CN115707779B - 重组柯萨奇病毒a16病毒样颗粒及其用途 - Google Patents
重组柯萨奇病毒a16病毒样颗粒及其用途 Download PDFInfo
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Abstract
本发明涉及医药领域，特别是涉及重组柯萨奇病毒A16病毒样颗粒及其用途，所述重组柯萨奇病毒A16病毒样颗粒由基因组中整合有编码柯萨奇病毒A16的VP0、VP1和VP3衣壳蛋白的细胞系产生。本发明还提供所述重组柯萨奇病毒A16病毒样颗粒在制备预防手足口病产品中的用途。所述预防手足口病产品为药物组合物，例如为疫苗组合物。在免疫原性研究中发现本发明的柯萨奇病毒A16VLP可在小鼠体内诱导良好的免疫反应，提示该VLP可作为柯萨奇病毒A16的候选疫苗。
Description
技术领域
本发明涉及医药领域，特别是涉及重组柯萨奇病毒A16病毒样颗粒及其用途。
背景技术
手足口病是一种常见的婴幼儿传染病，主要临床表现为手、足和口腔等部位出现小疱疹或小溃疡，少数患儿可引起肺水肿、无菌性脑膜脑炎、心肌炎等一系列并发症甚至导致死亡。手足口病是由人肠道病毒属的柯萨奇病毒A组16、4、5、7、9、10，B组2、5型以及肠道病毒71型和埃可病毒30感染引起的，其中肠道病毒71和柯萨奇病毒A16是导致手足口病暴发的主要病原体。目前，肠道病毒A71已有商品化的灭活疫苗，这将大大降低了肠道病毒A71相关手足口病的发病率，而对于柯萨奇病毒A16的疫苗还处于临床前研究。
柯萨奇病毒A16属于小RNA病毒科肠道病毒属A，是无包膜的二十面立体对称球形颗粒，直径约30nm，其基因组是单股正链RNA，两端为保守的非编码区，中间为含有1个开放阅读框的编码区，编码一个蛋白前体，这个蛋白前体可以进一步加工成结构蛋白P1和非结构蛋白P2和P3，而P1可被病毒编码的蛋白酶加工成为病毒衣壳蛋白VP0，VP1和VP3，这些病毒衣壳蛋白与病毒RNA一起组装为成熟的病毒，并伴随着VP0切割为VP2和VP4。据报道，柯萨奇病毒A16的结构蛋白P1与非结构蛋白3CD共表达，可切割为VP0、VP3和VP1衣壳蛋白，并进一步组装成柯萨奇病毒A16病毒样颗粒(Virus-like particle，VLP)与成熟病毒结构上相似，具有良好的免疫原性。VLP免疫后可保护小鼠免于柯萨奇A16病毒的攻击，但通过该方式获得的VLP-P1/3CD存在着P1切割不完全的现象，影响其组成的均一性。3CD是病毒的蛋白酶，其残留也存在潜在的安全性因素。此外，柯萨奇病毒A16 VLP的组分VP1衣壳蛋白易发生降解，也严重影响了其组成的一致性，这对产品的质量控制造成较大的潜在风险。
发明内容
鉴于以上所述现有技术的缺点，本发明的目的在于提供重组柯萨奇病毒A16病毒样颗粒及其用途，用于解决现有技术中的问题。
为实现上述目的及其他相关目的，本发明提供一种多核苷酸，所述多核苷酸包括编码柯萨奇病毒A16的VP0、VP1和VP3衣壳蛋白的核苷酸，所述多核苷酸不包括RBS序列和编码柯萨奇病毒A16其他衣壳蛋白的核苷酸。
本发明还提供一种核酸构建体，所述核酸构建体所述多核苷酸。
本发明还提供一种细胞系，所述细胞系中包括所述核酸构建体，或基因组中整合有所述多核苷酸。
本发明还提供一种重组柯萨奇病毒A16病毒样颗粒，所述重组柯萨奇病毒A16病毒样颗粒包括VP0、VP1和VP3衣壳蛋白，不包括柯萨奇病毒A16其他衣壳蛋白。
本发明还提供所述重组柯萨奇病毒A16病毒样颗粒在制备预防手足口病产品中的用途。
本发明还提供一种用于预防手足口病的药物组合物，所述药物组合物包括所述重组柯萨奇病毒A16病毒样颗粒和药学上可接受的载体。
如上所述，本发明的重组柯萨奇病毒A16病毒样颗粒及其用途，具有以下有益效果：病毒样颗粒与病毒在形态与组成上相似，可诱导较好的免疫反应，为柯萨奇病毒A16疫苗的开发提供了解决方案，为预防柯萨奇病毒A16感染提供有效方法。
附图说明
图1显示为本发明的表达框示意图，PAOX1为AOX1启动子，CYC1 TT为CYC1终止子，VP0、VP3和VP1为柯萨奇病毒A16衣壳蛋白序列。
图2显示为SDS-PAGE分析各A16 VLPs，(A)A16 VLP-P1/3CD的SDS-PAGE分析，(B)A16VLP-full的SDS-PAGE分析，(C)A16 VLP-N50的SDS-PAGE分析，(D)A16 VLP-N72的SDS-PAGE分析。
图3显示为柯萨奇病毒A16 VLPs粒径分析图，图中Bar＝100nm，(A)A16 VLP-P1/3CD电镜分析(B)A16 VLP-full电镜分析，(C)A16 VLP-full的动态光散射分析，(D)A16 VLP-N50的动态光散射分析，(E)A16 VLP-N72的动态光散射分析。
图4显示为柯萨奇病毒A16 VLPs免疫血清特异抗体滴度，(A)二免后血清滴度(VLP-P1/3CD与VLP-full免疫原性比较)；(B)二免后血清滴度(VLP-full、VLP-N50及VLP-N72免疫原性比较)；(C)三免后血清滴度(VLP-full、VLP-N50及VLP-N72免疫原性比较)。为了方便统计，将OD450nm吸光值大于0.15的最高稀释倍数的倒数定位该样品的特异抗体滴度，横线显示为几何平均值。
具体实施方式
为解决结构蛋白P1的不完全切割问题，本发明构建了含有柯萨奇病毒A16 VP0、VP3和VP1三个串联表达框的毕赤酵母表达菌株，并成功纯化了VLP-full；动物免疫结果显示，VLP-full的免疫原性与共表达P1和3CD获得的VLP-P1/3CD免疫原性相当。
为了解决VP1的降解问题，本发明在串联表达柯萨奇病毒A16 VP0、VP3和VP1的基础上，对VP1 N端进行50个和72个氨基酸的截短，并分别获得了毕赤酵母表达菌株和纯化后的VLP-N50和VLP-N72；SDS-PAGE显示VLP-N50和VLP-N72的VP1均无明显降解，且免疫小鼠发现不论VLP-N50还是VLP-N72诱导的免疫水平均与VLP-full相当。因此，经串联表达衣壳蛋白VP0、VP3和截短VP1获得的柯萨奇病毒A16 VLP不仅解决了P1不完全切割和VP1降解的组成均一性问题，同时兼具良好的免疫原性，为柯萨奇疫病毒A16疫苗的研发提供了新思路。在进一步的免疫原性研究发现柯萨奇病毒A16 VLP-N50和A16 VLP-N72均可在小鼠体内诱导良好的中和抗体水平，提示这两种VLP可作为柯萨奇病毒A16的候选疫苗。
本发明提供一种多核苷酸，所述多核苷酸包括编码柯萨奇病毒A16的VP0、VP1和VP3衣壳蛋白的核苷酸，所述多核苷酸不包括RBS序列和编码柯萨奇病毒A16其他衣壳蛋白的核苷酸。
在一种实施方式中，所述多核苷酸中编码柯萨奇病毒A16的VP0、VP1和VP3衣壳蛋白的核苷酸的排列顺序为：VP0-VP3-VP1。
如图1所示的实施方式中，表达VP0、VP1和VP3的三个表达框在所述多核苷酸中串联。所述多核苷酸中编码柯萨奇病毒A16的VP0、VP1和VP3衣壳蛋白的核苷酸的串联排列顺序为：VP0-VP3-VP1。具体的串联方式为启动子-VP0-终止子-启动子-VP3-终止子-启动子-VP1-终止子。当然，在其他实施方式中，三个表达框的串联方式也可以是以下中的任一种：启动子-VP0-终止子-启动子-VP1-终止子-启动子-VP3-终止子、启动子-VP3-终止子-启动子-VP0-终止子-启动子-VP1-终止子、启动子-VP3-终止子-启动子-VP1-终止子-启动子-VP0-终止子、启动子-VP1-终止子-启动子-VP3-终止子-启动子-VP0-终止子、启动子-VP1-终止子-启动子-VP0-终止子-启动子-VP3-终止子。在一种实施方式中，所述启动子为AOX1启动子，所述终止子为CYC1终止子。由于各蛋白均为独立的开放阅读框，因此不同的串联方式均能达到与实施例相同的效果。
所述编码柯萨奇病毒A16的VP0衣壳蛋白的核苷酸为VP0全长核苷酸序列或截短的核苷酸，所述编码柯萨奇病毒VP1衣壳蛋白的核苷酸为VP1全长核苷酸序列或截短的核苷酸，所述编码柯萨奇病毒VP3衣壳蛋白的核苷酸为编码柯萨奇病毒A16的VP3衣壳蛋白的全长核苷酸序列或截短的核苷酸序列。
在一种实施方式中，所述截短的核苷酸可以是VP1截短0-216个核苷酸，VP0截短0-243个核苷酸，VP3截短0-171个核苷酸。
在一种实施方式中，所述多核苷酸编码的柯萨奇病毒A16的VP1衣壳蛋白为截短45-75个氨基酸的VP1衣壳蛋白。优选的，为截短50～72个氨基酸。具体的，例如为以下中的任一：截短45～50个氨基酸、截短50～55个氨基酸、截短55～60个氨基酸、截短60～65个氨基酸、截短65～70个氨基酸、截短70～72个氨基酸、截短72～75个氨基酸。
在一种实施方式中，编码柯萨奇病毒A16的VP0衣壳蛋白的核苷酸序列如SEQ IDNO:8所示。编码柯萨奇病毒A16的VP3衣壳蛋白的核苷酸序列如SEQ ID NO:9所示。编码柯萨奇病毒A16的VP1衣壳蛋白的核苷酸序列的如SEQ ID NO:10或SEQ ID NO:11或SEQ ID NO:12所示。
SEQ ID NO:2所示的序列中，1-969为VP0核苷酸序列，970-1695为VP3核苷酸序列，1696-2586为VP1核苷酸序列。所述多核苷酸中不包括编码3CD蛋白的核苷酸。
所述多核苷酸的序列为经过密码子优化后得到的序列。
在一种实施方式中，所述编码柯萨奇病毒A16的VP0衣壳蛋白的核苷酸编码氨基酸序列如SEQ ID NO:3所示的VP0衣壳蛋白；所述编码柯萨奇病毒A16的VP3衣壳蛋白的核苷酸编码氨基酸序列如SEQ ID NO:4所示的VP3衣壳蛋白；所述编码柯萨奇病毒A16的VP1衣壳蛋白的核苷酸编码氨基酸序列如SEQ ID NO:5或SEQ ID NO:6或SEQ ID NO:7所示的VP1衣壳蛋白。
在一种实施方式中，所述柯萨奇病毒A16的VP1衣壳蛋白的氨基酸序列选自以下任一项：1)如SEQ ID NO:5或SEQ ID NO:6或SEQ ID NO:7所示的序列；2)与SEQ ID NO.5或SEQID NO:6或SEQ ID NO:7所示序列的同源性在95％、96％、97％、98％或99％以上的序列；3)与前两项任一所述的序列互补的序列。
本发明还提供一种核酸构建体，所述核酸构建体包括所述多核苷酸。
术语“核酸构建体”是指可以被引入靶细胞或组织中的人工构建的核酸区段，所述核酸构建体包括载体骨架即表达载体与表达框，所述核酸构建体可以为质粒。
所述核酸构建体中VP0、VP3和VP1三个表达框可以是各自独立的单拷贝或多拷贝。较佳的，所述核酸构建体中VP0、VP3和VP1三个表达框均为单拷贝。
所述核酸构建体中不包括编码柯萨奇病毒A16除VP0、VP1和VP3衣壳蛋白外的其他衣壳蛋白。
在一种实施方式中，所述核酸构建体还包括表达载体。所述表达载体可以是现有技术中任意适于表达柯萨奇病毒的表达载体，例如为酵母表达载体。较佳的为毕赤酵母表达载体pPink-HC(厂家：Invitrogen)。
在一种实施方式中，所述核酸构建体核苷酸序列如SEQ ID NO:15或SEQ ID NO:16或SEQ ID NO:17所示。
本发明还提供一种细胞系，所述细胞系中包括所述核酸构建体，或基因组中整合有所述多核苷酸。
所述细胞系为真核细胞。在一种实施方式中，所述细胞系为将所述核酸构建体转导入毕赤酵母细胞得到。
本申请的所述细胞系中所含的多核苷酸中不包括编码3CD蛋白的核苷酸，而是细胞系能够在胞内直接表达柯萨奇病毒A16的VP0、VP1、VP3衣壳蛋白，然后组装为直径约30nm的病毒样颗粒(VLP)，并非细胞系表达P1结构蛋白而后再被3CD切割加工成VP0、VP1、VP3衣壳蛋白。
本发明还提供一种重组柯萨奇病毒A16病毒样颗粒，所述重组柯萨奇病毒A16病毒样颗粒包括VP0、VP1和VP3衣壳蛋白，不包括柯萨奇病毒A16其他衣壳蛋白。
所述重组柯萨奇病毒A16病毒样颗粒由所述细胞系产生。
重组柯萨奇病毒A16病毒样颗粒的直径(指电镜下直径)为25nm～35nm。所述重组柯萨奇病毒A16病毒样颗粒的大小均一。
本发明还提供所述重组柯萨奇病毒A16病毒样颗粒的制备方法，所述制备方法包括如下步骤：
1)培养所述细胞系，使其表达重组柯萨奇病毒A16病毒样颗粒；
2)分离出所述细胞系表达的重组柯萨奇病毒A16病毒样颗粒。
在一种实施方式中，培养所述细胞系的条件为28℃-30℃，250-300rpm。
在一种实施方式中，所述细胞系通过将所述核酸构建体转导入宿主细胞得到。在一种实施方式中，所述宿主细胞为毕赤酵母细胞。
在一种实施方式中，所述核酸构建体的制备方法包括如下步骤：
1)将密码子优化后的表达VP0、VP1、VP3衣壳蛋白的核苷酸分别克隆入三个表达载体中，获得中间构建体；
2)将步骤1)获得的三个中间构建体重组后获得所述核酸构建体。
本发明还提供所述重组柯萨奇病毒A16病毒样颗粒在制备预防手足口病产品中的用途。
在一种实施方式中，所述手足口病为柯萨奇病毒A16感染的手足口病。
所述预防手足口病产品为药物组合物。所述药物组合物例如为疫苗组合物。
本发明还提供一种用于预防手足口病的药物组合物，所述药物组合物包括所述重组柯萨奇病毒A16病毒样颗粒和药学上可接受的载体。
所述药物组合物可以是单价的(仅含有一种病毒样颗粒)，也可以是多价的(含有多种病毒样颗粒)。
所述药物组合物可制备成各种常规剂型，例如：注射剂、粒剂、片剂、丸剂、栓剂、胶囊、悬浮液、喷雾剂等。
所述药物组合物包括预防或治疗有效量的本发明病毒样颗粒或多核苷酸。
术语“预防或治疗有效量”指药物组合物治疗、缓解或预防目标疾病或状况的量，或是表现出可检测的治疗或预防效果的量。即病毒样颗粒的量在所选用的给药路径中足以引发免疫应答，能有效促使保护宿主抵抗相关的疾病。该效果可通过例如抗原水平来检测。治疗效果也包括生理性症状的减少。对于某一对象的精确有效量取决于该对象的体型和健康状况、病症的性质和程度、以及选择给予的治疗剂和/或治疗剂的组合。因此，预先指定准确的有效量是没用的。然而，对于某给定的状况而言，可以用常规实验来确定该有效量。
在一种实施方式中，为了本发明的目的，有效的剂量为给予个体约0.001毫克/千克至1000毫克/千克，较佳地约0.01毫克/千克至100毫克/千克体重的病毒样颗粒。
药物组合物还可含有药学上可接受的载体。术语“药学上可接受的载体”指用于药物组合物(例如本发明的重组病毒样颗粒)给药的载体。该术语指这样一些药剂载体：它们本身不诱导产生对接受该组合物的个体有害的抗体，且给药后没有过分的毒性。合适的载体可以是大的、代谢缓慢的大分子，如蛋白质、多糖、聚乳酸(polylactic acid)、聚乙醇酸等。这些载体是本领域普通技术人员所熟知的。药学上可接受的载体可包括液体，如水、盐水、甘油和乙醇。另外，这些载体中还可能存在辅助性的物质，如润湿剂或乳化剂、pH缓冲物质等。通常，可将组合物制成可注射剂，例如液体溶液或悬液；还可制成在注射前适合配入溶液或悬液、液体赋形剂的固体形式。脂质体也包括在药学上可接受的载体的定义中。
一旦配成本发明的组合物，可将其直接给予对象。待治疗的对象可以是哺乳动物，尤其是人。
所述药物组合物例如为疫苗组合物。疫苗组合物可用已知的方法将本发明的病毒样颗粒直接施用于个体。通常采用与常规疫苗相同的施用途径和/或模拟病原体感染路径施用这些疫苗。
给予本发明药物组合物的途径包括：肌内、皮下、皮内、肺内、静脉内、经鼻、经口服或其它肠胃外给药途径。如果需要，可以组合给药途径，或根据疾病情况进行调节。疫苗组合物可以单剂量或多剂量给予，且可以包括给予加强剂量以引发和/或维持免疫力。
以下通过特定的具体实例说明本发明的实施方式，本领域技术人员可由本说明书所揭露的内容轻易地了解本发明的其他优点与功效。本发明还可以通过另外不同的具体实施方式加以实施或应用，本说明书中的各项细节也可以基于不同观点与应用，在没有背离本发明的精神下进行各种修饰或改变。
在进一步描述本发明具体实施方式之前，应理解，本发明的保护范围不局限于下述特定的具体实施方案；还应当理解，本发明实施例中使用的术语是为了描述特定的具体实施方案，而不是为了限制本发明的保护范围；在本发明说明书和权利要求书中，除非文中另外明确指出，单数形式“一个”、“一”和“这个”包括复数形式。
当实施例给出数值范围时，应理解，除非本发明另有说明，每个数值范围的两个端点以及两个端点之间任何一个数值均可选用。除非另外定义，本发明中使用的所有技术和科学术语与本技术领域技术人员通常理解的意义相同。除实施例中使用的具体方法、设备、材料外，根据本技术领域的技术人员对现有技术的掌握及本发明的记载，还可以使用与本发明实施例中所述的方法、设备、材料相似或等同的现有技术的任何方法、设备和材料来实现本发明。实施例1柯萨奇病毒A16表达质粒的构建
为了使表达达到最优，将柯萨奇病毒A16 P1氨基酸序列根据毕赤酵母密码子偏好性进行优化合成；利用EcoRI和KpnI位点连入pPinK-HC质粒中，得到质粒pPink/HC-A16 P1。柯萨奇病毒A16P1氨基酸序列如SEQ ID NO:1所示，其中1-323为VP0氨基酸序列(SEQ IDNO:3)，324-565为VP3氨基酸序列(SEQ ID NO:4)，566-862为VP1氨基酸序列(SEQ ID NO:5)。同时合成相应的3CD序列(核苷酸序列如SEQ ID NO:13所示)，并利用EcoRI和KpnI位点连入pPinK-HC质粒中，得到质粒pPink/HC-A16 3CD。柯萨奇病毒A16 P1优化后的核苷酸序列如SEQ ID NO:2所示。VP0的核苷酸序列如SEQ ID NO:8所示，即SEQ ID NO:2中的1-969。VP3的核苷酸序列如SEQ ID NO:9所示，即SEQ ID NO:2中的970-1695。VP1的核苷酸序列如SEQ ID NO:10所示，即SEQ ID NO:2中的1696-2586。VP1 N50的核苷酸序列如SEQ ID NO:11所示。VP1 N72的核苷酸序列如SEQ ID NO:12所示。VP1 N50的氨基酸序列如SEQ ID NO:6所示。VP1 N72的氨基酸序列如SEQ ID NO:7所示。
质粒pPink/HC-A16 P1/3CD的构建：用BglⅡ和BamHⅠ对质粒pPink/HC-A16 3CD进行双酶切，获取3CD表达框；然后将3CD表达框连入用BglⅡ和CIP酶处理pPink/HC-A16 P1中，最终获得质粒pPink/HC-A16 P1/3CD(核苷酸序列如SEQ ID NO:14所示)。
根据优化后柯萨奇病毒A16衣壳蛋白VP0、VP1、VP3及表达载体pPink-HC(购自Invitrogen)多克隆位点核苷酸处序列设计合成重组PCR引物(表1，其中N50-R和N72-R与HS1VP1-R序列相同，表1中未重复列出)，使用同源重组试剂盒(购自诺唯赞)中的同源重组酶将VP0、VP3、VP1、VP1 N50和VP1 N72分别以重组的方式连接到载体pPinK-HC中，分别得到中间质粒pPink/HC-A16 VP0、pPink/HC-A16 VP3、pPink/HC-A16 VP1、pPink/HC-A16VP1-N50和pPink/HC-A16 VP1 N72；利用同尾酶BglⅡ和BamHⅠ以酶切连接的方法依次将中间质粒中A16 VP3表达框和A16 VP0表达框连入pPink/HC-A16 VP1、pPink/HC-A16 VP1N50或pPink/HC-A16 VP1 N72中，分别得到终质粒pPink/HC-A16 VPN-full(核苷酸序列如SEQ IDNO:15所示)、pPink/HC-A16 VPN-N50(核苷酸序列如SEQ ID NO:16所示)和pPink/HC-A16VPN-N72(核苷酸序列如SEQ ID NO:17所示)，示意图如图1所示。
表1重组PCR引物序列
| 引物名称 | 引物序列 | 序列号 |
| HS16 VP0-F | 5’-caactaattattcgaaacggaattcaccatgggttctcaagtttctactc-3’ | SEQ ID NO:18 |
| HS16VP0-R | 5’-ctgtatttaaatggccggccggtacctcattattgcttaacagcttgtctc-3’ | SEQ ID NO:19 |
| HS16 VP3-F | 5’-caactaattattcgaaacggaattcaccatgggtattccaactgaattg-3’ | SEQ ID NO:20 |
| HS16VP3-R | 5’-cctgtatttaaatggccggccggtacctcattattgaatattagcagtttgct-3’ | SEQ ID NO:21 |
| HS16VP1-F | 5’-caactaattattcgaaacggaattcaccatgggagatccaatcgctgatatg-3’ | SEQ ID NO:22 |
| HS16VP1-R | 5’-cctgtatttaaatggccggccggtacctcattacaaagtagtaattttatctc-3’ | SEQ ID NO:23 |
| HS16VP1-N50-F | 5’-aacaactaattattcgaaacggaattcaccatggagactggtgcttcttc-3’ | SEQ ID NO:24 |
| HS16VP1-N72-F | 5’-aacaactaattattcgaaacggaattcaccatgcactctactcaagagac-3’ | SEQ ID NO:25 |
实施例2柯萨奇病毒A16高表达菌株的筛选、表达与纯化
高表达菌株的筛选
将终质粒pPink/HC-A16 P1/3CD、pPink/HC-A16VPN-full、pPink/HC-A16 VPN-N50或pPink/HC-A16 VPN-N72使用内切酶酶AflⅡ进行线性化，并用乙醇沉淀法进行纯化回收；利用电转的方法将线性化质粒导入毕赤酵母中进行基因重组，涂布PAD平板与30℃进行培养；3天后，挑取大的白色菌落与24孔深孔板中进行甲醇诱导表达，诱导表达48h后收取诱导菌体使用夹心ELISA的方法进行表达检测，经过筛选，将表达量高的作为高表达株A16 VLP-P1/3CD、A16 VLP-full、A16 VLP-N50和A16 VLP-N72，各高表达菌株目的基因序列经测序分析与理论核苷酸序列一致。
夹心ELISA方法所用的兔抗柯萨奇病毒A16多抗血清和柯萨奇病毒A16特异的鼠单抗均为本公司自制，制备步骤如下：(1)兔抗柯萨奇病毒A16多抗血清：将纯化后的柯萨奇病毒A16 VLP(500μg/只)与弗氏佐剂1:1混合乳化后皮下多点注射成年的新西兰大白兔(1ml/只)，两次免疫间隔4周共免疫4次，第4次免疫2周后采取兔血清备用；(2)柯萨奇病毒A16特异的鼠单抗：将纯化后的柯萨奇病毒A16 VLP(5μg/只)与铝佐剂(500μg/只)充分混合后，腹腔注射小鼠，两次免疫间隔2周共免疫4次，第4次免疫后2周取脾脏细胞与骨髓瘤细胞融合后筛选得到柯萨奇病毒A16特异的鼠单抗细胞株，将该细胞株腹腔注射小鼠后获得腹水，经protein G填料纯化后获得A16特异的鼠单抗备用。夹心ELISA操作步骤如下：将兔抗柯萨奇病毒A16多抗血清按1:2000进行稀释包被于96孔酶标板中，50μl/孔，4℃包被过夜后用5％脱脂奶粉进行封闭；将菌体用PBS重悬，加入等体积玻璃珠后70HZ破碎120s，离心后取上清备用；破菌上清和柯萨奇病毒A16 VLP自制标品用2％脱脂奶粉进行适当的稀释后加到封闭后的酶标板中，于37℃进行孵育；2h后，加入柯萨奇病毒A16特异的鼠单抗，于37℃进行孵育；2h后，加入1:5000稀释的HRP标记的山羊抗鼠二抗，37℃孵育1h后进行显色并读取450nm吸光值，并根据标曲计算VLP含量。
表达与纯化
将筛选得到的高表达株A16 VLP-P1/3CD、A16 VLP-full、A16 VLP-N50和A16 VLP-N72分别接种于BMGY培养基，培养24h后更换为BMMY培养基进行诱导表达，诱导48h后离心收获菌体。将菌体用PBS重悬后使用高压均浆机1200bar进行破菌，离心后收集上清进行PEG沉降，复溶后的上清使用DEAE填料进行纯化，最终分别获得纯化后的柯萨奇病毒A16VLP-P1/3CD、A16VLP-full、A16 VLP-N50和A16 VLP-N72。
将柯萨奇病毒A16 VLPs分别进行SDS-PAGE分析(图2)，结果显示各VLP均由VP0、VP1和VP3组成，A16 VLP-P1/3CD(图2A)和A16 VLP-full(图2B)的VP1均出现不同程度的降解，而VLP-N50(图2C)和A16 VLP-N72(图2D)无明显降解。此外，由于是串联表达VP0、VP3和VP1(全长与N端截短)衣壳蛋白，故A16 VLP-full、A16 VLP-N50和A16 VLP-N72不存在切割不完全的问题，也不存在3CD残留问题。
实施例3柯萨奇病毒A16 VLP的形态研究
负染：将纯化后的各柯萨奇病毒A16 VLP用PBS稀释至50-200ng/μl，进行电子显微镜分析，具体步骤如下：上样到铜网后使用醋酸铀进行染色，然后使用120kV冷冻电镜进行观察其形态，如图3(A)、(B)所示，电镜下A16 VLP-P1/3CD与A16 VLP-full形态相似，均呈规则的球形结构，直径约为30nm。因此，在毕赤酵母中串联表达柯萨奇病毒A16衣壳蛋白VP0、VP3和VP1可自发组装成VLP。
粒径测定：采用动态光散射的方法测定其水合直径，具体步骤如下：将待分析样品用PBS稀释至50-200ng/μl，取1ml加入样品池中，避免产生气泡，将样品池放入Zetasizer设备中进行检测和数据分析。动态光散射结果如图3(C)至(E)所示，显示A16 VLP-N50和A16VLP-N72的水合直径与A16 VLP-full相似均为40nm左右，故A16 VLP-P1/3CD、A16 VLP-full、A16VLP-N50和A16 VLP-N72均组装良好。
实施例4柯萨奇病毒A16 VLP的免疫原性
1.为了比较A16 VLP-P1/3CD和A16 VLP-full的免疫原性，将A16 VLP-P1/3CD、A16 VLP-full分别与铝佐剂混合后，按照下述方法进行小鼠免疫：
通过肌肉注射的方式免疫6-8周龄雌性Balb/C小鼠，共分为2组，每组10只。将VLP-P1/3CD(5μg/只)或VLP-full(5μg/只)与铝佐剂(500μg/只)室温振荡吸附1-2h，然后进行肌肉注射，共免疫2次，两次免疫之间间隔4周。第二次免疫后2周(即第6周)采取小鼠血清按照下述方法进行特异性抗体水平检测：将兔抗柯萨奇病毒A16 VLP包被于96孔酶标板中，20ng/孔，4℃包被过夜后用5％脱脂奶粉进行封闭；将血清样品用2％脱脂奶粉进行倍比稀释后加到封闭后的酶标板中，于37℃进行孵育；2h后，加入1:5000稀释的HRP标记的山羊抗鼠二抗，37℃孵育1h后进行显色并读取450nm吸光值。
结果如图4A所示，A16 VLP-P1/3CD、A16 VLP-full均可以诱导较高的特异性抗体，且两者水平相当。因此，利用酵母表达系统串联表达柯萨奇病毒A16 VP0、VP3和VP1衣壳蛋白获得VLP的方式可替代共表达P1和3CD获取VLP的方法用于进一步柯萨奇病毒A16疫苗的研发。
2.为了确定VP1 N端的截短是否影响柯萨奇病毒A16 VLP的免疫原性，
通过肌肉注射的方式免疫6-8周龄雌性ICR小鼠，共分为2组，每组5-6只。将VLP-full(10μg/只)、VLP-N50(10μg/只)或VLP-N72(10μg/只)分别与Al佐剂(80μg/只)室温振荡吸附1-2h，然后分别进行腹腔注射免疫小鼠，共免疫3次，每次免疫之间间隔2周。分别于第二次和第三次免疫后2周采取小鼠血清测定特异性抗体水平检测(方法同上)。如图4B-C所示，不论免疫2次(图4B)还是3次(图4C)VLP-N50和VLP-N72均可诱导与VLP-full相当水平的特异性抗体。
本发明的数据均使用GraphPad Prism 8.3.0进行数据处理。
本发明将含柯萨奇病毒A16 VP0、VP1与VP3串联表达框的表达载体导入毕赤酵母，以达到同时表达柯萨奇病毒A16 VP0、VP1与VP3衣壳蛋白的目的，经检测发现VP0、VP1与VP3衣壳蛋白可成功表达且可自发组装成VLP。与共表达P1和3CD获得的VLP-P1/3CD相比，VLP-full不存在P1切割不完全的问题，亦可在小鼠体内诱导与VLP-P1/3CD相当的的特异抗体反应，但VLP-full仍存在VP1不同程度降解的问题。为解决该问题，我们在衣壳蛋白串联表达的基础上对VP1 N端进行不同程度的截短，SDS-PAGE结果显示VLP-N50和VLP-N72的VP1均无明显的降解；此外，VLP-N50和VLP-N72，亦可诱导良好的免疫反应，且抗体水平与VLP-full相当。
