CN112999423A - 一种用于人皮肤创面覆盖及修复的活性基因改造猪皮肤及其应用 - Google Patents

一种用于人皮肤创面覆盖及修复的活性基因改造猪皮肤及其应用 Download PDF

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CN112999423A
CN112999423A CN202010048035.8A CN202010048035A CN112999423A CN 112999423 A CN112999423 A CN 112999423A CN 202010048035 A CN202010048035 A CN 202010048035A CN 112999423 A CN112999423 A CN 112999423A
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CN112999423B (zh
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王刚
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Shenzhen Zhenzhi Medical Technology Co ltd
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Abstract

本发明提供一种用于人皮肤创面覆盖及修复的活性基因改造猪皮肤及其应用，该猪皮肤去除了猪免疫抗原GGTA，B4GAL和CAMH，并且带有人CD55,59,46,47,39,141,HLEA和TFPI蛋白组合。得到的离体猪皮肤可以用于覆盖，封闭皮肤创面，并可以恢复创面有效血液循环和完整皮肤功能，可以挽救病人生命，促进创面修复，减少瘢痕形成，可以解决现有技术中皮肤创面移植猪皮肤无法成活的难题。

Description

一种用于人皮肤创面覆盖及修复的活性基因改造猪皮肤及其 应用
技术领域
本发明属于生物基因工程技术领域，涉及一种用于人皮肤创面覆盖及修复的活性基因改造猪皮肤及其应用。
背景技术
创伤特别是大面积烧伤临床处理的难点在于初始时的创面的覆盖。目前的临床策略是早期清创和自体皮肤移植。然而大面积的烧伤创面常常没有足够的自体皮肤移植覆盖，必须用同种异体的人尸体皮肤或者人工合成的皮肤材料暂时覆盖，但这样的皮肤来源非常有限。另外，病情危重的严重创伤伴皮肤软组织缺损，早期扩创后往往不能耐受I期植皮手术，需暂时覆盖创面以延期植皮。目前临床上使用的猪皮覆盖物基本上是无活性的猪的真皮基质。而野生型猪全层皮肤覆盖恢复血供后会很快(3-4天之内)被超急性免疫排斥反应排斥，很快失去功能。
最近有研究表明单基因敲除半乳糖抗原的猪皮肤在非人灵长类皮肤移植模型上的覆盖效果和时间同同种异体移植相似，这项研究为创面的覆盖提供了新的思路，但单次覆盖时间不超过14天。
发明内容
为了解决以上技术问题，本发明提供一种基因改造的猪皮肤能有效克服上述困难。
具体步骤包括：
步骤(一)：抗原去除和人源性蛋白表达
1.CAS9蛋白基因组水平敲除GGTA，B4Gal,CAMH基因取猪皮肤成纤维细胞，用Neo转染系统(美国赛默飞公司)，转染CAS9蛋白-引导RNA复合物。其中，猪皮成纤维细胞源于6月内月龄的小型猪包括但不限于巴马猪，版纳猪，哥廷根猪等。cas9蛋白0.5-2微克，引导RNA为100-200微摩尔
其引导RNA的序列如下：
GGTA基因的引导RNA为：GTC GTGACCATAACCAGA；
B4GAL基因的引导RNA为AGGAAAGCTATAACTTGG；
CMAH基因引导RNA为AGAAACTCCTGAA CTACA。
其中，中靶细胞用人GGTA基因编码的isolectin B4糖蛋白磁珠分选后，用B4GAL和CAMH编码的糖蛋白抗体流式细胞仪分选，获得GGTA,B4GAL和CAMH基因三敲出细胞后行核转移后获得30天胚胎成纤维细胞进行下一步。
步骤(二)：全合一载体构建，如图1所示。
质粒制作按Golden Gate克隆法即II型限制性内切酶结合和切割回文序列(例如GGATCC)进行。先设计3个转录单位序列，每个转录单元含有一个启动子、一个编码序列和一个终止子，利用IIs型限制性内切酶在识别位点之外切开质粒DNA，产生含粘性末端的片段，再用连接酶将几个片段按顺序连接，拼成不含酶识别位点的质粒，组建了含有3个转录单位质粒，可以构建单一质粒也可构建3个不同质粒。
具体步骤：含有上述序列的DNA序列从美国Integrated DNA technologies美国公司以gBlock形式购买(https://www.idtdna.com/site/order/gblockentry)，gblock按以下流程设计：5'-GCATCGTCTCATCGGTCTCACCCT转录单位AACGTGAGACCTGAGACGGCAT-3'；3'-CGTAGCAGAGTAGCCAGAGTAGGG转录单位CATAACTCTGGACTCTGCCGTA-5'。
第一转录单位序列：2841bp编码人补体负性蛋白CD55，CD59，CD46tcacgggtgtaaagaccaagcagcagccaggaaaggggtaaccagtagaagaactgttttttcagacagagaggtaccaccattttccagttgttcattgaagttacacaggtcttttttacaacagtagtaggtcagttcattttctcttaatctggtggtaacatcattgaagttacagtgttcaaatttccaacatttgttgtaaacctgcaggccagctttggtgatcagacaagcatcaaagtcagaagaacagttaacagctgttttacagtcagcagtagggttgggacagttgtaacactgaagagagtgaccagagtgacagaaaacagccagaaccagtaacagaccaaacagaacagaaccaccttggatacccataggccccgggttctcctctacgtccccggcctgcttgagcaggctgaaattcgtggctccgctgccggtcagtagccccatggtaaccagggtacccagtagaccagtcagggtgaaacaggtgtgaccagacagaagcctggtggtaccagaggtggtaccagaacctttgttaggggtggtttcatggaagtgtttggtggtcctagaaacgggggtagatctggtagcctgagcattgggggtggtggttttggtggtggttttctgagaggtgggagaaacttctgtggtgggaacattaactgtggtaggtttctgaactgtaggaggaactttagaggtcagagatttacccctacattcgggaggaggaccagaccattcaccttcatcattgttaacagtacagtagatagagtgttcaccaatcatggtgaaacctttgttacaagcataggtaacagactgcctgtaaccatagtgatcacgttcaccctggatgataccattgtctatctgaggaggagctggacagtagatttccctacattcgggtaaagggtcagaccactgaacagaagaaccagagatcagacagaaagaagaggtagaaccaaacagtttgtaaccagtgttacaagagaaagagatggtagcaccaaacaggataccaccaggaacatcaatctgaccattcctgatttcaccggggttgggacaagatttttttttacagaattcaacagcagtagaccatttcaggttctgtagacaggtcagtttgggagacagagagggttctcttctgtaaccaggtctacattcatattcaacaacagtaccaactgggaagtagttctgggtgatgtagggttgtttcagagaagcagagttcagcctggtgggaacttcacaagatctgttacagaattcttctatgtcagaccactgagaacctttcagacagataacagagtctttttcacctgggattttaacaaaagattcttcacatttgtaggtgataacagtatcctcagggaaagaggttctaccttccagagcaggttgagcattaggaacatctggaggtaaaccacagtcaccccaaacagcagggaggcacagtaaaaccagtaataaaagtcttggaagttcacctagaagtgggagtgctgctggaacagatggcctggctactgtcataggcccggggttctcctccacgtcgccagcctgcttaaggagtgagaagttggtggctccactgcccagagaggtgaattaacttctctgtgggtttcatctgtcaggtaggtaccttttttttttctcctttgaaggtacctgtaaggaacaacacagataacagcaacaccaacaacaatagctataactataacagcaataacccaaacatccagagagtccaggataccttcttcaggtttagggtaaccagggtagttagaaacgggaggtttgtaggtaggtcttggaccagaagcagaagaagcaggagatttggtggtagaagaggtagaaacagagtgagacagagcgggtggtttggtagaagagggtggtaaaactttcagacatttgggaactggtgggtcccaggtagagttagagtcacaaacaatggtgtcagaaccatccaggtagaaacctttgtcacattcaaacataacagtagctttgtagtagaattttttaccaaaaccagagatctgtttaccattttcaacaactgggaatctacatttaacaactttacattctggagcagctctagaccaaacagagttgtcaccacagtagatggtagattcaccaatcagagagaatgggtctggaccaggagcagggtcacaagagtaggtaacagcatccaggtattcaaaaacttcaacttcagagaaggtgtgtttaccatttttgattttgggtggtggggtacacagaactttttcacagatgggaggtttaccagaccagatagcaacagaacctttcagttcacagtacaggatttcttcacctatcaggtagtaaccttcattacagatgaagtgcatctggtaaccaaattcataggtaccattagctggaacagcctgaccattcagaggatctcggatgtagggacaggtttccctgtaacaagcatcatcagaaacaggtaaccaggtgtggtttctgtcacagatggtgtgggtagccagaggtgggatgtagaagtaaccttttttacatttgtagtcaactctttcacctatttcatagtatggttttggtttacctatcagttccatagcttcaaaggttggtggttcttcacaagcatcagagaaagagtacagtaaaagaaccatagcagccagtagtaaaccagggaatctccaagatgggaagggacactcccttctaccaggtggttccatcat
第二转录单位序列：2531bp，编码人巨噬细胞负性蛋白CD47和人自然伤蛋白HLAEctagatctgttgctcttgctgttcttgctctgttgtctctgtctggtctggaagctgtgatggcccctagaaccctgatcctcgggggcggaggttcaggaggcggtgggagcggcggagggggttccatccaaagaacccctaaaatccaggtttactctaggcacccagctgaaaatggtaaatctaacttcctgaactgttatgtttctggtttccacccctctgacattgaagttgacttactgaaaaatggtgaaaggatagaaaaagttgaacactctgacctgtctttctctaaagactggtctttctacttactgtactacactgaattcacccctacagaaaaagatgaatatgcttgtagagttaaccatgttaccctgtctcaaccaaaaattgttaaatgggacagagacatgggtggcggagggtctggcgggggtggaagcgggggtggaggctccggaggtgggggcagtggtagtcattccttaaagtacttccacacctctgtttcccgaccaggtaggggtgaacctaggttcatctctgttgggtatgttgatgatacccaatttgtcagatttgataatgatgctgcttctccaagaatggttccaagggctccttggatggaacaggaagggtcagaatactgggacagagaaaccagatctgctagagacactgctcaaatattcagagttaacttgagaactttaagaggttattataatcagtctgaggcaggttcccacactcttcaatggatgcatggttgtgaattgggtccagatggtagattcctcaggggttatgaacagtttgcctatgatggaaaagattatttgacccttaatgaggacctaaggtcctggactgcagttgatacagcagcccagatttcagaacaaaagtctaatgatgcttctgaagctgaacaccaaagagcgtatttagaggatacttgtgtagaatggttacacaagtacttggaaaagggtaaggaaaccttactacacttggaacctcctaagacccatgtcacacatcatccaatctctgaccatgaagcaacactaaggtgttgggcactaggtttttaccctgctgaaattaccctcacctggcaacaagatggtgaaggtcacacccaagacactgaactagtagagacaagacctgctggggatggtacatttcaaaaatgggctgctgtggtagttcctagtggggaagaacaaaggtatacctgtcatgttcaacatgaggggttaccagaaccagttacccttaggtggaaaccagcttctcaacctactattccaattgttggtatcattgctggtcttgtcttgttgggttctgttgtttctggtgctgttgtggcagcagtgatctggaggaaaaaatcatctggtggtaagggtggttcttactctaaggctgaatggtcagattcagctcaagggagtgaatctcactctttgggcagtggcgccaccaattttagcctgttaaagcaggctggcgacgtggaggagaatcctgggcctatgtggcctctggtagcagcacttcttttaggttcagcatgttgtggttcagctcaactactgttcaacaaaaccaaatctgttgaattcaccttctgtaatgacacagttgttatcccatgttttgttaccaacatggaagctcagaacaccacagaagtttatgttaaatggaaattcaaaggtagagacatctacacctttgatggtgctctgaacaaatctacagttcccactgacttctcttctgctaaaatagaagtttctcaattactgaaaggtgatgcttctctgaaaatggacaaatctgatgctgtttctcacacaggtaactacacctgtgaagttacagaactgaccagagaaggtgaaaccatcattgaactgaaatacagagttgtttcttggttctctcctaatgaaaacatcctgattgttatcttccccatctttgctatccttctgttctggggtcagtttggtatcaaaaccctgaaatacagatctggtggtatggatgaaaaaaccattgctttactggttgctggtctggttatcactgttatagttatagttggtgctatcctgtttgttccaggtgaatactctctgaaaaatgctacaggtctgggtctgatagttacctctactggtatcctgatcttacttcactactatgttttctctacagctattggtctgacctcttttgttatagctatcctggttatccaggttattgcttacatcctggctgttgttggtctgtctctgtgtattgctgcttgtatccccatgcatggtcctcttctgatctctggtctgtctatcctggctctggctcaattactgggtctggtttacatgaaatttgttgcttctaaccagaaaaccatccaaccacctaggaaagctgttgaagaacctctgaatgctttcaaagaatctaaaggtatgatgaatgacgaa
第三转录单位序列：5273bp,编码人凝血负性蛋白CD141，CD39和组织因子通路抑制蛋白
ttaggtgttctggttcttggtgcactggctctggcaggtttaggtttccccgctcctgctgaaccacaaccaggtggttctcagtgtgttgaacatgactgttttgctctgtaccccggtcccgctaccttcctgaatgcttctcagatctgtgatggtcttaggggtcacctgatgacagttcgcagctctgttgctgctgatgttatctctttattactgaatggtgatggtggtgttggtaggaggagactgtggattggactgcaactaccaccaggttgtggtgaccctaaaagactgggtcctcttagaggtttccagtgggttacaggtgacaacaacacctcttactctagatgggctagactggacctgaatggtgctcctctgtgtggtcctctgtgtgttgctgtttctgctgctgaagctactgttccttctgaacctatctgggaagaacaacagtgtgaagttaaagctgatggtttcctgtgtgaattccacttccccgctacctgtagaccactggctgttgaacccggtgctgctgctgctgctgtttctatcacctatggtaccccttttgctgctagaggtgctgacttccaggctctaccagttggttcttctgctgctgttgctcctctgggcttacaactgatgtgtacagctccacccggtgctgttcagggtcactgggctagagaagctcccggtgcttgggactgttctgttgaaaatggtggttgtgaacatgcttgtaatgctatccctggtgctcctaggtgtcagtgtcctgctggtgctgctcttcaggctgatggtagatcttgtactgcttctgctacccagtcttgtaatgacctgtgtgaacacttctgtgttcccaaccccgaccaacccggttcttactcttgtatgtgtgaaacaggttacagactggctgctgaccaacacagatgtgaagatgttgatgactgtatcctggaaccctctccatgtccacaaaggtgtgttaacacccagggtggttttgaatgtcactgttaccctaactatgacctggttgatggtgaatgtgttgaacccgttgacccctgtttcagggctaactgtgaataccagtgtcaacctctgaaccagacctcttacctgtgtgtttgtgctgaaggttttgctccaatccctcatgaacctcacaggtgtcagatgttctgtaaccagacagcttgtcccgctgactgtgaccctaacacccaggcttcttgtgaatgtccagaaggttacatcctggatgatggtttcatctgtacagacattgatgaatgtgaaaatggtggtttctgttctggtgtttgtcacaaccttcccggtacctttgaatgtatctgtggtcccgactctgctctggctagacacattggtacagactgtgactctggtaaagttgatggtggtgactctggttctggtgaacctcctccctctccaacccccggttctaccctgaccccaccagctgttggtctggttcactctggtctactgataggtatctctatagcttctctgtgtctggttgttgctctactggctctactgtgtcaccttaggaaaaaacagggtgctgctagggctaaaatggaatacaaatgtgctgctccatctaaagaagttgttttacaacatgttaggactgaaaggacccctcaaaggctgggcagcggcgcgaccaacttttcgctccttaagcaggccggggacgtggaggagaatccagggcctatctacactatgaaaaaagtacatgctttatgggcctctgtttgtttacttctgaacctggctcctgctcctctgaatgctgactctgaagaagatgaagaacacaccatcatcacagacactgaacttcctccactgaaactgatgcactctttctgtgctttcaaagctgatgatggtccttgtaaagctatcatgaaaaggttcttcttcaacatcttcaccagacagtgtgaagaattcatctatggtggttgtgaaggtaaccagaacagatttgaatctctggaagaatgtaagaaaatgtgtaccagggacaatgctaacaggatcatcaaaaccaccctacaacaggaaaaaccagacttctgtttcctggaagaggatcctggtatctgtagaggttacatcaccaggtacttctacaacaaccagaccaaacagtgtgaaagattcaaatatggtggttgtctgggtaacatgaacaactttgaaaccctggaagaatgtaaaaacatctgtgaagatggtcccaatggtttccaggttgacaactatggtacccaactgaatgctgttaacaactctctgacccctcagtctaccaaagttccctctctgtttgaattccatggtccttcttggtgtctgacccctgctgacagaggtctgtgtagagctaatgaaaacaggttctactacaactctgttataggtaaatgtagacccttcaaatactctggttgtggtggtaatgaaaacaacttcacctctaaacaggaatgtttaagggcttgtaaaaaaggtttcatccaaagaatctctaaaggtggtctgatcaaaaccaaaagaaaaagaaaaaaacaaagagttaaaatagcttatgaagaaatctttgttaaaaacatgtacttacaggaactgggaggttcagggggaggagggtccggtgggggtggttctggtggttgtagaaatggtaaaaccctgtctgtttctcaactggaacttcaggactctggtacctggacctgtacagttctacagaaccagaaaaaagttgaattcaaaatagacatagttgttctggctttccagaaagcttcttctatagtttacaaaaaagaaggtgaacaggttgaattctctttcccactggctttcactgttgaaaaactgactggttctggtgaactgtggtggcaggctgaaagggcttcttcttctaaatcttggatcacctttgacctgaaaaacaaagaagtttctgttaaaagggttacccaggacccaaaattacagatgggtaaaaaattacctcttcacctgaccctaccacaggctcttccacagtatgctggttctggtaacctgaccctggctctggaagctaaaactggtaaactacaccaggaagttaacctggttgttatgagagctacccaacttcagaaaaacctgacctgtgaagtttggggtccaacctctccaaaactgatgctgtctctgaaactggaaaacaaagaagctaaagtttctaaaagagaaaaagctgtttgggttctgaacccagaagctggtatgtggcagtgcctgctgtctgactctggtcaggttttactggaatctaacatcaaagttcttcctacctggtctacccctgttcaaccaatggctctgattgttctgggtggtgttgctgggcttcttctgttcataggtctgggtatcttcttctgtgttaggtgtcgacacagaaggagacaggctgaaagaatgtctcagatcaaaaggttccgtcagaaagatgatggtaaatgtccactgaacccacactctcacctgggtacctatggtgttttcaccaatgctgcttttgacccctctcctggcagcggagcgaccaactttagccttctgaaacaggctggggacgtggaggagaatcctgggcctatggaggataccaaagaatctaatgttaaaactttctgttctaaaaacatcctggctatcctgggtttctcttctatcattgctgttattgctttactggctgttggtctgacccagaacaaagctttacctgaaaatgttaaatatggtattgttctggatgctggttcttctcacacctctctgtacatctacaaatggcccgctgaaaaagaaaatgacacaggtgttgttcaccaggttgaagaatgtagagttaaaggtcctggtatctctaaatttgttcagaaagttaatgaaattggtatctacctgactgactgtatggaaagagctagggaagttatccctcgttcgcaacaccaggaaacccccgtttacctgggtgctactgctggtatgagattactaagaatggaatctgaagaactggctgacagagttctggatgttgttgaaagatctctgtctaactacccctttgacttccagggtgctaggatcatcacaggtcaggaagaaggtgcttatggttggatcaccatcaactaccttctgggtaaattctctcagaaaaccaggtggttctctatagttccatatgaaaccaacaaccaggaaacctttggtgctctggacctgggtggtgcttctacccaggttacctttgttcctcagaaccagaccattgaatctcctgacaatgctctacagttcagactgtatggtaaagactacaatgtttacacccactctttcctgtgttatggtaaagaccaggctctgtggcagaaactggctaaagacatccaggttgcttctaatgaaatccttagggacccttgtttccaccctggttacaaaaaagttgttaatgtttctgacctgtacaaaaccccttgtaccaaaagatttgaaatgaccttacccttccaacagtttgaaatccagggtattggtaactaccaacagtgtcaccagtctatcctggaactgttcaacacctcttactgtccctactctcagtgtgctttcaatggtatcttcttacctcctctacagggtgactttggtgctttctctgctttctactttgttatgaaattcctgaacctgacctctgaaaaagtttctcaggaaaaagttactgaaatgatgaaaaaattctgtgctcaaccctgggaagaaatcaaaacctcttatgctggtgttaaagaaaaatacctgtctgaatactgtttctctggtacctacatcctgtctttattattacagggttaccacttcactgctgactcttgggaacacatccacttcataggtaaaatccagggttctgatgctggttggaccctgggttacatgctgaacctgaccaacatgatccccgctgaacaacctctgtctaccccactgtctcactctacctatgttttcctgatggttctgttctctctggttctgttcacagttgctatcataggtctactgatcttccacaaaccatcttacttctggaaagacatggt。
步骤(三)：Piggybac法基因组整合全合一载体
步骤1：接着在同一20微升反应体系(空piggybac质粒载体17,7ng,2微升10xT4DNA连接酶缓冲液，1微升BsmBI酶，1微升T4DNA连接酶，加水至20微升)中，在PCR机上按步骤1，温度42℃，时间1.5分钟；
步骤2，温度16℃，时间3分钟，循环1-2次，重复25次；
步骤3，温度50℃，时间5分钟，步骤4，温度80℃，时间10分钟，进行反应。得到是终产物质粒，序列为全序列。序列表如下：
agaagatcctttgatcttttctacggggtctgacgctcagtggaacgaaaactcacgttaagggattttggtcatgagattatcaaaaaggatcttcacctagatccttttaaattaaaaatgaagttttaaatcaatctaaagtatatatgagtaaacttggtctgacagttaccaatgcttaatcagtgaggcacctatctcagcgatctgtctatttcgttcatccatagttgcctgactccccgtcgtgtagataactacgatacgggagggcttaccatctggccccagtgctgcaatgataccgcgggacccacgctcaccggctccagatttatcagcaataaaccagccagccggaagggccgagcgcagaagtggtcctgcaactttatccgcctccatccagtctattaattgttgccgggaagctagagtaagtagttcgccagttaatagtttgcgcaacgttgttgccattgctacaggcatcgtggtgtcacgctcgtcgtttggtatggcttcattcagctccggttcccaacgatcaaggcgagttacatgatcccccatgttgtgcaaaaaagcggttagctccttcggtcctccgatcgttgtcagaagtaagttggccgcagtgttatcactcatggttatggcagcactgcataattctcttactgtcatgccatccgtaagatgcttttctgtgactggtgagtactcaaccaagtcattctgagaatagtgtatgcggcgaccgagttgctcttgcccggcgtcaatacgggataataccgcgccacatagcagaactttaaaagtgctcatcattggaaaacgttcttcggggcgaaaactctcaaggatcttaccgctgttgagatccagttcgatgtaacccactcgtgcacccaactgatcttcagcatcttttactttcaccagcgtttctgggtgagcaaaaacaggaaggcaaaatgccgcaaaaaagggaataagggcgacacggaaatgttgaatactcatactcttcctttttcaatattattgaagcatttatcagggttattgtctcatgagcggatacatatttgaatgtatttagaaaaataaacaaataggggttccgcgcacatttccccgaaaagtgccacctaaattgtaagcgttaatattttgttaaaattcgcgttaaatttttgttaaatcagctcattttttaaccaataggccgaaatcggcaaaatcccttataaatcaaaagaatagaccgagatagggttgagtgttgttccagtttggaacaagagtccactattaaagaacgtggactccaacgtcaaagggcgaaaaaccgtctatcagggcgatggcccactacgtgaaccatcaccctaatcaagttttttggggtcgaggtgccgtaaagcactaaatcggaaccctaaagggagcccccgatttagagcttgacggggaaagccggcgaacgtggcgagaaaggaagggaagaaagcgaaaggagcgggcgctagggcgctggcaagtgtagcggtcacgctgcgcgtaaccaccacacccgccgcgcttaatgcgccgctacagggcgcgtcccattcgccattcaggctgcgcaactgttgggaagggcgatcggtgcgggcctcttcgctattacgccagctggcgaaagggggatgtgctgcaaggcgattaagttgggtaacgccagggttttcccagtcacgacgttgtaaaacgacggccagtgagcgcgcctcgttcattcacgtttttgaacccgtggaggacgggcagactcgcggtgcaaatgtgttttacagcgtgatggagcagatgaagatgctcgacacgctgcagaacacgcagctagattaaccctagaaagataatcatattgtgacgtacgttaaagataatcatgcgtaaaattgacgcatgtgttttatcggtctgtatatcgaggtttatttattaatttgaatagatattaagttttattatatttacacttacatactaataataaattcaacaaacaatttatttatgtttatttatttattaaaaaaaaacaaaaactcaaaatttcttctataaagtaacaaaacttttatgagggacagcccccccccaaagcccccagggatgtaattacgtccctcccccgctagggggcagcagcgagccgcccggggctccgctccggtccggcgctccccccgcatccccgagccggcagcgtgcggggacagcccgggcacggggaaggtggcacgggatcgctttcctctgaacgcttctcgctgctctttgagcctgcagacacctggggggatacggggaaaaggcctccacggcctaactttaaataattggcattatttaaagttagaatagtaatcaattacggggtcattagttcatagcccatatatggagttccgcgttacataacttacggtaaatggcccgcctggctgaccgcccaacgacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagggactttccattgacgtcaatgggtggagtatttacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctattgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttttggcagtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctccaccccattgacgtcaatgggagtttgttttggcaccaaaatcaacgggactttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggtctatataagcagagctggtttagtgaaccgtcagatccgctagaacaccgcatcgtacgcgtacgtgtgaggataacttcgtatagcatacattatacgaagttattggcgcgcctaactttaaataattggcattatttaaagttagccaccatggcacaatcaaaacatggattaactaaggaaatgacaatgaaatacagaatggaaggttgtgttgatggtcacaaatttgttatcactggtgaaggtattggttacccattcaaaggtaaacaggctatcaacctgtgtgttgttgaaggtggtcctctaccatttgctgaggatatcctgtctgctgctttcatgtatggtaacagggttttcactgaatacccacaggacatagttgactacttcaaaaactcttgtcccgctggttacacctgggacagatctttcctgtttgaagatggtgctgtttgtatctgtaatgctgacatcactgtttctgttgaagaaaactgtatgtaccatgaatctaaattctatggtgttaacttcccagctgatggtcccgttatgaaaaaaatgactgacaactgggaaccttcttgtgaaaaaatcatccctgttccaaaacagggtatcctgaaaggtgatgtttctatgtacttacttctgaaagatggtggtagacttagatgtcagtttgacacagtttacaaagctaaatctgttcctaggaaaatgcctgactggcacttcatccaacacaaactgaccagggaggataggtctgatgctaaaaaccagaaatggcacctgactgaacatgctatagcttctggttctgctctgccgggcagcggggccaccaatttttctctgctgaagcaagcaggcgacgtcgaggaaaacccggggcctatgactgaatacaaacccacagttagactggctaccagagatgatgttcctagagctgttaggaccctggctgctgcttttgctgactaccctgctaccaggcacactgttgaccctgacaggcacatagaaagagttacagaactacaggaactgttcctgaccagggttggtctggacattggtaaagtttgggttgctgatgatggtgctgctgttgctgtttggaccacccccgaatctgttgaagctggtgctgtttttgctgaaataggtccaaggatggctgaactgtctggttctaggctggctgctcaacaacagatggaaggtctactggctccacacaggcccaaagaacccgcttggttcctggctactgttggtgtttctccagaccaccagggtaaaggtctgggttctgctgttgttctacctggtgttgaagctgctgaaagggctggtgttccagctttcctggaaacctctgctcctagaaacttaccattctatgaaaggctgggtttcacagttactgctgatgttgaagttcccgaaggtcctaggacctggtgtatgaccaggaaacctggtgcttgataactttaaataattggcattatttaaagttagtagggataacagggtaatagcgcggggacagcccccccccaaagcccccagggatgtaattacgtccctcccccgctagggggcagcagcgagccgcccggggctccgctccggtccggcgctccccccgcatccccgagccggcagcgtgcggggacagcccgggcacggggaaggtggcacgggatcgctttcctctgaacgcttctcgctgctctttgagcctgcagacacctggggggatacggggaaaatgtgtctgagcctgcatgtttgatggtgtctggatgcaagcagaaggggtggaagagcttgcctggagagatacagctgggtcagtaggactgggacaggcagctggagaattgccatgtagatgttcatacaatcgtcaaatcatgaaggctggaaaagccctccaagatccccaagaccaaccccaacccacccaccgtgcccactggccatgtccctcagtgccacatcccc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本发明采用以上技术方案，其优点在于，本发明应用更为高级的基因改造猪作为创面覆盖的新型皮肤来源，进行创面覆盖，有利于创面修复和恢复，单次移植可以提供超过25天的移植物存活期。
本发明的基因改造的猪为去除半乳糖抗原，敲入负性补体通路调节蛋白(CD55，CD46和CD59)，敲入自然杀伤细胞负性调整蛋白(HLAE)，敲入巨噬细胞负性调节蛋白(CD47)和敲入凝血系统的负性调节蛋白THBD等等，可以克服超急性排斥反应，克服多种细胞免疫攻击和减轻猪－人凝血不和的问题。
本发明带来了如下效果：得到的离体猪皮肤可以用于覆盖，封闭皮肤创面，并可以恢复创面有效血液循环和完整皮肤功能，可以挽救病人生命，促进创面修复，减少瘢痕形成，可以解决现有技术中皮肤创面移植猪皮肤无法成活的难题。
本申请文件中的中英文翻译对照表如表1所示：
表1
Figure BDA0002370131260000211
Figure BDA0002370131260000221
附图说明
图1是本发明全合一载体构建示意图。
图2是本发明一种实施例中流式细胞仪检测提示野生型猪稳定表达GGTA，B4gal,Camh蛋白。
图3是本发明一种实施例中流式细胞仪检测提示野生型猪成纤维细胞不表达人源性CD55，CD59，CD46，CD47，CD39，THBD，TFPI和HLAE蛋白。
图4是本发明中流式细胞仪检测提示基因修饰猪(拯救者I)猪成纤维细胞不表达GGTA，B4gal,Camh蛋白相关糖蛋白，提示上述基因敲出成功。
图5是本发明一种实施例中流式细胞仪检测提示基因修饰猪(拯救者I)猪成纤维细胞表达人源性CD55，CD59，CD46，CD47，CD39，THBD，TFPI和HLAE蛋白。
图6-8是本发明一种实施例中所示混合人血清抗体结合实验。
图9是本发明一种实施例中野生型猪成纤维细胞荧光强度图。
图10是本发明一种实施例中人成纤维细胞荧光强度图。
图11是本发明一种实施例中基因改造猪人成纤维细胞1荧光强度图。
图12是本发明一种实施例中基因改造猪人成纤维细胞2荧光强度图。
图13是本发明一种实施例中图13是补体实验的柱状图。
图14是本发明一种实施例中实验结果对比图。
具体实施方式
下面结合附图，对本发明的较优的实施例作进一步的详细说明：
实施例1
离体猪皮肤的抗原去除和人源蛋白表达及功能鉴定，图2-5所示流式细胞仪检测提示基因改造猪稳定表达人源性CD55，CD59，CD46，CD47，CD39，THBD，TFPI和HLAE蛋白，显示上述基因成功敲入,流式细胞仪检测提示基因改造猪不表达GGTA，B4gal,Camh蛋白，显示半乳糖抗原基因敲除成功。
图6-8所示混合人血清抗体结合实验：猪耳成纤维细胞同75％(实验前100％的人混合血清生理盐水质量分数稀释为75％)的30位健康志愿者混合血清在37℃孵育30分钟，野生型猪细胞带有半乳糖抗原可以被人血清预存抗体结合，荧光抗体染色标记结合在猪细胞的人IgM,IgG抗体，流式细胞仪测定荧光强度，
图9-12是荧光抗体染色标记结合在猪细胞的人IgM,IgG抗体，流式细胞仪测定荧光强度，荧光强度同结合能力呈正比，相比野生型猪细胞，基因改造后猪细胞人血抗体结合能力显著下降，同人细胞相似。图13是补体实验的柱状图，根据图可看出实例没有人自然杀伤细胞，说明基因修饰猪成纤维细胞抵抗人补体毒性作用。
猪耳细胞在37℃同含有75％(血清生理盐水质量分数稀释为75％)补体活性的人血清孵育45分钟同时加入DNA荧光染料PI，野生型猪细胞由于激活补体系统导致细胞膜破裂死亡，染料进入细胞，信号由流式细胞仪捕获并量化，细胞死亡的程度同信号成正比。相比野生型猪细胞，基因改造猪细胞同人成纤维细胞类似能够不激活抗补体攻击，保持细胞膜完整，从而在流式细胞仪上显示极低信号。
实施例2
离体猪皮肤-石蟹猴皮肤异种移植
1.猪皮肤制备：按30mg/Kg剂量注射苯巴比妥钠进行麻醉，剃毛后，用肥皂和自来水反复刷洗，再用碘伏及体积分数70％酒精常规消毒、铺巾，取其背部皮肤，用电动取皮机取厚约0.6mm的猪皮片制成，剪成5cm×5cm大小皮片，用含抗生素的生理盐水反复漂洗置于4度冰箱备用。另外取新鲜皮片放入含体积分数5％DMSO的抗冻保护剂中渗透20min后取出装入无菌聚氯乙稀包装小袋密封，置于-80℃冰箱或液氮罐中备用。使用前，放入37℃水浴复温后用生理盐水冲洗3次。
2.基因改造的猪全层皮肤非人灵长类动物皮肤移植步骤：
普通级食蟹猴公猴6只，年龄4-6岁，体重6-7kg(广东省生物资源应用研究所提供，动物质量合格证号：SYXK(粤)2018-0187)。实验符合《关于善待实验动物的指导性意见》的相关内容(中华人民共和国科学技术部.关于善待实验动物的指导性意见.2006-09-30.)及国际实验动物饲养管理及使用委员会(AAALAC)要求。
动物皮肤移植方案：食蟹猴用舒泰-50(Zolitel-50)肌肉注射诱导麻醉后，插气管进行吸入麻醉(异氟烷)，取俯卧位,背部剃毛，碘伏及70％酒精常规消毒，用手术刀在背部造成3x3cm全层皮肤缺损直达肌层，将盐水/肾上腺素溶液应用于伤口部位直至完全止血，植入本发明基因改造的活性猪皮肤，缝合，然后用于修整伤口的绷带是由吸收人造丝/聚酯芯构成，夹在两层非粘附性高密度聚乙烯(HDPE)网之间。敷料经过灭菌和包装，将敷料在无菌水盘中润湿，排干，并施用于新制的全层皮肤伤口。通过在敷料上施加无菌水润湿的手术单将敷料保持在适当位置。使用Elastoplast和覆盖袜子将敷料和窗帘固定到位。穿猴衣保护术区。术前及术后分别静脉滴注头孢曲松钠(80mg/kg),术后单笼自由喂养,通风,接受自然光。术后在镇静情况下第7天开始拆开敷料包，观察移植物存活情况并清晰拍照，取组织标本做组织学检查，直至移植物完全排斥。
3.实验结果如图14所示。
基因改造猪－食蟹猴异种皮肤移植大体病理分析
1)自体移植组：皮肤移植金标准，术后完全恢复皮肤功能，血供良好，完全，永久性愈合。
2)同种异体皮肤移植组：临床处理严重烧伤病人金标准，大约在16天左右出现明显排斥，表皮层消退，真皮逐渐减少消退，仅仅剩下肉芽组织，肉芽组织整齐完整，可为下步确定性自体移植创造机会。
3)异种皮肤移植：可以完全恢复血供，从14天开始有逐步排斥，25天左右达高峰，并逐渐完全排斥，但优于异种皮肤移植。
4)脱细胞真皮基质，始终没有恢复血供，干燥，易碎，肉芽创面不整齐，完整，需要进行清创手术后才能进行下一步确定性自体移植。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。
序列表
<110> 深圳市臻质医疗科技有限公司
<120> 一种用于人皮肤创面覆盖及修复的活性基因改造猪皮肤及其应用
<160> 11
<170> SIPOSequenceListing 1.0
<210> 1
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Gly Thr Cys Gly Thr Gly Ala Cys Cys Ala Thr Ala Ala Cys Cys Ala
1 5 10 15
Gly Ala
<210> 2
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Ala Gly Gly Ala Ala Ala Gly Cys Thr Ala Thr Ala Ala Cys Thr Thr
1 5 10 15
Gly Gly
<210> 3
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Ala Gly Ala Ala Ala Cys Thr Cys Cys Thr Gly Ala Ala Cys Thr Ala
1 5 10 15
Cys Ala
<210> 4
<211> 24
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Gly Cys Ala Thr Cys Gly Thr Cys Thr Cys Ala Thr Cys Gly Gly Thr
1 5 10 15
Cys Thr Cys Ala Cys Cys Cys Thr
20
<210> 5
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Ala Ala Cys Gly Thr Gly Ala Gly Ala Cys Cys Thr Gly Ala Gly Ala
1 5 10 15
Cys Gly Gly Cys Ala Thr
20
<210> 6
<211> 24
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Cys Gly Thr Ala Gly Cys Ala Gly Ala Gly Thr Ala Gly Cys Cys Ala
1 5 10 15
Gly Ala Gly Thr Ala Gly Gly Gly
20
<210> 7
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Cys Ala Thr Ala Ala Cys Thr Cys Thr Gly Gly Ala Cys Thr Cys Thr
1 5 10 15
Gly Cys Cys Gly Thr Ala
20
<210> 8
<211> 2841
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 8
tcacgggtgt aaagaccaag cagcagccag gaaaggggta accagtagaa gaactgtttt 60
ttcagacaga gaggtaccac cattttccag ttgttcattg aagttacaca ggtctttttt 120
acaacagtag taggtcagtt cattttctct taatctggtg gtaacatcat tgaagttaca 180
