CN110062630A - 肿瘤靶向合成腺病毒及其用途 - Google Patents
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Abstract
本发明描述了合成腺病毒,其具有肝脏去靶向突变并表达腺病毒34型(Ad34)纤维蛋白或者具有Ad34隆突结构域的嵌合纤维蛋白。所述合成腺病毒运送至肿瘤部位。还描述了所述合成腺病毒用于将诊断性或治疗性转基因递送至肿瘤的用途。
Description
相关申请的交叉引用
本申请要求2016年12月12日提交的美国临时申请号62/433,140的优先权,该申请通过引用全文结合入本文。
技术领域
本公开涉及运送至肿瘤部位的具有嵌合纤维蛋白和肝脏去靶向突变的合成腺病毒。本公开还涉及合成腺病毒在肿瘤中表达诊断性或治疗性转基因的用途。
背景技术
腺病毒(Ad)是天然的多基因表达载体。该病毒的某些编码区例如E1、E3和E4区对于培养中的复制而言并非是必要的,或者可以通过可用的细胞系补充。因此,这些区的每一个可以被非病毒基因替代,以驱动多个转基因自单一病毒的表达。有68种不同的人腺病毒血清型,其每一种均具有不同的特性。Ad5是基础研究、基因疗法和溶瘤病毒疗法中使用的主要Ad载体。但是,Ad5的趋向性(tropism)有限,仅感染具有用于病毒摄入的柯萨奇腺病毒受体(CAR)的上皮细胞。而且,当静脉注射时,Ad5与血液因子结合,导致其在肝脏中被隔离,在肝脏中它可能潜在地触发限制性炎症和毒性。因此,仍需要有在静脉施用之后能够感染特定细胞类型的修饰的腺病毒载体。
发明内容
本文说明如下发现:表达具有腺病毒34型(Ad34)隆突结构域(knob domain)的纤维蛋白的肝脏去靶向合成腺病毒能够归巢至肿瘤部位。所述合成腺病毒可用于在肿瘤细胞(包括肿瘤基质细胞)中递送和表达诊断性或治疗性转基因。
本文提供在受试者肿瘤细胞中表达转基因的方法。在一些实施方式中,该方法包括给所述受试者施用合成腺病毒,所述合成腺病毒包括:转基因、使合成腺病毒自肝脏去靶向的天然或修饰的衣壳和Ad34纤维蛋白或包括腺病毒5型(Ad5)轴结构域(shaft domain)和Ad34纽结构域的嵌合纤维蛋白。例如,所述转基因可以是诊断性转基因或治疗性转基因。
本文还提供诊断受试者患有肿瘤的方法。在一些实施方式中,该方法包括给受试者施用合成腺病毒,所述合成腺病毒包括:诊断性转基因,使合成腺病毒自肝脏去靶向的天然或修饰的衣壳,和Ad34纤维蛋白或包括Ad5轴结构域和Ad34隆突结构域的嵌合纤维蛋白。在一些例子中,所述诊断性转基因是正电子发射断层成像术(PET)报道基因。在其它例子中,所述诊断性转基因编码荧光蛋白或酶。
本文还提供治疗受试者中肿瘤的方法。在一些实施方式中,该方法包括给所述受试者施用合成腺病毒,所述合成腺病毒包括:治疗性转基因、使合成腺病毒自肝脏去靶向的天然或修饰的衣壳和Ad34纤维蛋白或包括Ad5轴结构域和Ad34隆突结构域的嵌合纤维蛋白。在一些例子中,所述治疗性转基因编码抗癌药剂或者破坏或杀死肿瘤基质细胞的药剂。
本公开还提供与SEQ ID NO:2或SEQ ID NO:5具有至少95%序列同一性的合成腺病毒基因组。
以下详述参考附图进行,本公开内容的前述和其他目的和特征从以下详述将会更加地显而易见。
附图说明
