CN111926038A - Csf2rb基因人源化改造的非人动物的构建方法及其应用 - Google Patents
Csf2rb基因人源化改造的非人动物的构建方法及其应用 Download PDFInfo
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Abstract
本发明提供了一种CSF2RB基因人源化改造的非人动物的构建方法、一种人源化CSF2RB蛋白、一种人源化CSF2RB基因、一种CSF2RB基因的靶向载体和其在生物医药领域的应用,利用同源重组的方式将部分编码人CSF2RB蛋白的核苷酸序列导入非人动物基因组中,该非人动物体内能正常表达人源化CSF2RB蛋白,可以用于人CSF2RB信号机理研究、炎症、肿瘤及免疫相关疾病药物筛选,对免疫靶点的新药研发具有重要的应用价值。
Description
技术领域
本发明属于动物基因工程和基因遗传修饰领域,具体地说,涉及一种CSF2RB基因人源化改造的非人动物的构建方法和在生物医药领域的应用。
背景技术
粒细胞-巨噬细胞集落刺激因子(Granulocyte-macrophage colonystimulatingfactor,GM-CSF),也称为集落刺激因子2(CSF2),是一种具有细胞因子功能的单体糖蛋白。GM-CSF刺激干细胞产生粒细胞(嗜中性粒细胞、嗜酸性粒细胞和嗜碱性粒细胞)和单核细胞。单核细胞离开循环并迁移到组织中,然后它们成熟为巨噬细胞和树突状细胞。因此,其是免疫/炎症级联反应的一部分,通过这种级联反应,少量巨噬细胞的激活可以迅速导致其数量的增加,这是对抗感染至关重要的过程。
集落刺激因子2受体β(Colony Stimulating Factor2Receptor,Beta,CSF2RB)是一种跨膜蛋白,以β链的形式构成细胞因子IL-3、IL-5和GM-CSF受体的侧链。共同β链(hβc),即CSF2RB,在高亲和的配体结合及信号转导中是必需的。CSF2RB表达在嗜中性粒细胞、嗜酸性粒细胞和嗜碱性粒细胞的细胞中,多效细胞因子白细胞介素(IL)-3(IL-3)、IL-5和粒细胞-巨噬细胞集落刺激因子(GM-CSF)在髓系细胞的分化和功能中起关键的和重叠的作用。它们是宿主防御和先天免疫的重要介质,同时也可以显著促进炎症病理的发展和演进,所述炎症病理包括炎症性气道疾病如哮喘、慢性鼻-鼻窦炎伴或不伴鼻息肉(CRSwNP,CRSsNP)、慢性阻塞性肺病(COPD)和哮喘-COPD重叠综合征(ACOS)。研究发现,CSF2RB主要在血液系统疾病中研究较多,既促进造血细胞增殖又促进分化,在维持造血细胞增殖、分化、自我更新的平衡中具有重要作用。
实验动物疾病模型对于研究人类疾病发生的病因、发病机制、开发防治技术和药物是不可缺少的研究工具。由于人CSF2RB氨基酸序列与啮齿类动物中的对应蛋白存在显著差异,一致性仅为56%,因此,识别人CSF2RB蛋白的抗体通常无法识别小鼠CSF2RB,即无法用普通小鼠来筛选和评价靶向CSF2RB药物的药效。为了使临床前期的试验更有效并使研发失败最小化,本领域仍急需开发人源化CSF2RB相关的非人动物模型。
发明内容
本发明的第一方面,提供了一种CSF2RB基因人源化改造的非人动物的构建方法,所述的非人动物的基因组中包括编码SEQ ID NO.2第1至435位氨基酸的核苷酸序列。
进一步优选的,所述的非人动物的基因组中包括SEQ ID NO.5所示核苷酸序列。
优选的,所述的非人动物的基因组中包含人CSF2RB核苷酸序列的2号外显子的部分、3号至9号外显子的全部和10号外显子的部分,进一步优选的,包含2-3号内含子和/或9-10号内含子,更优选的,包含2-10号外显子之间的任一内含子;其中,所述人CSF2RB核苷酸序列的2号外显子的部分至少包含从编码信号肽的核苷酸序列开始至2号外显子最后1个核苷酸序列为止,10号外显子的部分至少包含从10号外显子第一个核苷酸开始至编码10号外显子最后1-5(例如1、2、3、4、5)个氨基酸的核苷酸序列为止。
优选的,所述的构建方法包括插入、翻转、敲除或替换。优选为原位替换。
优选的,所述的构建方法包括用包含人CSF2RB核苷酸序列的2号至10号外显子的全部或部分核苷酸序列插入或替换到非人动物CSF2RB基因座上,进一步优选的,用包含人CSF2RB核苷酸序列的2号外显子的部分、3号至9号外显子的全部和10号外显子的部分核苷酸序列插入或替换到非人动物CSF2RB基因座上,更优选的,包含2-3号内含子和/或9-10号内含子,更进一步优选的,包含2-10号外显子之间的任一内含子;其中,所述人CSF2RB基因的2号外显子的部分至少包含从编码信号肽的核苷酸序列开始至2号外显子最后1个核苷酸序列为止,10号外显子的部分至少包含从10号外显子第一个核苷酸开始至编码10号外显子最后1-5(例如1、2、3、4、5)个氨基酸的核苷酸序列为止。
优选的,所述的构建方法包括用包含编码SEQ ID NO.2第1至435位氨基酸的核苷酸序列或者包含SEQ ID NO.5所示核苷酸序列替换至非人动物CSF2RB基因座。
在本发明的一个具体实施方式中,所述的构建方法包括用包含编码SEQ ID NO.2第1至435位氨基酸的核苷酸序列或者包含SEQ ID NO.5所示核苷酸序列替换至非人动物CSF2RB基因的相应区域。
优选的,所述的构建方法包括用包含人CSF2RB核苷酸序列的2号至10号外显子全部或部分替换非人动物CSF2RB核苷酸序列的2号至10号外显子的全部或部分;其中,所述非人动物CSF2RB核苷酸序列包含编码非人动物2号外显子的部分、3号至9号外显子的全部、10号外显子的部分核苷酸序列,优选的,包含2-3号内含子和/或9-10号内含子,进一步优选的,包含2-10号外显子之间的任一内含子,其中,所述非人动物CSF2RB核苷酸序列的2号外显子的部分至少包含从编码信号肽的核苷酸序列开始至2号外显子最后1个核苷酸为止,10号外显子的部分至少包含从10号外显子第一个核苷酸开始至编码10号外显子最后1-5(例如1、2、3、4、5)个氨基酸的核苷酸序列为止。
优选的,所述的构建方法包括用包含所述人源化CSF2RB基因的核苷酸序列插入或替换到非人动物CSF2RB基因座上。
优选的,所述的构建方法包括用包含编码所述人源化CSF2RB蛋白的核苷酸序列插入或替换到非人动物CSF2RB基因座上。
优选的,所述的插入或替换位点为CSF2RB基因的内源调控元件之后。
优选的,所述的插入为首先破坏非人动物内源CSF2RB基因的编码框,随后进行插入操作,或者所述的插入步骤既可在内源CSF2RB基因处造成移码突变又可以实现插入人源序列的步骤。
优选的,所述的非人动物中人源化CSF2RB基因是纯合或杂合的。
优选的,所述非人动物的基因组中至少一个染色体上包含人源化CSF2RB基因。
优选的,所述的非人动物中至少一个细胞表达人或人源化CSF2RB蛋白。
优选的,使用基因编辑技术进行CSF2RB基因人源化改造的非人动物的构建,所述的基因编辑技术包括利用胚胎干细胞的基因打靶技术、CRISPR/Cas9技术、锌指核酸酶技术、转录激活子样效应因子核酸酶技术、归巢核酸内切酶或其他分子生物学技术。
本发明所述的非人动物为啮齿类动物;优选的,所述的啮齿类动物为大鼠或小鼠。
优选的,使用靶向载体进行CSF2RB基因人源化改造的非人动物的构建,其中,所述的靶向载体包含人CSF2RB的2号至10号外显子的全部或部分核苷酸序列;进一步优选的,包含2号外显子的部分、3号至9号外显子的全部和10号外显子的部分,更优选的,包含2-3号内含子和/或9-10号内含子,更进一步优选的,包含2-10号外显子之间的任一内含子,其中,所述人CSF2RB的核苷酸序列的2号外显子的部分至少包含从编码信号肽开始至2号外显子最后一个核苷酸为止,10号外显子的部分至少包含从10号外显子第一个核苷酸开始至编码10号外显子最后1-5(例如1、2、3、4、5)个氨基酸的核苷酸序列为止,更进一步优选的,所述靶向载体包含编码SEQ ID NO.2第1至435位氨基酸的核苷酸序列或SEQ ID NO.5所示核苷酸序列。
优选的,所述的靶向载体还包含与待改变的转换区5’端同源的DNA片段,即5’臂,其选自非人动物CSF2RB基因基因组DNA的100-10000个长度的核苷酸;优选的,所述的5’臂与NCBI登录号为NC_000081.6至少具有90%同源性的核苷酸;进一步优选的,所述5’臂序列与SEQ ID NO.3至少具有90%同源性,或者如SEQ ID NO.3所示。
优选的,所述的靶向载体还包含与待改变的转换区3’端同源的DNA片段,即3’臂,其选自非人动物CSF2RB基因基因组DNA的100-10000个长度的核苷酸;优选的,所述的3’臂与NCBI登录号为NC_000081.6至少具有90%同源性的核苷酸;进一步优选的,所述的3’臂序列与SEQ ID NO.4至少具有90%同源性,或者如SEQ ID NO.4所示。
优选的,所述的待改变的转换区位于非人动物CSF2RB基因座上。进一步优选的,位于非人动物CSF2RB基因的2号外显子至10号外显子上。
在本发明的一个具体实施方式中,所述的构建方法包括将上述靶向载体导入非人动物细胞中,培养该细胞(优选为胚胎干细胞),然后将培养后的细胞移植至雌性非人动物输卵管内,允许其发育,鉴定筛选获得非人动物模型。
优选的,所述的非人动物体内表达人或人源化CSF2RB蛋白,同时内源CSF2RB蛋白的表达降低或缺失。
优选的,所述的人源化CSF2RB蛋白包含人CSF2RB蛋白的信号肽和/或胞外区的全部或部分,进一步优选的,包含信号肽的全部和胞外区的部分,更优选的,所述的胞外区的部分包含C端去除0-15(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15)个氨基酸的人CSF2RB蛋白胞外区,更进一步优选的,包含与SEQ ID NO.2第1至435位或SEQ ID NO.7具有至少70%、80%、85%、90%、95%或至少99%同一性的氨基酸序列或者包含与SEQ ID NO.2第1至435位或SEQ ID NO.7所示氨基酸序列一致的氨基酸序列。
优选的,所述的人源化CSF2RB蛋白还包含非人动物CSF2RB蛋白的部分,优选为非人动物CSF2RB蛋白的胞外区、跨膜区和/或胞质区。
在本发明的一个具体实施方式中,所述的人源化CSF2RB蛋白包含下列组中的一种:
a)SEQ ID NO.7或SEQ ID NO.2第1至435位所示氨基酸序列的部分或全部;
b)与SEQ ID NO.7或SEQ ID NO.2第1至435位所示氨基酸的序列同一性程度为至少大约为90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%;
c)与SEQ ID NO.7或SEQ ID NO.2第1至435位所示的氨基酸的序列差异不超过10、9、8、7、6、5、4、3、2或不超过1个氨基酸;
d)具有SEQ ID NO.7或SEQ ID NO.2第1至435位所示的,包括取代、缺失和/或插入一个或多个氨基酸残基的氨基酸序列。
优选的,所述的非人动物的基因组中包含人源化CSF2RB基因,所述的人源化CSF2RB基因编码人源化CSF2RB蛋白。
优选的,所述的人源化CSF2RB基因包含SEQ ID NO.5所示的核苷酸序列,进一步优选的,所述的非人动物中包含的CSF2RB基因转录的mRNA序列包含SEQ ID NO.6所示的核苷酸序列。
在本发明的一个具体实施方式中,所述的人源化CSF2RB基因包含下列组中的一种:
a)人源化CSF2RB基因的mRNA序列为SEQ ID NO.6所示的序列的部分或全部;
b)人源化CSF2RB基因的mRNA序列与SEQ ID NO.6所示的核苷酸序列的部分或全部的同一性程度为至少大约为90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%;
c)人源化CSF2RB基因的mRNA序列与SEQ ID NO.6所示的核苷酸序列差异不超过10、9、8、7、6、5、4、3、2或不超过1个核苷酸;
d)人源化CSF2RB基因的mRNA序列具有SEQ ID NO.6所示的核苷酸序列所示的,包括取代、缺失和/或插入一个或多个核苷酸的核苷酸序列。
本发明的第二方面,提供了一种CSF2RB基因人源化改造的非人动物,所述的非人动物采用上述构建方法获得。
本发明的第三方面,提供了一种靶向载体,所述的靶向载体包含人CSF2RB核苷酸序列的部分,优选的,所述的靶向载体包含编码SEQ ID NO.2第1至435位氨基酸的核苷酸序列或者SEQ ID NO.5所示核苷酸序列。
优选的,所述的人CSF2RB核苷酸序列的部分包含人CSF2RB的2号至10号外显子的全部或部分核苷酸序列;进一步优选的,包含2号外显子的部分、3号至9号外显子的全部和10号外显子的部分,更优选的,包含2-3号内含子和/或9-10号内含子,更进一步优选的,包含2-10号外显子之间的任一内含子,其中,所述人CSF2RB的核苷酸序列的2号外显子的部分至少包含从编码信号肽开始至2号外显子最后一个核苷酸为止,10号外显子的部分至少包含从10号外显子第一个核苷酸开始至编码10号外显子最后1-5(例如1、2、3、4、5)个氨基酸的核苷酸序列为止。
优选的,所述的靶向载体还包含与待改变的转换区5’端同源的DNA片段,即5’臂,其选自非人动物CSF2RB基因基因组DNA的100-10000个长度的核苷酸;优选的,所述的5’臂与NCBI登录号为NC_000081.6至少具有90%同源性的核苷酸;进一步优选的,所述5’臂序列与SEQ ID NO.3至少具有90%同源性,或者如SEQ ID NO.3所示。
优选的,所述的靶向载体还包含与待改变的转换区3’端同源的DNA片段,即3’臂,其选自非人动物CSF2RB基因基因组DNA的100-10000个长度的核苷酸;优选的,所述的3’臂与NCBI登录号为NC_000081.6至少具有90%同源性的核苷酸;进一步优选的,所述的3’臂序列与SEQ ID NO.4至少具有90%同源性,或者如SEQ ID NO.4所示。
优选的,所述的待改变的转换区位于非人动物CSF2RB基因座上,进一步优选的,所述的待改变的转换区位于非人动物CSF2RB基因2号至10号外显子上。
本发明所述的非人动物为啮齿类动物;优选的,所述的啮齿类动物为大鼠或小鼠。
优选的,所述的靶向载体还包含标记基因,进一步优选的,所述标记基因为负筛选标记的编码基因,更进一步优选的,所述负筛选标记的编码基因为白喉毒素A亚基的编码基因(DTA)。
在本发明的一个具体实施方式中,所述的靶向载体中还包括阳性克隆筛选的抗性基因,进一步优选的,所述阳性克隆筛选的抗性基因为新霉素磷酸转移酶编码序列Neo。
在本发明的一个具体实施方式中,所述的靶向载体中还包括特异性重组系统,进一步优选的,所述特异性重组系统为Frt重组位点(也可选择常规的LoxP重组系统),所述的特异性重组系统为具有两个Frt重组位点,分别连接在抗性基因的两侧。
本发明的第四方面,提供了一种包含上述靶向载体的细胞。
本发明的第五方面,提供了上述靶向载体,或者上述的细胞在CSF2RB基因修饰中的应用,优选的,所述的应用包括但不限于翻转、敲除、插入或替换。
本发明的第六方面,涉及一种CSF2RB基因改造的人源化细胞,所述的人源化CSF2RB基因改造细胞的基因组中包括人CSF2RB基因的2号外显子至10号外显子。优选的,所述的人CSF2RB基因编码SEQ ID NO.2第1至435位氨基酸的核苷酸序列或包含SEQ ID NO.5所示核苷酸序列,其通过内源性CSF2RB调控元件调控;该人源化CSF2RB基因改造细胞体内表达人或人源化CSF2RB蛋白,同时内源CSF2RB蛋白的表达降低或缺失。优选的,所述的人CSF2RB基因通过内源性CSF2RB调控元件调控。
本发明的第七方面,涉及一种CSF2RB基因缺失的细胞,所述的CSF2RB基因缺失的细胞缺失内源CSF2RB基因的2号外显子至10号外显子。
本发明的第八方面,涉及一种荷瘤动物模型,所述的动物模型的制备方法包括通过上述的人源化CSF2RB基因改造非人动物的构建方法制备动物的步骤。
优选的,所述的荷瘤动物模型的制备方法还包括在上述方法制备的人源化基因改造动物或其后代植入肿瘤细胞的步骤。
本发明的第九方面,提供了一种上述的构建方法获得的非人动物在制备荷瘤动物模型中的应用。
本发明的第十方面,涉及一种细胞或细胞系或原代细胞培养物,所述细胞或细胞系或原代细胞培养物来源于上述的构建方法获得的CSF2RB基因人源化改造的非人动物、上述的CSF2RB基因人源化改造的非人动物或上述的荷瘤动物模型。
本发明的第十一方面,涉及一种组织或器官或其培养物,所述组织或器官或其培养物来源于上述的构建方法获得的CSF2RB基因人源化改造的非人动物、上述的CSF2RB基因人源化改造的非人动物或上述的荷瘤动物模型。
优选的,所述的组织或器官或其培养物为脾脏、肿瘤或其培养物。
本发明的第十二方面,提供了一种人源化CSF2RB蛋白,所述的人源化CSF2RB蛋白包含人CSF2RB蛋白的全部或部分,进一步优选的,所述的人源化CSF2RB蛋白包含人CSF2RB蛋白的信号肽和/或胞外区的全部或部分,进一步优选的,包含信号肽的全部和胞外区的部分,更优选的,所述的胞外区的部分包含C端去除0-15(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15)个氨基酸的人CSF2RB蛋白胞外区,。
优选的,所述的人源化CSF2RB蛋白包含与SEQ ID NO.2第1至435位或SEQ ID NO.7具有至少70%、80%、85%、90%、95%或至少99%同一性的氨基酸序列或者包含与SEQ ID NO.2第1至435位或SEQ ID NO.7所示氨基酸序列一致的氨基酸序列。
优选的,所述的人源化CSF2RB蛋白还包含非人动物CSF2RB蛋白的部分,优选为非人动物CSF2RB蛋白的胞外区、跨膜区、胞质区。
优选的,所述的人源化CSF2RB蛋白包含人CSF2RB基因的2号外显子至10号外显子编码的氨基酸序列,和非人动物CSF2RB蛋白的氨基酸序列。
在本发明的一个具体实施方式中,所述的人源化CSF2RB蛋白包含下列组中的一种:
a)SEQ ID NO.7或SEQ ID NO.2第1至435位所示氨基酸序列的部分或全部;
b)与SEQ ID NO.7或SEQ ID NO.2第1至435位所示氨基酸的序列同一性程度为至少大约为90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%;
c)与SEQ ID NO.7或SEQ ID NO.2第1至435位所示的氨基酸的序列差异不超过10、9、8、7、6、5、4、3、2或不超过1个氨基酸;
d)具有SEQ ID NO.7或SEQ ID NO.2第1至435位所示的,包括取代、缺失和/或插入一个或多个氨基酸残基的氨基酸序列。
本发明的第十三方面,提供了一种编码上述人源化CSF2RB蛋白的人源化CSF2RB基因,所述的人源化CSF2RB基因包含人CSF2RB基因的2号外显子至10号外显子,和非人动物CSF2RB基因的核苷酸序列。
优选的,所述的人源化CSF2RB基因包含SEQ ID NO.5所示的核苷酸序列。