gtgttcaaat ttccaacatt tgttgtaaac ctgcaggcca gctttggtga tcagacaagc 240
atcaaagtca gaagaacagt taacagctgt tttacagtca gcagtagggt tgggacagtt 300
gtaacactga agagagtgac cagagtgaca gaaaacagcc agaaccagta acagaccaaa 360
cagaacagaa ccaccttgga tacccatagg ccccgggttc tcctctacgt ccccggcctg 420
cttgagcagg ctgaaattcg tggctccgct gccggtcagt agccccatgg taaccagggt 480
acccagtaga ccagtcaggg tgaaacaggt gtgaccagac agaagcctgg tggtaccaga 540
ggtggtacca gaacctttgt taggggtggt ttcatggaag tgtttggtgg tcctagaaac 600
gggggtagat ctggtagcct gagcattggg ggtggtggtt ttggtggtgg ttttctgaga 660
ggtgggagaa acttctgtgg tgggaacatt aactgtggta ggtttctgaa ctgtaggagg 720
aactttagag gtcagagatt tacccctaca ttcgggagga ggaccagacc attcaccttc 780
atcattgtta acagtacagt agatagagtg ttcaccaatc atggtgaaac ctttgttaca 840
agcataggta acagactgcc tgtaaccata gtgatcacgt tcaccctgga tgataccatt 900
gtctatctga ggaggagctg gacagtagat ttccctacat tcgggtaaag ggtcagacca 960
ctgaacagaa gaaccagaga tcagacagaa agaagaggta gaaccaaaca gtttgtaacc 1020
agtgttacaa gagaaagaga tggtagcacc aaacaggata ccaccaggaa catcaatctg 1080
accattcctg atttcaccgg ggttgggaca agattttttt ttacagaatt caacagcagt 1140
agaccatttc aggttctgta gacaggtcag tttgggagac agagagggtt ctcttctgta 1200
accaggtcta cattcatatt caacaacagt accaactggg aagtagttct gggtgatgta 1260
gggttgtttc agagaagcag agttcagcct ggtgggaact tcacaagatc tgttacagaa 1320
ttcttctatg tcagaccact gagaaccttt cagacagata acagagtctt tttcacctgg 1380
gattttaaca aaagattctt cacatttgta ggtgataaca gtatcctcag ggaaagaggt 1440
tctaccttcc agagcaggtt gagcattagg aacatctgga ggtaaaccac agtcacccca 1500
aacagcaggg aggcacagta aaaccagtaa taaaagtctt ggaagttcac ctagaagtgg 1560
gagtgctgct ggaacagatg gcctggctac tgtcataggc ccggggttct cctccacgtc 1620
gccagcctgc ttaaggagtg agaagttggt ggctccactg cccagagagg tgaatttaac 1680
ttctctgtgg gtttcatctg tcaggtaggt accttttttt tttctccttt gaaggtacct 1740
gtaaggaaca acacagataa cagcaacacc aacaacaata gctataacta taacagcaat 1800
aacccaaaca tccagagagt ccaggatacc ttcttcaggt ttagggtaac cagggtagtt 1860
agaaacggga ggtttgtagg taggtcttgg accagaagca gaagaagcag gagatttggt 1920
ggtagaagag gtagaaacag agtgagacag agcgggtggt ttggtagaag agggtggtaa 1980
aactttcaga catttgggaa ctggtgggtc ccaggtagag ttagagtcac aaacaatggt 2040
gtcagaacca tccaggtaga aacctttgtc acattcaaac ataacagtag ctttgtagta 2100
gaatttttta ccaaaaccag agatctgttt accattttca acaactggga atctacattt 2160
aacaacttta cattctggag cagctctaga ccaaacagag ttgtcaccac agtagatggt 2220
agattcacca atcagagaga atgggtctgg accaggagca gggtcacaag agtaggtaac 2280
agcatccagg tattcaaaaa cttcaacttc agagaaggtg tgtttaccat ttttgatttt 2340
gggtggtggg gtacacagaa ctttttcaca gatgggaggt ttaccagacc agatagcaac 2400
agaacctttc agttcacagt acaggatttc ttcacctatc aggtagtaac cttcattaca 2460
gatgaagtgc atctggtaac caaattcata ggtaccatta gctggaacag cctgaccatt 2520
cagaggatct cggatgtagg gacaggtttc cctgtaacaa gcatcatcag aaacaggtaa 2580
ccaggtgtgg tttctgtcac agatggtgtg ggtagccaga ggtgggatgt agaagtaacc 2640
ttttttacat ttgtagtcaa ctctttcacc tatttcatag tatggttttg gtttacctat 2700
cagttccata gcttcaaagg ttggtggttc ttcacaagca tcagagaaag agtacagtaa 2760
aagaaccata gcagccagta gtaaaccagg gaatctccaa gatgggaagg gacactccct 2820
tctaccaggt ggttccatca t 2841
<210> 9
<211> 2531
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 9
ctagatctgt tgctcttgct gttcttgctc tgttgtctct gtctggtctg gaagctgtga 60
tggcccctag aaccctgatc ctcgggggcg gaggttcagg aggcggtggg agcggcggag 120
ggggttccat ccaaagaacc cctaaaatcc aggtttactc taggcaccca gctgaaaatg 180
gtaaatctaa cttcctgaac tgttatgttt ctggtttcca cccctctgac attgaagttg 240
acttactgaa aaatggtgaa aggatagaaa aagttgaaca ctctgacctg tctttctcta 300
aagactggtc tttctactta ctgtactaca ctgaattcac ccctacagaa aaagatgaat 360
atgcttgtag agttaaccat gttaccctgt ctcaaccaaa aattgttaaa tgggacagag 420
acatgggtgg cggagggtct ggcgggggtg gaagcggggg tggaggctcc ggaggtgggg 480
gcagtggtag tcattcctta aagtacttcc acacctctgt ttcccgacca ggtaggggtg 540
aacctaggtt catctctgtt gggtatgttg atgataccca atttgtcaga tttgataatg 600
atgctgcttc tccaagaatg gttccaaggg ctccttggat ggaacaggaa gggtcagaat 660
actgggacag agaaaccaga tctgctagag acactgctca aatattcaga gttaacttga 720
gaactttaag aggttattat aatcagtctg aggcaggttc ccacactctt caatggatgc 780
atggttgtga attgggtcca gatggtagat tcctcagggg ttatgaacag tttgcctatg 840
atggaaaaga ttatttgacc cttaatgagg acctaaggtc ctggactgca gttgatacag 900
cagcccagat ttcagaacaa aagtctaatg atgcttctga agctgaacac caaagagcgt 960
atttagagga tacttgtgta gaatggttac acaagtactt ggaaaagggt aaggaaacct 1020
tactacactt ggaacctcct aagacccatg tcacacatca tccaatctct gaccatgaag 1080
caacactaag gtgttgggca ctaggttttt accctgctga aattaccctc acctggcaac 1140
aagatggtga aggtcacacc caagacactg aactagtaga gacaagacct gctggggatg 1200
gtacatttca aaaatgggct gctgtggtag ttcctagtgg ggaagaacaa aggtatacct 1260
gtcatgttca acatgagggg ttaccagaac cagttaccct taggtggaaa ccagcttctc 1320
aacctactat tccaattgtt ggtatcattg ctggtcttgt cttgttgggt tctgttgttt 1380
ctggtgctgt tgtggcagca gtgatctgga ggaaaaaatc atctggtggt aagggtggtt 1440
cttactctaa ggctgaatgg tcagattcag ctcaagggag tgaatctcac tctttgggca 1500
gtggcgccac caattttagc ctgttaaagc aggctggcga cgtggaggag aatcctgggc 1560
ctatgtggcc tctggtagca gcacttcttt taggttcagc atgttgtggt tcagctcaac 1620
tactgttcaa caaaaccaaa tctgttgaat tcaccttctg taatgacaca gttgttatcc 1680
catgttttgt taccaacatg gaagctcaga acaccacaga agtttatgtt aaatggaaat 1740
tcaaaggtag agacatctac acctttgatg gtgctctgaa caaatctaca gttcccactg 1800
acttctcttc tgctaaaata gaagtttctc aattactgaa aggtgatgct tctctgaaaa 1860
tggacaaatc tgatgctgtt tctcacacag gtaactacac ctgtgaagtt acagaactga 1920
ccagagaagg tgaaaccatc attgaactga aatacagagt tgtttcttgg ttctctccta 1980
atgaaaacat cctgattgtt atcttcccca tctttgctat ccttctgttc tggggtcagt 2040
ttggtatcaa aaccctgaaa tacagatctg gtggtatgga tgaaaaaacc attgctttac 2100
tggttgctgg tctggttatc actgttatag ttatagttgg tgctatcctg tttgttccag 2160
gtgaatactc tctgaaaaat gctacaggtc tgggtctgat agttacctct actggtatcc 2220
tgatcttact tcactactat gttttctcta cagctattgg tctgacctct tttgttatag 2280
ctatcctggt tatccaggtt attgcttaca tcctggctgt tgttggtctg tctctgtgta 2340
ttgctgcttg tatccccatg catggtcctc ttctgatctc tggtctgtct atcctggctc 2400
tggctcaatt actgggtctg gtttacatga aatttgttgc ttctaaccag aaaaccatcc 2460
aaccacctag gaaagctgtt gaagaacctc tgaatgcttt caaagaatct aaaggtatga 2520
tgaatgacga a 2531
<210> 10
<211> 5273
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 10
ttaggtgttc tggttcttgg tgcactggct ctggcaggtt taggtttccc cgctcctgct 60
gaaccacaac caggtggttc tcagtgtgtt gaacatgact gttttgctct gtaccccggt 120
cccgctacct tcctgaatgc ttctcagatc tgtgatggtc ttaggggtca cctgatgaca 180
gttcgcagct ctgttgctgc tgatgttatc tctttattac tgaatggtga tggtggtgtt 240
ggtaggagga gactgtggat tggactgcaa ctaccaccag gttgtggtga ccctaaaaga 300
ctgggtcctc ttagaggttt ccagtgggtt acaggtgaca acaacacctc ttactctaga 360
tgggctagac tggacctgaa tggtgctcct ctgtgtggtc ctctgtgtgt tgctgtttct 420
gctgctgaag ctactgttcc ttctgaacct atctgggaag aacaacagtg tgaagttaaa 480
gctgatggtt tcctgtgtga attccacttc cccgctacct gtagaccact ggctgttgaa 540
cccggtgctg ctgctgctgc tgtttctatc acctatggta ccccttttgc tgctagaggt 600
gctgacttcc aggctctacc agttggttct tctgctgctg ttgctcctct gggcttacaa 660
ctgatgtgta cagctccacc cggtgctgtt cagggtcact gggctagaga agctcccggt 720
gcttgggact gttctgttga aaatggtggt tgtgaacatg cttgtaatgc tatccctggt 780
gctcctaggt gtcagtgtcc tgctggtgct gctcttcagg ctgatggtag atcttgtact 840
gcttctgcta cccagtcttg taatgacctg tgtgaacact tctgtgttcc caaccccgac 900
caacccggtt cttactcttg tatgtgtgaa acaggttaca gactggctgc tgaccaacac 960
agatgtgaag atgttgatga ctgtatcctg gaaccctctc catgtccaca aaggtgtgtt 1020
aacacccagg gtggttttga atgtcactgt taccctaact atgacctggt tgatggtgaa 1080
tgtgttgaac ccgttgaccc ctgtttcagg gctaactgtg aataccagtg tcaacctctg 1140
aaccagacct cttacctgtg tgtttgtgct gaaggttttg ctccaatccc tcatgaacct 1200
cacaggtgtc agatgttctg taaccagaca gcttgtcccg ctgactgtga ccctaacacc 1260
caggcttctt gtgaatgtcc agaaggttac atcctggatg atggtttcat ctgtacagac 1320
attgatgaat gtgaaaatgg tggtttctgt tctggtgttt gtcacaacct tcccggtacc 1380
tttgaatgta tctgtggtcc cgactctgct ctggctagac acattggtac agactgtgac 1440
tctggtaaag ttgatggtgg tgactctggt tctggtgaac ctcctccctc tccaaccccc 1500
ggttctaccc tgaccccacc agctgttggt ctggttcact ctggtctact gataggtatc 1560
tctatagctt ctctgtgtct ggttgttgct ctactggctc tactgtgtca ccttaggaaa 1620
aaacagggtg ctgctagggc taaaatggaa tacaaatgtg ctgctccatc taaagaagtt 1680
gttttacaac atgttaggac tgaaaggacc cctcaaaggc tgggcagcgg cgcgaccaac 1740
ttttcgctcc ttaagcaggc cggggacgtg gaggagaatc cagggcctat ctacactatg 1800
aaaaaagtac atgctttatg ggcctctgtt tgtttacttc tgaacctggc tcctgctcct 1860
ctgaatgctg actctgaaga agatgaagaa cacaccatca tcacagacac tgaacttcct 1920
ccactgaaac tgatgcactc tttctgtgct ttcaaagctg atgatggtcc ttgtaaagct 1980
atcatgaaaa ggttcttctt caacatcttc accagacagt gtgaagaatt catctatggt 2040
ggttgtgaag gtaaccagaa cagatttgaa tctctggaag aatgtaagaa aatgtgtacc 2100
agggacaatg ctaacaggat catcaaaacc accctacaac aggaaaaacc agacttctgt 2160
ttcctggaag aggatcctgg tatctgtaga ggttacatca ccaggtactt ctacaacaac 2220
cagaccaaac agtgtgaaag attcaaatat ggtggttgtc tgggtaacat gaacaacttt 2280
gaaaccctgg aagaatgtaa aaacatctgt gaagatggtc ccaatggttt ccaggttgac 2340
aactatggta cccaactgaa tgctgttaac aactctctga cccctcagtc taccaaagtt 2400
ccctctctgt ttgaattcca tggtccttct tggtgtctga cccctgctga cagaggtctg 2460
tgtagagcta atgaaaacag gttctactac aactctgtta taggtaaatg tagacccttc 2520
aaatactctg gttgtggtgg taatgaaaac aacttcacct ctaaacagga atgtttaagg 2580
gcttgtaaaa aaggtttcat ccaaagaatc tctaaaggtg gtctgatcaa aaccaaaaga 2640
aaaagaaaaa aacaaagagt taaaatagct tatgaagaaa tctttgttaa aaacatgtac 2700
ttacaggaac tgggaggttc agggggagga gggtccggtg ggggtggttc tggtggttgt 2760
agaaatggta aaaccctgtc tgtttctcaa ctggaacttc aggactctgg tacctggacc 2820
tgtacagttc tacagaacca gaaaaaagtt gaattcaaaa tagacatagt tgttctggct 2880
ttccagaaag cttcttctat agtttacaaa aaagaaggtg aacaggttga attctctttc 2940
ccactggctt tcactgttga aaaactgact ggttctggtg aactgtggtg gcaggctgaa 3000
agggcttctt cttctaaatc ttggatcacc tttgacctga aaaacaaaga agtttctgtt 3060
aaaagggtta cccaggaccc aaaattacag atgggtaaaa aattacctct tcacctgacc 3120
ctaccacagg ctcttccaca gtatgctggt tctggtaacc tgaccctggc tctggaagct 3180
aaaactggta aactacacca ggaagttaac ctggttgtta tgagagctac ccaacttcag 3240
aaaaacctga cctgtgaagt ttggggtcca acctctccaa aactgatgct gtctctgaaa 3300
ctggaaaaca aagaagctaa agtttctaaa agagaaaaag ctgtttgggt tctgaaccca 3360
gaagctggta tgtggcagtg cctgctgtct gactctggtc aggttttact ggaatctaac 3420
atcaaagttc ttcctacctg gtctacccct gttcaaccaa tggctctgat tgttctgggt 3480
ggtgttgctg ggcttcttct gttcataggt ctgggtatct tcttctgtgt taggtgtcga 3540
cacagaagga gacaggctga aagaatgtct cagatcaaaa ggttccgtca gaaagatgat 3600
ggtaaatgtc cactgaaccc acactctcac ctgggtacct atggtgtttt caccaatgct 3660
gcttttgacc cctctcctgg cagcggagcg accaacttta gccttctgaa acaggctggg 3720
gacgtggagg agaatcctgg gcctatggag gataccaaag aatctaatgt taaaactttc 3780
tgttctaaaa acatcctggc tatcctgggt ttctcttcta tcattgctgt tattgcttta 3840
ctggctgttg gtctgaccca gaacaaagct ttacctgaaa atgttaaata tggtattgtt 3900
ctggatgctg gttcttctca cacctctctg tacatctaca aatggcccgc tgaaaaagaa 3960
aatgacacag gtgttgttca ccaggttgaa gaatgtagag ttaaaggtcc tggtatctct 4020
aaatttgttc agaaagttaa tgaaattggt atctacctga ctgactgtat ggaaagagct 4080
agggaagtta tccctcgttc gcaacaccag gaaacccccg tttacctggg tgctactgct 4140
ggtatgagat tactaagaat ggaatctgaa gaactggctg acagagttct ggatgttgtt 4200
