CN113710805A - 用于诊断和治疗视网膜病变的组合物和方法 - Google Patents
用于诊断和治疗视网膜病变的组合物和方法 Download PDFInfo
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Abstract
本发明提供与用于治疗受试者的视网膜病变的细胞表面蛋白CRB1相关的组合物和方法，以及使用此类组合物的系统和试剂盒。
Description
相关申请的交叉引用
本申请要求2019年3月4日提交的美国临时申请第62/813,272号的优先权，其以全文引用的方式并入本文。
关于联邦资助研究的声明
本发明是在美国国立卫生研究院授予的联邦资助号F32EY026344的政府支持下完成的。政府享有本发明的某些权利。
序列表
本申请随附一份序列表，其以名为“2020-03-04_155554.00531_ST25.txt”的序列表的ASCII文本文件形式提交，所述文件大小为342KB并创建于2020年3月4日。所述序列表通过EFS-Web与本申请一起以电子方式提交，并以全文引用的方式并入本文。
背景技术
CRB1基因的功能丧失突变会导致多种视网膜变性疾病。基因治疗的最新进展为阻止单基因致盲疾病的渐进性视力丧失开辟了新的可能性。如果CRB1疾病要成为此种治疗的有力候选者，那么了解CRB1蛋白在体内视网膜中的正常和病理生物学功能是至关重要的。CRB1功能的流行模型假定它是外界膜(OLM)的结构完整性所必需的。CRB1蛋白(一种具有大细胞外结构域的细胞表面分子)已定位于连接光感受器和米勒胶质细胞(Müller glia)的OLM细胞-细胞粘附。CRB1功能的丧失被认为会削弱OLM粘附，导致结构缺陷，其最终导致光感受器死亡。根据这个模型，置换CRB1基因是一种很有前景的治疗策略：预计恢复粘附将提高OLM的完整性，从而减缓或甚至停止光感受器的死亡。要设计有效的基因置换策略，了解目前尚不清楚的两个关键信息非常重要。首先，应该置换哪种细胞类型中的CRB1？OLM连接的胶质细胞侧或光感受器侧是否需要它，或两侧都需要它？其次，应该使用CRB分子的哪种剪接变体进行置换？已知CRB1编码几种替代性的mRNA同种型；此外，由于人类转录组的真正复杂性仍然令人惊讶地模糊不清，因此可能仍有其他未描述的同种型。由于只能选择一种cDNA种类包含在基因治疗载体中，因此确定哪种同种型在重新引入成熟视网膜时最有效地阻止变性是至关重要的。
发明内容
在一方面，本公开提供一种分离的多核苷酸，其包含编码Crumbs 1-B(CRB1-B)同种型的多核苷酸序列，所述Crumbs 1-B(CRB1-B)同种型包含SEQ ID NO:1，所述多核苷酸序列可操作地连接到能够在视网膜细胞中表达所述同种型的异源启动子。在另一方面，本公开提供一种包含分离的多核苷酸的载体。
在另一方面，本公开提供一种包含编码Crumbs 1-B(CRB1-B)同种型的多核苷酸的重组载体，其中所述CRB1-B同种型包含连接到胞外多肽连接的N端信号肽，所述胞外多肽从N端到C端包含：两个EGF结构域、一个lamG结构域、一个EGF结构域、一个lamG结构域、一个EGF结构域、一个lamG结构域和四个EGF结构域；其中所述胞外多肽的C端连接到包含跨膜结构域和胞内结构域的C端结构域。
在另一方面，本公开提供了一种由本文所述的分离的多核苷酸或重组载体制成的分离的多肽。
在另一方面，本公开提供了一种药物组合物，其包含本文所述的分离的多核苷酸或重组载体和药学上可接受的载体。
在另一方面，本公开提供了一种治疗受试者的眼部病症的方法，所述方法包括向受试者施用治疗有效量的本文所述的多核苷酸、重组载体、分离的多肽或药物组合物，从而在所述受试者中治疗所述眼部病症。
在又一方面，本公开提供了一种在有需要的受试者中减少视力丧失进展或维持视力功能的方法，所述方法包括向受试者施用治疗有效量的本文所述的多核苷酸、重组载体、分离的多肽或药物组合物，从而减少视力丧失。
在又一个实施方案中，本公开提供了一种用于治疗受试者的眼部病症的试剂盒，所述试剂盒包括本文所述的分离的多核苷酸、重组载体、分离的多肽或药物组合物，用于将所述分离的多核苷酸、重组载体、分离的多肽或药物组合物递送至受试者的装置，以及使用说明。
在另一方面，本公开提供一种用于在受试者中减少视力丧失进展或减少视力丧失或维持视力功能的试剂盒，所述试剂盒包括本文所述的分离的多核苷酸、重组载体、分离的多肽或药物组合物，用于将所述分离的多核苷酸、重组载体、分离的多肽或药物组合物递送至受试者的装置，以及使用说明。
在另一方面，本公开提供一种用于将所述分离的多核苷酸、重组载体、分离的多肽或药物组合物递送至受试者的眼睛的系统，所述系统包括治疗有效量的本文所述的分离的多核苷酸、重组载体、分离的多肽或药物组合物，以及用于递送至受试者的装置。
附图说明
图1描绘了本文使用的用于鉴定表现出高同种型多样性的细胞表面受体的策略。(A)用于选择针对lrCaptureSeq的基因的筛选策略。针对如下测试了EGF、Ig和粘附GPCR家族的成员：1)在神经发育过程中的表达，使用来自视网膜和皮质的RNA-seq数据；和2)未注释的转录本多样性，基于与UCSC Genes公共数据库相比的RNA-seq读段比对。选择了30个显示例如选择性剪接、新颖外显子和新颖转录起始位点(星号)的未注释事件的有力证据的基因，用于全长转录本的靶向测序(B，C)。(B)lrCaptureSeq工作流程。cDNA经过5’标记，以能够鉴别全长读段。红色生物素化捕获探针覆盖已知外显子。为了获得富含完整cDNA的测序文库，使用了两轮扩增和大小选择。(C)对于每个lrCaptureSeq实验的全长读段的大小分布。在P1、P6、P10和成年时分析小鼠视网膜转录本；皮质数据来自成年小鼠。绝大多数读段都在靶向基因的cDNA的预期大小范围内。虚线，读段长度分布的四分位数。
图2说明了由lrCaptureSeq揭示的mRNA同种型多样性。(A)完成lrCaptureSeq生物信息学管道后，为每个基因编目的同种型总数。(B)UpSet图，将PacBio lrCaptureSeq数据集中的同种型数目与公共数据库(RefSeq，UCSC Genes)进行比较。交叉点显示在PacBio数据集中检测到53.9％的NCBI RefSeq同种型(255个RefSeq同种型，从左数第4列+第6列)。对于UCSC基因，在PacBio数据集中检测到该数据库中注释的72.3％的同种型(102个UCSC同种型，第5列+第6列)。(C)洛伦兹图描绘了为每个基因编目的同种型总数(右Y截距)，以及每个基因的每个同种型表示的每个基因总读数的分数(点)。曲线是累积函数，同种型按总基因读数的最高(左)到最低(右)分数的顺序显示。另请参见图10D。(D)香农多样性指数用于比较每个基因的相对多样性。更高的香农指数反映了更高的同种型数目和同种型表达的同等两者。(E)树状图，描绘了整个数据集中基因(颜色)和同种型(嵌套矩形)的相对丰度。矩形大小与总读取数成正比。最丰富的同种型属于Crb1；最丰富的基因是Nrcam。(F，G)在单基因水平上应用的无监督聚类鉴别了共享特定序列元素的相关同种型家族。以Ptprd基因为例。Ptprd同种型的子集聚集成5组(F，底部)。这些基于3个变量而不同：5'UTR的长度；3'UTR的长度；和可变外显子簇的剪接(F，顶部)。相同的组在主成分图(G)内分离。
图3表明转录本多样性有助于丰富的蛋白质多样性。(A)lrCaptureSeq数据集中每个基因的转录本和ORF的总数。ORF数目通常与转录本数目成比例，如大多数基因之间的相似线斜率所示。少数基因表现出的ORF远少于转录本同种型(陡峭斜率)。(B)同种型ORF分布的洛伦兹图，类似于图2C。许多预测的蛋白质同种型(点)预计将有助于整体基因表达。(另请参见图11A、B)。(C)每个基因的独特预测ORF的香农多样性指数。编码跨突触结合蛋白的基因以红色突出显示。(D)树状图，描绘了数据集中预测ORF的相对丰度。对于大多数基因，整体表达分布在许多ORF同种型中。与转录本树状图(图2E)相比，A中具有陡峭斜率的基因(例如Cntn4)在此处显示出差异。(E)用于富集细胞表面蛋白的蛋白质组学技术的示意图。(F)来自生物素标记的和富含链霉亲和素的细胞表面蛋白的考马斯染色蛋白质凝胶。与总裂解物输入(I)相比，洗脱泳道(E)显示了更高分子量蛋白质的富集。切下75kDa–250kDa的条带用于质谱分析。(G)图描绘了通过质谱发现的在UniProtKB数据库中不存在的未注释肽的数目。如果未被lrCaptureSeq预测到存在，那么这些肽就不会被检测到。
图4表明模块化选择性剪接驱动的Megf11的同种型多样性。(A)MEGF11蛋白示意图，显示域特征如何对应于外显子边界。大多数胞外结构域外显子编码单个EGF或EGF-层粘连蛋白(Lam)重复序列。截断EGF-Lam结构域的剪接(例如外显子14的跳过)预计会留下完整的EGF结构域，从而保持模块化。编码经典信号基序的胞内结构域外显子被标记为：+，基于免疫受体酪氨酸的激活基序(YxxL/Ix(6-8)YxxL/I)；–，基于免疫受体酪氨酸的抑制基序(S/I/V/LxYxxI/V/L)。TM，跨膜结构域；EMI，Emilin同源结构域。(B)由组合的PacBio数据集生成的Megf11 sashimi图。显示了变化最大的外显子簇(13-17和19-23)。这些簇中的外显子可以与簇内的任何下游外显子剪接。线宽对应于同种型数据库中剪接事件的频率。(C)Megf11同种型之间的外显子使用相关性。在显示最小剪接的外显子(例如1-8和17-19)之间，在短距离内看到高Pearson相关值(红色)。长距离相关性在很大程度上不存在，这表明大多数剪接是随机的。仅在可变转录终止位点(星号)下游的外显子的微不足道的情况下才观察到强烈的长距离负相关。(D)10种最丰富的Megf11同种型的预测蛋白质结构。选择性剪接改变蛋白质胞外部分上EGF和EGF-Lam结构域的数目和特性，并产生5个不同的细胞质结构域。同种型8是可变转录终止位点(C，外显子8b)的结果，并且预计编码分泌的同种型。*从外显子19到20的剪接产生了移码和早期终止密码子。**内含子24的保留产生了移码和早期终止密码子。(E)使用靶向指示的剪接点的探针，P10小鼠视网膜横截面的BaseScope原位杂交(红色)。组成型拼接(2-3，左上角)显示四种细胞类型中的完整Megf11表达模式：ON和OFF星爆无长突细胞(蓝色箭头)、水平细胞(红色箭头)和不明无长突细胞(黑色箭头)。钙结合蛋白(Calbindin)(绿色)标记星爆和水平细胞。每个拼接探针的染色强度与测序数据中的接合频率一致(参见Sashimi图，B)。所有拼接都由星爆和水平种群的所有单独细胞表达。比例尺＝10μm。
图5表明Crb1-B是小鼠和人类视网膜中最丰富的Crb1同种型。(A,B)来自小鼠视网膜(A)和皮质(B)的最丰富的Crb1同种型的转录图谱。A是典型的同种型；A2是A的次要剪接变体。这些同种型在视网膜和皮质之间共享，而Cortex 1、Cortex 2和Crb1-B是组织特异性的。相应的外显子覆盖率(深蓝色)和sashimi图(红线)由lrCaptureSeq数据集生成。请注意与Crb1-B同种型(A)相关的读数的普遍性。(C)染色质可及性测定(ATAC-seq；GSE102092、GSE83312)鉴定了Crb1-A和-B同种型的可能启动子。彩色条指示假定的A(绿色)和B(蓝色)启动子的位置。A-C中的图谱彼此对齐。Crb1-A启动子在发育过程中更加开放，但在成熟的视网膜中保持可及。Crb1-B启动子是开放的，并且推测在成熟的视杆细胞和两种类型的视锥细胞中都有活性。来自ENCODE项目的DNase I超敏数据揭示了额叶皮层中不同的染色质环境，这与A同种型以及较短的皮质同种型(cortex 1和2；顶部的灰色条)的表达一致。(D)小鼠发育过程中前3种Crb1同种型的视网膜表达，从PacBio数据集定量。A同种型在P1时占主导地位，但Crb1-B在P6时变得最丰富。在每个时间点，将数据归一化为总Crb1读取计数(P1＝923个读段，P6＝6,127个读段，P10＝14,007个读段，成人＝10,975个读段)标准化数据。(E)由lrCaptureSeq鉴定的最丰富的人类视网膜CRB1同种型的转录图谱。A和B同种型与小鼠(A)高度同源。CRB1-C编码一种假定的蛋白质分泌形式；它也在小鼠数据集中被鉴别，但其在小鼠中的相对丰度远低于A和B。注意在人类数据集中未检测到Crb1-A2。外显子覆盖率(深蓝色)和sashimi图(红线)由lrCaptureSeq数据生成。(F)人周边(per.)和黄斑(mac.)视网膜的ATAC-seq(GSE99287)显示开放的调控位点，其对应于CRB1-A(绿条)和CRB1-B(蓝条)的推定启动子。显示了两个生物学重复。E、F中的图谱彼此对齐。(G)前3种人类CRB1同种型的表达，从成人视网膜lrCaptureSeq数据集定量。(H，I)使用短读RNA-seq数据的、前3种小鼠(H)或人(I)CRB1同种型的定量。小鼠数据集(GSE101986)证实了PacBio数据(D)中观察到的每种同种型的发育调节。人类数据集(GSE94437)证实了CRB1-B是成人视网膜中的显性同种型。线(I)显示来自同一供体的测量值。统计(I)：使用Tukey事后比较的单向方差分析。****P<1×10-7。***P＝1.6×10-6(顶部)；P＝6.6×10-6(底部)。误差线、95％置信区间(H)或S.D.(I)。
图6表明CRB1-B由光感受器表达。(A)CRB1-A和CRB1-B蛋白同种型的结构域结构。绿色，A特异性区域；蓝色，B特异性区域。每个同种型在N端都有独特的序列，预计编码信号肽，在C端也都有独特的序列，预计编码跨膜(TM)和细胞内结构域。(B)独特CRB1-B序列(A中的蓝色)的ClustalW比对。N端和C端区域在脊椎动物物种中都高度保守。N端区域包含信号肽(左)，C端区域包含跨膜结构域(右)。说明的序列如下：SEQ ID NO:87为共有信号肽，SEQID NO:88为共有跨膜结构域，SEQ ID NO:89为智人(Homo sapiens)信号肽，SEQ ID NO:3为智人跨膜结构域，SEQ ID NO:90为黄牛(Bos taurus)信号肽，SEQ ID NO:91为黄牛跨膜结构域，SEQ ID NO:92为小鼠(Mus musculus)信号肽，SEQ ID NO:93为小鼠跨膜结构域，SEQID NO:94为大鼠(Rattus norvegicus)信号肽，SEQ ID NO:95为大鼠跨膜结构域，SEQ IDNO:96为斑马鱼(Danio rerio)信号肽，并且SEQ ID NO:97为斑马鱼跨膜结构域。(C)蛋白质印迹，验证视网膜裂解物中的CRB1-B蛋白的表达。针对独特的CRB1-B的C端产生CRB1-B抗体。突变小鼠中Crb1-B第一个外显子的缺失(Crb1delB等位基因；参见图7A)证明了抗体特异性，并且证明Crb1-B的独特的第一个和最后一个外显子主要一起使用，正如在转录水平预测的那样(图5A)。光感受器蛋白ABCA4用作加载对照。(D)视网膜裂解物的蛋白质印迹，所述视网膜裂解物被分离成可溶性(S)和膜相关(M)蛋白级分。在膜级分中检测到CRB1-B。加载对照：膜级分，ABCA4；可溶性级分，光导蛋白(Phosducin)。(E)示意图显示了表达CRB1的外层视网膜区域的解剖结构。左图，显微照片描绘光感受器核；内段(黑色)；和外段(棕色)。外界膜(OLM)将核层与内段层分开。右图，OLM解剖示意图。OLM由光感受器(灰色)和米勒细胞(蓝色)之间的连接(红点)组成。这些连接选择性地形成在每种细胞类型的特定亚细胞结构域中，即神经胶质顶端膜和光感受器内段中。CRB1-A由米勒细胞(F，G)表达，在那里它选择性地定位于OLM连接49。CRB1-B在整个光感受器中表达，包括内段和外段(F-H)。另请参见图14。(F)scRNA-seq数据中Crb1同种型的定位48。从>90,000个细胞的基因谱生成的热图，显示Crb1同种型和视网膜细胞类型标记基因的标准化表达。无监督聚类用于定义与Crb1同种型共表达的基因。Crb1-B与已知的视锥和视杆光感受器基因聚类，而Crb1-A与已知的米勒神经胶质基因聚类。(G)使用同种型特异性探针(红色)对P20小鼠视网膜进行的BaseScope原位杂交。蓝色，Hoeschst核复染。Crb1-A探针靶向外显子1-2拼接，Crb1-A2和Crb1-C也使用它(参见图5A)。信号主要限于中央INL，米勒细胞体位于其中(左)。Crb1-B探针靶向其独特的5’外显子和外显子6之间的拼接(图5A)。信号限于ONL内的光感受器。缩写：ONL＝外核层；INL＝内核层；GCL＝神经节细胞层。比例尺，100μm。(H)CRB1-B在视杆光感受器内的亚细胞定位，通过小鼠外层视网膜的连续10μm切向切片的蛋白质印迹评估。每条泳道对应于由顶部草图表示的光感受器细胞隔室。视紫红质(Rho，中心)是外段标记；GAPDH(底部)被排除在外段之外，但存在于细胞的其余部分中。CRB1-B蛋白(顶部)存在于所有隔室中；在对应于外段和内段的泳道中的表达是最强的。
图7表明Crb1同种型是外界膜完整性所必需的。(A)Crb1基因座示意图，显示与小鼠突变等位基因相关的遗传损伤。以前研究的突变体：Crb1ex1，外显子1的靶向缺失，不影响Crb1-B同种型；Crb1rd8，外显子9中的点突变。针对本研究产生的突变等位基因：Crb1delB，第一个Crb1-B外显子及其启动子区域的由CRISPR介导的缺失，使Crb1-A同种型保持完整；Crb1null，用于所有Crb1同种型中的连续外显子的由CRISPR介导的大型缺失。另请参见图15A以获取新等位基因的文献记录。(B，C)通过电子显微镜评估OLM连接。B：示意图，说明围绕光感受器内段的OLM连接(红色)的位置。C：野生型小鼠的电子显微照片。所有内段都与米勒细胞形成OLM连接。IS，内段。红色箭头，光感受器-神经胶质连接。蓝色箭头，神经胶质-神经胶质连接。(D，E)Crb1突变体中的OLM破坏表型。D：来自对照(野生型)小鼠的电子显微照片。OLM(红色箭头)将外核层(ONL)与IS层分开。在Crb1突变体(E)中，OLM中的间隙允许细胞核穿透至内段层。箭头标出缺少OLM连接的区域。该图像来自Crb1delB/null突变体，但代表在null、delB和rd8突变体中观察到的OLM表型(图15D-F)。(F-I)Crb1突变体中OLM间隙的高倍视图，显示缺乏OLM连接的内段(星号)。在每个等位基因组合中，都观察到缺乏米勒接触的光感受器。红色和蓝色箭头与C中一样。(J)OLM间隙频率的定量。在野生型或Crb1null/+杂合子中没有观察到间隙。OLM破坏的频率在rd8、null和delB/null突变体中相似，后者缺乏Crb1-B但仍表达Crb1-A。统计学，使用Tukeys事后检验的单向方差分析。null、rd8和delB/null都与野生型和杂合对照显著不同(各自的P值：0.014；0.005；0.019)，但彼此之间没有显著差异(rd8对比null P＝0.991；rd8对比delB/null P＝0.784；null对比delB/null P＝0.967)。间隙大小的定量也参见图15F。比例尺,2μm C，D(比例尺也适用于E)；1μm G(比例尺也适用于F)、H、I。
图8表明消融所有Crb1同种型会导致视网膜变性。(A)Crb1突变小鼠在P100时的视网膜组织学。显示了指定基因型的纯合突变体和野生型对照的通过下半球的薄塑性切片。箭头，含有光感受器细胞核的ONL层。在Crb1null视网膜中明显存在大的光感受器损失的病灶区域，并伴有视网膜脱离。最严重变性片之外的区域显示ONL变薄。Crb1delB和Crb1rd8突变体未显示ONL细胞的明显损失。ONH，视神经乳头。(B)视网膜组织学的更高放大倍数视图，450μm低于ONH。来自两种不同Crb1null动物的图像被证明突出了灶性变性的变异性。即使是轻度null(空白)情况也比年龄匹配的Crb1rd8具有更薄的ONL(橙线)和更少的细胞核。null突变体的外段长度(蓝线)也减少了。(C，D)在P100时ONL细胞数目的定量。C：蜘蛛图，显示均匀分布在视网膜切片上(例如B)的100μm箱中ONL核的计数。左边，下侧。对于Crb1delB蜘蛛图，请参见图15。D：在所有8个箱中计数的总ONL核数。统计学(C)：使用Sidak事后检验的双向方差分析。P值是指WT与null比较；rd8在任何位置都与WT没有显著差异。*P＝0.015；**P＝0.007，P＝0.004；****P<1×10-7。统计学(D)：使用Tukey事后检验的单向方差分析。Crb1null与所有其他组显著不同。对于所有比较，****P<1×10-5。其他Crb1突变体与WT均没有不同或彼此没有不同。图(D)上的点表示样本大小。
图9说明捕获的cDNA的PacBio测序。(A)试验性lrCaptureSeq实验的PacBio读段大小分布的直方图，其中未进行PCR扩增后的第二次大小选择(参见工作流程，图1B)。概述表明，这种大小选择对于长转录本的富集是必要的。虚线代表四分位距。FLNC，由Iso-Seq软件调用的全长非嵌合读数。(B)每个实验的目标读数百分比，计算为与我们的目标基因相对应的高质量(HQ)读数的数目相对于所有其他读数。由Iso-Seq软件调用的HQ读数。(C)来自每个单独lrCaptureSeq实验和组合数据集的测序统计学。(D，E)通过CAGE验证lrCaptureSeq同种型5’端。来自成年小鼠视网膜的三个独立的CAGE-seq重复被定位到成年小鼠视网膜lrCaptureSeq同种型。D：盒须图显示lrCaptureSeq同种型第一个外显子处的CAGE读段覆盖率。覆盖率是广泛的，支持lrCaptureSeq 5'端的准确性。盒代表IQR，水平线代表中值，须等于1.5*IQR。E：沿着定位到lrCaptureSeq同种型的CAGE读段的5'-3'轴的位置。CAGE覆盖范围仅限于转录本的5'端。
图10显示了lrCaptureSeq目录中的同种型长度和丰度。(A)UpSet图，比较lrCaptureSeq数据集中的“真实(ground-truth)”同种型的数目与Cufflinks或Stringtie从视网膜和皮质RNA-seq数据集计算预测的数目。lrCaptureSeq检测到的同种型比这两个程序组装的同种型多得多。然而，只有少数预测的同种型通过长读长测序得到验证：在PacBio数据集中检测到Cufflinks预测的186个同种型(第3列+第5列)(或Cufflinks同种型的38％)，并且检测到Stringtie预测的170个同种型(第4列+第5列)(或Stringtie同种型的17.7％)。(B)盒须图，显示定位到lrCaptureSeq同种型的RNA-seq读段的数目。比较了两类同种型：所有外显子拼接在RNA-seq数据中得到验证的那些(完整)，以及未100％验证的那些(部分)。后一组的读段计数较低，这表明未能验证所有拼接可能至少部分是由于这些特定同种型的低表达水平和/或RNA-seq读取覆盖率不足。盒代表IQR，水平线代表中值，须等于1.5*IQR。红色条表示平均值的95％置信区间。(C)包含非经典剪接点的同种型对总体同种型计数的贡献。曲线显示所有同种型(红色)的丰度排序，以及仅对于包含非经典剪接点的那些同种型(蓝色)的相同排序。非经典拼接占总同种型的一小部分。从每个基因中连续去除最低丰度的同种型(即沿X轴移动)会产生类似比例的使用非经典拼接的同种型，表明其中一些被大量表达。(D)图描绘了占每个基因的总读段计数前50％(D)或75％(E)的同种型数目(参见图2C)。这些图表明，即使有严格的丰度截止值，也存在许多同种型并贡献于整体基因表达。(E，F)同种型的长度差异很大。这通过描绘每个基因的同种型长度的点图(F)和描绘每个基因的同种型中使用的外显子数目的盒须图显示。盒代表IQR，水平线代表中值，须等于1.5*IQR。(G)所有同种型的t-SNE图。大多数同种型分离到各自的基因家族中，验证了用于比较同种型相似性的聚类算法的有效性。图中心不能很好分离的同种型通常包含大的基因组元件(即保留的内含子)，这阻碍了与同一基因的其他同种型的聚类。同种型的分布表明序列组成存在显著差异。图是通过1,000次迭代生成的，困惑度＝35。
图11显示了编码和非编码同种型的变化。(A，B)图描绘了占每个基因的总读段计数前50％(A)或75％(B)的独特预测ORF的数目(参见图3B)。(C)内含子保留是非蛋白质编码同种型多样性的主要来源，如由Vldlr基因例证。阐明了前20个最丰富的Vldlr同种型。粗黑条，外显子。注意广泛的、组合的内含子保留。星号，在lrCaptureSeq同种型中(即在多腺苷酸化转录本中)检测到的内含子。内含子保留产生了高度的转录本多样性，但不会转化为高ORF多样性。所有保留的内含子都引入了过早的终止密码子。(D)非编码转录本多样性可能源于基因的5'UTR区域的变异，如由Cntn4例证。图显示了前20个最丰富的Cntn4同种型的5'端。注意5'UTR中的可变转录起始位点和差异性外显子使用。(E)与lrCaptureSeq数据集中存在的预测胰蛋白酶肽产物的数目(左柱)相比,UniProtKb数据库中由我们的30个基因编码的独特胰蛋白酶肽产物的数目(右柱)。
图12显示了通过PacBio测序发现的Megf11同种型多样性。(A)Megf11RT-PCR产物的DNA电泳凝胶图像。通过将引物分别放置在外显子25或可变外显子23中，设计引物以扩增两种不同的Megf11变体(表示为长和短)。对视网膜(长)或皮质(短)cDNA进行PCR。RT-PCR产物的大小分布表明可以轻松扩增多种不同大小的Megf11同种型。(B)来自lrCaptureSeq和PCR数据集的Megf11同种型丰度的洛伦兹图。所有数据集都表明许多同种型对Megf11的整体表达有贡献。PCR数据集曲线的右移表明最丰富的同种型的过度表示，可能是由于PCR引起的偏差。(C)转录图，描绘来自3个不同PacBio测序数据集的Megf11(顶部)的长短形式和相应外显子覆盖率(蓝色)和sashimi图(红色)的。PCR1数据集是通过对Megf11长形式PCR产物进行测序生成的，而PCR2数据集是通过对短形式PCR产物进行测序生成的。这些与来自30基因lrCaptureSeq实验的Megf11读段进行了比较。所有三个实验都揭示了Megf11转录本的广泛选择性剪接。Sashimi图显示了不同数据集之间的显著相似性。
图13表明Crb1-B同种型在多种脊椎动物中均有表达。(A)基于公开可用的RNA-seq数据(牛，GES59911；大鼠，GSE84932；斑马鱼，GSE101544)对牛、大鼠和斑马鱼视网膜中的Crb1同种型进行定量。Crb1-B在所有物种中至少与Crb1-A一样丰富，并且在大鼠和斑马鱼中更丰富。在牛或斑马鱼视网膜中检测不到Crb1-A2。误差线代表95％的置信区间。(B)小鼠视网膜中Crb1同种型的定量(q)RT-PCR分析证实了使用PacBio和短读长RNA-seq鉴定的表达模式(图5)。Crb1-A在P1时含量最高，而Crb1-B在成年期含量最高。PCR引物被设计成跨越由指定同种型表达的剪接点。用从pan-Crb1引物获得的值标准化数据。对于每个年龄，N＝3只动物。(C)使用pan-Crb1引物(pan)或靶向Crb1-B剪接点的引物(B)对来自小鼠视网膜和皮质的cDNA进行RT-PCR。在小鼠皮质中未检测到Crb1-B带。Pan-Crb1引物在两种组织中都会产生条带。N＝3只小鼠。L，ladder(标准品)。
图14显示了Crb1同种型的细胞类型特异性表达。(A)Crb1外显子的皮尔逊相关表明Crb1-B特有的外显子(5c和11b)与Crb1-A同种型特有的外显子(1-5和12)负相关。独特的Crb1-B外显子(5c和11b)呈强正相关，表明它们主要一起使用。(B)从分离的视锥(顶部)和视杆(底部)光感受器的大样本量RNA-seq(数据集：GSE74660)定量Crb1同种型。Crb1-B是光感受器中唯一表达的同种型。误差线，95％置信区间。(C)在K562细胞中表达的CRB1同种型运输至质膜。图像描绘了在C端用YFP标记的CRB1-A和CRB1-B构建体的天然荧光。(D)Crb1同种型在单细胞RNA-seq数据31中的定位。抖动图表示单个细胞内的相对转录表达计数。每个点代表一个细胞，由注释的细胞类型着色。Crb1-A由米勒胶质细胞表达，而Crb1-B由视杆和视锥光感受器表达。显示了米勒胶质细胞(Aqp4)、视杆细胞(Gnat1)、视锥细胞(Gnat2)和双极细胞(Pcp2)的细胞类型特异性标记物以进行比较。
图15描绘了Crb1突变小鼠和OLM表型。(A)Crb1null和Crb1delB等位基因中的缺失位置，通过Sanger测序验证。红色文字表示缺失的基因组片段的大小。包含Crb1null等位基因的基因组区域是SEQ ID NO:98(前四个序列)，而包含Crb1delB等位基因的基因组区域是SEQID NO:99(第五、第七和第八个序列)。说明Crb1delB缺失的序列是SEQ ID NO:100(第六个序列)。(B)确认CRB1-B蛋白在Crb1null突变小鼠中被消除。如图6C所示对视网膜裂解物进行蛋白质印迹。ABCA4，加载对照。(C)蜘蛛图显示Crb1delB/delB小鼠在P100时没有光感受器损失。灰色，野生型对照。(D，E)代表性电子显微照片，显示Crb1null和Crb1rd8突变体中的OLM破坏。图像在比例上与图7D、E相似。箭头标出缺少OLM连接的区域。解剖学紊乱类似于先前针对rd836报道的那些以及在Crb1delB/null小鼠中观察到的那些，它们缺乏Crb1-B但仍保留一个Crb1-A拷贝(图7)。比例尺，5μm。(F)携带各种等位基因组合的Crb1突变体中的OLM间隙大小。OLM间隙的大小在各种突变体之间没有显著差异。统计学，单向方差分析(F＝2.19；P＝0.095)。
图16显示了CRB1-B同种型(SEQ ID NO:1)的多肽序列，其中EGF结构域以灰色突出显示(残基24-65、68-109、303-334、516-550、773-802、804-839、841-876和924-960)并且层粘连蛋白G结构域以红色突出显示(残基141-276、370-487和607-732)。序列下方显示了蛋白质结构域的示意图。
具体实施方式
对于由Crb1基因中的功能丧失突变引起的多种视网膜变性疾病，基因置换是一种很有前景的治疗策略。然而，要设计有效的基因置换策略，必须鉴定需要置换该基因的细胞类型和要提供的适当的Crb1同种型。
Crb1是进化上保守的Crumbs基因家族的成员，其编码介导顶端基底上皮极性的细胞表面蛋白33。值得注意的是，认为的标准惯例是将该基因的小鼠版本称为Crb1，并将该基因的人类版本称为CRB1。然而，在本申请中，命名法Crb1和CRB1可互换使用以指代该基因，并且不一定用于表示该基因的来源物种。
在视网膜中，CRB1定位于外界膜(OLM)，这是光感受器和称为米勒胶质细胞的相邻神经胶质细胞之间的一组结构上重要的连接。26OLM连接在每种细胞类型内的精确亚细胞结构域处形成，表明在建立这些细胞间接触时具有高度的分子特异性34。了解CRB1在OLM连接处的功能是备受关注的，因为人类CRB1中的功能丧失突变会导致一系列视网膜变性疾病35。已经提出OLM完整性的丧失可能在疾病发病机制中发挥作用26,36。然而，对小鼠的研究尚未为该模型提供令人信服的支持。例如，在小鼠中，删除已知的Crb1同种型既不会破坏OLM，也不会导致显著的光感受器变性37。
在本申请中，发明人鉴定了一种新的Crb1同种型，其在小鼠和人类视网膜中均比经典同种型丰富得多。使用小鼠模型，他们表明OLM完整性需要这种新的同种型，并且需要将其去除才能充分表型复制人类变性疾病。这些结果要求对流行的CRB1疾病遗传学和病理学模型进行重大修订。值得注意的是，发明人发现之前忽视了视网膜变性基因Crb1的主要同种型。这种同种型Crb1-B是唯一一种由光感受器表达的同种型，光感受器是CRB1疾病中受影响的细胞。使用小鼠模型，发明人鉴定了这种同种型在光感受器-胶质细胞连接处的功能，并证明了这种同种型的丧失会加速光感受器死亡。
本发明证明了主要同种型Crb1-B当以反式存在时足以保留光感受器功能，从而允许其用于维持视力和减少视力丧失。具体而言，将Crb1-B同种型引入视网膜光感受器细胞足以维持光感受器功能并减少光感受器功能的丧失。
同种型注释：
大多数基因会产生多种mRNA同种型。如本文所用，术语“同种型”用于描述从相同基因座产生但在其转录起始位点(TSS)、蛋白质编码DNA序列(CDS)和/或非翻译区(UTR)方面不同的mRNA。通过例如选择性剪接、内含子保留和可变转录起始/终止位点的机制产生可变同种型。可变同种型的蛋白质编码能力1–4通常不同，这有时会导致基因功能的改变。这些机制在中枢神经系统(CNS)中特别常见，在CNS中使用可变同种型尤为普遍1,5。此外，同种型表达的失调与若干神经疾病有关9–11。
尽管同种型多样性的重要性显而易见，但关于CNS mRNA同种型的数目和特性的信息仍然令人惊讶地稀少——即使在主要的转录组注释数据库中也是如此12。RNA测序(RNA-seq)产生了大量关于选择性剪接的新信息。然而，由于典型的RNA-seq读取长度小于200bp，因此这种方法无法解析数千碱基转录本的全长序列。因此，仅依靠RNA-seq，不可能确定由任何给定基因或其全长序列产生的同种型的数目。在缺乏可靠的全长转录本注释的情况下，遗传实验的设计和解释变得极其困难。例如，除非转录本序列是已知的，否则很难确定“敲除”小鼠等位基因是否已经过适当设计，由此其完全消除所有同种型的表达。未注释的同种型对于理解突变如何导致人类遗传疾病的病理学也可能存在问题。隐藏的同种型可能具有未表征的蛋白质编码序列或新颖的表达模式，这可能导致疾病相关突变的分子和细胞后果被误解。因此，缺乏全面的同种型序列信息仍然是我们理解正常基因功能和基因功能障碍的表型后果的主要障碍12。
在本申请中，发明人设计了一种策略，该策略利用Pacific Biosciences(PacBio)长读长测序技术来生成CNS细胞表面分子的综合目录。长读长测序是全长转录本鉴定的理想选择；然而，可用的测序深度不足以揭示同种型多样性的全部范围27–30。为了克服这一限制，发明人采用了来自短读长测序的策略，其中用针对已知外显子的生物素化探针拉下靶向cDNA31,32。这种方法在长读长覆盖率方面产生了重大改进，揭示了靶向基因所编码的同种型的出乎意料地丰富的多样性。为了理解这些复杂的数据集，发明人开发了生物信息学工具，用于同种型的分类和比较，以及使用短读长RNA-seq数据确定它们的表达模式。使用这些方法，发明人能够鉴定出一种新颖的Crb1同种型，它为治疗视网膜病提供了巨大的潜力。
组合物：
i.多核苷酸序列、载体和分离的蛋白质
眼部病症的基因治疗方案需要将多核苷酸或载体局部递送至眼睛细胞(例如视网膜细胞)以进行局部表达。在这些疾病中将成为治疗靶标的细胞可以包括尤其是一种或多种眼睛细胞(例如，光感受器、眼神经元等)。本公开的多核苷酸、载体、多肽、组合物、方法、系统和试剂盒至少部分基于以下发现：基因Crb1的某种未知同种型(称为Crb11 B)只在视网膜光感受器中表达。发明人已发现Crb1-B同种型是Crb1基因置换疗法的有吸引力的候选者，原因有很多，包括例如：(i)大小；(ii)它们局部表达在视网膜光感受器中——在视网膜营养不良中退化的细胞类型；(iii)存在独特的启动子以及独特的第一个和最后一个编码外显子，使它们在功能上与其他同种型不同；和(iv)与视网膜中的其他Crb1同种型相比，表达增加(例如，Crb1-B的表达高约10倍)，表明它们的功能对于置换以挽救视力来说可能是最重要的。如实施例中所证明，CRB1-B是视网膜光感受器中表达的主要同种型，而其他同种型在其他视网膜细胞类型中表达(例如，CRB1-A被发现在米勒细胞中表达)。因此，CRB1-B蛋白在受试者的光感受器内的反式表达本身就足以在受试者中保留光感受器功能并维持视力。
在一个实施方案中，本技术提供一种分离的多核苷酸，其包含编码Crumbs 1-B(CRB1-B)同种型的多核苷酸序列，所述Crumbs 1-B(CRB1-B)同种型包含SEQ ID NO:1(人CRB1-B蛋白)，所述多核苷酸序列与能够在视网膜细胞中表达所述同种型的异源启动子可操作地连接。CRB1-B同种型在光感受器细胞中特异性表达，主要在内段和外段内。这种定位与CRB1-A形成鲜明对比，CRB1-A已定位于OLM内的米勒细胞的顶端(见图6E)。在一个实施方案中，编码CRB1-B同种型的多核苷酸序列是SEQ ID NO:2。
在其他实施方案中，本技术提供了编码人Crumbs 1基因的其他同种型的分离的多核苷酸。在一个实施方案中，多核苷酸序列(SEQ ID NO:4)编码包含SEQ ID NO:5(人CRB1-A蛋白)的Crumbs 1-A(CRB1-A)同种型。在另一个实施方案中，多核苷酸序列(SEQ ID NO:6)编码包含SEQ ID NO:7(人CRB1-C蛋白)的Crumbs 1-C(CRB1-C)同种型。
在其他实施方案中，分离的多核苷酸编码小鼠Crumbs 1基因的同种型。在一个实施方案中，多核苷酸序列(SEQ ID NO:8)编码包含SEQ ID NO:9(小鼠CRB1-A蛋白)的Crumbs1-A(CRB1-A)同种型。在另一个实施方案中，多核苷酸序列(SEQ ID NO:10)编码包含SEQ IDNO:11(小鼠CRB1-B蛋白)的Crumbs 1-B(CRB1-B)同种型。在又一个实施方案中，多核苷酸序列(SEQ ID NO:12)编码包含SEQ ID NO:13(小鼠CRB1-C蛋白)的Crumbs 1-C(CRB1-C)同种型。在又一个实施方案中，多核苷酸序列编码Crumbs 1-A2(CRB1-A2)蛋白。
术语“多核苷酸”或“核酸”在本文中可互换使用并且指任何长度的核苷酸的聚合形式，是核糖核苷酸或脱氧核糖核苷酸。因此，该术语包括但不限于单链、双链或多链DNA或RNA、基因组DNA、cDNA、DNA-RNA杂交体，或包含嘌呤和嘧啶碱基的聚合物，或其他天然、化学或生化修饰的、非天然的或衍生的核苷酸碱基。多核苷酸的主链可包含糖和磷酸酯基团(如通常可在RNA或DNA中发现的)，或修饰或取代的糖或磷酸酯基团。或者，多核苷酸的主链可以包含合成亚基例如氨基磷酸酯的聚合物，因此可以是寡脱氧核苷氨基磷酸酯(P--NH2)或混合的氨基磷酸酯-磷酸二酯低聚物。此外，可以通过合成互补链并在适当条件下使链退火，或通过使用DNA聚合酶和适当引物从头合成互补链，从化学合成的单链多核苷酸产物中获得双链多核苷酸。本文提供的多核苷酸序列是作为编码目的CRB1同种型的cDNA提供的。
如本文所用，“治疗”剂(例如，治疗性多肽、核酸或转基因)是一种提供有益或期望的临床结果，例如上述示例性临床结果的治疗剂。因此，治疗剂可用于如本文所述的治疗中。在一些实施方案中，多核苷酸包含Crb1同种型。在一个优选的实施方案中，Crb1同种型是Crb1-B。在另一个实施方案中，同种型选自由Crb1-A、Crb1-A2、Crb1-B、Crb1-C及其组合组成的组。
“异源”是指从基因型上不同的实体衍生而来，该实体与它与之比较或被引入或掺入其中的实体的其余部分的基因型不同。例如，通过基因工程技术引入不同细胞类型中的多核苷酸是异源多核苷酸(并且当表达时，可以编码异源多肽)。类似地，掺入病毒载体中的细胞序列(例如，基因或其部分)是相对于载体而言的异源核苷酸序列。术语“转基因”是指被引入细胞中并且能够转录成RNA并且任选地在适当条件下翻译和/或表达的多核苷酸。在一些方面，它赋予引入它的细胞期望的特性，或以其他方式产生期望的治疗或诊断结果。在另一方面，它可以被转录成介导RNA干扰的分子，例如miRNA、siRNA或shRNA。用于本发明的转基因是Crb1的同种型，优选Crb1-B。
如本文所用，术语“分离的”是指材料是从其原始环境(例如，天然环境，如果它是天然存在的)移除。例如，存在于活微生物中的天然存在的多核苷酸或多肽不是分离的，但与天然系统中的一些或全部共存材料分离的相同多核苷酸或多肽则是分离的。这样的多核苷酸可以是载体的一部分和/或这样的多核苷酸或多肽可以是组合物的一部分并且仍然是分离的，因为这样的载体或组合物不是其天然环境的一部分。
因此，在本公开的另一方面，提供了一种重组载体，其包含包含Crb1同种型并编码CRB1-B蛋白的多核苷酸、由其组成或基本上由其组成。
术语“载体”或“重组载体”在本文中可互换使用，并且是指包含待体外或体内递送到宿主细胞中的核酸的重组质粒或病毒。载体可以是能够繁殖与其连接的另一核酸的核酸分子，并且包括术语“表达载体”。载体还包括其任何药物组合物(例如，如本文提供的重组载体和药学上可接受的载体/赋形剂)。术语载体包括作为自我复制核酸结构的载体，以及掺入其已被引入其中的宿主细胞基因组中的载体。包括表达载体的载体包含编码本文所述的CRB1-B同种型的核苷酸序列，和用于载体的适当增殖和所编码多肽的表达所必需的异源序列。异源序列(即，来自与多肽不同的物种的序列)可以包含允许多肽表达的异源启动子或异源转录调控区。如本文所用，术语“异源启动子”、“启动子”、“启动子区”或“启动子序列”一般指基因的转录调控区，其可以在本文中描述的多核苷酸的5'或3'侧找到，或处于多核苷酸的编码区内，或处于多核苷酸的内含子内。通常，启动子是DNA调控区，能够结合细胞中的RNA聚合酶并启动下游(3'方向)编码序列的转录。典型的5'启动子序列在其3'末端以转录起始位点为界，并向上游(5'方向)延伸，以包括以高于背景的可检测水平启动转录所需的最少数目的碱基或元件。启动子序列内有转录起始位点，以及负责结合RNA聚合酶的蛋白质结合结构域(共有序列)。任何能够在视网膜细胞中表达CRB1-B的启动子都考虑用于本发明的实践。
在一些实施方案中，重组载体包含编码Crumbs 1-B(CRB1-B)同种型的多核苷酸，其中所述CRB1-B同种型包含连接到胞外多肽的N端信号肽，所述胞外多肽从N端到C端包含以下结构域或由其组成：两个EGF结构域、一个lamG结构域、一个EGF结构域、一个lamG结构域、一个EGF结构域、一个lamG结构域和四个EGF结构域(关于具有注释的这些结构域的CRB1-B蛋白序列，参见图16)；其中所述胞外多肽的C端连接到包含跨膜结构域和胞内结构域的C端结构域。在一个优选实施方案中，所述多核苷酸可操作地连接到能够在视网膜细胞中表达所述同种型的异源启动子。在一些实施方案中，所述胞外多肽从CRB1-A同种型的第九个EGF结构域的N端延伸至所述CRB1-A同种型的第十六个EGF结构域的C端。在一些实施方案中，C端结构域包含氨基酸序列VSSLSFYVSLLFWQNLFQLLSYLILRMNDEPVVEWGEQEDY(SEQ IDNO:3)。
如本文所用，术语“EGF结构域”(也称为“EGF样结构域”)是进化保守的蛋白质结构域，其名称来源于表皮生长因子，其在表皮生长因子中被首次描述。大多数EGF样结构域出现在膜结合蛋白的胞外结构域中或已知会分泌的蛋白质中。EGF样结构域的主要结构是一个双链β-折叠，后跟连接到一个短的C端双链β-折叠的一个环。EGF样结构域经常以许多串联拷贝出现在蛋白质内中，它们通常折叠在一起形成单个线性螺线管结构域块。合适的EGF结构域包括但不限于SEQ ID NO:14-20和SEQ ID NO:52，它们是在人CRB1-B同种型中发现的EGF结构域。
如本文所用，术语“层粘连蛋白球状(G)结构域”和“lamG结构域”可互换使用，是指在层粘连蛋白蛋白家族的各种成员中以及大量其他细胞外蛋白中发现的结构域。合适的lamG结构域包括但不限于SEQ ID NO:21-23，它们是在人CRB1-B同种型中发现的lamG结构域。
术语“N端信号肽”(通常也称为“信号肽”、“信号序列”或“前导肽”)是指存在于蛋白质N端的短肽，它通过将其靶向细胞的分泌途径中来指导蛋白质的细胞定位。术语“细胞外多肽”是指定位于细胞外的细胞外空间(即，质膜外)中的多肽或其部分。
因此，本公开的另一方面提供了一种重组载体，其包含包含Crb1同种型的多核苷酸、由其组成或基本上由其组成，所述Crb1同种型选自由Crb1-A、Crb1-A2、Crb1-B、Crb1-C及其组合组成的组。在一个实施方案中，Crb1同种型包含Crb1-A。在另一个实施方案中，Crb1同种型包含Crb1-A2。在另一个实施方案中，Crb1同种型包含Crb1-B。在又一个实施方案中，Crb1同种型包含Crb1-C。
在一些实施方案中，载体包含病毒载体。如本文所用的术语病毒载体还包括含有通过病毒载体在细胞(例如细胞系)内表达产生的病毒载体的病毒颗粒，其中该细胞产生含有病毒载体的病毒颗粒(即病毒粒子)。病毒颗粒包含病毒DNA或RNA，其编码目的同种型并且能够在其被引入的细胞中表达目的同种型。因此，术语“病毒载体”包括含有病毒载体的成熟病毒颗粒，其能够在宿主细胞，优选视网膜细胞中表达目的同种型。将病毒载体引入或转导至宿主细胞，优选视网膜细胞中允许编码的CRB1-B同种型在宿主细胞内表达。将病毒载体包装成病毒粒子(即颗粒)的方法是本领域已知的。在一个优选的实施方案中，病毒载体是腺相关病毒(AAV)。应当理解，也可以使用其他基因递送载体，包括逆转录病毒、慢病毒、HSV载体或塞姆利基森林病毒(Semliki-Forrest-Virus)载体和腺病毒，并且它们被认为是本发明的一部分。AAV载体的优势在于它们通常可以浓缩至每毫升约1014病毒颗粒的滴度，这一水平的载体具有转导患者体内更多数目的靶细胞，例如视网膜细胞的潜力。此外，基于AAV的载体具有得到确认的安全记录，并且不会以显著水平整合到靶细胞基因组中，从而避免了有害基因的插入激活或必要基因的失活的可能性。因此，在某些实施方案中，病毒载体包括AAV载体。
在一些实施方案中，多核苷酸处于在视网膜中表达的启动子序列的控制之下。在其他实施方案中，多核苷酸与适合于在一种或多种视网膜细胞类型中表达多核苷酸的启动子可操作地连接。在一些实施方案中，视网膜细胞选自由光感受器细胞、视网膜色素上皮细胞、双极细胞、水平细胞、无长突细胞、米勒细胞(Müller cell)和/或神经节细胞组成的组。在某些实施方案中，视网膜细胞包含光感受器细胞。在一些实施方案中，启动子选自由视紫红质激酶(RK)启动子、视蛋白启动子、巨细胞病毒(CMV)启动子和鸡β-肌动蛋白(CBA启动子)等组成的组。
例如，在一个实施方案中，编码CRB1-B的分离的多核苷酸或重组载体的靶细胞是视网膜中的光感受器细胞。在另一个实施例中，分离的多核苷酸或重组载体编码CRB1-A并且靶细胞是米勒细胞。在一些实施方案中，一种或多种载体可以组合使用，其中一种载体编码CRB1-B同种型，并且一种或多种其他载体编码其他Crb同种型中的一种，例如CRB1-A、CRB1-A2或CRB-C。
“重组病毒载体”是指包含一个或多个异源序列(即，非病毒来源的核酸序列)的重组多核苷酸载体。在重组AAV载体的情况下，重组核酸的侧翼是至少一个反向末端重复序列(ITR)。在一些实施方案中，重组核酸的侧翼是两个ITR。
“重组AAV载体(rAAV载体)”是指包含一个或多个异源序列(即，非AAV来源的核酸序列)的多核苷酸载体，所述异源序列的侧翼是至少一个AAV反向末端重复序列(ITR)。当这些rAAV载体存在于已经被合适的辅助病毒感染(或正在表达合适的辅助功能)并且正在表达AAV rep和cap基因产物(即，AAV Rep和Cap蛋白)的宿主细胞中时，这些rAAV载体可以被复制并包装到感染性病毒颗粒中。当rAAV载体被掺入更大的多核苷酸中时(例如，在染色体中或在另一个载体中，例如用于克隆或转染的质粒)，那么rAAV载体可以被称为“原载体(pro-vector)”，它可以在AAV包装功能和合适的辅助功能存在的情况下，通过复制和衣壳化而被“拯救”。rAAV载体可以是多种形式中的任何一种，包括但不限于质粒、线性人工染色体、与脂质复合、封装在脂质体中以及在病毒颗粒例如AAV颗粒中衣壳化。rAAV载体可以被包装到AAV病毒衣壳中以产生“重组腺相关病毒颗粒(rAAV颗粒)”。用于制备AAV的方法和试剂盒是本领域已知的，例如但不限于AdEasy克隆系统(例如，可从德国海德堡的QBiogeneGmbH获得)。相应的载体和辅助载体是本领域广泛已知的(Nicklin S A,Baker AH,CurrGene Ther.,2002,2:273-93；Mah等人,Clin Pharmacokinet.,2002,41:901-11)。
“rAAV病毒”或“rAAV病毒颗粒”是指由至少一种AAV衣壳蛋白和一种衣壳化的rAAV载体基因组构成的病毒颗粒。
在一些实施方案中，载体包括重组AAV(rAAV)载体。在一些实施方案中，载体包含侧接一个或两个AAV反向末端重复(ITR)的转基因。核酸在AAV颗粒中被衣壳化。AAV载体还可包含衣壳蛋白。在一些实施方案中，核酸包含目的编码序列(例如，Crb1-A、Crb1-A2、Crb1-B、Crb1-C，优选地Crb1-B)在转录方向上可操作地连接的组分、控制序列(包括转录起始和终止序列)，从而形成表达盒。
在一些实施方案中，表达盒在5'和3'末端侧接至少一个功能性AAV ITR序列。“功能性AAV ITR序列”是指ITR序列如预期用于AAV病毒体的拯救、复制和包装那样起作用。参见Davidson等人,PNAS,2000,97(7)3428-32；Passini等人,J.Virol.,2003,77(12):7034-40；和Pechan i.,Gene Ther.,2009,16:10-16，它们均通过全文引用的方式并入本文。为了实施本公开的一些方面，重组载体至少包含衣壳化所必需的AAV的所有序列和用于rAAV感染的物理结构。用于本公开的载体中的AAV ITR不需要具有野生型核苷酸序列(例如，如Kotin,Hum.Gene Ther.,1994,5:793-801中所述)，并且可以通过核苷酸的插入、缺失或取代而改变，或者AAV ITR可以源自若干种AAV血清型中的任何一种。目前已知的AAV血清型超过40种，并且不断鉴定出新的血清型和现有血清型的变体。参见Gao等人,PNAS,2002,99(18):11854-6；Gao等人,PNAS,2003,100(10):6081-6；和Bossis等人,J.Virol.,2003,77(12):6799-810。
任何AAV血清型的使用被认为在本公开的范围内。在一些实施方案中，rAAV载体是源自AAV血清型的载体，包括但不限于AAV ITR是AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAVrh8、AAVrh8R、AAV9、AAV10、AAVrh10、AAV11、AAV12、AAV2R471A、AAV DJ、山羊AAV、牛AAV或小鼠AAV ITR等。在一些实施方案中，AAV中的核酸包含AAV ITR的ITR，AAV ITR是AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAVrh8、AAVrh8R、AAV9(Aschauer等人,2013)、AAV10、AAVrh10、AAV11、AAV12、AAV2R471A、AAV DJ、山羊AAV、牛AAV或小鼠AAV等。在某些实施方案中，AAV中的核酸包含AAV2 ITR。在一些实施方案中，载体可包括填充核酸。在一些实施方案中，填充核酸可以编码绿色荧光蛋白。在一些实施方案中，填充核酸可以位于启动子和编码CRB1-B同种型的核酸之间。
本领域已知许多用于生产病毒载体(包括rAAV载体)的方法，包括转染、稳定细胞系生产和感染性杂交病毒生产系统。这些系统中的一些包括但不限于例如，腺病毒-AAV杂交体、疱疹病毒-AAV杂交体(Conway,JE等人,(1997)J.Virology 71(11):8780-8789)和杆状病毒-AAV杂交体。用于生产rAAV病毒颗粒的rAAV生产培养物都需要：1)在杆状病毒生产系统的情况下，合适的宿主细胞，包括例如人源细胞系例如HeLa、A549或293细胞，或昆虫源细胞系例如SF-9；2)合适的辅助病毒功能，由野生型或突变型腺病毒(例如温度敏感腺病毒)、疱疹病毒、杆状病毒或提供辅助功能的质粒构建体提供；3)AAV rep和cap基因和基因产物；4)侧接至少一个AAV ITR序列的转基因(例如治疗性转基因)；和5)支持rAAV生产的合适培养基和培养基组分。本领域已知的合适培养基可用于生产rAAV载体。这些培养基包括但不限于由Hyclone Laboratories和JRH生产的培养基，包括改良伊格尔培养基(ModifiedEagle Medium，MEM)、达尔伯克氏改良伊格尔培养基(Dulbecco's Modified EagleMedium，DMEM)、定制配方(例如美国专利号6,566,118中描述的那些)和如美国专利号6,723,551中描述的Sf-900 II SFM培养基，每篇专利均以全文引用的方式并入本文，特别是关于用于生产重组AAV载体的定制培养基配方。
可以使用本领域已知的方法生产根据本公开的载体。参见例如美国专利号6,566,118、6,989,264和6,995,006。在实施本发明时，用于生产rAAV颗粒的宿主细胞包括哺乳动物细胞、昆虫细胞、植物细胞、微生物和酵母。宿主细胞也可以是其中AAV rep和cap基因稳定维持在宿主细胞中的包装细胞或其中AAV载体基因组被稳定维持的生产细胞。示例性的包装细胞和生产细胞来源于293、A549或HeLa细胞。使用本领域已知的标准技术纯化和配制AAV载体。
在一些实施方案中，根据本公开的载体可以通过三重转染方法产生，例如下文提供的示例性三重转染方法。简而言之，可以将含有rep基因和衣壳基因的质粒以及辅助腺病毒质粒转染(例如，使用磷酸钙方法)到细胞系(例如HEK-293细胞)中，并且可以收集病毒并将其任选地纯化。
在一些实施方案中，载体可以通过生产细胞系方法产生，例如下文提供的示例性生产细胞系方法(也参见(参考Martin等人,(2013))Human Gene Therapy Methods 24:253-269)。简而言之，细胞系(例如，HeLa细胞系)可以用含有rep基因、衣壳基因和启动子-转基因序列的质粒稳定转染。可以筛选细胞系以选择用于载体生产的先导克隆，然后可以将其在生产生物反应器中扩增并用腺病毒(例如，野生型腺病毒)作为辅助物进行感染以启动载体生产。随后可以收获病毒，可以灭活(例如通过加热)和/或去除腺病毒，并且可以纯化载体。
与病毒滴度相关的术语“基因组颗粒(gp)”、“基因组等效物”或“基因组拷贝”是指含有重组AAV DNA基因组的病毒体的数目，与感染性或功能性无关。特定载剂制剂中的基因组颗粒的数目可以通过例如在例如Clark等人(1999)Hum.Gene Ther.,10:1031-1039；Veldwijk等人(2002)Mol.Ther.,6:272-278中描述的程序测量。
如本文所用的术语“载体基因组(vg)”可以指一个或多个多核苷酸，其包含载体例如病毒载体的一组多核苷酸序列。载体基因组可以在病毒颗粒中衣壳化。取决于特定病毒载体，载体基因组可包含单链DNA、双链DNA或单链RNA或双链RNA。载体基因组可包括与特定病毒载体相关的内源序列和/或通过重组技术插入特定病毒载体的任何异源序列。例如，重组AAV载体基因组可以包括至少一个ITR序列，其侧翼为启动子、填充物、目的序列(例如，RNAi)和聚腺苷酸化序列。完整的载体基因组可以包括载体的多核苷酸序列的完整集合。在一些实施方案中，病毒载体的核酸滴度可以用vg/mL来测量。在另一个实施方案中，例如在使用AAV载体时，病毒滴度可以根据DNase抗性颗粒(DRP)测量，因为成熟的、有包膜的AAV颗粒是从未完全形成的AAV颗粒中计数的。适用于测量该滴度的方法是本领域已知的(例如，定量PCR)。
启动子：
在一些实施方案中，本公开的核酸(多核苷酸)(例如，Crb1同种型B，并且在其他实施方案中，Crb1同种型A、A2和/或C)与启动子可操作地连接。启动子可以是组成型、诱导型或抑制型启动子。优选地，启动子能够在靶细胞中表达多核苷酸中编码的同种型。示例性启动子包括但不限于巨细胞病毒(CMV)立即早期启动子、RSV LTR、MoMLV LTR、磷酸甘油酸激酶-1(PGK)启动子、猿猴病毒40(SV40)启动子和CK6启动子、转甲状腺素蛋白启动子(TTR)、TK启动子、四环素响应启动子(TRE)、HBV启动子、hAAT启动子、LSP启动子、嵌合肝特异性启动子(LSP)、E2F启动子、端粒酶(hTERT)启动子；巨细胞病毒增强子/鸡β-肌动蛋白/兔β-珠蛋白启动子(CAG启动子；Niwa等人,Gene,1991,108(2):193-9)和延伸因子1-α启动子(EF1-α)启动子(Kim等人,Gene,1990,91(2):217-23和Guo等人,Gene Ther.,1996,3(9):802-10)。
如本文所用，当启动子被置于与第二多核苷酸序列的功能关系中时，所述启动子“可操作地连接到”或“可操作地联接到”。例如，如果启动子连接到多核苷酸以致它可以影响多核苷酸编码序列的转录，则启动子可操作地连接到多核苷酸。在各种实施方案中，多核苷酸可以可操作地连接到至少1个、至少2个、至少3个、至少4个、至少5个或至少10个启动子。
有利地，启动子是驱动基因在视网膜细胞中表达的组织特异性启动子。许多视网膜特异性启动子是本领域已知的。例如，源自人视紫红质激酶基因(GenBank Entrez GeneID 6011)的视紫红质激酶(RK)启动子(SEQ ID NO:24)已被证明可在视杆细胞和视锥细胞以及视网膜细胞系例如WERI Rb-1中特异性地驱动表达(Khani,S.C.等人(2007)Invest.Ophthalmol.Vis.Sci.48(9):3954-61)。如本文所用，“视紫红质激酶启动子”可以指完整启动子序列或足以驱动光感受器特异性表达的启动子序列的片段，例如在Khani,S.C.等人(2007)Invest.Ophthalmol.Vis.Sci.48(9):3954-61和Young,J.E.等人(2003)Invest.Ophthalmol.Vis.Sci.44(9):4076-85中描述的序列。在一些实施方案中，相对于转录起始位点，RK启动子从-112跨越到+180。
视蛋白启动子及其衍生物也常用于驱动视网膜特异性基因表达。例如，最小启动子已经源自小鼠视蛋白基因(SEQ ID NO:25)，已被证明可驱动光感受器中的稳健表达(Pawlyk,B.S.等人(2005)Invest Ophthalmol Vis Sci,46(9),3039-45)。因此，在一些实施方案中，启动子是视紫红质激酶(RK)启动子或视蛋白启动子。
或者，启动子可以是非组织特异性的组成型启动子。当需要高水平的基因表达时，使用此类启动子可能是有利的。例如，巨细胞病毒(CMV)启动子(SEQ ID NO:26)通常包含在用于对哺乳动物细胞进行基因工程的载体中，因为它作为强组成型启动子被很好地表征(Boshart等人,Cell,41:521-530(1985))。常用组成型启动子的另一个实例是鸡β-肌动蛋白启动子(SEQ ID NO:27)，它也被称为“CAG启动子”(参见定义；Miyazaki,J.等人(1989)Gene 79(2):269-77)。CAG启动子是由通过组合巨细胞病毒(CMV)早期增强子元件、鸡β-肌动蛋白基因的启动子、第一外显子和第一内含子、以及兔β-珠蛋白基因的剪接受体形成的强合成启动子。因此，在一些实施方案中，启动子是巨细胞病毒(CMV)启动子或鸡β-肌动蛋白(CAG启动子)。69502412如本文所用，术语“CAG启动子”可与“CBA启动子”互换使用。
在一些实施方案中，启动子包含与鸡β-肌动蛋白(CBA)启动子连接的人β-葡萄糖醛酸酶启动子或巨细胞病毒增强子。在一些实施方案中，本发明提供一种包含编码本公开的异源转基因的核酸的重组载体，所述核酸与CBA启动子可操作地连接。示例性的启动子和描述可以在例如U.S.权前公开20140335054中找到。
组成型启动子的实例包括但不限于逆转录病毒劳斯肉瘤病毒(RSV)LTR启动子(任选地带有RSV增强子)、巨细胞病毒(CMV)启动子(任选地带有CMV增强子)[参见例如，Boshart等人,Cell,41:521-530(1985)]、SV40启动子、二氢叶酸还原酶启动子、13-肌动蛋白启动子、磷酸甘油激酶(PGK)启动子和EF1α启动子[Invitrogen]。
诱导型启动子允许调控基因表达，并且可以通过外源提供的化合物、环境因素例如温度或特定生理状态(例如，急性期、细胞的特定分化状态，或只在正在复制的细胞中)的存在而被调控。诱导型启动子和诱导型系统可从多种商业来源获得，包括但不限于Invitrogen、Clontech和Ariad。已经描述了许多其他系统并且本领域技术人员可以容易地选择这些系统。由外源提供的启动子调控的诱导型启动子的实例包括锌诱导型绵羊金属硫蛋白(MT)启动子、地塞米松(Dex)诱导型小鼠乳腺肿瘤病毒(MMTV)启动子、T7聚合酶启动子系统(WO 98/10088)；蜕皮激素昆虫启动子(No等人,Proc.Natl.Acad.Sci.USA,93:3346-3351(1996))、四环素阻遏型系统(Gossen等人,Proc.Natl.Acad.Sci.USA,89:5547-5551(1992))、四环素诱导型系统(Gossen等人,Science,268:1766-1769(1995)，也参见Harvey等人,Curr.Opin.Chem.Biol.,2:512-518(1998))、RU486诱导型系统(Wang等人,Nat.Biotech.,15:239-243(1997)，和Wang等人,Gene Ther.,4:432-441(1997))和雷帕霉素诱导型系统(Magari等人,J.Clin.Invest.,100:2865-2872(1997))。关于这点，可能有用的其他类型的诱导型启动子是受特定生理状态(例如温度、急性期、细胞的特定分化状态或只在正在复制的细胞中)调控的那些。
用于能够在视网膜细胞中表达的AAV载体中的合适启动子是本领域已知的，例如，如“在小鼠、非人灵长类动物和人类中使用合成启动子AAV靶向神经元和神经胶质细胞类型(Targeting neuronal and glial cell types with synthetic promoter AAVs inmice,non-human primates,and humans)”中所发现的，参见Jüttner等人,bioRxiv434720；doi:doi.org/10.1101/434720(2018年10月)中的表S1，该文献现在发布于NatureNeuroscience doi:10.1038/s41593-019-0431-2，其以全文引用的方式并入。
在另一个实施方案中，将针对转基因使用天然启动子或其片段。当期望转基因的表达应当模拟天然表达时，可以使用天然启动子。当转基因的表达必须在时间上或发育上，或以组织特异性方式，或响应于特定转录刺激物被调控时，可以使用天然启动子。在另一个实施方案中，也可以使用其他天然表达控制元件，例如增强子元件、聚腺苷酸化位点或Kozak共有序列来模拟天然表达。
在一些方面，本公开提供了一种包含CRB1-B同种型(例如，SEQ ID NO:1)或由其组成的分离的多肽。合适地，分离的多肽可从本文所述的多核苷酸或载体表达。术语“多肽”和“蛋白质”互换使用，是指氨基酸残基的聚合物，并且不限于最小长度。此类氨基酸残基聚合物可包含天然或非天然氨基酸残基，包括但不限于氨基酸残基的肽、寡肽、二聚体、三聚体和多聚体。该定义涵盖全长蛋白质及其片段两者。该术语还包括多肽的表达后修饰，例如糖基化、唾液酸化、乙酰化、磷酸化等。此外，就本发明而言，“多肽”是指一种蛋白质，其包括对天然序列的修饰，例如缺失、添加和取代(通常在性质上是保守的)，只要该蛋白质保持期望的活性即可。这些修饰可能是有意的，例如通过定点诱变，也可能是偶然的，例如通过产生蛋白质的宿主的突变或由于PCR扩增而产生的错误。
术语多核苷酸序列的“基本同一性”是指多核苷酸包含与编码本文所述的目的多肽的多核苷酸具有至少95％序列同一性的序列。或者，同一性百分比可以是从95％到100％的任何整数。在一个实施方案中，序列同一性为至少95％，或者至少99％。更优选的实施方案包括在使用本文描述的程序，优选地是所描述的使用标准参数的BLAST时，与参考序列相比至少96％、97％、98％、99％或100％相同。通过考虑密码子简并性、氨基酸相似性、阅读框定位等，可以适当地调整这些值以确定由两个核苷酸序列编码的蛋白质的相应同一性。
在一些优选的实施方案中，用于本发明目的的术语氨基酸序列的“基本同一性”是指至少95％、优选98％、最优选99％或100％的多肽序列同一性。优选的多肽同一性百分比可以是从95％到100％的任何整数。更优选的实施方案包括至少96％、97％、98％、99％或100％。
iii.药物组合物
本公开还提供了一种药物组合物。药物组合物可包含编码CRB1同种型的分离的多核苷酸、编码CRB1同种型、优选本文所述的CRB1-B同种型的重组载体和药学上可接受的载体或由其组成。在一个实施例中，药物组合物可包含编码CRB1-B同种型的病毒载体。药物组合物可包含浓度为约1×106DNase抗性颗粒(DRP)/ml至约1×1014DRP/ml的病毒载体，例如rAAV病毒载体。根据权利要求14或15所述的药物组合物，进一步包含编码CRB1-A、CRB1-A2、CRB1-C或其组合的第二载体。
根据本公开的载体还可以是药物组合物的形式。因此，在一些实施方案中，本文提供的载体还可包含缓冲剂和/或药学上可接受的赋形剂和/或药学上可接受的运载体(carrier)。如本领域众所周知的，药学上可接受的赋形剂和/或运载体是相对惰性的物质，其有利于药理学有效物质的给药并且可以作为液体溶液或悬浮液、作为乳液或作为适合于在使用前溶解或悬浮在液体中的固体形式提供。可根据期望的给药途径选择药学上可接受的运载体。例如，赋形剂可以提供形状或稠度，或充当稀释剂。合适的赋形剂包括但不限于稳定剂、润湿剂和乳化剂、用于变化渗透压的盐、包封剂、pH缓冲物质和缓冲剂。此类赋形剂包括适合直接递送至眼睛的任何药剂，其可在没有过度毒性的情况下给药。合适地，药学上可接受的运载体有助于在给药前维持病毒载体的病毒颗粒完整性，例如提供合适的pH平衡溶液。药学上可接受的赋形剂包括但不限于山梨糖醇、各种TWEEN(吐温)化合物中的任一种，和液体例如水、盐水、甘油和乙醇。其中可包括药学上可接受的盐，例如无机酸盐，例如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐等；以及有机酸的盐，例如乙酸盐、丙酸盐、丙二酸盐、苯甲酸盐等。药学上可接受的赋形剂的详尽描述可在REMINGTON'SPHARMACEUTICAL SCIENCES(Mack Pub.Co.,N.J.1991)获得。组合物可在给药前通过常规、众所周知的灭菌技术进行灭菌(例如过滤、添加灭菌剂等)。组合物可包含接近生理条件所需的药学上可接受的附加物质，例如pH调节剂和缓冲剂、毒性调节剂，例如乙酸钠、氯化钠、氯化钾、氯化钙、乳酸钠等。
在与眼部递送相关的一些实施方案中，药学上可接受的运载体包括例如无菌液体，例如水和油，包括石油、动物、植物或合成来源的那些，例如花生油、大豆油、矿物油等。盐水溶液和葡萄糖水溶液、聚乙二醇(PEG)和甘油溶液也可用作液体运载体，尤其是对于注射液来说。也可以使用附加成分，例如防腐剂、缓冲剂、张力剂、抗氧化剂和稳定剂、非离子润湿剂或澄清剂、粘度增加剂等。
在一些实施方案中，本公开的药物组合物被配制用于通过视网膜下注射给药。因此，这些组合物可以与药学上可接受的载体例如盐水、林格氏平衡盐溶液(pH 7.4)等组合。尽管不是必需的，但组合物可以任选地以适合于精确量给药的单位剂型提供。
在其他实施方案中，本公开的药物组合物被配制用于向眼睛局部给药。在此类实施方案中，可以使用常规的眼内递送试剂。例如，用于局部眼内递送的本公开的药物组合物可包含如上所述的盐水溶液、角膜渗透促进剂、不溶性颗粒、凡士林或其他凝胶基软膏、滴入眼内时粘度增加的聚合物、或粘膜粘附性聚合物。优选地，眼内递送试剂增加角膜渗透，通过粘度效应或通过与覆盖角膜上皮的粘蛋白层建立物理化学相互作用来延长siRNA的眼前滞留。
治疗方法：
本公开还提供了使用根据本公开的多核苷酸、载体和药物组合物治疗和/或预防受试者的眼部病症的方法。在一些实施方案中，治疗方法是针对此类眼部病症的基因治疗方案并且需要将根据本公开的多核苷酸或载体局部递送至视网膜中的细胞。在此类实施方案中将成为治疗靶标的细胞是视网膜中的光感受器细胞，或神经感觉视网膜下方的RPE细胞。因此，在一个实施方案中，根据本公开的多核苷酸和载体的递送通过注射到视网膜和RPE之间的视网膜下空间中来实现。因此，本公开的一方面提供了一种治疗和/或预防受试者的眼部病症的方法，所述方法包括向受试者施用治疗有效量的根据本公开的多核苷酸、重组载体或药物组合物、由其组成或基本上由其组成，从而在受试者中治疗眼部病症。优选地，所述多核苷酸或包含其的重组载体或药物组合物编码本文所述的CRB1-B同种型。
本公开提供一种在有需要的受试者中减少视力丧失的进展或维持视力功能的方法。所述方法包括向受试者施用治疗有效量的本文所述的分离的多核苷酸、重组载体、分离的多肽或药物组合物，使得视力丧失的进展被减少。在一些实施方案中，视力丧失维持在与治疗开始时的视力水平相似的水平，例如，视力维持在与治疗开始时的视力的约10％以内。不受任何理论的束缚，但在需要治疗的受试者的视网膜内的光感受器细胞中维持CRB1-B反式表达水平可以允许减少光感受器细胞的死亡和维持光感受器-神经胶质连接，保持受试者的视力。在一些实施方案中，玻璃体内、视网膜下或局部施用分离的多核苷酸、重组载体或药物组合物。
在一些实施方案中，本文所述的方法还可包括监测受试者的视觉功能，其中所述受试者的视觉功能在给药后得以维持且不降低。监测视觉功能的方法是本领域已知的(下文进一步描述)并且包括例如监测受试者的视敏度。
在一些实施例中，在用本文所述的分离的多核苷酸、重组载体、分离的多肽或药物组合物治疗之后，这种同种型在光感受器-胶质细胞连接处的功能得以维持。术语“施用/给药”涵盖将分离的多肽、载体或药物组合物递送至受试者视网膜内的一种或多种细胞的方法。在一个优选的实施方案中，同种型是CRB1-B并且一种或多种细胞是视网膜内的光感受器细胞。用于将根据本公开的分离的多核苷酸、载体或药物组合物递送至受试者的合适技术可包括本领域已知的多种方法，例如通过基因枪、电穿孔、纳米颗粒、病毒颗粒转导、微囊化、基因编辑等，或通过肠胃外和肠内给药途径。合适的肠胃外给药途径包括例如组织周围和组织内给药(例如，视网膜内注射或视网膜下注射)；直接(例如，局部)施用到新血管形成部位处或附近的区域，例如通过导管或其他放置装置(例如，角膜颗粒或栓剂、滴管或包含多孔、无孔或凝胶状材料的植入物)。合适的放置装置包括美国专利号5,902,598和6,375,972中描述的眼部植入物，和美国专利号6,331,313中描述的可生物降解的眼部植入物，其全部公开内容以引用的方式并入本文中。此类眼部植入物可从Control DeliverySystems,Inc.(Watertown,Mass.)和Oculex Pharmaceuticals,Inc.(Sunnyvale,CA)获得。在某些实施方案中，肠胃外给药途径包括眼内给药。应当理解，根据本公开的分离的多核苷酸、载体和药物组合物的眼内给药可以通过注射或直接(例如，局部)施用至眼睛来完成，只要给药途径允许所述分离的多核苷酸、载体或药物组合物进入眼睛。除了上述眼睛局部给药途径外，合适的眼内给药途径包括玻璃体内、视网膜内、视网膜下、腱下、眶周和眶后、经角膜和经巩膜给药。此类眼内给药途径在本领域技术范围内；参见例如Acheampong AA等人,2002，上文；和Bennett等人(1996),Hum.Gene Ther.7:1763-1769和Ambati J等人,2002,Progress in Retinal and Eye Res.21:145-151，其全部公开内容以引用的方式并入本文。
如本文所用，术语“局部地”是指应用于眼睛表面。
在一些实施方案中，根据本公开的分离的多核苷酸、载体或药物组合物通过视网膜下递送施用于受试者。本领域已知视网膜下递送方法。例如，参见WO 2009/105690，其以引用的方式并入本文。简而言之，将根据本公开的载体递送至黄斑和中央凹的视网膜下的一般方法可以通过以下简要概述来说明。该实例仅意在说明该方法的某些特征，而绝非限制性的。
通常，它们可以在使用手术显微镜的直接观察下以眼内(视网膜下)注射组合物的形式递送。该过程可能涉及玻璃体切除术，然后使用细套管通过一个或多个小视网膜切开术将载体悬浮液注射到视网膜下空间中。
简而言之，可以将输液套管缝合在适当位置以在整个手术过程中通过输注(例如盐水)保持正常的眼球体积。使用适当孔径(例如20至27号)的套管进行玻璃体切除术，其中被移除的玻璃体凝胶的体积通过从输液套管输注盐水或其他等渗溶液来替换。玻璃体切除术的实施是有利的，因为(1)去除其皮质(玻璃体后界膜)有利于套管穿透视网膜；(2)它的去除和替换为液体(例如，盐水)为眼内注射载体创造了空间，并且(3)它的受控去除减少了视网膜撕裂和非计划性视网膜脱离的可能性。
在一些实施方案中，根据本公开的分离的多核苷酸、载体或药物组合物通过利用适当孔径(例如，27-45号)的套管被直接注射到中央视网膜外的视网膜下空间中，从而在视网膜下空间中产生泡。在其他实施方案中，在视网膜下注射根据本公开的分离的多核苷酸、载体或药物组合物之前，视网膜下注射小体积(例如，约0.1至约0.5ml)的合适流体(例如盐水或林格氏液)进入中央视网膜外的视网膜下空间。这种对视网膜下空间的初始注射在视网膜下空间内产生了初始流体泡，导致初始流体泡位置处的局部视网膜脱离。该初始流体泡有助于将分离的多核苷酸、载体和/或药物组合物靶向递送至视网膜下空间(通过在载体和/或药物组合物递送之前限定注射平面)，并使分离的多核苷酸、载体和/或药物组合物给药到脉络膜中的可能性或回流到玻璃体腔中的可能性最小化。在一些实施方案中，该初始流体泡可以进一步与包含一种或多种分离的多核苷酸和/或药物组合物和/或一种或多种另外的治疗剂的流体一起被注射，通过用相同或额外的细孔套管将这些流体直接施用至所述初始流体泡。
根据本公开的分离的多核苷酸、载体或药物组合物和/或初始小体积流体的眼内施用可以使用连接到注射器的细孔套管(例如，规格27-45号)进行。在一些实施方案中，该注射器的柱塞可由机械化装置驱动，例如通过压下脚踏板。细孔套管通过巩膜切开术前进，穿过玻璃体腔并在每个受试者中在根据要靶向的视网膜区域(但在中央视网膜之外)预先确定的位点处进入视网膜。在直接可视化下，将所述分离的多核苷酸、载体或药物组合物悬浮液机械注射到感觉神经视网膜下，从而通过自密封非扩张视网膜切开术导致局部视网膜脱离。如上所述，可将分离的多核苷酸、载体或药物组合物直接注射到视网膜下空间中，从而在中央视网膜外产生泡，或者可将分离的多核苷酸、载体或药物组合物注射到中央视网膜外的初始泡中，导致它扩大(并扩大视网膜脱离的区域)。在一些实施方案中，在注射根据本公开的分离的多核苷酸、载体或药物组合物之后，将另一种流体注射到泡中。
不希望受理论束缚，视网膜下注射的速率和位置可产生局部剪切力，其可损伤黄斑、中央凹和/或下面的RPE细胞。视网膜下注射可以以最小化或避免剪切力的速率进行。在一些实施方案中，根据本公开的分离的多核苷酸、载体或药物组合物历时约15-17分钟注射。在一些实施方案中，载体历时约17-20分钟注射。在一些实施方案中，分离的多核苷酸、载体或药物组合物历时约20-22分钟注射。在一些实施方案中，分离的多核苷酸、载体和/或药物组合物以约35至约65μl/min的速率注射。在一些实施方案中，分离的多核苷酸、载体和/或药物组合物以约35μl/min的速率注射。在一些实施方案中，分离的多核苷酸、载体和/或药物组合物以约40μl/min的速率注射。在一些实施方案中，分离的多核苷酸、载体和/或药物组合物以约45μl/min的速率注射。在一些实施方案中，分离的多核苷酸、载体和/或药物组合物以约500min的速率注射。在一些实施方案中，分离的多核苷酸、载体和/或药物组合物以约55μl/min的速率注射。在一些实施方案中，分离的多核苷酸、载体和/或药物组合物以约60μl/min的速率注射。在一些实施方案中，分离的多核苷酸、载体和/或药物组合物以约65μl/min的速率注射。本领域普通技术人员将认识到，泡的注射速率和时间可以由例如以下因素指导：产生足够的视网膜脱离以进入中央视网膜的细胞所必需的载体和/或药物组合物的体积或泡的大小、用于递送分离的多核苷酸、载体和/或药物组合物的套管的尺寸，以及安全地保持本发明的套管的位置的能力。
在本公开的一些实施方案中，注射到视网膜的视网膜下空间的分离的多核苷酸或载体(在溶液中或在本文提供的药物组合物中)的体积大于约1μl、2μl、3μl、4μl、5μl、6μl、7μl、8μl、9μl、10μl、15μl、20μl、25μl、50μl、75μl、100μl、200μl、300μl、400μl、500μl、600μl、700μl、800μl、900μl或1mL中的任一者，或它们之间的任何量。
在一些实施方案中，所述方法包括向眼睛施用(例如，通过视网膜下和/或玻璃体内施用)有效量的根据本公开的分离的多核苷酸、载体或药物组合物。在一些实施方案中，病毒载体用于药物组合物中，并且组合物的病毒滴度为至少约5×1012、6×1012、7×1012、8×1012、9×1012、10×1012、11×1012、15×1012、20×1012、25×1012、30×1012或50×1012基因组拷贝/mL中的任一者。在一些实施方案中，组合物的病毒滴度为约5×1012至6×1012、6×1012至7×1012、7×1012至8×1012、8×1012至9×1012、9×1012至10×1012、10×1012至11×1012、11×1012至15×1012、15×1012至20×1012、20×1012至25×1012、25×1012至30×1012、30×1012至50×1012或50×1012至100×1012基因组拷贝/mL中的任一者。在一些实施方案中，组合物的病毒滴度为约5×1012至10×1012、10×1012至25×1012或25×1012至50×1012基因组拷贝/mL中的任一者。在一些实施方案中，组合物的病毒滴度为至少约5×109、6×109、7×109、8×109、9×109、10×109、11×109、15×109、20×109、25×109、30×109或50×109转导单位/mL中的任一者。在一些实施方案中，组合物的病毒滴度为约5×109至6×109、6×109至7×109、7×109至8×109、8×109至9×109、9×109至10×109、10×109至11×109、11×109至15×109、15×109至20×109、20×109至25×109、25×109至30×109、30×109至50×109或50×109至100×109转导单位/mL中的任一者。在一些实施方案中，组合物的病毒滴度为约5×109至10×109、10×109至15×109、15×109至25×109或25×109至50×109转导单位/mL中的任一者。在一些实施方案中，组合物的病毒滴度为至少约5×1010、6×1010、7×1010、8×1010、9×1010、10×1010、11×1010、15×1010、20×1010、25×1010、30×1010、40×1010或50×1010感染单位/mL中的任一者。在一些实施方案中，组合物的病毒滴度为至少约5×1010至6×1010、6×1010至7×1010、7×1010至8×1010、8×1010至9×1010、9×1010至10×1010、10×1010至11×1010、11×1010至15×1010、15×1010至20×1010、20×1010至25×1010、25×1010至30×1010、30×1010至40×1010、40×1010至50×1010或50×1010至100×1010感染单位/mL中的任一者。在一些实施方案中，组合物的病毒滴度为至少约5×1010至10×1010、10×1010至15×1010、15×1010至25×1010或25×1010至50×1010感染单位/mL中的任一者。
可以产生一个或多个(例如，2、3或更多个)泡。通常，由本发明的方法和系统产生的一个或多个水泡的总体积不能超过眼睛的流体体积，例如在典型的人类受试者中约为4ml。每个单独泡的总体积可为至少约0.3ml，或至少约0.5ml，以促进足够大小的视网膜脱离以暴露中央视网膜的细胞类型并产生对最佳操纵具有足够依赖性的泡。本领域的普通技术人员将理解，在根据本发明的方法和系统产生泡时，必须保持适当的眼内压以避免对眼部结构的损害。每个单独泡的大小可以是例如约0.5至约1.2ml、约0.8至约1.2ml、约0.9至约1.2ml、约0.9至约1.0ml、约1.0至约2.0ml、约1.0至约3.0ml。因此，在一个实施例中，为了注射总共3ml的分离的多核苷酸、载体和/或药物组合物悬浮液，可以创建3个泡，每个约1ml。组合的所有泡的总体积可为例如约0.5至约3.0ml、约0.8至约3.0ml、约0.9至约3.0ml、约1.0至约3.0ml、约0.5至约1.5ml、约0.5至约1.2ml、约0.9至约3.0ml、约0.9至约2.0ml、约0.9至约1.0ml。
为了安全有效地在泡的原始位置边缘外转导目标视网膜区域(例如，中央视网膜)，可以操纵泡以将泡重新定位到目标区域以进行转导。泡的操纵可以通过由泡的体积产生的泡的依赖性，重新定位包含泡的眼睛、重新定位具有一只或两只包含一个或多个泡的眼睛的人的头部，和/或通过流体-空气交换而发生。这与中央视网膜特别相关，因为该区域通常抵抗视网膜下注射引起的脱离。在一些实施方案中，流体-空气交换用于重新定位泡；来自输液套管的流体暂时被空气(例如，来自吹到视网膜表面上的空气)替代。由于空气体积从视网膜表面置换玻璃体腔流体，玻璃体腔中的流体可能流出套管。来自玻璃体腔流体的压力暂时缺乏导致泡移动并被吸引到眼睛的附属部分。通过适当地定位眼球，操纵视网膜下载体和/或药物组合物的位置的泡以涉及相邻区域(例如，黄斑和/或中央凹)。在某些情况下，即使不使用流体-空气交换，泡的质量也足以使其被吸引。可以通过改变受试者头部的位置来进一步促进泡移动到期望位置，从而允许泡被吸引到眼睛中的期望位置。一旦实现泡的期望构造，流体就会返回玻璃体腔。流体是合适的流体，例如新鲜盐水。通常，视网膜下载体和/或药物组合物可以留在原位而无需对视网膜切开术进行视网膜粘结并且无需眼内填塞，并且视网膜将在约48小时内自发地重新附着。
如本文所用，术语“泡”是指眼睛视网膜下空间内的流体空间。本发明的泡可以通过将流体单次注入单个空间、通过将一种或多种流体多次注入同一空间、或通过多次注入多个空间而产生，泡当重新定位时产生总的流体空间，可用于在视网膜下空间的期望部分上实现治疗效果。
通过用包含治疗性多肽(例如，CRB1-B)的载体安全有效地转导眼细胞(例如，RPE和/或光感受器细胞，例如黄斑和/或中央凹来源)，本发明的方法可用于治疗个体，例如患有眼部病症的人，其中转导的细胞以足以治疗眼部病症的量产生治疗性多肽CRB1-B或RNA序列。
取决于治疗的目的，施用有效量的根据本公开的分离的多核苷酸、载体或药物组合物。例如，在使用其中低百分比转导可以实现期望治疗效果的病毒载体时，治疗的目标通常是达到或超过该转导水平。在一些情况下，这种转导水平可以通过转导仅约1％至5％的靶细胞，在一些实施方案中至少约20％的期望组织类型的细胞，在一些实施方案中至少约50％，在一些实施方案中至少约80％，在一些实施方案中至少约95％，在一些实施方案中至少约99％的期望组织类型的细胞来实现。分离的多核苷酸、载体和/或药物组合物可以通过一次或多次视网膜下注射，在同一个程序中或间隔数天、数周、数月或数年来施用。在一些实施方案中，多种载体可用于治疗人。例如，在一个实施方案中，可以使用多种载体，每种载体编码不同的CRB1同种型或其他视网膜治疗剂。例如，编码CRB1-B的载体可单独或与第二载体组合使用并靶向视网膜内的光感受器细胞，所述第二载体编码选自CRB1-A和CRB1-A2的CRB1同种型并且可靶向视网膜内的米勒细胞。
在一些实施方案中，向视网膜施用有效量的根据本公开的分离的多核苷酸、载体或药物组合物在施用部位处或附近转导光感受器细胞。在一些实施方案中，当使用病毒载体时，超过约5％、10％、15％、20％、25％、30％、35％、40％、45％、50％、55％、60％、65％、70％、75％或100％中的任一者的光感受器细胞掺入了所述分离的多核苷酸或载体并表达了CRB1同种型。在一些实施方案中，当使用病毒载体时，超过约5％、10％、15％、20％、25％、30％、35％、40％、45％、50％、55％、60％、65％、70％、75％或100％中的任一者的光感受器细胞掺入了分离的多核苷酸或载体并表达了CRB1同种型，被转导。在一些实施方案中，约5％至约100％、约10％至约50％、约10％至约30％、约25％至约75％、约25％至约50％、或约30％至约50％的光感受器细胞被靶向(例如，用病毒载体转导)。鉴定由包含载体的AAV病毒颗粒转导或被所述药物组合物靶向的光感受器细胞的方法是本领域已知的，并且包括例如免疫组织化学或在多核苷酸或载体内使用标记物，例如增强的绿色荧光蛋白可用于检测载体或药物组合物的掺入或转导。
在本公开的一些实施方案中，所述方法包括向哺乳动物的视网膜下(例如，视网膜下空间)施用有效量的根据本公开的分离的多核苷酸、载体或药物组合物，用于治疗患有眼部病症的个体，例如患有眼部病症的人。在一些实施方案中，将分离的多核苷酸、载体或药物组合物注射到视网膜下的一个或多个位置以允许多核苷酸在光感受器细胞中表达。在一些实施方案中，将分离的多核苷酸、载体或药物组合物注射到视网膜下中的一个、两个、三个、四个、五个、六个、七个、八个、九个、十个或超过十个位置中的任何一个。
在一些实施方案中，将根据本公开的分离的多核苷酸、载体或药物组合物同时或顺序施用于超过一个位置。在一些实施方案中，分离的多核苷酸、载体或药物组合物的多次注射相隔不超过一小时、两小时、三小时、四小时、五小时、六小时、九小时、十二小时或24小时。
在其他实施方案中，根据本公开的分离的多核苷酸、载体或药物组合物可以玻璃体内施用于受试者。以下简要概述可以说明玻璃体内注射的一般方法。该实例仅意在说明该方法的某些特征，而绝非限制性的。玻璃体内注射的程序是本领域已知的(参见例如Peyman,G.A.等人(2009)Retina29(7):875-912，以及Fagan,X.J.和Al-Qureshi,S.(2013)Clin.Experiment.Ophthalmol.41(5):500-7)。
简而言之，玻璃体内注射的受试者可以通过瞳孔扩张、眼睛的消毒和麻醉剂的施用来准备用于该程序。本领域已知的任何合适的散瞳剂可用于瞳孔扩张。可以在治疗前确认瞳孔充分扩张。可以通过应用眼睛消毒处理剂，例如含有碘化物的溶液，例如聚维酮碘(BETADINETM)来实现消毒。类似的溶液也可用于清洁眼睑、睫毛和任何其他附近的组织(例如皮肤)。可以使用任何合适浓度的任何合适的麻醉剂，例如利多卡因或丙对卡因。麻醉剂可以通过本领域已知的任何方法施用，包括但不限于局部滴剂、凝胶剂或胶冻剂，以及麻醉剂的结膜下应用。
在注射之前，可以使用消过毒的开睑器清除该区域的睫毛。注射部位可以用注射器标记。可以基于患者的晶状体选择注射部位。例如，注射部位可以在假晶状体或无晶状体患者中距角膜缘3-3.5mm，而在有晶状体患者中距角膜缘3.5-4mm。患者可看向与注射部位相反的方向。
在一些实施方案中，所述方法包括向眼睛施用(例如，通过视网膜下和/或玻璃体内施用)有效量的根据本公开的分离的多核苷酸、载体或药物组合物。在一些实施方案中，病毒载体在药物组合物中施用，组合物的病毒滴度为至少约5×1012、6×1012、7×1012、8×1012、9×1012、10×1012、11×1012、15×1012、20×1012、25×1012、30×1012或50×1012基因组拷贝/mL中的任一者。在一些实施方案中，载体和/或药物组合物的病毒滴度为约5×1012至6×1012、6×1012至7×1012、7×1012至8×1012、8×1012至9×1012、9×1012至10×1012、10×1012至11×1012、11×1012至15×1012、15×1012至20×1012、20×1012至25×1012、25×1012至30×1012、30×1012至50×1012或50×1012至100×1012基因组拷贝/mL中的任一者。在一些实施方案中，组合物的病毒滴度为约5×109至10×109、10×109至15×109、15×109至25×109或25×109至50×109转导单位/mL中的任一者。在一些实施方案中，组合物的病毒滴度为至少约5×1010、6×1010、7×1010、8×1010、9×1010、10×1010、11×1010、15×1010、20×1010、25×1010、30×1010、40×1010或50×1010感染单位/mL中的任一者。在一些实施方案中，组合物的病毒滴度为至少约5×1010至6×1010、6×1010至7×1010、7×1010至8×1010、8×1010至9×1010、9×1010至10×1010、10×1010至11×1010、11×1010至15×1010、15×1010至20×1010、20×1010至25×1010、25×1010至30×1010、30×1010至40×1010、40×1010至50×1010或50×1010至100×1010感染单位/mL中的任一者。在一些实施方案中，组合物的病毒滴度为至少约5×1010至10×1010、10×1010至15×1010、15×1010至25×1010或25×1010至50×1010感染单位/mL，或5×1012至10×1012、10×1012至25×1012或25×1012至50×1012基因组拷贝/mL中的任一者。
在一些实施方案中，所述方法包括向个体(例如，人)的眼睛(例如，通过视网膜下和/或玻璃体内施用)施用有效量的根据本公开的载体。在一些实施方案中，施用至个体的载体和/或药物组合物的剂量为至少约1×108至约1×1013基因组拷贝/千克体重中的任一者。在一些实施方案中，施用于个体的载体和/或药物组合物的剂量为约1×108至约1×1013基因组拷贝/千克体重中的任一者。
在注射过程中，针头可以垂直于巩膜插入并指向眼睛的中心。可以插入针，使得尖端终止于玻璃体，而不是视网膜下空间。可以使用本领域已知的用于注射的任何合适的体积。注射后，眼睛可以用消毒剂如抗生素治疗。也可以冲洗眼睛以去除多余的消毒剂。
本公开的其他实施方案提供了一种确定根据本公开的载体或药物组合物的递送有效性的手段。通过视网膜下或玻璃体内注射根据本公开的载体或药物组合物的递送有效性可以通过如本文所述的若干标准来监测。例如，在使用本发明的方法对受试者进行治疗后，可以通过包括本文所述那些的一种或多种临床参数来评估受试者的例如疾病状态的一种或多种体征或症状的改善和/或稳定和/或进展延迟。此类测试的实例在本领域中是已知的，并且包括客观以及主观(例如，受试者报告的)测量。例如，为了测量治疗对受试者视觉功能的有效性，可以评估以下一项或多项：受试者主观视觉质量或改善的中央视觉功能(例如，受试者流利地阅读和识别面孔的能力的提高)、受试者视觉移动性(例如，在迷宫中导航所需的时间减少)、视敏度(例如，受试者Log MAR分数的提高)、微视野检查(例如，受试者dB分数的提高)、暗适应视野测量(例如，受试者dB分数的提高)、精细矩阵定位(例如，受试者dB分数的提高)、Goldmann视野(例如，暗点区域(即失明区域)的尺寸减小和分辨较小目标的能力的提高)、闪烁灵敏度(例如，赫兹的改善)、自发荧光和电生理学测量(例如，ERG的改善)。在一些实施方案中，视觉功能通过受试者的视觉移动性来测量。在一些实施方案中，视觉功能通过受试者的视敏度来测量。在一些实施方案中，视觉功能通过微视野检查来测量。在一些实施方案中，视觉功能通过暗适应视野测量来测量。在一些实施方案中，视觉功能通过ERG来测量。在一些实施方案中，视觉功能通过受试者的主观视觉质量来测量。
在导致进行性退行性视觉功能的疾病的情况下，在早期治疗受试者不仅可以导致疾病进展的减缓或停止，还可以改善或预防由于后天性弱视引起的视觉功能丧失。弱视可能有两种类型。在对从出生到甚至几个月大都处于完全黑暗中的非人类灵长类动物和小猫的研究中，甚至随后暴露在光线下，这些动物在功能上也是不可逆转的失明，尽管视网膜发出了功能信号。这种失明的发生是因为大脑皮层的神经连接和“教育”从出生起就因刺激停滞而在发育上停滞不前。不知道这个功能是否可以恢复。在视网膜变性疾病的情况下，正常的视觉皮层回路最初是“经过学习的”或在发育上适当的，直到变性产生显著的功能障碍为止。在功能失调的眼睛中，就信号传导而言，失去视觉刺激会导致“后天性”或“学习性”功能障碍(“后天性弱视”)，导致大脑无法解释信号或“使用”那只眼睛。在这些“后天性弱视”病例中，除了减缓疾病状态的进展或稳定疾病状态以外，还不清楚由于弱视眼的基因治疗而改善来自视网膜的信号传导是否会导致更正常的功能的获得。在一些实施方案中，接受治疗的人小于30岁。在一些实施方案中，接受治疗的人小于20岁。在一些实施方案中，接受治疗的人小于18岁。在一些实施方案中，接受治疗的人小于15岁。在一些实施方案中，接受治疗的人小于14岁。在一些实施方案中，接受治疗的人小于13岁。在一些实施方案中，接受治疗的人小于12岁。在一些实施方案中，接受治疗的人小于10岁。在一些实施方案中，接受治疗的人小于8岁。在一些实施方案中，接受治疗的人小于6岁。
在一些眼部病症中，存在“营养细胞”现象，其中改善一种类型的细胞的功能会改善另一种类型细胞的功能。例如，通过本公开的分离的多核苷酸、载体和/或药物组合物转导中央视网膜的视网膜色素上皮(RPE)于是可以改善视杆的功能，而改善的视杆功能又导致改善的视锥功能。因此，治疗一种类型的细胞可导致另一种类型细胞的功能的改善。
根据本公开的特定分离的多核苷酸、载体或药物组合物的选择取决于许多不同的因素，包括但不限于人类个体的病史和病症的特征以及被治疗的个体。对这些特征的评估和适当治疗方案的设计最终是处方医师的责任。
如本文所用，术语“个体”、“受试者”和“患者”在本文中可互换使用并且指人和非人动物两者。本公开的术语“非人动物”包括所有脊椎动物，例如哺乳动物和非哺乳动物，例如驯养动物(例如，牛、羊、猫、狗和马)、灵长类动物(例如人和非人灵长类动物，例如猴子)、兔子和啮齿动物(例如，小鼠和大鼠)、两栖动物、爬行动物等。在一些实施方案中，个体或受试者包括人。在某些实施方案中，受试者包括患有眼部病症或有患眼部病症风险的人。
在一些实施方案中，待治疗的受试者患有遗传性眼部病症，但尚未表现出临床体征或症状。在一些实施方案中，待治疗的人患有眼部病症。在一些实施方案中，待治疗的人已表现出眼部病症的一种或多种体征或症状。在一些实施方案中，待治疗的受试者在crb1基因的一个或两个等位基因中具有突变。
“等位基因”是指占据染色体上给定基因座的基因的几种可变形式之一。等位基因的长度可以小到一个核苷酸，但通常更大。如本文所用，“突变”是指基因的DNA序列的改变，使得所述序列不同于在大多数人中发现的序列。突变可以包括一个或多个核苷酸的取代、一个或多个核苷酸的插入、或一个或多个核苷酸的缺失。
在一些实施方案中，眼部病症包括视网膜病变。如本文所用，术语“视网膜病变”是指对眼睛视网膜的任何损伤。该术语通常是指视网膜血管疾病，或由异常血流引起的视网膜损伤。可由本发明的系统和方法治疗的眼部病症或视网膜病变的非限制性实例包括：常染色体隐性重度早发性视网膜变性(莱伯氏先天性黑蒙(Leber's CongenitalAmaurosis))、先天性全色盲、斯塔加特氏病(Stargardt's disease)、贝斯特氏病(Best'sdisease)、多因氏病(Doyne's disease)、视锥细胞营养不良、视网膜色素变性、X相关性视网膜劈裂、亚瑟氏综合征(Usher's syndrome)、年龄相关性黄斑变性、萎缩性年龄相关性黄斑变性、新生血管性年龄相关性黄斑变性(AMD)、糖尿病性黄斑病变、增殖性糖尿病视网膜病变(PDR)、囊样黄斑水肿、中心性浆液性视网膜病变、视网膜脱离、眼内炎症、青光眼、后葡萄膜炎、无脉络膜症和莱伯遗传性视神经病变(Leber hereditary optic neuropathy)。
根据本公开的分离的多核苷酸、载体或药物组合物可以单独使用或与一种或多种用于治疗眼部病症的另外的治疗剂组合使用。顺序给药之间的间隔可以是至少(或者，小于)数分钟、数小时或数天。
在一些实施方案中，一种或多种另外的治疗剂可被施用至视网膜下或玻璃体(例如，通过玻璃体内施用)。另外的治疗剂的非限制性实例包括多肽神经营养因子(例如GDNF、CNTF、BDNF、FGF2、PEDF、EPO)、多肽抗血管生成因子(例如sFlt、血管抑制素、内皮抑制素)、抗血管生成核酸(例如，siRNA、miRNA、核酶)(例如针对VEGF的抗血管生成核酸)、抗血管生成吗啉(例如针对VEGF的抗血管生成吗啉)、抗血管生成抗体和或抗体片段(例如，Fab片段)(例如针对VEGF的抗血管生成抗体和/或抗体片段)。
