CN113473850A - 具有遗传修饰的钠通道的啮齿动物及其使用方法 - Google Patents
具有遗传修饰的钠通道的啮齿动物及其使用方法 Download PDFInfo
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Abstract
本文中公开了啮齿动物(诸如小鼠和大鼠)，其在内源性Scn9a基因座处被遗传修饰以包含外源性Scn核苷酸序列诸如人SCN2A基因的编码序列。也公开了可用于制备这样的啮齿动物的方法和组合物，以及使用这样的啮齿动物生产抗‑NaV1.7抗体的方法。
Description
相关申请的交叉引用
本申请要求2019年2月22日提交的美国临时申请号62/808,957的优先权权益，其整个内容通过引用并入本文。
序列表的通过引用并入
于2020年2月20日创建并通过EFS-Web递交给美国专利和商标局(United StatesPatent and Trademark Office)的781KB的命名为36328PCT_10403WO01_SequenceListing.txt的ASCII文本文件中的序列表通过引用整体并入本文。
背景技术
电压门控通道α亚基9(Scn9a)是编码NaV1.7蛋白的基因。NaV1.7是电压门控钠通道家族的一个成员，并且对于大多数可兴奋细胞的电信号传递而言是重要的。NaV1.7存在于疼痛感知神经伤害感受器中，并且辅助传递疼痛的感觉。人SCN9A基因中的功能突变的获得已经与疼痛综合征相关联，而功能突变的丧失会造成对疼痛的不敏感性。
发明内容
本文中公开了遗传修饰成表达外源性NaV1蛋白(例如，NaV1.2蛋白)的非人动物的实施方案。在某些实施方案中，非人动物包含外源性Scn核苷酸序列(例如，Scn2a基因序列，例如，人SCN2A基因序列)。本文中也公开了可用于制备这样的遗传修饰的非人动物的方法和组合物的实施方案，以及使用这样的遗传修饰的非人动物产生结合NaV1.7蛋白(例如，人NaV1.7蛋白)的抗体或其功能部分的方法的实施方案。Scn9a是编码NaV1.7蛋白的基因的名称。Scn2a是编码NaV1.2蛋白的基因的名称。在某些实施方案中，非人动物是啮齿动物(例如，小鼠或大鼠)。
在实施方案的一个方面，本文中公开了遗传修饰的啮齿动物(例如，小鼠或大鼠)，其基因组(例如，种系基因组)包含编码NaV1.2蛋白的核酸分子。在某些实施方案中，编码NaV1.2蛋白的核酸分子是在内源性啮齿动物(例如，大鼠或小鼠)Scn9a基因座处。在某些实施方案中，编码NaV1.2蛋白的核酸分子是在包括在伤害感受器中表达的基因的基因座处。在某些实施方案中，编码NaV1.2蛋白的核酸分子是在转录上有活性的或允许的基因座处，例如，ROSA26基因座(Zambrowicz等人,1997,PNAS USA 94:3789-3794，其通过引用并入本文)、BT-5基因座(Michael等人,1999,Mech.Dev.85:35-47，其通过引用并入本文)或Oct4基因座(Wallace等人,2000,Nucleic Acids Res.28:1455-1464，其通过引用并入本文)。在某些实施方案中，从遗传修饰的啮齿动物(例如，大鼠或小鼠)的基因组中的编码NaV1.2蛋白的核酸分子表达NaV1.2蛋白。
在某些实施方案中，核酸分子编码人、黑猩猩、恒河猴、马来西亚飞行狐猴(sundaflying lemur)、兔、马、阿拉伯骆驼、杀人鲸、牛、绵羊、大鼠、小鼠、狗、鸡、绿海龟或眼镜王蛇的NaV1.2蛋白。在某些实施方案中，核酸分子编码人NaV1.2蛋白。在某些实施方案中，核酸分子编码包含与SEQ ID NO:4具有至少95％同一性的氨基酸序列的NaV1.2蛋白。在某些实施方案中，核酸分子编码包含与SEQ ID NO:4具有至少96％同一性的氨基酸序列的NaV1.2蛋白。在某些实施方案中，核酸分子编码包含与SEQ ID NO:4具有至少97％同一性的氨基酸序列的NaV1.2蛋白。在某些实施方案中，核酸分子编码包含与SEQ ID NO:4具有至少98％同一性的氨基酸序列的NaV1.2蛋白。在某些实施方案中，核酸分子编码包含与SEQ IDNO:4具有至少99％同一性的氨基酸序列的NaV1.2蛋白。在某些实施方案中，核酸分子编码包含与SEQ ID NO:4具有大于99％同一性的氨基酸序列的NaV1.2蛋白。在某些实施方案中，核酸分子编码包含与SEQ ID NO:4相同的氨基酸序列的NaV1.2蛋白。
在某些实施方案中，编码NaV1.2蛋白的核酸分子可操作地连接至啮齿动物(例如，大鼠或小鼠)Scn启动子。在某些实施方案中，编码NaV1.2蛋白的核酸分子可操作地连接至啮齿动物(例如，大鼠或小鼠)Scn9a启动子。在某些实施方案中，编码NaV1.2蛋白的核酸分子可操作地连接至在内源性啮齿动物(例如，大鼠或小鼠)Scn9a基因座处的内源性啮齿动物(例如，大鼠或小鼠)Scn9a启动子。
在某些实施方案中，编码NaV1.2蛋白的核酸分子是DNA(例如，基因组DNA或cDNA)。在某些实施方案中，编码NaV1.2蛋白的核酸分子包含从ATG起始密码子至Scn2a基因的终止密码子的邻接核苷酸的核苷酸序列。在某些实施方案中，编码NaV1.2蛋白的核酸分子包括编码内源性啮齿动物(例如，大鼠或小鼠)Scn9a基因的5'UTR的DNA序列。在某些实施方案中，编码NaV1.2蛋白的核酸分子包括编码Scn2a基因的5'UTR的DNA序列。在某些实施方案中，编码NaV1.2蛋白的核酸分子包括编码内源性啮齿动物(例如，大鼠或小鼠)Scn9a基因的3'UTR的DNA序列。在某些实施方案中，编码NaV1.2蛋白的核酸分子包括编码Scn2a基因的3'UTR的DNA序列。
在某些实施方案中，编码NaV1.2蛋白的核酸分子是在位于内源性啮齿动物(例如，大鼠或小鼠)Scn9a基因座的内源性啮齿动物(例如，大鼠或小鼠)Scn9a基因的基因组片段处。在某些实施方案中，基因组片段包含编码内源性啮齿动物(例如，大鼠或小鼠)NaV1.7蛋白的核苷酸序列。在某些实施方案中，内源性啮齿动物(例如，大鼠或小鼠)Scn9a基因的编码区(例如，从ATG密码子至终止密码子)已经被替换。
在某些实施方案中，编码NaV1.2蛋白的核酸分子是Scn2a基因的基因组片段。在某些实施方案中，编码NaV1.2蛋白的核酸分子是cDNA。在某些实施方案中，编码NaV1.2蛋白的核酸分子是重组DNA。在某些实施方案中，编码NaV1.2蛋白的核酸分子可以包含从野生型序列修饰的核苷酸序列。在某些实施方案中，编码NaV1.2蛋白的核酸分子可以包含从野生型序列修饰的核苷酸序列，例如，从野生型序列优化的密码子。在某些实施方案中，编码NaV1.2蛋白的核酸分子可以包含从野生型序列修饰的核苷酸序列，例如，经修饰以从野生型序列除去T-细胞表位。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)就编码NaV1.2蛋白的核酸分子而言是杂合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)就编码NaV1.2蛋白的核酸分子而言是纯合的。
在某些实施方案中，作为内源性啮齿动物(例如，大鼠或小鼠)Scn9a基因的灭活(例如，但不限于，完全或部分缺失，或完全或部分倒转)或替换(完全或部分)的结果，遗传修饰的啮齿动物(例如，大鼠或小鼠)不能表达啮齿动物(例如，大鼠或小鼠)NaV1.7蛋白。
在某些实施方案中，当用NaV1.7免疫原(例如，人NaV1.7免疫原)免疫时，遗传修饰的啮齿动物(例如，大鼠或小鼠)产生针对NaV1.7蛋白(例如，人NaV1.7蛋白)的抗体。在某些实施方案中，NaV1.7免疫原可以是蛋白免疫原、DNA免疫原或它们的组合。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含如本文中所述的人源化的免疫球蛋白重链基因座、人源化的免疫球蛋白轻链基因座或它们的组合。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白重链基因座，所述基因座包含一个或多个人VH基因区段、一个或多个人DH基因区段和一个或多个人JH基因区段，所述区段是在一个或多个啮齿动物(例如，大鼠或小鼠)免疫球蛋白重链恒定区基因(例如，一个或多个内源性啮齿动物(例如，大鼠或小鼠)免疫球蛋白重链恒定区基因)的上游(例如，与其可操作地连接)。这样的人源化的免疫球蛋白重链基因座在本文中被称作“人源化的HoH基因座”。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的HoH基因座处是纯合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的HoH基因座处是杂合的。
在某些实施方案中，包含人源化的HoH基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含重链，其中每个重链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)重链恒定结构域的人重链可变结构域。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白重链基因座，所述基因座包含一个或多个人VL基因区段和一个或多个人JL基因区段，所述区段是在一个或多个啮齿动物(例如，大鼠或小鼠)免疫球蛋白重链恒定区基因(例如，一个或多个内源性啮齿动物(例如，大鼠或小鼠)免疫球蛋白重链恒定区基因)的上游(例如，与其可操作地连接)。这样的人源化的免疫球蛋白重链基因座在本文中被称作“人源化的LoH基因座”。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoH基因座处是纯合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoH基因座处是杂合的。
在某些实施方案中，包含人源化的LoH基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含免疫球蛋白链，其中每个免疫球蛋白链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)重链恒定结构域的人轻链可变结构域。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白轻链基因座，所述基因座包含一个或多个人VL基因区段和一个或多个人JL基因区段，所述区段是在一个或多个免疫球蛋白轻链恒定区基因的上游(例如，与其可操作地连接)。在某些实施方案中，一个或多个人VL基因区段和一个或多个人JL基因区段是一个或多个人Vκ基因区段和一个或多个人Jκ基因区段。在某些实施方案中，一个或多个人VL基因区段和一个或多个人JL基因区段是一个或多个人Vλ基因区段和一个或多个人Jλ基因区段。在某些实施方案中，一个或多个免疫球蛋白轻链恒定区基因是或包含Cκ。在某些实施方案中，一个或多个免疫球蛋白轻链恒定区基因是或包含Cλ。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白轻链基因座，所述基因座包含一个或多个人Vκ基因区段和一个或多个人Jκ基因区段，所述区段是在Cκ基因的上游(例如，与其可操作地连接)。这样的人源化的免疫球蛋白重链基因座在本文中被称作“人源化的KoK基因座”。在某些实施方案中，人源化的KoK基因座的免疫球蛋白κ轻链恒定区基因是啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，人源化的KoK基因座的免疫球蛋白κ轻链恒定区基因是内源性啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，人源化的KoK基因座的免疫球蛋白κ轻链恒定区基因是在内源性免疫球蛋白κ轻链基因座处的内源性啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的KoK基因座处是纯合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的KoK基因座处是杂合的。
在某些实施方案中，包含人源化的KoK基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含κ轻链，其中每个κ轻链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)κ轻链恒定结构域的人κ轻链可变结构域。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白轻链基因座，所述基因座包含在一个或多个人Jλ基因区段和一个或多个Cλ基因的上游(例如，与其可操作地连接)的一个或多个人Vλ基因区段。这样的人源化的免疫球蛋白轻链基因座在本文中被称作“人源化的LoL基因座”。在某些实施方案中，人源化的LoL基因座的一个或多个人Jλ基因区段和一个或多个Cλ基因存在于Jλ-Cλ簇中。在某些实施方案中，人源化的LoL基因座的一个或多个Cλ基因包含一个或多个人Cλ基因。在某些实施方案中，人源化的LoL基因座的一个或多个Cλ基因包含一个或多个小鼠Cλ基因。在某些实施方案中，人源化的LoL基因座的一个或多个Cλ基因包含一个或多个人Cλ基因和一个或多个小鼠Cλ基因。在某些实施方案中，人源化的LoL基因座的一个或多个小鼠Cλ基因包含小鼠Cλ1基因。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoL基因座处是纯合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoL基因座处是杂合的。
在某些实施方案中，包含人源化的LoL基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含λ轻链，其中每个λ轻链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)λ轻链恒定结构域的人λ轻链可变结构域。在某些实施方案中，包含人源化的LoL基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含λ轻链，其中每个λ轻链包含可操作地连接至人λ轻链恒定结构域的人λ轻链可变结构域。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白轻链基因座，所述基因座包含在Cκ基因的上游(例如，与其可操作地连接)的一个或多个人Vλ基因区段和一个或多个人Jλ基因区段。这样的人源化的免疫球蛋白轻链基因座在本文中被称作“人源化的LoK基因座”。在某些实施方案中，人源化的LoK基因座的Cκ基因是啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，人源化的LoK基因座的Cκ基因是内源性啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，人源化的LoK基因座的Cκ基因是在内源性免疫球蛋白κ轻链基因座处的内源性啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoK基因座处是纯合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoK基因座处是杂合的。
在某些实施方案中，包含人源化的LoK基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含轻链，其中每个轻链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)κ轻链恒定结构域的人λ轻链可变结构域。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白κ轻链基因座，所述基因座包含在Cλ基因的上游(例如，与其可操作地连接)的一个或多个人Vλ基因区段和一个或多个人Jλ基因区段。这样的人源化的免疫球蛋白轻链基因座在本文中被称作“人源化的LiK基因座”。在某些实施方案中，人源化的LiK基因座的Cλ基因是啮齿动物(例如，大鼠或小鼠)Cλ基因。在某些实施方案中，人源化的LiK基因座的Cλ基因是小鼠Cλ1基因。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LiK基因座处是纯合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LiK基因座处是杂合的。
在某些实施方案中，包含人源化的LiK基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含λ轻链，其中每个λ轻链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)λ轻链恒定结构域的人λ轻链可变结构域。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白κ轻链基因座，所述基因座包含在一个或多个人Jλ基因区段和一个或多个人Cλ基因上游(例如，与其可操作地连接)的一个或多个人Vλ基因区段。在某些实施方案中，这样的人源化的免疫球蛋白κ轻链基因座的一个或多个人Jλ基因区段和一个或多个Cλ基因存在于Jλ-Cλ簇中。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)就这样的人源化的免疫球蛋白κ轻链基因座而言是纯合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)就这样的人源化的免疫球蛋白κ轻链基因座而言是杂合的。在某些实施方案中，包含这样的人源化的免疫球蛋白κ轻链基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含λ轻链，其中每个λ轻链包含可操作地连接至人λ轻链恒定结构域的人λ轻链可变结构域。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的HoH基因座和人源化的KoK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的HoH基因座和人源化的LoL基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的HoH基因座、人源化的KoK基因座和人源化的LoL基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的HoH基因座、人源化的KoK基因座、人源化的LoL基因座或它们的组合处是纯合的。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的HoH基因座、人源化的KoK基因座和人源化的LoK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的HoH基因座、人源化的KoK基因座和人源化的LiK基因座。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的HoH基因座和人源化的LoK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的HoH基因座、人源化的LoK基因座或它们的组合处是纯合的。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的HoH基因座和人源化的LiK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的HoH基因座、人源化的LiK基因座或它们的组合处是纯合的。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的LoH基因座和人源化的KoK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的LoH基因座和人源化的LoL基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的LoH基因座、人源化的KoK基因座和人源化的LoL基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoH基因座、人源化的KoK基因座、人源化的LoL基因座或它们的组合处是纯合的。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的LoH基因座、人源化的KoK基因座和人源化的LoK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的LoH基因座、人源化的KoK基因座和人源化的LiK基因座。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的LoH基因座和人源化的LoK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoH基因座、人源化的LoK基因座或它们的组合处是纯合的。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的LoH基因座和人源化的LiK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoH基因座、人源化的LiK基因座或它们的组合处是纯合的。
在某些实施方案中，本文提供的遗传修饰的啮齿动物(例如，大鼠或小鼠)具有包含人源化的免疫球蛋白重链(例如，HoH或LoH)基因座的基因组(例如，种系基因组)，所述基因座缺少功能性内源性啮齿动物Adam6基因。在某些实施方案中，本文提供的遗传修饰的啮齿动物(例如，大鼠或小鼠)具有包含一个或多个核苷酸序列的基因组(例如，种系基因组)，所述核苷酸序列编码一种或多种啮齿动物ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段。在某些实施方案中，所提供的遗传修饰的啮齿动物(例如，大鼠或小鼠)表达一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段。在某些实施方案中，所提供的遗传修饰的啮齿动物(例如，大鼠或小鼠)具有包含一个或多个核苷酸序列的基因组(例如，种系基因组)，所述核苷酸序列编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段，所述核苷酸序列被包括在与人源化的免疫球蛋白重链(例如，HoH或LoH)基因座相同的染色体上。在某些实施方案中，所提供的遗传修饰的啮齿动物(例如，大鼠或小鼠)具有包含人源化的免疫球蛋白重链(例如，HoH或LoH)基因座的基因组(例如，种系基因组)，所述基因座包含一个或多个核苷酸序列，所述核苷酸序列编码一种或多种啮齿动物ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段。在某些实施方案中，所提供的遗传修饰的啮齿动物(例如，大鼠或小鼠)具有替代人Adam6假基因的包含一个或多个核苷酸序列的基因组(例如，种系基因组)，所述核苷酸序列编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段。在某些实施方案中，所提供的遗传修饰的啮齿动物(例如，大鼠或小鼠)具有替换人Adam6假基因的包含一个或多个核苷酸序列的基因组(例如，种系基因组)，所述核苷酸序列编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段。
在某些实施方案中，所提供的遗传修饰的啮齿动物具有基因组(例如，种系基因组)，其含有包含第一和第二人VH基因区段的一个或多个人VH基因区段、以及在第一人VH基因区段和第二人VH基因区段之间的编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段的一个或多个核苷酸序列。在某些实施方案中，第一人VH基因区段是VH1-2且第二人VH基因区段是VH6-1。
在某些实施方案中，编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段的一个或多个核苷酸序列是在人VH基因区段和人DH基因区段之间。
在某些实施方案中，编码一种或多种啮齿动物ADAM6多肽的一个或多个核苷酸序列恢复或增强雄性啮齿动物的能育性。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)包含外源性末端脱氧核苷酸转移酶(TdT)基因。在某些实施方案中，与没有外源性TdT基因的啮齿动物相比，包含外源性末端脱氧核苷酸转移酶(TdT)基因的啮齿动物(例如，大鼠或小鼠)可以具有增加的抗原受体多样性。
在某些实施方案中，如本文中所述的啮齿动物具有包含可操作地连接至转录控制元件的外源性末端脱氧核苷酸基转移酶(TdT)基因的基因组。
在某些实施方案中，转录控制元件包括RAG1转录控制元件、RAG2转录控制元件、免疫球蛋白重链转录控制元件、免疫球蛋白κ轻链转录控制元件、免疫球蛋白λ轻链转录控制元件或它们的任意组合。
在某些实施方案中，外源性TdT位于免疫球蛋白κ轻链基因座、免疫球蛋白λ轻链基因座、免疫球蛋白重链基因座、RAG1基因座或RAG2基因座处。
在某些实施方案中，TdT是人TdT。在某些实施方案中，TdT是TdT的短异形体(TdTS)。
在实施方案的另一个方面，本文中公开了制备遗传修饰的啮齿动物(例如，小鼠或大鼠)的方法，所述方法包括修饰啮齿动物基因组(例如，种系基因组)，使得经修饰的啮齿动物基因组包含编码NaV1.2蛋白的核酸分子。在某些实施方案中，编码NaV1.2蛋白的核酸分子是在内源性啮齿动物(例如，大鼠或小鼠)Scn9a基因座处。在某些实施方案中，编码NaV1.2蛋白的核酸分子是在包括在伤害感受器中表达的基因的基因座处。在某些实施方案中，编码NaV1.2蛋白的核酸分子是在转录上有活性的或允许的基因座处，例如，ROSA26基因座(Zambrowicz等人,1997,PNAS USA 94:3789-3794，其通过引用并入本文)、BT-5基因座(Michael等人,1999,Mech.Dev.85:35-47，其通过引用并入本文)或Oct4基因座(Wallace等人,2000,Nucleic Acids Res.28:1455-1464，其通过引用并入本文)。在某些实施方案中，从在遗传修饰的啮齿动物(例如，大鼠或小鼠)的基因组中编码NaV1.2蛋白的核酸分子表达NaV1.2蛋白，并制备包含经修饰的基因组的啮齿动物。在某些实施方案中，所述啮齿动物不表达内源性NaV1.7。
在所述方法的某些实施方案中，通过包括以下步骤的方法来修饰啮齿动物基因组：(i)将编码NaV1.2蛋白的核酸分子引入啮齿动物胚胎干(ES)细胞，使得所述核酸分子整合进内源性啮齿动物Scn9a基因座；(ii)得到包含经修饰的基因组的啮齿动物ES细胞，其中所述核酸分子已经整合进内源性啮齿动物Scn9a基因座；和(iii)从得到的包含经修饰的基因组的啮齿动物ES细胞制备啮齿动物。
在所述方法的某些实施方案中，核酸分子编码人、黑猩猩、恒河猴、马来西亚飞行狐猴、兔、马、阿拉伯骆驼、杀人鲸、牛、绵羊、大鼠、小鼠、狗、鸡、绿海龟或眼镜王蛇的NaV1.2蛋白。在某些实施方案中，核酸分子编码人NaV1.2蛋白。在某些实施方案中，核酸分子编码包含与SEQ ID NO:4具有至少95％同一性的氨基酸序列的NaV1.2蛋白。在某些实施方案中，核酸分子编码包含与SEQ ID NO:4具有至少96％同一性的氨基酸序列的NaV1.2蛋白。在某些实施方案中，核酸分子编码包含与SEQ ID NO:4具有至少97％同一性的氨基酸序列的NaV1.2蛋白。在某些实施方案中，核酸分子编码包含与SEQ ID NO:4具有至少98％同一性的氨基酸序列的NaV1.2蛋白。在某些实施方案中，核酸分子编码包含与SEQ ID NO:4具有至少99％同一性的氨基酸序列的NaV1.2蛋白。在某些实施方案中，核酸分子编码包含与SEQ IDNO:4具有大于99％同一性的氨基酸序列的NaV1.2蛋白。在某些实施方案中，核酸分子编码包含与SEQ ID NO:4相同的氨基酸序列的NaV1.2蛋白。
在所述方法的某些实施方案中，编码NaV1.2蛋白的核酸分子可操作地连接至啮齿动物(例如，大鼠或小鼠)Scn启动子。在所述方法的某些实施方案中，编码NaV1.2蛋白的核酸分子可操作地连接至啮齿动物(例如，大鼠或小鼠)Scn9a启动子。在某些实施方案中，编码NaV1.2蛋白的核酸分子可操作地连接至在内源性啮齿动物(例如，大鼠或小鼠)Scn9a基因座处的内源性啮齿动物(例如，大鼠或小鼠)Scn9a启动子。
在所述方法的某些实施方案中，编码NaV1.2蛋白的核酸分子是DNA(例如，基因组DNA或cDNA)。在某些实施方案中，编码NaV1.2蛋白的核酸分子包含从ATG起始密码子至Scn2a基因的终止密码子的邻接核苷酸的核苷酸序列。在某些实施方案中，编码NaV1.2蛋白的核酸分子包括编码内源性啮齿动物(例如，大鼠或小鼠)Scn9a基因的5'UTR的DNA序列。在某些实施方案中，所述核苷酸序列可操作地连接至Scn2a基因的5'UTR。在某些实施方案中，编码NaV1.2蛋白的核酸分子包括编码内源性啮齿动物(例如，大鼠或小鼠)Scn9a基因的3'UTR的DNA序列。在某些实施方案中，编码NaV1.2蛋白的核酸分子包括编码Scn2a基因的3'UTR的DNA序列。
在所述方法的某些实施方案中，编码NaV1.2蛋白的核酸分子是在内源性啮齿动物(例如，大鼠或小鼠)Scn9a基因座的内源性啮齿动物(例如，大鼠或小鼠)Scn9a基因的基因组片段处。在某些实施方案中，基因组片段包含编码内源性啮齿动物(例如，大鼠或小鼠)NaV1.7蛋白的核苷酸序列。在某些实施方案中，内源性啮齿动物(例如，大鼠或小鼠)Scn9a基因的编码区(例如，从ATG密码子至终止密码子)已经被替换。
在所述方法的某些实施方案中，编码NaV1.2蛋白的核酸分子是Scn2a基因的基因组片段。在某些实施方案中，编码NaV1.2蛋白的核酸分子是cDNA。在某些实施方案中，编码NaV1.2蛋白的核酸分子是重组DNA。在某些实施方案中，编码NaV1.2蛋白的核酸分子可以包含从野生型序列修饰的核苷酸序列。在某些实施方案中，编码NaV1.2蛋白的核酸分子可以包含从野生型序列修饰的核苷酸序列，例如，从野生型序列优化的密码子。在某些实施方案中，编码NaV1.2蛋白的核酸分子可以包含从野生型序列修饰的核苷酸序列，例如，从野生型序列修饰以除去T-细胞表位。
在所述方法的某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)就编码NaV1.2蛋白的核酸分子而言是杂合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)就编码NaV1.2蛋白的核酸分子而言是纯合的。
在所述方法的某些实施方案中，由于内源性啮齿动物(例如，大鼠或小鼠)Scn9a基因的灭活(例如，但不限于，完全或部分缺失，或完全或部分倒转)或替换(完全或部分)，遗传修饰的啮齿动物(例如，大鼠或小鼠)不能表达啮齿动物(例如，大鼠或小鼠)NaV1.7蛋白。
在所述方法的某些实施方案中，当用NaV1.7免疫原(例如，人NaV1.7免疫原)免疫时，遗传修饰的啮齿动物(例如，大鼠或小鼠)产生针对NaV1.7蛋白(例如，人NaV1.7蛋白)的抗体。在某些实施方案中，NaV1.7免疫原可以是蛋白免疫原、DNA免疫原或它们的组合。
在所述方法的某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含如本文中所述的人源化的免疫球蛋白重链基因座、人源化的免疫球蛋白轻链基因座或它们的组合。
在所述方法的某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白重链基因座，所述基因座包含一个或多个人VH基因区段、一个或多个人DH基因区段和一个或多个人JH基因区段，所述区段是在一个或多个啮齿动物(例如，大鼠或小鼠)免疫球蛋白重链恒定区基因(例如，一个或多个内源性啮齿动物(例如，大鼠或小鼠)免疫球蛋白重链恒定区基因)的上游(例如，与其可操作地连接)。这样的人源化的免疫球蛋白重链基因座在本文中被称作“人源化的HoH基因座”。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的HoH基因座处是纯合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的HoH基因座处是杂合的。
在所述方法的某些实施方案中，包含人源化的HoH基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含重链，其中每个重链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)重链恒定结构域的人重链可变结构域。
在所述方法的某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白重链基因座，所述基因座包含一个或多个人VL基因区段和一个或多个人JL基因区段，所述区段是在一个或多个啮齿动物(例如，大鼠或小鼠)免疫球蛋白重链恒定区基因(例如，一个或多个内源性啮齿动物(例如，大鼠或小鼠)免疫球蛋白重链恒定区基因)的上游(例如，与其可操作地连接)。这样的人源化的免疫球蛋白重链基因座在本文中被称作“人源化的LoH基因座”。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoH基因座处是纯合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoH基因座处是杂合的。
在所述方法的某些实施方案中，包含人源化的LoH基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含免疫球蛋白链，其中每个免疫球蛋白链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)重链恒定结构域的人轻链可变结构域。
在所述方法的某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含含有一个或多个人VL基因区段和一个或多个人JL基因区段的人源化的免疫球蛋白轻链基因座，所述区段是在一个或多个免疫球蛋白轻链恒定区基因的上游(例如，与其可操作地连接)。在某些实施方案中，一个或多个人VL基因区段和一个或多个人JL基因区段是一个或多个人Vκ基因区段和一个或多个人Jκ基因区段。在某些实施方案中，一个或多个人VL基因区段和一个或多个人JL基因区段是一个或多个人Vλ基因区段和一个或多个人Jλ基因区段。在某些实施方案中，一个或多个免疫球蛋白轻链恒定区基因是或包含Cκ。在某些实施方案中，一个或多个免疫球蛋白轻链恒定区基因是或包含Cλ。
在所述方法的某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白轻链基因座，所述基因座包含一个或多个人Vκ基因区段和一个或多个人Jκ基因区段，所述区段是在Cκ基因的上游(例如，与其可操作地连接)。这样的人源化的免疫球蛋白重链基因座在本文中被称作“人源化的KoK基因座”。在某些实施方案中，人源化的KoK基因座的免疫球蛋白κ轻链恒定区基因是啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，人源化的KoK基因座的免疫球蛋白κ轻链恒定区基因是内源性啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，人源化的KoK基因座的免疫球蛋白κ轻链恒定区基因是在内源性免疫球蛋白κ轻链基因座处的内源性啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的KoK基因座处是纯合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的KoK基因座处是杂合的。
在所述方法的某些实施方案中，包含人源化的KoK基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含κ轻链，其中每个κ轻链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)κ轻链恒定结构域的人κ轻链可变结构域。
在所述方法的某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白轻链基因座，所述基因座包含在一个或多个人Jλ基因区段和一个或多个Cλ基因的上游(例如，与其可操作地连接)的一个或多个人Vλ基因区段。这样的人源化的免疫球蛋白轻链基因座在本文中被称作“人源化的LoL基因座”。在某些实施方案中，人源化的LoL基因座的一个或多个人Jλ基因区段和一个或多个Cλ基因存在于Jλ-Cλ簇中。在某些实施方案中，人源化的LoL基因座的一个或多个Cλ基因包含一个或多个人Cλ基因。在某些实施方案中，人源化的LoL基因座的一个或多个Cλ基因包含一个或多个小鼠Cλ基因。在某些实施方案中，人源化的LoL基因座的一个或多个Cλ基因包含一个或多个人Cλ基因和一个或多个小鼠Cλ基因。在某些实施方案中，人源化的LoL基因座的一个或多个小鼠Cλ基因包含小鼠Cλ1基因。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoL基因座处是纯合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoL基因座处是杂合的。
在所述方法的某些实施方案中，包含人源化的LoL基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含λ轻链，其中每个λ轻链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)λ轻链恒定结构域的人λ轻链可变结构域。在所述方法的某些实施方案中，包含人源化的LoL基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含λ轻链，其中每个λ轻链包含可操作地连接至人λ轻链恒定结构域的人λ轻链可变结构域。
在所述方法的某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白轻链基因座，所述基因座包含在Cκ基因的上游(例如，与其可操作地连接)的一个或多个人Vλ基因区段和一个或多个人Jλ基因区段。这样的人源化的免疫球蛋白轻链基因座在本文中被称作“人源化的LoK基因座”。在某些实施方案中，人源化的LoK基因座的Cκ基因是啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，人源化的LoK基因座的Cκ基因是内源性啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，人源化的LoK基因座的Cκ基因是在内源性免疫球蛋白κ轻链基因座处的内源性啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoK基因座处是纯合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoK基因座处是杂合的。
在所述方法的某些实施方案中，包含人源化的LoK基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含轻链，其中每个轻链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)κ轻链恒定结构域的人λ轻链可变结构域。
在所述方法的某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白κ轻链基因座，所述基因座包含在Cλ基因的上游(例如，与其可操作地连接)的一个或多个人Vλ基因区段和一个或多个人Jλ基因区段。这样的人源化的免疫球蛋白轻链基因座在本文中被称作“人源化的LiK基因座”。在某些实施方案中，人源化的LiK基因座的Cλ基因是啮齿动物(例如，大鼠或小鼠)Cλ基因。在某些实施方案中，人源化的LiK基因座的Cλ基因是小鼠Cλ1基因。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LiK基因座处是纯合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LiK基因座处是杂合的。
在所述方法的某些实施方案中，包含人源化的LiK基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含λ轻链，其中每个λ轻链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)λ轻链恒定结构域的人λ轻链可变结构域。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白κ轻链基因座，所述基因座包含在一个或多个人Jλ基因区段和一个或多个人Cλ基因上游(例如，与其可操作地连接)的一个或多个人Vλ基因区段。在某些实施方案中，这样的人源化的免疫球蛋白κ轻链基因座的一个或多个人Jλ基因区段和一个或多个Cλ基因存在于Jλ-Cλ簇中。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)就这样的人源化的免疫球蛋白κ轻链基因座而言是纯合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)就这样的人源化的免疫球蛋白κ轻链基因座而言是杂合的。在某些实施方案中，包含这样的人源化的免疫球蛋白κ轻链基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含λ轻链，其中每个λ轻链包含可操作地连接至人λ轻链恒定结构域的人λ轻链可变结构域。
在所述方法的某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的HoH基因座和人源化的KoK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的HoH基因座和人源化的LoL基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的HoH基因座、人源化的KoK基因座和人源化的LoL基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的HoH基因座、人源化的KoK基因座、人源化的LoL基因座或它们的组合处是纯合的。
在所述方法的某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的HoH基因座、人源化的KoK基因座和人源化的LoK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的HoH基因座、人源化的KoK基因座和人源化的LiK基因座。
在所述方法的某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的HoH基因座和人源化的LoK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的HoH基因座、人源化的LoK基因座或它们的组合处是纯合的。
在所述方法的某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的HoH基因座和人源化的LiK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的HoH基因座、人源化的LiK基因座或它们的组合处是纯合的。
在所述方法的某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的LoH基因座和人源化的KoK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的LoH基因座和人源化的LoL基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的LoH基因座、人源化的KoK基因座和人源化的LoL基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoH基因座、人源化的KoK基因座、人源化的LoL基因座或它们的组合处是纯合的。
在所述方法的某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的LoH基因座、人源化的KoK基因座和人源化的LoK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的LoH基因座、人源化的KoK基因座和人源化的LiK基因座。
在所述方法的某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的LoH基因座和人源化的LoK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoH基因座、人源化的LoK基因座或它们的组合处是纯合的。
在所述方法的某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的LoH基因座和人源化的LiK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoH基因座、人源化的LiK基因座或它们的组合处是纯合的。
在所述方法的某些实施方案中，本文提供的遗传修饰的啮齿动物(例如，大鼠或小鼠)具有包含人源化的免疫球蛋白重链(例如，HoH或LoH)基因座的基因组(例如，种系基因组)，所述基因座缺少功能性内源性啮齿动物Adam6基因。在某些实施方案中，本文提供的遗传修饰的啮齿动物(例如，大鼠或小鼠)具有包含一个或多个核苷酸序列的基因组(例如，种系基因组)，所述核苷酸序列编码一种或多种啮齿动物ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段。在某些实施方案中，所提供的遗传修饰的啮齿动物(例如，大鼠或小鼠)表达一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段。在某些实施方案中，所提供的遗传修饰的啮齿动物(例如，大鼠或小鼠)具有包含一个或多个核苷酸序列的基因组(例如，种系基因组)，所述核苷酸序列编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段，所述核苷酸序列被包括在与人源化的免疫球蛋白重链(例如，HoH或LoH)基因座相同的染色体上。在某些实施方案中，所提供的遗传修饰的啮齿动物(例如，大鼠或小鼠)具有包含人源化的免疫球蛋白重链(例如，HoH或LoH)基因座的基因组(例如，种系基因组)，所述基因座包含一个或多个核苷酸序列，所述核苷酸序列编码一种或多种啮齿动物ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段。在某些实施方案中，所提供的遗传修饰的啮齿动物(例如，大鼠或小鼠)具有替代人Adam6假基因的包含一个或多个核苷酸序列的基因组(例如，种系基因组)，所述核苷酸序列编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段。在某些实施方案中，所提供的遗传修饰的啮齿动物(例如，大鼠或小鼠)具有替换人Adam6假基因的包含一个或多个核苷酸序列的基因组(例如，种系基因组)，所述核苷酸序列编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段。
在所述方法的某些实施方案中，所提供的遗传修饰的啮齿动物具有基因组(例如，种系基因组)，其含有包含第一和第二人VH基因区段的一个或多个人VH基因区段、以及在第一人VH基因区段和第二人VH基因区段之间的编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段的一个或多个核苷酸序列。在某些实施方案中，第一人VH基因区段是VH1-2且第二人VH基因区段是VH6-1。
在所述方法的某些实施方案中，编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段的一个或多个核苷酸序列是在人VH基因区段和人DH基因区段之间。
在所述方法的某些实施方案中，编码一种或多种啮齿动物ADAM6多肽的一个或多个核苷酸序列恢复或增强雄性啮齿动物的能育性。
在所述方法的某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)包含外源性末端脱氧核苷酸转移酶(TdT)基因。在某些实施方案中，与没有外源性TdT基因的啮齿动物相比，包含外源性末端脱氧核苷酸转移酶(TdT)基因的啮齿动物(例如，大鼠或小鼠)可以具有增加的抗原受体多样性。
在所述方法的某些实施方案中，如本文中所述的啮齿动物具有包含可操作地连接至转录控制元件的外源性末端脱氧核苷酸基转移酶(TdT)基因的基因组。
在所述方法的某些实施方案中，转录控制元件包括RAG1转录控制元件、RAG2转录控制元件、免疫球蛋白重链转录控制元件、免疫球蛋白κ轻链转录控制元件、免疫球蛋白λ轻链转录控制元件或它们的任意组合。
在所述方法的某些实施方案中，外源性TdT位于免疫球蛋白κ轻链基因座、免疫球蛋白λ轻链基因座、免疫球蛋白重链基因座、RAG1基因座或RAG2基因座处。
在所述方法的某些实施方案中，TdT是人TdT。在某些实施方案中，TdT是TdT的短异形体(TdTS)。
在实施方案的另一个方面，本文中公开了分离的啮齿动物细胞或啮齿动物组织，其基因组包含在内源性啮齿动物Scn9a基因座处的编码NaV1.2蛋白的核酸分子。在某些实施方案中，所述分离的啮齿动物细胞或啮齿动物组织是小鼠细胞或小鼠组织或大鼠细胞或大鼠组织。在某些实施方案中，所述分离的啮齿动物细胞或啮齿动物组织是小鼠细胞或小鼠组织。在某些实施方案中，所述分离的啮齿动物细胞或啮齿动物组织是大鼠细胞或大鼠组织。
在某些实施方案中，分离的啮齿动物细胞是啮齿动物ES细胞。在某些实施方案中，分离的啮齿动物细胞是B细胞。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的免疫球蛋白重链基因座，所述基因座包含一个或多个人VH基因区段、一个或多个人DH基因区段和一个或多个人JH基因区段，所述区段是在一个或多个啮齿动物(例如，大鼠或小鼠)免疫球蛋白重链恒定区基因(例如，一个或多个内源性啮齿动物(例如，大鼠或小鼠)免疫球蛋白重链恒定区基因)的上游(例如，与其可操作地连接)。这样的人源化的免疫球蛋白重链基因座在本文中被称作“人源化的HoH基因座”。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的HoH基因座处是纯合的。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的HoH基因座处是杂合的。
在某些实施方案中，分离的啮齿动物细胞是包含人源化的HoH基因座的B细胞或脾细胞且产生抗体，例如，响应于抗原刺激，所述抗体尤其包含重链，其中每个重链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)重链恒定结构域的人重链可变结构域。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的免疫球蛋白轻链基因座，所述基因座包含一个或多个人VL基因区段和一个或多个人JL基因区段，所述区段是在一个或多个免疫球蛋白轻链恒定区基因的上游(例如，与其可操作地连接)。在某些实施方案中，一个或多个人VL基因区段和一个或多个人JL基因区段是一个或多个人Vκ基因区段和一个或多个人Jκ基因区段。在某些实施方案中，一个或多个人VL基因区段和一个或多个人JL基因区段是一个或多个人Vλ基因区段和一个或多个人Jλ基因区段。在某些实施方案中，一个或多个免疫球蛋白轻链恒定区基因是或包含Cκ。在某些实施方案中，一个或多个免疫球蛋白轻链恒定区基因是或包含Cλ。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的免疫球蛋白轻链基因座，所述基因座包含一个或多个人Vκ基因区段和一个或多个人Jκ基因区段，所述区段是在Cκ基因的上游(例如，与其可操作地连接)。这样的人源化的免疫球蛋白重链基因座在本文中被称作“人源化的KoK基因座”。在某些实施方案中，人源化的KoK基因座的免疫球蛋白κ轻链恒定区基因是啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，人源化的KoK基因座的免疫球蛋白κ轻链恒定区基因是内源性啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，人源化的KoK基因座的免疫球蛋白κ轻链恒定区基因是在内源性免疫球蛋白κ轻链基因座处的内源性啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的KoK基因座处是纯合的。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的KoK基因座处是杂合的。
在某些实施方案中，分离的啮齿动物细胞是包含人源化的KoK基因座的B细胞或脾细胞且产生抗体，例如，响应于抗原刺激，所述抗体尤其包含κ轻链，其中每个κ轻链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)κ轻链恒定结构域的人κ轻链可变结构域。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的免疫球蛋白轻链基因座，所述基因座包含在一个或多个人Jλ基因区段和一个或多个Cλ基因的上游(例如，与其可操作地连接)的一个或多个人Vλ基因区段。这样的人源化的免疫球蛋白轻链基因座在本文中被称作“人源化的LoL基因座”。在某些实施方案中，人源化的LoL基因座的一个或多个人Jλ基因区段和一个或多个Cλ基因存在于Jλ-Cλ簇中。在某些实施方案中，人源化的LoL基因座的一个或多个Cλ基因包含一个或多个人Cλ基因。在某些实施方案中，人源化的LoL基因座的一个或多个Cλ基因包含一个或多个小鼠Cλ基因。在某些实施方案中，人源化的LoL基因座的一个或多个Cλ基因包含一个或多个人Cλ基因和一个或多个小鼠Cλ基因。在某些实施方案中，人源化的LoL基因座的一个或多个小鼠Cλ基因包含小鼠Cλ1基因。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的LoL基因座处是纯合的。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的LoL基因座处是杂合的。
在某些实施方案中，分离的啮齿动物细胞是包含人源化的LoL基因座的B细胞或脾细胞且产生抗体，例如，响应于抗原刺激，所述抗体尤其包含λ轻链，其中每个λ轻链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)λ轻链恒定结构域的人λ轻链可变结构域。在某些实施方案中，分离的啮齿动物细胞是包含人源化的LoL基因座的B细胞或脾细胞且产生抗体，例如，响应于抗原刺激，所述抗体尤其包含λ轻链，其中每个λ轻链包含可操作地连接至人λ轻链恒定结构域的人λ轻链可变结构域。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的免疫球蛋白轻链基因座，所述基因座包含在Cκ基因的上游(例如，与其可操作地连接)的一个或多个人Vλ基因区段和一个或多个人Jλ基因区段。这样的人源化的免疫球蛋白轻链基因座在本文中被称作“人源化的LoK基因座”。在某些实施方案中，人源化的LoK基因座的Cκ基因是啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，人源化的LoK基因座的Cκ基因是内源性啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，人源化的LoK基因座的Cκ基因是在内源性免疫球蛋白κ轻链基因座处的内源性啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的LoK基因座处是纯合的。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的LoK基因座处是杂合的。
在某些实施方案中，分离的啮齿动物细胞是包含人源化的LoK基因座的B细胞或脾细胞且产生抗体，例如，响应于抗原刺激，所述抗体尤其包含轻链，其中每个轻链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)κ轻链恒定结构域的人λ轻链可变结构域。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的免疫球蛋白κ轻链基因座，所述基因座包含在Cλ基因的上游(例如，与其可操作地连接)的一个或多个人Vλ基因区段和一个或多个人Jλ基因区段。这样的人源化的免疫球蛋白轻链基因座在本文中被称作“人源化的LiK基因座”。在某些实施方案中，人源化的LiK基因座的Cλ基因是啮齿动物(例如，大鼠或小鼠)Cλ基因。在某些实施方案中，人源化的LiK基因座的Cλ基因是小鼠Cλ1基因。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的LiK基因座处是纯合的。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的LiK基因座处是杂合的。
在某些实施方案中，分离的啮齿动物细胞是包含人源化的LiK基因座的B细胞或脾细胞且产生抗体，例如，响应于抗原刺激，所述抗体尤其包含λ轻链，其中每个λ轻链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)λ轻链恒定结构域的人λ轻链可变结构域。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的免疫球蛋白κ轻链基因座，所述基因座包含在一个或多个人Jλ基因区段和一个或多个人Cλ基因上游(例如，与其可操作地连接)的一个或多个人Vλ基因区段。在某些实施方案中，这样的人源化的免疫球蛋白κ轻链基因座的一个或多个人Jλ基因区段和一个或多个Cλ基因存在于Jλ-Cλ簇中。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织就这样的人源化的免疫球蛋白κ轻链基因座而言是纯合的。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织就这样的人源化的免疫球蛋白κ轻链基因座而言是杂合的。在某些实施方案中，分离的啮齿动物细胞是B细胞或脾细胞，其包含这样的人源化的免疫球蛋白κ轻链基因座，且产生抗体，例如，响应于抗原刺激，所述抗体尤其包含λ轻链，其中每个λ轻链包含可操作地连接至人λ轻链恒定结构域的人λ轻链可变结构域。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的HoH基因座和人源化的KoK基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的HoH基因座和人源化的LoL基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的HoH基因座、人源化的KoK基因座和人源化的LoL基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的HoH基因座、人源化的KoK基因座、人源化的LoL基因座或它们的组合处是纯合的。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的HoH基因座、人源化的KoK基因座和人源化的LoK基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的HoH基因座、人源化的KoK基因座和人源化的LiK基因座。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的HoH基因座和人源化的LoK基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的HoH基因座、人源化的LoK基因座或它们的组合处是纯合的。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的HoH基因座和人源化的LiK基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的HoH基因座、人源化的LiK基因座或它们的组合处是纯合的。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的LoH基因座和人源化的KoK基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的LoH基因座和人源化的LoL基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的LoH基因座、人源化的KoK基因座和人源化的LoL基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的LoH基因座、人源化的KoK基因座、人源化的LoL基因座或它们的组合处是纯合的。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的LoH基因座、人源化的KoK基因座和人源化的LoK基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的LoH基因座、人源化的KoK基因座和人源化的LiK基因座。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的LoH基因座和人源化的LoK基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的LoH基因座、人源化的LoK基因座或它们的组合处是纯合的。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的LoH基因座和人源化的LiK基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的LoH基因座、人源化的LiK基因座或它们的组合处是纯合的。
在某些实施方案中，本文提供的分离的啮齿动物细胞或啮齿动物组织具有基因组，所述基因组包含缺乏内源性啮齿动物Adam6基因的人源化的免疫球蛋白重链(例如，HoH或LoH)基因座。在某些实施方案中，本文提供的分离的啮齿动物细胞或啮齿动物组织具有基因组，所述基因组包含编码一种或多种啮齿动物ADAM6多肽、其直系同源物、同系物或片段的一个或多个核苷酸序列。在某些实施方案中，所提供的分离的啮齿动物细胞或啮齿动物组织表达一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其直系同源物、同系物或片段。在某些实施方案中，所提供的分离的啮齿动物细胞或啮齿动物组织具有基因组，所述基因组包含编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其直系同源物、同系物或片段的一个或多个核苷酸序列，所述核苷酸序列被包括在与人源化的免疫球蛋白重链(例如，HoH或LoH)基因座相同的染色体上。在某些实施方案中，所提供的分离的啮齿动物细胞或啮齿动物组织具有基因组，所述基因组包含人源化的免疫球蛋白重链(例如，HoH或LoH)基因座，所述基因座包含编码一种或多种啮齿动物ADAM6多肽、其直系同源物、同系物或片段的一个或多个核苷酸序列。在某些实施方案中，所提供的分离的啮齿动物细胞或啮齿动物组织具有替代人Adam6假基因的基因组，所述基因组包含编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其直系同源物、同系物或片段的一个或多个核苷酸序列。在某些实施方案中，所提供的分离的啮齿动物细胞或啮齿动物组织具有替换人Adam6假基因的基因组，所述基因组包含编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其直系同源物、同系物或片段的一个或多个核苷酸序列。
在某些实施方案中，所提供的分离的啮齿动物细胞或啮齿动物组织具有基因组，所述基因组包含含有第一和第二人VH基因区段的一个或多个人VH基因区段、以及在第一人VH基因区段和第二人VH基因区段之间的编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其直系同源物、同系物或片段的一个或多个核苷酸序列。在某些实施方案中，第一人VH基因区段是VH1-2且第二人VH基因区段是VH6-1。
在某些实施方案中，编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其直系同源物、同系物或片段的一个或多个核苷酸序列是在人VH基因区段和人DH基因区段之间。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织包含外源性末端脱氧核苷酸转移酶(TdT)基因。在某些实施方案中，分离的啮齿动物细胞是包含外源性末端脱氧核苷酸转移酶(TdT)基因的B细胞或脾细胞，且当与不具有外源性TdT基因的分离的啮齿动物细胞(例如，B细胞或脾细胞)相比时可以具有增加的抗原受体多样性。
在某些实施方案中，如本文中所述的分离的啮齿动物细胞或啮齿动物组织具有包含可操作地连接至转录控制元件的外源性末端脱氧核苷酸基转移酶(TdT)基因的基因组。
在某些实施方案中，转录控制元件包括RAG1转录控制元件、RAG2转录控制元件、免疫球蛋白重链转录控制元件、免疫球蛋白κ轻链转录控制元件、免疫球蛋白λ轻链转录控制元件或它们的任意组合。
在某些实施方案中，外源性TdT位于免疫球蛋白κ轻链基因座、免疫球蛋白λ轻链基因座、免疫球蛋白重链基因座、RAG1基因座或RAG2基因座处。
在某些实施方案中，TdT是人TdT。在某些实施方案中，TdT是TdT的短异形体(TdTS)。
在实施方案的另一个方面，本文中公开了包含本文描述的啮齿动物ES细胞的啮齿动物胚胎。
在实施方案的一个方面，本文中公开了一种靶向核酸构建体，其包含编码NaV1.2蛋白的核酸分子，所述核酸分子侧接能够介导所述核酸分子向内源性啮齿动物Scn9a基因座中的同源重组和整合的5'和3'啮齿动物核苷酸序列。
在实施方案的另一个方面，本文中公开了生产抗-NaV1.7抗体的方法，所述方法包括用NaV1.7免疫原(例如，人NaV1.7免疫原)免疫本文描述的遗传修饰的啮齿动物(例如，大鼠或小鼠)。在某些实施方案中，生产抗-NaV1.7抗体的方法包括从经免疫的啮齿动物分离抗-NaV1.7抗体。在某些实施方案中，所述抗体是单克隆抗体。在某些实施方案中，生产抗-NaV1.7抗体的方法包括从经免疫的啮齿动物分离表达抗-NaV1.7抗体的B细胞。在某些实施方案中，还提供了生产抗-人NaV1.7抗体的杂交瘤。在某些实施方案中，生产抗-人NaV1.7抗体的杂交瘤源自从经免疫的啮齿动物分离的B细胞。
在实施方案的另一个方面，本文中公开了生产抗-NaV1.7抗体的人重链和/或轻链可变结构域的方法，所述方法包括用NaV1.7免疫原(例如，人NaV1.7免疫原)免疫本文描述的遗传修饰的啮齿动物(例如，大鼠或小鼠)。在某些实施方案中，生产抗-NaV1.7抗体的人重链和/或轻链可变结构域的方法包括使遗传修饰的小鼠产生对NaV1.7免疫原的免疫应答。在某些实施方案中，生产抗-NaV1.7抗体的人重链和/或轻链可变结构域的方法包括从表达抗-NaV1.7抗体的遗传修饰的小鼠分离B细胞。在某些实施方案中，生产抗-NaV1.7抗体的人重链和/或轻链可变结构域的方法包括确定由遗传修饰的小鼠产生的抗-NaV1.7抗体的人重链和/或轻链可变结构域的氨基酸序列。在某些实施方案中，生产抗-NaV1.7抗体的人重链和/或轻链可变结构域的方法包括表达多肽，所述多肽包含鉴定的人重链和/或轻链可变结构域。在某些实施方案中，确定人重链和/或轻链可变结构域的氨基酸序列包括确定分别编码人重链和/或轻链可变结构域的核苷酸序列。
在实施方案的另一个方面，本文中公开了生产分别编码抗-NaV1.7抗体的人重链和/或轻链可变结构域的人重链和/或轻链可变区的方法，所述方法包括用NaV1.7免疫原(例如，人NaV1.7免疫原)免疫本文描述的遗传修饰的啮齿动物(例如，大鼠或小鼠)。在某些实施方案中，生产分别编码抗-NaV1.7抗体的人重链和/或轻链可变结构域的人重链和/或轻链可变区的方法包括使遗传修饰的啮齿动物产生对NaV1.7免疫原的免疫应答。在某些实施方案中，生产分别编码抗-NaV1.7抗体的人重链和/或轻链可变结构域的人重链和/或轻链可变区的方法包括从表达抗-NaV1.7抗体的遗传修饰的啮齿动物分离B细胞。在某些实施方案中，生产分别编码抗-NaV1.7抗体的人重链和/或轻链可变结构域的人重链和/或轻链可变区的方法包括确定由遗传修饰的啮齿动物产生的抗-NaV1.7抗体的人重链和/或轻链可变区的核酸序列。
在实施方案的另一个方面，本文中公开了一种核酸，其编码与本文描述的啮齿动物(例如，大鼠或小鼠)相同或从其得到的抗-NaV1.7抗体的人重链和/或轻链可变结构域。
在实施方案的另一个方面，本文中公开了一种核酸，其编码与本文描述的啮齿动物(例如，大鼠或小鼠)相同或从其得到的包含抗-NaV1.7抗体的人重链可变结构域的免疫球蛋白重链。在某些实施方案中，编码免疫球蛋白重链的核酸进一步包含人重链恒定结构域。在某些实施方案中，编码免疫球蛋白重链的核酸进一步包含啮齿动物(例如，大鼠或小鼠)重链恒定结构域。
在实施方案的另一个方面，本文中公开了一种核酸，其编码与本文描述的啮齿动物(例如，大鼠或小鼠)相同或从其得到的包含抗-NaV1.7抗体的人轻链可变结构域的免疫球蛋白轻链。在某些实施方案中，编码免疫球蛋白轻链的核酸进一步包含人轻链恒定结构域。在某些实施方案中，编码免疫球蛋白轻链的核酸进一步包含啮齿动物(例如，大鼠或小鼠)轻链恒定结构域。
在实施方案的另一个方面，本文中公开了与本文描述的啮齿动物(例如，大鼠或小鼠)相同、从其得到或从其衍生出的抗-NaV1.7抗体的人重链和/或轻链可变结构域。
在实施方案的另一个方面，本文中公开了表达抗-NaV1.7抗体的哺乳动物细胞，所述抗体包含与本文描述的啮齿动物(例如，大鼠或小鼠)相同、从其得到或从其衍生出的抗-NaV1.7抗体的重链和轻链可变结构域。在某些实施方案中，哺乳动物细胞是CHO细胞(例如，CHO K1、DXB-11CHO、Veggie-CHO)、COS(例如，COS-7)、视网膜细胞、Vero细胞、CV1细胞、肾细胞(例如，HEK293、293EBNA、MSR 293、MDCK、HaK、BHK)、HeLa细胞、HepG2细胞、WI38细胞、MRC5细胞、Colo205细胞、HB8065细胞、HL-60细胞、(例如，BHK21)、Jurkat细胞、Daudi细胞、A431细胞(表皮)、U937细胞、3T3细胞、L细胞、C127细胞、SP2/0细胞、NS-0细胞、MMT 060562细胞、塞尔托利细胞、BRL 3A细胞、HT1080细胞、骨髓瘤细胞、肿瘤细胞和从前述细胞衍生出的细胞系的细胞。
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图1A-1D.用于将人SCN2A敲入小鼠Scn9a基因座中的示例性策略。图1A显示了人SCN2A和小鼠Scn9a基因的基因组组构的非按比例的简图。用置于基因组序列上方的细条代表外显子。指示了要删除的约84,847bp的小鼠基因组片段和要插入的约96,735bp的人基因组片段。用星号指示在实施例1的表1中描述的测定所使用的探针的位置。图1B非按比例解释了用于将人SCN2A敲入小鼠Scn9a基因座的示例性的修饰的BAC载体以及连接部序列(SEQID NO:17,18和19)。图1C非按比例解释了在新霉素盒已经删除后具有敲入的人SCN2A的人源化的小鼠Scn9a基因座，以及连接部序列(SEQ ID NO:17和21)。图1D描述了小鼠Scn9a(NaV1.7)蛋白的氨基酸2-1984(SEQ ID NO:2)和人SCN2A(NaV1.2)蛋白的氨基酸4-2005(SEQ ID NO:4)的序列比对。
图2.是显示使用蛋白和DNA免疫原在mNaV1.7 KO中的hNaV1.2KI/VI-3小鼠的免疫应答的示例性分析的一个实施方案。最初将小鼠用DNA免疫原免疫，并转换至蛋白免疫原作为强化。本文中使用的术语“VI-3”表示包括HoH基因座和KoK基因座的本文中公开的小鼠的一个实施方案。具体地，如该术语在本文中使用的，VI-3小鼠就包含80个人VH基因区段、27个人DH基因区段和六个人JH基因区段的HoH基因座而言是纯合的；VI-3小鼠就包含40个人Vκ基因区段和至少一个人Jκ基因区段的KoK基因座而言也是纯合的。
图3A.人NaV蛋白的示例性序列的比对，从上至下：分别是人NaV1.1(SEQ ID NO:22)、人NaV1.2(SEQ ID NO:4)、人NaV1.3(SEQ ID NO:23)、人NaV1.4(SEQ ID NO:24)、人NaV1.5(SEQ ID NO:25)、人NaV1.6(SEQ ID NO:26)、人NaV1.7(SEQ ID NO:27)、人NaV1.8(SEQ ID NO:28)和人NaV1.9(SEQ ID NO:29)。基于人NaV1.7来标记结构域。“cyto”:细胞质的(绿色)；“TM”:跨膜(蓝色)；“EC”:细胞外的(粉色)；“孔形成”:参与形成孔(离子在其中穿过)的细胞外结构域的部分(棕色)。
图3B.九种人NaV蛋白的系统树。
图4A.来自15个动物物种的NaV1.7蛋白的示例性序列的比对，从上至下：分别是人(SEQ ID NO:27)、黑猩猩(异形体X1)(SEQ ID NO:30)、恒河猴(SEQ ID NO:31)、马来西亚飞行狐猴(异形体X1)(SEQ ID NO:32)、牛(SEQ ID NO:33)、绵羊(异形体X1)(SEQ ID NO:34)、阿拉伯骆驼(SEQ ID NO:35)、杀人鲸(异形体X1)(SEQ ID NO:36)、马(SEQ ID NO:37)、狗(异形体X1)(SEQ ID NO:38)、小鼠(SEQ ID NO:2)、大鼠(SEQ ID NO:39)、兔(SEQ ID NO:40)、鸡(SEQ ID NO:41和眼镜王蛇(部分)(SEQ ID NO:42)。“cyto”:细胞质的(绿色)；“TM”:跨膜(蓝色)；“EC”:细胞外的(粉色)；“孔形成”:参与形成孔(离子在其中穿过)的细胞外结构域的部分(棕色)。
图4B.来自15个动物物种的NaV1.7蛋白的系统树。
图5A.来自15个动物物种的NaV1.2蛋白的示例性序列的比对，从上至下:分别是人(SEQ ID NO:4)、黑猩猩(异形体X1)(SEQ ID NO:43)、恒河猴(异形体X1)(SEQ ID NO:44)、马来西亚飞行狐猴(异形体X1)(SEQ ID NO:45)、牛(SEQ ID NO:46)、绵羊(异形体X1)(SEQID NO:47)、阿拉伯骆驼(SEQ ID NO:48)、杀人鲸(异形体1)(SEQ ID NO:49)、马(SEQ IDNO:50)、小鼠(异形体1)(SEQ ID NO:51)、大鼠(SEQ ID NO:52)、兔(异形体X1)(SEQ ID NO:53)、鸡(SEQ ID NO:54)、眼镜王蛇(部分)(SEQ ID NO:55)和绿海龟(SEQ ID NO:56)。“cyto”:细胞质的(绿色)；“TM”:跨膜(蓝色)；“EC”:细胞外的(粉色)；“孔形成”:参与形成孔(离子在其中穿过)的细胞外结构域的部分(棕色)。
图5B.来自15个动物物种的NaV1.2蛋白的系统树。
图6.显示了7506等位基因的核苷酸序列(SEQ ID NO:20)，即，在具有Neo自删除盒的小鼠Scn9a基因座中的人SCN2A，其包括小鼠核苷酸(小写字母)、SgrDI位点(粗体，下划线)、人核苷酸(粗体，大写字体)、XhoI位点(粗体，下划线)、LoxP(斜体字)、鱼精蛋白启动子(粗体，下划线)、Crei(斜体字)、SV40聚腺苷酸(小写字母)、hUbi prm(粗体)-EM7 prm(粗体，下划线)、NEO(斜体字)、PGK聚腺苷酸(下划线)、LoxP(斜体字)、ICeUI(下划线)、NheI(粗体，下划线)、小鼠核苷酸(小写字母)。
图7A-7C.在mNaV1.7 KO中的hNaV1.2 KI/VI-3小鼠具有对热刺激的受损应答和对组胺的显著降低的痒应答。7A,在mNaV1.7 KO中的hNaV1.2KI/VI-3小鼠表现出对热刺激的应答的显著延长的潜伏期(Hargreaves,在mNaV1.7 KO中的hNaV1.2 KI/VI-3小鼠为22.9±0.9s,n＝15，与此相比，WT小鼠为12.3±0.5s,n＝19，未配对Student氏t检验,p<0.0001)。7B,在热板试验中的爪缩回潜伏期。在mNaV1.7 KO中的hNaV1.2 KI/VI-3小鼠没有对52.5或55℃热刺激做出应答，并且在30秒的预定截止时间从热板移开以避免组织损伤。另一方面，WT小鼠快速地表现出响应于热刺激的防伤害行为(55℃:WT为6.5±0.5s,n＝9，和在mNaV1.7 KO中的hNaV1.2 KI/VI-3小鼠为30s,n＝7；52.5℃:WT为10.4±0.6s，和在mNaV1.7KO中的hNaV1.2 KI/VI-3小鼠为30s,n＝7；p<0.0001)。7C,在颈背中真皮内注射150μg组胺以后搔抓发作的总数。在mNaV1.7 KO中的hNaV1.2 KI/VI-3小鼠表现出比WT小鼠少3.7倍的搔抓发作(在mNaV1.7 KO中的hNaV1.2KI/VI-3小鼠为24±11次发作，与此相比，WT为81±20次发作，未配对的Student氏T检验p＝0.047)。
具体实施方式
本文中公开了遗传修饰成表达外源性NaV1蛋白(例如，NaV1.2蛋白)的非人动物的实施方案。在某些实施方案中，非人动物包含外源性Scn核苷酸序列(例如，Scn2a基因序列，例如，人SCN2A基因序列)。本文中也公开了可用于制备这样的遗传修饰的非人动物的方法和组合物的实施方案，以及使用这样的遗传修饰的非人动物产生结合NaV1.7蛋白(例如，人NaV1.7蛋白)的抗体或其功能部分的方法的实施方案。Scn9a是编码NaV1.7蛋白的基因的名称。Scn2a是编码NaV1.2蛋白的基因的名称。在某些实施方案中，非人动物是啮齿动物(例如，小鼠或大鼠)。
NaV家族
电压门控钠通道的家族具有九个已知的成员，在跨膜区段和细胞外环区域中具有>50％的氨基酸同一性。这些通道的蛋白被命名为NaV1.1至NaV1.9，且基因名被称作Scn1a至Scn11a。参见下面表1。
表1
| 蛋白名称 | 基因名称 |
| NaV1.1 | Scn1a |
| NaV1.2 | Scn2a |
| NaV1.3 | Scn3a |
| NaV1.4 | Scn4a |
| NaV1.5 | Scn5a |
| NaV1.6 | Scn8a |
| NaV1.7 | Scn9a |
| NaV1.8 | Scn10a |
| NaV1.9 | Scn11a |
示例性人NaV蛋白序列的比对提供在图3A中，在表2中阐述了登录号和序列标识符。在图3B中描绘了人NaV蛋白的相关性。
表2
钠通道家族的这些成员(参见表1)具有四个重复结构域，每个含有六个跨膜区段。参见图3A。第四个区段是高度保守的并作为通道的电压传感器起作用。该通道的电压敏感性是由于位于第四个区段的每第三位置的正氨基酸(Nicholls等人,(2012)“From Neuronto Brain”，第5版第86页，其通过引用整体并入本文)。当受到跨膜电压的变化刺激时，该区段向细胞膜的细胞外侧移动，使通道变成离子可渗透的。离子被引导穿过孔，所述孔可以分成两个区域。孔的更外部(即，更细胞外的)部分由四个结构域各自的第五和第六跨膜区段之间的区域(也被称作“P-环”)形成。该区域是孔的更狭窄部分并且负责其离子选择性。孔的更内部(即，更细胞质的)部分由四个结构域的组合的第五和第六跨膜区段形成。
NaV1.7
NaV1.7在背根神经节、交感神经元、许旺细胞和神经内分泌细胞处的伤害性(疼痛)神经元中表达。NaV1.7是膜兴奋性的关键组分，并且对于疼痛的感觉而言是重要的。人SCN9A基因中的功能突变的获得已经与疼痛综合征相关联，而功能突变的丧失与对疼痛的极度不敏感性有关。合乎需要的是，开发选择性的NaV1.7通道阻滞剂作为镇痛药。
NaV1.7是在物种之间高度保守的，如图4A中来自15个动物物种的NaV1.7蛋白的示例性序列的比对和图4B中的关系树所证实的。在比对中包括的示例性序列的登录号和序列标识符如下面表3中所示。
表3
| NaV1.7的物种 | 登记号 | SEQ ID NO |
| 人 | Q15858.3 | SEQ ID NO:27 |
| 黑猩猩 | XP_016804947.1 | SEQ ID NO:30 |
| 恒河猴 | XP_014965766.1 | SEQ ID NO:31 |
| 马来西亚飞行狐猴 | XP_008588371.1 | SEQ ID NO:32 |
| 牛 | NP_001104257.2 | SEQ ID NO:33 |
| 绵羊 | XP_004004679.1 | SEQ ID NO:34 |
| 阿拉伯骆驼 | XP_010980767.1 | SEQ ID NO:35 |
| 杀人鲸 | XP_004267302.1 | SEQ ID NO:36 |
| 马 | XP_001496473.1 | SEQ ID NO:37 |
| 狗 | XP_022270547.1 | SEQ ID NO:38 |
| 小鼠 | Q62205.2 | SEQ ID NO:2 |
| 大鼠 | O08562.1 | SEQ ID NO:39 |
| 兔 | Q28644.1 | SEQ ID NO:40 |
| 鸡 | NP_001280211.1 | SEQ ID NO:41 |
| 眼镜王蛇(部分序列) | DAA65084.1 | SEQ ID NO:42 |
NaV1.2
NaV1.2在中枢神经元和周围神经元中表达。人SCN2A基因(编码NaV1.2)中的突变已经与几种癫痫发作障碍和孤独症谱群障碍相关联。
NaV1.2是在物种之间高度保守的，如图5A中提供的来自15个动物物种的NaV1.2蛋白的示例性序列的比对所证实的。在比对中包括的示例性序列的登录号和序列标识符如下面表4中所示。
表4
| NaV1.2的物种 | 登记号 | SEQ ID NO |
| 人 | Q99250.3 | SEQ ID NO:4 |
| 黑猩猩 | XP_003820970.1 | SEQ ID NO:43 |
| 恒河猴 | XP_001100368.1 | SEQ ID NO:44 |
| 马来西亚飞行狐猴 | XP_008582720.1 | SEQ ID NO:45 |
| 牛 | NP_001137581.1 | SEQ ID NO:46 |
| 绵羊 | XP_014948870.1 | SEQ ID NO:47 |
| 阿拉伯骆驼 | XP_010980763.1 | SEQ ID NO:48 |
| 杀人鲸 | XP_004283641.1 | SEQ ID NO:49 |
| 马 | XP_014588001.1 | SEQ ID NO:50 |
| 小鼠 | NP_001092768.1 | SEQ ID NO:51 |
| 大鼠 | P04775.1 | SEQ ID NO:52 |
| 兔 | XP_008256915.1 | SEQ ID NO:53 |
| 鸡 | NP_001280210.1 | SEQ ID NO:54 |
| 眼镜王蛇(部分序列) | ETE69867.1 | SEQ ID NO:55 |
| 绿海龟 | XP_007056690.1 | SEQ ID NO:56 |
遗传修饰的啮齿动物
在一些实施方案的一个方面，本公开内容涉及遗传修饰的啮齿动物，其中遗传修饰包含外源性Scn基因的至少一部分向内源性Scn9a基因座中的插入。
在某些实施方案中，本公开内容提供了遗传修饰的啮齿动物，其基因组包含在内源性Scn9a基因座处的核酸分子，其中所述核酸分子编码NaV蛋白且包含外源性Scn基因的至少一部分。
本文中使用的术语“人源化的”包括被修饰成包含人序列。例如，人源化的基因座是已经被修饰成包含人序列(例如，基因区段或基因)的基因座(例如，内源性基因座)。
本文中使用的术语“种系基因组”表示在动物形成所用的生殖细胞(例如，配子，例如，精子或卵子)中发现的基因组。种系基因组是动物中的细胞的基因组DNA的来源。这样，在其种系基因组中具有修饰的动物(例如，小鼠或大鼠)被认为在其所有细胞的基因组DNA中具有修饰。
本文中使用的术语“替换”表示位置置换，其中第一核酸序列位于染色体中第二核酸序列的位置(例如，其中第二核酸序列在以前(例如，最初)位于染色体中，例如，在第二核酸序列的内源性基因座)。短语“替换”不要求第二核酸序列从例如基因座或染色体除去。在某些实施方案中，第二核酸序列和第一核酸序列是彼此相容的，因为，例如，第一和第二序列是彼此同源的，含有对应的元件(例如，蛋白编码元件、调节元件等)，和/或具有类似的或相同的序列。在某些实施方案中，第一和/或第二核酸序列包括启动子、增强子、剪接供体位点、剪接受体位点、内含子、外显子、非翻译区(UTR)中的一个或多个；在某些实施方案中，第一和/或第二核酸序列包括一个或多个编码序列。在某些实施方案中，第一核酸序列是第二核酸序列的同系物或变体(例如，突变体)。在某些实施方案中，第一核酸序列是第二序列的直系同源物或同系物。在某些实施方案中，第一核酸序列是或包含人核酸序列。在某些实施方案中，包括其中第一核酸序列是或包含人核酸序列，第二核酸序列是或包含啮齿动物序列(例如，小鼠或大鼠序列)。在某些实施方案中，包括其中第一核酸序列是或包含人核酸序列，第二核酸序列是或包含人序列。在某些实施方案中，第一核酸序列是第二序列的变体或突变体(即，与第二序列相比含有一个或多个序列差异(例如，置换)的序列)。如此放置的核酸序列可以包括一个或多个调节序列(例如，启动子、增强子、5'-或3'-非翻译区等)，所述调节序列是用于获得如此放置的序列的源核酸序列的部分。例如，在各个实施方案中，第一核酸序列是用异源序列对内源序列的置换，其导致从如此放置的核酸序列(其包含异源序列)产生基因产物，但是不表达内源序列；第一核酸序列属于内源性基因组序列，其具有编码多肽的核酸序列，所述多肽具有与内源序列所编码的多肽类似的功能(例如，内源性基因组序列完全地或部分地编码非人可变区多肽，且DNA片段完全地或部分地编码一个或多个人可变区多肽)。在各个实施方案中，人免疫球蛋白基因区段或其片段替换内源性非人免疫球蛋白基因区段或片段。
本文中使用的术语“NaV蛋白”包括(1)NaV家族的天然存在的(野生型)电压门控钠通道，即，NaV1.1、NaV1.2、NaV1.3、NaV1.4、NaV1.5、NaV1.6、NaV1.7、NaV1.8和NaV1.9，和(2)经工程改造的电压门控钠通道。经工程改造的NaV蛋白维持天然存在的NaV蛋白所特有的四个重复结构域结构，其中每个结构域含有六个跨膜区段，并且也作为电压门控钠通道(如天然存在的NaV蛋白)起作用。经工程改造的电压门控钠通道的一个非限制性实施方案是嵌合蛋白，其包括NaV1.2蛋白的细胞外结构域以及啮齿动物NaV1.7蛋白的跨膜和细胞质结构域。
本文中使用的术语“Scn基因”包括编码天然存在的NaV蛋白的核酸。“外源性Scn基因”是指不存在于啮齿动物Scn9a基因座内的Scn基因，因为该基因座存在于自然界中。在某些实施方案中，外源性Scn基因是并非啮齿动物Scn9a的Scn基因。在某些实施方案中，Scn基因是或包含Scn1a、Scn2a、Scn3a、Scn4a、Scn5a、Scn8a、Scn10a或Scn11a基因。在某些实施方案中，Scn基因来自动物物种，包括、但不限于，人、黑猩猩、恒河猴、马来西亚飞行狐猴、兔、马、阿拉伯骆驼、杀人鲸、牛、绵羊、大鼠、小鼠、狗、鸡、绿海龟或眼镜王蛇。在某些实施方案中，外源性Scn基因是来自不同于被修饰的啮齿动物的动物物种的Scn9a基因；例如，在啮齿动物Scn9a基因座处的外源性Scn基因可以是人、黑猩猩、恒河猴、马来西亚飞行狐猴、兔、马、阿拉伯骆驼、杀人鲸、牛、绵羊、狗、鸡、绿海龟或眼镜王蛇Scn9a基因，或来自不同于被遗传修饰的啮齿动物的啮齿动物物种的Scn基因。在某些实施方案中，外源性Scn基因是人SCN2A基因(编码人NaV1.2蛋白)。
对基因的“部分”的提及包括基因的至少6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30个或更多个核苷酸的邻接核苷酸序列，其可以是外显子或外显子与内含子的组合的核苷酸。基因的“部分”应当理解为短于全长基因。
对“包含外源性Scn基因的至少一部分的核酸分子”的提及包括，例如，对以下内容的提及：外源性Scn基因的完全或部分基因组DNA；包含外源性Scn基因的编码序列(从ATG密码子至终止密码子)的核酸分子(例如，基因组DNA或cDNA)；包含外源性Scn基因的一个或多个外显子的核苷酸的核酸(例如，基因组DNA或cDNA)，其编码由外源性Scn基因所编码的NaV蛋白的一个或多个细胞外结构域的氨基酸。
在本文所公开的遗传修饰的啮齿动物的某些实施方案中，遗传修饰的啮齿动物的基因组包含在内源性Scn9a基因座处的核酸分子，其中所述核酸分子包含外源性Scn基因的编码序列且编码与由外源性Scn基因编码的NaV蛋白相同的蛋白。
在某些实施方案中，在内源性啮齿动物Scn9a基因座处的核酸分子包含选自Scn1a、Scn2a、Scn3a、Scn4a、Scn5a、Scn8a、Scn10a和Scn11a的外源性Scn基因的编码序列。在某些实施方案中，在内源性啮齿动物Scn9a基因座处的核酸分子包含Scn2a基因的编码序列。
在某些实施方案中，在内源性啮齿动物Scn9a基因座处的核酸分子包含来自选自人、黑猩猩、恒河猴、马来西亚飞行狐猴、兔、马、阿拉伯骆驼、杀人鲸、牛、绵羊、大鼠、小鼠、狗、鸡、绿海龟和眼镜王蛇的物种的外源性Scn基因的编码序列。
在某些实施方案中，在内源性啮齿动物Scn9a基因座处的核酸分子包含Scn2a基因的编码序列，且Scn2a基因是来自选自人、黑猩猩、恒河猴、马来西亚飞行狐猴、兔、马、阿拉伯骆驼、杀人鲸、牛、绵羊、大鼠、小鼠、狗、鸡、绿海龟和眼镜王蛇的物种。
在某些实施方案中，在内源性啮齿动物Scn9a基因座处的核酸分子包含人SCN2A基因的编码序列。在某些实施方案中，人SCN2A基因的编码序列是包含人SCN2A基因的编码区(例如，从ATG密码子至终止密码子)的基因组片段。在某些实施方案中，人SCN2A基因的编码序列是cDNA。在某些实施方案中，人SCN2A基因的编码序列编码包含与SEQ ID NO:4具有至少95％、至少96％、至少97％、至少98％或至少99％同一性的氨基酸序列的NaV1.2蛋白。在某些实施方案中，人SCN2A基因的编码序列编码包含与SEQ ID NO:4具有至少95％同一性的氨基酸序列的NaV1.2蛋白。在某些实施方案中，人SCN2A基因的编码序列编码包含与SEQ IDNO:4具有至少96％同一性的氨基酸序列的NaV1.2蛋白。在某些实施方案中，人SCN2A基因的编码序列编码包含与SEQ ID NO:4具有至少97％同一性的氨基酸序列的NaV1.2蛋白。在某些实施方案中，人SCN2A基因的编码序列编码包含与SEQ ID NO:4具有至少98％同一性的氨基酸序列的NaV1.2蛋白。在某些实施方案中，人SCN2A基因的编码序列编码包含与SEQ IDNO:4具有至少99％同一性的氨基酸序列的NaV1.2蛋白。在某些实施方案中，人SCN2A基因的编码序列编码包含与SEQ ID NO:4具有大于99％同一性的氨基酸序列的NaV1.2蛋白。在某些实施方案中，人SCN2A基因的编码序列编码包含与SEQ ID NO:4相同的氨基酸序列的NaV1.2蛋白。
在本文所公开的遗传修饰的啮齿动物的某些实施方案中，啮齿动物的基因组包含在内源性Scn9a基因座处的核酸分子，其中所述核酸分子包含外源性Scn基因的部分和内源性Scn9a基因的部分，且其中所述核酸分子编码NaV蛋白，所述NaV蛋白包含由外源性Scn基因编码的NaV蛋白的部分。NaV蛋白的“部分”意在包括对NaV蛋白的至少2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20个或更多个氨基酸的连续序列的提及，但是短于全长NaV蛋白。在某些实施方案中，NaV蛋白的部分包含NaV蛋白的至少2个氨基酸的连续序列。在某些实施方案中，NaV蛋白的部分包含NaV蛋白的至少3个氨基酸的连续序列。在某些实施方案中，NaV蛋白的部分包含NaV蛋白的至少4个氨基酸的连续序列。在某些实施方案中，NaV蛋白的部分包含NaV蛋白的至少5个氨基酸的连续序列。在某些实施方案中，NaV蛋白的部分包含NaV蛋白的至少6个氨基酸的连续序列。在某些实施方案中，NaV蛋白的部分包含NaV蛋白的至少7个氨基酸的连续序列。在某些实施方案中，NaV蛋白的部分包含NaV蛋白的至少8个氨基酸的连续序列。在某些实施方案中，NaV蛋白的部分包含NaV蛋白的至少9个氨基酸的连续序列。在某些实施方案中，NaV蛋白的部分包含NaV蛋白的至少10个氨基酸的连续序列。在某些实施方案中，NaV蛋白的部分包含NaV蛋白的至少11个氨基酸的连续序列。在某些实施方案中，NaV蛋白的部分包含NaV蛋白的至少12个氨基酸的连续序列。在某些实施方案中，NaV蛋白的部分包含NaV蛋白的至少13个氨基酸的连续序列。在某些实施方案中，NaV蛋白的部分包含NaV蛋白的至少14个氨基酸的连续序列。在某些实施方案中，NaV蛋白的部分包含NaV蛋白的至少15个氨基酸的连续序列。在某些实施方案中，NaV蛋白的部分包含NaV蛋白的至少16个氨基酸的连续序列。在某些实施方案中，NaV蛋白的部分包含NaV蛋白的至少17个氨基酸的连续序列。在某些实施方案中，NaV蛋白的部分包含NaV蛋白的至少18个氨基酸的连续序列。在某些实施方案中，NaV蛋白的部分包含NaV蛋白的至少19个氨基酸的连续序列。在某些实施方案中，NaV蛋白的部分包含NaV蛋白的至少20个氨基酸的连续序列。在某些实施方案中，NaV蛋白的部分是NaV蛋白的结构域，诸如细胞外结构域、跨膜结构域或细胞质结构域。
在某些实施方案中，所述核酸分子包含外源性Scn基因的部分，其编码由外源性Scn基因编码的NaV蛋白的细胞外结构域，使得在内源性Scn9基因座处的核酸分子编码包含由外源性Scn基因编码的NaV蛋白的细胞外结构域的NaV蛋白。
在某些实施方案中，在内源性啮齿动物Scn9a基因座处的核酸分子包含外源性Scn基因的部分，所述部分编码由外源性Scn基因编码的NaV蛋白的细胞外结构域，其中所述外源性Scn基因选自Scn1a、Scn2a、Scn3a、Scn4a、Scn5a、Scn 8a、Scn10a和Scn11a基因。在某些实施方案中，在内源性啮齿动物Scn9a基因座处的核酸分子包含外源性Scn基因的部分，所述部分编码由外源性Scn基因编码的NaV蛋白的细胞外结构域，其中所述外源性Scn基因是Scn1a基因。在某些实施方案中，在内源性啮齿动物Scn9a基因座处的核酸分子包含外源性Scn基因的部分，所述部分编码由外源性Scn基因编码的NaV蛋白的细胞外结构域，其中所述外源性Scn基因是Scn2a基因。在某些实施方案中，在内源性啮齿动物Scn9a基因座处的核酸分子包含外源性Scn基因的部分，所述部分编码由外源性Scn基因编码的NaV蛋白的细胞外结构域，其中所述外源性Scn基因是Scn3a基因。在某些实施方案中，在内源性啮齿动物Scn9a基因座处的核酸分子包含外源性Scn基因的部分，所述部分编码由外源性Scn基因编码的NaV蛋白的细胞外结构域，其中所述外源性Scn基因是Scn5a基因。在某些实施方案中，在内源性啮齿动物Scn9a基因座处的核酸分子包含外源性Scn基因的部分，所述部分编码由外源性Scn基因编码的NaV蛋白的细胞外结构域，其中所述外源性Scn基因是Scn8a基因。在某些实施方案中，在内源性啮齿动物Scn9a基因座处的核酸分子包含外源性Scn基因的部分，所述部分编码由外源性Scn基因编码的NaV蛋白的细胞外结构域，其中所述外源性Scn基因是Scn10a基因。在某些实施方案中，在内源性啮齿动物Scn9a基因座处的核酸分子包含外源性Scn基因的部分，所述部分编码由外源性Scn基因编码的NaV蛋白的细胞外结构域，其中所述外源性Scn基因是Scn11a基因。在某些实施方案中，在内源性啮齿动物Scn9a基因座处的核酸分子包含Scn2a基因的部分，所述部分编码由外源性Scn2a基因编码的NaV1.2蛋白的细胞外结构域。
在某些实施方案中，在内源性啮齿动物Scn9a基因座处的核酸分子包含来自不同于被修饰的啮齿动物物种的物种的外源性Scn基因的部分，所述物种包括、但不限于人、黑猩猩、恒河猴、马来西亚飞行狐猴、兔、马、阿拉伯骆驼、杀人鲸、牛、绵羊、大鼠、小鼠、狗、鸡、绿海龟和眼镜王蛇。
在某些实施方案中，在内源性啮齿动物Scn9a基因座处的核酸分子包含外源性Scn2a基因的部分，所述部分编码由外源性Scn2a基因编码的NaV1.2蛋白的细胞外结构域，其中所述外源性Scn2a基因来自选自人、黑猩猩、恒河猴、马来西亚飞行狐猴、兔、马、阿拉伯骆驼、杀人鲸、牛、绵羊、大鼠、小鼠、狗、鸡、绿海龟和眼镜王蛇的物种。在某些实施方案中，所述外源性Scn2a基因是人SCN2A基因，且在内源性啮齿动物Scn9a基因座处的核酸分子包含人SCN2A基因的部分，所述部分编码人NaV1.2蛋白的细胞外结构域。在某些实施方案中，所述人NaV1.2蛋白包含与SEQ ID NO:4具有至少95％、至少96％、至少97％、至少98％、至少99％或大于99％同一性的氨基酸序列。在某些实施方案中，所述人NaV1.2蛋白包含与SEQID NO:4具有至少95％同一性的氨基酸序列。在某些实施方案中，所述人NaV1.2蛋白包含与SEQ ID NO:4具有至少96％同一性的氨基酸序列。在某些实施方案中，所述人NaV1.2蛋白包含与SEQ ID NO:4具有至少97％同一性的氨基酸序列。在某些实施方案中，所述人NaV1.2蛋白包含与SEQ ID NO:4具有至少98％同一性的氨基酸序列。在某些实施方案中，所述人NaV1.2蛋白包含与SEQ ID NO:4具有至少99％同一性的氨基酸序列。在某些实施方案中，所述人NaV1.2蛋白包含与SEQ ID NO:4具有大于99％同一性的氨基酸序列。在具体实施方案中，人SCN2A基因编码包含与SEQ ID NO:4相同的氨基酸序列的NaV1.2蛋白。在图1D中描绘了SEQ ID NO:4的人NaV1.2蛋白的细胞外结构域(在细胞外结构域与跨膜或细胞质结构域之间的连接部可以从图1D中描绘的那些偏移1-2个氨基酸)。
在某些实施方案中，除了编码细胞外结构域的外源性Scn基因的部分以外，在内源性啮齿动物Scn9a基因座处的核酸分子也包含编码内源性啮齿动物NaV1.7蛋白的跨膜和细胞质结构域的内源性啮齿动物Scn9a基因的部分。在某些实施方案中，所述啮齿动物是小鼠，且在内源性小鼠Scn9a基因座处的核酸分子包含编码内源性小鼠NaV1.7蛋白的跨膜和细胞质结构域的内源性小鼠Scn9a基因的部分。在某些实施方案中，内源性小鼠Scn9a基因编码与SEQ ID NO:2具有至少95％、至少96％、至少97％、至少98％、至少99％或大于99％同一性的小鼠NaV1.7蛋白。在某些实施方案中，内源性小鼠Scn9a基因编码与SEQ ID NO:2具有至少95％同一性的小鼠NaV1.7蛋白。在某些实施方案中，内源性小鼠Scn9a基因编码与SEQ ID NO:2具有至少96％同一性的小鼠NaV1.7蛋白。在某些实施方案中，内源性小鼠Scn9a基因编码与SEQ ID NO:2具有至少97％同一性的小鼠NaV1.7蛋白。在某些实施方案中，内源性小鼠Scn9a基因编码与SEQ ID NO:2具有至少98％同一性的小鼠NaV1.7蛋白。在某些实施方案中，内源性小鼠Scn9a基因编码与SEQ ID NO:2具有至少99％同一性的小鼠NaV1.7蛋白。在某些实施方案中，内源性小鼠Scn9a基因编码与SEQ ID NO:2具有大于99％同一性的小鼠NaV1.7蛋白。在一个具体实施方案中，内源性小鼠NaV1.7蛋白包含与SEQ IDNO:2相同的氨基酸序列。在图1D中描绘了SEQ ID NO:2的小鼠NaV1.7蛋白的跨膜和细胞质结构域(在细胞外结构域与跨膜或细胞质结构域之间的连接部可以从图1D中描绘的那些偏移1-2个氨基酸)。
在某些实施方案中，所述啮齿动物是大鼠，且在内源性大鼠Scn9a基因座处的核酸分子包含编码内源性大鼠NaV1.7蛋白的跨膜和细胞质结构域的内源性大鼠Scn9a基因的部分。在某些实施方案中，内源性大鼠Scn9a基因编码与SEQ ID NO:39具有至少95％、至少96％、至少97％、至少98％、至少99％或大于99％同一性的大鼠NaV1.7蛋白。在某些实施方案中，内源性大鼠Scn9a基因编码与SEQ ID NO:39具有至少95％同一性的大鼠NaV1.7蛋白。在某些实施方案中，内源性大鼠Scn9a基因编码与SEQ ID NO:39具有至少96％同一性的大鼠NaV1.7蛋白。在某些实施方案中，内源性大鼠Scn9a基因编码与SEQ ID NO:39具有至少97％同一性的大鼠NaV1.7蛋白。在某些实施方案中，内源性大鼠Scn9a基因编码与SEQ IDNO:39具有至少98％同一性的大鼠NaV1.7蛋白。在某些实施方案中，内源性大鼠Scn9a基因编码与SEQ ID NO:39具有至少99％同一性的大鼠NaV1.7蛋白。在某些实施方案中，内源性大鼠Scn9a基因编码与SEQ ID NO:39具有大于99％同一性的大鼠NaV1.7蛋白。在某些实施方案中，内源性大鼠NaV1.7蛋白包含与SEQ ID NO:39相同的氨基酸序列。
在本文公开的遗传修饰的啮齿动物的某些实施方案中，存在于内源性Scn9a基因座中的编码NaV蛋白且包含外源性Scn基因的至少一部分的核酸分子是cDNA分子。在某些实施方案中，存在于内源性Scn9a基因座中的编码NaV蛋白且包含外源性Scn基因的至少一部分的核酸分子是基因组DNA。
在某些实施方案中，存在于内源性Scn9a基因座中的编码NaV蛋白且包含外源性Scn基因的至少一部分的核酸可以源自遗传修饰，其中在内源性啮齿动物Scn9a基因座处的内源性Scn9a基因已经被完全或部分的外源性Scn基因完全或部分替换。在某些实施方案中，包含内源性啮齿动物Scn9a基因的编码序列(例如，从ATG密码子至终止密码子)的基因组片段已经被外源性Scn基因的编码序列(例如，从ATG密码子至终止密码子，在基因组DNA或cDNA中)替换；且在某些实施方案中，所述外源性Scn基因是Scn2a基因，例如，来自人、黑猩猩、恒河猴、马来西亚飞行狐猴、兔、马、阿拉伯骆驼、杀人鲸、牛、绵羊、大鼠、小鼠、狗、鸡、绿海龟或眼镜王蛇的Scn2a基因。在某些实施方案中，所述外源性Scn基因是人SCN2A基因。在某些实施方案中，编码内源性啮齿动物NaV1.7蛋白的一个或多个或全部细胞外结构域的内源性啮齿动物Scn9a基因的部分已经被编码由外源性Scn基因编码的NaV蛋白的对应细胞外结构域的外源性Scn基因的部分替换。在某些实施方案中，适合用于替换内源性啮齿动物Scn9a基因的外源性Scn基因包括上文描述的那些中的任一种，例如，Scn1a、Scn2a、Scn3a、Scn4a、Scn5a、Scn 8a、Scn10a或Scn11a基因，或来自不同于被修饰的啮齿动物的动物物种的Scn9a基因；且在某些实施方案中，所述外源性Scn基因是Scn2a基因，例如，来自人、黑猩猩、恒河猴、马来西亚飞行狐猴、兔、马、阿拉伯骆驼、杀人鲸、牛、绵羊、大鼠、小鼠、狗、鸡、绿海龟或眼镜王蛇的Scn2a基因。在某些实施方案中，所述外源性Scn基因是人SCN2A基因。
在某些实施方案中，在内源性Scn9a基因座处的编码NaV蛋白且包含外源性Scn基因的至少一部分的核酸分子可操作地连接至5'转录调节序列(例如，启动子和/或增强子)。在某些实施方案中，在内源性Scn9a基因座处的编码NaV蛋白且包含外源性Scn基因的至少一部分的核酸分子可操作地连接至内源性Scn9a基因的5'非翻译区(5'UTR)。在某些实施方案中，所述核酸分子可操作地连接至外源性Scn基因的5'非翻译区(5'UTR)。在某些实施方案中，在内源性Scn9a基因座处的编码NaV蛋白且包含外源性啮齿动物Scn基因的至少一部分的核酸分子可操作地连接至内源性Scn9a基因的5'UTR和5'转录调节序列(例如，启动子和/或增强子)。
在某些实施方案中，在内源性Scn9a基因座处的编码NaV蛋白且包含外源性Scn基因的至少一部分的核酸分子可操作地连接至内源性Scn9a基因的3'调节序列，例如，3'UTR。在某些实施方案中，在内源性Scn9a基因座处的编码NaV蛋白且包含外源性Scn基因的至少一部分的核酸分子包含外源性Scn基因的3'UTR。在某些实施方案中，所述核酸分子包含外源性Scn基因的3'UTR和在3'UTR之外的外源性Scn基因的另外基因组序列，例如，30-500bp或更大的基因组序列，所述基因组序列存在于在外源性Scn基因的3'UTR的下游紧邻处的外源性Scn基因基因座中。
在某些实施方案中，遗传修饰的啮齿动物就遗传修饰而言是异源的，即，就在内源性Scn9a基因座处的包含外源性Scn基因的至少一部分的核酸分子而言是异源的。在某些实施方案中，遗传修饰的啮齿动物就遗传修饰而言是纯合的，即，就在内源性Scn9a基因座处的包含外源性Scn基因的至少一部分的核酸分子而言是纯合的。
在某些实施方案中，本文中公开的遗传修饰的啮齿动物不能表达内源性啮齿动物NaV1.7蛋白，例如，由于对内源性啮齿动物Scn9a基因座的遗传修饰或内源性啮齿动物Scn9a基因的灭活(例如，完全或部分缺失)。
在某些实施方案中，如本文中所述的遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组中包含(例如，通过杂交育种或多基因靶向策略)：(i)人源化的免疫球蛋白重链基因座，其包含一个或多个人VH基因区段、一个或多个人DH基因区段和一个或多个人JH基因区段，所述区段是在一个或多个啮齿动物(例如，大鼠或小鼠)免疫球蛋白重链恒定区基因(例如，一个或多个内源性啮齿动物(例如，大鼠或小鼠)免疫球蛋白重链恒定区基因)的上游(例如，与其可操作地连接)。这样的人源化的免疫球蛋白重链基因座在本文中被称作“人源化的HoH基因座”。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的HoH基因座处是纯合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的HoH基因座处是杂合的。
在某些实施方案中，包含人源化的HoH基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含重链，其中每个重链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)重链恒定结构域的人重链可变结构域。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白重链基因座，所述基因座包含一个或多个人VL基因区段和一个或多个人JL基因区段，所述区段是在一个或多个啮齿动物(例如，大鼠或小鼠)免疫球蛋白重链恒定区基因(例如，一个或多个内源性啮齿动物(例如，大鼠或小鼠)免疫球蛋白重链恒定区基因)的上游(例如，与其可操作地连接)。这样的人源化的免疫球蛋白重链基因座在本文中被称作“人源化的LoH基因座”。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoH基因座处是纯合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoH基因座处是杂合的。
在某些实施方案中，包含人源化的LoH基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含免疫球蛋白链，其中每个免疫球蛋白链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)重链恒定结构域的人轻链可变结构域。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白轻链基因座(例如，κ和/或λ)，所述基因座包含一个或多个人VL基因区段和一个或多个人JL基因区段，所述区段是在一个或多个免疫球蛋白轻链恒定区基因的上游(例如，与其可操作地连接)。在某些实施方案中，一个或多个人VL基因区段和一个或多个人JL基因区段是一个或多个人Vκ基因区段和一个或多个人Jκ基因区段。在某些实施方案中，一个或多个人VL基因区段和一个或多个人JL基因区段是一个或多个人Vλ基因区段和一个或多个人Jλ基因区段。在某些实施方案中，一个或多个免疫球蛋白轻链恒定区基因是或包含Cκ。在某些实施方案中，一个或多个免疫球蛋白轻链恒定区基因是或包含Cλ。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白轻链基因座，所述基因座包含一个或多个人Vκ基因区段和一个或多个人Jκ基因区段，所述区段是在Cκ基因的上游(例如，与其可操作地连接)。这样的人源化的免疫球蛋白重链基因座在本文中被称作“人源化的KoK基因座”。在某些实施方案中，人源化的KoK基因座的免疫球蛋白κ轻链恒定区基因是啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，人源化的KoK基因座的免疫球蛋白κ轻链恒定区基因是内源性啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，人源化的KoK基因座的免疫球蛋白κ轻链恒定区基因是在内源性免疫球蛋白κ轻链基因座处的内源性啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的KoK基因座处是纯合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的KoK基因座处是杂合的。
在某些实施方案中，包含人源化的KoK基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含κ轻链，其中每个κ轻链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)κ轻链恒定结构域的人κ轻链可变结构域。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白轻链基因座，所述基因座包含在一个或多个人Jλ基因区段和一个或多个Cλ基因的上游(例如，与其可操作地连接)的一个或多个人Vλ基因区段。这样的人源化的免疫球蛋白轻链基因座在本文中被称作“人源化的LoL基因座”。在某些实施方案中，人源化的LoL基因座的一个或多个人Jλ基因区段和一个或多个Cλ基因存在于Jλ-Cλ簇中。在某些实施方案中，人源化的LoL基因座的一个或多个Cλ基因包含一个或多个人Cλ基因。在某些实施方案中，人源化的LoL基因座的一个或多个Cλ基因包含一个或多个小鼠Cλ基因。在某些实施方案中，人源化的LoL基因座的一个或多个Cλ基因包含一个或多个人Cλ基因和一个或多个小鼠Cλ基因。在某些实施方案中，人源化的LoL基因座的一个或多个小鼠Cλ基因包含小鼠Cλ1基因。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoL基因座处是纯合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoL基因座处是杂合的。
在某些实施方案中，包含人源化的LoL基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含λ轻链，其中每个λ轻链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)λ轻链恒定结构域的人λ轻链可变结构域。在某些实施方案中，包含人源化的LoL基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含λ轻链，其中每个λ轻链包含可操作地连接至人λ轻链恒定结构域的人λ轻链可变结构域。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白轻链基因座，所述基因座包含在Cκ基因的上游(例如，与其可操作地连接)的一个或多个人Vλ基因区段和一个或多个人Jλ基因区段。这样的人源化的免疫球蛋白轻链基因座在本文中被称作“人源化的LoK基因座”。在某些实施方案中，人源化的LoK基因座的Cκ基因是啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，人源化的LoK基因座的Cκ基因是内源性啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，人源化的LoK基因座的Cκ基因是在内源性免疫球蛋白κ轻链基因座处的内源性啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoK基因座处是纯合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoK基因座处是杂合的。
在某些实施方案中，包含人源化的LoK基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含轻链，其中每个轻链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)κ轻链恒定结构域的人λ轻链可变结构域。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白κ轻链基因座，所述基因座包含在Cλ基因的上游(例如，与其可操作地连接)的一个或多个人Vλ基因区段和一个或多个人Jλ基因区段。这样的人源化的免疫球蛋白轻链基因座在本文中被称作“人源化的LiK基因座”。在某些实施方案中，人源化的LiK基因座的Cλ基因是啮齿动物(例如，大鼠或小鼠)Cλ基因。在某些实施方案中，人源化的LiK基因座的Cλ基因是小鼠Cλ1基因。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LiK基因座处是纯合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LiK基因座处是杂合的。
在某些实施方案中，包含人源化的LiK基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含λ轻链，其中每个λ轻链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)λ轻链恒定结构域的人λ轻链可变结构域。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的免疫球蛋白κ轻链基因座，所述基因座包含在一个或多个人Jλ基因区段和一个或多个人Cλ基因上游(例如，与其可操作地连接)的一个或多个人Vλ基因区段。在某些实施方案中，这样的人源化的免疫球蛋白κ轻链基因座的一个或多个人Jλ基因区段和一个或多个Cλ基因存在于Jλ-Cλ簇中。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)就这样的人源化的免疫球蛋白κ轻链基因座而言是纯合的。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)就这样的人源化的免疫球蛋白κ轻链基因座而言是杂合的。在某些实施方案中，包含这样的人源化的免疫球蛋白κ轻链基因座的遗传修饰的啮齿动物(例如，大鼠或小鼠)产生抗体，例如，响应于抗原刺激，所述抗体尤其包含λ轻链，其中每个λ轻链包含可操作地连接至人λ轻链恒定结构域的人λ轻链可变结构域。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的HoH基因座和人源化的KoK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的HoH基因座和人源化的LoL基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的HoH基因座、人源化的KoK基因座和人源化的LoL基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的HoH基因座、人源化的KoK基因座、人源化的LoL基因座或它们的组合处是纯合的。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的HoH基因座、人源化的KoK基因座和人源化的LoK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的HoH基因座、人源化的KoK基因座和人源化的LiK基因座。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的HoH基因座和人源化的LoK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的HoH基因座、人源化的LoK基因座或它们的组合处是纯合的。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的HoH基因座和人源化的LiK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的HoH基因座、人源化的LiK基因座或它们的组合处是纯合的。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的LoH基因座和人源化的KoK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的LoH基因座和人源化的LoL基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的LoH基因座、人源化的KoK基因座和人源化的LoL基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoH基因座、人源化的KoK基因座、人源化的LoL基因座或它们的组合处是纯合的。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的LoH基因座、人源化的KoK基因座和人源化的LoK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的LoH基因座、人源化的KoK基因座和人源化的LiK基因座。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的LoH基因座和人源化的LoK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoH基因座、人源化的LoK基因座或它们的组合处是纯合的。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在其基因组(例如，其种系基因组)中包含人源化的LoH基因座和人源化的LiK基因座。在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)在人源化的LoH基因座、人源化的LiK基因座或它们的组合处是纯合的。
在某些实施方案中，本文描述的啮齿动物(例如，大鼠或小鼠)是如在例如美国专利号8,502,018、8,642,835、8,697,940、8,791,323、9,226,484和WO2019/113065中所述，它们都通过引用整体并入本文。可以按照本领域容易获得的方案进行育种(或“杂交”或“杂交育种”)；参见，例如，JoVE Science Education Database.Lab Animal Research,Fundamentals of Breeding and Weaning,JoVE,Cambridge,MA,(2018)(视频文章)；Breeding Strategies for Maintaining Colonies of Laboratory Mice,A JacksonLaboratory Resource Manual,
2007The Jackson Laboratory；都通过引用并入本文。可替换地，可以将经工程改造的Igλ轻链基因座工程改造进包含人源化的IgH基因座和/或人源化的Igκ基因座的ES细胞中，并将得到的ES细胞用于产生啮齿动物，或可以使包含人源化的Igλ轻链基因座的啮齿动物与包含人源化的IgH基因座和/或人源化的Igκ基因座的另一种啮齿动物繁殖。包含人源化的IgH基因座和/或人源化的Igκ基因座的各种啮齿动物是已知的，例如，
品系(参见，例如，美国专利号8,502,018和/或8,642,835；通过引用整体并入本文)、XENOMOUSETM品系(参见，例如，Mendez,M.J.等人,1997,Nat.Genetics 15(2):146-56和Jakobovits,A.等人,1995,Ann.NY Acad.Sci.764:525-35，通过引用整体并入)。
在某些实施方案中，本文描述的啮齿动物包含在以下文献中描述的有限免疫球蛋白轻链基因座：美国专利号9,796,788、9,969,814；美国专利申请公开号2011/0195454A1、2012/0021409A1、2012/0192300A1、2013/0045492A1、2013/0185821A1、2013/0302836A1；国际专利申请公开号WO 2011/097603、WO 2012/148873、WO 2013/134263、WO 2013/184761、WO 2014/160179、WO 2014/160202；它们中的每一篇特此通过引用整体并入。在某些实施方案中，本文描述的啮齿动物包含在WO2019/113065、WO2017214089、US20180125043和美国专利号9,035,128、9,066,502、9,163,092、9,150,662、9,334,333、9,006,511、9,029,628、9,206,261、9,012,717、9,394,373、9,206,262、9,206,263、9,226,484、9,540,452和9,399,683中描述的免疫球蛋白轻链基因座。
在某些实施方案中，本文提供的遗传修饰的啮齿动物(例如，大鼠或小鼠)具有包含人源化的免疫球蛋白重链(例如，HoH或LoH)基因座的基因组(例如，种系基因组)，所述基因座缺少功能性内源性啮齿动物Adam6基因。在某些实施方案中，本文提供的遗传修饰的啮齿动物(例如，大鼠或小鼠)具有包含一个或多个核苷酸序列的基因组(例如，种系基因组)，所述核苷酸序列编码一种或多种啮齿动物ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段。在某些实施方案中，所提供的遗传修饰的啮齿动物(例如，大鼠或小鼠)表达一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段。在某些实施方案中，所提供的遗传修饰的啮齿动物(例如，大鼠或小鼠)具有包含一个或多个核苷酸序列的基因组(例如，种系基因组)，所述核苷酸序列编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段，所述核苷酸序列被包括在与人源化的免疫球蛋白重链(例如，HoH或LoH)基因座相同的染色体上。在某些实施方案中，所提供的遗传修饰的啮齿动物(例如，大鼠或小鼠)具有包含人源化的免疫球蛋白重链(例如，HoH或LoH)基因座的基因组(例如，种系基因组)，所述基因座包含一个或多个核苷酸序列，所述核苷酸序列编码一种或多种啮齿动物ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段。在某些实施方案中，所提供的遗传修饰的啮齿动物(例如，大鼠或小鼠)具有替代人Adam6假基因的包含一个或多个核苷酸序列的基因组(例如，种系基因组)，所述核苷酸序列编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段。在某些实施方案中，所提供的遗传修饰的啮齿动物(例如，大鼠或小鼠)具有替换人Adam6假基因的包含一个或多个核苷酸序列的基因组(例如，种系基因组)，所述核苷酸序列编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段。
在某些实施方案中，所提供的遗传修饰的啮齿动物具有基因组(例如，种系基因组)，其含有包含第一和第二人VH基因区段的一个或多个人VH基因区段、以及在第一人VH基因区段和第二人VH基因区段之间的编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段的一个或多个核苷酸序列。在某些实施方案中，第一人VH基因区段是VH1-2且第二人VH基因区段是VH6-1。
在某些实施方案中，编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其功能性直系同源物、功能性同系物或功能片段的一个或多个核苷酸序列是在人VH基因区段和人DH基因区段之间。
在某些实施方案中，编码一种或多种啮齿动物ADAM6多肽的一个或多个核苷酸序列恢复或增强雄性啮齿动物的能育性。
在某些实施方案中，本文描述的啮齿动物包含如在美国专利号8,642,835、9,932,408、8,687,940和9,944,716中所述的Adam6基因。在某些实施方案中，所述重链基因座包含功能性的，例如，ADAM6a基因，ADAM6b基因，或二者。在某些实施方案中，遗传修饰的非人动物的基因组进一步包含功能性的，例如，ADAM6a基因，ADAM6b基因，或二者，其不位于小鼠重链可变区基因区段之间。在美国专利号8,642,835和8,697,940中描述了表达ADAM6a和/或ADAM6b的示例性啮齿动物，它们中的每一篇特此通过引用整体并入。
在某些实施方案中，遗传修饰的啮齿动物(例如，大鼠或小鼠)包含外源性末端脱氧核苷酸转移酶(TdT)基因。在某些实施方案中，与没有外源性TdT基因的啮齿动物相比，包含外源性末端脱氧核苷酸转移酶(TdT)基因的啮齿动物(例如，大鼠或小鼠)可以具有增加的抗原受体多样性。
在某些实施方案中，如本文中所述的啮齿动物具有包含可操作地连接至转录控制元件的外源性末端脱氧核苷酸基转移酶(TdT)基因的基因组。
在某些实施方案中，转录控制元件包括RAG1转录控制元件、RAG2转录控制元件、免疫球蛋白重链转录控制元件、免疫球蛋白κ轻链转录控制元件、免疫球蛋白λ轻链转录控制元件或它们的任意组合。
在某些实施方案中，外源性TdT位于免疫球蛋白κ轻链基因座、免疫球蛋白λ轻链基因座、免疫球蛋白重链基因座、RAG1基因座或RAG2基因座处。
在某些实施方案中，TdT是人TdT。在某些实施方案中，TdT是TdT的短异形体(TdTS)。
在某些实施方案中，本公开内容的啮齿动物包括，例如，小鼠、大鼠和仓鼠。在某些实施方案中，啮齿动物选自鼠总科(Muroidea)。在某些实施方案中，本公开内容的啮齿动物来自选自丽仓鼠科(Calomyscidae)(例如，小鼠-样仓鼠)、仓鼠科(Cricetidae)(例如，仓鼠、新世界大鼠和小鼠、田鼠)、鼠科(Muridae)(例如，真小鼠和大鼠、沙鼠、刺毛鼠、冠鼠)、马岛鼠科(Nesomyidae)(攀鼠、岩鼠、白尾大鼠、马达加斯加大鼠和小鼠)、刺睡鼠科(Platacanthomyidae)(例如，多刺睡鼠)和鼹形鼠科(Spalacidae)(例如，鼹鼠、竹鼠和鼢鼠)的科。在某些实施方案中，本公开内容的啮齿动物选自真小鼠或大鼠(鼠科)、沙鼠、刺毛鼠和冠鼠。在某些实施方案中，本公开内容的小鼠来自鼠科的成员。
遗传修饰的啮齿动物的表型
在某些实施方案中，遗传修饰的啮齿动物(其基因组包含在内源性Scn9a基因座处的核酸分子，其中所述核酸分子能够编码包含外源性Scn基因的至少一部分的NaV蛋白)在遗传修饰的啮齿动物中表达NaV蛋白。在某些实施方案中，以与对照啮齿动物(即在内源性Scn9a基因座处没有遗传修饰的啮齿动物)中的啮齿动物NaV1.7蛋白相当或基本相同的模式表达NaV蛋白。已知啮齿动物NaV1.7蛋白在背根神经节的伤害性(疼痛)神经元、交感神经元和神经内分泌细胞中表达。在某些实施方案中，以与对照啮齿动物(即在内源性Scn9a基因座处没有遗传修饰的啮齿动物)中的啮齿动物NaV1.7蛋白相当或基本相同的水平表达NaV蛋白。术语“相当”是指，被对比的模式或水平可能彼此不同，但允许相互对比，以便根据观察到的差异或相似之处合理得出结论；并且提及水平的术语“基本相同”是指，被对比的水平彼此相差不超过20％。
在某些实施方案中，遗传修饰的啮齿动物在用NaV1.7免疫原(例如，人NaV1.7免疫原)免疫接种能够提高体液免疫应答。NaV1.7免疫原可以是蛋白免疫原、DNA免疫原或它们的组合。基于血清中对NaV1.7蛋白特异性的抗体的滴度，可以确定啮齿动物中的体液免疫应答。可以采用多种测定法来确定抗体滴度，包括基于ELISA和流式细胞计量术的测定法(参见，例如，David H.Margulies,Induction of Immune Responses,Current Protocolsin Immunology,89,1,(2.0.1-2.0.3)(2010)；Henri V.van der Heyde等人,“Analysis ofantigen-specific antibodies and their isotypes in experimental malaria,”Cytometry,第71A(4)卷:242-250(2007)；二者通过引用并入本文。在某些实施方案中，测定利用在细胞表面上表达或被工程改造成表达NaV1.7的细胞，并且抗体滴度可通过测量与细胞结合的抗体来确定。在某些实施方案中，所述细胞是被工程改造成表达人NaV1.7蛋白的HEK细胞。在某些实施方案中，将抗体滴度定义为内插的血清稀释因子，其结合信号是背景的2倍。在某些实施方案中，与对照啮齿动物(即，没有遗传修饰的啮齿动物，即，不具有插入在内源性啮齿动物Scn9a基因座处的外源性Scn基因的至少一部分)相比，本文所公开的遗传修饰的啮齿动物以至少5、10、20、30、40、50、60、70、80、90或100倍或更大的滴度产生针对NaV1.7(例如，人NaV1.7)的抗体。
在某些实施方案中，啮齿动物能够产生对NaV1.7蛋白(例如，人NaV1.7蛋白)特异性的抗体。在某些实施方案中，基于抗体与被工程改造成表达NaV1.7蛋白的细胞系的结合相对于与没有NaV1.7蛋白的工程改造表达的亲本细胞系的结合之比，确定抗体特异性。在某些实施方案中，在至少2、3、4、5、6、7、8、9、10、15、20的比率或大于20的比率，抗体具有对NaV1.7(例如，但不限于，人NaV1.7)的特异性。
在某些实施方案中，本文所公开的遗传修饰的啮齿动物表现出对热刺激的受损应答。可以测量对热刺激的应答，例如，在Hargreaves试验(一种试验，其测量啮齿动物对指向后爪的辐射热刺激的缩回潜伏期；参见，例如，Shields等人,Journal of Neuroscience,2018,38(47):10180–10201)中，或在设置在有害温度(例如，52.5℃或55℃)的热板设备中(参见，例如，Shields等人.2018,出处同上)。在某些实施方案中，本文所公开的遗传修饰的啮齿动物(诸如向mNav1.7 KO小鼠中的hNav1.2 KI)表现出与野生型啮齿动物相比延长的对热刺激(例如，在Hargreaves试验中的辐射热刺激)的应答潜伏期，例如，遗传修饰的啮齿动物需要与野生型啮齿动物相比长至少25％、50％、75％或100％的时间来响应热刺激。
在某些实施方案中，本文所公开的遗传修饰的啮齿动物表现出减少的对组胺的痒应答。通过在啮齿动物的颈背皮内注射组胺并测量指定时间段内的搔抓发作次数，可以确定痒应答(参见，例如，参见，例如，Shields等人,2018,出处同上)。在某些实施方案中，本文所公开的遗传修饰的啮齿动物(诸如在mNav1.7小鼠中的hNav1.2 KI)通过在一段时间(诸如15分钟、20分钟、25分钟或30分钟)内比野生型啮齿动物少至少25％、50％、75％或100％的搔抓发作次数，表现出减少的对组胺的痒应答。
遗传修饰的啮齿动物组织和细胞
在一些实施方案的另一个方面，本文中公开了分离的啮齿动物细胞或组织，其包含如本文中所述的在内源性啮齿动物Scn9a基因座处的遗传修饰。
在某些实施方案中，啮齿动物组织是脂肪、膀胱、脑、乳房、骨髓、眼、心脏、肠、肾、肝、肺、淋巴结、肌肉、胰腺、血浆、血清、皮肤、脾、胃、胸腺、睾丸、卵子或它们的组合。
在某些实施方案中，啮齿动物细胞是淋巴细胞。在某些实施方案中，细胞选自B细胞、树突细胞、巨噬细胞、单核细胞和T细胞。
在某些实施方案中，将本文描述的遗传修饰的啮齿动物的B细胞用于生产结合NaV1.7(例如，人NaV1.7)的抗体。例如，可以从本文描述的啮齿动物分离B细胞，并直接用于或永生化用于产生杂交瘤。这样的啮齿动物可以用NaV1.7免疫原(DNA或蛋白)免疫，然后从啮齿动物分离B细胞。可以关于与表达NaV1.7(例如，人NaV1.7)的细胞的结合来筛选B细胞和/或杂交瘤。可以从这样的细胞克隆抗体并测序，并用于产生候选治疗剂。
在某些实施方案中，提供了从如本文中所述的分离的啮齿动物细胞或啮齿动物组织制备的永生化细胞。来自本文中公开的啮齿动物的细胞可以临时分离和使用，或者可以在培养物中维持多代。在某些实施方案中，将来自本文中公开的啮齿动物的细胞永生化(例如，通过使用病毒、细胞融合等)并在培养物中无限维持(例如，在系列培养中)。
在某些实施方案中，提供了啮齿动物胚胎干(ES)细胞，其基因组包含如本文中所述的在内源性Scn9a基因座处的遗传修饰。啮齿动物ES细胞可以用于制备啮齿动物胚胎和啮齿动物。
在某些实施方案中，啮齿动物ES细胞是小鼠胚胎干细胞，且在某些实施方案中来自129品系、C57BL品系、或其混合物。在某些实施方案中，啮齿动物ES细胞是小鼠胚胎干细胞且是129和C57BL品系的混合物。在某些实施方案中，啮齿动物ES细胞是大鼠胚胎干细胞。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的免疫球蛋白重链基因座，所述基因座包含一个或多个人VH基因区段、一个或多个人DH基因区段和一个或多个人JH基因区段，所述区段是在一个或多个啮齿动物(例如，大鼠或小鼠)免疫球蛋白重链恒定区基因(例如，一个或多个内源性啮齿动物(例如，大鼠或小鼠)免疫球蛋白重链恒定区基因)的上游(例如，与其可操作地连接)。这样的人源化的免疫球蛋白重链基因座在本文中被称作“人源化的HoH基因座”。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的HoH基因座处是纯合的。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的HoH基因座处是杂合的。
在某些实施方案中，分离的啮齿动物细胞是包含人源化的HoH基因座的B细胞或脾细胞且产生抗体，例如，响应于抗原刺激，所述抗体尤其包含重链，其中每个重链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)重链恒定结构域的人重链可变结构域。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的免疫球蛋白轻链基因座，所述基因座包含一个或多个人VL基因区段和一个或多个人JL基因区段，所述区段是在一个或多个免疫球蛋白轻链恒定区基因的上游(例如，与其可操作地连接)。在某些实施方案中，一个或多个人VL基因区段和一个或多个人JL基因区段是一个或多个人Vκ基因区段和一个或多个人Jκ基因区段。在某些实施方案中，一个或多个人VL基因区段和一个或多个人JL基因区段是一个或多个人Vλ基因区段和一个或多个人Jλ基因区段。在某些实施方案中，一个或多个免疫球蛋白轻链恒定区基因是或包含Cκ。在某些实施方案中，一个或多个免疫球蛋白轻链恒定区基因是或包含Cλ。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的免疫球蛋白轻链基因座，所述基因座包含一个或多个人Vκ基因区段和一个或多个人Jκ基因区段，所述区段是在Cκ基因的上游(例如，与其可操作地连接)。这样的人源化的免疫球蛋白重链基因座在本文中被称作“人源化的KoK基因座”。在某些实施方案中，人源化的KoK基因座的免疫球蛋白κ轻链恒定区基因是啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，人源化的KoK基因座的免疫球蛋白κ轻链恒定区基因是内源性啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，人源化的KoK基因座的免疫球蛋白κ轻链恒定区基因是在内源性免疫球蛋白κ轻链基因座处的内源性啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的KoK基因座处是纯合的。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的KoK基因座处是杂合的。
在某些实施方案中，分离的啮齿动物细胞是包含人源化的KoK基因座的B细胞或脾细胞且产生抗体，例如，响应于抗原刺激，所述抗体尤其包含κ轻链，其中每个κ轻链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)κ轻链恒定结构域的人κ轻链可变结构域。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的免疫球蛋白轻链基因座，所述基因座包含在一个或多个人Jλ基因区段和一个或多个Cλ基因的上游(例如，与其可操作地连接)的一个或多个人Vλ基因区段。这样的人源化的免疫球蛋白轻链基因座在本文中被称作“人源化的LoL基因座”。在某些实施方案中，人源化的LoL基因座的一个或多个人Jλ基因区段和一个或多个Cλ基因存在于Jλ-Cλ簇中。在某些实施方案中，人源化的LoL基因座的一个或多个Cλ基因包含一个或多个人Cλ基因。在某些实施方案中，人源化的LoL基因座的一个或多个Cλ基因包含一个或多个小鼠Cλ基因。在某些实施方案中，人源化的LoL基因座的一个或多个Cλ基因包含一个或多个人Cλ基因和一个或多个小鼠Cλ基因。在某些实施方案中，人源化的LoL基因座的一个或多个小鼠Cλ基因包含小鼠Cλ1基因。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的LoL基因座处是纯合的。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的LoL基因座处是杂合的。
在某些实施方案中，分离的啮齿动物细胞是包含人源化的LoL基因座的B细胞或脾细胞且产生抗体，例如，响应于抗原刺激，所述抗体尤其包含λ轻链，其中每个λ轻链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)λ轻链恒定结构域的人λ轻链可变结构域。在某些实施方案中，分离的啮齿动物细胞是包含人源化的LoL基因座的B细胞或脾细胞且产生抗体，例如，响应于抗原刺激，所述抗体尤其包含λ轻链，其中每个λ轻链包含可操作地连接至人λ轻链恒定结构域的人λ轻链可变结构域。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的免疫球蛋白轻链基因座，所述基因座包含在Cκ基因的上游(例如，与其可操作地连接)的一个或多个人Vλ基因区段和一个或多个人Jλ基因区段。这样的人源化的免疫球蛋白轻链基因座在本文中被称作“人源化的LoK基因座”。在某些实施方案中，人源化的LoK基因座的Cκ基因是啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，人源化的LoK基因座的Cκ基因是内源性啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，人源化的LoK基因座的Cκ基因是在内源性免疫球蛋白κ轻链基因座处的内源性啮齿动物(例如，大鼠或小鼠)Cκ基因。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的LoK基因座处是纯合的。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的LoK基因座处是杂合的。
在某些实施方案中，分离的啮齿动物细胞是包含人源化的LoK基因座的B细胞或脾细胞且产生抗体，例如，响应于抗原刺激，所述抗体尤其包含轻链，其中每个轻链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)κ轻链恒定结构域的人λ轻链可变结构域。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的免疫球蛋白κ轻链基因座，所述基因座包含在Cλ基因的上游(例如，与其可操作地连接)的一个或多个人Vλ基因区段和一个或多个人Jλ基因区段。这样的人源化的免疫球蛋白轻链基因座在本文中被称作“人源化的LiK基因座”。在某些实施方案中，人源化的LiK基因座的Cλ基因是啮齿动物(例如，大鼠或小鼠)Cλ基因。在某些实施方案中，人源化的LiK基因座的Cλ基因是小鼠Cλ1基因。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的LiK基因座处是纯合的。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的LiK基因座处是杂合的。
在某些实施方案中，分离的啮齿动物细胞是包含人源化的LiK基因座的B细胞或脾细胞且产生抗体，例如，响应于抗原刺激，所述抗体尤其包含λ轻链，其中每个λ轻链包含可操作地连接至啮齿动物(例如，大鼠或小鼠)λ轻链恒定结构域的人λ轻链可变结构域。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的免疫球蛋白κ轻链基因座，所述基因座包含在一个或多个人Jλ基因区段和一个或多个人Cλ基因上游(例如，与其可操作地连接)的一个或多个人Vλ基因区段。在某些实施方案中，这样的人源化的免疫球蛋白κ轻链基因座的一个或多个人Jλ基因区段和一个或多个Cλ基因存在于Jλ-Cλ簇中。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织就这样的人源化的免疫球蛋白κ轻链基因座而言是纯合的。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织就这样的人源化的免疫球蛋白κ轻链基因座而言是杂合的。在某些实施方案中，分离的啮齿动物细胞是B细胞或脾细胞，其包含这样的人源化的免疫球蛋白κ轻链基因座，且产生抗体，例如，响应于抗原刺激，所述抗体尤其包含λ轻链，其中每个λ轻链包含可操作地连接至人λ轻链恒定结构域的人λ轻链可变结构域。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的HoH基因座和人源化的KoK基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的HoH基因座和人源化的LoL基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的HoH基因座、人源化的KoK基因座和人源化的LoL基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的HoH基因座、人源化的KoK基因座、人源化的LoL基因座或它们的组合处是纯合的。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的HoH基因座、人源化的KoK基因座和人源化的LoK基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的HoH基因座、人源化的KoK基因座和人源化的LiK基因座。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的HoH基因座和人源化的LoK基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的HoH基因座、人源化的LoK基因座或它们的组合处是纯合的。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的HoH基因座和人源化的LiK基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的HoH基因座、人源化的LiK基因座或它们的组合处是纯合的。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的LoH基因座和人源化的KoK基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的LoH基因座和人源化的LoL基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的LoH基因座、人源化的KoK基因座和人源化的LoL基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的LoH基因座、人源化的KoK基因座、人源化的LoL基因座或它们的组合处是纯合的。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的LoH基因座、人源化的KoK基因座和人源化的LoK基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的LoH基因座、人源化的KoK基因座和人源化的LiK基因座。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的LoH基因座和人源化的LoK基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的LoH基因座、人源化的LoK基因座或它们的组合处是纯合的。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在其基因组中包含人源化的LoH基因座和人源化的LiK基因座。在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织在人源化的LoH基因座、人源化的LiK基因座或它们的组合处是纯合的。
在某些实施方案中，本文提供的分离的啮齿动物细胞或啮齿动物组织具有基因组，所述基因组包含缺乏内源性啮齿动物Adam6基因的人源化的免疫球蛋白重链(例如，HoH或LoH)基因座。在某些实施方案中，本文提供的分离的啮齿动物细胞或啮齿动物组织具有基因组，所述基因组包含编码一种或多种啮齿动物ADAM6多肽、其直系同源物、同系物或片段的一个或多个核苷酸序列。在某些实施方案中，所提供的分离的啮齿动物细胞或啮齿动物组织表达一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其直系同源物、同系物或片段。在某些实施方案中，所提供的分离的啮齿动物细胞或啮齿动物组织具有基因组，所述基因组包含编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其直系同源物、同系物或片段的一个或多个核苷酸序列，所述核苷酸序列被包括在与人源化的免疫球蛋白重链(例如，HoH或LoH)基因座相同的染色体上。在某些实施方案中，所提供的分离的啮齿动物细胞或啮齿动物组织具有基因组，所述基因组包含人源化的免疫球蛋白重链(例如，HoH或LoH)基因座，所述基因座包含编码一种或多种啮齿动物ADAM6多肽、其直系同源物、同系物或片段的一个或多个核苷酸序列。在某些实施方案中，所提供的分离的啮齿动物细胞或啮齿动物组织具有替代人Adam6假基因的基因组，所述基因组包含编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其直系同源物、同系物或片段的一个或多个核苷酸序列。在某些实施方案中，所提供的分离的啮齿动物细胞或啮齿动物组织具有替换人Adam6假基因的基因组，所述基因组包含编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其直系同源物、同系物或片段的一个或多个核苷酸序列。
在某些实施方案中，所提供的分离的啮齿动物细胞或啮齿动物组织具有基因组，所述基因组包含含有第一和第二人VH基因区段的一个或多个人VH基因区段、以及在第一人VH基因区段和第二人VH基因区段之间的编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其直系同源物、同系物或片段的一个或多个核苷酸序列。在某些实施方案中，第一人VH基因区段是VH1-2且第二人VH基因区段是VH6-1。
在某些实施方案中，编码一种或多种啮齿动物(例如，大鼠或小鼠)ADAM6多肽、其直系同源物、同系物或片段的一个或多个核苷酸序列是在人VH基因区段和人DH基因区段之间。
在某些实施方案中，分离的啮齿动物细胞或啮齿动物组织包含外源性末端脱氧核苷酸转移酶(TdT)基因。在某些实施方案中，分离的啮齿动物细胞是包含外源性末端脱氧核苷酸转移酶(TdT)基因的B细胞或脾细胞，且当与不具有外源性TdT基因的分离的啮齿动物细胞(例如，B细胞或脾细胞)相比时可以具有增加的抗原受体多样性。
在某些实施方案中，如本文中所述的分离的啮齿动物细胞或啮齿动物组织具有包含可操作地连接至转录控制元件的外源性末端脱氧核苷酸基转移酶(TdT)基因的基因组。
在某些实施方案中，转录控制元件包括RAG1转录控制元件、RAG2转录控制元件、免疫球蛋白重链转录控制元件、免疫球蛋白κ轻链转录控制元件、免疫球蛋白λ轻链转录控制元件或它们的任意组合。
在某些实施方案中，外源性TdT位于免疫球蛋白κ轻链基因座、免疫球蛋白λ轻链基因座、免疫球蛋白重链基因座、RAG1基因座或RAG2基因座处。
在某些实施方案中，TdT是人TdT。在某些实施方案中，TdT是TdT的短异形体(TdTS)。
用于制备遗传修饰的啮齿动物的组合物和方法
在一些实施方案的一个方面，本文公开了用于制备上述遗传修饰的啮齿动物的方法，以及适合用于制备遗传修饰的啮齿动物的核酸载体。
在某些实施方案中，本文中公开了靶向载体(或核酸构建体)，其包含期望整合进啮齿动物Scn9a基因座中的外源性Scn基因。在某些实施方案中，本文中公开了靶向载体(或核酸构建体)，其包含期望整合进啮齿动物Scn9a基因座中的外源性Scn基因的至少一部分。在某些实施方案中，靶载体包含外源性Scn基因的一部分，该部分编码由外源性Scn基因编码的NaV蛋白的细胞外结构域的连续氨基酸。在某些实施方案中，靶载体包含外源性Scn基因的部分，所述部分编码由外源性Scn基因编码的NaV蛋白的细胞外结构域的氨基酸，并且也包含内源性Scn9a基因的部分，所述部分编码跨膜和细胞质结构域的氨基酸，其中跨膜和细胞质结构域彼此可操作地连接。在某些实施方案中，靶载体包含外源性Scn基因的编码序列。在某些实施方案中，所述靶向载体也包括侧接要整合进啮齿动物Scn9a基因座中的核苷酸序列的5'和3'啮齿动物序列(也被称作同源性臂)，其介导所述核苷酸序列向靶啮齿动物Scn9a基因座中的同源重组和整合。在某些实施方案中，所述同源性臂包含核苷酸序列，其侧接在要被替换的靶啮齿动物基因座处的核苷酸序列。在一个示例性实施方案中，来自内源性啮齿动物Scn9a基因的从起始密码子至终止密码子的编码序列被人SCN2A基因的编码序列替换，5'侧翼序列可以包括在内源性啮齿动物Scn9a基因的ATG密码子上游的序列，且3'侧翼序列可以包括在内源性啮齿动物Scn9a基因的终止密码子下游的序列。
在某些实施方案中，靶向载体包含选择标记基因。在某些实施方案中，靶向载体包含一个或多个位点特异性的重组位点。在某些实施方案中，靶向载体包含选择标记基因，其侧接位点特异性的重组位点，使得选择标记基因可以由于位点直接的重组而被删除。
在示例性实施方案中，使用细菌同源重组和
技术(参见，例如，美国6,586,251和Valenzuela等人(2003)Nature Biotech.21(6):652-659；都通过引用整体并入本文)，可以修饰携带啮齿动物Scn9a基因的啮齿动物基因组片段的细菌人工染色体(BAC)克隆。所以，从原始BAC克隆删除啮齿动物Scn9a基因组序列，并插入外源性Scn核苷酸序列，从而产生经修饰的携带外源性Scn核苷酸序列的BAC克隆，其侧接5'和3'啮齿动物同源性臂。经修饰的BAC克隆一旦线性化就可以引入啮齿动物胚胎干(ES)细胞中。
在某些实施方案中，本发明提供了如本文中所述的靶向载体用于制备经修饰的啮齿动物胚胎干(ES)细胞的用途。例如，可以将靶向载体引入啮齿动物ES细胞，例如，通过电穿孔。在本领域中已经描述了小鼠ES细胞和大鼠ES细胞。参见，例如，US 7,576,259、US 7,659,442、US 7,294,754和US 2008-0078000 A1，它们描述了小鼠ES细胞和用于制备遗传修饰的小鼠的
方法；US 2014/0235933 A1(RegeneronPharmaceuticals Inc.),US 2014/0310828 A1(Regeneron Pharmaceuticals Inc.),Tong等人(2010)Nature 467:211-215,和Tong等人(2011)Nat Protoc.6(6):doi:10.1038/nprot.2011.338，它们描述了大鼠ES细胞和用于制备遗传上修饰的大鼠的方法，它们可以用于制备经修饰的啮齿动物胚胎，所述胚胎又可以用于制备啮齿动物。
在某些实施方案中，本文描述的经修饰的啮齿动物ES细胞在其基因组中包含人源化的HoH基因座和人源化的KoK基因座。在某些实施方案中，本文描述的经修饰的啮齿动物ES细胞在其基因组中包含人源化的HoH基因座和人源化的LoL基因座。在某些实施方案中，本文描述的经修饰的啮齿动物ES细胞在其基因组中包含人源化的HoH基因座、人源化的KoK基因座和人源化的LoL基因座。在某些实施方案中，本文描述的经修饰的啮齿动物ES细胞在人源化的HoH基因座、人源化的KoK基因座、人源化的LoL基因座或它们的组合处是纯合的。
在某些实施方案中，本文描述的经修饰的啮齿动物ES细胞在其基因组中包含人源化的HoH基因座、人源化的KoK基因座和人源化的LoK基因座。在某些实施方案中，本文描述的经修饰的啮齿动物ES细胞在其基因组中包含人源化的HoH基因座、人源化的KoK基因座和人源化的LiK基因座。
在某些实施方案中，本文描述的经修饰的啮齿动物ES细胞在其基因组中包含人源化的HoH基因座和人源化的LoK基因座。在某些实施方案中，本文描述的经修饰的啮齿动物ES细胞在人源化的HoH基因座、人源化的LoK基因座或它们的组合处是纯合的。
在某些实施方案中，本文描述的经修饰的啮齿动物ES细胞在其基因组中包含人源化的HoH基因座和人源化的LiK基因座。在某些实施方案中，本文描述的经修饰的啮齿动物ES细胞在人源化的HoH基因座、人源化的LiK基因座或它们的组合处是纯合的。
在某些实施方案中，本文描述的经修饰的啮齿动物ES细胞在其基因组中包含人源化的LoH基因座和人源化的KoK基因座。在某些实施方案中，本文描述的经修饰的啮齿动物ES细胞在其基因组中包含人源化的LoH基因座和人源化的LoL基因座。在某些实施方案中，本文描述的经修饰的啮齿动物ES细胞在其基因组中包含人源化的LoH基因座、人源化的KoK基因座和人源化的LoL基因座。在某些实施方案中，本文描述的经修饰的啮齿动物ES细胞在人源化的LoH基因座、人源化的KoK基因座、人源化的LoL基因座或它们的组合处是纯合的。
在某些实施方案中，本文描述的经修饰的啮齿动物ES细胞在其基因组中包含人源化的LoH基因座、人源化的KoK基因座和人源化的LoK基因座。在某些实施方案中，本文描述的经修饰的啮齿动物ES细胞在其基因组中包含人源化的LoH基因座、人源化的KoK基因座和人源化的LiK基因座。
在某些实施方案中，本文描述的经修饰的啮齿动物ES细胞在其基因组中包含人源化的LoH基因座和人源化的LoK基因座。在某些实施方案中，本文描述的经修饰的啮齿动物ES细胞在人源化的LoH基因座、人源化的LoK基因座或它们的组合处是纯合的。
在某些实施方案中，本文描述的经修饰的啮齿动物ES细胞在其基因组中包含人源化的LoH基因座和人源化的LiK基因座。在某些实施方案中，本文描述的经修饰的啮齿动物ES细胞在人源化的LoH基因座、人源化的LiK基因座或它们的组合处是纯合的。
在某些实施方案中，可以选择具有整合进基因组中的外源性Scn核苷酸序列的ES细胞。在某些实施方案中，基于啮齿动物等位基因的缺失和/或外源性核苷酸序列测定的获得，选择ES细胞。在某些实施方案中，然后通过使用
方法(参见，例如，US 7,576,259、US 7,659,442、US 7,294,754和US 2008-0078000 A1)，或在US 2014/0235933 A1和US 2014/0310828 A1中描述的方法，将选择的ES细胞用作供体ES细胞以注射进桑椹胚前阶段胚胎(例如，8-细胞阶段胚胎)中。在某些实施方案中，经修饰的啮齿动物ES细胞包含人源化的免疫球蛋白重链和/或轻链基因座和外源性Scn序列，且经修饰的啮齿动物ES细胞可以引入胚胎中。将包含供体ES细胞的胚胎温育直到胚泡期，并然后植入代孕母体以产生完全衍生自供体ES细胞的F0啮齿动物。使用啮齿动物Scn9a序列的缺失和/或外源性Scn序列测定的获得，通过分离自剪断的尾巴的DNA的基因分型，可以鉴定带有外源性Scn核苷酸序列的啮齿动物幼崽。
在某些实施方案中，可以将在内源性Scn9a基因座处的遗传修饰杂合的啮齿动物杂交(或杂交育种)以产生纯合的啮齿动物，例如，通过遵循本领域中容易获得的育种方案；参见，例如，JoVE Science Education Database.Lab Animal Research,Fundamentals ofBreeding and Weaning,JoVE,Cambridge,MA,(2018)(视频文章)；Breeding Strategiesfor Maintaining Colonies of Laboratory Mice,A Jackson Laboratory ResourceManual,
2007The Jackson Laboratory；都通过引用整体并入本文。
在某些实施方案中，包含在内源性Scn9a基因座处的遗传修饰的啮齿动物可以与包含人或人源化的免疫球蛋白重链和/或轻链基因座的啮齿动物杂交以获得包含如上所述的在内源性Scn9a基因座处的遗传修饰和人或人源化的免疫球蛋白重链和/或轻链基因座的啮齿动物。在某些实施方案中，包含人源化的免疫球蛋白重链和/或轻链基因座的啮齿动物ES细胞可用于接受外源性Scn序列以整合到内源性Scn9a基因座中，并且所得到的遗传修饰的啮齿动物ES细胞可用于制备遗传修饰的啮齿动物，其包含在内源性Scn9a基因座处的遗传修饰和人源化的免疫球蛋白重链和/或轻链基因座。
采用遗传修饰的啮齿动物的方法
在某些实施方案中，本文描述的遗传修饰的啮齿动物用于产生针对NaV1.7蛋白(例如，人NaV1.7蛋白)的抗体。
在某些实施方案中，通过经由各个途径(例如，但不限于，静脉内或腹膜内途径)将NaV1.7免疫原(例如，人NaV1.7)施用给本文描述的啮齿动物，可以产生抗体。NaV1.7免疫原是蛋白免疫原(即，NaV1.7蛋白或其片段)、DNA免疫原(能够在接受者啮齿动物中表达NaV1.7蛋白或其片段的DNA，例如，病毒载体)或它们的组合。在某些实施方案中，所述免疫原是在大肠杆菌中或在真核(例如，酵母)或哺乳动物细胞(例如，中国仓鼠卵巢(CHO)细胞)中表达的重组NaV1.7蛋白。在某些实施方案中，使用标准佐剂可以施用一次或多次加强注射。加强注射可以使用相同的NaV1.7免疫原，或从原始蛋白免疫原切换到DNA免疫原，或反之亦然。从经免疫的啮齿动物回收淋巴细胞(诸如B-细胞)，并可以直接筛选，或可以与骨髓瘤细胞系融合以制备永生化的杂交瘤细胞系，然后将其筛选以鉴定产生对NaV1.7特异性的抗体的细胞。筛选可以是基于相对于与不表达NaV1.7蛋白的亲代细胞(HEK细胞)的结合，评价候选抗体与被工程改造成表达NaV1.7蛋白的细胞(例如，被工程改造成表达人NaV1.7的HEK细胞)的结合。在某些实施方案中，在指定的抗体浓度与被工程改造成表达NaV1.7蛋白的细胞的结合相对于与不表达NaV1.7蛋白的亲代细胞的结合的比率被用于测量抗体的特异性，并且如果所述比率是至少2、3、4、5、6、7、8、9或10或大于10的比率，可以将抗体鉴定为NaV1.7蛋白的特异性结合剂。
可以分离编码所鉴定的细胞的重链和轻链的可变区的DNA，并将其连接到合乎需要的重和轻恒定区。可以在细胞、诸如CHO细胞中生产这样的抗体蛋白。
本说明书通过以下实施例进一步举例说明，不应将其解释为以任何方式进行限制。所有引用的参考文献(包括贯穿本申请引用的参考文献、授权专利和公开的专利申请)的内容特此明确地通过引用并入。
实施例
实施例1.包含在小鼠NaV1.7敲出(KO)中的人NaV1.2敲入(KI)的小鼠品系的制备
本实施例解释了制备遗传修饰的啮齿动物(例如，小鼠)的示例性方法，其中啮齿动物Scn基因(例如，小鼠Scn9a基因，其编码小鼠NaV1.7蛋白)被来自不同物种的Scn基因完全地或部分地替换(例如，人SCN2A基因，其编码人NaV1.2蛋白)。
使用细菌人工染色体(BAC)克隆和
技术(参见，例如，美国专利号6,586,251和Valenzuela等人(2003)High-throughput engineering of the mousegenome coupled with high-resolution expression analysis,Nature Biotech.21(6):652-659，其通过引用整体并入本文)，如下构建用于修饰内源性小鼠Scn9a基因的靶向载体。
简而言之，使用含有来自BAC克隆RP11-422D18的96,735bp的人SCN2A基因组DNA和4809bp的自删除新霉素盒的DNA片段(loxP-mPrm1-Crei-pA-hUb1-em7-Neo-pA-loxP)，通过细菌细胞中的同源重组来修饰含有小鼠Scn9a基因的细菌人工染色体(BAC)克隆RP23-454H3。人SCN2A基因组DNA含有人SCN2A ATG至超出终止密码子的2734bp，其包括在所述盒前面紧挨着的人3'UTR之后的约250bp的3'人序列。作为同源重组的结果，在BAC克隆RP23-454H3中的84,847bp的小鼠核苷酸序列(从ATG起始密码子至小鼠Scn9a基因的终止密码子)被96,735bp的人序列替换，随后是所述盒。得到的经修饰的BAC克隆(具有57Kb的5'同源性臂和43Kb的3'同源性臂，后者侧接人SCN2A基因组DNA和自删除盒)用作靶向载体以修饰内源性小鼠Scn9a基因。参见图1A-1B。
通过电穿孔将经修饰的BAC克隆引入小鼠胚胎干(ES)细胞。通过测定(Valenzuela等人,出处同上)来鉴定含有替代在内源性小鼠Scn9a基因座处的小鼠Scn9a基因的人SCN2A基因(“在小鼠Scn9a KO中的人SCN2A KI”或“在mNaV1.7 KO中的hNaV1.2 KI”)的正靶向的ES细胞，所述测定检测人序列的存在并证实小鼠序列的缺失和/或保留。表5描述了在测定中使用的引物和探针。也参见图1A，该图描绘了在测定中使用的引物和探针的位置。成功修饰的Scn9a基因座的核苷酸序列如SEQ ID NO:20所示。在选择具有期望修饰的靶向的ES细胞克隆以后，通过引入Cre重组酶，例如，通过电穿孔，可以切离新霉素选择盒。可替换地，通过使从ES克隆产生的后代与表达Cre重组酶的缺失啮齿动物品系杂交，可以除去新霉素选择盒。在删除盒以后的经修饰的Scn9a基因座如图1C所示，其中连接部序列显示在图1C的底部。
表5
使用
方法(参见，例如，美国专利号7,294,754和Poueymirou等人,2007,Nature Biotech.25(1):91-99)将选择的ES细胞克隆(具有或没有盒)用于植入雌性小鼠以产生一窝在基因组中含有人源化的Scn9a基因座的幼崽。使用检测人序列的存在的等位基因测定的改进(Valenzuela等人,出处同上)，通过分离自剪断的尾巴的DNA的基因分型，再次证实和鉴定带有这样的遗传修饰的小鼠。通过使杂合的动物杂交，制备就人源化的Scn9a基因座而言纯合的动物。
实施例2.在mNaV1.7敲出(KO)中的hNaV1.2敲入(KI)/VI-3小鼠的免疫接种和对免疫原的血清抗体应答的分析。
免疫接种.将在mNaV1.7 KO中的人NaV1.2敲入(KI)/VI-3小鼠用编码全长人Nav1.7蛋白的全长DNA或人NaV1.7蛋白免疫。使用标准的佐剂，在不同的时间间隔经由不同的途径强化小鼠。在免疫接种开始之前和在免疫原强化后定期给小鼠抽血，并在各种抗原上测定抗-血清滴度。
抗-血清滴度测定.使用Meso Scale Discovery(MSD)细胞结合ELISA测定血清中针对各种免疫原的抗体滴度。在37℃给九十六-孔碳表面平板涂布在PBS中的40,000个细胞/孔的HEK293/hNav1.7-GFP(来自Sanofi,SA)、HEK293/hNav1.7(Millipore)和HEK293亲代细胞1小时。倾析细胞涂布溶液，并将平板用150μL的在PBS中的2％牛血清白蛋白(BSA,Sigma-Aldrich)在室温(RT)封闭1h。使用洗板机(来自Molecular Devices的
2000)将平板用PBS洗涤三次。将免疫前和免疫抗-血清在1％BSA-PBS中连续稀释三倍，并加入平板在室温保持1h。将平板洗涤，然后将山羊抗-小鼠IgG-Fc钌缀合的第二抗体以1μg/mL加入平板并在室温温育1小时。将平板洗涤，并通过加入150μl/孔的MSD的4X无表面活性剂的Read Buffer T(稀释至1X)进行显影，并在MSD SECTORTM成像仪6000仪器上读出。使用Graphpad PRISM软件计算抗-血清滴度。将滴度定义为内插的血清稀释因子，其结合信号是背景的2倍。
结果.在用蛋白或DNA免疫原免疫接种以后，研究了在mNav1.7 KO中的hNav1.2KI/VI-3小鼠中的体液免疫应答。来自用蛋白免疫的小鼠的抗血清在Nav1.7过表达细胞上显示出高的特异性滴度，与亲代细胞的结合较低(图2)。对最初用DNA免疫的低应答小鼠施用蛋白强化，这导致在Nav1.7工程改造的细胞上引发高特异性滴度(图2)。
实施例3.来自在mNaV1.7 KO中的人NaV1.2 KI/VI小鼠的抗体的电化学发光细胞结合-来自初步筛选的上清液和纯化的抗体。
实验规程
将在实施例1中描述的在mNaV1.7 KO中的人NaV1.2 KI/VI小鼠用纯化的去污剂增溶的人NaV1.7蛋白免疫。通过来自这些免疫的小鼠的脾细胞与小鼠骨髓瘤P3X63Ag8.653细胞的融合，制备单克隆抗体。使用基于电化学发光(ECL)的检测，关于它们的结合人NaV1.7表达细胞的能力，评价来自杂交瘤的上清液。通过在NaV1.7工程改造的细胞和参考细胞系上的结合的对比，关于特异性来评价正NaV1.7细胞结合剂。24个NaV1.7-特异性的杂交瘤的子集是通过流式细胞计量术筛分的单个细胞，将其扩增，并纯化抗体。确定这些抗体的特异性地结合被工程改造成表达NaV1.7的细胞的能力。
简而言之，被工程改造成表达人NaV1.7的人胚胎肾细胞(HEK293)得自两个来源：Sanofi(SA 293/GFP-hNaV1.7，缩写“SA”，如在图2中所示)和Millipore(Millipore 293/hNaV1.7,缩写“Millipore”，如在图2中所示)。来自ATCC的HEK293细胞用作NaV1.7基线参考，因为它们具有低水平的NaV1.7 mRNA，如通过TAQMAN分析所确定的。先前分离的抗-人NaV1.7抗体用作NaV1.7阳性细胞结合对照。无关的小鼠IgG抗体(抗-hCD48 mIgG1或抗-hIgG4 mIgG2a对照)用作测定中的阴性结合对照。
根据下述规程进行实验。将来自上述系的细胞在不含Ca2+/Mg2+的1xPBS缓冲液中冲洗一次，并在37℃与无酶细胞解离溶液(Enzyme Free Cell Dissociation Solution)一起温育10分钟以使细胞脱离烧瓶。将所有细胞用含有Ca2+/Mg2+的1xPBS洗涤一次，并用CellometerTM Auto T4细胞计数器(Nexcelom Bioscience LLC,Lawrence,MA)计数。将大约2.0x104个HEK293、SA 293/GFP-hNaV1.7和Millipore 293/hNaV1.7细胞分别接种在96-孔碳电极平板(MULTI-ARRAY高结合平板,Meso Scale Discovery(MSD,Rockville,MD))上并在37℃温育1小时。将非特异性结合位点用在含有Ca2+/Mg2+的1xPBS中的2％BSA(w/v)在室温(RT)封闭1小时。向平板结合的HEK293、SA 293/GFP-hNaV1.7和Millipore 293/hNaV1.7细胞，以在PBS+0.5％BSA中的1:20的固定稀释度，加入抗-NaV1.7上清液或对照抗体的溶液作为单个点。对于纯化的抗体，一式两份地加入从1.7pM至100nM范围内的系列稀释物和不存在抗体的溶液。将平板在室温温育1小时，然后使用具有细胞洗涤头的AquaMax2000洗板机(MDS Analytical Technologies,Sunnyvale,CA)洗涤以除去未结合的抗体。用对Fcγ片段特异性的SULFO-TAGTM-缀合的山羊多克隆抗-人IgG抗体(Jackson Immunoresearch,WestGrove,PA)在室温检测平板结合的抗体1小时。将平板洗涤，并根据生产商的说明书用ReadBuffer(MSD,Rockville,MD)显影，用SECTOR IMAGER(MSD,Rockville,MD)记录发光信号。记录以相对光单位(RLU)测量的发光强度以指示在浓度范围处的每种抗体的结合强度。
对于3080个样品的初筛，将在SA 293/GFP-hNaV1.7或Millipore 293/hNaV1.7细胞系中具有大于300RLU的直接结合信号的上清液评分为阳性。用上述规程在所有三个细胞系中进一步试验145个阳性样品以确定特异性比。与HEK293细胞相比在人NaV1.7-表达细胞上具有大于或等于2的结合比的抗体被分类为NaV1.7-特异性结合剂，且计数值如表6所示。
