaggac

3660

tttgatatct atgatgagga tgagaaccag tctccaagaa gtttccagaa gaagaccagg

3720

cactacttta ttgctgctgt ggagagactg tgggactatg gaatgtcctc ctcccctcat

3780

gtcctgagaa atagagctca gtcaggatca gtgccccagt tcaagaaggt ggtgttccag

3840

gaattcacag atggaagttt tacccagcca ctgtatagag gtgaactgaa tgaacatctg

3900

ggtctgctgg ggccctatat cagggctgag gtggaggaca atattatggt gacctttaga

3960

aaccaggcct caaggcccta cagcttctac tcttccctca tttcatatga ggaagaccag

4020

agacagggag cagagcctag aaagaacttt gtcaagccca atgaaaccaa aacctatttc

4080

tggaaggtgc agcaccacat ggcacccacc aaagatgagt ttgactgcaa agcctgggcc

4140

tatttctcag atgtggatct ggagaaggat gtccattcag gtctgattgg accactcctg

4200

gtgtgccaca ccaacacact gaatccagct catggcagac aggtgacagt ccaggagttt

4260

gccctgtttt tcactatttt tgatgagacc aagagctggt attttacaga gaatatggaa

4320

agaaactgca gagccccttg taatatccag atggaggacc caacctttaa ggagaactac

4380

aggttccatg ccatcaatgg ctacattatg gataccctgc ctggcctggt tatggcccag

4440

gatcagagga tcaggtggta tctgctgtca atgggctcca atgagaacat tcatagtatt

4500

cacttttcag gacatgtgtt cacagtgaga aagaaggagg agtataagat ggccctctat

4560

aatctctacc caggggtgtt tgagacagtt gagatgctgc catctaaggc aggcatctgg

4620

agagtggaat gcctcattgg agagcacctg catgctggca tgtccaccct gtttctggtg

4680

tactccaaca aatgtcagac ccctcttggt atggcctctg gccacattag ggatttccag

4740

attactgcca gtggtcagta tgggcagtgg gcccctaagc tggccagact gcactattct

4800

gggagcatca atgcctggtc caccaaggaa cctttttctt ggattaaagt ggatctgctg

4860

gccccaatga tcatccatgg gatcaagacc cagggagcta ggcagaagtt cagcagcctg

4920

tacattagtc agttcatcat tatgtacagt ctggatggca aaaagtggca gacatacagg

4980

ggcaattcca ctggaaccct gatggtgttc tttggaaatg tggatagcag tggtatcaag

5040

cacaacattt tcaaccctcc catcattgcc aggtacatca gactgcatcc aacccactac

5100

agcattagga gcacccttag gatggagctc atggggtgtg acctgaactc ttgctctatg

5160

ccacttggaa tggagagcaa ggccatctct gatgcccaga ttactgctag ttcctacttc

5220

accaatatgt ttgccacctg gtcacccagc aaggccaggc tgcacctgca gggaaggtcc

5280

aatgcttgga ggcctcaggt gaacaatcca aaggagtggc tgcaggtgga cttccagaag

5340

actatgaagg tgacaggagt gaccactcag ggagtgaaga gcctgctgac ctccatgtat

5400

gtgaaggagt ttctgatctc cagctcccag gatggccacc agtggaccct gttctttcag

5460

aatggcaagg tgaaggtgtt tcaggggaat caggactcct tcaccccagt ggtgaattcc

5520

ctggatcccc ctctgctgac cagatacctg agaatccacc cccagtcttg ggtgcaccag

5580

attgccctta ggatggaggt gctgggctgt gaggcccagg acctgtactg attaattaag

5640

agcatcttac cgccatttat tcccatattt gttctgtttt tcttgatttg ggtatacatt

5700

taaatgttaa taaaacaaaa tggtggggca atcatttaca tttttaggga tatgtaatta

5760

ctagttcagg tgtattgcca caagacaaac atgttaagaa actttcccgt tatttacgct

5820

ctgttcctgt taatcaacct ctggattaca aaatttgtga aagattgact gatattctta

5880

actatgttgc tccttttacg ctgtgtggat atgctgcttt atagcctctg tatctagcta

5940

ttgcttcccg tacggctttc gttttctcct ccttgtataa atcctggttg ctgtctcttt

6000

tagaggagtt gtggcccgtt gtccgtcaac gtggcgtggt gtgctctgtg tttgctgacg

6060

caacccccac tggctggggc attgccacca cctgtcaact cctttctggg actttcgctt

6120

tccccctccc gatcgccacg gcagaactca tcgccgcctg ccttgcccgc tgctggacag

6180

gggctaggtt gctgggcact gataattccg tggtgttgtc tgtgccttct agttgccagc

6240

catctgttgt ttgcccctcc cccgtgcctt ccttgaccct ggaaggtgcc actcccactg

6300

tcctttccta ataaaatgag gaaattgcat cgcattgtct gagtaggtgt cattctattc

6360

tggggggtgg ggtggggcag gacagcaagg gggaggattg ggaagacaat agcaggcatg

6420

ctggggatgc ggtgggctct atggctctag agcatggcta cgtagataag tagcatggcg

6480

ggttaatcat taactacacc tgcaggagga acccctagtg atggagttgg ccactccctc

6540

tctgcgcgct cgctcgctca ctgaggccgg gcgaccaaag gtcgcccgac gcccgggcgg

6600

cctcagtgag cgagcgagcg cgcagctgcc tgcaggggcg cgcctcgagg catgcggtac

6660

caagcttgtc gagaagtact agaggatcat aatcagccat accacatttg tagaggtttt

6720

acttgcttta aaaaacctcc cacacctccc cctgaacctg aaacataaaa tgaatgcaat

6780

tgttgttgtt aacttgttta ttgcagctta taatggttac aaataaagca atagcatcac

6840

aaatttcaca aataaagcat ttttttcact gcattctagt tgtggtttgt ccaaactcat

6900

caatgtatct tatcatgtct ggatctgatc actgatatcg cctaggagat ccgaaccaga

6960

taagtgaaat ctagttccaa actattttgt catttttaat tttcgtatta gcttacgacg

7020

ctacacccag ttcccatcta ttttgtcact cttccctaaa taatccttaa aaactccatt

7080

tccacccctc ccagttccca actattttgt ccgcccacag cggggcattt ttcttcctgt

7140

tatgttttta atcaaacatc ctgccaactc catgtgacaa accgtcatct tcggctactt

7200

tttctctgtc acagaatgaa aatttttctg tcatctcttc gttattaatg tttgtaattg

7260

actgaatatc aacgcttatt tgcagcctga atggcgaatg ggacgcgccc tgtagcggcg

7320

cattaagcgc ggcgggtgtg gtggttacgc gcagcgtgac cgctacactt gccagcgccc

7380

tagcgcccgc tcctttcgct ttcttccctt cctttctcgc cacgttcgcc ggctttcccc

7440

gtcaagctct aaatcggggg ctccctttag ggttccgatt tagtgcttta cggcacctcg

7500

accccaaaaa acttgattag ggtgatggtt cacgtagtgg gccatcgccc tgatagacgg

7560

tttttcgccc tttgacgttg gagtccaacgt tctttaatag tggactcttg ttccaaactg

7620

gaacaacact caaccctatc tcggtctatt cttttgattt ataagggatt ttgccgattt

7680

cggcctattg gttaaaaaat gagctgattt aacaaaaatt taacgcgaat tttaacaaaa

7740

tattaacgtt tacaatttca ggtggcactt ttcggggaaa tgtgcgcgga acccctattt

7800

gtttattttt ctaaatacat tcaaatatgt atccgctcat gagacaataa ccctgataaa

7860

tgcttcaata atattgaaaa aggaagagta tgagtattca acatttccgt gtcgccctta

7920

ttcccttttt tgcggcattt tgccttcctg tttttgctca cccagaaacg ctggtgaaag

7980

taaaagatgc tgaagatcag ttgggtgcac gagtgggtta catcgaactg gatctcaaca

8040

gcggtaagat ccttgagagt tttcgccccg aagaacgttt tccaatgatg agcactttta

8100

aagttctgct atgtggcgcg gtattatccc gtattgacgc cgggcaagag caactcggtc

8160

gccgcataca ctattctcag aatgacttgg ttgagtactc accagtcaca gaaaagcatc

8220

ttacggatgg catgacagta agagaattat gcagtgctgc cataaccatg agtgataaca

8280

ctgcggccaa cttacttctg acaacgatcg gaggaccgaa ggagctaacc gcttttttgc

8340

acaacatggg ggatcatgta actcgccttg atcgttggga accggagctg aatgaagcca

8400

taccaaacga cgagcgtgac accacgatgc ctgtagcaat ggcaacaacg ttgcgcaaac

8460

tattaactgg cgaactactt actctagctt cccggcaaca attaatagac tggatggagg

8520

cggataaagt tgcaggacca cttctgcgct cggcccttcc ggctggctgg tttattgctg

8580

ataaatctgg agccggtgag cgtgggtctc gcggtatcat tgcagcactg gggccagatg

8640

gtaagccctc ccgtatcgta gttatctaca cgacggggag tcaggcaact atggatgaac

8700

gaaatagaca gatcgctgag ataggtgcct cactgattaa gcattggtaa ctgtcagacc

8760

aagtttactc atatatactt tagattgatt taaaacttca tttttaattt aaaaggatct

8820

aggtgaagat cctttttgat aatctcatga ccaaaatccc ttaacgtgag ttttcgttcc

8880

actgagcgtc agaccccgta gaaaagatca aaggatcttc ttgagatcct ttttttctgc

8940

gcgtaatctg ctgcttgcaa acaaaaaaac caccgctacc agcggtggtt tgtttgccgg

9000

atcaagagct accaactctt tttccgaagg taactggctt cagcagagcg cagataccaa

9060

atactgtcct tctagtgtag ccgtagttag gccaccactt caagaactct gtagcaccgc

9120

ctacatacct cgctctgcta atcctgttac cagtggctgc tgccagtggc gataagtcgt

9180

gtcttaccgg gttggactca agacgatagt taccggataa ggcgcagcgg tcgggctgaa

9240

cggggggttc gtgcacacag cccagcttgg agcgaacgac ctacaccgaa ctgagatacc

9300

tacagcgtga gcattgagaa agcgccacgc ttcccgaagg gagaaaggcg gacaggtatc

9360

cggtaagcgg cagggtcgga acaggagagc gcacgaggga gcttccaggg ggaaacgcct

9420

ggtatcttta tagtcctgtc gggtttcgcc acctctgact tgagcgtcga tttttgtgat

9480

gctcgtcagg ggggcggagc ctatggaaaa acgccagcaa cgcggccttt ttacggttcc

9540

tggccttttg ctggcctttt gctcacatgt tctttcctgc gttatcccct gattctgtgg

9600

ataaccgtat taccgccttt gagtgagctg ataccgctcg ccgcagccga acgaccgagc

9660

gcagcgagtc agtgagcgag gaagcggaag agcgcctgat gcggtatttt ctccttacgc

9720

atctgtgcgg tatttcacac cgcagaccag ccgcgtaacc tggcaaaatc ggttacggtt

9780

gagtaataaa tggatgccct gcgtaagcgg gtgtgggcgg acaataaagt cttaaactga

9840

acaaaataga tctaaactat gacaataaag tcttaaacta gacagaatag ttgtaaactg

9900

aaatcagtcc agttatgctg tgaaaaagca tactggactt ttgttatggc taaagcaaac

9960

tcttcatttt ctgaagtgca aattgcccgt cgtattaaag aggggcgtgg ccaagggcat

10020

ggtaaagact atattcgcgg cgttgtgaca atttaccgaa caactccgcg gccgggaagc

10080

cgatctcggc ttgaacgaat tgttaggtgg cggtacttgg gtcgatatca aagtgcatca

10140

cttcttcccg tatgcccaac tttgtataga gagccactgc gggatcgtca ccgtaatctg

10200

cttgcacgta gatcacataa gcaccaagcg cgttggcctc atgcttgagg agattgatga

10260

gcgcggtggc aatgccctgc ctccggtgct cgccggagac tgcgagatca tagatataga

10320

tctcactacg cggctgctca aacctgggca gaacgtaagc cgcgagagcg ccaacaaccg

10380

cttcttggtc gaaggcagca agcgcgatga atgtcttact acggagcaag ttcccgaggt

10440

aatcggagtc cggctgatgt tgggagtagg tggctacgtc tccgaactca cgaccgaaaa

10500

gatcaagagc agcccgcatg gatttgactt ggtcagggcc gagcctacat gtgcgaatga

10560

tgcccatact tgagccacct aactttgttt tagggcgact gccctgctgc gtaacatcgt

10620

tgctgctgcg taacatcgtt gctgctccat aacatcaaac atcgacccac ggcgtaacgc

10680

gcttgctgct tggatgcccg aggcatagac tgtacaaaaa aacagtcata acaagccatg

10740

aaaaccgcca ctgcgccgtt accaccgctg cgttcggtca aggttctgga ccagttgcgt

10800

gagcgcatac gctacttgca ttacagttta cgaaccgaac aggcttatgt caactgggtt

10860

cgtgccttca tccgtttcca cggtgtgcgt cacccggcaa ccttgggcag cagcgaagtc

10920

gaggcatttc tgtcctggct ggcgaacgag cgcaaggttt cggtctccac gcatcgtcag

10980

gcattggcgg ccttgctgtt cttctacggc aaggtgctgt gcacggatct gccctggctt

11040

caggagatcg gaagacctcg gccgtcgcgg cgcttgccgg tggtgctgac cccggatgaa

11100

gtggttcgca tcctcggttt tctggaaggc gagcatcgtt tgttcgccca ggactctagc

11160

tatagttcta gtggttggct acgtatactc cggaatatta atagatcatg gagataatta

11220

aaatgataac catctcgcaa ataaataagt attttactgt tttcgtaaca gttttgtaat

11280

aaaaaaacct ataaatattc cggattattc ataccgtccc accatcgggc gcggatctcg

11340

gtccgaaacc atgtcgtact accatcacca tcaccatcac gattacgata tcccaacgac

11400

cgaaaacctg tattttcagg gcgccatggg atcc

11434

<210> 215

<211> 13477

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 215

ggccggcccc tgcaggcagc tgcgcgctcg ctcgctcact gaggccgccc gggcaaagcc

60

cgggcgtcgg gcgacctttg gtcgcccggc ctcagtgagc gagcgagcgc gcagagaggg

120

agtggccaac tccatcacta ggggttcctt gtagttaatg attaacccgc catgctactt

180

atctacgtag ccatgctcta gacgggggag gctgctggtg aatattaacc aaggtcaccc

240

cagttatcgg aggagcaaac aggggctaag tccacacgcg tggtaccgtc tgtctgcaca

300

tttcgtagag cgagtgttcc gatactctaa tctccctagg caaggttcat atttgtgtag

360

gttacttatt ctccttttgt tgactaagtc aataatcaga atcagcaggt ttggagtcag

420

cttggcaggg atcagcagcc tgggttggaa ggagggggta taaaagcccc ttcaccagga

480

gaagccgtca cacagatcca caagctcctg aagaggtaag ggtttaaggg atggttggtt

540

ggtggggtat taatgtttaa ttacctggag cacctgcctg aaatcacttt ttttcaggtt

600

ggtttaaacg ccgccaccat gcaaatatagg ctctccacct gcttctttct gtgccttttg

660

cgattctgct ttagtgccac cagaagatac tacctgggtg cagtggaact gtcatgggac

720

tatatgcaaa gtgatctcgg tgagctgcct gtggacgcaa gatttcctcc tagagtgcca

780

aaatcttttc cattcaacac ctcagtcgtg tacaaaaaga ctctgtttgt agaattcacg

840

gatcaccttt tcaacatcgc taagccaagg ccaccctgga tgggtctgct aggtcctacc

900

atccaggctg aggtttatga tacagtggtc attacactta agaacatggc ttcccatcct

960

gtcagtcttc atgctgttgg tgtatcctac tggaaagctt ctgagggagc tgaatatgat

1020

gatcagacca gtcaaaggga gaaagaagat gataaagtct tccctggtgg aagccataca

1080

tatgtctggc aggtcctgaa agagaatggt ccaatggcct ctgacccact gtgccttacc

1140

tactcatatc tttctcatgt ggacctggta aaagacttga attcaggcct cattggagcc

1200

ctactagtat gtagagaagg gagtctggcc aaggaaaaga cacagacctt gcacaaattt

1260

atactacttt ttgctgtatt tgatgaaggg aaaagttggc actcagaaac aaagaactcc

1320

ttgatgcagg atagggatgc tgcatctgct cgggcctggc ctaaaatgca cacagtcaat

1380

ggttatgtaa acaggtctct gccaggtctg attggatgcc acaggaaatc agtctattgg

1440

catgtgattg gaatgggcac cactcctgaa gtgcactcaa tattcctcga aggtcacaca

1500

tttcttgtga ggaaccatcg ccaggcgtcc ttggaaatct cgccaataac tttccttact

1560

gctcaaacac tcttgatgga ccttggacag tttctactgt tttgtcatat ctcttcccac

1620

caacatgatg gcatggaagc ttatgtcaaa gtagacagct gtccagagga accccaacta

1680

cgaatgaaaa ataatgaaga agcggaagac tatgatgatg atcttactga ttctgaaatg

1740

gatgtggtca ggtttgatga tgacaactct ccttccttta tccaaattcg ctcagttgcc

1800

aagaagcatc ctaaaacttg ggtacattac attgctgctg aagaggagga ctgggactat

1860

gctcccttag tcctcgcccc cgatgacaga agttataaaa gtcaatattt gaacaatggc

1920

cctcagcgga ttggtaggaa gtacaaaaaa gtccgattta tggcatacac agatgaaacc

1980

tttaagactc gtgaagctat tcagcatgaa tcaggaatct tgggaccttt actttatggg

2040

gaagttggag acacactgtt gattatattt aagaatcaag caagcagacc atataacatc

2100

taccctcacg gaatcactga tgtccgtcct ttgtattcaa ggagattacc aaaaggtgta

2160

aaacatttga aggattttcc aattctgcca ggagaaatat tcaaatataa atggacagtg

2220

actgtagaag atgggccaac taaatcagat cctcggtgcc tgacccgcta ttactctagt

2280

ttcgttaata tggagagaga tctagcttca ggactcattg gccctctcct catctgctac

2340

aaagaatctg tagatcaaag aggaaaccag ataatgtcag acaagaggaa tgtcatcctg

2400

ttttctgtat ttgatgagaa ccgaagctgg tacctcacag agaatataca acgctttctc

2460

cccaatccag ctggagtgca gcttgaggat cccagttcc aagcctccaa catcatgcac

2520

agcatcaatg gctatgtttt tgatagtttg cagttgtcag tttgtttgca tgaggtggca

2580

tactggtaca ttctaagcat tggagcacag actgacttcc tttctgtctt cttctctgga

2640

tataccttca aacacaaaat ggtctatgaa gacacactca ccctattccc attctcagga

2700

gaaactgtct tcatgtcgat ggaaaaccca ggtctatgga ttctggggtg ccacaactca

2760

gactttcgga acagaggcat gaccgcctta ctgaaggttt ctagttgtga caagaacact

2820

ggtgattatt acgaggacag ttatgaagat atttcagcat acttgctgag taaaaacaat

2880

gccattgaac caagaagctt ctcccagaat tcaagacacc ctagcactag gcaaaagcaa

2940

tttaatgcca ccacaattcc agaaaatgac atagagaaga ctgacccttg gtttgcacac

3000

agaacaccta tgcctaaaat acaaaatgtc tcctctagtg atttgttgat gctcttgcga

3060

cagagtccta ctccacatgg gctatcctta tctgatctcc aagaagccaa atatgagact

3120

ttttctgatg atccatcacc tggagcaata gacagtaata acagcctgtc tgaaatgaca

3180

cacttcaggc cacagctcca tcacagtggg gacatggtat ttacccctga gtcaggcctc

3240

caattaagat taaatgagaa actggggaca actgcagcaa cagagttgaa gaaacttgat

3300

ttcaaagttt ctagtacatc aaataatctg atttcaacaa ttccatcaga caatttggca

3360

gcaggtactg aatacaag ttccttagga cccccaagta tgccagttca ttatgatagt

3420

caattagata ccactctatt tggcaaaaag tcatctcccc ttactgagtc tggtggacct

3480

ctgagcttga gtgaagaaaa taatgattca aagttgttag aatcaggttt aatgaatagc

3540

caagaaagtt catggggaaa aaatgtatcg tcaacagaga gtggtaggtt atttaaaggg

3600

aaaagagctc atggacctgc tttgttgact aaagataatg ccttattcaa agttagcatc

3660

tctttgttaa agacaaacaa aacttccaat aattcagcaa ctaatagaaa gactcacatt

3720

gatggcccat cattattaat tgagaatagt ccatcagtct ggcaaaatat attagaaagt

3780

gacactgagt ttaaaaaagt gacacctttg attcatgaca gaatgcttat ggacaaaaat

3840

gctacagctt tgaggctaaa tcatatgtca aataaaacta cttcatcaaa aaacatggaa

3900

atggtccaac agaaaaaaga gggccccatt ccaccagatg cacaaaatcc agatatgtcg

3960

ttctttaaga tgctattctt gccagaatca gcaaggtgga tacaaaggac tcatggaaag

4020

aactctctga actctgggca aggccccagt ccaaagcaat tagtatcctt aggaccagaa

4080

aaatctgtgg aaggtcagaa tttcttgtct gagaaaaaca aagtggtagt aggaaagggt

4140

gaatttacaa aggacgtagg actcaaagag atggtttttc caagcagcag aaacctattt

4200

cttactaact tggataattt acatgaaaat aatacacaca atcaagaaaa aaaaattcag

4260

gaagaaatag aaaagaagga aacattaatc caagagaatg tagttttgcc tcagatacat

4320

acagtgactg gcactaagaa tttcatgaag aaccttttct tactgagcac taggcaaaat

4380

gtagaaggtt catatgacgg ggcatatgct ccagtacttc aagattttag gtcattaaat

4440

gattcaacaa atagaacaaa gaaacacaca gctcatttct caaaaaaagg ggaggaagaa

4500

aacttggaag gcttgggaaa tcaaaccaag caaattgtag agaaatatgc atgcaccaca

4560

aggatatctc ctaatacaag ccagcagaat tttgtcacgc aacgtagtaa gagagctttg

4620

aaacaattca gactcccact agaagaaaca gaacttgaaa aaaggataat tgtggatgac

4680

acctcaaccc agtggtccaa aaacatgaaa catttgaccc cgagcaccct cacacagata

4740

gactacaatg agaaggagaa aggggccatt actcagtctc ccttatcaga ttgccttacg

4800

aggagtcata gcatccctca agcaaataga tctccattac ccattgcaaa ggtatcatca

4860

tttccatcta ttagacctat atatctgacc agggtcctat tccaagacaa ctcttctcat

4920

cttccagcag catcttatag aaagaaagat tctggggtcc aagaaagcag tcatttctta

4980

caaggagcca aaaaaaataa cctttcttta gccattctaa ccttggagat gactggtgat

5040

caaagagagg ttggctccct ggggacaagt gccacaaatt cagtcacata caagaaagtt

5100

gagaacactg ttctcccgaa accagacttg cccaaaacat ctggcaaagt tgaattgctt

5160

ccaaaagttc acatttatca gaaggaccta ttccctacgg aaactagcaa tgggtctcct

5220

ggccatctgg atctcgtgga agggagcctt cttcagggaa cagagggagc gattaagtgg

5280

aatgaagcaa acagacctgg aaaagttccc tttctgagag tagcaacaga aagctctgca

5340

aagactccct ccaagctatt ggatcctctt gcttgggata accactatgg tactcagata

5400

ccaaaagaag agtggaaatc ccaagagaag tcaccagaaa aaacagcttt taagaaaaag

5460

gataccattt tgtccctgaa cgcttgtgaa agcaatcatg caatagcagc aataaatgag

5520

ggacaaaata agcccgaaat agaagtcacc tgggcaaagc aaggtaggac tgaaaggctg

5580

tgctctcaaa acccaccagt cttgaaacgc catcaacggg aaataactcg tactactctt

5640

cagtcagatc aagaggaaat tgactatgat gataccatat cagttgaaat gaagaaggaa

5700

gattttgaca tttatgatga ggatgaaaat cagagccccc gcagctttca aaagaaaaca

5760

cgacactatt ttattgctgc agtggagagg ctctgggatt atgggatgag tagctcccca

5820

catgttctaa gaaacagggc tcagagtggc agtgtccctc agttcaagaa agttgttttc

5880

caggaattta ctgatggctc ctttactcag cccttatacc gtggagaact aaatgaacat

5940

ttgggactcc tggggccata tataagagca gaagttgaag ataatatcat ggtaactttc

6000

agaaatcagg cctctcgtcc ctattccttc tattctagcc ttatttctta tgaggaagat

6060

cagaggcaag gagcagaacc tagaaaaaac tttgtcaagc ctaatgaaac caaaacttac

6120

ttttggaaag tgcaacatca tatggcaccc actaaagatg agtttgactg caaagcctgg

6180

gcttatttct ctgatgttga cctggaaaaa gatgtgcact caggcctgat tggacccctt

6240

ctggtctgcc acactaacac actgaaccct gctcatggga gacaagtgac agtacaggaa

6300

tttgctctgt ttttcaccat ctttgatgag accaaaagct ggtacttcac tgaaaatatg

6360

gaaagaaact gcagggctcc ctgcaatatc cagatggaag atcccacttt taaagagaat

6420

tatcgcttcc atgcaatcaa tggctacata atggatacac tacctggctt agtaatggct

6480

caggatcaaa ggattcgatg gtatctgctc agcatgggca gcaatgaaaa catccattct

6540

attcatttca gtggacatgt gttcactgta cgaaaaaaag aggagtataa aatggcactg

6600

tacaatctct atccaggtgt ttttgagaca gtggaaatgt taccatccaa agctggaatt

6660

tggcgggtgg aatgccttat tggcgagcat ctacatgctg ggatgagcac actttttctg

6720

gtgtacagca ataagtgtca gactcccctg ggaatggctt ctggacacat tagagatttt

6780

cagattacag cttcaggaca atatggacag tgggccccaa agctggccag acttcattat

6840

tccggatcaa tcaatgcctg gagcaccaag gagccctttt cttggatcaa ggtggatctg

6900

ttggcaccaa tgattattca cggcatcaag acccagggtg cccgtcagaa gttctccagc

6960

ctctacatct ctcagtttat catcatgtat agtcttgatg ggaagaagtg gcagacttat

7020

cgaggaaatt ccactggaac cttaatggtc ttctttggca atgtggattc atctgggata

7080

aaacacaata tttttaaccc tccaattatt gctcgataca tccgtttgca cccaactcat

7140

tatagcattc gcagcactct tcgcatggag ttgatgggct gtgatttaaa tagttgcagc

7200

atgccattgg gaatggagag taaagcaata tcagatgcac agattactgc ttcatcctac

7260

tttaccaata tgtttgccac ctggtctcct tcaaaagctc gacttcacct ccaagggagg

7320

agtaatgcct ggagaacctca ggtgaataat ccaaaagagt ggctgcaagt ggacttccag

7380

aagacaatga aagtcacagg agtaactact cagggagtaa aatctctgct taccagcatg

7440

tatgtgaagg agttcctcat ctccagcagt caagatggcc atcagtggac tctctttttt

7500

cagaatggca aagtaaaggt ttttcaggga aatcaagact ccttcacacc tgtggtgaac

7560

tctctagacc caccgttact gactcgctac cttcgaattc acccccagag ttgggtgcac

7620

cagattgccc tgaggatgga ggttctgggc tgcgaggcac aggacctcta ctgattaatt

7680

aagagcatct taccgccatt tattcccata tttgttctgt ttttcttgat ttgggtatac

7740

atttaaatgt taataaaaca aaatggtggg gcaatcattt acatttttag ggatatgtaa

7800

ttactagttc aggtgtattg ccacaagaca aacatgttaa gaaactttcc cgttatttac

7860

gctctgttcc tgttaatcaa cctctggatt acaaaatttg tgaaagattg actgatattc

7920

ttaactatgt tgctcctttt acgctgtgtg gatatgctgc tttatagcct ctgtatctag

7980

ctattgcttc ccgtacggct ttcgttttct cctccttgta taaatcctgg ttgctgtctc

8040

ttttagagga gttgtggccc gttgtccgtc aacgtggcgt ggtgtgctct gtgtttgctg

8100

acgcaacccc cactggctgg ggcattgcca ccacctgtca actcctttct gggactttcg

8160

ctttccccct cccgatcgcc acggcagaac tcatcgccgc ctgccttgcc cgctgctgga

8220

caggggctag gttgctgggc actgataatt ccgtggtgtt gtctgtgcct tctagttgcc

8280

agccatctgt tgtttgcccc tcccccgtgc cttccttgac cctggaaggt gccactccca

8340

ctgtcctttc ctaataaaat gaggaaattg catcgcattg tctgagtagg tgtcattcta

8400

ttctgggggg tggggtgggg caggacagca agggggagga ttgggaagac aatagcaggc

8460

atgctgggga tgcggtgggc tctatggctc tagagcatgg ctacgtagat aagtagcatg

8520

gcgggttaat cattaactac acctgcagga ggaaccccta gtgatggagt tggccactcc

8580

ctctctgcgc gctcgctcgc tcactgaggc cgggcgacca aaggtcgccc gacgcccggg

8640

cggcctcagt gagcgagcga gcgcgcagct gcctgcaggg gcgcgcctcg aggcatgcgg

8700

taccaagctt gtcgagaagt actagaggat cataatcagc cataccacat ttgtagaggt

8760

tttacttgct ttaaaaaacc tcccacacct ccccctgaac ctgaaacata aaatgaatgc

8820

aattgttgtt gttaacttgt ttattgcagc ttataatggt tacaaataaa gcaatagcat

8880

cacaaatttc acaaataaag catttttttc actgcattct agttgtggtt tgtccaaact

8940

catcaatgta tcttatcatg tctggatctg atcactgata tcgcctagga gatccgaacc

9000

agataagtga aatctagttc caaactattt tgtcattttt aattttcgta ttagcttacg

9060

acgctacacc cagttcccat ctattttgtc actcttccct aaataatcct taaaaactcc

9120

atttccaccc ctcccagttc ccaactattt tgtccgccca cagcggggca tttttcttcc

9180

tgttatgttt ttaatcaaac atcctgccaa ctccatgtga caaaccgtca tcttcggcta

9240

ctttttctct gtcacagaat gaaaattttt ctgtcatctc ttcgttatta atgtttgtaa

9300

ttgactgaat atcaacgctt atttgcagcc tgaatggcga atgggacgcg ccctgtagcg

9360

gcgcattaag cgcggcgggt gtggtggtta cgcgcagcgt gaccgctaca cttgccagcg

9420

ccctagcgcc cgctcctttc gctttcttcc cttcctttct cgccacgttc gccggctttc

9480

cccgtcaagc tctaaatcgg gggctccctt tagggttccg atttagtgct ttacggcacc

9540

tcgaccccaa aaaacttgat tagggtgatg gttcacgtag tgggccatcg ccctgataga

9600

cggtttttcg ccctttgacg ttggagtcca cgttctttaa tagtggactc ttgttccaaa

9660

ctggaacaac actcaaccct atctcggtct attcttttga tttataaggg attttgccga

9720

tttcggccta ttggttaaaa aatgagctga tttaacaaaa atttaacgcg aattttaaca

9780

aaatattaac gtttacaatt tcaggtggca cttttcgggg aaatgtgcgc ggaaccccta

9840

tttgtttatt tttctaaata cattcaaata tgtatccgct catgagacaa taaccctgat

9900

aaatgcttca ataatattga aaaaggaaga gtatgagtat tcaacatttc cgtgtcgccc

9960

ttattccctt ttttgcggca ttttgccttc ctgtttttgc tcacccagaa acgctggtga

10020

aagtaaaaga tgctgaagat cagttgggtg cacgagtggg ttacatcgaa ctggatctca

10080

acagcggtaa gatccttgag agttttcgcc ccgaagaacg ttttccaatg atgagcactt

10140

ttaaagttct gctatgtggc gcggtattat cccgtattga cgccgggcaa gagcaactcg

10200

gtcgccgcat acactattct cagaatgact tggttgagta ctcaccagtc acagaaaagc

10260

atcttacgga tggcatgaca gtaagagaat tatgcagtgc tgccataacc atgagtgata

10320

acactgcggc caacttactt ctgacaacga tcggaggacc gaagggagcta accgcttttt

10380

tgcacaacat gggggatcat gtaactcgcc ttgatcgttg ggaaccggag ctgaatgaag

10440

ccataccaaa cgacgagcgt gacaccacga tgcctgtagc aatggcaaca acgttgcgca

10500

aactattaac tggcgaacta cttactctag cttcccggca acaattaata gactggatgg

10560

aggcggataa agttgcagga ccacttctgc gctcggccct tccggctggc tggtttattg

10620

ctgataaatc tggagccggt gagcgtgggt ctcgcggtat cattgcagca ctggggccag

10680

atggtaagcc ctcccgtatc gtagttatct acacgacggg gagtcaggca actatggatg

10740

aacgaaatag acagatcgct gagataggtg cctcactgat taagcattgg taactgtcag

10800

accaagttta ctcatatata ctttagattg atttaaaact tcatttttaa tttaaaagga

10860

tctaggtgaa gatccttttt gataatctca tgaccaaaat cccttaacgt gagttttcgt

10920

tccactgagc gtcagacccc gtagaaaaga tcaaaggatc ttcttgagat cctttttttc

10980

tgcgcgtaat ctgctgcttg caaacaaaaa aaccaccgct accagcggtg gtttgtttgc

11040

cggatcaaga gctaccaact ctttttccga aggtaactgg cttcagcaga gcgcagatac

11100

caaatactgt ccttctagtg tagccgtagt taggccacca cttcaagaac tctgtagcac

11160

cgcctacata cctcgctctg ctaatcctgt taccagtggc tgctgccagt ggcgataagt

11220

cgtgtcttac cgggttggac tcaagacgat agttaccgga taaggcgcag cggtcgggct

11280

gaacgggggg ttcgtgcaca cagcccagct tggagcgaac gacctacacc gaactgagat

11340

acctacagcg tgagcattga gaaagcgcca cgcttcccga agggaaaag gcggacaggt

11400

atccggtaag cggcagggtc ggaacaggag agcgcacgag ggagcttcca gggggaaacg

11460

cctggtatct ttatagtcct gtcgggtttc gccacctctg acttgagcgt cgatttttgt

11520

gatgctcgtc aggggggcgg agcctatgga aaaacgccag caacgcggcc tttttacggt

11580

tcctggcctt ttgctggcct tttgctcaca tgttctttcc tgcgttatcc cctgattctg

11640

tggataaccg tattaccgcc tttgagtgag ctgataccgc tcgccgcagc cgaacgaccg

11700

agcgcagcga gtcagtgagc gaggaagcgg aagagcgcct gatgcggtat tttctcctta

11760

cgcatctgtg cggtatttca caccgcagac cagccgcgta acctggcaaa atcggttacg

11820

gttgagtaat aaatggatgc cctgcgtaag cgggtgtggg cggacaataa agtcttaaac

11880

tgaacaaaat agatctaaac tatgacaata aagtcttaaa ctagacagaa tagttgtaaa

11940

ctgaaatcag tccagttatg ctgtgaaaaa gcatactgga cttttgttat ggctaaagca

12000

aactcttcat tttctgaagt gcaaattgcc cgtcgtatta aagaggggcg tggccaaggg

12060

catggtaaag actatattcg cggcgttgtg acaatttacc gaacaactcc gcggccggga

12120

agccgatctc ggcttgaacg aattgttagg tggcggtact tgggtcgata tcaaagtgca

12180

tcacttcttc ccgtatgccc aactttgtat agagagccac tgcgggatcg tcaccgtaat

12240

ctgcttgcac gtagatcaca taagcaccaa gcgcgttggc ctcatgcttg aggagattga

12300

tgagcgcggt ggcaatgccc tgcctccggt gctcgccgga gactgcgaga tcatagatat

12360

agatctcact acgcggctgc tcaaacctgg gcagaacgta agccgcgaga gcgccaacaa

12420

ccgcttcttg gtcgaaggca gcaagcgcga tgaatgtctt actacggagc aagttcccga

12480

ggtaatcgga gtccggctga tgttgggagt aggtggctac gtctccgaac tcacgaccga

12540

aaagatcaag agcagcccgc atggatttga cttggtcagg gccgagccta catgtgcgaa

12600

tgatgcccat acttgagcca cctaactttg ttttagggcg actgccctgc tgcgtaacat

12660

cgttgctgct gcgtaacatc gttgctgctc cataacatca aacatcgacc cacggcgtaa

12720

cgcgcttgct gcttggatgc ccgaggcata gactgtacaa aaaaacagtc ataacaagcc

12780

atgaaaaccg ccactgcgcc gttaccaccg ctgcgttcgg tcaaggttct ggaccagttg

12840

cgtgagcgca tacgctactt gcattacagt ttacgaaccg aacaggctta tgtcaactgg

12900

gttcgtgcct tcatccgttt ccacggtgtg cgtcacccgg caaccttggg cagcagcgaa

12960

gtcgaggcat ttctgtcctg gctggcgaac gagcgcaagg tttcggtctc cacgcatcgt

13020

caggcattgg cggccttgct gttcttctac ggcaaggtgc tgtgcacgga tctgccctgg

13080

cttcaggaga tcggaagacc tcggccgtcg cggcgcttgc cggtggtgct gaccccggat

13140

gaagtggttc gcatcctcgg ttttctggaa ggcgagcatc gtttgttcgc ccaggactct

13200

agctatagtt ctagtggttg gctacgtata ctccggaata ttaatagatc atggagataa

13260

ttaaaatgat aaccatctcg caaataaata agtattttac tgttttcgta acagttttgt

13320

aataaaaaaa cctataaata ttccggatta ttcataccgt cccaccatcg ggcgcggatc

13380