在另一个实施方案中，所使用的治疗剂可以是待用于眼睛视网膜以恢复细胞损失的干细胞疗法。组合使用的适合干细胞可以是本领域已知的，并且包括施用能够分化成视网膜光感受器细胞的祖干细胞。
在上述方面和实施方案的一些实施方案中，根据本公开的本文所述的分离的多核苷酸、重组载体、分离的多肽或药物组合物通过立体定向递送来递送。在一些实施方案中，根据本公开的分离的多核苷酸、分离的多肽、载体和/或药物组合物通过对流增强递送来递送。在一些实施方案中，根据本公开的分离的多核苷酸、分离的多肽、载体和/或药物组合物使用CED递送系统来施用。在一些实施方案中，套管是抗回流套管或阶梯套管。在一些实施方案中，CED递送系统包括套管和/或泵。在一些实施方案中，根据本公开的分离的多核苷酸、分离的多肽、载体和/或药物组合物使用CED递送系统来施用。在一些实施方案中，泵是手动泵。在一些实施方案中，泵是渗透泵。在一些实施方案中，泵是输液泵。
“有效量”或“治疗有效量”是足以实现有益的或期望的结果，包括临床结果(例如，症状的改善、临床终点的实现等)的量。有效量可以一次或多次给药来施用。就疾病状态而言，有效量是足以改善疾病、稳定疾病或延迟疾病发展的量。
如本文所用，“治疗(treatment)”、“治疗(treating)”、“疗法”和/或“治疗方案”可互换使用并且指获得有益或期望的临床结果的方法。出于本公开的目的，有益的或期望的临床结果包括但不限于症状的缓解、疾病程度的减轻、疾病的稳定(例如，非恶化)状态、防止疾病的传播(例如光感受器和视力的另外丧失)、疾病进展的延迟或减缓、疾病状态的改善或缓和，以及缓解(无论是部分的还是全部的)，无论是可检测的还是不可检测的。“治疗”也可能意味着与如果未接受治疗的预期视力丧失相比延长视力。
如本文所用，术语“预防性治疗”或“防治性治疗”是指治疗，其中个体已知或怀疑患有或处于患有病症的风险中，但还没有表现出病症的症状或仅表现出最小症状。经历预防性治疗的个体可以在症状出现之前进行治疗。在一些实施方案中，可在显示眼病的体征和/或症状之前治疗患有遗传性眼病的受试者。
如本文所用的术语“中央视网膜”是指外黄斑和/或内黄斑和/或中央凹。如本文所用，术语“中央视网膜细胞类型”是指中央视网膜的细胞类型，例如RPE和光感受器细胞。
术语“黄斑”是指灵长类动物的中央视网膜区域，与周边视网膜相比，所述区域包含更高相对浓度的光感受器细胞，特别是视杆细胞和视锥细胞。如本文所用的术语“外黄斑”也可称为“周边黄斑”。如本文使用的术语“内黄斑”也可称为“中央黄斑”。
术语“中央凹”是指灵长类动物中央视网膜中直径约等于或小于0.5mm的小区域，与周边视网膜和黄斑相比，所述区域包含更高相对浓度的光感受器细胞，特别是视锥细胞。
如本文所用的术语“视网膜下空间”是指光感受器细胞和视网膜色素上皮细胞之间的视网膜中的位置。视网膜下空间可以是潜在空间，例如在任何视网膜下注射流体之前。视网膜下空间还可包含注入潜在空间的流体。在这种情况下，流体“与视网膜下空间接触”。“与视网膜下空间接触”的细胞包括与视网膜下空间接壤的细胞，例如RPE和光感受器细胞。
系统和试剂盒：
根据本公开的分离的多核苷酸、载体或药物组合物可包含在被设计用于如本文提供的本公开的方法之一中的系统内。在这些方面，所述系统包括治疗有效量的如本文提供的载体和用于将载体递送至受试者的装置、由其组成或基本上由其组成。
在一些实施方案中，所述系统被设计用于将根据本公开的载体视网膜下递送至个体的眼睛。在其他实施方案中，所述系统被设计用于将根据本公开的载体玻璃体内递送至个体的眼睛。在其他实施方案中，所述系统被设计用于将根据本公开的载体局部递送至个体的眼睛。
一般而言，对于根据本公开的载体的玻璃体内或视网膜下递送，所述系统包括细孔套管(其中所述套管为规格27至45号)、一个或多个注射器(例如1、2、3、4或更多个)以及适用于本公开的方法中的一种或多种流体(例如，1、2、3、4或更多种)。细孔套管适用于视网膜下注射待注射到视网膜下空间中的载体和/或其他流体。在一些实施方案中，套管为规格27至45号。在一些实施方案中，细孔套管为规格35-41号。在一些实施方案中，细孔套管为规格40或41号。在一些实施方案中，细孔套管为规格41号。套管可以是任何合适类型的套管，例如，de-JuanTM套管或EagleTM套管。
注射器可以是任何合适的注射器，只要它能够连接到套管以递送流体。在一些实施方案中，注射器是AccurusTM系统注射器。在一些实施方案中，所述系统具有一个注射器。在一些实施方案中，所述系统具有两个注射器。在一些实施方案中，所述系统具有三个注射器。在一些实施方案中，所述系统具有四个或更多个注射器。
所述系统可以进一步包括自动注射泵，其可以通过例如脚踏板来启动。
适用于本公开的方法中的流体包括本文所述的那些，例如一种或多种各自包含有效量的一种或多种如本文所述的载体的流体、一种或多种用于产生初始泡的流体(例如盐水或其他合适的流体)以及一种或多种包含一种或多种治疗剂的流体。
适用于本公开的方法中的流体包括本文所述的那些，例如一种或多种各自包含有效量的一种或多种如本文所述的载体的流体、一种或多种用于产生初始泡的流体(例如盐水或其他合适的流体)以及一种或多种包含一种或多种治疗剂的流体。
在一些实施方案中，包含有效量的载体的流体的体积大于约0.8ml。在一些实施方案中，包含有效量的载体的流体的体积为至少约0.9ml。在一些实施方案中，包含有效量的载体的流体的体积为至少约1.0ml。在一些实施方案中，包含有效量的载体的流体的体积为至少约1.5ml。在一些实施方案中，包含有效量的载体的流体的体积为至少约2.0ml。在一些实施方案中，包含有效量的载体的流体的体积大于约0.8至约3.0ml。在一些实施方案中，包含有效量的载体的流体的体积大于约0.8至约2.5ml。在一些实施方案中，包含有效量的载体的流体的体积大于约0.8至约2.0ml。在一些实施方案中，包含有效量的载体的流体的体积大于约0.8至约1.5ml。在一些实施方案中，包含有效量的载体的流体的体积大于约0.8至约1.0ml。在一些实施方案中，包含有效量的载体的流体的体积为约0.9至约3.0ml。在一些实施方案中，包含有效量的载体的流体的体积为约0.9至约2.5ml。在一些实施方案中，包含有效量的载体的流体的体积为约0.9至约2.0ml。在一些实施方案中，包含有效量的载体的流体的体积为约0.9至约1.5ml。在一些实施方案中，包含有效量的载体的流体的体积为约0.9至约1.0ml。在一些实施方案中，包含有效量的载体的流体的体积为约1.0至约3.0ml。在一些实施方案中，包含有效量的载体的流体的体积为约1.0至约2.0ml。
用于产生初始泡的流体可以是例如约0.1至约0.5ml。在一些实施方案中，系统中所有流体的总体积为约0.5至约3.0ml。
在一些实施方案中，系统包含单一流体(例如，包含有效量的载体的流体)。在一些实施方案中，系统包含2种流体。在一些实施方案中，系统包含3种流体。在一些实施方案中，系统包含4种或更多种流体。
本公开的系统可以进一步被包装成试剂盒，其中所述试剂盒可以进一步包括使用说明。在一些实施方案中，所述试剂盒还包括用于递送根据本公开的载体的装置。在一些实施方案中，递送包括视网膜下递送。在其他实施方案中，递送包括局部递送。在其他实施方案中，递送包括玻璃体内递送。在一些实施方案中，使用说明包括根据本文所述方法之一的说明。在一些实施方案中，使用说明包括用于视网膜下、玻璃体内和/或局部递送根据本公开的载体的说明。
在另一个实施方案中，本公开提供了一种用于治疗受试者的眼部病症的试剂盒，所述试剂盒包括本文所述的分离的多核苷酸、重组载体、分离的多肽或药物组合物，和用于将分离的多核苷酸、重组载体、或分离的多肽或药物组合物递送至受试者的装置，以及使用说明。在一些实施方案中，用于递送的装置被设计用于视网膜下递送。在另一个实施方案中，用于递送的装置被设计用于玻璃体内递送。在另一个实施方案中，用于递送的装置被设计用于局部递送。
在另一方面，本公开提供了一种用于在受试者中减少视力丧失进展或减少视力丧失或维持视力功能的试剂盒，所述试剂盒包括分离的多核苷酸、重组载体、分离的多肽或药物组合物，和用于将分离的多核苷酸、重组载体、分离的多肽或药物组合物递送至受试者的装置，以及使用说明。在一个优选的实施方案中，试剂盒包括编码CRB1-B的第一载体和编码CRB1-A、CRB1-A2或CRB1-C的第二载体，以及使用说明。
本文所述的试剂盒可以以单一单位剂量或多剂量形式包装。试剂盒的内容物通常配制成无菌且基本等渗的溶液。
本公开的又一方面提供了本文公开和说明的所有内容。
为了促进对本公开的原理的理解，现在将参考优选实施方案并且将使用特定语言对其进行描述。然而，应当理解，本公开的范围并不由此旨在限制，如本文所示出的对本公开的这种改变和进一步修改被认为将是本公开所涉及领域的技术人员通常会想到的。
冠词“一个(a)”和“一个(an)”在本文中用于指代一个或多个(即至少一个)的该冠词的语法对象。举例来说，“一个元素”意味着至少一个元素并且可以包括多于一个元素。
“约”用于通过规定给定值可以“略高于”或“略低于”端点而不影响期望结果来为数值范围端点提供灵活性。
术语“包括”、“包含”或“具有”及其变体在本文中的使用意在涵盖其后列出的元素及其等同物以及附加元素。被描述为“包括”、“包含”或“具有”特定元素的实施方案也被设想为“基本上由那些特定元素组成”和“由那些特定元素组成”。如本文所用，“和/或”是指并涵盖相关所列项目中的一者或多者的任何和所有可能的组合，以及在替代方案(“或”)中解释的组合的缺失。
如本文所用，过渡短语“基本上由……组成”(和语法变体)应被解释为涵盖所列举的材料或步骤“以及对要求保护的发明的基本和新颖特征没有实质性影响的那些材料或步骤”。参见In re Herz,537F.2d 549,551-52,190U.S.P.Q.461,463(CCPA 1976)(强调原文)；还参见MPEP§2111.03。因此，本文使用的术语“基本上由……组成”不应被解释为等同于“包含”。
此外，本公开还预期在一些实施方案中，可以排除或省略在此阐述的任何特征或特征的组合。为了说明，如果说明书规定复合物包含组分A、B和C，则特别意指A、B或C中的任一个或其组合可以被单独地或以任何组合被省略和放弃。
除非本文另外指定，否则本文叙述的值的范围仅旨在用作个别地提及落在所述范围内的每一单独值的速记方法，且每一单独值都被纳入说明书中，就如同其在本文中个别地叙述一样。例如，如果浓度范围被规定为1％至50％，则意图在本说明书中明确列举例如2％至40％、10％至30％、或1％至3％等值。这些仅是具体意图的实例，并且在所列举的最低值和最高值之间并包括所列举的最低值和最高值的所有可能的数值组合都被认为是在本公开中明确陈述的。
除非另外定义，否则本文所用的所有科学术语的含义与本公开所属领域的技术人员通常所了解的含义相同。
对于本领域技术人员来说显而易见的是，在不脱离本发明构思的情况下，除了已经描述的那些之外的许多附加修改是可能的。在解释本公开时，所有术语都应以与上下文一致的最广泛的可能方式进行解释。术语“包括”的变体应被解释为以非排他的方式指代元素、组件或步骤，因此所引用的元素、组件或步骤可以与未明确引用的其他元素、组件或步骤组合。被描述为“包括”特定元素的实施方案也被设想为“基本上由那些特定元素组成”和“由那些特定元素组成”。术语“基本上由……组成”和“由……组成”应按照与MPEP和相关联邦巡回法院一致的方式进行解释。过渡短语“基本上由……组成”将权利要求的范围限定于指定的材料或步骤“以及那些不会对要求保护的发明的基本和新颖特征产生实质性影响的材料或步骤”。“由……组成”是封闭术语，不包括权利要求中未列举的任何元素、步骤或成分。例如，关于序列“由……组成”是指在SEQ ID NO.中列出的序列，并且不是指可能包含SEQ ID作为其一部分的更大的序列。
本文提及的所有出版物、专利申请、专利和其他参考文献以全文引用的方式并入本文中。如有冲突，则以本说明书(包括定义)为准。
本发明的其他特征和优点将从其优选实施方案的描述和权利要求中显而易见。除非另外定义，否则本文所用的所有科学技术术语的含义与本发明所属领域的技术人员通常所了解的含义相同。尽管在本发明的实践或测试中可以使用与本文所述的那些方法和材料相似或等同的方法和材料，但下文描述了合适的方法和材料。此外，材料、方法和实例只是说明性的，不打算构成限制。
实施例
编码细胞表面蛋白的基因控制神经系统发育并与神经系统病症有关。这些基因产生可变mRNA同种型，它们仍然没有得到很好地表征，阻碍了我们对疾病相关突变如何导致病理的理解。在这里，我们介绍了一种揭示由单个基因编码的完整全长同种型组合的策略。我们使用这种策略对多种神经细胞表面分子进行分类，识别出在视网膜和大脑中表达的数千种未注释的同种型。通过质谱法，我们确认了新发现的蛋白质在体内细胞表面上的表达。值得注意的是，我们发现视网膜变性基因CRB1的主要同种型以前被忽视了。这种同种型是光感受器(CRB1疾病中受影响的细胞)表达的唯一同种型。使用小鼠模型，我们鉴定了这种同种型在光感受器-胶质细胞连接处的功能，并证明了这种同种型的丧失会加速光感受器死亡。
材料和方法：
资源和试剂
本研究中使用的所有关键试剂，包括抗体、引物、数据集和动物品系，都列在关键资源表(表1)中。
表1：关键资源。提供本研究中使用的关键试剂和资源的名称和来源，例如抗体、小鼠品系、数据集、引物和化学品。
动物
本研究中小鼠的使用得到了杜克大学机构动物护理和使用委员会的批准。所有实验程序均遵循美国国立卫生研究院实验室动物护理和使用指南中概述的准则。将小鼠圈养在12小时明暗循环下，随意获取食物和水。
基因敲除小鼠产生
对于Crb1delB的产生，CRISPR引导被设计成靶向基因组坐标chr1:139,256,486和139,254,837，并在注射前在基因组DNA上进行体外验证。使用C57Bl6J/SJL F1杂交小鼠家系进行注射；两种品系在Crb1基因座处均为野生型(即它们不携带rd8)。使用PCR引物对创始小鼠进行基因分型以区分等位基因(引物序列见表1)。保留了两个具有基因组缺失的创始小鼠家系。一个携带缺失139,254,836–139,256,488(Δ1,652bp)加上两个额外的胞嘧啶，另一个携带139,254,836–139,256,488(Δ1,652bp)。两个等位基因都有效地缺失了Crb1-B的整个第一个外显子和启动子区域，并且目前在表型上无法区分。对于Crb1null的产生，CRISPR引导物被设计成靶向基因组坐标chr1:139,256,486–139,243,407，并在注射前在基因组DNA上进行体外验证。使用C57Bl6J/SJL F1杂交小鼠家系进行注射，并使用PCR引物(表1)对创始小鼠进行基因分型以区分等位基因。保留了两个具有基因组缺失的创始小鼠家系。一个携带缺失chr1:139,256,844–139,243,411(Δ13,433bp)，另一个携带139,257,194–139,243,411(Δ13,783bp)。除了Crb1-A的外显子6和部分外显子7之外，两个等位基因都有效地缺失了Crb1-B的整个第一个外显子和启动子区域。这种缺失将消除外显子7剪接受体，并预计将完全排除外显子7。从外显子5至8(如在Crb1-A中)和4至8(如在Crb1-A2中)的剪接将导致移码。外显子6之后的Crb1-C-特异性保留内含子也完全缺失。在分析之前，创始动物与C57Bl6J小鼠回交至少两代，并进行基因分型以确保它们不携带来自SJL背景的rd1突变。本研究中产生的动物将对于研究界是可获得的，用于非商业用途。
人视网膜组织
人类供体眼睛来自Miracles in Sight(Winston Salem,NC)，由BioSight(DukeUniversity Shared Resource)根据机构审查委员会协议#PRO-00050810分配。将死后的人类供体眼睛摘除并储存在冰上的PBS中直至解剖。从后极解剖视网膜并进行RNA分离。有视网膜疾病史的供体被排除在研究之外。
CRB1-B抗体
我们使用Pierce Custom抗体服务(Thermo Fisher Scientific)产生CRB1-B特异性抗体。抗原是CRB1-B的最后16个氨基酸(RMNDEPVVEWGAQENY；SEQ ID NO:53)，预计这些氨基酸在蛋白质水平上是该同种型独有的。根据90天方案在兔中制备抗体，初始接种后进行3次加强。对该抗体进行亲和纯化，并使用Crb1delB敲除对照通过蛋白质印迹法进行验证。CRB1-B产生大约150kDa的条带，大于110kDa的预测大小。实验大小与预测大小的这种差异可能是由于翻译后修饰，例如糖基化，因为添加PNGase F降低了条带大小(未显示)。本研究中产生的抗体将对于研究界是可获得的，用于非商业用途。
RNA提取
对于PacBio测序实验和qRT-PCR，使用C57Bl6/J小鼠。小鼠用异氟烷麻醉或冷冻麻醉(仅限新生小鼠)，然后斩首。摘除眼睛并切出视网膜，或从头骨上切下大脑并移除大脑皮层。根据制造商的方案，使用Tri Reagent(ThermoFisher Scientific AM9738)分离总RNA。组织在Tri Reagent中机械均质化，然后通过氯仿和异丙醇沉淀进行相分离。RNA样品储存在-80℃。使用生物分析仪计算RIN值。只有高于9的RIN值用于测序。
小鼠样品的PacBio文库制备
根据制造商的方案，使用Clontech SMARTer cDNA试剂盒进行逆转录。使用KAPAHiFi DNA聚合酶将cDNA扩增12个循环，然后进行大小选择(4.5至10Kb)。为了捕获，将1μgcDNA变性并用DTT引物和Clontech引物封闭，然后与Nimblegen的SeqCap EZ Developer(≤200Mb)定制诱饵在47℃下混合20小时。生物素化cDNA用链霉亲和素珠子下拉并用Nimblegen杂交缓冲液洗涤，以使非特异性结合最小化。使用Takara LA Taq将靶向cDNA文库扩增11个循环。构建SMRT bell文库，然后进行额外的大小选择(4.5至10Kb)，然后将聚合酶与P6-C4化学品(RSII)结合。使用MagBead加载以80pM(RSII)将文库加载到SMRT单元上。对于PacBio Sequel文库，使用聚合酶2.0版对测序引物2.1版进行退火和结合。结合的复合物用PB Ampure珠子清洗，并通过扩散以6pM加载，预延伸120分钟。
用于人类视网膜的PacBio文库制备
根据制造商的方案，使用Clontech SMARTer cDNA试剂盒进行逆转录。使用PrimeStar GXL聚合酶将cDNA扩增14个循环，然后进行Blue Pippin大小选择(4.5至10Kb)。为了捕获，使用1μg变性cDNA，然后与Twist定制探针在70℃下孵育20小时。生物素化cDNA用链霉亲和素珠子吸引下来并用Twist杂交缓冲液洗涤，以减少非特异性结合。使用Takara LATaq将靶向cDNA文库扩增11个循环，产生650ng用于文库制备的富集cDNA。使用SMRTbellTemplate Prep Kit(SMRTbell模板制备试剂盒)1.0后处理核酸外切酶进行文库制备，随后进行Blue Pippin大小选择(4Kb至50KB)。后大小选择产生了120ng DNA。使用聚合酶2.0版对测序引物3.0版进行退火和结合。结合的复合物用PB Ampure珠子清洗，并通过扩散以6pM加载到PacBio Sequel仪器上。
PacBio原始数据的处理
Iso-Seq软件用于原始PacBio数据的初始后处理。对于lrCaptureSeq实验，使用ConsensusTools.sh从PacBio原始读段生成插入读段，参数--minFullPasses 1--minPredictedAccuracy 80--parameters/smrtanalysis/current/analysis/etc/algorithm_parameters/2014-09/。根据全长插入物的读段，使用pbtranscript.pyclassify和以下参数生成非嵌合读段(FLNC读段)：min_seq_len 500，并且除了3’引物之前的聚腺苷酸尾巴之外还存在5’和3’Clontech引物。对于Megf11 PCR产物测序，参数相同，除了全长读段通过Megf11特异性引物序列(5'GGCTCCGGGGTATAGGA(SEQ ID NO:54)；对于Megf11长形式，3’序列为CTGGCTGCATTGCATTGG(SEQ ID NO:55)，或者对于Megf11短形式，3’序列为GGTGTCCAATAAAGTC(SEQ ID NO:56))的存在来区分。
同种型水平聚类
使用ToFU将FLNC读段聚类为同种型，ToFU由两部分组成：1)同种型水平聚类算法ICE(用于纠错的迭代聚类)，用于生成一致性同种型；和2)Quiver，用于完善一致性同种型。使用ToFU_wrap脚本生成转录同种型，参数--bin_manual"(0,4,6,9,30)"--quiver--hq_quiver_min_accuracy 0.99(对于Megf11 PCR数据，为0.98)。这生成了具有≥99％校正后准确度(对于Megf11 PCR数据，≥98％)的高质量全长转录本。使用GMAP(版本1.3.3b)将同种型与小鼠基因组mm10对齐，默认值是对齐精度(0.85)和覆盖率(0.99)。为了防止基于5'端长度的过度聚类，通过折叠所有共享完全相同的外显子结构的转录本来去除冗余簇。为了最小化截断的mRNA可能对膨胀同种型数目的影响，我们设置了≥2个独立的全长读段的阈值，这些读段必须聚类在一起才能定义同种型。
为了生成整个同种型目录，使用Iso-Seq(版本3)的聚类函数和默认参数分析了完整的数据集(所有时间点、视网膜和皮质)。只有来自每个实验的最高质量的全长读段(≥99％准确度或QV≥20)被传递到此分析。在Iso-Seq结束时，我们确定了30个基因的8,287个同种型。将HQ读段定位到基因组(小鼠为mm10，人类为hg19)Cupcake ToFU(github.com/Magdoll/cDNA_Cupcake)以进一步减少同种型细分的过度聚类。
最后，使用我们的IsoPops软件对假定的虚假同种型进行了额外过滤。这种过滤的目的是去除基因组DNA中因cDNA截断或多聚腺苷酸错误引发而产生的伪影。在下面描述软件包的部分中提供了过滤方法的细节。应用这些过滤器产生了4,116种同种型的最终目录。我们没有排除包含非规范拼接的同种型，因为许多这样的同种型非常丰富；然而，即使它们被排除在外，总体同种型计数也只会略微减少(图10C)。
最终的同种型目录不仅说明了同种型的数目，还说明了对于每个同种型获得的全长读段的数目。我们已经为我们的一些分析报告了这些读段计数(例如图2C、E；图3B、D)。这些数据有助于了解特定基因的整体表达如何在其同种型组合中分布。我们避免了对特定同种型的表达水平下结论，除非PacBio数据得到独立的短读长RNA-seq数据的支持(例如图5D、G、H、I)。
IsoPops R软件包
我们开发了一套R软件，方便分析和查看PacBio转录组序列输出。IsoPops R软件包允许用户对他们自己的长读长数据执行本研究中描述的许多分析。
该软件包提供以下特征。首先，它允许过滤截断的和虚假的同种型以有助于下游分析。其次，它显示外显子使用图，使用户能够直观地比较同种型的差异。第三，它生成的图总结了单个基因内和整个数据集内同种型的表达水平。这些包括树状图(图2E)和洛伦兹图上的一个变体，我们称之为水母图(图2C)。第四，它对相似的同种型进行聚类，并在各种降维图(例如系统树图和3维PCA图)中显示数据。第五，它提供了汇总统计数据，例如基因同种型的长度分布或每个同种型中使用的外显子数目。最后，它执行互相关，使用户能够询问某些外显子是否倾向于一起出现在相同的转录本中。与这些特征相关的方法描述如下。
过滤
IsoPops同种型过滤过程由3个步骤组成：首先，去除包含少于n个外显子的转录本。在我们的研究中，n设置为4，因为我们不对数据集中的基因预期任何如此短的同种型。为了定量外显子数目，我们没有参考外显子注释，而是将非连续基因组片段的数目(或拼接点的数目加1)定义为每个同种型的外显子计数。这个过滤步骤去除了由基因组多聚腺苷酸错误引发而产生的大多数虚假转录本，因为这些序列通常定位到单个“外显子”。
其次，我们过滤掉了截断伪影。为了鉴别截断的同种型，我们开发了一种算法，旨在尽可能彻底地过滤而不丢弃潜在有价值的独特转录本。特别是，我们希望保留所有独特的剪接事件并适度地容忍独特的转录起始位点(TSS)和转录终止位点(TTS)。该算法比较同种型对A和B的外显子边界集合(受体和供体剪接位点的坐标)，并应用以下两个规则。规则1：如果B中的所有外显子边界形成A中外显子边界的连续子集，则B是A的截断。我们要求该子集是连续的，以避免过滤带有保留内含子的转录本。规则2：如果满足以下所有3个条件，则B是A的截断。1)B的TSS落在A的外显子内；2)B的TTS要么在A中发现，要么在基因的3'端外显子之内/之外；3)B的内部外显子边界(即不包括B的最5'和最3'外显子边界)是A的连续子集。
第三，过滤掉每个基因中丰度最低的5％同种型，这基于这些极低丰度的同种型可能构成实验或生物噪音的假设。
皮尔逊相关
此功能使得能够分析跨同种型的外显子共现。给定基因中的每个同种型都用一系列二进制值标记，所述二进制值代表在其cDNA序列中调用的外显子。通过搜索转录本中每个外显子的前30bp或后30bp的精确匹配来确定外显子调用。外显子定义来源于PacBioisofom GFF文件。在计算外显子调用之间的成对皮尔逊相关之前，同种型通过它们的全长读段计数进行加权。
K聚体向量化
IsoPops能够定量同种型之间的序列差异。为了定量同种型之间的相对差异，我们计算了每个同种型的cDNA序列(或其预测的ORF氨基酸序列)的向量化之间的欧氏距离。我们使用text2vec R软件包为每个同种型生成向量，其中向量中的每个元素等于某个k聚体(序列片段)在同种型中出现的次数。我们计算了同种型中所有可能的6聚体，选择k＝6以最大化同种型之间的k聚体计数唯一性，而不需要过多的计算资源。然后将每个同种型的k聚体计数向量标准化为总和为1，因此从这些向量计算的同种型距离不会受到转录本之间长度差异的支配。
同种型聚类
为了对同种型进行聚类，我们计算了同种型的k聚体计数向量化之间的成对欧氏距离。然后，我们使用默认设置和“完全”聚集方法使用R基础算法hclust执行分层聚集聚类。聚类的系统树图由dendextend R软件包生成。
降维
直接对k聚体计数向量化执行PCA和t-SNE。我们使用R基础算法prcomp以默认设置进行PCA。对于t-SNE，我们运行了Rtsne软件包的针对精确t-SNE的算法(θ＝0，最大迭代次数＝1000，困惑度＝35)，其包括一轮PCA用于数据预处理。t-SNE结果绘制在与算法输出相同数目的维度上(即3D t-SNE图是使用ndim＝3生成的)。
洛伦兹(水母)图
对每个基因的同种型独立计算累积百分比丰度。首先，对整个基因的全长读段计数进行标准化，并标记为“百分比丰度”。接下来，给定基因的同种型按百分比丰度降序排列。最后，通过按降序对百分比丰度进行部分求和，计算每个同种型的累积百分比丰度。然后沿y轴按此顺序绘制同种型，并根据沿x轴的累积百分比丰度进行定位。
ORF预测
Sqanti67用于PacBio同种型的ORF预测和基因组校正。
RNA-seq分析
从NCBI GEO下载RNA-seq fastq文件，并且数据用Hisat2(2.1.0版)定位到参考数据集mm10(用于小鼠)、hg19(用于人类)、bosTau8(牛)、danRer11(斑马鱼)和rn6(大鼠)。数据集GSE101986和GSE74660用Cufflinks(2.2.1版)量化。数据集GSE94437、GSE101544、GES49911和GSE84932用StringTie(1.3.3b版)量化。同种型定量分析的所有参考注释都是使用30个基因中每一者的前3个最丰富的同种型从相应的参考GTF文件中生成的，这些文件与Iso-Seq GFF输出是合并的。
来自RNA-seq数据的同种型预测
使用没有参考程序集的Cufflinks(2.2.1版)或Stringtie(1.3.3b版)对RNA-seq数据集GSE101986和GSE79416执行同种型的计算预测。使用Cuffmerge合并生成的程序集以创建最终参考程序集。使用Sqanti执行数据集之间的同种型匹配。如果同种型被Sqanti确定为“完全剪接匹配”，则它们被认为是匹配。所有其他同种型都被认为是不匹配的。
lrCaptureSeq同种型与其他数据库的匹配
Sqanti用于验证公共数据库中的同种型，以及Cufflinks/Stringtie预测的同种型数据库。使用参考GTF(来自计算程序集、NCBI RefSeq或UCSC Genes)作为输入进行验证。如果同种型与参考“完全剪接匹配”，则它们得到验证。所有其他同种型被认为是不同的。
验证lrCaptureSeq同种型的剪接点和5'端
使用Sqanti软件评估RNA-seq数据对PacBio同种型的拼接覆盖率。对于Sqanti的拼接输入文件是使用STAR(STAR_2.6.0a)通过将小鼠视网膜和皮质RNA-seq数据(GSE101986和GSE79416)定位到mm10基因组生成的，使用由PacBio GFF输出制作的自定义索引。拼接被分类为规范(GT-AG、GC-AG和AT-AC)或非规范(所有其他组合)。
来自成年小鼠视网膜的CAGE RNA-seq数据(DRA002410；样品Sham1、Sham2和Sham3)使用Hisat2与基因组(mm10)对齐。使用BedTools(2.29.2版)确定lrCaptureSeq同种型的外显子1处的读段覆盖率。使用Qualimap(2.2.1版)进行跨标准化同种型长度的CAGE数据覆盖。
染色质可及性
公开可用的ATAC-seq数据用于评估小鼠和人类视网膜中的染色质可及性(即推定的启动子位点)68–70。来自ENCODE项目的DNAse I超敏数据用于评估小鼠皮质71。所有原始fastq文件均从SRA或来自ENCODE数据门户的对齐bam文件下载。使用fastqc(0.11.3版)和trim galore(0.4.1版)修剪读段，并使用bowtie2(2.2.5版)定位到mm9或hg19基因组。根据质量(>Q30)过滤对齐的bam文件并去除线粒体和黑名单区域。使用deeptools(3.1.0版)将文件转换为bigwigs，并在IGV(2.4.16版)中进行可视化。来自同一个实验的所有轨道都进行了分组缩放。
香农多样性指数
香农指数使用R软件包Vegan(https://github.com/vegandevs/vegan)根据以下等式计算
H'＝-∑p i ln pi
其中pi是在基因中发现的同种型的比例(pi＝ni/N)，ni是同种型i的读段数，N是基因的总读段数。
Sashimi图
Sashimi图是使用Gviz(1.24.0版)和由PacBio生成的GFF文件生成的。用于该图的读段是通过使用GMAP(2014-09-30版)将PacBio FLNC.fastq(≥85％准确度)文件定位到基因组(mm10，hg19)生成的。因为FLNC读段具有相对较高的错误率并且这些错误率还没有像在我们的最终数据集中那样被过滤掉，并且因为表达因基因而异，所以每个图的最小拼接覆盖率是可变的。最小拼接覆盖率对于Crb1小鼠视网膜设置为60，对于Crb1皮质设置为4，对于人CRB1设置为11，对于Megf11设置为4。
scRNA-seq
使用CellRanger(v3.0,10X Genomics)将分析小鼠视网膜发育的原始scRNAseq数据48与自定义的mm10小鼠基因组/转录组对齐。mm10参考基因组和转录组是从10X Genomics下载的，并且修改了GTF文件以将主要的Crb1同种型(Crb1-A和Crb1-B)鉴别为独立基因。由于CellRanger计数功能仅考虑唯一定位到单个基因的对齐，因此输出文件仅报告在独立3'外显子内定位或从最远端的最后一个共享外显子剪接到这些外显子中的读段。
随后完全按照先前报告的方式分析数据48。基于原稿中的分类，这项新分析的每个细胞条形码都被分配到一个细胞类型。Monocle(v3.0)72,73和自定义R脚本用于数据可视化和绘图。
BaseScope原位杂交
摘除眼睛并从眼杯上切下视网膜，在PBS中洗涤，并在补充有4％甲醛的PBS中在室温下固定24小时。视网膜在补充有30％蔗糖的PBS中在4度下通过渗透平衡过夜进行冷冻保护。将视网膜包埋在组织冷冻培养基中，并在用干冰冷却的2-甲基丁烷中快速冷冻。在Thermo Scientific Microm HM 550低温恒温器上将视网膜切向切片切成18μm，并粘附在Superfrost Plus载玻片上。
针对剪接点设计探针以检测各种剪接事件(序列见表1)。使用Red检测试剂盒进行探针检测。根据制造商的方案且稍作修改，进行BaseScope原位杂交。固定冷冻视网膜在60℃的烘箱中烘烤1小时，然后用标准固定冷冻预处理条件继续操作，但存在以下例外：预处理2中的孵育减少到2分钟，并且预处理3减少到13分钟，在室温下。将BaseScope探针添加到组织并在40℃下杂交2小时。用洗涤缓冲液洗涤载玻片，并使用Red Singleplex检测试剂盒检测探针。通过与一抗孵育过夜，在探针检测后进行免疫染色。对于Megf11 BaseScope，α-钙结合蛋白抗体用于标记星爆型无长突细胞和水平细胞。组织用PBS洗涤3次，添加二抗并在室温下孵育1小时。再次洗涤载玻片并安装盖玻片。
K562细胞中CRB1同种型的表达
标记的CRB1构建体是通过在CRB1-A和CRB1-B的C端在框内克隆YFP来构建的。标记的构建体被克隆到pCAG-YFP质粒(Addgene#11180)中。
K562细胞(
CCL-243TM)从ATCC获得、通过ATCC验证和通过ATCC测试支原体。细胞在含有10％牛生长血清、4.5g/L D-葡萄糖、2.0mM L-谷氨酰胺、1％青霉素/链霉素的达尔伯克氏改良伊格尔培养基(Dulbecco's Modified Eagle Medium，DMEM)中在10cm细胞培养皿中培养。细胞每2-3天传代一次，然后达到200万个细胞/ml。按照K562核转染手册中的说明，使用
Cell Line
Kit V转染细胞。具体而言，通过在Eppendorf管中在室温下以200Xg离心5分钟，将100万个细胞的等分试样沉淀。上清液完全，并且细胞沉淀悬浮于每份样品100μl
溶液中。添加2μg质粒DNA(pCAG:Crb1A-YFP、pCAG:Crb1B-YFP或pCAG:YFP)并与悬浮细胞轻轻混合。将细胞和DNA混合物转染到比色皿中，插入
Cuvette Holder，并用程序T-016转染。程序完成后，将比色皿从支架中取出，并立即添加500μl预平衡的培养基。然后将这些转染的细胞分开并转移到24孔玻璃底培养皿(MatTek Corporation)的两个孔中。细胞在转染后24小时用倒置共聚焦显微镜(尼康)成像。
视网膜薄切片和电子显微术
用异氟烷麻醉小鼠，然后斩首。用低温烧灼法标记上层视网膜以跟踪方位。将眼睛摘除并在室温下在Glut Buffer(40mM MOPS、0.005％CaCl2、2％甲醛、2％戊二醛的H2O溶液)中固定过夜。在解剖时标记背腹轴，以便随后可以在薄切片中鉴别上层和下层视网膜。将眼睛转移到含有PBS的新管中用于4℃储存，直到准备包埋。
对于薄切片，将角膜从眼杯中取出，并将眼杯浸入0.1％二甲胂酸盐缓冲液中的2％四氧化锇中。然后将眼杯脱水并包埋在Epon 812树脂中。通过视神经乳头从上视网膜到下视网膜切制0.5μm的半薄切片。切片用1％亚甲蓝复染，并在Olympus IX81亮场显微镜上成像。
对于电子显微术，如所述74对组织进行处理和成像。简而言之，在徕卡超薄切片机上修剪远周边视网膜并制备65-75μm切片。切片由每个视网膜的上半部分和下半部分分别制备，并用2％醋酸双氧铀+3.5％柠檬酸铅溶液复染。在配备Orius 1000相机的JEM-1400电子显微镜上进行成像。
视网膜核计数
视网膜半薄切片在Olympus IX81亮场显微镜上用60X油镜平铺扫描，并用cellSens软件缝接在一起。使用Fiji软件75，从视神经乳头到上视网膜和下视网膜的周边绘制了一条分割线。以500μm的间隔，绘制四个100μm的盒子来包裹外核层，使得盒子的中心是距视神经乳头500μm的因子。对于视网膜的每个半球，制作了四个盒子。使用ImageJ中的计数功能，在每个位置对每个盒子所封装的核总数进行计数。对每个位置之间的计数取平均值，并对所述计数以及针对每个视网膜的所有8个测量值的总计数制图。
通过电子显微术评估OLM连接
在电子显微镜上评估包括一个视网膜半薄切片的约90％(远周边视网膜在切片过程中被修剪)的每个切片的OLM间隙。对每个潜在间隙都成像，随后通过评估成像光感受器的内段上电子致密OLM连接的存在来离线确认间隙。使用Fiji软件定量每个切片的间隙数目以及每个间隙的大小。为了定量和统计，野生型和null/+杂合对照被分组在一起，因为两种基因型都没有显示任何OLM间隙。
使用蛋白质印迹法的视网膜连续切片
如所述50,51进行连续切片。简而言之，用异氟烷麻醉小鼠，然后斩首。摘除眼睛并在冰冷的林格氏液中解剖。用手术环钻从眼杯上切下视网膜穿孔(直径2mm)，位置邻近视盘，转移到PVDF膜上，光感受器层朝上，平坦安装在由塑料垫片(约240μm)隔开的两个载玻片之间并在干冰上冷冻。视网膜表面与低温恒温器的切割平面对齐，并修剪掉不平整的边缘。收集10-μm或20-μm的渐进切向切片——取决于切片的终点(分别是光感受器或内视网膜)。
蛋白质组学
视网膜胰蛋白酶胞外域提取
用异氟烷麻醉幼年P14小鼠，然后斩首。将眼睛摘除并在林格氏液(154mM NaCl、5.6mM KCl、1mM MgCl2、2.2mM CaCl2、10mM葡萄糖、20mM HEPES)中从眼杯中切出。将视网膜置于含有5μg胰蛋白酶/lys-c的100μl林格氏液中。具有视网膜的溶液在室温下孵育10分钟，同时定期温和混合。然后将内容物以300×G离心1.5分钟，并将上清液转移到新管中。将尿素添加到蛋白质混合物中至8M，然后在50℃下孵育。孵育1小时后，添加DTT至终浓度为10mM，并在50℃下孵育15分钟。通过添加3.25μl的20mM碘乙酰胺使肽烷基化，并在室温下避光孵育30分钟。通过添加DTT至50mM终浓度来淬灭反应。混合物用约270μl碳酸氢铵按1:3稀释。通过在37℃下添加1μg胰蛋白酶/lys-c进一步消化混合物过夜。
细胞表面蛋白标记和下拉
基于所描述的方案76进行膜蛋白的细胞表面标记。用异氟烷麻醉小鼠，然后斩首。摘除眼睛，并在冰冷的HBSS中从眼杯切下视网膜。用HBSS洗涤视网膜，然后在冰上在补充有EZ-Link磺基_NHS-SS-生物素(HBSS中0.5mg/ml)的HBSS中孵育45分钟。然后用HBSS+100μM赖氨酸洗涤视网膜3次以淬灭剩余的反应性酯。然后将视网膜收集在400μl(200μl/视网膜)裂解缓冲液(1％Triton X-100、20mM Tris、50mM NaCl、0.1％SDS、1mM EDTA)中。使用超声波仪上的短脉冲使视网膜均质化。裂解物在4℃下以21,000×G离心20分钟，并收集可溶性级分。对于免疫沉淀，将75μg蛋白质裂解物与100μl链霉亲和素磁珠(PierceTM)混合，并在室温下在旋转的同时孵育。使用磁铁分离链霉亲和素/生物素复合物并用裂解缓冲液洗涤。通过与洗脱缓冲液(含0.1％SDS 100mM DTT的PBS)在50℃下孵育30分钟，从珠子上洗脱蛋白质。实验样品(输入、富含生物素和非生物素标记的阴性对照)与4×SDS-PAGE样品缓冲液混合，并在90℃在加热块上孵育10分钟。然后将样品加载到4-15％mini PROTEAN TGX免染蛋白质凝胶上。在65V下通过堆叠凝胶进行电泳，然后调节至100V，直到染料前沿到达凝胶末端。
凝胶内胰蛋白酶消化
电泳后，凝胶用H2O洗涤两次，用50％甲醇、7％乙酸固定20分钟，并用基于胶体考马斯的GelCode Blue Stain试剂(Thermo Fischer Scientific，目录号24590)染色30分钟。凝胶在摇动的同时用蒸馏水在4℃下脱色2小时。蛋白质条带在Bio-Rad ChemiDocTouch成像仪上成像。使用干净的剃须刀片，切下75-250kDa之间的条带，切成约1×1mm的碎片并收集在0.5ml硅化(低保留度)离心管中。凝胶片用200μl脱色溶液(50mM碳酸氢铵，NH4HCO3溶于50:50乙腈:水中)在37℃振荡脱色30分钟。去除溶液并用200μl脱色溶液代替，并再次在37℃振荡孵育30分钟。从凝胶片中去除溶液，并在60℃下用20μl的含20mM DTT的50mM碳酸氢铵缓冲液(pH 7.8)还原肽15分钟。通过添加50μl烷基化缓冲液(含50mM碘乙酰胺的碳酸氢铵缓冲液)将半胱氨酸烷基化，并在室温下避光孵育1小时。从管中移除烷基化缓冲液并用200μl脱色缓冲液代替。样品在37℃振荡孵育30分钟，去除缓冲液，并再次用脱色缓冲液洗涤。凝胶片用75μl乙腈脱水并在室温下孵育15分钟。从管中移除乙腈，并将收缩的凝胶片晾干15分钟。将胰蛋白酶/lys-c(5ng/μl，在25μl碳酸氢铵缓冲液中)添加到凝胶片中并在室温下孵育1小时。将额外的25μl碳酸氢铵缓冲液添加到管中，并在37℃孵育过夜。用蒸馏水使样品体积达到125μl，并将含有胰蛋白酶化肽的液体放入干净的硅化0.5ml管中。
为质谱生成lrCaptureSeq肽文库
Sqanti软件用在从视网膜样品的Iso-seq输出上，以预测同种型的ORF和氨基酸序列。使用具有默认设置的python程序trypsin在计算机中对氨基酸序列进行胰蛋白酶化。遵循脯氨酸规则，如果赖氨酸或精氨酸紧接在脯氨酸之前，则不会切割赖氨酸或精氨酸。
视网膜样品的质谱分析
使用与Synapt G2 HDMS质谱仪(Waters Corp,Milford,MA)偶联的nanoAcquityUPLC系统，通过LC-MS/MS分析2μl等分试样的胰蛋白酶消化物。肽最初被捕获在180μm×20mm Symmetry C18柱上(在99.9％水、0.1％甲酸中以5μl/min的流速流动3分钟)。然后在填充有1.7μm C18 BEH树脂(Waters)的75μm×150mm柱上使用6至30％乙腈梯度和0.1％甲酸以0.3μl/min的流速在35℃进行肽分离90分钟。使用10μm PicoTip发射器(Waters)在3.0kV电压下将洗脱的肽喷射到Synapt G2的离子源中。
使用离子迁移率工作流程对每个样品进行数据独立分析(HDMSE)，以同时进行肽定量和鉴定。为了在所有HDMSE运行中对单个肽进行稳健的峰检测和比对，我们使用Progenesis QI软件对代表相同质量/保留时间特征的离子色谱峰进行了自动比对。为了对离子特征执行肽分配，使用PLGS2.5.1(Waters)生成可搜索文件，这些文件被提交到整合入用于蛋白质学的Progenesis QI中的IdentityE搜索引擎。对于肽鉴定，我们搜索了上述Iso-Seq自定义数据库。为了鉴定新的肽，所有鉴定的肽都与UniProtKb小鼠数据库进行了交叉引用。使用蛋白质和肽Prophet软件(Scaffold 4.4)和诱饵数据库-反向小鼠UniProt2016数据库确定蛋白质和肽的错误发现率。蛋白质和肽的FDR分别低于1％和5％。为了区分新发现的肽和含有翻译后修饰的已知肽，我们使用最常见的蛋白质修饰进行了额外的数据库搜索，这些蛋白质修饰包括S、T和Y处的磷酸化；E处的谷氨酰化；K处的乙酰化；D和E处的甲基化。未发现潜在的错误鉴定。
蛋白质印迹
来自同窝野生型小鼠和Crb1突变小鼠的视网膜在400μl裂解缓冲液中进行短暂的超声处理和涡旋，所述裂解缓冲液含有2％SDS于PBS溶液中加蛋白酶抑制剂混合液(cOmplete；罗氏)。裂解物在22℃下以20,000xg离心10分钟，收集上清液并通过DC蛋白质测定试剂盒(Bio-Rad)测定总蛋白质浓度。使用裂解缓冲液调整体积，已通过总蛋白质浓度以将裂解物标准化，然后添加含有400mM DTT的4×SDS-PAGE缓冲液并在90℃下加热裂解物10分钟。对等体积的各自含有15μg总蛋白质的裂解物进行SDS-PAGE，并将蛋白质转移到聚偏二氟乙烯膜(Bio-Rad)上。膜在Odyssey封闭缓冲液(LiCor Bioscience)中封闭，并与适当的一抗和Alexa Fluor 680或800偶联二抗(Invitrogen)一起孵育。蛋白质条带由OdysseyCLx红外成像系统(LiCor Bioscience)成像。
为了分离可溶性和不溶性蛋白质，小鼠视网膜在冰上在300μl水中进行了短暂的超声处理和低渗冲击。裂解的视网膜悬浮液在4℃下以20,000xg离心20分钟，收集所得上清液，并用水冲洗沉淀一次。沉淀和上清液在最终体积为400μL的裂解缓冲液中重构，所述裂解缓冲液含有2％SDS、1×PBS和蛋白酶抑制剂混合液(cOmplete；罗氏)。这些裂解物的等体积等分试样如上所述用于蛋白质印迹。
数据可及性
长读长测序数据可在NCBI BioProject存储库中获得(登录号PRJNA547800)。表2说明了lrCaptureSeq数据集中Crb1的所有同种型的序列、基因组位置和读段编号。
质谱蛋白质组学数据已通过PRIDE合作伙伴存储库存放在ProteomeXchangeConsortium中，数据集标识符为PXD017290(DOI：10.6019/PXD017290)。
代码可及性
IsoPops代码可在kellycochran.github.io/IsoPops/index.html获得，根据GNUGeneral Public License v3.0获得许可。
结果：
通过长读长捕获测序对同种型进行编目的工作流程
为了对CNS细胞表面分子的同种型多样性进行编目，我们首先手动筛选了来自小鼠视网膜和大脑的RNA-seq数据38,39，以鉴别显示出显著未注释mRNA多样性的基因。我们专注于表皮生长因子(EGF)、免疫球蛋白(Ig)和粘附G蛋白偶联受体超家族的细胞表面受体，因为这些基因在细胞-细胞识别中具有许多已知作用。对于每个筛选的基因(n＝402)，我们评估它是否在CNS发育过程中表达，并且如果是的话，则评估RNA-seq读段是否支持未注释的外显子或剪接点的存在(图1A)。我们发现约15％的基因(60/402)显示出多个未注释特征的有力证据。这些基因被选为长读长测序的候选基因。
为了全面鉴别这些基因的转录本，我们针对大cDNA(>4kb)和中等表达的cDNA，例如我们候选基因列表中的那些，开发了一种方法来提高PacBio测序深度。我们将这种策略称为长读长捕获测序(lrCaptureSeq)，因为我们调整了先前的CaptureSeq方法31,32,40以实现使用长读长PacBio平台对蛋白质编码cDNA进行表征。在lrCaptureSeq(图1B、C)中，生物素化探针被设计为在不跨越剪接点的情况下平铺已知外显子，以避免使捕获的转录本池偏向特定的同种型。这些探针用于从经过大小选择以过滤截断cDNA的文库中下拉cDNA。在初步实验中，我们发现大小选择对于获得全长读段至关重要(图9A)，因为较短的片段往往会主导测序输出15。
为了实施lrCaptureSeq，我们首先将60个候选者的初始列表过滤到30个，这些30个候选者预计编码相似长度(4-8kb)的cDNA。最终的目标列表包括参与轴突引导、突触发生和神经元-神经胶质相互作用的基因；它还包括视网膜疾病基因Crb1，该基因与遗传性光感受器变性有关。一些靶基因已知会产生许多同种型(Nrxn1、Nrxn3)，但在大多数情况下，同种型多样性以前还没有被表征。当在PacBio平台上对捕获的cDNA进行测序时，每个实验产生了约132,000个全长读段(图9C)。这些读段针对目标基因得到了大程度富集(图9B)，并且绝大多数读段都在目标长度范围内(图1C)。因此，lrCaptureSeq可以实现对其他长读长数据集中代表性不足的较大cDNA的深度全长覆盖。
lrCaptureSeq生成的综合性同种型目录
为了对跨发育和跨CNS区域的所有30个基因的同种型进行编目，我们在小鼠视网膜和大脑的不同时间点进行了lrCaptureSeq(图1C；图9C)。使用PacBio Iso-Seq软件以及我们为分析同种型群体(isoform populations)而开发的定制软件(IsoPops；https://github.com/kellycochran/IsoPops)，确定了同种型的数目和包含其的读段。在此处理流程之后，lrCaptureSeq目录包含30个目标基因的4,116个同种型(图2A、B；表2)——大约比公共数据库中当前为该基因集注释的同种型数目大一个数量级(图2B)。它也远高于流行的短读长转录组组装软件预测的同种型数目(图10A)。只有9％的lrCaptureSeq同种型出现在我们检查的任何数据库中，这表明它们中的大多数是新颖的。
为了确保这些新颖的同种型是真实的，我们使用独立的数据集来验证它们的转录起始位点和外显子拼接。使用基因表达帽分析(CAGE)鉴别起始位点，CAGE是一种用于鉴别与5'帽相关的序列的短读长方法41。来自成年小鼠视网膜的CAGE-seq读段42证实了由lrCaptureSeq鉴别的转录起始位点中的97.5％(1051/1078成年小鼠视网膜同种型在其5'末端具有CAGE-seq覆盖；图9D)。此外，CAGE-seq读段选择性地定位到lrCaptureSeq同种型的5'端(图9D、E)，进一步支持我们转录起始位点注释的准确性。为了验证剪接点，我们首先验证了绝大多数(98.9％)的lrCaptureSeq外显子拼接发生在规范剪接位点上(n＝80,590个拼接)。接下来，我们测试了来自视网膜和大脑的短读长数据集中lrCaptureSeq外显子拼接的存在38,39。绝大多数(98.1％)的lrCaptureSeq拼接(n＝79,020)都得到了这些短读长数据集的证实，提供了对其有效性的独立确认。这包括对于71％的lrCaptureSeq同种型(n＝2,925)的完整拼接覆盖。未被确认的拼接可能由于低表达水平而在RNA-seq数据中不存在，因为未显示完全覆盖的同种型的丰度明显较低(图10B)。与这种解释一致，未经确认的拼接可以通过RT-PCR产物的测序检测到，这表明它们仅低于RNA-seq检测阈值(通过RT-PCR检测到n＝9/12在Megf11基因中不存在的RNA-seq拼接)。总之，这些分析有力地支持了我们的lrCaptureSeq同种型目录的有效性。
通过lrCaptureSeq有效检测同种型
为了探索同种型检测的准确性和灵敏度，我们将我们的lrCaptureSeq数据与之前对Nrxn1和Nrxn3基因的同种型多样性进行编目的长读长测序研究进行了比较。在这些研究中，PCR用于生成α和β类Nrxn转录本的同种型文库，然后使用PacBio测序15,16对其进行表征。尽管文库制备方法和生物信息学工作流程完全不同，但我们鉴定的Nrxn1和Nrxn3同种型的总数在规模上与之前的研究(图2A)相似。选择性剪接位点(AS)1-AS4中的外显子使用模式也相似(数据未显示)。例如，在之前的工作中鉴定的一个确定性AS4剪接事件(其中Nrxn3外显子24总是与外显子25a剪接)在我们的数据中得到证实(n＝76个含有外显子24的同种型，全部与外显子25剪接)。这些发现表明我们的Nrxn 1和3同种型目录与过去的研究生成的目录基本匹配。尽管如此，我们能够找到之前目录中没有提出的neurexin基因的新特征。由于我们的方法未因PCR引物放置而有偏重，因此我们发现了不包含规范α或β转录本起始/终止位点的同种型。例如，我们的Nrxn3α读段中有64％包含独特的第一个外显子，位于加长5'UTR的带注释的α转录起始位点的上游。此外，我们鉴定了7个新颖的转录终止位点，由16种不同的Nrxn3α同种型使用，这些转录终止位点截断了跨膜结构域上游的mRNA(数据未显示)。用来自RNA-seq数据的拼接覆盖证实了所有这7个新位点。总之，这些发现证明了lrCaptureSeq在高效恢复同种型多样性方面的效用。
许多同种型有助于整体基因表达
鉴于在我们的lrCaptureSeq数据集中鉴别出大量同种型，我们接下来试图了解同种型多样性对基因功能影响的程度。要使多样性在功能上具有重要意义，必须满足两个条件：1)单个基因的多个同种型应该在有意义的水平上表达；和2)同种型的序列必须有足够的差异以编码功能差异。为了研究同种型表达水平，我们评估了每个基因的整体表达在其同种型组合中如何分布(图2C、E；图10D)。一些基因——例如，Egflam和Crb1——由少数同种型主导。然而，对于具有最大数目的同种型的基因，表达水平在同种型之间的分布要平衡得多(图2C、E)。使用香农多样性指数43，我们根据基因表达的mRNA种类的多样性对基因进行排序。已知Nrnx3产生广泛的多样性，是排名最高的基因。然而，蜘蛛毒素亲和蛋白(latrophilin)和蛋白酪氨酸磷酸酶受体(PTPR)家族的几个其他基因的得分几乎一样高(图2D)。因此，Nrxn3在表达大量同种型方面远非独一无二。我们得出的结论是，对于我们数据集中的基因，大部分同种型多样性都以可观的水平表达。
lrCaptureSeq同种型的预测的功能多样性
我们接下来研究了我们数据集中每个基因的同种型之间的序列差异程度。30个基因中的大多数编码的同种型在外显子的长度和数目上差异很大(图10E、F)，表明具有巨大功能多样性的潜力。为了鉴别最有可能在功能上发散的同种型，使用无监督聚类方法根据它们的序列相似性对同种型进行分组(图2F、G；图10G)。对于大多数基因，同种型聚类成相关同种型的不同组，这些相关同种型在可变mRNA元件中做出相似的选择(图2F、G)。因此，单个基因的同种型组合内存在主要的序列差异，这可以追溯到相关同种型家族纳入特定的外显子序列。
为了了解这些序列差异是否可能使蛋白质输出多样化，我们分析了预测的开放阅读框(ORF；表2)。发现我们数据集中的4,116种同种型中有一半以上包含独特的ORF(2,247；54.6％)。基因的一小部分表达了很大的mRNA多样性，但没有等效的ORF多样性(图3A)；这主要是由于5'UTR的变化或系统内含子保留(图11C、D)。然而，总体而言，同种型的数目与预测的ORF的数目之间存在很强的相关性(图3A)。表达的ORF多样性的数量因基因而异；但与mRNA相似，大量这种预测的蛋白质多样性以可观的水平表达(图3B-D；图11A、B)。值得注意的是，具有最多ORF多样性的基因倾向于编码特定类型的细胞表面蛋白：香农多样性指数靠前的基因都编码跨突触粘附分子(图3C)。这一结果表明mRNA多样性的一个主要功能是产生蛋白质变体，这些蛋白质变体被定位成影响突触连接的形成或稳定性。
为了确定mRNA多样性是否对蛋白质序列有显著影响，我们研究了单个基因的预测蛋白质输出。在许多情况下，预测的蛋白质在包括充分表征的特征或功能结构域方面存在很大差异。这种现象以Megf11基因为例，该基因编码与视网膜发育过程中的细胞-细胞识别有关的跨膜EGF重复蛋白44。Megf11受制于广泛的选择性剪接：在26个蛋白质编码外显子中，21个是选择性剪接的(81％)。事实上，我们在三个独立的长读长测序实验中在234个Megf11同种型中仅记录了10个组成型剪接点(图4A、B；图12)。对预测蛋白质的检查揭示了这种广泛剪接的潜在原因：大多数包含胞外结构域的EGF重复序列由单个外显子编码，因此选择性剪接导致它们以模块化方式部署(图4A-D)。胞内结构域外显子在使用ITAM或ITIM信号基序时也显示出模块化的潜力(图4A-D)，类似于其果蝇同源物Draper的情况45。由于这种模块化组织，预测的MEGF11蛋白在包含的EGF重复序列的数目和/或身份显示出显著可变性(图4D)。最可变的EGF重复序列由外显子14-16b编码(图4B)；然而，大多数EGF重复序列都受制于可变使用。使用BaseScopeTM原位杂交46,47，我们证实最可变的外显子拼接中的每一个都是由体内视网膜神经元表达的(图4E)。值得注意的是，发现单个表达Megf11的细胞使用我们测试的所有外显子拼接，这表明即使在单个神经元内也存在广泛的Megf11同种型多样性(图4E)。因此，与昆虫Dscam1类似，Megf11使用模块化胞外结构域特征的选择性剪接来创建编码不同细胞表面分子的同种型大家族。连同我们对完整lrCaptureSeq数据集的分析，这些发现有力地表明同种型多样性有助于体内神经元细胞表面蛋白质组的多样化。
lrCaptureSeq预测的细胞表面蛋白在发育中的视网膜中表达
为了确定新颖的lrCaptureSeq同种型是否被翻译成蛋白质，我们对从发育中的视网膜获得的细胞表面蛋白质样品进行了质谱分析。使用裂解或生物素化胞外表位的细胞不可渗透试剂捕获细胞表面蛋白(图3E、F)。为了了解任何捕获的肽是否来自新颖的蛋白质同种型，我们生成了一个来源于lrCaptureSeq目录中同种型的可能胰蛋白酶肽产物的数据库。这是必不可少的，因为蛋白质鉴定需要将原始质谱数据与参考肽数据库进行比较。在生成这个新的预测肽数据库时，我们发现对于我们的30个基因，该数据库包含的推定肽比大多数蛋白质组学实验中通常使用的UniProt小鼠参考数据库多约25％(图11E)。额外的推定肽代表lrCaptureSeq所预测的新颖蛋白质区域。
使用这个新数据库作为参考，我们发现了与28个基因相对应的686个总肽。UniProt标准参考中不存在这些肽中的35种，它们仅存在于我们的新参考数据库中(图3G)。该部分代表从我们的lrCaptureSeq同种型目录预测的新肽，它们在典型的质谱实验中不会检测到。对于我们的30个基因中的14个发现了新肽，验证了新的外显子序列、剪接点和剪接受体位点(数据未显示)。这些发现表明，至少一些预测的蛋白质在体内视网膜细胞表面上表达。因此，我们在此描述的mRNA多样性有助于视网膜细胞表面蛋白质组的多样性。
lrCaptureSeq数据库中最丰富的转录本是Crb1的新型同种型
为了研究新发现的同种型是否可以提供对基因功能的了解，我们重点研究了众所周知的视网膜疾病基因Crb1。我们的Crb1目录包含15种同种型，其中一些是组织特异性和发育调节性的(图5A、B；图13B、C)。在成熟的视网膜中，Crb1的表达由单一同种型主导，但所述同种型并不是几乎所有以前Crb1研究的主题。相反，主导同种型是一种视网膜特异性变体，其具有独特的5'和3'外显子(图5A、D；图14A)和恰好位于新5'外显子上游的独特启动子位点(图5C)。我们将此同种型命名为Crb1-B，以区别于典型的Crb1-A同种型。
尽管Crb1-B是我们数据集中的4,116种同种型中最丰富的(图2D)，但它并未在主要基因组数据库(RefSeq、GENCODE或UCSC)中进行注释。据我们所知，文献中也没有记载。CRB1-B也是人类视网膜中最丰富的同种型，如由人类视网膜cDNA生成的lrCaptureSeq数据集所示(图5E、G)。第三种变体CRB1-C也在人类视网膜中以中等水平表达——远高于小鼠——但它仍然不如CRB1-B丰富(图5E、G)。与小鼠一样，ATAC-seq数据揭示了人类视网膜中推定的B同种型启动子(图5C、F)。使用短读长数据集，我们证实了小鼠和人类的发现，然后将它们扩展到其他几种脊椎动物物种(图5H、I；图13A)。总之，这些结果表明，以前忽略了一个重要疾病基因的主要视网膜同种型：在一系列脊椎动物物种中，CRB1-B是视网膜中主要的CRB1同种型。
Crb1-A和Crb1-B编码在不同细胞类型中表达的细胞表面蛋白
预测Crb1-B编码与CRB1-A具有显著的细胞外结构域重叠，但却具有完全不同的细胞内结构域的跨膜蛋白(图6A、B)。因此，我们询问该蛋白质是否被表达，如果是，则该蛋白质位于何处。使用针对CRB1-B细胞内结构域的抗体进行的蛋白质印迹证明该蛋白质存在于体内(图6C)。此外，它以lrCaptureSeq预测的构造存在(图6A)，因为在改造为缺乏Crb1-B启动子和5'外显子的小鼠中不存在胞内结构域表达(图6C；关于小鼠设计请参见图7A)。与CRB1-B是跨膜蛋白的概念一致，它在膜级分中被检测到，但在视网膜裂解物的可溶性级分中未检测到(图6D)。此外，当在异源细胞中表达时，CRB1-B以与CRB1-A非常相似的方式行进至质膜(图14C)。这些数据表明两种主要的CRB1同种型都位于细胞表面。
为了确定Crb1-A和Crb1-B的表达模式，我们开发了一种评估单细胞(sc)-RNA-seq数据集中的lrCaptureSeq同种型表达的策略。将此策略应用于来自发育中的小鼠视网膜的scRNA-seq数据48，我们发现了每种同种型的不同表达模式。Crb1-A主要由米勒胶质细胞表达(图6E、F；图14D)，与之前的免疫组织化学研究一致37,49。相比之下，Crb1-B由视杆细胞和视锥细胞表达(图6E、F；图14B、D)。使用两种独立的方法验证了这些细胞类型特异性表达模式：首先，来自视杆细胞和视锥细胞的ATAC-seq数据显示光感受器选择性地使用Crb1-B启动子(图5C)。其次，BaseScope染色证实了这两种同种型的互斥表达，其中Crb1-A定位于米勒细胞，Crb1-B定位于光感受器(图6G)。
为了检查CRB1-B蛋白定位，我们最初尝试免疫组织化学，但发现我们的抗体不合适。因此，我们转向了一种将视网膜的连续切向冷冻切片与蛋白质印迹相结合的技术50,51。每个切向切片都包含一个特定的细胞和亚细胞结构子集，其可以被代表性蛋白质标记物识别(图6H)。这种方法证实了CRB1-B在光感受器层中的表达，主要是在内段和外段内。这种定位与CRB1-A形成鲜明对比，CRB1-A已使用对该同种型具有特异性的抗体定位到米勒细胞的顶端，在OLM内(图6E)37,49。
CRB1-B是外界膜完整性所必需的
我们接下来研究了CRB1-B同种型的功能。光感受器和米勒胶质细胞是表达主要CRB1同种型的两种细胞类型(图6F、G)，它们参与形成OLM的特化细胞-细胞连接(图6E；图7B、C)。有人提出CRB1疾病的变性病理学可能是由于这些连接的破坏造成的，但小鼠研究未能阐明CRB1实际上是否是OLM完整性所必需的。两种现有的Crb1突变系具有相互冲突的OLM表型：携带被称为rd8的Crb1点突变的小鼠显示出零星的OLM破坏36，而Crb1“敲除”等位基因(此处表示为Crb1ex1)没有干扰OLM连接37。我们的lrCaptureSeq数据揭示了这两个等位基因之间的关键差异：rd8影响Crb1-A和Crb1-B同种型，而“敲除的”ex1等位基因使Crb1-B完好无损(图7A)。因此，我们假设Crb1-B在OLM处的光感受器-米勒细胞连接的完整性中起关键作用。为了验证这一假设，我们生成了两个新的突变等位基因(图7A；图15A、B)。第一个是Crb1delB，它消除了Crb1-B，同时保留了包括Crb1-A在内的其他同种型。第二个是Crb1null，它是被设计成破坏所有Crb1同种型的大型缺失。
使用电子显微术评估OLM的完整性，我们发现Crb1null突变体在OLM处表现出破坏，从而光感受器细胞核侵入内段层，扰乱了外层视网膜的结构(图7B-E；图15D)。在被破坏的区域内，光感受器内段缺乏与米勒顶突的特征性电子致密连接，表明OLM间隙是由于光感受器-米勒细胞接触的破坏而产生的(图7F)。如先前报道的36，在Crb1rd8突变体中也观察到类似的表型(图7F、G、J；图15D-F)。为了探索每种同种型对OLM表型的贡献，我们检查了携带Crb1null和Crb1delB等位基因的各种组合的小鼠。在缺乏Crb1-B但保留两个Crb1-A拷贝的Crb1delB/delB小鼠中，OLM表型仍然明显，但比rd8或null纯合子弱(图7H、J)。相比之下，OLM表型在缺乏Crb1-B但保留了一个Crb1-A拷贝的Crb1delB/null小鼠中相当于rd8和null突变体(图7E、J；图15F)。这些发现表明，OLM连接完整性需要两种Crb1同种型，但Crb1-B的作用尤为重要，因为即使Crb1-A仍然存在，也会出现严重的OLM破坏。
缺乏所有Crb1同种型的小鼠中的视网膜变性
最后，我们询问是否可以使用对CRB1同种型的了解来改善CRB1变性疾病的动物模型。在现有的Crb1功能丧失小鼠中，光感受器变性不存在或极其缓慢，使它们成为人类变性表型的不良模型36,37,52。我们假设以前未注释的Crb1同种型例如Crb1-B可能有助于解释这些温和的表型。与这种可能性一致，我们注意到现有的Crb1突变等位基因都没有完全消除所有Crb1同种型(图7A)。为了测试新的Crb1同种型对光感受器变性的贡献，我们利用了我们新生成的Crb1delB和Crb1null系(图7A)。对年轻成年小鼠(P100)的光感受器数目的分析揭示，光感受器存活需要Crb1-A和Crb1-B同种型两者。Crb1delB突变体具有正常的光感受器数目(图8A、D；图15C)，类似于先前报道的Crb1ex1突变体37。因此，单独去除任一主要同种型的变性效应最小。相比之下，在Crb1null小鼠中缺失所有同种型导致显著的光感受器变性(图8A-D)。因此，显著的细胞损失需要Crb1-A和Crb1-B两者的妥协。在P100时在Crb1rd8突变体中还没有明显的变性(图8B-D)，与之前的报道一致，即显著变性需要大约2年36,52,53。总之，这些遗传实验支持了以下结论：多种Crb1同种型有助于光感受器的存活——包括新的Crb1-B同种型。因此，人类疾病的建模可以通过由lrCaptureSeq同种型目录指导的突变等位基因的合理设计来实现。
讨论：
尽管测序技术最近取得了进展，但CNS转录物组的真正多样性仍然令人惊讶地模糊不清12。对于大多数基因，仅记录了完整同种型组合的一小部分。在这里，我们展示了lrCaptureSeq可以以前所未有的细节水平揭示同种型多样性。LrCaptureSeq准确且高效，具有足够的深度来揭示甚至是低丰度同种型的全长序列。为了便于解释lrCaptureSeq数据，我们提供了配套的R软件包，用于分析和可视化同种型目录。将这些新工具应用于发育中的神经系统，我们发现了编码细胞表面蛋白的大量同种型，其中大部分是新的。许多被预测会改变功能性蛋白质结构域。此外，我们发现我们整个数据集中最丰富的同种型——Crb1疾病基因的一种新型同种型——具有与经典同种型不同的表达模式和功能，赋予它与疾病相关的功能。因此，CRB1用作全面全长同种型鉴定价值的一个突出实例。我们建议lrCaptureSeq可用于为许多不同的CNS区域和细胞类型生成全长同种型目录，这是一种可能会开启对CNS基因功能和功能障碍的许多新见解的方法。
同种型鉴定需要显著的测序深度。即使使用短读长RNA-seq，也可能只对于丰度最高的基因才能检测到完整的同种型组合，考虑到最低丰度的44％的转录本仅获得1％的读数31,54。靶向CaptureSeq方法已被用于改进低丰度转录本的短读长检测31,55。在这里，将这种策略应用于蛋白质编码mRNA的长读长测序，我们获得了一组基因的深度全长覆盖，这些基因在现有的PacBio转录组中没有被很好地表示，这归因于它们的cDNA大小和表达水平。从同种型丰度的分布(图2C)可以清楚地看出，只有丰度最低的同种型逃脱了检测。考虑到我们的文库制备方案的大小选择步骤，一些小于4.5kb的同种型也可能避开了检测(图1B)。由于这些原因，我们怀疑我们没有检测到每个最后的同种型。然而，即使我们对长转录本进行了富集，我们仍然获得了较短读段的大型样品(图10E)并鉴定了许多较小的同种型——包括Crb1-B(3.0kb)。因此，虽然lrCaptureSeq目录可能缺乏某些短和/或罕见的转录本，但我们得出结论，我们已经检测到在我们的靶向组织中表达的大多数同种型。我们通过靶向30个基因进行平行测序实现了这一深度，但现在可以使用更高通量的PacBio仪器；这些应该允许在不牺牲同种型覆盖率的情况下平行测序明显更多的靶向基因。
我们的结果表明lrCaptureSeq在转录组注释中的许多潜在用途。一个特别令人兴奋的例子是鉴定细胞类型特异性同种型表达模式。我们表明lrCaptureSeq数据可以与现有的短读长RNA-seq数据集(包括单细胞数据)整合，以揭示同种型表达的时间和地点。到目前为止，由于大多数单细胞文库制备方法中固有的3'偏差，这种表达作图最适用于3'末端不同的同种型。未来，随着scRNA-seq方法经过改进以提高深度和覆盖率，我们预计其他类型的同种型也可以通过这种方式进行作图。使用这种方法，无需为神经系统中的每种细胞类型生成lrCaptureSeq目录；相反，通过组合不同类型的测序数据，可以通过生物信息学确定细胞类型特异性同种型表达。
任何给定的基因会产生多少mRNA同种型？对于我们数据集中的30个基因，RefSeq同种型的中位数为11.5，并且没有基因超过51。相比之下，我们的lrCaptureSeq目录中同种型的中位数为50，而最多样化的基因Nrxn3接近900。总体而言，lrCaptureSeq同种型的数目超过了参考转录组中注释的数目近一个数量级(图2B)。相比之下，之前对长的非编码RNA的CaptureSeq研究只发现了两倍多的同种型40。因此，尽管人们普广泛认可大多数基因会产生多种同种型，但我们发现的细胞表面分子的多样性规模仍然令人惊讶。我们的30个基因可能比平均基因具有更多的同种型，它们被选中是因为它们显示出转录本多样性的证据(图1A)。这种多样性是否是其他基因类别和其他组织的典型特征仍有待确定——或许是通过lrCaptureSeq方法的更广泛应用来确定。
长期以来，人们一直怀疑细胞表面蛋白的广泛多样性可能与精确神经元连接的形成有关5,8,56。然而，最近有人质疑是否需要大量细胞表面线索57。在这种观点下，只有在某些选择的环境中才需要广泛的多样性，例如在由Dscam1和成簇的原钙粘蛋白介导的自我与非自我识别期间58,59。在这里，我们表明广泛的同种型多样性在许多细胞表面受体基因中广泛存在，并且单个神经元很可能表达某些基因的多种同种型(例如Megf11；图4E)。因此，“众多线索”模型的分子先决条件已经到位。引人注目的是，具有最多预测蛋白质多样性的基因具有共同的功能，作为跨突触细胞粘附分子(图3C)。许多这些基因在突触形成中具有已知的作用19,60,61。因此，这些不同的分子线索可能位于恰好正确的位置，以影响突触连接的精确度。了解这里描述的同种型在突触特异性中发挥作用的程度将是令人关注的。
Dscam1同种型多样性的一个显著特征是Ig重复序列的模块化部署以调节结合特异性。其他具有细胞外结构域基序模块化交换的同等高潜力的基因以前尚未被鉴别。在这里，我们展示了Megf11通过EGF样重复序列的广泛模块化应用使其细胞外结构域多样化，Megf11是一种在视网膜发育过程中介导同型细胞-细胞排斥的识别分子44。对于Netrin-G蛋白，之前已经观察到通过选择性剪接进行模块化EGF重复序列交换的现象，尽管规模较小62。因此，可能的是许多EGF重复基因会使用类似的模块化策略产生大家族的细胞表面蛋白。
我们对CRB1的研究说明了记录单个基因的完整同种型输出的价值和重要性。CRB1是遗传性视网膜变性疾病的主要致病基因，这些疾病包括莱伯氏先天性黑蒙、视网膜色素变性和黄斑营养不良63–65。因此，小鼠Crb1和人CRB1都得到了深入研究。尽管如此，成熟人类视网膜中的主要CRB1同种型——CRB1-B——已避开检测，直到如今。CRB1-B可能因为它的5’和3’外显子是转录本中唯一将其与CRB1-A区分开来的部分而一直被忽略了。使用短读长测序，很难告知这两个远距离外显子通常在同一个转录本中一起使用。相比之下，lrCaptureSeq清楚地表明，最丰富的视网膜CRB1同种型是包含这些非常规5’和3’外显子的新型变体。
由于它们不同的5’和3'端(图6A)，Crb1-A和-B在关键方面不同，这可能赋予它们不同的功能。它们的5’外显子具有不同的启动子，可驱动不同细胞类型中的表达——米勒胶质细胞中的Crb1-A和光感受器中的Crb1-B——而它们的3'外显子编码不同的细胞内结构域。与果蝇Crumbs的其他脊椎动物同源物一样，CRB1-A细胞内结构域包含两个高度保守的基序，它们介导与称为Crumbs复合物的极性蛋白的相互作用66。这些基序将Crumbs同源物定位到顶端连接处，在那里它们是维持上皮结构完整性和顶端-基底极性所必需的33。CRB1-B缺乏这些保守的基序，表明CRB1-A和-B通过不同的细胞内相互作用配对物在不同的细胞类型中运作的模型。
我们的研究结果对CRB1疾病的流行模型有影响，该模型假定CRB1和Crumbs复合物是米勒胶质细胞和光感受器之间的OLM连接完整性所必需的26。该模型的一个主要挑战一直是在缺乏CRB1-A的Crb1ex137突变体中缺乏OLM表型或光感受器变性(图7A)。由于该突变小鼠被认为是空白(null)等位基因，其弱表型表明CRB1可能对于小鼠的光感受器存活是非必要的26。在这里，我们表明CRB1确实是OLM完整性和光感受器存活所要求的，但该机制在很大程度上涉及光感受器特异性的CRB1-B同种型。此外，我们表明了两种同种型之间的遗传相互作用，揭示了Crb1ex1突变株中隐藏的CRB1-A的OLM完整性和促存活功能。我们提出，CRB1-A在胶质细胞中和CRB1-B在光感受器中的协同作用控制着OLM完整性和光感受器健康，这可能是通过在每个相应细胞类型中组装或维持连接蛋白复合物来实现的。
协同的Crb1-A和Crb1-B功能的概念由Crb1rd8比Crb1ex1表现出更多的变性这一事实进一步支持36,37,53，Crb1rd8是一种影响两种同种型的点突变(图7A)。然而，Crb1rd8显然不如Crb1null严重(图8)，即使A和B同种型在两个突变体中都受到影响。这种差异的一个可能原因是Crb1rd8可能不是mRNA或蛋白质空白的53。另一种可能性是Crb1-C同种型可能起到补偿作用，因为它不受Crb1rd8的影响(图7A)。无论哪种方式，我们的结果都表明，当完整的同种型目录可用时，小鼠疾病模型的设计得到显著增强。
总体而言，我们的工作突出了构建完整且准确的全长同种型目录的价值。缺乏此类信息会导致关键基因功能被忽视，并可能导致对遗传实验和疾病表型的误解。我们预计，深度长读长捕获测序提供的转录组学“基本事实”将成为转录组注释工具箱的重要补充，使得能够发现促成一系列正常和疾病过程的特定mRNA同种型。
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62.Yin,Y.,Miner,J.H.&Sanes,J.R.《Laminet：在不同的神经元亚群中表达的层粘连蛋白和网蛋白相关基因(Laminets:laminin-and netrin-related genes expressedin distinct neuronal subsets.)》Mol.Cell.Neurosci.19,344–58(2002).
63.den Hollander,A.I.等人《果蝇crumbs的人类同源物的突变导致视网膜色素变性(RP12)(Mutations in a human homologue of Drosophila crumbs causeretinitis pigmentosa(RP12).)》Nat.Genet.23,217–21(1999).
64.den Hollander,A.I.等人《莱伯氏先天性黑蒙和视网膜色素变性伴涂层样渗出性血管病变与Crumbs同源物1(CRB1)的突变相关(Leber Congenital Amaurosis andRetinitis Pigmentosa with Coats-like Exudative Vasculopathy Are Associatedwith Mutations in the Crumbs Homologue 1(CRB1))》Gene.Am.J.Hum.Genet.69,198–203(2001).
65.Khan,K.N.等人《CRB1相关性黄斑病变的临床和分子表征(A clinical andmolecular characterisation of CRB1-associated maculopathy.)》Eur.J.Hum.Genet.26,687–694(2018).
66.den Hollander,A.I.等人《CRB1具有在人类和果蝇之间功能保守的细胞质结构域(CRB1 has a cytoplasmic domain that is functionally conserved betweenhuman and Drosophila.)》Hum.Mol.Genet.10,2767–2773(2001).
67.Tardaguila,M.等人《SQANTI：长读长转录本序列的广泛表征，用于全长转录组鉴定和定量的质量控制(SQANTI:extensive characterization of long-readtranscript sequences for quality control in full-length transcriptomeidentification and quantification.)》Genome Res.28,396–411(2018).
68.Aldiri,I.等人《视网膜在发育、重编程和肿瘤发生过程中的动态表观遗传景观(The Dynamic Epigenetic Landscape of the Retina During Development,Reprogramming,and Tumorigenesis.)》Neuron 94,550-568.e10(2017).
69.Hughes,A.E.O.,Enright,J.M.,Myers,C.A.,Shen,S.Q.&Corbo,J.C.《细胞类型特异性表观基因组分析揭示了小鼠视杆细胞中独特的闭合染色质结构(Cell Type-Specific Epigenomic Analysis Reveals a Uniquely Closed Chromatin Architecturein Mouse Rod Photoreceptors.)》Sci.Rep.7,43184(2017).
70.Wang,J.等人《ATAC-Seq分析显示，在年龄相关性黄斑变性中染色质可及性普遍降低(ATAC-Seq analysis reveals a widespread decrease of chromatinaccessibility in age-related macular degeneration.)》Nat.Commun.9,1364(2018).
71.Davis,C.A.等人《DNA元件百科全书(ENCODE)：数据门户更新(TheEncyclopedia of DNAelements(ENCODE):data portal update.)》Nucleic AcidsRes.46,D794–D801(2018).
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序列表
<110> 杜克大学
J·凯
T·雷
<120> 用于诊断和治疗视网膜病变的组合物和方法
<130> 155554.00531
<150> 62/813,272
<151> 2019-03-04
<160> 100
<170> PatentIn version 3.5
<210> 1
<211> 1003
<212> PRT
<213> 智人
<400> 1
Met Phe Gly Ala Arg Thr His Gly Phe His Ile Leu Met Ala Met Leu
1 5 10 15
Ile Gly Ile His Cys Glu Glu Asp Val Asn Glu Cys Ser Ser Asn Pro
20 25 30
Cys Gln Asn Gly Gly Thr Cys Glu Asn Leu Pro Gly Asn Tyr Thr Cys
35 40 45
His Cys Pro Phe Asp Asn Leu Ser Arg Thr Phe Tyr Gly Gly Arg Asp
50 55 60
Cys Ser Asp Ile Leu Leu Gly Cys Thr His Gln Gln Cys Leu Asn Asn
65 70 75 80
Gly Thr Cys Ile Pro His Phe Gln Asp Gly Gln His Gly Phe Ser Cys
85 90 95
Leu Cys Pro Ser Gly Tyr Thr Gly Ser Leu Cys Glu Ile Ala Thr Thr
100 105 110
Leu Ser Phe Glu Gly Asp Gly Phe Leu Trp Val Lys Ser Gly Ser Val
115 120 125
Thr Thr Lys Gly Ser Val Cys Asn Ile Ala Leu Arg Phe Gln Thr Val
130 135 140
Gln Pro Met Ala Leu Leu Leu Phe Arg Ser Asn Arg Asp Val Phe Val
145 150 155 160
Lys Leu Glu Leu Leu Ser Gly Tyr Ile His Leu Ser Ile Gln Val Asn
165 170 175
Asn Gln Ser Lys Val Leu Leu Phe Ile Ser His Asn Thr Ser Asp Gly
180 185 190
Glu Trp His Phe Val Glu Val Ile Phe Ala Glu Ala Val Thr Leu Thr
195 200 205
Leu Ile Asp Asp Ser Cys Lys Glu Lys Cys Ile Ala Lys Ala Pro Thr
210 215 220
Pro Leu Glu Ser Asp Gln Ser Ile Cys Ala Phe Gln Asn Ser Phe Leu
225 230 235 240
Gly Gly Leu Pro Val Gly Met Thr Ser Asn Gly Val Ala Leu Leu Asn
245 250 255
Phe Tyr Asn Met Pro Ser Thr Pro Ser Phe Val Gly Cys Leu Gln Asp
260 265 270
Ile Lys Ile Asp Trp Asn His Ile Thr Leu Glu Asn Ile Ser Ser Gly
275 280 285
Ser Ser Leu Asn Val Lys Ala Gly Cys Val Arg Lys Asp Trp Cys Glu
290 295 300
Ser Gln Pro Cys Gln Ser Arg Gly Arg Cys Ile Asn Leu Trp Leu Ser
305 310 315 320
Tyr Gln Cys Asp Cys His Arg Pro Tyr Glu Gly Pro Asn Cys Leu Arg
325 330 335
Glu Tyr Val Ala Gly Arg Phe Gly Gln Asp Asp Ser Thr Gly Tyr Val
340 345 350
Ile Phe Thr Leu Asp Glu Ser Tyr Gly Asp Thr Ile Ser Leu Ser Met
355 360 365
Phe Val Arg Thr Leu Gln Pro Ser Gly Leu Leu Leu Ala Leu Glu Asn
370 375 380
Ser Thr Tyr Gln Tyr Ile Arg Val Trp Leu Glu Arg Gly Arg Leu Ala
385 390 395 400
Met Leu Thr Pro Asn Ser Pro Lys Leu Val Val Lys Phe Val Leu Asn
405 410 415
Asp Gly Asn Val His Leu Ile Ser Leu Lys Ile Lys Pro Tyr Lys Ile
420 425 430
Glu Leu Tyr Gln Ser Ser Gln Asn Leu Gly Phe Ile Ser Ala Ser Thr
435 440 445
Trp Lys Ile Glu Lys Gly Asp Val Ile Tyr Ile Gly Gly Leu Pro Asp
450 455 460
Lys Gln Glu Thr Glu Leu Asn Gly Gly Phe Phe Lys Gly Cys Ile Gln
465 470 475 480
Asp Val Arg Leu Asn Asn Gln Asn Leu Glu Phe Phe Pro Asn Pro Thr
485 490 495
Asn Asn Ala Ser Leu Asn Pro Val Leu Val Asn Val Thr Gln Gly Cys
500 505 510
Ala Gly Asp Asn Ser Cys Lys Ser Asn Pro Cys His Asn Gly Gly Val
515 520 525
Cys His Ser Arg Trp Asp Asp Phe Ser Cys Ser Cys Pro Ala Leu Thr
530 535 540
Ser Gly Lys Ala Cys Glu Glu Val Gln Trp Cys Gly Phe Ser Pro Cys
545 550 555 560
Pro His Gly Ala Gln Cys Gln Pro Val Leu Gln Gly Phe Glu Cys Ile
565 570 575
Ala Asn Ala Val Phe Asn Gly Gln Ser Gly Gln Ile Leu Phe Arg Ser
580 585 590
Asn Gly Asn Ile Thr Arg Glu Leu Thr Asn Ile Thr Phe Gly Phe Arg
595 600 605
Thr Arg Asp Ala Asn Val Ile Ile Leu His Ala Glu Lys Glu Pro Glu
610 615 620
Phe Leu Asn Ile Ser Ile Gln Asp Ser Arg Leu Phe Phe Gln Leu Gln
625 630 635 640
Ser Gly Asn Ser Phe Tyr Met Leu Ser Leu Thr Ser Leu Gln Ser Val
645 650 655
Asn Asp Gly Thr Trp His Glu Val Thr Leu Ser Met Thr Asp Pro Leu
660 665 670
Ser Gln Thr Ser Arg Trp Gln Met Glu Val Asp Asn Glu Thr Pro Phe
675 680 685
Val Thr Ser Thr Ile Ala Thr Gly Ser Leu Asn Phe Leu Lys Asp Asn
690 695 700
Thr Asp Ile Tyr Val Gly Asp Arg Ala Ile Asp Asn Ile Lys Gly Leu
705 710 715 720
Gln Gly Cys Leu Ser Thr Ile Glu Ile Gly Gly Ile Tyr Leu Ser Tyr
725 730 735
Phe Glu Asn Val His Gly Phe Ile Asn Lys Pro Gln Glu Glu Gln Phe
740 745 750
Leu Lys Ile Ser Thr Asn Ser Val Val Thr Gly Cys Leu Gln Leu Asn
755 760 765
Val Cys Asn Ser Asn Pro Cys Leu His Gly Gly Asn Cys Glu Asp Ile
770 775 780
Tyr Ser Ser Tyr His Cys Ser Cys Pro Leu Gly Trp Ser Gly Lys His
785 790 795 800
Cys Glu Leu Asn Ile Asp Glu Cys Phe Ser Asn Pro Cys Ile His Gly
805 810 815
Asn Cys Ser Asp Arg Val Ala Ala Tyr His Cys Thr Cys Glu Pro Gly
820 825 830
Tyr Thr Gly Val Asn Cys Glu Val Asp Ile Asp Asn Cys Gln Ser His
835 840 845
Gln Cys Ala Asn Gly Ala Thr Cys Ile Ser His Thr Asn Gly Tyr Ser
850 855 860
Cys Leu Cys Phe Gly Asn Phe Thr Gly Lys Phe Cys Arg Gln Ser Arg
865 870 875 880
Leu Pro Ser Thr Val Cys Gly Asn Glu Lys Thr Asn Leu Thr Cys Tyr
885 890 895
Asn Gly Gly Asn Cys Thr Glu Phe Gln Thr Glu Leu Lys Cys Met Cys
900 905 910
Arg Pro Gly Phe Thr Gly Glu Trp Cys Glu Lys Asp Ile Asp Glu Cys
915 920 925
Ala Ser Asp Pro Cys Val Asn Gly Gly Leu Cys Gln Asp Leu Leu Asn
930 935 940
Lys Phe Gln Cys Leu Cys Asp Val Ala Phe Ala Gly Glu Arg Cys Glu
945 950 955 960
Val Asp Val Ser Ser Leu Ser Phe Tyr Val Ser Leu Leu Phe Trp Gln
965 970 975
Asn Leu Phe Gln Leu Leu Ser Tyr Leu Ile Leu Arg Met Asn Asp Glu
980 985 990
Pro Val Val Glu Trp Gly Glu Gln Glu Asp Tyr
995 1000
<210> 2
<211> 5621
<212> DNA
<213> 智人
<220>
<221> misc_feature
<222> (204)..(206)
<223> 起始密码子
<400> 2
agcacaaatg agtcttacac taagccacac tgatccagct tggagggaaa tgagtcaaaa 60
ccaagtcccc atactctcta cctgcgagaa agaggtgaca ttgaagaaca agcccacact 120
tctggatatg gtccaaaatg atcagaaact cactctgtca acctagtagg tgtttggatg 180
gatacctctt ttttaacaga aagatgtttg gagccaggac acatggtttt cacattttaa 240
tggcaatgct cataggaatc cactgcgaag aagacgtcaa tgaatgttct tcaaaccctt 300
gccaaaatgg tggtacttgt gagaacttgc ctgggaatta tacttgccat tgcccatttg 360
ataacctttc tagaactttt tatggaggaa gggactgttc tgatattctc ctgggctgta 420
cccatcagca atgtctaaat aatggaacat gcatccctca cttccaagat ggccagcatg 480
gattcagctg cctatgtcca tctggctaca ccgggtccct gtgtgaaatc gcaaccacac 540
tttcatttga gggcgatggc ttcctgtggg tcaaaagtgg ctcagtgaca accaagggct 600
cagtttgtaa catagccctc aggtttcaga ctgttcagcc aatggctctt ctacttttcc 660
gaagcaacag ggatgtgttt gtgaagctgg agctgctaag tggctacatt cacttatcaa 720
ttcaggtcaa taatcagtca aaggtgcttc tgttcatttc ccacaacacc agcgatggag 780
agtggcattt cgtggaggta atatttgcag aggctgtgac ccttacctta atcgacgact 840
cctgtaagga gaaatgcatc gcgaaagctc ctactccact tgaaagtgat caatcaatat 900
gtgcttttca gaactccttt ttgggtggtt taccagtggg aatgaccagc aatggtgttg 960
ctctgcttaa cttctataat atgccatcca caccttcgtt tgtaggctgt ctccaagaca 1020
ttaaaattga ttggaatcac attaccctgg agaacatctc gtctggctca tcattaaatg 1080
tcaaggcagg ctgtgtgaga aaggattggt gtgaaagcca accttgtcaa agcagaggac 1140
gctgcatcaa cttgtggctg agttaccagt gtgactgcca caggccctat gaaggcccca 1200
actgtctgag agagtatgtg gcaggcagat ttggccagga tgactccact ggttatgtca 1260
tctttactct tgatgagagc tatggagaca ccatcagcct ctccatgttt gtccgaacgc 1320
ttcaaccatc aggcttactt ctagctttgg aaaacagcac ttatcaatat atccgtgtct 1380
ggctagagcg cggcagacta gcaatgctga ctccaaactc tcccaaatta gtagtaaaat 1440
ttgttcttaa tgatggaaat gtccacttga tatctttgaa aatcaagcca tataaaattg 1500
aactgtatca gtcttcacaa aacctaggat ttatttctgc ttctacgtgg aaaatcgaaa 1560
agggagatgt catctacatt ggtggcctac ctgacaagca agagactgaa cttaatggtg 1620
gattcttcaa aggctgtatc caagatgtaa gactaaacaa ccaaaatctg gaattctttc 1680
caaatccaac aaacaatgca tctctcaatc cagttcttgt caatgtaacc caaggctgtg 1740
ctggagacaa cagctgcaag tccaacccct gtcacaatgg aggtgtttgc cattcccggt 1800
gggatgactt ctcctgttcc tgtcctgccc tcacaagtgg gaaagcctgt gaggaggttc 1860
agtggtgtgg attcagcccg tgtcctcacg gagcccagtg ccagccggtg cttcaaggat 1920
ttgaatgtat tgcaaatgct gtttttaatg gacaaagcgg tcaaatatta ttcagaagca 1980
atgggaatat taccagagaa ctcaccaata tcacatttgg tttcagaaca agggatgcaa 2040
atgtaataat attgcatgca gaaaaagagc ctgaatttct taatattagc attcaagatt 2100
ccagattatt ctttcaattg caaagtggca acagctttta tatgctaagt ctgacaagtt 2160
tgcagtcagt gaatgatggc acatggcacg aagtgaccct ttccatgaca gacccactgt 2220
cccagacctc caggtggcaa atggaagtgg acaacgaaac accttttgtg accagcacaa 2280