综上，VLP-N50和VLP-N72组成均一且免疫原性良好，可用于柯萨奇病毒A16进一步的疫苗研发。
以上的实施例是为了说明本发明公开的实施方案，并不能理解为对本发明的限制。此外，本文所列出的各种修改以及发明中方法的变化，在不脱离本发明的范围和精神的前提下对本领域内的技术人员来说是显而易见的。虽然已结合本发明的多种具体优选实施例对本发明进行了具体的描述，但应当理解，本发明不应仅限于这些具体实施例。事实上，各种如上所述的对本领域内的技术人员来说显而易见的修改来获取发明都应包括在本发明的范围内。
序列表
<110> 华淞（上海）生物医药科技有限公司
<120> 重组柯萨奇病毒A16病毒样颗粒及其用途
<160> 25
<170> SIPOSequenceListing 1.0
<210> 1
<211> 862
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Met Gly Ser Gln Val Ser Thr Gln Arg Ser Gly Ser His Glu Asn Ser
1 5 10 15
Asn Ser Ala Ser Glu Gly Ser Thr Ile Asn Tyr Thr Thr Ile Asn Tyr
20 25 30
Tyr Lys Asp Ala Tyr Ala Ala Ser Ala Gly Arg Gln Asp Met Ser Gln
35 40 45
Asp Pro Lys Lys Phe Thr Asp Pro Val Met Asp Val Met His Glu Met
50 55 60
Ala Pro Pro Leu Lys Ser Pro Ser Ala Glu Ala Cys Gly Tyr Ser Asp
65 70 75 80
Arg Val Ala Gln Leu Thr Ile Gly Asn Ser Thr Ile Thr Thr Gln Glu
85 90 95
Ala Ala Asn Ile Val Ile Ala Tyr Gly Glu Trp Pro Glu Tyr Cys Pro
100 105 110
Asp Thr Asp Ala Thr Ala Val Asp Lys Pro Thr Arg Pro Asp Val Ser
115 120 125
Val Asn Arg Phe Phe Thr Leu Asp Thr Lys Ser Trp Ala Lys Asp Ser
130 135 140
Lys Gly Trp Tyr Trp Lys Phe Pro Asp Val Leu Thr Glu Val Gly Val
145 150 155 160
Phe Gly Gln Asn Ala Gln Phe His Tyr Leu Tyr Arg Ser Gly Phe Cys
165 170 175
Val His Val Gln Cys Asn Ala Ser Lys Phe His Gln Gly Ala Leu Leu
180 185 190
Val Ala Val Leu Pro Glu Tyr Val Leu Gly Thr Ile Ala Gly Gly Thr
195 200 205
Gly Asn Glu Asn Ser His Pro Pro Tyr Ala Thr Thr Gln Pro Gly Gln
210 215 220
Val Gly Ala Val Leu Thr His Pro Tyr Val Leu Asp Ala Gly Ile Pro
225 230 235 240
Leu Ser Gln Leu Thr Val Cys Pro His Gln Trp Ile Asn Leu Arg Thr
245 250 255
Asn Asn Cys Ala Thr Ile Ile Val Pro Tyr Met Asn Thr Val Pro Phe
260 265 270
Asp Ser Ala Leu Asn His Cys Asn Phe Gly Leu Leu Val Ile Pro Val
275 280 285
Val Pro Leu Asp Phe Asn Thr Gly Ala Thr Ser Glu Ile Pro Ile Thr
290 295 300
Val Thr Ile Ala Pro Met Cys Ala Glu Phe Ala Gly Leu Arg Gln Ala
305 310 315 320
Val Lys Gln Gly Ile Pro Thr Glu Leu Lys Pro Gly Thr Asn Gln Phe
325 330 335
Leu Thr Thr Asp Asp Gly Val Ser Ala Pro Ile Leu Pro Gly Phe His
340 345 350
Pro Thr Pro Pro Ile His Ile Pro Gly Glu Val His Asn Leu Leu Glu
355 360 365
Ile Cys Arg Val Glu Thr Ile Leu Glu Val Asn Asn Leu Lys Thr Asn
370 375 380
Glu Thr Thr Pro Met Gln Arg Leu Cys Phe Pro Val Ser Val Gln Ser
385 390 395 400
Lys Thr Gly Glu Leu Cys Ala Ala Phe Arg Ala Asp Pro Gly Arg Asp
405 410 415
Gly Pro Trp Gln Ser Thr Ile Leu Gly Gln Leu Cys Arg Tyr Tyr Thr
420 425 430
Gln Trp Ser Gly Ser Leu Glu Val Thr Phe Met Phe Ala Gly Ser Phe
435 440 445
Met Ala Thr Gly Lys Met Leu Ile Ala Tyr Thr Pro Pro Gly Gly Ser
450 455 460
Val Pro Ala Asp Arg Ile Thr Ala Met Leu Gly Thr His Val Ile Trp
465 470 475 480
Asp Phe Gly Leu Gln Ser Ser Val Thr Leu Val Val Pro Trp Ile Ser
485 490 495
Asn Thr His Tyr Arg Ala His Ala Arg Ala Gly Tyr Phe Asp Tyr Tyr
500 505 510
Thr Thr Gly Ile Ile Thr Ile Trp Tyr Gln Thr Asn Tyr Val Val Pro
515 520 525
Ile Gly Ala Pro Thr Thr Ala Tyr Ile Val Ala Leu Ala Ala Ala Gln
530 535 540
Asp Asn Phe Thr Met Lys Leu Cys Lys Asp Thr Glu Asp Ile Glu Gln
545 550 555 560
Thr Ala Asn Ile Gln Gly Asp Pro Ile Ala Asp Met Ile Asp Gln Thr
565 570 575
Val Asn Asn Gln Val Asn Arg Ser Leu Thr Ala Met Gln Val Leu Pro
580 585 590
Thr Ala Ala Asn Thr Glu Ala Ser Ser His Arg Leu Gly Thr Gly Val
595 600 605
Val Pro Ala Leu Gln Ala Ala Glu Thr Gly Ala Ser Ser Asn Ala Ser
610 615 620
Asp Lys Asn Leu Ile Glu Thr Arg Cys Val Leu Asn His His Ser Thr
625 630 635 640
Gln Glu Thr Ala Ile Gly Asn Phe Phe Ser Arg Ala Gly Leu Val Ser
645 650 655
Ile Ile Thr Met Pro Thr Met Gly Thr Gln Asn Thr Asp Gly Tyr Val
660 665 670
Asn Trp Asp Ile Asp Leu Met Gly Tyr Ala Gln Leu Arg Arg Lys Cys
675 680 685
Glu Leu Phe Thr Tyr Met Arg Phe Asp Ala Glu Phe Thr Phe Val Val
690 695 700
Ala Lys Pro Asn Gly Glu Leu Val Pro Gln Leu Leu Gln Tyr Met Tyr
705 710 715 720
Val Pro Pro Gly Ala Pro Lys Pro Thr Ser Arg Asp Ser Phe Ala Trp
725 730 735
Gln Thr Ala Thr Asn Pro Ser Val Phe Val Lys Met Thr Asp Pro Pro
740 745 750
Ala Gln Val Ser Val Pro Phe Met Ser Pro Ala Ser Ala Tyr Gln Trp
755 760 765
Phe Tyr Asp Gly Tyr Pro Thr Phe Gly Glu His Leu Gln Ala Asn Asp
770 775 780
Leu Asp Tyr Gly Gln Cys Pro Asn Asn Met Met Gly Thr Phe Ser Ile
785 790 795 800
Arg Thr Val Gly Thr Glu Lys Ser Pro His Ser Ile Thr Leu Arg Val
805 810 815
Tyr Met Arg Ile Lys His Val Arg Ala Trp Ile Pro Arg Pro Leu Arg
820 825 830
Asn Gln Pro Tyr Leu Phe Lys Thr Asn Pro Asn Tyr Lys Gly Asn Asp
835 840 845
Ile Lys Cys Thr Ser Thr Ser Arg Asp Lys Ile Thr Thr Leu
850 855 860
<210> 2
<211> 2586
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 2
atgggttctc aagtttctac tcaaagatcc ggttctcacg aaaactctaa ttctgcttct 60
gagggttcta ctattaacta cactactatt aattactaca aggatgctta cgctgcttct 120
gctggtagac aagatatgtc tcaagatcca aagaagttta ctgatccagt tatggatgtt 180
atgcatgaaa tggctccacc tttgaaatct ccatctgctg aggcttgtgg ttactctgat 240
agagttgctc aattgactat cggtaactct actatcacta ctcaagaagc tgctaatatt 300
gttattgctt acggtgaatg gccagagtat tgtcctgata ctgatgctac tgctgttgat 360
aagccaacta gacctgatgt ttctgttaac agatttttca ctttggatac taagtcttgg 420
gctaaggatt ctaaaggttg gtactggaaa ttcccagatg ttttgactga ggttggtgtt 480
tttggtcaaa acgctcaatt ccactacttg tatagatccg gtttttgtgt tcacgttcaa 540
tgtaatgctt ctaaattcca tcaaggtgct ttgttggttg ctgttttgcc tgaatatgtt 600
ttgggtacta ttgctggtgg tactggtaac gaaaactctc acccacctta cgctactact 660
caaccaggtc aagttggtgc tgttttgact catccatatg ttttggatgc tggtattcct 720
ttgtctcaat tgactgtttg tccacaccaa tggattaact tgagaactaa caactgtgct 780
actatcatcg ttccatacat gaacactgtt cctttcgatt ctgctttgaa ccattgtaac 840
ttcggtttgt tggttattcc agttgttcct ttggatttta acactggtgc tacttctgaa 900
atcccaatca ctgttactat tgctcctatg tgtgctgagt tcgctggttt gagacaagct 960
gttaagcaag gtattccaac tgaattgaaa cctggtacta accaattctt gactactgat 1020
gatggtgttt ctgctccaat tttgcctggt ttccatccaa ctccacctat tcacattcct 1080
ggtgaagttc ataacttgtt ggagatttgt agagttgaaa ctatcttgga ggttaacaat 1140
ttgaagacta acgaaactac tccaatgcaa agattgtgtt ttcctgtttc tgttcaatct 1200
aaaactggag agttgtgtgc tgctttcaga gctgatccag gtagagatgg tccttggcaa 1260
tctactattt tgggtcaatt gtgtagatac tatactcaat ggtctggttc tttggaagtt 1320
acttttatgt tcgctggttc ttttatggct actggtaaaa tgttgattgc ttacactcca 1380
cctggtggtt ctgttcctgc tgatagaatt actgctatgt tgggtactca cgttatttgg 1440
gattttggtt tgcaatcttc tgttactttg gttgttccat ggatttctaa cactcattac 1500
agagctcacg ctagagctgg ttatttcgat tactatacta ctggtatcat cactatctgg 1560
tatcaaacta actacgttgt tccaatcggt gctcctacta ctgcttatat tgttgctttg 1620
gctgctgctc aagataactt cactatgaag ttgtgtaagg atactgaaga tattgagcaa 1680
actgctaata ttcaaggaga tccaatcgct gatatgatcg atcaaactgt taacaaccaa 1740
gttaacagat ccttgactgc tatgcaagtt ttgcctactg ctgctaatac tgaagcttct 1800
tctcatagat tgggtactgg tgttgttcca gctttgcaag ctgctgagac tggtgcttct 1860
tctaacgctt ctgataagaa tttgatcgaa actagatgtg ttttgaacca tcactctact 1920
caagagactg ctattggtaa ctttttctct agagctggtt tggtttctat catcactatg 1980
ccaactatgg gtactcaaaa cactgatggt tacgttaatt gggatattga tttgatgggt 2040
tatgctcaat tgagaagaaa gtgtgaattg tttacttaca tgagattcga tgctgagttt 2100
actttcgttg ttgctaaacc aaacggtgaa ttggttcctc aattgttgca atacatgtat 2160
gttccacctg gtgctccaaa gcctacttct agagattctt ttgcttggca aactgctact 2220
aatccttctg ttttcgttaa aatgactgat ccacctgctc aagtttctgt tccattcatg 2280
tctcctgctt ctgcttacca atggttttac gatggttatc ctactttcgg tgaacatttg 2340
caagctaatg atttggatta tggtcaatgt ccaaacaata tgatgggtac tttctctatt 2400
agaactgttg gtactgagaa gtctccacac tctatcactt tgagagttta catgagaatt 2460
aaacatgtta gagcttggat tccaagacct ttgagaaacc aaccatactt gtttaagact 2520
aaccctaact acaagggtaa cgatatcaag tgtacttcta cttctagaga taaaattact 2580
actttg 2586
<210> 3
<211> 323
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Met Gly Ser Gln Val Ser Thr Gln Arg Ser Gly Ser His Glu Asn Ser
1 5 10 15
Asn Ser Ala Ser Glu Gly Ser Thr Ile Asn Tyr Thr Thr Ile Asn Tyr
20 25 30
Tyr Lys Asp Ala Tyr Ala Ala Ser Ala Gly Arg Gln Asp Met Ser Gln
35 40 45
Asp Pro Lys Lys Phe Thr Asp Pro Val Met Asp Val Met His Glu Met
50 55 60
Ala Pro Pro Leu Lys Ser Pro Ser Ala Glu Ala Cys Gly Tyr Ser Asp
65 70 75 80
Arg Val Ala Gln Leu Thr Ile Gly Asn Ser Thr Ile Thr Thr Gln Glu
85 90 95
Ala Ala Asn Ile Val Ile Ala Tyr Gly Glu Trp Pro Glu Tyr Cys Pro
100 105 110
Asp Thr Asp Ala Thr Ala Val Asp Lys Pro Thr Arg Pro Asp Val Ser
115 120 125
Val Asn Arg Phe Phe Thr Leu Asp Thr Lys Ser Trp Ala Lys Asp Ser
130 135 140
Lys Gly Trp Tyr Trp Lys Phe Pro Asp Val Leu Thr Glu Val Gly Val
145 150 155 160
Phe Gly Gln Asn Ala Gln Phe His Tyr Leu Tyr Arg Ser Gly Phe Cys
165 170 175
Val His Val Gln Cys Asn Ala Ser Lys Phe His Gln Gly Ala Leu Leu
180 185 190
Val Ala Val Leu Pro Glu Tyr Val Leu Gly Thr Ile Ala Gly Gly Thr
195 200 205
Gly Asn Glu Asn Ser His Pro Pro Tyr Ala Thr Thr Gln Pro Gly Gln
210 215 220
Val Gly Ala Val Leu Thr His Pro Tyr Val Leu Asp Ala Gly Ile Pro
225 230 235 240
Leu Ser Gln Leu Thr Val Cys Pro His Gln Trp Ile Asn Leu Arg Thr
245 250 255
Asn Asn Cys Ala Thr Ile Ile Val Pro Tyr Met Asn Thr Val Pro Phe
260 265 270
Asp Ser Ala Leu Asn His Cys Asn Phe Gly Leu Leu Val Ile Pro Val
275 280 285
Val Pro Leu Asp Phe Asn Thr Gly Ala Thr Ser Glu Ile Pro Ile Thr
290 295 300
Val Thr Ile Ala Pro Met Cys Ala Glu Phe Ala Gly Leu Arg Gln Ala
305 310 315 320
Val Lys Gln
<210> 4
<211> 243
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Met Gly Ile Pro Thr Glu Leu Lys Pro Gly Thr Asn Gln Phe Leu Thr
1 5 10 15
Thr Asp Asp Gly Val Ser Ala Pro Ile Leu Pro Gly Phe His Pro Thr
20 25 30
Pro Pro Ile His Ile Pro Gly Glu Val His Asn Leu Leu Glu Ile Cys
35 40 45
Arg Val Glu Thr Ile Leu Glu Val Asn Asn Leu Lys Thr Asn Glu Thr
50 55 60
Thr Pro Met Gln Arg Leu Cys Phe Pro Val Ser Val Gln Ser Lys Thr
65 70 75 80
Gly Glu Leu Cys Ala Ala Phe Arg Ala Asp Pro Gly Arg Asp Gly Pro
85 90 95
Trp Gln Ser Thr Ile Leu Gly Gln Leu Cys Arg Tyr Tyr Thr Gln Trp
100 105 110
Ser Gly Ser Leu Glu Val Thr Phe Met Phe Ala Gly Ser Phe Met Ala
115 120 125
Thr Gly Lys Met Leu Ile Ala Tyr Thr Pro Pro Gly Gly Ser Val Pro
130 135 140
Ala Asp Arg Ile Thr Ala Met Leu Gly Thr His Val Ile Trp Asp Phe
145 150 155 160
Gly Leu Gln Ser Ser Val Thr Leu Val Val Pro Trp Ile Ser Asn Thr
165 170 175
His Tyr Arg Ala His Ala Arg Ala Gly Tyr Phe Asp Tyr Tyr Thr Thr
180 185 190
Gly Ile Ile Thr Ile Trp Tyr Gln Thr Asn Tyr Val Val Pro Ile Gly
195 200 205
Ala Pro Thr Thr Ala Tyr Ile Val Ala Leu Ala Ala Ala Gln Asp Asn
210 215 220
Phe Thr Met Lys Leu Cys Lys Asp Thr Glu Asp Ile Glu Gln Thr Ala
225 230 235 240
Asn Ile Gln
<210> 5
<211> 298
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Met Gly Asp Pro Ile Ala Asp Met Ile Asp Gln Thr Val Asn Asn Gln
1 5 10 15
Val Asn Arg Ser Leu Thr Ala Met Gln Val Leu Pro Thr Ala Ala Asn
20 25 30
Thr Glu Ala Ser Ser His Arg Leu Gly Thr Gly Val Val Pro Ala Leu
35 40 45
Gln Ala Ala Glu Thr Gly Ala Ser Ser Asn Ala Ser Asp Lys Asn Leu
50 55 60
Ile Glu Thr Arg Cys Val Leu Asn His His Ser Thr Gln Glu Thr Ala
65 70 75 80
Ile Gly Asn Phe Phe Ser Arg Ala Gly Leu Val Ser Ile Ile Thr Met
85 90 95
Pro Thr Met Gly Thr Gln Asn Thr Asp Gly Tyr Val Asn Trp Asp Ile
100 105 110
Asp Leu Met Gly Tyr Ala Gln Leu Arg Arg Lys Cys Glu Leu Phe Thr
115 120 125
Tyr Met Arg Phe Asp Ala Glu Phe Thr Phe Val Val Ala Lys Pro Asn
130 135 140
Gly Glu Leu Val Pro Gln Leu Leu Gln Tyr Met Tyr Val Pro Pro Gly
145 150 155 160
Ala Pro Lys Pro Thr Ser Arg Asp Ser Phe Ala Trp Gln Thr Ala Thr
165 170 175
Asn Pro Ser Val Phe Val Lys Met Thr Asp Pro Pro Ala Gln Val Ser
180 185 190
Val Pro Phe Met Ser Pro Ala Ser Ala Tyr Gln Trp Phe Tyr Asp Gly
195 200 205
Tyr Pro Thr Phe Gly Glu His Leu Gln Ala Asn Asp Leu Asp Tyr Gly
210 215 220
Gln Cys Pro Asn Asn Met Met Gly Thr Phe Ser Ile Arg Thr Val Gly
225 230 235 240
Thr Glu Lys Ser Pro His Ser Ile Thr Leu Arg Val Tyr Met Arg Ile
245 250 255
Lys His Val Arg Ala Trp Ile Pro Arg Pro Leu Arg Asn Gln Pro Tyr
260 265 270
Leu Phe Lys Thr Asn Pro Asn Tyr Lys Gly Asn Asp Ile Lys Cys Thr
275 280 285
Ser Thr Ser Arg Asp Lys Ile Thr Thr Leu
290 295
<210> 6
<211> 248
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Met Glu Thr Gly Ala Ser Ser Asn Ala Ser Asp Lys Asn Leu Ile Glu