对于纯化的抗体，在人NaV1.7表达细胞上在1.2nM抗体检测到的结合信号相对于结合HEK293细胞的相同抗体浓度的比率显示在表7中，并用作NaV1.7结合的特异性的指示。在SA 293/GFP-hNaV1.7或Millipore 293/hNaV1.7细胞上具有>150RLU的结合信号并且具有与HEK293细胞相比大于或等于2的比率的抗体被归类为NaV1.7-特异性结合剂。具有小于2的结合比或<150RLU的结合信号的抗体被归类为非特异性结合剂。
结果总结和结论
使来自NaV1.7免疫的在mNaV1.7 KO中的人NaV1.2 KI/VI小鼠的三个脾融合以产生杂交瘤。使用电化学发光(ECL)关于人NaV1.7细胞结合和特异性评价来自那些细胞的上清液。使抗体结合人NaV1.7-表达细胞、293/GFP-hNaV1.7或Millipore 293/hNaV1.7，并且在一些实验中结合参考细胞系HEK293，并用SULFO-TAGTM-缀合的抗-小鼠IgG多克隆抗体检测。
如表6中的结果所示，以1:20稀释度试验了3080个杂交瘤上清液，其中145个结合SA 293/GFP-hNaV1.7和/或Millipore 293/hNaV1.7细胞，通过ECL检测到大于或等于300RLU的信号。所有三种融合体产生了NaV1.7阳性细胞结合剂。随后关于与两个NaV1.7细胞系以及参考HEK293细胞的结合试验了145个上清液。60个阳性杂交瘤特异性地结合NaV1.7细胞，与SA 293/GFP-hNaV1.7或Millipore 293/hNaV1.7细胞的结合相对于HEK293细胞的比率大于2倍。那60个上清液中的52个特异性地结合两个细胞系。三个融合体中的两个产生了通过ECL确定的NaV1.7-特异性的杂交瘤。
60个杂交瘤中的24个的子集是通过流式细胞计量术分选的单个细胞，将其扩增，并纯化抗体和在两个结合实验之一中评估NaV1.7细胞特异性结合。在表7中，报告了1.2nM抗体与SA 293/GFP-hNaV1.7和Millipore 293/hNaV1.7细胞相对于HEK293细胞的结合的比率。24种抗体中的20种与两种NaV1.7细胞系特异性结合，对SA 293/GFP-hNaV1.7的结合比对HEK293细胞的结合高2.4至57.9倍，且对Millipore 293/hNaV1.7细胞的结合比对HEK293细胞的结合高2.5-44.5倍。24种抗体中的四种是非特异性的，具有<150RLU的结合信号，和/或对NaV1.7细胞相对于参照细胞小于二的结合比率。先前分离的阳性NaV1.7对照抗体对SA293/GFP-hNaV1.7的结合比对HEK293细胞的结合高平均高23.5倍，且对Millipore 293/hNaV1.7细胞的结合比对HEK293细胞的结合的平均高17.3倍。同种型对照抗体具有<150RLU的结合，并且如预期的那样对所有细胞具有接近相等的结合。
表6.杂交瘤上清液初筛总结
表7
实施例4
收集选定的抗-Nav1.7杂交瘤克隆并使用Promega
16系统分离总RNA。接着，使用SMARTscribeTM逆转录酶(Clontech)和对小鼠重链IgG1、IgG2a、IgG2b、IgG3和小鼠κ轻链的小鼠恒定区特异性的反向引物以及模板转换寡物SMARTer II A寡物(Trombetta等人.2014,PMID:24984854,通过引用整体并入本文)，进行逆转录以产生含有人可变结构域和小鼠恒定区序列的部分的cDNA。使用
Ampure XP珠子(Beckman CoulterGenomics)纯化cDNA和随后的PCR产物。然后使用具有Illumina连接序列的对SMARTer II A寡物特异性的引物(5’-TCGTCGGCAGCGTCAGATGTGTATAAGAGACAG-3’,SEQ ID NO:57)和具有Illumina连接序列的对小鼠恒定区特异性的反向引物(5’-GTCTCGTGGGCTCGGAGATGTGTATAAGAGACAG-3’,SEQ ID NO:58)，通过PCR扩增纯化的cDNA。使用具有用于多路测序的索引序列的引物，通过PCR进一步扩增片段。将PCR产物纯化、处理和合并后，通过Miseq测序仪(Illumina)分析进行测序。
表8显示了抗-NaV1.7单克隆抗体中的V基因使用与VelocImmune小鼠中的V基因使用的对比，其在美国专利号8,502,018和8,642,835(通过引用整体并入本文)中有所描述。
表8
实施例5.在mNaV1.7 KO中的人NaV1.2 KI/VI小鼠具有对热刺激的受损应答和对组胺的降低的痒应答。
方法
热板-将小鼠置于热板装置(IITC,Woodland Hills,CA)上。在52.5℃或55℃(2种不同温度相隔10天进行试验)记录跳跃、立起和/或舔后爪的潜伏期。
Hargreaves-使用Hargreaves设备(IITC,Woodland Hills,CA)测量热痛觉过敏。在试验前至少60分钟将小鼠置于Plexiglas室中。在试验期间记录3次对施加到左后爪的辐射热刺激做出应答的热潜伏期，并使用总体平均潜伏期测量。
痒-在试验前使小鼠习惯Plexiglas室至少15分钟。在颈背的肩胛骨之间给小鼠真皮内注射150μg二盐酸组胺(15μl在PBS中,Sigma,目录号1309009)。向上定向以观察室底部的摄像机(Noldus)记录注射后长达25分钟的活动。关于组胺注射后的总搔抓发作，对视频文件进行手动评分。
结果
关于其对急性热刺激的应答，试验了在实施例1中描述的在mNav1.7 KO中的hNav1.2 KI的小鼠。首先，关于其对指向后爪的辐射热刺激的缩回潜伏期，试验了小鼠，也被称作Hargreaves试验。在小鼠Nav1.7中的hNav1.2的小鼠显示出显著延长的对热刺激的应答潜伏期(在小鼠Nav1.7中的hNav1.2小鼠为22.9±0.9s，n＝15，与此相比，WT小鼠为12.3±0.5s,n＝19，未配对Student氏t检验,p<0.0001)；参见图7A。接着，在热板设备上在2个有害温度52.5℃和55℃试验小鼠(2个温度相隔10天进行试验)。表达在小鼠Nav1.7中的hNav1.2的小鼠在任一温度都没有应答；所有小鼠都达到了30秒的截止时间，在此时停止试验以防止组织损伤，而WT小鼠在两种温度快速地表现出防伤害应答(在55℃为6.5±0.5s,n＝9，和在52.5℃为10.4±0.6s)；参见图7B。
为了试验表达在小鼠Nav1.7基因座中的hNav1.2小鼠的小鼠是否对瘙痒原具有受损的痒应答，将组胺(150μg)真皮内地注射到小鼠的颈背中，并记录搔抓发作最多25分钟。在mNav1.7中的hNav1.2小鼠表现出比WT小鼠少3.7倍的搔抓发作(在mNav1.7中的hNav1.2小鼠为24±11次发作，与此相比，WT为81±20次发作，未配对Student氏t检验p＝0.047)；参见图7C。
在本说明书中引用了各种出版物，包括专利、专利申请、公开的专利申请、登录号、技术文章和学术文章。这些引用的出版物中的每一篇通过引用以其整体并为了所有目的并入本文件中。
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<110> Regeneron Pharmaceuticals, Inc.
<120> 具有遗传修饰的钠通道的啮齿动物及其使用方法
<130> 36328PCT (10403WO01)
<150> 62/808,957
<151> 2019-02-22
<160> 58
<170> PatentIn version 3.5
<210> 1
<211> 9865
<212> DNA
<213> 小家鼠
<400> 1
gcacacaccc cacccagaga ggtggccgcg ggtgagaggc tgtgcgaccc acctcctgtc 60
ccttcttcta gcacggagta tagaggctgc cgcatcccta gcatcaccac gcccaatcgc 120
caggtctccg ccctgcaccg tctaccgggc tgggaggagg gagctagggg tggggacccg 180
agagctcagg gagcatcgag gaggcctagc gacgcggttg gcagccgagg gcggggtcgc 240
ttcatcctga gcagactaga aacagacaga ctccgtgcag gcctagcctg cgctccaatt 300
gcgactctag ccttttcaat cctgcccact gtgcaggctg gtctggtcta gcctgggtat 360
cccggactcc tagtagcagg cactgtgagc aacaggattt caaagaaaga agcagaggga 420
agaaagaagc ctgggaagag aggaagactt cccttggatc agaatccgca ggtgcactca 480
ccgggtgggc atgatccgtg gggccaggcc tcttaggtaa ggatccgaag gggaaataaa 540
acctacagga tgagaagatg gcgatgttgc ctccgccagg acctcagagc ttcgttcact 600
tcacaaaaca gtcccttgcc ctcattgaac aacgcatttc tgaagaaaaa gccaagggac 660
acaaagatga aaagaaagat gatgaggaag aaggtcccaa gcccagtagt gacttggaag 720
caggtaaaca gctacccttc atctacggag acattccccc gggaatggtg tcagagcccc 780
tggaggacct ggacccatac tatgcagaca aaaaaacttt tatagtattg aacaaaggga 840
aagcaatctt ccgtttcaac gccacccctg ctttgtacat gctgtctccc ttcagtcctc 900
tcagaagaat atctattaag attttagtgc actccttatt cagcatgcta atcatgtgca 960
caattctgac aaactgcata ttcatgacca tgagcaaccc tccagattgg accaaaaacg 1020
tagagtacac ttttactggg atatatactt ttgaatcact cataaaaatc cttgcaagag 1080
gcttttgcgt gggcgaattc accttcctcc gtgacccttg gaactggctg gactttgttg 1140
tcattgtttt tgcgtattta acagaatttg taaacctagg caatgtttca gctcttcgaa 1200
ctttcagagt cttgagagct ttgaaaacta tttctgtaat tccaggacta aaaaccatcg 1260
tgggggccct gatccaatca gtgaagaagc tctctgacgt catgatcctc actgtgttct 1320
gtctcagtgt gttcgcacta attggactac aactgtttat gggcaacttg aagcataaat 1380
gtttccggaa ggaccttgag cagaatgaaa cattagaaag catcatgagt actgctgaga 1440
gtgaagaaga attgaaaaga tatttttatt acttggaggg atccaaagat gctcttcttt 1500
gcggtttcag cacagattca gggcagtgtc ctgaagggta cgagtgtgtg acagctggca 1560
gaaacccaga ttatggctac acaagctttg acacgttcgg ctgggccttc ttggccttgt 1620
ttcggctaat gactcaggac tactgggaga acctttatca acagacactg cgtgctgctg 1680
gcaaaaccta catgattttc tttgtcgtgg tgatatttct gggatccttt tacctgataa 1740
acttgatcct ggctgtggta gccatggcgt acgaggaaca gaaccaggcc aacatcgaag 1800
aagctaaaca gaaagagtta gaatttcagc agatgttaga ccgactcaaa aaagagcagg 1860
aagaagccga ggcgatcgct gcagccgctg ctgagtacac gagtttaggg cggagcagga 1920
ttatgggact ctctgagagc tcttcagaaa cctccaggct gagctcaaag agtgccaagg 1980
agagaagaaa ccgaagaaag aaaaaaaaac agaagctgtc cagtggcgag gaaaagggtg 2040
atgatgagaa gctgtccaag tcagggtcag aggaaagcat ccgaaagaaa agcttccatc 2100
tcggcgtgga agggcaccac cgggccaggg aaaagaggct gtccaccccc aaccagtcac 2160
cactcagcat tcgtgggtcc ttgttttctg ccaggcgcag cagcagaaca agtctcttca 2220
gttttaaggg gcgaggaaga gatctgggat ctgaaacgga atttgctgat gatgagcata 2280
gcatttttgg agacaacgag agcagaaggg gttcactatt tgtaccccat agaccccggg 2340
agcggcgcag cagtaacatc agccaggcca gtaggtcccc accagtgctg ccggtgaacg 2400
ggaagatgca cagtgcagtg gactgcaatg gcgtggtgtc gcttgttgat ggaccctcag 2460
ccctcatgct ccccaatgga cagcttcttc cagaggtgat aatagataag gcaacttccg 2520
acgacagcgg cacaactaat cagatgcgta aaaaaaggct ctctagttct tactttttgt 2580
ctgaggacat gctgaatgac ccacatctca ggcaaagggc catgagcaga gcaagcattc 2640
taaccaacac agtagaagaa cttgaagaat ctagacaaaa atgtccacca tggtggtaca 2700
gatttgctca cacattttta atctggaatt gttctccata ttggataaaa ttcaaaaagt 2760
tcatctattt tattgtaatg gatccttttg tagatcttgc aattaccatt tgcatagttt 2820
taaacacctt gtttatggct atggagcacc atccaatgac ggatgaattc aaaaatgtac 2880
ttgcagtcgg gaacctggtc ttcacaggga tcttcgcagc tgaaatggta ctgaagttaa 2940
tagccatgga tccctatgaa tatttccaag tagggtggaa tatttttgac agcctgattg 3000
tgacgttgag tttggtggag cttttcctag cagatgtgga aggattatca gtcctgcggt 3060
cctttagatt gctgcgagtc ttcaagttgg caaaatcctg gcccacactg aatatgctca 3120
ttaagatcat cggcaactcg gtgggcgcac tgggcaacct gaccctggtg ctggccatca 3180
tcgtcttcat ttttgccgtg gtcggcatgc agctgtttgg aaagagctac aaggagtgtg 3240
tttgcaagat caacgagaac tgcaagctcc cacgctggca catgaacgac ttcttccact 3300
ccttcctgat cgtgttccgt gtgctgtgtg gggagtggat agagaccatg tgggactgca 3360
tggaggttgc gggccagacc atgtgcctta ttgtttacat gatggtcatg gtgattggga 3420
accttgtggt cctgaacctg tttctggctt tattactgag ttcctttagt tctgacaatc 3480
ttacagcaat tgaagaagac accgacgcaa acaacctcca gattgcagtg gccagaatta 3540
aaagagggat caattatgtg aaacagaccc tgcgtgaatt cattctaaag tcattttcca 3600
aaaagccaaa gggctccaag gacacaaaac gaacagcgga tcccaacaac aaaagagaaa 3660
actatatctc aaaccgtacc cttgcggaga taagcaaaga tcacaatttc ctcaaagaaa 3720
aggataagat cagtggtttt agcagcagtc tagacaaaag ctttatggat gaaaacgatt 3780
accagtcctt tattcataat cccagcctca cagtgacagt gcccattgca cctggggagt 3840
ctgatttgga gaatatgaac acagaagagc ttagcagtga ctcagatagt gactacagca 3900
aagagagacg gaaccgatca agttcttcag agtgcagcac agttgataac cctctgccag 3960
gagaagagga ggcagaagct gagcctatca atgcagatga gcccgaagcc tgttttacag 4020
atggctgtgt gaggagattt ccatgctgcc aagttaacat agactccggg aaagggaaag 4080
tttggtggac catccggaag acctgctaca ggatagtgga gcacagctgg tttgaaagct 4140
tcattgttct catgatcctg ctcagcagtg gagctctggc ttttgaggat atatatattg 4200
aaaagaaaaa gaccattaag attatcctgg agtatgctga caagatattc acctacatct 4260
tcattctgga aatgcttcta aaatgggtgg catacgggta taaaacatat ttcactaatg 4320
cctggtgttg gctggacttc ttaattgttg atgtgtctct agttacttta gtagccaaca 4380
ctcttggcta ctcagacctt ggccccatta aatctctacg gacactgagg gccctaagac 4440
ccctaagagc tttgtctaga tttgaaggaa tgagggtagt ggtcaacgca ctcataggag 4500
caatcccttc catcatgaat gtgcttcttg tgtgccttat attctggcta atatttagca 4560
tcatgggagt caatctgttt gctggcaagt tctatgagtg tgttaacacc acagatggct 4620
cacgattttc tgtatctcaa gttgcaaacc gttctgagtg ttttgccctg atgaatgtta 4680
gtggaaatgt gcgatggaaa aacctgaaag taaacttcga taacgttgga cttggttacc 4740
tgtcgctgct tcaagttgca acgttcaagg gctggatgga tattatgtat gcagcagttg 4800
actctgttaa tgtaaatgca caaccaatat atgaatacaa cctctacatg tacatttatt 4860
ttgtcatctt catcatcttt ggctcattct tcactttgaa cttgttcatt ggtgtcatca 4920
tcgataattt caaccaacag aagaagaagc ttggaggtca agatatcttt atgacagaag 4980
aacagaagaa atactataat gcaatgaaga agctggggtc caagaaacca caaaaaccaa 5040
ttccgaggcc agggaacaaa ttccaaggat gcatatttga cttagtgaca aaccaagctt 5100
ttgatatcac catcatggtt cttatctgcc tcaatatggt aaccatgatg gtagaaaaag 5160
aggggcaaac tgactacatg agttttgtgc tatactggat caacgtggtc ttcatcatcc 5220
tgttcactgg ggagtgtgtg ctgaagctga tctctctcag gcattactac ttcactgtgg 5280
gatggaacat ttttgatttt gtggtagtga tcctctccat tgtaggaatg tttctcgctg 5340
agatgataga gaagtatttc gtgtctccta ccctgttccg agtcattcgc ctggccagga 5400
ttggacgaat cctacgcctg atcaaaggcg ccaaggggat ccgcacgctg ctctttgctc 5460
tgatgatgtc ccttcctgcg ctgttcaaca tcggcctcct gcttttcctc gtcatgttca 5520
tctacgccat ctttgggatg tccaactttg cctacgttaa aaaggaagct ggaattaatg 5580
acatgttcaa ctttgagacc ttcggcaaca gcatgatctg cctgttccaa atcaccacct 5640
ctgcgggctg ggatggactg ctggccccca tcctcaacag tgcacctcct gactgtgacc 5700
caaaaaaggt tcacccagga agttcagtgg aaggggactg tggaaatcca tctgtgggaa 5760
ttttctactt tgtcagctac atcatcatat ccttcctggt tgtggtgaac atgtacattg 5820
ctgtcatcct ggagaacttc agcgttgcca cagaagaaag tactgagccc ctgagtgagg 5880
acgactttga gatgttctac gaagtctggg agaagttcga ccctgacgcc acccagttca 5940
tagagttctg caagctctct gactttgcag cagccctgga tcctcccctc ctcatcgcaa 6000
agccaaacaa agtccagctc attgccatgg acctgcccat ggtgagtgga gaccgcatcc 6060
actgcctgga catcttattt gcttttacaa agcgggtcct gggcgagagc ggagagatgg 6120
attcccttcg ttcacagatg gaagaaaggt ttatgtcagc caatccttct aaagtgtcct 6180
atgagcccat cacaaccaca ctgaagcgaa aacaagagga tgtatctgcg actatcattc 6240
agcgtgctta cagacggtac cgccttaggc aaaacgtcaa gaatatatca agtatatata 6300
taaaagatgg agacagagat gacgatttgc ccaataaaga agatatagtt tttgataatg 6360
ttaacgagaa ctcaagtcca gaaaagacag atgcaacagc ctctaccatc tctccacctt 6420
cctatgacag tgtcacaaag ccagatcaag agaaatatga aacagacaaa acggagaagg 6480
aagacaaaga gaaagacgaa agcaggaaat agagcttcgg ttttgataca ctgtttacag 6540
cctgcgaagg tgactcactc gtgttaataa gactctttta cggaggtcta tgccaaactc 6600
tttttatcaa atattctcaa aggcagcaca gccactagct ctgatccagt gaaacaagag 6660
agaagcattt acacatggct actttttgcg ttggtcaatg attctttaag aattgtgcat 6720
gtaactctac agggaataat cattattgca atcaagggtg acttaatgat tttaaatatc 6780
agaaaaccac atagaacatt ttctcttttg cctccatttc tttccctaga ttctaagtag 6840
atgtgtaccc atgtgaatat agaaattcag gcgcacatgc tcacagtcac aaacacaaac 6900
aggattagct gtgatttgga attcgatgta aatatttcac ctgtgatttg caatgaaatt 6960
ccttgtaaaa gaaatgcgaa ttagtgatga aggttttgtg aaaacatctt atcattaggg 7020
agtcagaatt tctgtccata aagaattcag tttatatttt gaggtgctga aacttatcct 7080
acattgcatc aaaatcaatt tataggtatc tgtaaaatgt catgggactg aaaaacatat 7140
ataggctact tgtttaagaa atggctttca ttcatataga taggcattca ccttgattta 7200
tggacatctt tggcattttg tgatcacatg attcttccac aaaattgctt agctggaact 7260
tcaggcacac atcacagaga acagctaccc agtcttatgc ccctctctgt ttgtacaata 7320
atcacagagc ttgaaacatt atttgaacta taaatatcag gtttctccac atagacatat 7380
gaatattgtt aacagaaaaa aattttattt acagcgtttt atttactaat atttatccaa 7440
tctagtttgc ccaatgagac agctcatgac tcacatctga aagccagttg ccacatttat 7500
cttcttatgt aactttggtt tgtcatactt tatgtctaag caaattgaat gtctcctttc 7560
taatgagatg taccctgaaa tgcagttagg tacttgatac tttagcgctt gtttgagcag 7620
atgactggag cacagtgtgg actgcatctc ttaaatacaa tccttaatgt gtttggcagc 7680
ttctcaggtt acaaggaaca cccggctttt agtgtctatc tgttcaccag gtgtttagta 7740
tgaatgaaac ggcattcaaa gagtgagtct cactggcttg ctttattact gatgccttcc 7800
ctatggagaa ttaatcctct gaagccccat tatgtccccc tgtaaataat gtagatgtca 7860
cttccttctt aatattctaa tccatactgt gaaatcgatt ttgcatttat cggtcaaata 7920
gagcattttg agatagttgg agttaccctg ccaaggatta gaaatctact tcatgttttt 7980
aaagtacttg ttaaaaatga acgaccctgg cacattctct cataatttta ttccagccat 8040
gtgaaatctt tcttctaaac actttatcct tgcggaggaa aaaaaaaatg agctgatgag 8100
ccatttaagc acaaaggggc tttatttaga agattccaag ggggaacttt gaagtaaata 8160
tataaaacat acttcatcaa tttgcctata aaactaaaag aggaacacag gaatattgat 8220
aaaataagtc attaaaacac attctttatt tcttgcccag tttaaaagaa agaactaaac 8280
atccctagag agaggaagag acatagagag agagtgacta atagaaagag ggagagaaga 8340
aacaaggcac caaggacaaa aagagataat tagacagaac ttgtccaggt tttcacacta 8400
tgtgctctgt ccagtaccgt acacaagaac ctctttccaa atatttgtcc taaggctcta 8460
agaagttaag tacgaggctg aaggttgaat acaactgtct ttaatcatta acagtttggg 8520
gagctacttt taaacgtcta tggaagatgc caagcagtgg taagccagac aatacagagc 8580
actgcatatc tgtcaagcag ctgaaatatg tttgggcaac ttaatggtga gccacacaaa 8640
acatccattt gtaacaattt taatacattc aattaagaaa ccaggatttt tattattttg 8700
cacccataaa aatataacta tattgttcat ttttattgat agagtatgtg tgaatcttat 8760
tgattatctg taatttacta ttaatgtttt tacagtgact gttttttttg tgtgtgtaaa 8820
cttaatatat gtcagcaact ggttcctcaa cacaattttt tttagcatta caaaaaaatg 8880
aacaggtata aaggttctct tttttctaca tcatgttgaa catattttgt tctgaattac 8940
atagttttaa atgtaatatt aagttttata ttcatatatg tttaacatca aaatcactac 9000
ttatgacatt gttatcaatt taaaaaatag tatttgacac taggatagca tttaattaaa 9060
gctaaaaagc ttacacccca tttcatgttg attagtgttt ggactaactc taaaatgtca 9120
tcaatggaag ctagtcactg aaattatttt atctattgtc atagaatggt gactacccaa 9180
aaaatataag ttagcattaa atagaagaaa gcgtacgtga ccacaaatcc atgcacaggg 9240
ttgtgtgaag acaggagaac ctcatttttc tgttttgtct ctttccactg tgtaaaaagt 9300
ctacatctgt gggctatttc taaattcaaa ttgtcacaat ttgcaatcat aaatgtttag 9360
catactttgt agaattttga tagttttgta aaagagtgaa aaacaaatgc atatgtaaat 9420
aaagcagccc atactagcag attcctcaaa tgttaatatg taaataaagc agcccttact 9480
agcagattca tcaaatgtta atatgtaaat aaagcagtcc ttattagcag atttgtcata 9540
tgttaagggg agtaatgata aggaggcaac taaatcagga tggtcagtaa ctgatctggg 9600
tttagaactg tgtttggagc catcaatttt taaatatatg ttctcactat gttattagtt 9660
gtctgaagaa gcaatcaaga attgctccca gaaaatgagt aagtagccat gaatatatga 9720
atgctgttta cagaacccat agacctatga atgctcaaaa tgtttgggtt tgtcaaaaaa 9780
ttacattgta gttatacttg atacttaaaa actgttaata gagtctaaaa taaaagtcgc 9840
taaaattaaa aaaaaaaaaa aaaaa 9865
<210> 2
<211> 1984
<212> PRT
<213> 小家鼠
<400> 2
Met Ala Met Leu Pro Pro Pro Gly Pro Gln Ser Phe Val His Phe Thr
1 5 10 15
Lys Gln Ser Leu Ala Leu Ile Glu Gln Arg Ile Ser Glu Glu Lys Ala
20 25 30
Lys Gly His Lys Asp Glu Lys Lys Asp Asp Glu Glu Glu Gly Pro Lys
35 40 45
Pro Ser Ser Asp Leu Glu Ala Gly Lys Gln Leu Pro Phe Ile Tyr Gly
50 55 60
Asp Ile Pro Pro Gly Met Val Ser Glu Pro Leu Glu Asp Leu Asp Pro
65 70 75 80
Tyr Tyr Ala Asp Lys Lys Thr Phe Ile Val Leu Asn Lys Gly Lys Ala
85 90 95
Ile Phe Arg Phe Asn Ala Thr Pro Ala Leu Tyr Met Leu Ser Pro Phe
100 105 110
Ser Pro Leu Arg Arg Ile Ser Ile Lys Ile Leu Val His Ser Leu Phe
115 120 125
Ser Met Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Ile Phe Met Thr
130 135 140
Met Ser Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr Thr Phe Thr
145 150 155 160
Gly Ile Tyr Thr Phe Glu Ser Leu Ile Lys Ile Leu Ala Arg Gly Phe
165 170 175
Cys Val Gly Glu Phe Thr Phe Leu Arg Asp Pro Trp Asn Trp Leu Asp
180 185 190
Phe Val Val Ile Val Phe Ala Tyr Leu Thr Glu Phe Val Asn Leu Gly
195 200 205
Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala Leu Lys Thr
210 215 220
Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala Leu Ile Gln
225 230 235 240
Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val Phe Cys Leu
245 250 255
Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly Asn Leu Lys
260 265 270
His Lys Cys Phe Arg Lys Asp Leu Glu Gln Asn Glu Thr Leu Glu Ser
275 280 285
Ile Met Ser Thr Ala Glu Ser Glu Glu Glu Leu Lys Arg Tyr Phe Tyr
290 295 300
Tyr Leu Glu Gly Ser Lys Asp Ala Leu Leu Cys Gly Phe Ser Thr Asp
305 310 315 320
Ser Gly Gln Cys Pro Glu Gly Tyr Glu Cys Val Thr Ala Gly Arg Asn
325 330 335
Pro Asp Tyr Gly Tyr Thr Ser Phe Asp Thr Phe Gly Trp Ala Phe Leu
340 345 350
Ala Leu Phe Arg Leu Met Thr Gln Asp Tyr Trp Glu Asn Leu Tyr Gln
355 360 365
Gln Thr Leu Arg Ala Ala Gly Lys Thr Tyr Met Ile Phe Phe Val Val
370 375 380
Val Ile Phe Leu Gly Ser Phe Tyr Leu Ile Asn Leu Ile Leu Ala Val
385 390 395 400
Val Ala Met Ala Tyr Glu Glu Gln Asn Gln Ala Asn Ile Glu Glu Ala
405 410 415
Lys Gln Lys Glu Leu Glu Phe Gln Gln Met Leu Asp Arg Leu Lys Lys
420 425 430
Glu Gln Glu Glu Ala Glu Ala Ile Ala Ala Ala Ala Ala Glu Tyr Thr
435 440 445
Ser Leu Gly Arg Ser Arg Ile Met Gly Leu Ser Glu Ser Ser Ser Glu
450 455 460
Thr Ser Arg Leu Ser Ser Lys Ser Ala Lys Glu Arg Arg Asn Arg Arg
465 470 475 480
Lys Lys Lys Lys Gln Lys Leu Ser Ser Gly Glu Glu Lys Gly Asp Asp
485 490 495
Glu Lys Leu Ser Lys Ser Gly Ser Glu Glu Ser Ile Arg Lys Lys Ser
500 505 510
Phe His Leu Gly Val Glu Gly His His Arg Ala Arg Glu Lys Arg Leu
515 520 525
Ser Thr Pro Asn Gln Ser Pro Leu Ser Ile Arg Gly Ser Leu Phe Ser
530 535 540
Ala Arg Arg Ser Ser Arg Thr Ser Leu Phe Ser Phe Lys Gly Arg Gly
545 550 555 560
Arg Asp Leu Gly Ser Glu Thr Glu Phe Ala Asp Asp Glu His Ser Ile
565 570 575
Phe Gly Asp Asn Glu Ser Arg Arg Gly Ser Leu Phe Val Pro His Arg
580 585 590
Pro Arg Glu Arg Arg Ser Ser Asn Ile Ser Gln Ala Ser Arg Ser Pro
595 600 605
Pro Val Leu Pro Val Asn Gly Lys Met His Ser Ala Val Asp Cys Asn
610 615 620
Gly Val Val Ser Leu Val Asp Gly Pro Ser Ala Leu Met Leu Pro Asn
625 630 635 640
Gly Gln Leu Leu Pro Glu Val Ile Ile Asp Lys Ala Thr Ser Asp Asp
645 650 655
Ser Gly Thr Thr Asn Gln Met Arg Lys Lys Arg Leu Ser Ser Ser Tyr
660 665 670
Phe Leu Ser Glu Asp Met Leu Asn Asp Pro His Leu Arg Gln Arg Ala
675 680 685
Met Ser Arg Ala Ser Ile Leu Thr Asn Thr Val Glu Glu Leu Glu Glu
690 695 700
Ser Arg Gln Lys Cys Pro Pro Trp Trp Tyr Arg Phe Ala His Thr Phe
705 710 715 720
Leu Ile Trp Asn Cys Ser Pro Tyr Trp Ile Lys Phe Lys Lys Phe Ile
725 730 735
Tyr Phe Ile Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile Cys
740 745 750
Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His His Pro Met Thr
755 760 765
Asp Glu Phe Lys Asn Val Leu Ala Val Gly Asn Leu Val Phe Thr Gly
770 775 780
Ile Phe Ala Ala Glu Met Val Leu Lys Leu Ile Ala Met Asp Pro Tyr
785 790 795 800
Glu Tyr Phe Gln Val Gly Trp Asn Ile Phe Asp Ser Leu Ile Val Thr
805 810 815
Leu Ser Leu Val Glu Leu Phe Leu Ala Asp Val Glu Gly Leu Ser Val
820 825 830
Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser Trp
835 840 845
Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly Ala
850 855 860
Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe Ala
865 870 875 880
Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val Cys
885 890 895
Lys Ile Asn Glu Asn Cys Lys Leu Pro Arg Trp His Met Asn Asp Phe
900 905 910
Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp Ile
915 920 925
Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Thr Met Cys Leu
930 935 940
Ile Val Tyr Met Met Val Met Val Ile Gly Asn Leu Val Val Leu Asn
945 950 955 960
Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu Thr
965 970 975
Ala Ile Glu Glu Asp Thr Asp Ala Asn Asn Leu Gln Ile Ala Val Ala
980 985 990
Arg Ile Lys Arg Gly Ile Asn Tyr Val Lys Gln Thr Leu Arg Glu Phe
995 1000 1005
Ile Leu Lys Ser Phe Ser Lys Lys Pro Lys Gly Ser Lys Asp Thr
1010 1015 1020
Lys Arg Thr Ala Asp Pro Asn Asn Lys Arg Glu Asn Tyr Ile Ser
1025 1030 1035
Asn Arg Thr Leu Ala Glu Ile Ser Lys Asp His Asn Phe Leu Lys
1040 1045 1050
Glu Lys Asp Lys Ile Ser Gly Phe Ser Ser Ser Leu Asp Lys Ser
1055 1060 1065
Phe Met Asp Glu Asn Asp Tyr Gln Ser Phe Ile His Asn Pro Ser
1070 1075 1080
Leu Thr Val Thr Val Pro Ile Ala Pro Gly Glu Ser Asp Leu Glu
1085 1090 1095
Asn Met Asn Thr Glu Glu Leu Ser Ser Asp Ser Asp Ser Asp Tyr
1100 1105 1110
Ser Lys Glu Arg Arg Asn Arg Ser Ser Ser Ser Glu Cys Ser Thr
1115 1120 1125
Val Asp Asn Pro Leu Pro Gly Glu Glu Glu Ala Glu Ala Glu Pro
1130 1135 1140
Ile Asn Ala Asp Glu Pro Glu Ala Cys Phe Thr Asp Gly Cys Val
1145 1150 1155
Arg Arg Phe Pro Cys Cys Gln Val Asn Ile Asp Ser Gly Lys Gly
1160 1165 1170
Lys Val Trp Trp Thr Ile Arg Lys Thr Cys Tyr Arg Ile Val Glu
1175 1180 1185
His Ser Trp Phe Glu Ser Phe Ile Val Leu Met Ile Leu Leu Ser
1190 1195 1200
Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile Glu Lys Lys Lys
1205 1210 1215
Thr Ile Lys Ile Ile Leu Glu Tyr Ala Asp Lys Ile Phe Thr Tyr
1220 1225 1230
Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Val Ala Tyr Gly Tyr
1235 1240 1245
Lys Thr Tyr Phe Thr Asn Ala Trp Cys Trp Leu Asp Phe Leu Ile
1250 1255 1260
Val Asp Val Ser Leu Val Thr Leu Val Ala Asn Thr Leu Gly Tyr
1265 1270 1275
Ser Asp Leu Gly Pro Ile Lys Ser Leu Arg Thr Leu Arg Ala Leu
1280 1285 1290
Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly Met Arg Val Val
1295 1300 1305
Val Asn Ala Leu Ile Gly Ala Ile Pro Ser Ile Met Asn Val Leu
1310 1315 1320
Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile Met Gly Val
1325 1330 1335
Asn Leu Phe Ala Gly Lys Phe Tyr Glu Cys Val Asn Thr Thr Asp
1340 1345 1350
Gly Ser Arg Phe Ser Val Ser Gln Val Ala Asn Arg Ser Glu Cys
1355 1360 1365
Phe Ala Leu Met Asn Val Ser Gly Asn Val Arg Trp Lys Asn Leu
1370 1375 1380
Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr Leu Ser Leu Leu
1385 1390 1395
Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile Met Tyr Ala Ala
1400 1405 1410
Val Asp Ser Val Asn Val Asn Ala Gln Pro Ile Tyr Glu Tyr Asn
1415 1420 1425
Leu Tyr Met Tyr Ile Tyr Phe Val Ile Phe Ile Ile Phe Gly Ser
1430 1435 1440
Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile Ile Asp Asn Phe
1445 1450 1455
Asn Gln Gln Lys Lys Lys Leu Gly Gly Gln Asp Ile Phe Met Thr
1460 1465 1470
Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys Leu Gly Ser
1475 1480 1485
Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Gly Asn Lys Phe Gln
1490 1495 1500
Gly Cys Ile Phe Asp Leu Val Thr Asn Gln Ala Phe Asp Ile Thr
1505 1510 1515
Ile Met Val Leu Ile Cys Leu Asn Met Val Thr Met Met Val Glu
1520 1525 1530
Lys Glu Gly Gln Thr Asp Tyr Met Ser Phe Val Leu Tyr Trp Ile
1535 1540 1545
Asn Val Val Phe Ile Ile Leu Phe Thr Gly Glu Cys Val Leu Lys
1550 1555 1560
Leu Ile Ser Leu Arg His Tyr Tyr Phe Thr Val Gly Trp Asn Ile
1565 1570 1575
Phe Asp Phe Val Val Val Ile Leu Ser Ile Val Gly Met Phe Leu
1580 1585 1590
Ala Glu Met Ile Glu Lys Tyr Phe Val Ser Pro Thr Leu Phe Arg
1595 1600 1605
Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg Leu Ile Lys
1610 1615 1620
Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu Met Met Ser
1625 1630 1635
Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu Phe Leu Val Met
1640 1645 1650
Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe Ala Tyr Val Lys
1655 1660 1665
Lys Glu Ala Gly Ile Asn Asp Met Phe Asn Phe Glu Thr Phe Gly
1670 1675 1680
Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr Ser Ala Gly Trp
1685 1690 1695
Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Ala Pro Pro Asp Cys
1700 1705 1710
Asp Pro Lys Lys Val His Pro Gly Ser Ser Val Glu Gly Asp Cys
1715 1720 1725
Gly Asn Pro Ser Val Gly Ile Phe Tyr Phe Val Ser Tyr Ile Ile
1730 1735 1740
Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile Ala Val Ile Leu
1745 1750 1755
Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Thr Glu Pro Leu Ser
1760 1765 1770
Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp Glu Lys Phe Asp
1775 1780 1785
Pro Asp Ala Thr Gln Phe Ile Glu Phe Cys Lys Leu Ser Asp Phe
1790 1795 1800
Ala Ala Ala Leu Asp Pro Pro Leu Leu Ile Ala Lys Pro Asn Lys
1805 1810 1815
Val Gln Leu Ile Ala Met Asp Leu Pro Met Val Ser Gly Asp Arg
1820 1825 1830
Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr Lys Arg Val Leu
1835 1840 1845
Gly Glu Ser Gly Glu Met Asp Ser Leu Arg Ser Gln Met Glu Glu
1850 1855 1860
Arg Phe Met Ser Ala Asn Pro Ser Lys Val Ser Tyr Glu Pro Ile
1865 1870 1875
Thr Thr Thr Leu Lys Arg Lys Gln Glu Asp Val Ser Ala Thr Ile
1880 1885 1890
Ile Gln Arg Ala Tyr Arg Arg Tyr Arg Leu Arg Gln Asn Val Lys
1895 1900 1905
Asn Ile Ser Ser Ile Tyr Ile Lys Asp Gly Asp Arg Asp Asp Asp
1910 1915 1920
Leu Pro Asn Lys Glu Asp Ile Val Phe Asp Asn Val Asn Glu Asn
1925 1930 1935
Ser Ser Pro Glu Lys Thr Asp Ala Thr Ala Ser Thr Ile Ser Pro
1940 1945 1950
Pro Ser Tyr Asp Ser Val Thr Lys Pro Asp Gln Glu Lys Tyr Glu
1955 1960 1965
Thr Asp Lys Thr Glu Lys Glu Asp Lys Glu Lys Asp Glu Ser Arg
1970 1975 1980
Lys
<210> 3
<211> 8876
<212> DNA
<213> 智人
<400> 3
ggctgcttca gacatatgtc tgtgtgtacg ctgtgaaggt gtttctcttc acagttcccc 60
gccctctagt ggtagttaca ataatgccat tttgtagtcc ctgtacagga aatgcctctt 120
cttacttcag ttaccagaat ccttttacag gaagttaggt gtggtctttg aaggagaatt 180
aaaaaaaaaa aaaaaaaaaa aaaaaaaaga tttttttttt tttaaagcat gatggaattt 240
tagctgcagt cttcttggtg ccagcttatc aatcccaaac tctgggtgta aaagattcta 300
cagggcactt tcttatgcaa ggagctaaac agtgattaaa ggagcaggat gaaaagatgg 360
cacagtcagt gctggtaccg ccaggacctg acagcttccg cttctttacc agggaatccc 420
ttgctgctat tgaacaacgc attgcagaag agaaagctaa gagacccaaa caggaacgca 480
aggatgagga tgatgaaaat ggcccaaagc caaacagtga cttggaagca ggaaaatctc 540
ttccatttat ttatggagac attcctccag agatggtgtc agtgcccctg gaggatctgg 600
acccctacta tatcaataag aaaacgttta tagtattgaa taaagggaaa gcaatctctc 660
gattcagtgc cacccctgcc ctttacattt taactccctt caaccctatt agaaaattag 720
ctattaagat tttggtacat tctttattca atatgctcat tatgtgcacg attcttacca 780
actgtgtatt tatgaccatg agtaaccctc cagactggac aaagaatgtg gagtatacct 840
ttacaggaat ttatactttt gaatcactta ttaaaatact tgcaaggggc ttttgtttag 900
aagatttcac atttttacgg gatccatgga attggttgga tttcacagtc attacttttg 960
catatgtgac agagtttgtg gacctgggca atgtctcagc gttgagaaca ttcagagttc 1020
tccgagcatt gaaaacaatt tcagtcattc caggcctgaa gaccattgtg ggggccctga 1080
tccagtcagt gaagaagctt tctgatgtca tgatcttgac tgtgttctgt ctaagcgtgt 1140
ttgcgctaat aggattgcag ttgttcatgg gcaacctacg aaataaatgt ttgcaatggc 1200
ctccagataa ttcttccttt gaaataaata tcacttcctt ctttaacaat tcattggatg 1260
ggaatggtac tactttcaat aggacagtga gcatatttaa ctgggatgaa tatattgagg 1320
ataaaagtca cttttatttt ttagaggggc aaaatgatgc tctgctttgt ggcaacagct 1380
cagatgcagg ccagtgtcct gaaggataca tctgtgtgaa ggctggtaga aaccccaact 1440
atggctacac gagctttgac acctttagtt gggccttttt gtccttattt cgtctcatga 1500
ctcaagactt ctgggaaaac ctttatcaac tgacactacg tgctgctggg aaaacgtaca 1560
tgatattttt tgtgctggtc attttcttgg gctcattcta tctaataaat ttgatcttgg 1620
ctgtggtggc catggcctat gaggaacaga atcaggccac attggaagag gctgaacaga 1680
aggaagctga atttcagcag atgctcgaac agttgaaaaa gcaacaagaa gaagctcagg 1740
cggcagctgc agccgcatct gctgaatcaa gagacttcag tggtgctggt gggataggag 1800
ttttttcaga gagttcttca gtagcatcta agttgagctc caaaagtgaa aaagagctga 1860
aaaacagaag aaagaaaaag aaacagaaag aacagtctgg agaagaagag aaaaatgaca 1920
gagtccgaaa atcggaatct gaagacagca taagaagaaa aggtttccgt ttttccttgg 1980
aaggaagtag gctgacatat gaaaagagat tttcttctcc acaccagtcc ttactgagca 2040
tccgtggctc ccttttctct ccaagacgca acagtagggc gagccttttc agcttcagag 2100
gtcgagcaaa ggacattggc tctgagaatg actttgctga tgatgagcac agcacctttg 2160
aggacaatga cagccgaaga gactctctgt tcgtgccgca cagacatgga gaacggcgcc 2220
acagcaatgt cagccaggcc agccgtgcct ccagggtgct ccccatcctg cccatgaatg 2280
ggaagatgca tagcgctgtg gactgcaatg gtgtggtctc cctggtcggg ggcccttcta 2340
ccctcacatc tgctgggcag ctcctaccag agggcacaac tactgaaaca gaaataagaa 2400
agagacggtc cagttcttat catgtttcca tggatttatt ggaagatcct acatcaaggc 2460
aaagagcaat gagtatagcc agtattttga ccaacaccat ggaagaactt gaagaatcca 2520
gacagaaatg cccaccatgc tggtataaat ttgctaatat gtgtttgatt tgggactgtt 2580
gtaaaccatg gttaaaggtg aaacaccttg tcaacctggt tgtaatggac ccatttgttg 2640
acctggccat caccatctgc attgtcttaa atacactctt catggctatg gagcactatc 2700
ccatgacgga gcagttcagc agtgtactgt ctgttggaaa cctggtcttc acagggatct 2760
tcacagcaga aatgtttctc aagataattg ccatggatcc atattattac tttcaagaag 2820
gctggaatat ttttgatggt tttattgtga gccttagttt aatggaactt ggtttggcaa 2880
atgtggaagg attgtcagtt ctccgatcat tccggctgct ccgagttttc aagttggcaa 2940
aatcttggcc aactctaaat atgctaatta agatcattgg caattctgtg ggggctctag 3000
gaaacctcac cttggtattg gccatcatcg tcttcatttt tgctgtggtc ggcatgcagc 3060
tctttggtaa gagctacaaa gaatgtgtct gcaagatttc caatgattgt gaactcccac 3120
gctggcacat gcatgacttt ttccactcct tcctgatcgt gttccgcgtg ctgtgtggag 3180
agtggataga gaccatgtgg gactgtatgg aggtcgctgg ccaaaccatg tgccttactg 3240
tcttcatgat ggtcatggtg attggaaatc tagtggttct gaacctcttc ttggccttgc 3300
ttttgagttc cttcagttct gacaatcttg ctgccactga tgatgataac gaaatgaata 3360
atctccagat tgctgtggga aggatgcaga aaggaatcga ttttgttaaa agaaaaatac 3420
gtgaatttat tcagaaagcc tttgttagga agcagaaagc tttagatgaa attaaaccgc 3480
ttgaagatct aaataataaa aaagacagct gtatttccaa ccataccacc atagaaatag 3540
gcaaagacct caattatctc aaagacggaa atggaactac tagtggcata ggcagcagtg 3600
tagaaaaata tgtcgtggat gaaagtgatt acatgtcatt tataaacaac cctagcctca 3660
ctgtgacagt accaattgct gttggagaat ctgactttga aaatttaaat actgaagaat 3720
tcagcagcga gtcagatatg gaggaaagca aagagaagct aaatgcaact agttcatctg 3780
aaggcagcac ggttgatatt ggagctcccg ccgagggaga acagcctgag gttgaacctg 3840
aggaatccct tgaacctgaa gcctgtttta cagaagactg tgtacggaag ttcaagtgtt 3900
gtcagataag catagaagaa ggcaaaggga aactctggtg gaatttgagg aaaacatgct 3960
ataagatagt ggagcacaat tggttcgaaa ccttcattgt cttcatgatt ctgctgagca 4020
gtggggctct ggcctttgaa gatatataca ttgagcagcg aaaaaccatt aagaccatgt 4080
tagaatatgc tgacaaggtt ttcacttaca tattcattct ggaaatgctg ctaaagtggg 4140
ttgcatatgg ttttcaagtg tattttacca atgcctggtg ctggctagac ttcctgattg 4200
ttgatgtctc actggttagc ttaactgcaa atgccttggg ttactcagaa cttggtgcca 4260
tcaaatccct cagaacacta agagctctga ggccactgag agctttgtcc cggtttgaag 4320
gaatgagggt tgttgtaaat gctcttttag gagccattcc atctatcatg aatgtacttc 4380
tggtttgtct gatcttttgg ctaatattca gtatcatggg agtgaatctc tttgctggca 4440
agttttacca ttgtattaat tacaccactg gagagatgtt tgatgtaagc gtggtcaaca 4500
actacagtga gtgcaaagct ctcattgaga gcaatcaaac tgccaggtgg aaaaatgtga 4560
aagtaaactt tgataacgta ggacttggat atctgtctct acttcaagta gccacgttta 4620
agggatggat ggatattatg tatgcagctg ttgattcacg aaatgtagaa ttacaaccca 4680
agtatgaaga caacctgtac atgtatcttt attttgtcat ctttattatt tttggttcat 4740
tctttacctt gaatcttttc attggtgtca tcatagataa cttcaaccaa cagaaaaaga 4800
agtttggagg tcaagacatt tttatgacag aagaacagaa gaaatactac aatgcaatga 4860
aaaaactggg ttcaaagaaa ccacaaaaac ccatacctcg acctgctaac aaattccaag 4920
gaatggtctt tgattttgta accaaacaag tctttgatat cagcatcatg atcctcatct 4980
gccttaacat ggtcaccatg atggtggaaa ccgatgacca gagtcaagaa atgacaaaca 5040
ttctgtactg gattaatctg gtgtttattg ttctgttcac tggagaatgt gtgctgaaac 5100
tgatctctct tcgttactac tatttcacta ttggatggaa tatttttgat tttgtggtgg 5160
tcattctctc cattgtagga atgtttctgg ctgaactgat agaaaagtat tttgtgtccc 5220
ctaccctgtt ccgagtgatc cgtcttgcca ggattggccg aatcctacgt ctgatcaaag 5280
gagcaaaggg gatccgcacg ctgctctttg ctttgatgat gtcccttcct gcgttgttta 5340
acatcggcct ccttcttttc ctggtcatgt tcatctacgc catctttggg atgtccaatt 5400
ttgcctatgt taagagggaa gttgggatcg atgacatgtt caactttgag acctttggca 5460
acagcatgat ctgcctgttc caaattacaa cctctgctgg ctgggatgga ttgctagcac 5520
ctattcttaa tagtggacct ccagactgtg accctgacaa agatcaccct ggaagctcag 5580
ttaaaggaga ctgtgggaac ccatctgttg ggattttctt ttttgtcagt tacatcatca 5640
tatccttcct ggttgtggtg aacatgtaca tcgcggtcat cctggagaac ttcagtgttg 5700
ctactgaaga aagtgcagag cctctgagtg aggatgactt tgagatgttc tatgaggttt 5760
gggagaagtt tgatcccgat gcgacccagt ttatagagtt tgccaaactt tctgattttg 5820
cagatgccct ggatcctcct cttctcatag caaaacccaa caaagtccag ctcattgcca 5880
tggatctgcc catggtgagt ggtgaccgga tccactgtct tgacatctta tttgctttta 5940
caaagcgtgt tttgggtgag agtggagaga tggatgccct tcgaatacag atggaagagc 6000
gattcatggc atcaaacccc tccaaagtct cttatgagcc cattacgacc acgttgaaac 6060
gcaaacaaga ggaggtgtct gctattatta tccagagggc ttacagacgc tacctcttga 6120
agcaaaaagt taaaaaggta tcaagtatat acaagaaaga caaaggcaaa gaatgtgatg 6180
gaacacccat caaagaagat actctcattg ataaactgaa tgagaattca actccagaga 6240
aaaccgatat gacgccttcc accacgtctc caccctcgta tgatagtgtg accaaaccag 6300
aaaaagaaaa atttgaaaaa gacaaatcag aaaaggaaga caaagggaaa gatatcaggg 6360
aaagtaaaaa gtaaaaagaa accaagaatt ttccattttg tgatcaattg tttacagccc 6420
gtgatggtga tgtgtttgtg tcaacaggac tcccacagga ggtctatgcc aaactgactg 6480
tttttacaaa tgtatactta aggtcagtgc ctataacaag acagagacct ctggtcagca 6540
aactggaact cagtaaactg gagaaatagt atcgatggga ggtttctatt ttcacaacca 6600
gctgacactg ctgaagagca gaggcgtaat ggctactcag acgataggaa ccaatttaaa 6660
ggggggaggg aagttaaatt tttatgtaaa ttcaacatgt gacacttgat aatagtaatt 6720
gtcaccagtg tttatgtttt aactgccaca cctgccatat ttttacaaaa cgtgtgctgt 6780
gaatttatca cttttctttt taattcacag gttgtttact attatatgtg actatttttg 6840
taaatgggtt tgtgtttggg gagagggatt aaagggaggg aattctacat ttctctattg 6900
tattgtataa ctggatatat tttaaatgga ggcatgctgc aattctcatt cacacataaa 6960
aaaatcacat cacaaaaggg aagagtttac ttcttgtttc aggatgtttt tagatttttg 7020
aggtgcttaa atagctattc gtatttttaa ggtgtctcat ccagaaaaaa tttaatgtgc 7080
ctgtaaatgt tccatagaat cacaagcatt aaagagttgt tttattttta cataacccat 7140
taaatgtaca tgtatatatg tatatatgta tatgtgcgtg tatatacata tatatgtata 7200
cacacatgca cacacagaga tatacacata ccattacatt gtcattcaca gtcccagcag 7260
catgactatc acatttttga taagtgtcct ttggcataaa ataaaaatat cctatcagtc 7320
ctttctaaga agcctgaatt gaccaaaaaa catccccacc accactttat aaagttgatt 7380
ctgctttatc ctgcagtatt gtttagccat cttctgctct tggtaaggtt gacatagtat 7440
atgtcaattt aaaaaataaa agtctgcttt gtaaatagta attttaccca gtggtgcatg 7500
tttgagcaaa caaaaatgat gatttaagca cactacttat tgcatcaaat atgtaccaca 7560
gtaagtatag tttgcaagct ttcaacaggt aatatgatgt aattggttcc attatagttt 7620
gaagctgtca ctgctgcatg tttatcttgc ctatgctgct gtatcttatt ccttccactg 7680
ttcagaagtc taatatggga agccatatat cagtggtaaa gtgaagcaaa ttgttctacc 7740
aagacctcat tcttcatgtc attaagcaat aggttgcagc aaacaaggaa gagcttcttg 7800
ctttttattc ttccaacctt aattgaacac tcaatgatga aaagcccgac tgtacaaaca 7860
tgttgcaagc tgcttaaatc tgtttaaaat atatggttag agttttctaa gaaaatataa 7920
atactgtaaa aagttcattt tattttattt ttcagccttt tgtacgtaaa atgagaaatt 7980
aaaagtatct tcaggtggat gtcacagtca ctattgttag tttctgttcc tagcactttt 8040
aaattgaagc acttcacaaa ataagaagca aggactagga tgcagtgtag gtttctgctt 8100
ttttattagt actgtaaact tgcacacatt tcaatgtgaa acaaatctca aactgagttc 8160
aatgtttatt tgctttcaat agtaatgcct tatcattgaa agaggcttaa agaaaaaaaa 8220
aatcagctga tactcttggc attgcttgaa tccaatgttt ccacctagtc tttttattca 8280
gtaatcatca gtcttttcca atgtttgttt acacagatag atcttattga cccatatggc 8340
actagaactg tatcagatat aatatgggat cccagctttt tttcctctcc cacaaaacca 8400
ggtagtgaag ttatattacc agttacagca aaatactttg tgtttcacaa gcaacaataa 8460
atgtagattc tttatactga agctattgac ttgtagtgtg ttggtgaaat gcatgcagga 8520
aaatgctgtt accataaaga acggtaaacc acattacaat caagccaaaa gaataaaggt 8580
ttcgcttttg tttttgtatt taattgttgt ctttgtttct atctttgaaa tgccatttaa 8640
aggtagattt ctatcatgta aaaataatct atctgaaaaa caaatgtaaa gaacacacat 8700
taattactat aattcatctt tcaatttttt catggaatgg aagttaatta agaagagtgt 8760
attggataac tactttaata ttggccaaaa agctagatat ggcatcaggt agactagtgg 8820
aaagttacaa aaattaataa aaaattgact aacattttaa aaaaaaaaaa aaaaaa 8876
<210> 4
<211> 2005
<212> PRT
<213> 智人
<400> 4
Met Ala Gln Ser Val Leu Val Pro Pro Gly Pro Asp Ser Phe Arg Phe
1 5 10 15
Phe Thr Arg Glu Ser Leu Ala Ala Ile Glu Gln Arg Ile Ala Glu Glu
20 25 30
Lys Ala Lys Arg Pro Lys Gln Glu Arg Lys Asp Glu Asp Asp Glu Asn
35 40 45
Gly Pro Lys Pro Asn Ser Asp Leu Glu Ala Gly Lys Ser Leu Pro Phe
50 55 60
Ile Tyr Gly Asp Ile Pro Pro Glu Met Val Ser Val Pro Leu Glu Asp
65 70 75 80
Leu Asp Pro Tyr Tyr Ile Asn Lys Lys Thr Phe Ile Val Leu Asn Lys
85 90 95
Gly Lys Ala Ile Ser Arg Phe Ser Ala Thr Pro Ala Leu Tyr Ile Leu
100 105 110
Thr Pro Phe Asn Pro Ile Arg Lys Leu Ala Ile Lys Ile Leu Val His
115 120 125
Ser Leu Phe Asn Met Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Val
130 135 140
Phe Met Thr Met Ser Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr
145 150 155 160
Thr Phe Thr Gly Ile Tyr Thr Phe Glu Ser Leu Ile Lys Ile Leu Ala
165 170 175
Arg Gly Phe Cys Leu Glu Asp Phe Thr Phe Leu Arg Asp Pro Trp Asn
180 185 190
Trp Leu Asp Phe Thr Val Ile Thr Phe Ala Tyr Val Thr Glu Phe Val
195 200 205
Asp Leu Gly Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala
210 215 220
Leu Lys Thr Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala
225 230 235 240
Leu Ile Gln Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val
245 250 255
Phe Cys Leu Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly
260 265 270
Asn Leu Arg Asn Lys Cys Leu Gln Trp Pro Pro Asp Asn Ser Ser Phe
275 280 285
Glu Ile Asn Ile Thr Ser Phe Phe Asn Asn Ser Leu Asp Gly Asn Gly
290 295 300
Thr Thr Phe Asn Arg Thr Val Ser Ile Phe Asn Trp Asp Glu Tyr Ile
305 310 315 320
Glu Asp Lys Ser His Phe Tyr Phe Leu Glu Gly Gln Asn Asp Ala Leu
325 330 335
Leu Cys Gly Asn Ser Ser Asp Ala Gly Gln Cys Pro Glu Gly Tyr Ile
340 345 350
Cys Val Lys Ala Gly Arg Asn Pro Asn Tyr Gly Tyr Thr Ser Phe Asp
355 360 365
Thr Phe Ser Trp Ala Phe Leu Ser Leu Phe Arg Leu Met Thr Gln Asp
370 375 380
Phe Trp Glu Asn Leu Tyr Gln Leu Thr Leu Arg Ala Ala Gly Lys Thr
385 390 395 400
Tyr Met Ile Phe Phe Val Leu Val Ile Phe Leu Gly Ser Phe Tyr Leu
405 410 415
Ile Asn Leu Ile Leu Ala Val Val Ala Met Ala Tyr Glu Glu Gln Asn
420 425 430
Gln Ala Thr Leu Glu Glu Ala Glu Gln Lys Glu Ala Glu Phe Gln Gln
435 440 445
Met Leu Glu Gln Leu Lys Lys Gln Gln Glu Glu Ala Gln Ala Ala Ala
450 455 460
Ala Ala Ala Ser Ala Glu Ser Arg Asp Phe Ser Gly Ala Gly Gly Ile
465 470 475 480
Gly Val Phe Ser Glu Ser Ser Ser Val Ala Ser Lys Leu Ser Ser Lys
485 490 495
Ser Glu Lys Glu Leu Lys Asn Arg Arg Lys Lys Lys Lys Gln Lys Glu
500 505 510
Gln Ser Gly Glu Glu Glu Lys Asn Asp Arg Val Arg Lys Ser Glu Ser
515 520 525
Glu Asp Ser Ile Arg Arg Lys Gly Phe Arg Phe Ser Leu Glu Gly Ser
530 535 540
Arg Leu Thr Tyr Glu Lys Arg Phe Ser Ser Pro His Gln Ser Leu Leu
545 550 555 560
Ser Ile Arg Gly Ser Leu Phe Ser Pro Arg Arg Asn Ser Arg Ala Ser
565 570 575
Leu Phe Ser Phe Arg Gly Arg Ala Lys Asp Ile Gly Ser Glu Asn Asp
580 585 590
Phe Ala Asp Asp Glu His Ser Thr Phe Glu Asp Asn Asp Ser Arg Arg
595 600 605
Asp Ser Leu Phe Val Pro His Arg His Gly Glu Arg Arg His Ser Asn
610 615 620
Val Ser Gln Ala Ser Arg Ala Ser Arg Val Leu Pro Ile Leu Pro Met
625 630 635 640
Asn Gly Lys Met His Ser Ala Val Asp Cys Asn Gly Val Val Ser Leu
645 650 655
Val Gly Gly Pro Ser Thr Leu Thr Ser Ala Gly Gln Leu Leu Pro Glu
660 665 670
Gly Thr Thr Thr Glu Thr Glu Ile Arg Lys Arg Arg Ser Ser Ser Tyr
675 680 685
His Val Ser Met Asp Leu Leu Glu Asp Pro Thr Ser Arg Gln Arg Ala
690 695 700
Met Ser Ile Ala Ser Ile Leu Thr Asn Thr Met Glu Glu Leu Glu Glu
705 710 715 720
Ser Arg Gln Lys Cys Pro Pro Cys Trp Tyr Lys Phe Ala Asn Met Cys
725 730 735
Leu Ile Trp Asp Cys Cys Lys Pro Trp Leu Lys Val Lys His Leu Val
740 745 750
Asn Leu Val Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile Cys
755 760 765
Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His Tyr Pro Met Thr
770 775 780
Glu Gln Phe Ser Ser Val Leu Ser Val Gly Asn Leu Val Phe Thr Gly
785 790 795 800
Ile Phe Thr Ala Glu Met Phe Leu Lys Ile Ile Ala Met Asp Pro Tyr
805 810 815
Tyr Tyr Phe Gln Glu Gly Trp Asn Ile Phe Asp Gly Phe Ile Val Ser
820 825 830
Leu Ser Leu Met Glu Leu Gly Leu Ala Asn Val Glu Gly Leu Ser Val
835 840 845
Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser Trp
850 855 860
Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly Ala
865 870 875 880
Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe Ala
885 890 895
Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val Cys
900 905 910
Lys Ile Ser Asn Asp Cys Glu Leu Pro Arg Trp His Met His Asp Phe
915 920 925
Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp Ile
930 935 940
Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Thr Met Cys Leu
945 950 955 960
Thr Val Phe Met Met Val Met Val Ile Gly Asn Leu Val Val Leu Asn
965 970 975
Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu Ala
980 985 990
Ala Thr Asp Asp Asp Asn Glu Met Asn Asn Leu Gln Ile Ala Val Gly
995 1000 1005
Arg Met Gln Lys Gly Ile Asp Phe Val Lys Arg Lys Ile Arg Glu
1010 1015 1020
Phe Ile Gln Lys Ala Phe Val Arg Lys Gln Lys Ala Leu Asp Glu
1025 1030 1035
Ile Lys Pro Leu Glu Asp Leu Asn Asn Lys Lys Asp Ser Cys Ile
1040 1045 1050
Ser Asn His Thr Thr Ile Glu Ile Gly Lys Asp Leu Asn Tyr Leu
1055 1060 1065
Lys Asp Gly Asn Gly Thr Thr Ser Gly Ile Gly Ser Ser Val Glu
1070 1075 1080
Lys Tyr Val Val Asp Glu Ser Asp Tyr Met Ser Phe Ile Asn Asn
1085 1090 1095
Pro Ser Leu Thr Val Thr Val Pro Ile Ala Val Gly Glu Ser Asp
1100 1105 1110
Phe Glu Asn Leu Asn Thr Glu Glu Phe Ser Ser Glu Ser Asp Met
1115 1120 1125
Glu Glu Ser Lys Glu Lys Leu Asn Ala Thr Ser Ser Ser Glu Gly
1130 1135 1140
Ser Thr Val Asp Ile Gly Ala Pro Ala Glu Gly Glu Gln Pro Glu
1145 1150 1155
Val Glu Pro Glu Glu Ser Leu Glu Pro Glu Ala Cys Phe Thr Glu
1160 1165 1170
Asp Cys Val Arg Lys Phe Lys Cys Cys Gln Ile Ser Ile Glu Glu
1175 1180 1185
Gly Lys Gly Lys Leu Trp Trp Asn Leu Arg Lys Thr Cys Tyr Lys
1190 1195 1200
Ile Val Glu His Asn Trp Phe Glu Thr Phe Ile Val Phe Met Ile
1205 1210 1215
Leu Leu Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile Glu
1220 1225 1230
Gln Arg Lys Thr Ile Lys Thr Met Leu Glu Tyr Ala Asp Lys Val
1235 1240 1245
Phe Thr Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Val Ala
1250 1255 1260
Tyr Gly Phe Gln Val Tyr Phe Thr Asn Ala Trp Cys Trp Leu Asp
1265 1270 1275
Phe Leu Ile Val Asp Val Ser Leu Val Ser Leu Thr Ala Asn Ala
1280 1285 1290
Leu Gly Tyr Ser Glu Leu Gly Ala Ile Lys Ser Leu Arg Thr Leu
1295 1300 1305
Arg Ala Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly Met
1310 1315 1320
Arg Val Val Val Asn Ala Leu Leu Gly Ala Ile Pro Ser Ile Met
1325 1330 1335
Asn Val Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile
1340 1345 1350
Met Gly Val Asn Leu Phe Ala Gly Lys Phe Tyr His Cys Ile Asn
1355 1360 1365
Tyr Thr Thr Gly Glu Met Phe Asp Val Ser Val Val Asn Asn Tyr
1370 1375 1380
Ser Glu Cys Lys Ala Leu Ile Glu Ser Asn Gln Thr Ala Arg Trp
1385 1390 1395
Lys Asn Val Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr Leu
1400 1405 1410
Ser Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile Met
1415 1420 1425
Tyr Ala Ala Val Asp Ser Arg Asn Val Glu Leu Gln Pro Lys Tyr
1430 1435 1440
Glu Asp Asn Leu Tyr Met Tyr Leu Tyr Phe Val Ile Phe Ile Ile
1445 1450 1455
Phe Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile Ile
1460 1465 1470
Asp Asn Phe Asn Gln Gln Lys Lys Lys Phe Gly Gly Gln Asp Ile
1475 1480 1485
Phe Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys
1490 1495 1500
Leu Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Ala Asn
1505 1510 1515
Lys Phe Gln Gly Met Val Phe Asp Phe Val Thr Lys Gln Val Phe
1520 1525 1530
Asp Ile Ser Ile Met Ile Leu Ile Cys Leu Asn Met Val Thr Met
1535 1540 1545
Met Val Glu Thr Asp Asp Gln Ser Gln Glu Met Thr Asn Ile Leu
1550 1555 1560
Tyr Trp Ile Asn Leu Val Phe Ile Val Leu Phe Thr Gly Glu Cys
1565 1570 1575
Val Leu Lys Leu Ile Ser Leu Arg Tyr Tyr Tyr Phe Thr Ile Gly
1580 1585 1590
Trp Asn Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile Val Gly
1595 1600 1605
Met Phe Leu Ala Glu Leu Ile Glu Lys Tyr Phe Val Ser Pro Thr
1610 1615 1620
Leu Phe Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg
1625 1630 1635
Leu Ile Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu
1640 1645 1650
Met Met Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu Phe
1655 1660 1665
Leu Val Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe Ala
1670 1675 1680
Tyr Val Lys Arg Glu Val Gly Ile Asp Asp Met Phe Asn Phe Glu
1685 1690 1695
Thr Phe Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr Ser
1700 1705 1710
Ala Gly Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Gly Pro
1715 1720 1725
Pro Asp Cys Asp Pro Asp Lys Asp His Pro Gly Ser Ser Val Lys
1730 1735 1740
Gly Asp Cys Gly Asn Pro Ser Val Gly Ile Phe Phe Phe Val Ser
1745 1750 1755
Tyr Ile Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile Ala
1760 1765 1770
Val Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Ala Glu
1775 1780 1785
Pro Leu Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp Glu
1790 1795 1800
Lys Phe Asp Pro Asp Ala Thr Gln Phe Ile Glu Phe Ala Lys Leu
1805 1810 1815
Ser Asp Phe Ala Asp Ala Leu Asp Pro Pro Leu Leu Ile Ala Lys
1820 1825 1830
Pro Asn Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val Ser
1835 1840 1845
Gly Asp Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr Lys
1850 1855 1860
Arg Val Leu Gly Glu Ser Gly Glu Met Asp Ala Leu Arg Ile Gln
1865 1870 1875
Met Glu Glu Arg Phe Met Ala Ser Asn Pro Ser Lys Val Ser Tyr
1880 1885 1890
Glu Pro Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Glu Val Ser
1895 1900 1905
Ala Ile Ile Ile Gln Arg Ala Tyr Arg Arg Tyr Leu Leu Lys Gln
1910 1915 1920
Lys Val Lys Lys Val Ser Ser Ile Tyr Lys Lys Asp Lys Gly Lys
1925 1930 1935
Glu Cys Asp Gly Thr Pro Ile Lys Glu Asp Thr Leu Ile Asp Lys
1940 1945 1950
Leu Asn Glu Asn Ser Thr Pro Glu Lys Thr Asp Met Thr Pro Ser
1955 1960 1965
Thr Thr Ser Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Glu Lys
1970 1975 1980
Glu Lys Phe Glu Lys Asp Lys Ser Glu Lys Glu Asp Lys Gly Lys
1985 1990 1995
Asp Ile Arg Glu Ser Lys Lys
2000 2005
<210> 5
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 寡核苷酸引物
<400> 5
tctgggcagc tacttgtgg 19
<210> 6
<211> 28
<212> DNA
<213> 人工序列
<220>
<223> 寡核苷酸引物
<400> 6
aatacgttga gcacagaggt cagaagga 28
<210> 7
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 寡核苷酸引物
<400> 7
gttgctctgc tttcttgaac ctc 23
<210> 8
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 寡核苷酸引物
<400> 8
atgtcagcca atccttctaa agtg 24
<210> 9
<211> 25
<212> DNA
<213> 人工序列
<220>
<223> 寡核苷酸引物
<400> 9
tcctatgagc ccatcacaac cacac 25
<210> 10
<211> 25
<212> DNA
<213> 人工序列
<220>
<223> 寡核苷酸引物
<400> 10
tcctatgagc ccatcacaac cacac 25
<210> 11
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 寡核苷酸引物
<400> 11
gaccgtgtaa tggaccaatg atc 23
<210> 12
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 寡核苷酸引物
<400> 12
gaccgtgtaa tggaccaatg atc 23
<210> 13
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 寡核苷酸引物
<400> 13
caccagttct ctgcctgtct c 21
<210> 14
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 寡核苷酸引物
<400> 14
tcaggtggat gtcacagtca 20
<210> 15
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> 寡核苷酸引物
<400> 15
tctgttccta gcacttttaa attgaagcac 30
<210> 16
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 寡核苷酸引物
<400> 16
tgcatcctag tccttgcttc tta 23
<210> 17
<211> 100
<212> DNA
<213> 人工序列
<220>
<223> 寡核苷酸序列
<400> 17
tcttaggtaa ggatccgaag gggaaataaa acctacagga tgagaagcgt cgacgatggc 60
acagtcagtg ctggtaccgc caggacctga cagcttccgc 100
<210> 18
<211> 150
<212> DNA
<213> 人工序列
<220>
<223> 寡核苷酸序列
<400> 18
cagcctatag atcacttaga tttagatccc taaaatttgc tgtcactctg taaagtgcac 60
ctcgagataa cttcgtataa tgtatgctat acgaagttat atgcatgcca gtagcagcac 120
ccacgtccac cttctgtcta gtaatgtcca 150
<210> 19
<211> 200
<212> DNA
<213> 人工序列
<220>
<223> 寡核苷酸序列
<400> 19
catacacttc attctcagta ttgttttgcc aagttctaat tccatcagac ctcgacctgc 60
agcccctaga taacttcgta taatgtatgc tatacgaagt tatgctagta actataacgg 120
tcctaaggta gcgagctagc agcttcggtt ttgatacact gtttacagcc tgcgaaggtg 180
actcactcgt gttaataaga 200
<210> 20
<211> 101673
<212> DNA
<213> 智人
<400> 20
gcctcttagg taaggatccg aaggggaaat aaaacctaca ggatgagaag cgtcgacgat 60
ggcacagtca gtgctggtac cgccaggacc tgacagcttc cgcttcttta ccagggaatc 120
ccttgctgct attgaacaac gcattgcaga agagaaagct aagagaccca aacaggaacg 180
caaggatgag gatgatgaaa atggcccaaa gccaaacagt gacttggaag caggaaaatc 240
tcttccattt atttatggag acattcctcc agagatggtg tcagtgcccc tggaggatct 300
ggacccctac tatatcaata agaaagtgag ttcttagtca agttgccttc actgcctatt 360
tactaattgg ttctgggcta gtcccaggga tgatggtgaa gaaggctggc ctccttccct 420
ctgtctaaag tatcactaag atgctggatg ggcctgaccg tgtaatggac caatgatcct 480
agaagtcttt tggaagcact catttgaacc tgcatttgtg agacaggcag agaactggtg 540
aggcatcctc cagcgcggga attaaggaag gacaaaagcc tattcacctt cttgaataca 600
aattatatgc ttaaaccagt gtaaattgac cctgattccc taataatgtt gagaagcaaa 660
aactgtaaac taggagtcta tttaaatttt attttttata tttgcaggag tagtatctaa 720
attcctcttt atagtctcta gctctccata agtcactttg atcttcagtg ggtttaatta 780
ttcctttata ccatactttc tcctttctat tgctctccac agaaggaata atagcaggtg 840
acttgtaggt gccaaataag attctgagca aagaacacac ctggaaaacc ttgaagttct 900
catgagaaaa ttttctaacc aaaaaaaaaa atcaaagcct caattttgtg ctttatgtga 960
attataaatg cggttttaaa atacttacat taaaacttga taaagttgct aagaattcct 1020
atggcattga tcacaaattt tcttaataat cctcatgtca tttatcaaat ttaggaaagt 1080
ttatagtgct cagaaaaaaa aagcatctat cttcatgtca tatgatggta attattatgt 1140
tatacactat tttacagggc aatatttata aataatggtt ttacttttct cttaaaatat 1200
tcttaatata tattctaagt tttattttat gtgttgtgtt ttctttttca gacgtttata 1260
gtattgaata aagggaaagc aatctctcga ttcagtgcca cccctgccct ttacatttta 1320
actcccttca accctattag aaaattagct attaagattt tggtacattc atatcctttt 1380
tcaaatcgtc acttaatatg attttcttct ttgaccaagt tattgagcta cacattttcc 1440
aaaatatctg tggttggcaa tgttatgtgt tctttctttt tctttccttt tactcaatcg 1500
ttagcatgtt gcaaaatgag atcacaggta agtgaattac tttcccccgt cttctaagtg 1560
tttcttctct acccaactca ctattacttc tttcttctct tttcttctcc cttacgaatt 1620
gcttgccaca tcccaagcct ttctcattaa ttttgaccat gttaccaggc tttcctcctg 1680
taagtcttca atttacaatg ttaggtaagg gagtaaactc catgagctaa ttttctttac 1740
tgcttttaca tttggaaaat aaatatacat aatctgaatt acaattttgt atgtttttgg 1800
tctgaatttt atgactttct tctattttag catttaaaag ctttgagtta gtaagcgttt 1860
acaattgtgt ctgtaggtat aacacccttt caaatacttt tccaaatttg tttcgcaaca 1920
gccttcttat tgatcttttg ctttctattc ttttcctttc tttttctttt tatcacttgt 1980
tcctatgttt tattgaagtc acaagtcttg ctacaattat ccctctccaa aggattaatg 2040
tctatctatc catatacatt ctcattttat tttttatact ccttattgaa gcacctgctt 2100
tccaaaaatg agattgatga catcttggtg ggagatggca atttgattga ttccttgaaa 2160
ttaaatagag tagttggaaa tgagagattt tattctaggc cagaaacaag tcttgttgac 2220
agccagtctt gggaatgcca atgaagcaaa ggcttggaag actgaagctg tgtggggcag 2280
gggcatttac acgaagaaca cagaagtcat gggaggagga gtgatatgct tcaggaatca 2340
gaggtaaggc aggggaactg aaattaagca aatcctcaga ttaggacagc atgttatttc 2400
ttcttcagaa agaatcgttg cttggaattc catgatgtgg ttagcccagg gcctggtatt 2460
aaggctttca gtataaatat tctccacctt tagcaggcct agaaaatatt tgaattagat 2520
aaggtatgga actaaattaa gtagggaatt caggaaatgg gataagcctg gtacagggta 2580
cttatgtcat ttctgggtgg aggggatgta aagcatgtcc ctagacttgc ctcccagtat 2640
ggcaaatgtt gtctttagaa gtgtaacatt ctgtaaagtc tccttttaac ctctaggttg 2700
ttcctcttcc ccagtttagg tggatatcaa catcttttat ttgatgttta tgtttcatgt 2760
tttaagattt cctagtttct tggcattacc ttaagcaata atgttttctt acctctctct 2820
gttttccaaa taagagaacc cagtagcatg tggggaaaaa gatgtctttg agttagcatt 2880
agaaataaat aataaagttg gaatttatat ttgggtctca tgattataaa ttatgatcta 2940
ttattatgtt tcaagcattt gtaatctgtg cagtgaataa atctctgcat aaactattca 3000
ttatatttta aaataattgt atgttcctta tgcaaacgta atttatatat aaaattacgt 3060
ggaaaattct agcctagaac tagacttctg ttcctagtag acattgggaa aatattcatt 3120
aaataaataa gtgactagta agtcagagat tagagaatca gatacaaaaa aagtgaaaaa 3180
ataagtttga atggatcaga aaaaatcttt cttgtcgtgc atctgaatga tgagatggag 3240
ttaagaaaac ccaatatatt tgttttttac aaaagcagat ttttgtttta aaacttttgt 3300
aatagaccat ggaaaatctc atgaaaacta ttgtccccac ttgaaaaaaa aaatcctagg 3360
agattatgaa tccccattta aaactccctg gaaaagagac tcctggtggt agagggtaag 3420
ggcagtttaa gaaattctga tcagagaata tgagtactaa ggacacagtt tgtgccagga 3480
cctctctaga tatccagata caacttgaat ctgtgggctt gtatttgctt cctgggggaa 3540
agaactcacc ctccacaggc tgaagtcatt gggaggcctg aggagatgca ggttgaaatg 3600
tgaagccagc caggcaaatc tattaaggta tgccaagttg agctgttgat tctctgagaa 3660
gtttacagat ggcttagagt cacaaattta ttccaatgta gaaaattaga ttttaaaaag 3720
tctctaattt cctgacttaa agtgttatat ttcagatgtc tcaccttgga gcagagatat 3780
aacaaaaggc agtgaggcta atagtctaag atacatgaat ccttccatgt tttggtgatg 3840
ctggtgcaat tgatcaaata gcccagtaaa gttagaggta tatagatgct gtagttagta 3900
actgattttc acaataattt tgtcctttat tcctcttgtt gcaaacccta gacttaaatc 3960
ctgattttct gacttcaagt acagtgtctt ttactgtaag ttaaaaatgc ttggagagat 4020
ggtcatggtt gtttggccac agttgggagg tcattgtata tttattacca ctagtttata 4080
aaccaacaag gagccattca tgttaaataa gtttttattt taaacttgga ctaatacctc 4140
tatttcaaac aaaaaccttg acttgtttct caaagagctg ttatctatta ggagctattg 4200
tgtatcaaat tagctttttt aaaaatttat tttggctgaa tgagaaatta tgcttgtgat 4260
atttttacca gggtgcattc tgaaaactga aaattctttt gatgtgccta gtgtcttatt 4320
tgatatttaa ataaaacatg atttattttc tagataacaa acaagttaaa aataatctat 4380
gttcctaaag ttccctacca agcttttaaa tgtgtttcct gtcagctttt attattttaa 4440
gttaatatat gcacactcct ctaatttatt ttgcatttgt tactcatttg ttcatttgca 4500
agtacttact gagtatctac catgtggtag atattcttgt aagcattggg atgcaacatt 4560
gaacaaagtg aagttcctac tctcatgtag ttacattcat gtgagtgtgt gtgtgtgttt 4620
ggaagaagaa agacaataaa caaatacgtc gattgggagc tagtgataag tgttactaag 4680
aaatataaat tagtgtcaaa gggaggagtg acaaggtgtt gttttagatt gtatggccag 4740
taaaatcctt tctgaaaagg taccagttga gcagagatcc gaaggaagca aaagagtgag 4800
atatgggaat ctagggataa agtcagttca aggagaacag caagtatgaa ggtaaagtct 4860
gaaggtggtg gtgcaactag tatgtttaac aatcagcaag gagacctgag tggctggagc 4920
agagtgggaa aggcaggaag cgagaggatg acatcagtgg gagtgaaggt caggggctaa 4980
agttgtaggc gaggtgcagt gggtcattgt gaggacacca catttactct gaatgagact 5040
ccaggagggt tttcagtagc aggatatcat gacttgactc acatatttaa aagatcactc 5100
tggctgcttc atggagaata gactgcataa ggggaaagag tggaagcaag gagactggga 5160
ccgattgtca ttatgaaggc aagagagcat ggtggcttgg agtatggtgg aaacaatgag 5220
gatggtaaaa tgtcatcaaa ttttgaggta ttttgcagaa gagctgacag gatttgctga 5280
gcaattggtt gtggtgtata ggaggaaggc agggactaag gatgattcca agcatttagt 5340
ctggtcaaga aagaaaaatg gagttgtgtt gactgagctt ggggcaactt gagcaaacca 5400
atttggtggg taagatcaag atcttggttt tgaacatgtt atgtttgaga cacctattag 5460
acatcattgg aggagttgag gagttaggtg gctgtgcaaa tctggagttc agaaaagggc 5520
tgggctggag gtgttcaact ttgggagctg tcagtgtaca gctggtattt aaagtcatga 5580
cattggacta ggctgccaaa gagctgagac cctccctcca aatcacacta gtaatgctga 5640
actacctatc atttgaaaat ggtaggaaaa tggaaaacat aggttttggt atcagaaaac 5700
gtagattcaa accctatctc taaaatttac tttttagcta tatgatctta gtccaagtta 5760
ctccaattct ttcgaatctc agtttctcta tctgtaaaat tataatcaca gcttagacat 5820
taataatgat aaaatgtatg acaagtatct agcaccagat cccatgctag tacttagtag 5880
gtactcaata aaggatatct atgacagtaa tagctaaaat tctagcagca actgctgtaa 5940
gattagcaaa aaggaaactc tcatattcct taaggaattg cacaaagaac tttatagaaa 6000
tccctactct gactctgcaa acaaaatctt tatatagcac cagagtttag acctgcaact 6060
gacccaaaca atgtggtcag ttctgtctca ttttgtagat gagttcactg aaacccagag 6120
atatttagtt ttttctaagg ctacattttc tatcagtggc agagctaaaa cttcagacca 6180
ggttttttga ttcttggctc tttgcatttt gcatccaata gaaaacaaat gatttttaaa 6240
ccctcggatt taatatactt ggggcattgc cagtgttctt gttttatgca tttcaaaggt 6300
gcttcttagt tgctccaact tactgattca ttaaatagtg tccatactga gatataaaat 6360
atcatggttt tccatgaaaa gaaatataca ggtttatatg aaagcagatg acacaacaat 6420
ttctctttct tttgttttca atgctcatat gttatcattt agttatctac tggcaaatag 6480
gagtttgttc atattaaaat taaacaatcc aatatttaac actgtatatg tgacatttac 6540
tcgatttttc tgctggctca gaaatatgca ctggtatgca gaaaaagacc tattctattc 6600
tacttcaaat tatccatttt tacattagaa aacctctaac atcaggctat cttctacttc 6660
tagtttatat ataggttaaa aactcctctg caacttctct ggatattata cattattaca 6720
aagtctctga acagagcata atgtcttttc cttcctatag aataacaaag aaatgtccta 6780
taattttata ctctataaat gagttattaa tggtaagaaa ccaataatta ttatcttagt 6840
ggataatgac tgtatactgt aagaaaagta ttatccacat ttatataaga aaactgagcc 6900
tcaaagaatt aaacaaattg ctgaagccca catggctggt aagggatgta tctgaccatg 6960
gttcattgct ctaaatctca tggtgcttca tcctcgctcc acggagacag gggtgggtgt 7020
gccagtgtta tgatgatcca ggctccatgt caagggctac ttaaacaatt ttcactaaaa 7080
acttgaagaa gtgtttcttc ataatataca caaaggaaat attttacatt tgccaactcg 7140
caggttagta tcaatcaaca ggtttaccca ctgttatgta tacctggcat aaagaaatta 7200
atagattaaa aaacatcttt gtcccctgat attataaaag gtttatctgc ctctatttta 7260
ttttacattg aaaagttctt aaagcaatat tgttccagga tacagtgttc ttttgaaaaa 7320
tgtactctat gacttggatt acacatttaa aaaataatat aggatgtatg cattttgcta 7380
ctagtttgag ccttttgaaa tctgctttga cgtggggttt ctatactttt ttgatgcatg 7440
gcatcaccaa tgcaaaatcc atacctacat taaatacttt tgtatttgag tttttgttat 7500
ttgagttttt tttttttttt ttttttttga gacgggttct cgctctgtcg ccctggctgg 7560
agtgcagcag cgcaatctcg gctcactgca agctccgcct tccgggttca cgccattctc 7620
ctgcctcagc ctccggagta gctgggacta caggcgcccg ccaccacgcc cggctgattt 7680
tttgtaattt tagtagagac ggtatttcac cgtgttagcc agggtggtct cgatctcctg 7740
acctcgtgat ccgcccgcct cggcctccca aagtgctggg attacaggcg tgagccaccg 7800
cgcctggcca tatttgagta tttttaagat catctgaaac tatttcagtc actcaccaga 7860
atccaggaat ttgtaaagta tgtgactgat gaaataaatt aacaatgatt tagaaactta 7920
gtgaatttta agcctttcta tttagagata cctatcaaac cacaagcgta aaaacttgac 7980
cctagttatc tactattttt ctattaaaag caaaattgtt ctttttatgt atcagaagtt 8040
ttaacttaag tgtatacttt tattaaaatg atagccatga aataaggaaa atgcctgttt 8100
tcgacttatt atcagtgact aattagaaaa taattatttc tcttgttaat gttgaaatat 8160
atattttact tttttatata taactaaatt ataccactat aaagagtaag tttttaagtg 8220
tcataaaacc attgccgagt ccataatgca gcataattgc ataaggctgt taatttccac 8280
cttatatttt tcttatattt ttaccctcaa aaaatgtaga aacttgtgta aacaatatgt 8340
atatatattt tagacagagt ctcactctgt cacccaggct ggagtgcaat ggcgtgatct 8400
tggctcactg ctacctctgc ctcctgggtt caagtgattc ccctgcctta gcctcctgat 8460
tagctgggat tacaggcatc cgtcacgcct ggctaatttt tgtattttta gtagagacag 8520
agtttcacca ttttacccgg gctggtctca aactcctaac ctcaagtgat ctgcctgcct 8580
cagcctcctg aaatgctgag attataggcg agagccatgg cacctggcca acaatatatt 8640
tgaagacaaa ctttatgctg tatttttaaa taatttatca gaaattgttt ttaaaaactc 8700
catttagtaa caaatgaatt gcaaaattaa tttcattagt caactgacac tgtgaaatag 8760
caaggctata atggtgaata atatagacat gattcctgtc ctcatgacgc tcagagagta 8820
gttgagaaga tcatcattaa aatttgtcat tagaggaata atataagggc tgctggggta 8880
tataactggt aataggtcaa tctgagtact aaagaaaaag agaggtgaca tttccaagac 8940
cctaaagtca gaaacagcat ataaaacatt cataacattt gacaacctaa aataattaca 9000
gtattatcca aatggggata atgcaatgaa gagaaaagaa aatgaaactg gagaagtaga 9060
cagggatcag acctcctagc gtcttgactc tgtgttaaga catttgatca tcatcctaag 9120
agtaatagaa agctaccaaa atgatgcata ttacatttac aatggtcgtg ttagcacagt 9180
atgcagaatg gattaaatgg agccaaacat gaatttggaa acatcagttt agaggagact 9240
gcaataatct agatggacta ttagatttga tgctagtctt gacagacact tggaccatgc 9300
agtgatatgg ggatggaaaa aagtaactga atccagagat agcaggcaga attgacaata 9360
tttgatggtt aattagatat gaacgtttaa ggggagacag aaatctaaga tttctcatag 9420
gtctctggct atattatgca cattttataa gacacagaga cgtcaaagga gtaagtaatt 9480
agcaggaatg gaggggtaga ttaaaagata cttttcaaaa gttcagtttt agaattcaaa 9540
atttgaagtg ttgataagat atgtaagtac agatgtccta tggacaatca agtatgtgga 9600
attcagaaga gcggtctcac ttggagagaa gtatctgaga atggtgggta tataatggtt 9660
atgtttgttg agcaatgttt gttgatggac tacactagga tgaggagagt agaagagagg 9720
tagatggctt acatacctta tgtctttctt ttcaaaaaga aaaatgccac atttcaaaga 9780
atacagagaa attggtgccc tgaggcatga agaagccagg gaattggaac ctcctgaaag 9840
cagagggaag ataacttaat gctaagggga ggaaccatcc ttgttgaatg ctgcttagaa 9900
agcatgtcaa atataatctc aaattatcct tttgttttta gtgacaaaac gtgaagatgt 9960
tgccatcttt agaaagaaaa gctggtaggc tgaatatatg atagatatat aagaaaagga 10020
aagataagca gctctttcaa aaagtttggc catgatatgg aaaagggaga taaggctgta 10080
gtagttaagg agggttgtga gtcataggag agaaatatcc tttcccctat gccaggacaa 10140
gggagacgta agcaagtttg tgttgctggg aaaaagccag taaggtggga gccattaagg 10200
ataagaaaag agagagataa gagattgctg aagtcttctg gaatggggaa ggtgtccaga 10260
ataccggtgg agggattgga aacctcccca ctgtaacagg aaggaggaaa gaattggtct 10320
caatgtggaa aagtttgttg atttgggggt gggaagtgga ggcggggcat tgtgatgctg 10380
tctcttctct gtaaagtaga aaataagttt tcagcttgaa atggagccgg aagaaagaag 10440
agggttggaa gctggaggaa agtggagaat atttgaaatt tttctttgca gagagtggga 10500
gatggagcct agtaggaaaa tacaggactg tgttgaggac cactgaggtt tgtgaccata 10560
aatttagaat ggtgccaatc tgccacgggg tgttattttt ccccaatagg gctcagcaga 10620
ccaacaagca caggggaccc tctagtttta tataccaata gcaagtcatt ctttatttaa 10680
tttagttttt tgtttgttat agcaataaag aaaaattgtg tttctttgaa atggtatttt 10740
gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgttc tctagattat 10800
agtgccctca cgtggctgat gcacatcatt tacttatgag tgttttcata tggatgaaaa 10860
aactgagaat taagcatggg ccttacagca cagctactaa aattaaaaaa taataattat 10920
tattattgtt ttgactaaaa ccagtactag atgcaaatga actttctttc tagatcaaca 10980
caacattgtc cagttgtaat agtgttgata tttcattatg tgtaagtaat gtgatcattt 11040
atagtaaaaa cattaggagt gagaaaagat atgaagagca cgtatttcct ctctggaatt 11100
tctataattg tgtccagatt cacaatgata aagagtgcca ctttacataa tggcaactaa 11160
atctttatta tgctttttat taaatatgaa agtcattact attatctgat actgaatatt 11220
ttcttaaata gttgttttgg tttttgtctt ttgctgtttt ttaatgtcaa ggaaagtgaa 11280
gggcattggc tatacctgca aagacaaagt gggatagggt gaaaccaacc caatatttgt 11340
aataaactgt gttctgtatg atccaggaag caattcattg agcatctatt acgcactagg 11400
gccattaagt tgaaggagac ttacatattt taacaaattt gatcttcata gcaatcctgt 11460
tacatgatta ctttttctta cttttataac caagtcaatt gagattcagg gaacttaata 11520
agtaattttg ccttagttac aaaccccaga aatgccagtg ctaacacctg ccatcttctc 11580
tcatagttca ggattttatg agcaattaca gtatattata ccctctgttt agaaaggacc 11640
ttattataag acattccacc agggtaactt ttagaatgat gttataatac atttaattaa 11700
ttacttgaat tgtcttgttg aatttttgcc agggtttaca tatgtgctga acttgcagtt 11760
ttaatgttca gttgagtctg tcgttaagaa aatttaagtt gataaattat tcactgatga 11820
actactttct ttgcatttaa tctttttaat tgctaaaggt acctaaatag cctcaaaata 11880
gttgatggct tggcctgaag acaagatcta aatatgaggt tgctgagtta tagaaatggc 11940
aaaaaaaagg gtcaataata gaataataag caacaaaata atagtaagca ctaaagtttt 12000
aaacttcatg gtggtgaagg catggtagtg cataaaagta agatttttcc attgaacttt 12060
gtcttccttg acgatattct actttattca atatgctcat tatgtgcacg attcttacca 12120
actgtgtatt tatgaccatg agtaaccctc cagactggac aaagaatgtg gagtaagtat 12180
aaatattttt caatattgac ctccctttat gtttcatatt gtgcttttaa caccttgaga 12240
cctcctcaat ttctttaaca aatcatgcta gctactgtta accagaccct gattcaaatt 12300
catttctgtc actaaatgtc ttctaggaca aagcttgtag tgggctcact tagttgtgta 12360
aattactgca gtagtttgac tgctattatc tgcagccctt tatcttcttt gtgagtctta 12420
tgttcttttg aagatcacca gtgatttact aatatctact gataaaaagt atacctagtt 12480
tttatgttcc ttttttaatg actaccacag ttctgtgtta ctagtatatg tttgatggct 12540
tttaatggtg catattttat gaaatacaaa tgcttcactc atttttgtat taatacctat 12600
ttgctcaaat cggactgaat gccagtgtat ttcagattat gtcttcatat agagccacat 12660
tatttggatc ctttaaatta attaatgtgg aaaatgcaat atacatttat ttacagtcaa 12720
tgagaatgtc ttttggaatt taatgtttct tttttgactt aagccccacc taaactctat 12780
atcgtagggg gaccaacctg gaagtgtcta atttttgttt gctgtttatg tcatctttaa 12840
gatatgtact tgtaaattaa ccactagatt tttaatgtga gcttggctat tttctctcag 12900
gtataccttt acaggaattt atacttttga atcacttatt aaaatacttg caaggggctt 12960
ttgtttagaa gatttcacat ttttacggga tccatggaat tggttggatt tcacagtcat 13020
tacttttgcg taagtatctt aatacatttt ctatcctgga agagtaaatc actggtggga 13080
gcctatacta tattttcctt ggtggcttgc cttgacagac caagcatttt tcttagtaat 13140
catagttttc ttccaatcaa attatccagt ttggagaaat taggaactat catagtaaat 13200
tacatggctt tggtttcaat tagcactgta aagtaataaa gtttcccaaa taacagagat 13260
tatgattgat gacaatgcca ttttcctctt aattgggaaa gctgatggcg acactcatga 13320
aattaaaaag gtcttgatga aagaccaagg aagacgtaga tttccctaaa ttctgaataa 13380
ctctgattta attctacagg tatgtaacag aatttgtaaa cctaggcaat gtttcagctc 13440
ttcgaacttt cagagtcttg agagctttga aaactatttc tgtaattcca ggtaagaaga 13500
aaatggtata aggtggtagg ccccttatat ctccaactgt ttcttgtgtt ctgtcattgt 13560
gtttgtgtgt gaacccccta ttacagatat gtgacagagt ttgtggacct gggcaatgtc 13620
tcagcgttga gaacattcag agttctccga gcattgaaaa caatttcagt cattccaggt 13680
gagagctagg ttaaacaccg aggctgactt tagctacagt ggtgctacaa tcacagcttt 13740
tgtgcagaag ccttgttgct agttgcatat tgcaaataaa tatgtaaaaa agcaagaatt 13800
ggtacatcat tttttggatg gatttgattc tttgcttttt actcgttgct ttctttaaaa 13860
ctattctaaa tcagcctttg agtttaacaa gtgttgcatg aggcatttgc agtaacaggc 13920
tacatggttt gcatcctata acatcaagct ttccgcatag aagctagact aagagacatt 13980
cagactgatg caaatttgac agtttaggcc taaaactggc aatcttttaa gctgcagata 14040
aatgaaagag caagggatag catgagtgct gcatggggct cagatttcag atgtcttcct 14100
ttttttaacc catactcaag cttgcagaat tcacaaatat ataacctcat aattcatcga 14160
cttcaagatt tcttactact ctattcacat agacttttct aaaaccaata aggggttagg 14220
gagtaagaca tctgcaaata aaagcaaaat atttacacaa ggttgatgtt taagcatgaa 14280
taacaaaatc attcttttgc tctaaagagt gtttggaaat acacatttgg ttcatttcca 14340
ttcacagttt tctaatgaac atacaagttc tgctttcatt cattttcacc agctagcagg 14400
cttttcatga aaatgttatt caatcacaaa cattaaacta atattgttgg cattctgcat 14460
gacattttta ttttccagga caagctcatg atatttttgc cggtaaaata gctgttgagt 14520
agtatattta aattccccct tctgattttg tttgtaggcc tgaagaccat tgtgggggcc 14580
ctgatccagt cagtgaagaa gctttctgat gtcatgatct tgactgtgtt ctgtctaagc 14640
gtgtttgcgc taataggatt gcagttgttc atgggcaacc tacgaaataa atgtttgcaa 14700
tggcctccag ataattcttc ctttgaaata aatatcactt ccttctttaa caattcattg 14760
gatgggaatg gtactacttt caataggaca gtgagcatat ttaactggga tgaatatatt 14820
gaggataaaa gtaagatata ctctataaac cattaagttg tttagttctc taaatattaa 14880
atattatata taatggaaat tatctcaatt tagatgtgaa tcaagtgact tagactaatt 14940
taagatgatt taatacatat aaaagagata tcaaatgata ccttattcta tttttcttat 15000
ctgtccattg atatagtaaa agttctcatt tgaaaatgtg ttgtcttata ctcatgttga 15060
aagtaatttc atattatgcc atattaaaaa atgtttattt ggtagacatt aatcaggttt 15120
ttcagtcatt ttaataaata agtcagtagt ttgaactatt cagtgtattc cactgaaatg 15180
tgttaagaag actgagggga aataatttgg ccctatttgg ttgatgcaac atatgtattg 15240
agtacatatg ctatatctga aaatagagaa accatttatc aagatgaaat aagaatttgt 15300
gtgctcctca gaaggttaag taaccctgat ttagccattc acttattcat attctaatta 15360
gtccctttag tgtcatcatt gtattgtagt taccagttta gtttgattat atttaaggta 15420
tgaacatcag aataagctta tgccatatac ttcagcatga tttcttaaca ttgagcccag 15480
cccctctgtc atttttcata tgtgtgtgca tgtttgtatg tgaatataaa aatacgtatg 15540
tttgcatgtg tgtgcatgtt ttctgagatc atctttgcaa cttactgaag ttatatgtca 15600
tgccttaaaa ataaaaacta gatagctctc catagcttaa aaataaaaac tagatatact 15660
cagacaacat atctctccaa agaaacaagt ttattttctt catttgaaag gcagaaatca 15720
agcaaaaatt tcaaacaaaa cacttattta cagtatcata agagggaata aatacctaat 15780
cccacttctc acaggaaatt aagttaaaat tggcgggaaa aaatgtctga atctattttg 15840
agcctgggga gaaaagtata tgtaaggtaa aatttatttg catgaaaaca cctagaaaca 15900
acaaggcttt cttctttctt actttttgtg cccagcaata gactggcagc tctttcttaa 15960
tgtatcccat gcaatttgag cttatatttg caatgaatgc tgatataaga atgttatcat 16020
agtaattcct tctgaacatt tttcttttta acatagattt gctaaccatt tgtataatca 16080
aaaatgttat atattgatat ttgttcaata ttgtgaaaaa tctctttagc catatatatt 16140
tattagttta tccatctcat tatgattgaa aacatttgtg agctttgcca cctaaacagg 16200
gtggctgaag tgttttacag gattttaatg attctttcta ttcctttctc tttaaatagg 16260
tcacttttat tttttagagg ggcaaaatga tgctctgctt tgtggcaaca gctcagatgc 16320
agggtaagtg atgcttccta ctgagtttca gtccacactg ctccatcagt gtcaataacc 16380
tgccacctcc cactcatcca gtcccactca ctcctcactc aaaaccctcc ataaattcta 16440
cttcacggtg actctcagaa tagccaggat aagtgtagat tctcacctct ttcacacagt 16500
catttactgc aattattttt ctatgctagg tcacatctaa tcttccaaat tagttcaatg 16560
taaaatagag aataaagcag tataatatgc atctgaagct taatagaatt cttaagcaca 16620
tactttttat aagtgtcata ttttatatat actaatgtgt tctccatagc ttaaaatgta 16680
agatctctga aaataatgtt aatatctgag acatggggag tatttagcat attttagcaa 16740
agtggttaca aacataaact ggagagtctg catagagtca gactttgact ccatcatata 16800
atctcatttc ttcttgcctt cgtttcctta tatgacaaat gggtataata atagggtttt 16860
tgtgatgatg aagtggatta ataaatgtat agctatttag atcgctcaat aagtgcttgt 16920
aattgttatt attgggatca tgcaaatgtt tgctattaag aaacatggag ctaaatccta 16980
ggaaaattta aaaacacagt taattttctt tatttagcaa gattttagag ccacacacaa 17040
aagtctaatg cactttcttt ggacgatgat actgtggaca ttagtagcta atacctgtag 17100
caaaattccc agtgataata ggctttccat ttggctccta cgatcagtgc tatgctgcct 17160
ttatcttcag attccaatga taagtaaatc aattgatttt cattccttgt ttgtactgta 17220
ctaaatgcgt tacatacagt atcttcttca atgtttgcaa atttgtgaga caggttctct 17280
tattagccca ttctcacatg cgaggtgcct gaagattagc aagttaagta acttgcccaa 17340
gatcgttcag ctcagaagtg tcaggcaaga cattgaagcc aggtctgctt gatcttcaag 17400
gtcctcctat gacattttta ccacacagtg tcattcactc cttgcagcat gccccaccta 17460
tccttttctc acttctttac cctgttccca cacttacaca catttctgcc tcaagacatc 17520
ctcagtgaaa atcaactttt tccttacaga cttttttaac tgcccttaag tcccagaaga 17580
tattaatcat gatatgattg cttttatatg gagacataat aaatataata atgacaatta 17640
tgaatcacag aggaatccac aaagtagacc ttatagattc tgttattata taaatcagtc 17700
cacttagtgc tgagttaagt actgggtaag gtgagagaaa tcggcttttt tctagtgcct 17760
gtataaaaca gacattggca tatattaaaa caggaaaacc aattagcaga cttgccgtta 17820
ttgacttcct ttctttcctc taacctaatt atagccagtg tcctgaagga tacatctgtg 17880
tgaaggctgg tagaaacccc aactatggct acacgagctt tgacaccttt agttgggcct 17940
ttttgtcctt atttcgtctc atgactcaag acttctggga aaacctttat caactggtga 18000
gaacagataa aatcattttt ctgagaatca taaaacaccg aactcaagag aattgctgta 18060
gaatatttta ttacttagag tgtaagtttg taacatccta tataaaattt attaaaatct 18120
ctcttccatt ttgcagacac tacgtgctgc tgggaaaacg tacatgatat tttttgtgct 18180
ggtcattttc ttgggctcat tctatctaat aaatttgatc ttggctgtgg tggccatggc 18240
ctatgaggaa cagaatcagg ccacattgga agaggctgaa cagaaggaag ctgaatttca 18300
gcagatgctc gaacagttga aaaagcaaca agaagaagct caggtatagt gaacaagcat 18360
acggtccttt gtttttcttt atctaaattc tttaacctaa atgttgaggt cagtggcaag 18420
gtagttgaca ttagaaatag gtcatatgtg tttggtaagt gctaggagcc tgtttggtta 18480
ttaagaagtt attactttat tgcaatgatc tctgtcaata gtgtcaatag taatggcatc 18540
aaaaaatgga taattataat tgctttactg acattttttt ctcccttgtg actccttgag 18600
gaaattaatg attaacaaag gcctcatgta ctcaaacttg cagagtagat aaacctacat 18660
gtcctcagtt gaagtatttt cttaggggaa gaggaattca gttacacttg cttcttcatt 18720
gcagtatcac cagaggtggt aagggtcaga aaaccagaat caaactaaga aaattatttc 18780
attgagtctg gaaaggcaaa ggcttattca atatttgttc tcttttatat aaagtgtaca 18840
aatgcaagtt tgtgggttac atcagtaaat cactagtgtg taaacatatt aaaacattag 18900
cactctctgc ctcctactct acaaatcctt taatttggac ttgacaagcc ttcaaaataa 18960
ggcaagaatt tctctaatta tatttgcttg acttaatggc attaactaat ccaattgcct 19020
atttttgtct tttcatgtat ggtgaataca attccctttt attaccgagt attcctaaat 19080
atgtaataaa ggtcaaagta tattgctgta atagcaacaa aactactgtt atactttaca 19140
agttcatgca gatgccatga tctaggattc tcaaataaac actctgtatt atgtctttgc 19200
tgtgcatttc ttagtgaaat acccaattta aatcacggag aaaaatgtca ttaaaataaa 19260
atacttgact gaattacatt taataattca gactagcact aaatttcttt attgtgtgaa 19320
aatggaatca aaggcaaatg tctaccaggt ttaaatagga agtctttaat tcccatatta 19380
tttccttctt aaaatattgt ttgaattata gaacatgtta ttatgatctt taagtgtctt 19440
gctcatatta ttagataatt agatatcata gtgtgaggac agagcttgaa ggttctcata 19500
aaagtcgtat gtatcatctt ccatatgaat gcccatttta ctctttgatt ggtctaataa 19560
caatgtactg ttttctaaaa cacagaataa aatggagaat tgtttttcaa gattatcttc 19620
atgatattga agctcaatta agcagtaaca tgataattac tttttaagtt tatatgcaac 19680
ttccacatac tttgcgccct tctaggcggc agctgcagcc gcatctgctg aatcaagaga 19740
cttcagtggt gctggtggga taggagtttt ttcagagagt tcttcagtag catctaagtt 19800
gagctccaaa agtgaaaaag agctgaaaaa cagaagaaag aaaaagaaac agaaagaaca 19860
gtctggagaa gaagagaaaa atgacagagt ccgaaaatcg gaatctgaag acagcataag 19920
aagaaaaggt ttccgttttt ccttggaagg aagtaggctg acatatgaaa agagattttc 19980
ttctccacac caggtaaaaa tattaaatta catgaattgt gttctcataa attttttaaa 20040
aaaatatgcc agaatttaat ggagagaaaa ccgccttcca cctggatggc acaatgcttt 20100
cagagtagtg atgattatca agtgttttgg ctatcacttc agagaatttg tgagttttgc 20160
aactttttgg aatcccagga aggaaatttt agatccctct gggtttggaa aaatttgcgg 20220
ttttgaggtt ttcttaaaga ctgaaaaatc ttggagaaat tttccacatc aggaattatc 20280
agcagatggt tcccatctct tcttaactat tgtgcgtgga tctagtgaac tttgggtttt 20340
ctgagtgaca aattcccaga agtggaccag agactctttt aggccacctg cggggttgtt 20400
cccataaggt gcaaacatca cttgccaagt gcattcttca tgcctttgtt tcaaagggga 20460
ctgaaacaaa atatctctaa aagtagccaa aactctcaga taggcaggta ctgagggaga 20520
tttatgacac gaaataaaaa gtggtgttta gttgtacttg attatctgtg tttcatgtta 20580
aacatgggac ttgcatttga agaatactgt gatttataaa ctgcaacaaa tattcactgg 20640
atgcctctgc cttttgtact catgcaagtt gttgaaattt taaaatttag aatcttaatt 20700
gtctttgaaa ttaccaagag aattcacagg aatacacagt acctcagaag acattttcac 20760
caggagtgaa accttaatac ctatacagta acaataacaa ttacaacaac aacattgata 20820
atggctaata tttatacact gtgttgttat ttgcaatatt aatgcattaa gcctttcact 20880
gcaaccctag gtaagttcta atttagttaa tatccccaat ttttatatgt gaagagaagc 20940
agggggctgc attctttgtt gagtacctat tttatgcttg gcattctttc tacattctca 21000
taattaatgc taacagttct gtagaatagt attattttca ttactataat gaaaaagcta 21060
ttttggatca gtaaagttaa atagttgcac aatgtcatat agcaatagaa aaagttatta 21120
tgatctttga gtgtcttgtt catattaggg ttgttggtat tcaaattttg cctggtactg 21180
aaaaccttaa agtttccact ttatcaagtt gcctatgaag aatgccttta aaaactgata 21240
aggaaattta caatataact ttatttaaaa tacacaatgg cattatactt tctcttttac 21300
ctttttataa tatagacaag ctcacataac ctcacatgtg atatatataa atttttttag 21360
gtcagcctta ttcatttcaa atccaaataa catcataaga ttgcatactt ggggattaat 21420
tcaaatttaa cataggatct ttaaatatca aaatttactt ggtctctttc attttgttgt 21480
cacaatcatg attccattag tagaaacatt aatcaataaa taggaatcct ttaaaaggca 21540
aaccccctgt ttacagtatt agtcattctg aaaaggaagg aagaaaaaga aagggaggga 21600
gggagggggg agagagagag agaggaaaaa agggagcaaa ggagggagga agatagagta 21660
tttttgccta catttttacc taagtttgtc tgaatttttg cctgaagttg tctaagtttt 21720
ggccaaaatt tgcctaaatt ttggcctaga tttgaaactt catatcaact tcatatcaaa 21780
cacttaccac agagattctc ttcaatttgc cttatttcta attgaataaa actaattcta 21840
ggcaaaatag tgaagcctga taaggctagg ctctgtcctt cctttttctg tacattttgt 21900
tcatagatat gatattctcc cagcagcctc ttcttcatac ctctacatac ctccatttcc 21960
cagctagttg ggtattataa gcaatcactg acttagaaga catggcatgg ctggctcata 22020
ttgatacttg tttcttaagc agtctctata taaaaataga gttaaagact ttattttgct 22080
tgataaagaa atagtcaaac aaatgtctaa gaggatggag agggagacag aaaaagacag 22140
agggaaaggg aaagaaagag aaagagagag gggggaaagg agaaaaggaa gaagagagga 22200
gagacagaaa accctgaaat cacaccaacc ccacttggca agccctgaaa gtaatactga 22260
aaatgtcaaa ccagatagaa gtacttaatc ttggtatagc aatggagggc ccatcgtgtc 22320
tgttagattt ttaagagttt gagaccccaa aatattagga attattgttt tgtgatgaca 22380
tgattgtgtt ggtaaccatc tctgtgtttg tattgaaaaa ctatacaatg caagccttta 22440
ctgcaagatt ataatttctt tagtagagta agtggaaata tgaattgttt ctcagactct 22500
