Compositions comprising curons and uses thereof
Patent Information
- Application Number
- IL271275
- Authority / Receiving Office
- IL · IL
- Patent Type
- Patents
- Current Assignee / Owner
- Priority Date
- 2018-05-25
- Filing Date
- 2018-06-13
- Publication Date
- 2026-08-01
- Estimated Expiration
- 2038-06-13
AI Technical Summary
Existing viral systems for delivering therapeutic agents are often immunogenic and pathogenic, posing risks and inefficiencies in treatment due to immune responses and potential disease associations.
Development of synthetic curons, which are non-immunogenic and non-pathogenic delivery vehicles comprising a genetic element enclosed in a proteinaceous exterior, capable of delivering therapeutic agents into eukaryotic cells with reduced integration frequency and immune response.
The synthetic curons effectively deliver therapeutic agents to eukaryotic cells with minimal immune response and pathogenicity, offering a safer and more efficient method for treating diseases by modulating cellular functions and reducing target protein levels.
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Abstract
Description
[0001] COMPOSITIONS COMPRISING CURONS AND USES THEREOF
[0002] RELATED APPLICATIONS
[0003] This application claims priority to U.S. Serial No. 62 / 518 , 898 filed June 13, 2017, U.S. Serial No. 62 / 597,387 filed December 11, 2017, and U.S. Serial No. 62 / 676,730 filed May 25, 2018, each of which is incorporated herein by reference in its entirety.
[0004] SEQUENCE LISTING
[0005] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on June 13, 2018, is named V2057-7000WO_SL.txt and is 1,066,292 bytes in size.
[0006] BACKGROUND
[0007] Existing viral systems for delivering therapeutic agents utilize viruses that can be associated with diseases or disorders, and can be highly immunogenic. There exists a need in the art for improved delivery vehicles that are substantially non-immunogenic and non-pathogenic.
[0008] SUMMARY
[0009] The present disclosure provides a curon, e.g., a synthetic curon, that can be used as a delivery vehicle, e.g., for delivering a therapeutic agent to a eukaryotic cell. In some embodiments, a curon comprises a particle comprising a genetic element encapsulated in a proteinaceous exterior, which is capable of introducing the genetic element into a cell (e.g., a human cell). In some instances, the genetic element comprises a payload, e.g., it encodes an exogenous effector (e.g., a nucleic acid effector, such as a non-coding RNA, or a polypeptide effector, e.g., a protein) that is expressed in the cell. For example, the curon can deliver an exogenous effector into a cell by contacting the cell and introducing a genetic element encoding the exogenous effector into the cell, such that the exogenous effector is made or expressed by the cell. The exogenous effector can, in some instances, modulate a function of the cell or modulate an activity or level of a target molecule in the cell. For example, the exogenous effector may decrease viability of a cancer cell (e.g., as described in Example 22) or decrease levels of a target protein, e.g., interferon, in the cell (e.g., as described in Examples 3 and 4). In another example, the exogenous effector may be a protein expressed by the cell (e.g., as described in Example 9).
[0010] A synthetic curon has at least one structural difference compared to a wild-type virus, e.g., a deletion, insertion, substitution, enzymatic modification, relative to a wild-type virus. Generally, synthetic curons include an exogenous genetic element enclosed within a proteinaceous exterior, which can be used as substantially non-immunogenic vehicles for delivering the genetic element, or an effector (e.g., an exogenous effector or an endogenous effector) encoded therein (e.g., a polypeptide or nucleic acid effector), into eukaryotic cells. Curons can be used for treatment of diseases and disorders, e.g., by delivering a therapeutic agent to a desired cell or tissue. The genetic element of a synthetic curon of the present disclosure can be a circular single-stranded DNA molecule, and generally includes a protein binding sequence that binds to the proteinaceous exterior, or a polypeptide attached thereto, which may facilitate enclosure of the genetic element within the proteinaceous exterior and / or enrichment of the genetic element, relative to other nucleic acids, within the proteinaceous exterior.
[0011] In an aspect, the invention features a synthetic curon comprising (i) a genetic element comprising a promoter element, a sequence encoding an exogenous effector, (e.g., a payload), and a protein binding sequence (e.g., an exterior protein binding sequence, e.g., a packaging signal). In some embodiments, the genetic element is a single-stranded DNA. Alternatively or in combination, the genetic element has one or both of the following properties: is circular and / or integrates into the genome of a eukaryotic cell at a frequency of less than about 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 1.5%, or 2% of the genetic element that enters the cell; and (ii) a proteinaceous exterior. In some embodiments, the genetic element is enclosed within the proteinaceous exterior. In some embodiments, the synthetic curon is capable of delivering the genetic element into a eukaryotic cell.
[0012] In an aspect, the invention features a synthetic curon comprising: (i) a genetic element comprising a promoter element and a sequence encoding an exogenous effector (e.g., a payload), and a protein binding sequence (e.g., an exterior protein binding sequence); and (ii) a proteinaceous exterior; wherein the genetic element is enclosed within the proteinaceous exterior; and wherein the synthetic curon is capable of delivering the genetic element into a eukaryotic cell. In some embodiments, the genetic element comprises a nucleic acid sequence (e.g., a nucleic acid sequence of between 300-4000 nucleotides, e.g., between 300-3500 nucleotides, between 300-3000 nucleotides, between 300-2500 nucleotides, between 300- 2000 nucleotides, between 300-1500 nucleotides) having at least 75% (e.g., at least 75, 76, 77, 78, 79, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%) sequence identity to a sequence of a wild-type Anellovirus (e.g., a wild-type Torque Teno virus (TTV), Torque Teno mini virus (TTMV), or TTMDV sequence, e.g., a wild-type Anellovirus sequence as listed in any of Tables 1, 3, 5, 7, 9, 11, or 13). In some embodiments, the genetic element comprises a nucleic acid sequence (e.g., a nucleic acid sequence of at least 300 nucleotides, 500 nucleotides, 1000 nucleotides, 1500 nucleotides, 2000 nucleotides, 2500 nucleotides, 3000 nucleotides or more) having at least 75% (e.g., at least 75, 76, 77, 78, 79, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%) sequence identity to a sequence of a wild- type Anellovirus (e.g., a wild-type Torque Teno virus (TTV), Torque Teno mini virus (TTMV), or TTMDV sequence, e.g., a wild-type Anellovirus sequence as listed in any of Tables 1, 3, 5, 7, 9, 11, or 13).
[0013] In an aspect, the invention features a method of treating a disease or disorder in a subject, the method comprising administering to the subject a curon, e.g., a synthetic curon, e.g., as described herein. In some embodiments, the curon comprises: (i) a genetic element comprising a promoter element and a sequence encoding an effector, e.g., a payload, and an exterior protein binding sequence. In some embodiments, the genetic element is a single-stranded DNA, and wherein the genetic element is circular and / or integrates at a frequency of less than about 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 1.5%, or 2% of the genetic element that enters the cell; and (ii) a proteinaceous exterior; wherein the genetic element is enclosed within the proteinaceous exterior; and wherein the curon is capable of delivering the genetic element into a eukaryotic cell.
[0014] In an aspect, the invention features a method of delivering a payload to a cell, tissue or subject, the method comprising administering to the subject a curon, e.g., a synthetic curon, e.g., as described herein, wherein the curon comprises a nucleic acid sequence encoding the payload. In some
[0015] embodiments, the curon comprises: (i) a genetic element comprising a promoter element and a sequence encoding an effector, e.g., a payload, and an exterior protein binding sequence. In some embodiments, the genetic element is a single-stranded DNA, and wherein the genetic element is circular and / or integrates at a frequency of less than about 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 1.5%, or 2% of the genetic element that enters the cell; and (ii) a proteinaceous exterior; wherein the genetic element is enclosed within the proteinaceous exterior; and wherein the curon is capable of delivering the genetic element into a eukaryotic cell. In embodiments, the payload is a nucleic acid. In embodiments, the payload is a protein.
[0016] In an aspect, the invention features a method of delivering a synthetic curon to a cell, comprising contacting the synthetic curon described herein, e.g., of any of the aspects herein (e.g., the preceding aspects) with a cell, e.g., a eukaryotic cell, e.g., a mammalian cell.
[0017] In an aspect, the invention features a pharmaceutical composition comprising a curon (e.g., a synthetic curon) as described herein. In embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient. In embodiments, the pharmaceutical composition comprises a dose comprising about 105-1014genome equivalents of the curon per kilogram.
[0018] In an aspect, the invention features a nucleic acid molecule comprising a genetic element comprising a promoter element and a sequence encoding an effector, e.g., a payload, and an exterior protein binding sequence. In embodiments, the genetic element is a single-stranded DNA, and wherein the genetic element is circular and / or integrates at a frequency of less than about 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 1.5%, or 2% of the genetic element that enters the cell. In embodiments, the effector does not originate from TTV and is not an SV40-miR-Sl. In embodiments, the nucleic acid molecule does not comprise the polynucleotide sequence of TTMV-LY. In embodiments, the promoter element is capable of directing expression of the effector in a eukaryotic cell.
[0019] In an aspect, the invention features a genetic element comprising one, two, or three of: (i) a promoter element and a sequence encoding an effector, e.g., a payload; wherein the effector is exogenous relative to a wild-type Anellovirus sequence; (ii) at least 72 contiguous nucleotides (e.g., at least 72, 73, 74, 75, 76, 77, 78, 79, 80, 90, 100, or 150 nucleotides) having at least 75% (e.g., at least 75, 76, 77, 78, 79, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%) sequence identity to a wild-type Anellovirus sequence; or at least 100 (e.g., at least 300, 500, 1000, 1500) contiguous nucleotides having at least 72% (e.g., at least 72, 73, 74, 75, 76, 77, 78, 79, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%) sequence identity to a wild-type Anellovirus sequence; and (iii) a protein binding sequence, e.g., an exterior protein binding sequence, and wherein the nucleic acid construct is a single-stranded DNA; and wherein the nucleic acid construct is circular and / or integrates at a frequency of less than about 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 1.5%, or 2% of the genetic element that enters the cell.
[0020] In an aspect, the invention features a method of manufacturing a synthetic curon composition, comprising:
[0021] a) providing a host cell comprising, e.g., expressing one or more components (e.g., all of the components) of a curon, e.g., a synthetic curon, e.g., as described herein;
[0022] b) producing a preparation of curons from the host cell, wherein the synthetic curons of the preparation comprise a proteinaceous exterior and a genetic element comprising a promoter element, a sequence encoding an exogenous effector, (e.g., a payload), and a protein binding sequence (e.g., an exterior protein binding sequence, e.g., a packaging signal), thereby making a preparation of synthetic curon; and
[0023] c) formulating the preparation of synthetic curons, e.g., as a pharmaceutical composition suitable for administration to a subject.
[0024] In an aspect, the invention features a method of manufacturing a synthetic curon composition, comprising: a) providing a plurality of synthetic curon described herein, or a pharmaceutical composition described herein; and b) formulating the synthetic curons, e.g., as a pharmaceutical composition suitable for administration to a subject.
[0025] In an aspect, the invention features a method of making a host cell, e.g., a first host cell or a producer cell (e.g., as shown in Figure 12), e.g., a population of first host cells, comprising a synthetic curon, the method comprising introducing a genetic element, e.g., as described herein, to a host cell and culturing the host cell under conditions suitable for production of the synthetic curon. In embodiments, the method further comprises introducing a helper, e.g., a helper virus, to the host cell. In embodiments, the introducing comprises transfection (e.g., chemical transfection) or electroporation of the host cell with the synthetic curon.
[0026] In an aspect, the invention features a method of making a synthetic curon, comprising providing a host cell, e.g., a first host cell or producer cell (e.g., as shown in Figure 12), comprising a synthetic curon, e.g., as described herein, and purifying the curon from the host cell. In some embodiments, the method further comprises, prior to the providing step, contacting the host cell with a synthetic curon, e.g., as described herein, and incubating the host cell under conditions suitable for production of the synthetic curon. In embodiments, the host cell is the first host cell or producer cell described in the above method of making a host cell. In embodiments, purifying the curon from the host cell comprises lysing the host cell.
[0027] In some embodiments, the method further comprises a second step of contacting the synthetic curon produced by the first host cell or producer cell with a second host cell, e.g., a permissive cell (e.g., as shown in Figure 12), e.g., a population of second host cells. In some embodiments, the method further comprises incubating the second host cell inder conditions suitable for production of the synthetic curon. In some embodiments, the method further comprises purifying a synthetic curon from the second host cell, e.g., thereby producing a curon seed population. In embodiments, at least about 2-100-fold more of the synthetic curon is produced from the population of second host cells than from the population of first host cells. In embodiments, purifying the curon from the second host cell comprises lysing the second host cell.
[0028] In some embodiments, the method further comprises a second step of contacting the synthetic curon produced by the second host cell with a third host cell, e.g., permissive cells (e.g., as shown in Figure 12), e.g., a population of third host cells. In some embodiments, the method further comprises incubating the third host cell inder conditions suitable for production of the synthetic curon. In some embodiments, the method further comprises purifying a synthetic curon from the third host cell, e.g., thereby producing a curon stock population. In embodiments, purifying the curon from the third host cell comprises lysing the third host cell. In embodiments, at least about 2-100-fold more of the synthetic curon is produced from the population of third host cells than from the population of second host cells.
[0029] In some embodiments, the method further comprises evaluating one or more synthetic curons from the curon seed population or the curon stock population for one or more quality control parameters, e.g., purity, titer, potency (e.g., in genomic equivalents per curon particle), and / or the nucleic acid sequence, e.g., from the genetic element comprised by the synthetic curon. In some embodiments, the evaluated nucleic acid sequence comprises the nucleic acid sequence encoding an exogenous effector.
[0030] In an aspect, the invention comprises evaluating one or more synthetic curons, e.g., from a curon seed population or a curon stock population, for one or more quality control parameters, e.g., purity, titer, potency, and / or the nucleic acid sequence, e.g., from the genetic element comprised by the synthetic curon. In some embodiments, the evaluated nucleic acid sequence comprises the nucleic acid sequence encoding an exogenous effector.
[0031] In an aspect, the invention features a reaction mixture comprising a synthetic curon described herein and a helper virus, wherein the helper virus comprises a polynucleotide, e.g., a polynucleotide encoding an exterior protein, (e.g., an exterior protein capable of binding to the exterior protein binding sequence and, optionally, a lipid envelope), a polynucleotide encoding a replication protein (e.g., a polymerase), or any combination thereof.
[0032] In some embodiments, a curon (e.g., a synthetic curon) is isolated, e.g., isolated from a host cell and / or isolated from other constituents in a solution (e.g., a supernatant). In some embodiments, a curon (e.g., a synthetic curon) is purified, e.g., from a solution (e.g., a supernatant). In some embodiments, a curon is enriched in a solution relative to other constituents in the solution.
[0033] In some embodiments of any of the aforesaid curons, compositions or methods, the genetic element comprises a minimal curon genome, e.g., as identified according to the method described in Example 9. In some embodiments, the minimal curon genome comprises a minimal Anellovirus genome sufficient for replication of the curon (e.g., in a host cell). In embodiments, the minimal curon genome comprises a TTV-tth8 nucleic acid sequence, e.g., a TTV-tth8 nucleic acid sequence shown in Table 5, having deletions of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100% of nucleotides 3436-3707 of the TTV-tth8 nucleic acid sequence. In embodiments, the minimal curon genome comprises a TTMV-LY2 nucleic acid sequence, e.g., a TTMV-LY2 nucleic acid sequence shown in Table 11, having deletions of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100% of nucleotides 574-1371, 1432-2210, 574-2210, and / or 2610-2809 of the TTMV-LY2 nucleic acid sequence. In embodiments, the minimal curon genome is a minimal curon genome capable of self- replication and / or self-amplification. In embodiments, the minimal curon genome is a minimal curon genome capable of replicating or being amplified in the presence of a helper, e.g., a helper virus.
[0034] Additional features of any of the aforesaid curons, compositions or methods include one or more of the following enumerated embodiments.
[0035] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following enumerated embodiments. Enumerated Embodiments
[0036] 1. A synthetic curon comprising:
[0037] (i) a genetic element comprising a promoter element, a nucleic acid sequence (e.g., a DNA sequence) encoding an exogenous effector, (e.g., a payload), and a protein binding sequence (e.g., an exterior protein binding sequence, e.g., a packaging signal), wherein the genetic element is a single- stranded DNA, and has one or both of the following properties: is circular and / or integrates into the genome of a eukaryotic cell at a frequency of less than about 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 1.5%, or 2% of the genetic element that enters the cell; and
[0038] (ii) a proteinaceous exterior;
[0039] wherein the genetic element is enclosed within the proteinaceous exterior; and
[0040] wherein the synthetic curon is capable of delivering the genetic element into a eukaryotic cell.
[0041] 2. A synthetic curon comprising:
[0042] (i) a genetic element comprising a promoter element and a nucleic acid sequence (e.g., a DNA sequence) encoding an exogenous effector (e.g., a payload), and a protein binding sequence (e.g., an exterior protein binding sequence),
[0043] wherein the genetic element has at least 75% (e.g., at least 75, 76, 77, 78, 79, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%) sequence identity to a wild-type Anellovirus sequence (e.g., a wild- type Torque Teno virus (TTV), Torque Teno mini virus (TTMV), or TTMDV sequence, e.g., a wild-type Anellovirus sequence, e.g., as listed in any of Tables 1, 3, 5, 7, 9, 11, or 13); and
[0044] (ii) a proteinaceous exterior;
[0045] wherein the genetic element is enclosed within the proteinaceous exterior; and
[0046] wherein the synthetic curon is capable of delivering the genetic element into a eukaryotic cell. 3. A synthetic curon comprising:
[0047] (i) a genetic element comprising a promoter element and a nucleic acid sequence (e.g., a DNA sequence) encoding an effector (e.g., an exogenous effector or endogenous effector, e.g., endogenous miRNA), and a protein binding sequence (e.g., an exterior protein binding sequence),
[0048] wherein the genetic element has at least 75% (e.g., at least 75, 76, 77, 78, 79, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%) sequence identity to a wild-type Anellovirus sequence (e.g., a wild- type Torque Teno virus (TTV), Torque Teno mini virus (TTMV), or TTMDV sequence, e.g., a wild-type Anellovirus sequence, e.g., as listed in any of Tables 1, 3, 5, 7, 9, 11, or 13); and
[0049] wherein the genetic element is not a naturally occurring sequence (e.g., comprises a deletion, substitution, or insertion relative to a wild-type Anellovirus sequence (e.g., a wild-type Torque Teno virus (XXV), Torque Teno mini virus (TTMV), or TTMDV sequence, e.g., a wild-type Anellovirus sequence, e.g., as listed in any of Tables 1, 3, 5, 7, 9, 11, or 13);
[0050] (ii) a proteinaceous exterior;
[0051] wherein the genetic element is enclosed within the proteinaceous exterior; and
[0052] wherein the synthetic curon is capable of delivering the genetic element into a eukaryotic cell.
[0053] 4. A synthetic curon comprising:
[0054] (i) a genetic element comprising a promoter element and a nucleic acid sequence (e.g., a DNA sequence) encoding an exogenous effector (e.g., a payload), and a protein binding sequence (e.g., an exterior protein binding sequence),
[0055] wherein the protein binding sequence has at least 75% (e.g., at least 75, 76, 77, 78, 79, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%) sequence identity to the Consensus 5' UTR sequence shown in Table 16-1, or to the Consensus GC-rich sequence shown in Table 16-2, or both of the Consensus 5' UTR sequence shown in Table 16-1 and to the Consensus GC-rich sequence shown in Table 16-2; and
[0056] (ii) a proteinaceous exterior;
[0057] wherein the genetic element is enclosed within the proteinaceous exterior; and
[0058] wherein the synthetic curon is capable of delivering the genetic element into a eukaryotic cell.
[0059] 5. A synthetic curon comprising:
[0060] (i) a genetic element comprising a promoter element and a nucleic acid sequence encoding an exogenous effector, and a protein binding sequence, wherein the genetic element comprises one or both of:
[0061] (a) a sequence having at least 85% sequence identity to the Anellovirus 5' UTR conserved domain nucleotide sequence of nucleotides 323 - 393 of the nucleic acid sequence of Table 11 , or
[0062] (b) a sequence having at least 85% sequence identity to the Anellovirus GC-rich region of nucleotides 2868 - 2929 of the nucleic acid sequence of Table 11;
[0063] and
[0064] (ii) a proteinaceous exterior; wherein the genetic element is enclosed within the proteinaceous exterior; and
[0065] wherein the synthetic curon is capable of delivering the genetic element into a eukaryotic cell.
[0066] 6. A synthetic curon comprising: (i) a genetic element comprising a promoter element and a nucleic acid sequence encoding an exogenous effector, and a protein binding sequence, wherein the genetic element comprises one or both of:
[0067] (a) a sequence having at least 85% sequence identity to the Anellovirus 5' UTR conserved domain of the nucleic acid sequence of Table 1, 3, 5, 7, 9 or 13; or
[0068] (b) a sequence having at least 85% sequence identity to the Anellovirus GC-rich region of the nucleic acid sequence of of Table 1, 3, 5, 7, 9 or 13;
[0069] and
[0070] (ii) a proteinaceous exterior; wherein the genetic element is enclosed within the proteinaceous exterior; and
[0071] wherein the synthetic curon is capable of delivering the genetic element into a eukaryotic cell.
[0072] 7. The synthetic curon of any of the preceding embodiments, wherein the promoter element comprises an RNA polymerase II-dependent promoter, an RNA polymerase Ill-dependent promoter, a PGK promoter, a CMV promoter, an EF-la promoter, an SV40 promoter, a CAGG promoter, or a UBC promoter, TTV viral promoters, Tissue specific, U6 (pollIII), minimal CMV promoter with upstream DNA binding sites for activator proteins (TetR-VP16, Gal4-VP16, dCas9-VP16, etc).
[0073] 8. The synthetic curon of any of the preceding embodiments, wherein the promoter element comprises a TATA box.
[0074] 9. The synthetic curon of any of the preceding embodiments, wherein the promoter element is endogenous to a wild-type Anellovirus, e.g., a wild-type Anellovirus sequence as listed in any of Tables 1, 3, 5, 6, 9, 11, or 13.
[0075] 10. The synthetic curon of any of embodiments 1-8, wherein the promoter element is exogenous to wild-type Anellovirus.
[0076] 11. The synthetic curon of any of the preceding embodiments, wherein the exogenous effector encodes a therapeutic agent, e.g., a therapeutic peptide or polypeptide or a therapeutic nucleic acid.
[0077] 12. The synthetic curon of any of the preceding embodiments, wherein the exogenous effector comprises a regulatory nucleic acid, e.g., an miRNA, siRNA, mRNA, IncRNA, RNA, DNA, an antisense RNA, gRNA; a fluorescent tag or marker, an antigen, a peptide, a synthetic or analog peptide from a naturally-bioactive peptide, an agonist or antagonist peptide, an anti-microbial peptide, a pore -forming peptide, a bicyclic peptide, a targeting or cytotoxic peptide, a degradation or self-destruction peptide, a small molecule, an immune effector (e.g., influences susceptibility to an immune response / signal), a death protein (e.g., an inducer of apoptosis or necrosis), a non-lytic inhibitor of a tumor (e.g., an inhibitor of an oncoprotein), an epigenetic modifying agent, an epigenetic enzyme, a transcription factor, a DNA or protein modification enzyme, a DNA-intercalating agent, an efflux pump inhibitor, a nuclear receptor activator or inhibitor, a proteasome inhibitor, a competitive inhibitor for an enzyme, a protein synthesis effector or inhibitor, a nuclease, a protein fragment or domain, a ligand, an antibody, a receptor, or a CRISPR system or component.
[0078] 13. The synthetic curon of any of the preceding embodiments, wherein the exogenous effector comprises a miRNA.
[0079] 14. The synthetic curon of any of the preceding embodiments, wherein the effector, e.g., miRNA, targets a host gene, e.g., modulates expression of the gene, e.g., increases or decreases expression of the gene.
[0080] 15. The synthetic curon of any of the preceding embodiments, wherein the exogenous effector comprises an miRNA, and decreases expression of a host gene.
[0081] 16. The synthetic curon of any of the preceding embodiments, wherein the exogenous effector comprises a nucleic acid sequence about 20-200, 30-180, 40-160, 50-140, or 60-120 nucleotides in length.
[0082] 17. The synthetic curon of any of the preceding embodiments, wherein the nucleic acid sequence encoding the exogenous effector is about 20-200, 30-180, 40-160, 50-140, or 60-120 nucleotides in length.
[0083] 18. The synthetic curon of any of the preceding embodiments, wherein the sequence encoding the exogenous effector has a size of at least about 100 nucleotides.
[0084] 19. The synthetic curon of any of the preceding embodiments, wherein the sequence encoding the exogenous effector has a size of about 100 to about 5000 nucleotides. 20. The synthetic curon of any of the preceding embodiments, wherein the sequence encoding the exogenous effector has a size of about 100-200, 200-300, 300-400, 400-500, 500-600, 600-700, 700- 800, 800-900, 900-1000, 1000-1500, or 1500-2000 nucleotides.
[0085] 21. The synthetic curon of any of the preceding embodiments, wherein the sequence encoding the exogenous effector is situated at, within, or adjacent to (e.g., 5' or 3' to) one or more of the ORFl locus (e.g., at the C-terminus of the ORFl locus), the miRNA locus, the 5' noncoding region upstream of the TATA box, the 5' UTR, the 3' noncoding region downstream of the poly- A region, or a noncoding region upstream of the GC-rich region of the genetic element.
[0086] 22. The synthetic curon of embodiment 21, wherein the sequence encoding the exogenous effector is located between the poly-A region and the GC-rich region of the genetic element.
[0087] 23. The synethtic curon of any of the preceding embodiments, which comprises (e.g., in the proteinaceous exterior) one or more of an amino acid sequence chosen from ORF2, ORF2 / 2, ORF2 / 3, ORFl, ORFl / 1, or ORFl / 2 of Table 12, or an amino acid sequence having at least 85% sequence identity thereto.
[0088] 24. The synethtic curon of any of the preceding embodiments, which comprises (e.g., in the proteinaceous exterior) one or more of an amino acid sequence chosen from ORF2, ORF2 / 2, ORF2 / 3, ORF2t / 3, ORFl, ORFl / 1, or ORFl / 2 of any of Tables 2, 4, 6, 8, 10, or 14, or an amino acid sequence having at least 85% sequence identity thereto.
[0089] 25. The synthetic curon of any of the preceding embodiments, wherein the protein binding sequence comprises a nucleic acid sequence having at least 75% (e.g., at least 75, 76, 77, 78, 79, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%) sequence identity to the 5' UTR conserved domain or the GC- rich domain of a wild-type Anellovirus, e.g., a wild-type Anellovirus sequence as listed in any of Tables 1, 3, 5, 6, 9, 11, 13, A, or B.
[0090] 26. The synthetic curon of any of the preceding embodiments, wherein the genetic element, e.g., protein binding sequence of the genetic element, comprises least about 75% (e.g., at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the Consensus 5' UTR nucleic acid sequence shown in Table 16-1. 27. The synthetic curon of any of the preceding embodiments, wherein the genetic element, e.g., protein binding sequence of the genetic element, comprises least about 75% (e.g., at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the exemplary TTV 5' UTR nucleic acid sequence shown in Table 16-1.
[0091] 28. The synthetic curon of any of the preceding embodiments, wherein the genetic element, e.g., protein binding sequence of the genetic element, comprises least about 75% (e.g., at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the TTV-CT30F 5' UTR nucleic acid sequence shown in Table 16-1.
[0092] 29. The synthetic curon of any of the preceding embodiments, wherein the genetic element, e.g., protein binding sequence of the genetic element, comprises least about 75% (e.g., at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the TTV-HD23a 5' UTR nucleic acid sequence shown in Table 16-1.
[0093] 30. The synthetic curon of any of the preceding embodiments, wherein the genetic element, e.g., protein binding sequence of the genetic element, comprises least about 75% (e.g., at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the TTV-JA20 5' UTR nucleic acid sequence shown in Table 16-1.
[0094] 31. The synthetic curon of any of the preceding embodiments, wherein the genetic element, e.g., protein binding sequence of the genetic element, comprises least about 75% (e.g., at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the TTV-TJN02 5' UTR nucleic acid sequence shown in Table 16-1.
[0095] 32. The synthetic curon of any of the preceding embodiments, wherein the genetic element, e.g., protein binding sequence of the genetic element, comprises least about 75% (e.g., at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the TTV-tth8 5' UTR nucleic acid sequence shown in Table 16-1.
[0096] 33. The synthetic curon of any of the preceding embodiments, wherein the genetic element, e.g., protein binding sequence of the genetic element, comprises least about 75% (e.g., at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the Consensus GC-rich region shown in Table 16-2.
[0097] 34. The synthetic curon of any of the preceding embodiments, wherein the genetic element, e.g., protein binding sequence of the genetic element, comprises least about 75% (e.g., at least 75%, 80%,
[0098] 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the exemplary TTV GC-rich region shown in Table 16-2.
[0099] 35. The synthetic curon of any of the preceding embodiments, wherein the genetic element, e.g., protein binding sequence of the genetic element, comprises least about 75% (e.g., at least 75%, 80%,
[0100] 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the TTV-CT30F GC-rich region shown in Table 16-2.
[0101] 36. The synthetic curon of any of the preceding embodiments, wherein the genetic element, e.g., protein binding sequence of the genetic element, comprises least about 75% (e.g., at least 75%, 80%,
[0102] 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the TTV-HD23a GC-rich region shown in Table 16-2.
[0103] 37. The synthetic curon of any of the preceding embodiments, wherein the genetic element, e.g., protein binding sequence of the genetic element, comprises least about 75% (e.g., at least 75%, 80%,
[0104] 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the TTV-JA20 GC-rich region shown in Table 16-2.
[0105] 38. The synthetic curon of any of the preceding embodiments, wherein the genetic element, e.g., protein binding sequence of the genetic element, comprises least about 75% (e.g., at least 75%, 80%,
[0106] 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the TTV-TJN02 GC-rich region shown in Table 16-2.
[0107] 39. The synthetic curon of any of the preceding embodiments, wherein the genetic element, e.g., protein binding sequence of the genetic element, comprises least about 75% (e.g., at least 75%, 80%,
[0108] 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) identity to the TTV-tth8 GC-rich region shown in Table 16-2. 40. The synthetic curon of any of the preceding embodiments, wherein at least 60% (e.g., at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%) of the protein binding sequence consists of G or C. 41. The synthetic curon of any of the preceding embodiments, wherein the genetic element comprises a sequence of at least 80, 90, 100, 110, 120, 130, or 140 nucleotides in length, which consists of G or C at at least 70% (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%) or about 70-100%, 75-95%, 80-95%, 85-95%, or 85-90% of the positions. 42. The synthetic curon of any of the preceding embodiments, wherein the genetic element comprises a sequence having at least 85% sequence identity to the Anellovirus 5' UTR conserved domain nucleotide sequence of nucleotides 1 - 393 of the nucleic acid sequence of Table 11 and a sequence having at least 85% sequence identity to the Anellovirus GC-rich region of nucleotides 2868 - 2929 of the nucleic acid sequence of Table 11.
[0109] 43. The synthetic curon of any of the preceding embodiments, wherein the protein binding sequence is capable of binding to an exterior protein, e.g., a capsid protein, e.g., an Anellovirus capsid protein, e.g., a capsid protein comprising an amino acid sequence having at least 75% (e.g., at least 75, 76, 77, 78, 79, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%) sequence identity to any of the sequences listed in Table 1-14, 16, or 18.
[0110] 44. The synthetic curon of any of the preceding embodiments, wherein the genetic element comprises at least 75% identity to the nucleotide sequence of Table 11. 45. The synthetic curon of any of the preceding embodiments, wherein the protein binding sequence binds an arginine-rich region of the proteinaceous exterior.
[0111] 46. The synthetic curon of any of the preceding embodiments, wherein the proteinaceous exterior comprises an exterior protein capable of specifically binding to the protein binding sequence.
[0112] 47. The synthetic curon of embodiment 46, wherein the exterior protein comprises a capsid protein e.g., an Anellovirus capsid protein, e.g., a capsid protein comprising an amino acid sequence having at least 75% (e.g., at least 75, 76, 77, 78, 79, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%) sequence identity to any of the sequences listed in any of Tables 1-14, 16, or 18 or an amino acid sequence encoded by any of the sequences listed in Table 1-14, 15, 17, or 19, or a fragment thereof.
[0113] 48. The synthetic curon of any of the preceding embodiments, wherein the proteinaceous exterior comprises one or more of the following: one or more glycosylated proteins, a hydrophilic DNA-binding region, an arginine-rich region, a threonine-rich region, a glutamine-rich region, a N-terminal polyarginine sequence, a variable region, a C-terminal polyglutamine / glutamate sequence, and one or more disulfide bridges. 49. The synthetic curon of any of the preceding embodiments, wherein the proteinaceous exterior comprises one or more of the following characteristics: an icosahedral symmetry, recognizes and / or binds a molecule that interacts with one or more host cell molecules to mediate entry into the host cell, lacks lipid molecules, lacks carbohydrates, is pH and temperature stable, is detergent resistant, and is substantially non-immunogenic or substantially non-pathogenic in a host.
[0114] 50. The synthetic curon of any of the preceding embodiments, wherein the proteinaceous exterior comprises at least one functional domain that provides one or more functions, e.g., species and / or tissue and / or cell selectivity, genetic element binding and / or packaging, immune evasion (substantial non- immunogenicity and / or tolerance), pharmacokinetics, endocytosis and / or cell attachment, nuclear entry, intracellular modulation and localization, exocytosis modulation, propagation, and nucleic acid protection.
[0115] 51. The synthetic curon of any of the preceding embodiments, wherein the portions of the genetic element excluding the effector have a combined size of about 2.5-5 kb (e.g., about 2.8-4kb, about 2.8- 3.2kb, about 3.6-3.9kb, or about 2.8-2.9kb), less than about 5kb (e.g., less than about 2.9kb, 3.2 kb, 3.6kb, 3.9kb, or 4kb), or at least 100 nucleotides (e.g., at least lkb).
[0116] 52. The synthetic curon of any of the preceding embodiments, wherein the genetic element is single-stranded.
[0117] 53. The synthetic curon of any of the preceding embodiments, wherein the genetic element is circular. 54. The synthetic curon of any of the preceding embodiments, wherein the genetic element is
[0118] DNA.
[0119] 55. The synthetic curon of any of the preceding embodiments, wherein the genetic element is a negative strand DNA.
[0120] 56. The synthetic curon of any of the preceding embodiments, wherein the genetic element comprises an episome. 57. The synthetic curon of any of the preceding embodiments, wherein the synthetic curon has a lipid content of less than 10%, 5%, 2%, or 1% by weight, e.g., does not comprise a lipid bilayer.
[0121] 58. The synthetic curon of any of the preceding embodiments, wherein the synthetic curon is resistant to degradation by a detergent (e.g., a mild detergent, e.g., a biliary salt, e.g., sodium
[0122] deoxycholate) relative to a viral particle comprising an external lipid bilayer, e.g., a retrovirus.
[0123] 59. The synthetic curon of embodiment 58, wherein at least about 50% (e.g., at least about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%) of the synthetic curon is not degraded after incubation the detergent (e.g., 0.5% by weight of the detergent) for 30 minutes at 37°C.
[0124] 60. The synthetic curon of any of the preceding embodiments, wherein the genetic element has at least 75% (e.g., at least 75, 76, 77, 78, 79, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%) sequence identity to a wild-type Circoviridae sequence or a wild-type Anellovirus sequence, e.g., a wild-type Torque Teno virus (TTV), Torque Teno mini virus (TTMV), or TTMDV sequence, e.g., a sequence as listed in any of Tables 1, 3, 5, 7, 9, 11, or 13.
[0125] 61. The synthetic curon of embodiment 60, wherein the genetic element comprises a deletion of at least one element, e.g., an element as listed in any of Tables 1, 3, 5, 7, 9, 11, or 13, relative to a wild- type Anellovirus sequence, e.g., a wild-type TTV sequence or a wild-type TTMV sequence.
[0126] 62. The synthetic curon of embodiment 61, wherein the genetic element comprises a deletion comprising a nucleic acid sequence corresponding to nucleotides 3436-3607 of a TTV-tth8 sequence, e.g., the nucleic acid sequence shown in Table 5. 63. The synthetic curon of embodiment 61 , wherein the genetic element comprises a deletion comprising a nucleic acid sequence corresponding to nucleotides 574-1371 and / or nucleotides 1432-2210 of a TTMV-LY2 sequence, e.g., the nucleic acid sequence shown in Table 11.
[0127] 64. The synthetic curon of embodiment 61 or 62, wherein the genetic element comprises a deletion comprising a nucleic acid sequence corresponding to nucleotides 1372-1431 of a TTMV-LY2 sequence, e.g., the nucleic acid sequence shown in Table 11.
[0128] 65. The synthetic curon of embodiment 61 , 63, or 64, wherein the genetic element comprises a deletion comprising a nucleic acid sequence corresponding to nucleotides 2610-2809 of a TTMV-LY2 sequence, e.g., the nucleic acid sequence shown in Table 11.
[0129] 66. The synthetic curon of any of the preceding embodiments, wherein the genetic element comprises at least 72 nucleotides (e.g., at least 73, 74, 75, etc. nt, optionally less than the full length of the genome) of a wild-type Anellovirus sequence, e.g., a wild-type Torque Teno virus (TTV), Torque Teno mini virus (TTMV), or TTMDV sequence, e.g., a sequence as listed in any of Tables 1 , 3, 5, 7, 9, 11 , or 13.
[0130] 67. The synthetic curon of any of the preceding embodiments, wherein the genetic element further comprises one or more of the following sequences: a sequence that encodes one or more miRNAs, a sequence that encodes one or more replication proteins, a sequence that encodes an exogenous gene, a sequence that encodes a therapeutic, a regulatory sequence (e.g., a promoter, enhancer), a sequence that encodes one or more regulatory sequences that targets endogenous genes (siRNA, IncRNAs, shRNA), a sequence that encodes a therapeutic mRNA or protein, and a sequence that encodes a cytolytic / cytotoxic RNA or protein.
[0131] 68. The synthetic curon of any of the preceding embodiments, wherein the synthetic curon further comprises a second genetic element, e.g., a second genetic element enclosed within the proteinaceous exterior.
[0132] 69. The synthetic curon of embodiment 68, wherein the second genetic element comprises a protein binding sequence, e.g., an exterior protein binding sequence, e.g., a packaging signal, e.g., a 5' UTR conserved domain or GC-rich region, e.g., as described herein. 70. The synthetic curon of any of the preceding embodiments, wherein the synthetic curon does not detectably infect bacterial cells, e.g., infects less than 1%, 0.5%, 0.1%, or 0.01% of bacterial cells.
[0133] 71. The synthetic curon of any of the preceding embodiments, wherein the synthetic curon is capable of infecting mammalian cells, e.g., human cells, e.g., immune cells, liver cells, epithelial cells, e.g., in vitro.
[0134] 72. The synthetic curon of any of the preceding embodiments, wherein the genetic element integrates at a frequency of less than 10%, 8%, 6%, 4%, 3%, 2%, 1%, 0.5%, 0.2%, 0.1% of the curons that enters the cell, e.g., wherein the synthetic curon is non-integrating.
[0135] 73. The synthetic curon of any of the preceding embodiments, wherein the genetic element is capable of replicating, e.g., capable of generating at least 102, 2 x 102, 5 x 102, 103, 2 x 103, 5 x 103, or 104genomic equivalents of the genetic element per cell, e.g., as measured by a quantitative PCR assay.
[0136] 74. The synthetic curon of any of the preceding embodiments, wherein the genetic element is capable of replicating, e.g., capable of generating at least 102, 2 x 102, 5 x 102, 103, 2 x 103, 5 x 103, or 104more genomic equivalents of the genetic element in a cell, e.g., as measured by a quantitative PCR assay, than were present in the synthetic curon prior to delivery of the genetic element into the cell.
[0137] 75. The synthetic curon of any of the preceding embodiments, wherein the genetic element is not capable of replicating, e.g., wherein the genetic element is altered at a replication origin or lacks a replication origin. 76. The synthetic curon of any of the preceding embodiments, wherein the genetic element is not capable of self-replicating, e.g., capable of being replicated without being integrated into a host cell genome.
[0138] 77. The synthetic curon of any of the preceding embodiments, wherein the synthetic curon is substantially non-pathogenic, e.g., does not induce a detectable deleterious symptom in a subject (e.g., elevated cell death or toxicity, e.g., relative to a subject not exposed to the curon). 78. The synthetic curon of any of the preceding embodiments, wherein the synthetic curon is substantially non-immunogenic, e.g., does not induce a detectable and / or unwanted immune response, e.g., as detected according to the method described in Example 4.
[0139] 79. The synthetic curon of embodiment 78, wherein the substantially non-immunogenic curon has an efficacy in a subject that is a least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% of the efficacy in a reference subject lacking an immune response.
[0140] 80. The synthetic curon of embodiment 78 or 79, wherein the immune response comprises one or more of an antibody specific to the curon; a cellular response (e.g., an immune effector cell (e.g., T cell- or NK cell) response) against the curon or cells comprising the curon; or macrophage engulf ment of the curon or cells comprising the curon.
[0141] 81. The synthetic curon of any of the preceding embodiments, wherein the synthetic curon is less immunogenic than an AAV, elicits an immune response below that detected for a comparable quantity of AAV, e.g., as measured by an assay described herein, induces an antibody prevalence of less than 70% (e.g., less than about 60%, 50%, 40%, 30%, 20%, or 10% antibody prevalence) as measured by an assay described herein, or is substantially non-immunogenic.
[0142] 82. The synthetic curon of any of the preceding embodiments, wherein a population of at least 1000 of the synthetic curons is capable of delivering at least 100 copies of the genetic element into one or more of the eukaryotic cells.
[0143] 83. The synthetic curon of any of the preceding embodiments, wherein a population of the synthetic curons is capable of delivering the genetic element into at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more of a population of the eukaryotic cells.
[0144] 84. The synthetic curon of any of the preceding embodiments, wherein a population of the synthetic curons is capable of delivering at least 1, 2, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 8,000, 1 x 104, 1 x 10s, 1 x 106, 1 x 107or greater copies of the genetic element per cell to a population of the eukaryotic cells.
[0145] 85. The synthetic curon of any of the preceding embodiments, wherein a population of the synthetic curons is capable of delivering 1 x 104-1 x 10s, 1 x 104-1 x 106, 1 x 104-1 x 107, 1 x 105-1 x 106, 1 x 105-1 x 107, or 1 x 106-1 x 107copies of the genetic element per cell to a population of the eukaryotic cells.
[0146] 86. The synthetic curon of any of the preceding embodiments, wherein the synthetic curon is present after at least two passages.
[0147] 87. The synthetic curon of any of the preceding embodiments, wherein the synthetic curon was produced by a process comprising at least two passages. 88. The synthetic curon of any of the preceding embodiments, wherein the synthetic curon selectively delivers the exogenous effector to a desired cell type, tissue, or organ (e.g., photoreceptors in the retina, epithelial linings, or pancreas).
[0148] 89. The synthetic curon of any of the preceding embodiments, wherein the synthetic curon shows greater selectivity in vitro for an embryonic kidney cell line (e.g., HEK293T) than a lung epithelial carcinoma cell line (e.g., A549).
[0149] 90. The synthetic curon of any of the preceding embodiments, wherein the synthetic curon is present at higher levels in (e.g., preferentially accumulates in) a desired organ or tissue relative to other organs or tissues.
[0150] 91. The synthetic curon of embodiment 90, wherein the desired organ or tissue comprises bone marrow, blood, heart, GI, or skin. 92. The synthetic curon of any of the preceding embodiments, wherein the eukaryotic cell is a mammalian cell, e.g., a human cell.
[0151] 93. The synthetic curon of any of the preceding embodiments, wherein the synthetic curon, or copies thereof, are detectable in a cell 24 hours (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 30 days, or 1 month) after delivery into the cell.
[0152] 94. The synthetic curon of any of the preceding embodiments, wherein the synthetic curon is produced in the cell pellet and the supernatant at at least about 108-fold (e.g., about 10s-fold, 106-fold, 107-fold, 108-fold, 109-fold, or 1010-fold) genomic equivalents / mL, e.g., relative to the quantity of the synthetic curon used to infect the cells, after 3-4 days post infection, e.g., using an infectivity assay, e.g., an assay according to Example 7.
[0153] 95. A composition comprising the synthetic curon of any of the preceding embodiments.
[0154] 96. A pharmaceutical composition comprising the synthetic curon of any of the preceding embodiments, and a pharmaceutically acceptable carrier or excipient.
[0155] 97. The composition or pharmaceutical composition of embodiment 95 or 96, which comprises at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or more curons, e.g., synthetic curons.
[0156] 98. The composition or pharmaceutical composition of any of embodiments 95-97, which comprises at least 103, 104, 10s, 106, 107, 10s, or 109synthetic curons. 99. A pharmaceutical composition comprising
[0157] a) at least 103, 104, 10s, 106, 107, 10s, or 109curons (e.g., synthetic curons described herein) comprising:
[0158] (i) a genetic element described herein, e.g., a genetic element comprising a promoter element, a nucleic acid sequence (e.g., a DNA sequence) encoding an exogenous effector, (e.g., a payload), and a protein binding sequence (e.g., an exterior protein binding sequence, e.g., a packaging signal), wherein the genetic element is a single-stranded DNA, and has one or both of the following properties: is circular and / or integrates into the genome of a eukaryotic cell at a frequency of less than about 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 1.5%, or 2% of the genetic element that enters the cell; and
[0159] (ii) a proteinaceous exterior,
[0160] wherein the genetic element is enclosed within the proteinaceous exterior; and wherein the synthetic curon is capable of delivering the genetic element into a eukaryotic cell;
[0161] b) a pharmaceutical excipient, and, optionally,
[0162] c) less than a pre-determined amount of: mycoplasma, endotoxin, host cell nucleic acids (e.g., host cell DNA and / or host cell RNA), animal-derived process impurities (e.g., serum albumin or trypsin), replication-competent agents (RCA), e.g., replication-competent virus or unwanted curons, free viral capsid protein, adventitious agents, and / or aggregates. 100. A pharmaceutical composition comprising
[0163] a) at least 103, 104, 10s, 106, 107, 10s, or 109curons (e.g., synthetic curons described herein) comprising:
[0164] (i) a genetic element described herein, e.g., a genetic element comprising a promoter element and a nucleic acid sequence (e.g., a DNA sequence) encoding an exogenous effector (e.g., a payload), and a protein binding sequence (e.g., an exterior protein binding sequence),
[0165] wherein the genetic element has at least 75% (e.g., at least 75, 76, 77, 78, 79, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%) sequence identity to a wild-type
[0166] Anellovirus sequence (e.g., a wild-type Torque Teno virus (TTV), Torque Teno mini virus (TTMV), or TTMDV sequence, e.g., a wild-type Anellovirus sequence, e.g., as listed in any of Tables 1, 3, 5, 7, 9, 11, or 13); and
[0167] (ii) a proteinaceous exterior;
[0168] wherein the genetic element is enclosed within the proteinaceous exterior; and wherein the synthetic curon is capable of delivering the genetic element into a eukaryotic cell
[0169] b) a pharmaceutical excipient, and, optionally,
[0170] c) less than a pre-determined amount of: mycoplasma, endotoxin, host cell nucleic acids (e.g., host cell DNA and / or host cell RNA), animal-derived process impurities (e.g., serum albumin or trypsin), replication-competent agents (RCA), e.g., replication-competent virus or unwanted curons, free viral capsid protein, adventitious agents, and / or aggregates.
[0171] 101. The composition or pharmaceutical composition of any of embodiments 95-100, having one or more of the following characteristics:
[0172] a) the pharmaceutical composition meets a pharmaceutical or good manufacturing practices (GMP) standard;
[0173] b) the pharmaceutical composition was made according to good manufacturing practices
[0174] (GMP);
[0175] c) the pharmaceutical composition has a pathogen level below a predetermined reference value, e.g., is substantially free of pathogens;
[0176] d) the pharmaceutical composition has a contaminant level below a predetermined reference value, e.g., is substantially free of contaminants; e) the pharmaceutical composition has a predetermined level of non-infectious particles or a predetermined ratio of particles infectious units (e.g., <300: 1, < 200: 1, <100: 1, or <50: 1), or
[0177] f) the pharmaceutical composition has low immunogenicity or is substantially non- immunogenic, e.g., as described herein.
[0178] 102. The composition or pharmaceutical composition of any of embodiments 95-101, wherein the pharmaceutical composition has a contaminant level below a predetermined reference value, e.g., is substantially free of contaminants. 103. The composition or pharmaceutical composition of embodiment 102, wherein the contaminant is selected from the group consisting of: mycoplasma, endotoxin, host cell nucleic acids (e.g., host cell DNA and / or host cell RNA), animal-derived process impurities (e.g., serum albumin or trypsin), replication-competent agents (RCA), e.g., replication-competent virus or unwanted curons (e.g., a curon other than the desired curon, e.g., a synthetic curon as described herein), free viral capsid protein, adventitious agents, and aggregates.
[0179] 104. The composition or pharmaceutical composition of embodiment 103, wherein the contaminant is host cell DNA and the threshold amount is about 500 ng of host cell DNA per dose of the pharmaceutical composition.