1 5 10 15
Thr Arg Cys Val Leu Asn His His Ser Thr Gln Glu Thr Ala Ile Gly
20 25 30
Asn Phe Phe Ser Arg Ala Gly Leu Val Ser Ile Ile Thr Met Pro Thr
35 40 45
Met Gly Thr Gln Asn Thr Asp Gly Tyr Val Asn Trp Asp Ile Asp Leu
50 55 60
Met Gly Tyr Ala Gln Leu Arg Arg Lys Cys Glu Leu Phe Thr Tyr Met
65 70 75 80
Arg Phe Asp Ala Glu Phe Thr Phe Val Val Ala Lys Pro Asn Gly Glu
85 90 95
Leu Val Pro Gln Leu Leu Gln Tyr Met Tyr Val Pro Pro Gly Ala Pro
100 105 110
Lys Pro Thr Ser Arg Asp Ser Phe Ala Trp Gln Thr Ala Thr Asn Pro
115 120 125
Ser Val Phe Val Lys Met Thr Asp Pro Pro Ala Gln Val Ser Val Pro
130 135 140
Phe Met Ser Pro Ala Ser Ala Tyr Gln Trp Phe Tyr Asp Gly Tyr Pro
145 150 155 160
Thr Phe Gly Glu His Leu Gln Ala Asn Asp Leu Asp Tyr Gly Gln Cys
165 170 175
Pro Asn Asn Met Met Gly Thr Phe Ser Ile Arg Thr Val Gly Thr Glu
180 185 190
Lys Ser Pro His Ser Ile Thr Leu Arg Val Tyr Met Arg Ile Lys His
195 200 205
Val Arg Ala Trp Ile Pro Arg Pro Leu Arg Asn Gln Pro Tyr Leu Phe
210 215 220
Lys Thr Asn Pro Asn Tyr Lys Gly Asn Asp Ile Lys Cys Thr Ser Thr
225 230 235 240
Ser Arg Asp Lys Ile Thr Thr Leu
245
<210> 7
<211> 226
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Met His Ser Thr Gln Glu Thr Ala Ile Gly Asn Phe Phe Ser Arg Ala
1 5 10 15
Gly Leu Val Ser Ile Ile Thr Met Pro Thr Met Gly Thr Gln Asn Thr
20 25 30
Asp Gly Tyr Val Asn Trp Asp Ile Asp Leu Met Gly Tyr Ala Gln Leu
35 40 45
Arg Arg Lys Cys Glu Leu Phe Thr Tyr Met Arg Phe Asp Ala Glu Phe
50 55 60
Thr Phe Val Val Ala Lys Pro Asn Gly Glu Leu Val Pro Gln Leu Leu
65 70 75 80
Gln Tyr Met Tyr Val Pro Pro Gly Ala Pro Lys Pro Thr Ser Arg Asp
85 90 95
Ser Phe Ala Trp Gln Thr Ala Thr Asn Pro Ser Val Phe Val Lys Met
100 105 110
Thr Asp Pro Pro Ala Gln Val Ser Val Pro Phe Met Ser Pro Ala Ser
115 120 125
Ala Tyr Gln Trp Phe Tyr Asp Gly Tyr Pro Thr Phe Gly Glu His Leu
130 135 140
Gln Ala Asn Asp Leu Asp Tyr Gly Gln Cys Pro Asn Asn Met Met Gly
145 150 155 160
Thr Phe Ser Ile Arg Thr Val Gly Thr Glu Lys Ser Pro His Ser Ile
165 170 175
Thr Leu Arg Val Tyr Met Arg Ile Lys His Val Arg Ala Trp Ile Pro
180 185 190
Arg Pro Leu Arg Asn Gln Pro Tyr Leu Phe Lys Thr Asn Pro Asn Tyr
195 200 205
Lys Gly Asn Asp Ile Lys Cys Thr Ser Thr Ser Arg Asp Lys Ile Thr
210 215 220
Thr Leu
225
<210> 8
<211> 969
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
atgggttctc aagtttctac tcaaagatcc ggttctcacg aaaactctaa ttctgcttct 60
gagggttcta ctattaacta cactactatt aattactaca aggatgctta cgctgcttct 120
gctggtagac aagatatgtc tcaagatcca aagaagttta ctgatccagt tatggatgtt 180
atgcatgaaa tggctccacc tttgaaatct ccatctgctg aggcttgtgg ttactctgat 240
agagttgctc aattgactat cggtaactct actatcacta ctcaagaagc tgctaatatt 300
gttattgctt acggtgaatg gccagagtat tgtcctgata ctgatgctac tgctgttgat 360
aagccaacta gacctgatgt ttctgttaac agatttttca ctttggatac taagtcttgg 420
gctaaggatt ctaaaggttg gtactggaaa ttcccagatg ttttgactga ggttggtgtt 480
tttggtcaaa acgctcaatt ccactacttg tatagatccg gtttttgtgt tcacgttcaa 540
tgtaatgctt ctaaattcca tcaaggtgct ttgttggttg ctgttttgcc tgaatatgtt 600
ttgggtacta ttgctggtgg tactggtaac gaaaactctc acccacctta cgctactact 660
caaccaggtc aagttggtgc tgttttgact catccatatg ttttggatgc tggtattcct 720
ttgtctcaat tgactgtttg tccacaccaa tggattaact tgagaactaa caactgtgct 780
actatcatcg ttccatacat gaacactgtt cctttcgatt ctgctttgaa ccattgtaac 840
ttcggtttgt tggttattcc agttgttcct ttggatttta acactggtgc tacttctgaa 900
atcccaatca ctgttactat tgctcctatg tgtgctgagt tcgctggttt gagacaagct 960
gttaagcaa 969
<210> 9
<211> 729
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
atgggtattc caactgaatt gaaacctggt actaaccaat tcttgactac tgatgatggt 60
gtttctgctc caattttgcc tggtttccat ccaactccac ctattcacat tcctggtgaa 120
gttcataact tgttggagat ttgtagagtt gaaactatct tggaggttaa caatttgaag 180
actaacgaaa ctactccaat gcaaagattg tgttttcctg tttctgttca atctaaaact 240
ggagagttgt gtgctgcttt cagagctgat ccaggtagag atggtccttg gcaatctact 300
attttgggtc aattgtgtag atactatact caatggtctg gttctttgga agttactttt 360
atgttcgctg gttcttttat ggctactggt aaaatgttga ttgcttacac tccacctggt 420
ggttctgttc ctgctgatag aattactgct atgttgggta ctcacgttat ttgggatttt 480
ggtttgcaat cttctgttac tttggttgtt ccatggattt ctaacactca ttacagagct 540
cacgctagag ctggttattt cgattactat actactggta tcatcactat ctggtatcaa 600
actaactacg ttgttccaat cggtgctcct actactgctt atattgttgc tttggctgct 660
gctcaagata acttcactat gaagttgtgt aaggatactg aagatattga gcaaactgct 720
aatattcaa 729
<210> 10
<211> 894
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
atgggagatc caatcgctga tatgatcgat caaactgtta acaaccaagt taacagatcc 60
ttgactgcta tgcaagtttt gcctactgct gctaatactg aagcttcttc tcatagattg 120
ggtactggtg ttgttccagc tttgcaagct gctgagactg gtgcttcttc taacgcttct 180
gataagaatt tgatcgaaac tagatgtgtt ttgaaccatc actctactca agagactgct 240
attggtaact ttttctctag agctggtttg gtttctatca tcactatgcc aactatgggt 300
actcaaaaca ctgatggtta cgttaattgg gatattgatt tgatgggtta tgctcaattg 360
agaagaaagt gtgaattgtt tacttacatg agattcgatg ctgagtttac tttcgttgtt 420
gctaaaccaa acggtgaatt ggttcctcaa ttgttgcaat acatgtatgt tccacctggt 480
gctccaaagc ctacttctag agattctttt gcttggcaaa ctgctactaa tccttctgtt 540
ttcgttaaaa tgactgatcc acctgctcaa gtttctgttc cattcatgtc tcctgcttct 600
gcttaccaat ggttttacga tggttatcct actttcggtg aacatttgca agctaatgat 660
ttggattatg gtcaatgtcc aaacaatatg atgggtactt tctctattag aactgttggt 720
actgagaagt ctccacactc tatcactttg agagtttaca tgagaattaa acatgttaga 780
gcttggattc caagaccttt gagaaaccaa ccatacttgt ttaagactaa ccctaactac 840
aagggtaacg atatcaagtg tacttctact tctagagata aaattactac tttg 894
<210> 11
<211> 744
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 11
atggagactg gtgcttcttc taacgcttct gataagaatt tgatcgaaac tagatgtgtt 60
ttgaaccatc actctactca agagactgct attggtaact ttttctctag agctggtttg 120
gtttctatca tcactatgcc aactatgggt actcaaaaca ctgatggtta cgttaattgg 180
gatattgatt tgatgggtta tgctcaattg agaagaaagt gtgaattgtt tacttacatg 240
agattcgatg ctgagtttac tttcgttgtt gctaaaccaa acggtgaatt ggttcctcaa 300
ttgttgcaat acatgtatgt tccacctggt gctccaaagc ctacttctag agattctttt 360
gcttggcaaa ctgctactaa tccttctgtt ttcgttaaaa tgactgatcc acctgctcaa 420
gtttctgttc cattcatgtc tcctgcttct gcttaccaat ggttttacga tggttatcct 480
actttcggtg aacatttgca agctaatgat ttggattatg gtcaatgtcc aaacaatatg 540
atgggtactt tctctattag aactgttggt actgagaagt ctccacactc tatcactttg 600
agagtttaca tgagaattaa acatgttaga gcttggattc caagaccttt gagaaaccaa 660
ccatacttgt ttaagactaa ccctaactac aagggtaacg atatcaagtg tacttctact 720
tctagagata aaattactac tttg 744
<210> 12
<211> 678
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 12
atgcactcta ctcaagagac tgctattggt aactttttct ctagagctgg tttggtttct 60
atcatcacta tgccaactat gggtactcaa aacactgatg gttacgttaa ttgggatatt 120
gatttgatgg gttatgctca attgagaaga aagtgtgaat tgtttactta catgagattc 180
gatgctgagt ttactttcgt tgttgctaaa ccaaacggtg aattggttcc tcaattgttg 240
caatacatgt atgttccacc tggtgctcca aagcctactt ctagagattc ttttgcttgg 300
caaactgcta ctaatccttc tgttttcgtt aaaatgactg atccacctgc tcaagtttct 360
gttccattca tgtctcctgc ttctgcttac caatggtttt acgatggtta tcctactttc 420
ggtgaacatt tgcaagctaa tgatttggat tatggtcaat gtccaaacaa tatgatgggt 480
actttctcta ttagaactgt tggtactgag aagtctccac actctatcac tttgagagtt 540
tacatgagaa ttaaacatgt tagagcttgg attccaagac ctttgagaaa ccaaccatac 600
ttgtttaaga ctaaccctaa ctacaagggt aacgatatca agtgtacttc tacttctaga 660
gataaaatta ctactttg 678
<210> 13
<211> 1941
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 13
atgggaccga gcttggactt tgccttatcc cttctaaggc gcaacatcag acaggtgcaa 60
actgaccaag gacatttcac tatgttagga gtgcgagatc gcctagccat tttgccgcgc 120
cactcgcaac caggaaaaac tatctgggtg gagcacaaat taatcaatgt gttagatgct 180
gttgaattgg tggatgagca aggtgtgaat ttggaactta cactagtaac cttggacacc 240
aacgaaaaat ttagagatgt caccaagttt attccagaga cgatcaccgg ggcaagcgac 300
gcaaccttgg ttatcaacac tgagcacatg ccctctatgt tcatcccagt aggtgatgtt 360
gtacagtatg ggtttttaaa tctcagcggt aagcccacac accgaaccat gatgtacaat 420
ttccccacaa aggcagggca gtgtggaggt gtggtcactt cagtcggtaa aattattgga 480
attcatatcg gtgggaatgg acgccaaggc ttctgtgctg gactgaagag aagttacttt 540
gccagtgaac aaggagagat ccaatggatg aagcccaata aagaaactgg gagactgaat 600
attaatggcc caacacgtac caaattggag cccagtgcat tctacgatgt gtttgagggc 660
agcaaagaac cagcagtctt aaccagtaag gatcccagac ttgaggttga ttttgagcaa 720
gctttgtttt ccaaatatgt aggaaatacc ctgcatgagc ctgatgagta tgtgacacag 780
gctgctctcc actatgcaaa ccagctaaag caattagata taaacactaa taagatgagt 840
atggaagaag catgctacgg cactaaattt ctagaggcta tagacttgca caccagtgcc 900
gggtacccct atagtgccct gggtgtcaag aaaagagaca tacttgaccc aaccactaga 960
gatactacca aaatgaaatt ctacatggat aaatacgggt tagacttgcc ctattccacc 1020
tatgtgaaag acgagcttag atccttagat aagattaaga aagggaaatc ccgcttgatt 1080
gaagccagta gtctaaatga ctcagtctac cttaggatga ctttcgggca tctttatgaa 1140
acttttcatg ccaacccggg gactgtgact gggtctgcag tagggtgtaa tcctgatgtg 1200
ttctggagta aattaccaat cctgctgcca ggatcgctct ttgcatttga ctattcagga 1260
tatgacgcaa gtcttagccc agtgtggttt agagctttgg aagtggttct ccgagagatc 1320
ggctactcag aggaagctgt atcactaata gaagggatca accacaccca tcatgtgtat 1380
cggaacagga cgtattgtgt ccttggtgga atgccttcag gttgttccgg cacttccatc 1440
ttcaattcca tgatcaataa cataataatc agaacccttt tgatcaaaac ttttaagggg 1500
attgatttag atgagctgaa tatggtagct tatggagatg atgtgttagc tagctatcca 1560
ttccccattg actgctcgga gctagccaga acaggtaaag agtatgggct aacaatgaca 1620
cctgctgaca agtcaccttg ctttaatgaa gttacctggg aaaatgctac attcttaaag 1680
agaggcttcc tgccagatca tcagttccca tttcttatcc atcctaccat gcccatgagg 1740
gagatccacg agtccattcg ctggactaaa gacgcacgca acactcagga ccacgtgcgc 1800
tctctgtgcc tcttagcgtg gcataatgga aaggaggaat atgaaaagtt tgtgagcaca 1860
attagatcag ttcctattgg aaaagctttg gctataccaa attttgagaa cttgagaaga 1920
aattggctcg agttatttta a 1941
<210> 14
<211> 13434
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 14
agatctaaca tccaaagacg aaaggttgaa tgaaaccttt ttgccatccg acatccacag 60
gtccattctc acacataagt gccaaacgca acaggagggg atacactagc agcagaccgt 120
tgcaaacgca ggacctccac tcctcttctc ctcaacaccc acttttgcca tcgaaaaacc 180
agcccagtta ttgggcttga ttggagctcg ctcattccaa ttccttctat taggctacta 240
acaccatgac tttattagcc tgtctatcct ggcccccctg gcgaggttca tgtttgttta 300
tttccgaatg caacaagctc cgcattacac ccgaacatca ctccagatga gggctttctg 360
agtgtggggt caaatagttt catgttcccc aaatggccca aaactgacag tttaaacgct 420
gtcttggaac ctaatatgac aaaagcgtga tctcatccaa gatgaactaa gtttggttcg 480
ttgaaatgct aacggccagt tggtcaaaaa gaaacttcca aaagtcggca taccgtttgt 540
cttgtttggt attgattgac gaatgctcaa aaataatctc attaatgctt agcgcagtct 600
ctctatcgct tctgaacccc ggtgcacctg tgccgaaacg caaatgggga aacacccgct 660
ttttggatga ttatgcattg tctccacatt gtatgcttcc aagattctgg tgggaatact 720
gctgatagcc taacgttcat gatcaaaatt taactgttct aacccctact tgacagcaat 780
atataaacag aaggaagctg ccctgtctta aacctttttt tttatcatca ttattagctt 840
actttcataa ttgcgactgg ttccaattga caagcttttg attttaacga cttttaacga 900
caacttgaga agatcaaaaa acaactaatt attcgaaacg gaattcacca tgggaccgag 960
cttggacttt gccttatccc ttctaaggcg caacatcaga caggtgcaaa ctgaccaagg 1020
acatttcact atgttaggag tgcgagatcg cctagccatt ttgccgcgcc actcgcaacc 1080
aggaaaaact atctgggtgg agcacaaatt aatcaatgtg ttagatgctg ttgaattggt 1140
ggatgagcaa ggtgtgaatt tggaacttac actagtaacc ttggacacca acgaaaaatt 1200
tagagatgtc accaagttta ttccagagac gatcaccggg gcaagcgacg caaccttggt 1260
tatcaacact gagcacatgc cctctatgtt catcccagta ggtgatgttg tacagtatgg 1320
gtttttaaat ctcagcggta agcccacaca ccgaaccatg atgtacaatt tccccacaaa 1380
ggcagggcag tgtggaggtg tggtcacttc agtcggtaaa attattggaa ttcatatcgg 1440
tgggaatgga cgccaaggct tctgtgctgg actgaagaga agttactttg ccagtgaaca 1500
aggagagatc caatggatga agcccaataa agaaactggg agactgaata ttaatggccc 1560
aacacgtacc aaattggagc ccagtgcatt ctacgatgtg tttgagggca gcaaagaacc 1620
agcagtctta accagtaagg atcccagact tgaggttgat tttgagcaag ctttgttttc 1680
caaatatgta ggaaataccc tgcatgagcc tgatgagtat gtgacacagg ctgctctcca 1740
ctatgcaaac cagctaaagc aattagatat aaacactaat aagatgagta tggaagaagc 1800
atgctacggc actaaatttc tagaggctat agacttgcac accagtgccg ggtaccccta 1860
tagtgccctg ggtgtcaaga aaagagacat acttgaccca accactagag atactaccaa 1920
aatgaaattc tacatggata aatacgggtt agacttgccc tattccacct atgtgaaaga 1980
cgagcttaga tccttagata agattaagaa agggaaatcc cgcttgattg aagccagtag 2040
tctaaatgac tcagtctacc ttaggatgac tttcgggcat ctttatgaaa cttttcatgc 2100