图1A-1B.AdSyn-CO176归巢至胰腺肿瘤。(图1A)Cre-LoxP KrasG12D/p53胰腺肿瘤模型概述。命名为“Kras;p53/p53”的小鼠编码KrasG12D致癌基因,该致癌基因位于编码LoxP-终止密码子-LoxP的序列的下游。该终止密码子在不存在Cre重组酶的情况下阻断KrasG12D的表达。但是,在Cre重组酶的存在下,终止密码子被移除并允许KrasG12D致癌基因的表达。在这些相同的小鼠中,p53基因的两个等位基因的侧翼为LoxP位点(LoxP-p53-LoxP)。命名为“p53/p53;Cre”的小鼠具有侧翼为LoxP位点的p53基因的两个等位基因(LoxP-p53-LoxP),并且还在胰十二指肠同源盒1(Pdx1)启动子的驱动下表达Cre重组酶转基因。Pdx1是在胰腺细胞中被特异性表达的基因,因此胰腺细胞中缺失两个拷贝的p53。株系之间的繁殖产生这样的后代,其中Pdx1启动子驱动的Cre在胰腺细胞中介导肿瘤抑制基因p53的两个等位基因的缺失和突变体KrasG12D的激活。命名为“Kras;p53/p53;Cre”的纯合子小鼠在5-7周内发展为胰腺肿瘤。(图1B)将具有包括Ad34隆突结构域的嵌合纤维蛋白的合成腺病毒AdSyn-CO176静脉注射至Kras;p53/p53和Kras;p53/p53;Cre小鼠中。注射病毒之后72小时,收集组织,与荧光素一起孵育5分钟,然后使用IVISTM成像系统扫描5分钟。Kras;p53/p53小鼠具有正常的胰腺,且荧光素酶信号主要来自于脾。Kras;p53/p53;Cre小鼠具有胰腺肿瘤,且信号主要来自胰腺肿瘤。
图2A-2B.在Cre-介导的基因操纵杂合模型中AdSyn-CO176在尾静脉注射之后感染胰腺肿瘤。(图2A)Kras;p53/p53小鼠如图1A所示。命名为“p53/+;Cre”的小鼠具有一个野生型p53等位基因和侧翼为LoxP位点的p53等位基因(LoxP-p53-LoxP)。这两个株系之间的繁殖产生这样的后代,其中Pdx1启动子驱动的Cre重组酶在胰腺细胞中介导肿瘤抑制基因p53的单个等位基因的缺失和突变体KrasG12D的激活。命名为“Kras;p53/+;Cre,”的这些杂合小鼠由于具有p53的一个野生型等位基因而在之后发展为肿瘤(4-9月龄时)。为使胰腺肿瘤发生,该野生型等位基因必须丧失或被突变。(图2B)将AdSyn-CO176静脉注射至p53/+;Cre和Kras;p53/+;Cre小鼠(4个月大)中。注射病毒之后72小时,收集组织,与荧光素一起孵育5分钟,然后使用IVISTM成像系统扫描5分钟。p53/+;Cre小鼠具有正常的胰腺,且信号主要来自于脾。4月龄的Kras;p53/+;Cre小鼠具有胰腺肿瘤,且信号主要来自肿瘤和肝脏。
图3A-3C.AdSyn-CO176在尾静脉注射之后可以感染和诊断早期胰腺肿瘤。杂合Kras;p53/+;Cre小鼠在4-9个月内发展为胰腺肿瘤。为了检验AdSyn-CO176是否可以感染肿瘤发展极早期(肿瘤可见之前)的胰腺肿瘤,将AdSyn-176注射至2月龄的Kras;p53/+;Cre小鼠中,测量荧光素酶的表达。(图3A)将AdSyn-CO176静脉注射至2月龄的Kras;p53/+;Cre小鼠中。注射病毒之后72小时,收集组织,与荧光素一起孵育5分钟,并使用IVISTM成像系统扫描5分钟。2月龄的Kras;p53/+;Cre小鼠的胰腺看起来是正常的,但是在该组织中发现了荧光素酶信号。(图3B)显示正常胰腺(a)和胰腺肿瘤(b)的典型组织学H&E染色。(图3C)来自2月龄的Kras;p53/+;Cre小鼠的胰腺的H&E染色,其表明小部分胰腺正在发展为肿瘤(如多边形中所示)。大多数胰腺看起来是正常的。该结果表明,AdSyn-CO176可以感染极早期胰腺肿瘤。
图4A-4B.AdSyn-CO176在胰腺肿瘤中感染基质细胞。在胰腺肿瘤中,仅有10%的细胞是癌细胞;其余90%是基质细胞。如通过免疫组织化学(IHC)和免疫荧光(IF)染色确定,被AdSyn-CO176感染的细胞是基质细胞。(图4A)用AdSyn-CO176感染的胰腺肿瘤的IHC染色。CK19是肿瘤细胞标记物,而平滑肌肌动蛋白(SMA)是基质细胞标记物。自AdSyn-CO176表达的GFP的染色,与SMA染色重叠,表明AdSyn-CO176靶向基质细胞。(图4B)被AdSyn-CO176感染的胰腺肿瘤的IF染色。GFP染色与SMA染色重叠,证实了基质细胞的AdSyn-CO176感染。