[0180] 105. The composition or pharmaceutical composition of any of embodiments 95-104, wherein the pharmaceutical composition comprises less than 10% (e.g., less than about 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1%) contaminant by weight. 106. Use of the synthetic curon, composition, or pharmaceutical composition of any of the preceding embodiments for treating a disease or disorder in a subject.
[0181] 107. The use of embodiment 106, wherein the disease or disorder is chosen from an immune disorder, an interferonopathy (e.g., Type I interferonopathy), infectious disease, inflammatory disorder, autoimmune condition, cancer (e.g., a solid tumor, e.g., lung cancer), and a gastrointestinal disorder.
[0182] 108. The synthetic curon, composition, or pharmaceutical composition of any of the preceding embodiments for use in treating a disease or disorder in a subject. 109. A method of treating a disease or disorder in a subject, the method comprising administering a synthetic curon of any of the preceding embodiments or the pharmaceutical composition of any of embodiments 95-105 to the subject. 110. The method of embodiment 109, wherein the disease or disorder is chosen from an immune disorder, an interferonopathy (e.g., Type I interferonopathy), infectious disease, inflammatory disorder, autoimmune condition, cancer (e.g., a solid tumor, e.g., lung cancer), and a gastrointestinal disorder.
[0183] 111. A method of modulating, e.g., enhancing, a biological function in a subject, the method comprising administering a synthetic curon of any of the preceding embodiments or the pharmaceutical composition of any of embodiments 95-105 to the subject.
[0184] 112. A method of treating a disease or disorder in a subject, the method comprising
[0185] administering to the subject a curon, e.g., synthetic curon, comprising:
[0186] (i) a genetic element comprising a promoter element and a sequence encoding an effector, e.g., a pay load, and an exterior protein binding sequence;
[0187] wherein the genetic element is a single-stranded DNA, and wherein the genetic element is circular and / or integrates at a frequency of less than about 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 1.5%, or 2% of the genetic element that enters a cell; and
[0188] (ii) a proteinaceous exterior;
[0189] wherein the genetic element is enclosed within the proteinaceous exterior; and
[0190] wherein the curon, e.g., synthetic curon, is capable of delivering the genetic element into a eukaryotic cell. 113. The method of embodiment 112, wherein the disease or disorder is chosen from an immune disorder, an interferonopathy (e.g., Type I interferonopathy), infectious disease, inflammatory disorder, autoimmune condition, cancer (e.g., a solid tumor, e.g., lung cancer), and a gastrointestinal disorder.
[0191] 114. The method of any of embodiments 109-113, wherein the effector is not an SV40-miR-Sl, e.g., wherein the effector is a protein-encoding payload.
[0192] 115. The method of any of embodiments 109-114, wherein the curon does not comprise an exogenous effector. 116. The method of any of embodiments 109-115, wherein the curon comprises a wild-type Circovirus or a wild-type Anellovirus, e.g., TTV or TTMV.
[0193] 117. The method of any of embodiments 109-116, wherein the administration of the curon, e.g., synthetic curon, results in delivery of the genetic element into at least 10%, 20%, 30%, 40%, 50%, 60%,
[0194] 70%, 80%, 90%, 95%, 99%, or more of a population of target cells in the subject.
[0195] 118. The method of any of embodiments 109-117, wherein the administration of the curon, e.g., synthetic curon, results in delivery of the exogenous effector into at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more of a population of target cells in the subject.
[0196] 119. The method of embodiment 117 or 118, wherein the target cells comprise mammalian cells, e.g., human cells, e.g., immune cells, liver cells, lung epithelial cells, e.g., in vitro. 120. The method of any of embodiments 117-119, wherein the target cells are present in the liver or lung.
[0197] 121. The method of any of embodiments 117-120, wherein the target cells into which the genetic element is delivered each receive at least 10, 50, 100, 500, 1000, 10,000, 50,000, 100,000, or more copies of the genetic element.
[0198] 122. The method of any of embodiments 109-121, wherein the effector comprises a miRNA and wherein the miRNA reduces the level of a target protein or RNA in a cell or in a population of cells, e.g., into which the curon is delivered, e.g., by at least 10%, 20%, 30%, 40%, or 50%.
[0199] 123. A method of delivering a synthetic curon to a cell, comprising contacting the synthetic curon of any of the preceding embodiments with a cell, e.g., a eukaryotic cell, e.g., a mammalian cell.
[0200] 124. The method of embodiment 123, further comprising contacting a helper virus with the cell, wherein the helper virus comprises a polynucleotide, e.g., a polynucleotide encoding an exterior protein, e.g., an exterior protein capable of binding to the exterior protein binding sequence and, optionally, a lipid envelope. 125. The method of embodiment 124, wherein the helper virus is contacted with the cell prior to, concurrently with, or after contacting the synthetic curon with the cell.
[0201] 126. The method of embodiment 123, further comprising contacting a helper polynucleotide with the cell.
[0202] 127. The method of embodiment 126, wherein the helper polynucleotide comprises a sequence polynucleotide encoding an exterior protein, e.g., an exterior protein capable of binding to the exterior protein binding sequence and a lipid envelope.
[0203] 128. The method of embodiment 126, wherein the helper polynucleotide is an RNA (e.g., mRNA), DNA, plasmid, viral polynucleotide, or any combination thereof.
[0204] 129. The method of any of embodiments 126-128, wherein the helper polynucleotide is contacted with the cell prior to, concurrently with, or after contacting the synthetic curon with the cell.
[0205] 130. The method of any of embodiments 123-129, further comprising contacting a helper protein with the cell. 131. The method of embodiment 130, wherein the helper protein comprises a viral replication protein or a capsid protein.
[0206] 132. A host cell comprising the synthetic curon of any of the preceding embodiments. 133. A nucleic acid molecule comprising a promoter element, a sequence encoding an effector
[0207] (e.g., a payload), and an exterior protein binding sequence,
[0208] wherein the nucleic acid molecule is a single-stranded DNA, and wherein the nucleic acid molecule is circular and / or integrates at a frequency of less than about 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 1.5%, or 2% of the nucleic acid molecule that enters a cell;
[0209] wherein the effector does not originate from TTV and is not an SV40-miR-Sl ;
[0210] wherein the nucleic acid molecule does not comprise the polynucleotide sequence of TTMV-LY; wherein the promoter element is capable of directing expression of the effector in a eukaryotic cell. 134. A nucleic acid molecule comprising a promoter element and a nucleic acid sequence encoding an exogenous effector, and a protein binding sequence, wherein the genetic element comprises one or both of:
[0211] (a) a sequence having at least 85% sequence identity to the Anellovirus 5' UTR conserved domain nucleotide sequence of nucleotides 323 - 393 of the nucleic acid sequence of Table 11 , or
[0212] (b) a sequence having at least 85% sequence identity to the Anellovirus GC-rich region of nucleotides 2868 - 2929 of the nucleic acid sequence of Table 11.
[0213] 135. A nucleic acid molecule comprising a promoter element and a nucleic acid sequence encoding an exogenous effector, and a protein binding sequence, wherein the genetic element comprises one or both of:
[0214] (a) a sequence having at least 85% sequence identity to the Anellovirus 5' UTR conserved domain of the nucleic acid sequence of Table 1, 3, 5, 7, 9 or 13; or
[0215] (b) a sequence having at least 85% sequence identity to the Anellovirus GC-rich region of the nucleic acid sequence of of Table 1, 3, 5, 7, 9 or 13.
[0216] 136. A genetic element comprising:
[0217] (i) a promoter element and a sequence encoding an effector, e.g., a payload, wherein the effector is exogenous relative to a wild-type Anellovirus sequence;
[0218] (ii) at least 72 contiguous nucleotides (e.g., at least 72, 73, 74, 75, 76, 77, 78, 79, 80, 90, 100, or 150 nucleotides) having at least 75% sequence identity to a wild-type Anellovirus sequence; or at least 100 contiguous nucleotides having at least 72% (e.g., at least 72, 73, 74, 75, 76, 77, 78, 79, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%) sequence identity to a wild-type Anellovirus sequence; and
[0219] (iii) a protein binding sequence, e.g., an exterior protein binding sequence, and
[0220] wherein the nucleic acid construct is a single-stranded DNA; and
[0221] wherein the nucleic acid construct is circular and / or integrates at a frequency of less than about 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 1.5%, or 2% of the genetic element that enters a cell.
[0222] 137. A method of manufacturing a synthetic curon composition, comprising:
[0223] a) providing a host cell comprising one or more nucleic acid molecules encoding the components of a synthetic curon, e.g., a synthetic curon described herein, wherein the synthetic curon comprises a proteinaceous exterior and a genetic element, e.g., a genetic element comprising a promoter element, a sequence encoding an exogenous effector, (e.g., a payload), and a protein binding sequence (e.g., an exterior protein binding sequence, e.g., a packaging signal);
[0224] b) producing a synthetic curon from the host cell, thereby making a synthetic curon; and c) formulating the synthetic curons, e.g., as a pharmaceutical composition suitable for administration to a subject.
[0225] 138. A method of manufacturing a synthetic curon composition, comprising:
[0226] a) providing a plurality of synthetic curons according to any of the preceding embodiments, or a composition or pharmaceutical composition of any of embodiments 95-105;
[0227] b) optionally evaluating the plurality for one or more of: a contaminant described herein, an optical density measurement (e.g., OD 260), particle number (e.g., by HPLC), infectivity (e.g., particle:infectious unit ratio); and
[0228] c) formulating the plurality of synthetic curons, e.g., as a pharmaceutical composition suitable for administration to a subject, e.g., if one or more of the paramaters of (b) meet a specified threshold.
[0229] 139. The method of embodiment 138, wherein the synthetic curon composition comprises at least 10s, 106, 107, 10s, 109, 1010, 10n, 1012, 1013, 1014, or 1015synthetic curons.
[0230] 140. The method of embodiment 138 or 139, wherein the synthetic curon composition comprises at least 10 ml, 20 ml, 50 ml, 100 ml, 200 ml, 500 ml, 1 L, 2 L, 5 L, 10 L, 20 L, or 50 L.
[0231] 141. A reaction mixture comprising the synthetic curon of any of the preceding embodiments and a helper virus, wherein the helper virus comprises a polynucleotide, e.g., a polynucleotide encoding an exterior protein, e.g., an exterior protein capable of binding to the exterior protein binding sequence and, optionally, a lipid envelope.
[0232] 142. A reaction mixture comprising the synthetic curon of any of the preceding embodiments and a second nucleic acid sequence encoding one or more of an amino acid sequence chosen from ORF2, ORF2 / 2, ORF2 / 3, ORFl, ORFl / 1, or ORFl / 2 of Table 12, or an amino acid sequence having at least 85% sequence identity thereto.
[0233] 143. A reaction mixture comprising the synthetic curon of any of the preceding embodiments and a second nucleic acid sequence encoding one or more of an amino acid sequence chosen from ORF2, ORF2 / 2, ORF2 / 3, ORF2t / 3, ORFl, ORFl / 1, or ORFl / 2 of any of Tables 2, 4, 6, 8, 10, or 14, or an amino acid sequence having at least 85% sequence identity thereto.
[0234] 144. The reaction mixture of embodiment 142 or 143, wherein the second nucleic acid sequence is part of the genetic element.
[0235] 145. The reaction mixture of embodiment 144, wherein the second nucleic acid sequence is not part of the genetic element, e.g., the second nucleic acid sequence is comprised by a helper cell or helper virus.
[0236] 146. A synthetic curon comprising:
[0237] a genetic element comprising (i) a sequence encoding a non-pathogenic exterior protein, (ii) an exterior protein binding sequence that binds the genetic element to the non-pathogenic exterior protein, and (iii) a sequence encoding an effector, e.g., a regulatory nucleic acid; and
[0238] a proteinaceous exterior that is associated with, e.g., envelops or encloses, the genetic element.
[0239] 147. A pharmaceutical composition comprising
[0240] a) a curon comprising:
[0241] a genetic element comprising (i) a sequence encoding a non-pathogenic exterior protein, (ii) an exterior protein binding sequence that binds the genetic element to the non-pathogenic exterior protein, and (iii) a sequence encoding an effector, e.g., a regulatory nucleic acid; and
[0242] a proteinaceous exterior that is associated with, e.g., envelops or encloses, the genetic element; and
[0243] b) a pharmaceutical excipient.
[0244] 148. A pharmaceutical composition comprising
[0245] a) at least 103, 104, 10s, 106, 107, 10s, or 109curons (e.g., synthetic curons described herein) comprising:
[0246] a genetic element comprising (i) a sequence encoding a non-pathogenic exterior protein, (ii) an exterior protein binding sequence that binds the genetic element to the non-pathogenic exterior protein, and (iii) a sequence encoding an effector, e.g., a regulatory nucleic acid; and
[0247] a proteinaceous exterior that is associated with, e.g., envelops or encloses, the genetic element; b) a pharmaceutical excipient, and, optionally,
[0248] c) less than a pre-determined amount of: mycoplasma, endotoxin, host cell nucleic acids (e.g., host cell DNA and / or host cell RNA), animal-derived process impurities (e.g., serum albumin or trypsin), replication-competent agents (RCA), e.g., replication-competent virus or unwanted curons, free viral capsid protein, adventitious agents, and / or aggregates.
[0249] 149. The curon or composition of any one of the previous embodiments, further comprising at least one of the following characteristics: the genetic element is a single-stranded DNA; the genetic element is circular; the curon is non-integrating; the curon has a sequence, structure, and / or function based on an anellovirus or other non-pathogenic virus, and the curon is non-pathogenic.
[0250] 150. The curon or composition of any one of the previous embodiments, wherein the proteinaceous exterior comprises the non-pathogenic exterior protein.
[0251] 151. The curon or composition of any one of the previous embodiments, wherein the proteinaceous exterior comprises one or more of the following: one or more glycosylated proteins, a hydrophilic DNA-binding region, an arginine-rich region, a threonine -rich region, a glutamine-rich region, a N-terminal polyarginine sequence, a variable region, a C-terminal polyglutamine / glutamate sequence, and one or more disulfide bridges.
[0252] 152. The curon or composition of any one of the previous embodiments, wherein the proteinaceous exterior comprises one or more of the following characteristics: an icosahedral symmetry, recognizes and / or binds a molecule that interacts with one or more host cell molecules to mediate entry into the host cell, lacks lipid molecules, lacks carbohydrates, is pH and temperature stable, is detergent resistant, and is non-immunogenic or non-pathogenic in a host.
[0253] 153. The curon or composition of any one of the previous embodiments, wherein the sequence encoding the non-pathogenic exterior protein comprise a sequence at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to one or more sequences or a fragment thereof listed in Table 15.
[0254] 154. The curon or composition of any one of the previous embodiments, wherein the nonpathogenic exterior protein comprises a sequence at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to one or more sequences or a fragment thereof listed in Table 16 or Table 17. 155. The curon or composition of any one of the previous embodiments, wherein the nonpathogenic exterior protein comprises at least one functional domain that provides one or more functions, e.g., species and / or tissue and / or cell tropism, viral genome binding and / or packaging, immune evasion (non-immunogenicity and / or tolerance), pharmacokinetics, endocytosis and / or cell attachment, nuclear entry, intracellular modulation and localization, exocytosis modulation, propagation, and nucleic acid protection.
[0255] 156. The curon or composition of any one of the previous embodiments, wherein the effector comprises a regulatory nucleic acid, e.g., an miRNA, siRNA, mRNA, IncRNA, RNA, DNA, an antisense RNA, gRNA; a therapeutic, e.g., fluorescent tag or marker, antigen, peptide therapeutic, synthetic or analog peptide from naturally-bioactive peptide, agonist or antagonist peptide, anti-microbial peptide, pore -forming peptide, a bicyclic peptide, a targeting or cytotoxic peptide, a degradation or self-destruction peptide, and degradation or self-destruction peptides, small molecule, immune effector (e.g., influences susceptibility to an immune response / signal), a death protein (e.g., an inducer of apoptosis or necrosis), a non-lytic inhibitor of a tumor (e.g., an inhibitor of an oncoprotein), an epigenetic modifying agent, epigenetic enzyme, a transcription factor, a DNA or protein modification enzyme, a DNA-intercalating agent, an efflux pump inhibitor, a nuclear receptor activator or inhibitor, a proteasome inhibitor, a competitive inhibitor for an enzyme, a protein synthesis effector or inhibitor, a nuclease, a protein fragment or domain, a ligand or a receptor, and a CRISPR system or component.
[0256] 157. The curon or composition of any one of the previous embodiments, wherein the effector comprises a sequence at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical to one or more miRNA sequences listed in Table 18. 158. The curon or composition of the previous embodiment, wherein the effector, e.g., miRNA, targets a host gene, e.g., modulates expression of the gene.
[0257] 159. The curon or composition of the previous embodiment, wherein the miRNA, e.g., has at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to one or more sequences listed in Table 16.
[0258] 160. The curon or composition of any one of the previous embodiments, wherein the genetic element further comprises one or more of the following sequences: a sequence that encodes one or more miRNAs, a sequence that encodes one or more replication proteins, a sequence that encodes an exogenous gene, a sequence that encodes a therapeutic, a regulatory sequence (e.g., a promoter, enhancer), a sequence that encodes one or more regulatory sequences that targets endogenous genes (siRNA,
[0259] IncRNAs, shRNA), a sequence that encodes a therapeutic mRNA or protein, and a sequence that encodes a cytolytic / cytotoxic RNA or protein.
[0260] 161. The curon or composition of any one of the previous embodiments, wherein the genetic element has one or more of the following characteristics: is non-integrating with a host cell's genome, is an episomal nucleic acid, is a single stranded DNA, is about 1 to 10 kb, exists within the nucleus of the cell, is capable of being bound by endogenous proteins, and produces a microRNA that targets host genes.
[0261] 162. The curon or composition of any one of the previous embodiments, wherein the genetic element comprises at least one viral sequence or at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identity to one or more sequences or a fragment thereof listed in Table 19 or Table 20.
[0262] 163. The curon or composition of the previous embodiment, wherein the viral sequence is from at least one of a single stranded DNA virus (e.g., Anellovirus, Bidnavirus, Circovirus, Geminivirus, Genomovirus, Inovirus, Microvirus, Nanovirus, Parvovirus, and Spiravirus), a double stranded DNA virus (e.g., Adenovirus, Ampullavirus, Ascovirus, Asfarvirus, Baculovirus, Fusellovirus, Globulovirus, Guttavirus, Hytrosavirus, Herpesvirus, Iridovirus, Lipothrixvirus, Nimavirus, and Poxvirus), a RNA virus (e.g., Alphavirus, Furovirus, Hepatitis virus, Hordeivirus, Tobamovirus, Tobravirus, Tricornavirus, Rubivirus, Birnavirus, Cystovirus, Partitivirus, and Reovirus).
[0263] 164. The curon or composition of the previous embodiment, wherein the viral sequence is from one or more non-anelloviruses, e.g., adenovirus, herpes virus, pox virus, vaccinia virus, SV40, papilloma virus, an RNA virus such as a retrovirus, e.g., lenti virus, a single-stranded RNA virus, e.g., hepatitis virus, or a double-stranded RNA virus e.g., rotavirus.
[0264] 165. The curon or composition of any one of the previous embodiments, wherein the protein binding sequence interacts with the arginine-rich region of the proteinaceous exterior.
[0265] 166. The curon or composition of any one of the previous embodiments, wherein the curon is capable of replicating in a mammalian cell, e.g., human cell. 167. The curon or composition of the previous embodiment, wherein the curon is nonpathogenic and / or non-integrating in a host cell.
[0266] 168. The curon or composition of any one of the previous embodiments, wherein the curon is non-immunogenic in a host.
[0267] 169. The curon or composition of any one of the previous embodiments, wherein the curon inhibits / enhances one or more viral properties, e.g., selectivity, e.g., infectivity, e.g.,
[0268] immunosuppression / activation, in a host or host cell.
[0269] 170. The curon or composition of the previous embodiment, wherein the curon is in an amount sufficient to modulate (e.g., phenotype, virus levels, gene expression, compete with other viruses, disease state, etc. at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more). 171. The composition of any one of the previous embodiments further comprising at least one virus or vector comprising a genome of the virus, e.g., a variant of the curon, e.g., a commensal / native virus.
[0270] 172. The composition of any one of the previous embodiments further comprising a heterologous moiety, at least one small molecule, antibody, polypeptide, nucleic acid, targeting agent, imaging agent, nanoparticle, and a combination thereof.
[0271] 173. A vector comprising a genetic element comprising (i) a sequence encoding a nonpathogenic exterior protein, (ii) an exterior protein binding sequence that binds the genetic element to the non-pathogenic exterior protein, and (iii) a sequence encoding an effector, e.g., a regulatory nucleic acid.
[0272] 174. The vector of the previous embodiment, wherein the genetic element fails to integrate with a host cell's genome. 175. The vector of any one of the previous embodiments, wherein the genetic element is capable of replicating in a mammalian cell, e.g., human cell.
[0273] 176. The vector of any one of the previous embodiments further comprising an exogenous nucleic acid sequence, e.g., selected to modulate expression of a gene, e.g., a human gene. 177. A pharmaceutical composition comprising the vector of any one of the previous embodiments and a pharmaceutical excipient. 178. The composition of the previous embodiment, wherein the vector is non-pathogenic and / or non-integrating in a host cell.
[0274] 179. The composition of any one of the previous embodiments, wherein the vector is non- immunogenic in a host.
[0275] 180. The composition of the previous embodiment, wherein the vector is in an amount sufficient to modulate (phenotype, virus levels, gene expression, compete with other viruses, disease state, etc. at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more).
[0276] 181. The composition of any one of the previous embodiments further comprising at least one virus or vector comprising a genome of the virus, e.g., a variant of the curon, a commensal / native virus, a helper virus, a non-anellovirus.
[0277] 182. The composition of any one of the previous embodiments further comprising a heterologous moiety, at least one small molecule, antibody, polypeptide, nucleic acid, targeting agent, imaging agent, nanoparticle, and a combination thereof.
[0278] 183. A method of producing, propagating, and harvesting the curon of any one of the previous embodiments.
[0279] 184. A method of designing and making the vector of any one of the previous embodiments.
[0280] 185. A method of administering to a subject an effective amount of the composition of any one of the previous embodiments.
[0281] 186. A method of identifying dysvirosis in a subject comprising:
[0282] analyzing genetic information from a sample obtained from a subject in need thereof, wherein viral genetic information is isolated from the subject's genetic information and other
[0283] microorganisms ; comparing the viral genetic information to a reference, e.g., a control, a healthy subject; and
[0284] identifying dysvirosis in the subject if comparison of the viral genetic information yields an imbalance or irregular ratio of viral genetic information in the subject.
[0285] 187. A method of delivering a nucleic acid or protein payload to a target cell, tissue or subject, the method comprising contacting the target cell, tissue or subject with a nucleic acid composition that comprises (a) a first DNA sequence derived from a virus wherein the first DNA sequence is suffient to enable the production of a particle capable of infecting the target cell, tissue or subject and (a) a second DNA sequence encoding the nucleic acid or protein payload, the improvement comprising:
[0286] the first DNA sequence comprises at least 500 (at least 600, 700, 800, 900, 1000, 1200, 1400, 1500, 1600, 1800, 2000) nucleotides having at least 80% (at least 85%, 90%, 95%, 97%, 99%, 100%) sequence identity to a corresponding sequence listed in any of Tables 1, 3, 5, 7, 9, 11, or 13, or
[0287] the first DNA sequence encodes a sequence having at least 80% (at least 85%, 90%, 95%, 97%, 99%, 100%) sequence identity to an ORF listed in Table 2, 4, 6, 8, 10, 12, or 14, or
[0288] the first DNA sequence comprises a sequence having at least 90% (at least 95%, 97%, 99%, 100%) sequence identity to a consensus sequence listed in Table 14-1.
[0289] Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
[0290] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
[0291] BRIEF DESCRIPTION OF THE DRAWINGS
[0292] The following detailed description of the embodiments of the invention will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments, which are presently exemplified. It should be understood, however, that the invention is not limited to the precise arrangement and instrumentalities of the embodiments shown in the drawings.
[0293] Figure 1 A is an illustration showing percent sequence similarity of amino acid regions of capsid protein sequences. Figure IB is an illustration showing percent sequence similarity of capsid protein sequences. Figure 2 is an illustration showing one embodiment of a curon.
[0294] Figure 3 depicts a schematic of a kanamycin vector encoding the LY1 strain of TTMiniV ("Curon
[0295] 1").
[0296] Figure 4 depicts a schematic of a kanamycin vector encoding the LY2 strain of TTMiniV ("Curon
[0297] 2").
[0298] Figure 5 depicts transfection efficiency of synthetic curons in 293T and A549 cells.
[0299] Figures 6A and 6B depict quantitative PCR results that illustrate successful infection of 293T cells by synthetic curons.
[0300] Figures 7 A and 7B depict quantitative PCR results that illustrate successful infection of A549 cells by synthetic curons.
[0301] Figures 8A and 8B depict quantitative PCR results that illustrate successful infection of Raji cells by synthetic curons.
[0302] Figures 9A and 9B depict quantitative PCR results that illustrate successful infection of Jurkat cells by synthetic curons.
[0303] Figures 10A and 10B depict quantitative PCR results that illustrate successful infection of Chang cells by synthetic curons.
[0304] Figures 11 A-l IB are a series of graphs showing luciferase expression from cells transfected or infected with TTMV-LY2A574-1371,A1432-2210,2610::nLuc. Luminescence was observed in infected cells, indicating successful replication and packaging.
[0305] Figure 11C is a diagram depicting the phylogenetic tree of alphatorquevirus (Torque Teno Virus; TTV), with clades highlighted. At least 100 Anellovirus strains are represented, divided into five clades. Exemplary sequences from each of the five clades is provided herein, e.g., in Tables 1-14. Top box = clade 1 ; Top middle box = clade 2; Middle box = clade 3, Lower middle box = clade 4; Bottom box = clade 5.
[0306] Figure 12 is a schematic showing an exemplary workflow for production of curons (e.g., replication-competent or replication-deficient curons as described herein).
[0307] Figure 13 is a graph showing primer specificity for primer sets designed for quantification of TTV and TTMV genomic equivalents. Quantitative PCR based on SYBR green chemistry shows one distinct peak for each of the amplification products using TTMV or TTV specific primer sets, as indicated, on plasmids encoding the respective genomes.
[0308] Figure 14 is a series of graphs showing PCR efficiencies in the quantification of TTV genome equivalents by qPCR. Increasing concentrations of primers and a fixed concentration of hydrolysis probe (250nM) were used with two different commercial qPCR master mixes. Efficiencies of 90-110% resulted in minimal error propagation during quantification.
[0309] Figure 15 is a graph showing an exemplary amplification plot for linear amplification of TTMV (Target 1) or TTV (Target 2) over a 7 loglO of genome equivalent concentrations. Genome equivalents were quantified over 7 10-fold dilutions with high PCR efficiencies and linearity (R2TTMV: 0.996; R2TTV: 0.997).
[0310] Figures 16A-16B are a series of graphs showing quantification of TTMV genome equivalents in a curon stock. (A) Amplification plot of two stocks, each diluted 1 : 10 and run in duplicate. (B) The same two samples as shown in panel A, here shown in the context of the linear range. Shown are the upper and lower limits in the two representative samples. PCR Efficiency: 99.58%, R2: 0988.
[0311] Figures 17A and 17B are a series of graphs showing the functional effects of a synthetic curon comprising an exogenous miRNA, miR-625. (A) Impact on cell viability of non-small cell lung cancer (NSCLC) cells when infected with curons expressing miR-625 in three different NSCLC cell lines (A549 cells, NCI-H40 cells, and SW900 cells). (B) Impact of curons expressing miR-625 on expression of a YFP reporter by HEK293T cells.
[0312] Figure 17C is a graph showing quantification of p65 immunoblot analysis normalized to total protein for SW900 cells, either contacted with the indicated curons or left untreated.
[0313] Figure 18 is a diagram showing pairwise identity for alignments of viral DNA sequences within the five alphatorquevirus clades. DNA sequences for viruses from each TTV clade were aligned. Pairwise percent identity across a 50-bp sliding window is shown along the length of the alignments for each clade. Average pairwise identity is indicated.
[0314] Figure 19 is a diagram showing pairwise identity for alignments of representative sequences from each alphatorquevirus clade. DNA sequences for TTV-CT30F, TTV-TJN02, TTV-tth8, TTV-JA20, and TTV-HD23a were aligned. Pairwise percent identity across a 50-bp sliding window is shown along the length of the alignment. Brackets above indicate non-coding and coding regions with pairwise identities are indicated. Brackets below indicate regions of high sequence conservation.
[0315] Figure 20 is a diagram showing pairwise identity for amino acid alignments for putative proteins across the five alphatorquevirus clades. Amino acid sequences for putative proteins from TTV-CT30F, TTV-TJN02, TTV-tth8, TTV-JA20, and TTV-HD23a were aligned. Pairwise percent identity across a 50- aa sliding window is shown along the length of each alignment. Pairwise identity for both open reading frame DNA sequence and protein amino acid sequence is indicated.
[0316] Figure 21 is a diagram showing that a domain within the 5' UTR is highly conserved across the five alphatorquevirus clades. The 71-bp 5'UTR conserved domain sequences for each representative alphatorquevirus were aligned. The sequence has 96.6% pairwise identity between the five clades. The sequences shown in Figure 21 (SEQ ID NOS 703-708, respectively, in order of appearance) are also listed, e.g., in Table 16-1 herein.
[0317] Figure 22 is a diagram showing an alignment of the GC-rich domains from the five
[0318] alphatorquevirus clades. Each anellovirus has a region downstream of the ORFs with greater than 70% GC content. Shown is an alignment of the GC-rich regions from TTV-CT30F, TTV-TJN02, TTV-tth8, TTV-JA20, and TTV-HD23a. The regions vary in length, but where they align, they show a 81.8% pairwise identity. The sequences shown in Figure 22 (SEQ ID NOS 709-714, respectively, in order of appearance) are also listed, e.g., in Table 16-2 herein. DETAILED DESCRIPTION OF CERTAIN EMB ODIMENTS
[0319] Definitions
[0320] The wording "compound, composition, product, etc. for treating, modulating, etc." is to be understood to refer a compound, composition, product, etc. per se which is suitable for the indicated purposes of treating, modulating, etc. The wording "compound, composition, product, etc. for treating, modulating, etc." additionally discloses that, as an embodiment, such compound, composition, product, etc. is for use in treating, modulating, etc.
[0321] The wording "compound, composition, product, etc. for use in ..." or "use of a compound, composition, product, etc in the manufacture of a medicament, pharmaceutical composition, veterinary composition, diagnostic composition, etc. for ..." indicates that such compounds, compositions, products, etc. are to be used in therapeutic methods which may be practiced on the human or animal body. They are considered as an equivalent disclosure of embodiments and claims pertaining to methods of treatment, etc. If an embodiment or a claim thus refers to "a compound for use in treating a human or animal being suspected to suffer from a disease", this is considered to be also a disclosure of a "use of a compound in the manufacture of a medicament for treating a human or animal being suspected to suffer from a disease" or a "method of treatment by administering a compound to a human or animal being suspected to suffer from a disease". The wording "compound, composition, product, etc. for treating, modulating, etc." is to be understood to refer a compound, composition, product, etc. per se which is suitable for the indicated purposes of treating, modulating, etc.
[0322] If hereinafter examples of a term, value, number, etc. are provided in parentheses, this is to be understood as an indication that the examples mentioned in the parentheses can constitute an
[0323] embodiment. For example, if it stated that "in embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 nucleotide sequence of Table 1 (e.g., nucleotides 571 - 2613 of the nucleic acid sequence of Table 1)", then some embodiments relate to nucleic acid molecules comprising a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to nucleotides 571 - 2613 of the nucleic acid sequence of Table 1.
[0324] As used herein, the term "curon" refers to a vehicle comprising a genetic element, e.g., an episome, e.g., circular DNA, enclosed in a proteinaceous exterior. A "synthetic curon," as used herein, generally refers to a curon that is not naturally occurring, e.g., has a sequence that is modified relative to a wild-type virus (e.g., a wild-type Anellovirus as described herein). In some embodiments, the synthetic curon is engineered or recombinant, e.g., comprises a genetic element that comprises a modification relative to a wild-type viral genome (e.g., a wild-type Anellovirus genome as described herein). In some embodiments, enclosed within a proteinaceous exterior encompasses 100% coverage by a proteinaceous exterior, as well as less than 100% coverage, e.g., 95%, 90%, 85%, 80%, 70%, 60%, 50% or less. For example, gaps or discontinuities (e.g., that render the proteinaceous exterior permeable to water, ions, peptides, or small molecules) may be present in the proteinaceous exterior, so long as the genetic element is retained in the proteinaceous exterior, e.g., prior to entry into a host cell. In some embodiments, the curon is purified, e.g., it is separated from its original source and / or substantially free (>50%, >60%, >70%, >80%, >90%) of other components.
[0325] As used herein, a nucleic acid "encoding" refers to a nucleic acid sequence encoding an amino acid sequence or a functional polynucleotide (e.g., a non-coding RNA, e.g., an siRNA or miRNA).
[0326] As used herein, the term "dysvirosis" refers to a dysregulation of the virome in a subject.
[0327] An "exogenous" agent (e.g., an effector, a nucleic acid (e.g., RNA), a gene, payload, protein) as used herein refers to an agent that is either not comprised by, or not encoded by, a corresponding wild- type virus, e.g., an Anellovirus as described herein. In some embodiments, the exogenous agent does not naturally exist, such as a protein or nucleic acid that has a sequence that is altered (e.g., by insertion, deletion, or substitution) relative to a naturally occurring protein or nucleic acid. In some embodiments, the exogenous agent does not naturally exist in the host cell. In some embodiments, the exogenous agent exists naturally in the host cell but is exogenous to the virus. In some embodiments, the exogenous agent exists naturally in the host cell, but is not present at a desired level or at a desired time.
[0328] As used herein, the term "genetic element" refers to a nucleic acid sequence, generally in a curon. It is understood that the genetic element can be produced as naked DNA and optionally further assembled into a proteinaceous exterior. It is also understood that a curon can insert its genetic element into a cell, resulting in the genetic element being present in the cell and the proteinaceous exterior not necessarily entering the cell.
[0329] As used herein, a "substantially non-pathogenic" organism, particle, or component, refers to an organism, particle (e.g., a virus or a curon, e.g., as described herein), or component thereof that does not cause or induce a detectable disease or pathogenic condition, e.g., in a host organism, e.g., a mammal, e.g., a human. In some embodiments, administration of a curon to a subject can result in minor reactions or side effects that are acceptable as part of standard of care.
[0330] As used herein, the term "non-pathogenic" refers to an organism or component thereof that does not cause or induce a detectable disease or pathogenic condition, e.g., in a host organism, e.g., a mammal, e.g., a human.
[0331] As used herein, a "substantially non-integrating" genetic element refers to a genetic element, e.g., a genetic element in a virus or curon, e.g., as described herein, wherein less than about 0.01%, 0.05%, 0.1%, 0.5%, or 1% of the genetic element that enter into a host cell (e.g., a eukaryotic cell) or organism (e.g., a mammal, e.g., a human) integrate into the genome. In some embodiments the genetic element does not detectably integrate into the genome of, e.g., a host cell. In some embodiments, integration of the genetic element into the genome can be detected using techniques as described herein, e.g., nucleic acid sequencing, PCR detection and / or nucleic acid hybridization.
[0332] As used herein, a "substantially non-immunogenic" organism, particle, or component, refers to an organism, particle (e.g., a virus or curon, e.g., as described herein), or component thereof, that does not cause or induce an undesired or untargeted immune response, e.g., in a host tissue or organism (e.g., a mammal, e.g., a human). In embodiments, the substantially non-immunogenic organism, particle, or component does not produce a detectable immune response. In embodiments, the substantially non- immunogenic curon does not produce a detectable immune response against a protein comprising an amino acid sequence or encoded by a nucleic acid sequence shown in any of Tables 1-14. In
[0333] embodiments, an immune response (e.g., an undesired or untargeted immune response) is detected by assaying antibody presence or level (e.g., presence or level of an anti-curon antibody, e.g., presence or level of an antibody against a synthetic curon as described herein) in a subject, e.g., according to the anti- TTV antibody detection method described in Tsuda et al. (1999; / . Virol. Methods 77: 199-206;
[0334] incorporated herein by reference) and / or the method for determining anti-TTV IgG levels described in Kakkola et al. (2008; Virology 382: 182-189; incorporated herein by reference). Antibodies against an Anellovirus or a curon based thereon can also be detected by methods in the art for detecting anti-viral antibodies, e.g., methods of detecting anti-AAV antibodies, e.g., as described in Calcedo et al. (2013; Front. Immunol. 4(341): 1-7; incorporated herein by reference).
[0335] As used herein, the term "proteinaceous exterior" refers to an exterior component that is predominantly protein.
[0336] As used herein, the term "regulatory nucleic acid" refers to a nucleic acid sequence that modifies expression, e.g., transcription and / or translation, of a DNA sequence that encodes an expression product. In embodiments, the expression product comprises RNA or protein. As used herein, the term "regulatory sequence" refers to a nucleic acid sequence that modifies transcription of a target gene product. In some embodiments, the regulatory sequence is a promoter or an enhancer.
[0337] As used herein, the term "replication protein" refers to a protein, e.g., a viral protein, that is utilized during infection, viral genome replication / expression, viral protein synthesis, and / or assembly of the viral components.
[0338] As used herein, "treatment", "treating" and cognates thereof refer to the medical management of a subject with the intent to improve, ameliorate, stabilize, prevent or cure a disease, pathological condition, or disorder. This term includes active treatment (treatment directed to improve the disease, pathological condition, or disorder), causal treatment (treatment directed to the cause of the associated disease, pathological condition, or disorder), palliative treatment (treatment designed for the relief of symptoms), preventative treatment (treatment directed to preventing, minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder); and supportive treatment (treatment employed to supplement another therapy).
[0339] As used herein, the term "virome" refers to viruses in a particular environment, e.g., a part of a body, e.g., in an organism, e.g. in a cell, e.g. in a tissue.
[0340] This invention relates generally to curons, e.g., synthetic curons, and uses thereof. The present disclosure provides synthetic curons, compositions comprising synthetic curons, and methods of making or using synthetic curons. Synthetic curons are generally useful as delivery vehicles, e.g., for delivering a therapeutic agent to a eukaryotic cell. Generally, a synthetic curon will include a genetic element comprising an exogenous nucleic acid sequence (e.g., encoding an exogenous effector) enclosed within a proteinaceous exterior. Synthetic curons can be used as a substantially non-immunogenic vehicle for delivering the genetic element, or an effector encoded therein (e.g., a polypeptide or nucleic acid effector, e.g., as described herein), into eukaryotic cells, e.g., to treat a disease or disorder in a subject comprising the cells.
[0341] Curon
[0342] In some aspects, the invention described herein comprises compositions and methods of using and making a synthetic curon. In some embodiments, a curon comprises a genetic element (e.g., circular DNA, e.g., single stranded DNA), which comprise at least one exogenous element relative to the remainder of the genetic element and / or the proteinaceous exterior (e.g., an exogenous element encoding an effector, e.g., as described herein). A curon may be a delivery vehicle (e.g., a substantially nonpathogenic delivery vehicle) for a payload into a host, e.g., a human. In some embodiments, the curon is capable of replicating in a eukaryotic cell, e.g., a mammalian cell, e.g., a human cell. In some embodiments, the curon is substantially non-pathogenic and / or substantially non-integrating in the mammalian (e.g., human) cell. In some embodiments, the curon is substantially non-immunogenic in a mammal, e.g., a human. In some embodiments, the curon has a sequence, structure, and / or function that is based on an Anellovirus (e.g., an Anellovirus as described, e.g., an Anellovirus comprising a nucleic acid or polypeptide comprising a sequence as shown in any of Tables 1-14) or other substantially nonpathogenic virus, e.g., a symbiotic virus, commensal virus, native virus. Generally, an Anellovirus -based curon comprises at least one element exogenous to that Anellovirus, e.g., an exogenous effector or a nucleic acid sequence encoding an exogenous effector disposed within a genetic element of the curon. In some embodiments, the curon is replication-deficient. In some embodiments, the curon is replication- competent.
[0343] In an aspect, the invention includes a synthetic curon comprising (i) a genetic element comprising a promoter element, a sequence encoding an exogenous effector, (e.g., a payload), and a protein binding sequence (e.g., an exterior protein binding sequence, e.g., a packaging signal), wherein the genetic element is a single-stranded DNA, and has one or both of the following properties: is circular and / or integrates into the genome of a eukaryotic cell at a frequency of less than about 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 1.5%, or 2% of the genetic element that enters the cell; and (ii) a proteinaceous exterior; wherein the genetic element is enclosed within the proteinaceous exterior; and wherein the synthetic curon is capable of delivering the genetic element into a eukaryotic cell.
[0344] In some embodiments of the synthetic curon described herein, the genetic element integrates at a frequency of less than about 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 1.5%, or 2% of the genetic element that enters a cell. In some embodiments, less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, or 5% of the genetic elements from a plurality of the synthetic curons administered to a subject will integrate into the genome of one or more host cells in the subject. In some embodiments, the genetic elements of a population of synthetic curons, e.g., as described herein, integrate into the genome of a host cell at a frequency less than that of a comparable population of AAV viruses, e.g., at about a 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or more lower frequency than the comparable population of AAV viruses.
[0345] In an aspect, the invention includes a synthetic curon comprising: (i) a genetic element comprising a promoter element and a sequence encoding an exogenous effector (e.g., a payload), and a protein binding sequence (e.g., an exterior protein binding sequence), wherein the genetic element has at least 75% (e.g., at least 75, 76, 77, 78, 79, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%) sequence identity to a wild-type Anellovirus sequence (e.g., a wild-type Torque Teno virus (TTV), Torque Teno mini virus (TTMV), or TTMDV sequence, e.g., a wild-type Anellovirus sequence as listed in any of Tables 1, 3, 5, 7, 9, 11, or 13); and (ii) a proteinaceous exterior; wherein the genetic element is enclosed within the proteinaceous exterior; and wherein the synthetic curon is capable of delivering the genetic element into a eukaryotic cell.
[0346] In one aspect, the invention includes a synthetic curon comprising:
[0347] a) a genetic element comprising (i) a sequence encoding a non-pathogenic exterior protein, (ii) an exterior protein binding sequence that binds the genetic element to the non-pathogenic exterior protein, and (iii) a sequence encoding a regulatory nucleic acid; and
[0348] b) a proteinaceous exterior that is associated with, e.g., envelops or encloses, the genetic element. In some embodiments, the curon includes sequences or expression products from (or having
[0349] >70 , 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 100% homology to) a non-enveloped, circular, single-stranded DNA virus. Animal circular single-stranded DNA viruses generally refer to a subgroup of single strand DNA (ssDNA) viruses, which infect eukaryotic non-plant hosts, and have a circular genome. Thus, animal circular ssDNA viruses are distinguishable from ssDNA viruses that infect prokaryotes (i.e. Microviridae and Inoviridae) and from ssDNA viruses that infect plants (i.e.
[0350] Gemini viridae and Nanoviridae). They are also distinguishable from linear ssDNA viruses that infect non-plant eukaryotes (i.e. Parvoviridiae).
[0351] In some embodiments, the curon modulates a host cellular function, e.g., transiently or long term. In certain embodiments, the cellular function is stably altered, such as a modulation that persists for at least about 1 hr to about 30 days, or at least about 2 hrs, 6 hrs, 12 hrs, 18 hrs, 24 hrs, 2 days, 3, days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 60 days, or longer or any time therebetween.
[0352] In certain embodiments, the cellular function is transiently altered, e.g., such as a modulation that persists for no more than about 30 mins to about 7 days, or no more than about 1 hr, 2 hrs, 3 hrs, 4 hrs, 5 hrs, 6 hrs, 7 hrs, 8 hrs, 9 hrs, 10 hrs, 11 hrs, 12 hrs, 13 hrs, 14 hrs, 15 hrs, 16 hrs, 17 hrs, 18 hrs, 19 hrs, 20 hrs, 21 hrs, 22 hrs, 24 hrs, 36 hrs, 48 hrs, 60 hrs, 72 hrs, 4 days, 5 days, 6 days, 7 days, or any time therebetween.
[0353] In some embodiments, the genetic element comprises a promoter element. In embodiments, the promoter element is selected from an RNA polymerase II-dependent promoter, an RNA polymerase Ill- dependent promoter, a PGK promoter, a CMV promoter, an EF- la promoter, an SV40 promoter, a CAGG promoter, or a UBC promoter, TTV viral promoters, Tissue specific, U6 (pollIII), minimal CMV promoter with upstream DNA binding sites for activator proteins (TetR-VP16, Gal4-VP16, dCas9-VP16, etc). In embodiments, the promoter element comprises a TATA box. In embodiments, the promoter element is endogenous to a wild-type Anellovirus, e.g., as described herein. In some embodiments, the genetic element comprises one or more of the following characteristics: single-stranded, circular, negative strand, and / or DNA. In embodiments, the genetic element comprises an episome. In some embodiments, the portions of the genetic element excluding the effector have a combined size of about 2.5-5 kb (e.g., about 2.8-4kb, about 2.8-3.2kb, about 3.6-3.9kb, or about 2.8-2.9kb), less than about 5kb (e.g., less than about 2.9kb, 3.2 kb, 3.6kb, 3.9kb, or 4kb), or at least 100 nucleotides (e.g., at least lkb).
[0354] The curons, compositions comprising curons, methods using such curons, etc., as described herein are, in some instances, based in part on the examples which illustrate how different effectors, for example miRNAs (e.g. against IFN or miR-625), shRNA, etc and protein binding sequences, for example DNA sequences that bind to capsid protein such as Q99153, are combined with proteinaceious exteriors, for example a capsid disclosed in Arch Virol (2007) 152: 1961-1975, to produce curons which can then be used to deliver an exogenous effector to cells (e.g., animal cells, e.g., human cells or non-human animal cells such as pig or mouse cells). In embodiments, the exogenous effector can silence expression of a factor such as an interferon. The examples further describe how curons can be made by inserting exogenous effectors into sequences derived, e.g., from Anellovirus. It is on the basis of these examples that the description hereinafter contemplates various variations of the specific findings and combinations considered in the examples. For example, the skilled person will understand from the examples that the specific miRNAs are used just as an example of an exogenous effector and that other exogenous effectors may be, e.g., other regulatory nucleic acids or therapeutic peptides. Similarly, the specific capsids used in the examples may be replaced by substantially non-pathogenic proteins described hereinafter. The specifc Anellovirus sequences described in the examples may also be replaced by the Anellovirus sequences described hereinafter. These considerations similarly apply to protein binding sequences, regulatory sequences such as promoters, and the like. Independent thereof, the person skilled in the art will in particular consider such embodiments which are closely related to the examples.
[0355] In some embodiments, a curon, or the genetic element comprised in the curon, is introduced into a cell (e.g., a human cell). In some embodiments, the exogenous effector (e.g., an RNA, e.g., an miRNA), e.g., encoded by the genetic element of a curon, is expressed in a cell (e.g., a human cell), e.g., once the curon or the genetic element has been introduced into the cell, e.g., as described in Example 19. In embodiments, introduction of the curon, or genetic element comprised therein, into a cell modulates (e.g., increases or decreases) the level of a target molecule (e.g., a target nucleic acid, e.g., RNA, or a target polypeptide) in the cell, e.g., by altering the expression level of the target molecule by the cell (e.g., as described in Example 22). In embodiments, introduction of the curon, or genetic element comprised therein, decreases level of interferon produced by the cell, e.g., as described in Examples 3 and 4. In embodiments, introduction of the curon, or genetic element comprised therein, into a cell modulates (e.g., increases or decreases) a function of the cell. In embodiments, introduction of the curon, or genetic element comprised therein, into a cell modulates (e.g., increases or decreases) the viability of the cell. In embodiments, introduction of the curon, or genetic element comprised therein, into a cell decreases viability of a cell (e.g., a cancer cell), e.g., as described in Example 22.
[0356] In some embodiments, a curon (e.g., a synthetic curon) described herein induces an antibody prevalence of less than 70% (e.g., less than about 60%, 50%, 40%, 30%, 20%, or 10% antibody prevalence). In embodiments, antibody prevalence is determined according to methods known in the art. In embodiments, antibody prevalence is determined by detecting antibodies against an Anellovirus (e.g., as described herein), or a curon based thereon, in a biological sample, e.g., according to the anti-TTV antibody detection method described in Tsuda et al. (1999; / . Virol. Methods 77: 199-206; incorporated herein by reference) and / or the method for determining anti-TTV IgG seroprevalence described in Kakkola et al. (2008; Virology 382: 182-189; incorporated herein by reference). Antibodies against an Anellovirus or a curon based thereon can also be detected by methods in the art for detecting anti-viral antibodies, e.g., methods of detecting anti-AAV antibodies, e.g., as described in Calcedo et al. (2013; Front. Immunol. 4(341): 1-7; incorporated herein by reference).