tcggtccgaa accatgtcgt actaccatca ccatcaccat cacgattacg atatcccaac

13440

gaccgaaaac ctgtattttc agggcgccat gggatcc

13477

<210> 216

<211> 11180

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 216

aaagtagccg aagatgacgg tttgtcacat ggagttggca ggatgtttga ttaaaaacat

60

aacaggaaga aaaatgcccc gctgtgggcg gacaaaatag ttgggaactg ggaggggtgg

120

aaatggagtt tttaaggatt atttagggaa gagtgacaaa atagatggga actgggtgta

180

gcgtcgtaag ctaatacgaa aattaaaaat gacaaaatag tttggaacta gatttcactt

240

atctggttcg gatctcctag gctcaagcag tgatcagatc cagacatgat aagatacatt

300

gatgagtttg gacaaaccac aactagaatg cagtgaaaaa aatgctttat ttgtgaaatt

360

tgtgatgcta ttgctttatt tgtaaccatt ataagctgca ataaacaagt taacaacaac

420

aattgcattc attttatgtt tcaggttcag ggggaggtgt gggaggtttt ttaaagcaag

480

taaaacctct acaaatgtgg tatggctgat tatgatcctc tagtacttct cgacaagctt

540

gtcgagactg caggctctag aggccggccc ctgcaggcag ctgcgcgctc gctcgctcac

600

tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt ggtcgcccgg cctcagtgag

660

cgagcgagcg cgcagagagg gagtggccaa ctccatcact aggggttcct tgtagttaat

720

gattaacccg ccatgctact tatctacgta gccatgcata tggagtcaat gggaaaaacc

780

cattggagcc aagtacactg actcaatagg gactttccat tgggttttgc ccagtacata

840

aggtcaatag ggggtgagtc aacaggaaag tcccattgga gccaagtaca ttgagtcaat

900

agggactttc caatgggttt tgcccagtac ataaggtcaa tgggaggtaa gccaatgggt

960

ttttcccatt actgacatgt atactgagtc attagggact ttccaatggg ttttgcccag

1020

tacataaggt caataggggt gaatcaacag gaaagtccca ttggagccaa gtacactgag

1080

tcaataggga ctttccatg ggttttgccc agtacaaaag gtcaataggg ggtgagtcaa

1140

tgggtttttc ccattattgg cacatacata aggtcaatag gggtgactag tggagaagag

1200

catgcttgag ggctgagtgc ccctcagtgg gcagagagca catggcccac agtccctgag

1260

aagttggggg gaggggtggg caattgaact ggtgcctaga gaaggtgggg cttgggtaaa

1320

ctgggaaagt gatgtggtgt actggctcca cctttttccc cagggtgggg gagaaccata

1380

tataagtgca gtagtctctg tgaacattca agcttctgcc ttctccctcc tgtgagtttg

1440

gtaagtcact gactgtctat gcctgggaaa gggtggggcag gagatggggc agtgcaggaa

1500

aagtggcact atgaaccctg cagccctaga caattgtact aaccttcttc tctttcctct

1560

cctgacaggt tggtgtacag tagcttccgt ttaaacagcc accatgcaga tagaattatc

1620

tacttgtttt tttctttgtc tgctcaggtt ctgcttctct gctacaagga ggtattactt

1680

aggtgctgta gagttatctt gggactacat gcagtctgat cttggggagc tccctgtgga

1740

tgcaagattt ccccctagag tacctaaaag tttccctttc aacacaagtg tggtgtataa

1800

gaagactctg tttgttgagt tcacagatca ccttttcaat attgccaagc ccagaccccc

1860

ctggatgggt ctactggggc caacaattca agcagaggta tatgatacag tggtgatcac

1920

attaaagaac atggcatccc accctgtaag cctgcatgct gttggtgtgt cctattggaa

1980

agcaagtgaa ggtgctgaat atgatgatca aacatcccaa agagagaagg aagatgacaa

2040

agtcttccca ggtggctctc acacctatgt gtggcaagtg ctcaaggaaa atgggcctat

2100

ggctagtgat ccattgtgcc tcacatatag ctacctgtcc catgtggact tagttaaaga

2160

tctgaactca ggtctgattg gtgccctgct ggtctgtagg gaaggatcac tagctaaaga

2220

aaaaacccag actttacaca agttcatctt attatttgct gtttttgatg agggaaagag

2280

ctggcactca gagactaaga attcactcat gcaggataga gatgcagctt ctgctagagc

2340

atggccaaaa atgcatactg tgaatgggta tgttaacagg agtctgcctg gcctcatagg

2400

ctgccataga aaatcagtgt actggcatgt cataggtatg ggcactactc ctgaggtgca

2460

ttccatttt ttggaggggc atactttcct tgtaagaaac cacaggcagg cttcattgga

2520

aattagtcca ataacctttc tcacagccca gactctgcta atggacttgg ggcagttttt

2580

attattttgt cacattagct ctcatcagca tgatggaatg gaagcctatg ttaaggttga

2640

ttcctgccca gaagagcccc agttgagaat gaagaacaat gaggaagcag aagactatga

2700

tgatgatcta acagactcag aaatggatgt tgtgagattt gatgatgata actccccaag

2760

ttttattcag atcaggtcag tggccaagaa acatccaaaa acatgggttc attatattgc

2820

agcagaagaa gaagactggg attatgcacc cttggtatta gcccctgatg acagaagcta

2880

taagtcacaa tatctcaaca atggacccca gagaattggc agaaagtaca aaaaagtcag

2940

gtttatggct tatactgatg agactttcaa aactagagag gctattcaac atgaatctgg

3000

catcctaggt cctttgttat atggggaagt aggggacacc ttattaatta tatttaaaaa

3060

ccaggccagt aggccttaca acatttaccc ccacggtata acagatgtca gaccactgta

3120

ctcaaggagg ctaccaaaag gggtgaagca cctaaaagac ttccccatcc tacctggtga

3180

gattttcaag tataagtgga cagtgactgt agaagatggt ccaaccaaat cagatcccag

3240

atgcctgaca aggtactaca gtagctttgt aaatatggag agagacctgg cctcagggtt

3300

aatagggccc ctactgatct gctacaagga gagtgtagac caaagaggca accaaattat

3360

gtcagacaag agaaatgtca tcctctttag tgtttttgat gagaataggt cctggtacct

3420

gacagaaaat atccaaagat tccttccaaa tccagcaggg gtacaactgg aggaccctga

3480

gttccaggcc tccaatatca tgcacagcat caatggttat gtgtttgaca gtttgcaact

3540

ttcagtgtgc cttcatgagg ttgcatactg gtatatactt tctatagggg cccagacaga

3600

cttcttgtca gttttctttt caggctatac tttcaagcat aagatggtat atgaagatac

3660

cctgactctt tttcccttta gtggtgagac agttttcatg tcaatggaaa acccagggct

3720

ttggatcttg ggatgccaca actctgactt tagaaacaga ggcatgactg cccttttaaa

3780

ggtgtcctct tgtgataaga atactggaga ctactatgag gacagctatg aggacatttc

3840

agcctatctg ctgtcaaaaa ataatgctat agagccaagg tcattttctc aaaatcctcc

3900

tgtcctgaag aggcaccaaa gagagataac caggactacc ttacagtctg accaggagga

3960

aattgattat gatgacacaa taagtgtgga gatgaaaaag gaggattttg atatttatga

4020

tgaggatgaa aaccaatctc caagatcttt ccagaagaag actagacact atttcattgc

4080

tgcagtggaa agactgtggg actatggaat gtcctccagc cctcatgttc tcaggaatag

4140

ggctcaaagt ggttctgtgc cacagttcaa gaaggtggtg tttcaggaat tcacagatgg

4200

gtcctttact caaccactgt ataggggaga actcaatgaa catctaggat tactaggtcc

4260

ctacattaga gctgaggtgg aggacaatat catggtcact ttcaggaacc aggcatctag

4320

accatactct ttttacagct ccttgatatc ttatgaagag gaccagagac agggtgcaga

4380

acccaggaag aactttgtga aacccaatga gaccaaaaca tacttctgga aggtccagca

4440

tcatatggct cctaccaagg atgaatttga ctgcaaagcc tgggcttact tctcagatgt

4500

ggatttggag aaagatgtgc acagtggctt gattgggcct cttttggtat gtcataccaa

4560

caccttaaac cctgctcatg gaagacaagt aacagtgcaa gagtttgccc tctttttcac

4620

tatatttgat gagacaaaaa gttggtactt tactgagaat atggagagga actgcagggc

4680

tccctgcaat atacagatgg aggatcctac tttcaaggaa aactataggt ttcatgccat

4740

taatggctat atcatggata cattgcctgg cttagttatg gcccaggatc agagaatcag

4800

atggtacctc cttagtatgg gaagcaatga aaacatacat tctattcact tcagtggaca

4860

tgtctttact gtgagaaaaa aggaagagta caagatggca ctgtacaatc tgtaccctgg

4920

agtgtttgag acagttgaga tgctgcccag caaggctggg atctggaggg tagaatgcct

4980

gattggagaa cacttacatg caggtatgtc cactctattc ttggtctatt ccaacaagtg

5040

tcagaccccc ctaggcatgg catctggcca tattagagat ttccagataa ctgcttctgg

5100

tcagtatggc cagtgggccc ccaagcttgc tagacttcac tacagtggtt caataaatgc

5160

ctggtccacc aaggagccct tcagctggat taaagtggac ttgctagccc ccatgatcat

5220

tcatgggata aaaacacagg gtgccagaca gaaattttca tctctgtaca tcagccagtt

5280

tatcatcatg tacagtctgg atggcaaaaa atggcagacc tacagaggta actctacagg

5340

tacactaatg gtattttttg gcaatgtaga ttcatcaggt atcaagcata atatctttaa

5400

tcctcccatt attgccagat acatcaggtt gcacccaact cattacagta taagatccac

5460

tttaaggatg gagcttatgg ggtgtgacct taatagctgc agtatgccct tgggaatgga

5520

aagtaaggcc atatcagatg cccagattac tgcaagcagc tactttacaa acatgtttgc

5580

aacctggtct cctagtaaag ccaggctgca cttgcagggt aggagcaatg catggagacc

5640

ccaggtcaat aacccaaaag agtggcttca agttgacttt caaaagacaa tgaaggtaac

5700

aggggtaacc acccaagggg taaagagtct gctgacatct atgtatgtaa aagaattcct

5760

catctcaagt agtcaagatg ggcaccagtg gacactgttc ttccagaatg gaaaagttaa

5820

ggtgttccaa ggtaatcaag acagcttcac tccagtggtg aacagtctgg atccaccact

5880

cctaaccagg tacctgagga tccaccctca gtcctgggtc caccagatag ctctgagaat

5940

ggaagtgctg ggctgtgaag ctcaggacct atactgatta attaataaaa tacagcatag

6000

caaaacttta acctccaaat caagcctcta cttgaatcct tttctgaggg atgaataagg

6060

cataggcatc aggggctgtt gccaatgtgc attagctgtt tgcagcctca ccttctttca

6120

tggagtttaa gatatagtgt attttcccaa ggtttgaact agctcttcat ttctttatgt

6180

tttaaatgca ctgacctccc acattccctt tttagtaaaa tattcagaaa taatttaaat

6240

acatcattgc aatgaaaata aatgtttttt attaggcaga atccagatgc tcaaggccct

6300

tcataatatc ccccagttta gtagttggac ttagggaaca aaggaacctt taatagaaat

6360

tggacagcaa gaaagcgagc tccataaagt aggaaacact acacgattcc ataaagtagg

6420

aaacactaca tcactccata aagtaggaaa cactacacag acatgataag atacattgat

6480

gagtttggac aaaccacaac tagaatgcag tgaaaaaaat gctttatttg tgaaatttgt

6540

gatgctattg ctttatttgt aaccattata agctgcaata aacaagttaa caacaacaat

6600

tgcattcatt ttatgtttca ggttcagggg gagatgtggg aggtttttta aagcaagtaa

6660

aacctctaca aatgtggtac ttaagcatgg ctacgtagat aagtagcatg gcgggttaat

6720

cattaactac acctgcagga ggaaccccta gtgatggagt tggccactcc ctctctgcgc

6780

gctcgctcgc tcactgaggc cgggcgacca aaggtcgccc gacgcccggg cggcctcagt

6840

gagcgagcga gcgcgcagct gcctgcaggg gcgcgccgct agcagctgat gcatagcatg

6900

cggtaccggg agatggggga ggctaactga aacacggaag gagacaatac cggaaggaac

6960

ccgcgctatg acggcaataa aaagacagaa taaaacgcac gggtgttggg tcgtttgttc

7020

ataaacgcgg ggttcggtcc cagggctggc actctgtcga taccccaccg agaccccatt

7080

gggaccaata cgcccgcgtt tcttcctttt ccccacccca acccccaagt tcgggtgaag

7140

gcccagggct cgcagccaac gtcggggcgg caagccctgc catagccact acgggtacgt

7200

aggccaacca ctagaactat agctagagtc ctgggcgaac aaacgatgct cgccttccag

7260

aaaaccgagg atgcgaacca cttcatccgg ggtcagcacc accggcaagc gccgcgacgg

7320

ccgaggtcta ccgatctcct gaagccaggg cagatccgtg cacagcacct tgccgtagaa

7380

gaacagcaag gccgccaatg cctgacgatg cgtggagacc gaaaccttgc gctcgttcgc

7440

cagccaggac agaaatgcct cgacttcgct gctgcccaag gttgccgggt gacgcacacc

7500

gtggaaacgg atgaaggcac gaacccagtt gacataagcc tgttcggttc gtaaactgta

7560

atgcaagtag cgtatgcgct cacgcaactg gtccagaacc ttgaccgaac gcagcggtgg

7620

taacggcgca gtggcggttt tcatggcttg ttatgactgt ttttttgtac agtctatgcc

7680

tcgggcatcc aagcagcaag cgcgttacgc cgtgggtcga tgtttgatgt tatggagcag

7740

caacgatgtt acgcagcagc aacgatgtta cgcagcaggg cagtcgccct aaaacaaagt

7800

taggtggctc aagtatgggc atcattcgca catgtaggct cggccctgac caagtcaaat

7860

ccatgcgggc tgctcttgat cttttcggtc gtgagttcgg agacgtagcc acctactccc

7920

aacatcagcc ggactccgat tacctcggga acttgctccg tagtaagaca ttcatcgcgc

7980

ttgctgcctt cgaccaagaa gcggttgttg gcgctctcgc ggcttacgtt ctgcccaggt

8040

ttgagcagcc gcgtagtgag atctatatct atgatctcgc agtctccggc gagcaccgga

8100

ggcagggcat tgccaccgcg ctcatcaatc tcctcaagca tgaggccaac gcgcttggtg

8160

cttatgtgat ctacgtgcaa gcagattacg gtgacgatcc cgcagtggct ctctatacaa

8220

agttgggcat acgggaagaa gtgatgcact ttgatatcga cccaagtacc gccacctaac

8280

aattcgttca agccgagatc ggcttcccgg ccgcggagtt gttcggtaaa ttgtcacaac

8340

gccgcgaata tagtctttac catgcccttg gccacgcccc tctttaatac gacgggcaat

8400

ttgcacttca gaaaatgaag agtttgcttt agccataaca aaagtccagt atgctttttc

8460

acagcataac tggactgatt tcagtttaca actattctgt ctagtttaag actttattgt

8520

catagtttag atctattttg ttcagtttaa gactttattg tccgcccaca cccgcttacg

8580

cagggcatcc atttattact caaccgtaac cgattttgcc aggttacgcg gctggtctgc

8640

ggtgtgaaat accgcacaga tgcgtaagga gaaaataccg catcaggcgc tcttccgctt

8700

cctcgctcac tgactcgctg cgctcggtcg ttcggctgcg gcgagcggta tcagctcact

8760

caaaggcggt aatacggtta tccacagaat caggggataa cgcaggaaag aacatgtgag

8820

caaaaggcca gcaaaaggcc aggaaccgta aaaaggccgc gttgctggcg tttttccata

8880

ggctccgccc ccctgacgag catcacaaaa atcgacgctc aagtcagagg tggcgaaacc

8940

cgacaggact ataaagatac caggcgtttc cccctggaag ctccctcgtg cgctctcctg

9000

ttccgaccct gccgcttacc ggatacctgt ccgcctttct cccttcggga agcgtggcgc

9060

tttctcaatg ctcacgctgt aggtatctca gttcggtgta ggtcgttcgc tccaagctgg

9120

gctgtgtgca cgaacccccc gttcagcccg accgctgcgc cttatccggt aactatcgtc

9180

ttgagtccaa cccggtaaga cacgacttat cgccactggc agcagccact ggtaacagga

9240

ttagcagagc gaggtatgta ggcggtgcta cagagttctt gaagtggtgg cctaactacg

9300

gctacactag aaggacagta tttggtatct gcgctctgct gaagccagtt accttcggaa

9360

aaagagttgg tagctcttga tccggcaaac aaaccaccgc tggtagcggt ggtttttttg

9420

tttgcaagca gcagattacg cgcagaaaaa aaggatctca agaagatcct ttgatctttt

9480

ctacggggtc tgacgctcag tggaacgaaa actcacgtta agggattttg gtcatgagat

9540

tatcaaaaag gatcttcacc tagatccttt taaattaaaa atgaagtttt aaatcaatct

9600

aaagtatata tgagtaaact tggtctgaca gttaccaatg cttaatcagt gaggcaccta

9660

tctcagcgat ctgtctattt cgttcatcca tagttgcctg actccccgtc gtgtagataa

9720

ctacgatacg ggagggctta ccatctggcc ccagtgctgc aatgataccg cgagacccac

9780

gctcaccggc tccagattta tcagcaataa accagccagc cggaagggcc gagcgcagaa

9840

gtggtcctgc aactttatcc gcctccatcc agtctattaa ttgttgccgg gaagctagag

9900

taagtagttc gccagttaat agtttgcgca acgttgttgc cattgctaca ggcatcgtgg

9960

tgtcacgctc gtcgtttggt atggcttcat tcagctccgg ttcccaacga tcaaggcgag

10020

ttacatgatc ccccatgttg tgcaaaaaag cggttagctc cttcggtcct ccgatcgttg

10080

tcagaagtaa gttggccgca gtgttatcac tcatggttat ggcagcactg cataattctc

10140

ttactgtcat gccatccgta agatgctttt ctgtgactgg tgagtactca accaagtcat

10200

tctgagaata gtgtatgcgg cgaccgagtt gctcttgccc ggcgtcaata cgggataata

10260

ccgcgccaca tagcagaact ttaaaagtgc tcatcattgg aaaacgttct tcggggcgaa

10320

aactctcaag gatcttaccg ctgttgagat ccagttcgat gtaacccact cgtgcaccca

10380

actgatcttc agcatctttt actttcacca gcgtttctgg gtgagcaaaa acaggaaggc

10440

aaaatgccgc aaaaaaggga ataagggcga cacggaaatg ttgaatactc atactcttcc

10500

tttttcaata ttattgaagc atttatcagg gttattgtct catgagcgga tacatatttg

10560

aatgtattta gaaaaataaa caaatagggg ttccgcgcac atttccccga aaagtgccac

10620

ctgaaattgt aaacgttaat attttgttaa aattcgcgtt aaatttttgt taaatcagct

10680

cattttttaa ccaataggcc gaaatcggca aaatccctta taaatcaaaa gaatagaccg

10740

agatagggtt gagtgttgtt ccagtttgga acaagagtcc actattaaag aacgtggact

10800

ccaacgtcaa agggcgaaaa accgtctatc agggcgatgg cccactacgt gaaccatcac

10860

cctaatcaag ttttttgggg tcgaggtgcc gtaaagcact aaatcggaac cctaaaggga

10920

gcccccgatt tagagcttga cggggaaagc cggcgaacgt ggcgagaaag gaagggaaga

10980

aagcgaaagg agcgggcgct agggcgctgg caagtgtagc ggtcacgctg cgcgtaacca

11040

ccacacccgc cgcgcttaat gcgccgctac agggcgcgtc ccattcgcca ttcaggctgc

11100

aaataagcgt tgatattcag tcaattacaa acattaataa cgaagagatg acagaaaaat

11160

tttcattctg tgacagagaa

11180

<210> 217

<211> 13862

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 217

aaagtagccg aagatgacgg tttgtcacat ggagttggca ggatgtttga ttaaaaacat

60

aacaggaaga aaaatgcccc gctgtgggcg gacaaaatag ttgggaactg ggaggggtgg

120

aaatggagtt tttaaggatt atttagggaa gagtgacaaa atagatggga actgggtgta

180

gcgtcgtaag ctaatacgaa aattaaaaat gacaaaatag tttggaacta gatttcactt

240

atctggttcg gatctcctag gctcaagcag tgatcagatc cagacatgat aagatacatt

300

gatgagtttg gacaaaccac aactagaatg cagtgaaaaa aatgctttat ttgtgaaatt

360

tgtgatgcta ttgctttatt tgtaaccatt ataagctgca ataaacaagt taacaacaac

420

aattgcattc attttatgtt tcaggttcag ggggaggtgt gggaggtttt ttaaagcaag

480

taaaacctct acaaatgtgg tatggctgat tatgatcctc tagtacttct cgacaagctt

540

gtcgagactg caggctctag aggccggccc ctgcaggcag ctgcgcgctc gctcgctcac

600

tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt ggtcgcccgg cctcagtgag

660

cgagcgagcg cgcagagagg gagtggccaa ctccatcact aggggttcct tgtagttaat

720

gattaacccg ccatgctact tatctacgta gccatgcata tggagtcaat gggaaaaacc

780

cattggagcc aagtacactg actcaatagg gactttccat tgggttttgc ccagtacata

840

aggtcaatag ggggtgagtc aacaggaaag tcccattgga gccaagtaca ttgagtcaat

900

agggactttc caatgggttt tgcccagtac ataaggtcaa tgggaggtaa gccaatgggt

960

ttttcccatt actgacatgt atactgagtc attagggact ttccaatggg ttttgcccag

1020

tacataaggt caataggggt gaatcaacag gaaagtccca ttggagccaa gtacactgag

1080

tcaataggga ctttccatg ggttttgccc agtacaaaag gtcaataggg ggtgagtcaa

1140

tgggtttttc ccattattgg cacatacata aggtcaatag gggtgactag tggagaagag

1200

catgcttgag ggctgagtgc ccctcagtgg gcagagagca catggcccac agtccctgag

1260

aagttggggg gaggggtggg caattgaact ggtgcctaga gaaggtgggg cttgggtaaa

1320

ctgggaaagt gatgtggtgt actggctcca cctttttccc cagggtgggg gagaaccata

1380

tataagtgca gtagtctctg tgaacattca agcttctgcc ttctccctcc tgtgagtttg

1440

gtaagtcact gactgtctat gcctgggaaa gggtggggcag gagatggggc agtgcaggaa

1500

aagtggcact atgaaccctg cagccctaga caattgtact aaccttcttc tctttcctct

1560

cctgacaggt tggtgtacag tagcttccgt ttaaacagcc accatgcaaa tagagctctc

1620

cacctgcttc tttctgtgcc ttttgcgatt ctgctttagt gccaccagaa gatactacct

1680

gggtgcagtg gaactgtcat gggactatat gcaaagtgat ctcggtgagc tgcctgtgga

1740

cgcaagattt cctcctagag tgccaaaatc ttttccattc aacacctcag tcgtgtacaa

1800

aaagactctg tttgtagaat tcacggatca ccttttcaac atcgctaagc caaggccacc

1860

ctggatgggt ctgctaggtc ctaccatcca ggctgaggtt tatgatacag tggtcattac

1920

acttaagaac atggcttccc atcctgtcag tcttcatgct gttggtgtat cctactggaa

1980

agcttctgag ggagctgaat atgatgatca gaccagtcaa agggagaaag aagatgataa

2040

agtcttccct ggtggaagcc atacatatgt ctggcaggtc ctgaaagaga atggtccaat

2100

ggcctctgac ccactgtgcc ttacctactc atatctttct catgtggacc tggtaaaaga

2160

cttgaattca ggcctcattg gagccctact agtatgtaga gaagggagtc tggccaagga

2220

aaagacacag accttgcaca aatttatact actttttgct gtatttgatg aagggaaaag

2280

ttggcactca gaaacaaaga actccttgat gcaggatagg gatgctgcat ctgctcgggc

2340

ctggcctaaa atgcacacag tcaatggtta tgtaaacagg tctctgccag gtctgattgg

2400

atgccacagg aaatcagtct attggcatgt gattggaatg ggcaccactc ctgaagtgca

2460

ctcaatattc ctcgaaggtc acacatttct tgtgaggaac catcgccagg cgtccttgga

2520

aatctcgcca ataactttcc ttactgctca aacactcttg atggaccttg gacagtttct

2580

actgttttgt catatctctt cccaccaaca tgatggcatg gaagcttatg tcaaagtaga

2640

cagctgtcca gaggaacccc aactacgaat gaaaaataat gaagaagcgg aagactatga

2700

tgatgatctt actgattctg aaatggatgt ggtcaggttt gatgatgaca actctccttc

2760

ctttatccaa attcgctcag ttgccaagaa gcatcctaaa acttgggtac attacattgc

2820

tgctgaagag gaggactggg actatgctcc cttagtcctc gcccccgatg acagaagtta

2880

taaaagtcaa tatttgaaca atggccctca gcggattggt aggaagtaca aaaaagtccg

2940

atttatggca tacacagatg aaacctttaa gactcgtgaa gctattcagc atgaatcagg

3000

aatcttggga cctttacttt atggggaagt tggagacaca ctgttgatta tatttaagaa

3060

tcaagcaagc agaccatata acatctaccc tcacggaatc actgatgtcc gtcctttgta

3120

ttcaaggaga ttaccaaaag gtgtaaaaca tttgaaggat tttccaattc tgccaggaga

3180

aatattcaaa tataaatgga cagtgactgt agaagatggg ccaactaaat cagatcctcg

3240

gtgcctgacc cgctattact ctagtttcgt taatatggag agagatctag cttcaggact

3300

cattggccct ctcctcatct gctacaaaga atctgtagat caaagaggaa accagataat

3360

gtcagacaag aggaatgtca tcctgttttc tgtatttgat gagaaccgaa gctggtacct

3420

cacagagaat atacaacgct ttctccccaa tccagctgga gtgcagcttg aggatccaga

3480

gttccaagcc tccaacatca tgcacagcat caatggctat gtttttgata gtttgcagtt

3540

gtcagtttgt ttgcatgagg tggcatactg gtacattcta agcattggag cacagactga

3600

cttcctttct gtcttcttct ctggatatac cttcaaacac aaaatggtct atgaagacac

3660

actcacccta ttcccattct caggagaaac tgtcttcatg tcgatggaaa acccaggtct

3720

atggattctg gggtgccaca actcagactt tcggaacaga ggcatgaccg ccttactgaa

3780

ggtttctagt tgtgacaaga acactggtga ttattacgag gacagttatg aagatatttc

3840

agcatacttg ctgagtaaaa acaatgccat tgaaccaaga agcttctccc agaattcaag

3900

acaccctagc actaggcaaa agcaatttaa tgccaccaca attccagaaa atgacataga

3960

gaagactgac ccttggtttg cacacagaac acctatgcct aaaatacaaa atgtctcctc

4020

tagtgatttg ttgatgctct tgcgacagag tcctactcca catgggctat ccttatctga

4080

tctccaagaa gccaaatatg agactttttc tgatgatcca tcacctggag caatagacag

4140

taataacagc ctgtctgaaa tgacacactt caggccacag ctccatcaca gtggggacat

4200

ggtatttacc cctgagtcag gcctccaatt aagattaaat gagaaactgg ggacaactgc

4260

agcaacagag ttgaagaaac ttgatttcaa agtttctagt acatcaaata atctgatttc

4320

aacaattcca tcagacaatt tggcagcagg tactgataat acaagttcct taggaccccc

4380

aagtatgcca gttcattatg atagtcaatt agataccact ctatttggca aaaagtcatc

4440

tccccttact gagtctggtg gacctctgag cttgagtgaa gaaaataatg attcaaagtt

4500

gttagaatca ggtttaatga atagccaaga aagttcatgg ggaaaaaatg tatcgtcaac

4560

agagagtggt aggttattta aagggaaaag agctcatgga cctgctttgt tgactaaaga

4620

taatgcctta ttcaaagtta gcatctcttt gttaaagaca aacaaaactt ccaataattc

4680

agcaactaat agaaagactc acattgatgg cccatcatta ttaattgaga atagtccatc

4740

agtctggcaa aatatattag aaagtgacac tgagtttaaa aaagtgacac ctttgattca

4800

tgacagaatg cttatggaca aaaatgctac agctttgagg ctaaatcata tgtcaaataa

4860

aactacttca tcaaaaaaca tggaaatggt ccaacagaaa aaagaggggcc ccattccacc

4920

agatgcacaa aatccagata tgtcgttctt taagatgcta ttcttgccag aatcagcaag

4980

gtggatacaa aggactcatg gaaagaactc tctgaactct gggcaaggcc ccagtccaaa

5040

gcaattagta tccttaggac cagaaaaatc tgtggaaggt cagaatttct tgtctgagaa

5100

aaacaaagtg gtagtaggaa agggtgaatt tacaaaggac gtaggactca aagagatggt

5160

ttttccaagc agcagaaacc tatttcttac taacttggat aatttacatg aaaataatac

5220

acacaatcaa gaaaaaaaaa ttcaggaaga aatagaaaag aaggaaacat taatccaaga

5280

gaatgtagtt ttgcctcaga tacatacagt gactggcact aagaatttca tgaagaacct

5340

tttcttactg agcactaggc aaaatgtaga aggttcatat gacggggcat atgctccagt

5400

acttcaagat tttaggtcat taaatgattc aacaaataga acaaagaaac acacagctca

5460

tttctcaaaa aaaggggagg aagaaaactt ggaaggcttg ggaaatcaaa ccaagcaaat

5520

tgtagagaaa tatgcatgca ccacaaggat atctcctaat acaagccagc agaattttgt

5580

cacgcaacgt agtaagagag ctttgaaaca attcagactc ccactagaag aaacagaact

5640

tgaaaaaagg ataattgtgg atgacacctc aacccagtgg tccaaaaaca tgaaacattt

5700

gaccccgagc accctcacac agatagacta caatgagaag gagaaagggg ccattactca

5760

gtctccctta tcagattgcc ttacgaggag tcatagcatc cctcaagcaa atagatctcc

5820

attacccatt gcaaaggtat catcatttcc atctattaga cctatatatc tgaccagggt

5880

cctattccaa gacaactctt ctcatcttcc agcagcatct tatagaaaga aagattctgg

5940

ggtccaagaa agcagtcatt tcttacaagg agccaaaaaa aataaccttt ctttagccat

6000

tctaaccttg gagatgactg gtgatcaaag agaggttggc tccctgggga caagtgccac

6060

aaattcagtc acatacaaga aagttgagaa cactgttctc ccgaaaccag acttgcccaa

6120

aacatctggc aaagttgaat tgcttccaaa agttcacatt tatcagaagg acctattccc

6180

tacggaaact agcaatgggt ctcctggcca tctggatctc gtggaaggga gccttcttca

6240

gggaacagag ggagcgatta agtggaatga agcaaacaga cctggaaaag ttccctttct

6300

gagagtagca acagaaagct ctgcaaagac tccctccaag ctattggatc ctcttgcttg

6360

ggataaccac tatggtactc agataccaaa agaagagtgg aaatcccaag agaagtcacc

6420

agaaaaaaca gcttttaaga aaaaggatac cattttgtcc ctgaacgctt gtgaaagcaa

6480

tcatgcaata gcagcaataa atgagggaca aaataagccc gaaatagaag tcacctgggc

6540

aaagcaaggt aggactgaaa ggctgtgctc tcaaaaccca ccagtcttga aacgccatca

6600

acgggaaata actcgtacta ctcttcagtc agatcaagag gaaattgact atgatgatac

6660

catatcagtt gaaatgaaga aggaagattt tgacatttat gatgaggatg aaaatcagag

6720

cccccgcagc tttcaaaaga aaacacgaca ctattttatt gctgcagtgg agaggctctg

6780

ggattatggg atgagtagct ccccacatgt tctaagaaac agggctcaga gtggcagtgt

6840

ccctcagttc aagaaagttg ttttccagga atttactgat ggctccttta ctcagccctt

6900

ataccgtgga gaactaaatg aacatttggg actcctgggg ccatatataa gagcagaagt

6960

tgaagataat atcatggtaa ctttcagaaa tcaggcctct cgtccctatt ccttctattc

7020

tagccttatt tcttatgagg aagatcagag gcaaggagca gaacctagaa aaaactttgt

7080

caagcctaat gaaaccaaaa cttacttttg gaaagtgcaa catcatatgg cacccactaa

7140

agatgagttt gactgcaaag cctgggctta tttctctgat gttgacctgg aaaaagatgt

7200

gcactcaggc ctgattggac cccttctggt ctgccacact aacacactga accctgctca

7260

tggggagacaa gtgacagtac aggaatttgc tctgtttttc accatctttg atgagaccaa

7320

aagctggtac ttcactgaaa atatggaaag aaactgcagg gctccctgca atatccagat

7380

ggaagatccc acttttaaag agaattatcg cttccatgca atcaatggct acataatgga

7440

tacactacct ggcttagtaa tggctcagga tcaaaggatt cgatggtatc tgctcagcat

7500

gggcagcaat gaaaacatcc attctattca tttcagtgga catgtgttca ctgtacgaaa

7560

aaaagaggag tataaaatgg cactgtacaa tctctatcca ggtgtttttg agacagtgga

7620

aatgttacca tccaaagctg gaatttggcg ggtggaatgc cttattggcg agcatctaca

7680

tgctgggatg agcacacttt ttctggtgta cagcaataag tgtcagactc ccctgggaat

7740

ggcttctgga cacattagag attttcagat tacagcttca ggacaatatg gacagtgggc

7800

cccaaagctg gccagacttc attattccgg atcaatcaat gcctggagca ccaaggagcc

7860

cttttcttgg atcaaggtgg atctgttggc accaatgatt attcacggca tcaagacca

7920

gggtgcccgt cagaagttct ccagcctcta catctctcag tttatcatca tgtatagtct

7980

tgatgggaag aagtggcaga cttatcgagg aaattccact ggaaccttaa tggtcttctt

8040

tggcaatgtg gattcatctg ggataaaaca caatattttt aaccctccaa ttattgctcg

8100

atacatccgt ttgcacccaa ctcattatag cattcgcagc actcttcgca tggagttgat

8160

gggctgtgat ttaaatagtt gcagcatgcc attgggaatg gagagtaaag caatatcaga

8220

tgcacagatt actgcttcat cctactttac caatatgttt gccacctggt ctccttcaaa

8280

agctcgactt cacctccaag ggaggagtaa tgcctggaga cctcaggtga ataatccaaa

8340

agagtggctg caagtggact tccagaagac aatgaaagtc acaggagtaa ctactcaggg

8400

agtaaaatct ctgcttacca gcatgtatgt gaaggagttc ctcatctcca gcagtcaaga

8460

tggccatcag tggactctct tttttcagaa tggcaaagta aaggtttttc agggaaatca

8520

agactccttc acacctgtgg tgaactctct agacccaccg ttactgactc gctaccttcg

8580

aattcacccc cagagttggg tgcaccagat tgccctgagg atggaggttc tgggctgcga

8640

ggcacaggac ctctactgat taattaataa aatacagcat agcaaaactt taacctccaa

8700

atcaagcctc tacttgaatc cttttctgag ggatgaataa ggcataggca tcaggggctg

8760

ttgccaatgt gcattagctg tttgcagcct caccttcttt catggagttt aagatatagt

8820

gtattttccc aaggtttgaa ctagctcttc atttctttat gttttaaatg cactgacctc

8880

ccacattccc tttttagtaa aatattcaga aataatttaa atacatcatt gcaatgaaaa

8940

taaatgtttt ttattaggca gaatccagat gctcaaggcc cttcataata tcccccagtt

9000

tagtagttgg acttagggaa caaaggaacc tttaatagaa attggacagc aagaaagcga

9060

gctccataaa gtaggaaaca ctacacgatt ccataaagta ggaaacacta catcactcca

9120

taaagtagga aacactacac agacatgata agatacattg atgagtttgg acaaaccaca

9180

actagaatgc agtgaaaaaa atgctttatt tgtgaaattt gtgatgctat tgctttattt

9240

gtaaccatta taagctgcaa taaacaagtt aacaacaaca attgcattca ttttatgttt

9300

caggttcagg gggagatgtg ggaggttttt taaagcaagt aaaacctcta caaatgtggt

9360

acttaagcat ggctacgtag ataagtagca tggcgggtta atcattaact acacctgcag

9420

gaggaacccc tagtgatgga gttggccact ccctctctgc gcgctcgctc gctcactgag

9480

gccgggcgac caaaggtcgc ccgacgcccg ggcggcctca gtgagcgagc gagcgcgcag

9540

ctgcctgcag gggcgcgccg ctagcagctg atgcatagca tgcggtaccg ggagatgggg

9600

gaggctaact gaaacacgga aggagacaat accggaagga acccgcgcta tgacggcaat

9660

aaaaagacag aataaaacgc acgggtgttg ggtcgtttgt tcataaacgc ggggttcggt

9720

cccagggctg gcactctgtc gataccccac cgagacccca ttgggaccaa tacgcccgcg

9780

tttcttcctt ttccccaccc caacccccaa gttcgggtga aggcccaggg ctcgcagcca

9840

acgtcggggc ggcaagccct gccatagcca ctacgggtac gtaggccaac cactagaact