ttgctactgg aagcctcaac tttttgaagg ataatacaga tatttatgtg ggagacagag 2340
ctattgacaa tataaagggc ctgcaagggt gtctaagtac aatagaaatc ggaggcattt 2400
atctctctta ctttgaaaat gttcatggtt tcattaataa acctcaggaa gagcaatttc 2460
tcaaaatctc taccaattca gtggtcactg gctgtttgca gttaaatgtc tgcaactcca 2520
acccctgttt gcatggagga aactgtgaag acatctatag ctcttatcat tgctcctgtc 2580
ccttgggatg gtcagggaaa cactgtgaac tcaacatcga tgaatgcttt tcaaacccct 2640
gtatccatgg caactgctct gacagagttg cagcctacca ctgcacatgt gagcctggat 2700
acactggtgt gaactgtgaa gtggatatag acaactgcca gagtcaccag tgtgcaaatg 2760
gagccacctg cattagtcat actaatggct attcttgcct ctgttttgga aattttacag 2820
gaaaattttg cagacagagc agattaccct caacagtctg tgggaatgag aagacaaatc 2880
tcacttgcta caatggaggc aactgcacag agttccagac tgaattaaaa tgtatgtgcc 2940
ggccaggttt tactggagaa tggtgtgaaa aggacattga tgagtgtgcc tctgatccgt 3000
gtgtcaatgg aggtctgtgc caggacttac tcaacaaatt ccagtgcctc tgtgatgttg 3060
cctttgctgg cgagcgctgc gaggtggacg taagcagcct ctccttttat gtctctctct 3120
tattctggca gaatcttttt cagcttcttt cttacctcat tttgcgtatg aatgacgagc 3180
cagttgttga gtggggtgaa caggaagatt attaacatac atttgaacat tcccaaatga 3240
aaaaaaaagc cattgaattt caagaaatgc cttgattcat tttagatctc tggggaagaa 3300
aaaggaaata aaaaccatct caataattaa ggtaaattca aggcttattt taaacatatc 3360
agaagcactt tgtctgtgta taaaatattt tcctattcta actttaaata tgaaaaaagt 3420
gttcttaata taactagaaa tatctcctta ttgtgtgtat ttagtacaaa catattatca 3480
ttctcaacac ttctatatgt gaatgaccac tgcaatttct tcccactcca tttctgggta 3540
ttttcacatt ttaagttgcc ctccatcact atgattctat tttcatttct gttctttcat 3600
tcttatctat tatttatgac acaaaaattg agaattacag gccaggtgtg gtggttcact 3660
cctataatcc cagcactatg ggaggctgaa gtgggcggaa cacctgaggc caggagtttg 3720
agaccagcct agccaacgtg gtgaaaacct gtctctacta aaaatacaaa agtaactggg 3780
agtggtggca catgcctgta atcccagcta ctcaggaggg tgaagcagga gacttgcttg 3840
aacccaggag gcggccgttg caatgagcca agattgtgcc actgcactcc agcctgggcg 3900
acaggtgaga ttctgtctaa aaaaaaaaaa aaaaaaagag agaattaccg attaaaatta 3960
ctgattatat tcatctatgt ttttacatga agctattcaa atgaattgtt acgttttctc 4020
tgatatatga ttaaatatat aaagagaaat caggaattta catcgagtcc ctaaattgta 4080
gaaaaacaat tatctagtat cagtactcaa attatacctc cctggtataa tttctgattc 4140
cataaaactg tctctctaac aaagttacaa ataatccttt ctctatttcc tttcctgcaa 4200
tactttccct tttcctaaca aatagaacaa tttttctgtt gtttctaaat ttatgagctc 4260
cttgactttt ctatcaaatg gactaatttc agttgctttt caatgaatat ttaataaaaa 4320
taagcactgt agtttataca taaatttaaa agtatatatt gtaaaacttg aattttctta 4380
gaagcatggt tttctaagat ttgcaagtaa atttattttc ttaagtatct ttcagaaaaa 4440
aatatgaaag catagtatac atcataacca aaatatattt gacattatga ttttttaaaa 4500
taaatgtata cctgaaataa tggatctata aagtatacta agatatgcaa aaattaatat 4560
attctttatt ataaatattt cagagattat aaaataataa tttaaaaaaa ctttcttaat 4620
gtttttattg tttccaccag tacgttatca tttatgctaa atatctttgt gtagatatac 4680
ccttccaaag aagacgttat ttgtgttcat ttaaaggaaa aatagtttga tcctatgaat 4740
taattcagaa agcaactaaa ataacaatgg cctgccaaat gtcattttgt aaatatacgt 4800
ctatgacttt aggagctgtc ctggtttgaa aacatgagga cagtttatcc attggatgcc 4860
atctatttag tcccaattaa gaaagttgtt tttttgtgag aatgaccaag gtaaatttaa 4920
atataccatt caaacaaaca aggacaaaat aatatccttg ttatagagta catgtagcat 4980
atagtatgaa gtaatatact acaaaagcaa agaaagtgta ttctatcttg caatagtaat 5040
agacaatttt tatatagcaa attcatatcc tttggagtag tgacaatcat ttcaaactgg 5100
gagcaactaa ttgtgaagat tttccttctt actcatccat tttcttcaca tccaaggctg 5160
aacgtgtgat gctgctgctt cagatgattt gttccaaagt taaattttgt gacaaaagac 5220
atggggaaaa ccttcccatc aatatttaca ttcacaagta tttgcaataa gcataaaata 5280
gattatagcc agaccatatg tatagttttc acatttactc ccttctagac atacctgtac 5340
ttatgtactt acaggctgtt ccaaatgtaa tatgttctct accaaatgtg gttaagaaat 5400
attcactcac aatttctttc tgtgtacaat tctgatgcct ctgttgtcac tgtaattgtc 5460
agttgctttt ctgttttcca aatgtcttct tgtcataagg tatctgactt taaaaaatgt 5520
tttccctttt ctttttattc ttctgtattt tccagctgca tgtgtgtgac tatggctttt 5580
acatatttgc acagaaaaat aaaacctttg tttctgtatc t 5621
<210> 3
<211> 41
<212> PRT
<213> 智人
<400> 3
Val Ser Ser Leu Ser Phe Tyr Val Ser Leu Leu Phe Trp Gln Asn Leu
1 5 10 15
Phe Gln Leu Leu Ser Tyr Leu Ile Leu Arg Met Asn Asp Glu Pro Val
20 25 30
Val Glu Trp Gly Glu Gln Glu Asp Tyr
35 40
<210> 4
<211> 5619
<212> DNA
<213> 智人
<400> 4
acactattct aatgtaggcc cttttgagga ggcagcatga acagaagaaa actcgcagca 60
aaggcttgag gggggaatga atccaatcca gcctgaaaaa atctgcacca ggtttgaaaa 120
atcaccccat cctcccgtgt aagtgatgct aagaagcaca aactgcattt tgaatctaag 180
tccctgtatt ttctgtgaag gagctgtaag tagggtggga cagagatggc acctgggggt 240
tctgaggcac ccgctcctct ctgagacaga cagggatcag gagccggact gggaccagac 300
caccagcaac acaccagagg atgttctcta aataagacca tggcacttaa gaacattaac 360
taccttctca tcttctacct cagtttctca ctgcttatct acataaaaaa ttccttttgc 420
aataaaaaca acaccaggtg cctctcaaat tcttgccaaa acaattctac atgcaaagat 480
ttttcaaaag acaatgattg ttcttgttca gacacagcca ataatttgga caaagactgt 540
gacaacatga aagacccttg cttctccaat ccctgtcaag gaagtgccac ttgtgtgaac 600
accccaggag aaaggagctt tctgtgcaaa tgtcctcctg ggtacagtgg gacaatctgt 660
gaaactacca ttggttcctg tggcaagaac tcctgccaac atggaggtat ttgccatcag 720
gaccctattt atcctgtctg catctgccct gctggatatg ctggaagatt ctgtgagata 780
gatcacgatg agtgtgcttc cagcccttgc caaaatgggg ccgtgtgcca ggatggaatt 840
gatggttact cctgcttctg tgtcccagga tatcaaggca gacactgcga cttggaagtg 900
gatgaatgtg cttcagatcc ctgcaagaac gaggctacat gcctcaatga aataggaaga 960
tatacttgta tctgtcccca caattattct ggtgtaaact gtgaattgga aattgacgaa 1020
tgttggtccc agccttgttt aaatggtgca acttgtcagg atgctctggg ggcctatttc 1080
tgcgactgtg cccctggatt cctgggggat cactgtgaac tcaacactga tgagtgtgcc 1140
agtcaacctt gtctccatgg agggctgtgt gtggatggag aaaacagata tagctgtaac 1200
tgcacgggta gtggattcac agggacacac tgtgagacct tgatgcctct ttgttggtca 1260
aaaccttgtc acaataatgc tacatgtgag gacagtgttg acaattacac ttgtcactgc 1320
tggcctggat acacaggtgc ccagtgtgag atcgacctca atgaatgcaa tagtaacccc 1380
tgccagtcca atggggaatg tgtggagctg tcctcagaga aacaatatgg acgcatcact 1440
ggactgcctt cttctttcag ctaccatgaa gcctcaggtt atgtctgtat ctgtcagcct 1500
ggattcacag gaatccactg cgaagaagac gtcaatgaat gttcttcaaa cccttgccaa 1560
aatggtggta cttgtgagaa cttgcctggg aattatactt gccattgccc atttgataac 1620
ctttctagaa ctttttatgg aggaagggac tgttctgata ttctcctggg ctgtacccat 1680
cagcaatgtc taaataatgg aacatgcatc cctcacttcc aagatggcca gcatggattc 1740
agctgcctat gtccatctgg ctacaccggg tccctgtgtg aaatcgcaac cacactttca 1800
tttgagggcg atggcttcct gtgggtcaaa agtggctcag tgacaaccaa gggctcagtt 1860
tgtaacatag ccctcaggtt tcagactgtt cagccaatgg ctcttctact tttccgaagc 1920
aacagggatg tgtttgtgaa gctggagctg ctaagtggct acattcactt atcaattcag 1980
gtcaataatc agtcaaaggt gcttctgttc atttcccaca acaccagcga tggagagtgg 2040
catttcgtgg aggtaatatt tgcagaggct gtgaccctta ccttaatcga cgactcctgt 2100
aaggagaaat gcatcgcgaa agctcctact ccacttgaaa gtgatcaatc aatatgtgct 2160
tttcagaact cctttttggg tggtttacca gtgggaatga ccagcaatgg tgttgctctg 2220
cttaacttct ataatatgcc atccacacct tcgtttgtag gctgtctcca agacattaaa 2280
attgattgga atcacattac cctggagaac atctcgtctg gctcatcatt aaatgtcaag 2340
gcaggctgtg tgagaaagga ttggtgtgaa agccaacctt gtcaaagcag aggacgctgc 2400
atcaacttgt ggctgagtta ccagtgtgac tgccacaggc cctatgaagg ccccaactgt 2460
ctgagagagt atgtggcagg cagatttggc caggatgact ccactggtta tgtcatcttt 2520
actcttgatg agagctatgg agacaccatc agcctctcca tgtttgtccg aacgcttcaa 2580
ccatcaggct tacttctagc tttggaaaac agcacttatc aatatatccg tgtctggcta 2640
gagcgcggca gactagcaat gctgactcca aactctccca aattagtagt aaaatttgtt 2700
cttaatgatg gaaatgtcca cttgatatct ttgaaaatca agccatataa aattgaactg 2760
tatcagtctt cacaaaacct aggatttatt tctgcttcta cgtggaaaat cgaaaaggga 2820
gatgtcatct acattggtgg cctacctgac aagcaagaga ctgaacttaa tggtggattc 2880
ttcaaaggct gtatccaaga tgtaagacta aacaaccaaa atctggaatt ctttccaaat 2940
ccaacaaaca atgcatctct caatccagtt cttgtcaatg taacccaagg ctgtgctgga 3000
gacaacagct gcaagtccaa cccctgtcac aatggaggtg tttgccattc ccggtgggat 3060
gacttctcct gttcctgtcc tgccctcaca agtgggaaag cctgtgagga ggttcagtgg 3120
tgtggattca gcccgtgtcc tcacggagcc cagtgccagc cggtgcttca aggatttgaa 3180
tgtattgcaa atgctgtttt taatggacaa agcggtcaaa tattattcag aagcaatggg 3240
aatattacca gagaactcac caatatcaca tttggtttca gaacaaggga tgcaaatgta 3300
ataatattgc atgcagaaaa agagcctgaa tttcttaata ttagcattca agattccaga 3360
ttattctttc aattgcaaag tggcaacagc ttttatatgc taagtctgac aagtttgcag 3420
tcagtgaatg atggcacatg gcacgaagtg accctttcca tgacagaccc actgtcccag 3480
acctccaggt ggcaaatgga agtggacaac gaaacacctt ttgtgaccag cacaattgct 3540
actggaagcc tcaacttttt gaaggataat acagatattt atgtgggaga cagagctatt 3600
gacaatataa agggcctgca agggtgtcta agtacaatag aaatcggagg catttatctc 3660
tcttactttg aaaatgttca tggtttcatt aataaacctc aggaagagca atttctcaaa 3720
atctctacca attcagtggt cactggctgt ttgcagttaa atgtctgcaa ctccaacccc 3780
tgtttgcatg gaggaaactg tgaagacatc tatagctctt atcattgctc ctgtcccttg 3840
ggatggtcag ggaaacactg tgaactcaac atcgatgaat gcttttcaaa cccctgtatc 3900
catggcaact gctctgacag agttgcagcc taccactgca catgtgagcc tggatacact 3960
ggtgtgaact gtgaagtgga tatagacaac tgccagagtc accagtgtgc aaatggagcc 4020
acctgcatta gtcatactaa tggctattct tgcctctgtt ttggaaattt tacaggaaaa 4080
ttttgcagac agagcagatt accctcaaca gtctgtggga atgagaagac aaatctcact 4140
tgctacaatg gaggcaactg cacagagttc cagactgaat taaaatgtat gtgccggcca 4200
ggttttactg gagaatggtg tgaaaaggac attgatgagt gtgcctctga tccgtgtgtc 4260
aatggaggtc tgtgccagga cttactcaac aaattccagt gcctctgtga tgttgccttt 4320
gctggcgagc gctgcgaggt ggacttggca gatgacttga tctccgacat tttcaccact 4380
attggctcag tgactgtcgc cttgttactg atcctcttgc tggccattgt tgcttctgtt 4440
gtcacctcca acaaaagggc aactcaggga acctacagcc ccagccgtca ggagaaggag 4500
ggctcccgag tggaaatgtg gaacttgatg ccaccccctg caatggagag actgatttag 4560
gagcattgtg tcccttcgag atggggatcc acacactgtg aatgtgatga ctgtacttca 4620
ggtatctctg acatacctga caatgttaat ctgcaactgg gattacactg gaactacagg 4680
aatgattcct ttgaccacct taaaaacttt cacagtggtt ccgctcgaca ccattgtttt 4740
attatattat atcagccaat tgcaaaaaaa gtctgtgcca gtaatttcag ccttataatt 4800
agcaaaaaca tcttccagag aataaagtct tctgtggctt tagtggctat cactgaaact 4860
ctttcctctt ttcaacctgg gaacaaattt tagttttcat tttaggtttc tgtactttct 4920
gtagtttctg tgtaaactgc catatgttta catggaaact acaggaaaaa attggctaca 4980
tttctcactt ctcctatcat gtggtcaaag ttattgttgt ataccagcga tgggatgtat 5040
acttttgtcc ttcattcatg gattcagaga aagctctggg aatgacttat ggtccaaaaa 5100
agtgacccaa tggcaacaaa taaaaattga aatgcagttg ttctcctttc tgagtacttt 5160
ttgcattttt gtgacattat gtgtgacaaa agtaacctct aggaacattt gaagaacctg 5220
cttatgaatt agacctttta cctaaatcat ttcaagttgg ttacattttc aaattattac 5280
tctttgtaaa gggttggtta aggcaaaacg cttcctagat agaaatcaaa acggggaaaa 5340
ctcagattct caagttcgaa aaatcgagtt cttttcttcc aactgctttt aggtaaatca 5400
gtgccaaaca gtgacattgt ttaaaggtaa gaactccaaa gttaaatgta tgcactttac 5460
ggagtatgtg ttttaagact atgggatatt tggagaaaat gctggggttt ctattcttat 5520
attttcttct acaaagcatc tgattatatt tttatatgtg ctttgaaata tatgaaacat 5580
gctactgctg tagaatataa ataaaactta agaatagat 5619
<210> 5
<211> 1406
<212> PRT
<213> 智人
<400> 5
Met Ala Leu Lys Asn Ile Asn Tyr Leu Leu Ile Phe Tyr Leu Ser Phe
1 5 10 15
Ser Leu Leu Ile Tyr Ile Lys Asn Ser Phe Cys Asn Lys Asn Asn Thr
20 25 30
Arg Cys Leu Ser Asn Ser Cys Gln Asn Asn Ser Thr Cys Lys Asp Phe
35 40 45
Ser Lys Asp Asn Asp Cys Ser Cys Ser Asp Thr Ala Asn Asn Leu Asp
50 55 60
Lys Asp Cys Asp Asn Met Lys Asp Pro Cys Phe Ser Asn Pro Cys Gln
65 70 75 80
Gly Ser Ala Thr Cys Val Asn Thr Pro Gly Glu Arg Ser Phe Leu Cys
85 90 95
Lys Cys Pro Pro Gly Tyr Ser Gly Thr Ile Cys Glu Thr Thr Ile Gly
100 105 110
Ser Cys Gly Lys Asn Ser Cys Gln His Gly Gly Ile Cys His Gln Asp
115 120 125
Pro Ile Tyr Pro Val Cys Ile Cys Pro Ala Gly Tyr Ala Gly Arg Phe
130 135 140
Cys Glu Ile Asp His Asp Glu Cys Ala Ser Ser Pro Cys Gln Asn Gly
145 150 155 160
Ala Val Cys Gln Asp Gly Ile Asp Gly Tyr Ser Cys Phe Cys Val Pro
165 170 175
Gly Tyr Gln Gly Arg His Cys Asp Leu Glu Val Asp Glu Cys Ala Ser
180 185 190
Asp Pro Cys Lys Asn Glu Ala Thr Cys Leu Asn Glu Ile Gly Arg Tyr
195 200 205
Thr Cys Ile Cys Pro His Asn Tyr Ser Gly Val Asn Cys Glu Leu Glu
210 215 220
Ile Asp Glu Cys Trp Ser Gln Pro Cys Leu Asn Gly Ala Thr Cys Gln
225 230 235 240
Asp Ala Leu Gly Ala Tyr Phe Cys Asp Cys Ala Pro Gly Phe Leu Gly
245 250 255
Asp His Cys Glu Leu Asn Thr Asp Glu Cys Ala Ser Gln Pro Cys Leu
260 265 270
His Gly Gly Leu Cys Val Asp Gly Glu Asn Arg Tyr Ser Cys Asn Cys
275 280 285
Thr Gly Ser Gly Phe Thr Gly Thr His Cys Glu Thr Leu Met Pro Leu
290 295 300
Cys Trp Ser Lys Pro Cys His Asn Asn Ala Thr Cys Glu Asp Ser Val
305 310 315 320
Asp Asn Tyr Thr Cys His Cys Trp Pro Gly Tyr Thr Gly Ala Gln Cys
325 330 335
Glu Ile Asp Leu Asn Glu Cys Asn Ser Asn Pro Cys Gln Ser Asn Gly
340 345 350
Glu Cys Val Glu Leu Ser Ser Glu Lys Gln Tyr Gly Arg Ile Thr Gly
355 360 365
Leu Pro Ser Ser Phe Ser Tyr His Glu Ala Ser Gly Tyr Val Cys Ile
370 375 380
Cys Gln Pro Gly Phe Thr Gly Ile His Cys Glu Glu Asp Val Asn Glu
385 390 395 400
Cys Ser Ser Asn Pro Cys Gln Asn Gly Gly Thr Cys Glu Asn Leu Pro
405 410 415
Gly Asn Tyr Thr Cys His Cys Pro Phe Asp Asn Leu Ser Arg Thr Phe
420 425 430
Tyr Gly Gly Arg Asp Cys Ser Asp Ile Leu Leu Gly Cys Thr His Gln
435 440 445
Gln Cys Leu Asn Asn Gly Thr Cys Ile Pro His Phe Gln Asp Gly Gln
450 455 460
His Gly Phe Ser Cys Leu Cys Pro Ser Gly Tyr Thr Gly Ser Leu Cys
465 470 475 480
Glu Ile Ala Thr Thr Leu Ser Phe Glu Gly Asp Gly Phe Leu Trp Val
485 490 495
Lys Ser Gly Ser Val Thr Thr Lys Gly Ser Val Cys Asn Ile Ala Leu
500 505 510
Arg Phe Gln Thr Val Gln Pro Met Ala Leu Leu Leu Phe Arg Ser Asn
515 520 525
Arg Asp Val Phe Val Lys Leu Glu Leu Leu Ser Gly Tyr Ile His Leu
530 535 540
Ser Ile Gln Val Asn Asn Gln Ser Lys Val Leu Leu Phe Ile Ser His
545 550 555 560
Asn Thr Ser Asp Gly Glu Trp His Phe Val Glu Val Ile Phe Ala Glu
565 570 575
Ala Val Thr Leu Thr Leu Ile Asp Asp Ser Cys Lys Glu Lys Cys Ile
580 585 590
Ala Lys Ala Pro Thr Pro Leu Glu Ser Asp Gln Ser Ile Cys Ala Phe
595 600 605
Gln Asn Ser Phe Leu Gly Gly Leu Pro Val Gly Met Thr Ser Asn Gly
610 615 620
Val Ala Leu Leu Asn Phe Tyr Asn Met Pro Ser Thr Pro Ser Phe Val
625 630 635 640
Gly Cys Leu Gln Asp Ile Lys Ile Asp Trp Asn His Ile Thr Leu Glu
645 650 655
Asn Ile Ser Ser Gly Ser Ser Leu Asn Val Lys Ala Gly Cys Val Arg
660 665 670
Lys Asp Trp Cys Glu Ser Gln Pro Cys Gln Ser Arg Gly Arg Cys Ile
675 680 685
Asn Leu Trp Leu Ser Tyr Gln Cys Asp Cys His Arg Pro Tyr Glu Gly
690 695 700
Pro Asn Cys Leu Arg Glu Tyr Val Ala Gly Arg Phe Gly Gln Asp Asp
705 710 715 720
Ser Thr Gly Tyr Val Ile Phe Thr Leu Asp Glu Ser Tyr Gly Asp Thr
725 730 735
Ile Ser Leu Ser Met Phe Val Arg Thr Leu Gln Pro Ser Gly Leu Leu
740 745 750
Leu Ala Leu Glu Asn Ser Thr Tyr Gln Tyr Ile Arg Val Trp Leu Glu
755 760 765
Arg Gly Arg Leu Ala Met Leu Thr Pro Asn Ser Pro Lys Leu Val Val
770 775 780
Lys Phe Val Leu Asn Asp Gly Asn Val His Leu Ile Ser Leu Lys Ile
785 790 795 800
Lys Pro Tyr Lys Ile Glu Leu Tyr Gln Ser Ser Gln Asn Leu Gly Phe
805 810 815
Ile Ser Ala Ser Thr Trp Lys Ile Glu Lys Gly Asp Val Ile Tyr Ile
820 825 830
Gly Gly Leu Pro Asp Lys Gln Glu Thr Glu Leu Asn Gly Gly Phe Phe
835 840 845
Lys Gly Cys Ile Gln Asp Val Arg Leu Asn Asn Gln Asn Leu Glu Phe
850 855 860
Phe Pro Asn Pro Thr Asn Asn Ala Ser Leu Asn Pro Val Leu Val Asn
865 870 875 880
Val Thr Gln Gly Cys Ala Gly Asp Asn Ser Cys Lys Ser Asn Pro Cys
885 890 895
His Asn Gly Gly Val Cys His Ser Arg Trp Asp Asp Phe Ser Cys Ser
900 905 910
Cys Pro Ala Leu Thr Ser Gly Lys Ala Cys Glu Glu Val Gln Trp Cys
915 920 925
Gly Phe Ser Pro Cys Pro His Gly Ala Gln Cys Gln Pro Val Leu Gln
930 935 940
Gly Phe Glu Cys Ile Ala Asn Ala Val Phe Asn Gly Gln Ser Gly Gln
945 950 955 960
Ile Leu Phe Arg Ser Asn Gly Asn Ile Thr Arg Glu Leu Thr Asn Ile
965 970 975
Thr Phe Gly Phe Arg Thr Arg Asp Ala Asn Val Ile Ile Leu His Ala
980 985 990
Glu Lys Glu Pro Glu Phe Leu Asn Ile Ser Ile Gln Asp Ser Arg Leu
995 1000 1005
Phe Phe Gln Leu Gln Ser Gly Asn Ser Phe Tyr Met Leu Ser Leu
1010 1015 1020
Thr Ser Leu Gln Ser Val Asn Asp Gly Thr Trp His Glu Val Thr
1025 1030 1035
Leu Ser Met Thr Asp Pro Leu Ser Gln Thr Ser Arg Trp Gln Met
1040 1045 1050
Glu Val Asp Asn Glu Thr Pro Phe Val Thr Ser Thr Ile Ala Thr
1055 1060 1065
Gly Ser Leu Asn Phe Leu Lys Asp Asn Thr Asp Ile Tyr Val Gly
1070 1075 1080
Asp Arg Ala Ile Asp Asn Ile Lys Gly Leu Gln Gly Cys Leu Ser
1085 1090 1095
Thr Ile Glu Ile Gly Gly Ile Tyr Leu Ser Tyr Phe Glu Asn Val
1100 1105 1110
His Gly Phe Ile Asn Lys Pro Gln Glu Glu Gln Phe Leu Lys Ile
1115 1120 1125
Ser Thr Asn Ser Val Val Thr Gly Cys Leu Gln Leu Asn Val Cys
1130 1135 1140
Asn Ser Asn Pro Cys Leu His Gly Gly Asn Cys Glu Asp Ile Tyr
1145 1150 1155
Ser Ser Tyr His Cys Ser Cys Pro Leu Gly Trp Ser Gly Lys His
1160 1165 1170
Cys Glu Leu Asn Ile Asp Glu Cys Phe Ser Asn Pro Cys Ile His
1175 1180 1185
Gly Asn Cys Ser Asp Arg Val Ala Ala Tyr His Cys Thr Cys Glu
1190 1195 1200
Pro Gly Tyr Thr Gly Val Asn Cys Glu Val Asp Ile Asp Asn Cys
1205 1210 1215
Gln Ser His Gln Cys Ala Asn Gly Ala Thr Cys Ile Ser His Thr
1220 1225 1230
Asn Gly Tyr Ser Cys Leu Cys Phe Gly Asn Phe Thr Gly Lys Phe
1235 1240 1245
Cys Arg Gln Ser Arg Leu Pro Ser Thr Val Cys Gly Asn Glu Lys
1250 1255 1260
Thr Asn Leu Thr Cys Tyr Asn Gly Gly Asn Cys Thr Glu Phe Gln
1265 1270 1275
Thr Glu Leu Lys Cys Met Cys Arg Pro Gly Phe Thr Gly Glu Trp
1280 1285 1290
Cys Glu Lys Asp Ile Asp Glu Cys Ala Ser Asp Pro Cys Val Asn
1295 1300 1305
Gly Gly Leu Cys Gln Asp Leu Leu Asn Lys Phe Gln Cys Leu Cys
1310 1315 1320
Asp Val Ala Phe Ala Gly Glu Arg Cys Glu Val Asp Leu Ala Asp
1325 1330 1335
Asp Leu Ile Ser Asp Ile Phe Thr Thr Ile Gly Ser Val Thr Val
1340 1345 1350
Ala Leu Leu Leu Ile Leu Leu Leu Ala Ile Val Ala Ser Val Val
1355 1360 1365
Thr Ser Asn Lys Arg Ala Thr Gln Gly Thr Tyr Ser Pro Ser Arg
1370 1375 1380
Gln Glu Lys Glu Gly Ser Arg Val Glu Met Trp Asn Leu Met Pro
1385 1390 1395
Pro Pro Ala Met Glu Arg Leu Ile
1400 1405
<210> 6
<211> 5541
<212> DNA
<213> 智人
<400> 6
gtcttggccc aacttacaaa cagcagaaat ctgagttgtg ggaatataat ttatgaacag 60
aaaagattac ttgtctgtga attattttct gaagatgaaa gtaaatatac aggaacatac 120
ggtattcctt taaaagttgc cagatcataa ttgtgtggca aggcagttat cagaaattaa 180
tccctctatt gagagcaatt gaagacacta ttctaatgta ggcccttttg aggaggcagc 240
atgaacagaa gaaaactcgc agcaaaggct tgagggggga atgaatccaa tccagcctga 300
aaaaatctgc accaggtttg aaaaatcacc ccatcctccc gtgtaagtga tgctaagaag 360
cacaaactgc attttgaatc taagtccctg tattttctgt gaaggagctg taagtagggt 420
gggacagaga tggcacctgg gggttctgag gcacccgctc ctctctgaga cagacaggga 480
tcaggagccg gactgggacc agaccaccag caacacacca gaggatgttc tctaaataag 540
accatggcac ttaagaacat taactacctt ctcatcttct acctcagttt ctcactgctt 600
atctacataa aaaattcctt ttgcaataaa aacaacacca ggtgcctctc aaattcttgc 660
caaaacaatt ctacatgcaa agatttttca aaagacaatg attgttcttg ttcagacaca 720
gccaataatt tggacaaaga ctgtgacaac atgaaagacc cttgcttctc caatccctgt 780
caaggaagtg ccacttgtgt gaacacccca ggagaaagga gctttctgtg caaatgtcct 840
cctgggtaca gtgggacaat ctgtgaaact accattggtt cctgtggcaa gaactcctgc 900
caacatggag gtatttgcca tcaggaccct atttatcctg tctgcatctg ccctgctgga 960
tatgctggaa gattctgtga gatagatcac gatgagtgtg cttccagccc ttgccaaaat 1020
ggggccgtgt gccaggatgg aattgatggt tactcctgct tctgtgtccc aggatatcaa 1080
ggcagacact gcgacttgga agtggatgaa tgtgcttcag atccctgcaa gaacgaggct 1140
acatgcctca atgaaatagg aagatatact tgtatctgtc cccacaatta ttctggtgta 1200
aactgtgaat tggaaattga cgaatgttgg tcccagcctt gtttaaatgg tgcaacttgt 1260
caggatgctc tgggggccta tttctgcgac tgtgcccctg gattcctggg ggatcactgt 1320
gaactcaaca ctgatgagtg tgccagtcaa ccttgtctcc atggagggct gtgtgtggat 1380
ggagaaaaca gatatagctg taactgcacg ggtagtggat tcacagggac acactgtgag 1440
accttgatgc ctctttgttg gtcaaaacct tgtcacaata atgctacatg tgaggacagt 1500
gttgacaatt acacttgtca ctgctggcct ggatacacag gtgcccagtg tgagatcgac 1560
ctcaatgaat gcaatagtaa cccctgccag tccaatgggg aatgtgtgga gctgtcctca 1620
gagaaacaat atggacgcat cactggactg ccttcttctt tcagctacca tgaagcctca 1680
ggttatgtct gtatctgtca gcctggattc acaggaatcc actgcgaaga agacgtcaat 1740
gaatgttctt caaacccttg ccaaaatggt ggtacttgtg agaacttgcc tgggaattat 1800
acttgccatt gcccatttga taacctttct agaacttttt atggaggaag ggactgttct 1860
gatattctcc tgggctgtac ccatcagcaa tgtctaaata atggaacatg catccctcac 1920
ttccaagatg gccagcatgg attcagctgc ctatgtccat ctggctacac cgggtccctg 1980
tgtgaaatcg caaccacact ttcatttgag ggcgatggct tcctgtgggt caaaagtggc 2040
tcagtgacaa ccaagggctc agtttgtaac atagccctca ggtttcagac tgttcagcca 2100
atggctcttc tacttttccg aagcaacagg gatgtgtttg tgaagctgga gctgctaagt 2160
ggctacattc acttatcaat tcaggtcaat aatcagtcaa aggtgcttct gttcatttcc 2220
cacaacacca gcgatggaga gtggcatttc gtggaggtaa tatttgcaga ggctgtgacc 2280
cttaccttaa tcgacgactc ctgtaaggag aaatgcatcg cgaaagctcc tactccactt 2340
gaaagtgatc aatcaatatg tgcttttcag aactcctttt tgggtggttt accagtggga 2400
atgaccagca atggtgttgc tctgcttaac ttctataata tgccatccac accttcgttt 2460
gtaggctgtc tccaagacat taaaattgat tggaatcaca ttaccctgga gaacatctcg 2520
tctggctcat cattaaatgt caaggcaggc tgtgtgagaa aggattggtg tgaaagccaa 2580
ccttgtcaaa gcagaggacg ctgcatcaac ttgtggctga gttaccagtg tgactgccac 2640
aggccctatg aaggccccaa ctgtctgaga ggtgagagaa agctgagtgc tatggctagg 2700
agtgccatgc ctcagagcag agcagaaaca gcaaaaacag ccagactgct tctgcctgct 2760
atgaaacata atgaccccac aagacttctg ctgctggttg cccactgatg agaaagaaaa 2820
gaagagggca gtgatgtgcg ttaattaatt ttgagtggat tcataggaca tcagtttcac 2880
tcatacagag aagtaaaaaa aataagcaga tagctctttt ccaaagaggt tttcatcttt 2940
gtgtttgcaa aatgctactg caattttacc attggtcaca tatcagaaat ttattgtaaa 3000
tcttatttga aagagaaata atcttttgaa aaaaaaaaac cttagacata aaatttgtca 3060
gtgccacata ctagcatgat atcttgtgca tagtaaattc tcggtaaata ttcatttcct 3120
tgctctcctt tccatgcaat tcacacttgc tccacaatca taattaagca tagcgttttt 3180
ataaaacgcc aattttattc aaaggtatct tttccaaggt tgccctggag aagacagata 3240
atatactagg tgtcttaaga aaaaaaaaaa agaaaaaaaa atgtggaaag taacaatagt 3300
agaacttggt agatgccata aactaattga tctaatttct ctagtaaacc acagtttgca 3360
aagtatttca aaatccttaa cttccaacat tgttctagag attgctgttg atagtgatca 3420
atatatacct gtttcttttt attattatta tcatacattg aaaaagtctg agaggtaatt 3480
gtaacggact gctttgaagt tcagctgtaa tttaccccaa gattttagag taacttgaag 3540
taggacaaca tctggtaagt agtcttctct gctttatatg aagtaaaatt aaaaccagtc 3600
ttagcctata ctctattcca tgttcaaatg tctaagaatt attagaaact actcaagggt 3660
ttcccccgac cacaatattc attacaaatc acggacctgt ttgacaatga agtatggtat 3720
ctactagctc tacgtaatat tttaagtaga atggcaagtt gttttgtgat tttttttaag 3780
gagaaaaagg gaaattatgc tgaggcaatg ttcacttttt gaagaaaaat ttaattgacc 3840
taaggcaata tttttactac atatacaaaa taacaaacag atgctgactc attttgactg 3900
gcttccagat gcagtgaccc atgaggttaa tactgaccat ggtgatgtta actgtcctag 3960
taaatagatt caagagatgc caatccactg ggttctggtt ttctttattt tatccaactt 4020
ggaaaaccat gaacttttca aaccaagttc ctgaattggt tacccttccc ccacttctcc 4080
cagtttcctt atactccaac attatttgaa actgcttaac cctcaagaaa atatttgact 4140
tcaaaagatc actttacaga cagagagagt tctgtgaaat cttttctttc tgaaaattct 4200
tggtataaat ttaaggaaaa ttatattttt catatcacct cttcattata aaattaaaat 4260
attctgtatt ttctgttatc ttgaaggaat gtttcctgga gagtttattc ccactaaaaa 4320
ctgcttttaa gtggtaatga gaacatggag tctttctgct actgtacata tacgtgcaag 4380
agggaggaga catactaaaa agcacaaagg caaacttcag cccattcatg acttgcactc 4440
atatttggct caatgttttc caaccatggt atacatttta atgaacaagg agactggata 4500
gaggattttg gtggctgact aaacacaaaa gacatagtga tttccaatgt atcaaggttg 4560
atctttttta aataatctaa tttctcaaca gaaagagtgc tgaaaaggat ttaactaagc 4620
ttaggtcaca gaagtgtcca taaggttctc tcagcatatc ttgtgttgac tgtttgtaag 4680
aacatgcagc attcaagata ctactactca gaataaatgg catcacctac ctcttgctct 4740
ctggtgaaca tttgacttac aaaagcaatt tacatatctc ttcttttcag ccatatacct 4800
agattttgag aattttattc tcttagaatt atagtttcct agatatagaa aaagattcat 4860
tctatgactg aatttttaac acaattgtac ctgccaaatg tagtggctca aatctctgct 4920
caaacacctt cacaaataga gagatcactc actccatctt gccaaaaatt gcccaaaagt 4980
tatttcctta tattgaaata gaataggatt tgcccgtagc tttccttcat tgaccttgtt 5040
gcatttctgg aacacatgca aataaaaatc tcaacttgcc tgctgcttga gaatacttaa 5100
tatctgaaga aaagtatctc gagccatcta aaccatcact tctattcagg ctaaacatcc 5160
tgtttcttct aatgtttgcc atatgacata gttttccgac acttcatcag ctgcttgcag 5220
gttttggaat atatttgctt ctttgtattc cttctaagat gtgatgtctg tatgtgctgg 5280
atgatacagt gacacacagg gccataacct cccttattct agataatgtg cttctgtttt 5340
tcagcttaat acaacattga ctttttggca gccacacttc gtgattgcgt cactttgtat 5400
cattgtcact catgatgcca catagtcctg tttctcccac tctaatctta taaacgcaca 5460
tttagatcga agtggctctt atttattctt gttaaatttc atcttgttgt attccatcaa 5520
tcattaaagc ttgccaaaat t 5541
<210> 7
<211> 754
<212> PRT
<213> 智人
<400> 7
Met Ala Leu Lys Asn Ile Asn Tyr Leu Leu Ile Phe Tyr Leu Ser Phe
1 5 10 15
Ser Leu Leu Ile Tyr Ile Lys Asn Ser Phe Cys Asn Lys Asn Asn Thr
20 25 30
Arg Cys Leu Ser Asn Ser Cys Gln Asn Asn Ser Thr Cys Lys Asp Phe
35 40 45
Ser Lys Asp Asn Asp Cys Ser Cys Ser Asp Thr Ala Asn Asn Leu Asp
50 55 60
Lys Asp Cys Asp Asn Met Lys Asp Pro Cys Phe Ser Asn Pro Cys Gln
65 70 75 80
Gly Ser Ala Thr Cys Val Asn Thr Pro Gly Glu Arg Ser Phe Leu Cys
85 90 95
Lys Cys Pro Pro Gly Tyr Ser Gly Thr Ile Cys Glu Thr Thr Ile Gly
100 105 110
Ser Cys Gly Lys Asn Ser Cys Gln His Gly Gly Ile Cys His Gln Asp
115 120 125
Pro Ile Tyr Pro Val Cys Ile Cys Pro Ala Gly Tyr Ala Gly Arg Phe
130 135 140
Cys Glu Ile Asp His Asp Glu Cys Ala Ser Ser Pro Cys Gln Asn Gly
145 150 155 160
Ala Val Cys Gln Asp Gly Ile Asp Gly Tyr Ser Cys Phe Cys Val Pro
165 170 175
Gly Tyr Gln Gly Arg His Cys Asp Leu Glu Val Asp Glu Cys Ala Ser
180 185 190
Asp Pro Cys Lys Asn Glu Ala Thr Cys Leu Asn Glu Ile Gly Arg Tyr
195 200 205
Thr Cys Ile Cys Pro His Asn Tyr Ser Gly Val Asn Cys Glu Leu Glu
210 215 220
Ile Asp Glu Cys Trp Ser Gln Pro Cys Leu Asn Gly Ala Thr Cys Gln
225 230 235 240
Asp Ala Leu Gly Ala Tyr Phe Cys Asp Cys Ala Pro Gly Phe Leu Gly
245 250 255
Asp His Cys Glu Leu Asn Thr Asp Glu Cys Ala Ser Gln Pro Cys Leu
260 265 270
His Gly Gly Leu Cys Val Asp Gly Glu Asn Arg Tyr Ser Cys Asn Cys
275 280 285
Thr Gly Ser Gly Phe Thr Gly Thr His Cys Glu Thr Leu Met Pro Leu
290 295 300
Cys Trp Ser Lys Pro Cys His Asn Asn Ala Thr Cys Glu Asp Ser Val
305 310 315 320
Asp Asn Tyr Thr Cys His Cys Trp Pro Gly Tyr Thr Gly Ala Gln Cys
325 330 335
Glu Ile Asp Leu Asn Glu Cys Asn Ser Asn Pro Cys Gln Ser Asn Gly
340 345 350
Glu Cys Val Glu Leu Ser Ser Glu Lys Gln Tyr Gly Arg Ile Thr Gly
355 360 365
Leu Pro Ser Ser Phe Ser Tyr His Glu Ala Ser Gly Tyr Val Cys Ile
370 375 380
Cys Gln Pro Gly Phe Thr Gly Ile His Cys Glu Glu Asp Val Asn Glu
385 390 395 400
Cys Ser Ser Asn Pro Cys Gln Asn Gly Gly Thr Cys Glu Asn Leu Pro
405 410 415
Gly Asn Tyr Thr Cys His Cys Pro Phe Asp Asn Leu Ser Arg Thr Phe
420 425 430
Tyr Gly Gly Arg Asp Cys Ser Asp Ile Leu Leu Gly Cys Thr His Gln
435 440 445
Gln Cys Leu Asn Asn Gly Thr Cys Ile Pro His Phe Gln Asp Gly Gln
450 455 460
His Gly Phe Ser Cys Leu Cys Pro Ser Gly Tyr Thr Gly Ser Leu Cys
465 470 475 480
Glu Ile Ala Thr Thr Leu Ser Phe Glu Gly Asp Gly Phe Leu Trp Val
485 490 495
Lys Ser Gly Ser Val Thr Thr Lys Gly Ser Val Cys Asn Ile Ala Leu
500 505 510
Arg Phe Gln Thr Val Gln Pro Met Ala Leu Leu Leu Phe Arg Ser Asn
515 520 525
Arg Asp Val Phe Val Lys Leu Glu Leu Leu Ser Gly Tyr Ile His Leu
530 535 540
Ser Ile Gln Val Asn Asn Gln Ser Lys Val Leu Leu Phe Ile Ser His
545 550 555 560
Asn Thr Ser Asp Gly Glu Trp His Phe Val Glu Val Ile Phe Ala Glu
565 570 575
Ala Val Thr Leu Thr Leu Ile Asp Asp Ser Cys Lys Glu Lys Cys Ile
580 585 590
Ala Lys Ala Pro Thr Pro Leu Glu Ser Asp Gln Ser Ile Cys Ala Phe
595 600 605
Gln Asn Ser Phe Leu Gly Gly Leu Pro Val Gly Met Thr Ser Asn Gly
610 615 620
Val Ala Leu Leu Asn Phe Tyr Asn Met Pro Ser Thr Pro Ser Phe Val
625 630 635 640
Gly Cys Leu Gln Asp Ile Lys Ile Asp Trp Asn His Ile Thr Leu Glu
645 650 655
Asn Ile Ser Ser Gly Ser Ser Leu Asn Val Lys Ala Gly Cys Val Arg
660 665 670
Lys Asp Trp Cys Glu Ser Gln Pro Cys Gln Ser Arg Gly Arg Cys Ile
675 680 685
Asn Leu Trp Leu Ser Tyr Gln Cys Asp Cys His Arg Pro Tyr Glu Gly
690 695 700
Pro Asn Cys Leu Arg Gly Glu Arg Lys Leu Ser Ala Met Ala Arg Ser
705 710 715 720
Ala Met Pro Gln Ser Arg Ala Glu Thr Ala Lys Thr Ala Arg Leu Leu
725 730 735
Leu Pro Ala Met Lys His Asn Asp Pro Thr Arg Leu Leu Leu Leu Val
740 745 750
Ala His
<210> 8
<211> 6170
<212> DNA
<213> 小鼠
<400> 8
attgttcacg gaagcctgag ggggacacga atccaatcca ggctggaaaa atctgctcca 60
ggattgactg gttaccgtct tcctgtgcct gtaaggtgct gtgaaagaga agtgctttct 120
gattctctgt ctgtggagga gccctgggag gggtgggaca gagatggcat cctggctctc 180
tgaggcacct gctcttctct gaaccacaca ggagtcaaga gccaaacagg gatagcttca 240
gcagcacttc agagggtgtt ctctaagtaa gaacatgaag ctcaagagaa ctgcctacct 300
tctcttcctg tacctcagct cctcactgct catctgcata aagaattcat tttgcaataa 360
aaacaatacc aggtgccttt caggtccttg ccaaaacaat tctacgtgca agcattttcc 420
acaagacaac aattgttgct tagacacagc caataatttg gacaaagact gtgaagatct 480
gaaagaccct tgcttctcga gtccctgcca aggaattgcc acttgtgtga aaatcccagg 540
ggaagggaac ttcctgtgtc agtgtcctcc tgggtacagc gggctgaact gtgaaactgc 600
caccaattcc tgtggaggga acctctgcca acatggaggc acctgccgta aagaccctga 660
gcaccctgtc tgtatctgcc ctcctggata tgctggaagg ttctgtgaga ctgatcacaa 720
tgagtgtgct tctagccctt gccacaatgg ggctatgtgc caggatggaa tcaatggcta 780
ctcctgcttc tgtgtgcctg gataccaagg caggcattgt gacttggaag tggatgaatg 840
tgtttctgat ccctgcaaga atgaggctgt gtgcctcaat gagataggaa gatacacttg 900
tgtctgccct caagagtttt ctggcgtgaa ctgtgagttg gaaattgatg aatgcagatc 960
ccagccttgt ctccacggtg ccacatgtca ggacgctcca gggggctact cctgtgactg 1020
tgcacctgga ttccttggag agcactgtga actcagcgtt aatgaatgtg aaagtcagcc 1080
gtgtctccat ggaggtctat gtgtggatgg aagaaacagt taccactgtg actgcacagg 1140
tagtggattc acagggatgc actgtgagtc cttgattcct ctttgttggt caaagccttg 1200
tcacaacgac gcgacatgtg aagatactgt tgacagctat atttgtcact gccggcctgg 1260
atacacaggt gccctgtgtg agacagacat aaatgaatgc agtagcaacc cctgccaatt 1320
ttggggggaa tgtgtcgagc tgtcctcaga gggtctatat ggaaacactg ctggcctgcc 1380
ttcctccttc agctatgttg gagcctcggg ctatgtgtgt atctgtcagc ctggattcac 1440
aggaattcac tgtgaagaag acgttgatga atgtttactg cacccttgcc taaatggtgg 1500
tacttgtgag aacctgcctg ggaattatgc ctgtcactgt ccctttgatg acacttctag 1560
gacattttat ggaggagaaa actgctcaga aattctcctg ggctgcactc atcaccagtg 1620
tctgaacaat ggaaaatgta tccctcattt ccaaaatggc cagcatggat tcacttgcca 1680
gtgtctttct ggctatgcgg ggcccctgtg tgaaactgtc accacacttt catttgggag 1740
caatggcttc ctatgggtca caagtggctc ccatacaggc atagggccag aatgtaacat 1800
atccttgagg tttcacactg ttcaaccaaa cgcacttctc ctcatccgag gcaacaagga 1860
cgtgtctatg aagctggagt tgctgaatgg ttgtgttcac ttatcaattg aagtctggaa 1920
tcagttaaag gtgctcctgt ctatttctca caacaccagt gatggagaat ggcatttcgt 1980
ggaggtaaca atcgcagaaa ctctaaccct tgccctagtt ggcggctcct gcaaggagaa 2040
gtgcaccacc aagtcttctg ttccagttga gaatcatcaa tcaatatgtg ctttgcagga 2100
ctcttttttg ggtggcttac caatggggac agccaacaac agtgtgtctg tgcttaacat 2160
ctataatgtg ccgtccacac cttcctttgt aggctgtctc caagacatta gatttgattt 2220
gaatcacatt actctggaga acgtttcatc tggcctgtca tcaaatgtta aagcaggctg 2280
cctgggaaag gactggtgtg aaagtcaacc ctgtcaaaac agaggacgct gcatcaactt 2340
gtggcagggt tatcagtgtg aatgtgacag gccctataca ggctccaact gcctgaaaga 2400
gtatgtagcg ggaagatttg gccaagatga ctccacagga tatgcggcct ttagtgttaa 2460
tgataattat ggacagaact tcagtctttc aatgtttgtc cgaacacgtc aacccctggg 2520
cttacttctg gctttggaaa atagtactta ccagtatgtc agtgtctggc tagagcacgg 2580
cagcctagca ctgcagactc caggctctcc caagttcatg gtaaactttt ttctcagtga 2640
tggaaatgtt cacttaatat ctttgagaat caaaccaaat gaaattgaac tgtatcagtc 2700
ttcacaaaac ctaggattca tttctgttcc tacatggaca attcgaagag gagacgtcat 2760
cttcattggt ggcttacctg acagagagaa gactgaagtt tatggtggct tcttcaaagg 2820
ctgtgttcaa gatgtcagat taaacagcca gactctggaa ttctttccca attcaacaaa 2880
caatgcatac gatgacccaa ttcttgtcaa tgtgactcaa ggctgtcccg gagacaacac 2940
atgtaagtcc aacccctgtc ataatggagg tgtctgccac tccctgtggg atgacttctc 3000
ctgctcctgc cctacaaaca cagcggggag agcctgcgag caagttcagt ggtgtcaact 3060
cagcccatgt cctcccactg cagagtgcca gctgctccct caagggtttg aatgtatcgc 3120
aaacgctgtt ttcagcggat taagcagaga aatactcttc agaagcaatg ggaacattac 3180
cagagaactc accaatatca catttgcttt cagaacacat gatacaaatg tgatgatatt 3240
gcatgcagaa aaagaaccag agtttcttaa tattagcatt caagatgcca gattattctt 3300
tcaattgcga agtggcaaca gcttttatac gctgcacctg atgggttccc aattggtgaa 3360
tgatggcaca tggcaccaag tgactttctc catgatagac ccagtggccc agacctcccg 3420
gtggcaaatg gaggtgaacg accagacacc ctttgtgata agtgaagttg ctactggaag 3480
cctgaacttt ttgaaggaca atacagacat ctatgtgggt gaccaatctg ttgacaatcc 3540
gaaaggcctg cagggctgtc tgagcacaat agagattgga ggcatatatc tttcttactt 3600
tgaaaatcta catggtttcc ctggtaagcc tcaggaagag caatttctca aagtttctac 3660
aaatatggta cttactggct gtttgccatc aaatgcctgc cactccagcc cctgtttgca 3720
tggaggaaac tgtgaagaca gctacagttc ttatcggtgt gcctgtctct cgggatggtc 3780
agggacacac tgtgaaatca acattgatga gtgcttttct agcccctgta tccatggcaa 3840
ctgctctgat ggagttgcag cctaccactg caggtgtgag cctggataca ccggtgtgaa 3900
ctgtgaggtg gatgtagaca attgcaagag tcatcagtgt gcaaatgggg ccacctgtgt 3960
tcctgaagct catggctact cttgtctctg ctttggaaat tttaccggga gattttgcag 4020
acacagcaga ttaccctcaa cagtctgtgg gaatgagaag agaaacttca cttgctacaa 4080
tggaggcagc tgctccatgt tccaggagga ctggcaatgt atgtgctggc caggtttcac 4140
tggagagtgg tgtgaagagg acatcaacga gtgtgcctcc gatccctgca tcaatggagg 4200
actgtgcagg gacttggtca acaggttcct atgcatctgt gatgtggcct tcgctggcga 4260
gcgctgtgag ctggacctgg ctgatgacag gctcctgggc attttcaccg ctgttggctc 4320
cggaactttg gccctgttct tcatcctctt gcttgctggg gttgcttctc ttattgcctc 4380
caacaaaagg gcgactcaag gaacctacag ccccagcggt caggagaagg ctggccctcg 4440
agtggaaatg tggatcagga tgccgccccc ggcactggaa aggctcatct aggagactgc 4500
tgctcttctc aggacagaga agaacatgat gagtaccggg tcgtgcctga gtgaagatgg 4560
ctttacatca ctagagatac atacagctgg gactgtggga aggaccttcc tgtggagtca 4620
ctgagtagtt atgtcatcca ttcacagaag agtgtccctg tgtttgcctg tcagcctcag 4680
aattagcaaa acatctagca gacagagaac acagtatttc agaagaactc cagaggctgc 4740
cccttaaact ctttactggt tgatccacat aaaatgctta gtagccaagt gccattaatt 4800
atacagagcc aagaagaaaa attagaatac aactttcact ttttattttg tagggaaggt 4860
tttatgtttt ggtttgttgt tgttgttgtg acagtgacag tgactcatta catagaccaa 4920
gctggcctca aaatcacatg gaccctcggg attacatgtg tccgaccatg ttcatcttat 4980
ttttgaatct tctgtcatat ggtaaaagat tccagtggga cctgaggagt gactagctag 5040
gtaaagcaag ggctgtgtaa gtgccagaac tggtgtttgt gtcctcatta tccacataag 5100
tgccaagtga gtgtggcccc tgcctgtcat cctaggcctc aggagatatc actgctcact 5160
ggagcaagcc ggttaaactg ttagggcagg taagttttga cttcaagtga gagaccctga 5220
ctcaatatga aaggcaatta gtgagtcaag atgaccctgt atgctaacct cttgcctata 5280
catgcatata cacacattta catatgtgcc caaacatgag gacacaagca cacgcgcgcg 5340
cgcacacaca cacacacaca cacacacaca cacacacaca cacacacacg agtctaattg 5400
tatatagtga taacagtaca ctttcctcct tctatttcgg atttagagaa agccatgaga 5460
agcgtgtatg gtttaaacca tgacccaagc ataacaaata aagttgaaat agttgttctc 5520
ctgtccaagc ttgtctttat tgttgtgcat tctgtaagct ggttgcttgg ttggctgatg 5580
gatggcttct gtttgtttgt tgttttttgt ttgtttgttt gtctgggata ttacatgtaa 5640
gaaaaataac tggtaagaac aatcaaagaa ctttgttatg aattaaatct tttgtctaag 5700
tcacttagag tcattattct ttatgtagat ttgcttccag tcaggacatt tcctagacag 5760
aatttaagac agtaagaaaa tgatttgtca cgtctgaaag aggttcttta ctttcaggga 5820
cttttgataa tgcccaacag agatggcatc gaaagaggag ctcatagcga gatgggcatt 5880
tgtgcatcct caaggagaaa atattgtacc ttctgtttgt atattgtcta ttctgtgatg 5940
gctgtatctt acatatgttt tgatgcatgt aacaatagta tcatatgaaa taaattatat 6000
atatatataa tatataatat atatcacaag ataaaaattg aaattacata aactttaaat 6060
ctaaaagaag aaacctatcc ttcccaagta ttatcagtgc agtcaccgag ctttttttgt 6120
ttttttgtat tagccatttc ttcataatac aggaagttct ataacttcaa 6170
<210> 9
<211> 1405
<212> PRT
<213> 小鼠
<400> 9
Met Lys Leu Lys Arg Thr Ala Tyr Leu Leu Phe Leu Tyr Leu Ser Ser
1 5 10 15
Ser Leu Leu Ile Cys Ile Lys Asn Ser Phe Cys Asn Lys Asn Asn Thr
20 25 30
Arg Cys Leu Ser Gly Pro Cys Gln Asn Asn Ser Thr Cys Lys His Phe
35 40 45
Pro Gln Asp Asn Asn Cys Cys Leu Asp Thr Ala Asn Asn Leu Asp Lys
50 55 60
Asp Cys Glu Asp Leu Lys Asp Pro Cys Phe Ser Ser Pro Cys Gln Gly
65 70 75 80
Ile Ala Thr Cys Val Lys Ile Pro Gly Glu Gly Asn Phe Leu Cys Gln
85 90 95
Cys Pro Pro Gly Tyr Ser Gly Leu Asn Cys Glu Thr Ala Thr Asn Ser
100 105 110
Cys Gly Gly Asn Leu Cys Gln His Gly Gly Thr Cys Arg Lys Asp Pro
115 120 125
Glu His Pro Val Cys Ile Cys Pro Pro Gly Tyr Ala Gly Arg Phe Cys
130 135 140
Glu Thr Asp His Asn Glu Cys Ala Ser Ser Pro Cys His Asn Gly Ala
145 150 155 160
Met Cys Gln Asp Gly Ile Asn Gly Tyr Ser Cys Phe Cys Val Pro Gly
165 170 175
Tyr Gln Gly Arg His Cys Asp Leu Glu Val Asp Glu Cys Val Ser Asp
180 185 190
Pro Cys Lys Asn Glu Ala Val Cys Leu Asn Glu Ile Gly Arg Tyr Thr
195 200 205
Cys Val Cys Pro Gln Glu Phe Ser Gly Val Asn Cys Glu Leu Glu Ile
210 215 220
Asp Glu Cys Arg Ser Gln Pro Cys Leu His Gly Ala Thr Cys Gln Asp
225 230 235 240
Ala Pro Gly Gly Tyr Ser Cys Asp Cys Ala Pro Gly Phe Leu Gly Glu
245 250 255
His Cys Glu Leu Ser Val Asn Glu Cys Glu Ser Gln Pro Cys Leu His
260 265 270
Gly Gly Leu Cys Val Asp Gly Arg Asn Ser Tyr His Cys Asp Cys Thr
275 280 285
Gly Ser Gly Phe Thr Gly Met His Cys Glu Ser Leu Ile Pro Leu Cys
290 295 300
Trp Ser Lys Pro Cys His Asn Asp Ala Thr Cys Glu Asp Thr Val Asp
305 310 315 320
Ser Tyr Ile Cys His Cys Arg Pro Gly Tyr Thr Gly Ala Leu Cys Glu
325 330 335
Thr Asp Ile Asn Glu Cys Ser Ser Asn Pro Cys Gln Phe Trp Gly Glu
340 345 350
Cys Val Glu Leu Ser Ser Glu Gly Leu Tyr Gly Asn Thr Ala Gly Leu
355 360 365
Pro Ser Ser Phe Ser Tyr Val Gly Ala Ser Gly Tyr Val Cys Ile Cys
370 375 380
Gln Pro Gly Phe Thr Gly Ile His Cys Glu Glu Asp Val Asp Glu Cys
385 390 395 400
Leu Leu His Pro Cys Leu Asn Gly Gly Thr Cys Glu Asn Leu Pro Gly
405 410 415
Asn Tyr Ala Cys His Cys Pro Phe Asp Asp Thr Ser Arg Thr Phe Tyr
420 425 430
Gly Gly Glu Asn Cys Ser Glu Ile Leu Leu Gly Cys Thr His His Gln
435 440 445
Cys Leu Asn Asn Gly Lys Cys Ile Pro His Phe Gln Asn Gly Gln His
450 455 460
Gly Phe Thr Cys Gln Cys Leu Ser Gly Tyr Ala Gly Pro Leu Cys Glu
465 470 475 480
Thr Val Thr Thr Leu Ser Phe Gly Ser Asn Gly Phe Leu Trp Val Thr
485 490 495
Ser Gly Ser His Thr Gly Ile Gly Pro Glu Cys Asn Ile Ser Leu Arg
500 505 510
Phe His Thr Val Gln Pro Asn Ala Leu Leu Leu Ile Arg Gly Asn Lys
515 520 525
Asp Val Ser Met Lys Leu Glu Leu Leu Asn Gly Cys Val His Leu Ser
530 535 540
Ile Glu Val Trp Asn Gln Leu Lys Val Leu Leu Ser Ile Ser His Asn
545 550 555 560
Thr Ser Asp Gly Glu Trp His Phe Val Glu Val Thr Ile Ala Glu Thr
565 570 575
Leu Thr Leu Ala Leu Val Gly Gly Ser Cys Lys Glu Lys Cys Thr Thr
580 585 590
Lys Ser Ser Val Pro Val Glu Asn His Gln Ser Ile Cys Ala Leu Gln
595 600 605
Asp Ser Phe Leu Gly Gly Leu Pro Met Gly Thr Ala Asn Asn Ser Val
610 615 620
Ser Val Leu Asn Ile Tyr Asn Val Pro Ser Thr Pro Ser Phe Val Gly
625 630 635 640
Cys Leu Gln Asp Ile Arg Phe Asp Leu Asn His Ile Thr Leu Glu Asn
645 650 655
Val Ser Ser Gly Leu Ser Ser Asn Val Lys Ala Gly Cys Leu Gly Lys
660 665 670
Asp Trp Cys Glu Ser Gln Pro Cys Gln Asn Arg Gly Arg Cys Ile Asn
675 680 685
Leu Trp Gln Gly Tyr Gln Cys Glu Cys Asp Arg Pro Tyr Thr Gly Ser
690 695 700
Asn Cys Leu Lys Glu Tyr Val Ala Gly Arg Phe Gly Gln Asp Asp Ser
705 710 715 720
Thr Gly Tyr Ala Ala Phe Ser Val Asn Asp Asn Tyr Gly Gln Asn Phe
725 730 735
Ser Leu Ser Met Phe Val Arg Thr Arg Gln Pro Leu Gly Leu Leu Leu
740 745 750
Ala Leu Glu Asn Ser Thr Tyr Gln Tyr Val Ser Val Trp Leu Glu His
755 760 765
Gly Ser Leu Ala Leu Gln Thr Pro Gly Ser Pro Lys Phe Met Val Asn
770 775 780
Phe Phe Leu Ser Asp Gly Asn Val His Leu Ile Ser Leu Arg Ile Lys
785 790 795 800
Pro Asn Glu Ile Glu Leu Tyr Gln Ser Ser Gln Asn Leu Gly Phe Ile
805 810 815
Ser Val Pro Thr Trp Thr Ile Arg Arg Gly Asp Val Ile Phe Ile Gly
820 825 830
Gly Leu Pro Asp Arg Glu Lys Thr Glu Val Tyr Gly Gly Phe Phe Lys
835 840 845
Gly Cys Val Gln Asp Val Arg Leu Asn Ser Gln Thr Leu Glu Phe Phe
850 855 860
Pro Asn Ser Thr Asn Asn Ala Tyr Asp Asp Pro Ile Leu Val Asn Val
865 870 875 880
Thr Gln Gly Cys Pro Gly Asp Asn Thr Cys Lys Ser Asn Pro Cys His
885 890 895
Asn Gly Gly Val Cys His Ser Leu Trp Asp Asp Phe Ser Cys Ser Cys
900 905 910
Pro Thr Asn Thr Ala Gly Arg Ala Cys Glu Gln Val Gln Trp Cys Gln
915 920 925
Leu Ser Pro Cys Pro Pro Thr Ala Glu Cys Gln Leu Leu Pro Gln Gly
930 935 940
Phe Glu Cys Ile Ala Asn Ala Val Phe Ser Gly Leu Ser Arg Glu Ile
945 950 955 960
Leu Phe Arg Ser Asn Gly Asn Ile Thr Arg Glu Leu Thr Asn Ile Thr
965 970 975
Phe Ala Phe Arg Thr His Asp Thr Asn Val Met Ile Leu His Ala Glu
980 985 990
Lys Glu Pro Glu Phe Leu Asn Ile Ser Ile Gln Asp Ala Arg Leu Phe
995 1000 1005
Phe Gln Leu Arg Ser Gly Asn Ser Phe Tyr Thr Leu His Leu Met
1010 1015 1020
Gly Ser Gln Leu Val Asn Asp Gly Thr Trp His Gln Val Thr Phe
1025 1030 1035
Ser Met Ile Asp Pro Val Ala Gln Thr Ser Arg Trp Gln Met Glu
1040 1045 1050
Val Asn Asp Gln Thr Pro Phe Val Ile Ser Glu Val Ala Thr Gly
1055 1060 1065
Ser Leu Asn Phe Leu Lys Asp Asn Thr Asp Ile Tyr Val Gly Asp
1070 1075 1080
Gln Ser Val Asp Asn Pro Lys Gly Leu Gln Gly Cys Leu Ser Thr
1085 1090 1095
Ile Glu Ile Gly Gly Ile Tyr Leu Ser Tyr Phe Glu Asn Leu His
1100 1105 1110
Gly Phe Pro Gly Lys Pro Gln Glu Glu Gln Phe Leu Lys Val Ser
1115 1120 1125
Thr Asn Met Val Leu Thr Gly Cys Leu Pro Ser Asn Ala Cys His
1130 1135 1140
Ser Ser Pro Cys Leu His Gly Gly Asn Cys Glu Asp Ser Tyr Ser
1145 1150 1155
Ser Tyr Arg Cys Ala Cys Leu Ser Gly Trp Ser Gly Thr His Cys
1160 1165 1170
Glu Ile Asn Ile Asp Glu Cys Phe Ser Ser Pro Cys Ile His Gly
1175 1180 1185
Asn Cys Ser Asp Gly Val Ala Ala Tyr His Cys Arg Cys Glu Pro
1190 1195 1200
Gly Tyr Thr Gly Val Asn Cys Glu Val Asp Val Asp Asn Cys Lys
1205 1210 1215
Ser His Gln Cys Ala Asn Gly Ala Thr Cys Val Pro Glu Ala His
1220 1225 1230
Gly Tyr Ser Cys Leu Cys Phe Gly Asn Phe Thr Gly Arg Phe Cys
1235 1240 1245
Arg His Ser Arg Leu Pro Ser Thr Val Cys Gly Asn Glu Lys Arg
1250 1255 1260
Asn Phe Thr Cys Tyr Asn Gly Gly Ser Cys Ser Met Phe Gln Glu
1265 1270 1275
Asp Trp Gln Cys Met Cys Trp Pro Gly Phe Thr Gly Glu Trp Cys
1280 1285 1290
Glu Glu Asp Ile Asn Glu Cys Ala Ser Asp Pro Cys Ile Asn Gly
1295 1300 1305
Gly Leu Cys Arg Asp Leu Val Asn Arg Phe Leu Cys Ile Cys Asp
