CN111139241A - Small interfering nucleic acid for inhibiting novel coronavirus, composition and application - Google Patents
Small interfering nucleic acid for inhibiting novel coronavirus, composition and application Download PDFInfo
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Abstract
The invention discloses a small interfering RNA for inhibiting novel coronavirus, a composition and application thereof. The invention claims to protect siRNA containing sense strand and antisense strand, wherein the siRNA is 21-si-SP-2069, 21-si-SP-2289, 21-si-SP-3292, 21-si-P3-244, 21-si-P8-62, 21-si-P8-164, 21-si-P10B-158, 21-si-P14-19, 21-si-NP-722, 21-si-NP-1123, 21-si-NS-2139 or 21-si-NS-2798, and part of the nucleotide of the sense strand or the antisense strand is 2' -O-methyl ribonucleotide, and part of the phosphate group is phosphorothioate group. The invention provides novel siRNA and a composition thereof, which can effectively prevent and/or treat novel coronavirus.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to a small interfering RNA for inhibiting the expression of a novel coronavirus gene and application of the small interfering RNA in preparing a pharmaceutical composition for preventing and/or treating novel coronavirus pneumonia.
Background
At the end of 2019 and early 2020, the city of wuhan, china developed a new type of coronavirus pneumonia (coronaivus disease2019, covi-19). covi-19 is an acute infectious pneumonia, researchers found that its pathogen was caused by a new type of β coronavirus that was not previously found in humans, which was subsequently named by the World Health Organization (WHO) as the initial symptoms of patients with SARS-CoV-2. covi-19 were mostly febrile, debilitated and dry cough, and gradually developed severe manifestations of dyspnea, most patients had a good prognosis, some severe cases may develop acute respiratory distress syndrome and septic shock, and even death, up to 3/1/2020, covi-19 had been infected with 88000 people, causing nearly 3000 deaths.
Disclosure of Invention
The invention aims to provide siRNA targeting a novel coronavirus gene and application thereof in preparation of a novel coronavirus pneumonia medicament.
The novel coronavirus (SARS-CoV-2) is similar to SARS-CoV and MERS-CoV viruses, and the genome of SARS-CoV-2 (2019-nCoV) is divided into two parts, i.e., a non-structural gene and a structural gene. Among them, the nonstructural gene, which occupies about two thirds of the total length of the SARS-CoV-2 genome, contains two sequences encoding proteins, designated ORF1a and ORF1 b. The structural gene region immediately after the sequence encodes structural proteins such as S protein, orf3a protein, E protein, M protein, orf6 protein, orf7a protein, orf8 protein, and N protein.
The invention provides a siRNA molecule, which contains a complementary sense strand and an antisense strand, wherein the sense strand contains a nucleotide sequence shown as SEQ ID NO: 5, and the antisense strand comprises the nucleotide sequence shown as SEQ ID NO: 6; alternatively, the sense strand comprises the sequence set forth as SEQ ID NO: 9, and the antisense strand comprises the nucleotide sequence shown as SEQ ID NO: 10; alternatively, the sense strand comprises the sequence set forth as SEQ ID NO: 57, and the antisense strand comprises the nucleotide sequence shown as SEQ ID NO: 58; alternatively, the sense strand comprises the sequence set forth as SEQ ID NO: 59, and the antisense strand comprises the nucleotide sequence shown as SEQ ID NO: 60; alternatively, the sense strand comprises the sequence set forth as SEQ ID NO: 69, and the antisense strand comprises the nucleotide sequence shown as SEQ ID NO: 70; alternatively, the sense strand comprises the sequence set forth as SEQ ID NO: 123, and the antisense strand comprises the nucleotide sequence shown as SEQ ID NO: 124; alternatively, the sense strand comprises the sequence set forth as SEQ ID NO: 131, and the antisense strand comprises the nucleotide sequence shown as SEQ ID NO: 132; alternatively, the sense strand comprises the sequence set forth as SEQ ID NO: 145, and the antisense strand comprises the nucleotide sequence shown as SEQ ID NO: 146; alternatively, the sense strand comprises the sequence set forth as SEQ ID NO: 171, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 172; alternatively, the sense strand comprises the sequence set forth as SEQ ID NO: 177, and the antisense strand comprises the nucleotide sequence shown as SEQ ID NO: 178; alternatively, the sense strand comprises the sequence set forth as SEQ ID NO: 185, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 186; alternatively, the sense strand comprises a sequence as set forth in seq id NO: 197, and the antisense strand comprises the nucleotide sequence shown as SEQ ID NO: 198;
wherein,
sense strand 5'-AGGGAUUGUACAGAAAGUGUG-3' (SEQ ID NO: 5),
antisense strand 5'-CACUUUCUGUACAAUCCCUUU-3' (SEQ ID NO: 6);
sense strand 5'-GGUGAUUGUGAAGAAGAAGAG-3' (SEQ ID NO: 9),
antisense strand 5'-CUUCUUCUUCACAAUCACCUU-3' (SEQ ID NO: 10);
sense strand 5'-AAUCCAUCAUUGCCUACACUA-3' (SEQ ID NO: 57),
antisense strand 5'-CAUAGUGUAGGCAAUGAUGGA-3' (SEQ ID NO: 58);
sense strand 5'-AAACCGUGCUUUAACUGGAAU-3' (SEQ ID NO: 59),
antisense strand 5'-CUAUUCCAGUUAAAGCACGGU-3' (SEQ ID NO: 60);
sense strand 5'-AAUGGCACACACUGGUUUGUA-3' (SEQ ID NO: 69),
antisense strand 5'-GUUACAAACCAGUGUGUGCCA-3' (SEQ ID NO: 70);
sense strand 5'-CAAGGCCAAACUGUCACUAAG-3' (SEQ ID NO: 123),
antisense strand 5'-UAGUGACAGUUUGGCCUUGUU-3' (SEQ ID NO: 124);
sense strand 5'-GGCUGAUGAAACUCAAGCCUU-3' (SEQ ID NO: 131),
antisense strand 5'-GGCUUGAGUUUCAUCAGCCUU-3' (SEQ ID NO: 132);
sense strand 5'-UCAGCACCUUUAAUUGAAUUG-3' (SEQ ID NO: 145),
antisense strand 5'-AUUCAAUUAAAGGUGCUGAUU-3' (SEQ ID NO: 146);
sense strand 5'-CUUCCUCAAGGAACAACAUUG-3' (SEQ ID NO: 171),
antisense strand 5'-AUGUUGUUCCUUGAGGAAGUU-3' (SEQ ID NO: 172);
sense strand 5'-GAGUGUGUUAGAGGUACAACA-3' (SEQ ID NO: 177),
antisense strand 5'-UUGUACCUCUAACACACUCUU-3' (SEQ ID NO: 178);
sense strand 5'-CUGACUUGCUUUAGCACUCAA-3' (SEQ ID NO: 185),
antisense strand 5'-GAGUGCUAAAGCAAGUCAGUU-3' (SEQ ID NO: 186);
sense strand 5'-CUUGCUGUUGUUGUUUGUAAC-3' (SEQ ID NO: 197),
antisense strand 5'-UACAAACAACAACAGCAAGUU-3' (SEQ ID NO: 198).
Preferably, at least one of the sense strand and the antisense strand of the siRNA, which are complementary to each other, is deleted or added with one or several nucleotides, thereby obtaining an siRNA derivative having the same function as the siRNA.
Preferably, at least a portion of the phosphate-sugar backbone of at least one of the sense strand and the antisense strand, which are complementary to each other, of the siRNA is a phosphorothioate backbone;
or, at least a part of nucleotides of at least one single strand of the sense strand and the antisense strand complementary to each other is subjected to nucleotide substitution or modification;
alternatively, at least one of the sense strand and the antisense strand, which are complementary to each other, is linked to a signaling molecule and/or an active molecule and/or a functional group.
Preferably, the sense strand of the siRNA is SEQ ID NO: 5 nucleotide sequence, wherein the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 st nucleotides are all 2' -O-methyl ribonucleotide, and the antisense strand of the siRNA is SEQ ID NO: the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 th nucleotides of the 6 th nucleotide sequence are all 2' -O-methyl ribonucleotides;
alternatively, the sense strand of the siRNA SEQ ID NO: 9 nucleotide sequence, wherein the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 st nucleotides are all 2' -O-methyl ribonucleotide, and the antisense strand of the siRNA is SEQ ID NO: 10 nucleotide sequence of 1, 2, 3, 19, 20, 21 nucleotides are all 2' -O-methyl ribonucleotide;
alternatively, the sense strand of the siRNA SEQ ID NO: the nucleotides 1, 2, 3, 19, 20 and 21 of the 57 nucleotide sequence are all 2' -O-methyl ribonucleotide, and the antisense strand of the siRNA is SEQ ID NO: the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 th nucleotides of the 58 nucleotide sequence are all 2' -O-methyl ribonucleotides;
alternatively, the sense strand of the siRNA SEQ ID NO: 59 nucleotide sequence of 2' -O-methyl ribonucleotide in 1 st, 2 nd, 3 rd, 19 th, 20 th, 21 st nucleotide, the antisense strand of said siRNA SEQ ID NO: the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 th nucleotides of the 60 th nucleotide sequence are all 2' -O-methyl ribonucleotides;
alternatively, the sense strand of the siRNA SEQ ID NO: 69 nucleotide sequence of 2' -O-methyl ribonucleotide at the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 st nucleotides, wherein the antisense strand of the siRNA is SEQ ID NO: the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 th nucleotides of the 70 th nucleotide sequence are all 2' -O-methyl ribonucleotides;
alternatively, the sense strand of the siRNA SEQ ID NO: 123, and 2' -O-methyl ribonucleotide in the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 st nucleotides of the siRNA, wherein the antisense strand of the siRNA is SEQ ID NO: the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 st nucleotides of the 124 th nucleotide sequence are all 2' -O-methyl ribonucleotides;
alternatively, the sense strand of the siRNA SEQ ID NO: 131 nucleotide sequence of 2' -O-methyl ribonucleotide at 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 st nucleotides, wherein the antisense strand of the siRNA is SEQ ID NO: the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 th nucleotides of the 132 nucleotide sequence are all 2' -O-methyl ribonucleotides;
alternatively, the sense strand of the siRNA SEQ ID NO: 145 nucleotide sequence is 2' -O-methyl ribonucleotide at nucleotides 1, 2, 3, 19, 20, 21, and the antisense strand of the siRNA is SEQ ID NO: the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 th nucleotides of the 146 nucleotide sequence are all 2' -O-methyl ribonucleotides;
alternatively, the sense strand of the siRNA SEQ ID NO: 171 of the siRNA, wherein the nucleotides at positions 1, 2, 3, 19, 20 and 21 are all 2' -O-methyl ribonucleotides, and the antisense strand of the siRNA is SEQ ID NO: the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 th nucleotides of the 172 nucleotide sequence are all 2' -O-methyl ribonucleotides;
alternatively, the sense strand of the siRNA SEQ ID NO: the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 st nucleotides of the 177 nucleotide sequence are all 2' -O-methyl ribonucleotides, and the antisense strand of the siRNA is SEQ ID NO: 178 nucleotide sequence, nucleotides 1, 2, 3, 19, 20, 21 are all 2' -O-methyl ribonucleotides;
alternatively, the sense strand of the siRNA SEQ ID NO: 185 nucleotide sequence, nucleotides 1, 2, 3, 19, 20, 21 are all 2' -O-methyl ribonucleotides, and the antisense strand of the siRNA is SEQ ID NO: 186 nucleotide sequence of nucleotides 1, 2, 3, 19, 20, 21 are all 2' -O-methyl ribonucleotides;
alternatively, the sense strand of the siRNA SEQ ID NO: 197, nucleotides 1, 2, 3, 19, 20, and 21 of the nucleotide sequence are all 2' -O-methyl ribonucleotides, and the antisense strand of the siRNA is SEQ ID NO: 198 and the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 th nucleotides of the nucleotide sequence are all 2' -O-methyl ribonucleotides.
Preferably, the phosphate groups between the 1 st, 2 rd and 3 rd nucleotides and the phosphate groups between the 19 th, 20 th and 21 st nucleotides of the nucleotide sequence of the sense strand and/or the antisense strand of the siRNA are all phosphorothioate groups.
Preferably, the 5' -end of the sense strand of the siRNA is cholesterol-modified.
The invention also provides application of the siRNA in preparation of a medicament for preventing and/or treating viral pneumonia.
Preferably, the viral pneumonia is novel coronavirus pneumonia COVID-19.
The invention also provides a kit, which comprises the siRNA and has the function of treating the novel coronavirus COVID-19.
Experiments prove that the siRNA modified by the invention has obvious inhibition effect on the novel coronavirus gene, lays a foundation for clinically treating the novel coronavirus pneumonia, and has great clinical significance and popularization value.
Drawings
FIG. 1 is a map of the dual luciferase reporter plasmid GP-mirGlo plasmid in example 3 of the present invention;
FIG. 2 is a graph showing the results of a dual luciferase assay carried out on the siRNAs numbered as mimicNC, 21si-NS-964, 21si-NS-1989 and 21si-NS-2139 in example 4 of the present invention and the corresponding reporter plasmid numbered as P17;
FIG. 3 is a graph showing the results of a dual luciferase assay experiment conducted on the siRNAs numbered as mimicNC, 21si-NS-2588, 21si-NS-2798 and 21si-NS-2915 in example 4 of the present invention and the corresponding reporter plasmid numbered as P18;
FIG. 4 is a graph showing the results of a dual luciferase assay experiment conducted on the siRNAs numbered as mimicNC, 21si-NS-5890, 21si-NS-6010, 21si-NS-6015 and 21si-NS-6201 in example 4 of the present invention and the corresponding reporter plasmid numbered as P19;
FIG. 5 is a graph showing the results of a dual luciferase assay experiment conducted on the siRNAs numbered as mimicNC, 21si-NS-17211, 21si-NS-17400, and 21si-NS-17447 and the corresponding reporter plasmid numbered as P20 in example 4 of the present invention;
FIG. 6 is a graph showing the results of a dual luciferase assay experiment conducted on the siRNAs numbered as mimicNC, 21si-NS-19760, 21si-NS-19831, and 21si-NS-19897 in example 4 of the present invention and the corresponding reporter plasmid numbered as P21;
FIG. 7 is a graph showing the results of a dual luciferase assay experiment conducted on siRNA's numbered as mimicNC, 21si-SP-88, 21si-SP-241, 21si-SP-337 and 21si-SP-450 in example 4 of the present invention with the corresponding reporter plasmid numbered as P22;
FIG. 8 is a graph showing the results of a dual luciferase assay experiment conducted on siRNA's numbered as mimicNC, 21si-SP-1027, 21si-SP-1060, 21si-SP-1493, 21si-SP-1547, 21si-SP-1816 and 21si-SP-1932 and a corresponding reporter plasmid numbered as P23 in example 4 of the present invention;
FIG. 9 is a graph showing the results of a dual luciferase assay carried out with siRNA's numbered as mimicNC, 21si-SP-2128, 21si-SP-2069, 21si-SP-2289, 21si-SP-2301 and 21si-SP-2643 and the corresponding reporter plasmid numbered as P24 in example 4 of the present invention;
FIG. 10 is a graph showing the results of a dual luciferase assay experiment conducted on the siRNAs numbered as mimicNC, 21si-SP-2956, 21si-SP-3051, 21si-SP-3292, 21si-SP-3387 and 21si-SP-3584 in example 4 of the present invention and the corresponding reporter plasmid numbered as P25;
FIG. 11 is a graph showing the results of a dual luciferase assay experiment conducted on siRNA's numbered as mimicsNC, 21si-P3-50, 21si-P3-223, 21si-P3-592, 21si-P3-735, 21si-P3-209, 21si-P3-244, 21si-P3-528, 21si-P3-704, 21si-P3-725 and 21si-P3-744 in example 4 of the present invention with a corresponding reporter plasmid numbered as P34;
FIG. 12 is a graph showing the results of a dual luciferase assay experiment conducted on siRNA's numbered as mimicNC, 21si-HY8-152, 21si-HY8-160, 21si-HY8-7, 21si-HY8-22 and 21si-HY8-119 in example 4 of the present invention with the corresponding reporter plasmid numbered as P30;
FIG. 13 is a graph showing the results of a dual luciferase assay experiment conducted on siRNA's numbered as mimicNC, 21si-P8-30, 21si-P8-62, 21si-P8-95, 21si-P8-98, 21si-P8-269 and 21si-P8-164 in example 4 of the present invention with a corresponding reporter plasmid numbered as P33;
FIG. 14 is a graph showing the results of a dual luciferase assay experiment conducted on siRNA's numbered as mimicNC, 21si-P10b-203, 21si-P10b-256, 21si-P10b-275, 21si-P10b-80, 21si-P10b-103, 21si-P10b-158, 21si-P10b-27, 21si-P10b-38 and 21si-P10b-95 in example 4 of the present invention with the corresponding reporter plasmid numbered as P29;
FIG. 15 is a graph showing the results of a dual luciferase assay experiment conducted on siRNA's numbered as mimicNC, 21si-EP-20, 21si-EP-83, 21si-EP-96 and 21si-EP-124 in example 4 of the present invention with the corresponding reporter plasmid numbered as P26;
FIG. 16 is a graph showing the results of a dual luciferase assay experiment conducted on siRNA's numbered as mimicsNC, 21si-MP-237, 21si-MP-13, 21si-MP-42, 21si-MP-249, 21si-MP-484, 21si-MP-501, 21si-MP-56, 21si-MP-220, 21si-MP-410 and 21si-MP-61 in example 4 of the present invention with the corresponding reporter plasmid numbered as P27;
FIG. 17 is a graph showing the results of a dual luciferase assay experiment conducted on the siRNAs numbered as mimicNC, 21si-P13-163, 21si-P13-199, and 21si-P13-213 in example 4 of the present invention and the corresponding reporter plasmid numbered as P31;
FIG. 18 is a graph showing the results of a dual luciferase assay experiment conducted on the siRNAs numbered as mimicNC, 21si-P14-8, 21si-P14-19 and 21si-P14-82 in example 4 of the present invention and the corresponding reporter plasmid numbered as P32;
FIG. 19 is a graph showing the results of a dual luciferase assay experiment conducted on siRNA's numbered as mimicsNC, 21si-NP-173, 21si-NP-209, 21si-NP-223, 21si-NP-229, 21si-NP-249, 21si-NP-448, 21si-NP-460, 21si-NP-468, 21si-NP-479, 21si-NP-698, 21si-NP-722, 21si-NP-745, 21si-NP-781, 21si-NP-796, 21si-NP-1123, and 21si-NP-1162 in example 4 of the present invention and a corresponding reporter plasmid numbered as P28.