9900

atagctagag tcctgggcga acaaacgatg ctcgccttcc agaaaaccga ggatgcgaac

9960

cacttcatcc ggggtcagca ccaccggcaa gcgccgcgac ggccgaggtc taccgatctc

10020

ctgaagccag ggcagatccg tgcacagcac cttgccgtag aagaacagca aggccgccaa

10080

tgcctgacga tgcgtggaga ccgaaacctt gcgctcgttc gccagccagg acagaaatgc

10140

ctcgacttcg ctgctgccca aggttgccgg gtgacgcaca ccgtggaaac ggatgaaggc

10200

acgaacccag ttgacataag cctgttcggt tcgtaaactg taatgcaagt agcgtatgcg

10260

ctcacgcaac tggtccagaa ccttgaccga acgcagcggt ggtaacggcg cagtggcggt

10320

tttcatggct tgttatgact gtttttttgt acagtctatg cctcgggcat ccaagcagca

10380

agcgcgttac gccgtgggtc gatgtttgat gttatggagc agcaacgatg ttacgcagca

10440

gcaacgatgt tacgcagcag ggcagtcgcc ctaaaacaaa gttaggtggc tcaagtatgg

10500

gcatcattcg cacatgtagg ctcggccctg accaagtcaa atccatgcgg gctgctcttg

10560

atcttttcgg tcgtgagttc ggagacgtag ccacctactc ccaacatcag ccggactccg

10620

attacctcgg gaacttgctc cgtagtaaga cattcatcgc gcttgctgcc ttcgaccaag

10680

aagcggttgt tggcgctctc gcggcttacg ttctgcccag gtttgagcag ccgcgtagtg

10740

agatctatat ctatgatctc gcagtctccg gcgagcaccg gaggcagggc attgccaccg

10800

cgctcatcaa tctcctcaag catgaggcca acgcgcttgg tgcttatgtg atctacgtgc

10860

aagcagatta cggtgacgat cccgcagtgg ctctctatac aaagttgggc atacgggaag

10920

aagtgatgca ctttgatatc gacccaagta ccgccaccta acaattcgtt caagccgaga

10980

tcggcttccc ggccgcggag ttgttcggta aattgtcaca acgccgcgaa tatagtcttt

11040

accatgccct tggccacgcc cctctttaat acgacgggca atttgcactt cagaaaatga

11100

agagtttgct ttagccataa caaaagtcca gtatgctttt tcacagcata actggactga

11160

tttcagttta caactattct gtctagttta agactttatt gtcatagttt agatctattt

11220

tgttcagttt aagactttat tgtccgccca cacccgctta cgcagggcat ccatttatta

11280

ctcaaccgta accgattttg ccaggttacg cggctggtct gcggtgtgaa ataccgcaca

11340

gatgcgtaag gagaaaatac cgcatcaggc gctcttccgc ttcctcgctc actgactcgc

11400

tgcgctcggt cgttcggctg cggcgagcgg tatcagctca ctcaaaggcg gtaatacggt

11460

tatccacaga atcaggggat aacgcaggaa agaacatgtg agcaaaaggc cagcaaaagg

11520

caccaggaaccg taaaaaggcc gcgttgctgg cgtttttcca taggctccgc ccccctgacg

11580

agcatcacaa aaatcgacgc tcaagtcaga ggtggcgaaa cccgacagga ctataaagat

11640

accaggcgtt tccccctgga agctccctcg tgcgctctcc tgttccgacc ctgccgctta

11700

ccggatacct gtccgccttt ctcccttcgg gaagcgtggc gctttctcaa tgctcacgct

11760

gtaggtatct cagttcggtg taggtcgttc gctccaagct gggctgtgtg cacgaacccc

11820

ccgttcagcc cgaccgctgc gccttatccg gtaactatcg tcttgagtcc aacccggtaa

11880

gacacgactt atcgccactg gcagcagcca ctggtaacag gattagcaga gcgaggtatg

11940

taggcggtgc tacagagttc ttgaagtggt ggcctaacta cggctacact agaaggacag

12000

tatttggtat ctgcgctctg ctgaagccag ttaccttcgg aaaaagagtt ggtagctctt

12060

gatccggcaa acaaaccacc gctggtagcg gtggtttttt tgtttgcaag cagcagatta

12120

cgcgcagaaa aaaaggatct caagaagatc ctttgatctt ttctacgggg tctgacgctc

12180

agtggaacga aaactcacgt taagggattt tggtcatgag attatcaaaa aggatcttca

12240

cctagatcct tttaaattaa aaatgaagtt ttaaatcaat ctaaagtata tatgagtaaa

12300

cttggtctga cagttaccaa tgcttaatca gtgaggcacc tatctcagcg atctgtctat

12360

ttcgttcatc catagttgcc tgactccccg tcgtgtagat aactacgata cgggaggggct

12420

taccatctgg ccccagtgct gcaatgatac cgcgagaccc acgctcaccg gctccagatt

12480

tatcagcaat aaaccagcca gccggaaggg ccgagcgcag aagtggtcct gcaactttat

12540

ccgcctccat ccagtctatt aattgttgcc gggaagctag agtaagtagt tcgccagtta

12600

atagtttgcg caacgttgtt gccattgcta caggcatcgt ggtgtcacgc tcgtcgtttg

12660

gtatggcttc attcagctcc ggttcccaac gatcaaggcg agttacatga tcccccatgt

12720

tgtgcaaaaa agcggttagc tccttcggtc ctccgatcgt tgtcagaagt aagttggccg

12780

cagtgttatc actcatggtt atggcagcac tgcataattc tcttactgtc atgccatccg

12840

taagatgctt ttctgtgact ggtgagtact caaccaagtc attctgagaa tagtgtatgc

12900

ggcgaccgag ttgctcttgc ccggcgtcaa tacgggataa taccgcgcca catagcagaa

12960

ctttaaaagt gctcatcatt ggaaaacgtt cttcggggcg aaaactctca aggatcttac

13020

cgctgttgag atccagttcg atgtaaccca ctcgtgcacc caactgatct tcagcatctt

13080

ttactttcac cagcgtttct gggtgagcaa aaacaggaag gcaaaatgcc gcaaaaaagg

13140

gaataagggc gacacggaaa tgttgaatac tcatactctt cctttttcaa tattattgaa

13200

gcatttatca gggttattgt ctcatgagcg gatacatatt tgaatgtatt tagaaaaata

13260

aacaaatagg ggttccgcgc acatttcccc gaaaagtgcc acctgaaatt gtaaacgtta

13320

atattttgtt aaaattcgcg ttaaattttt gttaaatcag ctcatttttt aaccaatagg

13380

ccgaaatcgg caaaatccct tataaatcaa aagaatagac cgagataggg ttgagtgttg

13440

ttccagtttg gaacaagagt ccactattaa agaacgtgga ctccaacgtc aaagggcgaa

13500

aaaccgtcta tcagggcgat ggcccactac gtgaaccatc accctaatca agttttttgg

13560

ggtcgaggtg ccgtaaagca ctaaatcgga accctaaagg gagcccccga tttagagctt

13620

gacggggaaa gccggcgaac gtggcgagaa aggaagggaa gaaagcgaaa ggagcgggcg

13680

ctagggcgct ggcaagtgta gcggtcacgc tgcgcgtaac caccacaccc gccgcgctta

13740

atgcgccgct acagggcgcg tcccattcgc cattcaggct gcaaataagc gttgatattc

13800

agtcaattac aaacattaat aacgaagaga tgacagaaaa attttcattc tgtgacagag

13860

aa

13862

<210> 218

<211> 2351

<212> PROTEIN

<213> Homo sapiens

<400> 218

Met Gln Ile Glu Leu Ser Thr Cys Phe Phe Leu Cys Leu Leu Arg Phe

1 5 10 15

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

20 25 30

Trp Asp Tyr Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg

35 40 45

Phe Pro Pro Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val

50 55 60

Tyr Lys Lys Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile

65 70 75 80

Ala Lys Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln

85 90 95

Ala Glu Val Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser

100 105 110

His Pro Val Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser

115 120 125

Glu Gly Ala Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp

130 135 140

Asp Lys Val Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu

145 150 155 160

Lys Glu Asn Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser

165 170 175

Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile

180 185 190

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

195 200 205

Gln Thr Leu His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly

210 215 220

Lys Ser Trp His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp

225 230 235 240

Ala Ala Ser Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr

245 250 255

Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val

260 265 270

Tyr Trp His Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile

275 280 285

Phe Leu Glu Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser

290 295 300

Leu Glu Ile Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met

305 310 315 320

Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His

325 330 335

Asp Gly Met Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro

340 345 350

Gln Leu Arg Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp

355 360 365

Leu Thr Asp Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser

370 375 380

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

385 390 395 400

Trp Val His Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro

405 410 415

Leu Val Leu Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn

420 425 430

Asn Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met

435 440 445

Ala Tyr Thr Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu

450 455 460

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

465 470 475 480

Leu Ile Ile Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro

485 490 495

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

500 505 510

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

515 520 525

Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp

530 535 540

Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg

545 550 555 560

Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu

565 570 575

Ser Val Asp Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val

580 585 590

Ile Leu Phe Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu

595 600 605

Asn Ile Gln Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp

610 615 620

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

625 630 635 640

Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp

645 650 655

Tyr Ile Leu Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe

660 665 670

Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr

675 680 685

Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro

690 695 700

Gly Leu Trp Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly

705 710 715 720

Met Thr Ala Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp

725 730 735

Tyr Tyr Glu Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys

740 745 750

Asn Asn Ala Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro

755 760 765

Ser Thr Arg Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp

770 775 780

Ile Glu Lys Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys

785 790 795 800

Ile Gln Asn Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser

805 810 815

Pro Thr Pro His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr

820 825 830

Glu Thr Phe Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn

835 840 845

Ser Leu Ser Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly

850 855 860

Asp Met Val Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu

865 870 875 880

Lys Leu Gly Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys

885 890 895

Val Ser Ser Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn

900 905 910

Leu Ala Ala Gly Thr Asp Asn Thr Ser Ser Leu Gly Pro Pro Ser Met

915 920 925

Pro Val His Tyr Asp Ser Gln Leu Asp Thr Thr Leu Phe Gly Lys Lys

930 935 940

Ser Ser Pro Leu Thr Glu Ser Gly Gly Pro Leu Ser Leu Ser Glu Glu

945 950 955 960

Asn Asn Asp Ser Lys Leu Leu Glu Ser Gly Leu Met Asn Ser Gln Glu

965 970 975

Ser Ser Trp Gly Lys Asn Val Ser Ser Thr Glu Ser Gly Arg Leu Phe

980 985 990

Lys Gly Lys Arg Ala His Gly Pro Ala Leu Leu Thr Lys Asp Asn Ala

995 1000 1005

Leu Phe Lys Val Ser Ile Ser Leu Leu Lys Thr Asn Lys Thr Ser

1010 1015 1020

Asn Asn Ser Ala Thr Asn Arg Lys Thr His Ile Asp Gly Pro Ser

1025 1030 1035

Leu Leu Ile Glu Asn Ser Pro Ser Val Trp Gln Asn Ile Leu Glu

1040 1045 1050

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

1055 1060 1065

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

1070 1075 1080

Ser Asn Lys Thr Thr Ser Ser Lys Asn Met Glu Met Val Gln Gln

1085 1090 1095

Lys Lys Glu Gly Pro Ile Pro Pro Asp Ala Gln Asn Pro Asp Met

1100 1105 1110

Ser Phe Phe Lys Met Leu Phe Leu Pro Glu Ser Ala Arg Trp Ile

1115 1120 1125

Gln Arg Thr His Gly Lys Asn Ser Leu Asn Ser Gly Gln Gly Pro

1130 1135 1140

Ser Pro Lys Gln Leu Val Ser Leu Gly Pro Glu Lys Ser Val Glu

1145 1150 1155

Gly Gln Asn Phe Leu Ser Glu Lys Asn Lys Val Val Val Gly Lys

1160 1165 1170

Gly Glu Phe Thr Lys Asp Val Gly Leu Lys Glu Met Val Phe Pro

1175 1180 1185

Ser Ser Arg Asn Leu Phe Leu Thr Asn Leu Asp Asn Leu His Glu

1190 1195 1200

Asn Asn Thr His Asn Gln Glu Lys Lys Ile Gln Glu Glu Ile Glu

1205 1210 1215

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

1220 1225 1230

His Thr Val Thr Gly Thr Lys Asn Phe Met Lys Asn Leu Phe Leu

1235 1240 1245

Leu Ser Thr Arg Gln Asn Val Glu Gly Ser Tyr Asp Gly Ala Tyr

1250 1255 1260

Ala Pro Val Leu Gln Asp Phe Arg Ser Leu Asn Asp Ser Thr Asn

1265 1270 1275

Arg Thr Lys Lys His Thr Ala His Phe Ser Lys Lys Gly Glu Glu

1280 1285 1290

Glu Asn Leu Glu Gly Leu Gly Asn Gln Thr Lys Gln Ile Val Glu

1295 1300 1305

Lys Tyr Ala Cys Thr Thr Arg Ile Ser Pro Asn Thr Ser Gln Gln

1310 1315 1320

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

1325 1330 1335

Leu Pro Leu Glu Glu Thr Glu Leu Glu Lys Arg Ile Ile Val Asp

1340 1345 1350

Asp Thr Ser Thr Gln Trp Ser Lys Asn Met Lys His Leu Thr Pro

1355 1360 1365

Ser Thr Leu Thr Gln Ile Asp Tyr Asn Glu Lys Glu Lys Gly Ala

1370 1375 1380

Ile Thr Gln Ser Pro Leu Ser Asp Cys Leu Thr Arg Ser His Ser

1385 1390 1395

Ile Pro Gln Ala Asn Arg Ser Pro Leu Pro Ile Ala Lys Val Ser

1400 1405 1410

Ser Phe Pro Ser Ile Arg Pro Ile Tyr Leu Thr Arg Val Leu Phe

1415 1420 1425

Gln Asp Asn Ser Ser His Leu Pro Ala Ala Ser Tyr Arg Lys Lys

1430 1435 1440

Asp Ser Gly Val Gln Glu Ser Ser His Phe Leu Gln Gly Ala Lys

1445 1450 1455

Lys Asn Asn Leu Ser Leu Ala Ile Leu Thr Leu Glu Met Thr Gly

1460 1465 1470

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

1475 1480 1485

Val Thr Tyr Lys Lys Val Glu Asn Thr Val Leu Pro Lys Pro Asp

1490 1495 1500

Leu Pro Lys Thr Ser Gly Lys Val Glu Leu Leu Pro Lys Val His

1505 1510 1515

Ile Tyr Gln Lys Asp Leu Phe Pro Thr Glu Thr Ser Asn Gly Ser

1520 1525 1530

Pro Gly His Leu Asp Leu Val Glu Gly Ser Leu Leu Gln Gly Thr

1535 1540 1545

Glu Gly Ala Ile Lys Trp Asn Glu Ala Asn Arg Pro Gly Lys Val

1550 1555 1560

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

1565 1570 1575

Lys Leu Leu Asp Pro Leu Ala Trp Asp Asn His Tyr Gly Thr Gln

1580 1585 1590

Ile Pro Lys Glu Glu Trp Lys Ser Gln Glu Lys Ser Pro Glu Lys

1595 1600 1605

Thr Ala Phe Lys Lys Lys Asp Thr Ile Leu Ser Leu Asn Ala Cys

1610 1615 1620

Glu Ser Asn His Ala Ile Ala Ala Ile Asn Glu Gly Gln Asn Lys

1625 1630 1635

Pro Glu Ile Glu Val Thr Trp Ala Lys Gln Gly Arg Thr Glu Arg

1640 1645 1650

Leu Cys Ser Gln Asn Pro Pro Val Leu Lys Arg His Gln Arg Glu

1655 1660 1665

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

1670 1675 1680

Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu Asp Phe Asp Ile

1685 1690 1695

Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser Phe Gln Lys Lys

1700 1705 1710

Thr Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu Trp Asp Tyr

1715 1720 1725

Gly Met Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala Gln Ser

1730 1735 1740

Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe Thr

1745 1750 1755

Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu

1760 1765 1770

His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp

1775 1780 1785

Asn Ile Met Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr Ser

1790 1795 1800

Phe Tyr Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly

1805 1810 1815

Ala Glu Pro Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr

1820 1825 1830

Tyr Phe Trp Lys Val Gln His His Met Ala Pro Thr Lys Asp Glu

1835 1840 1845

Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu

1850 1855 1860

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

1865 1870 1875

Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln Val Thr Val Gln

1880 1885 1890

Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu Thr Lys Ser Trp

1895 1900 1905

Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg Ala Pro Cys Asn

1910 1915 1920

Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn Tyr Arg Phe His

1925 1930 1935

Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro Gly Leu Val Met

1940 1945 1950

Ala Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu Ser Met Gly Ser

1955 1960 1965

Asn Glu Asn Ile His Ser Ile His Phe Ser Gly His Val Phe Thr

1970 1975 1980

Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Leu Tyr Asn Leu Tyr

1985 1990 1995

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

2000 2005 2010

Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His Leu His Ala Gly

2015 2020 2025

Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys Cys Gln Thr Pro

2030 2035 2040

Leu Gly Met Ala Ser Gly His Ile Arg Asp Phe Gln Ile Thr Ala

2045 2050 2055

Ser Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu Ala Arg Leu His

2060 2065 2070

Tyr Ser Gly Ser Ile Asn Ala Trp Ser Thr Lys Glu Pro Phe Ser

2075 2080 2085

Trp Ile Lys Val Asp Leu Leu Ala Pro Met Ile Ile His Gly Ile

2090 2095 2100

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

2105 2110 2115

Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys Lys Trp Gln Thr

2120 2125 2130

Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val Phe Phe Gly Asn

2135 2140 2145

Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe Asn Pro Pro Ile

2150 2155 2160

Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His Tyr Ser Ile Arg

2165 2170 2175

Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp Leu Asn Ser Cys

2180 2185 2190

Ser Met Pro Leu Gly Met Glu Ser Lys Ala Ile Ser Asp Ala Gln

2195 2200 2205

Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met Phe Ala Thr Trp Ser

2210 2215 2220

Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg Ser Asn Ala Trp

2225 2230 2235

Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu Gln Val Asp Phe

2240 2245 2250

Gln Lys Thr Met Lys Val Thr Gly Val Thr Thr Gln Gly Val Lys

2255 2260 2265

Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe Leu Ile Ser Ser

2270 2275 2280

Ser Gln Asp Gly His Gln Trp Thr Leu Phe Phe Gln Asn Gly Lys

2285 2290 2295

Val Lys Val Phe Gln Gly Asn Gln Asp Ser Phe Thr Pro Val Val

2300 2305 2310

Asn Ser Leu Asp Pro Pro Leu Leu Thr Arg Tyr Leu Arg Ile His

2315 2320 2325

Pro Gln Ser Trp Val His Gln Ile Ala Leu Arg Met Glu Val Leu

2330 2335 2340

Gly Cys Glu Ala Gln Asp Leu Tyr

2345 2350

<210> 219

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000

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000

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000

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<400> 285

000

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<400> 286

000

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000

<210> 288

<400> 288

000

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<400> 289

000

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<400> 290

000

<210> 291

<400> 291

000

<210> 292

<400> 292

000

<210> 293

<400> 293

000

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000

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000

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000

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000

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000

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<400> 300

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000

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000

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000

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000

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000

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000

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000

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<400> 359

000

<210> 360

<400> 360

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<210> 367

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000

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<400> 370

000

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<400> 374

000

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<400> 375

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<210> 376

<400> 376

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<210> 377

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<400> 378

000

<210> 379

<400> 379

000

<210> 380

<211> 4374

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 380

atgcagattg agctgagcac ctgcttcttc ctgtgcctgc tgaggttctg cttctctgcc

60

accaggagat actacctggg ggctgtggag ctgagctggg actacatgca gtctgacctg

120

ggggagctgc ctgtggatgc caggttcccc cccagagtgc ccaagagctt ccccttcaac

180

acctctgtgg tgtacaagaa gaccctgttt gtggagttca ctgaccacct gttcaacatt

240

gccaagccca ggcccccctg gatgggcctg ctgggcccca ccatccaggc tgaggtgtat

300

gacactgtgg tgatcaccct gaagaacatg gccagccacc ctgtgagcct gcatgctgtg

360

ggggtgagct actggaaggc ctctgagggg gctgagtatg atgaccagac cagccagagg

420

gagaaggagg atgacaaggt gttccctggg ggcagccaca cctatgtgtg gcaggtgctg

480

aaggagaatg gccccatggc ctctgacccc ctgtgcctga cctacagcta cctgagccat

540

gtggacctgg tgaaggacct gaactctggc ctgattgggg ccctgctggt gtgcagggag

600

ggcagcctgg ccaaggagaa gacccagacc ctgcacaagt tcatcctgct gtttgctgtg

660

tttgatgagg gcaagagctg gcactctgaa accaagaaca gcctgatgca ggacagggat

720

gctgcctctg ccagggcctg gcccaagatg cacactgtga atggctatgt gaacaggagc

780

ctgcctggcc tgattggctg ccacaggaag tctgtgtact ggcatgtgat tggcatgggc

840

accacccctg aggtgcacag catcttcctg gagggccaca ccttcctggt caggaaccac

900

aggcaggcca gcctggagat cagccccatc accttcctga ctgcccagac cctgctgatg

960

gacctgggcc agttcctgct gttctgccac atcagcagcc accagcatga tggcatggag

1020

gcctatgtga aggtggacag ctgccctgag gagccccagc tgaggatgaa gaacaatgag

1080

gaggctgagg actatgatga tgacctgact gactctgaga tggatgtggt gaggtttgat

1140

gatgacaaca gccccagctt catccagatc aggtctgtgg ccaagaagca ccccaagacc

1200

tgggtgcact acattgctgc tgaggaggag gactgggact atgcccccct ggtgctggcc

1260

cctgatgaca ggagctacaa gagccagtac ctgaacaatg gcccccagag gattggcagg

1320

aagtacaaga aggtcaggtt catggcctac actgatgaaa ccttcaagac cagggaggcc

1380

atccagcatg agtctggcat cctgggcccc ctgctgtatg gggaggtggg ggacaccctg

1440

ctgatcatct tcaagaacca ggccagcagg ccctacaaca tctaccccca tggcatcact

1500

gatgtgaggc ccctgtacag caggaggctg cccaaggggg tgaagcacct gaaggacttc

1560

cccatcctgc ctggggagat cttcaagtac aagtggactg tgactgtgga ggatggcccc

1620

accaagtctg accccaggtg cctgaccaga tactacagca gctttgtgaa catggagagg

1680

gacctggcct ctggcctgat tggccccctg ctgatctgct acaaggagtc tgtggaccag

1740

aggggcaacc agatcatgtc tgacaagagg aatgtgatcc tgttctctgt gtttgatgag

1800

aacaggagct ggtacctgac tgagaacatc cagaggttcc tgcccaaccc tgctggggtg

1860

cagctggagg accctgagtt ccaggccagc aacatcatgc acagcatcaa tggctatgtg

1920

tttgacagcc tgcagctgtc tgtgtgcctg catgaggtgg cctactggta catcctgagc

1980

attggggccc agactgactt cctgtctgtg ttcttctctg gctacacctt caagcacaag

2040

atggtgtatg aggacaccct gaccctgttc cccttctctg gggagactgt gttcatgagc

2100

atggagaacc ctggcctgtg gattctgggc tgccacaact ctgacttcag gaacaggggc

2160

atgactgccc tgctgaaagt ctccagctgt gacaagaaca ctggggacta ctatgaggac

2220

agctatgagg acatctctgc ctacctgctg agcaagaaca atgccattga gcccaggagc

2280

ttcagccaga accccccagt gctgaagagg caccagaggg agatcaccag gaccaccctg

2340

cagtctgacc aggagagat tgactatgat gacaccatct ctgtggagat gaagaaggag

2400

gactttgaca tctacgacga ggacgagaac cagagcccca ggagcttcca gaagaagacc

2460

aggcactact tcattgctgc tgtggagagg ctgtgggact atggcatgag cagcagcccc

2520

catgtgctga ggaacagggc ccagtctggc tctgtgcccc agttcaagaa ggtggtgttc

2580

caggagttca ctgatggcag cttcacccag cccctgtaca gaggggagct gaatgagcac

2640

ctgggcctgc tgggccccta catcagggct gaggtggagg acaacatcat ggtgaccttc

2700

aggaaccagg ccagcaggcc ctacagcttc tacagcagcc tgatcagcta tgaggaggac

2760

cagaggcagg gggctgagcc caggaagaac tttgtgaagc ccaatgaaac caagacctac

2820

ttctggaagg tgcagcacca catggccccc accaaggatg agtttgactg caaggcctgg

2880

gcctacttct ctgatgtgga cctggagaag gatgtgcact ctggcctgat tggccccctg

2940

ctggtgtgcc acaccaacac cctgaaccct gcccatggca ggcaggtgac tgtgcaggag

3000

tttgccctgt tcttcaccat ctttgatgaa accaagagct ggtacttcac tgagaacatg

3060

gagaggaact gcagggcccc ctgcaacatc cagatggagg accccacctt caaggagaac

3120

tacaggttcc atgccatcaa tggctacatc atggacaccc tgcctggcct ggtgatggcc

3180

caggaccaga ggatcaggtg gtacctgctg agcatgggca gcaatgagaa catccacagc

3240

atccacttct ctggccatgt gttcactgtg aggaagaagg aggagtacaa gatggccctg

3300

tacaacctgt accctggggt gtttgagact gtggagatgc tgcccagcaa ggctggcatc

3360

tggagggtgg agtgcctgat tggggagcac ctgcatgctg gcatgagcac cctgttcctg

3420

gtgtacagca acaagtgcca gacccccctg ggcatggcct ctggccacat caggacttc

3480

cagatcactg cctctggcca gtatggccag tgggccccca agctggccag gctgcactac

3540

tctggcagca tcaatgcctg gagcaccaag gagcccttca gctggatcaa ggtggacctg

3600

ctggccccca tgatcatcca tggcatcaag acccagggg ccaggcagaa gttcagcagc

3660

ctgtacatca gccagttcat catcatgtac agcctggatg gcaagaagtg gcagacctac

3720

aggggcaaca gcactggcac cctgatggtg ttctttggca atgtggacag ctctggcatc

3780

aagcacaaca tcttcaaccc ccccatcatt gccagataca tcaggctgca ccccacccac

3840

tacagcatca ggagcaccct gaggatggag ctgatgggct gtgacctgaa cagctgcagc

3900

atgcccctgg gcatggagag caaggccatc tctgatgccc agatcactgc cagcagctac

3960

ttcaccaaca tgtttgccac ctggagcccc agcaaggcca ggctgcacct gcagggcagg

4020

agcaatgcct ggaggcccca ggtcaacaac cccaaggagt ggctgcaggt ggacttccag

4080

aagaccatga aggtgactgg ggtgaccacc cagggggtga agagcctgct gaccagcatg

4140

tatgtgaagg agttcctgat cagcagcagc caggatggcc accagtggac cctgttcttc

4200

cagaatggca aggtgaaggt gttccagggc aaccaggaca gcttcacccc tgtggtgaac

4260

agcctggacc cccccctgct gaccagatac ctgaggattc acccccagag ctgggtgcac

4320

cagattgccc tgaggatgga ggtgctgggc tgtgaggccc aggacctgta ctga

4374

<210> 381

<211> 4374

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 381

atgcagattg agctgagcac ctgcttcttc ctgtgtctgc tgaggttctg cttctctgcc

60

accaggaggt attacctggg ggctgtggag ctgagctggg actatatgca gtctgacctg

120

ggggagctgc ctgtggatgc taggttcccc cccagggtgc ccaagagctt cccctttaac

180

acttctgtgg tgtacaagaa gaccctgttt gtggagttca ctgaccacct gttcaacatt

240

gccaagccca ggcccccctg gatggggctg ctggggccca ccatccaggc tgaggtgtat

300

gacactgtgg tgatcaccct gaagaacatg gccagccacc ctgtgagcct gcatgctgtg

360

ggggtgagct actggaaggc ttctgagggg gctgagtatg atgaccagac tagccagagg

420

gagaaggagg atgacaaggt gtttcctggg ggcagccata cctatgtgtg gcaggtgctg

480

aaggagaatg gccccatggc ctctgacccc ctgtgcctga cctacagcta cctgtctcat

540

gtggacctgg tgaaggacct gaactctggc ctgattgggg ctctgctggt gtgtagggag

600

ggcagcctgg ctaaggaaaa gacccagacc ctgcataagt ttatcctgct gtttgctgtg

660

tttgatgagg gcaagagctg gcactctgag accaagaaca gcctgatgca ggatagggat

720

gctgcctctg ccagggcttg gcctaagatg cacactgtga atgggtatgt gaataggagc

780

ctgcctggcc tgattggctg ccacaggaag tctgtgtact ggcatgtgat tgggatgggc

840

accacccctg aggtccatag catcttcctg gagggccaca ctttcctggt gaggaaccac

900

agacaggcct ctctggagat ctctcccatc accttcctga ctgctcagac tctgctgatg

960

gacctgggcc agttcctgct gttttgccat attagcagcc accagcatga tgggatggag

1020

gcctatgtga aggtggatag ctgccctgag gagcctcagc tgaggatgaa gaacaatgag

1080

gaggctgaag actatgatga tgacctgact gattctgaga tggatgtggt gaggtttgat

1140