gaaagatctc tgtctaacta cccctttgac ttccagggtg ctaggatcat cacaggtcag 4260
gaagaaggtg cttatggttg gatcaccatc aactaccttc tgggtaaatt ctctcagaaa 4320
accaggtggt tctctatagt tccatatgaa accaacaacc aggaaacctt tggtgctctg 4380
gacctgggtg gtgcttctac ccaggttacc tttgttcctc agaaccagac cattgaatct 4440
cctgacaatg ctctacagtt cagactgtat ggtaaagact acaatgttta cacccactct 4500
ttcctgtgtt atggtaaaga ccaggctctg tggcagaaac tggctaaaga catccaggtt 4560
gcttctaatg aaatccttag ggacccttgt ttccaccctg gttacaaaaa agttgttaat 4620
gtttctgacc tgtacaaaac cccttgtacc aaaagatttg aaatgacctt acccttccaa 4680
cagtttgaaa tccagggtat tggtaactac caacagtgtc accagtctat cctggaactg 4740
ttcaacacct cttactgtcc ctactctcag tgtgctttca atggtatctt cttacctcct 4800
ctacagggtg actttggtgc tttctctgct ttctactttg ttatgaaatt cctgaacctg 4860
acctctgaaa aagtttctca ggaaaaagtt actgaaatga tgaaaaaatt ctgtgctcaa 4920
ccctgggaag aaatcaaaac ctcttatgct ggtgttaaag aaaaatacct gtctgaatac 4980
tgtttctctg gtacctacat cctgtcttta ttattacagg gttaccactt cactgctgac 5040
tcttgggaac acatccactt cataggtaaa atccagggtt ctgatgctgg ttggaccctg 5100
ggttacatgc tgaacctgac caacatgatc cccgctgaac aacctctgtc taccccactg 5160
tctcactcta cctatgtttt cctgatggtt ctgttctctc tggttctgtt cacagttgct 5220
atcataggtc tactgatctt ccacaaacca tcttacttct ggaaagacat ggt 5273
<210> 11
<211> 32216
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 11
agaagatcct ttgatctttt ctacggggtc tgacgctcag tggaacgaaa actcacgtta 60
agggattttg gtcatgagat tatcaaaaag gatcttcacc tagatccttt taaattaaaa 120
atgaagtttt aaatcaatct aaagtatata tgagtaaact tggtctgaca gttaccaatg 180
cttaatcagt gaggcaccta tctcagcgat ctgtctattt cgttcatcca tagttgcctg 240
actccccgtc gtgtagataa ctacgatacg ggagggctta ccatctggcc ccagtgctgc 300
aatgataccg cgggacccac gctcaccggc tccagattta tcagcaataa accagccagc 360
cggaagggcc gagcgcagaa gtggtcctgc aactttatcc gcctccatcc agtctattaa 420
ttgttgccgg gaagctagag taagtagttc gccagttaat agtttgcgca acgttgttgc 480
cattgctaca ggcatcgtgg tgtcacgctc gtcgtttggt atggcttcat tcagctccgg 540
ttcccaacga tcaaggcgag ttacatgatc ccccatgttg tgcaaaaaag cggttagctc 600
cttcggtcct ccgatcgttg tcagaagtaa gttggccgca gtgttatcac tcatggttat 660
ggcagcactg cataattctc ttactgtcat gccatccgta agatgctttt ctgtgactgg 720
tgagtactca accaagtcat tctgagaata gtgtatgcgg cgaccgagtt gctcttgccc 780
ggcgtcaata cgggataata ccgcgccaca tagcagaact ttaaaagtgc tcatcattgg 840
aaaacgttct tcggggcgaa aactctcaag gatcttaccg ctgttgagat ccagttcgat 900
gtaacccact cgtgcaccca actgatcttc agcatctttt actttcacca gcgtttctgg 960
gtgagcaaaa acaggaaggc aaaatgccgc aaaaaaggga ataagggcga cacggaaatg 1020
ttgaatactc atactcttcc tttttcaata ttattgaagc atttatcagg gttattgtct 1080
catgagcgga tacatatttg aatgtattta gaaaaataaa caaatagggg ttccgcgcac 1140
atttccccga aaagtgccac ctaaattgta agcgttaata ttttgttaaa attcgcgtta 1200
aatttttgtt aaatcagctc attttttaac caataggccg aaatcggcaa aatcccttat 1260
aaatcaaaag aatagaccga gatagggttg agtgttgttc cagtttggaa caagagtcca 1320
ctattaaaga acgtggactc caacgtcaaa gggcgaaaaa ccgtctatca gggcgatggc 1380
ccactacgtg aaccatcacc ctaatcaagt tttttggggt cgaggtgccg taaagcacta 1440
aatcggaacc ctaaagggag cccccgattt agagcttgac ggggaaagcc ggcgaacgtg 1500
gcgagaaagg aagggaagaa agcgaaagga gcgggcgcta gggcgctggc aagtgtagcg 1560
gtcacgctgc gcgtaaccac cacacccgcc gcgcttaatg cgccgctaca gggcgcgtcc 1620
cattcgccat tcaggctgcg caactgttgg gaagggcgat cggtgcgggc ctcttcgcta 1680
ttacgccagc tggcgaaagg gggatgtgct gcaaggcgat taagttgggt aacgccaggg 1740
ttttcccagt cacgacgttg taaaacgacg gccagtgagc gcgcctcgtt cattcacgtt 1800
tttgaacccg tggaggacgg gcagactcgc ggtgcaaatg tgttttacag cgtgatggag 1860
cagatgaaga tgctcgacac gctgcagaac acgcagctag attaacccta gaaagataat 1920
catattgtga cgtacgttaa agataatcat gcgtaaaatt gacgcatgtg ttttatcggt 1980
ctgtatatcg aggtttattt attaatttga atagatatta agttttatta tatttacact 2040
tacatactaa taataaattc aacaaacaat ttatttatgt ttatttattt attaaaaaaa 2100
aacaaaaact caaaatttct tctataaagt aacaaaactt ttatgaggga cagccccccc 2160
ccaaagcccc cagggatgta attacgtccc tcccccgcta gggggcagca gcgagccgcc 2220
cggggctccg ctccggtccg gcgctccccc cgcatccccg agccggcagc gtgcggggac 2280
agcccgggca cggggaaggt ggcacgggat cgctttcctc tgaacgcttc tcgctgctct 2340
ttgagcctgc agacacctgg ggggatacgg ggaaaaggcc tccacggcct aactttaaat 2400
aattggcatt atttaaagtt agaatagtaa tcaattacgg ggtcattagt tcatagccca 2460
tatatggagt tccgcgttac ataacttacg gtaaatggcc cgcctggctg accgcccaac 2520
gacccccgcc cattgacgtc aataatgacg tatgttccca tagtaacgcc aatagggact 2580
ttccattgac gtcaatgggt ggagtattta cggtaaactg cccacttggc agtacatcaa 2640
gtgtatcata tgccaagtac gccccctatt gacgtcaatg acggtaaatg gcccgcctgg 2700
cattatgccc agtacatgac cttatgggac tttcctactt ggcagtacat ctacgtatta 2760
gtcatcgcta ttaccatggt gatgcggttt tggcagtaca tcaatgggcg tggatagcgg 2820
tttgactcac ggggatttcc aagtctccac cccattgacg tcaatgggag tttgttttgg 2880
caccaaaatc aacgggactt tccaaaatgt cgtaacaact ccgccccatt gacgcaaatg 2940
ggcggtaggc gtgtacggtg ggaggtctat ataagcagag ctggtttagt gaaccgtcag 3000
atccgctaga acaccgcatc gtacgcgtac gtgtgaggat aacttcgtat agcatacatt 3060
atacgaagtt attggcgcgc ctaactttaa ataattggca ttatttaaag ttagccacca 3120
tggcacaatc aaaacatgga ttaactaagg aaatgacaat gaaatacaga atggaaggtt 3180
gtgttgatgg tcacaaattt gttatcactg gtgaaggtat tggttaccca ttcaaaggta 3240
aacaggctat caacctgtgt gttgttgaag gtggtcctct accatttgct gaggatatcc 3300
tgtctgctgc tttcatgtat ggtaacaggg ttttcactga atacccacag gacatagttg 3360
actacttcaa aaactcttgt cccgctggtt acacctggga cagatctttc ctgtttgaag 3420
atggtgctgt ttgtatctgt aatgctgaca tcactgtttc tgttgaagaa aactgtatgt 3480
accatgaatc taaattctat ggtgttaact tcccagctga tggtcccgtt atgaaaaaaa 3540
tgactgacaa ctgggaacct tcttgtgaaa aaatcatccc tgttccaaaa cagggtatcc 3600
tgaaaggtga tgtttctatg tacttacttc tgaaagatgg tggtagactt agatgtcagt 3660
ttgacacagt ttacaaagct aaatctgttc ctaggaaaat gcctgactgg cacttcatcc 3720
aacacaaact gaccagggag gataggtctg atgctaaaaa ccagaaatgg cacctgactg 3780
aacatgctat agcttctggt tctgctctgc cgggcagcgg ggccaccaat ttttctctgc 3840
tgaagcaagc aggcgacgtc gaggaaaacc cggggcctat gactgaatac aaacccacag 3900
ttagactggc taccagagat gatgttccta gagctgttag gaccctggct gctgcttttg 3960
ctgactaccc tgctaccagg cacactgttg accctgacag gcacatagaa agagttacag 4020
aactacagga actgttcctg accagggttg gtctggacat tggtaaagtt tgggttgctg 4080
atgatggtgc tgctgttgct gtttggacca cccccgaatc tgttgaagct ggtgctgttt 4140
ttgctgaaat aggtccaagg atggctgaac tgtctggttc taggctggct gctcaacaac 4200
agatggaagg tctactggct ccacacaggc ccaaagaacc cgcttggttc ctggctactg 4260
ttggtgtttc tccagaccac cagggtaaag gtctgggttc tgctgttgtt ctacctggtg 4320
ttgaagctgc tgaaagggct ggtgttccag ctttcctgga aacctctgct cctagaaact 4380
taccattcta tgaaaggctg ggtttcacag ttactgctga tgttgaagtt cccgaaggtc 4440
ctaggacctg gtgtatgacc aggaaacctg gtgcttgata actttaaata attggcatta 4500
tttaaagtta gtagggataa cagggtaata gcgcggggac agcccccccc caaagccccc 4560
agggatgtaa ttacgtccct cccccgctag ggggcagcag cgagccgccc ggggctccgc 4620
tccggtccgg cgctcccccc gcatccccga gccggcagcg tgcggggaca gcccgggcac 4680
ggggaaggtg gcacgggatc gctttcctct gaacgcttct cgctgctctt tgagcctgca 4740
gacacctggg gggatacggg gaaaatgtgt ctgagcctgc atgtttgatg gtgtctggat 4800
gcaagcagaa ggggtggaag agcttgcctg gagagataca gctgggtcag taggactggg 4860
acaggcagct ggagaattgc catgtagatg ttcatacaat cgtcaaatca tgaaggctgg 4920
aaaagccctc caagatcccc aagaccaacc ccaacccacc caccgtgccc actggccatg 4980
tccctcagtg ccacatcccc acagttcttc atcacctcca gggacggtga cccccccacc 5040
tccgtgggca gctgtgccac tgcagcaccg ctctttggag aaggtaaatc ttgctaaatc 5100
cagcccgacc ctcccctggc acaacgtaag gccattatct ctcatccaac tccaggacgg 5160
agtcagtgag aatatttaaa taaacttata aattgtgaga gaaattaatg aatgtctaag 5220
ttaatgcaga aacggaggct cctcatttat ttttgaactt aaagacttaa tattgtgaag 5280
gtatactttc tttaataata agcctgcgcc caatatgttc accccaaaaa agctgtttgt 5340
taacttgtca acctcattta aaatatataa gaaacagccc aaagacaata acaaaagaat 5400
aataaaaaag aatgaaatat gtaattcttt cagagtaaaa atcacaccca tgacctggcc 5460
actgagggct tgatcaattc actttgaatt tggcattaaa taccattaag gtatattaac 5520
tgattttaaa ataagatata ttcggcacac caaataatga ttttattttg actgatagtg 5580
acctgttcgt tgcaacaaat tgatgagcaa tgctttttta taatgccaac tttgtacaaa 5640
aaagcagaat tctaccgggt aggggaggcg cttttcccaa ggcagtctgg agcatgcgct 5700
ttagcagccc cgctgggcac ttggcgctac acaagtggcc tctggcctcg cacacattcc 5760
acatccaccg gccggtaggc gccaaccggc tccgttcttt ggtggcccct tcgcgccacc 5820
ttctactcct cccctagtca ggaagttccc ccccgccccg cagctcgcgt cgtgcaggac 5880
gtgacaaatg gaagtagcaa gtctcactag tctcgtgcag atggacagca ccgctgagca 5940
atggaagcgg gtaggccttt ggggcagcgg ccaatagcag ctttgctcct tcgctttctg 6000
ggctcagagg ctgggaaggg gtgggtccgg gggcgggctc aggggcgggc tcaggggcgg 6060
ggcgggcgcc cgaaggtcct ccggaggccc ggcattctgc acgcttcaaa agcgcacgtc 6120
tgccgcgctg ttctcctctt cctcatctcc gggcctttgc caccatggct gaacaagttc 6180
tccctcaagc tctgtacctg tctaacatga gaaaagctgt aaaaatcaga gaaaggaccc 6240
ctgaggatat cttcaaacca accaatggta tcatccacca cttcaaaacc atgcacagat 6300
acaccctgga aatgttcaga acctgtcagt tctgtccaca gttcagggaa atcatccaca 6360
aagctctgat agacaggaac atccaggcta ccctggaatc tcagaaaaaa ctgaactggt 6420
gtagggaagt taggaaactg gttgctctga aaaccaatgg tgatggtaac tgtctgatgc 6480
atgctacctc tcagtacatg tggggtgttc aggacacaga cctggttcta agaaaagctc 6540
tgttctctac cctgaaagaa acagacacca gaaacttcaa attcaggtgg caactggaat 6600
ctctgaaatc tcaggaattt gttgaaacag gtctgtgtta tgacaccaga aactggaatg 6660
atgaatggga caacctgatc aaaatggctt ctactgacac ccccatggct aggtctggtt 6720
tacagtacaa ctctctggaa gaaatccaca tctttgttct gtgtaacatc cttcggaggc 6780
caatcatagt tatctctgac aaaatgcttc gctcactgga atctggttct aactttgctc 6840
ctctgaaagt tggtggtatc tacttacctc ttcactggcc agctcaggaa tgttacagat 6900
accccatagt tctgggttat gactctcacc actttgttcc actggttacc ctgaaagact 6960
ctggtccaga aatcagggct gttcctctgg ttaacagaga caggggtagg tttgaggatc 7020
tgaaagttca cttcctgaca gacccagaaa atgaaatgaa agaaaaatta ctgaaagaat 7080
acctgatggt tattgaaatc cctgttcagg gttgggacca tggtaccacc cacctgatca 7140
atgctgctaa actggatgaa gctaacttac ctaaagaaat caacctggtt gatgactact 7200
ttgaactggt tcaacatgaa tacaaaaaat ggcaggaaaa ctctgaacag ggtagaagag 7260
aaggtcatgc tcagaacccc atggaaccat ctgttcctca actgtctctg atggatgtta 7320
aatgtgaaac ccccaactgt cccttcttca tgtctgttaa cacccaacca ctgtgtcatg 7380
aatgttctga acgtcggcag aaaaaccaga acaaacttcc aaaactgaac tctaaacctg 7440
gtcccgaagg tttacctggt atggctctgg gtgcttctag aggtgaagct tatgaacctc 7500
tggcttggaa ccccgaagaa tctactggtg gtccacactc tgctcctcca acagctccat 7560
ctcctttcct gttctctgaa accactgcta tgaaatgtcg cagtcctggt tgtcccttca 7620
ccctgaatgt tcaacacaat ggtttctgtg aaagatgtca caatgctaga caacttcatg 7680
cttctcatgc tccagaccac accagacacc tggacccagg taaatgtcag gcttgcctcc 7740
aggatgttac cagaaccttc aatggtatct gttctacctg tttcaaaagg accactgctg 7800
aagcttcttc ttctctgtct acctctctac caccctcttg tcaccaaagg tctaaatctg 7860
acccatctag gctggttaga tctccttctc cacactcttg tcacagagct ggtaatgatg 7920
ctccagctgg ttgtctgtct caggctgcta ggacccccgg tgacagaaca ggtacctcta 7980
aatgtaggaa agctggttgt gtttactttg gtacccctga aaacaaaggt ttctgtaccc 8040
tgtgtttcat agaatacaga gaaaacaaac actttgctgc tgcttctggt aaagtttctc 8100
ccacagcttc taggttccag aacaccatcc catgtctggg tagagaatgt ggtaccctgg 8160
gttctaccat gtttgaaggt tactgtcaga aatgtttcat tgaagctcag aaccaaagat 8220
tccatgaagc taaaagaaca gaagaacaac ttagatcttc tcaaagaaga gatgttccta 8280
ggaccaccca gtctacctct agacctaaat gtgctagagc ttcttgtaaa aacatcctgg 8340