[0357] Anelloviruses
[0358] In some embodiments, a synthetic curon, e.g., as described herein, comprises sequences or expression products derived from an Anellovirus. Generally, a synthetic curon includes one or more sequences or expression products that are exogenous relative to the Anellovirus. The Anellovirus genus was once classified as a clade within the Circoviridae family, and has more recently been classified as a separate family. Anelloviruses generally have single-stranded circular DNA genomes with negative polarity. Anellovirus has not been linked to any human disease. However, attempts to link Anellovirus infection with human disease are confounded by the high incidence of asymptomatic Anellovirus viremia in control cohort population(s), the remarkable genomic diversity within the anellovirus viral family, the historical inability to propagate the agent in vitro, and the lack of animal model(s) of Anellovirus disease (Yzebe et al., Panminerva Med. (2002) 44: 167-177; Biagini, P., Vet. Microbiol. (2004) 98:95-101).
[0359] Anellovirus appears to be transmitted by oronasal or fecal-oral infection, mother-to-infant and / or in utero transmission (Gerner et al., Ped. Infect. Dis. J. (2000) 19: 1074-1077). Infected persons are characterized by a prolonged (months to years) Anellovirus viremia. Humans may be co-infected with more than one genogroup or strain (Saback, et al., Scad. J. Infect. Dis. (2001) 33: 121-125). There is a suggestion that these genogroups can recombine within infected humans (Rey et al., Infect. (2003) 31 :226-233). The double stranded isoform (replicative) intermediates have been found in several tissues, such as liver, peripheral blood mononuclear cells and bone marrow (Kikuchi et al., J. Med. Virol. (2000) 61 : 165-170; Okamoto et al., Biochem. Biophys. Res. Commun. (2002) 270:657-662; Rodriguez-lnigo et al., Am. J. Pathol. (2000) 156: 1227-1234).
[0360] In some embodiments, a curon as described herein comprises one or more nucleic acid molecules (e.g., a genetic element as described herein) comprising a sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an Anellovirus sequence, e.g., as described herein, or a fragment thereof. In embodiments, the Anellovirus sequence is selected from a sequence as shown in any of Tables 1, 3, 5, 7, 9, 11, or 13. In some embodiments, a curon as described herein comprises one or more nucleic acid molecules (e.g., a genetic element as described herein) comprising a sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a TATA box, cap site, transcriptional start site, 5' UTR conserved domain, ORF1, ORFl / 1, ORF1 / 2, ORF2, ORF2 / 2, ORF2 / 3, ORF2t / 3, three open-reading frame region, poly(A) signal, GC-rich region, or any combination thereof, of any of the Anelloviruses described herein (e.g., an Anellovirus sequence as annotated, or as encoded by a sequence listed, in any of Tables 1-16 or 19). In some embodiments, the nucleic acid molecule comprises a sequence encoding a capsid protein, e.g., an ORF1, ORFl / 1, ORF1 / 2, ORF2, ORF2 / 2, ORF2 / 3, ORF2t / 3 sequence of any of the Anelloviruses described herein (e.g., an Anellovirus sequence as annotated, or as encoded by a sequence listed, in any of Tables 1-16 or 19). In embodiments, the nucleic acid molecule comprises a sequence encoding a capsid protein comprising an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an Anellovirus ORF1 or ORF2 protein (e.g., an ORF1 or ORF2 amino acid sequence as shown in any of Tables 2, 4, 6, 8, 10, 12, 14, or 16, or an ORF1 or ORF2 amino acid sequence encoded by a nucleic acid sequence as shown in any of Tables 1, 3, 5, 7, 9, 11, 13, 15, or 19).
[0361] In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 nucleotide sequence of Table 1 (e.g., nucleotides 571 - 2613 of the nucleic acid sequence of Table 1). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl / 1 nucleotide sequence of Table 1 (e.g., nucleotides 571 - 587 and / or 2137 - 2613 of the nucleic acid sequence of Table 1). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 / 2 nucleotide sequence of Table 1 (e.g., nucleotides 571 - 687 and / or 2339 - 2659 of the nucleic acid sequence of Table 1). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 nucleotide sequence of Table 1 (e.g., nucleotides 299 - 691 of the nucleic acid sequence of Table 1). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 2 nucleotide sequence of Table 1 (e.g., nucleotides 299 - 687 and / or 2137 - 2659 of the nucleic acid sequence of Table 1). In
[0362] embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%,
[0363] 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 3 nucleotide sequence of Table 1 (e.g., nucleotides 299 - 687 and / or 2339 - 2831 of the nucleic acid sequence of Table 1). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2t / 3 nucleotide sequence of Table 1 (e.g., nucleotides 299 - 348 and / or 2339 - 2831 of the nucleic acid sequence of Table 1). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus TATA box nucleotide sequence of Table 1 (e.g., nucleotides 84 - 90 of the nucleic acid sequence of Table 1). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus Cap site nucleotide sequence of Table 1 (e.g., nucleotides 107 - 114 of the nucleic acid sequence of Table 1). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus transcriptional start site nucleotide sequence of Table 1 (e.g., nucleotide 114 of the nucleic acid sequence of Table 1). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus 5' UTR conserved domain nucleotide sequence of Table 1 (e.g., nucleotides 177 - 247 of the nucleic acid sequence of Table 1). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus three open-reading frame region nucleotide sequence of Table 1 (e.g., nucleotides 2325 - 2610 of the nucleic acid sequence of Table 1). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus poly(A) signal nucleotide sequence of Table 1 (e.g., nucleotides 2813 - 2818 of the nucleic acid sequence of Table 1). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus GC-rich nucleotide sequence of Table 1 (e.g., nucleotides 3415 - 3570 of the nucleic acid sequence of Table 1). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 nucleotide sequence of Table 3 (e.g., nucleotides 599 - 2839 of the nucleic acid sequence of Table 3). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl / 1 nucleotide sequence of Table 3 (e.g., nucleotides 599 - 727 and / or 2381 - 2839 of the nucleic acid sequence of Table 3). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 / 2 nucleotide sequence of Table 3 (e.g., nucleotides 599 - 727 and / or 2619 - 2813 of the nucleic acid sequence of Table 3). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 nucleotide sequence of Table 3 (e.g., nucleotides 357 - 731 of the nucleic acid sequence of Table 3). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 2 nucleotide sequence of Table 3 (e.g., nucleotides 357 - 727 and / or 2381 - 2813 of the nucleic acid sequence of Table 3). In
[0364] embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 3 nucleotide sequence of Table 3 (e.g., nucleotides 357 - 727 and / or 2619 - 3021 of the nucleic acid sequence of Table 3). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2t / 3 nucleotide sequence of Table 3 (e.g., nucleotides 357 - 406 and / or 2619 - 3021 of the nucleic acid sequence of Table 3). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus TATA box nucleotide sequence of Table 3 (e.g., nucleotides 89 - 90 of the nucleic acid sequence of Table 3). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus Cap site nucleotide sequence of Table 3 (e.g., nucleotides 107 - 114 of the nucleic acid sequence of Table 3). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus transcriptional start site nucleotide sequence of Table 3 (e.g., nucleotide 114 of the nucleic acid sequence of Table 3). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus 5' UTR conserved domain nucleotide sequence of Table 3 (e.g., nucleotides 174 - 244 of the nucleic acid sequence of Table 3). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus three open-reading frame region nucleotide sequence of Table 3 (e.g., nucleotides 2596 - 2810 of the nucleic acid sequence of Table 3). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus poly(A) signal nucleotide sequence of Table 3 (e.g., nucleotides 3017 - 3022 of the nucleic acid sequence of Table 3). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus GC-rich nucleotide sequence of Table 3 (e.g., nucleotides 3691 - 3794 of the nucleic acid sequence of Table 3).
[0365] In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 nucleotide sequence of Table 5 (e.g., nucleotides 599 - 2830 of the nucleic acid sequence of Table 5). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl / 1 nucleotide sequence of Table 5 (e.g., nucleotides 599 - 715 and / or 2363 - 2830 of the nucleic acid sequence of Table 5). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 / 2 nucleotide sequence of Table 5 (e.g., nucleotides 599 - 715 and / or 2565 - 2789 of the nucleic acid sequence of Table 5). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 nucleotide sequence of Table 5 (e.g., nucleotides 336 - 719 of the nucleic acid sequence of Table 5). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 2 nucleotide sequence of Table 5 (e.g., nucleotides 336 - 715 and / or 2363 - 2789 of the nucleic acid sequence of Table 5). In
[0366] embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 3 nucleotide sequence of Table 5 (e.g., nucleotides 336 - 715 and / or 2565 - 3015 of the nucleic acid sequence of Table 5). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2t / 3 nucleotide sequence of Table 5 (e.g., nucleotides 336 - 388 and / or 2565 - 3015 of the nucleic acid sequence of Table 5). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus TATA box nucleotide sequence of Table 5 (e.g., nucleotides 83 - 88 of the nucleic acid sequence of Table 5). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus Cap site nucleotide sequence of Table 5 (e.g., nucleotides 104
[0367] - 111 of the nucleic acid sequence of Table 5). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus transcriptional start site nucleotide sequence of Table 5 (e.g., nucleotide 111 of the nucleic acid sequence of Table 5). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus 5' UTR conserved domain nucleotide sequence of Table 5 (e.g., nucleotides 170 - 240 of the nucleic acid sequence of Table 5). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus three open-reading frame region nucleotide sequence of Table 5 (e.g., nucleotides 2551 - 2786 of the nucleic acid sequence of Table 5). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus poly(A) signal nucleotide sequence of Table 5 (e.g., nucleotides 3011 - 3016 of the nucleic acid sequence of Table 5). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus GC-rich nucleotide sequence of Table 5 (e.g., nucleotides 3632 - 3753 of the nucleic acid sequence of Table 5).
[0368] In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 nucleotide sequence of Table 7 (e.g., nucleotides 590 - 2899 of the nucleic acid sequence of Table 7). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl / 1 nucleotide sequence of Table 7 (e.g., nucleotides 590 - 712 and / or 2372 - 2899 of the nucleic acid sequence of Table 7). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 / 2 nucleotide sequence of Table 7 (e.g., nucleotides 590
[0369] - 712 and / or 2565 - 2873 of the nucleic acid sequence of Table 7). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 nucleotide sequence of Table 7 (e.g., nucleotides 354 - 716 of the nucleic acid sequence of Table 7). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 2 nucleotide sequence of Table 7 (e.g., nucleotides 354 - 712 and / or 2372 - 2873 of the nucleic acid sequence of Table 7). In
[0370] embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%,
[0371] 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 3 nucleotide sequence of Table 7 (e.g., nucleotides 354 - 712 and / or 2565 - 3075 of the nucleic acid sequence of Table 7). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2t / 3 nucleotide sequence of Table 7 (e.g., nucleotides 354 - 400 and / or 2565 - 3075 of the nucleic acid sequence of Table 7). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus TATA box nucleotide sequence of Table 7 (e.g., nucleotides 86 - 90 of the nucleic acid sequence of Table 7). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus Cap site nucleotide sequence of Table 7 (e.g., nucleotides 107 - 114 of the nucleic acid sequence of Table 7). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus transcriptional start site nucleotide sequence of Table 7 (e.g., nucleotide 114 of the nucleic acid sequence of Table 7). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus 5' UTR conserved domain nucleotide sequence of Table 7 (e.g., nucleotides 174 - 244 of the nucleic acid sequence of Table 7). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus three open-reading frame region nucleotide sequence of Table 7 (e.g., nucleotides 2551 - 2870 of the nucleic acid sequence of Table 7). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus poly(A) signal nucleotide sequence of Table 7 (e.g., nucleotides 3071 - 3076 of the nucleic acid sequence of Table 7). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus GC-rich nucleotide sequence of Table 7 (e.g., nucleotides 3733 - 3853 of the nucleic acid sequence of Table 7). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 nucleotide sequence of Table 9 (e.g., nucleotides 577 - 2787 of the nucleic acid sequence of Table 9). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl / 1 nucleotide sequence of Table 9 (e.g., nucleotides 577 - 699 and / or 2311— 2787 of the nucleic acid sequence of Table 9). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 / 2 nucleotide sequence of Table 9 (e.g., nucleotides 577 - 699 and / or 2504 - 2806 of the nucleic acid sequence of Table 9). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 nucleotide sequence of Table 9 (e.g., nucleotides 341 - 703 of the nucleic acid sequence of Table 9). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 2 nucleotide sequence of Table 9 (e.g., nucleotides 341 - 699 and / or 2311 - 2806 of the nucleic acid sequence of Table 9). In
[0372] embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 3 nucleotide sequence of Table 9 (e.g., nucleotides 341 - 699 and / or 2504 - 2978 of the nucleic acid sequence of Table 9). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2t / 3 nucleotide sequence of Table 9 (e.g., nucleotides 341 - 387 and / or 2504 - 2978 of the nucleic acid sequence of Table 9). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus TATA box nucleotide sequence of Table 9 (e.g., nucleotides 83- 87 of the nucleic acid sequence of Table 9). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus Cap site nucleotide sequence of Table 9 (e.g., nucleotides 104 - 111 of the nucleic acid sequence of Table 9). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus transcriptional start site nucleotide sequence of Table 9 (e.g., nucleotide 111 of the nucleic acid sequence of Table 9). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus 5' UTR conserved domain nucleotide sequence of Table 9 (e.g., nucleotides 171 - 241 of the nucleic acid sequence of Table 9). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus three open-reading frame region nucleotide sequence of Table 9 (e.g., nucleotides 2463 - 2784 of the nucleic acid sequence of Table 9). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus poly(A) signal nucleotide sequence of Table 9 (e.g., nucleotides 2974 - 2979 of the nucleic acid sequence of Table 9). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus GC-rich nucleotide sequence of Table 9 (e.g., nucleotides 3644 - 3758 of the nucleic acid sequence of Table 9).
[0373] In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 nucleotide sequence of Table 11 (e.g., nucleotides 612 - 2612 of the nucleic acid sequence of Table 11). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl / 1 nucleotide sequence of Table 11 (e.g., nucleotides 612 - 719 and / or 2274 - 2612 of the nucleic acid sequence of Table 11). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 / 2 nucleotide sequence of Table 11 (e.g., nucleotides 612 - 719 and / or 2449 - 2589 of the nucleic acid sequence of Table 11). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 nucleotide sequence of Table 11 (e.g., nucleotides 424 - 723 of the nucleic acid sequence of Table 11). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 2 nucleotide sequence of Table 11 (e.g., nucleotides 424 - 719 and / or 2274 - 2589 of the nucleic acid sequence of Table 11). In
[0374] embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 3 nucleotide sequence of Table 11 (e.g., nucleotides 424 - 719 and / or 2449 - 2812 of the nucleic acid sequence of Table 11). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus TATA box nucleotide sequence of Table 11 (e.g., nucleotides 237- 243 of the nucleic acid sequence of Table 11). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus Cap site nucleotide sequence of Table 11 (e.g., nucleotides 260 - 267 of the nucleic acid sequence of Table 11). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus transcriptional start site nucleotide sequence of Table 11 (e.g., nucleotide 267 of the nucleic acid sequence of Table 11). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus 5' UTR conserved domain nucleotide sequence of Table 11 (e.g., nucleotides 323 - 393 of the nucleic acid sequence of Table 11). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%,
[0375] 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus three open-reading frame region nucleotide sequence of Table 11 (e.g., nucleotides 2441 - 2586 of the nucleic acid sequence of Table 11). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus poly(A) signal nucleotide sequence of Table 11 (e.g., nucleotides 2808 - 2813 of the nucleic acid sequence of Table 11). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus GC-rich nucleotide sequence of Table 11 (e.g., nucleotides 2868 - 2929 of the nucleic acid sequence of Table 11).
[0376] In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 nucleotide sequence of Table 13 (e.g., nucleotides 432 - 2453 of the nucleic acid sequence of Table 13). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl / 1 nucleotide sequence of Table 13 (e.g., nucleotides 432 - 584 and / or 1977 - 2453 of the nucleic acid sequence of Table 13). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 / 2 nucleotide sequence of Table 13 (e.g., nucleotides 432 - 584 and / or 2197 - 2388 of the nucleic acid sequence of Table 13). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 nucleotide sequence of Table 13 (e.g., nucleotides 283 - 588 of the nucleic acid sequence of Table 13). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 2 nucleotide sequence of Table 13 (e.g., nucleotides 283 - 584 and / or 1977 - 2388 of the nucleic acid sequence of Table 13). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 3 nucleotide sequence of Table 13 (e.g., nucleotides 283 - 584 and / or 2197 - 2614 of the nucleic acid sequence of Table 13). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus TATA box nucleotide sequence of Table 13 (e.g., nucleotides 21- 25 of the nucleic acid sequence of Table 13). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus Cap site nucleotide sequence of Table 13 (e.g., nucleotides 42 - 49 of the nucleic acid sequence of Table 13). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus transcriptional start site nucleotide sequence of Table 13 (e.g., nucleotide 49 of the nucleic acid sequence of Table 13). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus 5' UTR conserved domain nucleotide sequence of Table 13 (e.g., nucleotides 117 - 187 of the nucleic acid sequence of Table 13). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus three open-reading frame region nucleotide sequence of Table 13 (e.g., nucleotides 2186 - 2385 of the nucleic acid sequence of Table 13). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus poly(A) signal nucleotide sequence of Table 13 (e.g., nucleotides 2676 - 2681 of the nucleic acid sequence of Table 13). In embodiments, the nucleic acid molecule comprises a nucleic acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the
[0377] Anellovirus GC-rich nucleotide sequence of Table 13 (e.g., nucleotides 3054 - 3172 of the nucleic acid sequence of Table 13).
[0378] In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 amino acid sequence of Table 2. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl / 1 amino acid sequence of Table 2. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 / 2 amino acid sequence of Table 2. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 amino acid sequence of Table 2. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 2 amino acid sequence of Table 2. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 3 amino acid sequence of Table 2. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2t / 3 amino acid sequence of Table 2.
[0379] In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 amino acid sequence of Table 4. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl / 1 amino acid sequence of Table 4. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 / 2 amino acid sequence of Table 4. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 amino acid sequence of Table 4. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 2 amino acid sequence of Table 4. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 3 amino acid sequence of Table 4. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2t / 3 amino acid sequence of Table 4.
[0380] In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 amino acid sequence of Table 6. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl / 1 amino acid sequence of Table 6. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 / 2 amino acid sequence of Table 6. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 amino acid sequence of Table 6. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 2 amino acid sequence of Table 6. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 3 amino acid sequence of Table 6. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2t / 3 amino acid sequence of Table 6.
[0381] In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 amino acid sequence of Table 8. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl / 1 amino acid sequence of Table 8. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 / 2 amino acid sequence of Table 8. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 amino acid sequence of Table 8. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 2 amino acid sequence of Table 8. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 3 amino acid sequence of Table 8. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2t / 3 amino acid sequence of Table 8.
[0382] In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl amino acid sequence of Table 10. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl / 1 amino acid sequence of Table 10. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 / 2 amino acid sequence of Table 10. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 amino acid sequence of Table 10. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 2 amino acid sequence of Table 10. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 3 amino acid sequence of Table 10. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2t / 3 amino acid sequence of Table 10.
[0383] In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl amino acid sequence of Table 12. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl / 1 amino acid sequence of Table 12. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 / 2 amino acid sequence of Table 12. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 amino acid sequence of Table 12. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 2 amino acid sequence of Table 12. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 3 amino acid sequence of Table 12.
[0384] In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl amino acid sequence of Table 14. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl / 1 amino acid sequence of Table 14. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 / 2 amino acid sequence of Table 14. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 amino acid sequence of Table 14. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 2 amino acid sequence of Table 14. In embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 3 amino acid sequence of Table 14.
[0385] In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl amino acid sequence of Table 2. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl / 1 amino acid sequence of Table 2. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 / 2 amino acid sequence of Table 2. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 amino acid sequence of Table 2. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 2 amino acid sequence of Table 2. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 3 amino acid sequence of Table 2. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2t / 3 amino acid sequence of Table 2.
[0386] In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 amino acid sequence of Table 4. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl / 1 amino acid sequence of Table 4. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 / 2 amino acid sequence of Table 4. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%,
[0387] 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 amino acid sequence of Table 4. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 2 amino acid sequence of Table 4. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%,
[0388] 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 3 amino acid sequence of Table 4. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2t / 3 amino acid sequence of Table 4.
[0389] In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 amino acid sequence of Table 6. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl / 1 amino acid sequence of Table 6. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 / 2 amino acid sequence of Table 6. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 amino acid sequence of Table 6. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 2 amino acid sequence of Table 6. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 3 amino acid sequence of Table 6. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2t / 3 amino acid sequence of Table 6.
[0390] In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 amino acid sequence of Table 8. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl / 1 amino acid sequence of Table 8. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 / 2 amino acid sequence of Table 8. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 amino acid sequence of Table 8. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or
[0391] 100% sequence identity to the Anellovirus ORF2 / 2 amino acid sequence of Table 8. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 3 amino acid sequence of Table 8. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2t / 3 amino acid sequence of Table 8.
[0392] In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 amino acid sequence of Table 10. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl / 1 amino acid sequence of Table 10. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 / 2 amino acid sequence of Table 10. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 amino acid sequence of Table 10. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 2 amino acid sequence of Table 10. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 3 amino acid sequence of Table 10. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2t / 3 amino acid sequence of Table 10.
[0393] In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 amino acid sequence of Table 12. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl / 1 amino acid sequence of Table 12. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 / 2 amino acid sequence of Table 12. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 amino acid sequence of Table 12. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 2 amino acid sequence of Table 12. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 3 amino acid sequence of Table 12.
[0394] In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 amino acid sequence of Table 14. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORFl / 1 amino acid sequence of Table 14. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF1 / 2 amino acid sequence of Table 14. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 amino acid sequence of Table 14. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 2 amino acid sequence of Table 14. In embodiments, the curon described herein comprises a protein having an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the Anellovirus ORF2 / 3 amino acid sequence of Table 14.
[0395] Table 1. Exemplary Anellovirus nucleic acid sequence (Alphatorquevirus, Clade 1)
[0396] Name TTV-CT30F
[0397] Genus / Clade Alphatorquevirus, Clade 1
[0398] Accession Number AB064597.1
[0399] Full Sequence: 3570
[0400] 1 10 20 30 40 50
[0401] ATTTTGTGCAGCCCGCCAATTCTCGTTCAAACAGGCCAATCAGGAGGCTC TACGTACACTTCCTGGGGTGTGTCTTCGAAGAGTATATAAGCAGAGGCGG TGACGAATGGTAGAGTTTTTCCTGGCCCGTCCGCGGCGAGAGCGCGAGCG GAGCGAGCGATCGAGCGTCCCGTGGGCGGGTGCCGTAGGTGAGTTTACAC ACCGCAGTCAAGGGGCAATTCGGGCTCGGGACTGGCCGGGCTATGGGCAA GATTCTTAAAAAATTCCCCCGATCCCTCTGTCGCCAGGACATAAAAACAT GCCGTGGAGACCGCCGGTGCATAGTGTCCAGGGGCGAGAGGATCAGTGGT TCGCGAGCTTTTTTCACGGCCACGCTTCATTTTGCGGTTGCGGTGACGCT GTTGGCCATCTTAATAGCATTGCTCCTCGCTTTCCTCGCGCCGGTCCACC AAGGCCCCCTCCGGGGCTAGAGCAGCCTAACCCCCCGCAGCAGGGCCCGG CCGGGCCCGGAGGGCCGCCCGCCATCTTGGCGCTGCCGGCTCCGCCCGCG GAGCCTGACGACCCGCAGCCACGGCGTGGTGGTGGGGACGGTGGCGCCGC CGCTGGCGCCGCAGGCGACCGTGGAGACCGAGACTACGACGAAGAAGAGC TAGACGAGCTTTTCCGCGCCGCCGCCGAAGACGATTTGTAAGTAGGAGAT GGCGCCGGCCTTACAGGCGCAGGAGGAGACGCGGGCGACGCAGACGCAGA CGCAGACGCAGACATAAGCCCACCCTAGTACTCAGACAGTGGCAACCTGA CGTTATCAGACACTGTAAGATAACAGGACGGATGCCCCTCATTATCTGTG GAAAGGGGTCCACCCAGTTCAACTACATCACCCACGCGGACGACATCACC CCCAGGGGAGCCTCCTACGGGGGCAACTTCACAAACATGACTTTCTCCCT GGAGGCAATATACGAACAGTTTCTGTACCACAGAAACAGGTGGTCAGCCT CCAACCACGACCTCGAACTCTGCAGATACAAGGGTACCACCCTAAAACTG TACAGGCACCCAGATGTAGACTACATAGTCACCTACAGCAGAACGGGACC CTTTGAGATCAGCCACATGACCTACCTCAGCACTCACCCCCTTCTCATGC TGCTAAACAAACACCACATAGTGGTGCCCAGCCTAAAGACTAAGCCCAGG GGCAGAAAGGCCATAAAAGTCAGAATAAGACCCCCCAAACTCATGAACAA CAAGTGGTACTTCACCAGAGACTTCTGTAACATAGGCCTCTTCCAGCTCT GGGCCACAGGCTTAGAACTCAGAAACCCCTGGCTCAGAATGAGCACCCTG AGCCCCTGCATAGGCTTCAATGTCCTTAAAAACAGCATTTACACAAACCT CAGCAACCTACCTCAGCACAGAGAAGACAGACTTAACATTATTAACAACA CATTACACCCACATGACATAACAGGACCAAACAATAAAAAATGGCAGTAC ACATATACCAAACTCATGGCCCCCATTTACTATTCAGCAAACAGGGCCAG CACCTATGACTTACTACGAGAGTATGGCCTCTACAGTCCATACTACCTAA ACCCCACAAGGATAAACCTTGACTGGATGACCCCCTACACACACGTCAGG TACAATCCACTAGTAGACAAGGGCTTCGGAAACAGAATATACATACAGTG GTGCTCAGAGGCAGATGTAAGCTACAACAGGACTAAATCCAAGTGTCTCT TACAAGACATGCCCCTGTTTTTCATGTGCTATGGCTACATAGACTGGGCA ATTAAAAACACAGGGGTCTCCTCACTAGCGAGAGACGCCAGAATCTGCAT CAGGTGTCCCTACACAGAGCCACAGCTGGTGGGCTCCACAGAAGACATAG GGTTCGTACCCATCACAGAGACCTTCATGAGGGGCGACATGCCGGTACTT GCACCATACATACCGTTGAGCTGGTTTTGCAAGTGGTATCCCAACATAGC TCACCAGAAGGAAGTACTTGAGGCAATCATTTCCTGCAGCCCCTTCATGC CCCGTGACCAGGGCATGAACGGTTGGGATATTACAATAGGTTACAAAATG GACTTCTTATGGGGCGGTTCCCCTCTCCCCTCACAGCCAATCGACGACCC CTGCCAGCAGGGAACCCACCCGATTCCCGACCCCGATAAGCACCCTCGCC TCCTACAAGTGTCGAACCCGAAACTGCTCGGACCGAGGACAGTGTTCCAC AAGTGGGACATCAGACGTGGGCAGTTTAGCAAAAGAAGTATTAAAAGAGT GTCAGAATACTCATCGGATGATGAATCTCTTGCGCCAGGTCTCCCATCAA AGCGAAACAAGCTCGACTCGGCCTTCAGAGGAGAAAACCCAGAGCAAAAA GAATGCTATTCTCTCCTCAAAGCACTCGAGGAAGAAGAGACCCCAGAAGA AGAAGAACCAGCACCCCAAGAAAAAGCCCAGAAAGAGGAGCTACTCCACC AGCTCCAGCTCCAGAGACGCCACCAGCGAGTCCTCAGACGAGGGCTCAAG CTCGTCTTTACAGACATCCTCCGACTCCGCCAGGGAGTCCACTGGAACCC CGAGCTCACATAGAGCCCCCACCTTACATACCAGACCTACTTTTTCCCAA TACTGGTAAAAAAAAAAAATTCTCTCCCTTCGACTGGGAAACGGAGGCCC AGCTAGCAGGGATATTCAAGCGTCCTATGCGCTTCTATCCCTCAGACACC CCTCACTACCCGTGGTTACCCCCCAAGCGCGATATCCCGAAAATATGTAA CATAAACTTCAAAATAAAGCTGCAAGAGTGAGTGATTCGAGGCCCTCCTC TGTTCACTTAGCGGTGTCTACCTCTTAAAGTCACCAAGCACTCCGAGCGT CAGCGAGGAGTGCGACCCTCCACCAAGGGGCAACTTCCTCGGGGTCCGGC GCTACGCGCTTCGCGCTGCGCCGGACGCCTCGGACCCCCCCCCGACCCGA ATCGCTCGCGCGATTCGGACCTGCGGCCTCGGGGGGGGTCGGGGGCTTTA CTAAACAGACTCCGAGTTGCCACTGGACTCAGGAGCTGTGAATCAGTAAC GAAAGTGAGTGGGGCCAGACTTCGCCATAGGGCCTTTAACTTGGGGTCGT CTGTCGGTGGCTTCCGGGTCCGCCTGGGCGCCGCCATTTTAGCTTTAGAC GCCATTTTAGGCCCTCGCGGGCACCCGTAGGCGCGTTTTAATGACGTCAC GGCAGCCATTTTGTCGTGACGTTTGAGACACGTGATGGGGGCGTGCCTAA ACCCGGAAGCATCCCTGGTCACGTGACTCTGACGTCACGGCGGCCATTTT GTGCTGTCCGCCATCTTGTGACTTCCTTCCGCTTTTTCAAAAAAAAAGAG GAAGTATGACAGTAGCGGCGGGGGGGCGGCCGCGTTCGCGCGCCGCCCAC CAGGGGGTGCTGCGCGCCCCCCCCCGCGCATGCGCGGGGCCCCCCCCCGG GGGGGCTCCGCCCCCCCGGCCCCCCCCCGTGCTAAACCCACCGCGCATGC GCGACCACGCCCCCGCCGCC (SEQ ID NO: 1)
[0402] Annotations:
[0403] Putative Domain Base range
[0404] TATA Box 84 - 90
[0405] Cap Site 107 - 114
[0406] Transcriptional Start Site 114
[0407] 5 ' UTR Conserved Domain 177 - 247
[0408] ORF2 299 - 691
[0409] ORF2 / 2 299 - 687 ; 2137 - 2659 ORF2 / 3 299 - 687 ; 2339
[0410] ORF2t / 3 299 - 348 ; 2339
[0411] ORF1 571-2613
[0412] ORFl / 1 571 -687; 2137
[0413] ORF1 / 2 571 - 687 ; 2339
[0414] Three open-reading frame region 2325-2610
[0415] Poly(A) Signal 2813-2818
[0416] GC-rich region 3415 - 3570
[0417] Table 2. Exemplary Anellovirus amino acid sequences (Alphatorquevirus, Clade 1)
[0418] VDYIVTYSRTGPFEISHMTYLSTHPLLMLLNKHHIVVPSLKTKPRGRKAIKVRIRPPK
[0419] LMNNKWYFTRDFCNIGLFQLWATGLELRNPWLRMSTLSPCIGFNVLKNSIYTNLSN
[0420] LPQHREDRLNIINNTLHPHDITGPNNKKWQYTYTKLMAPIYYSANRASTYDLLREY
[0421] GLYSPYYLNPTRINLDWMTPYTHVRYNPLVDKGFGNRIYIQWCSEADVSYNRTKSK
[0422] CLLQDMPLFFMCYGYIDWAIKNTGVSSLARDARICIRCPYTEPQLVGSTEDIGFVPIT
[0423] ETFMRGDMPVLAPYIPLSWFCKWYPNIAHQKEVLEAIISCSPFMPRDQGMNGWDITI
[0424] GYKMDFLWGGSPLPSQPIDDPCQQGTHPIPDPDKHPRLLQVSNPKLLGPRTVFHKW
[0425] DIRRGQFSKRSIKRVSEYSSDDESLAPGLPSKRNKLDSAFRGENPEQKECYSLLKALE
[0426] EEETPEEEEPAPQEKAQKEELLHQLQLQRRHQRVLRRGLKLVFTDILRLRQGVHWN
[0427] PELT (SEQ ID NO: 6)
[0428] ORFl / 1 TAWWWGRWRRRWRRRRPWRPRLRRRRARRAFPRRRRRRFPIDDPCQQGTHPIPDP
[0429] DKHPRLLQVSNPKLLGPRTVFHKWDIRRGQFSKRSIKRVSEYSSDDESLAPGLPSKR NKLDSAFRGENPEQKECYSLLKALEEEETPEEEEPAPQEKAQKEELLHQLQLQRRH QRVLRRGLKLVFTDILRLRQGVHWNPELT (SEQ ID NO: 7)
[0430] ORF1 / 2 TAWWWGRWRRRWRRRRPWRPRLRRRRARRAFPRRRRRRFVSHQSETSSTRPSEE
[0431] KTQSKKNAILSSKHSRKKRPQKKKNQHPKKKPRKRSYSTSSSSRDATSESSDEGSSS SLQTSSDSARESTGTPSSHRAPTLHTRPTFSQYW (SEQ ID NO: 8)