gatgacaata gccccagctt cattcagatc aggtctgtgg ccaagaaaca ccccaagacc

1200

tgggtgcact acattgctgc tgaggaagag gactgggact atgctcccct ggtgctggcc

1260

cctgatgata ggtcttataa gagccagtac ctgaacaatg ggccccagag gattggcagg

1320

aagtacaaga aggtgaggtt catggcctac actgatgaaa ccttcaaaac cagggaggcc

1380

attcagcatg agtctggcat cctgggccct ctgctgtatg gggaggtggg ggacaccctg

1440

ctgatcatct tcaagaacca ggccagcagg ccctacaaca tctatcctca tggcatcact

1500

gatgtgaggc ccctgtacag caggaggctg cccaaggggg tgaagcacct gaaagacttc

1560

cccatcctgc ctggggagat ctttaagtat aagtggactg tgactgtgga ggatggccct

1620

accaagtctg accccaggtg tctgaccagg tactattcta gctttgtgaa catggagagg

1680

gacctggcct ctggcctgat tgggcccctg ctgatctgct acaaggagtc tgtggaccag

1740

aggggcaacc agatcatgtc tgacaagagg aatgtgatcc tgttttctgt gtttgatgag

1800

aataggagct ggtacctgac tgagaacatc cagaggtttc tgcccaatcc tgctggggtg

1860

cagctggagg atcctgagtt ccaggccagc aatatcatgc atagcatcaa tggctatgtg

1920

tttgacagcc tgcagctgtc tgtgtgcctg catgaggtgg cctactggta catcctgagc

1980

attggggccc agactgactt tctgtctgtg ttcttttctg gctatacctt caagcacaag

2040

atggtgtatg aggataccct gaccctgttc cccttctctg gggagactgt gttcatgagc

2100

atggagaatc ctgggctgtg gatcctgggg tgccacaact ctgattttag gaacaggggg

2160

atgactgccc tgctgaaggt gtctagctgt gataagaaca ctggggacta ctatgaggac

2220

agctatgagg acatttctgc ttatctgctg tctaagaata atgccattga gcccagaagc

2280

ttcagccaga atccccctgt gctgaagaga catcagaggg agatcaccag aactaccctg

2340

cagtctgatc aggaggat tgactatgat gacactatct ctgtggagat gaagaaggag

2400

gactttgaca tctatgatga ggatgagaat cagtctccca ggagctttca gaagaagacc

2460

agacattact tcattgctgc tgtggagagg ctgtgggact atggcatgag ctctagccct

2520

catgtgctga ggaacagggc ccagtctggc tctgtgcccc agttcaagaa ggtggtgttc

2580

caggaattca ctgatggcag cttcacccag cccctgtaca ggggggagct gaatgagcac

2640

ctgggcctgc tggggcctta tatcagggct gaggtggagg ataatattat ggtgactttc

2700

aggaaccagg ccagcaggcc ctactctttc tatagcagcc tgatctctta tgaggaggat

2760

cagaggcagg gggctgagcc taggaagaac tttgtgaagc ccaatgagac taagacctac

2820

ttctggaagg tccagcacca catggcccct accaaggatg agtttgactg caaggcctgg

2880

gcctatttct ctgatgtgga tctggagaag gatgtccatt ctgggctgat tggccccctg

2940

ctggtgtgcc acactaacac tctgaatcct gcccatggca ggcaggtgac tgtccaggag

3000

tttgccctgt tcttcactat ctttgatgag accaagagct ggtactttac tgagaacatg

3060

gagaggaact gcagagctcc ttgcaatatt cagatggagg accccacctt caaggagaat

3120

tacaggttcc atgccattaa tgggtacatc atggacaccc tgcctggcct ggtgatggct

3180

caggaccaga ggatcaggtg gtacctgctg agcatgggct ctaatgagaa tatccacagc

3240

atccacttct ctgggcatgt gttcactgtg aggaagaagg aggagtacaa gatggctctg

3300

tataatctgt accctggggt gtttgaaact gtggagatgc tgccctctaa ggctggcatc

3360

tggagggtgg agtgcctgat tggggagcac ctgcatgctg gcatgagcac cctgttcctg

3420

gtgtacagca acaagtgcca gacccccctg ggcatggcct ctggccacat caggacttc

3480

cagatcactg cctctggcca gtatggccag tgggccccca agctggccag gctgcactat

3540

tctggcagca tcaatgcctg gagcaccaag gagcccttca gctggatcaa ggtggacctg

3600

ctggccccca tgatcattca tggcatcaag acccagggg ccaggcagaa gttcagctct

3660

ctgtacatct ctcagttcat catcatgtac tctctggatg ggaagaagtg gcagacctac

3720

aggggcaaca gcactggcac cctgatggtg ttctttggga atgtggactc ttctggcatc

3780

aagcacaaca tcttcaatcc ccccatcatt gctaggtata ttaggctgca tcccacccac

3840

tacagcatca ggtctaccct gaggatggag ctgatgggct gtgacctgaa ctcttgcagc

3900

atgcccctgg gcatggagtc taaggccatc tctgatgccc agattactgc cagcagctac

3960

ttcaccaaca tgtttgccac ctggagcccc tctaaggcca ggctgcatct gcaggggagg

4020

agcaatgcct ggaggcctca ggtgaacaac cccaaggagt ggctgcaggt ggatttccag

4080

aagaccatga aggtgactgg ggtgaccacc cagggggtca agagcctgct gaccagcatg

4140

tatgtgaagg agttcctgat cagcagcagc caggatggcc accagtggac tctgttcttt

4200

cagaatggga aggtgaaggt gtttcagggc aatcaggact ctttcacccc tgtggtgaac

4260

agcctggacc cccccctgct gaccagatac ctgaggatcc acccccagtc ttgggtgcat

4320

cagattgccc tgaggatgga ggtgctgggc tgtgaggctc aggatctgta ctga

4374

<210> 382

<211> 4374

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 382

atgcagatcg agctctccac ctgcttcttt ctgtgcctgt tgagattctg cttcagcgcc

60

accaggagat actacctggg ggctgtggag ctgagctggg actacatgca gtctgacctg

120

ggggagctgc ctgtggatgc caggttcccc cccagagtgc ccaagagctt ccccttcaac

180

acctctgtgg tgtacaagaa gaccctgttt gtggagttca ctgaccacct gttcaacatt

240

gccaagccca ggcccccctg gatgggcctg ctgggcccca ccatccaggc tgaggtgtat

300

gacactgtgg tgatcaccct gaagaacatg gccagccacc ctgtgagcct gcatgctgtg

360

ggggtgagct actggaaggc ctctgagggg gctgagtatg atgaccagac cagccagagg

420

gagaaggagg atgacaaggt gttccctggg ggcagccaca cctatgtgtg gcaggtgctg

480

aaggagaatg gccccatggc ctctgacccc ctgtgcctga cctacagcta cctgagccat

540

gtggacctgg tgaaggacct gaactctggc ctgattgggg ccctgctggt gtgcagggag

600

ggcagcctgg ccaaggagaa gacccagacc ctgcacaagt tcatcctgct gtttgctgtg

660

tttgatgagg gcaagagctg gcactctgaa accaagaaca gcctgatgca ggacagggat

720

gctgcctctg ccagggcctg gcccaagatg cacactgtga atggctatgt gaacaggagc

780

ctgcctggcc tgattggctg ccacaggaag tctgtgtact ggcatgtgat tggcatgggc

840

accacccctg aggtgcacag catcttcctg gagggccaca ccttcctggt caggaaccac

900

aggcaggcca gcctggagat cagccccatc accttcctga ctgcccagac cctgctgatg

960

gacctgggcc agttcctgct gttctgccac atcagcagcc accagcatga tggcatggag

1020

gcctatgtga aggtggacag ctgccctgag gagccccagc tgaggatgaa gaacaatgag

1080

gaggctgagg actatgatga tgacctgact gactctgaga tggatgtggt gaggtttgat

1140

gatgacaaca gccccagctt catccagatc aggtctgtgg ccaagaagca ccccaagacc

1200

tgggtgcact acattgctgc tgaggaggag gactgggact atgcccccct ggtgctggcc

1260

cctgatgaca ggagctacaa gagccagtac ctgaacaatg gcccccagag gattggcagg

1320

aagtacaaga aggtcaggtt catggcctac actgatgaaa ccttcaagac cagggaggcc

1380

atccagcatg agtctggcat cctgggcccc ctgctgtatg gggaggtggg ggacaccctg

1440

ctgatcatct tcaagaacca ggccagcagg ccctacaaca tctaccccca tggcatcact

1500

gatgtgaggc ccctgtacag caggaggctg cccaaggggg tgaagcacct gaaggacttc

1560

cccatcctgc ctggggagat cttcaagtac aagtggactg tgactgtgga ggatggcccc

1620

accaagtctg accccaggtg cctgaccaga tactacagca gctttgtgaa catggagagg

1680

gacctggcct ctggcctgat tggccccctg ctgatctgct acaaggagtc tgtggaccag

1740

aggggcaacc agatcatgtc tgacaagagg aatgtgatcc tgttctctgt gtttgatgag

1800

aacaggagct ggtacctgac tgagaacatc cagaggttcc tgcccaaccc tgctggggtg

1860

cagctggagg accctgagtt ccaggccagc aacatcatgc acagcatcaa tggctatgtg

1920

tttgacagcc tgcagctgtc tgtgtgcctg catgaggtgg cctactggta catcctgagc

1980

attggggccc agactgactt cctgtctgtg ttcttctctg gctacacctt caagcacaag

2040

atggtgtatg aggacaccct gaccctgttc cccttctctg gggagactgt gttcatgagc

2100

atggagaacc ctggcctgtg gattctgggc tgccacaact ctgacttcag gaacaggggc

2160

atgactgccc tgctgaaagt ctccagctgt gacaagaaca ctggggacta ctatgaggac

2220

agctatgagg acatctctgc ctacctgctg agcaagaaca atgccattga gcccaggagc

2280

ttcagccaga atccacccgt ccttaagcgc catcagcgcg agatcaccag gaccaccctg

2340

cagtctgacc aggagagat tgactatgat gacaccatct ctgtggagat gaagaaggag

2400

gactttgaca tctacgacga ggacgagaac cagagcccca ggagcttcca gaagaagacc

2460

aggcactact tcattgctgc tgtggagagg ctgtgggact atggcatgag cagcagcccc

2520

catgtgctga ggaacagggc ccagtctggc tctgtgcccc agttcaagaa ggtggtgttc

2580

caggagttca ctgatggcag cttcacccag cccctgtaca gaggggagct gaatgagcac

2640

ctgggcctgc tgggccccta catcagggct gaggtggagg acaacatcat ggtgaccttc

2700

aggaaccagg ccagcaggcc ctacagcttc tacagcagcc tgatcagcta tgaggaggac

2760

cagaggcagg gggctgagcc caggaagaac tttgtgaagc ccaatgaaac caagacctac

2820

ttctggaagg tgcagcacca catggccccc accaaggatg agtttgactg caaggcctgg

2880

gcctacttct ctgatgtgga cctggagaag gatgtgcact ctggcctgat tggccccctg

2940

ctggtgtgcc acaccaacac cctgaaccct gcccatggca ggcaggtgac tgtgcaggag

3000

tttgccctgt tcttcaccat ctttgatgaa accaagagct ggtacttcac tgagaacatg

3060

gagaggaact gcagggcccc ctgcaacatc cagatggagg accccacctt caaggagaac

3120

tacaggttcc atgccatcaa tggctacatc atggacaccc tgcctggcct ggtgatggcc

3180

caggaccaga ggatcaggtg gtacctgctg agcatgggca gcaatgagaa catccacagc

3240

atccacttct ctggccatgt gttcactgtg aggaagaagg aggagtacaa gatggccctg

3300

tacaacctgt accctggggt gtttgagact gtggagatgc tgcccagcaa ggctggcatc

3360

tggagggtgg agtgcctgat tggggagcac ctgcatgctg gcatgagcac cctgttcctg

3420

gtgtacagca acaagtgcca gacccccctg ggcatggcct ctggccacat caggacttc

3480

cagatcactg cctctggcca gtatggccag tgggccccca agctggccag gctgcactac

3540

tctggcagca tcaatgcctg gagcaccaag gagcccttca gctggatcaa ggtggacctg

3600

ctggccccca tgatcatcca tggcatcaag acccagggg ccaggcagaa gttcagcagc

3660

ctgtacatca gccagttcat catcatgtac agcctggatg gcaagaagtg gcagacctac

3720

aggggcaaca gcactggcac cctgatggtg ttctttggca atgtggacag ctctggcatc

3780

aagcacaaca tcttcaaccc ccccatcatt gccagataca tcaggctgca ccccacccac

3840

tacagcatca ggagcaccct gaggatggag ctgatgggct gtgacctgaa cagctgcagc

3900

atgcccctgg gcatggagag caaggccatc tctgatgccc agatcactgc cagcagctac

3960

ttcaccaaca tgtttgccac ctggagcccc agcaaggcca ggctgcatct gcagggcagg

4020

agcaatgcct ggaggcccca ggtcaacaac cccaaggagt ggctgcaggt ggacttccag

4080

aagaccatga aggtgactgg ggtgaccacc cagggggtga agagcctgct gaccagcatg

4140

tatgtgaagg agttcctgat cagcagcagc caggatggcc accagtggac cctgttcttc

4200

cagaatggca aggtgaaggt gttccagggc aaccaggaca gcttcacccc tgtggtgaac

4260

agcctggacc cccccctgct gaccagatac ctgaggattc acccccagag ctgggtgcac

4320

cagattgccc tgaggatgga ggtgctgggc tgtgaggccc aggacctgta ctga

4374

<210> 383

<211> 7056

<212> DNA

<213> Homo sapiens

<400> 383

atgcaaatag agctctccac ctgcttcttt ctgtgccttt tgcgattctg ctttagtgcc

60

accagaagat actacctggg tgcagtggaa ctgtcatggg actatatgca aagtgatctc

120

ggtgagctgc ctgtggacgc aagatttcct cctagagtgc caaaatcttt tccattcaac

180

acctcagtcg tgtacaaaaa gactctgttt gtagaattca cggatcacct tttcaacatc

240

gctaagccaa ggccaccctg gatgggtctg ctaggtccta ccatccaggc tgaggtttat

300

gatacagtgg tcattacact taagaacatg gcttcccatc ctgtcagtct tcatgctgtt

360

ggtgtatcct actggaaagc ttctgaggga gctgaatatg atgatcagac cagtcaaagg

420

gagaaagaag atgataaagt cttccctggt ggaagccata catatgtctg gcaggtcctg

480

aaagagaatg gtccaatggc ctctgaccca ctgtgcctta cctactcata tctttctcat

540

gtggacctgg taaaagactt gaattcaggc ctcattggag ccctactagt atgtagagaa

600

gggagtctgg ccaaggaaaa gacacagacc ttgcacaaat ttatactact ttttgctgta

660

tttgatgaag ggaaaagttg gcactcagaa acaaagaact ccttgatgca ggatagggat

720

gctgcatctg ctcggggcctg gcctaaaatg cacacagtca atggttatgt aaacaggtct

780

ctgccaggtc tgattggatg ccacaggaaa tcagtctatt ggcatgtgat tggaatgggc

840

accactcctg aagtgcactc aatattcctc gaaggtcaca catttcttgt gaggaaccat

900

cgccaggcgt ccttggaaat ctcgccaata actttcctta ctgctcaaac actcttgatg

960

gaccttggac agtttctact gttttgtcat atctcttccc accaacatga tggcatggaa

1020

gcttatgtca aagtagacag ctgtccagag gaaccccaac tacgaatgaa aaataatgaa

1080

gaagcggaag actatgatga tgatcttact gattctgaaa tggatgtggt caggtttgat

1140

gatgacaact ctccttcctt tatccaaatt cgctcagttg ccaagaagca tcctaaaact

1200

tgggtacatt acattgctgc tgaagaggag gactgggact atgctccctt agtcctcgcc

1260

cccgatgaca gaagttataa aagtcaatat ttgaacaatg gccctcagcg gattggtagg

1320

aagtacaaaa aagtccgatt tatggcatac acagatgaaa cctttaagac tcgtgaagct

1380

attcagcatg aatcaggaat cttgggacct ttactttatg gggaagttgg agacacactg

1440

ttgattatat ttaagaatca agcaagcaga ccatataaca tctaccctca cggaatcact

1500

gatgtccgtc ctttgtattc aaggatta ccaaaaggtg taaaacattt gaaggatttt

1560

ccaattctgc caggagaaat attcaaatat aaatggacag tgactgtaga agatgggcca

1620

actaaatcag atcctcggtg cctgacccgc tattactcta gtttcgttaa tatggagaga

1680

gatctagctt caggactcat tggccctctc ctcatctgct acaaagaatc tgtagatcaa

1740

agaggaaacc agataatgtc agacaagagg aatgtcatcc tgttttctgt atttgatgag

1800

aaccgaagct ggtacctcac agagaatata caacgctttc tccccaatcc agctggagtg

1860

cagcttgagg atccagagtt ccaagcctcc aacatcatgc acagcatcaa tggctatgtt

1920

tttgatagtt tgcagttgtc agtttgtttg catgaggtgg catactggta cattctaagc

1980

attggagcac agactgactt cctttctgtc ttcttctctg gatatacctt caaacacaaa

2040

atggtctatg aagacacact caccctattc ccattctcag gagaaactgt cttcatgtcg

2100

atggaaaacc caggtctatg gattctgggg tgccacaact cagactttcg gaacagaggc

2160

atgaccgcct tactgaaggt ttctagttgt gacaagaaca ctggtgatta ttacgaggac

2220

agttatgaag atatttcagc atacttgctg agtaaaaaca atgccattga accaagaagc

2280

ttctcccaga attcaagaca ccctagcact aggcaaaagc aatttaatgc caccacaatt

2340

ccagaaaatg acatagagaa gactgaccct tggtttgcac acagaacacc tatgcctaaa

2400

atacaaaatg tctcctctag tgatttgttg atgctcttgc gacagagtcc tactccacat

2460

gggctatcct tatctgatct ccaagaagcc aaatatgaga ctttttctga tgatccatca

2520

cctggagcaa tagacagtaa taacagcctg tctgaaatga cacacttcag gccacagctc

2580

catcacagtg gggacatggt atttacccct gagtcaggcc tccaattaag attaaatgag

2640

aaactgggga caactgcagc aacagagttg aagaaacttg atttcaaagt ttctagtaca

2700

tcaaataatc tgatttcaac aattccatca gacaatttgg cagcaggtac tgataataca

2760

agttccttag gacccccaag tatgccagtt cattatgata gtcaattaga taccactcta

2820

tttggcaaaa agtcatctcc ccttactgag tctggtggac ctctgagctt gagtgaagaa

2880

aataatgatt caaagttgtt agaatcaggt ttaatgaata gccaagaaag ttcatgggga

2940

aaaaatgtat cgtcaacaga gagtggtagg ttatttaaag ggaaaagagc tcatggacct

3000

gctttgttga ctaaagataa tgccttattc aaagttagca tctctttgtt aaagacaaac

3060

aaaacttcca ataattcagc aactaataga aagactcaca ttgatggccc atcattatta

3120

attgagaata gtccatcagt ctggcaaaat atattagaaa gtgacactga gtttaaaaaa

3180

gtgacacctt tgattcatga cagaatgctt atggacaaaa atgctacagc tttgaggcta

3240

aatcatatgt caaataaaac tacttcatca aaaaacatgg aaatggtcca acagaaaaaa

3300

gagggcccca ttccaccaga tgcacaaaat ccagatatgt cgttctttaa gatgctattc

3360

ttgccagaat cagcaaggtg gatacaaagg actcatggaa agaactctct gaactctggg

3420

caaggcccca gtccaaagca attagtatcc ttaggaccag aaaaatctgt ggaaggtcag

3480

aatttcttgt ctgagaaaaa caaagtggta gtaggaaagg gtgaatttac aaaggacgta

3540

ggactcaaag agatggtttt tccaagcagc agaaacctat ttcttactaa cttggataat

3600

ttacatgaaa ataatacaca caatcaagaa aaaaaaattc aggaagaaat agaaaagaag

3660

gaaacattaa tccaagagaa tgtagttttg cctcagatac atacagtgac tggcactaag

3720

aatttcatga agaacctttt cttactgagc actaggcaaa atgtagaagg ttcatatgac

3780

ggggcatatg ctccagtact tcaagatttt aggtcattaa atgattcaac aaatagaaca

3840

aagaaacaca cagctcattt ctcaaaaaaa ggggaggaag aaaacttgga aggcttggga

3900

aatcaaacca agcaaattgt agagaaatat gcatgcacca caaggatatc tcctaataca

3960

agccagcaga attttgtcac gcaacgtagt aagagagctt tgaaacaatt cagactccca

4020

ctagaagaaa cagaacttga aaaaaggata attgtggatg acacctcaac ccagtggtcc

4080

aaaaacatga aacatttgac cccgagcacc ctcacacaga tagactacaa tgagaaggag

4140

aaaggggcca ttactcagtc tcccttatca gattgcctta cgaggagtca tagcatccct

4200

caagcaaata gatctccatt acccattgca aaggtatcat catttccatc tattagacct

4260

atatatctga cccaggtcct attccaagac aactcttctc atcttccagc agcatcttat

4320

agaaagaaag attctggggt ccaagaaagc agtcatttct tacaaggagc caaaaaaaat

4380

aacctttctt tagccattct aaccttggag atgactggtg atcaaagaga ggttggctcc

4440

ctggggacaa gtgccacaaa ttcagtcaca tacaagaaag ttgagaacac tgttctcccg

4500

aaaccagact tgcccaaaac atctggcaaa gttgaattgc ttccaaaagt tcacatttat

4560

cagaaggacc tattccctac ggaaactagc aatgggtctc ctggccatct ggatctcgtg

4620

gaagggagcc ttcttcaggg aacagaggga gcgattaagt ggaatgaagc aaacagacct

4680

ggaaaagttc cctttctgag agtagcaaca gaaagctctg caaagactcc ctccaagcta

4740

ttggatcctc ttgcttggga taaccactat ggtactcaga taccaaaaga agagtggaaa

4800

tcccaagaga agtcaccaga aaaaacagct tttaagaaaa aggataccat tttgtccctg

4860

aacgcttgtg aaagcaatca tgcaatagca gcaataaatg agggacaaaa taagcccgaa

4920

atagaagtca cctgggcaaa gcaaggtagg actgaaaggc tgtgctctca aaacccacca

4980

gtcttgaaac gccatcaacg ggaaataact cgtactactc ttcagtcaga tcaagaggaa

5040

attgactatg atgataccat atcagttgaa atgaagaagg aagattttga catttatgat

5100

gaggatgaaa atcagagccc ccgcagcttt caaaagaaaa cacgacacta ttttattgct

5160

gcagtggaga ggctctggga ttatgggatg agtagctccc cacatgttct aagaaacagg

5220

gctcagagtg gcagtgtccc tcagttcaag aaagttgttt tccaggaatt tactgatggc

5280

tcctttactc agcccttata ccgtggagaa ctaaatgaac atttgggact cctggggcca

5340

tatataagag cagaagttga agataatatc atggtaactt tcagaaatca ggcctctcgt

5400

ccctattcct tctattctag ccttatttct tatgaggaag atcagaggca aggagcagaa

5460

cctagaaaaa actttgtcaa gcctaatgaa accaaaactt acttttggaa agtgcaacat

5520

catatggcac cccataaaga tgagtttgac tgcaaagcct gggcttattt ctctgatgtt

5580

gacctggaaa aagatgtgca ctcaggcctg attggacccc ttctggtctg cccacactaac

5640

acactgaacc ctgctcatgg gagacaagtg acagtacagg aatttgctct gtttttcacc

5700

atctttgatg agaccaaaag ctggtacttc actgaaaata tggaaagaaa ctgcagggct

5760

ccctgcaata tccagatgga agatcccact tttaaagaga attatcgctt ccatgcaatc

5820

aatggctaca taatggatac actacctggc ttagtaatgg ctcaggatca aaggattcga

5880

tggtatctgc tcagcatggg cagcaatgaa aacatccatt ctattcattt cagtggacat

5940

gtgttcactg tacgaaaaaa agaggagtat aaaatggcac tgtacaatct ctatccaggt

6000

gtttttgaga cagtggaaat gttaccatcc aaagctggaa tttggcgggt ggaatgcctt

6060

attggcgagc atctacatgc tgggatgagc acactttttc tggtgtacag caataagtgt

6120

cagactcccc tgggaatggc ttctggacac attagagatt ttcagattac agcttcagga

6180

caatatggac agtgggcccc aaagctggcc agacttcatt attccggatc aatcaatgcc

6240

tggagcacca aggagccctt ttcttggatc aaggtggatc tgttggcacc aatgattatt

6300

cacggcatca agacccagg tgcccgtcag aagttctcca gcctctacat ctctcagttt

6360

atcatcatgt atagtcttga tgggaagaag tggcagactt atcgaggaaa ttccactgga

6420

accttaatgg tcttctttgg caatgtggat tcatctggga taaaacacaa tatttttaac

6480

cctccaatta ttgctcgata catccgtttg cacccaactc attatagcat tcgcagcact

6540

cttcgcatgg agttgatggg ctgtgattta aatagttgca gcatgccatt gggaatggag

6600

agtaaagcaa tatcagatgc acagattact gcttcatcct actttaccaa tatgtttgcc

6660

acctggtctc cttcaaaagc tcgacttcac ctccaaggga ggagtaatgc ctggagacct

6720

caggtgaata atccaaaaga gtggctgcaa gtggacttcc agaagacaat gaaagtcaca

6780

ggagtaacta ctcagggagt aaaatctctg cttaccagca tgtatgtgaa ggagttcctc

6840

atctccagca gtcaagatgg ccatcagtgg actctctttt ttcagaatgg caaagtaaag

6900

gtttttcagg gaaatcaaga ctccttcaca cctgtggtga actctctaga cccaccgtta

6960

ctgactcgct accttcgaat tcacccccag agttgggtgc accagattgc cctgaggatg

7020

gaggttctgg gctgcgaggc acaggacctc tactga

7056

<210> 384

<211> 4425

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 384

atgcagattg agctgagcac ctgcttcttc ctgtgcctgc tgaggttctg cttctctgcc

60

accaggagat actacctggg ggctgtggag ctgagctggg actacatgca gtctgacctg

120

ggggagctgc ctgtggatgc caggttcccc cccagagtgc ccaagagctt ccccttcaac

180

acctctgtgg tgtacaagaa gaccctgttt gtggagttca ctgaccacct gttcaacatt

240

gccaagccca ggcccccctg gatgggcctg ctgggcccca ccatccaggc tgaggtgtat

300

gacactgtgg tgatcaccct gaagaacatg gccagccacc ctgtgagcct gcatgctgtg

360

ggggtgagct actggaaggc ctctgagggg gctgagtatg atgaccagac cagccagagg

420

gagaaggagg atgacaaggt gttccctggg ggcagccaca cctatgtgtg gcaggtgctg

480

aaggagaatg gccccatggc ctctgacccc ctgtgcctga cctacagcta cctgagccat

540

gtggacctgg tgaaggacct gaactctggc ctgattgggg ccctgctggt gtgcagggag

600

ggcagcctgg ccaaggagaa gacccagacc ctgcacaagt tcatcctgct gtttgctgtg

660

tttgatgagg gcaagagctg gcactctgaa accaagaaca gcctgatgca ggacagggat

720

gctgcctctg ccagggcctg gcccaagatg cacactgtga atggctatgt gaacaggagc

780

ctgcctggcc tgattggctg ccacaggaag tctgtgtact ggcatgtgat tggcatgggc

840

accacccctg aggtgcacag catcttcctg gagggccaca ccttcctggt caggaaccac

900

aggcaggcca gcctggagat cagccccatc accttcctga ctgcccagac cctgctgatg

960

gacctgggcc agttcctgct gttctgccac atcagcagcc accagcatga tggcatggag

1020

gcctatgtga aggtggacag ctgccctgag gagccccagc tgaggatgaa gaacaatgag

1080

gaggctgagg actatgatga tgacctgact gactctgaga tggatgtggt gaggtttgat

1140

gatgacaaca gccccagctt catccagatc aggtctgtgg ccaagaagca ccccaagacc

1200

tgggtgcact acattgctgc tgaggaggag gactgggact atgcccccct ggtgctggcc

1260

cctgatgaca ggagctacaa gagccagtac ctgaacaatg gcccccagag gattggcagg

1320

aagtacaaga aggtcaggtt catggcctac actgatgaaa ccttcaagac cagggaggcc

1380

atccagcatg agtctggcat cctgggcccc ctgctgtatg gggaggtggg ggacaccctg

1440

ctgatcatct tcaagaacca ggccagcagg ccctacaaca tctaccccca tggcatcact

1500

gatgtgaggc ccctgtacag caggaggctg cccaaggggg tgaagcacct gaaggacttc

1560

cccatcctgc ctggggagat cttcaagtac aagtggactg tgactgtgga ggatggcccc

1620

accaagtctg accccaggtg cctgaccaga tactacagca gctttgtgaa catggagagg

1680

gacctggcct ctggcctgat tggccccctg ctgatctgct acaaggagtc tgtggaccag

1740

aggggcaacc agatcatgtc tgacaagagg aatgtgatcc tgttctctgt gtttgatgag

1800

aacaggagct ggtacctgac tgagaacatc cagaggttcc tgcccaaccc tgctggggtg

1860

cagctggagg accctgagtt ccaggccagc aacatcatgc acagcatcaa tggctatgtg

1920

tttgacagcc tgcagctgtc tgtgtgcctg catgaggtgg cctactggta catcctgagc

1980

attggggccc agactgactt cctgtctgtg ttcttctctg gctacacctt caagcacaag

2040

atggtgtatg aggacaccct gaccctgttc cccttctctg gggagactgt gttcatgagc

2100

atggagaacc ctggcctgtg gattctgggc tgccacaact ctgacttcag gaacaggggc

2160

atgactgccc tgctgaaagt ctccagctgt gacaagaaca ctggggacta ctatgaggac

2220

agctatgagg acatctctgc ctacctgctg agcaagaaca atgccattga gcccaggagc

2280

ttcagccaga atgccactaa tgtgtctaac aacagcaaca ccagcaatga cagcaatgtg

2340

tctcccccag tgctgaagag gcaccagagg gagatcacca ggaccaccct gcagtctgac

2400

caggaggaga ttgactatga tgacaccatc tctgtggaga tgaagaagga ggactttgac

2460

atctacgacg aggacgagaa cccagcccc aggagcttcc agaagaagac caggcactac

2520

ttcattgctg ctgtggagag gctgtgggac tatggcatga gcagcagccc ccatgtgctg

2580

aggaacaggg cccagtctgg ctctgtgccc cagttcaaga aggtggtgtt ccaggagttc

2640

actgatggca gcttcaccca gcccctgtac agaggggagc tgaatgagca cctgggcctg

2700

ctgggcccct acatcagggc tgaggtggag gacaacatca tggtgacctt caggaaccag

2760

gccagcaggc cctacagctt ctacagcagc ctgatcagct atgaggagga ccagaggcag

2820

ggggctgagc ccaggaagaa ctttgtgaag cccaatgaaa ccaagaccta cttctggaag

2880

gtgcagcacc acatggcccc caccaaggat gagtttgact gcaaggcctg ggcctacttc

2940

tctgatgtgg acctggagaa ggatgtgcac tctggcctga ttggccccct gctggtgtgc

3000

cacaccaaca ccctgaaccc tgcccatggc aggcaggtga ctgtgcagga gtttgccctg

3060

ttcttcacca tctttgatga aaccaagagc tggtacttca ctgagaacat ggagaggaac

3120

tgcagggccc cctgcaacat ccagatggag gaccccacct tcaaggagaa ctacaggttc

3180

catgccatca atggctacat catggacacc ctgcctggcc tggtgatggc ccaggaccag

3240

aggatcaggt ggtacctgct gagcatgggc agcaatgaga acatccacag catccacttc

3300

tctggccatg tgttcactgt gaggaagaag gaggagtaca agatggccct gtacaacctg

3360

taccctgggg tgtttgagac tgtggagatg ctgcccagca aggctggcat ctggagggtg

3420

gagtgcctga ttggggagca cctgcatgct ggcatgagca ccctgttcct ggtgtacagc

3480

aacaagtgcc agacccccct gggcatggcc tctggccaca tcagggactt ccagatcact

3540

gcctctggcc agtatggcca gtgggccccc aagctggcca ggctgcacta ctctggcagc

3600

atcaatgcct ggagcaccaa ggagcccttc agctggatca aggtggacct gctggccccc

3660

atgatcatcc atggcatcaa gacccagggg gccaggcaga agttcagcag cctgtacatc

3720

agccagttca tcatcatgta cagcctggat ggcaagaagt ggcagaccta caggggcaac

3780

agcactggca ccctgatggt gttctttggc aatgtggaca gctctggcat caagcacaac

3840

atcttcaacc cccccatcat tgccagatac atcaggctgc accccaccca ctacagcatc

3900

aggagcaccc tgaggatgga gctgatgggc tgtgacctga acagctgcag catgcccctg

3960

ggcatggaga gcaaggccat ctctgatgcc cagatcactg ccagcagcta cttcaccaac

4020

atgtttgcca cctggagccc cagcaaggcc aggctgcacc tgcagggcag gagcaatgcc

4080

tggaggcccc aggtcaacaa ccccaaggag tggctgcagg tggacttcca gaagaccatg

4140

aaggtgactg gggtgaccac ccagggggtg aagagcctgc tgaccagcat gtatgtgaag

4200

gagttcctga tcagcagcag ccaggatggc caccagtgga ccctgttctt ccagaatggc

4260

aaggtgaagg tgttccaggg caaccaggac agcttcaccc ctgtggtgaa cagcctggac

4320

ccccccctgc tgaccagata cctgaggatt cacccccaga gctgggtgca ccagattgcc

4380

ctgaggatgg aggtgctggg ctgtgaggcc caggacctgt actga

4425

<210> 385

<211> 1474

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polypeptide

<400> 385

Met Gln Ile Glu Leu Ser Thr Cys Phe Phe Leu Cys Leu Leu Arg Phe

1 5 10 15

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

20 25 30

Trp Asp Tyr Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg

35 40 45

Phe Pro Pro Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val

50 55 60

Tyr Lys Lys Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile

65 70 75 80

Ala Lys Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln

85 90 95

Ala Glu Val Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser

100 105 110

His Pro Val Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser

115 120 125

Glu Gly Ala Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp

130 135 140

Asp Lys Val Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu

145 150 155 160

Lys Glu Asn Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser

165 170 175

Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile

180 185 190

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

195 200 205

Gln Thr Leu His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly

210 215 220

Lys Ser Trp His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp

225 230 235 240

Ala Ala Ser Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr

245 250 255

Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val

260 265 270

Tyr Trp His Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile

275 280 285

Phe Leu Glu Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser

290 295 300

Leu Glu Ile Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met

305 310 315 320

Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln His

325 330 335

Asp Gly Met Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro

340 345 350

Gln Leu Arg Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp

355 360 365

Leu Thr Asp Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser

370 375 380

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

385 390 395 400

Trp Val His Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro

405 410 415

Leu Val Leu Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn

420 425 430

Asn Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met

435 440 445

Ala Tyr Thr Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu

450 455 460

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

465 470 475 480

Leu Ile Ile Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro

485 490 495

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

500 505 510

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

515 520 525

Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp

530 535 540

Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg

545 550 555 560

Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu

565 570 575

Ser Val Asp Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val

580 585 590

Ile Leu Phe Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu

595 600 605

Asn Ile Gln Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp

610 615 620

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

625 630 635 640

Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp

645 650 655

Tyr Ile Leu Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe

660 665 670

Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr

675 680 685

Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro

690 695 700

Gly Leu Trp Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly

705 710 715 720

Met Thr Ala Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp

725 730 735

Tyr Tyr Glu Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys

740 745 750

Asn Asn Ala Ile Glu Pro Arg Ser Phe Ser Gln Asn Ala Thr Asn Val

755 760 765

Ser Asn Asn Ser Asn Thr Ser Asn Asp Ser Asn Val Ser Pro Pro Val

770 775 780

Leu Lys Arg His Gln Arg Glu Ile Thr Arg Thr Thr Leu Gln Ser Asp

785 790 795 800

Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys

805 810 815

Glu Asp Phe Asp Ile Tyr Asp Glu Asp Glu Asn Gln Ser Pro Arg Ser

820 825 830

Phe Gln Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu

835 840 845

Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala

850 855 860

Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe

865 870 875 880

Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu

885 890 895

His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn

900 905 910

Ile Met Val Thr Phe Arg Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr

915 920 925

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

930 935 940

Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys

945 950 955 960

Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala

965 970 975

Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val His Ser Gly

980 985 990

Leu Ile Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala

995 1000 1005

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

1010 1015 1020

Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu

1025 1030 1035

Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr

1040 1045 1050

Phe Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile Met

1055 1060 1065

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

1070 1075 1080

Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile

1085 1090 1095

His Phe Ser Gly His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr

1100 1105 1110

Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val

1115 1120 1125

Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu Cys Leu

1130 1135 1140

Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu Val

1145 1150 1155

Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His

1160 1165 1170

Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp

1175 1180 1185

Ala Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala

1190 1195 1200

Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu

1205 1210 1215

Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln

1220 1225 1230

Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser

1235 1240 1245

Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly

1250 1255 1260

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

1265 1270 1275

His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu

1280 1285 1290

His Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu

1295 1300 1305

Met Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu

1310 1315 1320

Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe

1325 1330 1335

Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu His

1340 1345 1350

Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val Asn Asn Pro

1355 1360 1365

Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val Thr

1370 1375 1380

Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr

1385 1390 1395

Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Gln Trp

1400 1405 1410

Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn

1415 1420 1425

Gln Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu

1430 1435 1440

Leu Thr Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln

1445 1450 1455

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

1460 1465 1470

Tyr

<210> 386

<211> 5052

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 386

atgcaaatag agctctccac ctgcttcttt ctgtgccttt tgcgattctg ctttagtgcc

60

accagaagat actacctggg tgcagtggaa ctgtcatggg actatatgca aagtgatctc

120

ggtgagctgc ctgtggacgc aagatttcct cctagagtgc caaaatcttt tccattcaac

180

acctcagtcg tgtacaaaaa gactctgttt gtagaattca cggatcacct tttcaacatc

240

gctaagccaa ggccaccctg gatgggtctg ctaggtccta ccatccaggc tgaggtttat

300

gatacagtgg tcattacact taagaacatg gcttcccatc ctgtcagtct tcatgctgtt

360

ggtgtatcct actggaaagc ttctgaggga gctgaatatg atgatcagac cagtcaaagg

420

gagaaagaag atgataaagt cttccctggt ggaagccata catatgtctg gcaggtcctg

480

aaagagaatg gtccaatggc ctctgaccca ctgtgcctta cctactcata tctttctcat

540

gtggacctgg taaaagactt gaattcaggc ctcattggag ccctactagt atgtagagaa

600

gggagtctgg ccaaggaaaa gacacagacc ttgcacaaat ttatactact ttttgctgta

660

tttgatgaag ggaaaagttg gcactcagaa acaaagaact ccttgatgca ggatagggat

720

gctgcatctg ctcggggcctg gcctaaaatg cacacagtca atggttatgt aaacaggtct

780

ctgccaggtc tgattggatg ccacaggaaa tcagtctatt ggcatgtgat tggaatgggc

840

accactcctg aagtgcactc aatattcctc gaaggtcaca catttcttgt gaggaaccat

900

cgccaggcgt ccttggaaat ctcgccaata actttcctta ctgctcaaac actcttgatg

960

gaccttggac agtttctact gttttgtcat atctcttccc accaacatga tggcatggaa

1020

gcttatgtca aagtagacag ctgtccagag gaaccccaac tacgaatgaa aaataatgaa

1080

gaagcggaag actatgatga tgatcttact gattctgaaa tggatgtggt caggtttgat

1140

gatgacaact ctccttcctt tatccaaatt cgctcagttg ccaagaagca tcctaaaact

1200

tgggtacatt acattgctgc tgaagaggag gactgggact atgctccctt agtcctcgcc

1260

cccgatgaca gaagttataa aagtcaatat ttgaacaatg gccctcagcg gattggtagg

1320

aagtacaaaa aagtccgatt tatggcatac acagatgaaa cctttaagac tcgtgaagct

1380

attcagcatg aatcaggaat cttgggacct ttactttatg gggaagttgg agacacactg

1440

ttgattatat ttaagaatca agcaagcaga ccatataaca tctaccctca cggaatcact

1500

gatgtccgtc ctttgtattc aaggatta ccaaaaggtg taaaacattt gaaggatttt

1560

ccaattctgc caggagaaat attcaaatat aaatggacag tgactgtaga agatgggcca

1620

actaaatcag atcctcggtg cctgacccgc tattactcta gtttcgttaa tatggagaga

1680

gatctagctt caggactcat tggccctctc ctcatctgct acaaagaatc tgtagatcaa

1740

agaggaaacc agataatgtc agacaagagg aatgtcatcc tgttttctgt atttgatgag

1800

aaccgaagct ggtacctcac agagaatata caacgctttc tccccaatcc agctggagtg

1860

cagcttgagg atccagagtt ccaagcctcc aacatcatgc acagcatcaa tggctatgtt

1920

tttgatagtt tgcagttgtc agtttgtttg catgaggtgg catactggta cattctaagc

1980

attggagcac agactgactt cctttctgtc ttcttctctg gatatacctt caaacacaaa

2040

atggtctatg aagacacact caccctattc ccattctcag gagaaactgt cttcatgtcg

2100

atggaaaacc caggtctatg gattctgggg tgccacaact cagactttcg gaacagaggc

2160

atgaccgcct tactgaaggt ttctagttgt gacaagaaca ctggtgatta ttacgaggac

2220

agttatgaag atatttcagc atacttgctg agtaaaaaca atgccattga accaagaagc

2280

ttctctcaaa acccaccagt cttgaaacgc catcaacggg aaataactcg tactactctt

2340

cagtcagatc aagaggaaat tgactatgat gataccatat cagttgaaat gaagaaggaa

2400

gattttgaca tttatgatga ggatgaaaat cagagccccc gcagctttca aaagaaaaca

2460

cgacactatt ttattgctgc agtggagagg ctctgggatt atgggatgag tagctcccca

2520

catgttctaa gaaacagggc tcagagtggc agtgtccctc agttcaagaa agttgttttc

2580

caggaattta ctgatggctc ctttactcag cccttatacc gtggagaact aaatgaacat

2640

ttgggactcc tggggccata tataagagca gaagttgaag ataatatcat ggtaactttc

2700

agaaatcagg cctctcgtcc ctattccttc tattctagcc ttatttctta tgaggaagat

2760

cagaggcaag gagcagaacc tagaaaaaac tttgtcaagc ctaatgaaac caaaacttac

2820

ttttggaaag tgcaacatca tatggcaccc actaaagatg agtttgactg caaagcctgg

2880

gcttatttct ctgatgttga cctggaaaaa gatgtgcact caggcctgat tggacccctt

2940

ctggtctgcc acactaacac actgaaccct gctcatggga gacaagtgac agtacaggaa

3000

tttgctctgt ttttcaccat ctttgatgag accaaaagct ggtacttcac tgaaaatatg

3060

gaaagaaact gcagggctcc ctgcaatatc cagatggaag atcccacttt taaagagaat

3120

tatcgcttcc atgcaatcaa tggctacata atggatacac tacctggctt agtaatggct

3180

caggatcaaa ggattcgatg gtatctgctc agcatgggca gcaatgaaaa catccattct

3240

attcatttca gtggacatgt gttcactgta cgaaaaaaag aggagtataa aatggcactg

3300

tacaatctct atccaggtgt ttttgagaca gtggaaatgt taccatccaa agctggaatt

3360

tggcgggtgg aatgccttat tggcgagcat ctacatgctg ggatgagcac actttttctg

3420

gtgtacagca ataagtgtca gactcccctg ggaatggctt ctggacacat tagagatttt

3480

cagattacag cttcaggaca atatggacag tgggccccaa agctggccag acttcattat

3540

tccggatcaa tcaatgcctg gagcaccaag gagccctttt cttggatcaa ggtggatctg

3600

ttggcaccaa tgattattca cggcatcaag acccagggtg cccgtcagaa gttctccagc

3660

ctctacatct ctcagtttat catcatgtat agtcttgatg ggaagaagtg gcagacttat

3720

cgaggaaatt ccactggaac cttaatggtc ttctttggca atgtggattc atctgggata

3780

aaacacaata tttttaaccc tccaattatt gctcgataca tccgtttgca cccaactcat

3840

tatagcattc gcagcactct tcgcatggag ttgatgggct gtgatttaaa tagttgcagc

3900

atgccattgg gaatggagag taaagcaata tcagatgcac agattactgc ttcatcctac

3960

tttaccaata tgtttgccac ctggtctcct tcaaaagctc gacttcacct ccaagggagg

4020

agtaatgcct ggagaacctca ggtgaataat ccaaaagagt ggctgcaagt ggacttccag

4080

aagacaatga aagtcacagg agtaactact cagggagtaa aatctctgct taccagcatg

4140

tatgtgaagg agttcctcat ctccagcagt caagatggcc atcagtggac tctctttttt

4200

cagaatggca aagtaaaggt ttttcaggga aatcaagact ccttcacacc tgtggtgaac

4260

tctctagacc caccgttact gactcgctac cttcgaattc acccccagag ttgggtgcac

4320

cagattgccc tgaggatgga ggttctgggc tgcgaggcac aggacctcta cgacaaaact

4380

cacacatgcc caccgtgccc agctccagaa ctcctgggcg gaccgtcagt cttcctcttc

4440

cccccaaaac ccaaggacac cctcatgatc tcccggaccc ctgaggtcac atgcgtggtg

4500

gtggacgtga gccacgaaga ccctgaggtc aagttcaact ggtacgtgga cggcgtggag

4560

gtgcataatg ccaagacaaa gccgcgggag gagcagtaca acagcacgta ccgtgtggtc

4620

agcgtcctca ccgtcctgca ccaggactgg ctgaatggca aggagtacaa gtgcaaggtc

4680

tccaacaaag ccctcccagc ccccatcgag aaaaccatct ccaaagccaa agggcagccc

4740

cgagaaccac aggtgtacac cctgccccca tcccgggatg agctgaccaa gaaccaggtc

4800

agcctgacct gcctggtcaa aggcttctat cccagcgaca tcgccgtgga gtggggagagc

4860

aatgggcagc cggagaacaa ctacaagacc acgcctcccg tgttggactc cgacggctcc

4920

ttcttcctct acagcaagct caccgtggac aagagcaggt ggcagcaggg gaacgtcttc

4980

tcatgctccg tgatgcatga ggctctgcac aaccactaca cgcagaagag cctctccctg

5040

tctccgggta aa

5052

<210> 387

<211> 4374

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 387

atgcagatcg agctgtctac ctgcttcttc ctgtgcctgc tgcggttctg cttcagcgcc

60

accagaagat attacctggg cgccgtggaa ctgagctggg actacatgca gtctgacctg

120

ggagagctgc ccgtggacgc tagatttcct ccaagagtgc ccaagagctt ccccttcaac

180

acctccgtgg tgtacaagaa aaccctgttc gtggaattca ccgaccacct gttcaatatc

240

gccaagcctc ggcctccttg gatgggactg ctgggaccta caattcaggc cgaggtgtac

300

gacaccgtgg tcatcaccct gaagaacatg gccagccatc ctgtgtctct gcacgccgtg

360

ggagtgtctt attggaaggc ttctgagggc gccgagtacg acgatcagac aagccagaga

420

gagaaagagg acgacaaggt tttccctggc ggcagccaca cctatgtctg gcaggtcctg

480

aaagaaaacg gccctatggc ctccgatcct ctgtgcctga catacagcta cctgagccac

540

gtggacctgg tcaaggacct gaattctggc ctgatcggag ccctgctcgt gtgtagagaa

600

ggcagcctgg ccaaagagaa aacccagaca ctgcacaagt tcatcctgct gttcgccgtg

660

ttcgacgagg gcaagagctg gcacagcgag acaaagaaca gcctgatgca ggacagggat

720

gccgcctctg ctagagcttg gcctaagatg cacaccgtga acggctacgt gaacagaagc

780

ctgcctggac tgatcggctg ccacagaaag tccgtgtact ggcacgtgat cggcatgggc

840

acaacacctg aggtgcacag catctttctg gaaggccaca ccttcctcgt gcggaaccac

900

agacaggcca gcctggaaat cagccctatc accttcctga ccgctcagac cctgctgatg

960

gatctgggcc agtttctgct gttctgccac atcagctccc accagcacga tggcatggaa

1020

gcctacgtga aggtggacag ctgccccgaa gaaccccagc tgcggatgaa gaacaacgag

1080

gaagccgagg actacgacga cgacctgacc gactctgaga tggacgtcgt cagattcgac

1140

gacgataaca gccccagctt catccagatc agaagcgtgg ccaagaagca ccccaagacc

1200

tgggtgcact atatcgccgc cgaggaagag gactgggatt acgctcctct ggtgctggcc

1260

cctgacgaca gaagctacaa gagccagtac ctgaacaacg gccctcagcg gatcggccgg

1320

aagtataaga aagtgcggtt catggcctac accgacgaga cattcaagac cagagaggcc

1380

atccagcacg agagcggaat tctgggccct ctgctgtatg gcgaagtggg cgatacactg

1440

ctgatcatct tcaagaacca ggccagcaga ccctacaaca tctaccctca cggcatcacc

1500

gatgtgcggc ccctgtattc tagaaggctg cccaagggcg tgaagcacct gaaggacttc

1560

cctatcctgc ctggcgagat tttcaagtac aagtggaccg tgaccgtgga agatggcccc

1620

accaagagcg accctagatg tctgacacgg tactacagca gcttcgtgaa catggaacgc

1680

gacctggcca gcggcctgat tggacctctg ctgatctgct acaaagaaag cgtggaccag

1740

cggggcaacc agatcatgag cgacaagcgg aacgtgatcc tgtttagcgt gttcgatgag

1800

aaccggtcct ggtatctgac cgagaacatc cagcggtttc tgcccaatcc tgccggggtg

1860

caactggaag atcctgagtt ccaggcaagc aacatcatgc actccatcaa tggctatgtg

1920

ttcgacagcc tgcagctgag cgtgtgcctg cacgaagtgg cctactggta catcctgagc

1980

attggcgccc agaccgactt cctgtccgtg ttctttagcg gctacacctt caagcacaag

2040

atggtgtacg aggataccct gacactgttc ccattcagcg gcgagacagt gttcatgagc

2100

atggaaaacc ccggcctgtg gattctgggc tgtcacaaca gcgacttccg gaacagaggc

2160

atgacagccc tgctgaaggt gtccagctgc gacaagaaca ccggcgacta ctacgaggac

2220

agctatgagg acatcagcgc ctacctgctg agcaagaaca atgccatcga gcctcggagc

2280

ttcagccaga atcctcctgt gctgaagcgg caccagcgcg agatcaccag aacaaccctg

2340

cagagcgacc aagaggaaat cgattacgac gacaccatca gcgtcgagat gaagaaagaa

2400

gatttcgaca tctacgacga ggacgagaat cagagcccca gaagctttca gaaaaagacc

2460

cggcactact tcattgccgc cgtcgagaga ctgtgggact acggcatgtc tagcagccct

2520

cacgtgctga gaaatagagc ccagagcggc agcgtgcccc agttcaagaa agtggtgttc

2580

caagagttca ccgacggcag cttcacccag ccactgtata gaggcgagct gaacgagcat

2640

ctgggcctgc tgggccctta tatcagagcc gaagtggaag ataacatcat ggtcaccttc

2700

cggaatcagg ctagccggcc ttacagcttc tacagctccc tgatcagcta cgaagaggac

2760

cagagacagg gcgctgagcc cagaaagaac ttcgtgaagc ccaacgagac taagacctac

2820

ttttggaagg tgcagcacca catggcccct acaaaggacg agttcgactg caaagcctgg

2880

gcctacttct ccgatgtgga tctggaaaag gacgtgcaca gcgggctcat cggaccactg

2940

cttgtgtgcc acaccaacac actgaacccc gctcacggca gacaagtgac agtgcaagag

3000

ttcgccctgt tcttcaccat cttcgacgaa acaaagagct ggtacttcac cgagaatatg

3060

gaacggaact gcagagcccc ttgcaacatc cagatggaag atcccacctt caaagagaac

3120

taccggttcc acgccatcaa cggctacatc atggacacac tgcccggcct ggttatggcc

3180

caggatcaga gaatccggtg gtatctgctg tccatgggct ccaacgagaa tatccacagc

3240

atccacttca gcggccacgt gttcaccgtg cggaaaaaag aagagtacaa aatggccctg

3300

tacaatctgt accctggggt gttcgaaacc gtggaaatgc tgccttccaa ggccggcatt

3360

tggagagtgg aatgtctgat tggagagcac ctccacgccg gaatgagcac cctgtttctg

3420

gtgtacagca acaagtgtca gacccctctc ggcatggcct ctggacacat cagagacttc

3480

cagatcaccg cctctggcca gtacggacag tgggctccta aactggctcg gctgcactac

3540

agcggcagca tcaatgcctg gtccaccaaa gagcccttca gctggatcaa ggtggacctg

3600

ctggctccca tgatcatcca cggaatcaag acccagggcg cgacagaa gttcagcagc

3660

ctgtacatca gccagttcat catcatgtac agcctggacg gcaagaagtg gcagacctac

3720

agaggcaaca gcaccggcac actcatggtg ttcttcggca acgtggactc cagcggcatt

3780

aagcacaaca tcttcaaccc tccaatcatt gcccggtaca tccggctgca ccccacacac

3840

tacagcatcc ggtctaccct gagaatggaa ctgatgggct gcgacctgaa cagctgctct

3900

atgcccctcg gaatggaaag caaggccatc agcgacgccc agatcacagc cagcagctac

3960

ttcaccaaca tgttcgccac ttggagcccc tccaaggcta gactgcatct gcagggcaga

4020

agcaacgctt ggaggcccca agtgaacaac cccaaagagt ggctgcaggt tgactttcaa

4080

aagaccatga aagtgaccgg cgtgaccaca cagggcgtca agtctctgct gacctctatg

4140

tacgtgaaag agttcctgat ctccagcagc caggacggcc atcagtggac cctgtttttc

4200

cagaacggca aagtgaaagt gttccagggc aatcaggaca gcttcacacc cgtggtcaat

4260

tctctggacc ctccactgct gaccagatac ctgcggattc accctcagtc ttgggtgcac

4320

cagatcgctc tgcggatgga agtgctgggc tgtgaagctc aggacctcta ctag

4374

<210> 388

<211> 4980

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 388

atgcagatcg agctgagcac ctgcttcttc ctgtgcctgc tgcgcttctg cttcagcgcc

60

acccgccgct actacctggg cgccgtggag ctgagctggg actacatgca gagcgacctg

120

ggcgagctgc ccgtggacgc ccgcttcccc ccccgcgtgc ccaagagctt ccccttcaac

180

accagcgtgg tgtacaagaa gaccctgttc gtggagttca ccgaccacct gttcaacatc

240

gccaagcccc gccccccctg gatgggcctg ctgggcccca ccatccaggc cgaggtgtac

300

gacaccgtgg tgatcaccct gaagaacatg gccagccacc ccgtgagcct gcacgccgtg

360

ggcgtgagct actggaaggc cagcgagggc gccgagtacg acgaccagac cagccagcgc

420

gagaaggagg acgacaaggt gttccccggc ggcagccaca cctacgtgtg gcaggtgctg

480

aaggagaacg gccccatggc cagcgacccc ctgtgcctga cctacagcta cctgagccac

540

gtggacctgg tgaaggacct gaacagcggc ctgatcggcg ccctgctggt gtgccgcgag

600

ggcagcctgg ccaaggagaa gacccagacc ctgcacaagt tcatcctgct gttcgccgtg

660

ttcgacgagg gcaagagctg gcacagcgag accaagaaca gcctgatgca ggaccgcgac

720

gccgccagcg cccgcgcctg gcccaagatg cacaccgtga acggctacgt gaaccgcagc

780

ctgcccggcc tgatcggctg ccaccgcaag agcgtgtact ggcacgtgat cggcatgggc

840

accacccccg aggtgcacag catcttcctg gagggccaca ccttcctggt gcgcaaccac

900

cgccaggcca gcctggagat cagccccatc accttcctga ccgcccagac cctgctgatg

960

gacctgggcc agttcctgct gttctgccac atcagcagcc accagcacga cggcatggag

1020

gcctacgtga aggtggacag ctgccccgag gagccccagc tgcgcatgaa gaacaacgag

1080

gaggccgagg actacgacga cgacctgacc gacagcgaga tggacgtggt gcgcttcgac

1140

gacgacaaca gccccagctt catccagatc cgcagcgtgg ccaagaagca ccccaagacc

1200

tgggtgcact acatcgccgc cgaggaggag gactgggact acgcccccct ggtgctggcc

1260

cccgacgacc gcagctacaa gagccagtac ctgaacaacg gcccccagcg catcggccgc

1320

aagtacaaga aggtgcgctt catggcctac accgacgaga ccttcaagac ccgcgaggcc

1380

atccagcacg agagcggcat cctgggcccc ctgctgtacg gcgaggtggg cgacaccctg

1440

ctgatcatct tcaagaacca ggccagccgc ccctacaaca tctaccccca cggcatcacc

1500

gacgtgcgcc ccctgtacag ccgccgcctg cccaagggcg tgaagcacct gaaggacttc

1560

cccatcctgc ccggcgagat cttcaagtac aagtggaccg tgaccgtgga ggacggcccc

1620

accaagagcg acccccgctg cctgacccgc tactacagca gcttcgtgaa catggagcgc

1680

gacctggcca gcggcctgat cggccccctg ctgatctgct acaagggagag cgtggaccag

1740

cgcggcaacc agatcatgag cgacaagcgc aacgtgatcc tgttcagcgt gttcgacgag

1800

aaccgcagct ggtacctgac cgagaacatc cagcgcttcc tgcccaaccc cgccggcgtg

1860

cagctggagg accccgagtt ccaggccagc aacatcatgc acagcatcaa cggctacgtg

1920

ttcgacagcc tgcagctgag cgtgtgcctg cacgaggtgg cctactggta catcctgagc

1980

atcggcgccc agaccgactt cctgagcgtg ttcttcagcg gctacacctt caagcacaag

2040

atggtgtacg aggacaccct gaccctgttc cccttcagcg gcgagaccgt gttcatgagc

2100

atggagaacc ccggcctgtg gatcctgggc tgccacaaca gcgacttccg caaccgcggc

2160

atgaccgccc tgctgaaggt gagcagctgc gacaagaaca ccggcgacta ctacgaggac

2220

agctacgagg acatcagcgc ctacctgctg agcaagaaca acgccatcga gccccgcagc

2280

ttcagccaga acagccgcca ccccagcacc cgccagaagc agttcaacgc caccaccatc

2340

cccgagaacg acatcgagaa gaccgacccc tggttcgccc accgcacccc catgcccaag

2400

atccagaacg tgagcagcag cgacctgctg atgctgctgc gccagagccc caccccccac

2460

ggcctgagcc tgagcgacct gcaagaggcc aagtacgaga ccttcagcga cgaccccagc

2520

cccggcgcca tcgacagcaa caacagcctg agcgagatga cccacttccg cccccagctg

2580

caccacagcg gcgacatggt gttcaccccc gagagcggcc tgcagctgcg cctgaacgag

2640

aagctgggca ccaccgccgc caccgagctg aagaagctgg acttcaaggt gagcagcacc

2700

agcaacaacc tgatcagcac catccccagc gacaacctgg ccgccggcac cgacaacacc

2760

agcagcctgg gcccccccag catgcccgtg cactacgaca gccagctgga caccaccctg

2820

ttcggcaaga agagcagccc cctgaccgag agcggcggcc ccctgagcct gagcgaggag

2880

aacaacgaca gcaagctgcc ccccgtgctg aagcgccacc agcgcgagat cacccgcacc

2940

accctgcaga gcgaccagga ggagatcgac tacgacgaca ccatcagcgt ggagatgaag

3000

aaggaggact tcgacatcta cgacgaggac gagaaccaga gcccccgcag cttccagaag

3060

aagacccgcc actacttcat cgccgccgtg gagcgcctgt gggactacgg catgagcagc

3120

agcccccacg tgctgcgcaa ccgcgcccag agcggcagcg tgccccagtt caagaaggtg

3180

gtgttccagg agttcaccga cggcagcttc acccagcccc tgtaccgcgg cgagctgaac

3240

gagcacctgg gcctgctggg cccctacatc cgcgccgagg tggaggacaa catcatggtg

3300

accttccgca accaggccag ccgcccctac agcttctaca gcagcctgat cagctacgag

3360

gaggaccagc gccagggcgc cgagccccgc aagaacttcg tgaagcccaa cgagaccaag

3420

acctacttct ggaaggtgca gcaccacatg gcccccacca aggacgagtt cgactgcaag

3480

gcctgggcct acttcagcga cgtggacctg gagaaggacg tgcacagcgg cctgatcggc

3540

cccctgctgg tgtgccacac caacaccctg aaccccgccc acggccgcca ggtgaccgtg

3600

caggagttcg ccctgttctt caccatcttc gacgagacca agagctggta cttcaccgag

3660

aacatggagc gcaactgccg cgccccctgc aacatccaga tggaggaccc caccttcaag

3720

gagaactacc gcttccacgc catcaacggc tacatcatgg acaccctgcc cggcctggtg

3780

atggcccagg accagcgcat ccgctggtac ctgctgagca tgggcagcaa cgagaacatc

3840

cacagcatcc acttcagcgg ccacgtgttc accgtgcgca agaagggagga gtacaagatg

3900

gccctgtaca acctgtaccc cggcgtgttc gagaccgtgg agatgctgcc cagcaaggcc

3960

ggcatctggc gcgtggagtg cctgatcggc gagcacctgc acgccggcat gagcaccctg

4020

ttcctggtgt acagcaacaa gtgccagacc cccctgggca tggccagcgg ccacatccgc

4080

gacttccaga tcaccgccag cggccagtac ggccagtggg cccccaagct ggcccgcctg

4140

cactacagcg gcagcatcaa cgcctggagc accaaggagc ccttcagctg gatcaaggtg

4200

gacctgctgg cccccatgat catccacggc atcaagaccc agggcgcccg ccagaagttc

4260

agcagcctgt acatcagcca gttcatcatc atgtacagcc tggacggcaa gaagtggcag

4320

acctaccgcg gcaacagcac cggcaccctg atggtgttct tcggcaacgt ggacagcagc

4380

ggcatcaagc acaacatctt caaccccccc atcatcgccc gctacatccg cctgcacccc

4440

acccactaca gcatccgcag caccctgcgc atggagctga tgggctgcga cctgaacagc

4500

tgcagcatgc ccctgggcat ggagagcaag gccatcagcg acgcccagat caccgccagc

4560

agctacttca ccaacatgtt cgccacctgg agccccagca aggcccgcct gcacctgcaa

4620

ggccgcagca acgcctggcg cccccaggtg aacaacccca aggagtggct gcaggtggac

4680

ttccagaaga ccatgaaggt gaccggcgtg accacccagg gcgtgaagag cctgctgacc

4740

agcatgtacg tgaaggagtt cctgatcagc agcagccagg acggccacca gtggaccctg

4800

ttcttccaga acggcaaggt gaaggtgttc cagggcaacc aggacagctt cacccccgtg

4860

gtgaacagcc tggacccccc cctgctgacc cgctacctgc gcatccaccc ccagagctgg

4920

gtgcaccaga tcgccctgcg catggaggtg ctgggctgcg aggcccagga cctgtactaa

4980

<210> 389

<211> 7056

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 389

atgcagatcg agctgagcac ctgcttcttc ctgtgcctgc tgcgcttctg cttcagcgcc

60

acccgccgct actacctggg cgccgtggag ctgagctggg actacatgca gagcgacctg

120

ggcgagctgc ccgtggacgc ccgcttcccc ccccgcgtgc ccaagagctt ccccttcaac

180

accagcgtgg tgtacaagaa gaccctgttc gtggagttca ccgaccacct gttcaacatc

240

gccaagcccc gccccccctg gatgggcctg ctgggcccca ccatccaggc cgaggtgtac

300

gacaccgtgg tgatcaccct gaagaacatg gccagccacc ccgtgagcct gcacgccgtg

360

ggcgtgagct actggaaggc cagcgagggc gccgagtacg acgaccagac cagccagcgc

420

gagaaggagg acgacaaggt gttccccggc ggcagccaca cctacgtgtg gcaggtgctg

480

aaggagaacg gccccatggc cagcgacccc ctgtgcctga cctacagcta cctgagccac

540

gtggacctgg tgaaggacct gaacagcggc ctgatcggcg ccctgctggt gtgccgcgag

600

ggcagcctgg ccaaggagaa gacccagacc ctgcacaagt tcatcctgct gttcgccgtg

660

ttcgacgagg gcaagagctg gcacagcgag accaagaaca gcctgatgca ggaccgcgac

720

gccgccagcg cccgcgcctg gcccaagatg cacaccgtga acggctacgt gaaccgcagc

780

ctgcccggcc tgatcggctg ccaccgcaag agcgtgtact ggcacgtgat cggcatgggc

840

accacccccg aggtgcacag catcttcctg gagggccaca ccttcctggt gcgcaaccac

900

cgccaggcca gcctggagat cagccccatc accttcctga ccgcccagac cctgctgatg

960

gacctgggcc agttcctgct gttctgccac atcagcagcc accagcacga cggcatggag

1020

gcctacgtga aggtggacag ctgccccgag gagccccagc tgcgcatgaa gaacaacgag

1080

gaggccgagg actacgacga cgacctgacc gacagcgaga tggacgtggt gcgcttcgac

1140

gacgacaaca gccccagctt catccagatc cgcagcgtgg ccaagaagca ccccaagacc

1200

tgggtgcact acatcgccgc cgaggaggag gactgggact acgcccccct ggtgctggcc

1260

cccgacgacc gcagctacaa gagccagtac ctgaacaacg gcccccagcg catcggccgc

1320

aagtacaaga aggtgcgctt catggcctac accgacgaga ccttcaagac ccgcgaggcc

1380

atccagcacg agagcggcat cctgggcccc ctgctgtacg gcgaggtggg cgacaccctg

1440

ctgatcatct tcaagaacca ggccagccgc ccctacaaca tctaccccca cggcatcacc

1500

gacgtgcgcc ccctgtacag ccgccgcctg cccaagggcg tgaagcacct gaaggacttc

1560

cccatcctgc ccggcgagat cttcaagtac aagtggaccg tgaccgtgga ggacggcccc

1620

accaagagcg acccccgctg cctgacccgc tactacagca gcttcgtgaa catggagcgc

1680

gacctggcca gcggcctgat cggccccctg ctgatctgct acaagggagag cgtggaccag

1740

cgcggcaacc agatcatgag cgacaagcgc aacgtgatcc tgttcagcgt gttcgacgag

1800

aaccgcagct ggtacctgac cgagaacatc cagcgcttcc tgcccaaccc cgccggcgtg

1860

cagctggagg accccgagtt ccaggccagc aacatcatgc acagcatcaa cggctacgtg

1920

ttcgacagcc tgcagctgag cgtgtgcctg cacgaggtgg cctactggta catcctgagc

1980

atcggcgccc agaccgactt cctgagcgtg ttcttcagcg gctacacctt caagcacaag

2040

atggtgtacg aggacaccct gaccctgttc cccttcagcg gcgagaccgt gttcatgagc

2100

atggagaacc ccggcctgtg gatcctgggc tgccacaaca gcgacttccg caaccgcggc

2160

atgaccgccc tgctgaaggt gagcagctgc gacaagaaca ccggcgacta ctacgaggac

2220

agctacgagg acatcagcgc ctacctgctg agcaagaaca acgccatcga gccccgcagc

2280

ttcagccaga acagccgcca ccccagcacc cgccagaagc agttcaacgc caccaccatc

2340

cccgagaacg acatcgagaa gaccgacccc tggttcgccc accgcacccc catgcccaag

2400

atccagaacg tgagcagcag cgacctgctg atgctgctgc gccagagccc caccccccac

2460

ggcctgagcc tgagcgacct gcaagaggcc aagtacgaga ccttcagcga cgaccccagc

2520

cccggcgcca tcgacagcaa caacagcctg agcgagatga cccacttccg cccccagctg

2580

caccacagcg gcgacatggt gttcaccccc gagagcggcc tgcagctgcg cctgaacgag

2640

aagctgggca ccaccgccgc caccgagctg aagaagctgg acttcaaggt gagcagcacc

2700

agcaacaacc tgatcagcac catccccagc gacaacctgg ccgccggcac cgacaacacc

2760