gatttgactt gttagtgtgg taaagagggg agaagaaagt caagaatgta atctctaaac 22560
aagtttcaag ataatctgga tttttttgaa acctttataa ggtacaattg accttaaatc 22620
attactttat tatttatttg tgataagcta ggagtttagg agttttgctt tttaaagatt 22680
ggtttggtat ggggaatatt tcttactggc catctttttt gtgtgttaca gcatttgatt 22740
actatgcatt tatgtaatga atgtcagcaa aagaagttga tgctaacgga tggggcacaa 22800
tcatttctca tatagctgtc acatgtaaac tacgtttttg tatagcttaa ttcatccatg 22860
atccttgaga aacatgcaaa cttataactt attttcttcc aacccttcta tggctccagc 22920
tgaatggggt actggcagtt aaaatataaa ctcttactaa aagcgataga aacattcttc 22980
attgcaaagc atgtattgtt tgcctttctt ttttagctaa tgaggagcag tatgtcacac 23040
atcctgcaaa tcccgtaact gttatttcct catagctaat tcgaagtccc ttgttagagg 23100
agagaaagga gacacgaaaa aggatggata gtctaagaaa ggctttaaaa aataactact 23160
tgtatggaaa atgataaaag aaaagaatga atgttactaa tgtagttaat aggattaaaa 23220
agcatgggaa caacaagagg agagatgact tctgttgtgg gagcagtaag tcttcttaga 23280
agtagttcta ggccgggtgt ggtggctcat gcctgtaatc ccagcatttt gggaggccga 23340
gacgggcaga tcatgagatc aggagatgag accatcctgg ctaacacggt gaaaccccat 23400
ctctactaaa aaatacaaaa aattagccag gcgtggtggc aggtgcctgt agtcccagct 23460
gctcgggagg ctgaggcagg agaatggtgt gaacctggga ggtggagctt gcagtgagcc 23520
gagatcacgc cactgcactc cagcctgggt gacagagtga gactccgtct caaaaaataa 23580
ataaataaaa aaaaagaagt ggttcttact gtaaataatg aatagaatca cataagatag 23640
tgtttaacat ttacagacat ttaatagaaa ctaacagata ttattgagaa aaagtaattc 23700
tttagctgga aagaaaataa aaagcatact tattggtcag tgtattactc tgttttcatg 23760
ctgctgataa agttataccc aagactgggc aatttggcaa aggaagaggt ttaattggac 23820
ttacagttcc atgtggctgg caaagcctca caatcatggc agaaagcaaa gaggagcaag 23880
ccacacctta catggatggt ggcaagcaaa gagagagtga aagccaagca aaagaagttt 23940
ctccccatat aaccaccaga tctcatgaga cccattcagt accatgagaa cagtatgggg 24000
aaaaccccta ccatgattta actatctctg accaggtccc tcccacaaca gtgggaatta 24060
tgggaaatat aactcaagat gagatctggg tggggacaca gagaaatcat gtcattccac 24120
ccccggcccc tcccaaatct catgtcctca catttcaaaa tgaatcatgc cttcccaaca 24180
gtcccccaaa gtcttaactc atttcagcat taattcaaaa gtccacagtc caaacaaagc 24240
ctcatcggag acaaggcaag tcctttccat ctatgagcct gaaaaatcaa aagcaagtta 24300
gttacttcct agatacaata gggatacaga cattagctaa atacagccat tccaaatggg 24360
agaaattggc caaaacaaag gggctacatg ccccatgcaa gttcaaaatc cagcagggca 24420
gtcaaatctt aaagctcaaa aatgatctcc tttgactcca tgtctcacat ccaggttacg 24480
ctgatgcaag aggtgggttc ccttggtctt cagcagctcc acccctgtca ctttgcaggg 24540
tacagcttcc ctcctgacta cttccatggg ctggcattga atgtctgtgg cttttccagg 24600
tacacggttc aagatgttgg tggatctatt attcttgggt ctggaggaca gtggctctct 24660
tctcacagct ccagcaggca gtgccccagt agggaccctg tgttggggct ctgaccccac 24720
atttcccttc ctcactgcct tggcagaggt tctccatgag agccctgccc ctgcagcaaa 24780
cttctgcctg tacatccagg tgtttctata catcctctga aatctaggca gatgttccca 24840
aatcccagtt attgacttct gtgcactgac aggctcaaca ccatgtggaa gctgccaagg 24900
cttgaggctt gcaccctctg aagccatggg cctagctcta catttgcccc tttcagccat 24960
ggctggagcc gcagagatac agggcaccaa gttcctaggc tgcacacagc gtgggactct 25020
ggacccggca catgaaacca ctttttcctc ctaggcctcc gagcctgtga cgggaggggc 25080
tgctgcaaag atctctgaca tgccctggag acattttctc cattgtcttg gggattaaca 25140
ttcagctcct cattacttat gcaaatttct acagcctgct tgaatttctc ttcaggaaat 25200
gggattttct tttctgtcac attgtcaggc tgcaaatttt ccaaactttt atgttctgct 25260
tcccttatga aactgaatac ctttagcagt acctaagtca ccacttgaat gctttgctgc 25320
ttagaaattt cttctgccag atactctaaa tcatctctcc caagttcaaa gttccacaaa 25380
tctctaggac agggccaaaa tgccaccagt ctctttgcta aaatataaca agagtcacct 25440
ttgctccatt tcccaacaag ttcctcatct ccatgagaga ccactttagc ctggacctta 25500
ttgtccatat tgccatcagg cttttggtca aagccattca ataagtctct agaaagttcc 25560
aaactttctc acattttcct gtgttcttcc gagccctcca aactgttcca tcctctgcct 25620
gttatccagt tccaaagctg cttccacatt tttgggtatc ttttcagcag cgtcccactc 25680
ctggtatcaa tttactgtat taatctgttt tcatgctgct gataaagaca tacctgagac 25740
tgggcaattt accaaagaaa gacatttaat tggacttaca gttccatgtg gctggggaag 25800
cctcacaatc atggcagaag gcaaagagga gcaagtcaca tcttacatgg atggtgtcag 25860
gcaaagagag agtgagagcc aagtgaaagg gatttctccc cataaaatca ttagatctca 25920
tgagacttat tcactaccat gagaacagta tggagaaaac tgccactatg attcaactat 25980
ttcccaccat gtccctcccc caacaatgga aattatggga gatacaactc aagatgagat 26040
ctgggtgggg acacagccaa accatattag tcaggcatat aaaaacctag atattagtag 26100
gtataaaata atggttttag ttagttttga acctttggag aggaaaagat caaaccaata 26160
atacttaaat gatgaagtta gtattctttc caataataat tacataaatc caatgcaagc 26220
tggctgaagt aaaaaagaga atgtattaga tgatataaat tatgtctgtg agtagcttta 26280
ggcatggatg gatccagaag ctcaagacat gttaccatga ccatgtcttt ctccatatct 26340
gaatctaggt tcctcccaca tggtggcaag atgtcactgc agctccaaac ttaaagccaa 26400
tatttttagc agcctcaagt gaaaaagcac catttcctca acagttgtaa aagacaggga 26460
tatctttcaa ttgaccaagc aggatttcat gaccatcttt aaattacgta tcgaatacac 26520
tgattggcta ggcctaggac agtgcctgga acactgggag acccgagcct caagtcctgc 26580
tgcatccagg agttgaaatt agtgtctccc agataacctg gtctgagagt tgaggattat 26640
ttctcaaggc tgaacagggt actgatttaa aaaaacaaaa aattaaatgg ttgtgatcag 26700
cctcttagtg aaaattaagt ttttgtaaat attgccctca gatttcttga gacagagaca 26760
aaggggtgaa aattggggaa taaatcatac agttatttca gcttgattta atttattcat 26820
gaagaccatc ataaaatatg caaagggaag tggagaagct gccccgtgta ctataattaa 26880
acatccctac tagcaagatt aattatattt cctccatggt aagatttgca tcagggtgtg 26940
gtcactagcg agctcttact ggctacattt ttgacctcag aggatctaaa ggtagatttg 27000
tgtttaattg ttttccattg ggttgttaac tgaaattaac ttctaaagaa gggtctatca 27060
acagtatcag ttctagatgc ccgtaacagg acaaaacatt atggggacac ttctgactat 27120
gttgaggtgt gggtaaagta ggagaaaaga gagcagaaga tggaaaatgg aggaaggaga 27180
aaaagcgaga gtgaaataga aaaggtgaac cttgtagaaa gtgccaaaat gccaccagca 27240
gtcatcagag gggtgctttc ttccacatgt ccaatgactt atccttgagt aagtcaatga 27300
ctatgacaca atgaatcaaa ttctgttttt cagaatgcca gctcttaact ctcttcatct 27360
catttttgtt tcttctcttg ttattcatag tccttactga gcatccgtgg ctcccttttc 27420
tctccaagac gcaacagtag ggcgagcctt ttcagcttca gaggtcgagc aaaggacatt 27480
ggctctgaga atgactttgc tgatgatgag cacagcacct ttgaggacaa tgacagccga 27540
agagactctc tgttcgtgcc gcacagacat ggagaacggc gccacagcaa tgtcagccag 27600
gccagccgtg cctccagggt gctccccatc ctgcccatga atgggaagat gcatagcgct 27660
gtggactgca atggtgtggt ctccctggtc gggggccctt ctaccctcac atctgctggg 27720
cagctcctac cagaggtgag gccaattaaa attgcagctg atgtgaagag agttgtgact 27780
ggtgcaggca ggagtgtttt tccatttcca catctaagaa tttgttgagt ttgttgccca 27840
aaggctggga gtttgttcaa tcaagctgtt aactgtcttg tgaaactgtt ctattcagac 27900
ttttctacaa agtaattaaa aacctaggtt ggctgtcaga gaatataatt agaagtaatc 27960
tttcatcatt attactatgg tatgaaactc gccaaaaagc aaagcaacaa tttatcaagc 28020
ataatgtttg attaatatag ttaaattaaa tccaaggaaa ttaatgctca ctaattaaat 28080
aaatacttaa ggattttgtg attgttgttc atttaaaagg agatttgaat acttccactt 28140
gcagtagata ctattactaa atagatttaa atcccatagt acaacattgc ctctctttgc 28200
aggtcagagt gttgtaacct ttttagcatc cactctaatg atctcaacca ttgtaaattt 28260
atacatgaag agccattcaa aaagtacctg gtttggaatc atgggctgtc atttttagag 28320
cagattccaa tttttatatt actgtcataa actcttattg taaacaaagt ggcccaaaac 28380
caatcacatg gaaaaggatt tcagctacat actagacact tacagggcta tattattgaa 28440
atttacttca taaaccataa gaagctttta atgttggtat taaataaaat tccattagct 28500
atcaagacat attttggcaa tgtcacttga ttgtatttta tagcattcaa aatgtcttct 28560
tatgattttt ttttcacata gctccattta ttatcattga acaagctctt tgagccacat 28620
taaaatgata cggagttcgt tttcagttac ctaatggagg agcttcttat cttggattat 28680
aaaatagcca ttatcttctt cacatttttt gcatggcctc tccccacctc cttctaccag 28740
agaagtgtcc aggtatcctg cagtcaggtt gaaccatgag aaaagtagaa ctttatagtg 28800
gaggaaccag gaagaatgaa gagaggacat cagctcttct taaaaaatga tcatagataa 28860
ccatgtacca gacactgtcc agaacactgt acatgtgtta agaatcattt aagcatcata 28920
acaacccttt ttgatagtta gtaacattat cccaatttta cagaggagga aactgaggct 28980
tgtgcgtggt ggagctaaga tttgacccca ggtatgctgg ttactgaacc tacattctat 29040
caacagtgaa atattgcctc ccactgagtt atttttaatt tctttaaatc aaaaagaaga 29100
gatggttaag gaaataaaca cataaacact ttcattttaa ccaatgtttc tcaaaatata 29160
cttcactttc atactactta catcagaatc tcatgggagg cttcttaaaa ctagagattc 29220
ctgtgcctac ccagaccttt tcagaccaaa ccactgagga gaacaaggtc tgggaatctt 29280
cttccttaac aagcatccca cataattctt atacataata aagtatgttt atcactgatc 29340
ttgataaatg ttaattgggt aaacaaaagc aaatctacaa ttaccatgca ggaatacaga 29400
cagactgtca gtctgtcaga aattatttag catttatcaa taattatcat aaatctcctg 29460
tcctatcaga gatgatggga caaatcgctg aaggcaaagt tggggccagc ttgaagcaaa 29520
gctttgtgtg gtccctttat ttcctgcttc ctcaacttca ttctttaatc ttacaatctt 29580
aagtgctttg aggcagggca ctgtactatt gcaaagttga gctgaaggtg caaacaaatg 29640
aagtaggctt ttggagaatg cagaggtgaa atgacaatag aaaataaata gctatgggca 29700
aatgacaccc ttgaaagcac atcatttcct gtactttaca cataaattca atcgagtaat 29760
gtcattagca gttttggaat ctatttgaaa attagacaaa tctaggtttg tacatgtgct 29820
tctgtgtaga acagaaggga ctagatgatc ttcatgtgac tatttttttt ttccttaaaa 29880
ctttgcctct ttctgacaag ctgaaatatt ttaaattcta agaggcaccc tttggattaa 29940
aagactttta tttttagaga taggttattt cttttcttac taattttact tgttttttta 30000
ccttaaaatt aattttagaa tgacctatat gaatagttat caccattagt gacaatcata 30060
tgcaatgagt ggaaattttg gttttgaata tgtatgcatt aaaataattc aacttacaaa 30120
agataaaata ctgctaattg ttcacatcat aataggatgt gaccaaaata aataatattt 30180
tgatcatatt attatatttt gatcatattg ttcttttaga aatagggaaa gtcctcaaag 30240
gaatgaaact ttttaattta ttattaacac tcagacctgc atttgaaatt ctttagcttt 30300
accttttttt ttcctgtgat aattgacatc attgtttgat ctcctgaagt aggaataaat 30360
ttccacccat gttgaaatcc tgatgagttt attctggagt aggagattat cagatcattg 30420
tatcattact aaaaatcaca gtcccccaca ttggtattat ctccttaaat tatagtctca 30480
gtgccaaggg tggattgttt tgtggattaa gttgtttttc aaatatagga caaagttata 30540
gactagttct aaaatttagt tttgtaatta ggaatgttgg gaaatattac ctgtgtctaa 30600
tgaatgaagg cattttgcaa ctggaattca cattttaggg gaactgttac tgatgcatat 30660
gaaggagact ttcaaacctt tttgttcata tattaaacta cctgaatata tgtctataaa 30720
gatctaaaaa ctcaacctgg gtgaaaatta agaaacaata tgttttggtc tgaagtccta 30780
agtgggattg gctgaaatgc taaaaggtta tctgtccagt agtggacctg gtccctccag 30840
cccaaatccc tgggatagag gcataggaaa gcccaccttg acaaacccag ggctccccaa 30900
aagctgaaaa tctgacagac ttttaaacaa cccccaaaga attatcattc caacaatatc 30960
ttagtgagct ttttacatct gagaaagcat ggtgtatatt tagttaaata acacctgttg 31020
taggaatgct ttgggctttg ctgctttcaa aaatagtggt tatttcatct gaaattctac 31080
ttctagggca caactactga aacagaaata agaaagagac ggtccagttc ttatcatgtt 31140
tccatggatt tattggaaga tcctacatca aggcaaagag caatgagtat agccagtatt 31200
ttgaccaaca ccatggaagg tatgttaaaa gtcctgcgtc acagttactt ggtgctttgg 31260
taatgatgaa aaaacacttc ataaatttca ataaaatact tcctgacttg atattgtatc 31320
attattacac attttactaa ataacagtaa aatccgtgca taactcatgg attctattat 31380
cttccacaga tttttttttt ttatatttag cctccagaaa gctgctgcaa atgtaaggta 31440
tattttgaac accactttca tacattaaat tctaaacatt gaaacttgtg tgcatgacgt 31500
tgaaaagagt gtaatgataa atgcttatac ttatgatgat gctaagccat ttggattata 31560
ttaactgctt gagacacaag ttataaaatc ctatgactta accagaaata taaattaaaa 31620
atgtgaatta gggtttgata ttaacttcct tgaagcaaag tgtttaaaat tttgtagtcc 31680
tacttttgcc tttctctgac cagattctta caatatatca gctttctctt tagttgcaga 31740
ttttatctga atagttaaca taatgtgtag cagtctggat ctcagaatgc caaaataaag 31800
actttgggga cagcttaatc tgtgatcaat ttctggctct gccatatgtt aaatgtgtta 31860
atttgtgact ttgaatttca gtctcctcat cagtaaaatg tggatgatga tgtttaggca 31920
taaggttgtt gaatggatta aataagcctt cttagataaa acactgatgt atttggcatg 31980
cagaagacag ttaataaata ttatcaatat tagttgtttt gttgttgtta tttttgttaa 32040
ttcacatgtt tttgcctttc catactgtaa gtgaattcaa acaactgtca acttcaacta 32100
cttggaaaat attttcatgt aaaatgtatt ctatccccct tccttgccct cctattccct 32160
cctctcccta tctctttaca aaccttctcc cttgtacccc ttcccaggta tgtgtgtgag 32220
tgtgagtgtg tgtagatgtg tcaagggaga agagaaaagg agaatgaaag caaaagagag 32280
caagcataca cgtccctttc ttattgataa ttagattttc tcttgagatt ggatagattc 32340
ctggaataat tcttttcctg tctgtatgca aagatcccat aatattatta ataccaatac 32400
gaaaagcctg aaaatcacag ccagaaaaaa ttcacagtgt agacgactgt gtacatcaca 32460
gacaagtcag tattacaaaa cccaattttc atagtgtcct atttcagtat cctaatgcaa 32520
ttcactgatt tcaattgaat attaaactct agtacgttct tccccaacct cgcctgcgtt 32580
agcttgcact ccctcttccc cccagctgcc agtagcttgc tcctccctgt ccctccaggt 32640
aaatcttttg aagattgtct ggccttccgc tccttgccat agcaaaacca ctgagaggaa 32700
gctgccagtg gttctgctac cgatgtcagc agcatgtctg ctccctaaag caggaagtag 32760
agaaggagac agggtaagtc taaatcaaca gtcatgcttt gcacttctga tagcattaag 32820
tttgagctaa ataagacatt acttaaaaaa cctcaaatat ccacaagatt ggacttgcca 32880
actaattaag atttggagtt caaaataaat gcacccacac ctttctccat ggaactatgt 32940
gacatggggt tgcttaggat ggaaaggatg ttctaggaat aagtgcaatc taggaagctg 33000
aagactgaga gtgttttcgt tttattatct gcagagcttt tgacttgtgt atttgtgaga 33060
aataatggcc aagtttttat tctgttttta atcagttatc tagaatgaaa actgactttt 33120
ctttattcaa ttgtatgtag acacattgag tgtgacattt gtcaaggttg gttgttagca 33180
atatcacata catgcatact caagcagact taagatagtc cttttttttt tttttttttt 33240
ttttggtttc tgataatggt gcaaagtttt cctggttgac ataatctctt ttcttgggga 33300
tcctttcttc tatgtctgat tattgtttat ttcacctttc ctttttatga accaggcttg 33360
ttgatccggt tggcaatttt tgttctcctt ctttttaact acagccaagt ctccgttgtc 33420
cagggtaatg gatagcctca tgcttaatga agcagtagtg gataagcaaa aatgaaccat 33480
ttgcgtttca aatttttaaa agtgcaaaat cacatagaaa tgttttctgg tcacaccttt 33540
gtgaaggatg gtgggagggt gagttagaag cgcctgaaga atcaaggtga gccagcaaaa 33600
gacacagatt tactgtaagt gattctatgt ggataaccca tgcaggaata atggagatgt 33660
ggctgcagtt ctctcctgaa tgctttgctt tgttttaaag tgtgagattc cccccttttt 33720
tttggaatga ataattgaat gattttattt tagaacttaa acaactttgc tccggttatt 33780
cctactgtca agatgagcca cacctgctga atttcatttt ttaaactttt ctccagttta 33840
ttttttttct atccagttcc tgtttgcttc tcgttatttg ctaaatgaca gctggcatgg 33900
aaagaaaaaa ccatattatg gcagtataca gacaaaatta aattttgtag tttctttttt 33960
gttatttact gtaaataata atacctcctt tttaccttca atgtaaatat aaggttattt 34020
gggagtttag aagtatttac aaaataacta gtgcataata actatatttt tctctgaatt 34080
ataaatcaaa tattatttat tgtttacaaa gttatgtatt aagggaaatg gaaacaaact 34140
gggcacttga agaatttcaa tatccaaaga gacaattgac aaatctattt ttagtggaaa 34200
ttttaaaaac aataagcaat aaattaattt acttaggaaa atagtattat agaattaatt 34260
agtggcaaat gttgattagt agaagaaaca ttatcatctg tggttgtgat tgtcctttta 34320
tatgctggtt ccacctttac aaggtttagt tcatagcaaa ctgtgccaga tatggacaga 34380
tgttccagtt gccacaatag tattaaagtg actgactaga gtcaactatg ccatggattt 34440
aaaaagaaga aaccttccct ctatttcagt gctaagaggt ggtggccaca ttttggcaga 34500
acaggtaata gggtgtacag caatgatatt gacagaaaac aacaaattct gcatattttt 34560
ccactcataa gttgatgaag agattatctt gccaaaggaa gatggtagac agtttttcac 34620
ttcctaattc cccaaatttc tttgccaata ttcaccaaat ttcagtattt tgggtgtgac 34680
cttaaagatc tgtgcatttc tgtcttctct cccaatgttt ggttgaaatt cttcttgaca 34740
tcattgtaca ttttccttga ataaatgcat tttaatataa aattttatgt catgtttgat 34800
atgagagtta tatatttaaa tacatttaaa taaatgttta ccatgaaaat gtatgaatta 34860
tatgtatgtt tcacctaaaa tcctttgtat ttttccagta ataaatgagt tccactttgt 34920
gaaatgttga tttgtaacaa cagtgaggac tccagttcct taggctgggg tattttctct 34980
tcttttatgc cctctagtta aatgagaaat gtagagagat ggaactttgt tgtgtctaat 35040
atgcaagcct ataatctaat aaaatttaat ttgagacttt taaactgaga ttggtgacac 35100
tgacaaaatt atctaattag aagatcacca aaacatatct aatccaagaa actgacattc 35160
agtgtgactg attaaggttc ttaggacatc tcctgagata tctctgataa catatatact 35220
tcttgctcta cctggaacat ggatgagctt taagtgtatg caatgcaagt tctacccatt 35280
agtttctagc agccttgaag ataagtatca gacagtttag tgttgccaat agaatcttgg 35340
aagctatgtt tagccaggat acatttggaa agcttactag cctttctgta ctgatccttt 35400
ctatgacagc aaacccattg taaaattttc cctgttcctc cagcagatta acccataata 35460
tcttttaaca actttagatt ttttaaattc cttttaattt aaaccaaatc tgcttaatag 35520
aaagtaagca gttttcatga ggattctaac tttttttctt ccagaacttg aagaatccag 35580
acagaaatgc ccaccatgct ggtataaatt tgctaatatg tgtttgattt gggactgttg 35640
taaaccatgg ttaaaggtga aacaccttgt caacctggtt gtaatggacc catttgttga 35700
cctggccatc accatctgca ttgtcttaaa tacactcttc atggctatgg agcactatcc 35760
catgacggag cagttcagca gtgtactgtc tgttggaaac ctggtaagcc tcactgagag 35820
tttctcttcc tcttgaaaga gtttataatt gccttagtga attttacata ttgctctcaa 35880
attaaatatc aactaattgg ccatgtatat cttgacatca aatgtttagc atccctttta 35940
aataacaaaa aaatgttgct accatagtgc aaaagagtca aagaatttat gtacaatttg 36000
atttagaatt gaatttaaat tgcttattta ttagaagatg attctgaatt gtcctccaag 36060
gacattgatc tatagcaaaa ttctgacata tttttaagaa ccttagaata ggttctttag 36120
gacatgtctg tgtttactaa acaaatgata aaatatgccc aagtcagata attttgaaat 36180
atcacttgta agtacttgaa gatggactat gtagggaggg gacatcatct gggggattat 36240
tattttttgt ttttgtttct tctacagtct tagcaatatt aaatttagaa attatttatt 36300
taattttgtt aaaatatata ttagcattta ctggatacat attgatatta taatatagta 36360
tactatagtg atagatttta aagtggtctt atacagagag acaaaatgaa gaaaatcacg 36420
caaaaaagta tatttataca agtataaaat gcttattaag ttcccagctt gataaatgaa 36480
catataagca ggttatatag agattgtaaa taatacggtc taaagtataa tatacaatat 36540
ttttaggctc tgaagtaacc actatatttt cgaattatat ttcaggtagg acttaactga 36600
attaaatgat aaagttggca tatgttggcc tcttattttg tatcagatat tggactaaat 36660
ggtttacatt aaatctctct ctctagattc ccacaaaacc agtcttaaga tatttactat 36720
aaattgtctg tatttcgcag ttgggaaact gtatccatga gaaattaaca gagaaatgga 36780
aggtctgaat gctgtatcag actctgaaag ctatttcaga gactatcata agctatgggc 36840
aaagatcaca gacgcttaga gtaggaaagg ataataattt tacctagttc aaatttagag 36900
ctatgtaaga atttcttcaa cattatttct aaaaaaaagc agggtggtgg ggtggcaatt 36960
gaaacaagaa agcctttgga ggtaatatat tgtgatccaa attgaatgag cttaagcaaa 37020
aataaaggga attcattacc tcactttact gaagcccatt tggaactagt tctaggttct 37080
aacctggcta gattcaggtt ctcagccagc atcattggga atcagcttct tgtctctctt 37140
cttcccaata tgtgaccttc ctctctggct gggcattttc ctactattgc caagattcta 37200
tcaactttta ttctactaat gtagctccat gtacagaaag tttgtgcctc ctaactagta 37260
gctttaatta aggcccacaa attgaatatc attgacctgg ttggagttac atggccattt 37320
ctaaaccagt cagttaccct agctcttggt tttaatgcca tattcgccta aatcagaatc 37380
atatcttatc actggaggca gagtaaatga gtgaaattat gaagacaata attaggatac 37440
cattaccaga aggaggatgg attctagaaa gaaataaaca ataaatagac aactcaagct 37500
ggggctggtc ttacgtgtta aggaatgtag gatctgtatc taaggtgaat tatggaatag 37560
tagaaaatcc ataggcagga tacacattct tctcaaatgc ctataggata ttccctagga 37620
taagttatag gttaggtcat aaaacacaca tcaataaact taaaaaaatt aaaataatac 37680
agaatatttt tctgataaaa aataaaatga aattagaaac caataacaag tcaatgtgga 37740
aaatcacaaa tatttggaaa ttaaacaact tgctcttaaa taaccaatga gtcaataaga 37800
tgtcatgaga gaaattagaa aatactttag gatgactgaa aatcaaaaca aaccaaactg 37860
aaattaatga gggcagctaa aacaatattt aaagacaaat ttatactcta aatgtctata 37920
gtaaaatagg agatttccca aattgctaat ttaagctcct ttttaataaa ctagataaag 37980
aatagcaaat taaacctgaa gttaacagaa aagacaaata ttaaagaaga gaaaaacaac 38040
agagaaaaat caataaaacc aaaagttatt tctttgaaaa aatcaacaca attgacaaat 38100
ctttagttgg gctaaccaag aaaaaaagag gaaagacact aattattaga agtaggaatg 38160
aagagaggat attaccatgg atcttttaga aagaaaaagg gagcataaga aataaaataa 38220
aattaaacgc cagcaaacta gataacctat gtgaaattga aaaattccta gggagtaaca 38280
agcgcctgaa actgactcaa gaagtaatag actatctcaa tatacttata ataagtaaac 38340
attgaattca caattaaaaa aaagaaaact tcctgccaaa aaaagcctga gcccagatag 38400
tatcactggt gaattttgcc aaatgttcaa tggagcgtta acatcaatcc ttaacaaact 38460
gttccaacac atagaagaga agggaatact tctcacctca ctttctgaag ctagaattac 38520
cctgatatta atgccagaca aaaataatgc aagaaaagaa cacagacaca aatatagacc 38580
agccatatcc catatgaaca taggcacaac aatcctcaac aaaatactag aagccaaatc 38640
acataacata tttagatttt tagattatgt actctgaata agtgaaattt atcccagtga 38700
tgcagggctg gaccagcata aaaaattaat gtaatatatc atattaattt taaaaaacta 38760
tacaatcatc tctatagatg ctgtaatcac atggaaaaag ccaaagtgtt tcatgataaa 38820
aacactcagc aaacttgaaa tagaaaagaa cttcagcctg ataaacacca tctcaaaaga 38880
ccccacacct atcatcattc ttaatagtta ctttagatgc ttttatcttc aggtcaagaa 38940
gaaggcaagg atatttgctc ttgctacttc ttttcaatat tgtactgaaa gttctaacca 39000
gggaaataag acaagaaaaa gaaattaatg gcatctagat tggaacacaa gaagtaaatt 39060
ctattaacga atacataatc ttgtatttag aaaatcctat aaaatacaca cacacacaca 39120
cacagctgtt agaactaata aataagattg cagaatacaa gatcaatata caaaactcaa 39180
ttatatttct aaacactact aatgaacaat cagaaaataa aattaggaaa attctattta 39240
taacaacatg aaaaataata aaatacttag gaataaattt aataaaataa gtgtgagatt 39300
tgtacactca aagctataaa atattgttga aagaaattaa agaactacta aataaatgaa 39360
agcacatttt atattcatag attagaggaa aatattgtta agatggcaat actcaccaaa 39420
ttaatctaca aatttaacgc tattcatatc aaaatcccag ctacctattt tgcagaaagt 39480
gataaattga ctgtaaattt tatatgaaaa tgcaagagac tatatgccac acaatcttaa 39540
ctagaaaaaa aataaagttg gagaactcaa acttccaaat tttaaaactt actacaaagc 39600
aaaagtaagc aagatagttt ggtactggca taaggatagc tatatacatc aatggaataa 39660
aattgaaatt ccaacagtaa gtcttcatat ttatgttaaa ttaattttca acaagaccac 39720
tagacaattt tattaaggaa agaagccttt tcaacaaatg gtgcttggac aagtgaatat 39780
ccacatatga aagaatggaa ttgaaccctt acttaataac atatataaaa attaagatag 39840
gtcataggcc taaaggtaga gctaaaacta tgaactgtta gaaggaaatt tagaagtaaa 39900
tcttcatgac ctattattaa gcaatgattt cttagatatg ataccaaaag cacacacaat 39960
agcaataaga aaaaaaaggt tcattggact ttatcaaaat tagaaacttt catactgcaa 40020
acaatatcat caagtaaaaa gacaacttaa agaatggaag aagacatttg caacccagat 40080
atctgatcat gatttgtatc taatatatgt aaaggattat tataactcca caacaaataa 40140
aatagataac tcactaaaaa tgatcaaaat atttgaatag acatattgaa aaaggagtta 40200
gacaaaaggc caataagcac ataaaagatg gtcagcgtca ctggctaatt ttaggggaaa 40260
ggcaaatcaa aactaaaatg agataccact tcacacacac taagatggct ataatcagaa 40320
agaaagccaa taccattttt tatcaaggat gtggaaaaat tagaatggtt atgctttact 40380
ttgagaatat aaaatgatgc agtcactttg gataataatt tagctgttcc ccaaaaagtt 40440
tggggtagag ttaccacatg acctggcagt tttactaatt tcttcggata tatatatcta 40500
agagaattaa aaacatattt caacatgaat gcttatagaa tattattcat aatactaaaa 40560
attaaaaaca attcaaatgt ctatcacttg atgaatggat aaacaatatc catccaataa 40620
atgttattca tccataaaaa agaatgaagt attgctacaa tctacaacat gaataaacct 40680
tgaatatatt atattaagtg aacaaagcca gtcacaaaat ttacatatca tattgctaca 40740
tttatatgaa atgttcataa caggcaaatc catagagaca gaaaggagat gagtggttgc 40800
caggcagtag ggattagggt aaatgggagc aacaactaac taatgggtat gcagcttctt 40860
tttaaggcga tgaaaatgtt ctaaaattca ataatggtga tgattttaca agtctgtgaa 40920
tatattacaa gccactgaat tgcatactaa tatttcatag tatgcatgta tcactatttt 40980
ttcttccaat cacctattga tggatgttca agttgattcc agatacttta cccccatgtt 41040
gcagtaaatg ttcttgtata tatcaccttt cataatgctg tattaacttc tagaagatag 41100
atttccagga ttgaagtatt cccaatatta aacatattca tgtcacataa aaattagatg 41160
atatgcaacg aaatagggaa atgtgactca tagttaatag attaaagcgg tacatagaaa 41220
tagatctgga caggaacaaa ttgttagaat aaacaaaaaa ggactttgga ggcactattg 41280
taaatatgtt gagcaattta aaggaaaaaa aggggtcata aggaataaac agagaacatg 41340
agcagaaaaa aatgaaaact gtaaaaagga ataactcaga cattttataa ttgaaaagta 41400
cacattctaa tatgaaaaat tcactggatg tgtttaaaac aaaattgcag atgtcagaag 41460
aaatagttgt taacttggag cacattaata gaaattatcc aatttgaaca ctagagaatt 41520
aaaaggaaaa atgaactgag tctaactata atatgggata atatcaagta gtctaaatat 41580
ttatataatg ggagaatcag aaggagaaaa tagaaagaat ggaacagagc aaatatttga 41640
agaaacaatg gccaaaaatt tcccaaagtt ggtgaaaaat agtaacttac agaccttaat 41700
gttaccttat aaaatgttag tgaacatcaa caggataaat ataaagtaag ccatacttag 41760
gcacatctta gtcatgctgc tgaaaacaac aataacaaaa agctttggaa acaaccggaa 41820
gaaaaatatt tactatatac atgagactaa tgtcttacca gaaataattc aggccagaag 41880
aaagtggcca gataaaataa agaaataaaa gcccattatt ctacagaaag tgaaactatc 41940
catcagaaat taaaatgaaa taaagaattt taagataaac aaaaacctaa aaaagctgtt 42000
accaccagaa ctacactaca agaaatgtta atggaagttc tttaggccga ataggaaaaa 42060
tatcagatgg aaatttgttt ctgggaatga tggtcactag atatgaataa atgtgggtaa 42120
atacgaaaga ctatcttttt ttccttaatt tttttcacat ttattttagg ttcaggggta 42180
tgtagacagc tttgttgcat aaataaattg taaatcacag gggtttggca tacagattat 42240
ttcatcatcc aggtaataag catagtactc tatagatagt tcttcaattc tcatcctcct 42300
tccaccctcc accctcaagt gtctgttgtt cccttctttg tgttcctgtg aactcaatgt 42360
ttagttccca cttataagtg agaacatgca gtatttggtt ttctgttgct gtggtaaatt 42420
ttttaaaaag acaactgatt gtttaaagtg gggatttata acataggtaa gtgtaaaatt 42480
atgaaaagat ttgaactttt tttttttttt ttgagacgga gtctcgctct ctcgcccagg 42540
ctggagtgca gtggtgcgat ctcggctcac tgcaagctcc gcctccccgg ttcacgttgt 42600
tctgctgcct tagcctcccg agtagctggg actacatgca ccagccacca agcctggcta 42660
attttgttgc atttttagta gagacggggt ttcatcgtgt tagccaggat ggtcttgatc 42720
tcctgacctc atgatccgcc cgtctcggcc tcccaaagtg ctgggattac aggcatgagc 42780
caccacgccg ggccagaaca ttttatctaa agtgttacaa tattaatttt acatagaaaa 42840
ttacaagaaa gtatccctca tgaacacaga agcaaaaaat cattagcaaa atattatcaa 42900
taaaatctag caatagagaa aaaagtaata aatacttctt aaacatgtgg ggattatctc 42960
agaaaagtaa gattcattta acatttgaaa agtgatcaat taattggcca tattacctct 43020
aaaagaataa aggaaagcct aagatcatct caatagatgc agaaaaggat ctgacaaaac 43080
tcaacagtca tttgtgagaa aaactgtcag taaactagga atagaaagta gctatctcaa 43140
gttgttaagg acgtttcaga aaaccctaca tctagccggg cgtggaggct cacgcctgta 43200
atcccagcac tttgtgaggc tgaggcagtg gatcacttga ggtcaggagt tcgagaccag 43260
cctggccaac atagtgaaac cccgtctgta ctaaaaatag aaaaaattag ctgagcgtgg 43320
tggcaggcgc ctgcaatacc agctaacagg gaggctgagg caggagaatt gcttgaaccc 43380
gggaggcgga ggttgcagtg agccgagatt aagccactgc actccacact tcagcctggg 43440
caacaagagt gaaactctgt ctcaaaaaaa aaaaaagaaa aagaaagaaa accctacacc 43500
taatatttta cttatcagtg aaatgttgag gtagtgaatt cttgcccctt agaaaaattg 43560
agtgctttcc ccttaacata gacaaatatg tctattttta ccatttttat ttgaccttgc 43620
actggaagtt ttatcaactg aactaaagga aaaaaaaaca aaacaaataa aatgcataaa 43680
tattgaaatg tggtaaatta tctatttcat caacatgatc atattgtaga caatcctaat 43740
aaatctttaa aactgattag aaataaacgc gatattaaat attttattta ccataatatc 43800
aaaaaacacg aagaatatag taataaattt aacaaatcat ttcgagacac ctattactaa 43860
aaacctcaaa acatggctga gaataattac agaagattta aacaaatgga aatatatatg 43920
ccatgttcat gcaatggaag attcaatatt attaagaaat taattctacc caaatgtatc 43980
tatcaattca acccaatccc agtaaaaatg tcacagattt tctttgtaga aattgatgaa 44040
ctgactttct atgcaaatac acagtgctta aaattgccaa aacaatactg ataaaagaat 44100
aatgaaaaca ttaacctacc tgacttcaag gcttgttata aagctgtact aatcaagaat 44160
ctacagtatt ggcataaaca aagatatcaa tggaacataa tgctgagttc ataaatagat 44220
ccaaactaca tgtcaatgga ttttttgaaa taaacactac agaaaggaaa tagaagaaag 44280
gaagtgtttt caacaaaata tcaggaacac ataaataaat gtatggaaaa taaatgaacc 44340
tccacttcga tcttatgcca agtgccagaa tcaataagga ttgtagacta agcagaaaag 44400
ctaaatcaat aaaacatctg aaataaaaca caggagaaca tctttgagac cttggggtag 44460
gcaaaaattt attggaaaac agacaaaaag tgctatctat tatttaaatg tccatgaaat 44520
ttcaaacaat ggagacctac tgaacaaaaa agaaaagtct agtaatatac acatgggtga 44580
atttcaattt gaagtattca agtaatattt ggaaaagtca ctaagactgt caggtctctg 44640
aggtaaccac ctaggtagag agagattcca tttactgagt tagcaaatat cagaagagaa 44700
gcaaaactgt ggagaaaaag cagtaagatg aattttggac ctgttgaatt tgagatgcct 44760
gggagatagt ctttcaaatg taggtattga ataggcaggt gggtatgtat ttctagagac 44820
taggaggtat gcttgaacag aaaaatagat tttgaaatat gaactattat aaaaatgtaa 44880
cttattataa aaggaaaact aaagtaagag gggtctagac agagagagtt ctgaataaat 44940
ccagtatcaa atgatttgtt agaggaagaa aatcaggtga gtagcatcca gggaggtgtg 45000
gatcacagaa gctaagggca gaaaatattt caatgaacaa ggaacagaaa acaatgcctg 45060
aaacttctaa aagggcaagc aagcaagata attgtttaaa aaatttcgtt tggatttatt 45120
ggtgatgtcg gtcttgttgg tgaagtttgt taaagccatt tggtgggttg tggagtaagg 45180
tgaagaaatg gaactggcaa gtgtagacaa gtatgcaatc ttcgaaagaa atctggccat 45240
aaggaaagga tagatggtgg cacctggaag gggaaataga gtgcaaggag agtttctctt 45300
atgacagtgg tgatatatat attttttgtt tgtttgtttg ttttttgaga cggagtcttg 45360
ctctttcgcc caggctggag tgcagtggcg ctatctcggc tcactgcaag ctccgactcc 45420
cgggttcatg ccattctcct gcctcagcct cccgagtagc taagactaca ggcgcccgcc 45480
accgcgcccg gctaattttt tgtattttta gtagagaaga ggtttcaccg tgttagccag 45540
gatagtctcg atctcctgac ctcgtgatct gcccacctcg gcctcccaaa gtgctgggat 45600
tacaggcgtg agccaccgcg cccggcccac agtggtgata tttttaaggg agagaaggac 45660
tcggtaactg ttactttcta taaagaaacg ggaagtagcc agtagtagaa atgttggtta 45720
attgagaatg aattccttgc aaagtccaaa ggaaaacaca taacacaatt tgagagatta 45780
gctcaaaaca ggggcacttc tttcatttta acaagaagag aaaggcaaag cacagttacg 45840
gatgtaagta gtctagtaga taaagggaaa caaagttcag gctggctgac tttcatcacc 45900
tctaagacgc tgaagtactg agactgtgct tctcagatgg gaaggcataa gcaaaaatgg 45960
ctgaggttat gtgcagaaga gaaagtttga aatagtttta gataatagaa atggagaaag 46020
gaaaatactg cttccctttc gccaacaaaa ggaaattttt ttaagagttc ttactatctg 46080
tagagctagc cgtgagcatg tttattacag cttacatgac atcttagcac cagtctcatc 46140
tgcagggcca agggagggga ccaatccatt tggcttggtg atggaagccc gcactgctag 46200
gtaatcattt ggtaagtttt tggagggcta gaaagatcag agacagagcc aaacagttga 46260
tcacaatgag tcagttgcac ctttcatatg aaaataatat taattttatt gacttaatcc 46320
gtgtactctt tatcatttga taaacattat atatagtgaa caattattga tttgaatgca 46380
aagcatttgt agatactaag ttgttggacc taaaccaatt ttttaaaatc agaatttaat 46440
ttatatttgt tgggagtaaa ttaagttgct caataattat tcgtgtttca agagtatttg 46500
ctcatataat gaactacact tctcatttag gtcttcacag ggatcttcac agcagaaatg 46560
tttctcaaga taattgccat ggatccatat tattactttc aagaaggctg gaatattttt 46620
gatggtttta ttgtgagcct tagtttaatg gaacttggtt tggcaaatgt ggaaggattg 46680
tcagttctcc gatcattccg gctggtaaat taactgggag tgttcataaa atgtactttg 46740
taattaatta gtcttcattc tcatctagta aaaatggcaa gatttcccat cattataata 46800
ttatttgaat acacttctaa aacaaattgg attgccatac caccaaatgg tagtttcttc 46860
ttcatcatag ctttaataaa gttcacttaa atgaatagtc tacacttctc ttcttagtta 46920
ttgaatggaa ggctaataga gaggaggaaa cagggagtca cagataaact cgaatcacaa 46980
ttaaacaaca ccatagtcaa ctctcagtta tctgaggttt gcataactgc gtacaaagct 47040
tccttgggac ctaggatgag ctcccctttc tgccaggaac taaagaatta tggaattgtt 47100
cattgctcac cttgtccccg tagaggaaag agttaagaca ggggatagtg tacaaaggag 47160
aaggataagc aaacagagct ccccatatga ctgctgccac atcagaaaat caccaaatca 47220
ctctttgaaa gagttaactg tactatattt tgttaatttt aaagaaagta tctttctttg 47280
atcttttata aaaactatta gatcttaaaa ttcagagata aaatatcact tgacacattt 47340
ccagtgaaag tttgatatgt tttgttatac tattactttg agttggctct aagttagtga 47400
tttattttca aataacagag gctgtacacg gttactaagg acacgttcct atagatgatt 47460
taccttagta gtgattaggc tgaagacttt ttcatgaaat ctgtttacaa tttccctttc 47520
tgctttcaat gttcaaattt gagttgtaat ccttagaact atatttcctt ccctaatcct 47580
caaagatagt tatgaatcta atttgaatct agaaggatgc aaaaaacaga acaaaaattt 47640
aaaatgataa aacaagtaat atgggcaaga acttaaaaaa atatatttag taaaccttca 47700
tgatagtgtg atgcagttaa gggaaatagg aagcatagta tcactagaat cttacttagt 47760
gtgtcaggct cttttgcata aattattctc tggaataaat taaatacttt ggtgcatgta 47820
tttactcctt tgggtcactt tgatgccatt aaataatgca ctactttcag cctgacattt 47880
actgaagcat cagaaataaa atgctgctgc tctttaacca taaatggtac ttcagtgaac 47940
tctaaagcta atacaaccaa tatgtcaaac acaatgagaa agacatttac acactacact 48000
gaattaagtc tatgaagata taaaggttaa aaagaagcct agcgttttac ttaagtttaa 48060
gtatttttgt atttgaatat aatatatgtt taaaatatag cctaaagtta cagcaagcta 48120
aagatatagc tagattaaaa caatctaaag acaaagaaat tagttcattt ctgcttccac 48180
tttatgtaat ttaagtgttg atattattct cacctgtgca tttcagcata tttaaagtac 48240
actgaaaact atatctgctt tggcctttta aaaataatga gagttcctac ttctctgaaa 48300
ctggatctct gctaattaac caccattaat ctgaaatatc ttaattcctt aaggagaaac 48360
aaaagtgtat attacatatg cttatgtagg atacttgaaa atttggtgta tcttattaaa 48420
ctgccaattt aaaaactgta taatttaatt atttcattta cagtatggac catttcaaaa 48480
tgaaaaaaag aatgctctat ggtagcaagt cactgctata tttgttagtg atcatttgac 48540
aaataaataa ttcatcattc tataattgag acagttacct gtacatttgc cctgttaata 48600
aaattacaga tttttccctt cctgtgtcca tgtgactaac ctgcacattg tgcacatgta 48660
ccctaaaact taaagtataa taataataaa ataaaataaa aataaaaaat aaaaaaataa 48720
aaataaaata aaattgcaga tttttttaga aatgcagagc attaacactg ttcttgcttt 48780
tatttccagc tccgagtttt caagttggca aaatcttggc caactctaaa tatgctaatt 48840
aagatcattg gcaattctgt gggggctcta ggaaacctca ccttggtatt ggccatcatc 48900
gtcttcattt ttgctgtggt cggcatgcag ctctttggta agagctacaa agaatgtgtc 48960
tgcaagattt ccaatgattg tgaactccca cgctggcaca tgcatgactt tttccactcc 49020
ttcctgatcg tgttccgcgt gctgtgtgga gagtggatag agaccatgtg ggactgtatg 49080
gaggtcgctg gccaaaccat gtgccttact gtcttcatga tggtcatggt gattggaaat 49140
ctagtggtat gtagcaaaaa cattttcctc attttcatta aaagataatg taatcattaa 49200
aaagtgtgtt caactgaaga atattttgta ttttttaaat caaggccact tcctattgtc 49260
tattactcat gactgtaaga gccatgtata gtttagacca ttgtaatcca cacaaaccct 49320
taaactacct tttgaaccaa agttattctt tctttcatta tccttcttgc tacaaggaga 49380
gaaacttttc tgttatttat ctttcagttc ttgtactaga gcatggaagt gttacttaga 49440
acactcattt tatttataag tactagcaat aacacctgaa aacgtttcag atttggtttt 49500
ctacaaattt aaaaactagc aacaatctca gtttattaag agctcatggg gttttcggtg 49560
cctagaaact atggtatgag caagtaacat tgtctctaaa aacattaatt gtcatttctg 49620
cataaaatta accaccccta acaccatata tatttaggat agttagctct tcttgttgca 49680
ttgatccctt ttaccattat gtagtgtctt tctttgtctt tttttaatct ttgttggttt 49740
aaagtctgtt ttatcaaaga ctaggattgc aaaccctgct tttttttttt ctttccattt 49800
gcttggtaaa tattcctcca tccgtttttt ttgtgcctat gtgtgtcttt gcatgtgaga 49860
tgggtcacag cacaccgatg ggtcttgact ctatccaatt tgccagtctg tgtcttttaa 49920
ttggggcatt tagcccattt acatttaagg ttaatattgt tatgtgtgaa tttgaccctg 49980
tcattatgat gctagctggc tattttgctc attagctgct gcggtttttt cataatgttg 50040
atggtcttaa caatttggta tgtttttgca gtggctggta ctggtttttc cttgccatat 50100
ttagtgcttc cttcaggagc tcttgtaagt caggcctggt ggtggcaaaa tctcttggca 50160
tttgcttgtc tgtaaatgat tttatttctc ctttgcttat gaagcttagt ttggctggat 50220
atgaaattct gggttgaaaa ttcttttctt taataatgtt taatattggc tcccactctc 50280
ttctggcttg tagggtttct gccgagagat ctgctgttag tctggtgggc ttccctttgt 50340
gggtaacccg acctttctct ctggctgcca ttaacatttt ttccttcatt tctaccttgg 50400
tgtatctgac aattatgtgt cttggggttg cttttctcaa ggagcttctt tgtggtgttc 50460
tctgtatttc ctgaatttga atgttggcct gtcttgctag gttggggaag ttctcctggt 50520
tatcctgaag agtgttttcc aacttggttc cattctccca gtcactttca ggtacaccaa 50580
tcaaacttag ggttggtctt ttcacatagt cccatgtttc ttggagactt tgttcgttcc 50640
ttttcattct tttttctcta atcttatctt catgctttac aaatttaact caacatggat 50700
taaagactta aatgtaagac ctaaaaccat aaaaacctta gaagaaaacc taggcaatac 50760
cattcaggac attggcatgg gcaaagactt catgactgaa acaccaaaag caatggtaac 50820
aaaagccaaa attgacaaat gggatctaat taaactaaag agcttctgca cagcaaaaga 50880
aactatcatc agagtgaaca ggcaacctac agaatgggag aaaatttttg caatctatcc 50940
atctaatatc cagaatctac aaaaaactta aacaaattta caagaaaaac acaaccctat 51000
caaaaagtgg gtgaaggata tgaacagaca cttctcaaaa gaagacattt atgtggccaa 51060
caaacatatg aataaaagct catcatcact ggtcattaga gaaatgcaaa tcaaaaccac 51120
aatgagatac cacttcacgc cagttagaat ggcgatcatt aaaaagtcag gaaaccacag 51180
atgctggaga ggatgtggag aaataggaat gcttttacat tgttggtggg agtgtaaact 51240
agttcaacca ttgtggaaaa cagtgtggca attcctcaag gatctagaac cagaaatacc 51300
atttgaccca ggaatcccat aactgggtat atacccaaag ggttataaat cattctgcta 51360
taaagatgca tgcacacgta tgcttattgc agcactattc ataatagcaa agatttggaa 51420
ccaacccaaa tgcccatcaa tgatagactg gataaagaaa atgtggcaca tatacaccat 51480
gaaatactat gcagccataa aaaagagtga gttcatgtcc tttgcaggga catggatgaa 51540
gctggaaacc attattctcg gcaaactaac acaggaacag aaaaccaaac actatatgtt 51600
ctcactcata agtgggagtt gaacaatgag aacacatgga cacagggagg ggaacatcac 51660
acactgaggc ctgtcgaggg gtggggggct aggggaggga gagcattagg agaaataact 51720
aatgtagatt acgggttaat ggatgcagca aaccaccatg gcaagtgtat atgtatgtaa 51780
caaatctgca tgttctacac atgtatccca aaacttagag tataataata atttaaaaaa 51840
attaaccata cccaacacta gtgtcctgaa tcttgaaggc atggagaagt tgggaaggca 51900
tgggaagata aatataacaa agtgatataa catgtactca aatagaatta aaaataggaa 51960
gtaactaata tgtgtccaaa aatatgaaaa caaagtgcca tgtgtcaagt ttacaaaatg 52020
taaaccttgc tttacaatag gaaggttgat cagggaagtc tttgtcaaag agtttggacc 52080
taaaatatat ttaactgaga tgtaagattt agcttggtag gaagaaagac catcccaaac 52140
aaggaaacaa ggtacccagt gactgaggga tacaggacag tagactctgt gagaagtatc 52200
aggctcttat gctttaaata tgaagtaatt acaccgagtt gcttaattag aacccaaacc 52260
aatggaatag aaaaatgact accataacaa gtaatttaat gtatatactc ttgccaggct 52320
cagtggctca cgcctgtaat cgcagcattt tgggagactg aagtgggcgt ttcacttgag 52380
gacagtagtt cgcgaccagc ctagtcaaca tggcaaaacc ccatctctac tagaaataca 52440
aaaattagcc aggcgtgatg atgcacacct gtaatcccag ctacttggga agctgaggca 52500
cgagaattgc ttgagcctgg gaggcagagg tggcagtgac ccgagattgt gccattgcat 52560
tccagcctgg gtgaaagagc gagactctgt tgcaaaaaaa aaaaaaaaaa agcatatact 52620
ctttagacat gatttcctct catataaagg taacctccaa gtccccaaag atagagaaag 52680
gggaagggaa aaaggcaaag tattatttta tttttattca ttgccaaatt tcagcctctt 52740
caacattact tttgataatt ctgatctatt tttaaagtaa caagaaacat aaacagtgta 52800
caatctagaa ttataaacag tggcttaaaa caataaacac tgattacttc atagtttctg 52860
tgggtcagga tttggggaat aagttagctg ggtggttctg gtttaggatc agtcatgaag 52920
ttgctgtcga gatgttagct gaggttacag ttatcttgac tggggctgga ggatcagctt 52980
ctaagaaggc tcaatctcat gattattgga aggaggtttc agttcctttt tggcagttag 53040
ttgaaggtct cagtttttct ctgcaggacc ttttccatag gactgttgag tgtccttatg 53100
atatggcagc tggcttcttc cagggaaggt gatgtaagag agaaggcaag gagaaaatcc 53160
tctttatgtt ctactcttga aagtcactct tcaccacttc tgccatattg tattcattag 53220
aagctagtca ctaagaagag ctcaagctac tataatcccc aagacaactt taaaatgttt 53280
gctttcagaa aagtataaga tcacatagaa cagaaagtgc catagggtta catagaacag 53340
aaacaaagaa aagataatat aattatgtta tagatttgat ttcattttct ctgtatgtat 53400
atttggtata tgttggaaga agaaaagaaa acgcagagaa cagaatcctt tatgacaaca 53460
tgaatgatca gacagcaatg gggaattaag aaatataagt ttgggaccag attgggtaga 53520
atttaattta tgaaaaggct gactgtgcat aataaaatgt attttccttt aggcaattca 53580
aagctacaga tgatttttta tcaggaaagt gacagtgaac cagtgatatt tttcagaaat 53640
atacgtagca ggagaatgca gaatagattt aaagaggatg aaactcagcc caccacatgt 53700
tatctattag tttactgaaa ttaacatatc tctctaatgt ataaatgtgc agaaaattga 53760
agttgaaaag agaatttcag gaaatatcaa gtacttatgg ttgacatcag tattaattta 53820
gattgtgatg tatgcataaa aagatatagt ttataaaata atcatttcca tctactgggt 53880
gtaaatttaa tttttgttct tttaagagag aaaaattaaa ggttctcctt tctttttgac 53940
tatcagttaa aataacttct ttgtcttgtg ataacctggg tatgtttctg gagtagctaa 54000
ggtagtcata tatatcatgt ttaccactat taaggaaatg tgcttatata acatttgctt 54060
aagactgaat gaacttgata tactcactcc ttactacaat tcttccttcc tattctcact 54120
ggaaaaatgg gaaaggtgtc ccaaagacaa aatggcataa cttcctttta acacacatga 54180
actatcagat gtggctccac ccaaatagat gtagtagtca caatggatgg gactgccagc 54240
ctagtctaca gacaagacag agctgggacc acaaactact gtttcccaga ccaggatttt 54300
tatgagccat tcttagtttc cagacacgat ggcaagagac ccttcattgg ttgaagatag 54360
gtgctgcaga aaaagaatgt gactttctga aaactgatag ttctagaagc agagaagaca 54420
acttcctctc tccctaagtg aaggtgaggc aatagcacac aggagggatg tgaaggtttt 54480
ggcttcctct cacaagttgg gaatcaggat ggagaaacaa ttaaaatatg taatatgttt 54540
caaccttgaa ttcaaaatgg aaattatggt aacatttcca ttccaagagg ctaatttgag 54600
acacaagaaa gagttgattt catttactga gctagcacat ttgtgaaaca ggattcagga 54660
tttcagtccc tgagtgagct tgctgaactg ttttctttct tttttttttt tttttttttt 54720
tttttgagac ggagtctcgc tctgtcgccc aggctggagt gcagtggcgg gatctcggct 54780
cactgcaagc tccgcctccc gggttcacgc cattctcctg cctcagcctc ccaagtagct 54840
gagactacag gcgcccgcca ctacacccgg ccaatttttt gtatttttag tagagacggg 54900
gtttcaccgt tttagccggg atggtctcga tctcctgacc tcgtgatccg cccgaggcct 54960
cccaaagtgc tgggattaca ggcgtgagcc accgcgcccg gcctgaactg ttttcttaaa 55020
ttgtcatgga tcacaccaaa cacctgtgcc agctgttatg cgcataccct tcggtaacaa 55080
aggaagtcca gaaaaagaga ataacttgac tcacacaaat atttctaggg aaataaggta 55140
aataaaaaga tagtgttgtg gaggataagt tggataatag taagtgataa cagctaaact 55200
ttctcaaagg ttcactatgt gccaagaact gtgctgaaag ccacatgaat tctgtcactg 55260
aatcctttca acaaccttgt aagctgggca ctagaaaaac gattacattt attttataga 55320
tgaggaaact gaggctcaga ttggttatgc tacttagtag gtaacagaaa atcgattctt 55380
acctagcact cgaattctaa aatatgtgct cctctatgtc aagtaatcta tagaactaag 55440
ataaacatgc tgatgaaagt tagtgtctag tgggtattaa taaacgcggt ttcaaaactg 55500
tgtcaccacg ggtagattgg ctgctttaaa aaaaataaaa acttcaatgg atttatgaga 55560
aagaaaagtc atatgttcca gggatattta tttattttcc tgacagtgga atagcattga 55620
attgagttat caattcataa aagatcagag aaacaattcg aaaattaata gtaaacccta 55680
ttatactgac taaatatggt agcagttcaa agaaaggaag tatcggtaag agtaaacatg 55740
gaatactgtt tcctcactta ttctgcaaac atcacaatta ggagaaaaga ccttgtagtt 55800
agactttcaa aaaaaaaaaa gcttctctac ttattaactg tggtcttgga caagtcatgt 55860
aagttgtgca gaagcatttt catctgtaaa atagtaataa ttcctgcctt atagagttgt 55920
gagaaataaa tcacataaac cttgaaaatg ctttgcacaa taactggtat ttactaagag 55980
ctcaactaaa aagctggttt tacttttatt gttattatga tctggtattg atactgctct 56040
aggacttggc tctaaggcat gtttctgacc aaaagatctc ccaatctatc agtaaagctg 56100
tgcttgtttt tttttttttt ttaaagaatc caatataatg tgatagggat gtggatgaga 56160
aatttaacag gacagaatga gaaatgggag caggctatat aaatgtcaca gtaaatgaca 56220
tttgtaaata gagtatttgt ccagtacaga ggcaatataa ttggctcccg ccctggggaa 56280
ggattgatgg atgtgtatca agaaaaattt ccaaatagac aaatgacaga actttaatat 56340
actttaggaa aataagtcta ggaaatagca ccaaaataga taaaataaaa attttacatg 56400
caattttttc ttcctttgtc tgttttttta atccaaataa taagttcaaa agcaaattac 56460
aataaaacat aattttattg gtaaattcca gaggcaaagg agcaggtctg gtcttaatgt 56520
gattatcagg agtcatagta tagagactga cagattgtca gtacactctc aaaatcaaac 56580
gtggtcttca ttggatctta catattttta ctttaaaaaa aatcaccatt ggttagacta 56640
acttacaact aattagacaa aggtgctgta agcctcatta gcatgataga agcatgagaa 56700
tatagcaaga atgtagaatc ctttttattg aagttttact taaaaatttt cctaagattc 56760
tacttttgta ctacagtttg agcatcccta atctgaaaat ttgaaatcca aaatgctcgg 56820
aagttcaaag cttttgagca ccaacctgat actacaagag gaaaattcac atctggcctc 56880
ctgtaatgaa tcgcagttaa accacagtca aaatgttgtt tcctgaacta aattattaaa 56940
aatattgtat aatattacct tcaggctatg tgtatgtgta tgaaacttaa atgaatttta 57000
tgtttacaca tgtgtctcat tctcaagact tgtcattatg tacatgcaaa tattttaaaa 57060
tctaaaatcc aaaacacttc tggccccaag catttcaaat aagggatatg caacttgtat 57120
ttactttgtg catttgcccc cctttactgc tatatctttc ttttgttctg tatgttatgt 57180
gtgcttaaat aatcaggaat tcattgatat tgtcaatcaa atcctgaaaa aaaattatat 57240
gactcagtct tgtacccctg agaatgtctg atttcttcgt aagttgtctt tttttttttt 57300
tccacaatag tgagtttaat gtcatgaatc ttttcactca ttcatactgg tggagcctat 57360
ttttaaagac ccaatttgca gactgattac tgtccttatt catggcaata cttcaactcc 57420
acaatcttta attcaacaat aacatcataa ttattgtata ataaccattt tatagtattt 57480
ctcactattg tataattata gtagccataa ttgtcttaat aaaaattggg acttttcatc 57540
cagcaataaa tacgtttttg tctgatttgt ccagttatct aggtacaaaa aatggtacaa 57600
aggcacaaaa ataaaatcat atttaaatat attgggataa ttgttgattt taggaataaa 57660
ttatcagtgt ttccggaaat ccaaattaca tagtcaaaat agcatctgta ttaggccatt 57720
cttgcattgt tacagataaa tacctgagac tgggtaattt ataaagaaaa gagatttaat 57780
tagctcatgg ttctgcagtg agcttggtgc tggcatctgc ttggcttctg gtgaagtctc 57840
aaagagcttt caatcatggc agaaggcaaa gtggagcaag catttcacat gatgaaagca 57900
ggaacaagca agagagaatg tgggcaggag gcactacaaa cttttaaata acaacatctc 57960
atgagaactc actaacatga ggacagcacc aaggcatgag ggatctgacc ccatcatcca 58020
aacacctacc accaggcccc acgtctagtg ctggggatta caattccaca tgagacttgg 58080
gagggggcaa atgtccaaaa tatatcagca tcccaaataa aagggttttt tttgtacagt 58140
tgtctatatt tatcttttgg aactgagctt aatagaaatg tttcatttag caatgatttc 58200
agtattttct gcaatgacta aaaagcaaat agtgataata gtattatttt atattgacca 58260
agcattttta tttcattcac tttttttcag aatagtgtat catgaattag cagaaatgca 58320
tgttagaata aaataaggtg tcaagaacaa tcttagaaaa ctaatgatgg aaagcaattg 58380
aagcaataga atgttttgat cacctgtttt tcctgctgtg tttcaggttc tgaacctctt 58440
cttggccttg cttttgagtt ccttcagttc tgacaatctt gctgccactg atgatgataa 58500
cgaaatgaat aatctccaga ttgctgtggg aaggatgcag aaaggaatcg attttgttaa 58560
aagaaaaata cgtgaattta ttcagaaagc ctttgttagg aagcagaaag ctttagatga 58620
aattaaaccg cttgaagatc taaataataa aaaagacagc tgtatttcca accataccac 58680
catagaaata ggcaaagacc tcaattatct caaagacgga aatggaacta ctagtggcat 58740
aggcagcagt gtagaaaaat atgtcgtgga tgaaagtgat tacatgtcat ttataaacaa 58800
ccctagcctc actgtgacag taccaattgc tgttggagaa tctgactttg aaaatttaaa 58860
tactgaagaa ttcagcagcg agtcagatat ggaggaaagc aaagaggtaa aaatgtttaa 58920
ataaggagat attttggtgt tatataattc tgttgtttaa aattatcagg tgtttttaaa 58980
ttgcgtgttt ccttcctgtt aagaaaatag aaaatatctg tctagcaata tattttccat 59040
ggaaaagttg gtaataaata aattaatgat agattaaaat atagctagat taacaatatg 59100
ctgacttatg tttccaatac tgacattttg aattcttgac agtattcttg atatgaattt 59160
tttcagtatt tataaataat tttaaatttc tcaaaatgcc tcaatttctc cactttcttc 59220
cttgtaattt gcccacaaca gtgttttttg tacgtactgg aaaaatatct gatgagaggg 59280
tagttgcaat tctcatcttg ctatgttctt agttcttaat tcttacgaaa tacgtcataa 59340
aatagtattg tattttgttt gcacagacat atttactcaa ggaagatctg attgggatct 59400
tggcttgata tttatgtata gtttatcttt cctgaagtca gtcagttttt ttgaagagaa 59460
ggtattgatg aggaatcaca ctaaaaacat atttaaccct actgagctca gtgttcactg 59520
tttaaagaaa caaaaatcct taatacatta tagaatgtaa aattctgaat ttaccaactc 59580
agtaagtcct ggtaacttaa tgtattcttt gatttacaag aagggtatga gcaacagaat 59640
atattttttg ttttgtttgc tattaacctg ttgctcaata agtacagagt tggaggtaaa 59700
gagaggaatt taaaaccttg atatttaatt gtttatacaa aaatgaagac aagatttcca 59760
gtaattaaag tttgcactaa ctaacaaaaa taacaaggaa aaacaaagat tcgttccttc 59820
ctcatacgaa ctgtttggcg aggaagataa aagcttctat tcctgatgtc gggaaagaaa 59880
gaatgacgac atgggggagt gtgggcactg aaaggtaaaa tttaagtagc acaacatgat 59940
catgataatt aacaatcagc caaaattatg agggaaaata tagttataaa aaaagaacaa 60000
agatgggtgg atcacgaggt caggagttcg agaccagcgt ggccaacatg gtgaaaccct 60060
gtctctacta gagattcaaa aaaattagcc aggcgtggtg gtgcgtgcct gtaatcccag 60120
ctactcggga ggctgaggca agagaatcgc ttgaacccag gaggcagaga ttgcagtgag 60180
ccgagatcac cccattgcac tccagcctgg gcaacaggat gaaactctgt ctcaaaaaaa 60240
aaaaaaaaga actagctatt tcagacactt tttctgtatt tatttgataa aattactaaa 60300
gagtatgtta ttttccattt tttcttgttt gtaagttacg tagtattgct gttagtgatt 60360
aggtagaagt agatgtttaa tgggaaattc agacaatctt tgaatatagg aaggtataaa 60420
taacagggac ataggtatca gtttcacaag aaataactga tgagattcaa gggaaaagta 60480
ataaaacctt ctgtcctggg gcaaagaatt actttaattg gttgaactta aatttttact 60540
aactagatta ttgtttgaaa gttgaataat atcttaaaat cttattaaca aaattttgaa 60600
caagtgttgt tacaatagtt gggttatgct ggaagggtgg agtggcccaa tttcatatac 60660
agtgtactgc tcttatagaa gctgaagtcg gcatttataa aatagaattc ggtcatttga 60720
attttgatgt atattcccct ctcattattt tgaaattatg cctaatggtg aatatttccc 60780
taatagtaaa aaaagtcaat ttttattttc acacatgttt agttttaggc tgtcatataa 60840
actaagaatg aattatacag tatcaaacgt tgaagccatt ggctagttta atcttttagc 60900
taagtttcag tatcttttga ggaatgttta acttgacatc cagtcttctt aactttaaga 60960
gattttacag ccgtgggttt tccaaaagag cgtgtatttt gccttaactt aagccattat 61020
gtctgaagta agagggaagt ccagtgatgt ggggtttaga gtagggacat ctcttgtttc 61080
tcttgttatc attaagcttt ttgatttgtt ttcccattaa gttagctctg agttaaatac 61140
tctaaaataa tatttgtgaa ttcagtattt cagaattgga ggaagagaac tgacctgcca 61200
ggtggaagca gacaggatta ttttattgct tgagttgtgg agtccttcca ataccttccc 61260
agcatagaga ctgttacttc agtgttaaca ttatttggag gggtttttaa ttctggcttt 61320
atatcaaact ttctagacat aaatttataa aataataaat gatgagggtt atcgccgtga 61380
aagaggttat gtgtaggttt tgatctttca gaattttacc tggtagctct acactaaaaa 61440
actagagaat taaaacaatt attgaagaat ttcagacact cgcatttgaa atagcatttc 61500
ttgcctgcct tctagtcatt tttgtctggt catttttcta actgggggac aggattacat 61560
tgttaaatat cacaaagtag taagaaacat catgaggctt attaccaatc ctttctaaat 61620
taatttttta attaaagaaa aaatgaggct tttttactgg aatgtctaaa tgaatttttt 61680
tataaggcag actgagtgga ctcagaggtt ttttaggtgt tcacagtaag tcctctgcaa 61740
tgtctttgct aaatttgtat gattcttcag tagttttctg tagattctct agagtaggcc 61800
atttaaaatc atgtcataat cccctatgct ttaattttaa tgttatttcg attatattaa 61860
tgtaattcct tttgtgattt tgaatgattg ttttttcttt tagagtattt aataatgtgg 61920
aagccatgct tgaatgacta tttttcgaag tgaaatttag tagtgcgata tggtgacctt 61980
caccgcttac cattcttact tctcacagga gtaaaatcaa gctggagcca tcaagaatgc 62040
agctctggtg ttttttaacc agccagaggc tcgtgccacc acttttaccc aggttaccca 62100
agcaagttgt acatctataa atataatcag tttctaaatg acttttgact ggcctgcatg 62160
ttactcagct acgttccttg cccttccatt ggcagtaaaa taaaaacatg cacagctgct 62220
attatgctga gtcatacaaa gcatggtcag gcaagtctga caaccctaac ttaaaaaaaa 62280
gtgatttagc tgctaatttt cttacataga ttttaataga aattttattc aatgaaaagt 62340
aaaagtgcat gcctttatgg attatttaat ttccttttaa tgttacagag ttttgaacat 62400
attaggagcc caaaggagaa atgtaggtgc tctttgaaaa cttgcaaaaa tgctttttat 62460
cctctgtctt taaaaaaaag atagcccagt tactgtactt aagtcttgac agttttttat 62520
ttagtgtaat gtttttctga agggtaatct tcaaattaaa gcaatccctt attcatatgc 62580
aaacttccca aaggatgttt taatgtgata ataatgtaaa tgaataggaa tgtctgtgtt 62640
tcagttgcta gcagcatggg tataatattt atctgcttca ttttagggaa aatggcactg 62700
ctttatttag gagttgacca acagtatttt gtatttagaa tataatttct ttggaaagtc 62760
tgtttatatt tacccttaaa actcttagac tgaaagaaaa ggaaatcatg tcttttgtat 62820
accaaataat aataataata gtgataatga gagacttata gatggtatgc tccttctaaa 62880
aatagattta gagtccatct tcttcatttt cttggctcct ctgtgctttc tctcccctct 62940
attttattga gacctgctgg aaaactttct cccgaagaat attatttaaa tttatcatga 63000
tccacaaact cctgtatagg aaaagaatca gaaactcttg ctcctagggt gtttttaaaa 63060
tgaagagact tccctatcat gtgacaatag caataaacgt aacatcattc tatgggatcc 63120
attagtcgac cttcatttct taatgttgaa atcacagttt tatgcacaaa tatttaacca 63180
aaatgcctaa acccaattta atcattttta agaaatgtta attattttgt cacttagata 63240
cagtttcctc tccttttgcc aataaaacta taaaacagca ctaatataaa agtgtagttg 63300
gctatttgga agaagcaata atcatgccat tcctggagca ttcttttata ctttggaaca 63360
aaatattcca tcactggctc tccagattca tgagctataa tgcctcatat attggaggaa 63420
tgggatgtaa aatgggatcc aagatgcgta attgtttaca gttaaacaca gatgcgcata 63480
tacacaggga ctacagataa ttactttttc ctattatgta ttaattcttc agaaaagcat 63540
gagatttagg cactttcgga taatagcttg tttctcggaa agaggcaagg gtagtttcct 63600
tattctctga gtatcccatt ttgccaattt cctgtttaga aagatacttg aggcatatta 63660
tccatcaacg tatctagggg attcagctgg agtaaaggtg gtagaataga agctaagaag 63720
gaactggttc gtttattttc aatcctcaca ttatggcaat ttttgatttc cttgtaaaag 63780
tctatgattc tccctcagga aacattgtcc acttcctaaa aaaatatact aatttctaat 63840
acaggggttt ggaaagggga caaaaatgtg cagggaaggt ttgcgtaagc aatggtggaa 63900
tgggttcaac agacacctgt ctatgacttt atcctggaga atgtgtagtc ctcatgggaa 63960
agttttccag tgggatagtg attaagatgg aaaaaaatgc ccaaaatatc tttaatataa 64020
gaacaaaatg ggccaaacac gtgtctttgg gtcactggta atctactgag cagtaggaca 64080
tcatgacata agagttcctt ttgccatccg aagaaaaata tttaaaatcc tattatttgt 64140
ggttttaaaa atgttataat gtattcatta taaacactaa aatgactttc tggataatat 64200
agtatactgt gagtaattat tttgatttta ccatattctt ttttagttct cagaaaccaa 64260
aattgtcaga tatgggatac ttgatttaat ctgtatttga agttttctct tttttaagtg 64320
ccaatttttt aattaaatta aattaaaatc tctctctctt ttcccaaatt atatacaata 64380
tctactaatt atgttttctt cgaaatgtat cttagcttca taatgagaag tgagtgtgcc 64440
catgaaaaat ttaataggaa gttatgtttt ctcttccatt ttctgttgtg attcattatt 64500
tttgaaaata atttactttc atttgctcac atttgctgtc taaagaaaaa ctattcatct 64560
ggcacattca tatttagtag tattattaaa gcagaaagca taagttggaa gtataatatc 64620
taaaaataca aaatgaagta ttgtaccttg atgtttatta gatcattaag caaaatatga 64680
ttctgccctg cttaaatcat ttgattataa ttatccagca tataaaagaa tcacagtaga 64740
ttttcaatag gaagagtcct ataatattag gtatccacca aaaacattgt tcaagtaata 64800
tttccacctg aaagtaaatg attgccaatg ctttttttca gagcatataa aattggctat 64860
tcctatttga tctcgttatt gtcctggcat ccttattttg ttaaatttta actaggcaag 64920
ggctatgcta caaacatcag ttagtccgct agtttcctga taaataagta caggtaatta 64980
aaaagtgaac ctaaatatcc aaattatacc aaagggacat atatagaact ttttaaactg 65040
gatctgcttc tagccagttc atattttggt cacttactaa tgtagtattt caccataaat 65100
tatgcctaga ttggagcatt tacaggcact ctttatctga aaattcttaa gtgcatgagt 65160
tgtaacagtt tcacatagtg atcatctcac tgttctaatt ggtgactatg tactacagtt 65220
aggttgatcg taattatgac cttaaatgaa gctgaatatt tttatattcc taatttgatt 65280
aattttattt tatgggcttt tacacatttt aactgcttta gtcaacatat tttataatat 65340
tatgacattt gcctagaatg taattttaag aaagtcattt aattgatgtt atcaagaagg 65400
gttttataaa tcagaatttc ctgcctatgt ttcaagatca ttgcttaaag aaaacttttt 65460
gttcatgtaa tattccaatg tgtatttagc tttactctac attaaaatat gttaacaact 65520
atgaatataa cttgaattaa tactaaagtt catggttttg aaacatggaa atcaacaata 65580
tcataagcac tatcttgaac ctacaatatt tgattacata tctagtctac taaatgtttt 65640
aaattgataa acattgggtt tacttttgaa tcatcaaaaa gattctttag agaagcttgg 65700
cagaatgggg tgcagaagat ctggaatcca accactgatt cgctataact tttcacaaga 65760
cgataaaact cacatttcct tctctaaata aatactggat tggctgacat taaggatcaa 65820
tgtgctgcct agattctttg ttatttgtaa atcaagtacc acaagtggaa aagtattcaa 65880
gtaacacatg tgacagatcc tgtgctgctc cgcttcagaa gacagtgggg aaggataaga 65940
ttgcattcct taaagaggcc ccattcatca ctggagctat agatccttgt atacagagtg 66000
aaaagaggga aaacactgtc aaaatgattt agtaatagtt ttcctgactc cacagttaaa 66060
ctacagttca cctcatacac tcacattagg tccgaataat tggcagactg gttttaagac 66120
aatactccta gttctaagag ttgttcgtca ttgcccacac aattcagaat cttaaaagat 66180
ttgtgttact ctgcaattaa gagaaaatat tgtgtgtatt cttttgaatg tgaaagtaaa 66240
tatcagatag gaagtgttag tagttagtgg ttggataaaa gagtcctcgc actggtcatt 66300
cattcattta cccaaaattt attaaacaca aacattggtg ctagagatac aagggtgacg 66360
aaaacatgat ctttcctcca aaaaattaag tctgatgaga tgcattttct agaaacacaa 66420
aatacttttg aactgaacct tggaaaaagt aaaaacttga cctttcaata gataaatatt 66480
tggctttagg aaaaaggtat cttaattcta catcagaact aaggtagtgc actaaaatga 66540
aagggagcaa tgttaattct tctactttta atgtgattta aataagagaa aatacaggaa 66600
tgtcttttat aatttgaaat tccagagaaa atgaataaaa aagcaattaa aaaaaacacc 66660
tcaacatgct tctcattttc agccaagtac agcaaactct gtttgatatt ctctgatttt 66720
aaccttggat caaactattt ggcaaattgc taatttgaac aggctattga aaacagacag 66780
tgtatctagc aattcattca ttcattcaat acttaatgaa cagcattttg gcaattcaaa 66840
gcctgttcct tgtattgaac tatattggtg tattatccat atggcctaga gtacatgtgt 66900
attattcata ttatccatat tggtgtatta tccatagggc ctagagtacg tggcttctgc 66960
ccccaaatgt cttacaagca tgttaaagta cccaaaatcc atccaactga aataatttga 67020
cccatacatt atcaaggttc aagatgtgtg ataagccatg aaaaggttgg tgaatagcct 67080
agggtgcata tggtgagtga agatggatgg aagaaattag gagtccagat ttattgggga 67140
gactttatga aagcaaggaa tcatgattgt tgcaaaatag acagtgaaga aagaaatggt 67200
gtggtggtga aagtcttccc aaagtcattt aaagtattgg caacccagat acttggcagc 67260
aggagtgata attgatgtta caggaatcct atgtaaactt ttgcacattt taatgaagat 67320
tttctataat atgctgtctg gtgacttctc ccaatcactg tcaagggcta gacttcatta 67380
ttttaagatg tctttcattc atttattcac tcactcattc ttttttttaa gcaaaattta 67440
ttaagacctg taacatactt agcactgatg taagctctga tacagtcatt cagtaatgtc 67500
agcctgagca tttgcagaac cctgaatatg gatcctcatt tttcccttgg ggtcacccga 67560
agtcttaccc cgttctgtgt ttacagtgtg aaccttattc ttataaggaa tattttttgt 67620
ttcttattgt ggattgtctg tacttccatc agatgtgact cagcttcagt ttttctgatt 67680
acctgtgtta ttttccaaca tgttgcaagt gataagatca gtattatcag gtccctaata 67740
gcataacagg ttcgtgtgaa ttagatatat taaaatgaga agatttttaa gtcatttttt 67800
agtcaattac gtgtatagaa acatagttat acttatctca gaaagattcc aattcaaagg 67860
ataggaaatt agaaaaacat gtaatgtttc ttctgagaac aaatatattc aaattttaat 67920
gacaaagata ttaggattat ttttctagta atttgatata cctgataaat taaaataaga 67980
aatcatcaac cttcaagcac cttataatat ataatctttg atttaacttt tttggacaaa 68040
ttaaaaaata attctctaac tcaaagcagg cagaagtatc taatatttat gcttccatca 68100
ttagtatttt taaagtacaa gagacaaaag catttttaat ctcatgtata tcatacatca 68160
atatttttta agtcatcagc atcactatgc taaggaaata ttttatataa agaaaattat 68220
tttcataaaa taaagaaacc atctttctag agaaaatcca cataatccta tgcccaaata 68280
taaatataac atttacagta ctgactacag catccatctt attctagttt aacatacttc 68340
agtgtgcatt ttatcatgtg cttacctcat cctttttata aagtatctct tatcagctca 68400
accatttcct aatgttatgc actaatggta ataacattgt aacaggtccg agaatgctgt 68460
ggcccaaact actctgattc ctgtgtggca ctcacacctg gccctgcatc atttctagag 68520
cattttaaga ccaggttaaa gactgggatc ccttcatgta tgctgatccc aagaatggac 68580
cgacctggct aaagtttatt gcatttcaag atataaaaca acttctatta tatttttctt 68640
ttggtgatat ttgatttaac ctaaaggaaa acaaaagaac aactaaatat tcatttctgc 68700
ctgtactaac agggcaggta agagtgccag agtaacaagt agtttccaaa tgcacaatga 68760
aacacaggag tgcattggcc aaagagaatg caaaatatca gctcttgcta tatagctaac 68820
aatgtgctgc tctttttgga attagaaaat tatagaatat atttaataac aatctggtat 68880
atgttttcat gtcaatgaaa agtggataaa tttagatggt tgctgtttat gtgcatttga 68940
tcaaatcttt tctgaatttg acatgaaaat acacttgtgc agctttcatt ggttgggtca 69000
caattttaga ataaaacaaa ctatttgaaa accatttgca aactaatgta caaaagcaag 69060
atcgcagatg attatatgac tctggcagct tacataagct ttctgcagga ttttctttca 69120
gaatctctat acataggctc aaacagaagt tatttccgtt gttagcacca tattttaaag 69180
aaaaaaaata ctatggtgtt gtatctaatc ttgtgacccc tgacctttac caaagcggat 69240
tggcattatg tttaagttct taaattacag atcaagaaaa tgcatacaga agatgggggg 69300
ggggcacacc taattaattt ttatatttag attaaagaaa ataattaaat gtgttttttt 69360
gtgggattga ttttcagaag ctaaatgcaa ctagttcatc tgaaggcagc acggttgata 69420
ttggagctcc cgccgaggga gaacagcctg aggttgaacc tgaggaatcc cttgaacctg 69480
aagcctgttt tacagaaggt aagcaaaaca ataacatatg tggtcttgag tatcctcttt 69540
tctacccatt ttttcctatt tatttaaatg tctgtttatt tgtctaccat ctattatcta 69600
tctatctgta tctatctatc tatctatcta tctagtaatc atctatacct atccaacaac 69660
tgtacattta tttgtttttt tttgcatttg ctgtttgaaa aaaaatgcaa ctttttaaaa 69720
ggcaaagttt aatttatgta attagatatt ttcattttta tgaatcattt ttaactctaa 69780
gaaattatta actggctttt ctgtggcctt ctaaaatatc ttacaggaga gaaagccaaa 69840
tcacacacat ctctctttag tttaaaaatt caataaataa gaaagtgaga gaagtaattt 69900
attatgtact attttgtgat attataatgg gtaataattg ataagtgtac atttaaattt 69960
gtccttgact gaaacagctc ctatttcagt caaggtcaaa tattttttat tatttctgaa 70020
aaaagataga tcataaaaat gccaaaatat actatgagtc atatgatatg gggcaatatg 70080
tcactggagt aatcgcaaaa ggattttctg aagaaagcta aaattatgta atttgaggta 70140
tggatcagtt atatattgta atagcaatgc tgtgtatcaa accaccaaaa accctgggct 70200
ctaagctgct tttctagttt tgactcctat ttccttctgt gtaactcaca gactttcttg 70260
tcactaagtt ttacttgtat cattgtttct ctattcttac agcttcattt tctacatatg 70320
tctcttatat atccttcaag atctagtctc aaatccattt cctccataaa gctcagaaat 70380
taaagtttac cagaaaactc tcataatact ttgttttgtg ataattgttg ctttccataa 70440
ctatagaatt gtagacaaat tgccccaact taaaatgtac attctttgag gacaaggcta 70500
tgttttacat gttatagtat tacaatttgt tctatgcaat tttttgacaa tagtagatac 70560
tcaataagta tttgttgaag agcctttgat ctagcaatcc agaaattata caaaggtgtt 70620
tattggattg ttattgataa tggccagatt taaagcaaac gaagtattca ataatggtgg 70680
aattgggctg ggcacagtgg ctcacacctg taatcccagc actttgggag gccgaggcag 70740
gcggatcact tgaggtcagg agttcaagac cagccaggca aacatggtaa gaccccatct 70800
ctaccgggcg tagtggtatg tgcctgtaat accagctact tgggaggctg aggcaggaga 70860
atcgcttgaa cctgggagac agaggctgca gtgcatgagc cgaggtcagg ccactgcact 70920
ccagcccgga caatagagtg agactccctc tcaaaaaaaa aaaaaaaagg tggaatagtt 70980
atattaatta tagtaatcat atttagagaa atattatgaa atctttcaca aatttattta 71040
cttataataa agatgggaaa tagttatacc attaagtgaa ctaatcagaa ttcaaatatg 71100
taaagtgtcc atatagagtg gaattacact cataggataa ggacaggatg gaaataccaa 71160
cttttggtaa gtttattttc tttttggttc ttctattttt tatatattgt gtttttgtaa 71220
tgtaatccat tatagtagtg ctataaacat aaaaataaat atttattaaa caaatgatta 71280
aaaagccata tagatgattt taagatagct tttgtaagcg gaagctatct taaaaattaa 71340
tgttatttac aatgtattat caggtaataa tgtaaatgaa tctcccacca acacaaatat 71400
acctaatcaa agagtaattt tttgtcttca tttttttccc acatatttta gactgtgtac 71460
ggaagttcaa gtgttgtcag ataagcatag aagaaggcaa agggaaactc tggtggaatt 71520
tgaggaaaac atgctataag atagtggagc acaattggtt cgaaaccttc attgtcttca 71580
tgattctgct gagcagtggg gctctggtag gtgatgcatg atccactcct tcacctttca 71640
tctgaaatct tttccctttc ccttcaatca actcatatta cccactttta aattaaggtg 71700
tttgtaagaa tgagaagaaa tatgtgtgac gtgtttagca catatgagag gcttagtaaa 71760
tagcaatttt tgtcactctg tctggagtag ccctcgggtg gaaccaaact cagatcatta 71820
tggtttctta taatgtttaa agaaggatct ttctgacttt cagtcatcag aggcagttct 71880
tattaagact ggttatgtag acatgatgta ggattatcag ctaaatatca gactgaagca 71940
cgatatttcc ctgacccctt tgcaggtgag aactagagtg catgggtgcc ggtaggagcg 72000
aactccactc actcactgct ccacccctca caggaggggg agcgcaggtg actgggtgca 72060
ggagccaagg caaatgcatt tgggcactgc aagagtgaac tccataccgg ccccacagga 72120
gcgtctaggg gagggtgcct gcgatccttg aagccctaga ggaagtgtta cagtgccctt 72180
ttagctttgc catccatgga tggcttaaat gttaacagtt cagtggaggg tcagagtgac 72240
agccttttgc acccacactt gtggtaccca agttcatgtc cggcgtccag gaggaatgag 72300
tttgtacaaa tgacttgaag atggtaaata caggggattt tattgccagc gaaagtggct 72360
ctcagaggga agaggagctg aaaggagatg gagcaggaag gtaatcttcc cctggagtct 72420
ggccatcccc agccagactc ctctccgaag ctatgctgtc aagctgtccc tctgatgtca 72480
agctacttct ctctaatgtc caactgtagt ctctgatgtc cagctgttcc tcctgtctgc 72540
ctgctgagtt ctgggcttta tataggcaca ggatgggggc agggtgcacc atgggtggtt 72600
ttggaaaagg caacatttaa gtgagaaaac agggatgtat attctcactt tgggccacgg 72660
ttccaggctt gagggtggag ccctcgccag gtacccgtcc tcttctgccc agaatttctc 72720
tgcctcttgt tcctgtcaaa attgcttaac ataaactcca tgctgcaggg gactcctctg 72780
tcttcttcac actgattcgc tattgccaac cacagtgaat gataagaagt agactcactt 72840
aattactgac tagcaaaaaa atgatggcat tacaaactta tgtctgattt cattcaatga 72900
aatgatcaac tggatcaaaa tattaatata atgaaaatga tatgacctat tttcttaatt 72960
ggtgatacaa atgtggttgc attcctttta ctgtttcaat ttaattaata actagagtgt 73020
ttggtgagtt gatttcatta ggagaattac tgcattggat ctggaggcct ctaaggcgaa 73080
ttctgatttg actaagaatc ctgtgtcctg ccatatactc agtttaaaga ggatcagcca 73140
tgctttattt tctttacctt tattattatt attattattt tttagacagt cttgctgttg 73200
cccaggctgg agtgcagtgg tgtgatctcg actcactgca gcctccatct cttgggttca 73260
tgccattctt gtgccttaac ctcgcaagta gctgggatta caggtgtgag ctaccacacc 73320
tggctaattt ttgtactttt agtaatagag actgggtttt gccatcttgg ccaggctggt 73380
ctcgaactcc tggcctcaag agatctgccc gtcttggcct cttaaagtgc tggaacgacg 73440
ggcgtgaacc accgcacctt gccagacatg ctttctaaag ccaagtagag agagaactat 73500
gaagtctcat tagtgactag tacctttgct gtaggagctc tttgttctca gttacaccca 73560
gtcagtgctc accaaattgc acaacgtgct ggcacagtgg ctggctcctc aggggtttac 73620
agcttcagct ataagcaaag cccagaaacc tttaggtcct tgtatggagc tctggttaca 73680
agccctgatt cttgttatct aaaaaagaaa atgttccttt gtctttaatc caggctgcca 73740
ggttttcctg ataatttttc cgataagaag atcaagttag ataaatagtc ttttcattct 73800
ggaagcctca ggagttcctg caaatgagtt acccactctt tcccaagggc tctggaaaat 73860
tctgtcaaag ggaatttcca aacgtacacc cacccgcctc cacacacaca cagacacaca 73920
gagagaggga gagagacaag aaagtgagca atgacaatcc tttccttttt ctgtaggctg 73980
agggacctcc ctgctttata tctgcattac tagaggatgc attccattga gtctgcactg 74040
aatgagacca atctactccc aggcgttcca ctgcctcctg atgtagagag aagcagctgg 74100
cagtctctca aaaattttaa gctctttggg ggtacactga gaccaaaatt taaaaattac 74160
tgaaaccctt ggttgactga aatgcccagt cagcagtcat ttatgatcag ataatgataa 74220
agtaaaattc agccatggga aacattaaac cttccagcct taggcacctg ataagagctt 74280
gcatcgtttc cttttttaag aaatcatcaa ttagagactg tttctgatca taaaatttaa 74340
tagaattttt tgacttacag gcctttgaag atatatacat tgagcagcga aaaaccatta 74400
agaccatgtt agaatatgct gacaaggttt tcacttacat attcattctg gaaatgctgc 74460
taaagtgggt tgcatatggt tttcaagtgt attttaccaa tgcctggtgc tggctagact 74520
tcctgattgt tgatgtgagt atgctgcact ttgctgcttt attcattggc atatatgtaa 74580
tagttctagc aatggtgcct gacacagtgt aggcactcag taacactgta tcagcccaaa 74640
tataaattat gtttctcatt tcacagtgag aggatgcctc aaaacatttt ttaccaattt 74700
aaatacatat acattcatag ataaaaatca aatgccatca tactatactt attcacttaa 74760
tttcaaatta atatttaaaa tctcaagtta tgcaaaataa aatatgaatt tagaaatttt 74820
gctttttgca cactcacatt tcgcaaaata acttgtattt aaatttttca caggcatctt 74880
tgacattagt atgtttgtca tcactaaagc ctgttgagtt taggtcacac agatgaatca 74940
ttaattacaa agaaatttga aagtccaaaa agcaagagac accacttgat ttgtatgata 75000
tagaagcaaa ttggctattg accaagtagc caaagatttt attaaaccac attggtgttg 75060
aaataaaata agatagagta ctaaaatatg agggttttta tataattgaa tatgaggcaa 75120
atctaccatt aaatgtacta ctactattaa atgtataaag gttacatgca gaattacatt 75180
aacagtctct ggcaataaag gaagacaata aataatattt agaactacat aagtgtggac 75240
attacaaaca atagaaaatg caccaaaact ataaccattc ttttatttgt ataatgggat 75300
tatgcatgat actatttctt ttctctattt tctgtatgta cttatcatag gttggtaaat 75360
ccataataaa aatatctgat acttgatata tctatgttag gataaaagta tcaagtcagc 75420
actgcttgaa tataaggaaa ctcttcagag aaatctagtt gtcctgcagc taatgatcat 75480
attacccaaa gtactctgat atttaccttt ttagatttaa gaaaactatt atgatagtat 75540
atgaaactga tcaacacttt gccttaaatc aaatatgctt attgctcatc tatttcatta 75600
tgaaagatac aaatataaat aagtcatttt tctagtcctg cagtagctta cagttgaaaa 75660
gtgaggacag ctgcgtacac agtaagtcga cacctgtatt acaagtgcca cctctttact 75720
tgaggaagga ggaaaggctt caatagggaa gtggagtgtg agctggagct tgagagatgt 75780
gaatgctagc aggcacagct gagggaggaa cacggattcg ttaaaacgtt ggtgcatgac 75840
atgcagggcg ggttccagaa acaagtagat agggtgaggt aagcctttgt aatgggatga 75900
taaggtaaga aagataagtt agaaaagatc tgaagaacct gagatgccat ccaaggaaat 75960
ttggacttat tatttaatac agaggaagct attgaagaat tacatatagg gaagtgacaa 76020
gacctgcttg ttcttttagt gagggaagtt aggtggaggt gagaatgacg gaatagaaag 76080
gagatttatt tagagatcaa aacaccaatt aggagattgc tgcaatgtcc cagaaagaga 76140
aggcctatat gtatcttctt ttccacattt agctacacaa gtcacataaa actgaatatt 76200
ttacaacttc ttttcagcca gtaaatacta ccccattcaa aatattttcc tctgtctaac 76260
ttttatcttt catcctttaa cttatgctta tctctttttg gttctgtctt cagagaaggt 76320
aaagtactac aggtccttat atcttaaata cagaaaagct tcacaactca tgataattca 76380
gtaactattt ttcaattatc tgttaaaaag ggacttacaa agcctaagag tttggatttt 76440
aagggaacta tatgaactat gtaagacata attttacaac tcattgtttt ctgtattcaa 76500
gaggcttcac tttcaaattg catgtgcaaa attattttga ataagttgtt ttttgtaaca 76560
actttcaatg tgcttcactt attttcctta aaaaatatat ttttcaaata tattaacacc 76620
atactcttaa aagctgtatt gcatatttat ttttatttat ctgcttttga aattcaggtg 76680
tactttagaa caaaatagct tatataattt taataatttt tctatatgtt ttcaaggaaa 76740
ttggacatgt gtatgtcccc cgaccgtttt tctttttctt tttagctaag actttataat 76800
ttttctcaac tacattagtc aactgtatga ataactaaag acaacattgt tcttgcaatt 76860
tctaatttat cataaaatct caactttttt tattcactaa ttttgtctga cctaattaat 76920
gatattatgc ccttcaaact gaaatttaca aaagtcaaag ctgcttttta gaggcctatt 76980
cctttttaaa tgtgttcatg ctcatattca ccagtggttt gtatagttta cttgtgtatc 77040
aaatgttact ttccatttca gatctgctca atattattag aaatgataca gaaataagtt 77100
ttacagatct gtagaggaag atcacatttc tctctctttt ttttctttac ttttaatttt 77160
ttaaaaacat ttcctaccaa gaatcttgaa aaagagcaca tatatgggct tcttttttat 77220
aagtgttcgc agactagtat cattaacttc accctgggaa cctgtagaaa tgcaaattct 77280
taggcctttc cccaaactta ctaagtcaga ctctgctatt ggtgttttta acaagacccc 77340
tgggtgattt tgaaactcat gaaagttcga gaattactga ttcattgcat agagcaaggc 77400
tgaactgtgt agacattttt atatgtaaat aagaaaattg tgttgctttt tctgtatagg 77460
tctcactggt tagcttaact gcaaatgcct tgggttactc agaacttggt gccatcaaat 77520
ccctcagaac actaagagct ctgaggccac tgagagcttt gtcccggttt gaaggaatga 77580
gggtaagact gaatgcctta gagtttgtca gaattattat tgagagcaga ctgacacttt 77640
gtaccatgga aatgtcaaat ttatggagaa tttgtgtctt acacattcat actgacatag 77700
ctaatcaatc aaaaataata tttaccagat gcccataata cttggcactg ctggagtcac 77760
tcacagagta gtatattgcc agagggattg tttctgatta gctagatttt cacttcttgg 77820
aaaatctcta tagttatgct gctgatttga atcaagatta tttatgttca cttcatttat 77880
aaatgtgcag gaaatcctac tcgctgtagt ttaagcctac caaatcattg ctcatcattt 77940
cttcactact ccgctgtgat acactttgag ccttttgatg tttgaatcag gccttttagt 78000
tcttaaacac aggctgaaat ggctaaaaag taggtcaact ggaaatctaa cgctcattta 78060
gaagggtggt acaaaagaac agaggagttt gtgctgacat ttgtcgtccc ctgaggcaca 78120
aaacctgaga ccacataccc tcaccaccta gaaaatgatg atgccttgtc tcagttgttt 78180
tagctggttc aaagaggatt ttaaaaaaat gatacttttt gtgatatttg aaaataagtt 78240
gcttagactt tatctgcatg ttatagtgat actagctcat attttctaac taagaaaata 78300
gttacttaga ctttatctag tgttacaatc acaactagag atgaatggtg tgtgtagatg 78360
tgtgtctgta tatgcatggt tacatagaaa agtgttatta gcggtaaaat tctttttact 78420
ttaccaatta gaaagaacag tttttgcagt agaaggctta ataaacaaaa ggtatcaatc 78480
tttcagtacc agaatactgt ttatattttc tgtgtggaat ttgatcccca agtggtctct 78540
tttactctca aattttggac agcaaattgt atggtttgta tgattttttg aaagtgatgt 78600
tcacttctat attcatgcca ctgtttatac tcttaattat ttttggcatt tgctgttagt 78660
tccatccttt gaggtaaatt tgctacatgt gtgttattac ctcttgagaa aacattctcc 78720
aatataaaat tcgttgtata ctcttctgat ttataatttt aaaattctta gttggagcta 78780
ccagagtcta gtttctaccc aatattcaac tttgaaacag atttttttaa tcatttgact 78840
gttcttttaa taatgtttaa aaataagtaa atatttgttg ttggcttttc acttattttt 78900
ccttctcatc ctgtgccagg ttgttgtaaa tgctctttta ggagccattc catctatcat 78960
gaatgtactt ctggtttgtc tgatcttttg gctaatattc agtatcatgg gagtgaatct 79020
ctttgctggc aagttttacc attgtattaa ttacaccact ggagagatgt ttgatgtaag 79080
cgtggtcaac aactacagtg agtgcaaagc tctcattgag agcaatcaaa ctgccaggtg 79140
gaaaaatgtg aaagtaaact ttgataacgt aggacttgga tatctgtctc tacttcaagt 79200
agtaagtaat cactttatta ttttccatga tgtgtaatta aaatgagtct aaagtttttc 79260
ttcctcataa tgagatatcc acctgttaga atggctatta tcaaacagat aaatgacaat 79320
aaatgctggc aagaatgtga agaaaaggga acccttgtac attgttggca gggatgtaaa 79380
ttagtatagc ttttatggaa aacagtatgg aggtttctca aaaaactaaa aatagaacca 79440
ctatgtgatc caacaattcc attactgggt atatatacaa aggaaattaa atcaacatgt 79500
caaagagatg tctgcactct cacactcact gcagcactat tcacaatagc caaaatatgg 79560
aaacaaccta attgtccatc aacagatatg tggataaaga aaagtgtgtg tgtgtgtgtg 79620
tgtgtgtaca tatatgtata tgtatatata tacacacacg tatttctata tacacacgta 79680
tagatataca ctgtatatgt atatatctat acacatatat agacatacac agaaacagtg 79740
tttgtgtatg tgtgcgtgta tatagaagta gtcagggaag gggcagagcc tgtggcacta 79800
agaaactgag aaaatgtaca agacttttgt tttcagaatt actatgtccg cacaacagaa 79860
aaagtatttc aaaaagtaaa tgcgcttgaa tgtatttgtt ttcagtttag gaaactgctt 79920
ctttttgtag agtgccttaa aatagtatgt tcaacaatat taaaaagatt ttcaaaaata 79980
agccctcgtg attgatgatt ggtaataatc atttaaaaac ttattggatg tatatatatg 80040
tgtgtgtata cacgcacaca cacacacaca cacccctata gacatacaca atgaaatagt 80100
attcagcctt taaagaagaa ggaaatcctg tccttttata caacattgat tcacctggag 80160
gaaattaagt gaaataagcc aggcacagaa agacaaatga cacatgatgt cacttatata 80220
tggaatctaa aaaacacaaa ctcacagaaa cagaaagcag aatgacaatc accaggggct 80280
gggggatgat gggagatgtt ggtcaaagga tacaaaattc aattcgacag gaagaataca 80340
ttctgtagag ctattgtaca gcatggtgac tatagttaat aataatatat tatatacttg 80400
aaaatagcta agtgagtaga tatgttttct catcagaaaa aaataagtat aagaagcgat 80460
aattatatat tacttagctt gagttagcca tttcacaata tatatatatt tgaaaacatc 80520
attttgtaca acataaatat attcattttt atttgtcaat taaaaaatga atatattttt 80580
gaaaagcaat taaaataaaa atgcatatac attttaggaa ctctatatag atgcactaaa 80640
actatataaa aatgatataa tactatacaa caataaaata aaatttttct tcctctgtgt 80700
ttacaaatac ttccttaggc ccatctgcct agattcctct taccatgatt gaactatctt 80760
ttctgcccca cgctggaaac atgatggttc taaaaacttt attgtctccc tgactatgca 80820
tttggtagca tagccaagtc ctttgttact gggagtttaa tctaggcact cattgttttc 80880
ctcccttcct actctgagga aagaagtgct ggccccaagg ggggttgaaa aggggtgtgt 80940
gtgtgtgtgt gtatgtgtcc acacgcgtgt gtgtagatag agaaagagag agagactttc 81000
aaataggaaa attgctctct tgcaaatgaa aactttccaa ttaagactat tgtgtctgct 81060
atgcactcat aataattcat tcagctattc aactgactgc agtattaaat ctccactagc 81120
tcctggacac aatccactta cacgatcctc aagactatta aaatagtcag gaaaggggaa 81180
gagcctgtgg cactaaggaa ctgaaaaaat gtacaagagt tttattttca agatcattat 81240
gtcaacggag cagaaaacaa atatttaaaa aaggaaatgc agtagaatat attgttttca 81300
gattaggaaa ctgcttcctc ttatagagta atcacctcaa aatagtatga tcaacaatat 81360
taagaagatt ttcaagaata agctgtcatg attggtgatt ggtgtaataa tcatttagaa 81420
aagaataagt agaaaggaag cattaagata aataatgcag catacttttg agcttgtctc 81480
atgctgctac tatacacatg aaattttttc atcaaagttc atgatatatt tttatataaa 81540
cacatcagag tcaaagattg ttcatattgt ttttatgata gcatattgtt acagtagatc 81600
attatttaat tatatatgct aaatatccac ataagatgtt atagaggaat ataaatttga 81660
agtattttca atgcatatcg caaaacattg ccccaaaagt gaatacaaat ttcaagctta 81720
tttatatgcc tgtattgaat acatgtcaaa tagaattttg atcaattatt caatttattt 81780
tctaaaatta taattttggg aaaaaagaaa atgatatgac ttttcttaca ggccacgttt 81840
aagggatgga tggatattat gtatgcagct gttgattcac gaaatgtaag tctagttaga 81900
gggaaattgt ttagtttgat taaatgtata tttctacaat attgtaattt agtgatattg 81960
tcaataaaat aaaattatgt gcttaattta taaaacccat ctatattata aggataaaat 82020
atttaatcat actatttctt tcaaaattat cataggatga ttttctctaa tcactctgta 82080
tcttttaaca tatcttttct agtatttagc aaggcacctg acacaaaact ttattgtatg 82140
tattttcaaa atgagacatt ttatttttgg ctctgatagt cctggtcatt tgtgcattag 82200
aagttctcac aggcaatatt ttttatctgt aatatatttc ctccagcttt tgatcttcct 82260
tataatagga aggatatgac taaaaacggg gacaaaaata aacaatttag tgtttctctt 82320
gggaaagtga gattaagtgg tagaagggag ggacttccct aatctacttt atacatacca 82380
gtactttgaa ttcttttcta taattttcat taatttctca ctatttaatg aggaatgaag 82440
tcacattttg aaaaaaaaaa aaaaagagat tgatttctgg tatgccagag catgataata 82500
aagctcaaaa tgctctttcc ctagcaccag cagctagctt tctgagtgaa gaattcctga 82560
ggtttttttt tttctttttt ccacttcata aaaacagaga gggagcaaga aagcatgaaa 82620
agccctgcat tgtatctcta taagtgctat caggaattcc agttatgaga tttttctgaa 82680
tagtaataat aatttattga ttatcactat tcactgtgcc aaggactttc tcacattatc 82740
ccatttaatc ctaaatgaca accttattgt ataggtgata ctagctctat tttactactg 82800
aagcaaagag gcttaatgcg ttaaatggga aaacaagttt ttgaaccctg accacaaata 82860
atggctcata cccactttcc acagtggttc ttaccttttt gattaattaa ttcaatgctc 82920
tctccacctt ccttatcaat agcttatatg ccatgaaaca ttttcagttt cttctttaat 82980
aacttagcag accttttccg ctgcaaaact cctggaattt ccagcacatt acaaaagatg 83040
aaagccaatt gagcactaca tttatgaaaa gttgctggat cttgaacttt aattagtaaa 83100
ttgcatcaga taaatgcaaa tttaaaccaa aataaaacat tatctacaca cctaccagat 83160
tggcaatacc aaaaagtctg acaataccaa gttttaccaa ggataaacag caataagaac 83220
actcgtacaa tgctgatagg aaaaaaaata gttaaataat cctttaaaaa cagttgggta 83280
tgatcacatt atttgagaaa gttaaagata ttttttaata ctgcaattct actttgaaca 83340
acgtatccta aagaaactta tgcacatgtt taggataatc tatgtacaaa aatgaatata 83400
actttttttt gcacttgcaa aaaactggga gcaactcaaa aacagtagaa ataggcaaat 83460
aattgaatac tatatagtga tgaaaatgaa tgaataccgc catatacaac cacatggatg 83520
agccttaaaa atacaacatt gagttaaaga aactagacac atactataat tctacttata 83580
taaagttcga aattgacaaa actaagctta ttgttcaaaa ctgcatactg aggtgttaac 83640
ttgaaagaaa aagcagggac atcattacca taaaagtcag gataatgatt acctccagca 83700
gggatgatgg agtttatgtt tgagaagggt acaccaaggg tttctgaagt tgtagcaatg 83760
tcctgggtta tggatttcac ttataaaaca tattatattt tgcatttatg tattatgcac 83820
tttcctgtat gtatattgtc ttttaaaaat tttaaaaata taattttaca tcactgttaa 83880
ctaaactcac atacacaaat aaaatctcat cgaagaatag cagttttaca atattcctga 83940
tattttccat tttgctgtat ttccttagaa acaaaattat gctggtcata atcctctaaa 84000
ttgatttcat aacacagtgg gttataactt gcatctatta tcatcatcag ggattggtta 84060
actgagttgg ttagaacaat gtcctattag acctgtgaaa gcttacagct aaggcgcaaa 84120
cctactatca cacagttttc taaacaaaag tggattagac aagagatagt atcattgtta 84180
cagaaacagt ccctactgaa taggataaag caatagattc attttcagaa aggaaagatc 84240
aacctatata cctacatgca gacctactac aatgattctt gcctatctaa agaaatgtat 84300
tataccaaac ccttacactt agcaattact actggccgcc actgttctaa gcatatttat 84360
atgttaatat agttaatctt cacaaccaca ctatgaggtt taagtttgat tattttcatc 84420
tcacagatga gaaaactgag tcagagaaag taaatcttaa aagttttgac atagaataat 84480
gtgacgctga catctctttt gtaagaagag gaaatcttta atttgcatgc tgtgttggga 84540