优选的,所述的人源化CSF2RB基因转录的mRNA序列包含SEQ ID NO.6所示的核苷酸序列。
在本发明的一个具体实施方式中,所述的人源化CSF2RB基因中包含的人CSF2RB核苷酸序列的部分选自下列组中的一种:
(A)包含SEQ ID NO.5所示核苷酸序列的全部或部分;
(B)包含与SEQ ID NO.5所示核苷酸序列的同一性至少为75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%的核苷酸序列;
(C)包含与SEQ ID NO.5所示核苷酸序列差异不超过10、9、8、7、6、5、4、3、2或不超过1个核苷酸的核苷酸序列;
(D)具有SEQ ID NO.5所示核苷酸序列的,包括取代、缺失和/或插入一个或多个核苷酸的核苷酸序列。
在本发明的一个具体实施方式中,所述的人源化CSF2RB基因的核苷酸序列转录的mRNA选自下列组中的一种:
(a)包含SEQ ID NO.6所示核苷酸序列的全部或部分;
(b)包含与SEQ ID NO.6所示核苷酸序列的同一性至少为75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%的核苷酸序列;
(c)包含与SEQ ID NO.6所示的核苷酸序列差异不超过10、9、8、7、6、5、4、3、2或不超过1个核苷酸的核苷酸序列;或
(d)包含SEQ ID NO.6所示的核苷酸序列所示的,包括取代、缺失和/或插入一个或多个核苷酸的核苷酸序列。
本发明的第十四方面,涉及一种表达上述的人源化CSF2RB蛋白的构建体。
本发明的第十五方面,涉及一种包含上述构建体的细胞。
本发明的第十六方面,涉及一种包含上述细胞的组织。
本发明的第十七方面,涉及了一种上述的构建方法获得的非人动物、上述的细胞或细胞系或原代细胞培养物、上述的组织或器官或其培养物、上述的人源化CSF2RB蛋白或上述的人源化CSF2RB基因在制备治疗或预防肿瘤的药物中的应用。
本发明的第十八方面,涉及一种上述的构建方法获得的非人动物、上述的细胞或细胞系或原代细胞培养物、上述的组织或器官或其培养物、上述的人源化CSF2RB蛋白或上述的人源化CSF2RB基因在CSF2RB基因或蛋白中相关研究中的应用,所述的应用包括:
A)涉及人类细胞的免疫过程的产品开发,制造或筛选人类抗体中的应用;
B)作为药理学、免疫学、微生物学和医学研究的模型系统中的应用;
C)涉及人类细胞的免疫过程的生产和利用动物实验疾病模型,用于病原学研究、用于开发诊断策略或用于开发治疗策略中的应用;
D)在体内研究人CSF2RB信号通路调节剂的筛选、药效检测、评估疗效、验证或评价;或者,
E)研究CSF2RB基因功能,研究人CSF2RB抗体,研究针对人CSF2RB靶位点的药物、药效,研究免疫相关疾病药物以及抗肿瘤或炎症药物方面的用途。
优选的,所述应用包括在制备药物组合物或者检测试剂盒中的用途。
优选的,所述应用不是疾病的诊断和治疗方法。
本发明所述的“肿瘤”包括但不限于淋巴瘤、B细胞肿瘤、T细胞肿瘤、骨髓/单核细胞肿瘤、非小细胞肺癌、白血病、卵巢癌、鼻咽癌、乳腺癌、子宫内膜癌、结肠癌、直肠癌、胃癌、膀胱癌、肺癌、支气管癌、骨癌、前列腺癌、胰腺癌、肝和胆管癌、食管癌、肾癌、甲状腺癌、头颈部癌、睾丸癌、胶质母细胞瘤、星形细胞瘤、黑色素瘤、骨髓增生异常综合征、以及肉瘤。其中,所述的白血病选自急性淋巴细胞性(成淋巴细胞性)白血病、急性骨髓性白血病、髓性白血病、慢性淋巴细胞性白血病、多发性骨髓瘤、浆细胞白血病、以及慢性骨髓性白血病;所述淋巴瘤选自霍奇金淋巴瘤和非霍奇金淋巴瘤,包括B细胞淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、套细胞淋巴瘤、边缘区B细胞淋巴瘤、T细胞淋巴瘤、和瓦尔登斯特伦巨球蛋白血症;所述肉瘤选自骨肉瘤、尤文肉瘤、平滑肌肉瘤、滑膜肉瘤、软组织肉瘤、血管肉瘤、脂肪肉瘤、纤维肉瘤、横纹肌肉瘤、及软骨肉瘤。在本发明的一个具体实施方式中,所述的肿瘤选自B细胞肿瘤、T细胞肿瘤、骨髓/单核细胞肿瘤。优选包括B或T细胞急性淋巴细胞白血病(ALL)、急性髓细胞白血病(AML)、非霍奇金淋巴瘤(NHL)和多发性骨髓瘤(MM)、鼻咽癌、肺癌。
本发明所述的“免疫相关疾病”包括但不限于过敏、哮喘、心肌炎、肾炎、肝炎、系统性红斑狼疮、类风湿性关节炎、硬皮病、甲状腺功能亢进、原发性血小板减少性紫癜、自身免疫性溶血性贫血、溃疡性结肠炎、自身免疫性肝病、糖尿病、疼痛或神经障碍等。在本发明的一个具体实施方式中。所述的免疫相关疾病为类风湿性关节炎。
本发明所述的“炎症”包括急性炎症,也包括慢性炎症。具体的,包括但不限于变质性炎症、渗出性炎症(浆液性炎、纤维素性炎、化脓性炎、出血性炎、坏死性炎、卡他性炎)、增生性炎症、特异性炎症(结核、梅毒、麻疯、淋巴肉芽肿等)。
本发明所述的CSF2RB基因人源化的非人动物体内可以正常表达人或人源化CSF2RB蛋白。可用于针对人CSF2RB靶位点的药物筛选、药效评估、免疫相关疾病和肿瘤治疗,可以加快新药研发过程、节约时间和成本。对于研究CSF2RB蛋白功能及相关疾病药物筛选提供了有效的保障。
本发明所述的“全部或部分”,“全部”为整体,“部分”为整体中的局部,或者组成整体的个体。
本发明所述的“人源化CSF2RB蛋白”,包含来源于人CSF2RB蛋白的部分和非人CSF2RB蛋白的部分。其中,所述的“人CSF2RB蛋白”同“人CSF2RB蛋白的全部”,即其氨基酸序列与人CSF2RB蛋白的全长氨基酸序列一致。所述的“人CSF2RB蛋白的部分”,为连续或间隔的5-897个(优选为10-435个)氨基酸序列与人CSF2RB蛋白的氨基酸序列一致或与人CSF2RB蛋白的氨基酸序列具有70%以上同源性。
本发明所述的“人CSF2RB蛋白的信号肽的全部”或“人CSF2RB蛋白的胞外区的全部”,代表其氨基酸序列分别与人CSF2RB蛋白的信号肽或胞外区的全长氨基酸序列一致。
本发明所述的“人CSF2RB蛋白的胞外区的部分”,为连续或间隔5-427个(优选为5-419个)氨基酸序列与人CSF2RB蛋白的胞外区氨基酸序列一致,或与人CSF2RB蛋白的胞外区氨基酸序列具有70%以上同源性。
本发明所述的“人源化CSF2RB基因”,包含来源于人CSF2RB核苷酸序列的部分和非人CSF2RB基因的部分。其中,所述的“人CSF2RB核苷酸序列”同“人CSF2RB核苷酸序列的全部”,即其核苷酸序列与人CSF2RB核苷酸序列的全长核苷酸序列一致。所述的“人CSF2RB核苷酸序列的部分”为连续或间隔的20-26876bp(优选为20-11777bp)个核苷酸序列与人CSF2RB核苷酸序列一致或与人CSF2RB核苷酸序列具有70%以上同源性。
本发明所述的“xx号至xxx号外显子”或“xx号至xxx号外显子的全部”包含外显子及其期间的内含子的核苷酸序列,例如所述的“2号至10号外显子”包含2号外显子、2-3号内含子、3号外显子、3-4号内含子、4号外显子、4-5号内含子、5号外显子、5-6号内含子、6号外显子、6-7号内含子、7号外显子、7-8号内含子、8号外显子、8-9号内含子、9号外显子、9-10号内含子、10号外显子的全部核苷酸序列。
本发明所述的“x-xx号内含子”表示x号外显子与xx号外显子之间的内含子。例如“2-3号内含子”表示2号外显子与3号外显子之间的内含子。
本发明所述的“外显子的部分”表示连续或间隔几个、几十个或几百个核苷酸序列与全部的外显子核苷酸序列一致。例如人CSF2RB核苷酸序列的2号外显子的部分,包含连续或间隔的5-248bp个,优选10-76bp个核苷酸序列与人CSF2RB核苷酸序列的2号外显子核苷酸序列一致。在本发明的一个具体实施方式中,所述的“人源化CSF2RB基因”中包含的“2号外显子的部分”至少包括从2号外显子编码信号肽的核苷酸开始至2号外显子的最后一个核苷酸序列为止。
本发明所述的“基因座”广义上讲代表基因在染色体上所占的位置,狭义上讲代表某一基因上的一段DNA片段,即可以是一个基因也可以是一个基因的一部分。例如所述的“CSF2RB基因座”表示CSF2RB基因1号至15号外显子上的任选一段的DNA片段。优选为1号外显子、2号外显子、3号外显子、4号外显子、5号外显子、6号外显子、7号外显子、8号外显子、9号外显子、10号外显子、11号外显子、12号外显子、13号外显子、14号外显子、15号外显子或其期间的内含子中的任一个或两个或多个的组合,或一个或两个或多个的全部或部分,更优选为CSF2RB基因的2号至10号外显子上。
本发明所述的“核苷酸序列”包含天然的或经过修饰的核糖核苷酸序列、脱氧核糖核苷酸序列。优选为DNA、cDNA、pre-mRNA、mRNA、rRNA、hnRNA、miRNAs、scRNA、snRNA、siRNA、sgRNA、tRNA。
本发明所述“治疗(treating)”(或“治疗(treat)”或“治疗(treatment)”)表示减缓、中断、阻止、控制、停止、减轻、或逆转一种体征、症状、失调、病症、或疾病的进展或严重性,但不一定涉及所有疾病相关体征、症状、病症、或失调的完全消除。术语“治疗(treating)”等是指在疾病已开始发展后改善疾病或病理状态的体征、症状等等的治疗干预。
本发明所述“同源性”,是指在使用蛋白序列或核苷酸序列的方面,本领域技术人员可以根据实际工作需要对序列进行调整,使使用序列与现有技术获得的序列相比,具有(包括但不限于)1%,2%,3%,4%,5%,6%,7%,8%,9%,10%,11%,12%,13%,14%,15%,16%,17%,18%,19%,20%,21%,22%,23%,24%,25%,26%,27%,28%,29%,30%,31%,32%,33%,34%,35%,36%,37%,38%,39%,40%,41%,42%,43%,44%,45%,46%,47%,48%,49%,50%,51%,52%,53%,54%,55%,56%,57%,58%,59%,60%,70%,80%,81%,82%,83%,84%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%,99.1%,99.2%,99.3%,99.4%,99.5%,99.6%,99.7%,99.8%,99.9%的同一性。
本领域的技术人员能够确定并比较序列元件或同一性程度,以区分另外的小鼠和人序列。
在一个方面,所述非人动物是哺乳动物。在一个方面,所述非人动物是小型哺乳动物,例如跳鼠科或鼠总科超家族。在一个实施方式中,所述基因修饰的动物是啮齿动物。在一个实施方式中,所述啮齿动物选自小鼠、大鼠和仓鼠。在一个实施方式中,所述啮齿动物选自鼠家族。在一个实施方式中,所述基因修饰的动物来自选自丽仓鼠科(例如小鼠样仓鼠)、仓鼠科(例如仓鼠、新世界大鼠和小鼠、田鼠)、鼠总科(真小鼠和大鼠、沙鼠、刺毛鼠、冠毛大鼠)、马岛鼠科(登山小鼠、岩小鼠、有尾大鼠、马达加斯加大鼠和小鼠)、刺睡鼠科(例如多刺睡鼠)和鼹形鼠科(例如摩尔大鼠、竹大鼠和鼢鼠)家族。在一个特定实施方式中,所述基因修饰的啮齿动物选自真小鼠或大鼠(鼠总科)、沙鼠、刺毛鼠和冠毛大鼠。在一个实施方式中,所述基因修饰的小鼠来自鼠科家族成员。在一个实施方式中,所述动物是啮齿动物。在一个特定实施方式中,所述啮齿动物选自小鼠和大鼠。在一个实施方式中,所述非人动物是小鼠。
在一个特定实施方式中,所述非人动物是啮齿动物,其为选自BALB/c、A、A/He、A/J、A/WySN、AKR、AKR/A、AKR/J、AKR/N、TA1、TA2、RF、SWR、C3H、C57BR、SJL、C57L、DBA/2、KM、NIH、ICR、CFW、FACA、C57BL/A、C57BL/An、C57BL/GrFa、C57BL/KaLwN、C57BL/6、C57BL/6J、C57BL/6ByJ、C57BL/6NJ、C57BL/10、 C57BL/10ScSn、C57BL/10Cr和C57BL/Ola的C57BL、C58、CBA/Br、CBA/Ca、CBA/J、CBA/st、CBA/H品系的小鼠。
除非特别说明,本发明的实践将采取细胞生物学、细胞培养、分子生物学、转基因生物学、微生物学、重组DNA和免疫学的传统技术。这些技术在以下文献中进行了详细的解释。例如:Molecular Cloning A Laboratory Manual,2ndEd.,ed. By Sambrook,FritschandManiatis (Cold Spring Harbor Laboratory Press:1989);DNA Cloning,Volumes I and II (D.N.Glovered.,1985);Oligonucleotide Synthesis (M.J.Gaited.,1984);Mullisetal. U.S. Pat.No.4,683,195;Nucleic Acid Hybridization(B.D.Hames& S.J.Higginseds.1984);Transcription And Translation (B.D.Hames&S.J.Higginseds.1984);Culture Of Animal Cells (R.I.Freshney,AlanR.Liss,Inc.,1987);Immobilized Cells And Enzymes (IRL Press,1986);B.Perbal,A PracticalGuide To Molecular Cloning(1984);the series,Methods In ENZYMOLOGY (J.Abelsonand M.Simon,eds.inchief,Academic Press,Inc.,New York),specifically,Vols. 154and 155 (Wuetal.eds.) and Vol.185,″Gene Expression Technology″ (D.Goeddel,ed.);Gene Transfer Vectors For Mammalian Cells (J.H.Miller and M.P.Caloseds.,1987,Cold Spring Harbor Laboratory);Immunochemical Methods In Cell AndMolecular Biology (Mayer and Walker,eds.,Academic Press,London,1987);HandbookOf Experimental Immunology,Volumes V (D.M.Weir and C.C.Blackwell,eds.,1986);and Manipulating the Mouse Embryo,(Cold Spring Harbor Laboratory Press,ColdSpring Harbor,N.Y.,1986)。
以上只是概括了本发明的一些方面,不是也不应该认为是在任何方面限制本发明。
本说明书提到的所有专利和出版物都是通过参考文献作为整体而引入本发明的。本领域的技术人员应认识到,对本发明可作某些改变并不偏离本发明的构思或范围。
下面的实施例进一步详细说明本发明,不能认为是限制本发明或本发明所说明的具体方法的范围。
附图说明
以下,结合附图来详细说明本发明的实施例,其中:
图1:人和小鼠CSF2RB基因对比示意图(非按比例);
图2:人源化CSF2RB基因座示意图(非按比例);
图3:CSF2RB打靶策略示意图,其中,靶向载体包含5’同源臂、3’同源臂以及含有人CSF2RB DNA片段的A片段,(非按比例);
图4:阳性克隆PCR检测结果,其中,+为阳性对照组,WT为野生型小鼠,M为Marker组,H2O为水;
图5:采用5’探针、3’探针-A和Neo(3’)探针进行Southern Blot鉴定的结果图,其中,WT为野生型小鼠;
图6:去Neo示意图;
图7:CSF2RB人源化小鼠F1代鼠尾PCR鉴定结果,其中,图A使用引物对WT-F和WT-R用于扩增小鼠内源的野生型CSF2RB基因片段;图B使用引物对WT-F和Mut-R用于扩增修饰后的CSF2RB基因片段,用以验证靶向载体是否正确插入小鼠基因组位点,图C使用引物对Frt-F和Frt-R用于扩增去Neo后的CSF2RB基因片段,其中编号为F1-001、F1-002、F1-003的小鼠为阳性杂合小鼠,PC为阳性对照组,WT为野生型小鼠,M为Marker组,H2O为水;
图8:CSF2RB基因人源化F1杂合小鼠RT-PCR检测结果,其中WT为野生型小鼠,H/+为CSF2RB基因人源化杂合子小鼠,H2O为水对照。
具体实施方式
下面结合具体实施例来进一步描述本发明,本发明的优点和特点将会随着描述而更为清楚。但这些实施例仅是范例性的,并不对本发明的范围构成任何限制。本领域技术人员应该理解的是,在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换,但这些修改和替换均落入本发明的保护范围内。
在下述每一实施例中,设备和材料是从以下所指出的几家公司获得:
EcoRI、BclI、AseI酶购自NEB,货号分别为R3101V、R3160V、R0526V;
C57BL/6小鼠和Flp工具鼠购自中国食品药品检定研究院国家啮齿类实验动物种子中心;
Ambion体外转录试剂盒购自Ambion,货号AM1354。
实施例1 CSF2RB基因人源化小鼠的制备
小鼠CSF2RB基因(NCBI Gene ID:12983,位于15号染色体NC_000081.6的第78325800至78351001位,基于转录本NM_007780.4及其编码蛋白NP_031806.3(SEQ ID NO.1))和人CSF2RB基因(NCBI Gene ID:1439,位于22号染色体NC_000022.11的第36913574至36940449位,基于转录本NM_000395.3 及其编码蛋白NP_000386.1(SEQ ID NO.2))对比示意图如图1所示。
为了达到本发明的目的,可在小鼠内源CSF2RB基因座引入编码人CSF2RB蛋白的基因序列,使得该小鼠表达人源化CSF2RB蛋白。具体来说,可以通过基因编辑技术在小鼠内源CSF2RB基因座上用人CSF2RB基因的序列替换特定小鼠CSF2RB基因序列,如将至少包含小鼠CSF2RB基因的2号外显子部分至10号外显子部分序列替换小鼠2号外显子部分至10号外显子部分,得到人源化CSF2RB基因座(示意图如图2所示),实现对小鼠CSF2RB基因的人源化改造。
进一步设计如图3所示的打靶策略示意图,图中的靶向载体上含有5’同源臂、3’同源臂以及包含人CSF2RB的DNA序列(人DNA片段)的A片段。其中,5’同源臂(SEQ ID NO.3)与NCBI登录号与NC_000081.6第78330587至78335206位核苷酸序列相同;3’同源臂(SEQ IDNO.4)与NCBI登录号与NC_000081.6的第78345850 至78349934位核苷酸序列相同;人CSF2RBDNA的序列(人DNA片段,SEQ ID NO.5)与NCBI登录号为NC_000022.11的第36922208至36933984位核苷酸序列相同。
