CN110283850A - 一种免疫缺陷裸鼠模型的制备方法及应用 - Google Patents
一种免疫缺陷裸鼠模型的制备方法及应用 Download PDFInfo
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Abstract
本发明公开了一种基于基因敲除技术建立的裸(nude)鼠模型的方法，具体涉及将小鼠的Foxn1基因敲除，得到Foxn1基因缺失、不表达功能性FOXN1蛋白的裸鼠，再将获得的裸鼠的“nude”基因导入NOD‑Prkdcscid IL‑2rgnull小鼠或与NOD‑Prkdcscid IL‑2rgnull小鼠交配，从而得到表现出裸鼠症状的NOD‑Prkdcscid IL‑2rgnull nude小鼠。本发明还公开了敲除Foxn1基因而表现裸鼠症状的非人动物或其子代，及其在蛋白或基因领域的应用。
Description
技术领域
本申请涉及生物技术领域，具体而言，涉及具有用于生物医学研究的遗传优势的小鼠的构建方法及其在生物医药领域的应用。
背景技术
免疫缺陷动物(immunodeficient animal)是指由于先天性遗传突变或用人工的方法造成一种或多种免疫系统组成成分缺陷的动物。近几年来，随着技术的迅猛发展，一些新的免疫缺陷动物尤其是多种联合免疫缺陷动物品种的培育成功，在医学领域的研究中发挥了重要作用。其中，NOD-Prkdcscid IL-2rgnull小鼠作为目前国际上公认的免疫缺陷程度最高的小鼠，在人源化动物研究、肿瘤药物及其他疾病的治疗机理方面已经得到广泛应用。
NOD-Prkdcscid IL-2rgnull小鼠，其中NOD是自发性I型糖尿病小鼠，其巨噬细胞对人源细胞吞噬作用弱；补体系统和树突状细胞等先天免疫系统功能较低；Prkdcscid的含义是Prkdc(Protein kinase DNA-activated catalytic)基因突变，小鼠的T细胞和B细胞缺失，表现为细胞免疫和体液免疫的重度联合免疫缺陷(SCID)；IL-2rgnull的含义是白细胞介素2受体的gamma链(IL-2Rγc)缺失，该链是具有重要免疫功能的细胞因子IL-4、IL-7、IL-9、IL-15和IL21等多种细胞因子受体共有的功能组成单元，缺失后小鼠机体免疫功能严重降低，尤其是NK细胞的活性几乎丧失。现有研究表明该小鼠对人源细胞和组织几乎没有排斥反应，少量细胞即可成瘤(依赖于细胞系或细胞类型)，同时也没有B淋巴细胞泄漏，是最适合人源细胞或组织移植的工具小鼠，并已广泛用于新的人源化动物模型研发。
在动物实验中，为了便于手术经常需要给动物备皮，一般有两种方法。一种是物理方法，即通过使用剃刀或剪刀或镊子等工具去除动物身上的毛。但该过程不仅繁琐、费时，还很容易损伤动物皮肤，尤其是对皮肤特别薄的动物，如小鼠，剃毛过程可能出现剃伤或者剃不干净的现象，可能会直接影响试验结果。另一种方式是使用药物，如脱毛剂。但药物容易粘在操作人员的皮肤粘膜上，可能造成不必要的损伤，另外方法掌握不好的话，动物表皮容易受到腐蚀。而且，有些试验要求毛刮到很干净，而以上两种方法可能都达不到。
无胸腺裸鼠(Nude mouse，以下简称裸鼠)是由于第11号染色体上“裸体”(nude)位点的等位基因发生突变从而形成的一种免疫缺陷动物，主要表现为全身无毛以及缺乏正常胸腺。裸鼠作为最早发现的免疫缺陷动物，已成为医学生物学研究领域中不可缺少的实验动物模型。已有研究发现，可将“nude”基因通过传统的交配方式，导入不同近交系动物，得到其它遗传背景明确、表型类似的“裸体”动物模型。但裸鼠作为单一T细胞免疫功能缺陷动物，仍然具有正常的B细胞和NK细胞，免疫缺陷程度不深，且研究表明随着鼠龄增加，NK细胞从中优先选择2个(分别是sgRNA1和sgRNA8)进行后续实验。在其5’端加上TAGG得到正向寡核苷酸，其互补链加上AAAC得到反向寡核苷酸(见表2)，退火后将退火产物分别连接至pT7-sgRNA质粒(质粒先用BbsI线性化)，获得表达载体pT7-sgRNA1、pT7-sgRNA8，其中PCR反应体系见表3。
表1 UCA检测结果
表2 sgRNA1和sgRNA8序列列表
表3 PCR连接反应体系(10μL)
| sgRNA退火产物 | 1μL(0.5μM) |
Foxn1基因，经遗传修饰后，使得所述动物的细胞、组织或器官中不表达FOXN1蛋白或表达的FOXN1蛋白不具有功能。优选的，所述不表达FOXN1蛋白或表达的FOXN1蛋白不具有功能的非人动物或其子代表现出无毛鼠或裸鼠的症状。
优选的，所述的非人动物或其子代基因组中缺失Foxn1基因的全部或部分序列。
进一步优选的，所述的非人动物或其子代动物基因组中缺失Foxn1基因的第4号外显子至3’UTR的全部或部分。
在本发明的一个具体实施例中，敲除动物基因组中Foxn1基因的第4号外显子至3’UTR的约10192bp(SEQ ID NO：29)的碱基片段，并伴有7个碱基的随机插入，所述敲除Foxn1基因后基因片段长度约19893bp(SEQ ID NO：30)。其中，随机插入片段为AGTGCAT。
在本发明的一个具体实施方式中，敲除动物基因组中Foxn1基因的第4号外显子至3’UTR的约10182bp(SEQ ID NO：31)的碱基片段，所述敲除Foxn1基因后基因片段长度约19896bp(SEQ ID NO：32)。
在本发明的一个具体实施方式中，敲除动物基因组中Foxn1基因的第4号外显子至3’UTR的约9095kb(SEQ ID NO：33)和/或31bp(SEQ ID NO：34)的碱基片段，所述敲除Foxn1基因后基因片段长度约20952bp(SEQ ID NO：35)。
优选的，所述非人动物或其子代为免疫缺陷动物或人源化动物。
优选的，所述非人动物或其子代为啮齿类动物；进一步优选的，所述啮齿类动物为小鼠。
在本发明的一个具体实施例中，所述小鼠为NOD/scid或NOD-Prkdcscid IL-2rgnull小鼠背景。优选的，所述NOD-Prkdcscid IL-2rgnull小鼠为B-NDG小鼠。
在本发明的一个具体实施例中，所述的小鼠为基因PD-1、PD-L1、IL3、IL6、IL15、CSF1、CSF2、CTLA-4、LAG-3、BTLA、CD27、CD28、TIGIT、TIM-3、GITR、CD137或OX40人源化小鼠。
优选的，所述非人动物或其子代进一步包含在非人动物或其子代体内进行人免疫系统重建。
进一步优选的，所述人免疫系统重建使用人外周血细胞移入，或使用人造血干细胞移入。
本发明的第二方面，涉及一种经遗传修饰的细胞株，所述细胞株基因组中的Foxn1基因，经遗传修饰后，使得所述细胞株中不表达FOXN1蛋白或表达的FOXN1蛋白不具有功能。
优选的，所述细胞株中缺失Foxn1基因的全部或部分序列。进一步优选的，使用靶向Foxn1基因的sgRNA序列敲除细胞株基因组中Foxn1基因的全部或部分序列。
在本发明的一个具体实施方式中，使用靶向Foxn1基因的sgRNA序列敲除细胞株基因组中Foxn1基因的第4号外显子至3’UTR的全部或部分序列。
优选的，所述细胞株来源于非人动物或其子代。
优选的，所述动物为啮齿类动物；进一步优选的，所述啮齿类动物为小鼠；更进一步优选的，所述的小鼠为免疫缺陷小鼠。
优选的，所述细胞株为免疫缺陷小鼠细胞株；进一步优选的，所述免疫缺陷小鼠的遗传背景为NOD-Prkdcscid IL-2rgnull。
本发明的第三方面，涉及一种构建裸鼠或其子代的方法，所述鼠基因组中的Foxn1基因，经遗传修饰后，使得鼠体内FOXN1蛋白不表达或表达的FOXN1蛋白不具有功能。
优选的，所述的方法包括敲除小鼠体内Foxn1基因的全部或部分序列。
优选的，使用基因编辑技术进行裸鼠或其子代的构建，所述基因编辑技术包括基于胚胎干细胞的DNA同源重组技术、CRISPR/Cas9技术、锌指核酸酶技术、转录激活子样效应因子核酸酶技术、归巢核酸内切酶或其他分子生物学技术；优选的，使用基于CRISPR/Cas9的基因编辑技术进行裸鼠或其子代的构建。
优选的，所述的方法包括使用靶向Foxn1基因的sgRNA序列敲除小鼠体内Foxn1基因全部或部分序列。进一步优选的，敲除Foxn1基因的的第4号外显子至3’UTR的全部或部分序列。
优选的，所述的方法，包括如下步骤：
1)提供一种包含一种或多种靶向Foxn1基因的sgRNA序列和/或一种或多种含有靶向Foxn1基因的sgRNA序列的构建体和/或一种或多种所述构建体的体外转录产物的细胞；
2)将步骤1)所述的细胞在培养液中进行培养；
3)将步骤2)培养后的细胞移植至受体雌性小鼠的输卵管内，允许所述细胞在所述小鼠的子宫中发育；
4)鉴定步骤3)的怀孕雌性子代基因敲除小鼠的种系传递。
进一步优选的，所述的方法，包括如下步骤：
1)利用靶向Foxn1基因的sgRNA序列，制备获得sgRNA载体；
2)将步骤1)获得的sgRNA载体的体外转录产物和Cas9mRNA进行混合，获得混合液，将混合液注射至小鼠受精卵细胞质或细胞核中，将注射后的受精卵转移至培养液中进行培养，然后移植至受体母鼠的输卵管中发育，得到F0代小鼠；
3)将F0代小鼠利用PCR技术进行检验，验证细胞中的Foxn1基因敲除成功，获得阳性裸鼠；
4)将步骤3)筛选出的阳性小鼠通过杂交和/或自交的方式，扩大种群数量，建立稳定的裸鼠。
优选的，所述步骤3)中使用的PCR检测引物对序列如SEQ ID NO：20和SEQ ID NO：21所示。
优选的，所述的sgRNA序列靶向5’端靶位点序列如SEQ ID NO：1-7任一项所示，3’端靶位点序列如SEQ ID NO：8-14任一项所示。
优选的，所述的裸鼠为免疫缺陷裸鼠或人源化裸鼠。
更优选的，所述免疫缺陷裸鼠是NOD-Prkdcscid IL-2rgnull nude鼠。更优选的，所述的人源化裸鼠中人源化的基因选自PD-1、PD-L1、IL3、IL6、IL15、CSF1、CSF2、CTLA-4、LAG-3、BTLA、CD27、CD28、TIGIT、TIM-3、GITR、CD137或OX40。
优选的，所述小鼠的受精卵细胞遗传背景为NOD-Prkdcscid IL-2rgnull小鼠。
优选的，所述裸鼠用作动物模型。更优选的，所述动物模型为荷瘤动物模型。
优选的，所述的方法进一步包含在免疫缺陷裸鼠或其子代体内进行人免疫系统重建；更优选的，所述人免疫系统重建使用人外周血细胞移入，或使用人造血干细胞移入。
本发明的第四方面，涉及根据上述的方法构建的裸鼠或其子代。
优选的，所述的裸鼠为免疫缺陷裸鼠或人源化裸鼠。
在本发明的一个具体实施方式中，所述的裸鼠或其子代为免疫缺陷裸鼠或其子代。
本发明的第五方面，涉及一种构建NOD-Prkdcscid IL-2rgnull nude鼠的方法，将上述的非人动物或其子代或上述的裸鼠的“nude”基因导入NOD-Prkdcscid IL-2rgnull鼠，或将上述的非人动物或其子代或上述的裸鼠与NOD-Prkdcscid IL-2rgnull鼠交配；并进行筛选，得到NOD-Prkdcscid IL-2rgnull nude鼠。
本发明的第六方面，涉及根据上述的方法构建的NOD-Prkdcscid IL-2rgnull nude鼠。
本发明的第七方面，涉及一种制备多基因改造非人动物或其子代的方法，包括如下步骤：
a)利用上述的方法构建的裸鼠或其子代，或者，上述的裸鼠或其子代，或者，上述构建的NOD-Prkdcscid IL-2rgnull nude鼠；
b)将步骤a)获得的裸鼠或其子代，或NOD-Prkdcscid IL-2rgnull nude鼠与其他基因改造动物交配或体外授精或直接进行基因编辑/修饰，并进行筛选，得到多基因改造非人动物或其子代。优选的，所述的裸鼠为免疫缺陷裸鼠或人源化裸鼠。
优选的，所述多基因改造非人动物或其子代可以是双基因改造动物、三基因改造动物、四基因改造动物、五基因改造动物、六基因改造动物、七基因改造动物、八基因改造动物或九基因改造动物。
本发明的第八方面，涉及上述的方法产生的多基因改造非人动物或其子代；优选的，所述非人动物为啮齿类动物；更优选的，所述啮齿类动物为小鼠。
本发明的第九方面，涉及一种靶向动物Foxn1基因的sgRNA序列，所述sgRNA序列在待改变的Foxn1基因上的靶序列上是唯一的，且符合5’-NNN(20)-NGG-3’或5’-CCN-N(20)-3’的序列的排列规则。
优选的，所述动物为啮齿类动物；更优选的，所述啮齿类动物为小鼠。
优选的，所述sgRNA序列在小鼠Foxn1基因的靶位点位于小鼠Foxn1基因的第4号外显子和/或3’UTR上。
优选的，所述sgRNA序列靶向的5’端靶位点的序列如SEQ ID NO：1-7任一项所示，所述sgRNA序列靶向的3’端靶位点的序列如SEQ ID NO：8-14任一项所示。
进一步优选的，所述sgRNA序列靶向的5’端靶位点的序列如SEQ ID NO：1所示，所述sgRNA序列靶向的3’端靶位点的序列如SEQ ID NO：8所示。
优选的，所述的sgRNA序列，编码sgRNA的DNA分子双链序列为SEQ ID NO：15和SEQID NO：16，或SEQ ID NO：17和SEQ ID NO：18。
本发明的第十方面，涉及一种包含上述的sgRNA序列的构建体。
本发明的第十一方面，涉及一种制备sgRNA载体的方法，包括以下步骤：
(1)提供一种sgRNA序列，制备获得正向寡核苷酸序列和反向寡核苷酸序列，所述sgRNA序列靶向非人动物Foxn1基因，同时所述sgRNA在待改变的非人动物Foxn1基因上的靶序列上是唯一的，且符合5’-NNN(20)-NGG3’或5’-CCN-N(20)-3’的序列排列规则；
(2)合成含有T7启动子及sgRNA scaffold的片段DNA，并将所述片段DNA通过EcoRI和BamHI酶切连接至骨架载体上，经测序验证，获得pT7-sgRNA载体；
(3)将步骤(1)设计的制备获得正向寡核苷酸序列和反向寡核苷酸序列变性、退火，形成可以连入步骤(2)所述的pT7-sgRNA载体的双链；
(4)将步骤(3)中退火的双链sgRNA的正、反向寡核苷酸序列分别与pT7-sgRNA载体进行链接，筛选获得sgRNA载体。
优选的，所述动物为啮齿类动物；更优选的，所述啮齿类动物为小鼠。
优选的，所述的方法，包括如下步骤：
(1)将序列如SEQ ID NO：1-7所示的任一项sgRNA靶序列和/或SEQ ID NO：8-14所示的任一项sgRNA靶序列，制备获得正向寡核苷酸序列和反向寡核苷酸序列；
优选的，所述sgRNA靶序列为SEQ ID NO：1和SEQ ID NO：8，获得的正向寡核苷酸序列如SEQ ID NO：15或SEQ ID NO：17所示；反向寡核苷酸序列如SEQ ID NO：16或SEQ ID NO：18所示，其中SEQ ID NO：15和SEQ ID NO：16为A组，SEQ ID NO：17和SEQ ID NO：18为B组；
(2)合成含有T7启动子及sgRNA scaffold的片段DNA，其中含有T7启动子及sgRNAscaffold的片段DNA如SEQ ID NO：19所示，将上述片段通过EcoRI和BamHI酶切连接至骨架载体上，经测序验证，获得pT7-sgRNA载体；
(3)分别合成步骤(1)中所述的正向寡核苷酸序列和反向寡核苷酸序列，优选为A组和B组中的正向寡核苷酸序列和反向寡核苷酸序列，将合成的sgRNA的正、反向寡核苷酸序列变性、退火，形成可以连入步骤(2)所述的pT7-sgRNA载体的双链；
(4)将步骤(3)中退火的双链sgRNA的正、反向寡核苷酸序列分别与pT7-sgRNA载体进行链接，筛选获得sgRNA载体。
本发明的第十二方面，涉及一种细胞，所述细胞包含一种或多种上述的sgRNA序列和/或一种或多种上述的构建体和/或上述方法获得sgRNA载体。
本发明的第十三方面，涉及根据上述的sgRNA序列、上述的构建体或上述的细胞在构建免疫缺陷裸鼠或Foxn1基因敲除/敲入动物或Foxn1基因人源化动物中的应用。
本发明的第十四方面，涉及一种荷瘤动物模型，所述荷瘤动物来源于上述的非人动物或其子代，或者，上述的方法构建的裸鼠或其子代，或者，上述的裸鼠或其子代，或者上述的多基因改造非人动物或其子代，或者，上述的NOD-Prkdcscid IL-2rgnull nude鼠。
本发明的第十五方面，涉及一种细胞或细胞系或原代细胞培养物，所述细胞或细胞系或原代细胞培养物来源于上述的非人动物或其子代，或者，上述的方法构建的裸鼠或其子代，或者，上述的裸鼠或其子代，或者上述的多基因改造非人动物或其子代，或者，上述的NOD-Prkdcscid IL-2rgnull nude鼠。
本发明的第十六方面，涉及一种组织或器官，所述组织或器官来源于上述的非人动物或其子代，或者，上述的方法构建的裸鼠或其子代，或者，上述的裸鼠或其子代，或者上述的多基因改造非人动物或其子代，或者，上述的NOD-Prkdcscid IL-2rgnull nude鼠。优选的，所述的动物为啮齿类动物；更优选的，所述的啮齿类动物为小鼠。最优选的，所述的小鼠为B-NDG背景。
优选的，所述组织或器官为脾脏、肿瘤或其培养物。
优选的，上述细胞或细胞系或原代细胞培养物，组织或器官不是动物品种。
本发明的第十七方面，涉及一种上述的非人动物或其子代、上述的细胞株、上述方法构建的裸鼠或其子代、上述的裸鼠或其子代、上述的多基因改造非人动物或其子代、上述的NOD-Prkdcscid IL-2rgnull nude鼠、上述的细胞或细胞系或原代细胞培养物在制备动物模型中的用途。
本发明的第十八方面，涉及一种上述的非人动物或其子代、上述的细胞株、上述的方法构建的裸鼠或其子代、上述的裸鼠或其子代、上述的多基因改造非人动物或其子代、上述的NOD-Prkdcscid IL-2rgnull nude鼠、上述的荷瘤动物模型、上述的细胞或细胞系或原代细胞培养物或上述的组织或器官在Foxn1基因或FOXN1蛋白相关领域或者免疫相关领域的应用。
优选的，所述的应用包括需要涉及人类细胞的免疫过程的产品开发，制造人类抗体，或者作为药理学、免疫学、微生物学和医学研究的模型系统中的应用或在生产和利用动物疾病模型，用于人源细胞移植、免疫系统重建、病原学研究和/或用于开发新的诊断策略和/或治疗策略中的应用或筛选、验证、评价或研究药物、药效研究，相关疾病药物以及抗肿瘤药物方面的用途。
进一步优选的，所述应用包括使用人PBMC进行免疫系统重建后，对抗人单抗、双抗或联合用药的药效评价、药物筛选，或人CAR-T体内评估或筛选。
本发明的第十九方面，涉及一种人用药物筛选或评价的方法，包括将人肿瘤细胞移入已有人PMBC重建的动物体内，向移入人肿瘤细胞的动物给予候选药物，对给予药物的动物进行药效检测和比较，其中，所述的动物为上述的非人动物或其子代、上述方法构建的裸鼠或其子代、上述的裸鼠或其子代、上述的多基因改造非人动物或其子代、上述的NOD-Prkdcscid IL-2rgnull nude鼠或者上述的荷瘤动物模型。
优选的，所述药物筛选方法不是治疗方法。该方法用来筛选药物，对候选药物的药效进行检测和比较，以确定哪些候选药物可以作为药物，哪些不能作为药物，或者，比较不同药物的药效敏感程度，即治疗效果不是必然的，只是一种可能性。
优选的，所述候选药物为单抗或双特异性抗体或两种及两种以上药物的联合使用。
优选的，所述检测包括测定肿瘤细胞的大小和/或增殖速率；优选的，所述检测的方法包括游标卡尺测量、流式细胞检测和/或动物活体成像检测。
本发明的第二十方面，涉及一种CAR-T体内验证的方法，包括向动物体内植入人肿瘤细胞，向植入人肿瘤细胞的动物注射人CAR-T，对注射人CAR-T后的动物进行肿瘤抑制效果检测和评价，所述动物为上述非人动物或其子代、上述方法构建的裸鼠或其子代、上述的裸鼠或其子代、上述的NOD-Prkdcscid IL-2rgnull nude鼠或上述的多基因改造非人动物或其子代，或已通过移植人PMBC重建人免疫系统的上述非人动物或其子代、上述方法构建的裸鼠或其子代、上述的裸鼠或其子代、上述的NOD-Prkdcscid IL-2rgnull nude鼠或上述的多基因改造非人动物或其子代。
优选的，所述CAR-T体内验证的方法不是治疗方法。该方法对CAR-T的效果进行检测和评价，以确定该方法是否有治疗效果，即治疗效果不是必然的，只是一种可能性。
本发明所述“治疗(treating)”(或“治疗(treat)”或“治疗(treatment)”)表示减缓、中断、阻止、控制、停止、减轻、或逆转一种体征、症状、失调、病症、或疾病的进展或严重性，但不一定涉及所有疾病相关体征、症状、病症、或失调的完全消除。术语“治疗(treating)”等是指在疾病已开始发展后改善疾病或病理状态的体征、症状等等的治疗干预。
在一个方面，所述非人动物是哺乳动物。在一个方面，所述非人动物是小型哺乳动物，例如跳鼠科或鼠总科超家族。在一个实施方式中，所述基因修饰的动物是啮齿动物。在一个实施方式中，所述啮齿动物选自小鼠、大鼠和仓鼠。在一个实施方式中，所述啮齿动物选自鼠家族。在一个实施方式中，所述基因修饰的动物选自丽仓鼠科(例如小鼠样仓鼠)、仓鼠科(例如仓鼠、新世界大鼠和小鼠、田鼠)、鼠总科(真小鼠和大鼠、沙鼠、刺毛鼠、冠毛大鼠)、马岛鼠科(登山小鼠、岩小鼠、有尾大鼠、马达加斯加大鼠和小鼠)、刺睡鼠科(例如多刺睡鼠)和鼹形鼠科(例如摩尔大鼠、竹大鼠和鼢鼠)家族。在一个特定实施方式中，所述基因修饰的啮齿动物选自真小鼠或大鼠(鼠总科)、沙鼠、刺毛鼠和冠毛大鼠。在一个实施方式中，所述基因修饰的小鼠来自鼠科家族成员。在一个实施方式中，所述动物是啮齿动物。在一个特定实施方式中，所述啮齿动物选自小鼠和大鼠。在一个实施方式中，所述非人动物是小鼠。
在一个特定实施方式中，所述非人动物是啮齿动物，其为选自BALB/c、A、A/He、A/J、A/WySN、AKR、AKR/A、AKR/J、AKR/N、TA1、TA2、RF、SWR、C3H、C57BR、SJL、C57L、DBA/2、KM、NIH、ICR、CFW、FACA、C57BL/A、C57BL/An、C57BL/GrFa、C57BL/KaLwN、C57BL/6、C57BL/6J、C57BL/6ByJ、C57BL/6NJ、C57BL/10、C57BL/10ScSn、C57BL/10Cr和C57BL/Ola的C57BL、C58、CBA/Br、CBA/Ca、CBA/J、CBA/st、CBA/H品系的小鼠。
除非特别说明，本发明的实践将采取细胞生物学、细胞培养、分子生物学、转基因生物学、微生物学、重组DNA和免疫学的传统技术。这些技术在以下文献中进行了详细的解释。例如：Molecular Cloning A Laboratory Manual，2ndEd.，ed.By Sambrook，Fritschand Maniatis(Cold Spring Harbor Laboratory Press：1989)；DNA Cloning，Volumes I and II(D.N.Glovered.，1985)；Oligonucleotide Synthesis(M.J.Gaited.，1984)；Mullisetal.U.S.Pat.No.4，683，195；Nucleic Acid Hybridization(B.D.Hames&S.J.Higginseds.1984)；Transcription And Translation(B.D.Hames&S.J.Higginseds.1984)；Culture Of Animal Cells(R.I.Freshney，AlanR.Liss，Inc.，1987)；Immobilized Cells And Enzymes(IRL Press，1986)；B.Perbal，A PracticalGuide To Molecular Cloning(1984)；the series，Methods In ENZYMOLOGY(J.Abelsonand M.Simon，eds.-in-chief，Academic Press，Inc.，New York)，specifically，Vols.154and 155(Wuetal.eds.)and Vol.185，″Gene Expression Technology″(D.Goeddel，ed.)；Gene Transfer Vectors For Mammalian Cells(J.H.Miller andM.P.Caloseds.，1987，Cold Spring Harbor Laboratory)；Immunochemical Methods InCell And Molecular Biology(Mayer and Walker，eds.，Academic Press，London，1987)；Handbook Of Experimental Immunology，Volumes V(D.M.Weir and C.C.Blackwell，eds.，1986)；and Manipulating the Mouse Embryo，(Cold Spring Harbor LaboratoryPress，Cold Spring Harbor，N.Y.，1986)。
以上只是概括了本发明的一些方面，不是也不应该认为是在任何方面限制本发明。
本说明书提到的所有专利和出版物都是通过参考文献作为整体而引入本发明的。本领域的技术人员应认识到，对本发明可作某些改变并不偏离本发明的构思或范围。下面的实施例进一步详细说明本发明，不能认为是限制本发明或本发明所说明的具体方法的范围。
附图说明
以下，结合附图来详细说明本发明的实施例，其中：
图1：A：sgRNA1-sgRNA7活性检测结果，其中nc为阴性对照，pc为阳性对照，blank为空白对照；B：sgRNA8-sgRNA14活性检测结果，其中nc为阴性对照，pc为阳性对照，blank为空白对照；
图2：pT7-sgRNA质粒图谱示意图；
图3：鼠尾PCR鉴定结果(F0)，其中，WT为野生型，H2O为水对照，1-44为小鼠编号；
图4：NOD-Prkdcscid IL-2rgnull nude小鼠表型为无毛；
图5：在B-NDG nude、B-NDG小鼠单侧乳垫接种人乳腺癌MDA-mB-231细胞，其中，A：B-NDG nude鼠成瘤照片；B：B-NDG鼠成瘤照片。
具体实施方式
下面结合具体实施例来进一步描述本发明，本发明的优点和特点将会随着描述而更为清楚。但这些实施例仅是范例性的，并不对本发明的范围构成任何限制。本领域技术人员应该理解的是，在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换，但这些修改和替换均落入本发明的保护范围内。
在下述每一实施例中，设备和材料是从以下所指出的几家公司获得：
NOD/scid小鼠购自北京华阜康生物科技股份有限公司，
NOD-Prkdcscid IL-2rgnull(B-NDG)小鼠来源北京百奥赛图基因生物技术有限公司，货号B-CM-002或B-CM-001，
UCA试剂盒来源北京百奥赛图基因生物技术有限公司，货号BCG-DX-001；
EcoRI，BamHI、BbsI酶购自NEB，货号分别为；R3101M，R3136M，R0539L；
Ambion体外转录试剂盒购自Ambion，货号AM1354；
Cas9mRNA来源SIGMA，货号CAS9MRNA-1EA；
大肠杆菌TOP10感受态细胞购自Tiangen公司，货号为CB104-02；
卡那霉素购自Amresco，货号为0408。
实施例1pT7-sgRNA1、pT7-sgRNA8的构建
根据“nude”基因的特点，本发明拟通过将NOD/scid小鼠体内Foxn1基因(小鼠Foxn1基因序列见SEQ ID NO：26，mRNA序列见SEQ ID NO：27，蛋白序列见SEQ ID NO：28)的第4号外显子至3’UTR的约10kb的碱基敲除，以使小鼠的Foxn1基因的功能失活，不表达功能性的FOXN1蛋白，从而表现出裸鼠症状；再将获得的NOD/scid裸鼠与免疫缺陷程度更高的NOD-Prkdcscid IL-2rgnull小鼠交配，得到无毛的NOD-Prkdcscid IL-2rgnull nude小鼠。
设计并合成识别5’端靶位点(sgRNA1-sgRNA7)、3’端靶位点(sgRNA8-sgRNA14)的sgRNA序列。其中5’端靶位点位于4号外显子，3’端靶位点位于3’UTR，各sgRNA靶向“nude”基因靶位点序列如SEQ ID NO：1至SEQ ID NO：14所示。所述的“nude”基因为Foxn1基因。
sgRNA-1靶位点序列(SEQ ID NO：1)：5’-GGCTGGTAGCAGTACATCCCAGG-3’
sgRNA-2靶位点序列(SEQ ID NO：2)：5’-CAGTACATATGTTGCAAGGGAGG-3’
sgRNA-3靶位点序列(SEQ ID NO：3)：5’-AGACTTACCTGATGGAAGGCAGG-3’
sgRNA-4靶位点序列(SEQ ID NO：4)：5’-ACATATGTTGCAAGGGAGGCTGG-3’
sgRNA-5靶位点序列(SEQ ID NO：5)：5’-CCTCAGACTTACCTGATGGAAGG-3’
sgRNA-6靶位点序列(SEQ ID NO：6)：5’-CAAGGTCAAGCCCCAAGCTCTGG-3’
sgRNA-7靶位点序列(SEQ ID NO：7)：5’-GGACCACTGTCCAGAGCTTGGGG-3’
sgRNA-8靶位点序列(SEQ ID NO：8)：5’-GTGTGAGATGCGGGTCCACCAGG-3’
sgRNA-9靶位点序列(SEQ ID NO：9)：5’-CCTTTAAGGTGAGCCCAATATGG-3’
sgRNA-10靶位点序列(SEQ ID NO：10)：5’-CAAAGGCCGCAGCTGATGTTGGG-3’
sgRNA-11靶位点序列(SEQ ID NO：11)：5’-CCACCAGGTAGCATCCTAGATGG-3’
sgRNA-12靶位点序列(SEQ ID NO：12)：5’-GGGGGCCCCGTGTGAGATGCGGG-3’
sgRNA-13靶位点序列(SEQ ID NO：13)：5’-AGATGGATGCCCCCAACTTCTGG-3’
sgRNA-14靶位点序列(SEQ ID NO：14)：5’-CTTCTGGCTAACAAATAAGTTGG-3’
利用UCA试剂盒检测多个sgRNA的活性，具体活性数值见表1，从结果可见sgRNA具有不同活性，检测结果参见图1。其中sgRNA-4、sgRNA-9、sgRNA-10及sgRNA-11活性相对较低，sgRNA-1活性最高，这可能由于靶位点序列的特殊性导致，但根据我们的实验，sgRNA-4、sgRNA-9、sgRNA-10及sgRNA-11的数值仍显著高于对照组nc数值，仍可判断sgRNA-4、sgRNA-9、sgRNA-10及sgRNA-11是具有活性的，活性满足基因打靶实验要求。从中优先选择2个(分别是sgRNA1和sgRNA8)进行后续实验。在其5’端加上TAGG得到正向寡核苷酸，其互补链加上AAAC得到反向寡核苷酸(见表2)，退火后将退火产物分别连接至pT7-sgRNA质粒(质粒先用BbsI线性化)，获得表达载体pT7-sgRNA1、pT7-sgRNA8，其中PCR反应体系见表3。
表1 UCA检测结果
表2 sgRNA1和sgRNA8序列列表
表3 PCR连接反应体系(10μL)
反应条件：
室温连接10-30min，转化至30μL TOP10感受态细胞中，然后取200μL涂布于Kan抗性的平板，37℃培养至少12小时后挑选2个克隆接种含有Kan抗性的LB培养基(5mL)中，37℃，250rpm摇培至少12小时。
pT7-sgRNA质粒来源：
pT7-sgRNA载体图谱，参见图2。该质粒骨架来源Takara，货号3299。由质粒合成公司合成含有T7启动子及sgRNA scaffold的片段DNA并依次通过酶切(EcoRI及BamHI)连接至骨架载体上，经专业测序公司测序验证，结果表明获得了目的质粒。
含有T7启动子及sgRNA scaffold的片段DNA(SEQ ID NO:19)：
gaattctaatacgactcactatagggggtcttcgagaagacctgttttagagctagaaatagcaagttaaaataaggctagtccgttatcaacttgaaaaagtggcaccgagtcggtgcttttaaaggatcc
实施例2显微注射及胚胎移植
取NOD/scid小鼠的原核期受精卵，利用显微注射仪将预混好的pT7-sgRNA1、pT7-sgRNA8质粒的体外转录产物(使用Ambion体外转录试剂盒，按照说明书方法进行转录)和Cas9mRNA注射至小鼠受精卵细胞质或细胞核中。按照《小鼠胚胎操作实验手册(第三版)》中的方法进行胚胎的显微注射，注射后的受精卵转移至培养液中短暂培养，然后移植至受体母鼠的输卵管，生产基因敲除小鼠(即为F0代)。
实施例3敲除小鼠的鉴定
对得到的F0代小鼠的鼠尾基因组DNA进行PCR分析，反应体系及反应条件分别见表4、5，引物PCR-1位置位于5’端靶位点左侧，引物PCR-2位置位于3’端靶位点右侧，引物序列如下：
上游引物：PCR-1(SEQ ID NO：20)：5’-AGCCCCTCTACTGACTTGCTGATTT-3’；
下游引物：PCR-2(SEQ ID NO：21)：5’-TAAGGGGTTCACAGGTCATACGGGA-3’
被成功敲除的小鼠PCR条带应为约776bp，否则应无条带。
表4 PCR反应体系(20μL)
| 10×缓冲液 | 2μL |
| dNTP(2mM) | 2μL |
| MgSO<sub>4</sub>(25mM) | 0.8μL |
| 上游引物(10μM) | 0.6μL |
| 下游引物(10μM) | 0.6μL |
| 鼠尾基因组DNA | 200ng |
| KOD-Plus-(1U/μL) | 0.6μL |
表5 PCR扩增反应条件
44只F0代小鼠的PCR鉴定结果见图3。其中编号为2、16和37的小鼠为阳性小鼠。将2、37号小鼠进行进一步的测序验证(由测序公司进行)，确认2号小鼠缺失10182bp(SEQ IDNO：31)，37号小鼠缺失10192bp(SEQ ID NO：29)，但存在7个碱基的随机插入(AGTGCAT)。后续测序验证表明16号小鼠存在9126bp的基因缺失，其中第一段缺失9095bp(SEQ ID NO：33)，第二段缺失31bp(SEQ ID NO：34)。
实施例4具有“nude”表型的NOD-PrkdcscidIL-2rgnull小鼠(B-NDGnude小鼠)的获得
将F0鉴定为阳性的小鼠与NOD/scid小鼠交配得到F1代小鼠，经PCR分析确认后，将F1代杂合子小鼠互交获得F2代纯合子小鼠，该小鼠即可表现出“nude”表型。将F2代纯合子小鼠与NOD-Prkdcscid IL-2rgnull(B-NDG)小鼠杂交后互交，即可从后代中获得具有无毛表型的NOD-Prkdcscid IL-2rgnull nude小鼠，结果如图4所示。
实施例5显微注射及胚胎移植直接获得B-NDG nude小鼠
取NOD-Prkdcscid IL-2rgnull(B-NDG)小鼠的受精卵，利用显微注射仪将预混好的pT7-sgRNA1、pT7-sgRNA8质粒的体外转录产物(使用Ambion体外转录试剂盒，按照说明书方法进行转录)和Cas9mRNA注射至小鼠受精卵细胞质或细胞核中。按照《小鼠胚胎操作实验手册(第三版)》中的方法进行胚胎的显微注射，注射后的受精卵转移至培养液中短暂培养，然后移植至受体母鼠的输卵管，直接得到Foxn1基因敲除的B-NDG小鼠。将获得的小鼠通过杂交和自交，扩大种群数量，即可建立稳定的B-NDG nude小鼠品系。
实施例6 B-NDG nude小鼠的鉴定及验证
取同龄C57BL/6、B-NDG、NOD/scid小鼠各5只，B-NDG nude小鼠4只，分别取全血(EDTA抗凝)，加入裂红液后，流式检测mCD3、mCD19及NKp46的表达量。流式结果显示，在C57BL/6和NOD/scid小鼠中分离的全血白细胞中有明显的的T、B细胞分群和NK细胞分群，但在B-NDG nude和B-NDG小鼠中未检测到T、B细胞和NK细胞，说明B-NDG裸鼠和B-NDG小鼠在血液中的T、B、NK是缺失的，B-NDG裸鼠具有高度免疫缺陷。
在多只B-NDG nude、B-NDG小鼠单侧乳垫接种人乳腺癌MDA-mB-231细胞(1×107)，观察肿瘤生长情况。在接种后40天左右肿瘤体积达到400-600mm3时拍照记录成瘤情况，对比照片见图5(A)和5(B)，B-NDG nude鼠成瘤后明显比B-NDG小鼠更易观察和测量其生长情况。
实施例7 B-NDG nude小鼠的人免疫系统重建
使用本发明方法获得的B-NDG nude小鼠，在移植人外周血细胞(hPBMC)或人造血干细胞后，可以在小鼠体内构建人免疫系统重建的人源化小鼠模型。
以hPBMC重建为例，选取5只使用本方法制备的B-NDG nude小鼠，通过尾静脉注射1×107人外周血细胞(hPBMC)，2周后取血进行流式细胞检测。流式数据显示，通过注射人外周血细胞(hPBMC)，可以在5只B-NDG nude小鼠体内检测到表达人白细胞表面分子标记(CD45+)的细胞。本实验结果表明通过移植人外周血细胞，可以初步在小鼠体内重建人免疫系统。且进一步的分析表明，外周血细胞的重建以T细胞为主。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。采用其它基因编辑系统和制备方法也可以得到本发明的非人哺乳动物，包括但不限于基于胚胎干细胞(embryonic stem cell，ES)的基因同源重组技术、锌指核酸酶(ZFN)技术、转录激活子样效应因子核酸酶(TALEN)技术、归巢核酸内切酶(兆碱基大范围核酶)或其他分子生物学技术。
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本发明对各种可能的组合方式不再另行说明。
此外，本发明的各种不同的实施方式之间也可以进行任意组合，只要其不违背本发明的思想，其同样应当视为本发明所公开的内容。
序列表
<110> 北京百奥赛图基因生物技术有限公司
<120> 一种免疫缺陷裸鼠模型的制备方法及应用
<130> 1
<160> 35
<170> PatentIn version 3.5
<210> 1
<211> 23
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 1
ggctggtagc agtacatccc agg 23
<210> 2
<211> 23
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 2
cagtacatat gttgcaaggg agg 23
<210> 3
<211> 23
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 3
agacttacct gatggaaggc agg 23
<210> 4
<211> 23
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 4
acatatgttg caagggaggc tgg 23
<210> 5
<211> 23
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 5
cctcagactt acctgatgga agg 23
<210> 6
<211> 23
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 6
caaggtcaag ccccaagctc tgg 23
<210> 7
<211> 23
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 7
ggaccactgt ccagagcttg ggg 23
<210> 8
<211> 23
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 8
gtgtgagatg cgggtccacc agg 23
<210> 9
<211> 23
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 9
cctttaaggt gagcccaata tgg 23
<210> 10
<211> 23
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 10
caaaggccgc agctgatgtt ggg 23
<210> 11
<211> 23
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 11
ccaccaggta gcatcctaga tgg 23
<210> 12
<211> 23
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 12
gggggccccg tgtgagatgc ggg 23
<210> 13
<211> 23
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 13
agatggatgc ccccaacttc tgg 23
<210> 14
<211> 23
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 14
cttctggcta acaaataagt tgg 23
<210> 15
<211> 22
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 15
taggctggta gcagtacatc cc 22
<210> 16
<211> 22
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 16
aaacgggatg tactgctacc ag 22
<210> 17
<211> 23
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 17
taggtgtgag atgcgggtcc acc 23
<210> 18
<211> 23
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 18
aaacggtgga cccgcatctc aca 23
<210> 19
<211> 132
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 19
gaattctaat acgactcact atagggggtc ttcgagaaga cctgttttag agctagaaat 60
agcaagttaa aataaggcta gtccgttatc aacttgaaaa agtggcaccg agtcggtgct 120
tttaaaggat cc 132
<210> 20
<211> 25
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 20
agcccctcta ctgacttgct gattt 25
<210> 21
<211> 25
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 21
taaggggttc acaggtcata cggga 25
<210> 22
<211> 18
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 22
ctggtagcag tacatccc 18
<210> 23
<211> 18
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 23
gggatgtact gctaccag 18
<210> 24
<211> 19
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 24
tgtgagatgc gggtccacc 19
<210> 25
<211> 19
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 25
ggtggacccg catctcaca 19
<210> 26
<211> 30078
<212> DNA
<213> 小鼠(Mouse)
<400> 26
aagaggagga agagagtggg ggagggaagg agggagggag aggatgggga catgaaacag 60
caatgggacc aaaagtctgt ggaggagcaa ggacaggccc caggcctatt caggtaagac 120
tcagggtagc cacttcctag acctgctgcg cactgcacct caactgtaga ccctgagggg 180
ctggggacca acagccactc aaatatttcc attctggaga tcatgaagag tgactgaggg 240
gatgatgaca tagaactaag catcctccat ctccacccac acccatacat ggggcatgat 300
gacccagagc ggagacacat ggctagaaac tcaatgacac cgtagcgtgg agacacaagc 360
ctgagtacag ggacaagagc cacagatgca cagacattag agaaaacata gacgcaaaca 420
gacaaatccc tgcgaggacc tgtggagaag caggcatgcc cacagacatg ggagggaagt 480
cacatggatt tggggctaca cactgccaca cataaggtca gataatatga catgagatga 540
gccaaccctg tggacatctc ccagaaatca ttggatcctt ggggaggggg tctctgctgg 600
tccacactat acctgagagg gctcagtgct gcaaccatgt gctgcttccc agaaccccct 660
tactagctcc gtgaacacac atgtggcggc tgggctctcc tgacacacag gtgcatgtcc 720
caacaggcct gggccccacc catgggggct gacatctctg ttctggggtg caggtggggg 780
ccacagagcc accccttccc ccgcaagcca caggccatgc ccactggcag ggactggggg 840
cccaggctgg cacaggaggg gaggcctgga ggaggggggg acccgggcgc ggccagggcg 900
ggcacaggag cctgtacctg tcaaacaaga gccaaggagc aaactagctt cttagtcacc 960
tttctcttct ccccgttttt ggcagcaacc cctcggggca aggggaagct gatatcataa 1020
ttattggctc acccagcagc tgcctcccct cacctgatgt cagcccagac ccaggacaat 1080
caggctgacg gactgacaga cggtcggagc tcctggcccc ccagacccag gcccccacgc 1140
cgacctgctt cactgagcag gtaagaggag acctggccca agtcagccgt ggaggccaac 1200
aggggagggg gcttggtttt tttaatgggc cccaggaggc actgggtgct tctcagagtc 1260
tcattgtctc tccagggaga ctcaggatca gggtgagtac ctggaggctg aggggacccc 1320
tcctccactc tcctctctct ttcctggccc aggccttctg actttgatcc ttcttgctgt 1380
aatgtaggac tctgttttgc tgtacatggt gtctctgtgt ggtaggtctg tgtggtggca 1440
cccaccttga gttgggaggc aattatgact ccagatggac agctagagtt taaagataga 1500
cagataggca gattccctgc cgaggactga gtggctggct aagtggaaag ttgggtaccc 1560
cccccccagc tctggcaact tccatctctc tggaatacct ggtcttgggt ctgcacgacc 1620
cagattctat gggggaggct tggcatgcag aacggagaat ggtgcacctt gtgcagaagc 1680
ggacaggcgg caacaggtgc tgcggctagg agccgatgcc aagctggagg cacacctctc 1740
tgatcgccgg agatgtttct cttctttaag atcgctgcag tagagaggag tggccagcag 1800
acctgagaca ggcagagagt tcacagaccc cccaccccca ccccaactta gaattgggaa 1860
atctagctgc cagaaacccc tttatctact gagactacct accctttgcc ccatacctga 1920
ccaggcaaaa tcctggaatt tgctatagag ctccccaacc caccttcagc atccaaagaa 1980
gcatgttggg ttaaagctag agttataagt gggcgtgttt gcctctttgc tctgtaccta 2040
caagtgcagg ggacatgtct gggtatgtgc agtggcaggg tacagctgct cagcaagaaa 2100
ggaccagatg gagaagatgc ctcctctagg gacaccatct catcccctgt gtcccctacc 2160
cctgtgccgg gtagctccca caacagacag agtgtggtcc tctctgtgtt ctaaactgtt 2220
cagtaggaga ctcagtgagt tccttcatcg tttttttttg aaatcgtaac ttctgtagcg 2280