actttgctta gaaaggaaag tgcattcata atctgggcat ttgttgggtg aaattgtcta 84600
taatcattca gacttctata tggttatttc attttcccag gtaatgaata gtcttgcaga 84660
actcttcaat aagcatgtga gatttgaagg ttcataaaat ctgtttagtg tttggtttat 84720
tttcattcca gagattaaaa catgcttaga taattaaaaa ctcactgatg tactttttgt 84780
gaaacaagta ctagatataa tggttacaat tcttcatatt ctttaggtag aattacaacc 84840
caagtatgaa gacaacctgt acatgtatct ttattttgtc atctttatta tttttggttc 84900
attctttacc ttgaatcttt tcattggtgt catcatagat aacttcaacc aacagaaaaa 84960
gaagataagt atattaaaac ttcatccttg ctctgaaata tgaactaaat atttcatact 85020
ctttccttta gcctccaaaa tgcaatcacc aaaaaaagaa tataaaattc agaaattatt 85080
ttgagacatt tgataatcga taagctttta agcaattaat aattcagata gcatgttttt 85140
gatattttta gtctagaaat atgactaata tggcataatt tatatattga ataaaggcat 85200
ctctataaat acagatatta gtaacaatag aatgaaatgt gggagccaat tttcacatga 85260
ttactaaggt ggattttata gccagcaaag aacacaattt taacaagtgt tgctttcatt 85320
tctttacttt ggaggtcaag acatttttat gacagaagaa cagaagaaat actacaatgc 85380
aatgaaaaaa ctgggttcaa agaaaccaca aaaacccata cctcgacctg ctgtaagaat 85440
aacatatttt cattgcctgt taaaactata ttacctaacc gtttcacagc ccgaatttct 85500
agaaactagt tatttttgtg gatttgtaac acaaagtttt ttaccttaac aatgggacta 85560
gctagcctaa atagcttgaa aaatgtactt tacatatata atatgtataa attatataat 85620
gcataacata ttttatatgt aaacatataa aatacataga aataaaattt gctatactta 85680
agtgccagtg gtatcataca agctgatgtc attaagacac ttctaataac atcaaaaata 85740
aaatacatac atacataatg tgaaaatatt aaatgttctc agagtacaga ggagacagat 85800
cggaataatt ggtacgtcac agattggcct cagtttttgt ccaactctgc agattgaatg 85860
gaatcattaa tgaaacaggc cacaggtttt gcttttttct ggttaaacaa aaaaaagaca 85920
aacctcatat tttcccctac tatcccaccc ttaaatgaga tgatatcatt ctttgtaggg 85980
ctttttattg gctcttccag gtgtacattt gccagtgata ctgttcgttc agtttggctg 86040
ctgcagggag ttgctgccag gagaatcgct aagtttttct atcactcctg aaggactagc 86100
tcatatatta agtctcagaa aatcttcccc aacgtatacg tggtataaaa cacttcagtg 86160
tttctcagaa atcttgactc tataaatcta ttggtgacaa tataaaacag accgtaatta 86220
agtgttcagt tggtaagccg gccaataact caaagaaaat ggatagctat attgggtcaa 86280
acacaaaggg tgtacaactt gagcctagtc tttaggaaat aatacaattt gaatgaatag 86340
agagagaagc agagaacatt tactgtatga gaaaatgtat acttcatagc catatagaca 86400
aatatatcag tgcagaatag tgatgcattt gaattagtga gtagtagaca ctggttttcc 86460
gagttacatg agacaaggtt accatacgag tctgaagaaa tttgttctaa ttaagcaata 86520
caaatgcaat atagttaaca gaacagccta gtaatgtgaa aagaaagatt ttagagagtt 86580
taacctagag actggtgtgg aacaatatta gaggcaaaat aaccctcggc catagacaag 86640
aagataaacc cttacataca agaagatagt ccataatctg tgtccaacca gcaggactgg 86700
aactactcca ggagtgaagt tagccaataa gaagactcaa ttgggatgaa acacaggaaa 86760
agagggagga tgcaatgaaa aaactgggtt caaagaaacc acaataaccc atacctcgac 86820
ctgctgtaag aatagcatat tttcattgcc tgttatgaaa cacaggaaaa gagggaggat 86880
atgtaaataa cagagaatct aaaatataag ctagttgata ttttgtgaaa ctgttggttc 86940
cactatcata tactgaagtc atatgaaggc actgggaaaa atagtgttag agcctatgaa 87000
atgtccagac tgaaataagg attttagcat tgtcagaaca aaattcaatt gagctctgaa 87060
acacagattc atttttgaaa aataattaga atagagaaaa aaacaaaatt ctcagaatga 87120
ggccttgcat acttcatcaa gatataggaa gaaataaatc aatgaagaaa tgagcttgag 87180
tttgtttcca tcaaatgaca tggatttacc tgtagtggta ggggtgtgtg gaaaaagttc 87240
aacacattca gctagaatat tatcagtgtc aatttggcaa tttagcaagt aactagtaaa 87300
atccatttat tcctgcattg acaatatgta ctatgtagta tgctaagcat ttgaacttaa 87360
atatcgaaca gtatggagtc tagttaatgc aacggatagt aatcaaatag tcctgccaaa 87420
aaatggaagt atcccagaaa aaaagggata ctttcagctg tgagagctga ttagggggaa 87480
ggggctgatt aatcagggaa gttagggaag gctttattaa aaaaatatac tagctgagga 87540
tggaaaaaga atagaaagca tcaatagcca gagtgggatg agaagagccc tgtagaaggg 87600
gaatgaattt gtgaaggtcc ttatgtagga gggctggtga gactggagtg cagaaagtca 87660
aggttcattt gggacacact gagaataaag aggttaggat aagcccaaac ttttctgggc 87720
cttggaggcc gtgttaagga gtagttttca tcctaagagc agtaagaaac cgttaacgtg 87780
gacccagtca gtctgggctt tgtggtgatc actcaatcag tttcacagag gccgtgtgaa 87840
tacattgtag acttgttttg gagctatttc agagatggta ggtagcctga accatagcaa 87900
tgtgcagatt aataaaagtg gatggatttg tgagctatca ccagagtgaa atttaaaagt 87960
ttgtctatta attgaatatg ggaactaaag aaggaaccaa caagaatgac tggtgtcttt 88020
ctgctttgca caactggata aatactgatg tcatgcagga aatgaagaag ggacagaaag 88080
tggtgagaaa attggagatg ctagtttgca gaatttggca aacgagtcag agtgagagag 88140
tgagaggaag gaggaaggga gagaaatgat gaatatttag aagtagcaaa ataaaggttt 88200
cttaagattc agagattagg tttaaaggaa agcaaaagga attttagaga ggaaaagatc 88260
gaagacagag ggaataatta cggcataaaa atgcacaaga tgtgggacaa ggacatagtg 88320
gtctagggta gctttagaaa gaaaaagggg ctgagtcctc taatgaattt ggagtaatat 88380
atgaaaagaa catggaaatt aaaataatat gaaatgcaaa aggaaacaga ggagtttatt 88440
taaactgttt aaatttaatg ttctaaaaaa agtaaaaata gagggcaaga gaatggaaat 88500
ttatgagaag tttggaatta tctttggagc aaatgaagga caaaggattg ctaattgtta 88560
aatctgaagg gccaagatga agttagagaa cataaatttt tggtgaataa gatcttcaga 88620
attatacatc ttgttccagc atatttgaca ccctaggatt taaatgggag aacagaacac 88680
agagactcga gactggagtt gtacattgag atgtctgtct cattggacaa ctctatgaac 88740
agggaatcta aacagttttt tattagtcat ggtgatatta aaattaagac caaatttctg 88800
cttttaagat attttgaact tactatactc taggagccat atctgagaga aaaatgatac 88860
tgctcctgct tttgaggggc ctcaaaacaa gtggaaggga aagaaaacta aaattgaata 88920
agagcaaacc atttgcaata caatgccata cattttatga tcaatgaaag cactcagttt 88980
tctgagagca ctaagtgctt taaactcaaa actgagttag aattcatgag acagagaagg 89040
agtgggggac atgtgtttta gacagaatag tagacagata aactatgtaa aatgatacag 89100
tagaacctgc ctaagcttct aagagtggta ggcaggaaat atcagagggt ggaagtaagg 89160
ggaagatgcc agacttggaa agttaaacta cagtaaatta ataattaata aggaagggtt 89220
tgaactaaaa gtagacacat ttattgggtt gaaaaaggcc ctgagaagac agatccagct 89280
ggagtaatag aaatctagtt cagcaggcca aatacgcatt cagagaaaag agcaaaacaa 89340
aatagaacaa gtagtgtttg atgtccaaaa atcaccattg gaagtaatag aagcctccca 89400
atagaaagag ggcagaacac taagatgtag aatccaggcc actaaaagtg tcaggatctg 89460
ggaaagcaag ccattaggtg tatatgtagc agagtattag tcattctagt tgagaaggta 89520
gagaaaggca gcccaacaga ggttaagtca agaccagatc cctagattac ctgagaaaca 89580
aagcagatac gtgcaaaatg gaacaataca gaaaccaatg atcagaactg gtttacaagt 89640
tggggacttc atttcataag caagacataa ggcaattagt acttggaaat aaggtccaaa 89700
tagactaggg caaagattga atatttccat tgtgactttt taaaagataa ttttattctt 89760
acagaagagt tactcataat gaatactcta atgaatctat acacagtgtc ctcttgtttt 89820
aacatcttat gcaaccatag atcagttctc acaactaaga aattaatctt gatataatac 89880
cattaaataa aatacagaac tgagtcagat ttcaccagtt tttccactga agccttttct 89940
ctagaatgat gatttttaaa acatcttagc tgaactttaa aatgaaattt aagatgctgt 90000
agctttagtg agagaatata aagtcagaaa tcagacgaaa aatttaaaaa gagagaggaa 90060
aacttggaga agtatttatt tattagttgc ttaaagtaaa attaataccc tcccaacaca 90120
tgggataaaa aattttatta catgacaaat atttactaac tgtccgtcat aacatgatgg 90180
tgttctgtgc actgagaaca taatacgtga gtttataaaa cctggtatca atgtgagtat 90240
aaataaaaca aatacatttg aatacagttg aatatacaat atacaaaatt ttcttccaag 90300
tataaaacga aaataaaata cactactttc tttaatagaa tagaacattg taataatgtt 90360
ccattgcatt tgaccctcac ataaatgcta tgaggtagca ttaagagata agatttgagg 90420
ctgggcatgg tggctcatgc ctgtaattcc agcactttgg gaggtcgagg tgggcagatc 90480
attaggtcag gagtttgaga ccagcctgac caatacggtg aaatcccgtc tctactaaaa 90540
ttacaaaaag tagtcgggca tggtggcatg tacctgtaat cccagctact caggaggctg 90600
aggcaggagt atcgcttgaa cccgggaggc agaggttgca gtgagccaag atcgtgccac 90660
tgcactccaa cctgtgcaac agagcgagac tccatctcaa aaaataaaaa aaattaaaaa 90720
aaagagagag agataagatt tgagatctga catggagctt ccctatttac actacttacc 90780
tgctttgtga cctaaggcaa gttacctcag ctctccaatc actggttttg caaggaattt 90840
ttttttttgt aaaatgttgt gaggattaaa gatgtgtttt tataaaagct acattttttg 90900
ttgctttctt aaaatcagaa gaattgaatt cgattttttt taaggtttct aatggaactt 90960
ttacatatta tttgttccag aacaaattcc aaggaatggt ctttgatttt gtaaccaaac 91020
aagtctttga tatcagcatc atgatcctca tctgccttaa catggtcacc atgatggtgg 91080
aaaccgatga ccagagtcaa gaaatgacaa acattctgta ctggattaat ctggtgttta 91140
ttgttctgtt cactggagaa tgtgtgctga aactgatctc tcttcgttac tactatttca 91200
ctattggatg gaatattttt gattttgtgg tggtcattct ctccattgta ggtaagaaga 91260
ggtgctttta ttcagttaag gaatatagtg gtaaaaatat gtgttttaaa actttagagg 91320
tgtttttcac taatctttct cattcatccc aaactcccaa ataaaaatct aatagtccat 91380
tgttttagtt ttagtttgcc atttctctaa ttgcatgctg tgcttgaaat gatgagtgga 91440
atacaaggaa tttatatttt cagctttcat ttattctcat ttaatatttt catctgttct 91500
catctcagaa gacaataact gcaactttgg tagaatagtc ttgtacctgg tcatactcct 91560
gtggtattga cagttactgc tttgaataaa caatcaatcc acacacatat atacataaat 91620
catttgaagt agtcacataa ttcataaata tgacctctta aataattgga atagtgtata 91680
tgtgcagtta tatatataat aacacatata taagtttcat gttatctttg ggtgcagaca 91740
gttttctgtg gtttgcaata tctctttttg gaagcagata gtttgtttga aaatccaaaa 91800
cagatttgtt atcatcaatg atacattaat gttaggatac atacatacat taagtcctag 91860
gaatgcaaaa gatttattgg aaaaaatata tatatacagt gtttatgtat aagatattaa 91920
atgaggtact ggaagtaaat ataagaagat ttaagagaag gttctaccta tttggggaaa 91980
cagaacattc acatggaggg gaaaattata tagcactctt taaactactt tctttagtcg 92040
aatagaacat tgtaacaatg ttccactgca tttgattctc acataagtgc tatgaggtag 92100
cattaagagg taagatttga gatctgacct ggagcttccc tatttacact acttaccttc 92160
tcagtgacct aagagaagtt acctcagctc tccaatctct ggttttgcaa ggaatttttc 92220
tgtaaaatgt tattgtgagg attaaatcag attatgtata tatatgcact tagcactgtg 92280
cctagcatga agaaaagact tagtaaatgt tcagtttgac cacaagaaaa agttgatatt 92340
atcaccattt actcatgcat aaaagcaagt gccaggattc agtcccaagt acatctgtct 92400
ccaaagccta tgttttcttc tgtacatcac gctgcctact cccaaataac atagaatctc 92460
agaaagtaaa gaactctcat attcctgacc caaaatcata cacctttagt tcttatgcaa 92520
atactagaac tagtattttg gacatataaa ttaatttctg tacttggcca ctgtatgctt 92580
catgatgtct ttggaccttc cagggttgag tcattttttt gatagatgct ttccttgaac 92640
taggaaaaat ggcccttatt atcttcattt aatataaaga tgtaaatgtt ataacaccaa 92700
acataccagt ttcattttgc tcaacaaaca ttgcagatta tttgcatata tacatgtacc 92760
taactgtcct gttcacattt tgtaaaacta atgtacttat gtaaactttc atttgctact 92820
attaagtata acaatatttt tgttatttgt tgattttcta caggaatgtt tctggctgaa 92880
ctgatagaaa agtattttgt gtcccctacc ctgttccgag tgatccgtct tgccaggatt 92940
ggccgaatcc tacgtctgat caaaggagca aaggggatcc gcacgctgct ctttgctttg 93000
atgatgtccc ttcctgcgtt gtttaacatc ggcctccttc ttttcctggt catgttcatc 93060
tacgccatct ttgggatgtc caattttgcc tatgttaaga gggaagttgg gatcgatgac 93120
atgttcaact ttgagacctt tggcaacagc atgatctgcc tgttccaaat tacaacctct 93180
gctggctggg atggattgct agcacctatt cttaatagtg gacctccaga ctgtgaccct 93240
gacaaagatc accctggaag ctcagttaaa ggagactgtg ggaacccatc tgttgggatt 93300
ttcttttttg tcagttacat catcatatcc ttcctggttg tggtgaacat gtacatcgcg 93360
gtcatcctgg agaacttcag tgttgctact gaagaaagtg cagagcctct gagtgaggat 93420
gactttgaga tgttctatga ggtttgggag aagtttgatc ccgatgcgac ccagtttata 93480
gagtttgcca aactttctga ttttgcagat gccctggatc ctcctcttct catagcaaaa 93540
cccaacaaag tccagctcat tgccatggat ctgcccatgg tgagtggtga ccggatccac 93600
tgtcttgaca tcttatttgc ttttacaaag cgtgttttgg gtgagagtgg agagatggat 93660
gcccttcgaa tacagatgga agagcgattc atggcatcaa acccctccaa agtctcttat 93720
gagcccatta cgaccacgtt gaaacgcaaa caagaggagg tgtctgctat tattatccag 93780
agggcttaca gacgctacct cttgaagcaa aaagttaaaa aggtatcaag tatatacaag 93840
aaagacaaag gcaaagaatg tgatggaaca cccatcaaag aagatactct cattgataaa 93900
ctgaatgaga attcaactcc agagaaaacc gatatgacgc cttccaccac gtctccaccc 93960
tcgtatgata gtgtgaccaa accagaaaaa gaaaaatttg aaaaagacaa atcagaaaag 94020
gaagacaaag ggaaagatat cagggaaagt aaaaagtaaa aagaaaccaa gaattttcca 94080
ttttgtgatc aattgtttac agcccgtgat ggtgatgtgt ttgtgtcaac aggactccca 94140
caggaggtct atgccaaact gactgttttt acaaatgtat acttaaggtc agtgcctata 94200
acaagacaga gacctctggt cagcaaactg gaactcagta aactggagaa atagtatcga 94260
tgggaggttt ctattttcac aaccagctga cactgctgaa gagcagaggc gtaatggcta 94320
ctcagacgat aggaaccaat ttaaaggggg gagggaagtt aaatttttat gtaaattcaa 94380
catgtgacac ttgataatag taattgtcac cagtgtttat gttttaactg ccacacctgc 94440
catattttta caaaacgtgt gctgtgaatt tatcactttt ctttttaatt cacaggttgt 94500
ttactattat atgtgactat ttttgtaaat gggtttgtgt ttggggagag ggattaaagg 94560
gagggaattc tacatttctc tattgtattg tataactgga tatattttaa atggaggcat 94620
gctgcaattc tcattcacac ataaaaaaat cacatcacaa aagggaagag tttacttctt 94680
gtttcaggat gtttttagat ttttgaggtg cttaaatagc tattcgtatt tttaaggtgt 94740
ctcatccaga aaaaatttaa tgtgcctgta aatgttccat agaatcacaa gcattaaaga 94800
gttgttttat ttttacataa cccattaaat gtacatgtat atatgtatat atgtatatgt 94860
gcgtgtatat acatatatat gtatacacac atgcacacac agagatatac acataccatt 94920
acattgtcat tcacagtccc agcagcatga ctatcacatt tttgataagt gtcctttggc 94980
ataaaataaa aatatcctat cagtcctttc taagaagcct gaattgacca aaaaacatcc 95040
ccaccaccac tttataaagt tgattctgct ttatcctgca gtattgttta gccatcttct 95100
gctcttggta aggttgacat agtatatgtc aatttaaaaa ataaaagtct gctttgtaaa 95160
tagtaatttt acccagtggt gcatgtttga gcaaacaaaa atgatgattt aagcacacta 95220
cttattgcat caaatatgta ccacagtaag tatagtttgc aagctttcaa caggtaatat 95280
gatgtaattg gttccattat agtttgaagc tgtcactgct gcatgtttat cttgcctatg 95340
ctgctgtatc ttattccttc cactgttcag aagtctaata tgggaagcca tatatcagtg 95400
gtaaagtgaa gcaaattgtt ctaccaagac ctcattcttc atgtcattaa gcaataggtt 95460
gcagcaaaca aggaagagct tcttgctttt tattcttcca accttaattg aacactcaat 95520
gatgaaaagc ccgactgtac aaacatgttg caagctgctt aaatctgttt aaaatatatg 95580
gttagagttt tctaagaaaa tataaatact gtaaaaagtt cattttattt tatttttcag 95640
ccttttgtac gtaaaatgag aaattaaaag tatcttcagg tggatgtcac agtcactatt 95700
gttagtttct gttcctagca cttttaaatt gaagcacttc acaaaataag aagcaaggac 95760
taggatgcag tgtaggtttc tgctttttta ttagtactgt aaacttgcac acatttcaat 95820
gtgaaacaaa tctcaaactg agttcaatgt ttatttgctt tcaatagtaa tgccttatca 95880
ttgaaagagg cttaaagaaa aaaaaaatca gctgatactc ttggcattgc ttgaatccaa 95940
tgtttccacc tagtcttttt attcagtaat catcagtctt ttccaatgtt tgtttacaca 96000
gatagatctt attgacccat atggcactag aactgtatca gatataatat gggatcccag 96060
ctttttttcc tctcccacaa aaccaggtag tgaagttata ttaccagtta cagcaaaata 96120
ctttgtgttt cacaagcaac aataaatgta gattctttat actgaagcta ttgacttgta 96180
gtgtgttggt gaaatgcatg caggaaaatg ctgttaccat aaagaacggt aaaccacatt 96240
acaatcaagc caaaagaata aaggtttcgc ttttgttttt gtatttaatt gttgtctttg 96300
tttctatctt tgaaatgcca tttaaaggta gatttctatc atgtaaaaat aatctatctg 96360
aaaaacaaat gtaaagaaca cacattaatt actataattc atctttcaat tttttcatgg 96420
aatggaagtt aattaagaag agtgtattgg ataactactt taatattggc caaaaagcta 96480
gatatggcat caggtagact agtggaaagt tacaaaaatt aataaaaaat tgactaacat 96540
tttaagttgt gcatcttttc tccttcctgt ccacctattg ttcttttttt cacttttcca 96600
tttcaatttc ttccttatgt attcttgatc tacttttctt tatatccttc tatcctttcc 96660
ttgcgctctc agtatttttc atttaggata ttctccttgt ttcttttctg ttcaccaaat 96720
gtcttgttta ttacagccta tagatcactt agatttagat ccctaaaatt tgctgtcact 96780
ctgtaaagtg cacctcgaga taacttcgta taatgtatgc tatacgaagt tatatgcatg 96840
ccagtagcag cacccacgtc caccttctgt ctagtaatgt ccaacacctc cctcagtcca 96900
aacactgctc tgcatccatg tggctcccat ttatacctga agcacttgat ggggcctcaa 96960
tgttttacta gagcccaccc ccctgcaact ctgagaccct ctggatttgt ctgtcagtgc 97020
ctcactgggg cgttggataa tttcttaaaa ggtcaagttc cctcagcagc attctctgag 97080
cagtctgaag atgtgtgctt ttcacagttc aaatccatgt ggctgtttca cccacctgcc 97140
tggccttggg ttatctatca ggacctagcc tagaagcagg tgtgtggcac ttaacaccta 97200
agctgagtga ctaactgaac actcaagtgg atgccatctt tgtcacttct tgactgtgac 97260
acaagcaact cctgatgcca aagccctgcc cacccctctc atgcccatat ttggacatgg 97320
tacaggtcct cactggccat ggtctgtgag gtcctggtcc tctttgactt cataattcct 97380
aggggccact agtatctata agaggaagag ggtgctggct cccaggccac agcccacaaa 97440
attccacctg ctcacaggtt ggctggctcg acccaggtgg tgtcccctgc tctgagccag 97500
ctcccggcca agccagcacc atgggaaccc ccaagaagaa gaggaaggtg cgtaccgatt 97560
taaattccaa tttactgacc gtacaccaaa atttgcctgc attaccggtc gatgcaacga 97620
gtgatgaggt tcgcaagaac ctgatggaca tgttcaggga tcgccaggcg ttttctgagc 97680
atacctggaa aatgcttctg tccgtttgcc ggtcgtgggc ggcatggtgc aagttgaata 97740
accggaaatg gtttcccgca gaacctgaag atgttcgcga ttatcttcta tatcttcagg 97800
cgcgcggtct ggcagtaaaa actatccagc aacatttggg ccagctaaac atgcttcatc 97860
gtcggtccgg gctgccacga ccaagtgaca gcaatgctgt ttcactggtt atgcggcgga 97920
tccgaaaaga aaacgttgat gccggtgaac gtgcaaaaca ggtaaatata aaatttttaa 97980
gtgtataatg atgttaaact actgattcta attgtttgtg tattttaggc tctagcgttc 98040
gaacgcactg atttcgacca ggttcgttca ctcatggaaa atagcgatcg ctgccaggat 98100
atacgtaatc tggcatttct ggggattgct tataacaccc tgttacgtat agccgaaatt 98160
gccaggatca gggttaaaga tatctcacgt actgacggtg ggagaatgtt aatccatatt 98220
ggcagaacga aaacgctggt tagcaccgca ggtgtagaga aggcacttag cctgggggta 98280
actaaactgg tcgagcgatg gatttccgtc tctggtgtag ctgatgatcc gaataactac 98340
ctgttttgcc gggtcagaaa aaatggtgtt gccgcgccat ctgccaccag ccagctatca 98400
actcgcgccc tggaagggat ttttgaagca actcatcgat tgatttacgg cgctaaggat 98460
gactctggtc agagatacct ggcctggtct ggacacagtg cccgtgtcgg agccgcgcga 98520
gatatggccc gcgctggagt ttcaataccg gagatcatgc aagctggtgg ctggaccaat 98580
gtaaatattg tcatgaacta tatccgtaac ctggatagtg aaacaggggc aatggtgcgc 98640
ctgctggaag atggcgatta ggcggccggc cgctaatcag ccataccaca tttgtagagg 98700
ttttacttgc tttaaaaaac ctcccacacc tccccctgaa cctgaaacat aaaatgaatg 98760
caattgttgt tgttaacttg tttattgcag cttataatgg ttacaaataa agcaatagca 98820
tcacaaattt cacaaataaa gcattttttt cactgcattc tagttgtggt ttgtccaaac 98880
tcatcaatgt atcttatcat gtctggatcc cccggctaga gtttaaacac tagaactagt 98940
ggatcccccg ggatcatggc ctccgcgccg ggttttggcg cctcccgcgg gcgcccccct 99000
cctcacggcg agcgctgcca cgtcagacga agggcgcagc gagcgtcctg atccttccgc 99060
ccggacgctc aggacagcgg cccgctgctc ataagactcg gccttagaac cccagtatca 99120
gcagaaggac attttaggac gggacttggg tgactctagg gcactggttt tctttccaga 99180
gagcggaaca ggcgaggaaa agtagtccct tctcggcgat tctgcggagg gatctccgtg 99240
gggcggtgaa cgccgatgat tatataagga cgcgccgggt gtggcacagc tagttccgtc 99300
gcagccggga tttgggtcgc ggttcttgtt tgtggatcgc tgtgatcgtc acttggtgag 99360
tagcgggctg ctgggctggc cggggctttc gtggccgccg ggccgctcgg tgggacggaa 99420
gcgtgtggag agaccgccaa gggctgtagt ctgggtccgc gagcaaggtt gccctgaact 99480
gggggttggg gggagcgcag caaaatggcg gctgttcccg agtcttgaat ggaagacgct 99540
tgtgaggcgg gctgtgaggt cgttgaaaca aggtgggggg catggtgggc ggcaagaacc 99600
caaggtcttg aggccttcgc taatgcggga aagctcttat tcgggtgaga tgggctgggg 99660
caccatctgg ggaccctgac gtgaagtttg tcactgactg gagaactcgg tttgtcgtct 99720
gttgcggggg cggcagttat ggcggtgccg ttgggcagtg cacccgtacc tttgggagcg 99780
cgcgccctcg tcgtgtcgtg acgtcacccg ttctgttggc ttataatgca gggtggggcc 99840
acctgccggt aggtgtgcgg taggcttttc tccgtcgcag gacgcagggt tcgggcctag 99900
ggtaggctct cctgaatcga caggcgccgg acctctggtg aggggaggga taagtgaggc 99960
gtcagtttct ttggtcggtt ttatgtacct atcttcttaa gtagctgaag ctccggtttt 100020
gaactatgcg ctcggggttg gcgagtgtgt tttgtgaagt tttttaggca ccttttgaaa 100080
tgtaatcatt tgggtcaata tgtaattttc agtgttagac tagtaaattg tccgctaaat 100140
tctggccgtt tttggctttt ttgttagacg tgttgacaat taatcatcgg catagtatat 100200
cggcatagta taatacgaca aggtgaggaa ctaaaccatg ggatcggcca ttgaacaaga 100260
tggattgcac gcaggttctc cggccgcttg ggtggagagg ctattcggct atgactgggc 100320
acaacagaca atcggctgct ctgatgccgc cgtgttccgg ctgtcagcgc aggggcgccc 100380
ggttcttttt gtcaagaccg acctgtccgg tgccctgaat gaactgcagg acgaggcagc 100440
gcggctatcg tggctggcca cgacgggcgt tccttgcgca gctgtgctcg acgttgtcac 100500
tgaagcggga agggactggc tgctattggg cgaagtgccg gggcaggatc tcctgtcatc 100560
tcaccttgct cctgccgaga aagtatccat catggctgat gcaatgcggc ggctgcatac 100620
gcttgatccg gctacctgcc cattcgacca ccaagcgaaa catcgcatcg agcgagcacg 100680
tactcggatg gaagccggtc ttgtcgatca ggatgatctg gacgaagagc atcaggggct 100740
cgcgccagcc gaactgttcg ccaggctcaa ggcgcgcatg cccgacggcg atgatctcgt 100800
cgtgacccat ggcgatgcct gcttgccgaa tatcatggtg gaaaatggcc gcttttctgg 100860
attcatcgac tgtggccggc tgggtgtggc ggaccgctat caggacatag cgttggctac 100920
ccgtgatatt gctgaagagc ttggcggcga atgggctgac cgcttcctcg tgctttacgg 100980
tatcgccgct cccgattcgc agcgcatcgc cttctatcgc cttcttgacg agttcttctg 101040
aggggatccg ctgtaagtct gcagaaattg atgatctatt aaacaataaa gatgtccact 101100
aaaatggaag tttttcctgt catactttgt taagaagggt gagaacagag tacctacatt 101160
ttgaatggaa ggattggagc tacgggggtg ggggtggggt gggattagat aaatgcctgc 101220
tctttactga aggctcttta ctattgcttt atgataatgt ttcatagttg gatatcataa 101280
tttaaacaag caaaaccaaa ttaagggcca gctcattcct cccactcatg atctatagat 101340
ctatagatct ctcgtgggat cattgttttt ctcttgattc ccactttgtg gttctaagta 101400
ctgtggtttc caaatgtgtc agtttcatag cctgaagaac gagatcagca gcctctgttc 101460
cacatacact tcattctcag tattgttttg ccaagttcta attccatcag acctcgacct 101520
gcagccccta gataacttcg tataatgtat gctatacgaa gttatgctag taactataac 101580
ggtcctaagg tagcgagcta gcagcttcgg ttttgataca ctgtttacag cctgcgaagg 101640
tgactcactc gtgttaataa gactctttta cgg 101673
<210> 21
<211> 197
<212> DNA
<213> 人工序列
<220>
<223> 寡核苷酸序列
<400> 21
cagcctatag atcacttaga tttagatccc taaaatttgc tgtcactctg taaagtgcac 60
ctcgagataa cttcgtataa tgtatgctat acgaagttat gctagtaact ataacggtcc 120
taaggtagcg agctagcagc ttcggttttg atacactgtt tacagcctgc gaaggtgact 180
cactcgtgtt aataaga 197
<210> 22
<211> 2009
<212> PRT
<213> 智人
<400> 22
Met Glu Gln Thr Val Leu Val Pro Pro Gly Pro Asp Ser Phe Asn Phe
1 5 10 15
Phe Thr Arg Glu Ser Leu Ala Ala Ile Glu Arg Arg Ile Ala Glu Glu
20 25 30
Lys Ala Lys Asn Pro Lys Pro Asp Lys Lys Asp Asp Asp Glu Asn Gly
35 40 45
Pro Lys Pro Asn Ser Asp Leu Glu Ala Gly Lys Asn Leu Pro Phe Ile
50 55 60
Tyr Gly Asp Ile Pro Pro Glu Met Val Ser Glu Pro Leu Glu Asp Leu
65 70 75 80
Asp Pro Tyr Tyr Ile Asn Lys Lys Thr Phe Ile Val Leu Asn Lys Gly
85 90 95
Lys Ala Ile Phe Arg Phe Ser Ala Thr Ser Ala Leu Tyr Ile Leu Thr
100 105 110
Pro Phe Asn Pro Leu Arg Lys Ile Ala Ile Lys Ile Leu Val His Ser
115 120 125
Leu Phe Ser Met Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Val Phe
130 135 140
Met Thr Met Ser Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr Thr
145 150 155 160
Phe Thr Gly Ile Tyr Thr Phe Glu Ser Leu Ile Lys Ile Ile Ala Arg
165 170 175
Gly Phe Cys Leu Glu Asp Phe Thr Phe Leu Arg Asp Pro Trp Asn Trp
180 185 190
Leu Asp Phe Thr Val Ile Thr Phe Ala Tyr Val Thr Glu Phe Val Asp
195 200 205
Leu Gly Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala Leu
210 215 220
Lys Thr Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala Leu
225 230 235 240
Ile Gln Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val Phe
245 250 255
Cys Leu Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly Asn
260 265 270
Leu Arg Asn Lys Cys Ile Gln Trp Pro Pro Thr Asn Ala Ser Leu Glu
275 280 285
Glu His Ser Ile Glu Lys Asn Ile Thr Val Asn Tyr Asn Gly Thr Leu
290 295 300
Ile Asn Glu Thr Val Phe Glu Phe Asp Trp Lys Ser Tyr Ile Gln Asp
305 310 315 320
Ser Arg Tyr His Tyr Phe Leu Glu Gly Phe Leu Asp Ala Leu Leu Cys
325 330 335
Gly Asn Ser Ser Asp Ala Gly Gln Cys Pro Glu Gly Tyr Met Cys Val
340 345 350
Lys Ala Gly Arg Asn Pro Asn Tyr Gly Tyr Thr Ser Phe Asp Thr Phe
355 360 365
Ser Trp Ala Phe Leu Ser Leu Phe Arg Leu Met Thr Gln Asp Phe Trp
370 375 380
Glu Asn Leu Tyr Gln Leu Thr Leu Arg Ala Ala Gly Lys Thr Tyr Met
385 390 395 400
Ile Phe Phe Val Leu Val Ile Phe Leu Gly Ser Phe Tyr Leu Ile Asn
405 410 415
Leu Ile Leu Ala Val Val Ala Met Ala Tyr Glu Glu Gln Asn Gln Ala
420 425 430
Thr Leu Glu Glu Ala Glu Gln Lys Glu Ala Glu Phe Gln Gln Met Ile
435 440 445
Glu Gln Leu Lys Lys Gln Gln Glu Ala Ala Gln Gln Ala Ala Thr Ala
450 455 460
Thr Ala Ser Glu His Ser Arg Glu Pro Ser Ala Ala Gly Arg Leu Ser
465 470 475 480
Asp Ser Ser Ser Glu Ala Ser Lys Leu Ser Ser Lys Ser Ala Lys Glu
485 490 495
Arg Arg Asn Arg Arg Lys Lys Arg Lys Gln Lys Glu Gln Ser Gly Gly
500 505 510
Glu Glu Lys Asp Glu Asp Glu Phe Gln Lys Ser Glu Ser Glu Asp Ser
515 520 525
Ile Arg Arg Lys Gly Phe Arg Phe Ser Ile Glu Gly Asn Arg Leu Thr
530 535 540
Tyr Glu Lys Arg Tyr Ser Ser Pro His Gln Ser Leu Leu Ser Ile Arg
545 550 555 560
Gly Ser Leu Phe Ser Pro Arg Arg Asn Ser Arg Thr Ser Leu Phe Ser
565 570 575
Phe Arg Gly Arg Ala Lys Asp Val Gly Ser Glu Asn Asp Phe Ala Asp
580 585 590
Asp Glu His Ser Thr Phe Glu Asp Asn Glu Ser Arg Arg Asp Ser Leu
595 600 605
Phe Val Pro Arg Arg His Gly Glu Arg Arg Asn Ser Asn Leu Ser Gln
610 615 620
Thr Ser Arg Ser Ser Arg Met Leu Ala Val Phe Pro Ala Asn Gly Lys
625 630 635 640
Met His Ser Thr Val Asp Cys Asn Gly Val Val Ser Leu Val Gly Gly
645 650 655
Pro Ser Val Pro Thr Ser Pro Val Gly Gln Leu Leu Pro Glu Val Ile
660 665 670
Ile Asp Lys Pro Ala Thr Asp Asp Asn Gly Thr Thr Thr Glu Thr Glu
675 680 685
Met Arg Lys Arg Arg Ser Ser Ser Phe His Val Ser Met Asp Phe Leu
690 695 700
Glu Asp Pro Ser Gln Arg Gln Arg Ala Met Ser Ile Ala Ser Ile Leu
705 710 715 720
Thr Asn Thr Val Glu Glu Leu Glu Glu Ser Arg Gln Lys Cys Pro Pro
725 730 735
Cys Trp Tyr Lys Phe Ser Asn Ile Phe Leu Ile Trp Asp Cys Ser Pro
740 745 750
Tyr Trp Leu Lys Val Lys His Val Val Asn Leu Val Val Met Asp Pro
755 760 765
Phe Val Asp Leu Ala Ile Thr Ile Cys Ile Val Leu Asn Thr Leu Phe
770 775 780
Met Ala Met Glu His Tyr Pro Met Thr Asp His Phe Asn Asn Val Leu
785 790 795 800
Thr Val Gly Asn Leu Val Phe Thr Gly Ile Phe Thr Ala Glu Met Phe
805 810 815
Leu Lys Ile Ile Ala Met Asp Pro Tyr Tyr Tyr Phe Gln Glu Gly Trp
820 825 830
Asn Ile Phe Asp Gly Phe Ile Val Thr Leu Ser Leu Val Glu Leu Gly
835 840 845
Leu Ala Asn Val Glu Gly Leu Ser Val Leu Arg Ser Phe Arg Leu Leu
850 855 860
Arg Val Phe Lys Leu Ala Lys Ser Trp Pro Thr Leu Asn Met Leu Ile
865 870 875 880
Lys Ile Ile Gly Asn Ser Val Gly Ala Leu Gly Asn Leu Thr Leu Val
885 890 895
Leu Ala Ile Ile Val Phe Ile Phe Ala Val Val Gly Met Gln Leu Phe
900 905 910
Gly Lys Ser Tyr Lys Asp Cys Val Cys Lys Ile Ala Ser Asp Cys Gln
915 920 925
Leu Pro Arg Trp His Met Asn Asp Phe Phe His Ser Phe Leu Ile Val
930 935 940
Phe Arg Val Leu Cys Gly Glu Trp Ile Glu Thr Met Trp Asp Cys Met
945 950 955 960
Glu Val Ala Gly Gln Ala Met Cys Leu Thr Val Phe Met Met Val Met
965 970 975
Val Ile Gly Asn Leu Val Val Leu Asn Leu Phe Leu Ala Leu Leu Leu
980 985 990
Ser Ser Phe Ser Ala Asp Asn Leu Ala Ala Thr Asp Asp Asp Asn Glu
995 1000 1005
Met Asn Asn Leu Gln Ile Ala Val Asp Arg Met His Lys Gly Val
1010 1015 1020
Ala Tyr Val Lys Arg Lys Ile Tyr Glu Phe Ile Gln Gln Ser Phe
1025 1030 1035
Ile Arg Lys Gln Lys Ile Leu Asp Glu Ile Lys Pro Leu Asp Asp
1040 1045 1050
Leu Asn Asn Lys Lys Asp Ser Cys Met Ser Asn His Thr Ala Glu
1055 1060 1065
Ile Gly Lys Asp Leu Asp Tyr Leu Lys Asp Val Asn Gly Thr Thr
1070 1075 1080
Ser Gly Ile Gly Thr Gly Ser Ser Val Glu Lys Tyr Ile Ile Asp
1085 1090 1095
Glu Ser Asp Tyr Met Ser Phe Ile Asn Asn Pro Ser Leu Thr Val
1100 1105 1110
Thr Val Pro Ile Ala Val Gly Glu Ser Asp Phe Glu Asn Leu Asn
1115 1120 1125
Thr Glu Asp Phe Ser Ser Glu Ser Asp Leu Glu Glu Ser Lys Glu
1130 1135 1140
Lys Leu Asn Glu Ser Ser Ser Ser Ser Glu Gly Ser Thr Val Asp
1145 1150 1155
Ile Gly Ala Pro Val Glu Glu Gln Pro Val Val Glu Pro Glu Glu
1160 1165 1170
Thr Leu Glu Pro Glu Ala Cys Phe Thr Glu Gly Cys Val Gln Arg
1175 1180 1185
Phe Lys Cys Cys Gln Ile Asn Val Glu Glu Gly Arg Gly Lys Gln
1190 1195 1200
Trp Trp Asn Leu Arg Arg Thr Cys Phe Arg Ile Val Glu His Asn
1205 1210 1215
Trp Phe Glu Thr Phe Ile Val Phe Met Ile Leu Leu Ser Ser Gly
1220 1225 1230
Ala Leu Ala Phe Glu Asp Ile Tyr Ile Asp Gln Arg Lys Thr Ile
1235 1240 1245
Lys Thr Met Leu Glu Tyr Ala Asp Lys Val Phe Thr Tyr Ile Phe
1250 1255 1260
Ile Leu Glu Met Leu Leu Lys Trp Val Ala Tyr Gly Tyr Gln Thr
1265 1270 1275
Tyr Phe Thr Asn Ala Trp Cys Trp Leu Asp Phe Leu Ile Val Asp
1280 1285 1290
Val Ser Leu Val Ser Leu Thr Ala Asn Ala Leu Gly Tyr Ser Glu
1295 1300 1305
Leu Gly Ala Ile Lys Ser Leu Arg Thr Leu Arg Ala Leu Arg Pro
1310 1315 1320
Leu Arg Ala Leu Ser Arg Phe Glu Gly Met Arg Val Val Val Asn
1325 1330 1335
Ala Leu Leu Gly Ala Ile Pro Ser Ile Met Asn Val Leu Leu Val
1340 1345 1350
Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile Met Gly Val Asn Leu
1355 1360 1365
Phe Ala Gly Lys Phe Tyr His Cys Ile Asn Thr Thr Thr Gly Asp
1370 1375 1380
Arg Phe Asp Ile Glu Asp Val Asn Asn His Thr Asp Cys Leu Lys
1385 1390 1395
Leu Ile Glu Arg Asn Glu Thr Ala Arg Trp Lys Asn Val Lys Val
1400 1405 1410
Asn Phe Asp Asn Val Gly Phe Gly Tyr Leu Ser Leu Leu Gln Val
1415 1420 1425
Ala Thr Phe Lys Gly Trp Met Asp Ile Met Tyr Ala Ala Val Asp
1430 1435 1440
Ser Arg Asn Val Glu Leu Gln Pro Lys Tyr Glu Glu Ser Leu Tyr
1445 1450 1455
Met Tyr Leu Tyr Phe Val Ile Phe Ile Ile Phe Gly Ser Phe Phe
1460 1465 1470
Thr Leu Asn Leu Phe Ile Gly Val Ile Ile Asp Asn Phe Asn Gln
1475 1480 1485
Gln Lys Lys Lys Phe Gly Gly Gln Asp Ile Phe Met Thr Glu Glu
1490 1495 1500
Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys Leu Gly Ser Lys Lys
1505 1510 1515
Pro Gln Lys Pro Ile Pro Arg Pro Gly Asn Lys Phe Gln Gly Met
1520 1525 1530
Val Phe Asp Phe Val Thr Arg Gln Val Phe Asp Ile Ser Ile Met
1535 1540 1545
Ile Leu Ile Cys Leu Asn Met Val Thr Met Met Val Glu Thr Asp
1550 1555 1560
Asp Gln Ser Glu Tyr Val Thr Thr Ile Leu Ser Arg Ile Asn Leu
1565 1570 1575
Val Phe Ile Val Leu Phe Thr Gly Glu Cys Val Leu Lys Leu Ile
1580 1585 1590
Ser Leu Arg His Tyr Tyr Phe Thr Ile Gly Trp Asn Ile Phe Asp
1595 1600 1605
Phe Val Val Val Ile Leu Ser Ile Val Gly Met Phe Leu Ala Glu
1610 1615 1620
Leu Ile Glu Lys Tyr Phe Val Ser Pro Thr Leu Phe Arg Val Ile
1625 1630 1635
Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg Leu Ile Lys Gly Ala
1640 1645 1650
Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu Met Met Ser Leu Pro
1655 1660 1665
Ala Leu Phe Asn Ile Gly Leu Leu Leu Phe Leu Val Met Phe Ile
1670 1675 1680
Tyr Ala Ile Phe Gly Met Ser Asn Phe Ala Tyr Val Lys Arg Glu
1685 1690 1695
Val Gly Ile Asp Asp Met Phe Asn Phe Glu Thr Phe Gly Asn Ser
1700 1705 1710
Met Ile Cys Leu Phe Gln Ile Thr Thr Ser Ala Gly Trp Asp Gly
1715 1720 1725
Leu Leu Ala Pro Ile Leu Asn Ser Lys Pro Pro Asp Cys Asp Pro
1730 1735 1740
Asn Lys Val Asn Pro Gly Ser Ser Val Lys Gly Asp Cys Gly Asn
1745 1750 1755
Pro Ser Val Gly Ile Phe Phe Phe Val Ser Tyr Ile Ile Ile Ser
1760 1765 1770
Phe Leu Val Val Val Asn Met Tyr Ile Ala Val Ile Leu Glu Asn
1775 1780 1785
Phe Ser Val Ala Thr Glu Glu Ser Ala Glu Pro Leu Ser Glu Asp
1790 1795 1800
Asp Phe Glu Met Phe Tyr Glu Val Trp Glu Lys Phe Asp Pro Asp
1805 1810 1815
Ala Thr Gln Phe Met Glu Phe Glu Lys Leu Ser Gln Phe Ala Ala
1820 1825 1830
Ala Leu Glu Pro Pro Leu Asn Leu Pro Gln Pro Asn Lys Leu Gln
1835 1840 1845
Leu Ile Ala Met Asp Leu Pro Met Val Ser Gly Asp Arg Ile His
1850 1855 1860
Cys Leu Asp Ile Leu Phe Ala Phe Thr Lys Arg Val Leu Gly Glu
1865 1870 1875
Ser Gly Glu Met Asp Ala Leu Arg Ile Gln Met Glu Glu Arg Phe
1880 1885 1890
Met Ala Ser Asn Pro Ser Lys Val Ser Tyr Gln Pro Ile Thr Thr
1895 1900 1905
Thr Leu Lys Arg Lys Gln Glu Glu Val Ser Ala Val Ile Ile Gln
1910 1915 1920
Arg Ala Tyr Arg Arg His Leu Leu Lys Arg Thr Val Lys Gln Ala
1925 1930 1935
Ser Phe Thr Tyr Asn Lys Asn Lys Ile Lys Gly Gly Ala Asn Leu
1940 1945 1950
Leu Ile Lys Glu Asp Met Ile Ile Asp Arg Ile Asn Glu Asn Ser
1955 1960 1965
Ile Thr Glu Lys Thr Asp Leu Thr Met Ser Thr Ala Ala Cys Pro
1970 1975 1980
Pro Ser Tyr Asp Arg Val Thr Lys Pro Ile Val Glu Lys His Glu
1985 1990 1995
Gln Glu Gly Lys Asp Glu Lys Ala Lys Gly Lys
2000 2005
<210> 23
<211> 2000
<212> PRT
<213> 智人
<400> 23
Met Ala Gln Ala Leu Leu Val Pro Pro Gly Pro Glu Ser Phe Arg Leu
1 5 10 15
Phe Thr Arg Glu Ser Leu Ala Ala Ile Glu Lys Arg Ala Ala Glu Glu
20 25 30
Lys Ala Lys Lys Pro Lys Lys Glu Gln Asp Asn Asp Asp Glu Asn Lys
35 40 45
Pro Lys Pro Asn Ser Asp Leu Glu Ala Gly Lys Asn Leu Pro Phe Ile
50 55 60
Tyr Gly Asp Ile Pro Pro Glu Met Val Ser Glu Pro Leu Glu Asp Leu
65 70 75 80
Asp Pro Tyr Tyr Ile Asn Lys Lys Thr Phe Ile Val Met Asn Lys Gly
85 90 95
Lys Ala Ile Phe Arg Phe Ser Ala Thr Ser Ala Leu Tyr Ile Leu Thr
100 105 110
Pro Leu Asn Pro Val Arg Lys Ile Ala Ile Lys Ile Leu Val His Ser
115 120 125
Leu Phe Ser Met Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Val Phe
130 135 140
Met Thr Leu Ser Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr Thr
145 150 155 160
Phe Thr Gly Ile Tyr Thr Phe Glu Ser Leu Ile Lys Ile Leu Ala Arg
165 170 175
Gly Phe Cys Leu Glu Asp Phe Thr Phe Leu Arg Asp Pro Trp Asn Trp
180 185 190
Leu Asp Phe Ser Val Ile Val Met Ala Tyr Val Thr Glu Phe Val Ser
195 200 205
Leu Gly Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala Leu
210 215 220
Lys Thr Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala Leu
225 230 235 240
Ile Gln Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val Phe
245 250 255
Cys Leu Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly Asn
260 265 270
Leu Arg Asn Lys Cys Leu Gln Trp Pro Pro Ser Asp Ser Ala Phe Glu
275 280 285
Thr Asn Thr Thr Ser Tyr Phe Asn Gly Thr Met Asp Ser Asn Gly Thr
290 295 300
Phe Val Asn Val Thr Met Ser Thr Phe Asn Trp Lys Asp Tyr Ile Gly
305 310 315 320
Asp Asp Ser His Phe Tyr Val Leu Asp Gly Gln Lys Asp Pro Leu Leu
325 330 335
Cys Gly Asn Gly Ser Asp Ala Gly Gln Cys Pro Glu Gly Tyr Ile Cys
340 345 350
Val Lys Ala Gly Arg Asn Pro Asn Tyr Gly Tyr Thr Ser Phe Asp Thr
355 360 365
Phe Ser Trp Ala Phe Leu Ser Leu Phe Arg Leu Met Thr Gln Asp Tyr
370 375 380
Trp Glu Asn Leu Tyr Gln Leu Thr Leu Arg Ala Ala Gly Lys Thr Tyr
385 390 395 400
Met Ile Phe Phe Val Leu Val Ile Phe Leu Gly Ser Phe Tyr Leu Val
405 410 415
Asn Leu Ile Leu Ala Val Val Ala Met Ala Tyr Glu Glu Gln Asn Gln
420 425 430
Ala Thr Leu Glu Glu Ala Glu Gln Lys Glu Ala Glu Phe Gln Gln Met
435 440 445
Leu Glu Gln Leu Lys Lys Gln Gln Glu Glu Ala Gln Ala Val Ala Ala
450 455 460
Ala Ser Ala Ala Ser Arg Asp Phe Ser Gly Ile Gly Gly Leu Gly Glu
465 470 475 480
Leu Leu Glu Ser Ser Ser Glu Ala Ser Lys Leu Ser Ser Lys Ser Ala
485 490 495
Lys Glu Trp Arg Asn Arg Arg Lys Lys Arg Arg Gln Arg Glu His Leu
500 505 510
Glu Gly Asn Asn Lys Gly Glu Arg Asp Ser Phe Pro Lys Ser Glu Ser
515 520 525
Glu Asp Ser Val Lys Arg Ser Ser Phe Leu Phe Ser Met Asp Gly Asn
530 535 540
Arg Leu Thr Ser Asp Lys Lys Phe Cys Ser Pro His Gln Ser Leu Leu
545 550 555 560
Ser Ile Arg Gly Ser Leu Phe Ser Pro Arg Arg Asn Ser Lys Thr Ser
565 570 575
Ile Phe Ser Phe Arg Gly Arg Ala Lys Asp Val Gly Ser Glu Asn Asp
580 585 590
Phe Ala Asp Asp Glu His Ser Thr Phe Glu Asp Ser Glu Ser Arg Arg
595 600 605
Asp Ser Leu Phe Val Pro His Arg His Gly Glu Arg Arg Asn Ser Asn
610 615 620
Val Ser Gln Ala Ser Met Ser Ser Arg Met Val Pro Gly Leu Pro Ala
625 630 635 640
Asn Gly Lys Met His Ser Thr Val Asp Cys Asn Gly Val Val Ser Leu
645 650 655
Val Gly Gly Pro Ser Ala Leu Thr Ser Pro Thr Gly Gln Leu Pro Pro
660 665 670
Glu Gly Thr Thr Thr Glu Thr Glu Val Arg Lys Arg Arg Leu Ser Ser
675 680 685
Tyr Gln Ile Ser Met Glu Met Leu Glu Asp Ser Ser Gly Arg Gln Arg
690 695 700
Ala Val Ser Ile Ala Ser Ile Leu Thr Asn Thr Met Glu Glu Leu Glu
705 710 715 720
Glu Ser Arg Gln Lys Cys Pro Pro Cys Trp Tyr Arg Phe Ala Asn Val
725 730 735
Phe Leu Ile Trp Asp Cys Cys Asp Ala Trp Leu Lys Val Lys His Leu
740 745 750
Val Asn Leu Ile Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile
755 760 765
Cys Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His Tyr Pro Met
770 775 780
Thr Glu Gln Phe Ser Ser Val Leu Thr Val Gly Asn Leu Val Phe Thr
785 790 795 800
Gly Ile Phe Thr Ala Glu Met Val Leu Lys Ile Ile Ala Met Asp Pro
805 810 815
Tyr Tyr Tyr Phe Gln Glu Gly Trp Asn Ile Phe Asp Gly Ile Ile Val
820 825 830
Ser Leu Ser Leu Met Glu Leu Gly Leu Ser Asn Val Glu Gly Leu Ser
835 840 845
Val Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser
850 855 860
Trp Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly
865 870 875 880
Ala Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe
885 890 895
Ala Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val
900 905 910
Cys Lys Ile Asn Asp Asp Cys Thr Leu Pro Arg Trp His Met Asn Asp
915 920 925
Phe Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp
930 935 940
Ile Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Thr Met Cys
945 950 955 960
Leu Ile Val Phe Met Leu Val Met Val Ile Gly Asn Leu Val Val Leu
965 970 975
Asn Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu
980 985 990
Ala Ala Thr Asp Asp Asp Asn Glu Met Asn Asn Leu Gln Ile Ala Val
995 1000 1005
Gly Arg Met Gln Lys Gly Ile Asp Tyr Val Lys Asn Lys Met Arg
1010 1015 1020
Glu Cys Phe Gln Lys Ala Phe Phe Arg Lys Pro Lys Val Ile Glu
1025 1030 1035
Ile His Glu Gly Asn Lys Ile Asp Ser Cys Met Ser Asn Asn Thr
1040 1045 1050
Gly Ile Glu Ile Ser Lys Glu Leu Asn Tyr Leu Arg Asp Gly Asn
1055 1060 1065
Gly Thr Thr Ser Gly Val Gly Thr Gly Ser Ser Val Glu Lys Tyr
1070 1075 1080
Val Ile Asp Glu Asn Asp Tyr Met Ser Phe Ile Asn Asn Pro Ser
1085 1090 1095
Leu Thr Val Thr Val Pro Ile Ala Val Gly Glu Ser Asp Phe Glu
1100 1105 1110
Asn Leu Asn Thr Glu Glu Phe Ser Ser Glu Ser Glu Leu Glu Glu
1115 1120 1125
Ser Lys Glu Lys Leu Asn Ala Thr Ser Ser Ser Glu Gly Ser Thr
1130 1135 1140
Val Asp Val Val Leu Pro Arg Glu Gly Glu Gln Ala Glu Thr Glu
1145 1150 1155
Pro Glu Glu Asp Leu Lys Pro Glu Ala Cys Phe Thr Glu Gly Cys
1160 1165 1170
Ile Lys Lys Phe Pro Phe Cys Gln Val Ser Thr Glu Glu Gly Lys
1175 1180 1185
Gly Lys Ile Trp Trp Asn Leu Arg Lys Thr Cys Tyr Ser Ile Val
1190 1195 1200
Glu His Asn Trp Phe Glu Thr Phe Ile Val Phe Met Ile Leu Leu
1205 1210 1215
Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile Glu Gln Arg
1220 1225 1230
Lys Thr Ile Lys Thr Met Leu Glu Tyr Ala Asp Lys Val Phe Thr
1235 1240 1245
Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Val Ala Tyr Gly
1250 1255 1260
Phe Gln Thr Tyr Phe Thr Asn Ala Trp Cys Trp Leu Asp Phe Leu
1265 1270 1275
Ile Val Asp Val Ser Leu Val Ser Leu Val Ala Asn Ala Leu Gly
1280 1285 1290
Tyr Ser Glu Leu Gly Ala Ile Lys Ser Leu Arg Thr Leu Arg Ala
1295 1300 1305
Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly Met Arg Val
1310 1315 1320
Val Val Asn Ala Leu Val Gly Ala Ile Pro Ser Ile Met Asn Val
1325 1330 1335
Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile Met Gly
1340 1345 1350
Val Asn Leu Phe Ala Gly Lys Phe Tyr His Cys Val Asn Met Thr
1355 1360 1365
Thr Gly Asn Met Phe Asp Ile Ser Asp Val Asn Asn Leu Ser Asp
1370 1375 1380
Cys Gln Ala Leu Gly Lys Gln Ala Arg Trp Lys Asn Val Lys Val
1385 1390 1395
Asn Phe Asp Asn Val Gly Ala Gly Tyr Leu Ala Leu Leu Gln Val
1400 1405 1410
Ala Thr Phe Lys Gly Trp Met Asp Ile Met Tyr Ala Ala Val Asp
1415 1420 1425
Ser Arg Asp Val Lys Leu Gln Pro Val Tyr Glu Glu Asn Leu Tyr
1430 1435 1440
Met Tyr Leu Tyr Phe Val Ile Phe Ile Ile Phe Gly Ser Phe Phe
1445 1450 1455
Thr Leu Asn Leu Phe Ile Gly Val Ile Ile Asp Asn Phe Asn Gln
1460 1465 1470
Gln Lys Lys Lys Phe Gly Gly Gln Asp Ile Phe Met Thr Glu Glu
1475 1480 1485
Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys Leu Gly Ser Lys Lys
1490 1495 1500
Pro Gln Lys Pro Ile Pro Arg Pro Ala Asn Lys Phe Gln Gly Met
1505 1510 1515
Val Phe Asp Phe Val Thr Arg Gln Val Phe Asp Ile Ser Ile Met
1520 1525 1530
Ile Leu Ile Cys Leu Asn Met Val Thr Met Met Val Glu Thr Asp
1535 1540 1545
Asp Gln Gly Lys Tyr Met Thr Leu Val Leu Ser Arg Ile Asn Leu
1550 1555 1560
Val Phe Ile Val Leu Phe Thr Gly Glu Phe Val Leu Lys Leu Val
1565 1570 1575
Ser Leu Arg His Tyr Tyr Phe Thr Ile Gly Trp Asn Ile Phe Asp
1580 1585 1590
Phe Val Val Val Ile Leu Ser Ile Val Gly Met Phe Leu Ala Glu
1595 1600 1605
Met Ile Glu Lys Tyr Phe Val Ser Pro Thr Leu Phe Arg Val Ile
1610 1615 1620
Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg Leu Ile Lys Gly Ala
1625 1630 1635
Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu Met Met Ser Leu Pro
1640 1645 1650
Ala Leu Phe Asn Ile Gly Leu Leu Leu Phe Leu Val Met Phe Ile
1655 1660 1665
Tyr Ala Ile Phe Gly Met Ser Asn Phe Ala Tyr Val Lys Lys Glu
1670 1675 1680
Ala Gly Ile Asp Asp Met Phe Asn Phe Glu Thr Phe Gly Asn Ser
1685 1690 1695
Met Ile Cys Leu Phe Gln Ile Thr Thr Ser Ala Gly Trp Asp Gly
1700 1705 1710
Leu Leu Ala Pro Ile Leu Asn Ser Ala Pro Pro Asp Cys Asp Pro
1715 1720 1725
Asp Thr Ile His Pro Gly Ser Ser Val Lys Gly Asp Cys Gly Asn
1730 1735 1740
Pro Ser Val Gly Ile Phe Phe Phe Val Ser Tyr Ile Ile Ile Ser
1745 1750 1755
Phe Leu Val Val Val Asn Met Tyr Ile Ala Val Ile Leu Glu Asn
1760 1765 1770
Phe Ser Val Ala Thr Glu Glu Ser Ala Glu Pro Leu Ser Glu Asp
1775 1780 1785
Asp Phe Glu Met Phe Tyr Glu Val Trp Glu Lys Phe Asp Pro Asp
1790 1795 1800
Ala Thr Gln Phe Ile Glu Phe Ser Lys Leu Ser Asp Phe Ala Ala
1805 1810 1815
Ala Leu Asp Pro Pro Leu Leu Ile Ala Lys Pro Asn Lys Val Gln
1820 1825 1830
Leu Ile Ala Met Asp Leu Pro Met Val Ser Gly Asp Arg Ile His
1835 1840 1845
Cys Leu Asp Ile Leu Phe Ala Phe Thr Lys Arg Val Leu Gly Glu
1850 1855 1860
Ser Gly Glu Met Asp Ala Leu Arg Ile Gln Met Glu Asp Arg Phe
1865 1870 1875
Met Ala Ser Asn Pro Ser Lys Val Ser Tyr Glu Pro Ile Thr Thr
1880 1885 1890
Thr Leu Lys Arg Lys Gln Glu Glu Val Ser Ala Ala Ile Ile Gln
1895 1900 1905
Arg Asn Phe Arg Cys Tyr Leu Leu Lys Gln Arg Leu Lys Asn Ile
1910 1915 1920
Ser Ser Asn Tyr Asn Lys Glu Ala Ile Lys Gly Arg Ile Asp Leu
1925 1930 1935
Pro Ile Lys Gln Asp Met Ile Ile Asp Lys Leu Asn Gly Asn Ser
1940 1945 1950
Thr Pro Glu Lys Thr Asp Gly Ser Ser Ser Thr Thr Ser Pro Pro
1955 1960 1965
Ser Tyr Asp Ser Val Thr Lys Pro Asp Lys Glu Lys Phe Glu Lys
1970 1975 1980
Asp Lys Pro Glu Lys Glu Ser Lys Gly Lys Glu Val Arg Glu Asn
1985 1990 1995
Gln Lys
2000
<210> 24
<211> 1836
<212> PRT
<213> 智人
<400> 24
Met Ala Arg Pro Ser Leu Cys Thr Leu Val Pro Leu Gly Pro Glu Cys
1 5 10 15
Leu Arg Pro Phe Thr Arg Glu Ser Leu Ala Ala Ile Glu Gln Arg Ala
20 25 30
Val Glu Glu Glu Ala Arg Leu Gln Arg Asn Lys Gln Met Glu Ile Glu
35 40 45
Glu Pro Glu Arg Lys Pro Arg Ser Asp Leu Glu Ala Gly Lys Asn Leu
50 55 60
Pro Met Ile Tyr Gly Asp Pro Pro Pro Glu Val Ile Gly Ile Pro Leu
65 70 75 80
Glu Asp Leu Asp Pro Tyr Tyr Ser Asn Lys Lys Thr Phe Ile Val Leu
85 90 95
Asn Lys Gly Lys Ala Ile Phe Arg Phe Ser Ala Thr Pro Ala Leu Tyr
100 105 110
Leu Leu Ser Pro Phe Ser Val Val Arg Arg Gly Ala Ile Lys Val Leu
115 120 125
Ile His Ala Leu Phe Ser Met Phe Ile Met Ile Thr Ile Leu Thr Asn
130 135 140
Cys Val Phe Met Thr Met Ser Asp Pro Pro Pro Trp Ser Lys Asn Val
145 150 155 160
Glu Tyr Thr Phe Thr Gly Ile Tyr Thr Phe Glu Ser Leu Ile Lys Ile
165 170 175
Leu Ala Arg Gly Phe Cys Val Asp Asp Phe Thr Phe Leu Arg Asp Pro
180 185 190
Trp Asn Trp Leu Asp Phe Ser Val Ile Met Met Ala Tyr Leu Thr Glu
195 200 205
Phe Val Asp Leu Gly Asn Ile Ser Ala Leu Arg Thr Phe Arg Val Leu
210 215 220
Arg Ala Leu Lys Thr Ile Thr Val Ile Pro Gly Leu Lys Thr Ile Val
225 230 235 240
Gly Ala Leu Ile Gln Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu
245 250 255
Thr Val Phe Cys Leu Ser Val Phe Ala Leu Val Gly Leu Gln Leu Phe
260 265 270
Met Gly Asn Leu Arg Gln Lys Cys Val Arg Trp Pro Pro Pro Phe Asn
275 280 285
Asp Thr Asn Thr Thr Trp Tyr Ser Asn Asp Thr Trp Tyr Gly Asn Asp
290 295 300
Thr Trp Tyr Gly Asn Glu Met Trp Tyr Gly Asn Asp Ser Trp Tyr Ala
305 310 315 320
Asn Asp Thr Trp Asn Ser His Ala Ser Trp Ala Thr Asn Asp Thr Phe
325 330 335
Asp Trp Asp Ala Tyr Ile Ser Asp Glu Gly Asn Phe Tyr Phe Leu Glu
340 345 350
Gly Ser Asn Asp Ala Leu Leu Cys Gly Asn Ser Ser Asp Ala Gly His
355 360 365
Cys Pro Glu Gly Tyr Glu Cys Ile Lys Thr Gly Arg Asn Pro Asn Tyr
370 375 380
Gly Tyr Thr Ser Tyr Asp Thr Phe Ser Trp Ala Phe Leu Ala Leu Phe
385 390 395 400
Arg Leu Met Thr Gln Asp Tyr Trp Glu Asn Leu Phe Gln Leu Thr Leu
405 410 415
Arg Ala Ala Gly Lys Thr Tyr Met Ile Phe Phe Val Val Ile Ile Phe
420 425 430
Leu Gly Ser Phe Tyr Leu Ile Asn Leu Ile Leu Ala Val Val Ala Met
435 440 445
Ala Tyr Ala Glu Gln Asn Glu Ala Thr Leu Ala Glu Asp Lys Glu Lys
450 455 460
Glu Glu Glu Phe Gln Gln Met Leu Glu Lys Phe Lys Lys His Gln Glu
465 470 475 480
Glu Leu Glu Lys Ala Lys Ala Ala Gln Ala Leu Glu Gly Gly Glu Ala
485 490 495
Asp Gly Asp Pro Ala His Gly Lys Asp Cys Asn Gly Ser Leu Asp Thr
500 505 510
Ser Gln Gly Glu Lys Gly Ala Pro Arg Gln Ser Ser Ser Gly Asp Ser
515 520 525
Gly Ile Ser Asp Ala Met Glu Glu Leu Glu Glu Ala His Gln Lys Cys
530 535 540
Pro Pro Trp Trp Tyr Lys Cys Ala His Lys Val Leu Ile Trp Asn Cys
545 550 555 560
Cys Ala Pro Trp Leu Lys Phe Lys Asn Ile Ile His Leu Ile Val Met
565 570 575
Asp Pro Phe Val Asp Leu Gly Ile Thr Ile Cys Ile Val Leu Asn Thr
580 585 590
Leu Phe Met Ala Met Glu His Tyr Pro Met Thr Glu His Phe Asp Asn
595 600 605
Val Leu Thr Val Gly Asn Leu Val Phe Thr Gly Ile Phe Thr Ala Glu
610 615 620
Met Val Leu Lys Leu Ile Ala Met Asp Pro Tyr Glu Tyr Phe Gln Gln
625 630 635 640
Gly Trp Asn Ile Phe Asp Ser Ile Ile Val Thr Leu Ser Leu Val Glu
645 650 655
Leu Gly Leu Ala Asn Val Gln Gly Leu Ser Val Leu Arg Ser Phe Arg
660 665 670
Leu Leu Arg Val Phe Lys Leu Ala Lys Ser Trp Pro Thr Leu Asn Met
675 680 685
Leu Ile Lys Ile Ile Gly Asn Ser Val Gly Ala Leu Gly Asn Leu Thr
690 695 700
Leu Val Leu Ala Ile Ile Val Phe Ile Phe Ala Val Val Gly Met Gln
705 710 715 720
Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val Cys Lys Ile Ala Leu Asp
725 730 735
Cys Asn Leu Pro Arg Trp His Met His Asp Phe Phe His Ser Phe Leu
740 745 750
Ile Val Phe Arg Ile Leu Cys Gly Glu Trp Ile Glu Thr Met Trp Asp
755 760 765
Cys Met Glu Val Ala Gly Gln Ala Met Cys Leu Thr Val Phe Leu Met
770 775 780
Val Met Val Ile Gly Asn Leu Val Val Leu Asn Leu Phe Leu Ala Leu
785 790 795 800
Leu Leu Ser Ser Phe Ser Ala Asp Ser Leu Ala Ala Ser Asp Glu Asp
805 810 815
Gly Glu Met Asn Asn Leu Gln Ile Ala Ile Gly Arg Ile Lys Leu Gly
820 825 830
Ile Gly Phe Ala Lys Ala Phe Leu Leu Gly Leu Leu His Gly Lys Ile
835 840 845
Leu Ser Pro Lys Asp Ile Met Leu Ser Leu Gly Glu Ala Asp Gly Ala
850 855 860
Gly Glu Ala Gly Glu Ala Gly Glu Thr Ala Pro Glu Asp Glu Lys Lys
865 870 875 880
Glu Pro Pro Glu Glu Asp Leu Lys Lys Asp Asn His Ile Leu Asn His
885 890 895
Met Gly Leu Ala Asp Gly Pro Pro Ser Ser Leu Glu Leu Asp His Leu
900 905 910
Asn Phe Ile Asn Asn Pro Tyr Leu Thr Ile Gln Val Pro Ile Ala Ser
915 920 925
Glu Glu Ser Asp Leu Glu Met Pro Thr Glu Glu Glu Thr Asp Thr Phe
930 935 940
Ser Glu Pro Glu Asp Ser Lys Lys Pro Pro Gln Pro Leu Tyr Asp Gly
945 950 955 960
Asn Ser Ser Val Cys Ser Thr Ala Asp Tyr Lys Pro Pro Glu Glu Asp
965 970 975
Pro Glu Glu Gln Ala Glu Glu Asn Pro Glu Gly Glu Gln Pro Glu Glu
980 985 990
Cys Phe Thr Glu Ala Cys Val Gln Arg Trp Pro Cys Leu Tyr Val Asp
995 1000 1005
Ile Ser Gln Gly Arg Gly Lys Lys Trp Trp Thr Leu Arg Arg Ala
1010 1015 1020
Cys Phe Lys Ile Val Glu His Asn Trp Phe Glu Thr Phe Ile Val
1025 1030 1035
Phe Met Ile Leu Leu Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile
1040 1045 1050
Tyr Ile Glu Gln Arg Arg Val Ile Arg Thr Ile Leu Glu Tyr Ala
1055 1060 1065
Asp Lys Val Phe Thr Tyr Ile Phe Ile Met Glu Met Leu Leu Lys
1070 1075 1080
Trp Val Ala Tyr Gly Phe Lys Val Tyr Phe Thr Asn Ala Trp Cys
1085 1090 1095
Trp Leu Asp Phe Leu Ile Val Asp Val Ser Ile Ile Ser Leu Val
1100 1105 1110
Ala Asn Trp Leu Gly Tyr Ser Glu Leu Gly Pro Ile Lys Ser Leu
1115 1120 1125
Arg Thr Leu Arg Ala Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe
1130 1135 1140
Glu Gly Met Arg Val Val Val Asn Ala Leu Leu Gly Ala Ile Pro
1145 1150 1155
Ser Ile Met Asn Val Leu Leu Val Cys Leu Ile Phe Trp Leu Ile
1160 1165 1170
Phe Ser Ile Met Gly Val Asn Leu Phe Ala Gly Lys Phe Tyr Tyr
1175 1180 1185
Cys Ile Asn Thr Thr Thr Ser Glu Arg Phe Asp Ile Ser Glu Val
1190 1195 1200
Asn Asn Lys Ser Glu Cys Glu Ser Leu Met His Thr Gly Gln Val
1205 1210 1215
Arg Trp Leu Asn Val Lys Val Asn Tyr Asp Asn Val Gly Leu Gly
1220 1225 1230
Tyr Leu Ser Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp
1235 1240 1245
Ile Met Tyr Ala Ala Val Asp Ser Arg Glu Lys Glu Glu Gln Pro
1250 1255 1260
Gln Tyr Glu Val Asn Leu Tyr Met Tyr Leu Tyr Phe Val Ile Phe
1265 1270 1275
Ile Ile Phe Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val
1280 1285 1290
Ile Ile Asp Asn Phe Asn Gln Gln Lys Lys Lys Leu Gly Gly Lys
1295 1300 1305
Asp Ile Phe Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met
1310 1315 1320
Lys Lys Leu Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro
1325 1330 1335
Gln Asn Lys Ile Gln Gly Met Val Tyr Asp Leu Val Thr Lys Gln
1340 1345 1350
Ala Phe Asp Ile Thr Ile Met Ile Leu Ile Cys Leu Asn Met Val
1355 1360 1365
Thr Met Met Val Glu Thr Asp Asn Gln Ser Gln Leu Lys Val Asp
1370 1375 1380
Ile Leu Tyr Asn Ile Asn Met Ile Phe Ile Ile Ile Phe Thr Gly
1385 1390 1395
Glu Cys Val Leu Lys Met Leu Ala Leu Arg Gln Tyr Tyr Phe Thr
1400 1405 1410
Val Gly Trp Asn Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile
1415 1420 1425
Val Gly Leu Ala Leu Ser Asp Leu Ile Gln Lys Tyr Phe Val Ser
1430 1435 1440
Pro Thr Leu Phe Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Val
1445 1450 1455
Leu Arg Leu Ile Arg Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe
1460 1465 1470
Ala Leu Met Met Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu
1475 1480 1485
Leu Phe Leu Val Met Phe Ile Tyr Ser Ile Phe Gly Met Ser Asn
1490 1495 1500
Phe Ala Tyr Val Lys Lys Glu Ser Gly Ile Asp Asp Met Phe Asn
1505 1510 1515
Phe Glu Thr Phe Gly Asn Ser Ile Ile Cys Leu Phe Glu Ile Thr
1520 1525 1530
Thr Ser Ala Gly Trp Asp Gly Leu Leu Asn Pro Ile Leu Asn Ser
1535 1540 1545
Gly Pro Pro Asp Cys Asp Pro Asn Leu Glu Asn Pro Gly Thr Ser
1550 1555 1560
Val Lys Gly Asp Cys Gly Asn Pro Ser Ile Gly Ile Cys Phe Phe
1565 1570 1575
Cys Ser Tyr Ile Ile Ile Ser Phe Leu Ile Val Val Asn Met Tyr
1580 1585 1590
Ile Ala Ile Ile Leu Glu Asn Phe Asn Val Ala Thr Glu Glu Ser
1595 1600 1605
Ser Glu Pro Leu Gly Glu Asp Asp Phe Glu Met Phe Tyr Glu Thr
1610 1615 1620
Trp Glu Lys Phe Asp Pro Asp Ala Thr Gln Phe Ile Ala Tyr Ser
1625 1630 1635
Arg Leu Ser Asp Phe Val Asp Thr Leu Gln Glu Pro Leu Arg Ile
1640 1645 1650
Ala Lys Pro Asn Lys Ile Lys Leu Ile Thr Leu Asp Leu Pro Met
1655 1660 1665
Val Pro Gly Asp Lys Ile His Cys Leu Asp Ile Leu Phe Ala Leu
1670 1675 1680
Thr Lys Glu Val Leu Gly Asp Ser Gly Glu Met Asp Ala Leu Lys
1685 1690 1695
Gln Thr Met Glu Glu Lys Phe Met Ala Ala Asn Pro Ser Lys Val
1700 1705 1710
Ser Tyr Glu Pro Ile Thr Thr Thr Leu Lys Arg Lys His Glu Glu
1715 1720 1725
Val Cys Ala Ile Lys Ile Gln Arg Ala Tyr Arg Arg His Leu Leu
1730 1735 1740
Gln Arg Ser Met Lys Gln Ala Ser Tyr Met Tyr Arg His Ser His
1745 1750 1755
Asp Gly Ser Gly Asp Asp Ala Pro Glu Lys Glu Gly Leu Leu Ala
1760 1765 1770
Asn Thr Met Ser Lys Met Tyr Gly His Glu Asn Gly Asn Ser Ser
1775 1780 1785
Ser Pro Ser Pro Glu Glu Lys Gly Glu Ala Gly Asp Ala Gly Pro
1790 1795 1800
Thr Met Gly Leu Met Pro Ile Ser Pro Ser Asp Thr Ala Trp Pro
1805 1810 1815
Pro Ala Pro Pro Pro Gly Gln Thr Val Arg Pro Gly Val Lys Glu
1820 1825 1830
Ser Leu Val
1835
<210> 25
<211> 2016
<212> PRT
<213> 智人
<400> 25
Met Ala Asn Phe Leu Leu Pro Arg Gly Thr Ser Ser Phe Arg Arg Phe
1 5 10 15
Thr Arg Glu Ser Leu Ala Ala Ile Glu Lys Arg Met Ala Glu Lys Gln
20 25 30
Ala Arg Gly Ser Thr Thr Leu Gln Glu Ser Arg Glu Gly Leu Pro Glu
35 40 45
Glu Glu Ala Pro Arg Pro Gln Leu Asp Leu Gln Ala Ser Lys Lys Leu
50 55 60
Pro Asp Leu Tyr Gly Asn Pro Pro Gln Glu Leu Ile Gly Glu Pro Leu
65 70 75 80
Glu Asp Leu Asp Pro Phe Tyr Ser Thr Gln Lys Thr Phe Ile Val Leu
85 90 95
Asn Lys Gly Lys Thr Ile Phe Arg Phe Ser Ala Thr Asn Ala Leu Tyr
100 105 110
Val Leu Ser Pro Phe His Pro Ile Arg Arg Ala Ala Val Lys Ile Leu
115 120 125
Val His Ser Leu Phe Asn Met Leu Ile Met Cys Thr Ile Leu Thr Asn
130 135 140
Cys Val Phe Met Ala Gln His Asp Pro Pro Pro Trp Thr Lys Tyr Val
145 150 155 160
Glu Tyr Thr Phe Thr Ala Ile Tyr Thr Phe Glu Ser Leu Val Lys Ile
165 170 175
Leu Ala Arg Gly Phe Cys Leu His Ala Phe Thr Phe Leu Arg Asp Pro
180 185 190
Trp Asn Trp Leu Asp Phe Ser Val Ile Ile Met Ala Tyr Thr Thr Glu
195 200 205
Phe Val Asp Leu Gly Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu
210 215 220
Arg Ala Leu Lys Thr Ile Ser Val Ile Ser Gly Leu Lys Thr Ile Val
225 230 235 240
Gly Ala Leu Ile Gln Ser Val Lys Lys Leu Ala Asp Val Met Val Leu
245 250 255
Thr Val Phe Cys Leu Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe
260 265 270
Met Gly Asn Leu Arg His Lys Cys Val Arg Asn Phe Thr Ala Leu Asn
275 280 285
Gly Thr Asn Gly Ser Val Glu Ala Asp Gly Leu Val Trp Glu Ser Leu
290 295 300
Asp Leu Tyr Leu Ser Asp Pro Glu Asn Tyr Leu Leu Lys Asn Gly Thr
305 310 315 320
Ser Asp Val Leu Leu Cys Gly Asn Ser Ser Asp Ala Gly Thr Cys Pro
325 330 335
Glu Gly Tyr Arg Cys Leu Lys Ala Gly Glu Asn Pro Asp His Gly Tyr
340 345 350
Thr Ser Phe Asp Ser Phe Ala Trp Ala Phe Leu Ala Leu Phe Arg Leu
355 360 365
Met Thr Gln Asp Cys Trp Glu Arg Leu Tyr Gln Gln Thr Leu Arg Ser
370 375 380
Ala Gly Lys Ile Tyr Met Ile Phe Phe Met Leu Val Ile Phe Leu Gly
385 390 395 400
Ser Phe Tyr Leu Val Asn Leu Ile Leu Ala Val Val Ala Met Ala Tyr
405 410 415
Glu Glu Gln Asn Gln Ala Thr Ile Ala Glu Thr Glu Glu Lys Glu Lys
420 425 430
Arg Phe Gln Glu Ala Met Glu Met Leu Lys Lys Glu His Glu Ala Leu
435 440 445
Thr Ile Arg Gly Val Asp Thr Val Ser Arg Ser Ser Leu Glu Met Ser
450 455 460
Pro Leu Ala Pro Val Asn Ser His Glu Arg Arg Ser Lys Arg Arg Lys
465 470 475 480
Arg Met Ser Ser Gly Thr Glu Glu Cys Gly Glu Asp Arg Leu Pro Lys
485 490 495
Ser Asp Ser Glu Asp Gly Pro Arg Ala Met Asn His Leu Ser Leu Thr
500 505 510
Arg Gly Leu Ser Arg Thr Ser Met Lys Pro Arg Ser Ser Arg Gly Ser
515 520 525
Ile Phe Thr Phe Arg Arg Arg Asp Leu Gly Ser Glu Ala Asp Phe Ala
530 535 540
Asp Asp Glu Asn Ser Thr Ala Gly Glu Ser Glu Ser His His Thr Ser
545 550 555 560
Leu Leu Val Pro Trp Pro Leu Arg Arg Thr Ser Ala Gln Gly Gln Pro
565 570 575
Ser Pro Gly Thr Ser Ala Pro Gly His Ala Leu His Gly Lys Lys Asn
580 585 590
Ser Thr Val Asp Cys Asn Gly Val Val Ser Leu Leu Gly Ala Gly Asp
595 600 605
Pro Glu Ala Thr Ser Pro Gly Ser His Leu Leu Arg Pro Val Met Leu
610 615 620
Glu His Pro Pro Asp Thr Thr Thr Pro Ser Glu Glu Pro Gly Gly Pro
625 630 635 640
Gln Met Leu Thr Ser Gln Ala Pro Cys Val Asp Gly Phe Glu Glu Pro
645 650 655
Gly Ala Arg Gln Arg Ala Leu Ser Ala Val Ser Val Leu Thr Ser Ala
660 665 670
Leu Glu Glu Leu Glu Glu Ser Arg His Lys Cys Pro Pro Cys Trp Asn
675 680 685
Arg Leu Ala Gln Arg Tyr Leu Ile Trp Glu Cys Cys Pro Leu Trp Met
690 695 700
Ser Ile Lys Gln Gly Val Lys Leu Val Val Met Asp Pro Phe Thr Asp
705 710 715 720
Leu Thr Ile Thr Met Cys Ile Val Leu Asn Thr Leu Phe Met Ala Leu
725 730 735
Glu His Tyr Asn Met Thr Ser Glu Phe Glu Glu Met Leu Gln Val Gly
740 745 750
Asn Leu Val Phe Thr Gly Ile Phe Thr Ala Glu Met Thr Phe Lys Ile
755 760 765
Ile Ala Leu Asp Pro Tyr Tyr Tyr Phe Gln Gln Gly Trp Asn Ile Phe
770 775 780
Asp Ser Ile Ile Val Ile Leu Ser Leu Met Glu Leu Gly Leu Ser Arg
785 790 795 800
Met Ser Asn Leu Ser Val Leu Arg Ser Phe Arg Leu Leu Arg Val Phe
805 810 815
Lys Leu Ala Lys Ser Trp Pro Thr Leu Asn Thr Leu Ile Lys Ile Ile
820 825 830
Gly Asn Ser Val Gly Ala Leu Gly Asn Leu Thr Leu Val Leu Ala Ile
835 840 845
Ile Val Phe Ile Phe Ala Val Val Gly Met Gln Leu Phe Gly Lys Asn
850 855 860
Tyr Ser Glu Leu Arg Asp Ser Asp Ser Gly Leu Leu Pro Arg Trp His
865 870 875 880
Met Met Asp Phe Phe His Ala Phe Leu Ile Ile Phe Arg Ile Leu Cys
885 890 895
Gly Glu Trp Ile Glu Thr Met Trp Asp Cys Met Glu Val Ser Gly Gln
900 905 910
Ser Leu Cys Leu Leu Val Phe Leu Leu Val Met Val Ile Gly Asn Leu
915 920 925
Val Val Leu Asn Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ala
930 935 940
Asp Asn Leu Thr Ala Pro Asp Glu Asp Arg Glu Met Asn Asn Leu Gln
945 950 955 960
Leu Ala Leu Ala Arg Ile Gln Arg Gly Leu Arg Phe Val Lys Arg Thr
965 970 975
Thr Trp Asp Phe Cys Cys Gly Leu Leu Arg Gln Arg Pro Gln Lys Pro
980 985 990
Ala Ala Leu Ala Ala Gln Gly Gln Leu Pro Ser Cys Ile Ala Thr Pro
995 1000 1005
Tyr Ser Pro Pro Pro Pro Glu Thr Glu Lys Val Pro Pro Thr Arg
1010 1015 1020
Lys Glu Thr Arg Phe Glu Glu Gly Glu Gln Pro Gly Gln Gly Thr
1025 1030 1035
Pro Gly Asp Pro Glu Pro Val Cys Val Pro Ile Ala Val Ala Glu
1040 1045 1050
Ser Asp Thr Asp Asp Gln Glu Glu Asp Glu Glu Asn Ser Leu Gly
1055 1060 1065
Thr Glu Glu Glu Ser Ser Lys Gln Gln Glu Ser Gln Pro Val Ser
1070 1075 1080
Gly Gly Pro Glu Ala Pro Pro Asp Ser Arg Thr Trp Ser Gln Val
1085 1090 1095
Ser Ala Thr Ala Ser Ser Glu Ala Glu Ala Ser Ala Ser Gln Ala
1100 1105 1110
Asp Trp Arg Gln Gln Trp Lys Ala Glu Pro Gln Ala Pro Gly Cys
1115 1120 1125
Gly Glu Thr Pro Glu Asp Ser Cys Ser Glu Gly Ser Thr Ala Asp
1130 1135 1140
Met Thr Asn Thr Ala Glu Leu Leu Glu Gln Ile Pro Asp Leu Gly
1145 1150 1155
Gln Asp Val Lys Asp Pro Glu Asp Cys Phe Thr Glu Gly Cys Val
1160 1165 1170
Arg Arg Cys Pro Cys Cys Ala Val Asp Thr Thr Gln Ala Pro Gly
1175 1180 1185
Lys Val Trp Trp Arg Leu Arg Lys Thr Cys Tyr His Ile Val Glu
1190 1195 1200
His Ser Trp Phe Glu Thr Phe Ile Ile Phe Met Ile Leu Leu Ser
1205 1210 1215
Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Leu Glu Glu Arg Lys
1220 1225 1230
Thr Ile Lys Val Leu Leu Glu Tyr Ala Asp Lys Met Phe Thr Tyr
1235 1240 1245
Val Phe Val Leu Glu Met Leu Leu Lys Trp Val Ala Tyr Gly Phe
1250 1255 1260
Lys Lys Tyr Phe Thr Asn Ala Trp Cys Trp Leu Asp Phe Leu Ile
1265 1270 1275
Val Asp Val Ser Leu Val Ser Leu Val Ala Asn Thr Leu Gly Phe
1280 1285 1290
Ala Glu Met Gly Pro Ile Lys Ser Leu Arg Thr Leu Arg Ala Leu
1295 1300 1305
Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly Met Arg Val Val
1310 1315 1320
Val Asn Ala Leu Val Gly Ala Ile Pro Ser Ile Met Asn Val Leu
1325 1330 1335
Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile Met Gly Val
1340 1345 1350
Asn Leu Phe Ala Gly Lys Phe Gly Arg Cys Ile Asn Gln Thr Glu
1355 1360 1365
Gly Asp Leu Pro Leu Asn Tyr Thr Ile Val Asn Asn Lys Ser Gln
1370 1375 1380
Cys Glu Ser Leu Asn Leu Thr Gly Glu Leu Tyr Trp Thr Lys Val
1385 1390 1395
Lys Val Asn Phe Asp Asn Val Gly Ala Gly Tyr Leu Ala Leu Leu
1400 1405 1410
Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile Met Tyr Ala Ala
1415 1420 1425
Val Asp Ser Arg Gly Tyr Glu Glu Gln Pro Gln Trp Glu Tyr Asn
1430 1435 1440
Leu Tyr Met Tyr Ile Tyr Phe Val Ile Phe Ile Ile Phe Gly Ser
1445 1450 1455
Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile Ile Asp Asn Phe
1460 1465 1470
Asn Gln Gln Lys Lys Lys Leu Gly Gly Gln Asp Ile Phe Met Thr
1475 1480 1485
Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys Leu Gly Ser
1490 1495 1500
Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Leu Asn Lys Tyr Gln
1505 1510 1515
Gly Phe Ile Phe Asp Ile Val Thr Lys Gln Ala Phe Asp Val Thr
1520 1525 1530
Ile Met Phe Leu Ile Cys Leu Asn Met Val Thr Met Met Val Glu
1535 1540 1545
Thr Asp Asp Gln Ser Pro Glu Lys Ile Asn Ile Leu Ala Lys Ile
1550 1555 1560
Asn Leu Leu Phe Val Ala Ile Phe Thr Gly Glu Cys Ile Val Lys
1565 1570 1575
Leu Ala Ala Leu Arg His Tyr Tyr Phe Thr Asn Ser Trp Asn Ile
1580 1585 1590
Phe Asp Phe Val Val Val Ile Leu Ser Ile Val Gly Thr Val Leu
1595 1600 1605
Ser Asp Ile Ile Gln Lys Tyr Phe Phe Ser Pro Thr Leu Phe Arg
1610 1615 1620
Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg Leu Ile Arg
1625 1630 1635
Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu Met Met Ser
1640 1645 1650
Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu Phe Leu Val Met
1655 1660 1665
Phe Ile Tyr Ser Ile Phe Gly Met Ala Asn Phe Ala Tyr Val Lys
1670 1675 1680
Trp Glu Ala Gly Ile Asp Asp Met Phe Asn Phe Gln Thr Phe Ala
1685 1690 1695
Asn Ser Met Leu Cys Leu Phe Gln Ile Thr Thr Ser Ala Gly Trp
1700 1705 1710
Asp Gly Leu Leu Ser Pro Ile Leu Asn Thr Gly Pro Pro Tyr Cys
1715 1720 1725
Asp Pro Thr Leu Pro Asn Ser Asn Gly Ser Arg Gly Asp Cys Gly
1730 1735 1740
Ser Pro Ala Val Gly Ile Leu Phe Phe Thr Thr Tyr Ile Ile Ile
1745 1750 1755
Ser Phe Leu Ile Val Val Asn Met Tyr Ile Ala Ile Ile Leu Glu
1760 1765 1770
Asn Phe Ser Val Ala Thr Glu Glu Ser Thr Glu Pro Leu Ser Glu
1775 1780 1785
Asp Asp Phe Asp Met Phe Tyr Glu Ile Trp Glu Lys Phe Asp Pro
1790 1795 1800
Glu Ala Thr Gln Phe Ile Glu Tyr Ser Val Leu Ser Asp Phe Ala
1805 1810 1815
Asp Ala Leu Ser Glu Pro Leu Arg Ile Ala Lys Pro Asn Gln Ile
1820 1825 1830
Ser Leu Ile Asn Met Asp Leu Pro Met Val Ser Gly Asp Arg Ile
1835 1840 1845
His Cys Met Asp Ile Leu Phe Ala Phe Thr Lys Arg Val Leu Gly
1850 1855 1860
Glu Ser Gly Glu Met Asp Ala Leu Lys Ile Gln Met Glu Glu Lys
1865 1870 1875
Phe Met Ala Ala Asn Pro Ser Lys Ile Ser Tyr Glu Pro Ile Thr
1880 1885 1890
Thr Thr Leu Arg Arg Lys His Glu Glu Val Ser Ala Met Val Ile
1895 1900 1905
Gln Arg Ala Phe Arg Arg His Leu Leu Gln Arg Ser Leu Lys His
1910 1915 1920
Ala Ser Phe Leu Phe Arg Gln Gln Ala Gly Ser Gly Leu Ser Glu
1925 1930 1935
Glu Asp Ala Pro Glu Arg Glu Gly Leu Ile Ala Tyr Val Met Ser
1940 1945 1950
Glu Asn Phe Ser Arg Pro Leu Gly Pro Pro Ser Ser Ser Ser Ile
1955 1960 1965
Ser Ser Thr Ser Phe Pro Pro Ser Tyr Asp Ser Val Thr Arg Ala
1970 1975 1980
Thr Ser Asp Asn Leu Gln Val Arg Gly Ser Asp Tyr Ser His Ser
1985 1990 1995
Glu Asp Leu Ala Asp Phe Pro Pro Ser Pro Asp Arg Asp Arg Glu
2000 2005 2010
Ser Ile Val
2015
<210> 26
<211> 1980
<212> PRT
<213> 智人
<400> 26
Met Ala Ala Arg Leu Leu Ala Pro Pro Gly Pro Asp Ser Phe Lys Pro
1 5 10 15
Phe Thr Pro Glu Ser Leu Ala Asn Ile Glu Arg Arg Ile Ala Glu Ser
20 25 30
Lys Leu Lys Lys Pro Pro Lys Ala Asp Gly Ser His Arg Glu Asp Asp
35 40 45
Glu Asp Ser Lys Pro Lys Pro Asn Ser Asp Leu Glu Ala Gly Lys Ser
50 55 60
Leu Pro Phe Ile Tyr Gly Asp Ile Pro Gln Gly Leu Val Ala Val Pro
65 70 75 80
Leu Glu Asp Phe Asp Pro Tyr Tyr Leu Thr Gln Lys Thr Phe Val Val
85 90 95
Leu Asn Arg Gly Lys Thr Leu Phe Arg Phe Ser Ala Thr Pro Ala Leu
100 105 110
Tyr Ile Leu Ser Pro Phe Asn Leu Ile Arg Arg Ile Ala Ile Lys Ile
115 120 125
Leu Ile His Ser Val Phe Ser Met Ile Ile Met Cys Thr Ile Leu Thr
130 135 140
Asn Cys Val Phe Met Thr Phe Ser Asn Pro Pro Asp Trp Ser Lys Asn
145 150 155 160
Val Glu Tyr Thr Phe Thr Gly Ile Tyr Thr Phe Glu Ser Leu Val Lys
165 170 175
Ile Ile Ala Arg Gly Phe Cys Ile Asp Gly Phe Thr Phe Leu Arg Asp
180 185 190
Pro Trp Asn Trp Leu Asp Phe Ser Val Ile Met Met Ala Tyr Ile Thr
195 200 205
Glu Phe Val Asn Leu Gly Asn Val Ser Ala Leu Arg Thr Phe Arg Val
210 215 220
Leu Arg Ala Leu Lys Thr Ile Ser Val Ile Pro Gly Leu Lys Thr Ile
225 230 235 240
Val Gly Ala Leu Ile Gln Ser Val Lys Lys Leu Ser Asp Val Met Ile
245 250 255
Leu Thr Val Phe Cys Leu Ser Val Phe Ala Leu Ile Gly Leu Gln Leu
260 265 270
Phe Met Gly Asn Leu Arg Asn Lys Cys Val Val Trp Pro Ile Asn Phe
275 280 285
Asn Glu Ser Tyr Leu Glu Asn Gly Thr Lys Gly Phe Asp Trp Glu Glu
290 295 300
Tyr Ile Asn Asn Lys Thr Asn Phe Tyr Thr Val Pro Gly Met Leu Glu
305 310 315 320
Pro Leu Leu Cys Gly Asn Ser Ser Asp Ala Gly Gln Cys Pro Glu Gly
325 330 335
Tyr Gln Cys Met Lys Ala Gly Arg Asn Pro Asn Tyr Gly Tyr Thr Ser
340 345 350
Phe Asp Thr Phe Ser Trp Ala Phe Leu Ala Leu Phe Arg Leu Met Thr
355 360 365
Gln Asp Tyr Trp Glu Asn Leu Tyr Gln Leu Thr Leu Arg Ala Ala Gly
370 375 380
Lys Thr Tyr Met Ile Phe Phe Val Leu Val Ile Phe Val Gly Ser Phe
385 390 395 400
Tyr Leu Val Asn Leu Ile Leu Ala Val Val Ala Met Ala Tyr Glu Glu
405 410 415
Gln Asn Gln Ala Thr Leu Glu Glu Ala Glu Gln Lys Glu Ala Glu Phe
420 425 430
Lys Ala Met Leu Glu Gln Leu Lys Lys Gln Gln Glu Glu Ala Gln Ala
435 440 445
Ala Ala Met Ala Thr Ser Ala Gly Thr Val Ser Glu Asp Ala Ile Glu
450 455 460
Glu Glu Gly Glu Glu Gly Gly Gly Ser Pro Arg Ser Ser Ser Glu Ile
465 470 475 480
Ser Lys Leu Ser Ser Lys Ser Ala Lys Glu Arg Arg Asn Arg Arg Lys
485 490 495
Lys Arg Lys Gln Lys Glu Leu Ser Glu Gly Glu Glu Lys Gly Asp Pro
500 505 510
Glu Lys Val Phe Lys Ser Glu Ser Glu Asp Gly Met Arg Arg Lys Ala
515 520 525
Phe Arg Leu Pro Asp Asn Arg Ile Gly Arg Lys Phe Ser Ile Met Asn
530 535 540
Gln Ser Leu Leu Ser Ile Pro Gly Ser Pro Phe Leu Ser Arg His Asn
545 550 555 560
Ser Lys Ser Ser Ile Phe Ser Phe Arg Gly Pro Gly Arg Phe Arg Asp
565 570 575
Pro Gly Ser Glu Asn Glu Phe Ala Asp Asp Glu His Ser Thr Val Glu
580 585 590
Glu Ser Glu Gly Arg Arg Asp Ser Leu Phe Ile Pro Ile Arg Ala Arg
595 600 605
Glu Arg Arg Ser Ser Tyr Ser Gly Tyr Ser Gly Tyr Ser Gln Gly Ser
610 615 620
Arg Ser Ser Arg Ile Phe Pro Ser Leu Arg Arg Ser Val Lys Arg Asn
625 630 635 640
Ser Thr Val Asp Cys Asn Gly Val Val Ser Leu Ile Gly Gly Pro Gly
645 650 655
Ser His Ile Gly Gly Arg Leu Leu Pro Glu Ala Thr Thr Glu Val Glu
660 665 670
Ile Lys Lys Lys Gly Pro Gly Ser Leu Leu Val Ser Met Asp Gln Leu
675 680 685
Ala Ser Tyr Gly Arg Lys Asp Arg Ile Asn Ser Ile Met Ser Val Val
690 695 700
Thr Asn Thr Leu Val Glu Glu Leu Glu Glu Ser Gln Arg Lys Cys Pro
705 710 715 720
Pro Cys Trp Tyr Lys Phe Ala Asn Thr Phe Leu Ile Trp Glu Cys His
725 730 735
Pro Tyr Trp Ile Lys Leu Lys Glu Ile Val Asn Leu Ile Val Met Asp
740 745 750
Pro Phe Val Asp Leu Ala Ile Thr Ile Cys Ile Val Leu Asn Thr Leu
755 760 765
Phe Met Ala Met Glu His His Pro Met Thr Pro Gln Phe Glu His Val
770 775 780
Leu Ala Val Gly Asn Leu Val Phe Thr Gly Ile Phe Thr Ala Glu Met
785 790 795 800
Phe Leu Lys Leu Ile Ala Met Asp Pro Tyr Tyr Tyr Phe Gln Glu Gly
805 810 815
Trp Asn Ile Phe Asp Gly Phe Ile Val Ser Leu Ser Leu Met Glu Leu
820 825 830
Ser Leu Ala Asp Val Glu Gly Leu Ser Val Leu Arg Ser Phe Arg Leu
835 840 845
Leu Arg Val Phe Lys Leu Ala Lys Ser Trp Pro Thr Leu Asn Met Leu
850 855 860
Ile Lys Ile Ile Gly Asn Ser Val Gly Ala Leu Gly Asn Leu Thr Leu
865 870 875 880
Val Leu Ala Ile Ile Val Phe Ile Phe Ala Val Val Gly Met Gln Leu
885 890 895
Phe Gly Lys Ser Tyr Lys Glu Cys Val Cys Lys Ile Asn Gln Asp Cys
900 905 910
Glu Leu Pro Arg Trp His Met His Asp Phe Phe His Ser Phe Leu Ile
915 920 925
Val Phe Arg Val Leu Cys Gly Glu Trp Ile Glu Thr Met Trp Asp Cys
930 935 940
Met Glu Val Ala Gly Gln Ala Met Cys Leu Ile Val Phe Met Met Val
945 950 955 960
Met Val Ile Gly Asn Leu Val Val Leu Asn Leu Phe Leu Ala Leu Leu
965 970 975
Leu Ser Ser Phe Ser Ala Asp Asn Leu Ala Ala Thr Asp Asp Asp Gly
980 985 990
Glu Met Asn Asn Leu Gln Ile Ser Val Ile Arg Ile Lys Lys Gly Val
995 1000 1005
Ala Trp Thr Lys Leu Lys Val His Ala Phe Met Gln Ala His Phe
1010 1015 1020
Lys Gln Arg Glu Ala Asp Glu Val Lys Pro Leu Asp Glu Leu Tyr
1025 1030 1035
Glu Lys Lys Ala Asn Cys Ile Ala Asn His Thr Gly Ala Asp Ile
1040 1045 1050
His Arg Asn Gly Asp Phe Gln Lys Asn Gly Asn Gly Thr Thr Ser
1055 1060 1065
Gly Ile Gly Ser Ser Val Glu Lys Tyr Ile Ile Asp Glu Asp His
1070 1075 1080
Met Ser Phe Ile Asn Asn Pro Asn Leu Thr Val Arg Val Pro Ile
1085 1090 1095
Ala Val Gly Glu Ser Asp Phe Glu Asn Leu Asn Thr Glu Asp Val
1100 1105 1110
Ser Ser Glu Ser Asp Pro Glu Gly Ser Lys Asp Lys Leu Asp Asp
1115 1120 1125
Thr Ser Ser Ser Glu Gly Ser Thr Ile Asp Ile Lys Pro Glu Val
1130 1135 1140
Glu Glu Val Pro Val Glu Gln Pro Glu Glu Tyr Leu Asp Pro Asp
1145 1150 1155
Ala Cys Phe Thr Glu Gly Cys Val Gln Arg Phe Lys Cys Cys Gln
1160 1165 1170
Val Asn Ile Glu Glu Gly Leu Gly Lys Ser Trp Trp Ile Leu Arg
1175 1180 1185
Lys Thr Cys Phe Leu Ile Val Glu His Asn Trp Phe Glu Thr Phe
1190 1195 1200
Ile Ile Phe Met Ile Leu Leu Ser Ser Gly Ala Leu Ala Phe Glu
1205 1210 1215
Asp Ile Tyr Ile Glu Gln Arg Lys Thr Ile Arg Thr Ile Leu Glu
1220 1225 1230
Tyr Ala Asp Lys Val Phe Thr Tyr Ile Phe Ile Leu Glu Met Leu
1235 1240 1245
Leu Lys Trp Thr Ala Tyr Gly Phe Val Lys Phe Phe Thr Asn Ala
1250 1255 1260
Trp Cys Trp Leu Asp Phe Leu Ile Val Ala Val Ser Leu Val Ser
1265 1270 1275
Leu Ile Ala Asn Ala Leu Gly Tyr Ser Glu Leu Gly Ala Ile Lys
1280 1285 1290
Ser Leu Arg Thr Leu Arg Ala Leu Arg Pro Leu Arg Ala Leu Ser
1295 1300 1305
Arg Phe Glu Gly Met Arg Val Val Val Asn Ala Leu Val Gly Ala
1310 1315 1320
Ile Pro Ser Ile Met Asn Val Leu Leu Val Cys Leu Ile Phe Trp
1325 1330 1335
Leu Ile Phe Ser Ile Met Gly Val Asn Leu Phe Ala Gly Lys Tyr
1340 1345 1350
His Tyr Cys Phe Asn Glu Thr Ser Glu Ile Arg Phe Glu Ile Glu
1355 1360 1365
Asp Val Asn Asn Lys Thr Glu Cys Glu Lys Leu Met Glu Gly Asn
1370 1375 1380
Asn Thr Glu Ile Arg Trp Lys Asn Val Lys Ile Asn Phe Asp Asn
1385 1390 1395
Val Gly Ala Gly Tyr Leu Ala Leu Leu Gln Val Ala Thr Phe Lys
1400 1405 1410
Gly Trp Met Asp Ile Met Tyr Ala Ala Val Asp Ser Arg Lys Pro
1415 1420 1425
Asp Glu Gln Pro Lys Tyr Glu Asp Asn Ile Tyr Met Tyr Ile Tyr
1430 1435 1440
Phe Val Ile Phe Ile Ile Phe Gly Ser Phe Phe Thr Leu Asn Leu
1445 1450 1455
Phe Ile Gly Val Ile Ile Asp Asn Phe Asn Gln Gln Lys Lys Lys
1460 1465 1470
Phe Gly Gly Gln Asp Ile Phe Met Thr Glu Glu Gln Lys Lys Tyr
1475 1480 1485
Tyr Asn Ala Met Lys Lys Leu Gly Ser Lys Lys Pro Gln Lys Pro
1490 1495 1500
Ile Pro Arg Pro Leu Asn Lys Ile Gln Gly Ile Val Phe Asp Phe
1505 1510 1515
Val Thr Gln Gln Ala Phe Asp Ile Val Ile Met Met Leu Ile Cys
1520 1525 1530
Leu Asn Met Val Thr Met Met Val Glu Thr Asp Thr Gln Ser Lys
1535 1540 1545
Gln Met Glu Asn Ile Leu Tyr Trp Ile Asn Leu Val Phe Val Ile
1550 1555 1560
Phe Phe Thr Cys Glu Cys Val Leu Lys Met Phe Ala Leu Arg His
1565 1570 1575
Tyr Tyr Phe Thr Ile Gly Trp Asn Ile Phe Asp Phe Val Val Val
1580 1585 1590
Ile Leu Ser Ile Val Gly Met Phe Leu Ala Asp Ile Ile Glu Lys
1595 1600 1605
Tyr Phe Val Ser Pro Thr Leu Phe Arg Val Ile Arg Leu Ala Arg
1610 1615 1620
Ile Gly Arg Ile Leu Arg Leu Ile Lys Gly Ala Lys Gly Ile Arg
1625 1630 1635
Thr Leu Leu Phe Ala Leu Met Met Ser Leu Pro Ala Leu Phe Asn
1640 1645 1650
Ile Gly Leu Leu Leu Phe Leu Val Met Phe Ile Phe Ser Ile Phe
1655 1660 1665
Gly Met Ser Asn Phe Ala Tyr Val Lys His Glu Ala Gly Ile Asp
1670 1675 1680
Asp Met Phe Asn Phe Glu Thr Phe Gly Asn Ser Met Ile Cys Leu
1685 1690 1695
Phe Gln Ile Thr Thr Ser Ala Gly Trp Asp Gly Leu Leu Leu Pro
1700 1705 1710
Ile Leu Asn Arg Pro Pro Asp Cys Ser Leu Asp Lys Glu His Pro
1715 1720 1725
Gly Ser Gly Phe Lys Gly Asp Cys Gly Asn Pro Ser Val Gly Ile
1730 1735 1740
Phe Phe Phe Val Ser Tyr Ile Ile Ile Ser Phe Leu Ile Val Val
1745 1750 1755
Asn Met Tyr Ile Ala Ile Ile Leu Glu Asn Phe Ser Val Ala Thr
1760 1765 1770
Glu Glu Ser Ala Asp Pro Leu Ser Glu Asp Asp Phe Glu Thr Phe
1775 1780 1785
Tyr Glu Ile Trp Glu Lys Phe Asp Pro Asp Ala Thr Gln Phe Ile
1790 1795 1800
Glu Tyr Cys Lys Leu Ala Asp Phe Ala Asp Ala Leu Glu His Pro
1805 1810 1815
Leu Arg Val Pro Lys Pro Asn Thr Ile Glu Leu Ile Ala Met Asp
1820 1825 1830
Leu Pro Met Val Ser Gly Asp Arg Ile His Cys Leu Asp Ile Leu
1835 1840 1845
Phe Ala Phe Thr Lys Arg Val Leu Gly Asp Ser Gly Glu Leu Asp
1850 1855 1860
Ile Leu Arg Gln Gln Met Glu Glu Arg Phe Val Ala Ser Asn Pro
1865 1870 1875
Ser Lys Val Ser Tyr Glu Pro Ile Thr Thr Thr Leu Arg Arg Lys
1880 1885 1890
Gln Glu Glu Val Ser Ala Val Val Leu Gln Arg Ala Tyr Arg Gly
1895 1900 1905
His Leu Ala Arg Arg Gly Phe Ile Cys Lys Lys Thr Thr Ser Asn
1910 1915 1920
Lys Leu Glu Asn Gly Gly Thr His Arg Glu Lys Lys Glu Ser Thr
1925 1930 1935
Pro Ser Thr Ala Ser Leu Pro Ser Tyr Asp Ser Val Thr Lys Pro
1940 1945 1950
Glu Lys Glu Lys Gln Gln Arg Ala Glu Glu Gly Arg Arg Glu Arg
1955 1960 1965
Ala Lys Arg Gln Lys Glu Val Arg Glu Ser Lys Cys
1970 1975 1980
<210> 27
<211> 1988
<212> PRT
<213> 智人
<400> 27
Met Ala Met Leu Pro Pro Pro Gly Pro Gln Ser Phe Val His Phe Thr
1 5 10 15
Lys Gln Ser Leu Ala Leu Ile Glu Gln Arg Ile Ala Glu Arg Lys Ser
20 25 30
Lys Glu Pro Lys Glu Glu Lys Lys Asp Asp Asp Glu Glu Ala Pro Lys
35 40 45
Pro Ser Ser Asp Leu Glu Ala Gly Lys Gln Leu Pro Phe Ile Tyr Gly
50 55 60
Asp Ile Pro Pro Gly Met Val Ser Glu Pro Leu Glu Asp Leu Asp Pro
65 70 75 80
Tyr Tyr Ala Asp Lys Lys Thr Phe Ile Val Leu Asn Lys Gly Lys Thr
85 90 95
Ile Phe Arg Phe Asn Ala Thr Pro Ala Leu Tyr Met Leu Ser Pro Phe
100 105 110
Ser Pro Leu Arg Arg Ile Ser Ile Lys Ile Leu Val His Ser Leu Phe
115 120 125
Ser Met Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Ile Phe Met Thr
130 135 140
Met Asn Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr Thr Phe Thr
145 150 155 160
Gly Ile Tyr Thr Phe Glu Ser Leu Val Lys Ile Leu Ala Arg Gly Phe
165 170 175
Cys Val Gly Glu Phe Thr Phe Leu Arg Asp Pro Trp Asn Trp Leu Asp
180 185 190
Phe Val Val Ile Val Phe Ala Tyr Leu Thr Glu Phe Val Asn Leu Gly
195 200 205
Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala Leu Lys Thr
210 215 220
Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala Leu Ile Gln
225 230 235 240
Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val Phe Cys Leu
245 250 255
Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly Asn Leu Lys
260 265 270
His Lys Cys Phe Arg Asn Ser Leu Glu Asn Asn Glu Thr Leu Glu Ser
275 280 285
Ile Met Asn Thr Leu Glu Ser Glu Glu Asp Phe Arg Lys Tyr Phe Tyr
290 295 300
Tyr Leu Glu Gly Ser Lys Asp Ala Leu Leu Cys Gly Phe Ser Thr Asp
305 310 315 320
Ser Gly Gln Cys Pro Glu Gly Tyr Thr Cys Val Lys Ile Gly Arg Asn
325 330 335
Pro Asp Tyr Gly Tyr Thr Ser Phe Asp Thr Phe Ser Trp Ala Phe Leu
340 345 350
Ala Leu Phe Arg Leu Met Thr Gln Asp Tyr Trp Glu Asn Leu Tyr Gln
355 360 365
Gln Thr Leu Arg Ala Ala Gly Lys Thr Tyr Met Ile Phe Phe Val Val
370 375 380
Val Ile Phe Leu Gly Ser Phe Tyr Leu Ile Asn Leu Ile Leu Ala Val
385 390 395 400
Val Ala Met Ala Tyr Glu Glu Gln Asn Gln Ala Asn Ile Glu Glu Ala
405 410 415
Lys Gln Lys Glu Leu Glu Phe Gln Gln Met Leu Asp Arg Leu Lys Lys
420 425 430
Glu Gln Glu Glu Ala Glu Ala Ile Ala Ala Ala Ala Ala Glu Tyr Thr
435 440 445
Ser Ile Arg Arg Ser Arg Ile Met Gly Leu Ser Glu Ser Ser Ser Glu
450 455 460
Thr Ser Lys Leu Ser Ser Lys Ser Ala Lys Glu Arg Arg Asn Arg Arg
465 470 475 480
Lys Lys Lys Asn Gln Lys Lys Leu Ser Ser Gly Glu Glu Lys Gly Asp
485 490 495
Ala Glu Lys Leu Ser Lys Ser Glu Ser Glu Asp Ser Ile Arg Arg Lys
500 505 510
Ser Phe His Leu Gly Val Glu Gly His Arg Arg Ala His Glu Lys Arg
515 520 525
Leu Ser Thr Pro Asn Gln Ser Pro Leu Ser Ile Arg Gly Ser Leu Phe
530 535 540
Ser Ala Arg Arg Ser Ser Arg Thr Ser Leu Phe Ser Phe Lys Gly Arg
545 550 555 560
Gly Arg Asp Ile Gly Ser Glu Thr Glu Phe Ala Asp Asp Glu His Ser
565 570 575
Ile Phe Gly Asp Asn Glu Ser Arg Arg Gly Ser Leu Phe Val Pro His
580 585 590
Arg Pro Gln Glu Arg Arg Ser Ser Asn Ile Ser Gln Ala Ser Arg Ser
595 600 605
Pro Pro Met Leu Pro Val Asn Gly Lys Met His Ser Ala Val Asp Cys
610 615 620
Asn Gly Val Val Ser Leu Val Asp Gly Arg Ser Ala Leu Met Leu Pro
625 630 635 640
Asn Gly Gln Leu Leu Pro Glu Val Ile Ile Asp Lys Ala Thr Ser Asp
645 650 655
Asp Ser Gly Thr Thr Asn Gln Ile His Lys Lys Arg Arg Cys Ser Ser
660 665 670
Tyr Leu Leu Ser Glu Asp Met Leu Asn Asp Pro Asn Leu Arg Gln Arg
675 680 685
Ala Met Ser Arg Ala Ser Ile Leu Thr Asn Thr Val Glu Glu Leu Glu
690 695 700
Glu Ser Arg Gln Lys Cys Pro Pro Trp Trp Tyr Arg Phe Ala His Lys
705 710 715 720
Phe Leu Ile Trp Asn Cys Ser Pro Tyr Trp Ile Lys Phe Lys Lys Cys
725 730 735
Ile Tyr Phe Ile Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile
740 745 750
Cys Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His His Pro Met
755 760 765
Thr Glu Glu Phe Lys Asn Val Leu Ala Ile Gly Asn Leu Val Phe Thr
770 775 780
Gly Ile Phe Ala Ala Glu Met Val Leu Lys Leu Ile Ala Met Asp Pro
785 790 795 800
Tyr Glu Tyr Phe Gln Val Gly Trp Asn Ile Phe Asp Ser Leu Ile Val
805 810 815
Thr Leu Ser Leu Val Glu Leu Phe Leu Ala Asp Val Glu Gly Leu Ser
820 825 830
Val Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser
835 840 845
Trp Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly
850 855 860
Ala Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe
865 870 875 880
Ala Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val
885 890 895
Cys Lys Ile Asn Asp Asp Cys Thr Leu Pro Arg Trp His Met Asn Asp
900 905 910
Phe Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp
915 920 925
Ile Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Ala Met Cys
930 935 940
Leu Ile Val Tyr Met Met Val Met Val Ile Gly Asn Leu Val Val Leu
945 950 955 960