cttgtaggtc tgaagaactg tgtatggaat gtcaacaccc taaccaaaga atgggtcctg 8400
gtgctcacag gggtgaacct gctccagagg atcctccaaa acaaagatgt agagctcctg 8460
cttgtgacca ctttggtaat gctaaatgta atggttactg taatgaatgt ttccagttca 8520
aacagatgta cggtggcagc ggcgccacca actttagctt gctgaagcaa gcaggggacg 8580
tcgaagagaa tcctgggcct atgaggatct ttgctgtttt tatcttcatg acttactggc 8640
accttctgaa tgctttcaca gttactgttc caaaagacct gtatgttgtt gaatatggtt 8700
ctaacatgac catagaatgt aaattcccag ttgaaaaaca actggacctg gctgctctga 8760
ttgtttactg ggaaatggag gataaaaaca tcatccagtt tgttcatggt gaagaggatc 8820
tgaaagttca acactcttct tacagacaaa gagctaggtt actgaaagac caactgtctc 8880
tgggtaatgc tgctctacag atcacagatg ttaaattaca ggatgctggt gtttacagat 8940
gtatgatctc ttatggtggt gctgactaca aaaggatcac agttaaagtt aatgctccct 9000
acaacaaaat caaccaaaga atcctggttg ttgaccccgt tacctctgaa catgaactga 9060
cctgtcaggc tgaaggttac cctaaagctg aagttatctg gacctcttct gaccaccagg 9120
ttctgtctgg taaaaccacc accaccaact ctaaaaggga agaaaaactg ttcaatgtta 9180
cctctacctt aagaatcaac accaccacca atgaaatctt ctactgtacc ttcaggaggc 9240
tggacccaga agaaaaccac actgctgaac tggttatccc tgaattacct ctggctcacc 9300
ctcccaatga aagaacccac ctggttatcc tgggtgctat cctactgtgt ctgggtgttg 9360
ctctgacctt catcttcagg ttaaggaaag gtagaatgat ggatgttaaa aaatgtggta 9420
tccaggacac caactctaaa aaacagtctg acacccacct ggaagaaacc ggcagcggcg 9480
ccaccaattt ctcactactg aaacaggccg gtgacgtcga ggagaacccc gggcctatgc 9540
aacaaccctt caactatcct tatcctcaga tctattgggt tgattcctca gcttcctctc 9600
cctgggctcc tcccggtaca gttctacctt gtccaacctc tgttccaaga aggccaggtc 9660
aacgacgccc tcctcctcct cctccacctc caccactacc accacctcca ccaccaccac 9720
ctctaccacc attaccttta cctcctctga aaaaaagggg taaccactct actggtctgt 9780
gcctgctggt tatgttcttc atggttctgg ttgctctggt tggtctgggt ctgggtatgt 9840
tccaactgtt ccaccttcag aaagaaccat ctccaccacc cgaaaaaaaa gaactaagaa 9900
aagttgctca cctgactggt aaatctaact ctaggtctat gccactggaa tgggaggata 9960
cctatggtat tgttctactg tctggtgtta aatacaaaaa aggtggtctg gttatcaatg 10020
aaacaggtct gtactttgtt tactctaaag tttacttcag gggtcagtct tgtaacaacc 10080
tacctctgtc tcacaaagtt tacatgagga actctaaata cccacaggac ctggttatga 10140
tggaaggtaa aatgatgtct tactgtacca caggtcagat gtgggctaga tcttcttacc 10200
tgggtgctgt tttcaacctg acctctgctg accacctgta tgttaatgtt tctgaactgt 10260
ctctggttaa ctttgaagaa tctcagacct tctttggtct gtacaaactg tgataaacgg 10320
gtggcatccc tgtgacccct ccccagtgcc tctcctggcc ctggaagttg ccactccagt 10380
gcccaccagc cttgtcctaa taaaattaag ttgcatcatt ttgtctgact aggtgtcctt 10440
ctataatatt atggggtgga ggggggtggt atggagcaag gggcaagttg ggaagacaac 10500
ctgtagggcc tgcggggtct attgggaacc aagctggagt gcagtggcac aatcttggct 10560
cactgcaatc tccgcctcct gggttcaagc gattctcctg cctcagcctc ccgagttgtt 10620
gggattccag gcatgcatga ccaggctcag ctaatttttg tttttttggt agagacaggg 10680
tttcaccata ttggccaggc tggtctacaa ctcctaatct caggtgatct acccaccttg 10740
gcctcccaaa ttgctgggat tacaggcgtg aaccactgct cccttccctg tccttctgat 10800
tttaaaataa ctataccagc aggaggagcc taaataatga ttttattttg actgatagtg 10860
acctgttcgt tgcaacaaat tgatgagcaa tgctttttta taatgccaac tttgtataca 10920
aaagttggcc ctgaaggcaa tttctaagtt ggatagttac agactgttta taattggacc 10980
tattattacc ttgcataagt tagctatgtt gaggttgcaa aaggacggga ggttactcag 11040
gatggaaact gtttggaata gaacaaggac atgcccaaac cgtttcaatt atctgtgttt 11100
gtttgttttg tgtcatgatc ctgaaagaaa ttttgtgtag gagttcaatc ttaaaatgag 11160
cgttgagttt cattaagata cattgatgag tttggacaaa ccacaactag aatgcagtga 11220
aaaaaatgct ttatttgtga aatttgtgat gctattgctt tatttgtaac cattataagc 11280
tgcaataaac aagttaacaa caacaattgc attcatttta tgtttcaggt tcagggggag 11340
gtgtgggagg ttttttaaag caagtaaaac ctctacaaat gtggtatggc tgattatgat 11400
cagttatcta gatttatcac gggtgtaaag accaagcagc agccaggaaa ggggtaacca 11460
gtagaagaac tgttttttca gacagagagg taccaccatt ttccagttgt tcattgaagt 11520
tacacaggtc ttttttacaa cagtagtagg tcagttcatt ttctcttaat ctggtggtaa 11580
catcattgaa gttacagtgt tcaaatttcc aacatttgtt gtaaacctgc aggccagctt 11640
tggtgatcag acaagcatca aagtcagaag aacagttaac agctgtttta cagtcagcag 11700
tagggttggg acagttgtaa cactgaagag agtgaccaga gtgacagaaa acagccagaa 11760
ccagtaacag accaaacaga acagaaccac cttggatacc cataggcccc gggttctcct 11820
ctacgtcccc ggcctgcttg agcaggctga aattcgtggc tccgctgccg gtcagtagcc 11880
ccatggtaac cagggtaccc agtagaccag tcagggtgaa acaggtgtga ccagacagaa 11940
gcctggtggt accagaggtg gtaccagaac ctttgttagg ggtggtttca tggaagtgtt 12000
tggtggtcct agaaacgggg gtagatctgg tagcctgagc attgggggtg gtggttttgg 12060
tggtggtttt ctgagaggtg ggagaaactt ctgtggtggg aacattaact gtggtaggtt 12120
tctgaactgt aggaggaact ttagaggtca gagatttacc cctacattcg ggaggaggac 12180
cagaccattc accttcatca ttgttaacag tacagtagat agagtgttca ccaatcatgg 12240
tgaaaccttt gttacaagca taggtaacag actgcctgta accatagtga tcacgttcac 12300
cctggatgat accattgtct atctgaggag gagctggaca gtagatttcc ctacattcgg 12360
gtaaagggtc agaccactga acagaagaac cagagatcag acagaaagaa gaggtagaac 12420
caaacagttt gtaaccagtg ttacaagaga aagagatggt agcaccaaac aggataccac 12480
caggaacatc aatctgacca ttcctgattt caccggggtt gggacaagat ttttttttac 12540
agaattcaac agcagtagac catttcaggt tctgtagaca ggtcagtttg ggagacagag 12600
agggttctct tctgtaacca ggtctacatt catattcaac aacagtacca actgggaagt 12660
agttctgggt gatgtagggt tgtttcagag aagcagagtt cagcctggtg ggaacttcac 12720
aagatctgtt acagaattct tctatgtcag accactgaga acctttcaga cagataacag 12780
agtctttttc acctgggatt ttaacaaaag attcttcaca tttgtaggtg ataacagtat 12840
cctcagggaa agaggttcta ccttccagag caggttgagc attaggaaca tctggaggta 12900
aaccacagtc accccaaaca gcagggaggc acagtaaaac cagtaataaa agtcttggaa 12960
gttcacctag aagtgggagt gctgctggaa cagatggcct ggctactgtc ataggcccgg 13020
ggttctcctc cacgtcgcca gcctgcttaa ggagtgagaa gttggtggct ccactgccca 13080
gagaggtgaa tttaacttct ctgtgggttt catctgtcag gtaggtacct tttttttttc 13140
tcctttgaag gtacctgtaa ggaacaacac agataacagc aacaccaaca acaatagcta 13200
taactataac agcaataacc caaacatcca gagagtccag gataccttct tcaggtttag 13260
ggtaaccagg gtagttagaa acgggaggtt tgtaggtagg tcttggacca gaagcagaag 13320
aagcaggaga tttggtggta gaagaggtag aaacagagtg agacagagcg ggtggtttgg 13380
tagaagaggg tggtaaaact ttcagacatt tgggaactgg tgggtcccag gtagagttag 13440
agtcacaaac aatggtgtca gaaccatcca ggtagaaacc tttgtcacat tcaaacataa 13500
cagtagcttt gtagtagaat tttttaccaa aaccagagat ctgtttacca ttttcaacaa 13560
ctgggaatct acatttaaca actttacatt ctggagcagc tctagaccaa acagagttgt 13620
caccacagta gatggtagat tcaccaatca gagagaatgg gtctggacca ggagcagggt 13680
cacaagagta ggtaacagca tccaggtatt caaaaacttc aacttcagag aaggtgtgtt 13740
taccattttt gattttgggt ggtggggtac acagaacttt ttcacagatg ggaggtttac 13800
cagaccagat agcaacagaa cctttcagtt cacagtacag gatttcttca cctatcaggt 13860
agtaaccttc attacagatg aagtgcatct ggtaaccaaa ttcataggta ccattagctg 13920
gaacagcctg accattcaga ggatctcgga tgtagggaca ggtttccctg taacaagcat 13980
catcagaaac aggtaaccag gtgtggtttc tgtcacagat ggtgtgggta gccagaggtg 14040
ggatgtagaa gtaacctttt ttacatttgt agtcaactct ttcacctatt tcatagtatg 14100
gttttggttt acctatcagt tccatagctt caaaggttgg tggttcttca caagcatcag 14160
agaaagagta cagtaaaaga accatagcag ccagtagtaa accagggaat ctccaagatg 14220
ggaagggaca ctcccttcta ccaggtggtt ccatcatggt ggctcacgac acctgaaatg 14280
gaagaaaaaa actttgaacc actgtctgag gcttgagaat gaaccaagat ccaaactcaa 14340
aaagggcaaa ttccaaggag aattacatca agtgccaagc tggcctaact tcagtctcca 14400
cccactcagt gtggggaaac tccatcgcat aaaacccctc cccccaacct aaagacgacg 14460
tactccaaaa gctcgagaac taatcgaggt gcctggacgg cgcccggtac tccgtggagt 14520
cacatgaagc gacggctgag gacggaaagg cccttttcct ttgtgtgggt gactcacccg 14580
cccgctctcc cgagcgccgc gtcctccatt ttgagctccc tgcagcaggg ccgggaagcg 14640
gccatctttc cgctcacgca actggtgccg accgggccag ccttgccgcc cagggcgggg 14700
cgatacacgg cggcgcgagg ccaggcacca gagcaggccg gccagcttga gactaccccc 14760
gtccgattct cggtggccgc gctcgcaggc cccgcctcgc cgaacatgtg cgctgggacg 14820
cacgggcccc gtcgccgccc gcggccccaa aaaccgaaat accagtgtgc agatcttggc 14880
ccgcatttac aagactatct tgccagaaaa aaagcgtcgc agcaggtcat caaaaatttt 14940
aaatggctag agacttatcg aaagcagcga gacaggcgcg aaggtgccac cagattcgca 15000
cgcggcggcc ccagcgccca ggccaggcct caactcaagc acgaggcgaa ggggctcctt 15060
aagcgcaagg cctcgaactc tcccacccac ttccaacccg aagctcggga tcaagaatca 15120
cgtactgcag ccaggtggaa gtaattcaag gcacgcaagg gccataaccc gtaaagaggc 15180
caggcccgcg ggaaccacac acggcactta cctgtgttct ggcggcaaac ccgttgcgaa 15240
aaagaacgtt cacggcgact actgcactta tatacggttc tcccccaccc tcgggaaaaa 15300
ggcggagcca gtacacgaca tcactttccc agtttacccc gcgccacctt ctctaggcac 15360
cggttcaatt gccgacccct ccccccaact tctcggggac tgtgggcgat gtgcgctctg 15420
cccactgacg ggcaccggag cctcaggcac atagtgactg gatatgttgt gttttacagt 15480
attatgtagt ctgtttttta tgcaaaatct aatttaatat attgatattt atatcatttt 15540
acgtttctcg ttcaactttt ctatacaaag ttgtccgagg agacaccgtg gcccccgaag 15600
cagcgtgctt tagaaaggga ataagaattc ccgcctccgc gccccacttt caccccagcg 15660
gggcagcgtc cgccatgtga aagctcccca tcccccaccc ccagtgaagg gaaatggcgc 15720
cgggaggctg agggtgggga agctgtttgt acgctcaggc ctccgctcaa gaccccgttc 15780
ataaacctta agccccactg ctactgaatt ggtccgattt cctgcctctc tcccacggag 15840
gcggctggcc gacttccact gaggcgccaa cggcctcgcc atgccctttt caataactca 15900
ttgatttcaa acccgttacc tccatcgcgg actcagtcgc ttcagcccga tttcccgcag 15960
ccgagcgaga tgagagagat cgatctccgc ggacgaacac gaaccggact cgtcctggcg 16020
ctgtagtgag aactgccgct gctcgagaaa caactctgcg aggagcacct ccgcacggga 16080
cccggcgctg ctgctactgc cgctagagcc gctgccgccg cttttctaga accttccccc 16140
ccactaacgc gtcttccgct acgtcaggcc gtcgcgtaaa cgccctatcc gccgccaatg 16200
gcgggaaggc tctacgcccc accttacgcc aaatgcgtac tcctcccacc cttgcggcca 16260
gagacagtac ccgacgttac ttccgtaaat gcgctcaatg aattgcggaa ggctagagtc 16320
ctgctagtta ctacctcttg gaatagggtc ccggcccctg ccttggcgaa ggcaggtgag 16380
aaacgtcgcg cagtttgaaa ttaacgccga cgggaggggc ttaatccgca gcctggagat 16440
ccagccccct caacccggga ggtggtccct gcagttacgc caatgataac ccccgccaga 16500
aaaatcttag tagccttccc tttttgtttt ccgtgcccca actcggcgga ttgactcggc 16560
cccttccgga aacacccgaa tcaacttcta gtcaaattat tgttcacgcc gcaatgaccc 16620
acccctggcc cgcgtctgtg gaactgaccc ctggtgtaca ggagagttcg ctgctgaaag 16680
tggtcccaaa ggggtactag tttttaagct cccaactccc cctcccccag cgtctggagg 16740
attccacacc ctcgcaccgg cgggcgagga agtgggcgga gtccggtttt ggcgccagcc 16800
gctgaggctg ccaagcagaa aagccaccgc tgaggagact ccggtcactg tcctcgcccc 16860
gcctccccct tccctcccct tggggaccac cgggcgccac gccgcgaacg gtaagtgccg 16920
cggtcgtcgg cgcctccgcc ctccccctag ggccccaatt cccagcgggc gcggcgccgg 16980
cccctccccc cgccgcgcgc gcgcccgctg ccccgccctt cgtggccgcc cggcgtgggc 17040
ggtgccaccc ctccccccgg cggccccgcg cgcagctccc ggctccctcc cccttcggat 17100
gtggcttgag ctgtaggcgc ggagggccag cgtcattagt tcatagccca tatatggagt 17160
tccgcgttac ataacttacg gtaaatggcc cgcctggctg accgcccaac gacccccgcc 17220
cattgacgtc aataatgacg tatgttccca tagtaacgcc aatagggact ttccattgac 17280
gtcaatgggt ggactattta cggtaaactg cccacttggc agtacatcaa gtgtatcata 17340
tgccaagtac gccccctatt gacgtcaatg acggtaaatg gcccgcctgg cattatgccc 17400
agtacatgac cttatgggac tttcctactt ggcagtacat ctacgtatta gtcatcgcta 17460
ttaccatggg tcgaggtgag ccccacgttc tgcttcactc tccccatctc ccccccctcc 17520
ccacccccaa ttttgtattt atttattttt taattatttt gtgcagcgat gggggcgggg 17580
gggggggggg ggcgcgcgcc aggcggggcg gggcggggcg aggggcgggg cggggcgagg 17640
cggagaggtg cggcggcagc caatcagagc ggcgcgctcc gaaagtttcc ttttatggcg 17700
aggcggcggc ggcggcggcc ctataaaaag cgaagcgcgc ggcgggcggg agtcgctgcg 17760