tctacctcta gcttctccac ttccttctct ttcttctact gatgaagccc agttcccctg 2340
cacagatgga tgagcacagg gtagaaaggg tggcagtgaa ctccagccct atccccactg 2400
ggctttagca agagctttct tcccatcctg acctacagac caggacaaga tgctggtagc 2460
agaatggcat cccagctgat gaggcctggc tcttctctct tgtggctttg tgaggggcta 2520
agacagagct gagctgggac caggggaaga acagagggtc caagtgctgc cctgggttga 2580
ggatcctctg gggtgaggat gccgtggggg gtggcacttg ccctcccagc tctccacccg 2640
gccccgcccg ggcagcctat gccgagctca gctcccggct gcaaggcctg ccgaggcacg 2700
ctgcaccccc aggcctctca cctcactcca ggccaggaac ctgttctccc gggaatgctg 2760
gggagttctc agaggacttt agttcccagg ggtttaggga aagaaatcct ctggaccagt 2820
gagtgagcca tggaaaagca agaaaatgga aagactgggg ggcagaggtg ggtcacaagg 2880
gcccattgcc ctcttcatct gtgtctatcc acacacagat cccacacttc tagctgacag 2940
cttttattgc tcttcgtgag aatgaagcct tgggacagtt aaagacaaaa gaaaaagccc 3000
ctcatggcac atgctttctg ccacatgcca tcatttggcc cccatggaaa gtcccttctg 3060
ccctctaaga aaatgacagg gcatcatccc agttggaccc aacaactccc atccagggag 3120
tctttcctac taacctttcc tcattgagcc tggtcttcac agaccagcag aaacacacac 3180
acacacacac acacacacac acatacacac atgcacacac acacacgcac acacacacac 3240
acacacacac acacacgcac acacacgcac acacacacgc acacacacgc acacacacgc 3300
gcacacacac acacacacac acacactacc tgccctgcac acatagcttg aacctgttcc 3360
tcagtacata aaagtcttgg ggacttctca gcctgctgcc ccattattct ctccagcacc 3420
atattctgac aagattgggg ccacctctct gtctattttt tgagacacga tctccctatc 3480
tagcctgagc taccctggaa ccctcagcct tctgggtgct gaaattaaag gtgtgcagta 3540
ccccactcac ctatgggcca cttctggttc cgcataccat agggacagag aggataaagg 3600
gcagaggcca tcatccctgt tgcagcctgc cagacttcca cagtgggaga tggtgacttc 3660
gggaagatag ttcagcattt taaatttagt tcttgcatgc agcccatgtc acccgagaag 3720
gcaatttcct ggggagggca ggccagcact gatctgggat gcattgtcgg gcaacatact 3780
cagtgcaagg gaaagacttg ctgcactctg agagacttcg tccccaaagc gcccacccag 3840
tgaccctcca gtaagatgca ctcctatccc ttccagcctg cctcggtccc tgcctccttt 3900
tgcatcccca gccctaaacc catttccctt taccagccct ctgtacgtat ctcagatttg 3960
acctgagctg gagcttctgt tgcgtgggtc tcctgtgtcc tgagattaca ggtgcagccg 4020
tgacaccagg tcctccctta tctcactcgc agccccagct cagacctgct ttccaccttt 4080
tctccctatc ctcaacttta ccaaagtttg tacaatccca ccccccccca cacacacaca 4140
tacacacaca cttcctctcc ttatttctta cttggcttcc ccactcctcc caccatccct 4200
cccagcccta tgagcccatc agcaccccca caggatggat gggcatccct gtgcacagtc 4260
agagaatcca aaacctcccg cagtgttccc taatttagtc tctgaactga gaggcccaga 4320
gccatgtccc aaggacaggt gggttgtatg ggatcatccc tagagaagct ctcagcttcc 4380
tgatcccata tgggccctaa aaaactggct gttggcagat agtaaaatgg agtctggctg 4440
aagcatggtt tggtgggaaa tcctgtgctt tatacgtctg aggtcctgga tgccagcctc 4500
agcccccaaa taaaaatgaa accatctagg tgagttcaga tacaagtatc tgatgctaca 4560
gcagtttgtc aagcaagggg gggtggggtg ggggagagct ggagggatga ctgatcccgt 4620
cagacatggc taggccaagg caggaagatg gacagcagct gaagcaaagc ccgctgggtt 4680
ctttaggaat gactgccact gtcatgagta tcccccagtc tctaccccgc ctgtggctct 4740
tgcttagtca gctcagatta atgggactgg ggaaagaatt agctgaatcg tgatctctcg 4800
ggggaactag agcctgcagt gagtcacagg gaagggaacc tgagctctca gggagattct 4860
ggaggctccc tgggtgtgtg ggggagggga gggggttatt ccctaagact tctctgagat 4920
gctacctaga gcctgcatgc tgggaggcac agccctggct ctctacccca aatttgcaga 4980
atgataatgt gattaaccag ctaccagcat gccccccaaa accctccaag ggccctcggc 5040
actctcgcat cctgaaacca ctatttgtga caaactgcag ccagtctagc accaacacat 5100
agtgggctta cttggcacca tcacacagtc agtatacaca cagacagcag aacagggcgt 5160
ggccctggaa ccggattgcc tgcagacaga tggaagtccc acctacactt gtaaattcca 5220
caatcacgtc ccaggctgta gcagcctatc gggttcagcg ccataggatg tgaacaagga 5280
tgaacacaca cacacacaca cacacacaca gcactgtgag gtgaagacca gttatcacac 5340
ttatcaactc ttgctctgta cagagccaga agaactacat caatgttcag tcaatggtag 5400
tctgtatcct gaccctctgt agaagaggtc ctagagtcta ccctgggcac ttacagatca 5460
gtaacttgtc tcttgtaatc ccagcagtga gcagactgag gcaggaggat tgctgagttt 5520
gaagccaccg tgggtagttc aagctacata gcgagtttga agtcaacttg gaatccatga 5580
tgagactctg tctaaaagaa aataagaaca acaaacaaac aaataaaaag aacagtcagg 5640
tagtggtggc ccacgccttt aatcccagaa ctcaggaagc agaggcaggt ggatctctgt 5700
gagttcaagg ccaggctgag ctacagagtg agttccagga cagaaaagaa tacacagaga 5760
aaccatgcct caaaaaaaca aaaacaaaaa caaacaaaca aaaaacccac caataatcaa 5820
aaagaaaaag agaaaagaaa gagaatctga atgttgatgg gtctttctat gcctatttgc 5880
aacacactta agagtgtgag gggttggaag aggaaattta gggtgacaga aaagccagaa 5940
ggatgtagag tgtcaaggaa ggaagctgga accaagtagc agagcaactc aggaagtccc 6000
tccaaacctc tcacttctcc aaaggcatgc tgggatctca gagccagctc accatgacca 6060
gcatccggaa gaaggagggg tgtgtacaac acacctgcct aggaaatcat ccctagcctg 6120
gcatggcagc gcaggtctct aatcccagct actcaggagg ctgaggcagg cagataagat 6180
gttcaaggct tgcctgaatg ttcaaagcca gctgaagcaa tttagtgatg cgaccttgtt 6240
tcaatatttt tttttaaaaa gctcattggg tctaaagctc attggtaaag cacttgccag 6300
gcacaggcaa gacccatgtt cagtcctagt cccacaaaaa caaacaaagc catctgtctc 6360
cttggttggc ttcagttctc ctctctgtca cacagacagg ctttggatgg aagcatcttc 6420
caatgtgctt cctcctcctt ggtccatgct tggagccaat agctgccctg cctgcccttt 6480
gctcggacgt agggcaggaa gtgcgccagc ttgcatccat cttgtgctga atcagggtta 6540
ttagcagtgg tggcagaatt aataccccta ataatagatt ggtggtaatg agcagtgctg 6600
gtaataatat gtacagagag aagcctctga ccaagggaca gtggcatcca cagccacctg 6660
aggcccctat caaggtgagc aggcaaaggg cgactgatac acccacactt ctatagggaa 6720
cataggaggt tctcatgcag tgccatggct ccctaggatc ctgggggagg aggcagaaaa 6780
aatggttctc acctgctcct agggacagga cagcagggga tgagtgcaag ggcagaatga 6840
agtcactatt tcatagagga ggaaaaaagc ttcatcctag tcactagccc aagctgatga 6900
cagagccagg acatggtcct cccatagtgc ccaagaggga aagagggatt ctgtaagaag 6960
caggggactc caagcttgac gaagccttca ggagagaacc caggttaggg gaggagatga 7020
cagaagttcc catcatgcct gatgggttta cagagcaaat cctcagctgc cagctactgg 7080
catagccaat tggcccggca cctgatttta ggggttgtga gaggaggctc agttccaaat 7140
gatgtcattg tggggtgggg tttcttggcc tctaatgggc tctcagaagc cagcggcttc 7200
ttctgcccct cagcctgtcc tccttcgcat ctcttcagca gatgtggctc acctcaggaa 7260
ggatgaaggt gataaaccct cctggccctt cagtccttcc ctcacctact tctcccgtct 7320
ctgatcatgg ctaagcagtc tgagggtttg agggaaaatt ccactctgga gaccagtgtc 7380
taaggcccca gatccctgtt ctctgtacgg tgcatccaga gggttacaca ttgcccccac 7440
cccaccccca ccccccagct cttcactgat atcctaatgt ttccttttag attatgatgg 7500
ttgtcactgt tgtttttctg agacagggtt tctctgtgta gccctggctg tactggaact 7560
cactctgtag accaggctgg cctcgaactc agggatcctc ctgagtactg ggattaaagg 7620
ccaccaacca ctgcctgtcc tttttcccgt tttccttgtg tgtgtgtgtg tgtgtgtgtg 7680
tgtgtgtgtg agagagagag agagagagag agagagagag aggtggggtc tcacaaatgc 7740
agcccaggct gaccttacat ttgtgattct cctctctcca cctcctgagt actaagatta 7800
cacagtcaac ccaactagga aacagttcta tctccaaatt ctttgtcagt ctgtccccac 7860
tgctcggggc ttcaaaattc ccctggaaag gtggagctgg gggcttttcc ctctctggct 7920
atccaaaggt gtcatgttcg tgaatatgag aatgcctgct aaccttgaag gggaagccac 7980
cttgctccta gacttgctcc tagacacaag atctcagggt tgcaggggca ccagcagagg 8040
caggtaggca gaagggagga aaaggcaggt cataaatggc tcccaagaag aaatgcaaac 8100
attactgtgg gtgagggcag tggagtagac atgaaaggtc tctagaaaga ggtctctaag 8160
gagggagagt ccaggaggac caatctctta aattaggtgg ccatggtaag gaagagggag 8220
gggaagacct aaaacaatcc taggagtaga tggtagcttt gaggaccagc atttcttgtt 8280
tctttaaaat ctctttctga tcatttacaa gacaggcacc cataggtatt gcaaagacat 8340
ccatccatcc acctgtctat ccatagccca tctatctgtt caaagtcacc catctatctc 8400
ttcatccatc tatcttccat ccaaccatcc acccatctat ccatctacct gtctagagag 8460
gtcagggcta ctgggaaggg cctgtggtcc tgtggcattt atggggcatg tgacttacct 8520
gcttggcctg gggaggcagt cccacccctg ccctggggca gggggccggt cctggcatgt 8580
gggtgtattt atacctggat ggaggctccc ctgaagctga aagctgcatg actccccaaa 8640
gccgggatgg tgtccacggc ccagagccca ctgtaagtgt ttagacatgg ctgcgttggg 8700
ggtcaggacg gggtggaaga agagggggag gggctggggt gtactgccca gaggtggtaa 8760
agactatgga aagagaggca tgctgggcag atgtttgtga gaaaagagga ggctgccagc 8820
atcagacatt ctcagcaaag ctgggacctt ccatggagac ggaatgagcc tatttccctt 8880
agctagtggg gagtggtcat tgacacataa ggcaagtgaa cgagattata agaattaaga 8940
acaaatatct aggaaagttt ccaggtcacc ccaggcagag aaggtagctc aagtgttttt 9000
ttgttttttg ttttttgttt ttgttttttt ttccgaaagg atgctttctg agcagactgc 9060
ttgaagaggc tgggggaatg tcaggtacct ttataaaaga cccgacagag attggaacta 9120
cctgactgca ggtgtgaatg gctcacagga tgctgtaaga gggatatgac tgcttttctt 9180
actacagtgt gtgtgtgtat gtgtgtatgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt 9240
gtgtgtgtgt gtgtacatgt gcatgcatgt cacagcaaga gtgtggaggc cagggaagaa 9300
aatgctgtag ttggtcctct ccggccacca tgtgggtcct aggaatcaaa ctcaggttgt 9360
cagggttgaa ggtgggtacc tacacctgcc tctggctaat tttcatccat cattctttac 9420
aaacccaggc agcatccaga gacagagagt ctagaggggc cttcaggacc ccagactggt 9480
aagaagaaac ctgttagaaa ccccatcttc ttgacacccc tagactccca gaatcctgag 9540
aggtgtgagc ctcaggcata gtccccaggt ctttcgctgc cacccccagc aagggtaatt 9600
agggacctgc tccagggaac ccctcccagc agccaggcag gtggagcctc gggtggggct 9660
gcaggcgaac actgggcaca gccccacccc tcgtaaaaca agctgccaca gccggcaaca 9720
gaaaccatta aggtggaact gagccggctc cgcctgctca taaagaacgg gcaggagggc 9780
gccgacaggt ggggggtggg ggggggggag agagagtgtg tgtgtgtgtg tgtgtgtgtg 9840
tgtgtgtgtg tgtgtgtgtg cagaactgct tctgagtgtc cttggccagg cagaagtgtg 9900
tgactggcct ctgtgactca gctgccagta ggggctccat ggacagaccc tcccagggaa 9960
acctccacct tgctgaggcg gggctgtgtg gtatagtggt taaggagaga ttagctttga 10020
agcctgggcc tgaatgagga gcacagttta ctagctgggg gacttgggcg agtcaggtta 10080
atctctctga gcctcagttt cctgatccat aaaaaggggt gacagtgcag tgcgtccctc 10140
ctaggacaga atccctggtg caagtctgac aggccactct gtccacttca cacacgtcca 10200
taggaccaac accagcatct taagatcaaa tgatccctgg gtttcctttt gcctatagaa 10260
gaactgaaat gcagatgagg aaataactta tccatggcca caaatccagc aaattaggtg 10320
tcccccaccc ccaccccagg acccaccctt aaacagcccc ttctgcctga gtgccgagaa 10380
gacagtctct cagaggcaga ggtagcaatg gctgaaggca gtgtagggct gactgttgca 10440
ggaagggtac aaggtgagga tgccagtgtc tggggacatg gggcagccac ctagcaatgc 10500
ttaccatgga ttcatcaccc gtccagttct cactgtctgg aggggcttcc tcccaacctc 10560
cctcctcagg ccagtgggcc ctttctctct ccctttgctt cagggtcgat cgggtctatt 10620
ttctttgtcc ccaaactttc cttcccctct ccaagaatca tggaaggaaa gtttgcccag 10680
gacgtccaga ccttgagagg gtcttcaaca cgtcttgcta aagttgtagc tctggataag 10740
agtgtctgga gcccttgagg tacaagagag gatttttcat tctctctgtg tggtcctagg 10800
catgcttctt ctctcttggc ctccttcccc caccccctgt gagaaacgga gtgaatacca 10860
ttgcttctct accttcagtg tgttggtaaa ttgtcatcaa ttatcagcta tcaaaaaggg 10920
ggaggggaaa ttctgattta gttttatgtt ggtttggttt ttgttttttt taggacaggg 10980
tctcactatt cagccttagc tatcctggaa ctcactatgt agaccaggct ggccttgaat 11040
ccatagagat ctacctgctt ctgcctcccc tgtgctggga ttaaaggtgt gtgccaacac 11100
attaggcagc attctggttg ataatgtgtg agatttttgc atgggcagct atgtagctat 11160
ggccagtttg cctttatttt gctgaatgtg gaattggaag tgatggattc agtttgctcc 11220
ctaaagcact ggctccagta tgctgtgttc actgtccaca gggacagagg cgagaagaga 11280
tagcaaagat aaaaagcatg caacttggac ttctgagtgt tccaatgatg cgggtctatg 11340
atgattatgg tcttgcggta gaagggaatt tgacccacat cttcctccat agtctcctgt 11400
ccaggaagga gacatagggt gggcagatga cagttctgag tggcggcata tgtgctctga 11460
accggctccc agagattctg gatttgggag aaggggagaa gaggaaggag atgagaagtc 11520
agtttgctga cactggcgca caggcaatac actgttctgt gaaaccagac gaggtgggct 11580
caaggtttga caacaaaagg ttccttctaa gttcataggc cactatcagg acactggagc 11640
cagcatggat gcttcctggg ggatccaaag cagtagggac accctatcca ttccatttca 11700
ggacattgaa gtttctgcag ccactggctc tactgcaggg gaatgaacaa aatggcctca 11760
gaggcccgag tcaagaggaa gttcagtcgg tggaggaagc ttatgacagg gagatgggtg 11820
ggggtgggga gaagacagga aagggcaaga aaaggtggtt ccctccccca caccagagcc 11880
catgccttaa attaactctg tcccactgct aattattaat aatagctatc atttattgag 11940
tatgtactgt gaggtaagct atttacaagc aatatttcat ccaatcctcc aaagaggtat 12000
gtattatcag ctccatttta cagaggagga aactgaggcc cagggaagga agttaaataa 12060
tgtgtccaac caaattctca ccctgatcat gattcagacc caaacctgac taccaagttg 12120
ggagctttaa gaactccaca cctctctctc tcccctctct gtgctgaaag gaccctcccc 12180
aaacattaac taggggccct ttgtccagcc cttgaagctg gtgacccttt aggataaagt 12240
tgattgaggg ctcacatttc ctagacagtg tggctttaga aaactcagtt catttcttga 12300
agggactcat ggtcactgag ctaggcgtca gtacttacag aacccaccca gaagaaaacc 12360
tgggtgagga ccactctggg acatctgtat ccccaatgca aatcaaggag agcctatgaa 12420
ccctgcaaag acaagcttag gtcctggaaa aaagggtggg ggttttcaga gccagagtct 12480
gttagtcctg gctaggaaca gaaggccttt gatgtacagg cgctctgcct ggggcttata 12540
caaatagctc catctaagga tgagggattg cagagtgagg cagaggtgct actaaacaag 12600
acagaacttt gagaggggaa ggcccagcta gagctcaggt tcgagtcagt aaagcagggc 12660
tggtgtctga gtcttccggg aggtcatgat aaatgaagac caggcaggca ggagaggcca 12720
gcaagggcag ctgctaccag gggacagcgt catctgcacc tctctcctag actatgaggc 12780
ctgaagcaac aagactgtca tggaaactgt agagcctgga attagaggcc tttggggaca 12840
gctacattta gccaactgaa gccagagata tgaggtgtgt ccccggccat tttctgggta 12900
tcagcaccat accacttaat cttcaagagg tcctagtgag ataggtctac acacctcatt 12960
tctcagacgg agaaagtgaa atatagactt acatagtgtg ttcaaaaatc acagaggcag 13020
aacgtgacaa ggcttggaac taaagtcaga tttgcctcaa gcccaaccat tactgttctc 13080
cctcctgggg ctgcagagcc tgaaatgggg agaaaaagcc cccggcctca cacctggagg 13140
gagatgagat tgtatttgga tggcgtcaag ttcacacgac accacctcct ctgggaaagg 13200
cagctctgag ccaggatgag gcatggcagg caggcctgag ctgtccaggg aacaggggcc 13260
agggcaggca gtcatgcaaa gccagagatg gggtgtcctc acccctacct gctcccttga 13320
agtgtccagt tacagccagc tccacgcttc cccgtcacgc cacatttagc attgctgaga 13380
gtgagcctgc gcagggatat agagaagggg tggtagggac tctttgaggg gtgggagaga 13440
acctccccac cttcaaaccc atctacactt acttcagcca ccagccgcct cccagcctaa 13500
tcctatgtgg gactctggac aggttccctt ccctctttga caccattagc ctctctgaag 13560
atggctaatt catcaaagat gtgtcaactg ctgactaggc caaactcaga aagatgaggc 13620
ctgccctctc tcccagattt cccagaactg caccactgct gtgacttgag gggtcttggg 13680
tagatggcat aagtcgaaag ctctggtttt tatttctgtt tggctcccag aacattccac 13740
tctgactccc atcaaataca gtagcggggg gtgggggggt agccaaagct tagttcaggt 13800
tctgacagtc aagggttata tgtgagactg ggaggtcacg gaatccctca gggcctcagt 13860
tctcttattt gaaagactgg attaataata tggcatcctt gaagtaaagc aatgagcttg 13920
ggcctgctta taatgccagc ccttgggcag ctgaggtcaa tagtttgtcg atagaggcag 13980
agggctgcct atagttcctg gcctatgtag tgagtttcag gccagcatag actatatggc 14040
gagagcctgt cgcacacctt taatcccagc acttgggagg cagaggcagg tggatttctg 14100
agtccgaggc cagcctggtc tacaaagtga gttccaggac aaccagggct acacagagaa 14160
accctgtctt gaaaaaccaa aaaaaacaat aggggcgggc tggagagatg gctcagtagg 14220
tgagagcact gactgctctt ccagagatcc tgagttcaaa tcccagcatc tacatggtgg 14280
ctcacaacca tcgagatctg acgccctctt ctggtgtgtc tgtagacagc tacttacata 14340
taataaataa ataaatctta aaaaaaaaaa aaaaccaata ggggctacag attttcactg 14400
agtaaagcaa ctatcaggaa gccctaggtc agaacccaaa actgagcaca aaggtccgtg 14460
tccataatcc cagcacgtgg gaggtggaga aaagcagaaa cctaaggtca tcttcagcag 14520
gtggaaaacc ttccaaagtg ctacccagga gtcagtacag agcagtccct cggtaaacaa 14580
tggctgctgt cagggatgaa ctcagggacg tgagttcaaa ggctgttgct gataatggaa 14640
gagccccagg gataacacca ttaataatga gacctggcgt gtggatcaag ccctgtgtgc 14700
ttgtgctgtg ctccgagctt tctctgcatg atttcatttc actctcagcg ccctgtgcga 14760
ggctctgtca ctcatcttgt ttgcagatgc tgctgtggaa gtgcagagag ctctgctgac 14820
acagcctgga atggacagcc tcgcctggcg ctgagcccca aggcctccca gctgctctgt 14880
ggtgctgggt cagggttcta caacaacagt tcagaagggg tcagtgctca gatctagtcc 14940
aagccttagc atttcatagg caagctgaag agttcagaaa gaggccaggg atgggagcca 15000
gggagcatcc tgggaggcag tgggctcgat cccacacaga acagggaagg agaggagaag 15060
agaggggcta aggaaatgag acgtgcttgg tacaaagtca cggacaaaga ttgatagagg 15120
ttaaaaaaac aacacttccc agatatccca cgggccctac cagcaaggcc ccttggtcat 15180
cccacagggt taccctctgt gtcattggga ttgctgtcac ataaagccta ggcatgatac 15240
atctcctgac tcctcctctt ctcagggcct acccagcaac tgataaggtc accttgcata 15300
gacataggaa acctagcagc caggctccct gggaagcaag ggctcactga ctcactgact 15360
gaccaggtca cttgctgacc agcaaagctt gagttgagac aggagctctc ctccgagtat 15420
ccaatctggc tcagtttctc tctcatgata gctctttcct catcctcttc agcatttgcc 15480
taccagcatg taacaatttc tcaccttggc tatctatcta tcatctgtct gtctgactgt 15540
ctgtctatca tctcttccct tctctcccta tgtccctaat ccgatggcta gctccagcca 15600
gggtcccagt ccagggaaag ggtaggaatg gaggtggtgg gcctggggtt ggccatgcct 15660
agacgttggt cctcattctc attgtagctg gctttcttcg aggccaggac tgggtgatgg 15720
tgtcgctact ccctccgcag tctgacgtca cacttccagg ctccacccga ctggagggcg 15780
aaccccaagg ggacctcatg caggctccgg gcctcccaga ctcccctgcc ccacagaacg 15840
taagtacctg gaacctaggc ctggaatagg gcaagcctgg tagctctaag agcattgagt 15900
agatggtcac tgccccacac aaggaccttc gggatctact ttgtccctta cacagaaaaa 15960
atgatgatga ctctagaccc agaagggcca agtcacagat ctctgtccat ccttggtttg 16020
gtgtttcccc agatatggaa cccatcagcc tcaggggacc caggtttaga agaagtatgc 16080
ttgtatcaga ttggaatccc aagagcaggt tgccttcccc gtcactttgg gactcctgtg 16140
aactcagcca tactctatta tctcagtaca gcacagggtc ctggcagatg ccctggtcca 16200
acccccattt acagattctc tattctgtct gcccagaagc atgctaactt cagctgctcg 16260
tcgtttgtgc ctgacggccc tccagagagg acaccctcac tgcccccaca cagccccagc 16320
atcgcatctc cagacccaga gcagatccag ggccactgca cagccggacc cggcccgggc 16380
tccttccgcc tttctccttc agaaaagtat cctggctttg gctttgagga gggcccagca 16440
ggcagcccag ggcgcttcct caagggcaac cacatgcctt tccaccccta caagaggcac 16500
ttccatgagg acatcttctc tgaggcccag acggccatgg cacttgatgg acactccttt 16560
aagactcagg gggcactgga agcctttgag gagatccctg tggacatggg cgatgctgag 16620
gccttcctgc ctagcttccc agcagaggct tggtgcaata aactccctta ccccagccag 16680
gaacacaacc aaattctggt gagtgccagt ggccgagggc cttccacctc ctctctccta 16740
gctgcctaga aagactcttc aaagccatgc ctggtggcac atgcctgtaa tcctactact 16800
caggaggctg aggcaggagg actgcttgag gcagaggcca gcctctgcct atgtatggag 16860
accctgtctc caaatcagag ctccagagga ggcagcaagc acagagggtg ggggcctcct 16920
ggttccatac tggtcccctg gggaggggga tgctagcctg gcaggcgtgg agagggcagg 16980
tggagggggc aggtgaggga agctcatgag ggaagggagc tggcagcttc ccagaggctg 17040
ctgagtcaag attccagagg gtgacttctc tgtttattta agtgtcaaag aatgccaagc 17100
cagaccaaca cacccctatg caaatgtgag gaggaaaaga cacattccag agagagaagg 17160
ttctagacag agcatcagaa caaaaacccc accaaataag gactggggac ttcactgcta 17220
gctccaggcc ccttccagac cctgcttttt tatttatttt catgggtgag acagaaaaca 17280
gctatgttgc ctaaggccgt ccatgaacta gagatcctcc tggtgctgga attactggtg 17340
gggttctgga cctattctaa ggccagagca ggcttctatg gataagtgcc ttgggacacc 17400
tcagaaggtt gactagcact tccgcagcca gatctgcagg ccctgtgacc tcgggcaagt 17460
cacttaatct ctctgagcct cgtgggaaaa gttctgttaa gggtttcctg tctcaggctt 17520
gccccctgct cccgatctct gattcccaag gcaccccagt gtgataattc atcctggact 17580
ctgctcctcc aggggtccac cggccttctt tacctcctac ttccaaatag gcccattcta 17640
gtccttagcc acacctatca ggaaggaaga gggggaaaac agatgaacac ccaggtgggt 17700
caggtgtggc caagacagga tcttctgctg tttctggagc catgactgct ttttctcaag 17760
cctttagaat gtggtgggag ccacagcttg gcacccagaa agccagcagt tgtcccccat 17820
tgtccactcg ttgtagctcc ttgtcactca gccaggagat ttccttccag ggttgcatca 17880
atagagttct cactatctcc atcttgagaa tcaggacccg gccctctctg gttgaggcct 17940
tatgacttac caggacatcc acaacctata aacagaagtc cacctggccc catggacaca 18000
agctgtaccc aactgcctgg tccactctat gggtgacagg tgccatgtag tttcccctct 18060
ttgggagcag ctgtatcatc tgtgaaatga aggggttgga ctcagtgctt gtggcccttg 18120
caggctcaag atcctgtgat tacggcaatc tctgcatcag ctgccctgag gcatacccag 18180
aaagtggtca cagctagctt tcacccctct gggcccaaat gctgccttcc caaaggcccg 18240
tgggaatcct agtttcagga gcctgatcct ggcttgtcta tctgccaggt aggtctgagc 18300
cgcacgccct tgctaactct atgcagggct cagctctggg ttaggccctg aggacttcac 18360
atgggtctct cagaactctc gggtcccatt caagtctatg tgacaagtcc cctccatttc 18420
tcttggtggc ccagactagc ctgccgcctg cagtgaggtg gaatgtgagg aacactgtcc 18480
tttctagcct agcccctcta ctgacttgct gatttccctc aggaaaaccc ctatccatct 18540
ctgttctctg ttccttgcct aagagttagc tttgagaggg tcacagaaag gattcttcca 18600
gtgtgaagtt caagacaaga aaaagaaatg gaggcccgtc attggtggtg cacatcttta 18660
atcccagcac ttgggaggca gaggcaggca gatttctgag tttgaggtca gcctggtcta 18720
caaagtgagt tccaggacag ccagggctac acagagaaac cgtgcctcaa aaaagaaaaa 18780
aaaaaaaaag aagaagaaga agaagggggg aaactttctt ttccactttt ccagcagggg 18840
tcagaggtca aggtcaagcc ccaagctctg gacagtggtc ctgggatgta ctgctaccag 18900
cctcccttgc aacatatgta ctgttcttct cagcctgcct tccatcaggt aagtctgagg 18960
caagtggtta tactccctgg agctctcaga aggctctgtg ggtgtcgctg tgggcagtgt 19020
acgtgaggac aggcaggtga agatatcaga gtcctgaacc tcaggctggg ctagcccaga 19080
tatagaacag tggctagtgg gaagagaaac catttccctt tcctaggggc ttacagactt 19140
ttctgaaccc ctggtggagg ctagggagtc tcaaacagaa agtgcagccg agactgaggc 19200
agagacatgg tgtgaaccaa agagggaggg gaggagaatc gagaagcatc ctagacagac 19260
aggagcaaag aggggtgtgt ggtatgacac actggctgag cagggacggg aacaaaggct 19320
cccatcgagg tcacaccttg ctgtgtgacc ttgtccttac acttccctta ggcagagagt 19380
ggtgggcaca agcgcgaggc tggggtcctc cctagtcttt accatccttg cccttcccca 19440
ctccactgcc cagtttagcc tctccaggat ggatgagatt ctcaatcatt gccccacact 19500
ggcaagggat ggaggatttt ttagaagaga cagaagagag ccccagagca gccaggcagc 19560
tcccttggag tcaccgggca agacagagca agtggctgcc cagcgcccag ctccatccac 19620
ctgcagcctg gcactcagac aggccctgcc tgtggagcag gttctactcc cgctctggca 19680
ttggccctga tcctggccaa gccaggaggc aggctggcgg gggggggggg ggtaatgtgt 19740
caggttgcct gtagtgggta caagtgacag agagggacaa agagacatat cacatgaggg 19800
ggcatccttg tcttttagaa agggcctcgc tgcaaaggcc taaacttttc tgaggtttct 19860
ggtctgattc agggcgcgtg tgtccctaag gcagtctgcc acatcaggga ccaagtcacc 19920
acagcataaa ggtgatcgga cgctaagtgc ccttgctctg cccagccctg ctttgaagcc 19980
ctctgcagtc aacgtccttg aacaagatgg ccgcgcccag ggctttatgg agcccagaga 20040
gagggtgact caggcactaa gtgtctttcg gtgacctgga aagaacactt cagcctggag 20100
cagctggggg agtcagagtc tccaaccccc agcccccata aaacaccatt cctggcaccg 20160
cagccactcc ctctgccgtg taaaactacc tcctaccccc acctgcccac catcatgacc 20220
tgctctttca aagagccact gaaactcata aaggtggccg tgcctagaac acacccaggc 20280
tggacatctc acttccggcc cattgctcca agagaggccc aggagaggag gcttggggtg 20340
cctgcctgga aagtgcagag ggtgggcttt tcaccatcct attaccatga cgaccagggt 20400
acctcaaagc ctgagaggca agagctggag gaaaacagct tcgatacctt tgagagtctg 20460
agttctagag tgtggatctc tatccaagtc caaaatgtcc attccattgc tccatagcat 20520
tgggaatatc gtcgggtcca tggccaatgg aaggagaatc tggcttcagc ttcctctcca 20580