Asn Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu
965 970 975
Thr Ala Ile Glu Glu Asp Pro Asp Ala Asn Asn Leu Gln Ile Ala Val
980 985 990
Thr Arg Ile Lys Lys Gly Ile Asn Tyr Val Lys Gln Thr Leu Arg Glu
995 1000 1005
Phe Ile Leu Lys Ala Phe Ser Lys Lys Pro Lys Ile Ser Arg Glu
1010 1015 1020
Ile Arg Gln Ala Glu Asp Leu Asn Thr Lys Lys Glu Asn Tyr Ile
1025 1030 1035
Ser Asn His Thr Leu Ala Glu Met Ser Lys Gly His Asn Phe Leu
1040 1045 1050
Lys Glu Lys Asp Lys Ile Ser Gly Phe Gly Ser Ser Val Asp Lys
1055 1060 1065
His Leu Met Glu Asp Ser Asp Gly Gln Ser Phe Ile His Asn Pro
1070 1075 1080
Ser Leu Thr Val Thr Val Pro Ile Ala Pro Gly Glu Ser Asp Leu
1085 1090 1095
Glu Asn Met Asn Ala Glu Glu Leu Ser Ser Asp Ser Asp Ser Glu
1100 1105 1110
Tyr Ser Lys Val Arg Leu Asn Arg Ser Ser Ser Ser Glu Cys Ser
1115 1120 1125
Thr Val Asp Asn Pro Leu Pro Gly Glu Gly Glu Glu Ala Glu Ala
1130 1135 1140
Glu Pro Met Asn Ser Asp Glu Pro Glu Ala Cys Phe Thr Asp Gly
1145 1150 1155
Cys Val Trp Arg Phe Ser Cys Cys Gln Val Asn Ile Glu Ser Gly
1160 1165 1170
Lys Gly Lys Ile Trp Trp Asn Ile Arg Lys Thr Cys Tyr Lys Ile
1175 1180 1185
Val Glu His Ser Trp Phe Glu Ser Phe Ile Val Leu Met Ile Leu
1190 1195 1200
Leu Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile Glu Arg
1205 1210 1215
Lys Lys Thr Ile Lys Ile Ile Leu Glu Tyr Ala Asp Lys Ile Phe
1220 1225 1230
Thr Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Ile Ala Tyr
1235 1240 1245
Gly Tyr Lys Thr Tyr Phe Thr Asn Ala Trp Cys Trp Leu Asp Phe
1250 1255 1260
Leu Ile Val Asp Val Ser Leu Val Thr Leu Val Ala Asn Thr Leu
1265 1270 1275
Gly Tyr Ser Asp Leu Gly Pro Ile Lys Ser Leu Arg Thr Leu Arg
1280 1285 1290
Ala Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly Met Arg
1295 1300 1305
Val Val Val Asn Ala Leu Ile Gly Ala Ile Pro Ser Ile Met Asn
1310 1315 1320
Val Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile Met
1325 1330 1335
Gly Val Asn Leu Phe Ala Gly Lys Phe Tyr Glu Cys Ile Asn Thr
1340 1345 1350
Thr Asp Gly Ser Arg Phe Pro Ala Ser Gln Val Pro Asn Arg Ser
1355 1360 1365
Glu Cys Phe Ala Leu Met Asn Val Ser Gln Asn Val Arg Trp Lys
1370 1375 1380
Asn Leu Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr Leu Ser
1385 1390 1395
Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Thr Ile Ile Met Tyr
1400 1405 1410
Ala Ala Val Asp Ser Val Asn Val Asp Lys Gln Pro Lys Tyr Glu
1415 1420 1425
Tyr Ser Leu Tyr Met Tyr Ile Tyr Phe Val Val Phe Ile Ile Phe
1430 1435 1440
Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile Ile Asp
1445 1450 1455
Asn Phe Asn Gln Gln Lys Lys Lys Leu Gly Gly Gln Asp Ile Phe
1460 1465 1470
Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys Leu
1475 1480 1485
Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Gly Asn Lys
1490 1495 1500
Ile Gln Gly Cys Ile Phe Asp Leu Val Thr Asn Gln Ala Phe Asp
1505 1510 1515
Ile Ser Ile Met Val Leu Ile Cys Leu Asn Met Val Thr Met Met
1520 1525 1530
Val Glu Lys Glu Gly Gln Ser Gln His Met Thr Glu Val Leu Tyr
1535 1540 1545
Trp Ile Asn Val Val Phe Ile Ile Leu Phe Thr Gly Glu Cys Val
1550 1555 1560
Leu Lys Leu Ile Ser Leu Arg His Tyr Tyr Phe Thr Val Gly Trp
1565 1570 1575
Asn Ile Phe Asp Phe Val Val Val Ile Ile Ser Ile Val Gly Met
1580 1585 1590
Phe Leu Ala Asp Leu Ile Glu Thr Tyr Phe Val Ser Pro Thr Leu
1595 1600 1605
Phe Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg Leu
1610 1615 1620
Val Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu Met
1625 1630 1635
Met Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu Phe Leu
1640 1645 1650
Val Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe Ala Tyr
1655 1660 1665
Val Lys Lys Glu Asp Gly Ile Asn Asp Met Phe Asn Phe Glu Thr
1670 1675 1680
Phe Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr Ser Ala
1685 1690 1695
Gly Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Lys Pro Pro
1700 1705 1710
Asp Cys Asp Pro Lys Lys Val His Pro Gly Ser Ser Val Glu Gly
1715 1720 1725
Asp Cys Gly Asn Pro Ser Val Gly Ile Phe Tyr Phe Val Ser Tyr
1730 1735 1740
Ile Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile Ala Val
1745 1750 1755
Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Thr Glu Pro
1760 1765 1770
Leu Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp Glu Lys
1775 1780 1785
Phe Asp Pro Asp Ala Thr Gln Phe Ile Glu Phe Ser Lys Leu Ser
1790 1795 1800
Asp Phe Ala Ala Ala Leu Asp Pro Pro Leu Leu Ile Ala Lys Pro
1805 1810 1815
Asn Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val Ser Gly
1820 1825 1830
Asp Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr Lys Arg
1835 1840 1845
Val Leu Gly Glu Ser Gly Glu Met Asp Ser Leu Arg Ser Gln Met
1850 1855 1860
Glu Glu Arg Phe Met Ser Ala Asn Pro Ser Lys Val Ser Tyr Glu
1865 1870 1875
Pro Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Asp Val Ser Ala
1880 1885 1890
Thr Val Ile Gln Arg Ala Tyr Arg Arg Tyr Arg Leu Arg Gln Asn
1895 1900 1905
Val Lys Asn Ile Ser Ser Ile Tyr Ile Lys Asp Gly Asp Arg Asp
1910 1915 1920
Asp Asp Leu Leu Asn Lys Lys Asp Met Ala Phe Asp Asn Val Asn
1925 1930 1935
Glu Asn Ser Ser Pro Glu Lys Thr Asp Ala Thr Ser Ser Thr Thr
1940 1945 1950
Ser Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Asp Lys Glu Lys
1955 1960 1965
Tyr Glu Gln Asp Arg Thr Glu Lys Glu Asp Lys Gly Lys Asp Ser
1970 1975 1980
Lys Glu Ser Lys Lys
1985
<210> 28
<211> 1988
<212> PRT
<213> 智人
<400> 28
Met Ala Met Leu Pro Pro Pro Gly Pro Gln Ser Phe Val His Phe Thr
1 5 10 15
Lys Gln Ser Leu Ala Leu Ile Glu Gln Arg Ile Ala Glu Arg Lys Ser
20 25 30
Lys Glu Pro Lys Glu Glu Lys Lys Asp Asp Asp Glu Glu Ala Pro Lys
35 40 45
Pro Ser Ser Asp Leu Glu Ala Gly Lys Gln Leu Pro Phe Ile Tyr Gly
50 55 60
Asp Ile Pro Pro Gly Met Val Ser Glu Pro Leu Glu Asp Leu Asp Pro
65 70 75 80
Tyr Tyr Ala Asp Lys Lys Thr Phe Ile Val Leu Asn Lys Gly Lys Thr
85 90 95
Ile Phe Arg Phe Asn Ala Thr Pro Ala Leu Tyr Met Leu Ser Pro Phe
100 105 110
Ser Pro Leu Arg Arg Ile Ser Ile Lys Ile Leu Val His Ser Leu Phe
115 120 125
Ser Met Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Ile Phe Met Thr
130 135 140
Met Asn Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr Thr Phe Thr
145 150 155 160
Gly Ile Tyr Thr Phe Glu Ser Leu Val Lys Ile Leu Ala Arg Gly Phe
165 170 175
Cys Val Gly Glu Phe Thr Phe Leu Arg Asp Pro Trp Asn Trp Leu Asp
180 185 190
Phe Val Val Ile Val Phe Ala Tyr Leu Thr Glu Phe Val Asn Leu Gly
195 200 205
Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala Leu Lys Thr
210 215 220
Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala Leu Ile Gln
225 230 235 240
Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val Phe Cys Leu
245 250 255
Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly Asn Leu Lys
260 265 270
His Lys Cys Phe Arg Asn Ser Leu Glu Asn Asn Glu Thr Leu Glu Ser
275 280 285
Ile Met Asn Thr Leu Glu Ser Glu Glu Asp Phe Arg Lys Tyr Phe Tyr
290 295 300
Tyr Leu Glu Gly Ser Lys Asp Ala Leu Leu Cys Gly Phe Ser Thr Asp
305 310 315 320
Ser Gly Gln Cys Pro Glu Gly Tyr Thr Cys Val Lys Ile Gly Arg Asn
325 330 335
Pro Asp Tyr Gly Tyr Thr Ser Phe Asp Thr Phe Ser Trp Ala Phe Leu
340 345 350
Ala Leu Phe Arg Leu Met Thr Gln Asp Tyr Trp Glu Asn Leu Tyr Gln
355 360 365
Gln Thr Leu Arg Ala Ala Gly Lys Thr Tyr Met Ile Phe Phe Val Val
370 375 380
Val Ile Phe Leu Gly Ser Phe Tyr Leu Ile Asn Leu Ile Leu Ala Val
385 390 395 400
Val Ala Met Ala Tyr Glu Glu Gln Asn Gln Ala Asn Ile Glu Glu Ala
405 410 415
Lys Gln Lys Glu Leu Glu Phe Gln Gln Met Leu Asp Arg Leu Lys Lys
420 425 430
Glu Gln Glu Glu Ala Glu Ala Ile Ala Ala Ala Ala Ala Glu Tyr Thr
435 440 445
Ser Ile Arg Arg Ser Arg Ile Met Gly Leu Ser Glu Ser Ser Ser Glu
450 455 460
Thr Ser Lys Leu Ser Ser Lys Ser Ala Lys Glu Arg Arg Asn Arg Arg
465 470 475 480
Lys Lys Lys Asn Gln Lys Lys Leu Ser Ser Gly Glu Glu Lys Gly Asp
485 490 495
Ala Glu Lys Leu Ser Lys Ser Glu Ser Glu Asp Ser Ile Arg Arg Lys
500 505 510
Ser Phe His Leu Gly Val Glu Gly His Arg Arg Ala His Glu Lys Arg
515 520 525
Leu Ser Thr Pro Asn Gln Ser Pro Leu Ser Ile Arg Gly Ser Leu Phe
530 535 540
Ser Ala Arg Arg Ser Ser Arg Thr Ser Leu Phe Ser Phe Lys Gly Arg
545 550 555 560
Gly Arg Asp Ile Gly Ser Glu Thr Glu Phe Ala Asp Asp Glu His Ser
565 570 575
Ile Phe Gly Asp Asn Glu Ser Arg Arg Gly Ser Leu Phe Val Pro His
580 585 590
Arg Pro Gln Glu Arg Arg Ser Ser Asn Ile Ser Gln Ala Ser Arg Ser
595 600 605
Pro Pro Met Leu Pro Val Asn Gly Lys Met His Ser Ala Val Asp Cys
610 615 620
Asn Gly Val Val Ser Leu Val Asp Gly Arg Ser Ala Leu Met Leu Pro
625 630 635 640
Asn Gly Gln Leu Leu Pro Glu Val Ile Ile Asp Lys Ala Thr Ser Asp
645 650 655
Asp Ser Gly Thr Thr Asn Gln Ile His Lys Lys Arg Arg Cys Ser Ser
660 665 670
Tyr Leu Leu Ser Glu Asp Met Leu Asn Asp Pro Asn Leu Arg Gln Arg
675 680 685
Ala Met Ser Arg Ala Ser Ile Leu Thr Asn Thr Val Glu Glu Leu Glu
690 695 700
Glu Ser Arg Gln Lys Cys Pro Pro Trp Trp Tyr Arg Phe Ala His Lys
705 710 715 720
Phe Leu Ile Trp Asn Cys Ser Pro Tyr Trp Ile Lys Phe Lys Lys Cys
725 730 735
Ile Tyr Phe Ile Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile
740 745 750
Cys Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His His Pro Met
755 760 765
Thr Glu Glu Phe Lys Asn Val Leu Ala Ile Gly Asn Leu Val Phe Thr
770 775 780
Gly Ile Phe Ala Ala Glu Met Val Leu Lys Leu Ile Ala Met Asp Pro
785 790 795 800
Tyr Glu Tyr Phe Gln Val Gly Trp Asn Ile Phe Asp Ser Leu Ile Val
805 810 815
Thr Leu Ser Leu Val Glu Leu Phe Leu Ala Asp Val Glu Gly Leu Ser
820 825 830
Val Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser
835 840 845
Trp Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly
850 855 860
Ala Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe
865 870 875 880
Ala Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val
885 890 895
Cys Lys Ile Asn Asp Asp Cys Thr Leu Pro Arg Trp His Met Asn Asp
900 905 910
Phe Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp
915 920 925
Ile Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Ala Met Cys
930 935 940
Leu Ile Val Tyr Met Met Val Met Val Ile Gly Asn Leu Val Val Leu
945 950 955 960
Asn Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu
965 970 975
Thr Ala Ile Glu Glu Asp Pro Asp Ala Asn Asn Leu Gln Ile Ala Val
980 985 990
Thr Arg Ile Lys Lys Gly Ile Asn Tyr Val Lys Gln Thr Leu Arg Glu
995 1000 1005
Phe Ile Leu Lys Ala Phe Ser Lys Lys Pro Lys Ile Ser Arg Glu
1010 1015 1020
Ile Arg Gln Ala Glu Asp Leu Asn Thr Lys Lys Glu Asn Tyr Ile
1025 1030 1035
Ser Asn His Thr Leu Ala Glu Met Ser Lys Gly His Asn Phe Leu
1040 1045 1050
Lys Glu Lys Asp Lys Ile Ser Gly Phe Gly Ser Ser Val Asp Lys
1055 1060 1065
His Leu Met Glu Asp Ser Asp Gly Gln Ser Phe Ile His Asn Pro
1070 1075 1080
Ser Leu Thr Val Thr Val Pro Ile Ala Pro Gly Glu Ser Asp Leu
1085 1090 1095
Glu Asn Met Asn Ala Glu Glu Leu Ser Ser Asp Ser Asp Ser Glu
1100 1105 1110
Tyr Ser Lys Val Arg Leu Asn Arg Ser Ser Ser Ser Glu Cys Ser
1115 1120 1125
Thr Val Asp Asn Pro Leu Pro Gly Glu Gly Glu Glu Ala Glu Ala
1130 1135 1140
Glu Pro Met Asn Ser Asp Glu Pro Glu Ala Cys Phe Thr Asp Gly
1145 1150 1155
Cys Val Trp Arg Phe Ser Cys Cys Gln Val Asn Ile Glu Ser Gly
1160 1165 1170
Lys Gly Lys Ile Trp Trp Asn Ile Arg Lys Thr Cys Tyr Lys Ile
1175 1180 1185
Val Glu His Ser Trp Phe Glu Ser Phe Ile Val Leu Met Ile Leu
1190 1195 1200
Leu Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile Glu Arg
1205 1210 1215
Lys Lys Thr Ile Lys Ile Ile Leu Glu Tyr Ala Asp Lys Ile Phe
1220 1225 1230
Thr Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Ile Ala Tyr
1235 1240 1245
Gly Tyr Lys Thr Tyr Phe Thr Asn Ala Trp Cys Trp Leu Asp Phe
1250 1255 1260
Leu Ile Val Asp Val Ser Leu Val Thr Leu Val Ala Asn Thr Leu
1265 1270 1275
Gly Tyr Ser Asp Leu Gly Pro Ile Lys Ser Leu Arg Thr Leu Arg
1280 1285 1290
Ala Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly Met Arg
1295 1300 1305
Val Val Val Asn Ala Leu Ile Gly Ala Ile Pro Ser Ile Met Asn
1310 1315 1320
Val Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile Met
1325 1330 1335
Gly Val Asn Leu Phe Ala Gly Lys Phe Tyr Glu Cys Ile Asn Thr
1340 1345 1350
Thr Asp Gly Ser Arg Phe Pro Ala Ser Gln Val Pro Asn Arg Ser
1355 1360 1365
Glu Cys Phe Ala Leu Met Asn Val Ser Gln Asn Val Arg Trp Lys
1370 1375 1380
Asn Leu Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr Leu Ser
1385 1390 1395
Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Thr Ile Ile Met Tyr
1400 1405 1410
Ala Ala Val Asp Ser Val Asn Val Asp Lys Gln Pro Lys Tyr Glu
1415 1420 1425
Tyr Ser Leu Tyr Met Tyr Ile Tyr Phe Val Val Phe Ile Ile Phe
1430 1435 1440
Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile Ile Asp
1445 1450 1455
Asn Phe Asn Gln Gln Lys Lys Lys Leu Gly Gly Gln Asp Ile Phe
1460 1465 1470
Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys Leu
1475 1480 1485
Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Gly Asn Lys
1490 1495 1500
Ile Gln Gly Cys Ile Phe Asp Leu Val Thr Asn Gln Ala Phe Asp
1505 1510 1515
Ile Ser Ile Met Val Leu Ile Cys Leu Asn Met Val Thr Met Met
1520 1525 1530
Val Glu Lys Glu Gly Gln Ser Gln His Met Thr Glu Val Leu Tyr
1535 1540 1545
Trp Ile Asn Val Val Phe Ile Ile Leu Phe Thr Gly Glu Cys Val
1550 1555 1560
Leu Lys Leu Ile Ser Leu Arg His Tyr Tyr Phe Thr Val Gly Trp
1565 1570 1575
Asn Ile Phe Asp Phe Val Val Val Ile Ile Ser Ile Val Gly Met
1580 1585 1590
Phe Leu Ala Asp Leu Ile Glu Thr Tyr Phe Val Ser Pro Thr Leu
1595 1600 1605
Phe Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg Leu
1610 1615 1620
Val Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu Met
1625 1630 1635
Met Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu Phe Leu
1640 1645 1650
Val Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe Ala Tyr
1655 1660 1665
Val Lys Lys Glu Asp Gly Ile Asn Asp Met Phe Asn Phe Glu Thr
1670 1675 1680
Phe Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr Ser Ala
1685 1690 1695
Gly Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Lys Pro Pro
1700 1705 1710
Asp Cys Asp Pro Lys Lys Val His Pro Gly Ser Ser Val Glu Gly
1715 1720 1725
Asp Cys Gly Asn Pro Ser Val Gly Ile Phe Tyr Phe Val Ser Tyr
1730 1735 1740
Ile Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile Ala Val
1745 1750 1755
Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Thr Glu Pro
1760 1765 1770
Leu Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp Glu Lys
1775 1780 1785
Phe Asp Pro Asp Ala Thr Gln Phe Ile Glu Phe Ser Lys Leu Ser
1790 1795 1800
Asp Phe Ala Ala Ala Leu Asp Pro Pro Leu Leu Ile Ala Lys Pro
1805 1810 1815
Asn Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val Ser Gly
1820 1825 1830
Asp Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr Lys Arg
1835 1840 1845
Val Leu Gly Glu Ser Gly Glu Met Asp Ser Leu Arg Ser Gln Met
1850 1855 1860
Glu Glu Arg Phe Met Ser Ala Asn Pro Ser Lys Val Ser Tyr Glu
1865 1870 1875
Pro Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Asp Val Ser Ala
1880 1885 1890
Thr Val Ile Gln Arg Ala Tyr Arg Arg Tyr Arg Leu Arg Gln Asn
1895 1900 1905
Val Lys Asn Ile Ser Ser Ile Tyr Ile Lys Asp Gly Asp Arg Asp
1910 1915 1920
Asp Asp Leu Leu Asn Lys Lys Asp Met Ala Phe Asp Asn Val Asn
1925 1930 1935
Glu Asn Ser Ser Pro Glu Lys Thr Asp Ala Thr Ser Ser Thr Thr
1940 1945 1950
Ser Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Asp Lys Glu Lys
1955 1960 1965
Tyr Glu Gln Asp Arg Thr Glu Lys Glu Asp Lys Gly Lys Asp Ser
1970 1975 1980
Lys Glu Ser Lys Lys
1985
<210> 29
<211> 1791
<212> PRT
<213> 智人
<400> 29
Met Asp Asp Arg Cys Tyr Pro Val Ile Phe Pro Asp Glu Arg Asn Phe
1 5 10 15
Arg Pro Phe Thr Ser Asp Ser Leu Ala Ala Ile Glu Lys Arg Ile Ala
20 25 30
Ile Gln Lys Glu Lys Lys Lys Ser Lys Asp Gln Thr Gly Glu Val Pro
35 40 45
Gln Pro Arg Pro Gln Leu Asp Leu Lys Ala Ser Arg Lys Leu Pro Lys
50 55 60
Leu Tyr Gly Asp Ile Pro Arg Glu Leu Ile Gly Lys Pro Leu Glu Asp
65 70 75 80
Leu Asp Pro Phe Tyr Arg Asn His Lys Thr Phe Met Val Leu Asn Arg
85 90 95
Lys Arg Thr Ile Tyr Arg Phe Ser Ala Lys His Ala Leu Phe Ile Phe
100 105 110
Gly Pro Phe Asn Ser Ile Arg Ser Leu Ala Ile Arg Val Ser Val His
115 120 125
Ser Leu Phe Ser Met Phe Ile Ile Gly Thr Val Ile Ile Asn Cys Val
130 135 140
Phe Met Ala Thr Gly Pro Ala Lys Asn Ser Asn Ser Asn Asn Thr Asp
145 150 155 160
Ile Ala Glu Cys Val Phe Thr Gly Ile Tyr Ile Phe Glu Ala Leu Ile
165 170 175
Lys Ile Leu Ala Arg Gly Phe Ile Leu Asp Glu Phe Ser Phe Leu Arg
180 185 190
Asp Pro Trp Asn Trp Leu Asp Ser Ile Val Ile Gly Ile Ala Ile Val
195 200 205
Ser Tyr Ile Pro Gly Ile Thr Ile Lys Leu Leu Pro Leu Arg Thr Phe
210 215 220
Arg Val Phe Arg Ala Leu Lys Ala Ile Ser Val Val Ser Arg Leu Lys
225 230 235 240
Val Ile Val Gly Ala Leu Leu Arg Ser Val Lys Lys Leu Val Asn Val
245 250 255
Ile Ile Leu Thr Phe Phe Cys Leu Ser Ile Phe Ala Leu Val Gly Gln
260 265 270
Gln Leu Phe Met Gly Ser Leu Asn Leu Lys Cys Ile Ser Arg Asp Cys
275 280 285
Lys Asn Ile Ser Asn Pro Glu Ala Tyr Asp His Cys Phe Glu Lys Lys
290 295 300
Glu Asn Ser Pro Glu Phe Lys Met Cys Gly Ile Trp Met Gly Asn Ser
305 310 315 320
Ala Cys Ser Ile Gln Tyr Glu Cys Lys His Thr Lys Ile Asn Pro Asp
325 330 335
Tyr Asn Tyr Thr Asn Phe Asp Asn Phe Gly Trp Ser Phe Leu Ala Met
340 345 350
Phe Arg Leu Met Thr Gln Asp Ser Trp Glu Lys Leu Tyr Gln Gln Thr
355 360 365
Leu Arg Thr Thr Gly Leu Tyr Ser Val Phe Phe Phe Ile Val Val Ile
370 375 380
Phe Leu Gly Ser Phe Tyr Leu Ile Asn Leu Thr Leu Ala Val Val Thr
385 390 395 400
Met Ala Tyr Glu Glu Gln Asn Lys Asn Val Ala Ala Glu Ile Glu Ala
405 410 415
Lys Glu Lys Met Phe Gln Glu Ala Gln Gln Leu Leu Lys Glu Glu Lys
420 425 430
Glu Ala Leu Val Ala Met Gly Ile Asp Arg Ser Ser Leu Thr Ser Leu
435 440 445
Glu Thr Ser Tyr Phe Thr Pro Lys Lys Arg Lys Leu Phe Gly Asn Lys
450 455 460
Lys Arg Lys Ser Phe Phe Leu Arg Glu Ser Gly Lys Asp Gln Pro Pro
465 470 475 480
Gly Ser Asp Ser Asp Glu Asp Cys Gln Lys Lys Pro Gln Leu Leu Glu
485 490 495
Gln Thr Lys Arg Leu Ser Gln Asn Leu Ser Leu Asp His Phe Asp Glu
500 505 510
His Gly Asp Pro Leu Gln Arg Gln Arg Ala Leu Ser Ala Val Ser Ile
515 520 525
Leu Thr Ile Thr Met Lys Glu Gln Glu Lys Ser Gln Glu Pro Cys Leu
530 535 540
Pro Cys Gly Glu Asn Leu Ala Ser Lys Tyr Leu Val Trp Asn Cys Cys
545 550 555 560
Pro Gln Trp Leu Cys Val Lys Lys Val Leu Arg Thr Val Met Thr Asp
565 570 575
Pro Phe Thr Glu Leu Ala Ile Thr Ile Cys Ile Ile Ile Asn Thr Val
580 585 590
Phe Leu Ala Met Glu His His Lys Met Glu Ala Ser Phe Glu Lys Met
595 600 605
Leu Asn Ile Gly Asn Leu Val Phe Thr Ser Ile Phe Ile Ala Glu Met
610 615 620
Cys Leu Lys Ile Ile Ala Leu Asp Pro Tyr His Tyr Phe Arg Arg Gly
625 630 635 640
Trp Asn Ile Phe Asp Ser Ile Val Ala Leu Leu Ser Phe Ala Asp Val
645 650 655
Met Asn Cys Val Leu Gln Lys Arg Ser Trp Pro Phe Leu Arg Ser Phe
660 665 670
Arg Val Leu Arg Val Phe Lys Leu Ala Lys Ser Trp Pro Thr Leu Asn
675 680 685
Thr Leu Ile Lys Ile Ile Gly Asn Ser Val Gly Ala Leu Gly Ser Leu
690 695 700
Thr Val Val Leu Val Ile Val Ile Phe Ile Phe Ser Val Val Gly Met
705 710 715 720
Gln Leu Phe Gly Arg Ser Phe Asn Ser Gln Lys Ser Pro Lys Leu Cys
725 730 735
Asn Pro Thr Gly Pro Thr Val Ser Cys Leu Arg His Trp His Met Gly
740 745 750
Asp Phe Trp His Ser Phe Leu Val Val Phe Arg Ile Leu Cys Gly Glu
755 760 765
Trp Ile Glu Asn Met Trp Glu Cys Met Gln Glu Ala Asn Ala Ser Ser
770 775 780
Ser Leu Cys Val Ile Val Phe Ile Leu Ile Thr Val Ile Gly Lys Leu
785 790 795 800
Val Val Leu Asn Leu Phe Ile Ala Leu Leu Leu Asn Ser Phe Ser Asn
805 810 815
Glu Glu Arg Asn Gly Asn Leu Glu Gly Glu Ala Arg Lys Thr Lys Val
820 825 830
Gln Leu Ala Leu Asp Arg Phe Arg Arg Ala Phe Cys Phe Val Arg His
835 840 845
Thr Leu Glu His Phe Cys His Lys Trp Cys Arg Lys Gln Asn Leu Pro
850 855 860
Gln Gln Lys Glu Val Ala Gly Gly Cys Ala Ala Gln Ser Lys Asp Ile
865 870 875 880
Ile Pro Leu Val Met Glu Met Lys Arg Gly Ser Glu Thr Gln Glu Glu
885 890 895
Leu Gly Ile Leu Thr Ser Val Pro Lys Thr Leu Gly Val Arg His Asp
900 905 910
Trp Thr Trp Leu Ala Pro Leu Ala Glu Glu Glu Asp Asp Val Glu Phe
915 920 925
Ser Gly Glu Asp Asn Ala Gln Arg Ile Thr Gln Pro Glu Pro Glu Gln
930 935 940
Gln Ala Tyr Glu Leu His Gln Glu Asn Lys Lys Pro Thr Ser Gln Arg
945 950 955 960
Val Gln Ser Val Glu Ile Asp Met Phe Ser Glu Asp Glu Pro His Leu
965 970 975
Thr Ile Gln Asp Pro Arg Lys Lys Ser Asp Val Thr Ser Ile Leu Ser
980 985 990
Glu Cys Ser Thr Ile Asp Leu Gln Asp Gly Phe Gly Trp Leu Pro Glu
995 1000 1005
Met Val Pro Lys Lys Gln Pro Glu Arg Cys Leu Pro Lys Gly Phe
1010 1015 1020
Gly Cys Cys Phe Pro Cys Cys Ser Val Asp Lys Arg Lys Pro Pro
1025 1030 1035
Trp Val Ile Trp Trp Asn Leu Arg Lys Thr Cys Tyr Gln Ile Val
1040 1045 1050
Lys His Ser Trp Phe Glu Ser Phe Ile Ile Phe Val Ile Leu Leu
1055 1060 1065
Ser Ser Gly Ala Leu Ile Phe Glu Asp Val His Leu Glu Asn Gln
1070 1075 1080
Pro Lys Ile Gln Glu Leu Leu Asn Cys Thr Asp Ile Ile Phe Thr
1085 1090 1095
His Ile Phe Ile Leu Glu Met Val Leu Lys Trp Val Ala Phe Gly
1100 1105 1110
Phe Gly Lys Tyr Phe Thr Ser Ala Trp Cys Cys Leu Asp Phe Ile
1115 1120 1125
Ile Val Ile Val Ser Val Thr Thr Leu Ile Asn Leu Met Glu Leu
1130 1135 1140
Lys Ser Phe Arg Thr Leu Arg Ala Leu Arg Pro Leu Arg Ala Leu
1145 1150 1155
Ser Gln Phe Glu Gly Met Lys Val Val Val Asn Ala Leu Ile Gly
1160 1165 1170
Ala Ile Pro Ala Ile Leu Asn Val Leu Leu Val Cys Leu Ile Phe
1175 1180 1185
Trp Leu Val Phe Cys Ile Leu Gly Val Tyr Phe Phe Ser Gly Lys
1190 1195 1200
Phe Gly Lys Cys Ile Asn Gly Thr Asp Ser Val Ile Asn Tyr Thr
1205 1210 1215
Ile Ile Thr Asn Lys Ser Gln Cys Glu Ser Gly Asn Phe Ser Trp
1220 1225 1230
Ile Asn Gln Lys Val Asn Phe Asp Asn Val Gly Asn Ala Tyr Leu
1235 1240 1245
Ala Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile Ile
1250 1255 1260
Tyr Ala Ala Val Asp Ser Thr Glu Lys Glu Gln Gln Pro Glu Phe
1265 1270 1275
Glu Ser Asn Ser Leu Gly Tyr Ile Tyr Phe Val Val Phe Ile Ile
1280 1285 1290
Phe Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile Ile
1295 1300 1305
Asp Asn Phe Asn Gln Gln Gln Lys Lys Leu Gly Gly Gln Asp Ile
1310 1315 1320
Phe Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys
1325 1330 1335
Leu Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Leu Asn
1340 1345 1350
Lys Cys Gln Gly Leu Val Phe Asp Ile Val Thr Ser Gln Ile Phe
1355 1360 1365
Asp Ile Ile Ile Ile Ser Leu Ile Ile Leu Asn Met Ile Ser Met
1370 1375 1380
Met Ala Glu Ser Tyr Asn Gln Pro Lys Ala Met Lys Ser Ile Leu
1385 1390 1395
Asp His Leu Asn Trp Val Phe Val Val Ile Phe Thr Leu Glu Cys
1400 1405 1410
Leu Ile Lys Ile Phe Ala Leu Arg Gln Tyr Tyr Phe Thr Asn Gly
1415 1420 1425
Trp Asn Leu Phe Asp Cys Val Val Val Leu Leu Ser Ile Val Ser
1430 1435 1440
Thr Met Ile Ser Thr Leu Glu Asn Gln Glu His Ile Pro Phe Pro
1445 1450 1455
Pro Thr Leu Phe Arg Ile Val Arg Leu Ala Arg Ile Gly Arg Ile
1460 1465 1470
Leu Arg Leu Val Arg Ala Ala Arg Gly Ile Arg Thr Leu Leu Phe
1475 1480 1485
Ala Leu Met Met Ser Leu Pro Ser Leu Phe Asn Ile Gly Leu Leu
1490 1495 1500
Leu Phe Leu Ile Met Phe Ile Tyr Ala Ile Leu Gly Met Asn Trp
1505 1510 1515
Phe Ser Lys Val Asn Pro Glu Ser Gly Ile Asp Asp Ile Phe Asn
1520 1525 1530
Phe Lys Thr Phe Ala Ser Ser Met Leu Cys Leu Phe Gln Ile Ser
1535 1540 1545
Thr Ser Ala Gly Trp Asp Ser Leu Leu Ser Pro Met Leu Arg Ser
1550 1555 1560
Lys Glu Ser Cys Asn Ser Ser Ser Glu Asn Cys His Leu Pro Gly
1565 1570 1575
Ile Ala Thr Ser Tyr Phe Val Ser Tyr Ile Ile Ile Ser Phe Leu
1580 1585 1590
Ile Val Val Asn Met Tyr Ile Ala Val Ile Leu Glu Asn Phe Asn
1595 1600 1605
Thr Ala Thr Glu Glu Ser Glu Asp Pro Leu Gly Glu Asp Asp Phe
1610 1615 1620
Asp Ile Phe Tyr Glu Val Trp Glu Lys Phe Asp Pro Glu Ala Thr
1625 1630 1635
Gln Phe Ile Lys Tyr Ser Ala Leu Ser Asp Phe Ala Asp Ala Leu
1640 1645 1650
Pro Glu Pro Leu Arg Val Ala Lys Pro Asn Lys Tyr Gln Phe Leu
1655 1660 1665
Val Met Asp Leu Pro Met Val Ser Glu Asp Arg Leu His Cys Met
1670 1675 1680
Asp Ile Leu Phe Ala Phe Thr Ala Arg Val Leu Gly Gly Ser Asp
1685 1690 1695
Gly Leu Asp Ser Met Lys Ala Met Met Glu Glu Lys Phe Met Glu
1700 1705 1710
Ala Asn Pro Leu Lys Lys Leu Tyr Glu Pro Ile Val Thr Thr Thr
1715 1720 1725
Lys Arg Lys Glu Glu Glu Arg Gly Ala Ala Ile Ile Gln Lys Ala
1730 1735 1740
Phe Arg Lys Tyr Met Met Lys Val Thr Lys Gly Asp Gln Gly Asp
1745 1750 1755
Gln Asn Asp Leu Glu Asn Gly Pro His Ser Pro Leu Gln Thr Leu
1760 1765 1770
Cys Asn Gly Asp Leu Ser Ser Phe Gly Val Ala Lys Gly Lys Val
1775 1780 1785
His Cys Asp
1790
<210> 30
<211> 1791
<212> PRT
<213> 黑猩猩
<400> 30
Met Asp Asp Arg Cys Tyr Pro Val Ile Phe Pro Asp Glu Arg Asn Phe
1 5 10 15
Arg Pro Phe Thr Ser Asp Ser Leu Ala Ala Ile Glu Lys Arg Ile Ala
20 25 30
Ile Gln Lys Glu Lys Lys Lys Ser Lys Asp Gln Thr Gly Glu Val Pro
35 40 45
Gln Pro Arg Pro Gln Leu Asp Leu Lys Ala Ser Arg Lys Leu Pro Lys
50 55 60
Leu Tyr Gly Asp Ile Pro Arg Glu Leu Ile Gly Lys Pro Leu Glu Asp
65 70 75 80
Leu Asp Pro Phe Tyr Arg Asn His Lys Thr Phe Met Val Leu Asn Arg
85 90 95
Lys Arg Thr Ile Tyr Arg Phe Ser Ala Lys His Ala Leu Phe Ile Phe
100 105 110
Gly Pro Phe Asn Ser Ile Arg Ser Leu Ala Ile Arg Val Ser Val His
115 120 125
Ser Leu Phe Ser Met Phe Ile Ile Gly Thr Val Ile Ile Asn Cys Val
130 135 140
Phe Met Ala Thr Gly Pro Ala Lys Asn Ser Asn Ser Asn Asn Thr Asp
145 150 155 160
Ile Ala Glu Cys Val Phe Thr Gly Ile Tyr Ile Phe Glu Ala Leu Ile
165 170 175
Lys Ile Leu Ala Arg Gly Phe Ile Leu Asp Glu Phe Ser Phe Leu Arg
180 185 190
Asp Pro Trp Asn Trp Leu Asp Ser Ile Val Ile Gly Ile Ala Ile Val
195 200 205
Ser Tyr Ile Pro Gly Ile Thr Ile Lys Leu Leu Pro Leu Arg Thr Phe
210 215 220
Arg Val Phe Arg Ala Leu Lys Ala Ile Ser Val Val Ser Arg Leu Lys
225 230 235 240
Val Ile Val Gly Ala Leu Leu Arg Ser Val Lys Lys Leu Val Asn Val
245 250 255
Ile Ile Leu Thr Phe Phe Cys Leu Ser Ile Phe Ala Leu Val Gly Gln
260 265 270
Gln Leu Phe Met Gly Ser Leu Asn Leu Lys Cys Ile Ser Arg Asp Cys
275 280 285
Lys Asn Ile Ser Asn Pro Glu Ala Tyr Asp His Cys Phe Glu Lys Lys
290 295 300
Glu Asn Ser Pro Glu Phe Lys Met Cys Gly Ile Trp Met Gly Asn Ser
305 310 315 320
Ala Cys Ser Ile Gln Tyr Glu Cys Lys His Thr Lys Ile Asn Pro Asp
325 330 335
Tyr Asn Tyr Thr Asn Phe Asp Asn Phe Gly Trp Ser Phe Leu Ala Met
340 345 350
Phe Arg Leu Met Thr Gln Asp Ser Trp Glu Lys Leu Tyr Gln Gln Thr
355 360 365
Leu Arg Thr Thr Gly Leu Tyr Ser Val Phe Phe Phe Ile Val Val Ile
370 375 380
Phe Leu Gly Ser Phe Tyr Leu Ile Asn Leu Thr Leu Ala Val Val Thr
385 390 395 400
Met Ala Tyr Glu Glu Gln Asn Lys Asn Val Ala Ala Glu Ile Glu Ala
405 410 415
Lys Glu Lys Met Phe Gln Glu Ala Gln Gln Leu Leu Lys Glu Glu Lys
420 425 430
Glu Ala Leu Val Ala Met Gly Ile Asp Arg Ser Ser Leu Thr Ser Leu
435 440 445
Glu Thr Ser Tyr Phe Thr Pro Lys Lys Arg Lys Leu Phe Gly Asn Lys
450 455 460
Lys Arg Lys Ser Phe Phe Leu Arg Glu Ser Gly Lys Asp Gln Pro Pro
465 470 475 480
Gly Ser Asp Ser Asp Glu Asp Cys Gln Lys Lys Pro Gln Leu Leu Glu
485 490 495
Gln Thr Lys Arg Leu Ser Gln Asn Leu Ser Leu Asp His Phe Asp Glu
500 505 510
His Gly Asp Pro Leu Gln Arg Gln Arg Ala Leu Ser Ala Val Ser Ile
515 520 525
Leu Thr Ile Thr Met Lys Glu Gln Glu Lys Ser Gln Glu Pro Cys Leu
530 535 540
Pro Cys Gly Glu Asn Leu Ala Ser Lys Tyr Leu Val Trp Asn Cys Cys
545 550 555 560
Pro Gln Trp Leu Cys Val Lys Lys Val Leu Arg Thr Val Met Thr Asp
565 570 575
Pro Phe Thr Glu Leu Ala Ile Thr Ile Cys Ile Ile Ile Asn Thr Val
580 585 590
Phe Leu Ala Met Glu His His Lys Met Glu Ala Ser Phe Glu Lys Met
595 600 605
Leu Asn Ile Gly Asn Leu Val Phe Thr Ser Ile Phe Ile Ala Glu Met
610 615 620
Cys Leu Lys Ile Ile Ala Leu Asp Pro Tyr His Tyr Phe Arg Arg Gly
625 630 635 640
Trp Asn Ile Phe Asp Ser Ile Val Ala Leu Leu Ser Phe Ala Asp Val
645 650 655
Met Asn Cys Val Leu Gln Lys Arg Ser Trp Pro Phe Leu Arg Ser Phe
660 665 670
Arg Val Leu Arg Val Phe Lys Leu Ala Lys Ser Trp Pro Thr Leu Asn
675 680 685
Thr Leu Ile Lys Ile Ile Gly Asn Ser Val Gly Ala Leu Gly Ser Leu
690 695 700
Thr Val Val Leu Val Ile Val Ile Phe Ile Phe Ser Val Val Gly Met
705 710 715 720
Gln Leu Phe Gly Arg Ser Phe Asn Ser Gln Lys Ser Pro Lys Leu Cys
725 730 735
Asn Pro Thr Gly Pro Thr Val Ser Cys Leu Arg His Trp His Met Gly
740 745 750
Asp Phe Trp His Ser Phe Leu Val Val Phe Arg Ile Leu Cys Gly Glu
755 760 765
Trp Ile Glu Asn Met Trp Glu Cys Met Gln Glu Ala Asn Ala Ser Ser
770 775 780
Ser Leu Cys Val Ile Val Phe Ile Leu Ile Thr Val Ile Gly Lys Leu
785 790 795 800
Val Val Leu Asn Leu Phe Ile Ala Leu Leu Leu Asn Ser Phe Ser Asn
805 810 815
Glu Glu Arg Asn Gly Asn Leu Glu Gly Glu Ala Arg Lys Thr Lys Val
820 825 830
Gln Leu Ala Leu Asp Arg Phe Arg Arg Ala Phe Cys Phe Val Arg His
835 840 845
Thr Leu Glu His Phe Cys His Lys Trp Cys Arg Lys Gln Asn Leu Pro
850 855 860
Gln Gln Lys Glu Val Ala Gly Gly Cys Ala Ala Gln Ser Lys Asp Ile
865 870 875 880
Ile Pro Leu Val Met Glu Met Lys Arg Gly Ser Glu Thr Gln Glu Glu
885 890 895
Leu Gly Ile Leu Thr Ser Val Pro Lys Thr Leu Gly Val Arg His Asp
900 905 910
Trp Thr Trp Leu Ala Pro Leu Ala Glu Glu Glu Asp Asp Val Glu Phe
915 920 925
Ser Gly Glu Asp Asn Ala Gln Arg Ile Thr Gln Pro Glu Pro Glu Gln
930 935 940
Gln Ala Tyr Glu Leu His Gln Glu Asn Lys Lys Pro Thr Ser Gln Arg
945 950 955 960
Val Gln Ser Val Glu Ile Asp Met Phe Ser Glu Asp Glu Pro His Leu
965 970 975
Thr Ile Gln Asp Pro Arg Lys Lys Ser Asp Val Thr Ser Ile Leu Ser
980 985 990
Glu Cys Ser Thr Ile Asp Leu Gln Asp Gly Phe Gly Trp Leu Pro Glu
995 1000 1005
Met Val Pro Lys Lys Gln Pro Glu Arg Cys Leu Pro Lys Gly Phe
1010 1015 1020
Gly Cys Cys Phe Pro Cys Cys Ser Val Asp Lys Arg Lys Pro Pro
1025 1030 1035
Trp Val Ile Trp Trp Asn Leu Arg Lys Thr Cys Tyr Gln Ile Val
1040 1045 1050
Lys His Ser Trp Phe Glu Ser Phe Ile Ile Phe Val Ile Leu Leu
1055 1060 1065
Ser Ser Gly Ala Leu Ile Phe Glu Asp Val His Leu Glu Asn Gln
1070 1075 1080
Pro Lys Ile Gln Glu Leu Leu Asn Cys Thr Asp Ile Ile Phe Thr
1085 1090 1095
His Ile Phe Ile Leu Glu Met Val Leu Lys Trp Val Ala Phe Gly
1100 1105 1110
Phe Gly Lys Tyr Phe Thr Ser Ala Trp Cys Cys Leu Asp Phe Ile
1115 1120 1125
Ile Val Ile Val Ser Val Thr Thr Leu Ile Asn Leu Met Glu Leu
1130 1135 1140
Lys Ser Phe Arg Thr Leu Arg Ala Leu Arg Pro Leu Arg Ala Leu
1145 1150 1155
Ser Gln Phe Glu Gly Met Lys Val Val Val Asn Ala Leu Ile Gly
1160 1165 1170
Ala Ile Pro Ala Ile Leu Asn Val Leu Leu Val Cys Leu Ile Phe
1175 1180 1185
Trp Leu Val Phe Cys Ile Leu Gly Val Tyr Phe Phe Ser Gly Lys
1190 1195 1200
Phe Gly Lys Cys Ile Asn Gly Thr Asp Ser Val Ile Asn Tyr Thr
1205 1210 1215
Ile Ile Thr Asn Lys Ser Gln Cys Glu Ser Gly Asn Phe Ser Trp
1220 1225 1230
Ile Asn Gln Lys Val Asn Phe Asp Asn Val Gly Asn Ala Tyr Leu
1235 1240 1245
Ala Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile Ile
1250 1255 1260
Tyr Ala Ala Val Asp Ser Thr Glu Lys Glu Gln Gln Pro Glu Phe
1265 1270 1275
Glu Ser Asn Ser Leu Gly Tyr Ile Tyr Phe Val Val Phe Ile Ile
1280 1285 1290
Phe Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile Ile
1295 1300 1305
Asp Asn Phe Asn Gln Gln Gln Lys Lys Leu Gly Gly Gln Asp Ile
1310 1315 1320
Phe Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys
1325 1330 1335
Leu Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Leu Asn
1340 1345 1350
Lys Cys Gln Gly Leu Val Phe Asp Ile Val Thr Ser Gln Ile Phe
1355 1360 1365
Asp Ile Ile Ile Ile Ser Leu Ile Ile Leu Asn Met Ile Ser Met
1370 1375 1380
Met Ala Glu Ser Tyr Asn Gln Pro Lys Ala Met Lys Ser Ile Leu
1385 1390 1395
Asp His Leu Asn Trp Val Phe Val Val Ile Phe Thr Leu Glu Cys
1400 1405 1410
Leu Ile Lys Ile Phe Ala Leu Arg Gln Tyr Tyr Phe Thr Asn Gly
1415 1420 1425
Trp Asn Leu Phe Asp Cys Val Val Val Leu Leu Ser Ile Val Ser
1430 1435 1440
Thr Met Ile Ser Thr Leu Glu Asn Gln Glu His Ile Pro Phe Pro
1445 1450 1455
Pro Thr Leu Phe Arg Ile Val Arg Leu Ala Arg Ile Gly Arg Ile
1460 1465 1470
Leu Arg Leu Val Arg Ala Ala Arg Gly Ile Arg Thr Leu Leu Phe
1475 1480 1485
Ala Leu Met Met Ser Leu Pro Ser Leu Phe Asn Ile Gly Leu Leu
1490 1495 1500
Leu Phe Leu Ile Met Phe Ile Tyr Ala Ile Leu Gly Met Asn Trp
1505 1510 1515
Phe Ser Lys Val Asn Pro Glu Ser Gly Ile Asp Asp Ile Phe Asn
1520 1525 1530
Phe Lys Thr Phe Ala Ser Ser Met Leu Cys Leu Phe Gln Ile Ser
1535 1540 1545
Thr Ser Ala Gly Trp Asp Ser Leu Leu Ser Pro Met Leu Arg Ser
1550 1555 1560
Lys Glu Ser Cys Asn Ser Ser Ser Glu Asn Cys His Leu Pro Gly
1565 1570 1575
Ile Ala Thr Ser Tyr Phe Val Ser Tyr Ile Ile Ile Ser Phe Leu
1580 1585 1590
Ile Val Val Asn Met Tyr Ile Ala Val Ile Leu Glu Asn Phe Asn
1595 1600 1605
Thr Ala Thr Glu Glu Ser Glu Asp Pro Leu Gly Glu Asp Asp Phe
1610 1615 1620
Asp Ile Phe Tyr Glu Val Trp Glu Lys Phe Asp Pro Glu Ala Thr
1625 1630 1635
Gln Phe Ile Lys Tyr Ser Ala Leu Ser Asp Phe Ala Asp Ala Leu
1640 1645 1650
Pro Glu Pro Leu Arg Val Ala Lys Pro Asn Lys Tyr Gln Phe Leu
1655 1660 1665
Val Met Asp Leu Pro Met Val Ser Glu Asp Arg Leu His Cys Met
1670 1675 1680
Asp Ile Leu Phe Ala Phe Thr Ala Arg Val Leu Gly Gly Ser Asp
1685 1690 1695
Gly Leu Asp Ser Met Lys Ala Met Met Glu Glu Lys Phe Met Glu
1700 1705 1710
Ala Asn Pro Leu Lys Lys Leu Tyr Glu Pro Ile Val Thr Thr Thr
1715 1720 1725
Lys Arg Lys Glu Glu Glu Arg Gly Ala Ala Ile Ile Gln Lys Ala
1730 1735 1740
Phe Arg Lys Tyr Met Met Lys Val Thr Lys Gly Asp Gln Gly Asp
1745 1750 1755
Gln Asn Asp Leu Glu Asn Gly Pro His Ser Pro Leu Gln Thr Leu
1760 1765 1770
Cys Asn Gly Asp Leu Ser Ser Phe Gly Val Ala Lys Gly Lys Val
1775 1780 1785
His Cys Asp
1790
<210> 31
<211> 1988
<212> PRT
<213> 恒河猴
<400> 31
Met Ala Met Leu Pro Pro Pro Gly Pro Gln Ser Phe Val His Phe Thr
1 5 10 15
Lys Gln Ser Leu Ala Leu Ile Glu Gln Arg Ile Ala Glu Arg Lys Ser
20 25 30
Lys Glu Pro Lys Glu Glu Lys Lys Asp Asp Asp Glu Glu Ala Pro Lys
35 40 45
Pro Ser Ser Asp Leu Glu Ala Gly Lys Gln Leu Pro Phe Ile Tyr Gly
50 55 60
Asp Ile Pro Pro Gly Met Val Ser Glu Pro Leu Glu Asp Leu Asp Pro
65 70 75 80
Tyr Tyr Ala Asp Lys Lys Thr Phe Ile Val Leu Asn Lys Gly Lys Thr
85 90 95
Ile Phe Arg Phe Asn Ala Thr Pro Ala Leu Tyr Met Leu Ser Pro Phe
100 105 110
Ser Pro Leu Arg Arg Ile Ser Ile Lys Ile Leu Val His Ser Leu Phe
115 120 125
Ser Met Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Ile Phe Met Thr
130 135 140
Met Ser Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr Thr Phe Thr
145 150 155 160
Gly Ile Tyr Thr Phe Glu Ser Leu Val Lys Ile Leu Ala Arg Gly Phe
165 170 175
Cys Val Gly Glu Phe Thr Phe Leu Arg Asp Pro Trp Asn Trp Leu Asp
180 185 190
Phe Ile Val Ile Val Phe Ala Tyr Leu Thr Glu Phe Val Asn Leu Gly
195 200 205
Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala Leu Lys Thr
210 215 220
Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala Leu Ile Gln
225 230 235 240
Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val Phe Cys Leu
245 250 255
Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly Asn Leu Lys
260 265 270
His Lys Cys Val Gln Asn Ser Leu Val Asn Asn Glu Thr Leu Glu Ser
275 280 285
Ile Met Asn Thr Leu Glu Ser Glu Glu Asp Phe Arg Lys Tyr Phe Tyr
290 295 300
Tyr Leu Glu Gly Ser Lys Asp Ala Leu Leu Cys Gly Phe Ser Thr Asp
305 310 315 320
Ser Gly Gln Cys Pro Glu Gly Tyr Thr Cys Met Lys Ile Gly Arg Asn
325 330 335
Pro Asp Tyr Gly Tyr Thr Ser Phe Asp Thr Phe Ser Trp Ala Phe Leu
340 345 350
Ala Leu Phe Arg Leu Met Thr Gln Asp Tyr Trp Glu Asn Leu Tyr Gln
355 360 365
Gln Thr Leu Arg Ala Ala Gly Lys Thr Tyr Met Ile Phe Phe Val Val
370 375 380
Val Ile Phe Leu Gly Ser Phe Tyr Leu Ile Asn Leu Ile Leu Ala Val
385 390 395 400
Val Ala Met Ala Tyr Glu Glu Gln Asn Gln Ala Asn Ile Glu Glu Ala
405 410 415
Lys Gln Lys Glu Leu Glu Phe Gln Gln Met Leu Asp Arg Leu Lys Lys
420 425 430
Glu Gln Glu Glu Ala Glu Ala Ile Ala Ala Ala Ala Ala Glu Tyr Thr
435 440 445
Ser Ile Arg Arg Ser Arg Ile Met Gly Leu Ser Glu Ser Ser Ser Glu
450 455 460
Thr Ser Lys Leu Ser Ser Lys Ser Ala Lys Glu Arg Arg Asn Arg Arg
465 470 475 480
Lys Lys Lys Asn Gln Lys Lys Leu Ser Ser Gly Glu Glu Lys Gly Asp
485 490 495
Ala Glu Lys Leu Ser Lys Ser Asp Ser Glu Glu Asn Ile Arg Arg Lys
500 505 510
Ser Phe His Leu Gly Val Glu Gly His Arg Arg Ala His Glu Lys Arg
515 520 525
Leu Ser Thr Pro Ser Gln Ser Pro Leu Ser Ile Arg Gly Ser Leu Phe
530 535 540
Ser Ala Arg Arg Ser Ser Arg Thr Ser Leu Phe Ser Phe Lys Gly Arg
545 550 555 560
Gly Arg Asp Ile Gly Ser Glu Thr Glu Phe Ala Asp Asp Glu His Ser
565 570 575
Ile Phe Gly Asp Asn Glu Ser Arg Arg Gly Ser Leu Phe Val Pro His
580 585 590
Arg Pro Gln Glu Arg Arg Ser Ser Asn Ile Ser Gln Ala Ser Arg Ser
595 600 605
Pro Pro Ile Leu Pro Val Asn Gly Lys Met His Ser Ala Val Asp Cys
610 615 620
Asn Gly Val Val Ser Leu Val Asp Gly Arg Ser Ala Leu Met Leu Pro
625 630 635 640
Asn Gly Gln Leu Leu Pro Glu Val Ile Ile Asp Lys Ala Thr Ser Asp
645 650 655
Asp Ser Gly Thr Thr Asn Gln Ile His Lys Lys Arg Arg Cys Ser Ser
660 665 670
Tyr Leu Leu Ser Glu Asp Met Leu Asn Asp Pro Asn Leu Arg Gln Arg
675 680 685
Ala Met Ser Arg Ala Ser Ile Leu Thr Asn Thr Val Glu Glu Leu Glu
690 695 700
Glu Ser Arg Gln Lys Cys Pro Pro Trp Trp Tyr Arg Phe Ala His Lys
705 710 715 720
Phe Leu Ile Trp Asn Cys Ser Pro Tyr Trp Ile Lys Phe Lys Lys Cys
725 730 735
Ile Tyr Phe Ile Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile
740 745 750
Cys Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His His Pro Met
755 760 765
Thr Glu Glu Phe Lys Asn Val Leu Ala Ile Gly Asn Leu Val Phe Thr
770 775 780
Gly Ile Phe Ala Ala Glu Met Val Leu Lys Leu Ile Ala Met Asp Pro
785 790 795 800
Tyr Glu Tyr Phe Gln Val Gly Trp Asn Ile Phe Asp Ser Leu Ile Val
805 810 815
Thr Leu Ser Leu Val Glu Leu Phe Leu Ala Asp Val Glu Gly Leu Ser
820 825 830
Val Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser
835 840 845
Trp Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly
850 855 860
Ala Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe
865 870 875 880
Ala Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val
885 890 895
Cys Lys Ile Asn Asp Asp Cys Thr Leu Pro Arg Trp His Met Asn Asp
900 905 910
Phe Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp
915 920 925
Ile Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Ala Met Cys
930 935 940
Leu Ile Val Tyr Met Met Val Met Val Ile Gly Asn Leu Val Val Leu
945 950 955 960
Asn Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu
965 970 975
Thr Ala Ile Glu Glu Asp Pro Asp Ala Asn Asn Leu Gln Ile Ala Val
980 985 990
Thr Arg Ile Lys Lys Gly Ile Asn Tyr Val Lys Gln Thr Leu Arg Glu
995 1000 1005
Phe Ile Leu Lys Thr Phe Ser Lys Lys Pro Lys Ile Ser Arg Glu
1010 1015 1020
Ile Arg Gln Thr Glu Asp Leu Asn Thr Lys Lys Glu Asn Tyr Ile
1025 1030 1035
Ser Asn Tyr Thr Leu Ala Glu Met Ser Lys Gly His Asn Phe Leu
1040 1045 1050
Lys Glu Lys Asp Lys Ile Ser Gly Phe Gly Ser Cys Val Asp Lys
1055 1060 1065
Tyr Leu Met Glu Asp Ser Asp Gly Gln Ser Phe Ile His Asn Pro
1070 1075 1080
Ser Leu Thr Val Thr Val Pro Ile Ala Pro Gly Glu Ser Asp Leu
1085 1090 1095
Glu Asn Met Asn Thr Glu Glu Leu Ser Ser Asp Ser Asp Ser Glu
1100 1105 1110
Tyr Ser Lys Val Arg Leu Asn Gln Ser Ser Ser Ser Glu Cys Ser
1115 1120 1125
Thr Val Asp Asn Pro Leu Pro Gly Glu Gly Glu Glu Ala Glu Ala
1130 1135 1140
Glu Pro Met Asn Ser Asp Glu Pro Glu Ala Cys Phe Thr Asp Gly
1145 1150 1155
Cys Val Arg Arg Phe Ser Cys Cys Gln Val Asn Ile Glu Ser Gly
1160 1165 1170
Lys Gly Lys Ile Trp Trp Asn Ile Arg Lys Thr Cys Tyr Lys Ile
1175 1180 1185
Val Glu His Ser Trp Phe Glu Ser Phe Ile Val Leu Met Ile Leu
1190 1195 1200
Leu Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile Glu Arg
1205 1210 1215
Lys Lys Thr Ile Lys Ile Ile Leu Glu Tyr Ala Asp Lys Ile Phe
1220 1225 1230
Thr Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Ile Ala Tyr
1235 1240 1245
Gly Tyr Lys Thr Tyr Phe Thr Asn Ala Trp Cys Trp Leu Asp Phe
1250 1255 1260
Leu Ile Val Asp Val Ser Leu Val Thr Leu Val Ala Asn Thr Leu
1265 1270 1275
Gly Tyr Ser Asp Leu Gly Pro Ile Lys Ser Leu Arg Thr Leu Arg
1280 1285 1290
Ala Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly Met Arg
1295 1300 1305
Val Val Val Asn Ala Leu Ile Gly Ala Ile Pro Ser Ile Met Asn
1310 1315 1320
Val Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile Met
1325 1330 1335
Gly Val Asn Leu Phe Ala Gly Lys Phe Tyr Glu Cys Ile Asn Thr
1340 1345 1350
Thr Asp Gly Ser Arg Phe Pro Ala Ser Gln Val Pro Asn Arg Ser
1355 1360 1365
Glu Cys Phe Ala Leu Met Asn Val Ser Gln Asn Val Arg Trp Lys
1370 1375 1380
Asn Leu Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr Leu Ser
1385 1390 1395
Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Thr Ile Ile Met Tyr
1400 1405 1410
Ala Ala Val Asp Ser Val Asn Val Asp Lys Gln Pro Lys Tyr Glu
1415 1420 1425
Tyr Ser Leu Tyr Met Tyr Ile Tyr Phe Val Ile Phe Ile Ile Phe
1430 1435 1440
Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile Ile Asp
1445 1450 1455
Asn Phe Asn Gln Gln Lys Lys Lys Leu Gly Gly Gln Asp Ile Phe
1460 1465 1470
Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys Leu
1475 1480 1485
Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Gly Asn Lys
1490 1495 1500
Ile Gln Gly Cys Ile Phe Asp Leu Val Thr Asn Gln Ala Phe Asp
1505 1510 1515
Ile Ser Ile Met Val Leu Ile Cys Leu Asn Met Val Thr Met Met
1520 1525 1530
Val Glu Lys Glu Gly Gln Ser Pro Tyr Met Thr Asp Val Leu Tyr
1535 1540 1545
Trp Ile Asn Val Val Phe Ile Ile Leu Phe Thr Gly Glu Cys Val
1550 1555 1560
Leu Lys Leu Ile Ser Leu Arg Tyr Tyr Tyr Phe Thr Ile Gly Trp
1565 1570 1575
Asn Ile Phe Asp Phe Val Val Val Ile Ile Ser Ile Val Gly Met
1580 1585 1590
Phe Leu Ala Asp Leu Ile Glu Thr Tyr Phe Val Ser Pro Thr Leu
1595 1600 1605
Phe Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg Leu
1610 1615 1620
Val Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu Met
1625 1630 1635
Met Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu Phe Leu
1640 1645 1650
Val Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe Ala Tyr
1655 1660 1665
Val Lys Lys Glu Asp Gly Ile Asn Asp Met Phe Asn Phe Glu Thr
1670 1675 1680
Phe Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr Ser Ala
1685 1690 1695
Gly Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Lys Pro Pro
1700 1705 1710
Asp Cys Asp Pro Lys Lys Val His Pro Gly Ser Ser Val Glu Gly
1715 1720 1725
Asp Cys Gly Asn Pro Ser Val Gly Ile Phe Tyr Phe Val Ser Tyr
1730 1735 1740
Ile Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile Ala Val
1745 1750 1755
Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Thr Glu Pro
1760 1765 1770
Leu Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp Glu Lys
1775 1780 1785
Phe Asp Pro Asp Ala Thr Gln Phe Ile Glu Tyr Asn Lys Leu Ser
1790 1795 1800
Asp Phe Ala Ala Ala Leu Asp Pro Pro Leu Leu Ile Ala Lys Pro
1805 1810 1815
Asn Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val Ser Gly
1820 1825 1830
Asp Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr Lys Arg
1835 1840 1845
Val Leu Gly Glu Ser Gly Glu Met Asp Ser Leu Arg Ser Gln Met
1850 1855 1860
Glu Glu Arg Phe Met Ser Ala Asn Pro Ser Lys Val Ser Tyr Glu
1865 1870 1875
Pro Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Asp Val Ser Ala
1880 1885 1890
Thr Val Ile Gln Arg Ala Tyr Arg Arg Tyr Arg Leu Arg Gln Asn
1895 1900 1905
Val Lys Asn Ile Ser Ser Ile Tyr Ile Lys Asp Gly Asp Arg Asp
1910 1915 1920
Asp Asp Leu Leu Asn Lys Lys Asp Met Ala Phe Asp Asn Val Asn
1925 1930 1935
Glu Asn Ser Ser Pro Glu Lys Thr Asp Ala Thr Ser Ser Thr Thr
1940 1945 1950
Ser Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Asp Lys Glu Lys
1955 1960 1965
Tyr Glu Gln Asp Arg Thr Glu Lys Glu Asp Lys Gly Lys Asp Ser
1970 1975 1980
Lys Glu Ser Lys Lys
1985
<210> 32
<211> 1988
<212> PRT
<213> 人工序列
<220>
<223> 马来西亚飞行狐猴
<400> 32
Met Ala Met Leu Pro Pro Pro Arg Pro Gln Ser Phe Val Arg Phe Thr
1 5 10 15
Lys Gln Ser Leu Ala Leu Ile Glu Gln Arg Ile Ala Glu Gly Lys Thr
20 25 30
Lys Glu Pro Lys Glu Glu Lys Lys Asp Ser Asp Glu Glu Gly Pro Lys
35 40 45
Pro Ser Ser Asp Leu Glu Ala Gly Lys Gln Leu Pro Phe Ile Tyr Gly
50 55 60
Asp Ile Pro Pro Asp Met Val Ser Glu Pro Leu Glu Asp Leu Asp Pro
65 70 75 80
Phe Tyr Ala Asp Lys Lys Thr Phe Ile Val Leu Asn Lys Gly Lys Ala
85 90 95
Ile Phe Arg Phe Asn Ala Thr Pro Ala Leu Tyr Met Leu Ser Pro Phe
100 105 110
Ser Pro Leu Arg Arg Ile Ser Ile Lys Ile Leu Val His Ser Phe Phe
115 120 125
Ser Met Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Ile Phe Met Thr
130 135 140
Leu Ser Thr Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr Thr Phe Thr
145 150 155 160
Gly Ile Tyr Thr Phe Glu Ser Leu Ile Lys Ile Leu Ala Arg Gly Phe
165 170 175
Cys Val Gly Glu Phe Thr Phe Leu Arg Asp Pro Trp Asn Trp Leu Asp
180 185 190
Phe Val Val Ile Val Phe Ala Tyr Leu Thr Glu Phe Val Asn Leu Gly
195 200 205
Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala Leu Lys Thr
210 215 220
Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala Leu Ile Gln
225 230 235 240
Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val Phe Cys Leu
245 250 255
Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly Asn Leu Lys
260 265 270
His Lys Cys Phe Arg Asn Ser Leu Glu Asn Asn Glu Thr Leu Gln Ser
275 280 285
Ile Ile Glu Thr Leu Glu Thr Glu Glu Asp Tyr Arg Arg Tyr Phe Tyr
290 295 300
Tyr Leu Glu Gly Ser Lys Asp Ala Leu Leu Cys Gly Phe Ser Thr Asp
305 310 315 320
Ser Gly Gln Cys Pro Glu Gly Tyr Thr Cys Val Lys Ala Gly Arg Asn
325 330 335
Pro Asp Tyr Gly Tyr Thr Ser Phe Asp Thr Phe Ser Trp Ala Phe Leu
340 345 350
Ala Leu Phe Arg Leu Met Thr Gln Asp Tyr Trp Glu Asn Leu Tyr Gln
355 360 365
Gln Thr Leu Arg Ala Ala Gly Lys Thr Tyr Met Ile Phe Phe Val Val
370 375 380
Val Ile Phe Leu Gly Ser Phe Tyr Leu Ile Asn Leu Ile Leu Ala Val
385 390 395 400
Val Ala Met Ala Tyr Glu Glu Gln Asn Gln Ala Asn Ile Glu Glu Ala
405 410 415
Arg Gln Lys Glu Leu Glu Phe Gln Gln Met Leu Glu Gln Leu Lys Lys
420 425 430
Glu Gln Glu Glu Ala Glu Ala Ile Ala Val Ala Val Ala Glu His Thr
435 440 445
Ser Ile Gly Arg Ser Arg Ile Met Gly Val Ser Glu Ser Ser Ser Glu
450 455 460
Thr Ser Lys Leu Ser Ser Lys Ser Ala Lys Glu Arg Arg Asn Arg Arg
465 470 475 480
Lys Lys Lys Asn Gln Lys Lys Leu Ser Ser Gly Glu Glu Lys Gly Asp
485 490 495
Asp Glu Lys Leu Ser Lys Ser Glu Ser Glu Glu Ser Ile Arg Arg Lys
500 505 510
Ser Phe Tyr Leu Gly Val Glu Gly His Gly Arg Ala Arg Glu Lys Arg
515 520 525
Leu Ser Thr Pro Asn Gln Ser Pro Leu Ser Ile Arg Gly Ser Leu Phe
530 535 540
Ser Ala Arg Arg Ser Ser Arg Thr Ser Leu Phe Ser Phe Lys Gly Arg
545 550 555 560
Gly Lys Asp Ile Gly Ser Glu Thr Glu Phe Ala Asp Asp Glu His Ser
565 570 575
Ile Phe Gly Asp Asn Glu Ser Arg Arg Gly Ser Leu Phe Val Pro His
580 585 590
Arg Pro Arg Glu Arg Arg Ser Ser Asn Ile Ser Gln Ala Ser Arg Ser
595 600 605
Pro Pro Met Leu Pro Val Asn Gly Lys Met His Ser Ala Val Asp Cys
610 615 620
Asn Gly Val Val Ser Leu Val Asp Gly Pro Ser Ala Leu Met Leu Pro
625 630 635 640
Asn Gly Gln Leu Leu Pro Glu Val Ile Ile Asp Lys Ala Thr Ser Asp
645 650 655
Asp Ser Gly Thr Thr Asn Gln Ile Arg Lys Lys Arg Arg Ser Ser Ser
660 665 670
Tyr Leu Leu Ser Glu Asp Met Leu Asn Asp Pro Asn Leu Arg Gln Arg
675 680 685
Ala Met Ser Arg Ala Ser Ile Leu Thr Asn Thr Met Glu Glu Leu Glu
690 695 700
Glu Ser Arg Gln Lys Cys Pro Pro Trp Trp Tyr Lys Phe Ala His Thr
705 710 715 720
Phe Leu Ile Trp Asn Cys Ser Pro Phe Trp Ile Lys Phe Lys Lys Leu
725 730 735
Ile Tyr Phe Ile Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile
740 745 750
Cys Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His His Pro Met
755 760 765
Thr Asn Glu Phe Lys Asn Ala Leu Ala Val Gly Asn Leu Val Phe Thr
770 775 780
Gly Ile Phe Ala Ala Glu Met Val Leu Lys Leu Ile Ala Met Asp Pro
785 790 795 800
Tyr Glu Tyr Phe Gln Val Gly Trp Asn Ile Phe Asp Ser Leu Ile Val
805 810 815
Thr Leu Ser Leu Val Glu Leu Cys Leu Ser Glu Val Glu Gly Leu Ser
820 825 830
Val Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser
835 840 845
Trp Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly
850 855 860
Ala Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe
865 870 875 880
Ala Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val
885 890 895
Cys Lys Ile Ser Asp Asp Cys Thr Leu Pro Arg Trp His Met Thr Asp
900 905 910
Phe Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp
915 920 925
Ile Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Ala Met Cys
930 935 940
Leu Ile Val Tyr Met Met Val Met Val Ile Gly Asn Leu Val Val Leu
945 950 955 960
Asn Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu
965 970 975
Thr Ala Ile Glu Glu Asp Thr Asp Ala Asn Asn Leu Gln Ile Ala Val
980 985 990
Ala Arg Ile Asn Lys Gly Val Asn Tyr Met Lys Gln Ser Leu Arg Glu
995 1000 1005
Cys Ile Leu Lys Ala Phe Ser Lys Lys Pro Lys Ile Ser Gly Glu
1010 1015 1020
Ile Lys Arg Ala Glu Asn Ile Asn Ser Lys Lys Glu Asn Tyr Val
1025 1030 1035
Ser Asn Arg Thr Leu Ala Glu Met Ser Lys Asp His Ser Phe Tyr
1040 1045 1050
Lys Glu Lys Asp Lys Ile Gly Gly Leu Gly Ser Ser Met Asp Lys
1055 1060 1065
Tyr Leu Met Asp Glu Ser Asp Tyr Gln Ser Phe Ile His Asn Pro
1070 1075 1080
Ser Leu Thr Val Thr Val Pro Ile Ala Pro Gly Glu Ser Asp Leu
1085 1090 1095
Glu Asn Met Asn Thr Glu Glu Leu Ser Ser Asp Ser Asp Ser Glu
1100 1105 1110
Cys Thr Lys Glu Val Leu Asn Arg Ser Ser Ser Ser Glu Cys Ser
1115 1120 1125
Thr Val Asp Asn Pro Val Pro Gly Glu Gly Glu Glu Ala Glu Ala
1130 1135 1140
Glu Pro Val Asn Ser Asp Glu Pro Glu Ala Cys Phe Thr Asp Gly
1145 1150 1155
Cys Val Arg Arg Phe Pro Cys Cys Gln Val Asn Ile Glu Ser Gly
1160 1165 1170
Lys Gly Lys Ile Trp Trp Asn Ile Arg Lys Thr Cys Tyr Lys Ile
1175 1180 1185
Val Glu His Ser Trp Phe Glu Ser Phe Ile Val Leu Met Ile Leu
1190 1195 1200
Leu Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile Glu Arg
1205 1210 1215
Lys Lys Thr Ile Lys Ile Ile Leu Glu Tyr Ala Asp Lys Ile Phe
1220 1225 1230
Thr Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Val Ala Tyr
1235 1240 1245
Gly Tyr Lys Thr Tyr Phe Thr Asn Ala Trp Cys Trp Leu Asp Phe
1250 1255 1260
Leu Ile Val Asp Val Ser Leu Val Thr Leu Val Ala Asn Thr Leu
1265 1270 1275
Gly Tyr Ser Asp Leu Gly Pro Ile Lys Ser Leu Arg Thr Leu Arg
1280 1285 1290
Ala Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly Met Arg
1295 1300 1305
Val Val Val Asn Ala Leu Ile Gly Ala Ile Pro Ser Ile Met Asn
1310 1315 1320
Val Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile Met
1325 1330 1335
Gly Val Asn Leu Phe Ala Gly Lys Phe Tyr Glu Cys Ile Asn Thr
1340 1345 1350
Thr Asp Gly Ser Arg Phe Pro Thr Thr Gln Val Ser Asn Arg Ser
1355 1360 1365
Asp Cys Phe Ala Leu Met Asn Val Ser Gln Asn Val Arg Trp Lys
1370 1375 1380
Asn Leu Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr Leu Ser
1385 1390 1395
Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile Met Tyr
1400 1405 1410
Ala Ala Val Asp Ser Val Asn Val Asp Lys Gln Pro Lys Tyr Glu
1415 1420 1425
Tyr Ser Ile Tyr Met Tyr Ile Tyr Phe Val Ile Phe Ile Ile Phe
1430 1435 1440
Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile Ile Asp
1445 1450 1455
Asn Phe Asn Gln Gln Lys Lys Lys Leu Gly Gly Gln Asp Ile Phe
1460 1465 1470
Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys Leu
1475 1480 1485
Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Gly Asn Lys
1490 1495 1500
Phe Gln Gly Cys Ile Phe Asp Leu Val Thr Asn Gln Val Phe Asp
1505 1510 1515
Ile Thr Ile Met Val Leu Ile Cys Leu Asn Met Val Thr Met Met
1520 1525 1530
Val Glu Lys Glu Glu Gln Ser Gln Tyr Met Val Asp Val Leu Tyr
1535 1540 1545
Trp Ile Asn Val Ala Phe Ile Ile Leu Phe Thr Gly Glu Cys Val
1550 1555 1560
Leu Lys Leu Ile Ser Leu Arg His Tyr Tyr Phe Thr Val Gly Trp
1565 1570 1575
Asn Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile Val Gly Met
1580 1585 1590
Phe Leu Ala Asp Leu Ile Glu Lys Tyr Phe Val Ser Pro Thr Leu
1595 1600 1605
Phe Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg Leu
1610 1615 1620
Ile Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu Met
1625 1630 1635
Met Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu Phe Leu
1640 1645 1650
Val Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe Ala Tyr
1655 1660 1665
Val Lys Lys Glu Ala Gly Ile Asn Asp Met Phe Asn Phe Glu Thr
1670 1675 1680
Phe Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr Ser Ala
1685 1690 1695
Gly Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Ala Pro Pro
1700 1705 1710
Asp Cys Asp Pro Lys Lys Val His Pro Gly Ser Ser Val Glu Gly
1715 1720 1725
Asp Cys Gly Asn Pro Ser Val Gly Ile Phe Tyr Phe Val Ser Tyr
1730 1735 1740
Ile Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile Ala Val
1745 1750 1755
Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Thr Glu Pro
1760 1765 1770
Leu Gly Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp Glu Lys
1775 1780 1785
Phe Asp Pro Asp Ala Thr Gln Phe Ile Glu Tyr Ser Lys Leu Ser
1790 1795 1800
Asp Phe Ala Ala Ala Leu Asp Pro Pro Leu Leu Ile Ala Lys Pro
1805 1810 1815
Asn Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val Ser Gly
1820 1825 1830
Asp Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr Lys Arg
1835 1840 1845
Val Leu Gly Glu Ser Gly Glu Met Asp Ser Leu Arg Ser Gln Met
1850 1855 1860
Glu Glu Arg Phe Met Ser Ala Asn Pro Ser Lys Val Ser Tyr Glu
1865 1870 1875
Pro Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Asp Val Ser Ala
1880 1885 1890
Thr Val Ile Gln Arg Ala Phe Arg Arg Tyr Arg Leu Arg Gln Asn
1895 1900 1905
Val Lys Asn Ile Ser Ser Met Tyr Ile Lys Asp Gly Asp Arg Asp
1910 1915 1920
Asp Asp Leu Pro His Lys Glu Asp Val Val Phe Gly Asn Val Asn
1925 1930 1935
Gly Asn Ser Ser Pro Glu Lys Thr Asp Ala Thr Pro Ser Thr Val
1940 1945 1950
Ser Pro Pro Ser Tyr Asp Ser Val Thr Met Pro Asp Lys Glu Lys
1955 1960 1965
Tyr Glu Lys Asp Lys Thr Glu Lys Glu Asp Lys Gly Lys Asp Gly
1970 1975 1980
Lys Glu Ser Lys Lys
1985
<210> 33
<211> 1987
<212> PRT
<213> 牛
<400> 33
Met Ala Met Leu Pro Pro Pro Gly Pro Gln Ser Phe Val Phe Phe Thr
1 5 10 15
Lys Gln Ser Leu Ala Leu Ile Glu Gln Arg Ile Ala Glu Gly Lys Ala
20 25 30
Lys Glu Pro Lys Glu Glu Lys Lys Asp Asp Asp Asp Glu Gly Pro Lys
35 40 45
Pro Ser Ser Asp Leu Glu Ala Gly Lys Gln Leu Pro Phe Ile Tyr Gly
50 55 60
Asp Ile Pro Pro Gly Met Val Ser Glu Pro Leu Glu Asp Leu Asp Pro
65 70 75 80
Tyr Tyr Ala Asp Lys Lys Thr Phe Ile Val Leu Asn Lys Gly Lys Ala
85 90 95
Ile Phe Arg Phe Asn Ala Thr Pro Ala Leu Tyr Met Leu Ser Pro Phe
100 105 110
Ser Pro Leu Arg Arg Ile Ser Ile Lys Ile Leu Val His Ala Ala Phe
115 120 125
Ser Met Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Ile Phe Met Thr
130 135 140
Met Ser Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr Thr Phe Thr
145 150 155 160
Gly Ile Tyr Thr Phe Glu Ser Leu Val Lys Ile Leu Ala Arg Gly Phe
165 170 175
Cys Val Gly Glu Phe Thr Phe Leu Arg Asp Pro Trp Asn Trp Leu Asp
180 185 190
Phe Ile Val Ile Val Phe Ala Tyr Leu Thr Glu Phe Val Asn Leu Gly
195 200 205
Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala Leu Lys Thr
210 215 220
Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala Leu Ile Gln
225 230 235 240
Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val Phe Cys Leu
245 250 255
Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly Asn Leu Lys
260 265 270
His Lys Cys Val Gln Ser Ser Leu Ala Asn Asn Glu Thr Met Glu Asn
275 280 285
Ile Leu Asn Thr Leu Asp Glu Glu Glu Tyr Ala Lys Tyr Phe Tyr Tyr
290 295 300
Leu Glu Gly Ser Lys Asp Ala Leu Leu Cys Gly Phe Ser Ser Asp Ser
305 310 315 320
Gly Gln Cys Pro Glu Gly Tyr Thr Cys Lys Lys Ile Gly Arg Asn Pro
325 330 335
Asp Tyr Gly Tyr Thr Ser Phe Asp Thr Phe Ser Trp Ala Phe Leu Ala
340 345 350
Leu Phe Arg Leu Met Thr Gln Asp Tyr Trp Glu Asn Leu Tyr Gln Gln
355 360 365
Thr Leu Arg Ala Ala Gly Lys Thr Tyr Met Ile Phe Phe Val Val Val
370 375 380
Ile Phe Leu Gly Ser Phe Tyr Leu Ile Asn Leu Ile Leu Ala Val Val
385 390 395 400
Ala Met Ala Tyr Glu Glu Gln Asn Gln Ala Asn Ile Glu Glu Ala Arg
405 410 415
Gln Lys Glu Leu Glu Phe Gln Gln Met Leu Asp Arg Leu Lys Lys Glu
420 425 430
Gln Glu Glu Ala Glu Ala Ile Ala Leu Ala Ala Ala Glu Tyr Thr Ser
435 440 445
Ile Gly Arg Ser Arg Ile Met Gly Leu Ser Glu Ser Ser Ser Glu Thr
450 455 460
Ser Lys Leu Ser Ser Lys Ser Ala Lys Glu Arg Arg Asn Arg Arg Arg
465 470 475 480
Lys Lys Asn Gln Lys Lys Leu Ser Ser Gly Glu Glu Lys Gly Asp Asp
485 490 495
Glu Lys Leu Ser Lys Ser Glu Ser Glu Glu Ser Ile Arg Arg Lys Ser
500 505 510
Phe His Leu Gly Val Glu Gly His Arg Arg Ala Arg Glu Lys Arg Leu
515 520 525
Ser Thr Pro Asn Gln Ser Pro Leu Ser Ile Arg Gly Ser Leu Phe Ser
530 535 540
Ala Arg Arg Ser Ser Arg Thr Ser Leu Phe Ser Phe Lys Gly Arg Gly
545 550 555 560
Arg Asp Ile Gly Ser Glu Thr Glu Phe Ala Asp Asp Glu His Ser Ile
565 570 575
Phe Gly Asp Asn Glu Ser Arg Arg Gly Ser Leu Phe Val Pro His Arg
580 585 590
Pro Arg Glu Arg Arg Ser Ser Asn Ile Ser Gln Ala Ser Arg Ser Pro
595 600 605
Pro Val Leu Pro Val Asn Gly Lys Met His Ser Ala Val Asp Cys Asn
610 615 620
Gly Val Val Ser Leu Val Asp Gly Pro Ser Ala Leu Met Leu Pro Asn
625 630 635 640
Gly Gln Leu Leu Pro Glu Val Ile Ile Asp Lys Ala Thr Ser Asp Asp
645 650 655
Ser Gly Thr Thr Asn Gln Ile His Lys Lys Arg Arg His Ser Ser Tyr
660 665 670
Leu Leu Ser Glu Asp Met Leu Asn Asp Pro Asn Leu Arg Gln Arg Ala
675 680 685
Met Ser Arg Ala Ser Ile Leu Thr Asn Thr Val Glu Glu Leu Glu Glu
690 695 700
Ser Arg Gln Lys Cys Pro Pro Trp Trp Tyr Arg Phe Ala His Thr Phe
705 710 715 720
Leu Ile Trp Asn Cys Ser Pro Tyr Trp Ile Lys Phe Lys Lys Phe Ile
725 730 735
Tyr Phe Ile Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile Cys
740 745 750
Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His His Pro Met Thr
755 760 765
Glu Glu Phe Lys Asn Val Leu Val Val Gly Asn Leu Val Phe Thr Gly
770 775 780
Ile Phe Ala Ala Glu Met Val Leu Lys Leu Ile Ala Met Asp Pro Tyr
785 790 795 800
Glu Tyr Phe Gln Ile Gly Trp Asn Ile Phe Asp Ser Leu Ile Val Thr
805 810 815
Leu Ser Leu Val Glu Leu Phe Leu Ser Asp Val Glu Gly Leu Ser Val
820 825 830
Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser Trp
835 840 845
Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly Ala
850 855 860
Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe Ala
865 870 875 880
Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val Cys
885 890 895
Lys Ile Asn Glu Asp Cys Thr Leu Pro Arg Trp His Met Asn Asp Phe
900 905 910
Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp Ile
915 920 925
Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Ala Met Cys Leu
930 935 940
Ile Val Tyr Met Met Val Met Val Ile Gly Asn Leu Val Val Leu Asn
945 950 955 960
Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu Thr
965 970 975
Ala Ile Glu Glu Asp Thr Asp Ala Asn Asn Leu Gln Ile Ala Val Ala
980 985 990
Arg Ile Lys Lys Gly Ile Asn Tyr Val Lys Gln Thr Leu Arg Glu Phe
995 1000 1005
Val Leu Lys Ala Phe Ser Lys Lys Pro Lys Ile Ser Lys Glu Ile
1010 1015 1020
Arg Gln Thr Glu Asp Leu Asn Cys Lys Lys Glu Asn Tyr Ile Ser
1025 1030 1035
Asn Arg Thr Leu Ala Glu Met Ser Lys Asp His Lys Phe His Lys
1040 1045 1050
Glu Lys Asp Lys Thr Ser Gly Phe Gly Asn Ser Met Asp Lys Tyr
1055 1060 1065
Leu Met Glu Glu Ser Asp Gly Gln Ser Phe Ile His Asn Pro Ser
1070 1075 1080
Leu Thr Val Thr Val Pro Ile Ala Pro Gly Glu Ser Asp Leu Glu
1085 1090 1095
Ile Met Asn Thr Glu Glu Leu Ser Ser Asp Ser Asp Ser Glu Tyr
1100 1105 1110
Ser Lys Gly Arg Leu Asn Gln Ser Ser Ser Ser Glu Cys Ser Thr
1115 1120 1125
Val Asp Asn Pro Val Pro Gly Glu Gly Glu Glu Ala Glu Ala Glu
1130 1135 1140
Pro Val Asn Ser Asp Glu Pro Glu Ala Cys Phe Thr Asp Gly Cys
1145 1150 1155
Val Gln Arg Phe Pro Cys Cys Gln Val Asn Ile Glu Ser Gly Lys
1160 1165 1170
Gly Lys Ile Trp Trp Asn Ile Arg Lys Thr Cys Phe Arg Ile Val
1175 1180 1185
Glu His Ser Trp Phe Glu Ser Phe Ile Val Leu Met Ile Leu Leu
1190 1195 1200
Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile Glu Lys Lys
1205 1210 1215
Lys Asn Ile Lys Ile Ile Leu Glu Tyr Ala Asp Lys Ile Phe Thr
1220 1225 1230
Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Val Ala Tyr Gly
1235 1240 1245
Tyr Lys Thr Tyr Phe Thr Asn Ala Trp Cys Trp Leu Asp Phe Leu
1250 1255 1260
Ile Val Asp Val Ser Leu Val Thr Leu Val Ala Asn Thr Leu Gly
1265 1270 1275
Tyr Ser Asp Leu Gly Pro Ile Lys Ser Leu Arg Thr Leu Arg Ala
1280 1285 1290
Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly Met Arg Val
1295 1300 1305
Val Val Asn Ala Leu Ile Gly Ala Ile Pro Ser Ile Met Asn Val
1310 1315 1320
Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile Met Gly
1325 1330 1335
Val Asn Leu Phe Ala Gly Lys Phe Tyr Glu Cys Ile Asn Thr Thr
1340 1345 1350
Asn Gly Leu Arg Phe Pro Thr Ser Glu Val Glu Asn Arg Ser Ala
1355 1360 1365
Cys Leu Ala Leu Met Asn Val Ser Gln Asn Val Arg Trp Lys Asn
1370 1375 1380
Leu Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr Leu Ser Leu
1385 1390 1395
Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile Met Tyr Ala
1400 1405 1410
Ala Val Asp Ser Val Asn Val Asn Lys Gln Pro Ile Tyr Glu Tyr
1415 1420 1425
Ser Leu Tyr Met Tyr Ile Tyr Phe Val Ile Phe Ile Ile Phe Gly
1430 1435 1440
Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile Ile Asp Asn
1445 1450 1455
Phe Asn Gln Gln Lys Lys Lys Leu Gly Gly Gln Asp Ile Phe Met
1460 1465 1470
Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys Leu Gly
1475 1480 1485
Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Gly Asn Lys Phe
1490 1495 1500
Gln Gly Cys Ile Phe Asp Leu Val Thr Asn Gln Ala Phe Asp Ile
1505 1510 1515
Ala Ile Met Val Leu Ile Cys Leu Asn Met Val Thr Met Met Val
1520 1525 1530
Glu Lys Glu Gly Gln Ser Asp Tyr Val Thr Glu Val Leu Asn Trp
1535 1540 1545
Ile Asn Val Val Phe Ile Ile Leu Phe Ser Gly Glu Cys Val Leu
1550 1555 1560
Lys Leu Ile Ser Leu Arg Cys Tyr Tyr Phe Thr Val Gly Trp Asn
1565 1570 1575
Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile Val Gly Met Phe
1580 1585 1590
Leu Ala Asp Leu Ile Glu Arg Tyr Phe Val Ser Pro Thr Leu Phe
1595 1600 1605
Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg Leu Ile
1610 1615 1620
Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu Met Met
1625 1630 1635
Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu Phe Leu Val
1640 1645 1650
Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe Ala Tyr Val
1655 1660 1665
Lys Lys Glu Ala Gly Ile Asn Asp Met Phe Asn Phe Glu Thr Phe
1670 1675 1680
Ala Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr Ser Ala Gly
1685 1690 1695
Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Lys Pro Pro Asp
1700 1705 1710
Cys Asp Pro Lys Lys Val His Pro Gly Ser Ser Val Glu Gly Asp
1715 1720 1725
Cys Gly Asn Pro Ser Val Gly Ile Phe Tyr Phe Val Ser Tyr Ile
1730 1735 1740
Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile Ala Val Ile
1745 1750 1755
Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Thr Glu Pro Leu
1760 1765 1770
Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp Glu Lys Phe
1775 1780 1785
Asp Pro Asp Ala Thr Gln Phe Ile Glu Tyr Ser Lys Leu Ser Asp
1790 1795 1800
Phe Ala Ala Ala Leu Asp Pro Pro Leu Leu Ile Ala Lys Pro Asn
1805 1810 1815
Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val Ser Gly Asp
1820 1825 1830
Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr Lys Arg Val
1835 1840 1845
Leu Gly Glu Gly Gly Glu Met Asp Ser Leu Arg Ser Gln Met Glu
1850 1855 1860
Glu Arg Phe Met Ser Ala Asn Pro Ser Lys Val Ser Tyr Glu Pro
1865 1870 1875
Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Asp Val Ser Ala Thr
1880 1885 1890
Val Ile Gln Arg Ala Tyr Arg Arg Tyr Arg Leu Arg Gln Asn Val
1895 1900 1905
Lys Asn Ile Ser Ser Ile Tyr Ile Lys Asp Gly Asp Arg Asp Asp
1910 1915 1920
Asp Leu Pro Asn Lys Glu Asp Met Val Phe Asp Asn Val Asn Glu
1925 1930 1935
Asn Ser Ser Pro Glu Lys Thr Gly Ala Thr Pro Ser Thr Val Ser
1940 1945 1950
Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Asp Arg Glu Lys Tyr
1955 1960 1965
Glu Lys Asp Lys Thr Glu Lys Glu Asp Lys Gly Lys Asp Gly Lys
1970 1975 1980
Glu Gly Lys Lys
1985
<210> 34
<211> 1987
<212> PRT
<213> 绵羊
<400> 34
Met Ala Met Leu Pro Pro Pro Gly Pro Gln Ser Phe Val Phe Phe Thr
1 5 10 15
Lys Gln Ser Leu Ala Leu Ile Glu Gln Arg Ile Ala Glu Gly Lys Ala
20 25 30
Lys Glu Pro Lys Glu Glu Lys Lys Asp Asp Asp Glu Glu Gly Pro Lys
35 40 45
Pro Ser Ser Asp Leu Glu Ala Gly Lys Gln Leu Pro Phe Ile Tyr Gly
50 55 60
Asp Ile Pro Pro Gly Met Val Ser Glu Pro Leu Glu Asp Leu Asp Pro
65 70 75 80
Tyr Tyr Ala Asp Lys Lys Thr Phe Ile Val Leu Asn Lys Gly Lys Ala
85 90 95
Ile Phe Arg Phe Asn Ala Thr Pro Ala Leu Tyr Met Leu Ser Pro Phe
100 105 110
Ser Pro Leu Arg Arg Ile Ser Ile Lys Ile Leu Val His Ala Ala Phe
115 120 125
Ser Met Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Ile Phe Met Thr
130 135 140
Met Ser Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr Thr Phe Thr
145 150 155 160
Gly Ile Tyr Thr Phe Glu Ser Leu Val Lys Ile Leu Ala Arg Gly Phe
165 170 175
Cys Val Gly Glu Phe Thr Phe Leu Arg Asp Pro Trp Asn Trp Leu Asp
180 185 190
Phe Ile Val Ile Val Phe Ala Tyr Leu Thr Glu Phe Val Asn Leu Gly
195 200 205
Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala Leu Lys Thr
210 215 220
Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala Leu Ile Gln
225 230 235 240
Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val Phe Cys Leu
245 250 255
Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly Asn Leu Lys
260 265 270
His Lys Cys Val Gln Thr Ser Leu Ala Asn Asn Glu Thr Ile Glu Asp
275 280 285
Ile Leu Asn Ala Leu Asp Glu Glu Glu Tyr Ala Lys Tyr Phe Tyr Tyr
290 295 300
Leu Glu Gly Ser Lys Asp Ala Leu Leu Cys Gly Phe Ser Thr Asp Ser
305 310 315 320
Gly Gln Cys Pro Glu Gly Tyr Thr Cys Lys Lys Ile Gly Arg Asn Pro
325 330 335
Asp Tyr Gly Tyr Thr Ser Phe Asp Thr Phe Ser Trp Ala Phe Leu Ala
340 345 350
Leu Phe Arg Leu Met Thr Gln Asp Tyr Trp Glu Asn Leu Tyr Gln Gln
355 360 365
Thr Leu Arg Ala Ala Gly Lys Thr Tyr Met Ile Phe Phe Val Val Val
370 375 380
Ile Phe Leu Gly Ser Phe Tyr Leu Ile Asn Leu Ile Leu Ala Val Val
385 390 395 400
Ala Met Ala Tyr Glu Glu Gln Asn Gln Ala Asn Ile Glu Glu Ala Arg
405 410 415
Gln Lys Glu Leu Glu Phe Gln Gln Met Leu Asp Arg Leu Lys Lys Glu
420 425 430
Gln Glu Glu Ala Glu Ala Ile Ala Leu Ala Ala Ala Glu Tyr Thr Ser
435 440 445
Ile Gly Arg Ser Arg Ile Met Gly Leu Ser Glu Ser Ser Ser Glu Thr
450 455 460
Ser Lys Leu Ser Ser Lys Ser Ala Lys Glu Arg Arg Asn Arg Arg Arg
465 470 475 480
Lys Lys Asn Gln Lys Lys Leu Ser Ser Gly Glu Glu Lys Gly Asp Asp
485 490 495
Glu Lys Leu Ser Lys Ser Glu Ser Glu Glu Ser Ile Arg Arg Lys Ser
500 505 510
Phe His Leu Gly Val Glu Gly His Arg Arg Ala Arg Glu Lys Arg Leu
515 520 525
Ser Thr Pro Asn Gln Ser Pro Leu Ser Ile Arg Gly Ser Leu Phe Ser
530 535 540
Ala Arg Arg Ser Ser Arg Thr Ser Leu Phe Ser Phe Lys Gly Arg Gly
545 550 555 560
Arg Asp Ile Gly Ser Glu Thr Glu Phe Ala Asp Asp Glu His Ser Ile
565 570 575
Phe Gly Asp Asn Glu Ser Arg Arg Gly Ser Leu Phe Val Pro His Arg
580 585 590
Pro Arg Glu Arg Arg Ser Ser Asn Ile Ser Gln Ala Ser Arg Ser Pro
595 600 605
Pro Val Leu Pro Val Asn Gly Lys Met His Ser Ala Val Asp Cys Asn
610 615 620
Gly Val Val Ser Leu Val Asp Gly Pro Ser Ala Leu Met Leu Pro Asn
625 630 635 640
Gly Gln Leu Leu Pro Glu Val Ile Ile Asp Lys Ala Thr Ser Asp Asp
645 650 655
Ser Gly Thr Thr Asn Gln Ile Tyr Lys Lys Arg Arg His Ser Ser Tyr
660 665 670
Leu Leu Ser Glu Asp Met Leu Asn Asp Pro Asn Leu Arg Gln Arg Ala
675 680 685
Met Ser Arg Ala Ser Ile Leu Thr Asn Thr Val Glu Glu Leu Glu Glu
690 695 700
Ser Arg Gln Lys Cys Pro Pro Trp Trp Tyr Arg Phe Ala His Thr Phe
705 710 715 720
Leu Ile Trp Asn Cys Ser Pro Tyr Trp Ile Lys Phe Lys Lys Phe Ile
725 730 735
Tyr Phe Ile Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile Cys
740 745 750
Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His His Pro Met Thr
755 760 765
Glu Glu Phe Lys Asn Val Leu Val Val Gly Asn Leu Val Phe Thr Gly
770 775 780
Ile Phe Ala Ala Glu Met Val Leu Lys Leu Ile Ala Met Asp Pro Tyr
785 790 795 800
Glu Tyr Phe Gln Ile Gly Trp Asn Ile Phe Asp Ser Leu Ile Val Thr
805 810 815
Leu Ser Leu Val Glu Leu Phe Leu Ser Asp Val Glu Gly Leu Ser Val
820 825 830
Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser Trp
835 840 845
Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly Ala
850 855 860
Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe Ala
865 870 875 880
Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val Cys
885 890 895
Lys Ile Asn Glu Asp Cys Lys Leu Pro Arg Trp His Met Asn Asp Phe
900 905 910
Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp Ile
915 920 925
Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Ala Met Cys Leu
930 935 940
Ile Val Tyr Met Met Val Met Val Ile Gly Asn Leu Val Val Leu Asn
945 950 955 960
Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu Thr
965 970 975
Ala Ile Glu Glu Asp Thr Asp Ala Asn Asn Leu Gln Ile Ala Val Ala
980 985 990
Arg Ile Lys Thr Gly Ile Asn Tyr Val Lys Gln Thr Leu Arg Glu Phe
995 1000 1005
Val Leu Lys Ala Phe Ser Lys Lys Pro Lys Ile Ser Lys Glu Ile
1010 1015 1020
Arg Gln Thr Glu Asp Leu Asn Cys Lys Lys Glu Asn Tyr Ile Ser
1025 1030 1035
Asn Arg Thr Leu Ala Glu Met Ser Lys Asp His Asn Phe His Lys
1040 1045 1050
Glu Lys Asp Lys Thr Ser Gly Phe Gly Asn Asn Met Asp Lys Tyr
1055 1060 1065
Leu Met Glu Glu Ser Asp Gly Gln Ser Phe Ile His Asn Pro Ser
1070 1075 1080
Leu Thr Val Thr Val Pro Ile Ala Pro Gly Glu Ser Asp Leu Glu
1085 1090 1095
Ile Met Asn Thr Glu Glu Leu Ser Ser Asp Ser Asp Ser Glu Tyr
1100 1105 1110
Ser Lys Gly Arg Leu Asn Gln Ser Ser Ser Ser Glu Cys Ser Thr
1115 1120 1125
Val Asp Asn Pro Val Pro Gly Glu Gly Glu Glu Ala Glu Ala Glu
1130 1135 1140
Pro Val Asn Ser Asp Glu Pro Glu Ala Cys Phe Thr Asp Gly Cys
1145 1150 1155
Val Gln Arg Phe Pro Cys Cys Gln Val Asn Ile Glu Ser Gly Lys
1160 1165 1170
Gly Lys Ile Trp Trp Asn Ile Arg Lys Thr Cys Phe Arg Ile Val
1175 1180 1185
Glu His Ser Trp Phe Glu Ser Phe Ile Val Leu Met Ile Leu Leu
1190 1195 1200
Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile Glu Lys Lys
1205 1210 1215
Lys Thr Ile Lys Ile Ile Leu Glu Tyr Ala Asp Lys Ile Phe Thr
1220 1225 1230
Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Val Ala Tyr Gly
1235 1240 1245
Tyr Lys Thr Tyr Phe Thr Asn Ala Trp Cys Trp Leu Asp Phe Leu
1250 1255 1260
Ile Val Asp Val Ser Leu Val Thr Leu Val Ala Asn Thr Leu Gly
1265 1270 1275
Tyr Ser Asp Leu Gly Pro Ile Lys Ser Leu Arg Thr Leu Arg Ala
1280 1285 1290
Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly Met Arg Val
1295 1300 1305
Val Val Asn Ala Leu Ile Gly Ala Ile Pro Ser Ile Met Asn Val
1310 1315 1320
Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile Met Gly
1325 1330 1335
Val Asn Leu Phe Ala Gly Lys Phe Tyr Glu Cys Ile Asn Thr Thr
1340 1345 1350
Asn Gly Leu Arg Phe Pro Thr Asn Glu Val Glu Asn Arg Ser Ala
1355 1360 1365
Cys Leu Ala Leu Met Asn Val Ser Gln Asn Val Arg Trp Lys Asn
1370 1375 1380
Leu Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr Leu Ser Leu
1385 1390 1395
Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile Met Tyr Ala
1400 1405 1410
Ala Val Asp Ser Val Asn Val Asp Lys Gln Pro Ile Tyr Glu Tyr
1415 1420 1425
Ser Leu Tyr Met Tyr Ile Tyr Phe Val Ile Phe Ile Ile Phe Gly
1430 1435 1440
Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile Ile Asp Asn
1445 1450 1455
Phe Asn Gln Gln Lys Lys Lys Leu Gly Gly Gln Asp Ile Phe Met
1460 1465 1470
Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys Leu Gly
1475 1480 1485
Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Gly Asn Lys Phe
1490 1495 1500
Gln Gly Cys Ile Phe Asp Leu Val Thr Asn Gln Ala Phe Asp Ile
1505 1510 1515
Ala Ile Met Val Leu Ile Cys Leu Asn Met Val Thr Met Met Val
1520 1525 1530
Glu Lys Glu Gly Gln Ser Glu Tyr Met Thr Glu Val Leu Tyr Trp
1535 1540 1545
Ile Asn Val Val Phe Ile Ile Leu Phe Ser Gly Glu Cys Val Leu
1550 1555 1560
Lys Leu Ile Ser Leu Arg Cys Tyr Tyr Phe Thr Val Gly Trp Asn
1565 1570 1575
Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile Val Gly Met Phe
1580 1585 1590
Leu Ala Asp Leu Ile Glu Arg Tyr Phe Val Ser Pro Thr Leu Phe
1595 1600 1605
Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg Leu Ile
1610 1615 1620
Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu Met Met
1625 1630 1635
Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu Phe Leu Val
1640 1645 1650
Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe Ala Tyr Val
1655 1660 1665
Lys Lys Glu Ala Gly Ile Asn Asp Met Phe Asn Phe Glu Thr Phe
1670 1675 1680
Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr Ser Ala Gly
1685 1690 1695
Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Ala Pro Pro Asp
1700 1705 1710
Cys Asp Pro Lys Lys Val His Pro Gly Ser Ser Val Glu Gly Asp
1715 1720 1725
Cys Gly Asn Pro Ser Val Gly Ile Phe Tyr Phe Val Ser Tyr Ile
1730 1735 1740
Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile Ala Val Ile
1745 1750 1755
Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Thr Glu Pro Leu
1760 1765 1770
Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp Glu Lys Phe
1775 1780 1785
Asp Pro Asp Ala Thr Gln Phe Ile Glu Tyr Ser Lys Leu Ser Asp
1790 1795 1800
Phe Ala Ala Ala Leu Asp Pro Pro Leu Leu Ile Ala Lys Pro Asn
1805 1810 1815
Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val Ser Gly Asp
1820 1825 1830
Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr Lys Arg Val
1835 1840 1845
Leu Gly Glu Gly Gly Glu Met Asp Ser Leu Arg Ser Gln Met Glu
1850 1855 1860
Glu Arg Phe Met Ser Ala Asn Pro Ser Lys Val Ser Tyr Glu Pro
1865 1870 1875
Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Asp Val Ser Ala Thr
1880 1885 1890
Val Ile Gln Arg Ala Tyr Arg Arg Tyr Arg Leu Arg Gln His Val
1895 1900 1905
Lys Asn Ile Ser Ser Ile Tyr Ile Lys Asp Gly Asp Arg Asp Asp
1910 1915 1920
Asp Leu Pro Asn Lys Glu His Met Val Phe Asp Asn Val Asn Glu
1925 1930 1935
Asn Ser Ser Pro Glu Lys Thr Asp Ala Thr Pro Ser Thr Val Ser
1940 1945 1950
Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Asp Arg Glu Lys Tyr
1955 1960 1965
Glu Lys Asp Lys Thr Glu Lys Glu Asp Lys Gly Lys Asp Gly Lys
1970 1975 1980
Glu Gly Lys Lys
1985
<210> 35
<211> 1981
<212> PRT
<213> 单峰驼
<400> 35
Met Ala Met Leu Pro Pro Pro Gly Pro Gln Ser Phe Val Tyr Phe Thr
1 5 10 15
Lys Gln Ser Leu Ala Leu Ile Glu Gln Arg Ile Ala Glu Gly Lys Thr
20 25 30
Lys Glu Pro Lys Glu Glu Lys Lys Asp Asp Asp Glu Glu Gly Pro Lys
35 40 45
Pro Ser Ser Asp Leu Glu Ala Gly Lys Gln Leu Pro Phe Ile Tyr Gly
50 55 60
Asp Ile Pro Pro Gly Met Val Ser Glu Pro Leu Glu Asp Leu Asp Pro
65 70 75 80
Tyr Tyr Ala Asp Lys Lys Thr Phe Ile Val Leu Asn Lys Gly Lys Ala
85 90 95
Ile Phe Arg Phe Asn Ala Ala Pro Ala Leu Tyr Leu Leu Ser Pro Phe
100 105 110
Asn Pro Leu Arg Arg Ile Ser Ile Lys Ile Leu Val His Ser Leu Phe
115 120 125
Ser Met Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Ile Phe Met Thr
130 135 140
Leu Ser Ser Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr Thr Phe Thr
145 150 155 160
Gly Ile Tyr Thr Phe Glu Ser Leu Val Lys Ile Leu Ala Arg Gly Phe
165 170 175
Cys Val Gly Glu Phe Thr Phe Leu Arg Asp Pro Trp Asn Trp Leu Asp
180 185 190
Phe Val Val Ile Val Phe Ala Tyr Leu Thr Glu Phe Val Asn Leu Gly
195 200 205
Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala Leu Lys Thr
210 215 220
Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala Leu Ile Gln
225 230 235 240
Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val Phe Cys Leu
245 250 255
Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly Asn Leu Lys
260 265 270
His Lys Cys Val Trp Thr Pro Phe Glu Asn Asn Glu Thr Ile Glu Ser
275 280 285
Met Leu Asp Ser Leu Asp Glu Glu Asp Arg Ser Lys Tyr Phe Tyr Tyr
290 295 300
Leu Glu Gly Ser Lys Asp Ala Leu Leu Cys Gly Phe Ser Thr Asp Ser
305 310 315 320
Gly Gln Cys Pro Glu Gly Tyr Thr Cys Met Lys Ile Gly Arg Asn Pro
325 330 335