[0432] Table 3. Exemplary Anellovirus nucleic acid sequence (Alphatorquevirus, Clade 2)
[0433] Name TTV-TJN02
[0434] Genus / Clade Alphatorquevirus, Clade 2
[0435] Accession Number AB028669.1
[0436] Full Sequence: 3794 bp
[0437] 1 1 0 2 0 3 0 4 0 5 0
[0438] CCCGAAGTCCGTCACTAACCACGTGACTCCTGTCGCCCAATCAGAGTGTA TGTCGTGCATTTCCTGGGCATGGTCTACATCCTGATATAACTAAGTGCAC TTCCGAATGGCTGAGTTTTCCACGCCCGTCCGCAGCGAGGGAGCGACGGA GGAGCTCCCGAGCGTCCCGAGGGCGGGTGCCGGAGGTGAGTTTACACACC GCAGTCAAGGGGCAATTCGGGCTCGGGACTGGCCGGGCTATGGGCAAGGC TCTTAGGGTCTTCATTCTTAATATGTTTCTTGGCAGAGTTTACCGCCACA AGAAAAGGAAAGTGCTACTGTCCACACTGCGAGCTCCACAGGCGTCTCGC AGGGCTATGAGTTGGCGACCCCCGGTACACGATGCACCCGGCATCGAGCG CAATTGGTACGAGGCCTGTTTCAGAGCCCACGCTGGAGCTTGTGGCTGTG GCAATTTTATTATGCACCTTAATCTTTTGGCTGGGCGTTATGGTTTTACT CCGGGGTCAGCGCCGCCAGGTGGTCCTCCTCCGGGCACCCCGCAGATAAG GAGAGCCAGGCCTAGTCCCGCCGCACCAGAGCAGCCCGCTGCCCTACCAT GGCATGGGGATGGTGGAGATGGCGGCGCCGCTGGCCCGCCAGACGCTGGA GGAGACGCCGTCGCCGGCGCCCCGTACGGAGAACAAGAGCTCGCCGACCT GCTCGACGCTATAGAAGACGACGAACAGTAAGAACCAGGCGAAGGCGGTG GGGGCGCAGACGGTACAGACGGGGCTGGAGACGCAGGACTTATGTGAGAA AGGGGCGACACAGAAAAAAGAAAAAGAGACTGATACTGAGACAGTGGCAA CCAGCCACAAGACGCAGATGTACCATAACTGGGTACCTGCCCATAGTGTT CTGCGGCCACACTAGGGGCAATAAAAACTATGCACTACACTCTGACGACT ACACCCCCCAAGGACAACCATTTGGAGGGGCTCTAAGCACTACCTCATTC TCTTTAAAAGTACTATTTGACCAGCATCAGAGAGGACTAAACAAGTGGTC TTTTCCAAACGACCAACTAGACCTCGCCAGATATAGAGGCTGCAAATTTA TATTTTATAGAACAAAACAAACTGACTGGGTGGGCCAGTATGACATATCA GAACCCTACAAGCTAGACAAATACAGCTGCCCCAACTATCACCCTGGAAA CATGATTAAGGCAAAGCACAAATTTTTAATACCAAGCTATGACACTAATC CTAGAGGCAGACAAAAAATTATAGTTAAAATTCCCCCCCCAGACCTCTTT GTAGACAAGTGGTACACTCAAGAGGATCTGTGTTCCGTTAATCTTGTGTC ACTTGCGGTTTCTGCGGCTTCCTTTCTCCACCCATTCGGCTCACCACAAA CTGACAACCCTTGCTACACCTTCCAGGTGTTGAAAGAGTTCTACTATCAG GCAATAGGCTTCTCTGCAAGCACACAAGCAATGACATCAGTATTAGACAC GCTATACACACAAAACAGTTATTGGGAATCTAATCTAACTCAGTTTTATG TACTTAATGCAAAAAAAGGCAGTGATACAACACAGCCTTTAACTAGCAAT ATGCCAACTCGTGAAGAGTTTATGGCAAAAAAAAATACCAATTACAACTG GTATACATACAAGGCCGCGTCAGTAAAAAATAAACTACATCAAATGAGAC AAACCTATTTTGAGGAGTTAACCTCTAAGGGGCCACAAACAACAAAAAGT GAGGAAGGCTACAGTCAGCACTGGACCACCCCCTCCACAAACGCCTACGA ATATCACTTAGGAATGTTTAGTGCAATATTTCTAGCCCCAGACAGGCCAG TACCTAGATTTCCATGCGCCTACCAAGATGTAACTTACAACCCCTTAATG GACAAAGGGGTGGGAAACCACATTTGGTTTCAGTACAACACAAAGGCAGA CACTCAGCTAATAGTCACAGGAGGGTCCTGCAAAGCACACATACAAGACA TACCACTGTGGGCGGCCTTCTATGGATACAGTGACTTTATAGAGTCAGAA CTAGGCCCCTTTGTAGATGCAGAGACGGTAGGCTTAGTGTGTGTAATATG CCCTTATACAAAACCCCCCATGTACAACAAGACAAACCCCGCCATGGGCT ACGTGTTCTATGACAGAAACTTTGGTGACGGAAAATGGACTGACGGACGG GGCAAAATAGAGCCCTACTGGCAAGTTAGGTGGAGGCCCGAAATGCTTTT CCAAGAAACTGTAATGGCAGACCTAGTTCAGACTGGGCCCTTTAGCTACA AAGACGAACTTAAAAACAGCACCCTAGTGTGCAAGTACAAATTCTATTTC ACCTGGGGAGGTAACATGATGTTCCAACAGACGATCAAAAACCCGTGCAA GACGGACGGACAACCCACCGACTCCAGTAGACACCCTAGAGGAATACAAG TGGCGGACCCGGAACAAATGGGACCCCGCTGGGTGTTCCACTCCTTTGAC TGGCGAAGGGGCTATCTTAGCGAGAAAGCTCTCAAACGCCTGCAAGAAAA ACCTCTTGACTATGACGAATATTTTACACAACCAAAAAGACCTAGAATCT TTCCTCCAACAGAATCAGCAGAGGGAGAGTTCCGAGAGCCCGAAAAAGGC TCGTATTCAGAGGAAGAAAGGTCGCAAGCCTCTGCCGAAGAGCAGACGCA GGAGGCGACAGTACTCCTCCTCAAGCGACGACTCAGAGAGCAACAGCAGC TCCAGCAGCAGCTCCAATTCCTCACCCGAGAAATGTTCAAAACGCAAGCG GGTCTCCACCTAAACCCTATGTTATTAAACCAGCGATAAACCAAGTGTAC CTGTTTCCAGAGAGGGCCCCAAAACCCCCTCCTAGCAGCCAAGACTGGCA GCAGGAGTACGAGGCCTGCGCAGCCTGGGACAGGCCCCCTAGATACAATC TGTCCTCTCCTCCTTTCTACCCCAGCTGCCCTTCAAAATTCTGTGTAAAA TTCAGCCTTGGCTTTAAATAAATGGCAACTTTACTGTGCAAGGCCGTGGG AGTTTCACTGGTCGGTGTCTACCTCTAAAGGTCACTAAGCACTCCGAGCG TTAGCGAGGAGTGCGACCCTTCCCCCTGACTCAACTTCTTCGGAGCCGCG CGCTACGCCTTCGGCTGCGCGCGGCACCTCAGACCCCCGCTCGTGCTGAC ACGCTCGCGCGTGTCAGACCACTTCGGGCTCGCGGGGGTCGGGAATTTTG CTAAACAGACTCCGAGTTGCTCTTGGACACTGAGGGGGCATATCAGTAAC GAAAGTGAGTGGGGCCAGACTTCGCCATAAGGCCTTTATCTTCTTGCCAT TGGATAGTATCGAGGGTTGCCATAGGCTTCGACCTCCATTTTAGGCCTTC CGGACTACAAAAATGGCCGTTTTAGTGACGTCACGGCCGCCATTTTAAGT AAGGCGGAAGCAGCTCGGCGTACACAAAATGGCGGCGGAGCACTTCCGGC TTGCCCAAAATGGTGGGCAACTTCTTCCGGGTCAAAGGTCACAGCTACGT CACAAGTCACGTGGGGAGGGTTGGCGTTTAACCCGGAAGCCAATCCTCTT ACGTGGCCTGTCACGTGACTTGTACGTCACGACCACCATTTTGTTTTACA AAATGGCCGACTTCCTTCCTCTTTTTTAAAAATAACGGTTCGGCGGCGGC GCGCGCGCTACGCGCGCGCGCCGGGGGGCTGCCGCCCCCCCCCCGCGCAT GCGCGGGGCCCCCCCCCGCGGGGGGCTCCGCCCCCCGGCCCCCC (SEQ ID NO: 9)
[0439] Annotations:
[0440] Putative Domain Base range
[0441] TATA Box 89-90
[0442] Cap Site 107-114
[0443] Transcriptional Start Site 114
[0444] 5' UTR Conserved Domain 174 _ 244
[0445] ORF2 357-731
[0446] ORF2 / 2 357-727 ; 2381 -2813
[0447] ORF2 / 3 357-727 ; 2619 -3021
[0448] ORF2t / 3 357-406 ; 2619 -3021
[0449] ORF1 599 - 2839
[0450] ORFl / 1 599-727 ; 2381 -2839
[0451] ORF1 / 2 599-727 ; 2619 -2813
[0452] Three open-reading frame region 2596-2810
[0453] Poly(A) Signal 3017 - 3022
[0454] GC-rich region 3691 - 3794
[0455] Table 4. Exemplary Anellovirus amino acid sequences (Alphatorquevirus, Clade 2)
[0456] C A AWDRPPRYNLS SPPF YPSCPS KFC VKFSLGFK (SEQ ID NO: 12)
[0457] ORF2t / 3 MSWRPPVHDAPGIERNCRGRVPRARKRLVFRGRKVASLCRRADAGGDSTPPQATT
[0458] QRATAAPAAAPIPHPRNVQNASGSPPKPYVIKPAINQVYLFPERAPKPPPSSQDWQQ EYEACAAWDRPPRYNLSSPPFYPSCPSKFCVKFSLGFK (SEQ ID NO: 13)
[0459] ORF1 MAWGWWRWRRRWPARRWRRRRRRRPVRRTRARRPARRYRRRRTVRTRRRRWG
[0460] RRRYRRGWRRRTYVRKGRHRKKKKRLILRQWQPATRRRCTITGYLPIVFCGHTRG
[0461] NKNYALHSDDYTPQGQPFGGALSTTSFSLKVLFDQHQRGLNKWSFPNDQLDLARY
[0462] RGCKFIFYRTKQTDWVGQYDISEPYKLDKYSCPNYHPGNMIKAKHKFLIPSYDTNP
[0463] RGRQKIIVKIPPPDLFVDKWYTQEDLCSVNLVSLAVSAASFLHPFGSPQTDNPCYTF
[0464] QVLKEFYYQAIGFSASTQAMTSVLDTLYTQNSYWESNLTQFYVLNAKKGSDTTQPL
[0465] TSNMPTREEFMAKKNTNYNWYTYKAASVKNKLHQMRQTYFEELTSKGPQTTKSE
[0466] EGYSQHWTTPSTNAYEYHLGMFSAIFLAPDRPVPRFPCAYQDVTYNPLMDKGVGN
[0467] HIWFQYNTKADTQLIVTGGSCKAHIQDIPLWAAFYGYSDFIESELGPFVDAETVGLV
[0468] CVICPYTKPPMYNKTNPAMGYVFYDRNFGDGKWTDGRGKIEPYWQVRWRPEMLF
[0469] QETVMADLVQTGPFSYKDELKNSTLVCKYKFYFTWGGNMMFQQTIKNPCKTDGQ
[0470] PTDSSRHPRGIQVADPEQMGPRWVFHSFDWRRGYLSEKALKRLQEKPLDYDEYFT
[0471] QPKRPRIFPPTESAEGEFREPEKGSYSEEERSQASAEEQTQEATVLLLKRRLREQQQL
[0472] QQQLQFLTREMFKTQAGLHLNPMLLNQR (SEQ ID NO: 14)
[0473] ORFl / 1 MAWGWWRWRRRWPARRWRRRRRRRPVRRTRARRPARRYRRRRTTIKNPCKTDG
[0474] QPTDSSRHPRGIQVADPEQMGPRWVFHSFDWRRGYLSEKALKRLQEKPLDYDEYF TQPKRPRIFPPTESAEGEFREPEKGSYSEEERSQASAEEQTQEATVLLLKRRLREQQQ LQQQLQFLTREMFKTQAGLHLNPMLLNQR (SEQ ID NO: 15)
[0475] ORF1 / 2 MAWGWWRWRRRWPARRWRRRRRRRPVRRTRARRPARRYRRRRTQRESSESPKK
[0476] ARIQRKKGRKPLPKSRRRRRQYSSSSDDSESNSSSSSSSNSSPEKCSKRKRVST (SEQ ID NO: 16)
[0477] Table 5. Exemplary Anellovirus nucleic acid sequence (Alphatorquevirus, Clade 3)
[0478] Name TTV-tth8
[0479] Genus / Clade Alphatorquevirus, Clade 3
[0480] Accession Number AJ620231.1
[0481] Full Sequence: 3753
[0482] 1 10 20 30 40 50
[0483] TGCTACGTCACTAACCCACGTGTCCTCTACAGGCCAATCGCAGTCTATGT CGTGCACTTCCTGGGCATGGTCTACATAATTATATAAATGCTTGCACTTC CGAATGGCTGAGTTTTTGCTGCCCGTCCGCGGAGAGGAGCCACGGCAGGG GATCCGAACGTCCTGAGGGCGGGTGCCGGAGGTGAGTTTACACACCGAAG TCAAGGGGCAATTCGGGCTCAGGACTGGCCGGGCTTTGGGCAAGGCTCTT AAAAATGCACTTTTCTCGAATAAGCAGAAAGAAAAGGAAAGTGCTACTGC TTTGCGTGCCAGCAGCTAAGAAAAAACCAACTGCTATGAGCTTCTGGAAA CCTCCGGTACACAATGTCACGGGGATCCAACGCATGTGGTATGAGTCCTT TCACCGTGGCCACGCTTCTTTTTGTGGTTGTGGGAATCCTATACTTCACA TTACTGCACTTGCTGAAACATATGGCCATCCAACAGGCCCGAGACCTTCT GGGCCACCGGGAGTAGACCCCAACCCCCACATCCGTAGAGCCAGGCCTGC CCCGGCCGCTCCGGAGCCCTCACAGGTTGATTCGAGACCAGCCCTGACAT GGCATGGGGATGGTGGAAGCGACGGAGGCGCTGGTGGTTCCGGAAGCGGT GGACCCGTGGCAGACTTCGCAGACGATGGCCTCGATCAGCTCGTCGCCGC CCTAGACGACGAAGAGTAAGGAGGCGCAGACGGTGGAGGAGGGGGAGACG AAAAACAAGGACTTACAGACGCAGGAGACGCTTTAGACGCAGGGGACGAA AAGCAAAACTTATAATAAAACTGTGGCAACCTGCAGTAATTAAAAGATGC AGAATAAAGGGATACATACCACTGATTATAAGTGGGAACGGTACCTTTGC CACAAACTTTACCAGTCACATAAATGACAGAATAATGAAAGGCCCCTTCG GGGGAGGACACAGCACTATGAGGTTCAGCCTCTACATTTTGTTTGAGGAG CACCTCAGACACATGAACTTCTGGACCAGAAGCAACGATAACCTAGAGCT AACCAGATACTTGGGGGCTTCAGTAAAAATATACAGGCACCCAGACCAAG ACTTTATAGTAATATACAACAGAAGAACCCCTCTAGGAGGCAACATCTAC ACAGCACCCTCTCTACACCCAGGCAATGCCATTTTAGCAAAACACAAAAT ATTAGTACCAAGTTTACAGACAAGACCAAAGGGTAGAAAAGCAATTAGAC TAAGAATAGCACCCCCCACACTCTTTACAGACAAGTGGTACTTTCAAAAG GACATAGCCGACCTCACCCTTTTCAACATCATGGCAGTTGAGGCTGACTT GCGGTTTCCGTTCTGCTCACCACAAACTGACAACACTTGCATCAGCTTCC AGGTCCTTAGTTCCGTTTACAACAACTACCTCAGTATTAATACCTTTAAT AATGACAACTCAGACTCAAAGTTAAAAGAATTTTTAAATAAAGCATTTCC AACAACAGGCACAAAAGGAACAAGTTTAAATGCACTAAATACATTTAGAA CAGAAGGATGCATAAGTCACCCACAACTAAAAAAACCAAACCCACAAATA AACAAACCATTAGAGTCACAATACTTTGCACCTTTAGATGCCCTCTGGGG AGACCCCATATACTATAATGATCTAAATGAAAACAAAAGTTTGAACGATA TCATTGAGAAAATACTAATAAAAAACATGATTACATACCATGCAAAACTA AGAGAATTTCCAAATTCATACCAAGGAAACAAGGCCTTTTGCCACCTAAC AGGCATATACAGCCCACCATACCTAAACCAAGGCAGAATATCTCCAGAAA TATTTGGACTGTACACAGAAATAATTTACAACCCTTACACAGACAAAGGA ACTGGAAACAAAGTATGGATGGACCCACTAACTAAAGAGAACAACATATA TAAAGAAGGACAGAGCAAATGCCTACTGACTGACATGCCCCTATGGACTT TACTTTTTGGATATACAGACTGGTGTAAAAAGGACACTAATAACTGGGAC TTACCACTAAACTACAGACTAGTACTAATATGCCCTTATACCTTTCCAAA ATTGTACAATGAAAAAGTAAAAGACTATGGGTACATCCCGTACTCCTACA AATTCGGAGCGGGTCAGATGCCAGACGGCAGCAACTACATACCCTTTCAG TTTAGAGCAAAGTGGTACCCCACAGTACTACACCAGCAACAGGTAATGGA GGACATAAGCAGGAGCGGGCCCTTTGCACCTAAGGTAGAAAAACCAAGCA CTCAGCTGGTAATGAAGTACTGTTTTAACTTTAACTGGGGCGGTAACCCT ATCATTGAACAGATTGTTAAAGACCCCAGCTTCCAGCCCACCTATGAAAT ACCCGGTACCGGTAACATCCCTAGAAGAATACAAGTCATCGACCCGCGGG TCCTGGGACCGCACTACTCGTTCCGGTCATGGGACATGCGCAGACACACA TTTAGCAGAGCAAGTATTAAGAGAGTGTCAGAACAACAAGAAACTTCTGA CCTTGTATTCTCAGGCCCAAAAAAGCCTCGGGTCGACATCCCAAAACAAG AAACCCAAGAAGAAAGCTCACATTCACTCCAAAGAGAATCGAGACCGTGG GAGACCGAGGAAGAAAGCGAGACAGAAGCCCTCTCGCAAGAGAGCCAAGA GGTCCCCTTCCAACAGCAGTTGCAGCAGCAGTACCAAGAGCAGCTCAAGC TCAGACAGGGAATCAAAGTCCTCTTCGAGCAGCTCATAAGGACCCAACAA GGGGTCCATGTAAACCCATGCCTACGGTAGGTCCCAGGCAGTGGCTGTTT CCAGAGAGAAAGCCAGCCCCAGCTCCTAGCAGTGGAGACTGGGCCATGGA GTTTCTCGCAGCAAAAATATTTGATAGGCCAGTTAGAAGCAACCTTAAAG ATACCCCTTACTACCCATATGTTAAAAACCAATACAATGTCTACTTTGAC CTTAAATTTGAATAAACAGCAGCTTCAAACTTGCAAGGCCGTGGGAGTTT CACTGGTCGGTGTCTACCTCTAAAGGTCACTAAGCACTCCGAGCGTAAGC GAGGAGTGCGACCCTCCCCCCTGGAACAACTTCTTCGGAGTCCGGCGCTA CGCCTTCGGCTGCGCCGGACACCTCAGACCCCCCCTCCACCCGAAACGCT TGCGCGTTTCGGACCTTCGGCGTCGGGGGGGTCGGGAGCTTTATTAAACG GACTCCGAAGTGCTCTTGGACACTGAGGGGGTGAACAGCAACGAAAGTGA GTGGGGCCAGACTTCGCCATAAGGCCTTTATCTTCTTGCCATTTGTCAGT GTCCGGGGTCGCCATAGGCTTCGGGCTCGTTTTTAGGCCTTCCGGACTAC AAAAATCGCCATTTTGGTGACGTCACGGCCGCCATCTTAAGTAGTTGAGG CGGACGGTGGCGTGAGTTCAAAGGTCACCATCAGCCACACCTACTCAAAA TGGTGGACAATTTCTTCCGGGTCAAAGGTTACAGCCGCCATGTTAAAACA CGTGACGTATGACGTCACGGCCGCCATTTTGTGACACAAGATGGCCGACT TCCTTCCTCTTTTTCAAAAAAAAGCGGAAGTGCCGCCGCGGCGGCGGGGG GCGGCGCGCTGCGCGCGCCGCCCAGTAGGGGGAGCCATGCGCCCCCCCCC GCGCATGCGCGGGGCCCCCCCCCGCGGGGGGCTCCGCCCCCCGGCCCCCC CCG (SEQ ID NO: 17)
[0484] Annotations:
[0485] Putative Domain Base range
[0486] TATA Box 83 - ! 38
[0487] Cap Site 104 - 111
[0488] Transcriptional Start Site 111
[0489] 5' UTR Conserved Domain 170 - 240
[0490] ORF2 336 - 719
[0491] ORF2 / 2 336 - 715 ; 2363 - 2789
[0492] ORF2 / 3 336 - 715 ; 2565 - 3015
[0493] ORF2t / 3 336 -■388 ; 2565 - 3015
[0494] ORF1 599 -■2830
[0495] ORFl / 1 599 - 715 ; 2363 - 2830
[0496] ORF1 / 2 599 - 715 ; 2565 - 2789
[0497] Three open-reading frame region 2551 - 2786
[0498] Poly(A) Signal 3011 - 3016
[0499] GC-rich region 3632 - 3753
[0500] Table 6. Exemplary Anellovirus amino acid sequences (Alphatorquevirus, Clade 3)
[0501] PPGVDPNPHIRRARPAPAAPEPSQVDSRPALTWHGDGGSDGGAGGSGSGGPVADFA DDGLDQLVAALDDEELLKTPASSPPMKYPVPVTSLEEYKSSTRGSWDRTTRSGHGT CADTHLAEQVLRECQNNKKLLTLYSQAQKSLGSTSQNKKPKKKAHIHSKENRDRG RPRKKARQKPSRKRAKRSPSNSSCSSSTKSSSSSDRESKSSSSSS (SEQ ID NO: 19)
[0502] ORF2 / 3 MSFWKPPVHNVTGIQRMWYESFHRGHASFCGCGNPILHITALAETYGHPTGPRPSG
[0503] PPGVDPNPHIRRARPAPAAPEPSQVDSRPALTWHGDGGSDGGAGGSGSGGPVADFA
[0504] DDGLDQLVAALDDEEPKKASGRHPKTRNPRRKLTFTPKRIETVGDRGRKRDRSPLA
[0505] REPRGPLPTAVAAAVPRAAQAQTGNQSPLRAAHKDPTRGPCKPMPTVGPRQWLFP
[0506] ERKPAPAPSSGDWAMEFLAAKIFDRPVRSNLKDTPYYPYVKNQYNVYFDLKFE
[0507] (SEQ ID NO: 20)
[0508] ORF2t / 3 MSFWKPPVHNVTGIQRMWPKKASGRHPKTRNPRRKLTFTPKRIETVGDRGRKRDR
[0509] SPLAREPRGPLPTAVAAAVPRAAQAQTGNQSPLRAAHKDPTRGPCKPMPTVGPRQ WLFPERKPAPAPSSGDWAMEFLAAKIFDRPVRSNLKDTPYYPYVKNQYNVYFDLK FE (SEQ ID NO: 21)
[0510] ORF1 MAWGWWKRRRRWWFRKRWTRGRLRRRWPRSARRRPRRRRVRRRRRWRRGRRK
[0511] TRTYRRRRRFRRRGRKAKLIIKLWQPAVIKRCRIKGYIPLIISGNGTFATNFTSHINDR
[0512] IMKGPFGGGHSTMRFSLYILFEEHLRHMNFWTRSNDNLELTRYLGASVKIYRHPDQ
[0513] DFIVIYNRRTPLGGNIYTAPSLHPGNAILAKHKILVPSLQTRPKGRKAIRLRIAPPTLFT
[0514] DKWYFQKDIADLTLFNIMAVEADLRFPFCSPQTDNTCISFQVLSSVYNNYLSINTFN
[0515] NDNSDSKLKEFLNKAFPTTGTKGTSLNALNTFRTEGCISHPQLKKPNPQINKPLESQ
[0516] YFAPLDALWGDPIYYNDLNENKSLNDIIEKILIKNMITYHAKLREFPNSYQGNKAFC
[0517] HLTGIYSPPYLNQGRISPEIFGLYTEIIYNPYTDKGTGNKVWMDPLTKENNIYKEGQS
[0518] KCLLTDMPLWTLLFGYTDWCKKDTNNWDLPLNYRLVLICPYTFPKLYNEKVKDY
[0519] GYIPYSYKFGAGQMPDGSNYIPFQFRAKWYPTVLHQQQVMEDISRSGPFAPKVEKP
[0520] STQLVMKYCFNFNWGGNPIIEQIVKDPSFQPTYEIPGTGNIPRRIQVIDPRVLGPHYSF
[0521] RSWDMRRHTFSRASIKRVSEQQETSDLVFSGPKKPRVDIPKQETQEESSHSLQRESR
[0522] PWETEEESETEALSQESQEVPFQQQLQQQYQEQLKLRQGIKVLFEQLIRTQQGVHV
[0523] NPCLR (SEQ ID NO: 22)
[0524] ORFl / 1 MAWGWWKRRRRWWFRKRWTRGRLRRRWPRSARRRPRRRRIVKDPSFQPTYEIPG
[0525] TGNIPRRIQVIDPRVLGPHYSFRSWDMRRHTFSRASIKRVSEQQETSDLVFSGPKKPR VDIPKQETQEESSHSLQRESRPWETEEESETEALSQESQEVPFQQQLQQQYQEQLKL RQGIKVLFEQLIRTQQGVHVNPCLR (SEQ ID NO: 23)
[0526] ORF1 / 2 MAWGWWKRRRRWWFRKRWTRGRLRRRWPRSARRRPRRRRAQKSLGSTSQNKK
[0527] Table 7. Exemplary Anellovirus nucleic acid sequence (Alphatorquevirus, Clade 4)
[0528] Name TTV-JA20
[0529] Genus / Clade Alphatorquevirus, Clade 4 Accession Number AF122914.3
[0530] Full Sequence: 3853
[0531] 1 20 30 40 50
[0532] GGCTTAGTGCGTCACCACCCACGTGACCCGCCTCCGCCAATTAACAGGTA CTTCGTACACTTCCTGGGCGGGCTTATAAGACTAATATAAGTAGCTGCAC TTCCGAATGGCTGAGTTTTCCACGCCCGTCCGCAGCGGTGAAGCCACGGA GGGAGCTCAGCGCGTCCCGAGGGCGGGTGCCGGAGGTGAGTTTACACACC GCAGTCAAGGGGCAATTCGGGCTCGGGACTGGCCGGGCTTTGGGCAAGGC TCTTAAAAAAGCTATGTTTATTGGCAGGCACTACCGAAAGAAAAGGGCGC TGCTACTGCTATCTGTGCATTCTACAAAGACAAAAGGGAAACTTCTAATA GCTATGTGGACTCCCCCACGCAATGATCAACAATACCTTAACTGGCAATG GTACACTTCTGTACTTAGCTCCCACTCTGCTATGTGCGGGTGTTCCGACG CTATCGCTCATCTTAATCATCTTGCTAATCTGCTTCGTGCCCCGCAAAAT CCGCCCCCGCCTGATAATCCAAGACCCCTACCCGTGCGAGCACTGCCTGC TCCCCCGGCTGCCCACGAGGCAGCCGGTGATCGAGCACCATGGCCTATGG GTGGTGGAGGAGACGCCGGAGGCGCTGGCGCAGGTGGAGACGCCGACCAT GGAGGCGCCGCTGGAGGACCCGCAGACGCAGACCTGCTAGACGCCGTGGC CGCCGCAGAAACGTAAGGAGACGGCGCAGAGGGAGGTGGAGAAGGAGGTA CAGGAGGTGGAAAAGAAAGGGCAGACGTAGAAGAAAAGCAAAAATAATAA TAAGACAGTGGCAGCCAAACTACAGAAGAAGATGTAATATAGTGGGCTAC CTCCCTATACTTATCTGTGGTGGAAATACTGTTTCTAGAAACTATGCCAC ACACTCAGACGATACTAACTATCCAGGACCCTTTGGGGGAGGCATGACCA CAGACAAATTCAGCCTTAGAATACTATATGATGAATACAAAAGATTTATG AACTACTGGACAGCCTCAAATGAGGACCTAGATCTCTGTAGATATCTAGG ATGCACTTTTTACTTCTTTAGACACCCTGAAGTAGACTTTATTATAAAAA TAAACACCATGCCCCCATTCTTAGATACAACCATAACAGCACCTAGCATA CACCCAGGCCTCATGGCCCTAGACAAAAGAGCCAGATGGATTCCTTCTCT TAAAAATAGACCAGGTAAAAAACACTATATAAAAATTAGAGTAGGGGCTC CTAAAATGTTCACAGATAAATGGTACCCTCAAACAGACCTCTGTGACATG ACACTGCTAACTATCTATGCAACCGCAGCGGATATGCAATATCCGTTCGG CTCACCACTAACTGACACTGTGGTTGTTAACTCCCAAGTTCTGCAATCCA TGTATGATGAAACAATTAGCATATTACCTGATGAAAAAACTAAAAGAAAT AGCCTTCTTACTTCTATAAGAAGCTACATACCTTTTTATAATACTACACA AACAATAGCTCAATTAAAACCATTTGTAGATGCAGGAGGACACACAACAG GCTCAACAACAACTACATGGGGACAACTATTAAACACAACTAAATTTACC ACTACCACAACAACCACATACACATACCCTGGCACCACAAATACAGCAGT AACATTTATAACAGCCAATGATACCTGGTACAGGGGAACAGCATATAAAG ATAACATTAAAGATGTACCACAAAAAGCAGCACAATTATACTTTCAAACA ACACAAAAACTACTAGGAAACACATTCCATGGCTCAGATGAAACACTTGA ATACCATGCAGGCCTATACAGCTCTATCTGGCTATCACCAGGTAGATCCT ACTTTGAAACACCAGGTGCATACACAGACATTAAATATAACCCTTTTACA GACAGAGGAGAAGGCAACATGCTGTGGATAGACTGGCTAAGTAAAAAAAA CATGAAATATGACAAAGTGCAAAGTAAGTGCCTAGTAGCAGACCTACCAC TGTGGGCAGCAGCATATGGTTATGTAGAATTCTGCTCTAAAAGCACAGGA GACACAAACATACACATGAATGCCAGACTACTAATAAGAAGTCCTTTTAC AGACCCCCAGCTAATAGTACACACAGACCCCACTAAAGGCTTTGTACCCT ATTCTTTAAACTTTGGAAATGGTAAAATGCCAGGAGGTAGCAGCAATGTT CCCATAAGAATGAGAGCTAAGTGGTACCCCACTTTATCCCACCAACAAGA AGTTCTAGAGGCCTTAGCACAGTCAGGACCCTTTGCTTATCACTCAGACA TTAAAAAAGTATCTCTAGGCATAAAATACCGTTTTAAGTGGATCTGGGGT GGAAACCCCGTTCGCCAACAGGTTGTTAGAAATCCCTGCAAGGAACCCCA CTCCTCGGGCAATAGAGTCCCTAGAAGCATACAAATCGTTGACCCGAGAT ACAACTCACCGGAACTTACCATCCATGCCTGGGACTTCAGACGTGGCTTC TTTGGCCCGAAAGCTATTCAAAGAATGCAACAACAACCAACTGCTACTGA ATTTTTTTCAGCAGGCCGCAAGAGACCCAGAAGGGACACAGAAGTGTATC AGTCCGACCAAGAAAAGGAGCAAAAAGAAAGCTCGCTTTTCCCCCCAGTC AAGCTCCTCCGAAGAGTCCCCCCGTGGGAGGACTCGGAACAGGAGCAAAG CGGGTCGCAAAGCTCAGAGGAAGAGACGGCGACCCTCTCCCAGCAGCTCA AACAGCAGCTGCAGCAGCAGCGAGTCTTGGGAGTCAAACTCAGACTCCTG TTCAACCAAGTCCAAAAAATCCAACAAAATCAAGATATCAACCCTACCTT GTTACCAAGGGGGGGGGATCTAGTATCCTTCTTTCAGGCTGTACCATAAA TATGTTTCCAGACCCTAAACCTTACTGCCCCTCCAGCAATGACTGGAAAG AAGAGTATGAGGCCTGTAAATATTGGGATAGACCTCCCAGACACAACCTT AGAGACCCCCCCTTTTACCCCTGGGCCCCTAAAAACAATCCTTGCAATGT AAGCTTTAAACTTGGCTTCAAATAAACTAGGCCGTGGGAGTTTCACTTGT CGGTGTCTACCTCTATAAGTCACTAAGCACTCCGAGCGCAGCGAGGAGTG CGACCCTTCCCCCTGGTGCAACGCCCTCGGCGGCCGCGCGCTACGCCTTC GGCTGCGCGCGGCACCTCGGACCCCCGCTCGTGCTGACACGCTTGCGCGT GTCAGACCACTTCGGGCTCGCGGGGGTCGGGAAATTTGCTAAACAGACTC CGAGTTGCCATTGGACACTGTAGCTATGAATCAGTAACGAAAGTGAGTGG GGCCAGACTTCGCCATAAGGCCTTTATCTTCTTGCCATTTGTCAGTATTG GGGGTCGCCATAAACTTTGGGCTCCATTTTAGGCCTTCCGGACTACAAAA ATCGCCATATTTGTGACGTCAGAGCCGCCATTTTAAGTCAGCTCTGGGGA GGCGTGACTTCCAGTTCAAAGGTCATCCTCACCATAACTGGCACAAAATG GCCGCCAACTTCTTCCGGGTCAAAGGTCACTGCTACGTCATAGGTGACGT GGGGGGGGACCTACTTAAACACGGAAGTAGGCCCCGACACGTCACTGTCA CGTGACAGTACGTCACAGCCGCCATTTTGTTTTACAAAATAGCCGACTTC CTTCCTCTTTTTTAAAAAAAGGCGCCAAAAAACCGTCGGCGGGGGGGCCG CGCGCTGCGCGCGCGGCCCCCGGGGGAGGCACAGCCTCCCCCCCCCGCGC GCATGCGCGCGGGTCCCCCCCCCTCCGGGGGGCTCCGCCCCCCGGCCCCC CCC (SEQ ID NO: 25)
[0533] Annotations:
[0534] Putative Domain Base range
[0535] TATA Box 86 - 90
[0536] Cap Site 107 - 114
[0537] Transcriptional Start Site 114
[0538] 5' UTR Conserved Domain 174 _ 244
[0539] ORF2 354 - 716
[0540] ORF2 / 2 354 - 712 ; 2372 - 2873
[0541] ORF2 / 3 354 - 712 ; 2565 - 3075
[0542] ORF2t / 3 354 - 400 ; 2565 - 3075
[0543] ORF1 590 - 2899 ORFl / 1 590 -712; 2372 ORF1 / 2 590 -712; 2565
[0544] Three open-reading frame region 2551 -2870
[0545] Poly(A) Signal 3071 - 3076
[0546] GC-rich region 3733 - 3853
[0547] Table 8. Exemplary Anellovirus amino acid sequences (Alphatorquevirus, Clade 4)
[0548] GNTFHGSDETLEYHAGLYSSIWLSPGRSYFETPGAYTDIKYNPFTDRGEGNMLWID
[0549] WLSKKNMKYDKVQSKCLVADLPLWAAAYGYVEFCSKSTGDTNIHMNARLLIRSPF
[0550] TDPQLIVHTDPTKGFVPYSLNFGNGKMPGGSSNVPIRMRAKWYPTLSHQQEVLEAL
[0551] AQSGPFAYHSDIKKVSLGIKYRFKWIWGGNPVRQQVVRNPCKEPHSSGNRVPRSIQI
[0552] VDPRYNSPELTIHAWDFRRGFFGPKAIQRMQQQPTATEFFSAGRKRPRRDTEVYQS
[0553] DQEKEQKESSLFPPVKLLRRVPPWEDSEQEQSGSQSSEEETATLSQQLKQQLQQQR
[0554] VLGVKLRLLFNQVQKIQQNQDINPTLLPRGGDLVSFFQAVP (SEQ ID NO: 30)
[0555] ORFl / 1 MAYGWWRRRRRRWRRWRRRPWRRRWRTRRRRPARRRGRRRNVVRNPCKEPHSS
[0556] GNRVPRSIQIVDPRYNSPELTIHAWDFRRGFFGPKAIQRMQQQPTATEFFSAGRKRP RRDTEVYQSDQEKEQKESSLFPPVKLLRRVPPWEDSEQEQSGSQSSEEETATLSQQL KQQLQQQRVLGVKLRLLFNQVQKIQQNQDINPTLLPRGGDLVSFFQAVP (SEQ ID NO: 31)
[0557] ORF1 / 2 MAYGWWRRRRRRWRRWRRRPWRRRWRTRRRRPARRRGRRRNAARDPEGTQKCI
[0558] SPTKKRSKKKARFSPQSSSSEESPRGRTRNRSKAGRKAQRKRRRPSPSSSNSSCSSSE SWESNSDSCSTKSKKSNKIKISTLPCYQGGGI (SEQ ID NO: 32)
[0559] Table 9. Exemplary Anellovirus nucleic acid sequence (Alphatorquevirus, Clade 5)
[0560] Name TTV-HD23a
[0561] Genus / Clade Alphatorquevirus, Clade 5
[0562] Accession Number FR751500.1
[0563] Full Sequence: 3758
[0564] 1 20 30 40 50
[0565] AAAGTACGTCACTAACCACGTGACTCCCACAGGCCAACCACAGTCTACGT CGTGCATTTCCTGGGCATGGTCTACATCATAATATAAGAAGGCGCACTTC CGAATGGCTGAGTTTTCCACGCCCGTCCGCAGCGAGAACGCCACGGAGGG AGATCCTCGCGTCCCGAGGGCGGGTGCCGGAGGTGAGTTTACACACCGCA GTCAAGGGGCAATTCGGGCTCGGGACTGGCCGGGCCCTGGGCAAGGCTCT TAAAAAATGCGCTTTCGCAGGGTTGCGGAGAAAAGGAAAGTGCTTCTGCA AACTCTGCGAGCTGCAAAGCAGGCTAGGCGGCTTCTAGGTATGTGGCAGC CCCCCGCGCACAATGTCCCCGGCATCGAGAGAAACTGGTACGAGAGCTGC TTCAGGTCTCACGCTGCTGTTTGTGGCTGTGGCGACTTTGTTGGCCATAT TAATCATTTGGCAACTACTCTGGGTCGTCCTCCGCGTCCTGGGCCCCCAG GCGGACCCCGCACGCCGCAAATAAGAAACCTGCCAGCGCTCCCGGCGCCC CAGGGCGAGCCCGGTGACAGAGCGCCATGGCGTGGGGTTTCTGGGGCCGA CGCCGCCGGTGGAGACGGTGGAGAGCGCGGCGCAGACGGTGGAGACCCCG GAGACGTAGGAGACGACGCCCTGCTCGCCGCTTTCGAGCTCGTCGAAGAG TAAGGAGACGCGGGGGGAGGTGGCGCAGACGCTACAGAAAATGGCGACGG GGCAGACGCAGACGGACTCACAGAAAAAAGATAATTATAAAACAGTGGCA ACCAAACTTTATTAGACGCTGCTACATAATAGGATGCCTACCTCTCGTTT TCTGTGGCGAAAATACAACCGCCCAGAACTATGCCACTCACTCAGACGAT ATGATAAGCAAAGGACCGTACGGGGGGGGCATGACTACCACGAAATTCAC TCTGAGAATACTGTACGACGAGTTTACCAGGTTTATGAACTTTTGGACT G TCAGTAACGAAGACCTAGACCTGTGTAGATACGTGGGCTGCAAACTGATA TTTTTTAAACACCCCACGGTGGACTTTATGGTACAGATAAACACTCAGC C TCCTTTCTTAGACACAAGCCTCACCGCGGCCAGCATACACCCGGGCATCA TGATGCTCAGCAAGAGACGCATATTAATACCCTCTCTAAAGACCCGGCC G AGCAGAAAACACAGGGTGGTCGTCAGGGTGGGCGCCCCAAGACTTTTTCA GGACAAGTGGTACCCCCAGTCAGACCTATGTGACACAGTTCTGCTTTCCA TATTTGCAACCGCCCGCGACTTGCAATATCCGTTCGGCTCACCACTAAC T GACAACCCTTGCGTCAACTTCCAGATCCTGGGGCCCCAGTACAAAAAACA CCTTAGTATTAGCTCCACTATGGATGATACTAACAAACAGCACTATAACA GCAACTTATTTAATAAAACTGCACTATACAACACCTTTCAAACCATAGC C CGGCTTAAAGAGACAGGACAAACTGCAAACATTAGTCCAAGTTGGAGTGA AGTACAAAACACAAAACTACTAGATCACACAGGTGCTAATGCAACTGCCA GCAGAGACACTTGGTACAAGGGAAACACATACAATGACTACATACAACAG TTAGCAGAGAAAACAAGAGAAAGGTTTAAAAAAGCAACAATGTCAGCAC T ACCAAACTACCCCACAATAATGTCCACAGACTTATACGAATACCACTCAG GCATATACTCCAGCATATTTCTATCAGCTGGCAGGAGCTACTTTGAAAC C ACTGGGGCCTACTCTGACATTATATACAACCCTTTGACAGACAAAGGCAC AGGCAACATAATCTGGATAGACTACCTTACAAAAGACGACACAATCTTT G TAAAAAACAAAAGCAAATGTGAGATAATGGACATGCCCCTGTGGGCGGC C GGCACAGGATACACAGAGTTTTGTGCAAAGTACACAGGAGACTCTGCCAT TATTTACAATGCCAGAATACTCATAAGATGCCCATACACTGAACCCATGC TAATAGACCACTCAGACCCAAACAAAGGCTTTGTACCGTACTCATTTAAC TTTGGCAACGGAAAGATGCCGGGAGGCAGCTCCAACGTGCCCATAAGAAT GAGAGCCAAGTGGTACGTAAACATATTCCACCAAAAAGAAGTATTGGAGA GCATAGTACAGTCCGGACCGTTCGGGTACAGGGGCGACATAAAATCAGC T GTACTGTCCATGAAATACAGATTTCACTGGAAATGGGGCGGAAACCCTAT ATCCAAACAGGTCGTCAGGAATCCCTGCTCCAACTCCAGCACCTCCGCGG CCCATAGAGGACCTCGCAGCGTACAAGCGGTTGACCCGAAATACAATAC C CCAGAAGTCACTTGGCACTCGTGGGACATCAGACGAGGACTCTTTGGCAA AGCAGGTATTAAAAGAATGCAACAAGAATCAGATGCTCTTTACGTTCCT G CAGGACCACTCAAGAGGCCTCGCAGAGACACCAACGCCCAAGACCCGGAA AAGCAAAACGAAAGCTCACGTTTCGGAGTCCAGCAGCGACTCCCGTGGGT CCACTCCAGCCAAGAGACGCAAAGCTCCGAAGAAGAGACGCAGGCGCAGG GGTCGGTACAAGACCAACTACTCCTCCAGCTCCGAGAGCAGCGAGTACT C CGACTCCAGCTCCAACAACTCGCACCCCAAGTCCTCAAAGTTCAAGCAGG ACACAGCCTACACCCCCTATTATCCTCCCAAGCATAAACAAAGCCTATAT GTTTGAACCCCAGGGTCCTAAACCCATACAGGGGTACAACGATTGGCTAG AGGAGTACACTAGTTGCAAGTTCCGGGACAGACCCCCGAGAATGCTACAC ACAGACTTACCCTTTTACCCCTGGGCACCAAAACCCCAAGACCAAGTCAG GGTAACCTTTAAACTCAACTTTCAATAAAAATTCTAGGCCGTGGGACTT T CACTTGTCGGTGTCTGCTTCTTAAGGTCGCCAAGCACTCCGAGCGTCAGC GAGGAGTGCGACCCCCCCCCTCGGTAGCAACGCCTTCGGAGCCGCGCGC T ACGCCTTCGGCTGCGCGCGGCACCTCAGACCCCCCCTCCACCCGAAACGC TTGCGCGTTTCGGACCTTCGGCGTCGGGGGGGTCGGGAGCTTTATTAAAC AGACTCCGAGTTGCCATTGGACACTGGAGCTGTGAATCAGTAACGAAAGT GAGTGGGGCCAGACTTCGCCATAGGGCCTTTATCTTCTCGCCATTGGATA GTGTCCGGGGTTGCCGTAGGCTTCGGCCTCGTTTTTAGGCCTTCCGGAC T ACAAAAATGGCGGATTTTGTGACGTCACGGCCGCCATTTTAAGTAAGGC G GAAGCAGCTCCACCCTCTCACATAATGGCGGCGGAGCACTCCCGGCTTGC CCAAAATGGCGGGCAAGCTCTTCCGGGTCAAAGGTTGGCAGCTACGTCAC AAGTCACCTGACTGGGGAGGAGTTACATCCCGGAAGTTCTCCTCGGTCAC GTGACTGTACACGTGACTGCTACGTCATTGACGCCATCTTGTGTCACAAA ATGGCGGTGCACTTCCGCTTTTTTGAAAAAAGGCGCGAAAAAACGGCGGC GGCGGCGCGCGCGCTGCGCGCGCGCGCCGGGGGGGCGCCAGCGCCCCCC C CCCCGCGCATGCACGGGTCCCCCCCCCCACGGGGGGCTCCGCCCCCCGGC CCCCCCCC (SEQ ID NO: 33)
[0566] Annotations:
[0567] Putative Domain Base range
[0568] TATA Box 83- 87
[0569] Cap Site 104-111
[0570] Transcriptional Start Site 111
[0571] 5' UTR Conserved Domain 171-241
[0572] ORF2 341 - 703
[0573] ORF2 / 2 341 -699; 2311 -2806
[0574] ORF2 / 3 341 - 699 ; 2504 -2978
[0575] ORF2t / 3 341 - 387 ; 2504 -2978
[0576] ORF1 577 - 2787
[0577] ORFl / 1 577-699 ; 2311 -2787
[0578] ORF1 / 2 577 - 699 ; 2504 -2806
[0579] Three open-reading frame region 2463 - 2784
[0580] Poly(A) Signal 2974 - 2979
[0581] GC-rich region 3644 - 3758
[0582] Table 10. Exemplary Anellovirus amino acid sequences (Alphatorquevirus, Clade 5)
[0583] PIQGYNDWLEEYTSCKFRDRPPRMLHTDLPFYPWAPKPQDQVRVTFKLNFQ (SEQ ID NO: 36)
[0584] ORF2t / 3 MWQPPAHNVPGIERNWTTQEASQRHQRPRPGKAKRKLTFRSPAATPVGPLQPRDA
[0585] KLRRRDAGAGVGTRPTTPPAPRAASTPTPAPTTRTPSPQSSSRTQPTPPIILPSINKAY MFEPQGPKPIQGYNDWLEEYTSCKFRDRPPRMLHTDLPFYPWAPKPQDQVRVTFKL NFQ (SEQ ID NO: 37)
[0586] ORF1 MAWGFWGRRRRWRRWRARRRRWRPRRRRRRRPARRFRARRRVRRRGGRWRRR
[0587] YRKWRRGRRRRTHRKKIIIKQWQPNFIRRCYIIGCLPLVFCGENTTAQNYATHSDDM
[0588] ISKGPYGGGMTTTKFTLRILYDEFTRFMNFWTVSNEDLDLCRYVGCKLIFFKHPTVD
[0589] FMVQINTQPPFLDTSLTAASIHPGIMMLSKRRILIPSLKTRPSRKHRVVVRVGAPRLF
[0590] QDKWYPQSDLCDTVLLSIFATARDLQYPFGSPLTDNPCVNFQILGPQYKKHLSISST
[0591] MDDTNKQHYNSNLFNKTALYNTFQTIARLKETGQTANISPSWSEVQNTKLLDHTG
[0592] ANATASRDTWYKGNTYNDYIQQLAEKTRERFKKATMSALPNYPTIMSTDLYEYHS
[0593] GIYSSIFLSAGRSYFETTGAYSDIIYNPLTDKGTGNIIWIDYLTKDDTIFVKNKSKCEI
[0594] MDMPLWAAGTGYTEFCAKYTGDSAIIYNARILIRCPYTEPMLIDHSDPNKGFVPYSF
[0595] NFGNGKMPGGSSNVPIRMRAKWYVNIFHQKEVLESIVQSGPFGYRGDIKSAVLSMK
[0596] YRFHWKWGGNPISKQVVRNPCSNSSTSAAHRGPRSVQAVDPKYNTPEVTWHSWDI
[0597] RRGLFGKAGIKRMQQESDALYVPAGPLKRPRRDTNAQDPEKQNESSRFGVQQRLP
[0598] WVHSSQETQSSEEETQAQGSVQDQLLLQLREQRVLRLQLQQLAPQVLKVQAGHSL
[0599] HPLLSSQA (SEQ ID NO: 38)
[0600] ORFl / 1 MAWGFWGRRRRWRRWRARRRRWRPRRRRRRRPARRFRARRRVVRNPCSNSSTS
[0601] AAHRGPRSVQAVDPKYNTPEVTWHSWDIRRGLFGKAGIKRMQQESDALYVPAGPL KRPRRDTNAQDPEKQNESSRFGVQQRLPWVHSSQETQSSEEETQAQGSVQDQLLLQ LREQRVLRLQLQQLAPQVLKVQAGHSLHPLLSSQA (SEQ ID NO: 39)
[0602] ORF1 / 2 MAWGFWGRRRRWRRWRARRRRWRPRRRRRRRPARRFRARRRDHSRGLAETPTP
[0603] KTRKSKTKAHVSESSSDSRGSTPAKRRKAPKKRRRRRGRYKTNYSSSSESSEYSDSS SNNSHPKSSKFKQDTAYTPYYPPKHKQSLYV (SEQ ID NO: 40)
[0604] Table 11. Exemplary Anellovirus nucleic acid sequence {Betatorquevirus)
[0605] Name TTMV-LY2
[0606] Genus / Clade Betatorquevirus
[0607] Accession Number JX 134045.1
[0608] Full Sequence: 2797 bp 1 1 0 2 0 30 4 0 50
[0609] TAATAAATATTCAACAGGAAAACCACCTAATTTAAATTGCCGACCACAAA CCGTCACTTAGTTCCCCTTTTTGCAACAACTTCTGCTTTTTTCCAACTGC CGGAAAACCACATAATTTGCATGGCTAACCACAAACTGATATGCTAATTA ACTTCCACAAAACAACTTCCCCTTTTAAAACCACACCTACAAATTAATTA TTAAACACAGTCACATCCTGGGAGGTACTACCACACTATAATACCAAGT G CACTTCCGAATGGCTGAGTTTATGCCGCTAGACGGAGAACGCATCAGTTA CTGACTGCGGACTGAACTTGGGCGGGTGCCGAAGGTGAGTGAAACCACC G AAGTCAAGGGGCAATTCGGGCTAGTTCAGTCTAGCGGAACGGGCAAGAAA CTTAAAATTATTTTATTTTTCAGATGAGCGACTGCTTTAAACCAACATGC TACAACAACAAAACAAAGCAAACTCACTGGATTAATAACCTGCATTTAAC CCACGACCTGATCTGCTTCTGCCCAACACCAACTAGACACTTATTACTAG CTTTAGCAGAACAACAAGAAACAATTGAAGTGTCTAAACAAGAAAAAGAA AAAATAACAAGATGCCTTATTACTACAGAAGAAGACGGTACAACTACAGA CGTCCTAGATGGTATGGACGAGGTTGGATTAGACGCCCTTTTCGCAGAAG ATTTCGAAGAAAAAGAAGGGTAAGACCTACTTATACTACTATTCCTCTAA AGCAATGGCAACCGCCATATAAAAGAACATGCTATATAAAAGGACAAGAC TGTTTAATATACTATAGCAACTTAAGACTGGGAATGAATAGTACAATGTA TGAAAAAAGTATTGTACCTGTACATTGGCCGGGAGGGGGTTCTTTTTCT G TAAGCATGTTAACTTTAGATGCCTTGTATGATATACATAAACTTTGTAGA AACTGGTGGACATCCACAAACCAAGACTTACCACTAGTAAGATATAAAGG ATGCAAAATAACATTTTATCAAAGCACATTTACAGACTACATAGTAAGAA TACATACAGAACTACCAGCTAACAGTAACAAACTAACATACCCAAACACA CATCCACTAATGATGATGATGTCTAAGTACAAACACATTATACCTAGTAG ACAAACAAGAAGAAAAAAGAAACCATACACAAAAATATTTGTAAAACCAC CTCCGCAATTTGAAAACAAATGGTACTTTGCTACAGACCTCTACAAAAT T CCATTACTACAAATACACTGCACAGCATGCAACTTACAAAACCCATTTGT AAAACCAGACAAATTATCAAACAATGTTACATTATGGTCACTAAACACCA TAAGCATACAAAATAGAAACATGTCAGTGGATCAAGGACAATCATGGCCA TTTAAAATACTAGGAACACAAAGCTTTTATTTTTACTTTTACACCGGAGC AAACCTACCAGGTGACACAACACAAATACCAGTAGCAGACCTATTACCAC TAACAAACCCAAGAATAAACAGACCAGGACAATCACTAAATGAGGCAAAA ATTACAGACCATATTACTTTCACAGAATACAAAAACAAATTTACAAATTA TTGGGGTAACCCATTTAATAAACACATTCAAGAACACCTAGATATGATAC TATACTCACTAAAAAGTCCAGAAGCAATAAAAAACGAATGGACAACAGAA AACATGAAATGGAACCAATTAAACAATGCAGGAACAATGGCATTAACAC C ATTTAACGAGCCAATATTCACACAAATACAATATAACCCAGATAGAGACA CAGGAGAAGACACTCAATTATACCTACTCTCTAACGCTACAGGAACAGGA TGGGACCCACCAGGAATTCCAGAATTAATACTAGAAGGATTTCCACTAT G GTTAATATATTGGGGATTTGCAGACTTTCAAAAAAACCTAAAAAAAGTAA CAAACATAGACACAAATTACATGTTAGTAGCAAAAACAAAATTTACACAA AAACCTGGCACATTCTACTTAGTAATACTAAATGACACCTTTGTAGAAGG CAATAGCCCATATGAAAAACAACCTTTACCTGAAGACAACATTAAATGGT ACCCACAAGTACAATACCAATTAGAAGCACAAAACAAACTACTACAAAC T GGGCCATTTACACCAAACATACAAGGACAACTATCAGACAATATATCAAT GTTTTATAAATTTTACTTTAAATGGGGAGGAAGCCCACCAAAAGCAATTA ATGTTGAAAATCCTGCCCACCAGATTCAATATCCCATACCCCGTAACGAG CATGAAACAACTTCGTTACAGAGTCCAGGGGAAGCCCCAGAATCCATCT T ATACTCCTTCGACTATAGACACGGGAACTACACAACAACAGCTTTGTCAC GAATTAGCCAAGACTGGGCACTTAAAGACACTGTTTCTAAAATTACAGAG CCAGATCGACAGCAACTGCTCAAACAAGCCCTCGAATGCCTGCAAATCT C GGAAGAAACGCAGGAGAAAAAAGAAAAAGAAGTACAGCAGCTCATCAGCA ACCTCAGACAGCAGCAGCAGCTGTACAGAGAGCGAATAATATCATTATTA AAGGACCAATAACTTTTAACTGTGTAAAAAAGGTGAAATTGTTTGATGAT AAACCAAAAAACCGTAGATTTACACCTGAGGAATTTGAAACTGAGTTACA AATAGCAAAATGGTTAAAGAGACCCCCAAGATCCTTTGTAAATGATCCT C CCTTTTACCCATGGTTACCACCTGAACCTGTTGTAAACTTTAAGCTTAAT
[0610] TTTACTGAATAAAGGCCAGCATTAATTCACTTAAGGAGTCTGTTTATTTA AGTTAAACCTTAATAAACGGTCACCGCCTCCCTAATACGCAGGCGCAGAA AGGGGGCTCCGCCCCCTTTAACCCCCAGGGGGCTCCGCCCCCTGAAACCC CCAAGGGGGCTACGCCCCCTTACACCCCC (SEQ ID NO: 41)
[0611] Annotations:
[0612] Putative Domain Base range
[0613] TATA Box 237- 243
[0614] Cap Site 260- -267
[0615] Transcriptional Start Site 267
[0616] 5' UTR Conserved Domain 323- -393
[0617] ORF2 424- -723
[0618] ORF2 / 2 424- -719 ; 2274- 2589
[0619] ORF2 / 3 424- -719 ; 2449- 2812
[0620] ORF1 612- -2612
[0621] ORFl / 1 612- -719 ; 2274- 2612
[0622] ORF1 / 2 612- -719 ; 2449- 2589
[0623] Three open-reading frame region 2441 -2586
[0624] Poly(A) Signal 2808 -2813
[0625] GC-rich region 2868 -2929
[0626] Table 12. Exemplary Anellovirus amino acid sequences (Betatorquevirus)
[0627] TCYIKGQDCLIYYSNLRLGMNSTMYEKSIVPVHWPGGGSFSVSMLTLDALYDIHKL
[0628] CRNWWTSTNQDLPLVRYKGCKITFYQSTFTDYIVRIHTELPANSNKLTYPNTHPLM
[0629] MMMSKYKHIIPSRQTRRKKKPYTKIFVKPPPQFENKWYFATDLYKIPLLQIHCTACN
[0630] LQNPFVKPDKLSNNVTLWSLNTISIQNRNMSVDQGQSWPFKILGTQSFYFYFYTGA
[0631] NLPGDTTQIPVADLLPLTNPRINRPGQSLNEAKITDHITFTEYKNKFTNYWGNPFNK
[0632] HIQEHLDMILYSLKSPEAIKNEWTTENMKWNQLNNAGTMALTPFNEPIFTQIQYNP
[0633] DRDTGEDTQLYLLSNATGTGWDPPGIPELILEGFPLWLIYWGFADFQKNLKKVTNID
[0634] TNYMLVAKTKFTQKPGTFYLVILNDTFVEGNSPYEKQPLPEDNIKWYPQVQYQLEA
[0635] QNKLLQTGPFTPNIQGQLSDNISMFYKFYFKWGGSPPKAINVENPAHQIQYPIPRNE
[0636] HETTSLQSPGEAPESILYSFDYRHGNYTTTALSRISQDWALKDTVSKITEPDRQQLLK
[0637] QALECLQISEETQEKKEKEVQQLISNLRQQQQLYRERIISLLKDQ (SEQ ID NO: 45)
[0638] ORFl / 1 MPYYYRRRRYNYRRPRWYGRGWIRRPFRRRFRRKRRIQYPIPRNEHETTSLQSPGE
[0639] APESILYSFDYRHGNYTTTALSRISQDWALKDTVSKITEPDRQQLLKQALECLQISEE TQEKKEKEVQQLISNLRQQQQLYRERIISLLKDQ (SEQ ID NO: 46)
[0640] ORF1 / 2 MPYYYRRRRYNYRRPRWYGRGWIRRPFRRRFRRKRRSQIDSNCSNKPSNACKSRK
[0641] KRRRKKKKKYSSSSATSDSSSSCTESE (SEQ ID NO: 47)
[0642] Table 13. Exemplary Anellovirus nucleic acid sequence {Gammatorquevirus)
[0643] Name TTMDV-MD 1-073
[0644] Genus / Clade Gammatorquevirus
[0645] Accession Number AB290918.1
[0646] Full Sequence: 3242 bp
[0647] 1 1 0 2 0 3 0 4 0 50
[0648] AGGTGGAGACTCTTAAGCTATATAACCAAGTGGGGTGGCGAATGGCTGAG TTTACCCCGCTAGACGGTGCAGGGACCGGATCGAGCGCAGCGAGGAGGT C CCCGGCTGCCCGTGGGCGGGAGCCCGAGGTGAGTGAAACCACCGAGGTC T AGGGGCAATTCGGGCTAGGGCAGTCTAGCGGAACGGGCAAGAAACTTAAA AATATTTCTTTTACAGATGCAAAACCTATCAGCCAAAGACTTCTACAAAC CATGCAGATACAACTGTGAAACTAAAAACCAAATGTGGATGTCTGGCAT T GCTGACTCCCATGACAGTTGGTGTGACTGTGATACTCCTTTTGCTCACC T CCTGGCTAGTATTTTTCCTCCTGGTCACACAGATCGCACACGAACCATC C AAGAAATACTTACCAGAGATTTTAGGAAAACATGCCTTTCTGGTGGGGC C GACGCAACAAATTCTGGTATGGCCGAAACTATAGAAGAAAAAAGAGAAGA TTTCCAAAAAGAAGAAAAAGAAGATTTTACAGAAGAACAAAATATAGAAG ACCTGCTCGCCGCCGTCGCAGACGCAGAAGGAAGGTAAGAAGAAAAAAAA AAACTCTTATAGTAAGACAATGGCAGCCAGACTCTATTGTACTCTGTAAA ATTAAAGGGTATGACTCTATAATATGGGGAGCTGAAGGCACACAGTTTCA ATGTTCTACACATGAAATGTATGAATATACAAGACAAAAGTACCCTGGGG GAGGAGGATTTGGTGTACAACTTTACAGCTTAGAGTATTTGTATGACCAA TGGAAACTTAGAAATAATATATGGACTAAAACAAATCAACTCAAAGATT T GTGTAGATACTTAAAATGTGTTATGACCTTTTACAGACACCAACACATAG ATTTTGTAATTGTATATGAAAGACAACCCCCATTTGAAATAGATAAACTA ACATACATGAAATATCATCCATATATGTTATTACAAAGAAAGCATAAAAT AATTTTACCTAGTCAAACAACTAATCCTAGAGGTAAATTAAAAAAAAAGA AAACTATTAAACCTCCCAAACAAATGCTCAGCAAATGGTTTTTTCAACAA CAATTTGCTAAATATGATCTACTACTTATTGCTGCAGCAGCATGTAGTTT AAGATACCCTAGAATAGGCTGCTGCAATGAAAATAGAATGATAACCTTAT ACTGTTTAAATACTAAATTTTATCAAGATACAGAATGGGGAACTACAAAA CAGGCCCCCCACTACTTTAAACCATATGCAACAATTAATAAATCCATGAT ATTTGTCTCTAACTATGGAGGTAAAAAAACAGAATATAACATAGGCCAAT GGATAGAAACAGATATACCTGGAGAAGGTAATCTAGCAAGATACTACAGA TCAATAAGTAAAGAAGGAGGTTACTTTTCACCTAAAATACTGCAAGCATA TCAAACAAAAGTAAAGTCTGTAGACTACAAACCTTTACCAATTGTTTTAG GTAGATATAACCCAGCAATAGATGATGGAAAAGGCAACAAAATTTACTTA CAAACTATAATGAATGGCCATTGGGGCCTACCTCAAAAAACACCAGATTA TATAATAGAAGAGGTCCCTCTTTGGCTAGGCTTCTGGGGATACTATAACT ACTTAAAACAAACAAGAACTGAAGCTATATTTCCACTACACATGTTTGTA GTGCAAAGCAAATACATTCAAACACAACAAACAGAAACACCTAACAATTT TTGGGCATTTATAGACAACAGCTTTATACAGGGCAAAAACCCATGGGACT CAGTTATTACTTACTCAGAACAAAAGCTATGGTTTCCTACAGTTGCATGG CAACTAAAAACCATAAATGCTATTTGTGAAAGTGGACCATATGTACCTAA ACTAGACAATCAAACATATAGTACCTGGGAACTAGCAACTCATTACTCAT TTCACTTTAAATGGGGTGGTCCACAGATATCAGACCAACCAGTTGAAGAC CCAGGAAACAAAAACAAATATGATGTGCCCGATACAATCAAAGAAGCATT ACAAATTGTTAACCCAGCAAAAAACATTGCTGCCACGATGTTCCATGACT GGGACTACAGACGGGGTTGCATTACATCAACAGCTATTAAAAGAATGCAA CAAAACCTCCCAACTGATTCATCTCTCGAATCTGATTCAGACTCAGAACC AGCACCCAAGAAAAAAAGACTACTACCAGTCCTCCACGACCCACAAAAGA AAACGGAAAAGATCAACCAATGTCTCCTCTCTCTCTGCGAAGAAAGTACA TGCCAGGAGCAGGAAACGGAGGAAAACATCCTCAAGCTCATCCAGCAGCA GCAGCAGCAGCAGCAGAAACTCAAGCACAACCTCTTAGTACTAATCAAGG ACTTAAAAGTGAAACAAAGATTATTACAACTACAAACGGGGGTACTAGAA TAACCCTTACCAGATTTAAACCAGGATTTGAGCAAGAAACTGAAAAAGAG TTAGCACAAGCATTTAACAGACCCCCTAGACTGTTCAAAGAAGATAAACC CTTTTACCCCTGGCTACCCAGATTTACACCCCTTGTAAACTTTCACCTTA ATTTTAAAGGCTAGGCCTACACTGCTCACTTAGTGGTGTATGTTTATTAA AGTTTGCACCCCAGAAAAATTGTAAAATAAAAAAAAAAAAAAAAAATAAA AAATTGCAAAAATTCGGCGCTCGCGCGCGCTGCGCGCGCGAGCGCCGTCA CGCGCCGGCGCTCGCGCGCCGCGCGTATGTGCTAACACACCACGCACCTA GATTGGGGTGCGCGCGTAGCGCGCGCACCCCAATGCGCCCCGCCCTCGTT CCGACCCGCTTGCGCGGGTCGGACCACTTCGGGCTCGGGGGGGCGCGCCT GCGGCGCTTATTTACTAAACAGACTCCGAGTCGCCATTGGGCCCCCCCTA AGCTCCGCCCCCCTCATGAATATTCATAAAGGAAACCACAAAATTAGAAT TGCCGACCACAAACTGCCATATGCTAATTAGTTCCCCTTTTACACAGTAA AAAGGGGAAGTGGGGGGGCAGAGCCCCCCCACACCCCCCGCGGGGGGGGC AGAGCCCCCCCCGCACCCCCCCTACGTCACAGGCCACGCCCCCGCCGCCA TCTTGGGTGCGGCAGGGCGGGGACTAAAATGGCGGGACCCAATCATTTTA TACTTTCACTTTCCAATTAAAACCCGCCACGTCACACAAAAG (SEQ ID
[0649] Annotations:
[0650] Putative Domain Base range
[0651] TATA Box 21- 25
[0652] Cap Site 42 - 49
[0653] Transcriptional Start Site 49 5' UTR Conserved Domain 117-187
[0654] ORF2 283-588
[0655] ORF2 / 2 283 - 584 ; 1977
[0656] ORF2 / 3 283 -584; 2197
[0657] ORF1 432 - 2453
[0658] ORFl / 1 432-584 ; 1977
[0659] ORF1 / 2 432 -584; 2197
[0660] Three open-reading frame region 2186-2385 Poly(A) Signal 2676-2681 GC-rich region 3054-3172
[0661] Table 14. Exemplary Anellovirus amino acid sequences ( Gam matorque virus )
[0662] QGKNPWDSVITYSEQKLWFPTVAWQLKTINAICESGPYVPKLDNQTYSTWELATH YSFHFKWGGPQISDQPVEDPGNKNKYDVPDTIKEALQIVNPAKNIAATMFHDWDY RRGCITSTAIKRMQQNLPTDSSLESDSDSEPAPKKKRLLPVLHDPQKKTEKINQCLLS LCEESTCQEQETEENILKLIQQQQQQQQKLKHNLLVLIKDLKVKQRLLQLQTGVLE
[0663] (SEQ ID NO: 52)
[0664] ORFl / 1 MPFWWGRRNKFWYGRNYRRKKRRFPKRRKRRFYRRTKYRRPARRRRRRRRKISD
[0665] QPVEDPGNKNKYDVPDTIKEALQIVNPAKNIAATMFHDWDYRRGCITSTAIKRMQQ NLPTDSSLESDSDSEPAPKKKRLLPVLHDPQKKTEKINQCLLSLCEESTCQEQETEEN ILKLIQQQQQQQQKLKHNLLVLIKDLKVKQRLLQLQTGVLE (SEQ ID NO: 53)
[0666] ORF1 / 2 MPFWWGRRNKFWYGRNYRRKKRRFPKRRKRRFYRRTKYRRPARRRRRRRRKISD
[0667] QPVEDPGNKNKYDVPDTIKEALQIVNPAKNIAATMFHDWDYRRGCITSTAIKRMQQ NLPTDSSLESDSDSEPAPKKKRLLPVLHDPQKKTEKINQCLLSLCEESTCQEQETEEN ILKLIQQQQQQQQKLKHNLLVLIKDLKVKQRLLQLQTGVLE (SEQ ID NO: 54)
[0668] In some embodiments, a synthetic curon comprises a minimal Anellovirus genome, e.g., as identified according to the method described in Example 9. In some embodiments, a synthetic curon comprises an Anellovirus sequence, or a portion thereof, as described in Example 13.