gacgtgtctg catgaggagg ggttccccac ttgggaaggc atcatggtga ccactctgtc 20640
ccttttggcc cctacagtac tccccgggtg gaggcagcta ccctgtgccc tacctgggct 20700
cacctcacta tccctatcag aggattgcac cccaggccaa cgccgaaggt caccagccac 20760
tcttcccaaa gcccatctac tcttacaggt acatatccta gcacaactgg ggcagaacta 20820
ggagcaagga ggggccctgg gaaagctaag gtacggtgat cctcatcact taagggttat 20880
tgcaggggat agaaatcacg cccagtaact tccaaggatg ctggagaaac gatgcccgag 20940
ggtgggtagg tagtagctac ctttgacctt ttgtcagacc ctgaggagtc ttaactctgg 21000
ttggactcag tagatgctgc tgacttgggc gggtgggcct gtgaggtccc atgctggagc 21060
cctggtcata gagtttaggt gggagattaa gagagctgct cgctgctcat tgcctttccc 21120
ctcttccaac attaaagcaa aaccctctaa cagctgccct gctacttact aactgagaaa 21180
ctggttgtct ggaaggcaaa tggggagaca agccaggcta tttgaagttt tatgtaagag 21240
aatgtgggca gaacagtgtg tggcacccag caggaagcct tgtccccttc ctattgtctc 21300
acagaagcac gaggagctgt gggctgagtg gtcagggtca cttccgtgca atgatggatg 21360
caaagcctcc atccccacgg ctctgaggag gccagctact gtatttttgt catttcaaaa 21420
ctaaggaaac ggactcaaaa gagaggttca gacaagctca cacatctagg ggctaagcca 21480
ggcggcaaac tggttttcca gattccacaa aatgctcgta gatttcagtc tcagcctcac 21540
agaacgtgtc ggccaaggag agctgaagat ggaggcctgg tcaggagggc tgggctctca 21600
ggatctctct tttgcagcat cctcatcttc atggccctta agaacagtaa gaccggaagc 21660
cttccagtca gtgaaatcta caatttcatg acggagcact tcccttactt caaggtgagt 21720
ctaaaaccca cccttgcccc cagcccagca tgaaagcagt aggggtttgg ccctaagatg 21780
ctttctctct gtgtccgtgg tgaaatgcaa agctcccaag ggggctggat ttttcaggac 21840
tgcacatgac ttaaagagag agaatcacct cacatctacc aggcccaagg ctccatcctc 21900
catagcaaaa gggggggggg ggggactgtg aacagagagc tctagctgct tgctctggga 21960
tacacagcaa ttgagaggag ctggagaagg ggttgggggg agtcctgaca ggcttcggag 22020
ctcagctact tacctcccaa ttgagagagg aaggcaagtg atggaagtct tttccggcct 22080
cagacagggt gctatctatg gggctggagg aattccaagt cagagctgat cactaaggtg 22140
acgatcgatt gccttccaga gtgagattaa catctgcctc tagaggtggc atggcgagct 22200
tcacttgtac ccaaaagtgg ggctcacagt cttggggtgt cccaaggatt gagcgggttc 22260
tcccccaaac ccatgggcag cattaattat ttcctagtct ccacggaaga gacttcaggc 22320
aactcccagc agtttcttcc cagtagccct gggacaggag gactgagagg gaccctgggg 22380
aaactgaggc atgagattta tcaatatgta acagttacag ttgcatgagg tggaggtcca 22440
acccagtaga tttttcaaat gtcctacaag atttctacac aggggttggg ggtaagaatc 22500
gatcatccct gacccttgat ctaaccctga ggagtcatgt ctgtctctgg gtgagcctgc 22560
tgaagtccaa cctcctgggg acatgacaga tacccttcta tccaggtgag caaatttgtc 22620
agagggcggt ttatccttct aagatcacac agcagatgga ccaattgttg ggtcaagaaa 22680
aacacaccct tatcccttga tacatgtccc ctgagaccct cttgcacaga caccttctcc 22740
tgaggtaggt gcaggagaga caagatcttt tgttggggaa tccggtcccc aggacttaca 22800
cccttgtcaa cactgtctca cctactaacc aggcaagaca gatgctgagg tgcaggtgat 22860
ccagagccag ctctgtgggc aggggcgatt cctgccccca actatctgca ctatagtctg 22920
gcccggggac aggttgctag tgtgcagaca gctttgcacc tgctgtgctc ccagcagaca 22980
gggagtggga aaaaacatct tgcagcatgg ctttggctgg aatggaaatg tccacagact 23040
tgaggttctg ggagcgagaa acaccatagt ctggatgggc tgttcctgaa tcccagactc 23100
tccaggtaga gataggcgct cccctcctcc taaggtgaca gcaaagtcct ccaaaaacta 23160
aacagagaaa gggaggcgag gcccctccct ctcctctggg ccttcttccc tgcccactcc 23220
tggccttacc cccagcccct ccctgcatct catcttcctg gcttaattat ttttcctggg 23280
agccgtgtaa tccctgtttt atgggactga agagtgaaga ggtctgacag ctttttcggt 23340
tcggttgttt ttcttagccg gttgcatcac ccctgcatgc cagagtttac atttgacttc 23400
agagagactg tgtgaggatc tgaccagccc cattggcaag gcaggccccc acgggaatga 23460
cctgggcaag gccctcagct aaggaacagg gctgaagtcc atacccggtt atcgttttcc 23520
tcatgtgatc caaggccagc tgttttcttc tctgggcctc agcttccctc tctgtaacat 23580
gtcagtttgg acgagttggt acctagattc cttctaagcc aacaggttct cttcgaacct 23640
ctccaaagag agagttccaa ggctctaaac ctctcagtcc ttatttggaa gtcatttttt 23700
agggcaaaga cagagtggac tctgaagtgg tcagtactca cacccaaggc agctactgtg 23760
ggcgtcccat agttccatga gtcaggggct gaggaagtgt ccagccacca tgcataattg 23820
ttaatgctga ccatccctct tccaaacagg aagtggctgc ggtgggggct gccctggcat 23880
ccgaagtcac acatttatgg gaccataaaa gttcccggtg cccattaagt ctgctctggg 23940
gtgatggagc tttggttctt agtagagtca gctgtgggag cttaagaagg tccagcagct 24000
caagatgctc gctggtaacc cctgatgaac cttggggtca tcaggaccag ccccatgatg 24060
ggttagctgt ccccaagaaa ggctccggca gctgctgcca gcaactctag tgagactggc 24120
atcaggaccc agggcccggt tctgctaggc gtgattcagc ttggctgcac cctggggcaa 24180
gggagctagg gaggagggcg tggccatctc tcattaacca gaaagagggg ctgaaagcga 24240
gaggagccag ggtgtaagga agtatcatca actggagagg tagctctacc caccgccagc 24300
cctcgtcggg ctcagggtgg tcaactgagc cagatgtggg ggacaggagg cccatgcccc 24360
tccaccacca tccctgccac cgcctctcac ccaactgagt cagcttaatg gtttttacaa 24420
ccctccttgg gcacaattac tgcactggtg gcatgaccgg gcctcctaat gggtgtttat 24480
tctgttggca cgagcacccc ctgcctgagg gctggcctcc ccaccagggc acacctccag 24540
ggcacactca tgcgaactca cacccacaca ctcaatcatg ggtacacacg tactctgaga 24600
tactttctca cacatagcca tcctcactca ggagttcaga gacctatggt aggagacgcc 24660
actcccaccg agagatgtcg aaggatctgg tgaatattca gtcacatacg actaccccag 24720
cctctaccaa caccgcatct gccatcaaac atagaggcag caggtgtgct aactcccacc 24780
tgttcaccaa cccttttctg cccagcttgc tctggaggga tgaggtggac ccagaggaaa 24840
cgcattatgc tgttctccct ttaaagctgt ccccaaagac tttaaaatgg cgatcttccc 24900
ctttctacaa ggggacacat aggccagaag gcccagtgag catatcctgc ttcagtgggg 24960
aaatagacca ggggcctcaa tggcatttac cagttgtccc ttaaagaaag atcacaagtt 25020
ggacattgtg acttatgcct gctgcaatct cagcacccaa gagactctga gcatcttact 25080
gtgagcctgg actacaagtg aggtcccatc tccaaaagga gtggtggcta acaaatatcg 25140
gagagagctg gggggggggt gcacaccttt aatcccagca ctcgggaggc agaaggcagg 25200
gggatctctg aacttgaggt cagtctggtc cacaaagtga gttctaggac agccaggact 25260
atacagagaa accttgtctc aaaaaagaac ccccaaaaca aacaaacaag caaacaaaaa 25320
caaacaaaca agcaaacaag caaacaaaaa caataaaagc agtgaggtgg tggttaagaa 25380
cactggctgc tcttgcagag gacttgaatt cagttcccag ccccacatgg tggtttacaa 25440
actatctata actccagttc caggagattc agtgccctct ttgacagact cctgtatgca 25500
tgtggtgcat agacagacat acaggcaccc acatgtacac ataaagtgca taataaatat 25560
acaaagggtc acatcctctg aagggtctag actaagagct aggtagggta acagcagctt 25620
ttagatttta gctaaaaaaa aactaactta ggccaggcag tggtggtgca cgcctttaat 25680
cccagcactt gggaggcaga ggctggtgga tttctgagtt cgaggtcagc ctggtctaca 25740
gagtgagttc caggacagcc agggctatac agagaaaccc tgtctcgaaa aaccaaacca 25800
aaccaaacca aaccaaacaa accaaaaaac aaaaactaac ttaggatcaa cgattctgcc 25860
cactaaaggg ttctacgaat gcttttggag ctgaatacat caagccagag tgtgtagaga 25920
ccctatgtat agaattggcg aaggaatgtt ctagaatccc cagacctaga gccatttctt 25980
gccgcctgaa cccaacctgg attcttgttc tgctctggta gactgctcct gatggctgga 26040
agaattctgt tcgccataac ctgtccctca acaagtgctt tgagaaggtg gagaataaat 26100
ccggaagttc ctctcgaaag ggctgtctgt gggccctcaa tccttccaaa atcgacaaga 26160
tgcaggaaga actgcagaag tggaagagga aagaccccat tgctgtgcgc aaaagcatgg 26220
ccaaaccagg tgaggctgtc aggcctgtgt gagaaaggcc aagggacctg ggtaccagaa 26280
tgaagaagag cagagcctgg ggagagaggg atacagggag gggggtctgg gctgggaggc 26340
tacaaaggag agaggcctca tggtgttttc ttttgggcct ttgcagaaga gctggacagc 26400
ctcattggag acaaaaggga aaaactgggc tctccgctgc tgggctgtcc accccctggg 26460
ctggcaggcc caggtcccat ccggcccatg gcaccatcag ctggtctttc ccagcctctg 26520
cacccaatgc atccagctcc aggccccatg cctggcaaga accccctgca ggacctactg 26580
ggtggccatg ctccctcctg ctatgggcag acctacccac acctttcccc cagcctggcc 26640
ccttctggac accagcagcc attgttccca cagccagatg ggcatcttga gctgcaggcc 26700
cagccaggca ccccccagga ctcacctcta cctgcccaca caccacccag ccacggtgcc 26760
aagctgatgg ctgagccttc ctcagccagg accatgcacg atactctact gccagatgga 26820
gaccttggga ctgacctgga tgctatcaac ccttctctca ctgacttcga cttccagggt 26880
gagctgggag ctgggagctg ggaagggtgg gacaggacta gagaggtgct cttggctgcg 26940
tggcctagcc tcttcatgtc tctaggctgc cacctgctgg ctcctgagtt tcttgtcacc 27000
tgaggcggat gactaggaat gttaaattcg catttgctcc ctgccctcca gatcatgagc 27060
taaaaggctc tttcccccat ctcccccctc ctggtactct gatcatgtac cagatggctt 27120
catcatcaaa ccgctcatct gacaaagctg ggaaaagccg gaagttccat tggtgtactt 27180
gactgtgagg gactgggagg ctaaacgttc caaaatcatt tgcgttttat cagaatttag 27240
ctttcacttc aggagacaga ctttctatgg aatggaagac ctcagagcta agcatgtcct 27300
agagagattt gagggtacaa gcccagagag gtgaatcttt acattctcct ccatcttgcc 27360
cgctccatcc tacaggcagc caagccccac cctctaccct tctaagcccc gccccttccc 27420
gtttgaactg tagtgtaccg agcaagcctt tttggaggag gctgttgatc tataccttag 27480
actgttagaa ataaacttca catagacctt cattccagac ctgctgcggc tgcagagaac 27540
aggcggctgc agaggaggct atgtggacgt gggatactat aaattctatc agaaggctag 27600
agatgtgggt agggggtaaa gcgtttgcct agcatgcacc aatccttagt tagggtcaat 27660
accccagcat cacaaaaccc ttaattaata cccactcaag ctcctactga gtaccaggca 27720
tcttgcaaac agctttacat atgttcttcc catctggacc tagcaaacaa tactatacag 27780
agagatacat ccactcaagg tcgctgggcc agaaagaagg agttgaaccc aggtggccaa 27840
gagcagccag cgttgtcagg tctctttctc caccctgcgg tgatgatgtt ccaggcagcg 27900
actccagtca ctggcctgcc acgcggcagg tcacacgacc ctaggaggaa ctcagtgaca 27960
gcactgtttg ttcctcagag tcaagtgtcc tttctggttc tatccctgta ccttgggtcc 28020
tgtgaggggg cggggaggag ggtctaggga gccagacctg tgtacctcat caagttcggt 28080
ggtgcactgt gggaagactg taggcggcaa atcaaccttt gggaaccaag gcagaagcct 28140
gagtgaagag gttcaggggg gcctctaggc cgcttccaag aagagctttg caacaacctt 28200
caaatgggca aatccttaac cttaatctag taccctgttc ttctcgaaga ggcccagagg 28260
ttacctgcaa ctatggcagt ggttctcaac ctctgggtcg cgaccccgat ggaaagtctg 28320
atgacccttt cataggggtc gcctgcatct atggctttta caccgtgcta ccttggagct 28380
cggagctgga ctctgaggct caggaaaaaa aaaaaaaagt tcagtgatta cttgaggtcc 28440
cagagtggat gccaagatag gcttccagtc cgcatcacca gactcctgtt ctctgaggct 28500
tctgaggtac ttgggtggga gacagactgg gcttaactct ctatggcctg ccaatgatga 28560
ggcttcttcc ctctccccga ctaggaaatc tgtgggagca gctgaaggat gacagcttgg 28620
ccctggaccc cctcgtattg gtgacctcgt cgccgacgtc atcctccatg ttgccacccc 28680
caccagcagc ccattgcttc cccccagggc cttgtctggc agaaacaggc aatgaggcag 28740
gtgaactggc acctccaggc agcggcggct ccggtgctct gggagacatg cacctcagca 28800
ctctctactc cgcctttgtg gaactggagt ccacgccctc ctcagcagct gccggccctg 28860
ccgtgtacct cagtcccggc tcaaagccat tggctctggc ttgagctatg cccaacatca 28920
gctgcggcct ttgcctagct ggctgcccca tattgggctc accttaaagg tcaaagaagg 28980
aaaacactac ctgtctccta tgccactcag ccaacttatt tgttagccag aagttggggg 29040
catccatcta ggatgctacc tggtggaccc gcatctcaca cggggccccc agcaaggaaa 29100
gtgtcggaaa agaagcaaca gcgcgccccc tagcgccagc tcactcgaac ttcagctctc 29160
gagcgtgaac tcaagctcta cacacctgct catcatgtgc cttacactca gaggaagcct 29220
tgggtcacag agtctgattt gatttctggg gcagctgaga gctaaaagct ttagttagca 29280
aagctcaggg ccagtgtgac aggtcaaaga tcacccctcc aaacctcatc ccaatcccca 29340
tgtgctctac agacttggcc ctctcccaga aatctctatt tattctccca tcttacaccc 29400
ttaaagccta caggggctcc tcccgtatga cctgtgaacc ccttagggag acaactactt 29460
catagaattt atctatacat cttcagtata tactctggtt ggccatctcc aaggtgacac 29520
acagaagggg cagcatctac cctgggacca aactgagccc aaatccaaca caacatgttt 29580
ggaaaaaaaa aaaaaaactt gtcctcagaa acttgaaccc cctctcttag tctcagccac 29640
aggaaaggcc cccttcaggt tgccaagtct cactctttct caatgagagg ttcatatagt 29700
tcaagcccca gcctattgga tgcggtcaac tgtcttaagc atcctgagta actagggttt 29760
gcaacccgct acaggatgat gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gatacccccc 29820
cacacacaca cacacataca cacacctgca tagcagactt ggggctccca gggagccggc 29880
agaatgtccg tggagctgag ctgtgactca gatgcccacc atgacccacc aaatgggatc 29940
cccagctttc ccagggcctg agggcaacca gaacctccat aggttgtccc caagctcaca 30000
cgagggtggg cggatccctc agtcatctac cattgtcccc tgtcctggaa caataaagta 30060
agcgcctgat ggttgcaa 30078
<210> 27
<211> 3270
<212> RNA
<213> 小鼠(Mouse)
<400> 27
ccctcacctg atgtcagccc agacccagga caatcaggct gacggactga cagacggtcg 60
gagctcctgg ccccccagac ccaggccccc acgccgacct gcttcactga gcagctggct 120
ttcttcgagg ccaggactgg gtgatggtgt cgctactccc tccgcagtct gacgtcacac 180
ttccaggctc cacccgactg gagggcgaac cccaagggga cctcatgcag gctccgggcc 240
tcccagactc ccctgcccca cagaaccatg ctaacttcag ctgctcgtcg tttgtgcctg 300
acggccctcc agagaggaca ccctcactgc ccccacacag ccccagcatc gcatctccag 360
acccagagca gatccagggc cactgcacag ccggacccgg cccgggctcc ttccgccttt 420
ctccttcaga aaagtatcct ggctttggct ttgaggaggg cccagcaggc agcccagggc 480
gcttcctcaa gggcaaccac atgcctttcc acccctacaa gaggcacttc catgaggaca 540
tcttctctga ggcccagacg gccatggcac ttgatggaca ctcctttaag actcaggggg 600
cactggaagc ctttgaggag atccctgtgg acatgggcga tgctgaggcc ttcctgccta 660
gcttcccagc agaggcttgg tgcaataaac tcccttaccc cagccaggaa cacaaccaaa 720
ttctgcaggg gtcagaggtc aaggtcaagc cccaagctct ggacagtggt cctgggatgt 780
actgctacca gcctcccttg caacatatgt actgttcttc tcagcctgcc ttccatcagt 840
actccccggg tggaggcagc taccctgtgc cctacctggg ctcacctcac tatccctatc 900
agaggattgc accccaggcc aacgccgaag gtcaccagcc actcttccca aagcccatct 960
actcttacag catcctcatc ttcatggccc ttaagaacag taagaccgga agccttccag 1020
tcagtgaaat ctacaatttc atgacggagc acttccctta cttcaagact gctcctgatg 1080
gctggaagaa ttctgttcgc cataacctgt ccctcaacaa gtgctttgag aaggtggaga 1140
ataaatccgg aagttcctct cgaaagggct gtctgtgggc cctcaatcct tccaaaatcg 1200
acaagatgca ggaagaactg cagaagtgga agaggaaaga ccccattgct gtgcgcaaaa 1260
gcatggccaa accagaagag ctggacagcc tcattggaga caaaagggaa aaactgggct 1320
ctccgctgct gggctgtcca ccccctgggc tggcaggccc aggtcccatc cggcccatgg 1380
caccatcagc tggtctttcc cagcctctgc acccaatgca tccagctcca ggccccatgc 1440
ctggcaagaa ccccctgcag gacctactgg gtggccatgc tccctcctgc tatgggcaga 1500
cctacccaca cctttccccc agcctggccc cttctggaca ccagcagcca ttgttcccac 1560
agccagatgg gcatcttgag ctgcaggccc agccaggcac cccccaggac tcacctctac 1620
ctgcccacac accacccagc cacggtgcca agctgatggc tgagccttcc tcagccagga 1680
ccatgcacga tactctactg ccagatggag accttgggac tgacctggat gctatcaacc 1740
cttctctcac tgacttcgac ttccagggaa atctgtggga gcagctgaag gatgacagct 1800
tggccctgga ccccctcgta ttggtgacct cgtcgccgac gtcatcctcc atgttgccac 1860
ccccaccagc agcccattgc ttccccccag ggccttgtct ggcagaaaca ggcaatgagg 1920
caggtgaact ggcacctcca ggcagcggcg gctccggtgc tctgggagac atgcacctca 1980
gcactctcta ctccgccttt gtggaactgg agtccacgcc ctcctcagca gctgccggcc 2040
ctgccgtgta cctcagtccc ggctcaaagc cattggctct ggcttgagct atgcccaaca 2100
tcagctgcgg cctttgccta gctggctgcc ccatattggg ctcaccttaa aggtcaaaga 2160
aggaaaacac tacctgtctc ctatgccact cagccaactt atttgttagc cagaagttgg 2220
gggcatccat ctaggatgct acctggtgga cccgcatctc acacggggcc cccagcaagg 2280
aaagtgtcgg aaaagaagca acagcgcgcc ccctagcgcc agctcactcg aacttcagct 2340
ctcgagcgtg aactcaagct ctacacacct gctcatcatg tgccttacac tcagaggaag 2400
ccttgggtca cagagtctga tttgatttct ggggcagctg agagctaaaa gctttagtta 2460
gcaaagctca gggccagtgt gacaggtcaa agatcacccc tccaaacctc atcccaatcc 2520
ccatgtgctc tacagacttg gccctctccc agaaatctct atttattctc ccatcttaca 2580
cccttaaagc ctacaggggc tcctcccgta tgacctgtga accccttagg gagacaacta 2640
cttcatagaa tttatctata catcttcagt atatactctg gttggccatc tccaaggtga 2700
cacacagaag gggcagcatc taccctggga ccaaactgag cccaaatcca acacaacatg 2760
tttggaaaaa aaaaaaaaaa cttgtcctca gaaacttgaa ccccctctct tagtctcagc 2820
cacaggaaag gcccccttca ggttgccaag tctcactctt tctcaatgag aggttcatat 2880
agttcaagcc ccagcctatt ggatgcggtc aactgtctta agcatcctga gtaactaggg 2940
tttgcaaccc gctacaggat gatgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgataccc 3000
ccccacacac acacacacat acacacacct gcatagcaga cttggggctc ccagggagcc 3060
ggcagaatgt ccgtggagct gagctgtgac tcagatgccc accatgaccc accaaatggg 3120
atccccagct ttcccagggc ctgagggcaa ccagaacctc cataggttgt ccccaagctc 3180
acacgagggt gggcggatcc ctcagtcatc taccattgtc ccctgtcctg gaacaataaa 3240
gtaagcgcct gatggttgca aaaaaaaaaa 3270
<210> 28
<211> 647
<212> PRT
<213> 小鼠(Mouse)
<400> 28
Met Val Ser Leu Leu Pro Pro Gln Ser Asp Val Thr Leu Pro Gly Ser
1 5 10 15
Thr Arg Leu Glu Gly Glu Pro Gln Gly Asp Leu Met Gln Ala Pro Gly
20 25 30
Leu Pro Asp Ser Pro Ala Pro Gln Asn His Ala Asn Phe Ser Cys Ser
35 40 45
Ser Phe Val Pro Asp Gly Pro Pro Glu Arg Thr Pro Ser Leu Pro Pro
50 55 60
His Ser Pro Ser Ile Ala Ser Pro Asp Pro Glu Gln Ile Gln Gly His
65 70 75 80
Cys Thr Ala Gly Pro Gly Pro Gly Ser Phe Arg Leu Ser Pro Ser Glu
85 90 95
Lys Tyr Pro Gly Phe Gly Phe Glu Glu Gly Pro Ala Gly Ser Pro Gly
100 105 110
Arg Phe Leu Lys Gly Asn His Met Pro Phe His Pro Tyr Lys Arg His
115 120 125
Phe His Glu Asp Ile Phe Ser Glu Ala Gln Thr Ala Met Ala Leu Asp
130 135 140
Gly His Ser Phe Lys Thr Gln Gly Ala Leu Glu Ala Phe Glu Glu Ile
145 150 155 160
Pro Val Asp Met Gly Asp Ala Glu Ala Phe Leu Pro Ser Phe Pro Ala
165 170 175
Glu Ala Trp Cys Asn Lys Leu Pro Tyr Pro Ser Gln Glu His Asn Gln
180 185 190
Ile Leu Gln Gly Ser Glu Val Lys Val Lys Pro Gln Ala Leu Asp Ser
195 200 205
Gly Pro Gly Met Tyr Cys Tyr Gln Pro Pro Leu Gln His Met Tyr Cys
210 215 220
Ser Ser Gln Pro Ala Phe His Gln Tyr Ser Pro Gly Gly Gly Ser Tyr
225 230 235 240
Pro Val Pro Tyr Leu Gly Ser Pro His Tyr Pro Tyr Gln Arg Ile Ala
245 250 255
Pro Gln Ala Asn Ala Glu Gly His Gln Pro Leu Phe Pro Lys Pro Ile
260 265 270
Tyr Ser Tyr Ser Ile Leu Ile Phe Met Ala Leu Lys Asn Ser Lys Thr
275 280 285
Gly Ser Leu Pro Val Ser Glu Ile Tyr Asn Phe Met Thr Glu His Phe
290 295 300
Pro Tyr Phe Lys Thr Ala Pro Asp Gly Trp Lys Asn Ser Val Arg His
305 310 315 320
Asn Leu Ser Leu Asn Lys Cys Phe Glu Lys Val Glu Asn Lys Ser Gly
325 330 335
Ser Ser Ser Arg Lys Gly Cys Leu Trp Ala Leu Asn Pro Ser Lys Ile
340 345 350
Asp Lys Met Gln Glu Glu Leu Gln Lys Trp Lys Arg Lys Asp Pro Ile
355 360 365
Ala Val Arg Lys Ser Met Ala Lys Pro Glu Glu Leu Asp Ser Leu Ile
370 375 380
Gly Asp Lys Arg Glu Lys Leu Gly Ser Pro Leu Leu Gly Cys Pro Pro
385 390 395 400
Pro Gly Leu Ala Gly Pro Gly Pro Ile Arg Pro Met Ala Pro Ser Ala
405 410 415
Gly Leu Ser Gln Pro Leu His Pro Met His Pro Ala Pro Gly Pro Met
420 425 430
Pro Gly Lys Asn Pro Leu Gln Asp Leu Leu Gly Gly His Ala Pro Ser
435 440 445
Cys Tyr Gly Gln Thr Tyr Pro His Leu Ser Pro Ser Leu Ala Pro Ser
450 455 460
Gly His Gln Gln Pro Leu Phe Pro Gln Pro Asp Gly His Leu Glu Leu
465 470 475 480
Gln Ala Gln Pro Gly Thr Pro Gln Asp Ser Pro Leu Pro Ala His Thr
485 490 495
Pro Pro Ser His Gly Ala Lys Leu Met Ala Glu Pro Ser Ser Ala Arg
500 505 510
Thr Met His Asp Thr Leu Leu Pro Asp Gly Asp Leu Gly Thr Asp Leu
515 520 525
Asp Ala Ile Asn Pro Ser Leu Thr Asp Phe Asp Phe Gln Gly Asn Leu
530 535 540
Trp Glu Gln Leu Lys Asp Asp Ser Leu Ala Leu Asp Pro Leu Val Leu
545 550 555 560
Val Thr Ser Ser Pro Thr Ser Ser Ser Met Leu Pro Pro Pro Pro Ala
565 570 575
Ala His Cys Phe Pro Pro Gly Pro Cys Leu Ala Glu Thr Gly Asn Glu
580 585 590
Ala Gly Glu Leu Ala Pro Pro Gly Ser Gly Gly Ser Gly Ala Leu Gly
595 600 605
Asp Met His Leu Ser Thr Leu Tyr Ser Ala Phe Val Glu Leu Glu Ser
610 615 620
Thr Pro Ser Ser Ala Ala Ala Gly Pro Ala Val Tyr Leu Ser Pro Gly
625 630 635 640
Ser Lys Pro Leu Ala Leu Ala
645
<210> 29
<211> 10192
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 29
gtcctgggat gtactgctac cagcctccct tgcaacatat gtactgttct tctcagcctg 60
ccttccatca ggtaagtctg aggcaagtgg ttatactccc tggagctctc agaaggctct 120
gtgggtgtcg ctgtgggcag tgtacgtgag gacaggcagg tgaagatatc agagtcctga 180
acctcaggct gggctagccc agatatagaa cagtggctag tgggaagaga aaccatttcc 240
ctttcctagg ggcttacaga cttttctgaa cccctggtgg aggctaggga gtctcaaaca 300
gaaagtgcag ccgagactga ggcagagaca tggtgtgaac caaagaggga ggggaggaga 360
atcgagaagc atcctagaca gacaggagca aagaggggtg tgtggtatga cacactggct 420
gagcagggac gggaacaaag gctcccatcg aggtcacacc ttgctgtgtg accttgtcct 480
tacacttccc ttaggcagag agtggtgggc acaagcgcga ggctggggtc ctccctagtc 540
tttaccatcc ttgcccttcc ccactccact gcccagttta gcctctccag gatggatgag 600
attctcaatc attgccccac actggcaagg gatggaggat tttttagaag agacagaaga 660
gagccccaga gcagccaggc agctcccttg gagtcaccgg gcaagacaga gcaagtggct 720
gcccagcgcc cagctccatc cacctgcagc ctggcactca gacaggccct gcctgtggag 780
caggttctac tcccgctctg gcattggccc tgatcctggc caagccagga ggcaggctgg 840
cggggggggg gggggtaatg tgtcaggttg cctgtagtgg gtacaagtga cagagaggga 900
caaagagaca tatcacatga gggggcatcc ttgtctttta gaaagggcct cgctgcaaag 960
gcctaaactt ttctgaggtt tctggtctga ttcagggcgc gtgtgtccct aaggcagtct 1020
gccacatcag ggaccaagtc accacagcat aaaggtgatc ggacgctaag tgcccttgct 1080
ctgcccagcc ctgctttgaa gccctctgca gtcaacgtcc ttgaacaaga tggccgcgcc 1140
cagggcttta tggagcccag agagagggtg actcaggcac taagtgtctt tcggtgacct 1200
ggaaagaaca cttcagcctg gagcagctgg gggagtcaga gtctccaacc cccagccccc 1260
ataaaacacc attcctggca ccgcagccac tccctctgcc gtgtaaaact acctcctacc 1320
cccacctgcc caccatcatg acctgctctt tcaaagagcc actgaaactc ataaaggtgg 1380
ccgtgcctag aacacaccca ggctggacat ctcacttccg gcccattgct ccaagagagg 1440
cccaggagag gaggcttggg gtgcctgcct ggaaagtgca gagggtgggc ttttcaccat 1500
cctattacca tgacgaccag ggtacctcaa agcctgagag gcaagagctg gaggaaaaca 1560
gcttcgatac ctttgagagt ctgagttcta gagtgtggat ctctatccaa gtccaaaatg 1620
tccattccat tgctccatag cattgggaat atcgtcgggt ccatggccaa tggaaggaga 1680
atctggcttc agcttcctct ccagacgtgt ctgcatgagg aggggttccc cacttgggaa 1740
ggcatcatgg tgaccactct gtcccttttg gcccctacag tactccccgg gtggaggcag 1800
ctaccctgtg ccctacctgg gctcacctca ctatccctat cagaggattg caccccaggc 1860
caacgccgaa ggtcaccagc cactcttccc aaagcccatc tactcttaca ggtacatatc 1920
ctagcacaac tggggcagaa ctaggagcaa ggaggggccc tgggaaagct aaggtacggt 1980
gatcctcatc acttaagggt tattgcaggg gatagaaatc acgcccagta acttccaagg 2040
atgctggaga aacgatgccc gagggtgggt aggtagtagc tacctttgac cttttgtcag 2100
accctgagga gtcttaactc tggttggact cagtagatgc tgctgacttg ggcgggtggg 2160
cctgtgaggt cccatgctgg agccctggtc atagagttta ggtgggagat taagagagct 2220
gctcgctgct cattgccttt cccctcttcc aacattaaag caaaaccctc taacagctgc 2280
cctgctactt actaactgag aaactggttg tctggaaggc aaatggggag acaagccagg 2340
ctatttgaag ttttatgtaa gagaatgtgg gcagaacagt gtgtggcacc cagcaggaag 2400
ccttgtcccc ttcctattgt ctcacagaag cacgaggagc tgtgggctga gtggtcaggg 2460
tcacttccgt gcaatgatgg atgcaaagcc tccatcccca cggctctgag gaggccagct 2520
actgtatttt tgtcatttca aaactaagga aacggactca aaagagaggt tcagacaagc 2580
tcacacatct aggggctaag ccaggcggca aactggtttt ccagattcca caaaatgctc 2640
gtagatttca gtctcagcct cacagaacgt gtcggccaag gagagctgaa gatggaggcc 2700
tggtcaggag ggctgggctc tcaggatctc tcttttgcag catcctcatc ttcatggccc 2760
ttaagaacag taagaccgga agccttccag tcagtgaaat ctacaatttc atgacggagc 2820