1310 1315 1320
Val Ala Phe Ala Gly Glu Arg Cys Glu Leu Asp Leu Ala Asp Asp
1325 1330 1335
Arg Leu Leu Gly Ile Phe Thr Ala Val Gly Ser Gly Thr Leu Ala
1340 1345 1350
Leu Phe Phe Ile Leu Leu Leu Ala Gly Val Ala Ser Leu Ile Ala
1355 1360 1365
Ser Asn Lys Arg Ala Thr Gln Gly Thr Tyr Ser Pro Ser Gly Gln
1370 1375 1380
Glu Lys Ala Gly Pro Arg Val Glu Met Trp Ile Arg Met Pro Pro
1385 1390 1395
Pro Ala Leu Glu Arg Leu Ile
1400 1405
<210> 10
<211> 5764
<212> DNA
<213> 小鼠
<400> 10
ttacagaagg gaggcaccgt gtctcctgcg gggtaggagc taagaatata gcaaagctgc 60
ttgggaagtg gcacagctga ctcttacatt aagccccact gatccagctt gaagaggagt 120
gaggcaaagc tgaaccctcc cactctcctt gacaagtgca agcccacact tttggaaaaa 180
agcacaaaga cgtcagaaac ggttcctgtc gacctactag gctttggatg gctaagtgtt 240
tttgctttgt atggaaatat gtttggacac aagacacaag gttttcacat tttaatggca 300
gtgctcatag gaattcactg tgaagaagac gttgatgaat gtttactgca cccttgccta 360
aatggtggta cttgtgagaa cctgcctggg aattatgcct gtcactgtcc ctttgatgac 420
acttctagga cattttatgg aggagaaaac tgctcagaaa ttctcctggg ctgcactcat 480
caccagtgtc tgaacaatgg aaaatgtatc cctcatttcc aaaatggcca gcatggattc 540
acttgccagt gtctttctgg ctatgcgggg cccctgtgtg aaactgtcac cacactttca 600
tttgggagca atggcttcct atgggtcaca agtggctccc atacaggcat agggccagaa 660
tgtaacatat ccttgaggtt tcacactgtt caaccaaacg cacttctcct catccgaggc 720
aacaaggacg tgtctatgaa gctggagttg ctgaatggtt gtgttcactt atcaattgaa 780
gtctggaatc agttaaaggt gctcctgtct atttctcaca acaccagtga tggagaatgg 840
catttcgtgg aggtaacaat cgcagaaact ctaacccttg ccctagttgg cggctcctgc 900
aaggagaagt gcaccaccaa gtcttctgtt ccagttgaga atcatcaatc aatatgtgct 960
ttgcaggact cttttttggg tggcttacca atggggacag ccaacaacag tgtgtctgtg 1020
cttaacatct ataatgtgcc gtccacacct tcctttgtag gctgtctcca agacattaga 1080
tttgatttga atcacattac tctggagaac gtttcatctg gcctgtcatc aaatgttaaa 1140
gcaggctgcc tgggaaagga ctggtgtgaa agtcaaccct gtcaaaacag aggacgctgc 1200
atcaacttgt ggcagggtta tcagtgtgaa tgtgacaggc cctatacagg ctccaactgc 1260
ctgaaagagt atgtagcggg aagatttggc caagatgact ccacaggata tgcggccttt 1320
agtgttaatg ataattatgg acagaacttc agtctttcaa tgtttgtccg aacacgtcaa 1380
cccctgggct tacttctggc tttggaaaat agtacttacc agtatgtcag tgtctggcta 1440
gagcacggca gcctagcact gcagactcca ggctctccca agttcatggt aaactttttt 1500
ctcagtgatg gaaatgttca cttaatatct ttgagaatca aaccaaatga aattgaactg 1560
tatcagtctt cacaaaacct aggattcatt tctgttccta catggacaat tcgaagagga 1620
gacgtcatct tcattggtgg cttacctgac agagagaaga ctgaagttta tggtggcttc 1680
ttcaaaggct gtgttcaaga tgtcagatta aacagccaga ctctggaatt ctttcccaat 1740
tcaacaaaca atgcatacga tgacccaatt cttgtcaatg tgactcaagg ctgtcccgga 1800
gacaacacat gtaagtccaa cccctgtcat aatggaggtg tctgccactc cctgtgggat 1860
gacttctcct gctcctgccc tacaaacaca gcggggagag cctgcgagca agttcagtgg 1920
tgtcaactca gcccatgtcc tcccactgca gagtgccagc tgctccctca agggtttgaa 1980
tgtatcgcaa acgctgtttt cagcggatta agcagagaaa tactcttcag aagcaatggg 2040
aacattacca gagaactcac caatatcaca tttgctttca gaacacatga tacaaatgtg 2100
atgatattgc atgcagaaaa agaaccagag tttcttaata ttagcattca agatgccaga 2160
ttattctttc aattgcgaag tggcaacagc ttttatacgc tgcacctgat gggttcccaa 2220
ttggtgaatg atggcacatg gcaccaagtg actttctcca tgatagaccc agtggcccag 2280
acctcccggt ggcaaatgga ggtgaacgac cagacaccct ttgtgataag tgaagttgct 2340
actggaagcc tgaacttttt gaaggacaat acagacatct atgtgggtga ccaatctgtt 2400
gacaatccga aaggcctgca gggctgtctg agcacaatag agattggagg catatatctt 2460
tcttactttg aaaatctaca tggtttccct ggtaagcctc aggaagagca atttctcaaa 2520
gtttctacaa atatggtact tactggctgt ttgccatcaa atgcctgcca ctccagcccc 2580
tgtttgcatg gaggaaactg tgaagacagc tacagttctt atcggtgtgc ctgtctctcg 2640
ggatggtcag ggacacactg tgaaatcaac attgatgagt gcttttctag cccctgtatc 2700
catggcaact gctctgatgg agttgcagcc taccactgca ggtgtgagcc tggatacacc 2760
ggtgtgaact gtgaggtgga tgtagacaat tgcaagagtc atcagtgtgc aaatggggcc 2820
acctgtgttc ctgaagctca tggctactct tgtctctgct ttggaaattt taccgggaga 2880
ttttgcagac acagcagatt accctcaaca gtctgtggga atgagaagag aaacttcact 2940
tgctacaatg gaggcagctg ctccatgttc caggaggact ggcaatgtat gtgctggcca 3000
ggtttcactg gagagtggtg tgaagaggac atcaacgagt gtgcctccga tccctgcatc 3060
aatggaggac tgtgcaggga cttggtcaac aggttcctat gcatctgtga tgtggccttc 3120
gctggcgagc gctgtgagct ggacgtaagc ggcctttcct tttatgtgtc cctcttacta 3180
tggcaaaacc tctttcagct cctgtcctac ctcgtactgc gcatgaatga tgagccagtt 3240
gtagagtggg gggcacagga aaattattaa tgtgcatggg agcattcaca agtgtaaaac 3300
attgacttgc aagaaacatc ttgtctcagt gtaggtttct aggaaagaca aagggaacat 3360
tagggaatag actccatcta gagcactggt tctcagtctt cctaatgctg caacccttta 3420
gtacagctct tcctgttgta gtgatcgcag ccataacatt attttcattg ccacttcata 3480
actgtaatcc ttctactgct gtgaatcaca atggaaatat ttatgttttc tgatggtctt 3540
aagcaacacc tctgaaaaag tcattgaccc cccccccaaa ggggctgtga tccacaggtt 3600
gagaaatgct catctggaag gtaaccatgc atttaagtgt acctctagta gtttgggtct 3660
atagaagata ttctcctatt ctaccttttt agacacgcca gaagagggca tctgattcca 3720
ttaaagatga ttgggagcca ccgtgtggtt cctgagaact gtactcgggc cctttggaag 3780
agcaatcagt gctctttcca gcccctaaga atatttttaa tacagccaga aaggtctcat 3840
tacccagtgt actgagccct aaggcacttt catcctcaat cgttccatgt tgaatggttt 3900
tcattacatt tggaaaatgt tttctctcca ctctaccttt acatgttcct attttcctat 3960
tgacaatttg ccccttcact gtaattctaa tttggtgtgg tccttcttct cataagttta 4020
tatgtgacat gaacatttaa aaatatctat gaatatttta tagtcatgta tgtctttctg 4080
caaagctatt caaatgaact atggacagtt cttttctaca cgaagaagag atgagtttaa 4140
tccccagtaa catgagaaaa agatgagtga gggacagtgc tcacagtatc cctcactagc 4200
atcatttgtg attccatggg ccattttttt ccaccagcaa atagcagaga gccctttccc 4260
tattcgtttc tcttacactt ccccttttct gttacaactg aacactttac attagttact 4320
cctttgtagg gggtttgact tttccaccgt tttctctggt tcactattta tgctaagtat 4380
ctgtgcaggg cgggtatatc agtccaacag aggtgtcatt agtgttcatt gaggaggaaa 4440
tactttgcat gaattcatga catcattgaa gtagcagtgg ccagaaagat acccttctgc 4500
gaatgtgtct gtgtattcag aagctgccct ggttagaaaa catgtgggtc acttttcctt 4560
tgcatgttac cagtgctcac tgggtcatga ttgttttaag acagagcttt tgctgtggca 4620
atgaccaagg tgaatccaga gatgcagatc agacaaagga caagacaatg tactatctga 4680
gtaaaaccct gccttgactt actcctcagt acttagagat tttacatagc aacctccacc 4740
ctgtggcaac ccgttcacac tagcagtgat gctgagattt gcccttcctt ctcatcatct 4800
tcctcacatc caaagcattt tgtgtccaca ctgctgtttc agataactgt ttctaaagtg 4860
ggattgttgt agccagaaag gtagggaaaa tgttccccaa aatatttgca ttcttaagta 4920
tgtgaagtaa gtagattata gtcagagaca atatgtaagg tttcaggttc actcccttct 4980
acacatatct tcaactgtgt atttgcagaa tattctgaat gtgacatact cccaacagaa 5040
tatatttaag gagtatttat ccacagtatt gttctctgta cagttctagt gcttctattg 5100
tcactgcaat tgtcaattgt ttttctgctt tccaactgtc ttattatcat ttaatagcat 5160
cttgctaaat gccctctttc tattctcctt atttctccat agttcatgtg tgtctgtgtg 5220
actaaggatt ctcctcattt ttgcagaaaa ataaaatctt ttcttcttta tgtcctgctt 5280
gtcattctct ggtgacacat gtctttgctt acttggactg agggttgtac agtaagtaca 5340
gaagcaggct cagtcacaca gacagagaca caccaccacc agcagcagca gcaccaccac 5400
caccaccacc accaccagaa aacagtatga gtactcatct cttgattaca tgtcatttca 5460
agtaagcacc atgacaccga gggccaggtt ccatggactt tctctgttag gcacgtgatt 5520
ctttagctga cctttgagaa cagactccaa caacctcact tatttttact gttgacttat 5580
atcatctctg acaacactgg acttcgtttg agctagtcaa gaggaaagac catgacacct 5640
aagggacaga aattcacaca ctcggttttt cataattcac acacattcct atgtatcaaa 5700
tctctgtaat agatgacatt tacttgaata aaaagtcatt tccctttgct gatgtttcat 5760
cttt 5764
<210> 11
<211> 1003
<212> PRT
<213> 小鼠
<400> 11
Met Phe Gly His Lys Thr Gln Gly Phe His Ile Leu Met Ala Val Leu
1 5 10 15
Ile Gly Ile His Cys Glu Glu Asp Val Asp Glu Cys Leu Leu His Pro
20 25 30
Cys Leu Asn Gly Gly Thr Cys Glu Asn Leu Pro Gly Asn Tyr Ala Cys
35 40 45
His Cys Pro Phe Asp Asp Thr Ser Arg Thr Phe Tyr Gly Gly Glu Asn
50 55 60
Cys Ser Glu Ile Leu Leu Gly Cys Thr His His Gln Cys Leu Asn Asn
65 70 75 80
Gly Lys Cys Ile Pro His Phe Gln Asn Gly Gln His Gly Phe Thr Cys
85 90 95
Gln Cys Leu Ser Gly Tyr Ala Gly Pro Leu Cys Glu Thr Val Thr Thr
100 105 110
Leu Ser Phe Gly Ser Asn Gly Phe Leu Trp Val Thr Ser Gly Ser His
115 120 125
Thr Gly Ile Gly Pro Glu Cys Asn Ile Ser Leu Arg Phe His Thr Val
130 135 140
Gln Pro Asn Ala Leu Leu Leu Ile Arg Gly Asn Lys Asp Val Ser Met
145 150 155 160
Lys Leu Glu Leu Leu Asn Gly Cys Val His Leu Ser Ile Glu Val Trp
165 170 175
Asn Gln Leu Lys Val Leu Leu Ser Ile Ser His Asn Thr Ser Asp Gly
180 185 190
Glu Trp His Phe Val Glu Val Thr Ile Ala Glu Thr Leu Thr Leu Ala
195 200 205
Leu Val Gly Gly Ser Cys Lys Glu Lys Cys Thr Thr Lys Ser Ser Val
210 215 220
Pro Val Glu Asn His Gln Ser Ile Cys Ala Leu Gln Asp Ser Phe Leu
225 230 235 240
Gly Gly Leu Pro Met Gly Thr Ala Asn Asn Ser Val Ser Val Leu Asn
245 250 255
Ile Tyr Asn Val Pro Ser Thr Pro Ser Phe Val Gly Cys Leu Gln Asp
260 265 270
Ile Arg Phe Asp Leu Asn His Ile Thr Leu Glu Asn Val Ser Ser Gly
275 280 285
Leu Ser Ser Asn Val Lys Ala Gly Cys Leu Gly Lys Asp Trp Cys Glu
290 295 300
Ser Gln Pro Cys Gln Asn Arg Gly Arg Cys Ile Asn Leu Trp Gln Gly
305 310 315 320
Tyr Gln Cys Glu Cys Asp Arg Pro Tyr Thr Gly Ser Asn Cys Leu Lys
325 330 335
Glu Tyr Val Ala Gly Arg Phe Gly Gln Asp Asp Ser Thr Gly Tyr Ala
340 345 350
Ala Phe Ser Val Asn Asp Asn Tyr Gly Gln Asn Phe Ser Leu Ser Met
355 360 365
Phe Val Arg Thr Arg Gln Pro Leu Gly Leu Leu Leu Ala Leu Glu Asn
370 375 380
Ser Thr Tyr Gln Tyr Val Ser Val Trp Leu Glu His Gly Ser Leu Ala
385 390 395 400
Leu Gln Thr Pro Gly Ser Pro Lys Phe Met Val Asn Phe Phe Leu Ser
405 410 415
Asp Gly Asn Val His Leu Ile Ser Leu Arg Ile Lys Pro Asn Glu Ile
420 425 430
Glu Leu Tyr Gln Ser Ser Gln Asn Leu Gly Phe Ile Ser Val Pro Thr
435 440 445
Trp Thr Ile Arg Arg Gly Asp Val Ile Phe Ile Gly Gly Leu Pro Asp
450 455 460
Arg Glu Lys Thr Glu Val Tyr Gly Gly Phe Phe Lys Gly Cys Val Gln
465 470 475 480
Asp Val Arg Leu Asn Ser Gln Thr Leu Glu Phe Phe Pro Asn Ser Thr
485 490 495
Asn Asn Ala Tyr Asp Asp Pro Ile Leu Val Asn Val Thr Gln Gly Cys
500 505 510
Pro Gly Asp Asn Thr Cys Lys Ser Asn Pro Cys His Asn Gly Gly Val
515 520 525
Cys His Ser Leu Trp Asp Asp Phe Ser Cys Ser Cys Pro Thr Asn Thr
530 535 540
Ala Gly Arg Ala Cys Glu Gln Val Gln Trp Cys Gln Leu Ser Pro Cys
545 550 555 560
Pro Pro Thr Ala Glu Cys Gln Leu Leu Pro Gln Gly Phe Glu Cys Ile
565 570 575
Ala Asn Ala Val Phe Ser Gly Leu Ser Arg Glu Ile Leu Phe Arg Ser
580 585 590
Asn Gly Asn Ile Thr Arg Glu Leu Thr Asn Ile Thr Phe Ala Phe Arg
595 600 605
Thr His Asp Thr Asn Val Met Ile Leu His Ala Glu Lys Glu Pro Glu
610 615 620
Phe Leu Asn Ile Ser Ile Gln Asp Ala Arg Leu Phe Phe Gln Leu Arg
625 630 635 640
Ser Gly Asn Ser Phe Tyr Thr Leu His Leu Met Gly Ser Gln Leu Val
645 650 655
Asn Asp Gly Thr Trp His Gln Val Thr Phe Ser Met Ile Asp Pro Val
660 665 670
Ala Gln Thr Ser Arg Trp Gln Met Glu Val Asn Asp Gln Thr Pro Phe
675 680 685
Val Ile Ser Glu Val Ala Thr Gly Ser Leu Asn Phe Leu Lys Asp Asn
690 695 700
Thr Asp Ile Tyr Val Gly Asp Gln Ser Val Asp Asn Pro Lys Gly Leu
705 710 715 720
Gln Gly Cys Leu Ser Thr Ile Glu Ile Gly Gly Ile Tyr Leu Ser Tyr
725 730 735
Phe Glu Asn Leu His Gly Phe Pro Gly Lys Pro Gln Glu Glu Gln Phe
740 745 750
Leu Lys Val Ser Thr Asn Met Val Leu Thr Gly Cys Leu Pro Ser Asn
755 760 765
Ala Cys His Ser Ser Pro Cys Leu His Gly Gly Asn Cys Glu Asp Ser
770 775 780
Tyr Ser Ser Tyr Arg Cys Ala Cys Leu Ser Gly Trp Ser Gly Thr His
785 790 795 800
Cys Glu Ile Asn Ile Asp Glu Cys Phe Ser Ser Pro Cys Ile His Gly
805 810 815
Asn Cys Ser Asp Gly Val Ala Ala Tyr His Cys Arg Cys Glu Pro Gly
820 825 830
Tyr Thr Gly Val Asn Cys Glu Val Asp Val Asp Asn Cys Lys Ser His
835 840 845
Gln Cys Ala Asn Gly Ala Thr Cys Val Pro Glu Ala His Gly Tyr Ser
850 855 860
Cys Leu Cys Phe Gly Asn Phe Thr Gly Arg Phe Cys Arg His Ser Arg
865 870 875 880
Leu Pro Ser Thr Val Cys Gly Asn Glu Lys Arg Asn Phe Thr Cys Tyr
885 890 895
Asn Gly Gly Ser Cys Ser Met Phe Gln Glu Asp Trp Gln Cys Met Cys
900 905 910
Trp Pro Gly Phe Thr Gly Glu Trp Cys Glu Glu Asp Ile Asn Glu Cys
915 920 925
Ala Ser Asp Pro Cys Ile Asn Gly Gly Leu Cys Arg Asp Leu Val Asn
930 935 940
Arg Phe Leu Cys Ile Cys Asp Val Ala Phe Ala Gly Glu Arg Cys Glu
945 950 955 960
Leu Asp Val Ser Gly Leu Ser Phe Tyr Val Ser Leu Leu Leu Trp Gln
965 970 975
Asn Leu Phe Gln Leu Leu Ser Tyr Leu Val Leu Arg Met Asn Asp Glu
980 985 990
Pro Val Val Glu Trp Gly Ala Gln Glu Asn Tyr
995 1000
<210> 12
<211> 5801
<212> DNA
<213> 小鼠
<400> 12
tgttcacgga agcctgaggg ggacacgaat ccaatccagg ctggaaaaat ctgctccagg 60
attgactggt taccgtcttc ctgtgcctgt aaggtgctgt gaaagagaag tgctttctga 120
ttctctgtct gtggaggagc cctgggaggg gtgggacaga gatggcatcc tggctctctg 180
aggcacctgc tcttctctga accacacagg agtcaagagc caaacaggga tagcttcagc 240
agcacttcag agggtgttct ctaagtaaga acatgaagct caagagaact gcctaccttc 300
tcttcctgta cctcagctcc tcactgctca tctgcataaa gaattcattt tgcaataaaa 360
acaataccag gtgcctttca ggtccttgcc aaaacaattc tacgtgcaag cattttccac 420
aagacaacaa ttgttgctta gacacagcca ataatttgga caaagactgt gaagatctga 480
aagacccttg cttctcgagt ccctgccaag gaattgccac ttgtgtgaaa atcccagggg 540
aagggaactt cctgtgtcag tgtcctcctg ggtacagcgg gctgaactgt gaaactgcca 600
ccaattcctg tggagggaac ctctgccaac atggaggcac ctgccgtaaa gaccctgagc 660
accctgtctg tatctgccct cctggatatg ctggaaggtt ctgtgagact gatcacaatg 720
agtgtgcttc tagcccttgc cacaatgggg ctatgtgcca ggatggaatc aatggctact 780
cctgcttctg tgtgcctgga taccaaggca ggcattgtga cttggaagtg gatgaatgtg 840
tttctgatcc ctgcaagaat gaggctgtgt gcctcaatga gataggaaga tacacttgtg 900
tctgccctca agagttttct ggcgtgaact gtgagttgga aattgatgaa tgcagatccc 960
agccttgtct ccacggtgcc acatgtcagg acgctccagg gggctactcc tgtgactgtg 1020
cacctggatt ccttggagag cactgtgaac tcagcgttaa tgaatgtgaa agtcagccgt 1080
gtctccatgg aggtctatgt gtggatggaa gaaacagtta ccactgtgac tgcacaggta 1140
gtggattcac agggatgcac tgtgagtcct tgattcctct ttgttggtca aagccttgtc 1200
acaacgacgc gacatgtgaa gatactgttg acagctatat ttgtcactgc cggcctggat 1260
acacaggtgc cctgtgtgag acagacataa atgaatgcag tagcaacccc tgccaatttt 1320
ggggggaatg tgtcgagctg tcctcagagg gtctatatgg aaacactgct ggcctgcctt 1380
cctccttcag ctatgttgga gcctcgggct atgtgtgtat ctgtcagcct ggattcacag 1440
gaattcactg tgaagaagac gttgatgaat gtttactgca cccttgccta aatggtggta 1500
cttgtgagaa cctgcctggg aattatgcct gtcactgtcc ctttgatgac acttctagga 1560
cattttatgg aggagaaaac tgctcagaaa ttctcctggg ctgcactcat caccagtgtc 1620
tgaacaatgg aaaatgtatc cctcatttcc aaaatggcca gcatggattc acttgccagt 1680
gtctttctgg ctatgcgggg cccctgtgtg aaactgtcac cacactttca tttgggagca 1740
atggcttcct atgggtcaca agtggctccc atacaggcat agggccagaa tgtaacatat 1800
ccttgaggtt tcacactgtt caaccaaacg cacttctcct catccgaggc aacaaggacg 1860
tgtctatgaa gctggagttg ctgaatggtt gtgttcactt atcaattgaa gtctggaatc 1920
agttaaaggt gctcctgtct atttctcaca acaccagtga tggagaatgg catttcgtgg 1980
aggtaacaat cgcagaaact ctaacccttg ccctagttgg cggctcctgc aaggagaagt 2040
gcaccaccaa gtcttctgtt ccagttgaga atcatcaatc aatatgtgct ttgcaggact 2100
cttttttggg tggcttacca atggggacag ccaacaacag tgtgtctgtg cttaacatct 2160
ataatgtgcc gtccacacct tcctttgtag gctgtctcca agacattaga tttgatttga 2220
atcacattac tctggagaac gtttcatctg gcctgtcatc aaatgttaaa gcaggctgcc 2280
tgggaaagga ctggtgtgaa agtcaaccct gtcaaaacag aggacgctgc atcaacttgt 2340
ggcagggtta tcagtgtgaa tgtgacaggc cctatacagg ctccaactgc ctgaaaggtg 2400
agaggagtgg ggtgccccag agtgctgtgc ctctgagcag agccatctct aatcacccag 2460
ggtgccgtcc cctgttagga aacataagga cccctcagga cttatgctgg tatttgttca 2520
ctaatgagat aaaatggcat agtcatgata tgtattaatt atgagtgggt ttcataggat 2580
agctgagctt ttttgggctg aaaagtaaaa ttaataataa taacaataag caaataactc 2640
caattaatgt ggtgttttat ctagttagca aaatgctctt agcaatttgc cattcattgt 2700
gtatcagaaa tatatagaaa actttagttc tttgtacaag atgtcatctt ttagagaaag 2760
gggagttttg gacagaaaaa ctagttactg ccacgtacta ataccacacc ttgtgcttgc 2820
tagagtctca gtgaataaac cctttgctga tctctctgtg taactcatac ttccgtaaga 2880
atcgtggtta agattagcat gttgacaagc catcagttct agtcaagact gtctcctaaa 2940
aggccttgtt ttctaaagag gagagatgtc ttcagtcgga aaaagcaaga agacatgaac 3000
tgtattatca ggaaaacttg gtagttgtca cgcacagatc cgtgattcct ctagtgaatc 3060
agtttgaagt ggatttccaa tccctcactt ttgacatcac tctgaaggct gccatcaata 3120
gcgatcaata catacctgct cacttttatt attattatca tgtattgaga gggctgaaag 3180
ggaactctaa cagactgctt tgaagttcag ctgcaattta ctctagcatt ttagaatgag 3240
tccaagaaga acaacatatg gcaaataggc tacgctgttc cgtatgaagg aaaattaaaa 3300
ccagccgtag cctatactct actccatgtt caatggctaa gaattattag aaactattcg 3360
caggttttcc cctaaccaca atattcatta caatcatgga cctgcttgac aatgaggcat 3420
ggcatctgct gctccgcgca atattttaaa tggcgtggca agttgttttg tgattatttt 3480
taaaggtgaa attatgccga ggcaatggtt cacgttttga agaaaaatct aattgaccca 3540
aagcaatatt tttactacat atacaaaata acaaacagat gcggactaat tttgactggc 3600
ttccagatgc ggtgaccctt gaggttagca ctgacctggg aatgctgact gtcctaggaa 3660
atagattcga gagatgccaa gccagcaggt tctggttttc tttacatttt tttttccaac 3720
ttggaaaata atgaactttt gaaacaaaat tcctgatttg gttacacttt ccatattccc 3780
ccaaatagtg tgattacacc cctccactca caccgagtgt aactatatcc cctaccctta 3840
tacaaagtgt gattaaatct tctattttca cagtttgaaa ctgtttagct caacatttga 3900
tatcaaatga ttatagggca ggaatttcat aaaacccttc acttctgaaa atttaggagg 3960
agaattttaa aagaaagtta tatttttcat gtgaccctga gatcataaag ttaaagtatt 4020
ctttattgct gagatccata aggaaatatt ttctgtattt tattccttaa acacacacac 4080
acacacttaa gactccaaat gagactctat atacatatag agccattcta tatgcatatt 4140
caggatgagg cacactaaaa atcaagaggg gaagccatca aagtaacaat tttttaaaga 4200
tgtattttat tattctatgt gtgtgggtct gagtgtatgc ttctgcacca ggtgagtgga 4260
gattcccctg gaacaggagt taatgacagt tttgagctgc ctgatgtggg tattgggatc 4320
aaaccttggt cctctacaag gacagctcat acttttaacc actgagtcac ctctccagtt 4380
ctcaaacaat gattttggaa caatgcttgc cagtgttaaa cccaatgaaa gaagaaggca 4440
tgttgaataa agggtggagt tatctgaatg atacaaaatg tagatagaca ttgccaatat 4500
cttgaaactg atctcaagtc atttatgccc cccataaggt ttctgtaaca acctgaactg 4560
cctgcagtga taacattgta tgtcttgcat tatgtgttag aagaaggtct tctgggatat 4620
tggtctaaag cagttgttct caaccttcct aatgctgtga ccctttaata tagctccttg 4680
tgttttgctg acctcccaac catacagtta ttttgttgct acttcacaac tgtaactttt 4740
gctacttttg tgaattataa tataaatgtc tgtgttttcc aatggtctta gacaagccct 4800
gtgacagccc tgtgtcattc atctccaaag gcttacggcc cacaggtcct aagagaacat 4860
gtaacgtacc tctttctatg ttcggaaagt ctctaattta aaaaaaaaaa caatttatat 4920
atgcttgtct tcctttgtac gcccagactt ttagaatgct attatattag agtcagtgat 4980
agttaggttt gacagagcct catcagcagc tggatttctt atggaaccct ctgctttgaa 5040
cccacttcag gaatcgagaa gtcactatcc catctggccc caaattttga aacaattatt 5100
tctgatgacg atttaaccca gcttcccttt tcccacacag ttaccactgc ggatattctc 5160
acttagggct ttaacatccc ctcttgaaaa ttcctaaata tttgaagaaa aatattccat 5220
gcatagcatc cactcccagc atcctacaca cattccttac ctctagtatc tctggaaggc 5280
acgtcccagt gggacatcat tagctacctt acatgctcct ttgccataca tttgcctctt 5340
tctaacaggt ggtatctaaa tgtgcttgat gatgcactga catggaacca caacttccct 5400
ctttctatat aataggctct catttatcat gttagcacta catttaattt ttgggagagt 5460
ttacacactg tcttttgtca gtcattgtca ttgtgaagct agagagtcct cttctattgt 5520
atactgataa gtcacattta atatcaatgc ctcctattaa cctctcacta aacttcacct 5580
tatagtccat cagcattaaa atctctcaaa ttaaattttt ttctccatac atctttagaa 5640
catatccact acctgtatta gtatcaaatc ttccatgtgt agagttgggt ccttcctatg 5700
tggcttaccg tgtttctaaa atcaagtaac acatcacaca ctctgactac ctgcttgtga 5760
tttctgaaga ataggcttac tggagagtca agtttctaag g 5801
<210> 13
<211> 761
<212> PRT
<213> 小鼠
<400> 13
Met Lys Leu Lys Arg Thr Ala Tyr Leu Leu Phe Leu Tyr Leu Ser Ser
1 5 10 15
Ser Leu Leu Ile Cys Ile Lys Asn Ser Phe Cys Asn Lys Asn Asn Thr
20 25 30
Arg Cys Leu Ser Gly Pro Cys Gln Asn Asn Ser Thr Cys Lys His Phe
35 40 45
Pro Gln Asp Asn Asn Cys Cys Leu Asp Thr Ala Asn Asn Leu Asp Lys
50 55 60
Asp Cys Glu Asp Leu Lys Asp Pro Cys Phe Ser Ser Pro Cys Gln Gly
65 70 75 80
Ile Ala Thr Cys Val Lys Ile Pro Gly Glu Gly Asn Phe Leu Cys Gln
85 90 95
Cys Pro Pro Gly Tyr Ser Gly Leu Asn Cys Glu Thr Ala Thr Asn Ser
100 105 110
Cys Gly Gly Asn Leu Cys Gln His Gly Gly Thr Cys Arg Lys Asp Pro
115 120 125
Glu His Pro Val Cys Ile Cys Pro Pro Gly Tyr Ala Gly Arg Phe Cys
130 135 140
Glu Thr Asp His Asn Glu Cys Ala Ser Ser Pro Cys His Asn Gly Ala
145 150 155 160
Met Cys Gln Asp Gly Ile Asn Gly Tyr Ser Cys Phe Cys Val Pro Gly
165 170 175
Tyr Gln Gly Arg His Cys Asp Leu Glu Val Asp Glu Cys Val Ser Asp
180 185 190
Pro Cys Lys Asn Glu Ala Val Cys Leu Asn Glu Ile Gly Arg Tyr Thr
195 200 205
Cys Val Cys Pro Gln Glu Phe Ser Gly Val Asn Cys Glu Leu Glu Ile
210 215 220
Asp Glu Cys Arg Ser Gln Pro Cys Leu His Gly Ala Thr Cys Gln Asp
225 230 235 240
Ala Pro Gly Gly Tyr Ser Cys Asp Cys Ala Pro Gly Phe Leu Gly Glu
245 250 255
His Cys Glu Leu Ser Val Asn Glu Cys Glu Ser Gln Pro Cys Leu His
260 265 270
Gly Gly Leu Cys Val Asp Gly Arg Asn Ser Tyr His Cys Asp Cys Thr
275 280 285
Gly Ser Gly Phe Thr Gly Met His Cys Glu Ser Leu Ile Pro Leu Cys
290 295 300
Trp Ser Lys Pro Cys His Asn Asp Ala Thr Cys Glu Asp Thr Val Asp
305 310 315 320
Ser Tyr Ile Cys His Cys Arg Pro Gly Tyr Thr Gly Ala Leu Cys Glu
325 330 335
Thr Asp Ile Asn Glu Cys Ser Ser Asn Pro Cys Gln Phe Trp Gly Glu
340 345 350
Cys Val Glu Leu Ser Ser Glu Gly Leu Tyr Gly Asn Thr Ala Gly Leu
355 360 365
Pro Ser Ser Phe Ser Tyr Val Gly Ala Ser Gly Tyr Val Cys Ile Cys
370 375 380
Gln Pro Gly Phe Thr Gly Ile His Cys Glu Glu Asp Val Asp Glu Cys
385 390 395 400
Leu Leu His Pro Cys Leu Asn Gly Gly Thr Cys Glu Asn Leu Pro Gly
405 410 415
Asn Tyr Ala Cys His Cys Pro Phe Asp Asp Thr Ser Arg Thr Phe Tyr
420 425 430
Gly Gly Glu Asn Cys Ser Glu Ile Leu Leu Gly Cys Thr His His Gln
435 440 445
Cys Leu Asn Asn Gly Lys Cys Ile Pro His Phe Gln Asn Gly Gln His
450 455 460
Gly Phe Thr Cys Gln Cys Leu Ser Gly Tyr Ala Gly Pro Leu Cys Glu
465 470 475 480
Thr Val Thr Thr Leu Ser Phe Gly Ser Asn Gly Phe Leu Trp Val Thr
485 490 495
Ser Gly Ser His Thr Gly Ile Gly Pro Glu Cys Asn Ile Ser Leu Arg
500 505 510
Phe His Thr Val Gln Pro Asn Ala Leu Leu Leu Ile Arg Gly Asn Lys
515 520 525
Asp Val Ser Met Lys Leu Glu Leu Leu Asn Gly Cys Val His Leu Ser
530 535 540
Ile Glu Val Trp Asn Gln Leu Lys Val Leu Leu Ser Ile Ser His Asn
545 550 555 560
Thr Ser Asp Gly Glu Trp His Phe Val Glu Val Thr Ile Ala Glu Thr
565 570 575
Leu Thr Leu Ala Leu Val Gly Gly Ser Cys Lys Glu Lys Cys Thr Thr
580 585 590
Lys Ser Ser Val Pro Val Glu Asn His Gln Ser Ile Cys Ala Leu Gln
595 600 605
Asp Ser Phe Leu Gly Gly Leu Pro Met Gly Thr Ala Asn Asn Ser Val
610 615 620
Ser Val Leu Asn Ile Tyr Asn Val Pro Ser Thr Pro Ser Phe Val Gly
625 630 635 640
Cys Leu Gln Asp Ile Arg Phe Asp Leu Asn His Ile Thr Leu Glu Asn
645 650 655
Val Ser Ser Gly Leu Ser Ser Asn Val Lys Ala Gly Cys Leu Gly Lys
660 665 670
Asp Trp Cys Glu Ser Gln Pro Cys Gln Asn Arg Gly Arg Cys Ile Asn
675 680 685
Leu Trp Gln Gly Tyr Gln Cys Glu Cys Asp Arg Pro Tyr Thr Gly Ser
690 695 700
Asn Cys Leu Lys Gly Glu Arg Ser Gly Val Pro Gln Ser Ala Val Pro
705 710 715 720
Leu Ser Arg Ala Ile Ser Asn His Pro Gly Cys Arg Pro Leu Leu Gly
725 730 735
Asn Ile Arg Thr Pro Gln Asp Leu Cys Trp Tyr Leu Phe Thr Asn Glu
740 745 750
Ile Lys Trp His Ser His Asp Met Tyr
755 760
<210> 14
<211> 42
<212> PRT
<213> 智人
<400> 14
Asp Val Asn Glu Cys Ser Ser Asn Pro Cys Gln Asn Gly Gly Thr Cys
1 5 10 15
Glu Asn Leu Pro Gly Asn Tyr Thr Cys His Cys Pro Phe Asp Asn Leu
20 25 30
Ser Arg Thr Phe Tyr Gly Gly Arg Asp Cys
35 40
<210> 15
<211> 32
<212> PRT
<213> 智人
<400> 15
Cys Glu Ser Gln Pro Cys Gln Ser Arg Gly Arg Cys Ile Asn Leu Trp
1 5 10 15
Leu Ser Tyr Gln Cys Asp Cys His Arg Pro Tyr Glu Gly Pro Asn Cys
20 25 30
<210> 16
<211> 35
<212> PRT
<213> 智人
<400> 16
Asn Ser Cys Lys Ser Asn Pro Cys His Asn Gly Gly Val Cys His Ser
1 5 10 15
Arg Trp Asp Asp Phe Ser Cys Ser Cys Pro Ala Leu Thr Ser Gly Lys
20 25 30
Ala Cys Glu
35
<210> 17
<211> 30
<212> PRT
<213> 智人
<400> 17
Asn Pro Cys Leu His Gly Gly Asn Cys Glu Asp Ile Tyr Ser Ser Tyr
1 5 10 15
His Cys Ser Cys Pro Leu Gly Trp Ser Gly Lys His Cys Glu
20 25 30
<210> 18
<211> 29
<212> PRT
<213> 智人
<400> 18
Asn Pro Cys Ile His Gly Asn Cys Ser Asp Arg Val Ala Ala Tyr His
1 5 10 15
Cys Thr Cys Glu Pro Gly Tyr Thr Gly Val Asn Cys Glu
20 25
<210> 19
<211> 36
<212> PRT
<213> 智人
<400> 19
Asp Ile Asp Asn Cys Gln Ser His Gln Cys Ala Asn Gly Ala Thr Cys
1 5 10 15
Ile Ser His Thr Asn Gly Tyr Ser Cys Leu Cys Phe Gly Asn Phe Thr
20 25 30
Gly Lys Phe Cys
35
<210> 20
<211> 37
<212> PRT
<213> 智人
<400> 20
Asp Ile Asp Glu Cys Ala Ser Asp Pro Cys Val Asn Gly Gly Leu Cys
1 5 10 15
Gln Asp Leu Leu Asn Lys Phe Gln Cys Leu Cys Asp Val Ala Phe Ala
20 25 30
Gly Glu Arg Cys Glu
35
<210> 21
<211> 136
<212> PRT
<213> 智人
<400> 21
Phe Gln Thr Val Gln Pro Met Ala Leu Leu Leu Phe Arg Ser Asn Arg
1 5 10 15
Asp Val Phe Val Lys Leu Glu Leu Leu Ser Gly Tyr Ile His Leu Ser
20 25 30
Ile Gln Val Asn Asn Gln Ser Lys Val Leu Leu Phe Ile Ser His Asn
35 40 45
Thr Ser Asp Gly Glu Trp His Phe Val Glu Val Ile Phe Ala Glu Ala
50 55 60
Val Thr Leu Thr Leu Ile Asp Asp Ser Cys Lys Glu Lys Cys Ile Ala
65 70 75 80
Lys Ala Pro Thr Pro Leu Glu Ser Asp Gln Ser Ile Cys Ala Phe Gln
85 90 95
Asn Ser Phe Leu Gly Gly Leu Pro Val Gly Met Thr Ser Asn Gly Val
100 105 110
Ala Leu Leu Asn Phe Tyr Asn Met Pro Ser Thr Pro Ser Phe Val Gly
115 120 125
Cys Leu Gln Asp Ile Lys Ile Asp
130 135
<210> 22
<211> 118
<212> PRT
<213> 智人
<400> 22
Val Arg Thr Leu Gln Pro Ser Gly Leu Leu Leu Ala Leu Glu Asn Ser
1 5 10 15
Thr Tyr Gln Tyr Ile Arg Val Trp Leu Glu Arg Gly Arg Leu Ala Met
20 25 30
Leu Thr Pro Asn Ser Pro Lys Leu Val Val Lys Phe Val Leu Asn Asp
35 40 45
Gly Asn Val His Leu Ile Ser Leu Lys Ile Lys Pro Tyr Lys Ile Glu
50 55 60
Leu Tyr Gln Ser Ser Gln Asn Leu Gly Phe Ile Ser Ala Ser Thr Trp
65 70 75 80
Lys Ile Glu Lys Gly Asp Val Ile Tyr Ile Gly Gly Leu Pro Asp Lys
85 90 95
Gln Glu Thr Glu Leu Asn Gly Gly Phe Phe Lys Gly Cys Ile Gln Asp
100 105 110
Val Arg Leu Asn Asn Gln
115
<210> 23
<211> 126
<212> PRT
<213> 智人
<400> 23
Phe Arg Thr Arg Asp Ala Asn Val Ile Ile Leu His Ala Glu Lys Glu
1 5 10 15
Pro Glu Phe Leu Asn Ile Ser Ile Gln Asp Ser Arg Leu Phe Phe Gln
20 25 30
Leu Gln Ser Gly Asn Ser Phe Tyr Met Leu Ser Leu Thr Ser Leu Gln
35 40 45
Ser Val Asn Asp Gly Thr Trp His Glu Val Thr Leu Ser Met Thr Asp
50 55 60
Pro Leu Ser Gln Thr Ser Arg Trp Gln Met Glu Val Asp Asn Glu Thr
65 70 75 80
Pro Phe Val Thr Ser Thr Ile Ala Thr Gly Ser Leu Asn Phe Leu Lys
85 90 95
Asp Asn Thr Asp Ile Tyr Val Gly Asp Arg Ala Ile Asp Asn Ile Lys
100 105 110
Gly Leu Gln Gly Cys Leu Ser Thr Ile Glu Ile Gly Gly Ile
115 120 125
<210> 24
<211> 292
<212> DNA
<213> 智人
<400> 24
ctcaggggat tgtctttttc tagcaccttc ttgccactcc taagcgtcct ccgtgacccc 60
ggctgggatt tagcctggtg ctgtgtcagc cccgggctcc caggggcttc ccagtggtcc 120
ccaggaaccc tcgacagggc cagggcgtct ctctcgtcca gcaagggcag ggacgggcca 180
caggccaagg gcagcagtca ggcctgctct gtctgtgaac gctcccggct tggcctcggc 240
tgatgggccc tcacgcctga agcgggcagg aagctccggg atggatttcg gg 292
<210> 25
<211> 235
<212> DNA
<213> 小鼠
<400> 25
caattaggcc ccggtggcag cagtgggatt agcgttagta tgatatctcg cggatgctga 60
atcagcctct ggcttaggga gagaaggtca ctttataagg gtctgggggg ggtcagtgcc 120
tggagttgcg ctgtgggagc cgtcagtggc tgagctcgcc aagcagcctt ggtctctgtc 180
tacgaagagc ccgtggggca gcctcgagag ccgcagccat gaacggcaca gaggg 235
<210> 26
<211> 508
<212> DNA
<213> 巨细胞病毒
<400> 26
cgttacataa cttacggtaa atggcccgcc tggctgaccg cccaacgacc cccgcccatt 60
gacgtcaata atgacgtatg ttcccatagt aacgccaata gggactttcc attgacgtca 120
atgggtggag tatttacggt aaactgccca cttggcagta catcaagtgt atcatatgcc 180
aagtacgccc cctattgacg tcaatgacgg taaatggccc gcctggcatt atgcccagta 240
catgacctta tgggactttc ctacttggca gtacatctac gtattagtca tcgctattac 300
catggtgatg cggttttggc agtacatcaa tgggcgtgga tagcggtttg actcacgggg 360
atttccaagt ctccacccca ttgacgtcaa tgggagtttg ttttggcacc aaaatcaacg 420
ggactttcca aaatgtcgta acaactccgc cccattgacg caaatgggcg gtaggcgtgt 480
acggtgggag gtctatataa gcagagct 508
<210> 27
<211> 584
<212> DNA
<213> 人工序列
<220>
<223> 合成鸡β-肌动蛋白(CBA启动子)
<400> 27
gcgttacata acttacggta aatggcccgc ctggctgacc gcccaacgac ccccgcccat 60
tgacgtcaat aatgacgtat gttcccatag taacgccaat agggactttc cattgacgtc 120
aatgggtgga gtatttacgg taaactgccc acttggcagt acatcaagtg tatcatatgc 180
caagtacgcc ccctattgac gtcaatgacg gtaaatggcc cgcctggcat tatgcccagt 240
acatgacctt atgggacttt cctacttggc agtacatcta cgtattagtc atcgctatta 300
ccatggtcga ggtgagcccc acgttctgct tcactctccc catctccccc ccctccccac 360
ccccaatttt gtatttattt attttttaat tattttgtgc agcgatgggg gcgggggggg 420
ggggggggcg cgcgccaggc ggggcggggc ggggcgaggg gcggggcggg gcgaggcgga 480
gaggtgcggc ggcagccaat cagagcggcg cgctccgaaa gtttcctttt atggcgaggc 540
ggcggcggcg gcggccctat aaaaagcgaa gcgcgcggcg ggcg 584
<210> 28
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - 用于制备Crb1 AB和B小鼠的CRISPR gRNA引物
<400> 28
gaataagtac ccgttccttg 20
<210> 29
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - 用于制备Crb1 B小鼠的CRISPR gRNA引物
<400> 29
aaagcgatta ggtgatgccc 20
<210> 30
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - 用于制备Crb1 AB小鼠的CRISPR gRNA引物
<400> 30
tgtccgaaca cgtcaacccc 20
<210> 31
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - RT-PCR引物
<400> 31
gcttgctcac tcgttctcag t 21
<210> 32
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - RT-PCR引物
<400> 32
agctctctcc ttccaaaccc 20
<210> 33
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - RT-PCR引物
<400> 33
acccacaagc gtttgctaag 20
<210> 34
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - 基因分型引物
<400> 34
cagtatccca ggagcattcc 20
<210> 35
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - 基因分型引物
<400> 35
tttttcagtg tgccaggaag t 21
<210> 36
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - 基因分型引物
<400> 36
aagactttcc gaagccatga 20
<210> 37
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - 基因分型引物
<400> 37
caagacaccc aggaccaagt 20
<210> 38
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - 基因分型引物
<400> 38
cttccctctt tggacattgc 20
<210> 39
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - 基因分型引物
<400> 39
aacttgggag agcctggagt 20
<210> 40
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - qPCR引物
<400> 40
gcctcgggct atgtgtgtat 20
<210> 41
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - qPCR引物
<400> 41
aaacggttcc tgtcgaccta 20
<210> 42
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - qPCR引物
<400> 42
ggcaagggtg cagtaaacat 20
<210> 43
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - qPCR引物
<400> 43
tgcatcaatg gaggactgtg 20
<210> 44
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - qPCR引物
<400> 44
tcatgcgcag tacgaggtag 20
<210> 45
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - qPCR引物
<400> 45
tgaagaacag ggccaaagtt 20
<210> 46
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - qPCR引物
<400> 46
agaggacgct gcatcaactt 20
<210> 47
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - qPCR引物
<400> 47
tcatcttggc caaatcttcc 20
<210> 48
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - qPCR引物
<400> 48
gctccctcaa gggtttgaat 20
<210> 49
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - qPCR引物
<400> 49
ccatcaggtg cagcgtataa 20
<210> 50
<211> 48
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - BaseScope探针
<400> 50
cacaaggttt tcacatttta atggcagtgc tcataggaat tcactgtg 48
<210> 51
<211> 45
<212> DNA
<213> 人工序列
<220>
<223> 合成的 - BaseScope探针
<400> 51
acctcagctc ctcactgctc atctgcataa agaattcatt ttgca 45
<210> 52
<211> 42
<212> PRT
<213> 智人
<400> 52
Ile Leu Leu Gly Cys Thr His Gln Gln Cys Leu Asn Asn Gly Thr Cys
1 5 10 15
Ile Pro His Phe Gln Asp Gly Gln His Gly Phe Ser Cys Leu Cys Pro
20 25 30
Ser Gly Tyr Thr Gly Ser Leu Cys Glu Ile
35 40
<210> 53
<211> 16
<212> PRT
<213> 小鼠
<400> 53
Arg Met Asn Asp Glu Pro Val Val Glu Trp Gly Ala Gln Glu Asn Tyr
1 5 10 15
<210> 54
<211> 17
<212> DNA
<213> 人工序列
<220>
<223> Megf11特异性引物
<400> 54
ggctccgggg tatagga 17
<210> 55
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> Megf11特异性引物
<400> 55
ctggctgcat tgcattgg 18
<210> 56
<211> 16
<212> DNA
<213> 人工序列
<220>
<223> Megf11特异性引物
<400> 56
ggtgtccaat aaagtc 16
<210> 57
<211> 5764
<212> DNA
<213> 小鼠
<400> 57
ttacagaagg gaggcaccgt gtctcctgcg gggtaggagc taagaatata gcaaagctgc 60
ttgggaagtg gcacagctga ctcttacatt aagccccact gatccagctt gaagaggagt 120
gaggcaaagc tgaaccctcc cactctcctt gacaagtgca agcccacact tttggaaaaa 180
agcacaaaga cgtcagaaac ggttcctgtc gacctactag gctttggatg gctaagtgtt 240
tttgctttgt atggaaatat gtttggacac aagacacaag gttttcacat tttaatggca 300
gtgctcatag gaattcactg tgaagaagac gttgatgaat gtttactgca cccttgccta 360
aatggtggta cttgtgagaa cctgcctggg aattatgcct gtcactgtcc ctttgatgac 420
acttctagga cattttatgg aggagaaaac tgctcagaaa ttctcctggg ctgcactcat 480
caccagtgtc tgaacaatgg aaaatgtatc cctcatttcc aaaatggcca gcatggattc 540
acttgccagt gtctttctgg ctatgcgggg cccctgtgtg aaactgtcac cacactttca 600
tttgggagca atggcttcct atgggtcaca agtggctccc atacaggcat agggccagaa 660
tgtaacatat ccttgaggtt tcacactgtt caaccaaacg cacttctcct catccgaggc 720
aacaaggacg tgtctatgaa gctggagttg ctgaatggtt gtgttcactt atcaattgaa 780
gtctggaatc agttaaaggt gctcctgtct atttctcaca acaccagtga tggagaatgg 840
catttcgtgg aggtaacaat cgcagaaact ctaacccttg ccctagttgg cggctcctgc 900
aaggagaagt gcaccaccaa gtcttctgtt ccagttgaga atcatcaatc aatatgtgct 960
ttgcaggact cttttttggg tggcttacca atggggacag ccaacaacag tgtgtctgtg 1020
cttaacatct ataatgtgcc gtccacacct tcctttgtag gctgtctcca agacattaga 1080
tttgatttga atcacattac tctggagaac gtttcatctg gcctgtcatc aaatgttaaa 1140
gcaggctgcc tgggaaagga ctggtgtgaa agtcaaccct gtcaaaacag aggacgctgc 1200
atcaacttgt ggcagggtta tcagtgtgaa tgtgacaggc cctatacagg ctccaactgc 1260
ctgaaagagt atgtagcggg aagatttggc caagatgact ccacaggata tgcggccttt 1320
agtgttaatg ataattatgg acagaacttc agtctttcaa tgtttgtccg aacacgtcaa 1380
cccctgggct tacttctggc tttggaaaat agtacttacc agtatgtcag tgtctggcta 1440
gagcacggca gcctagcact gcagactcca ggctctccca agttcatggt aaactttttt 1500
ctcagtgatg gaaatgttca cttaatatct ttgagaatca aaccaaatga aattgaactg 1560
tatcagtctt cacaaaacct aggattcatt tctgttccta catggacaat tcgaagagga 1620
gacgtcatct tcattggtgg cttacctgac agagagaaga ctgaagttta tggtggcttc 1680
ttcaaaggct gtgttcaaga tgtcagatta aacagccaga ctctggaatt ctttcccaat 1740
tcaacaaaca atgcatacga tgacccaatt cttgtcaatg tgactcaagg ctgtcccgga 1800
gacaacacat gtaagtccaa cccctgtcat aatggaggtg tctgccactc cctgtgggat 1860
gacttctcct gctcctgccc tacaaacaca gcggggagag cctgcgagca agttcagtgg 1920
tgtcaactca gcccatgtcc tcccactgca gagtgccagc tgctccctca agggtttgaa 1980
tgtatcgcaa acgctgtttt cagcggatta agcagagaaa tactcttcag aagcaatggg 2040
aacattacca gagaactcac caatatcaca tttgctttca gaacacatga tacaaatgtg 2100
atgatattgc atgcagaaaa agaaccagag tttcttaata ttagcattca agatgccaga 2160
ttattctttc aattgcgaag tggcaacagc ttttatacgc tgcacctgat gggttcccaa 2220
ttggtgaatg atggcacatg gcaccaagtg actttctcca tgatagaccc agtggcccag 2280
acctcccggt ggcaaatgga ggtgaacgac cagacaccct ttgtgataag tgaagttgct 2340
actggaagcc tgaacttttt gaaggacaat acagacatct atgtgggtga ccaatctgtt 2400
gacaatccga aaggcctgca gggctgtctg agcacaatag agattggagg catatatctt 2460
tcttactttg aaaatctaca tggtttccct ggtaagcctc aggaagagca atttctcaaa 2520
gtttctacaa atatggtact tactggctgt ttgccatcaa atgcctgcca ctccagcccc 2580
tgtttgcatg gaggaaactg tgaagacagc tacagttctt atcggtgtgc ctgtctctcg 2640
ggatggtcag ggacacactg tgaaatcaac attgatgagt gcttttctag cccctgtatc 2700
catggcaact gctctgatgg agttgcagcc taccactgca ggtgtgagcc tggatacacc 2760
ggtgtgaact gtgaggtgga tgtagacaat tgcaagagtc atcagtgtgc aaatggggcc 2820
acctgtgttc ctgaagctca tggctactct tgtctctgct ttggaaattt taccgggaga 2880
ttttgcagac acagcagatt accctcaaca gtctgtggga atgagaagag aaacttcact 2940
tgctacaatg gaggcagctg ctccatgttc caggaggact ggcaatgtat gtgctggcca 3000
ggtttcactg gagagtggtg tgaagaggac atcaacgagt gtgcctccga tccctgcatc 3060
aatggaggac tgtgcaggga cttggtcaac aggttcctat gcatctgtga tgtggccttc 3120
gctggcgagc gctgtgagct ggacgtaagc ggcctttcct tttatgtgtc cctcttacta 3180
tggcaaaacc tctttcagct cctgtcctac ctcgtactgc gcatgaatga tgagccagtt 3240
gtagagtggg gggcacagga aaattattaa tgtgcatggg agcattcaca agtgtaaaac 3300
attgacttgc aagaaacatc ttgtctcagt gtaggtttct aggaaagaca aagggaacat 3360
tagggaatag actccatcta gagcactggt tctcagtctt cctaatgctg caacccttta 3420
gtacagctct tcctgttgta gtgatcgcag ccataacatt attttcattg ccacttcata 3480
actgtaatcc ttctactgct gtgaatcaca atggaaatat ttatgttttc tgatggtctt 3540
aagcaacacc tctgaaaaag tcattgaccc cccccccaaa ggggctgtga tccacaggtt 3600
gagaaatgct catctggaag gtaaccatgc atttaagtgt acctctagta gtttgggtct 3660
atagaagata ttctcctatt ctaccttttt agacacgcca gaagagggca tctgattcca 3720
ttaaagatga ttgggagcca ccgtgtggtt cctgagaact gtactcgggc cctttggaag 3780
agcaatcagt gctctttcca gcccctaaga atatttttaa tacagccaga aaggtctcat 3840
tacccagtgt actgagccct aaggcacttt catcctcaat cgttccatgt tgaatggttt 3900
tcattacatt tggaaaatgt tttctctcca ctctaccttt acatgttcct attttcctat 3960
tgacaatttg ccccttcact gtaattctaa tttggtgtgg tccttcttct cataagttta 4020
tatgtgacat gaacatttaa aaatatctat gaatatttta tagtcatgta tgtctttctg 4080
caaagctatt caaatgaact atggacagtt cttttctaca cgaagaagag atgagtttaa 4140
tccccagtaa catgagaaaa agatgagtga gggacagtgc tcacagtatc cctcactagc 4200
atcatttgtg attccatggg ccattttttt ccaccagcaa atagcagaga gccctttccc 4260
tattcgtttc tcttacactt ccccttttct gttacaactg aacactttac attagttact 4320
cctttgtagg gggtttgact tttccaccgt tttctctggt tcactattta tgctaagtat 4380
ctgtgcaggg cgggtatatc agtccaacag aggtgtcatt agtgttcatt gaggaggaaa 4440
tactttgcat gaattcatga catcattgaa gtagcagtgg ccagaaagat acccttctgc 4500
gaatgtgtct gtgtattcag aagctgccct ggttagaaaa catgtgggtc acttttcctt 4560
tgcatgttac cagtgctcac tgggtcatga ttgttttaag acagagcttt tgctgtggca 4620
atgaccaagg tgaatccaga gatgcagatc agacaaagga caagacaatg tactatctga 4680
gtaaaaccct gccttgactt actcctcagt acttagagat tttacatagc aacctccacc 4740
ctgtggcaac ccgttcacac tagcagtgat gctgagattt gcccttcctt ctcatcatct 4800
tcctcacatc caaagcattt tgtgtccaca ctgctgtttc agataactgt ttctaaagtg 4860
ggattgttgt agccagaaag gtagggaaaa tgttccccaa aatatttgca ttcttaagta 4920
tgtgaagtaa gtagattata gtcagagaca atatgtaagg tttcaggttc actcccttct 4980
acacatatct tcaactgtgt atttgcagaa tattctgaat gtgacatact cccaacagaa 5040
tatatttaag gagtatttat ccacagtatt gttctctgta cagttctagt gcttctattg 5100
tcactgcaat tgtcaattgt ttttctgctt tccaactgtc ttattatcat ttaatagcat 5160
cttgctaaat gccctctttc tattctcctt atttctccat agttcatgtg tgtctgtgtg 5220
actaaggatt ctcctcattt ttgcagaaaa ataaaatctt ttcttcttta tgtcctgctt 5280
gtcattctct ggtgacacat gtctttgctt acttggactg agggttgtac agtaagtaca 5340
gaagcaggct cagtcacaca gacagagaca caccaccacc agcagcagca gcaccaccac 5400
caccaccacc accaccagaa aacagtatga gtactcatct cttgattaca tgtcatttca 5460
agtaagcacc atgacaccga gggccaggtt ccatggactt tctctgttag gcacgtgatt 5520
ctttagctga cctttgagaa cagactccaa caacctcact tatttttact gttgacttat 5580
atcatctctg acaacactgg acttcgtttg agctagtcaa gaggaaagac catgacacct 5640
aagggacaga aattcacaca ctcggttttt cataattcac acacattcct atgtatcaaa 5700
tctctgtaat agatgacatt tacttgaata aaaagtcatt tccctttgct gatgtttcat 5760
cttt 5764
<210> 58
<211> 1003
<212> PRT
<213> 小鼠
<400> 58
Met Phe Gly His Lys Thr Gln Gly Phe His Ile Leu Met Ala Val Leu
1 5 10 15
Ile Gly Ile His Cys Glu Glu Asp Val Asp Glu Cys Leu Leu His Pro
20 25 30
Cys Leu Asn Gly Gly Thr Cys Glu Asn Leu Pro Gly Asn Tyr Ala Cys
35 40 45
His Cys Pro Phe Asp Asp Thr Ser Arg Thr Phe Tyr Gly Gly Glu Asn
50 55 60
Cys Ser Glu Ile Leu Leu Gly Cys Thr His His Gln Cys Leu Asn Asn
65 70 75 80
Gly Lys Cys Ile Pro His Phe Gln Asn Gly Gln His Gly Phe Thr Cys
85 90 95
Gln Cys Leu Ser Gly Tyr Ala Gly Pro Leu Cys Glu Thr Val Thr Thr
100 105 110
Leu Ser Phe Gly Ser Asn Gly Phe Leu Trp Val Thr Ser Gly Ser His
115 120 125
Thr Gly Ile Gly Pro Glu Cys Asn Ile Ser Leu Arg Phe His Thr Val
130 135 140
Gln Pro Asn Ala Leu Leu Leu Ile Arg Gly Asn Lys Asp Val Ser Met
145 150 155 160
Lys Leu Glu Leu Leu Asn Gly Cys Val His Leu Ser Ile Glu Val Trp
165 170 175
Asn Gln Leu Lys Val Leu Leu Ser Ile Ser His Asn Thr Ser Asp Gly
180 185 190
Glu Trp His Phe Val Glu Val Thr Ile Ala Glu Thr Leu Thr Leu Ala
195 200 205
Leu Val Gly Gly Ser Cys Lys Glu Lys Cys Thr Thr Lys Ser Ser Val
210 215 220
Pro Val Glu Asn His Gln Ser Ile Cys Ala Leu Gln Asp Ser Phe Leu
225 230 235 240
Gly Gly Leu Pro Met Gly Thr Ala Asn Asn Ser Val Ser Val Leu Asn
245 250 255
Ile Tyr Asn Val Pro Ser Thr Pro Ser Phe Val Gly Cys Leu Gln Asp
260 265 270
Ile Arg Phe Asp Leu Asn His Ile Thr Leu Glu Asn Val Ser Ser Gly
275 280 285
Leu Ser Ser Asn Val Lys Ala Gly Cys Leu Gly Lys Asp Trp Cys Glu
290 295 300
Ser Gln Pro Cys Gln Asn Arg Gly Arg Cys Ile Asn Leu Trp Gln Gly
305 310 315 320
Tyr Gln Cys Glu Cys Asp Arg Pro Tyr Thr Gly Ser Asn Cys Leu Lys
325 330 335
Glu Tyr Val Ala Gly Arg Phe Gly Gln Asp Asp Ser Thr Gly Tyr Ala
340 345 350
Ala Phe Ser Val Asn Asp Asn Tyr Gly Gln Asn Phe Ser Leu Ser Met
355 360 365
Phe Val Arg Thr Arg Gln Pro Leu Gly Leu Leu Leu Ala Leu Glu Asn
370 375 380
Ser Thr Tyr Gln Tyr Val Ser Val Trp Leu Glu His Gly Ser Leu Ala
385 390 395 400
Leu Gln Thr Pro Gly Ser Pro Lys Phe Met Val Asn Phe Phe Leu Ser
405 410 415
Asp Gly Asn Val His Leu Ile Ser Leu Arg Ile Lys Pro Asn Glu Ile
420 425 430
Glu Leu Tyr Gln Ser Ser Gln Asn Leu Gly Phe Ile Ser Val Pro Thr
435 440 445
Trp Thr Ile Arg Arg Gly Asp Val Ile Phe Ile Gly Gly Leu Pro Asp
450 455 460
Arg Glu Lys Thr Glu Val Tyr Gly Gly Phe Phe Lys Gly Cys Val Gln
465 470 475 480
Asp Val Arg Leu Asn Ser Gln Thr Leu Glu Phe Phe Pro Asn Ser Thr
485 490 495
Asn Asn Ala Tyr Asp Asp Pro Ile Leu Val Asn Val Thr Gln Gly Cys
500 505 510
Pro Gly Asp Asn Thr Cys Lys Ser Asn Pro Cys His Asn Gly Gly Val
515 520 525
Cys His Ser Leu Trp Asp Asp Phe Ser Cys Ser Cys Pro Thr Asn Thr
530 535 540
Ala Gly Arg Ala Cys Glu Gln Val Gln Trp Cys Gln Leu Ser Pro Cys
545 550 555 560
Pro Pro Thr Ala Glu Cys Gln Leu Leu Pro Gln Gly Phe Glu Cys Ile
565 570 575
Ala Asn Ala Val Phe Ser Gly Leu Ser Arg Glu Ile Leu Phe Arg Ser
580 585 590
Asn Gly Asn Ile Thr Arg Glu Leu Thr Asn Ile Thr Phe Ala Phe Arg
595 600 605
Thr His Asp Thr Asn Val Met Ile Leu His Ala Glu Lys Glu Pro Glu
610 615 620
Phe Leu Asn Ile Ser Ile Gln Asp Ala Arg Leu Phe Phe Gln Leu Arg
625 630 635 640
Ser Gly Asn Ser Phe Tyr Thr Leu His Leu Met Gly Ser Gln Leu Val
645 650 655
Asn Asp Gly Thr Trp His Gln Val Thr Phe Ser Met Ile Asp Pro Val
660 665 670
Ala Gln Thr Ser Arg Trp Gln Met Glu Val Asn Asp Gln Thr Pro Phe
675 680 685