caacccgggg actgtgactg ggtctgcagt agggtgtaat cctgatgtgt tctggagtaa 2160
attaccaatc ctgctgccag gatcgctctt tgcatttgac tattcaggat atgacgcaag 2220
tcttagccca gtgtggttta gagctttgga agtggttctc cgagagatcg gctactcaga 2280
ggaagctgta tcactaatag aagggatcaa ccacacccat catgtgtatc ggaacaggac 2340
gtattgtgtc cttggtggaa tgccttcagg ttgttccggc acttccatct tcaattccat 2400
gatcaataac ataataatca gaaccctttt gatcaaaact tttaagggga ttgatttaga 2460
tgagctgaat atggtagctt atggagatga tgtgttagct agctatccat tccccattga 2520
ctgctcggag ctagccagaa caggtaaaga gtatgggcta acaatgacac ctgctgacaa 2580
gtcaccttgc tttaatgaag ttacctggga aaatgctaca ttcttaaaga gaggcttcct 2640
gccagatcat cagttcccat ttcttatcca tcctaccatg cccatgaggg agatccacga 2700
gtccattcgc tggactaaag acgcacgcaa cactcaggac cacgtgcgct ctctgtgcct 2760
cttagcgtgg cataatggaa aggaggaata tgaaaagttt gtgagcacaa ttagatcagt 2820
tcctattgga aaagctttgg ctataccaaa ttttgagaac ttgagaagaa attggctcga 2880
gttattttaa tgaggtaccg gccggccatt taaatacagg ccccttttcc tttgtcgata 2940
tcatgtaatt agttatgtca cgcttacatt cacgccctcc tcccacatcc gctctaaccg 3000
aaaaggaagg agttagacaa cctgaagtct aggtccctat ttattttttt taatagttat 3060
gttagtatta agaacgttat ttatatttca aatttttctt ttttttctgt acaaacgcgt 3120
gtacgcatgt aacattatac tgaaaacctt gcttgagaag gttttgggac gctcgaaggc 3180
tttaatttgc aagctggatc taacatccaa agacgaaagg ttgaatgaaa cctttttgcc 3240
atccgacatc cacaggtcca ttctcacaca taagtgccaa acgcaacagg aggggataca 3300
ctagcagcag accgttgcaa acgcaggacc tccactcctc ttctcctcaa cacccacttt 3360
tgccatcgaa aaaccagccc agttattggg cttgattgga gctcgctcat tccaattcct 3420
tctattaggc tactaacacc atgactttat tagcctgtct atcctggccc ccctggcgag 3480
gttcatgttt gtttatttcc gaatgcaaca agctccgcat tacacccgaa catcactcca 3540
gatgagggct ttctgagtgt ggggtcaaat agtttcatgt tccccaaatg gcccaaaact 3600
gacagtttaa acgctgtctt ggaacctaat atgacaaaag cgtgatctca tccaagatga 3660
actaagtttg gttcgttgaa atgctaacgg ccagttggtc aaaaagaaac ttccaaaagt 3720
cggcataccg tttgtcttgt ttggtattga ttgacgaatg ctcaaaaata atctcattaa 3780
tgcttagcgc agtctctcta tcgcttctga accccggtgc acctgtgccg aaacgcaaat 3840
ggggaaacac ccgctttttg gatgattatg cattgtctcc acattgtatg cttccaagat 3900
tctggtggga atactgctga tagcctaacg ttcatgatca aaatttaact gttctaaccc 3960
ctacttgaca gcaatatata aacagaagga agctgccctg tcttaaacct ttttttttat 4020
catcattatt agcttacttt cataattgcg actggttcca attgacaagc ttttgatttt 4080
aacgactttt aacgacaact tgagaagatc aaaaaacaac taattattcg aaacggaatt 4140
caccatgggt tctcaagttt ctactcaaag atccggttct cacgaaaact ctaattctgc 4200
ttctgagggt tctactatta actacactac tattaattac tacaaggatg cttacgctgc 4260
ttctgctggt agacaagata tgtctcaaga tccaaagaag tttactgatc cagttatgga 4320
tgttatgcat gaaatggctc cacctttgaa atctccatct gctgaggctt gtggttactc 4380
tgatagagtt gctcaattga ctatcggtaa ctctactatc actactcaag aagctgctaa 4440
tattgttatt gcttacggtg aatggccaga gtattgtcct gatactgatg ctactgctgt 4500
tgataagcca actagacctg atgtttctgt taacagattt ttcactttgg atactaagtc 4560
ttgggctaag gattctaaag gttggtactg gaaattccca gatgttttga ctgaggttgg 4620
tgtttttggt caaaacgctc aattccacta cttgtataga tccggttttt gtgttcacgt 4680
tcaatgtaat gcttctaaat tccatcaagg tgctttgttg gttgctgttt tgcctgaata 4740
tgttttgggt actattgctg gtggtactgg taacgaaaac tctcacccac cttacgctac 4800
tactcaacca ggtcaagttg gtgctgtttt gactcatcca tatgttttgg atgctggtat 4860
tcctttgtct caattgactg tttgtccaca ccaatggatt aacttgagaa ctaacaactg 4920
tgctactatc atcgttccat acatgaacac tgttcctttc gattctgctt tgaaccattg 4980
taacttcggt ttgttggtta ttccagttgt tcctttggat tttaacactg gtgctacttc 5040
tgaaatccca atcactgtta ctattgctcc tatgtgtgct gagttcgctg gtttgagaca 5100
agctgttaag caaggtattc caactgaatt gaaacctggt actaaccaat tcttgactac 5160
tgatgatggt gtttctgctc caattttgcc tggtttccat ccaactccac ctattcacat 5220
tcctggtgaa gttcataact tgttggagat ttgtagagtt gaaactatct tggaggttaa 5280
caatttgaag actaacgaaa ctactccaat gcaaagattg tgttttcctg tttctgttca 5340
atctaaaact ggagagttgt gtgctgcttt cagagctgat ccaggtagag atggtccttg 5400
gcaatctact attttgggtc aattgtgtag atactatact caatggtctg gttctttgga 5460
agttactttt atgttcgctg gttcttttat ggctactggt aaaatgttga ttgcttacac 5520
tccacctggt ggttctgttc ctgctgatag aattactgct atgttgggta ctcacgttat 5580
ttgggatttt ggtttgcaat cttctgttac tttggttgtt ccatggattt ctaacactca 5640
ttacagagct cacgctagag ctggttattt cgattactat actactggta tcatcactat 5700
ctggtatcaa actaactacg ttgttccaat cggtgctcct actactgctt atattgttgc 5760
tttggctgct gctcaagata acttcactat gaagttgtgt aaggatactg aagatattga 5820
gcaaactgct aatattcaag gagatccaat cgctgatatg atcgatcaaa ctgttaacaa 5880
ccaagttaac agatccttga ctgctatgca agttttgcct actgctgcta atactgaagc 5940
ttcttctcat agattgggta ctggtgttgt tccagctttg caagctgctg agactggtgc 6000
ttcttctaac gcttctgata agaatttgat cgaaactaga tgtgttttga accatcactc 6060
tactcaagag actgctattg gtaacttttt ctctagagct ggtttggttt ctatcatcac 6120
tatgccaact atgggtactc aaaacactga tggttacgtt aattgggata ttgatttgat 6180
gggttatgct caattgagaa gaaagtgtga attgtttact tacatgagat tcgatgctga 6240
gtttactttc gttgttgcta aaccaaacgg tgaattggtt cctcaattgt tgcaatacat 6300
gtatgttcca cctggtgctc caaagcctac ttctagagat tcttttgctt ggcaaactgc 6360
tactaatcct tctgttttcg ttaaaatgac tgatccacct gctcaagttt ctgttccatt 6420
catgtctcct gcttctgctt accaatggtt ttacgatggt tatcctactt tcggtgaaca 6480
tttgcaagct aatgatttgg attatggtca atgtccaaac aatatgatgg gtactttctc 6540
tattagaact gttggtactg agaagtctcc acactctatc actttgagag tttacatgag 6600
aattaaacat gttagagctt ggattccaag acctttgaga aaccaaccat acttgtttaa 6660
gactaaccct aactacaagg gtaacgatat caagtgtact tctacttcta gagataaaat 6720
tactactttg taatgaggta ccggccggcc atttaaatac aggccccttt tcctttgtcg 6780
atatcatgta attagttatg tcacgcttac attcacgccc tcctcccaca tccgctctaa 6840
ccgaaaagga aggagttaga caacctgaag tctaggtccc tatttatttt ttttaatagt 6900
tatgttagta ttaagaacgt tatttatatt tcaaattttt cttttttttc tgtacaaacg 6960
cgtgtacgca tgtaacatta tactgaaaac cttgcttgag aaggttttgg gacgctcgaa 7020
ggctttaatt tgcaagctgg atccgcggcc gccttccaaa ctctcatgga ttctcaggta 7080
ataggtattc taggaggagg ccagctaggc cgaatgattg ttgaggccgc tagcaggctc 7140
aatatcaaga ccgtgattct tgatgatggt ttttcacctg ctaagcacat taatgctgcg 7200
caagaccaca tcgacggatc attcaaagat gaggaggcta tcgccaagtt agctgccaaa 7260
tgtgatgttc tcactgtaga gattgagcat gtcaacacag atgctctaaa gagagttcaa 7320
gacagaactg gaatcaagat atatccttta ccagagacaa tcgaactaat caaggataag 7380
tacttgcaaa aggaacattt gatcaagcac aacatttcgg tgacaaagtc tcagggtata 7440
gaatctaatg aaaaggcgct gcttttgttt ggagaagaga atggatttcc atatctgttg 7500
aagtcccgga ctatggctta tgatggaaga ggcaattttg tagtggagtc taaagaggac 7560
atcagtaagg cattagagtt cttgaaagat cgtccattgt atgccgagaa gtttgctcct 7620
tttgttaaag aattagcggt aatggttgtg agatcactgg aaggcgaagt attctcctac 7680
ccaaccgtag aaactgtgca caaggacaat atctgtcata ttgtgtatgc tccggccaga 7740
gttaatgaca ccatccaaaa gaaagctcaa atattagctg aaaacactgt gaagactttc 7800
ccaggcgctg gaatcttcgg agttgagatg ttcctattgt ctgatggaga acttcttgta 7860
aatgagattg ctccaaggcc ccacaattct ggtcactata caatcgatgc atgtgtaaca 7920
tctcagttcg aagcacatgt aagagccata actggtctgc caatgccact agatttcacc 7980
aaactatcta cttccaacac caacgctatt atgctcaatg ttttgggtgc tgaaaaatct 8040
cacggggaat tagagttttg tagaagagcc ttagaaacac ccggtgcttc tgtatatctg 8100
tacggaaaga ccacccgatt ggctcgtaag atgggtcata tcaacataat aggatcttcc 8160
atgttggaag cagaacaaaa gttagagtac attctagaag aatcaaccca cttaccatcc 8220
agtactgtat cagctgacac taaaccgttg gttggagtta tcatgggttc agactctgat 8280
ctacctgtga tttcgaaagg ttgcgatatt ttaaaacagt ttggtgttcc attcgaagtt 8340
actattgtct ctgctcatag aacaccacag agaatgacca gatatgcctt tgaagccgct 8400
agtagaggta tcaaggctat cattgcaggt gctggtggtg ctgctcatct tccaggaatg 8460
gttgctgcca tgactccgtt gccagtcatt ggtgttcctg tcaagggctc tacgttggat 8520
ggtgtagact cgctacactc gattgtccaa atgcctagag gtgttcctgt ggctacggtt 8580
gctatcaaca acgccaccaa tgccgctctg ttggccatca ggattttagg tacaattgac 8640
cacaaatggc aaaaggaaat gtccaagtat atgaatgcaa tggagaccga agtgttgggg 8700
aaggcatcca acttggaatc tgaagggtat gaatcctatt tgaagaatcg tctttgaatt 8760
tagtattgtt ttttaataga tgtatatata atagtacacg taacttatct attccattca 8820
taattttatt ttaaaggttc ggtagaaatt tgtcctccaa aaagttggtt agagcctggc 8880
agttttgata ggcattatta tagattgggt aatatttacc ctgcacctgg aggaactttg 8940
caaagagcct catgtgcggc gcgccaggcc ataatggcca aacggtttct caattactat 9000
atactactaa ccatttacct gtagcgtatt tcttttccct cttcgcgaaa gctcaagggc 9060
atcttcttga ctcatgaaaa atatctggat ttcttctgac agatcatcac ccttgagccc 9120
aactctctag cctatgagtg taagtgatag tcatcttgca acagattatt ttggaacgca 9180
actaacaaag cagatacacc cttcagcaga atcctttctg gatattgtga agaatgatcg 9240
ccaaagtcac agtcctgaga cagttcctaa tctttacccc atttacaagt tcatccaatc 9300
agacttctta acgcctcatc tggcttatat caagcttacc aacagttcag aaactcccag 9360
tccaagtttc ttgcttgaaa gtgcgaagaa tggtgacacc gttgacaggt acacctttat 9420
gggacattcc cccagaaaaa taatcaagac tgggccttta gagggtgctg aagttgaccc 9480
cttggtgctt ctggaaaaag aactgaaggg caccagacaa gcgcaacttc ctggtattcc 9540
tcgtctaagt ggtggtgcca taggatacat ctcgtacgat tgtattaagt actttgaacc 9600
aaaaactgaa agaaaactga aagatgtttt gcaacttccg gaagcagctt tgatgttgtt 9660
cgacacgatc gtggcttttg acaatgttta tcaaagattc caggtaattg gaaacgtttc 9720
tctatccgtt gatgactcgg acgaagctat tcttgagaaa tattataaga caagagaaga 9780
agtggaaaag atcagtaaag tggtatttga caataaaact gttccctact atgaacagaa 9840
agatattatt caaggccaaa cgttcacctc taatattggt caggaagggt atgaaaacca 9900
tgttcgcaag ctgaaagaac atattctgaa aggagacatc ttccaagctg ttccctctca 9960
aagggtagcc aggccgacct cattgcaccc tttcaacatc tatcgtcatt tgagaactgt 10020
caatccttct ccatacatgt tctatattga ctatctagac ttccaagttg ttggtgcttc 10080
acctgaatta ctagttaaat ccgacaacaa caacaaaatc atcacacatc ctattgctgg 10140
aactcttccc agaggtaaaa ctatcgaaga ggacgacaat tatgctaagc aattgaagtc 10200
gtctttgaaa gacagggccg agcacgtcat gctggtagat ttggccagaa atgatattaa 10260
ccgtgtgtgt gagcccacca gtaccacggt tgatcgttta ttgactgtgg agagattttc 10320
tcatgtgatg catcttgtgt cagaagtcag tggaacattg agaccaaaca agactcgctt 10380
cgatgctttc agatccattt tcccagcagg aaccgtctcc ggtgctccga aggtaagagc 10440
aatgcaactc ataggagaat tggaaggaga aaagagaggt gtttatgcgg gggccgtagg 10500
acactggtcg tacgatggaa aatcgatgga cacatgtatt gccttaagaa caatggtcgt 10560
caaggacggt gtcgcttacc ttcaagccgg aggtggaatt gtctacgatt ctgaccccta 10620
tgacgagtac atcgaaacca tgaacaaaat gagatccaac aataacacca tcttggaggc 10680
tgagaaaatc tggaccgata ggttggccag agacgagaat caaagtgaat ccgaagaaaa 10740
cgatcaatga acggaggacg taagtaggaa tttatggttt ggccataatg gcctagcttg 10800
gcgtaatcat ggtcatagct gtttcctgtg tgaaattgtt atccgctcac aattccacac 10860
aacatacgag ccggaagcat aaagtgtaaa gcctggggtg cctaatgagt gagctaactc 10920
acattaattg cgttgcgctc actgcccgct ttccagtcgg gaaacctgtc gtgccagctg 10980
cattaatgaa tcggccaacg cgcggggaga ggcggtttgc gtattgggcg ctcttccgct 11040
tcctcgctca ctgactcgct gcgctcggtc gttcggctgc ggcgagcggt atcagctcac 11100
tcaaaggcgg taatacggtt atccacagaa tcaggggata acgcaggaaa gaacatgtga 11160
gcaaaaggcc agcaaaaggc caggaaccgt aaaaaggccg cgttgctggc gtttttccat 11220
aggctccgcc cccctgacga gcatcacaaa aatcgacgct caagtcagag gtggcgaaac 11280
ccgacaggac tataaagata ccaggcgttt ccccctggaa gctccctcgt gcgctctcct 11340
gttccgaccc tgccgcttac cggatacctg tccgcctttc tcccttcggg aagcgtggcg 11400
ctttctcata gctcacgctg taggtatctc agttcggtgt aggtcgttcg ctccaagctg 11460
ggctgtgtgc acgaaccccc cgttcagccc gaccgctgcg ccttatccgg taactatcgt 11520
cttgagtcca acccggtaag acacgactta tcgccactgg cagcagccac tggtaacagg 11580
attagcagag cgaggtatgt aggcggtgct acagagttct tgaagtggtg gcctaactac 11640
ggctacacta gaaggacagt atttggtatc tgcgctctgc tgaagccagt taccttcgga 11700
aaaagagttg gtagctcttg atccggcaaa caaaccaccg ctggtagcgg tggttttttt 11760
gtttgcaagc agcagattac gcgcagaaaa aaaggatctc aagaagatcc tttgatcttt 11820
tctacggggt ctgacgctca gtggaacgaa aactcacgtt aagggatttt ggtcatgaga 11880
ttatcaaaaa ggatcttcac ctagatcctt ttaaattaaa aatgaagttt taaatcaatc 11940
taaagtatat atgagtaaac ttggtctgac agttaccaat gcttaatcag tgaggcacct 12000
atctcagcga tctgtctatt tcgttcatcc atagttgcct gactccccgt cgtgtagata 12060
actacgatac gggagggctt accatctggc cccagtgctg caatgatacc gcgagaccca 12120
cgctcaccgg ctccagattt atcagcaata aaccagccag ccggaagggc cgagcgcaga 12180
agtggtcctg caactttatc cgcctccatc cagtctatta attgttgccg ggaagctaga 12240
gtaagtagtt cgccagttaa tagtttgcgc aacgttgttg ccattgctac aggcatcgtg 12300
gtgtcacgct cgtcgtttgg tatggcttca ttcagctccg gttcccaacg atcaaggcga 12360
gttacatgat cccccatgtt gtgcaaaaaa gcggttagct ccttcggtcc tccgatcgtt 12420