acttccctta cttcaaggtg agtctaaaac ccacccttgc ccccagccca gcatgaaagc 2880
agtaggggtt tggccctaag atgctttctc tctgtgtccg tggtgaaatg caaagctccc 2940
aagggggctg gatttttcag gactgcacat gacttaaaga gagagaatca cctcacatct 3000
accaggccca aggctccatc ctccatagca aaaggggggg gggggggact gtgaacagag 3060
agctctagct gcttgctctg ggatacacag caattgagag gagctggaga aggggttggg 3120
gggagtcctg acaggcttcg gagctcagct acttacctcc caattgagag aggaaggcaa 3180
gtgatggaag tcttttccgg cctcagacag ggtgctatct atggggctgg aggaattcca 3240
agtcagagct gatcactaag gtgacgatcg attgccttcc agagtgagat taacatctgc 3300
ctctagaggt ggcatggcga gcttcacttg tacccaaaag tggggctcac agtcttgggg 3360
tgtcccaagg attgagcggg ttctccccca aacccatggg cagcattaat tatttcctag 3420
tctccacgga agagacttca ggcaactccc agcagtttct tcccagtagc cctgggacag 3480
gaggactgag agggaccctg gggaaactga ggcatgagat ttatcaatat gtaacagtta 3540
cagttgcatg aggtggaggt ccaacccagt agatttttca aatgtcctac aagatttcta 3600
cacaggggtt gggggtaaga atcgatcatc cctgaccctt gatctaaccc tgaggagtca 3660
tgtctgtctc tgggtgagcc tgctgaagtc caacctcctg gggacatgac agataccctt 3720
ctatccaggt gagcaaattt gtcagagggc ggtttatcct tctaagatca cacagcagat 3780
ggaccaattg ttgggtcaag aaaaacacac ccttatccct tgatacatgt cccctgagac 3840
cctcttgcac agacaccttc tcctgaggta ggtgcaggag agacaagatc ttttgttggg 3900
gaatccggtc cccaggactt acacccttgt caacactgtc tcacctacta accaggcaag 3960
acagatgctg aggtgcaggt gatccagagc cagctctgtg ggcaggggcg attcctgccc 4020
ccaactatct gcactatagt ctggcccggg gacaggttgc tagtgtgcag acagctttgc 4080
acctgctgtg ctcccagcag acagggagtg ggaaaaaaca tcttgcagca tggctttggc 4140
tggaatggaa atgtccacag acttgaggtt ctgggagcga gaaacaccat agtctggatg 4200
ggctgttcct gaatcccaga ctctccaggt agagataggc gctcccctcc tcctaaggtg 4260
acagcaaagt cctccaaaaa ctaaacagag aaagggaggc gaggcccctc cctctcctct 4320
gggccttctt ccctgcccac tcctggcctt acccccagcc cctccctgca tctcatcttc 4380
ctggcttaat tatttttcct gggagccgtg taatccctgt tttatgggac tgaagagtga 4440
agaggtctga cagctttttc ggttcggttg tttttcttag ccggttgcat cacccctgca 4500
tgccagagtt tacatttgac ttcagagaga ctgtgtgagg atctgaccag ccccattggc 4560
aaggcaggcc cccacgggaa tgacctgggc aaggccctca gctaaggaac agggctgaag 4620
tccatacccg gttatcgttt tcctcatgtg atccaaggcc agctgttttc ttctctgggc 4680
ctcagcttcc ctctctgtaa catgtcagtt tggacgagtt ggtacctaga ttccttctaa 4740
gccaacaggt tctcttcgaa cctctccaaa gagagagttc caaggctcta aacctctcag 4800
tccttatttg gaagtcattt tttagggcaa agacagagtg gactctgaag tggtcagtac 4860
tcacacccaa ggcagctact gtgggcgtcc catagttcca tgagtcaggg gctgaggaag 4920
tgtccagcca ccatgcataa ttgttaatgc tgaccatccc tcttccaaac aggaagtggc 4980
tgcggtgggg gctgccctgg catccgaagt cacacattta tgggaccata aaagttcccg 5040
gtgcccatta agtctgctct ggggtgatgg agctttggtt cttagtagag tcagctgtgg 5100
gagcttaaga aggtccagca gctcaagatg ctcgctggta acccctgatg aaccttgggg 5160
tcatcaggac cagccccatg atgggttagc tgtccccaag aaaggctccg gcagctgctg 5220
ccagcaactc tagtgagact ggcatcagga cccagggccc ggttctgcta ggcgtgattc 5280
agcttggctg caccctgggg caagggagct agggaggagg gcgtggccat ctctcattaa 5340
ccagaaagag gggctgaaag cgagaggagc cagggtgtaa ggaagtatca tcaactggag 5400
aggtagctct acccaccgcc agccctcgtc gggctcaggg tggtcaactg agccagatgt 5460
gggggacagg aggcccatgc ccctccacca ccatccctgc caccgcctct cacccaactg 5520
agtcagctta atggttttta caaccctcct tgggcacaat tactgcactg gtggcatgac 5580
cgggcctcct aatgggtgtt tattctgttg gcacgagcac cccctgcctg agggctggcc 5640
tccccaccag ggcacacctc cagggcacac tcatgcgaac tcacacccac acactcaatc 5700
atgggtacac acgtactctg agatactttc tcacacatag ccatcctcac tcaggagttc 5760
agagacctat ggtaggagac gccactccca ccgagagatg tcgaaggatc tggtgaatat 5820
tcagtcacat acgactaccc cagcctctac caacaccgca tctgccatca aacatagagg 5880
cagcaggtgt gctaactccc acctgttcac caaccctttt ctgcccagct tgctctggag 5940
ggatgaggtg gacccagagg aaacgcatta tgctgttctc cctttaaagc tgtccccaaa 6000
gactttaaaa tggcgatctt cccctttcta caaggggaca cataggccag aaggcccagt 6060
gagcatatcc tgcttcagtg gggaaataga ccaggggcct caatggcatt taccagttgt 6120
cccttaaaga aagatcacaa gttggacatt gtgacttatg cctgctgcaa tctcagcacc 6180
caagagactc tgagcatctt actgtgagcc tggactacaa gtgaggtccc atctccaaaa 6240
ggagtggtgg ctaacaaata tcggagagag ctgggggggg ggtgcacacc tttaatccca 6300
gcactcggga ggcagaaggc agggggatct ctgaacttga ggtcagtctg gtccacaaag 6360
tgagttctag gacagccagg actatacaga gaaaccttgt ctcaaaaaag aacccccaaa 6420
acaaacaaac aagcaaacaa aaacaaacaa acaagcaaac aagcaaacaa aaacaataaa 6480
agcagtgagg tggtggttaa gaacactggc tgctcttgca gaggacttga attcagttcc 6540
cagccccaca tggtggttta caaactatct ataactccag ttccaggaga ttcagtgccc 6600
tctttgacag actcctgtat gcatgtggtg catagacaga catacaggca cccacatgta 6660
cacataaagt gcataataaa tatacaaagg gtcacatcct ctgaagggtc tagactaaga 6720
gctaggtagg gtaacagcag cttttagatt ttagctaaaa aaaaactaac ttaggccagg 6780
cagtggtggt gcacgccttt aatcccagca cttgggaggc agaggctggt ggatttctga 6840
gttcgaggtc agcctggtct acagagtgag ttccaggaca gccagggcta tacagagaaa 6900
ccctgtctcg aaaaaccaaa ccaaaccaaa ccaaaccaaa caaaccaaaa aacaaaaact 6960
aacttaggat caacgattct gcccactaaa gggttctacg aatgcttttg gagctgaata 7020
catcaagcca gagtgtgtag agaccctatg tatagaattg gcgaaggaat gttctagaat 7080
ccccagacct agagccattt cttgccgcct gaacccaacc tggattcttg ttctgctctg 7140
gtagactgct cctgatggct ggaagaattc tgttcgccat aacctgtccc tcaacaagtg 7200
ctttgagaag gtggagaata aatccggaag ttcctctcga aagggctgtc tgtgggccct 7260
caatccttcc aaaatcgaca agatgcagga agaactgcag aagtggaaga ggaaagaccc 7320
cattgctgtg cgcaaaagca tggccaaacc aggtgaggct gtcaggcctg tgtgagaaag 7380
gccaagggac ctgggtacca gaatgaagaa gagcagagcc tggggagaga gggatacagg 7440
gaggggggtc tgggctggga ggctacaaag gagagaggcc tcatggtgtt ttcttttggg 7500
cctttgcaga agagctggac agcctcattg gagacaaaag ggaaaaactg ggctctccgc 7560
tgctgggctg tccaccccct gggctggcag gcccaggtcc catccggccc atggcaccat 7620
cagctggtct ttcccagcct ctgcacccaa tgcatccagc tccaggcccc atgcctggca 7680
agaaccccct gcaggaccta ctgggtggcc atgctccctc ctgctatggg cagacctacc 7740
cacacctttc ccccagcctg gccccttctg gacaccagca gccattgttc ccacagccag 7800
atgggcatct tgagctgcag gcccagccag gcacccccca ggactcacct ctacctgccc 7860
acacaccacc cagccacggt gccaagctga tggctgagcc ttcctcagcc aggaccatgc 7920
acgatactct actgccagat ggagaccttg ggactgacct ggatgctatc aacccttctc 7980
tcactgactt cgacttccag ggtgagctgg gagctgggag ctgggaaggg tgggacagga 8040
ctagagaggt gctcttggct gcgtggccta gcctcttcat gtctctaggc tgccacctgc 8100
tggctcctga gtttcttgtc acctgaggcg gatgactagg aatgttaaat tcgcatttgc 8160
tccctgccct ccagatcatg agctaaaagg ctctttcccc catctccccc ctcctggtac 8220
tctgatcatg taccagatgg cttcatcatc aaaccgctca tctgacaaag ctgggaaaag 8280
ccggaagttc cattggtgta cttgactgtg agggactggg aggctaaacg ttccaaaatc 8340
atttgcgttt tatcagaatt tagctttcac ttcaggagac agactttcta tggaatggaa 8400
gacctcagag ctaagcatgt cctagagaga tttgagggta caagcccaga gaggtgaatc 8460
tttacattct cctccatctt gcccgctcca tcctacaggc agccaagccc caccctctac 8520
ccttctaagc cccgcccctt cccgtttgaa ctgtagtgta ccgagcaagc ctttttggag 8580
gaggctgttg atctatacct tagactgtta gaaataaact tcacatagac cttcattcca 8640
gacctgctgc ggctgcagag aacaggcggc tgcagaggag gctatgtgga cgtgggatac 8700
tataaattct atcagaaggc tagagatgtg ggtagggggt aaagcgtttg cctagcatgc 8760
accaatcctt agttagggtc aataccccag catcacaaaa cccttaatta atacccactc 8820
aagctcctac tgagtaccag gcatcttgca aacagcttta catatgttct tcccatctgg 8880
acctagcaaa caatactata cagagagata catccactca aggtcgctgg gccagaaaga 8940
aggagttgaa cccaggtggc caagagcagc cagcgttgtc aggtctcttt ctccaccctg 9000
cggtgatgat gttccaggca gcgactccag tcactggcct gccacgcggc aggtcacacg 9060
accctaggag gaactcagtg acagcactgt ttgttcctca gagtcaagtg tcctttctgg 9120
ttctatccct gtaccttggg tcctgtgagg gggcggggag gagggtctag ggagccagac 9180
ctgtgtacct catcaagttc ggtggtgcac tgtgggaaga ctgtaggcgg caaatcaacc 9240
tttgggaacc aaggcagaag cctgagtgaa gaggttcagg ggggcctcta ggccgcttcc 9300
aagaagagct ttgcaacaac cttcaaatgg gcaaatcctt aaccttaatc tagtaccctg 9360
ttcttctcga agaggcccag aggttacctg caactatggc agtggttctc aacctctggg 9420
tcgcgacccc gatggaaagt ctgatgaccc tttcataggg gtcgcctgca tctatggctt 9480
ttacaccgtg ctaccttgga gctcggagct ggactctgag gctcaggaaa aaaaaaaaaa 9540
agttcagtga ttacttgagg tcccagagtg gatgccaaga taggcttcca gtccgcatca 9600
ccagactcct gttctctgag gcttctgagg tacttgggtg ggagacagac tgggcttaac 9660
tctctatggc ctgccaatga tgaggcttct tccctctccc cgactaggaa atctgtggga 9720
gcagctgaag gatgacagct tggccctgga ccccctcgta ttggtgacct cgtcgccgac 9780
gtcatcctcc atgttgccac ccccaccagc agcccattgc ttccccccag ggccttgtct 9840
ggcagaaaca ggcaatgagg caggtgaact ggcacctcca ggcagcggcg gctccggtgc 9900
tctgggagac atgcacctca gcactctcta ctccgccttt gtggaactgg agtccacgcc 9960
ctcctcagca gctgccggcc ctgccgtgta cctcagtccc ggctcaaagc cattggctct 10020
ggcttgagct atgcccaaca tcagctgcgg cctttgccta gctggctgcc ccatattggg 10080
ctcaccttaa aggtcaaaga aggaaaacac tacctgtctc ctatgccact cagccaactt 10140
atttgttagc cagaagttgg gggcatccat ctaggatgct acctggtgga cc 10192
<210> 30
<211> 19893
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 30
aagaggagga agagagtggg ggagggaagg agggagggag aggatgggga catgaaacag 60
caatgggacc aaaagtctgt ggaggagcaa ggacaggccc caggcctatt caggtaagac 120
tcagggtagc cacttcctag acctgctgcg cactgcacct caactgtaga ccctgagggg 180
ctggggacca acagccactc aaatatttcc attctggaga tcatgaagag tgactgaggg 240
gatgatgaca tagaactaag catcctccat ctccacccac acccatacat ggggcatgat 300
gacccagagc ggagacacat ggctagaaac tcaatgacac cgtagcgtgg agacacaagc 360
ctgagtacag ggacaagagc cacagatgca cagacattag agaaaacata gacgcaaaca 420
gacaaatccc tgcgaggacc tgtggagaag caggcatgcc cacagacatg ggagggaagt 480
cacatggatt tggggctaca cactgccaca cataaggtca gataatatga catgagatga 540
gccaaccctg tggacatctc ccagaaatca ttggatcctt ggggaggggg tctctgctgg 600
tccacactat acctgagagg gctcagtgct gcaaccatgt gctgcttccc agaaccccct 660
tactagctcc gtgaacacac atgtggcggc tgggctctcc tgacacacag gtgcatgtcc 720
caacaggcct gggccccacc catgggggct gacatctctg ttctggggtg caggtggggg 780
ccacagagcc accccttccc ccgcaagcca caggccatgc ccactggcag ggactggggg 840
cccaggctgg cacaggaggg gaggcctgga ggaggggggg acccgggcgc ggccagggcg 900
ggcacaggag cctgtacctg tcaaacaaga gccaaggagc aaactagctt cttagtcacc 960
tttctcttct ccccgttttt ggcagcaacc cctcggggca aggggaagct gatatcataa 1020
ttattggctc acccagcagc tgcctcccct cacctgatgt cagcccagac ccaggacaat 1080
caggctgacg gactgacaga cggtcggagc tcctggcccc ccagacccag gcccccacgc 1140
cgacctgctt cactgagcag gtaagaggag acctggccca agtcagccgt ggaggccaac 1200
aggggagggg gcttggtttt tttaatgggc cccaggaggc actgggtgct tctcagagtc 1260
tcattgtctc tccagggaga ctcaggatca gggtgagtac ctggaggctg aggggacccc 1320
tcctccactc tcctctctct ttcctggccc aggccttctg actttgatcc ttcttgctgt 1380
aatgtaggac tctgttttgc tgtacatggt gtctctgtgt ggtaggtctg tgtggtggca 1440
cccaccttga gttgggaggc aattatgact ccagatggac agctagagtt taaagataga 1500
cagataggca gattccctgc cgaggactga gtggctggct aagtggaaag ttgggtaccc 1560
cccccccagc tctggcaact tccatctctc tggaatacct ggtcttgggt ctgcacgacc 1620
cagattctat gggggaggct tggcatgcag aacggagaat ggtgcacctt gtgcagaagc 1680
ggacaggcgg caacaggtgc tgcggctagg agccgatgcc aagctggagg cacacctctc 1740
tgatcgccgg agatgtttct cttctttaag atcgctgcag tagagaggag tggccagcag 1800
acctgagaca ggcagagagt tcacagaccc cccaccccca ccccaactta gaattgggaa 1860
atctagctgc cagaaacccc tttatctact gagactacct accctttgcc ccatacctga 1920
ccaggcaaaa tcctggaatt tgctatagag ctccccaacc caccttcagc atccaaagaa 1980
gcatgttggg ttaaagctag agttataagt gggcgtgttt gcctctttgc tctgtaccta 2040
caagtgcagg ggacatgtct gggtatgtgc agtggcaggg tacagctgct cagcaagaaa 2100
ggaccagatg gagaagatgc ctcctctagg gacaccatct catcccctgt gtcccctacc 2160
cctgtgccgg gtagctccca caacagacag agtgtggtcc tctctgtgtt ctaaactgtt 2220
cagtaggaga ctcagtgagt tccttcatcg tttttttttg aaatcgtaac ttctgtagcg 2280
tctacctcta gcttctccac ttccttctct ttcttctact gatgaagccc agttcccctg 2340
cacagatgga tgagcacagg gtagaaaggg tggcagtgaa ctccagccct atccccactg 2400
ggctttagca agagctttct tcccatcctg acctacagac caggacaaga tgctggtagc 2460
agaatggcat cccagctgat gaggcctggc tcttctctct tgtggctttg tgaggggcta 2520
agacagagct gagctgggac caggggaaga acagagggtc caagtgctgc cctgggttga 2580
ggatcctctg gggtgaggat gccgtggggg gtggcacttg ccctcccagc tctccacccg 2640
gccccgcccg ggcagcctat gccgagctca gctcccggct gcaaggcctg ccgaggcacg 2700
ctgcaccccc aggcctctca cctcactcca ggccaggaac ctgttctccc gggaatgctg 2760
gggagttctc agaggacttt agttcccagg ggtttaggga aagaaatcct ctggaccagt 2820
gagtgagcca tggaaaagca agaaaatgga aagactgggg ggcagaggtg ggtcacaagg 2880
gcccattgcc ctcttcatct gtgtctatcc acacacagat cccacacttc tagctgacag 2940
cttttattgc tcttcgtgag aatgaagcct tgggacagtt aaagacaaaa gaaaaagccc 3000
ctcatggcac atgctttctg ccacatgcca tcatttggcc cccatggaaa gtcccttctg 3060
ccctctaaga aaatgacagg gcatcatccc agttggaccc aacaactccc atccagggag 3120
tctttcctac taacctttcc tcattgagcc tggtcttcac agaccagcag aaacacacac 3180
acacacacac acacacacac acatacacac atgcacacac acacacgcac acacacacac 3240
acacacacac acacacgcac acacacgcac acacacacgc acacacacgc acacacacgc 3300
gcacacacac acacacacac acacactacc tgccctgcac acatagcttg aacctgttcc 3360
tcagtacata aaagtcttgg ggacttctca gcctgctgcc ccattattct ctccagcacc 3420
atattctgac aagattgggg ccacctctct gtctattttt tgagacacga tctccctatc 3480
tagcctgagc taccctggaa ccctcagcct tctgggtgct gaaattaaag gtgtgcagta 3540
ccccactcac ctatgggcca cttctggttc cgcataccat agggacagag aggataaagg 3600
gcagaggcca tcatccctgt tgcagcctgc cagacttcca cagtgggaga tggtgacttc 3660
gggaagatag ttcagcattt taaatttagt tcttgcatgc agcccatgtc acccgagaag 3720
gcaatttcct ggggagggca ggccagcact gatctgggat gcattgtcgg gcaacatact 3780
cagtgcaagg gaaagacttg ctgcactctg agagacttcg tccccaaagc gcccacccag 3840
tgaccctcca gtaagatgca ctcctatccc ttccagcctg cctcggtccc tgcctccttt 3900
tgcatcccca gccctaaacc catttccctt taccagccct ctgtacgtat ctcagatttg 3960
acctgagctg gagcttctgt tgcgtgggtc tcctgtgtcc tgagattaca ggtgcagccg 4020
tgacaccagg tcctccctta tctcactcgc agccccagct cagacctgct ttccaccttt 4080
tctccctatc ctcaacttta ccaaagtttg tacaatccca ccccccccca cacacacaca 4140
tacacacaca cttcctctcc ttatttctta cttggcttcc ccactcctcc caccatccct 4200
cccagcccta tgagcccatc agcaccccca caggatggat gggcatccct gtgcacagtc 4260
agagaatcca aaacctcccg cagtgttccc taatttagtc tctgaactga gaggcccaga 4320
gccatgtccc aaggacaggt gggttgtatg ggatcatccc tagagaagct ctcagcttcc 4380
tgatcccata tgggccctaa aaaactggct gttggcagat agtaaaatgg agtctggctg 4440
aagcatggtt tggtgggaaa tcctgtgctt tatacgtctg aggtcctgga tgccagcctc 4500
agcccccaaa taaaaatgaa accatctagg tgagttcaga tacaagtatc tgatgctaca 4560
gcagtttgtc aagcaagggg gggtggggtg ggggagagct ggagggatga ctgatcccgt 4620
cagacatggc taggccaagg caggaagatg gacagcagct gaagcaaagc ccgctgggtt 4680
ctttaggaat gactgccact gtcatgagta tcccccagtc tctaccccgc ctgtggctct 4740
tgcttagtca gctcagatta atgggactgg ggaaagaatt agctgaatcg tgatctctcg 4800
ggggaactag agcctgcagt gagtcacagg gaagggaacc tgagctctca gggagattct 4860
ggaggctccc tgggtgtgtg ggggagggga gggggttatt ccctaagact tctctgagat 4920
gctacctaga gcctgcatgc tgggaggcac agccctggct ctctacccca aatttgcaga 4980
atgataatgt gattaaccag ctaccagcat gccccccaaa accctccaag ggccctcggc 5040
actctcgcat cctgaaacca ctatttgtga caaactgcag ccagtctagc accaacacat 5100
agtgggctta cttggcacca tcacacagtc agtatacaca cagacagcag aacagggcgt 5160
ggccctggaa ccggattgcc tgcagacaga tggaagtccc acctacactt gtaaattcca 5220
caatcacgtc ccaggctgta gcagcctatc gggttcagcg ccataggatg tgaacaagga 5280
tgaacacaca cacacacaca cacacacaca gcactgtgag gtgaagacca gttatcacac 5340
ttatcaactc ttgctctgta cagagccaga agaactacat caatgttcag tcaatggtag 5400
tctgtatcct gaccctctgt agaagaggtc ctagagtcta ccctgggcac ttacagatca 5460
gtaacttgtc tcttgtaatc ccagcagtga gcagactgag gcaggaggat tgctgagttt 5520
gaagccaccg tgggtagttc aagctacata gcgagtttga agtcaacttg gaatccatga 5580
tgagactctg tctaaaagaa aataagaaca acaaacaaac aaataaaaag aacagtcagg 5640
tagtggtggc ccacgccttt aatcccagaa ctcaggaagc agaggcaggt ggatctctgt 5700
gagttcaagg ccaggctgag ctacagagtg agttccagga cagaaaagaa tacacagaga 5760
aaccatgcct caaaaaaaca aaaacaaaaa caaacaaaca aaaaacccac caataatcaa 5820
aaagaaaaag agaaaagaaa gagaatctga atgttgatgg gtctttctat gcctatttgc 5880
aacacactta agagtgtgag gggttggaag aggaaattta gggtgacaga aaagccagaa 5940
ggatgtagag tgtcaaggaa ggaagctgga accaagtagc agagcaactc aggaagtccc 6000
tccaaacctc tcacttctcc aaaggcatgc tgggatctca gagccagctc accatgacca 6060
gcatccggaa gaaggagggg tgtgtacaac acacctgcct aggaaatcat ccctagcctg 6120
gcatggcagc gcaggtctct aatcccagct actcaggagg ctgaggcagg cagataagat 6180
gttcaaggct tgcctgaatg ttcaaagcca gctgaagcaa tttagtgatg cgaccttgtt 6240
tcaatatttt tttttaaaaa gctcattggg tctaaagctc attggtaaag cacttgccag 6300
gcacaggcaa gacccatgtt cagtcctagt cccacaaaaa caaacaaagc catctgtctc 6360
cttggttggc ttcagttctc ctctctgtca cacagacagg ctttggatgg aagcatcttc 6420
caatgtgctt cctcctcctt ggtccatgct tggagccaat agctgccctg cctgcccttt 6480
gctcggacgt agggcaggaa gtgcgccagc ttgcatccat cttgtgctga atcagggtta 6540
ttagcagtgg tggcagaatt aataccccta ataatagatt ggtggtaatg agcagtgctg 6600
gtaataatat gtacagagag aagcctctga ccaagggaca gtggcatcca cagccacctg 6660
aggcccctat caaggtgagc aggcaaaggg cgactgatac acccacactt ctatagggaa 6720
cataggaggt tctcatgcag tgccatggct ccctaggatc ctgggggagg aggcagaaaa 6780
aatggttctc acctgctcct agggacagga cagcagggga tgagtgcaag ggcagaatga 6840
agtcactatt tcatagagga ggaaaaaagc ttcatcctag tcactagccc aagctgatga 6900
cagagccagg acatggtcct cccatagtgc ccaagaggga aagagggatt ctgtaagaag 6960
caggggactc caagcttgac gaagccttca ggagagaacc caggttaggg gaggagatga 7020
cagaagttcc catcatgcct gatgggttta cagagcaaat cctcagctgc cagctactgg 7080
catagccaat tggcccggca cctgatttta ggggttgtga gaggaggctc agttccaaat 7140
gatgtcattg tggggtgggg tttcttggcc tctaatgggc tctcagaagc cagcggcttc 7200
ttctgcccct cagcctgtcc tccttcgcat ctcttcagca gatgtggctc acctcaggaa 7260
ggatgaaggt gataaaccct cctggccctt cagtccttcc ctcacctact tctcccgtct 7320
ctgatcatgg ctaagcagtc tgagggtttg agggaaaatt ccactctgga gaccagtgtc 7380
taaggcccca gatccctgtt ctctgtacgg tgcatccaga gggttacaca ttgcccccac 7440
cccaccccca ccccccagct cttcactgat atcctaatgt ttccttttag attatgatgg 7500
ttgtcactgt tgtttttctg agacagggtt tctctgtgta gccctggctg tactggaact 7560
cactctgtag accaggctgg cctcgaactc agggatcctc ctgagtactg ggattaaagg 7620
ccaccaacca ctgcctgtcc tttttcccgt tttccttgtg tgtgtgtgtg tgtgtgtgtg 7680
tgtgtgtgtg agagagagag agagagagag agagagagag aggtggggtc tcacaaatgc 7740
agcccaggct gaccttacat ttgtgattct cctctctcca cctcctgagt actaagatta 7800
cacagtcaac ccaactagga aacagttcta tctccaaatt ctttgtcagt ctgtccccac 7860
tgctcggggc ttcaaaattc ccctggaaag gtggagctgg gggcttttcc ctctctggct 7920
atccaaaggt gtcatgttcg tgaatatgag aatgcctgct aaccttgaag gggaagccac 7980
cttgctccta gacttgctcc tagacacaag atctcagggt tgcaggggca ccagcagagg 8040
caggtaggca gaagggagga aaaggcaggt cataaatggc tcccaagaag aaatgcaaac 8100
attactgtgg gtgagggcag tggagtagac atgaaaggtc tctagaaaga ggtctctaag 8160
gagggagagt ccaggaggac caatctctta aattaggtgg ccatggtaag gaagagggag 8220
gggaagacct aaaacaatcc taggagtaga tggtagcttt gaggaccagc atttcttgtt 8280
tctttaaaat ctctttctga tcatttacaa gacaggcacc cataggtatt gcaaagacat 8340
ccatccatcc acctgtctat ccatagccca tctatctgtt caaagtcacc catctatctc 8400
ttcatccatc tatcttccat ccaaccatcc acccatctat ccatctacct gtctagagag 8460
gtcagggcta ctgggaaggg cctgtggtcc tgtggcattt atggggcatg tgacttacct 8520
gcttggcctg gggaggcagt cccacccctg ccctggggca gggggccggt cctggcatgt 8580
gggtgtattt atacctggat ggaggctccc ctgaagctga aagctgcatg actccccaaa 8640
gccgggatgg tgtccacggc ccagagccca ctgtaagtgt ttagacatgg ctgcgttggg 8700
ggtcaggacg gggtggaaga agagggggag gggctggggt gtactgccca gaggtggtaa 8760
agactatgga aagagaggca tgctgggcag atgtttgtga gaaaagagga ggctgccagc 8820
atcagacatt ctcagcaaag ctgggacctt ccatggagac ggaatgagcc tatttccctt 8880
agctagtggg gagtggtcat tgacacataa ggcaagtgaa cgagattata agaattaaga 8940
acaaatatct aggaaagttt ccaggtcacc ccaggcagag aaggtagctc aagtgttttt 9000
ttgttttttg ttttttgttt ttgttttttt ttccgaaagg atgctttctg agcagactgc 9060
ttgaagaggc tgggggaatg tcaggtacct ttataaaaga cccgacagag attggaacta 9120
cctgactgca ggtgtgaatg gctcacagga tgctgtaaga gggatatgac tgcttttctt 9180
actacagtgt gtgtgtgtat gtgtgtatgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt 9240
gtgtgtgtgt gtgtacatgt gcatgcatgt cacagcaaga gtgtggaggc cagggaagaa 9300
aatgctgtag ttggtcctct ccggccacca tgtgggtcct aggaatcaaa ctcaggttgt 9360
cagggttgaa ggtgggtacc tacacctgcc tctggctaat tttcatccat cattctttac 9420
aaacccaggc agcatccaga gacagagagt ctagaggggc cttcaggacc ccagactggt 9480
aagaagaaac ctgttagaaa ccccatcttc ttgacacccc tagactccca gaatcctgag 9540
aggtgtgagc ctcaggcata gtccccaggt ctttcgctgc cacccccagc aagggtaatt 9600
agggacctgc tccagggaac ccctcccagc agccaggcag gtggagcctc gggtggggct 9660
gcaggcgaac actgggcaca gccccacccc tcgtaaaaca agctgccaca gccggcaaca 9720
gaaaccatta aggtggaact gagccggctc cgcctgctca taaagaacgg gcaggagggc 9780
gccgacaggt ggggggtggg ggggggggag agagagtgtg tgtgtgtgtg tgtgtgtgtg 9840
tgtgtgtgtg tgtgtgtgtg cagaactgct tctgagtgtc cttggccagg cagaagtgtg 9900
tgactggcct ctgtgactca gctgccagta ggggctccat ggacagaccc tcccagggaa 9960
acctccacct tgctgaggcg gggctgtgtg gtatagtggt taaggagaga ttagctttga 10020
agcctgggcc tgaatgagga gcacagttta ctagctgggg gacttgggcg agtcaggtta 10080
atctctctga gcctcagttt cctgatccat aaaaaggggt gacagtgcag tgcgtccctc 10140
ctaggacaga atccctggtg caagtctgac aggccactct gtccacttca cacacgtcca 10200
taggaccaac accagcatct taagatcaaa tgatccctgg gtttcctttt gcctatagaa 10260
gaactgaaat gcagatgagg aaataactta tccatggcca caaatccagc aaattaggtg 10320
tcccccaccc ccaccccagg acccaccctt aaacagcccc ttctgcctga gtgccgagaa 10380
gacagtctct cagaggcaga ggtagcaatg gctgaaggca gtgtagggct gactgttgca 10440
ggaagggtac aaggtgagga tgccagtgtc tggggacatg gggcagccac ctagcaatgc 10500
ttaccatgga ttcatcaccc gtccagttct cactgtctgg aggggcttcc tcccaacctc 10560
cctcctcagg ccagtgggcc ctttctctct ccctttgctt cagggtcgat cgggtctatt 10620
ttctttgtcc ccaaactttc cttcccctct ccaagaatca tggaaggaaa gtttgcccag 10680
gacgtccaga ccttgagagg gtcttcaaca cgtcttgcta aagttgtagc tctggataag 10740
agtgtctgga gcccttgagg tacaagagag gatttttcat tctctctgtg tggtcctagg 10800
catgcttctt ctctcttggc ctccttcccc caccccctgt gagaaacgga gtgaatacca 10860
ttgcttctct accttcagtg tgttggtaaa ttgtcatcaa ttatcagcta tcaaaaaggg 10920
ggaggggaaa ttctgattta gttttatgtt ggtttggttt ttgttttttt taggacaggg 10980
tctcactatt cagccttagc tatcctggaa ctcactatgt agaccaggct ggccttgaat 11040