Val Ile Ser Glu Val Ala Thr Gly Ser Leu Asn Phe Leu Lys Asp Asn
690 695 700
Thr Asp Ile Tyr Val Gly Asp Gln Ser Val Asp Asn Pro Lys Gly Leu
705 710 715 720
Gln Gly Cys Leu Ser Thr Ile Glu Ile Gly Gly Ile Tyr Leu Ser Tyr
725 730 735
Phe Glu Asn Leu His Gly Phe Pro Gly Lys Pro Gln Glu Glu Gln Phe
740 745 750
Leu Lys Val Ser Thr Asn Met Val Leu Thr Gly Cys Leu Pro Ser Asn
755 760 765
Ala Cys His Ser Ser Pro Cys Leu His Gly Gly Asn Cys Glu Asp Ser
770 775 780
Tyr Ser Ser Tyr Arg Cys Ala Cys Leu Ser Gly Trp Ser Gly Thr His
785 790 795 800
Cys Glu Ile Asn Ile Asp Glu Cys Phe Ser Ser Pro Cys Ile His Gly
805 810 815
Asn Cys Ser Asp Gly Val Ala Ala Tyr His Cys Arg Cys Glu Pro Gly
820 825 830
Tyr Thr Gly Val Asn Cys Glu Val Asp Val Asp Asn Cys Lys Ser His
835 840 845
Gln Cys Ala Asn Gly Ala Thr Cys Val Pro Glu Ala His Gly Tyr Ser
850 855 860
Cys Leu Cys Phe Gly Asn Phe Thr Gly Arg Phe Cys Arg His Ser Arg
865 870 875 880
Leu Pro Ser Thr Val Cys Gly Asn Glu Lys Arg Asn Phe Thr Cys Tyr
885 890 895
Asn Gly Gly Ser Cys Ser Met Phe Gln Glu Asp Trp Gln Cys Met Cys
900 905 910
Trp Pro Gly Phe Thr Gly Glu Trp Cys Glu Glu Asp Ile Asn Glu Cys
915 920 925
Ala Ser Asp Pro Cys Ile Asn Gly Gly Leu Cys Arg Asp Leu Val Asn
930 935 940
Arg Phe Leu Cys Ile Cys Asp Val Ala Phe Ala Gly Glu Arg Cys Glu
945 950 955 960
Leu Asp Val Ser Gly Leu Ser Phe Tyr Val Ser Leu Leu Leu Trp Gln
965 970 975
Asn Leu Phe Gln Leu Leu Ser Tyr Leu Val Leu Arg Met Asn Asp Glu
980 985 990
Pro Val Val Glu Trp Gly Ala Gln Glu Asn Tyr
995 1000
<210> 59
<211> 6170
<212> DNA
<213> 小鼠
<400> 59
attgttcacg gaagcctgag ggggacacga atccaatcca ggctggaaaa atctgctcca 60
ggattgactg gttaccgtct tcctgtgcct gtaaggtgct gtgaaagaga agtgctttct 120
gattctctgt ctgtggagga gccctgggag gggtgggaca gagatggcat cctggctctc 180
tgaggcacct gctcttctct gaaccacaca ggagtcaaga gccaaacagg gatagcttca 240
gcagcacttc agagggtgtt ctctaagtaa gaacatgaag ctcaagagaa ctgcctacct 300
tctcttcctg tacctcagct cctcactgct catctgcata aagaattcat tttgcaataa 360
aaacaatacc aggtgccttt caggtccttg ccaaaacaat tctacgtgca agcattttcc 420
acaagacaac aattgttgct tagacacagc caataatttg gacaaagact gtgaagatct 480
gaaagaccct tgcttctcga gtccctgcca aggaattgcc acttgtgtga aaatcccagg 540
ggaagggaac ttcctgtgtc agtgtcctcc tgggtacagc gggctgaact gtgaaactgc 600
caccaattcc tgtggaggga acctctgcca acatggaggc acctgccgta aagaccctga 660
gcaccctgtc tgtatctgcc ctcctggata tgctggaagg ttctgtgaga ctgatcacaa 720
tgagtgtgct tctagccctt gccacaatgg ggctatgtgc caggatggaa tcaatggcta 780
ctcctgcttc tgtgtgcctg gataccaagg caggcattgt gacttggaag tggatgaatg 840
tgtttctgat ccctgcaaga atgaggctgt gtgcctcaat gagataggaa gatacacttg 900
tgtctgccct caagagtttt ctggcgtgaa ctgtgagttg gaaattgatg aatgcagatc 960
ccagccttgt ctccacggtg ccacatgtca ggacgctcca gggggctact cctgtgactg 1020
tgcacctgga ttccttggag agcactgtga actcagcgtt aatgaatgtg aaagtcagcc 1080
gtgtctccat ggaggtctat gtgtggatgg aagaaacagt taccactgtg actgcacagg 1140
tagtggattc acagggatgc actgtgagtc cttgattcct ctttgttggt caaagccttg 1200
tcacaacgac gcgacatgtg aagatactgt tgacagctat atttgtcact gccggcctgg 1260
atacacaggt gccctgtgtg agacagacat aaatgaatgc agtagcaacc cctgccaatt 1320
ttggggggaa tgtgtcgagc tgtcctcaga gggtctatat ggaaacactg ctggcctgcc 1380
ttcctccttc agctatgttg gagcctcggg ctatgtgtgt atctgtcagc ctggattcac 1440
aggaattcac tgtgaagaag acgttgatga atgtttactg cacccttgcc taaatggtgg 1500
tacttgtgag aacctgcctg ggaattatgc ctgtcactgt ccctttgatg acacttctag 1560
gacattttat ggaggagaaa actgctcaga aattctcctg ggctgcactc atcaccagtg 1620
tctgaacaat ggaaaatgta tccctcattt ccaaaatggc cagcatggat tcacttgcca 1680
gtgtctttct ggctatgcgg ggcccctgtg tgaaactgtc accacacttt catttgggag 1740
caatggcttc ctatgggtca caagtggctc ccatacaggc atagggccag aatgtaacat 1800
atccttgagg tttcacactg ttcaaccaaa cgcacttctc ctcatccgag gcaacaagga 1860
cgtgtctatg aagctggagt tgctgaatgg ttgtgttcac ttatcaattg aagtctggaa 1920
tcagttaaag gtgctcctgt ctatttctca caacaccagt gatggagaat ggcatttcgt 1980
ggaggtaaca atcgcagaaa ctctaaccct tgccctagtt ggcggctcct gcaaggagaa 2040
gtgcaccacc aagtcttctg ttccagttga gaatcatcaa tcaatatgtg ctttgcagga 2100
ctcttttttg ggtggcttac caatggggac agccaacaac agtgtgtctg tgcttaacat 2160
ctataatgtg ccgtccacac cttcctttgt aggctgtctc caagacatta gatttgattt 2220
gaatcacatt actctggaga acgtttcatc tggcctgtca tcaaatgtta aagcaggctg 2280
cctgggaaag gactggtgtg aaagtcaacc ctgtcaaaac agaggacgct gcatcaactt 2340
gtggcagggt tatcagtgtg aatgtgacag gccctataca ggctccaact gcctgaaaga 2400
gtatgtagcg ggaagatttg gccaagatga ctccacagga tatgcggcct ttagtgttaa 2460
tgataattat ggacagaact tcagtctttc aatgtttgtc cgaacacgtc aacccctggg 2520
cttacttctg gctttggaaa atagtactta ccagtatgtc agtgtctggc tagagcacgg 2580
cagcctagca ctgcagactc caggctctcc caagttcatg gtaaactttt ttctcagtga 2640
tggaaatgtt cacttaatat ctttgagaat caaaccaaat gaaattgaac tgtatcagtc 2700
ttcacaaaac ctaggattca tttctgttcc tacatggaca attcgaagag gagacgtcat 2760
cttcattggt ggcttacctg acagagagaa gactgaagtt tatggtggct tcttcaaagg 2820
ctgtgttcaa gatgtcagat taaacagcca gactctggaa ttctttccca attcaacaaa 2880
caatgcatac gatgacccaa ttcttgtcaa tgtgactcaa ggctgtcccg gagacaacac 2940
atgtaagtcc aacccctgtc ataatggagg tgtctgccac tccctgtggg atgacttctc 3000
ctgctcctgc cctacaaaca cagcggggag agcctgcgag caagttcagt ggtgtcaact 3060
cagcccatgt cctcccactg cagagtgcca gctgctccct caagggtttg aatgtatcgc 3120
aaacgctgtt ttcagcggat taagcagaga aatactcttc agaagcaatg ggaacattac 3180
cagagaactc accaatatca catttgcttt cagaacacat gatacaaatg tgatgatatt 3240
gcatgcagaa aaagaaccag agtttcttaa tattagcatt caagatgcca gattattctt 3300
tcaattgcga agtggcaaca gcttttatac gctgcacctg atgggttccc aattggtgaa 3360
tgatggcaca tggcaccaag tgactttctc catgatagac ccagtggccc agacctcccg 3420
gtggcaaatg gaggtgaacg accagacacc ctttgtgata agtgaagttg ctactggaag 3480
cctgaacttt ttgaaggaca atacagacat ctatgtgggt gaccaatctg ttgacaatcc 3540
gaaaggcctg cagggctgtc tgagcacaat agagattgga ggcatatatc tttcttactt 3600
tgaaaatcta catggtttcc ctggtaagcc tcaggaagag caatttctca aagtttctac 3660
aaatatggta cttactggct gtttgccatc aaatgcctgc cactccagcc cctgtttgca 3720
tggaggaaac tgtgaagaca gctacagttc ttatcggtgt gcctgtctct cgggatggtc 3780
agggacacac tgtgaaatca acattgatga gtgcttttct agcccctgta tccatggcaa 3840
ctgctctgat ggagttgcag cctaccactg caggtgtgag cctggataca ccggtgtgaa 3900
ctgtgaggtg gatgtagaca attgcaagag tcatcagtgt gcaaatgggg ccacctgtgt 3960
tcctgaagct catggctact cttgtctctg ctttggaaat tttaccggga gattttgcag 4020
acacagcaga ttaccctcaa cagtctgtgg gaatgagaag agaaacttca cttgctacaa 4080
tggaggcagc tgctccatgt tccaggagga ctggcaatgt atgtgctggc caggtttcac 4140
tggagagtgg tgtgaagagg acatcaacga gtgtgcctcc gatccctgca tcaatggagg 4200
actgtgcagg gacttggtca acaggttcct atgcatctgt gatgtggcct tcgctggcga 4260
gcgctgtgag ctggacctgg ctgatgacag gctcctgggc attttcaccg ctgttggctc 4320
cggaactttg gccctgttct tcatcctctt gcttgctggg gttgcttctc ttattgcctc 4380
caacaaaagg gcgactcaag gaacctacag ccccagcggt caggagaagg ctggccctcg 4440
agtggaaatg tggatcagga tgccgccccc ggcactggaa aggctcatct aggagactgc 4500
tgctcttctc aggacagaga agaacatgat gagtaccggg tcgtgcctga gtgaagatgg 4560
ctttacatca ctagagatac atacagctgg gactgtggga aggaccttcc tgtggagtca 4620
ctgagtagtt atgtcatcca ttcacagaag agtgtccctg tgtttgcctg tcagcctcag 4680
aattagcaaa acatctagca gacagagaac acagtatttc agaagaactc cagaggctgc 4740
cccttaaact ctttactggt tgatccacat aaaatgctta gtagccaagt gccattaatt 4800
atacagagcc aagaagaaaa attagaatac aactttcact ttttattttg tagggaaggt 4860
tttatgtttt ggtttgttgt tgttgttgtg acagtgacag tgactcatta catagaccaa 4920
gctggcctca aaatcacatg gaccctcggg attacatgtg tccgaccatg ttcatcttat 4980
ttttgaatct tctgtcatat ggtaaaagat tccagtggga cctgaggagt gactagctag 5040
gtaaagcaag ggctgtgtaa gtgccagaac tggtgtttgt gtcctcatta tccacataag 5100
tgccaagtga gtgtggcccc tgcctgtcat cctaggcctc aggagatatc actgctcact 5160
ggagcaagcc ggttaaactg ttagggcagg taagttttga cttcaagtga gagaccctga 5220
ctcaatatga aaggcaatta gtgagtcaag atgaccctgt atgctaacct cttgcctata 5280
catgcatata cacacattta catatgtgcc caaacatgag gacacaagca cacgcgcgcg 5340
cgcacacaca cacacacaca cacacacaca cacacacaca cacacacacg agtctaattg 5400
tatatagtga taacagtaca ctttcctcct tctatttcgg atttagagaa agccatgaga 5460
agcgtgtatg gtttaaacca tgacccaagc ataacaaata aagttgaaat agttgttctc 5520
ctgtccaagc ttgtctttat tgttgtgcat tctgtaagct ggttgcttgg ttggctgatg 5580
gatggcttct gtttgtttgt tgttttttgt ttgtttgttt gtctgggata ttacatgtaa 5640
gaaaaataac tggtaagaac aatcaaagaa ctttgttatg aattaaatct tttgtctaag 5700
tcacttagag tcattattct ttatgtagat ttgcttccag tcaggacatt tcctagacag 5760
aatttaagac agtaagaaaa tgatttgtca cgtctgaaag aggttcttta ctttcaggga 5820
cttttgataa tgcccaacag agatggcatc gaaagaggag ctcatagcga gatgggcatt 5880
tgtgcatcct caaggagaaa atattgtacc ttctgtttgt atattgtcta ttctgtgatg 5940
gctgtatctt acatatgttt tgatgcatgt aacaatagta tcatatgaaa taaattatat 6000
atatatataa tatataatat atatcacaag ataaaaattg aaattacata aactttaaat 6060
ctaaaagaag aaacctatcc ttcccaagta ttatcagtgc agtcaccgag ctttttttgt 6120
ttttttgtat tagccatttc ttcataatac aggaagttct ataacttcaa 6170
<210> 60
<211> 1405
<212> PRT
<213> 小鼠
<400> 60
Met Lys Leu Lys Arg Thr Ala Tyr Leu Leu Phe Leu Tyr Leu Ser Ser
1 5 10 15
Ser Leu Leu Ile Cys Ile Lys Asn Ser Phe Cys Asn Lys Asn Asn Thr
20 25 30
Arg Cys Leu Ser Gly Pro Cys Gln Asn Asn Ser Thr Cys Lys His Phe
35 40 45
Pro Gln Asp Asn Asn Cys Cys Leu Asp Thr Ala Asn Asn Leu Asp Lys
50 55 60
Asp Cys Glu Asp Leu Lys Asp Pro Cys Phe Ser Ser Pro Cys Gln Gly
65 70 75 80
Ile Ala Thr Cys Val Lys Ile Pro Gly Glu Gly Asn Phe Leu Cys Gln
85 90 95
Cys Pro Pro Gly Tyr Ser Gly Leu Asn Cys Glu Thr Ala Thr Asn Ser
100 105 110
Cys Gly Gly Asn Leu Cys Gln His Gly Gly Thr Cys Arg Lys Asp Pro
115 120 125
Glu His Pro Val Cys Ile Cys Pro Pro Gly Tyr Ala Gly Arg Phe Cys
130 135 140
Glu Thr Asp His Asn Glu Cys Ala Ser Ser Pro Cys His Asn Gly Ala
145 150 155 160
Met Cys Gln Asp Gly Ile Asn Gly Tyr Ser Cys Phe Cys Val Pro Gly
165 170 175
Tyr Gln Gly Arg His Cys Asp Leu Glu Val Asp Glu Cys Val Ser Asp
180 185 190
Pro Cys Lys Asn Glu Ala Val Cys Leu Asn Glu Ile Gly Arg Tyr Thr
195 200 205
Cys Val Cys Pro Gln Glu Phe Ser Gly Val Asn Cys Glu Leu Glu Ile
210 215 220
Asp Glu Cys Arg Ser Gln Pro Cys Leu His Gly Ala Thr Cys Gln Asp
225 230 235 240
Ala Pro Gly Gly Tyr Ser Cys Asp Cys Ala Pro Gly Phe Leu Gly Glu
245 250 255
His Cys Glu Leu Ser Val Asn Glu Cys Glu Ser Gln Pro Cys Leu His
260 265 270
Gly Gly Leu Cys Val Asp Gly Arg Asn Ser Tyr His Cys Asp Cys Thr
275 280 285
Gly Ser Gly Phe Thr Gly Met His Cys Glu Ser Leu Ile Pro Leu Cys
290 295 300
Trp Ser Lys Pro Cys His Asn Asp Ala Thr Cys Glu Asp Thr Val Asp
305 310 315 320
Ser Tyr Ile Cys His Cys Arg Pro Gly Tyr Thr Gly Ala Leu Cys Glu
325 330 335
Thr Asp Ile Asn Glu Cys Ser Ser Asn Pro Cys Gln Phe Trp Gly Glu
340 345 350
Cys Val Glu Leu Ser Ser Glu Gly Leu Tyr Gly Asn Thr Ala Gly Leu
355 360 365
Pro Ser Ser Phe Ser Tyr Val Gly Ala Ser Gly Tyr Val Cys Ile Cys
370 375 380
Gln Pro Gly Phe Thr Gly Ile His Cys Glu Glu Asp Val Asp Glu Cys
385 390 395 400
Leu Leu His Pro Cys Leu Asn Gly Gly Thr Cys Glu Asn Leu Pro Gly
405 410 415
Asn Tyr Ala Cys His Cys Pro Phe Asp Asp Thr Ser Arg Thr Phe Tyr
420 425 430
Gly Gly Glu Asn Cys Ser Glu Ile Leu Leu Gly Cys Thr His His Gln
435 440 445
Cys Leu Asn Asn Gly Lys Cys Ile Pro His Phe Gln Asn Gly Gln His
450 455 460
Gly Phe Thr Cys Gln Cys Leu Ser Gly Tyr Ala Gly Pro Leu Cys Glu
465 470 475 480
Thr Val Thr Thr Leu Ser Phe Gly Ser Asn Gly Phe Leu Trp Val Thr
485 490 495
Ser Gly Ser His Thr Gly Ile Gly Pro Glu Cys Asn Ile Ser Leu Arg
500 505 510
Phe His Thr Val Gln Pro Asn Ala Leu Leu Leu Ile Arg Gly Asn Lys
515 520 525
Asp Val Ser Met Lys Leu Glu Leu Leu Asn Gly Cys Val His Leu Ser
530 535 540
Ile Glu Val Trp Asn Gln Leu Lys Val Leu Leu Ser Ile Ser His Asn
545 550 555 560
Thr Ser Asp Gly Glu Trp His Phe Val Glu Val Thr Ile Ala Glu Thr
565 570 575
Leu Thr Leu Ala Leu Val Gly Gly Ser Cys Lys Glu Lys Cys Thr Thr
580 585 590
Lys Ser Ser Val Pro Val Glu Asn His Gln Ser Ile Cys Ala Leu Gln
595 600 605
Asp Ser Phe Leu Gly Gly Leu Pro Met Gly Thr Ala Asn Asn Ser Val
610 615 620
Ser Val Leu Asn Ile Tyr Asn Val Pro Ser Thr Pro Ser Phe Val Gly
625 630 635 640
Cys Leu Gln Asp Ile Arg Phe Asp Leu Asn His Ile Thr Leu Glu Asn
645 650 655
Val Ser Ser Gly Leu Ser Ser Asn Val Lys Ala Gly Cys Leu Gly Lys
660 665 670
Asp Trp Cys Glu Ser Gln Pro Cys Gln Asn Arg Gly Arg Cys Ile Asn
675 680 685
Leu Trp Gln Gly Tyr Gln Cys Glu Cys Asp Arg Pro Tyr Thr Gly Ser
690 695 700
Asn Cys Leu Lys Glu Tyr Val Ala Gly Arg Phe Gly Gln Asp Asp Ser
705 710 715 720
Thr Gly Tyr Ala Ala Phe Ser Val Asn Asp Asn Tyr Gly Gln Asn Phe
725 730 735
Ser Leu Ser Met Phe Val Arg Thr Arg Gln Pro Leu Gly Leu Leu Leu
740 745 750
Ala Leu Glu Asn Ser Thr Tyr Gln Tyr Val Ser Val Trp Leu Glu His
755 760 765
Gly Ser Leu Ala Leu Gln Thr Pro Gly Ser Pro Lys Phe Met Val Asn
770 775 780
Phe Phe Leu Ser Asp Gly Asn Val His Leu Ile Ser Leu Arg Ile Lys
785 790 795 800
Pro Asn Glu Ile Glu Leu Tyr Gln Ser Ser Gln Asn Leu Gly Phe Ile
805 810 815
Ser Val Pro Thr Trp Thr Ile Arg Arg Gly Asp Val Ile Phe Ile Gly
820 825 830
Gly Leu Pro Asp Arg Glu Lys Thr Glu Val Tyr Gly Gly Phe Phe Lys
835 840 845
Gly Cys Val Gln Asp Val Arg Leu Asn Ser Gln Thr Leu Glu Phe Phe
850 855 860
Pro Asn Ser Thr Asn Asn Ala Tyr Asp Asp Pro Ile Leu Val Asn Val
865 870 875 880
Thr Gln Gly Cys Pro Gly Asp Asn Thr Cys Lys Ser Asn Pro Cys His
885 890 895
Asn Gly Gly Val Cys His Ser Leu Trp Asp Asp Phe Ser Cys Ser Cys
900 905 910
Pro Thr Asn Thr Ala Gly Arg Ala Cys Glu Gln Val Gln Trp Cys Gln
915 920 925
Leu Ser Pro Cys Pro Pro Thr Ala Glu Cys Gln Leu Leu Pro Gln Gly
930 935 940
Phe Glu Cys Ile Ala Asn Ala Val Phe Ser Gly Leu Ser Arg Glu Ile
945 950 955 960
Leu Phe Arg Ser Asn Gly Asn Ile Thr Arg Glu Leu Thr Asn Ile Thr
965 970 975
Phe Ala Phe Arg Thr His Asp Thr Asn Val Met Ile Leu His Ala Glu
980 985 990
Lys Glu Pro Glu Phe Leu Asn Ile Ser Ile Gln Asp Ala Arg Leu Phe
995 1000 1005
Phe Gln Leu Arg Ser Gly Asn Ser Phe Tyr Thr Leu His Leu Met
1010 1015 1020
Gly Ser Gln Leu Val Asn Asp Gly Thr Trp His Gln Val Thr Phe
1025 1030 1035
Ser Met Ile Asp Pro Val Ala Gln Thr Ser Arg Trp Gln Met Glu
1040 1045 1050
Val Asn Asp Gln Thr Pro Phe Val Ile Ser Glu Val Ala Thr Gly
1055 1060 1065
Ser Leu Asn Phe Leu Lys Asp Asn Thr Asp Ile Tyr Val Gly Asp
1070 1075 1080
Gln Ser Val Asp Asn Pro Lys Gly Leu Gln Gly Cys Leu Ser Thr
1085 1090 1095
Ile Glu Ile Gly Gly Ile Tyr Leu Ser Tyr Phe Glu Asn Leu His
1100 1105 1110
Gly Phe Pro Gly Lys Pro Gln Glu Glu Gln Phe Leu Lys Val Ser
1115 1120 1125
Thr Asn Met Val Leu Thr Gly Cys Leu Pro Ser Asn Ala Cys His
1130 1135 1140
Ser Ser Pro Cys Leu His Gly Gly Asn Cys Glu Asp Ser Tyr Ser
1145 1150 1155
Ser Tyr Arg Cys Ala Cys Leu Ser Gly Trp Ser Gly Thr His Cys
1160 1165 1170
Glu Ile Asn Ile Asp Glu Cys Phe Ser Ser Pro Cys Ile His Gly
1175 1180 1185
Asn Cys Ser Asp Gly Val Ala Ala Tyr His Cys Arg Cys Glu Pro
1190 1195 1200
Gly Tyr Thr Gly Val Asn Cys Glu Val Asp Val Asp Asn Cys Lys
1205 1210 1215
Ser His Gln Cys Ala Asn Gly Ala Thr Cys Val Pro Glu Ala His
1220 1225 1230
Gly Tyr Ser Cys Leu Cys Phe Gly Asn Phe Thr Gly Arg Phe Cys
1235 1240 1245
Arg His Ser Arg Leu Pro Ser Thr Val Cys Gly Asn Glu Lys Arg
1250 1255 1260
Asn Phe Thr Cys Tyr Asn Gly Gly Ser Cys Ser Met Phe Gln Glu
1265 1270 1275
Asp Trp Gln Cys Met Cys Trp Pro Gly Phe Thr Gly Glu Trp Cys
1280 1285 1290
Glu Glu Asp Ile Asn Glu Cys Ala Ser Asp Pro Cys Ile Asn Gly
1295 1300 1305
Gly Leu Cys Arg Asp Leu Val Asn Arg Phe Leu Cys Ile Cys Asp
1310 1315 1320
Val Ala Phe Ala Gly Glu Arg Cys Glu Leu Asp Leu Ala Asp Asp
1325 1330 1335
Arg Leu Leu Gly Ile Phe Thr Ala Val Gly Ser Gly Thr Leu Ala
1340 1345 1350
Leu Phe Phe Ile Leu Leu Leu Ala Gly Val Ala Ser Leu Ile Ala
1355 1360 1365
Ser Asn Lys Arg Ala Thr Gln Gly Thr Tyr Ser Pro Ser Gly Gln
1370 1375 1380
Glu Lys Ala Gly Pro Arg Val Glu Met Trp Ile Arg Met Pro Pro
1385 1390 1395
Pro Ala Leu Glu Arg Leu Ile
1400 1405
<210> 61
<211> 5894
<212> DNA
<213> 小鼠
<400> 61
gcctttccag gaggcattgt tcacggaagc ctgaggggga cacgaatcca atccaggctg 60
gaaaaatctg ctccaggatt gactggttac cgtcttcctg tgcctgtaag gtgctgtgaa 120
agagaagtgc tttctgattc tctgtctgtg gaggagccct gggaggggtg ggacagagat 180
ggcatcctgg ctctctgagg cacctgctct tctctgaacc acacaggagt caagagccaa 240
acagggatag cttcagcagc acttcagagg gtgttctcta agtaagaaca tgaagctcaa 300
gagaactgcc taccttctct tcctgtacct cagctcctca ctgctcatct gcataaagaa 360
ttcattttgc aataaaaaca ataccaggtg cctttcaggt ccttgccaaa acaattctac 420
gtgcaagcat tttccacaag acaacaattg ttgcttagac acagccaata atttggacaa 480
agactgtgaa gatctgaaag acccttgctt ctcgagtccc tgccaaggaa ttgccacttg 540
tgtgaaaatc ccaggggaag ggaacttcct gtgtcagtgt cctcctgggt acagcgggct 600
gaactgtgaa actgccacca attcctgtgg agggaacctc tgccaacatg gaggcacctg 660
ccgtaaagac cctgagcacc ctgtctgtat ctgccctcct ggatatgctg gaaggttctg 720
tgagactgat cacaatgagt gtgcttctag cccttgccac aatggggcta tgtgccagga 780
tggaatcaat ggctactcct gcttctgtgt gcctggatac caaggcaggc attgtgactt 840
ggaagtggat gaatgtgttt ctgatccctg caagaatgag gctgtgtgcc tcaatgagat 900
aggaagatac acttgtgtct gccctcaaga gttttctggc gtgaactgtg agttggaaat 960
tgatgaatgc agatcccagc cttgtctcca cggtgccaca tgtcaggacg ctccaggggg 1020
ctactcctgt gactgtgcac ctggattcct tggagagcac tgtgaactca gcgttaatga 1080
atgtgaaagt cagccgtgtc tccatggagg tctatgtgtg gatggaagaa acagttacca 1140
ctgtgactgc acaggtagtg gattcacagg gatgcactgt gagtccttga ttcctctttg 1200
ttggtcaaag ccttgtcaca acgacgcgac atgtgaagat actgttgaca gctatatttg 1260
tcactgccgg cctggaattc actgtgaaga agacgttgat gaatgtttac tgcacccttg 1320
cctaaatggt ggtacttgtg agaacctgcc tgggaattat gcctgtcact gtccctttga 1380
tgacacttct aggacatttt atggaggaga aaactgctca gaaattctcc tgggctgcac 1440
tcatcaccag tgtctgaaca atggaaaatg tatccctcat ttccaaaatg gccagcatgg 1500
attcacttgc cagtgtcttt ctggctatgc ggggcccctg tgtgaaactg tcaccacact 1560
ttcatttggg agcaatggct tcctatgggt cacaagtggc tcccatacag gcatagggcc 1620
agaatgtaac atatccttga ggtttcacac tgttcaacca aacgcacttc tcctcatccg 1680
aggcaacaag gacgtgtcta tgaagctgga gttgctgaat ggttgtgttc acttatcaat 1740
tgaagtctgg aatcagttaa aggtgctcct gtctatttct cacaacacca gtgatggaga 1800
atggcatttc gtggaggtaa caatcgcaga aactctaacc cttgccctag ttggcggctc 1860
ctgcaaggag aagtgcacca ccaagtcttc tgttccagtt gagaatcatc aatcaatatg 1920
tgctttgcag gactcttttt tgggtggctt accaatgggg acagccaaca acagtgtgtc 1980
tgtgcttaac atctataatg tgccgtccac accttccttt gtaggctgtc tccaagacat 2040
tagatttgat ttgaatcaca ttactctgga gaacgtttca tctggcctgt catcaaatgt 2100
taaagcaggc tgcctgggaa aggactggtg tgaaagtcaa ccctgtcaaa acagaggacg 2160
ctgcatcaac ttgtggcagg gttatcagtg tgaatgtgac aggccctata caggctccaa 2220
ctgcctgaaa gagtatgtag cgggaagatt tggccaagat gactccacag gatatgcggc 2280
ctttagtgtt aatgataatt atggacagaa cttcagtctt tcaatgtttg tccgaacacg 2340
tcaacccctg ggcttacttc tggctttgga aaatagtact taccagtatg tcagtgtctg 2400
gctagagcac ggcagcctag cactgcagac tccaggctct cccaagttca tggtaaactt 2460
ttttctcagt gatggaaatg ttcacttaat atctttgaga atcaaaccaa atgaaattga 2520
actgtatcag tcttcacaaa acctaggatt catttctgtt cctacatgga caattcgaag 2580
aggagacgtc atcttcattg gtggcttacc tgacagagag aagactgaag tttatggtgg 2640
cttcttcaaa ggctgtgttc aagatgtcag attaaacagc cagactctgg aattctttcc 2700
caattcaaca aacaatgcat acgatgaccc aattcttgtc aatgtgactc aaggctgtcc 2760
cggagacaac acatgtaagt ccaacccctg tcataatgga ggtgtctgcc actccctgtg 2820
ggatgacttc tcctgctcct gccctacaaa cacagcgggg agagcctgcg agcaagttca 2880
gtggtgtcaa ctcagcccat gtcctcccac tgcagagtgc cagctgctcc ctcaagggtt 2940
tgaatgtatc gcaaacgctg ttttcagcgg attaagcaga gaaatactct tcagaagcaa 3000
tgggaacatt accagagaac tcaccaatat cacatttgct ttcagaacac atgatacaaa 3060
tgtgatgata ttgcatgcag aaaaagaacc agagtttctt aatattagca ttcaagatgc 3120
cagattattc tttcaattgc gaagtggcaa cagcttttat acgctgcacc tgatgggttc 3180
ccaattggtg aatgatggca catggcacca agtgactttc tccatgatag acccagtggc 3240
ccagacctcc cggtggcaaa tggaggtgaa cgaccagaca ccctttgtga taagtgaagt 3300
tgctactgga agcctgaact ttttgaagga caatacagac atctatgtgg gtgaccaatc 3360
tgttgacaat ccgaaaggcc tgcagggctg tctgagcaca atagagattg gaggcatata 3420
tctttcttac tttgaaaatc tacatggttt ccctggtaag cctcaggaag agcaatttct 3480
caaagtttct acaaatatgg tacttactgg ctgtttgcca tcaaatgcct gccactccag 3540
cccctgtttg catggaggaa actgtgaaga cagctacagt tcttatcggt gtgcctgtct 3600
ctcgggatgg tcagggacac actgtgaaat caacattgat gagtgctttt ctagcccctg 3660
tatccatggc aactgctctg atggagttgc agcctaccac tgcaggtgtg agcctggata 3720
caccggtgtg aactgtgagg tggatgtaga caattgcaag agtcatcagt gtgcaaatgg 3780
ggccacctgt gttcctgaag ctcatggcta ctcttgtctc tgctttggaa attttaccgg 3840
gagattttgc agacacagca gattaccctc aacagtctgt gggaatgaga agagaaactt 3900
cacttgctac aatggaggca gctgctccat gttccaggag gactggcaat gtatgtgctg 3960
gccaggtttc actggagagt ggtgtgaaga ggacatcaac gagtgtgcct ccgatccctg 4020
catcaatgga ggactgtgca gggacttggt caacaggttc ctatgcatct gtgatgtggc 4080
cttcgctggc gagcgctgtg agctggacct ggctgatgac aggctcctgg gcattttcac 4140
cgctgttggc tccggaactt tggccctgtt cttcatcctc ttgcttgctg gggttgcttc 4200
tcttattgcc tccaacaaaa gggcgactca aggaacctac agccccagcg gtcaggagaa 4260
ggctggccct cgagtggaaa tgtggatcag gatgccgccc ccggcactgg aaaggctcat 4320
ctaggagact gctgctcttc tcaggacaga gaagaacatg atgagtaccg ggtcgtgcct 4380
gagtgaagat ggctttacat cactagagat acatacagct gggactgtgg gaaggacctt 4440
cctgtggagt cactgagtag ttatgtcatc cattcacaga agagtgtccc tgtgtttgcc 4500
tgtcagcctc agaattagca aaacatctag cagacagaga acacagtatt tcagaagaac 4560
tccagaggct gccccttaaa ctctttactg gttgatccac ataaaatgct tagtagccaa 4620
gtgccattaa ttatacagag ccaagaagaa aaattagaat acaactttca ctttttattt 4680
tgtagggaag gttttatgtt ttggtttgtt gttgttgttg tgacagtgac agtgactcat 4740
tacatagacc aagctggcct caaaatcaca tggaccctcg ggattacatg tgtccgacca 4800
tgttcatctt atttttgaat cttctgtcat atggtaaaag attccagtgg gacctgagga 4860
gtgactagct aggtaaagca agggctgtgt aagtgccaga actggtgttt gtgtcctcat 4920
tatccacata agtgccaagt gagtgtggcc cctgcctgtc atcctaggcc tcaggagata 4980
tcactgctca ctggagcaag ccggttaaac tgttagggca ggtaagtttt gacttcaagt 5040
gagagaccct gactcaatat gaaaggcaat tagtgagtca agatgaccct gtatgctaac 5100
ctcttgccta tacatgcata tacacacatt tacatatgtg cccaaacatg aggacacaag 5160
cacacgcgcg cgcgcacaca cacacacaca cacacacaca cacacacaca cacacacaca 5220
cgagtctaat tgtatatagt gataacagta cactttcctc cttctatttc ggatttagag 5280
aaagccatga gaagcgtgta tggtttaaac catgacccaa gcataacaaa taaagttgaa 5340
atagttgttc tcctgtccaa gcttgtcttt attgttgtgc attctgtaag ctggttgctt 5400
ggttggctga tggatggctt ctgtttgttt gttgtttttt gtttgtttgt ttgtctggga 5460
tattacatgt aagaaaaata actggtaaga acaatcaaag aactttgtta tgaattaaat 5520
cttttgtcta agtcacttag agtcattatt ctttatgtag atttgcttcc agtcaggaca 5580
tttcctagac agaatttaag acagtaagaa aatgatttgt cacgtctgaa agaggttctt 5640
tactttcagg gacttttgat aatgcccaac agagatggca tcgaaagagg agctcatagc 5700
gagatgggca tttgtgcatc ctcaaggaga aaatattgta ccttctgttt gtatattgtc 5760
tattctgtga tggctgtatc ttacatatgt tttgatgcat gtaacaatag tatcatatga 5820
aataaattat atatatatat aatatataat atatatcaca agataaaaat tgaaattaca 5880
taaactttaa atct 5894
<210> 62
<211> 1344
<212> PRT
<213> 小鼠
<400> 62
Met Lys Leu Lys Arg Thr Ala Tyr Leu Leu Phe Leu Tyr Leu Ser Ser
1 5 10 15
Ser Leu Leu Ile Cys Ile Lys Asn Ser Phe Cys Asn Lys Asn Asn Thr
20 25 30
Arg Cys Leu Ser Gly Pro Cys Gln Asn Asn Ser Thr Cys Lys His Phe
35 40 45
Pro Gln Asp Asn Asn Cys Cys Leu Asp Thr Ala Asn Asn Leu Asp Lys
50 55 60
Asp Cys Glu Asp Leu Lys Asp Pro Cys Phe Ser Ser Pro Cys Gln Gly
65 70 75 80
Ile Ala Thr Cys Val Lys Ile Pro Gly Glu Gly Asn Phe Leu Cys Gln
85 90 95
Cys Pro Pro Gly Tyr Ser Gly Leu Asn Cys Glu Thr Ala Thr Asn Ser
100 105 110
Cys Gly Gly Asn Leu Cys Gln His Gly Gly Thr Cys Arg Lys Asp Pro
115 120 125
Glu His Pro Val Cys Ile Cys Pro Pro Gly Tyr Ala Gly Arg Phe Cys
130 135 140
Glu Thr Asp His Asn Glu Cys Ala Ser Ser Pro Cys His Asn Gly Ala
145 150 155 160
Met Cys Gln Asp Gly Ile Asn Gly Tyr Ser Cys Phe Cys Val Pro Gly
165 170 175
Tyr Gln Gly Arg His Cys Asp Leu Glu Val Asp Glu Cys Val Ser Asp
180 185 190
Pro Cys Lys Asn Glu Ala Val Cys Leu Asn Glu Ile Gly Arg Tyr Thr
195 200 205
Cys Val Cys Pro Gln Glu Phe Ser Gly Val Asn Cys Glu Leu Glu Ile
210 215 220
Asp Glu Cys Arg Ser Gln Pro Cys Leu His Gly Ala Thr Cys Gln Asp
225 230 235 240
Ala Pro Gly Gly Tyr Ser Cys Asp Cys Ala Pro Gly Phe Leu Gly Glu
245 250 255
His Cys Glu Leu Ser Val Asn Glu Cys Glu Ser Gln Pro Cys Leu His
260 265 270
Gly Gly Leu Cys Val Asp Gly Arg Asn Ser Tyr His Cys Asp Cys Thr
275 280 285
Gly Ser Gly Phe Thr Gly Met His Cys Glu Ser Leu Ile Pro Leu Cys
290 295 300
Trp Ser Lys Pro Cys His Asn Asp Ala Thr Cys Glu Asp Thr Val Asp
305 310 315 320
Ser Tyr Ile Cys His Cys Arg Pro Gly Ile His Cys Glu Glu Asp Val
325 330 335
Asp Glu Cys Leu Leu His Pro Cys Leu Asn Gly Gly Thr Cys Glu Asn
340 345 350
Leu Pro Gly Asn Tyr Ala Cys His Cys Pro Phe Asp Asp Thr Ser Arg
355 360 365
Thr Phe Tyr Gly Gly Glu Asn Cys Ser Glu Ile Leu Leu Gly Cys Thr
370 375 380
His His Gln Cys Leu Asn Asn Gly Lys Cys Ile Pro His Phe Gln Asn
385 390 395 400
Gly Gln His Gly Phe Thr Cys Gln Cys Leu Ser Gly Tyr Ala Gly Pro
405 410 415
Leu Cys Glu Thr Val Thr Thr Leu Ser Phe Gly Ser Asn Gly Phe Leu
420 425 430
Trp Val Thr Ser Gly Ser His Thr Gly Ile Gly Pro Glu Cys Asn Ile
435 440 445
Ser Leu Arg Phe His Thr Val Gln Pro Asn Ala Leu Leu Leu Ile Arg
450 455 460
Gly Asn Lys Asp Val Ser Met Lys Leu Glu Leu Leu Asn Gly Cys Val
465 470 475 480
His Leu Ser Ile Glu Val Trp Asn Gln Leu Lys Val Leu Leu Ser Ile
485 490 495
Ser His Asn Thr Ser Asp Gly Glu Trp His Phe Val Glu Val Thr Ile
500 505 510
Ala Glu Thr Leu Thr Leu Ala Leu Val Gly Gly Ser Cys Lys Glu Lys
515 520 525
Cys Thr Thr Lys Ser Ser Val Pro Val Glu Asn His Gln Ser Ile Cys
530 535 540
Ala Leu Gln Asp Ser Phe Leu Gly Gly Leu Pro Met Gly Thr Ala Asn
545 550 555 560
Asn Ser Val Ser Val Leu Asn Ile Tyr Asn Val Pro Ser Thr Pro Ser
565 570 575
Phe Val Gly Cys Leu Gln Asp Ile Arg Phe Asp Leu Asn His Ile Thr
580 585 590
Leu Glu Asn Val Ser Ser Gly Leu Ser Ser Asn Val Lys Ala Gly Cys
595 600 605
Leu Gly Lys Asp Trp Cys Glu Ser Gln Pro Cys Gln Asn Arg Gly Arg
610 615 620
Cys Ile Asn Leu Trp Gln Gly Tyr Gln Cys Glu Cys Asp Arg Pro Tyr
625 630 635 640
Thr Gly Ser Asn Cys Leu Lys Glu Tyr Val Ala Gly Arg Phe Gly Gln
645 650 655
Asp Asp Ser Thr Gly Tyr Ala Ala Phe Ser Val Asn Asp Asn Tyr Gly
660 665 670
Gln Asn Phe Ser Leu Ser Met Phe Val Arg Thr Arg Gln Pro Leu Gly
675 680 685
Leu Leu Leu Ala Leu Glu Asn Ser Thr Tyr Gln Tyr Val Ser Val Trp
690 695 700
Leu Glu His Gly Ser Leu Ala Leu Gln Thr Pro Gly Ser Pro Lys Phe
705 710 715 720
Met Val Asn Phe Phe Leu Ser Asp Gly Asn Val His Leu Ile Ser Leu
725 730 735
Arg Ile Lys Pro Asn Glu Ile Glu Leu Tyr Gln Ser Ser Gln Asn Leu
740 745 750
Gly Phe Ile Ser Val Pro Thr Trp Thr Ile Arg Arg Gly Asp Val Ile
755 760 765
Phe Ile Gly Gly Leu Pro Asp Arg Glu Lys Thr Glu Val Tyr Gly Gly
770 775 780
Phe Phe Lys Gly Cys Val Gln Asp Val Arg Leu Asn Ser Gln Thr Leu
785 790 795 800
Glu Phe Phe Pro Asn Ser Thr Asn Asn Ala Tyr Asp Asp Pro Ile Leu
805 810 815
Val Asn Val Thr Gln Gly Cys Pro Gly Asp Asn Thr Cys Lys Ser Asn
820 825 830
Pro Cys His Asn Gly Gly Val Cys His Ser Leu Trp Asp Asp Phe Ser
835 840 845
Cys Ser Cys Pro Thr Asn Thr Ala Gly Arg Ala Cys Glu Gln Val Gln
850 855 860
Trp Cys Gln Leu Ser Pro Cys Pro Pro Thr Ala Glu Cys Gln Leu Leu
865 870 875 880
Pro Gln Gly Phe Glu Cys Ile Ala Asn Ala Val Phe Ser Gly Leu Ser
885 890 895
Arg Glu Ile Leu Phe Arg Ser Asn Gly Asn Ile Thr Arg Glu Leu Thr
900 905 910
Asn Ile Thr Phe Ala Phe Arg Thr His Asp Thr Asn Val Met Ile Leu
915 920 925
His Ala Glu Lys Glu Pro Glu Phe Leu Asn Ile Ser Ile Gln Asp Ala
930 935 940
Arg Leu Phe Phe Gln Leu Arg Ser Gly Asn Ser Phe Tyr Thr Leu His
945 950 955 960
Leu Met Gly Ser Gln Leu Val Asn Asp Gly Thr Trp His Gln Val Thr
965 970 975
Phe Ser Met Ile Asp Pro Val Ala Gln Thr Ser Arg Trp Gln Met Glu
980 985 990
Val Asn Asp Gln Thr Pro Phe Val Ile Ser Glu Val Ala Thr Gly Ser
995 1000 1005
Leu Asn Phe Leu Lys Asp Asn Thr Asp Ile Tyr Val Gly Asp Gln
1010 1015 1020
Ser Val Asp Asn Pro Lys Gly Leu Gln Gly Cys Leu Ser Thr Ile
1025 1030 1035
Glu Ile Gly Gly Ile Tyr Leu Ser Tyr Phe Glu Asn Leu His Gly
1040 1045 1050
Phe Pro Gly Lys Pro Gln Glu Glu Gln Phe Leu Lys Val Ser Thr
1055 1060 1065
Asn Met Val Leu Thr Gly Cys Leu Pro Ser Asn Ala Cys His Ser
1070 1075 1080
Ser Pro Cys Leu His Gly Gly Asn Cys Glu Asp Ser Tyr Ser Ser
1085 1090 1095
Tyr Arg Cys Ala Cys Leu Ser Gly Trp Ser Gly Thr His Cys Glu
1100 1105 1110
Ile Asn Ile Asp Glu Cys Phe Ser Ser Pro Cys Ile His Gly Asn
1115 1120 1125
Cys Ser Asp Gly Val Ala Ala Tyr His Cys Arg Cys Glu Pro Gly
1130 1135 1140
Tyr Thr Gly Val Asn Cys Glu Val Asp Val Asp Asn Cys Lys Ser
1145 1150 1155
His Gln Cys Ala Asn Gly Ala Thr Cys Val Pro Glu Ala His Gly
1160 1165 1170
Tyr Ser Cys Leu Cys Phe Gly Asn Phe Thr Gly Arg Phe Cys Arg
1175 1180 1185
His Ser Arg Leu Pro Ser Thr Val Cys Gly Asn Glu Lys Arg Asn
1190 1195 1200
Phe Thr Cys Tyr Asn Gly Gly Ser Cys Ser Met Phe Gln Glu Asp
1205 1210 1215
Trp Gln Cys Met Cys Trp Pro Gly Phe Thr Gly Glu Trp Cys Glu
1220 1225 1230
Glu Asp Ile Asn Glu Cys Ala Ser Asp Pro Cys Ile Asn Gly Gly
1235 1240 1245
Leu Cys Arg Asp Leu Val Asn Arg Phe Leu Cys Ile Cys Asp Val
1250 1255 1260
Ala Phe Ala Gly Glu Arg Cys Glu Leu Asp Leu Ala Asp Asp Arg
1265 1270 1275
Leu Leu Gly Ile Phe Thr Ala Val Gly Ser Gly Thr Leu Ala Leu
1280 1285 1290
Phe Phe Ile Leu Leu Leu Ala Gly Val Ala Ser Leu Ile Ala Ser
1295 1300 1305
Asn Lys Arg Ala Thr Gln Gly Thr Tyr Ser Pro Ser Gly Gln Glu
1310 1315 1320
Lys Ala Gly Pro Arg Val Glu Met Trp Ile Arg Met Pro Pro Pro
1325 1330 1335
Ala Leu Glu Arg Leu Ile
1340
<210> 63
<211> 5554
<212> DNA
<213> 小鼠
<400> 63
cccactgatc cagcttgaag aggagtgagg caaagctgaa ccctcccact ctccttgaca 60
agtgcaagcc cacacttttg gaaaaaagca caaagacgtc agaaacggtt cctgtcgacc 120
tactaggctt tggatggcta agtgtttttg ctttgtatgg aaatatgttt ggacacaaga 180
cacaaggttt tcacatttta atggcagtgc tcataggaat tcactgtgaa gaagacgttg 240
atgaatgttt actgcaccct tgcctaaatg gtggtacttg tgagaacctg cctgggaatt 300
atgcctgtca ctgtcccttt gatgacactt ctaggacatt ttatggagga gaaaactgct 360
cagaaattct cctgggctgc actcatcacc agtgtctgaa caatggaaaa tgtatccctc 420
atttccaaaa tggccagcat ggattcactt gccagtgtct ttctggctat gcggggcccc 480
tgtgtgaaac tgtcaccaca ctttcatttg ggagcaatgg cttcctatgg gtcacaagtg 540
gctcccatac aggcataggg ccagaatgta acatatcctt gaggtttcac actgttcaac 600
caaacgcact tctcctcatc cgaggcaaca aggacgtgtc tatgaagctg gagttgctga 660
atggttgtgt tcacttatca attgaagtct ggaatcagtt aaaggtgctc ctgtctattt 720
ctcacaacac cagtgatgga gaatggcatt tcgtggaggt aacaatcgca gaaactctaa 780
cccttgccct agttggcggc tcctgcaagg agaagtgcac caccaagtct tctgttccag 840
ttgagaatca tcaatcaata tgtgctttgc aggactcttt tttgggtggc ttaccaatgg 900
ggacagccaa caacagtgtg tctgtgctta acatctataa tgtgccgtcc acaccttcct 960
ttgtaggctg tctccaagac attagatttg atttgaatca cattactctg gagaacgttt 1020
catctggcct gtcatcaaat gttaaagcag gctgcctggg aaaggactgg tgtgaaagtc 1080
aaccctgtca aaacagagga cgctgcatca acttgtggca gggttatcag tgtgaatgtg 1140
acaggcccta tacaggctcc aactgcctga aagagtatgt agcgggaaga tttggccaag 1200
atgactccac aggatatgcg gcctttagtg ttaatgataa ttatggacag aacttcagtc 1260
tttcaatgtt tgtccgaaca cgtcaacccc tgggcttact tctggctttg gaaaatagta 1320
cttaccagta tgtcagtgtc tggctagagc acggcagcct agcactgcag actccaggct 1380
ctcccaagtt catggtaaac ttttttctca gtgatggaaa tgttcactta atatctttga 1440
gaatcaaacc aaatgaaatt gaactgtatc agtcttcaca aaacctagga ttcatttctg 1500
ttcctacatg gacaattcga agaggagacg tcatcttcat tggtggctta cctgacagag 1560
agaagactga agtttatggt ggcttcttca aaggctgtgt tcaagatgtc agattaaaca 1620
gccagactct ggaattcttt cccaattcaa caaacaatgc atacgatgac ccaattcttg 1680
tcaatgtgac tcaaggctgt cccggagaca acacatgtaa gtccaacccc tgtcataatg 1740
gaggtgtctg ccactccctg tgggatgact tctcctgctc ctgccctaca aacacagcgg 1800
ggagagcctg cgagcaagtt cagtggtgtc aactcagccc atgtcctccc actgcagagt 1860
gccagctgct ccctcaaggg tttgaataac acatgataca aatgtgatga tattgcatgc 1920
agaaaaagaa ccagagtttc ttaatattag cattcaagat gccagattat tctttcaatt 1980
gcgaagtggc aacagctttt atacgctgca cctgatgggt tcccaattgg tgaatgatgg 2040
cacatggcac caagtgactt tctccatgat agacccagtg gcccagacct cccggtggca 2100
aatggaggtg aacgaccaga caccctttgt gataagtgaa gttgctactg gaagcctgaa 2160
ctttttgaag gacaatacag acatctatgt gggtgaccaa tctgttgaca atccgaaagg 2220
cctgcagggc tgtctgagca caatagagat tggaggcata tatctttctt actttgaaaa 2280
tctacatggt ttccctggta agcctcagga agagcaattt ctcaaagttt ctacaaatat 2340
ggtacttact ggctgtttgc catcaaatgc ctgccactcc agcccctgtt tgcatggagg 2400
aaactgtgaa gacagctaca gttcttatcg gtgtgcctgt ctctcgggat ggtcagggac 2460
acactgtgaa atcaacattg atgagtgctt ttctagcccc tgtatccatg gcaactgctc 2520
tgatggagtt gcagcctacc actgcaggtg tgagcctgga tacaccggtg tgaactgtga 2580
ggtggatgta gacaattgca agagtcatca gtgtgcaaat ggggccacct gtgttcctga 2640
agctcatggc tactcttgtc tctgctttgg aaattttacc gggagatttt gcagacacag 2700
cagattaccc tcaacagtct gtgggaatga gaagagaaac ttcacttgct acaatggagg 2760
cagctgctcc atgttccagg aggactggca atgtatgtgc tggccaggtt tcactggaga 2820
gtggtgtgaa gaggacatca acgagtgtgc ctccgatccc tgcatcaatg gaggactgtg 2880
cagggacttg gtcaacaggt tcctatgcat ctgtgatgtg gccttcgctg gcgagcgctg 2940
tgagctggac gtaagcggcc tttcctttta tgtgtccctc ttactatggc aaaacctctt 3000
tcagctcctg tcctacctcg tactgcgcat gaatgatgag ccagttgtag agtggggggc 3060
acaggaaaat tattaatgtg catgggagca ttcacaagtg taaaacattg acttgcaaga 3120
aacatcttgt ctcagtgtag gtttctagga aagacaaagg gaacattagg gaatagactc 3180
catctagagc actggttctc agtcttccta atgctgcaac cctttagtac agctcttcct 3240
gttgtagtga tcgcagccat aacattattt tcattgccac ttcataactg taatccttct 3300
actgctgtga atcacaatgg aaatatttat gttttctgat ggtcttaagc aacacctctg 3360
aaaaagtcat tgaccccccc cccaaagggg ctgtgatcca caggttgaga aatgctcatc 3420
tggaaggtaa ccatgcattt aagtgtacct ctagtagttt gggtctatag aagatattct 3480
cctattctac ctttttagac acgccagaag agggcatctg attccattaa agatgattgg 3540
gagccaccgt gtggttcctg agaactgtac tcgggccctt tggaagagca atcagtgctc 3600
tttccagccc ctaagaatat ttttaataca gccagaaagg tctcattacc cagtgtactg 3660
agccctaagg cactttcatc ctcaatcgtt ccatgttgaa tggttttcat tacatttgga 3720
aaatgttttc tctccactct acctttacat gttcctattt tcctattgac aatttgcccc 3780
ttcactgtaa ttctaatttg gtgtggtcct tcttctcata agtttatatg tgacatgaac 3840
atttaaaaat atctatgaat attttatagt catgtatgtc tttctgcaaa gctattcaaa 3900
tgaactatgg acagttcttt tctacacgaa gaagagatga gtttaatccc cagtaacatg 3960
agaaaaagat gagtgaggga cagtgctcac agtatccctc actagcatca tttgtgattc 4020
catgggccat ttttttccac cagcaaatag cagagagccc tttccctatt cgtttctctt 4080
acacttcccc ttttctgtta caactgaaca ctttacatta gttactcctt tgtagggggt 4140
ttgacttttc caccgttttc tctggttcac tatttatgct aagtatctgt gcagggcggg 4200
tatatcagtc caacagaggt gtcattagtg ttcattgagg aggaaatact ttgcatgaat 4260
tcatgacatc attgaagtag cagtggccag aaagataccc ttctgcgaat gtgtctgtgt 4320
attcagaagc tgccctggtt agaaaacatg tgggtcactt ttcctttgca tgttaccagt 4380
gctcactggg tcatgattgt tttaagacag agcttttgct gtggcaatga ccaaggtgaa 4440
tccagagatg cagatcagac aaaggacaag acaatgtact atctgagtaa aaccctgcct 4500
tgacttactc ctcagtactt agagatttta catagcaacc tccaccctgt ggcaacccgt 4560
tcacactagc agtgatgctg agatttgccc ttccttctca tcatcttcct cacatccaaa 4620
gcattttgtg tccacactgc tgtttcagat aactgtttct aaagtgggat tgttgtagcc 4680
agaaaggtag ggaaaatgtt ccccaaaata tttgcattct taagtatgtg aagtaagtag 4740
attatagtca gagacaatat gtaaggtttc aggttcactc ccttctacac atatcttcaa 4800
ctgtgtattt gcagaatatt ctgaatgtga catactccca acagaatata tttaaggagt 4860
atttatccac agtattgttc tctgtacagt tctagtgctt ctattgtcac tgcaattgtc 4920
aattgttttt ctgctttcca actgtcttat tatcatttaa tagcatcttg ctaaatgccc 4980
tctttctatt ctccttattt ctccatagtt catgtgtgtc tgtgtgacta aggattctcc 5040
tcatttttgc agaaaaataa aatcttttct tctttatgtc ctgcttgtca ttctctggtg 5100
acacatgtct ttgcttactt ggactgaggg ttgtacagta agtacagaag caggctcagt 5160
cacacagaca gagacacacc accaccagca gcagcagcac caccaccacc accaccacca 5220
ccagaaaaca gtatgagtac tcatctcttg attacatgtc atttcaagta agcaccatga 5280
caccgagggc caggttccat ggactttctc tgttaggcac gtgattcttt agctgacctt 5340
tgagaacaga ctccaacaac ctcacttatt tttactgttg acttatatca tctctgacaa 5400
cactggactt cgtttgagct agtcaagagg aaagaccatg acacctaagg gacagaaatt 5460
cacacactcg gtttttcata attcacacac attcctatgt atcaaatctc tgtaatagat 5520
gacatttact tgaataaaaa gtcatttccc tttg 5554
<210> 64
<211> 574
<212> PRT
<213> 小鼠
<400> 64
Met Phe Gly His Lys Thr Gln Gly Phe His Ile Leu Met Ala Val Leu
1 5 10 15
Ile Gly Ile His Cys Glu Glu Asp Val Asp Glu Cys Leu Leu His Pro
20 25 30
Cys Leu Asn Gly Gly Thr Cys Glu Asn Leu Pro Gly Asn Tyr Ala Cys
35 40 45
His Cys Pro Phe Asp Asp Thr Ser Arg Thr Phe Tyr Gly Gly Glu Asn
50 55 60
Cys Ser Glu Ile Leu Leu Gly Cys Thr His His Gln Cys Leu Asn Asn
65 70 75 80
Gly Lys Cys Ile Pro His Phe Gln Asn Gly Gln His Gly Phe Thr Cys
85 90 95
Gln Cys Leu Ser Gly Tyr Ala Gly Pro Leu Cys Glu Thr Val Thr Thr
100 105 110
Leu Ser Phe Gly Ser Asn Gly Phe Leu Trp Val Thr Ser Gly Ser His
115 120 125
Thr Gly Ile Gly Pro Glu Cys Asn Ile Ser Leu Arg Phe His Thr Val
130 135 140
Gln Pro Asn Ala Leu Leu Leu Ile Arg Gly Asn Lys Asp Val Ser Met
145 150 155 160
Lys Leu Glu Leu Leu Asn Gly Cys Val His Leu Ser Ile Glu Val Trp
165 170 175
Asn Gln Leu Lys Val Leu Leu Ser Ile Ser His Asn Thr Ser Asp Gly
180 185 190
Glu Trp His Phe Val Glu Val Thr Ile Ala Glu Thr Leu Thr Leu Ala
195 200 205
Leu Val Gly Gly Ser Cys Lys Glu Lys Cys Thr Thr Lys Ser Ser Val
210 215 220
Pro Val Glu Asn His Gln Ser Ile Cys Ala Leu Gln Asp Ser Phe Leu
225 230 235 240
Gly Gly Leu Pro Met Gly Thr Ala Asn Asn Ser Val Ser Val Leu Asn
245 250 255
Ile Tyr Asn Val Pro Ser Thr Pro Ser Phe Val Gly Cys Leu Gln Asp
260 265 270
Ile Arg Phe Asp Leu Asn His Ile Thr Leu Glu Asn Val Ser Ser Gly
275 280 285
Leu Ser Ser Asn Val Lys Ala Gly Cys Leu Gly Lys Asp Trp Cys Glu
290 295 300
Ser Gln Pro Cys Gln Asn Arg Gly Arg Cys Ile Asn Leu Trp Gln Gly
305 310 315 320
Tyr Gln Cys Glu Cys Asp Arg Pro Tyr Thr Gly Ser Asn Cys Leu Lys
325 330 335
Glu Tyr Val Ala Gly Arg Phe Gly Gln Asp Asp Ser Thr Gly Tyr Ala
340 345 350
Ala Phe Ser Val Asn Asp Asn Tyr Gly Gln Asn Phe Ser Leu Ser Met
355 360 365
Phe Val Arg Thr Arg Gln Pro Leu Gly Leu Leu Leu Ala Leu Glu Asn
370 375 380
Ser Thr Tyr Gln Tyr Val Ser Val Trp Leu Glu His Gly Ser Leu Ala
385 390 395 400
Leu Gln Thr Pro Gly Ser Pro Lys Phe Met Val Asn Phe Phe Leu Ser
405 410 415
Asp Gly Asn Val His Leu Ile Ser Leu Arg Ile Lys Pro Asn Glu Ile
420 425 430
Glu Leu Tyr Gln Ser Ser Gln Asn Leu Gly Phe Ile Ser Val Pro Thr
435 440 445
Trp Thr Ile Arg Arg Gly Asp Val Ile Phe Ile Gly Gly Leu Pro Asp
450 455 460
Arg Glu Lys Thr Glu Val Tyr Gly Gly Phe Phe Lys Gly Cys Val Gln
465 470 475 480
Asp Val Arg Leu Asn Ser Gln Thr Leu Glu Phe Phe Pro Asn Ser Thr
485 490 495
Asn Asn Ala Tyr Asp Asp Pro Ile Leu Val Asn Val Thr Gln Gly Cys
500 505 510
Pro Gly Asp Asn Thr Cys Lys Ser Asn Pro Cys His Asn Gly Gly Val
515 520 525
Cys His Ser Leu Trp Asp Asp Phe Ser Cys Ser Cys Pro Thr Asn Thr
530 535 540
Ala Gly Arg Ala Cys Glu Gln Val Gln Trp Cys Gln Leu Ser Pro Cys
545 550 555 560
Pro Pro Thr Ala Glu Cys Gln Leu Leu Pro Gln Gly Phe Glu
565 570
<210> 65
<211> 4783
<212> DNA
<213> 小鼠
<400> 65
gatccagctt gaagaggagt gaggcaaagc tgaaccctcc cactctcctt gacaagtgca 60
agcccacact tttggaaaaa agcacaaaga cgtcagaaac ggttcctgtc gacctactag 120
gctttggatg gctaagtgtt tttgctttgt atggaaatat gtttggacac aagacacaag 180
gttttcacat tttaatggca gtgctcatag gaattcactg tgaagaagac gttgatgaat 240
gtttactgca cccttgccta aatggtggta cttgtgagaa cctgcctggg aattatgcct 300
gtcactgtcc ctttgatgac acttctagga cattttatgg aggagaaaac tgctcagaaa 360
ttctcctggg ctgcactcat caccagtgtc tgaacaatgg aaaatgtatc cctcatttcc 420
aaaatggcca gcatggattc acttgccagt gtctttctgg ctatgcgggg cccctgtgtg 480
aaactgtcac cacactttca tttgggagca atggcttcct atgggtcaca agtggctccc 540
atacaggcat agggccagaa tgtaacatat ccttgaggtt tcacactgtt caaccaaacg 600
cacttctcct catccgaggc aacaaggacg tgtctatgaa gctggagttg ctgaatggtt 660
gtgttcactt atcaattgaa gtctggaatc agttaaaggt gctcctgtct atttctcaca 720
acaccagtga tggagaatgg catttcgtgg aggtaacaat cgcagaaact ctaacccttg 780
ccctagttgg cggctcctgc aaggagaagt gcaccaccaa gtcttctgtt ccagttgaga 840
atcatcaatc aatatgtgct ttgcaggact cttttttggg tggcttacca atggggacag 900
ccaacaacag tgtgtctgtg cttaacatct ataatgtgcc gtccacacct tcctttgtag 960
gctgtctcca agacattaga tttgatttga atcacattac tctggagaac gtttcatctg 1020
gcctgtcatc aaatgttaaa gcaggctgcc tgggaaagga ctggtgtgaa agtcaaccct 1080
gtcaaaacag aggacgctgc atcaacttgt ggcagggtta tcagtgtgaa tgtgacaggc 1140
cctatacagg ctccaactgc ctgaaagagt atgtagcggg aagatttggc caagatgact 1200
ccacaggata tgcggccttt agtgttaatg ataattatgg acagaacttc agtctttcaa 1260
tgtttgtccg aacacgtcaa cccctgggct tacttctggc tttggaaaat agtacttacc 1320
agtatgtcag tgtctggcta gagcacggca gcctagcact gcagactcca ggctctccca 1380
agttcatggt aaactttttt ctcagtgatg gaaatgttca cttaatatct ttgagaatca 1440
aaccaaatga aattgaactg tatcagtctt cacaaaacct aggattcatt tctgttccta 1500
catggacaat tcgaagagga gacgtcatct tcattggtgg cttacctgac agagagaaga 1560
ctgaagttta tggtggcttc ttcaaaggct gtgttcaaga tgtcagatta aacagccaga 1620
ctctggaatt ctttcccaat tcaacaaaca atgcatacga tgacccaatt cttgtcaatg 1680
tgactcaagg ctgtcccgga gacaacacat gtaagtccaa cccctgtcat aatggaggtg 1740
tctgccactc cctgtgggat gacttctcct gctcctgccc tacaaacaca gcggggagag 1800
cctgcgagca agttcagtgg tgtcaactca gcccatgtcc tcccactgca gagtgccagc 1860
tgctccctca agggtttgaa tgtatcgcaa acgctgtttt cagcggatta agcagagaaa 1920
tactcttcag aagcaatggg aacattacca gagaactcac caatatcaca tttgctttca 1980
gaacacatga tacaaatgtg atgatattgc atgcagaaaa agaaccagag tttcttaata 2040
ttagcattca agatgccaga ttattctttc aattgcgaag tggcaacagc ttttatacgc 2100
tgcacctgat gggttcccaa ttggtgaatg atggcacatg gcaccaagtg actttctcca 2160
tgatagaccc agtggcccag acctcccggt ggcaaatgga ggtgaacgac cagacaccct 2220
ttgtgataag tgaagttgct actggaagcc tgaacttttt gaaggacaat acagacatct 2280
atgtgggtga ccaatctgtt gacaatccga aaggcctgca gggctgtctg agcacaatag 2340
agattggagg catatatctt tcttactttg aaaatctaca tggtttccct ggtaagcctc 2400
aggaagagca atttctcaaa gtttctacaa atatggtact tactggctgt ttgccatcaa 2460
atgcctgcca ctccagcccc tgtttgcatg gaggaaactg tgaagacagc tacagttctt 2520
atcggtgtgc ctgtctctcg ggatggtcag ggacacactg tgaaatcaac attgatgagt 2580