ttgccttcgc cccgtgcccc gctccgcgcc gcctcgcgcc gcccgccccg gctctgactg 17820
accgcgttac tcccacaggt gagcgggcgg gacggccctt ctcctccggg ctgtaattag 17880
cgcttggttt aatgacggct cgtttctttt ctgtggctgc gtgaaagcct taaagggctc 17940
cgggagggcc ctttgtgcgg gggggagcgg ctcggggggt gcgtgcgtgt gtgtgtgcgt 18000
ggggagcgcc gcgtgcggcc cgcgctgccc ggcggctgtg agcgctgcgg gcgcggcgcg 18060
gggctttgtg cgctccgcgt gtgcgcgagg ggagcgcggc cgggggcggt gccccgcggt 18120
gcgggggggc tgcgagggga acaaaggctg cgtgcggggt gtgtgcgtgg gggggtgagc 18180
agggggtgtg ggcgcggcgg tcgggctgta acccccccct gcacccccct ccccgagttg 18240
ctgagcacgg cccggcttcg ggtgcggggc tccgtgcggg gcgtggcgcg gggctcgccg 18300
tgccgggcgg ggggtggcgg caggtggggg tgccgggcgg ggcggggccg cctcgggccg 18360
gggagggctc gggggagggg cgcggcggcc ccggagcgcc ggcggctgtc gaggcgcggc 18420
gagccgcagc cattgccttt tatggtaatc gtgcgagagg gcgcagggac ttcctttgtc 18480
ccaaatctgg cggagccgaa atctgggagg cgccgccgca ccccctctag cgggcgcggg 18540
cgaagcggtg cggcgccggc aggaaggaaa tgggcgggga gggccttcgt gcgtcgccgc 18600
gccgccgtcc ccttctccat ctccagcctc ggggctgccg cagggggacg gctgccttcg 18660
ggggggacgg ggcagggcgg ggttcggctt ctggcgtgtg accggcggct ctagagcctc 18720
tgctaaccat gttcatgcct tcttcttttt cctacagctc ctgggcaacg tgctggttgc 18780
caccatgtct agatctgttg ctcttgctgt tcttgctctg ttgtctctgt ctggtctgga 18840
agctgtgatg gcccctagaa ccctgatcct cgggggcgga ggttcaggag gcggtgggag 18900
cggcggaggg ggttccatcc aaagaacccc taaaatccag gtttactcta ggcacccagc 18960
tgaaaatggt aaatctaact tcctgaactg ttatgtttct ggtttccacc cctctgacat 19020
tgaagttgac ttactgaaaa atggtgaaag gatagaaaaa gttgaacact ctgacctgtc 19080
tttctctaaa gactggtctt tctacttact gtactacact gaattcaccc ctacagaaaa 19140
agatgaatat gcttgtagag ttaaccatgt taccctgtct caaccaaaaa ttgttaaatg 19200
ggacagagac atgggtggcg gagggtctgg cgggggtgga agcgggggtg gaggctccgg 19260
aggtgggggc agtggtagtc attccttaaa gtacttccac acctctgttt cccgaccagg 19320
taggggtgaa cctaggttca tctctgttgg gtatgttgat gatacccaat ttgtcagatt 19380
tgataatgat gctgcttctc caagaatggt tccaagggct ccttggatgg aacaggaagg 19440
gtcagaatac tgggacagag aaaccagatc tgctagagac actgctcaaa tattcagagt 19500
taacttgaga actttaagag gttattataa tcagtctgag gcaggttccc acactcttca 19560
atggatgcat ggttgtgaat tgggtccaga tggtagattc ctcaggggtt atgaacagtt 19620
tgcctatgat ggaaaagatt atttgaccct taatgaggac ctaaggtcct ggactgcagt 19680
tgatacagca gcccagattt cagaacaaaa gtctaatgat gcttctgaag ctgaacacca 19740
aagagcgtat ttagaggata cttgtgtaga atggttacac aagtacttgg aaaagggtaa 19800
ggaaacctta ctacacttgg aacctcctaa gacccatgtc acacatcatc caatctctga 19860
ccatgaagca acactaaggt gttgggcact aggtttttac cctgctgaaa ttaccctcac 19920
ctggcaacaa gatggtgaag gtcacaccca agacactgaa ctagtagaga caagacctgc 19980
tggggatggt acatttcaaa aatgggctgc tgtggtagtt cctagtgggg aagaacaaag 20040
gtatacctgt catgttcaac atgaggggtt accagaacca gttaccctta ggtggaaacc 20100
agcttctcaa cctactattc caattgttgg tatcattgct ggtcttgtct tgttgggttc 20160
tgttgtttct ggtgctgttg tggcagcagt gatctggagg aaaaaatcat ctggtggtaa 20220
gggtggttct tactctaagg ctgaatggtc agattcagct caagggagtg aatctcactc 20280
tttgggcagt ggcgccacca attttagcct gttaaagcag gctggcgacg tggaggagaa 20340
tcctgggcct atgtggcctc tggtagcagc acttctttta ggttcagcat gttgtggttc 20400
agctcaacta ctgttcaaca aaaccaaatc tgttgaattc accttctgta atgacacagt 20460
tgttatccca tgttttgtta ccaacatgga agctcagaac accacagaag tttatgttaa 20520
atggaaattc aaaggtagag acatctacac ctttgatggt gctctgaaca aatctacagt 20580
tcccactgac ttctcttctg ctaaaataga agtttctcaa ttactgaaag gtgatgcttc 20640
tctgaaaatg gacaaatctg atgctgtttc tcacacaggt aactacacct gtgaagttac 20700
agaactgacc agagaaggtg aaaccatcat tgaactgaaa tacagagttg tttcttggtt 20760
ctctcctaat gaaaacatcc tgattgttat cttccccatc tttgctatcc ttctgttctg 20820
gggtcagttt ggtatcaaaa ccctgaaata cagatctggt ggtatggatg aaaaaaccat 20880
tgctttactg gttgctggtc tggttatcac tgttatagtt atagttggtg ctatcctgtt 20940
tgttccaggt gaatactctc tgaaaaatgc tacaggtctg ggtctgatag ttacctctac 21000
tggtatcctg atcttacttc actactatgt tttctctaca gctattggtc tgacctcttt 21060
tgttatagct atcctggtta tccaggttat tgcttacatc ctggctgttg ttggtctgtc 21120
tctgtgtatt gctgcttgta tccccatgca tggtcctctt ctgatctctg gtctgtctat 21180
cctggctctg gctcaattac tgggtctggt ttacatgaaa tttgttgctt ctaaccagaa 21240
aaccatccaa ccacctagga aagctgttga agaacctctg aatgctttca aagaatctaa 21300
aggtatgatg aatgacgaat gataacgtag aattccggac ttgactcatg cttgtttcac 21360
tttcacatgg aatttcccag ttatgaaatt aataaaaatc aatggtttcc acatctctca 21420
gtgcctctat ctggaggcca ggtagggctg gccttggggg agggggaggc cagaatgact 21480
ccaagagcta caggaaggca ggtcagagac accactggac aaacagtggc tggactctgc 21540
accataacac acaatcaaca ggggagtgag ctggaggggg atcatgagcc ctgaaggcaa 21600
tttctaagtt ggatagttac agactgttta taattggacc tattattacc ttgcataagt 21660
tagctatgtt gaggttgcaa aaggacggga ggttactcag gatggaaact gtttggaata 21720
gaacaaggac atgcccaaac cgtttcaatt atctgtgttt gtttgttttg tgtcatgatc 21780
ctgaaagaaa ttttgtgtag gagttcaatc ttaaaatgag cgttgagttc cataaataat 21840
gattttattt tgactgatag tgacctgttc gttgcaacaa attgatgagc aatgcttttt 21900
tataatgcca actttgtata ataaagttgc tagaaacaca ctgcaagtcc tcagccctac 21960
ccccccccat caaggccccc tgtctggagt gggggtgcac cctaagctag cccaggaagc 22020
ctccccgagt tacttctgtc tgcgcctgct ggggactatg ctggggctgc tggggactat 22080
gctgagtgcg tttccctcaa gttgtctttt tttttttttt ttttttgtct tttgtccttt 22140
tatggaggtc cccaagctag gggtctaatc ggagctgtag ctgccggcct acaccacagc 22200
cacagcaacg ccggatcctt atcccactga gcaaggccag ggatcgaacc tcaacctcat 22260
ggttcctagt cagattcatt tccgctgcgc catgatggga gtgccgccct caagttgtct 22320
tgtatcaggg agtcaggggc tggctgagat tgaaagcgga gtgtccaggt ttaagcagac 22380
ttgtgccagg cagttgacta aagcaccagc agttcctgcc cgggtttctc tgcccactta 22440
gtcatggtga ctgcatgccc tggccgggtc ctgactttgg atagtccctt cccagagggg 22500
accctgacag tgtgtcctct gggatttggg gctccccaga tctggggctt gtgggcatca 22560
ctgtcctccg tgcacatgca gcactgtcac atgtgtcccc tgatgggagc atgccaggat 22620
gacaaggtta tccctgctta tcagctcttt cccagcttcc tctgcctgtt gcttatagac 22680
atgagccctg ggcgccacgt cttcctcaaa taatgagagg aagtgtggtc atcggcacac 22740
agatggctgg gggttccgga ttgcggctcc cggccaccac tccctgacct gcgcccccat 22800
ctctcgccag gcggtcctcg gctctttcct gccaccatgt taggtgttct ggttcttggt 22860
gcactggctc tggcaggttt aggtttcccc gctcctgctg aaccacaacc aggtggttct 22920
cagtgtgttg aacatgactg ttttgctctg taccccggtc ccgctacctt cctgaatgct 22980
tctcagatct gtgatggtct taggggtcac ctgatgacag ttcgcagctc tgttgctgct 23040
gatgttatct ctttattact gaatggtgat ggtggtgttg gtaggaggag actgtggatt 23100
ggactgcaac taccaccagg ttgtggtgac cctaaaagac tgggtcctct tagaggtttc 23160
cagtgggtta caggtgacaa caacacctct tactctagat gggctagact ggacctgaat 23220
ggtgctcctc tgtgtggtcc tctgtgtgtt gctgtttctg ctgctgaagc tactgttcct 23280
tctgaaccta tctgggaaga acaacagtgt gaagttaaag ctgatggttt cctgtgtgaa 23340
ttccacttcc ccgctacctg tagaccactg gctgttgaac ccggtgctgc tgctgctgct 23400
gtttctatca cctatggtac cccttttgct gctagaggtg ctgacttcca ggctctacca 23460
gttggttctt ctgctgctgt tgctcctctg ggcttacaac tgatgtgtac agctccaccc 23520
ggtgctgttc agggtcactg ggctagagaa gctcccggtg cttgggactg ttctgttgaa 23580
aatggtggtt gtgaacatgc ttgtaatgct atccctggtg ctcctaggtg tcagtgtcct 23640
gctggtgctg ctcttcaggc tgatggtaga tcttgtactg cttctgctac ccagtcttgt 23700
aatgacctgt gtgaacactt ctgtgttccc aaccccgacc aacccggttc ttactcttgt 23760
atgtgtgaaa caggttacag actggctgct gaccaacaca gatgtgaaga tgttgatgac 23820
tgtatcctgg aaccctctcc atgtccacaa aggtgtgtta acacccaggg tggttttgaa 23880
tgtcactgtt accctaacta tgacctggtt gatggtgaat gtgttgaacc cgttgacccc 23940
tgtttcaggg ctaactgtga ataccagtgt caacctctga accagacctc ttacctgtgt 24000
gtttgtgctg aaggttttgc tccaatccct catgaacctc acaggtgtca gatgttctgt 24060
aaccagacag cttgtcccgc tgactgtgac cctaacaccc aggcttcttg tgaatgtcca 24120
gaaggttaca tcctggatga tggtttcatc tgtacagaca ttgatgaatg tgaaaatggt 24180
ggtttctgtt ctggtgtttg tcacaacctt cccggtacct ttgaatgtat ctgtggtccc 24240
gactctgctc tggctagaca cattggtaca gactgtgact ctggtaaagt tgatggtggt 24300
gactctggtt ctggtgaacc tcctccctct ccaacccccg gttctaccct gaccccacca 24360
gctgttggtc tggttcactc tggtctactg ataggtatct ctatagcttc tctgtgtctg 24420
gttgttgctc tactggctct actgtgtcac cttaggaaaa aacagggtgc tgctagggct 24480
aaaatggaat acaaatgtgc tgctccatct aaagaagttg ttttacaaca tgttaggact 24540
gaaaggaccc ctcaaaggct gggcagcggc gcgaccaact tttcgctcct taagcaggcc 24600
ggggacgtgg aggagaatcc agggcctatc tacactatga aaaaagtaca tgctttatgg 24660
gcctctgttt gtttacttct gaacctggct cctgctcctc tgaatgctga ctctgaagaa 24720
gatgaagaac acaccatcat cacagacact gaacttcctc cactgaaact gatgcactct 24780
ttctgtgctt tcaaagctga tgatggtcct tgtaaagcta tcatgaaaag gttcttcttc 24840
aacatcttca ccagacagtg tgaagaattc atctatggtg gttgtgaagg taaccagaac 24900
agatttgaat ctctggaaga atgtaagaaa atgtgtacca gggacaatgc taacaggatc 24960
atcaaaacca ccctacaaca ggaaaaacca gacttctgtt tcctggaaga ggatcctggt 25020
atctgtagag gttacatcac caggtacttc tacaacaacc agaccaaaca gtgtgaaaga 25080
ttcaaatatg gtggttgtct gggtaacatg aacaactttg aaaccctgga agaatgtaaa 25140
aacatctgtg aagatggtcc caatggtttc caggttgaca actatggtac ccaactgaat 25200
gctgttaaca actctctgac ccctcagtct accaaagttc cctctctgtt tgaattccat 25260
ggtccttctt ggtgtctgac ccctgctgac agaggtctgt gtagagctaa tgaaaacagg 25320
ttctactaca actctgttat aggtaaatgt agacccttca aatactctgg ttgtggtggt 25380
aatgaaaaca acttcacctc taaacaggaa tgtttaaggg cttgtaaaaa aggtttcatc 25440
caaagaatct ctaaaggtgg tctgatcaaa accaaaagaa aaagaaaaaa acaaagagtt 25500
aaaatagctt atgaagaaat ctttgttaaa aacatgtact tacaggaact gggaggttca 25560
gggggaggag ggtccggtgg gggtggttct ggtggttgta gaaatggtaa aaccctgtct 25620
gtttctcaac tggaacttca ggactctggt acctggacct gtacagttct acagaaccag 25680
aaaaaagttg aattcaaaat agacatagtt gttctggctt tccagaaagc ttcttctata 25740
gtttacaaaa aagaaggtga acaggttgaa ttctctttcc cactggcttt cactgttgaa 25800
aaactgactg gttctggtga actgtggtgg caggctgaaa gggcttcttc ttctaaatct 25860
tggatcacct ttgacctgaa aaacaaagaa gtttctgtta aaagggttac ccaggaccca 25920
aaattacaga tgggtaaaaa attacctctt cacctgaccc taccacaggc tcttccacag 25980
tatgctggtt ctggtaacct gaccctggct ctggaagcta aaactggtaa actacaccag 26040
gaagttaacc tggttgttat gagagctacc caacttcaga aaaacctgac ctgtgaagtt 26100
tggggtccaa cctctccaaa actgatgctg tctctgaaac tggaaaacaa agaagctaaa 26160
gtttctaaaa gagaaaaagc tgtttgggtt ctgaacccag aagctggtat gtggcagtgc 26220
ctgctgtctg actctggtca ggttttactg gaatctaaca tcaaagttct tcctacctgg 26280
tctacccctg ttcaaccaat ggctctgatt gttctgggtg gtgttgctgg gcttcttctg 26340
ttcataggtc tgggtatctt cttctgtgtt aggtgtcgac acagaaggag acaggctgaa 26400
agaatgtctc agatcaaaag gttccgtcag aaagatgatg gtaaatgtcc actgaaccca 26460
cactctcacc tgggtaccta tggtgttttc accaatgctg cttttgaccc ctctcctggc 26520
agcggagcga ccaactttag ccttctgaaa caggctgggg acgtggagga gaatcctggg 26580
cctatggagg ataccaaaga atctaatgtt aaaactttct gttctaaaaa catcctggct 26640
atcctgggtt tctcttctat cattgctgtt attgctttac tggctgttgg tctgacccag 26700
aacaaagctt tacctgaaaa tgttaaatat ggtattgttc tggatgctgg ttcttctcac 26760
acctctctgt acatctacaa atggcccgct gaaaaagaaa atgacacagg tgttgttcac 26820
caggttgaag aatgtagagt taaaggtcct ggtatctcta aatttgttca gaaagttaat 26880
gaaattggta tctacctgac tgactgtatg gaaagagcta gggaagttat ccctcgttcg 26940
caacaccagg aaacccccgt ttacctgggt gctactgctg gtatgagatt actaagaatg 27000
gaatctgaag aactggctga cagagttctg gatgttgttg aaagatctct gtctaactac 27060
ccctttgact tccagggtgc taggatcatc acaggtcagg aagaaggtgc ttatggttgg 27120