Detailed Description
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The following non-limiting examples will allow those skilled in the art to better understand the present invention.
Any person skilled in the art can substitute or change the technical scheme and concept of the present invention within the careless scope of the present invention.
The 293T cell line used in the examples below was purchased from the classical collection of cells of the Central institute of technology.
Example 1
Synthesis of Small interfering nucleic acids
A novel coronavirus (SARS-CoV-2) genome (Genbank accession No. MN 988668.1) (SEQ ID NO: 227) with a relatively conserved sequence was selected as a template. Respectively aiming at the conserved regions of SARS-CoV-2 gene, selecting nucleotide sequence of 21bp, and designing small interfering nucleic acid (siRNA).
The siRNA designed in this example was synthesized by shanghai gimar pharmaceutical technology ltd, and the sequences of the synthesized siRNA are shown in table 1.
TABLE 1
As shown in table 1, the present example also provides a sense strand nucleotide sequence as shown in seq id no: 207, the nucleotide sequence of the antisense strand is shown as SEQ ID NO: 208, M-mimicsNC as a negative control, which is an unrelated sequence without a target site corresponding to a novel coronavirus (SARS-CoV-2) gene.
Example 2
Synthesis of modified Small interfering nucleic acids
The modified siRNA shown in Table 2 is obtained by chemically modifying the sense strand and the antisense strand of the sequence in Table 1, namely, the 2' hydroxyl group of the pentose group in the nucleotide residues of the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 st bases of the sense strand is modified by methoxy, the phosphate group between the 1 st, 2 nd and 3 rd bases of the sense strand is phosphorothioate group, and the phosphate group between the 19 th, 20 th and 21 st bases of the sense strand is phosphorothioate group; the 2' hydroxyl of pentose group in the nucleotide residues of 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 st bases of antisense chain is modified by methoxy, the phosphate group between 1 st, 2 nd and 3 rd bases of antisense chain is phosphorothioate group, the phosphate group between 19 th, 20 th and 21 st bases of antisense chain is phosphorothioate group; the siRNA designed in this example was synthesized by shanghai gimar pharmaceutical technology ltd, and cholesterol was linked to the 5' end of the sense strand of siRNA for modification.
TABLE 2
Wherein m represents a pentose group in the nucleotide residue on the left side as a 2' -methoxyribosyl group, and s represents a phosphate group between deoxyribonucleotide residues on the left and right sides thereof as a phosphorothioate group.
Example 3
Construction of dual-luciferase reporter plasmid
The dual-luciferase reporter plasmid used in this example was GP-mirGlo plasmid (the sequence of the empty vector is shown in the specification), purchased from Promega, and the map information is shown in FIG. 1. A dual-luciferase reporter plasmid, as shown in Table 3, was prepared by inserting a novel coronavirus (SARS-CoV-2) genome sequence into the GP-mirTLO plasmid.
TABLE 3
Example 4
Cell transfection
1.293T cells were cultured in 10cm dishes to 80-90% confluency, the culture broth was decanted and the cells were washed twice with 2ml PBS.
2. Adding 2ml of Trypsin-EDTAsolution, mixing uniformly, and standing at 37 ℃ for 1 minute.
3. The pancreatin solution was carefully aspirated, 2ml of DMEM medium containing 10% FBS was added, and the cells were pipetted to form a single cell suspension.
4. Counting with a hemocytometer, diluting the cells to 1X 106Cells/ml. By 5X 105Inoculating 12-well plate at the concentration of cells/well, mixing uniformly at 37 ℃ and 5% CO2The culture was carried out for 24 hours.
5. Each 1OD260120 μ l DEPC-H for siRNA2O dissolved to a final concentration of about 20. mu.M.
6. Adding 100 μ l serum-free DMEM into 1.5ml EP tube, adding 7ul siRNA, adding 1.2ug of corresponding dual-fluorescence report carrier, and mixing; another 1.5ml EP tube was added with 100. mu.l serum-free DMEM, 4. mu.l Lipofectamine2000, mixed well, left at room temperature for 5 minutes, then mixed and left at room temperature for 20 minutes.
Grouping was performed according to the correspondence between plasmids and siRNA molecules, as shown in Table 2.
Each group was done 3 more wells, averaged, and tested at time point 24/48h, once.
The culture medium was aspirated from the 12-well plate, and the transfection mixture was added dropwise to the 12-well plate, mixed well, and incubated in an incubator for 5 hours.
7. The transfection solution was aspirated off, and 500ul of DMEM medium containing 10% FBS was added. 37 ℃ C5% CO2The culture was continued for 24 and 48 hours, and the samples were collected.
Dual luciferase systemic detection
The Dual-Luciferase assay was performed using the Dual-Luciferase reporter assay kit (promega) (see instructions for specific methods of use).
Preparation of reagents:
1. preparation of passive lysis buffer 1 × PLB: 1 volume of 5XpassiveLysis buffer (PLB) was added to 4 volumes of distilled water. And (4) uniformly mixing. And storing at 4 ℃ for later use.
2. LAR II, dissolving the freeze-dried powder of LuciferaseAssaySubstrate by LuciferaseAssayBuffer II. Storing at-20 ℃ for later use.
3. Preparing 1Xstop & Glo reagents (prepared at present): according to the amount required by the experiment, a certain amount of 50XStop and Glo are added into the corresponding amount of Stop and Glo Buffer, and the final concentration of the mixture is 1 × for later use.
A detection step:
1. the culture medium in the 12-well plate was decanted and the cells were washed twice with 500ul PBS.
2. 1 XPLB 300ul was added to the culture wells. Passive lysis of cells: the plate was gently shaken at room temperature for 15 minutes and the lysate was transferred to the assay plate. 100ul per well, 3 wells per experimental design.
3. Turning on a TecanM1000 microplate reader, preheating and selecting a dual-luciferase detection system.
4. Add 10ul LARII reagent to each well, select 1-2 seconds delay, read 5-10, detect firefly luciferase activity on the microplate reader.
5. Taking out the test board, adding 10ul Stop & Glo reagents into each hole, selecting 1-2 second delay and 5-10 readings, and detecting the renilla luciferase activity on an enzyme-linked immunosorbent assay (ELISA) instrument.
6. And (5) counting and analyzing results.
The results of the dual luciferase assay are shown in FIGS. 2-19, and the results show that siRNAs numbered 21-si-SP-2069, 21-si-SP-2289, 21-si-SP-3292, 21-si-P3-244, 21-si-P8-62, 21-si-P8-164, 21-si-P10B-158, 21-si-P14-19, 21-si-NP-1123, 21-si-NS-2139 and 21-si-NS-2798 can effectively inhibit the expression of novel coronavirus genes.
The present invention has been described in detail above. It will be apparent to those skilled in the art that the invention can be practiced in a wide range of equivalent parameters, concentrations, and conditions without departing from the spirit and scope of the invention and without undue experimentation. While the invention has been described with reference to specific embodiments, it will be appreciated that the invention can be further modified. In general, the invention is intended to encompass any variations, uses, or adaptations of the invention following, in general, the principles of the invention, including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains.
Sequence listing
<110> Suzhou Jima Gene GmbH
Shanghai Jima pharmaceutical technology Limited
<120> small interfering nucleic acid for inhibiting novel coronavirus, composition and application
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caaaggucca accagaagug a21
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aaaguugagg cugaagugca a 21
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auuugcacuu cagccucaac u 21
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aaucagagcu ucugcuaauc u 21
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caagauuagc agaagcucug a 21
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aauggcacac acugguuugu a 21
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guuacaaacc agugugugcc a 21
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aauaggaauu gucaacaaca c 21
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cuguguuguu gacaauuccu a 21
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aaucucucau cgaucuccaa g 21
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uucuuggaga ucgaugagag a 21
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gagacaggua cguuaauagu u 21
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cuauuaacgu accugucucu u 21
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guuacacuag ccauccuuac u 21
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uaaggauggc uaguguaacu u 21
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uccuuacugc gcuucgauug u 21
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aaucgaagcg caguaaggau u 21
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cugcugcaau auuguuaacg u 21
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guuaacaaua uugcagcagu u 21
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uugcuaucgc aauggcuugu c 21
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caagccauug cgauagcaau u 21
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cgguacuauu accguugaag a 21
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uucaacggua auaguaccgu u 21
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agcuccuuga acaauggaac c 21
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uuccauuguu caaggagcuu u 21
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auuggaucac cgguggaauu g 21
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auuccaccgg ugauccaauu u 21
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ggaccugccu aaagaaauca c 21
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gauuucuuua ggcagguccu u 21
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ucacuguugc uacaucacga a 21
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cgugauguag caacagugau u 21
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uggaaccuag uaauagguuu c 21
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aaccuauuac uagguuccau u 21
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uuggaucacc gguggaauug c 21
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aauuccaccg gugauccaau u 21
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cucguaaucg gagcugugau c 21
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ucacagcucc gauuacgagu u 21
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ccuaguaaua gguuuccuau u 21
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uaggaaaccu auuacuaggu u 21
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cauggcaagg aagaccuuaa a 21
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uaaggucuuc cuugccaugu u 21
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ggcguuccaa uuaacaccaa u 21
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ugguguuaau uggaacgccu u 21
<210>107
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>107
caccaauagc aguccagaug a 21
<210>108
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>108
aucuggacug cuauuggugu u 21
<210>109
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>109
uagcagucca gaugaccaaa u 21
<210>110
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>110
uuggucaucu ggacugcuau u 21
<210>111
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>111
uuggcuacua ccgaagagcu a 21
<210>112
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>112
gcucuucggu aguagccaau u 21
<210>113
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>113
uccugcuaac aaugcugcaa u 21
<210>114
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>114
ugcagcauug uuagcaggau u 21
<210>115
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>115
ugcugcaauc gugcuacaac u 21
<210>116
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>116
uuguagcacg auugcagcau u 21
<210>117
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>117
ucgugcuaca acuuccucaa g 21
<210>118
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>118
ugaggaaguu guagcacgau u 21
<210>119
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>119
cuuccucaag gaacaacauu g 21
<210>120
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>120
auguuguucc uugaggaagu u21
<210>121
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>121
augucuggua aaggccaaca a 21
<210>122
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>122
guuggccuuu accagacauu u 21
<210>123
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>123
caaggccaaa cugucacuaa g 21
<210>124
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>124
uagugacagu uuggccuugu u 21
<210>125
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>125
aucugcugcu gaggcuucua a 21
<210>126
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>126
agaagccuca gcagcagauu u 21
<210>127
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>127
acguacugcc acuaaagcau a 21
<210>128
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>128
ugcuuuagug gcaguacguu u 21
<210>129
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>129
agcauacaau guaacacaag c 21
<210>130
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>130
uuguguuaca uuguaugcuu u 21
<210>131
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>131
ggcugaugaa acucaagccu u 21
<210>132
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>132
ggcuugaguu ucaucagccu u 21
<210>133
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>133
acagcaaacu gugacucuuc u 21
<210>134
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>134
aagagucaca guuugcuguu u21
<210>135
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>135
ucacccauuc aguacaucga u 21
<210>136
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>136
cgauguacug aaugggugau u 21
<210>137
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>137
uugccaggaa ccuaaauugg g 21
<210>138
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>138
caauuuaggu uccuggcaau u 21
<210>139
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>139
ccuaaauugg guagucuugu a 21
<210>140
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>140
caagacuacc caauuuaggu u 21
<210>141
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>141
caucaaccau auguaguuga u 21
<210>142
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>142
caacuacaua ugguugaugu u 21
<210>143
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>143
cccguguccu auucacuucu a 21
<210>144