gtcagaagta agttggccgc agtgttatca ctcatggtta tggcagcact gcataattct 12480
cttactgtca tgccatccgt aagatgcttt tctgtgactg gtgagtactc aaccaagtca 12540
ttctgagaat agtgtatgcg gcgaccgagt tgctcttgcc cggcgtcaat acgggataat 12600
accgcgccac atagcagaac tttaaaagtg ctcatcattg gaaaacgttc ttcggggcga 12660
aaactctcaa ggatcttacc gctgttgaga tccagttcga tgtaacccac tcgtgcaccc 12720
aactgatctt cagcatcttt tactttcacc agcgtttctg ggtgagcaaa aacaggaagg 12780
caaaatgccg caaaaaaggg aataagggcg acacggaaat gttgaatact catactcttc 12840
ctttttcaat attattgaag catttatcag ggttattgtc tcatgagcgg atacatattt 12900
gaatgtattt agaaaaataa acaaataggg gttccgcgca catttccccg aaaagtgcca 12960
cctgacgtct aagaaaccat tattatcatg acattaacct ataaaaatag gcgtatcacg 13020
aggccctttc gtctcgcgcg tttcggtgat gacggtgaaa acctctgaca catgcagctc 13080
ccggagacgg tcacagcttg tctgtaagcg gatgccggga gcagacaagc ccgtcagggc 13140
gcgtcagcgg gtgttggcgg gtgtcggggc tggcttaact atgcggcatc agagcagatt 13200
gtactgagag tgcaccatat gcggtgtgaa ataccgcaca gatgcgtaag gagaaaatac 13260
cgcatcaggc gccattcgcc attcaggctg cgcaactgtt gggaagggcg atcggtgcgg 13320
gcctcttcgc tattacgcca gctggcgaaa gggggatgtg ctgcaaggcg attaagttgg 13380
gtaacgccag ggttttccca gtcacgacgt tgtaaaacga cggccagtga attg 13434
<210> 15
<211> 12759
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 15
agatctaaca tccaaagacg aaaggttgaa tgaaaccttt ttgccatccg acatccacag 60
gtccattctc acacataagt gccaaacgca acaggagggg atacactagc agcagaccgt 120
tgcaaacgca ggacctccac tcctcttctc ctcaacaccc acttttgcca tcgaaaaacc 180
agcccagtta ttgggcttga ttggagctcg ctcattccaa ttccttctat taggctacta 240
acaccatgac tttattagcc tgtctatcct ggcccccctg gcgaggttca tgtttgttta 300
tttccgaatg caacaagctc cgcattacac ccgaacatca ctccagatga gggctttctg 360
agtgtggggt caaatagttt catgttcccc aaatggccca aaactgacag tttaaacgct 420
gtcttggaac ctaatatgac aaaagcgtga tctcatccaa gatgaactaa gtttggttcg 480
ttgaaatgct aacggccagt tggtcaaaaa gaaacttcca aaagtcggca taccgtttgt 540
cttgtttggt attgattgac gaatgctcaa aaataatctc attaatgctt agcgcagtct 600
ctctatcgct tctgaacccc ggtgcacctg tgccgaaacg caaatgggga aacacccgct 660
ttttggatga ttatgcattg tctccacatt gtatgcttcc aagattctgg tgggaatact 720
gctgatagcc taacgttcat gatcaaaatt taactgttct aacccctact tgacagcaat 780
atataaacag aaggaagctg ccctgtctta aacctttttt tttatcatca ttattagctt 840
actttcataa ttgcgactgg ttccaattga caagcttttg attttaacga cttttaacga 900
caacttgaga agatcaaaaa acaactaatt attcgaaacg gaattcacca tgggttctca 960
agtttctact caaagatccg gttctcacga aaactctaat tctgcttctg agggttctac 1020
tattaactac actactatta attactacaa ggatgcttac gctgcttctg ctggtagaca 1080
agatatgtct caagatccaa agaagtttac tgatccagtt atggatgtta tgcatgaaat 1140
ggctccacct ttgaaatctc catctgctga ggcttgtggt tactctgata gagttgctca 1200
attgactatc ggtaactcta ctatcactac tcaagaagct gctaatattg ttattgctta 1260
cggtgaatgg ccagagtatt gtcctgatac tgatgctact gctgttgata agccaactag 1320
acctgatgtt tctgttaaca gatttttcac tttggatact aagtcttggg ctaaggattc 1380
taaaggttgg tactggaaat tcccagatgt tttgactgag gttggtgttt ttggtcaaaa 1440
cgctcaattc cactacttgt atagatccgg tttttgtgtt cacgttcaat gtaatgcttc 1500
taaattccat caaggtgctt tgttggttgc tgttttgcct gaatatgttt tgggtactat 1560
tgctggtggt actggtaacg aaaactctca cccaccttac gctactactc aaccaggtca 1620
agttggtgct gttttgactc atccatatgt tttggatgct ggtattcctt tgtctcaatt 1680
gactgtttgt ccacaccaat ggattaactt gagaactaac aactgtgcta ctatcatcgt 1740
tccatacatg aacactgttc ctttcgattc tgctttgaac cattgtaact tcggtttgtt 1800
ggttattcca gttgttcctt tggattttaa cactggtgct acttctgaaa tcccaatcac 1860
tgttactatt gctcctatgt gtgctgagtt cgctggtttg agacaagctg ttaagcaata 1920
atgaggtacc ggccggccat ttaaatacag gccccttttc ctttgtcgat atcatgtaat 1980
tagttatgtc acgcttacat tcacgccctc ctcccacatc cgctctaacc gaaaaggaag 2040
gagttagaca acctgaagtc taggtcccta tttatttttt ttaatagtta tgttagtatt 2100
aagaacgtta tttatatttc aaatttttct tttttttctg tacaaacgcg tgtacgcatg 2160
taacattata ctgaaaacct tgcttgagaa ggttttggga cgctcgaagg ctttaatttg 2220
caagctggat ctaacatcca aagacgaaag gttgaatgaa acctttttgc catccgacat 2280
ccacaggtcc attctcacac ataagtgcca aacgcaacag gaggggatac actagcagca 2340
gaccgttgca aacgcaggac ctccactcct cttctcctca acacccactt ttgccatcga 2400
aaaaccagcc cagttattgg gcttgattgg agctcgctca ttccaattcc ttctattagg 2460
ctactaacac catgacttta ttagcctgtc tatcctggcc cccctggcga ggttcatgtt 2520
tgtttatttc cgaatgcaac aagctccgca ttacacccga acatcactcc agatgagggc 2580
tttctgagtg tggggtcaaa tagtttcatg ttccccaaat ggcccaaaac tgacagttta 2640
aacgctgtct tggaacctaa tatgacaaaa gcgtgatctc atccaagatg aactaagttt 2700
ggttcgttga aatgctaacg gccagttggt caaaaagaaa cttccaaaag tcggcatacc 2760
gtttgtcttg tttggtattg attgacgaat gctcaaaaat aatctcatta atgcttagcg 2820
cagtctctct atcgcttctg aaccccggtg cacctgtgcc gaaacgcaaa tggggaaaca 2880
cccgcttttt ggatgattat gcattgtctc cacattgtat gcttccaaga ttctggtggg 2940
aatactgctg atagcctaac gttcatgatc aaaatttaac tgttctaacc cctacttgac 3000
agcaatatat aaacagaagg aagctgccct gtcttaaacc ttttttttta tcatcattat 3060
tagcttactt tcataattgc gactggttcc aattgacaag cttttgattt taacgacttt 3120
taacgacaac ttgagaagat caaaaaacaa ctaattattc gaaacggaat tcaccatggg 3180
tattccaact gaattgaaac ctggtactaa ccaattcttg actactgatg atggtgtttc 3240
tgctccaatt ttgcctggtt tccatccaac tccacctatt cacattcctg gtgaagttca 3300
taacttgttg gagatttgta gagttgaaac tatcttggag gttaacaatt tgaagactaa 3360
cgaaactact ccaatgcaaa gattgtgttt tcctgtttct gttcaatcta aaactggaga 3420
gttgtgtgct gctttcagag ctgatccagg tagagatggt ccttggcaat ctactatttt 3480
gggtcaattg tgtagatact atactcaatg gtctggttct ttggaagtta cttttatgtt 3540
cgctggttct tttatggcta ctggtaaaat gttgattgct tacactccac ctggtggttc 3600
tgttcctgct gatagaatta ctgctatgtt gggtactcac gttatttggg attttggttt 3660
gcaatcttct gttactttgg ttgttccatg gatttctaac actcattaca gagctcacgc 3720
tagagctggt tatttcgatt actatactac tggtatcatc actatctggt atcaaactaa 3780
ctacgttgtt ccaatcggtg ctcctactac tgcttatatt gttgctttgg ctgctgctca 3840
agataacttc actatgaagt tgtgtaagga tactgaagat attgagcaaa ctgctaatat 3900
tcaataatga ggtaccggcc ggccatttaa atacaggccc cttttccttt gtcgatatca 3960
tgtaattagt tatgtcacgc ttacattcac gccctcctcc cacatccgct ctaaccgaaa 4020
aggaaggagt tagacaacct gaagtctagg tccctattta ttttttttaa tagttatgtt 4080
agtattaaga acgttattta tatttcaaat ttttcttttt tttctgtaca aacgcgtgta 4140
cgcatgtaac attatactga aaaccttgct tgagaaggtt ttgggacgct cgaaggcttt 4200
aatttgcaag ctggatctaa catccaaaga cgaaaggttg aatgaaacct ttttgccatc 4260
cgacatccac aggtccattc tcacacataa gtgccaaacg caacaggagg ggatacacta 4320
gcagcagacc gttgcaaacg caggacctcc actcctcttc tcctcaacac ccacttttgc 4380
catcgaaaaa ccagcccagt tattgggctt gattggagct cgctcattcc aattccttct 4440
attaggctac taacaccatg actttattag cctgtctatc ctggcccccc tggcgaggtt 4500
catgtttgtt tatttccgaa tgcaacaagc tccgcattac acccgaacat cactccagat 4560
gagggctttc tgagtgtggg gtcaaatagt ttcatgttcc ccaaatggcc caaaactgac 4620
agtttaaacg ctgtcttgga acctaatatg acaaaagcgt gatctcatcc aagatgaact 4680
aagtttggtt cgttgaaatg ctaacggcca gttggtcaaa aagaaacttc caaaagtcgg 4740
cataccgttt gtcttgtttg gtattgattg acgaatgctc aaaaataatc tcattaatgc 4800
ttagcgcagt ctctctatcg cttctgaacc ccggtgcacc tgtgccgaaa cgcaaatggg 4860
gaaacacccg ctttttggat gattatgcat tgtctccaca ttgtatgctt ccaagattct 4920
ggtgggaata ctgctgatag cctaacgttc atgatcaaaa tttaactgtt ctaaccccta 4980
cttgacagca atatataaac agaaggaagc tgccctgtct taaacctttt tttttatcat 5040
cattattagc ttactttcat aattgcgact ggttccaatt gacaagcttt tgattttaac 5100
gacttttaac gacaacttga gaagatcaaa aaacaactaa ttattcgaaa cggaattcac 5160
catgggagat ccaatcgctg atatgatcga tcaaactgtt aacaaccaag ttaacagatc 5220
cttgactgct atgcaagttt tgcctactgc tgctaatact gaagcttctt ctcatagatt 5280
gggtactggt gttgttccag ctttgcaagc tgctgagact ggtgcttctt ctaacgcttc 5340
tgataagaat ttgatcgaaa ctagatgtgt tttgaaccat cactctactc aagagactgc 5400
tattggtaac tttttctcta gagctggttt ggtttctatc atcactatgc caactatggg 5460
tactcaaaac actgatggtt acgttaattg ggatattgat ttgatgggtt atgctcaatt 5520
gagaagaaag tgtgaattgt ttacttacat gagattcgat gctgagttta ctttcgttgt 5580
tgctaaacca aacggtgaat tggttcctca attgttgcaa tacatgtatg ttccacctgg 5640
tgctccaaag cctacttcta gagattcttt tgcttggcaa actgctacta atccttctgt 5700
tttcgttaaa atgactgatc cacctgctca agtttctgtt ccattcatgt ctcctgcttc 5760
tgcttaccaa tggttttacg atggttatcc tactttcggt gaacatttgc aagctaatga 5820
tttggattat ggtcaatgtc caaacaatat gatgggtact ttctctatta gaactgttgg 5880
tactgagaag tctccacact ctatcacttt gagagtttac atgagaatta aacatgttag 5940
agcttggatt ccaagacctt tgagaaacca accatacttg tttaagacta accctaacta 6000
caagggtaac gatatcaagt gtacttctac ttctagagat aaaattacta ctttgtaatg 6060
aggtaccggc cggccattta aatacaggcc ccttttcctt tgtcgatatc atgtaattag 6120
ttatgtcacg cttacattca cgccctcctc ccacatccgc tctaaccgaa aaggaaggag 6180
ttagacaacc tgaagtctag gtccctattt atttttttta atagttatgt tagtattaag 6240
aacgttattt atatttcaaa tttttctttt ttttctgtac aaacgcgtgt acgcatgtaa 6300
cattatactg aaaaccttgc ttgagaaggt tttgggacgc tcgaaggctt taatttgcaa 6360
gctggatccg cggccgcctt ccaaactctc atggattctc aggtaatagg tattctagga 6420
ggaggccagc taggccgaat gattgttgag gccgctagca ggctcaatat caagaccgtg 6480
attcttgatg atggtttttc acctgctaag cacattaatg ctgcgcaaga ccacatcgac 6540
ggatcattca aagatgagga ggctatcgcc aagttagctg ccaaatgtga tgttctcact 6600
gtagagattg agcatgtcaa cacagatgct ctaaagagag ttcaagacag aactggaatc 6660
aagatatatc ctttaccaga gacaatcgaa ctaatcaagg ataagtactt gcaaaaggaa 6720
catttgatca agcacaacat ttcggtgaca aagtctcagg gtatagaatc taatgaaaag 6780
gcgctgcttt tgtttggaga agagaatgga tttccatatc tgttgaagtc ccggactatg 6840
gcttatgatg gaagaggcaa ttttgtagtg gagtctaaag aggacatcag taaggcatta 6900
gagttcttga aagatcgtcc attgtatgcc gagaagtttg ctccttttgt taaagaatta 6960
gcggtaatgg ttgtgagatc actggaaggc gaagtattct cctacccaac cgtagaaact 7020
gtgcacaagg acaatatctg tcatattgtg tatgctccgg ccagagttaa tgacaccatc 7080
caaaagaaag ctcaaatatt agctgaaaac actgtgaaga ctttcccagg cgctggaatc 7140
ttcggagttg agatgttcct attgtctgat ggagaacttc ttgtaaatga gattgctcca 7200
aggccccaca attctggtca ctatacaatc gatgcatgtg taacatctca gttcgaagca 7260
catgtaagag ccataactgg tctgccaatg ccactagatt tcaccaaact atctacttcc 7320
aacaccaacg ctattatgct caatgttttg ggtgctgaaa aatctcacgg ggaattagag 7380
ttttgtagaa gagccttaga aacacccggt gcttctgtat atctgtacgg aaagaccacc 7440
cgattggctc gtaagatggg tcatatcaac ataataggat cttccatgtt ggaagcagaa 7500
caaaagttag agtacattct agaagaatca acccacttac catccagtac tgtatcagct 7560
gacactaaac cgttggttgg agttatcatg ggttcagact ctgatctacc tgtgatttcg 7620
aaaggttgcg atattttaaa acagtttggt gttccattcg aagttactat tgtctctgct 7680
catagaacac cacagagaat gaccagatat gcctttgaag ccgctagtag aggtatcaag 7740
gctatcattg caggtgctgg tggtgctgct catcttccag gaatggttgc tgccatgact 7800
ccgttgccag tcattggtgt tcctgtcaag ggctctacgt tggatggtgt agactcgcta 7860
cactcgattg tccaaatgcc tagaggtgtt cctgtggcta cggttgctat caacaacgcc 7920
accaatgccg ctctgttggc catcaggatt ttaggtacaa ttgaccacaa atggcaaaag 7980
gaaatgtcca agtatatgaa tgcaatggag accgaagtgt tggggaaggc atccaacttg 8040
gaatctgaag ggtatgaatc ctatttgaag aatcgtcttt gaatttagta ttgtttttta 8100
atagatgtat atataatagt acacgtaact tatctattcc attcataatt ttattttaaa 8160
ggttcggtag aaatttgtcc tccaaaaagt tggttagagc ctggcagttt tgataggcat 8220
tattatagat tgggtaatat ttaccctgca cctggaggaa ctttgcaaag agcctcatgt 8280
gcggcgcgcc aggccataat ggccaaacgg tttctcaatt actatatact actaaccatt 8340
tacctgtagc gtatttcttt tccctcttcg cgaaagctca agggcatctt cttgactcat 8400
gaaaaatatc tggatttctt ctgacagatc atcacccttg agcccaactc tctagcctat 8460
gagtgtaagt gatagtcatc ttgcaacaga ttattttgga acgcaactaa caaagcagat 8520
acacccttca gcagaatcct ttctggatat tgtgaagaat gatcgccaaa gtcacagtcc 8580
tgagacagtt cctaatcttt accccattta caagttcatc caatcagact tcttaacgcc 8640
tcatctggct tatatcaagc ttaccaacag ttcagaaact cccagtccaa gtttcttgct 8700
tgaaagtgcg aagaatggtg acaccgttga caggtacacc tttatgggac attcccccag 8760
aaaaataatc aagactgggc ctttagaggg tgctgaagtt gaccccttgg tgcttctgga 8820
aaaagaactg aagggcacca gacaagcgca acttcctggt attcctcgtc taagtggtgg 8880
tgccatagga tacatctcgt acgattgtat taagtacttt gaaccaaaaa ctgaaagaaa 8940
actgaaagat gttttgcaac ttccggaagc agctttgatg ttgttcgaca cgatcgtggc 9000
ttttgacaat gtttatcaaa gattccaggt aattggaaac gtttctctat ccgttgatga 9060
ctcggacgaa gctattcttg agaaatatta taagacaaga gaagaagtgg aaaagatcag 9120
taaagtggta tttgacaata aaactgttcc ctactatgaa cagaaagata ttattcaagg 9180
ccaaacgttc acctctaata ttggtcagga agggtatgaa aaccatgttc gcaagctgaa 9240