agcagcctgg gcccccccag catgcccgtg cactacgaca gccagctgga caccaccctg

2820

ttcggcaaga agagcagccc cctgaccgag agcggcggcc ccctgagcct gagcgaggag

2880

aacaacgaca gcaagctgct ggagagcggc ctgatgaaca gccaggagag cagctggggc

2940

aagaacgtga gcagcaccga gagcggcagg ctgttcaagg gcaagcgcgc ccacggcccc

3000

gccctgctga ccaaggacaa cgccctgttc aaggtgagca tcagcctgct gaagaccaac

3060

aagaccagca acaacagcgc caccaaccgc aagacccaca tcgacggccc cagcctgctg

3120

atcgagaaca gccccagcgt gtggcagaac atcctggaga gcgacaccga gttcaagaag

3180

gtgacccccc tgatccacga ccgcatgctg atggacaaga acgccaccgc cctgcgcctg

3240

aaccacatga gcaacaagac caccagcagc aagaacatgg agatggtgca gcagaagaag

3300

gagggcccca tcccccccga cgcccagaac cccgacatga gcttcttcaa gatgctgttc

3360

ctgcccgaga gcgcccgctg gatccagcgc acccacggca agaacagcct gaacagcggc

3420

cagggcccca gccccaagca gctggtgagc ctgggccccg agaagagcgt ggagggccag

3480

aacttcctga gcgagaagaa caaggtggtg gtgggcaagg gcgagttcac caaggacgtg

3540

ggcctgaagg agatggtgtt ccccagcagc cgcaacctgt tcctgaccaa cctggacaac

3600

ctgcacgaga acaacaccca caaccaggag aagaagatcc aggaggat cgagaagaag

3660

gagaccctga tccaggagaa cgtggtgctg ccccagatcc acaccgtgac cggcaccaag

3720

aacttcatga agaacctgtt cctgctgagc acccgccaga acgtggaggg cagctacgac

3780

ggcgcctacg cccccgtgct gcaggacttc cgcagcctga acgacagcac caaccgcacc

3840

aagaagcaca ccgcccactt cagcaagaag ggcgaggagg agaacctgga gggcctgggc

3900

aaccagacca agcagatcgt ggagaagtac gcctgcacca cccgcatcag ccccaacacc

3960

agccagcaga acttcgtgac ccagcgcagc aagcgcgccc tgaagcagtt ccgcctgccc

4020

ctggaggaga ccgagctgga gaagcgcatc atcgtggacg acaccagcac ccagtggagc

4080

aagaacatga agcacctgac ccccagcacc ctgacccaga tcgactacaa cgagaaggag

4140

aagggcgcca tcacccagag ccccctgagc gactgcctga cccgcagcca cagcatcccc

4200

caggccaacc gcagccccct gcccatcgcc aaggtgagca gcttccccag catccgcccc

4260

atctacctga cccgcgtgct gttccaggac aacagcagcc acctgcccgc cgccagctac

4320

cgcaagaagg acagcggcgt gcaggagagc agccacttcc tgcaaggcgc caagaagaac

4380

aacctgagcc tggccatcct gaccctggag atgaccggcg accagcgcga ggtgggcagc

4440

ctgggcacca gcgccaccaa cagcgtgacc tacaagaagg tggagaacac cgtgctgccc

4500

aagcccgacc tgcccaagac cagcggcaag gtggagctgc tgcccaaggt gcacatctac

4560

cagaaggacc tgttccccac cgagaccagc aacggcagcc ccggccacct ggacctggtg

4620

gagggcagcc tgctgcaggg caccgagggc gccatcaagt ggaacgaggc caaccgcccc

4680

ggcaaggtgc ccttcctgcg cgtggccacc gagagcagcg ccaagacccc cagcaagctg

4740

ctggaccccc tggcctggga caaccactac ggcacccaga tccccaagga ggagtggaag

4800

agccaggaga agagccccga gaagaccgcc ttcaagaaga aggacaccat cctgagcctg

4860

aacgcctgcg agagcaacca cgccatcgcc gccatcaacg agggccagaa caagcccgag

4920

atcgaggtga cctggggccaa gcagggccgc accgagcgcc tgtgcagcca gaaccccccc

4980

gtgctgaagc gccaccagcg cgagatcacc cgcaccaccc tgcagagcga cccaggagg

5040

atcgactacg acgacaccat cagcgtggag atgaagaagg aggacttcga catctacgac

5100

gaggacgaga accagagccc ccgcagcttc cagaagaaga cccgccacta cttcatcgcc

5160

gccgtggagc gcctgtggga ctacggcatg agcagcagcc cccacgtgct gcgcaaccgc

5220

gccgagcg gcagcgtgcc ccagttcaag aaggtggtgt tccaggagtt caccgacggc

5280

agcttcaccc agcccctgta ccgcggcgag ctgaacgagc acctgggcct gctgggcccc

5340

tacatccgcg ccgaggtgga ggacaacatc atggtgacct tccgcaacca ggccagccgc

5400

ccctacagct tctacagcag cctgatcagc tacgaggagg accagcgcca gggcgccgag

5460

ccccgcaaga acttcgtgaa gcccaacgag accaagacct acttctggaa ggtgcagcac

5520

cacatggccc ccaccaagga cgagttcgac tgcaaggcct gggcctactt cagcgacgtg

5580

gacctggaga aggacgtgca cagcggcctg atcggccccc tgctggtgtg ccacaccaac

5640

accctgaacc ccgcccacgg ccgccaggtg accgtgcagg agttcgccct gttcttcacc

5700

atcttcgacg agaccaagag ctggtacttc accgagaaca tggagcgcaa ctgccgcgcc

5760

ccctgcaaca tccagatgga ggaccccacc ttcaaggaga actaccgctt ccacgccatc

5820

aacggctaca tcatggacac cctgcccggc ctggtgatgg cccaggacca gcgcatccgc

5880

tggtacctgc tgagcatggg cagcaacgag aacatccaca gcatccactt cagcggccac

5940

gtgttcaccg tgcgcaagaa ggagagtac aagatggccc tgtacaacct gtaccccggc

6000

gtgttcgaga ccgtggagat gctgcccagc aaggccggca tctggcgcgt ggagtgcctg

6060

atcggcgagc acctgcacgc cggcatgagc accctgttcc tggtgtacag caacaagtgc

6120

cagacccccc tgggcatggc cagcggccac atccgcgact tccagatcac cgccagcggc

6180

cagtacggcc agtgggcccc caagctggcc cgcctgcact acagcggcag catcaacgcc

6240

tggagcacca aggagccctt cagctggatc aaggtggacc tgctggcccc catgatcatc

6300

cacggcatca agacccagg cgcccgccag aagttcagca gcctgtacat cagccagttc

6360

atcatcatgt acagcctgga cggcaagaag tggcagacct accgcggcaa cagcaccggc

6420

accctgatgg tgttcttcgg caacgtggac agcagcggca tcaagcacaa catcttcaac

6480

ccccccatca tcgcccgcta catccgcctg caccccaccc actacagcat ccgcagcacc

6540

ctgcgcatgg agctgatggg ctgcgacctg aacagctgca gcatgcccct gggcatggag

6600

agcaaggcca tcagcgacgc cgatcacc gccagcagct acttcaccaa catgttcgcc

6660

acctggagcc ccagcaaggc ccgcctgcac ctgcaaggcc gcagcaacgc ctggcgcccc

6720

caggtgaaca accccaagga gtggctgcag gtggacttcc agaagaccat gaaggtgacc

6780

ggcgtgacca cccagggcgt gaagagcctg ctgaccagca tgtacgtgaa ggagttcctg

6840

atcagcagca gccaggacgg ccaccagtgg accctgttct tccagaacgg caaggtgaag

6900

gtgttccagg gcaaccagga cagcttcacc cccgtggtga acagcctgga cccccccctg

6960

ctgacccgct acctgcgcat ccacccccag agctgggtgc accagatcgc cctgcgcatg

7020

gaggtgctgg gctgcgaggc ccaggacctg tactaa

7056

<210> 390

<211> 4374

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 390

atgcagatcg agctgagcac ctgcttcttc ctgtgcctgc tgcgcttctg cttcagcgcc

60

acccgccgct actacctggg cgccgtggag ctgagctggg actacatgca gagcgacctg

120

ggcgagctgc ccgtggacgc ccgcttcccc ccccgcgtgc ccaagagctt ccccttcaac

180

accagcgtgg tgtacaagaa gaccctgttc gtggagttca ccgaccacct gttcaacatc

240

gccaagcccc gccccccctg gatgggcctg ctgggcccca ccatccaggc cgaggtgtac

300

gacaccgtgg tgatcaccct gaagaacatg gccagccacc ccgtgagcct gcacgccgtg

360

ggcgtgagct actggaaggc cagcgagggc gccgagtacg acgaccagac cagccagcgc

420

gagaaggagg acgacaaggt gttccccggc ggcagccaca cctacgtgtg gcaggtgctg

480

aaggagaacg gccccatggc cagcgacccc ctgtgcctga cctacagcta cctgagccac

540

gtggacctgg tgaaggacct gaacagcggc ctgatcggcg ccctgctggt gtgccgcgag

600

ggcagcctgg ccaaggagaa gacccagacc ctgcacaagt tcatcctgct gttcgccgtg

660

ttcgacgagg gcaagagctg gcacagcgag accaagaaca gcctgatgca ggaccgcgac

720

gccgccagcg cccgcgcctg gcccaagatg cacaccgtga acggctacgt gaaccgcagc

780

ctgcccggcc tgatcggctg ccaccgcaag agcgtgtact ggcacgtgat cggcatgggc

840

accacccccg aggtgcacag catcttcctg gagggccaca ccttcctggt gcgcaaccac

900

cgccaggcca gcctggagat cagccccatc accttcctga ccgcccagac cctgctgatg

960

gacctgggcc agttcctgct gttctgccac atcagcagcc accagcacga cggcatggag

1020

gcctacgtga aggtggacag ctgccccgag gagccccagc tgcgcatgaa gaacaacgag

1080

gaggccgagg actacgacga cgacctgacc gacagcgaga tggacgtggt gcgcttcgac

1140

gacgacaaca gccccagctt catccagatc cgcagcgtgg ccaagaagca ccccaagacc

1200

tgggtgcact acatcgccgc cgaggaggag gactgggact acgcccccct ggtgctggcc

1260

cccgacgacc gcagctacaa gagccagtac ctgaacaacg gcccccagcg catcggccgc

1320

aagtacaaga aggtgcgctt catggcctac accgacgaga ccttcaagac ccgcgaggcc

1380

atccagcacg agagcggcat cctgggcccc ctgctgtacg gcgaggtggg cgacaccctg

1440

ctgatcatct tcaagaacca ggccagccgc ccctacaaca tctaccccca cggcatcacc

1500

gacgtgcgcc ccctgtacag ccgccgcctg cccaagggcg tgaagcacct gaaggacttc

1560

cccatcctgc ccggcgagat cttcaagtac aagtggaccg tgaccgtgga ggacggcccc

1620

accaagagcg acccccgctg cctgacccgc tactacagca gcttcgtgaa catggagcgc

1680

gacctggcca gcggcctgat cggccccctg ctgatctgct acaagggagag cgtggaccag

1740

cgcggcaacc agatcatgag cgacaagcgc aacgtgatcc tgttcagcgt gttcgacgag

1800

aaccgcagct ggtacctgac cgagaacatc cagcgcttcc tgcccaaccc cgccggcgtg

1860

cagctggagg accccgagtt ccaggccagc aacatcatgc acagcatcaa cggctacgtg

1920

ttcgacagcc tgcagctgag cgtgtgcctg cacgaggtgg cctactggta catcctgagc

1980

atcggcgccc agaccgactt cctgagcgtg ttcttcagcg gctacacctt caagcacaag

2040

atggtgtacg aggacaccct gaccctgttc cccttcagcg gcgagaccgt gttcatgagc

2100

atggagaacc ccggcctgtg gatcctgggc tgccacaaca gcgacttccg caaccgcggc

2160

atgaccgccc tgctgaaggt gagcagctgc gacaagaaca ccggcgacta ctacgaggac

2220

agctacgagg acatcagcgc ctacctgctg agcaagaaca acgccatcga gccccgcagc

2280

ttcagccaga acccccccgt gctgaagcgc caccagcgcg agatcacccg caccaccctg

2340

cagagcgacc aggaggagat cgactacgac gacaccatca gcgtggagat gaagaaggag

2400

gacttcgaca tctacgacga ggacgagaac cagagccccc gcagcttcca gaagaagacc

2460

cgccactact tcatcgccgc cgtggagcgc ctgtgggact acggcatgag cagcagcccc

2520

cacgtgctgc gcaaccgcgc cccagcggc agcgtgcccc agttcaagaa ggtggtgttc

2580

caggagttca ccgacggcag cttcacccag cccctgtacc gcggcgagct gaacgagcac

2640

ctgggcctgc tgggccccta catccgcgcc gaggtggagg acaacatcat ggtgaccttc

2700

cgcaaccagg ccagccgccc ctacagcttc tacagcagcc tgatcagcta cgaggaggac

2760

cagcgccagg gcgccgagcc ccgcaagaac ttcgtgaagc ccaacgagac caagacctac

2820

ttctggaagg tgcagcacca catggccccc accaaggacg agttcgactg caaggcctgg

2880

gcctacttca gcgacgtgga cctggagaag gacgtgcaca gcggcctgat cggccccctg

2940

ctggtgtgcc acaccaacac cctgaacccc gcccacggcc gccaggtgac cgtgcaggag

3000

ttcgccctgt tcttcaccat cttcgacgag accaagagct ggtacttcac cgagaacatg

3060

gagcgcaact gccgcgcccc ctgcaacatc cagatggagg accccacctt caaggagaac

3120

taccgcttcc acgccatcaa cggctacatc atggacaccc tgcccggcct ggtgatggcc

3180

caggaccagc gcatccgctg gtacctgctg agcatgggca gcaacgagaa catccacagc

3240

atccacttca gcggccacgt gttcaccgtg cgcaagaagg aggagtacaa gatggccctg

3300

tacaacctgt accccggcgt gttcgagacc gtggagatgc tgcccagcaa ggccggcatc

3360

tggcgcgtgg agtgcctgat cggcgagcac ctgcacgccg gcatgagcac cctgttcctg

3420

gtgtacagca acaagtgcca gacccccctg ggcatggcca gcggccacat ccgcgacttc

3480

cagatcaccg ccagcggcca gtacggccag tgggccccca agctggcccg cctgcactac

3540

agcggcagca tcaacgcctg gagcaccaag gagcccttca gctggatcaa ggtggacctg

3600

ctggccccca tgatcatcca cggcatcaag acccagggcg cccgccagaa gttcagcagc

3660

ctgtacatca gccagttcat catcatgtac agcctggacg gcaagaagtg gcagacctac

3720

cgcggcaaca gcaccggcac cctgatggtg ttcttcggca acgtggacag cagcggcatc

3780

aagcacaaca tcttcaaccc ccccatcatc gcccgctaca tccgcctgca cccccaccac

3840

tacagcatcc gcagcaccct gcgcatggag ctgatgggct gcgacctgaa cagctgcagc

3900

atgcccctgg gcatggagag caaggccatc agcgacgccc agatcaccgc cagcagctac

3960

ttcaccaaca tgttcgccac ctggagcccc agcaaggccc gcctgcacct gcaaggccgc

4020

agcaacgcct ggcgccccca ggtgaacaac cccaaggagt ggctgcaggt ggacttccag

4080

aagaccatga aggtgaccgg cgtgaccacc cagggcgtga agagcctgct gaccagcatg

4140

tacgtgaagg agttcctgat cagcagcagc caggacggcc accagtggac cctgttcttc

4200

cagaacggca aggtgaaggt gttccagggc aaccaggaca gcttcacccc cgtggtgaac

4260

agcctggacc cccccctgct gacccgctac ctgcgcatcc acccccagag ctgggtgcac

4320

cagatcgccc tgcgcatgga ggtgctgggc tgcgaggccc aggacctgta ctaa

4374

<210> 391

<211> 7056

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 391

atgcagatcg agctgtctac ctgcttcttc ctgtgcctgc tgcggttctg cttcagcgcc

60

accagaagat attacctggg cgccgtggaa ctgagctggg actacatgca gtctgacctg

120

ggagagctgc ccgtggacgc tagatttcct ccaagagtgc ccaagagctt ccccttcaac

180

acctccgtgg tgtacaagaa aaccctgttc gtggaattca ccgaccacct gttcaatatc

240

gccaagcctc ggcctccttg gatgggactg ctgggaccta caattcaggc cgaggtgtac

300

gacaccgtgg tcatcaccct gaagaacatg gccagccatc ctgtgtctct gcacgccgtg

360

ggagtgtctt attggaaggc ttctgagggc gccgagtacg acgatcagac aagccagaga

420

gagaaagagg acgacaaggt tttccctggc ggcagccaca cctatgtctg gcaggtcctg

480

aaagaaaacg gccctatggc ctccgatcct ctgtgcctga catacagcta cctgagccac

540

gtggacctgg tcaaggacct gaattctggc ctgatcggag ccctgctcgt gtgtagagaa

600

ggcagcctgg ccaaagagaa aacccagaca ctgcacaagt tcatcctgct gttcgccgtg

660

ttcgacgagg gcaagagctg gcacagcgag acaaagaaca gcctgatgca ggacagggat

720

gccgcctctg ctagagcttg gcctaagatg cacaccgtga acggctacgt gaacagaagc

780

ctgcctggac tgatcggctg ccacagaaag tccgtgtact ggcacgtgat cggcatgggc

840

acaacacctg aggtgcacag catctttctg gaaggccaca ccttcctcgt gcggaaccac

900

agacaggcca gcctggaaat cagccctatc accttcctga ccgctcagac cctgctgatg

960

gatctgggcc agtttctgct gttctgccac atcagctccc accagcacga tggcatggaa

1020

gcctacgtga aggtggacag ctgccccgaa gaaccccagc tgcggatgaa gaacaacgag

1080

gaagccgagg actacgacga cgacctgacc gactctgaga tggacgtcgt cagattcgac

1140

gacgataaca gccccagctt catccagatc agaagcgtgg ccaagaagca ccccaagacc

1200

tgggtgcact atatcgccgc cgaggaagag gactgggatt acgctcctct ggtgctggcc

1260

cctgacgaca gaagctacaa gagccagtac ctgaacaacg gccctcagcg gatcggccgg

1320

aagtataaga aagtgcggtt catggcctac accgacgaga cattcaagac cagagaggcc

1380

atccagcacg agagcggaat tctgggccct ctgctgtatg gcgaagtggg cgatacactg

1440

ctgatcatct tcaagaacca ggccagcaga ccctacaaca tctaccctca cggcatcacc

1500

gatgtgcggc ccctgtattc tagaaggctg cccaagggcg tgaagcacct gaaggacttc

1560

cctatcctgc ctggcgagat tttcaagtac aagtggaccg tgaccgtgga agatggcccc

1620

accaagagcg accctagatg tctgacacgg tactacagca gcttcgtgaa catggaacgc

1680

gacctggcca gcggcctgat tggacctctg ctgatctgct acaaagaaag cgtggaccag

1740

cggggcaacc agatcatgag cgacaagcgg aacgtgatcc tgtttagcgt gttcgatgag

1800

aaccggtcct ggtatctgac cgagaacatc cagcggtttc tgcccaatcc tgccggggtg

1860

caactggaag atcctgagtt ccaggcaagc aacatcatgc actccatcaa tggctatgtg

1920

ttcgacagcc tgcagctgag cgtgtgcctg cacgaagtgg cctactggta catcctgagc

1980

attggcgccc agaccgactt cctgtccgtg ttctttagcg gctacacctt caagcacaag

2040

atggtgtacg aggataccct gacactgttc ccattcagcg gcgagacagt gttcatgagc

2100

atggaaaacc ccggcctgtg gattctgggc tgtcacaaca gcgacttccg gaacagaggc

2160

atgacagccc tgctgaaggt gtccagctgc gacaagaaca ccggcgacta ctacgaggac

2220

agctatgagg acatcagcgc ctacctgctg agcaagaaca atgccatcga gcccagaagc

2280

ttcagccaga atagcagaca cccctccacc agacagaagc agttcaacgc cacaacaatc

2340

cccgagaacg acatcgagaa aaccgatcct tggtttgccc acagaacccc tatgcctaag

2400

atccagaacg tgtcctccag cgatctgctg atgctcctga gacagagccc tacacctcac

2460

ggactgagcc tgtccgatct gcaagaggcc aaatacgaaa ccttcagcga cgacccttct

2520

cctggcgcca tcgacagcaa caatagcctg agcgagatga cccacttcag accaccagctg

2580

caccacagcg gcgacatggt gtttacacct gagagcggcc tccagctgag actgaatgag

2640

aagctgggaa ccaccgccgc caccgagctg aagaaactgg acttcaaggt gtcctctacc

2700

agcaacaacc tgatcagcac aatcccctcc gacaacctgg ctgccggcac cgacaacaca

2760

tcttctctgg gcccacctag catgcccgtg cactacgata gccagctgga taccacactg

2820

ttcggcaaga agtctagccc tctgacagag tctggcggcc ctctgtctct gagcgaggaa

2880

aacaacgaca gcaagctgct ggaatccggc ctgatgaaca gccaagagtc ctcctggggc

2940

aagaatgtgt ccagcaccga gtccggcaga ctgttcaagg gaaagagagc ccacggacct

3000

gctctgctga ccaaggataa cgccctgttc aaagtgtcca tcagcctgct caagaccaac

3060

aagacctcca acaactccgc caccaacaga aagacccaca tcgacggccc tagcctgctg

3120

atcgagaata gccctagcgt ctggcagaat atcctggaaa gcgacaccga gttcaagaaa

3180

gtgacccctc tgatccacga ccggatgctc atggacaaga acgccaccgc tctgcggctg

3240

aaccacatga gcaacaagac aaccagcagc aagaatatgg aaatggtgca gcagaagaaa

3300

gagggcccca ttcctccaga cgctcagaac cccgatatga gcttcttcaa gatgctcttt

3360

ctgcccgaga gcgcccggtg gattcagaga acacacggca agaactccct gaactccggc

3420

cagggacctt ctccaaagca gctggtttcc ctgggacctg agaagtccgt ggaaggacag

3480

aacttcctga gcgaaaagaa caaagtggtc gtcggcaagg gcgagttcac caaggatgtg

3540

ggcctgaaag agatggtctt tcccagcagc cggaacctgt tcctgaccaa cctggacaac

3600

ctgcacgaga acaacaccca caatcaagag aagaagatcc aagaggaaat cgaaaagaaa

3660

gagacactca tccaagagaa cgtggtgctg cctcagatcc acacagtgac cggcaccaag

3720

aactttatga agaatctgtt cctgctgagt acccggcaga acgtggaagg cagctacgat

3780

ggcgcttatg cccctgtgct gcaggacttc agatccctga acgactccac caatcggaca

3840

aagaagcaca cagcccactt ctccaagaag ggcgaagaag agaacctgga aggactgggc

3900

aatcagacca agcagatcgt cgagaagtac gcctgcacca ccagaatcag ccccaacaca

3960

agccagcaga acttcgtgac ccagcggagc aaaagagccc tgaagcagtt tcggctgccc

4020

ctggaagaaa ccgagctgga aaagcggatc atcgtggacg acaccagcac acagtggtcc

4080

aagaacatga agcacttgac ccctagcaca ctgacccaga tcgactacaa cgagaaagag

4140

aagggcgcta tcacacagag cccactgagc gactgtctga ccagaagcca cagcatccct

4200

caggccaaca gatcccctct gccaatcgcc aaagtgtcta gcttccccag catcagaccc

4260

atctacctga ccagagtgct gttccaggac aacagcagcc atctgccagc cgccagctac

4320

cggaagaaag attctggcgt gcaagagagc agccactttc tgcagggcgc taagaagaac

4380

aatctgagcc tggctattct gaccctggaa atgaccggcg atcagagaga agtcggctct

4440

ctgggcacca gcgccacaaa tagcgtgacc tacaaaaagg tggaaaacac cgtgctgcct

4500

aagcctgacc tgccaaagac aagcggcaag gtggaactgc tgccaaaggt gcacatctac

4560

cagaaggacc tgtttcctac cgagacaagc aacggctctc ccggccatct ggatctggtg

4620

gaaggatctc tgctgcaggg aaccgagggc gccatcaagt ggaacgaggc caatagacct

4680

ggcaaggtgc ccttcctgag agtggccaca gagtccagcg ccaagacacc ctctaaactg

4740

ctggaccctc tggcctggga caaccactat ggcactcaga tccccaaaga ggaatggaag

4800

tcccaagaga agtcccctga aaagaccgcc ttcaagaaga aggacaccat tctgtccctg

4860

aatgcctgcg agagcaacca cgccattgcc gccatcaatg agggccagaa caagcccgag

4920

atcgaagtga cctggggccaa gcagggaaga accgagagac tgtgtagcca gaatcctcct

4980

gtgctgaagc ggcaccagag agaaatcacc cggaccacac tgcagagcga ccaagaagag

5040

atcgattacg acgataccat cagcgtcgag atgaagaaag aagatttcga catctacgac

5100

gaggacgaga atcagagccc tcggagcttc cagaagaaaa ccaggcacta ctttattgcc

5160

gccgtcgagc ggctgtggga ctacggaatg tctagctctc ctcacgtgct gcggaataga

5220

gcccagtctg gtagcgtgcc ccagttcaaa aaggtcgtgt tccaagagtt caccgacggc

5280

agcttcaccc agccactgta tagaggcgag ctgaacgagc atctgggcct gctgggccct

5340

tatatcagag ccgaagtgga agataacatc atggtcacct tccggaatca ggctagccgg

5400

ccttacagct tctacagctc cctgatctcc tacgaagagg accagagaca gggcgcagag

5460

ccccggaaga atttcgtgaa gcccaacgag actaagacct acttttggaa ggtgcagcac

5520

catatggccc ctacaaagga cgagttcgac tgcaaagcct gggcctactt ctccgatgtg

5580

gacctcgaaa aggacgtgca cagcggactc atcggcccac tgcttgtgtg ccacaccaac

5640

acactgaacc ccgctcacgg cagacaagtg acagtgcaag agttcgccct gtttttcacc

5700

atcttcgacg aaacgaagtc ctggtacttc accgaaaaca tggaaagaaa ctgcagggcc

5760

ccttgcaaca ttcagatgga agatcccacc ttcaaagaga actaccggtt ccacgccatc

5820

aacggctaca tcatggacac actgcccggc ctggttatgg cccaggatca gagaatccgg

5880

tggtatctgc tgtccatggg ctccaacgag aatatccact ccatccactt cagcggccac

5940

gtgttcaccg tgcggaaaaa agaagagtac aaaatggccc tgtacaatct gtaccctggg

6000

gtgttcgaaa ccgttgagat gctgcctagc aaggccggaa tttggagagt ggaatgtctg

6060

attggagagc acctccacgc cgggatgagc accctgtttc tggtgtactc caacaagtgt

6120

cagacccctc tcggcatggc ctctggccac attagagact tccagatcac cgccagcgga

6180

cagtatggac agtgggcccc taaactggcc agactgcact actccggcag catcaatgcc

6240

tggtccacca aagagccttt cagctggatc aaagtggacc tgctggctcc catgatcatc

6300

cacggaatca agacccagg cgccagacaa aagttcagca gcctgtacat cagccagttc

6360

atcatcatgt acagcctgga cggaaagaag tggcagacct accggggcaa tagcaccggc

6420

acactgatgg tgttcttcgg caacgtggac tccagcggca ttaagcacaa catcttcaac

6480

cctccaatca ttgcccggta catccggctg caccccacac actacagcat caggtctacc

6540

ctgagaatgg aactgatggg ctgcgacctg aacagctgct ctatgcccct cggaatggaa

6600

agcaaggcca tcagcgacgc ccagatcaca gcctctagct acttcaccaa catgttcgcc

6660

acttggagcc cctctaaggc ccggcttcat ctgcaaggca gaagcaacgc ttggaggccc

6720

caagtgaaca accccaaaga atggctccag gtggactttc agaaaaccat gaaagtgaca

6780

ggcgtgacca cacagggcgt caagtccctg ctgacctcta tgtacgtgaa agagtttctg

6840

atcagctcca gccaggacgg ccaccagtgg accctgttct tccagaacgg caaagtgaaa

6900

gtgttccagg gaaatcagga cagcttcaca cccgtggtca atagtctgga cccaccactg

6960

ctgacccgct acctgcgaat tcaccctcag tcttgggtgc accagattgc cctgcggatg

7020

gaagtgctgg gctgtgaagc tcaggacctc tactag

7056

<210> 392

<211> 4980

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 392

atgcagatcg agctgtctac ctgcttcttc ctgtgcctgc tgcggttctg cttcagcgcc

60

accagaagat attacctggg cgccgtggaa ctgagctggg actacatgca gtctgacctg

120

ggagagctgc ccgtggacgc tagatttcct ccaagagtgc ccaagagctt ccccttcaac

180

acctccgtgg tgtacaagaa aaccctgttc gtggaattca ccgaccacct gttcaatatc

240

gccaagcctc ggcctccttg gatgggactg ctgggaccta caattcaggc cgaggtgtac

300

gacaccgtgg tcatcaccct gaagaacatg gccagccatc ctgtgtctct gcacgccgtg

360

ggagtgtctt attggaaggc ttctgagggc gccgagtacg acgatcagac aagccagaga

420

gagaaagagg acgacaaggt tttccctggc ggcagccaca cctatgtctg gcaggtcctg

480

aaagaaaacg gccctatggc ctccgatcct ctgtgcctga catacagcta cctgagccac

540

gtggacctgg tcaaggacct gaattctggc ctgatcggag ccctgctcgt gtgtagagaa

600

ggcagcctgg ccaaagagaa aacccagaca ctgcacaagt tcatcctgct gttcgccgtg

660

ttcgacgagg gcaagagctg gcacagcgag acaaagaaca gcctgatgca ggacagggat

720

gccgcctctg ctagagcttg gcctaagatg cacaccgtga acggctacgt gaacagaagc

780

ctgcctggac tgatcggctg ccacagaaag tccgtgtact ggcacgtgat cggcatgggc

840

acaacacctg aggtgcacag catctttctg gaaggccaca ccttcctcgt gcggaaccac

900

agacaggcca gcctggaaat cagccctatc accttcctga ccgctcagac cctgctgatg

960

gatctgggcc agtttctgct gttctgccac atcagctccc accagcacga tggcatggaa

1020

gcctacgtga aggtggacag ctgccccgaa gaaccccagc tgcggatgaa gaacaacgag

1080

gaagccgagg actacgacga cgacctgacc gactctgaga tggacgtcgt cagattcgac

1140

gacgataaca gccccagctt catccagatc agaagcgtgg ccaagaagca ccccaagacc

1200

tgggtgcact atatcgccgc cgaggaagag gactgggatt acgctcctct ggtgctggcc

1260

cctgacgaca gaagctacaa gagccagtac ctgaacaacg gccctcagcg gatcggccgg

1320

aagtataaga aagtgcggtt catggcctac accgacgaga cattcaagac cagagaggcc

1380

atccagcacg agagcggaat tctgggccct ctgctgtatg gcgaagtggg cgatacactg

1440

ctgatcatct tcaagaacca ggccagcaga ccctacaaca tctaccctca cggcatcacc

1500

gatgtgcggc ccctgtattc tagaaggctg cccaagggcg tgaagcacct gaaggacttc

1560

cctatcctgc ctggcgagat tttcaagtac aagtggaccg tgaccgtgga agatggcccc

1620

accaagagcg accctagatg tctgacacgg tactacagca gcttcgtgaa catggaacgc

1680

gacctggcca gcggcctgat tggacctctg ctgatctgct acaaagaaag cgtggaccag

1740

cggggcaacc agatcatgag cgacaagcgg aacgtgatcc tgtttagcgt gttcgatgag

1800

aaccggtcct ggtatctgac cgagaacatc cagcggtttc tgcccaatcc tgccggggtg

1860

caactggaag atcctgagtt ccaggcaagc aacatcatgc actccatcaa tggctatgtg

1920

ttcgacagcc tgcagctgag cgtgtgcctg cacgaagtgg cctactggta catcctgagc

1980

attggcgccc agaccgactt cctgtccgtg ttctttagcg gctacacctt caagcacaag

2040

atggtgtacg aggataccct gacactgttc ccattcagcg gcgagacagt gttcatgagc

2100

atggaaaacc ccggcctgtg gattctgggc tgtcacaaca gcgacttccg gaacagaggc

2160

atgacagccc tgctgaaggt gtccagctgc gacaagaaca ccggcgacta ctacgaggac

2220

agctatgagg acatcagcgc ctacctgctg agcaagaaca atgccatcga gcccagaagc

2280

ttcagccaga atagcagaca cccctccacc agacagaagc agttcaacgc cacaacaatc

2340

cccgagaacg acatcgagaa aaccgatcct tggtttgccc acagaacccc tatgcctaag

2400

atccagaacg tgtcctccag cgatctgctg atgctcctga gacagagccc tacacctcac

2460

ggactgagcc tgtccgatct gcaagaggcc aaatacgaaa ccttcagcga cgacccttct

2520

cctggcgcca tcgacagcaa caatagcctg agcgagatga cccacttcag accaccagctg

2580

caccacagcg gcgacatggt gtttacacct gagagcggcc tccagctgag actgaatgag

2640

aagctgggaa ccaccgccgc caccgagctg aagaaactgg acttcaaggt gtcctctacc

2700

agcaacaacc tgatcagcac aatcccctcc gacaacctgg ctgccggcac cgacaacaca

2760

tcttctctgg gcccacctag catgcccgtg cactacgata gccagctgga taccacactg

2820

ttcggcaaga agtctagccc tctgacagag tctggcggcc ctctgtctct gagcgaggaa

2880

aacaacgaca gcaagctgcc tcctgtgctg aagcggcacc agcgggaaat caccagaacc

2940

acactgcaga gcgaccaaga ggaaatcgat tacgacgaca ccatcagcgt cgagatgaag

3000

aaagaagatt tcgacatcta cgacgaggac gagaatcaga gccccagatc ctttcagaaa

3060

aagacccggc actacttcat tgccgccgtc gagagactgt gggactacgg catgtctagc

3120

agccctcacg tgctgagaaa tagagcccag agcggcagcg tgccccagtt caagaaagtg

3180

gtgttccaag agttcaccga cggcagcttc acccagccac tgtatagagg cgagctgaac

3240

gagcatctgg gcctgctggg cccttatatc agagccgaag tggaagataa catcatggtc

3300

accttccgga atcaggctag ccggccttac agcttctaca gctccctgat ctcctacgaa

3360

gaggaccaga gacagggcgc tgagccccgg aagaatttcg tgaagcccaa cgagactaag

3420

acctactttt ggaaggtgca gcaccacatg gcccctacaa aggacgagtt cgactgcaaa

3480

gcctgggcct acttctccga tgtggatctg gaaaaggacg tgcacagcgg gctcatcgga

3540

ccactgcttg tgtgccacac caacacactg aaccccgctc acggcagaca agtgacagtg

3600

caagagttcg ccctgttctt caccatcttc gacgaaacaa agagctggta cttcaccgag

3660

aatatggaac ggaactgcag ggccccttgc aacatccaga tggaagatcc caccttcaaa

3720

gagaactacc ggttccacgc catcaacggc tacatcatgg acacactgcc cggcctggtt

3780

atggcccagg atcagagaat ccggtggtat ctgctgtcca tgggctccaa cgagaatatc

3840

cacagcatcc acttcagcgg ccacgtgttc accgtgcgga aaaaagaaga gtacaaaatg

3900

gccctgtaca atctgtaccc tggggtgttc gaaaccgtgg aaatgctgcc ttccaaggcc

3960

ggcatttgga gagtggaatg tctgattgga gagcacctcc acgccggaat gagcaccctg

4020

tttctggtgt actccaacaa gtgtcagacc cctctcggca tggcctctgg acacatcaga

4080

gacttccaga tcaccgcctc tggccagtac ggacagtggg ctcctaaact ggctcggctg

4140

cactactccg gcagcatcaa tgcctggtcc accaaagagc ccttcagctg gatcaaggtg

4200

gacctgctgg ctcccatgat catccacgga atcaagaccc agggcgcaag acagaagttc

4260

agcagcctgt acatcagcca gttcatcatc atgtacagcc tggacggaaa gaagtggcag

4320

acctaccggg gcaatagcac cggcacactc atggtgttct tcggcaacgt ggactccagc

4380

ggcattaagc acaacatctt caaccctcca atcattgccc ggtacatccg gctgcacccc

4440

acacactaca gcatccggtc taccctgaga atggaactga tgggctgcga cctgaacagc

4500

tgctctatgc ccctcggaat ggaaagcaag gccatcagcg acgcccagat cacagccagc

4560

agctacttca ccaacatgtt cgccacttgg agcccctcca aggctagact gcatctgcag

4620

ggcagaagca acgcttggag gccccaagtg aacaacccca aagagtggct gcaggttgac

4680

tttcaaaaga ccatgaaagt gaccggcgtg accacacagg gcgtcaagtc tctgctgacc

4740

tctatgtacg tgaaagagtt cctgattagc agcagccagg acggccacca gtggaccctg

4800

tttttccaga acggcaaagt gaaagtgttc cagggcaatc aggacagctt cacacccgtg

4860

gtcaattctc tggaccctcc actgctgacc agatacctgc ggattcaccc tcagtcttgg

4920

gtgcaccaga tcgctctgcg gatggaagtg ctgggctgtg aagctcagga cctctactag

4980

<210> 393

<211> 4374

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 393

atgcagatag aattatctac ttgttttttt ctttgtctgc tcaggttctg cttctctgct

60

acaaggaggt attacttagg tgctgtagag ttatcttggg actacatgca gtctgatctt

120

ggggagctcc ctgtggatgc aagatttccc cctagagtac ctaaaagttt ccctttcaac

180

acaagtgtgg tgtataagaa gactctgttt gttgagttca cagatcacct tttcaatatt

240

gccaagccca gacccccctg gatgggtcta ctggggccaa caattcaagc agaggtatat

300

gatacagtgg tgatcacatt aaagaacatg gcatcccacc ctgtaagcct gcatgctgtt

360