[0669] In some embodiments, a synthetic curon comprises a genetic element comprising a consensus Anellovirus motif, e.g., as shown in Table 14-1. In some embodiments, a synthetic curon comprises a genetic element comprising a consensus Anellovirus ORF1 motif, e.g., as shown in Table 14-1. In some embodiments, a synthetic curon comprises a genetic element comprising a consensus Anellovirus ORFl / 1 motif, e.g., as shown in Table 14-1. In some embodiments, a synthetic curon comprises a genetic element comprising a consensus Anellovirus ORF1 / 2 motif, e.g., as shown in Table 14-1. In some embodiments, a synthetic curon comprises a genetic element comprising a consensus Anellovirus ORF2 / 2 motif, e.g., as shown in Table 14-1. In some embodiments, a synthetic curon comprises a genetic element comprising a consensus Anellovirus ORF2 / 3 motif, e.g., as shown in Table 14-1. In some embodiments, a synthetic curon comprises a genetic element comprising a consensus Anellovirus ORF2t / 3 motif, e.g., as shown in Table 14-1. In some embodiments, X, as shown in Table 14-1, indicates any amino acid. In some embodiments, Z, as shown in Table 14-1, indicates glutamic acid or glutamine. In some embodiments, B, as shown in Table 14-1, indicates aspartic acid or asparagine. In some embodiments, J, as shown in Table 14-1, indicates leucine or isoleucine. Table 14-1. Consensus motifs in open reading frames (ORFs) of Anelloviruses
[0670] 50 ORF2 / 3 281 DXPFYPWXP 81
[0671] 50 ORF2 / 3 300 VXFKLXF 82
[0672] 50 ORF2t / 3 4 WXPPVHBVXGIERXW 83
[0673] 50 ORF2t / 3 37 AKRKLX 84
[0674] 50 ORF2t / 3 140 PSSXDWXXEY 85
[0675] 50 ORF2t / 3 156 DRPPR 86
[0676] 50 ORF2t / 3 167 PFYPW 87
[0677] 50 ORF2t / 3 183 NVXFKLXF 88
[0678] 50 ORF1 84 JXXXXWQPXXXXXCXIXGXXXJWQP 89
[0679] 50 ORF1 149 NXWXXXNXXXXLXRY 90
[0680] 50 ORF1 448 YNPXXDXG 91
[0681] Genetic Element
[0682] In some embodiments, the curon comprises a genetic element. In some embodiments, the genetic element has one or more of the following characteristics: is substantially non-integrating with a host cell's genome, an episomal nucleic acid, a single stranded DNA, is circular, is about 1 to 10 kb, exists within the nucleus of the cell, can be bound by endogenous proteins, and produces a microRNA that targets host genes. In one embodiment, the genetic element is a substantially non-integrating DNA. In some embodiments, the genetic element has at least about 70%, 75%, 80%, 8%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an Anellovirus sequence, e.g., as described herein (e.g., as described in any of Tables 1-14), or a fragment thereof. In embodiments, the genetic element comprises a sequence encoding an exogenous effector (e.g., a payload), e.g., a polypeptide effector (e.g., a protein) or nucleic acid effector (e.g., a non-coding RNA, e.g., a miRNA, siRNA, mRNA, IncRNA, RNA, DNA, an antisense RNA, gRNA).
[0683] In some embodiments, the genetic element has a length less than 20kb (e.g., less than about 19kb, 18kb, 17kb, 16kb, 15kb, 14kb, 13kb, 12kb, l lkb, lOkb, 9kb, 8kb, 7kb, 6kb, 5kb, 4kb, 3kb, 2kb, lkb, or less). In some embodiments, the genetic element has, independently or in addition to, a length greater than 1000b (e.g., at least about l. lkb, 1.2kb, 1.3kb, 1.4kb, 1.5kb, 1.6kb, 1.7kb, 1.8kb, 1.9kb, 2kb, 2.1kb, 2.2kb, 2.3kb, 2.4kb, 2.5kb, 2.6kb, 2.7kb, 2.8kb, 2.9kb, 3kb, 3. lkb, 3.2kb, 3.3kb, 3.4kb, 3.5kb, 3.6kb, 3.7kb, 3.8kb, 3.9kb, 4kb, 4. lkb, 4.2kb, 4.3kb, 4.4kb, 4.5kb, 4.6kb, 4.7kb, 4.8kb, 4.9kb, 5kb, or greater). In some embodiments, the genetic element has a length of about 2.5-4.6, 2.8-4.0, 3.0-3.8, or 3.2-3.7 kb.
[0684] In some embodiments, the genetic element comprises one or more of the features described herein, e.g., a sequence encoding a substantially non-pathogenic protein, a protein binding sequence, one or more sequences encoding a regulatory nucleic acid, one or more regulatory sequences, one or more sequences encoding a replication protein, and other sequences.
[0685] In one embodiment, the invention includes a genetic element comprising a nucleic acid sequence (e.g., a DNA sequence) encoding (i) a substantially non-pathogenic exterior protein, (ii) an exterior protein binding sequence that binds the genetic element to the substantially non-pathogenic exterior protein, and (iii) a regulatory nucleic acid. In such an embodiment, the genetic element may comprise one or more sequences with at least about 60%, 70% 80%, 85%, 90% 95%, 96%, 97%, 98% and 99% nucleotide sequence identity to any one of the nucleotide sequences to a native viral sequence.
[0686] Proteins, e.g.. Substantially Non-Pathogenic Protein
[0687] In some embodiments, the genetic element comprises a sequence that encodes a protein, e.g., a substantially non-pathogenic protein. In embodiments, the substantially non-pathogenic protein is a major component of the proteinaceous exterior of the curon. Multiple substantially non -pathogenic protein molecules may self-assemble into an icosahedral formation that makes up the proteinaceous exterior. In embodiments, the protein is present in the proteinaceous exterior.
[0688] In some embodiments, the protein, e.g., substantially non-pathogenic protein and / or
[0689] proteinaceous exterior protein, comprises one or more glycosylated amino acids, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more.
[0690] In some embodiments, the protein, e.g., substantially non-pathogenic protein and / or
[0691] proteinaceous exterior protein comprises at least one hydrophilic DNA-binding region, an arginine-rich region, a threonine-rich region, a glutamine-rich region, a N-terminal polyarginine sequence, a variable region, a C-terminal polyglutamine / glutamate sequence, and one or more disulfide bridges.
[0692] In some embodiments, the genetic element comprises a nucleotide sequence encoding a capsid protein or a fragment of a capsid protein or a sequence having at least about 60%, 65%, 70%, 75%, 80%, 85%, 90% 95%, 96%, 97%, 98%, 99%, or 100% nucleotide sequence identity to any one of the nucleotide sequences encoding a capsid protein described herein, e.g., as listed in any of Tables 1-16 or 19. In some embodiments, the genetic element comprises a nucleotide sequence encoding a capsid protein or a functional fragment of a capsid protein or a nucleotide sequence having at least about 60%, 70% 80%, 85%, 90% 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to any one of the nucleotide sequences described herein, e.g., as listed in any of Tables 1-16 or 19. In some embodiments, the substantially non- pathogenic protein comprises a capsid protein or a functional fragment of a capsid protein that is encoded by a capsid nucleotide sequence or a sequence having at least about 60%, 65%, 70%, 75%, 80%, 85%, 90% 95%, 96%, 97%, 98%, 99%, or 100% nucleotide sequence identity to any one of the nucleotide sequences described herein, e.g., as listed in any of Tables 1, 3, 5, 7, 9, 11, 13, or 15. Table 15: Examples of viral sequences that encode viral proteins, e.g., capsid proteins.
[0693] ATGGGCAGCAGTATACGGGTACCCAGAATACTGTGCCAAGAGCAC
[0694] CGGAGACTCAAACATAGACATGAACGCCAGAGTAGTAATAAGGTG
[0695] CCCCTACACCGTCCCCCAGATGATAGACACCAGCGACGAACTAAG
[0696] GGGCTTCATAGTATACAGCTTTAACTTTGGCAGGGGCAAAATGCC
[0697] CGGAGGCAGCAGCGAGGTACCCATAAGAATGAGAGCCAAGTGGT
[0698] ACCCCTGCCTGTTTCACCAAAAAGAAGTTCTAGAAGCCTTGGGACA
[0699] GTCGGGCCCCTTCGCCTACCACTGCGACCAAAAAAAAGCAGTGCT
[0700] AGGTCTAAAATACAGATTTCACTGGATATGGGGCGGAAGCCCCGT
[0701] GTTTCCACAGGTTGTTAGAAACCCCTGCAAAGACACACACGGTTC
[0702] CTCGGGCCCTAGAAAGCCTCGCTCAATACAAATCATTGACCCGAA
[0703] GTACAACACACCAGAGCTCACAATCCACGCGTGGGATTTCAGACG
[0704] TGGCTTCTTTGGCTCAAAAGCTATTAAAAGAATGCAACAACAACCA
[0705] ACAGATGCTGAACTTCTTCCACCAGGCCGCAAGAGGAGCAGGCGA
[0706] GACACAGAAGCCCTCCAAAGCAGCCAAGAAAAGCAAAAAGAAAGC
[0707] TTAC I I I I CAAACACCTCCAGCTCCAGCGACGAATACCCCCATGGG
[0708] AAAGCTCGCAGGCCTCGCAGACAGAGGCAGAGAGCGAAAAAGAG
[0709] CAAGAGGGCAGTCTCTCCCAGCAGCTCCGAGAGCAGCTTTACCAG
[0710] CAAAAGCTCCTCGGCAAGCAGCTCAGGGAAATGTTCCTACAACTC
[0711] CACAAAATCCAACAAAATCAACACGTCAACCCTACCTTATTGCCAA
[0712] GGGATCAGGCTTTAATCTGCTGGTCTCAGATTCAGTAA
[0713] AAD45642.1 AF122917.1 ATGTTTGGAGACCCTAAACCATACAAACCCTCCAGCAACGACTGG 94
[0714] AAAGAGGAGTACGAGGCCGCTAAGTATTGGGACAGGCCCCCCAG ATCTAACCTTAGAGATAACCCCTTCTATCCCTGGGCCCCCCCAAGC AATCCCTACAAAGTAAACTTTAAACTAGGCTTCCAATAA
[0715] AAD45646.1 AF122919.1 ATGCACTTTTCTAGGATATCCAGAAAGAAAAGGCTACTGCTACTGC 95
[0716] AAACAGAGCCAGCTCCACAGAAGACTCTCAAAC I I I I AAAAGGTAT
[0717] GTGGAGTCCTCCCACTGACGATGAACGTGTCCGCGAGCGAAAATG
[0718] GTTCCTCGCCACTGTTTATTCTCACTCTGCTTTCTGTGGCTGCAAT
[0719] GATCCTGTCGGCCACCTCTGTCGCTTGGCTACTCTATCTAACCGTC
[0720] CGGAGAACCCGGGACCCTCCGGGGGACGTCGTGCTCCTTCGATC
[0721] GGGATCCTACCCGCTCTCCCGGCTGCTACCGAGCAGCCCGGTGA
[0722] TCGAGCACCATGGCCTATGGGTGGTGGAGGAGACGCCGCAGAAG
[0723] GTGGAAGAGATGGAGGAGAAGGCCCAGGTGGAGACGCCCATGGA
[0724] GGACCCGCAGACGCAGACCTGCTAGACGCCGTGGACGCCGCAGA
[0725] ACAGTAA
[0726] AAD45647.1 AF122919_2 ATGGCCTATGGGTGGTGGAGGAGACGCCGCAGAAGGTGGAAGAG 96
[0727] ATGGAGGAGAAGGCCCAGGTGGAGACGCCCATGGAGGACCCGCA
[0728] GACGCAGACCTGCTAGACGCCGTGGACGCCGCAGAACAGTAAGG
[0729] AGACGGAGGCGCGGGAGGTGGAGGAGGCGCTATAGGAGGTGGA
[0730] GGAGAAAGGGCAGACGCGGGAGAAAAAAGAAACTTATAATAAAAC
[0731] AATGGCAGCCAAACTATACCAGAGAGTGCAACATAGTAGGCTACA
[0732] TGCCAGTAATCATGTGTGGAGAGAACACTCTAATAAGAAACTATGC
[0733] CACACACGCAGACGACTGCTACTGGCCGGGACCCTTTGGGGGCG
[0734] GCATGGCCACCCAGAAATTCACACTCAGAATCCTGTACGATGACTA
[0735] CAAGAGGTTTATGAACTACTGGACCTCCTCAAACGAGGACCTAGA
[0736] CCTCTGTAGATACAGGGGAGTCACCCTGTACTTTTTCAGAAACCCA GATGTAGACTTTATCATCCTCATAAACACCACACCTCCGTTCGTAG
[0737] ATACAGAGATCACAGGACCCAGCATACATCCGGGCATGATGGCCC
[0738] TCAACAAAAGAGCCAGGTTCATCCCCAGCCTAAAAACTAGACCTG
[0739] GCAGAAGACACATAGTAAAGATTAAAGTGGGGGCCCCCAAACTGT
[0740] ACGAGGACAAGTGGTACCCCCAGTCAGAACTCTGTGACATGCCCC
[0741] TACTAACCGTCTACGCCACCGCAGCGGATATGCAATATCCGTTCG
[0742] GCTCACCACTAACTGACACTCCTGTTGTAACCTTCCAAGTGTTGCG
[0743] CAGCATGTACAACGACGCCCTTAGCATACTTCCCTCTAACTTTCAA
[0744] AGCCCAGACAGTCCAGGCCAAAAACTTTACGAACAAATATCTAAGT
[0745] ATTTACCATACTACAACACCACAGAAACAATGGCACAACTAAAGAG
[0746] ATATATAGAAAATACAGAAAAAAATACCACATCGCCAAACCCATGG
[0747] CAAACAAAATATGTAAACACTACTGCCTTCACCACTCCACAAACTG
[0748] TTACAACTCAACAGCCATACACCAGCTTCTCAGACAGCTGGTACAG
[0749] GGGCACAGTATACACAAACGAAATCACTAAGGTGCCACTTGCCGC
[0750] AGCAAAAGTGTATGAAACTCAAACAAAAAACCTGCTGTCTACAACA
[0751] TTTACAGGAGGGTCAGAGTACCTAGAATACCATGGAGGCCTGTAC
[0752] AGCTCCATATGGCTATCAGCAGGCCGATCCTACTTTGAAACAAAG
[0753] GGAGCATACACAGACATCTGCTACAACCCCTACACAGACAGAGGA
[0754] GAGGGCAACATGGTGTGGATAGACTGGCTATCAAAAACAGACTCC
[0755] AGATATGACAAAACCCGCAGCAAATGCCTTATAGAAAAGCTACCCC
[0756] TATGGGCAGCAGTATACGGGTACGCAGAATACTGTGCCAAGAGCA
[0757] CCGGAGACTCAAACATAGACATGAACGCCAGAGTAGTAATTAGGT
[0758] GCCCCTACACCACCCCCCAGATGATAGACACCAGCGACGAACTAA
[0759] GGGGCTTCATAGTATACAGCTTTAACTTTGGCAGGGGCAAAATGC
[0760] CCGGAGGCAGCAGCGAGGTACCCATTAGAATGAGAGCCAAGTGG
[0761] TACCCCTGCCTACTTCACCAAAAAGGAGTTCTAGAAGCCTTAGGAC
[0762] AGTCAGGCCCCTTCGCCTACCACCGCGACCAAAAAAAAGCAGTGC
[0763] TAGGTCTAAAATACAGATTTCACTGGATATGGGGCGGAAACCCCG
[0764] TGTTTCCACAGGTTGTTAGAAACCCCTGCAAAGACACACACGGTTC
[0765] CTCGGGCCCTAGAAAGCCTCGCTCAATACAAATCATTGACCCGAA
[0766] GTACAACACACCAGAGCTCACAATCCACGCGTGGGATTTCAGACG
[0767] TGGCTTCTTTGGCCCAAAAGCTATTAAGAGAATGCAACAACAACCA
[0768] ACAGATGCTGAACTTCTTCCACCAGGCCGCAAGAGGAGCAGGCGA
[0769] GACACCGAAGCCCTCCAAAGCAGCCAAGAAAAGCAGAAAGAAAGC
[0770] TTAC I I I I CAAACAGCTCCAGCTCCGGCGACGAGTACCCCCGTGG
[0771] GAAAGCTCGCAGGCCTCGCAGACAGAGGCAGAGAGCGAAAAAGA
[0772] GCAAGAGGACAGTCTCTCCCAGCAGCTCCGAGAGCAGCTTCACCA
[0773] GCAAAAGCTCCTCGGCAAGCAGCTCAGGGAAATGTTCCTACAACT
[0774] CCACAAAATCCAACAAAATCAACACGTCAACCCTACCCTATTGCCA
[0775] AAAGATCAGGCTTTAATATGCTGGTCTCAGATTCAGTAA
[0776] AAD45648.1 AF122919_3 ATGTTCGGAGACCCTAAACCATACAAACCCTCCAGCAACGACTGG 97
[0777] AAAGAGGAGTACGAGGCCGCTAAATATTGGGACAGGCCCCCCAG ATTTGACCTTAGAGATAAGCCCTTCTATCCCTGGGCCCCCCCAAG CAATCCCTACAAAGTAAACTTTAAACTAGGCTTTCAATAA
[0778] AAG 16247.1 AF298585_1 ATGGCTGAGTTTTCCACGCCCGTCCGCAGCGGTGAAGCCACGGA 98
[0779] GGGACCTCAGCGCGTCCCGAGGGCGGGTGCCGAAGGTGAGTTTA CACACCGCAGTCAAGGGGCAATTCGGGCTCGGGACTGGCCGGGC
[0780] TATGGGCAAGG CTCTTA A
[0781] AAG16248.1 AF298585_2 ATGTTTCTCGGTAAACTTTACAGAAAGAAAAGGAAAGTGCTTCTGC 99
[0782] AGACTGTGCCAGACCCACAGAAGGCTAGGCGGCTTCTGATTATGT
[0783] GGCAGCCCCCCGTGCACAAAGTACCCGGGATCGAGAGAAACTGG
[0784] TACGAGAGTTGCTTTCGATCCCATGCTGCTGTGTGTGGCTGTGGC
[0785] GACTTTGTTGGCCATCTTAATCATCTGGCAGCTACTCTGGGTCGCC
[0786] CTCCGCGTTCTCGGCACCCCGGGGGCCCCGGCACTCCGCAGATA
[0787] AGAAACCTGCCAGCGCTCCCGGCACCCCAGGGTGAGCCCGGTGA
[0788] CAGAGCGCCATGGCCTACGGATGGTGGGGCCGCCGGCGCCGCT
[0789] GGAGAAGATGGAGGACGCGGCGCAGACCGTGGAGAACCAGGAG
[0790] ACGTAGAAGACGACGCGCTCCTCGCCGCTTTCGACCTCGTCGAAG
[0791] AGTAA
[0792] AAG16249.1 AF298585_3 ATGGCCTACGGATGGTGGGGCCGCCGGCGCCGCTGGAGAAGATG 100
[0793] GAGGACGCGGCGCAGACCGTGGAGAACCAGGAGACGTAGAAGAC
[0794] GACGCGCTCCTCGCCGCTTTCGACCTCGTCGAAGAGTAAGGAGG
[0795] CGCAGGGGGCGGTGGCGCAGACGGTATAGAAAATGGAGGAGACG
[0796] CAGGGGCAGACGGACGCACAGAAAAAAGATAATCATAAAACAGTG
[0797] GCAGCCGAACTTTATAAGACGCTGCTACATAATAGGCTACCTGCCT
[0798] CTCATATTCTGTGGCGAGAACACCACCGCCAATAACTTTGCCACCC
[0799] ACTCGGACGACATGATAGCCAAAGGACCGTGGGGGGGGGGCATG
[0800] ACTACCACTAAGTTCACTTTGAGAATCCTGTACGACGAGTTTACCA
[0801] GGTTTATGAACTTCTGGACTGTCAGTAACGAAGACCTAGACCTGTG
[0802] TAGATACGTGAGCTGCAAACTGATATTCTTTAAGCACCCCACGGTA
[0803] GACTTTATAGTCAGGATAAACACAGAGCCTCCGTTCCTAGACACTA
[0804] ACCTGACCGCGGCACAGATTCACCCGGGCATCATGATGCTAAGCA
[0805] AAAAACACATACTCATACCCTCTCTAAAGACCAGGCCTAGCAGAAA
[0806] ACACAGGGTGGTCGTCAGGGTGGGCCCACCTAGACTGTTTCAAGA
[0807] CAAGTGGTACCCCCAGTCAGACCTGTGTGACACAGTTCTGCTTTC
[0808] CGTGTTTGCAACGGCCTGTGACTTGCAATATCCGTTCGGCTCACC
[0809] ACTAACTGACAACCCTTGCGTCAACTTCCAGATTCTGGGGCACCA
[0810] GTACAAAAACCACCTTAGTATTAGCTCCACAAACGATACCACTAAC
[0811] AAACAACACTATGACAACACTTTATTTAACAAAATAGTATTATATAA
[0812] CAC I I I I CAAACAATAGCTCAGCTCAAAGAAACAGGACAACTCACA
[0813] AACTTATGGAACGAAGTACAAAACACAACAGCACTGTCACCAAAAG
[0814] GCACAAATGCAACTATAAGCAAAGACACCTGGTACAAAGGAAACA
[0815] CATACAAAGACAAGATTAAAGAGTTAGCAGAAAAAACTCGAAGTAG
[0816] ATTTGCAGCTGCAACAAAAGCAGCCCTGCCAAACTACCCTACAATC
[0817] ATGTCCACAGACCTGTATGAGTACCACTCAGGCATATACTCCAGCA
[0818] TATTCCTAGCAGCAGGCAGGAGCTACTTTGAGACCCCGGGGGCCT
[0819] ACACAGACGTCATATACAACCC I I I I ACAGACAAAGGCACAGGAAA
[0820] CATGGTCTGGATAGACTACCTCACAAAACCAGACTCCATATACACA
[0821] AAGAACAAAAGCAAATGCGAGATATTTGACGTACCCCTGTGGGCC
[0822] ACCTTCACAGGATACTCAGAATTCTGTTCAAAAGTTACAGGAGACA
[0823] CCGCCATTCACCTAACTGCCAGAGTAGTAGTCAGATGCCCCTACA
[0824] CCGAGCCCATGCTAATAGACCACTCAGACCCCAACAGGGGCTTTG TACCATACTCCTTTAACTTTGGAGAGGGCAAGATGCCCGGAGGCT
[0825] CCTCAAAAGTACCCATAAGAATGAGAGCCAAGTGGTACGTGAACA
[0826] TGTTTCACCAGCAAGAATTCATGGAGGCCATAGTTGAGAGCGGAC
[0827] CGCTTGCTTACAAGGGCGACATAAAATCAGCGGTACTCACCATGA
[0828] AATACAGATTCCACTGGAAATGGGGCGGAAACCCTATATCCAAACA
[0829] GGTCGTCCGGAATCCCTGCTCCACCTCCAGCACCTCCGCGGGCC
[0830] ATCGAGGACCTCGCAGCATACAAGTCGTTGACCCGAAGCACGTTA
[0831] CCCCGGAAGTCACCTGGCACTCGTGGGACATCAAGCGAGGTCTCT
[0832] TTGGCAAAGCAGGTATTAAGAGAATGCAACAAGAATCAGATGCTCT
[0833] TTACATTCCTACAGGACCACTCAAGAGGCCACGGAGGGACACCAA
[0834] CGCCCAAGACCCAGAAGAGCAAAACGAAAGCTCAGGTTTCAGAGT
[0835] CCAGCAGCGACTCCCCTGGGTCCACTCCAGCCAAGAAACGCAAA
[0836] GCTCCCAAGAGGAGATGCAAGCGGAGGGGACGGTACAAGAACAA
[0837] CTCCTCCTCCAGCTCCGAGAGCAGCGAGTACTCCGGTTCCAGCTC
[0838] CAACAGCTCGCCAGCCAAGTCCTCAAAGTGCAAGCAGGGCAAGG
[0839] CCTACACCCCCTATTATCTTCCCAAGCGTAA
[0840] AAG16250.1 AF298585_4 ATGTTTGAGCCCCAGGGTCCCAAACCCATACAGGGCTACAACGAT 101
[0841] TGGTTAGAAGAGTACACCTGCTGTAAATTCTGGGACAGGCCTCCC AGAAAGCTACACACAGATACACCC I I I I ACCCCTGGGCACCAAAAC CCCCAGACCAAGTGAGAGTCTCCTTTAAACTTAACTTCCAATAA
[0842] AAL37158.1 AF315076_2 ATGTTTCTTGGCAGGGCCTGGAGAAAGAAAAGGCAAGTGCCACTG 102
[0843] CCGACACTGCCAGTGGTGCCGCTTCCACAACCTTCACCTATGAGC
[0844] AGCCAGTGGAGACCCCCGGTTCACAATGTCCAGGGGCTGGAGCG
[0845] CAATTGGTGGGAGTGCTTCTTCCGTTCTCATGCTTGTTTTTGTGGC
[0846] TGTGGTGATGCTATTACTCATATTAATCATCTGGCGACTCG I I I I G
[0847] GACGTCCTCCTACTACCTCAACTCCCCGAGGACCGCAGGCACCTC
[0848] CAGTGACTCCGTACCCGGCCCTGCCGGCCCCAGAGCCTAGCCCT
[0849] GAGCCATGGCGTGGCGCCGGTGGCGATGGCGGCCGTGGTGGAG
[0850] ACGCCGGAGGCGCCGCCGGTGGAGAAGGAGACGGAGGAGACCC
[0851] AGACGACGCCGCCCTTATCGACGCCGTCGACCTCGCAGAGTAA
[0852] AAL37157.1 AF315076_1 ATGGCGTGGCGCCGGTGGCGATGGCGGCCGTGGTGGAGACGCC 103
[0853] GGAGGCGCCGCCGGTGGAGAAGGAGACGGAGGAGACCCAGACG
[0854] ACGCCGCCCTTATCGACGCCGTCGACCTCGCAGAGTAAGGAGGC
[0855] GCAGGGGGCGGTGGAGGCGCGCGTACAGACGTTGGGGGCGACG
[0856] CAGACGCAGACGCAGGCACAAAAAGAAACTTGTACTGACTCAGTG
[0857] GCAACCAGCAGTAGTTAAGAGGTGCCTAATAGTGGGCTTTGACCC
[0858] CCTTATAATATGTGGCATTAACAGAACAATATTTAACTACACTACAC
[0859] ACTCTGAAGACTTTAC I I I I AACAACGACAGCTTTGGAGGGGGGCT
[0860] CTGTACCGCTCAGTACACACTAAGAATCC I I I I CCAAGAAAAGCTG
[0861] GCCCAGCACAACTTCTGGTCAGCTAGCAACGAAGACCTAGACCTT
[0862] GCCAGGTACCTAGGAGCCACAATAGTACTTTACAGACACCCTACA
[0863] GTAGACTTCTTAGTTAGAATTCGCACCAGTCCTCCCTTTGAGGACA
[0864] CAGACATGACAGCCATGACACTACATCCAGGCATGATGATGCTAG
[0865] CTAAAAAGACAATTAAAATTCCCAGTCTTAAAACAAGACCGTCCAG
[0866] AAAACACGTAGTAAGGATTAGAGTAGGGGCCCCTAAACTATTTGAA
[0867] GACAAGTGGTACCCCCAGAACGAGCTATGTGATGTAACTCTGCTA ACCATACAGGCAACCACAGCTGATTTCCAATATCCGTTCGGCTCAC
[0868] CACTAACGAACTCCCCCTGTTGCAACTTCCAGGTTCTTAACAGTAA
[0869] CTATGACAATGCACATTCCATACTTAACTTGTCAAACGAACCAACA
[0870] AACAAATGGCACACCTATAGAAATAACTGCTATAAATTTCTACTAGA
[0871] ACAGTACAGCTACTACAACACTAAACAAGTAGTAGCACAACTTAAA
[0872] TATAAATGGAACCCTAATCAAAACCCTACTATGCCAAATACAAGCA
[0873] ATGCATCACTTTCTAAAAAACCTGATGACCTTACTAAAACCAAAACA
[0874] ACAAACGAGTATCCACATTGGGACACCCTATATGGTGGTTTAGCAT
[0875] ATGGACACAGCACTGTAACACCTGGCACTACCTCATCACCAACAG
[0876] ACCTAAAAACACAAATGCTTACAGGCAACGAA I I I I ATACAACAGC
[0877] AGGCAAAAAGTTAATAGATACATTTCACCCAATTCCTTACTATGAAA
[0878] ACGGATCTTCTAAAGCCAACACCAACATATTTGACTACTACACAGG
[0879] CATGTACAGTAGTA I I I I CCTGTCTTCAGGCAGATCAAACCCAGAA
[0880] GTAAAGGGCAGCTACACAGACATCTCTTACAACCCTCTGACAGAC
[0881] AAGGGAGTAGGTAACATGATTTGGATAGACTGGCTCACTAAAGGA
[0882] GACACAGTATACGACCCCAAAAAAAGCAAGTGCCTACTCTCAGACT
[0883] TTCCATTGTGGTCACTTTGTTATGGATACCCAGACTACTGCAGAAA
[0884] ACAAACCGGAGACTCAGGTATTTACTATGACTACAGAGTACTTATA
[0885] AGATGTCCATACACATACCCTCAATTAATAAAACACAACGACAAAT
[0886] ACTTTGGCTTCGTAGTGTACAGCGAAAACTTTGGACTGGGGCGAC
[0887] TACCAGGAGGCAACCCTAACCCCCCAACTAGAATGAGACTGCACT
[0888] GGTACCCTAATATGTTCCACCAAACAGAAGTACTAGAGTGCATAGC
[0889] TCAAAGCGGACCGTTTGCTTATCATGGAGACGAGAGAAAAGCTGT
[0890] TCTGACTGCCAAATACAAGTTCAGATGGAAGTGGGGAGGCAATCC
[0891] TGTGTTTCAACAGGTTCTCCGAGACCCCTGCACCGGAGGTGCCGT
[0892] GGCGCCCCACACCAGTCGACACCCTCGTGCAATACAAGTCCATGA
[0893] CCCGAAGTATCAGGCCCCGGAGTACCTCTTCCACAAATGGGACTT
[0894] CAGAAGGGGACTGTTTAGCACTAAAGGTATTAAGAGAGTGTCAGA
[0895] ACAACCAGTACATGATGAGTA I I I I ACAGGGAGCAGCAAGAGACC
[0896] CAAGAAAGACACCAACCCAAGCCCCCAAGGAGAAGAGCAAAAAGA
[0897] AGGCTCGCGTTTCAGAGTCCCAGAGCTCAGACCCTGGCTCCCCTC
[0898] CAGCCAGGAAACGCAGAGCCAAAGCGAGCAAGAAGAAACAGCCC
[0899] CGAAAACGGTCCAAGAGCAGCTACAAGAACAACTCCAGCAGCAGC
[0900] AGCTCATGGGAATCCAGCTCAGAAACGTCTGTCTCCAGCTCGCAA
[0901] GAGTCCAAGCGGGGCACAGTCTCCACCCCG I I I I CCAATGCCATG
[0902] CATAA
[0903] AAL37159.1 AF315076_3 ATGACCCGAAGTATCAGGCCCCGGAGTACCTCTTCCACAAATGGG 104
[0904] ACTTCAGAAGGGGACTGTTTAGCACTAAAGGTATTAAGAGAGTGTC
[0905] AGAACAACCAGTACATGATGAGTA I I I I ACAGGGAGCAGCAAGAG
[0906] ACCCAAGAAAGACACCAACCCAAGCCCCCAAGGAGAAGAGCAAAA
[0907] AGAAGGCTCGCGTTTCAGAGTCCCAGAGCTCAGACCCTGGCTCCC
[0908] CTCCAGCCAGGAAACGCAGAGCCAAAGCGAGCAAGAAGAAACAG
[0909] CCCCGAAAACGGTCCAAGAGCAGCTACAAGAACAACTCCAGCAGC
[0910] AGCAGCTCATGGGAATCCAGCTCAGAAACGTCTGTCTCCAGCTCG
[0911] CAAGAGTCCAAGCGGGGCACAGTCTCCACCCCG I I I I CCAATGCC
[0912] ATGCATAAACAAAGTTTTTATTTTCCCTGA AAL37160.1 AF315077_1 ATGTTTCTCGGTAAACTTTACAGAAAGAAAAGGAAACTGCTACTGC 105
[0913] AAGCTGTGCGAGCTCCACAGGCGCCATCTTCCATGAGCTCCTCCT
[0914] GGCGAGTGCCCCGCGGCGATGTCTCCGCCCGCGAGCTATGTTGG
[0915] TACCGCTCAGTTCGAGAGAGCCACGATGCTTTTTGTGGCTGTCGT
[0916] GATCCTGTTTTTCATCTTTCTCGTCTGGCTGCACGTTCTAACCATCA
[0917] GGGACCTCCGACGCCCCCCACGGACGAGCGCCCGTCGGCGTCTA
[0918] CCCCAGTGAGGCGCCTGCTGCCGCTGCCCTCCTACCCCGGCGAG
[0919] GGTCCCCAGGCTAGATGGCCTGGTGGAGATGGAGAAGGCGCTGG
[0920] TGACGCCCGCGGAGGCGCTGGAGATGGCGGCGCCCGCGCAGGC
[0921] GAAGAAGAGTACCGGCCCGAAGACCTCGACGAGCTGTTCGGCGC
[0922] TACCGAACAAGAACAGTAA
[0923] AAL37161 .1 AF315077_2 ATGCCAGTTATCTGGGCGGGCATGGGCACGGGGGGCCAAAACTA 106
[0924] CGCCGTCCGCTCAGATGACTTTGTAGTAGACAAGGGCTTCGGGGG
[0925] CTCCTTCGCTACAGAGACTTTCTCCTTGAGAGTACTGTATGACCAG
[0926] CACCAGAGGGGCTTTAACCGGTGGTCCCACACCAACGAGGACCTA
[0927] GACCTTGCCCGTTACAGGGGATGCAAATGGACC I I I I ACAGACAC
[0928] CCAGACACTGACTTTATAGTGTACTTCACTAACAATCCCCCCATGA
[0929] AAACTAACCAGTACACTGCCCCTCTCACCACTCCTGGAATGCTCAT
[0930] GAGAAGCAAATATAAGATACTAATACCTAG I I I I AAAACAAAACCCA
[0931] AGGGAAAAAAGACAATAAGCTTCAGAGCCAGACCCCCAAAACTAT
[0932] TCCAAGACAAGTGGTACACTCAACAAGACCTCTGCCCTGTGCCCC
[0933] TCATCCAACTGAACTTAACCGCAGCTGATTTCACACATCCGTTCGG
[0934] CTTACCACTAACTGACTCTCCTTGCGTAAGGTTCCAAGTCCTCGGA
[0935] GACTTGTACAATAACTGTCTCAATATAGACCTTCCGCAATTTGATGA
[0936] CAAGGGTACAATTTCAGACGCATCCTCTTACAGTAGAGATAATAAG
[0937] CAGCAGTTAGAAGAATTATATAAAACTCTATTTGTTAAAAAGGGCTG
[0938] CGGACACTACTGGCAAACATTCATGACCAATAGCATGGTAAAAGCA
[0939] CACATAGATGCTGCACAGGCACAAAACCATCAACAAGACACCTCA
[0940] GGCCCTCAAAGTGCAAAAGATCCATTTCCAACAAAACCTGACAGAA
[0941] ACCAATTTGAACAATGGAAAAACAAATTCACAGACCCCAGAGACAG
[0942] CAACTTTCTCTTTGCCACTTATCACCCAGAAAACATTACACAGACTA
[0943] TCAAAACAATGAGAGACAATAACTTTGCTCTAGAAACTGGAAAGAA
[0944] TGACCTTTATGGTGATTATCAGGCCCAGTATACTAGAAACACTCAC
[0945] CTTCTAGACTACTACCTGGGCTTCTACAGCCCCATATTCTTGTCCA
[0946] GTGGCAGATCCAATACTGAATTCTTTACTGCCTACAGAGACATAAT
[0947] ATACAATCCACTACTAGACAAAGGCACAGGTAATATGATTTGGTTC
[0948] CAATACCACACAAAGACTGACAACATATTTAAAAAACCAGAGTGCC
[0949] ACTGGGAAATACTAGACATGCCCCTGTGGGCCCTCTGCAACGGCT
[0950] ACAAAGAGTACCTAGAGAGCCAAATAAAATATGGTGATATCTTAGT
[0951] AGAAGGCAAAGTCCTCATAAGATGCCCATACACCAAACCTCCCCTA
[0952] GCAGACCCCAACAACAGTCTAGCAGGATATGTAGTCTACAACACA
[0953] AACTTTGGACAAGGCAAGTGGATCGACGGCAAGGGCTACATACCC
[0954] CTAAGACACAGGAGCAAGTGGTATGTCATGCTCATGTACCAGACG
[0955] GACGTACTCCATGACCTAGTGACTTGTGGACCCTGGCAATACAGA
[0956] GACGATAATAAGAACTCTCAACTGATAGCCAAGTATAGATTTACTTT
[0957] CTACTGGGGAGGTAACATGGTACATTCTCAGGTCATCAGGAACCC GTGCAAAGACACCCAAGTATCCGGCCCCCGTCGACAGCCTAGAGA
[0958] GATACAAGTCGTTGACCCGCAACTCATCACCCCGCCGTGGGTCCT
[0959] CCACTCGTTCGACCAGAGACGAGGAATGTTTACTGAGACAGCTAT
[0960] CAGACGTCTGCTCAGACAACCACTACCTGGCGAGTATGCTCCTCC
[0961] AGCACTCAGGGTCCCGCTCCTCTTTCCCTCCTCAGAGTTCCAACG
[0962] AGAGGGAGAAGGTGCAGAAAGCGACTTATCTTCCCCGGCCAAAAG
[0963] ACCACGACTCTGGCAAGAAGAGGACAGCGAGACGCAGACGCAGT
[0964] CCTCGGAGGGGCCGGCGGAGACGACGAGGGAGCTCCTCGAGCG
[0965] AAAGCTCAGAGAGCAGCGAGTCCTCAACCTCCAACTCCAGCAATT
[0966] CGCCGTACAACTCGCCAAGACCCAAGCGAACCTCCACATAAACCC
[0967] CTTATTATACTCCCAGCAGTAA
[0968] AAL37162.1 AF315077_3 ATGCTCCTCCAGCACTCAGGGTCCCGCTCCTCTTTCCCTCCTCAG 107
[0969] AGTTCCAACGAGAGGGAGAAGGTGCAGAAAGCGACTTATCTTCCC
[0970] CGGCCAAAAGACCACGACTCTGGCAAGAAGAGGACAGCGAGACG
[0971] CAGACGCAGTCCTCGGAGGGGCCGGCGGAGACGACGAGGGAGC
[0972] TCCTCGAGCGAAAGCTCAGAGAGCAGCGAGTCCTCAACCTCCAAC
[0973] TCCAGCAATTCGCCGTACAACTCGCCAAGACCCAAGCGAACCTCC
[0974] ACATAA
[0975] CAF05717.1 AJ620212.1 ATGTACTTTTCCAGAAAAAGAAGACCCAAGAAGGAGAGGCCGCTG 108
[0976] CCACTGCGATACGTGTGTGGCCTACCGCCTAGCAGGCCTGATCCG
[0977] ATGAGCTGGCGTCCACCTGCCCACGATGTCCCAGGACAAGAGGG
[0978] CCTGTGGTACCGATCAGTTTTTACTTCTCATGGCGCTTTTTGTGGT
[0979] TGCGGTGA I I I I GTGGGTCATCTTCAGAGACTTAGCGAACGCCTG
[0980] GGTAGACCCCAACCACCAAGACCACCGGGCGAGCCGCCGGGCCC
[0981] TGCTGTGAGAGTTCTGCCTGCCCTGCCGCCTCCAGTACCTGAACC
[0982] AAGAAGACACGTCCAGAGAGAGAACCCGGGATGTGGTGGTGGAG
[0983] ACGCCGCAGATGGAGGGCCCCATGGAGAAGGAGGCGATGGAGAC
[0984] GACGCAGACCTCGGACCAGAAGATTTAGACGAGCTGCTCGACGTC
[0985] CTAGACGCCCCAGAGTAA
[0986] CAF05718.1 AJ620212.1 ATGTGGTGGTGGAGACGCCGCAGATGGAGGGCCCCATGGAGAAG 109
[0987] GAGGCGATGGAGACGACGCAGACCTCGGACCAGAAGATTTAGAC
[0988] GAGCTGCTCGACGTCCTAGACGCCCCAGAGTAAGGAGACCTCGG
[0989] CGCCGCAGGGGGTGGGCTCGTAGATATAGACTTAGAAGGAGGCG
[0990] AAGGAGGAGAAGAAGGAGAAAGCTTATACTAACACAATGGCAGCC
[0991] AGCAAAAATAAGAAAATGTCTAGTAATAGGTTATCTTGCTCTAGTAC
[0992] TATGTGGGAACGGGACATTCAGTAAAAACTATGCCTCCCACTCAGA
[0993] TGACTATGTACAGAAAGGACCCTTTGGAGGGGGACTGAGCAGCAT
[0994] GAGATTTAACATGAGAATACTATATGATCAATTTAAAAGACACCTTA
[0995] ACTTCTGGACACACACAAACCAGGACCTAGACCTAGTTAGATACAG
[0996] AGGCTGCACCATGACA I I I I ATAGACACCCAGAGGTGGACTTCATA
[0997] GTAAAATTCAACAGAAAACCTCCATTCCTAGACACAATAGTATCAG
[0998] GTCCAGCCATGCACCCAGGCATGCTAATGACAACAAAACACAAAA
[0999] TACTAGTAAAAAGCTTTAAAACAAAACCCAAAGGAAAAGGCACAGT
[1000] AAAGGTGCGCATTCGCCCCCCCACACTCTTTGACGACCGTTGGTA
[1001] CTTTCAACATGACATCTGCAAAACCACACTGTTCACCATTAGCGCA
[1002] ACACCATGTGACCTGCGGTTTCCGTTCTGCTCACCACAAACTGACA ACCCTTGCGTCAACTTCCTAGTTCTTGCAGGAGTGTATAACGGCAA
[1003] ACTTAGCATAGAACCCACAAACGTAGAATCACAATATAATTCACTA
[1004] CTTTCAGCTATAGAGACACACACCCAAGGCACTCTATTTAATACAT
[1005] TTAAAACACCAGAAATGATAAAGTGCCCCCCAGCAGTAAAAGCCC
[1006] CAGAAACTGGAGACATATCCACAAACTGCTACAAAAAACTAGACAT
[1007] CGCCTGGGGAGACACTATATGGAACCAAAGCACCATAGGCAACTT
[1008] TAAAAAGAACACAGAGAACTTGTGGAATGCAAGACACAATCAAACA
[1009] ATGACTGGTAGCAAATACCTAAACTACAGAACAGGAATATACAGTG
[1010] CCATATTCCTTTCAGCAGGCAGACTGTCACCAGACTTTCCAGGACT
[1011] ATACAATGACATAGTATACAATCCCACCACAGACGAAGGCATAGGA
[1012] AACATTGTGTGGATAGACTGGTGTACAAAAGCAGACTGCAACTTCA
[1013] ATGAGACACAGTCCAAAGGAGTAATAAAAGACATTCCACTGTGGG
[1014] CAGCACTGTTTGGCTATGTAGACTTTCTAAAAAAGACATTTAAAGA
[1015] CGACCAGCTAGACAAAACTGCCAGACTCACTCTCATAAGCCCCTAT
[1016] ACAAAGCCTCAACTAATAGGACCTACACAACCCAACAAAGGGTTTG
[1017] TTCCGTACGACTACAACTTTGGCAGAGCACACATGCCCTCCGGAG
[1018] AATCCTACATACCTATGTACTACAGATTTAGATGGTACATCTGCCTA
[1019] TTTCACCAACAAAAGTTTATAGACGACATTGTAAGCAGCGGGCCCT
[1020] TCGCATACCACGGCTCACAGCCCTCAGCAACTCTCACCACTAAATA
[1021] CAAATTCCACTTTCTCTTTGGGGGCAACCCCGTTCCCCAACAGACT
[1022] GTCAGAGACCCTTGTAACCAACCAGTCTTTGACATTCCCGGAGCC
[1023] GGTGGACTCCCTCGTCCGATACAAGTCGTTGACCCGAAATACGTC
[1024] AACGAAGGCTACACGTTCCACGCCTGGGACTTCCGTAGAGGGCTC
[1025] TTTGGCCAAGCAGCTATTAAAAGAGTGTCGGGAGAACAAACAAAT
[1026] GCTTCACTTTATTCATCAGGTCCAAAACGGCCAAGAACAGAAATTC
[1027] CTCCAGAAAATGCAGAAGAAGGCTCATATTCCAGGGAACAAAAAC
[1028] TCCAGCCCTGGCTCGACTCGAGCGACCAGGAAGAGAGCGAGACA
[1029] GAAGCCCCAGAAGAAGAAGCGACCTCGCCGCCGTCGCTACAGCT
[1030] CCAGCTCAAGCAGCAGATCAGGGAGCAGCGACAACTCAGATGTG
[1031] GAATCCAACACCTCTTCCAGCAACTAGTGAAAACCCAGCAAAACTT
[1032] GCATATCGACCCATGCCTACAATAG
[1033] CAF05719.1 AJ620213.1 ATGTACTTTTCCAGAAAAAGAAGACCCAAGAAGGAGAGGCCGCTG 1 10
[1034] CCACTGCGATACGTGTGTGGCCTACCGCCTAGCAGGCCTGATCCG
[1035] ATGAGCTGGCGTCCACCTGCCCACGATGTCCCAGGACAAGAGGG
[1036] CCTGTGGTACCGATCAGTTTTTACTTCTCATGGCGCTTTTTGTGGT
[1037] TGCGGTGA I I I I GTGGGTCATCTTCAGAGACTTAGCGAACGCCTG
[1038] GGTAGACCCCAACCACCAAGACCACCGGGCGGACCGCCGGGCCC
[1039] TGCTGTGAGAGCTCTGCCTGCCCTGCCGCCTCCGGAACCTGAACC
[1040] AAGAAGACACGTCCAGAGAGAGAACCCGGGATGTGGTGGTGGAG
[1041] ACGCCGCAGATGGAGGGCCCCATGGAGAAGGAGGCGATGGAGAC
[1042] GACGCAGACCTCGGACCAGAAGATTTAGACGAGCTGCTCGACGTC
[1043] CTAGACGCCCCAGAGTAA
[1044] CAF05720.1 AJ620213.1 ATGTGGTGGTGGAGACGCCGCAGATGGAGGGCCCCATGGAGAAG 1 11
[1045] GAGGCGATGGAGACGACGCAGACCTCGGACCAGAAGATTTAGAC GAGCTGCTCGACGTCCTAGACGCCCCAGAGTAAGGAGACCTCGG CGCCGCAGGGGGTGGGCTCGTAGATATAGACTTAGAAGGAGGCG GAGGAGGAGAAGAAGGAGAAAGCTTATACTAACACAATGGCAGTC