靶向载体上还包括用于阳性克隆筛选的抗性基因,即新霉素磷酸转移酶编码序列Neo,并在抗性基因的两侧装上两个同向排列的位点特异性重组系统Frt重组位点,组成Neo盒(Neo cassette)。其中Neo盒5’端与小鼠的连接设计为5’-AGTCTATCTATGTACACAGATAAATTGGAAGGTTGGTGGGACCCATTCGGTCGACGGTATCGATAAGCTTGATATCGAATTCCGAAGTTCCTATTCTCTAGAAAGTATAGGA-3’(SEQ ID NO.8)内,其中序列“TTCG”的“G”是小鼠的最后一个核苷酸,序列“GTCG”中的第一个“G”是Neo盒的第一个核苷酸;Neo盒3’端与小鼠的连接设计为5’- CTCTAGAAAGTATAGGAACTTCATCAGTCAGGTACATAATGGTGGATCCAATATTTCCTGCTGATTTCCCTTCCCTTGAACCCTGCAGTCAGTGCTGGTGTGTCC -3’(SEQ ID NO.9)内,其中序列“ATATT”的最后一个“T”是Neo盒的最后一个核苷酸,序列“TCCTG”的第一个“T”是小鼠的第一个核苷酸。此外,还在重组载体3’同源臂下游构建了具有负筛选标记的编码基因(白喉毒素A亚基的编码基因(DTA)。改造后的人源化小鼠CSF2RB的mRNA序列及其蛋白序列分别如SEQ ID NO.6和SEQ IDNO.7所示。
实施例2 阳性克隆筛选
靶向载体构建可采用常规方法进行,如酶切连接等。构建好的靶向载体通过酶切进行初步验证后,再送测序公司进行测序验证。将测序验证正确的靶向载体电穿孔转染入野生型小鼠的胚胎干细胞中,利用阳性克隆筛选标记基因对得到的细胞进行筛选,并利用PCR检测,PCR检测使用引物序列:
D-F(SEQ ID NO.10):5’-AGCGCACGTCTGCCGCGCTGTTC-3’;
D-R(SEQ ID NO.11):5’-TGGATTGTCAAGAGGGTGGTGATGG-3’;
将PCR检测结果为阳性的克隆进行Southern Blot(分别使用EcoRI、BclI、AseI消化细胞)检测,筛选出正确的阳性克隆细胞,Southern检测包括如下探针引物:
5’探针(5’Probe):
5’Probe-F(SEQ ID NO.12):5’- AACCTGGGCAAGAAACAGAGCATCA-3’;
5’Probe-R(SEQ ID NO.13):5’- AGCAACAACGTGTCTCACACATGGA-3’;
3’探针(3’Probe-A):
3’Probe-A-F(SEQ ID NO.14):5’- ATCTCTTGCTGTTCACCTCCTTGGC-3’;
3’Probe-A-R(SEQ ID NO.15):5- ACCACTTCTCTTGCTTACTTCAATGCT-3;
Neo探针(Neo(3’) Probe):
Neo Probe(3’)-F(SEQ ID NO.16):5’-GGATCGGCCATTGAACAAGAT-3’,
Neo Probe(3’)-R(SEQ ID NO.17):5’-CAGAAGAACTCGTCAAGAAGGC-3’。
PCR检测结果见图4,表明D01、D02、D03和D04全部为阳性克隆,Southern检测进一步确认D01为阳性克隆且无随机插入(图5)。
实施例3 CSR2RB基因人源化F1代小鼠表达检测
将筛选出的正确阳性克隆细胞(黑色鼠)按照本领域已知的技术导入已分离好的囊胚中(白色鼠),得到的嵌合囊胚转移至培养液中短暂培养后移植至受体母鼠(白色鼠)的输卵管,可生产F0代嵌合体鼠(黑白相间)。将F0代嵌合鼠与野生型小鼠回交获得F1代鼠,再将F1代杂合小鼠互相交配即可获得F2代纯合子鼠。还可将阳性鼠与Flp工具鼠交配去除阳性克隆筛选标记基因后,再通过互相交配即可得到CSF2RB基因人源化纯合子小鼠(图7)。可通过PCR鉴定子代小鼠体细胞的基因型。示例性的F1代小鼠(已去除Neo标记基因)的鉴定结果见图6,其中,编号为F1-001、F1-002、F1-003为阳性杂合小鼠。PCR检测引物序列如下表:
表1 CSF2RB人源化F1小鼠检测引物
将获得的阳性小鼠进行RT-PCR检测,PCR检测引物如下,从图8检测结果可以
看出,使用小鼠的CSF2RB基因检测引物既可以在野生型小鼠中检测到目的条带,也可以在F1杂合小鼠中检测到目的条带,使用人CSF2RB基因检测引物只能在F1杂合小鼠中检测到目的条带,说明在CSF2RB基因人源化F1小鼠内有表达人源化CSF2RB。
RT-PCR检测引物如下:
hCSF2RB-F2(SEQ ID NO.23):5’-CTCTCAGGACGTCCCAGCAA-3’;
hCSF2RB-R2(SEQ ID NO.24):5’-AGCAAGGTGAGGATGAGAAAGAC-3’;
mCSF2RB-F1(SEQ ID NO.25):5’-TGGACCAGCAAATGGCACT-3’;
mCSF2RB-R1(SEQ ID NO.26):5’-GGTGTAGACACTGGCCCC-3’;
GAPDHF1(SEQ ID NO.27):5’-CTCAGGAGAGTGTTTCCTCGTC-3’;
GAPDHR1(SEQ ID NO.28):5’-CCCTGTTGCTGTAGCCGTAT-3’。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,这些简单变型均属于本发明的保护范围。
另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合,为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。
此外,本发明的各种不同的实施方式之间也可以进行任意组合,只要其不违背本发明的思想,其同样应当视为本发明所公开的内容。
序列表
<110> 北京百奥赛图基因生物技术有限公司
<120> CSF2RB基因人源化改造的非人动物的构建方法及其应用
<130> 1
<160> 28
<170> SIPOSequenceListing 1.0
<210> 1
<211> 896
<212> PRT
<213> 小鼠(Mouse)
<400> 1
Met Asp Gln Gln Met Ala Leu Thr Trp Gly Leu Cys Tyr Met Ala Leu
1 5 10 15
Val Ala Leu Cys Trp Gly His Gly Val Thr Glu Ala Glu Glu Thr Val
20 25 30
Pro Leu Lys Thr Leu Gln Cys Tyr Asn Asp Tyr Thr Asn His Ile Ile
35 40 45
Cys Ser Trp Ala Asp Thr Glu Asp Ala Gln Gly Leu Ile Asn Met Thr
50 55 60
Leu Tyr His Gln Leu Glu Lys Lys Gln Pro Val Ser Cys Glu Leu Ser
65 70 75 80
Glu Glu Leu Met Trp Ser Glu Cys Pro Ser Ser His Arg Cys Val Pro
85 90 95
Arg Arg Cys Val Ile Pro Tyr Thr Arg Phe Ser Ile Thr Asn Glu Asp
100 105 110
Tyr Tyr Ser Phe Arg Pro Asp Ser Asp Leu Gly Ile Gln Leu Met Val
115 120 125
Pro Leu Ala Gln Asn Val Gln Pro Pro Leu Pro Lys Asn Val Ser Ile
130 135 140
Ser Ser Ser Glu Asp Arg Phe Leu Leu Glu Trp Ser Val Ser Leu Gly
145 150 155 160
Asp Ala Gln Val Ser Trp Leu Ser Ser Lys Asp Ile Glu Phe Glu Val
165 170 175
Ala Tyr Lys Arg Leu Gln Asp Ser Trp Glu Asp Ala Tyr Ser Leu His
180 185 190
Thr Ser Lys Phe Gln Val Asn Phe Glu Pro Lys Leu Phe Leu Pro Asn
195 200 205
Ser Ile Tyr Ala Ala Arg Val Arg Thr Arg Leu Ser Pro Gly Ser Ser
210 215 220
Leu Ser Gly Arg Pro Ser Arg Trp Ser Pro Glu Val His Trp Asp Ser
225 230 235 240
Gln Pro Gly Asp Lys Ala Gln Pro Gln Asn Leu Gln Cys Phe Phe Asp
245 250 255
Gly Ile Gln Ser Leu His Cys Ser Trp Glu Val Trp Thr Gln Thr Thr
260 265 270
Gly Ser Val Ser Phe Gly Leu Phe Tyr Arg Pro Ser Pro Val Ala Pro
275 280 285
Glu Glu Lys Cys Ser Pro Val Val Lys Glu Pro Pro Gly Ala Ser Val
290 295 300
Tyr Thr Arg Tyr His Cys Ser Leu Pro Val Pro Glu Pro Ser Ala His
305 310 315 320
Ser Gln Tyr Thr Val Ser Val Lys His Leu Glu Gln Gly Lys Phe Ile
325 330 335
Met Ser Tyr Asn His Ile Gln Met Glu Pro Pro Thr Leu Asn Leu Thr
340 345 350
Lys Asn Arg Asp Ser Tyr Ser Leu His Trp Glu Thr Gln Lys Met Ala
355 360 365
Tyr Ser Phe Ile Glu His Thr Phe Gln Val Gln Tyr Lys Lys Lys Ser
370 375 380
Asp Ser Trp Glu Asp Ser Lys Thr Glu Asn Leu Asp Arg Ala His Ser
385 390 395 400
Met Asp Leu Ser Gln Leu Glu Pro Asp Thr Ser Tyr Cys Ala Arg Val
405 410 415
Arg Val Lys Pro Ile Ser Asn Tyr Asp Gly Ile Trp Ser Lys Trp Ser
420 425 430
Glu Glu Tyr Thr Trp Lys Thr Asp Trp Val Met Pro Thr Leu Trp Ile
435 440 445
Val Leu Ile Leu Val Phe Leu Ile Leu Thr Leu Leu Leu Ile Leu Arg
450 455 460
Phe Gly Cys Val Ser Val Tyr Arg Thr Tyr Arg Lys Trp Lys Glu Lys
465 470 475 480
Ile Pro Asn Pro Ser Lys Ser Leu Leu Phe Gln Asp Gly Gly Lys Gly
485 490 495
Leu Trp Pro Pro Gly Ser Met Ala Ala Phe Ala Thr Lys Asn Pro Ala
500 505 510
Leu Gln Gly Pro Gln Ser Arg Leu Leu Ala Glu Gln Gln Gly Glu Ser
515 520 525
Tyr Ala His Leu Glu Asp Asn Asn Val Ser Pro Leu Thr Ile Glu Asp
530 535 540
Pro Asn Ile Ile Arg Val Pro Pro Ser Gly Pro Asp Thr Thr Pro Ala
545 550 555 560
Ala Ser Ser Glu Ser Thr Glu Gln Leu Pro Asn Val Gln Val Glu Gly
565 570 575
Pro Thr Pro Asn Arg Pro Arg Lys Gln Leu Pro Ser Phe Asp Phe Asn
580 585 590
Gly Pro Tyr Leu Gly Pro Pro Gln Ser His Ser Leu Pro Asp Leu Pro
595 600 605
Asp Gln Leu Gly Ser Pro Gln Val Gly Gly Ser Leu Lys Pro Ala Leu
610 615 620
Pro Gly Ser Leu Glu Tyr Met Cys Leu Pro Pro Gly Gly Gln Ala Gln
625 630 635 640
Leu Val Pro Leu Ser Gln Val Met Gly Gln Gly Gln Ala Met Asp Val
645 650 655
Gln Cys Gly Ser Ser Leu Glu Thr Ser Gly Ser Pro Ser Val Glu Pro
660 665 670
Lys Glu Asn Pro Pro Val Glu Leu Ser Met Glu Glu Gln Glu Ala Arg
675 680 685
Asp Asn Pro Val Thr Leu Pro Ile Ser Ser Gly Gly Pro Glu Gly Ser
690 695 700
Met Met Ala Ser Asp Tyr Val Thr Pro Gly Asp Pro Val Leu Thr Leu
705 710 715 720
Pro Thr Gly Pro Leu Ser Thr Ser Leu Gly Pro Ser Leu Gly Leu Pro
725 730 735
Ser Ala Gln Ser Pro Ser Leu Cys Leu Lys Leu Pro Arg Val Pro Ser
740 745 750
Gly Ser Pro Ala Leu Gly Pro Pro Gly Phe Glu Asp Tyr Val Glu Leu
755 760 765
Pro Pro Ser Val Ser Gln Ala Ala Lys Ser Pro Pro Gly His Pro Ala
770 775 780
Pro Pro Val Ala Ser Ser Pro Thr Val Ile Pro Gly Glu Pro Arg Glu
785 790 795 800
Glu Val Gly Pro Ala Ser Pro His Pro Glu Gly Leu Leu Val Leu Gln
805 810 815
Gln Val Gly Asp Tyr Cys Phe Leu Pro Gly Leu Gly Pro Gly Ser Leu
820 825 830
Ser Pro His Ser Lys Pro Pro Ser Pro Ser Leu Cys Ser Glu Thr Glu
835 840 845
Asp Leu Val Gln Asp Leu Ser Val Lys Lys Phe Pro Tyr Gln Pro Met
850 855 860
Pro Gln Ala Pro Ala Ile Gln Phe Phe Lys Ser Leu Lys His Gln Asp
865 870 875 880
Tyr Leu Ser Leu Pro Pro Trp Asp Asn Ser Gln Ser Gly Lys Val Cys
885 890 895
<210> 2
<211> 897
<212> PRT
<213> 人(human)
<400> 2
Met Val Leu Ala Gln Gly Leu Leu Ser Met Ala Leu Leu Ala Leu Cys
1 5 10 15
Trp Glu Arg Ser Leu Ala Gly Ala Glu Glu Thr Ile Pro Leu Gln Thr
20 25 30
Leu Arg Cys Tyr Asn Asp Tyr Thr Ser His Ile Thr Cys Arg Trp Ala
35 40 45
Asp Thr Gln Asp Ala Gln Arg Leu Val Asn Val Thr Leu Ile Arg Arg
50 55 60
Val Asn Glu Asp Leu Leu Glu Pro Val Ser Cys Asp Leu Ser Asp Asp
65 70 75 80
Met Pro Trp Ser Ala Cys Pro His Pro Arg Cys Val Pro Arg Arg Cys
85 90 95
Val Ile Pro Cys Gln Ser Phe Val Val Thr Asp Val Asp Tyr Phe Ser
100 105 110
Phe Gln Pro Asp Arg Pro Leu Gly Thr Arg Leu Thr Val Thr Leu Thr
115 120 125
Gln His Val Gln Pro Pro Glu Pro Arg Asp Leu Gln Ile Ser Thr Asp
130 135 140
Gln Asp His Phe Leu Leu Thr Trp Ser Val Ala Leu Gly Ser Pro Gln
145 150 155 160
Ser His Trp Leu Ser Pro Gly Asp Leu Glu Phe Glu Val Val Tyr Lys
165 170 175
Arg Leu Gln Asp Ser Trp Glu Asp Ala Ala Ile Leu Leu Ser Asn Thr
180 185 190
Ser Gln Ala Thr Leu Gly Pro Glu His Leu Met Pro Ser Ser Thr Tyr
195 200 205
Val Ala Arg Val Arg Thr Arg Leu Ala Pro Gly Ser Arg Leu Ser Gly
210 215 220
Arg Pro Ser Lys Trp Ser Pro Glu Val Cys Trp Asp Ser Gln Pro Gly
225 230 235 240
Asp Glu Ala Gln Pro Gln Asn Leu Glu Cys Phe Phe Asp Gly Ala Ala
245 250 255