atcaccatca actaccttct gggtaaattc tctcagaaaa ccaggtggtt ctctatagtt 27180
ccatatgaaa ccaacaacca ggaaaccttt ggtgctctgg acctgggtgg tgcttctacc 27240
caggttacct ttgttcctca gaaccagacc attgaatctc ctgacaatgc tctacagttc 27300
agactgtatg gtaaagacta caatgtttac acccactctt tcctgtgtta tggtaaagac 27360
caggctctgt ggcagaaact ggctaaagac atccaggttg cttctaatga aatccttagg 27420
gacccttgtt tccaccctgg ttacaaaaaa gttgttaatg tttctgacct gtacaaaacc 27480
ccttgtacca aaagatttga aatgacctta cccttccaac agtttgaaat ccagggtatt 27540
ggtaactacc aacagtgtca ccagtctatc ctggaactgt tcaacacctc ttactgtccc 27600
tactctcagt gtgctttcaa tggtatcttc ttacctcctc tacagggtga ctttggtgct 27660
ttctctgctt tctactttgt tatgaaattc ctgaacctga cctctgaaaa agtttctcag 27720
gaaaaagtta ctgaaatgat gaaaaaattc tgtgctcaac cctgggaaga aatcaaaacc 27780
tcttatgctg gtgttaaaga aaaatacctg tctgaatact gtttctctgg tacctacatc 27840
ctgtctttat tattacaggg ttaccacttc actgctgact cttgggaaca catccacttc 27900
ataggtaaaa tccagggttc tgatgctggt tggaccctgg gttacatgct gaacctgacc 27960
aacatgatcc ccgctgaaca acctctgtct accccactgt ctcactctac ctatgttttc 28020
ctgatggttc tgttctctct ggttctgttc acagttgcta tcataggtct actgatcttc 28080
cacaaaccat cttacttctg gaaagacatg gtttgataat cgataatcaa cctctggatt 28140
acaaaatttg tgaaagattg actggtattc ttaactatgt tgctcctttt acgctatgtg 28200
gatacgctgc tttaatgcct ttgtatcatg ctattgcttc ccgtatggct ttcattttct 28260
cctccttgta taaatcctgg ttgctgtctc tttatgagga gttgtggccc gttgtcaggc 28320
aacgtggcgt ggtgtgcact gtgtttgctg acgcaacccc cactggttgg ggcattgcca 28380
ccacctgtca gctcctttcc gggactttcg ctttccccct ccctattgcc acggcggaac 28440
tcatcgccgc ctgccttgcc cgctgctgga caggggctcg gctgttgggc actgacaatt 28500
ccgtggtgtt gtcggggaag ctgacgtcct ttccatggct gctcgcctgt gttgccacct 28560
ggattctgcg cgggacgtcc ttctgctacg tcccttcggc cctcaatcca gcggaccttc 28620
cttcccgcgg cctgctgccg gctctgcggc ctcttccgcg tcttcgcctt cgccctcaga 28680
cgagtcggat ctccctttgg gccgcctccc cgctgtgcct tctagttgcc agccatctgt 28740
tgtttgcccc tcccccgtgc cttccttgac cctggaaggt gccactccca ctgtcctttc 28800
ctaataaaat gaggaaattg catcgcattg tctgagtagg tgtcattcta ttctgggggg 28860
tggggtgggg caggacagca agggggagga ttgggaagac aatagcaggc atgctgggga 28920
tgcggtgggc tctatggcca gctttcttgt acaaagttgg cattataaga aagcattgct 28980
tatcaatttg ttgcaacgaa caggtcacta tcagtcaaaa taaaatcatt atttgtttat 29040
gacggggaca gccccccccc aaagccccca gggatgtaat tacgtccctc ccccgctagg 29100
gggcagcagc gagccgcccg gggctccgct ccggtccggc gctccccccg catccccgag 29160
ccggcagcgt gcggggacag cccgggcacg gggaaggtgg cacgggatcg ctttcctctg 29220
aacgcttctc gctgctcttt gagcctgcag acacctgggg ggatacgggg aaaatgtgtc 29280
tgagcctgca tgtttgatgg tgtctggatg caagcagaag gggtggaaga gcttgcctgg 29340
agagatacag ctgggtcagt aggactggga caggcagctg gagaattgcc atgtagatgt 29400
tcatacaatc gtcaaatcat gaaggctgga aaagccctcc aagatcccca agaccaaccc 29460
caacccaccc accgtgccca ctggccatgt ccctcagtgc cacatcccca cagttcttca 29520
tcacctccag ggacggtgac ccccccacct ccgtgggcag ctgtgccact gcagcaccgc 29580
tctttggaga aggtaaatct tgctaaatcc agcccgaccc tcccctggca caacgtaagg 29640
ccattatctc tcatccaact ccaggacgga gtcagtgaga atatttaaat aaacttataa 29700
attgtgagag aaattaatga atgtctaagt taatgcagaa acggaggctc ctcatttatt 29760
tttgaactta aagacttaat attgtgaagg tatactttct ttaataataa gcctgcgccc 29820
aatatgttca ccccaaaaaa gctgtttgtt aacttgtcaa cctcatttaa aatatataag 29880
aaacagccca aagacaataa caaaagaata ataaaaaaga atgaaatatg taattctttc 29940
agagtaaaaa tcacacccat gacctggcca ctgagggctt gatcaattca ctttgaattt 30000
ggcattaaat accattaagg tatattaact gattttaaaa taagatatat tcgcggccgc 30060
ataacttcgt ataatgtgta ctatacgaag ttatataact tcgtatagga tactttatac 30120
gaagttatgc atcgtacgcg tacgtgtgag ggtttcagcg gccgcgattc cttttttagg 30180
gcccattggt atggcttttt ccccgtatcc ccccaggtgt ctgcaggctc aaagagcagc 30240
gagaagcgtt cagaggaaag cgatcccgtg ccaccttccc cgtgcccggg ctgtccccgc 30300
acgctgccgg ctcggggatg cggggggagc gccggaccgg agcggagccc cgggcggctc 30360
gctgctgccc cctagcgggg gagggacgta attacatccc tgggggcttt gggggggggc 30420
tgtccctgat atctataaca agaaaatata tatataataa gttatcacgt aagtagaaca 30480
tgaaataaca atataattat cgtatgagtt aaatcttaaa agtcacgtaa aagataatca 30540
tgcgtcattt tgactcacgc ggtcgttata gttcaaaatc agtgacactt accgcattga 30600
caagcacgcc tcacgggagc tccaagcggc gactgagatg tcctaaatgc acagcgacgg 30660
attcgcgcta tttagaaaga gagagcaata tttcaagaat gcatgcgtca attttacgca 30720
gactatcttt ctagggttaa tctagctgca tcaggatcat atcgtcgggt cttttttccg 30780
gctcagtcat cgcccaagct ggcgctatct gggcatcggg gaggaagaag cccgtgcctt 30840
ttcccgcgag gttgaagcgg catggaaaga gtttgccgag gatgactgct gctgcattga 30900
cgttgagcga aaacgcacgt ttaccatgat gattcgggaa ggtgtggcca tgcacgcctt 30960
taacggtgaa ctgttcgttc aggccacctg ggataccagt tcgtcgcggc ttttccggac 31020
acagttccgg atggtcagcc cgaagcgcat cagcaacccg aacaataccg gcgacagccg 31080
gaactgccgt gccggtgtgc agattaatga cagcggtgcg gcgctgggat attacgtcag 31140
cgaggacggg tatcctggct ggatgccgca gaaatggaca tggatacccc gtgagttacc 31200
cggcgggcgc gcttggcgta atcatggtca tagctgtttc ctgtgtgaaa ttgttatccg 31260
ctcacaattc cacacaacat acgagccgga agcataaagt gtaaagcctg gggtgcctaa 31320
tgagtgagct aactcacatt aattgcgttg cgctcactgc ccgctttcca gtcgggaaac 31380
ctgtcgtgcc agctgcatta atgaatcggc caacgcgcgg ggagaggcgg tttgcgtatt 31440
gggcgctctt ccgcttcctc gctcactgac tcgctgcgct cggtcgttcg gctgcggcga 31500
gcggtatcag ctcactcaaa ggcggtaata cggttatcca cagaatcagg ggataacgca 31560
ggaaagaaca tgtgagcaaa aggccagcaa aaggccagga accgtaaaaa ggccgcgttg 31620
ctggcgtttt tccataggct ccgcccccct gacgagcatc acaaaaatcg acgctcaagt 31680
cagaggtggc gaaacccgac aggactataa agataccagg cgtttccccc tggaagctcc 31740
ctcgtgcgct ctcctgttcc gaccctgccg cttaccggat acctgtccgc ctttctccct 31800
tcgggaagcg tggcgctttc tcatagctca cgctgtaggt atctcagttc ggtgtaggtc 31860
gttcgctcca agctgggctg tgtgcacgaa ccccccgttc agcccgaccg ctgcgcctta 31920
tccggtaact atcgtcttga gtccaacccg gtaagacacg acttatcgcc actggcagca 31980
gccactggta acaggattag cagagcgagg tatgtaggcg gtgctacaga gttcttgaag 32040
tggtggccta actacggcta cactagaagg acagtatttg gtatctgcgc tctgctgaag 32100
ccagttacct tcggaaaaag agttggtagc tcttgatccg gcaaacaaac caccgctggt 32160
agcggtggtt tttttgtttg caagcagcag attacgcgca gaaaaaaagg atctca 32216

Claims (7)

1.一种用于人皮肤创面覆盖及修复的活性基因改造猪皮肤，其特征在于，该猪皮肤去除了猪免疫抗原GGTA，B4GAL和CAMH，并且带有人CD55,59,46,47,39,141,HLEA和TFPI蛋白组合。
2.如权利要求1所述的用于人皮肤创面覆盖及修复的活性基因改造猪皮肤，其特征在于，GGTA基因的引导RNA为：TCGTGACCATAACCAGA; B4GAL基因的引导RNA为AGGAAAGCTATAACTTGG；CMAH基因引导RNA为 AGAAACTCCTGAA CTACA 。
3.如权利要求1所述的用于人皮肤创面覆盖及修复的活性基因改造猪皮肤，其特征在于，所述CD55，CD59，CD46的序列表为：
tcacgggtgtaaagaccaagcagcagccaggaaaggggtaaccagtagaagaactgttttttcagacagagaggtaccaccattttccagttgttcattgaagttacacaggtcttttttacaacagtagtaggtcagttcattttctcttaatctggtggtaacatcattgaagttacagtgttcaaatttccaacatttgttgtaaacctgcaggccagctttggtgatcagacaagcatcaaagtcagaagaacagttaacagctgttttacagtcagcagtagggttgggacagttgtaacactgaagagagtgaccagagtgacagaaaacagccagaaccagtaacagaccaaacagaacagaaccaccttggatacccataggccccgggttctcctctacgtccccggcctgcttgagcaggctgaaattcgtggctccgctgccggtcagtagccccatggtaaccagggtacccagtagaccagtcagggtgaaacaggtgtgaccagacagaagcctggtggtaccagaggtggtaccagaacctttgttaggggtggtttcatggaagtgtttggtggtcctagaaacgggggtagatctggtagcctgagcattgggggtggtggttttggtggtggttttctgagaggtgggagaaacttctgtggtgggaacattaactgtggtaggtttctgaactgtaggaggaactttagaggtcagagatttacccctacattcgggaggaggaccagaccattcaccttcatcattgttaacagtacagtagatagagtgttcaccaatcatggtgaaacctttgttacaagcataggtaacagactgcctgtaaccatagtgatcacgttcaccctggatgataccattgtctatctgaggaggagctggacagtagatttccctacattcgggtaaagggtcagaccactgaacagaagaaccagagatcagacagaaagaagaggtagaaccaaacagtttgtaaccagtgttacaagagaaagagatggtagcaccaaacaggataccaccaggaacatcaatctgaccattcctgatttcaccggggttgggacaagatttttttttacagaattcaacagcagtagaccatttcaggttctgtagacaggtcagtttgggagacagagagggttctcttctgtaaccaggtctacattcatattcaacaacagtaccaactgggaagtagttctgggtgatgtagggttgtttcagagaagcagagttcagcctggtgggaacttcacaagatctgttacagaattcttctatgtcagaccactgagaacctttcagacagataacagagtctttttcacctgggattttaacaaaagattcttcacatttgtaggtgataacagtatcctcagggaaagaggttctaccttccagagcaggttgagcattaggaacatctggaggtaaaccacagtcaccccaaacagcagggaggcacagtaaaaccagtaataaaagtcttggaagttcacctagaagtgggagtgctgctggaacagatggcctggctactgtcataggcccggggttctcctccacgtcgccagcctgcttaaggagtgagaagttggtggctccactgcccagagaggtgaatttaacttctctgtgggtttcatctgtcaggtaggtaccttttttttttctcctttgaaggtacctgtaaggaacaacacagataacagcaacaccaacaacaatagctataactataacagcaataacccaaacatccagagagtccaggataccttcttcaggtttagggtaaccagggtagttagaaacgggaggtttgtaggtaggtcttggaccagaagcagaagaagcaggagatttggtggtagaagaggtagaaacagagtgagacagagcgggtggtttggtagaagagggtggtaaaactttcagacatttgggaactggtgggtcccaggtagagttagagtcacaaacaatggtgtcagaaccatccaggtagaaacctttgtcacattcaaacataacagtagctttgtagtagaattttttaccaaaaccagagatctgtttaccattttcaacaactgggaatctacatttaacaactttacattctggagcagctctagaccaaacagagttgtcaccacagtagatggtagattcaccaatcagagagaatgggtctggaccaggagcagggtcacaagagtaggtaacagcatccaggtattcaaaaacttcaacttcagagaaggtgtgtttaccatttttgattttgggtggtggggtacacagaactttttcacagatgggaggtttaccagaccagatagcaacagaacctttcagttcacagtacaggatttcttcacctatcaggtagtaaccttcattacagatgaagtgcatctggtaaccaaattcataggtaccattagctggaacagcctgaccattcagaggatctcggatgtagggacaggtttccctgtaacaagcatcatcagaaacaggtaaccaggtgtggtttctgtcacagatggtgtgggtagccagaggtgggatgtagaagtaaccttttttacatttgtagtcaactctttcacctatttcatagtatggttttggtttacctatcagttccatagcttcaaaggttggtggttcttcacaagcatcagagaaagagtacagtaaaagaaccatagcagccagtagtaaaccagggaatctccaagatgggaagggacactcccttctaccaggtggttccatcat。
4.如权利要求1所述的用于人皮肤创面覆盖及修复的活性基因改造猪皮肤，其特征在于，编码人巨噬细胞负性蛋白CD47和人自然伤蛋白HLAE的序列表为：
ctagatctgttgctcttgctgttcttgctctgttgtctctgtctggtctggaagctgtgatggcccctagaaccctgatcctcgggggcggaggttcaggaggcggtgggagcggcggagggggttccatccaaagaacccctaaaatccaggtttactctaggcacccagctgaaaatggtaaatctaacttcctgaactgttatgtttctggtttccacccctctgacattgaagttgacttactgaaaaatggtgaaaggatagaaaaagttgaacactctgacctgtctttctctaaagactggtctttctacttactgtactacactgaattcacccctacagaaaaagatgaatatgcttgtagagttaaccatgttaccctgtctcaaccaaaaattgttaaatgggacagagacatgggtggcggagggtctggcgggggtggaagcgggggtggaggctccggaggtgggggcagtggtagtcattccttaaagtacttccacacctctgtttcccgaccaggtaggggtgaacctaggttcatctctgttgggtatgttgatgatacccaatttgtcagatttgataatgatgctgcttctccaagaatggttccaagggctccttggatggaacaggaagggtcagaatactgggacagagaaaccagatctgctagagacactgctcaaatattcagagttaacttgagaactttaagaggttattataatcagtctgaggcaggttcccacactcttcaatggatgcatggttgtgaattgggtccagatggtagattcctcaggggttatgaacagtttgcctatgatggaaaagattatttgacccttaatgaggacctaaggtcctggactgcagttgatacagcagcccagatttcagaacaaaagtctaatgatgcttctgaagctgaacaccaaagagcgtatttagaggatacttgtgtagaatggttacacaagtacttggaaaagggtaaggaaaccttactacacttggaacctcctaagacccatgtcacacatcatccaatctctgaccatgaagcaacactaaggtgttgggcactaggtttttaccctgctgaaattaccctcacctggcaacaagatggtgaaggtcacacccaagacactgaactagtagagacaagacctgctggggatggtacatttcaaaaatgggctgctgtggtagttcctagtggggaagaacaaaggtatacctgtcatgttcaacatgaggggttaccagaaccagttacccttaggtggaaaccagcttctcaacctactattccaattgttggtatcattgctggtcttgtcttgttgggttctgttgtttctggtgctgttgtggcagcagtgatctggaggaaaaaatcatctggtggtaagggtggttcttactctaaggctgaatggtcagattcagctcaagggagtgaatctcactctttgggcagtggcgccaccaattttagcctgttaaagcaggctggcgacgtggaggagaatcctgggcctatgtggcctctggtagcagcacttcttttaggttcagcatgttgtggttcagctcaactactgttcaacaaaaccaaatctgttgaattcaccttctgtaatgacacagttgttatcccatgttttgttaccaacatggaagctcagaacaccacagaagtttatgttaaatggaaattcaaaggtagagacatctacacctttgatggtgctctgaacaaatctacagttcccactgacttctcttctgctaaaatagaagtttctcaattactgaaaggtgatgcttctctgaaaatggacaaatctgatgctgtttctcacacaggtaactacacctgtgaagttacagaactgaccagagaaggtgaaaccatcattgaactgaaatacagagttgtttcttggttctctcctaatgaaaacatcctgattgttatcttccccatctttgctatccttctgttctggggtcagtttggtatcaaaaccctgaaatacagatctggtggtatggatgaaaaaaccattgctttactggttgctggtctggttatcactgttatagttatagttggtgctatcctgtttgttccaggtgaatactctctgaaaaatgctacaggtctgggtctgatagttacctctactggtatcctgatcttacttcactactatgttttctctacagctattggtctgacctcttttgttatagctatcctggttatccaggttattgcttacatcctggctgttgttggtctgtctctgtgtattgctgcttgtatccccatgcatggtcctcttctgatctctggtctgtctatcctggctctggctcaattactgggtctggtttacatgaaatttgttgcttctaaccagaaaaccatccaaccacctaggaaagctgttgaagaacctctgaatgctttcaaagaatctaaaggtatgatgaatgacgaa。