gcttttctag cccctgtatc catggcaact gctctgatgg agttgcagcc taccactgca 2640
ggtgtgagcc tggatacacc ggtgtgaact gtgaggtgga tgtagacaat tgcaagagtc 2700
atcagtgtgc aaatggggcc acctgtgttc ctgaagctca tggctactct tgtctctgct 2760
ttggaaattt taccgggaga ttttgcagac acagcagatt accctcaaca gtctgtggga 2820
atgagaagag aaacttcact tgctacaatg gaggcagctg ctccatgttc caggaggact 2880
ggcaatgtat gtgctggcca ggtttcactg gagagtggtg tgaagaggac atcaacgagt 2940
gtgcctccga tccctgcatc aatggaggac tgtgcaggga cttggtcaac aggttcctat 3000
gcatctgtga tgtggccttc gctggcgagc gctgtgagct ggacctggct gatgacaggc 3060
tcctgggcat tttcaccgct gttggctccg gaactttggc cctgttcttc atcctcttgc 3120
ttgctggggt tgcttctctt attgcctcca acaaaagggc gactcaagga acctacagcc 3180
ccagcggtca ggagaaggct ggccctcgag tggaaatgtg gatcaggatg ccgcccccgg 3240
cactggaaag gctcatctag gagactgctg ctcttctcag gacagagaag aacatgatga 3300
gtaccgggtc gtgcctgagt gaagatggct ttacatcact agagatacat acagctggga 3360
ctgtgggaag gaccttcctg tggagtcact gagtagttat gtcatccatt cacagaagag 3420
tgtccctgtg tttgcctgtc agcctcagaa ttagcaaaac atctagcaga cagagaacac 3480
agtatttcag aagaactcca gaggctgccc cttaaactct ttactggttg atccacataa 3540
aatgcttagt agccaagtgc cattaattat acagagccaa gaagaaaaat tagaatacaa 3600
ctttcacttt ttattttgta gggaaggttt tatgttttgg tttgttgttg ttgttgtgac 3660
agtgacagtg actcattaca tagaccaagc tggcctcaaa atcacatgga ccctcgggat 3720
tacatgtgtc cgaccatgtt catcttattt ttgaatcttc tgtcatatgg taaaagattc 3780
cagtgggacc tgaggagtga ctagctaggt aaagcaaggg ctgtgtaagt gccagaactg 3840
gtgtttgtgt cctcattatc cacataagtg ccaagtgagt gtggcccctg cctgtcatcc 3900
taggcctcag gagatatcac tgctcactgg agcaagccgg ttaaactgtt agggcaggta 3960
agttttgact tcaagtgaga gaccctgact caatatgaaa ggcaattagt gagtcaagat 4020
gaccctgtat gctaacctct tgcctataca tgcatataca cacatttaca tatgtgccca 4080
aacatgagga cacaagcaca cgcgcgcgcg cacacacaca cacacacaca cacacacaca 4140
cacacacaca cacacacgag tctaattgta tatagtgata acagtacact ttcctccttc 4200
tatttcggat ttagagaaag ccatgagaag cgtgtatggt ttaaaccatg acccaagcat 4260
aacaaataaa gttgaaatag ttgttctcct gtccaagctt gtctttattg ttgtgcattc 4320
tgtaagctgg ttgcttggtt ggctgatgga tggcttctgt ttgtttgttg ttttttgttt 4380
gtttgtttgt ctgggatatt acatgtaaga aaaataactg gtaagaacaa tcaaagaact 4440
ttgttatgaa ttaaatcttt tgtctaagtc acttagagtc attattcttt atgtagattt 4500
gcttccagtc aggacatttc ctagacagaa tttaagacag taagaaaatg atttgtcacg 4560
tctgaaagag gttctttact ttcagggact tttgataatg cccaacagag atggcatcga 4620
aagaggagct catagcgaga tgggcatttg tgcatcctca aggagaaaat attgtacctt 4680
ctgtttgtat attgtctatt ctgtgatggc tgtatcttac atatgttttg atgcatgtaa 4740
caatagtatc atatgaaata aattatatat atatataata tat 4783
<210> 66
<211> 1033
<212> PRT
<213> 小鼠
<400> 66
Met Phe Gly His Lys Thr Gln Gly Phe His Ile Leu Met Ala Val Leu
1 5 10 15
Ile Gly Ile His Cys Glu Glu Asp Val Asp Glu Cys Leu Leu His Pro
20 25 30
Cys Leu Asn Gly Gly Thr Cys Glu Asn Leu Pro Gly Asn Tyr Ala Cys
35 40 45
His Cys Pro Phe Asp Asp Thr Ser Arg Thr Phe Tyr Gly Gly Glu Asn
50 55 60
Cys Ser Glu Ile Leu Leu Gly Cys Thr His His Gln Cys Leu Asn Asn
65 70 75 80
Gly Lys Cys Ile Pro His Phe Gln Asn Gly Gln His Gly Phe Thr Cys
85 90 95
Gln Cys Leu Ser Gly Tyr Ala Gly Pro Leu Cys Glu Thr Val Thr Thr
100 105 110
Leu Ser Phe Gly Ser Asn Gly Phe Leu Trp Val Thr Ser Gly Ser His
115 120 125
Thr Gly Ile Gly Pro Glu Cys Asn Ile Ser Leu Arg Phe His Thr Val
130 135 140
Gln Pro Asn Ala Leu Leu Leu Ile Arg Gly Asn Lys Asp Val Ser Met
145 150 155 160
Lys Leu Glu Leu Leu Asn Gly Cys Val His Leu Ser Ile Glu Val Trp
165 170 175
Asn Gln Leu Lys Val Leu Leu Ser Ile Ser His Asn Thr Ser Asp Gly
180 185 190
Glu Trp His Phe Val Glu Val Thr Ile Ala Glu Thr Leu Thr Leu Ala
195 200 205
Leu Val Gly Gly Ser Cys Lys Glu Lys Cys Thr Thr Lys Ser Ser Val
210 215 220
Pro Val Glu Asn His Gln Ser Ile Cys Ala Leu Gln Asp Ser Phe Leu
225 230 235 240
Gly Gly Leu Pro Met Gly Thr Ala Asn Asn Ser Val Ser Val Leu Asn
245 250 255
Ile Tyr Asn Val Pro Ser Thr Pro Ser Phe Val Gly Cys Leu Gln Asp
260 265 270
Ile Arg Phe Asp Leu Asn His Ile Thr Leu Glu Asn Val Ser Ser Gly
275 280 285
Leu Ser Ser Asn Val Lys Ala Gly Cys Leu Gly Lys Asp Trp Cys Glu
290 295 300
Ser Gln Pro Cys Gln Asn Arg Gly Arg Cys Ile Asn Leu Trp Gln Gly
305 310 315 320
Tyr Gln Cys Glu Cys Asp Arg Pro Tyr Thr Gly Ser Asn Cys Leu Lys
325 330 335
Glu Tyr Val Ala Gly Arg Phe Gly Gln Asp Asp Ser Thr Gly Tyr Ala
340 345 350
Ala Phe Ser Val Asn Asp Asn Tyr Gly Gln Asn Phe Ser Leu Ser Met
355 360 365
Phe Val Arg Thr Arg Gln Pro Leu Gly Leu Leu Leu Ala Leu Glu Asn
370 375 380
Ser Thr Tyr Gln Tyr Val Ser Val Trp Leu Glu His Gly Ser Leu Ala
385 390 395 400
Leu Gln Thr Pro Gly Ser Pro Lys Phe Met Val Asn Phe Phe Leu Ser
405 410 415
Asp Gly Asn Val His Leu Ile Ser Leu Arg Ile Lys Pro Asn Glu Ile
420 425 430
Glu Leu Tyr Gln Ser Ser Gln Asn Leu Gly Phe Ile Ser Val Pro Thr
435 440 445
Trp Thr Ile Arg Arg Gly Asp Val Ile Phe Ile Gly Gly Leu Pro Asp
450 455 460
Arg Glu Lys Thr Glu Val Tyr Gly Gly Phe Phe Lys Gly Cys Val Gln
465 470 475 480
Asp Val Arg Leu Asn Ser Gln Thr Leu Glu Phe Phe Pro Asn Ser Thr
485 490 495
Asn Asn Ala Tyr Asp Asp Pro Ile Leu Val Asn Val Thr Gln Gly Cys
500 505 510
Pro Gly Asp Asn Thr Cys Lys Ser Asn Pro Cys His Asn Gly Gly Val
515 520 525
Cys His Ser Leu Trp Asp Asp Phe Ser Cys Ser Cys Pro Thr Asn Thr
530 535 540
Ala Gly Arg Ala Cys Glu Gln Val Gln Trp Cys Gln Leu Ser Pro Cys
545 550 555 560
Pro Pro Thr Ala Glu Cys Gln Leu Leu Pro Gln Gly Phe Glu Cys Ile
565 570 575
Ala Asn Ala Val Phe Ser Gly Leu Ser Arg Glu Ile Leu Phe Arg Ser
580 585 590
Asn Gly Asn Ile Thr Arg Glu Leu Thr Asn Ile Thr Phe Ala Phe Arg
595 600 605
Thr His Asp Thr Asn Val Met Ile Leu His Ala Glu Lys Glu Pro Glu
610 615 620
Phe Leu Asn Ile Ser Ile Gln Asp Ala Arg Leu Phe Phe Gln Leu Arg
625 630 635 640
Ser Gly Asn Ser Phe Tyr Thr Leu His Leu Met Gly Ser Gln Leu Val
645 650 655
Asn Asp Gly Thr Trp His Gln Val Thr Phe Ser Met Ile Asp Pro Val
660 665 670
Ala Gln Thr Ser Arg Trp Gln Met Glu Val Asn Asp Gln Thr Pro Phe
675 680 685
Val Ile Ser Glu Val Ala Thr Gly Ser Leu Asn Phe Leu Lys Asp Asn
690 695 700
Thr Asp Ile Tyr Val Gly Asp Gln Ser Val Asp Asn Pro Lys Gly Leu
705 710 715 720
Gln Gly Cys Leu Ser Thr Ile Glu Ile Gly Gly Ile Tyr Leu Ser Tyr
725 730 735
Phe Glu Asn Leu His Gly Phe Pro Gly Lys Pro Gln Glu Glu Gln Phe
740 745 750
Leu Lys Val Ser Thr Asn Met Val Leu Thr Gly Cys Leu Pro Ser Asn
755 760 765
Ala Cys His Ser Ser Pro Cys Leu His Gly Gly Asn Cys Glu Asp Ser
770 775 780
Tyr Ser Ser Tyr Arg Cys Ala Cys Leu Ser Gly Trp Ser Gly Thr His
785 790 795 800
Cys Glu Ile Asn Ile Asp Glu Cys Phe Ser Ser Pro Cys Ile His Gly
805 810 815
Asn Cys Ser Asp Gly Val Ala Ala Tyr His Cys Arg Cys Glu Pro Gly
820 825 830
Tyr Thr Gly Val Asn Cys Glu Val Asp Val Asp Asn Cys Lys Ser His
835 840 845
Gln Cys Ala Asn Gly Ala Thr Cys Val Pro Glu Ala His Gly Tyr Ser
850 855 860
Cys Leu Cys Phe Gly Asn Phe Thr Gly Arg Phe Cys Arg His Ser Arg
865 870 875 880
Leu Pro Ser Thr Val Cys Gly Asn Glu Lys Arg Asn Phe Thr Cys Tyr
885 890 895
Asn Gly Gly Ser Cys Ser Met Phe Gln Glu Asp Trp Gln Cys Met Cys
900 905 910
Trp Pro Gly Phe Thr Gly Glu Trp Cys Glu Glu Asp Ile Asn Glu Cys
915 920 925
Ala Ser Asp Pro Cys Ile Asn Gly Gly Leu Cys Arg Asp Leu Val Asn
930 935 940
Arg Phe Leu Cys Ile Cys Asp Val Ala Phe Ala Gly Glu Arg Cys Glu
945 950 955 960
Leu Asp Leu Ala Asp Asp Arg Leu Leu Gly Ile Phe Thr Ala Val Gly
965 970 975
Ser Gly Thr Leu Ala Leu Phe Phe Ile Leu Leu Leu Ala Gly Val Ala
980 985 990
Ser Leu Ile Ala Ser Asn Lys Arg Ala Thr Gln Gly Thr Tyr Ser Pro
995 1000 1005
Ser Gly Gln Glu Lys Ala Gly Pro Arg Val Glu Met Trp Ile Arg
1010 1015 1020
Met Pro Pro Pro Ala Leu Glu Arg Leu Ile
1025 1030
<210> 67
<211> 6739
<212> DNA
<213> 小鼠
<400> 67
gcaatcaagg accctatcct aaaacaaagc ctttccagga ggcattgttc acggaagcct 60
gagggggaca cgaatccaat ccaggctgga aaaatctgct ccaggattga ctggttaccg 120
tcttcctgtg cctgtaaggt gctgtgaaag agaagtgctt tctgattctc tgtctgtgga 180
ggagccctgg gaggggtggg acagagatgg catcctggct ctctgaggca cctgctcttc 240
tctgaaccac acaggagtca agagccaaac agggatagct tcagcagcac ttcagagggt 300
gttctctaag taagaacatg aagctcaaga gaactgccta ccttctcttc ctgtacctca 360
gctcctcact gctcatctgc ataaagaatt cattttgcaa taaaaacaat accaggtgcc 420
tttcaggtcc ttgccaaaac aattctacgt gcaagcattt tccacaagac aacaattgtt 480
gcttagacac agccaataat ttggacaaag actgtgaaga tctgaaagac ccttgcttct 540
cgagtccctg ccaaggaatt gccacttgtg tgaaaatccc aggggaaggg aacttcctgt 600
gtcagtgtcc tcctgggtac agcgggctga actgtgaaac tgccaccaat tcctgtggag 660
ggaacctctg ccaacatgga ggcacctgcc gtaaagaccc tgagcaccct gtctgtatct 720
gccctcctgg atatgctgga aggttctgtg agactgatca caatgagtgt gcttctagcc 780
cttgccacaa tggggctatg tgccaggatg gaatcaatgg ctactcctgc ttctgtgtgc 840
ctggatacca aggcaggcat tgtgacttgg aagtggatga atgtgtttct gatccctgca 900
agaatgaggc tgtgtgcctc aatgagatag gaagatacac ttgtgtctgc cctcaagagt 960
tttctggcgt gaactgtgag ttggaaattg atgaatgcag atcccagcct tgtctccacg 1020
gtgccacatg tcaggacgct ccagggggct actcctgtga ctgtgcacct ggattccttg 1080
gagagcactg tgaactcagc gttaatgaat gtgaaagtca gccgtgtctc catggaggtc 1140
tatgtgtgga tggaagaaac agttaccact gtgactgcac aggtagtgga ttcacaggga 1200
tgcactgtga gtccttgatt cctctttgtt ggtcaaagcc ttgtcacaac gacgcgacat 1260
gtgaagatac tgttgacagc tatatttgtc actgccggcc tggaattcac tgtgaagaag 1320
acgttgatga atgtttactg cacccttgcc taaatggtgg tacttgtgag aacctgcctg 1380
ggaattatgc ctgtcactgt ccctttgatg acacttctag gacattttat ggaggagaaa 1440
actgctcaga aattctcctg ggctgcactc atcaccagtg tctgaacaat ggaaaatgta 1500
tccctcattt ccaaaatggc cagcatggat tcacttgcca gtgtctttct ggctatgcgg 1560
ggcccctgtg tgaaactgtc accacacttt catttgggag caatggcttc ctatgggtca 1620
caagtggctc ccatacaggc atagggccag aatgtaacat atccttgagg tttcacactg 1680
ttcaaccaaa cgcacttctc ctcatccgag gcaacaagga cgtgtctatg aagctggagt 1740
tgctgaatgg ttgtgttcac ttatcaattg aagtctggaa tcagttaaag gtgctcctgt 1800
ctatttctca caacaccagt gatggagaat ggcatttcgt ggaggtaaca atcgcagaaa 1860
ctctaaccct tgccctagtt ggcggctcct gcaaggagaa gtgcaccacc aagtcttctg 1920
ttccagttga gaatcatcaa tcaatatgtg ctttgcagga ctcttttttg ggtggcttac 1980
caatggggac agccaacaac agtgtgtctg tgcttaacat ctataatgtg ccgtccacac 2040
cttcctttgt aggctgtctc caagacatta gatttgattt gaatcacatt actctggaga 2100
acgtttcatc tggcctgtca tcaaatgtta aagcaggctg cctgggaaag gactggtgtg 2160
aaagtcaacc ctgtcaaaac agaggacgct gcatcaactt gtggcagggt tatcagtgtg 2220
aatgtgacag gccctataca ggctccaact gcctgaaaga gtatgtagcg ggaagatttg 2280
gccaagatga ctccacagga tatgcggcct ttagtgttaa tgataattat ggacagaact 2340
tcagtctttc aatgtttgtc cgaacacgtc aacccctggg cttacttctg gctttggaaa 2400
atagtactta ccagtatgtc agtgtctggc tagagcacgg cagcctagca ctgcagactc 2460
caggctctcc caagttcatg gtaaactttt ttctcagtga tggaaatgtt cacttaatat 2520
ctttgagaat caaaccaaat gaaattgaac tgtatcagtc ttcacaaaac ctaggattca 2580
tttctgttcc tacatggaca attcgaagag gagacgtcat cttcattggt ggcttacctg 2640
acagagagaa gactgaagtt tatggtggct tcttcaaagg ctgtgttcaa gatgtcagat 2700
taaacagcca gactctggaa ttctttccca attcaacaaa caatgcatac gatgacccaa 2760
ttcttgtcaa tgtgactcaa ggctgtcccg gagacaacac atgtaagtcc aacccctgtc 2820
ataatggagg tgtctgccac tccctgtggg atgacttctc ctgctcctgc cctacaaaca 2880
cagcggggag agcctgcgag caagttcagt ggtgtcaact cagcccatgt cctcccactg 2940
cagagtgcca gctgctccct caagggtttg aatgtatcgc aaacgctgtt ttcagcggat 3000
taagcagaga aatactcttc agaagcaatg ggaacattac cagagaactc accaatatca 3060
catttgcttt cagaacacat gatacaaatg tgatgatatt gcatgcagaa aaagaaccag 3120
agtttcttaa tattagcatt caagatgcca gattattctt tcaattgcga agtggcaaca 3180
gcttttatac gctgcacctg atgggttccc aattggtgaa tgatggcaca tggcaccaag 3240
tgactttctc catgatagac ccagtggccc agacctcccg gtggcaaatg gaggtgaacg 3300
accagacacc ctttgtgata agtgaagttg ctactggaag cctgaacttt ttgaaggaca 3360
atacagacat ctatgtgggt gaccaatctg ttgacaatcc gaaaggcctg cagggctgtc 3420
tgagcacaat agagattgga ggcatatatc tttcttactt tgaaaatcta catggtttcc 3480
ctggtaagcc tcaggaagag caatttctca aagtttctac aaatatggta cttactggct 3540
gtttgccatc aaatgcctgc cactccagcc cctgtttgca tggaggaaac tgtgaagaca 3600
gctacagttc ttatcggtgt gcctgtctct cgggatggtc agggacacac tgtgaaatca 3660
acattgatga gtgcttttct agcccctgta tccatggcaa ctgctctgat ggagttgcag 3720
cctaccactg caggtgtgag cctggataca ccggtgtgaa ctgtgaggtg gatgtagaca 3780
attgcaagag tcatcagtgt gcaaatgggg ccacctgtgt tcctgaagct catggctact 3840
cttgtctctg ctttggaaat tttaccggga gattttgcag acacagcaga ttaccctcaa 3900
cagtctgtgg gaatgagaag agaaacttca cttgctacaa tggaggcagc tgctccatgt 3960
tccaggagga ctggcaatgt atgtgctggc caggtttcac tggagagtgg tgtgaagagg 4020
acatcaacga gtgtgcctcc gatccctgca tcaatggagg actgtgcagg gacttggtca 4080
acaggttcct atgcatctgt gatgtggcct tcgctggcga gcgctgtgag ctggacgtaa 4140
gcggcctttc cttttatgtg tccctcttac tatggcaaaa cctctttcag ctcctgtcct 4200
acctcgtact gcgcatgaat gatgagccag ttgtagagtg gggggcacag gaaaattatt 4260
aatgtgcatg ggagcattca caagtgtaaa acattgactt gcaagaaaca tcttgtctca 4320
gtgtaggttt ctaggaaaga caaagggaac attagggaat agactccatc tagagcactg 4380
gttctcagtc ttcctaatgc tgcaaccctt tagtacagct cttcctgttg tagtgatcgc 4440
agccataaca ttattttcat tgccacttca taactgtaat ccttctactg ctgtgaatca 4500
caatggaaat atttatgttt tctgatggtc ttaagcaaca cctctgaaaa agtcattgac 4560
ccccccccca aaggggctgt gatccacagg ttgagaaatg ctcatctgga aggtaaccat 4620
gcatttaagt gtacctctag tagtttgggt ctatagaaga tattctccta ttctaccttt 4680
ttagacacgc cagaagaggg catctgattc cattaaagat gattgggagc caccgtgtgg 4740
ttcctgagaa ctgtactcgg gccctttgga agagcaatca gtgctctttc cagcccctaa 4800
gaatattttt aatacagcca gaaaggtctc attacccagt gtactgagcc ctaaggcact 4860
ttcatcctca atcgttccat gttgaatggt tttcattaca tttggaaaat gttttctctc 4920
cactctacct ttacatgttc ctattttcct attgacaatt tgccccttca ctgtaattct 4980
aatttggtgt ggtccttctt ctcataagtt tatatgtgac atgaacattt aaaaatatct 5040
atgaatattt tatagtcatg tatgtctttc tgcaaagcta ttcaaatgaa ctatggacag 5100
ttcttttcta cacgaagaag agatgagttt aatccccagt aacatgagaa aaagatgagt 5160
gagggacagt gctcacagta tccctcacta gcatcatttg tgattccatg ggccattttt 5220
ttccaccagc aaatagcaga gagccctttc cctattcgtt tctcttacac ttcccctttt 5280
ctgttacaac tgaacacttt acattagtta ctcctttgta gggggtttga cttttccacc 5340
gttttctctg gttcactatt tatgctaagt atctgtgcag ggcgggtata tcagtccaac 5400
agaggtgtca ttagtgttca ttgaggagga aatactttgc atgaattcat gacatcattg 5460
aagtagcagt ggccagaaag atacccttct gcgaatgtgt ctgtgtattc agaagctgcc 5520
ctggttagaa aacatgtggg tcacttttcc tttgcatgtt accagtgctc actgggtcat 5580
gattgtttta agacagagct tttgctgtgg caatgaccaa ggtgaatcca gagatgcaga 5640
tcagacaaag gacaagacaa tgtactatct gagtaaaacc ctgccttgac ttactcctca 5700
gtacttagag attttacata gcaacctcca ccctgtggca acccgttcac actagcagtg 5760
atgctgagat ttgcccttcc ttctcatcat cttcctcaca tccaaagcat tttgtgtcca 5820
cactgctgtt tcagataact gtttctaaag tgggattgtt gtagccagaa aggtagggaa 5880
aatgttcccc aaaatatttg cattcttaag tatgtgaagt aagtagatta tagtcagaga 5940
caatatgtaa ggtttcaggt tcactccctt ctacacatat cttcaactgt gtatttgcag 6000
aatattctga atgtgacata ctcccaacag aatatattta aggagtattt atccacagta 6060
ttgttctctg tacagttcta gtgcttctat tgtcactgca attgtcaatt gtttttctgc 6120
tttccaactg tcttattatc atttaatagc atcttgctaa atgccctctt tctattctcc 6180
ttatttctcc atagttcatg tgtgtctgtg tgactaagga ttctcctcat ttttgcagaa 6240
aaataaaatc ttttcttctt tatgtcctgc ttgtcattct ctggtgacac atgtctttgc 6300
ttacttggac tgagggttgt acagtaagta cagaagcagg ctcagtcaca cagacagaga 6360
cacaccacca ccagcagcag cagcaccacc accaccacca ccaccaccag aaaacagtat 6420
gagtactcat ctcttgatta catgtcattt caagtaagca ccatgacacc gagggccagg 6480
ttccatggac tttctctgtt aggcacgtga ttctttagct gacctttgag aacagactcc 6540
aacaacctca cttattttta ctgttgactt atatcatctc tgacaacact ggacttcgtt 6600
tgagctagtc aagaggaaag accatgacac ctaagggaca gaaattcaca cactcggttt 6660
ttcataattc acacacattc ctatgtatca aatctctgta atagatgaca tttacttgaa 6720
taaaaagtca tttcccttt 6739
<210> 68
<211> 1314
<212> PRT
<213> 小鼠
<400> 68
Met Lys Leu Lys Arg Thr Ala Tyr Leu Leu Phe Leu Tyr Leu Ser Ser
1 5 10 15
Ser Leu Leu Ile Cys Ile Lys Asn Ser Phe Cys Asn Lys Asn Asn Thr
20 25 30
Arg Cys Leu Ser Gly Pro Cys Gln Asn Asn Ser Thr Cys Lys His Phe
35 40 45
Pro Gln Asp Asn Asn Cys Cys Leu Asp Thr Ala Asn Asn Leu Asp Lys
50 55 60
Asp Cys Glu Asp Leu Lys Asp Pro Cys Phe Ser Ser Pro Cys Gln Gly
65 70 75 80
Ile Ala Thr Cys Val Lys Ile Pro Gly Glu Gly Asn Phe Leu Cys Gln
85 90 95
Cys Pro Pro Gly Tyr Ser Gly Leu Asn Cys Glu Thr Ala Thr Asn Ser
100 105 110
Cys Gly Gly Asn Leu Cys Gln His Gly Gly Thr Cys Arg Lys Asp Pro
115 120 125
Glu His Pro Val Cys Ile Cys Pro Pro Gly Tyr Ala Gly Arg Phe Cys
130 135 140
Glu Thr Asp His Asn Glu Cys Ala Ser Ser Pro Cys His Asn Gly Ala
145 150 155 160
Met Cys Gln Asp Gly Ile Asn Gly Tyr Ser Cys Phe Cys Val Pro Gly
165 170 175
Tyr Gln Gly Arg His Cys Asp Leu Glu Val Asp Glu Cys Val Ser Asp
180 185 190
Pro Cys Lys Asn Glu Ala Val Cys Leu Asn Glu Ile Gly Arg Tyr Thr
195 200 205
Cys Val Cys Pro Gln Glu Phe Ser Gly Val Asn Cys Glu Leu Glu Ile
210 215 220
Asp Glu Cys Arg Ser Gln Pro Cys Leu His Gly Ala Thr Cys Gln Asp
225 230 235 240
Ala Pro Gly Gly Tyr Ser Cys Asp Cys Ala Pro Gly Phe Leu Gly Glu
245 250 255
His Cys Glu Leu Ser Val Asn Glu Cys Glu Ser Gln Pro Cys Leu His
260 265 270
Gly Gly Leu Cys Val Asp Gly Arg Asn Ser Tyr His Cys Asp Cys Thr
275 280 285
Gly Ser Gly Phe Thr Gly Met His Cys Glu Ser Leu Ile Pro Leu Cys
290 295 300
Trp Ser Lys Pro Cys His Asn Asp Ala Thr Cys Glu Asp Thr Val Asp
305 310 315 320
Ser Tyr Ile Cys His Cys Arg Pro Gly Ile His Cys Glu Glu Asp Val
325 330 335
Asp Glu Cys Leu Leu His Pro Cys Leu Asn Gly Gly Thr Cys Glu Asn
340 345 350
Leu Pro Gly Asn Tyr Ala Cys His Cys Pro Phe Asp Asp Thr Ser Arg
355 360 365
Thr Phe Tyr Gly Gly Glu Asn Cys Ser Glu Ile Leu Leu Gly Cys Thr
370 375 380
His His Gln Cys Leu Asn Asn Gly Lys Cys Ile Pro His Phe Gln Asn
385 390 395 400
Gly Gln His Gly Phe Thr Cys Gln Cys Leu Ser Gly Tyr Ala Gly Pro
405 410 415
Leu Cys Glu Thr Val Thr Thr Leu Ser Phe Gly Ser Asn Gly Phe Leu
420 425 430
Trp Val Thr Ser Gly Ser His Thr Gly Ile Gly Pro Glu Cys Asn Ile
435 440 445
Ser Leu Arg Phe His Thr Val Gln Pro Asn Ala Leu Leu Leu Ile Arg
450 455 460
Gly Asn Lys Asp Val Ser Met Lys Leu Glu Leu Leu Asn Gly Cys Val
465 470 475 480
His Leu Ser Ile Glu Val Trp Asn Gln Leu Lys Val Leu Leu Ser Ile
485 490 495
Ser His Asn Thr Ser Asp Gly Glu Trp His Phe Val Glu Val Thr Ile
500 505 510
Ala Glu Thr Leu Thr Leu Ala Leu Val Gly Gly Ser Cys Lys Glu Lys
515 520 525
Cys Thr Thr Lys Ser Ser Val Pro Val Glu Asn His Gln Ser Ile Cys
530 535 540
Ala Leu Gln Asp Ser Phe Leu Gly Gly Leu Pro Met Gly Thr Ala Asn
545 550 555 560
Asn Ser Val Ser Val Leu Asn Ile Tyr Asn Val Pro Ser Thr Pro Ser
565 570 575
Phe Val Gly Cys Leu Gln Asp Ile Arg Phe Asp Leu Asn His Ile Thr
580 585 590
Leu Glu Asn Val Ser Ser Gly Leu Ser Ser Asn Val Lys Ala Gly Cys
595 600 605
Leu Gly Lys Asp Trp Cys Glu Ser Gln Pro Cys Gln Asn Arg Gly Arg
610 615 620
Cys Ile Asn Leu Trp Gln Gly Tyr Gln Cys Glu Cys Asp Arg Pro Tyr
625 630 635 640
Thr Gly Ser Asn Cys Leu Lys Glu Tyr Val Ala Gly Arg Phe Gly Gln
645 650 655
Asp Asp Ser Thr Gly Tyr Ala Ala Phe Ser Val Asn Asp Asn Tyr Gly
660 665 670
Gln Asn Phe Ser Leu Ser Met Phe Val Arg Thr Arg Gln Pro Leu Gly
675 680 685
Leu Leu Leu Ala Leu Glu Asn Ser Thr Tyr Gln Tyr Val Ser Val Trp
690 695 700
Leu Glu His Gly Ser Leu Ala Leu Gln Thr Pro Gly Ser Pro Lys Phe
705 710 715 720
Met Val Asn Phe Phe Leu Ser Asp Gly Asn Val His Leu Ile Ser Leu
725 730 735
Arg Ile Lys Pro Asn Glu Ile Glu Leu Tyr Gln Ser Ser Gln Asn Leu
740 745 750
Gly Phe Ile Ser Val Pro Thr Trp Thr Ile Arg Arg Gly Asp Val Ile
755 760 765
Phe Ile Gly Gly Leu Pro Asp Arg Glu Lys Thr Glu Val Tyr Gly Gly
770 775 780
Phe Phe Lys Gly Cys Val Gln Asp Val Arg Leu Asn Ser Gln Thr Leu
785 790 795 800
Glu Phe Phe Pro Asn Ser Thr Asn Asn Ala Tyr Asp Asp Pro Ile Leu
805 810 815
Val Asn Val Thr Gln Gly Cys Pro Gly Asp Asn Thr Cys Lys Ser Asn
820 825 830
Pro Cys His Asn Gly Gly Val Cys His Ser Leu Trp Asp Asp Phe Ser
835 840 845
Cys Ser Cys Pro Thr Asn Thr Ala Gly Arg Ala Cys Glu Gln Val Gln
850 855 860
Trp Cys Gln Leu Ser Pro Cys Pro Pro Thr Ala Glu Cys Gln Leu Leu
865 870 875 880
Pro Gln Gly Phe Glu Cys Ile Ala Asn Ala Val Phe Ser Gly Leu Ser
885 890 895
Arg Glu Ile Leu Phe Arg Ser Asn Gly Asn Ile Thr Arg Glu Leu Thr
900 905 910
Asn Ile Thr Phe Ala Phe Arg Thr His Asp Thr Asn Val Met Ile Leu
915 920 925
His Ala Glu Lys Glu Pro Glu Phe Leu Asn Ile Ser Ile Gln Asp Ala
930 935 940
Arg Leu Phe Phe Gln Leu Arg Ser Gly Asn Ser Phe Tyr Thr Leu His
945 950 955 960
Leu Met Gly Ser Gln Leu Val Asn Asp Gly Thr Trp His Gln Val Thr
965 970 975
Phe Ser Met Ile Asp Pro Val Ala Gln Thr Ser Arg Trp Gln Met Glu
980 985 990
Val Asn Asp Gln Thr Pro Phe Val Ile Ser Glu Val Ala Thr Gly Ser
995 1000 1005
Leu Asn Phe Leu Lys Asp Asn Thr Asp Ile Tyr Val Gly Asp Gln
1010 1015 1020
Ser Val Asp Asn Pro Lys Gly Leu Gln Gly Cys Leu Ser Thr Ile
1025 1030 1035
Glu Ile Gly Gly Ile Tyr Leu Ser Tyr Phe Glu Asn Leu His Gly
1040 1045 1050
Phe Pro Gly Lys Pro Gln Glu Glu Gln Phe Leu Lys Val Ser Thr
1055 1060 1065
Asn Met Val Leu Thr Gly Cys Leu Pro Ser Asn Ala Cys His Ser
1070 1075 1080
Ser Pro Cys Leu His Gly Gly Asn Cys Glu Asp Ser Tyr Ser Ser
1085 1090 1095
Tyr Arg Cys Ala Cys Leu Ser Gly Trp Ser Gly Thr His Cys Glu
1100 1105 1110
Ile Asn Ile Asp Glu Cys Phe Ser Ser Pro Cys Ile His Gly Asn
1115 1120 1125
Cys Ser Asp Gly Val Ala Ala Tyr His Cys Arg Cys Glu Pro Gly
1130 1135 1140
Tyr Thr Gly Val Asn Cys Glu Val Asp Val Asp Asn Cys Lys Ser
1145 1150 1155
His Gln Cys Ala Asn Gly Ala Thr Cys Val Pro Glu Ala His Gly
1160 1165 1170
Tyr Ser Cys Leu Cys Phe Gly Asn Phe Thr Gly Arg Phe Cys Arg
1175 1180 1185
His Ser Arg Leu Pro Ser Thr Val Cys Gly Asn Glu Lys Arg Asn
1190 1195 1200
Phe Thr Cys Tyr Asn Gly Gly Ser Cys Ser Met Phe Gln Glu Asp
1205 1210 1215
Trp Gln Cys Met Cys Trp Pro Gly Phe Thr Gly Glu Trp Cys Glu
1220 1225 1230
Glu Asp Ile Asn Glu Cys Ala Ser Asp Pro Cys Ile Asn Gly Gly
1235 1240 1245
Leu Cys Arg Asp Leu Val Asn Arg Phe Leu Cys Ile Cys Asp Val
1250 1255 1260
Ala Phe Ala Gly Glu Arg Cys Glu Leu Asp Val Ser Gly Leu Ser
1265 1270 1275
Phe Tyr Val Ser Leu Leu Leu Trp Gln Asn Leu Phe Gln Leu Leu
1280 1285 1290
Ser Tyr Leu Val Leu Arg Met Asn Asp Glu Pro Val Val Glu Trp
1295 1300 1305
Gly Ala Gln Glu Asn Tyr
1310
<210> 69
<211> 5481
<212> DNA
<213> 小鼠
<400> 69
gatccagctt gaagaggagt gaggcaaagc tgaaccctcc cactctcctt gacaagtgca 60
agcccacact tttggaaaaa agcacaaaga cgtcagaaac ggttcctgtc gacctactag 120
gctttggatg gctaagtgtt tttgctttgt atggaaatat gtttggacac aagacacaag 180
gttttcacat tttaatggca gtgctcatag gaattcactg tgaagaagac gttgatgaat 240
gtttactgca cccttgccta aatggtggta cttgtgagaa cctgcctggg aattatgcct 300
gtcactgtcc ctttgatgac acttctagga cattttatgg aggagaaaac tgctcagaaa 360
ttctcctggg ctgcactcat caccagtgtc tgaacaatgg aaaatgtatc cctcatttcc 420
aaaatggcca gcatggattc acttgccagt gtctttctgg ctatgcgggg cccctgtgtg 480
aaactgtcac cacactttca tttgggagca atggcttcct atgggtcaca agtggctccc 540
atacaggcat agggccagaa tgtaacatat ccttgaggtt tcacactgtt caaccaaacg 600
cacttctcct catccgaggc aacaaggacg tgtctatgaa gctggagttg ctgaatggtt 660
gtgttcactt atcaattgaa gtctggaatc agttaaaggt gctcctgtct atttctcaca 720
acaccagtga tggagaatgg catttcgtgg aggtaacaat cgcagaaact ctaacccttg 780
ccctagttgg cggctcctgc aaggagaagt gcaccaccaa gtcttctgtt ccagttgaga 840
atcatcaatc aatatgtgct ttgcaggact cttttttggg tggcttacca atggggacag 900
ccaacaacag tgtgtctgtg cttaacatct ataatgtgcc gtccacacct tcctttgtag 960
gctgtctcca agacattaga tttgatttga atcacattac tctggagaac gtttcatctg 1020
gcctgtcatc aaatgttaaa gcaggctgcc tgggaaagga ctggtgtgaa agtcaaccct 1080
gtcaaaacag aggacgctgc atcaacttgt ggcagggtta tcagtgtgaa tgtgacaggc 1140
cctatacagg ctccaactgc ctgaaagagt atgtagcggg aagatttggc caagatgact 1200
ccacaggata tgcggccttt agtgttaatg ataattatgg acagaacttc agtctttcaa 1260
tgtttgtccg aacacgtcaa cccctgggct tacttctggc tttggaaaat agtacttacc 1320
agtatgtcag tgtctggcta gagcacggca gcctagcact gcagactcca ggctctccca 1380
agttcatggt aaactttttt ctcagtgatg gaaatgttca cttaatatct ttgagaatca 1440
aaccaaatga aattgaactg tatcagtctt cacaaaacct aggattcatt tctgttccta 1500
catggacaat tcgaagagga gacgtcatct tcattggtgg cttacctgac agagagaaga 1560
ctgaagttta tggtggcttc ttcaaaggct gtgttcaaga tgtcagatta aacagccaga 1620
ctctggaatt ctttcccaat tcaacaaaca atgcatacga tgacccaatt cttgtcaatg 1680
tgactcaagg ctgtcccgga gacaacacat gtaaggtatc gcaaacgctg ttttcagcgg 1740
attaagcaga gaaatactct tcagaagcaa tgggaacatt accagagaac tcaccaatat 1800
cacatttgct ttcagaacac atgatacaaa tgtgatgata ttgcatgcag aaaaagaacc 1860
agagtttctt aatattagca ttcaagatgc cagattattc tttcaattgc gaagtggcaa 1920
cagcttttat acgctgcacc tgatgggttc ccaattggtg aatgatggca catggcacca 1980
agtgactttc tccatgatag acccagtggc ccagacctcc cggtggcaaa tggaggtgaa 2040
cgaccagaca ccctttgtga taagtgaagt tgctactgga agcctgaact ttttgaagga 2100
caatacagac atctatgtgg gtgaccaatc tgttgacaat ccgaaaggcc tgcagggctg 2160
tctgagcaca atagagattg gaggcatata tctttcttac tttgaaaatc tacatggttt 2220
ccctggtaag cctcaggaag agcaatttct caaagtttct acaaatatgg tacttactgg 2280
ctgtttgcca tcaaatgcct gccactccag cccctgtttg catggaggaa actgtgaaga 2340
cagctacagt tcttatcggt gtgcctgtct ctcgggatgg tcagggacac actgtgaaat 2400
caacattgat gagtgctttt ctagcccctg tatccatggc aactgctctg atggagttgc 2460
agcctaccac tgcaggtgtg agcctggata caccggtgtg aactgtgagg tggatgtaga 2520
caattgcaag agtcatcagt gtgcaaatgg ggccacctgt gttcctgaag ctcatggcta 2580
ctcttgtctc tgctttggaa attttaccgg gagattttgc agacacagca gattaccctc 2640
aacagtctgt gggaatgaga agagaaactt cacttgctac aatggaggca gctgctccat 2700
gttccaggag gactggcaat gtatgtgctg gccaggtttc actggagagt ggtgtgaaga 2760
ggacatcaac gagtgtgcct ccgatccctg catcaatgga ggactgtgca gggacttggt 2820
caacaggttc ctatgcatct gtgatgtggc cttcgctggc gagcgctgtg agctggacgt 2880
aagcggcctt tccttttatg tgtccctctt actatggcaa aacctctttc agctcctgtc 2940
ctacctcgta ctgcgcatga atgatgagcc agttgtagag tggggggcac aggaaaatta 3000
ttaatgtgca tgggagcatt cacaagtgta aaacattgac ttgcaagaaa catcttgtct 3060
cagtgtaggt ttctaggaaa gacaaaggga acattaggga atagactcca tctagagcac 3120
tggttctcag tcttcctaat gctgcaaccc tttagtacag ctcttcctgt tgtagtgatc 3180
gcagccataa cattattttc attgccactt cataactgta atccttctac tgctgtgaat 3240
cacaatggaa atatttatgt tttctgatgg tcttaagcaa cacctctgaa aaagtcattg 3300
accccccccc caaaggggct gtgatccaca ggttgagaaa tgctcatctg gaaggtaacc 3360
atgcatttaa gtgtacctct agtagtttgg gtctatagaa gatattctcc tattctacct 3420
ttttagacac gccagaagag ggcatctgat tccattaaag atgattggga gccaccgtgt 3480
ggttcctgag aactgtactc gggccctttg gaagagcaat cagtgctctt tccagcccct 3540
aagaatattt ttaatacagc cagaaaggtc tcattaccca gtgtactgag ccctaaggca 3600
ctttcatcct caatcgttcc atgttgaatg gttttcatta catttggaaa atgttttctc 3660
tccactctac ctttacatgt tcctattttc ctattgacaa tttgcccctt cactgtaatt 3720
ctaatttggt gtggtccttc ttctcataag tttatatgtg acatgaacat ttaaaaatat 3780
ctatgaatat tttatagtca tgtatgtctt tctgcaaagc tattcaaatg aactatggac 3840
agttcttttc tacacgaaga agagatgagt ttaatcccca gtaacatgag aaaaagatga 3900
gtgagggaca gtgctcacag tatccctcac tagcatcatt tgtgattcca tgggccattt 3960
ttttccacca gcaaatagca gagagccctt tccctattcg tttctcttac acttcccctt 4020
ttctgttaca actgaacact ttacattagt tactcctttg tagggggttt gacttttcca 4080
ccgttttctc tggttcacta tttatgctaa gtatctgtgc agggcgggta tatcagtcca 4140
acagaggtgt cattagtgtt cattgaggag gaaatacttt gcatgaattc atgacatcat 4200
tgaagtagca gtggccagaa agataccctt ctgcgaatgt gtctgtgtat tcagaagctg 4260
ccctggttag aaaacatgtg ggtcactttt cctttgcatg ttaccagtgc tcactgggtc 4320
atgattgttt taagacagag cttttgctgt ggcaatgacc aaggtgaatc cagagatgca 4380
gatcagacaa aggacaagac aatgtactat ctgagtaaaa ccctgccttg acttactcct 4440
cagtacttag agattttaca tagcaacctc caccctgtgg caacccgttc acactagcag 4500
tgatgctgag atttgccctt ccttctcatc atcttcctca catccaaagc attttgtgtc 4560
cacactgctg tttcagataa ctgtttctaa agtgggattg ttgtagccag aaaggtaggg 4620
aaaatgttcc ccaaaatatt tgcattctta agtatgtgaa gtaagtagat tatagtcaga 4680
gacaatatgt aaggtttcag gttcactccc ttctacacat atcttcaact gtgtatttgc 4740
agaatattct gaatgtgaca tactcccaac agaatatatt taaggagtat ttatccacag 4800
tattgttctc tgtacagttc tagtgcttct attgtcactg caattgtcaa ttgtttttct 4860
gctttccaac tgtcttatta tcatttaata gcatcttgct aaatgccctc tttctattct 4920
ccttatttct ccatagttca tgtgtgtctg tgtgactaag gattctcctc atttttgcag 4980
aaaaataaaa tcttttcttc tttatgtcct gcttgtcatt ctctggtgac acatgtcttt 5040
gcttacttgg actgagggtt gtacagtaag tacagaagca ggctcagtca cacagacaga 5100
gacacaccac caccagcagc agcagcacca ccaccaccac caccaccacc agaaaacagt 5160
atgagtactc atctcttgat tacatgtcat ttcaagtaag caccatgaca ccgagggcca 5220
ggttccatgg actttctctg ttaggcacgt gattctttag ctgacctttg agaacagact 5280
ccaacaacct cacttatttt tactgttgac ttatatcatc tctgacaaca ctggacttcg 5340
tttgagctag tcaagaggaa agaccatgac acctaaggga cagaaattca cacactcggt 5400
ttttcataat tcacacacat tcctatgtat caaatctctg taatagatga catttacttg 5460
aataaaaagt catttccctt t 5481
<210> 70
<211> 528
<212> PRT
<213> 小鼠
<400> 70
Met Phe Gly His Lys Thr Gln Gly Phe His Ile Leu Met Ala Val Leu
1 5 10 15
Ile Gly Ile His Cys Glu Glu Asp Val Asp Glu Cys Leu Leu His Pro
20 25 30
Cys Leu Asn Gly Gly Thr Cys Glu Asn Leu Pro Gly Asn Tyr Ala Cys
35 40 45
His Cys Pro Phe Asp Asp Thr Ser Arg Thr Phe Tyr Gly Gly Glu Asn
50 55 60
Cys Ser Glu Ile Leu Leu Gly Cys Thr His His Gln Cys Leu Asn Asn
65 70 75 80
Gly Lys Cys Ile Pro His Phe Gln Asn Gly Gln His Gly Phe Thr Cys
85 90 95
Gln Cys Leu Ser Gly Tyr Ala Gly Pro Leu Cys Glu Thr Val Thr Thr
100 105 110
Leu Ser Phe Gly Ser Asn Gly Phe Leu Trp Val Thr Ser Gly Ser His
115 120 125
Thr Gly Ile Gly Pro Glu Cys Asn Ile Ser Leu Arg Phe His Thr Val
130 135 140
Gln Pro Asn Ala Leu Leu Leu Ile Arg Gly Asn Lys Asp Val Ser Met
145 150 155 160
Lys Leu Glu Leu Leu Asn Gly Cys Val His Leu Ser Ile Glu Val Trp
165 170 175
Asn Gln Leu Lys Val Leu Leu Ser Ile Ser His Asn Thr Ser Asp Gly
180 185 190
Glu Trp His Phe Val Glu Val Thr Ile Ala Glu Thr Leu Thr Leu Ala
195 200 205
Leu Val Gly Gly Ser Cys Lys Glu Lys Cys Thr Thr Lys Ser Ser Val
210 215 220
Pro Val Glu Asn His Gln Ser Ile Cys Ala Leu Gln Asp Ser Phe Leu
225 230 235 240
Gly Gly Leu Pro Met Gly Thr Ala Asn Asn Ser Val Ser Val Leu Asn
245 250 255
Ile Tyr Asn Val Pro Ser Thr Pro Ser Phe Val Gly Cys Leu Gln Asp
260 265 270
Ile Arg Phe Asp Leu Asn His Ile Thr Leu Glu Asn Val Ser Ser Gly
275 280 285
Leu Ser Ser Asn Val Lys Ala Gly Cys Leu Gly Lys Asp Trp Cys Glu
290 295 300
Ser Gln Pro Cys Gln Asn Arg Gly Arg Cys Ile Asn Leu Trp Gln Gly
305 310 315 320
Tyr Gln Cys Glu Cys Asp Arg Pro Tyr Thr Gly Ser Asn Cys Leu Lys
325 330 335
Glu Tyr Val Ala Gly Arg Phe Gly Gln Asp Asp Ser Thr Gly Tyr Ala
340 345 350
Ala Phe Ser Val Asn Asp Asn Tyr Gly Gln Asn Phe Ser Leu Ser Met
355 360 365
Phe Val Arg Thr Arg Gln Pro Leu Gly Leu Leu Leu Ala Leu Glu Asn
370 375 380
Ser Thr Tyr Gln Tyr Val Ser Val Trp Leu Glu His Gly Ser Leu Ala
385 390 395 400
Leu Gln Thr Pro Gly Ser Pro Lys Phe Met Val Asn Phe Phe Leu Ser
405 410 415
Asp Gly Asn Val His Leu Ile Ser Leu Arg Ile Lys Pro Asn Glu Ile
420 425 430
Glu Leu Tyr Gln Ser Ser Gln Asn Leu Gly Phe Ile Ser Val Pro Thr
435 440 445
Trp Thr Ile Arg Arg Gly Asp Val Ile Phe Ile Gly Gly Leu Pro Asp
450 455 460
Arg Glu Lys Thr Glu Val Tyr Gly Gly Phe Phe Lys Gly Cys Val Gln
465 470 475 480
Asp Val Arg Leu Asn Ser Gln Thr Leu Glu Phe Phe Pro Asn Ser Thr
485 490 495
Asn Asn Ala Tyr Asp Asp Pro Ile Leu Val Asn Val Thr Gln Gly Cys
500 505 510
Pro Gly Asp Asn Thr Cys Lys Val Ser Gln Thr Leu Phe Ser Ala Asp
515 520 525
<210> 71
<211> 6950
<212> DNA
<213> 小鼠
<400> 71
gtcagaagaa attaatttct ctattaggag caatcaagga ccctatccta aaacaaagcc 60
tttccaggag gcattgttca cggaagcctg agggggacac gaatccaatc caggctggaa 120
aaatctgctc caggattgac tggttaccgt cttcctgtgc ctgtaaggtg ctgtgaaaga 180
gaagtgcttt ctgattctct gtctgtggag gagccctggg aggggtggga cagagatggc 240
atcctggctc tctgaggcac ctgctcttct ctgaaccaca caggagtcaa gagccaaaca 300
gggatagctt cagcagcact tcagagggtg ttctctaagt aagaacatga agctcaagag 360
aactgcctac cttctcttcc tgtacctcag ctcctcactg ctcatctgca taaagaattc 420
attttgcaat aaaaacaata ccaggtgcct ttcaggtcct tgccaaaaca attctacgtg 480
caagcatttt ccacaagaca acaattgttg cttagacaca gccaataatt tggacaaaga 540
ctgtgaagat ctgaaagacc cttgcttctc gagtccctgc caaggaattg ccacttgtgt 600
gaaaatccca ggggaaggga acttcctgtg tcagtgtcct cctgggtaca gcgggctgaa 660
ctgtgaaact gccaccaatt cctgtggagg gaacctctgc caacatggag gcacctgccg 720
taaagaccct gagcaccctg tctgtatctg ccctcctgga tatgctggaa ggttctgtga 780
gactgatcac aatgagtgtg cttctagccc ttgccacaat ggggctatgt gccaggatgg 840
aatcaatggc tactcctgct tctgtgtgcc tggataccaa ggcaggcatt gtgacttgga 900
agtggatgaa tgtgtttctg atccctgcaa gaatgaggct gtgtgcctca atgagatagg 960
aagatacact tgtgtctgcc ctcaagagtt ttctggcgtg aactgtgagt tggaaattga 1020
tgaatgcaga tcccagcctt gtctccacgg tgccacatgt caggacgctc cagggggcta 1080
ctcctgtgac tgtgcacctg gattccttgg agagcactgt gaactcagcg ttaatgaatg 1140
tgaaagtcag ccgtgtctcc atggaggtct atgtgtggat ggaagaaaca gttaccactg 1200
tgactgcaca ggtagtggat tcacagggat gcactgtgag tccttgattc ctctttgttg 1260
gtcaaagcct tgtcacaacg acgcgacatg tgaagatact gttgacagct atatttgtca 1320
ctgccggcct ggatacacag gtgccctgtg tgagacagac ataaatgaat gcagtagcaa 1380
cccctgccaa ttttgggggg aatgtgtcga gctgtcctca gagggtctat atggaaacac 1440
tgctggcctg ccttcctcct tcagctatgt tggagcctcg ggctatgtgt gtatctgtca 1500
gcctggattc acaggaattc actgtgaaga agacgttgat gaatgtttac tgcacccttg 1560
cctaaatggt ggtacttgtg agaacctgcc tgggaattat gcctgtcact gtccctttga 1620
tgacacttct aggacatttt atggaggaga aaactgctca gaaattctcc tgggctgcac 1680
tcatcaccag tgtctgaaca atggaaaatg tatccctcat ttccaaaatg gccagcatgg 1740
attcacttgc cagtgtcttt ctggctatgc ggggcccctg tgtgaaactg tcaccacact 1800
ttcatttggg agcaatggct tcctatgggt cacaagtggc tcccatacag gcatagggcc 1860
agaatgtaac atatccttga ggtttcacac tgttcaacca aacgcacttc tcctcatccg 1920
aggcaacaag gacgtgtcta tgaagctgga gttgctgaat ggttgtgttc acttatcaat 1980
tgaagtctgg aatcagttaa aggtgctcct gtctatttct cacaacacca gtgatggaga 2040
atggcatttc gtggaggtaa caatcgcaga aactctaacc cttgccctag ttggcggctc 2100
ctgcaaggag aagtgcacca ccaagtcttc tgttccagtt gagaatcatc aatcaatatg 2160
tgctttgcag gactcttttt tgggtggctt accaatgggg acagccaaca acagtgtgtc 2220
tgtgcttaac atctataatg tgccgtccac accttccttt gtaggctgtc tccaagacat 2280
tagatttgat ttgaatcaca ttactctgga gaacgtttca tctggcctgt catcaaatgt 2340
taaagcaggc tgcctgggaa aggactggtg tgaaagtcaa ccctgtcaaa acagaggacg 2400
ctgcatcaac ttgtggcagg gttatcagtg tgaatgtgac aggccctata caggctccaa 2460
ctgcctgaaa gagtatgtag cgggaagatt tggccaagat gactccacag gatatgcggc 2520
ctttagtgtt aatgataatt atggacagaa cttcagtctt tcaatgtttg tccgaacacg 2580
tcaacccctg ggcttacttc tggctttgga aaatagtact taccagtatg tcagtgtctg 2640
gctagagcac ggcagcctag cactgcagac tccaggctct cccaagttca tggtaaactt 2700
ttttctcagt gatggaaatg ttcacttaat atctttgaga atcaaaccaa atgaaattga 2760
actgtatcag tcttcacaaa acctaggatt catttctgtt cctacatgga caattcgaag 2820
aggagacgtc atcttcattg gtggcttacc tgacagagag aagactgaag tttatggtgg 2880
cttcttcaaa ggctgtgttc aagatgtcag attaaacagc cagactctgg aattctttcc 2940
caattcaaca aacaatgcat acgatgaccc aattcttgtc aatgtgactc aaggctgtcc 3000
cggagacaac acatgtaagt ccaacccctg tcataatgga ggtgtctgcc actccctgtg 3060
ggatgacttc tcctgctcct gccctacaaa cacagcgggg agagcctgcg agcaagttca 3120
gtggtgtcaa ctcagcccat gtcctcccac tgcagagtgc cagctgctcc ctcaagggtt 3180
tgaatgtatc gcaaacgctg ttttcagcgg attaagcaga gaaatactct tcagaagcaa 3240
tgggaacatt accagagaac tcaccaatat cacatttgct ttcagaacac atgatacaaa 3300
tgtgatgata ttgcatgcag aaaaagaacc agagtttctt aatattagca ttcaagatgc 3360
cagattattc tttcaattgc gaagtggcaa cagcttttat acgctgcacc tgatgggttc 3420
ccaattggtg aatgatggca catggcacca agtgactttc tccatgatag acccagtggc 3480
ccagacctcc cggtggcaaa tggaggtgaa cgaccagaca ccctttgtga taagtgaagt 3540
tgctactgga agcctgaact ttttgaagga caatacagac atctatgtgg gtgaccaatc 3600
tgttgacaat ccgaaaggcc tgcagggctg tctgagcaca atagagattg gaggcatata 3660
tctttcttac tttgaaaatc tacatggttt ccctggtaag cctcaggaag agcaatttct 3720
caaagtttct acaaatatgg tacttactgg ctgtttgcca tcaaatgcct gccactccag 3780
cccctgtttg catggaggaa actgtgaaga cagctacagt tcttatcggt gtgcctgtct 3840
ctcgggatgg tcagggacac actgtgaaat caacattgat gagtgctttt ctagcccctg 3900
tatccatggc aactgctctg atggagttgc agcctaccac tgcaggtgtg agcctggata 3960
caccggtgtg aactgtgagg tggatgtaga caattgcaag agtcatcagt gtgcaaatgg 4020
ggccacctgt gttcctgaag ctcatggcta ctcttgtctc tgctttggaa attttaccgg 4080
gagattttgc agacacagca gattaccctc aacagtctgt gggaatgaga agagaaactt 4140
cacttgctac aatggaggca gctgctccat gttccaggag gactggcaat gtatgtgctg 4200
gccaggtttc actggagagt ggtgtgaaga ggacatcaac gagtgtgcct ccgatccctg 4260
catcaatgga ggactgtgca gggacttggt caacaggttc ctatgcatct gtgatgtggc 4320
cttcgctggc gagcgctgtg agctggacgt aagcggcctt tccttttatg tgtccctctt 4380
actatggcaa aacctctttc agctcctgtc ctacctcgta ctgcgcatga atgatgagcc 4440
agttgtagag tggggggcac aggaaaatta ttaatgtgca tgggagcatt cacaagtgta 4500
aaacattgac ttgcaagaaa catcttgtct cagtgtaggt ttctaggaaa gacaaaggga 4560
acattaggga atagactcca tctagagcac tggttctcag tcttcctaat gctgcaaccc 4620
tttagtacag ctcttcctgt tgtagtgatc gcagccataa cattattttc attgccactt 4680
cataactgta atccttctac tgctgtgaat cacaatggaa atatttatgt tttctgatgg 4740
tcttaagcaa cacctctgaa aaagtcattg accccccccc caaaggggct gtgatccaca 4800
ggttgagaaa tgctcatctg gaaggtaacc atgcatttaa gtgtacctct agtagtttgg 4860
gtctatagaa gatattctcc tattctacct ttttagacac gccagaagag ggcatctgat 4920
tccattaaag atgattggga gccaccgtgt ggttcctgag aactgtactc gggccctttg 4980
gaagagcaat cagtgctctt tccagcccct aagaatattt ttaatacagc cagaaaggtc 5040
tcattaccca gtgtactgag ccctaaggca ctttcatcct caatcgttcc atgttgaatg 5100
gttttcatta catttggaaa atgttttctc tccactctac ctttacatgt tcctattttc 5160
ctattgacaa tttgcccctt cactgtaatt ctaatttggt gtggtccttc ttctcataag 5220
tttatatgtg acatgaacat ttaaaaatat ctatgaatat tttatagtca tgtatgtctt 5280
tctgcaaagc tattcaaatg aactatggac agttcttttc tacacgaaga agagatgagt 5340
ttaatcccca gtaacatgag aaaaagatga gtgagggaca gtgctcacag tatccctcac 5400
tagcatcatt tgtgattcca tgggccattt ttttccacca gcaaatagca gagagccctt 5460
tccctattcg tttctcttac acttcccctt ttctgttaca actgaacact ttacattagt 5520
tactcctttg tagggggttt gacttttcca ccgttttctc tggttcacta tttatgctaa 5580
gtatctgtgc agggcgggta tatcagtcca acagaggtgt cattagtgtt cattgaggag 5640
gaaatacttt gcatgaattc atgacatcat tgaagtagca gtggccagaa agataccctt 5700
ctgcgaatgt gtctgtgtat tcagaagctg ccctggttag aaaacatgtg ggtcactttt 5760
cctttgcatg ttaccagtgc tcactgggtc atgattgttt taagacagag cttttgctgt 5820
ggcaatgacc aaggtgaatc cagagatgca gatcagacaa aggacaagac aatgtactat 5880
ctgagtaaaa ccctgccttg acttactcct cagtacttag agattttaca tagcaacctc 5940
caccctgtgg caacccgttc acactagcag tgatgctgag atttgccctt ccttctcatc 6000
atcttcctca catccaaagc attttgtgtc cacactgctg tttcagataa ctgtttctaa 6060
agtgggattg ttgtagccag aaaggtaggg aaaatgttcc ccaaaatatt tgcattctta 6120
agtatgtgaa gtaagtagat tatagtcaga gacaatatgt aaggtttcag gttcactccc 6180
ttctacacat atcttcaact gtgtatttgc agaatattct gaatgtgaca tactcccaac 6240
agaatatatt taaggagtat ttatccacag tattgttctc tgtacagttc tagtgcttct 6300
attgtcactg caattgtcaa ttgtttttct gctttccaac tgtcttatta tcatttaata 6360
gcatcttgct aaatgccctc tttctattct ccttatttct ccatagttca tgtgtgtctg 6420
tgtgactaag gattctcctc atttttgcag aaaaataaaa tcttttcttc tttatgtcct 6480
gcttgtcatt ctctggtgac acatgtcttt gcttacttgg actgagggtt gtacagtaag 6540
tacagaagca ggctcagtca cacagacaga gacacaccac caccagcagc agcagcacca 6600
ccaccaccac caccaccacc agaaaacagt atgagtactc atctcttgat tacatgtcat 6660
ttcaagtaag caccatgaca ccgagggcca ggttccatgg actttctctg ttaggcacgt 6720
gattctttag ctgacctttg agaacagact ccaacaacct cacttatttt tactgttgac 6780
ttatatcatc tctgacaaca ctggacttcg tttgagctag tcaagaggaa agaccatgac 6840
acctaaggga cagaaattca cacactcggt ttttcataat tcacacacat tcctatgtat 6900
caaatctctg taatagatga catttacttg aataaaaagt catttccctt 6950
<210> 72
<211> 1375
<212> PRT
<213> 小鼠
<400> 72
Met Lys Leu Lys Arg Thr Ala Tyr Leu Leu Phe Leu Tyr Leu Ser Ser
1 5 10 15
Ser Leu Leu Ile Cys Ile Lys Asn Ser Phe Cys Asn Lys Asn Asn Thr
20 25 30
Arg Cys Leu Ser Gly Pro Cys Gln Asn Asn Ser Thr Cys Lys His Phe
35 40 45
Pro Gln Asp Asn Asn Cys Cys Leu Asp Thr Ala Asn Asn Leu Asp Lys
50 55 60
Asp Cys Glu Asp Leu Lys Asp Pro Cys Phe Ser Ser Pro Cys Gln Gly
65 70 75 80
Ile Ala Thr Cys Val Lys Ile Pro Gly Glu Gly Asn Phe Leu Cys Gln
85 90 95
Cys Pro Pro Gly Tyr Ser Gly Leu Asn Cys Glu Thr Ala Thr Asn Ser
100 105 110
Cys Gly Gly Asn Leu Cys Gln His Gly Gly Thr Cys Arg Lys Asp Pro
115 120 125
Glu His Pro Val Cys Ile Cys Pro Pro Gly Tyr Ala Gly Arg Phe Cys
130 135 140
Glu Thr Asp His Asn Glu Cys Ala Ser Ser Pro Cys His Asn Gly Ala
145 150 155 160
Met Cys Gln Asp Gly Ile Asn Gly Tyr Ser Cys Phe Cys Val Pro Gly
165 170 175
Tyr Gln Gly Arg His Cys Asp Leu Glu Val Asp Glu Cys Val Ser Asp
180 185 190
Pro Cys Lys Asn Glu Ala Val Cys Leu Asn Glu Ile Gly Arg Tyr Thr
195 200 205
Cys Val Cys Pro Gln Glu Phe Ser Gly Val Asn Cys Glu Leu Glu Ile
210 215 220
Asp Glu Cys Arg Ser Gln Pro Cys Leu His Gly Ala Thr Cys Gln Asp
225 230 235 240
Ala Pro Gly Gly Tyr Ser Cys Asp Cys Ala Pro Gly Phe Leu Gly Glu
245 250 255
His Cys Glu Leu Ser Val Asn Glu Cys Glu Ser Gln Pro Cys Leu His
260 265 270
Gly Gly Leu Cys Val Asp Gly Arg Asn Ser Tyr His Cys Asp Cys Thr
275 280 285
Gly Ser Gly Phe Thr Gly Met His Cys Glu Ser Leu Ile Pro Leu Cys
290 295 300
Trp Ser Lys Pro Cys His Asn Asp Ala Thr Cys Glu Asp Thr Val Asp
305 310 315 320
Ser Tyr Ile Cys His Cys Arg Pro Gly Tyr Thr Gly Ala Leu Cys Glu
325 330 335
Thr Asp Ile Asn Glu Cys Ser Ser Asn Pro Cys Gln Phe Trp Gly Glu
340 345 350
Cys Val Glu Leu Ser Ser Glu Gly Leu Tyr Gly Asn Thr Ala Gly Leu
355 360 365
Pro Ser Ser Phe Ser Tyr Val Gly Ala Ser Gly Tyr Val Cys Ile Cys
370 375 380
Gln Pro Gly Phe Thr Gly Ile His Cys Glu Glu Asp Val Asp Glu Cys
385 390 395 400
Leu Leu His Pro Cys Leu Asn Gly Gly Thr Cys Glu Asn Leu Pro Gly
405 410 415
Asn Tyr Ala Cys His Cys Pro Phe Asp Asp Thr Ser Arg Thr Phe Tyr
420 425 430
Gly Gly Glu Asn Cys Ser Glu Ile Leu Leu Gly Cys Thr His His Gln
435 440 445
Cys Leu Asn Asn Gly Lys Cys Ile Pro His Phe Gln Asn Gly Gln His
450 455 460
Gly Phe Thr Cys Gln Cys Leu Ser Gly Tyr Ala Gly Pro Leu Cys Glu
465 470 475 480