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>144
gaagugaaua ggacacgggu u 21
<210>145
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>145
ucagcaccuu uaauugaauu g 21
<210>146
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>146
auucaauuaa aggugcugau u 21
<210>147
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>147
ucacaacugu agcugcauuu c 21
<210>148
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>148
aaugcagcua caguugugau u21
<210>149
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>149
gcugcauuuc accaagaaug u 21
<210>150
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>150
auucuuggug aaaugcagcu u 21
<210>151
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>151
guugaugacc cguguccuau u 21
<210>152
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>152
uaggacacgg gucaucaacu u 21
<210>153
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>153
uuagaugaag agcaaccaau g 21
<210>154
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>154
uugguugcuc uucaucuaau u 21
<210>155
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>155
agagcaacca auggagauug a 21
<210>156
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>156
aaucuccauu gguugcucuu u 21
<210>157
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>157
ucucguugac uuucagguua c 21
<210>158
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>158
aaccugaaag ucaacgagau u 21
<210>159
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>159
gguuacuaua gcagagauau u 21
<210>160
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>160
uaucucugcu auaguaaccu u 21
<210>161
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>161
ucuaagucac uaacugagaa u 21
<210>162
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>162
ucucaguuag ugacuuagau u 21
<210>163
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>163
cauggcaagg aagaccuuaa a 21
<210>164
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>164
uaaggucuuc cuugccaugu u 21
<210>165
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>165
ggcguuccaa uuaacaccaa u 21
<210>166
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>166
ugguguuaau uggaacgccu u 21
<210>167
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>167
caccaauagc aguccagaug a 21
<210>168
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>168
aucuggacug cuauuggugu u 21
<210>169
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>169
ucgugcuaca acuuccucaa g 21
<210>170
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>170
ugaggaaguu guagcacgau u 21
<210>171
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>171
cuuccucaag gaacaacauu g 21
<210>172
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>172
auguuguucc uugaggaagu u 21
<210>173
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>173
gccucuucuc guuccucauc a 21
<210>174
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>174
augaggaacg agaagaggcu u 21
<210>175
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>175
cacucgcuac uugugagcuu u 21
<210>176
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>176
agcucacaag uagcgagugu u 21
<210>177
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>177
gaguguguua gagguacaac a 21
<210>178
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>178
uuguaccucu aacacacucu u 21
<210>179
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>179
gaaccuugcu cuucuggaac a 21
<210>180
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>180
uuccagaaga gcaagguucu u 21
<210>181
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>181
ccuugcucuu cuggaacaua c 21
<210>182
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>182
auguuccaga agagcaaggu u 21
<210>183
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>183
gaggaaguuc aagaacuuua c 21
<210>184
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>184
aaaguucuug aacuuccucu u 21
<210>185
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>185
cugacuugcu uuagcacuca a 21
<210>186
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>186
gagugcuaaa gcaagucagu u 21
<210>187
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>187
ggugaaauca aggaugcuac u 21
<210>188
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>188
uagcauccuu gauuucaccu u 21
<210>189
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>189
ggguguucac uuuguuugca a 21
<210>190
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>190
gcaaacaaag ugaacacccu u 21
<210>191
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>191
agacuguguu guauuacaca g 21
<210>192
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>192
guguaauaca acacagucuu u 21
<210>193
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>193
uucacacaau cgacgguuca u 21
<210>194
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>194
gaaccgucga uugugugaau u 21
<210>195
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>195
cuagcacucu ccaagggugu u 21
<210>196
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>196
cacccuugga gagugcuagu u 21
<210>197
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>197
cuugcuguug uuguuuguaa c 21
<210>198
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>198
uacaaacaac aacagcaagu u 21
<210>199
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>199
guccuauuuc ugaacaugac u 21
<210>200
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>200
ucauguucag aaauaggacu u 21
<210>201
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>201
auuguugaug agccugaaga a 21
<210>202
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>202
cuucaggcuc aucaacaauu u 21
<210>203
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>203
cauguccaaa uucacacaau c 21
<210>204
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>204
uugugugaau uuggacaugu u 21
<210>205
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>205
ucgacgguuc auccggaguu g 21
<210>206
<211>21
<212>RNA
<213> Artificial Sequence (Artificial Sequence)
<400>206
acuccggaug aaccgucgau u 21
<210>207
<211>21
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>207
uucuccgaac gugucacgut t 21
<210>208
<211>21
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>208
acgugacacg uucggagaat t 21
<210>209
<211>1500
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>209
tggggaatgt ccaaattttg tatttccctt aaattccata atcaagacta ttcaaccaag 60
ggttgaaaag aaaaagcttg atggctttat gggtagaatt cgatctgtct atccagttgc 120
gtcaccaaat gaatgcaacc aaatgtgcct ttcaactctc atgaagtgtg atcattgtgg 180
tgaaacttca tggcagacgg gcgattttgt taaagccact tgcgaatttt gtggcactga 240
gaatttgact aaagaaggtg ccactacttg tggttactta ccccaaaatg ctgttgttaa 300
aatttattgt ccagcatgtc acaattcaga agtaggacct gagcatagtc ttgccgaata 360
ccataatgaa tctggcttga aaaccattct tcgtaagggt ggtcgcacta ttgcctttgg 420
aggctgtgtg ttctcttatg ttggttgcca taacaagtgt gcctattggg ttccacgtgc 480
tagcgctaac ataggttgta accatacagg tgttgttgga gaaggttccg aaggtcttaa 540
tgacaacctt cttgaaatac tccaaaaaga gaaagtcaac atcaatattg ttggtgactt 600
taaacttaat gaagagatcg ccattatttt ggcatctttt tctgcttcca caagtgcttt 660
tgtggaaact gtgaaaggtt tggattataa agcattcaaa caaattgttg aatcctgtgg 720
taattttaaa gttacaaaag gaaaagctaa aaaaggtgcc tggaatattg gtgaacagaa 780
atcaatactg agtcctcttt atgcatttgc atcagaggct gctcgtgttg tacgatcaat 840
tttctcccgc actcttgaaa ctgctcaaaa ttctgtgcgt gttttacaga aggccgctat 900
aacaatacta gatggaattt cacagtattc actgagactc attgatgcta tgatgttcac 960
atctgatttg gctactaaca atctagttgt aatggcctac attacaggtg gtgttgttca 1020
gttgacttcg cagtggctaa ctaacatctt tggcactgtt tatgaaaaac tcaaacccgt 1080
ccttgattgg cttgaagaga agtttaagga aggtgtagag tttcttagag acggttggga 1140
aattgttaaa tttatctcaa cctgtgcttg tgaaattgtc ggtggacaaa ttgtcacctg 1200
tgcaaaggaa attaaggaga gtgttcagac attctttaag cttgtaaata aatttttggc 1260
tttgtgtgct gactctatca ttattggtgg agctaaactt aaagccttga atttaggtga 1320
aacatttgtc acgcactcaa agggattgta cagaaagtgt gttaaatcca gagaagaaac 1380
tggcctactc atgcctctaa aagccccaaa agaaattatc ttcttagagg gagaaacact 1440
tcccacagaa gtgttaacag aggaagttgt cttgaaaact ggtgatttac aaccattaga 1500
<210>210
<211>500
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>210
aaggttacaa gagtgtgaat atcacttttg aacttgatga aaggattgat aaagtactta 60
atgagaagtg ctctgcctat acagttgaac tcggtacaga agtaaatgag ttcgcctgtg 120
ttgtggcaga tgctgtcata aaaactttgc aaccagtatc tgaattactt acaccactgg 180
gcattgattt agatgagtgg agtatggcta catactactt atttgatgag tctggtgagt 240
ttaaattggc ttcacatatg tattgttctt tctaccctcc agatgaggat gaagaagaag 300
gtgattgtga agaagaagag tttgagccat caactcaata tgagtatggt actgaagatg 360
attaccaagg taaacctttg gaatttggtg ccacttctgc tgctcttcaa cctgaagaag 420
agcaagaaga agattggtta gatgatgata gtcaacaaac tgttggtcaa caagacggca 480
gtgaggacaa tcagacaact 500
<210>211
<211>500
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>211
atatcaaatt tgctgatgat ttaaaccagt taactggtta taagaaacct gcttcaagag 60
agcttaaagt tacatttttc cctgacttaa atggtgatgt ggtggctatt gattataaac 120
actacacacc ctcttttaag aaaggagcta aattgttaca taaacctatt gtttggcatg 180
ttaacaatgc aactaataaa gccacgtata aaccaaatac ctggtgtata cgttgtcttt 240
ggagcacaaa accagttgaa acatcaaatt cgtttgatgt actgaagtca gaggacgcgc 300
agggaatgga taatcttgcc tgcgaagatc taaaaccagt ctctgaagaa gtagtggaaa 360
atcctaccat acagaaagac gttcttgagt gtaatgtgaa aactaccgaa gttgtaggag 420
acattatact taaaccagca aataatagtt taaaaattac agaagaggtt ggccacacag 480
atctaatggc tgcttatgta 500
<210>212
<211>500
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>212
caatggccac aaattatgat ttgagtgttg tcaatgccag attacgtgct aagcactatg 60
tgtacattgg cgaccctgct caattacctg caccacgcac attgctaact aagggcacac 120
tagaaccaga atatttcaat tcagtgtgta gacttatgaa aactataggt ccagacatgt 180
tcctcggaac ttgtcggcgt tgtcctgctg aaattgttga cactgtgagt gctttggttt 240
atgataataa gcttaaagca cataaagaca aatcagctca atgctttaaa atgttttata 300
agggtgttat cacgcatgat gtttcatctg caattaacag gccacaaata ggcgtggtaa 360
gagaattcct tacacgtaac cctgcttgga gaaaagctgt ctttatttca ccttataatt 420
cacagaatgc tgtagcctca aagattttgg gactaccaac tcaaactgtt gattcatcac 480
agggctcaga atatgactat 500
<210>213
<211>440
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>213
tactgtgatc tgggactaca aaagagatgc tccagcacat atatctacta ttggtgtttg 60
ttctatgact gacatagcca agaaaccaac tgaaacgatt tgtgcaccac tcactgtctt 120
ttttgatggt agagttgatg gtcaagtaga cttatttaga aatgcccgta atggtgttct 180
tattacagaa ggtagtgtta aaggtttaca accatctgta ggtcccaaac aagctagtct 240
taatggagtc acattaattg gagaagccgt aaaaacacag ttcaattatt ataagaaagt 300
tgatggtgtt gtccaacaat tacctgaaac ttactttact cagagtagaa atttacaaga 360
atttaaaccc aggagtcaaa tggaaattga tttcttagaa ttagctatgg atgaattcat 420
tgaacggtat aaattagaag 440
<210>214
<211>960
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>214
atgtttgttt ttcttgtttt attgccacta gtctctagtc agtgtgttaa tcttacaacc 60
agaactcaat taccccctgc atacactaat tctttcacac gtggtgttta ttaccctgac 120
aaagttttca gatcctcagt tttacattca actcaggact tgttcttacc tttcttttcc 180
aatgttactt ggttccatgc tatacatgtc tctgggacca atggtactaa gaggtttgat 240
aaccctgtcc taccatttaa tgatggtgtt tattttgctt ccactgagaa gtctaacata 300
ataagaggct ggatttttgg tactacttta gattcgaaga cccagtccct acttattgtt 360
aataacgcta ctaatgttgt tattaaagtc tgtgaatttc aattttgtaa tgatccattt 420
ttgggtgttt attaccacaa aaacaacaaa agttggatgg aaagtgagtt cagagtttat 480
tctagtgcga ataattgcac ttttgaatat gtctctcagc cttttcttat ggaccttgaa 540
ggaaaacagg gtaatttcaa aaatcttagg gaatttgtgt ttaagaatat tgatggttat 600
tttaaaatat attctaagca cacgcctatt aatttagtgc gtgatctccc tcagggtttt 660
tcggctttag aaccattggt agatttgcca ataggtatta acatcactag gtttcaaact 720
ttacttgctt tacatagaag ttatttgact cctggtgatt cttcttcagg ttggacagct 780
ggtgctgcag cttattatgt gggttatctt caacctagga cttttctatt aaaatataat 840
gaaaatggaa ccattacaga tgctgtagac tgtgcacttg accctctctc agaaacaaag 900
tgtacgttga aatccttcac tgtagaaaaa ggaatctatc aaacttctaa ctttagagtc 960
<210>215
<211>940
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>215
caaccaacag aatctattgt tagatttcct aatattacaa acttgtgccc ttttggtgaa 60
gtttttaacg ccaccagatt tgcatctgtt tatgcttgga acaggaagag aatcagcaac 120
tgtgttgctg attattctgt cctatataat tccgcatcat tttccacttt taagtgttat 180
ggagtgtctc ctactaaatt aaatgatctc tgctttacta atgtctatgc agattcattt 240
gtaattagag gtgatgaagt cagacaaatc gctccagggc aaactggaaa gattgctgat 300
tataattata aattaccaga tgattttaca ggctgcgtta tagcttggaa ttctaacaat 360
cttgattcta aggttggtgg taattataat tacctgtata gattgtttag gaagtctaat 420
ctcaaacctt ttgagagaga tatttcaact gaaatctatc aggccggtag cacaccttgt 480
aatggtgttg aaggttttaa ttgttacttt cctttacaat catatggttt ccaacccact 540
aatggtgttg gttaccaacc atacagagta gtagtacttt cttttgaact tctacatgca 600
ccagcaactg tttgtggacc taaaaagtct actaatttgg ttaaaaacaa atgtgtcaat 660
ttcaacttca atggtttaac aggcacaggt gttcttactg agtctaacaa aaagtttctg 720
cctttccaac aatttggcag agacattgct gacactactg atgctgtccg tgatccacag 780
acacttgaga ttcttgacat tacaccatgt tcttttggtg gtgtcagtgt tataacacca 840
ggaacaaata cttctaacca ggttgctgtt ctttatcagg atgttaactg cacagaagtc 900
cctgttgcta ttcatgcaga tcaacttact cctacttggc 940
<210>216
<211>960
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>216
gtgtttattc tacaggttct aatgtttttc aaacacgtgc aggctgttta ataggggctg 60
aacatgtcaa caactcatat gagtgtgaca tacccattgg tgcaggtata tgcgctagtt 120
atcagactca gactaattct cctcggcggg cacgtagtgt agctagtcaa tccatcattg 180
cctacactat gtcacttggt gcagaaaatt cagttgctta ctctaataac tctattgcca 240
tacccacaaa ttttactatt agtgttacca cagaaattct accagtgtct atgaccaaga 300
catcagtaga ttgtacaatg tacatttgtg gtgattcaac tgaatgcagc aatcttttgt 360
tgcaatatgg cagtttttgt acacaattaa accgtgcttt aactggaata gctgttgaac 420
aagacaaaaa cacccaagaa gtttttgcac aagtcaaaca aatttacaaa acaccaccaa 480
ttaaagattt tggtggtttt aatttttcac aaatattacc agatccatca aaaccaagca 540
agaggtcatt tattgaagat ctacttttca acaaagtgac acttgcagat gctggcttca 600
tcaaacaata tggtgattgc cttggtgata ttgctgctag agacctcatt tgtgcacaaa 660
agtttaacgg ccttactgtt ttgccacctt tgctcacaga tgaaatgatt gctcaataca 720
cttctgcact gttagcgggt acaatcactt ctggttggac ctttggtgca ggtgctgcat 780
tacaaatacc atttgctatg caaatggctt ataggtttaa tggtattgga gttacacaga 840
atgttctcta tgagaaccaa aaattgattg ccaaccaatt taatagtgct attggcaaaa 900
ttcaagactc actttcttcc acagcaagtg cacttggaaa acttcaagat gtggtcaacc 960
<210>217
<211>962
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>217
aaaatgcaca agctttaaac acgcttgtta aacaacttag ctccaatttt ggtgcaattt 60
caagtgtttt aaatgatatc ctttcacgtc ttgacaaagt tgaggctgaa gtgcaaattg 120
ataggttgat cacaggcaga cttcaaagtt tgcagacata tgtgactcaa caattaatta 180
gagctgcaga aatcagagct tctgctaatc ttgctgctac taaaatgtca gagtgtgtac 240
ttggacaatc aaaaagagtt gatttttgtg gaaagggcta tcatcttatg tccttccctc 300
agtcagcacc tcatggtgta gtcttcttgc atgtgactta tgtccctgca caagaaaaga 360
acttcacaac tgctcctgcc atttgtcatg atggaaaagc acactttcct cgtgaaggtg 420
tctttgtttc aaatggcaca cactggtttg taacacaaag gaatttttat gaaccacaaa 480