ccatagagat ctacctgctt ctgcctcccc tgtgctggga ttaaaggtgt gtgccaacac 11100
attaggcagc attctggttg ataatgtgtg agatttttgc atgggcagct atgtagctat 11160
ggccagtttg cctttatttt gctgaatgtg gaattggaag tgatggattc agtttgctcc 11220
ctaaagcact ggctccagta tgctgtgttc actgtccaca gggacagagg cgagaagaga 11280
tagcaaagat aaaaagcatg caacttggac ttctgagtgt tccaatgatg cgggtctatg 11340
atgattatgg tcttgcggta gaagggaatt tgacccacat cttcctccat agtctcctgt 11400
ccaggaagga gacatagggt gggcagatga cagttctgag tggcggcata tgtgctctga 11460
accggctccc agagattctg gatttgggag aaggggagaa gaggaaggag atgagaagtc 11520
agtttgctga cactggcgca caggcaatac actgttctgt gaaaccagac gaggtgggct 11580
caaggtttga caacaaaagg ttccttctaa gttcataggc cactatcagg acactggagc 11640
cagcatggat gcttcctggg ggatccaaag cagtagggac accctatcca ttccatttca 11700
ggacattgaa gtttctgcag ccactggctc tactgcaggg gaatgaacaa aatggcctca 11760
gaggcccgag tcaagaggaa gttcagtcgg tggaggaagc ttatgacagg gagatgggtg 11820
ggggtgggga gaagacagga aagggcaaga aaaggtggtt ccctccccca caccagagcc 11880
catgccttaa attaactctg tcccactgct aattattaat aatagctatc atttattgag 11940
tatgtactgt gaggtaagct atttacaagc aatatttcat ccaatcctcc aaagaggtat 12000
gtattatcag ctccatttta cagaggagga aactgaggcc cagggaagga agttaaataa 12060
tgtgtccaac caaattctca ccctgatcat gattcagacc caaacctgac taccaagttg 12120
ggagctttaa gaactccaca cctctctctc tcccctctct gtgctgaaag gaccctcccc 12180
aaacattaac taggggccct ttgtccagcc cttgaagctg gtgacccttt aggataaagt 12240
tgattgaggg ctcacatttc ctagacagtg tggctttaga aaactcagtt catttcttga 12300
agggactcat ggtcactgag ctaggcgtca gtacttacag aacccaccca gaagaaaacc 12360
tgggtgagga ccactctggg acatctgtat ccccaatgca aatcaaggag agcctatgaa 12420
ccctgcaaag acaagcttag gtcctggaaa aaagggtggg ggttttcaga gccagagtct 12480
gttagtcctg gctaggaaca gaaggccttt gatgtacagg cgctctgcct ggggcttata 12540
caaatagctc catctaagga tgagggattg cagagtgagg cagaggtgct actaaacaag 12600
acagaacttt gagaggggaa ggcccagcta gagctcaggt tcgagtcagt aaagcagggc 12660
tggtgtctga gtcttccggg aggtcatgat aaatgaagac caggcaggca ggagaggcca 12720
gcaagggcag ctgctaccag gggacagcgt catctgcacc tctctcctag actatgaggc 12780
ctgaagcaac aagactgtca tggaaactgt agagcctgga attagaggcc tttggggaca 12840
gctacattta gccaactgaa gccagagata tgaggtgtgt ccccggccat tttctgggta 12900
tcagcaccat accacttaat cttcaagagg tcctagtgag ataggtctac acacctcatt 12960
tctcagacgg agaaagtgaa atatagactt acatagtgtg ttcaaaaatc acagaggcag 13020
aacgtgacaa ggcttggaac taaagtcaga tttgcctcaa gcccaaccat tactgttctc 13080
cctcctgggg ctgcagagcc tgaaatgggg agaaaaagcc cccggcctca cacctggagg 13140
gagatgagat tgtatttgga tggcgtcaag ttcacacgac accacctcct ctgggaaagg 13200
cagctctgag ccaggatgag gcatggcagg caggcctgag ctgtccaggg aacaggggcc 13260
agggcaggca gtcatgcaaa gccagagatg gggtgtcctc acccctacct gctcccttga 13320
agtgtccagt tacagccagc tccacgcttc cccgtcacgc cacatttagc attgctgaga 13380
gtgagcctgc gcagggatat agagaagggg tggtagggac tctttgaggg gtgggagaga 13440
acctccccac cttcaaaccc atctacactt acttcagcca ccagccgcct cccagcctaa 13500
tcctatgtgg gactctggac aggttccctt ccctctttga caccattagc ctctctgaag 13560
atggctaatt catcaaagat gtgtcaactg ctgactaggc caaactcaga aagatgaggc 13620
ctgccctctc tcccagattt cccagaactg caccactgct gtgacttgag gggtcttggg 13680
tagatggcat aagtcgaaag ctctggtttt tatttctgtt tggctcccag aacattccac 13740
tctgactccc atcaaataca gtagcggggg gtgggggggt agccaaagct tagttcaggt 13800
tctgacagtc aagggttata tgtgagactg ggaggtcacg gaatccctca gggcctcagt 13860
tctcttattt gaaagactgg attaataata tggcatcctt gaagtaaagc aatgagcttg 13920
ggcctgctta taatgccagc ccttgggcag ctgaggtcaa tagtttgtcg atagaggcag 13980
agggctgcct atagttcctg gcctatgtag tgagtttcag gccagcatag actatatggc 14040
gagagcctgt cgcacacctt taatcccagc acttgggagg cagaggcagg tggatttctg 14100
agtccgaggc cagcctggtc tacaaagtga gttccaggac aaccagggct acacagagaa 14160
accctgtctt gaaaaaccaa aaaaaacaat aggggcgggc tggagagatg gctcagtagg 14220
tgagagcact gactgctctt ccagagatcc tgagttcaaa tcccagcatc tacatggtgg 14280
ctcacaacca tcgagatctg acgccctctt ctggtgtgtc tgtagacagc tacttacata 14340
taataaataa ataaatctta aaaaaaaaaa aaaaccaata ggggctacag attttcactg 14400
agtaaagcaa ctatcaggaa gccctaggtc agaacccaaa actgagcaca aaggtccgtg 14460
tccataatcc cagcacgtgg gaggtggaga aaagcagaaa cctaaggtca tcttcagcag 14520
gtggaaaacc ttccaaagtg ctacccagga gtcagtacag agcagtccct cggtaaacaa 14580
tggctgctgt cagggatgaa ctcagggacg tgagttcaaa ggctgttgct gataatggaa 14640
gagccccagg gataacacca ttaataatga gacctggcgt gtggatcaag ccctgtgtgc 14700
ttgtgctgtg ctccgagctt tctctgcatg atttcatttc actctcagcg ccctgtgcga 14760
ggctctgtca ctcatcttgt ttgcagatgc tgctgtggaa gtgcagagag ctctgctgac 14820
acagcctgga atggacagcc tcgcctggcg ctgagcccca aggcctccca gctgctctgt 14880
ggtgctgggt cagggttcta caacaacagt tcagaagggg tcagtgctca gatctagtcc 14940
aagccttagc atttcatagg caagctgaag agttcagaaa gaggccaggg atgggagcca 15000
gggagcatcc tgggaggcag tgggctcgat cccacacaga acagggaagg agaggagaag 15060
agaggggcta aggaaatgag acgtgcttgg tacaaagtca cggacaaaga ttgatagagg 15120
ttaaaaaaac aacacttccc agatatccca cgggccctac cagcaaggcc ccttggtcat 15180
cccacagggt taccctctgt gtcattggga ttgctgtcac ataaagccta ggcatgatac 15240
atctcctgac tcctcctctt ctcagggcct acccagcaac tgataaggtc accttgcata 15300
gacataggaa acctagcagc caggctccct gggaagcaag ggctcactga ctcactgact 15360
gaccaggtca cttgctgacc agcaaagctt gagttgagac aggagctctc ctccgagtat 15420
ccaatctggc tcagtttctc tctcatgata gctctttcct catcctcttc agcatttgcc 15480
taccagcatg taacaatttc tcaccttggc tatctatcta tcatctgtct gtctgactgt 15540
ctgtctatca tctcttccct tctctcccta tgtccctaat ccgatggcta gctccagcca 15600
gggtcccagt ccagggaaag ggtaggaatg gaggtggtgg gcctggggtt ggccatgcct 15660
agacgttggt cctcattctc attgtagctg gctttcttcg aggccaggac tgggtgatgg 15720
tgtcgctact ccctccgcag tctgacgtca cacttccagg ctccacccga ctggagggcg 15780
aaccccaagg ggacctcatg caggctccgg gcctcccaga ctcccctgcc ccacagaacg 15840
taagtacctg gaacctaggc ctggaatagg gcaagcctgg tagctctaag agcattgagt 15900
agatggtcac tgccccacac aaggaccttc gggatctact ttgtccctta cacagaaaaa 15960
atgatgatga ctctagaccc agaagggcca agtcacagat ctctgtccat ccttggtttg 16020
gtgtttcccc agatatggaa cccatcagcc tcaggggacc caggtttaga agaagtatgc 16080
ttgtatcaga ttggaatccc aagagcaggt tgccttcccc gtcactttgg gactcctgtg 16140
aactcagcca tactctatta tctcagtaca gcacagggtc ctggcagatg ccctggtcca 16200
acccccattt acagattctc tattctgtct gcccagaagc atgctaactt cagctgctcg 16260
tcgtttgtgc ctgacggccc tccagagagg acaccctcac tgcccccaca cagccccagc 16320
atcgcatctc cagacccaga gcagatccag ggccactgca cagccggacc cggcccgggc 16380
tccttccgcc tttctccttc agaaaagtat cctggctttg gctttgagga gggcccagca 16440
ggcagcccag ggcgcttcct caagggcaac cacatgcctt tccaccccta caagaggcac 16500
ttccatgagg acatcttctc tgaggcccag acggccatgg cacttgatgg acactccttt 16560
aagactcagg gggcactgga agcctttgag gagatccctg tggacatggg cgatgctgag 16620
gccttcctgc ctagcttccc agcagaggct tggtgcaata aactccctta ccccagccag 16680
gaacacaacc aaattctggt gagtgccagt ggccgagggc cttccacctc ctctctccta 16740
gctgcctaga aagactcttc aaagccatgc ctggtggcac atgcctgtaa tcctactact 16800
caggaggctg aggcaggagg actgcttgag gcagaggcca gcctctgcct atgtatggag 16860
accctgtctc caaatcagag ctccagagga ggcagcaagc acagagggtg ggggcctcct 16920
ggttccatac tggtcccctg gggaggggga tgctagcctg gcaggcgtgg agagggcagg 16980
tggagggggc aggtgaggga agctcatgag ggaagggagc tggcagcttc ccagaggctg 17040
ctgagtcaag attccagagg gtgacttctc tgtttattta agtgtcaaag aatgccaagc 17100
cagaccaaca cacccctatg caaatgtgag gaggaaaaga cacattccag agagagaagg 17160
ttctagacag agcatcagaa caaaaacccc accaaataag gactggggac ttcactgcta 17220
gctccaggcc ccttccagac cctgcttttt tatttatttt catgggtgag acagaaaaca 17280
gctatgttgc ctaaggccgt ccatgaacta gagatcctcc tggtgctgga attactggtg 17340
gggttctgga cctattctaa ggccagagca ggcttctatg gataagtgcc ttgggacacc 17400
tcagaaggtt gactagcact tccgcagcca gatctgcagg ccctgtgacc tcgggcaagt 17460
cacttaatct ctctgagcct cgtgggaaaa gttctgttaa gggtttcctg tctcaggctt 17520
gccccctgct cccgatctct gattcccaag gcaccccagt gtgataattc atcctggact 17580
ctgctcctcc aggggtccac cggccttctt tacctcctac ttccaaatag gcccattcta 17640
gtccttagcc acacctatca ggaaggaaga gggggaaaac agatgaacac ccaggtgggt 17700
caggtgtggc caagacagga tcttctgctg tttctggagc catgactgct ttttctcaag 17760
cctttagaat gtggtgggag ccacagcttg gcacccagaa agccagcagt tgtcccccat 17820
tgtccactcg ttgtagctcc ttgtcactca gccaggagat ttccttccag ggttgcatca 17880
atagagttct cactatctcc atcttgagaa tcaggacccg gccctctctg gttgaggcct 17940
tatgacttac caggacatcc acaacctata aacagaagtc cacctggccc catggacaca 18000
agctgtaccc aactgcctgg tccactctat gggtgacagg tgccatgtag tttcccctct 18060
ttgggagcag ctgtatcatc tgtgaaatga aggggttgga ctcagtgctt gtggcccttg 18120
caggctcaag atcctgtgat tacggcaatc tctgcatcag ctgccctgag gcatacccag 18180
aaagtggtca cagctagctt tcacccctct gggcccaaat gctgccttcc caaaggcccg 18240
tgggaatcct agtttcagga gcctgatcct ggcttgtcta tctgccaggt aggtctgagc 18300
cgcacgccct tgctaactct atgcagggct cagctctggg ttaggccctg aggacttcac 18360
atgggtctct cagaactctc gggtcccatt caagtctatg tgacaagtcc cctccatttc 18420
tcttggtggc ccagactagc ctgccgcctg cagtgaggtg gaatgtgagg aacactgtcc 18480
tttctagcct agcccctcta ctgacttgct gatttccctc aggaaaaccc ctatccatct 18540
ctgttctctg ttccttgcct aagagttagc tttgagaggg tcacagaaag gattcttcca 18600
gtgtgaagtt caagacaaga aaaagaaatg gaggcccgtc attggtggtg cacatcttta 18660
atcccagcac ttgggaggca gaggcaggca gatttctgag tttgaggtca gcctggtcta 18720
caaagtgagt tccaggacag ccagggctac acagagaaac cgtgcctcaa aaaagaaaaa 18780
aaaaaaaaag aagaagaaga agaagggggg aaactttctt ttccactttt ccagcagggg 18840
tcagaggtca aggtcaagcc ccaagctctg gacagtgagt gcatcgcatc tcacacgggg 18900
cccccagcaa ggaaagtgtc ggaaaagaag caacagcgcg ccccctagcg ccagctcact 18960
cgaacttcag ctctcgagcg tgaactcaag ctctacacac ctgctcatca tgtgccttac 19020
actcagagga agccttgggt cacagagtct gatttgattt ctggggcagc tgagagctaa 19080
aagctttagt tagcaaagct cagggccagt gtgacaggtc aaagatcacc cctccaaacc 19140
tcatcccaat ccccatgtgc tctacagact tggccctctc ccagaaatct ctatttattc 19200
tcccatctta cacccttaaa gcctacaggg gctcctcccg tatgacctgt gaacccctta 19260
gggagacaac tacttcatag aatttatcta tacatcttca gtatatactc tggttggcca 19320
tctccaaggt gacacacaga aggggcagca tctaccctgg gaccaaactg agcccaaatc 19380
caacacaaca tgtttggaaa aaaaaaaaaa aacttgtcct cagaaacttg aaccccctct 19440
cttagtctca gccacaggaa aggccccctt caggttgcca agtctcactc tttctcaatg 19500
agaggttcat atagttcaag ccccagccta ttggatgcgg tcaactgtct taagcatcct 19560
gagtaactag ggtttgcaac ccgctacagg atgatgtgtg tgtgtgtgtg tgtgtgtgtg 19620
tgtgtgatac ccccccacac acacacacac atacacacac ctgcatagca gacttggggc 19680
tcccagggag ccggcagaat gtccgtggag ctgagctgtg actcagatgc ccaccatgac 19740
ccaccaaatg ggatccccag ctttcccagg gcctgagggc aaccagaacc tccataggtt 19800
gtccccaagc tcacacgagg gtgggcggat ccctcagtca tctaccattg tcccctgtcc 19860
tggaacaata aagtaagcgc ctgatggttg caa 19893
<210> 31
<211> 10182
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 31
atgtactgct accagcctcc cttgcaacat atgtactgtt cttctcagcc tgccttccat 60
caggtaagtc tgaggcaagt ggttatactc cctggagctc tcagaaggct ctgtgggtgt 120
cgctgtgggc agtgtacgtg aggacaggca ggtgaagata tcagagtcct gaacctcagg 180
ctgggctagc ccagatatag aacagtggct agtgggaaga gaaaccattt ccctttccta 240
ggggcttaca gacttttctg aacccctggt ggaggctagg gagtctcaaa cagaaagtgc 300
agccgagact gaggcagaga catggtgtga accaaagagg gaggggagga gaatcgagaa 360
gcatcctaga cagacaggag caaagagggg tgtgtggtat gacacactgg ctgagcaggg 420
acgggaacaa aggctcccat cgaggtcaca ccttgctgtg tgaccttgtc cttacacttc 480
ccttaggcag agagtggtgg gcacaagcgc gaggctgggg tcctccctag tctttaccat 540
ccttgccctt ccccactcca ctgcccagtt tagcctctcc aggatggatg agattctcaa 600
tcattgcccc acactggcaa gggatggagg attttttaga agagacagaa gagagcccca 660
gagcagccag gcagctccct tggagtcacc gggcaagaca gagcaagtgg ctgcccagcg 720
cccagctcca tccacctgca gcctggcact cagacaggcc ctgcctgtgg agcaggttct 780
actcccgctc tggcattggc cctgatcctg gccaagccag gaggcaggct ggcggggggg 840
gggggggtaa tgtgtcaggt tgcctgtagt gggtacaagt gacagagagg gacaaagaga 900
catatcacat gagggggcat ccttgtcttt tagaaagggc ctcgctgcaa aggcctaaac 960
ttttctgagg tttctggtct gattcagggc gcgtgtgtcc ctaaggcagt ctgccacatc 1020
agggaccaag tcaccacagc ataaaggtga tcggacgcta agtgcccttg ctctgcccag 1080
ccctgctttg aagccctctg cagtcaacgt ccttgaacaa gatggccgcg cccagggctt 1140
tatggagccc agagagaggg tgactcaggc actaagtgtc tttcggtgac ctggaaagaa 1200
cacttcagcc tggagcagct gggggagtca gagtctccaa cccccagccc ccataaaaca 1260
ccattcctgg caccgcagcc actccctctg ccgtgtaaaa ctacctccta cccccacctg 1320
cccaccatca tgacctgctc tttcaaagag ccactgaaac tcataaaggt ggccgtgcct 1380
agaacacacc caggctggac atctcacttc cggcccattg ctccaagaga ggcccaggag 1440
aggaggcttg gggtgcctgc ctggaaagtg cagagggtgg gcttttcacc atcctattac 1500
catgacgacc agggtacctc aaagcctgag aggcaagagc tggaggaaaa cagcttcgat 1560
acctttgaga gtctgagttc tagagtgtgg atctctatcc aagtccaaaa tgtccattcc 1620
attgctccat agcattggga atatcgtcgg gtccatggcc aatggaagga gaatctggct 1680
tcagcttcct ctccagacgt gtctgcatga ggaggggttc cccacttggg aaggcatcat 1740
ggtgaccact ctgtcccttt tggcccctac agtactcccc gggtggaggc agctaccctg 1800
tgccctacct gggctcacct cactatccct atcagaggat tgcaccccag gccaacgccg 1860
aaggtcacca gccactcttc ccaaagccca tctactctta caggtacata tcctagcaca 1920
actggggcag aactaggagc aaggaggggc cctgggaaag ctaaggtacg gtgatcctca 1980
tcacttaagg gttattgcag gggatagaaa tcacgcccag taacttccaa ggatgctgga 2040
gaaacgatgc ccgagggtgg gtaggtagta gctacctttg accttttgtc agaccctgag 2100
gagtcttaac tctggttgga ctcagtagat gctgctgact tgggcgggtg ggcctgtgag 2160
gtcccatgct ggagccctgg tcatagagtt taggtgggag attaagagag ctgctcgctg 2220
ctcattgcct ttcccctctt ccaacattaa agcaaaaccc tctaacagct gccctgctac 2280
ttactaactg agaaactggt tgtctggaag gcaaatgggg agacaagcca ggctatttga 2340
agttttatgt aagagaatgt gggcagaaca gtgtgtggca cccagcagga agccttgtcc 2400
ccttcctatt gtctcacaga agcacgagga gctgtgggct gagtggtcag ggtcacttcc 2460
gtgcaatgat ggatgcaaag cctccatccc cacggctctg aggaggccag ctactgtatt 2520
tttgtcattt caaaactaag gaaacggact caaaagagag gttcagacaa gctcacacat 2580
ctaggggcta agccaggcgg caaactggtt ttccagattc cacaaaatgc tcgtagattt 2640
cagtctcagc ctcacagaac gtgtcggcca aggagagctg aagatggagg cctggtcagg 2700
agggctgggc tctcaggatc tctcttttgc agcatcctca tcttcatggc ccttaagaac 2760
agtaagaccg gaagccttcc agtcagtgaa atctacaatt tcatgacgga gcacttccct 2820
tacttcaagg tgagtctaaa acccaccctt gcccccagcc cagcatgaaa gcagtagggg 2880
tttggcccta agatgctttc tctctgtgtc cgtggtgaaa tgcaaagctc ccaagggggc 2940
tggatttttc aggactgcac atgacttaaa gagagagaat cacctcacat ctaccaggcc 3000
caaggctcca tcctccatag caaaaggggg ggggggggga ctgtgaacag agagctctag 3060
ctgcttgctc tgggatacac agcaattgag aggagctgga gaaggggttg gggggagtcc 3120
tgacaggctt cggagctcag ctacttacct cccaattgag agaggaaggc aagtgatgga 3180
agtcttttcc ggcctcagac agggtgctat ctatggggct ggaggaattc caagtcagag 3240
ctgatcacta aggtgacgat cgattgcctt ccagagtgag attaacatct gcctctagag 3300
gtggcatggc gagcttcact tgtacccaaa agtggggctc acagtcttgg ggtgtcccaa 3360
ggattgagcg ggttctcccc caaacccatg ggcagcatta attatttcct agtctccacg 3420
gaagagactt caggcaactc ccagcagttt cttcccagta gccctgggac aggaggactg 3480
agagggaccc tggggaaact gaggcatgag atttatcaat atgtaacagt tacagttgca 3540
tgaggtggag gtccaaccca gtagattttt caaatgtcct acaagatttc tacacagggg 3600
ttgggggtaa gaatcgatca tccctgaccc ttgatctaac cctgaggagt catgtctgtc 3660
tctgggtgag cctgctgaag tccaacctcc tggggacatg acagataccc ttctatccag 3720
gtgagcaaat ttgtcagagg gcggtttatc cttctaagat cacacagcag atggaccaat 3780
tgttgggtca agaaaaacac acccttatcc cttgatacat gtcccctgag accctcttgc 3840
acagacacct tctcctgagg taggtgcagg agagacaaga tcttttgttg gggaatccgg 3900
tccccaggac ttacaccctt gtcaacactg tctcacctac taaccaggca agacagatgc 3960
tgaggtgcag gtgatccaga gccagctctg tgggcagggg cgattcctgc ccccaactat 4020
ctgcactata gtctggcccg gggacaggtt gctagtgtgc agacagcttt gcacctgctg 4080
tgctcccagc agacagggag tgggaaaaaa catcttgcag catggctttg gctggaatgg 4140
aaatgtccac agacttgagg ttctgggagc gagaaacacc atagtctgga tgggctgttc 4200
ctgaatccca gactctccag gtagagatag gcgctcccct cctcctaagg tgacagcaaa 4260
gtcctccaaa aactaaacag agaaagggag gcgaggcccc tccctctcct ctgggccttc 4320
ttccctgccc actcctggcc ttacccccag cccctccctg catctcatct tcctggctta 4380
attatttttc ctgggagccg tgtaatccct gttttatggg actgaagagt gaagaggtct 4440
gacagctttt tcggttcggt tgtttttctt agccggttgc atcacccctg catgccagag 4500
tttacatttg acttcagaga gactgtgtga ggatctgacc agccccattg gcaaggcagg 4560
cccccacggg aatgacctgg gcaaggccct cagctaagga acagggctga agtccatacc 4620
cggttatcgt tttcctcatg tgatccaagg ccagctgttt tcttctctgg gcctcagctt 4680
ccctctctgt aacatgtcag tttggacgag ttggtaccta gattccttct aagccaacag 4740
gttctcttcg aacctctcca aagagagagt tccaaggctc taaacctctc agtccttatt 4800
tggaagtcat tttttagggc aaagacagag tggactctga agtggtcagt actcacaccc 4860
aaggcagcta ctgtgggcgt cccatagttc catgagtcag gggctgagga agtgtccagc 4920
caccatgcat aattgttaat gctgaccatc cctcttccaa acaggaagtg gctgcggtgg 4980
gggctgccct ggcatccgaa gtcacacatt tatgggacca taaaagttcc cggtgcccat 5040
taagtctgct ctggggtgat ggagctttgg ttcttagtag agtcagctgt gggagcttaa 5100
gaaggtccag cagctcaaga tgctcgctgg taacccctga tgaaccttgg ggtcatcagg 5160
accagcccca tgatgggtta gctgtcccca agaaaggctc cggcagctgc tgccagcaac 5220
tctagtgaga ctggcatcag gacccagggc ccggttctgc taggcgtgat tcagcttggc 5280
tgcaccctgg ggcaagggag ctagggagga gggcgtggcc atctctcatt aaccagaaag 5340
aggggctgaa agcgagagga gccagggtgt aaggaagtat catcaactgg agaggtagct 5400
ctacccaccg ccagccctcg tcgggctcag ggtggtcaac tgagccagat gtgggggaca 5460
ggaggcccat gcccctccac caccatccct gccaccgcct ctcacccaac tgagtcagct 5520
taatggtttt tacaaccctc cttgggcaca attactgcac tggtggcatg accgggcctc 5580
ctaatgggtg tttattctgt tggcacgagc accccctgcc tgagggctgg cctccccacc 5640
agggcacacc tccagggcac actcatgcga actcacaccc acacactcaa tcatgggtac 5700
acacgtactc tgagatactt tctcacacat agccatcctc actcaggagt tcagagacct 5760
atggtaggag acgccactcc caccgagaga tgtcgaagga tctggtgaat attcagtcac 5820
atacgactac cccagcctct accaacaccg catctgccat caaacataga ggcagcaggt 5880
gtgctaactc ccacctgttc accaaccctt ttctgcccag cttgctctgg agggatgagg 5940
tggacccaga ggaaacgcat tatgctgttc tccctttaaa gctgtcccca aagactttaa 6000
aatggcgatc ttcccctttc tacaagggga cacataggcc agaaggccca gtgagcatat 6060
cctgcttcag tggggaaata gaccaggggc ctcaatggca tttaccagtt gtcccttaaa 6120
gaaagatcac aagttggaca ttgtgactta tgcctgctgc aatctcagca cccaagagac 6180
tctgagcatc ttactgtgag cctggactac aagtgaggtc ccatctccaa aaggagtggt 6240
ggctaacaaa tatcggagag agctgggggg ggggtgcaca cctttaatcc cagcactcgg 6300
gaggcagaag gcagggggat ctctgaactt gaggtcagtc tggtccacaa agtgagttct 6360
aggacagcca ggactataca gagaaacctt gtctcaaaaa agaaccccca aaacaaacaa 6420
acaagcaaac aaaaacaaac aaacaagcaa acaagcaaac aaaaacaata aaagcagtga 6480
ggtggtggtt aagaacactg gctgctcttg cagaggactt gaattcagtt cccagcccca 6540
catggtggtt tacaaactat ctataactcc agttccagga gattcagtgc cctctttgac 6600
agactcctgt atgcatgtgg tgcatagaca gacatacagg cacccacatg tacacataaa 6660
gtgcataata aatatacaaa gggtcacatc ctctgaaggg tctagactaa gagctaggta 6720
gggtaacagc agcttttaga ttttagctaa aaaaaaacta acttaggcca ggcagtggtg 6780
gtgcacgcct ttaatcccag cacttgggag gcagaggctg gtggatttct gagttcgagg 6840
tcagcctggt ctacagagtg agttccagga cagccagggc tatacagaga aaccctgtct 6900
cgaaaaacca aaccaaacca aaccaaacca aacaaaccaa aaaacaaaaa ctaacttagg 6960
atcaacgatt ctgcccacta aagggttcta cgaatgcttt tggagctgaa tacatcaagc 7020
cagagtgtgt agagacccta tgtatagaat tggcgaagga atgttctaga atccccagac 7080
ctagagccat ttcttgccgc ctgaacccaa cctggattct tgttctgctc tggtagactg 7140
ctcctgatgg ctggaagaat tctgttcgcc ataacctgtc cctcaacaag tgctttgaga 7200
aggtggagaa taaatccgga agttcctctc gaaagggctg tctgtgggcc ctcaatcctt 7260
ccaaaatcga caagatgcag gaagaactgc agaagtggaa gaggaaagac cccattgctg 7320
tgcgcaaaag catggccaaa ccaggtgagg ctgtcaggcc tgtgtgagaa aggccaaggg 7380
acctgggtac cagaatgaag aagagcagag cctggggaga gagggataca gggagggggg 7440
tctgggctgg gaggctacaa aggagagagg cctcatggtg ttttcttttg ggcctttgca 7500
gaagagctgg acagcctcat tggagacaaa agggaaaaac tgggctctcc gctgctgggc 7560
tgtccacccc ctgggctggc aggcccaggt cccatccggc ccatggcacc atcagctggt 7620
ctttcccagc ctctgcaccc aatgcatcca gctccaggcc ccatgcctgg caagaacccc 7680
ctgcaggacc tactgggtgg ccatgctccc tcctgctatg ggcagaccta cccacacctt 7740
tcccccagcc tggccccttc tggacaccag cagccattgt tcccacagcc agatgggcat 7800
cttgagctgc aggcccagcc aggcaccccc caggactcac ctctacctgc ccacacacca 7860
cccagccacg gtgccaagct gatggctgag ccttcctcag ccaggaccat gcacgatact 7920
ctactgccag atggagacct tgggactgac ctggatgcta tcaacccttc tctcactgac 7980
ttcgacttcc agggtgagct gggagctggg agctgggaag ggtgggacag gactagagag 8040
gtgctcttgg ctgcgtggcc tagcctcttc atgtctctag gctgccacct gctggctcct 8100
gagtttcttg tcacctgagg cggatgacta ggaatgttaa attcgcattt gctccctgcc 8160
ctccagatca tgagctaaaa ggctctttcc cccatctccc ccctcctggt actctgatca 8220
tgtaccagat ggcttcatca tcaaaccgct catctgacaa agctgggaaa agccggaagt 8280
tccattggtg tacttgactg tgagggactg ggaggctaaa cgttccaaaa tcatttgcgt 8340
tttatcagaa tttagctttc acttcaggag acagactttc tatggaatgg aagacctcag 8400
agctaagcat gtcctagaga gatttgaggg tacaagccca gagaggtgaa tctttacatt 8460
ctcctccatc ttgcccgctc catcctacag gcagccaagc cccaccctct acccttctaa 8520
gccccgcccc ttcccgtttg aactgtagtg taccgagcaa gcctttttgg aggaggctgt 8580
tgatctatac cttagactgt tagaaataaa cttcacatag accttcattc cagacctgct 8640
gcggctgcag agaacaggcg gctgcagagg aggctatgtg gacgtgggat actataaatt 8700
ctatcagaag gctagagatg tgggtagggg gtaaagcgtt tgcctagcat gcaccaatcc 8760
ttagttaggg tcaatacccc agcatcacaa aacccttaat taatacccac tcaagctcct 8820
actgagtacc aggcatcttg caaacagctt tacatatgtt cttcccatct ggacctagca 8880
aacaatacta tacagagaga tacatccact caaggtcgct gggccagaaa gaaggagttg 8940
aacccaggtg gccaagagca gccagcgttg tcaggtctct ttctccaccc tgcggtgatg 9000
atgttccagg cagcgactcc agtcactggc ctgccacgcg gcaggtcaca cgaccctagg 9060
aggaactcag tgacagcact gtttgttcct cagagtcaag tgtcctttct ggttctatcc 9120
ctgtaccttg ggtcctgtga gggggcgggg aggagggtct agggagccag acctgtgtac 9180
ctcatcaagt tcggtggtgc actgtgggaa gactgtaggc ggcaaatcaa cctttgggaa 9240
ccaaggcaga agcctgagtg aagaggttca ggggggcctc taggccgctt ccaagaagag 9300
ctttgcaaca accttcaaat gggcaaatcc ttaaccttaa tctagtaccc tgttcttctc 9360
gaagaggccc agaggttacc tgcaactatg gcagtggttc tcaacctctg ggtcgcgacc 9420
ccgatggaaa gtctgatgac cctttcatag gggtcgcctg catctatggc ttttacaccg 9480