Thr Val Thr Thr Leu Ser Phe Gly Ser Asn Gly Phe Leu Trp Val Thr
485 490 495
Ser Gly Ser His Thr Gly Ile Gly Pro Glu Cys Asn Ile Ser Leu Arg
500 505 510
Phe His Thr Val Gln Pro Asn Ala Leu Leu Leu Ile Arg Gly Asn Lys
515 520 525
Asp Val Ser Met Lys Leu Glu Leu Leu Asn Gly Cys Val His Leu Ser
530 535 540
Ile Glu Val Trp Asn Gln Leu Lys Val Leu Leu Ser Ile Ser His Asn
545 550 555 560
Thr Ser Asp Gly Glu Trp His Phe Val Glu Val Thr Ile Ala Glu Thr
565 570 575
Leu Thr Leu Ala Leu Val Gly Gly Ser Cys Lys Glu Lys Cys Thr Thr
580 585 590
Lys Ser Ser Val Pro Val Glu Asn His Gln Ser Ile Cys Ala Leu Gln
595 600 605
Asp Ser Phe Leu Gly Gly Leu Pro Met Gly Thr Ala Asn Asn Ser Val
610 615 620
Ser Val Leu Asn Ile Tyr Asn Val Pro Ser Thr Pro Ser Phe Val Gly
625 630 635 640
Cys Leu Gln Asp Ile Arg Phe Asp Leu Asn His Ile Thr Leu Glu Asn
645 650 655
Val Ser Ser Gly Leu Ser Ser Asn Val Lys Ala Gly Cys Leu Gly Lys
660 665 670
Asp Trp Cys Glu Ser Gln Pro Cys Gln Asn Arg Gly Arg Cys Ile Asn
675 680 685
Leu Trp Gln Gly Tyr Gln Cys Glu Cys Asp Arg Pro Tyr Thr Gly Ser
690 695 700
Asn Cys Leu Lys Glu Tyr Val Ala Gly Arg Phe Gly Gln Asp Asp Ser
705 710 715 720
Thr Gly Tyr Ala Ala Phe Ser Val Asn Asp Asn Tyr Gly Gln Asn Phe
725 730 735
Ser Leu Ser Met Phe Val Arg Thr Arg Gln Pro Leu Gly Leu Leu Leu
740 745 750
Ala Leu Glu Asn Ser Thr Tyr Gln Tyr Val Ser Val Trp Leu Glu His
755 760 765
Gly Ser Leu Ala Leu Gln Thr Pro Gly Ser Pro Lys Phe Met Val Asn
770 775 780
Phe Phe Leu Ser Asp Gly Asn Val His Leu Ile Ser Leu Arg Ile Lys
785 790 795 800
Pro Asn Glu Ile Glu Leu Tyr Gln Ser Ser Gln Asn Leu Gly Phe Ile
805 810 815
Ser Val Pro Thr Trp Thr Ile Arg Arg Gly Asp Val Ile Phe Ile Gly
820 825 830
Gly Leu Pro Asp Arg Glu Lys Thr Glu Val Tyr Gly Gly Phe Phe Lys
835 840 845
Gly Cys Val Gln Asp Val Arg Leu Asn Ser Gln Thr Leu Glu Phe Phe
850 855 860
Pro Asn Ser Thr Asn Asn Ala Tyr Asp Asp Pro Ile Leu Val Asn Val
865 870 875 880
Thr Gln Gly Cys Pro Gly Asp Asn Thr Cys Lys Ser Asn Pro Cys His
885 890 895
Asn Gly Gly Val Cys His Ser Leu Trp Asp Asp Phe Ser Cys Ser Cys
900 905 910
Pro Thr Asn Thr Ala Gly Arg Ala Cys Glu Gln Val Gln Trp Cys Gln
915 920 925
Leu Ser Pro Cys Pro Pro Thr Ala Glu Cys Gln Leu Leu Pro Gln Gly
930 935 940
Phe Glu Cys Ile Ala Asn Ala Val Phe Ser Gly Leu Ser Arg Glu Ile
945 950 955 960
Leu Phe Arg Ser Asn Gly Asn Ile Thr Arg Glu Leu Thr Asn Ile Thr
965 970 975
Phe Ala Phe Arg Thr His Asp Thr Asn Val Met Ile Leu His Ala Glu
980 985 990
Lys Glu Pro Glu Phe Leu Asn Ile Ser Ile Gln Asp Ala Arg Leu Phe
995 1000 1005
Phe Gln Leu Arg Ser Gly Asn Ser Phe Tyr Thr Leu His Leu Met
1010 1015 1020
Gly Ser Gln Leu Val Asn Asp Gly Thr Trp His Gln Val Thr Phe
1025 1030 1035
Ser Met Ile Asp Pro Val Ala Gln Thr Ser Arg Trp Gln Met Glu
1040 1045 1050
Val Asn Asp Gln Thr Pro Phe Val Ile Ser Glu Val Ala Thr Gly
1055 1060 1065
Ser Leu Asn Phe Leu Lys Asp Asn Thr Asp Ile Tyr Val Gly Asp
1070 1075 1080
Gln Ser Val Asp Asn Pro Lys Gly Leu Gln Gly Cys Leu Ser Thr
1085 1090 1095
Ile Glu Ile Gly Gly Ile Tyr Leu Ser Tyr Phe Glu Asn Leu His
1100 1105 1110
Gly Phe Pro Gly Lys Pro Gln Glu Glu Gln Phe Leu Lys Val Ser
1115 1120 1125
Thr Asn Met Val Leu Thr Gly Cys Leu Pro Ser Asn Ala Cys His
1130 1135 1140
Ser Ser Pro Cys Leu His Gly Gly Asn Cys Glu Asp Ser Tyr Ser
1145 1150 1155
Ser Tyr Arg Cys Ala Cys Leu Ser Gly Trp Ser Gly Thr His Cys
1160 1165 1170
Glu Ile Asn Ile Asp Glu Cys Phe Ser Ser Pro Cys Ile His Gly
1175 1180 1185
Asn Cys Ser Asp Gly Val Ala Ala Tyr His Cys Arg Cys Glu Pro
1190 1195 1200
Gly Tyr Thr Gly Val Asn Cys Glu Val Asp Val Asp Asn Cys Lys
1205 1210 1215
Ser His Gln Cys Ala Asn Gly Ala Thr Cys Val Pro Glu Ala His
1220 1225 1230
Gly Tyr Ser Cys Leu Cys Phe Gly Asn Phe Thr Gly Arg Phe Cys
1235 1240 1245
Arg His Ser Arg Leu Pro Ser Thr Val Cys Gly Asn Glu Lys Arg
1250 1255 1260
Asn Phe Thr Cys Tyr Asn Gly Gly Ser Cys Ser Met Phe Gln Glu
1265 1270 1275
Asp Trp Gln Cys Met Cys Trp Pro Gly Phe Thr Gly Glu Trp Cys
1280 1285 1290
Glu Glu Asp Ile Asn Glu Cys Ala Ser Asp Pro Cys Ile Asn Gly
1295 1300 1305
Gly Leu Cys Arg Asp Leu Val Asn Arg Phe Leu Cys Ile Cys Asp
1310 1315 1320
Val Ala Phe Ala Gly Glu Arg Cys Glu Leu Asp Val Ser Gly Leu
1325 1330 1335
Ser Phe Tyr Val Ser Leu Leu Leu Trp Gln Asn Leu Phe Gln Leu
1340 1345 1350
Leu Ser Tyr Leu Val Leu Arg Met Asn Asp Glu Pro Val Val Glu
1355 1360 1365
Trp Gly Ala Gln Glu Asn Tyr
1370 1375
<210> 73
<211> 5434
<212> DNA
<213> 小鼠
<400> 73
tcactgtgaa gaagacgttg atgaatgttt actgcaccct tgcctaaatg gtggtacttg 60
tgagaacctg cctgggaatt atgcctgtca ctgtcccttt gatgacactt ctaggacatt 120
ttatggagga gaaaactgct cagaaattct cctgggctgc actcatcacc agtgtctgaa 180
caatggaaaa tgtatccctc atttccaaaa tggccagcat ggattcactt gccagtgtct 240
ttctggctat gcggggcccc tgtgtgaaac tgtcaccaca ctttcatttg ggagcaatgg 300
cttcctatgg gtcacaagtg gctcccatac aggcataggg ccagaatgta acatatcctt 360
gaggtttcac actgttcaac caaacgcact tctcctcatc cgaggcaaca aggacgtgtc 420
tatgaagctg gagttgctga atggttgtgt tcacttatca attgaagtct ggaatcagtt 480
aaaggtgctc ctgtctattt ctcacaacac cagtgatgga gaatggcatt tcgtggaggt 540
aacaatcgca gaaactctaa cccttgccct agttggcggc tcctgcaagg agaagtgcac 600
caccaagtct tctgttccag ttgagaatca tcaatcaata tgtgctttgc aggactcttt 660
tttgggtggc ttaccaatgg ggacagccaa caacagtgtg tctgtgctta acatctataa 720
tgtgccgtcc acaccttcct ttgtaggctg tctccaagac attagatttg atttgaatca 780
cattactctg gagaacgttt catctggcct gtcatcaaat gttaaagcag gctgcctggg 840
aaaggactgg tgtgaaagtc aaccctgtca aaacagagga cgctgcatca acttgtggca 900
gggttatcag tgtgaatgtg acaggcccta tacaggctcc aactgcctga aagagtatgt 960
agcgggaaga tttggccaag atgactccac aggatatgcg gcctttagtg ttaatgataa 1020
ttatggacag aacttcagtc tttcaatgtt tgtccgaaca cgtcaacccc tgggcttact 1080
tctggctttg gaaaatagta cttaccagta tgtcagtgtc tggctagagc acggcagcct 1140
agcactgcag actccaggct ctcccaagtt catggtaaac ttttttctca gtgatggaaa 1200
tgttcactta atatctttga gaatcaaacc aaatgaaatt gaactgtatc agtcttcaca 1260
aaacctagga ttcatttctg ttcctacatg gacaattcga agaggagacg tcatcttcat 1320
tggtggctta cctgacagag agaagactga agtttatggt ggcttcttca aaggctgtgt 1380
tcaagatgtc agattaaaca gccagactct ggaattcttt cccaattcaa caaacaatgc 1440
atacgatgac ccaattcttg tcaatgtgac tcaaggctgt cccggagaca acacatgtaa 1500
gtccaacccc tgtcataatg gaggtgtctg ccactccctg tgggatgact tctcctgctc 1560
ctgccctaca aacacagcgg ggagagcctg cgagcaagtt cagtggtgtc aactcagccc 1620
atgtcctccc actgcagagt gccagctgct ccctcaaggg tttgaatgta tcgcaaacgc 1680
tgttttcagc ggattaagca gagaaatact cttcagaagc aatgggaaca ttaccagaga 1740
actcaccaat atcacatttg ctttcagaac acatgataca aatgtgatga tattgcatgc 1800
agaaaaagaa ccagagtttc ttaatattag cattcaagat gccagattat tctttcaatt 1860
gcgaagtggc aacagctttt atacgctgca cctgatgggt tcccaattgg tgaatgatgg 1920
cacatggcac caagtgactt tctccatgat agacccagtg gcccagacct cccggtggca 1980
aatggaggtg aacgaccaga caccctttgt gataagtgaa gttgctactg gaagcctgaa 2040
ctttttgaag gacaatacag acatctatgt gggtgaccaa tctgttgaca atccgaaagg 2100
cctgcagggc tgtctgagca caatagagat tggaggcata tatctttctt actttgaaaa 2160
tctacatggt ttccctggta agcctcagga agagcaattt ctcaaagttt ctacaaatat 2220
ggtacttact ggctgtttgc catcaaatgc ctgccactcc agcccctgtt tgcatggagg 2280
aaactgtgaa gacagctaca gttcttatcg gtgtgcctgt ctctcgggat ggtcagggac 2340
acactgtgaa atcaacattg atgagtgctt ttctagcccc tgtatccatg gcaactgctc 2400
tgatggagtt gcagcctacc actgcaggtg tgagcctgga tacaccggtg tgaactgtga 2460
ggtggatgta gacaattgca agagtcatca gtgtgcaaat ggggccacct gtgttcctga 2520
agctcatggc tactcttgtc tctgctttgg aaattttacc gggagatttt gcagacacag 2580
cagattaccc tcaacagtct gtgggaatga gaagagaaac ttcacttgct acaatggagg 2640
cagctgctcc atgttccagg aggactggca atgtatgtgc tggccaggtt tcactggaga 2700
gtggtgtgaa gaggacatca acgagtgtgc ctccgatccc tgcatcaatg gaggactgtg 2760
cagggacttg gtcaacaggt tcctatgcat ctgtgatgtg gccttcgctg gcgagcgctg 2820
tgagctggac gtaagcggcc tttcctttta tgtgtccctc ttactatggc aaaacctctt 2880
tcagctcctg tcctacctcg tactgcgcat gaatgatgag ccagttgtag agtggggggc 2940
acaggaaaat tattaatgtg catgggagca ttcacaagtg taaaacattg acttgcaaga 3000
aacatcttgt ctcagtgtag gtttctagga aagacaaagg gaacattagg gaatagactc 3060
catctagagc actggttctc agtcttccta atgctgcaac cctttagtac agctcttcct 3120
gttgtagtga tcgcagccat aacattattt tcattgccac ttcataactg taatccttct 3180
actgctgtga atcacaatgg aaatatttat gttttctgat ggtcttaagc aacacctctg 3240
aaaaagtcat tgaccccccc cccaaagggg ctgtgatcca caggttgaga aatgctcatc 3300
tggaaggtaa ccatgcattt aagtgtacct ctagtagttt gggtctatag aagatattct 3360
cctattctac ctttttagac acgccagaag agggcatctg attccattaa agatgattgg 3420
gagccaccgt gtggttcctg agaactgtac tcgggccctt tggaagagca atcagtgctc 3480
tttccagccc ctaagaatat ttttaataca gccagaaagg tctcattacc cagtgtactg 3540
agccctaagg cactttcatc ctcaatcgtt ccatgttgaa tggttttcat tacatttgga 3600
aaatgttttc tctccactct acctttacat gttcctattt tcctattgac aatttgcccc 3660
ttcactgtaa ttctaatttg gtgtggtcct tcttctcata agtttatatg tgacatgaac 3720
atttaaaaat atctatgaat attttatagt catgtatgtc tttctgcaaa gctattcaaa 3780
tgaactatgg acagttcttt tctacacgaa gaagagatga gtttaatccc cagtaacatg 3840
agaaaaagat gagtgaggga cagtgctcac agtatccctc actagcatca tttgtgattc 3900
catgggccat ttttttccac cagcaaatag cagagagccc tttccctatt cgtttctctt 3960
acacttcccc ttttctgtta caactgaaca ctttacatta gttactcctt tgtagggggt 4020
ttgacttttc caccgttttc tctggttcac tatttatgct aagtatctgt gcagggcggg 4080
tatatcagtc caacagaggt gtcattagtg ttcattgagg aggaaatact ttgcatgaat 4140
tcatgacatc attgaagtag cagtggccag aaagataccc ttctgcgaat gtgtctgtgt 4200
attcagaagc tgccctggtt agaaaacatg tgggtcactt ttcctttgca tgttaccagt 4260
gctcactggg tcatgattgt tttaagacag agcttttgct gtggcaatga ccaaggtgaa 4320
tccagagatg cagatcagac aaaggacaag acaatgtact atctgagtaa aaccctgcct 4380
tgacttactc ctcagtactt agagatttta catagcaacc tccaccctgt ggcaacccgt 4440
tcacactagc agtgatgctg agatttgccc ttccttctca tcatcttcct cacatccaaa 4500
gcattttgtg tccacactgc tgtttcagat aactgtttct aaagtgggat tgttgtagcc 4560
agaaaggtag ggaaaatgtt ccccaaaata tttgcattct taagtatgtg aagtaagtag 4620
attatagtca gagacaatat gtaaggtttc aggttcactc ccttctacac atatcttcaa 4680
ctgtgtattt gcagaatatt ctgaatgtga catactccca acagaatata tttaaggagt 4740
atttatccac agtattgttc tctgtacagt tctagtgctt ctattgtcac tgcaattgtc 4800
aattgttttt ctgctttcca actgtcttat tatcatttaa tagcatcttg ctaaatgccc 4860
tctttctatt ctccttattt ctccatagtt catgtgtgtc tgtgtgacta aggattctcc 4920
tcatttttgc agaaaaataa aatcttttct tctttatgtc ctgcttgtca ttctctggtg 4980
acacatgtct ttgcttactt ggactgaggg ttgtacagta agtacagaag caggctcagt 5040
cacacagaca gagacacacc accaccagca gcagcagcac caccaccacc accaccacca 5100
ccagaaaaca gtatgagtac tcatctcttg attacatgtc atttcaagta agcaccatga 5160
caccgagggc caggttccat ggactttctc tgttaggcac gtgattcttt agctgacctt 5220
tgagaacaga ctccaacaac ctcacttatt tttactgttg acttatatca tctctgacaa 5280
cactggactt cgtttgagct agtcaagagg aaagaccatg acacctaagg gacagaaatt 5340
cacacactcg gtttttcata attcacacac attcctatgt atcaaatctc tgtaatagat 5400
gacatttact tgaataaaaa gtcatttccc tttg 5434
<210> 74
<211> 844
<212> PRT
<213> 小鼠
<400> 74
Met Lys Leu Glu Leu Leu Asn Gly Cys Val His Leu Ser Ile Glu Val
1 5 10 15
Trp Asn Gln Leu Lys Val Leu Leu Ser Ile Ser His Asn Thr Ser Asp
20 25 30
Gly Glu Trp His Phe Val Glu Val Thr Ile Ala Glu Thr Leu Thr Leu
35 40 45
Ala Leu Val Gly Gly Ser Cys Lys Glu Lys Cys Thr Thr Lys Ser Ser
50 55 60
Val Pro Val Glu Asn His Gln Ser Ile Cys Ala Leu Gln Asp Ser Phe
65 70 75 80
Leu Gly Gly Leu Pro Met Gly Thr Ala Asn Asn Ser Val Ser Val Leu
85 90 95
Asn Ile Tyr Asn Val Pro Ser Thr Pro Ser Phe Val Gly Cys Leu Gln
100 105 110
Asp Ile Arg Phe Asp Leu Asn His Ile Thr Leu Glu Asn Val Ser Ser
115 120 125
Gly Leu Ser Ser Asn Val Lys Ala Gly Cys Leu Gly Lys Asp Trp Cys
130 135 140
Glu Ser Gln Pro Cys Gln Asn Arg Gly Arg Cys Ile Asn Leu Trp Gln
145 150 155 160
Gly Tyr Gln Cys Glu Cys Asp Arg Pro Tyr Thr Gly Ser Asn Cys Leu
165 170 175
Lys Glu Tyr Val Ala Gly Arg Phe Gly Gln Asp Asp Ser Thr Gly Tyr
180 185 190
Ala Ala Phe Ser Val Asn Asp Asn Tyr Gly Gln Asn Phe Ser Leu Ser
195 200 205
Met Phe Val Arg Thr Arg Gln Pro Leu Gly Leu Leu Leu Ala Leu Glu
210 215 220
Asn Ser Thr Tyr Gln Tyr Val Ser Val Trp Leu Glu His Gly Ser Leu
225 230 235 240
Ala Leu Gln Thr Pro Gly Ser Pro Lys Phe Met Val Asn Phe Phe Leu
245 250 255
Ser Asp Gly Asn Val His Leu Ile Ser Leu Arg Ile Lys Pro Asn Glu
260 265 270
Ile Glu Leu Tyr Gln Ser Ser Gln Asn Leu Gly Phe Ile Ser Val Pro
275 280 285
Thr Trp Thr Ile Arg Arg Gly Asp Val Ile Phe Ile Gly Gly Leu Pro
290 295 300
Asp Arg Glu Lys Thr Glu Val Tyr Gly Gly Phe Phe Lys Gly Cys Val
305 310 315 320
Gln Asp Val Arg Leu Asn Ser Gln Thr Leu Glu Phe Phe Pro Asn Ser
325 330 335
Thr Asn Asn Ala Tyr Asp Asp Pro Ile Leu Val Asn Val Thr Gln Gly
340 345 350
Cys Pro Gly Asp Asn Thr Cys Lys Ser Asn Pro Cys His Asn Gly Gly
355 360 365
Val Cys His Ser Leu Trp Asp Asp Phe Ser Cys Ser Cys Pro Thr Asn
370 375 380
Thr Ala Gly Arg Ala Cys Glu Gln Val Gln Trp Cys Gln Leu Ser Pro
385 390 395 400
Cys Pro Pro Thr Ala Glu Cys Gln Leu Leu Pro Gln Gly Phe Glu Cys
405 410 415
Ile Ala Asn Ala Val Phe Ser Gly Leu Ser Arg Glu Ile Leu Phe Arg
420 425 430
Ser Asn Gly Asn Ile Thr Arg Glu Leu Thr Asn Ile Thr Phe Ala Phe
435 440 445
Arg Thr His Asp Thr Asn Val Met Ile Leu His Ala Glu Lys Glu Pro
450 455 460
Glu Phe Leu Asn Ile Ser Ile Gln Asp Ala Arg Leu Phe Phe Gln Leu
465 470 475 480
Arg Ser Gly Asn Ser Phe Tyr Thr Leu His Leu Met Gly Ser Gln Leu
485 490 495
Val Asn Asp Gly Thr Trp His Gln Val Thr Phe Ser Met Ile Asp Pro
500 505 510
Val Ala Gln Thr Ser Arg Trp Gln Met Glu Val Asn Asp Gln Thr Pro
515 520 525
Phe Val Ile Ser Glu Val Ala Thr Gly Ser Leu Asn Phe Leu Lys Asp
530 535 540
Asn Thr Asp Ile Tyr Val Gly Asp Gln Ser Val Asp Asn Pro Lys Gly
545 550 555 560
Leu Gln Gly Cys Leu Ser Thr Ile Glu Ile Gly Gly Ile Tyr Leu Ser
565 570 575
Tyr Phe Glu Asn Leu His Gly Phe Pro Gly Lys Pro Gln Glu Glu Gln
580 585 590
Phe Leu Lys Val Ser Thr Asn Met Val Leu Thr Gly Cys Leu Pro Ser
595 600 605
Asn Ala Cys His Ser Ser Pro Cys Leu His Gly Gly Asn Cys Glu Asp
610 615 620
Ser Tyr Ser Ser Tyr Arg Cys Ala Cys Leu Ser Gly Trp Ser Gly Thr
625 630 635 640
His Cys Glu Ile Asn Ile Asp Glu Cys Phe Ser Ser Pro Cys Ile His
645 650 655
Gly Asn Cys Ser Asp Gly Val Ala Ala Tyr His Cys Arg Cys Glu Pro
660 665 670
Gly Tyr Thr Gly Val Asn Cys Glu Val Asp Val Asp Asn Cys Lys Ser
675 680 685
His Gln Cys Ala Asn Gly Ala Thr Cys Val Pro Glu Ala His Gly Tyr
690 695 700
Ser Cys Leu Cys Phe Gly Asn Phe Thr Gly Arg Phe Cys Arg His Ser
705 710 715 720
Arg Leu Pro Ser Thr Val Cys Gly Asn Glu Lys Arg Asn Phe Thr Cys
725 730 735
Tyr Asn Gly Gly Ser Cys Ser Met Phe Gln Glu Asp Trp Gln Cys Met
740 745 750
Cys Trp Pro Gly Phe Thr Gly Glu Trp Cys Glu Glu Asp Ile Asn Glu
755 760 765
Cys Ala Ser Asp Pro Cys Ile Asn Gly Gly Leu Cys Arg Asp Leu Val
770 775 780
Asn Arg Phe Leu Cys Ile Cys Asp Val Ala Phe Ala Gly Glu Arg Cys
785 790 795 800
Glu Leu Asp Val Ser Gly Leu Ser Phe Tyr Val Ser Leu Leu Leu Trp
805 810 815
Gln Asn Leu Phe Gln Leu Leu Ser Tyr Leu Val Leu Arg Met Asn Asp
820 825 830
Glu Pro Val Val Glu Trp Gly Ala Gln Glu Asn Tyr
835 840
<210> 75
<211> 5678
<212> DNA
<213> 小鼠
<400> 75
acgaatccaa tccaggctgg aaaaatctgc tccaggattg actggttacc gtcttcctgt 60
gcctgtaagg tgctgtgaaa gagaagtgct ttctgattct ctgtctgtgg aggagccctg 120
ggaggggtgg gacagagatg gcatcctggc tctctgaggc acctgctctt ctctgaacca 180
cacaggagtc aagagccaaa cagggatagc ttcagcagca cttcagaggg tgttctctaa 240
gtaagaacat gaagctcaag agaactgcct accttctctt cctgtacctc agctcctcac 300
tgctcatctg cataaagaat tcattttgca ataaaaacaa taccaggtgc ctttcaggtc 360
cttgccaaaa caattctacg tgcaagcatt ttccacaaga caacaattgt tgcttagaca 420
cagccaataa tttggacaaa gactgtgaag atctgaaaga cccttgcttc tcgagtccct 480
gccaaggaat tgccacttgt gtgaaaatcc caggggaagg gaacttcctg tgtcagtgtc 540
ctcctgggta cagcgggctg aactgtgaaa ctgccaccaa ttcctgtgga gggaacctct 600
gccaacatgg aggcacctgc cgtaaagacc ctgagcaccc tgtctgtatc tgccctcctg 660
gatatgctgg aaggttctgt gagactgatc acaatgagtg tgcttctagc ccttgccaca 720
atggggctat gtgccaggat ggaatcaatg gctactcctg cttctgtgtg cctggatacc 780
aaggcaggca ttgtgacttg gaagtggatg aatgtgtttc tgatccctgc aagaatgagg 840
ctgtgtgcct caatgagata ggaagataca cttgtgtctg ccctcaagag ttttctggcg 900
tgaactgtga gttggaaatt gatgaatgca gatcccagcc ttgtctccac ggtgccacat 960
gtcaggacgc tccagggggc tactcctgtg actgtgcacc tggattcctt ggagagcact 1020
gtgaactcag cgttaatgaa tgtgaaagtc agccgtgtct ccatggaggt ctatgtgtgg 1080
atggaagaaa caggaattca ctgtgaagaa gacgttgatg aatgtttact gcacccttgc 1140
ctaaatggtg gtacttgtga gaacctgcct gggaattatg cctgtcactg tccctttgat 1200
gacacttcta ggacatttta tggaggagaa aactgctcag aaattctcct gggctgcact 1260
catcaccagt gtctgaacaa tggaaaatgt atccctcatt tccaaaatgg ccagcatgga 1320
ttcacttgcc agtgtctttc tggctatgcg gggcccctgt gtgaaactgt caccacactt 1380
tcatttggga gcaatggctt cctatgggtc acaagtggct cccatacagg catagggcca 1440
gaatgtaaca tatccttgag gtttcacact gttcaaccaa acgcacttct cctcatccga 1500
ggcaacaagg acgtgtctat gaagctggag ttgctgaatg gttgtgttca cttatcaatt 1560
gaagtctgga atcagttaaa ggtgctcctg tctatttctc acaacaccag tgatggagaa 1620
tggcatttcg tggaggtaac aatcgcagaa actctaaccc ttgccctagt tggcggctcc 1680
tgcaaggaga agtgcaccac caagtcttct gttccagttg agaatcatca atcaatatgt 1740
gctttgcagg actctttttt gggtggctta ccaatgggga cagccaacaa cagtgtgtct 1800
gtgcttaaca tctataatgt gccgtccaca ccttcctttg taggctgtct ccaagacatt 1860
agatttgatt tgaatcacat tactctggag aacgtttcat ctggcctgtc atcaaatgtt 1920
aaagcaggct gcctgggaaa ggactggtgt gaaagtcaac cctgtcaaaa cagaggacgc 1980
tgcatcaact tgtggcaggg ttatcagtgt gaatgtgaca ggccctatac aggctccaac 2040
tgcctgaaag agtatgtagc gggaagattt ggccaagatg actccacagg atatgcggcc 2100
tttagtgtta atgataatta tggacagaac ttcagtcttt caatgtttgt ccgaacacgt 2160
caacccctgg gcttacttct ggctttggaa aatagtactt accagtatgt cagtgtctgg 2220
ctagagcacg gcagcctagc actgcagact ccaggctctc ccaagttcat ggtaaacttt 2280
tttctcagtg atggaaatgt tcacttaata tctttgagaa tcaaaccaaa tgaaattgaa 2340
ctgtatcagt cttcacaaaa cctaggattc atttctgttc ctacatggac aattcgaaga 2400
ggagacgtca tcttcattgg tggcttacct gacagagaga agactgaagt ttatggtggc 2460
ttcttcaaag gctgtgttca agatgtcaga ttaaacagcc agactctgga attctttccc 2520
aattcaacaa acaatgcata cgatgaccca attcttgtca atgtgactca aggctgtccc 2580
ggagacaaca catgtaagtc caacccctgt cataatggag gtgtctgcca ctccctgtgg 2640
gatgacttct cctgctcctg ccctacaaac acagcgggga gagcctgcga gcaagttcag 2700
tggtgtcaac tcagcccatg tcctcccact gcagagtgcc agctgctccc tcaagggttt 2760
gaatgtatcg caaacgctgt tttcagcgga ttaagcagag aaatactctt cagaagcaat 2820
gggaacatta ccagagaact caccaatatc acatttgctt tcagaacaca tgatacaaat 2880
gtgatgatat tgcatgcaga aaaagaacca gagtttctta atattagcat tcaagatgcc 2940
agattattct ttcaattgcg aagtggcaac agcttttata cgctgcacct gatgggttcc 3000
caattggtga atgatggcac atggcaccaa gtgactttct ccatgataga cccagtggcc 3060
cagacctccc ggtggcaaat ggaggtgaac gaccagacac cctttgtgat aagtgaagtt 3120
gctactggaa gcctgaactt tttgaaggac aatacagaca tctatgtggg tgaccaatct 3180
gttgacaatc cgaaaggcct gcagggctgt ctgagcacaa tagagattgg aggcatatat 3240
ctttcttact ttgaaaatct acatggtttc cctggtaagc ctcaggaaga gcaatttctc 3300
aaagtttcta caaatatggt acttactggc tgtttgccat caaatgcctg ccactccagc 3360
ccctgtttgc atggaggaaa ctgtgaagac agctacagtt cttatcggtg tgcctgtctc 3420
tcgggatggt cagggacaca ctgtgaaatc aacattgatg agtgcttttc tagcccctgt 3480
atccatggca actgctctga tggagttgca gcctaccact gcaggtgtga gcctggatac 3540
accggtgtga actgtgaggt ggatgtagac aattgcaaga gtcatcagtg tgcaaatggg 3600
gccacctgtg ttcctgaagc tcatggctac tcttgtctct gctttggaaa ttttaccggg 3660
agattttgca gacacagcag attaccctca acagtctgtg ggaatgagaa gagaaacttc 3720
acttgctaca atggaggcag ctgctccatg ttccaggagg actggcaatg tatgtgctgg 3780
ccaggtttca ctggagagtg gtgtgaagag gacatcaacg agtgtgcctc cgatccctgc 3840
atcaatggag gactgtgcag ggacttggtc aacaggttcc tatgcatctg tgatgtggcc 3900
ttcgctggcg agcgctgtga gctggacctg gctgatgaca ggctcctggg cattttcacc 3960
gctgttggct ccggaacttt ggccctgttc ttcatcctct tgcttgctgg ggttgcttct 4020
cttattgcct ccaacaaaag ggcgactcaa ggaacctaca gccccagcgg tcaggagaag 4080
gctggccctc gagtggaaat gtggatcagg atgccgcccc cggcactgga aaggctcatc 4140
taggagactg ctgctcttct caggacagag aagaacatga tgagtaccgg gtcgtgcctg 4200
agtgaagatg gctttacatc actagagata catacagctg ggactgtggg aaggaccttc 4260
ctgtggagtc actgagtagt tatgtcatcc attcacagaa gagtgtccct gtgtttgcct 4320
gtcagcctca gaattagcaa aacatctagc agacagagaa cacagtattt cagaagaact 4380
ccagaggctg ccccttaaac tctttactgg ttgatccaca taaaatgctt agtagccaag 4440
tgccattaat tatacagagc caagaagaaa aattagaata caactttcac tttttatttt 4500
gtagggaagg ttttatgttt tggtttgttg ttgttgttgt gacagtgaca gtgactcatt 4560
acatagacca agctggcctc aaaatcacat ggaccctcgg gattacatgt gtccgaccat 4620
gttcatctta tttttgaatc ttctgtcata tggtaaaaga ttccagtggg acctgaggag 4680
tgactagcta ggtaaagcaa gggctgtgta agtgccagaa ctggtgtttg tgtcctcatt 4740
atccacataa gtgccaagtg agtgtggccc ctgcctgtca tcctaggcct caggagatat 4800
cactgctcac tggagcaagc cggttaaact gttagggcag gtaagttttg acttcaagtg 4860
agagaccctg actcaatatg aaaggcaatt agtgagtcaa gatgaccctg tatgctaacc 4920
tcttgcctat acatgcatat acacacattt acatatgtgc ccaaacatga ggacacaagc 4980
acacgcgcgc gcgcacacac acacacacac acacacacac acacacacac acacacacac 5040
gagtctaatt gtatatagtg ataacagtac actttcctcc ttctatttcg gatttagaga 5100
aagccatgag aagcgtgtat ggtttaaacc atgacccaag cataacaaat aaagttgaaa 5160
tagttgttct cctgtccaag cttgtcttta ttgttgtgca ttctgtaagc tggttgcttg 5220
gttggctgat ggatggcttc tgtttgtttg ttgttttttg tttgtttgtt tgtctgggat 5280
attacatgta agaaaaataa ctggtaagaa caatcaaaga actttgttat gaattaaatc 5340
ttttgtctaa gtcacttaga gtcattattc tttatgtaga tttgcttcca gtcaggacat 5400
ttcctagaca gaatttaaga cagtaagaaa atgatttgtc acgtctgaaa gaggttcttt 5460
actttcaggg acttttgata atgcccaaca gagatggcat cgaaagagga gctcatagcg 5520
agatgggcat ttgtgcatcc tcaaggagaa aatattgtac cttctgtttg tatattgtct 5580
attctgtgat ggctgtatct tacatatgtt ttgatgcatg taacaatagt atcatatgaa 5640
ataaattata tatatatata atatataata tatatcac 5678
<210> 76
<211> 874
<212> PRT
<213> 小鼠
<400> 76
Met Lys Leu Glu Leu Leu Asn Gly Cys Val His Leu Ser Ile Glu Val
1 5 10 15
Trp Asn Gln Leu Lys Val Leu Leu Ser Ile Ser His Asn Thr Ser Asp
20 25 30
Gly Glu Trp His Phe Val Glu Val Thr Ile Ala Glu Thr Leu Thr Leu
35 40 45
Ala Leu Val Gly Gly Ser Cys Lys Glu Lys Cys Thr Thr Lys Ser Ser
50 55 60
Val Pro Val Glu Asn His Gln Ser Ile Cys Ala Leu Gln Asp Ser Phe
65 70 75 80
Leu Gly Gly Leu Pro Met Gly Thr Ala Asn Asn Ser Val Ser Val Leu
85 90 95
Asn Ile Tyr Asn Val Pro Ser Thr Pro Ser Phe Val Gly Cys Leu Gln
100 105 110
Asp Ile Arg Phe Asp Leu Asn His Ile Thr Leu Glu Asn Val Ser Ser
115 120 125
Gly Leu Ser Ser Asn Val Lys Ala Gly Cys Leu Gly Lys Asp Trp Cys
130 135 140
Glu Ser Gln Pro Cys Gln Asn Arg Gly Arg Cys Ile Asn Leu Trp Gln
145 150 155 160
Gly Tyr Gln Cys Glu Cys Asp Arg Pro Tyr Thr Gly Ser Asn Cys Leu
165 170 175
Lys Glu Tyr Val Ala Gly Arg Phe Gly Gln Asp Asp Ser Thr Gly Tyr
180 185 190
Ala Ala Phe Ser Val Asn Asp Asn Tyr Gly Gln Asn Phe Ser Leu Ser
195 200 205
Met Phe Val Arg Thr Arg Gln Pro Leu Gly Leu Leu Leu Ala Leu Glu
210 215 220
Asn Ser Thr Tyr Gln Tyr Val Ser Val Trp Leu Glu His Gly Ser Leu
225 230 235 240
Ala Leu Gln Thr Pro Gly Ser Pro Lys Phe Met Val Asn Phe Phe Leu
245 250 255
Ser Asp Gly Asn Val His Leu Ile Ser Leu Arg Ile Lys Pro Asn Glu
260 265 270
Ile Glu Leu Tyr Gln Ser Ser Gln Asn Leu Gly Phe Ile Ser Val Pro
275 280 285
Thr Trp Thr Ile Arg Arg Gly Asp Val Ile Phe Ile Gly Gly Leu Pro
290 295 300
Asp Arg Glu Lys Thr Glu Val Tyr Gly Gly Phe Phe Lys Gly Cys Val
305 310 315 320
Gln Asp Val Arg Leu Asn Ser Gln Thr Leu Glu Phe Phe Pro Asn Ser
325 330 335
Thr Asn Asn Ala Tyr Asp Asp Pro Ile Leu Val Asn Val Thr Gln Gly
340 345 350
Cys Pro Gly Asp Asn Thr Cys Lys Ser Asn Pro Cys His Asn Gly Gly
355 360 365
Val Cys His Ser Leu Trp Asp Asp Phe Ser Cys Ser Cys Pro Thr Asn
370 375 380
Thr Ala Gly Arg Ala Cys Glu Gln Val Gln Trp Cys Gln Leu Ser Pro
385 390 395 400
Cys Pro Pro Thr Ala Glu Cys Gln Leu Leu Pro Gln Gly Phe Glu Cys
405 410 415
Ile Ala Asn Ala Val Phe Ser Gly Leu Ser Arg Glu Ile Leu Phe Arg
420 425 430
Ser Asn Gly Asn Ile Thr Arg Glu Leu Thr Asn Ile Thr Phe Ala Phe
435 440 445
Arg Thr His Asp Thr Asn Val Met Ile Leu His Ala Glu Lys Glu Pro
450 455 460
Glu Phe Leu Asn Ile Ser Ile Gln Asp Ala Arg Leu Phe Phe Gln Leu
465 470 475 480
Arg Ser Gly Asn Ser Phe Tyr Thr Leu His Leu Met Gly Ser Gln Leu
485 490 495
Val Asn Asp Gly Thr Trp His Gln Val Thr Phe Ser Met Ile Asp Pro
500 505 510
Val Ala Gln Thr Ser Arg Trp Gln Met Glu Val Asn Asp Gln Thr Pro
515 520 525
Phe Val Ile Ser Glu Val Ala Thr Gly Ser Leu Asn Phe Leu Lys Asp
530 535 540
Asn Thr Asp Ile Tyr Val Gly Asp Gln Ser Val Asp Asn Pro Lys Gly
545 550 555 560
Leu Gln Gly Cys Leu Ser Thr Ile Glu Ile Gly Gly Ile Tyr Leu Ser
565 570 575
Tyr Phe Glu Asn Leu His Gly Phe Pro Gly Lys Pro Gln Glu Glu Gln
580 585 590
Phe Leu Lys Val Ser Thr Asn Met Val Leu Thr Gly Cys Leu Pro Ser
595 600 605
Asn Ala Cys His Ser Ser Pro Cys Leu His Gly Gly Asn Cys Glu Asp
610 615 620
Ser Tyr Ser Ser Tyr Arg Cys Ala Cys Leu Ser Gly Trp Ser Gly Thr
625 630 635 640
His Cys Glu Ile Asn Ile Asp Glu Cys Phe Ser Ser Pro Cys Ile His
645 650 655
Gly Asn Cys Ser Asp Gly Val Ala Ala Tyr His Cys Arg Cys Glu Pro
660 665 670
Gly Tyr Thr Gly Val Asn Cys Glu Val Asp Val Asp Asn Cys Lys Ser
675 680 685
His Gln Cys Ala Asn Gly Ala Thr Cys Val Pro Glu Ala His Gly Tyr
690 695 700
Ser Cys Leu Cys Phe Gly Asn Phe Thr Gly Arg Phe Cys Arg His Ser
705 710 715 720
Arg Leu Pro Ser Thr Val Cys Gly Asn Glu Lys Arg Asn Phe Thr Cys
725 730 735
Tyr Asn Gly Gly Ser Cys Ser Met Phe Gln Glu Asp Trp Gln Cys Met
740 745 750
Cys Trp Pro Gly Phe Thr Gly Glu Trp Cys Glu Glu Asp Ile Asn Glu
755 760 765
Cys Ala Ser Asp Pro Cys Ile Asn Gly Gly Leu Cys Arg Asp Leu Val
770 775 780
Asn Arg Phe Leu Cys Ile Cys Asp Val Ala Phe Ala Gly Glu Arg Cys
785 790 795 800
Glu Leu Asp Leu Ala Asp Asp Arg Leu Leu Gly Ile Phe Thr Ala Val
805 810 815
Gly Ser Gly Thr Leu Ala Leu Phe Phe Ile Leu Leu Leu Ala Gly Val
820 825 830
Ala Ser Leu Ile Ala Ser Asn Lys Arg Ala Thr Gln Gly Thr Tyr Ser
835 840 845
Pro Ser Gly Gln Glu Lys Ala Gly Pro Arg Val Glu Met Trp Ile Arg
850 855 860
Met Pro Pro Pro Ala Leu Glu Arg Leu Ile
865 870
<210> 77
<211> 5277
<212> DNA
<213> 小鼠
<400> 77
gccccactga tccagcttga agaggagtga ggcaaagctg aaccctccca ctctccttga 60
caagtgcaag cccacacttt tggaaaaaag cacaaagacg tcagaaacgg ttcctgtcga 120
cctactaggc tttggatggc taagtgtttt tgctttgtat ggaaatatgt ttggacacaa 180
gacacaaggt tttcacattt taatggcagt gctcatagga attcactgtg aagaagacgt 240
tgatgaatgt ttactgcacc cttgcctaaa tggtggtact tgtgagaacc tgcctgggaa 300
ttatgcctgt cactgtccct ttgatgacac ttctaggaca ttttatggag gagaaaactg 360
ctcagaaatt ctcctgggct gcactcatca ccagtgtctg aacaatggaa aatgtatccc 420
tcatttccaa aatggccagc atggattcac ttgccagtgt ctttctggct atgcggggcc 480
cctgtgtgaa actgtcacca cactttcatt tgggagcaat ggcttcctat gggtcacaag 540
tggctcccat acaggcatag ggccagaatg taacatatcc ttgaggtttc acactgttca 600
accaaacgca cttctcctca tccgaggcaa caaggacgtg tctatgaagc tggagttgct 660
gaatggttgt gttcacttat caattgaagt ctggaatcag ttaaaggtgc tcctgtctat 720
ttctcacaac accagtgatg gagaatggca tttcgtggag gtaacaatcg cagaaactct 780
aacccttgcc ctagttggcg gctcctgcaa ggagaagtgc accaccaagt cttctgttcc 840
agttgagaat catcaatcaa tatgtgcttt gcaggactct tttttgggtg gcttaccaat 900
ggggacagcc aacaacagtg tgtctgtgct taacatctat aatgtgccgt ccacaccttc 960
ctttgtaggc tgtctccaag acattagatt tgatttgaat cacattactc tggagaacgt 1020
ttcatctggc ctgtcatcaa atgttaaagc aggctgcctg ggaaaggact ggtgtgaaag 1080
tcaaccctgt caaaacagag gacgctgcat caacttgtgg cagggttatc agtgtgaatg 1140
tgacaggccc tatacaggct ccaactgcct gaaagagtat gtagcgggaa gatttggcca 1200
agatgactcc acaggatatg cggcctttag tgttaatgat aattatggac agaacttcag 1260
tctttcaatg tttgtccgaa cacgtcaacc cctgggctta cttctggctt tggaaaatag 1320
tacttaccag tatgtcagtg tctggctaga gcacggcagc ctagcactgc agactccagg 1380
ctctcccaag ttcatggtaa acttttttct cagtgatgga aatgttcact taatatcttt 1440
gagaatcaaa ccaaatgaaa ttgaactgta tcagtcttca caaaacctag gattcatttc 1500
tgttcctaca tggacaattc gaagaggaga cgtcatcttc attggtggct tacctgacag 1560
agagaagact gaagtttatg gtggcttctt caaaggctgt gttcaagatg tcagattaaa 1620
cagccagact ctggaattct ttcccaattc aacaaacaat gcatacgatg acccaattct 1680
tgtcaatgtg actcaaggct gtcccggaga caacacatgt aagctttaaa catgcgggat 1740
gattatctct ttatgagctt ttgaagaatg agaagaaaca tcactggcat gacttgaaca 1800
tctatgagcc ccaataatta cttccaaccc ctgtcataat ggaggtgtct gccactccct 1860
gtgggatgac ttctcctgct cctgccctac aaacacagcg gggagagcct gcgagcaagt 1920
tcagtggtgt caactcagcc catgtcctcc cactgcagag tgccagctgc tccctcaagg 1980
gtttgaatgt atcgcaaacg ctgttttcag cggattaagc agagaaatac tcttcagaag 2040
caatgggaac attaccagag aactcaccaa tatcacattt gctttcagaa cacatgatac 2100
aaatgtgatg atattgcatg cagaaaaaga accagagttt cttaatatta gcattcaaga 2160
tgccagatta ttctttcaat tgcgaagtgg caacagcttt tatacgctgc acctgatggg 2220
ttcccaattg gtgaatgatg gcacatggca ccaagtgact ttctccatga tagacccagt 2280
ggcccagacc tcccggtggc aaatggaggt gaacgaccag acaccctttg tgataagtga 2340
agttgctact ggaagcctga actttttgaa ggacaataca gacatctatg tgggtgacca 2400
atctgttgac aatccgaaag gcctgcaggg ctgtctgagc acaatagaga ttggaggcat 2460
atatctttct tactttgaaa atctacatgg tttccctggt aagcctcagg aagagcaatt 2520
tctcaaagtt tctacaaata tggtacttac tggctgtttg ccatcaaatg cctgccactc 2580
cagcccctgt ttgcatggag gaaactgtga agacagctac agttcttatc ggtgtgcctg 2640
tctctcggga tggtcaggga cacactgtga aatcaacatt gatgagtgct tttctagccc 2700
ctgtatccat ggcaactgct ctgatggagt tgcagcctac cactgcaggt gtgagcctgg 2760
atacaccggt gtgaactgtg aggtggatgt agacaattgc aagagtcatc agtgtgcaaa 2820
tggggccacc tgtgttcctg aagctcatgg ctactcttgt ctctgctttg gaaattttac 2880
cgggagattt tgcagacaca gcagattacc ctcaacagtc tgtgggaatg agaagagaaa 2940
cttcacttgc tacaatggag gcagctgctc catgttccag gaggactggc aatgtatgtg 3000
ctggccaggt ttcactggag agtggtgtga agaggacatc aacgagtgtg cctccgatcc 3060
ctgcatcaat ggaggactgt gcagggactt ggtcaacagg ttcctatgca tctgtgatgt 3120
ggccttcgct ggcgagcgct gtgagctgga cgtaagcggc ctttcctttt atgtgtccct 3180
cttactatgg caaaacctct ttcagctcct gtcctacctc gtactgcgca tgaatgatga 3240
gccagttgta gagtgggggg cacaggaaaa ttattaatgt gcatgggagc attcacaagt 3300
gtaaaacatt gacttgcaag aaacatcttg tctcagtgta ggtttctagg aaagacaaag 3360
ggaacattag ggaatagact ccatctagag cactggttct cagtcttcct aatgctgcaa 3420
ccctttagta cagctcttcc tgttgtagtg atcgcagcca taacattatt ttcattgcca 3480
cttcataact gtaatccttc tactgctgtg aatcacaatg gaaatattta tgttttctga 3540
tggtcttaag caacacctct gaaaaagtca ttgacccccc ccccaaaggg gctgtgatcc 3600
acaggttgag aaatgctcat ctggaaggta accatgcatt taagtgtacc tctagtagtt 3660
tgggtctata gaagatattc tcctattcta cctttttaga cacgccagaa gagggcatct 3720
gattccatta aagatgattg ggagccaccg tgtggttcct gagaactgta ctcgggccct 3780
ttggaagagc aatcagtgct ctttccagcc cctaagaata tttttaatac agccagaaag 3840
gtctcattac ccagtgtact gagccctaag gcactttcat cctcaatcgt tccatgttga 3900
atggttttca ttacatttgg aaaatgtttt ctctccactc tacctttaca tgttcctatt 3960
ttcctattga caatttgccc cttcactgta attctaattt ggtgtggtcc ttcttctcat 4020
aagtttatat gtgacatgaa catttaaaaa tatctatgaa tattttatag tcatgtatgt 4080
ctttctgcaa agctattcaa atgaactatg gacagttctt ttctacacga agaagagatg 4140
agtttaatcc ccagtaacat gagaaaaaga tgagtgaggg acagtgctca cagtatccct 4200
cactagcatc atttgtgatt ccatgggcca tttttttcca ccagcaaata gcagagagcc 4260
ctttccctat tcgtttctct tacacttccc cttttctgtt acaactgaac actttacatt 4320
agttactcct ttgtaggggg tttgactttt ccaccgtttt ctctggttca ctatttatgc 4380
taagtatctg tgcagggcgg gtatatcagt ccaacagagg tgtcattagt gttcattgag 4440
gaggaaatac tttgcatgaa ttcatgacat cattgaagta gcagtggcca gaaagatacc 4500
cttctgcgaa tgtgtctgtg tattcagaag ctgccctggt tagaaaacat gtgggtcact 4560
tttcctttgc atgttaccag tgctcactgg gtcatgattg ttttaagaca gagcttttgc 4620
tgtggcaatg accaaggtga atccagagat gcagatcaga caaaggacaa gacaatgtac 4680
tatctgagta aaaccctgcc ttgacttact cctcagtact tagagatttt acatagcaac 4740
ctccaccctg tggcaacccg ttcacactag cagtgatgct gagatttgcc cttccttctc 4800
atcatcttcc tcacatccaa agcattttgt gtccacactg ctgtttcaga taactgtttc 4860
taaagtggga ttgttgtagc cagaaaggta gggaaaatgt tccccaaaat atttgcattc 4920
ttaagtatgt gaagtaagta gattatagtc agagacaata tgtaaggttt caggttcact 4980
cccttctaca catatcttca actgtgtatt tgcagaatat tctgaatgtg acatactccc 5040
aacagaatat atttaaggag tatttatcca cagtattgtt ctctgtacag ttctagtgct 5100
tctattgtca ctgcaattgt caattgtttt tctgctttcc aactgtctta ttatcattta 5160
atagcatctt gctaaatgcc ctctttctat tctccttatt tctccatagt tcatgtgtgt 5220
ctgtgtgact aaggattctc ctcatttttg cagaaaaata aaatcttttc ttcttta 5277
<210> 78
<211> 520
<212> PRT
<213> 小鼠
<400> 78
Met Phe Gly His Lys Thr Gln Gly Phe His Ile Leu Met Ala Val Leu
1 5 10 15
Ile Gly Ile His Cys Glu Glu Asp Val Asp Glu Cys Leu Leu His Pro
20 25 30
Cys Leu Asn Gly Gly Thr Cys Glu Asn Leu Pro Gly Asn Tyr Ala Cys
35 40 45
His Cys Pro Phe Asp Asp Thr Ser Arg Thr Phe Tyr Gly Gly Glu Asn
50 55 60
Cys Ser Glu Ile Leu Leu Gly Cys Thr His His Gln Cys Leu Asn Asn
65 70 75 80
Gly Lys Cys Ile Pro His Phe Gln Asn Gly Gln His Gly Phe Thr Cys
85 90 95
Gln Cys Leu Ser Gly Tyr Ala Gly Pro Leu Cys Glu Thr Val Thr Thr
100 105 110
Leu Ser Phe Gly Ser Asn Gly Phe Leu Trp Val Thr Ser Gly Ser His
115 120 125
Thr Gly Ile Gly Pro Glu Cys Asn Ile Ser Leu Arg Phe His Thr Val
130 135 140
Gln Pro Asn Ala Leu Leu Leu Ile Arg Gly Asn Lys Asp Val Ser Met
145 150 155 160
Lys Leu Glu Leu Leu Asn Gly Cys Val His Leu Ser Ile Glu Val Trp
165 170 175
Asn Gln Leu Lys Val Leu Leu Ser Ile Ser His Asn Thr Ser Asp Gly
180 185 190
Glu Trp His Phe Val Glu Val Thr Ile Ala Glu Thr Leu Thr Leu Ala
195 200 205
Leu Val Gly Gly Ser Cys Lys Glu Lys Cys Thr Thr Lys Ser Ser Val
210 215 220
Pro Val Glu Asn His Gln Ser Ile Cys Ala Leu Gln Asp Ser Phe Leu
225 230 235 240
Gly Gly Leu Pro Met Gly Thr Ala Asn Asn Ser Val Ser Val Leu Asn
245 250 255
Ile Tyr Asn Val Pro Ser Thr Pro Ser Phe Val Gly Cys Leu Gln Asp
260 265 270
Ile Arg Phe Asp Leu Asn His Ile Thr Leu Glu Asn Val Ser Ser Gly
275 280 285
Leu Ser Ser Asn Val Lys Ala Gly Cys Leu Gly Lys Asp Trp Cys Glu
290 295 300
Ser Gln Pro Cys Gln Asn Arg Gly Arg Cys Ile Asn Leu Trp Gln Gly
305 310 315 320
Tyr Gln Cys Glu Cys Asp Arg Pro Tyr Thr Gly Ser Asn Cys Leu Lys
325 330 335
Glu Tyr Val Ala Gly Arg Phe Gly Gln Asp Asp Ser Thr Gly Tyr Ala
340 345 350
Ala Phe Ser Val Asn Asp Asn Tyr Gly Gln Asn Phe Ser Leu Ser Met
355 360 365
Phe Val Arg Thr Arg Gln Pro Leu Gly Leu Leu Leu Ala Leu Glu Asn
370 375 380
Ser Thr Tyr Gln Tyr Val Ser Val Trp Leu Glu His Gly Ser Leu Ala
385 390 395 400
Leu Gln Thr Pro Gly Ser Pro Lys Phe Met Val Asn Phe Phe Leu Ser
405 410 415
Asp Gly Asn Val His Leu Ile Ser Leu Arg Ile Lys Pro Asn Glu Ile
420 425 430
Glu Leu Tyr Gln Ser Ser Gln Asn Leu Gly Phe Ile Ser Val Pro Thr
435 440 445
Trp Thr Ile Arg Arg Gly Asp Val Ile Phe Ile Gly Gly Leu Pro Asp
450 455 460
Arg Glu Lys Thr Glu Val Tyr Gly Gly Phe Phe Lys Gly Cys Val Gln
465 470 475 480
Asp Val Arg Leu Asn Ser Gln Thr Leu Glu Phe Phe Pro Asn Ser Thr
485 490 495
Asn Asn Ala Tyr Asp Asp Pro Ile Leu Val Asn Val Thr Gln Gly Cys
500 505 510
Pro Gly Asp Asn Thr Cys Lys Leu
515 520
<210> 79
<211> 5530
<212> DNA
<213> 小鼠
<400> 79
agccccactg atccagcttg aagaggagtg aggcaaagct gaaccctccc actctccttg 60
acaagtgcaa gcccacactt ttggaaaaaa gcacaaagac gtcagaaacg gttcctgtcg 120
acctactagg ctttggatgg ctaagtgttt ttgctttgta tggaaatatg tttggacaca 180
agacacaagg ttttcacatt ttaatggcag tgctcatagg aattcactgt gaagaagacg 240
ttgatgaatg tttactgcac ccttgcctaa atggtggtac ttgtgagaac ctgcctggga 300
attatgcctg tcactgtccc tttgatgaca cttctaggac attttatgga ggagaaaact 360
gctcagaaat tctcctgggc tgcactcatc accagtgtct gaacaatgga aaatgtatcc 420
ctcatttcca aaatggccag catggattca cttgccagtg tctttctggc tatgcggggc 480
ccctgtgtga aactgtcacc acactttcat ttgggagcaa tggcttccta tgggtcacaa 540
gtggctccca tacaggcata gggccagaat gtaacatatc cttgaggttt cacactgttc 600
aaccaaacgc acttctcctc atccgaggca acaaggacgt gtctatgaag ctggagttgc 660
tgaatggttg tgttcactta tcaattgaag tctggaatca gttaaaggtg ctcctgtcta 720
tttctcacaa caccagtgat ggagaatggc atttcgtgga ggtaacaatc gcagaaactc 780
taacccttgc cctagttggc ggctcctgca aggagaagtg caccaccaag tcttctgttc 840
cagttgagaa tcatcaatca atatgtgctt tgcaggactc ttttttgggt ggcttaccaa 900
tggggacagc caacaacagt gtgtctgtgc ttaacatcta taatgtgccg tccacacctt 960
cctttgtagg ctgtctccaa gacattagat ttgatttgaa tcacattact ctggagaacg 1020
tttcatctgg cctgtcatca aatgttaaag caggctgcct gggaaaggac tggtgtgaaa 1080
gtcaaccctg tcaaaacaga ggacgctgca tcaacttgtg gcagggttat cagtgtgaat 1140
gtgacaggcc ctatacaggc tccaactgcc tgaaagagta tgtagcggga agatttggcc 1200
aagatgactc cacaggatat gcggccttta gtgttaatga taattatgga cagaacttca 1260
gtctttcaat gtttgtccga acacgtcaac ccctgggctt acttctggct ttggaaaata 1320
gtacttacca gtatgtcagt gtctggctag agcacggcag cctagcactg cagactccag 1380
gctctcccaa gttcatggta aacttttttc tcagtgatgg aaatgttcac ttaatatctt 1440
tgagaatcaa accaaatgaa attgaactgt atcagtcttc acaaaaccta ggattcattt 1500
ctgttcctac atggacaatt cgaagaggag acgtcatctt cattggtggc ttacctgaca 1560
gagagaagac tgaagtttat ggtggcttct tcaaaggctg tgttcaagat gtcagattaa 1620
acagccagac tctggaattc tttcccaatt caacaaacaa tgcatacgat gacccaattc 1680
ttgtcaatgt gactcaaggc tgtcccggag acaacacatg taagtccaac ccctgtcata 1740
atggaggtgt ctgccactcc ctgtgggatg acttctcctg ctcctgccct acaaacacag 1800
cggggagagc ctgcgagcaa gttcagtggt gtcaactcag cccatgtcct cccactgcag 1860
agtgccagct gctccctcaa gggtttgaat gtatcgcaaa cgctgttttc agcggattaa 1920
gcagagaaat actcttcaga agcaatggga acattaccag agaactcacc aatatcacat 1980
ttgctttcag aacacatgat acaaatgtga tgatattgca tgcagaaaaa gaaccagagt 2040
ttcttaatat tagcattcaa gatgccagat tattctttca attgcgaagt ggcaacagct 2100
tttatacgct gcacctgatg ggttcccaat tggtgaatga tggcacatgg caccaagtga 2160
ctttctccat gatagaccca gtggcccaga cctcccggtg gcaaatggag gtgaacgacc 2220
agacaccctt tgtgataagt gaagttgcta ctggaagcct gaactttttg aaggacaata 2280
cagacatcta tgtgggtgac caatctgttg acaatccgaa aggcctgcag ggctgtctga 2340
gcacaataga gattggaggc atatatcttt cttactttga aaatctacat ggtttccctg 2400
gtaagcctca ggaagagcaa tttctcaaag tttctacaaa tatggtactt actggctgtt 2460
tgccatcaaa tgcctgccac tccagcccct gtttgcatgg aggaaactgt gaagacagct 2520
acagttctta tcggtgtgcc tgtctctcgg gatggtcagg gacacactgt gaaatcaaca 2580
ttgatgagtg cttttctagc ccctgtatcc atggcaactg ctctgatgga gttgcagcct 2640
accactgcag gtgtgagcct ggatacaccg gtgtgaactg tgaggtggat gtagacaatt 2700
gcaagagtca tcagtgtgca aatggggcca cctgtgttcc tgaagctcat ggctactctt 2760
gtctctgctt tggaaatttt accgggagat tttgcaggtg tgaagaggac atcaacgagt 2820
gtgcctccga tccctgcatc aatggaggac tgtgcaggga cttggtcaac aggttcctat 2880
gcatctgtga tgtggccttc gctggcgagc gctgtgagct ggacgtaagc ggcctttcct 2940
tttatgtgtc cctcttacta tggcaaaacc tctttcagct cctgtcctac ctcgtactgc 3000
gcatgaatga tgagccagtt gtagagtggg gggcacagga aaattattaa tgtgcatggg 3060
agcattcaca agtgtaaaac attgacttgc aagaaacatc ttgtctcagt gtaggtttct 3120
aggaaagaca aagggaacat tagggaatag actccatcta gagcactggt tctcagtctt 3180
cctaatgctg caacccttta gtacagctct tcctgttgta gtgatcgcag ccataacatt 3240
attttcattg ccacttcata actgtaatcc ttctactgct gtgaatcaca atggaaatat 3300
ttatgttttc tgatggtctt aagcaacacc tctgaaaaag tcattgaccc cccccccaaa 3360
ggggctgtga tccacaggtt gagaaatgct catctggaag gtaaccatgc atttaagtgt 3420
acctctagta gtttgggtct atagaagata ttctcctatt ctaccttttt agacacgcca 3480
gaagagggca tctgattcca ttaaagatga ttgggagcca ccgtgtggtt cctgagaact 3540
gtactcgggc cctttggaag agcaatcagt gctctttcca gcccctaaga atatttttaa 3600
tacagccaga aaggtctcat tacccagtgt actgagccct aaggcacttt catcctcaat 3660
cgttccatgt tgaatggttt tcattacatt tggaaaatgt tttctctcca ctctaccttt 3720
acatgttcct attttcctat tgacaatttg ccccttcact gtaattctaa tttggtgtgg 3780
tccttcttct cataagttta tatgtgacat gaacatttaa aaatatctat gaatatttta 3840
tagtcatgta tgtctttctg caaagctatt caaatgaact atggacagtt cttttctaca 3900
cgaagaagag atgagtttaa tccccagtaa catgagaaaa agatgagtga gggacagtgc 3960
tcacagtatc cctcactagc atcatttgtg attccatggg ccattttttt ccaccagcaa 4020
atagcagaga gccctttccc tattcgtttc tcttacactt ccccttttct gttacaactg 4080
aacactttac attagttact cctttgtagg gggtttgact tttccaccgt tttctctggt 4140
tcactattta tgctaagtat ctgtgcaggg cgggtatatc agtccaacag aggtgtcatt 4200
agtgttcatt gaggaggaaa tactttgcat gaattcatga catcattgaa gtagcagtgg 4260
ccagaaagat acccttctgc gaatgtgtct gtgtattcag aagctgccct ggttagaaaa 4320
catgtgggtc acttttcctt tgcatgttac cagtgctcac tgggtcatga ttgttttaag 4380
acagagcttt tgctgtggca atgaccaagg tgaatccaga gatgcagatc agacaaagga 4440
caagacaatg tactatctga gtaaaaccct gccttgactt actcctcagt acttagagat 4500
tttacatagc aacctccacc ctgtggcaac ccgttcacac tagcagtgat gctgagattt 4560
gcccttcctt ctcatcatct tcctcacatc caaagcattt tgtgtccaca ctgctgtttc 4620
agataactgt ttctaaagtg ggattgttgt agccagaaag gtagggaaaa tgttccccaa 4680
aatatttgca ttcttaagta tgtgaagtaa gtagattata gtcagagaca atatgtaagg 4740
tttcaggttc actcccttct acacatatct tcaactgtgt atttgcagaa tattctgaat 4800
gtgacatact cccaacagaa tatatttaag gagtatttat ccacagtatt gttctctgta 4860
cagttctagt gcttctattg tcactgcaat tgtcaattgt ttttctgctt tccaactgtc 4920
ttattatcat ttaatagcat cttgctaaat gccctctttc tattctcctt atttctccat 4980
agttcatgtg tgtctgtgtg actaaggatt ctcctcattt ttgcagaaaa ataaaatctt 5040
ttcttcttta tgtcctgctt gtcattctct ggtgacacat gtctttgctt acttggactg 5100
agggttgtac agtaagtaca gaagcaggct cagtcacaca gacagagaca caccaccacc 5160
agcagcagca gcaccaccac caccaccacc accaccagaa aacagtatga gtactcatct 5220
cttgattaca tgtcatttca agtaagcacc atgacaccga gggccaggtt ccatggactt 5280
tctctgttag gcacgtgatt ctttagctga cctttgagaa cagactccaa caacctcact 5340
tatttttact gttgacttat atcatctctg acaacactgg acttcgtttg agctagtcaa 5400
gaggaaagac catgacacct aagggacaga aattcacaca ctcggttttt cataattcac 5460
acacattcct atgtatcaaa tctctgtaat agatgacatt tacttgaata aaaagtcatt 5520
tccctttgct 5530
<210> 80
<211> 960
<212> PRT
<213> 小鼠
<400> 80
Met Phe Gly His Lys Thr Gln Gly Phe His Ile Leu Met Ala Val Leu
1 5 10 15
Ile Gly Ile His Cys Glu Glu Asp Val Asp Glu Cys Leu Leu His Pro
20 25 30
Cys Leu Asn Gly Gly Thr Cys Glu Asn Leu Pro Gly Asn Tyr Ala Cys
35 40 45
His Cys Pro Phe Asp Asp Thr Ser Arg Thr Phe Tyr Gly Gly Glu Asn
50 55 60
Cys Ser Glu Ile Leu Leu Gly Cys Thr His His Gln Cys Leu Asn Asn
65 70 75 80