Val Leu Ser Cys Ser Trp Glu Val Arg Lys Glu Val Ala Ser Ser Val
260 265 270
Ser Phe Gly Leu Phe Tyr Lys Pro Ser Pro Asp Ala Gly Glu Glu Glu
275 280 285
Cys Ser Pro Val Leu Arg Glu Gly Leu Gly Ser Leu His Thr Arg His
290 295 300
His Cys Gln Ile Pro Val Pro Asp Pro Ala Thr His Gly Gln Tyr Ile
305 310 315 320
Val Ser Val Gln Pro Arg Arg Ala Glu Lys His Ile Lys Ser Ser Val
325 330 335
Asn Ile Gln Met Ala Pro Pro Ser Leu Asn Val Thr Lys Asp Gly Asp
340 345 350
Ser Tyr Ser Leu Arg Trp Glu Thr Met Lys Met Arg Tyr Glu His Ile
355 360 365
Asp His Thr Phe Glu Ile Gln Tyr Arg Lys Asp Thr Ala Thr Trp Lys
370 375 380
Asp Ser Lys Thr Glu Thr Leu Gln Asn Ala His Ser Met Ala Leu Pro
385 390 395 400
Ala Leu Glu Pro Ser Thr Arg Tyr Trp Ala Arg Val Arg Val Arg Thr
405 410 415
Ser Arg Thr Gly Tyr Asn Gly Ile Trp Ser Glu Trp Ser Glu Ala Arg
420 425 430
Ser Trp Asp Thr Glu Ser Val Leu Pro Met Trp Val Leu Ala Leu Ile
435 440 445
Val Ile Phe Leu Thr Ile Ala Val Leu Leu Ala Leu Arg Phe Cys Gly
450 455 460
Ile Tyr Gly Tyr Arg Leu Arg Arg Lys Trp Glu Glu Lys Ile Pro Asn
465 470 475 480
Pro Ser Lys Ser His Leu Phe Gln Asn Gly Ser Ala Glu Leu Trp Pro
485 490 495
Pro Gly Ser Met Ser Ala Phe Thr Ser Gly Ser Pro Pro His Gln Gly
500 505 510
Pro Trp Gly Ser Arg Phe Pro Glu Leu Glu Gly Val Phe Pro Val Gly
515 520 525
Phe Gly Asp Ser Glu Val Ser Pro Leu Thr Ile Glu Asp Pro Lys His
530 535 540
Val Cys Asp Pro Pro Ser Gly Pro Asp Thr Thr Pro Ala Ala Ser Asp
545 550 555 560
Leu Pro Thr Glu Gln Pro Pro Ser Pro Gln Pro Gly Pro Pro Ala Ala
565 570 575
Ser His Thr Pro Glu Lys Gln Ala Ser Ser Phe Asp Phe Asn Gly Pro
580 585 590
Tyr Leu Gly Pro Pro His Ser Arg Ser Leu Pro Asp Ile Leu Gly Gln
595 600 605
Pro Glu Pro Pro Gln Glu Gly Gly Ser Gln Lys Ser Pro Pro Pro Gly
610 615 620
Ser Leu Glu Tyr Leu Cys Leu Pro Ala Gly Gly Gln Val Gln Leu Val
625 630 635 640
Pro Leu Ala Gln Ala Met Gly Pro Gly Gln Ala Val Glu Val Glu Arg
645 650 655
Arg Pro Ser Gln Gly Ala Ala Gly Ser Pro Ser Leu Glu Ser Gly Gly
660 665 670
Gly Pro Ala Pro Pro Ala Leu Gly Pro Arg Val Gly Gly Gln Asp Gln
675 680 685
Lys Asp Ser Pro Val Ala Ile Pro Met Ser Ser Gly Asp Thr Glu Asp
690 695 700
Pro Gly Val Ala Ser Gly Tyr Val Ser Ser Ala Asp Leu Val Phe Thr
705 710 715 720
Pro Asn Ser Gly Ala Ser Ser Val Ser Leu Val Pro Ser Leu Gly Leu
725 730 735
Pro Ser Asp Gln Thr Pro Ser Leu Cys Pro Gly Leu Ala Ser Gly Pro
740 745 750
Pro Gly Ala Pro Gly Pro Val Lys Ser Gly Phe Glu Gly Tyr Val Glu
755 760 765
Leu Pro Pro Ile Glu Gly Arg Ser Pro Arg Ser Pro Arg Asn Asn Pro
770 775 780
Val Pro Pro Glu Ala Lys Ser Pro Val Leu Asn Pro Gly Glu Arg Pro
785 790 795 800
Ala Asp Val Ser Pro Thr Ser Pro Gln Pro Glu Gly Leu Leu Val Leu
805 810 815
Gln Gln Val Gly Asp Tyr Cys Phe Leu Pro Gly Leu Gly Pro Gly Pro
820 825 830
Leu Ser Leu Arg Ser Lys Pro Ser Ser Pro Gly Pro Gly Pro Glu Ile
835 840 845
Lys Asn Leu Asp Gln Ala Phe Gln Val Lys Lys Pro Pro Gly Gln Ala
850 855 860
Val Pro Gln Val Pro Val Ile Gln Leu Phe Lys Ala Leu Lys Gln Gln
865 870 875 880
Asp Tyr Leu Ser Leu Pro Pro Trp Glu Val Asn Lys Pro Gly Glu Val
885 890 895
Cys
<210> 3
<211> 4620
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 3
cgtgtgtgat catggatgtg tgggtacatt tgtgtgtaag tgcatgtgga ggccagagga 60
cactctcagg tgtccttcct taggtacaga atatcttctt cttgagacag ggtttctcat 120
gggcctgaaa ctcagtaagt agactaggct ggcctggaac tcagtaagta gcctaggctg 180
gcccaccagg aagcccctgg gatctgcctt tctctctgcc tcctagtgct tggatcagaa 240
gtgtaggcca ccatacttga cctttttcca gtggcctctg ggcctctgac tcaggtccac 300
atgcttgcta acaaggttgt tacgcactaa gcgacctcgt cagccctgtc tgttggtttg 360
acttttgttt tgctttgtgg tttctggctt caatgtttta ctcaacccct aaaattaaag 420
acatagttta atggtcttaa tggcttagtt ttgagtttca gatctttaat tcaccttgga 480
tgtggatgta aagaaacaag ttcacttgaa agcacggttc cctcattgat tagaagccac 540
cagtcacgag tgtgcagccc ctctgtgcct cagtggctgg agacagtagt ctagctttct 600
aagctctggc acacttggtt agattcaccc ctgctttgat ctttgctctg actatgggtg 660
tttagtagca gatgctcatg cctttctgct ctgtattttg gactcagagt cagctcagtc 720
aggcactcac atccttctct attctttgtt actatctctc taagcctcag gagtcctctc 780
agcacactga tccctggaga cagagctggg tctctctcct ttgctagcat tggccggggg 840
ctggggcagc ccaagtcctc tctggctctg acattggcat ggggatcagg gggacaaact 900
caggtcatca gaacagtttg cacactgaac attcccatgg ccctggcaag taagttggcc 960
ctgtagcctc ttgctatgga tgcactgtgg gtggacgttt gagcttctct ccttccctgg 1020
tgaagtgctc caaacatggc caccatgcac acttctttaa caaatctgga tctgactggt 1080
ttgtgaaatg gttctgtctg ccctcccctc aatcatattt cttcatacac tcagggatca 1140
gggtgtgcaa acacttctgg tttcctgcac ttctccctct ctgccacctc caccctgccc 1200
ctttttttcc taggtcctca tctctctata cttatccttc gtcttcaaag gctatcaagc 1260
ctaacttgtt tttttttttc agactggtgc tcactgtgtt gcccaggcta gccccacatt 1320
cctagtctgg aataatcctt ccttactagc agctggaatt gtatgccccc caaggacctg 1380
actcagtcct taaggtcaat gctccctcct acttatattc tacaccagca cttgggttta 1440
attagcattt ttgagccctc ataaagccag gcatgtctca gcccattttc agttctcctc 1500
ttaccccgcc gccccccccc ccatcctcct ccaccacctc agagccacct cccaccttag 1560
tcatctgagg ttttgcctgg ttcttgcccc tgctgtgtgc tgcctcactg ttgcttcctg 1620
cagtgcaaat ctcccctaca tctctgcaag gcatgctgct ttctctgttc ccatactgca 1680
cgctgtcttg ctttaaacct gtctttcctg aaaaacatga tagaataact tcttttcagg 1740
aaccatctgg acatttcttc tctgccttcg tgcaaccaaa ccagacattg ggctggggtg 1800
gttacctcag agggacatga ggctttgcat gtggcttccg tcctttcctt gtgatccaaa 1860
atggtgactg gagtgccaac cgtcctttct gagatatagg aaagaaaaga aaaaagtgaa 1920
gacaaacgga ccttttacca tgccttttaa gtagtctttc ggaaagatac gtacagggct 1980
tccctcatgg ctccttggac agcatttaat caagtgaccc tgcctagtgg caggagagag 2040
taaaaggtat tattactttt attcttgtga aaaataatcc ccaaaaggca agggacagtg 2100
agggaagctg ccactgctgg ccatgcatat ccctgatcct cagcttgttc ccctttccag 2160
tgcttccacg gtgttctgga gagtgtcccc tgccttgtcc ttatccccat ttttgcacat 2220
ccccctcagt tgggttcttc tctgtggtgt ctattctgtg gtgtcactca tcattgcact 2280
gatctttcta aaatcccgag tctcctatct taggacttct tgttttttgt ttttgctttt 2340
gtttttacaa cagcagtctg tgtttaaata gctttaggct ctgcagtaac taagggatac 2400
aagctcagag attcaacttt tctcgccttg ggctctgtct ggtcaatata agtatggcag 2460
agcagtctga gttggggcag acataggaca ccaacgatca ggaaacacaa cctctcaggg 2520
aagcatggtg agagagggcg ggtcctcagc caacccacct gggctctgtc ccagcctgcc 2580
tcacacagct gtggcactgt ggcccatcac tccacatccc tataccgttt cctgtctgca 2640
aggattctca cagctgcctt gatcaagatg cattgatttc cccaaagcgc tttgcacact 2700
ggttgatggt gggcattaaa cctcaggcgc ctgctcatgg attctctgtg tgtatttaaa 2760
tactctgctg taggtgtttg atgacacagc tctgttgtct tttacagtag ataataactt 2820
attctccatg atttcaattg ttagggactg aatactcgtg caccccaaaa cccttatgtg 2880
gaaactactt tcccaggggg aggatacagg agactggtgt ccttctatta gacatcccag 2940
gacgctccct tgatgcctcc actgtggcag tagcagccag aaaagcctat gaggaagagg 3000
tctcatctga cctcaaacct gcatgtgcct tgaccttggc cttgccactt tccagaaact 3060
caagaaataa atgtctgtgg tttctatgaa ctatgggtgg tcttttgtga cagcctcctc 3120
ccaatgaaga cattggtcat tgatacatct gttttgttcc ccccttactt ggtgactctg 3180
ttggctttat gaaaggcagg cagttggctg caaacccttt catccctctt tgtcacagaa 3240
tcttttggtt acttgtaagg ttgacagctc aagggcacca gcagcaaagg tttgatgtga 3300
tttagcatgg gactttttaa ttaacctcac atatagggag gcttgtgaga cagaggtttg 3360
ggatttgtgt gtgttgttat tcaatcatct tagcattttc caatggaaca ttccatcatt 3420
ttatgctctt tcctggttcc tccttcattc atattgagca ttatggaggt aaaatgacac 3480
tcgttgcagt caaggggtcc aaagagtaga gatgtatatg gctgataggt aagagataga 3540
taaagataaa aacatagata gatgatagat agatagatag atagatagat agatagatag 3600
atagatgata gatagataga tagttgatac atgatagaga gacaatagat aaaagataga 3660
tgataggtag ataaattata gacataatga tagatgattg aaagatagat gatagatgga 3720
taatagataa atagatgaat agatagacag acagacagac agatagttga tacacgaata 3780
aataggcacg tgatgcaggc acatggatgg ttgcaagaat agatgtgcac atacagagat 3840
gaataataca taggtacatg gatgaactga taaatggatg atagaaggac agatgggtgt 3900
aggctgtgtg catcttgact caagtttcaa atgccggtag gagaaggggt cacagcaatg 3960
gctctgcaac tctggtactt cccaagagaa ctcaatgaaa acaaggaaat ccccagactt 4020
cagagaaagg ggaactggga agcagagggg cctgtgggag acctgatggt aaactaagca 4080
gaggcaggga gagcaccagg ctctgcctgt gctggagaac atagctgggt aggtgtgtgc 4140
agacagaaac aagagagcaa tcacacctag gcttgccccg accccacggc cacatccatc 4200
aaaggtgtgg gtctcagctc ctctatgtgg cctggtgcaa gcttaacagc agcttcactc 4260
tcacctctcc acactgcagt gtggtctgag gaaggatctg ctgcctcaga ggccatcaat 4320