5.如权利要求1所述的用于人皮肤创面覆盖及修复的活性基因改造猪皮肤，其特征在于，编码人凝血负性蛋白CD141， CD39的基因序列表为：
ttaggtgttctggttcttggtgcactggctctggcaggtttaggtttccccgctcctgctgaaccacaaccaggtggttctcagtgtgttgaacatgactgttttgctctgtaccccggtcccgctaccttcctgaatgcttctcagatctgtgatggtcttaggggtcacctgatgacagttcgcagctctgttgctgctgatgttatctctttattactgaatggtgatggtggtgttggtaggaggagactgtggattggactgcaactaccaccaggttgtggtgaccctaaaagactgggtcctcttagaggtttccagtgggttacaggtgacaacaacacctcttactctagatgggctagactggacctgaatggtgctcctctgtgtggtcctctgtgtgttgctgtttctgctgctgaagctactgttccttctgaacctatctgggaagaacaacagtgtgaagttaaagctgatggtttcctgtgtgaattccacttccccgctacctgtagaccactggctgttgaacccggtgctgctgctgctgctgtttctatcacctatggtaccccttttgctgctagaggtgctgacttccaggctctaccagttggttcttctgctgctgttgctcctctgggcttacaactgatgtgtacagctccacccggtgctgttcagggtcactgggctagagaagctcccggtgcttgggactgttctgttgaaaatggtggttgtgaacatgcttgtaatgctatccctggtgctcctaggtgtcagtgtcctgctggtgctgctcttcaggctgatggtagatcttgtactgcttctgctacccagtcttgtaatgacctgtgtgaacacttctgtgttcccaaccccgaccaacccggttcttactcttgtatgtgtgaaacaggttacagactggctgctgaccaacacagatgtgaagatgttgatgactgtatcctggaaccctctccatgtccacaaaggtgtgttaacacccagggtggttttgaatgtcactgttaccctaactatgacctggttgatggtgaatgtgttgaacccgttgacccctgtttcagggctaactgtgaataccagtgtcaacctctgaaccagacctcttacctgtgtgtttgtgctgaaggttttgctccaatccctcatgaacctcacaggtgtcagatgttctgtaaccagacagcttgtcccgctgactgtgaccctaacacccaggcttcttgtgaatgtccagaaggttacatcctggatgatggtttcatctgtacagacattgatgaatgtgaaaatggtggtttctgttctggtgtttgtcacaaccttcccggtacctttgaatgtatctgtggtcccgactctgctctggctagacacattggtacagactgtgactctggtaaagttgatggtggtgactctggttctggtgaacctcctccctctccaacccccggttctaccctgaccccaccagctgttggtctggttcactctggtctactgataggtatctctatagcttctctgtgtctggttgttgctctactggctctactgtgtcaccttaggaaaaaacagggtgctgctagggctaaaatggaatacaaatgtgctgctccatctaaagaagttgttttacaacatgttaggactgaaaggacccctcaaaggctgggcagcggcgcgaccaacttttcgctccttaagcaggccggggacgtggaggagaatccagggcctatctacactatgaaaaaagtacatgctttatgggcctctgtttgtttacttctgaacctggctcctgctcctctgaatgctgactctgaagaagatgaagaacacaccatcatcacagacactgaacttcctccactgaaactgatgcactctttctgtgctttcaaagctgatgatggtccttgtaaagctatcatgaaaaggttcttcttcaacatcttcaccagacagtgtgaagaattcatctatggtggttgtgaaggtaaccagaacagatttgaatctctggaagaatgtaagaaaatgtgtaccagggacaatgctaacaggatcatcaaaaccaccctacaacaggaaaaaccagacttctgtttcctggaagaggatcctggtatctgtagaggttacatcaccaggtacttctacaacaaccagaccaaacagtgtgaaagattcaaatatggtggttgtctgggtaacatgaacaactttgaaaccctggaagaatgtaaaaacatctgtgaagatggtcccaatggtttccaggttgacaactatggtacccaactgaatgctgttaacaactctctgacccctcagtctaccaaagttccctctctgtttgaattccatggtccttcttggtgtctgacccctgctgacagaggtctgtgtagagctaatgaaaacaggttctactacaactctgttataggtaaatgtagacccttcaaatactctggttgtggtggtaatgaaaacaacttcacctctaaacaggaatgtttaagggcttgtaaaaaaggtttcatccaaagaatctctaaaggtggtctgatcaaaaccaaaagaaaaagaaaaaaacaaagagttaaaatagcttatgaagaaatctttgttaaaaacatgtacttacaggaactgggaggttcagggggaggagggtccggtgggggtggttctggtggttgtagaaatggtaaaaccctgtctgtttctcaactggaacttcaggactctggtacctggacctgtacagttctacagaaccagaaaaaagttgaattcaaaatagacatagttgttctggctttccagaaagcttcttctatagtttacaaaaaagaaggtgaacaggttgaattctctttcccactggctttcactgttgaaaaactgactggttctggtgaactgtggtggcaggctgaaagggcttcttcttctaaatcttggatcacctttgacctgaaaaacaaagaagtttctgttaaaagggttacccaggacccaaaattacagatgggtaaaaaattacctcttcacctgaccctaccacaggctcttccacagtatgctggttctggtaacctgaccctggctctggaagctaaaactggtaaactacaccaggaagttaacctggttgttatgagagctacccaacttcagaaaaacctgacctgtgaagtttggggtccaacctctccaaaactgatgctgtctctgaaactggaaaacaaagaagctaaagtttctaaaagagaaaaagctgtttgggttctgaacccagaagctggtatgtggcagtgcctgctgtctgactctggtcaggttttactggaatctaacatcaaagttcttcctacctggtctacccctgttcaaccaatggctctgattgttctgggtggtgttgctgggcttcttctgttcataggtctgggtatcttcttctgtgttaggtgtcgacacagaaggagacaggctgaaagaatgtctcagatcaaaaggttccgtcagaaagatgatggtaaatgtccactgaacccacactctcacctgggtacctatggtgttttcaccaatgctgcttttgacccctctcctggcagcggagcgaccaactttagccttctgaaacaggctggggacgtggaggagaatcctgggcctatggaggataccaaagaatctaatgttaaaactttctgttctaaaaacatcctggctatcctgggtttctcttctatcattgctgttattgctttactggctgttggtctgacccagaacaaagctttacctgaaaatgttaaatatggtattgttctggatgctggttcttctcacacctctctgtacatctacaaatggcccgctgaaaaagaaaatgacacaggtgttgttcaccaggttgaagaatgtagagttaaaggtcctggtatctctaaatttgttcagaaagttaatgaaattggtatctacctgactgactgtatggaaagagctagggaagttatccctcgttcgcaacaccaggaaacccccgtttacctgggtgctactgctggtatgagattactaagaatggaatctgaagaactggctgacagagttctggatgttgttgaaagatctctgtctaactacccctttgacttccagggtgctaggatcatcacaggtcaggaagaaggtgcttatggttggatcaccatcaactaccttctgggtaaattctctcagaaaaccaggtggttctctatagttccatatgaaaccaacaaccaggaaacctttggtgctctggacctgggtggtgcttctacccaggttacctttgttcctcagaaccagaccattgaatctcctgacaatgctctacagttcagactgtatggtaaagactacaatgtttacacccactctttcctgtgttatggtaaagaccaggctctgtggcagaaactggctaaagacatccaggttgcttctaatgaaatccttagggacccttgtttccaccctggttacaaaaaagttgttaatgtttctgacctgtacaaaaccccttgtaccaaaagatttgaaatgaccttacccttccaacagtttgaaatccagggtattggtaactaccaacagtgtcaccagtctatcctggaactgttcaacacctcttactgtccctactctcagtgtgctttcaatggtatcttcttacctcctctacagggtgactttggtgctttctctgctttctactttgttatgaaattcctgaacctgacctctgaaaaagtttctcaggaaaaagttactgaaatgatgaaaaaattctgtgctcaaccctgggaagaaatcaaaacctcttatgctggtgttaaagaaaaatacctgtctgaatactgtttctctggtacctacatcctgtctttattattacagggttaccacttcactgctgactcttgggaacacatccacttcataggtaaaatccagggttctgatgctggttggaccctgggttacatgctgaacctgaccaacatgatccccgctgaacaacctctgtctaccccactgtctcactctacctatgttttcctgatggttctgttctctctggttctgttcacagttgctatcataggtctactgatcttccacaaaccatcttacttctggaaagacatggt。
6.如权利要求1所述的用于人皮肤创面覆盖及修复的活性基因改造猪皮肤，其特征在于，得到的终产物质粒，序列表如下：
agaagatcctttgatcttttctacggggtctgacgctcagtggaacgaaaactcacgttaagggattttggtcatgagattatcaaaaaggatcttcacctagatccttttaaattaaaaatgaagttttaaatcaatctaaagtatatatgagtaaacttggtctgacagttaccaatgcttaatcagtgaggcacctatctcagcgatctgtctatttcgttcatccatagttgcctgactccccgtcgtgtagataactacgatacgggagggcttaccatctggccccagtgctgcaatgataccgcgggacccacgctcaccggctccagatttatcagcaataaaccagccagccggaagggccgagcgcagaagtggtcctgcaactttatccgcctccatccagtctattaattgttgccgggaagctagagtaagtagttcgccagttaatagtttgcgcaacgttgttgccattgctacaggcatcgtggtgtcacgctcgtcgtttggtatggcttcattcagctccggttcccaacgatcaaggcgagttacatgatcccccatgttgtgcaaaaaagcggttagctccttcggtcctccgatcgttgtcagaagtaagttggccgcagtgttatcactcatggttatggcagcactgcataattctcttactgtcatgccatccgtaagatgcttttctgtgactggtgagtactcaaccaagtcattctgagaatagtgtatgcggcgaccgagttgctcttgcccggcgtcaatacgggataataccgcgccacatagcagaactttaaaagtgctcatcattggaaaacgttcttcggggcgaaaactctcaaggatcttaccgctgttgagatccagttcgatgtaacccactcgtgcacccaactgatcttcagcatcttttactttcaccagcgtttctgggtgagcaaaaacaggaaggcaaaatgccgcaaaaaagggaataagggcgacacggaaatgttgaatactcatactcttcctttttcaatattattgaagcatttatcagggttattgtctcatgagcggatacatatttgaatgtatttagaaaaataaacaaataggggttccgcgcacatttccccgaaaagtgccacctaaattgtaagcgttaatattttgttaaaattcgcgttaaatttttgttaaatcagctcattttttaaccaataggccgaaatcggcaaaatcccttataaatcaaaagaatagaccgagatagggttgagtgttgttccagtttggaacaagagtccactattaaagaacgtggactccaacgtcaaagggcgaaaaaccgtctatcagggcgatggcccactacgtgaaccatcaccctaatcaagttttttggggtcgaggtgccgtaaagcactaaatcggaaccctaaagggagcccccgatttagagcttgacggggaaagccggcgaacgtggcgagaaaggaagggaagaaagcgaaaggagcgggcgctagggcgctggcaagtgtagcggtcacgctgcgcgtaaccaccacacccgccgcgcttaatgcgccgctacagggcgcgtcccattcgccattcaggctgcgcaactgttgggaagggcgatcggtgcgggcctcttcgctattacgccagctggcgaaagggggatgtgctgcaaggcgattaagttgggtaacgccagggttttcccagtcacgacgttgtaaaacgacggccagtgagcgcgcctcgttcattcacgtttttgaacccgtggaggacgggcagactcgcggtgcaaatgtgttttacagcgtgatggagcagatgaagatgctcgacacgctgcagaacacgcagctagattaaccctagaaagataatcatattgtgacgtacgttaaagataatcatgcgtaaaattgacgcatgtgttttatcggtctgtatatcgaggtttatttattaatttgaatagatattaagttttattatatttacacttacatactaataataaattcaacaaacaatttatttatgtttatttatttattaaaaaaaaacaaaaactcaaaatttcttctataaagtaacaaaacttttatgagggacagcccccccccaaagcccccagggatgtaattacgtccctcccccgctagggggcagcagcgagccgcccggggctccgctccggtccggcgctccccccgcatccccgagccggcagcgtgcggggacagcccgggcacggggaaggtggcacgggatcgctttcctctgaacgcttctcgctgctctttgagcctgcagacacctggggggatacggggaaaaggcctccacggcctaactttaaataattggcattatttaaagttagaatagtaatcaattacggggtcattagttcatagcccatatatggagttccgcgttacataacttacggtaaatggcccgcctggctgaccgcccaacgacccccgcccattgacgtcaataatgacgtatgttcccatagtaacgccaatagggactttccattgacgtcaatgggtggagtatttacggtaaactgcccacttggcagtacatcaagtgtatcatatgccaagtacgccccctattgacgtcaatgacggtaaatggcccgcctggcattatgcccagtacatgaccttatgggactttcctacttggcagtacatctacgtattagtcatcgctattaccatggtgatgcggttttggcagtacatcaatgggcgtggatagcggtttgactcacggggatttccaagtctccaccccattgacgtcaatgggagtttgttttggcaccaaaatcaacgggactttccaaaatgtcgtaacaactccgccccattgacgcaaatgggcggtaggcgtgtacggtgggaggtctatataagcagagctggtttagtgaaccgtcagatccgctagaacaccgcatcgtacgcgtacgtgtgaggataacttcgtatagcatacattatacgaagttattggcgcgcctaactttaaataattggcattatttaaagttagccaccatggcacaatcaaaacatggattaactaaggaaatgacaatgaaatacagaatggaaggttgtgttgatggtcacaaatttgttatcactggtgaaggtattggttacccattcaaaggtaaacaggctatcaacctgtgtgttgttgaaggtggtcctctaccatttgctgaggatatcctgtctgctgctttcatgtatggtaacagggttttcactgaatacccacaggacatagttgactacttcaaaaactcttgtcccgctggttacacctgggacagatctttcctgtttgaagatggtgctgtttgtatctgtaatgctgacatcactgtttctgttgaagaaaactgtatgtaccatgaatctaaattctatggtgttaacttcccagctgatggtcccgttatgaaaaaaatgactgacaactgggaaccttcttgtgaaaaaatcatccctgttccaaaacagggtatcctgaaaggtgatgtttctatgtacttacttctgaaagatggtggtagacttagatgtcagtttgacacagtttacaaagctaaatctgttcctaggaaaatgcctgactggcacttcatccaacacaaactgaccagggaggataggtctgatgctaaaaaccagaaatggcacctgactgaacatgctatagcttctggttctgctctgccgggcagcggggccaccaatttttctctgctgaagcaagcaggcgacgtcgaggaaaacccggggcctatgactgaatacaaacccacagttagactggctaccagagatgatgttcctagagctgttaggaccctggctgctgcttttgctgactaccctgctaccaggcacactgttgaccctgacaggcacatagaaagagttacagaactacaggaactgttcctgaccagggttggtctggacattggtaaagtttgggttgctgatgatggtgctgctgttgctgtttggaccacccccgaatctgttgaagctggtgctgtttttgctgaaataggtccaaggatggctgaactgtctggttctaggctggctgctcaacaacagatggaaggtctactggctccacacaggcccaaagaacccgcttggttcctggctactgttggtgtttctccagaccaccagggtaaaggtctgggttctgctgttgttctacctggtgttgaagctgctgaaagggctggtgttccagctttcctggaaacctctgctcctagaaacttaccattctatgaaaggctgggtttcacagttactgctgatgttgaagttcccgaaggtcctaggacctggtgtatgaccaggaaacctggtgcttgataactttaaataattggcattatttaaagttagtagggataacagggtaatagcgcggggacagcccccccccaaagcccccagggatgtaattacgtccctcccccgctagggggcagcagcgagccgcccggggctccgctccggtccggcgctccccccgcatccccgagccggcagcgtgcggggacagcccgggcacggggaaggtggcacgggatcgctttcctctgaacgcttctcgctgctctttgagcctgcagacacctggggggatacggggaaaatgtgtctgagcctgcatgtttgatggtgtctggatgcaagcagaaggggtggaagagcttgcctggagagatacagctgggtcagtaggactgggacaggcagctggagaattgccatgtagatgttcatacaatcgtcaaatcatgaaggctggaaaagccctccaagatccccaagaccaaccccaacccacccaccgtgcccactggccatgtccctcagtgccacatcccc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7.如权利要求1所述的改造猪皮肤在皮肤创面覆盖及修复中的应用。
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