图5A-5D.AdSyn-CO176在尾静脉注射之后感染成胶质细胞瘤。将合成腺病毒AdSyn-CO176通过尾静脉注射到具有成胶质细胞瘤的小鼠中,在成胶质细胞瘤中发现荧光素酶信号。(图5A)Cre介导的基因操纵成胶质细胞瘤模型的示意图。将慢病毒直接注射到GFAP-Cre小鼠的大脑中。胶质原纤维酸性蛋白(GFAP)启动子驱动的Cre重组酶将RFP自编码慢病毒的基因中切除,并诱导主要在星形细胞中的HRasV12和GFP的表达。编码慢病毒的U6-p53shRNA的表达敲低了摄入病毒的脑细胞中的p53表达。从注射之后1周起,HRasV12的表达和p53的敲低诱导大脑中的肿瘤发生。GFP信号用来指示成胶质细胞瘤的形成。(图5B)将盐水、AdSyn-CO171或AdSyn-CO176经由静脉内(IV)施用注射到在4周前接受过肿瘤诱导慢病毒的GFAP-Cre小鼠中。注射病毒之后48小时,腹腔内注射荧光素之后,将小鼠用IVISTM成像系统扫描1分钟。在AdSyn-CO176-感染的小鼠中检测到荧光素酶信号(箭头),而在盐水处理或AdSyn-CO171-注射的小鼠中没有检测到信号。(图5C)给野生型小鼠(正常大脑)和注射有慢病毒的GFAP-Cre小鼠(发展为脑肿瘤)注射AdSyn-CO171或AdSyn-CO176。注射合成腺病毒之后72小时收集脑组织,与荧光素一起孵育5分钟,并用IVISTM成像系统扫描5分钟。仅有注射有肿瘤诱导慢病毒的GFAP-Cre小鼠显示出来自AdSyn-CO176的荧光素酶信号。这说明AdSyn-CO176将仅在存在肿瘤时运送至脑组织。(图5D)还对脑组织进行GFP信号的扫描。GFP信号用于识别成胶质细胞瘤。接受过肿瘤诱导慢病毒的两种GFAP-Cre小鼠均在大脑中具有GFP信号,而没有接受过慢病毒的小鼠中没有检测到GFP。在接受过肿瘤诱导慢病毒和AdSyn-CO176的GFAP-Cre小鼠中,GFP信号与荧光素酶信号完美地重合。
图6A-6B.AdSyn-CO176运送至成胶质细胞瘤受肿瘤而非损伤驱动。注射肿瘤诱导慢病毒在注射部位处引起暂时的脑损伤。尽管合成腺病毒(AdSyn-CO171和AdSyn-CO176)在最初注射慢病毒之后4周注射,但仍不明确AdSyn-CO176运送至成胶质细胞瘤是通过肿瘤还是通过注射部位损伤来驱动。为了回答该问题,在无注射、假注射或注射肿瘤诱导慢病毒之后4周,给GFAP-Cre小鼠注射合成腺病毒。(图6A)给GFAP-Cre小鼠注射汉克斯平衡盐溶液(Hanks’balanced salt solution,HBSS)或肿瘤诱导腺病毒。4周之后,静脉内注射AdSyn-CO171。在任一组小鼠的脑中均没有来自AdSyn-CO171的荧光素酶信号。(图6B)给GFAP-Cre小鼠注射HBSS或肿瘤诱导慢病毒,或者不接受注射。4周之后,给小鼠静脉内注射AdSyn-CO176。仅在接受了肿瘤诱导慢病毒的小鼠的大脑中检测到荧光素酶信号,而接受HBSS或无注射的小鼠则不产生信号。这些结果说明,AdSyn-CO176的特异性是通过肿瘤驱动,而不是通过注射部位的损伤驱动。
图7A-7B.AdSyn-CO176可以运送至人成胶质细胞瘤异种移植肿瘤。(图7A)人成胶质细胞瘤异种移植物模型的示意图。将表达tdTomato荧光蛋白(U87-tdTomato)的人成胶质细胞瘤U87细胞颅内注射到NOD scid gamma(NSG)小鼠中,以产生成胶质细胞瘤肿瘤。(图7B)接受U87-tdTomato颅内注射之后4周,将AdSyn-CO171和AdSyn-CO176通过尾静脉注射静脉内注射到NSG小鼠中。注射病毒之后48小时,收集图中指出的组织,与荧光素一起孵育5分钟,然后使用IVISTM成像系统扫描1分钟。仅注射AdSyn-CO176的小鼠在大脑中显示出荧光素酶信号,该信号与tdTomato表达完全重合。