agaacatatt ctgaaaggag acatcttcca agctgttccc tctcaaaggg tagccaggcc 9300
gacctcattg caccctttca acatctatcg tcatttgaga actgtcaatc cttctccata 9360
catgttctat attgactatc tagacttcca agttgttggt gcttcacctg aattactagt 9420
taaatccgac aacaacaaca aaatcatcac acatcctatt gctggaactc ttcccagagg 9480
taaaactatc gaagaggacg acaattatgc taagcaattg aagtcgtctt tgaaagacag 9540
ggccgagcac gtcatgctgg tagatttggc cagaaatgat attaaccgtg tgtgtgagcc 9600
caccagtacc acggttgatc gtttattgac tgtggagaga ttttctcatg tgatgcatct 9660
tgtgtcagaa gtcagtggaa cattgagacc aaacaagact cgcttcgatg ctttcagatc 9720
cattttccca gcaggaaccg tctccggtgc tccgaaggta agagcaatgc aactcatagg 9780
agaattggaa ggagaaaaga gaggtgttta tgcgggggcc gtaggacact ggtcgtacga 9840
tggaaaatcg atggacacat gtattgcctt aagaacaatg gtcgtcaagg acggtgtcgc 9900
ttaccttcaa gccggaggtg gaattgtcta cgattctgac ccctatgacg agtacatcga 9960
aaccatgaac aaaatgagat ccaacaataa caccatcttg gaggctgaga aaatctggac 10020
cgataggttg gccagagacg agaatcaaag tgaatccgaa gaaaacgatc aatgaacgga 10080
ggacgtaagt aggaatttat ggtttggcca taatggccta gcttggcgta atcatggtca 10140
tagctgtttc ctgtgtgaaa ttgttatccg ctcacaattc cacacaacat acgagccgga 10200
agcataaagt gtaaagcctg gggtgcctaa tgagtgagct aactcacatt aattgcgttg 10260
cgctcactgc ccgctttcca gtcgggaaac ctgtcgtgcc agctgcatta atgaatcggc 10320
caacgcgcgg ggagaggcgg tttgcgtatt gggcgctctt ccgcttcctc gctcactgac 10380
tcgctgcgct cggtcgttcg gctgcggcga gcggtatcag ctcactcaaa ggcggtaata 10440
cggttatcca cagaatcagg ggataacgca ggaaagaaca tgtgagcaaa aggccagcaa 10500
aaggccagga accgtaaaaa ggccgcgttg ctggcgtttt tccataggct ccgcccccct 10560
gacgagcatc acaaaaatcg acgctcaagt cagaggtggc gaaacccgac aggactataa 10620
agataccagg cgtttccccc tggaagctcc ctcgtgcgct ctcctgttcc gaccctgccg 10680
cttaccggat acctgtccgc ctttctccct tcgggaagcg tggcgctttc tcatagctca 10740
cgctgtaggt atctcagttc ggtgtaggtc gttcgctcca agctgggctg tgtgcacgaa 10800
ccccccgttc agcccgaccg ctgcgcctta tccggtaact atcgtcttga gtccaacccg 10860
gtaagacacg acttatcgcc actggcagca gccactggta acaggattag cagagcgagg 10920
tatgtaggcg gtgctacaga gttcttgaag tggtggccta actacggcta cactagaagg 10980
acagtatttg gtatctgcgc tctgctgaag ccagttacct tcggaaaaag agttggtagc 11040
tcttgatccg gcaaacaaac caccgctggt agcggtggtt tttttgtttg caagcagcag 11100
attacgcgca gaaaaaaagg atctcaagaa gatcctttga tcttttctac ggggtctgac 11160
gctcagtgga acgaaaactc acgttaaggg attttggtca tgagattatc aaaaaggatc 11220
ttcacctaga tccttttaaa ttaaaaatga agttttaaat caatctaaag tatatatgag 11280
taaacttggt ctgacagtta ccaatgctta atcagtgagg cacctatctc agcgatctgt 11340
ctatttcgtt catccatagt tgcctgactc cccgtcgtgt agataactac gatacgggag 11400
ggcttaccat ctggccccag tgctgcaatg ataccgcgag acccacgctc accggctcca 11460
gatttatcag caataaacca gccagccgga agggccgagc gcagaagtgg tcctgcaact 11520
ttatccgcct ccatccagtc tattaattgt tgccgggaag ctagagtaag tagttcgcca 11580
gttaatagtt tgcgcaacgt tgttgccatt gctacaggca tcgtggtgtc acgctcgtcg 11640
tttggtatgg cttcattcag ctccggttcc caacgatcaa ggcgagttac atgatccccc 11700
atgttgtgca aaaaagcggt tagctccttc ggtcctccga tcgttgtcag aagtaagttg 11760
gccgcagtgt tatcactcat ggttatggca gcactgcata attctcttac tgtcatgcca 11820
tccgtaagat gcttttctgt gactggtgag tactcaacca agtcattctg agaatagtgt 11880
atgcggcgac cgagttgctc ttgcccggcg tcaatacggg ataataccgc gccacatagc 11940
agaactttaa aagtgctcat cattggaaaa cgttcttcgg ggcgaaaact ctcaaggatc 12000
ttaccgctgt tgagatccag ttcgatgtaa cccactcgtg cacccaactg atcttcagca 12060
tcttttactt tcaccagcgt ttctgggtga gcaaaaacag gaaggcaaaa tgccgcaaaa 12120
aagggaataa gggcgacacg gaaatgttga atactcatac tcttcctttt tcaatattat 12180
tgaagcattt atcagggtta ttgtctcatg agcggataca tatttgaatg tatttagaaa 12240
aataaacaaa taggggttcc gcgcacattt ccccgaaaag tgccacctga cgtctaagaa 12300
accattatta tcatgacatt aacctataaa aataggcgta tcacgaggcc ctttcgtctc 12360
gcgcgtttcg gtgatgacgg tgaaaacctc tgacacatgc agctcccgga gacggtcaca 12420
gcttgtctgt aagcggatgc cgggagcaga caagcccgtc agggcgcgtc agcgggtgtt 12480
ggcgggtgtc ggggctggct taactatgcg gcatcagagc agattgtact gagagtgcac 12540
catatgcggt gtgaaatacc gcacagatgc gtaaggagaa aataccgcat caggcgccat 12600
tcgccattca ggctgcgcaa ctgttgggaa gggcgatcgg tgcgggcctc ttcgctatta 12660
cgccagctgg cgaaaggggg atgtgctgca aggcgattaa gttgggtaac gccagggttt 12720
tcccagtcac gacgttgtaa aacgacggcc agtgaattg 12759
<210> 16
<211> 12609
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 16
agatctaaca tccaaagacg aaaggttgaa tgaaaccttt ttgccatccg acatccacag 60
gtccattctc acacataagt gccaaacgca acaggagggg atacactagc agcagaccgt 120
tgcaaacgca ggacctccac tcctcttctc ctcaacaccc acttttgcca tcgaaaaacc 180
agcccagtta ttgggcttga ttggagctcg ctcattccaa ttccttctat taggctacta 240
acaccatgac tttattagcc tgtctatcct ggcccccctg gcgaggttca tgtttgttta 300
tttccgaatg caacaagctc cgcattacac ccgaacatca ctccagatga gggctttctg 360
agtgtggggt caaatagttt catgttcccc aaatggccca aaactgacag tttaaacgct 420
gtcttggaac ctaatatgac aaaagcgtga tctcatccaa gatgaactaa gtttggttcg 480
ttgaaatgct aacggccagt tggtcaaaaa gaaacttcca aaagtcggca taccgtttgt 540
cttgtttggt attgattgac gaatgctcaa aaataatctc attaatgctt agcgcagtct 600
ctctatcgct tctgaacccc ggtgcacctg tgccgaaacg caaatgggga aacacccgct 660
ttttggatga ttatgcattg tctccacatt gtatgcttcc aagattctgg tgggaatact 720
gctgatagcc taacgttcat gatcaaaatt taactgttct aacccctact tgacagcaat 780
atataaacag aaggaagctg ccctgtctta aacctttttt tttatcatca ttattagctt 840
actttcataa ttgcgactgg ttccaattga caagcttttg attttaacga cttttaacga 900
caacttgaga agatcaaaaa acaactaatt attcgaaacg gaattcacca tgggttctca 960
agtttctact caaagatccg gttctcacga aaactctaat tctgcttctg agggttctac 1020
tattaactac actactatta attactacaa ggatgcttac gctgcttctg ctggtagaca 1080
agatatgtct caagatccaa agaagtttac tgatccagtt atggatgtta tgcatgaaat 1140
ggctccacct ttgaaatctc catctgctga ggcttgtggt tactctgata gagttgctca 1200
attgactatc ggtaactcta ctatcactac tcaagaagct gctaatattg ttattgctta 1260
cggtgaatgg ccagagtatt gtcctgatac tgatgctact gctgttgata agccaactag 1320
acctgatgtt tctgttaaca gatttttcac tttggatact aagtcttggg ctaaggattc 1380
taaaggttgg tactggaaat tcccagatgt tttgactgag gttggtgttt ttggtcaaaa 1440
cgctcaattc cactacttgt atagatccgg tttttgtgtt cacgttcaat gtaatgcttc 1500
taaattccat caaggtgctt tgttggttgc tgttttgcct gaatatgttt tgggtactat 1560
tgctggtggt actggtaacg aaaactctca cccaccttac gctactactc aaccaggtca 1620
agttggtgct gttttgactc atccatatgt tttggatgct ggtattcctt tgtctcaatt 1680
gactgtttgt ccacaccaat ggattaactt gagaactaac aactgtgcta ctatcatcgt 1740
tccatacatg aacactgttc ctttcgattc tgctttgaac cattgtaact tcggtttgtt 1800
ggttattcca gttgttcctt tggattttaa cactggtgct acttctgaaa tcccaatcac 1860
tgttactatt gctcctatgt gtgctgagtt cgctggtttg agacaagctg ttaagcaata 1920
atgaggtacc ggccggccat ttaaatacag gccccttttc ctttgtcgat atcatgtaat 1980
tagttatgtc acgcttacat tcacgccctc ctcccacatc cgctctaacc gaaaaggaag 2040
gagttagaca acctgaagtc taggtcccta tttatttttt ttaatagtta tgttagtatt 2100
aagaacgtta tttatatttc aaatttttct tttttttctg tacaaacgcg tgtacgcatg 2160
taacattata ctgaaaacct tgcttgagaa ggttttggga cgctcgaagg ctttaatttg 2220
caagctggat ctaacatcca aagacgaaag gttgaatgaa acctttttgc catccgacat 2280
ccacaggtcc attctcacac ataagtgcca aacgcaacag gaggggatac actagcagca 2340
gaccgttgca aacgcaggac ctccactcct cttctcctca acacccactt ttgccatcga 2400
aaaaccagcc cagttattgg gcttgattgg agctcgctca ttccaattcc ttctattagg 2460
ctactaacac catgacttta ttagcctgtc tatcctggcc cccctggcga ggttcatgtt 2520
tgtttatttc cgaatgcaac aagctccgca ttacacccga acatcactcc agatgagggc 2580
tttctgagtg tggggtcaaa tagtttcatg ttccccaaat ggcccaaaac tgacagttta 2640
aacgctgtct tggaacctaa tatgacaaaa gcgtgatctc atccaagatg aactaagttt 2700
ggttcgttga aatgctaacg gccagttggt caaaaagaaa cttccaaaag tcggcatacc 2760
gtttgtcttg tttggtattg attgacgaat gctcaaaaat aatctcatta atgcttagcg 2820
cagtctctct atcgcttctg aaccccggtg cacctgtgcc gaaacgcaaa tggggaaaca 2880
cccgcttttt ggatgattat gcattgtctc cacattgtat gcttccaaga ttctggtggg 2940
aatactgctg atagcctaac gttcatgatc aaaatttaac tgttctaacc cctacttgac 3000
agcaatatat aaacagaagg aagctgccct gtcttaaacc ttttttttta tcatcattat 3060
tagcttactt tcataattgc gactggttcc aattgacaag cttttgattt taacgacttt 3120
taacgacaac ttgagaagat caaaaaacaa ctaattattc gaaacggaat tcaccatggg 3180
tattccaact gaattgaaac ctggtactaa ccaattcttg actactgatg atggtgtttc 3240
tgctccaatt ttgcctggtt tccatccaac tccacctatt cacattcctg gtgaagttca 3300
taacttgttg gagatttgta gagttgaaac tatcttggag gttaacaatt tgaagactaa 3360
cgaaactact ccaatgcaaa gattgtgttt tcctgtttct gttcaatcta aaactggaga 3420
gttgtgtgct gctttcagag ctgatccagg tagagatggt ccttggcaat ctactatttt 3480
gggtcaattg tgtagatact atactcaatg gtctggttct ttggaagtta cttttatgtt 3540
cgctggttct tttatggcta ctggtaaaat gttgattgct tacactccac ctggtggttc 3600
tgttcctgct gatagaatta ctgctatgtt gggtactcac gttatttggg attttggttt 3660
gcaatcttct gttactttgg ttgttccatg gatttctaac actcattaca gagctcacgc 3720
tagagctggt tatttcgatt actatactac tggtatcatc actatctggt atcaaactaa 3780
ctacgttgtt ccaatcggtg ctcctactac tgcttatatt gttgctttgg ctgctgctca 3840
agataacttc actatgaagt tgtgtaagga tactgaagat attgagcaaa ctgctaatat 3900
tcaataatga ggtaccggcc ggccatttaa atacaggccc cttttccttt gtcgatatca 3960
tgtaattagt tatgtcacgc ttacattcac gccctcctcc cacatccgct ctaaccgaaa 4020
aggaaggagt tagacaacct gaagtctagg tccctattta ttttttttaa tagttatgtt 4080
agtattaaga acgttattta tatttcaaat ttttcttttt tttctgtaca aacgcgtgta 4140
cgcatgtaac attatactga aaaccttgct tgagaaggtt ttgggacgct cgaaggcttt 4200
aatttgcaag ctggatctaa catccaaaga cgaaaggttg aatgaaacct ttttgccatc 4260
cgacatccac aggtccattc tcacacataa gtgccaaacg caacaggagg ggatacacta 4320
gcagcagacc gttgcaaacg caggacctcc actcctcttc tcctcaacac ccacttttgc 4380
catcgaaaaa ccagcccagt tattgggctt gattggagct cgctcattcc aattccttct 4440
attaggctac taacaccatg actttattag cctgtctatc ctggcccccc tggcgaggtt 4500
catgtttgtt tatttccgaa tgcaacaagc tccgcattac acccgaacat cactccagat 4560
gagggctttc tgagtgtggg gtcaaatagt ttcatgttcc ccaaatggcc caaaactgac 4620
agtttaaacg ctgtcttgga acctaatatg acaaaagcgt gatctcatcc aagatgaact 4680
aagtttggtt cgttgaaatg ctaacggcca gttggtcaaa aagaaacttc caaaagtcgg 4740
cataccgttt gtcttgtttg gtattgattg acgaatgctc aaaaataatc tcattaatgc 4800
ttagcgcagt ctctctatcg cttctgaacc ccggtgcacc tgtgccgaaa cgcaaatggg 4860
gaaacacccg ctttttggat gattatgcat tgtctccaca ttgtatgctt ccaagattct 4920
ggtgggaata ctgctgatag cctaacgttc atgatcaaaa tttaactgtt ctaaccccta 4980
cttgacagca atatataaac agaaggaagc tgccctgtct taaacctttt tttttatcat 5040
cattattagc ttactttcat aattgcgact ggttccaatt gacaagcttt tgattttaac 5100
gacttttaac gacaacttga gaagatcaaa aaacaactaa ttattcgaaa cggaattcac 5160
catggagact ggtgcttctt ctaacgcttc tgataagaat ttgatcgaaa ctagatgtgt 5220
tttgaaccat cactctactc aagagactgc tattggtaac tttttctcta gagctggttt 5280
ggtttctatc atcactatgc caactatggg tactcaaaac actgatggtt acgttaattg 5340
ggatattgat ttgatgggtt atgctcaatt gagaagaaag tgtgaattgt ttacttacat 5400
gagattcgat gctgagttta ctttcgttgt tgctaaacca aacggtgaat tggttcctca 5460
attgttgcaa tacatgtatg ttccacctgg tgctccaaag cctacttcta gagattcttt 5520
tgcttggcaa actgctacta atccttctgt tttcgttaaa atgactgatc cacctgctca 5580
agtttctgtt ccattcatgt ctcctgcttc tgcttaccaa tggttttacg atggttatcc 5640
tactttcggt gaacatttgc aagctaatga tttggattat ggtcaatgtc caaacaatat 5700
gatgggtact ttctctatta gaactgttgg tactgagaag tctccacact ctatcacttt 5760
gagagtttac atgagaatta aacatgttag agcttggatt ccaagacctt tgagaaacca 5820
accatacttg tttaagacta accctaacta caagggtaac gatatcaagt gtacttctac 5880
ttctagagat aaaattacta ctttgtaatg aggtaccggc cggccattta aatacaggcc 5940
ccttttcctt tgtcgatatc atgtaattag ttatgtcacg cttacattca cgccctcctc 6000
ccacatccgc tctaaccgaa aaggaaggag ttagacaacc tgaagtctag gtccctattt 6060
atttttttta atagttatgt tagtattaag aacgttattt atatttcaaa tttttctttt 6120
ttttctgtac aaacgcgtgt acgcatgtaa cattatactg aaaaccttgc ttgagaaggt 6180
tttgggacgc tcgaaggctt taatttgcaa gctggatccg cggccgcctt ccaaactctc 6240
atggattctc aggtaatagg tattctagga ggaggccagc taggccgaat gattgttgag 6300
gccgctagca ggctcaatat caagaccgtg attcttgatg atggtttttc acctgctaag 6360
cacattaatg ctgcgcaaga ccacatcgac ggatcattca aagatgagga ggctatcgcc 6420
aagttagctg ccaaatgtga tgttctcact gtagagattg agcatgtcaa cacagatgct 6480
ctaaagagag ttcaagacag aactggaatc aagatatatc ctttaccaga gacaatcgaa 6540
ctaatcaagg ataagtactt gcaaaaggaa catttgatca agcacaacat ttcggtgaca 6600
aagtctcagg gtatagaatc taatgaaaag gcgctgcttt tgtttggaga agagaatgga 6660
tttccatatc tgttgaagtc ccggactatg gcttatgatg gaagaggcaa ttttgtagtg 6720