ccatctcttc tatgttcctg ctttagcaca atgaggctta agagaaggga acagctctag 4380
ggcagcatgc atcagggcct cttctctggg ttcaggtcac ttggcatcgc agggtactgg 4440
acagctctca gccttacgca tctttttaca gccacaaagg atgcagtcta ggagggaaga 4500
atcacaagcc ctgtaagatg agtggagcca aacccccagc caagcaccaa tacagaaccc 4560
cgggacaatg aggacacccc cctgcccata gcttccagtg cagccaccaa aagtgccaaa 4620
<210> 4
<211> 4085
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 4
tcctgctgat ttcccttccc ttgaaccctg cagtcagtgc tggtgtgtcc catagtgact 60
gcctgacaca cactgtgcaa ggtggatgtg gggtggggga tggtaatgaa gcattccgca 120
tagtcagccc tgtcagaagg ggggatctca gagtgagagt cattctggaa gaaagagggc 180
tagagccatg aactccagag atggggaggg gacttacaag gccccattca agaaggctag 240
gggaccttct gctggaaacc ttcccatctc ctctgaccct ccctgcatca gtaagccata 300
gcccatgctc ctcatttcaa gaagtccccc agttgacaag ctcagtcacc ccccacccag 360
ggtacttgct gctgcttagg gcagaacttc cccatattga agacagggag cggacccagg 420
gtttcttccc aggttcctgg cctttctcac agagggcatg ggagacacta gcttcctccc 480
ttagcctgca gcttgtgcct cccatctaat gctgcttctc cttgttgacc aagtgatgcc 540
cacgctgtgg atagtcctca tcctggtctt tctcatcctc accttgctcc tgatccttcg 600
ctttggctgt gtctctgtat acaggtaagt gcactctgtg cgcagaggaa agtggaaact 660
gggctccggg gtcacagaga tgacacagct ggatacactc tcgttcccag cctaccattc 720
actcccctgg tttcagtttt ctctctatac gtgggcacag aagtagctgg cacagaggtc 780
tatggaatct cacatacacg tgtccccacc ctcctgctgt cttccaggac gtacaggaag 840
tggaaggaaa agatccccaa ccccagcaag agcctcctgt tccaggtagg aaggcaggcc 900
ctgctgctgg ctccctgtcc cattcctgtg tccgtgggaa agcgagggga agctggaagg 960
ctaggcagca ggaggtgggt atctggtatt gcctgggtgc ctgaaggagg agtctcacaa 1020
attggcctgc gttctgtctg gagccacaga cagaactcag agccttctag tgcacaaaat 1080
ggctcagaag agtcggctcc tggaggtaga gacagggctg agtgtctcca ggacaggact 1140
tgagcactgc acagcaagat gccttagagc tggtgggaga gctgattgca accagggtgt 1200
ctccaggggg tcagctcctg agacaggaat gggaatgaca gaaggacacg gctgtccatg 1260
tctcacagaa caatggtcat ggggagacac cagtgccatg agagaagagg ctatagggaa 1320
cagcatggct gcttacctca ggagctttag ggctaaggga acacaacccc taggatgcct 1380
cttctttctt ggagtcagag gcctgagctg ggccctacca gggggacatt cttcccatgt 1440
ccagagctta tggaagacac catatgcaca tgtgtccttc ctgaggtgcc acattcacag 1500
acacaaatgc cctttccttt gtaggatgga ggtaaaggtc tctggcctcc tggcagcatg 1560
gcagccttcg ccactaagaa ccccgctctc caggggccac agagcaggct tcttgctgag 1620
caacaggggt gagtgtttgg gctctgaccc ttggggagcc tgtgggagga aacctgtcca 1680
tggtgcacat cattgtagcc tgtgggtctc tgaatttgag aggagaggct gcccactgta 1740
gtaaacagca ctccaggtag acatgaggaa gactttttct gactccccgg ttggcgtgaa 1800
acagacaagg gaccagaggc agcatcccag agcaggaagc ctctccttgc caagtgacct 1860
atgtaagccc tgcactgcaa tggcctcatg ggtgactgag agtgcacact gtgggacttc 1920
agcctgctaa gcccacatgt cagggagtca gcagccccat atgggcaggt gtgaacccgg 1980
ccctgaaggt tcacacttgc tgcaaggagc agaagagagc aaacattagg atgggggtgt 2040
gaactgagcc ctgagcacgt gacactttgg gacactggac acacaccatg tcattcacag 2100
gacctcatgc ctcggtgctt actgtgaggc ccagagggga ttcaggcctt cctagagctc 2160
acctgctctg gctatacact aagtgcctag gttcaacatc tctgccccta ttgtcccgac 2220
agggagtcat atgcacattt ggaagacaac aacgtgtcac ctctcactat agaggaccct 2280
aatataattc gagttccacc atccgggcct gatacaaccc cagctgcctc atccgaatcc 2340
acagagcaac ttcccaatgt tcaagtagag ggaccaactc ctaacagacc taggaagcaa 2400
ttacccagct ttgacttcaa tgggccctac ctggggcctc cccaatccca ctctctgcct 2460
gatctcccag accagctggg ttccccccag gtgggtggga gcctgaagcc agcactgcca 2520
ggctccttgg agtacatgtg tctgccccct ggaggtcaag cgcaactggt tccattgtcc 2580
caggtgatgg ggcagggcca ggctatggat gtgcagtgtg ggtccagcct ggagacctca 2640
gggagccctt ctgtggagcc aaaggagaac cctccagttg agctgagcat ggaggaacag 2700
gaggcacggg acaacccagt gactctgccc ataagctctg ggggccctga gggcagtatg 2760
atggcctctg attatgtcac tcctggagat ccggtgctca ctctgcccac agggcccctg 2820
tctacctctc tgggcccctc tctagggttg ccctcagccc aaagccccag tctctgtctt 2880
aagctgccca gggtcccctc tggaagccca gctctagggc caccagggtt tgaggactat 2940
gtggagctgc ctccaagtgt gagccaggct gccaagtccc ctccaggcca tcctgctcct 3000
cctgtggcaa gcagccccac agtgatccca ggagagccca gggaggaagt gggcccagca 3060
tccccacatc ccgaaggcct ccttgttctt cagcaggttg gggactactg cttcctccct 3120
ggcctgggac ctggctccct ctcaccacac agtaagccac cctctccaag tctgtgttct 3180
gagactgagg acctagtcca ggacttgtct gtcaaaaagt ttccctatca gcccatgccc 3240
caggcgccag ccattcagtt tttcaagtcc ctaaagcatc aggactacct gtccctgccc 3300
ccttgggaca atagccagtc tgggaaggtg tgctgagtct gtctcctccc aatctcacca 3360
gcagcctggc accgcagcct gtggtcctca gcctgagcat caccacagaa gcctctctga 3420
gttcacactc ctccttgctc ccagccctga catggcaata ccccacctgt gcttttctct 3480
tccccctctg tccctcttcc cctccctcca tgcaccccca tctctctctc tgcagttttc 3540
tgccttctat gggaacttcc ttcctattcc tctgacctgt tggagtgggg atgaggcctg 3600
tgagggtatg ggctgtttag ggtttacaaa cctgtgaggc cggacggtgg tggcgcattc 3660
ccttaatccc agcactctgg aggcagaggc aggcagattt ctgagtttga gtccagcctg 3720
gtctacaaag tgagttccag gacagccagg actatacaga gaacccctgt ctcgagaaac 3780
caaaaagaaa aaaaaaaaag aactgctgag gtcggcttgt ccaccacagg cattggtaat 3840
acagcacatt tctggctctg tgtgaaaggt gggagtctca ggtgagcccc ttgggaggtc 3900
agactgtaca attgggcagg ctcttgtcgc tacaagaata gacatggtcc tctatggttg 3960
tctgaaactc ctggggagac ctggggaacc ttgtagaggg tacttggtac cctccttata 4020
tacagaaatc actgatgtgc acaaagctgg acacagctat ggccaggctg gagggatgag 4080
aagca 4085
<210> 5
<211> 11777
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 5
atggtgctgg cccaggggct gctctccatg gccctgctgg ccctgtgctg ggagcgcagc 60
ctggcagggg cagaaggtga gtcccgtggc tcccacccac ttccctgtcc ctgtcctcac 120
tgctgcaccc tgggggaggg ccgcagcgta tcctcaggat cctgcccgcc agccctcctc 180
ctgctcccct ccctctgtct ctccccctgg ccttccctgg gcctcccccg cttccctcct 240
cctgcacatt cctgctcatc ctgtcttgga aagtccagct gagcgtgtct ggcttccttg 300
cccacatttc tcagggcggc actcccggcc cctaggctcc aggatggctg ctctggccgt 360
ttccctgccc ctccttcccc agcagacact ctctgtgcct cagtggttcc cacctccggg 420
actttgctcc tgcagggcct tggctggggt tctctccctg cttcagccgc tagcaccctc 480
cttgtgcctg aagcccgcac tgggatgctc ctgggctctt gaggtgaaat ggcccctccc 540
aagggctccc agagacctgg cttctgtgat aatgctggga ccacagtccc cttaacaaat 600
accaggctcc tgaggacggg gactagagag gaggtgggag gttgcagggt agaactctgc 660
cacgctgcat cccagggctg agtgtgtgcc ccctcccagg ctgcacagtc ggtccagggg 720
ccaggcctgt gcttgatgca tgtccctgtc ctggggtggg gggaggggac cgtgcccagg 780
aacagcacac tgcggaggcc cagaaaccat gctgagaacc aacagaatgt cttgcttctg 840
ccaggagagg agggtccgca accaggagcc caccccggca gacatgaaca catgtacatg 900
tgcctggcca cctggtgcct ctgcagggac ctgggagacc cctccccaga gcgggacatc 960
ccaaagcagc tgggggtgat ggtgacaagg gtccctgcag gaaagagagg tgaccccctt 1020
ctacccctct tgtcagaaac catcccgctg cagaccctgc gctgctacaa cgactacacc 1080
agccacatca cctgcaggtg ggcagacacc caggatgccc agcggctcgt caacgtgacc 1140
ctcattcgcc gggtgaatga gtgagtgatg ctgggggcag gggccacggg caggggctac 1200
gacgtcccct gtgcctggca tggggcgaca gtgtagagag ggacctgtca ggtcagcctc 1260
ggggtgggag tggacagagg acagaggagg agggaggccc tgcaagagct cctgctccgc 1320
caggcacctg cgaggccggg tgctgccgtc tgacctgggg tttctgcgga gtgcctccta 1380
cactgatgtt ggtgacaatg gtggtggtgg caatggtgaa aatcttctct tgtttcatca 1440
caatttaaca caattgcccc acatgaccta tcttagttcc tcctcactgt gaggtgggca 1500
gggccaggcc acgaagcccc agctgtgcca ctgcctgcct gtccagagta gaccaaggag 1560
agatggcgct agcctgggag ttcacagatg ggaaaactga ggccctggag gtgaggtgcc 1620
agccctggcc acggggtaga cagtggcaga gcaagctgtg tggacgtgtc tgggaggggg 1680
ctccgcgctc tcccaggccc cccctccgta tgtgggctgc cacctctccc acccaagctc 1740
tcctgggcac gtgccacaag ggaaggggac cagaatcgct ctggggtgtt ggccagggtc 1800
taaatcagcc ataaattaag taattaaata gctggaacca gagaggcaga tgacaaccca 1860
ttggaggtca ccccagcgtt ggggggcggg gccggctctg ccacccccac ccctccaccg 1920
ccttcagttc tccagggcgt ctctgtcgga ccttctccat tctcctcaaa gaccatcctg 1980
cccctccctg tgacctgctt cctgctgctc tgacacaaca ggggaccagg gagaagctcc 2040
ccacccaccc cacactcaca ctccccaccc cctttgccca ccgccggggc ctgggcctgg 2100
accagggctc ctgtctgagg cctgagacac gatgctgtct ggtcctgttg ctcaggaaca 2160
tcacggcccc caagtcccca ctctgccctg tgccacccac catgccctct cccaggatct 2220
ttcccaattg ccttgcaaac ctgccccaac cccctctcag atgcccacag gagtgcagcg 2280
cctgggcatc tcctgacctg gcaaccctgc ggcccctctt tctctgcttc ctttgacagc 2340
agcattccct aaagagttgt ccacattcac cacgtccagt gtctttccag ccatttcctc 2400