tgctaccttg gagctcggag ctggactctg aggctcagga aaaaaaaaaa aaagttcagt 9540
gattacttga ggtcccagag tggatgccaa gataggcttc cagtccgcat caccagactc 9600
ctgttctctg aggcttctga ggtacttggg tgggagacag actgggctta actctctatg 9660
gcctgccaat gatgaggctt cttccctctc cccgactagg aaatctgtgg gagcagctga 9720
aggatgacag cttggccctg gaccccctcg tattggtgac ctcgtcgccg acgtcatcct 9780
ccatgttgcc acccccacca gcagcccatt gcttcccccc agggccttgt ctggcagaaa 9840
caggcaatga ggcaggtgaa ctggcacctc caggcagcgg cggctccggt gctctgggag 9900
acatgcacct cagcactctc tactccgcct ttgtggaact ggagtccacg ccctcctcag 9960
cagctgccgg ccctgccgtg tacctcagtc ccggctcaaa gccattggct ctggcttgag 10020
ctatgcccaa catcagctgc ggcctttgcc tagctggctg ccccatattg ggctcacctt 10080
aaaggtcaaa gaaggaaaac actacctgtc tcctatgcca ctcagccaac ttatttgtta 10140
gccagaagtt gggggcatcc atctaggatg ctacctggtg ga 10182
<210> 32
<211> 19896
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 32
aagaggagga agagagtggg ggagggaagg agggagggag aggatgggga catgaaacag 60
caatgggacc aaaagtctgt ggaggagcaa ggacaggccc caggcctatt caggtaagac 120
tcagggtagc cacttcctag acctgctgcg cactgcacct caactgtaga ccctgagggg 180
ctggggacca acagccactc aaatatttcc attctggaga tcatgaagag tgactgaggg 240
gatgatgaca tagaactaag catcctccat ctccacccac acccatacat ggggcatgat 300
gacccagagc ggagacacat ggctagaaac tcaatgacac cgtagcgtgg agacacaagc 360
ctgagtacag ggacaagagc cacagatgca cagacattag agaaaacata gacgcaaaca 420
gacaaatccc tgcgaggacc tgtggagaag caggcatgcc cacagacatg ggagggaagt 480
cacatggatt tggggctaca cactgccaca cataaggtca gataatatga catgagatga 540
gccaaccctg tggacatctc ccagaaatca ttggatcctt ggggaggggg tctctgctgg 600
tccacactat acctgagagg gctcagtgct gcaaccatgt gctgcttccc agaaccccct 660
tactagctcc gtgaacacac atgtggcggc tgggctctcc tgacacacag gtgcatgtcc 720
caacaggcct gggccccacc catgggggct gacatctctg ttctggggtg caggtggggg 780
ccacagagcc accccttccc ccgcaagcca caggccatgc ccactggcag ggactggggg 840
cccaggctgg cacaggaggg gaggcctgga ggaggggggg acccgggcgc ggccagggcg 900
ggcacaggag cctgtacctg tcaaacaaga gccaaggagc aaactagctt cttagtcacc 960
tttctcttct ccccgttttt ggcagcaacc cctcggggca aggggaagct gatatcataa 1020
ttattggctc acccagcagc tgcctcccct cacctgatgt cagcccagac ccaggacaat 1080
caggctgacg gactgacaga cggtcggagc tcctggcccc ccagacccag gcccccacgc 1140
cgacctgctt cactgagcag gtaagaggag acctggccca agtcagccgt ggaggccaac 1200
aggggagggg gcttggtttt tttaatgggc cccaggaggc actgggtgct tctcagagtc 1260
tcattgtctc tccagggaga ctcaggatca gggtgagtac ctggaggctg aggggacccc 1320
tcctccactc tcctctctct ttcctggccc aggccttctg actttgatcc ttcttgctgt 1380
aatgtaggac tctgttttgc tgtacatggt gtctctgtgt ggtaggtctg tgtggtggca 1440
cccaccttga gttgggaggc aattatgact ccagatggac agctagagtt taaagataga 1500
cagataggca gattccctgc cgaggactga gtggctggct aagtggaaag ttgggtaccc 1560
cccccccagc tctggcaact tccatctctc tggaatacct ggtcttgggt ctgcacgacc 1620
cagattctat gggggaggct tggcatgcag aacggagaat ggtgcacctt gtgcagaagc 1680
ggacaggcgg caacaggtgc tgcggctagg agccgatgcc aagctggagg cacacctctc 1740
tgatcgccgg agatgtttct cttctttaag atcgctgcag tagagaggag tggccagcag 1800
acctgagaca ggcagagagt tcacagaccc cccaccccca ccccaactta gaattgggaa 1860
atctagctgc cagaaacccc tttatctact gagactacct accctttgcc ccatacctga 1920
ccaggcaaaa tcctggaatt tgctatagag ctccccaacc caccttcagc atccaaagaa 1980
gcatgttggg ttaaagctag agttataagt gggcgtgttt gcctctttgc tctgtaccta 2040
caagtgcagg ggacatgtct gggtatgtgc agtggcaggg tacagctgct cagcaagaaa 2100
ggaccagatg gagaagatgc ctcctctagg gacaccatct catcccctgt gtcccctacc 2160
cctgtgccgg gtagctccca caacagacag agtgtggtcc tctctgtgtt ctaaactgtt 2220
cagtaggaga ctcagtgagt tccttcatcg tttttttttg aaatcgtaac ttctgtagcg 2280
tctacctcta gcttctccac ttccttctct ttcttctact gatgaagccc agttcccctg 2340
cacagatgga tgagcacagg gtagaaaggg tggcagtgaa ctccagccct atccccactg 2400
ggctttagca agagctttct tcccatcctg acctacagac caggacaaga tgctggtagc 2460
agaatggcat cccagctgat gaggcctggc tcttctctct tgtggctttg tgaggggcta 2520
agacagagct gagctgggac caggggaaga acagagggtc caagtgctgc cctgggttga 2580
ggatcctctg gggtgaggat gccgtggggg gtggcacttg ccctcccagc tctccacccg 2640
gccccgcccg ggcagcctat gccgagctca gctcccggct gcaaggcctg ccgaggcacg 2700
ctgcaccccc aggcctctca cctcactcca ggccaggaac ctgttctccc gggaatgctg 2760
gggagttctc agaggacttt agttcccagg ggtttaggga aagaaatcct ctggaccagt 2820
gagtgagcca tggaaaagca agaaaatgga aagactgggg ggcagaggtg ggtcacaagg 2880
gcccattgcc ctcttcatct gtgtctatcc acacacagat cccacacttc tagctgacag 2940
cttttattgc tcttcgtgag aatgaagcct tgggacagtt aaagacaaaa gaaaaagccc 3000
ctcatggcac atgctttctg ccacatgcca tcatttggcc cccatggaaa gtcccttctg 3060
ccctctaaga aaatgacagg gcatcatccc agttggaccc aacaactccc atccagggag 3120
tctttcctac taacctttcc tcattgagcc tggtcttcac agaccagcag aaacacacac 3180
acacacacac acacacacac acatacacac atgcacacac acacacgcac acacacacac 3240
acacacacac acacacgcac acacacgcac acacacacgc acacacacgc acacacacgc 3300
gcacacacac acacacacac acacactacc tgccctgcac acatagcttg aacctgttcc 3360
tcagtacata aaagtcttgg ggacttctca gcctgctgcc ccattattct ctccagcacc 3420
atattctgac aagattgggg ccacctctct gtctattttt tgagacacga tctccctatc 3480
tagcctgagc taccctggaa ccctcagcct tctgggtgct gaaattaaag gtgtgcagta 3540
ccccactcac ctatgggcca cttctggttc cgcataccat agggacagag aggataaagg 3600
gcagaggcca tcatccctgt tgcagcctgc cagacttcca cagtgggaga tggtgacttc 3660
gggaagatag ttcagcattt taaatttagt tcttgcatgc agcccatgtc acccgagaag 3720
gcaatttcct ggggagggca ggccagcact gatctgggat gcattgtcgg gcaacatact 3780
cagtgcaagg gaaagacttg ctgcactctg agagacttcg tccccaaagc gcccacccag 3840
tgaccctcca gtaagatgca ctcctatccc ttccagcctg cctcggtccc tgcctccttt 3900
tgcatcccca gccctaaacc catttccctt taccagccct ctgtacgtat ctcagatttg 3960
acctgagctg gagcttctgt tgcgtgggtc tcctgtgtcc tgagattaca ggtgcagccg 4020
tgacaccagg tcctccctta tctcactcgc agccccagct cagacctgct ttccaccttt 4080
tctccctatc ctcaacttta ccaaagtttg tacaatccca ccccccccca cacacacaca 4140
tacacacaca cttcctctcc ttatttctta cttggcttcc ccactcctcc caccatccct 4200
cccagcccta tgagcccatc agcaccccca caggatggat gggcatccct gtgcacagtc 4260
agagaatcca aaacctcccg cagtgttccc taatttagtc tctgaactga gaggcccaga 4320
gccatgtccc aaggacaggt gggttgtatg ggatcatccc tagagaagct ctcagcttcc 4380
tgatcccata tgggccctaa aaaactggct gttggcagat agtaaaatgg agtctggctg 4440
aagcatggtt tggtgggaaa tcctgtgctt tatacgtctg aggtcctgga tgccagcctc 4500
agcccccaaa taaaaatgaa accatctagg tgagttcaga tacaagtatc tgatgctaca 4560
gcagtttgtc aagcaagggg gggtggggtg ggggagagct ggagggatga ctgatcccgt 4620
cagacatggc taggccaagg caggaagatg gacagcagct gaagcaaagc ccgctgggtt 4680
ctttaggaat gactgccact gtcatgagta tcccccagtc tctaccccgc ctgtggctct 4740
tgcttagtca gctcagatta atgggactgg ggaaagaatt agctgaatcg tgatctctcg 4800
ggggaactag agcctgcagt gagtcacagg gaagggaacc tgagctctca gggagattct 4860
ggaggctccc tgggtgtgtg ggggagggga gggggttatt ccctaagact tctctgagat 4920
gctacctaga gcctgcatgc tgggaggcac agccctggct ctctacccca aatttgcaga 4980
atgataatgt gattaaccag ctaccagcat gccccccaaa accctccaag ggccctcggc 5040
actctcgcat cctgaaacca ctatttgtga caaactgcag ccagtctagc accaacacat 5100
agtgggctta cttggcacca tcacacagtc agtatacaca cagacagcag aacagggcgt 5160
ggccctggaa ccggattgcc tgcagacaga tggaagtccc acctacactt gtaaattcca 5220
caatcacgtc ccaggctgta gcagcctatc gggttcagcg ccataggatg tgaacaagga 5280
tgaacacaca cacacacaca cacacacaca gcactgtgag gtgaagacca gttatcacac 5340
ttatcaactc ttgctctgta cagagccaga agaactacat caatgttcag tcaatggtag 5400
tctgtatcct gaccctctgt agaagaggtc ctagagtcta ccctgggcac ttacagatca 5460
gtaacttgtc tcttgtaatc ccagcagtga gcagactgag gcaggaggat tgctgagttt 5520
gaagccaccg tgggtagttc aagctacata gcgagtttga agtcaacttg gaatccatga 5580
tgagactctg tctaaaagaa aataagaaca acaaacaaac aaataaaaag aacagtcagg 5640
tagtggtggc ccacgccttt aatcccagaa ctcaggaagc agaggcaggt ggatctctgt 5700
gagttcaagg ccaggctgag ctacagagtg agttccagga cagaaaagaa tacacagaga 5760
aaccatgcct caaaaaaaca aaaacaaaaa caaacaaaca aaaaacccac caataatcaa 5820
aaagaaaaag agaaaagaaa gagaatctga atgttgatgg gtctttctat gcctatttgc 5880
aacacactta agagtgtgag gggttggaag aggaaattta gggtgacaga aaagccagaa 5940
ggatgtagag tgtcaaggaa ggaagctgga accaagtagc agagcaactc aggaagtccc 6000
tccaaacctc tcacttctcc aaaggcatgc tgggatctca gagccagctc accatgacca 6060
gcatccggaa gaaggagggg tgtgtacaac acacctgcct aggaaatcat ccctagcctg 6120
gcatggcagc gcaggtctct aatcccagct actcaggagg ctgaggcagg cagataagat 6180
gttcaaggct tgcctgaatg ttcaaagcca gctgaagcaa tttagtgatg cgaccttgtt 6240
tcaatatttt tttttaaaaa gctcattggg tctaaagctc attggtaaag cacttgccag 6300
gcacaggcaa gacccatgtt cagtcctagt cccacaaaaa caaacaaagc catctgtctc 6360
cttggttggc ttcagttctc ctctctgtca cacagacagg ctttggatgg aagcatcttc 6420
caatgtgctt cctcctcctt ggtccatgct tggagccaat agctgccctg cctgcccttt 6480
gctcggacgt agggcaggaa gtgcgccagc ttgcatccat cttgtgctga atcagggtta 6540
ttagcagtgg tggcagaatt aataccccta ataatagatt ggtggtaatg agcagtgctg 6600
gtaataatat gtacagagag aagcctctga ccaagggaca gtggcatcca cagccacctg 6660
aggcccctat caaggtgagc aggcaaaggg cgactgatac acccacactt ctatagggaa 6720
cataggaggt tctcatgcag tgccatggct ccctaggatc ctgggggagg aggcagaaaa 6780
aatggttctc acctgctcct agggacagga cagcagggga tgagtgcaag ggcagaatga 6840
agtcactatt tcatagagga ggaaaaaagc ttcatcctag tcactagccc aagctgatga 6900
cagagccagg acatggtcct cccatagtgc ccaagaggga aagagggatt ctgtaagaag 6960
caggggactc caagcttgac gaagccttca ggagagaacc caggttaggg gaggagatga 7020
cagaagttcc catcatgcct gatgggttta cagagcaaat cctcagctgc cagctactgg 7080
catagccaat tggcccggca cctgatttta ggggttgtga gaggaggctc agttccaaat 7140
gatgtcattg tggggtgggg tttcttggcc tctaatgggc tctcagaagc cagcggcttc 7200
ttctgcccct cagcctgtcc tccttcgcat ctcttcagca gatgtggctc acctcaggaa 7260
ggatgaaggt gataaaccct cctggccctt cagtccttcc ctcacctact tctcccgtct 7320
ctgatcatgg ctaagcagtc tgagggtttg agggaaaatt ccactctgga gaccagtgtc 7380
taaggcccca gatccctgtt ctctgtacgg tgcatccaga gggttacaca ttgcccccac 7440
cccaccccca ccccccagct cttcactgat atcctaatgt ttccttttag attatgatgg 7500
ttgtcactgt tgtttttctg agacagggtt tctctgtgta gccctggctg tactggaact 7560
cactctgtag accaggctgg cctcgaactc agggatcctc ctgagtactg ggattaaagg 7620
ccaccaacca ctgcctgtcc tttttcccgt tttccttgtg tgtgtgtgtg tgtgtgtgtg 7680
tgtgtgtgtg agagagagag agagagagag agagagagag aggtggggtc tcacaaatgc 7740
agcccaggct gaccttacat ttgtgattct cctctctcca cctcctgagt actaagatta 7800
cacagtcaac ccaactagga aacagttcta tctccaaatt ctttgtcagt ctgtccccac 7860
tgctcggggc ttcaaaattc ccctggaaag gtggagctgg gggcttttcc ctctctggct 7920
atccaaaggt gtcatgttcg tgaatatgag aatgcctgct aaccttgaag gggaagccac 7980
cttgctccta gacttgctcc tagacacaag atctcagggt tgcaggggca ccagcagagg 8040
caggtaggca gaagggagga aaaggcaggt cataaatggc tcccaagaag aaatgcaaac 8100
attactgtgg gtgagggcag tggagtagac atgaaaggtc tctagaaaga ggtctctaag 8160
gagggagagt ccaggaggac caatctctta aattaggtgg ccatggtaag gaagagggag 8220
gggaagacct aaaacaatcc taggagtaga tggtagcttt gaggaccagc atttcttgtt 8280
tctttaaaat ctctttctga tcatttacaa gacaggcacc cataggtatt gcaaagacat 8340
ccatccatcc acctgtctat ccatagccca tctatctgtt caaagtcacc catctatctc 8400
ttcatccatc tatcttccat ccaaccatcc acccatctat ccatctacct gtctagagag 8460
gtcagggcta ctgggaaggg cctgtggtcc tgtggcattt atggggcatg tgacttacct 8520
gcttggcctg gggaggcagt cccacccctg ccctggggca gggggccggt cctggcatgt 8580
gggtgtattt atacctggat ggaggctccc ctgaagctga aagctgcatg actccccaaa 8640
gccgggatgg tgtccacggc ccagagccca ctgtaagtgt ttagacatgg ctgcgttggg 8700
ggtcaggacg gggtggaaga agagggggag gggctggggt gtactgccca gaggtggtaa 8760
agactatgga aagagaggca tgctgggcag atgtttgtga gaaaagagga ggctgccagc 8820
atcagacatt ctcagcaaag ctgggacctt ccatggagac ggaatgagcc tatttccctt 8880
agctagtggg gagtggtcat tgacacataa ggcaagtgaa cgagattata agaattaaga 8940
acaaatatct aggaaagttt ccaggtcacc ccaggcagag aaggtagctc aagtgttttt 9000
ttgttttttg ttttttgttt ttgttttttt ttccgaaagg atgctttctg agcagactgc 9060
ttgaagaggc tgggggaatg tcaggtacct ttataaaaga cccgacagag attggaacta 9120
cctgactgca ggtgtgaatg gctcacagga tgctgtaaga gggatatgac tgcttttctt 9180
actacagtgt gtgtgtgtat gtgtgtatgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt 9240
gtgtgtgtgt gtgtacatgt gcatgcatgt cacagcaaga gtgtggaggc cagggaagaa 9300
aatgctgtag ttggtcctct ccggccacca tgtgggtcct aggaatcaaa ctcaggttgt 9360
cagggttgaa ggtgggtacc tacacctgcc tctggctaat tttcatccat cattctttac 9420
aaacccaggc agcatccaga gacagagagt ctagaggggc cttcaggacc ccagactggt 9480
aagaagaaac ctgttagaaa ccccatcttc ttgacacccc tagactccca gaatcctgag 9540
aggtgtgagc ctcaggcata gtccccaggt ctttcgctgc cacccccagc aagggtaatt 9600
agggacctgc tccagggaac ccctcccagc agccaggcag gtggagcctc gggtggggct 9660
gcaggcgaac actgggcaca gccccacccc tcgtaaaaca agctgccaca gccggcaaca 9720
gaaaccatta aggtggaact gagccggctc cgcctgctca taaagaacgg gcaggagggc 9780
gccgacaggt ggggggtggg ggggggggag agagagtgtg tgtgtgtgtg tgtgtgtgtg 9840
tgtgtgtgtg tgtgtgtgtg cagaactgct tctgagtgtc cttggccagg cagaagtgtg 9900
tgactggcct ctgtgactca gctgccagta ggggctccat ggacagaccc tcccagggaa 9960
acctccacct tgctgaggcg gggctgtgtg gtatagtggt taaggagaga ttagctttga 10020
agcctgggcc tgaatgagga gcacagttta ctagctgggg gacttgggcg agtcaggtta 10080
atctctctga gcctcagttt cctgatccat aaaaaggggt gacagtgcag tgcgtccctc 10140
ctaggacaga atccctggtg caagtctgac aggccactct gtccacttca cacacgtcca 10200
taggaccaac accagcatct taagatcaaa tgatccctgg gtttcctttt gcctatagaa 10260
gaactgaaat gcagatgagg aaataactta tccatggcca caaatccagc aaattaggtg 10320
tcccccaccc ccaccccagg acccaccctt aaacagcccc ttctgcctga gtgccgagaa 10380
gacagtctct cagaggcaga ggtagcaatg gctgaaggca gtgtagggct gactgttgca 10440
ggaagggtac aaggtgagga tgccagtgtc tggggacatg gggcagccac ctagcaatgc 10500
ttaccatgga ttcatcaccc gtccagttct cactgtctgg aggggcttcc tcccaacctc 10560
cctcctcagg ccagtgggcc ctttctctct ccctttgctt cagggtcgat cgggtctatt 10620
ttctttgtcc ccaaactttc cttcccctct ccaagaatca tggaaggaaa gtttgcccag 10680
gacgtccaga ccttgagagg gtcttcaaca cgtcttgcta aagttgtagc tctggataag 10740
agtgtctgga gcccttgagg tacaagagag gatttttcat tctctctgtg tggtcctagg 10800
catgcttctt ctctcttggc ctccttcccc caccccctgt gagaaacgga gtgaatacca 10860
ttgcttctct accttcagtg tgttggtaaa ttgtcatcaa ttatcagcta tcaaaaaggg 10920
ggaggggaaa ttctgattta gttttatgtt ggtttggttt ttgttttttt taggacaggg 10980
tctcactatt cagccttagc tatcctggaa ctcactatgt agaccaggct ggccttgaat 11040
ccatagagat ctacctgctt ctgcctcccc tgtgctggga ttaaaggtgt gtgccaacac 11100
attaggcagc attctggttg ataatgtgtg agatttttgc atgggcagct atgtagctat 11160
ggccagtttg cctttatttt gctgaatgtg gaattggaag tgatggattc agtttgctcc 11220
ctaaagcact ggctccagta tgctgtgttc actgtccaca gggacagagg cgagaagaga 11280
tagcaaagat aaaaagcatg caacttggac ttctgagtgt tccaatgatg cgggtctatg 11340
atgattatgg tcttgcggta gaagggaatt tgacccacat cttcctccat agtctcctgt 11400
ccaggaagga gacatagggt gggcagatga cagttctgag tggcggcata tgtgctctga 11460
accggctccc agagattctg gatttgggag aaggggagaa gaggaaggag atgagaagtc 11520
agtttgctga cactggcgca caggcaatac actgttctgt gaaaccagac gaggtgggct 11580
caaggtttga caacaaaagg ttccttctaa gttcataggc cactatcagg acactggagc 11640
cagcatggat gcttcctggg ggatccaaag cagtagggac accctatcca ttccatttca 11700
ggacattgaa gtttctgcag ccactggctc tactgcaggg gaatgaacaa aatggcctca 11760
gaggcccgag tcaagaggaa gttcagtcgg tggaggaagc ttatgacagg gagatgggtg 11820
ggggtgggga gaagacagga aagggcaaga aaaggtggtt ccctccccca caccagagcc 11880
catgccttaa attaactctg tcccactgct aattattaat aatagctatc atttattgag 11940
tatgtactgt gaggtaagct atttacaagc aatatttcat ccaatcctcc aaagaggtat 12000
gtattatcag ctccatttta cagaggagga aactgaggcc cagggaagga agttaaataa 12060
tgtgtccaac caaattctca ccctgatcat gattcagacc caaacctgac taccaagttg 12120
ggagctttaa gaactccaca cctctctctc tcccctctct gtgctgaaag gaccctcccc 12180
aaacattaac taggggccct ttgtccagcc cttgaagctg gtgacccttt aggataaagt 12240
tgattgaggg ctcacatttc ctagacagtg tggctttaga aaactcagtt catttcttga 12300
agggactcat ggtcactgag ctaggcgtca gtacttacag aacccaccca gaagaaaacc 12360
tgggtgagga ccactctggg acatctgtat ccccaatgca aatcaaggag agcctatgaa 12420
ccctgcaaag acaagcttag gtcctggaaa aaagggtggg ggttttcaga gccagagtct 12480
gttagtcctg gctaggaaca gaaggccttt gatgtacagg cgctctgcct ggggcttata 12540
caaatagctc catctaagga tgagggattg cagagtgagg cagaggtgct actaaacaag 12600
acagaacttt gagaggggaa ggcccagcta gagctcaggt tcgagtcagt aaagcagggc 12660
tggtgtctga gtcttccggg aggtcatgat aaatgaagac caggcaggca ggagaggcca 12720
gcaagggcag ctgctaccag gggacagcgt catctgcacc tctctcctag actatgaggc 12780
ctgaagcaac aagactgtca tggaaactgt agagcctgga attagaggcc tttggggaca 12840
gctacattta gccaactgaa gccagagata tgaggtgtgt ccccggccat tttctgggta 12900
tcagcaccat accacttaat cttcaagagg tcctagtgag ataggtctac acacctcatt 12960
tctcagacgg agaaagtgaa atatagactt acatagtgtg ttcaaaaatc acagaggcag 13020
aacgtgacaa ggcttggaac taaagtcaga tttgcctcaa gcccaaccat tactgttctc 13080
cctcctgggg ctgcagagcc tgaaatgggg agaaaaagcc cccggcctca cacctggagg 13140
gagatgagat tgtatttgga tggcgtcaag ttcacacgac accacctcct ctgggaaagg 13200
cagctctgag ccaggatgag gcatggcagg caggcctgag ctgtccaggg aacaggggcc 13260
agggcaggca gtcatgcaaa gccagagatg gggtgtcctc acccctacct gctcccttga 13320
agtgtccagt tacagccagc tccacgcttc cccgtcacgc cacatttagc attgctgaga 13380
gtgagcctgc gcagggatat agagaagggg tggtagggac tctttgaggg gtgggagaga 13440
acctccccac cttcaaaccc atctacactt acttcagcca ccagccgcct cccagcctaa 13500
tcctatgtgg gactctggac aggttccctt ccctctttga caccattagc ctctctgaag 13560
atggctaatt catcaaagat gtgtcaactg ctgactaggc caaactcaga aagatgaggc 13620
ctgccctctc tcccagattt cccagaactg caccactgct gtgacttgag gggtcttggg 13680
tagatggcat aagtcgaaag ctctggtttt tatttctgtt tggctcccag aacattccac 13740
tctgactccc atcaaataca gtagcggggg gtgggggggt agccaaagct tagttcaggt 13800
tctgacagtc aagggttata tgtgagactg ggaggtcacg gaatccctca gggcctcagt 13860
tctcttattt gaaagactgg attaataata tggcatcctt gaagtaaagc aatgagcttg 13920
ggcctgctta taatgccagc ccttgggcag ctgaggtcaa tagtttgtcg atagaggcag 13980
agggctgcct atagttcctg gcctatgtag tgagtttcag gccagcatag actatatggc 14040
gagagcctgt cgcacacctt taatcccagc acttgggagg cagaggcagg tggatttctg 14100
agtccgaggc cagcctggtc tacaaagtga gttccaggac aaccagggct acacagagaa 14160
accctgtctt gaaaaaccaa aaaaaacaat aggggcgggc tggagagatg gctcagtagg 14220
tgagagcact gactgctctt ccagagatcc tgagttcaaa tcccagcatc tacatggtgg 14280
ctcacaacca tcgagatctg acgccctctt ctggtgtgtc tgtagacagc tacttacata 14340
taataaataa ataaatctta aaaaaaaaaa aaaaccaata ggggctacag attttcactg 14400
agtaaagcaa ctatcaggaa gccctaggtc agaacccaaa actgagcaca aaggtccgtg 14460
tccataatcc cagcacgtgg gaggtggaga aaagcagaaa cctaaggtca tcttcagcag 14520
gtggaaaacc ttccaaagtg ctacccagga gtcagtacag agcagtccct cggtaaacaa 14580
tggctgctgt cagggatgaa ctcagggacg tgagttcaaa ggctgttgct gataatggaa 14640
gagccccagg gataacacca ttaataatga gacctggcgt gtggatcaag ccctgtgtgc 14700
ttgtgctgtg ctccgagctt tctctgcatg atttcatttc actctcagcg ccctgtgcga 14760
ggctctgtca ctcatcttgt ttgcagatgc tgctgtggaa gtgcagagag ctctgctgac 14820
acagcctgga atggacagcc tcgcctggcg ctgagcccca aggcctccca gctgctctgt 14880
ggtgctgggt cagggttcta caacaacagt tcagaagggg tcagtgctca gatctagtcc 14940
aagccttagc atttcatagg caagctgaag agttcagaaa gaggccaggg atgggagcca 15000
gggagcatcc tgggaggcag tgggctcgat cccacacaga acagggaagg agaggagaag 15060
agaggggcta aggaaatgag acgtgcttgg tacaaagtca cggacaaaga ttgatagagg 15120
ttaaaaaaac aacacttccc agatatccca cgggccctac cagcaaggcc ccttggtcat 15180
cccacagggt taccctctgt gtcattggga ttgctgtcac ataaagccta ggcatgatac 15240
atctcctgac tcctcctctt ctcagggcct acccagcaac tgataaggtc accttgcata 15300
gacataggaa acctagcagc caggctccct gggaagcaag ggctcactga ctcactgact 15360
gaccaggtca cttgctgacc agcaaagctt gagttgagac aggagctctc ctccgagtat 15420
ccaatctggc tcagtttctc tctcatgata gctctttcct catcctcttc agcatttgcc 15480
taccagcatg taacaatttc tcaccttggc tatctatcta tcatctgtct gtctgactgt 15540
ctgtctatca tctcttccct tctctcccta tgtccctaat ccgatggcta gctccagcca 15600
gggtcccagt ccagggaaag ggtaggaatg gaggtggtgg gcctggggtt ggccatgcct 15660
agacgttggt cctcattctc attgtagctg gctttcttcg aggccaggac tgggtgatgg 15720
tgtcgctact ccctccgcag tctgacgtca cacttccagg ctccacccga ctggagggcg 15780
aaccccaagg ggacctcatg caggctccgg gcctcccaga ctcccctgcc ccacagaacg 15840
taagtacctg gaacctaggc ctggaatagg gcaagcctgg tagctctaag agcattgagt 15900
agatggtcac tgccccacac aaggaccttc gggatctact ttgtccctta cacagaaaaa 15960
atgatgatga ctctagaccc agaagggcca agtcacagat ctctgtccat ccttggtttg 16020
gtgtttcccc agatatggaa cccatcagcc tcaggggacc caggtttaga agaagtatgc 16080
ttgtatcaga ttggaatccc aagagcaggt tgccttcccc gtcactttgg gactcctgtg 16140
aactcagcca tactctatta tctcagtaca gcacagggtc ctggcagatg ccctggtcca 16200
acccccattt acagattctc tattctgtct gcccagaagc atgctaactt cagctgctcg 16260
tcgtttgtgc ctgacggccc tccagagagg acaccctcac tgcccccaca cagccccagc 16320
atcgcatctc cagacccaga gcagatccag ggccactgca cagccggacc cggcccgggc 16380
tccttccgcc tttctccttc agaaaagtat cctggctttg gctttgagga gggcccagca 16440
ggcagcccag ggcgcttcct caagggcaac cacatgcctt tccaccccta caagaggcac 16500
ttccatgagg acatcttctc tgaggcccag acggccatgg cacttgatgg acactccttt 16560
aagactcagg gggcactgga agcctttgag gagatccctg tggacatggg cgatgctgag 16620
gccttcctgc ctagcttccc agcagaggct tggtgcaata aactccctta ccccagccag 16680
gaacacaacc aaattctggt gagtgccagt ggccgagggc cttccacctc ctctctccta 16740
gctgcctaga aagactcttc aaagccatgc ctggtggcac atgcctgtaa tcctactact 16800
caggaggctg aggcaggagg actgcttgag gcagaggcca gcctctgcct atgtatggag 16860
accctgtctc caaatcagag ctccagagga ggcagcaagc acagagggtg ggggcctcct 16920
ggttccatac tggtcccctg gggaggggga tgctagcctg gcaggcgtgg agagggcagg 16980
tggagggggc aggtgaggga agctcatgag ggaagggagc tggcagcttc ccagaggctg 17040
ctgagtcaag attccagagg gtgacttctc tgtttattta agtgtcaaag aatgccaagc 17100
cagaccaaca cacccctatg caaatgtgag gaggaaaaga cacattccag agagagaagg 17160
ttctagacag agcatcagaa caaaaacccc accaaataag gactggggac ttcactgcta 17220
gctccaggcc ccttccagac cctgcttttt tatttatttt catgggtgag acagaaaaca 17280
gctatgttgc ctaaggccgt ccatgaacta gagatcctcc tggtgctgga attactggtg 17340
gggttctgga cctattctaa ggccagagca ggcttctatg gataagtgcc ttgggacacc 17400
tcagaaggtt gactagcact tccgcagcca gatctgcagg ccctgtgacc tcgggcaagt 17460
cacttaatct ctctgagcct cgtgggaaaa gttctgttaa gggtttcctg tctcaggctt 17520
gccccctgct cccgatctct gattcccaag gcaccccagt gtgataattc atcctggact 17580