gagtctaaag aggacatcag taaggcatta gagttcttga aagatcgtcc attgtatgcc 6780
gagaagtttg ctccttttgt taaagaatta gcggtaatgg ttgtgagatc actggaaggc 6840
gaagtattct cctacccaac cgtagaaact gtgcacaagg acaatatctg tcatattgtg 6900
tatgctccgg ccagagttaa tgacaccatc caaaagaaag ctcaaatatt agctgaaaac 6960
actgtgaaga ctttcccagg cgctggaatc ttcggagttg agatgttcct attgtctgat 7020
ggagaacttc ttgtaaatga gattgctcca aggccccaca attctggtca ctatacaatc 7080
gatgcatgtg taacatctca gttcgaagca catgtaagag ccataactgg tctgccaatg 7140
ccactagatt tcaccaaact atctacttcc aacaccaacg ctattatgct caatgttttg 7200
ggtgctgaaa aatctcacgg ggaattagag ttttgtagaa gagccttaga aacacccggt 7260
gcttctgtat atctgtacgg aaagaccacc cgattggctc gtaagatggg tcatatcaac 7320
ataataggat cttccatgtt ggaagcagaa caaaagttag agtacattct agaagaatca 7380
acccacttac catccagtac tgtatcagct gacactaaac cgttggttgg agttatcatg 7440
ggttcagact ctgatctacc tgtgatttcg aaaggttgcg atattttaaa acagtttggt 7500
gttccattcg aagttactat tgtctctgct catagaacac cacagagaat gaccagatat 7560
gcctttgaag ccgctagtag aggtatcaag gctatcattg caggtgctgg tggtgctgct 7620
catcttccag gaatggttgc tgccatgact ccgttgccag tcattggtgt tcctgtcaag 7680
ggctctacgt tggatggtgt agactcgcta cactcgattg tccaaatgcc tagaggtgtt 7740
cctgtggcta cggttgctat caacaacgcc accaatgccg ctctgttggc catcaggatt 7800
ttaggtacaa ttgaccacaa atggcaaaag gaaatgtcca agtatatgaa tgcaatggag 7860
accgaagtgt tggggaaggc atccaacttg gaatctgaag ggtatgaatc ctatttgaag 7920
aatcgtcttt gaatttagta ttgtttttta atagatgtat atataatagt acacgtaact 7980
tatctattcc attcataatt ttattttaaa ggttcggtag aaatttgtcc tccaaaaagt 8040
tggttagagc ctggcagttt tgataggcat tattatagat tgggtaatat ttaccctgca 8100
cctggaggaa ctttgcaaag agcctcatgt gcggcgcgcc aggccataat ggccaaacgg 8160
tttctcaatt actatatact actaaccatt tacctgtagc gtatttcttt tccctcttcg 8220
cgaaagctca agggcatctt cttgactcat gaaaaatatc tggatttctt ctgacagatc 8280
atcacccttg agcccaactc tctagcctat gagtgtaagt gatagtcatc ttgcaacaga 8340
ttattttgga acgcaactaa caaagcagat acacccttca gcagaatcct ttctggatat 8400
tgtgaagaat gatcgccaaa gtcacagtcc tgagacagtt cctaatcttt accccattta 8460
caagttcatc caatcagact tcttaacgcc tcatctggct tatatcaagc ttaccaacag 8520
ttcagaaact cccagtccaa gtttcttgct tgaaagtgcg aagaatggtg acaccgttga 8580
caggtacacc tttatgggac attcccccag aaaaataatc aagactgggc ctttagaggg 8640
tgctgaagtt gaccccttgg tgcttctgga aaaagaactg aagggcacca gacaagcgca 8700
acttcctggt attcctcgtc taagtggtgg tgccatagga tacatctcgt acgattgtat 8760
taagtacttt gaaccaaaaa ctgaaagaaa actgaaagat gttttgcaac ttccggaagc 8820
agctttgatg ttgttcgaca cgatcgtggc ttttgacaat gtttatcaaa gattccaggt 8880
aattggaaac gtttctctat ccgttgatga ctcggacgaa gctattcttg agaaatatta 8940
taagacaaga gaagaagtgg aaaagatcag taaagtggta tttgacaata aaactgttcc 9000
ctactatgaa cagaaagata ttattcaagg ccaaacgttc acctctaata ttggtcagga 9060
agggtatgaa aaccatgttc gcaagctgaa agaacatatt ctgaaaggag acatcttcca 9120
agctgttccc tctcaaaggg tagccaggcc gacctcattg caccctttca acatctatcg 9180
tcatttgaga actgtcaatc cttctccata catgttctat attgactatc tagacttcca 9240
agttgttggt gcttcacctg aattactagt taaatccgac aacaacaaca aaatcatcac 9300
acatcctatt gctggaactc ttcccagagg taaaactatc gaagaggacg acaattatgc 9360
taagcaattg aagtcgtctt tgaaagacag ggccgagcac gtcatgctgg tagatttggc 9420
cagaaatgat attaaccgtg tgtgtgagcc caccagtacc acggttgatc gtttattgac 9480
tgtggagaga ttttctcatg tgatgcatct tgtgtcagaa gtcagtggaa cattgagacc 9540
aaacaagact cgcttcgatg ctttcagatc cattttccca gcaggaaccg tctccggtgc 9600
tccgaaggta agagcaatgc aactcatagg agaattggaa ggagaaaaga gaggtgttta 9660
tgcgggggcc gtaggacact ggtcgtacga tggaaaatcg atggacacat gtattgcctt 9720
aagaacaatg gtcgtcaagg acggtgtcgc ttaccttcaa gccggaggtg gaattgtcta 9780
cgattctgac ccctatgacg agtacatcga aaccatgaac aaaatgagat ccaacaataa 9840
caccatcttg gaggctgaga aaatctggac cgataggttg gccagagacg agaatcaaag 9900
tgaatccgaa gaaaacgatc aatgaacgga ggacgtaagt aggaatttat ggtttggcca 9960
taatggccta gcttggcgta atcatggtca tagctgtttc ctgtgtgaaa ttgttatccg 10020
ctcacaattc cacacaacat acgagccgga agcataaagt gtaaagcctg gggtgcctaa 10080
tgagtgagct aactcacatt aattgcgttg cgctcactgc ccgctttcca gtcgggaaac 10140
ctgtcgtgcc agctgcatta atgaatcggc caacgcgcgg ggagaggcgg tttgcgtatt 10200
gggcgctctt ccgcttcctc gctcactgac tcgctgcgct cggtcgttcg gctgcggcga 10260
gcggtatcag ctcactcaaa ggcggtaata cggttatcca cagaatcagg ggataacgca 10320
ggaaagaaca tgtgagcaaa aggccagcaa aaggccagga accgtaaaaa ggccgcgttg 10380
ctggcgtttt tccataggct ccgcccccct gacgagcatc acaaaaatcg acgctcaagt 10440
cagaggtggc gaaacccgac aggactataa agataccagg cgtttccccc tggaagctcc 10500
ctcgtgcgct ctcctgttcc gaccctgccg cttaccggat acctgtccgc ctttctccct 10560
tcgggaagcg tggcgctttc tcatagctca cgctgtaggt atctcagttc ggtgtaggtc 10620
gttcgctcca agctgggctg tgtgcacgaa ccccccgttc agcccgaccg ctgcgcctta 10680
tccggtaact atcgtcttga gtccaacccg gtaagacacg acttatcgcc actggcagca 10740
gccactggta acaggattag cagagcgagg tatgtaggcg gtgctacaga gttcttgaag 10800
tggtggccta actacggcta cactagaagg acagtatttg gtatctgcgc tctgctgaag 10860
ccagttacct tcggaaaaag agttggtagc tcttgatccg gcaaacaaac caccgctggt 10920
agcggtggtt tttttgtttg caagcagcag attacgcgca gaaaaaaagg atctcaagaa 10980
gatcctttga tcttttctac ggggtctgac gctcagtgga acgaaaactc acgttaaggg 11040
attttggtca tgagattatc aaaaaggatc ttcacctaga tccttttaaa ttaaaaatga 11100
agttttaaat caatctaaag tatatatgag taaacttggt ctgacagtta ccaatgctta 11160
atcagtgagg cacctatctc agcgatctgt ctatttcgtt catccatagt tgcctgactc 11220
cccgtcgtgt agataactac gatacgggag ggcttaccat ctggccccag tgctgcaatg 11280
ataccgcgag acccacgctc accggctcca gatttatcag caataaacca gccagccgga 11340
agggccgagc gcagaagtgg tcctgcaact ttatccgcct ccatccagtc tattaattgt 11400
tgccgggaag ctagagtaag tagttcgcca gttaatagtt tgcgcaacgt tgttgccatt 11460
gctacaggca tcgtggtgtc acgctcgtcg tttggtatgg cttcattcag ctccggttcc 11520
caacgatcaa ggcgagttac atgatccccc atgttgtgca aaaaagcggt tagctccttc 11580
ggtcctccga tcgttgtcag aagtaagttg gccgcagtgt tatcactcat ggttatggca 11640
gcactgcata attctcttac tgtcatgcca tccgtaagat gcttttctgt gactggtgag 11700
tactcaacca agtcattctg agaatagtgt atgcggcgac cgagttgctc ttgcccggcg 11760
tcaatacggg ataataccgc gccacatagc agaactttaa aagtgctcat cattggaaaa 11820
cgttcttcgg ggcgaaaact ctcaaggatc ttaccgctgt tgagatccag ttcgatgtaa 11880
cccactcgtg cacccaactg atcttcagca tcttttactt tcaccagcgt ttctgggtga 11940
gcaaaaacag gaaggcaaaa tgccgcaaaa aagggaataa gggcgacacg gaaatgttga 12000
atactcatac tcttcctttt tcaatattat tgaagcattt atcagggtta ttgtctcatg 12060
agcggataca tatttgaatg tatttagaaa aataaacaaa taggggttcc gcgcacattt 12120
ccccgaaaag tgccacctga cgtctaagaa accattatta tcatgacatt aacctataaa 12180
aataggcgta tcacgaggcc ctttcgtctc gcgcgtttcg gtgatgacgg tgaaaacctc 12240
tgacacatgc agctcccgga gacggtcaca gcttgtctgt aagcggatgc cgggagcaga 12300
caagcccgtc agggcgcgtc agcgggtgtt ggcgggtgtc ggggctggct taactatgcg 12360
gcatcagagc agattgtact gagagtgcac catatgcggt gtgaaatacc gcacagatgc 12420
gtaaggagaa aataccgcat caggcgccat tcgccattca ggctgcgcaa ctgttgggaa 12480
gggcgatcgg tgcgggcctc ttcgctatta cgccagctgg cgaaaggggg atgtgctgca 12540
aggcgattaa gttgggtaac gccagggttt tcccagtcac gacgttgtaa aacgacggcc 12600
agtgaattg 12609
<210> 17
<211> 12543
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 17
agatctaaca tccaaagacg aaaggttgaa tgaaaccttt ttgccatccg acatccacag 60
gtccattctc acacataagt gccaaacgca acaggagggg atacactagc agcagaccgt 120
tgcaaacgca ggacctccac tcctcttctc ctcaacaccc acttttgcca tcgaaaaacc 180
agcccagtta ttgggcttga ttggagctcg ctcattccaa ttccttctat taggctacta 240
acaccatgac tttattagcc tgtctatcct ggcccccctg gcgaggttca tgtttgttta 300
tttccgaatg caacaagctc cgcattacac ccgaacatca ctccagatga gggctttctg 360
agtgtggggt caaatagttt catgttcccc aaatggccca aaactgacag tttaaacgct 420
gtcttggaac ctaatatgac aaaagcgtga tctcatccaa gatgaactaa gtttggttcg 480
ttgaaatgct aacggccagt tggtcaaaaa gaaacttcca aaagtcggca taccgtttgt 540
cttgtttggt attgattgac gaatgctcaa aaataatctc attaatgctt agcgcagtct 600
ctctatcgct tctgaacccc ggtgcacctg tgccgaaacg caaatgggga aacacccgct 660
ttttggatga ttatgcattg tctccacatt gtatgcttcc aagattctgg tgggaatact 720
gctgatagcc taacgttcat gatcaaaatt taactgttct aacccctact tgacagcaat 780
atataaacag aaggaagctg ccctgtctta aacctttttt tttatcatca ttattagctt 840
actttcataa ttgcgactgg ttccaattga caagcttttg attttaacga cttttaacga 900
caacttgaga agatcaaaaa acaactaatt attcgaaacg gaattcacca tgggttctca 960
agtttctact caaagatccg gttctcacga aaactctaat tctgcttctg agggttctac 1020
tattaactac actactatta attactacaa ggatgcttac gctgcttctg ctggtagaca 1080
agatatgtct caagatccaa agaagtttac tgatccagtt atggatgtta tgcatgaaat 1140
ggctccacct ttgaaatctc catctgctga ggcttgtggt tactctgata gagttgctca 1200
attgactatc ggtaactcta ctatcactac tcaagaagct gctaatattg ttattgctta 1260
cggtgaatgg ccagagtatt gtcctgatac tgatgctact gctgttgata agccaactag 1320
acctgatgtt tctgttaaca gatttttcac tttggatact aagtcttggg ctaaggattc 1380
taaaggttgg tactggaaat tcccagatgt tttgactgag gttggtgttt ttggtcaaaa 1440
cgctcaattc cactacttgt atagatccgg tttttgtgtt cacgttcaat gtaatgcttc 1500
taaattccat caaggtgctt tgttggttgc tgttttgcct gaatatgttt tgggtactat 1560
tgctggtggt actggtaacg aaaactctca cccaccttac gctactactc aaccaggtca 1620
agttggtgct gttttgactc atccatatgt tttggatgct ggtattcctt tgtctcaatt 1680
gactgtttgt ccacaccaat ggattaactt gagaactaac aactgtgcta ctatcatcgt 1740
tccatacatg aacactgttc ctttcgattc tgctttgaac cattgtaact tcggtttgtt 1800
ggttattcca gttgttcctt tggattttaa cactggtgct acttctgaaa tcccaatcac 1860
tgttactatt gctcctatgt gtgctgagtt cgctggtttg agacaagctg ttaagcaata 1920
atgaggtacc ggccggccat ttaaatacag gccccttttc ctttgtcgat atcatgtaat 1980
tagttatgtc acgcttacat tcacgccctc ctcccacatc cgctctaacc gaaaaggaag 2040
gagttagaca acctgaagtc taggtcccta tttatttttt ttaatagtta tgttagtatt 2100
aagaacgtta tttatatttc aaatttttct tttttttctg tacaaacgcg tgtacgcatg 2160
taacattata ctgaaaacct tgcttgagaa ggttttggga cgctcgaagg ctttaatttg 2220
caagctggat ctaacatcca aagacgaaag gttgaatgaa acctttttgc catccgacat 2280
ccacaggtcc attctcacac ataagtgcca aacgcaacag gaggggatac actagcagca 2340
gaccgttgca aacgcaggac ctccactcct cttctcctca acacccactt ttgccatcga 2400
aaaaccagcc cagttattgg gcttgattgg agctcgctca ttccaattcc ttctattagg 2460
ctactaacac catgacttta ttagcctgtc tatcctggcc cccctggcga ggttcatgtt 2520
tgtttatttc cgaatgcaac aagctccgca ttacacccga acatcactcc agatgagggc 2580
tttctgagtg tggggtcaaa tagtttcatg ttccccaaat ggcccaaaac tgacagttta 2640
aacgctgtct tggaacctaa tatgacaaaa gcgtgatctc atccaagatg aactaagttt 2700
ggttcgttga aatgctaacg gccagttggt caaaaagaaa cttccaaaag tcggcatacc 2760
gtttgtcttg tttggtattg attgacgaat gctcaaaaat aatctcatta atgcttagcg 2820
cagtctctct atcgcttctg aaccccggtg cacctgtgcc gaaacgcaaa tggggaaaca 2880
cccgcttttt ggatgattat gcattgtctc cacattgtat gcttccaaga ttctggtggg 2940
aatactgctg atagcctaac gttcatgatc aaaatttaac tgttctaacc cctacttgac 3000
agcaatatat aaacagaagg aagctgccct gtcttaaacc ttttttttta tcatcattat 3060
tagcttactt tcataattgc gactggttcc aattgacaag cttttgattt taacgacttt 3120
taacgacaac ttgagaagat caaaaaacaa ctaattattc gaaacggaat tcaccatggg 3180
tattccaact gaattgaaac ctggtactaa ccaattcttg actactgatg atggtgtttc 3240
tgctccaatt ttgcctggtt tccatccaac tccacctatt cacattcctg gtgaagttca 3300
taacttgttg gagatttgta gagttgaaac tatcttggag gttaacaatt tgaagactaa 3360
cgaaactact ccaatgcaaa gattgtgttt tcctgtttct gttcaatcta aaactggaga 3420
gttgtgtgct gctttcagag ctgatccagg tagagatggt ccttggcaat ctactatttt 3480
gggtcaattg tgtagatact atactcaatg gtctggttct ttggaagtta cttttatgtt 3540
cgctggttct tttatggcta ctggtaaaat gttgattgct tacactccac ctggtggttc 3600
tgttcctgct gatagaatta ctgctatgtt gggtactcac gttatttggg attttggttt 3660
gcaatcttct gttactttgg ttgttccatg gatttctaac actcattaca gagctcacgc 3720
tagagctggt tatttcgatt actatactac tggtatcatc actatctggt atcaaactaa 3780
ctacgttgtt ccaatcggtg ctcctactac tgcttatatt gttgctttgg ctgctgctca 3840
agataacttc actatgaagt tgtgtaagga tactgaagat attgagcaaa ctgctaatat 3900
tcaataatga ggtaccggcc ggccatttaa atacaggccc cttttccttt gtcgatatca 3960
tgtaattagt tatgtcacgc ttacattcac gccctcctcc cacatccgct ctaaccgaaa 4020
aggaaggagt tagacaacct gaagtctagg tccctattta ttttttttaa tagttatgtt 4080
agtattaaga acgttattta tatttcaaat ttttcttttt tttctgtaca aacgcgtgta 4140
cgcatgtaac attatactga aaaccttgct tgagaaggtt ttgggacgct cgaaggcttt 4200
aatttgcaag ctggatctaa catccaaaga cgaaaggttg aatgaaacct ttttgccatc 4260
cgacatccac aggtccattc tcacacataa gtgccaaacg caacaggagg ggatacacta 4320