ctgggcccac tcccctagga tgctgccccc accaggccac ccaaactgct ctggtccaag 2460
tcagcaaatg tcccagggag caggatctca tggttgggcc tccgccttct tcctacttga 2520
ccaggggcag cccctgacaa ggaggaccac cgcggcctcc ctgcagtttc tcttgcacct 2580
gactctgccc acagctcacc cagtgccccc ggggccctgc ccatcctcct ctttctcctt 2640
gtctgctgcc tcctgatggc aagacaccca ggcccagtcc atggacctcc tctctgctgt 2700
atccactctg cagagacccc ctcaggcccc tggggcatct cccaaaggtg acctcaagcc 2760
cacaattccc ctaagctcca gccctccagg cgtactggcc tctccacctg tcacttagac 2820
aacaggtgtc tccgactcca aacgtcctca accaaagtcc cgctctcacc cgagctgcgc 2880
tgctgcctct gtcttcccca tctccctttc taaatgggag ctcctagtgg ctcaaactaa 2940
acaacaggga ggattttgtt ttgtttttaa gtctcttttg tcaccattcc ttcctgactg 3000
ctacatccct ccaccagcaa atgctgccaa ccttatctca agcagaacat gaatctcacc 3060
cacgccagcc tgaccaccct gttgcacgcc acttcctgtc acctgaatat tccagaagcc 3120
tcgtaactgg gctccctgct tccaacattg ccacattccc acctcagtct attcgcaacc 3180
gaggaccctc aggaatcctt tcaaagcatt tatcaaaatc tacaacacct ctgctcatga 3240
ctgtttccca ctcactcgca gtgagatcca atcccatcat gtagatggat gggtctccta 3300
gacctcccta tcacacgctc tactccctgc gcactggttt taggccaagc cacgcagcac 3360
accaaactct gcctgtccca gggcctttgc acgtgctgtt cccatttcct gaaatcctca 3420
caatttgcac agtccctccc tcaatgcctt taacattctg cccccaggtc acctccttag 3480
agaagcctgc ttgtcccata tttcaaattg cctccctggc ccagcccttc ctccctcctc 3540
acctgcttct tgctttattt ttccacatga agttctctcc actgcacacg ctacacactt 3600
tgttccatgc gggtcccctt ctcccaggat ggcagctccg tgggcaggat ttttgtgtgt 3660
tttatcactg ctggcccctg attctgaaca gagccaggca tgtggtgagc actcgaggaa 3720
cctttcgtga gtcagtgata cccatacacc ctgggctaag ccgtgtcctc tcccaacagg 3780
gacctcctgg agccagtgtc ctgtgacctc agtgatgaca tgccctggtc agcctgcccc 3840
catccccgct gcgtgcccag gagatgtgtc attccctgcc agagttttgt cgtcactgac 3900
gttgactact tctcattcca accagacagg cctctgggca cccggctcac cgtcactctg 3960
acccagcatg gtgaggggct gggggccctg cccggggctt ggtttcctgt gtggacagcg 4020
ggggcaccag gggtggtcca gggagtcttc aaggcagaag gctgtggctt ggggttgggt 4080
gagggtttct tgagggatga gggtatggtc tggttacatg gagacttcag agcagagggg 4140
cccctgacaa aggcttctcc tgtgcccctg gctgctacca cctcccacta agccatgggc 4200
ttccagcact gcaggcttgt cttgaagaaa accgttctca ccactcactt agaaacctac 4260
caagttagaa aactctgtcc gcttagttgt ttcatctcat ctctgaagca acccatttcc 4320
tggatgtggc ccttgaggcc caggaggtca gatgcctcct ctgaagtccc acagctgagc 4380
agtaatgaca gagatggggt cagccttccc gggggcttcc tgcatggtag acagggagct 4440
tgtctcctcg ctgccctgga ggaggggccc cggtgtgggc cgaaatccca cagtggtcca 4500
tgaagccatc tgtggtctag ggtggggtag atgattattt tatgtagtta ggttttattt 4560
gcctctatat tagaaagaaa tataacctgc acttcgaagt cctggattca aggaaatggt 4620
tgcttagaat gaagctaaac ctgaaaaggg acacgtttta tgaaagtttt cgttgacgtg 4680
gcaaaaaccc atgctggtgg caggctggta ggaggtactg caggctgtca ttgggagtct 4740
cagaaccacg gcaggcttgg tgctgttatt ggtgcctttg gctgctgctg aaacggagac 4800
agagggaggt gactagtcca aggcctctct actgctgctg gcagagctga gatccagtgc 4860
aggatggtct gagtccccgg tcctaaccac cgaaccacct ggtgctcttt gcaagggtca 4920
cacggaaggg gctctgacca tggcttcctg cccttttttg ccacaacatc ataaagccac 4980
tgccagagga ggggatcagt taggccacca ggagtccatc agaagcaaca tttccacaca 5040
tgggtttgat ggacacgaga gtcccttcct tcccgaatgg agctcagggg gcccaggctg 5100
gagggagggg aaacactgta tgccgtccac cgtgagaact tactgacagt ggcgggtggg 5160
tgcctcatgc agggggtaaa gggcagggcc cctgggagat cagaacaggc ttcccagagg 5220
gaagagcttt gcaactcaga tctgaagggt agacaggagg ggagggcagt aagagcctct 5280
ctggcagggt aacagctgtg cagaggctgg gggatcagaa gggcatgggc agctggggaa 5340
cctgctcacc attgtgtcca gggagcatca gcttcaaggg ctggacagcg gtgggaagaa 5400
gcaggagaca caggtaagga cctgtccctg gagaggcttc tgtctcctgc agtctcaggt 5460
agaggggacc ctctaggcat ggagagcact gaggggaaat gacatgatca gatgtggatg 5520
tgagaatgct ggggacaggg gacttacagg gtagattgga ggagcattag ttgggaaaga 5580
agttgaaatt caggctgtgg cctaaagcac tcattcctag aaatgatgag gacacaactg 5640
gctaggagat ggggacatga gggcatgcaa atcatagttc agatatacac acaattcatt 5700
cattcaacct tctttccttg agcgcctaca taagccaacg aagcagtcaa caaaccagcc 5760
agcaaccctg cccttggagc ttacagcctg gaaacaagga aggtttctaa ggcgatggag 5820
acaacttaga tatagggaga gaagtgtggc ccttggcctc ctggagcctg tgttgagtag 5880
cgaggtaggg tccagcctaa tgcagattag caatgaatca aggatgctgg gaggtactgg 5940
gcaggcgaca ggcatgcatc tgatctgctc tgagtctcca tgtttggaga ccttggacat 6000
tttacttcct ctatgagttt ctccgtctgt gaaatgagct ggtggactca agaggtttct 6060
cttgagttgg ctgagcaggt ttctgatggg gctcccagtc tgcgcagttt gtggcagctt 6120
ccgagagggc tctgccggga agagctcccc ctccatgaca gcctcggggg ctgggagtgc 6180
agtgacccat gagggacgcc tgtcctggct gtgggtgagg aggggcggtt cccctgctgt 6240
gtgtctgccg ttctgggttg atggttcctg acatgctcta gcatgccata acccatgtcc 6300
agcagagagc acttacatcc tatgtgtgag gatgttttcg tttgaaagcc atccctcagc 6360
aagcagacac cagaaaccag aaatcaggtg ccgtgtcttc attctgcatt ttcttgaaca 6420
acccagagtt cccaggagat agatgcttgc cttgtggctg caaggatttc atgagaagcc 6480
ccaaagttgc ttacgcgtat ttgttcattc attcactcat tcaccttgcc ccataattca 6540
ctgagaagcc gcatctcagc ctggaggtag ggaagggggt caggaccaat cccacccacc 6600
cccatctcct cacaccttag gggaggcaga cacagaagca taggaatccc tcagctgtgg 6660
taaggccctg gtggagggaa ttccactgag ctatggtgaa atgagagaag gaatgaggga 6720
ttccgcctgg agatgcagat ccgaggatgt tcctagagcc ggaggcattt gcccggggca 6780
ctgacaacag gaaggaccct gggcaggagg aagggagctt ggacagcagg aggggggagg 6840
ccgctgaacc gcaggcccct ctgctagcag gagccaccca ggccgcagcg tgggcagtgg 6900
ggagcctcag gacagaggag gctccaatga gtttcctcgc cagcgctttt tatggagttc 6960
gggtcacgtg cgcattgcaa tctgcacggc tttccattgc tttcatgttg aaaccctaca 7020
gttttgcaga tgaagggctg aggctcacag aggagacggg tcttgctcaa ggtccctcag 7080
ctgctggggg caggggtggc ctggaacccc ctgtgtccac acaaaaggcc atgcaggccc 7140
tgactgcccc ccagcggtcc agcccttagg tgcccttcac ttcctcccct ccagtccagc 7200
ctcctgagcc cagggacctg cagatcagca ccgaccagga ccacttcctg ctgacctgga 7260
gtgtggccct tgggagtccc cagagccact ggttgtcccc aggggatctg gagtttgagg 7320
tggtctacaa gcggcttcag gactcttggg aggtaggaac cacggccagc tctgccccag 7380
cccgaaggga tgggcagcac ccctcctcca gcacccactg tctcctgaca ggacgcagcc 7440
atcctcctct ccaacacctc ccaggccacc ctggggccag agcacctcat gcccagcagc 7500
acctacgtgg cccgagtacg gacccgcctg gccccaggtt ctcggctctc aggacgtccc 7560
agcaagtgga gcccagaggt ttgctgggac tcccagccag gtaatgttgc cagagcccag 7620
gaaatgcccc gtggtgggag ggcaggctca tcaggagctc ctggcacagc agggttcctg 7680
ggctccacct gggggcttcc cagatctcct gctgccatct ttccagtagc gtccctgggc 7740
cgtcccacct ctactgtgac cactgaccag taggactctg catctgttca ctttgggttt 7800
ccagttttct gcacgttctc tgccaatggc aattacaata ataacaacaa cagtgctatt 7860
agcagctgtg tgttaatgga ggctacagga tgctcagggc ttacccacat ttttcagttc 7920
aatccccaaa cactgaaact tagatactat ttccattctc ccgggagggc gtgcaggtgc 7980
acagaactct ctctctctct ctcggagctg ttggacacac agctggcagg ttcaggctga 8040
agtttcagcc ctggtctttt ggccccagag ctcatgacct ctgtgtgatg aatcacacgg 8100
tgggcaccca ctgagagcta tgggagggat gaatgacgga gtacatgagg acctgtctcc 8160
aacccagggg atgaggccca gccccagaac ctggagtgct tctttgacgg ggccgccgtg 8220
ctcagctgct cctgggaggt gaggaaggag gtggccagct cggtctcctt tggcctattc 8280
tacaagccca gcccagatgc agggtgagca tcttttttct ccatcccctc ccctcctctt 8340
ggccttgctc tctccaagct tcctcctgtc cctggggccc cagcagaagc cacagcccac 8400
cctaagctct cctccctccc gtgtgccctc cctctccctg ccctcagctc tgctgtgctc 8460
ctcagggagg aagagtgctc cccagtgctg agggaggggc tcggcagcct ccacaccagg 8520
caccactgcc agattcccgt gcccgacccc gcgacccacg gccaatacat cgtctctgtt 8580
cagccaagga gggcagagaa acacataaag agctcagtga acagtgagtt tgctcctagc 8640
ccgctgtggg gatggtctgg gaccagcaca ccctcattgt gtaacccgaa tcagttcagg 8700
gttcctcctg gccccgtctt catgtttgtc actttcaaag agatgcagtc cagtgaccaa 8760
aagtgaacag agaagcaatg aaaccacgac ggcagtggcc aaaaacagga gcagatcttt 8820
aaaacctctg atctcttgtc cttttcttct gcttccctct cccatcctgc agctctctaa 8880
atctccactg ctagccacac cctcctggtc ctgtcaccaa aaccttccct ttcattcctc 8940
attggatttt cctctttctg atatccgaaa ttccccaccg actgatattc tatctttaat 9000
gtaattgatc tatgatgtac ttttcaactg gagcctgtgg tgtgtacaaa tagtgttgat 9060
ccttggaggt taacatccct cgtttctgtg atgtaacaag gaccccagtg caatggaacc 9120
tctcacgttg tttcatgatg accaagttct tccatccagt ctttagcata tgtgaagggc 9180
agaggccaat ttgtcttaat tacctgggtt tgaatttacc attaactctc ttgggatcct 9240
cactggaaaa aggaattctg attgttcaaa agcacaggat atattaaggg cctcatataa 9300
tgcctggcac ataagagacc tcagcaaatt acgggcattc atattatgtt tatacagtga 9360