tcattactac agacaacaca tttgtgtctg gtaactgtga tgttgtaata ggaattgtca 540
acaacacagt ttatgatcct ttgcaacctg aattagactc attcaaggag gagttagata 600
aatattttaa gaatcataca tcaccagatg ttgatttagg tgacatctct ggcattaatg 660
cttcagttgt aaacattcaa aaagaaattg accgcctcaa tgaggttgcc aagaatttaa 720
atgaatctct catcgatctc caagaacttg gaaagtatga gcagtatata aaatggccat 780
ggtacatttg gctaggtttt atagctggct tgattgccat agtaatggtg acaattatgc 840
tttgctgtat gaccagttgc tgtagttgtc tcaagggctg ttgttcttgt ggatcctgct 900
gcaaatttga tgaagacgac tctgagccag tgctcaaagg agtcaaatta cattacacat 960
aa 962
<210>218
<211>228
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>218
atgtactcat tcgtttcgga agagacaggt acgttaatag ttaatagcgt acttcttttt 60
cttgctttcg tggtattctt gctagttaca ctagccatcc ttactgcgct tcgattgtgt 120
gcgtactgct gcaatattgt taacgtgagt cttgtaaaac cttcttttta cgtttactct 180
cgtgttaaaa atctgaattc ttctagagtt cctgatcttc tggtctaa 228
<210>219
<211>669
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>219
atggcagatt ccaacggtac tattaccgtt gaagagctta aaaagctcct tgaacaatgg 60
aacctagtaa taggtttcct attccttaca tggatttgtc ttctacaatt tgcctatgcc 120
aacaggaata ggtttttgta tataattaag ttaattttcc tctggctgtt atggccagta 180
actttagctt gttttgtgct tgctgctgtt tacagaataa attggatcac cggtggaatt 240
gctatcgcaa tggcttgtct tgtaggcttg atgtggctca gctacttcat tgcttctttc 300
agactgtttg cgcgtacgcg ttccatgtgg tcattcaatc cagaaactaa cattcttctc 360
aacgtgccac tccatggcac tattctgacc agaccgcttc tagaaagtga actcgtaatc 420
ggagctgtga tccttcgtgg acatcttcgt attgctggac accatctagg acgctgtgac 480
atcaaggacc tgcctaaaga aatcactgtt gctacatcac gaacgctttc ttattacaaa 540
ttgggagctt cgcagcgtgt agcaggtgac tcaggttttg ctgcatacag tcgctacagg 600
attggcaact ataaattaaa cacagaccat tccagtagca gtgacaatat tgctttgctt 660
gtacagtaa 669
<210>220
<211>1069
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>220
taaattccct cgaggacaag gcgttccaat taacaccaat agcagtccag atgaccaaat 60
tggctactac cgaagagcta ccagacgaat tcgtggtggt gacggtaaaa tgaaagatct 120
cagtccaaga tggtatttct actacctagg aactgggcca gaagctggac ttccctatgg 180
tgctaacaaa gacggcatca tatgggttgc aactgaggga gccttgaata caccaaaaga 240
tcacattggc acccgcaatc ctgctaacaa tgctgcaatc gtgctacaac ttcctcaagg 300
aacaacattg ccaaaaggct tctacgcaga agggagcaga ggcggcagtc aagcctcttc 360
tcgttcctca tcacgtagtc gcaacagttc aagaaattca actccaggca gcagtagggg 420
aacttctcct gctagaatgg ctggcaatgg cggtgatgct gctcttgctt tgctgctgct 480
tgacagattg aaccagcttg agagcaaaat gtctggtaaa ggccaacaac aacaaggcca 540
aactgtcact aagaaatctg ctgctgaggc ttctaagaag cctcggcaaa aacgtactgc 600
cactaaagca tacaatgtaa cacaagcttt cggcagacgt ggtccagaac aaacccaagg 660
aaattttggg gaccaggaac taatcagaca aggaactgat tacaaacatt ggccgcaaat 720
tgcacaattt gcccccagcg cttcagcgtt cttcggaatg tcgcgcattg gcatggaagt 780
cacaccttcg ggaacgtggt tgacctacac agctgccatc aaattggatg acaaagatcc 840
aaatttcaaa gatcaagtca ttttgctgaa taagcatatt gacgcataca aaacattccc 900
accaacagag cctaaaaagg acaaaaagaa gaaggctgat gaaactcaag ccttaccgca 960
gagacagaag aaacagcaaa ctgtgactct tcttcctgct gcagatttgg atgatttctc 1020
caaacaattg caacaatcca tgagcagtgc tgactcaact caggcctaa 1069
<210>221
<211>366
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>221
atgaaatttc ttgttttctt aggaatcatc acaactgtag ctgcatttca ccaagaatgt 60
agtttacagt catgtactca acatcaacca tatgtagttg atgacccgtg tcctattcac 120
ttctattcta aatggtatat tagagtagga gctagaaaat cagcaccttt aattgaattg 180
tgcgtggatg aggctggttc taaatcaccc attcagtaca tcgatatcgg taattataca 240
gtttcctgtt taccttttac aattaattgc caggaaccta aattgggtag tcttgtagtg 300
cgttgttcgt tctatgaaga ctttttagag tatcatgacg ttcgtgttgt tttagatttc 360
atctaa 366
<210>222
<211>186
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>222
atgtttcatc tcgttgactt tcaggttact atagcagaga tattactaat tattatgagg 60
acttttaaag tttccatttg gaatcttgat tacatcataa acctcataat taaaaattta 120
tctaagtcac taactgagaa taaatattct caattagatg aagagcaacc aatggagatt 180
gattaa 186
<210>223
<211>294
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>223
atggacccca aaatcagcga aatgcacccc gcattacgtt tggtggaccc tcagattcaa 60
ctggcagtaa ccagaatgga gaacgcagtg gggcgcgatc aaaacaacgt cggccccaag 120
gtttacccaa taatactgcg tcttggttca ccgctctcac tcaacatggc aaggaagacc 180
ttaaattccc tcgaggacaa ggcgttccaa ttaacaccaa tagcagtcca gatgaccaaa 240
ttggctacta ccgaagagct accagacgaa ttcgtggtgg tgacggtaaa atga 294
<210>224
<211>222
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>224
atgctgcaat cgtgctacaa cttcctcaag gaacaacatt gccaaaaggc ttctacgcag 60
aagggagcag aggcggcagt caagcctctt ctcgttcctc atcacgtagt cgcaacagtt 120
caagaaattc aactccaggc agcagtaggg gaacttctcc tgctagaatg gctggcaatg 180
gcggtgatgc tgctcttgct ttgctgctgc ttgacagatt ga 222
<210>225
<211>368
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>225
atgaaaatta ttcttttctt ggcactgata acactcgcta cttgtgagct ttatcactac 60
caagagtgtg ttagaggtac aacagtactt ttaaaagaac cttgctcttc tggaacatac 120
gagggcaatt caccatttca tcctctagct gataacaaat ttgcactgac ttgctttagc 180
actcaatttg cttttgcttg tcctgacggc gtaaaacacg tctatcagtt acgtgccaga 240
tcagtttcac ctaaactgtt catcagacaa gaggaagttc aagaacttta ctctccaatt 300
tttcttattg ttgcggcaat agtgtttata acactttgct tcacactcaa aagaaagaca 360
gaatgatt 368
<210>226
<211>828
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>226
atggatttgt ttatgagaat cttcacaatt ggaactgtaa ctttgaagca aggtgaaatc 60
aaggatgcta ctccttcaga ttttgttcgc gctactgcaa cgataccgat acaagcctca 120
ctccctttcg gatggcttat tgttggcgtt gcacttcttg ctgtttttca gagcgcttcc 180
aaaatcataa ccctcaaaaa gagatggcaa ctagcactct ccaagggtgt tcactttgtt 240
tgcaacttgc tgttgttgtt tgtaacagtt tactcacacc ttttgctcgt tgctgctggc 300
cttgaagccc cttttctcta tctttatgct ttagtctact tcttgcagag tataaacttt 360
gtaagaataa taatgaggct ttggctttgc tggaaatgcc gttccaaaaa cccattactt 420
tatgatgcca actattttct ttgctggcat actaattgtt acgactattg tataccttac 480
aatagtgtaa cttcttcaat tgtcattact tcaggtgatg gcacaacaag tcctatttct 540
gaacatgact accagattgg tggttatact gaaaaatggg aatctggagt aaaagactgt 600
gttgtattac acagttactt cacttcagac tattaccagc tgtactcaac tcaattgagt 660
acagacactg gtgttgaaca tgttaccttc ttcatctaca ataaaattgt tgatgagcct 720
gaagaacatg tccaaattca cacaatcgac ggttcatccg gagttgttaa tccagtaatg 780
gaaccaattt atgatgaacc gacgacgact actagcgtgc ctttgtaa 828
<210>227
<211>29881
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>227
ttaaaggttt ataccttccc aggtaacaaa ccaaccaact ttcgatctct tgtagatctg 60
ttctctaaac gaactttaaa atctgtgtgg ctgtcactcg gctgcatgct tagtgcactc 120
acgcagtata attaataact aattactgtc gttgacagga cacgagtaac tcgtctatct 180
tctgcaggct gcttacggtt tcgtccgtgt tgcagccgat catcagcaca tctaggtttc 240
gtccgggtgt gaccgaaagg taagatggag agccttgtcc ctggtttcaa cgagaaaaca 300
cacgtccaac tcagtttgcc tgttttacag gttcgcgacg tgctcgtacg tggctttgga 360
gactccgtgg aggaggtctt atcagaggca cgtcaacatc ttaaagatgg cacttgtggc 420
ttagtagaag ttgaaaaagg cgttttgcct caacttgaac agccctatgt gttcatcaaa 480
cgttcggatg ctcgaactgc acctcatggt catgttatgg ttgagctggt agcagaactc 540
gaaggcattc agtacggtcg tagtggtgag acacttggtg tccttgtccc tcatgtgggc 600
gaaataccag tggcttaccg caaggttctt cttcgtaaga acggtaataa aggagctggt 660
ggccatagtt acggcgccga tctaaagtca tttgacttag gcgacgagct tggcactgat 720
ccttatgaag attttcaaga aaactggaac actaaacata gcagtggtgt tacccgtgaa 780
ctcatgcgtg agcttaacgg aggggcatac actcgctatg tcgataacaa cttctgtggc 840
cctgatggct accctcttga gtgcattaaa gaccttctag cacgtgctgg taaagcttca 900
tgcactttgt ccgaacaact ggactttatt gacactaaga ggggtgtata ctgctgccgt 960
gaacatgagc atgaaattgc ttggtacacg gaacgttctg aaaagagcta tgaattgcag 1020
acaccttttg aaattaaatt ggcaaagaaa tttgacacct tcaatgggga atgtccaaat 1080
tttgtatttc ccttaaattc cataatcaag actattcaac caagggttga aaagaaaaag 1140
cttgatggct ttatgggtag aattcgatct gtctatccag ttgcgtcacc aaatgaatgc 1200
aaccaaatgt gcctttcaac tctcatgaag tgtgatcatt gtggtgaaac ttcatggcag 1260
acgggcgatt ttgttaaagc cacttgcgaa ttttgtggca ctgagaattt gactaaagaa 1320
ggtgccacta cttgtggtta cttaccccaa aatgctgttg ttaaaattta ttgtccagca 1380
tgtcacaatt cagaagtagg acctgagcat agtcttgccg aataccataa tgaatctggc 1440
ttgaaaacca ttcttcgtaa gggtggtcgc actattgcct ttggaggctg tgtgttctct 1500
tatgttggtt gccataacaa gtgtgcctat tgggttccac gtgctagcgc taacataggt 1560
tgtaaccata caggtgttgt tggagaaggt tccgaaggtc ttaatgacaa ccttcttgaa 1620
atactccaaa aagagaaagt caacatcaat attgttggtg actttaaact taatgaagag 1680
atcgccatta ttttggcatc tttttctgct tccacaagtg cttttgtgga aactgtgaaa 1740
ggtttggatt ataaagcatt caaacaaatt gttgaatcct gtggtaattt taaagttaca 1800
aaaggaaaag ctaaaaaagg tgcctggaatattggtgaac agaaatcaat actgagtcct 1860
ctttatgcat ttgcatcaga ggctgctcgt gttgtacgat caattttctc ccgcactctt 1920
gaaactgctc aaaattctgt gcgtgtttta cagaaggccg ctataacaat actagatgga 1980
atttcacagt attcactgag actcattgat gctatgatgt tcacatctga tttggctact 2040
aacaatctag ttgtaatggc ctacattaca ggtggtgttg ttcagttgac ttcgcagtgg 2100
ctaactaaca tctttggcac tgtttatgaa aaactcaaac ccgtccttga ttggcttgaa 2160
gagaagttta aggaaggtgt agagtttctt agagacggtt gggaaattgt taaatttatc 2220
tcaacctgtg cttgtgaaat tgtcggtgga caaattgtca cctgtgcaaa ggaaattaag 2280
gagagtgttc agacattctt taagcttgta aataaatttt tggctttgtg tgctgactct 2340
atcattattg gtggagctaa acttaaagcc ttgaatttag gtgaaacatt tgtcacgcac 2400
tcaaagggat tgtacagaaa gtgtgttaaa tccagagaag aaactggcct actcatgcct 2460
ctaaaagccc caaaagaaat tatcttctta gagggagaaa cacttcccac agaagtgtta 2520
acagaggaag ttgtcttgaa aactggtgat ttacaaccat tagaacaacc tactagtgaa 2580
gctgttgaag ctccattggt tggtacacca gtttgtatta acgggcttat gttgctcgaa 2640
atcaaagaca cagaaaagta ctgtgccctt gcacctaata tgatggtaac aaacaatacc 2700
ttcacactca aaggcggtgc accaacaaag gttacttttg gtgatgacac tgtgatagaa 2760
gtgcaaggtt acaagagtgt gaatatcact tttgaacttg atgaaaggat tgataaagta 2820
cttaatgaga agtgctctgc ctatacagtt gaactcggta cagaagtaaa tgagttcgcc 2880
tgtgttgtgg cagatgctgt cataaaaact ttgcaaccag tatctgaatt acttacacca 2940
ctgggcattg atttagatga gtggagtatg gctacatact acttatttga tgagtctggt 3000
gagtttaaat tggcttcaca tatgtattgt tctttctacc ctccagatga ggatgaagaa 3060
gaaggtgatt gtgaagaaga agagtttgag ccatcaactc aatatgagta tggtactgaa 3120
gatgattacc aaggtaaacc tttggaattt ggtgccactt ctgctgctct tcaacctgaa 3180
gaagagcaag aagaagattg gttagatgat gatagtcaac aaactgttgg tcaacaagac 3240
ggcagtgagg acaatcagac aactactatt caaacaattg ttgaggttca acctcaatta 3300
gagatggaac ttacaccagt tgttcagact attgaagtga atagttttag tggttattta 3360
aaacttactg acaatgtata cattaaaaat gcagacattg tggaagaagc taaaaaggta 3420
aaaccaacag tggttgttaa tgcagccaat gtttacctta aacatggagg aggtgttgca 3480
ggagccttaa ataaggctac taacaatgcc atgcaagttg aatctgatga ttacatagct 3540
actaatggac cacttaaagt gggtggtagt tgtgttttaa gcggacacaa tcttgctaaa 3600
cactgtcttc atgttgtcgg cccaaatgtt aacaaaggtg aagacattca acttcttaag 3660
agtgcttatg aaaattttaa tcagcacgaa gttctacttg caccattatt atcagctggt 3720
atttttggtg ctgaccctat acattcttta agagtttgtg tagatactgt tcgcacaaat 3780
gtctacttag ctgtctttga taaaaatctc tatgacaaac ttgtttcaag ctttttggaa 3840
atgaagagtg aaaagcaagt tgaacaaaag atcgctgaga ttcctaaaga ggaagttaag 3900
ccatttataa ctgaaagtaa accttcagtt gaacagagaa aacaagatga taagaaaatc3960
aaagcttgtg ttgaagaagt tacaacaact ctggaagaaa ctaagttcct cacagaaaac 4020
ttgttacttt atattgacat taatggcaat cttcatccag attctgccac tcttgttagt 4080
gacattgaca tcactttctt aaagaaagat gctccatata tagtgggtga tgttgttcaa 4140
gagggtgttt taactgctgt ggttatacct actaaaaagg ctggtggcac tactgaaatg 4200
ctagcgaaag ctttgagaaa agtgccaaca gacaattata taaccactta cccgggtcag 4260
ggtttaaatg gttacactgt agaggaggca aagacagtgc ttaaaaagtg taaaagtgcc 4320
ttttacattc taccatctat tatctctaat gagaagcaag aaattcttgg aactgtttct 4380
tggaatttgc gagaaatgct tgcacatgca gaagaaacac gcaaattaat gcctgtctgt 4440
gtggaaacta aagccatagt ttcaactata cagcgtaaat ataagggtat taaaatacaa 4500
gagggtgtgg ttgattatgg tgctagattt tacttttaca ccagtaaaac aactgtagcg 4560
tcacttatca acacacttaa cgatctaaat gaaactcttg ttacaatgcc acttggctat 4620
gtaacacatg gcttaaattt ggaagaagct gctcggtata tgagatctct caaagtgcca 4680
gctacagttt ctgtttcttc acctgatgct gttacagcgt ataatggtta tcttacttct 4740
tcttctaaaa cacctgaaga acattttatt gaaaccatct cacttgctgg ttcctataaa 4800
gattggtcct attctggaca atctacacaa ctaggtatag aatttcttaa gagaggtgat 4860
aaaagtgtat attacactag taatcctacc acattccacc tagatggtga agttatcacc 4920
tttgacaatc ttaagacact tctttctttg agagaagtga ggactattaa ggtgtttaca 4980
acagtagaca acattaacct ccacacgcaa gttgtggaca tgtcaatgac atatggacaa 5040
cagtttggtc caacttattt ggatggagct gatgttacta aaataaaacc tcataattca 5100
catgaaggta aaacatttta tgttttacct aatgatgaca ctctacgtgt tgaggctttt 5160
gagtactacc acacaactga tcctagtttt ctgggtaggt acatgtcagc attaaatcac 5220
actaaaaagt ggaaataccc acaagttaat ggtttaactt ctattaaatg ggcagataac 5280
aactgttatc ttgccactgc attgttaaca ctccaacaaa tagagttgaa gtttaatcca 5340
cctgctctac aagatgctta ttacagagca agggctggtg aagctgctaa cttttgtgca 5400
cttatcttag cctactgtaa taagacagta ggtgagttag gtgatgttag agaaacaatg 5460
agttacttgt ttcaacatgc caatttagat tcttgcaaaa gagtcttgaa cgtggtgtgt 5520
aaaacttgtg gacaacagca gacaaccctt aagggtgtag aagctgttat gtacatgggc 5580
acactttctt atgaacaatt taagaaaggt gttcagatac cttgtacgtg tggtaaacaa 5640
gctacaaaat atctagtaca acaggagtca ccttttgtta tgatgtcagc accacctgct 5700
cagtatgaac ttaagcatgg tacatttact tgtgctagtg agtacactgg taattaccag 5760
tgtggtcact ataaacatat aacttctaaa gaaactttgt attgcataga cggtgcttta 5820
cttacaaagt cctcagaata caaaggtcct attacggatg ttttctacaa agaaaacagt 5880
tacacaacaa ccataaaacc agttacttat aaattggatg gtgttgtttg tacagaaatt 5940
gaccctaagt tggacaatta ttataagaaa gacaattctt atttcacaga gcaaccaatt 6000
gatcttgtac caaaccaacc atatccaaac gcaagcttcg ataattttaa gtttgtatgt 6060
gataatatca aatttgctga tgatttaaac cagttaactg gttataagaa acctgcttca 6120
agagagctta aagttacatt tttccctgac ttaaatggtg atgtggtggc tattgattat 6180
aaacactaca caccctcttt taagaaagga gctaaattgt tacataaacc tattgtttgg 6240
catgttaaca atgcaactaa taaagccacg tataaaccaa atacctggtg tatacgttgt 6300
ctttggagca caaaaccagt tgaaacatca aattcgtttg atgtactgaa gtcagaggac 6360
gcgcagggaa tggataatct tgcctgcgaa gatctaaaac cagtctctga agaagtagtg 6420
gaaaatccta ccatacagaa agacgttctt gagtgtaatg tgaaaactac cgaagttgta 6480
ggagacatta tacttaaacc agcaaataat agtttaaaaa ttacagaaga ggttggccac 6540
acagatctaa tggctgctta tgtagacaat tctagtctta ctattaagaa acctaatgaa 6600
ttatctagag tattaggttt gaaaaccctt gctactcatg gtttagctgc tgttaatagt 6660
gtcccttggg atactatagc taattatgct aagccttttc ttaacaaagt tgttagtaca 6720
actactaaca tagttacacg gtgtttaaac cgtgtttgta ctaattatat gccttatttc 6780
tttactttat tgctacaatt gtgtactttt actagaagta caaattctag aattaaagca 6840
tctatgccga ctactatagc aaagaatact gttaagagtg tcggtaaatt ttgtctagag 6900
gcttcattta attatttgaa gtcacctaat ttttctaaac tgataaatat tataatttgg 6960
tttttactat taagtgtttg cctaggttct ttaatctact caaccgctgc tttaggtgtt 7020
ttaatgtcta atttaggcat gccttcttac tgtactggtt acagagaagg ctatttgaac 7080
tctactaatg tcactattgc aacctactgt actggttcta taccttgtag tgtttgtctt7140