ggtgtgtcct attggaaagc aagtgaaggt gctgaatatg atgatcaaac atcccaaaga

420

gagaaggaag atgacaaagt cttcccaggt ggctctcaca cctatgtgtg gcaagtgctc

480

aaggaaaatg ggcctatggc tagtgatcca ttgtgcctca catatagcta cctgtcccat

540

gtggacttag ttaaagatct gaactcaggt ctgattggtg ccctgctggt ctgtagggaa

600

ggatcactag ctaaagaaaa aacccagact ttacacaagt tcatcttatt atttgctgtt

660

tttgatgagg gaaagagctg gcactcagag actaagaatt cactcatgca ggatagat

720

gcagcttctg ctagagcatg gccaaaaatg catactgtga atgggtatgt taacaggagt

780

ctgcctggcc tcataggctg ccatagaaaa tcagtgtact ggcatgtcat aggtatgggc

840

actactcctg aggtgcattc catttttttg gaggggcata ctttccttgt aagaaaccac

900

aggcaggctt cattggaaat tagtccaata acctttctca cagcccagac tctgctaatg

960

gacttggggc agtttttatt attttgtcac attagctctc atcagcatga tggaatggaa

1020

gcctatgtta aggttgattc ctgcccagaa gagccccagt tgagaatgaa gaacaatgag

1080

gaagcagaag actatgatga tgatctaaca gactcagaaa tggatgttgt gagatttgat

1140

gatgataact ccccaagttt tattcagatc aggtcagtgg ccaagaaaca tccaaaaaca

1200

tgggttcatt atattgcagc agaagaagaa gactgggatt atgcaccctt ggtattagcc

1260

cctgatgaca gaagctataa gtcacaatat ctcaacaatg gaccccagag aattggcaga

1320

aagtacaaaa aagtcaggtt tatggcttat actgatgaga ctttcaaaac tagagaggct

1380

attcaacatg aatctggcat cctaggtcct ttgttatatg gggaagtagg ggacacctta

1440

ttaattatat ttaaaaacca ggccagtagg ccttacaaca tttaccccca cggtataaca

1500

gatgtcagac cactgtactc aaggaggcta ccaaaagggg tgaagcacct aaaagacttc

1560

cccatcctac ctggtgagat tttcaagtat aagtggacag tgactgtaga agatggtcca

1620

accaaatcag atcccagatg cctgacaagg tactacagta gctttgtaaa tatggagaga

1680

gacctggcct cagggttaat agggccccta ctgatctgct acaagggagag tgtagaccaa

1740

agaggcaacc aaattatgtc agacaagaga aatgtcatcc tctttagtgt ttttgatgag

1800

aataggtcct ggtacctgac agaaaatatc caaagattcc ttccaaatcc agcaggggta

1860

caactggagg accctgagtt ccaggcctcc aatatcatgc acagcatcaa tggttatgtg

1920

tttgacagtt tgcaactttc agtgtgcctt catgaggttg catactggta tatactttct

1980

ataggggccc agacagactt cttgtcagtt ttcttttcag gctatacttt caagcataag

2040

atggtatatg aagataccct gactcttttt ccctttagtg gtgagacagt tttcatgtca

2100

atggaaaacc cagggctttg gatcttggga tgccacaact ctgactttag aaacagaggc

2160

atgactgccc ttttaaaggt gtcctcttgt gataagaata ctggagacta ctatgaggac

2220

agctatgagg acatttcagc ctatctgctg tcaaaaaata atgctataga gccaaggtca

2280

ttttctcaaa atcctcctgt cctgaagagg caccaaagag agataaccag gactacctta

2340

cagtctgacc aggaggaaat tgattatgat gacacaataa gtgtggagat gaaaaaggag

2400

gattttgata tttatgatga ggatgaaaac caatctccaa gatctttcca gaagaagact

2460

agacactatt tcattgctgc agtggaaaga ctgtgggact atggaatgtc ctccagccct

2520

catgttctca ggaatagggc tcaaagtggt tctgtgccac agttcaagaa ggtggtgttt

2580

caggaattca cagatgggtc ctttactcaa ccactgtata ggggagaact caatgaacat

2640

ctaggattac taggtcccta cattagagct gaggtggagg acaatatcat ggtcactttc

2700

aggaaccagg catctagacc atactctttt tacagctcct tgatatctta tgaagaggac

2760

cagagacagg gtgcagaacc caggaagaac tttgtgaaac ccaatgagac caaaacatac

2820

ttctggaagg tccagcatca tatggctcct accaaggatg aatttgactg caaagcctgg

2880

gcttacttct cagatgtgga tttggagaaa gatgtgcaca gtggcttgat tgggcctctt

2940

ttggtatgtc ataccaacac cttaaaccct gctcatggaa gacaagtaac agtgcaagag

3000

tttgccctct ttttcactat atttgatgag acaaaaagtt ggtactttac tgagaatatg

3060

gagaggaact gcagggctcc ctgcaatata cagatggagg atcctacttt caaggaaaac

3120

tataggtttc atgccattaa tggctatatc atggatacat tgcctggctt agttatggcc

3180

caggatcaga gaatcagatg gtacctcctt agtatgggaa gcaatgaaaa catacattct

3240

attcacttca gtggacatgt ctttactgtg agaaaaaagg aagagtacaa gatggcactg

3300

tacaatctgt accctggagt gtttgagaca gttgagatgc tgcccagcaa ggctgggatc

3360

tggagggtag aatgcctgat tggagaacac ttacatgcag gtatgtccac tctattcttg

3420

gtctattcca acaagtgtca gaccccccta ggcatggcat ctggccatat tagagatttc

3480

cagataactg cttctggtca gtatggccag tgggccccca agcttgctag acttcactac

3540

agtggttcaa taaatgcctg gtccaccaag gagcccttca gctggattaa agtggacttg

3600

ctagccccca tgatcattca tgggataaaa acacagggtg cgacagaa attttcatct

3660

ctgtacatca gccagtttat catcatgtac agtctggatg gcaaaaaatg gcagacctac

3720

agaggtaact ctacaggtac actaatggta ttttttggca atgtagattc atcaggtatc

3780

aagcataata tctttaatcc tcccattatt gccagataca tcaggttgca cccaactcat

3840

tacagtataa gatccacttt aaggatggag cttatggggt gtgaccttaa tagctgcagt

3900

atgcccttgg gaatggaaag taaggccata tcagatgccc agattactgc aagcagctac

3960

tttacaaaca tgtttgcaac ctggtctcct agtaaagcca ggctgcactt gcagggtagg

4020

agcaatgcat ggagacccca ggtcaataac ccaaaagagt ggcttcaagt tgactttcaa

4080

aagacaatga aggtaacagg ggtaaccacc caaggggtaa agagtctgct gacatctatg

4140

tatgtaaaag aattcctcat ctcaagtagt caagatgggc accagtggac actgttcttc

4200

cagaatggaa aagttaaggt gttccaaggt aatcaagaca gcttcactcc agtggtgaac

4260

agtctggatc caccactcct aaccaggtac ctgaggatcc accctcagtc ctgggtccac

4320

cagatagctc tgagaatgga agtgctgggc tgtgaagctc aggacctata ctga

4374

<210> 394

<211> 7056

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 394

atgcaaattg aattgagtac ctgttttttc ctctgtctat taaggttttg tttcagtgca

60

acaagaaggt attatctggg agctgttgag ttatcctggg actacatgca gtctgacctg

120

ggagagctcc cagtggatgc taggtttccc ccaagagtac ccaaaagctt ccctttcaac

180

acttctgttg tctataaaaa gactctgttt gtagaattca cagatcatct gtttaacatt

240

gccaagccta gacctccatg gatggggctg ctgggaccaa ctattcaggc agaggtttat

300

gacactgtgg tgattacact taagaatatg gcatcccacc cagtgagcct gcatgctgtt

360

ggggtttcct actggaaggc aagtgaagga gctgagtatg atgaccagac tagccaaaga

420

gagaaggagg atgacaaggt ctttccaggt ggcagccaca cctatgtctg gcaggtgctg

480

aaggagaatg gccctatggc ctctgatcct ttgtgtctaa cctacagtta tttgtctcat

540

gtggacctgg tgaaggacct taactcaggg ctgatagggg ccttgctggt gtgtagggag

600

ggaagcctgg ctaaggaaaa gacacagact ctgcataagt ttattctctt gtttgcagtg

660

tttgatgagg gtaaaagctg gcactctgaa acaaaaaaca gcttgatgca ggacagggat

720

gctgccagtg ctagggcttg gcctaagatg cacacagtca atggctatgt taacagatca

780

ctgcctggtt tgattggctg ccacagaaag tctgtttact ggcatgtaat tgggatgggg

840

acaaccccag aagttcactc tatcttcctg gaagggcaca ccttcctggt tagaaatcat

900

agacaggcat ccttagagat ttctcctatt acattcctga ctgccgac cctcctcatg

960

gacctgggtc agttcctgct tttttgccac atttcctccc accagcatga tggcatggag

1020

gcctatgtga aagttgattc ttgccctgag gagcctcagc ttaggatgaa gaacaatgaa

1080

gaggctgagg actatgatga tgacctaaca gacagtgaga tggatgttgt gaggtttgat

1140

gatgacaatt cacctagttt catccagatt aggtctgtgg ctaagaaaca tccaaagacc

1200

tgggttcact acattgcagc agaggaggag gactgggatt atgcccccct ggttctggca

1260

cctgatgaca gaagctataa gtcccagtat ctcaacaatg gcccccagag gattggaaga

1320

aaatacaaaa aagtcagatt tatggcctat acagatgaga cttttaaaac tagggaagct

1380

attcagcatg agtcagggat cctgggacct cttctttatg gagaggtggg ggacactctt

1440

ctgataattt ttaaaaatca ggcaagtaga ccttataaca tctaccccca tgggatcact

1500

gatgtcaggc ctctgtactc aagaaggctg cccaagggtg tcaaacacct caaggatttc

1560

cctattcttc ctggggagat cttcaaatac aagtggacag ttactgtgga ggatggcccc

1620

accaaatctg acccaaggtg cctcaccaga tattacagct cctttgtgaa tatggaaaga

1680

gacctagcta gtggtctcat tggcccactg ctcatctgtt acaaggagtc agtggaccag

1740

agagggaatc aaattatgtc tgacaagaga aatgtgatcc ttttctcagt gtttgatgag

1800

aacagaagct ggtatctgac agagaacatt caaaggtttc tgccaaaccc agctggagtt

1860

cagctggagg accctgaatt ccaggcatct aatattatgc attctatcaa tggatatgtg

1920

tttgatagtc tgcagctgtc tgtgtgcctg catgaagtgg cctactggta tatcctctct

1980

attggtgccc agacagattt cttgtctgtg tttttcagtg gttacacatt taaacataaa

2040

atggtgtatg aggacacact tacattattc ccttttagtg gagagacagt gtttatgtcc

2100

atggagaatc caggcctgtg gatcttgggg tgtcataata gtgactttag gaatagaggt

2160

atgacagctc tgctcaaagt gtcttcctgt gacaagaaca caggggacta ttatgaggac

2220

tcttatgagg acatttcagc ctatttactg tccaagaaca atgccattga accaagatct

2280

ttctctcaga actcaagaca ccccagcacc aggcagaagc agttcaatgc aaccaccatc

2340

ccagagaatg atattgaaaa aactgaccct tggtttgccc acaggactcc catgcctaag

2400

attcagaatg tatcttcatc agacttgctg atgctcctga gacagagccc aactcctcat

2460

ggcctgagct taagtgacct caccagggct aagtatgaaa ctttctcaga tgatcccagt

2520

cctggtgcca ttgattctaa taattccctg tctgagatga cacacttcag accccagctc

2580

caccactctg gagatatggt ctttactcct gaatcaggcc tgcagctgag gctgaatgaa

2640

aagcttggca ccacagcagc tactgaactg aaaaagctgg attttaaagt gagctccaca

2700

tccaacaacc tgatttccac tatcccctca gataacttgg cagcagggac tgataacaca

2760

agctcactgg gtcccccttc catgcctgtc cattatgata gtcagctgga tactactctg

2820

tttggtaaga aatcctctcc cctgactgaa agtggaggcc ctctttccct gtcagaggag

2880

aacaatgaca gcaaactgtt agagtctgga ctcatgaact cacaggaaag ttcttggggc

2940

aagaatgtgt ctagcactga gtctgggaga ctgtttaagg gcaagagggc ccatggacca

3000

gccctgctga caaaggataa tgcactgttt aaggtctcaa tcagcctgtt gaagaccaac

3060

aaaaccagta ataattctgc aacaaacagg aagacccaca ttgatggacc ctctcttctc

3120

attgagaatt ccccttctgt ctggcagaac atcttggaat cagatacaga gttcaagaag

3180

gtgactcccc tgatccatga taggatgctc atggataaga atgccacagc actcaggctc

3240

aatcacatga gcaacaagac tacctcctcc aaaaatatgg agatggtgca gcagaagaag

3300

gaaggtccca ttccccctga tgcacagaat ccagatatga gcttctttaa gatgctgttt

3360

ttgcctgagt ctgccaggtg gattcagagg acacatggga agaactcact taactctggc

3420

caaggtccca gtcctaagca gttggtgagc ttggggcctg agaaaagtgt ggagggacag

3480

aatttcctgt ctgaaaagaa caaagtggtt gtgggcaaag gagagttcac taaagatgtg

3540

ggactgaagg agatggtgtt tcctagttca agaaatctct ttcttaccaa tcttgataac

3600

ctgcatgaga acaacaccca caatcaggaa aagaagatcc aggaggaaat tgagaagaag

3660

gaaaccctga tccaggaaaa tgttgtgctg ccacagatcc acactgttac tgggaccaaa

3720

aatttcatga aaaacctgtt tctcctgtct accagacaga atgtagaggg aagctatgat

3780

ggggcctatg cccctgttct ccaggacttc agatccctga atgactccac caacaggact

3840

aagaaacata ctgcacactt tagtaagaag ggggaggagg agaacctgga gggattggga

3900

aaccagacca agcagattgt ggagaaatat gcttgcacca ctagaatctc acctaacaca

3960

agccagcaga actttgtgac ccagaggtct aagagggccc tcaaacagtt tagattgcct

4020

ttggaggaga ctgagctgga aaagaggatt attgtggatg acacctctac ccagtggagc

4080

aagaatatga agcacctgac cccaagcacc cttactcaga ttgattacaa tgaaaaagaa

4140

aagggtgcca tcacccagag ccccttgagt gactgtttga caaggtccca cagtatccca

4200

caggctaaca gatctcctct gcctattgcc aaggtcagct ccttcccttc catcagaccc

4260

atctatctga ccagagtgct gttccaggac aactcctctc atctgccagc tgcctcctat

4320

aggaagaagg atagtggtgt gcaggaatca tctcactttc tgcagggagc caagaagaac

4380

aatctgagcc tggcaattct cacacttgag atgacaggag accagaggga agtgggaagt

4440

ctgggcactt ctgctaccaa ttctgtcacc tacaagaaag tggagaatac agttctgccc

4500

aagccagacc tgcctaaaac atctggaaag gttgagctgc tgcctaaggt gcacatatac

4560

cagaaggacc tattccctac agagacatcc aatggctccc caggccacct ggacttggta

4620

gaggggtctc tcctgcaggg cactgaaggt gctatcaagt ggaatgaggc taatagacct

4680

gggaaggtgc catttctgag ggtggccaca gagagctcag ctaagacacc cagcaagctg

4740

cttgatcccc tggcctggga caatcactat ggaacccaga ttcctaagga ggagtggaag

4800

tcccaggaga agtccccaga gaagactgct ttcaagaaga aggacactat cctctccctg

4860

aatgcctgtg agtctaacca tgctattgct gccatcaatg aaggccagaa caagcctgaa

4920

attgaggtga catgggccaa gcagggcaga acagagaggc tgtgcagcca gaacccacct

4980

gtgctcaaga ggcaccagag agagatcact agaaccactc tgcagtcaga cccaggaagag

5040

attgactatg atgacaccat ctcagttgag atgaaaaagg aggattttga tatttatgat

5100

gaggatgaga atcaatcccc aagatctttt cagaagaaga caagacatta cttcattgct

5160

gcagtggaga gactgtggga ttatggcatg tcctcctcac ctcatgtgct gagaaataga

5220

gcccagtctg gctctgtgcc ccagttcaaa aaagtggtgt ttcaggagtt cacagatggt

5280

tccttcacac agcccctgta caggggtgag ctgaatgagc acctggggtt gctgggcccc

5340

tacatcagag ctgaagttga ggataatatt atggtgacct tcaggaatca ggccagtagg

5400

ccttactctt tctactccag cctgatctca tatgaggagg accagagaca gggggctgaa

5460

cctaggaaga attttgtgaa gcccaatgaa acaaagacat acttctggaa ggtgcagcac

5520

cacatggctc ctaccaagga tgaatttgat tgcaaggctt gggcctattt ttctgatgtg

5580

gacctggaga aggatgtgca ttctggcctc attggccctc tcttggtgtg tcacaccaat

5640

accttgaatc cagcccatgg cagacaggtg actgttcagg agtttgctct gtttttcacc

5700

atctttgatg agacaaagtc ctggtatttt acagagaata tggagaggaa ttgcagggcc

5760

ccctgcaaca tccagatgga agacccaacc ttcaaggaga actacagatt ccatgcaatc

5820

aatggatata tcatggacac cctgcctggc ctggttatgg ctcaggatca gagaatcagg

5880

tggtatctgc tgtctatggg gtcaaatgag aacatccata gtatccactt ctctggccat

5940

gtgtttacag tgagaaagaa ggaagaatat aagatggccc tgtacaacct ctaccctgga

6000

gtgtttgaaa ctgttgaaat gctgccttca aaggctggaa tctggagggt ggaatgcctg

6060

attggagagc accttcatgc tggcatgtcc accctgtttc tggtgtacag caataagtgt

6120

cagactcctc tgggtatggc ttcaggccac atcagggact tccagatcac tgcctcagga

6180

cagtatggac agtgggctcc caaactggca aggctccact actcaggcag cattaatgcc

6240

tggtccacca aagagccttt cagctggatt aaggtggatc tcctggcacc tatgatcatc

6300

catgggatca agactcaggg agctaggcag aagtttagca gcctgtacat ttctcagttt

6360

atcattatgt acagcctgga tggaaaaaag tggcagacct atagaggaaa ctccactgga

6420

acactgatgg tgttttttgg caatgtggac tcaagtggga tcaagcacaa tatcttcaac

6480

ccccctatca ttgccagata catcaggctc caccctacac actactctat cagatctaca

6540

cttaggatgg agctgatggg atgtgatctg aactcttgca gtatgcctct gggtatggag

6600

tccaaggcca tctctgatgc tcagatcaca gccagctctt actttactaa tatgtttgct

6660

acctggtccc caagcaaggc aagactgcac ctgcagggca gatccaatgc ttggagaaccc

6720

caggtgaata acccaaaaga gtggcttcag gtggacttcc agaagactat gaaggtgact

6780

ggagtgacca cccagggggt gaagtcactg ctgacctcca tgtatgtgaa ggagttcctg

6840

atctccagct cccaggatgg ccaccagtgg accctgttct tccagaatgg aaaggtgaag

6900

gtgttccagg gaaaccagga ctcctttacc cctgtggtga actccctgga ccccccactg

6960

ctgaccagat acctgagaat ccatccccag agctgggtgc accagattgc ccttaggatg

7020

gaggtgctgg gatgtgaagc ccaggacctg tactaa

7056

<210> 395

<211> 5013

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 395

atgcaaattg agttaagtac ctgttttttc ctgtgcctgt tgagattttg cttctctgct

60

accagaaggt attacctggg agctgtggag ctgtcatggg actacatgca gtctgacctg

120

ggagagctcc ctgttgatgc taggtttccc cctagggtgc caaagtcctt tccttttaac

180

acctcagtgg tgtacaagaa gacactgttt gtggagttta ctgaccacct cttcaatatt

240

gctaagccaa gacccccttg gatgggtctc ttgggcccta ccatccaggc tgaggtttat

300

gatacagtgg tgattaccct caagaatatg gcttctcatc ctgttagtct gcatgcagta

360

ggggtcagct attggaaggc cagtgaagga gctgagtatg atgaccagac cagccagaga

420

gagaaagagg atgacaaggt gttccctggg ggatcacaca cctatgtgtg gcaggtgttg

480

aaggaaaatg gacccatggc ctctgaccca ctctgcctga cttactccta cctgtctcat

540

gtggacctgg tcaaagatct gaactctggc ctgattgggg cactgttggt gtgcagagaa

600

gggtctcttg ccaaggagaa gactcagacc ctgcacaagt tcatcctgct gtttgctgtg

660

tttgatgaag gcaagtcttg gcattctgag actaagaaca gcctgatgca agatagagat

720

gctgcatctg cccaggcctg gcctaagatg cacactgtga atggatatgt gaataggtcc

780

ttgcctggcc tgattggatg ccataggaag tctgtgtact ggcatgtgat tggcatgggc

840

accacccctg aggttcactc tatttttctg gagggccata ctttccttgt gaggaatcat

900

agacaggcct ctctggagat tagccctatt acatttctga ctgctcagac cctcctcatg

960

gacttggggc agtttctgtt attctgccac atcagcagcc atcaacatga tggtatggaa

1020

gcctatgtca aagtggatag ctgccctgaa gaaccacagc ttaggatgaa gaacaatgag

1080

gaggcagagg actatgatga tgatctgact gattctgaaa tggatgtggt gagattgat

1140

gatgataata gcccttcctt tatccagatc aggtcagtgg ccaagaagca cccaaagacc

1200

tgggtgcatt atattgctgc tgaggaggag gactgggact atgcccctct ggtgctggcc

1260

cctgatgata gaagctataa gtctcaatac ttgaataatg gcccacagag gattgggaga

1320

aagtacaaaa aggtgagatt tatggcctac actgatgaga ctttcaagac cagagaggcc

1380

atccagcatg aatcaggcat tttgggtccc ctgctgtatg gagaggtggg ggataccctg

1440

ctgatcatct ttaagaacca ggccagcaga ccttacaaca tttaccctca tgggatcaca

1500

gatgtgaggc cactctactc taggagattg cccaagggag tcaagcatct taaggacttt

1560

ccaatcctgc ctggggagat cttcaagtac aaatggacag tgacagttga ggatggacct

1620

actaagagtg accccaggtg tctgaccaga tattactcta gctttgtcaa tatggaaaga

1680

gacctggctt caggcttgat aggccctctt ctcatctgct acaaagagtc tgtggaccag

1740

agaggaaatc agattatgtc tgacaagaga aatgttattc tgttttcagt ctttgatgag

1800

aacagaagtt ggtacttgac agagaacatt cagagatttc tgcctaaccc tgcaggagtg

1860

cagcttgagg accctgagtt tcaggcttcc aatatcatgc attctatcaa tggctatgtg

1920

tttgatagcc tgcagctgtc tgtgtgcctg catgaggttg cctattggta catcctgtct

1980

attggggccc aaactgattt cttgtctgtg tttttcagtg gatatacctt taagcataag

2040

atggtgtatg aagatacctt gacacttttc cctttctcag gagagactgt cttcatgtct

2100

atggagaacc ctggactgtg gatcctggga tgccacaact cagacttcag aaacaggggt

2160

atgacagctc tgcttaaggt ctcctcatgt gacaaaaata caggagacta ctatgaagat

2220

tcctatgagg acatctctgc ttacctgctc agcaaaaaca atgccattga gcccagaagc

2280

ttcagccaga attccagaca tcccagtact aggcagaagc agtttaatgc caccaccatc

2340

ccagaaaatg acattgagaa gacagaccct tggtttgccc atagaacccc aatgcccaag

2400

attcagaatg tgagcagctc agacttgctg atgctgctga ggcagtctcc tactccccat

2460

ggcctgtccc tctcagatct gcaggaagcc aagtatgaga cattttctga tgacccctcc

2520

ccaggggcta ttgacagtaa caacagcctg tctgaaatga cccacttcag acctcagctc

2580

caccacagtg gggatatggt gtttacccca gagtcaggcc tgcagctgag actgaatgag

2640

aagctgggaa ccacagctgc cacagaactg aagaagctgg atttcaaggt gagctctact

2700

tcaaataatc tgatttccac tatcccatct gacaatttgg cagctggcac tgacaataca

2760

agctctctgg gcccacctag catgccagtg cattatgaca gccagttgga caccactctt

2820

tttggaaaga aatccagtcc cctgacagag tcaggaggac ccctttctct gtctgaggag

2880

aacaatgata gtaagcttct ggagtcaggc ttgatgaact cccaggagag ttcttggggc

2940

aagaatgtga gctctaggga gatcaccaga accactctgc agtctgacca agaagagatt

3000

gattatgatg acactatctc tgttgagatg aagaaggagg actttgatat ctatgatgag

3060

gatgagaacc agtctccaag aagtttccag aagaagacca ggcactactt tattgctgct

3120

gtggagagac tgtgggacta tggaatgtcc tcctcccctc atgtcctgag aaatagagct

3180

cagtcaggat cagtgcccca gttcaagaag gtggtgttcc aggaattcac agatggaagt

3240

tttacccagc cactgtatag aggtgaactg aatgaacatc tgggtctgct ggggccctat

3300

atcagggctg aggtggagga caatattatg gtgaccttta gaaaccaggc ctcaaggccc

3360

tacagcttct actcttccct catttcatat gaggaagacc agagacaggg agcagagcct

3420

agaaagaact ttgtcaagcc caatgaaacc aaaacctatt tctggaaggt gcagcaccac

3480

atggcaccca ccaaagatga gtttgactgc aaagcctggg cctatttctc agatgtggat

3540

ctggagaagg atgtccattc aggtctgatt ggaccactcc tggtgtgcca caccaacaca

3600

ctgaatccag ctcatggcag acaggtgaca gtccaggagt ttgccctgtt tttcactatt

3660

tttgatgaga ccaagagctg gtattttaca gagaatatgg aaagaaactg cagagcccct

3720

tgtaatatcc agatggagga cccaaccttt aaggagaact acaggttcca tgccatcaat

3780

ggctacatta tggataccct gcctggcctg gttatggccc aggatcagag gatcaggtgg

3840

tatctgctgt caatgggctc caatgagaac attcatagta ttcacttttc aggacatgtg

3900

ttcacagtga gaaagaagga ggagtataag atggccctct ataatctcta cccaggggtg

3960

tttgagacag ttgagatgct gccatctaag gcaggcatct ggagagtgga atgcctcatt

4020

ggagagcacc tgcatgctgg catgtccacc ctgtttctgg tgtactccaa caaatgtcag

4080

acccctcttg gtatggcctc tggccacatt agggatttcc agattactgc cagtggtcag

4140

tatgggcagt gggcccctaa gctggccaga ctgcactatt ctgggagcat caatgcctgg

4200

tccaccaagg aacctttttc ttggattaaa gtggatctgc tggccccaat gatcatccat

4260

gggatcaaga cccagggagc taggcagaag ttcagcagcc tgtacattag tcagttcatc

4320

attatgtaca gtctggatgg caaaaagtgg cagacataca ggggcaattc cactggaacc

4380

ctgatggtgt tctttggaaa tgtggatagc agtggtatca agcacaacat tttcaaccct

4440

cccatcattg ccaggtacat cagactgcat ccaacccact acagcattag gagcaccctt

4500

aggatggagc tcatggggtg tgacctgaac tcttgctcta tgccacttgg aatggagagc

4560

aaggccatct ctgatgccca gattactgct agttcctact tcaccaatat gtttgccacc

4620

tggtcaccca gcaaggccag gctgcacctg cagggaaggt ccaatgcttg gaggcctcag

4680

gtgaacaatc caaaggagtg gctgcaggtg gacttccaga agactatgaa ggtgacagga

4740

gtgaccactc agggagtgaa gagcctgctg acctccatgt atgtgaagga gtttctgatc

4800

tccagctccc aggatggcca ccagtggacc ctgttctttc agaatggcaa ggtgaaggtg

4860

tttcagggga atcaggactc cttcacccca gtggtgaatt ccctggatcc ccctctgctg

4920

accagatacc tgagaatcca cccccagtct tgggtgcacc agattgccct taggatggag

4980

gtgctgggct gtgaggccca ggacctgtac tga

5013

<210> 396

<211> 5013

<212> DNA

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polynucleotide

<400> 396

atgcaaattg agttaagtac ctgttttttc ctgtgcctgt tgagattttg cttctctgct

60

accagaaggt attacctggg agctgtggag ctgtcatggg actacatgca gtctgacctg

120

ggagagctcc ctgttgatgc taggtttccc cctagggtgc caaagtcctt tccttttaac

180

acctcagtgg tgtacaagaa gacactgttt gtggagttta ctgaccacct cttcaatatt

240

gctaagccaa gacccccttg gatgggtctc ttgggcccta ccatccaggc tgaggtttat

300

gatacagtgg tgattaccct caagaatatg gcttctcatc ctgttagtct gcatgcagta

360

ggggtcagct attggaaggc cagtgaagga gctgagtatg atgaccagac cagccagaga

420

gagaaagagg atgacaaggt gttccctggg ggatcacaca cctatgtgtg gcaggtgttg

480

aaggaaaatg gacccatggc ctctgaccca ctctgcctga cttactccta cctgtctcat

540

gtggacctgg tcaaagatct gaactctggc ctgattgggg cactgttggt gtgcagagaa

600

gggtctcttg ccaaggagaa gactcagacc ctgcacaagt tcatcctgct gtttgctgtg

660

tttgatgaag gcaagtcttg gcattctgag actaagaaca gcctgatgca agatagagat

720

gctgcatctg cccaggcctg gcctaagatg cacactgtga atggatatgt gaataggtcc

780

ttgcctggcc tgattggatg ccataggaag tctgtgtact ggcatgtgat tggcatgggc

840

accacccctg aggttcactc tatttttctg gagggccata ctttccttgt gaggaatcat

900

agacaggcct ctctggagat tagccctatt acatttctga ctgctcagac cctcctcatg

960

gacttggggc agtttctgtt aagctgccac atcagcagcc atcaacatga tggtatggaa

1020

gcctatgtca aagtggatag ctgccctgaa gaaccacagc ttaggatgaa gaacaatgag

1080

gaggcagagg actatgatga tgatctgact gattctgaaa tggatgtggt gagattgat

1140

gatgataata gcccttcctt tatccagatc aggtcagtgg ccaagaagca cccaaagacc

1200

tgggtgcatt atattgctgc tgaggaggag gactgggact atgcccctct ggtgctggcc

1260

cctgatgata gaagctataa gtctcaatac ttgaataatg gcccacagag gattgggaga

1320

aagtacaaaa aggtgagatt tatggcctac actgatgaga ctttcaagac cagagaggcc

1380

atccagcatg aatcaggcat tttgggtccc ctgctgtatg gagaggtggg ggataccctg

1440

ctgatcatct ttaagaacca ggccagcaga ccttacaaca tttaccctca tgggatcaca

1500

gatgtgaggc cactctactc taggagattg cccaagggag tcaagcatct taaggacttt

1560

ccaatcctgc ctggggagat cttcaagtac aaatggacag tgacagttga ggatggacct

1620

actaagagtg accccaggtg tctgaccaga tattactcta gctttgtcaa tatggaaaga

1680

gacctggctt caggcttgat aggccctctt ctcatctgct acaaagagtc tgtggaccag

1740

agaggaaatc agattatgtc tgacaagaga aatgttattc tgttttcagt ctttgatgag

1800

aacagaagtt ggtacttgac agagaacatt cagagatttc tgcctaaccc tgcaggagtg

1860

cagcttgagg accctgagtt tcaggcttcc aatatcatgc attctatcaa tggctatgtg

1920

tttgatagcc tgcagctgtc tgtgtgcctg catgaggttg cctattggta catcctgtct

1980

attggggccc aaactgattt cttgtctgtg tttttcagtg gatatacctt taagcataag

2040

atggtgtatg aagatacctt gacacttttc cctttctcag gagagactgt cttcatgtct

2100

atggagaacc ctggactgtg gatcctggga tgccacaact cagacttcag aaacaggggt

2160

atgacagctc tgcttaaggt ctcctcatgt gacaaaaata caggagacta ctatgaagat

2220

tcctatgagg acatctctgc ttacctgctc agcaaaaaca atgccattga gcccagaagc

2280

ttcagccaga attccagaca tcccagtact aggcagaagc agtttaatgc caccaccatc

2340

ccagaaaatg acattgagaa gacagaccct tggtttgccc atagaacccc aatgcccaag

2400

attcagaatg tgagcagctc agacttgctg atgctgctga ggcagtctcc tactccccat

2460

ggcctgtccc tctcagatct gcaggaagcc aagtatgaga cattttctga tgacccctcc

2520

ccaggggcta ttgacagtaa caacagcctg tctgaaatga cccacttcag acctcagctc

2580

caccacagtg gggatatggt gtttacccca gagtcaggcc tgcagctgag actgaatgag

2640

aagctgggaa ccacagctgc cacagaactg aagaagctgg atttcaaggt gagctctact

2700

tcaaataatc tgatttccac tatcccatct gacaatttgg cagctggcac tgacaataca

2760

agctctctgg gcccacctag catgccagtg cattatgaca gccagttgga caccactctt

2820

tttggaaaga aatccagtcc cctgacagag tcaggaggac ccctttctct gtctgaggag

2880

aacaatgata gtaagcttct ggagtcaggc ttgatgaact cccaggagag ttcttggggc

2940

aagaatgtga gctctaggga gatcaccaga accactctgc agtctgacca agaagagatt

3000

gattatgatg acactatctc tgttgagatg aagaaggagg actttgatat ctatgatgag

3060

gatgagaacc agtctccaag aagtttccag aagaagacca ggcactactt tattgctgct

3120

gtggagagac tgtgggacta tggaatgtcc tcctcccctc atgtcctgag aaatagagct

3180

cagtcaggat cagtgcccca gttcaagaag gtggtgttcc aggaattcac agatggaagt

3240

tttacccagc cactgtatag aggtgaactg aatgaacatc tgggtctgct ggggccctat

3300

atcagggctg aggtggagga caatattatg gtgaccttta gaaaccaggc ctcaaggccc

3360

tacagcttct actcttccct catttcatat gaggaagacc agagacaggg agcagagcct

3420

agaaagaact ttgtcaagcc caatgaaacc aaaacctatt tctggaaggt gcagcaccac

3480

atggcaccca ccaaagatga gtttgactgc aaagcctggg cctatttctc agatgtggat

3540

ctggagaagg atgtccattc aggtctgatt ggaccactcc tggtgtgcca caccaacaca

3600

ctgaatccag ctcatggcag acaggtgaca gtccaggagt ttgccctgtt tttcactatt

3660

tttgatgaga ccaagagctg gtattttaca gagaatatgg aaagaaactg cagagcccct

3720

tgtaatatcc agatggagga cccaaccttt aaggagaact acaggttcca tgccatcaat

3780

ggctacatta tggataccct gcctggcctg gttatggccc aggatcagag gatcaggtgg

3840

tatctgctgt caatgggctc caatgagaac attcatagta ttcacttttc aggacatgtg

3900

ttcacagtga gaaagaagga ggagtataag atggccctct ataatctcta cccaggggtg

3960

tttgagacag ttgagatgct gccatctaag gcaggcatct ggagagtgga atgcctcatt

4020

ggagagcacc tgcatgctgg catgtccacc ctgtttctgg tgtactccaa caaatgtcag

4080

acccctcttg gtatggcctc tggccacatt agggatttcc agattactgc cagtggtcag

4140

tatgggcagt gggcccctaa gctggccaga ctgcactatt ctgggagcat caatgcctgg

4200

tccaccaagg aacctttttc ttggattaaa gtggatctgc tggccccaat gatcatccat

4260

gggatcaaga cccagggagc taggcagaag ttcagcagcc tgtacattag tcagttcatc

4320

attatgtaca gtctggatgg caaaaagtgg cagacataca ggggcaattc cactggaacc

4380

ctgatggtgt tctttggaaa tgtggatagc agtggtatca agcacaacat tttcaaccct

4440

cccatcattg ccaggtacat cagactgcat ccaacccact acagcattag gagcaccctt

4500

aggatggagc tcatggggtg tgacctgaac tcttgctcta tgccacttgg aatggagagc

4560

aaggccatct ctgatgccca gattactgct agttcctact tcaccaatat gtttgccacc

4620

tggtcaccca gcaaggccag gctgcacctg cagggaaggt ccaatgcttg gaggcctcag

4680

gtgaacaatc caaaggagtg gctgcaggtg gacttccaga agactatgaa ggtgacagga

4740

gtgaccactc agggagtgaa gagcctgctg acctccatgt atgtgaagga gtttctgatc

4800

tccagctccc aggatggcca ccagtggacc ctgttctttc agaatggcaa ggtgaaggtg

4860

tttcagggga atcaggactc cttcacccca gtggtgaatt ccctggatcc ccctctgctg

4920

accagatacc tgagaatcca cccccagtct tgggtgcacc agattgccct taggatggag

4980

gtgctgggct gtgaggccca ggacctgtac tga

5013

<210> 397

<211> 1670