aggcatcaag gttataagca ttctcttttt tcttttgggt agactgaagc tcagagaggt 9420
tgagtggctt acttaaagct gcacagctat tagtaggcag atcaagatta gagttcagaa 9480
cttctcactc cctgcccagt ttctgctttc tttacccttt gcctctttca agttgtgggt 9540
ctgccggcca ggtgggaggt gctgtctgca aagggcttcc ctttctcttt ggccactatc 9600
tggctgggga gaggcctcac ctagatgttg ttgaaggcct gttacagccg ctttattggg 9660
gattttctgg cgatgagaac gtgtgaatgt cctggccttt agtcaactcc ctacacctct 9720
gagagtgtca gacaagagag cccatcacac tggtgggatt gcaatctttg cctctaccac 9780
tgcttagctg cctttcctta gggcaagtta cttaatggtt ctgtgactca gtttccctgt 9840
ttgtgaaaag tgaaggttaa tagtacccac catatagggc tgttagaatg gagtggaata 9900
attcatgtag aataagtatg tataacagtg gctaaaacat agtcaggctg ggcgcggtgg 9960
ctcacgcctg taatcccagc actttgggag gccaaggcat gtggatcacg tgaggtcagg 10020
agctcaagac cagcctggcc aacatggtga aaccccgtct ccactgaaaa tacaaaaatt 10080
agctgggctt ggtggcgggt gcctgtaatc ccagctactc gggaggctga ggcaggagaa 10140
tcacttgaac ccaggaggca gaggttgcag ttagccaaga tcacaccact gcactccagc 10200
ctgggcaaca gagtgagact ccgtctcaaa aaaaaaaaaa aaaaaaatag ccagttgcct 10260
agaatagaac caactaacag tggttttatt tttactgcaa aaaataaaaa taaaaatagg 10320
agtagtgcaa gcactgggcc acatcactac aaaacaagtg tatctcagca tctcccacga 10380
gaataccact caggtcaaaa catgatatag tgaagtgggg atgaaaagga tccaaccatg 10440
ggcagaacct ggggtctggt gccagtggag acagccccag tgtctagcat gagacacggg 10500
gaatgttccg ttggagggtg ggtatgatga ctctcctgaa agcttccctc cctccagtcc 10560
agatggcccc tccatccctc aacgtgacca aggatggaga cagctacagc ctgcgctggg 10620
aaacaatgaa aatgcgatac gaacacatag accacacatt tgagatccag tacaggaaag 10680
acacggccac gtggaaggtg agggcctttg cccagggagg ggagaaacac tggggagggc 10740
gggagaaggg aaagcaacca gaggcattcc acctgcaagg cgtcgggccc ttggcaggtg 10800
accagtgaga ggtagccact gggacgtggt gatcactagg ctgtgtggtc agcaggtcac 10860
tgtcctgtct cttggtgaag taactgaggt ttggaaaagt ggcgtggctt ggccaacgtg 10920
aacagctgac cctgagtccc caggcaacag aagaccctct gggcagggag gggttgaaag 10980
gccactggga agaaggtttt caaaagtcat gaaagtttgg ggttatttcc tcagaggaat 11040
ctcatctgga cacacatgga ggctcagaca gagctgcttc taatgagtcg ggggtgcgcc 11100
caggccaggg ctcggtcccc tgcctccaca gagcccagaa cagaaaccac agaaccaacc 11160
ccacaccttc agtctagaaa tggggcaact gaggctagga gggaggtggg ccagtggtgg 11220
agccaggagc gggccctggg gtcctgaacc cccattctca gggtccagag tccagtcggc 11280
ctgcactgcg ttcctaaaaa ggccacaata tgggtgcaag ctgccccaga agggctggga 11340
gctgagaagg ctcaaaatag ggtgggacag gtggcttcag ggttctgggc ctcagtgttg 11400
tcaatgtcag gggctgcact gacaggtgga gtccccggtg ccatccgaag tgctgtccgt 11460
gggtgggccc tcagggagga tccacggtgg tgagagagaa gccgcagcag gcctggggta 11520
tggcaggagc taggagccag cgaagccgag ggtccaggtg ggagggattt gcagctgctc 11580
ccacgggcac cgggccaggc ctcaccctca gtgccaaccc acaggacagc aagaccgaga 11640
ccctccagaa cgcccacagc atggccctgc cagccctgga gccctccacc aggtactggg 11700
ccagggtgag ggtcaggacc tcccgcaccg gctacaacgg gatctggagc gagtggagtg 11760
aggcgcgctc ctgggac 11777
<210> 6
<211> 4776
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 6
aatctgctct ctgtttcctc cagatggggc acagataaat aggaagagcc tgcaactcac 60
tggcacttgg aggctcccga aggaggctgc ctgtcgccca agcacagagc cacaaaggat 120
gcagtctagg agggaagaat cacaagccct gtaagatgag tggagccaaa cccccagcca 180
agcaccaata cagaaccccg ggacaatgag gacacccccc tgcccatagc ttccagtgca 240
gccaccaaaa gtgccaaaat ggtgctggcc caggggctgc tctccatggc cctgctggcc 300
ctgtgctggg agcgcagcct ggcaggggca gaagaaacca tcccgctgca gaccctgcgc 360
tgctacaacg actacaccag ccacatcacc tgcaggtggg cagacaccca ggatgcccag 420
cggctcgtca acgtgaccct cattcgccgg gtgaatgagg acctcctgga gccagtgtcc 480
tgtgacctca gtgatgacat gccctggtca gcctgccccc atccccgctg cgtgcccagg 540
agatgtgtca ttccctgcca gagttttgtc gtcactgacg ttgactactt ctcattccaa 600
ccagacaggc ctctgggcac ccggctcacc gtcactctga cccagcatgt ccagcctcct 660
gagcccaggg acctgcagat cagcaccgac caggaccact tcctgctgac ctggagtgtg 720
gcccttggga gtccccagag ccactggttg tccccagggg atctggagtt tgaggtggtc 780
tacaagcggc ttcaggactc ttgggaggac gcagccatcc tcctctccaa cacctcccag 840
gccaccctgg ggccagagca cctcatgccc agcagcacct acgtggcccg agtacggacc 900
cgcctggccc caggttctcg gctctcagga cgtcccagca agtggagccc agaggtttgc 960
tgggactccc agccagggga tgaggcccag ccccagaacc tggagtgctt ctttgacggg 1020
gccgccgtgc tcagctgctc ctgggaggtg aggaaggagg tggccagctc ggtctccttt 1080
ggcctattct acaagcccag cccagatgca ggggaggaag agtgctcccc agtgctgagg 1140
gaggggctcg gcagcctcca caccaggcac cactgccaga ttcccgtgcc cgaccccgcg 1200
acccacggcc aatacatcgt ctctgttcag ccaaggaggg cagagaaaca cataaagagc 1260
tcagtgaaca tccagatggc ccctccatcc ctcaacgtga ccaaggatgg agacagctac 1320
agcctgcgct gggaaacaat gaaaatgcga tacgaacaca tagaccacac atttgagatc 1380
cagtacagga aagacacggc cacgtggaag gacagcaaga ccgagaccct ccagaacgcc 1440
cacagcatgg ccctgccagc cctggagccc tccaccaggt actgggccag ggtgagggtc 1500
aggacctccc gcaccggcta caacgggatc tggagcgagt ggagtgaggc gcgctcctgg 1560
gacacttgga agactgactg ggtgatgccc acgctgtgga tagtcctcat cctggtcttt 1620
ctcatcctca ccttgctcct gatccttcgc tttggctgtg tctctgtata caggacgtac 1680
aggaagtgga aggaaaagat ccccaacccc agcaagagcc tcctgttcca ggatggaggt 1740
aaaggtctct ggcctcctgg cagcatggca gccttcgcca ctaagaaccc cgctctccag 1800
gggccacaga gcaggcttct tgctgagcaa cagggggagt catatgcaca tttggaagac 1860
aacaacgtgt cacctctcac tatagaggac cctaatataa ttcgagttcc accatccggg 1920
cctgatacaa ccccagctgc ctcatccgaa tccacagagc aacttcccaa tgttcaagta 1980
gagggaccaa ctcctaacag acctaggaag caattaccca gctttgactt caatgggccc 2040
tacctggggc ctccccaatc ccactctctg cctgatctcc cagaccagct gggttccccc 2100
caggtgggtg ggagcctgaa gccagcactg ccaggctcct tggagtacat gtgtctgccc 2160
cctggaggtc aagcgcaact ggttccattg tcccaggtga tggggcaggg ccaggctatg 2220
gatgtgcagt gtgggtccag cctggagacc tcagggagcc cttctgtgga gccaaaggag 2280
aaccctccag ttgagctgag catggaggaa caggaggcac gggacaaccc agtgactctg 2340
cccataagct ctgggggccc tgagggcagt atgatggcct ctgattatgt cactcctgga 2400
gatccggtgc tcactctgcc cacagggccc ctgtctacct ctctgggccc ctctctaggg 2460
ttgccctcag cccaaagccc cagtctctgt cttaagctgc ccagggtccc ctctggaagc 2520
ccagctctag ggccaccagg gtttgaggac tatgtggagc tgcctccaag tgtgagccag 2580
gctgccaagt cccctccagg ccatcctgct cctcctgtgg caagcagccc cacagtgatc 2640
ccaggagagc ccagggagga agtgggccca gcatccccac atcccgaagg cctccttgtt 2700
cttcagcagg ttggggacta ctgcttcctc cctggcctgg gacctggctc cctctcacca 2760
cacagtaagc caccctctcc aagtctgtgt tctgagactg aggacctagt ccaggacttg 2820
tctgtcaaaa agtttcccta tcagcccatg ccccaggcgc cagccattca gtttttcaag 2880
tccctaaagc atcaggacta cctgtccctg cccccttggg acaatagcca gtctgggaag 2940
gtgtgctgag tctgtctcct cccaatctca ccagcagcct ggcaccgcag cctgtggtcc 3000
tcagcctgag catcaccaca gaagcctctc tgagttcaca ctcctccttg ctcccagccc 3060
tgacatggca ataccccacc tgtgcttttc tcttccccct ctgtccctct tcccctccct 3120
ccatgcaccc ccatctctct ctctgcagtt ttctgccttc tatgggaact tccttcctat 3180
tcctctgacc tgttggagtg gggatgaggc ctgtgagggt atgggctgtt tagggtttac 3240
aaacctgtga ggccggacgg tggtggcgca ttcccttaat cccagcactc tggaggcaga 3300
ggcaggcaga tttctgagtt tgagtccagc ctggtctaca aagtgagttc caggacagcc 3360
aggactatac agagaacccc tgtctcgaga aaccaaaaag aaaaaaaaaa aagaactgct 3420
gaggtcggct tgtccaccac aggcattggt aatacagcac atttctggct ctgtgtgaaa 3480
ggtgggagtc tcaggtgagc cccttgggag gtcagactgt acaattgggc aggctcttgt 3540
cgctacaaga atagacatgg tcctctatgg ttgtctgaaa ctcctgggga gacctgggga 3600
accttgtaga gggtacttgg taccctcctt atatacagaa atcactgatg tgcacaaagc 3660
tggacacagc tatggccagg ctggagggat gagaagcaat gggaaggctg tgtgtctaga 3720
actcatggtc tcaactgcag acaagcttag ttgtggatcc tggacagcac acccagatac 3780
taagtctaga cagctgagct gttcgttagt tctccctcca gagcaaagcc tggatacctg 3840
tgctcccacc ggcctcagat gagggtctgc tgtgagactg tggcccttgg ccatcaccac 3900
cctcttgaca atccatgcac aatgccatta cctcattctg ttctcactgg agttgtttgt 3960
tcatggtcac gtttgcacat ggcctttgtg tgtgtctcga gcattggctt tttgggtggt 4020
agcgaggaag tagacttgga agttgagctc atgaacagtt ttgtgcttca gactgtcttt 4080
tttggatgag actgaatagc tcttcccaca tggcctcttg tgggccacac gtgtctcccc 4140
tgagtgtcct aattttgtgc aggaggcaca ccagctctgt cagccattgc gtgtctgcat 4200
tgctatgaga tgggttgccg agccacacct gtctttgggt ccctgtttgc aggggtcttt 4260
gctgtaagtg cacacgtgcc tttgtttatg ttctttctgg ttccttctgt gtctaaagcc 4320
ttgagtgaga gacttggagt tttctagaac acatgatctc tctacagagt tcagtcttga 4380
tgtgttctat ggacctggag tcaatggaca ttgtatcatt tcttcaccta tttgtgctct 4440