agtggtttag attctttaga cacctatcct tctttagaaa ctatacaaat taccatttca 7200
tcttttaaat gggatttaac tgcttttggc ttagttgcag agtggttttt ggcatatatt 7260
cttttcacta ggtttttcta tgtacttgga ttggctgcaa tcatgcaatt gtttttcagc 7320
tattttgcag tacattttat tagtaattct tggcttatgt ggttaataat taatcttgta 7380
caaatggccc cgatttcagc tatggttaga atgtacatct tctttgcatc attttattat 7440
gtatggaaaa gttatgtgca tgttgtagac ggttgtaatt catcaacttg tatgatgtgt 7500
tacaaacgta atagagcaac aagagtcgaa tgtacaacta ttgttaatgg tgttagaagg 7560
tccttttatg tctatgctaa tggaggtaaa ggcttttgca aactacacaa ttggaattgt 7620
gttaattgtg atacattctg tgctggtagt acatttatta gtgatgaagt tgcgagagac 7680
ttgtcactac agtttaaaag accaataaat cctactgacc agtcttctta catcgttgat 7740
agtgttacag tgaagaatgg ttccatccat ctttactttg ataaagctgg tcaaaagact 7800
tatgaaagac attctctctc tcattttgtt aacttagaca acctgagagc taataacact 7860
aaaggttcat tgcctattaa tgttatagtt tttgatggta aatcaaaatg tgaagaatca 7920
tctgcaaaat cagcgtctgt ttactacagt cagcttatgt gtcaacctat actgttacta 7980
gatcaggcat tagtgtctga tgttggtgat agtgcggaag ttgcagttaa aatgtttgat 8040
gcttacgtta atacgttttc atcaactttt aacgtaccaa tggaaaaact caaaacacta 8100
gttgcaactg cagaagctga acttgcaaag aatgtgtcct tagacaatgt cttatctact 8160
tttatttcag cagctcggca agggtttgtt gattcagatg tagaaactaa agatgttgtt 8220
gaatgtctta aattgtcaca tcaatctgac atagaagtta ctggcgatag ttgtaataac 8280
tatatgctca cctataacaa agttgaaaac atgacacccc gtgaccttgg tgcttgtatt 8340
gactgtagtg cgcgtcatat taatgcgcag gtagcaaaaa gtcacaacat tgctttgata 8400
tggaacgtta aagatttcat gtcattgtct gaacaactac gaaaacaaat acgtagtgct 8460
gctaaaaaga ataacttacc ttttaagttg acatgtgcaa ctactagaca agttgttaat 8520
gttgtaacaa caaagatagc acttaagggt ggtaaaattg ttaataattg gttgaagcag 8580
ttaattaaag ttacacttgt gttccttttt gttgctgcta ttttctattt aataacacct 8640
gttcatgtca tgtctaaaca tactgacttt tcaagtgaaa tcataggata caaggctatt 8700
gatggtggtg tcactcgtga catagcatct acagatactt gttttgctaa caaacatgct 8760
gattttgaca catggtttag ccagcgtggt ggtagttata ctaatgacaa agcttgccca 8820
ttgattgctg cagtcataac aagagaagtg ggttttgtcg tgcctggttt gcctggcacg 8880
atattacgca caactaatgg tgactttttg catttcttac ctagagtttt tagtgcagtt 8940
ggtaacatct gttacacacc atcaaaactt atagagtaca ctgactttgc aacatcagct 9000
tgtgttttgg ctgctgaatg tacaattttt aaagatgctt ctggtaagcc agtaccatat 9060
tgttatgata ccaatgtact agaaggttct gttgcttatg aaagtttacg ccctgacaca 9120
cgttatgtgc tcatggatgg ctctattatt caatttccta acacctacct tgaaggttct 9180
gttagagtgg taacaacttt tgattctgag tactgtaggc acggcacttg tgaaagatca 9240
gaagctggtg tttgtgtatc tactagtggt agatgggtac ttaacaatga ttattacaga 9300
tctttaccag gagttttctg tggtgtagat gctgtaaatt tacttactaa tatgtttaca 9360
ccactaattc aacctattgg tgctttggac atatcagcat ctatagtagc tggtggtatt 9420
gtagctatcg tagtaacatg ccttgcctac tattttatga ggtttagaag agcttttggt 9480
gaatacagtc atgtagttgc ctttaatact ttactattcc ttatgtcatt cactgtactc 9540
tgtttaacac cagtttactc attcttacct ggtgtttatt ctgttattta cttgtacttg 9600
acattttatc ttactaatga tgtttctttt ttagcacata ttcagtggat ggttatgttc 9660
acacctttag tacctttctg gataacaatt gcttatatca tttgtatttc cacaaagcat 9720
ttctattggt tctttagtaa ttacctaaag agacgtgtag tctttaatgg tgtttccttt 9780
agtacttttg aagaagctgc gctgtgcacc tttttgttaa ataaagaaat gtatctaaag 9840
ttgcgtagtg atgtgctatt acctcttacg caatataata gatacttagc tctttataat 9900
aagtacaagt attttagtgg agcaatggat acaactagct acagagaagc tgcttgttgt 9960
catctcgcaa aggctctcaa tgacttcagt aactcaggtt ctgatgttct ttaccaacca 10020
ccacaaacct ctatcacctc agctgttttg cagagtggtt ttagaaaaat ggcattccca 10080
tctggtaaag ttgagggttg tatggtacaa gtaacttgtg gtacaactac acttaacggt 10140
ctttggcttg atgacgtagt ttactgtcca agacatgtga tctgcacctc tgaagacatg 10200
cttaacccta attatgaaga tttactcatt cgtaagtcta atcataattt cttggtacag 10260
gctggtaatg ttcaactcag ggttattgga cattctatgc aaaattgtgt acttaagctt 10320
aaggttgata cagccaatcc taagacacct aagtataagt ttgttcgcat tcaaccagga 10380
cagacttttt cagtgttagc ttgttacaat ggttcaccat ctggtgttta ccaatgtgct 10440
atgaggccca atttcactat taagggttca ttccttaatg gttcatgtgg tagtgttggt 10500
tttaacatag attatgactg tgtctctttt tgttacatgc accatatgga attaccaact 10560
ggagttcatg ctggcacaga cttagaaggt aacttttatg gaccttttgt tgacaggcaa 10620
acagcacaag cagctggtac ggacacaact attacagtta atgttttagc ttggttgtac 10680
gctgctgtta taaatggaga caggtggttt ctcaatcgat ttaccacaac tcttaatgac 10740
tttaaccttg tggctatgaa gtacaattat gaacctctaa cacaagacca tgttgacata 10800
ctaggacctc tttctgctca aactggaatt gccgttttag atatgtgtgc ttcattaaaa 10860
gaattactgc aaaatggtat gaatggacgt accatattgg gtagtgcttt attagaagat 10920
gaatttacac cttttgatgt tgttagacaa tgctcaggtg ttactttcca aagtgcagtg 10980
aaaagaacaa tcaagggtac acaccactgg ttgttactca caattttgac ttcactttta 11040
gttttagtcc agagtactca atggtctttg ttcttttttt tgtatgaaaa tgccttttta 11100
ccttttgcta tgggtattat tgctatgtct gcttttgcaa tgatgtttgt caaacataag 11160
catgcatttc tctgtttgtt tttgttacct tctcttgcca ctgtagctta ttttaatatg 11220
gtctatatgc ctgctagttg ggtgatgcgt attatgacat ggttggatat ggttgatact 11280
agtttgtctg gttttaagct aaaagactgt gttatgtatg catcagctgt agtgttacta 11340
atccttatga cagcaagaactgtgtatgat gatggtgcta ggagagtgtg gacacttatg 11400
aatgtcttga cactcgttta taaagtttat tatggtaatg ctttagatca agccatttcc 11460
atgtgggctc ttataatctc tgttacttct aactactcag gtgtagttac aactgtcatg 11520
tttttggcca gaggtattgt ttttatgtgt gttgagtatt gccctatttt cttcataact 11580
ggtaatacac ttcagtgtat aatgctagtt tattgtttct taggctattt ttgtacttgt 11640
tactttggcc tcttttgttt actcaaccgc tactttagac tgactcttgg tgtttatgat 11700
tacttagttt ctacacagga gtttagatat atgaattcac agggactact cccacccaag 11760
aatagcatag atgccttcaa actcaacatt aaattgttgg gtgttggtgg caaaccttgt 11820
atcaaagtag ccactgtaca gtctaaaatg tcagatgtaa agtgcacatc agtagtctta 11880
ctctcagttt tgcaacaact cagagtagaa tcatcatcta aattgtgggc tcaatgtgtc 11940
cagttacaca atgacattct cttagctaaa gatactactg aagcctttga aaaaatggtt 12000
tcactacttt ctgttttgct ttccatgcag ggtgctgtag acataaacaa gctttgtgaa 12060
gaaatgctgg acaacagggc aaccttacaa gctatagcct cagagtttag ttcccttcca 12120
tcatatgcag cttttgctac tgctcaagaa gcttatgagc aggctgttgc taatggtgat 12180
tctgaagttg ttcttaaaaa gttgaagaag tctttgaatg tggctaaatc tgaatttgac 12240
cgtgatgcag ccatgcaacg taagttggaa aagatggctg atcaagctat gacccaaatg 12300
tataaacagg ctagatctga ggacaagagg gcaaaagtta ctagtgctat gcagacaatg 12360
cttttcacta tgcttagaaa gttggataat gatgcactca acaacattat caacaatgca 12420
agagatggtt gtgttccctt gaacataata cctcttacaa cagcagccaa actaatggtt 12480
gtcataccag actataacac atataaaaat acgtgtgatg gtacaacatt tacttatgca 12540
tcagcattgt gggaaatcca acaggttgta gatgcagata gtaaaattgt tcaacttagt 12600
gaaattagta tggacaattc acctaattta gcatggcctc ttattgtaac agctttaagg 12660
gccaattctg ctgtcaaatt acagaataat gagcttagtc ctgttgcact acgacagatg 12720
tcttgtgctg ccggtactac acaaactgct tgcactgatg acaatgcgtt agcttactac 12780
aacacaacaa agggaggtag gtttgtactt gcactgttat ccgatttaca ggatttgaaa 12840
tgggctagat tccctaagag tgatggaact ggtactatct atacagaact ggaaccacct 12900
tgtaggtttg ttacagacac acctaaaggt cctaaagtga agtatttata ctttattaaa 12960
ggattaaaca acctaaatag aggtatggta cttggtagtt tagctgccac agtacgtcta 13020
caagctggta atgcaacaga agtgcctgcc aattcaactg tattatcttt ctgtgctttt 13080
gctgtagatg ctgctaaagc ttacaaagat tatctagcta gtgggggaca accaatcact 13140
aattgtgtta agatgttgtg tacacacact ggtactggtc aggcaataac agttacaccg 13200
gaagccaata tggatcaaga atcctttggt ggtgcatcgt gttgtctgta ctgccgttgc 13260
cacatagatc atccaaatcc taaaggattt tgtgacttaa aaggtaagta tgtacaaata 13320
cctacaactt gtgctaatga ccctgtgggt tttacactta aaaacacagt ctgtaccgtc 13380
tgcggtatgt ggaaaggtta tggctgtagt tgtgatcaac tccgcgaacc catgcttcag 13440
tcagctgatg cacaatcgtt tttaaacggg tttgcggtgt aagtgcagcc cgtcttacac 13500
cgtgcggcac aggcactagt actgatgtcg tatacagggc ttttgacatc tacaatgata 13560
aagtagctgg ttttgctaaa ttcctaaaaa ctaattgttg tcgcttccaa gaaaaggacg 13620
aagatgacaa tttaattgat tcttactttg tagttaagag acacactttc tctaactacc 13680
aacatgaaga aacaatttat aatttactta aggattgtcc agctgttgct aaacatgact 13740
tctttaagtt tagaatagac ggtgacatgg taccacatat atcacgtcaa cgtcttacta 13800
aatacacaat ggcagacctc gtctatgctt taaggcattt tgatgaaggt aattgtgaca 13860
cattaaaaga aatacttgtc acatacaatt gttgtgatga tgattatttc aataaaaagg 13920
actggtatga ttttgtagaa aacccagata tattacgcgt atacgccaac ttaggtgaac 13980
gtgtacgcca agctttgtta aaaacagtac aattctgtga tgccatgcga aatgctggta 14040
ttgttggtgt actgacatta gataatcaag atctcaatgg taactggtat gatttcggtg 14100
atttcataca aaccacgcca ggtagtggag ttcctgttgt agattcttat tattcattgt 14160
taatgcctat attaaccttg accagggctt taactgcaga gtcacatgtt gacactgact 14220
taacaaagcc ttacattaag tgggatttgt taaaatatga cttcacggaa gagaggttaa 14280
aactctttga ccgttatttt aaatattggg atcagacata ccacccaaat tgtgttaact 14340
gtttggatga cagatgcatt ctgcattgtg caaactttaa tgttttattc tctacagtgt 14400
tcccacctac aagttttgga ccactagtga gaaaaatatt tgttgatggt gttccatttg 14460
tagtttcaac tggataccac ttcagagagc taggtgttgt acataatcag gatgtaaact 14520
tacatagctc tagacttagt tttaaggaat tacttgtgta tgctgctgac cctgctatgc 14580
acgctgcttc tggtaatcta ttactagata aacgcactac gtgcttttca gtagctgcac 14640
ttactaacaa tgttgctttt caaactgtca aacccggtaa ttttaacaaa gacttctatg 14700
actttgctgt gtctaagggt ttctttaagg aaggaagttc tgttgaatta aaacacttct 14760
tctttgctca ggatggtaat gctgctatca gcgattatga ctactatcgt tataatctac 14820
caacaatgtg tgatatcaga caactactat ttgtagttga agttgttgat aagtactttg 14880
attgttacga tggtggctgt attaatgcta accaagtcat cgtcaacaac ctagacaaat 14940
cagctggttt tccatttaat aaatggggta aggctagact ttattatgat tcaatgagtt 15000
atgaggatca agatgcactt ttcgcatata caaaacgtaa tgtcatccct actataactc 15060
aaatgaatct taagtatgcc attagtgcaa agaatagagc tcgcaccgta gctggtgtct 15120
ctatctgtag tactatgacc aatagacagt ttcatcaaaa attattgaaa tcaatagccg 15180
ccactagagg agctactgta gtaattggaa caagcaaatt ctatggtggt tggcacaaca 15240
tgttaaaaac tgtttatagt gatgtagaaa accctcacct tatgggttgg gattatccta 15300
aatgtgatag agccatgcct aacatgctta gaattatggc ctcacttgtt cttgctcgca 15360
aacatacaac gtgttgtagc ttgtcacacc gtttctatag attagctaat gagtgtgctc 15420
aagtattgag tgaaatggtc atgtgtggcg gttcactata tgttaaacca ggtggaacct 15480
catcaggaga tgccacaact gcttatgcta atagtgtttt taacatttgt caagctgtca 15540
cggccaatgt taatgcactt ttatctactg atggtaacaa aattgccgat aagtatgtcc 15600
gcaatttaca acacagactt tatgagtgtc tctatagaaa tagagatgtt gacacagact 15660
ttgtgaatga gttttacgca tatttgcgta aacatttctc aatgatgata ctctctgacg 15720
atgctgttgt gtgtttcaat agcacttatg catctcaagg tctagtggct agcataaaga 15780
actttaagtc agttctttat tatcaaaaca atgtttttat gtctgaagca aaatgttgga 15840
ctgagactga ccttactaaa ggacctcatg aattttgctc tcaacataca atgctagtta 15900
aacagggtga tgattatgtg taccttcctt acccagatcc atcaagaatc ctaggggccg 15960
gctgttttgt agatgatatc gtaaaaacag atggtacact tatgattgaa cggttcgtgt 16020
ctttagctat agatgcttac ccacttacta aacatcctaa tcaggagtat gctgatgtct 16080
ttcatttgta cttacaatac ataagaaagc tacatgatga gttaacagga cacatgttag 16140
acatgtattc tgttatgctt actaatgata acacttcaag gtattgggaa cctgagtttt 16200
atgaggctat gtacacaccg catacagtct tacaggctgt tggggcttgt gttctttgca 16260
attcacagac ttcattaaga tgtggtgctt gcatacgtag accattctta tgttgtaaat 16320
gctgttacga ccatgtcata tcaacatcac ataaattagt cttgtctgtt aatccgtatg 16380
tttgcaatgc tccaggttgt gatgtcacag atgtgactca actttactta ggaggtatga 16440
gctattattg taaatcacat aaaccaccca ttagttttcc attgtgtgct aatggacaag 16500
tttttggttt atataaaaat acatgtgttg gtagcgataa tgttactgac tttaatgcaa 16560
ttgcaacatg tgactggaca aatgctggtg attacatttt agctaacacc tgtactgaaa 16620
gactcaagct ttttgcagca gaaacgctca aagctactga ggagacattt aaactgtctt 16680
atggtattgc tactgtacgt gaagtgctgt ctgacagaga attacatctt tcatgggaag 16740
ttggtaaacc tagaccacca cttaaccgaa attatgtctt tactggttat cgtgtaacta 16800
aaaacagtaa agtacaaata ggagagtaca cctttgaaaa aggtgactat ggtgatgctg 16860
ttgtttaccg aggtacaaca acttacaaat taaatgttgg tgattatttt gtgctgacat 16920
cacatacagt aatgccatta agtgcaccta cactagtgcc acaagagcac tatgttagaa 16980
ttactggctt atacccaaca ctcaatatct cagatgagtt ttctagcaat gttgcaaatt 17040
atcaaaaggt tggtatgcaa aagtattcta cactccaggg accacctggt actggtaaga 17100
gtcattttgc tattggccta gctctctact acccttctgc tcgcatagtg tatacagctt 17160
gctctcatgc cgctgttgat gcactatgtg agaaggcatt aaaatatttg cctatagata 17220
aatgtagtag aattatacct gcacgtgctc gtgtagagtg ttttgataaa ttcaaagtga 17280
attcaacatt agaacagtat gtcttttgta ctgtaaatgc attgcctgag acgacagcag 17340
atatagttgt ctttgatgaa atttcaatgg ccacaaatta tgatttgagt gttgtcaatg 17400
ccagattacg tgctaagcac tatgtgtaca ttggcgaccc tgctcaatta cctgcaccac 17460
gcacattgct aactaagggc acactagaac cagaatattt caattcagtg tgtagactta 17520
tgaaaactat aggtccagac atgttcctcg gaacttgtcg gcgttgtcct gctgaaattg 17580
ttgacactgt gagtgctttg gtttatgata ataagcttaa agcacataaa gacaaatcag 17640
ctcaatgctt taaaatgttt tataagggtg ttatcacgca tgatgtttca tctgcaatta 17700
acaggccaca aataggcgtg gtaagagaat tccttacacg taaccctgct tggagaaaag 17760
ctgtctttat ttcaccttat aattcacaga atgctgtagc ctcaaagatt ttgggactac 17820
caactcaaac tgttgattca tcacagggct cagaatatga ctatgtcata ttcactcaaa 17880
ccactgaaac agctcactct tgtaatgtaa acagatttaa tgttgctatt accagagcaa 17940
aagtaggcat actttgcata atgtctgata gagaccttta tgacaagttg caatttacaa 18000
gtcttgaaat tccacgtagg aatgtggcaa ctttacaagc tgaaaatgta acaggactct 18060
ttaaagattg tagtaaggta atcactgggt tacatcctac acaggcacct acacacctca 18120
gtgttgacac taaattcaaa actgaaggtt tatgtgttga catacctggc atacctaagg 18180
acatgaccta tagaagactc atctctatga tgggttttaa aatgaattat caagttaatg 18240
gttaccctaa catgtttatc acccgcgaag aagctataag acatgtacgt gcatggattg 18300
gcttcgatgt cgaggggtgt catgctacta gagaagctgt tggtaccaat ttacctttac 18360
agctaggttt ttctacaggt gttaacctag ttgctgtacc tacaggttat gttgatacac 18420
ctaataatac agatttttcc agagttagtg ctaaaccacc gcctggagat caatttaaac 18480
acctcatacc acttatgtac aaaggacttc cttggaatgt agtgcgtata aagattgtac 18540
aaatgttaag tgacacactt aaaaatctct ctgacagagt cgtatttgtc ttatgggcac 18600
atggctttga gttgacatct atgaagtatt ttgtgaaaat aggacctgag cgcacctgtt 18660
gtctatgtga tagacgtgcc acatgctttt ccactgcttc agacacttat gcctgttggc 18720
atcattctat tggatttgat tacgtctata atccgtttat gattgatgtt caacaatggg 18780
gttttacagg taacctacaa agcaaccatg atctgtattg tcaagtccat ggtaatgcac 18840
atgtagctag ttgtgatgca atcatgacta ggtgtctagc tgtccacgag tgctttgtta 18900
agcgtgttga ctggactatt gaatatccta taattggtga tgaactgaag attaatgcgg 18960
cttgtagaaa ggttcaacac atggttgtta aagctgcatt attagcagac aaattcccag 19020
ttcttcacga cattggtaac cctaaagcta ttaagtgtgt acctcaagct gatgtagaat 19080
ggaagttcta tgatgcacag ccttgtagtg acaaagctta taaaatagaa gaattattct 19140
attcttatgc cacacattct gacaaattca cagatggtgt atgcctattt tggaattgca 19200
atgtcgatag atatcctgct aattccattg tttgtagatt tgacactaga gtgctatcta 19260
accttaactt gcctggttgt gatggtggca gtttgtatgt aaataaacat gcattccaca 19320
caccagcttt tgataaaagt gcttttgtta atttaaaaca attaccattt ttctattact 19380
ctgacagtcc atgtgagtct catggaaaac aagtagtgtc agatatagat tatgtaccac 19440