ctgctcctcc aggggtccac cggccttctt tacctcctac ttccaaatag gcccattcta 17640
gtccttagcc acacctatca ggaaggaaga gggggaaaac agatgaacac ccaggtgggt 17700
caggtgtggc caagacagga tcttctgctg tttctggagc catgactgct ttttctcaag 17760
cctttagaat gtggtgggag ccacagcttg gcacccagaa agccagcagt tgtcccccat 17820
tgtccactcg ttgtagctcc ttgtcactca gccaggagat ttccttccag ggttgcatca 17880
atagagttct cactatctcc atcttgagaa tcaggacccg gccctctctg gttgaggcct 17940
tatgacttac caggacatcc acaacctata aacagaagtc cacctggccc catggacaca 18000
agctgtaccc aactgcctgg tccactctat gggtgacagg tgccatgtag tttcccctct 18060
ttgggagcag ctgtatcatc tgtgaaatga aggggttgga ctcagtgctt gtggcccttg 18120
caggctcaag atcctgtgat tacggcaatc tctgcatcag ctgccctgag gcatacccag 18180
aaagtggtca cagctagctt tcacccctct gggcccaaat gctgccttcc caaaggcccg 18240
tgggaatcct agtttcagga gcctgatcct ggcttgtcta tctgccaggt aggtctgagc 18300
cgcacgccct tgctaactct atgcagggct cagctctggg ttaggccctg aggacttcac 18360
atgggtctct cagaactctc gggtcccatt caagtctatg tgacaagtcc cctccatttc 18420
tcttggtggc ccagactagc ctgccgcctg cagtgaggtg gaatgtgagg aacactgtcc 18480
tttctagcct agcccctcta ctgacttgct gatttccctc aggaaaaccc ctatccatct 18540
ctgttctctg ttccttgcct aagagttagc tttgagaggg tcacagaaag gattcttcca 18600
gtgtgaagtt caagacaaga aaaagaaatg gaggcccgtc attggtggtg cacatcttta 18660
atcccagcac ttgggaggca gaggcaggca gatttctgag tttgaggtca gcctggtcta 18720
caaagtgagt tccaggacag ccagggctac acagagaaac cgtgcctcaa aaaagaaaaa 18780
aaaaaaaaag aagaagaaga agaagggggg aaactttctt ttccactttt ccagcagggg 18840
tcagaggtca aggtcaagcc ccaagctctg gacagtggtc ctgggcccgc atctcacacg 18900
gggcccccag caaggaaagt gtcggaaaag aagcaacagc gcgcccccta gcgccagctc 18960
actcgaactt cagctctcga gcgtgaactc aagctctaca cacctgctca tcatgtgcct 19020
tacactcaga ggaagccttg ggtcacagag tctgatttga tttctggggc agctgagagc 19080
taaaagcttt agttagcaaa gctcagggcc agtgtgacag gtcaaagatc acccctccaa 19140
acctcatccc aatccccatg tgctctacag acttggccct ctcccagaaa tctctattta 19200
ttctcccatc ttacaccctt aaagcctaca ggggctcctc ccgtatgacc tgtgaacccc 19260
ttagggagac aactacttca tagaatttat ctatacatct tcagtatata ctctggttgg 19320
ccatctccaa ggtgacacac agaaggggca gcatctaccc tgggaccaaa ctgagcccaa 19380
atccaacaca acatgtttgg aaaaaaaaaa aaaaacttgt cctcagaaac ttgaaccccc 19440
tctcttagtc tcagccacag gaaaggcccc cttcaggttg ccaagtctca ctctttctca 19500
atgagaggtt catatagttc aagccccagc ctattggatg cggtcaactg tcttaagcat 19560
cctgagtaac tagggtttgc aacccgctac aggatgatgt gtgtgtgtgt gtgtgtgtgt 19620
gtgtgtgtga taccccccca cacacacaca cacatacaca cacctgcata gcagacttgg 19680
ggctcccagg gagccggcag aatgtccgtg gagctgagct gtgactcaga tgcccaccat 19740
gacccaccaa atgggatccc cagctttccc agggcctgag ggcaaccaga acctccatag 19800
gttgtcccca agctcacacg agggtgggcg gatccctcag tcatctacca ttgtcccctg 19860
tcctggaaca ataaagtaag cgcctgatgg ttgcaa 19896
<210> 33
<211> 9095
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 33
ggtcctggga tgtactgcta ccagcctccc ttgcaacata tgtactgttc ttctcagcct 60
gccttccatc aggtaagtct gaggcaagtg gttatactcc ctggagctct cagaaggctc 120
tgtgggtgtc gctgtgggca gtgtacgtga ggacaggcag gtgaagatat cagagtcctg 180
aacctcaggc tgggctagcc cagatataga acagtggcta gtgggaagag aaaccatttc 240
cctttcctag gggcttacag acttttctga acccctggtg gaggctaggg agtctcaaac 300
agaaagtgca gccgagactg aggcagagac atggtgtgaa ccaaagaggg aggggaggag 360
aatcgagaag catcctagac agacaggagc aaagaggggt gtgtggtatg acacactggc 420
tgagcaggga cgggaacaaa ggctcccatc gaggtcacac cttgctgtgt gaccttgtcc 480
ttacacttcc cttaggcaga gagtggtggg cacaagcgcg aggctggggt cctccctagt 540
ctttaccatc cttgcccttc cccactccac tgcccagttt agcctctcca ggatggatga 600
gattctcaat cattgcccca cactggcaag ggatggagga ttttttagaa gagacagaag 660
agagccccag agcagccagg cagctccctt ggagtcaccg ggcaagacag agcaagtggc 720
tgcccagcgc ccagctccat ccacctgcag cctggcactc agacaggccc tgcctgtgga 780
gcaggttcta ctcccgctct ggcattggcc ctgatcctgg ccaagccagg aggcaggctg 840
gcgggggggg ggggggtaat gtgtcaggtt gcctgtagtg ggtacaagtg acagagaggg 900
acaaagagac atatcacatg agggggcatc cttgtctttt agaaagggcc tcgctgcaaa 960
ggcctaaact tttctgaggt ttctggtctg attcagggcg cgtgtgtccc taaggcagtc 1020
tgccacatca gggaccaagt caccacagca taaaggtgat cggacgctaa gtgcccttgc 1080
tctgcccagc cctgctttga agccctctgc agtcaacgtc cttgaacaag atggccgcgc 1140
ccagggcttt atggagccca gagagagggt gactcaggca ctaagtgtct ttcggtgacc 1200
tggaaagaac acttcagcct ggagcagctg ggggagtcag agtctccaac ccccagcccc 1260
cataaaacac cattcctggc accgcagcca ctccctctgc cgtgtaaaac tacctcctac 1320
ccccacctgc ccaccatcat gacctgctct ttcaaagagc cactgaaact cataaaggtg 1380
gccgtgccta gaacacaccc aggctggaca tctcacttcc ggcccattgc tccaagagag 1440
gcccaggaga ggaggcttgg ggtgcctgcc tggaaagtgc agagggtggg cttttcacca 1500
tcctattacc atgacgacca gggtacctca aagcctgaga ggcaagagct ggaggaaaac 1560
agcttcgata cctttgagag tctgagttct agagtgtgga tctctatcca agtccaaaat 1620
gtccattcca ttgctccata gcattgggaa tatcgtcggg tccatggcca atggaaggag 1680
aatctggctt cagcttcctc tccagacgtg tctgcatgag gaggggttcc ccacttggga 1740
aggcatcatg gtgaccactc tgtccctttt ggcccctaca gtactccccg ggtggaggca 1800
gctaccctgt gccctacctg ggctcacctc actatcccta tcagaggatt gcaccccagg 1860
ccaacgccga aggtcaccag ccactcttcc caaagcccat ctactcttac aggtacatat 1920
cctagcacaa ctggggcaga actaggagca aggaggggcc ctgggaaagc taaggtacgg 1980
tgatcctcat cacttaaggg ttattgcagg ggatagaaat cacgcccagt aacttccaag 2040
gatgctggag aaacgatgcc cgagggtggg taggtagtag ctacctttga ccttttgtca 2100
gaccctgagg agtcttaact ctggttggac tcagtagatg ctgctgactt gggcgggtgg 2160
gcctgtgagg tcccatgctg gagccctggt catagagttt aggtgggaga ttaagagagc 2220
tgctcgctgc tcattgcctt tcccctcttc caacattaaa gcaaaaccct ctaacagctg 2280
ccctgctact tactaactga gaaactggtt gtctggaagg caaatgggga gacaagccag 2340
gctatttgaa gttttatgta agagaatgtg ggcagaacag tgtgtggcac ccagcaggaa 2400
gccttgtccc cttcctattg tctcacagaa gcacgaggag ctgtgggctg agtggtcagg 2460
gtcacttccg tgcaatgatg gatgcaaagc ctccatcccc acggctctga ggaggccagc 2520
tactgtattt ttgtcatttc aaaactaagg aaacggactc aaaagagagg ttcagacaag 2580
ctcacacatc taggggctaa gccaggcggc aaactggttt tccagattcc acaaaatgct 2640
cgtagatttc agtctcagcc tcacagaacg tgtcggccaa ggagagctga agatggaggc 2700
ctggtcagga gggctgggct ctcaggatct ctcttttgca gcatcctcat cttcatggcc 2760
cttaagaaca gtaagaccgg aagccttcca gtcagtgaaa tctacaattt catgacggag 2820
cacttccctt acttcaaggt gagtctaaaa cccacccttg cccccagccc agcatgaaag 2880
cagtaggggt ttggccctaa gatgctttct ctctgtgtcc gtggtgaaat gcaaagctcc 2940
caagggggct ggatttttca ggactgcaca tgacttaaag agagagaatc acctcacatc 3000
taccaggccc aaggctccat cctccatagc aaaagggggg ggggggggac tgtgaacaga 3060
gagctctagc tgcttgctct gggatacaca gcaattgaga ggagctggag aaggggttgg 3120
ggggagtcct gacaggcttc ggagctcagc tacttacctc ccaattgaga gaggaaggca 3180
agtgatggaa gtcttttccg gcctcagaca gggtgctatc tatggggctg gaggaattcc 3240
aagtcagagc tgatcactaa ggtgacgatc gattgccttc cagagtgaga ttaacatctg 3300
cctctagagg tggcatggcg agcttcactt gtacccaaaa gtggggctca cagtcttggg 3360
gtgtcccaag gattgagcgg gttctccccc aaacccatgg gcagcattaa ttatttccta 3420
gtctccacgg aagagacttc aggcaactcc cagcagtttc ttcccagtag ccctgggaca 3480
ggaggactga gagggaccct ggggaaactg aggcatgaga tttatcaata tgtaacagtt 3540
acagttgcat gaggtggagg tccaacccag tagatttttc aaatgtccta caagatttct 3600
acacaggggt tgggggtaag aatcgatcat ccctgaccct tgatctaacc ctgaggagtc 3660
atgtctgtct ctgggtgagc ctgctgaagt ccaacctcct ggggacatga cagataccct 3720
tctatccagg tgagcaaatt tgtcagaggg cggtttatcc ttctaagatc acacagcaga 3780
tggaccaatt gttgggtcaa gaaaaacaca cccttatccc ttgatacatg tcccctgaga 3840
ccctcttgca cagacacctt ctcctgaggt aggtgcagga gagacaagat cttttgttgg 3900
ggaatccggt ccccaggact tacacccttg tcaacactgt ctcacctact aaccaggcaa 3960
gacagatgct gaggtgcagg tgatccagag ccagctctgt gggcaggggc gattcctgcc 4020
cccaactatc tgcactatag tctggcccgg ggacaggttg ctagtgtgca gacagctttg 4080
cacctgctgt gctcccagca gacagggagt gggaaaaaac atcttgcagc atggctttgg 4140
ctggaatgga aatgtccaca gacttgaggt tctgggagcg agaaacacca tagtctggat 4200
gggctgttcc tgaatcccag actctccagg tagagatagg cgctcccctc ctcctaaggt 4260
gacagcaaag tcctccaaaa actaaacaga gaaagggagg cgaggcccct ccctctcctc 4320
tgggccttct tccctgccca ctcctggcct tacccccagc ccctccctgc atctcatctt 4380
cctggcttaa ttatttttcc tgggagccgt gtaatccctg ttttatggga ctgaagagtg 4440
aagaggtctg acagcttttt cggttcggtt gtttttctta gccggttgca tcacccctgc 4500
atgccagagt ttacatttga cttcagagag actgtgtgag gatctgacca gccccattgg 4560
caaggcaggc ccccacggga atgacctggg caaggccctc agctaaggaa cagggctgaa 4620
gtccataccc ggttatcgtt ttcctcatgt gatccaaggc cagctgtttt cttctctggg 4680
cctcagcttc cctctctgta acatgtcagt ttggacgagt tggtacctag attccttcta 4740
agccaacagg ttctcttcga acctctccaa agagagagtt ccaaggctct aaacctctca 4800
gtccttattt ggaagtcatt ttttagggca aagacagagt ggactctgaa gtggtcagta 4860
ctcacaccca aggcagctac tgtgggcgtc ccatagttcc atgagtcagg ggctgaggaa 4920
gtgtccagcc accatgcata attgttaatg ctgaccatcc ctcttccaaa caggaagtgg 4980
ctgcggtggg ggctgccctg gcatccgaag tcacacattt atgggaccat aaaagttccc 5040
ggtgcccatt aagtctgctc tggggtgatg gagctttggt tcttagtaga gtcagctgtg 5100
ggagcttaag aaggtccagc agctcaagat gctcgctggt aacccctgat gaaccttggg 5160
gtcatcagga ccagccccat gatgggttag ctgtccccaa gaaaggctcc ggcagctgct 5220
gccagcaact ctagtgagac tggcatcagg acccagggcc cggttctgct aggcgtgatt 5280
cagcttggct gcaccctggg gcaagggagc tagggaggag ggcgtggcca tctctcatta 5340
accagaaaga ggggctgaaa gcgagaggag ccagggtgta aggaagtatc atcaactgga 5400
gaggtagctc tacccaccgc cagccctcgt cgggctcagg gtggtcaact gagccagatg 5460
tgggggacag gaggcccatg cccctccacc accatccctg ccaccgcctc tcacccaact 5520
gagtcagctt aatggttttt acaaccctcc ttgggcacaa ttactgcact ggtggcatga 5580
ccgggcctcc taatgggtgt ttattctgtt ggcacgagca ccccctgcct gagggctggc 5640
ctccccacca gggcacacct ccagggcaca ctcatgcgaa ctcacaccca cacactcaat 5700
catgggtaca cacgtactct gagatacttt ctcacacata gccatcctca ctcaggagtt 5760
cagagaccta tggtaggaga cgccactccc accgagagat gtcgaaggat ctggtgaata 5820
ttcagtcaca tacgactacc ccagcctcta ccaacaccgc atctgccatc aaacatagag 5880
gcagcaggtg tgctaactcc cacctgttca ccaacccttt tctgcccagc ttgctctgga 5940
gggatgaggt ggacccagag gaaacgcatt atgctgttct ccctttaaag ctgtccccaa 6000
agactttaaa atggcgatct tcccctttct acaaggggac acataggcca gaaggcccag 6060
tgagcatatc ctgcttcagt ggggaaatag accaggggcc tcaatggcat ttaccagttg 6120
tcccttaaag aaagatcaca agttggacat tgtgacttat gcctgctgca atctcagcac 6180
ccaagagact ctgagcatct tactgtgagc ctggactaca agtgaggtcc catctccaaa 6240
aggagtggtg gctaacaaat atcggagaga gctggggggg gggtgcacac ctttaatccc 6300
agcactcggg aggcagaagg cagggggatc tctgaacttg aggtcagtct ggtccacaaa 6360
gtgagttcta ggacagccag gactatacag agaaaccttg tctcaaaaaa gaacccccaa 6420
aacaaacaaa caagcaaaca aaaacaaaca aacaagcaaa caagcaaaca aaaacaataa 6480
aagcagtgag gtggtggtta agaacactgg ctgctcttgc agaggacttg aattcagttc 6540
ccagccccac atggtggttt acaaactatc tataactcca gttccaggag attcagtgcc 6600
ctctttgaca gactcctgta tgcatgtggt gcatagacag acatacaggc acccacatgt 6660
acacataaag tgcataataa atatacaaag ggtcacatcc tctgaagggt ctagactaag 6720
agctaggtag ggtaacagca gcttttagat tttagctaaa aaaaaactaa cttaggccag 6780
gcagtggtgg tgcacgcctt taatcccagc acttgggagg cagaggctgg tggatttctg 6840
agttcgaggt cagcctggtc tacagagtga gttccaggac agccagggct atacagagaa 6900
accctgtctc gaaaaaccaa accaaaccaa accaaaccaa acaaaccaaa aaacaaaaac 6960
taacttagga tcaacgattc tgcccactaa agggttctac gaatgctttt ggagctgaat 7020
acatcaagcc agagtgtgta gagaccctat gtatagaatt ggcgaaggaa tgttctagaa 7080
tccccagacc tagagccatt tcttgccgcc tgaacccaac ctggattctt gttctgctct 7140
ggtagactgc tcctgatggc tggaagaatt ctgttcgcca taacctgtcc ctcaacaagt 7200
gctttgagaa ggtggagaat aaatccggaa gttcctctcg aaagggctgt ctgtgggccc 7260
tcaatccttc caaaatcgac aagatgcagg aagaactgca gaagtggaag aggaaagacc 7320
ccattgctgt gcgcaaaagc atggccaaac caggtgaggc tgtcaggcct gtgtgagaaa 7380
ggccaaggga cctgggtacc agaatgaaga agagcagagc ctggggagag agggatacag 7440
ggaggggggt ctgggctggg aggctacaaa ggagagaggc ctcatggtgt tttcttttgg 7500
gcctttgcag aagagctgga cagcctcatt ggagacaaaa gggaaaaact gggctctccg 7560
ctgctgggct gtccaccccc tgggctggca ggcccaggtc ccatccggcc catggcacca 7620
tcagctggtc tttcccagcc tctgcaccca atgcatccag ctccaggccc catgcctggc 7680
aagaaccccc tgcaggacct actgggtggc catgctccct cctgctatgg gcagacctac 7740
ccacaccttt cccccagcct ggccccttct ggacaccagc agccattgtt cccacagcca 7800
gatgggcatc ttgagctgca ggcccagcca ggcacccccc aggactcacc tctacctgcc 7860
cacacaccac ccagccacgg tgccaagctg atggctgagc cttcctcagc caggaccatg 7920
cacgatactc tactgccaga tggagacctt gggactgacc tggatgctat caacccttct 7980
ctcactgact tcgacttcca gggtgagctg ggagctggga gctgggaagg gtgggacagg 8040
actagagagg tgctcttggc tgcgtggcct agcctcttca tgtctctagg ctgccacctg 8100
ctggctcctg agtttcttgt cacctgaggc ggatgactag gaatgttaaa ttcgcatttg 8160
ctccctgccc tccagatcat gagctaaaag gctctttccc ccatctcccc cctcctggta 8220
ctctgatcat gtaccagatg gcttcatcat caaaccgctc atctgacaaa gctgggaaaa 8280
gccggaagtt ccattggtgt acttgactgt gagggactgg gaggctaaac gttccaaaat 8340
catttgcgtt ttatcagaat ttagctttca cttcaggaga cagactttct atggaatgga 8400
agacctcaga gctaagcatg tcctagagag atttgagggt acaagcccag agaggtgaat 8460
ctttacattc tcctccatct tgcccgctcc atcctacagg cagccaagcc ccaccctcta 8520
cccttctaag ccccgcccct tcccgtttga actgtagtgt accgagcaag cctttttgga 8580
ggaggctgtt gatctatacc ttagactgtt agaaataaac ttcacataga ccttcattcc 8640
agacctgctg cggctgcaga gaacaggcgg ctgcagagga ggctatgtgg acgtgggata 8700
ctataaattc tatcagaagg ctagagatgt gggtaggggg taaagcgttt gcctagcatg 8760
caccaatcct tagttagggt caatacccca gcatcacaaa acccttaatt aatacccact 8820
caagctccta ctgagtacca ggcatcttgc aaacagcttt acatatgttc ttcccatctg 8880
gacctagcaa acaatactat acagagagat acatccactc aaggtcgctg ggccagaaag 8940
aaggagttga acccaggtgg ccaagagcag ccagcgttgt caggtctctt tctccaccct 9000
gcggtgatga tgttccaggc agcgactcca gtcactggcc tgccacgcgg caggtcacac 9060
gaccctagga ggaactcagt gacagcactg tttgt 9095
<210> 34
<211> 31
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 34
catctaggat gctacctggt ggacccgcat c 31
<210> 35
<211> 20952
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 35
aagaggagga agagagtggg ggagggaagg agggagggag aggatgggga catgaaacag 60
caatgggacc aaaagtctgt ggaggagcaa ggacaggccc caggcctatt caggtaagac 120
tcagggtagc cacttcctag acctgctgcg cactgcacct caactgtaga ccctgagggg 180
ctggggacca acagccactc aaatatttcc attctggaga tcatgaagag tgactgaggg 240
gatgatgaca tagaactaag catcctccat ctccacccac acccatacat ggggcatgat 300
gacccagagc ggagacacat ggctagaaac tcaatgacac cgtagcgtgg agacacaagc 360
ctgagtacag ggacaagagc cacagatgca cagacattag agaaaacata gacgcaaaca 420
gacaaatccc tgcgaggacc tgtggagaag caggcatgcc cacagacatg ggagggaagt 480
cacatggatt tggggctaca cactgccaca cataaggtca gataatatga catgagatga 540
gccaaccctg tggacatctc ccagaaatca ttggatcctt ggggaggggg tctctgctgg 600
tccacactat acctgagagg gctcagtgct gcaaccatgt gctgcttccc agaaccccct 660
tactagctcc gtgaacacac atgtggcggc tgggctctcc tgacacacag gtgcatgtcc 720
caacaggcct gggccccacc catgggggct gacatctctg ttctggggtg caggtggggg 780
ccacagagcc accccttccc ccgcaagcca caggccatgc ccactggcag ggactggggg 840
cccaggctgg cacaggaggg gaggcctgga ggaggggggg acccgggcgc ggccagggcg 900
ggcacaggag cctgtacctg tcaaacaaga gccaaggagc aaactagctt cttagtcacc 960
tttctcttct ccccgttttt ggcagcaacc cctcggggca aggggaagct gatatcataa 1020
ttattggctc acccagcagc tgcctcccct cacctgatgt cagcccagac ccaggacaat 1080
caggctgacg gactgacaga cggtcggagc tcctggcccc ccagacccag gcccccacgc 1140
cgacctgctt cactgagcag gtaagaggag acctggccca agtcagccgt ggaggccaac 1200
aggggagggg gcttggtttt tttaatgggc cccaggaggc actgggtgct tctcagagtc 1260
tcattgtctc tccagggaga ctcaggatca gggtgagtac ctggaggctg aggggacccc 1320
tcctccactc tcctctctct ttcctggccc aggccttctg actttgatcc ttcttgctgt 1380
aatgtaggac tctgttttgc tgtacatggt gtctctgtgt ggtaggtctg tgtggtggca 1440
cccaccttga gttgggaggc aattatgact ccagatggac agctagagtt taaagataga 1500
cagataggca gattccctgc cgaggactga gtggctggct aagtggaaag ttgggtaccc 1560
cccccccagc tctggcaact tccatctctc tggaatacct ggtcttgggt ctgcacgacc 1620
cagattctat gggggaggct tggcatgcag aacggagaat ggtgcacctt gtgcagaagc 1680
ggacaggcgg caacaggtgc tgcggctagg agccgatgcc aagctggagg cacacctctc 1740
tgatcgccgg agatgtttct cttctttaag atcgctgcag tagagaggag tggccagcag 1800
acctgagaca ggcagagagt tcacagaccc cccaccccca ccccaactta gaattgggaa 1860
atctagctgc cagaaacccc tttatctact gagactacct accctttgcc ccatacctga 1920
ccaggcaaaa tcctggaatt tgctatagag ctccccaacc caccttcagc atccaaagaa 1980
gcatgttggg ttaaagctag agttataagt gggcgtgttt gcctctttgc tctgtaccta 2040
caagtgcagg ggacatgtct gggtatgtgc agtggcaggg tacagctgct cagcaagaaa 2100
ggaccagatg gagaagatgc ctcctctagg gacaccatct catcccctgt gtcccctacc 2160
cctgtgccgg gtagctccca caacagacag agtgtggtcc tctctgtgtt ctaaactgtt 2220
cagtaggaga ctcagtgagt tccttcatcg tttttttttg aaatcgtaac ttctgtagcg 2280
tctacctcta gcttctccac ttccttctct ttcttctact gatgaagccc agttcccctg 2340
cacagatgga tgagcacagg gtagaaaggg tggcagtgaa ctccagccct atccccactg 2400
ggctttagca agagctttct tcccatcctg acctacagac caggacaaga tgctggtagc 2460
agaatggcat cccagctgat gaggcctggc tcttctctct tgtggctttg tgaggggcta 2520
agacagagct gagctgggac caggggaaga acagagggtc caagtgctgc cctgggttga 2580
ggatcctctg gggtgaggat gccgtggggg gtggcacttg ccctcccagc tctccacccg 2640
gccccgcccg ggcagcctat gccgagctca gctcccggct gcaaggcctg ccgaggcacg 2700
ctgcaccccc aggcctctca cctcactcca ggccaggaac ctgttctccc gggaatgctg 2760
gggagttctc agaggacttt agttcccagg ggtttaggga aagaaatcct ctggaccagt 2820
gagtgagcca tggaaaagca agaaaatgga aagactgggg ggcagaggtg ggtcacaagg 2880
gcccattgcc ctcttcatct gtgtctatcc acacacagat cccacacttc tagctgacag 2940
cttttattgc tcttcgtgag aatgaagcct tgggacagtt aaagacaaaa gaaaaagccc 3000
ctcatggcac atgctttctg ccacatgcca tcatttggcc cccatggaaa gtcccttctg 3060
ccctctaaga aaatgacagg gcatcatccc agttggaccc aacaactccc atccagggag 3120
tctttcctac taacctttcc tcattgagcc tggtcttcac agaccagcag aaacacacac 3180
acacacacac acacacacac acatacacac atgcacacac acacacgcac acacacacac 3240
acacacacac acacacgcac acacacgcac acacacacgc acacacacgc acacacacgc 3300
gcacacacac acacacacac acacactacc tgccctgcac acatagcttg aacctgttcc 3360
tcagtacata aaagtcttgg ggacttctca gcctgctgcc ccattattct ctccagcacc 3420
atattctgac aagattgggg ccacctctct gtctattttt tgagacacga tctccctatc 3480
tagcctgagc taccctggaa ccctcagcct tctgggtgct gaaattaaag gtgtgcagta 3540
ccccactcac ctatgggcca cttctggttc cgcataccat agggacagag aggataaagg 3600
gcagaggcca tcatccctgt tgcagcctgc cagacttcca cagtgggaga tggtgacttc 3660
gggaagatag ttcagcattt taaatttagt tcttgcatgc agcccatgtc acccgagaag 3720
gcaatttcct ggggagggca ggccagcact gatctgggat gcattgtcgg gcaacatact 3780
cagtgcaagg gaaagacttg ctgcactctg agagacttcg tccccaaagc gcccacccag 3840
tgaccctcca gtaagatgca ctcctatccc ttccagcctg cctcggtccc tgcctccttt 3900
tgcatcccca gccctaaacc catttccctt taccagccct ctgtacgtat ctcagatttg 3960
acctgagctg gagcttctgt tgcgtgggtc tcctgtgtcc tgagattaca ggtgcagccg 4020
tgacaccagg tcctccctta tctcactcgc agccccagct cagacctgct ttccaccttt 4080
tctccctatc ctcaacttta ccaaagtttg tacaatccca ccccccccca cacacacaca 4140
tacacacaca cttcctctcc ttatttctta cttggcttcc ccactcctcc caccatccct 4200
cccagcccta tgagcccatc agcaccccca caggatggat gggcatccct gtgcacagtc 4260
agagaatcca aaacctcccg cagtgttccc taatttagtc tctgaactga gaggcccaga 4320
gccatgtccc aaggacaggt gggttgtatg ggatcatccc tagagaagct ctcagcttcc 4380
tgatcccata tgggccctaa aaaactggct gttggcagat agtaaaatgg agtctggctg 4440
aagcatggtt tggtgggaaa tcctgtgctt tatacgtctg aggtcctgga tgccagcctc 4500
agcccccaaa taaaaatgaa accatctagg tgagttcaga tacaagtatc tgatgctaca 4560
gcagtttgtc aagcaagggg gggtggggtg ggggagagct ggagggatga ctgatcccgt 4620
cagacatggc taggccaagg caggaagatg gacagcagct gaagcaaagc ccgctgggtt 4680
ctttaggaat gactgccact gtcatgagta tcccccagtc tctaccccgc ctgtggctct 4740
tgcttagtca gctcagatta atgggactgg ggaaagaatt agctgaatcg tgatctctcg 4800
ggggaactag agcctgcagt gagtcacagg gaagggaacc tgagctctca gggagattct 4860
ggaggctccc tgggtgtgtg ggggagggga gggggttatt ccctaagact tctctgagat 4920
gctacctaga gcctgcatgc tgggaggcac agccctggct ctctacccca aatttgcaga 4980
atgataatgt gattaaccag ctaccagcat gccccccaaa accctccaag ggccctcggc 5040
actctcgcat cctgaaacca ctatttgtga caaactgcag ccagtctagc accaacacat 5100
agtgggctta cttggcacca tcacacagtc agtatacaca cagacagcag aacagggcgt 5160
ggccctggaa ccggattgcc tgcagacaga tggaagtccc acctacactt gtaaattcca 5220
caatcacgtc ccaggctgta gcagcctatc gggttcagcg ccataggatg tgaacaagga 5280
tgaacacaca cacacacaca cacacacaca gcactgtgag gtgaagacca gttatcacac 5340
ttatcaactc ttgctctgta cagagccaga agaactacat caatgttcag tcaatggtag 5400
tctgtatcct gaccctctgt agaagaggtc ctagagtcta ccctgggcac ttacagatca 5460
gtaacttgtc tcttgtaatc ccagcagtga gcagactgag gcaggaggat tgctgagttt 5520
gaagccaccg tgggtagttc aagctacata gcgagtttga agtcaacttg gaatccatga 5580
tgagactctg tctaaaagaa aataagaaca acaaacaaac aaataaaaag aacagtcagg 5640
tagtggtggc ccacgccttt aatcccagaa ctcaggaagc agaggcaggt ggatctctgt 5700
gagttcaagg ccaggctgag ctacagagtg agttccagga cagaaaagaa tacacagaga 5760
aaccatgcct caaaaaaaca aaaacaaaaa caaacaaaca aaaaacccac caataatcaa 5820
aaagaaaaag agaaaagaaa gagaatctga atgttgatgg gtctttctat gcctatttgc 5880
aacacactta agagtgtgag gggttggaag aggaaattta gggtgacaga aaagccagaa 5940
ggatgtagag tgtcaaggaa ggaagctgga accaagtagc agagcaactc aggaagtccc 6000
tccaaacctc tcacttctcc aaaggcatgc tgggatctca gagccagctc accatgacca 6060
gcatccggaa gaaggagggg tgtgtacaac acacctgcct aggaaatcat ccctagcctg 6120
gcatggcagc gcaggtctct aatcccagct actcaggagg ctgaggcagg cagataagat 6180
gttcaaggct tgcctgaatg ttcaaagcca gctgaagcaa tttagtgatg cgaccttgtt 6240
tcaatatttt tttttaaaaa gctcattggg tctaaagctc attggtaaag cacttgccag 6300
gcacaggcaa gacccatgtt cagtcctagt cccacaaaaa caaacaaagc catctgtctc 6360
cttggttggc ttcagttctc ctctctgtca cacagacagg ctttggatgg aagcatcttc 6420
caatgtgctt cctcctcctt ggtccatgct tggagccaat agctgccctg cctgcccttt 6480
gctcggacgt agggcaggaa gtgcgccagc ttgcatccat cttgtgctga atcagggtta 6540
ttagcagtgg tggcagaatt aataccccta ataatagatt ggtggtaatg agcagtgctg 6600
gtaataatat gtacagagag aagcctctga ccaagggaca gtggcatcca cagccacctg 6660
aggcccctat caaggtgagc aggcaaaggg cgactgatac acccacactt ctatagggaa 6720
cataggaggt tctcatgcag tgccatggct ccctaggatc ctgggggagg aggcagaaaa 6780
aatggttctc acctgctcct agggacagga cagcagggga tgagtgcaag ggcagaatga 6840