[1046] AGCAAAAATAAGAAAATGTCTAGTAATAGGTTATCTTGCTCTAGTAC
[1047] TATGTGGAAACGGGACATTCAGTAAAAACTATGCCTCGCACTCAGA
[1048] TGACTATGTACAGAAAGGACCCTTTGGAGGGGGACTAAGCAGCAT
[1049] GAGATTTAACATGAGAATACTATATGATCAATTTAAAAGACACCTTA
[1050] ACTTCTGGACACACACAAACCAGGACCTAGACCTAGTTAGATACAG
[1051] AGGCTGCACCATGACA I I I I ATAGACACCCAGAGGTGGACTTCATA
[1052] GTAAAATTCAACAGAAAACCTCCATTCCTAGACACAATAGTATCAG
[1053] GTCCAGCCATGCACCCAGGCATGCTAATGACAACAAAACACAAAA
[1054] TACTAGTAAAAAGCTTTAAAACAAAACCCAAAGGAAAAGGCACAGT
[1055] AAAGGTGCGCATTCGCCCCCCCACACTCTTTGACGACCGTTGGTA
[1056] CTTTCAACATGACATCTGCAAAACCACACTGTTCACCATTAGCGCA
[1057] ACACCATGTGACCTGCGGTTTCCGTTCTGCTCACCACAAACTGACA
[1058] ACCCTTGCGTCAACTTCCTAGTTCTTGCAGGAGTGTATAACGGCAA
[1059] ACTTAGCATAGAAGCCACAAAGTTAGAATCACAATATAATTCACTA
[1060] GTTTCATCTATAGAAATACCCACCCAAGGCACTCTATTTAATACATT
[1061] TAAAACACCAGAAATGATAAAGTGCCCCCCAGCAGTAAAAGCCTTA
[1062] GAACATTCAGACGTAAACAGAAGCTGCTACAAAAAACTAGACAGC
[1063] GCCTGGGGAGACACTATATGGAACCAGAACACCATACAGAACTTT
[1064] AAAGAAAACACAGACAAGTTGTGGGAAGCAAGAGGCAACCAAACA
[1065] ATGACTGGTAGCAAATACCTAAACTACAGAACAGGAATATACAGTG
[1066] CCATATTCCTTTCAGCAGGCAGACTGTCACCAGACTTTGGGGGAC
[1067] TATACAATGACATAGTATACAATCCCACCACAGACGAAGGCATAGG
[1068] AAACATTGTGTGGATAGACTGGTGTACAAAAGCAGACTGCAACTTC
[1069] AATGAGACACAGTCCAAAGGAGTAATAAAAGACATTCCACTGTGG
[1070] GCAGCACTGTTTGGCTATGTAGACTTTCTAAAAAAGACATTTAAAG
[1071] ACGAACAGCTAGACAAAATTGCCAGACTCACTCTCATAAGCCCCTA
[1072] TACAAAGCCTCAACTAATAGGACCTACACAACCCAACAAAGGGTTT
[1073] GTTCCGTACGACTACAACTTTGGCAGAGCACACATGCCCTCCGGA
[1074] GAATCCTACATACCTATGTACTACAGATTTAGATGGTACATCTGCC
[1075] TATTTCACCAACAAAAGTTTATAGACGACATTGTAAGCAGCGGGCC
[1076] CTTCGCATACCACGGCTCACAGCCCTCAGCAACTCTCACCACTAA
[1077] ATACAAATTCCACTTTCTCTTTGGGGGCAACCCCGTTCCCCAACAG
[1078] ACTGTCAGAGACTCTTGTAACCAACCAGTCTTTGACATTCCCGGAG
[1079] CCGGTGGACTCCCTCGTCCGATACAAGTCGTTGACCCGAAATACG
[1080] TCAACGAAGGCTACACGTTCCACGCCTGGGACTTCCGTAGAGGGC
[1081] TCTTTGGCCAAGCAGCTATTAAAAGAGTGTCGGGAGAACAAACAAA
[1082] TGCTTCACTTTATTCATCAGGTCCAAAACGGCCAAGAACAGAAATT
[1083] CCTCCACAAAATGCAGAAGAAGGCTCATATTCCAGGGAACAAAAA
[1084] CTCCAGCCCTGGCTCGACTCGAGCGACCAGGAAGAGAGCGAGAC
[1085] AGAAGCCCCAGAAGAAGAAGCGACCTCGCCACCGTCGCTACAGC
[1086] TCCAGCTCAAGCAGCAGATCAGGGAGCAGCGACAACTCAGATGTG
[1087] GAATCCAACACCTCTTCCAGCAACTAGTGAAAACCCAGCAAAACTT
[1088] GCATATCAATCCATGCCTACAGTAG
[1089] CAF05775.1 AJ620214.1 ATGTACTTTTCCAGAAAAAGAAGACCCAAGAAGGAGAGGCCGCTG 1 12
[1090] CCACTGCGATACGTGTGTGGCCTACCGCCTAGCAGGCCTGATCCG ATGAGCTGGCGTCCACCTGCCCACGATGTCCCAGGACAAGAGGG
[1091] CCTGTGGTACCGATCAGTTTTTACTTCTCATGGCGCTTTTTGTGGT
[1092] TGCGGTGA I I I I GTGGGTCATCTTCAGAGACTTAGCGAACGCCTG
[1093] GGTAGACCCCAACCACCAAGACCACCGGGCGGACCGCCGGGCCC
[1094] TGCTGTGAGAGCTCTGCCTGCCCTGCCGCCTCCGGAGCCTGAAC
[1095] CAAGAAGACACGTCCAGAGAGAGAACCCGGGATGTGGTGGTGGA
[1096] GACGCCGCAGATGGAGGGCCCCATGGAGAAGGAGGCGATGGAG
[1097] ACGACGCAGACCTCGGACCAGAAGATTTAGACGAGCTGCTCGACG
[1098] TCCTAGACGCCCCAGAGTAA
[1099] CAF05776.1 AJ620214.1 ATGTGGTGGTGGAGACGCCGCAGATGGAGGGCCCCATGGAGAAG 1 13
[1100] GAGGCGATGGAGACGACGCAGACCTCGGACCAGAAGATTTAGAC
[1101] GAGCTGCTCGACGTCCTAGACGCCCCAGAGTAAGGAGACCTCGG
[1102] CGCCGCAGGGGGTGGGCTCGTAGATATAGACTTAGAAGGAGGCG
[1103] GAGGAGGAGAAGAAGGAGAAAGCTTATACTAACACAATGGCAGCC
[1104] AGCAAAAATAAGAAAATGTCTAGTAATAGGTTATCTTGCTCTAGTAC
[1105] TATGTGGAAACGGGACATTCAGTAAAAACTATGCCTCGCACTCAGA
[1106] TGACTATGTACAGAAAGGACCCTTTGGAGGGGGACTAAGCAGCAT
[1107] GAGATTTAACATGAGAATACTATATGATCAATTTAAAAGACACCTTA
[1108] ACTTCTGGACACACACAAACCAGGACCTAGACCTAGTTAGATACAG
[1109] AGGCTGCACCATGACA I I I I ATAGACACCCAGAGGTGGACTTCATA
[1110] GTAAAATTCAACAGAAAACCTCCATTCCTAGACACAATAGTATCAG
[1111] GTCCAGCCATGCACCCAGGCATGCTAATGACAACAAAACACAAAA
[1112] TACTAGTAAAAAGCTTTAAAACAAAACCCAAAGGAAAAGGCACAGT
[1113] AAAGGTACGCATTCGCCCCCCCCACACTCTTTGA
[1114] CAF05777.1 AJ620214.1 ATGATAAAGTGCCCCCCAGCAGTAAAAGCCTTAGAACATTCAGAC 1 14
[1115] GTAAACAGAAACTGCTACAAAAAACTAGACAGCGCCTGGGGAGAC
[1116] ACTATATGGAACCAGAACACCATACAGAACTTTAAAGAAAACACAG
[1117] ACAAGTTGTGGGAAGCAAGAGGCAACCAAACAATGACTGGTAGCA
[1118] AATACCTAAACTACAGAACAGGAATATACAGTGCCATATTCCTTTCA
[1119] GCAGGCAGACTGTCACCAGACTTTGGGGGACTATACAATGACATA
[1120] GTATACAATCCCACCACAGGCGAAGGCATAGAAAACATTGTGTGG
[1121] ATAGACTGGTGTACAAAAGCAGACTGCAACTTCAATGAGACACAGT
[1122] CCAAAGGAGTAATAAAAGACATTCCACTGTGGGCAGCACTGTTTG
[1123] GCTATGTAGACTTTCTAAAAAAGACATTTAAAGACGAACAGCTAGA
[1124] CAAAATTGCCAGACTCACTCTCATAAGCCCCTATACAAAGCCTCAA
[1125] CTAATAGGACCTACACAACCCAACAAAGGGTTTGTTCCGTACGACT
[1126] ACAACTTTGGCAGAGCACACATGCCCTCCGGAGAATCCTACATAC
[1127] CTATGTACTACAGATTTAGATGGTACACCTGCCTATTTCACCAACA
[1128] AAAGTCTATAGACGACATTGTAAGCAGCGGGCCCTTCGCATACCA
[1129] CGGCTCACAGCCCTCAGCAACTCTCACCACTAAATACAAATTCCAC
[1130] TTTCTCTTTGGGGGCAACCCCGTTCCCCAACAGACTGTCAGAGAC
[1131] CCTTGTAACCAACCAATCTTTGACATTCCCGGAGCCGGTGGACTC
[1132] CCTCGTCCGATACAAGTCGTTGACCCGAAATACGTCAACGAAGGC
[1133] TACACGTTCCACGCCTGGGACTTCCGTAGAGGGCTCTTTGGCCAA
[1134] GCAGCTATTAAAAGAGTGTCGGGAGAACAAACAAATGCTTCACTTT
[1135] ATTCATCAGGTCCAAAACGGCCAAGAACAGAAATTCCTCCACAAAA TGCAGAAGAAGGCTCATATTCCAGGGAACAAAAACTCCAGCCCTG
[1136] GCTCGACTCGAGCGACCAGGAAGAAAGCGAGACAGAAGCCCCAG
[1137] AAGAAGAAGCGACCTCGCCACCGTCGCTACAGCTCCAGCTCAAGC
[1138] AGCAGATCAGGGAGCAGCGACAACTCAGATGTGGAATCCAACACC
[1139] TCTTCCAGCAACTAGTGAAAACCCAGCAAAACTTGCATATCAACCC
[1140] ATGCCTACAATAG
[1141] CAF05721.1 AJ620215.1 ATGTACTTTTCCAGAAAAAGAAGACCCAAGAAGGAGAGGCCGCTG 1 15
[1142] CCACTGCGATACGTGTGTGGCCTACCGCCTAGCAGGCCTGATCCG
[1143] ATGAGCTGGCGTCCACCTGCCCACGATGTCCCAGGACAAGAGGG
[1144] CCTGTGGTACCGATCAGTTTTTACTTCTCATGGCGCTTTTTGTGGT
[1145] TGCGGTGA I I I I GTGGGTCATCTTCAGAGACTTAGCGAACGCCTG
[1146] GGTAGACCCCAACCACCAAGACCACCGGGCGGACCGCCGGGCCC
[1147] TGCTGTGAGAGCTCTGCCTGCCCTGCCGCCTCCGGAGCCTGAAC
[1148] CAAGAAGACACGTCCAGAGAGAGAACCCGGGATGTGGTGGTGGA
[1149] GACGCCGCAGATGGAGGGCCCCATGGAGAAGAAGGCGATGGAGA
[1150] CGACGCAGACCTCGGGCCAGAAGATTTAGACGAGCTGCTCGACG
[1151] TCCTAGACGCCCCAGAGTAA
[1152] CAF05722.1 AJ620215.1 ATGTGGTGGTGGAGACGCCGCAGATGGAGGGCCCCATGGAGAAG 1 16
[1153] AAGGCGATGGAGACGACGCAGACCTCGGGCCAGAAGATTTAGAC
[1154] GAGCTGCTCGACGTCCTAGACGCCCCAGAGTAAGGAGACCTCGG
[1155] CGCCGCAGGGGGTGGGCTCGTAGATATAGACTTAGAAGGAGGCG
[1156] GAGGAGGAGAAGAAGGAGAAAGCTTATACTAACACAATGGCAGCC
[1157] AGCAAAAATAAGAAAATGTCTAGTAATAGGTTATCTCGCTCTAGTA
[1158] CTATGTGGAAACGGGACATTCAGTAAAAACTATGCCACGCACTCA
[1159] GATGACTATGTACAGAAAGGACCCTTTGGAGGGGGACTAAGCAGC
[1160] ATGAGATTTAACATGAGAATACTATATGATCAATTTAAAAGACACCT
[1161] TAACTTCTGGACACACACAAACCAGGACCTAGACCTAGTTAGATAC
[1162] AGAGGCTGCACCATGACA I I I I ATAGACACCCAGAGGTGGACTTC
[1163] ATAGTAAAATTCAACAGAAAACCTCCATTCCTAGACACAATAGTATC
[1164] AGGTCCAGCCATCCACCCAGGCATGCTAATGACAACAAAACACAA
[1165] AATACTAGTAAAAAGCTTTAAAACAAAACCCAAAGGAAAAGGCACA
[1166] GTAAAGGTGCGCATTCGCCCCCCCACACTCTTTGACGACCGTTGG
[1167] TACTTTCAACATGACATCTGCAAAACCACACTGTTCACCATTAGCG
[1168] CAACACCATGTGACCTGCGGTTTCCGTTCTGCTCACCACAAACTGA
[1169] CAACCCTTGCGTCAACTTCCTAGTTCTTGCAGGAGTGTATAACGGC
[1170] AAACTTAGCATAGAAGCCACAAAGTTAGAATCACAATATAATTCACT
[1171] AGTTTCATCTATAGAAATACCCACCCAAGGCACTCTATTTAATACAT
[1172] TTAAAACACCAGAAATGATAAAGTGCCCCCCAGCAGTAAAAGCCTT
[1173] AGAACATTCAGACGTAAACAGAAACTGCTACAAAAAACTAGACAGC
[1174] GCCTGGGGAGACACTATATGGAACCAGAACACCATACAGAACTTT
[1175] AAAGAAAACACAGACAAGTTGTGGGAAGCAAGAGGCAACCAAACA
[1176] ATGACTGGTAGCAAATACCTAAACTACAGAACAGGAATATACAGTG
[1177] CCATATTCCTTTCAGCAGGCAGACTGTCACCAGACTTTGGGGGAC
[1178] TATACAATGACATAGTATACAATCCCACCACAGACGAAGGCATAGG
[1179] AAACATTGTGTGGATAGACTGGTGTACAAAAGCAGACTGCAACTTC
[1180] AATGAGACACAGTCCAAAGGAGTAATAAAAGACATTCCACTGTGG GCAGCACTGTTTGGCTATGTAGACTTTCTAAAAAAGACATTTAAAG
[1181] ACGAACAGCTAGACAAAATTGCCAGACTCACTCTCATAAGCCCCTA
[1182] TACAAAGCCTCAACTAATAGGACCTACACAACCCAACAAAGGGTTT
[1183] GTTCCGTACGACTACAACTTTGGCAGAGCACACATGCCCTCCGGA
[1184] GAATCCTACATACCTATGTACTACAGATTTAGATGGTACATCTGCC
[1185] TATTTCACCAACAAAAGTTTATAGACGACATTGTAAGCAGCGGGCC
[1186] CTTCGCATACCACGGCTCACAGCCCTCAGCAACTCTCACCACTAA
[1187] ATACAAATTCCACTTTCTCTTTGGGGGCAACCCCGTTCCCCAACAG
[1188] ACTGTCAGAGACCCTTGTAACCAACCAGTCTTTGACATTCCCGGAG
[1189] CCGGTGGACTCCCCCGTCCGATACAAGTCGTTGACCCGAAATACG
[1190] TCAACGAAGGCTACACGTTCCACGCCTGGGACTTCCGTAGAGGGC
[1191] TCTTTGGCCAAGCAGCTATTAAAAGAGTGTCGGGAGAACAAACAAA
[1192] TGCTTCACTTTATTCATCAGGTCCAAAACGGCCAAGAACAGAAATT
[1193] CCTCCACAAAATGCAGAAGAAGGCTCATATTCCAGGGAACAAAAA
[1194] CTCCAGCCCTGGCTCGACTCGAGCGACCAGGAAGAGAGCGAGAC
[1195] AGAAGCCCCAGAAGAAGAAGCGACCTCGCCACCGTCGCTACAGC
[1196] TCCAGCTCAAGCAGCAGATCAGGGAGCAGCGACAACTCAGATGTG
[1197] GAATCCAACACCTCTTCCAGCAACTAGTGAAAACCCAGCAAAACTT
[1198] GCATATCAATCCATGCCTACAGTAG
[1199] CAF05723.1 AJ620216.1 ATGTACTTTTCCAGAAAAAGAAGACCCAAGAAGGAGAGGCCGCTG 1 17
[1200] CCACTGCGATACGTGTGTGGCCTACCGCCTAGCAGGCCTGATCCG
[1201] ATGAGCTGGCGTCCACCTGCCCACGATGTCCCAGGACAAGAGGG
[1202] CCTGTGGTACCGATCAGTTTTTACTTCTCATGGCGCTTTTTGTGGT
[1203] TGCGGTGA I I I I GTGGGTCATCTTCAGAGACTTAGCGAACGCCTG
[1204] GGTAGACCCCAACCACCAAGACCACCGGGCGAACCGCCGGGCCC
[1205] TGCTGTGAGAGTTCTGCCTGCCCTGCCGCCTCCGGTACCTGAACC
[1206] AAGAAGACACGTCCAGAGAGAGAACCCGGGATGTGGTGGTGGAG
[1207] ACGCCGCAGATGGAGGGCCCCATGGAGAAGGAGGCGATGGAGAC
[1208] GACGCAGACCTCGGACCAGAAGATTTAGACGAGCTGCTCGACGTC
[1209] CTAGACGCCCCAGAGTAA
[1210] CAF05724.1 AJ620216.1 ATGTGGTGGTGGAGACGCCGCAGATGGAGGGCCCCATGGAGAAG 1 18
[1211] GAGGCGATGGAGACGACGCAGACCTCGGACCAGAAGATTTAGAC
[1212] GAGCTGCTCGACGTCCTAGACGCCCCAGAGTAAGGAGACCTCGG
[1213] CGCCGCAGGGGGTGGGCTCGTAGATATAGACTTAGAAGGAGGCG
[1214] AAGGAGGAGAAGAAGGAGAAAGCTTATACTAACACAATGGCAGCC
[1215] AGCAAAAATAAGAAAATGTCTAGTAATAGGTTATCTTGCTCTAGTAC
[1216] TATGTGGGAACGGGACATTCAGTAAAAACTATGCCTCCCACTCAGA
[1217] TGACTATGTACAGAAAGGACCCTTTGGAGGGGGACTAAGCAGCAT
[1218] GAGATTTAACATGAGAATACTATATGATCAATTTAAAAGACACCTTA
[1219] ACTTCTGGACACACACGAACCAGGACCTAGACCTAGTTAGATACA
[1220] GAGGCTGCACCATGACA I I I I ATAGACACCCAGAGGTGGACTTCA
[1221] TAGTAAAATTCAACAGAAAACCTCCATTCCTAGACACAATAGTATCA
[1222] GGTCCAGCCATGCACCCAGGCATGCTAATGACAACAAAACACAAA
[1223] ATACTAGTAAAAAGCTTTAAAACAAAACCCAAAGGAAAAGGCACAG
[1224] TAAAGGTGCGCATTCGCCCCCCCACACTCTTTGACGACCGTTGGT
[1225] ACTTTCAACATGACATCTGCAAAACCACACTGTTCACCATTAGCGC AACACCATGTGACCTGCGGTTTCCGTTCTGCTCACCACAAACTGAC
[1226] AACCCTTGCGTCAACTTCCTAGTTCTTGCAGGAGTGTATAACGGCA
[1227] AACTTAGCATAGAACCCACAAACGTAGAATCACAATATAATTCACTA
[1228] CTTTCAGCTATAGAGACGAACACCCAAGGCACTCTATTTAATACAT
[1229] TTAAAACACCAGAAATGATAAAGTGCCCCGCAGCAGGAAAAGCCC
[1230] CAGAAACTGGAGACATATCCACAAACTGCTACAAAAAACTAGACAG
[1231] CGCCTGGGGAGACACTATATGGAACCAAAACACCATAGCCAACTT
[1232] TAAAAAGAACACAGACAACTTGTGGAATGCAGGACACAATCAAACA
[1233] ATGACTGGTAGCAAATACCTAAACTACAGAACAGGAATATACAGTG
[1234] CCATATTCCTTTCAGCAGGCAGACTGTCACCAGACTTTCCAGGACT
[1235] ATACGATGACATAGTATACAATCCCACCACAGACGAAGGCATAGG
[1236] AAACATTGTGTGGATAGACTGGTGTACAAAAGCAGACTGCAACTTC
[1237] AATGAGACACAGTCCAAAGGAGTAATAAAAGACATTCCACTGTGG
[1238] GCAGCACTGTTTGGCTATGTAGACTTTCTAAAAAAGACATTTAAAG
[1239] ACGACCAGCTAGACAAAACTGCCAGACTCACTCTCATAAGCCCCT
[1240] ATACAAAGCCTCAACTAATAGGACCTACACAACCCAACAAAGGGTT
[1241] TGTTCCGTACGACTACAACTTTGGCAGAGCACACATGCCCTCCGG
[1242] AGAATCCTACATACCTATGTACTACAGATTTAGATGGTACATCTGC
[1243] CTATTTCACCAACAAAAGTTTATAGACAACATTGTAAGCAGCGGGC
[1244] CCTTCGCATACCACGGCTCACAGCCCTCAGCAACTCTCACCACTA
[1245] AATACAAATTCCACTTTCTCTTTGGGGGCAACCCCGTTCCCCAACA
[1246] GACTGTCAGAGACCCTTGTAACCAACCAGTCTTTGACATTCCCGGA
[1247] GCCGGTGGACTCCCTCGTCCGATACAAGTCGTTGACCCGAAATAC
[1248] GTCAACGAAGGCTACACGTTCCACGCCTGGGACTTCCGTAGAGGG
[1249] CTCTTTGGCCAAGCAGCTATTAAAAGAGTGTCGGGAGAACAAACA
[1250] AATGCTTCACTTTATTCATCAGGCCCAAAACGGCCAAGAACAGAAA
[1251] TTCCTCCAGAAAATGCAGAAGAAGGCTCATATTCCAGGGAACAAAA
[1252] ACTCCAGCCCTGGCTCGACTCGAGCGACCAGGAAGGGAGCGAGA
[1253] CAGAAGCCCCAGAAGAAGAAGCGACCTCGCCGCCGTCGCTACAG
[1254] CTCCAGCTCAAGCAGCAGATCAGGGAGCAGCGACAACTCAGATGT
[1255] GGAATCCAACACCTCTTCCAGCAACTAGTGAAAACCCAGCAAAACT
[1256] TGCATATCAACCCATGCCTACAATAG
[1257] CAF05725.1 AJ620217.1 ATGTACTTTTCCAGAAAAAGAAGACCCAAGAAGGAGAGGCCGCTG 1 19
[1258] CCACTGCGATACGTGTGTGGCCTACCGCCTAGCAGGCCTGATCCG
[1259] ATGAGCTGGCGTCCACCTGCCCACGATGTCCCAGGACAAGAGGG
[1260] CCTGTGGTACCGATCAGTTTTTACTTCTCATGGCGCTTTTTGTGGT
[1261] TGCGGTGA I I I I GTGGGTCATCTTCAGAGACTTAGCGAACGCCTG
[1262] GGTAGACCCCAACCACCAAGACCACCGGGCGGACCGCCGGGCCC
[1263] TGCTGTGAGAGCTCTGCCTGCCCTGCCGCCTCCGGAGCCTGAAC
[1264] CAAGAAGACACGTCCAGAGAGAGAACCCGGGATGTGGTGGTGGA
[1265] GACGCCGCAGATGGAGGGCCCCATGGAGAAGGAGGCGATGGAG
[1266] ACGACGCAGACCTCGGACCAGAAGATTTAGACGAGCTGCTCGACG
[1267] TCCTAGACGCCCCAGAGTAA
[1268] CAF05726.1 AJ620217.1 ATGTGGTGGTGGAGACGCCGCAGATGGAGGGCCCCATGGAGAAG 120
[1269] GAGGCGATGGAGACGACGCAGACCTCGGACCAGAAGATTTAGAC
[1270] GAGCTGCTCGACGTCCTAGACGCCCCAGAGTAAGGAGACCTCGG CGCCGCAGGGGGTGGGCTCGTAGATATAGACTTAGAAGGAGGCG
[1271] GAGGAGGAGAAGAAGGAGAAAGCTTATACTAACACAATGGCAGCC
[1272] AGCAAAAATAAGAAAATGTCTAGTAATAGGTTATCTTGCTCTAGTAC
[1273] TATGTGGAAACGGGACATTCAGTAAAAACTATGCCTCGCACTCAGA
[1274] TGACTATGTACAGAAAGGACCCTTTGGAGGGGGACTAAGCAGCAT
[1275] GAGATTTAACATGAGAGTACTATATGATCAATTTAAAAGACACCTTA
[1276] ACTTCTGGACACACACAAACCAGGACCTAGACCTAGTTAGATACAG
[1277] AGGCTGCACCATGACA I I I I ATAGACACCCAGAGGTGGACTTCATA
[1278] GTAAAATTCAACAGAAAACCTCCATTCCTAGACACAATAGTATCAG
[1279] GTCCAGCCATGCACCCAGGCATGCTAATGACAACAAAACACAAAA
[1280] TACTAGTAAAAAGCTTTAAAACAAAACCCAAAGGAAAAGGCACAGT
[1281] AAAGGTGCGCATTCGCCCCCCCACACTCTTTGACGGCCGTTGGTA
[1282] CTTTCAACATGACATCTACAAAACCACACTGTTCACCATTAGCGCA
[1283] ACACCGTGTGACCTGCGGTTTCCGTTCTGCTCACCACAAACTGAC
[1284] AACCCTTGCGTCAACCTCCTAGTTCTTGCAGGAGTGTATAACGGCA
[1285] AACTTAGCATAGAAGCCACAAAGTTAGAATCACAATATAATTCACTA
[1286] GTTTCATCTATAGAAATACCCACCCAAGGCACTCTATTTAATACATT
[1287] TAAAACACCAGAAATGATAAAGTGCCCCCCAGCAGTAAAAGCCTC
[1288] AGAACATTCAGACGTAAACAGAAACTGCTACAAAAAACTAGACAGC
[1289] GCCTGGGGAGACACTATATGGAACCCGAGCACCATACAGAACTTT
[1290] AAAGAAAACACAGAGAAGTTGTGGGAAGCAAGAGGCAACCAAACA
[1291] ATGACTGGTAGCAAATACCTAAACTACAGAACAGGAATATACAGTG
[1292] CCATATTCCTTTCAGCAGGCAGACTGTCACCAGACTTTGGGGGAC
[1293] TATACAATGACATAGTATACAATCCCACCACAGACGAAGGCATAGG
[1294] AAACATTGTGTGGATAGACTGGTGTACAAAAGCAGACTGCAACTTC
[1295] AATGAGACACAGTCCAAAGGGGTAATAAAAGACATTCCACCGTGG
[1296] GCAGCACTGTTTGGCTATGTAGACTTTCTAAAAAAGACATTTAAAG
[1297] ACGAACAGCTAGACAAAATTGCCAGACTCACTCTCATAAGCCCCTA
[1298] TACAAAGCCTCAACTAATAGGACCTACACAACCCAACAAAGGGTTT
[1299] GTTCCGTACGACTACAACTTTGGCAGAGCACACATGCCCTCCGGA
[1300] GAATCCTACATACCTATGTACTACAGATTTAGATGGTACATCTGCC
[1301] TATTTCACCAACAAAAGTTTATAGACGACATTGTAAGCAGCGGGCC
[1302] CTTCGCATACCACGGCTCACAGCCCTCAGCAACTCTCACCACTAA
[1303] ATACAAATTCCACTTTCTCTTTGGGGGCAACCCCGTTCCCCAACAG
[1304] ACTGTCAGAGACCCTTGTAACCAACCAGTCTTTGACATTCCCGGAG
[1305] CCGGTGGACTCCCTCGTCCGATACAAGTCGTTGACCCGAAATACG
[1306] TCAACGAAGGCTACACGTTCCACGCCTGGGACTTCCGTAGAGGGC
[1307] TCTTTGGCCAAGCAGCTATTAAAAGAGTGTCGGGAGAACAAACAAA
[1308] TGCTTCACTTTATTCATCAGGTCCAAAACGGCCAAGAACAGAAATT
[1309] CCTCCACAAAATGCAGAAGAAGGCTCATATTCCAGGGAACAAAAA
[1310] CTCCAGCCCTGGCTCGACTCGAGCGACCAGGAAGAGAGCGAGAC
[1311] AGAAGCCCCAGAAGAAGAAGCGACCTCGCCACCGTCGCTACAGC
[1312] TCCAGCTCAAGCAGCAGATCAGGGAGCAGCGACAACTCAGATGTG
[1313] GAATCCAACACCTCTTCCAGCAACTAGTGAAAACCCAGCAAAACTT
[1314] GCATATCAACCCATGCCTACAATAG
[1315] CAF05727.1 AJ620218.1 ATGCGTTTTCGCAGGGTTGCCCAGAAAAGGAAAGTGCTTTTGCAA 121 ACTGTGCCAGCTGCAAAGAAGGCTAGGCGGCTTCTAGGTATGTGG
[1316] CAGCCCCCCACGCACAATGTCCCGGGCATCGAGAGAAACTGGTA
[1317] CGAGAGCTG I I I I AGATCCCACGCTGCTGTTTGTGGCTGTGGCGA
[1318] I I I I GTTGGCCATCTTAATCATCTGGCAACTACTCTGGGTCGTCCT
[1319] CCGCGTCCTGGGCCCCCAGGCGGACCCCGCACGCCGCAAATAAG
[1320] AAACCTGCCAGCGCTCCCGGCGCCCCAGGGCGAGCCCGGTGACA
[1321] GAGCGTCATGGCGTGGGGCTTCTGGGGCCGACGCCGCCGGTGG
[1322] AGACGATGGAGAGCGCGGCGCAGACGGTGGAGACCCCGCAGAC
[1323] GTAGGAGACGACGCCCTCCTCGCCGCTTTCGAGCTCGTCGAAGA
[1324] GTAA
[1325] CAF05728.1 AJ620218.1 ATGGCGTGGGGCTTCTGGGGCCGACGCCGCCGGTGGAGACGAT 122
[1326] GGAGAGCGCGGCGCAGACGGTGGAGACCCCGCAGACGTAGGAG
[1327] ACGACGCCCTCCTCGCCGCTTTCGAGCTCGTCGAAGAGTAAGGAG
[1328] GCGCGGGGGGAGGTGGCGCAGACGCTACAGAAAATGGCGACGG
[1329] GGCAGACGCAGACGGACTCACAGAAAAAAGATAGTCATAAAACAG
[1330] TGGCAACCTAACTTTATAAGACGCTGCTACATCATAGGGTACTTAC
[1331] CACTTATATTCTGCGGCGAAAATACAACCGCCCAGAACTTTGCCAC
[1332] TCACTCGGACGACATGATAAGCAAAGGACCGTACGGGGGGGGCA
[1333] TGACTACCACCAAATTCACTCTGAGAATACTGTACGACGAGTTTAC
[1334] CAGGTTTATGAAC I I I I GGACTGTCAGTAACGAAGACCTAGACCTG
[1335] TGTAGATACGTGGGCTGCAAACTAATATTTTTTAAACACCCCACGG
[1336] TGGACTTTATAGTACAGATAAACACTCAGCCTCCTTTCTTAGACAC
[1337] GCACCTCACCGCGGCCAGCATACACCCGGGCATCATGATGCTCA
[1338] GCAAGAGACACATACTAATACCCTCTCTAAAGACCCGGCCCAGCA
[1339] GAAAACACAGGGTGGTCGTCAGGGTGGGCGCCCCAAGACTTTTTC
[1340] AGGACAAGTGGTACCCCCAGTCAGACCTGTGTGACACAGTTCTGC
[1341] TTTCCATATTCGCAACCGCCTGCGACTTGCAATATCCGTTCGGCTC
[1342] ACCACTAACTGACAACCCTTGCGTCAACTTCCAGATCCTGGGGCC
[1343] CCAGTACAAAAAACACCTTAGTATTAGCTCCACTATGGATGACACT
[1344] AACAAAGCACATTATGAAGAAAACTTATTTAAGAAAATTGAACTATA
[1345] CAACACCTTTCAAACCATAGCTCAGCTTAAAGAGACAGGAACAATT
[1346] TCAGGCATGCAACCTTCTTGGACTGAAGTCCAGAATTCAAAAACAC
[1347] TTAATGAAACAGGTAGCAATGCCACTGAGAGTAGAGACACTTGGTA
[1348] TAAAGGAAATACATACAACGACAAGATACACCAGTTAGCAGAAAAA
[1349] ACCAGAAAGAGATTTAAAAATGCAACAAAAGCAGCACTACCAAACT
[1350] ACCCCACAATAATGTCCGCAGACTTATATGAATACCACTCAGGCAT
[1351] ATACTCCAGCATATATCTATCAGCTGGCAGGAGCTACTTTGAAACC
[1352] ACCGGGGCCTACTCTGACATTATATACAACCCTTTCACAGACAAGG
[1353] GCACAGGCAACATAATCTGGATAGACTACCTCACAAAAGAAGACA
[1354] CCATTTTTGTAAAAAACAAAAGCAAATGCGAGATAATGGACATGCC
[1355] CCTGTGGGCGGCCTGCACAGGATACACAGAG I I I I GTGCAAAGTA
[1356] TACAGGCGACTCTGCCATTATTTACAATGCAAGAATAGTCATAAGA
[1357] TGCCCATACACTGAGCCCATGTTAATAGACCACTCAGACCCAAACA
[1358] AAGGCTTCGTTCCCTACTCATTTAGCTTTGGCAACGGAAAGATGCC
[1359] CGGAGGCAGCTCCAACGTGCCCATAAGAATGAGAGCCAAGTGGTA
[1360] CGTGAACATATTCCACCAAAAAGAAGTATTGGAGAGCATAGTACAG TCCGGACCGTTTGGGTACAAGGGCGACATAAAATCAGCTGTACTA
[1361] GCCATGAAATACAGATTTCACTGGAAGTGGGGCGGAAACCCTATA
[1362] TCCAAACAGGTCGTCAGGAATCCCTGCTCCAACTCCAGCTCATCC
[1363] GCGGCCCATAGAGGACCTCGCAGCGTACAAGCGGTTGACCCGAA
[1364] ATACAATACCCCAGAGGTCACGTGGCACTCGTGGGACATTAGACG
[1365] AGGACTCTTTGGCAAAGCAGGTATTAAAAGAATGCAACAGGAATCA
[1366] GATGCTCTTTACATTCCTCCAGGACCAATCAAGAGACCTCGCAGG
[1367] GACACCAACGCCCAAGACCCAGAAGAGCAAAACGAAAGCTCAGGT
[1368] TTCAGAGTCCAGCAGCGACTCCCGTGGGTCCACTCCAGCCAAGAG
[1369] ACGCAAAGCTCCCAAGAAGAGACGGAGGCGCAGGGGTCGGTACA
[1370] AGACCAACTACTCCTCCAGCTCCGAGAGCAGCGAGTTCTCCGACT
[1371] CCAGCTCCAGCAACTCGCAACCCAAGTCCTCAAAGTCCAAGCAGG
[1372] GCACAGCCTACACCCCCTATTATCTTCCCAAGCATAA
[1373] CAF05729.1 AJ620219.1 ATGCGTTTTCGCAGGGTTGCCCAGAAAAGGAAAGTGCTTTTGCAA 123
[1374] ACTGTGCCAGCTGCAAAGAAGGCTAGGCGGCTTCTAGGTATGTGG
[1375] CAGCCCCCCACGCATAATGTCCCGGGCATCGAGAGAAACTGGTAC
[1376] GAGAGCTG I I I I AGATCCCACGCTGCTGTTTGTGGCTGTGGCGAT
[1377] TTTGTTGGCCATCTTAATCATCTGGCAACTACTCTGGGTCGTCCTC
[1378] CGCGTCCTGGGCCCCCAGGCGGACCCCGCACGCCGCAAATAAGA
[1379] AACCTGCCAGCGCTCCCGGCGCCCCAGGGCGAGCCCGGTGACA
[1380] GAGCGTCATGGCGTGGGGCTTCTGGGGCCGACGCCGCCGGTGG
[1381] AGACGATGGAGAGCGCGGCGCAGACGGTGGAGACCCCGCAGAC
[1382] GTAGGAGACGACGCCCTCCTCGCCGCTTTCGAGCTCGTCGAAGA
[1383] GTAA
[1384] CAF05730.1 AJ620219.1 ATGGCGTGGGGCTTCTGGGGCCGACGCCGCCGGTGGAGACGAT 124
[1385] GGAGAGCGCGGCGCAGACGGTGGAGACCCCGCAGACGTAGGAG
[1386] ACGACGCCCTCCTCGCCGCTTTCGAGCTCGTCGAAGAGTAAGGAG
[1387] GCGCGGGGGGAGGTGGCGCAGACGCTACAGAAAATGGCGACGG
[1388] GGCAGACGCAGACGGACTCACAGAAAAAAGATAGTCATAAAACAG
[1389] TGGCAACCTAACTTTATAAGACGCTGCTACATCATAGGGTACTTAC
[1390] CACTTATATTCTGCGGCGAAAATACAACCGCCCAGAACTTTGCCAC
[1391] TCACTCGGACGACATGATAAGCAAAGGACCGTACGGGGGGGGCA
[1392] TGACTACCACCAAATTCACTCTGAGAATACTGTACGACGAGTTTAC
[1393] CAGGTTTATGAAC I I I I GGACTATCAGTAACGAAGACCTAGACCTG
[1394] TGTAGATACGTGGGCTGCAAACTAATATTTTTTAAACACCCCACGG
[1395] TGGACTTTATAGTACAGATAAACACTCAGCCTCCTTTCTTAGACAC
[1396] GCACCTCACCGCGGCCAGCATACACCCGGGCATCATGATGCTCA
[1397] GCAAGAGACACATACTAATACCCTCTCTAAAGACCCGGCCCAGCA
[1398] GAAAACACAGGGTGGTCGTCAGGGTGGGCGCCCCAAGACTTTTTC
[1399] AGGACAAGTGGTACCCCCAGTCAGACCTGTGTGACACAGTTCTGC
[1400] TTTCCATATTCGCAACCGCCTGCGACTTGCAATATCCGTTTGGCTC
[1401] ACCACTAACTGACAACCCTTGCGTCAACTTCCAGATCCTGGGGCC
[1402] CCAGTACAAAAAACACCTTAGTATTAGCTCCACTATGGATGAAAGT
[1403] AACATATCACATTATAAAGAAAACTTATTTAAGAAAACTGAACTATA
[1404] CAACACCTTTCAAACCATAGCTCAGCTTAAAGAGACAGGAAACATT
[1405] TCAGGCATTAGTCCTAATTGGACTGAAGTCCAGAATTCAACAACAC TTAATCAAACAGGTGACAATGCCACTAACAGTAGAGACACTTGGTA
[1406] TAAAGGAAATACATACAACCACAAGATATGCGACTTAGCAGAAAAA
[1407] ACCAGAAACAGATTTAAAAATGCAACCAAAGCAGCACTACCAAACT
[1408] ACCCCACAATAATGTCCACAGACCTATATGAATACCACTCAGGCAT
[1409] ATACTCCAGCATATATTTATCAGCTGGCAGGAGCTACTTTGAAACC
[1410] ACCGGGGCCTACTCTGACATTATATACAACCCTTTCACAGACAAAG
[1411] GCACAGGCAACATAATCTGGATAGACTACCTCACAAAAGAAGACA
[1412] CCATTTTTGTAAAAAACAAAAGCAAATGCGAGATAATGGACATGCC
[1413] CCTGTGGGCGGCCTGCACAGGATACACAGAG I I I I GTGCAAAGTA
[1414] TACAGGCGACTCTGCCATTATCTACAATGCAAGAATACTCATAAGA
[1415] TGCCCATACACTGAGCCCATGTTAATAGACCACTCAGACCCAAACA
[1416] AAGGCTTCGTTCCCTACTCATTTAACTTTGGCAACGGAAAGATGCC
[1417] CGGAGGCAGCTCCAACGTACCCATAAGAATGAGAGCCAAATGGTA
[1418] CGCGAACATATTCCACCAAAAGGAGGTTCTAGAGGCTATAGTACAA
[1419] AGCGGACCGTTCGGGTACAAGGGCGACATAAAATCAGCTGTACTA
[1420] GCCATGAAATACAGATTTCACTGGAAGTGGGGCGGAAACCCTATA
[1421] TCCAAACAGGTCGTCAGGAATCCCTGCTCCAACTCCAGCTCATCC
[1422] GCGGCCCATAGAGGACCTCGCAGCGTACAAGCGGTTGACCCGAA
[1423] ATACAATACCCCAGAGGTCACGTGGCACTCGTGGGACATTAGACG
[1424] AGGACTCTTTGGCAAAGCAGGTATTAAAAGAATGCAACAGGAATCA
[1425] GATGCTCTTTACATTCCTCCAGGACCAATCAAGAGACCTCGCAGG
[1426] GACACCAACGCCCAAGACCCAGAAGAGCAAAACGAAAGCTCAGGT
[1427] TTCAGAGTCCAGCAGCGACTCCCGTGGGTCCACTCCAGCCAAGAG
[1428] ACGCAAAGCTCCCAAGAAGAGACGGAGGCGCAGGGGTCGGTACA
[1429] AGACCAACTACTCCTCCAGCTCCGAGAGCAGCGAGTTCTCCGACT
[1430] CCAGCTCCAGCAACTCGCAGCCCAAGTCCCCAAAGTCCAAGCAGG
[1431] GCACAGCCTACACCCCCTATTATCTTCCCAAGCATAA
[1432] CAF05731.1 AJ620220.1 ATGCGTTTTCGCAGGGTTGCCCAGAAAAGGAAAGTGCTTTTGCAA 125
[1433] ACTGTGCCAGCTGCAAAGAAGGCTAGGCGGCTTCTAGGTATGTGG
[1434] CAGCCCCCCACGCACAATGTCCCGGGCATCGAGAGAAACTGGTA
[1435] CGAGAGCTG I I I I AGATCCCACGCTGCTGTTTGTGGCTGTGGCGA
[1436] I I I I GTTGGCCATCTTAATCATCTGGCAACTACTCTGGGTCGTCCT
[1437] CCGCGTCCTGGGCCCCCAGGCGGACCCCGCACGCCGCAAATAAG
[1438] AAACCTGCCAGCGCTCCCGGCGCCCCAGGGCGAGCCCGGTGACA
[1439] GAGCGTCATGGCGTGGGGCTTCTGGGGCCGACGCCGCCGGTGG
[1440] AGACGATGGAGAGCGCGGCGCAGACGGTGGAGACCCCGCAGAC
[1441] GTAGGAGACGACGCCCTCCTCGCCGCTTTCGAGCTCGTCGAAGA
[1442] GTAA
[1443] CAF05732.1 AJ620220.1 ATGGCGTGGGGCTTCTGGGGCCGACGCCGCCGGTGGAGACGAT 126
[1444] GGAGAGCGCGGCGCAGACGGTGGAGACCCCGCAGACGTAGGAG
[1445] ACGACGCCCTCCTCGCCGCTTTCGAGCTCGTCGAAGAGTAAGGAG
[1446] GCGCGGGGGGAGGTGGCGCAGACGCTACAGAAAATGGCGACGG
[1447] GGCAGACGCAGACGGACTCACAGAAAAAAGATAGTCATAAAACAG
[1448] TGGCAACCAAACTTTATAAGACGCTGCTACATCATAGGGTACTTAC
[1449] CACTTATATTCTGCGGCGAAAATACAACCGCCCAGAACTTTGCCAC
[1450] TCACTCGGACGACATGATAAGCAAAGGACCGTACGGGGGGGGCA TGACTACCACCAAATTCACTCTGAGAATACTGTACGACGAGTTTAC
[1451] CAGGTTTATGAAC I I I I GGACTGTCAGTAACGAAGACCTAGACCTG
[1452] TGTAGATACGTGGGCTGCAAACTAATATTTTTTAAACACCCCACGG
[1453] TGGACTTTATAGTACAGATAAACACTCAGCCTCCTTTCTTAGACAC
[1454] GCACCTCACCGCGGCCAGCATACACCCGGGCATCATGATGCTCA
[1455] GCAAGAGACACATACTAATACCCTCTCTAAAGACCCGGCCCAGCA
[1456] GAAAACACAGGGTGGTCGTCAGGGTGGGCGCCCCAAGACTTTTTC
[1457] AGGACAAGTGGTACCCCCAGTCAGACCTGTGTGACACAGTTCTGC
[1458] TTTCCATATTCGCAACCGCCTGCGACTTGCAATATCCGTTCGGCTC
[1459] ACCACTAACTGACAACCCTTGCGTCAACTTCCAGATCCTGGGGCC
[1460] CCAGTACAAAAAACACCTTAGTATTAGCTCCACTATGGATGACACT
[1461] AACAAAGCACATTATGAAGAAAACTTATTTAATAAAACTGAACTATA
[1462] CAACACCTTTCAAACCATAGCTCAGCTTAGAGACACAGGACAAACT
[1463] ACAAACGCTAGTCCTAATTGGAATCAGGTCCAGAATACAGCAGCA
[1464] CTTGAGTTATCAGGTGCAAATGCCACTAGCAGCAAAGACACTTGGT
[1465] ATAAAGGTAATACATACACGAAAGACATATCAAAGTTAGCAGAAAA
[1466] AACCAGACAAAGATTTAAAGCTGCAACAATAGCAGCACTACCAAAC
[1467] TACCCCACAATAATGTCCACAGACCTATATGAATACCACTCAGGCA
[1468] TATACTCCAGCATATATTTATCAGCTGGCAGGAGCTACTTTGAAAC
[1469] CACCGGGGCCTACTCTGACATTATATACAACCCTTTCACAGACAAA
[1470] GGCACAGGCAACATAATCTGGATAGACTACCTCACAAAAGAAGAC
[1471] ACCATTTTTGTAAAAAACAAAAGCAAATGCGAGATAATGGACATGC
[1472] CCCTGTGGGCGGCCTGCACAGGATACACAGAG I I I I GTGCAAAGT
[1473] ATACAGGCGACTCTGCCATTATCTACAATGCAAGAATACTCATAAG
[1474] ATGCCCACACACTGAGCCCATGTTAATAGACCACTCAGACCCAAA
[1475] CAAAGGCTTCGTTCCCTACTCATTCGACTTTGGCAATGGAAAGATG
[1476] CCCGGAGGCAGCTCCAACGTACCGATAAGAATGAGGGCCAAATG
[1477] GTACGTGAACATATTCCACCAAAAGGAGGTTCTAGAGGCTATAGTA
[1478] CAAAGCGGACCGTTCGGGTACAAGGGCGACATAAAATCAGCTGTA
[1479] CTAGCCATGAAATACAGATTTCACTGGAAGTGGGGCGGAAACCCT
[1480] ATATCCAAACAGGTCGTCAGGAATCCCTGCTCCAACTCCAGCTCAT
[1481] CCGCGGCCCATAGAGGACCTCGCAGCGTACAAGCGGTTGACCCG
[1482] AAATACAATACCCCAGAGGTCACGTGGCACTCGTGGGACATTAGA
[1483] CGAGGACTCTTTGGCAAAGCAGGTATTAAAAGAATGCAACAGGAA
[1484] TCAGATGCTCTTTACATTCCTCCAGGACCAATCAAGAGACCTCGCA
[1485] GGGACACCAACGCCCAAGACCCAGAAGAGCAAAACGAAAGCTCA
[1486] GGTTTCAGAGTCCAGCAGCGACTCCCGTGGGTCCACTCCAGCCAA
[1487] GAGACGCAAAGCTCCCAAGAAGAGACGGAGGCGCAGGGGTCGGT
[1488] ACAAGACCAACTACTCCTCCAGCTCCGAGAGCAGCGAGTTCTCCG
[1489] ACTCCAGCTCCAGCAACTCGCAACCCAAGTCCTCAAAGTCCAAGC
[1490] AGGGCACAGCCTACACCCCCTATTATCTTCCCAAGCATAA
[1491] CAF05733.1 AJ620221.1 ATGCGTTTTCGCAGGGTTGCCCAGAAAAGGAAAGTGCTTTTGCAA 127
[1492] ACTGTGCCAGCTGCAAAGAAGGCTAGGCGGCTTCTAGGTATGTGG CAGCCCCCCACGCACAATGTCCCGGGCATCGAGAGAAACTGGTA CGAGAGCTG I I I I AGATCCCACGCTGCTGTTTGTGGCTGTGGCGA I I I I GTTGGCCATCTTAATCATCTGGCAACTACTCTGGGTCGTCCT CCGTGTCCTGGGCCCCCAGGCGGACCCCGCACGCCGCAAATAAG
[1493] AAACCTGCCAGCGCTCCCGGCGCCCCAGGGCGAGCCCGGTGACA
[1494] GAGCGCCATGGCGTGGGGCTTCTGGGGCCGACGCCGCCGGTGG
[1495] AGACGATGGAGAGCGCGGCGCAGACGGTGGAGACCCCGCAGAC
[1496] GTAGGAGACGACGCCCTACTCGCCGCTTTCGAGCTCGTCGAAGA
[1497] GTAA
[1498] CAF05734.1 AJ620221.1 ATGGCGTGGGGCTTCTGGGGCCGACGCCGCCGGTGGAGACGAT 128
[1499] GGAGAGCGCGGCGCAGACGGTGGAGACCCCGCAGACGTAGGAG
[1500] ACGACGCCCTACTCGCCGCTTTCGAGCTCGTCGAAGAGTAAGGAG
[1501] GCGCGGGGGGAGGTGGCGCAGACGCTACAGAAAATGGCGACGG
[1502] GGCAGACGCAGACGGACTCATAGAAAAAAGATAGTCATAAAACAG
[1503] TGGCAACCAAACTTTATAAGACGCTGCTACATCATAGGGTACTTAC
[1504] CACTTATATTCTGCGGCGAAAATACAACCGCCCAGAACTTTGCCAC
[1505] TCGCTCGGACGACATGATAAGCAAAGGACCGTACGGGGGGGGCA
[1506] TGACTACCACCAAATTCACTCTGAGAATACTGTACGACGAGTTTAC
[1507] CAGGTTTATGAAC I I I I GGACTGTCAGTAACGAAGACCTAGACCTG
[1508] TGTAGATACGTGGGCTGCAAACTAATATTTTTTAAACACCCCACGG
[1509] TGGACTTTATAGTACAGATAAACACTCAGCCTCCTTTCTTAGACAC
[1510] GCACCTCACCGCGGCCAGCATACACCCGGGCATCATGATGCTCA
[1511] GCAAGAGACACATACTAATACCCTCTCTAAAGACCCGGCCCAGCA
[1512] GAAAACACAGGGTGGTCGTCAGGGTGGGCGCCCCAAGACTTTTTC
[1513] AGGACAAGTGGTACCCCCAGTCAGACCTGTGTGACACAGTTCTGC
[1514] TTTCCATATTCGCAACCGCCTGCGACTTGCAATATCCGTTCGGCTC
[1515] ACCACTAACTGACAACCCTTGCGTCAACTTCCAGATCCTGGGGCC
[1516] CCAGTACAAAAAACACCTTAGTATTAGCTCCACTATGGATGAAAGT
[1517] AACAAAGCACATTATGAACAAAACTTATTTAAGAAAACTGAACTATA
[1518] CAACACCTTTCAAACCATAGCTCAGCTTAAAGAGACAGGAAACATT
[1519] TCAGGCATTACTCCTACTTGGACTGAAGTCCAGAATTCAACAACAC
[1520] TTAATCAAGCAGGTAACAATGCCACTGACAGTAGAGACACTTGGTA
[1521] TAAAGGAAATACATACAACGAGAAGATATCCGAGTTAGCACAAATA
[1522] ACCAGAAACAGATTTAAAAATGCAACCAAAACAGCACTACCAAACT
[1523] ACCCCACAATAATGTCCACAGACCTATATGAATACCACTCAGGCAT
[1524] ATACTCCAGCATATATTTATCAGCTGGCAGGAGCTACTTTGAAACC
[1525] ACCGGGGCCTACTCTGACATTATATACAACCCTTTCACAGACAAAG
[1526] GCACAGGCAACATAATCTGGATAGACTACCTCACAAAAGAAGACA
[1527] CCATTTTTGTAAAAAACAAAAGCAAATGCGAGATAATGGACATGCC
[1528] CCTGTGGGCGGCCTGCACAGGATACACAGAG I I I I GTGCAAAGTA
[1529] TACAGGCGACTCTGCCATTATTTACAATGCAAGAATAGTCATAAGA
[1530] TGCCCATACACTGAGCCCATGTTAATAGACCACTCAGACCCAAACA