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polypeptide

<400> 397

Met Gln Ile Glu Leu Ser Thr Cys Phe Phe Leu Cys Leu Leu Arg Phe

1 5 10 15

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

20 25 30

Trp Asp Tyr Met Gln Ser Asp Leu Gly Glu Leu Pro Val Asp Ala Arg

35 40 45

Phe Pro Pro Arg Val Pro Lys Ser Phe Pro Phe Asn Thr Ser Val Val

50 55 60

Tyr Lys Lys Thr Leu Phe Val Glu Phe Thr Asp His Leu Phe Asn Ile

65 70 75 80

Ala Lys Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile Gln

85 90 95

Ala Glu Val Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala Ser

100 105 110

His Pro Val Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala Ser

115 120 125

Glu Gly Ala Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu Asp

130 135 140

Asp Lys Val Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val Leu

145 150 155 160

Lys Glu Asn Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr Ser

165 170 175

Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu Ile

180 185 190

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

195 200 205

Gln Thr Leu His Lys Phe Ile Leu Leu Phe Ala Val Phe Asp Glu Gly

210 215 220

Lys Ser Trp His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg Asp

225 230 235 240

Ala Ala Ser Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly Tyr

245 250 255

Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser Val

260 265 270

Tyr Trp His Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser Ile

275 280 285

Phe Leu Glu Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala Ser

290 295 300

Leu Glu Ile Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu Met

305 310 315 320

Asp Leu Gly Gln Phe Leu Leu Ser Cys His Ile Ser Ser His Gln His

325 330 335

Asp Gly Met Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu Pro

340 345 350

Gln Leu Arg Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp Asp

355 360 365

Leu Thr Asp Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn Ser

370 375 380

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

385 390 395 400

Trp Val His Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala Pro

405 410 415

Leu Val Leu Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu Asn

420 425 430

Asn Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe Met

435 440 445

Ala Tyr Thr Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln His Glu

450 455 460

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

465 470 475 480

Leu Ile Ile Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr Pro

485 490 495

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

500 505 510

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

515 520 525

Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser Asp

530 535 540

Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Met Glu Arg

545 550 555 560

Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys Glu

565 570 575

Ser Val Asp Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn Val

580 585 590

Ile Leu Phe Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr Glu

595 600 605

Asn Ile Gln Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu Asp

610 615 620

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

625 630 635 640

Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr Trp

645 650 655

Tyr Ile Leu Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe Phe

660 665 670

Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu Thr

675 680 685

Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn Pro

690 695 700

Gly Leu Trp Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg Gly

705 710 715 720

Met Thr Ala Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly Asp

725 730 735

Tyr Tyr Glu Asp Ser Tyr Glu Asp Ile Ser Ala Tyr Leu Leu Ser Lys

740 745 750

Asn Asn Ala Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His Pro

755 760 765

Ser Thr Arg Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn Asp

770 775 780

Ile Glu Lys Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro Lys

785 790 795 800

Ile Gln Asn Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln Ser

805 810 815

Pro Thr Pro His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys Tyr

820 825 830

Glu Thr Phe Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn Asn

835 840 845

Ser Leu Ser Glu Met Thr His Phe Arg Pro Gln Leu His His Ser Gly

850 855 860

Asp Met Val Phe Thr Pro Glu Ser Gly Leu Gln Leu Arg Leu Asn Glu

865 870 875 880

Lys Leu Gly Thr Thr Ala Ala Thr Glu Leu Lys Lys Leu Asp Phe Lys

885 890 895

Val Ser Ser Thr Ser Asn Asn Leu Ile Ser Thr Ile Pro Ser Asp Asn

900 905 910

Leu Ala Ala Gly Thr Asp Asn Thr Ser Ser Leu Gly Pro Pro Ser Met

915 920 925

Pro Val His Tyr Asp Ser Gln Leu Asp Thr Thr Leu Phe Gly Lys Lys

930 935 940

Ser Ser Pro Leu Thr Glu Ser Gly Gly Pro Leu Ser Leu Ser Glu Glu

945 950 955 960

Asn Asn Asp Ser Lys Leu Leu Glu Ser Gly Leu Met Asn Ser Gln Glu

965 970 975

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

980 985 990

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

995 1000 1005

Glu Met Lys Lys Glu Asp Phe Asp Ile Tyr Asp Glu Asp Glu Asn

1010 1015 1020

Gln Ser Pro Arg Ser Phe Gln Lys Lys Thr Arg His Tyr Phe Ile

1025 1030 1035

Ala Ala Val Glu Arg Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro

1040 1045 1050

His Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val Pro Gln Phe

1055 1060 1065

Lys Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe Thr Gln

1070 1075 1080

Pro Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu Gly

1085 1090 1095

Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe

1100 1105 1110

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

1115 1120 1125

Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn

1130 1135 1140

Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln

1145 1150 1155

His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp

1160 1165 1170

Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val His Ser Gly

1175 1180 1185

Leu Ile Gly Pro Leu Leu Val Cys His Thr Asn Thr Leu Asn Pro

1190 1195 1200

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

1205 1210 1215

Thr Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met

1220 1225 1230

Glu Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro

1235 1240 1245

Thr Phe Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile

1250 1255 1260

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

1265 1270 1275

Arg Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser

1280 1285 1290

Ile His Phe Ser Gly His Val Phe Thr Val Arg Lys Lys Glu Glu

1295 1300 1305

Tyr Lys Met Ala Leu Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr

1310 1315 1320

Val Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu Cys

1325 1330 1335

Leu Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu

1340 1345 1350

Val Tyr Ser Asn Lys Cys Gln Thr Pro Leu Gly Met Ala Ser Gly

1355 1360 1365

His Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln

1370 1375 1380

Trp Ala Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn

1385 1390 1395

Ala Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu

1400 1405 1410

Leu Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg

1415 1420 1425

Gln Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr

1430 1435 1440

Ser Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr

1445 1450 1455

Gly Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile

1460 1465 1470

Lys His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg

1475 1480 1485

Leu His Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu

1490 1495 1500

Leu Met Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met

1505 1510 1515

Glu Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr

1520 1525 1530

Phe Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu

1535 1540 1545

His Leu Gln Gly Arg Ser Asn Ala Trp Arg Pro Gln Val Asn Asn

1550 1555 1560

Pro Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val

1565 1570 1575

Thr Gly Val Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met

1580 1585 1590

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

1595 1600 1605

Trp Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly

1610 1615 1620

Asn Gln Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro

1625 1630 1635

Leu Leu Thr Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His

1640 1645 1650

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

1655 1660 1665

Leu Tyr

1670

<210> 398

<211> 31

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Description of artificial sequence: synthetic

polypeptide

<400> 398

Ser Phe Ser Gln Asn Ala Thr Asn Val Ser Asn Asn Ser Asn Thr Ser

1 5 10 15

Asn Asp Ser Asn Val Ser Pro Pro Val Leu Lys Arg His Gln Arg

20 25 30

<---

Claims (55)

1. A non-capsid closed-end DNA (ccDNA) vector for the expression of factor VIII (FVIII) protein, containing: at least one nucleic acid sequence located between flanking inverted terminal repeats (ITRs), wherein the at least one nucleic acid sequence encodes at least one factor VIII (FVIII) protein and is codon optimized for expression in a cell, wherein said at least one nucleic acid sequence encoding said at least one FVIII protein has at least 85% identity with a sequence selected from the group consisting of sequences SEQ ID NO: 380-397. 2. The cDNA vector according to claim 1, characterized in that said at least one FVIII protein has at least 85% identity with a sequence selected from the group consisting of SEQ IS NO: 380, 387 and 393. 3. The cccDNA vector according to claim 1, wherein said ccDNA vector contains a nucleic acid sequence having at least 85% identity with a sequence selected from the group consisting of sequences SEQ ID NO: 192-217. 4. The cccDNA vector according to claim 1 or 3, characterized in that said ccDNA vector contains a nucleic acid sequence that is at least 85% identical to SEQ ID NO: 210. 5. The cccDNA vector according to claim 1 or 3, characterized in that said ccDNA vector contains a nucleic acid sequence that is at least 85% identical to SEQ ID NO: 214. 6. CctDNA vector according to any one of paragraphs. 1-5, characterized in that said cDNA vector contains a promoter operably linked to at least one nucleic acid sequence that encodes said at least one FVIII protein. 7. CctDNA vector according to any one of paragraphs. 1-6, characterized in that said cDNA vector contains an enhancer. 8. CctDNA vector according to any one of paragraphs. 1-7, characterized in that said cDNA vector contains a 5'-UTR and/or intron sequence. 9. CctDNA vector according to any one of paragraphs. 1-8, characterized in that said cDNA vector contains a 3'-UTR sequence. 10. CctDNA vector according to any one of paragraphs. 1-9, characterized in that said cDNA vector contains at least one poly(A) sequence. 11. CctDNA vector according to any one of paragraphs. 1-10, characterized in that said at least one nucleic acid sequence is cDNA. 12. CctDNA vector according to any one of paragraphs. 1-11, characterized in that at least one of these flanking ITRs contains a functional end resolution site and a replication protein (Rep) binding site. 13. CctDNA vector according to any one of paragraphs. 1-12, characterized in that one or both of said flanking ITRs are derived from a virus selected from the group consisting of parvovirus, dependovirus and adeno-associated virus (AAV). 14. CctDNA vector according to any one of paragraphs. 1-13, characterized in that said flanking ITRs are symmetrical or asymmetrical. ] 5. The cctDNA vector according to claim 14, characterized in that said flanking ITRs are symmetrical or substantially symmetrical. 16. CctDNA vector according to claim 14, characterized in that said flanking ITRs are asymmetric. 17. CctDNA vector according to any one of paragraphs. 1-16, characterized in that one of these ITRs is wild type, or both of these ITRs are wild type ITRs. 18. CctDNA vector according to any one of paragraphs. 1-17, characterized in that said flanking ITRs come from different viral serotypes. 19. CctDNA vector according to any one of paragraphs. 1-18, characterized in that said flanking ITRs come from a pair of viral serotypes selected from the group consisting of pairs of viral serotypes AAB1, AAB1; AAV2, AAV2; AAV3, AAV3; AAV4, AAV4; AAV5, AAV5; AAV1, AAV2; AAV2, AAV3; AAV3, AAV4; AAV4, AAV5; AAV5, AAV6; AAV1, AAV3; AAV2, AAV4; AAV3, AAV5; AAV4, AAV6; AAV5, AAV7; AAV1, AAV4; AAV2, AAV5; AAV3, AAV6; AAV4, AAV7; AAV5, AAV8; AAV1, AAV5; AAV2, AAV6; AAV3, AAV7; AAV4, AAV8; AAV5, AAV9; AAV1, AAV6; AAV2, AAV7; AAV3, AAV8; AAV4, AAV9; AAV5, AAV10; AAV1, AAV7; AAV2, AAV8; AAV3, AAV9; AAV4, AAV10; AAV5, AAV11; AAV1, AAV8; AAV2, AAV9; AAV3, AAV10; AAV4, AAVN; AAV5, AAV12; AAV1, AAV9; AAV2, AAV10; AAV3, AAV11; AAV4, AAV12; AAB5, AABRH8; AAV1, AAV10; AAV2, AAV11; AAV3, AAV12; AAB4, AABRH8; AAB5, AABRH10; AAV1, AAV11; AAV2, AAV12; AAB3, AABRH8; AAB4, AABRH10; AAV5, AAV13; AAV1, AAV12; AAB2, AABRH8; AAB3, AABRH10; AAV4, AAV13; AAB5, AABDJ; AAB1, AABRH8; AAB2, AABRH10; AAV3, AAV13; AAB4, AABDJ; AAB5, AABDJ8; AAB1, AABRH10; AAB2, AAB13; AAB3, AABDJ; AAB4, AABDJ8; AAB5, avian; AAB1, AAB13; AAB2,AABDJ; AAB3, AABDJ8; AAB4, avian; AAB5, bovine; AAB1, AABDJ; AAB2, AABDJ8; AAB3, avian; AAB4, bovine; AAB5, canine; AAB1, AABDJ8; AAV2, avian; AAB3, bovine; AAB4, canine; AAB5, equine; AAB1, avian; AAB2, bovine; AAB3, canine; AAB4, equine; AAB5, goat; AAB1, bovine; AAV2, canine; AAB3, equine; AAB4, goat; AAB5, shrimp; AAB1, canine; AAB2, equine; AAB3, goat; AAB4, shrimp; AAV5, porcine; AAB1, equine; AAB2, goat; AAB3, shrimp; AAB4, porcine; AAB5, insects; AAB1, goat; AAB2, shrimp; AAB3, porcine; AAB4, insects; AAB5, sheep; AAB1, shrimp; AAV2, porcine; AAB3, insects; AAB4, sheep; AAV5, B19; AAV1, porcine; AAB2, insects; AAB3, sheep; AAV4, B19; AAB5, MVM; AAB1, insects; AAB2, sheep; AAV3, B19; AAB4, MVM; AAB5, goose; AAB1, sheep; AAV2, B19; AAB3, MVM; AAB4, goose; AAB5, serpentine; AAV1, B19; AAB2, MVM; AAB3, anserine; AAB4, serpentine; AAB1, MVM; AAB2, anserine; AAB3, serpentine; AAB1, anserine; AAB2, serpentine; AAB1, serpentine; AAV6, AAV6; AAB7, AAV7; AAB8, AAV8; AAB9, AAV9; AAV10, AAV10; AAV6, AAV7; AAB7, AAV8; AAV8, AAV9; AAV9, AAV10; AAV10, AAV11; AAV6, AAV8; AAV7, AAV9; AAV8, AAV10; AAV9, AAV11; AAV10, AAV12; AAV6, AAV9; AAV7, AAV10; AAV8, AAV11; AAV9, AAV12; AAB10, AABRH8; AAV6, AAV10; AAV7, AAV11; AAV8, AAV12; AAB9, AABRH8; AAB10, AABRH10; AAV6, AAV11; AAV7, AAV12; AAB8, AABRH8; AAB9, AABRH10; AAV10, AAV13; AAV6, AAV12; AAB7, AABRH8; AAB8, AABRH10; AAV9, AAV13; AAB10, AABDJ; AAB6, AABRH8; AAB7, AABRH10; AAV8, AAV13; AAB9, AABDJ; AAB10, AABDJ8; AAB6, AABRH10; AAV7, AAV13; AAB8, AABDJ; AAB9, AABDJ8; AAB10, avian; AAV6, AAV13; AAB7, AABDJ; AAB8, AABDJ8; AAB9, avian; AAB10, bovine; AAB6, AABDJ; AAB7, AABDJ8; AAB8, avian; AAB9, bull; AAB10, canine; AAB6, AABDJ8; AAB7, avian; AAB8, bovine; AAB9, canine; AAB10, equine; AAB6, avian; AAB7, bovine; AAB8, canine; AAB9, equine; AAB10, goat; AAB6, bovine; AAB7, canine; AAB8, equine; AAB9, goat; AAB10, shrimp; AAB6, canine; AAB7, equine; AAB8, goat; AAB9, shrimp; AAB10, porcine; AAB6, equine; AAB7, goat; AAB8, shrimp; AAB9, pork; AAB10, insects; AAB6, goat; AAB7, shrimp; AAB8, porcine; AAB9, insects; AAB10, sheep; AAB6, shrimp; AAV7, porcine; AAB8, insects; AAB9, sheep; AAV10, B19; AAV6, porcine; AAB7, insects; AAB8, sheep; AAV9, B19; AAB10, MVM; AAB6, insects; AAB7, sheep; AAB8, B19; AAB9, MVM; AAB10, goose; AAB6, sheep; AAV7, B19; AAB8, MVM; AAB9, goose; AAB10, serpentine; AAV6, B19; AAB7, MVM; AAB8, goose; AAB9, serpentine; AAB6, MVM; AAB7, goose; AAB8, serpentine; AAB6, goose; AAB7, serpentine; AAB6, serpentine; AAV11, AAV11; AAV12, AAV12; AABRH8, AABRH8; AABRH10, AABRH10; AAV13, AAV13; AAV11, AAV12; AAB12, AABRH8; AABRH8, AABRH10; AABRH10, AAB13; AAB13, AABDJ; AAB11, AABRH8; AAB12, AABRH10; AABRH8, AAB13; AABRH10, AABDJ; AAB13, AABDJ8; AAB11, AABRH10; AAV12, AAV13; AABRH8, AABDJ; AABRH10, AABDJ8; AAB13, avian; AAV11, AAV13; AAB12, AABDJ; AABRH8, AABDJ8; AABRH10, avian; AAB13, bovine; AAB11, AABDJ; AAB12, AABDJ8; AABRH8, avian; AABRH10, bovine; AAB13, canine; AAB11, AABDJ8; AB12, avian; AABRH8, bovine; AABRH10, canine; AAB13, equine; AAB11, avian; AAB12, bovine; AABRH8, canine; AABRH10, equine; AAB13, goat; AAB11, bovine; AAB12, canine; AABRH8, equine; AABRH10, goat; AAB13, shrimp; AAB11, canine; AAB12, equine; AABRH8, goat; AABRH10, shrimp; AAV13, porcine; AAB11, equine; AAB12, goat; AABRH8, shrimp; AABRH10, porcine; AAB13, insects; AAB11, goat; AAB12, shrimp; AABRH8, porcine; AABRH10, insects; AAB13, sheep; AAB11, shrimp; AAV12, porcine; AABRH8, insects; AABRH10, sheep; AAV13, B19; AAV11, porcine; AAB12, insects; AABRH8, sheep; AABRH10, B19; AAB13, MVM; AAB11, insects; AAB12, sheep; AABRH8, B19; AABRH10, MVM; AAB13, goose; AAB11, sheep; AAV12, B19; AABRH8, MVM; AABRH10, goose; AAB13, serpentine; AAV11, B19; AAB12, MVM; AABRH8, goose; AABRH10, serpentine; AAB11, MVM; AAB12, goose; AABRH8, serpentine; AAB11, goose; AAB12, serpentine; AAB11, serpentine; AABDJ, AABDJ; AABDJ8, AVVDJ8; avian, avian; bullish, bullish; canine, canine; AABDJ, AABDJ8; AABDJ8, avian; avian, bovine; bull, dog; canine, equine; AABDJ, avian; AABDJ8, bovine; bird, dog; bull, horse; canine, goat; AABDJ, bovine; AABDJ8, canine; bird, horse; bovine, goat; dog, shrimp; AABDJ, canine; AABDJ8, equine; bird, goat; bovine, shrimp; dog, pork; AABDJ, equine; AABDJ8, goat; bird, shrimp; bovine, pork; canine, insects; AABDJ, goat; AABDJ8, shrimp; poultry, pork; bovine, insects; canine, sheep; AABDJ, shrimp; AABDJ8, porcine; avian, insects; bovine, sheep; canine, B19; AABDJ, pork; AABDJ8, insects; bird, sheep; bullish, B19; canine, MVM; AABDJ, insects; AABDJ8, sheep; avian, B19; bullish, MVM; canine, goose; AABDJ, sheep; AABDJ8, B19; avian, MVM; bovine, goose; canine, snake; AABDJ, B19; AABDJ8, MVM; bird, goose; bull, snake; AABDJ, MVM; AABDJ8, goose; bird, snake; AABDJ, goose; AABDJ8, serpentine; AABDJ, serpentine; equine, equine; goat, goat; prawns, prawns; pork, pork; insects, insects; horse, goat; goat, shrimp; shrimp, pork; pork, insects; insects, sheep; horse, shrimp; goat, pork; shrimp, insects; pork, sheep; insects, B19; horse, pork; goat, insects; shrimp, sheep; pork, B19; insects, MVM; equine, insects; goat, sheep; shrimp, B19; pork, MVM; insects, goose; horse, sheep; goat, B19; shrimp, MVM; pork, goose; insects, snake; equine, B19; goat, MVM; shrimp, goose; pork, snake; equine, MVM; goat, goose; shrimp, snake; horse, goose; goat, snake; horse, snake; sheep, sheep; B19, B19; MVM, MVM; goose, goose; serpentine, serpentine; sheep, B19; B19, MVM; MVM, anserine; goose, snake; sheep, MVM; B19, goose; MVM, serpentine; sheep, goose; B19, serpentine; sheep, snake. 20. CctDNA vector according to any one of paragraphs. 1-19, characterized in that one or both of said flanking ITRs contain a sequence selected from the group consisting of sequences SEQ ID NO: 1-2, 5-48. 21. CctDNA vector according to any one of paragraphs. 1-20, wherein at least one of said flanking ITRs is altered relative to the wild-type AAB ITR sequence by deletion, addition or substitution that affects the overall three-dimensional conformation of said ITR. 22. CctDNA vector according to any one of paragraphs. 1-21, characterized in that one or both of said flanking ITRs are derived from an AAV serotype selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11 and AAV12. 23. CctDNA vector according to any one of paragraphs. 1-22, characterized in that one or both of said flanking ITRs are synthetic. 24. CctDNA vector according to any one of paragraphs. 1-23, wherein one of the flanking ITRs is not a wild-type ITR, or both of the flanking ITRs are not a wild-type ITR. 25. CctDNA vector according to any one of paragraphs. 1-24, characterized in that one or both of said flanking ITRs are modified by deletion, insertion and/or substitution in at least one of the regions of said ITRs selected from the group consisting of A, A', B, B', C, C', D and D'. 26. The cctDNA vector according to claim 25, characterized in that said deletion, insertion and/or substitution results in the deletion of all or part of the stem-loop structure formed by said regions A, A', B, B', C or C' . 27. CctDNA vector according to any one of paragraphs. 1-26, wherein one or both of said flanking ITRs is modified by deletion, insertion and/or substitution that results in the deletion of all or part of the stem-loop structure formed by said regions B and B'. 28. CctDNA vector according to any one of paragraphs. 1-26, wherein one or both of said flanking ITRs is modified by deletion, insertion and/or substitution that results in the deletion of all or part of the stem-loop structure formed by said regions C and C'. 29. CctDNA vector according to any one of paragraphs. 1-26, characterized in that one or both of said flanking ITRs are modified by deletion, insertion and/or substitution which results in the deletion of all or part of the stem-loop structure formed by said regions B and B' and/or all or part of the stem-loop structure formed by said regions C and C'. 30. CctDNA vector according to any one of paragraphs. 1-29, characterized in that one or both of said flanking ITRs contain a single stem-loop structure in a region which, in a wild-type ITR, contains a first stem-loop structure formed by said regions B and B', and a second stem-loop structure -loop formed by the indicated regions C and C'. 31. CctDNA vector according to any one of paragraphs. 1-30, characterized in that one or both of said flanking ITRs comprise one stem and two loops in a region which, in a wild-type ITR, contains a first stem-loop structure formed by said regions B and B', and a second stem structure -loop formed by the indicated regions C and C'. 32. CctDNA vector according to any one of paragraphs. 1-31, characterized in that one or both of said flanking ITRs comprise one stem and one loop in a region which, in a wild-type ITR, contains a first stem-loop structure formed by said regions B and B', and a second stem structure -loop formed by the indicated regions C and C'. 33. CctDNA vector according to any one of paragraphs. 1-32, characterized in that both flanking ITRs are modified in such a way that this results in an overall three-dimensional symmetry in which said ITRs are inverted with respect to each other. 34. CctDNA vector according to any one of paragraphs. 1-33, characterized in that one or both of said flanking ITRs contain a sequence selected from the group consisting of sequences SEQ ID NO: 1-2, 5-48. 35. CctDNA vector according to any one of paragraphs. 1-34, characterized in that said cDNA vector includes at least one regulatory switch. 36. The cccDNA vector according to claim 35, characterized in that said at least one regulatory switch is selected from the group consisting of a binary regulatory switch, a small molecule regulatory switch, a passcode regulatory switch, a nucleic acid-based regulatory switch, post-transcriptional regulatory switch, radiation-controlled or ultrasound-controlled regulatory switch, hypoxia-mediated regulatory switch, inflammatory response regulatory switch, shift-activated regulatory switch and kill switch. 37. A method for expressing FVIII protein in a cell, including bringing said cell into contact with a cDNA vector according to any one of claims. 1-36. 38. The method according to claim 37, characterized in that said cell is a liver cell. 39. The method according to claim 37 or 38, characterized in that said cell is in vitro or in vivo. 40. Method according to any one of paragraphs. 37-39, characterized in that said at least one nucleic acid sequence is a sequence having at least 85% identity with a sequence selected from the group consisting of sequences SEQ ID NO: 380-397. 41. A method of treating a subject suffering from hemophilia A, comprising administering to said subject a cccDNA vector according to any one of claims. 1-36, characterized in that at least one heterologous nucleotide sequence encodes at least one FVIII protein. 42. The method of claim 41, wherein the levels of FVIII in the subject's serum are increased in subjects administered the cccDNA vector compared to controls. 43. The method of claim 42, wherein said increase in FVIII levels is greater than about 40% compared to the control. 44. The method of claim 41, wherein said at least one nucleic acid sequence is a sequence having at least 85% identity with a sequence selected from the group consisting of sequences SEQ ID NO: 380-397. 45. Method according to any one of paragraphs. 41-44, characterized in that said cDNA vector is introduced into a liver cell. 46. Method according to any one of paragraphs. 41-45, characterized in that said cDNA vector expresses said FVIII protein in a liver cell. 47. Method according to any one of paragraphs. 41-46, characterized in that said cccDNA vector is administered via any one or more routes selected from the group consisting of: intravenous injection, intramuscular injection and infusion. 48. Pharmaceutical composition for gene therapy containing a cccDNA vector according to any one of paragraphs. 1-36. 49. A cell for producing FVIII protein, containing a cDNA vector according to any one of claims. 1-36. 50. The cell according to claim 49, characterized in that said cell is a liver cell. 51. A composition for delivering a cDNA vector, containing a cDNA vector according to any one of claims. 1-36 and lipid. 52. The composition according to claim 51, characterized in that said lipid is a lipid nanoparticle (LNP). 53. A kit for delivering a cDNA vector, containing a cDNA vector according to any one of claims. 1-36, a pharmaceutical composition according to claim 48, a cell according to claim 49 or 50, or a composition according to claim 51 or 52 and instructions for use.