taaagtctgc tacgtgtata acacgttgca atttaggtgg tgctgtctgt agacatcatg 19500
ctaatgagta cagattgtat ctcgatgctt ataacatgat gatctcagct ggctttagct 19560
tgtgggttta caaacaattt gatacttata acctctggaa cacttttaca agacttcaga 19620
gtttagaaaa tgtggctttt aatgttgtaa ataagggaca ctttgatgga caacagggtg 19680
aagtaccagt ttctatcatt aataacactg tttacacaaa agttgatggt gttgatgtag 19740
aattgtttga aaataaaaca acattacctg ttaatgtagc atttgagctt tgggctaagc 19800
gcaacattaa accagtacca gaggtgaaaa tactcaataa tttgggtgtg gacattgctg 19860
ctaatactgt gatctgggac tacaaaagag atgctccagc acatatatct actattggtg 19920
tttgttctat gactgacata gccaagaaac caactgaaac gatttgtgca ccactcactg 19980
tcttttttga tggtagagtt gatggtcaag tagacttatt tagaaatgcc cgtaatggtg 20040
ttcttattac agaaggtagt gttaaaggtt tacaaccatc tgtaggtccc aaacaagcta 20100
gtcttaatgg agtcacatta attggagaag ccgtaaaaac acagttcaat tattataaga 20160
aagttgatgg tgttgtccaa caattacctg aaacttactt tactcagagt agaaatttac 20220
aagaatttaa acccaggagt caaatggaaa ttgatttctt agaattagct atggatgaat 20280
tcattgaacg gtataaatta gaaggctatg ccttcgaaca tatcgtttat ggagatttta 20340
gtcatagtca gttaggtggt ttacatctac tgattggact agctaaacgt tttaaggaat 20400
caccttttga attagaagat tttattccta tggacagtac agttaaaaac tatttcataa 20460
cagatgcgca aacaggttca tctaagtgtg tgtgttctgt tattgattta ttacttgatg 20520
attttgttga aataataaaa tcccaagatt tatctgtagt ttctaaggtt gtcaaagtga 20580
ctattgacta tacagaaatt tcatttatgc tttggtgtaa agatggccat gtagaaacat 20640
tttacccaaa attacaatct agtcaagcgt ggcaaccggg tgttgctatg cctaatcttt 20700
acaaaatgca aagaatgcta ttagaaaagt gtgaccttca aaattatggt gatagtgcaa 20760
cattacctaa aggcataatg atgaatgtcg caaaatatac tcaactgtgt caatatttaa 20820
acacattaac attagctgta ccctataata tgagagttat acattttggt gctggttctg 20880
ataaaggagt tgcaccaggt acagctgttt taagacagtg gttgcctacg ggtacgctgc 20940
ttgtcgattc agatcttaat gactttgtct ctgatgcaga ttcaactttg attggtgatt 21000
gtgcaactgt acatacagct aataaatggg atctcattat tagtgatatg tacgacccta 21060
agactaaaaa tgttacaaaa gaaaatgact ctaaagaggg ttttttcact tacatttgtg 21120
ggtttataca acaaaagcta gctcttggag gttccgtggc tataaagata acagaacatt 21180
cttggaatgc tgatctttat aagctcatgg gacacttcgc atggtggaca gcctttgtta 21240
ctaatgtgaa tgcgtcatca tctgaagcat ttttaattgg atgtaattat cttggcaaac 21300
cacgcgaaca aatagatggt tatgtcatgc atgcaaatta catattttgg aggaatacaa 21360
atccaattca gttgtcttcc tattctttat ttgacatgag taaatttccc cttaaattaa 21420
ggggtactgc tgttatgtct ttaaaagaag gtcaaatcaa tgatatgatt ttatctcttc 21480
ttagtaaagg tagacttata attagagaaa acaacagagt tgttatttct agtgatgttc 21540
ttgttaacaa ctaaacgaac aatgtttgtt tttcttgttt tattgccact agtctctagt 21600
cagtgtgtta atcttacaac cagaactcaa ttaccccctg catacactaa ttctttcaca 21660
cgtggtgttt attaccctga caaagttttc agatcctcag ttttacattc aactcaggac 21720
ttgttcttac ctttcttttc caatgttact tggttccatg ctatacatgt ctctgggacc 21780
aatggtacta agaggtttga taaccctgtc ctaccattta atgatggtgt ttattttgct 21840
tccactgaga agtctaacat aataagaggc tggatttttg gtactacttt agattcgaag 21900
acccagtccc tacttattgt taataacgct actaatgttg ttattaaagt ctgtgaattt 21960
caattttgta atgatccatt tttgggtgtt tattaccaca aaaacaacaa aagttggatg 22020
gaaagtgagt tcagagttta ttctagtgcg aataattgca cttttgaata tgtctctcag 22080
ccttttctta tggaccttga aggaaaacag ggtaatttca aaaatcttag ggaatttgtg 22140
tttaagaata ttgatggtta ttttaaaata tattctaagc acacgcctat taatttagtg 22200
cgtgatctcc ctcagggttt ttcggcttta gaaccattgg tagatttgcc aataggtatt 22260
aacatcacta ggtttcaaac tttacttgct ttacatagaa gttatttgac tcctggtgat 22320
tcttcttcag gttggacagc tggtgctgca gcttattatg tgggttatct tcaacctagg 22380
acttttctat taaaatataa tgaaaatgga accattacag atgctgtaga ctgtgcactt 22440
gaccctctct cagaaacaaa gtgtacgttg aaatccttca ctgtagaaaa aggaatctat 22500
caaacttcta actttagagt ccaaccaaca gaatctattg ttagatttcc taatattaca 22560
aacttgtgcc cttttggtga agtttttaac gccaccagat ttgcatctgt ttatgcttgg 22620
aacaggaaga gaatcagcaa ctgtgttgct gattattctg tcctatataa ttccgcatca 22680
ttttccactt ttaagtgtta tggagtgtct cctactaaat taaatgatct ctgctttact 22740
aatgtctatg cagattcatt tgtaattaga ggtgatgaag tcagacaaat cgctccaggg 22800
caaactggaa agattgctga ttataattat aaattaccag atgattttac aggctgcgtt 22860
atagcttgga attctaacaa tcttgattct aaggttggtg gtaattataa ttacctgtat 22920
agattgttta ggaagtctaa tctcaaacct tttgagagag atatttcaac tgaaatctat 22980
caggccggta gcacaccttg taatggtgtt gaaggttttaattgttactt tcctttacaa 23040
tcatatggtt tccaacccac taatggtgtt ggttaccaac catacagagt agtagtactt 23100
tcttttgaac ttctacatgc accagcaact gtttgtggac ctaaaaagtc tactaatttg 23160
gttaaaaaca aatgtgtcaa tttcaacttc aatggtttaa caggcacagg tgttcttact 23220
gagtctaaca aaaagtttct gcctttccaa caatttggca gagacattgc tgacactact 23280
gatgctgtcc gtgatccaca gacacttgag attcttgaca ttacaccatg ttcttttggt 23340
ggtgtcagtg ttataacacc aggaacaaat acttctaacc aggttgctgt tctttatcag 23400
gatgttaact gcacagaagt ccctgttgct attcatgcag atcaacttac tcctacttgg 23460
cgtgtttatt ctacaggttc taatgttttt caaacacgtg caggctgttt aataggggct 23520
gaacatgtca acaactcata tgagtgtgac atacccattg gtgcaggtat atgcgctagt 23580
tatcagactc agactaattc tcctcggcgg gcacgtagtg tagctagtca atccatcatt 23640
gcctacacta tgtcacttgg tgcagaaaat tcagttgctt actctaataa ctctattgcc 23700
atacccacaa attttactat tagtgttacc acagaaattc taccagtgtc tatgaccaag 23760
acatcagtag attgtacaat gtacatttgt ggtgattcaa ctgaatgcag caatcttttg 23820
ttgcaatatg gcagtttttg tacacaatta aaccgtgctt taactggaat agctgttgaa 23880
caagacaaaa acacccaaga agtttttgca caagtcaaac aaatttacaa aacaccacca 23940
attaaagatt ttggtggttt taatttttca caaatattac cagatccatc aaaaccaagc 24000
aagaggtcat ttattgaaga tctacttttc aacaaagtga cacttgcaga tgctggcttc 24060
atcaaacaat atggtgattg ccttggtgat attgctgcta gagacctcat ttgtgcacaa 24120
aagtttaacg gccttactgt tttgccacct ttgctcacag atgaaatgat tgctcaatac 24180
acttctgcac tgttagcggg tacaatcact tctggttgga cctttggtgc aggtgctgca 24240
ttacaaatac catttgctat gcaaatggct tataggttta atggtattgg agttacacag 24300
aatgttctct atgagaacca aaaattgatt gccaaccaat ttaatagtgc tattggcaaa 24360
attcaagact cactttcttc cacagcaagt gcacttggaa aacttcaaga tgtggtcaac 24420
caaaatgcac aagctttaaa cacgcttgtt aaacaactta gctccaattt tggtgcaatt 24480
tcaagtgttt taaatgatat cctttcacgt cttgacaaag ttgaggctga agtgcaaatt 24540
gataggttga tcacaggcag acttcaaagt ttgcagacat atgtgactca acaattaatt 24600
agagctgcag aaatcagagc ttctgctaat cttgctgcta ctaaaatgtc agagtgtgta 24660
cttggacaat caaaaagagt tgatttttgt ggaaagggct atcatcttat gtccttccct 24720
cagtcagcac ctcatggtgt agtcttcttg catgtgactt atgtccctgc acaagaaaag 24780
aacttcacaa ctgctcctgc catttgtcat gatggaaaag cacactttcc tcgtgaaggt 24840
gtctttgttt caaatggcac acactggttt gtaacacaaa ggaattttta tgaaccacaa 24900
atcattacta cagacaacac atttgtgtct ggtaactgtg atgttgtaat aggaattgtc 24960
aacaacacag tttatgatcc tttgcaacct gaattagact cattcaagga ggagttagat 25020
aaatatttta agaatcatac atcaccagat gttgatttag gtgacatctc tggcattaat 25080
gcttcagttg taaacattca aaaagaaatt gaccgcctca atgaggttgc caagaattta 25140
aatgaatctc tcatcgatct ccaagaactt ggaaagtatg agcagtatat aaaatggcca 25200
tggtacattt ggctaggttt tatagctggc ttgattgcca tagtaatggt gacaattatg 25260
ctttgctgta tgaccagttg ctgtagttgt ctcaagggct gttgttcttg tggatcctgc 25320
tgcaaatttg atgaagacga ctctgagcca gtgctcaaag gagtcaaatt acattacaca 25380
taaacgaact tatggatttg tttatgagaa tcttcacaat tggaactgta actttgaagc 25440
aaggtgaaat caaggatgct actccttcag attttgttcg cgctactgca acgataccga 25500
tacaagcctc actccctttc ggatggctta ttgttggcgt tgcacttctt gctgtttttc 25560
agagcgcttc caaaatcata accctcaaaa agagatggca actagcactc tccaagggtg 25620
ttcactttgt ttgcaacttg ctgttgttgt ttgtaacagt ttactcacac cttttgctcg 25680
ttgctgctgg ccttgaagcc ccttttctct atctttatgc tttagtctac ttcttgcaga 25740
gtataaactt tgtaagaata ataatgaggc tttggctttg ctggaaatgc cgttccaaaa 25800
acccattact ttatgatgcc aactattttc tttgctggca tactaattgt tacgactatt 25860
gtatacctta caatagtgta acttcttcaa ttgtcattac ttcaggtgat ggcacaacaa 25920
gtcctatttc tgaacatgac taccagattg gtggttatac tgaaaaatgg gaatctggag 25980
taaaagactg tgttgtatta cacagttact tcacttcaga ctattaccag ctgtactcaa 26040
ctcaattgag tacagacact ggtgttgaac atgttacctt cttcatctac aataaaattg 26100
ttgatgagcc tgaagaacat gtccaaattc acacaatcga cggttcatcc ggagttgtta 26160
atccagtaat ggaaccaatt tatgatgaac cgacgacgac tactagcgtg cctttgtaag 26220
cacaagctga tgagtacgaa cttatgtact cattcgtttc ggaagagaca ggtacgttaa 26280
tagttaatag cgtacttctt tttcttgctt tcgtggtatt cttgctagtt acactagcca 26340
tccttactgc gcttcgattg tgtgcgtact gctgcaatat tgttaacgtg agtcttgtaa 26400
aaccttcttt ttacgtttac tctcgtgtta aaaatctgaa ttcttctaga gttcctgatc 26460
ttctggtcta aacgaactaa atattatatt agtttttctg tttggaactt taattttagc 26520
catggcagat tccaacggta ctattaccgt tgaagagctt aaaaagctcc ttgaacaatg 26580
gaacctagta ataggtttcc tattccttac atggatttgt cttctacaat ttgcctatgc 26640
caacaggaat aggtttttgt atataattaa gttaattttc ctctggctgt tatggccagt 26700
aactttagct tgttttgtgc ttgctgctgt ttacagaata aattggatca ccggtggaat 26760
tgctatcgca atggcttgtc ttgtaggctt gatgtggctc agctacttca ttgcttcttt 26820
cagactgttt gcgcgtacgc gttccatgtg gtcattcaat ccagaaacta acattcttct 26880
caacgtgcca ctccatggca ctattctgac cagaccgctt ctagaaagtg aactcgtaat 26940
cggagctgtg atccttcgtg gacatcttcg tattgctgga caccatctag gacgctgtga 27000
catcaaggac ctgcctaaag aaatcactgt tgctacatca cgaacgcttt cttattacaa 27060
attgggagct tcgcagcgtg tagcaggtga ctcaggtttt gctgcataca gtcgctacag 27120
gattggcaac tataaattaa acacagacca ttccagtagc agtgacaata ttgctttgct 27180
tgtacagtaa gtgacaacag atgtttcatc tcgttgactt tcaggttact atagcagaga 27240
tattactaat tattatgagg acttttaaag tttccatttg gaatcttgat tacatcataa 27300
acctcataat taaaaattta tctaagtcac taactgagaa taaatattct caattagatg 27360
aagagcaacc aatggagatt gattaaacga acatgaaaat tattcttttc ttggcactga 27420
taacactcgc tacttgtgag ctttatcact accaagagtg tgttagaggt acaacagtac 27480
ttttaaaaga accttgctct tctggaacat acgagggcaa ttcaccattt catcctctag 27540
ctgataacaa atttgcactg acttgcttta gcactcaatt tgcttttgct tgtcctgacg 27600
gcgtaaaaca cgtctatcag ttacgtgcca gatcagtttc acctaaactg ttcatcagac 27660
aagaggaagt tcaagaactt tactctccaa tttttcttat tgttgcggca atagtgttta 27720
taacactttg cttcacactc aaaagaaaga cagaatgatt gaactttcat taattgactt 27780
ctatttgtgc tttttagcct ttctgctatt ccttgtttta attatgctta ttatcttttg 27840
gttctcactt gaactgcaag atcataatga aacttgtcac gcctaaacga acatgaaatt 27900
tcttgttttc ttaggaatca tcacaactgt agctgcattt caccaagaat gtagtttaca 27960
gtcatgtact caacatcaac catatgtagt tgatgacccg tgtcctattc acttctattc 28020
taaatggtat attagagtag gagctagaaa atcagcacct ttaattgaat tgtgcgtgga 28080
tgaggctggt tctaaatcac ccattcagta catcgatatc ggtaattata cagtttcctg 28140
tttacctttt acaattaatt gccaggaacc taaattgggt agtcttgtag tgcgttgttc 28200
gttctatgaa gactttttag agtatcatga cgttcgtgtt gttttagatt tcatctaaac 28260
gaacaaacta aaatgtctga taatggaccc caaaatcagc gaaatgcacc ccgcattacg 28320
tttggtggac cctcagattc aactggcagt aaccagaatg gagaacgcag tggggcgcga 28380
tcaaaacaac gtcggcccca aggtttaccc aataatactg cgtcttggtt caccgctctc 28440
actcaacatg gcaaggaaga ccttaaattc cctcgaggac aaggcgttcc aattaacacc 28500
aatagcagtc cagatgacca aattggctac taccgaagag ctaccagacg aattcgtggt 28560
ggtgacggta aaatgaaaga tctcagtcca agatggtatt tctactacct aggaactggg 28620
ccagaagctg gacttcccta tggtgctaac aaagacggca tcatatgggt tgcaactgag 28680
ggagccttga atacaccaaa agatcacatt ggcacccgca atcctgctaa caatgctgca 28740
atcgtgctac aacttcctca aggaacaaca ttgccaaaag gcttctacgc agaagggagc 28800
agaggcggca gtcaagcctc ttctcgttcc tcatcacgta gtcgcaacag ttcaagaaat 28860
tcaactccag gcagcagtag gggaacttct cctgctagaa tggctggcaa tggcggtgat 28920
gctgctcttg ctttgctgct gcttgacaga ttgaaccagc ttgagagcaa aatgtctggt 28980
aaaggccaac aacaacaagg ccaaactgtc actaagaaat ctgctgctga ggcttctaag 29040
aagcctcggc aaaaacgtac tgccactaaa gcatacaatg taacacaagc tttcggcaga 29100
cgtggtccag aacaaaccca aggaaatttt ggggaccagg aactaatcag acaaggaact 29160
gattacaaac attggccgca aattgcacaa tttgccccca gcgcttcagc gttcttcgga 29220
atgtcgcgca ttggcatgga agtcacacct tcgggaacgt ggttgaccta cacaggtgcc 29280
atcaaattgg atgacaaaga tccaaatttc aaagatcaag tcattttgct gaataagcat 29340
attgacgcat acaaaacatt cccaccaaca gagcctaaaa aggacaaaaa gaagaaggct 29400
gatgaaactc aagccttacc gcagagacag aagaaacagc aaactgtgac tcttcttcct 29460
gctgcagatt tggatgattt ctccaaacaa ttgcaacaat ccatgagcag tgctgactca 29520
actcaggcct aaactcatgc agaccacaca aggcagatgg gctatataaa cgttttcgct 29580
tttccgttta cgatatatag tctactcttg tgcagaatga attctcgtaa ctacatagca 29640
caagtagatg tagttaactt taatctcaca tagcaatctt taatcagtgt gtaacattag 29700
ggaggacttg aaagagccac cacattttca ccgaggccac gcggagtacg atcgagtgta 29760
cagtgaacaa tgctagggag agctgcctat atggaagagc cctaatgtgt aaaattaatt 29820
ttagtagtgc tatccccatg tgattttaat agcttcttag gagaatgaca aaaaaaaaaa 29880
a 29881
<210>228
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>228
gmsumsgmug aucauugugg ugaamsamsc m 31
<210>229
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>229
umsumscmac cacaaugauc acacmsumsu m 31
<210>230
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>230
umsumsgmuc accugugcaa aggamsamsa m 31
<210>231
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>231
umscmscmuu ugcacaggug acaamsumsu m 31
<210>232
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>232
amsgmsgmga uuguacagaa agugmsumsg m 31
<210>233
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>233
cmsamscmuu ucuguacaau cccumsumsu m 31
<210>234
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>234
cmsumscmgg uacagaagua aaugmsamsg m 31
<210>235
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>235
cmsamsumuu acuucuguac cgagmsumsu m 31
<210>236
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>236
gmsgmsumga uugugaagaa gaagmsamsg m 31
<210>237
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>237
cmsumsumcu ucuucacaau caccmsumsu m 31
<210>238
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>238
gmsamsamga gcaagaagaa gauumsgmsg m 31
<210>239
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>239
amsamsumcu ucuucuugcu cuucmsumsu m 31
<210>240
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>240
umsgmsgmug augugguggc uauumsgmsa m 31
<210>241
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>241
amsamsumag ccaccacauc accamsumsu m 31
<210>242
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>242
amscmscmaa auaccuggug uauamscmsg m 31
<210>243
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>243
umsamsumac accagguauu uggumsumsu m 31
<210>244
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>244
amsumsamcc ugguguauac guugmsumsc m 31
<210>245
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>245
cmsamsamcg uauacaccag guaumsumsu m 31
<210>246
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>246
cmsumsamcc gaaguuguag gagamscmsa m 31
<210>247
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>247
umscmsumcc uacaacuucg guagmsumsu m 31
<210>248
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>248