agtcactatt tcatagagga ggaaaaaagc ttcatcctag tcactagccc aagctgatga 6900
cagagccagg acatggtcct cccatagtgc ccaagaggga aagagggatt ctgtaagaag 6960
caggggactc caagcttgac gaagccttca ggagagaacc caggttaggg gaggagatga 7020
cagaagttcc catcatgcct gatgggttta cagagcaaat cctcagctgc cagctactgg 7080
catagccaat tggcccggca cctgatttta ggggttgtga gaggaggctc agttccaaat 7140
gatgtcattg tggggtgggg tttcttggcc tctaatgggc tctcagaagc cagcggcttc 7200
ttctgcccct cagcctgtcc tccttcgcat ctcttcagca gatgtggctc acctcaggaa 7260
ggatgaaggt gataaaccct cctggccctt cagtccttcc ctcacctact tctcccgtct 7320
ctgatcatgg ctaagcagtc tgagggtttg agggaaaatt ccactctgga gaccagtgtc 7380
taaggcccca gatccctgtt ctctgtacgg tgcatccaga gggttacaca ttgcccccac 7440
cccaccccca ccccccagct cttcactgat atcctaatgt ttccttttag attatgatgg 7500
ttgtcactgt tgtttttctg agacagggtt tctctgtgta gccctggctg tactggaact 7560
cactctgtag accaggctgg cctcgaactc agggatcctc ctgagtactg ggattaaagg 7620
ccaccaacca ctgcctgtcc tttttcccgt tttccttgtg tgtgtgtgtg tgtgtgtgtg 7680
tgtgtgtgtg agagagagag agagagagag agagagagag aggtggggtc tcacaaatgc 7740
agcccaggct gaccttacat ttgtgattct cctctctcca cctcctgagt actaagatta 7800
cacagtcaac ccaactagga aacagttcta tctccaaatt ctttgtcagt ctgtccccac 7860
tgctcggggc ttcaaaattc ccctggaaag gtggagctgg gggcttttcc ctctctggct 7920
atccaaaggt gtcatgttcg tgaatatgag aatgcctgct aaccttgaag gggaagccac 7980
cttgctccta gacttgctcc tagacacaag atctcagggt tgcaggggca ccagcagagg 8040
caggtaggca gaagggagga aaaggcaggt cataaatggc tcccaagaag aaatgcaaac 8100
attactgtgg gtgagggcag tggagtagac atgaaaggtc tctagaaaga ggtctctaag 8160
gagggagagt ccaggaggac caatctctta aattaggtgg ccatggtaag gaagagggag 8220
gggaagacct aaaacaatcc taggagtaga tggtagcttt gaggaccagc atttcttgtt 8280
tctttaaaat ctctttctga tcatttacaa gacaggcacc cataggtatt gcaaagacat 8340
ccatccatcc acctgtctat ccatagccca tctatctgtt caaagtcacc catctatctc 8400
ttcatccatc tatcttccat ccaaccatcc acccatctat ccatctacct gtctagagag 8460
gtcagggcta ctgggaaggg cctgtggtcc tgtggcattt atggggcatg tgacttacct 8520
gcttggcctg gggaggcagt cccacccctg ccctggggca gggggccggt cctggcatgt 8580
gggtgtattt atacctggat ggaggctccc ctgaagctga aagctgcatg actccccaaa 8640
gccgggatgg tgtccacggc ccagagccca ctgtaagtgt ttagacatgg ctgcgttggg 8700
ggtcaggacg gggtggaaga agagggggag gggctggggt gtactgccca gaggtggtaa 8760
agactatgga aagagaggca tgctgggcag atgtttgtga gaaaagagga ggctgccagc 8820
atcagacatt ctcagcaaag ctgggacctt ccatggagac ggaatgagcc tatttccctt 8880
agctagtggg gagtggtcat tgacacataa ggcaagtgaa cgagattata agaattaaga 8940
acaaatatct aggaaagttt ccaggtcacc ccaggcagag aaggtagctc aagtgttttt 9000
ttgttttttg ttttttgttt ttgttttttt ttccgaaagg atgctttctg agcagactgc 9060
ttgaagaggc tgggggaatg tcaggtacct ttataaaaga cccgacagag attggaacta 9120
cctgactgca ggtgtgaatg gctcacagga tgctgtaaga gggatatgac tgcttttctt 9180
actacagtgt gtgtgtgtat gtgtgtatgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt 9240
gtgtgtgtgt gtgtacatgt gcatgcatgt cacagcaaga gtgtggaggc cagggaagaa 9300
aatgctgtag ttggtcctct ccggccacca tgtgggtcct aggaatcaaa ctcaggttgt 9360
cagggttgaa ggtgggtacc tacacctgcc tctggctaat tttcatccat cattctttac 9420
aaacccaggc agcatccaga gacagagagt ctagaggggc cttcaggacc ccagactggt 9480
aagaagaaac ctgttagaaa ccccatcttc ttgacacccc tagactccca gaatcctgag 9540
aggtgtgagc ctcaggcata gtccccaggt ctttcgctgc cacccccagc aagggtaatt 9600
agggacctgc tccagggaac ccctcccagc agccaggcag gtggagcctc gggtggggct 9660
gcaggcgaac actgggcaca gccccacccc tcgtaaaaca agctgccaca gccggcaaca 9720
gaaaccatta aggtggaact gagccggctc cgcctgctca taaagaacgg gcaggagggc 9780
gccgacaggt ggggggtggg ggggggggag agagagtgtg tgtgtgtgtg tgtgtgtgtg 9840
tgtgtgtgtg tgtgtgtgtg cagaactgct tctgagtgtc cttggccagg cagaagtgtg 9900
tgactggcct ctgtgactca gctgccagta ggggctccat ggacagaccc tcccagggaa 9960
acctccacct tgctgaggcg gggctgtgtg gtatagtggt taaggagaga ttagctttga 10020
agcctgggcc tgaatgagga gcacagttta ctagctgggg gacttgggcg agtcaggtta 10080
atctctctga gcctcagttt cctgatccat aaaaaggggt gacagtgcag tgcgtccctc 10140
ctaggacaga atccctggtg caagtctgac aggccactct gtccacttca cacacgtcca 10200
taggaccaac accagcatct taagatcaaa tgatccctgg gtttcctttt gcctatagaa 10260
gaactgaaat gcagatgagg aaataactta tccatggcca caaatccagc aaattaggtg 10320
tcccccaccc ccaccccagg acccaccctt aaacagcccc ttctgcctga gtgccgagaa 10380
gacagtctct cagaggcaga ggtagcaatg gctgaaggca gtgtagggct gactgttgca 10440
ggaagggtac aaggtgagga tgccagtgtc tggggacatg gggcagccac ctagcaatgc 10500
ttaccatgga ttcatcaccc gtccagttct cactgtctgg aggggcttcc tcccaacctc 10560
cctcctcagg ccagtgggcc ctttctctct ccctttgctt cagggtcgat cgggtctatt 10620
ttctttgtcc ccaaactttc cttcccctct ccaagaatca tggaaggaaa gtttgcccag 10680
gacgtccaga ccttgagagg gtcttcaaca cgtcttgcta aagttgtagc tctggataag 10740
agtgtctgga gcccttgagg tacaagagag gatttttcat tctctctgtg tggtcctagg 10800
catgcttctt ctctcttggc ctccttcccc caccccctgt gagaaacgga gtgaatacca 10860
ttgcttctct accttcagtg tgttggtaaa ttgtcatcaa ttatcagcta tcaaaaaggg 10920
ggaggggaaa ttctgattta gttttatgtt ggtttggttt ttgttttttt taggacaggg 10980
tctcactatt cagccttagc tatcctggaa ctcactatgt agaccaggct ggccttgaat 11040
ccatagagat ctacctgctt ctgcctcccc tgtgctggga ttaaaggtgt gtgccaacac 11100
attaggcagc attctggttg ataatgtgtg agatttttgc atgggcagct atgtagctat 11160
ggccagtttg cctttatttt gctgaatgtg gaattggaag tgatggattc agtttgctcc 11220
ctaaagcact ggctccagta tgctgtgttc actgtccaca gggacagagg cgagaagaga 11280
tagcaaagat aaaaagcatg caacttggac ttctgagtgt tccaatgatg cgggtctatg 11340
atgattatgg tcttgcggta gaagggaatt tgacccacat cttcctccat agtctcctgt 11400
ccaggaagga gacatagggt gggcagatga cagttctgag tggcggcata tgtgctctga 11460
accggctccc agagattctg gatttgggag aaggggagaa gaggaaggag atgagaagtc 11520
agtttgctga cactggcgca caggcaatac actgttctgt gaaaccagac gaggtgggct 11580
caaggtttga caacaaaagg ttccttctaa gttcataggc cactatcagg acactggagc 11640
cagcatggat gcttcctggg ggatccaaag cagtagggac accctatcca ttccatttca 11700
ggacattgaa gtttctgcag ccactggctc tactgcaggg gaatgaacaa aatggcctca 11760
gaggcccgag tcaagaggaa gttcagtcgg tggaggaagc ttatgacagg gagatgggtg 11820
ggggtgggga gaagacagga aagggcaaga aaaggtggtt ccctccccca caccagagcc 11880
catgccttaa attaactctg tcccactgct aattattaat aatagctatc atttattgag 11940
tatgtactgt gaggtaagct atttacaagc aatatttcat ccaatcctcc aaagaggtat 12000
gtattatcag ctccatttta cagaggagga aactgaggcc cagggaagga agttaaataa 12060
tgtgtccaac caaattctca ccctgatcat gattcagacc caaacctgac taccaagttg 12120
ggagctttaa gaactccaca cctctctctc tcccctctct gtgctgaaag gaccctcccc 12180
aaacattaac taggggccct ttgtccagcc cttgaagctg gtgacccttt aggataaagt 12240
tgattgaggg ctcacatttc ctagacagtg tggctttaga aaactcagtt catttcttga 12300
agggactcat ggtcactgag ctaggcgtca gtacttacag aacccaccca gaagaaaacc 12360
tgggtgagga ccactctggg acatctgtat ccccaatgca aatcaaggag agcctatgaa 12420
ccctgcaaag acaagcttag gtcctggaaa aaagggtggg ggttttcaga gccagagtct 12480
gttagtcctg gctaggaaca gaaggccttt gatgtacagg cgctctgcct ggggcttata 12540
caaatagctc catctaagga tgagggattg cagagtgagg cagaggtgct actaaacaag 12600
acagaacttt gagaggggaa ggcccagcta gagctcaggt tcgagtcagt aaagcagggc 12660
tggtgtctga gtcttccggg aggtcatgat aaatgaagac caggcaggca ggagaggcca 12720
gcaagggcag ctgctaccag gggacagcgt catctgcacc tctctcctag actatgaggc 12780
ctgaagcaac aagactgtca tggaaactgt agagcctgga attagaggcc tttggggaca 12840
gctacattta gccaactgaa gccagagata tgaggtgtgt ccccggccat tttctgggta 12900
tcagcaccat accacttaat cttcaagagg tcctagtgag ataggtctac acacctcatt 12960
tctcagacgg agaaagtgaa atatagactt acatagtgtg ttcaaaaatc acagaggcag 13020
aacgtgacaa ggcttggaac taaagtcaga tttgcctcaa gcccaaccat tactgttctc 13080
cctcctgggg ctgcagagcc tgaaatgggg agaaaaagcc cccggcctca cacctggagg 13140
gagatgagat tgtatttgga tggcgtcaag ttcacacgac accacctcct ctgggaaagg 13200
cagctctgag ccaggatgag gcatggcagg caggcctgag ctgtccaggg aacaggggcc 13260
agggcaggca gtcatgcaaa gccagagatg gggtgtcctc acccctacct gctcccttga 13320
agtgtccagt tacagccagc tccacgcttc cccgtcacgc cacatttagc attgctgaga 13380
gtgagcctgc gcagggatat agagaagggg tggtagggac tctttgaggg gtgggagaga 13440
acctccccac cttcaaaccc atctacactt acttcagcca ccagccgcct cccagcctaa 13500
tcctatgtgg gactctggac aggttccctt ccctctttga caccattagc ctctctgaag 13560
atggctaatt catcaaagat gtgtcaactg ctgactaggc caaactcaga aagatgaggc 13620
ctgccctctc tcccagattt cccagaactg caccactgct gtgacttgag gggtcttggg 13680
tagatggcat aagtcgaaag ctctggtttt tatttctgtt tggctcccag aacattccac 13740
tctgactccc atcaaataca gtagcggggg gtgggggggt agccaaagct tagttcaggt 13800
tctgacagtc aagggttata tgtgagactg ggaggtcacg gaatccctca gggcctcagt 13860
tctcttattt gaaagactgg attaataata tggcatcctt gaagtaaagc aatgagcttg 13920
ggcctgctta taatgccagc ccttgggcag ctgaggtcaa tagtttgtcg atagaggcag 13980
agggctgcct atagttcctg gcctatgtag tgagtttcag gccagcatag actatatggc 14040
gagagcctgt cgcacacctt taatcccagc acttgggagg cagaggcagg tggatttctg 14100
agtccgaggc cagcctggtc tacaaagtga gttccaggac aaccagggct acacagagaa 14160
accctgtctt gaaaaaccaa aaaaaacaat aggggcgggc tggagagatg gctcagtagg 14220
tgagagcact gactgctctt ccagagatcc tgagttcaaa tcccagcatc tacatggtgg 14280
ctcacaacca tcgagatctg acgccctctt ctggtgtgtc tgtagacagc tacttacata 14340
taataaataa ataaatctta aaaaaaaaaa aaaaccaata ggggctacag attttcactg 14400
agtaaagcaa ctatcaggaa gccctaggtc agaacccaaa actgagcaca aaggtccgtg 14460
tccataatcc cagcacgtgg gaggtggaga aaagcagaaa cctaaggtca tcttcagcag 14520
gtggaaaacc ttccaaagtg ctacccagga gtcagtacag agcagtccct cggtaaacaa 14580
tggctgctgt cagggatgaa ctcagggacg tgagttcaaa ggctgttgct gataatggaa 14640
gagccccagg gataacacca ttaataatga gacctggcgt gtggatcaag ccctgtgtgc 14700
ttgtgctgtg ctccgagctt tctctgcatg atttcatttc actctcagcg ccctgtgcga 14760
ggctctgtca ctcatcttgt ttgcagatgc tgctgtggaa gtgcagagag ctctgctgac 14820
acagcctgga atggacagcc tcgcctggcg ctgagcccca aggcctccca gctgctctgt 14880
ggtgctgggt cagggttcta caacaacagt tcagaagggg tcagtgctca gatctagtcc 14940
aagccttagc atttcatagg caagctgaag agttcagaaa gaggccaggg atgggagcca 15000
gggagcatcc tgggaggcag tgggctcgat cccacacaga acagggaagg agaggagaag 15060
agaggggcta aggaaatgag acgtgcttgg tacaaagtca cggacaaaga ttgatagagg 15120
ttaaaaaaac aacacttccc agatatccca cgggccctac cagcaaggcc ccttggtcat 15180
cccacagggt taccctctgt gtcattggga ttgctgtcac ataaagccta ggcatgatac 15240
atctcctgac tcctcctctt ctcagggcct acccagcaac tgataaggtc accttgcata 15300
gacataggaa acctagcagc caggctccct gggaagcaag ggctcactga ctcactgact 15360
gaccaggtca cttgctgacc agcaaagctt gagttgagac aggagctctc ctccgagtat 15420
ccaatctggc tcagtttctc tctcatgata gctctttcct catcctcttc agcatttgcc 15480
taccagcatg taacaatttc tcaccttggc tatctatcta tcatctgtct gtctgactgt 15540
ctgtctatca tctcttccct tctctcccta tgtccctaat ccgatggcta gctccagcca 15600
gggtcccagt ccagggaaag ggtaggaatg gaggtggtgg gcctggggtt ggccatgcct 15660
agacgttggt cctcattctc attgtagctg gctttcttcg aggccaggac tgggtgatgg 15720
tgtcgctact ccctccgcag tctgacgtca cacttccagg ctccacccga ctggagggcg 15780
aaccccaagg ggacctcatg caggctccgg gcctcccaga ctcccctgcc ccacagaacg 15840
taagtacctg gaacctaggc ctggaatagg gcaagcctgg tagctctaag agcattgagt 15900
agatggtcac tgccccacac aaggaccttc gggatctact ttgtccctta cacagaaaaa 15960
atgatgatga ctctagaccc agaagggcca agtcacagat ctctgtccat ccttggtttg 16020
gtgtttcccc agatatggaa cccatcagcc tcaggggacc caggtttaga agaagtatgc 16080
ttgtatcaga ttggaatccc aagagcaggt tgccttcccc gtcactttgg gactcctgtg 16140
aactcagcca tactctatta tctcagtaca gcacagggtc ctggcagatg ccctggtcca 16200
acccccattt acagattctc tattctgtct gcccagaagc atgctaactt cagctgctcg 16260
tcgtttgtgc ctgacggccc tccagagagg acaccctcac tgcccccaca cagccccagc 16320
atcgcatctc cagacccaga gcagatccag ggccactgca cagccggacc cggcccgggc 16380
tccttccgcc tttctccttc agaaaagtat cctggctttg gctttgagga gggcccagca 16440
ggcagcccag ggcgcttcct caagggcaac cacatgcctt tccaccccta caagaggcac 16500
ttccatgagg acatcttctc tgaggcccag acggccatgg cacttgatgg acactccttt 16560
aagactcagg gggcactgga agcctttgag gagatccctg tggacatggg cgatgctgag 16620
gccttcctgc ctagcttccc agcagaggct tggtgcaata aactccctta ccccagccag 16680
gaacacaacc aaattctggt gagtgccagt ggccgagggc cttccacctc ctctctccta 16740
gctgcctaga aagactcttc aaagccatgc ctggtggcac atgcctgtaa tcctactact 16800
caggaggctg aggcaggagg actgcttgag gcagaggcca gcctctgcct atgtatggag 16860
accctgtctc caaatcagag ctccagagga ggcagcaagc acagagggtg ggggcctcct 16920
ggttccatac tggtcccctg gggaggggga tgctagcctg gcaggcgtgg agagggcagg 16980
tggagggggc aggtgaggga agctcatgag ggaagggagc tggcagcttc ccagaggctg 17040
ctgagtcaag attccagagg gtgacttctc tgtttattta agtgtcaaag aatgccaagc 17100
cagaccaaca cacccctatg caaatgtgag gaggaaaaga cacattccag agagagaagg 17160
ttctagacag agcatcagaa caaaaacccc accaaataag gactggggac ttcactgcta 17220
gctccaggcc ccttccagac cctgcttttt tatttatttt catgggtgag acagaaaaca 17280
gctatgttgc ctaaggccgt ccatgaacta gagatcctcc tggtgctgga attactggtg 17340
gggttctgga cctattctaa ggccagagca ggcttctatg gataagtgcc ttgggacacc 17400
tcagaaggtt gactagcact tccgcagcca gatctgcagg ccctgtgacc tcgggcaagt 17460
cacttaatct ctctgagcct cgtgggaaaa gttctgttaa gggtttcctg tctcaggctt 17520
gccccctgct cccgatctct gattcccaag gcaccccagt gtgataattc atcctggact 17580
ctgctcctcc aggggtccac cggccttctt tacctcctac ttccaaatag gcccattcta 17640
gtccttagcc acacctatca ggaaggaaga gggggaaaac agatgaacac ccaggtgggt 17700
caggtgtggc caagacagga tcttctgctg tttctggagc catgactgct ttttctcaag 17760
cctttagaat gtggtgggag ccacagcttg gcacccagaa agccagcagt tgtcccccat 17820
tgtccactcg ttgtagctcc ttgtcactca gccaggagat ttccttccag ggttgcatca 17880
atagagttct cactatctcc atcttgagaa tcaggacccg gccctctctg gttgaggcct 17940
tatgacttac caggacatcc acaacctata aacagaagtc cacctggccc catggacaca 18000
agctgtaccc aactgcctgg tccactctat gggtgacagg tgccatgtag tttcccctct 18060
ttgggagcag ctgtatcatc tgtgaaatga aggggttgga ctcagtgctt gtggcccttg 18120
caggctcaag atcctgtgat tacggcaatc tctgcatcag ctgccctgag gcatacccag 18180
aaagtggtca cagctagctt tcacccctct gggcccaaat gctgccttcc caaaggcccg 18240
tgggaatcct agtttcagga gcctgatcct ggcttgtcta tctgccaggt aggtctgagc 18300
cgcacgccct tgctaactct atgcagggct cagctctggg ttaggccctg aggacttcac 18360
atgggtctct cagaactctc gggtcccatt caagtctatg tgacaagtcc cctccatttc 18420
tcttggtggc ccagactagc ctgccgcctg cagtgaggtg gaatgtgagg aacactgtcc 18480
tttctagcct agcccctcta ctgacttgct gatttccctc aggaaaaccc ctatccatct 18540
ctgttctctg ttccttgcct aagagttagc tttgagaggg tcacagaaag gattcttcca 18600
gtgtgaagtt caagacaaga aaaagaaatg gaggcccgtc attggtggtg cacatcttta 18660
atcccagcac ttgggaggca gaggcaggca gatttctgag tttgaggtca gcctggtcta 18720
caaagtgagt tccaggacag ccagggctac acagagaaac cgtgcctcaa aaaagaaaaa 18780
aaaaaaaaag aagaagaaga agaagggggg aaactttctt ttccactttt ccagcagggg 18840
tcagaggtca aggtcaagcc ccaagctctg gacagttcct cagagtcaag tgtcctttct 18900
ggttctatcc ctgtaccttg ggtcctgtga gggggcgggg aggagggtct agggagccag 18960
acctgtgtac ctcatcaagt tcggtggtgc actgtgggaa gactgtaggc ggcaaatcaa 19020
cctttgggaa ccaaggcaga agcctgagtg aagaggttca ggggggcctc taggccgctt 19080
ccaagaagag ctttgcaaca accttcaaat gggcaaatcc ttaaccttaa tctagtaccc 19140
tgttcttctc gaagaggccc agaggttacc tgcaactatg gcagtggttc tcaacctctg 19200
ggtcgcgacc ccgatggaaa gtctgatgac cctttcatag gggtcgcctg catctatggc 19260
ttttacaccg tgctaccttg gagctcggag ctggactctg aggctcagga aaaaaaaaaa 19320
aaagttcagt gattacttga ggtcccagag tggatgccaa gataggcttc cagtccgcat 19380
caccagactc ctgttctctg aggcttctga ggtacttggg tgggagacag actgggctta 19440
actctctatg gcctgccaat gatgaggctt cttccctctc cccgactagg aaatctgtgg 19500
gagcagctga aggatgacag cttggccctg gaccccctcg tattggtgac ctcgtcgccg 19560
acgtcatcct ccatgttgcc acccccacca gcagcccatt gcttcccccc agggccttgt 19620
ctggcagaaa caggcaatga ggcaggtgaa ctggcacctc caggcagcgg cggctccggt 19680
gctctgggag acatgcacct cagcactctc tactccgcct ttgtggaact ggagtccacg 19740
ccctcctcag cagctgccgg ccctgccgtg tacctcagtc ccggctcaaa gccattggct 19800
ctggcttgag ctatgcccaa catcagctgc ggcctttgcc tagctggctg ccccatattg 19860
ggctcacctt aaaggtcaaa gaaggaaaac actacctgtc tcctatgcca ctcagccaac 19920
ttatttgtta gccagaagtt gggggcatct cacacggggc ccccagcaag gaaagtgtcg 19980
gaaaagaagc aacagcgcgc cccctagcgc cagctcactc gaacttcagc tctcgagcgt 20040
gaactcaagc tctacacacc tgctcatcat gtgccttaca ctcagaggaa gccttgggtc 20100
acagagtctg atttgatttc tggggcagct gagagctaaa agctttagtt agcaaagctc 20160
agggccagtg tgacaggtca aagatcaccc ctccaaacct catcccaatc cccatgtgct 20220
ctacagactt ggccctctcc cagaaatctc tatttattct cccatcttac acccttaaag 20280
cctacagggg ctcctcccgt atgacctgtg aaccccttag ggagacaact acttcataga 20340
atttatctat acatcttcag tatatactct ggttggccat ctccaaggtg acacacagaa 20400
ggggcagcat ctaccctggg accaaactga gcccaaatcc aacacaacat gtttggaaaa 20460
aaaaaaaaaa acttgtcctc agaaacttga accccctctc ttagtctcag ccacaggaaa 20520
ggcccccttc aggttgccaa gtctcactct ttctcaatga gaggttcata tagttcaagc 20580
cccagcctat tggatgcggt caactgtctt aagcatcctg agtaactagg gtttgcaacc 20640
cgctacagga tgatgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtgatacc cccccacaca 20700
cacacacaca tacacacacc tgcatagcag acttggggct cccagggagc cggcagaatg 20760
tccgtggagc tgagctgtga ctcagatgcc caccatgacc caccaaatgg gatccccagc 20820
tttcccaggg cctgagggca accagaacct ccataggttg tccccaagct cacacgaggg 20880
tgggcggatc cctcagtcat ctaccattgt cccctgtcct ggaacaataa agtaagcgcc 20940
tgatggttgc aa 20952
Claims (26)
1.一种构建裸鼠或其子代的方法，其特征在于，所述鼠基因组中的Foxn1基因，经遗传修饰后，使得鼠体内FOXN1蛋白不表达或表达的FOXN1蛋白不具有功能。
2.根据权利要求1所述的方法，其特征在于，所述的方法包括敲除小鼠体内Foxn1基因的全部或部分序列。
3.根据权利要求1或2所述的方法，其特征在于，使用基因编辑技术进行裸鼠或其子代的构建，所述基因编辑技术包括基于胚胎干细胞的DNA同源重组技术、CRISPR/Cas9技术、锌指核酸酶技术、转录激活子样效应因子核酸酶技术、归巢核酸内切酶或其他分子生物学技术；优选的，使用基于CRISPR/Cas9的基因编辑技术进行裸鼠或其子代的构建。
4.根据权利要求1-3任一所述的方法，其特征在于，所述的方法包括使用靶向Foxn1基因的sgRNA序列敲除小鼠体内Foxn1基因的全部或部分序列；优选的，敲除Foxn1基因的第4号外显子至3’UTR的全部或部分序列。
5.根据权利要求1-4任一所述的方法，其特征在于，包括如下步骤：
1)利用靶向Foxn1基因的sgRNA序列，制备获得sgRNA载体；
2)将步骤1)获得的sgRNA载体的体外转录产物和Cas9mRNA进行混合，获得混合液，将混合液注射至小鼠受精卵细胞质或细胞核中，将注射后的受精卵转移至培养液中进行培养，然后移植至受体母鼠的输卵管中发育，得到F0代小鼠；
3)将F0代小鼠利用PCR技术进行检验，验证细胞中的Foxn1基因敲除成功，获得阳性裸鼠；
4)将步骤3)筛选出的阳性小鼠通过杂交和/或自交的方式，扩大种群数量，建立稳定的裸鼠；
优选的，所述步骤3)中使用的PCR检测引物对序列如SEQ ID NO：20和SEQ ID NO：21所示；
优选的，所述的sgRNA序列靶向5’端靶位点序列如SEQ ID NO：1-7任一项所示，3’端靶位点序列如SEQ ID NO：8-14任一项所示。
6.根据权利要求1-5任一所述的方法，其特征在于，所述裸鼠用作动物模型；优选的，所述动物模型为荷瘤动物模型。
7.根据权利要求1-6任一所述的方法，其特征在于，所述的裸鼠为免疫缺陷裸鼠或人源化裸鼠。
8.根据权利要求7所述的方法，其特征在于，进一步包含在免疫缺陷裸鼠或其子代体内进行人免疫系统重建；优选的，所述人免疫系统重建使用人外周血细胞移入，或使用人造血干细胞移入。
9.根据权利要求1-8任一所述的方法构建的裸鼠或其子代。
10.一种经遗传修饰的细胞株，其特征在于，所述细胞株基因组中的Foxn1基因，经遗传修饰后，使得所述细胞株中不表达FOXN1蛋白或表达的FOXN1蛋白不具有功能。
11.根据权利要求10所述的细胞株，其特征在于，所述细胞株中缺失Foxn1基因的全部或部分序列；优选的，使用靶向Foxn1基因的sgRNA序列敲除细胞株基因组中Foxn1基因的第4号外显子至3’UTR的全部或部分序列。
12.根据权利要求10或11所述的细胞株，其特征在于，所述细胞株来源于非人动物或其子代；优选的，所述动物为啮齿类动物；更优选的，所述啮齿类动物为小鼠，所述的小鼠为免疫缺陷小鼠。
13.一种制备多基因改造非人动物或其子代的方法，其特征在于，包括如下步骤：
a)利用权利要求1-8任一所述的方法制备的裸鼠或其子代，或者，权利要求9所述的裸鼠或其子代；
b)将步骤a)获得的裸鼠或其子代与其他基因改造动物交配或体外授精或直接进行基因编辑/修饰，并进行筛选，得到多基因改造非人动物或其子代。
14.根据权利要求13所述的方法产生的多基因改造非人动物或其子代。
15.一种靶向动物Foxn1基因的sgRNA序列，其特征在于，所述sgRNA序列在待改变的Foxn1基因上的靶序列上是唯一的，且符合5’-NNN(20)-NGG-3’或5’-CCN-N(20)-3’的序列的排列规则。
16.根据权利要求15所述的sgRNA序列，其特征在于，所述sgRNA序列在小鼠Foxn1基因的靶位点位于小鼠Foxn1基因的第4号外显子和/或3’UTR上；
所述sgRNA序列靶向的5’端靶位点的序列如SEQ ID NO：1-7任一项所示，所述sgRNA序列靶向的3’端靶位点的序列如SEQ ID NO：8-14任一项所示；优选的，所述sgRNA序列靶向的5’端靶位点的序列如SEQ ID NO：1所示，所述sgRNA序列靶向的3’端靶位点的序列如SEQ IDNO：8所示。
17.一种包含权利要求15或16所述的sgRNA序列的构建体。
18.一种细胞，其特征在于，所述细胞包含一种或多种权利要求15-16任一所述的sgRNA序列和/或一种或多种权利要求17所述的构建体。
19.根据权利要求15-16任一所述的sgRNA序列、权利要求17所述的构建体或权利要求18所述的细胞在构建免疫缺陷裸鼠或Foxn1基因敲除/敲入动物或Foxn1基因人源化动物中的应用。
20.一种荷瘤动物模型，其特征在于，所述荷瘤动物来源于权利要求1-8任一所述的方法构建的裸鼠或其子代，或者，权利要求9所述的裸鼠或其子代，或者，权利要求14所述的多基因改造非人动物或其子代。
21.一种细胞或细胞系或原代细胞培养物，其特征在于，所述细胞或细胞系或原代细胞培养物来源于权利要求1-8任一所述的方法构建的裸鼠或其子代，或者，权利要求9所述的裸鼠或其子代，或者，权利要求14所述的多基因改造非人动物或其子代。
22.一种组织或器官，其特征在于，所述组织或器官来源于权利要求1-8任一所述的方法构建的裸鼠或其子代，或者，权利要求9所述的裸鼠或其子代，或者，权利要求14所述的多基因改造非人动物或其子代。
23.一种权利要求1-8任一所述的方法构建的裸鼠或其子代、权利要求9所述的裸鼠或其子代、权利要求10-12任一所述的细胞株、权利要求14所述的多基因改造非人动物或其子代、权利要求20所述的荷瘤动物模型、权利要求21所述的细胞或细胞系或原代细胞培养物或权利要求22所述的组织或器官在Foxn1基因或FOXN1蛋白相关领域或者免疫相关领域的应用。
24.根据权利要求23所述的应用，其特征在于，所述的应用包括需要涉及人类细胞的免疫过程的产品开发，制造人类抗体，或者作为药理学、免疫学、微生物学和医学研究的模型系统中的应用或在生产和利用动物疾病模型，用于人源细胞移植、免疫系统重建、病原学研究和/或用于开发新的诊断策略和/或治疗策略中的应用或筛选、验证、评价或研究药物、药效研究，相关疾病药物以及抗肿瘤药物方面的用途；优选的，所述应用包括使用人PBMC进行人免疫系统重建后，对抗人单抗、双抗或联合用药的药效评价、药物筛选，或人CAR-T体内评估或筛选。
25.一种人用药物筛选或评价的方法，其特征在于，包括将人肿瘤细胞移入已用人PMBC重建的动物体内，向移入人肿瘤细胞的动物给予候选药物，对给予药物的动物进行药效检测和比较，其中，所述的动物为权利要求1-8任一所述方法构建的裸鼠或其子代、权利要求9所述的裸鼠或其子代、权利要求14所述的多基因改造非人动物或其子代或者权利要求20所述的荷瘤动物模型。
26.一种CAR-T体内验证的方法，其特征在于，包括向动物体内植入人肿瘤细胞，向植入人肿瘤细胞的动物注射人CAR-T，对注射人CAR-T后的动物进行肿瘤抑制效果检测和评价，所述动物为权利要求1-8所述方法构建的裸鼠或其子代、权利要求9所述的裸鼠或其子代、权利要求14所述的多基因改造非人动物或其子代或者权利要求20所述的荷瘤动物模型，或者，通过移植人PMBC重建人免疫系统的权利要求1-8所述方法构建的裸鼠或其子代、权利要求9所述的裸鼠或其子代、权利要求14所述的多基因改造非人动物或其子代或者权利要求20所述的荷瘤动物模型。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113106101A (zh) * | 2021-05-11 | 2021-07-13 | 广州欣意生物技术有限公司 | 一种nod遗传背景双基因缺陷小鼠模型的制备方法及应用 |
| WO2022062055A1 (zh) * | 2020-09-23 | 2022-03-31 | 南京启真基因工程有限公司 | Crispr系统及其在制备多基因联合敲除的重症免疫缺陷克隆猪核供体细胞中的应用 |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113930446A (zh) * | 2020-07-13 | 2022-01-14 | 黄菁 | 对非人动物基因改造的方法及构建的免疫缺陷动物模型 |
| KR20230144171A (ko) * | 2022-04-06 | 2023-10-16 | 서울대학교산학협력단 | 신규한 Foxn1 변이체 및 이의 용도 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011149102A1 (ja) * | 2010-05-24 | 2011-12-01 | 国立大学法人熊本大学 | 生体イメージングに最適化された高度免疫不全マウス |
| CN106661593A (zh) * | 2016-02-25 | 2017-05-10 | 深圳市体内生物医药科技有限公司 | 一种免疫缺陷小鼠、其制备方法及应用 |
-
2019
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011149102A1 (ja) * | 2010-05-24 | 2011-12-01 | 国立大学法人熊本大学 | 生体イメージングに最適化された高度免疫不全マウス |
| CN106661593A (zh) * | 2016-02-25 | 2017-05-10 | 深圳市体内生物医药科技有限公司 | 一种免疫缺陷小鼠、其制备方法及应用 |
Non-Patent Citations (4)
| Title |
|---|
| MICHAEL NEHLS ET AL.: "New Member of the Winged-Helix Protein Family Disrupted In Mouse And Rat Nude Mutations", 《NATURE》 * |
| MICHAEL NEHLS ET AL.: "Two Genetically Separable Steps in the Differentiation of Thymic Epithelium", 《SCIENCE》 * |
| TEPPEI GOTO ET AL.: "Hypomorphic phenotype of Foxn1 gene-modified rats by CRISPR/Cas9 system", 《TRANSGENIC RES》 * |
| XINRU WEI ET AL.: "CRISPR/Cas9-Mediated Deletion of Foxn1 in NOD/SCID/IL2rg−/− Mice Results in Severe Immunodeficiency", 《SCIENTIFIC REPORTS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022062055A1 (zh) * | 2020-09-23 | 2022-03-31 | 南京启真基因工程有限公司 | Crispr系统及其在制备多基因联合敲除的重症免疫缺陷克隆猪核供体细胞中的应用 |
| CN113106101A (zh) * | 2021-05-11 | 2021-07-13 | 广州欣意生物技术有限公司 | 一种nod遗传背景双基因缺陷小鼠模型的制备方法及应用 |
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