[1531] AAGGCTTCGTCCCCTACTCATTTAACTTTGGCAACGGAAAGATGCC
[1532] CGGAGGCAGCTCCAACGTGCCCATAAGAATGAGAGCCAAGTGGTA
[1533] CGTGAACATATTCCACCAAAAAGAAGTATTGGAGAGCATAGTACAG
[1534] TCCGGACCGTTTGGGTACAAGGGCGACATAAAATCAGCTGTACTA
[1535] GCCATGAAATACAGATTTCACTGGAAGTGGGGCGGAAACCCTATA
[1536] TCCAAACAGGTCGTCAGGAATCCCTGCTCCAACTCCAGCTCATCC
[1537] GCGGCCCATAGAGGACCTCGCAGCGTACAAGCGGTTGACCCGAA ATACAATACCCCAGAGGTCACGTGGCACTCGTGGGACATTAGACG
[1538] AGGACTCTTTGGCAAAGCAGGTATTAAAAGAATGCAACAGGAATCA
[1539] GATGCTCTTTACATTCCTCCAGGACCAATCAAGAGACCTCGCAGG
[1540] GACACCAACGCCCAAGACCCAGAAGAGCAAAACGAAAGCTCAGGT
[1541] TTCAGAGTCCAGCAGCGACTCCCGTGGGTCCACTCCAGCCAAGAG
[1542] ACGCAAAGCTCCCAAGAAGAGACGGAGGCGCAGGGGTCGGTACA
[1543] AGACCAACTACTCCTCCAGCTCCGAGAGCAGCGAGTTCTCCGACT
[1544] CCAGCTCCAGCAACTCGCAACCCAAGTCCTCAAAGTCCAAGCAGG
[1545] GCACAGCCTACACCCCCTATTATCTTCCCAAGCATAA
[1546] CAF05735.1 AJ620222.1 ATGCGTTTTCGCAGGGTTGCCCAGAAAAGGAAAGTGCTTTTGCAA 129
[1547] ACTGTGCCAGCTGCAAAGAAGGCTAGGCGGCTTCTAGGTATGTGG
[1548] CAGCCCCCCACGCACAATGTCCCGGGCATCGAGAGAAACTGGTA
[1549] CGAGAGCTG I I I I AGATCCCACGCTGCTGTTTGTGGCTGTGGCGA
[1550] I I I I GTTGGCCATCTTAATCATCTGGCAACTACTCTGGGTCGTCCT
[1551] CCGCGTCCTGGGCCCCCAGGCGGACCCCGCACGCCGCAAATAAG
[1552] AAACCTGCCAGCGCTCCCGGCGCCCCAGGGCGAGCCCGGTGACA
[1553] GAGCGCCATGGCATGGGGCTTCTGGGGCCGACGCCGCCGGTGG
[1554] AGACGATGGAGAGCGCGGCGCAGACGGTGGAGACCCCGCAGAC
[1555] GTAGGAGACGACGCCCTACTCGCCGCTTTCGAGCTCGTCGAAGA
[1556] GTAA
[1557] CAF05736.1 AJ620222.1 ATGGCATGGGGCTTCTGGGGCCGACGCCGCCGGTGGAGACGATG 130
[1558] GAGAGCGCGGCGCAGACGGTGGAGACCCCGCAGACGTAGGAGA
[1559] CGACGCCCTACTCGCCGCTTTCGAGCTCGTCGAAGAGTAAGGAG
[1560] GCGCGGGGGGAGGTGGCGCAGACGCTACAGAAAATGGCGACGG
[1561] GGCAGACGCAGACGGACTCATAGAAAAAAGATAGTCATAAAACAG
[1562] TGGCAACCAAACTTTATAAGACGCTGCTACGTCATAGGGTACTTAC
[1563] CACTTATATTCTGCGGCGAAAATACAACCGCCCAGAACTTTGCCAC
[1564] TCACTCGGACGACATGATAAGCAAAGGACCGTACGGGGGGGGCA
[1565] TGACTACCACCAAATTCACTCTGAGAATACTGTACGACGAGTTTAC
[1566] CAGGTTTATGAAC I I I I GGACTGTCAGTAACGAAGACCTAGACCTG
[1567] TGTAGATACGTGGGCTGCAAACTAATATTTTTTAAACACCCCACGG
[1568] TGGACTTTATAGTACAGATAAACACTCAGCCTCCTTTCTTAGACAC
[1569] GCACCTCACCGCGGCCAGCATACACCCGGGCATCATGATGCTCA
[1570] GCAAGAGACACATACTAATACCCTCTCTAAAGACCCGGCCCAGCA
[1571] GAAAACACAGGGTGGTCGTCAGGGTGGGCGCCCCAAGACTTTTTC
[1572] AGGACAAGTGGTACCCCCAGTCAGACCTGTGTGACACAGTTCTGC
[1573] TTTCCATATTTGCAACCGCCTGCGACTTGCAATATCCGTTCGGCTC
[1574] ACCACTAACTGACAACCCTTGCGTCAACTTCCAGATCCTGGGGCC
[1575] CCAGTACAAAAAACACCTTAGTATTAGCTCCACTATGGATCAAACT
[1576] AACGAAAACCATTATAAAGAAAACTTATTTAACAAAACTGAACTATA
[1577] CAACACCTTTCAAACCATAGCTCAGCTTAAAGAGACAGGACACATT
[1578] TCAGGCATTAGTCCTACTTGGAATGAAGTCCAGAATTCAACAACAC
[1579] TTACTAAAGGAGGTGACAATGCCACTCAGAGTAGAGACACTTGGT
[1580] ATAAAGGAAATACATACAACGAGAAGATATGCGAGTTAGCACAAAT
[1581] AACCAGAAACAGATTTAAAAATGCAACCAAAGGAGCACTACCAAAC
[1582] TACCCCACAATAATGTCCACAGACCTATATGAATACCACTCAGGCA TACACTCCAGCATATATCTATCAGCTGGCAGGAGCTACTTTGAAAC
[1583] CACCGGGGCCTACTCTGACATTATATACAACCCTTTCACAGACAAA
[1584] GGCACAGGCAACATAATCTGGATAGACTACCTCACAAAAGAAGAC
[1585] ACCATTTTTGTGAAAAACAAAAGCAAATGCGAGATAATGGACATGC
[1586] CCCTGTGGGCGGCCTGCACAGGATACACAGAG I I I I GTGCAAAGT
[1587] ATACAGGCGACTCTGCCATTATCTACAATGCAAGAATACTCATAAG
[1588] ATGCCCATACACTGAGCCCATGTTAATAGACCACTCAGACCCAAAC
[1589] AAAAGCTTCGTTCCCTACTCATTTAACTTTGGCAACGGAAAGATGC
[1590] CCGGAGGCAGCTCCAACGTGCCCATAAGAATGAGAGCCAAGTGG
[1591] TACGTGAACATATTCCACCAAAAAGAAGTATTAGAGAGCATAGTAC
[1592] AGTCCGGACCGTTTGGGTACAAGGGCGACATAAGATCAGCTGTAC
[1593] TAGCCATGAAATACAGATTTCACTGGAAGTGGGGCGGAAACCCTA
[1594] TATCCAAACAGGTCGTCAGGAATCCCTGCTCCAACTCCAGCTCCT
[1595] CCGCGGCCCATAGAGGACCTCGCAGCGTACAAGCGGTTGACCCG
[1596] AAATACAATACCCCAGAGGTCACGTGGCACTCGTGGGACATTAGA
[1597] CGAGGACTCTTTGGCAAAGCAGGTATTAAAAGAATGCAACAGGAA
[1598] TCAGATGCTCTTTACATTCCTCCAGGACCAATCAAGAGACCTCGCA
[1599] GGGACACCAACGCCCAAGACCCAGAAGAGCAAAACGAAAGCTCA
[1600] GGTTTCAGAGTCCAGCAGCGACTCCCGTGGGTCCACTCCAGCCAA
[1601] GAGACGCAAAGCTCCCAAGAAGAGACGGAGGCGCAGGGGTCGGT
[1602] ACAAGACCAACTACTCCTCCAGCTCCGAGAGCAGCGAGTTCTCCG
[1603] ACTCCAGCTCCAGCAACTCGCAACCCAAGTCCTCAAAGTCCAAGC
[1604] AGGGCACAGCCTACACCCCCTATTATCTTCCCAAGCATAA
[1605] CAF05737.1 AJ620223.1 ATGCGTTTTCGCAGGGTTGCCCAGAAAAGGAAAGTGCTTTTGCAA 131
[1606] ACTGTGCCAGCTGCAAAGAAGGCTAGGCGGCTTCTAGGTATGTGG
[1607] CAGCCCCCCACGCACAATGTCCCGGGCATCGAGAGAAACTGGTA
[1608] CGAGAGCTG I I I I AGATCCCACGCTGCTGTTTGTGGCTGTGGCGA
[1609] I I I I GTTGGCCATCTTAATCATCTGGCAACTACTCTGGGTCGTCCT
[1610] CCGCGTCCTGGGCCCCCAGGCGGACCCCGCACGCCGCAAATAAG
[1611] AAACCTGCCAGCGCTCCCGGCGCCCCAGGGCGAGCCCGGTGACA
[1612] GAGCGCCATGGCATGGGGCTTCTGGGGCCGACGCCGCCGGTGG
[1613] AGACGATGGAGAGCGCGGCGCAGACGGTGGAGACCCCGCAGAC
[1614] GTAGGAGACGACGCCCTACTCGCCGCTTTCGAGCTCGTCGAAGA
[1615] GTAA
[1616] CAF05738.1 AJ620223.1 ATGGCATGGGGCTTCTGGGGCCGACGCCGCCGGTGGAGACGATG 132
[1617] GAGAGCGCGGCGCAGACGGTGGAGACCCCGCAGACGTAGGAGA
[1618] CGACGCCCTACTCGCCGCTTTCGAGCTCGTCGAAGAGTAAGGAG
[1619] GCGCGGGGGGAGGTGGCGCAGACGCTACAGAAAATGGCGACGG
[1620] GGCAGACGCAGACGGACTCATAGAAAAAAGATAGTCATAAAACAG
[1621] TGGCAACCAAACTTTATAAGACGCTGCTACATCATAGGGTACTTAC
[1622] CACTTATATTCTGCGGCGAAAATACAACCGCCCAGAACTTTGCCAC
[1623] TCACTCGGACGACATGATAAGCAAAGGACCGTACGGGGGGGGCA
[1624] TGACTACCACCAAATTCACTCTGAGAATACTGTACGACGAGTTTAC
[1625] CAGGTTTATGAAC I I I I GGACTGTCAGTAACGGAGACCTAGACCTG
[1626] TGTAGATACGTGGGCTGCAAACTAATATTTTTTAAACACCCCACGG
[1627] TGGACTTTATAGTACAGATAAACACTCAGCCTCCTTTCTTAGACAC GCACCTCACCGCGGCCAGCATACACCCGGGCATCATGATGCTCA
[1628] GCAAGAGACACATACTAATACCCTCTCTAAAGACCCGGCCCAGCA
[1629] GAAAACACAGGGTGGTCGTCAGGGTGGGCGCCCCAAGACTTTTTC
[1630] AGGACAAGTGGTACCCCCAGTCAGACCTGTGTGACACAGTTCTGC
[1631] TTTCCATATTTGCAACCGCCTGCGACTTGCAATATCCGTTCGGCTC
[1632] ACCACTAACTGACAACCCTTGCGTCAACTTCCAGATCCTGGGGCC
[1633] CCAGTACAAAAAACACCTTAGTATTAGCTCCACTATGGATCAAACT
[1634] AACGAAAACCATTATAAAGAAAACTTATTTAACAAAACTGAACTATA
[1635] CAACACCTTTCAAACCATAGCTCAGCTTAAAGAGACAGGACACATT
[1636] TCAGGCATTAGTCCTACTTGGAATGAAGTCCAGAATTCAACAACAC
[1637] TTACTAAAGAAGGTGACAATGCCACTCAGAGTAGAGACACTTGGTA
[1638] TAAAGGAAATACATACAACGGTAAGATATGCCAGTTAGCACAAATA
[1639] ACCAGAAACAGGTTTAAAAATGCAACCAAAGGAGCACTACCAAACT
[1640] ACCCCACAATAATGTCCACAGACCTATATGAATACCACTCAGGCAT
[1641] ATACTCCAGCATATGTCTATCAGCTGGCAGGAGCTACTTTGAAACC
[1642] ACCGGGGCCTACTCTGACATTATATACAACCCTTTCACAGACAAAG
[1643] GCACAGGCAACATAATCTGGATAGACTACCTCACAAAAGAAGACA
[1644] CCATTTTTGTGAAAAACAAAAGCAAATGCGAGATAATGGACATGCC
[1645] CCTGTGGGCGGCCTGCACAGGATACACAGAG I I I I GTGCAAAGTA
[1646] TACAGGCGACTCTGCCATTATCTACAATGCAAGAATACTCATAAGA
[1647] TGCCCATACACTGAGCCCATGTTAATAGACCACTCAGACCCAAACA
[1648] AAGGCTTCGTTCCCTACTCATTTAACTTTGGCAACGGAAAGATGCC
[1649] CGGAGGCAGCTCCAACGTGCCCATAAGAATGAGAGCCAAGTGGTA
[1650] CGTGAACATATTCCACCAAAAAGAAGTATTAGAGAGCATAGTACAG
[1651] TCCGGACCGTTTGGGTACAAGGGCGACATAAAATCAGCTGTACTA
[1652] GCCATGAAATACAGATTTCACTGGAAGTGGGGCGGAAACCCTATA
[1653] TCCAAACAGGTCGTCAGGAATCCCTGCTCCAACTCCAGCTCCTCC
[1654] GCGGCCCATAGAGGACCTCGCAGCGTACAAGCGGTTGACCCGAA
[1655] ATACAATACCCCAGAGGTCACGTGGCACTCGTGGGACATTAGACG
[1656] AGGACTCTTTGGCAAAGCAGGTATTAAAAGAATGCAACAGGAATCA
[1657] GATGCTCTTTACATTCCTCCAGGACCAATCAAGAGACCTCGCAGG
[1658] GACACCAACGCCCAAGACCCAGAAGAGCAAAACGAAAGCTCAGGT
[1659] TTCAGAGTCCAGCAGCGACTCCCGTGGGTCCACTCCAGCCAAGAG
[1660] ACGCAAAGCTCCCAAGAAGAGACGGAGGCGCAGGGGTCGGTACA
[1661] AGACCAACTACTCCTCCAGCTCCGAGAGCAGCGAGTTCTCCGACT
[1662] CCAGCTCCAGCAACTCGCAACCCAAGTCCTCAAAGTCCAAGCAGG
[1663] GCACAGCCTACACCCCCTATTATCTTCCCAAGCATAA
[1664] CAF05778.1 AJ620224.1 ATGCGTTTTCGCAGGGTTGCCCAGAAAAGGAAAGTGCTTTTGCAA 133
[1665] ACTGTGCCAGCTGCAAAGAAGGCTAGGCGGCTTCTAGGTATGTGG
[1666] CAGCCCCCCACGCACAATGTCCCGGGCATCGAGAGAAACTGGTA
[1667] CGAGAGCTG I I I I AGATCCCACGCTGCTGTTTGTGGCTGTGGCGA
[1668] I I I I GTTGGCCATCTTAATCATCTGGCAACTACTCTGGGTCGTCCT
[1669] CCGCGTCCTGGGCCCCCAGGCGGACCCCGCACGCCGCAAATAAG
[1670] AAACCTGCCAGCGCTCCCGGCGCCCCAGGGCGAGCCCGGTGACA
[1671] GAGCGCCATGGCATGGGGCTTCTGGGGCCGACGCCGCCGGTGG
[1672] AGACGATGGAGAGCGCGGCGCAGACGGTGGAGATCCCGCAGAC GTAGGAGACGACGCCCTACTCGCCGCTTTCGAGCTCGTCGAAGA
[1673] GTAA
[1674] CAF05779.1 AJ620224.1 ATGGCATGGGGCTTCTGGGGCCGACGCCGCCGGTGGAGACGATG 134
[1675] GAGAGCGCGGCGCAGACGGTGGAGATCCCGCAGACGTAGGAGA
[1676] CGACGCCCTACTCGCCGCTTTCGAGCTCGTCGAAGAGTAAGGAG
[1677] GCGCGGGGGGAGGTGGCGCAGACGCTACAGAAAATGGCGACGG
[1678] GGCAGACGCAGACGGACTCATAGAAAAAAGATAGTCATAAAACAG
[1679] TGGCAACCAAACTTTATAAGACGCTGCTACATCATAGGGTACTTAC
[1680] CACTTATATTCTGCGGCGAAAATACAACCGCCCAGAACTTTGCCAC
[1681] TCACTCGGACGACATGATAAGCAAAGGACCGTACGGGGGGGGCA
[1682] TGACTACCACCAAATTCACTCTGAGAATACTGTACGACGAGTTTAC
[1683] CAGGTTTATGAAC I I I I GGACTGTCAGTAACGAAGACCTAGACCTG
[1684] TGTAGATACGTGGGCTGCAAACTAATATTTTTTAAACACCCCACGG
[1685] TGGACTTTATAGTACAGATAAACACTCAGCCTCCTTTCTTAGACAC
[1686] GCACCTCACCGCGGCCAGCATACACCCGGGCATCATGATGCTCA
[1687] GCAAGAGACACATACTAATACCCTCTCTAAAGACCCGGCCCAGCA
[1688] GAAAGCACAGGGTGGTCGTCAGGGTGGGCGCCCCAAGACTTTTT
[1689] CAGGACAAGTGGTACCCCCAGTCAGACCTGTGTGACACAGTTCTG
[1690] CTTTCCATATTTGCAACCGCCTGCGACTTGCAATATCCGTTCGGCT
[1691] CACCACTAACTGACAACCCTTGCGTCAACTTCCAGATCCTGGGGC
[1692] CCCAGTACAAAAAACACCTTAGTATTAGCTCCACTATGGATCAAAC
[1693] TAACGAAAACCATTATAAAGAAAACTTATTTAACAAAACTGAACTAT
[1694] ACAACACCTTTCAAACCATAGCTCAGCTTAAAGAGACAGGACACAT
[1695] TTCAGGCATTAGTCCTACTTGGAATGAAGTCCAGAATTCAACAACA
[1696] CTTACTAAAGGAGGTGACAATGCCACTCAGAGTAGAGACACTTGG
[1697] TATAAAGGAAATACATACAACGAGAACATATGCAAGTTAGCAGAGG
[1698] TAACCAGAAACAGATTTAAAAATGCAACCAAAGGAGCACTACCAAA
[1699] CTACCCCACAATAATGTCCACAGACCTATATGAATACCACTCAGGC
[1700] ATATACTCCAGCATATATCTATCAGCGGGCAGGAGCTACTTTGAAA
[1701] CCACCGGGGCCTACTCTGACATTATATACAACCCTTTCACAGACAA
[1702] AGGCACAGGCAACATAATCTGGATAGACTACCTCACAAAAGAAGA
[1703] CACCATTTTTGTGAAAAACAAAAGCAAATGCGAAATAATGGACATG
[1704] CCCCTGTGGGCGGCCTGCACGGGATACACAGAG I I I I GTGCAAAG
[1705] TATACAGGCGACTCTGCCATTATCTACAATGCAAGAATACTCATAA
[1706] GATGCCCATACACTGAGCCCATGTTAATAGACCACTCAGACCCAAA
[1707] CAAAGGCTTCGTTCCCTACTCATTTAACTTTGGCAACGGAAAGATG
[1708] CCCGGAGGCAGCTCCAACGTGCCCATAAGAATGAGAGCCAAGTG
[1709] GTACGTGAACATATTCCACCAAAAAGAAGTATTAGAGAGCATAGTA
[1710] CAGTCCGGACCGTTTGGGTACAAGGGCGACATAAAATCAGCTGTA
[1711] CTAGCCATGAAATACAGATTTCACTGGAAGTGGGGCGGAAACCCT
[1712] ATATCCAAACAGGTCGTCAGGAATCCCTGCTCCAACTCCAGCCCC
[1713] TCCGCGGCCCATAGAGGACCTCGCAGCGTACAAGCGGTTGACCC
[1714] GAAATACAATACCCCAGAGGTCACGTGGCACTCGTGGGACATTAG
[1715] ACGAGGACTCTTTGGCAAAGCAGGTATTAAAAGAATGCAACAGGA
[1716] ATCAGATGCTCTTTACATTCCTCCAGGACCAATCAAGAGACCTCGC
[1717] AGGGACACCAACGCCCAAGACCCAGAAGAGCAAAACGAAAGCTC AGGTTTCAGGGTCCAGCAGCGACTCCCGTGGGTCCACTCCAGCC
[1718] AAGAGACGCAAAGCTCCCAAGAAGAGACGGAGGCGCAGGGGTCG
[1719] GTACAAGACCAACTACTCCTCCAGCTCCGAGAGCAGCGAGTTCTC
[1720] CGACTCCAGCTCCAGCAACTCGCAACCCAAGTCCTCAAAGTCCAA
[1721] GCAGGGCACAGCCTACACCCCCTATTATCTTCCCAAGCATAA
[1722] CAF05739.1 AJ620225.1 ATGCGTTTTCGCAGGGTTGCCCAGAAAAGGAAAGTGCTTTTGCAA 135
[1723] ACTGTGCCAGCTGCAAAGAAGGCTAGGCGGCTTCTAGGTATGTGG
[1724] CAGCCCCCCACGCACAATGTCCCGGGCATCGAGAGAAACTGGTA
[1725] CGAGAGCTG I I I I AGATCCCACGCTGCTGTTTGTGGCTGTGGCGA
[1726] I I I I GTTGGCCATCTTAATCATCTGGCAACTACTCTGGGTCGTCCT
[1727] CCGCGTCCTGGGCCCCCAGGCGGACCCCGCACGCCGCAAATAAG
[1728] AAACCTGCCAGCGCTCCCGGCGCCCCAGGGCGAGCCCGGTGACA
[1729] GAGCGTCATGGCGTGGGGCTTCTGGGGCCGACGCCGCCGGTGG
[1730] AGACGATGGAGAGCGCGGCGCAGACGGTGGGGACCCCGCAGAC
[1731] GTAGGAGACGACGCCCTCCTC
[1732] CAF05740.1 AJ620225.1 ATGGCGTGGGGCTTCTGGGGCCGACGCCGCCGGTGGAGACGAT 136
[1733] GGAGAGCGCGGCGCAGACGGTGGGGACCCCGCAGACGTAGGAG
[1734] ACGACGCCCTCCTCGCCGCTTTCGAGCTCGTCGAAGAGTAAGGAG
[1735] GCGCGGGGGGAGGTGGCGCAGACGCTACAGAAAATGGCGACGG
[1736] GGCAGACGCAGACGGACTCACAGAAAAAAGATAGTCATAAAACAG
[1737] TGGCAACCAAACTTTATAAGACGCTGCTACATCATAGGGTACTTAC
[1738] CACTTATATTCTGCGGCGAAAATACAACCGCCCAGAACTTTGCCAC
[1739] TCACTCGGACGACATGATAAGCAAAGGACCGTACGGGGGGGGCA
[1740] TGACTACCACCAAATTCACTCTGAGAATACTGTACGACGAGTTTAC
[1741] CAGGTTTATGAAC I I I I GGACTGTCAGTAACGAAGACCTAGACCTG
[1742] TGTAGATACGTGGGCTGCAAACTAATATTTTTTAAACACCCCACGG
[1743] TGGACTTTATAGTACAGATAAACACTCAGCCTCCTTTCTTAGACAC
[1744] GCACCTCACCGCGGCCAGCATACACCCGGGCATCATGATGCTCA
[1745] GCAAGAGACACATACTAATACCCTCTCTAAAGACCCGGCCCAGCA
[1746] GAAAACACAGGGTGGTCGTCAGGGTGGGCGCCCCAAGACTTTTTC
[1747] AGGACAAGTGGTACCCCCAGTCAGACCTGTGTGACACAGTTCTGC
[1748] TTTCCATATTCGCAACCGCCTGCGACTTGCAATATCCGTTCGGCTC
[1749] ACCACTAACTGACAACCCTTGCGTCAACTTCCAGATCCTGGGGCC
[1750] CCAGTACAAAAAACACCTTAGTATTAGCTCCACTATGGATGACACT
[1751] AACAAAGCACATTATGAAGAAAACTTATTTAATAAAACTGAACTATA
[1752] CAACACCTTTCAAACCATAGCTCAGCTTAGAGACACAGGACAAACT
[1753] GCAAACGCTAGTCCTAATTGGAATGAGGTCCAGAATACAGCAGCA
[1754] CTTCAGTTATCAGGTGCAAATGCCACTAGCAGCAAAGACACTTGGT
[1755] ATAAAGGTAATACATACACGAAAGACATATCAAAGTTAGCAGAAAA
[1756] AACCAGACAAAGATTTAAAGCTGCAACAATAGCAGCACTACCAAAC
[1757] TACCCCACAATAATGTCCACAGACCTATATGAATACCACTCAGGCA
[1758] TATACTCCAGCATATATTTATCAGCTGGCAGGAGCTACTTTGAAAC
[1759] CACCGGGGCCTACTCTGACATTATATACAACCCTTTCACAGACAAA
[1760] GGCACAGGCAACATAATCTGGATAGACTACCTCACAAAAGAAGAC
[1761] ACCATTTTTGTAAAAAACAAAAGCAAATGCGAGATAATGGACATGC
[1762] CCCTGTGGGCGGCCTGCACAGGATACACAGAG I I I I GTGCAAAGT ATACAGGCGACTCTGCCATTATCTACAATGCAAGAATACTCATAAG
[1763] ATGCCCATACACTGAGCCCATGTTAATAGACCACTCAGACCCAAAC
[1764] AAAGGCTTCGTTCCCTACTCATTTAACTTTGGCAACGGAAAGATGC
[1765] CCGGAGGCAGCTCCAACGTACCGATAAGAATGAGAGCCAAATGGT
[1766] ACGTGAACATATTCCACCAAAAGGAGGTTCTAGAGGCTATAGTACA
[1767] AAGCGGACCGTTCGGGTACAAGGGCGACATAAAATCAGCTGTACT
[1768] AGCCATGAAATACAGATTTCACTGGAAGTGGGGCGGAAACCCTAT
[1769] ATCCAAACAGGTCGTCAGGAATCCCTGCTCCAACTCCAGCTCATC
[1770] CGCGGCCCATAGAGGACCTCGCAGCGTACAAGCGGTTGACCCGA
[1771] AATACAATACCTCAGAGGTCACGTGGCACTCGTGGGACATTAGAC
[1772] GAGGACTCTTTGACAAAGCAGGTATTAAAAGAATGCAACAGGAATC
[1773] AGATGCTCTTTACATTCCTCCAGGACCAATCAAGAGACCTCGCAG
[1774] GGACACCAACGCCCAAGACCCAGAAGAGCAAAACGAAAGCTCAG
[1775] GTTTCAGAGTCCAGCAGCGACTCCCGTGGGTCCACTCCAGCCAAG
[1776] AGACGCAAAGCTTCCAAGAAGAGACGGAGGCGCAGGGGTCGGTA
[1777] CAAGACCAACTACTCCTCCAGCTCCGAGAGCAGCGAGTTCTCCGA
[1778] CTCCAGCACCAGCAACTCGCAACCCAAGTCCTCAAAGTCCAAGCA
[1779] GGGCACAGCCTACACCCCCTATTATCTTCCCAAGCATAA
[1780] CAF05741.1 AJ620226.1 ATGCGTTTTTCCAGGATTGCTCGCTCGAAAAGGAAAGTGCCACTG 137
[1781] CCAACACTGCCAATACCACCGCCGCCTGGGACTATGAGCTGGCG
[1782] CCCTCCGGTCCACAATGCCGCTGGAATCGACCGTAACTGGTTCGA
[1783] ATCCTGTTTCAGATCTCACGCTAGCAGTTGCGGCTGTGGAAA I I I I
[1784] ATTGGCCATCTTAATACTCTCGCTACTCGCTACGGCTTTACTCCTG
[1785] GGCCCGCGCCGCCGCCTGGTGGTCCAGGCCCGCGGCCGCCAGT
[1786] ACCAGTGAGGCCCCGGCACCTGGCCGGAGACGGTAACCAGCCCA
[1787] GGGCCCTGCCATGGCGTGGGGATGGTGGAGACGCAGACGCTGG
[1788] CCCACCTACAGAAGGTGGCGGCGCTGGAGACGCCGCAGGAGAGT
[1789] ACCGCGACGAAGACCTCGAAGAGCTGTTCGCCGCTATGGAAAGA
[1790] GACGAGTAA
[1791] CAF05742.1 AJ620226.1 ATGGTGGAGACGCAGACGCTGGCCCACCTACAGAAGGTGGCGGC 138
[1792] GCTGGAGACGCCGCAGGAGAGTACCGCGACGAAGACCTCGAAGA
[1793] GCTGTTCGCCGCTATGGAAAGAGACGAGTAAGGAGGCGCCGGTG
[1794] GGGAGGCGGCGGTACCGAAGGGGCTACAGACGCAGGGTCGCGG
[1795] TCAGACTGAGACGCAGACGCAGACGGGGACGTAAGAGACTTGTA
[1796] CTTACTCAGTGGCAGCCCCAGACCCGTAGAAAGTGCACCATCACC
[1797] GGGTACCTCCCGGTGGTATGGTGCGGCTACCTCCGGGCCGCCAA
[1798] AAACTATGCCTACCACTCTGACGACTCCACAAAGCAGCCGGACCC
[1799] CTTTGGGGGCGCGCTGAGCACTACCTCCTTTAACCTTAAGGTGCT
[1800] GTACGACCAGCACCAGAGAGGACTCAACAGGTGGTCTTTCCCTAA
[1801] CGACCAACTGGACCTAGCTCGCTACAGGGGGTGCACACTTACGTT
[1802] CTACAGACAGAAAGCCACTGACTTTATAGCTATTTATGACATCTCC
[1803] GCCCCATACAAACTAGACAAGTACAGCTCTCCCAGCTATCACCCC
[1804] GGCAACATGATAATGCAGAAAAAGAAAATTCTCATTCCCAGCTACG
[1805] ACACTAACCCCAGGGGCCGCCAAAAAATAGTAGTTAAAATCCCCC
[1806] CCCCTAAACTGTTCGTGGATAAGTGGTATGCACAGGAGGACCTGT
[1807] GCGACGTTAATCTTGTGACACTTGCGGTCAGCGCAGCTTCCTTTAC ACATCCGTTCGGCTCACCACTAACGAACAACCCTTGTGTAACCTTC
[1808] CAGGTACTTGACTCAATATACTATTCCGTAATAGGTTACGGTTCCT
[1809] CAGATCAGAAAAAAAAACAAGTACTTGAAACTCTCTATAACGAAAA
[1810] TGCATACTGGGCCTCACACTTAACTCCTTACTTTACCACTGGCCTT
[1811] AAAATTCCATATCCAGATACTAAGAATCCCAGCACTACTGCATCTG
[1812] TTACTCCAAACACGCTATTTACAACAGGTAGCTACGACTCAAACAT
[1813] TAAAATAGCAGGAGACAGCAACTACAACTGGTACCCCTACAACCTT
[1814] AAAAACAAAATAGACAAACTTCATAAAATTAGAGAACAATACTTTAA
[1815] ATGGGAAACAGATGAAGGCCCCCAAGCCACATCTGATTATGGCAA
[1816] ACACCACACTTGGACTAAACCCACCGATGACTACTACGAATACCAC
[1817] CTAGGTTTATTTAGTCCCATATTCATAGGACCCACCAGAAGCAACA
[1818] AACTATTTGCAACCGCCTACCAGGACGTTACTTACAACCCCCTAAA
[1819] CGACAAGGCGGTGGGAAACAAGTTCTGGTTTCAGTACAACACAAA
[1820] AGCAGACACCCAGGTGGCCAAACAAGGCTGCTACTGCATGCTAGA
[1821] AGACATTCCCCTCTGGGCCGCCATGTATGGCTACTCTGACTTTATA
[1822] GAGACCGAGCTAGGCCCCTTCCAAGACGCAGAGACGGTGGGCTA
[1823] TATCTGTGTAATATGCCCCTACACCGAGCCCCCCATGTACAACAAA
[1824] CACAATCCCATGCAGGGTTACGTGTTTTATGACTCGTTTTTTGGCA
[1825] ATGGCAAGTGGATAGACGGACGGGGACACATAGAGCCTTACTGG
[1826] CTCTGCCGCTGGAGGCCAGAAATGC I I I I CCAGCAGCAGGTTATG
[1827] AGAGACATTGTGCAGACCGGGCCCTGGAGCTATAAAGACGAAAGC
[1828] AAAAACTGTGTTCTGCCCATGAAGTATAAGTTCAGATTCACATGGG
[1829] GCGGCAATATGGTCTCCCAACAGACAATCAGAAACCCCTGCAAGA
[1830] CTGACGGACAACTTGCCCCCTCCGGTAGACAGCCTAGAGAAGTAC
[1831] AAGTTGTTGACCCACTCACCATGGGTCCCCGCTGGG I I I I CCACT
[1832] CCTGGGACTGGAGACGTGGCTACCTTAGTGAGACAGCTCTCAGAC
[1833] GCCTGCGAGAAAAACCACTCGACTATGAGGCGTATATGCAAAAAC
[1834] CAAAAAGACCTAGACTGTTCCCTGTTACAGAGGGCGACGACCAGT
[1835] CCCCGCAGCAAGGCGACGACTGGTGTTCAGAGGAAGAAAAGTCG
[1836] CCGCAGTTTACCGAAGAGACGACGCAGACGCTACAGCTCCAGCTC
[1837] CAGCGCCAGCTCCGGCGACAGCAGCGACTCGGAGAGCAGCTCCA
[1838] ACTCCTACAACACCACCTCCTCAAAACGCAAGCGGGCCTCCAAAT
[1839] AAACCCATTATTATTGGTCCGGCAGTAA
[1840] CAF05743.1 AJ620227.1 ATGCACTTTTCTCGAATAAGCAGAAAGAAAGGGAAAGTGCTACTGC 139
[1841] TTTGCGTGCCAGCAGTTAAGAAAAAACCAACTGCTATGAGCTTCTG
[1842] GAGACCTCCGATGCACAATGTCACGGGGATCCAACGCCTGTGGTA
[1843] CGAGTCCTTTCACCGTGGCCATGCTGCTTTTTGTGGTTGTGGGGA
[1844] TCCTGTACTTCACATTACTGCACTTGCTGAGACATATGGCCATCCA
[1845] ACAGGCCCGAGACCTTCTGGGTCATCGGGAATAGATCCCACTCCG
[1846] CCCATCCGTAGAGCCAGGCCTGCCCCGGCCGCTCCGGAACCCCC
[1847] ACAGGTTGACTCCAGACCGGCCCTGCCATGGCATGGAGATGGTG
[1848] GAAGCGACGGAGGCGCTGGTGGCTCCGCAAGCGGTGGACCCGT
[1849] GGCAGACTTCGCAGACGATGGCCTAGACCAGCTCGTCGCCGCCC
[1850] TAGACGACGAAGAGTAA
[1851] CAF05744.1 AJ620227.1 ATGGCATGGAGATGGTGGAAGCGACGGAGGCGCTGGTGGCTCCG 140
[1852] CAAGCGGTGGACCCGTGGCAGACTTCGCAGACGATGGCCTAGAC CAGCTCGTCGCCGCCCTAGACGACGAAGAGTAAGGAGACGCAGA
[1853] CGGTGGAGGAGGGGGCGACCCAGACGCAGGCTGTACCGACGCT
[1854] ACAGACGCAAAAAACGTAGGAGACGAAAGCCCAAAATAATCTTAAA
[1855] ACAATGGCAGCCAGACATTGTAAAGAGGTGCTACATAGTGGGCTA
[1856] CATTCCTGCCATAATATGTGGGGCGGGCACCTGGTCTCACAACTA
[1857] CACCAGCCACCTCCTAGACATTATCCCCAAAGGACCCTTTGGAGG
[1858] AGGGCACAGCACTATGAGGTTCTCCCTAAAAGTACTCTTTGAAGAA
[1859] CACCTCAGACACTTAAACTTTTGGACAAAAAGCAACCAGGACCTAG
[1860] AACTCATAAGATACTTTAGATGCTCCTTTAAATTCTATAGAGACCAA
[1861] GACACAGACTACATAGTACACTACAGCAGAAAAACTCCCCTGGGA
[1862] GGAAACAGACTAACAGCGCCTAGCCTACACCCCGGTGTACAGATG
[1863] CTTAGCAAAAACAAAATATTAGTACCTAGCTATGCTACAAAACCCAA
[1864] GGGTGGGAGCTATGTAAAAGTAACCATAGCACCCCCCACACTACT
[1865] AACTGACAAGTGGTACTTTAGCAAAGACATTTGTGACACAACCTTG
[1866] GTTAACTTAGACGTTGTACTCTGCAACTTGCGGTTTCCGTTCTGCT
[1867] CACCACAAACTGACAACCCTTGCATCACATTCCAAGTTCTGCATTC
[1868] CTTGTACAACGACTTCCTCTCCATAGTAGATACTGAAAATTACAAAA
[1869] CCACTTTTGTTACTACACTGACAACAAAATTAGGTACAACATGGGG
[1870] TTCAAGACTAAATACATTTAGAACAGAAGGCTGCTACTCACACCCT
[1871] AAACTACCTAAAAAACAACTAATTGCTGCAAATGACACAACATACTT
[1872] TACATCACCTGATGGGCTCTGGGGAGACGCAGTTTTCGACATCTC
[1873] AAAACCTCAAGTAATTACCGAAAATATGGAGTCTTACGCTAACTCA
[1874] GCCAAACAAAGAGGGGTGAACGGAGACCCCGCTTTTTGCCACCTA
[1875] ACAGGAATATACTCACCTCCCTGGCTAACACCAGGCAGAATATCC
[1876] CCTGAAACCCCAGGACTTTACACAGACGTGACTTACAACCCATAC
[1877] GCTGACAAAGGAGTAGGCAACAGAATATGGGTCGACTACTGCAGT
[1878] AAAAAAGGCAACAAATATGACAATACAAGTAAATGCCTTTTAGAAG
[1879] ACATGCCACTATGGATGGTATGCTTTGGATACGTAGACTGGGTAAA
[1880] AAAAGAGACTGGCAACTGGGGTATTCCACTATGGGCTAGAGTACT
[1881] TATCAGAAGCCCATACGCTGTTCCAAAACTGTATAATGAAGCAGAC
[1882] CCAAACTATGGATGGGTACCTATTTCTTACTACTTTGGAGAAGGCA
[1883] AAATGCCAAACGGAGACATGTACGTACCATTTAAAATAAGAATGAA
[1884] ATGGTACCCTTCAATGTGGAACCAAGAGCCAGTGTTAAATGACTTA
[1885] GCAAAGAGCGGACCGTTTGCATACAAAAACACAAAAACAAGCGTG
[1886] ACTGTGACTGCCAAATATAAATTTACATTTAACTTCGGGGGCAACC
[1887] CCGTACCCTCACAGATTGTACAAGATCCCTGCACACAGTCCACCTA
[1888] CGACATCCCCGGCACCGGTAACCTGCCTCGCAGAACACAAGTCAT
[1889] TGACCCGAAATTCCTCGGTCCCCACTATTCCTTCCACCGGTGGGA
[1890] CTTCAGGCGTGGCCTCTTTGGCTCACAAGCTATTAAGAGAGTGTC
[1891] AGAACAACCAACAACTTCTGAGTTTTTATTCTCAGGCCCAAAGAGA
[1892] CCCAGAATCGATCAAGGTCCTTACATCCCGCCAGAAAAAGACTCA
[1893] GGTTCACTCCAAAGAGAATCGAGACCGTGGAGCAGCTCGGAGAC
[1894] CGAGGCAGAGACAGAAGCCCCCTCGGAAGAAGAGCCGGAGAACC
[1895] AAGAAGAACAAGTACTCCAGTTGCAGCTCAGACAGCAGCTTCGAG
[1896] AACAGCGAAAACTCAGACAGGGAATCCAGTGCCTATTCGAGCAAC
[1897] TGATAACAACCCAACAGGGGGTCCACAAAAACCCATTGTTAGAGTA G
[1898] CAF05745.1 AJ620228.1 ATGCACTTTTCTCGAATAAGCAGAAAGAAAAGGAAAGTGCTACTGC 141
[1899] TTTGCGTGCCAGCAGTTAAGAAAAAACCAACTGCTATGAGCTTCTG
[1900] GAGACCTCCGATGCACAATGTCACGGGGATCCAACGCCTGTGGTA
[1901] CGAGTCCCTTCACCGTGGCCATGCTGCTTTTTGTGGTTGTGGGGA
[1902] TCCTGTACTTCACATTACTGCACTTGCTGAGACATATGGCCATCCA
[1903] ACAGGCCCGAGACCTTCTGGGTCATCGGGAATAGATCCCACTCCG
[1904] CCCATCCGTAGAGCCAGGCCTGCCCCGGCCGCTCCGGAACCCCC
[1905] ACAGGTTGACTCCAGACCGGCCCTGCCATGGCATGGAGATGGTG
[1906] GGAGCGACGGAGGCGCTGGTGGCTCCGCAAGCGGTGGACCCGT
[1907] GGCAGACTTCGCAGACGATGGCCTAGACCAGCTCGTCGCCGCCC
[1908] TAGACGACGAAGAGTAA
[1909] CAF05746.1 AJ620228.1 ATGGCATGGAGATGGTGGGAGCGACGGAGGCGCTGGTGGCTCCG 142
[1910] CAAGCGGTGGACCCGTGGCAGACTTCGCAGACGATGGCCTAGAC
[1911] CAGCTCGTCGCCGCCCTAGACGACGAAGAGTAAGGAGACGCAGA
[1912] CGGTGGAGGAGGGGGCGACCCAGACGCAGACTGTACCGACGCTA
[1913] CAGACGCAAAAAACGTAGGAGACGAAAGCCCAAAATAATCTTAAAA
[1914] CAATGGCAGCCAGACATTGTAAAGAGGTGCTACATAGTGGGCTAC
[1915] ATTCCTGCCATAATATGTGGGGCGGGCACCTGGTCTCACAACTAC
[1916] ACCAGCCACCTCCTAGACATTATCCCCAAAGGACCCTTTGGAGGA
[1917] GGGCACAGCACTATGAGGTTCTCCCTAAAAGTACTCTTTGAAGAAC
[1918] ACCTCAGACACTTAAAC I I I I GGACAAAAAGCAACCAGGACCTAGA
[1919] ACTCATAAGATACTTTAGATGCTCCTTTAAATTCTATAGAGACCAAG
[1920] ACACAGACTACATAGTACACTACAGCAGAAAAACTCCCCTGGGAG
[1921] GAAACAGACTAACAGCGCCTAGCCTACACCCCGGTGTACAGATGC
[1922] TTAGCAAAAACAAAATATTAGTACCTAGCTATGCTACAAAACCCAA
[1923] GGGTGGGAGCTATGTAAAAGTAACCATAGCACCCCCCACACTACT
[1924] AACTGACAAGTGGTACTTTAGCAAAGACATTTGTGACACAACCTTG
[1925] GTTAACTTAGACGTTGTACTCTGCAACTTGCGGTTTCCGTTCTGCT
[1926] CACCACAAACTGACAACCCTTGCATCACATTCCAAGTTCTGCATTC
[1927] CTTGTACAACGACTTCCTCTCTATAGTAGATACTGAAAATTACAAAA
[1928] CCAC I I I I GTTACTACACTGACAACAAAATTAGGTACAACATGGGG
[1929] TTCAAGACTAAATACATTTAGAACAGAAGGCTGCTACTCACACCCT
[1930] AAACTACCTAAAAAACAACTAATTGCTGCAAATGACACAACATACTT
[1931] TACATCACCTGATGGGCTCTGGGGAGACGCAG I I I I CGACATCTC
[1932] AAAACCTCAAGTAATTACCGAAAATATGGAGTCTTACGCTAACTCA
[1933] GCCAAACAAAGAGGGGTGAACGGAGACCCCGCTTTTTGCCACCTA
[1934] ACAGGAATATACTCACCTCCCTGGCTAACACCAGGCAGAATATCC
[1935] CCTGAAACCCCAGGACTTTACACAGACGTGACTTACAACCCATAC
[1936] GCTGACAAAGGAGTAGGCAACAGAATATGGGTCGACTACTGCAGT
[1937] AAAAAAGGCAACAAATATGACAATACAAGTAAATGCC I I I I AGAAG
[1938] ACATGCCACTATGGATGGTATGCTTTGGATACGTAGACTGGGTAAA
[1939] AAAAGAGACTGGCAANTGGGGTATTCCACTATGGGCTAGAGTACT
[1940] TATCAGAAGCCCATACACTGTTCCAAAACTGTATAATGAAGCAGAC
[1941] CCAAACTATGGATGGGTACCTATTTCTTACTACTTTGGAGAAGGCA
[1942] AAATGCCAAACGGAGACATGTACGTACCATTTAAAATGAGAATGAA ATGGCACCCTTCAATGTGGAACCAAGAGCCAGTGTTAAATGACTTA
[1943] GCAAAGAGCGGACCGTTTGCATACAAAAACACAAAAACAAGCGTG
[1944] ACTGTGACTGCCAAATATAAATTTACATTTAACTTCGGGGGCAACC
[1945] CCGTACCCTCACAGATTGTACAAGGTCCCTGCACACAGTCCACCT
[1946] ACGACATCCCCGGCACCGGTAACCTGCCTCGCAGAATACAGGTCA
[1947] TTGACCCGAAATTCCTCGGTCCCCACTATTCCTTCCACCGGTGGG
[1948] ACTTCAGGCGTGGCCTCTTTGGCTCACAAGCTATTAAGAGAGTGT
[1949] CAGAACAACCAACAACTTCTGAGTTTTTATTCTCAGGCCCAAAGAG
[1950] ACCCAGAATCGATCAAGGTCCTTACATCCCGCCAGAAAAAGACTC
[1951] AGGTTCACTCCAAAGAGAATCGAGACCGTGGAGCAGCTCGGAGAC
[1952] CGAGGCAGAGACAGAAGCCCCCTCGGAAGAAGAGCCGGAGAACC
[1953] AAGAAGAACAAGTACTCCAGTTGCAGCTCAGACAGCAGCTTCGAG
[1954] AACAGCGAAAACTCAGACAGGGAATCCAGTGCCTATTCGAGCAAC
[1955] TGATAACAACCCAACAGGGGGTCCACAAAAACCCATTGTTAGAGTA
[1956] G
[1957] CAF05747.1 AJ620229.1 ATGCACTTTTCTCGAATAAGCAGAAAGAAAAGGAAAGTGCTACTGC 143
[1958] TTTGCGTGCCAGCAGTTAAGAAAAAACCAACTGCTATGAGCTTCTG
[1959] GAGACCTCCGATGCACAATGTCACGGGGATCCAACGCCTGTGGTA
[1960] CGAGTCCCTTCACCGTGGCCATGCTGCTTTTTGTGGTTGTGGGGA
[1961] TCCTGTACTTCACATTACCGCACTTGCTGAGACATATGGCCATCCA
[1962] ACAGGCCCGAGACCTTCTGGGTCATCGGGAATAGATCCCACTCCG
[1963] CCCATCCGTAGAGCCAGGCCTGCCCCGGCCGCTCCGGAACCCCC
[1964] ACAGGTTGACTCCAGACCGGCCCTGCCATGGCATGGAGATGGTG
[1965] GAAGCGACGGAGGCGCTGGTGGCTCCGCAAGCGGTGGACCCGT
[1966] GGCAGACTTCGCAGACGATGGCCTAGACCAGCTCGTCGCCGCCC
[1967] TAGACGACGAAGAGTAA
[1968] CAF05748.1 AJ620229.1 ATGGCATGGAGATGGTGGAAGCGACGGAGGCGCTGGTGGCTCCG 144
[1969] CAAGCGGTGGACCCGTGGCAGACTTCGCAGACGATGGCCTAGAC
[1970] CAGCTCGTCGCCGCCCTAGACGACGAAGAGTAAGGAGACGCAGA
[1971] CGGTGGAGGAGGGGGCGACCCAGACGCAGACTGTACCGACGCTA
[1972] CAGACGCAAAAAACGTAGGAGACGAAAGCCCAAAATAATCTTAAAA
[1973] CAATGGCAGCCAGACATTGTAAAGAGGTGCTACATAGTGGGCTAC
[1974] ATTCCTGCCATAATATGTGGGGCGGGCACCTGGTCTCACAACTAC
[1975] ACCAGCCACCTCCTAGACATTATCCCCAAAGGACTCTTTGGAGGA
[1976] GGGCACAGCACTATGAGGTTCTCCCTAAAAGTACTCTTTGAAGAAC
[1977] ACCTCAGACACTTAAAC I I I I GGACAAAAAGCAACCAGGACCTAGA
[1978] ACTCATAAGATACTTTAGATGCTCCTTTAAATTCTATAGAGACCAAG
[1979] ACACAGACTACATAGTACACTACAGCAGAAAAACTCCCCTGGGAG
[1980] GAAACAGACTAACAGCGCCTAGCCTACACCCCGGTGTACAGTTGC
[1981] TTAGCAAAAACAAAATATTAGTACCTAGCTATGCTACAAAACCCAA
[1982] GGGTGGGAGCTATGTAAAAGTAACCATAGCACCCCCCACACTACT
[1983] AACTGACAAGTGGTACTTTAGCAAAGACATTTGTGACACAACCTTG
[1984] GTTAACTTAGACGTTGTACTCTGCAACTTGCGGTTTCCGTTCTGCT
[1985] CACCACAAACTGACAACCCTTGCATCACATTCCAAGTTCTGCATTC
[1986] CTTGTACAACGACTTCCTCTCTATAGTAGATACTGAAAATTACAAAA
[1987] CCAC I I I I GTTACTACACTGACAACAAAATTAGGTACAACATGGGG TTCAAGACTAAATACATTTAGAACAGAAGGCTGCTACTCACACCCT
[1988] AAACTACCTAAAAAACAACTAATTGCTGCAAATGACACAACATACTT
[1989] TACATCACCTGATGGGCTCTGGGGAGACGCAG I I I I CAACATCTC
[1990] AAAACCTCAAGTAATTACCGAAAATATGGAGTCTTACGCTAACTCA
[1991] GCCAAACAAAGAGGGGTGAACGGAGACCCCGCTTTTTGCCACCTA
[1992] ACAGGAATATACTCACCTCCCTGGCTAACACCAGGCAGAATATCC
[1993] CCTGAAACCCCAGGACTTTACACAGACGTGACTTACAACCCATAC
[1994] GCTGACAAAGGAGTAGGCAACAGAATATGGGTCGACTACTGCAGT
[1995] AAAAAAGGCAACAAATATGACAATACAAGTAAATGCC I I I I AGAAG
[1996] ACATGCCACTATGGATGGTATGCTTTGGATACGTAGACTGGGTAAA
[1997] AAAAGAGACTGGCAACTGGGGTATTCCACTATGGGCTAGAGTACT
[1998] TATCAGAAGCCCATACACTGTTCCAAAACTGTATAATGAAGCAGAC
[1999] CCAAACTATGGATGGGTACCTATTTCTTACTACTTTGGAGAAGGCA
[2000] AAATGCCAAACGGAGACATGTACGTACCATTTAAAATAAGAATGAA
[2001] ATGGCACCCTTCAATGTGGAACCAAGAGCCAGTGTTAAATGACTTA
[2002] GCAAAGAGCGGACCGTTTGCATACAAAAACACAAAAACAAGCGTG
[2003] ACTGTGACTGCCAAATATAAATTTACATTTAACTTCGGGGGCAACC
[2004] CCGTACCCTCACAGATTGTACAAGATCCCTGCACACAGTCCACCTA
[2005] CGACATCCCCGGCACCGGTAACCTGCCTCGCAGAATACAAGTCAT
[2006] TGACCCGAAATTCCTCGGTCCCCACTATTCCTTCCACCGGTGGGA
[2007] CTTCAGGCGTGGCCTCTTTGGCTCACAAGCTATTAAGAGAGTGTC
[2008] AGAACAACCAACAACTTCTGAGTTTTTATTCTCAGGCCCAAAGAGA
[2009] CCCAGAATCGATCAAGGTCCTTACATCCCGCCAGAAAAAGACTCA
[2010] GGTTCACTCCAAAGAGAATCGAGACCGTGGAGCAGCTCGGAGAC
[2011] CGAGGCAGAGACAGAAGCCCCCTCGGAAGAAGAGCCGGAGAACC
[2012] AAGAAGAACAAGTACTCCAGTTGCAGCTCAGACAGCAGCTTCGAG
[2013] AACAGCGAAAACTCAGACAGGGAATCCAGTGCCTATTCGAGCAAC
[2014] TGATAACAACCCAACAGGGGGTCCACAAAAACCCATTGTTAGAGTA
[2015] G
[2016] CAF05780.1 AJ620230.1 ATGCACTTTTCTCGAATAAGCAGAAAGAAAAGGAAAGTGCTACTGC 145
[2017] TTTGCGTGCCAGCAGCTAAGAAAAAACCAACTGCTATGAGCTTCTG
[2018] GAAACCTCCGGTACACAATGTCACGGGGATCCAACGCATGTGGTA
[2019] TGAGTCCTTTCACCGTGGCCACGCTTCTTTTTGTGGTTGTGGGAAT
[2020] CCTATACTTCACATTACTGCACTTGCTGAAACATATGGCCATCCAA