Gly Lys Cys Ile Pro His Phe Gln Asn Gly Gln His Gly Phe Thr Cys
85 90 95
Gln Cys Leu Ser Gly Tyr Ala Gly Pro Leu Cys Glu Thr Val Thr Thr
100 105 110
Leu Ser Phe Gly Ser Asn Gly Phe Leu Trp Val Thr Ser Gly Ser His
115 120 125
Thr Gly Ile Gly Pro Glu Cys Asn Ile Ser Leu Arg Phe His Thr Val
130 135 140
Gln Pro Asn Ala Leu Leu Leu Ile Arg Gly Asn Lys Asp Val Ser Met
145 150 155 160
Lys Leu Glu Leu Leu Asn Gly Cys Val His Leu Ser Ile Glu Val Trp
165 170 175
Asn Gln Leu Lys Val Leu Leu Ser Ile Ser His Asn Thr Ser Asp Gly
180 185 190
Glu Trp His Phe Val Glu Val Thr Ile Ala Glu Thr Leu Thr Leu Ala
195 200 205
Leu Val Gly Gly Ser Cys Lys Glu Lys Cys Thr Thr Lys Ser Ser Val
210 215 220
Pro Val Glu Asn His Gln Ser Ile Cys Ala Leu Gln Asp Ser Phe Leu
225 230 235 240
Gly Gly Leu Pro Met Gly Thr Ala Asn Asn Ser Val Ser Val Leu Asn
245 250 255
Ile Tyr Asn Val Pro Ser Thr Pro Ser Phe Val Gly Cys Leu Gln Asp
260 265 270
Ile Arg Phe Asp Leu Asn His Ile Thr Leu Glu Asn Val Ser Ser Gly
275 280 285
Leu Ser Ser Asn Val Lys Ala Gly Cys Leu Gly Lys Asp Trp Cys Glu
290 295 300
Ser Gln Pro Cys Gln Asn Arg Gly Arg Cys Ile Asn Leu Trp Gln Gly
305 310 315 320
Tyr Gln Cys Glu Cys Asp Arg Pro Tyr Thr Gly Ser Asn Cys Leu Lys
325 330 335
Glu Tyr Val Ala Gly Arg Phe Gly Gln Asp Asp Ser Thr Gly Tyr Ala
340 345 350
Ala Phe Ser Val Asn Asp Asn Tyr Gly Gln Asn Phe Ser Leu Ser Met
355 360 365
Phe Val Arg Thr Arg Gln Pro Leu Gly Leu Leu Leu Ala Leu Glu Asn
370 375 380
Ser Thr Tyr Gln Tyr Val Ser Val Trp Leu Glu His Gly Ser Leu Ala
385 390 395 400
Leu Gln Thr Pro Gly Ser Pro Lys Phe Met Val Asn Phe Phe Leu Ser
405 410 415
Asp Gly Asn Val His Leu Ile Ser Leu Arg Ile Lys Pro Asn Glu Ile
420 425 430
Glu Leu Tyr Gln Ser Ser Gln Asn Leu Gly Phe Ile Ser Val Pro Thr
435 440 445
Trp Thr Ile Arg Arg Gly Asp Val Ile Phe Ile Gly Gly Leu Pro Asp
450 455 460
Arg Glu Lys Thr Glu Val Tyr Gly Gly Phe Phe Lys Gly Cys Val Gln
465 470 475 480
Asp Val Arg Leu Asn Ser Gln Thr Leu Glu Phe Phe Pro Asn Ser Thr
485 490 495
Asn Asn Ala Tyr Asp Asp Pro Ile Leu Val Asn Val Thr Gln Gly Cys
500 505 510
Pro Gly Asp Asn Thr Cys Lys Ser Asn Pro Cys His Asn Gly Gly Val
515 520 525
Cys His Ser Leu Trp Asp Asp Phe Ser Cys Ser Cys Pro Thr Asn Thr
530 535 540
Ala Gly Arg Ala Cys Glu Gln Val Gln Trp Cys Gln Leu Ser Pro Cys
545 550 555 560
Pro Pro Thr Ala Glu Cys Gln Leu Leu Pro Gln Gly Phe Glu Cys Ile
565 570 575
Ala Asn Ala Val Phe Ser Gly Leu Ser Arg Glu Ile Leu Phe Arg Ser
580 585 590
Asn Gly Asn Ile Thr Arg Glu Leu Thr Asn Ile Thr Phe Ala Phe Arg
595 600 605
Thr His Asp Thr Asn Val Met Ile Leu His Ala Glu Lys Glu Pro Glu
610 615 620
Phe Leu Asn Ile Ser Ile Gln Asp Ala Arg Leu Phe Phe Gln Leu Arg
625 630 635 640
Ser Gly Asn Ser Phe Tyr Thr Leu His Leu Met Gly Ser Gln Leu Val
645 650 655
Asn Asp Gly Thr Trp His Gln Val Thr Phe Ser Met Ile Asp Pro Val
660 665 670
Ala Gln Thr Ser Arg Trp Gln Met Glu Val Asn Asp Gln Thr Pro Phe
675 680 685
Val Ile Ser Glu Val Ala Thr Gly Ser Leu Asn Phe Leu Lys Asp Asn
690 695 700
Thr Asp Ile Tyr Val Gly Asp Gln Ser Val Asp Asn Pro Lys Gly Leu
705 710 715 720
Gln Gly Cys Leu Ser Thr Ile Glu Ile Gly Gly Ile Tyr Leu Ser Tyr
725 730 735
Phe Glu Asn Leu His Gly Phe Pro Gly Lys Pro Gln Glu Glu Gln Phe
740 745 750
Leu Lys Val Ser Thr Asn Met Val Leu Thr Gly Cys Leu Pro Ser Asn
755 760 765
Ala Cys His Ser Ser Pro Cys Leu His Gly Gly Asn Cys Glu Asp Ser
770 775 780
Tyr Ser Ser Tyr Arg Cys Ala Cys Leu Ser Gly Trp Ser Gly Thr His
785 790 795 800
Cys Glu Ile Asn Ile Asp Glu Cys Phe Ser Ser Pro Cys Ile His Gly
805 810 815
Asn Cys Ser Asp Gly Val Ala Ala Tyr His Cys Arg Cys Glu Pro Gly
820 825 830
Tyr Thr Gly Val Asn Cys Glu Val Asp Val Asp Asn Cys Lys Ser His
835 840 845
Gln Cys Ala Asn Gly Ala Thr Cys Val Pro Glu Ala His Gly Tyr Ser
850 855 860
Cys Leu Cys Phe Gly Asn Phe Thr Gly Arg Phe Cys Arg Cys Glu Glu
865 870 875 880
Asp Ile Asn Glu Cys Ala Ser Asp Pro Cys Ile Asn Gly Gly Leu Cys
885 890 895
Arg Asp Leu Val Asn Arg Phe Leu Cys Ile Cys Asp Val Ala Phe Ala
900 905 910
Gly Glu Arg Cys Glu Leu Asp Val Ser Gly Leu Ser Phe Tyr Val Ser
915 920 925
Leu Leu Leu Trp Gln Asn Leu Phe Gln Leu Leu Ser Tyr Leu Val Leu
930 935 940
Arg Met Asn Asp Glu Pro Val Val Glu Trp Gly Ala Gln Glu Asn Tyr
945 950 955 960
<210> 81
<211> 5692
<212> DNA
<213> 小鼠
<400> 81
attaagcccc actgatccag cttgaagagg agtgaggcaa agctgaaccc tcccactctc 60
cttgacaagt gcaagcccac acttttggaa aaaagcacaa agacgtcaga aacggttcct 120
gtcgacctac taggctttgg atggctaagt gtttttgctt tgtatggaaa tatgtttgga 180
cacaagacac aaggttttca cattttaatg gcagtgctca taggaattca ctgtgaagaa 240
gacgttgatg aatgtttact gcacccttgc ctaaatggtg gtacttgtga gaacctgcct 300
gggaattatg cctgtcactg tccctttgat gacacttcta ggacatttta tggaggagaa 360
aactgctcag aaattctcct gggctgcact catcaccagt gtctgaacaa tggaaaatgt 420
atccctcatt tccaaaatgg ccagcatgga ttcacttgcc agtgtctttc tggctatgcg 480
gggcccctgt gtgaaactgt caccacactt tcatttggga gcaatggctt cctatgggtc 540
acaagtggct cccatacagg catagggcca gaatgtaaca tatccttgag gtttcacact 600
gttcaaccaa acgcacttct cctcatccga ggcaacaagg acgtgtctat gaagctggag 660
ttgctgaatg gttgtgttca cttatcaatt gaagtctgga atcagttaaa ggtgctcctg 720
tctatttctc acaacaccag tgatggagaa tggcatttcg tggaggtaac aatcgcagaa 780
actctaaccc ttgccctagt tggcggctcc tgcaaggaga agtgcaccac caagtcttct 840
gttccagttg agaatcatca atcaatatgt gctttgcagg actctttttt gggtggctta 900
ccaatgggga cagccaacaa cagtgtgtct gtgcttaaca tctataatgt gccgtccaca 960
ccttcctttg taggctgtct ccaagacatt agatttgatt tgaatcacat tactctggag 1020
aacgtttcat ctggcctgtc atcaaatgtt aaagcaggct gcctgggaaa ggactggtgt 1080
gaaagtcaac cctgtcaaaa cagaggacgc tgcatcaact tgtggcaggg ttatcagtgt 1140
gaatgtgaca ggccctatac aggctccaac tgcctgaaag agtatgtagc gggaagattt 1200
ggccaagatg actccacagg atatgcggcc tttagtgtta atgataatta tggacagaac 1260
ttcagtcttt caatgtttgt ccgaacacgt caacccctgg gcttacttct ggctttggaa 1320
aatagtactt accagtatgt cagtgtctgg ctagagcacg gcagcctagc actgcagact 1380
ccaggctctc ccaagttcat ggtaaacttt tttctcagtg atggaaatgt tcacttaata 1440
tctttgagaa tcaaaccaaa tgaaattgaa ctgtatcagt cttcacaaaa cctaggattc 1500
atttctgttc ctacatggac aattcgaaga ggagacgtca tcttcattgg tggcttacct 1560
gacagagaga agactgaagt ttatggtggc ttcttcaaag gctgtgttca agatgtcaga 1620
ttaaacagcc agactctgga attctttccc aattcaacaa acaatgcata cgatgaccca 1680
attcttgtca atgtgactca aggctgtccc ggagacaaca catgtaagtc caacccctgt 1740
cataatggag gtgtctgcca ctccctgtgg gatgacttct cctgctcctg ccctacaaac 1800
acagcgggga gagcctgcga gcaagttcag tggtgtcaac tcagcccatg tcctcccact 1860
gcagagtgcc agctgctccc tcaagggttt gaatgtaggt agcattcaaa gctgtcatcc 1920
atccaggtat cgcaaacgct gttttcagcg gattaagcag agaaatactc ttcagaagca 1980
atgggaacat taccagagaa ctcaccaata tcacatttgc tttcagaaca catgatacaa 2040
atgtgatgat attgcatgca gaaaaagaac cagagtttct taatattagc attcaagatg 2100
ccagattatt ctttcaattg cgaagtggca acagctttta tacgctgcac ctgatgggtt 2160
cccaattggt gaatgatggc acatggcacc aagtgacttt ctccatgata gacccagtgg 2220
cccagacctc ccggtggcaa atggaggtga acgaccagac accctttgtg ataagtgaag 2280
ttgctactgg aagcctgaac tttttgaagg acaatacaga catctatgtg ggtgaccaat 2340
ctgttgacaa tccgaaaggc ctgcagggct gtctgagcac aatagagatt ggaggcatat 2400
atctttctta ctttgaaaat ctacatggtt tccctggtaa gcctcaggaa gagcaatttc 2460
tcaaagtttc tacaaatatg gtacttactg gctgtttgcc atcaaatgcc tgccactcca 2520
gcccctgttt gcatggagga aactgtgaag acagctacag ttcttatcgg tgtgcctgtc 2580
tctcgggatg gtcagggaca cactgtgaaa tcaacattga tgagtgcttt tctagcccct 2640
gtatccatgg caactgctct gatggagttg cagcctacca ctgcaggtgt gagcctggat 2700
acaccggtgt gaactgtgag gtggatgtag acaattgcaa gagtcatcag tgtgcaaatg 2760
gggccacctg tgttcctgaa gctcatggct actcttgtct ctgctttgga aattttaccg 2820
ggagattttg cagacacagc agattaccct caacagtctg tgggaatgag aagagaaact 2880
tcacttgcta caatggaggc agctgctcca tgttccagga ggactggcaa tgtatgtgct 2940
ggccaggttt cactggagag tggtgtgaag aggacatcaa cgagtgtgcc tccgatccct 3000
gcatcaatgg aggactgtgc agggacttgg tcaacaggtt cctatgcatc tgtgatgtgg 3060
ccttcgctgg cgagcgctgt gagctggacg taagcggcct ttccttttat gtgtccctct 3120
tactatggca aaacctcttt cagctcctgt cctacctcgt actgcgcatg aatgatgagc 3180
cagttgtaga gtggggggca caggaaaatt attaatgtgc atgggagcat tcacaagtgt 3240
aaaacattga cttgcaagaa acatcttgtc tcagtgtagg tttctaggaa agacaaaggg 3300
aacattaggg aatagactcc atctagagca ctggttctca gtcttcctaa tgctgcaacc 3360
ctttagtaca gctcttcctg ttgtagtgat cgcagccata acattatttt cattgccact 3420
tcataactgt aatccttcta ctgctgtgaa tcacaatgga aatatttatg ttttctgatg 3480
gtcttaagca acacctctga aaaagtcatt gacccccccc ccaaaggggc tgtgatccac 3540
aggttgagaa atgctcatct ggaaggtaac catgcattta agtgtacctc tagtagtttg 3600
ggtctataga agatattctc ctattctacc tttttagaca cgccagaaga gggcatctga 3660
ttccattaaa gatgattggg agccaccgtg tggttcctga gaactgtact cgggcccttt 3720
ggaagagcaa tcagtgctct ttccagcccc taagaatatt tttaatacag ccagaaaggt 3780
ctcattaccc agtgtactga gccctaaggc actttcatcc tcaatcgttc catgttgaat 3840
ggttttcatt acatttggaa aatgttttct ctccactcta cctttacatg ttcctatttt 3900
cctattgaca atttgcccct tcactgtaat tctaatttgg tgtggtcctt cttctcataa 3960
gtttatatgt gacatgaaca tttaaaaata tctatgaata ttttatagtc atgtatgtct 4020
ttctgcaaag ctattcaaat gaactatgga cagttctttt ctacacgaag aagagatgag 4080
tttaatcccc agtaacatga gaaaaagatg agtgagggac agtgctcaca gtatccctca 4140
ctagcatcat ttgtgattcc atgggccatt tttttccacc agcaaatagc agagagccct 4200
ttccctattc gtttctctta cacttcccct tttctgttac aactgaacac tttacattag 4260
ttactccttt gtagggggtt tgacttttcc accgttttct ctggttcact atttatgcta 4320
agtatctgtg cagggcgggt atatcagtcc aacagaggtg tcattagtgt tcattgagga 4380
ggaaatactt tgcatgaatt catgacatca ttgaagtagc agtggccaga aagataccct 4440
tctgcgaatg tgtctgtgta ttcagaagct gccctggtta gaaaacatgt gggtcacttt 4500
tcctttgcat gttaccagtg ctcactgggt catgattgtt ttaagacaga gcttttgctg 4560
tggcaatgac caaggtgaat ccagagatgc agatcagaca aaggacaaga caatgtacta 4620
tctgagtaaa accctgcctt gacttactcc tcagtactta gagattttac atagcaacct 4680
ccaccctgtg gcaacccgtt cacactagca gtgatgctga gatttgccct tccttctcat 4740
catcttcctc acatccaaag cattttgtgt ccacactgct gtttcagata actgtttcta 4800
aagtgggatt gttgtagcca gaaaggtagg gaaaatgttc cccaaaatat ttgcattctt 4860
aagtatgtga agtaagtaga ttatagtcag agacaatatg taaggtttca ggttcactcc 4920
cttctacaca tatcttcaac tgtgtatttg cagaatattc tgaatgtgac atactcccaa 4980
cagaatatat ttaaggagta tttatccaca gtattgttct ctgtacagtt ctagtgcttc 5040
tattgtcact gcaattgtca attgtttttc tgctttccaa ctgtcttatt atcatttaat 5100
agcatcttgc taaatgccct ctttctattc tccttatttc tccatagttc atgtgtgtct 5160
gtgtgactaa ggattctcct catttttgca gaaaaataaa atcttttctt ctttatgtcc 5220
tgcttgtcat tctctggtga cacatgtctt tgcttacttg gactgagggt tgtacagtaa 5280
gtacagaagc aggctcagtc acacagacag agacacacca ccaccagcag cagcagcacc 5340
accaccacca ccaccaccac cagaaaacag tatgagtact catctcttga ttacatgtca 5400
tttcaagtaa gcaccatgac accgagggcc aggttccatg gactttctct gttaggcacg 5460
tgattcttta gctgaccttt gagaacagac tccaacaacc tcacttattt ttactgttga 5520
cttatatcat ctctgacaac actggacttc gtttgagcta gtcaagagga aagaccatga 5580
cacctaaggg acagaaattc acacactcgg tttttcataa ttcacacaca ttcctatgta 5640
tcaaatctct gtaatagatg acatttactt gaataaaaag tcatttccct tt 5692
<210> 82
<211> 576
<212> PRT
<213> 小鼠
<400> 82
Met Phe Gly His Lys Thr Gln Gly Phe His Ile Leu Met Ala Val Leu
1 5 10 15
Ile Gly Ile His Cys Glu Glu Asp Val Asp Glu Cys Leu Leu His Pro
20 25 30
Cys Leu Asn Gly Gly Thr Cys Glu Asn Leu Pro Gly Asn Tyr Ala Cys
35 40 45
His Cys Pro Phe Asp Asp Thr Ser Arg Thr Phe Tyr Gly Gly Glu Asn
50 55 60
Cys Ser Glu Ile Leu Leu Gly Cys Thr His His Gln Cys Leu Asn Asn
65 70 75 80
Gly Lys Cys Ile Pro His Phe Gln Asn Gly Gln His Gly Phe Thr Cys
85 90 95
Gln Cys Leu Ser Gly Tyr Ala Gly Pro Leu Cys Glu Thr Val Thr Thr
100 105 110
Leu Ser Phe Gly Ser Asn Gly Phe Leu Trp Val Thr Ser Gly Ser His
115 120 125
Thr Gly Ile Gly Pro Glu Cys Asn Ile Ser Leu Arg Phe His Thr Val
130 135 140
Gln Pro Asn Ala Leu Leu Leu Ile Arg Gly Asn Lys Asp Val Ser Met
145 150 155 160
Lys Leu Glu Leu Leu Asn Gly Cys Val His Leu Ser Ile Glu Val Trp
165 170 175
Asn Gln Leu Lys Val Leu Leu Ser Ile Ser His Asn Thr Ser Asp Gly
180 185 190
Glu Trp His Phe Val Glu Val Thr Ile Ala Glu Thr Leu Thr Leu Ala
195 200 205
Leu Val Gly Gly Ser Cys Lys Glu Lys Cys Thr Thr Lys Ser Ser Val
210 215 220
Pro Val Glu Asn His Gln Ser Ile Cys Ala Leu Gln Asp Ser Phe Leu
225 230 235 240
Gly Gly Leu Pro Met Gly Thr Ala Asn Asn Ser Val Ser Val Leu Asn
245 250 255
Ile Tyr Asn Val Pro Ser Thr Pro Ser Phe Val Gly Cys Leu Gln Asp
260 265 270
Ile Arg Phe Asp Leu Asn His Ile Thr Leu Glu Asn Val Ser Ser Gly
275 280 285
Leu Ser Ser Asn Val Lys Ala Gly Cys Leu Gly Lys Asp Trp Cys Glu
290 295 300
Ser Gln Pro Cys Gln Asn Arg Gly Arg Cys Ile Asn Leu Trp Gln Gly
305 310 315 320
Tyr Gln Cys Glu Cys Asp Arg Pro Tyr Thr Gly Ser Asn Cys Leu Lys
325 330 335
Glu Tyr Val Ala Gly Arg Phe Gly Gln Asp Asp Ser Thr Gly Tyr Ala
340 345 350
Ala Phe Ser Val Asn Asp Asn Tyr Gly Gln Asn Phe Ser Leu Ser Met
355 360 365
Phe Val Arg Thr Arg Gln Pro Leu Gly Leu Leu Leu Ala Leu Glu Asn
370 375 380
Ser Thr Tyr Gln Tyr Val Ser Val Trp Leu Glu His Gly Ser Leu Ala
385 390 395 400
Leu Gln Thr Pro Gly Ser Pro Lys Phe Met Val Asn Phe Phe Leu Ser
405 410 415
Asp Gly Asn Val His Leu Ile Ser Leu Arg Ile Lys Pro Asn Glu Ile
420 425 430
Glu Leu Tyr Gln Ser Ser Gln Asn Leu Gly Phe Ile Ser Val Pro Thr
435 440 445
Trp Thr Ile Arg Arg Gly Asp Val Ile Phe Ile Gly Gly Leu Pro Asp
450 455 460
Arg Glu Lys Thr Glu Val Tyr Gly Gly Phe Phe Lys Gly Cys Val Gln
465 470 475 480
Asp Val Arg Leu Asn Ser Gln Thr Leu Glu Phe Phe Pro Asn Ser Thr
485 490 495
Asn Asn Ala Tyr Asp Asp Pro Ile Leu Val Asn Val Thr Gln Gly Cys
500 505 510
Pro Gly Asp Asn Thr Cys Lys Ser Asn Pro Cys His Asn Gly Gly Val
515 520 525
Cys His Ser Leu Trp Asp Asp Phe Ser Cys Ser Cys Pro Thr Asn Thr
530 535 540
Ala Gly Arg Ala Cys Glu Gln Val Gln Trp Cys Gln Leu Ser Pro Cys
545 550 555 560
Pro Pro Thr Ala Glu Cys Gln Leu Leu Pro Gln Gly Phe Glu Cys Arg
565 570 575
<210> 83
<211> 5801
<212> DNA
<213> 小鼠
<400> 83
tgttcacgga agcctgaggg ggacacgaat ccaatccagg ctggaaaaat ctgctccagg 60
attgactggt taccgtcttc ctgtgcctgt aaggtgctgt gaaagagaag tgctttctga 120
ttctctgtct gtggaggagc cctgggaggg gtgggacaga gatggcatcc tggctctctg 180
aggcacctgc tcttctctga accacacagg agtcaagagc caaacaggga tagcttcagc 240
agcacttcag agggtgttct ctaagtaaga acatgaagct caagagaact gcctaccttc 300
tcttcctgta cctcagctcc tcactgctca tctgcataaa gaattcattt tgcaataaaa 360
acaataccag gtgcctttca ggtccttgcc aaaacaattc tacgtgcaag cattttccac 420
aagacaacaa ttgttgctta gacacagcca ataatttgga caaagactgt gaagatctga 480
aagacccttg cttctcgagt ccctgccaag gaattgccac ttgtgtgaaa atcccagggg 540
aagggaactt cctgtgtcag tgtcctcctg ggtacagcgg gctgaactgt gaaactgcca 600
ccaattcctg tggagggaac ctctgccaac atggaggcac ctgccgtaaa gaccctgagc 660
accctgtctg tatctgccct cctggatatg ctggaaggtt ctgtgagact gatcacaatg 720
agtgtgcttc tagcccttgc cacaatgggg ctatgtgcca ggatggaatc aatggctact 780
cctgcttctg tgtgcctgga taccaaggca ggcattgtga cttggaagtg gatgaatgtg 840
tttctgatcc ctgcaagaat gaggctgtgt gcctcaatga gataggaaga tacacttgtg 900
tctgccctca agagttttct ggcgtgaact gtgagttgga aattgatgaa tgcagatccc 960
agccttgtct ccacggtgcc acatgtcagg acgctccagg gggctactcc tgtgactgtg 1020
cacctggatt ccttggagag cactgtgaac tcagcgttaa tgaatgtgaa agtcagccgt 1080
gtctccatgg aggtctatgt gtggatggaa gaaacagtta ccactgtgac tgcacaggta 1140
gtggattcac agggatgcac tgtgagtcct tgattcctct ttgttggtca aagccttgtc 1200
acaacgacgc gacatgtgaa gatactgttg acagctatat ttgtcactgc cggcctggat 1260
acacaggtgc cctgtgtgag acagacataa atgaatgcag tagcaacccc tgccaatttt 1320
ggggggaatg tgtcgagctg tcctcagagg gtctatatgg aaacactgct ggcctgcctt 1380
cctccttcag ctatgttgga gcctcgggct atgtgtgtat ctgtcagcct ggattcacag 1440
gaattcactg tgaagaagac gttgatgaat gtttactgca cccttgccta aatggtggta 1500
cttgtgagaa cctgcctggg aattatgcct gtcactgtcc ctttgatgac acttctagga 1560
cattttatgg aggagaaaac tgctcagaaa ttctcctggg ctgcactcat caccagtgtc 1620
tgaacaatgg aaaatgtatc cctcatttcc aaaatggcca gcatggattc acttgccagt 1680
gtctttctgg ctatgcgggg cccctgtgtg aaactgtcac cacactttca tttgggagca 1740
atggcttcct atgggtcaca agtggctccc atacaggcat agggccagaa tgtaacatat 1800
ccttgaggtt tcacactgtt caaccaaacg cacttctcct catccgaggc aacaaggacg 1860
tgtctatgaa gctggagttg ctgaatggtt gtgttcactt atcaattgaa gtctggaatc 1920
agttaaaggt gctcctgtct atttctcaca acaccagtga tggagaatgg catttcgtgg 1980
aggtaacaat cgcagaaact ctaacccttg ccctagttgg cggctcctgc aaggagaagt 2040
gcaccaccaa gtcttctgtt ccagttgaga atcatcaatc aatatgtgct ttgcaggact 2100
cttttttggg tggcttacca atggggacag ccaacaacag tgtgtctgtg cttaacatct 2160
ataatgtgcc gtccacacct tcctttgtag gctgtctcca agacattaga tttgatttga 2220
atcacattac tctggagaac gtttcatctg gcctgtcatc aaatgttaaa gcaggctgcc 2280
tgggaaagga ctggtgtgaa agtcaaccct gtcaaaacag aggacgctgc atcaacttgt 2340
ggcagggtta tcagtgtgaa tgtgacaggc cctatacagg ctccaactgc ctgaaaggtg 2400
agaggagtgg ggtgccccag agtgctgtgc ctctgagcag agccatctct aatcacccag 2460
ggtgccgtcc cctgttagga aacataagga cccctcagga cttatgctgg tatttgttca 2520
ctaatgagat aaaatggcat agtcatgata tgtattaatt atgagtgggt ttcataggat 2580
agctgagctt ttttgggctg aaaagtaaaa ttaataataa taacaataag caaataactc 2640
caattaatgt ggtgttttat ctagttagca aaatgctctt agcaatttgc cattcattgt 2700
gtatcagaaa tatatagaaa actttagttc tttgtacaag atgtcatctt ttagagaaag 2760
gggagttttg gacagaaaaa ctagttactg ccacgtacta ataccacacc ttgtgcttgc 2820
tagagtctca gtgaataaac cctttgctga tctctctgtg taactcatac ttccgtaaga 2880
atcgtggtta agattagcat gttgacaagc catcagttct agtcaagact gtctcctaaa 2940
aggccttgtt ttctaaagag gagagatgtc ttcagtcgga aaaagcaaga agacatgaac 3000
tgtattatca ggaaaacttg gtagttgtca cgcacagatc cgtgattcct ctagtgaatc 3060
agtttgaagt ggatttccaa tccctcactt ttgacatcac tctgaaggct gccatcaata 3120
gcgatcaata catacctgct cacttttatt attattatca tgtattgaga gggctgaaag 3180
ggaactctaa cagactgctt tgaagttcag ctgcaattta ctctagcatt ttagaatgag 3240
tccaagaaga acaacatatg gcaaataggc tacgctgttc cgtatgaagg aaaattaaaa 3300
ccagccgtag cctatactct actccatgtt caatggctaa gaattattag aaactattcg 3360
caggttttcc cctaaccaca atattcatta caatcatgga cctgcttgac aatgaggcat 3420
ggcatctgct gctccgcgca atattttaaa tggcgtggca agttgttttg tgattatttt 3480
taaaggtgaa attatgccga ggcaatggtt cacgttttga agaaaaatct aattgaccca 3540
aagcaatatt tttactacat atacaaaata acaaacagat gcggactaat tttgactggc 3600
ttccagatgc ggtgaccctt gaggttagca ctgacctggg aatgctgact gtcctaggaa 3660
atagattcga gagatgccaa gccagcaggt tctggttttc tttacatttt tttttccaac 3720
ttggaaaata atgaactttt gaaacaaaat tcctgatttg gttacacttt ccatattccc 3780
ccaaatagtg tgattacacc cctccactca caccgagtgt aactatatcc cctaccctta 3840
tacaaagtgt gattaaatct tctattttca cagtttgaaa ctgtttagct caacatttga 3900
tatcaaatga ttatagggca ggaatttcat aaaacccttc acttctgaaa atttaggagg 3960
agaattttaa aagaaagtta tatttttcat gtgaccctga gatcataaag ttaaagtatt 4020
ctttattgct gagatccata aggaaatatt ttctgtattt tattccttaa acacacacac 4080
acacacttaa gactccaaat gagactctat atacatatag agccattcta tatgcatatt 4140
caggatgagg cacactaaaa atcaagaggg gaagccatca aagtaacaat tttttaaaga 4200
tgtattttat tattctatgt gtgtgggtct gagtgtatgc ttctgcacca ggtgagtgga 4260
gattcccctg gaacaggagt taatgacagt tttgagctgc ctgatgtggg tattgggatc 4320
aaaccttggt cctctacaag gacagctcat acttttaacc actgagtcac ctctccagtt 4380
ctcaaacaat gattttggaa caatgcttgc cagtgttaaa cccaatgaaa gaagaaggca 4440
tgttgaataa agggtggagt tatctgaatg atacaaaatg tagatagaca ttgccaatat 4500
cttgaaactg atctcaagtc atttatgccc cccataaggt ttctgtaaca acctgaactg 4560
cctgcagtga taacattgta tgtcttgcat tatgtgttag aagaaggtct tctgggatat 4620
tggtctaaag cagttgttct caaccttcct aatgctgtga ccctttaata tagctccttg 4680
tgttttgctg acctcccaac catacagtta ttttgttgct acttcacaac tgtaactttt 4740
gctacttttg tgaattataa tataaatgtc tgtgttttcc aatggtctta gacaagccct 4800
gtgacagccc tgtgtcattc atctccaaag gcttacggcc cacaggtcct aagagaacat 4860
gtaacgtacc tctttctatg ttcggaaagt ctctaattta aaaaaaaaaa caatttatat 4920
atgcttgtct tcctttgtac gcccagactt ttagaatgct attatattag agtcagtgat 4980
agttaggttt gacagagcct catcagcagc tggatttctt atggaaccct ctgctttgaa 5040
cccacttcag gaatcgagaa gtcactatcc catctggccc caaattttga aacaattatt 5100
tctgatgacg atttaaccca gcttcccttt tcccacacag ttaccactgc ggatattctc 5160
acttagggct ttaacatccc ctcttgaaaa ttcctaaata tttgaagaaa aatattccat 5220
gcatagcatc cactcccagc atcctacaca cattccttac ctctagtatc tctggaaggc 5280
acgtcccagt gggacatcat tagctacctt acatgctcct ttgccataca tttgcctctt 5340
tctaacaggt ggtatctaaa tgtgcttgat gatgcactga catggaacca caacttccct 5400
ctttctatat aataggctct catttatcat gttagcacta catttaattt ttgggagagt 5460
ttacacactg tcttttgtca gtcattgtca ttgtgaagct agagagtcct cttctattgt 5520
atactgataa gtcacattta atatcaatgc ctcctattaa cctctcacta aacttcacct 5580
tatagtccat cagcattaaa atctctcaaa ttaaattttt ttctccatac atctttagaa 5640
catatccact acctgtatta gtatcaaatc ttccatgtgt agagttgggt ccttcctatg 5700
tggcttaccg tgtttctaaa atcaagtaac acatcacaca ctctgactac ctgcttgtga 5760
tttctgaaga ataggcttac tggagagtca agtttctaag g 5801
<210> 84
<211> 761
<212> PRT
<213> 小鼠
<400> 84
Met Lys Leu Lys Arg Thr Ala Tyr Leu Leu Phe Leu Tyr Leu Ser Ser
1 5 10 15
Ser Leu Leu Ile Cys Ile Lys Asn Ser Phe Cys Asn Lys Asn Asn Thr
20 25 30
Arg Cys Leu Ser Gly Pro Cys Gln Asn Asn Ser Thr Cys Lys His Phe
35 40 45
Pro Gln Asp Asn Asn Cys Cys Leu Asp Thr Ala Asn Asn Leu Asp Lys
50 55 60
Asp Cys Glu Asp Leu Lys Asp Pro Cys Phe Ser Ser Pro Cys Gln Gly
65 70 75 80
Ile Ala Thr Cys Val Lys Ile Pro Gly Glu Gly Asn Phe Leu Cys Gln
85 90 95
Cys Pro Pro Gly Tyr Ser Gly Leu Asn Cys Glu Thr Ala Thr Asn Ser
100 105 110
Cys Gly Gly Asn Leu Cys Gln His Gly Gly Thr Cys Arg Lys Asp Pro
115 120 125
Glu His Pro Val Cys Ile Cys Pro Pro Gly Tyr Ala Gly Arg Phe Cys
130 135 140
Glu Thr Asp His Asn Glu Cys Ala Ser Ser Pro Cys His Asn Gly Ala
145 150 155 160
Met Cys Gln Asp Gly Ile Asn Gly Tyr Ser Cys Phe Cys Val Pro Gly
165 170 175
Tyr Gln Gly Arg His Cys Asp Leu Glu Val Asp Glu Cys Val Ser Asp
180 185 190
Pro Cys Lys Asn Glu Ala Val Cys Leu Asn Glu Ile Gly Arg Tyr Thr
195 200 205
Cys Val Cys Pro Gln Glu Phe Ser Gly Val Asn Cys Glu Leu Glu Ile
210 215 220
Asp Glu Cys Arg Ser Gln Pro Cys Leu His Gly Ala Thr Cys Gln Asp
225 230 235 240
Ala Pro Gly Gly Tyr Ser Cys Asp Cys Ala Pro Gly Phe Leu Gly Glu
245 250 255
His Cys Glu Leu Ser Val Asn Glu Cys Glu Ser Gln Pro Cys Leu His
260 265 270
Gly Gly Leu Cys Val Asp Gly Arg Asn Ser Tyr His Cys Asp Cys Thr
275 280 285
Gly Ser Gly Phe Thr Gly Met His Cys Glu Ser Leu Ile Pro Leu Cys
290 295 300
Trp Ser Lys Pro Cys His Asn Asp Ala Thr Cys Glu Asp Thr Val Asp
305 310 315 320
Ser Tyr Ile Cys His Cys Arg Pro Gly Tyr Thr Gly Ala Leu Cys Glu
325 330 335
Thr Asp Ile Asn Glu Cys Ser Ser Asn Pro Cys Gln Phe Trp Gly Glu
340 345 350
Cys Val Glu Leu Ser Ser Glu Gly Leu Tyr Gly Asn Thr Ala Gly Leu
355 360 365
Pro Ser Ser Phe Ser Tyr Val Gly Ala Ser Gly Tyr Val Cys Ile Cys
370 375 380
Gln Pro Gly Phe Thr Gly Ile His Cys Glu Glu Asp Val Asp Glu Cys
385 390 395 400
Leu Leu His Pro Cys Leu Asn Gly Gly Thr Cys Glu Asn Leu Pro Gly
405 410 415
Asn Tyr Ala Cys His Cys Pro Phe Asp Asp Thr Ser Arg Thr Phe Tyr
420 425 430
Gly Gly Glu Asn Cys Ser Glu Ile Leu Leu Gly Cys Thr His His Gln
435 440 445
Cys Leu Asn Asn Gly Lys Cys Ile Pro His Phe Gln Asn Gly Gln His
450 455 460
Gly Phe Thr Cys Gln Cys Leu Ser Gly Tyr Ala Gly Pro Leu Cys Glu
465 470 475 480
Thr Val Thr Thr Leu Ser Phe Gly Ser Asn Gly Phe Leu Trp Val Thr
485 490 495
Ser Gly Ser His Thr Gly Ile Gly Pro Glu Cys Asn Ile Ser Leu Arg
500 505 510
Phe His Thr Val Gln Pro Asn Ala Leu Leu Leu Ile Arg Gly Asn Lys
515 520 525
Asp Val Ser Met Lys Leu Glu Leu Leu Asn Gly Cys Val His Leu Ser
530 535 540
Ile Glu Val Trp Asn Gln Leu Lys Val Leu Leu Ser Ile Ser His Asn
545 550 555 560
Thr Ser Asp Gly Glu Trp His Phe Val Glu Val Thr Ile Ala Glu Thr
565 570 575
Leu Thr Leu Ala Leu Val Gly Gly Ser Cys Lys Glu Lys Cys Thr Thr
580 585 590
Lys Ser Ser Val Pro Val Glu Asn His Gln Ser Ile Cys Ala Leu Gln
595 600 605
Asp Ser Phe Leu Gly Gly Leu Pro Met Gly Thr Ala Asn Asn Ser Val
610 615 620
Ser Val Leu Asn Ile Tyr Asn Val Pro Ser Thr Pro Ser Phe Val Gly
625 630 635 640
Cys Leu Gln Asp Ile Arg Phe Asp Leu Asn His Ile Thr Leu Glu Asn
645 650 655
Val Ser Ser Gly Leu Ser Ser Asn Val Lys Ala Gly Cys Leu Gly Lys
660 665 670
Asp Trp Cys Glu Ser Gln Pro Cys Gln Asn Arg Gly Arg Cys Ile Asn
675 680 685
Leu Trp Gln Gly Tyr Gln Cys Glu Cys Asp Arg Pro Tyr Thr Gly Ser
690 695 700
Asn Cys Leu Lys Gly Glu Arg Ser Gly Val Pro Gln Ser Ala Val Pro
705 710 715 720
Leu Ser Arg Ala Ile Ser Asn His Pro Gly Cys Arg Pro Leu Leu Gly
725 730 735
Asn Ile Arg Thr Pro Gln Asp Leu Cys Trp Tyr Leu Phe Thr Asn Glu
740 745 750
Ile Lys Trp His Ser His Asp Met Tyr
755 760
<210> 85
<211> 5547
<212> DNA
<213> 小鼠
<400> 85
acagctgact cttacattaa gccccactga tccagcttga agaggagtga ggcaaagctg 60
aaccctccca ctctccttga caagtgcaag cccacacttt tggaaaaaag cacaaagacg 120
tcagaaacgg ttcctgtcga cctactaggc tttggatggc taagtgtttt tgctttgtat 180
ggaaatatgt ttggacacaa gacacaaggt tttcacattt taatggcagt gctcatagga 240
attcactgtg aagaagacgt tgatgaatgt ttactgcacc cttgcctaaa tggtggtact 300
tgtgagaacc tgcctgggaa ttatgcctgt cactgtccct ttgatgacac ttctaggaca 360
ttttatggag gagaaaactg ctcagaaatt ctcctgggct gcactcatca ccagtgtctg 420
aacaatggaa aatgtatccc tcatttccaa aatggccagc atggattcac ttgccagtgt 480
ctttctggct atgcggggcc cctgtgtgaa actgtcacca cactttcatt tgggagcaat 540
ggcttcctat gggtcacaag tggctcccat acaggcatag ggccagaatg taacatatcc 600
ttgaggtttc acactgttca accaaacgca cttctcctca tccgaggcaa caaggacgtg 660
tctatgaagc tggagttgct gaatggttgt gttcacttat caattgaagt ctggaatcag 720
ttaaaggtgc tcctgtctat ttctcacaac accagtgatg gagaatggca tttcgtggag 780
gtaacaatcg cagaaactct aacccttgcc ctagttggcg gctcctgcaa ggagaagtgc 840
accaccaagt cttctgttcc agttgagaat catcaatcaa tatgtgcttt gcaggactct 900
tttttgggtg gcttaccaat ggggacagcc aacaacagtg tgtctgtgct taacatctat 960
aatgtgccgt ccacaccttc ctttgtaggc tgtctccaag acattagatt tgatttgaat 1020
cacattactc tggagaacgt ttcatctggc ctgtcatcaa atgttaaagc aggctgcctg 1080
ggaaaggact ggtgtgaaag tcaaccctgt caaaacagag gacgctgcat caacttgtgg 1140
cagggttatc agtgtgaatg tgacaggccc tatacaggct ccaactgcct gaaagagtat 1200
gtagcgggaa gatttggcca agatgactcc acaggatatg cggcctttag tgttaatgat 1260
aattatggac agaacttcag tctttcaatg tttgtccgaa cacgtcaacc cctgggctta 1320
cttctggctt tggaaaatag tacttaccag tatgtcagtg tctggctaga gcacggcagc 1380
ctagcactgc agactccagg ctctcccaag ttcatgagga gacgtcatct tcattggtgg 1440
cttacctgac agagagaaga ctgaagttta tggtggcttc ttcaaaggct gtgttcaaga 1500
tgtcagatta aacagccaga ctctggaatt ctttcccaat tcaacaaaca atgcatacga 1560
tgacccaatt cttgtcaatg tgactcaagg ctgtcccgga gacaacacat gtaagtccaa 1620
cccctgtcat aatggaggtg tctgccactc cctgtgggat gacttctcct gctcctgccc 1680
tacaaacaca gcggggagag cctgcgagca agttcagtgg tgtcaactca gcccatgtcc 1740
tcccactgca gagtgccagc tgctccctca agggtttgaa tgtatcgcaa acgctgtttt 1800
cagcggatta agcagagaaa tactcttcag aagcaatggg aacattacca gagaactcac 1860
caatatcaca tttgctttca gaacacatga tacaaatgtg atgatattgc atgcagaaaa 1920
agaaccagag tttcttaata ttagcattca agatgccaga ttattctttc aattgcgaag 1980
tggcaacagc ttttatacgc tgcacctgat gggttcccaa ttggtgaatg atggcacatg 2040
gcaccaagtg actttctcca tgatagaccc agtggcccag acctcccggt ggcaaatgga 2100
ggtgaacgac cagacaccct ttgtgataag tgaagttgct actggaagcc tgaacttttt 2160
gaaggacaat acagacatct atgtgggtga ccaatctgtt gacaatccga aaggcctgca 2220
gggctgtctg agcacaatag agattggagg catatatctt tcttactttg aaaatctaca 2280
tggtttccct ggtaagcctc aggaagagca atttctcaaa gtttctacaa atatggtact 2340
tactggctgt ttgccatcaa atgcctgcca ctccagcccc tgtttgcatg gaggaaactg 2400
tgaagacagc tacagttctt atcggtgtgc ctgtctctcg ggatggtcag ggacacactg 2460
tgaaatcaac attgatgagt gcttttctag cccctgtatc catggcaact gctctgatgg 2520
agttgcagcc taccactgca ggtgtgagcc tggatacacc ggtgtgaact gtgaggtgga 2580
tgtagacaat tgcaagagtc atcagtgtgc aaatggggcc acctgtgttc ctgaagctca 2640
tggctactct tgtctctgct ttggaaattt taccgggaga ttttgcagac acagcagatt 2700
accctcaaca gtctgtggga atgagaagag aaacttcact tgctacaatg gaggcagctg 2760
ctccatgttc caggaggact ggcaatgtat gtgctggcca ggtttcactg gagagtggtg 2820
tgaagaggac atcaacgagt gtgcctccga tccctgcatc aatggaggac tgtgcaggga 2880
cttggtcaac aggttcctat gcatctgtga tgtggccttc gctggcgagc gctgtgagct 2940
ggacgtaagc ggcctttcct tttatgtgtc cctcttacta tggcaaaacc tctttcagct 3000
cctgtcctac ctcgtactgc gcatgaatga tgagccagtt gtagagtggg gggcacagga 3060
aaattattaa tgtgcatggg agcattcaca agtgtaaaac attgacttgc aagaaacatc 3120
ttgtctcagt gtaggtttct aggaaagaca aagggaacat tagggaatag actccatcta 3180
gagcactggt tctcagtctt cctaatgctg caacccttta gtacagctct tcctgttgta 3240
gtgatcgcag ccataacatt attttcattg ccacttcata actgtaatcc ttctactgct 3300
gtgaatcaca atggaaatat ttatgttttc tgatggtctt aagcaacacc tctgaaaaag 3360
tcattgaccc cccccccaaa ggggctgtga tccacaggtt gagaaatgct catctggaag 3420
gtaaccatgc atttaagtgt acctctagta gtttgggtct atagaagata ttctcctatt 3480
ctaccttttt agacacgcca gaagagggca tctgattcca ttaaagatga ttgggagcca 3540
ccgtgtggtt cctgagaact gtactcgggc cctttggaag agcaatcagt gctctttcca 3600
gcccctaaga atatttttaa tacagccaga aaggtctcat tacccagtgt actgagccct 3660
aaggcacttt catcctcaat cgttccatgt tgaatggttt tcattacatt tggaaaatgt 3720
tttctctcca ctctaccttt acatgttcct attttcctat tgacaatttg ccccttcact 3780
gtaattctaa tttggtgtgg tccttcttct cataagttta tatgtgacat gaacatttaa 3840
aaatatctat gaatatttta tagtcatgta tgtctttctg caaagctatt caaatgaact 3900
atggacagtt cttttctaca cgaagaagag atgagtttaa tccccagtaa catgagaaaa 3960
agatgagtga gggacagtgc tcacagtatc cctcactagc atcatttgtg attccatggg 4020
ccattttttt ccaccagcaa atagcagaga gccctttccc tattcgtttc tcttacactt 4080
ccccttttct gttacaactg aacactttac attagttact cctttgtagg gggtttgact 4140
tttccaccgt tttctctggt tcactattta tgctaagtat ctgtgcaggg cgggtatatc 4200
agtccaacag aggtgtcatt agtgttcatt gaggaggaaa tactttgcat gaattcatga 4260
catcattgaa gtagcagtgg ccagaaagat acccttctgc gaatgtgtct gtgtattcag 4320
aagctgccct ggttagaaaa catgtgggtc acttttcctt tgcatgttac cagtgctcac 4380
tgggtcatga ttgttttaag acagagcttt tgctgtggca atgaccaagg tgaatccaga 4440
gatgcagatc agacaaagga caagacaatg tactatctga gtaaaaccct gccttgactt 4500
actcctcagt acttagagat tttacatagc aacctccacc ctgtggcaac ccgttcacac 4560
tagcagtgat gctgagattt gcccttcctt ctcatcatct tcctcacatc caaagcattt 4620
tgtgtccaca ctgctgtttc agataactgt ttctaaagtg ggattgttgt agccagaaag 4680
gtagggaaaa tgttccccaa aatatttgca ttcttaagta tgtgaagtaa gtagattata 4740
gtcagagaca atatgtaagg tttcaggttc actcccttct acacatatct tcaactgtgt 4800
atttgcagaa tattctgaat gtgacatact cccaacagaa tatatttaag gagtatttat 4860
ccacagtatt gttctctgta cagttctagt gcttctattg tcactgcaat tgtcaattgt 4920
ttttctgctt tccaactgtc ttattatcat ttaatagcat cttgctaaat gccctctttc 4980
tattctcctt atttctccat agttcatgtg tgtctgtgtg actaaggatt ctcctcattt 5040
ttgcagaaaa ataaaatctt ttcttcttta tgtcctgctt gtcattctct ggtgacacat 5100
gtctttgctt acttggactg agggttgtac agtaagtaca gaagcaggct cagtcacaca 5160
gacagagaca caccaccacc agcagcagca gcaccaccac caccaccacc accaccagaa 5220
aacagtatga gtactcatct cttgattaca tgtcatttca agtaagcacc atgacaccga 5280
gggccaggtt ccatggactt tctctgttag gcacgtgatt ctttagctga cctttgagaa 5340
cagactccaa caacctcact tatttttact gttgacttat atcatctctg acaacactgg 5400
acttcgtttg agctagtcaa gaggaaagac catgacacct aagggacaga aattcacaca 5460
ctcggttttt cataattcac acacattcct atgtatcaaa tctctgtaat agatgacatt 5520
tacttgaata aaaagtcatt tcccttt 5547
<210> 86
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His Cys Pro Phe Asp Asp Thr Ser Arg Thr Phe Tyr Gly Gly Glu Asn
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Cys Ser Glu Ile Leu Leu Gly Cys Thr His His Gln Cys Leu Asn Asn
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Gln Cys Leu Ser Gly Tyr Ala Gly Pro Leu Cys Glu Thr Val Thr Thr
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Leu Ser Phe Gly Ser Asn Gly Phe Leu Trp Val Thr Ser Gly Ser His
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Thr Gly Ile Gly Pro Glu Cys Asn Ile Ser Leu Arg Phe His Thr Val
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Gln Pro Asn Ala Leu Leu Leu Ile Arg Gly Asn Lys Asp Val Ser Met
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Lys Leu Glu Leu Leu Asn Gly Cys Val His Leu Ser Ile Glu Val Trp
165 170 175
Asn Gln Leu Lys Val Leu Leu Ser Ile Ser His Asn Thr Ser Asp Gly
180 185 190
Glu Trp His Phe Val Glu Val Thr Ile Ala Glu Thr Leu Thr Leu Ala
195 200 205
Leu Val Gly Gly Ser Cys Lys Glu Lys Cys Thr Thr Lys Ser Ser Val
210 215 220
Pro Val Glu Asn His Gln Ser Ile Cys Ala Leu Gln Asp Ser Phe Leu
225 230 235 240
Gly Gly Leu Pro Met Gly Thr Ala Asn Asn Ser Val Ser Val Leu Asn
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Ile Tyr Asn Val Pro Ser Thr Pro Ser Phe Val Gly Cys Leu Gln Asp
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Ile Arg Phe Asp Leu Asn His Ile Thr Leu Glu Asn Val Ser Ser Gly
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Leu Ser Ser Asn Val Lys Ala Gly Cys Leu Gly Lys Asp Trp Cys Glu
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Ser Gln Pro Cys Gln Asn Arg Gly Arg Cys Ile Asn Leu Trp Gln Gly
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Tyr Gln Cys Glu Cys Asp Arg Pro Tyr Thr Gly Ser Asn Cys Leu Lys
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Glu Tyr Val Ala Gly Arg Phe Gly Gln Asp Asp Ser Thr Gly Tyr Ala
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Ala Phe Ser Val Asn Asp Asn Tyr Gly Gln Asn Phe Ser Leu Ser Met
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Phe Val Arg Thr Arg Gln Pro Leu Gly Leu Leu Leu Ala Leu Glu Asn
370 375 380
Ser Thr Tyr Gln Tyr Val Ser Val Trp Leu Glu His Gly Ser Leu Ala
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Trp Trp Leu Thr
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<210> 87
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<220>
<223> 计算机内产生的共有信号肽
<220>
<221> misc_feature
<222> (4)..(4)
<223> Xaa可以是任何天然存在的氨基酸
<400> 87
Met Phe Gly Xaa Arg Thr Gln Gly Phe His Ile Leu Met Ala Met Leu
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Ile Gly
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<220>
<223> 计算机内产生的共有跨膜域
<220>
<221> misc_feature
<222> (37)..(37)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> misc_feature
<222> (40)..(40)
<223> Xaa可以是任何天然存在的氨基酸
<400> 88
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Val Glu Trp Gly Xaa Gln Glu Xaa Tyr
35 40
<210> 89
<211> 18
<212> PRT
<213> 智人
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Met Phe Gly Ala Arg Thr His Gly Phe His Ile Leu Met Ala Met Leu
1 5 10 15
Ile Gly
<210> 90
<211> 18
<212> PRT
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Met Phe Gly Ala Arg Thr Gln Gly Phe His Ile Leu Met Ala Met Leu
1 5 10 15
Ile Gly
<210> 91
<211> 41
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Val Ser Gly Leu Ser Phe Tyr Val Ser Leu Leu Leu Trp Gln Asn Leu
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Phe Gln Leu Leu Ser Tyr Leu Ile Leu Arg Leu Asn Asp Glu Pro Val
20 25 30
Val Glu Trp Gly Asp Gln Asp Asp Tyr
35 40
<210> 92
<211> 18
<212> PRT
<213> 小鼠
<400> 92
Met Phe Gly His Lys Thr Gln Gly Phe His Ile Leu Met Ala Val Leu
1 5 10 15
Ile Gly
<210> 93
<211> 41
<212> PRT
<213> 小鼠
<400> 93
Val Ser Gly Leu Ser Phe Tyr Val Ser Leu Leu Leu Trp Gln Asn Leu
1 5 10 15
Phe Gln Leu Leu Ser Tyr Leu Val Leu Arg Met Asn Asp Glu Pro Val
20 25 30
Val Glu Trp Gly Ala Gln Glu Asn Tyr
35 40
<210> 94
<211> 18
<212> PRT
<213> 大鼠
<400> 94
Met Phe Gly His Arg Thr Gln Gly Phe Tyr Ile Phe Met Ala Ile Leu
1 5 10 15
Ile Gly
<210> 95
<211> 41
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<213> 大鼠
<400> 95
Val Ser Gly Leu Ser Phe Tyr Val Ser Leu Leu Leu Trp Gln Asn Leu
1 5 10 15
Phe Gln Leu Leu Ser Tyr Leu Ile Leu Arg Met Asn Asp Glu Pro Glu
20 25 30
Val Glu Trp Gly Ala Gln Glu Asn Tyr
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<210> 96
<211> 16
<212> PRT
<213> 斑马鱼
<400> 96
Met Glu Val Val Val Gly Ile Trp Ser Val Leu Leu Leu Ile Ser Gly
1 5 10 15
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<211> 39
<212> PRT
<213> 斑马鱼
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Val Ser Asp Leu Tyr Phe Tyr Met Ala Ala Leu Phe Trp Gln Asn Leu
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Phe Gln Phe Leu Ser Tyr Leu Ile Leu Arg Leu Asp Asp Glu Pro Glu
20 25 30
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<400> 98
aaacaaaaac taaagcatct tattccctgg gcttacttct ggctttggaa 50
<210> 99
<211> 50
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<213> 小鼠
<400> 99
aagaagaata agtacccgtt cccatcacct aatcgcttta ttctgataga 50
<210> 100
<211> 48
<212> DNA
<213> 人工序列
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<223> Crb1 delB等位基因
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aagaagaata agtacccgtt catcacctaa tcgctttatt ctgataga 48
Claims (39)
1.一种分离的多核苷酸，其包含编码Crumbs 1-B(CRB1-B)同种型的多核苷酸序列，所述Crumbs 1-B(CRB1-B)同种型包含SEQ ID NO:1，所述多核苷酸序列可操作地连接到能够在视网膜细胞中表达所述同种型的异源启动子。
2.根据权利要求1所述的分离的多核苷酸，其中所述编码CRB1-B同种型的序列是SEQID NO:2。
3.一种重组载体，其包含权利要求1或2中任一项的分离的多核苷酸。
4.一种包含编码Crumbs 1-B(CRB1-B)同种型的多核苷酸的重组载体，其中所述CRB1-B同种型包含连接到胞外多肽的N端信号肽，所述胞外多肽从N端到C端包含：两个EGF结构域、一个lamG结构域、一个EGF结构域、一个lamG结构域、一个EGF结构域、一个lamG结构域和四个EGF结构域；其中所述胞外多肽的C端连接到包含跨膜结构域和胞内结构域的C端结构域。
5.根据权利要求4所述的重组载体，其中所述多核苷酸可操作地连接到能够在视网膜细胞中表达所述同种型的异源启动子。
6.根据权利要求4或5所述的重组载体，其中所述胞外多肽从CRB1-A同种型的第九个EGF结构域的N端延伸至所述CRB1-A同种型的第十六个EGF结构域的C端。
7.根据权利要求4至6中任一项所述的重组载体，其中所述C端结构域包含氨基酸序列VSSLSFYVSLLFWQNLFQLLSYLILRMNDEPVVEWGEQEDY(SEQ ID NO:3)。
8.根据权利要求1-3或5-7中任一项所述的分离的多肽或重组载体，其中所述视网膜细胞选自由光感受器细胞、视网膜色素上皮细胞、双极细胞、水平细胞、无长突细胞、米勒细胞和/或神经节细胞组成的组。
9.根据权利要求8所述的重组载体，其中所述视网膜细胞包括光感受器细胞。
10.根据权利要求1-3或5-9中任一项所述的分离的多核苷酸或重组载体，其中所述启动子选自由视紫红质激酶(RK)启动子、视蛋白启动子、巨细胞病毒(CMV)启动子和鸡β-肌动蛋白(CBA启动子)组成的组。
11.根据权利要求3-10中任一项所述的重组载体，其中所述载体是病毒载体。
12.根据权利要求11所述的重组载体，其中所述病毒载体是AAV载体。
13.一种由权利要求1-12中任一项所述的分离的多核苷酸或重组载体制成的分离的多肽。
14.一种药物组合物，其包含权利要求1或2所述的分离的多核苷酸或权利要求3-12中任一项所述的重组载体和药学上可接受的载体。
15.根据权利要求14所述的药物组合物，其中所述药物组合物包含约1×106DRP/ml至约1×1014DRP/ml的浓度的病毒载体。
16.根据权利要求14或15所述的药物组合物，其进一步包含编码CRB1-A、CRB1-A2、CRB1-C或其组合的第二载体。
17.一种治疗受试者的眼部病症的方法，所述方法包括向所述受试者施用治疗有效量的权利要求1或2所述的多核苷酸、权利要求3-12中任一项所述的重组载体、权利要求13所述的分离的多肽或权利要求14-16中任一项所述的药物组合物，从而治疗所述受试者的所述眼部病症。
18.一种在有需要的受试者中减少视力丧失进展或维持视力功能的方法，所述方法包括向所述受试者施用治疗有效量的权利要求1或2所述的多核苷酸、权利要求3-12中任一项所述的重组载体、权利要求13所述的分离的多肽或权利要求14-16中任一项所述的药物组合物，从而减少视力丧失。
19.根据权利要求18所述的方法，其中所述受试者具有眼部病症。
20.根据权利要求17-19中任一项所述的方法，其中所述受试者在CRB1的一个或多个等位基因中具有突变。
21.根据权利要求17、19或20所述的方法，其中所述眼部病症包括视网膜病变。
22.根据权利要求21所述的方法，其中所述视网膜病变选自由以下组成的组：常染色体隐性重度早发性视网膜变性(莱伯氏先天性黑蒙(Leber's Congenital Amaurosis))、先天性全色盲、斯塔加特氏病(Stargardt's disease)、贝斯特氏病(Best's disease)、多因氏病(Doyne's disease)、视锥细胞营养不良、视网膜色素变性、X相关性视网膜劈裂、亚瑟氏综合征(Usher's syndrome)、年龄相关性黄斑变性、萎缩性年龄相关性黄斑变性、新生血管性AMD、糖尿病性黄斑病变、增殖性糖尿病视网膜病变(PDR)、囊样黄斑水肿、中心性浆液性视网膜病变、视网膜脱离、眼内炎症、青光眼和后葡萄膜炎。
23.根据权利要求17-22中任一项所述的方法，其中所述多核苷酸、重组载体、多肽或药物组合物在玻璃体内施用。
24.根据权利要求17-22中任一项所述的方法，其中所述多肽、重组载体、多肽或药物组合物在视网膜下施用。
25.根据权利要求17-22中任一项所述的方法，其中所述多核苷酸、重组载体、多肽或药物组合物局部施用。
26.根据权利要求17-25中任一项所述的方法，其中所述方法进一步包括监测所述受试者的视觉功能，其中所述受试者的视觉功能在给药后得以维持且不降低。
27.根据权利要求26所述的方法，其中所述视觉功能通过微视野检查、暗适应视野测量、视觉移动性评估、视敏度、ERG或阅读评估来评估。
28.一种用于治疗受试者的眼部病症的试剂盒，所述试剂盒包括权利要求1或2所述的分离的多核苷酸、权利要求3-12中任一项所述的重组载体、权利要求13所述的分离的多肽或权利要求14-16中任一项所述的药物组合物，用于将所述分离的多核苷酸、重组载体或分离的多肽或药物组合物递送至所述受试者的装置，以及使用说明。
29.根据权利要求28所述的试剂盒，其中所述递送包括视网膜下递送。
30.根据权利要求28所述的试剂盒，其中所述递送包括玻璃体内递送。
31.根据权利要求28所述的试剂盒，其中所述递送包括局部递送。
32.一种用于在受试者中减少视力丧失进展或减少视力丧失或维持视力功能的试剂盒，所述试剂盒包括权利要求1或2所述的分离的多核苷酸、权利要求3-12中任一项所述的重组载体、权利要求13所述的分离的多肽或权利要求14-16中任一项所述的药物组合物，用于将所述分离的多核苷酸、重组载体、分离的多肽或药物组合物递送至所述受试者的装置，以及使用说明。
33.一种试剂盒，其包括权利要求3-12中任一项所述的重组载体和编码CRB1-A、CRB1-A2或CRB1-C的第二载体，以及使用说明。
34.一种用于将所述分离的多核苷酸、重组载体、分离的多肽或药物组合物递送至受试者的眼睛的系统，所述系统包括治疗有效量的权利要求1或2所述的分离的多核苷酸、权利要求3-12中任一项所述的重组载体、权利要求13所述的分离的多肽或权利要求14-16中任一项所述的药物组合物，以及用于递送至所述受试者的装置。
35.根据权利要求34所述的系统，其中所述重组载体被递送。
36.根据权利要求34或35所述的系统，其中所述递送包括视网膜下递送。
37.根据权利要求34或35所述的系统，其中所述递送包括玻璃体内递送。
38.根据权利要求34-37中任一项所述的系统，其中所述装置包括细孔套管和注射器，其中所述细孔套管为规格27至45号。
39.根据权利要求38所述的系统，其中所述递送包括局部递送。
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| PCT/US2020/020977 WO2020180981A1 (en) | 2019-03-04 | 2020-03-04 | Compositions and methods for the diagnosis and treatment of retinopathies |
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| CA3236369A1 (en) * | 2021-11-08 | 2023-05-11 | Mark R. Prausnitz | Methods for administration of drug to the retina |
| WO2023245131A1 (en) * | 2022-06-15 | 2023-12-21 | The Trustees Of Columbia University In The City Of New York | Vectors and compositions for gene augmentation of crumbs complex homologue 1 (crb1) mutations |
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| CN105209619A (zh) * | 2013-03-11 | 2015-12-30 | 泰莱托恩基金会 | miR-204和miR-211及其用途 |
| US20160194374A1 (en) * | 2013-08-05 | 2016-07-07 | Academisch Ziekenhuis Leiden H.O.D.N. Leids Universitair Medisch Centrum | Recombinant aav-crumbs homologue composition and methods for treating lca-8 and progressive rp |
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2020
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- 2020-03-04 JP JP2021552829A patent/JP2022525017A/ja active Pending
- 2020-03-04 US US17/436,419 patent/US20220125948A1/en active Pending
- 2020-03-04 CA CA3132369A patent/CA3132369A1/en active Pending
- 2020-03-04 EP EP20766561.3A patent/EP3935078A4/en active Pending
- 2020-03-04 AU AU2020233396A patent/AU2020233396A1/en active Pending
- 2020-03-04 CN CN202080030025.XA patent/CN113710805A/zh active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105209619A (zh) * | 2013-03-11 | 2015-12-30 | 泰莱托恩基金会 | miR-204和miR-211及其用途 |
| US20160194374A1 (en) * | 2013-08-05 | 2016-07-07 | Academisch Ziekenhuis Leiden H.O.D.N. Leids Universitair Medisch Centrum | Recombinant aav-crumbs homologue composition and methods for treating lca-8 and progressive rp |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113999873A (zh) * | 2021-12-31 | 2022-02-01 | 北京市疾病预防控制中心 | 一种基因修饰的非人动物的构建方法及其应用 |
| CN113999873B (zh) * | 2021-12-31 | 2022-05-20 | 北京市疾病预防控制中心 | 一种基因修饰的非人动物的构建方法及其应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2022525017A (ja) | 2022-05-11 |
| US20220125948A1 (en) | 2022-04-28 |
| AU2020233396A1 (en) | 2021-09-30 |
| EP3935078A4 (en) | 2022-12-21 |
| WO2020180981A1 (en) | 2020-09-10 |
| EP3935078A1 (en) | 2022-01-12 |
| CA3132369A1 (en) | 2020-09-10 |
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