gtcaggcact ccatgatcca ccaagtcatg aactggatct ggtctgtcct atcccctggc 4500
ctcactcaca tgatggcaga catagaatgt ggcagatcaa atgtcccttg gtctctgttc 4560
attgcagcaa agaaaaccac taacatcttg agtgtgttgc agtggcaatg ttcaacatca 4620
gcctgtcaat actttccaaa gtgaccactc tagagaaaca aacaggagtg gcctccatgt 4680
taagatgtga atgccaaagt gccttgcata agaggaaata ttgtaataaa catgtttaca 4740
tacaataaaa cagcaaaaca aggcaaaaaa aaaaaa 4776
<210> 7
<211> 893
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Met Val Leu Ala Gln Gly Leu Leu Ser Met Ala Leu Leu Ala Leu Cys
1 5 10 15
Trp Glu Arg Ser Leu Ala Gly Ala Glu Glu Thr Ile Pro Leu Gln Thr
20 25 30
Leu Arg Cys Tyr Asn Asp Tyr Thr Ser His Ile Thr Cys Arg Trp Ala
35 40 45
Asp Thr Gln Asp Ala Gln Arg Leu Val Asn Val Thr Leu Ile Arg Arg
50 55 60
Val Asn Glu Asp Leu Leu Glu Pro Val Ser Cys Asp Leu Ser Asp Asp
65 70 75 80
Met Pro Trp Ser Ala Cys Pro His Pro Arg Cys Val Pro Arg Arg Cys
85 90 95
Val Ile Pro Cys Gln Ser Phe Val Val Thr Asp Val Asp Tyr Phe Ser
100 105 110
Phe Gln Pro Asp Arg Pro Leu Gly Thr Arg Leu Thr Val Thr Leu Thr
115 120 125
Gln His Val Gln Pro Pro Glu Pro Arg Asp Leu Gln Ile Ser Thr Asp
130 135 140
Gln Asp His Phe Leu Leu Thr Trp Ser Val Ala Leu Gly Ser Pro Gln
145 150 155 160
Ser His Trp Leu Ser Pro Gly Asp Leu Glu Phe Glu Val Val Tyr Lys
165 170 175
Arg Leu Gln Asp Ser Trp Glu Asp Ala Ala Ile Leu Leu Ser Asn Thr
180 185 190
Ser Gln Ala Thr Leu Gly Pro Glu His Leu Met Pro Ser Ser Thr Tyr
195 200 205
Val Ala Arg Val Arg Thr Arg Leu Ala Pro Gly Ser Arg Leu Ser Gly
210 215 220
Arg Pro Ser Lys Trp Ser Pro Glu Val Cys Trp Asp Ser Gln Pro Gly
225 230 235 240
Asp Glu Ala Gln Pro Gln Asn Leu Glu Cys Phe Phe Asp Gly Ala Ala
245 250 255
Val Leu Ser Cys Ser Trp Glu Val Arg Lys Glu Val Ala Ser Ser Val
260 265 270
Ser Phe Gly Leu Phe Tyr Lys Pro Ser Pro Asp Ala Gly Glu Glu Glu
275 280 285
Cys Ser Pro Val Leu Arg Glu Gly Leu Gly Ser Leu His Thr Arg His
290 295 300
His Cys Gln Ile Pro Val Pro Asp Pro Ala Thr His Gly Gln Tyr Ile
305 310 315 320
Val Ser Val Gln Pro Arg Arg Ala Glu Lys His Ile Lys Ser Ser Val
325 330 335
Asn Ile Gln Met Ala Pro Pro Ser Leu Asn Val Thr Lys Asp Gly Asp
340 345 350
Ser Tyr Ser Leu Arg Trp Glu Thr Met Lys Met Arg Tyr Glu His Ile
355 360 365
Asp His Thr Phe Glu Ile Gln Tyr Arg Lys Asp Thr Ala Thr Trp Lys
370 375 380
Asp Ser Lys Thr Glu Thr Leu Gln Asn Ala His Ser Met Ala Leu Pro
385 390 395 400
Ala Leu Glu Pro Ser Thr Arg Tyr Trp Ala Arg Val Arg Val Arg Thr
405 410 415
Ser Arg Thr Gly Tyr Asn Gly Ile Trp Ser Glu Trp Ser Glu Ala Arg
420 425 430
Ser Trp Asp Thr Asp Trp Val Met Pro Thr Leu Trp Ile Val Leu Ile
435 440 445
Leu Val Phe Leu Ile Leu Thr Leu Leu Leu Ile Leu Arg Phe Gly Cys
450 455 460
Val Ser Val Tyr Arg Thr Tyr Arg Lys Trp Lys Glu Lys Ile Pro Asn
465 470 475 480
Pro Ser Lys Ser Leu Leu Phe Gln Asp Gly Gly Lys Gly Leu Trp Pro
485 490 495
Pro Gly Ser Met Ala Ala Phe Ala Thr Lys Asn Pro Ala Leu Gln Gly
500 505 510
Pro Gln Ser Arg Leu Leu Ala Glu Gln Gln Gly Glu Ser Tyr Ala His
515 520 525
Leu Glu Asp Asn Asn Val Ser Pro Leu Thr Ile Glu Asp Pro Asn Ile
530 535 540
Ile Arg Val Pro Pro Ser Gly Pro Asp Thr Thr Pro Ala Ala Ser Ser
545 550 555 560
Glu Ser Thr Glu Gln Leu Pro Asn Val Gln Val Glu Gly Pro Thr Pro
565 570 575
Asn Arg Pro Arg Lys Gln Leu Pro Ser Phe Asp Phe Asn Gly Pro Tyr
580 585 590
Leu Gly Pro Pro Gln Ser His Ser Leu Pro Asp Leu Pro Asp Gln Leu
595 600 605
Gly Ser Pro Gln Val Gly Gly Ser Leu Lys Pro Ala Leu Pro Gly Ser
610 615 620
Leu Glu Tyr Met Cys Leu Pro Pro Gly Gly Gln Ala Gln Leu Val Pro
625 630 635 640
Leu Ser Gln Val Met Gly Gln Gly Gln Ala Met Asp Val Gln Cys Gly
645 650 655
Ser Ser Leu Glu Thr Ser Gly Ser Pro Ser Val Glu Pro Lys Glu Asn
660 665 670
Pro Pro Val Glu Leu Ser Met Glu Glu Gln Glu Ala Arg Asp Asn Pro
675 680 685
Val Thr Leu Pro Ile Ser Ser Gly Gly Pro Glu Gly Ser Met Met Ala
690 695 700
Ser Asp Tyr Val Thr Pro Gly Asp Pro Val Leu Thr Leu Pro Thr Gly
705 710 715 720
Pro Leu Ser Thr Ser Leu Gly Pro Ser Leu Gly Leu Pro Ser Ala Gln
725 730 735
Ser Pro Ser Leu Cys Leu Lys Leu Pro Arg Val Pro Ser Gly Ser Pro
740 745 750
Ala Leu Gly Pro Pro Gly Phe Glu Asp Tyr Val Glu Leu Pro Pro Ser
755 760 765
Val Ser Gln Ala Ala Lys Ser Pro Pro Gly His Pro Ala Pro Pro Val
770 775 780
Ala Ser Ser Pro Thr Val Ile Pro Gly Glu Pro Arg Glu Glu Val Gly
785 790 795 800
Pro Ala Ser Pro His Pro Glu Gly Leu Leu Val Leu Gln Gln Val Gly
805 810 815
Asp Tyr Cys Phe Leu Pro Gly Leu Gly Pro Gly Ser Leu Ser Pro His
820 825 830
Ser Lys Pro Pro Ser Pro Ser Leu Cys Ser Glu Thr Glu Asp Leu Val
835 840 845
Gln Asp Leu Ser Val Lys Lys Phe Pro Tyr Gln Pro Met Pro Gln Ala
850 855 860
Pro Ala Ile Gln Phe Phe Lys Ser Leu Lys His Gln Asp Tyr Leu Ser
865 870 875 880
Leu Pro Pro Trp Asp Asn Ser Gln Ser Gly Lys Val Cys
885 890
<210> 8
<211> 112
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
agtctatcta tgtacacaga taaattggaa ggttggtggg acccattcgg tcgacggtat 60
cgataagctt gatatcgaat tccgaagttc ctattctcta gaaagtatag ga 112
<210> 9
<211> 105
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
ctctagaaag tataggaact tcatcagtca ggtacataat ggtggatcca atatttcctg 60
ctgatttccc ttcccttgaa ccctgcagtc agtgctggtg tgtcc 105
<210> 10
<211> 23
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 10
agcgcacgtc tgccgcgctg ttc 23
<210> 11
<211> 25
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 11
tggattgtca agagggtggt gatgg 25
<210> 12
<211> 25
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 12
aacctgggca agaaacagag catca 25
<210> 13
<211> 25
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 13
agcaacaacg tgtctcacac atgga 25
<210> 14
<211> 25
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 14
atctcttgct gttcacctcc ttggc 25
<210> 15
<211> 27
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 15
accacttctc ttgcttactt caatgct 27
<210> 16
<211> 21
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 16
ggatcggcca ttgaacaaga t 21
<210> 17
<211> 22
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 17
cagaagaact cgtcaagaag gc 22
<210> 18
<211> 25
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 18
gacagctctc agccttacgc atctt 25
<210> 19
<211> 24
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 19
cagagagcca ccagtgccat gtag 24
<210> 20
<211> 24
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 20
cagtgaggac agggacaggg aagt 24
<210> 21
<211> 25
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 21
cctttgtgga agccatgata ggcca 25
<210> 22
<211> 25
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 22
tggagttcat ggctctagcc ctctt 25
<210> 23
<211> 20
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 23
ctctcaggac gtcccagcaa 20
<210> 24
<211> 23
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 24
agcaaggtga ggatgagaaa gac 23
<210> 25
<211> 19
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 25
tggaccagca aatggcact 19
<210> 26
<211> 18
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 26
ggtgtagaca ctggcccc 18
<210> 27
<211> 22
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 27
ctcaggagag tgtttcctcg tc 22
<210> 28
<211> 20
<212> DNA/RNA
<213> 人工序列(Artificial Sequence)
<400> 28
ccctgttgct gtagccgtat 20
Claims (7)
1.一种CSF2RB基因人源化改造的非人动物的构建方法,其特征在于,所述的非人动物的基因组中包含编码SEQ IDNO.2第1至435位氨基酸的核苷酸序列或SEQ ID NO.5所示核苷酸序列,所述的构建方法包括用包含编码SEQ ID NO.2第1至435位氨基酸的核苷酸序列或者包含SEQ ID NO.5所示核苷酸序列插入或替换至非人动物CSF2RB基因座上,所述的非人动物表达人源化CSF2RB蛋白,所述的人源化CSF2RB蛋白包括人CSF2RB蛋白的胞外区和/或信号肽,所述的人源化CSF2RB蛋白包含SEQ ID NO.7所示的氨基酸序列。
2.根据权利要求1所述的构建方法,其特征在于,使用靶向载体进行非人动物的构建,其中,所述的靶向载体包含编码SEQ ID NO.2第1至435位氨基酸的核苷酸序列或包含SEQID NO.5所示核苷酸序列。
3.根据权利要求1-2任一所述的构建方法,其特征在于,所述的非人动物为大鼠或小鼠。
4.一种靶向载体,其特征在于,所述的靶向载体包含编码SEQ ID NO.2第1至435位氨基酸的核苷酸序列或包含SEQ ID NO.5所示核苷酸序列,所述的靶向载体还包含5’臂、3’臂,所述的5’臂如SEQ ID NO.3所示,所述的3’臂如SEQ ID NO.4所示。
5.一种人源化CSF2RB蛋白,其特征在于,所述的人源化CSF2RB蛋白包含人CSF2RB蛋白的胞外区和/或信号肽,所述的人源化CSF2RB蛋白包含SEQ ID NO.7所示的氨基酸序列。
6.一种编码权利要求5所述的人源化CSF2RB蛋白的人源化CSF2RB基因,其特征在于,所述的人源化CSF2RB基因包含SEQ ID NO.5所示核苷酸序列。
7.权利要求1-3任一构建方法构建的非人动物,权利要求5所述的人源化CSF2RB蛋白、权利要求6所述的人源化CSF2RB基因在CSF2RB基因或蛋白相关研究中的应用,所述的应用包括:
A)涉及人类细胞的免疫过程的产品开发,制造或筛选人类抗体中的应用;
B)作为药理学、免疫学、微生物学和医学研究的模型系统中的应用;
C)涉及人类细胞的免疫过程的生产和利用动物实验疾病模型,用于病原学研究、用于开发诊断策略或用于开发治疗策略中的应用;
D)在体内研究人CSF2RB信号通路调节剂的筛选、药效检测、评估疗效、验证或评价;或者,
E)研究CSF2RB基因功能,研究人CSF2RB抗体,研究针对人CSF2RB靶位点的药物、药效,研究免疫相关疾病药物以及抗肿瘤或炎症药物方面的用途。
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