[2021] CAGGCCCGAGACCTTCTGGGCCACCGGGAGTAGACCCCAACCCC
[2022] CACATCCGTAGAGCCAGGCCTGCCCCGGCCGCTCCGGGGCCCTC
[2023] ACAGGTTGATTCGAGACCAGCCCTGACATGGCATGGGGATGGTG
[2024] GAAGCGACGGAGGCGCTGGTGGTTCCGGAAGCGGTGGACCCGT
[2025] GGCAGACTTCGCAGACGATGGCCTCGATCAGCTCGTCGCCGCCC
[2026] TAGACGACGAAGAGTAA
[2027] CAF05781.1 AJ620230.1 ATGGCATGGGGATGGTGGAAGCGACGGAGGCGCTGGTGGTTCCG 146
[2028] GAAGCGGTGGACCCGTGGCAGACTTCGCAGACGATGGCCTCGAT
[2029] CAGCTCGTCGCCGCCCTAGACGACGAAGAGTAAGGAGGCGCAGA
[2030] CGGTGGAGGAGGGGGAGACGAAAAACAGGGACTTACAGACGCAG
[2031] GAGACGCTTTAGACGCAGGAGACGAAAAGCAAAACTTATAATAAAA
[2032] CTGTGGCAACCTGCAGTAATTAAAAGATGCAGAATAAAGGGATACA TACCACTGATTATAAGTGGGAACGGTACCTTTGCCACAAACTTTAC
[2033] CAGTCACATAAATGACAGAATAATGAAAGGCCCCTTCGGGGGAGG ACACAGCACTATGAGGTTCAGCCTCTACA I I I I GTTTGAGGAGCAC CTCAGACACATGAACTTCTAG
[2034] CAF05782.1 AJ620230.1 ATGGCAGTTGAGGCTGACTTGCGGTTTCCGTTCTGCTCACCACAA 147
[2035] ACTGACAACACTTGCATCAGCTTCCAGGTCCTTAGTTCCGTTTACA
[2036] ACAACTACCTCAGTATTAATACCTTTAATAATGACAACTCAGACTCA
[2037] AAGTTAAAAGAATTTTTAAATAAAGCATTTCCGACAACAGGCACAAA
[2038] AGGAACAAGTTTAAATGCACTAAATACATTTAGAACAGAAGGATGC
[2039] ATAAGTCACCCACAACTAAAAAAACCAAACCCACAAATAAACAAAC
[2040] CATTAGAGTCACAATACTTTGCACCTTTAGATGCCCTCTGGGGAGA
[2041] CCCCATATACTATAATGATCTAAATGAAAACAAAAGTTTGAACGATA
[2042] TCATTGAGAAAATACTAATAAAAAACATGATTACATACCATGCAAAA
[2043] CTAAGAGAATTTCCAAATTCATACCAAGGAAACAAGGCC I I I I GCC
[2044] ACCTAACAGGCATATACAGCCCACCATACCTAAACCAAGGCAGAAT
[2045] ATCTCCAGAAATATTTGGACTGTACACAGAAATAATTTACAACCCTT
[2046] ACACAGACAAAGGAACTGGAAACAAAGTATGGATGGACCCACTAA
[2047] CTAAAGAGAACAACATATATAAAGAAGGACAGAGCAAATGCCTACT
[2048] GACTGACATGCCCCTATGGACTTTACTTTTTGGATATACAGACTGG
[2049] TGTAAAAAGGACACTAATAACTGGGACTTACCACTAAACTACAGAC
[2050] TAGTACTAATATGCCCTTATACCTTTCCAAAATTGTACAATGAAAAG
[2051] GTAAAAGACTATGGGTACATCCCGTACTCCTACAAATTCGGAGCG
[2052] GGTCAGATGCCAGACGGCAGCAACTACATACCCTTTCAGTTTAGA
[2053] GCAAAGTGGTACCCCACAGTACTACACCAGCAACAGGTAATGGAG
[2054] GACATAAGCAGGAGCGGGCCCTTTGCACCTAAGGTAGAAAAACCA
[2055] AGCACTCAGCTGGTAATGAAGTACTG I I I I AACTTTAACTGGGGCG
[2056] GTAACCCTATCATTGAACAGATTGTTAAAGACCCCAGCTTCCAGCC
[2057] CACCTATGAAATACCCGGTACCGGTAACATCCCTAGAAGAATACAA
[2058] GTCATCGACCCGCGGGTCCTGGGACCGCACTACTCGTTCCGGTC
[2059] ATGGGACATGCGCAGACACACATTTAGCAGAGCAAGTATTAAGAG
[2060] AGTGTCAGAACAACAAGAAACTTCTGACCTTGTATTCTCAGGCCCA
[2061] AAAAAGCCTCGGGTCGACATCCCAAAACAAGAAACCCAAGAAGAA
[2062] AGCTCACATTCACTCCAAAGAGAATCGAGACCGTGGGAGACCGAG
[2063] GAAGAAAGCGAGACAGAAGCCCTCTCGCAAGAGAGCCAAGAGGT
[2064] CCCCTTCCAACAGCAGTTGCAGCAGCAGTACCAAGAGCAGCTCAA
[2065] GCTCAGACAGGGAATCAAAGTCCTCTTCGAGCAGCTCATAAGGAC
[2066] CCAACAAGGGGTCCATGTAAACCCATGCCTACAGTAG
[2067] CAF05749.1 AJ620231.1 ATGCACTTTTCTCGAATAAGCAGAAAGAAAAGGAAAGTGCTACTGC 148
[2068] TTTGCGTGCCAGCAGCTAAGAAAAAACCAACTGCTATGAGCTTCTG
[2069] GAAACCTCCGGTACACAATGTCACGGGGATCCAACGCATGTGGTA
[2070] TGAGTCCTTTCACCGTGGCCACGCTTCTTTTTGTGGTTGTGGGAAT
[2071] CCTATACTTCACATTACTGCACTTGCTGAAACATATGGCCATCCAA
[2072] CAGGCCCGAGACCTTCTGGGCCACCGGGAGTAGACCCCAACCCC
[2073] CACATCCGTAGAGCCAGGCCTGCCCCGGCCGCTCCGGAGCCCTC
[2074] ACAGGTTGATTCGAGACCAGCCCTGACATGGCATGGGGATGGTG
[2075] GAAGCGACGGAGGCGCTGGTGGTTCCGGAAGCGGTGGACCCGT GGCAGACTTCGCAGACGATGGCCTCGATCAGCTCGTCGCCGCCC
[2076] TAGACGACGAAGAGTAA
[2077] CAF05750.1 AJ620231.1 ATGGCATGGGGATGGTGGAAGCGACGGAGGCGCTGGTGGTTCCG 149
[2078] GAAGCGGTGGACCCGTGGCAGACTTCGCAGACGATGGCCTCGAT
[2079] CAGCTCGTCGCCGCCCTAGACGACGAAGAGTAAGGAGGCGCAGA
[2080] CGGTGGAGGAGGGGGAGACGAAAAACAAGGACTTACAGACGCAG
[2081] GAGACGCTTTAGACGCAGGGGACGAAAAGCAAAACTTATAATAAA
[2082] ACTGTGGCAACCTGCAGTAATTAAAAGATGCAGAATAAAGGGATAC
[2083] ATACCACTGATTATAAGTGGGAACGGTACCTTTGCCACAAACTTTA
[2084] CCAGTCACATAAATGACAGAATAATGAAAGGCCCCTTCGGGGGAG
[2085] GACACAGCACTATGAGGTTCAGCCTCTACA I I I I GTTTGAGGAGCA
[2086] CCTCAGACACATGAACTTCTGGACCAGAAGCAACGATAACCTAGA
[2087] GCTAACCAGATACTTGGGGGCTTCAGTAAAAATATACAGGCACCC
[2088] AGACCAAGACTTTATAGTAATATACAACAGAAGAACCCCTCTAGGA
[2089] GGCAACATCTACACAGCACCCTCTCTACACCCAGGCAATGCCATTT
[2090] TAGCAAAACACAAAATATTAGTACCAAGTTTACAGACAAGACCAAA
[2091] GGGTAGAAAAGCAATTAGACTAAGAATAGCACCCCCCACACTCTTT
[2092] ACAGACAAGTGGTACTTTCAAAAGGACATAGCCGACCTCACCCTTT
[2093] TCAACATCATGGCAGTTGAGGCTGACTTGCGGTTTCCGTTCTGCTC
[2094] ACCACAAACTGACAACACTTGCATCAGCTTCCAGGTCCTTAGTTCC
[2095] GTTTACAACAACTACCTCAGTATTAATACCTTTAATAATGACAACTC
[2096] AGACTCAAAGTTAAAAGAATTTTTAAATAAAGCATTTCCAACAACAG
[2097] GCACAAAAGGAACAAGTTTAAATGCACTAAATACATTTAGAACAGA
[2098] AGGATGCATAAGTCACCCACAACTAAAAAAACCAAACCCACAAATA
[2099] AACAAACCATTAGAGTCACAATACTTTGCACCTTTAGATGCCCTCT
[2100] GGGGAGACCCCATATACTATAATGATCTAAATGAAAACAAAAGTTT
[2101] GAACGATATCATTGAGAAAATACTAATAAAAAACATGATTACATACC
[2102] ATGCAAAACTAAGAGAATTTCCAAATTCATACCAAGGAAACAAGGC
[2103] C I I I I GCCACCTAACAGGCATATACAGCCCACCATACCTAAACCAA
[2104] GGCAGAATATCTCCAGAAATATTTGGACTGTACACAGAAATAATTT
[2105] ACAACCCTTACACAGACAAAGGAACTGGAAACAAAGTATGGATGG
[2106] ACCCACTAACTAAAGAGAACAACATATATAAAGAAGGACAGAGCAA
[2107] ATGCCTACTGACTGACATGCCCCTATGGACTTTACTTTTTGGATAT
[2108] ACAGACTGGTGTAAAAAGGACACTAATAACTGGGACTTACCACTAA
[2109] ACTACAGACTAGTACTAATATGCCCTTATACCTTTCCAAAATTGTAC
[2110] AATGAAAAAGTAAAAGACTATGGGTACATCCCGTACTCCTACAAAT
[2111] TCGGAGCGGGTCAGATGCCAGACGGCAGCAACTACATACCCTTTC
[2112] AGTTTAGAGCAAAGTGGTACCCCACAGTACTACACCAGCAACAGG
[2113] TAATGGAGGACATAAGCAGGAGCGGGCCCTTTGCACCTAAGGTAG
[2114] AAAAACCAAGCACTCAGCTGGTAATGAAGTACTG I I I I AACTTTAA
[2115] CTGGGGCGGTAACCCTATCATTGAACAGATTGTTAAAGACCCCAG
[2116] CTTCCAGCCCACCTATGAAATACCCGGTACCGGTAACATCCCTAG
[2117] AAGAATACAAGTCATCGACCCGCGGGTCCTGGGACCGCACTACTC
[2118] GTTCCGGTCATGGGACATGCGCAGACACACATTTAGCAGAGCAAG
[2119] TATTAAGAGAGTGTCAGAACAACAAGAAACTTCTGACCTTGTATTC
[2120] TCAGGCCCAAAAAAGCCTCGGGTCGACATCCCAAAACAAGAAACC CAAGAAGAAAGCTCACATTCACTCCAAAGAGAATCGAGACCGTGG
[2121] GAGACCGAGGAAGAAAGCGAGACAGAAGCCCTCTCGCAAGAGAG CCAAGAGGTCCCCTTCCAACAGCAGTTGCAGCAGCAGTACCAAGA GCAGCTCAAGCTCAGACAGGGAATCAAAGTCCTCTTCGAGCAGCT CATAAGGACCCAACAAGGGGTCCATGTAAACCCATGCCTACGGTA G
[2122] CAF05751.1 AJ620232.1 ATGCACTTTTCTCGAATAAGCAGAAAGAAAAGGAAAGTGCTACTGC 150
[2123] TTTGCGTGCCAGCAGCTAAGAAAAAACCAACTGCTATGAGCTTCTG
[2124] GAAACCTCCGGTACACAATGTCACGGGGATCCAACGCATGTGGTA
[2125] TGAGTCCTTTCACCGTGGCCACGCTTCTTTTTGTGGTTGTGGGAAT
[2126] CCTATACTTCACATTACTGCACTTGCTGAAACATATGGCCATCCAA
[2127] CAGGCCCGAGACCTTCTGGGCCACCGGGAGTAGACCCCAACCCC
[2128] CACATCCGTAGAGCCAGGCCTGCCCCGGCCGCTCCGGAGCCCTC
[2129] ACAGGTTGATTCGAGACCAGCCCTGACGTGGCATGGGGATGGTG
[2130] GAAGCGACGGAGGCGCTGGTGGTTCCGGAAGCGGTGGACCCGT
[2131] GGCAGACTTCGCAGACGATGGCCTCGATCAGCTCGTCGCCGCCC
[2132] TAGACGACGAAGAGTAA
[2133] CAF05752.1 AJ620232.1 ATGAAAGGCCCCTTCGGGGGAGGACACAGCACTATGAGGTTCAG 151
[2134] CCTCTACA I I I I GTTTGAGGAGCGCCTCAGACACATGAACTTCTGG
[2135] ACCAGAAGCAACGATAACCTAGAGCTAACCAGATACTTGGGGGCT
[2136] TCAGTAAAAATATACAGGCACCCAGACCAAGACTTTATAGTAATAT
[2137] ACAACAGAAGAACCCCTCTAGGAGGCAACATCTACACAGCACCCT
[2138] CTCTACACCCAGGCAATGCCA I I I I AGCAAAACACAAAATATTAGT
[2139] ACCAAGTTTACAGACAAGACCAAAGGGTAGAAAAGCAATTAGACTA
[2140] AGAATAGCACCCCCCACACTCTTTACAGACAAGTGGTACTTTCAAA
[2141] AGGACATAGCCGACCTCACCC I I I I CAACATCATGGCAGTTGAGG
[2142] CTGACTTGCGGTTTCCGTTCTGCTCACCACAAACTGGCAACACTTG
[2143] CATCAGCTTCCAGGTCCTTAATTCCGTTTACAACAACTACCTCAGT
[2144] ATTAATACCTTTAATAATGACAACTCAGACTCAAAGTTAAAAGAATT
[2145] TTTAAATAAAGCATTTCCAACAACAGGCACAAAAGGAACAAGTTTA
[2146] AATGCACTAAATACATTTAGAACAGAAGGATGCATAAGTCACCCAC
[2147] AACTAAAAAAACCAAACCCACAAATAAACAAACCATTAGATTCACAA
[2148] TACTTTGCACCTTTAGACGCCCTCTGGGGAGACCCCATATACTATA
[2149] ATGATCTAAATGAAAAGAAAAGTTTGAAGGATATCATTGAGAACAT
[2150] ACTAATAAAAAACATGATTACATACCATGAAAAACTAAGAGAGTTTC
[2151] CAAATTCATACCAAGGAAACAAGGCC I I I I GCCACCTAACAGGCAT
[2152] ATACAGCCCACCATACCTAAACCAAGGCAGAATATCTCCAGAAATA
[2153] TTTGGACTGTACACAGAAATAATTTACAACCCTTACACAGACAAAG
[2154] GAACTGGAAACAAAGTATGGATGGACCCACTAACTAAAGAGAACA
[2155] ACATATATAAAGAAGGACAGAGCAAATGCCTACTGACTGACATGCC
[2156] CCTATGGACTTTACTTTTTGGATATACAGACTGGTGTAAAAAGGAC
[2157] ACTAATAACTGGGACTTACCACTAAACTACAGACTAGTACTAATAT
[2158] GCCCTTATACCTTTCCAAAATTGTACAATGAAAAGGTAAAAGACTAT
[2159] GGGTACATCCCGTACTCCTACAAATTCGGAGCGGGTCAGATGCCA
[2160] GACGGCAGCAACTACATACCCTTTCAGTTTAGAGCAAAGTGGTAC
[2161] CCCACAGTACTACACCAGCAACAGGTAATGGAGGACATAAGCAGG AGCGGGCCCTTTGCACCTAAGGTAGAAAAACCAGGCACTCAGCTG
[2162] GTAATGAAGTACTG I I I I AACTTTAACTGGGGCGGTAACCCTATCA
[2163] TTGAACAGATTGTTAAAGACCCCAGCTTCCAGCCCACCTATGAAAT
[2164] ACCCGGTACCGGTGACATCCCTAGAAGAATACAAGTCATCGACCC
[2165] GCGGGTCCTGGGACCGCACTACTCGTTCCGGTCATGGGACACGC
[2166] GCAGACACACATTTAGCAGAGCAAGTATTAAGAGAGTGTCAGAAC
[2167] AACAAGAAGCTTCTGACCTTGTATTCTCAGGCCCAAAAAAGCCTCG
[2168] GGTCGACATCCCAAAACAAGAAACCCAAGAAGAAAGCTCACATTC
[2169] ACTCCAAAGAGAATCGAGACCGTGGGAGACCGAGGAAGAAAGCG
[2170] AGACAGAAGCCCTCTCGCAAGAGAGCCAAGAGGTCCCCTTCCAAC
[2171] AGCAGTTGCAGCAGCAGTACCAAGAGCAGCTCAAGCTCAGACAGG
[2172] GAATCAAAGTCCTCTTCGAGCAGCTCATAAGGACCCAACAAGGGG
[2173] TCCATGTAAACCCATGCCTACAGTAG
[2174] CAF05753.1 AJ620233.1 ATGCACTTTTCTCGAATAAGCAGAAAGAAAAGGAAAGTGCTACTGC 152
[2175] TTTGCGTGCCAGCAGCTAAGAAAAAACCAACTGCTATGAGCTTCTG
[2176] GAAACCTCCGGTACACAATGTCACGGGGATCCAACGCATGTGGTA
[2177] TGAGTCCTTTCACCGTGGCCACGCTTCTTTTTGTGGTTGTGGGAAT
[2178] CCTATACTTCACATTACTGCACTTGCTGAAACATATGGCCGTCCAA
[2179] CAGGCCCGAGACCTTCTGGGCCACCGGGAGTAGACCCCAACCCC
[2180] CACATCCGTAGAGCCAGGCCTGCCCCGGCCGCTCCGGAGCCCTC
[2181] ACAGGTTGATTCGAGACCAGCCCTGACATGGCATGGGGATGGTG
[2182] GAAGCGACGGAGGCGCTGGTGGTTCCGGAAGCGGTGGACCCGT
[2183] GGCAGACTTCGCAGACGATGGCCTCGATCAGCTCGTCGCCGCCC
[2184] TAGACGACGAAGAGTAA
[2185] CAF05754.1 AJ620233.1 ATGGCATGGGGATGGTGGAAGCGACGGAGGCGCTGGTGGTTCCG 153
[2186] GAAGCGGTGGACCCGTGGCAGACTTCGCAGACGATGGCCTCGAT
[2187] CAGCTCGTCGCCGCCCTAGACGACGAAGAGTAAGGGGGCGCAGA
[2188] CGGTGGAGGAGGGGGAGACGAAAAACAAGGACTTACAGACGCAG
[2189] GAGACGCTTTAGACGCAGGAGACGAAAAGCAAAACTTATAGTAAA
[2190] ACTGTGGCAACCTGCAGTAATTAAAAGATGCAGAATAAAGGGATAC
[2191] ATACCACTGATTATAGGTGGGAACGGTACCTTTGCCACAAACTTTA
[2192] CCAGTCACATAAATGACAGAATAATGAAAGGCCCCTTCGGGGGAG
[2193] GACACAGCACTATGAGGTTCAGCCTCTACA I I I I GTTTGAGGAGCA
[2194] CCTCAGACACATGAACTTCTGGACCAGAAGCAACGATAACCTAGA
[2195] GCTAACCAGATACTTGGGGGCTTCAGTAAAAATATACAGGCACCC
[2196] AGACCAAGACTTTATAGTAATATACAACAGAAGAACCCCTCTAGGA
[2197] GGCAACATCTACACAGCACCCTCTCTACACCCAGGCAATGCCATTT
[2198] TAGCAAAACACAAAATATTAGTACCAAGTTTACAGACAAGACCAAA
[2199] GGGTAGAAAAGCAATTAGACTAAGAATAGCACCCCCCACACTCTTT
[2200] ACAGACAAGTGGTACTTTCAAAAGGACATAGCCGACCTCACCCTTT
[2201] TCAACATCATGGCAGTTGAGGCTGACTTGCGGTTTCCGTTCTGCTC
[2202] ACCACAAACTGACAACACTTGCATCAGCTTCCAGGTCCTTAGTTCC
[2203] GTTTACAACAACTACCTCAGTATTAATACCTTTAATAATGACAACTC
[2204] AGACTCAAAGTTAAAAGAATTTTTAAATAAAGCATTTCCAACAACAG
[2205] GCACAAAAGGAACAAGTTTAAATGCACTAAATACATTTAGAACAGA
[2206] AGGATGCATAAGTCACCCACAACTAAAAAAACCAAACCCACAAATA AACAAACCATTAGAGTCACAATACTTTGCACCTTTAGATGCCCTCT
[2207] GGGGAGACCCCATATACTATAATGATCTAAATGAAAACAAAAGTTT
[2208] GAACGATATCATTGAGAAAATACTAATAAAAAACATGATTACATACC
[2209] ATGCAAAACTAAGAGAATTTCCAAATTCATACCAAGGAAACAAGGC
[2210] C I I I I GCCACCTAACAGGCATATACAGCCCACCATACCTAAACCAA
[2211] GGCAGAATATCTCCAGAAATATTTGGACTGTACACAGAAATAATTT
[2212] ACAACCCTTACACAGACAAAGGAACTGGAAACAAAGTATGGATGG
[2213] ACCCACTAACTAAAGAGAACAACATATATAAAGAAGGACAGAGCAA
[2214] ATGCCTACTGACTGACATGCCCCTATGGACTTTACTTTTTGGATAT
[2215] ACAGACTGGTGTAAAAAGGACACTAATAACTGGGACTTACCACTAA
[2216] ACTACAGACTAGTACTAATATGCCCTTATACCTTTCCAAAATTGTAC
[2217] AATGAAAAGGTAAAAGACTATGGGTACATCCCGTACTCCTACAAAT
[2218] TCGGAGCGGGTCAGATGCCAGACGGCAGCAACTACATACCCTTTC
[2219] AGTTTAGAGCAAAGTGGTACCCCACAGTACTACACCAGCAACAGG
[2220] TAATGGAGGACATAAGCAGGAGCGGGCCCTTTGTACCTAAGGTAG
[2221] AAAAACCAAGCACTCAGCTGGTAATGAAGTACTG I I I I AACTTTAA
[2222] CTGGGGCGGTAACCCTATCATTGAACAGATTGTTAAAGACCCCAG
[2223] CTTCCAGCCCACCTATGAAATACCCGGTACCGGTAACATCCCTAG
[2224] AAGAATACAAGTCATCGACCCGCGGGTCCTGGGACCGCACTACTC
[2225] GTTCCGGCCATGGGACATGCGCAGACACACATTTAGCAGAGCAAG
[2226] TATTAAGAGAGTGTCAGAACAACAAGAAACTTCTGACCTTGTATTC
[2227] TCAGGCCCAAAAAAGCCTCGGGTCGACATCCCAAAACAAGAAACC
[2228] CAAGAAGAAAGCTCACATTCACTCCAAAGAGAATCGAGACCGTGG
[2229] GAGACCGAGGAAGAAAGCGAGACAGAAGCCCTCTCGCAAGAGAG
[2230] CCAAGAGGTCCCCTTCCAACAGCAGTTGCAGCAGCAGTACCAAGA
[2231] ACAGCTCAAGCTCAGACAGGGAATCAAAGTCCTCTTCGAGCAGCT
[2232] CATAAGGACCCAACAAGGGGTCCATGTAAACCCATGCCTACAGTA
[2233] G
[2234] CAF05755.1 AJ620234.1 ATGCACTTTTCTCGAATAAGCAGAAAGAAAAGGAAAGTGCTACTGC 154
[2235] TTTGCGTGCCAGCAGCTAAGAAAAAACCAACTGCTATGAGCTTCTG
[2236] GAAACCTCCGGTACACAATGTCACGGGGATCCAACGCATGTGGTA
[2237] TGGGTCCTTTCACCGTGGCCACGCTTCTTTTTGTGGTTGTGGGAAT
[2238] CCTATACTTCACATTACTGCACTTGCTGAAACATATGGCCATCCAA
[2239] CAGGCCCGAGACCTTCTGGGCCACCGGGAGTAGACCCCAACCCC
[2240] CACATCCGTAGAGCCAGGCCTGCCCCGGCCGCTCCGGAGCCCTC
[2241] ACAGGTTGATTCGAGACCAGCCCTGACATGGCATGGGGATGGTG
[2242] GAAGCGACGGAGGCGCTGGTGGTCCCGGAAGCGGTGGACCCGT
[2243] GGCAGACTTCGCAGACGATGGCCTCGATCAGCTCGTCGCCGCCC
[2244] TAGACGACGAAGAGTAA
[2245] CAF05756.1 AJ620234.1 ATGGCATGGGGATGGTGGAAGCGACGGAGGCGCTGGTGGTCCCG 155
[2246] GAAGCGGTGGACCCGTGGCAGACTTCGCAGACGATGGCCTCGAT
[2247] CAGCTCGTCGCCGCCCTAGACGACGAAGAGTAAGGAGGCGCAGA
[2248] CGGTGGAGGAGGGGGAGACGAAAAACAAGGACTTACAGACGCAG
[2249] GAGACGCTTTAGACGCAGGAGACGAAAAGCAAAACTTATAATAAAA
[2250] CTGTGA
[2251] CAF05757.1 AJ620234.1 ATGAAAGGCCCCTTCGGGGGAGGACACAGCACTATGAGGTTCAG 156 CCTCTACATTTTGTTTGAGGAGCACCTCAGACACATGAACTTCTGG
[2252] ACCAGAAGCAACGATAACCTAGAGCTAACCAGATACTTGGGGGCT
[2253] TCAGTAAAAATATACAGGCACCCAGACCAAGACTTTATAGTAATAT
[2254] ACAACAGAAGAACCCCTCTAGGAGGCAACATCTACACAGCACCCT
[2255] CTCTACACCCAGGCAATGCCA I I I I AGCAAAACACAAAATATTAGT
[2256] ACCAAGTTTACAGACAAGACCAAAGGGTAGAAAAGCAATTAGACTA
[2257] AGAATAGCACCCCCCACACTCTTTACAGACAAGTAG
[2258] CAF05758.1 ATGGCAGTTGAGGCTGACTTGCGGTTTCCGTTCTGCTCACCACAA 157
[2259] ACTGACAACACTTGCATCAGCTTCCAGGTCCTTAGTTCCGTTTACA
[2260] ACAACTACCTCAGTATTAATACCTTTAATAATGACAACTCAGACTCA
[2261] AAGTTAAAAGAATTTTTAAATAAAGCATTTCCAACAACAGGCACAAA
[2262] AGGAACAAGTTTAAATGCACTAAATACATTTAGAACAGAAGGATGC
[2263] ATAAGTCACCCACAACTAAAAAAACCAAACCCACAAACAAACAAAC
[2264] CATCAGAGTCACAATACTTTGCACCTTTAGATGCCCTCTGGGGAGA
[2265] CCCC...
Claims
What is claimed is:
1. A synthetic curon comprising:(i) a genetic element comprising a promoter element and a nucleic acid sequence encoding an exogenous effector, and a protein binding sequence, wherein the genetic element comprises one or both of:(a) a sequence having at least 85% sequence identity to the Anellovirus 5' UTR conserved domain nucleotide sequence of nucleotides 323 - 393 of the nucleic acid sequence of Table 11 , or(b) a sequence having at least 85% sequence identity to the Anellovirus GC-rich region of nucleotides 2868 - 2929 of the nucleic acid sequence of Table 11;and(ii) a proteinaceous exterior; wherein the genetic element is enclosed within the proteinaceous exterior; andwherein the synthetic curon is capable of delivering the genetic element into a eukaryotic cell.
2. The synthetic curon of claim 1 , wherein the genetic element is single-stranded.
3. The synthetic curon of any of the preceding claims, wherein the genetic element is DNA.
4. The synthetic curon of claim 3, wherein the genetic element is a negative strand DNA.
5. The synthetic curon of any of the preceding claims, wherein the genetic element integrates at a frequency of less than 10%, 8%, 6%, 4%, 3%, 2%, 1%, 0.5%, 0.2%, 0.1% of the curons that enters the cell, e.g., wherein the synthetic curon is non-integrating.
6. The synthetic curon of any of the preceding claims, wherein the genetic element comprises a sequence of the Consensus 5' UTR nucleic acid sequence shown in Table 16-1.
7. The synthetic curon of any of the preceding claims, wherein the genetic element comprises a sequence of the Consensus GC-rich region shown in Table 16-2.
8. The synthetic curon of any of the preceding claims, wherein the genetic element comprises a sequence of at least 100 nucleotides in length, which consists of G or C at at least 70% (e.g., about 70- 100%, 75-95%, 80-95%, 85-95%, or 85-90%) of the positions.
9. The synthetic curon of any of the preceding claims, wherein the genetic element comprises a sequence having at least 85% sequence identity to the Anellovirus 5' UTR conserved domain nucleotide sequence of nucleotides 1 - 393 of the nucleic acid sequence of Table 11 and a sequence having at least 85% sequence identity to the Anellovirus GC-rich region of nucleotides 2868 - 2929 of the nucleic acid sequence of Table 11.
10. The synthetic curon of any of the preceding claims, wherein the genetic element comprises at least 75% identity to the nucleotide sequence of Table 11.
11. The synthetic curon of any of the preceding claims, wherein the promoter element is exogenous to wild-type Anellovirus.
12. The synthetic curon of any of claims 1-10, wherein the promoter element is endogenous to wild-type Anellovirus.
13. The synthetic curon of any of the preceding claims, wherein the exogenous effector encodes a therapeutic agent, e.g., a therapeutic peptide or polypeptide or a therapeutic nucleic acid.
14. The synthetic curon of any of the preceding claims, wherein the exogenous effector comprises a regulatory nucleic acid, e.g., an miRNA, siRNA, mRNA, IncRNA, RNA, DNA, an antisense RNA, gRNA; a fluorescent tag or marker, an antigen, a peptide, a synthetic or analog peptide from a naturally-bioactive peptide, an agonist or antagonist peptide, an anti-microbial peptide, a pore -forming peptide, a bicyclic peptide, a targeting or cytotoxic peptide, a degradation or self-destruction peptide, a small molecule, an immune effector (e.g., influences susceptibility to an immune response / signal), a death protein (e.g., an inducer of apoptosis or necrosis), a non-lytic inhibitor of a tumor (e.g., an inhibitor of an oncoprotein), an epigenetic modifying agent, an epigenetic enzyme, a transcription factor, a DNA or protein modification enzyme, a DNA-intercalating agent, an efflux pump inhibitor, a nuclear receptor activator or inhibitor, a proteasome inhibitor, a competitive inhibitor for an enzyme, a protein synthesis effector or inhibitor, a nuclease, a protein fragment or domain, a ligand, an antibody, a receptor, or a CRISPR system or component.
15. The synthetic curon of any of the preceding claims, wherein the exogenous effector comprises an miRNA, and decreases expression of a host gene.
16. The synthetic curon of any of the preceding claims, wherein the exogenous effector comprises a nucleic acid sequence about 20-200, 30-180, 40-160, 50-140, or 60-120 nucleotides in length.
17. The synthetic curon of any of the preceding claims, wherein the nucleic acid sequence encoding the exogenous effector is about 20-200, 30-180, 40-160, 50-140, or 60-120 nucleotides in length.
18. The synthetic curon of any of the preceding claims, wherein the sequence encoding the exogenous effector is situated at, within, or adjacent to (e.g., 5' or 3' to) one or more of the ORFl locus, e.g., at the C-terminus of the ORFl locus, or the 3' noncoding region downstream of the poly-A region.
19. The synthetic curon of any of the preceding claims, wherein the sequence encoding the exogenous effector is located between the poly-A region and the GC-rich region of the genetic element.
20. The synethtic curon of any of the preceding claims, which comprises (e.g., in the proteinaceous exterior) one or more of an amino acid sequence chosen from ORF2, ORF2 / 2, ORF2 / 3, ORFl, ORFl / 1, or ORFl / 2 of Table 12, or an amino acid sequence having at least 85% sequence identity thereto.
21. The synthetic curon of any of the preceding claims, wherein the portions of the genetic element excluding the effector have a combined size of about 2.5-5 kb (e.g., about 2.8-4kb, about 2.8- 3.2kb, about 3.6-3.9kb, or about 2.8-2.9kb), less than about 5kb (e.g., less than about 2.9kb, 3.2 kb, 3.6kb, 3.9kb, or 4kb), or at least 100 nucleotides (e.g., at least lkb).
22. The synthetic curon of any of the preceding claims, wherein the synthetic curon does not comprise a lipid bilayer.
23. The synthetic curon of any of the preceding claims, wherein the synthetic curon is capable of infecting mammalian cells, e.g., human cells, e.g., immune cells, liver cells, or lung epithelial cells.
24. The synthetic curon of any of the preceding claims, wherein the genetic element is capable of replicating, e.g., capable of generating at least 102, 2 x 102, 5 x 102, 103, 2 x 103, 5 x 103, or 104genomic equivalents of the genetic element per cell, e.g., as measured by a quantitative PCR assay.
25. The synthetic curon of any of the preceding claims, which is substantially nonpathogenic, e.g., does not induce a detectable deleterious symptom in a subject (e.g., elevated cell death or toxicity, e.g., relative to a subject not exposed to the curon).
26. The synthetic curon of any of the preceding claims, which is substantially non-immunogenic, e.g., does not induce a detectable and / or unwanted immune response, e.g., as detected according to the method described in Example 4.
27. The synthetic curon of claim 26, wherein the substantially non-immunogenic curon has an efficacy in a subject that is a least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% of the efficacy in a reference subject lacking an immune response.
28. The synthetic curon of claim 26 or 27, wherein the immune response comprises one or more of an antibody specific to the curon; a cellular response (e.g., an immune effector cell (e.g., T cell- or NK cell) response) against the curon or cells comprising the curon; or macrophage engulfment of the curon or cells comprising the curon.
29. The synthetic curon of any of the preceding claims, wherein a population of at least 1000 of the synthetic curons is capable of delivering at least 100 copies of the genetic element into one or more of the eukaryotic cells.
30. A synthetic curon comprising:(i) a genetic element comprising a promoter element and a nucleic acid sequence encoding an exogenous effector, and a protein binding sequence, wherein the genetic element comprises one or both of:(a) a sequence having at least 85% sequence identity to the Anellovirus 5' UTR conserved domain of the nucleic acid sequence of Table 1, 3, 5, 7, 9 or 13; or(b) a sequence having at least 85% sequence identity to the Anellovirus GC-rich region of the nucleic acid sequence of of Table 1, 3, 5, 7, 9 or 13;and(ii) a proteinaceous exterior; wherein the genetic element is enclosed within the proteinaceous exterior; andwherein the synthetic curon is capable of delivering the genetic element into a eukaryotic cell.
31. The synethtic curon of claim 30, which comprises (e.g., in the proteinaceous exterior) one or more of an amino acid sequence chosen from ORF2, ORF2 / 2, ORF2 / 3, ORF2t / 3, ORFl, ORFl / 1, or ORF1 / 2 of any of Tables 2, 4, 6, 8, 10, or 14, or an amino acid sequence having at least 85% sequence identity thereto.
32. A nucleic acid molecule comprising a promoter element and a nucleic acid sequence encoding an exogenous effector, and a protein binding sequence, wherein the genetic element comprises one or both of:(a) a sequence having at least 85% sequence identity to the Anellovirus 5' UTR conserved domain nucleotide sequence of nucleotides 323 - 393 of the nucleic acid sequence of Table 11 , or(b) a sequence having at least 85% sequence identity to the Anellovirus GC-rich region of nucleotides 2868 - 2929 of the nucleic acid sequence of Table 11.
33. A nucleic acid molecule comprising a promoter element and a nucleic acid sequence encoding an exogenous effector, and a protein binding sequence, wherein the genetic element comprises one or both of:(a) a sequence having at least 85% sequence identity to the Anellovirus 5' UTR conserved domain nucleotide sequence of the nucleic acid sequence of Table 1, 3, 5, 7, or 13, or(b) a sequence having at least 85% sequence identity to the Anellovirus GC-rich region of the nucleic acid sequence of Table 1, 3, 5, 7, or 13.
34. A pharmaceutical composition comprising the synthetic curon of any of the preceding claims, and a pharmaceutically acceptable carrier or excipient.
35. The pharmaceutical composition of claim 34, which comprises at least 103, 104, 10s, 106, 107, 10s, or 109synthetic curons.
36. A reaction mixture comprising the synthetic curon of any of claims 1-31 and a second nucleic acid sequence encoding one or more of an amino acid sequence chosen from ORF2, ORF2 / 2, ORF2 / 3, ORFl, ORFl / 1, or ORFl / 2 of Table 12, or an amino acid sequence having at least 85% sequence identity thereto.
37. A reaction mixture comprising the synthetic curon of any of claims 1-31 and a second nucleic acid sequence encoding one or more of an amino acid sequence chosen from ORF2, ORF2 / 2, ORF2 / 3, ORF2t / 3, ORFl, ORFl / 1, or ORFl / 2 of any of Tables 2, 4, 6, 8, 10, or 14, or an amino acid sequence having at least 85% sequence identity thereto.
38. The reaction mixture of claim 36 or 37, wherein the second nucleic acid sequence is part of the genetic element.
39. The reaction mixture of claim 36 or 37, wherein the second nucleic acid sequence is not part of the genetic element, e.g., the second nucleic acid sequence is comprised by a helper cell or helper virus.
40. Use of a synthetic curon of any of the claims 1-31 or the pharmaceutical composition of any of claims 34-35 for delivering the genetic element to a host cell.
41. Use of a synthetic curon of any of the claims 1-31 or the pharmaceutical composition of any of claims 34-35 for treating a disease or disorder in a subject.
42. The use of claim 41, wherein the disease or disorder is chosen from an immune disorder, an interferonopathies (e.g., Type I interferonopathy), infectious disease, inflammatory disorder, autoimmune condition, cancer (e.g., a solid tumor, e.g., lung cancer), and a gastrointestinal disorder.
43. A synthetic curon of any of claims 1-31 or the pharmaceutical composition of any of claims 34-35, for use in treating a disease or disorder in a subject.
44. A method of treating a disease or disorder in a subject, the method comprising administering a synthetic curon of any of claims 1-31 or the pharmaceutical composition of any of claims 34-35 to the subject, wherein the disease or disorder is chosen from an immune disorder, an interferonopathy (e.g.,Type I interferonopathy), infectious disease, inflammatory disorder, autoimmune condition, cancer (e.g., a solid tumor, e.g., lung cancer), and a gastrointestinal disorder.
45. A method of manufacturing a synthetic curon composition, comprising:a) providing a plurality of synthetic curons according to claims 1-31, or a composition orpharmaceutical composition of any of claims 34-35;b) optionally evaluating the plurality for one or more of: a contaminant described herein, an optical density measurement (e.g., OD 260), particle number (e.g., by HPLC), infectivity (e.g., particle:infectious unit ratio); andc) formulating the plurality of synthetic curons, e.g., as a pharmaceutical composition suitable for administration to a subject, e.g., if one or more of the paramaters of (b) meet a specified threshold.