图8A-8C.施用具有治疗性转基因的合成腺病毒。(图8A)KPCL(KrasG12D;p53敲除;Pdx1-Cre;萤火虫荧光素酶)小鼠模型的示意图。KPCL小鼠与纯合的“Kras;p53/p53;Cre”小鼠类似,其在胰腺中特异性地表达KrasG12D,并且仅在胰腺中敲除p53基因。但是,KPCL小鼠在胰腺中还特异性地表达萤火虫荧光素酶。KPCL小鼠中肿瘤的发展也类似于“Kras;p53/p53;Cre”小鼠。(图8B)显示每种处理(每处理组至少4只小鼠)的KPCL小鼠的平均存活的表格。AdSyn-CO987是基于AdSyn-CO176的合成腺病毒。将单纯性疱疹病毒-1胸苷激酶(TK)/更昔洛韦(ganciclovir)(GCV)自杀基因克隆到AdSyn-CO176中,以代替萤火成荧光素酶/GFP基因。在AdSyn-CO176的基因组中在TK之后紧接着另外插入海肾荧光素酶(Renillaluciferase)。通过将TK-P2A-海肾荧光素酶克隆到AdSyn-CO171中以代替原始的萤火虫荧光素酶/GFP基因,产生对照病毒AdSyn-CO989。在5-6周龄时,经由尾部静脉给KPCL小鼠静脉内注射1x106噬斑形成单位(PFU)的所示病毒。2天之后,给小鼠腹腔内(i.p.)或静脉内(i.v.)注射GCV。使用3个对照组:AdSyn-CO989+GCV;AdSyn-CO987之后注射盐水(AdSyn-CO987+盐水)和仅GCV注射(i.p.或i.v.)。与对照相比,用AdSyn-CO987+GCV治疗延长了小鼠的存活。(图8C)显示萤火虫荧光素酶信号的代表性小鼠的图像。在治疗过程中对萤火虫荧光素酶信号(由肿瘤表达)进行分析,以监测肿瘤生长。对Z619R小鼠的治疗为AdSyn-CO987+盐水,将其用作对照。将小鼠Z601R和Z607R用AdSyn-CO987+GCV(i.p.)治疗。尽管在对照小鼠Z619R中萤火虫荧光素酶信号的强度增加(表明肿瘤大小的增加),在小鼠Z601R和Z607R中信号降低(表明肿瘤大小的降低)。
图9A-9B.用AdSyn-CO987治疗的小鼠中的肿瘤组织学。(图9A)胰腺肿瘤的H&E染色图像。小鼠Z655、1806、Z619和Z621均为对照小鼠。小鼠Z655仅用i.p.注射的GCV治疗;小鼠1806仅用i.v.注射的GCV治疗;小鼠Z619用AdSyn-CO987+盐水治疗;小鼠Z621不接受治疗。小鼠Z656接受AdSyn-CO987+GCV i.v.治疗。与对照相比,来自Z656的肿瘤具有更多的坏死区(如箭头所示)。(图9B)放大的Z656的肿瘤中的代表性坏死区。该区也在图9A中示出。
序列表
所附序列表中列出的核酸和氨基酸序列使用37C.F.R.1.822中定义的核苷酸碱基标准字母缩写和氨基酸三字母代码显示。每个核酸序列仅示出一条链,但应理解,在任何提及所展示的链时,其互补链也包括在内。序列表以ASCII文本文档提交,于2017年11月30日生成,215KB,其通过引用并入本文。在所附序列表中:
SEQ ID NO:1是合成腺病毒AdSyn-CO171的核苷酸序列。
SEQ ID NO:2是合成腺病毒AdSyn-CO176的核苷酸序列。
SEQ ID NO:3是Ad5六邻体的氨基酸序列。
SEQ ID NO:4是Ad5六邻体E451Q的氨基酸序列。
SEQ ID NO:5是合成腺病毒AdSyn-CO987的核苷酸序列。