gmsgmsgmca cacuagaacc agaamsumsa m 31
<210>249
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>249
umsumscmug guucuagugu gcccmsumsu m 31
<210>250
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>250
gmsgmsgmug uuaucacgca ugaumsgmsu m 31
<210>251
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>251
amsumscmau gcgugauaac acccmsumsu m 31
<210>252
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>252
umsamsgmgc gugguaagag aauumscmsc m 31
<210>253
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>253
amsamsumuc ucuuaccacg ccuamsumsu m 31
<210>254
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>254
amsumsgmcc cguaauggug uucumsumsa m 31
<210>255
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>255
amsgmsamac accauuacgg gcaumsumsu m 31
<210>256
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>256
gmscmsumag ucuuaaugga gucamscmsa m 31
<210>257
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>257
umsgmsamcu ccauuaagac uagcmsumsu m 31
<210>258
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>258
gmsumsumga ugguguuguc caacmsamsa m 31
<210>259
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>259
gmsumsumgg acaacaccau caacmsumsu m 31
<210>260
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>260
umsumscmuu ucacacgugg uguumsumsa m 31
<210>261
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>261
amsamscmac cacgugugaa agaamsumsu m 31
<210>262
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>262
cmscmscmug uccuaccauu uaaumsgmsa m 31
<210>263
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>263
amsumsumaa augguaggac agggmsumsu m 31
<210>264
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>264
amsamsgmac ccagucccua cuuamsumsu m 31
<210>265
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>265
amscmsamau aaguagggac ugggmsumsc m 31
<210>266
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>266
amsamsgmuu ggauggaaag ugagmsumsu m 31
<210>267
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>267
umsgmsamac ucacuuucca uccamsamsc m 31
<210>268
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>268
amsamsgmug uacguugaaa uccumsumsc m 31
<210>269
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>269
gmsumsgmaa ggauuucaac guacmsamsc m 31
<210>270
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>270
amsamscmgc caccagauuu gcaumscmsu m 31
<210>271
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>271
amscmsamga ugcaaaucug guggmscmsg m 31
<210>272
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>272
amsamscmag gaagagaauc agcamsamsc m 31
<210>273
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>273
cmsamsgmuu gcugauucuc uuccmsumsg m 31
<210>274
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>274
amsamscmcc acuaauggug uuggmsumsu m 31
<210>275
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>275
gmsumsamac caacaccauu agugmsgmsg m 31
<210>276
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>276
amsamscmuu cuacaugcac cagcmsamsa m 31
<210>277
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>277
amsgmsumug cuggugcaug uagamsamsg m 31
<210>278
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>278
amsamscmca gguugcuguu cuuumsamsu m 31
<210>279
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>279
umsgmsamua aagaacagca accumsgmsg m 31
<210>280
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>280
amsamscmac gugcaggcug uuuamsamsu m 31
<210>281
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>281
cmsumsamuu aaacagccug cacgmsumsg m 31
<210>282
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>282
cmsumscmua uugccauacc cacamsamsa m 31
<210>283
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>283
umsgmsumgg guauggcaau agagmsumsu m 31
<210>284
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>284
amsamsumcc aucauugccu acacmsumsa m 31
<210>285
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>285
cmsamsumag uguaggcaau gaugmsgmsa m 31
<210>286
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>286
amsamsamcc gugcuuuaac uggamsamsu m 31
<210>287
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>287
cmsumsamuu ccaguuaaag cacgmsgmsu m 31
<210>288
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>288
amsamscmug gaauagcugu ugaamscmsa m 31
<210>289
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>289
cmsumsumgu ucaacagcua uuccmsamsg m 31
<210>290
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>290
amsamsumca cuucugguug gaccmsumsu m 31
<210>291
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>291
cmsamsamag guccaaccag aagumsgmsa m 31
<210>292
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>292
amsamsamgu ugaggcugaa gugcmsamsa m 31
<210>293
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>293
amsumsumug cacuucagcc ucaamscmsu m 31
<210>294
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>294
amsamsumca gagcuucugc uaaumscmsu m 31
<210>295
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>295
cmsamsamga uuagcagaag cucumsgmsa m 31
<210>296
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>296
amsamsumgg cacacacugg uuugmsumsa m 31
<210>297
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>297
gmsumsumac aaaccagugu gugcmscmsa m 31
<210>298
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>298
amsamsumag gaauugucaa caacmsamsc m 31
<210>299
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>299
cmsumsgmug uuguugacaa uuccmsumsa m 31
<210>300
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>300
amsamsumcu cucaucgauc uccamsamsg m 31
<210>301
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>301
umsumscmuu ggagaucgau gagamsgmsa m 31
<210>302
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>302
gmsamsgmac agguacguua auagmsumsu m 31
<210>303
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>303
cmsumsamuu aacguaccug ucucmsumsu m31
<210>304
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>304
gmsumsumac acuagccauc cuuamscmsu m 31
<210>305
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>305
umsamsamgg auggcuagug uaacmsumsu m 31
<210>306
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>306
umscmscmuu acugcgcuuc gauumsgmsu m 31
<210>307
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>307
amsamsumcg aagcgcagua aggamsumsu m 31
<210>308
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>308
cmsumsgmcu gcaauauugu uaacmsgmsu m 31
<210>309
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>309
gmsumsumaa caauauugca gcagmsumsu m 31
<210>310
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>310
umsumsgmcu aucgcaaugg cuugmsumsc m 31
<210>311
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>311
cmsamsamgc cauugcgaua gcaamsumsu m 31
<210>312
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>312
cmsgmsgmua cuauuaccgu ugaamsgmsa m 31
<210>313
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>313
umsumscmaa cgguaauagu accgmsumsu m 31
<210>314
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>314
amsgmscmuc cuugaacaau ggaamscmsc m 31
<210>315
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>315
umsumscmca uuguucaagg agcumsumsu m 31
<210>316
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>316
amsumsumgg aucaccggug gaaumsumsg m 31
<210>317
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>317
amsumsumcc accggugauc caaumsumsu m 31
<210>318
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>318
gmsgmsamcc ugccuaaaga aaucmsamsc m 31
<210>319
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>319
gmsamsumuu cuuuaggcag guccmsumsu m 31
<210>320
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>320
umscmsamcu guugcuacau cacgmsamsa m 31
<210>321
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>321
cmsgmsumga uguagcaaca gugamsumsu m 31
<210>322
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>322
umsgmsgmaa ccuaguaaua gguumsumsc m 31
<210>323
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>323
amsamscmcu auuacuaggu uccamsumsu m 31
<210>324
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>324
umsumsgmga ucaccggugg aauumsgmsc m 31
<210>325
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>325
amsamsumuc caccggugau ccaamsumsu m 31
<210>326
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>326
cmsumscmgu aaucggagcu gugamsumsc m 31
<210>327
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>327
umscmsamca gcuccgauua cgagmsumsu m 31
<210>328
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>328
cmscmsumag uaauagguuu ccuamsumsu m 31
<210>329
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>329
umsamsgmga aaccuauuac uaggmsumsu m 31
<210>330
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>330
cmsamsumgg caaggaagac cuuamsamsa m 31
<210>331
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>331
umsamsamgg ucuuccuugc caugmsumsu m 31
<210>332
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>332
gmsgmscmgu uccaauuaac accamsamsu m 31
<210>333
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>333
umsgmsgmug uuaauuggaa cgccmsumsu m 31
<210>334
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>334
cmsamscmca auagcagucc agaumsgmsa m 31
<210>335
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>335
amsumscmug gacugcuauu ggugmsumsu m 31
<210>336
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>336
umsamsgmca guccagauga ccaamsamsu m 31
<210>337
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>337
umsumsgmgu caucuggacu gcuamsumsu m 31
<210>338
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>338
umsumsgmgc uacuaccgaa gagcmsumsa m 31
<210>339
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>339
gmscmsumcu ucgguaguag ccaamsumsu m 31
<210>340
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>340
umscmscmugcuaacaaugc ugcamsamsu m 31
<210>341
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>341
umsgmscmag cauuguuagc aggamsumsu m 31
<210>342
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>342
umsgmscmug caaucgugcu acaamscmsu m 31
<210>343
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>343
umsumsgmua gcacgauugc agcamsumsu m 31
<210>344
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>344
umscmsgmug cuacaacuuc cucamsamsg m 31
<210>345
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>345
umsgmsamgg aaguuguagc acgamsumsu m 31
<210>346
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>346
cmsumsumcc ucaaggaaca acaumsumsg m 31
<210>347
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>347
amsumsgmuu guuccuugag gaagmsumsu m 31
<210>348
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>348
amsumsgmuc ugguaaaggc caacmsamsa m 31
<210>349
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>349
gmsumsumgg ccuuuaccag acaumsumsu m 31
<210>350
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>350
cmsamsamgg ccaaacuguc acuamsamsg m 31
<210>351
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>351
umsamsgmug acaguuuggc cuugmsumsu m 31
<210>352
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>352
amsumscmug cugcugaggc uucumsamsa m 31
<210>353
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>353
amsgmsamag ccucagcagc agaumsumsu m 31
<210>354
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>354
amscmsgmua cugccacuaa agcamsumsa m 31
<210>355
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>355
umsgmscmuu uaguggcagu acgumsumsu m 31
<210>356
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>356
amsgmscmau acaauguaac acaamsgmsc m 31
<210>357
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>357
umsumsgmug uuacauugua ugcumsumsu m 31
<210>358
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>358
gmsgmscmug augaaacuca agccmsumsu m 31
<210>359
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>359
gmsgmscmuu gaguuucauc agccmsumsu m 31
<210>360
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>360
amscmsamgc aaacugugac ucuumscmsu m 31
<210>361
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>361
amsamsgmag ucacaguuug cugumsumsu m 31
<210>362
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>362
umscmsamcc cauucaguac aucgmsamsu m 31
<210>363
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>363
cmsgmsamug uacugaaugg gugamsumsu m31
<210>364
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>364
umsumsgmcc aggaaccuaa auugmsgmsg m 31
<210>365
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>365
cmsamsamuu uagguuccug gcaamsumsu m 31
<210>366
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>366
cmscmsumaa auuggguagu cuugmsumsa m 31
<210>367
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>367
cmsamsamga cuacccaauu uaggmsumsu m 31
<210>368
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>368
cmsamsumca accauaugua guugmsamsu m 31
<210>369
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>369
cmsamsamcu acauaugguu gaugmsumsu m 31
<210>370
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>370
cmscmscmgu guccuauuca cuucmsumsa m 31
<210>371
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>371
gmsamsamgu gaauaggaca cgggmsumsu m 31
<210>372
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>372
umscmsamgc accuuuaauu gaaumsumsg m 31
<210>373
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>373
amsumsumca auuaaaggug cugamsumsu m 31
<210>374
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>374
umscmsamca acuguagcug cauumsumsc m 31
<210>375
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>375
amsamsumgc agcuacaguu gugamsumsu m 31
<210>376
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>376
gmscmsumgc auuucaccaa gaaumsgmsu m 31
<210>377
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>377
amsumsumcu uggugaaaug cagcmsumsu m 31
<210>378
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>378
gmsumsumga ugacccgugu ccuamsumsu m 31
<210>379
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>379
umsamsgmga cacgggucau caacmsumsu m 31
<210>380
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>380
umsumsamga ugaagagcaa ccaamsumsg m 31
<210>381
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>381
umsumsgmgu ugcucuucau cuaamsumsu m 31
<210>382
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>382
amsgmsamgc aaccaaugga gauumsgmsa m 31
<210>383
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>383
amsamsumcu ccauugguug cucumsumsu m 31
<210>384
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>384
umscmsumcg uugacuuuca gguumsamsc m 31
<210>385
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>385
amsamscmcu gaaagucaac gagamsumsu m 31
<210>386
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>386
gmsgmsumua cuauagcaga gauamsumsu m31
<210>387
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>387
umsamsumcu cugcuauagu aaccmsumsu m 31
<210>388
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>388
umscmsumaa gucacuaacu gagamsamsu m 31