gcagcagacc gttgcaaacg caggacctcc actcctcttc tcctcaacac ccacttttgc 4380
catcgaaaaa ccagcccagt tattgggctt gattggagct cgctcattcc aattccttct 4440
attaggctac taacaccatg actttattag cctgtctatc ctggcccccc tggcgaggtt 4500
catgtttgtt tatttccgaa tgcaacaagc tccgcattac acccgaacat cactccagat 4560
gagggctttc tgagtgtggg gtcaaatagt ttcatgttcc ccaaatggcc caaaactgac 4620
agtttaaacg ctgtcttgga acctaatatg acaaaagcgt gatctcatcc aagatgaact 4680
aagtttggtt cgttgaaatg ctaacggcca gttggtcaaa aagaaacttc caaaagtcgg 4740
cataccgttt gtcttgtttg gtattgattg acgaatgctc aaaaataatc tcattaatgc 4800
ttagcgcagt ctctctatcg cttctgaacc ccggtgcacc tgtgccgaaa cgcaaatggg 4860
gaaacacccg ctttttggat gattatgcat tgtctccaca ttgtatgctt ccaagattct 4920
ggtgggaata ctgctgatag cctaacgttc atgatcaaaa tttaactgtt ctaaccccta 4980
cttgacagca atatataaac agaaggaagc tgccctgtct taaacctttt tttttatcat 5040
cattattagc ttactttcat aattgcgact ggttccaatt gacaagcttt tgattttaac 5100
gacttttaac gacaacttga gaagatcaaa aaacaactaa ttattcgaaa cggaattcac 5160
catgcactct actcaagaga ctgctattgg taactttttc tctagagctg gtttggtttc 5220
tatcatcact atgccaacta tgggtactca aaacactgat ggttacgtta attgggatat 5280
tgatttgatg ggttatgctc aattgagaag aaagtgtgaa ttgtttactt acatgagatt 5340
cgatgctgag tttactttcg ttgttgctaa accaaacggt gaattggttc ctcaattgtt 5400
gcaatacatg tatgttccac ctggtgctcc aaagcctact tctagagatt cttttgcttg 5460
gcaaactgct actaatcctt ctgttttcgt taaaatgact gatccacctg ctcaagtttc 5520
tgttccattc atgtctcctg cttctgctta ccaatggttt tacgatggtt atcctacttt 5580
cggtgaacat ttgcaagcta atgatttgga ttatggtcaa tgtccaaaca atatgatggg 5640
tactttctct attagaactg ttggtactga gaagtctcca cactctatca ctttgagagt 5700
ttacatgaga attaaacatg ttagagcttg gattccaaga cctttgagaa accaaccata 5760
cttgtttaag actaacccta actacaaggg taacgatatc aagtgtactt ctacttctag 5820
agataaaatt actactttgt aatgaggtac cggccggcca tttaaataca ggcccctttt 5880
cctttgtcga tatcatgtaa ttagttatgt cacgcttaca ttcacgccct cctcccacat 5940
ccgctctaac cgaaaaggaa ggagttagac aacctgaagt ctaggtccct atttattttt 6000
tttaatagtt atgttagtat taagaacgtt atttatattt caaatttttc ttttttttct 6060
gtacaaacgc gtgtacgcat gtaacattat actgaaaacc ttgcttgaga aggttttggg 6120
acgctcgaag gctttaattt gcaagctgga tccgcggccg ccttccaaac tctcatggat 6180
tctcaggtaa taggtattct aggaggaggc cagctaggcc gaatgattgt tgaggccgct 6240
agcaggctca atatcaagac cgtgattctt gatgatggtt tttcacctgc taagcacatt 6300
aatgctgcgc aagaccacat cgacggatca ttcaaagatg aggaggctat cgccaagtta 6360
gctgccaaat gtgatgttct cactgtagag attgagcatg tcaacacaga tgctctaaag 6420
agagttcaag acagaactgg aatcaagata tatcctttac cagagacaat cgaactaatc 6480
aaggataagt acttgcaaaa ggaacatttg atcaagcaca acatttcggt gacaaagtct 6540
cagggtatag aatctaatga aaaggcgctg cttttgtttg gagaagagaa tggatttcca 6600
tatctgttga agtcccggac tatggcttat gatggaagag gcaattttgt agtggagtct 6660
aaagaggaca tcagtaaggc attagagttc ttgaaagatc gtccattgta tgccgagaag 6720
tttgctcctt ttgttaaaga attagcggta atggttgtga gatcactgga aggcgaagta 6780
ttctcctacc caaccgtaga aactgtgcac aaggacaata tctgtcatat tgtgtatgct 6840
ccggccagag ttaatgacac catccaaaag aaagctcaaa tattagctga aaacactgtg 6900
aagactttcc caggcgctgg aatcttcgga gttgagatgt tcctattgtc tgatggagaa 6960
cttcttgtaa atgagattgc tccaaggccc cacaattctg gtcactatac aatcgatgca 7020
tgtgtaacat ctcagttcga agcacatgta agagccataa ctggtctgcc aatgccacta 7080
gatttcacca aactatctac ttccaacacc aacgctatta tgctcaatgt tttgggtgct 7140
gaaaaatctc acggggaatt agagttttgt agaagagcct tagaaacacc cggtgcttct 7200
gtatatctgt acggaaagac cacccgattg gctcgtaaga tgggtcatat caacataata 7260
ggatcttcca tgttggaagc agaacaaaag ttagagtaca ttctagaaga atcaacccac 7320
ttaccatcca gtactgtatc agctgacact aaaccgttgg ttggagttat catgggttca 7380
gactctgatc tacctgtgat ttcgaaaggt tgcgatattt taaaacagtt tggtgttcca 7440
ttcgaagtta ctattgtctc tgctcataga acaccacaga gaatgaccag atatgccttt 7500
gaagccgcta gtagaggtat caaggctatc attgcaggtg ctggtggtgc tgctcatctt 7560
ccaggaatgg ttgctgccat gactccgttg ccagtcattg gtgttcctgt caagggctct 7620
acgttggatg gtgtagactc gctacactcg attgtccaaa tgcctagagg tgttcctgtg 7680
gctacggttg ctatcaacaa cgccaccaat gccgctctgt tggccatcag gattttaggt 7740
acaattgacc acaaatggca aaaggaaatg tccaagtata tgaatgcaat ggagaccgaa 7800
gtgttgggga aggcatccaa cttggaatct gaagggtatg aatcctattt gaagaatcgt 7860
ctttgaattt agtattgttt tttaatagat gtatatataa tagtacacgt aacttatcta 7920
ttccattcat aattttattt taaaggttcg gtagaaattt gtcctccaaa aagttggtta 7980
gagcctggca gttttgatag gcattattat agattgggta atatttaccc tgcacctgga 8040
ggaactttgc aaagagcctc atgtgcggcg cgccaggcca taatggccaa acggtttctc 8100
aattactata tactactaac catttacctg tagcgtattt cttttccctc ttcgcgaaag 8160
ctcaagggca tcttcttgac tcatgaaaaa tatctggatt tcttctgaca gatcatcacc 8220
cttgagccca actctctagc ctatgagtgt aagtgatagt catcttgcaa cagattattt 8280
tggaacgcaa ctaacaaagc agatacaccc ttcagcagaa tcctttctgg atattgtgaa 8340
gaatgatcgc caaagtcaca gtcctgagac agttcctaat ctttacccca tttacaagtt 8400
catccaatca gacttcttaa cgcctcatct ggcttatatc aagcttacca acagttcaga 8460
aactcccagt ccaagtttct tgcttgaaag tgcgaagaat ggtgacaccg ttgacaggta 8520
cacctttatg ggacattccc ccagaaaaat aatcaagact gggcctttag agggtgctga 8580
agttgacccc ttggtgcttc tggaaaaaga actgaagggc accagacaag cgcaacttcc 8640
tggtattcct cgtctaagtg gtggtgccat aggatacatc tcgtacgatt gtattaagta 8700
ctttgaacca aaaactgaaa gaaaactgaa agatgttttg caacttccgg aagcagcttt 8760
gatgttgttc gacacgatcg tggcttttga caatgtttat caaagattcc aggtaattgg 8820
aaacgtttct ctatccgttg atgactcgga cgaagctatt cttgagaaat attataagac 8880
aagagaagaa gtggaaaaga tcagtaaagt ggtatttgac aataaaactg ttccctacta 8940
tgaacagaaa gatattattc aaggccaaac gttcacctct aatattggtc aggaagggta 9000
tgaaaaccat gttcgcaagc tgaaagaaca tattctgaaa ggagacatct tccaagctgt 9060
tccctctcaa agggtagcca ggccgacctc attgcaccct ttcaacatct atcgtcattt 9120
gagaactgtc aatccttctc catacatgtt ctatattgac tatctagact tccaagttgt 9180
tggtgcttca cctgaattac tagttaaatc cgacaacaac aacaaaatca tcacacatcc 9240
tattgctgga actcttccca gaggtaaaac tatcgaagag gacgacaatt atgctaagca 9300
attgaagtcg tctttgaaag acagggccga gcacgtcatg ctggtagatt tggccagaaa 9360
tgatattaac cgtgtgtgtg agcccaccag taccacggtt gatcgtttat tgactgtgga 9420
gagattttct catgtgatgc atcttgtgtc agaagtcagt ggaacattga gaccaaacaa 9480
gactcgcttc gatgctttca gatccatttt cccagcagga accgtctccg gtgctccgaa 9540
ggtaagagca atgcaactca taggagaatt ggaaggagaa aagagaggtg tttatgcggg 9600
ggccgtagga cactggtcgt acgatggaaa atcgatggac acatgtattg ccttaagaac 9660
aatggtcgtc aaggacggtg tcgcttacct tcaagccgga ggtggaattg tctacgattc 9720
tgacccctat gacgagtaca tcgaaaccat gaacaaaatg agatccaaca ataacaccat 9780
cttggaggct gagaaaatct ggaccgatag gttggccaga gacgagaatc aaagtgaatc 9840
cgaagaaaac gatcaatgaa cggaggacgt aagtaggaat ttatggtttg gccataatgg 9900
cctagcttgg cgtaatcatg gtcatagctg tttcctgtgt gaaattgtta tccgctcaca 9960
attccacaca acatacgagc cggaagcata aagtgtaaag cctggggtgc ctaatgagtg 10020
agctaactca cattaattgc gttgcgctca ctgcccgctt tccagtcggg aaacctgtcg 10080
tgccagctgc attaatgaat cggccaacgc gcggggagag gcggtttgcg tattgggcgc 10140
tcttccgctt cctcgctcac tgactcgctg cgctcggtcg ttcggctgcg gcgagcggta 10200
tcagctcact caaaggcggt aatacggtta tccacagaat caggggataa cgcaggaaag 10260
aacatgtgag caaaaggcca gcaaaaggcc aggaaccgta aaaaggccgc gttgctggcg 10320
tttttccata ggctccgccc ccctgacgag catcacaaaa atcgacgctc aagtcagagg 10380
tggcgaaacc cgacaggact ataaagatac caggcgtttc cccctggaag ctccctcgtg 10440
cgctctcctg ttccgaccct gccgcttacc ggatacctgt ccgcctttct cccttcggga 10500
agcgtggcgc tttctcatag ctcacgctgt aggtatctca gttcggtgta ggtcgttcgc 10560
tccaagctgg gctgtgtgca cgaacccccc gttcagcccg accgctgcgc cttatccggt 10620
aactatcgtc ttgagtccaa cccggtaaga cacgacttat cgccactggc agcagccact 10680
ggtaacagga ttagcagagc gaggtatgta ggcggtgcta cagagttctt gaagtggtgg 10740
cctaactacg gctacactag aaggacagta tttggtatct gcgctctgct gaagccagtt 10800
accttcggaa aaagagttgg tagctcttga tccggcaaac aaaccaccgc tggtagcggt 10860
ggtttttttg tttgcaagca gcagattacg cgcagaaaaa aaggatctca agaagatcct 10920
ttgatctttt ctacggggtc tgacgctcag tggaacgaaa actcacgtta agggattttg 10980
gtcatgagat tatcaaaaag gatcttcacc tagatccttt taaattaaaa atgaagtttt 11040
aaatcaatct aaagtatata tgagtaaact tggtctgaca gttaccaatg cttaatcagt 11100
gaggcaccta tctcagcgat ctgtctattt cgttcatcca tagttgcctg actccccgtc 11160
gtgtagataa ctacgatacg ggagggctta ccatctggcc ccagtgctgc aatgataccg 11220
cgagacccac gctcaccggc tccagattta tcagcaataa accagccagc cggaagggcc 11280
gagcgcagaa gtggtcctgc aactttatcc gcctccatcc agtctattaa ttgttgccgg 11340
gaagctagag taagtagttc gccagttaat agtttgcgca acgttgttgc cattgctaca 11400
ggcatcgtgg tgtcacgctc gtcgtttggt atggcttcat tcagctccgg ttcccaacga 11460
tcaaggcgag ttacatgatc ccccatgttg tgcaaaaaag cggttagctc cttcggtcct 11520
ccgatcgttg tcagaagtaa gttggccgca gtgttatcac tcatggttat ggcagcactg 11580
cataattctc ttactgtcat gccatccgta agatgctttt ctgtgactgg tgagtactca 11640
accaagtcat tctgagaata gtgtatgcgg cgaccgagtt gctcttgccc ggcgtcaata 11700
cgggataata ccgcgccaca tagcagaact ttaaaagtgc tcatcattgg aaaacgttct 11760
tcggggcgaa aactctcaag gatcttaccg ctgttgagat ccagttcgat gtaacccact 11820
cgtgcaccca actgatcttc agcatctttt actttcacca gcgtttctgg gtgagcaaaa 11880
acaggaaggc aaaatgccgc aaaaaaggga ataagggcga cacggaaatg ttgaatactc 11940
atactcttcc tttttcaata ttattgaagc atttatcagg gttattgtct catgagcgga 12000
tacatatttg aatgtattta gaaaaataaa caaatagggg ttccgcgcac atttccccga 12060
aaagtgccac ctgacgtcta agaaaccatt attatcatga cattaaccta taaaaatagg 12120
cgtatcacga ggccctttcg tctcgcgcgt ttcggtgatg acggtgaaaa cctctgacac 12180
atgcagctcc cggagacggt cacagcttgt ctgtaagcgg atgccgggag cagacaagcc 12240
cgtcagggcg cgtcagcggg tgttggcggg tgtcggggct ggcttaacta tgcggcatca 12300
gagcagattg tactgagagt gcaccatatg cggtgtgaaa taccgcacag atgcgtaagg 12360
agaaaatacc gcatcaggcg ccattcgcca ttcaggctgc gcaactgttg ggaagggcga 12420
tcggtgcggg cctcttcgct attacgccag ctggcgaaag ggggatgtgc tgcaaggcga 12480
ttaagttggg taacgccagg gttttcccag tcacgacgtt gtaaaacgac ggccagtgaa 12540
ttg 12543
<210> 18
<211> 50
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 18
caactaatta ttcgaaacgg aattcaccat gggttctcaa gtttctactc 50
<210> 19
<211> 51
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 19
ctgtatttaa atggccggcc ggtacctcat tattgcttaa cagcttgtct c 51
<210> 20
<211> 49
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 20
caactaatta ttcgaaacgg aattcaccat gggtattcca actgaattg 49
<210> 21
<211> 53
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 21
cctgtattta aatggccggc cggtacctca ttattgaata ttagcagttt gct 53
<210> 22
<211> 52
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 22
caactaatta ttcgaaacgg aattcaccat gggagatcca atcgctgata tg 52
<210> 23
<211> 53
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 23
cctgtattta aatggccggc cggtacctca ttacaaagta gtaattttat ctc 53
<210> 24
<211> 50
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 24
aacaactaat tattcgaaac ggaattcacc atggagactg gtgcttcttc 50
<210> 25
<211> 50
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 25
aacaactaat tattcgaaac ggaattcacc atgcactcta ctcaagagac 50
Claims (13)
1.一种多核苷酸，其特征在于，所述多核苷酸包括编码柯萨奇病毒A16的VP0、VP1和VP3衣壳蛋白的核苷酸，所述多核苷酸不包括RBS序列和编码柯萨奇病毒A16其他衣壳蛋白的核苷酸，所述编码柯萨奇病毒A16的VP0衣壳蛋白的核苷酸编码氨基酸序列如SEQ ID NO:3所示的VP0衣壳蛋白；所述编码柯萨奇病毒A16的VP3衣壳蛋白的核苷酸编码氨基酸序列如SEQID NO:4所示的VP3衣壳蛋白；所述多核苷酸编码的柯萨奇病毒A16的VP1衣壳蛋白为在SEQID NO:5所示的氨基酸序列的N端截短50-72个氨基酸后得到的VP1衣壳蛋白；所述多核苷酸中各核苷酸的排列顺序为：启动子-VP0-终止子-启动子-VP3-终止子-启动子-VP1-终止子。
2.如权利要求1所述的多核苷酸，其特征在于，还包括以下中的一项或几项：
1)编码柯萨奇病毒A16的VP0衣壳蛋白的核苷酸的序列如SEQ ID NO:8所示；
2)编码柯萨奇病毒A16的VP1衣壳蛋白的核苷酸的序列如SEQ ID NO:11或SEQ ID NO:12所示；
3)编码柯萨奇病毒A16的VP3衣壳蛋白的核苷酸的序列如SEQ ID NO:9所示。
3.如权利要求1所述的多核苷酸，其特征在于，还包括：
所述编码柯萨奇病毒A16的VP1衣壳蛋白的核苷酸编码氨基酸序列如SEQ ID NO:6或SEQ ID NO:7所示的VP1衣壳蛋白。
4.如权利要求1所述的多核苷酸，其特征在于，所述多核苷酸的序列如SEQ ID NO:2所示。
5.一种核酸构建体，其特征在于，所述核酸构建体包括权利要求1-4任一所述的多核苷酸。
6.根据权利要求5所述的核酸构建体，其特征在于，所述核酸构建体的表达载体为酵母表达载体。
7.根据权利要求5所述的核酸构建体，其特征在于，所述核酸构建体的核苷酸序列如SEQ ID NO:16或SEQ ID NO:17所示。
8.一种细胞系，其特征在于，所述细胞系中包括权利要求5-7任一所述的核酸构建体，或基因组中整合有权利要求1-4任一所述的多核苷酸。
9.根据权利要求8所述的细胞系，其特征在于，所述细胞系为毕赤酵母细胞系。
10.一种重组柯萨奇病毒A16病毒样颗粒，其特征在于，所述重组柯萨奇病毒A16病毒样颗粒包括VP0、VP1和VP3衣壳蛋白，不包括柯萨奇病毒A16其他衣壳蛋白，所述重组柯萨奇病毒A16病毒样颗粒由权利要求8或9所述的细胞系产生。
11.权利要求10所述的重组柯萨奇病毒A16病毒样颗粒在制备预防手足口病产品中的用途。
12.一种用于预防手足口病的药物组合物，其特征在于，所述药物组合物包括权利要求10所述的重组柯萨奇病毒A16病毒样颗粒和药学上可接受的载体。
13.根据权利要求12所述的药物组合物，所述药物组合物为疫苗组合物。
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| CN103834618A (zh) * | 2012-11-28 | 2014-06-04 | 中国科学院上海巴斯德研究所 | 一种能有效感染小鼠的柯萨奇a16型病毒突变株 |
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