Asp Tyr Gly Tyr Thr Ser Phe Asp Thr Phe Ser Trp Ala Phe Leu Ala
340 345 350
Leu Phe Arg Leu Met Thr Gln Asp Tyr Trp Glu Asn Leu Tyr Gln Gln
355 360 365
Thr Leu Arg Ala Ala Gly Lys Thr Tyr Met Ile Phe Phe Val Val Val
370 375 380
Ile Phe Leu Gly Ser Phe Tyr Leu Ile Asn Leu Ile Leu Ala Val Val
385 390 395 400
Ala Met Ala Tyr Glu Glu Gln Asn Gln Ala Asn Ile Glu Glu Ala Arg
405 410 415
Gln Lys Glu Ile Glu Phe Gln Gln Met Leu Asp His Leu Lys Lys Glu
420 425 430
Gln Glu Glu Ala Glu Ala Ile Ala Met Ala Ala Ala Glu Tyr Thr Ser
435 440 445
Ile Gly Arg Ser Arg Ile Met Gly Leu Ser Glu Ser Ser Ser Glu Thr
450 455 460
Ser Arg Leu Ser Ser Lys Ser Ala Lys Glu Arg Arg Asn Arg Arg Lys
465 470 475 480
Lys Arg Asn Gln Lys Lys Leu Ser Ser Gly Glu Glu Lys Gly Asp Asp
485 490 495
Glu Lys Leu Ser Lys Ser Glu Ser Glu Glu Asn Ile Arg Arg Lys Ser
500 505 510
Phe Arg Leu Gly Val Glu Gly Pro Trp Arg Ala His Glu Lys Arg Leu
515 520 525
Ser Thr Pro Asn Gln Ser Pro Leu Ser Ile Arg Gly Ser Leu Phe Ser
530 535 540
Ala Arg Arg Ser Ser Arg Thr Ser Leu Phe Ser Phe Lys Gly Arg Gly
545 550 555 560
Lys Asp Ile Gly Ser Glu Thr Glu Phe Ala Asp Asp Glu His Ser Ile
565 570 575
Phe Gly Asp Ser Glu Ser Arg Arg Gly Ser Leu Phe Val Pro His Arg
580 585 590
Pro Arg Glu Arg Arg Ser Ser Ser Ile Ser Gln Ala Ser Arg Ser Pro
595 600 605
Pro Val Leu Pro Val Asn Gly Lys Met His Ser Ala Val Asp Cys Asn
610 615 620
Gly Val Val Ser Leu Val Asp Gly Pro Ala Ala Leu Met Leu Pro Asn
625 630 635 640
Gly Gln Leu Leu Pro Glu Val Ile Ile Asp Lys Ala Thr Ser Asp Asp
645 650 655
Ser Gly Thr Thr Asn Gln Ile His Lys Lys Arg Arg Pro Ser Ser Tyr
660 665 670
Leu Leu Ser Glu Asp Met Leu Asn Asp Pro Asn Leu Arg Lys Arg Ala
675 680 685
Met Ser Arg Ala Ser Ile Leu Thr Asn Thr Val Glu Glu Leu Glu Glu
690 695 700
Ser Arg Gln Lys Cys Pro Pro Trp Trp Tyr Arg Phe Ala His Thr Phe
705 710 715 720
Leu Ile Trp Asn Cys Ser Pro Tyr Trp Ile Lys Phe Lys Lys Val Ile
725 730 735
Tyr Phe Ile Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile Cys
740 745 750
Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His His Pro Met Thr
755 760 765
Asp Glu Phe Lys Asn Val Leu Thr Val Gly Asn Leu Val Phe Thr Gly
770 775 780
Ile Phe Ala Ala Glu Met Val Leu Lys Leu Ile Ala Met Asp Pro Tyr
785 790 795 800
Glu Tyr Phe Gln Val Gly Trp Asn Ile Phe Asp Ser Leu Ile Val Thr
805 810 815
Leu Ser Leu Val Glu Leu Phe Leu Ala Asp Val Glu Gly Leu Ser Val
820 825 830
Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser Trp
835 840 845
Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly Ala
850 855 860
Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe Ala
865 870 875 880
Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Arg Glu Cys Val Cys
885 890 895
Lys Ile Ser Glu Glu Cys Thr Leu Pro Arg Trp His Met Asn Asp Ser
900 905 910
Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp Ile Glu Thr Met
915 920 925
Trp Asp Cys Met Glu Val Ala Gly Gln Ala Met Cys Leu Ile Val Tyr
930 935 940
Met Met Val Met Val Ile Gly Asn Leu Val Val Leu Asn Leu Phe Leu
945 950 955 960
Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu Thr Ala Ile Glu
965 970 975
Glu Asp Thr Asp Ala Asn Asn Leu Gln Ile Ala Val Ala Arg Ile Lys
980 985 990
Lys Gly Ile Asn Tyr Val Lys Gln Thr Leu His Glu Phe Ile Leu Lys
995 1000 1005
Ala Phe Ser Lys Lys Pro Lys Val Ser Lys Glu Ile Arg Arg Ala
1010 1015 1020
Asp Leu Asn Cys Lys Lys Glu Asn Phe Ile Ser Asn Arg Thr Leu
1025 1030 1035
Ala Glu Met Ser Lys Asp His His Phe His Lys Glu Lys Asp Lys
1040 1045 1050
Thr Ser Gly Phe Gly Asn Ser Val Asp Lys Tyr Leu Met Glu Glu
1055 1060 1065
Ser Asp Gly Gln Ser Phe Ile His Asn Pro Ser Leu Thr Val Thr
1070 1075 1080
Val Pro Ile Ala Pro Gly Glu Ser Asp Leu Glu Ile Met Asn Thr
1085 1090 1095
Glu Glu Leu Ser Ser Asp Ser Asp Ser Glu Tyr Ser Lys Gly Arg
1100 1105 1110
Leu Asn Arg Ser Ser Ser Ser Glu Cys Ser Thr Val Asp Asn Ala
1115 1120 1125
Leu Pro Glu Lys Glu Ala Glu Ala Glu Pro Val Asn Pro Asp Glu
1130 1135 1140
Pro Ala Ala Cys Phe Thr Asp Gly Cys Val Arg Arg Phe Pro Cys
1145 1150 1155
Cys Gln Val Asn Ile Glu Ser Gly Lys Gly Arg Ile Trp Trp Asn
1160 1165 1170
Ile Arg Lys Thr Cys Tyr Arg Ile Val Glu His Ser Trp Phe Glu
1175 1180 1185
Ser Phe Ile Val Leu Met Ile Leu Leu Ser Ser Gly Ala Leu Ala
1190 1195 1200
Phe Glu Asp Ile Tyr Ile Glu Lys Lys Arg Thr Ile Lys Thr Ile
1205 1210 1215
Leu Glu Tyr Ala Asp Lys Ile Phe Thr Tyr Ile Phe Ile Leu Glu
1220 1225 1230
Met Leu Leu Lys Trp Val Ala Tyr Gly Tyr Lys Ile Tyr Phe Thr
1235 1240 1245
Asn Ala Trp Cys Trp Leu Asp Phe Leu Ile Val Asp Val Ser Leu
1250 1255 1260
Val Thr Leu Val Ala Ala Ala Phe Gly Tyr Ser Asp Leu Gly Pro
1265 1270 1275
Ile Arg Ser Leu Arg Thr Leu Arg Ala Leu Arg Pro Leu Arg Ala
1280 1285 1290
Leu Ser Arg Phe Glu Gly Met Arg Val Val Val Asn Ala Leu Ile
1295 1300 1305
Gly Ala Ile Pro Ser Ile Met Asn Val Leu Leu Val Cys Leu Ile
1310 1315 1320
Phe Trp Leu Ile Phe Ser Ile Met Gly Val Asn Leu Phe Ala Gly
1325 1330 1335
Lys Phe Tyr Glu Cys Ile Asn Thr Thr Asp Gly Ser Arg Phe His
1340 1345 1350
Thr Asn Arg Val Glu Asn Arg Ser Glu Cys Phe Ala Leu Met Asn
1355 1360 1365
Val Ser Gln Asn Val Arg Trp Lys Asn Leu Lys Val Asn Phe Asp
1370 1375 1380
Asn Val Gly Leu Gly Tyr Leu Ser Leu Leu Gln Val Ala Thr Phe
1385 1390 1395
Lys Gly Trp Met Asp Ile Met Tyr Ala Ala Val Asp Ser Val Asn
1400 1405 1410
Val Asp Lys Gln Pro Ile Tyr Glu Tyr Asn Leu Tyr Met Tyr Ile
1415 1420 1425
Tyr Phe Val Ile Phe Ile Ile Phe Gly Ser Phe Phe Thr Leu Asn
1430 1435 1440
Leu Phe Ile Gly Val Ile Ile Asp Asn Phe Asn Gln Gln Lys Lys
1445 1450 1455
Lys Leu Gly Gly Gln Asp Ile Phe Met Thr Glu Glu Gln Lys Lys
1460 1465 1470
Tyr Tyr Asn Ala Met Lys Lys Leu Gly Ser Lys Lys Pro Gln Lys
1475 1480 1485
Pro Ile Pro Arg Pro Gly Asn Lys Phe Gln Gly Cys Ile Phe Asp
1490 1495 1500
Leu Val Thr Asn Gln Ala Phe Asp Ile Thr Ile Met Val Leu Ile
1505 1510 1515
Cys Leu Asn Met Val Thr Met Met Val Glu Lys Glu Gly Gln Ser
1520 1525 1530
Glu Tyr Met Thr Glu Val Leu Tyr Trp Ile Asn Val Val Phe Ile
1535 1540 1545
Ile Leu Phe Thr Gly Glu Phe Val Leu Lys Leu Ile Ser Leu Arg
1550 1555 1560
Cys Tyr Tyr Phe Thr Val Gly Trp Asn Ile Phe Asp Phe Val Val
1565 1570 1575
Val Ile Leu Ser Ile Val Gly Met Phe Leu Ala Asp Leu Ile Glu
1580 1585 1590
Lys Tyr Phe Val Ser Pro Thr Leu Phe Arg Val Ile Arg Leu Ala
1595 1600 1605
Arg Ile Gly Arg Ile Leu Arg Leu Ile Lys Gly Ala Lys Gly Ile
1610 1615 1620
Arg Thr Leu Leu Phe Ala Leu Met Met Ser Leu Pro Ala Leu Phe
1625 1630 1635
Asn Ile Gly Leu Leu Leu Phe Leu Val Met Phe Ile Tyr Ala Ile
1640 1645 1650
Phe Gly Met Ser Asn Phe Ala Tyr Val Lys Lys Glu Ala Gly Ile
1655 1660 1665
Asn Asp Met Phe Asn Phe Glu Thr Phe Gly Asn Ser Met Ile Cys
1670 1675 1680
Leu Phe Gln Ile Thr Thr Ser Ala Gly Trp Asp Gly Leu Leu Ala
1685 1690 1695
Pro Ile Leu Asn Ser Gly Pro Pro Asp Cys Asp Pro Lys Lys Val
1700 1705 1710
His Pro Gly Ser Ser Val Glu Gly Asp Cys Gly Asn Pro Ser Val
1715 1720 1725
Gly Ile Phe Tyr Phe Val Ser Tyr Ile Ile Ile Ser Phe Leu Val
1730 1735 1740
Val Val Asn Met Tyr Ile Ala Val Ile Leu Glu Asn Phe Ser Val
1745 1750 1755
Ala Thr Glu Glu Ser Thr Glu Pro Leu Ser Glu Asp Asp Phe Glu
1760 1765 1770
Met Phe Tyr Glu Val Trp Glu Lys Phe Asp Pro Asp Ala Thr Gln
1775 1780 1785
Phe Ile Glu Tyr Ser Lys Leu Ser Asp Phe Ala Ala Ala Leu Asp
1790 1795 1800
Pro Pro Leu Leu Ile Ala Lys Pro Asn Lys Val Gln Leu Ile Ala
1805 1810 1815
Met Asp Leu Pro Met Val Ser Gly Asp Arg Ile His Cys Leu Asp
1820 1825 1830
Ile Leu Phe Ala Phe Thr Lys Arg Val Leu Gly Glu Ser Gly Glu
1835 1840 1845
Met Asp Ser Leu Arg Leu Gln Met Glu Glu Arg Phe Met Ser Ala
1850 1855 1860
Asn Pro Ser Lys Val Ser Tyr Glu Pro Ile Thr Thr Thr Leu Lys
1865 1870 1875
Arg Lys Gln Glu Asp Val Ser Ala Thr Val Ile Gln Arg Ala Tyr
1880 1885 1890
Arg Arg Tyr Arg Leu Arg Gln Asn Val Lys Asn Ile Ser Ser Ile
1895 1900 1905
Tyr Ile Lys Asp Gly Gly Lys Asp Asp Asp Leu Pro Lys Lys Glu
1910 1915 1920
Asp Thr Val Phe Asp Asn Val Asn Gly Asn Ser Ser Pro Glu Lys
1925 1930 1935
Thr Asp Ala Thr Ser Ser Thr Thr Ser Pro Pro Ser Tyr Asp Ser
1940 1945 1950
Val Thr Lys Pro Asp Lys Glu Lys Tyr Glu Lys Asp Lys Thr Glu
1955 1960 1965
Lys Glu Asp Lys Gly Lys Asp Gly Lys Glu Ser Lys Lys
1970 1975 1980
<210> 36
<211> 1987
<212> PRT
<213> 虎鲸
<400> 36
Met Ala Met Leu Pro Pro Pro Gly Pro Gln Ser Phe Val Tyr Phe Thr
1 5 10 15
Lys Gln Ser Leu Ala Leu Ile Glu Gln Arg Ile Ala Glu Gly Lys Thr
20 25 30
Lys Glu Pro Lys Glu Glu Lys Lys Asp Asp Asp Glu Glu Gly Pro Lys
35 40 45
Pro Ser Ser Asp Leu Glu Ala Gly Lys Gln Leu Pro Phe Ile Tyr Gly
50 55 60
Asp Ile Pro Gln Gly Met Val Ser Glu Pro Leu Glu Asp Leu Asp Pro
65 70 75 80
Tyr Tyr Ala Asp Lys Lys Thr Phe Ile Val Leu Asn Lys Gly Lys Ala
85 90 95
Ile Phe Arg Phe Asn Ala Thr Pro Ala Leu Tyr Ile Leu Ser Pro Phe
100 105 110
Ser Pro Leu Arg Arg Ile Ser Ile Lys Ile Leu Val His Ser Ala Phe
115 120 125
Ser Met Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Ile Phe Met Thr
130 135 140
Met Ser Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr Thr Phe Thr
145 150 155 160
Gly Ile Tyr Thr Phe Glu Ser Leu Val Lys Ile Leu Ala Arg Gly Phe
165 170 175
Cys Val Gly Glu Phe Thr Phe Leu Arg Asp Pro Trp Asn Trp Leu Asp
180 185 190
Phe Ile Val Ile Val Phe Ala Tyr Leu Thr Glu Phe Val Asn Leu Gly
195 200 205
Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala Leu Lys Thr
210 215 220
Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala Leu Ile Gln
225 230 235 240
Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val Phe Cys Leu
245 250 255
Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly Asn Leu Lys
260 265 270
Gln Lys Cys Val Arg Thr Leu Leu Glu Asn Asn Glu Thr Ile Glu Ser
275 280 285
Ile Leu Asn Thr Leu Asp Glu Glu Asp Tyr Gly Lys Tyr Phe Tyr Tyr
290 295 300
Leu Glu Gly Ser Lys Asp Ala Leu Leu Cys Gly Phe Ser Thr Asp Ser
305 310 315 320
Gly Gln Cys Pro Glu Gly Tyr Thr Cys Val Lys Val Gly Lys Asn Pro
325 330 335
Asp Tyr Gly Tyr Thr Ser Phe Asp Thr Phe Ser Trp Ala Phe Leu Ala
340 345 350
Leu Phe Arg Leu Met Thr Gln Asp Tyr Trp Glu Asn Leu Tyr Gln Gln
355 360 365
Thr Leu Arg Ala Ala Gly Lys Thr Tyr Met Ile Phe Phe Val Val Val
370 375 380
Ile Phe Leu Gly Ser Phe Tyr Leu Ile Asn Leu Ile Leu Ala Val Val
385 390 395 400
Ala Met Ala Tyr Glu Glu Gln Asn Gln Ala Asn Ile Glu Glu Ala Arg
405 410 415
Gln Lys Glu Leu Glu Phe Gln Gln Met Leu Asp Arg Leu Lys Lys Glu
420 425 430
Gln Glu Glu Ala Glu Ala Ile Ala Met Ala Ala Ala Glu Tyr Thr Ser
435 440 445
Ile Glu Arg Ser Arg Ile Met Gly Leu Ser Glu Ser Ser Ser Glu Thr
450 455 460
Ser Lys Met Ser Ser Lys Ser Ala Lys Glu Arg Arg Asn Arg Arg Lys
465 470 475 480
Lys Asn Asn Gln Lys Lys Leu Ser Ile Gly Glu Glu Lys Gly Asp Asp
485 490 495
Glu Lys Leu Ser Lys Ser Glu Ser Glu Glu Ser Ile Arg Arg Lys Ser
500 505 510
Phe His Leu Gly Val Glu Gly His Arg Arg Ala Arg Glu Lys Arg Phe
515 520 525
Ser Thr Pro Asn Gln Ser Pro Leu Ser Ile His Gly Ser Leu Phe Ser
530 535 540
Ala Arg Arg Ser Ser Arg Thr Ser Leu Phe Ser Phe Lys Gly Arg Gly
545 550 555 560
Lys Asp Ile Gly Ser Glu Thr Glu Phe Ala Asp Asp Glu His Ser Ile
565 570 575
Phe Gly Asp Asn Glu Ser Arg Arg Gly Ser Leu Phe Val Pro His Arg
580 585 590
Pro Arg Glu Arg Arg Ser Ser Asn Ile Ser Gln Ala Ser Arg Ser Pro
595 600 605
Pro Gly Leu Pro Val Asn Arg Lys Met His Ser Ala Val Asp Cys Asn
610 615 620
Gly Val Val Ser Leu Val Asp Gly Pro Ser Ala Leu Met Leu Pro Asn
625 630 635 640
Gly Gln Leu Leu Pro Glu Val Ile Ile Asp Lys Ala Thr Ser Asp Asp
645 650 655
Ser Gly Thr Asn Asn Gln Ile His Lys Lys Arg Arg Ser Ser Ser Tyr
660 665 670
Leu Leu Ser Glu Asp Met Leu Asn Asp Pro Asn Leu Arg Gln Arg Ala
675 680 685
Met Ser Arg Ala Ser Ile Leu Thr Asn Thr Val Glu Glu Leu Glu Glu
690 695 700
Ser Arg Gln Lys Cys Pro Pro Trp Trp Tyr Arg Phe Ala His Thr Phe
705 710 715 720
Leu Ile Trp Asn Cys Ser Pro Tyr Trp Ile Lys Phe Lys Arg Leu Ile
725 730 735
Tyr Phe Ile Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile Cys
740 745 750
Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His His Pro Met Thr
755 760 765
Asp Glu Phe Lys Asn Val Leu Thr Val Gly Asn Leu Val Phe Thr Gly
770 775 780
Ile Phe Ala Ala Glu Met Val Leu Lys Leu Ile Ala Met Asp Pro Tyr
785 790 795 800
Glu Tyr Phe Gln Val Gly Trp Asn Ile Phe Asp Ser Leu Ile Val Thr
805 810 815
Leu Ser Leu Val Glu Leu Phe Leu Ala Asp Val Glu Gly Leu Ser Val
820 825 830
Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser Trp
835 840 845
Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly Ala
850 855 860
Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe Ala
865 870 875 880
Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val Cys
885 890 895
Lys Ile Asn Glu Asp Cys Thr Leu Pro Arg Trp His Met Asn Asp Phe
900 905 910
Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp Ile
915 920 925
Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Ala Met Cys Leu
930 935 940
Ile Val Tyr Met Met Val Met Val Ile Gly Asn Leu Val Val Leu Asn
945 950 955 960
Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu Thr
965 970 975
Ala Ile Glu Glu Asp Thr Asp Ala Asn Asn Leu Gln Thr Ala Val Ala
980 985 990
Arg Ile Lys Lys Gly Ile Asn Tyr Val Lys Gln Thr Leu Arg Glu Phe
995 1000 1005
Phe Leu Lys Gly Phe Ser Thr Lys Pro Lys Ile Ser Lys Glu Ile
1010 1015 1020
Arg Arg Thr Glu Asp Leu Asn Tyr Lys Lys Glu Asn Tyr Ile Ser
1025 1030 1035
Asn His Thr Leu Ala Glu Met Ser Lys Asp His Asn Phe His Lys
1040 1045 1050
Glu Lys Asp Lys Thr Ser Gly Phe Gly Asn Ser Met Asp Lys Tyr
1055 1060 1065
Leu Val Glu Glu Ser Asp Gly Gln Ser Phe Ile His Asn Ala Ser
1070 1075 1080
Leu Thr Val Thr Val Pro Ile Ala Pro Gly Glu Ser Asp Leu Glu
1085 1090 1095
Ile Met Asn Thr Glu Glu Leu Ser Ser Asp Ser Asp Ser Glu Tyr
1100 1105 1110
Ser Lys Gly Arg Leu Asn Gly Ser Ser Ser Ser Glu Cys Ser Thr
1115 1120 1125
Val Asp Asn Pro Val Pro Gly Glu Gly Glu Glu Ala Glu Ala Glu
1130 1135 1140
Pro Val Asn Ser Asp Glu Pro Glu Ala Cys Phe Thr Asp Gly Cys
1145 1150 1155
Val Gln Arg Leu Pro Cys Cys Gln Val Asn Thr Glu Ser Gly Lys
1160 1165 1170
Gly Lys Ile Trp Trp Asn Ile Arg Lys Thr Cys Tyr Arg Ile Val
1175 1180 1185
Glu His Ser Trp Phe Glu Ser Phe Ile Val Leu Met Ile Leu Leu
1190 1195 1200
Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile Glu Lys Lys
1205 1210 1215
Lys Thr Ile Lys Ile Ile Leu Glu Tyr Ala Asp Lys Ile Phe Thr
1220 1225 1230
Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Ile Ala Tyr Gly
1235 1240 1245
Tyr Lys Thr Tyr Phe Thr Asn Ala Trp Cys Trp Leu Asp Phe Leu
1250 1255 1260
Ile Val Asp Val Ser Leu Val Thr Leu Val Ala Asn Thr Leu Gly
1265 1270 1275
Tyr Ser Asp Leu Gly Pro Ile Lys Ser Leu Arg Thr Leu Arg Ala
1280 1285 1290
Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly Met Arg Val
1295 1300 1305
Val Val Asn Ala Leu Ile Gly Ala Ile Pro Ser Ile Met Asn Val
1310 1315 1320
Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile Met Gly
1325 1330 1335
Val Asn Leu Phe Ala Gly Lys Phe Tyr Gln Cys Val Asn Thr Thr
1340 1345 1350
Asp Gly Ser Pro Phe Pro Thr Ser Glu Val Glu Asn Arg Ser Glu
1355 1360 1365
Cys Phe Ala Leu Met Asn Val Ser Gln Asn Val Gln Trp Lys Asn
1370 1375 1380
Leu Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr Leu Ser Leu
1385 1390 1395
Leu Gln Val Ala Thr Phe Lys Gly Trp Met Val Ile Met Tyr Ala
1400 1405 1410
Ala Val Asp Ser Val Asn Val Asp Arg Gln Pro Ile Tyr Glu Tyr
1415 1420 1425
Ser Leu Tyr Met Tyr Ile Tyr Phe Val Ile Phe Ile Ile Phe Gly
1430 1435 1440
Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile Ile Asp Asn
1445 1450 1455
Phe Asn Gln Gln Lys Lys Lys Leu Gly Gly Gln Asp Ile Phe Met
1460 1465 1470
Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys Leu Gly
1475 1480 1485
Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Gly Asn Lys Phe
1490 1495 1500
Gln Gly Cys Ile Phe Asp Leu Val Thr Asn Gln Ala Phe Asp Ile
1505 1510 1515
Ala Ile Met Val Leu Ile Cys Leu Asn Met Val Thr Met Met Val
1520 1525 1530
Glu Lys Glu Gly Gln Ser Ala Tyr Met Thr Glu Val Leu Tyr Trp
1535 1540 1545
Ile Asn Val Val Phe Val Ile Leu Phe Thr Gly Glu Cys Val Leu
1550 1555 1560
Lys Leu Ile Ser Leu Arg Cys Tyr Tyr Phe Thr Val Gly Trp Asn
1565 1570 1575
Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile Val Gly Met Phe
1580 1585 1590
Leu Ala Asp Leu Ile Glu Arg Tyr Phe Val Ser Pro Thr Leu Phe
1595 1600 1605
Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg Leu Ile
1610 1615 1620
Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu Met Met
1625 1630 1635
Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu Phe Leu Val
1640 1645 1650
Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe Ala Tyr Val
1655 1660 1665
Lys Lys Glu Ala Gly Ile Asn Asp Met Phe Asn Phe Glu Thr Phe
1670 1675 1680
Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr Ser Ala Gly
1685 1690 1695
Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Ala Pro Pro Asp
1700 1705 1710
Cys Asp Pro Arg Lys Val His Pro Gly Ser Ser Val Glu Gly Asp
1715 1720 1725
Cys Gly Asn Pro Ser Val Gly Ile Phe Tyr Phe Val Ser Tyr Ile
1730 1735 1740
Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile Ala Val Ile
1745 1750 1755
Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Thr Glu Pro Leu
1760 1765 1770
Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp Glu Lys Phe
1775 1780 1785
Asp Pro Asp Ala Thr Gln Phe Ile Glu Tyr Ser Lys Leu Ser Asp
1790 1795 1800
Phe Ala Ala Ala Leu Asp Pro Pro Leu Leu Val Ala Lys Pro Asn
1805 1810 1815
Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val Ser Gly Asp
1820 1825 1830
Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr Lys Arg Val
1835 1840 1845
Leu Gly Glu Ser Gly Glu Met Asp Ser Leu Arg Ser Gln Met Glu
1850 1855 1860
Glu Arg Phe Met Ser Ala Asn Pro Ser Lys Val Ser Tyr Glu Pro
1865 1870 1875
Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Asp Val Ser Ala Thr
1880 1885 1890
Val Ile Gln Arg Ala Tyr Arg Arg Tyr Arg Leu Arg Gln Asn Val
1895 1900 1905
Lys Asn Ile Ser Ser Ile Tyr Ile Lys Asp Gly Asp Arg Asp Asp
1910 1915 1920
Asp Leu Pro Asn Lys Glu Asp Met Val Phe Asp Asn Val Asn Glu
1925 1930 1935
Asn Ser Ser Pro Glu Lys Thr Asp Gly Thr Pro Ser Thr Ile Ser
1940 1945 1950
Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Asp Lys Glu Lys Tyr
1955 1960 1965
Glu Lys Asp Lys Thr Glu Lys Glu Asp Lys Gly Lys Asp Gly Lys
1970 1975 1980
Glu Gly Lys Lys
1985
<210> 37
<211> 1975
<212> PRT
<213> 家马
<400> 37
Met Ala Met Leu Pro Pro Pro Gly Pro Gln Ser Phe Val Tyr Phe Thr
1 5 10 15
Lys Gln Ser Leu Ala Arg Ile Glu Gln Arg Ile Ala Glu Gly Lys Thr
20 25 30
Lys Glu Pro Lys Glu Glu Lys Lys Asp Asp Asp Glu Glu Gly Pro Lys
35 40 45
Pro Ser Ser Asp Leu Glu Ala Gly Lys Gln Leu Pro Phe Ile Tyr Arg
50 55 60
Asp Ile Pro Pro Gly Met Val Ser Glu Pro Leu Glu Asp Leu Asp Pro
65 70 75 80
Tyr Tyr Ala Asp Lys Lys Thr Phe Ile Val Leu Asn Lys Gly Lys Ala
85 90 95
Ile Phe Arg Phe Asn Ala Thr Pro Ala Leu Tyr Ile Leu Ser Pro Phe
100 105 110
Ser Pro Leu Arg Arg Ile Ser Ile Lys Ile Leu Val His Ser Leu Phe
115 120 125
Ser Met Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Ile Phe Met Thr
130 135 140
Met Ser Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr Thr Phe Thr
145 150 155 160
Gly Ile Tyr Thr Phe Glu Ser Leu Val Lys Ile Leu Ala Arg Gly Phe
165 170 175
Cys Ile Gly Glu Phe Thr Phe Leu Arg Asp Pro Trp Asn Trp Leu Asp
180 185 190
Phe Val Val Ile Val Phe Ala Tyr Leu Thr Glu Phe Val Asn Leu Gly
195 200 205
Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala Leu Lys Thr
210 215 220
Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala Leu Ile Gln
225 230 235 240
Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val Phe Cys Leu
245 250 255
Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly Asn Leu Lys
260 265 270
His Lys Cys Leu Arg Asn Pro Leu Glu Asn Asn Glu Thr Leu Glu Ser
275 280 285
Ile Met Asp Thr Leu Glu Glu Glu Asp Phe Arg Lys Tyr Phe Tyr Tyr
290 295 300
Leu Glu Gly Ser Lys Asp Ala Leu Leu Cys Gly Phe Ser Thr Asp Ser
305 310 315 320
Gly Gln Cys Pro Glu Gly Tyr Ile Cys Val Lys Ala Gly Arg Asn Pro
325 330 335
Asp Tyr Gly Tyr Thr Ser Phe Asp Thr Phe Ser Trp Ala Phe Leu Ala
340 345 350
Leu Phe Arg Leu Met Thr Gln Asp Tyr Trp Glu Asn Leu Tyr Gln Gln
355 360 365
Thr Leu Arg Ala Ala Gly Lys Thr Tyr Met Ile Phe Phe Val Val Val
370 375 380
Ile Phe Leu Gly Ser Phe Tyr Leu Ile Asn Leu Ile Leu Ala Val Val
385 390 395 400
Ala Met Ala Tyr Glu Glu Gln Asn Gln Ala Asn Ile Glu Glu Ala Arg
405 410 415
Gln Lys Glu Leu Glu Phe Gln Gln Met Leu Asp Arg Leu Lys Lys Glu
420 425 430
Gln Glu Glu Ala Glu Ala Ile Ala Met Ala Ala Ala Glu Tyr Thr Ser
435 440 445
Ile Gly Arg Ser Arg Ile Met Gly Leu Ser Glu Ser Ser Ser Glu Thr
450 455 460
Ser Lys Leu Ser Ser Lys Ser Ala Lys Glu Arg Arg Asn Arg Arg Arg
465 470 475 480
Lys Lys Asn Gln Lys Lys Leu Ser Ser Gly Glu Glu Lys Gly Asp Asp
485 490 495
Glu Lys Leu Ser Lys Ser Glu Ser Glu Glu Ser Ile Arg Arg Lys Ser
500 505 510
Phe His Leu Gly Ile Glu Gly His Arg Arg Ala His Glu Lys Arg Leu
515 520 525
Ser Thr Pro Asn Gln Ser Pro Leu Ser Ile Arg Gly Ser Leu Phe Ser
530 535 540
Ala Arg Arg Ser Ser Arg Thr Ser Leu Phe Ser Phe Lys Gly Arg Gly
545 550 555 560
Lys Asp Ile Gly Ser Glu Thr Glu Phe Ala Asp Asp Glu His Ser Ile
565 570 575
Phe Gly Asp Asn Glu Ser Arg Arg Gly Ser Leu Phe Val Pro His Arg
580 585 590
Pro Arg Glu Arg Arg Ser Ser Asn Ile Ser Gln Ala Ser Arg Ser Pro
595 600 605
Pro Met Leu Pro Val Asn Gly Lys Met His Ser Ala Val Asp Cys Asn
610 615 620
Gly Val Val Ser Leu Val Asp Gly Pro Ser Ala Leu Met Leu Pro Asn
625 630 635 640
Gly Gln Leu Leu Pro Glu Gly Thr Thr Asn Gln Ile His Lys Lys Arg
645 650 655
Arg Ser Ser Ser Tyr Leu Leu Ser Glu Asp Met Leu Asn Asp Pro Asn
660 665 670
Leu Arg Gln Arg Ala Met Ser Arg Ala Ser Ile Leu Thr Asn Thr Val
675 680 685
Glu Glu Leu Glu Glu Ser Arg Gln Lys Cys Pro Pro Trp Trp Tyr Arg
690 695 700
Phe Ala His Thr Phe Leu Ile Trp Asn Cys Ser Pro Tyr Trp Ile Lys
705 710 715 720
Phe Lys Lys Leu Ile His Phe Ile Val Met Asp Pro Phe Val Asp Leu
725 730 735
Ala Ile Thr Ile Cys Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu
740 745 750
His His Pro Met Thr Asp Glu Phe Lys Asn Val Leu Thr Val Gly Asn
755 760 765
Leu Val Phe Thr Gly Ile Phe Ala Ala Glu Met Val Leu Lys Leu Ile
770 775 780
Ala Met Asp Pro Tyr Glu Tyr Phe Gln Val Gly Trp Asn Ile Phe Asp
785 790 795 800
Ser Leu Ile Val Thr Leu Ser Leu Val Glu Leu Phe Leu Ala Asp Val
805 810 815
Glu Gly Leu Ser Val Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys
820 825 830
Leu Ala Lys Ser Trp Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly
835 840 845
Asn Ser Val Gly Ala Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile
850 855 860
Val Phe Ile Phe Ala Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr
865 870 875 880
Lys Glu Cys Val Cys Lys Ile Asn Glu Asp Cys Glu Leu Pro Arg Trp
885 890 895
His Met Asn Asp Phe Phe His Ser Phe Leu Ile Val Phe Arg Val Leu
900 905 910
Cys Gly Glu Trp Ile Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly
915 920 925
Gln Ala Met Cys Leu Ile Val Tyr Met Met Val Met Val Ile Gly Asn
930 935 940
Leu Val Val Leu Asn Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser
945 950 955 960
Ser Asp Asn Leu Thr Ala Ile Glu Glu Asp Thr Asp Thr Asn Asn Leu
965 970 975
Gln Ile Ala Val Thr Arg Ile Lys Lys Gly Ile Asn Tyr Val Lys Gln
980 985 990
Thr Leu Arg Glu Phe Ile Leu Lys Ala Phe Ser Lys Lys Pro Lys Ile
995 1000 1005
Ser Lys Glu Ile Arg Arg Ala Asp Leu Asn Ser Lys Lys Glu Asn
1010 1015 1020
Tyr Ile Ser Asn Arg Thr Leu Ala Glu Met Ser Lys Asp His Asn
1025 1030 1035
Phe His Lys Asp Lys Asp Lys Thr Gly Gly Phe Arg Ser Ser Val
1040 1045 1050
Asp Lys Tyr Leu Met Glu Glu Ser Asp Cys Gln Ser Phe Ile His
1055 1060 1065
Asn Pro Ser Leu Thr Val Thr Val Pro Ile Ala Pro Gly Glu Ser
1070 1075 1080
Asp Leu Glu Asn Met Asn Thr Glu Glu Leu Ser Ser Asp Ser Glu
1085 1090 1095
Ser Glu Tyr Ser Lys Gly Arg Leu Asn Gln Ser Ser Ser Ser Glu
1100 1105 1110
Cys Ser Thr Val Asp Asn Pro Leu Pro Gly Glu Gly Glu Glu Ala
1115 1120 1125
Glu Ala Glu Pro Val Asn Ser Asp Glu Pro Glu Ala Cys Phe Thr
1130 1135 1140
Asp Gly Cys Val Gln Arg Phe Pro Cys Cys Gln Val Asn Ile Glu
1145 1150 1155
Ser Glu Lys Gly Lys Ile Trp Trp Asn Ile Arg Lys Thr Cys Tyr
1160 1165 1170
Arg Ile Val Glu His Ser Trp Phe Glu Ser Phe Ile Val Leu Met
1175 1180 1185
Ile Leu Leu Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile
1190 1195 1200
Glu Lys Lys Lys Asn Ile Lys Ile Ile Leu Glu Tyr Ala Asp Lys
1205 1210 1215
Ile Phe Thr Tyr Val Phe Ile Leu Glu Met Leu Leu Lys Trp Val
1220 1225 1230
Ala Tyr Gly Tyr Lys Thr Tyr Phe Thr Asn Ala Trp Cys Trp Leu
1235 1240 1245
Asp Phe Leu Ile Val Asp Val Ser Leu Val Thr Leu Val Ala Asn
1250 1255 1260
Thr Leu Gly Tyr Ser Asp Leu Gly Pro Ile Lys Ser Leu Arg Thr
1265 1270 1275
Leu Arg Ala Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly
1280 1285 1290
Met Arg Val Val Val Asn Ala Leu Ile Gly Ala Ile Pro Ser Ile
1295 1300 1305
Met Asn Val Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser
1310 1315 1320
Ile Met Gly Val Asn Leu Phe Ala Gly Lys Phe Tyr Gln Cys Val
1325 1330 1335
Asn Thr Thr Asp Gly Ser Arg Phe Leu Thr Asn Glu Val Gln Asn
1340 1345 1350
Arg Ser Asp Cys Phe Ala Leu Met Asn Val Ser Gln Asn Val Arg
1355 1360 1365
Trp Lys Asn Leu Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr
1370 1375 1380
Leu Ser Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile
1385 1390 1395
Met Tyr Ala Ala Val Asp Ser Val Asn Val Asp Lys Gln Pro Ile
1400 1405 1410
Tyr Glu Tyr Ser Leu Tyr Met Tyr Ile Tyr Phe Val Ile Phe Ile
1415 1420 1425
Ile Phe Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile
1430 1435 1440
Ile Asp Asn Phe Asn Gln Gln Lys Lys Lys Leu Gly Gly Gln Asp
1445 1450 1455
Ile Phe Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys
1460 1465 1470
Lys Leu Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Gly
1475 1480 1485
Asn Lys Phe Gln Gly Cys Ile Phe Asp Leu Val Thr Asn Gln Ala
1490 1495 1500
Phe Asp Ile Ser Ile Met Val Leu Ile Cys Leu Asn Met Val Thr
1505 1510 1515
Met Met Val Glu Lys Glu Gly Gln Ser Asp Tyr Met Thr Asp Val
1520 1525 1530
Leu Tyr Trp Ile Asn Val Val Phe Ile Ile Leu Phe Thr Gly Glu
1535 1540 1545
Cys Val Leu Lys Leu Val Ser Leu Arg His Tyr Tyr Phe Thr Val
1550 1555 1560
Gly Trp Asn Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile Val
1565 1570 1575
Gly Met Phe Leu Ala Asp Leu Ile Glu Lys Tyr Phe Val Ser Pro
1580 1585 1590
Thr Leu Phe Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu
1595 1600 1605
Arg Leu Ile Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala
1610 1615 1620
Leu Met Met Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu
1625 1630 1635
Phe Leu Val Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe
1640 1645 1650
Ala Tyr Val Lys Lys Glu Ala Gly Ile Asn Asp Met Phe Asn Phe
1655 1660 1665
Glu Thr Phe Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr
1670 1675 1680
Ser Ala Gly Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Ala
1685 1690 1695
Pro Pro Asp Cys Asp Pro Arg Lys Val His Pro Gly Ser Ser Val
1700 1705 1710
Glu Gly Asp Cys Gly Asn Pro Ser Val Gly Ile Phe Tyr Phe Val
1715 1720 1725
Ser Tyr Ile Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile
1730 1735 1740
Ala Val Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Thr
1745 1750 1755
Glu Pro Leu Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp
1760 1765 1770
Glu Lys Phe Asp Pro Asp Ala Thr Gln Phe Ile Glu Phe Ser Lys
1775 1780 1785
Leu Ser Asp Phe Ala Ala Ala Leu Asp Pro Pro Leu Leu Ile Ala
1790 1795 1800
Lys Pro Asn Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val
1805 1810 1815
Ser Gly Asp Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr
1820 1825 1830
Lys Arg Val Leu Gly Glu Ser Gly Glu Met Asp Ser Leu Arg Ser
1835 1840 1845
Gln Met Glu Glu Arg Phe Met Ser Ala Asn Pro Ser Lys Val Ser
1850 1855 1860
Tyr Glu Pro Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Asp Val
1865 1870 1875
Ser Ala Thr Val Ile Gln Arg Ala Tyr Arg Arg Tyr Arg Leu Arg
1880 1885 1890
Gln Asn Val Lys Asn Ile Ser Ser Ile Tyr Ile Lys Asp Gly Glu
1895 1900 1905
Arg Asp Asp Asp Leu Pro Ser Lys Lys Asp Met Val Phe Asp Asn
1910 1915 1920
Val Asn Glu Asn Ser Ser Thr Glu Lys Thr Asp Ala Thr Pro Ser
1925 1930 1935
Thr Val Ser Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Asp Lys
1940 1945 1950
Glu Lys Tyr Glu Lys Asp Lys Thr Glu Lys Glu Asp Lys Glu Lys
1955 1960 1965
Asp Gly Lys Glu Ser Lys Lys
1970 1975
<210> 38
<211> 1986
<212> PRT
<213> 灰狼
<400> 38
Met Ala Thr Leu Pro Pro Pro Gly Pro Gln Ser Phe Val Tyr Phe Thr
1 5 10 15
Lys Gln Ser Leu Ala Leu Ile Glu Gln Arg Ile Ala Glu Gly Lys Thr
20 25 30
Lys Glu Pro Lys Glu Glu Lys Lys Asp Asp Asp Glu Glu Gly Pro Arg
35 40 45
Pro Ser Ser Asp Leu Glu Ala Gly Lys Gln Leu Pro Phe Ile Tyr Gly
50 55 60
Asp Ile Pro Pro Gly Met Val Ser Glu Pro Leu Glu Asp Leu Asp Pro
65 70 75 80
Tyr Tyr Ala Asp Lys Lys Thr Phe Ile Val Leu Asn Lys Gly Lys Ala
85 90 95
Ile Phe Arg Phe Asn Ala Thr Pro Ala Leu Tyr Met Leu Ser Pro Phe
100 105 110
Ser Pro Leu Arg Arg Ile Ser Ile Lys Ile Leu Val His Ser Leu Phe
115 120 125
Ser Met Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Ile Phe Met Thr
130 135 140
Met Ser Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr Thr Phe Thr
145 150 155 160
Gly Ile Tyr Thr Phe Glu Ser Leu Val Lys Ile Leu Ala Arg Gly Phe
165 170 175
Cys Val Gly Glu Phe Thr Phe Leu Arg Asp Pro Trp Asn Trp Leu Asp
180 185 190
Phe Val Val Ile Val Phe Ala Tyr Leu Thr Glu Phe Val Asn Leu Gly
195 200 205
Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala Leu Lys Thr
210 215 220
Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala Leu Ile Gln
225 230 235 240
Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val Phe Cys Leu
245 250 255
Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly Asn Leu Lys
260 265 270
His Lys Cys Leu Arg Asp Pro Leu Asp Asp Asn Glu Thr Leu Thr Ser
275 280 285
Leu Leu Asp Thr Leu Glu Glu Glu Asp Tyr Lys Lys Tyr Phe Tyr Tyr
290 295 300
Leu Glu Gly Ser Lys Asp Ala Leu Leu Cys Gly Leu Ser Thr Asp Ser
305 310 315 320
Gly Gln Cys Pro Glu Gly Tyr Lys Cys Val Lys Ala Gly Arg Asn Pro
325 330 335
Asp Tyr Gly Tyr Thr Ser Phe Asp Thr Phe Ser Trp Ala Phe Leu Ala
340 345 350
Leu Phe Arg Leu Met Thr Gln Asp Tyr Trp Glu Asn Leu Tyr Gln Gln
355 360 365
Thr Leu Arg Ala Ala Gly Lys Thr Tyr Met Ile Phe Phe Val Val Val
370 375 380
Ile Phe Leu Gly Ser Phe Tyr Leu Ile Asn Leu Ile Leu Ala Val Val
385 390 395 400
Ala Met Ala Tyr Glu Glu Gln Asn Gln Ala Asn Ile Glu Glu Ala Arg
405 410 415
Gln Lys Glu Leu Glu Phe Gln Gln Met Leu Asp Arg Leu Lys Lys Glu
420 425 430
Gln Glu Glu Ala Glu Ala Ile Ala Ile Ala Ala Ala Glu Tyr Thr Ser
435 440 445
Ile Gly Arg Ser Arg Met Met Gly Phe Ser Glu Ser Ser Ser Glu Thr
450 455 460
Ser Lys Leu Ser Ser Lys Ser Ala Lys Glu Arg Arg Asn Arg Arg Lys
465 470 475 480
Lys Arg Asn Gln Lys Lys Leu Ser Ser Gly Glu Glu Lys Gly Asp Asn
485 490 495
Glu Lys Leu Ser Lys Ser Glu Ser Glu Glu Ser Ile Arg Arg Gln Ser
500 505 510
Phe His Leu Gly Val Glu Gly His Arg Arg Ala Arg Glu Lys Arg Leu
515 520 525
Ser Thr Pro Asn Gln Ser Pro Leu Ser Ile Arg Gly Ser Leu Phe Ser
530 535 540
Gly Arg Arg Ser Ser Arg Thr Ser Leu Phe Ser Phe Lys Gly Arg Gly
545 550 555 560
Lys Asp Ile Gly Ser Glu Thr Glu Phe Ala Asp Asp Glu His Ser Ile
565 570 575
Phe Gly Asp Ser Glu Ser Arg Arg Gly Ser Leu Phe Val Pro His Arg
580 585 590
Pro Arg Glu Arg Arg Ser Ser Asn Ile Ser Gln Ala Ser Arg Ser Pro
595 600 605
Pro Val Leu Pro Val Asn Gly Lys Met His Ser Ala Val Asp Cys Asn
610 615 620
Gly Val Val Ser Leu Val Asp Gly Pro Ser Ala Leu Met Leu Pro Asn
625 630 635 640
Gly Gln Leu Leu Pro Glu Val Ile Ile Asp Lys Ala Thr Ser Asp Asp
645 650 655
Ser Gly Thr Thr Asn Gln Ile His Lys Lys Arg Arg Ser Ser Ser Tyr
660 665 670
Leu Leu Ser Glu Asp Met Leu Asn Asp Pro Asn Leu Arg Gln Arg Ala
675 680 685
Met Ser Arg Val Ser Ile Leu Thr Asn Thr Val Glu Glu Leu Glu Glu
690 695 700
Ser Arg Gln Lys Cys Pro Pro Trp Trp Tyr Arg Phe Ala His Thr Phe
705 710 715 720
Leu Ile Trp Asn Cys Ser Pro Tyr Trp Ile Lys Phe Lys Lys Leu Val
725 730 735
Tyr Phe Ile Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile Cys
740 745 750
Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His His Pro Met Thr
755 760 765
Asp Glu Phe Lys Asn Val Leu Thr Val Gly Asn Leu Val Phe Thr Gly
770 775 780
Ile Phe Ala Ala Glu Met Val Leu Lys Leu Ile Ala Met Asp Pro Tyr
785 790 795 800
Glu Tyr Phe Gln Val Gly Trp Asn Ile Phe Asp Ser Leu Ile Val Thr
805 810 815
Leu Ser Leu Val Glu Leu Phe Leu Ala Asp Val Glu Gly Leu Ser Val
820 825 830
Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser Trp
835 840 845
Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly Ala
850 855 860
Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe Ala
865 870 875 880
Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val Cys
885 890 895
Lys Ile Asn Glu Asp Cys Thr Leu Pro Arg Trp His Met Asn Asp Phe
900 905 910
Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp Ile
915 920 925
Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Ala Met Cys Leu
930 935 940
Ile Val Tyr Met Met Val Met Val Ile Gly Asn Leu Val Val Leu Asn
945 950 955 960
Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu Thr
965 970 975
Ala Ile Glu Glu Asp Thr Asp Ala Asn Asn Leu Gln Ile Ala Val Ala
980 985 990
Arg Ile Lys Lys Gly Val Asn Tyr Val Lys Gln Thr Leu Arg Glu Phe
995 1000 1005
Ile Leu Lys Ala Phe Ser Lys Lys Pro Lys Ile Ser Lys Asp Thr
1010 1015 1020
Arg Arg Ala Glu Asp Gln Asn Ser Lys Lys Glu Asn Cys Ile Ser
1025 1030 1035
Asn Arg Thr Leu Ala Glu Met Asn Lys Asp His Asn Phe His Lys
1040 1045 1050
Glu Lys Glu Lys Ile Ser Gly Phe Gly Ser Ser Met Asp Lys Tyr
1055 1060 1065
Leu Met Glu Glu Ser Asp Cys Gln Ser Phe Ile His Asn Pro Ser
1070 1075 1080
Leu Thr Val Thr Val Pro Ile Ala Pro Gly Glu Ser Asp Leu Glu
1085 1090 1095
Asn Met Asn Thr Glu Glu Leu Ser Ser Asp Ser Asp Ser Glu Tyr
1100 1105 1110
Ser Lys Gly Arg Leu Asn Arg Ser Ser Ser Ser Glu Cys Ser Thr
1115 1120 1125
Val Asp Asn Pro Leu Pro Gly Glu Gly Glu Glu Ala Glu Ala Glu
1130 1135 1140
Pro Val Asn Ser Asp Glu Pro Glu Ala Cys Phe Thr Asp Gly Cys
1145 1150 1155
Val Arg Arg Phe Pro Cys Cys Gln Val Asp Ile Glu Ser Gly Lys
1160 1165 1170
Gly Lys Ile Trp Trp Asn Ile Arg Lys Thr Cys Tyr Arg Ile Val
1175 1180 1185
Glu His Ser Trp Phe Glu Ser Phe Ile Val Leu Met Ile Leu Leu
1190 1195 1200
Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile Glu Lys Lys
1205 1210 1215
Lys Thr Ile Lys Ile Ile Leu Glu Tyr Ala Asp Lys Ile Phe Thr
1220 1225 1230
Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Val Ala Tyr Gly
1235 1240 1245
Tyr Lys Thr Tyr Phe Thr Asn Ala Trp Cys Trp Leu Asp Phe Leu
1250 1255 1260
Ile Val Asp Val Ser Leu Val Thr Leu Val Ala Asn Thr Leu Gly
1265 1270 1275
Tyr Ser Asp Leu Gly Pro Ile Lys Ser Leu Arg Thr Leu Arg Ala
1280 1285 1290
Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly Met Arg Val
1295 1300 1305
Val Val Asn Ala Leu Ile Gly Ala Ile Pro Ser Ile Met Asn Val
1310 1315 1320
Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile Met Gly
1325 1330 1335
Val Asn Leu Phe Ala Gly Lys Phe Tyr Glu Cys Val Asn Thr Thr
1340 1345 1350
Asp Gly Ser Arg Phe Pro Thr Asn Leu Val Gln Asn His Ser Asp
1355 1360 1365
Cys Phe Ala Leu Met Asn Val Ser Gln Asn Val Arg Trp Lys Asn
1370 1375 1380
Leu Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr Leu Ser Leu
1385 1390 1395
Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile Met Tyr Ala
1400 1405 1410
Ala Val Asp Ser Val Asn Val Asp Lys Gln Pro Ile Tyr Glu Tyr
1415 1420 1425
Asn Leu Tyr Met Tyr Ile Tyr Phe Val Ile Phe Ile Ile Phe Gly
1430 1435 1440
Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile Ile Asp Asn
1445 1450 1455
Phe Asn Gln Gln Lys Lys Lys Leu Gly Gly Gln Asp Ile Phe Met
1460 1465 1470
Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys Leu Gly
1475 1480 1485
Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Gly Asn Lys Phe
1490 1495 1500
Gln Gly Cys Ile Phe Asp Leu Val Thr Asn Gln Val Phe Asp Ile
1505 1510 1515
Thr Ile Met Val Leu Ile Cys Leu Asn Met Val Thr Met Met Val
1520 1525 1530
Glu Lys Glu Gly Gln Ser Lys Tyr Met Thr Asp Val Leu Tyr Trp
1535 1540 1545
Ile Asn Val Val Phe Ile Ile Leu Phe Thr Gly Glu Cys Val Leu
1550 1555 1560
Lys Leu Ile Ser Leu Arg His Tyr Tyr Phe Thr Val Gly Trp Asn
1565 1570 1575
Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile Val Gly Met Phe
1580 1585 1590
Leu Ala Glu Leu Ile Glu Lys Tyr Phe Val Ser Pro Thr Leu Phe
1595 1600 1605
Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg Leu Ile
1610 1615 1620
Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu Met Met
1625 1630 1635
Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu Phe Leu Val
1640 1645 1650
Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe Ala Tyr Val
1655 1660 1665
Lys Lys Glu Ala Gly Ile Asn Asp Met Phe Asn Phe Glu Thr Phe
1670 1675 1680
Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr Ser Ala Gly
1685 1690 1695
Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Ala Pro Pro Asp
1700 1705 1710
Cys Asp Pro Lys Lys Val His Pro Gly Ser Ser Val Glu Gly Asp
1715 1720 1725
Cys Gly Asn Pro Ser Val Gly Ile Phe Tyr Phe Val Ser Tyr Ile
1730 1735 1740
Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile Ala Val Ile
1745 1750 1755
Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Thr Glu Pro Leu
1760 1765 1770
Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp Glu Lys Phe
1775 1780 1785
Asp Pro Asp Ala Thr Gln Phe Ile Glu Tyr Ser Lys Leu Ser Asp
1790 1795 1800
Phe Ala Ala Ala Leu Asp Pro Pro Leu Leu Ile Ala Lys Pro Asn
1805 1810 1815
Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val Ser Gly Asp
1820 1825 1830
Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr Lys Arg Val
1835 1840 1845
Leu Gly Glu Ser Gly Glu Met Asp Ser Leu Arg Ser Gln Met Glu
1850 1855 1860
Glu Arg Phe Met Ser Ala Asn Pro Ser Lys Val Ser Tyr Glu Pro
1865 1870 1875
Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Asp Val Ser Ala Thr
1880 1885 1890
Val Ile Gln Arg Ala Tyr Arg Arg Tyr Arg Leu Arg Gln Asn Val
1895 1900 1905
Lys Asn Ile Ser Ser Ile Tyr Ile Lys Asp Gly Asp Arg Asp Asp
1910 1915 1920
Asp Leu Pro Asn Lys Glu Asp Met Val Phe Asp Asn Ile Glu Asn
1925 1930 1935
Ser Ser Pro Glu Lys Thr Asp Ala Thr Pro Ser Thr Val Ser Pro
1940 1945 1950
Pro Ser Tyr Asp Ser Val Thr Lys Pro Asp Lys Glu Lys Tyr Glu
1955 1960 1965
Lys Asp Lys Thr Glu Lys Glu Asp Lys Gly Lys Asp Gly Lys Glu
1970 1975 1980
Ser Lys Lys
1985
<210> 39
<211> 1984
<212> PRT
<213> 褐家鼠
<400> 39
Met Ala Met Leu Pro Pro Pro Gly Pro Gln Ser Phe Val His Phe Thr
1 5 10 15
Lys Gln Ser Leu Ala Leu Ile Glu Gln Arg Ile Ser Glu Glu Lys Ala
20 25 30
Lys Glu His Lys Asp Glu Lys Lys Asp Asp Glu Glu Glu Gly Pro Lys
35 40 45
Pro Ser Ser Asp Leu Glu Ala Gly Lys Gln Leu Pro Phe Ile Tyr Gly
50 55 60
Asp Ile Pro Pro Gly Met Val Ser Glu Pro Leu Glu Asp Leu Asp Pro
65 70 75 80
Tyr Tyr Ala Asp Lys Lys Thr Phe Ile Val Leu Asn Lys Gly Lys Ala
85 90 95
Ile Phe Arg Phe Asn Ala Thr Pro Ala Leu Tyr Met Leu Ser Pro Phe
100 105 110
Ser Pro Leu Arg Arg Ile Ser Ile Lys Ile Leu Val His Ser Leu Phe
115 120 125
Ser Met Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Ile Phe Met Thr
130 135 140
Leu Ser Asn Pro Pro Glu Trp Thr Lys Asn Val Glu Tyr Thr Phe Thr
145 150 155 160
Gly Ile Tyr Thr Phe Glu Ser Leu Ile Lys Ile Leu Ala Arg Gly Phe
165 170 175
Cys Val Gly Glu Phe Thr Phe Leu Arg Asp Pro Trp Asn Trp Leu Asp
180 185 190
Phe Val Val Ile Val Phe Ala Tyr Leu Thr Glu Phe Val Asn Leu Gly
195 200 205
Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala Leu Lys Thr
210 215 220
Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala Leu Ile Gln
225 230 235 240
Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val Phe Cys Leu
245 250 255
Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly Asn Leu Lys
260 265 270
His Lys Cys Phe Arg Lys Glu Leu Glu Glu Asn Glu Thr Leu Glu Ser
275 280 285
Ile Met Asn Thr Ala Glu Ser Glu Glu Glu Leu Lys Lys Tyr Phe Tyr
290 295 300
Tyr Leu Glu Gly Ser Lys Asp Ala Leu Leu Cys Gly Phe Ser Thr Asp
305 310 315 320
Ser Gly Gln Cys Pro Glu Gly Tyr Ile Cys Val Lys Ala Gly Arg Asn
325 330 335
Pro Asp Tyr Gly Tyr Thr Ser Phe Asp Thr Phe Ser Trp Ala Phe Leu
340 345 350
Ala Leu Phe Arg Leu Met Thr Gln Asp Tyr Trp Glu Asn Leu Tyr Gln
355 360 365
Gln Thr Leu Arg Ala Ala Gly Lys Thr Tyr Met Ile Phe Phe Val Val
370 375 380
Val Ile Phe Leu Gly Ser Phe Tyr Leu Ile Asn Leu Ile Leu Ala Val
385 390 395 400
Val Ala Met Ala Tyr Glu Glu Gln Asn Gln Ala Asn Ile Glu Glu Ala
405 410 415
Lys Gln Lys Glu Leu Glu Phe Gln Gln Met Leu Asp Arg Leu Lys Lys
420 425 430
Glu Gln Glu Glu Ala Glu Ala Ile Ala Ala Ala Ala Ala Glu Phe Thr
435 440 445
Ser Ile Gly Arg Ser Arg Ile Met Gly Leu Ser Glu Ser Ser Ser Glu
450 455 460
Thr Ser Arg Leu Ser Ser Lys Ser Ala Lys Glu Arg Arg Asn Arg Arg
465 470 475 480
Lys Lys Lys Lys Gln Lys Met Ser Ser Gly Glu Glu Lys Gly Asp Asp
485 490 495
Glu Lys Leu Ser Lys Ser Gly Ser Glu Glu Ser Ile Arg Lys Lys Ser
500 505 510
Phe His Leu Gly Val Glu Gly His His Arg Thr Arg Glu Lys Arg Leu
515 520 525
Ser Thr Pro Asn Gln Ser Pro Leu Ser Ile Arg Gly Ser Leu Phe Ser
530 535 540
Ala Arg Arg Ser Ser Arg Thr Ser Leu Phe Ser Phe Lys Gly Arg Gly
545 550 555 560
Arg Asp Leu Gly Ser Glu Thr Glu Phe Ala Asp Asp Glu His Ser Ile
565 570 575
Phe Gly Asp Asn Glu Ser Arg Arg Gly Ser Leu Phe Val Pro His Arg
580 585 590
Pro Arg Glu Arg Arg Ser Ser Asn Ile Ser Gln Ala Ser Arg Ser Pro
595 600 605
Pro Val Leu Pro Val Asn Gly Lys Met His Ser Ala Val Asp Cys Asn
610 615 620
Gly Val Val Ser Leu Val Asp Gly Pro Ser Ala Leu Met Leu Pro Asn
625 630 635 640
Gly Gln Leu Leu Pro Glu Val Ile Ile Asp Lys Ala Thr Ser Asp Asp
645 650 655
Ser Gly Thr Thr Asn Gln Met Arg Lys Lys Arg Leu Ser Ser Ser Tyr
660 665 670
Phe Leu Ser Glu Asp Met Leu Asn Asp Pro His Leu Arg Gln Arg Ala
675 680 685
Met Ser Arg Ala Ser Ile Leu Thr Asn Thr Val Glu Glu Leu Glu Glu
690 695 700
Ser Arg Gln Lys Cys Pro Pro Trp Trp Tyr Arg Phe Ala His Thr Phe
705 710 715 720
Leu Ile Trp Asn Cys Ser Pro Tyr Trp Ile Lys Phe Lys Lys Leu Ile
725 730 735
Tyr Phe Ile Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile Cys
740 745 750
Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His His Pro Met Thr
755 760 765
Glu Glu Phe Lys Asn Val Leu Ala Val Gly Asn Leu Ile Phe Thr Gly
770 775 780
Ile Phe Ala Ala Glu Met Val Leu Lys Leu Ile Ala Met Asp Pro Tyr
785 790 795 800
Glu Tyr Phe Gln Val Gly Trp Asn Ile Phe Asp Ser Leu Ile Val Thr
805 810 815
Leu Ser Leu Ile Glu Leu Phe Leu Ala Asp Val Glu Gly Leu Ser Val
820 825 830
Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser Trp
835 840 845
Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly Ala
850 855 860
Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe Ala
865 870 875 880
Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val Cys
885 890 895
Lys Ile Asn Val Asp Cys Lys Leu Pro Arg Trp His Met Asn Asp Phe
900 905 910
Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp Ile
915 920 925
Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Thr Met Cys Leu
930 935 940
Ile Val Tyr Met Met Val Met Val Ile Gly Asn Leu Val Val Leu Asn
945 950 955 960
Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu Thr
965 970 975
Ala Ile Glu Glu Asp Thr Asp Ala Asn Asn Leu Gln Ile Ala Val Ala
980 985 990
Arg Ile Lys Arg Gly Ile Asn Tyr Val Lys Gln Thr Leu Arg Glu Phe
995 1000 1005
Ile Leu Lys Ser Phe Ser Lys Lys Pro Lys Gly Ser Lys Asp Thr
1010 1015 1020
Lys Arg Thr Ala Asp Pro Asn Asn Lys Lys Glu Asn Tyr Ile Ser
1025 1030 1035
Asn Arg Thr Leu Ala Glu Met Ser Lys Asp His Asn Phe Leu Lys
1040 1045 1050
Glu Lys Asp Arg Ile Ser Gly Tyr Gly Ser Ser Leu Asp Lys Ser
1055 1060 1065
Phe Met Asp Glu Asn Asp Tyr Gln Ser Phe Ile His Asn Pro Ser
1070 1075 1080
Leu Thr Val Thr Val Pro Ile Ala Pro Gly Glu Ser Asp Leu Glu
1085 1090 1095
Ile Met Asn Thr Glu Glu Leu Ser Ser Asp Ser Asp Ser Asp Tyr
1100 1105 1110
Ser Lys Glu Lys Arg Asn Arg Ser Ser Ser Ser Glu Cys Ser Thr
1115 1120 1125
Val Asp Asn Pro Leu Pro Gly Glu Glu Glu Ala Glu Ala Glu Pro
1130 1135 1140
Val Asn Ala Asp Glu Pro Glu Ala Cys Phe Thr Asp Gly Cys Val
1145 1150 1155
Arg Arg Phe Pro Cys Cys Gln Val Asn Val Asp Ser Gly Lys Gly
1160 1165 1170
Lys Val Trp Trp Thr Ile Arg Lys Thr Cys Tyr Arg Ile Val Glu
1175 1180 1185
His Ser Trp Phe Glu Ser Phe Ile Val Leu Met Ile Leu Leu Ser
1190 1195 1200
Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile Glu Lys Lys Lys
1205 1210 1215
Thr Ile Lys Ile Ile Leu Glu Tyr Ala Asp Lys Ile Phe Thr Tyr
1220 1225 1230
Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Val Ala Tyr Gly Tyr
1235 1240 1245
Lys Thr Tyr Phe Thr Asn Ala Trp Cys Trp Leu Asp Phe Leu Ile
1250 1255 1260
Val Asp Val Ser Leu Val Thr Leu Val Ala Asn Thr Leu Gly Tyr
1265 1270 1275
Ser Asp Leu Gly Pro Ile Lys Ser Leu Arg Thr Leu Arg Ala Leu
1280 1285 1290
Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly Met Arg Val Val
1295 1300 1305
Val Asn Ala Leu Ile Gly Ala Ile Pro Ser Ile Met Asn Val Leu
1310 1315 1320
Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile Met Gly Val
1325 1330 1335
Asn Leu Phe Ala Gly Lys Phe Tyr Glu Cys Val Asn Thr Thr Asp
1340 1345 1350
Gly Ser Arg Phe Pro Thr Ser Gln Val Ala Asn Arg Ser Glu Cys
1355 1360 1365
Phe Ala Leu Met Asn Val Ser Gly Asn Val Arg Trp Lys Asn Leu
1370 1375 1380
Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr Leu Ser Leu Leu
1385 1390 1395
Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile Met Tyr Ala Ala
1400 1405 1410
Val Asp Ser Val Asn Val Asn Glu Gln Pro Lys Tyr Glu Tyr Ser
1415 1420 1425
Leu Tyr Met Tyr Ile Tyr Phe Val Ile Phe Ile Ile Phe Gly Ser
1430 1435 1440
Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile Ile Asp Asn Phe
1445 1450 1455
Asn Gln Gln Lys Lys Lys Leu Gly Gly Gln Asp Ile Phe Met Thr
1460 1465 1470
Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys Leu Gly Ser
1475 1480 1485
Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Gly Asn Lys Phe Gln
1490 1495 1500
Gly Cys Ile Phe Asp Leu Val Thr Asn Gln Ala Phe Asp Ile Thr
1505 1510 1515
Ile Met Val Leu Ile Cys Leu Asn Met Val Thr Met Met Val Glu
1520 1525 1530
Lys Glu Gly Gln Thr Glu Tyr Met Asp Tyr Val Leu His Trp Ile
1535 1540 1545
Asn Met Val Phe Ile Ile Leu Phe Thr Gly Glu Cys Val Leu Lys
1550 1555 1560
Leu Ile Ser Leu Arg His Tyr Tyr Phe Thr Val Gly Trp Asn Ile
1565 1570 1575
Phe Asp Phe Val Val Val Ile Leu Ser Ile Val Gly Met Phe Leu
1580 1585 1590
Ala Glu Met Ile Glu Lys Tyr Phe Val Ser Pro Thr Leu Phe Arg
1595 1600 1605
Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg Leu Ile Lys
1610 1615 1620
Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu Met Met Ser
1625 1630 1635
Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu Phe Leu Val Met
1640 1645 1650
Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe Ala Tyr Val Lys
1655 1660 1665
Lys Glu Ala Gly Ile Asn Asp Met Phe Asn Phe Glu Thr Phe Gly
1670 1675 1680
Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr Ser Ala Gly Trp
1685 1690 1695
Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Ala Pro Pro Asp Cys
1700 1705 1710
Asp Pro Lys Lys Val His Pro Gly Ser Ser Val Glu Gly Asp Cys
1715 1720 1725
Gly Asn Pro Ser Val Gly Ile Phe Tyr Phe Val Ser Tyr Ile Ile
1730 1735 1740
Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile Ala Val Ile Leu
1745 1750 1755
Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Thr Glu Pro Leu Ser
1760 1765 1770
Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp Glu Lys Phe Asp
1775 1780 1785
Pro Asp Ala Thr Gln Phe Ile Glu Phe Cys Lys Leu Ser Asp Phe
1790 1795 1800
Ala Ala Ala Leu Asp Pro Pro Leu Leu Ile Ala Lys Pro Asn Lys
1805 1810 1815
Val Gln Leu Ile Ala Met Asp Leu Pro Met Val Ser Gly Asp Arg
1820 1825 1830
Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr Lys Arg Val Leu
1835 1840 1845
Gly Glu Gly Gly Glu Met Asp Ser Leu Arg Ser Gln Met Glu Glu
1850 1855 1860
Arg Phe Met Ser Ala Asn Pro Ser Lys Val Ser Tyr Glu Pro Ile
1865 1870 1875
Thr Thr Thr Leu Lys Arg Lys Gln Glu Glu Val Ser Ala Thr Ile
1880 1885 1890
Ile Gln Arg Ala Tyr Arg Arg Tyr Arg Leu Arg Gln His Val Lys
1895 1900 1905
Asn Ile Ser Ser Ile Tyr Ile Lys Asp Gly Asp Arg Asp Asp Asp
1910 1915 1920
Leu Pro Asn Lys Glu Asp Thr Val Phe Asp Asn Val Asn Glu Asn
1925 1930 1935
Ser Ser Pro Glu Lys Thr Asp Val Thr Ala Ser Thr Ile Ser Pro
1940 1945 1950
Pro Ser Tyr Asp Ser Val Thr Lys Pro Asp Gln Glu Lys Tyr Glu
1955 1960 1965
Thr Asp Lys Thr Glu Lys Glu Asp Lys Glu Lys Asp Glu Ser Arg
1970 1975 1980
Lys
<210> 40
<211> 1984
<212> PRT
<213> 穴兔
<400> 40
Met Ala Met Leu Pro Pro Pro Gly Pro Gln Ser Phe Val Arg Phe Thr
1 5 10 15
Lys Gln Ser Leu Ala Leu Ile Glu Gln Arg Ile Ala Glu Gly Lys Thr
20 25 30
Lys Glu Pro Lys Glu Glu Lys Lys Asp Asp His Asp Glu Gly Pro Lys
35 40 45
Pro Ser Ser Asp Leu Glu Ala Gly Lys Gln Leu Pro Phe Ile Tyr Gly
50 55 60
Asp Ile Pro Ala Gly Met Val Ser Glu Pro Leu Glu Asp Leu Asp Pro
65 70 75 80
Tyr Tyr Ala Asp Lys Lys Thr Phe Ile Val Leu Asn Lys Gly Lys Ala
85 90 95
Ile Phe Arg Phe Asn Ala Thr Pro Ala Leu Tyr Ile Leu Ser Pro Phe
100 105 110
Ser Pro Leu Arg Arg Ile Ser Ile Lys Ile Leu Val His Ser Leu Phe
115 120 125
Ser Met Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Ile Phe Met Thr
130 135 140
Met Asn Asn Pro Ala Glu Trp Thr Lys Asn Val Glu Tyr Thr Phe Thr
145 150 155 160
Gly Ile Tyr Thr Phe Glu Ser Leu Val Lys Ile Phe Ala Arg Gly Phe
165 170 175
Cys Val Gly Glu Phe Thr Phe Leu Arg Asp Pro Trp Asn Trp Leu Asp
180 185 190
Phe Ile Val Ile Val Phe Ala Tyr Leu Thr Glu Phe Val Asn Leu Gly
195 200 205
Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala Leu Lys Thr
210 215 220
Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala Leu Ile Gln
225 230 235 240
Ser Val Lys Lys Leu Ser Asp Val Ile Ile Leu Thr Val Phe Cys Leu
245 250 255
Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly His Leu Lys
260 265 270
His Lys Cys Leu Arg Lys Ile Glu Asn Glu Thr Leu Glu Ser Ile Met
275 280 285
Ser Ser Ile Glu Ser Glu Glu Asp Tyr Lys Lys Tyr Phe Tyr Tyr Leu
290 295 300
Glu Gly Ser Lys Asp Ala Leu Leu Cys Gly Phe Ser Thr Asp Ser Gly
305 310 315 320
Gln Cys Pro Glu Gly Tyr Tyr Cys Val Lys Ala Gly Arg Asn Pro Asp
325 330 335
Tyr Gly Tyr Thr Ser Phe Asp Thr Phe Ser Trp Ala Phe Leu Ala Leu
340 345 350
Phe Arg Leu Met Thr Gln Asp Tyr Trp Glu Asn Leu Tyr Gln Gln Thr
355 360 365
Leu Arg Ala Ala Gly Lys Thr Tyr Met Ile Phe Phe Val Val Val Ile
370 375 380
Phe Leu Gly Ser Phe Tyr Leu Ile Asn Leu Ile Leu Ala Val Val Ala
385 390 395 400
Met Ala Tyr Glu Glu Gln Asn Gln Ala Asn Ile Glu Glu Ala Lys Gln
405 410 415
Lys Glu Leu Glu Phe Gln Gln Met Leu Asp Arg Leu Lys Lys Glu Gln
420 425 430
Glu Glu Ala Glu Ala Ile Ala Ala Ala Ala Ala Glu Tyr Thr Ser Ile
435 440 445
Gly Arg Ser Arg Ile Met Gly Leu Ser Glu Ser Ser Ser Glu Thr Ser
450 455 460
Lys Leu Ser Ser Lys Ser Ala Lys Glu Arg Arg Asn Arg Arg Lys Lys
465 470 475 480
Lys Asn Gln Lys Lys Leu Ser Ser Gly Glu Glu Lys Gly Asp Asp Glu
485 490 495
Lys Leu Ser Lys Ser Glu Ser Glu Glu Ser Ile Ser Arg Lys Gln Phe
500 505 510
His Leu Gly Val Glu Gly His Arg Leu Ala Arg Glu Lys Arg Leu Ser
515 520 525
Ala Pro Asn Gln Ser Pro Leu Ser Ile Arg Gly Ser Leu Phe Ser Ala
530 535 540
Arg Arg Ser Ser Arg Thr Ser Leu Phe Ser Phe Lys Gly Arg Gly Lys
545 550 555 560
Asp Ile Gly Ser Glu Thr Glu Phe Ala Asp Asp Glu His Ser Ile Phe
565 570 575
Gly Asp Asn Glu Ser Arg Arg Gly Ser Leu Phe Val Pro Gln Arg Pro
580 585 590
Gln Glu Arg Arg Ser Ser Asn Leu Ser Gln Ala Ser Arg Ser Pro Pro
595 600 605
Met Leu Gln Met Asn Gly Lys Met His Ser Ala Val Asp Cys Asn Gly
610 615 620
Val Val Ser Leu Val Asp Gly Pro Ser Ala Leu Met Leu Pro Asn Gly
625 630 635 640
Gln Leu Leu Pro Glu Val Ile Ile Asp Lys Ala Thr Ser Asp Asp Ser
645 650 655
Gly Thr Thr Gln Ile Arg Lys Lys Arg Arg Ser Ser Ser Tyr Leu Leu
660 665 670
Ser Glu Asp Met Leu Asn Asp Pro His Leu Arg Gln Arg Ala Met Ser
675 680 685
Arg Ala Ser Ile Leu Thr Asn Thr Val Glu Glu Leu Glu Glu Ser Arg
690 695 700
Gln Lys Cys Pro Ser Trp Trp Tyr Arg Phe Ala His Thr Phe Leu Ile
705 710 715 720
Trp Asn Cys Ser Pro Phe Trp Ile Lys Phe Lys Lys Phe Ile Tyr Ile
725 730 735
Ile Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile Cys Ile Val
740 745 750
Leu Asn Thr Leu Phe Met Ala Met Glu His His Pro Met Thr Glu Glu
755 760 765
Phe Lys Asn Val Leu Val Val Gly Asn Leu Val Phe Thr Gly Ile Phe
770 775 780
Ala Ala Glu Met Val Leu Lys Leu Ile Ala Met Asp Pro Tyr Glu Tyr
785 790 795 800
Phe Gln Val Gly Trp Asn Val Phe Asp Ser Leu Ile Val Thr Leu Ser
805 810 815
Leu Val Glu Leu Phe Leu Ala Asp Val Glu Gly Leu Ser Val Leu Arg
820 825 830
Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser Trp Pro Thr
835 840 845
Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly Pro Leu Gly
850 855 860
Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe Ala Val Val
865 870 875 880
Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val Cys Lys Ile
885 890 895
Asn Asp Asp Cys Ser Leu Pro Arg Trp His Met Asn Asp Phe Phe His
900 905 910
Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp Ile Glu Thr
915 920 925
Met Trp Asp Cys Met Glu Val Ala Gly Gln Ala Met Cys Leu Ile Val
930 935 940
Tyr Met Met Val Met Val Ile Gly Asn Leu Val Val Leu Asn Leu Phe
945 950 955 960
Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu Ser Ala Ile
965 970 975
Glu Glu Asp Thr Asp Ala Asn Asn Leu Gln Ile Ala Val Thr Arg Ile
980 985 990
Lys Lys Gly Ile Asn Tyr Val Lys Gln Thr Leu Arg Glu Leu Ile Leu
995 1000 1005
Lys Ala Phe Ser Lys Lys Pro Lys Ile Ser Lys Glu Ile Arg Gln
1010 1015 1020
Ala Glu Asp Leu Asn Ser Lys Lys Glu Asn Tyr Ile Ser Asn Arg
1025 1030 1035
Thr Leu Ala Glu Met Ser Lys Asp Tyr Asn Phe His Lys Glu Lys
1040 1045 1050
Asp Lys Ile Ser Gly Phe Gly Ser Ser Met Asp Lys Tyr Leu Met
1055 1060 1065
Glu Glu Ser Asp His Gln Ser Phe Ile His Asn Pro Ser Leu Thr
1070 1075 1080
Val Thr Val Pro Ile Ala Pro Gly Glu Ser Asp Leu Glu Asn Met
1085 1090 1095
Asn Thr Glu Glu Leu Ser Ser Asp Ser Glu Ser Glu Tyr Ser Lys
1100 1105 1110
Glu Arg Leu Asn Arg Ser Ser Ser Ser Glu Cys Ser Thr Val Asp
1115 1120 1125
Asn Ala Leu Pro Gly Glu Gly Glu Glu Ala Glu Ala Glu Pro Val
1130 1135 1140
Asn Ser Asp Glu Pro Glu Ala Cys Phe Thr Asp Gly Cys Val Arg
1145 1150 1155
Arg Phe Pro Cys Cys Gln Val Ser Ile Glu Ser Gly Lys Gly Lys
1160 1165 1170
Ile Trp Trp Asn Ile Arg Lys Thr Cys Tyr Arg Ile Val Glu His
1175 1180 1185
Ser Trp Phe Glu Ser Phe Ile Val Leu Met Ile Leu Leu Ser Ser
1190 1195 1200
Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile Glu Lys Lys Lys Thr
1205 1210 1215
Ile Lys Ile Ile Leu Glu Tyr Ala Asp Lys Ile Phe Thr Tyr Ile
1220 1225 1230
Phe Ile Leu Glu Met Leu Leu Lys Trp Val Ala Tyr Gly Tyr Lys
1235 1240 1245
Thr Tyr Phe Thr Asn Ala Trp Cys Trp Leu Asp Phe Leu Ile Val
1250 1255 1260
Asp Val Ser Leu Val Thr Leu Val Ala Asn Thr Leu Gly Tyr Ser
1265 1270 1275
Asp Leu Gly Pro Ile Lys Ser Leu Arg Thr Leu Arg Ala Leu Arg
1280 1285 1290
Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly Met Arg Val Val Val
1295 1300 1305
Asn Ala Leu Ile Gly Ala Ile Pro Ser Ile Met Asn Val Leu Leu
1310 1315 1320
Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile Met Gly Val Asn
1325 1330 1335
Leu Phe Ala Gly Lys Phe Tyr Gln Cys Val Asn Thr Thr Asp Asp
1340 1345 1350
Ser Arg Phe Pro Thr Lys Gln Val Ser Asn Arg Ser Glu Cys Phe
1355 1360 1365
Ala Leu Met Asn Gly Ser Gln Asn Val Arg Trp Lys Asn Leu Lys
1370 1375 1380
Val Asn Phe Asp Asn Val Gly Leu Arg Tyr Leu Ser Leu Leu Gln
1385 1390 1395
Val Ala Thr Phe Lys Gly Trp Met Asp Ile Met Tyr Ala Ala Val
1400 1405 1410
Asp Ser Val Asn Val Asp Gln Gln Pro Ser Tyr Glu His Asn Leu
1415 1420 1425
Tyr Met Tyr Ile Tyr Phe Val Ile Phe Ile Ile Phe Gly Ser Phe
1430 1435 1440
Phe Thr Leu Asn Leu Phe Ile Gly Val Ile Ile Asp Asn Phe Asn
1445 1450 1455
Gln Gln Lys Lys Lys Leu Gly Gly Gln Asp Ile Phe Met Thr Glu
1460 1465 1470
Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys Leu Gly Ser Lys
1475 1480 1485
Lys Pro Gln Lys Pro Ile Pro Arg Pro Gly Asn Lys Phe Gln Gly
1490 1495 1500
Cys Ile Phe Asp Leu Val Thr Asn Gln Ala Phe Asp Ile Thr Ile
1505 1510 1515
Met Ile Leu Ile Cys Leu Asn Met Val Thr Met Met Val Glu Lys
1520 1525 1530
Glu Gly Gln Ser Asp Tyr Met Thr Asp Val Leu Tyr Trp Ile Asn
1535 1540 1545
Val Val Phe Ile Ile Leu Phe Thr Gly Glu Cys Val Leu Lys Leu
1550 1555 1560
Ile Ser Leu Arg His Tyr Tyr Phe Thr Ile Gly Trp Asn Ile Phe
1565 1570 1575
Asp Phe Val Val Val Ile Leu Ser Ile Val Gly Met Phe Leu Ala
1580 1585 1590
Glu Leu Ile Glu Thr Tyr Phe Val Ser Pro Thr Leu Phe Arg Val
1595 1600 1605
Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg Leu Ile Lys Gly
1610 1615 1620
Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu Met Met Ser Leu
1625 1630 1635
Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu Phe Leu Val Met Phe
1640 1645 1650
Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe Ala Tyr Val Lys Lys
1655 1660 1665
Glu Ala Gly Ile Asn Asp Met Phe Asn Phe Glu Thr Phe Gly Asn
1670 1675 1680
Ser Met Ile Cys Leu Phe Gln Ile Thr Thr Ser Ala Gly Trp Asp
1685 1690 1695
Gly Leu Leu Ala Pro Ile Leu Asn Ser Ala Pro Pro Asp Cys Asp
1700 1705 1710
Pro Lys Lys Val His Pro Gly Ser Ser Thr Glu Gly Asp Cys Gly
1715 1720 1725
Ser Pro Ser Val Gly Ile Phe Tyr Phe Val Ser Tyr Ile Ile Ile
1730 1735 1740
Ser Phe Leu Val Val Val Asn Met Tyr Ile Ala Val Ile Leu Glu
1745 1750 1755
Asn Phe Ser Val Ala Thr Glu Glu Ser Thr Glu Pro Leu Ser Glu
1760 1765 1770
Asp Asp Phe Glu Met Phe Tyr Glu Val Trp Glu Lys Phe Asp Pro
1775 1780 1785
Asp Ala Thr Gln Phe Ile Glu Tyr Ser Lys Leu Ser Asp Phe Ala
1790 1795 1800
Ala Ala Leu Asp Pro Pro Leu Leu Ile Ala Lys Pro Asn Lys Val
1805 1810 1815
Gln Leu Ile Ala Met Asp Leu Pro Met Val Ser Gly Asp Arg Ile
1820 1825 1830
His Cys Leu Asp Ile Leu Phe Ala Phe Thr Lys Arg Val Leu Gly
1835 1840 1845
Glu Ser Gly Glu Met Asp Ser Leu Arg Ser Gln Met Glu Glu Arg
1850 1855 1860
Phe Met Ser Ala Asn Pro Ser Lys Val Ser Tyr Glu Pro Ile Thr
1865 1870 1875
Thr Thr Leu Lys Arg Lys Gln Glu Asp Val Ser Ala Thr Val Ile
1880 1885 1890
Gln Arg Ala Tyr Arg Arg Tyr Arg Leu Arg Gln Asn Val Lys Asn
1895 1900 1905
Ile Ser Ser Ile Tyr Ile Lys Glu Gly Asp Lys Asp Asp Asp Leu
1910 1915 1920
Pro Asn Lys Gly Asp Ile Val Phe Asp Asn Val Asn Ser Ser Ser
1925 1930 1935
Pro Glu Lys Thr Asp Ala Thr Ala Ser Thr Ile Ser Pro Pro Ser
1940 1945 1950
Tyr Asp Ser Val Thr Lys Pro Asp Lys Glu Lys Tyr Glu Lys Asp
1955 1960 1965
Lys Thr Glu Lys Glu Asp Lys Gly Lys Asp Gly Lys Glu Thr Lys
1970 1975 1980
Lys
<210> 41
<211> 1984
<212> PRT
<213> 原鸡
<400> 41
Met Ala Met Leu Pro Pro Pro Gly Pro Gln Ser Phe Val Arg Phe Thr
1 5 10 15
Lys Gln Ser Leu Ala Leu Ile Glu Gln Arg Ile Ala Glu Gly Lys Thr
20 25 30
Lys Glu Pro Lys Glu Glu Lys Lys Asp Asp His Asp Glu Gly Pro Lys
35 40 45
Pro Ser Ser Asp Leu Glu Ala Gly Lys Gln Leu Pro Phe Ile Tyr Gly
50 55 60
Asp Ile Pro Ala Gly Met Val Ser Glu Pro Leu Glu Asp Leu Asp Pro
65 70 75 80
Tyr Tyr Ala Asp Lys Lys Thr Phe Ile Val Leu Asn Lys Gly Lys Ala
85 90 95
Ile Phe Arg Phe Asn Ala Thr Pro Ala Leu Tyr Ile Leu Ser Pro Phe
100 105 110
Ser Pro Leu Arg Arg Ile Ser Ile Lys Ile Leu Val His Ser Leu Phe
115 120 125
Ser Met Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Ile Phe Met Thr
130 135 140
Met Asn Asn Pro Ala Glu Trp Thr Lys Asn Val Glu Tyr Thr Phe Thr
145 150 155 160
Gly Ile Tyr Thr Phe Glu Ser Leu Val Lys Ile Phe Ala Arg Gly Phe
165 170 175
Cys Val Gly Glu Phe Thr Phe Leu Arg Asp Pro Trp Asn Trp Leu Asp
180 185 190
Phe Ile Val Ile Val Phe Ala Tyr Leu Thr Glu Phe Val Asn Leu Gly
195 200 205
Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala Leu Lys Thr
210 215 220
Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala Leu Ile Gln
225 230 235 240
Ser Val Lys Lys Leu Ser Asp Val Ile Ile Leu Thr Val Phe Cys Leu
245 250 255
Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly His Leu Lys
260 265 270
His Lys Cys Leu Arg Lys Ile Glu Asn Glu Thr Leu Glu Ser Ile Met
275 280 285
Ser Ser Ile Glu Ser Glu Glu Asp Tyr Lys Lys Tyr Phe Tyr Tyr Leu
290 295 300
Glu Gly Ser Lys Asp Ala Leu Leu Cys Gly Phe Ser Thr Asp Ser Gly
305 310 315 320
Gln Cys Pro Glu Gly Tyr Tyr Cys Val Lys Ala Gly Arg Asn Pro Asp
325 330 335
Tyr Gly Tyr Thr Ser Phe Asp Thr Phe Ser Trp Ala Phe Leu Ala Leu
340 345 350
Phe Arg Leu Met Thr Gln Asp Tyr Trp Glu Asn Leu Tyr Gln Gln Thr
355 360 365
Leu Arg Ala Ala Gly Lys Thr Tyr Met Ile Phe Phe Val Val Val Ile
370 375 380
Phe Leu Gly Ser Phe Tyr Leu Ile Asn Leu Ile Leu Ala Val Val Ala
385 390 395 400
Met Ala Tyr Glu Glu Gln Asn Gln Ala Asn Ile Glu Glu Ala Lys Gln
405 410 415
Lys Glu Leu Glu Phe Gln Gln Met Leu Asp Arg Leu Lys Lys Glu Gln
420 425 430
Glu Glu Ala Glu Ala Ile Ala Ala Ala Ala Ala Glu Tyr Thr Ser Ile
435 440 445
Gly Arg Ser Arg Ile Met Gly Leu Ser Glu Ser Ser Ser Glu Thr Ser
450 455 460
Lys Leu Ser Ser Lys Ser Ala Lys Glu Arg Arg Asn Arg Arg Lys Lys
465 470 475 480
Lys Asn Gln Lys Lys Leu Ser Ser Gly Glu Glu Lys Gly Asp Asp Glu
485 490 495
Lys Leu Ser Lys Ser Glu Ser Glu Glu Ser Ile Ser Arg Lys Gln Phe
500 505 510
His Leu Gly Val Glu Gly His Arg Leu Ala Arg Glu Lys Arg Leu Ser
515 520 525
Ala Pro Asn Gln Ser Pro Leu Ser Ile Arg Gly Ser Leu Phe Ser Ala
530 535 540
Arg Arg Ser Ser Arg Thr Ser Leu Phe Ser Phe Lys Gly Arg Gly Lys
545 550 555 560
Asp Ile Gly Ser Glu Thr Glu Phe Ala Asp Asp Glu His Ser Ile Phe
565 570 575
Gly Asp Asn Glu Ser Arg Arg Gly Ser Leu Phe Val Pro Gln Arg Pro
580 585 590
Gln Glu Arg Arg Ser Ser Asn Leu Ser Gln Ala Ser Arg Ser Pro Pro
595 600 605
Met Leu Gln Met Asn Gly Lys Met His Ser Ala Val Asp Cys Asn Gly
610 615 620
Val Val Ser Leu Val Asp Gly Pro Ser Ala Leu Met Leu Pro Asn Gly
625 630 635 640
Gln Leu Leu Pro Glu Val Ile Ile Asp Lys Ala Thr Ser Asp Asp Ser
645 650 655
Gly Thr Thr Gln Ile Arg Lys Lys Arg Arg Ser Ser Ser Tyr Leu Leu
660 665 670
Ser Glu Asp Met Leu Asn Asp Pro His Leu Arg Gln Arg Ala Met Ser
675 680 685
Arg Ala Ser Ile Leu Thr Asn Thr Val Glu Glu Leu Glu Glu Ser Arg
690 695 700
Gln Lys Cys Pro Ser Trp Trp Tyr Arg Phe Ala His Thr Phe Leu Ile
705 710 715 720
Trp Asn Cys Ser Pro Phe Trp Ile Lys Phe Lys Lys Phe Ile Tyr Ile
725 730 735
Ile Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile Cys Ile Val
740 745 750
Leu Asn Thr Leu Phe Met Ala Met Glu His His Pro Met Thr Glu Glu
755 760 765
Phe Lys Asn Val Leu Val Val Gly Asn Leu Val Phe Thr Gly Ile Phe
770 775 780
Ala Ala Glu Met Val Leu Lys Leu Ile Ala Met Asp Pro Tyr Glu Tyr
785 790 795 800
Phe Gln Val Gly Trp Asn Val Phe Asp Ser Leu Ile Val Thr Leu Ser
805 810 815
Leu Val Glu Leu Phe Leu Ala Asp Val Glu Gly Leu Ser Val Leu Arg
820 825 830
Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser Trp Pro Thr
835 840 845
Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly Pro Leu Gly
850 855 860
Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe Ala Val Val
865 870 875 880
Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val Cys Lys Ile
885 890 895
Asn Asp Asp Cys Ser Leu Pro Arg Trp His Met Asn Asp Phe Phe His
900 905 910
Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp Ile Glu Thr
915 920 925
Met Trp Asp Cys Met Glu Val Ala Gly Gln Ala Met Cys Leu Ile Val
930 935 940
Tyr Met Met Val Met Val Ile Gly Asn Leu Val Val Leu Asn Leu Phe
945 950 955 960
Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu Ser Ala Ile
965 970 975
Glu Glu Asp Thr Asp Ala Asn Asn Leu Gln Ile Ala Val Thr Arg Ile
980 985 990
Lys Lys Gly Ile Asn Tyr Val Lys Gln Thr Leu Arg Glu Leu Ile Leu
995 1000 1005
Lys Ala Phe Ser Lys Lys Pro Lys Ile Ser Lys Glu Ile Arg Gln
1010 1015 1020
Ala Glu Asp Leu Asn Ser Lys Lys Glu Asn Tyr Ile Ser Asn Arg
1025 1030 1035
Thr Leu Ala Glu Met Ser Lys Asp Tyr Asn Phe His Lys Glu Lys
1040 1045 1050
Asp Lys Ile Ser Gly Phe Gly Ser Ser Met Asp Lys Tyr Leu Met
1055 1060 1065
Glu Glu Ser Asp His Gln Ser Phe Ile His Asn Pro Ser Leu Thr
1070 1075 1080
Val Thr Val Pro Ile Ala Pro Gly Glu Ser Asp Leu Glu Asn Met
1085 1090 1095
Asn Thr Glu Glu Leu Ser Ser Asp Ser Glu Ser Glu Tyr Ser Lys
1100 1105 1110
Glu Arg Leu Asn Arg Ser Ser Ser Ser Glu Cys Ser Thr Val Asp
1115 1120 1125
Asn Ala Leu Pro Gly Glu Gly Glu Glu Ala Glu Ala Glu Pro Val
1130 1135 1140
Asn Ser Asp Glu Pro Glu Ala Cys Phe Thr Asp Gly Cys Val Arg
1145 1150 1155
Arg Phe Pro Cys Cys Gln Val Ser Ile Glu Ser Gly Lys Gly Lys
1160 1165 1170
Ile Trp Trp Asn Ile Arg Lys Thr Cys Tyr Arg Ile Val Glu His
1175 1180 1185
Ser Trp Phe Glu Ser Phe Ile Val Leu Met Ile Leu Leu Ser Ser
1190 1195 1200
Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile Glu Lys Lys Lys Thr
1205 1210 1215
Ile Lys Ile Ile Leu Glu Tyr Ala Asp Lys Ile Phe Thr Tyr Ile
1220 1225 1230
Phe Ile Leu Glu Met Leu Leu Lys Trp Val Ala Tyr Gly Tyr Lys
1235 1240 1245
Thr Tyr Phe Thr Asn Ala Trp Cys Trp Leu Asp Phe Leu Ile Val
1250 1255 1260
Asp Val Ser Leu Val Thr Leu Val Ala Asn Thr Leu Gly Tyr Ser
1265 1270 1275
Asp Leu Gly Pro Ile Lys Ser Leu Arg Thr Leu Arg Ala Leu Arg
1280 1285 1290
Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly Met Arg Val Val Val
1295 1300 1305
Asn Ala Leu Ile Gly Ala Ile Pro Ser Ile Met Asn Val Leu Leu
1310 1315 1320
Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile Met Gly Val Asn
1325 1330 1335
Leu Phe Ala Gly Lys Phe Tyr Gln Cys Val Asn Thr Thr Asp Asp
1340 1345 1350
Ser Arg Phe Pro Thr Lys Gln Val Ser Asn Arg Ser Glu Cys Phe
1355 1360 1365
Ala Leu Met Asn Gly Ser Gln Asn Val Arg Trp Lys Asn Leu Lys
1370 1375 1380
Val Asn Phe Asp Asn Val Gly Leu Arg Tyr Leu Ser Leu Leu Gln
1385 1390 1395
Val Ala Thr Phe Lys Gly Trp Met Asp Ile Met Tyr Ala Ala Val
1400 1405 1410
Asp Ser Val Asn Val Asp Gln Gln Pro Ser Tyr Glu His Asn Leu
1415 1420 1425
Tyr Met Tyr Ile Tyr Phe Val Ile Phe Ile Ile Phe Gly Ser Phe
1430 1435 1440
Phe Thr Leu Asn Leu Phe Ile Gly Val Ile Ile Asp Asn Phe Asn
1445 1450 1455
Gln Gln Lys Lys Lys Leu Gly Gly Gln Asp Ile Phe Met Thr Glu
1460 1465 1470
Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys Leu Gly Ser Lys
1475 1480 1485
Lys Pro Gln Lys Pro Ile Pro Arg Pro Gly Asn Lys Phe Gln Gly
1490 1495 1500
Cys Ile Phe Asp Leu Val Thr Asn Gln Ala Phe Asp Ile Thr Ile
1505 1510 1515
Met Ile Leu Ile Cys Leu Asn Met Val Thr Met Met Val Glu Lys
1520 1525 1530
Glu Gly Gln Ser Asp Tyr Met Thr Asp Val Leu Tyr Trp Ile Asn
1535 1540 1545
Val Val Phe Ile Ile Leu Phe Thr Gly Glu Cys Val Leu Lys Leu
1550 1555 1560
Ile Ser Leu Arg His Tyr Tyr Phe Thr Ile Gly Trp Asn Ile Phe
1565 1570 1575
Asp Phe Val Val Val Ile Leu Ser Ile Val Gly Met Phe Leu Ala
1580 1585 1590
Glu Leu Ile Glu Thr Tyr Phe Val Ser Pro Thr Leu Phe Arg Val
1595 1600 1605
Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg Leu Ile Lys Gly
1610 1615 1620
Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu Met Met Ser Leu
1625 1630 1635
Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu Phe Leu Val Met Phe
1640 1645 1650
Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe Ala Tyr Val Lys Lys
1655 1660 1665
Glu Ala Gly Ile Asn Asp Met Phe Asn Phe Glu Thr Phe Gly Asn
1670 1675 1680
Ser Met Ile Cys Leu Phe Gln Ile Thr Thr Ser Ala Gly Trp Asp
1685 1690 1695
Gly Leu Leu Ala Pro Ile Leu Asn Ser Ala Pro Pro Asp Cys Asp
1700 1705 1710
Pro Lys Lys Val His Pro Gly Ser Ser Thr Glu Gly Asp Cys Gly
1715 1720 1725
Ser Pro Ser Val Gly Ile Phe Tyr Phe Val Ser Tyr Ile Ile Ile
1730 1735 1740
Ser Phe Leu Val Val Val Asn Met Tyr Ile Ala Val Ile Leu Glu
1745 1750 1755
Asn Phe Ser Val Ala Thr Glu Glu Ser Thr Glu Pro Leu Ser Glu
1760 1765 1770
Asp Asp Phe Glu Met Phe Tyr Glu Val Trp Glu Lys Phe Asp Pro
1775 1780 1785
Asp Ala Thr Gln Phe Ile Glu Tyr Ser Lys Leu Ser Asp Phe Ala
1790 1795 1800
Ala Ala Leu Asp Pro Pro Leu Leu Ile Ala Lys Pro Asn Lys Val
1805 1810 1815
Gln Leu Ile Ala Met Asp Leu Pro Met Val Ser Gly Asp Arg Ile
1820 1825 1830
His Cys Leu Asp Ile Leu Phe Ala Phe Thr Lys Arg Val Leu Gly
1835 1840 1845
Glu Ser Gly Glu Met Asp Ser Leu Arg Ser Gln Met Glu Glu Arg
1850 1855 1860
Phe Met Ser Ala Asn Pro Ser Lys Val Ser Tyr Glu Pro Ile Thr
1865 1870 1875
Thr Thr Leu Lys Arg Lys Gln Glu Asp Val Ser Ala Thr Val Ile
1880 1885 1890
Gln Arg Ala Tyr Arg Arg Tyr Arg Leu Arg Gln Asn Val Lys Asn
1895 1900 1905
Ile Ser Ser Ile Tyr Ile Lys Glu Gly Asp Lys Asp Asp Asp Leu
1910 1915 1920
Pro Asn Lys Gly Asp Ile Val Phe Asp Asn Val Asn Ser Ser Ser
1925 1930 1935
Pro Glu Lys Thr Asp Ala Thr Ala Ser Thr Ile Ser Pro Pro Ser
1940 1945 1950
Tyr Asp Ser Val Thr Lys Pro Asp Lys Glu Lys Tyr Glu Lys Asp
1955 1960 1965
Lys Thr Glu Lys Glu Asp Lys Gly Lys Asp Gly Lys Glu Thr Lys
1970 1975 1980
Lys
<210> 42
<211> 1730
<212> PRT
<213> 眼镜王蛇
<400> 42
Leu Lys Thr Ile Val Gly Ala Leu Ile Gln Ser Val Lys Lys Leu Ser
1 5 10 15
Asp Val Met Ile Leu Thr Leu Phe Cys Leu Ser Val Phe Ala Leu Ile
20 25 30
Gly Leu Gln Leu Phe Met Gly His Leu Arg His Lys Cys Leu Leu Trp
35 40 45
Pro Leu Ser Asn Thr Ser Tyr Lys Asp Pro Arg Phe Met Glu Tyr Tyr
50 55 60
Asn Gly Thr Glu Leu Met Trp Ser Lys Tyr Ile Glu Asn Lys Glu His
65 70 75 80
Phe Tyr Phe Leu Glu Gly Ala Lys Asp Ala Leu Leu Cys Gly Asn Ser
85 90 95
Thr Asp Ala Gly Gln Cys Pro Glu Gly Tyr Lys Cys Ile Pro Ala Gly
100 105 110
Arg Asn Pro Asp Tyr Gly Tyr Thr Ser Phe Asp Ser Phe Ser Trp Ala
115 120 125
Phe Leu Ser Leu Phe Arg Leu Met Thr Gln Asp Tyr Trp Glu Asn Leu
130 135 140
Tyr Gln Gln Thr Leu Arg Ala Ala Gly Lys Gly Tyr Met Phe Phe Phe
145 150 155 160
Val Val Val Ile Phe Leu Gly Ser Phe Tyr Leu Val Asn Leu Ile Leu
165 170 175
Ala Val Val Ala Met Ala Tyr Asp Glu Gln Asn Gln Ala Thr Ile Glu
180 185 190
Glu Ala Leu Arg Lys Glu Thr Glu Tyr Gln Gln Met Leu Glu His Leu
195 200 205
Lys Arg Gln Gln Glu Glu Ala Gln Ala Leu Ala Ala Ala Val Ala Cys
210 215 220
Lys Asp Phe Arg Asp Asp Gly Ala Leu Gly Arg Leu Ser Glu Thr Ser
225 230 235 240
Ser Glu Leu Ser Ser Ser Lys Ser Ala Lys Glu Arg Arg Asn Arg Arg
245 250 255
Lys Lys Arg Arg Gln Arg Glu Leu Ser Val Gly Glu Pro Gly Gly Asn
260 265 270
Ser Lys Met Phe Pro Lys Ser Glu Ser Asp Ser Ser Ile Arg Arg Lys
275 280 285
Gly Phe Arg Phe Ser Leu Glu Gly Asn Arg Leu Thr Tyr Glu Asn Arg
290 295 300
Val Ile Ser Pro Tyr Gln Ser Met Leu Phe Pro Thr Arg Arg Asn Ser
305 310 315 320
Arg Ala Ser Phe Ser Ser Phe Lys Gly Pro Thr Ala Glu Gly Ser Ser
325 330 335
Asp Ala Asp Ser Glu His Ser Thr Phe Glu Glu Asn Gly Ser Arg Asn
340 345 350
Gly Ser Tyr Phe Val Val Arg Arg His Ser Asp Arg Arg Ser Ser Asn
355 360 365
Ile Ser Gln Thr Met Phe Pro Met Asn Gly Lys Met Gln Ser Ser Val
370 375 380
Asp Cys Asn Gly Val Val Ser Leu Val Gly Gly Pro Pro Val Leu Leu
385 390 395 400
Ser Pro Thr Gly Gln Leu Leu Pro Glu Val Ile Ile Asp Lys Ala Thr
405 410 415
Thr Asn Asp Asn Gly Thr Ala Ser Glu Met Glu Gly Lys Lys Arg Arg
420 425 430
Ser Ser Ser Phe Gln Ile Ser Met Asp Leu Leu Glu Asp Pro Thr Ile
435 440 445
Arg Gln Arg Ala Met Ser Ile Ala Ser Ile Ile Thr Asn Thr Met Glu
450 455 460
Glu Leu Glu Glu Ser Arg Gln Lys Cys Pro Pro Cys Trp Tyr Lys Phe
465 470 475 480
Ala His Ser Tyr Leu Ile Trp Asn Cys Ser Asp Arg Trp Leu Gln Ile
485 490 495
Lys Arg Ile Ile His Leu Ile Val Met Asp Pro Phe Val Asp Leu Gly
500 505 510
Ile Thr Ile Cys Ile Ile Leu Asn Thr Leu Phe Met Ser Met Glu His
515 520 525
Tyr Pro Ile Asp Asp Ser Phe Ser Gly Val Leu Lys Asn Gly Asn Met
530 535 540
Val Phe Thr Gly Ile Phe Thr Ala Glu Met Val Leu Lys Ile Ile Ala
545 550 555 560
Met Asp Pro Tyr Tyr Tyr Phe Gln Glu Gly Trp Asn Ile Phe Asp Ser
565 570 575
Ile Ile Val Thr Leu Ser Leu Met Glu Leu Gly Leu Gln Asp Val Glu
580 585 590
Gly Leu Ser Val Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu
595 600 605
Ala Lys Ser Trp Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn
610 615 620
Ser Val Gly Ala Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val
625 630 635 640
Phe Ile Phe Ala Val Val Gly Met Gln Leu Phe Gly Lys Asn Tyr Asp
645 650 655
Ser Cys Lys Cys Lys Ile Ser Glu Asp Cys Lys Leu Pro Arg Trp His
660 665 670
Met Asn Asp Phe Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys
675 680 685
Gly Glu Trp Ile Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln
690 695 700
Ala Leu Cys Leu Thr Val Phe Met Met Val Met Val Ile Gly Asn Leu
705 710 715 720
Val Leu Leu Asn Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser
725 730 735
Asp Ser Leu Ala Ala Pro Glu Gln Glu Thr Glu Ala Asn Asn Leu Gln
740 745 750
Ile Ala Ile Ser Arg Ile Gln Arg Gly Ile Asn Tyr Ile Lys Arg Lys
755 760 765
Ile Cys Glu Phe Val Gln Ile Val Phe Leu Gln Lys Cys Lys Gly Thr
770 775 780
Ser Gly Leu Ser Ala Ala Asp Gln Gln Asn Asn Lys Lys Asp Gln Cys
785 790 795 800
Ile Pro Asn His Thr Val Val Glu Ile Asn Gln Thr Phe Gly Tyr Gln
805 810 815
Lys Pro Lys Met Thr Thr Thr Cys Met Asp Asn Ser Asp His Met Ser
820 825 830
Phe Ile Asn Asn Pro Asn Leu Thr Val Thr Val Pro Ile Ala Val Gly
835 840 845
Glu Ser Asp Phe Glu His Phe Asn Thr Glu Glu Leu Thr Ser Ile Ser
850 855 860
Glu Leu Glu Glu Thr Lys Glu Lys Thr Ser Leu Cys Ser Ser Thr Glu
865 870 875 880
Gly Ser Thr Ile Ile Phe Ala Ser Val Gly Asp Lys Glu Ser Asp Thr
885 890 895
Ala Ala Lys Gly Pro Pro Gln Pro Gln Pro Cys Phe Thr Asp Gly Cys
900 905 910
Val Gln Lys Phe Arg Cys Cys Gln Ile Asn Ile Glu Ser Gly Lys Gly
915 920 925
Lys Cys Trp Trp Asn Leu Arg Lys Thr Cys Phe Lys Ile Val Glu His
930 935 940
Asn Trp Phe Glu Thr Phe Ile Val Phe Met Ile Leu Leu Ser Ser Gly
945 950 955 960
Ala Leu Ala Phe Glu Asp Ile Tyr Ile Glu Gln Arg Lys Thr Ile Lys
965 970 975
Thr Val Leu Glu Tyr Ala Asp Lys Val Phe Thr Tyr Ile Phe Ile Leu
980 985 990
Glu Met Leu Leu Lys Trp Val Ala Tyr Gly Phe Gln Val Tyr Phe Thr
995 1000 1005
Asn Ala Trp Cys Trp Leu Asp Phe Met Ile Val Asp Val Ser Leu
1010 1015 1020
Val Ser Leu Ile Ala Asn Ala Leu Asn Tyr Ser Glu Leu Gly Pro
1025 1030 1035
Ile Lys Ser Leu Arg Thr Leu Arg Ala Leu Arg Pro Leu Arg Ala
1040 1045 1050
Leu Ser Arg Phe Glu Gly Met Arg Val Val Val Asn Ala Leu Val
1055 1060 1065
Gly Ala Ile Pro Ser Ile Met Asn Val Leu Leu Val Cys Leu Ile
1070 1075 1080
Phe Trp Leu Ile Phe Ser Ile Met Gly Val Asn Leu Phe Ala Gly
1085 1090 1095
Thr Phe Phe Glu Cys Val Asn Lys Thr Asp Gly Val Arg Ile Ser
1100 1105 1110
His Leu Ile Val Pro Phe Lys Asn Val Cys Glu Thr Leu Asp Tyr
1115 1120 1125
Ala Arg Trp Arg Asn Val Lys Val Asn Phe Asp Asn Val Gly Ala
1130 1135 1140
Gly Tyr Leu Ser Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Met
1145 1150 1155
Glu Ile Met Tyr Ala Ala Val Asp Ser Thr Gly Ile Glu Lys Gln
1160 1165 1170
Pro Gln Tyr Glu His Asn Leu Tyr Met Tyr Leu Tyr Phe Val Gly
1175 1180 1185
Phe Ile Ile Phe Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly
1190 1195 1200
Val Ile Ile Asp Asn Phe Asn Gln Gln Lys Lys Lys Leu Gly Gly
1205 1210 1215
Gln Asp Ile Phe Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala
1220 1225 1230
Met Lys Lys Leu Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg
1235 1240 1245
Pro Ser Asn Lys Ile Gln Gly Phe Ile Phe Asp Phe Val Thr Lys
1250 1255 1260
Gln Ala Phe Asp Ile Gly Ile Met Ile Leu Ile Cys Leu Asn Met
1265 1270 1275
Val Thr Met Met Val Glu Thr Ala Asp Gln Asp Ser Ser Val Glu
1280 1285 1290
Glu Ile Leu Tyr Trp Ile Asn Leu Phe Phe Ile Val Ile Phe Thr
1295 1300 1305
Gly Glu Cys Leu Leu Lys Leu Ile Ala Leu Arg Tyr Tyr Tyr Phe
1310 1315 1320