<210>389
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>389
umscmsumca guuagugacu uagamsumsu m 31
<210>390
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>390
cmsamsumgg caaggaagac cuuamsamsa m 31
<210>391
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>391
umsamsamgg ucuuccuugc caugmsumsu m 31
<210>392
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>392
gmsgmscmgu uccaauuaac accamsamsu m 31
<210>393
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>393
umsgmsgmug uuaauuggaa cgccmsumsu m 31
<210>394
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>394
cmsamscmca auagcagucc agaumsgmsa m 31
<210>395
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>395
amsumscmug gacugcuauu ggugmsumsu m 31
<210>396
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>396
umscmsgmug cuacaacuuc cucamsamsg m 31
<210>397
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>397
umsgmsamgg aaguuguagc acgamsumsu m 31
<210>398
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>398
cmsumsumcc ucaaggaaca acaumsumsg m 31
<210>399
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>399
amsumsgmuu guuccuugag gaagmsumsu m 31
<210>400
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>400
gmscmscmuc uucucguucc ucaumscmsa m 31
<210>401
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>401
amsumsgmag gaacgagaag aggcmsumsu m 31
<210>402
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>402
cmsamscmuc gcuacuugug agcumsumsu m 31
<210>403
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>403
amsgmscmuc acaaguagcg agugmsumsu m 31
<210>404
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>404
gmsamsgmug uguuagaggu acaamscmsa m 31
<210>405
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>405
umsumsgmua ccucuaacac acucmsumsu m 31
<210>406
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>406
gmsamsamcc uugcucuucu ggaamscmsa m 31
<210>407
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>407
umsumscmca gaagagcaag guucmsumsu m 31
<210>408
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>408
cmscmsumug cucuucugga acaumsamsc m 31
<210>409
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>409
amsumsgmuu ccagaagagc aaggmsumsu m 31
<210>410
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>410
gmsamsgmga aguucaagaa cuuumsamsc m 31
<210>411
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>411
amsamsamgu ucuugaacuu ccucmsumsu m 31
<210>412
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>412
cmsumsgmac uugcuuuagc acucmsamsa m 31
<210>413
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>413
gmsamsgmug cuaaagcaag ucagmsumsu m 31
<210>414
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>414
gmsgmsumga aaucaaggau gcuamscmsu m 31
<210>415
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>415
umsamsgmca uccuugauuu caccmsumsu m 31
<210>416
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>416
gmsgmsgmug uucacuuugu uugcmsamsa m 31
<210>417
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>417
gmscmsamaa caaagugaac acccmsumsu m 31
<210>418
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>418
amsgmsamcu guguuguauu acacmsamsg m 31
<210>419
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>419
gmsumsgmua auacaacaca gucumsumsu m 31
<210>420
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>420
umsumscmac acaaucgacg guucmsamsu m 31
<210>421
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>421
gmsamsamcc gucgauugug ugaamsumsu m 31
<210>422
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>422
cmsumsamgc acucuccaag ggugmsumsu m 31
<210>423
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>423
cmsamscmcc uuggagagug cuagmsumsu m 31
<210>424
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>424
cmsumsumgc uguuguuguu uguamsamsc m 31
<210>425
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>425
umsamscmaa acaacaacag caagmsumsu m 31
<210>426
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>426
gmsumscmcu auuucugaac augamscmsu m 31
<210>427
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>427
umscmsamug uucagaaaua ggacmsumsu m 31
<210>428
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>428
amsumsumgu ugaugagccu gaagmsamsa m 31
<210>429
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>429
cmsumsumca ggcucaucaa caaumsumsu m 31
<210>430
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>430
cmsamsumgu ccaaauucac acaamsumsc m 31
<210>431
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>431
umsumsgmug ugaauuugga caugmsumsu m 31
<210>432
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>432
umscmsgmac gguucauccg gagumsumsg m 31
<210>433
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>433
amscmsumcc ggaugaaccg ucgamsumsu m 31
<210>434
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>434
umsumscmuc cgaacguguc acgumstmst m 31
<210>435
<211>31
<212>DNA/RNA
<213> Artificial Sequence (Artificial Sequence)
<400>435
amscmsgmug acacguucgg agaamstmst m 31
Claims (8)
1. An siRNA, comprising a sense strand and an antisense strand, wherein said sense strand comprises the sequence set forth in SEQ ID NO: 5, and the antisense strand comprises the nucleotide sequence shown as SEQ ID NO: 6; alternatively, the sense strand comprises the sequence set forth as SEQ ID NO: 9, and the antisense strand contains a nucleotide sequence shown as SEQ ID NO: 10; alternatively, the sense strand comprises the sequence set forth as SEQ ID NO: 57, and the antisense strand comprises the nucleotide sequence shown as seq id NO: 58; alternatively, the sense strand comprises the sequence set forth as SEQ ID NO: 59, and the antisense strand comprises the nucleotide sequence shown as SEQ ID NO: 60; alternatively, the sense strand comprises the sequence set forth as SEQ ID NO: 69, and the antisense strand comprises the nucleotide sequence shown as SEQ ID NO: 70; alternatively, the sense strand comprises the sequence set forth as SEQ ID NO: 123, and the antisense strand comprises the nucleotide sequence shown as SEQ ID NO: 124; alternatively, the sense strand comprises the sequence set forth as SEQ ID NO: 131, and the antisense strand comprises the nucleotide sequence shown as seq id NO: 132; alternatively, the sense strand comprises the sequence set forth as SEQ ID NO: 145, and the antisense strand comprises the nucleotide sequence shown as SEQ ID NO: 146; alternatively, the sense strand comprises the sequence set forth as SEQ ID NO: 171, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 172; alternatively, the sense strand comprises the sequence set forth as SEQ ID NO: 177, and the antisense strand comprises the nucleotide sequence shown as SEQ ID NO: 178; alternatively, the sense strand comprises the sequence set forth as SEQ ID NO: 185, and the antisense strand comprises the nucleotide sequence shown in SEQ ID NO: 186; alternatively, the sense strand comprises the sequence set forth as SEQ ID NO: 197, and the antisense strand comprises the nucleotide sequence shown as SEQ ID NO: 198;
wherein,
sense strand 5'-AGGGAUUGUACAGAAAGUGUG-3' (SEQ ID NO: 5),
antisense strand 5'-CACUUUCUGUACAAUCCCUUU-3' (SEQ ID NO: 6);
sense strand 5'-GGUGAUUGUGAAGAAGAAGAG-3' (SEQ ID NO: 9),
antisense strand 5'-CUUCUUCUUCACAAUCACCUU-3' (SEQ ID NO: 10);
sense strand 5'-AAUCCAUCAUUGCCUACACUA-3' (SEQ ID NO: 57),
antisense strand 5'-CAUAGUGUAGGCAAUGAUGGA-3' (SEQ ID NO: 58);
sense strand 5'-AAACCGUGCUUUAACUGGAAU-3' (SEQ ID NO: 59),
antisense strand 5'-CUAUUCCAGUUAAAGCACGGU-3' (SEQ ID NO: 60);
sense strand 5'-AAUGGCACACACUGGUUUGUA-3' (SEQ ID NO: 69),
antisense strand 5'-GUUACAAACCAGUGUGUGCCA-3' (SEQ ID NO: 70);
sense strand 5'-CAAGGCCAAACUGUCACUAAG-3' (SEQ ID NO: 123),
antisense strand 5'-UAGUGACAGUUUGGCCUUGUU-3' (SEQ ID NO: 124);
sense strand 5'-GGCUGAUGAAACUCAAGCCUU-3' (SEQ ID NO: 131),
antisense strand 5'-GGCUUGAGUUUCAUCAGCCUU-3' (SEQ ID NO: 132);
sense strand 5'-UCAGCACCUUUAAUUGAAUUG-3' (SEQ ID NO: 145),
antisense strand 5'-AUUCAAUUAAAGGUGCUGAUU-3' (SEQ ID NO: 146);
sense strand 5'-CUUCCUCAAGGAACAACAUUG-3' (SEQ ID NO: 171),
antisense strand 5'-AUGUUGUUCCUUGAGGAAGUU-3' (SEQ ID NO: 172);
sense strand 5'-GAGUGUGUUAGAGGUACAACA-3' (SEQ ID NO: 177),
antisense strand 5'-UUGUACCUCUAACACACUCUU-3' (SEQ ID NO: 178);
sense strand 5'-CUGACUUGCUUUAGCACUCAA-3' (SEQ ID NO: 185),
antisense strand 5'-GAGUGCUAAAGCAAGUCAGUU-3' (SEQ ID NO: 186);
sense strand 5'-CUUGCUGUUGUUGUUUGUAAC-3' (SEQ ID NO: 197),
antisense strand 5'-UACAAACAACAACAGCAAGUU-3' (SEQ ID NO: 198).
2. The siRNA of claim 1, wherein at least a portion of the phosphate-sugar backbone of at least one single strand of the sense strand and the antisense strand of the siRNA is a phosphorothioate backbone;
or, at least a portion of the nucleotides of at least one single strand of the sense strand and the antisense strand are nucleotide modified;
alternatively, at least one single strand of the sense strand and the antisense strand is linked to a signaling molecule and/or an active molecule and/or a functional group.
3. The siRNA of claim 2, wherein the sense strand of the siRNA is SEQ ID NO: 5 nucleotide sequence, wherein the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 st nucleotides are all 2' -O-methyl ribonucleotide, and the antisense strand of the siRNA is SEQ ID NO: the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 th nucleotides of the 6 th nucleotide sequence are all 2' -O-methyl ribonucleotides;
alternatively, the sense strand of the siRNA SEQ ID NO: 9 nucleotide sequence, wherein the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 st nucleotides are all 2' -O-methyl ribonucleotide, and the antisense strand of the siRNA is SEQ ID NO: 10 nucleotide sequence of 1, 2, 3, 19, 20, 21 nucleotides are all 2' -O-methyl ribonucleotide;
alternatively, the sense strand of the siRNA SEQ ID NO: the nucleotides 1, 2, 3, 19, 20 and 21 of the 57 nucleotide sequence are all 2' -O-methyl ribonucleotide, and the antisense strand of the siRNA is SEQ ID NO: the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 th nucleotides of the 58 nucleotide sequence are all 2' -O-methyl ribonucleotides;
alternatively, the sense strand of the siRNA SEQ ID NO: 59 nucleotide sequence of 2' -O-methyl ribonucleotide in 1 st, 2 nd, 3 rd, 19 th, 20 th, 21 st nucleotide, the antisense strand of said siRNA SEQ ID NO: the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 th nucleotides of the 60 th nucleotide sequence are all 2' -O-methyl ribonucleotides;
alternatively, the sense strand of the siRNA SEQ ID NO: 69 nucleotide sequence of 2' -O-methyl ribonucleotide at the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 st nucleotides, wherein the antisense strand of the siRNA is SEQ ID NO: the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 th nucleotides of the 70 th nucleotide sequence are all 2' -O-methyl ribonucleotides;
alternatively, the sense strand of the siRNA SEQ ID NO: 123, and 2' -O-methyl ribonucleotide in the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 st nucleotides of the siRNA, wherein the antisense strand of the siRNA is SEQ ID NO: the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 st nucleotides of the 124 th nucleotide sequence are all 2' -O-methyl ribonucleotides;
alternatively, the sense strand of the siRNA SEQ ID NO: 131 nucleotide sequence of 2' -O-methyl ribonucleotide at 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 st nucleotides, wherein the antisense strand of the siRNA is SEQ ID NO: the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 th nucleotides of the 132 nucleotide sequence are all 2' -O-methyl ribonucleotides;
alternatively, the sense strand of the siRNA SEQ ID NO: 145 nucleotide sequence is 2' -O-methyl ribonucleotide at nucleotides 1, 2, 3, 19, 20, 21, and the antisense strand of the siRNA is SEQ ID NO: the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 th nucleotides of the 146 nucleotide sequence are all 2' -O-methyl ribonucleotides;
alternatively, the sense strand of the siRNA SEQ ID NO: 171 of the siRNA, wherein the nucleotides at positions 1, 2, 3, 19, 20 and 21 are all 2' -O-methyl ribonucleotides, and the antisense strand of the siRNA is SEQ ID NO: the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 th nucleotides of the 172 nucleotide sequence are all 2' -O-methyl ribonucleotides;
alternatively, the sense strand of the siRNA SEQ ID NO: the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 st nucleotides of the 177 nucleotide sequence are all 2' -O-methyl ribonucleotides, and the antisense strand of the siRNA is SEQ ID NO: 178 nucleotide sequence, nucleotides 1, 2, 3, 19, 20, 21 are all 2' -O-methyl ribonucleotides;
alternatively, the sense strand of the siRNA SEQ ID NO: 185 nucleotide sequence, nucleotides 1, 2, 3, 19, 20, 21 are all 2' -O-methyl ribonucleotides, and the antisense strand of the siRNA is SEQ ID NO: 186 nucleotide sequence of nucleotides 1, 2, 3, 19, 20, 21 are all 2' -O-methyl ribonucleotides;
alternatively, the sense strand of the siRNA SEQ ID NO: 197, nucleotides 1, 2, 3, 19, 20, and 21 of the nucleotide sequence are all 2' -O-methyl ribonucleotides, and the antisense strand of the siRNA is SEQ ID NO: 198 and the 1 st, 2 nd, 3 rd, 19 th, 20 th and 21 th nucleotides of the nucleotide sequence are all 2' -O-methyl ribonucleotides.
4. An siRNA according to claim 3, characterized in that the phosphate groups between nucleotides 1, 2 and 3 and between nucleotides 19, 20 and 21 of the nucleotide sequence of said sense strand and/or said antisense strand of said siRNA are phosphorothioate groups.
5. The siRNA of claim 4, wherein the 5' end of the sense strand of said siRNA is cholesterol modified.
6. Use of the siRNA of any one of claims 1-5 in the manufacture of a medicament for the prevention and/or treatment of viral pneumonia.
7. The use of claim 6, wherein the viral pneumonia is a novel coronavirus pneumonia COVID-19.
8. A kit comprising the siRNA of any one of claims 1 to 5, wherein the kit is functional for treating a novel coronavirus COVID-19.
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CN202010746189.4A CN111748557B (en) | 2020-04-03 | 2020-04-03 | Small interfering nucleic acid for inhibiting novel coronavirus, composition and application |
CN202010746188.XA CN111876419B (en) | 2020-04-03 | 2020-04-03 | Small interfering nucleic acid for inhibiting novel coronavirus, composition and application |
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CN111748557A (en) | 2020-10-09 |
CN111748557B (en) | 2022-03-11 |
CN111876419B (en) | 2022-03-11 |
CN111876419A (en) | 2020-11-03 |
CN111778254A (en) | 2020-10-16 |
CN111778254B (en) | 2022-02-18 |
CN111139241B (en) | 2020-09-01 |
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