Thr Ile Gly Trp Asn Ile Phe Asp Phe Val Val Val Ile Phe Ser
1325 1330 1335
Ile Val Gly Met Cys Leu Ser Gln Ile Ile Glu Lys Phe Phe Val
1340 1345 1350
Ser Pro Thr Leu Phe Arg Val Val Arg Leu Ala Arg Ile Gly Arg
1355 1360 1365
Val Leu Arg Leu Ile Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu
1370 1375 1380
Phe Ala Leu Met Met Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu
1385 1390 1395
Leu Leu Phe Leu Val Met Phe Ile Tyr Ala Ile Phe Gly Met Ser
1400 1405 1410
Gln Phe Ala Tyr Val Lys Lys Glu Ser Gly Ile Asp Asp Met Phe
1415 1420 1425
Asn Phe Glu Thr Phe Ala Asn Ser Met Ile Cys Leu Phe Gln Ile
1430 1435 1440
Thr Thr Ser Gly Gly Trp Asn Tyr Leu Leu Phe Pro Ile Leu Asn
1445 1450 1455
Lys Glu Pro Asp Cys Asp Pro Lys Lys Val His Pro Gly Ser Ser
1460 1465 1470
Val Glu Gly Asp Cys Gly Asn Pro Ser Val Gly Ile Phe Phe Phe
1475 1480 1485
Val Ser Tyr Ile Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr
1490 1495 1500
Ile Ala Val Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser
1505 1510 1515
Ala Glu Pro Leu Gly Glu Asp Asp Phe Glu Met Phe Tyr Glu Val
1520 1525 1530
Trp Glu Lys Phe Asp Pro Gly Ala Thr Gln Phe Ile Glu Phe Ser
1535 1540 1545
Lys Leu Phe Asp Phe Ala Ala Ser Leu Glu Pro Pro Leu Leu Ile
1550 1555 1560
Pro Lys Pro Asn Lys Val Gln Leu Ile Ala Met Asp Leu Pro Ile
1565 1570 1575
Val Ser Gly Asp Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe
1580 1585 1590
Thr Lys Arg Val Leu Gly Glu Ser Asp Glu Met Asp Ala Leu Arg
1595 1600 1605
Val Gln Met Glu Asp Arg Phe Met Ala Ala Asn Pro Ser Lys Val
1610 1615 1620
Ser Tyr Glu Pro Ile Thr Thr Thr Leu Lys Arg Lys Leu Glu Glu
1625 1630 1635
Gln Ser Ala Lys Val Ile Gln Arg Ala Phe Arg His Tyr Arg Leu
1640 1645 1650
Arg Lys Pro Val Cys Asn Thr Ser Tyr Leu Tyr Arg Asp Gly Asp
1655 1660 1665
Val Phe Pro Ser Lys Thr Glu Met Ala Phe Asp Lys Leu Ser Leu
1670 1675 1680
Ser Leu Thr Leu Glu Lys Thr Glu Arg Ser Ser Ser Thr Thr Ser
1685 1690 1695
Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Asp Lys Tyr Glu Gln
1700 1705 1710
Glu Lys Ser Glu Lys Glu Glu Lys Gly Lys Asp Asp Lys Asp Tyr
1715 1720 1725
Arg Lys
1730
<210> 43
<211> 2005
<212> PRT
<213> 倭黑猩猩
<400> 43
Met Ala Gln Ser Val Leu Val Pro Pro Gly Pro Asp Ser Phe Arg Phe
1 5 10 15
Phe Thr Arg Glu Ser Leu Ala Ala Ile Glu Gln Arg Ile Ala Glu Glu
20 25 30
Lys Ala Lys Arg Pro Lys Gln Glu Arg Lys Asp Glu Asp Asp Glu Asn
35 40 45
Gly Pro Lys Pro Asn Ser Asp Leu Glu Ala Gly Lys Ser Leu Pro Phe
50 55 60
Ile Tyr Gly Asp Ile Pro Pro Glu Met Val Ser Val Pro Leu Glu Asp
65 70 75 80
Leu Asp Pro Phe Tyr Ile Asn Lys Lys Thr Phe Ile Val Leu Asn Lys
85 90 95
Gly Lys Ala Ile Ser Arg Phe Ser Ala Thr Pro Ala Leu Tyr Ile Leu
100 105 110
Thr Pro Phe Asn Pro Ile Arg Lys Leu Ala Ile Lys Ile Leu Val His
115 120 125
Ser Leu Phe Asn Met Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Val
130 135 140
Phe Met Thr Met Ser Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr
145 150 155 160
Thr Phe Thr Gly Ile Tyr Thr Phe Glu Ser Leu Ile Lys Ile Leu Ala
165 170 175
Arg Gly Phe Cys Leu Glu Asp Phe Thr Phe Leu Arg Asp Pro Trp Asn
180 185 190
Trp Leu Asp Phe Thr Val Ile Thr Phe Ala Tyr Val Thr Glu Phe Val
195 200 205
Asp Leu Gly Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala
210 215 220
Leu Lys Thr Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala
225 230 235 240
Leu Ile Gln Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val
245 250 255
Phe Cys Leu Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly
260 265 270
Asn Leu Arg Asn Lys Cys Leu Gln Trp Pro Pro Asp Asn Ser Ser Phe
275 280 285
Glu Ile Asn Ile Thr Ser Phe Phe Asn Asn Ser Leu Asp Gly Asn Gly
290 295 300
Thr Thr Phe Asn Arg Thr Val Ser Ile Phe Asn Trp Asp Glu Tyr Ile
305 310 315 320
Glu Asp Lys Ser His Phe Tyr Phe Leu Glu Gly Gln Asn Asp Ala Leu
325 330 335
Leu Cys Gly Asn Ser Ser Asp Ala Gly Gln Cys Pro Glu Gly Tyr Ile
340 345 350
Cys Val Lys Ala Gly Arg Asn Pro Asn Tyr Gly Tyr Thr Ser Phe Asp
355 360 365
Thr Phe Ser Trp Ala Phe Leu Ser Leu Phe Arg Leu Met Thr Gln Asp
370 375 380
Phe Trp Glu Asn Leu Tyr Gln Leu Thr Leu Arg Ala Ala Gly Lys Thr
385 390 395 400
Tyr Met Ile Phe Phe Val Leu Val Ile Phe Leu Gly Ser Phe Tyr Leu
405 410 415
Ile Asn Leu Ile Leu Ala Val Val Ala Met Ala Tyr Glu Glu Gln Asn
420 425 430
Gln Ala Thr Leu Glu Glu Ala Glu Gln Lys Glu Ala Glu Phe Gln Gln
435 440 445
Met Leu Glu Gln Leu Lys Lys Gln Gln Glu Glu Ala Gln Ala Ala Ala
450 455 460
Ala Ala Ala Ser Ala Glu Ser Arg Asp Phe Ser Gly Ala Gly Gly Ile
465 470 475 480
Gly Val Phe Ser Glu Ser Ser Ser Val Ala Ser Lys Leu Ser Ser Lys
485 490 495
Ser Glu Lys Glu Leu Lys Asn Arg Arg Lys Lys Lys Lys Gln Lys Glu
500 505 510
Gln Ser Gly Glu Glu Glu Lys Asn Asp Arg Val Arg Lys Ser Glu Ser
515 520 525
Glu Asp Ser Ile Arg Arg Lys Gly Phe Arg Phe Ser Leu Glu Gly Ser
530 535 540
Arg Leu Thr Tyr Glu Lys Arg Phe Ser Ser Pro His Gln Ser Leu Leu
545 550 555 560
Ser Ile Arg Gly Ser Leu Phe Ser Pro Arg Arg Asn Ser Arg Ala Ser
565 570 575
Leu Phe Ser Phe Arg Gly Arg Ala Lys Asp Ile Gly Ser Glu Asn Asp
580 585 590
Phe Ala Asp Asp Glu His Ser Thr Phe Glu Asp Asn Asp Ser Arg Arg
595 600 605
Asp Ser Leu Phe Val Pro His Arg His Gly Glu Arg Arg His Ser Asn
610 615 620
Val Ser Gln Ala Ser Arg Ala Ser Arg Val Leu Pro Ile Leu Pro Met
625 630 635 640
Asn Gly Lys Met His Ser Ala Val Asp Cys Asn Gly Val Val Ser Leu
645 650 655
Val Gly Gly Pro Ser Thr Leu Thr Ser Ala Gly Gln Leu Leu Pro Glu
660 665 670
Gly Thr Thr Thr Glu Thr Glu Ile Arg Lys Arg Arg Ser Ser Ser Tyr
675 680 685
His Val Ser Met Asp Leu Leu Glu Asp Pro Thr Ser Arg Gln Arg Ala
690 695 700
Met Ser Ile Ala Ser Ile Leu Thr Asn Thr Met Glu Glu Leu Glu Glu
705 710 715 720
Ser Arg Gln Lys Cys Pro Pro Cys Trp Tyr Lys Phe Ala Asn Met Cys
725 730 735
Leu Ile Trp Asp Cys Cys Lys Pro Trp Leu Lys Val Lys His Leu Val
740 745 750
Asn Leu Val Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile Cys
755 760 765
Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His Tyr Pro Met Thr
770 775 780
Glu Gln Phe Ser Ser Val Leu Ser Val Gly Asn Leu Val Phe Thr Gly
785 790 795 800
Ile Phe Thr Ala Glu Met Phe Leu Lys Ile Ile Ala Met Asp Pro Tyr
805 810 815
Tyr Tyr Phe Gln Glu Gly Trp Asn Ile Phe Asp Gly Phe Ile Val Ser
820 825 830
Leu Ser Leu Met Glu Leu Gly Leu Ala Asn Val Glu Gly Leu Ser Val
835 840 845
Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser Trp
850 855 860
Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly Ala
865 870 875 880
Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe Ala
885 890 895
Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val Cys
900 905 910
Lys Ile Ser Asn Asp Cys Glu Leu Pro Arg Trp His Met His Asp Phe
915 920 925
Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp Ile
930 935 940
Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Thr Met Cys Leu
945 950 955 960
Thr Val Phe Met Met Val Met Val Ile Gly Asn Leu Val Val Leu Asn
965 970 975
Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu Ala
980 985 990
Ala Thr Asp Asp Asp Asn Glu Met Asn Asn Leu Gln Ile Ala Val Gly
995 1000 1005
Arg Met Gln Lys Gly Ile Asp Phe Val Lys Arg Lys Ile Arg Glu
1010 1015 1020
Phe Ile Gln Lys Ala Phe Val Arg Lys Gln Lys Ala Leu Asp Glu
1025 1030 1035
Ile Lys Pro Leu Glu Asp Leu Asn Asn Lys Lys Asp Ser Cys Ile
1040 1045 1050
Ser Asn His Thr Thr Ile Glu Ile Gly Lys Asp Leu Asn Tyr Leu
1055 1060 1065
Lys Asp Gly Asn Gly Thr Thr Ser Gly Ile Gly Ser Ser Val Glu
1070 1075 1080
Lys Tyr Val Val Asp Glu Ser Asp Tyr Leu Ser Phe Ile Asn Asn
1085 1090 1095
Pro Ser Leu Thr Val Thr Val Pro Ile Ala Val Gly Glu Ser Asp
1100 1105 1110
Phe Glu Asn Leu Asn Thr Glu Glu Phe Ser Ser Glu Ser Asp Met
1115 1120 1125
Glu Glu Ser Lys Glu Lys Leu Asn Ala Thr Ser Ser Ser Glu Gly
1130 1135 1140
Ser Thr Val Asp Ile Gly Ala Pro Ala Glu Gly Glu Gln Pro Glu
1145 1150 1155
Val Glu Pro Glu Glu Ser Leu Glu Pro Glu Ala Cys Phe Thr Glu
1160 1165 1170
Asp Cys Val Arg Lys Phe Lys Cys Cys Gln Ile Ser Ile Glu Glu
1175 1180 1185
Gly Lys Gly Lys Leu Trp Trp Asn Leu Arg Lys Thr Cys Tyr Lys
1190 1195 1200
Ile Val Glu His Asn Trp Phe Glu Thr Phe Ile Val Phe Met Ile
1205 1210 1215
Leu Leu Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile Glu
1220 1225 1230
Gln Arg Lys Thr Ile Lys Thr Met Leu Glu Tyr Ala Asp Lys Val
1235 1240 1245
Phe Thr Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Val Ala
1250 1255 1260
Tyr Gly Phe Gln Val Tyr Phe Thr Asn Ala Trp Cys Trp Leu Asp
1265 1270 1275
Phe Leu Ile Val Asp Val Ser Leu Val Ser Leu Thr Ala Asn Ala
1280 1285 1290
Leu Gly Tyr Ser Glu Leu Gly Ala Ile Lys Ser Leu Arg Thr Leu
1295 1300 1305
Arg Ala Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly Met
1310 1315 1320
Arg Val Val Val Asn Ala Leu Leu Gly Ala Ile Pro Ser Ile Met
1325 1330 1335
Asn Val Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile
1340 1345 1350
Met Gly Val Asn Leu Phe Ala Gly Lys Phe Tyr His Cys Ile Asn
1355 1360 1365
Tyr Thr Thr Gly Glu Met Phe Asp Val Ser Val Val Asn Asn Tyr
1370 1375 1380
Ser Glu Cys Lys Ala Leu Ile Glu Ser Asn Gln Thr Ala Arg Trp
1385 1390 1395
Lys Asn Val Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr Leu
1400 1405 1410
Ser Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile Met
1415 1420 1425
Tyr Ala Ala Val Asp Ser Arg Asn Val Glu Leu Gln Pro Lys Tyr
1430 1435 1440
Glu Asp Asn Leu Tyr Met Tyr Leu Tyr Phe Val Ile Phe Ile Ile
1445 1450 1455
Phe Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile Ile
1460 1465 1470
Asp Asn Phe Asn Gln Gln Lys Lys Lys Phe Gly Gly Gln Asp Ile
1475 1480 1485
Phe Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys
1490 1495 1500
Leu Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Ala Asn
1505 1510 1515
Lys Phe Gln Gly Met Val Phe Asp Phe Val Thr Lys Gln Val Phe
1520 1525 1530
Asp Ile Ser Ile Met Ile Leu Ile Cys Leu Asn Met Val Thr Met
1535 1540 1545
Met Val Glu Thr Asp Asp Gln Ser Gln Glu Met Thr Asn Ile Leu
1550 1555 1560
Tyr Trp Ile Asn Leu Val Phe Ile Val Leu Phe Thr Gly Glu Cys
1565 1570 1575
Val Leu Lys Leu Ile Ser Leu Arg Tyr Tyr Tyr Phe Thr Ile Gly
1580 1585 1590
Trp Asn Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile Val Gly
1595 1600 1605
Met Phe Leu Ala Glu Leu Ile Glu Lys Tyr Phe Val Ser Pro Thr
1610 1615 1620
Leu Phe Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg
1625 1630 1635
Leu Ile Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu
1640 1645 1650
Met Met Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu Phe
1655 1660 1665
Leu Val Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe Ala
1670 1675 1680
Tyr Val Lys Arg Glu Val Gly Ile Asp Asp Met Phe Asn Phe Glu
1685 1690 1695
Thr Phe Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr Ser
1700 1705 1710
Ala Gly Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Gly Pro
1715 1720 1725
Pro Asp Cys Asp Pro Glu Lys Asp His Pro Gly Ser Ser Val Lys
1730 1735 1740
Gly Asp Cys Gly Asn Pro Ser Val Gly Ile Phe Phe Phe Val Ser
1745 1750 1755
Tyr Ile Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile Ala
1760 1765 1770
Val Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Ala Glu
1775 1780 1785
Pro Leu Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp Glu
1790 1795 1800
Lys Phe Asp Pro Asp Ala Thr Gln Phe Ile Glu Phe Ala Lys Leu
1805 1810 1815
Ser Asp Phe Ala Asp Ala Leu Asp Pro Pro Leu Leu Ile Ala Lys
1820 1825 1830
Pro Asn Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val Ser
1835 1840 1845
Gly Asp Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr Lys
1850 1855 1860
Arg Val Leu Gly Glu Ser Gly Glu Met Asp Ala Leu Arg Ile Gln
1865 1870 1875
Met Glu Glu Arg Phe Met Ala Ser Asn Pro Ser Lys Val Ser Tyr
1880 1885 1890
Glu Pro Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Glu Val Ser
1895 1900 1905
Ala Ile Ile Ile Gln Arg Ala Tyr Arg Arg Tyr Leu Leu Lys Gln
1910 1915 1920
Lys Val Lys Lys Val Ser Ser Ile Tyr Lys Lys Asp Lys Gly Lys
1925 1930 1935
Glu Cys Asp Gly Thr Pro Ile Lys Glu Asp Thr Leu Ile Asp Lys
1940 1945 1950
Leu Asn Glu Asn Ser Thr Pro Glu Lys Thr Asp Met Thr Pro Ser
1955 1960 1965
Thr Thr Ser Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Glu Lys
1970 1975 1980
Glu Lys Phe Glu Lys Asp Lys Ser Glu Lys Glu Asp Lys Gly Lys
1985 1990 1995
Asp Ile Arg Glu Ser Lys Lys
2000 2005
<210> 44
<211> 2005
<212> PRT
<213> 恒河猴
<400> 44
Met Ala Gln Ser Val Leu Val Pro Pro Gly Pro Asp Ser Phe Arg Phe
1 5 10 15
Phe Thr Arg Glu Ser Leu Ala Ala Ile Glu Gln Arg Ile Ala Glu Glu
20 25 30
Lys Ala Lys Arg Pro Lys Gln Glu Arg Lys Asp Glu Asp Asp Glu Asn
35 40 45
Gly Pro Lys Pro Asn Ser Asp Leu Glu Ala Gly Lys Ser Leu Pro Phe
50 55 60
Ile Tyr Gly Asp Ile Pro Pro Glu Met Val Ser Val Pro Leu Glu Asp
65 70 75 80
Leu Asp Pro Tyr Tyr Ile Asn Lys Lys Thr Phe Ile Val Leu Asn Lys
85 90 95
Gly Lys Ala Ile Ser Arg Phe Ser Ala Thr Pro Ala Leu Tyr Ile Leu
100 105 110
Thr Pro Phe Asn Pro Ile Arg Lys Leu Ala Ile Lys Ile Leu Val His
115 120 125
Ser Leu Phe Asn Met Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Val
130 135 140
Phe Met Thr Met Ser Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr
145 150 155 160
Thr Phe Thr Gly Ile Tyr Thr Phe Glu Ser Leu Ile Lys Ile Leu Ala
165 170 175
Arg Gly Phe Cys Leu Glu Asp Phe Thr Phe Leu Arg Asp Pro Trp Asn
180 185 190
Trp Leu Asp Phe Thr Val Ile Thr Phe Ala Tyr Val Thr Glu Phe Val
195 200 205
Asp Leu Gly Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala
210 215 220
Leu Lys Thr Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala
225 230 235 240
Leu Ile Gln Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val
245 250 255
Phe Cys Leu Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly
260 265 270
Asn Leu Arg Asn Lys Cys Leu Gln Trp Pro Pro Asp Asn Ser Ser Phe
275 280 285
Glu Ile Asn Ile Thr Ser Phe Phe Asn Asn Ser Leu Asp Gly Asn Gly
290 295 300
Thr Thr Phe Asn Arg Thr Val Ser Met Phe Asn Trp Asp Glu Tyr Ile
305 310 315 320
Glu Asp Lys Ser His Phe Tyr Phe Leu Glu Gly Gln Asn Asp Ala Leu
325 330 335
Leu Cys Gly Asn Ser Ser Asp Ala Gly Gln Cys Pro Glu Gly Tyr Ile
340 345 350
Cys Val Lys Ala Gly Arg Asn Pro Asn Tyr Gly Tyr Thr Ser Phe Asp
355 360 365
Thr Phe Ser Trp Ala Phe Leu Ser Leu Phe Arg Leu Met Thr Gln Asp
370 375 380
Phe Trp Glu Asn Leu Tyr Gln Leu Thr Leu Arg Ala Ala Gly Lys Thr
385 390 395 400
Tyr Met Ile Phe Phe Val Leu Val Ile Phe Leu Gly Ser Phe Tyr Leu
405 410 415
Ile Asn Leu Ile Leu Ala Val Val Ala Met Ala Tyr Glu Glu Gln Asn
420 425 430
Gln Ala Thr Leu Glu Glu Ala Glu Gln Lys Glu Ala Glu Phe Gln Gln
435 440 445
Met Leu Glu Gln Leu Lys Lys Gln Gln Glu Glu Ala Gln Ala Ala Ala
450 455 460
Ala Ala Ala Ser Ala Glu Ser Arg Asp Phe Ser Gly Ala Gly Gly Ile
465 470 475 480
Gly Val Phe Ser Glu Ser Ser Ser Val Ala Ser Lys Leu Ser Ser Lys
485 490 495
Ser Glu Lys Glu Leu Lys Asn Arg Arg Lys Lys Lys Lys Gln Lys Glu
500 505 510
Gln Ser Gly Glu Glu Glu Lys Asn Asp Arg Val Arg Lys Ser Glu Ser
515 520 525
Glu Asp Ser Ile Arg Arg Lys Gly Phe Arg Phe Ser Leu Glu Gly Ser
530 535 540
Arg Leu Thr Tyr Glu Lys Arg Phe Ser Ser Pro His Gln Ser Leu Leu
545 550 555 560
Ser Ile Arg Gly Ser Leu Phe Ser Pro Arg Arg Asn Ser Arg Ala Ser
565 570 575
Leu Phe Ser Phe Arg Gly Arg Thr Lys Asp Ile Gly Ser Glu Asn Asp
580 585 590
Phe Ala Asp Asp Glu His Ser Thr Phe Glu Asp Asn Asp Ser Arg Arg
595 600 605
Asp Ser Leu Phe Val Pro His Arg His Gly Glu Arg Arg His Ser Asn
610 615 620
Val Ser Gln Ala Ser Arg Ala Ser Arg Val Leu Pro Ile Leu Pro Met
625 630 635 640
Asn Gly Lys Met His Ser Ala Val Asp Cys Asn Gly Val Val Ser Leu
645 650 655
Val Gly Gly Pro Ser Thr Leu Thr Ser Ala Gly Gln Leu Leu Pro Glu
660 665 670
Gly Thr Thr Thr Glu Thr Glu Ile Arg Lys Arg Arg Ser Ser Ser Tyr
675 680 685
His Val Ser Met Asp Leu Leu Glu Asp Pro Thr Ser Arg Gln Arg Ala
690 695 700
Met Ser Ile Ala Ser Ile Leu Thr Asn Thr Met Glu Glu Leu Glu Glu
705 710 715 720
Ser Arg Gln Lys Cys Pro Pro Cys Trp Tyr Lys Phe Ala Asn Met Cys
725 730 735
Leu Ile Trp Asp Cys Cys Lys Pro Trp Leu Lys Val Lys His Leu Val
740 745 750
Asn Leu Val Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile Cys
755 760 765
Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His Tyr Pro Met Thr
770 775 780
Glu Gln Phe Ser Ser Val Leu Ser Val Gly Asn Leu Val Phe Thr Gly
785 790 795 800
Ile Phe Thr Ala Glu Met Phe Leu Lys Ile Ile Ala Met Asp Pro Tyr
805 810 815
Tyr Tyr Phe Gln Glu Gly Trp Asn Ile Phe Asp Gly Phe Ile Val Ser
820 825 830
Leu Ser Leu Met Glu Leu Gly Leu Ala Asn Val Glu Gly Leu Ser Val
835 840 845
Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser Trp
850 855 860
Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly Ala
865 870 875 880
Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe Ala
885 890 895
Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val Cys
900 905 910
Lys Ile Ser Asn Asp Cys Glu Leu Pro Arg Trp His Met His Asp Phe
915 920 925
Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp Ile
930 935 940
Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Thr Met Cys Leu
945 950 955 960
Thr Val Phe Met Met Val Met Val Ile Gly Asn Leu Val Val Leu Asn
965 970 975
Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu Ala
980 985 990
Ala Thr Asp Asp Asp Asn Glu Met Asn Asn Leu Gln Ile Ala Val Gly
995 1000 1005
Arg Met Gln Lys Gly Ile Asp Phe Val Lys Arg Lys Ile Arg Glu
1010 1015 1020
Phe Ile Gln Lys Ala Phe Val Arg Lys Gln Lys Ala Leu Asp Glu
1025 1030 1035
Ile Lys Pro Leu Glu Asp Leu Asn Asn Lys Lys Asp Ser Cys Ile
1040 1045 1050
Ser Asn His Thr Thr Ile Glu Ile Gly Lys Asp Leu Asn Tyr Leu
1055 1060 1065
Lys Asp Gly Asn Gly Thr Thr Ser Gly Ile Gly Ser Ser Val Glu
1070 1075 1080
Lys Tyr Val Val Asp Glu Ser Asp Tyr Met Ser Phe Ile Asn Asn
1085 1090 1095
Pro Ser Leu Thr Val Thr Val Pro Ile Ala Val Gly Glu Ser Asp
1100 1105 1110
Phe Glu Asn Leu Asn Thr Glu Glu Phe Ser Ser Glu Ser Asp Met
1115 1120 1125
Glu Glu Ser Lys Glu Lys Leu Asn Ala Thr Ser Ser Ser Glu Gly
1130 1135 1140
Ser Thr Val Asp Ile Gly Ala Pro Ala Glu Gly Glu Gln Pro Glu
1145 1150 1155
Val Glu Pro Glu Glu Ser Leu Glu Pro Glu Ala Cys Phe Thr Glu
1160 1165 1170
Asp Cys Val Arg Lys Phe Lys Cys Cys Gln Ile Ser Ile Glu Glu
1175 1180 1185
Gly Lys Gly Lys Leu Trp Trp Asn Leu Arg Lys Thr Cys Tyr Lys
1190 1195 1200
Ile Val Glu His Asn Trp Phe Glu Thr Phe Ile Val Phe Met Ile
1205 1210 1215
Leu Leu Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile Glu
1220 1225 1230
Gln Arg Lys Thr Ile Lys Thr Met Leu Glu Tyr Ala Asp Lys Val
1235 1240 1245
Phe Thr Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Val Ala
1250 1255 1260
Tyr Gly Phe Gln Val Tyr Phe Thr Asn Ala Trp Cys Trp Leu Asp
1265 1270 1275
Phe Leu Ile Val Asp Val Ser Leu Val Ser Leu Thr Ala Asn Ala
1280 1285 1290
Leu Gly Tyr Ser Glu Leu Gly Ala Ile Lys Ser Leu Arg Thr Leu
1295 1300 1305
Arg Ala Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly Met
1310 1315 1320
Arg Val Val Val Asn Ala Leu Leu Gly Ala Ile Pro Ser Ile Met
1325 1330 1335
Asn Val Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile
1340 1345 1350
Met Gly Val Asn Leu Phe Ala Gly Lys Phe Tyr His Cys Ile Asn
1355 1360 1365
Tyr Thr Thr Gly Glu Met Phe Asp Val Ser Val Val Asn Asn Tyr
1370 1375 1380
Ser Glu Cys Lys Ala Leu Ile Glu Ser Asn Gln Thr Ala Arg Trp
1385 1390 1395
Lys Asn Val Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr Leu
1400 1405 1410
Ser Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile Met
1415 1420 1425
Tyr Ala Ala Val Asp Ser Arg Asn Val Glu Leu Gln Pro Lys Tyr
1430 1435 1440
Glu Asp Asn Leu Tyr Met Tyr Leu Tyr Phe Val Ile Phe Ile Ile
1445 1450 1455
Phe Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile Ile
1460 1465 1470
Asp Asn Phe Asn Gln Gln Lys Lys Lys Phe Gly Gly Gln Asp Ile
1475 1480 1485
Phe Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys
1490 1495 1500
Leu Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Ala Asn
1505 1510 1515
Lys Phe Gln Gly Met Val Phe Asp Phe Val Thr Lys Gln Val Phe
1520 1525 1530
Asp Ile Ser Ile Met Ile Leu Ile Cys Leu Asn Met Val Thr Met
1535 1540 1545
Met Val Glu Thr Asp Asp Gln Ser Gln Glu Met Thr Asn Ile Leu
1550 1555 1560
Tyr Trp Ile Asn Leu Val Phe Ile Val Leu Phe Thr Gly Glu Cys
1565 1570 1575
Val Leu Lys Leu Ile Ser Leu Arg Tyr Tyr Tyr Phe Thr Ile Gly
1580 1585 1590
Trp Asn Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile Val Gly
1595 1600 1605
Met Phe Leu Ala Glu Leu Ile Glu Lys Tyr Phe Val Ser Pro Thr
1610 1615 1620
Leu Phe Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg
1625 1630 1635
Leu Ile Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu
1640 1645 1650
Met Met Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu Phe
1655 1660 1665
Leu Val Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe Ala
1670 1675 1680
Tyr Val Lys Arg Glu Val Gly Ile Asp Asp Met Phe Asn Phe Glu
1685 1690 1695
Thr Phe Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr Ser
1700 1705 1710
Ala Gly Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Gly Pro
1715 1720 1725
Pro Asp Cys Asp Pro Glu Lys Asp His Pro Gly Ser Ser Val Lys
1730 1735 1740
Gly Asp Cys Gly Asn Pro Ser Val Gly Ile Phe Phe Phe Val Ser
1745 1750 1755
Tyr Ile Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile Ala
1760 1765 1770
Val Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Ala Glu
1775 1780 1785
Pro Leu Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp Glu
1790 1795 1800
Lys Phe Asp Pro Asp Ala Thr Gln Phe Ile Glu Phe Ala Lys Leu
1805 1810 1815
Ser Asp Phe Ala Asp Ala Leu Asp Pro Pro Leu Leu Ile Ala Lys
1820 1825 1830
Pro Asn Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val Ser
1835 1840 1845
Gly Asp Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr Lys
1850 1855 1860
Arg Val Leu Gly Glu Ser Gly Glu Met Asp Ala Leu Arg Ile Gln
1865 1870 1875
Met Glu Glu Arg Phe Met Ala Ser Asn Pro Ser Lys Val Ser Tyr
1880 1885 1890
Glu Pro Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Glu Val Ser
1895 1900 1905
Ala Ile Ile Ile Gln Arg Ala Tyr Arg Arg Tyr Leu Leu Lys Gln
1910 1915 1920
Lys Val Lys Lys Val Ser Ser Ile Tyr Lys Lys Asp Lys Gly Lys
1925 1930 1935
Glu Cys Asp Gly Thr Pro Ile Lys Glu Asp Thr Leu Ile Asp Lys
1940 1945 1950
Leu Asn Glu Asn Ser Thr Pro Glu Lys Thr Asp Met Thr Pro Ser
1955 1960 1965
Thr Thr Ser Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Glu Lys
1970 1975 1980
Glu Lys Phe Glu Lys Asp Lys Ser Glu Lys Glu Asp Lys Gly Lys
1985 1990 1995
Asp Ile Arg Glu Ser Lys Lys
2000 2005
<210> 45
<211> 1932
<212> PRT
<213> 人工序列
<220>
<223> 鼯猴
<400> 45
Pro Glu Met Val Ser Glu Pro Leu Glu Asp Leu Asp Pro Tyr Tyr Ile
1 5 10 15
Asn Lys Lys Thr Phe Ile Val Leu Asn Lys Gly Lys Ala Ile Ser Arg
20 25 30
Phe Ser Ala Thr Pro Ala Leu Tyr Ile Leu Thr Pro Phe Asn Pro Ile
35 40 45
Arg Lys Leu Ala Ile Lys Ile Leu Val His Ser Leu Phe Asn Val Leu
50 55 60
Ile Met Cys Thr Ile Leu Thr Asn Cys Val Phe Met Thr Met Ser Asn
65 70 75 80
Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr Thr Phe Thr Gly Ile Tyr
85 90 95
Thr Phe Glu Ser Leu Ile Lys Ile Leu Ala Arg Gly Phe Cys Leu Glu
100 105 110
Asp Phe Thr Phe Leu Arg Asp Pro Trp Asn Trp Leu Asp Phe Thr Val
115 120 125
Ile Thr Phe Ala Tyr Val Thr Glu Phe Val Asp Leu Gly Asn Val Ser
130 135 140
Ala Leu Arg Thr Phe Arg Val Leu Arg Ala Leu Lys Thr Ile Ser Val
145 150 155 160
Ile Pro Gly Leu Lys Thr Ile Val Gly Ala Leu Ile Gln Ser Val Lys
165 170 175
Lys Leu Ser Asp Val Met Ile Leu Thr Val Phe Cys Leu Ser Val Phe
180 185 190
Ala Leu Ile Gly Leu Gln Leu Phe Met Gly Asn Leu Arg Asn Lys Cys
195 200 205
Leu Gln Trp Pro Pro Asp Asn Ser Ser Phe Glu Ile Asn Ile Thr Ser
210 215 220
Phe Phe Asn Asn Ser Leu Asp Gly Asn Gly Thr Thr Phe Asn Arg Thr
225 230 235 240
Val Ser Met Phe Asn Trp Asp Glu Tyr Ile Glu Asp Glu Ser His Phe
245 250 255
Tyr Phe Leu Glu Gly Gln Asn Asp Ala Leu Leu Cys Gly Asn Ser Ser
260 265 270
Asp Ala Gly Gln Cys Pro Glu Gly Tyr Val Cys Val Lys Ala Gly Arg
275 280 285
Asn Pro Asn Tyr Gly Tyr Thr Ser Phe Asp Thr Phe Ser Trp Ala Phe
290 295 300
Leu Ser Leu Phe Arg Leu Met Thr Gln Asp Phe Trp Glu Asn Leu Tyr
305 310 315 320
Gln Leu Thr Leu Arg Ala Ala Gly Lys Thr Tyr Met Ile Phe Phe Val
325 330 335
Leu Val Ile Phe Leu Gly Ser Phe Tyr Leu Ile Asn Leu Ile Leu Ala
340 345 350
Val Val Ala Met Ala Tyr Glu Glu Gln Asn Gln Ala Thr Leu Glu Glu
355 360 365
Ala Glu Gln Lys Glu Ala Glu Phe Gln Gln Met Leu Glu Gln Leu Lys
370 375 380
Lys Gln Gln Glu Glu Ala Gln Ala Ala Ala Ala Ala Ala Ser Ala Glu
385 390 395 400
Ser Arg Asp Phe Ser Gly Ala Gly Gly Ile Gly Val Phe Ser Glu Ser
405 410 415
Ser Ser Val Ala Ser Lys Leu Ser Ser Lys Ser Glu Lys Glu Leu Lys
420 425 430
Asn Arg Arg Lys Lys Lys Lys Gln Lys Glu Gln Ser Gly Glu Glu Glu
435 440 445
Lys Glu Asp Gly Val Arg Lys Ser Glu Ser Glu Asp Ser Ile Arg Arg
450 455 460
Lys Gly Phe Arg Phe Ser Leu Glu Gly Ser Arg Leu Thr Tyr Glu Lys
465 470 475 480
Arg Phe Ser Ser Pro His Gln Ser Leu Leu Ser Ile Arg Gly Ser Leu
485 490 495
Phe Ser Pro Arg Arg Asn Ser Arg Ala Ser Leu Phe Ser Phe Arg Gly
500 505 510
Arg Ala Lys Asp Ile Gly Ser Glu Asn Asp Phe Ala Asp Asp Glu His
515 520 525
Ser Thr Phe Glu Asp Asn Asp Ser Arg Arg Asp Ser Leu Phe Val Pro
530 535 540
His Arg His Gly Glu Arg Arg His Ser Asn Val Ser Gln Ala Ser Arg
545 550 555 560
Ala Ser Arg Leu Leu Pro Thr Leu Pro Met Asn Gly Lys Met His Ser
565 570 575
Ala Val Asp Cys Asn Gly Val Val Ser Leu Val Gly Gly Pro Ser Pro
580 585 590
Ala Gly Gln Leu Leu Pro Glu Gly Thr Thr Thr Glu Thr Glu Ile Arg
595 600 605
Lys Arg Arg Ser Ser Ser Tyr His Val Ser Met Asp Leu Leu Glu Asp
610 615 620
Pro Thr Ser Arg Gln Arg Ala Met Ser Ile Ala Ser Ile Leu Thr Asn
625 630 635 640
Thr Met Glu Glu Leu Glu Glu Ser Arg Gln Lys Cys Pro Pro Cys Trp
645 650 655
Tyr Lys Phe Ala Asn Met Cys Leu Ile Trp Asp Cys Cys Lys Pro Trp
660 665 670
Leu Lys Val Lys Arg Leu Val Asn Leu Val Val Met Asp Pro Phe Val
675 680 685
Asp Leu Ala Ile Thr Ile Cys Ile Val Leu Asn Thr Leu Phe Met Ala
690 695 700
Met Glu His Tyr Pro Met Thr Glu Gln Phe Ser Ser Val Leu Ser Val
705 710 715 720
Gly Asn Leu Val Phe Thr Gly Ile Phe Thr Ala Glu Met Phe Leu Lys
725 730 735
Ile Ile Ala Met Asp Pro Tyr Tyr Tyr Phe Gln Glu Gly Trp Asn Ile
740 745 750
Phe Asp Gly Phe Ile Val Ser Leu Ser Leu Met Glu Leu Gly Leu Ala
755 760 765
Asn Val Glu Gly Leu Ser Val Leu Arg Ser Phe Arg Leu Leu Arg Val
770 775 780
Phe Lys Leu Ala Lys Ser Trp Pro Thr Leu Asn Met Leu Ile Lys Ile
785 790 795 800
Ile Gly Asn Ser Val Gly Ala Leu Gly Asn Leu Thr Leu Val Leu Ala
805 810 815
Ile Ile Val Phe Ile Phe Ala Val Val Gly Met Gln Leu Phe Gly Lys
820 825 830
Ser Tyr Lys Glu Cys Val Cys Lys Ile Ser Asn Asp Cys Glu Leu Pro
835 840 845
Arg Trp His Met His Asp Phe Phe His Ser Phe Leu Ile Val Phe Arg
850 855 860
Val Leu Cys Gly Glu Trp Ile Glu Thr Met Trp Asp Cys Met Glu Val
865 870 875 880
Ala Gly Gln Thr Met Cys Leu Thr Val Phe Met Met Val Met Val Ile
885 890 895
Gly Asn Leu Val Val Leu Asn Leu Phe Leu Ala Leu Leu Leu Ser Ser
900 905 910
Phe Ser Ser Asp Asn Leu Ala Ala Thr Asp Asp Asp Asn Glu Met Asn
915 920 925
Asn Leu Gln Ile Ala Val Gly Arg Met Gln Lys Gly Ile Asp Phe Val
930 935 940
Lys Arg Lys Ile Arg Glu Phe Ile Gln Lys Ala Phe Val Arg Lys Gln
945 950 955 960
Lys Ala Leu Asp Glu Ile Lys Pro Leu Glu Asp Leu Asn Asn Lys Lys
965 970 975
Asp Ser Cys Ile Ser Asn His Thr Thr Ile Glu Ile Gly Lys Asp Leu
980 985 990
Asn Tyr Leu Lys Asp Gly Asn Gly Thr Thr Ser Gly Ile Gly Ser Ser
995 1000 1005
Val Glu Lys Tyr Val Val Asp Glu Ser Asp Tyr Met Ser Phe Ile
1010 1015 1020
Asn Asn Pro Ser Leu Thr Val Thr Val Pro Ile Ala Leu Gly Glu
1025 1030 1035
Ser Asp Phe Glu Asn Leu Asn Thr Glu Glu Phe Ser Ser Glu Ser
1040 1045 1050
Asp Met Glu Glu Ser Lys Glu Lys Leu Asn Ala Thr Ser Ser Ser
1055 1060 1065
Glu Gly Ser Thr Val Asp Ile Gly Ala Pro Ala Glu Gly Glu Gln
1070 1075 1080
Pro Glu Val Glu Pro Glu Glu Ser Leu Glu Pro Glu Ala Cys Phe
1085 1090 1095
Thr Glu Asp Cys Val Arg Lys Phe Lys Cys Cys Gln Ile Ser Ile
1100 1105 1110
Glu Glu Gly Lys Gly Lys Leu Trp Trp Asn Leu Arg Lys Thr Cys
1115 1120 1125
Tyr Lys Ile Val Glu His Asn Trp Phe Glu Thr Phe Ile Val Phe
1130 1135 1140
Met Ile Leu Leu Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr
1145 1150 1155
Ile Glu Gln Arg Lys Thr Ile Lys Thr Met Leu Glu Tyr Ala Asp
1160 1165 1170
Lys Val Phe Thr Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp
1175 1180 1185
Val Ala Tyr Gly Phe Gln Met Tyr Phe Thr Asn Ala Trp Cys Trp
1190 1195 1200
Leu Asp Phe Leu Ile Val Asp Val Ser Leu Val Ser Leu Thr Ala
1205 1210 1215
Asn Ala Leu Gly Tyr Ser Glu Leu Gly Ala Ile Lys Ser Leu Arg
1220 1225 1230
Thr Leu Arg Ala Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu
1235 1240 1245
Gly Met Arg Val Val Val Asn Ala Leu Leu Gly Ala Ile Pro Ser
1250 1255 1260
Ile Met Asn Val Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe
1265 1270 1275
Ser Ile Met Gly Val Asn Leu Phe Ala Gly Lys Phe Tyr His Cys
1280 1285 1290
Ile Asn Tyr Thr Thr Gly Glu Met Phe Asp Val Ser Val Val Asn
1295 1300 1305
Asn Tyr Ser Glu Cys Lys Ala Leu Ile Glu Ser Asn Gln Thr Ala
1310 1315 1320
Arg Trp Lys Asn Val Lys Val Asn Phe Asp Asn Val Gly Leu Gly
1325 1330 1335
Tyr Leu Ser Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp
1340 1345 1350
Ile Met Tyr Ala Ala Val Asp Ser Arg Asn Val Glu Leu Gln Pro
1355 1360 1365
Lys Tyr Glu Asp Asn Leu Tyr Met Tyr Leu Tyr Phe Val Ile Phe
1370 1375 1380
Ile Ile Phe Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val
1385 1390 1395
Ile Ile Asp Asn Phe Asn Gln Gln Lys Lys Lys Phe Gly Gly Gln
1400 1405 1410
Asp Ile Phe Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met
1415 1420 1425
Lys Lys Leu Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro
1430 1435 1440
Ala Asn Lys Phe Gln Gly Met Val Phe Asp Phe Val Thr Lys Gln
1445 1450 1455
Val Phe Asp Ile Ser Ile Met Ile Leu Ile Cys Leu Asn Met Val
1460 1465 1470
Thr Met Met Val Glu Thr Asp Asp Gln Ser Gln Glu Met Thr Asn
1475 1480 1485
Ile Leu Tyr Trp Ile Asn Leu Val Phe Ile Val Leu Phe Thr Gly
1490 1495 1500
Glu Cys Val Leu Lys Leu Ile Ser Leu Arg Tyr Tyr Tyr Phe Thr
1505 1510 1515
Ile Gly Trp Asn Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile
1520 1525 1530
Val Gly Met Phe Leu Ala Glu Leu Ile Glu Lys Tyr Phe Val Ser
1535 1540 1545
Pro Thr Leu Phe Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile
1550 1555 1560
Leu Arg Leu Ile Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe
1565 1570 1575
Ala Leu Met Met Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu
1580 1585 1590
Leu Phe Leu Val Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn
1595 1600 1605
Phe Ala Tyr Val Lys Arg Glu Val Gly Ile Asp Asp Met Phe Asn
1610 1615 1620
Phe Glu Thr Phe Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr
1625 1630 1635
Thr Ser Ala Gly Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser
1640 1645 1650
Gly Pro Pro Asp Cys Asp Pro Glu Lys Asp His Pro Gly Ser Ser
1655 1660 1665
Val Lys Gly Asp Cys Gly Asn Pro Ser Val Gly Ile Phe Phe Phe
1670 1675 1680
Val Ser Tyr Ile Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr
1685 1690 1695
Ile Ala Val Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser
1700 1705 1710
Ala Glu Pro Leu Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val
1715 1720 1725
Trp Glu Lys Phe Asp Pro Asp Ala Thr Gln Phe Ile Glu Phe Ala
1730 1735 1740
Lys Leu Ser Asp Phe Ala Asp Ala Leu Asp Pro Pro Leu Leu Ile
1745 1750 1755
Ala Lys Pro Asn Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met
1760 1765 1770
Val Ser Gly Asp Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe
1775 1780 1785
Thr Lys Arg Val Leu Gly Glu Ser Gly Glu Met Asp Ala Leu Arg
1790 1795 1800
Ile Gln Met Glu Glu Arg Phe Met Ala Ser Asn Pro Ser Lys Val
1805 1810 1815
Ser Tyr Glu Pro Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Glu
1820 1825 1830
Val Ser Ala Ile Ile Ile Gln Arg Ala Tyr Arg Arg Tyr Leu Leu
1835 1840 1845
Lys Gln Lys Val Lys Lys Val Ser Ser Ile Tyr Lys Lys Asp Lys
1850 1855 1860
Gly Lys Glu Cys Asp Gly Thr Pro Ile Lys Glu Asp Thr Leu Ile
1865 1870 1875
Asp Lys Leu Asn Glu Asn Ser Thr Pro Glu Lys Thr Asp Met Thr
1880 1885 1890
Pro Ser Thr Thr Ser Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro
1895 1900 1905
Glu Lys Glu Lys Phe Glu Lys Asp Lys Ser Glu Lys Glu Asp Lys
1910 1915 1920
Gly Lys Asp Ile Arg Glu Ser Lys Lys
1925 1930
<210> 46
<211> 2006
<212> PRT
<213> 牛
<400> 46
Met Ala Gln Ser Val Leu Val Pro Pro Gly Pro Asp Ser Phe Arg Phe
1 5 10 15
Phe Thr Arg Glu Ser Leu Ala Ala Ile Glu Gln Arg Ile Ala Glu Glu
20 25 30
Lys Ala Lys Arg Pro Lys Gln Glu Arg Lys Asp Glu Asp Asp Glu Ser
35 40 45
Gly Pro Lys Pro Asn Ser Asp Leu Glu Ala Gly Lys Ser Leu Pro Phe
50 55 60
Ile Tyr Gly Asp Ile Pro Pro Glu Met Val Ser Glu Pro Leu Glu Asp
65 70 75 80
Leu Asp Pro Tyr Tyr Ile Asn Lys Lys Thr Phe Ile Val Leu Asn Lys
85 90 95
Gly Lys Ala Ile Ser Arg Phe Ser Ala Thr Pro Ala Leu Tyr Ile Leu
100 105 110
Thr Pro Phe Asn Pro Ile Arg Lys Leu Ala Ile Lys Ile Leu Val His
115 120 125
Ser Leu Phe Asn Val Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Val
130 135 140
Phe Met Thr Met Ser Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr
145 150 155 160
Thr Phe Thr Gly Ile Tyr Thr Phe Glu Ser Leu Ile Lys Ile Leu Ala
165 170 175
Arg Gly Phe Cys Leu Glu Asp Phe Thr Phe Leu Arg Asp Pro Trp Asn
180 185 190
Trp Leu Asp Phe Thr Val Ile Thr Phe Ala Tyr Val Thr Glu Phe Val
195 200 205
Asp Leu Gly Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala
210 215 220
Leu Lys Thr Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala
225 230 235 240
Leu Ile Gln Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val
245 250 255
Phe Cys Leu Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly
260 265 270
Asn Leu Arg Asn Lys Cys Leu Gln Trp Pro Pro Asp Asn Ser Ser Phe
275 280 285
Glu Leu Asn Ile Thr Ser Phe Phe Asn Asn Ser Leu Asp Gly Asn Gly
290 295 300
Thr Thr Phe Asn Arg Thr Val Ser Met Phe Asn Trp Asp Glu Tyr Ile
305 310 315 320
Glu Asp Lys Ser His Phe Tyr Phe Leu Glu Gly Gln Asn Asp Ala Leu
325 330 335
Leu Cys Gly Asn Ser Ser Asp Ala Gly Gln Cys Pro Glu Gly Tyr Ile
340 345 350
Cys Val Lys Ala Gly Arg Asn Pro Asn Tyr Gly Tyr Thr Ser Phe Asp
355 360 365
Thr Phe Ser Trp Ala Phe Leu Ser Leu Phe Arg Leu Met Thr Gln Asp
370 375 380
Phe Trp Glu Asn Leu Tyr Gln Leu Thr Leu Arg Ala Ala Gly Lys Thr
385 390 395 400
Tyr Met Ile Phe Phe Val Leu Val Ile Phe Leu Gly Ser Phe Tyr Leu
405 410 415
Ile Asn Leu Ile Leu Ala Val Val Ala Met Ala Tyr Glu Glu Gln Asn
420 425 430
Gln Ala Thr Leu Glu Glu Ala Glu Gln Lys Glu Ala Glu Phe Gln Gln
435 440 445
Met Leu Glu Gln Leu Lys Lys Gln Gln Glu Glu Ala Gln Ala Ala Ala
450 455 460
Ala Ala Ala Ser Ala Glu Ser Arg Glu Phe Ser Gly Ala Gly Gly Ile
465 470 475 480
Gly Val Phe Ser Glu Ser Ser Ser Val Ala Ser Lys Leu Ser Ser Lys
485 490 495
Ser Glu Lys Glu Leu Lys Asn Arg Arg Lys Lys Lys Lys Gln Lys Glu
500 505 510
Gln Ser Gly Glu Glu Glu Lys Glu Asp Gly Val Arg Lys Ser Glu Ser
515 520 525
Glu Asp Ser Ile Arg Arg Lys Gly Phe Arg Phe Ser Leu Glu Gly Ser
530 535 540
Arg Leu Thr Tyr Glu Lys Arg Phe Ser Ser Pro His Gln Ser Leu Leu
545 550 555 560
Ser Ile Arg Gly Ser Leu Phe Ser Pro Arg Arg Asn Ser Arg Ala Ser
565 570 575
Leu Phe Ser Phe Arg Gly Arg Ala Lys Asp Ile Gly Ser Glu Asn Asp
580 585 590
Phe Ala Asp Asp Glu His Ser Thr Phe Glu Asp Asn Asp Ser Arg Arg
595 600 605
Asp Ser Leu Phe Val Pro His Arg His Gly Glu Arg Arg His Ser Asn
610 615 620
Val Ser Gln Ala Ser Arg Ala Ser Arg Val Leu Pro Ile Leu Pro Met
625 630 635 640
Asn Gly Lys Met His Ser Ala Val Asp Cys Asn Gly Val Val Ser Leu
645 650 655
Val Gly Gly Pro Ser Ala Leu Thr Ser Pro Ala Gly Gln Leu Leu Pro
660 665 670
Glu Gly Thr Thr Thr Glu Thr Glu Ile Arg Lys Arg Arg Ser Ser Ser
675 680 685
Tyr His Val Ser Met Asp Leu Leu Glu Asp Pro Thr Ala Arg Gln Arg
690 695 700
Ala Met Ser Met Ala Ser Ile Leu Thr Asn Thr Met Glu Glu Leu Glu
705 710 715 720
Glu Ser Arg Gln Lys Cys Pro Pro Cys Trp Tyr Lys Phe Ala Asn Met
725 730 735
Cys Leu Ile Trp Asp Cys Cys Lys Pro Trp Leu Lys Val Lys His Val
740 745 750
Val Asn Leu Val Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile
755 760 765
Cys Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His Tyr Pro Met
770 775 780
Thr Glu Gln Phe Ser Ser Val Leu Ser Val Gly Asn Leu Val Phe Thr
785 790 795 800
Gly Ile Phe Thr Ala Glu Met Phe Leu Lys Ile Ile Ala Met Asp Pro
805 810 815
Tyr Tyr Tyr Phe Gln Glu Gly Trp Asn Ile Phe Asp Gly Leu Ile Val
820 825 830
Ser Leu Ser Leu Met Glu Leu Gly Leu Ala Asn Val Glu Gly Leu Ser
835 840 845
Val Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser
850 855 860
Trp Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly
865 870 875 880
Ala Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe
885 890 895
Ala Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val
900 905 910
Cys Lys Ile Ser Asn Asp Cys Glu Leu Pro Arg Trp His Met His Asp
915 920 925
Phe Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp
930 935 940
Ile Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Thr Met Cys
945 950 955 960
Leu Thr Val Phe Met Met Val Met Val Ile Gly Asn Leu Val Val Leu
965 970 975
Asn Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu
980 985 990
Ala Ala Thr Asp Asp Asp Asn Glu Met Asn Asn Leu Gln Ile Ala Val
995 1000 1005
Gly Arg Met Gln Lys Gly Ile Asp Phe Val Lys Arg Lys Ile Arg
1010 1015 1020
Glu Phe Ile Gln Lys Ala Phe Val Arg Lys Gln Lys Ala Leu Asp
1025 1030 1035
Glu Ile Lys Pro Leu Glu Asp Leu Asn Asn Lys Lys Asp Ser Cys
1040 1045 1050
Ile Ser Asn His Thr Thr Ile Glu Ile Gly Lys Asp Leu Asn Tyr
1055 1060 1065
Leu Lys Asp Gly Asn Gly Thr Thr Ser Gly Ile Gly Ser Ser Val
1070 1075 1080
Glu Lys Tyr Val Val Asp Glu Ser Asp Tyr Met Ser Phe Ile Asn
1085 1090 1095
Asn Pro Ser Leu Thr Val Thr Val Pro Ile Ala Val Gly Glu Ser
1100 1105 1110
Asp Phe Glu Asn Leu Asn Thr Glu Glu Phe Ser Ser Glu Ser Asp
1115 1120 1125
Met Glu Glu Ser Lys Glu Lys Leu Asn Ala Thr Ser Ser Ser Glu
1130 1135 1140
Gly Ser Thr Val Asp Ile Gly Ala Pro Ala Glu Gly Glu Gln Pro
1145 1150 1155
Glu Ala Glu Pro Glu Glu Ser Leu Glu Pro Glu Ala Cys Phe Thr
1160 1165 1170
Glu Asp Cys Val Arg Lys Phe Lys Cys Cys Gln Ile Ser Ile Glu
1175 1180 1185
Glu Gly Lys Gly Lys Leu Trp Trp Asn Leu Arg Lys Thr Cys Tyr
1190 1195 1200
Lys Ile Val Glu His Asn Trp Phe Glu Thr Phe Ile Val Phe Met
1205 1210 1215
Ile Leu Val Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile
1220 1225 1230
Glu Gln Arg Lys Thr Ile Lys Thr Met Leu Glu Tyr Ala Asp Lys
1235 1240 1245
Val Phe Thr Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Val
1250 1255 1260
Ala Tyr Gly Phe Gln Val Tyr Phe Thr Asn Ala Trp Cys Trp Leu
1265 1270 1275
Asp Phe Leu Ile Val Asp Val Ser Leu Val Ser Leu Thr Ala Asn
1280 1285 1290
Ala Leu Gly Tyr Ser Glu Leu Gly Ala Ile Lys Ser Leu Arg Thr
1295 1300 1305
Leu Arg Ala Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly
1310 1315 1320
Met Arg Val Val Val Asn Ala Leu Leu Gly Ala Ile Pro Ser Ile
1325 1330 1335
Met Asn Val Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser
1340 1345 1350
Ile Met Gly Val Asn Leu Phe Ala Gly Lys Phe Tyr His Cys Ile
1355 1360 1365
Asn Tyr Thr Thr Gly Glu Met Phe Asp Val Ser Val Val Asn Asn
1370 1375 1380
Tyr Ser Glu Cys Lys Ala Leu Ile Asp Ser Asn Gln Thr Ala Arg
1385 1390 1395
Trp Lys Asn Val Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr
1400 1405 1410
Leu Ser Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile
1415 1420 1425
Met Tyr Ala Ala Val Asp Ser Arg Asn Val Glu Leu Gln Pro Lys
1430 1435 1440
Tyr Glu Asp Asn Leu Tyr Met Tyr Leu Tyr Phe Val Ile Phe Ile
1445 1450 1455
Ile Phe Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile
1460 1465 1470
Ile Asp Asn Phe Asn Gln Gln Lys Lys Lys Phe Gly Gly Gln Asp
1475 1480 1485
Ile Phe Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys
1490 1495 1500
Lys Leu Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Ala
1505 1510 1515
Asn Lys Phe Gln Gly Met Val Phe Asp Phe Val Thr Lys Gln Val
1520 1525 1530
Phe Asp Ile Ser Ile Met Ile Leu Ile Cys Leu Asn Met Val Thr
1535 1540 1545
Met Met Val Glu Thr Asp Asp Gln Ser Gln Glu Met Thr Asn Ile
1550 1555 1560
Leu Tyr Trp Ile Asn Leu Val Phe Ile Val Leu Phe Thr Gly Glu
1565 1570 1575
Cys Val Leu Lys Leu Ile Ser Leu Arg Tyr Tyr Tyr Phe Thr Ile
1580 1585 1590
Gly Trp Asn Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile Val
1595 1600 1605
Gly Met Phe Leu Ala Glu Leu Ile Glu Lys Tyr Phe Val Ser Pro
1610 1615 1620
Thr Leu Phe Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu
1625 1630 1635
Arg Leu Ile Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala
1640 1645 1650
Leu Met Met Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu
1655 1660 1665
Phe Leu Val Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe
1670 1675 1680
Ala Tyr Val Lys Arg Glu Val Gly Ile Asp Asp Met Phe Asn Phe
1685 1690 1695
Glu Thr Phe Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr
1700 1705 1710
Ser Ala Gly Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Gly
1715 1720 1725
Pro Pro Asp Cys Asp Pro Glu Lys Asp His Pro Gly Ser Ser Val
1730 1735 1740
Lys Gly Asp Cys Gly Asn Pro Ser Val Gly Ile Phe Phe Phe Val
1745 1750 1755
Ser Tyr Ile Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile
1760 1765 1770
Ala Val Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Ala
1775 1780 1785
Glu Pro Leu Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp
1790 1795 1800
Glu Lys Phe Asp Pro Asp Ala Thr Gln Phe Ile Glu Phe Ser Lys
1805 1810 1815
Leu Ser Asp Phe Ala Ala Ala Leu Asp Pro Pro Leu Leu Ile Ala
1820 1825 1830
Lys Pro Asn Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val
1835 1840 1845
Ser Gly Asp Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr
1850 1855 1860
Lys Arg Val Leu Gly Glu Ser Gly Glu Met Asp Ala Leu Arg Ile
1865 1870 1875
Gln Met Glu Glu Arg Phe Met Ala Ser Asn Pro Ser Lys Val Ser
1880 1885 1890
Tyr Glu Pro Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Glu Val
1895 1900 1905
Ser Ala Ile Val Ile Gln Arg Ala Tyr Arg Arg Tyr Leu Leu Lys
1910 1915 1920
Gln Lys Val Lys Lys Val Ser Cys Ile Tyr Lys Lys Asp Lys Gly
1925 1930 1935
Lys Glu Gly Glu Gly Thr Pro Ile Lys Glu Asp Ile Leu Ile Asp
1940 1945 1950
Lys Leu Asn Glu Asn Ser Thr Pro Glu Lys Thr Asp Met Thr Pro
1955 1960 1965
Ser Thr Thr Ser Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Glu
1970 1975 1980
Lys Glu Lys Phe Glu Lys Asp Lys Ser Glu Lys Glu Asp Lys Gly
1985 1990 1995
Lys Asp Ile Arg Glu Ser Lys Lys
2000 2005
<210> 47
<211> 2006
<212> PRT
<213> 绵羊
<400> 47
Met Ala Gln Ser Val Leu Val Pro Pro Gly Pro Asp Ser Phe Arg Phe
1 5 10 15
Phe Thr Arg Glu Ser Leu Ala Ala Ile Glu Gln Arg Ile Ala Glu Glu
20 25 30
Lys Ala Lys Arg Pro Lys Gln Glu Arg Lys Asp Glu Asp Asp Glu Ser
35 40 45
Gly Pro Lys Pro Asn Ser Asp Leu Glu Ala Gly Lys Ser Leu Pro Phe
50 55 60
Ile Tyr Gly Asp Ile Pro Pro Glu Met Val Ser Glu Pro Leu Glu Asp
65 70 75 80
Leu Asp Pro Tyr Tyr Ile Asn Lys Lys Thr Phe Ile Val Leu Asn Lys
85 90 95
Gly Lys Ala Ile Ser Arg Phe Ser Ala Thr Pro Ala Leu Tyr Ile Leu
100 105 110
Thr Pro Phe Asn Pro Ile Arg Lys Leu Ala Ile Lys Ile Leu Val His
115 120 125
Ser Leu Phe Asn Val Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Val
130 135 140
Phe Met Thr Met Ser Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr
145 150 155 160
Thr Phe Thr Gly Ile Tyr Thr Phe Glu Ser Leu Ile Lys Ile Leu Ala
165 170 175
Arg Gly Phe Cys Leu Glu Asp Phe Thr Phe Leu Arg Asp Pro Trp Asn
180 185 190
Trp Leu Asp Phe Thr Val Ile Thr Phe Ala Tyr Val Thr Glu Phe Val
195 200 205
Asp Leu Gly Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala
210 215 220
Leu Lys Thr Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala
225 230 235 240
Leu Ile Gln Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val
245 250 255
Phe Cys Leu Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly
260 265 270
Asn Leu Arg Asn Lys Cys Leu Gln Trp Pro Pro Asp Asn Ser Ser Phe
275 280 285
Glu Leu Asn Ile Thr Ser Phe Phe Asn Asn Ser Leu Asp Gly Asn Gly
290 295 300
Thr Thr Phe Asn Arg Thr Val Ser Met Phe Asn Trp Asp Glu Tyr Ile
305 310 315 320
Glu Asp Lys Ser His Phe Tyr Phe Leu Glu Gly Gln Asn Asp Ala Leu
325 330 335
Leu Cys Gly Asn Ser Ser Asp Ala Gly Gln Cys Pro Glu Gly Tyr Ile
340 345 350
Cys Val Lys Ala Gly Arg Asn Pro Asn Tyr Gly Tyr Thr Ser Phe Asp
355 360 365
Thr Phe Ser Trp Ala Phe Leu Ser Leu Phe Arg Leu Met Thr Gln Asp
370 375 380
Phe Trp Glu Asn Leu Tyr Gln Leu Thr Leu Arg Ala Ala Gly Lys Thr
385 390 395 400
Tyr Met Ile Phe Phe Val Leu Val Ile Phe Leu Gly Ser Phe Tyr Leu
405 410 415
Ile Asn Leu Ile Leu Ala Val Val Ala Met Ala Tyr Glu Glu Gln Asn
420 425 430
Gln Ala Thr Leu Glu Glu Ala Glu Gln Lys Glu Ala Glu Phe Gln Gln
435 440 445
Met Leu Glu Gln Leu Lys Lys Gln Gln Glu Glu Ala Gln Ala Ala Ala
450 455 460
Ala Ala Ala Ser Ala Glu Ser Arg Asp Phe Ser Gly Ala Gly Gly Ile
465 470 475 480
Gly Val Phe Ser Glu Ser Ser Ser Val Ala Ser Lys Leu Ser Ser Lys
485 490 495
Ser Glu Lys Glu Leu Lys Asn Arg Arg Lys Lys Lys Lys Gln Lys Glu
500 505 510
Gln Ser Gly Glu Glu Glu Lys Glu Asp Gly Val His Lys Ser Glu Ser
515 520 525
Glu Asp Ser Ile Arg Arg Lys Gly Phe Arg Phe Ser Leu Glu Gly Ser
530 535 540
Arg Leu Thr Tyr Glu Lys Arg Phe Ser Ser Pro His Gln Ser Leu Leu
545 550 555 560
Ser Ile Arg Gly Ser Leu Phe Ser Pro Arg Arg Asn Ser Arg Ala Ser
565 570 575
Leu Phe Ser Phe Arg Gly Arg Ala Lys Asp Ile Gly Ser Glu Asn Asp
580 585 590
Phe Ala Asp Asp Glu His Ser Thr Phe Glu Asp Asn Asp Ser Arg Arg
595 600 605
Asp Ser Leu Phe Val Pro His Arg His Gly Glu Arg Arg His Ser Asn
610 615 620
Val Ser Gln Ala Ser Arg Ala Ser Arg Val Leu Pro Ile Leu Pro Met
625 630 635 640
Asn Gly Lys Met His Ser Ala Val Asp Cys Asn Gly Val Val Ser Leu
645 650 655
Val Gly Gly Pro Ser Ala Leu Thr Ser Pro Ala Gly Gln Leu Leu Pro
660 665 670
Glu Gly Thr Thr Thr Glu Thr Glu Ile Arg Lys Arg Arg Ser Ser Ser
675 680 685
Tyr His Val Ser Met Asp Leu Leu Glu Asp Pro Thr Ala Arg Gln Arg
690 695 700
Ala Met Ser Met Ala Ser Ile Leu Thr Asn Thr Met Glu Glu Leu Glu
705 710 715 720
Glu Ser Arg Gln Lys Cys Pro Pro Cys Trp Tyr Lys Phe Ala Asn Met
725 730 735
Cys Leu Ile Trp Asp Cys Cys Lys Pro Trp Leu Lys Val Lys His Val
740 745 750
Val Asn Leu Val Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile
755 760 765
Cys Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His Tyr Pro Met
770 775 780
Thr Glu Gln Phe Ser Ser Val Leu Ser Val Gly Asn Leu Val Phe Thr
785 790 795 800
Gly Ile Phe Thr Ala Glu Met Phe Leu Lys Ile Ile Ala Met Asp Pro
805 810 815
Tyr Tyr Tyr Phe Gln Glu Gly Trp Asn Ile Phe Asp Gly Leu Ile Val
820 825 830
Ser Leu Ser Leu Met Glu Leu Gly Leu Ala Asn Val Glu Gly Leu Ser
835 840 845
Val Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser
850 855 860
Trp Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly
865 870 875 880
Ala Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe
885 890 895
Ala Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val
900 905 910
Cys Lys Ile Ser Asn Asp Cys Glu Leu Pro Arg Trp His Met His Asp
915 920 925
Phe Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp
930 935 940
Ile Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Thr Met Cys
945 950 955 960
Leu Thr Val Phe Met Met Val Met Val Ile Gly Asn Leu Val Val Leu
965 970 975
Asn Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu
980 985 990
Ala Ala Thr Asp Asp Asp Asn Glu Met Asn Asn Leu Gln Ile Ala Val
995 1000 1005
Gly Arg Met Gln Lys Gly Ile Asp Phe Val Lys Arg Lys Ile Arg
1010 1015 1020
Glu Phe Ile Gln Lys Ala Phe Val Arg Lys Gln Lys Ala Leu Asp
1025 1030 1035
Glu Ile Lys Pro Leu Glu Asp Leu Asn Asn Lys Lys Asp Ser Cys
1040 1045 1050
Ile Ser Asn His Thr Thr Ile Glu Ile Gly Lys Asp Leu Asn Tyr
1055 1060 1065
Leu Lys Asp Gly Asn Gly Thr Thr Ser Gly Ile Gly Ser Ser Val
1070 1075 1080
Glu Lys Tyr Val Val Asp Glu Ser Asp Tyr Met Ser Phe Ile Asn
1085 1090 1095
Asn Pro Ser Leu Thr Val Thr Val Pro Ile Ala Val Gly Glu Ser
1100 1105 1110
Asp Phe Glu Asn Leu Asn Thr Glu Glu Phe Ser Ser Glu Ser Asp
1115 1120 1125
Met Glu Glu Ser Lys Glu Lys Leu Asn Ala Thr Ser Ser Ser Glu
1130 1135 1140
Gly Ser Thr Val Asp Ile Gly Ala Pro Ala Glu Gly Glu Gln Pro
1145 1150 1155
Glu Ala Glu Pro Glu Glu Ser Leu Glu Pro Glu Ala Cys Phe Thr
1160 1165 1170
Glu Asp Cys Val Arg Lys Phe Lys Cys Cys Gln Ile Ser Ile Glu
1175 1180 1185
Glu Gly Lys Gly Lys Leu Trp Trp Asn Leu Arg Lys Thr Cys Tyr
1190 1195 1200
Lys Ile Val Glu His Asn Trp Phe Glu Thr Phe Ile Val Phe Met
1205 1210 1215
Ile Leu Val Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile
1220 1225 1230
Glu Gln Arg Lys Thr Ile Lys Thr Met Leu Glu Tyr Ala Asp Lys
1235 1240 1245
Val Phe Thr Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Val
1250 1255 1260
Ala Tyr Gly Phe Gln Val Tyr Phe Thr Asn Ala Trp Cys Trp Leu
1265 1270 1275
Asp Phe Leu Ile Val Asp Val Ser Leu Val Ser Leu Thr Ala Asn
1280 1285 1290
Ala Leu Gly Tyr Ser Glu Leu Gly Ala Ile Lys Ser Leu Arg Thr
1295 1300 1305
Leu Arg Ala Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly
1310 1315 1320
Met Arg Val Val Val Asn Ala Leu Leu Gly Ala Ile Pro Ser Ile
1325 1330 1335
Met Asn Val Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser
1340 1345 1350
Ile Met Gly Val Asn Leu Phe Ala Gly Lys Phe Tyr His Cys Ile
1355 1360 1365
Asn Tyr Thr Thr Gly Glu Met Phe Asp Val Ser Val Val Asn Asn
1370 1375 1380
Tyr Ser Glu Cys Lys Ala Leu Ile Asp Ser Asn Gln Thr Ala Arg
1385 1390 1395
Trp Lys Asn Val Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr
1400 1405 1410
Leu Ser Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile
1415 1420 1425
Met Tyr Ala Ala Val Asp Ser Arg Asn Val Glu Leu Gln Pro Lys
1430 1435 1440
Tyr Glu Asp Asn Leu Tyr Met Tyr Leu Tyr Phe Val Ile Phe Ile
1445 1450 1455
Ile Phe Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile
1460 1465 1470
Ile Asp Asn Phe Asn Gln Gln Lys Lys Lys Phe Gly Gly Gln Asp
1475 1480 1485
Ile Phe Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys
1490 1495 1500
Lys Leu Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Ala
1505 1510 1515
Asn Lys Phe Gln Gly Met Val Phe Asp Phe Val Thr Lys Gln Val
1520 1525 1530
Phe Asp Ile Ser Ile Met Ile Leu Ile Cys Leu Asn Met Val Thr
1535 1540 1545
Met Met Val Glu Thr Asp Asp Gln Ser Gln Glu Met Thr Asn Ile
1550 1555 1560
Leu Tyr Trp Ile Asn Leu Val Phe Ile Val Leu Phe Thr Gly Glu
1565 1570 1575
Cys Val Leu Lys Leu Ile Ser Leu Arg Tyr Tyr Tyr Phe Thr Ile
1580 1585 1590
Gly Trp Asn Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile Val
1595 1600 1605
Gly Met Phe Leu Ala Glu Leu Ile Glu Lys Tyr Phe Val Ser Pro
1610 1615 1620
Thr Leu Phe Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu
1625 1630 1635
Arg Leu Ile Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala
1640 1645 1650
Leu Met Met Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu
1655 1660 1665
Phe Leu Val Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe
1670 1675 1680
Ala Tyr Val Lys Arg Glu Val Gly Ile Asp Asp Met Phe Asn Phe
1685 1690 1695
Glu Thr Phe Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr
1700 1705 1710
Ser Ala Gly Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Gly
1715 1720 1725
Pro Pro Asp Cys Asp Pro Glu Lys Asp His Pro Gly Ser Ser Val
1730 1735 1740
Lys Gly Asp Cys Gly Asn Pro Ser Val Gly Ile Phe Phe Phe Val
1745 1750 1755
Ser Tyr Ile Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile
1760 1765 1770
Ala Val Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Ala
1775 1780 1785
Glu Pro Leu Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp
1790 1795 1800
Glu Lys Phe Asp Pro Asp Ala Thr Gln Phe Ile Glu Phe Ser Lys
1805 1810 1815
Leu Ser Asp Phe Ala Ala Ala Leu Asp Pro Pro Leu Leu Ile Ala
1820 1825 1830
Lys Pro Asn Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val
1835 1840 1845
Ser Gly Asp Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr
1850 1855 1860
Lys Arg Val Leu Gly Glu Ser Gly Glu Met Asp Ala Leu Arg Ile
1865 1870 1875
Gln Met Glu Glu Arg Phe Met Ala Ser Asn Pro Ser Lys Val Ser
1880 1885 1890
Tyr Glu Pro Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Glu Val
1895 1900 1905
Ser Ala Ile Val Ile Gln Arg Ala Tyr Arg Arg Tyr Leu Leu Lys
1910 1915 1920
Gln Lys Val Lys Lys Val Ser Cys Ile Tyr Lys Lys Asp Lys Gly
1925 1930 1935
Lys Glu Gly Glu Gly Thr Pro Ile Lys Glu Asp Ile Leu Ile Asp
1940 1945 1950
Lys Leu Asn Glu Asn Ser Thr Pro Glu Lys Thr Asp Met Thr Pro
1955 1960 1965
Ser Thr Thr Ser Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Glu
1970 1975 1980
Lys Glu Lys Phe Glu Lys Asp Lys Ser Glu Lys Glu Asp Lys Gly
1985 1990 1995
Lys Asp Ile Arg Glu Ser Lys Lys
2000 2005
<210> 48
<211> 2006
<212> PRT
<213> 单峰驼
<400> 48
Met Ala Gln Ser Val Leu Val Pro Pro Gly Pro Asp Ser Phe Arg Phe
1 5 10 15
Phe Thr Arg Glu Ser Leu Ala Ala Ile Glu Gln Arg Ile Ala Glu Glu
20 25 30
Lys Ala Lys Arg Pro Lys Gln Glu Arg Lys Asp Glu Asp Asp Glu Asn
35 40 45
Gly Pro Lys Pro Asn Ser Asp Leu Glu Ala Gly Lys Ser Leu Pro Phe
50 55 60
Ile Tyr Gly Asp Ile Pro Pro Glu Met Val Ser Glu Pro Leu Glu Asp
65 70 75 80
Leu Asp Pro Tyr Tyr Ile Asn Lys Lys Thr Phe Ile Val Leu Asn Lys
85 90 95
Gly Lys Ala Ile Ser Arg Phe Ser Ala Thr Pro Ala Leu Tyr Ile Leu
100 105 110
Thr Pro Phe Asn Pro Ile Arg Lys Leu Ala Ile Lys Ile Leu Val His
115 120 125
Ser Leu Phe Asn Val Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Val
130 135 140
Phe Met Thr Met Ser Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr
145 150 155 160
Thr Phe Thr Gly Ile Tyr Thr Phe Glu Ser Leu Ile Lys Ile Leu Ala
165 170 175
Arg Gly Phe Cys Leu Glu Asp Phe Thr Phe Leu Arg Asp Pro Trp Asn
180 185 190
Trp Leu Asp Phe Thr Val Ile Thr Phe Ala Tyr Val Thr Glu Phe Val
195 200 205
Asp Leu Gly Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala
210 215 220
Leu Lys Thr Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala
225 230 235 240
Leu Ile Gln Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val
245 250 255
Phe Cys Leu Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly
260 265 270
Asn Leu Arg Asn Lys Cys Leu Gln Trp Pro Pro Asp Asn Ser Ser Leu
275 280 285
Glu Ile Asn Ile Thr Ser Phe Phe Asn Asn Ser Leu Asp Gly Asn Gly
290 295 300
Thr Thr Phe Asn Arg Thr Val Ser Met Phe Asn Trp Asp Asp Tyr Ile
305 310 315 320
Glu Asp Lys Ser His Phe Tyr Phe Leu Glu Gly Gln Asn Asp Ala Leu
325 330 335
Leu Cys Gly Asn Ser Ser Asp Ala Gly Gln Cys Pro Glu Gly Tyr Ile
340 345 350
Cys Val Lys Ala Gly Arg Asn Pro Asn Tyr Gly Tyr Thr Ser Phe Asp
355 360 365
Thr Phe Ser Trp Ala Phe Leu Ser Leu Phe Arg Leu Met Thr Gln Asp
370 375 380
Phe Trp Glu Asn Leu Tyr Gln Leu Thr Leu Arg Ala Ala Gly Lys Thr
385 390 395 400
Tyr Met Ile Phe Phe Val Leu Val Ile Phe Leu Gly Ser Phe Tyr Leu
405 410 415
Ile Asn Leu Ile Leu Ala Val Val Ala Met Ala Tyr Glu Glu Gln Asn
420 425 430
Gln Ala Thr Leu Glu Glu Ala Glu Gln Lys Glu Ala Glu Phe Gln Gln
435 440 445
Met Leu Glu Gln Leu Lys Lys Gln Gln Glu Glu Ala Gln Ala Ala Ala
450 455 460
Ala Ala Ala Ser Ala Glu Ser Arg Asp Phe Ser Gly Ala Gly Gly Ile
465 470 475 480
Gly Val Phe Ser Glu Ser Ser Ser Val Ala Ser Lys Leu Ser Ser Lys
485 490 495
Ser Glu Lys Glu Leu Lys Asn Arg Arg Lys Lys Lys Lys Gln Lys Glu
500 505 510
Gln Ser Gly Glu Glu Glu Lys Glu Asp Gly Val His Lys Ser Glu Ser
515 520 525
Glu Asp Ser Ile Arg Arg Lys Gly Phe Arg Phe Ser Leu Glu Gly Ser
530 535 540
Arg Leu Thr Tyr Glu Lys Arg Phe Ser Ser Pro His Gln Ser Leu Leu
545 550 555 560
Ser Ile Arg Gly Ser Leu Phe Ser Pro Arg Arg Asn Ser Arg Ala Ser
565 570 575
Leu Phe Ser Phe Arg Gly Arg Ala Lys Asp Ile Gly Ser Glu Asn Asp
580 585 590
Phe Ala Asp Asp Glu His Ser Thr Phe Glu Asp Asn Asp Ser Arg Arg
595 600 605
Asp Ser Leu Phe Val Pro His Arg His Gly Glu Arg Arg His Ser Asn
610 615 620
Val Ser Gln Ala Ser Arg Ala Ser Arg Val Leu Pro Ile Leu Pro Met
625 630 635 640
Asn Gly Lys Met His Ser Ala Val Asp Cys Asn Gly Val Val Ser Leu
645 650 655
Val Gly Gly Pro Ser Ala Leu Thr Ser Pro Ala Gly Gln Leu Leu Pro
660 665 670
Glu Gly Thr Thr Thr Glu Thr Glu Ile Arg Lys Arg Arg Ser Ser Ser
675 680 685
Tyr His Val Ser Met Asp Leu Leu Glu Asp Pro Thr Ala Arg Gln Arg
690 695 700
Ala Met Ser Met Ala Ser Ile Leu Thr Asn Thr Met Glu Glu Leu Glu
705 710 715 720
Glu Ser Arg Gln Lys Cys Pro Pro Cys Trp Tyr Lys Phe Ala Asn Thr
725 730 735
Cys Leu Ile Trp Asp Cys Cys Lys Pro Trp Leu Lys Val Lys His Leu
740 745 750
Val Asn Leu Val Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile
755 760 765
Cys Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His Tyr Pro Met
770 775 780
Thr Glu Gln Phe Ser Ser Val Leu Ser Val Gly Asn Leu Val Phe Thr
785 790 795 800
Gly Ile Phe Thr Ala Glu Met Phe Leu Lys Ile Ile Ala Met Asp Pro
805 810 815
Tyr Tyr Tyr Phe Gln Glu Gly Trp Asn Ile Phe Asp Gly Leu Ile Val
820 825 830
Ser Leu Ser Leu Met Glu Leu Gly Leu Ala Asn Val Glu Gly Leu Ser
835 840 845
Val Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser
850 855 860
Trp Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly
865 870 875 880
Ala Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe
885 890 895
Ala Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val
900 905 910
Cys Lys Ile Ser Asn Asp Cys Glu Leu Pro Arg Trp His Met His Asp
915 920 925
Phe Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp
930 935 940
Ile Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Thr Met Cys
945 950 955 960
Leu Thr Val Phe Met Met Val Met Val Ile Gly Asn Leu Val Val Leu
965 970 975
Asn Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu
980 985 990
Ala Ala Thr Asp Asp Asp Asn Glu Met Asn Asn Leu Gln Ile Ala Val
995 1000 1005
Gly Arg Met Gln Lys Gly Ile Asp Tyr Val Lys Arg Lys Ile Arg
1010 1015 1020
Glu Phe Ile Gln Lys Ala Phe Val Arg Lys Gln Lys Ala Leu Asp
1025 1030 1035
Glu Ile Lys Pro Leu Glu Asp Leu Asn Asn Lys Lys Asp Ser Cys
1040 1045 1050
Ile Ser Asn His Thr Thr Ile Glu Ile Gly Lys Asp Leu Asn Tyr
1055 1060 1065
Leu Lys Asp Gly Asn Gly Thr Thr Ser Gly Ile Gly Ser Ser Val
1070 1075 1080
Glu Lys Tyr Val Val Asp Glu Ser Asp Tyr Met Ser Phe Ile Asn
1085 1090 1095
Asn Pro Ser Leu Thr Val Thr Val Pro Ile Ala Val Gly Glu Ser
1100 1105 1110
Asp Phe Glu Asn Leu Asn Thr Glu Glu Phe Ser Ser Glu Ser Asp
1115 1120 1125
Met Glu Glu Ser Lys Glu Lys Leu Asn Ala Thr Ser Ser Ser Glu
1130 1135 1140
Gly Ser Thr Val Asp Ile Gly Ala Pro Ala Glu Gly Glu Gln Pro
1145 1150 1155
Glu Val Glu Pro Glu Glu Ser Leu Glu Pro Glu Ala Cys Phe Thr
1160 1165 1170
Glu Asp Cys Val Arg Lys Phe Lys Cys Cys Gln Ile Ser Ile Glu
1175 1180 1185
Glu Gly Lys Gly Lys Leu Trp Trp Asn Val Arg Lys Thr Cys Tyr
1190 1195 1200
Lys Ile Val Glu His Asn Trp Phe Glu Thr Phe Ile Val Phe Met
1205 1210 1215
Ile Leu Leu Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile
1220 1225 1230
Glu Gln Arg Lys Thr Ile Lys Thr Met Leu Glu Tyr Ala Asp Lys
1235 1240 1245
Val Phe Thr Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Val
1250 1255 1260
Ala Tyr Gly Phe Gln Val Tyr Phe Thr Asn Ala Trp Cys Trp Leu
1265 1270 1275
Asp Phe Leu Ile Val Asp Val Ser Leu Val Ser Leu Thr Ala Asn
1280 1285 1290
Ala Leu Gly Tyr Ser Glu Leu Gly Ala Ile Lys Ser Leu Arg Thr
1295 1300 1305
Leu Arg Ala Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly
1310 1315 1320
Met Arg Val Val Val Asn Ala Leu Leu Gly Ala Ile Pro Ser Ile
1325 1330 1335
Met Asn Val Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser
1340 1345 1350
Ile Met Gly Val Asn Leu Phe Ala Gly Lys Phe Tyr His Cys Ile
1355 1360 1365
Asn Tyr Thr Thr Gly Glu Met Phe Asp Val Ser Val Val Asn Asn
1370 1375 1380
Tyr Ser Glu Cys Lys Ala Leu Ile Glu Ser Asn Gln Thr Ala Arg
1385 1390 1395
Trp Lys Asn Val Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr
1400 1405 1410
Leu Ser Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile
1415 1420 1425
Met Tyr Ala Ala Val Asp Ser Arg Asn Val Glu Leu Gln Pro Lys
1430 1435 1440
Tyr Glu Asp Asn Leu Tyr Met Tyr Leu Tyr Phe Val Ile Phe Ile
1445 1450 1455
Ile Phe Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile
1460 1465 1470
Ile Asp Asn Phe Asn Gln Gln Lys Lys Lys Phe Gly Gly Gln Asp
1475 1480 1485
Ile Phe Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys
1490 1495 1500
Lys Leu Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Ala
1505 1510 1515
Asn Lys Phe Gln Gly Met Val Phe Asp Phe Val Thr Lys Gln Val
1520 1525 1530
Phe Asp Ile Ser Ile Met Ile Leu Ile Cys Leu Asn Met Val Thr
1535 1540 1545
Met Met Val Glu Thr Asp Asp Gln Ser Gln Glu Met Thr Asn Ile
1550 1555 1560
Leu Tyr Trp Ile Asn Leu Val Phe Ile Val Leu Phe Thr Gly Glu
1565 1570 1575
Cys Val Leu Lys Leu Ile Ser Leu Arg Tyr Tyr Tyr Phe Thr Ile
1580 1585 1590
Gly Trp Asn Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile Val
1595 1600 1605
Gly Met Phe Leu Ala Glu Leu Ile Glu Lys Tyr Phe Val Ser Pro
1610 1615 1620
Thr Leu Phe Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu
1625 1630 1635
Arg Leu Ile Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala
1640 1645 1650
Leu Met Met Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu
1655 1660 1665
Phe Leu Val Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe
1670 1675 1680
Ala Tyr Val Lys Arg Glu Val Gly Ile Asp Asp Met Phe Asn Phe
1685 1690 1695
Glu Thr Phe Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr
1700 1705 1710
Ser Ala Gly Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Gly
1715 1720 1725
Pro Pro Asp Cys Asp Pro Glu Lys Asp His Pro Gly Ser Ser Val
1730 1735 1740
Lys Gly Asp Cys Gly Asn Pro Ser Val Gly Ile Phe Phe Phe Val
1745 1750 1755
Ser Tyr Ile Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile
1760 1765 1770
Ala Val Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Ala
1775 1780 1785
Glu Pro Leu Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp
1790 1795 1800
Glu Lys Phe Asp Pro Asp Ala Thr Gln Phe Ile Glu Phe Ser Lys
1805 1810 1815
Leu Ser Asp Phe Ala Ala Ala Leu Asp Pro Pro Leu Leu Ile Ala
1820 1825 1830
Lys Pro Asn Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val
1835 1840 1845
Ser Gly Asp Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr
1850 1855 1860
Lys Arg Val Leu Gly Glu Ser Gly Glu Met Asp Ala Leu Arg Ile
1865 1870 1875
Gln Met Glu Glu Arg Phe Met Ala Ser Asn Pro Ser Lys Val Ser
1880 1885 1890
Tyr Glu Pro Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Glu Val
1895 1900 1905
Ser Ala Ile Val Ile Gln Arg Ala Tyr Arg Arg Tyr Leu Leu Lys
1910 1915 1920
Gln Lys Val Lys Lys Val Ser Cys Ile Tyr Lys Lys Asp Lys Gly
1925 1930 1935
Lys Glu Gly Asp Gly Thr Pro Ile Lys Glu Asp Thr Leu Ile Asp
1940 1945 1950
Lys Leu Asn Glu Asn Ser Thr Pro Glu Lys Thr Asp Gly Thr Pro
1955 1960 1965
Ser Thr Thr Ser Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Glu
1970 1975 1980
Lys Glu Lys Phe Glu Lys Asp Lys Ser Glu Lys Glu Asp Lys Gly
1985 1990 1995
Lys Asp Ile Arg Glu Ser Lys Lys
2000 2005
<210> 49
<211> 2006
<212> PRT
<213> 虎鲸
<400> 49
Met Ala Gln Ser Val Leu Val Pro Pro Gly Pro Asp Ser Phe Arg Phe
1 5 10 15
Phe Thr Arg Glu Ser Leu Ala Ala Ile Glu Gln Arg Ile Ala Glu Glu
20 25 30
Lys Ala Lys Arg Pro Lys Gln Glu Arg Lys Asp Glu Asp Asp Glu Asn
35 40 45
Gly Pro Lys Pro Asn Ser Asp Leu Glu Ala Gly Lys Ser Leu Pro Phe
50 55 60
Ile Tyr Gly Asp Ile Pro Pro Glu Met Val Ser Glu Pro Leu Glu Asp
65 70 75 80
Leu Asp Pro Tyr Tyr Ile Asn Lys Lys Thr Phe Ile Val Leu Asn Lys
85 90 95
Gly Lys Ala Ile Ser Arg Phe Ser Ala Thr Pro Ala Leu Tyr Ile Leu
100 105 110
Thr Pro Phe Asn Pro Ile Arg Lys Leu Ala Ile Lys Ile Leu Val His
115 120 125
Ser Leu Phe Asn Val Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Val
130 135 140
Phe Met Thr Met Ser Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr
145 150 155 160
Thr Phe Thr Gly Ile Tyr Thr Phe Glu Ser Leu Ile Lys Ile Leu Ala
165 170 175
Arg Gly Phe Cys Leu Glu Asp Phe Thr Phe Leu Arg Asp Pro Trp Asn
180 185 190
Trp Leu Asp Phe Thr Val Ile Thr Phe Ala Tyr Val Thr Glu Phe Val
195 200 205
Asp Leu Gly Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala
210 215 220
Leu Lys Thr Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala
225 230 235 240
Leu Ile Gln Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val
245 250 255
Phe Cys Leu Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly
260 265 270
Asn Leu Arg Asn Lys Cys Leu Gln Trp Pro Pro Asp Asn Ser Ser Phe
275 280 285
Glu Ile Asn Ile Thr Ser Phe Phe Asn Asn Ser Leu Asp Gly Asn Gly
290 295 300
Thr Thr Phe Asn Arg Thr Val Ser Met Phe Asn Trp Asp Glu Tyr Ile
305 310 315 320
Glu Asp Lys Ser His Phe Tyr Phe Leu Glu Gly Gln Asn Asp Ala Leu
325 330 335
Leu Cys Gly Asn Ser Ser Asp Ala Gly Gln Cys Pro Glu Gly Tyr Ile
340 345 350
Cys Val Lys Ala Gly Arg Asn Pro Asn Tyr Gly Tyr Thr Ser Phe Asp
355 360 365
Thr Phe Ser Trp Ala Phe Leu Ser Leu Phe Arg Leu Met Thr Gln Asp
370 375 380
Phe Trp Glu Asn Leu Tyr Gln Leu Thr Leu Arg Ala Ala Gly Lys Thr
385 390 395 400
Tyr Met Ile Phe Phe Val Leu Val Ile Phe Leu Gly Ser Phe Tyr Leu
405 410 415
Ile Asn Leu Ile Leu Ala Val Val Ala Met Ala Tyr Glu Glu Gln Asn
420 425 430
Gln Ala Thr Leu Glu Glu Ala Glu Gln Lys Glu Ala Glu Phe Gln Gln
435 440 445
Met Leu Glu Gln Leu Lys Lys Gln Gln Glu Glu Ala Gln Ala Ala Ala
450 455 460
Ala Ala Ala Ser Ala Glu Ser Arg Asp Phe Ser Gly Ala Gly Gly Ile
465 470 475 480
Gly Val Phe Ser Glu Ser Ser Ser Val Ala Ser Lys Leu Ser Ser Lys
485 490 495
Ser Glu Lys Glu Leu Lys Asn Arg Arg Lys Lys Lys Lys Gln Lys Glu
500 505 510
Gln Ser Gly Glu Glu Glu Lys Glu Asp Gly Val His Lys Ser Glu Ser
515 520 525
Glu Asp Ser Ile Arg Arg Lys Gly Phe Arg Phe Ser Leu Glu Gly Ser
530 535 540
Arg Leu Thr Tyr Glu Lys Arg Phe Ser Ser Pro His Gln Ser Leu Leu
545 550 555 560
Ser Ile Arg Gly Ser Leu Phe Ser Pro Arg Arg Asn Ser Arg Ala Ser
565 570 575
Leu Phe Ser Phe Arg Gly Arg Ala Lys Asp Ile Gly Ser Glu Asn Asp
580 585 590
Phe Ala Asp Asp Glu His Ser Thr Phe Glu Asp Asn Asp Ser Arg Arg
595 600 605
Asp Ser Leu Phe Val Pro His Arg His Gly Glu Arg Arg Pro Ser Asn
610 615 620
Val Ser Gln Ala Ser Arg Ala Ser Arg Val Leu Pro Val Leu Pro Val
625 630 635 640
Asn Gly Lys Met His Ser Ala Val Asp Cys Asn Gly Val Val Ser Leu
645 650 655
Val Gly Gly Pro Ser Ala Leu Thr Ser Pro Ala Gly Gln Leu Leu Pro
660 665 670
Glu Gly Thr Thr Thr Glu Thr Glu Ile Arg Lys Arg Arg Ser Ser Ser
675 680 685
Tyr His Val Ser Met Asp Leu Leu Glu Asp Pro Thr Ala Lys Gln Arg
690 695 700
Ala Thr Ser Met Ala Ser Ile Leu Thr Asn Thr Met Glu Glu Leu Glu
705 710 715 720
Glu Ser Arg Gln Lys Cys Pro Pro Cys Trp Tyr Lys Phe Ala Asn Met
725 730 735
Cys Leu Ile Trp Asp Cys Cys Lys Pro Trp Leu Lys Val Lys His Leu
740 745 750
Val Asn Leu Val Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile
755 760 765
Cys Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His Tyr Pro Met
770 775 780
Thr Glu Gln Phe Ser Ser Val Leu Ser Val Gly Asn Leu Val Phe Thr
785 790 795 800
Gly Ile Phe Thr Ala Glu Met Phe Leu Lys Ile Ile Ala Met Asp Pro
805 810 815
Tyr Tyr Tyr Phe Gln Glu Gly Trp Asn Ile Phe Asp Gly Leu Ile Val
820 825 830
Ser Leu Ser Leu Met Glu Leu Gly Leu Ala Asn Val Glu Gly Leu Ser
835 840 845
Val Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser
850 855 860
Trp Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly
865 870 875 880
Ala Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe
885 890 895
Ala Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val
900 905 910
Cys Lys Ile Ser Asn Asp Cys Glu Leu Pro Arg Trp His Met His Asp
915 920 925
Phe Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp
930 935 940
Ile Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Thr Met Cys
945 950 955 960
Leu Thr Val Phe Met Met Val Met Val Ile Gly Asn Leu Val Val Leu
965 970 975
Asn Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu
980 985 990
Ala Ala Thr Asp Asp Asp Asn Glu Met Asn Asn Leu Gln Ile Ala Val
995 1000 1005
Gly Arg Met Gln Lys Gly Ile Asp Tyr Val Lys Arg Lys Ile Arg
1010 1015 1020
Glu Phe Ile Gln Lys Ala Phe Val Arg Lys Gln Lys Ala Leu Asp
1025 1030 1035
Glu Ile Lys Pro Leu Glu Asp Leu Asn Asn Lys Lys Asp Ser Cys
1040 1045 1050
Ile Ser Asn His Thr Thr Ile Glu Ile Gly Lys Asp Leu Asn Tyr
1055 1060 1065
Leu Lys Asp Gly Asn Gly Thr Thr Ser Gly Ile Gly Ser Ser Val
1070 1075 1080
Glu Lys Tyr Val Val Asp Glu Ser Asp Tyr Met Ser Phe Ile Asn
1085 1090 1095
Asn Pro Ser Leu Thr Val Thr Val Pro Ile Ala Val Gly Glu Ser
1100 1105 1110
Asp Phe Glu Asn Leu Asn Thr Glu Glu Phe Ser Ser Glu Ser Asp
1115 1120 1125
Met Glu Glu Ser Lys Glu Lys Leu Asn Ala Thr Ser Ser Ser Glu
1130 1135 1140
Gly Ser Thr Val Asp Ile Gly Ala Pro Ala Glu Gly Glu Gln Pro
1145 1150 1155
Glu Val Glu Pro Glu Glu Ser Leu Glu Pro Glu Ala Cys Phe Thr
1160 1165 1170
Glu Asp Cys Val Arg Lys Phe Lys Cys Cys Gln Ile Ser Ile Glu
1175 1180 1185
Glu Gly Lys Gly Lys Leu Trp Trp Asn Leu Arg Lys Thr Cys Tyr
1190 1195 1200
Lys Ile Val Glu His Asn Trp Phe Glu Thr Phe Ile Val Phe Met
1205 1210 1215
Ile Leu Leu Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile
1220 1225 1230
Glu Gln Arg Lys Thr Ile Lys Thr Met Leu Glu Tyr Ala Asp Lys
1235 1240 1245
Val Phe Thr Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Val
1250 1255 1260
Ala Tyr Gly Phe Gln Val Tyr Phe Thr Asn Ala Trp Cys Trp Leu
1265 1270 1275
Asp Phe Leu Ile Val Asp Val Ser Leu Val Ser Leu Thr Ala Asn
1280 1285 1290
Ala Leu Gly Tyr Ser Glu Leu Gly Ala Ile Lys Ser Leu Arg Thr
1295 1300 1305
Leu Arg Ala Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly
1310 1315 1320
Met Arg Val Val Val Asn Ala Leu Leu Gly Ala Ile Pro Ser Ile
1325 1330 1335
Met Asn Val Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser
1340 1345 1350
Ile Met Gly Val Asn Leu Phe Ala Gly Lys Phe Tyr His Cys Ile
1355 1360 1365
Asn Tyr Thr Thr Gly Glu Met Phe Asp Val Ser Val Val Asn Asn
1370 1375 1380
Tyr Ser Glu Cys Lys Ala Leu Ile Glu Ser Asn Gln Thr Ala Arg
1385 1390 1395
Trp Lys Asn Val Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr
1400 1405 1410
Leu Ser Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile
1415 1420 1425
Met Tyr Ala Ala Val Asp Ser Arg Asn Val Glu Leu Gln Pro Lys
1430 1435 1440
Tyr Glu Asp Asn Leu Tyr Met Tyr Leu Tyr Phe Val Ile Phe Ile
1445 1450 1455
Ile Phe Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile
1460 1465 1470
Ile Asp Asn Phe Asn Gln Gln Lys Lys Lys Phe Gly Gly Gln Asp
1475 1480 1485
Ile Phe Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys
1490 1495 1500
Lys Leu Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Ala
1505 1510 1515
Asn Lys Phe Gln Gly Met Val Phe Asp Phe Val Thr Lys Gln Val
1520 1525 1530
Phe Asp Ile Ser Ile Met Ile Leu Ile Cys Leu Asn Met Val Thr
1535 1540 1545
Met Met Val Glu Thr Asp Asp Gln Ser Gln Glu Met Thr Asn Ile
1550 1555 1560
Leu Tyr Trp Ile Asn Leu Val Phe Ile Val Leu Phe Thr Gly Glu
1565 1570 1575
Cys Val Leu Lys Leu Ile Ser Leu Arg Tyr Tyr Tyr Phe Thr Ile
1580 1585 1590
Gly Trp Asn Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile Val
1595 1600 1605
Gly Met Phe Leu Ala Glu Leu Ile Glu Lys Tyr Phe Val Ser Pro
1610 1615 1620
Thr Leu Phe Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu
1625 1630 1635
Arg Leu Ile Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala
1640 1645 1650
Leu Met Met Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu
1655 1660 1665
Phe Leu Val Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe
1670 1675 1680
Ala Tyr Val Lys Arg Glu Val Gly Ile Asp Asp Met Phe Asn Phe
1685 1690 1695
Glu Thr Phe Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr
1700 1705 1710
Ser Ala Gly Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Gly
1715 1720 1725
Pro Pro Asp Cys Asp Pro Glu Lys Asp His Pro Gly Ser Ser Val
1730 1735 1740
Lys Gly Asp Cys Gly Asn Pro Ser Val Gly Ile Phe Phe Phe Val
1745 1750 1755
Ser Tyr Ile Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile
1760 1765 1770
Ala Val Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Ala
1775 1780 1785
Glu Pro Leu Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp
1790 1795 1800
Glu Lys Phe Asp Pro Asp Ala Thr Gln Phe Ile Glu Phe Ser Lys
1805 1810 1815
Leu Ser Asp Phe Ala Ala Ala Leu Asp Pro Pro Leu Leu Ile Ala
1820 1825 1830
Lys Pro Asn Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val
1835 1840 1845
Ser Gly Asp Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr
1850 1855 1860
Lys Arg Val Leu Gly Glu Ser Gly Glu Met Asp Ala Leu Arg Ile
1865 1870 1875
Gln Met Glu Glu Arg Phe Met Ala Ser Asn Pro Ser Lys Val Ser
1880 1885 1890
Tyr Glu Pro Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Glu Val
1895 1900 1905
Ser Ala Ile Val Ile Gln Arg Ala Tyr Arg Arg Tyr Leu Leu Lys
1910 1915 1920
Gln Lys Val Lys Lys Val Ser Cys Ile Tyr Lys Lys Asp Lys Gly
1925 1930 1935
Lys Glu Ala Asp Gly Thr Pro Ile Lys Glu Asp Ile Leu Thr Asp
1940 1945 1950
Lys Leu Asn Glu Asn Ser Thr Pro Glu Lys Thr Asp Val Thr Pro
1955 1960 1965
Ser Thr Thr Ser Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Glu
1970 1975 1980
Lys Glu Lys Phe Glu Lys Asp Lys Ser Glu Lys Glu Asp Lys Gly
1985 1990 1995
Lys Asp Ile Arg Glu Ser Lys Lys
2000 2005
<210> 50
<211> 2006
<212> PRT
<213> 家马
<400> 50
Met Ala Gln Ser Val Leu Val Pro Pro Gly Pro Asp Ser Phe Arg Phe
1 5 10 15
Phe Thr Arg Glu Ser Leu Ala Ala Ile Glu Gln Arg Ile Ala Glu Glu
20 25 30
Lys Ala Lys Arg Pro Lys Gln Glu Arg Lys Asp Glu Asp Asp Glu Asn
35 40 45
Gly Pro Lys Pro Asn Ser Asp Leu Glu Ala Gly Lys Ser Leu Pro Phe
50 55 60
Ile Tyr Gly Asp Ile Pro Pro Glu Met Val Ser Glu Pro Leu Glu Asp
65 70 75 80
Leu Asp Pro Tyr Tyr Ile Asn Lys Lys Thr Phe Ile Val Leu Asn Lys
85 90 95
Gly Lys Ala Ile Ser Arg Phe Ser Ala Thr Ser Ala Leu Tyr Ile Leu
100 105 110
Thr Pro Phe Asn Pro Ile Arg Lys Leu Ala Ile Lys Ile Leu Val His
115 120 125
Ser Leu Phe Asn Val Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Val
130 135 140
Phe Met Thr Met Ser Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr
145 150 155 160
Thr Phe Thr Gly Ile Tyr Thr Phe Glu Ser Leu Ile Lys Ile Leu Ala
165 170 175
Arg Gly Phe Cys Leu Glu Asp Phe Thr Phe Leu Arg Asp Pro Trp Asn
180 185 190
Trp Leu Asp Phe Thr Val Ile Thr Phe Ala Tyr Val Thr Glu Phe Val
195 200 205
Asp Leu Gly Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala
210 215 220
Leu Lys Thr Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala
225 230 235 240
Leu Ile Gln Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val
245 250 255
Phe Cys Leu Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly
260 265 270
Asn Leu Arg Asn Lys Cys Leu Gln Trp Pro Pro Asp Asn Ser Ser Phe
275 280 285
Glu Ile Asn Ile Thr Ser Phe Phe Asn Asn Ser Leu Asp Gly Asn Gly
290 295 300
Thr Ile Phe Asn Arg Thr Val Ser Met Phe Asn Trp Asp Asp Tyr Ile
305 310 315 320
Glu Asp Lys Ser His Phe Tyr Phe Leu Glu Gly Gln Asn Asp Ala Leu
325 330 335
Leu Cys Gly Asn Ser Ser Asp Ala Gly Gln Cys Pro Glu Gly Tyr Ile
340 345 350
Cys Val Lys Ala Gly Arg Asn Pro Asn Tyr Gly Tyr Thr Ser Phe Asp
355 360 365
Thr Phe Ser Trp Ala Phe Leu Ser Leu Phe Arg Leu Met Thr Gln Asp
370 375 380
Phe Trp Glu Asn Leu Tyr Gln Leu Thr Leu Arg Ala Ala Gly Lys Thr
385 390 395 400
Tyr Met Ile Phe Phe Val Leu Val Ile Phe Leu Gly Ser Phe Tyr Leu
405 410 415
Ile Asn Leu Ile Leu Ala Val Val Ala Met Ala Tyr Glu Glu Gln Asn
420 425 430
Gln Ala Thr Leu Glu Glu Ala Glu Gln Lys Glu Ala Glu Phe Gln Gln
435 440 445
Met Leu Glu Gln Leu Lys Lys Gln Gln Glu Glu Ala Gln Ala Ala Ala
450 455 460
Ala Ala Ala Ser Ala Glu Ser Arg Asp Phe Ser Gly Ala Gly Gly Val
465 470 475 480
Gly Val Phe Ser Glu Ser Ser Ser Val Ala Ser Lys Leu Ser Ser Lys
485 490 495
Ser Glu Lys Glu Leu Lys Asn Arg Arg Lys Lys Lys Lys Gln Lys Glu
500 505 510
Gln Ser Gly Glu Glu Glu Lys Glu Asp Gly Val Arg Lys Ser Glu Ser
515 520 525
Glu Asp Ser Ile Arg Arg Lys Gly Phe Arg Phe Ser Leu Glu Gly Ser
530 535 540
Arg Leu Thr Tyr Glu Lys Arg Phe Ser Ser Pro His Gln Ser Leu Leu
545 550 555 560
Ser Ile Arg Gly Ser Leu Phe Ser Pro Arg Arg Asn Ser Arg Ala Ser
565 570 575
Leu Phe Ser Phe Arg Gly Arg Ala Lys Asp Ile Gly Ser Glu Asn Asp
580 585 590
Phe Ala Asp Asp Glu His Ser Thr Phe Glu Asp Asn Asp Ser Arg Arg
595 600 605
Asp Ser Leu Phe Val Pro His Arg His Gly Glu Arg Arg His Ser Asn
610 615 620
Val Ser Gln Ala Ser Arg Ala Ser Arg Val Leu Pro Ile Leu Pro Met
625 630 635 640
Asn Gly Lys Met His Ser Ala Val Asp Cys Asn Gly Val Val Ser Leu
645 650 655
Val Gly Gly Pro Ser Ala Leu Thr Ser Pro Ala Gly Gln Leu Leu Pro
660 665 670
Glu Gly Thr Thr Thr Glu Thr Glu Ile Arg Lys Arg Arg Ser Ser Ser
675 680 685
Tyr His Val Ser Met Asp Leu Leu Glu Asp Pro Thr Ala Arg Gln Arg
690 695 700
Ala Met Ser Met Ala Ser Ile Leu Thr Asn Thr Met Glu Glu Leu Glu
705 710 715 720
Glu Ser Arg Gln Lys Cys Pro Pro Cys Trp Tyr Lys Phe Ala Asn Met
725 730 735
Cys Leu Ile Trp Asp Cys Cys Lys Pro Trp Leu Lys Val Lys His Leu
740 745 750
Val Asn Leu Val Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile
755 760 765
Cys Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His Tyr Pro Met
770 775 780
Thr Glu Gln Phe Ser Ser Val Leu Ser Val Gly Asn Leu Val Phe Thr
785 790 795 800
Gly Ile Phe Thr Ala Glu Met Phe Leu Lys Ile Ile Ala Met Asp Pro
805 810 815
Tyr Tyr Tyr Phe Gln Glu Gly Trp Asn Ile Phe Asp Gly Phe Ile Val
820 825 830
Ser Leu Ser Leu Met Glu Leu Gly Leu Ala Asn Val Glu Gly Leu Ser
835 840 845
Val Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser
850 855 860
Trp Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly
865 870 875 880
Ala Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe
885 890 895
Ala Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val
900 905 910
Cys Lys Ile Ser Asn Asp Cys Glu Leu Pro Arg Trp His Met His Asp
915 920 925
Phe Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp
930 935 940
Ile Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Thr Met Cys
945 950 955 960
Leu Thr Val Phe Met Met Val Met Val Ile Gly Asn Leu Val Val Leu
965 970 975
Asn Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu
980 985 990
Ala Ala Thr Asp Asp Asp Asn Glu Met Asn Asn Leu Gln Ile Ala Val
995 1000 1005
Gly Arg Met Gln Lys Gly Ile Asp Tyr Val Lys Arg Lys Leu Arg
1010 1015 1020
Glu Phe Ile Gln Lys Ala Phe Val Arg Lys Gln Lys Ala Leu Asp
1025 1030 1035
Glu Ile Lys Pro Leu Glu Asp Leu Asn Asn Lys Lys Asp Ser Cys
1040 1045 1050
Ile Ser Asn His Thr Thr Ile Glu Ile Gly Lys Asp Leu Asn Tyr
1055 1060 1065
Leu Lys Asp Gly Asn Gly Thr Thr Ser Gly Ile Gly Ser Ser Val
1070 1075 1080
Glu Lys Tyr Val Val Asp Glu Ser Asp Tyr Met Ser Phe Ile Asn
1085 1090 1095
Asn Pro Ser Leu Thr Val Thr Val Pro Ile Ala Val Gly Glu Ser
1100 1105 1110
Asp Phe Glu Asn Leu Asn Thr Glu Glu Phe Ser Ser Glu Ser Asp
1115 1120 1125
Met Glu Glu Ser Lys Glu Lys Leu Asn Ala Thr Ser Ser Ser Glu
1130 1135 1140
Gly Ser Thr Val Asp Ile Gly Ala Pro Ala Glu Gly Glu Gln Pro
1145 1150 1155
Glu Ala Glu Pro Glu Glu Ser Leu Glu Pro Glu Ala Cys Phe Thr
1160 1165 1170
Glu Asp Cys Val Arg Lys Phe Lys Cys Cys Gln Ile Ser Ile Glu
1175 1180 1185
Glu Gly Lys Gly Lys Leu Trp Trp Asn Val Arg Lys Thr Cys Tyr
1190 1195 1200
Lys Ile Val Glu His Asn Trp Phe Glu Thr Phe Ile Val Phe Met
1205 1210 1215
Ile Leu Leu Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile
1220 1225 1230
Glu Gln Arg Lys Thr Ile Lys Thr Met Leu Glu Tyr Ala Asp Lys
1235 1240 1245
Val Phe Thr Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Val
1250 1255 1260
Ala Tyr Gly Phe Gln Val Tyr Phe Thr Asn Ala Trp Cys Trp Leu
1265 1270 1275
Asp Phe Leu Ile Val Asp Val Ser Leu Val Ser Leu Thr Ala Asn
1280 1285 1290
Ala Leu Gly Tyr Ser Glu Leu Gly Ala Ile Lys Ser Leu Arg Thr
1295 1300 1305
Leu Arg Ala Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly
1310 1315 1320
Met Arg Val Val Val Asn Ala Leu Leu Gly Ala Ile Pro Ser Ile
1325 1330 1335
Met Asn Val Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser
1340 1345 1350
Ile Met Gly Val Asn Leu Phe Ala Gly Lys Phe Tyr His Cys Ile
1355 1360 1365
Asn Tyr Thr Thr Gly Glu Met Phe Asp Val Ser Val Val Asn Asn
1370 1375 1380
Tyr Ser Glu Cys Lys Ala Leu Ile Glu Ser Asn Gln Thr Ala Arg
1385 1390 1395
Trp Lys Asn Val Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr
1400 1405 1410
Leu Ser Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile
1415 1420 1425
Met Tyr Ala Ala Val Asp Ser Arg Asn Val Glu Leu Gln Pro Lys
1430 1435 1440
Tyr Glu Asp Asn Leu Tyr Met Tyr Leu Tyr Phe Val Ile Phe Ile
1445 1450 1455
Ile Phe Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile
1460 1465 1470
Ile Asp Asn Phe Asn Gln Gln Lys Lys Lys Phe Gly Gly Gln Asp
1475 1480 1485
Ile Phe Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys
1490 1495 1500
Lys Leu Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Ala
1505 1510 1515
Asn Lys Phe Gln Gly Met Val Phe Asp Phe Val Thr Lys Gln Val
1520 1525 1530
Phe Asp Ile Ser Ile Met Ile Leu Ile Cys Leu Asn Met Val Thr
1535 1540 1545
Met Met Val Glu Thr Asp Asp Gln Ser Gln Glu Met Thr Asn Ile
1550 1555 1560
Leu Tyr Trp Ile Asn Leu Val Phe Ile Val Leu Phe Thr Gly Glu
1565 1570 1575
Cys Val Leu Lys Leu Ile Ser Leu Arg Tyr Tyr Tyr Phe Thr Ile
1580 1585 1590
Gly Trp Asn Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile Val
1595 1600 1605
Gly Met Phe Leu Ala Glu Leu Ile Glu Lys Tyr Phe Val Ser Pro
1610 1615 1620
Thr Leu Phe Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu
1625 1630 1635
Arg Leu Ile Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala
1640 1645 1650
Leu Met Met Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu
1655 1660 1665
Phe Leu Val Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe
1670 1675 1680
Ala Tyr Val Lys Arg Glu Val Gly Ile Asp Asp Met Phe Asn Phe
1685 1690 1695
Glu Thr Phe Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr
1700 1705 1710
Ser Ala Gly Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Gly
1715 1720 1725
Pro Pro Asp Cys Asp Pro Glu Lys Asp His Pro Gly Ser Ser Val
1730 1735 1740
Lys Gly Asp Cys Gly Asn Pro Ser Val Gly Ile Phe Phe Phe Val
1745 1750 1755
Ser Tyr Ile Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile
1760 1765 1770
Ala Val Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Ala
1775 1780 1785
Glu Pro Leu Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp
1790 1795 1800
Glu Lys Phe Asp Pro Asp Ala Thr Gln Phe Ile Glu Phe Ser Lys
1805 1810 1815
Leu Ser Asp Phe Ala Ala Ala Leu Asp Pro Pro Leu Leu Ile Ala
1820 1825 1830
Lys Pro Asn Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val
1835 1840 1845
Ser Gly Asp Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr
1850 1855 1860
Lys Arg Val Leu Gly Glu Ser Gly Glu Met Asp Ala Leu Arg Ile
1865 1870 1875
Gln Met Glu Glu Arg Phe Met Ala Ser Asn Pro Ser Lys Val Ser
1880 1885 1890
Tyr Glu Pro Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Glu Val
1895 1900 1905
Ser Ala Ile Val Ile Gln Arg Ala Tyr Arg Arg Tyr Leu Leu Lys
1910 1915 1920
Gln Lys Val Lys Lys Val Ser Cys Ile Tyr Lys Lys Asp Lys Val
1925 1930 1935
Lys Glu Gly Asp Gly Thr Pro Ile Lys Glu Asp Ile Leu Ile Asp
1940 1945 1950
Lys Leu Asn Glu Asn Ser Thr Pro Glu Lys Thr Asp Val Thr Pro
1955 1960 1965
Ser Thr Thr Ser Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Glu
1970 1975 1980
Lys Glu Lys Phe Glu Lys Asp Lys Ser Glu Lys Glu Asp Lys Gly
1985 1990 1995
Lys Asp Ile Arg Glu Ser Lys Lys
2000 2005
<210> 51
<211> 2006
<212> PRT
<213> 小家鼠
<400> 51
Met Ala Gln Ser Val Leu Val Pro Pro Gly Pro Asp Ser Phe Arg Phe
1 5 10 15
Phe Thr Arg Glu Ser Leu Ala Ala Ile Glu Gln Arg Ile Ala Glu Glu
20 25 30
Lys Ala Lys Arg Pro Lys Gln Glu Arg Lys Asp Glu Asp Asp Glu Asn
35 40 45
Gly Pro Lys Pro Asn Ser Asp Leu Glu Ala Gly Lys Ser Leu Pro Phe
50 55 60
Ile Tyr Gly Asp Ile Pro Pro Glu Met Val Ser Glu Pro Leu Glu Asp
65 70 75 80
Leu Asp Pro Tyr Tyr Ile Asn Lys Lys Thr Phe Ile Val Leu Asn Lys
85 90 95
Gly Lys Ala Ile Ser Arg Phe Ser Ala Thr Ser Ala Leu Tyr Ile Leu
100 105 110
Thr Pro Phe Asn Pro Ile Arg Lys Leu Ala Ile Lys Ile Leu Val His
115 120 125
Ser Leu Phe Asn Val Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Val
130 135 140
Phe Met Thr Met Ser Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr
145 150 155 160
Thr Phe Thr Gly Ile Tyr Thr Phe Glu Ser Leu Ile Lys Ile Leu Ala
165 170 175
Arg Gly Phe Cys Leu Glu Asp Phe Thr Phe Leu Arg Asp Pro Trp Asn
180 185 190
Trp Leu Asp Phe Thr Val Ile Thr Phe Ala Tyr Val Thr Glu Phe Val
195 200 205
Asn Leu Gly Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala
210 215 220
Leu Lys Thr Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala
225 230 235 240
Leu Ile Gln Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val
245 250 255
Phe Cys Leu Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly
260 265 270
Asn Leu Arg Asn Lys Cys Leu Gln Trp Pro Pro Asp Asn Ser Thr Phe
275 280 285
Glu Ile Asn Ile Thr Ser Phe Phe Asn Asn Ser Leu Asp Trp Asn Gly
290 295 300
Thr Ala Phe Asn Arg Thr Met Asn Met Phe Asn Trp Asp Glu Tyr Ile
305 310 315 320
Glu Asp Lys Ser His Phe Tyr Phe Leu Glu Gly Gln Asn Asp Ala Leu
325 330 335
Leu Cys Gly Asn Ser Ser Asp Ala Gly Gln Cys Pro Glu Gly Tyr Ile
340 345 350
Cys Val Lys Ala Gly Arg Asn Pro Asn Tyr Gly Tyr Thr Ser Phe Asp
355 360 365
Thr Phe Ser Trp Ala Phe Leu Ser Leu Phe Arg Leu Met Thr Gln Asp
370 375 380
Phe Trp Glu Asn Leu Tyr Gln Leu Thr Leu Arg Ala Ala Gly Lys Thr
385 390 395 400
Tyr Met Ile Phe Phe Val Leu Val Ile Phe Leu Gly Ser Phe Tyr Leu
405 410 415
Ile Asn Leu Ile Leu Ala Val Val Ala Met Ala Tyr Glu Glu Gln Asn
420 425 430
Gln Ala Thr Leu Glu Glu Ala Glu Gln Lys Glu Ala Glu Phe Gln Gln
435 440 445
Met Leu Glu Gln Leu Lys Lys Gln Gln Glu Glu Ala Gln Ala Ala Ala
450 455 460
Ala Ala Ala Ser Ala Glu Ser Arg Asp Phe Ser Gly Ala Gly Gly Ile
465 470 475 480
Gly Val Phe Ser Glu Ser Ser Ser Val Ala Ser Lys Leu Ser Ser Lys
485 490 495
Ser Glu Lys Glu Leu Lys Asn Arg Arg Lys Lys Lys Lys Gln Lys Glu
500 505 510
Gln Ala Gly Glu Glu Glu Lys Glu Asp Ala Val Arg Lys Ser Ala Ser
515 520 525
Glu Asp Ser Ile Arg Lys Lys Gly Phe Arg Phe Ser Leu Glu Gly Ser
530 535 540
Arg Leu Thr Tyr Glu Lys Arg Phe Ser Ser Pro His Gln Ser Leu Leu
545 550 555 560
Ser Ile Arg Gly Ser Leu Phe Ser Pro Arg Arg Asn Ser Arg Ala Ser
565 570 575
Leu Phe Ser Phe Lys Gly Arg Val Lys Asp Ile Gly Ser Glu Asn Asp
580 585 590
Phe Ala Asp Asp Glu His Ser Thr Phe Glu Asp Asn Asp Ser Arg Arg
595 600 605
Asp Ser Leu Phe Val Pro His Arg His Gly Glu Arg Arg Pro Ser Asn
610 615 620
Val Ser Gln Ala Ser Arg Ala Ser Arg Gly Ile Pro Thr Leu Pro Met
625 630 635 640
Asn Gly Lys Met His Ser Ala Val Asp Cys Asn Gly Val Val Ser Leu
645 650 655
Val Gly Gly Pro Ser Ala Leu Thr Ser Pro Val Gly Gln Leu Leu Pro
660 665 670
Glu Gly Thr Thr Thr Glu Thr Glu Ile Arg Lys Arg Arg Ser Ser Ser
675 680 685
Tyr His Val Ser Met Asp Leu Leu Glu Asp Pro Thr Ser Arg Gln Arg
690 695 700
Ala Met Ser Met Ala Ser Ile Leu Thr Asn Thr Met Glu Glu Leu Glu
705 710 715 720
Glu Ser Arg Gln Lys Cys Pro Pro Cys Trp Tyr Lys Phe Ala Asn Met
725 730 735
Cys Leu Ile Trp Asp Cys Cys Lys Pro Trp Leu Lys Val Lys His Val
740 745 750
Val Asn Leu Val Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile
755 760 765
Cys Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His Tyr Pro Met
770 775 780
Thr Glu Gln Phe Ser Ser Val Leu Ser Val Gly Asn Leu Val Phe Thr
785 790 795 800
Gly Ile Phe Thr Ala Glu Met Phe Leu Lys Ile Ile Ala Met Asp Pro
805 810 815
Tyr Tyr Tyr Phe Gln Glu Gly Trp Asn Ile Phe Asp Gly Phe Ile Val
820 825 830
Ser Leu Ser Leu Met Glu Leu Gly Leu Ala Asn Val Glu Gly Leu Ser
835 840 845
Val Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser
850 855 860
Trp Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly
865 870 875 880
Ala Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe
885 890 895
Ala Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val
900 905 910
Cys Lys Ile Ser Asn Asp Cys Glu Leu Pro Arg Trp His Met His Asp
915 920 925
Phe Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp
930 935 940
Ile Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Thr Met Cys
945 950 955 960
Leu Thr Val Phe Met Met Val Met Val Ile Gly Asn Leu Val Val Leu
965 970 975
Asn Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu
980 985 990
Ala Ala Thr Asp Asp Asp Asn Glu Met Asn Asn Leu Gln Ile Ala Val
995 1000 1005
Gly Arg Met Gln Lys Gly Ile Asp Phe Val Lys Arg Lys Ile Arg
1010 1015 1020
Glu Phe Ile Gln Lys Ala Phe Val Arg Lys Gln Lys Ala Leu Asp
1025 1030 1035
Glu Ile Lys Pro Leu Glu Asp Leu Asn Asn Lys Lys Asp Ser Cys
1040 1045 1050
Ile Ser Asn His Thr Thr Ile Glu Ile Gly Lys Asp Leu Asn Tyr
1055 1060 1065
Leu Lys Asp Gly Asn Gly Thr Thr Ser Gly Ile Gly Ser Ser Val
1070 1075 1080
Glu Lys Tyr Val Val Asp Glu Ser Asp Tyr Met Ser Phe Ile Asn
1085 1090 1095
Asn Pro Ser Leu Thr Val Thr Val Pro Ile Ala Val Gly Glu Ser
1100 1105 1110
Asp Phe Glu Asn Leu Asn Thr Glu Glu Phe Ser Ser Glu Ser Asp
1115 1120 1125
Met Glu Glu Ser Lys Glu Lys Leu Asn Ala Thr Ser Ser Ser Glu
1130 1135 1140
Gly Ser Thr Val Asp Ile Gly Ala Pro Ala Glu Gly Glu Gln Pro
1145 1150 1155
Glu Ala Glu Pro Glu Glu Ser Leu Glu Pro Glu Ala Cys Phe Thr
1160 1165 1170
Glu Asp Cys Val Arg Lys Phe Lys Cys Cys Gln Ile Ser Ile Glu
1175 1180 1185
Glu Gly Lys Gly Lys Leu Trp Trp Asn Leu Arg Lys Thr Cys Tyr
1190 1195 1200
Lys Ile Val Glu His Asn Trp Phe Glu Thr Phe Ile Val Phe Met
1205 1210 1215
Ile Leu Leu Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile
1220 1225 1230
Glu Gln Arg Lys Thr Ile Lys Thr Met Leu Glu Tyr Ala Asp Lys
1235 1240 1245
Val Phe Thr Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Val
1250 1255 1260
Ala Tyr Gly Phe Gln Met Tyr Phe Thr Asn Ala Trp Cys Trp Leu
1265 1270 1275
Asp Phe Leu Ile Val Asp Val Ser Leu Val Ser Leu Thr Ala Asn
1280 1285 1290
Ala Leu Gly Tyr Ser Glu Leu Gly Ala Ile Lys Ser Leu Arg Thr
1295 1300 1305
Leu Arg Ala Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly
1310 1315 1320
Met Arg Val Val Val Asn Ala Leu Leu Gly Ala Ile Pro Ser Ile
1325 1330 1335
Met Asn Val Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser
1340 1345 1350
Ile Met Gly Val Asn Leu Phe Ala Gly Lys Phe Tyr His Cys Ile
1355 1360 1365
Asn Tyr Thr Thr Gly Glu Met Phe Asp Val Ser Val Val Asn Asn
1370 1375 1380
Tyr Ser Glu Cys Gln Ala Leu Ile Glu Ser Asn Gln Thr Ala Arg
1385 1390 1395
Trp Lys Asn Val Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr
1400 1405 1410
Leu Ser Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile
1415 1420 1425
Met Tyr Ala Ala Val Asp Ser Arg Asn Val Glu Leu Gln Pro Lys
1430 1435 1440
Tyr Glu Asp Asn Leu Tyr Met Tyr Leu Tyr Phe Val Ile Phe Ile
1445 1450 1455
Ile Phe Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile
1460 1465 1470
Ile Asp Asn Phe Asn Gln Gln Lys Lys Lys Phe Gly Gly Gln Asp
1475 1480 1485
Ile Phe Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys
1490 1495 1500
Lys Leu Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Ala
1505 1510 1515
Asn Lys Phe Gln Gly Met Val Phe Asp Phe Val Thr Lys Gln Val
1520 1525 1530
Phe Asp Ile Ser Ile Met Ile Leu Ile Cys Leu Asn Met Val Thr
1535 1540 1545
Met Met Val Glu Thr Asp Asp Gln Ser Gln Glu Met Thr Asn Ile
1550 1555 1560
Leu Tyr Trp Ile Asn Leu Val Phe Ile Val Leu Phe Thr Gly Glu
1565 1570 1575
Cys Val Leu Lys Leu Ile Ser Leu Arg His Tyr Tyr Phe Thr Ile
1580 1585 1590
Gly Trp Asn Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile Val
1595 1600 1605
Gly Met Phe Leu Ala Glu Leu Ile Glu Lys Tyr Phe Val Ser Pro
1610 1615 1620
Thr Leu Phe Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu
1625 1630 1635
Arg Leu Ile Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala
1640 1645 1650
Leu Met Met Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu
1655 1660 1665
Phe Leu Val Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe
1670 1675 1680
Ala Tyr Val Lys Arg Glu Val Gly Ile Asp Asp Met Phe Asn Phe
1685 1690 1695
Glu Thr Phe Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr
1700 1705 1710
Ser Ala Gly Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Gly
1715 1720 1725
Pro Pro Asp Cys Asp Pro Glu Lys Asp His Pro Gly Ser Ser Val
1730 1735 1740
Lys Gly Asp Cys Gly Asn Pro Ser Val Gly Ile Phe Phe Phe Val
1745 1750 1755
Ser Tyr Ile Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile
1760 1765 1770
Ala Val Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Ala
1775 1780 1785
Glu Pro Leu Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp
1790 1795 1800
Glu Lys Phe Asp Pro Asp Ala Thr Gln Phe Ile Glu Phe Cys Lys
1805 1810 1815
Leu Ser Asp Phe Ala Ala Ala Leu Asp Pro Pro Leu Leu Ile Ala
1820 1825 1830
Lys Pro Asn Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val
1835 1840 1845
Ser Gly Asp Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr
1850 1855 1860
Lys Arg Val Leu Gly Glu Ser Gly Glu Met Asp Ala Leu Arg Ile
1865 1870 1875
Gln Met Glu Glu Arg Phe Met Ala Ser Asn Pro Ser Lys Val Ser
1880 1885 1890
Tyr Glu Pro Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Glu Val
1895 1900 1905
Ser Ala Ile Val Ile Gln Arg Ala Tyr Arg Arg Tyr Leu Leu Lys
1910 1915 1920
Gln Lys Val Lys Lys Val Ser Ser Ile Tyr Lys Lys Asp Lys Gly
1925 1930 1935
Lys Glu Asp Glu Gly Thr Pro Ile Lys Glu Asp Ile Ile Thr Asp
1940 1945 1950
Lys Leu Asn Glu Asn Ser Thr Pro Glu Lys Thr Asp Val Thr Pro
1955 1960 1965
Ser Thr Thr Ser Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Glu
1970 1975 1980
Lys Glu Lys Phe Glu Lys Asp Lys Ser Glu Lys Glu Asp Lys Gly
1985 1990 1995
Lys Asp Ile Arg Glu Ser Lys Lys
2000 2005
<210> 52
<211> 2005
<212> PRT
<213> 褐家鼠
<400> 52
Met Ala Arg Ser Val Leu Val Pro Pro Gly Pro Asp Ser Phe Arg Phe
1 5 10 15
Phe Thr Arg Glu Ser Leu Ala Ala Ile Glu Gln Arg Ile Ala Glu Glu
20 25 30
Lys Ala Lys Arg Pro Lys Gln Glu Arg Lys Asp Glu Asp Asp Glu Asn
35 40 45
Gly Pro Lys Pro Asn Ser Asp Leu Glu Ala Gly Lys Ser Leu Pro Phe
50 55 60
Ile Tyr Gly Asp Ile Pro Pro Glu Met Val Ser Glu Pro Leu Glu Asp
65 70 75 80
Leu Asp Pro Tyr Tyr Ile Asn Lys Lys Thr Phe Ile Val Leu Asn Lys
85 90 95
Gly Lys Ala Ile Ser Arg Phe Ser Ala Thr Ser Ala Leu Tyr Ile Leu
100 105 110
Thr Pro Phe Asn Pro Ile Arg Lys Leu Ala Ile Lys Ile Leu Val His
115 120 125
Ser Leu Phe Asn Val Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Val
130 135 140
Phe Met Thr Met Ser Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr
145 150 155 160
Thr Phe Thr Gly Ile Tyr Thr Phe Glu Ser Leu Ile Lys Ile Leu Ala
165 170 175
Arg Gly Phe Cys Leu Glu Asp Phe Thr Phe Leu Arg Asn Pro Trp Asn
180 185 190
Trp Leu Asp Phe Thr Val Ile Thr Phe Ala Tyr Val Thr Glu Phe Val
195 200 205
Asn Leu Gly Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala
210 215 220
Leu Lys Thr Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala
225 230 235 240
Leu Ile Gln Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val
245 250 255
Phe Cys Leu Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly
260 265 270
Asn Leu Arg Asn Lys Cys Leu Gln Trp Pro Pro Asp Asn Ser Thr Phe
275 280 285
Glu Ile Asn Ile Thr Ser Phe Phe Asn Asn Ser Leu Asp Trp Asn Gly
290 295 300
Thr Ala Phe Asn Arg Thr Val Asn Met Phe Asn Trp Asp Glu Tyr Ile
305 310 315 320
Glu Asp Lys Ser His Phe Tyr Phe Leu Glu Gly Gln Asn Asp Ala Leu
325 330 335
Leu Cys Gly Asn Ser Ser Asp Ala Gly Gln Cys Pro Glu Gly Tyr Ile
340 345 350
Cys Val Lys Ala Gly Arg Asn Pro Asn Tyr Gly Tyr Thr Ser Phe Asp
355 360 365
Thr Phe Ser Trp Ala Phe Leu Ser Leu Phe Arg Leu Met Thr Gln Asp
370 375 380
Phe Trp Glu Asn Leu Tyr Gln Leu Thr Leu Arg Ala Ala Gly Lys Thr
385 390 395 400
Tyr Met Ile Phe Phe Val Leu Val Ile Phe Leu Gly Ser Phe Tyr Leu
405 410 415
Ile Asn Leu Ile Leu Ala Val Val Ala Met Ala Tyr Glu Glu Gln Asn
420 425 430
Gln Ala Thr Leu Glu Glu Ala Glu Gln Lys Glu Ala Glu Phe Gln Gln
435 440 445
Met Leu Glu Gln Leu Lys Lys Gln Gln Glu Glu Ala Gln Ala Ala Ala
450 455 460
Ala Ala Ala Ser Ala Glu Ser Arg Asp Phe Ser Gly Ala Gly Gly Ile
465 470 475 480
Gly Val Phe Ser Glu Ser Ser Ser Val Ala Ser Lys Leu Ser Ser Lys
485 490 495
Ser Glu Lys Glu Leu Lys Asn Arg Arg Lys Lys Lys Lys Gln Lys Glu
500 505 510
Gln Ala Gly Glu Glu Glu Lys Glu Asp Ala Val Arg Lys Ser Ala Ser
515 520 525
Glu Asp Ser Ile Arg Lys Lys Gly Phe Gln Phe Ser Leu Glu Gly Ser
530 535 540
Arg Leu Thr Tyr Glu Lys Arg Phe Ser Ser Pro His Gln Ser Leu Leu
545 550 555 560
Ser Ile Arg Gly Ser Leu Phe Ser Pro Arg Arg Asn Ser Arg Ala Ser
565 570 575
Leu Phe Asn Phe Lys Gly Arg Val Lys Asp Ile Gly Ser Glu Asn Asp
580 585 590
Phe Ala Asp Asp Glu His Ser Thr Phe Glu Asp Asn Asp Ser Arg Arg
595 600 605
Asp Ser Leu Phe Val Pro His Arg His Gly Glu Arg Arg Pro Ser Asn
610 615 620
Val Ser Gln Ala Ser Arg Ala Ser Arg Gly Ile Pro Thr Leu Pro Met
625 630 635 640
Asn Gly Lys Met His Ser Ala Val Asp Cys Asn Gly Val Val Ser Leu
645 650 655
Val Gly Gly Pro Ser Ala Leu Thr Ser Pro Val Gly Gln Leu Leu Pro
660 665 670
Glu Gly Thr Thr Thr Glu Thr Glu Ile Arg Lys Arg Arg Ser Ser Ser
675 680 685
Tyr His Val Ser Met Asp Leu Leu Glu Asp Pro Ser Arg Gln Arg Ala
690 695 700
Met Ser Met Ala Ser Ile Leu Thr Asn Thr Met Glu Glu Leu Glu Glu
705 710 715 720
Ser Arg Gln Lys Cys Pro Pro Cys Trp Tyr Lys Phe Ala Asn Met Cys
725 730 735
Leu Ile Trp Asp Cys Cys Lys Pro Trp Leu Lys Val Lys His Val Val
740 745 750
Asn Leu Val Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile Cys
755 760 765
Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His Tyr Pro Met Thr
770 775 780
Glu Gln Phe Ser Ser Val Leu Ser Val Gly Asn Leu Val Phe Thr Gly
785 790 795 800
Ile Phe Thr Ala Glu Met Phe Leu Lys Ile Ile Ala Met Asp Pro Tyr
805 810 815
Tyr Tyr Phe Gln Glu Gly Trp Asn Ile Phe Asp Gly Phe Ile Val Ser
820 825 830
Leu Ser Leu Met Glu Leu Gly Leu Ala Asn Val Glu Gly Leu Ser Val
835 840 845
Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser Trp
850 855 860
Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly Ala
865 870 875 880
Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe Ala
885 890 895
Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val Cys
900 905 910
Lys Ile Ser Asn Asp Cys Glu Leu Pro Arg Trp His Met His His Phe
915 920 925
Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp Ile
930 935 940
Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Thr Met Cys Leu
945 950 955 960
Thr Val Phe Met Met Val Met Val Ile Gly Asn Leu Val Val Leu Asn
965 970 975
Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu Ala
980 985 990
Ala Thr Asp Asp Asp Asn Glu Met Asn Asn Leu Gln Ile Ala Val Gly
995 1000 1005
Arg Met Gln Lys Gly Ile Asp Phe Val Lys Arg Lys Ile Arg Glu
1010 1015 1020
Phe Ile Gln Lys Ala Phe Val Arg Lys Gln Lys Ala Leu Asp Glu
1025 1030 1035
Ile Lys Pro Leu Glu Asp Leu Asn Asn Lys Lys Asp Ser Cys Ile
1040 1045 1050
Ser Asn His Thr Thr Ile Glu Ile Gly Lys Asp Leu Asn Tyr Leu
1055 1060 1065
Lys Asp Gly Asn Gly Thr Thr Ser Gly Ile Gly Ser Ser Val Glu
1070 1075 1080
Lys Tyr Val Val Asp Glu Ser Asp Tyr Met Ser Phe Ile Asn Asn
1085 1090 1095
Pro Ser Leu Thr Val Thr Val Pro Ile Ala Leu Gly Glu Ser Asp
1100 1105 1110
Phe Glu Asn Leu Asn Thr Glu Glu Phe Ser Ser Glu Ser Asp Met
1115 1120 1125
Glu Glu Ser Lys Glu Lys Leu Asn Ala Thr Ser Ser Ser Glu Gly
1130 1135 1140
Ser Thr Val Asp Ile Gly Ala Pro Ala Glu Gly Glu Gln Pro Glu
1145 1150 1155
Ala Glu Pro Glu Glu Ser Leu Glu Pro Glu Ala Cys Phe Thr Glu
1160 1165 1170
Asp Cys Val Arg Lys Phe Lys Cys Cys Gln Ile Ser Ile Glu Glu
1175 1180 1185
Gly Lys Gly Lys Leu Trp Trp Asn Leu Arg Lys Thr Cys Tyr Lys
1190 1195 1200
Ile Val Glu His Asn Trp Phe Glu Thr Phe Ile Val Phe Met Ile
1205 1210 1215
Leu Leu Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile Glu
1220 1225 1230
Gln Arg Lys Thr Ile Lys Thr Met Leu Glu Tyr Ala Asp Lys Val
1235 1240 1245
Phe Thr Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Val Ala
1250 1255 1260
Tyr Gly Phe Gln Met Tyr Phe Thr Asn Ala Trp Cys Trp Leu Asp
1265 1270 1275
Phe Leu Ile Val Asp Val Ser Leu Val Ser Leu Thr Ala Asn Ala
1280 1285 1290
Leu Gly Tyr Ser Glu Leu Gly Ala Ile Lys Ser Leu Arg Thr Leu
1295 1300 1305
Arg Ala Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly Met
1310 1315 1320
Arg Val Val Val Asn Ala Leu Leu Gly Ala Ile Pro Ser Ile Met
1325 1330 1335
Asn Val Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile
1340 1345 1350
Met Gly Val Asn Leu Phe Ala Gly Lys Phe Tyr His Cys Ile Asn
1355 1360 1365
Tyr Thr Thr Gly Glu Met Phe Asp Val Ser Val Val Asn Asn Tyr
1370 1375 1380
Ser Glu Cys Gln Ala Leu Ile Glu Ser Asn Gln Thr Ala Arg Trp
1385 1390 1395
Lys Asn Val Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr Leu
1400 1405 1410
Ser Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile Met
1415 1420 1425
Tyr Ala Ala Val Asp Ser Arg Asn Val Glu Leu Gln Pro Lys Tyr
1430 1435 1440
Glu Asp Asn Leu Tyr Met Tyr Leu Tyr Phe Val Ile Phe Ile Ile
1445 1450 1455
Phe Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile Ile
1460 1465 1470
Asp Asn Phe Asn Gln Gln Lys Lys Lys Phe Gly Gly Gln Asp Ile
1475 1480 1485
Phe Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys
1490 1495 1500
Leu Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Ala Asn
1505 1510 1515
Lys Phe Gln Gly Met Val Phe Asp Phe Val Thr Lys Gln Val Phe
1520 1525 1530
Asp Ile Ser Ile Met Ile Leu Ile Cys Leu Asn Met Val Thr Met
1535 1540 1545
Met Val Glu Thr Asp Asp Gln Ser Gln Glu Met Thr Asn Ile Leu
1550 1555 1560
Tyr Trp Ile Asn Leu Val Phe Ile Val Leu Phe Thr Gly Glu Cys
1565 1570 1575
Val Leu Lys Leu Ile Ser Leu Arg His Tyr Tyr Phe Thr Ile Gly
1580 1585 1590
Trp Asn Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile Val Gly
1595 1600 1605
Met Phe Leu Ala Glu Leu Ile Glu Lys Tyr Phe Val Ser Pro Thr
1610 1615 1620
Leu Phe Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg
1625 1630 1635
Leu Ile Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu
1640 1645 1650
Met Met Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu Phe
1655 1660 1665
Leu Val Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe Ala
1670 1675 1680
Tyr Val Lys Arg Glu Val Gly Ile Asp Asp Met Phe Asn Phe Glu
1685 1690 1695
Thr Phe Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr Ser
1700 1705 1710
Ala Gly Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Gly Pro
1715 1720 1725
Pro Asp Cys Asp Pro Glu Lys Asp His Pro Gly Ser Ser Val Lys
1730 1735 1740
Gly Asp Cys Gly Asn Pro Ser Val Gly Ile Phe Phe Phe Val Ser
1745 1750 1755
Tyr Ile Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile Ala
1760 1765 1770
Val Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Ala Glu
1775 1780 1785
Pro Leu Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp Glu
1790 1795 1800
Lys Phe Asp Pro Asp Ala Thr Gln Phe Ile Glu Phe Cys Lys Leu
1805 1810 1815
Ser Asp Phe Ala Ala Ala Leu Asp Pro Pro Leu Leu Ile Ala Lys
1820 1825 1830
Pro Asn Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val Ser
1835 1840 1845
Gly Asp Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr Lys
1850 1855 1860
Arg Val Leu Gly Glu Ser Gly Glu Met Asp Ala Leu Arg Ile Gln
1865 1870 1875
Met Glu Glu Arg Phe Met Ala Ser Asn Pro Ser Lys Val Ser Tyr
1880 1885 1890
Glu Pro Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Glu Val Ser
1895 1900 1905
Ala Ile Val Ile Gln Arg Ala Tyr Arg Arg Tyr Leu Leu Lys Gln
1910 1915 1920
Lys Val Lys Lys Val Ser Ser Ile Tyr Lys Lys Asp Lys Gly Lys
1925 1930 1935
Glu Asp Glu Gly Thr Pro Ile Lys Glu Asp Ile Ile Thr Asp Lys
1940 1945 1950
Leu Asn Glu Asn Ser Thr Pro Glu Lys Thr Asp Val Thr Pro Ser
1955 1960 1965
Thr Thr Ser Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Glu Lys
1970 1975 1980
Glu Lys Phe Glu Lys Asp Lys Ser Glu Lys Glu Asp Lys Gly Lys
1985 1990 1995
Asp Ile Arg Glu Ser Lys Lys
2000 2005
<210> 53
<211> 2021
<212> PRT
<213> 穴兔
<400> 53
Met Ala Gln Ser Val Leu Val Pro Pro Gly Pro Asp Ser Phe Arg Phe
1 5 10 15
Phe Thr Arg Glu Ser Leu Ala Ala Ile Glu Gln Arg Ile Ala Glu Glu
20 25 30
Lys Ala Lys Arg Pro Lys Gln Glu Arg Lys Asp Glu Asp Asp Glu Asn
35 40 45
Gly Pro Lys Pro Asn Ser Asp Leu Glu Ala Gly Lys Ser Leu Pro Phe
50 55 60
Ile Tyr Gly Asp Ile Pro Pro Glu Met Val Ser Glu Pro Leu Glu Asp
65 70 75 80
Leu Asp Pro Tyr Tyr Ile Asn Lys Lys Thr Phe Ile Val Leu Asn Lys
85 90 95
Gly Lys Ala Ile Ser Arg Phe Ser Ala Thr Pro Ala Leu Tyr Ile Leu
100 105 110
Thr Pro Phe Asn Pro Ile Arg Lys Leu Ala Ile Lys Ile Leu Val His
115 120 125
Ser Leu Phe Asn Val Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Val
130 135 140
Phe Met Thr Met Ser Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr
145 150 155 160
Thr Phe Thr Gly Ile Tyr Thr Phe Glu Ser Leu Ile Lys Ile Leu Ala
165 170 175
Arg Gly Phe Cys Leu Glu Asp Phe Thr Phe Leu Arg Asp Pro Trp Asn
180 185 190
Trp Leu Asp Phe Thr Val Ile Thr Phe Ala Tyr Val Thr Glu Phe Val
195 200 205
Asp Leu Gly Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala
210 215 220
Leu Lys Thr Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala
225 230 235 240
Leu Ile Gln Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val
245 250 255
Phe Cys Leu Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly
260 265 270
Asn Leu Arg Asn Lys Cys Leu Gln Trp Pro Pro Asp Asn Ser Ser Phe
275 280 285
Glu Ile Asn Val Thr Ser Phe Phe Asn Asn Ser Leu Asp Gly Asn Gly
290 295 300
Thr Thr Phe Asn Arg Thr Met Ser Ile Phe Asn Trp Asp Glu Tyr Ile
305 310 315 320
Glu Asp Lys Ser His Phe Tyr Phe Leu Glu Gly Gln Asn Asp Ala Leu
325 330 335
Leu Cys Gly Asn Ser Ser Asp Ala Gly Gln Cys Pro Glu Gly Tyr Ile
340 345 350
Cys Val Lys Ala Gly Arg Asn Pro Asn Tyr Gly Tyr Thr Ser Phe Asp
355 360 365
Thr Phe Ser Trp Ala Phe Leu Ser Leu Phe Arg Leu Met Thr Gln Asp
370 375 380
Phe Trp Glu Asn Leu Tyr Gln Leu Thr Leu Arg Ala Ala Gly Lys Thr
385 390 395 400
Tyr Met Ile Phe Phe Val Leu Val Ile Phe Leu Gly Ser Phe Tyr Leu
405 410 415
Ile Asn Leu Ile Leu Ala Val Val Ala Met Ala Tyr Glu Glu Gln Asn
420 425 430
Gln Ala Thr Leu Glu Glu Ala Glu Gln Lys Glu Ala Glu Phe Gln Gln
435 440 445
Met Leu Glu Gln Leu Lys Lys Gln Gln Glu Glu Ala Gln Ala Ala Ala
450 455 460
Ala Ala Ala Ser Ala Glu Ser Arg Glu Phe Ser Gly Ala Gly Gly Val
465 470 475 480
Gly Val Phe Ser Glu Ser Ser Ser Val Ala Ser Lys Leu Ser Ser Lys
485 490 495
Ser Glu Lys Glu Leu Lys Asn Arg Arg Lys Lys Lys Lys Gln Lys Glu
500 505 510
Gln Ser Gly Glu Glu Glu Lys Glu Asp Gly Val Arg Lys Ser Glu Ser
515 520 525
Glu Asp Ser Ile Arg Arg Lys Gly Phe Arg Phe Ser Leu Glu Gly Ser
530 535 540
Arg Leu Thr Tyr Glu Lys Arg Phe Ser Ser Pro His Gln Ser Leu Leu
545 550 555 560
Ser Ile Arg Gly Ser Leu Phe Ser Pro Arg Arg Asn Ser Arg Ala Ser
565 570 575
Leu Phe Ser Phe Arg Gly Arg Thr Lys Asp Val Gly Ser Glu Asn Asp
580 585 590
Phe Ala Asp Asp Glu His Ser Thr Phe Glu Asp Asn Asp Ser Arg Arg
595 600 605
Asp Ser Leu Phe Val Pro His Arg His Gly Glu Arg Arg His Ser Asn
610 615 620
Val Ser Gln Ala Ser Arg Thr Ser Arg Val Leu Pro Ile Leu Pro Met
625 630 635 640
Asn Gly Lys Met His Ser Ala Val Asp Cys Asn Gly Val Val Ser Leu
645 650 655
Val Gly Gly Pro Ser Ala Leu Thr Ser Pro Thr Gly Gln Leu Leu Pro
660 665 670
Glu Gly Thr Thr Thr Glu Thr Glu Ile Arg Lys Arg Arg Ser Ser Ser
675 680 685
Tyr His Val Ser Met Asp Leu Leu Glu Asp Pro Thr Ser Arg Gln Arg
690 695 700
Ala Met Ser Ile Ala Ser Ile Leu Thr Asn Thr Met Glu Glu Leu Glu
705 710 715 720
Glu Ser Arg Gln Lys Cys Pro Pro Cys Trp Tyr Lys Phe Ala Asn Met
725 730 735
Cys Leu Ile Trp Asp Cys Cys Lys Pro Trp Leu Lys Val Lys His Leu
740 745 750
Val Asn Leu Val Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile
755 760 765
Cys Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His Tyr Pro Met
770 775 780
Thr Glu Gln Phe Ser Ser Val Leu Ser Val Gly Asn Leu Val Phe Thr
785 790 795 800
Gly Ile Phe Thr Ala Glu Met Phe Leu Lys Ile Ile Ala Met Asp Pro
805 810 815
Tyr Tyr Tyr Phe Gln Glu Gly Trp Asn Ile Phe Asp Gly Phe Ile Val
820 825 830
Ser Leu Ser Leu Met Glu Leu Gly Leu Ala Asn Val Glu Gly Leu Ser
835 840 845
Val Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser
850 855 860
Trp Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly
865 870 875 880
Ala Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe
885 890 895
Ala Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val
900 905 910
Cys Lys Ile Ser Asn Asp Cys Glu Leu Pro Arg Trp His Met His Asp
915 920 925
Phe Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp
930 935 940
Ile Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Thr Met Cys
945 950 955 960
Leu Thr Val Phe Met Met Val Met Val Ile Gly Asn Leu Val Val Leu
965 970 975
Asn Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu
980 985 990
Ala Ala Thr Asp Asp Asp Asn Glu Met Asn Asn Leu Gln Ile Ala Val
995 1000 1005
Gly Arg Met Gln Lys Gly Ile Asp Phe Val Lys Arg Lys Ile Arg
1010 1015 1020
Glu Phe Ile Gln Lys Ala Phe Val Arg Lys Gln Lys Ala Leu Asp
1025 1030 1035
Glu Ile Lys Pro Leu Glu Asp Leu Asn Asn Lys Lys Asp Ser Cys
1040 1045 1050
Ile Ser Asn His Thr Thr Ile Glu Ile Gly Lys Asp Leu Asn Tyr
1055 1060 1065
Leu Lys Asp Gly Asn Gly Thr Thr Ser Gly Ile Gly Ser Ser Val
1070 1075 1080
Glu Lys Tyr Val Val Asp Glu Ser Asp Tyr Met Ser Phe Ile Asn
1085 1090 1095
Asn Pro Ser Leu Thr Val Thr Val Pro Ile Ala Val Gly Glu Ser
1100 1105 1110
Asp Phe Glu Asn Leu Asn Thr Glu Glu Phe Ser Ser Glu Ser Asp
1115 1120 1125
Met Glu Glu Ser Lys Glu Ile Lys Glu Asp Ile Glu Thr Leu Ser
1130 1135 1140
Cys Gly Ile Asp Phe Gln Lys Leu Asn Ala Thr Ser Ser Ser Glu
1145 1150 1155
Gly Ser Thr Val Asp Ile Gly Ala Pro Ala Glu Gly Glu Gln Pro
1160 1165 1170
Glu Ala Glu Pro Glu Glu Ser Leu Glu Pro Glu Ala Cys Phe Thr
1175 1180 1185
Glu Asp Cys Val Arg Lys Phe Lys Cys Cys Gln Ile Ser Ile Glu
1190 1195 1200
Glu Gly Lys Gly Lys Leu Trp Trp Asn Leu Arg Lys Thr Cys Tyr
1205 1210 1215
Lys Ile Val Glu His Asn Trp Phe Glu Thr Phe Ile Val Phe Met
1220 1225 1230
Ile Leu Leu Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile
1235 1240 1245
Glu Gln Arg Lys Thr Ile Lys Thr Met Leu Glu Tyr Ala Asp Lys
1250 1255 1260
Val Phe Thr Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Val
1265 1270 1275
Ala Tyr Gly Phe Gln Met Tyr Phe Thr Asn Ala Trp Cys Trp Leu
1280 1285 1290
Asp Phe Leu Ile Val Asp Val Ser Leu Val Ser Leu Thr Ala Asn
1295 1300 1305
Ala Leu Gly Tyr Ser Glu Leu Gly Ala Ile Lys Ser Leu Arg Thr
1310 1315 1320
Leu Arg Ala Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly
1325 1330 1335
Met Arg Val Val Val Asn Ala Leu Leu Gly Ala Ile Pro Ser Ile
1340 1345 1350
Met Asn Val Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser
1355 1360 1365
Ile Met Gly Val Asn Leu Phe Ala Gly Lys Phe Tyr His Cys Ile
1370 1375 1380
Asn Phe Thr Thr Gly Glu Met Phe Asp Val Ser Val Val Asn Asn
1385 1390 1395
Tyr Ser Glu Cys Lys Ala Leu Ile Glu Ser Asn Gln Thr Ala Arg
1400 1405 1410
Trp Lys Asn Val Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr
1415 1420 1425
Leu Ser Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile
1430 1435 1440
Met Tyr Ala Ala Val Asp Ser Arg Asn Val Glu Leu Gln Pro Lys
1445 1450 1455
Tyr Glu Asp Asn Leu Tyr Met Tyr Leu Tyr Phe Val Ile Phe Ile
1460 1465 1470
Ile Phe Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile
1475 1480 1485
Ile Asp Asn Phe Asn Gln Gln Lys Lys Lys Phe Gly Gly Gln Asp
1490 1495 1500
Ile Phe Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys
1505 1510 1515
Lys Leu Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Ala
1520 1525 1530
Asn Lys Phe Gln Gly Met Val Phe Asp Phe Val Thr Lys Gln Val
1535 1540 1545
Phe Asp Ile Ser Ile Met Ile Leu Ile Cys Leu Asn Met Val Thr
1550 1555 1560
Met Met Val Glu Thr Asp Asp Gln Ser Gln Glu Met Thr Asn Ile
1565 1570 1575
Leu Tyr Trp Ile Asn Leu Val Phe Ile Val Leu Phe Thr Gly Glu
1580 1585 1590
Cys Val Leu Lys Leu Ile Ser Leu Arg Tyr Tyr Tyr Phe Thr Ile
1595 1600 1605
Gly Trp Asn Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile Val
1610 1615 1620
Gly Met Phe Leu Ala Glu Leu Ile Glu Lys Tyr Phe Val Ser Pro
1625 1630 1635
Thr Leu Phe Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu
1640 1645 1650
Arg Leu Ile Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala
1655 1660 1665
Leu Met Met Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu
1670 1675 1680
Phe Leu Val Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe
1685 1690 1695
Ala Tyr Val Lys Arg Glu Val Gly Ile Asp Asp Met Phe Asn Phe
1700 1705 1710
Glu Thr Phe Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr
1715 1720 1725
Ser Ala Gly Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Gly
1730 1735 1740
Pro Pro Asp Cys Asp Pro Glu Lys Asp His Pro Gly Ser Ser Val
1745 1750 1755
Lys Gly Asp Cys Gly Asn Pro Ser Val Gly Ile Phe Phe Phe Val
1760 1765 1770
Ser Tyr Ile Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile
1775 1780 1785
Ala Val Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Ala
1790 1795 1800
Glu Pro Leu Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp
1805 1810 1815
Glu Lys Phe Asp Pro Asp Ala Thr Gln Phe Ile Glu Phe Ser Lys
1820 1825 1830
Leu Ser Asp Phe Ala Ala Ala Leu Asp Pro Pro Leu Leu Ile Ala
1835 1840 1845
Lys Pro Asn Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val
1850 1855 1860
Ser Gly Asp Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr
1865 1870 1875
Lys Arg Val Leu Gly Glu Ser Gly Glu Met Asp Ala Leu Arg Ile
1880 1885 1890
Gln Met Glu Glu Arg Phe Met Ala Ser Asn Pro Ser Lys Val Ser
1895 1900 1905
Tyr Glu Pro Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Glu Val
1910 1915 1920
Ser Ala Ile Val Ile Gln Arg Ala Tyr Arg Arg Tyr Leu Leu Lys
1925 1930 1935
Gln Lys Val Lys Lys Val Ser Ser Ile Tyr Lys Lys Asp Lys Gly
1940 1945 1950
Lys Glu Gly Asp Gly Thr Pro Ile Lys Glu Asp Ile Leu Ile Asp
1955 1960 1965
Lys Leu Asn Glu Asn Ser Thr Pro Glu Lys Thr Asp Met Thr Pro
1970 1975 1980
Ser Thr Thr Ser Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Glu
1985 1990 1995
Lys Glu Lys Phe Glu Lys Asp Lys Ser Glu Lys Glu Asp Lys Gly
2000 2005 2010
Lys Asp Ser Arg Glu Ser Lys Lys
2015 2020
<210> 54
<211> 2006
<212> PRT
<213> 原鸡
<400> 54
Met Ala Gln Ser Val Leu Val Pro Pro Gly Pro Asp Ser Phe Arg Tyr
1 5 10 15
Phe Thr Arg Glu Ser Leu Ala Ala Ile Glu Gln Arg Ile Asn Glu Glu
20 25 30
Lys Ala Lys Lys Ser Lys Gln Glu Arg Lys Asp Asp Asp Asp Glu Asp
35 40 45
Gly Pro Lys Pro Asn Ser Asp Leu Glu Ala Gly Lys Thr Leu Pro Phe
50 55 60
Ile Tyr Gly Asp Ile Pro Pro Gly Met Val Ser Glu Pro Leu Glu Asp
65 70 75 80
Leu Asp Pro Tyr Tyr Ile Asn Lys Lys Thr Phe Ile Val Leu Asn Lys
85 90 95
Gly Lys Ala Ile Phe Arg Phe Ser Ala Thr Ser Ala Leu Tyr Met Leu
100 105 110
Thr Pro Phe Asn Pro Leu Arg Lys Ile Ala Ile Lys Ile Leu Val His
115 120 125
Ser Leu Phe Ser Met Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Val
130 135 140
Phe Met Thr Met Ser Asn Pro Pro Asp Trp Thr Lys Asn Val Glu Tyr
145 150 155 160
Thr Phe Thr Gly Ile Tyr Thr Phe Glu Ser Leu Ile Lys Ile Leu Ala
165 170 175
Arg Gly Phe Cys Leu Glu Asp Phe Thr Phe Leu Arg Asp Pro Trp Asn
180 185 190
Trp Leu Asp Phe Thr Val Ile Thr Phe Ala Tyr Val Thr Glu Phe Val
195 200 205
Asp Leu Gly Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala
210 215 220
Leu Lys Thr Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala
225 230 235 240
Leu Ile Gln Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val
245 250 255
Phe Cys Leu Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly
260 265 270
Asn Leu Arg Asn Lys Cys Leu Gln Trp Pro Pro Asp Asn Ser Thr Phe
275 280 285
Glu Thr Thr Val Ile Thr Tyr Phe Asn Ser Ser Ile Gly Glu Asn Gly
290 295 300
Thr Phe Ile Asn Thr Thr Met Thr Ile Phe Asn Trp Asp Glu Tyr Ile
305 310 315 320
Glu Asp Glu Asn His Phe Tyr Phe Leu Glu Gly Gln Asn Asp Ala Leu
325 330 335
Leu Cys Gly Asn Ser Ser Asp Ala Gly Gln Cys Pro Glu Gly Tyr Ile
340 345 350
Cys Val Lys Ala Gly Arg Asn Pro Asn Tyr Gly Tyr Thr Ser Phe Asp
355 360 365
Thr Phe Ser Trp Ala Phe Leu Ser Leu Phe Arg Leu Met Thr Gln Asp
370 375 380
Phe Trp Glu Asn Leu Tyr Gln Leu Thr Leu Arg Ala Ala Gly Lys Thr
385 390 395 400
Tyr Met Ile Phe Phe Val Leu Val Ile Phe Leu Gly Ser Phe Tyr Leu
405 410 415
Ile Asn Leu Ile Leu Ala Val Val Ala Met Ala Tyr Glu Glu Gln Asn
420 425 430
Gln Ala Thr Met Glu Glu Ala Glu Gln Lys Glu Ala Glu Phe Gln Gln
435 440 445
Met Leu Glu Gln Leu Lys Lys Gln Gln Glu Glu Ala Gln Ala Ala Ala
450 455 460
Ala Ala Ala Ala Ala Asp Ser Arg Asp Tyr Ser Gly Val Gly Gly Ile
465 470 475 480
Gly Gly Phe Ser Glu Ser Ser Ser Glu Ala Ser Lys Leu Ser Ser Lys
485 490 495
Ser Ala Lys Glu Arg Arg Asn Arg Arg Lys Lys Lys Lys Gln Lys Glu
500 505 510
Gln Ala Glu Gly Glu Lys Asp Glu Glu Glu Phe Arg Lys Ser Glu Ser
515 520 525
Glu Asp Ser Ile Lys Arg Lys Gly Phe Arg Phe Ser Ile Glu Gly Asn
530 535 540
Arg Leu Thr Tyr Glu Lys Arg Phe Ser Ser Pro His Gln Ser Leu Leu
545 550 555 560
Ser Ile Arg Gly Ser Leu Phe Ser Pro Arg Arg Asn Ser Arg Thr Ser
565 570 575
Leu Phe Ser Phe Arg Gly Arg Ala Lys Asp Val Gly Ser Glu Asn Asp
580 585 590
Phe Ala Asp Asp Glu His Ser Thr Phe Glu Asp Asn Glu Ser Arg Arg
595 600 605
Asp Ser Leu Phe Val Pro His Arg His Gly Glu Arg Arg Asn Ser Asn
610 615 620
Ile Ser Gln Ala Ser Arg Ser Ser Arg Thr Val Pro Pro Leu Pro Val
625 630 635 640
Asn Gly Lys Met His Ser Thr Val Asp Cys Asn Gly Val Val Ser Leu
645 650 655
Val Gly Gly Pro Pro Ala Leu Thr Ser Pro Thr Gly Gln Leu Leu Pro
660 665 670
Glu Gly Thr Thr Thr Glu Thr Asp Leu Arg Lys Arg Arg Ser Ser Ser
675 680 685
Tyr Gln Val Pro Met Asp Tyr Leu Thr Asp Pro Ser Ala Arg Gln Arg
690 695 700
Ala Met Ser Ile Ala Ser Met Leu Thr Asn Thr Met Glu Glu Leu Glu
705 710 715 720
Glu Ser Arg Gln Lys Cys Pro Pro Cys Trp Tyr Lys Phe Ala Asn Thr
725 730 735
Cys Leu Ile Trp Asp Cys Cys Thr Pro Trp Leu Lys Val Lys His Ile
740 745 750
Val Asn Leu Ile Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile
755 760 765
Cys Ile Val Leu Asn Thr Leu Phe Met Ala Met Glu His Tyr Pro Met
770 775 780
Thr Glu Gln Phe Ser Gly Val Leu Ser Val Gly Asn Leu Val Phe Thr
785 790 795 800
Gly Ile Phe Thr Ala Glu Met Phe Leu Lys Ile Ile Ala Met Asp Pro
805 810 815
Tyr Tyr Tyr Phe Gln Glu Gly Trp Asn Ile Phe Asp Gly Phe Ile Val
820 825 830
Ser Leu Ser Leu Met Glu Leu Gly Leu Ala Asn Val Glu Gly Leu Ser
835 840 845
Val Leu Arg Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser
850 855 860
Trp Pro Thr Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly
865 870 875 880
Ala Leu Gly Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe
885 890 895
Ala Val Val Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val
900 905 910
Cys Lys Ile Ser Ser Asp Cys Glu Leu Pro Arg Trp His Met His Asp
915 920 925
Phe Phe His Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp
930 935 940
Ile Glu Thr Met Trp Asp Cys Met Glu Val Ala Gly Gln Thr Met Cys
945 950 955 960
Leu Thr Val Phe Met Met Val Met Val Ile Gly Asn Leu Val Val Leu
965 970 975
Asn Leu Phe Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu
980 985 990
Ala Ala Thr Asp Asp Asp Asn Glu Met Asn Asn Leu Gln Ile Ala Val
995 1000 1005
Ala Arg Ile Gln Lys Gly Ile Asp Phe Val Lys Arg Lys Val Arg
1010 1015 1020
Glu Phe Ile Gln Lys Ala Phe Val Arg Lys Gln Lys Val Leu Asp
1025 1030 1035
Glu Ile Lys Pro Leu Glu Asp Leu Asn Asn Lys Lys Asp Ser Cys
1040 1045 1050
Ile Ser Asn His Thr Ile Val Glu Ile Gly Lys Asn Leu Ala Tyr
1055 1060 1065
Leu Lys Glu Gly Asn Gly Thr Thr Ser Gly Ile Gly Ser Ser Val
1070 1075 1080
Glu Lys Tyr Val Val Asp Glu Ser Asp Tyr Met Ser Phe Ile Asn
1085 1090 1095
Asn Pro Ser Leu Thr Val Thr Val Pro Ile Ala Val Gly Glu Ser
1100 1105 1110
Asp Phe Glu Asn Leu Asn Thr Glu Glu Phe Ser Ser Glu Ser Asp
1115 1120 1125
Leu Glu Glu Ser Lys Glu Lys Leu Asn Ala Ser Ser Ser Ser Glu
1130 1135 1140
Gly Ser Thr Val Asp Ile Gly Leu Pro Pro Glu Gly Glu Gln Pro
1145 1150 1155
Glu Val Glu Pro Glu Glu Ser Leu Glu Pro Glu Ala Cys Phe Thr
1160 1165 1170
Glu Gly Cys Val Arg Arg Phe Lys Cys Cys Gln Val Ser Val Glu
1175 1180 1185
Asp Gly Lys Gly Lys Ile Trp Trp Asn Leu Arg Lys Thr Cys Tyr
1190 1195 1200
Lys Ile Val Glu His Asn Trp Phe Glu Thr Phe Ile Val Phe Met
1205 1210 1215
Ile Leu Leu Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile
1220 1225 1230
Glu Gln Arg Lys Thr Ile Lys Thr Met Leu Glu Tyr Ala Asp Lys
1235 1240 1245
Val Phe Thr Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Val
1250 1255 1260
Ala Tyr Gly Phe Gln Thr Tyr Phe Thr Asn Ala Trp Cys Trp Leu
1265 1270 1275
Asp Phe Leu Ile Val Asp Val Ser Leu Val Ser Leu Thr Ala Asn
1280 1285 1290
Ala Leu Gly Tyr Ser Glu Leu Gly Ala Ile Lys Ser Leu Arg Thr
1295 1300 1305
Leu Arg Ala Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly
1310 1315 1320
Met Arg Val Val Val Asn Ala Leu Leu Gly Ala Ile Pro Ser Ile
1325 1330 1335
Met Asn Val Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser
1340 1345 1350
Ile Met Gly Val Asn Leu Phe Ala Gly Lys Phe Tyr Tyr Cys Val
1355 1360 1365
Asn Thr Thr Thr Asp Glu Arg Phe Asp Ile Ser Gln Ile Asn Asn
1370 1375 1380
Tyr Ser Gln Cys Glu Glu Leu Ile Lys Asn Asn Glu Thr Ala Arg
1385 1390 1395
Trp Lys Asn Val Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr
1400 1405 1410
Leu Ser Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile
1415 1420 1425
Met Tyr Ala Ala Val Asp Ser Arg Asn Val Leu Asp Gln Pro Lys
1430 1435 1440
Tyr Glu Asp Asn Leu Tyr Met Tyr Leu Tyr Phe Val Ile Phe Ile
1445 1450 1455
Ile Phe Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile
1460 1465 1470
Ile Asp Asn Phe Asn Gln Gln Lys Lys Lys Phe Gly Gly Gln Asp
1475 1480 1485
Ile Phe Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys
1490 1495 1500
Lys Leu Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Ala
1505 1510 1515
Asn Lys Phe Gln Gly Met Val Phe Asp Phe Val Thr Lys Gln Ala
1520 1525 1530
Phe Asp Ile Ser Ile Met Ile Leu Ile Cys Leu Asn Met Val Thr
1535 1540 1545
Met Met Val Glu Thr Asp Asp Gln Ser Glu Asp Met Glu Asn Ile
1550 1555 1560
Leu Tyr Trp Ile Asn Leu Val Phe Ile Val Leu Phe Thr Gly Glu
1565 1570 1575
Phe Val Leu Lys Leu Ile Ser Leu Arg His Tyr Tyr Phe Thr Ile
1580 1585 1590
Gly Trp Asn Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile Val
1595 1600 1605
Gly Met Phe Leu Ala Glu Met Ile Glu Lys Tyr Phe Val Ser Pro
1610 1615 1620
Thr Leu Phe Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu
1625 1630 1635
Arg Leu Ile Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala
1640 1645 1650
Leu Met Met Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu
1655 1660 1665
Phe Leu Val Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe
1670 1675 1680
Ala Tyr Val Lys Arg Glu Val Gly Ile Asp Asp Met Phe Asn Phe
1685 1690 1695
Glu Thr Phe Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr
1700 1705 1710
Ser Ala Gly Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Gly
1715 1720 1725
Glu Pro Asp Cys Asp Pro His Lys Asp His Pro Gly Ser Ser Val
1730 1735 1740
Lys Gly Asp Cys Gly Asn Pro Ser Val Gly Ile Phe Phe Phe Val
1745 1750 1755
Ser Tyr Ile Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile
1760 1765 1770
Ala Val Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Ala
1775 1780 1785
Glu Pro Leu Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp
1790 1795 1800
Glu Lys Phe Asp Pro Asp Ala Thr Gln Phe Ile Glu Phe Ser Lys
1805 1810 1815
Leu Ser Asp Phe Ala Ala Ser Leu Asp Pro Pro Leu Leu Ile Ala
1820 1825 1830
Lys Pro Asn Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val
1835 1840 1845
Ser Gly Asp Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr
1850 1855 1860
Lys Arg Val Leu Gly Glu Ser Gly Glu Met Asp Ala Leu Arg Ile
1865 1870 1875
Gln Met Glu Asp Arg Phe Met Ala Ala Asn Pro Ser Lys Val Ser
1880 1885 1890
Tyr Glu Pro Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Glu Val
1895 1900 1905
Ser Ala Val Val Ile Gln Arg Ala Phe Arg Arg His Leu Leu Arg
1910 1915 1920
Gln Lys Val Lys Lys Val Ser Cys Ile Phe Asn Gln Asp Lys Gly
1925 1930 1935
Lys Asp Glu Asp Asp Leu Pro Met Lys Glu Asp Met Ile Met Asp
1940 1945 1950
Lys Leu Asn Glu Asn Ser Thr Pro Glu Lys Thr Asp Met Thr Pro
1955 1960 1965
Ser Thr Thr Ser Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Asp
1970 1975 1980
Lys Asp Lys Tyr Glu Lys Asp Lys Ser Glu Lys Glu Asp Lys Gly
1985 1990 1995
Lys Asp Ser Arg Glu Ser Lys Lys
2000 2005
<210> 55
<211> 1867
<212> PRT
<213> 眼镜王蛇
<400> 55
Met Glu Lys Arg Glu Ala Ser Ser Phe Ser Leu Arg Leu Gly Cys Thr
1 5 10 15
Asp Ala Ser Lys Glu Glu Gln Gly Lys Phe Lys Ala Met Leu Asp Tyr
20 25 30
Pro Ala Glu Leu Arg Ala Arg Ala Lys Ser Asn Phe Asn Val Gln Asp
35 40 45
Glu Lys Met Ala Gln Thr Leu Leu Val Pro Pro Gly Pro Asp Ser Phe
50 55 60
Arg Phe Phe Thr Arg Glu Ser Leu Ala Ala Ile Glu Lys Arg Cys Thr
65 70 75 80
Glu Glu Lys Ala Lys Arg Pro Lys Gln Glu His Thr Asp Asn Asp Asp
85 90 95
Glu Ser Gly Pro Lys Pro Asn Ser Asp Leu Glu Ala Gly Lys Thr Leu
100 105 110
Pro Phe Ile Tyr Gly Asp Ile Pro Pro Gly Met Val Ser Glu Pro Leu
115 120 125
Glu Asp Leu Asp Pro Tyr Tyr Ser Asn Lys Lys Thr Phe Ile Val Leu
130 135 140
Asn Arg Gly Lys Ala Ile Phe Arg Phe Ser Ala Thr Ser Ala Leu Tyr
145 150 155 160
Ile Leu Thr Pro Phe Asn Pro Leu Arg Lys Ile Ala Ile Lys Ile Leu
165 170 175
Gly Val Thr Pro Leu Asn Ile Trp Glu Gln Leu Phe Leu Lys Phe Tyr
180 185 190
Leu Leu Leu Asn Ile Lys Ser Val Ser Lys Leu Arg Ser Val Trp Asn
195 200 205
Ser Thr Phe Phe Asn Phe His Leu Pro Ala Ser Arg Tyr Thr Phe Thr
210 215 220
Gly Ile Tyr Thr Phe Glu Ser Leu Ile Lys Ile Leu Ala Arg Gly Phe
225 230 235 240
Cys Leu Glu Gly Phe Thr Phe Leu Arg Asp Pro Trp Asn Trp Leu Asp
245 250 255
Phe Ser Val Ile Leu Met Ala Tyr Val Thr Glu Phe Val Asn Leu Gly
260 265 270
Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala Leu Lys Thr
275 280 285
Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala Leu Ile Gln
290 295 300
Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val Phe Cys Leu
305 310 315 320
Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly Asn Leu Arg
325 330 335
His Lys Cys Leu Leu Trp Pro Leu Asp Asn Ala Thr Phe Glu Gly Asn
340 345 350
Ile Thr Ser His Phe Asn Ser Thr Glu Gly Glu Asn Asp Thr Phe Val
355 360 365
Asn Met Thr Val Thr Thr Phe Asn Trp Glu Glu Tyr Ile Glu Asp Glu
370 375 380
Ser His Phe Tyr Val Leu Glu Gly Gln Arg Asp Ala Leu Leu Cys Gly
385 390 395 400
Asn Ser Ser Asp Ala Gly Gln Cys Pro Glu Gly Tyr Val Cys Ile Lys
405 410 415
Ala Gly Arg Asn Pro Asn Tyr Gly Tyr Thr Ser Phe Asp Thr Phe Ser
420 425 430
Trp Ala Phe Leu Ser Leu Phe Arg Leu Met Thr Gln Asp Phe Trp Glu
435 440 445
Asn Leu Tyr Gln Leu Thr Leu Arg Ala Ala Gly Lys Thr Tyr Met Ile
450 455 460
Phe Phe Val Leu Val Ile Phe Leu Gly Ser Phe Tyr Leu Ile Asn Leu
465 470 475 480
Ile Leu Ala Val Val Ala Met Ala Tyr Glu Glu Gln Asn Gln Ala Thr
485 490 495
Met Glu Glu Ala Glu Gln Lys Glu Ala Glu Phe Gln Gln Met Leu Glu
500 505 510
Gln Leu Lys Lys Gln Gln Glu Glu Ala Gln Ile Thr Ile Arg Glu Ala
515 520 525
Thr His Leu Leu Ile Thr Pro Asn Asn Asn Trp Phe Gly Leu Cys Ser
530 535 540
Val Leu Pro Pro Leu Gln Ser Leu Leu Ser Phe Arg Gly Ser Leu Phe
545 550 555 560
Ser Pro Arg Arg Asn Ser Arg Thr Ser Ile Phe Ser Phe Arg Gly Arg
565 570 575
Ala Lys Asp Ile Gly Ser Glu Asn Asp Phe Ala Asp Asp Glu His Ser
580 585 590
Thr Leu Glu Asp Asn Glu Ser Arg Arg Asp Ser Leu Phe Val Pro Asn
595 600 605
Arg Gln Thr Ser Glu Arg Arg Asn Ser Thr Thr Ser Gln Met Ser Leu
610 615 620
Ser Ser Lys Met Val Pro Val Leu Pro Ala Asn Gly Lys Met His Ser
625 630 635 640
Thr Val Asp Cys Asn Gly Val Val Ser Leu Met Gly Gly Pro Pro Ala
645 650 655
Leu Pro Ser Pro Thr Gly Gln Phe Leu Pro Glu Gly Thr Thr Thr Glu
660 665 670
Thr Glu Ile Arg Lys Arg Arg Leu Ser Ser Tyr Gln Ile Ser Met Glu
675 680 685
Leu Met Glu Glu Ser Ala Ala Arg Gln Arg Ala Met Ser Ile Ala Ser
690 695 700
Ile Leu Thr Asn Thr Met Glu Glu Leu Glu Glu Ser Arg Gln Lys Cys
705 710 715 720
Pro Pro Cys Trp Tyr Arg Phe Ala Asn Val Phe Leu Ile Trp Asp Cys
725 730 735
Trp Ser Pro Trp Leu Lys Val Lys His Ile Val Asn Leu Ile Val Met
740 745 750
Asp Pro Phe Val Asp Leu Ala Ile Thr Ile Cys Ile Val Leu Asn Thr
755 760 765
Leu Phe Met Ala Met Glu His Tyr Pro Met Thr Ser Asp Phe Tyr Gln
770 775 780
Val Leu Ser Val Gly Asn Leu Val Phe Thr Gly Ile Phe Thr Ala Glu
785 790 795 800
Met Ile Leu Lys Ile Ile Ala Met Asp Pro Tyr Tyr Tyr Phe Gln Glu
805 810 815
Gly Trp Asn Ile Phe Asp Gly Ile Ile Val Ser Leu Ser Leu Met Glu
820 825 830
Leu Gly Leu Ala Asn Val Glu Gly Leu Ser Val Leu Arg Ser Phe Arg
835 840 845
Leu Leu Arg Val Phe Lys Leu Ala Lys Ser Trp Pro Thr Leu Asn Met
850 855 860
Leu Ile Lys Ile Ile Gly Asn Ser Val Gly Ala Leu Gly Asn Leu Thr
865 870 875 880
Leu Val Leu Ala Ile Ile Val Phe Ile Phe Ala Val Val Gly Met Gln
885 890 895
Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val Cys Lys Ile Ala Glu Asp
900 905 910
Cys Glu Leu Pro Arg Trp His Met Asn Asp Phe Phe His Ser Phe Leu
915 920 925
Ile Val Phe Arg Val Leu Cys Gly Glu Trp Ile Glu Thr Met Trp Asp
930 935 940
Cys Met Glu Val Ala Gly Gln Thr Met Cys Leu Ile Val Phe Met Leu
945 950 955 960
Val Met Val Ile Gly Asn Leu Val Val Leu Asn Leu Phe Leu Ala Leu
965 970 975
Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu Ala Ala Thr Asp Asp Asp
980 985 990
Asn Glu Thr Asn Asn Leu Gln Ile Ala Val Ala Arg Ile Gln Lys Gly
995 1000 1005
Ile Asp Tyr Ile Lys Lys Lys Leu Gly Glu Ile Val Gln Lys Ser
1010 1015 1020
Thr Val Arg Lys Gln Lys Ala Ile Asp Asp Ile Lys Val Phe Glu
1025 1030 1035
Glu Leu Asn His Lys Lys Asp Val Tyr Ile Ser Asn His Thr Met
1040 1045 1050
Val Glu Ile Thr Lys Asp Val Asn Tyr Leu Arg Asp Gly Asn Gly
1055 1060 1065
Thr Thr Ser Gly Leu Gly Thr Gly Ser Ser Val Glu Lys Tyr Ile
1070 1075 1080
Ile Asp Glu Asn Asp Tyr Met Ser Phe Ile Asn Asn Pro Gly Leu
1085 1090 1095
Thr Val Thr Val Pro Ile Ala Val Gly Glu Ser Asp Phe Glu Asn
1100 1105 1110
Ile Asn Thr Glu Glu Phe Ser Ser Glu Ser Asp Leu Glu Gly Ser
1115 1120 1125
Lys Glu Lys Ile Asn Ala Thr Ser Ser Ser Glu Gly Ser Thr Val
1130 1135 1140
Asp Val Ala Leu Pro Gly Glu Gly Glu Gln Ala Glu Ile Glu Pro
1145 1150 1155
Glu Glu Ala Leu Glu Pro Glu Ala Cys Phe Thr Glu Gly Cys Ile
1160 1165 1170
Gln Lys Phe Pro Cys Cys Gln Val Ser Ile Glu Asp Gly Lys Gly
1175 1180 1185
Lys Ile Trp Trp Asn Phe Arg Lys Thr Cys Tyr Ser Ile Val Glu
1190 1195 1200
His Asn Trp Phe Glu Thr Phe Ile Val Phe Met Ile Leu Leu Ser
1205 1210 1215
Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Val Glu Gln Arg Lys
1220 1225 1230
Thr Ile Lys Thr Met Leu Glu Tyr Ala Asp Lys Val Phe Thr Tyr
1235 1240 1245
Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Val Ala Tyr Gly Phe
1250 1255 1260
Gln Ile Tyr Phe Thr Asn Ala Trp Cys Trp Leu Asp Phe Leu Ile
1265 1270 1275
Val Asp Val Ser Leu Val Ser Leu Ile Ala Asn Ala Leu Gly Tyr
1280 1285 1290
Ser Glu Leu Gly Ala Ile Lys Ser Leu Arg Thr Leu Arg Ala Leu
1295 1300 1305
Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly Met Arg Val Val
1310 1315 1320
Val Asn Ala Leu Ile Gly Ala Ile Pro Ser Ile Met Asn Val Leu
1325 1330 1335
Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile Met Gly Val
1340 1345 1350
Asn Leu Phe Ala Gly Lys Phe Tyr His Cys Val Asn Thr Thr Thr
1355 1360 1365
Gly Glu Met Phe Asn Ile Ser Asp Val Asn Asn Lys Thr Glu Cys
1370 1375 1380
Asp Glu Leu Ile His Asn Asn Gln Gln Ala Arg Trp Lys Asn Val
1385 1390 1395
Lys Val Asn Phe Asp Asn Val Gly Ala Gly Tyr Leu Ala Leu Leu
1400 1405 1410
Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile Met Tyr Ala Ala
1415 1420 1425
Val Asp Ser Arg Asp Val Glu Glu Gln Pro Tyr Tyr Glu Asp Asn
1430 1435 1440
Leu Tyr Met Tyr Leu Tyr Phe Val Ile Phe Ile Ile Phe Gly Ser
1445 1450 1455
Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile Ile Asp Asn Phe
1460 1465 1470
Asn Gln Gln Lys Lys Lys Ile Arg Gln Asp Ile Phe Met Thr Glu
1475 1480 1485
Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys Leu Gly Ser Lys
1490 1495 1500
Lys Pro Gln Lys Pro Ile Pro Arg Pro Gly Asn Lys Phe Gln Gly
1505 1510 1515
Leu Val Phe Asp Phe Val Thr Lys Gln Ala Phe Asp Ile Ser Ile
1520 1525 1530
Met Ile Leu Ile Cys Leu Asn Met Val Thr Met Met Val Glu Thr
1535 1540 1545
Asp Asp Gln Ser Lys Glu Met Glu Ile Ile Leu Ser Arg Ile Asn
1550 1555 1560
Leu Val Phe Ile Ile Leu Phe Thr Gly Glu Cys Ile Leu Lys Leu
1565 1570 1575
Ile Ser Leu Arg His Tyr Tyr Phe Thr Ile Gly Trp Asn Ile Phe
1580 1585 1590
Asp Phe Val Val Val Ile Leu Ser Ile Val Gly Met Phe Leu Ala
1595 1600 1605
Glu Ile Ile Glu Lys Tyr Phe Val Ser Pro Thr Leu Phe Arg Val
1610 1615 1620
Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg Leu Ile Lys Gly
1625 1630 1635
Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu Met Met Ser Leu
1640 1645 1650
Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu Phe Leu Val Met Phe
1655 1660 1665
Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe Ala Tyr Val Lys Arg
1670 1675 1680
Glu Val Gly Ile Asp Asp Leu Phe Asn Phe Glu Thr Phe Gly Asn
1685 1690 1695
Ser Met Leu Cys Leu Phe Gln Ile Thr Thr Ser Ala Gly Trp Asp
1700 1705 1710
Gly Leu Leu Ala Pro Ile Leu Asn Ser Gly Pro Pro Asp Cys Asp
1715 1720 1725
Pro Glu Ile Asp His Pro Gly Ser Ser Val Lys Gly Asp Cys Gly
1730 1735 1740
Asn Pro Ser Val Gly Ile Phe Phe Phe Val Ser Tyr Ile Ile Ile
1745 1750 1755
Ser Phe Leu Val Val Val Asn Met Tyr Ile Ala Val Ile Leu Glu
1760 1765 1770
Asn Phe Ser Arg Ala Phe Arg Arg Phe Leu Leu Lys Gln Lys Val
1775 1780 1785
Lys Lys Val Thr Ser Met Tyr Asn Lys Glu Lys Cys Arg Asp Gly
1790 1795 1800
Glu Ile Leu Pro Ile Lys Asp Val Thr Ser Asp Arg Phe Asn Gly
1805 1810 1815
Asn Ser Ser Pro Glu Lys Thr Asp Glu Ser Ser Ser Thr Thr Ser
1820 1825 1830
Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Asn Lys Glu Lys Tyr
1835 1840 1845
Glu Lys Gly Lys Thr Asp Arg Asp Phe Lys Gly Lys Asp Ile Lys
1850 1855 1860
Ile Ser Lys Lys
1865
<210> 56
<211> 2019
<212> PRT
<213> 绿海龟
<400> 56
Met Ala Gln Ser Val Leu Val Pro Pro Gly Pro Asp Ser Phe His Tyr
1 5 10 15
Phe Thr Arg Glu Ser Leu Ala Ala Ile Glu Gln Arg Ile Ala Glu Glu
20 25 30
Lys Ala Lys Lys Ser Lys Gln Glu Arg Lys Asp Asp Asp Asp Glu Asn
35 40 45
Gly Pro Lys Pro Asn Ser Asp Leu Glu Ala Gly Lys Thr Leu Pro Phe
50 55 60
Ile Tyr Gly Asp Ile Pro Pro Gly Met Val Ser Glu Pro Leu Glu Asp
65 70 75 80
Leu Asp Pro Tyr Tyr Ile Asn Lys Lys Thr Phe Ile Val Leu Asn Arg
85 90 95
Gly Lys Ala Ile Phe Arg Phe Ser Ala Thr Ser Ala Val Tyr Met Leu
100 105 110
Thr Pro Phe Asn Pro Leu Arg Lys Ile Ala Ile Lys Ile Leu Val His
115 120 125
Ser Leu Phe Ser Met Leu Ile Met Cys Thr Ile Leu Thr Asn Cys Val
130 135 140
Phe Met Thr Met Ser Asn Pro Pro Glu Trp Thr Lys Asn Val Glu Tyr
145 150 155 160
Thr Phe Thr Gly Ile Tyr Thr Phe Glu Ser Leu Val Lys Ile Leu Ala
165 170 175
Arg Gly Phe Cys Leu Glu Asp Phe Thr Phe Leu Arg Asp Pro Trp Asn
180 185 190
Trp Leu Asp Phe Thr Val Ile Thr Phe Ala Tyr Val Thr Glu Phe Val
195 200 205
Asp Leu Gly Asn Val Ser Ala Leu Arg Thr Phe Arg Val Leu Arg Ala
210 215 220
Leu Lys Thr Ile Ser Val Ile Pro Gly Leu Lys Thr Ile Val Gly Ala
225 230 235 240
Leu Ile Gln Ser Val Lys Lys Leu Ser Asp Val Met Ile Leu Thr Val
245 250 255
Phe Cys Leu Ser Val Phe Ala Leu Ile Gly Leu Gln Leu Phe Met Gly
260 265 270
Asn Leu Arg His Lys Cys Leu Gln Trp Pro Pro Asp Asn Ser Thr Leu
275 280 285
Glu Ile Asn Val Ile Ser Tyr Phe Asn Ser Thr Ile Gly Glu Asn Gly
290 295 300
Ser Phe Val Asn Thr Thr Val Ser Thr Phe Asn Trp Glu Glu Tyr Ile
305 310 315 320
Glu Asp Arg Ser His Phe Tyr Phe Leu Glu Gly Gln Asn Asp Ala Leu
325 330 335
Leu Cys Gly Asn Ser Ser Asp Ala Gly Gln Cys Pro Glu Gly Tyr Ile
340 345 350
Cys Val Lys Ala Gly Arg Asn Pro Asn Tyr Gly Tyr Thr Ser Phe Asp
355 360 365
Thr Phe Ser Trp Ala Phe Leu Ser Leu Phe Arg Leu Met Thr Gln Asp
370 375 380
Phe Trp Glu Asn Leu Tyr Gln Leu Thr Leu Arg Ala Ala Gly Lys Thr
385 390 395 400
Tyr Met Ile Phe Phe Val Leu Val Ile Phe Leu Gly Ser Phe Tyr Leu
405 410 415
Ile Asn Leu Ile Leu Ala Val Val Ala Met Ala Tyr Glu Glu Gln Asn
420 425 430
Gln Ala Thr Met Glu Glu Ala Glu Gln Lys Glu Ala Glu Phe Gln Gln
435 440 445
Met Leu Glu Gln Leu Lys Lys Gln Gln Glu Glu Ala Gln Ala Ala Ala
450 455 460
Ala Ala Ala Val Ala Ala Asp Ser Arg Glu Phe Ser Gly Val Gly Gly
465 470 475 480
Val Gly Gly Phe Ser Glu Ser Ser Ser Glu Ala Ser Lys Leu Ser Ser
485 490 495
Lys Ser Ala Lys Glu Arg Arg Asn Arg Arg Lys Lys Arg Lys Gln Lys
500 505 510
Glu Gln Ser Glu Gly Glu Glu Lys Asp Glu Glu Asp Phe His Lys Ser
515 520 525
Glu Ser Glu Asp Ser Met Arg Arg Lys Gly Phe Arg Phe Ser Ile Glu
530 535 540
Gly Asn Arg Leu Thr Tyr Glu Lys Arg Phe Ser Ser Pro His Gln Ser
545 550 555 560
Leu Leu Ser Ile Arg Gly Ser Leu Phe Ser Pro Arg Arg Ser Ser Arg
565 570 575
Thr Ser Leu Phe Ser Phe Arg Gly Arg Ala Lys Asp Val Gly Ser Glu
580 585 590
Asn Asp Phe Ala Asp Asp Glu His Ser Thr Phe Glu Asp Asn Glu Ser
595 600 605
Arg Arg Gly Ser Leu Phe Val Pro His Arg His Gly Glu Arg Arg Asn
610 615 620
Ser Asn Ile Ser Gln Ala Ser Arg Ser Ser Arg Met Val Pro Ala Leu
625 630 635 640
Pro Ala Asn Gly Lys Met His Ser Thr Val Asp Cys Asn Gly Val Val
645 650 655
Ser Leu Val Gly Gly Pro Pro Ala Leu Thr Ser Pro Thr Gly Gln Leu
660 665 670
Leu Pro Glu Val Ile Ile Ala Ser Lys Ala Thr Gln Glu Asn Gly Thr
675 680 685
Thr Thr Glu Thr Glu Leu Arg Lys Arg Arg Thr Ser Ser Tyr His Val
690 695 700
Ser Met Asp Phe Leu Ser Glu Pro Ser Ala Arg Gln Arg Ala Met Ser
705 710 715 720
Ile Ala Ser Ile Leu Thr Asn Thr Met Glu Glu Leu Glu Glu Ser Arg
725 730 735
Gln Lys Cys Pro Pro Cys Trp Tyr Lys Phe Ala Asn Thr Cys Leu Ile
740 745 750
Trp Asp Cys Cys Thr Pro Trp Leu Arg Val Lys His Ile Val Asn Leu
755 760 765
Ile Val Met Asp Pro Phe Val Asp Leu Ala Ile Thr Ile Cys Ile Val
770 775 780
Leu Asn Thr Leu Phe Met Ala Met Glu His Tyr Pro Met Thr Glu Gln
785 790 795 800
Phe Ser His Val Leu Ser Val Gly Asn Leu Val Phe Thr Gly Ile Phe
805 810 815
Thr Ala Glu Met Phe Leu Lys Ile Val Ala Met Asp Pro Tyr Tyr Tyr
820 825 830
Phe Gln Glu Gly Trp Asn Ile Phe Asp Gly Phe Ile Val Ser Leu Ser
835 840 845
Leu Met Glu Leu Gly Leu Ala Asn Val Glu Gly Leu Ser Val Leu Arg
850 855 860
Ser Phe Arg Leu Leu Arg Val Phe Lys Leu Ala Lys Ser Trp Pro Thr
865 870 875 880
Leu Asn Met Leu Ile Lys Ile Ile Gly Asn Ser Val Gly Ala Leu Gly
885 890 895
Asn Leu Thr Leu Val Leu Ala Ile Ile Val Phe Ile Phe Ala Val Val
900 905 910
Gly Met Gln Leu Phe Gly Lys Ser Tyr Lys Glu Cys Val Cys Lys Ile
915 920 925
Ser Asn Asp Cys Glu Leu Pro Arg Trp His Met His Asp Phe Phe His
930 935 940
Ser Phe Leu Ile Val Phe Arg Val Leu Cys Gly Glu Trp Ile Glu Thr
945 950 955 960
Met Trp Asp Cys Met Glu Val Ala Gly Gln Ala Met Cys Leu Ile Val
965 970 975
Phe Met Met Val Met Val Ile Gly Asn Leu Val Val Leu Asn Leu Phe
980 985 990
Leu Ala Leu Leu Leu Ser Ser Phe Ser Ser Asp Asn Leu Ala Ala Thr
995 1000 1005
Asp Asp Asp Asn Glu Met Asn Asn Leu Gln Ile Ala Val Ala Arg
1010 1015 1020
Ile Gln Lys Gly Ile Asp Tyr Val Lys Arg Lys Ala Arg Glu Phe
1025 1030 1035
Ile Gln Lys Ala Phe Val Arg Lys Gln Lys Ala Leu Asp Glu Ile
1040 1045 1050
Lys Pro Leu Glu Asp Leu Asn Asn Lys Lys Asp Ser Cys Ile Ser
1055 1060 1065
Asn His Thr Val Ile Glu Ile Gly Lys Asp Leu Asn Tyr Leu Lys
1070 1075 1080
Asp Gly Asn Gly Thr Thr Ser Gly Val Gly Ser Ser Val Glu Lys
1085 1090 1095
Tyr Val Val Asp Glu Ser Asp Tyr Met Ser Phe Ile Asn Asn Pro
1100 1105 1110
Ser Leu Thr Val Thr Val Pro Ile Ala Val Gly Glu Ser Asp Phe
1115 1120 1125
Glu Asn Leu Asn Thr Glu Glu Phe Ser Ser Glu Ser Asp Leu Glu
1130 1135 1140
Glu Ser Lys Glu Lys Leu Asn Ala Ser Ser Ser Ser Glu Gly Ser
1145 1150 1155
Thr Val Asp Ile Gly Leu Pro Gln Glu Gly Glu Gln Pro Glu Ile
1160 1165 1170
Glu Pro Glu Glu Ala Leu Glu Pro Glu Ala Cys Phe Thr Glu Gly
1175 1180 1185
Cys Val Arg Lys Phe Lys Cys Cys Gln Val Ser Thr Glu Asp Gly
1190 1195 1200
Lys Gly Lys Ile Trp Trp Asn Leu Arg Lys Thr Cys Tyr Lys Ile
1205 1210 1215
Val Glu His Asn Trp Phe Glu Thr Phe Ile Val Phe Met Ile Leu
1220 1225 1230
Leu Ser Ser Gly Ala Leu Ala Phe Glu Asp Ile Tyr Ile Glu Gln
1235 1240 1245
Arg Lys Thr Ile Lys Thr Met Leu Glu Tyr Ala Asp Lys Val Phe
1250 1255 1260
Thr Tyr Ile Phe Ile Leu Glu Met Leu Leu Lys Trp Val Ala Tyr
1265 1270 1275
Gly Phe Gln Thr Tyr Phe Thr Asn Ala Trp Cys Trp Leu Asp Phe
1280 1285 1290
Leu Ile Val Asp Val Ser Leu Val Ser Leu Thr Ala Asn Ala Leu
1295 1300 1305
Gly Tyr Ser Glu Leu Gly Ala Ile Lys Ser Leu Arg Thr Leu Arg
1310 1315 1320
Ala Leu Arg Pro Leu Arg Ala Leu Ser Arg Phe Glu Gly Met Arg
1325 1330 1335
Val Val Val Asn Ala Leu Leu Gly Ala Ile Pro Ser Ile Met Asn
1340 1345 1350
Val Leu Leu Val Cys Leu Ile Phe Trp Leu Ile Phe Ser Ile Met
1355 1360 1365
Gly Val Asn Leu Phe Ala Gly Lys Phe Tyr Tyr Cys Val Asn Thr
1370 1375 1380
Thr Asn Asp Glu Arg Phe Asp Ile Ser Gln Ile Asn Asn Tyr Ser
1385 1390 1395
Gln Cys Glu Asp Leu Ile Asn Asn Asn Glu Thr Ala Arg Trp Lys
1400 1405 1410
Asn Val Lys Val Asn Phe Asp Asn Val Gly Leu Gly Tyr Leu Ser
1415 1420 1425
Leu Leu Gln Val Ala Thr Phe Lys Gly Trp Met Asp Ile Met Tyr
1430 1435 1440
Ala Ala Val Asp Ser Arg Lys Val Leu Asp Gln Pro Lys Tyr Glu
1445 1450 1455
Asp Asn Leu Tyr Met Tyr Leu Tyr Phe Val Ile Phe Ile Ile Phe
1460 1465 1470
Gly Ser Phe Phe Thr Leu Asn Leu Phe Ile Gly Val Ile Ile Asp
1475 1480 1485
Asn Phe Asn Gln Gln Lys Lys Lys Phe Gly Gly Gln Asp Ile Phe
1490 1495 1500
Met Thr Glu Glu Gln Lys Lys Tyr Tyr Asn Ala Met Lys Lys Leu
1505 1510 1515
Gly Ser Lys Lys Pro Gln Lys Pro Ile Pro Arg Pro Ala Asn Lys
1520 1525 1530
Phe Gln Gly Met Val Phe Asp Phe Val Thr Lys Gln Val Phe Asp
1535 1540 1545
Ile Ser Ile Met Ile Leu Ile Cys Leu Asn Met Val Thr Met Met
1550 1555 1560
Val Glu Thr Asp Asn Gln Ser Asp Glu Met Gln Asp Asn Leu Trp
1565 1570 1575
Trp Ile Asn Leu Val Phe Ile Val Leu Phe Thr Gly Glu Cys Ile
1580 1585 1590
Leu Lys Leu Ile Ser Leu Arg Tyr Tyr Tyr Phe Thr Ile Gly Trp
1595 1600 1605
Asn Ile Phe Asp Phe Val Val Val Ile Leu Ser Ile Val Gly Met
1610 1615 1620
Phe Leu Ala Asp Leu Ile Glu Lys Tyr Phe Val Ser Pro Thr Leu
1625 1630 1635
Phe Arg Val Ile Arg Leu Ala Arg Ile Gly Arg Ile Leu Arg Leu
1640 1645 1650
Ile Lys Gly Ala Lys Gly Ile Arg Thr Leu Leu Phe Ala Leu Met
1655 1660 1665
Met Ser Leu Pro Ala Leu Phe Asn Ile Gly Leu Leu Leu Phe Leu
1670 1675 1680
Val Met Phe Ile Tyr Ala Ile Phe Gly Met Ser Asn Phe Ala Tyr
1685 1690 1695
Val Lys Arg Glu Val Gly Ile Asp Asp Met Phe Asn Phe Glu Thr
1700 1705 1710
Phe Gly Asn Ser Met Ile Cys Leu Phe Gln Ile Thr Thr Ser Ala
1715 1720 1725
Gly Trp Asp Gly Leu Leu Ala Pro Ile Leu Asn Ser Gly Glu Pro
1730 1735 1740
Asp Cys Asp Pro Tyr Lys Asp His Pro Gly Ser Ser Val Lys Gly
1745 1750 1755
Asp Cys Gly Asn Pro Ser Val Gly Ile Phe Phe Phe Val Ser Tyr
1760 1765 1770
Ile Ile Ile Ser Phe Leu Val Val Val Asn Met Tyr Ile Ala Val
1775 1780 1785
Ile Leu Glu Asn Phe Ser Val Ala Thr Glu Glu Ser Ala Glu Pro
1790 1795 1800
Leu Ser Glu Asp Asp Phe Glu Met Phe Tyr Glu Val Trp Glu Lys
1805 1810 1815
Phe Asp Pro Asp Ala Thr Gln Phe Ile Glu Phe Ser Lys Leu Ser
1820 1825 1830
Asp Phe Ala Ala Ser Leu Asp Pro Pro Leu Leu Ile Ala Lys Pro
1835 1840 1845
Asn Lys Val Gln Leu Ile Ala Met Asp Leu Pro Met Val Ser Gly
1850 1855 1860
Asp Arg Ile His Cys Leu Asp Ile Leu Phe Ala Phe Thr Lys Arg
1865 1870 1875
Val Leu Gly Glu Ser Gly Glu Met Asp Thr Leu Arg Ile Gln Met
1880 1885 1890
Glu Asp Arg Phe Met Ala Ala Asn Pro Ser Lys Val Ser Tyr Glu
1895 1900 1905
Pro Ile Thr Thr Thr Leu Lys Arg Lys Gln Glu Glu Val Ser Ala
1910 1915 1920
Val Ile Ile Gln Arg Ala Phe Arg Arg Tyr Leu Leu Lys Gln Lys
1925 1930 1935
Ile Lys Lys Val Ser Cys Met Phe Asn Gln Asp Lys Asp Lys Asp
1940 1945 1950
Glu Asp Asp Leu Pro Ile Lys Glu Asp Met Ile Ile Asp Lys Leu
1955 1960 1965
Asn Glu Asn Ser Thr Pro Glu Lys Thr Asp Met Thr Pro Ser Thr
1970 1975 1980
Thr Ser Pro Pro Ser Tyr Asp Ser Val Thr Lys Pro Asp Lys Glu
1985 1990 1995
Lys Tyr Glu Lys Asp Lys Ser Glu Lys Glu Asp Lys Gly Lys Asp
2000 2005 2010
Val Arg Glu Ser Lys Lys
2015
<210> 57
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 寡核苷酸
<400> 57
tcgtcggcag cgtcagatgt gtataagaga cag 33
<210> 58
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 寡核苷酸
<400> 58
gtctcgtggg ctcggagatg tgtataagag acag 34
Claims (60)
1.一种遗传修饰的啮齿动物，其基因组包含：
在内源性啮齿动物Scn9a基因座处的编码NaV1.2蛋白的核酸分子，
其中在所述遗传修饰的啮齿动物中表达NaV1.2蛋白，并且
其中所述啮齿动物是小鼠或大鼠。
2.根据权利要求1所述的遗传修饰的啮齿动物，其中所述啮齿动物不能表达啮齿动物NaV1.7蛋白。
3.根据权利要求1或2所述的遗传修饰的啮齿动物，其中所述NaV1.2蛋白是选自人、黑猩猩、恒河猴、马来西亚飞行狐猴、兔、马、阿拉伯骆驼、杀人鲸、牛、绵羊、大鼠、小鼠、狗、鸡、绿海龟或眼镜王蛇的动物物种的NaV1.2蛋白。
4.根据权利要求1或2所述的遗传修饰的啮齿动物，其中所述NaV1.2蛋白是人NaV1.2蛋白。
5.根据权利要求1或2所述的遗传修饰的啮齿动物，其中所述NaV1.2蛋白包含与SEQ IDNO:4具有至少95％同一性的氨基酸序列。
6.根据权利要求1-5中任一项所述的遗传修饰的啮齿动物，其中所述编码NaV1.2蛋白的核酸分子可操作地连接至在所述内源性啮齿动物Scn9a基因座处的内源性啮齿动物Scn9a启动子。
7.根据权利要求1-6中任一项所述的遗传修饰的啮齿动物，其中所述编码NaV1.2蛋白的核酸分子包含从ATG起始密码子开始至Scn2a基因的终止密码子的连续的所述Scn2a基因的核苷酸序列。
8.根据权利要求7所述的遗传修饰的啮齿动物，其中所述核苷酸序列可操作地连接至所述内源性啮齿动物Scn9a基因的5'UTR。
9.根据权利要求7或8所述的遗传修饰的啮齿动物，其中所述核苷酸序列可操作地连接至所述Scn2a基因的3'UTR。
10.根据权利要求1-9中任一项所述的遗传修饰的啮齿动物，
其中所述编码NaV1.2蛋白的核酸分子替代在所述内源性啮齿动物Scn9a基因座处的内源性啮齿动物Scn9a基因的基因组片段，并且
其中所述基因组片段编码所述内源性啮齿动物NaV1.7蛋白。
11.根据权利要求1-10中任一项所述的遗传修饰的啮齿动物，其中所述编码NaV1.2蛋白的核酸分子是Scn2a基因的基因组片段。
12.根据权利要求1-10中任一项所述的遗传修饰的啮齿动物，其中所述编码NaV1.2蛋白的核酸分子是cDNA。
13.根据权利要求1-12中任一项所述的遗传修饰的啮齿动物，其中所述啮齿动物就所述编码NaV1.2蛋白的核酸分子而言是杂合的。
14.根据权利要求1-12中任一项所述的遗传修饰的啮齿动物，其中所述啮齿动物就所述编码NaV1.2蛋白的核酸分子而言是纯合的。
15.根据权利要求14所述的遗传修饰的啮齿动物，其中所述啮齿动物当用人NaV1.7免疫原免疫时产生针对人NaV1.7蛋白的抗体。
16.根据权利要求1-15中任一项所述的遗传修饰的啮齿动物，所述啮齿动物进一步包含：
人源化的免疫球蛋白重链基因座，其包含一个或多个人VH基因区段、一个或多个人DH基因区段和一个或多个人JH基因区段，
其中所述一个或多个人VH基因区段、一个或多个人DH基因区段和一个或多个人JH基因区段可操作地连接至一个或多个啮齿动物免疫球蛋白重链恒定区基因，
其中所述遗传修饰的啮齿动物能够响应于抗原刺激而产生包含人重链可变结构域和啮齿动物重链恒定结构域的抗体。
17.根据权利要求1-16中任一项所述的遗传修饰的啮齿动物，所述啮齿动物进一步包含：
人源化的免疫球蛋白轻链基因座，其包含一个或多个人VL基因区段和一个或多个人JL基因区段，
其中所述一个或多个人VL基因区段和一个或多个人JL基因区段可操作地连接至一个或多个啮齿动物轻链恒定区基因，
其中所述遗传修饰的啮齿动物能够响应于抗原刺激而产生包含人轻链可变结构域和啮齿动物轻链恒定结构域的抗体。
18.根据权利要求1-16中任一项所述的遗传修饰的啮齿动物，所述啮齿动物进一步包含：
人源化的免疫球蛋白轻链基因座，其包含一个或多个人VL基因区段和一个或多个人JL基因区段，
其中所述一个或多个人VL基因区段和一个或多个人JL基因区段可操作地连接至一个或多个人轻链恒定区基因，
其中所述遗传修饰的啮齿动物能够响应于抗原刺激而产生包含人轻链可变结构域和人轻链恒定结构域的抗体。
19.根据权利要求17所述的遗传修饰的啮齿动物，其中所述一个或多个人VL和一个或多个人JL基因区段是一个或多个人Vλ基因区段和一个或多个人Jλ基因区段。
20.根据权利要求17所述的遗传修饰的啮齿动物，其中所述一个或多个人VL和一个或多个人JL基因区段是一个或多个人Vκ基因区段和一个或多个人Jκ基因区段。
21.根据权利要求17所述的遗传修饰的啮齿动物，其中所述一个或多个啮齿动物轻链恒定区基因是一个或多个啮齿动物Cλ基因。
22.根据权利要求17所述的遗传修饰的啮齿动物，其中所述一个或多个啮齿动物轻链恒定区基因是一个或多个啮齿动物Cκ基因。
23.根据权利要求1-22中任一项所述的遗传修饰的啮齿动物，其中所述啮齿动物包含编码啮齿动物ADAM6蛋白或其功能片段或直系同源物的核苷酸。
24.根据权利要求1-22中任一项所述的遗传修饰的啮齿动物，其中所述啮齿动物包含外源性TdT基因。
25.一种制备遗传修饰的啮齿动物的方法，所述方法包括：
修饰啮齿动物基因组，使得经修饰的基因组包含在内源性啮齿动物Scn9a基因座处的编码NaV1.2蛋白的核酸分子，和
产生包含经修饰的基因组的啮齿动物，其中在所述遗传修饰的啮齿动物中表达所述NaV1.2蛋白，并且其中所述啮齿动物是小鼠或大鼠。
26.一种制备遗传修饰的啮齿动物的方法，所述方法包括：
(i)将编码NaV1.2蛋白的核酸分子引入啮齿动物胚胎干(ES)细胞，使得所述核酸分子整合进内源性啮齿动物Scn9a基因座；
(ii)得到包含经修饰的基因组的啮齿动物ES细胞，其中所述核酸分子已经整合进内源性啮齿动物Scn9a基因座；以及
(iii)使用包含所述经修饰的基因组的啮齿动物ES细胞产生啮齿动物。
27.根据权利要求26所述的方法，其中步骤(iii)包括将所述啮齿动物ES细胞引入胚胎。
28.根据权利要求25或26所述的方法，其中所述NaV1.2蛋白是选自人、黑猩猩、恒河猴、马来西亚飞行狐猴、兔、马、阿拉伯骆驼、杀人鲸、牛、绵羊、大鼠、小鼠、狗、鸡、绿海龟或眼镜王蛇的动物物种的NaV1.2蛋白。
29.根据权利要求25或26所述的方法，其中所述NaV1.2蛋白是人NaV1.2蛋白。
30.根据权利要求25或26所述的方法，其中所述NaV1.2蛋白包含与SEQ ID NO:4具有至少95％同一性的氨基酸序列。
31.根据权利要求25-30中任一项所述的方法，其中所述编码NaV1.2蛋白的核酸分子可操作地连接至在所述内源性啮齿动物Scn9a基因座处的内源性啮齿动物Scn9a启动子。
32.根据权利要求25-31中任一项所述的方法，其中所述编码NaV1.2蛋白的核酸分子包含从ATG起始密码子至Scn2a基因的终止密码子的所述Scn2a基因的核苷酸序列。
33.根据权利要求32所述的方法，其中所述核苷酸序列可操作地连接至所述内源性啮齿动物Scn9a基因的5'UTR。
34.根据权利要求32或33所述的方法，其中所述核苷酸序列可操作地连接至所述Scn2a基因的3'UTR。
35.根据权利要求25-34中任一项所述的方法，其中所述编码NaV1.2蛋白的核酸分子替换在所述内源性啮齿动物Scn9a基因座处的内源性啮齿动物Scn9a基因的基因组片段，并且其中所述基因组片段编码所述内源性啮齿动物NaV1.7蛋白。
36.根据权利要求25-35中任一项所述的方法，其中所述编码NaV1.2蛋白的核酸分子是Scn2a基因的基因组片段。
37.根据权利要求25-35中任一项所述的方法，其中所述编码NaV1.2蛋白的核酸分子是cDNA。
38.根据权利要求25-37中任一项所述的方法，其中所述遗传修饰的啮齿动物进一步包含：
人源化的免疫球蛋白重链基因座，其包含一个或多个人VH基因区段、一个或多个人DH基因区段和一个或多个人JH基因区段，
其中所述一个或多个人VH基因区段、一个或多个人DH基因区段和一个或多个人JH基因区段可操作地连接至一个或多个啮齿动物免疫球蛋白重链恒定区基因，
其中所述遗传修饰的啮齿动物能够响应于抗原刺激而产生包含人重链可变结构域和啮齿动物重链恒定结构域的抗体。
39.根据权利要求25-38中任一项所述的方法，其中所述遗传修饰的啮齿动物进一步包含：
人源化的免疫球蛋白轻链基因座，其包含一个或多个人VL基因区段和一个或多个人JL基因区段，
其中所述一个或多个人VL基因区段和一个或多个人JL基因区段可操作地连接至一个或多个内源性啮齿动物轻链恒定区基因，
其中所述遗传修饰的啮齿动物能够响应于抗原刺激而产生包含人轻链可变结构域和啮齿动物轻链恒定结构域的抗体。
40.根据权利要求25-38中任一项所述的方法，其中所述遗传修饰的啮齿动物进一步包含：
人源化的免疫球蛋白轻链基因座，其包含一个或多个人VL基因区段和一个或多个人JL基因区段，
其中所述一个或多个人VL基因区段和一个或多个人JL基因区段可操作地连接至一个或多个内源性人轻链恒定区基因，
其中所述遗传修饰的啮齿动物能够响应于抗原刺激而产生包含人轻链可变结构域和人轻链恒定结构域的抗体。
41.根据权利要求39所述的方法，其中所述一个或多个人VL和一个或多个人JL基因区段是一个或多个人Vλ基因区段和一个或多个人Jλ基因区段。
42.根据权利要求39所述的方法，其中所述一个或多个人VL和一个或多个人JL基因区段是一个或多个人Vκ基因区段和一个或多个人Jκ基因区段。
43.根据权利要求39所述的方法，其中所述一个或多个啮齿动物轻链恒定区基因是一个或多个啮齿动物Cλ基因。
44.根据权利要求39所述的方法，其中所述一个或多个啮齿动物轻链恒定区基因是一个或多个啮齿动物Cκ基因。
45.根据权利要求25-44中任一项所述的方法，其中所述啮齿动物包含外源性Adam6基因。
46.根据权利要求25-44中任一项所述的方法，其中所述啮齿动物包含外源性TdT基因。
47.一种分离的啮齿动物细胞或组织，其基因组包含：
在内源性啮齿动物Scn9a基因座处的编码NaV1.2蛋白的核酸分子，
其中所述啮齿动物是小鼠或大鼠。
48.根据权利要求47所述的分离的啮齿动物细胞或组织，其中所述啮齿动物细胞是啮齿动物ES细胞。
49.根据权利要求47所述的分离的啮齿动物细胞或组织，其中所述啮齿动物细胞是B细胞。
50.根据权利要求47或48所述的分离的啮齿动物细胞或组织，其中所述啮齿动物细胞进一步包含：
人源化的免疫球蛋白重链基因座，其包含一个或多个人VH基因区段、一个或多个人DH基因区段和一个或多个人JH基因区段，所述区段可操作地连接至一个或多个啮齿动物免疫球蛋白重链恒定区基因，和/或
人源化的免疫球蛋白轻链基因座，其包含一个或多个人VL基因区段和一个或多个人JL基因区段，所述区段可操作地连接至一个或多个啮齿动物轻链恒定区基因。
51.从根据权利要求47所述的分离的细胞建立的永生细胞系。
52.一种啮齿动物胚胎，其包含根据权利要求48所述的啮齿动物ES细胞。
53.一种靶向核酸构建体，其包含：
编码NaV1.2蛋白的核酸分子，
其中所述核酸侧接能够介导所述核酸分子向内源性啮齿动物Scn9a基因座中的同源重组和整合的5'和3'啮齿动物核苷酸序列。
54.一种生产抗-NaV1.7抗体的方法，所述方法包括
用NaV1.7免疫原免疫根据权利要求1-24中任一项所述的遗传修饰的啮齿动物，从而产生经免疫的啮齿动物，和
使用所述经免疫的啮齿动物制备所述抗-NaV1.7抗体。
55.根据权利要求53所述的方法，其中所述NaV1.7免疫原是人NaV1.7免疫原，并且所述抗-NaV1.7抗体是抗-人NaV1.7抗体。
56.根据权利要求53所述的方法，其中所述NaV1.7免疫原是人NaV1.7蛋白。
57.根据权利要求54-56中任一项所述的方法，其中所述抗体是单克隆抗体。
58.根据权利要求54所述的方法，其中所述NaV1.7免疫原是人NaV1.7 DNA。
59.一种产生抗-人NaV1.7抗体的杂交瘤。
60.通过根据权利要求54所述的方法制备的产生抗-人NaV1.7抗体的杂交瘤。
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- 2020-02-21 AU AU2020226865A patent/AU2020226865A1/en not_active Abandoned
- 2020-02-21 CN CN202080015769.4A patent/CN113473850A/zh active Pending
- 2020-02-21 US US16/797,280 patent/US11464217B2/en active Active
- 2020-02-21 EP EP20714362.9A patent/EP3927153A1/en not_active Withdrawn
- 2020-02-21 JP JP2021547412A patent/JP2022520819A/ja active Pending
-
2021
- 2021-08-17 IL IL285663A patent/IL285663A/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130115171A1 (en) * | 2011-11-09 | 2013-05-09 | Stefan I. McDonough | Nav1.7-related assays |
| CN105189553A (zh) * | 2013-03-14 | 2015-12-23 | 瑞泽恩制药公司 | Nav1.7的人抗体 |
| WO2017210586A8 (en) * | 2016-06-03 | 2018-05-03 | Regeneron Pharmaceuticals, Inc. | Non-human animals expressing exogenous terminal deoxynucleotidyltransferase |
Non-Patent Citations (2)
| Title |
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| ANNA HRABOVSKA ET AL: "A Novel System for the Efficient", 《PLOS ONE》 * |
| JACINTHE GINGRAS ET AL: "Global Navf .7 Knockout Mice", 《PLOS ONE》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116200472A (zh) * | 2023-04-04 | 2023-06-02 | 西北农林科技大学 | 一种牛SCN9A基因InDel标记在肉质性状早期选择中的应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| IL285663A (en) | 2021-10-31 |
| WO2020172505A1 (en) | 2020-08-27 |
| US20200267950A1 (en) | 2020-08-27 |
| EP3927153A1 (en) | 2021-12-29 |
| KR20210129083A (ko) | 2021-10-27 |
| CA3127153A1 (en) | 2020-08-27 |
| AU2020226865A1 (en) | 2021-07-29 |
| SG11202107589PA (en) | 2021-08-30 |
| MX2021009855A (es) | 2021-09-10 |
| US11464217B2 (en) | 2022-10-11 |
| BR112021016173A2 (pt) | 2021-11-03 |
| JP2022520819A (ja) | 2022-04-01 |
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