SEQ ID NO:6是合成腺病毒AdSyn-CO989的核苷酸序列。
具体实施方式
I.缩写
Ad 腺病毒
CAR 柯萨奇腺病毒受体
CEA 癌胚抗原
EGF 表皮生长因子
EGFR 表皮生长因子受体
FLT3 Fms-相关酪氨酸激酶3
GCV 更昔洛韦
GFAP 胶质原纤维酸性蛋白
GFP 绿色荧光蛋白
GM-CSF 粒细胞巨噬细胞集落刺激因子
H&E 苏木精和曙红
HSV 单纯性疱疹病毒
ICAM 细胞间粘附分子
IF 免疫荧光
IHC 免疫组织化学
IL 白介素
IRES 内部核糖体进入位点
i.p. 腹腔内
i.v. 静脉内
KPCL KrasG12D;p53敲除;Pdx1-Cre;萤火虫荧光素
LFA 淋巴细胞功能相关抗原
miR 微小RNA
MUC1 粘蛋白1
NOD 非肥胖型糖尿病
NSG NOD scid gamma
PD-1 程序性细胞死亡蛋白1
PDGF 血小板源性生长因子
PET 正电子发射断层成像术
PFU 噬斑形成单位
shRNA 短发卡RNA
SMA 平滑肌肌动蛋白
TGF 转化生长因子
TK 胸苷激酶
TNF 肿瘤坏死因子
UTR 非翻译区
VEGF 血管内皮生长因子
WT 野生型
II.术语和方法
除非另外指出,技术术语根据常规用法使用。分子生物学中常用术语的定义可见于Benjamin Lewin,Genes V,由Oxford University Press出版,1994(ISBN 0-19-854287-9);Kendrew et al.(eds.),The Encyclopedia of Molecular Biology,由BlackwellScience Ltd.出版,1994(ISBN 0-632-02182-9);和Robert A.Meyers(ed.),MolecularBiology and Biotechnology:a Comprehensive Desk Reference,由VCH Publishers,Inc.出版,1995(ISBN 1-56081-569-8)。
为了便于审阅本公开的各个实施方式,提供以下特定术语的解释:
腺病毒:具有线性双链DNA基因组和二十面体衣壳的无包膜病毒。目前已知有68种人腺病毒血清型,将其分成7个种类(种类A、B、C、D、E、F和G)。腺病毒的不同血清型与不同类型的疾病相关,其中一些血清型导致呼吸道疾病(主要是种类B和C)、结膜炎(种类B和D)和/或肠胃炎(种类F和G)。
施用:通过任何有效路径提供或给予受试者药剂,例如治疗性药剂(例如重组病毒)。示例性的施用路径包括,但不限于,注射(例如皮下、肌肉内、皮内、腹腔内、瘤内和静脉内)、口服、管内、舌下、直肠、经皮、鼻内、阴道和吸入路径。
嵌合:由至少2个具有不同来源的部分组成。在本公开的上下文中,“嵌合腺病毒”是具有源自至少2个不同血清型(例如源自Ad5和第二血清型腺病毒)的基因材料和/或蛋白质的腺病毒。在该上下文中,“衣壳交换(capsid-swapped)”腺病毒是指其中衣壳蛋白源自一血清型腺病毒并且其余蛋白质源自另一腺病毒血清型的嵌合腺病毒。类似地,“嵌合纤维”是具有源自至少2种不同血清型腺病毒的氨基酸序列的纤维蛋白。例如,嵌合纤维可以由来自Ad5的纤维轴和来自第二血清型腺病毒的纤维隆突组成。
接触:置于直接的物理结合下;包括固体和液体形式。
简并变体:在本公开的上下文中,“简并变体”是指编码肽的多核苷酸,所述肽包括由于遗传密码而简并的序列。有20种天然氨基酸,其大多数由一种以上的密码子指定。因此,编码肽的所有简并核苷酸序列均包括在内,只要由核苷酸序列编码的氨基酸序列不变即可。
去靶向:在本公开的上下文中,“去靶向”腺病毒是包括一个或多个修饰的重组或合成腺病毒,所述修饰改变病毒的趋向性,使得不再感染、或者基本上不再感染特定的细胞或组织类型。在一些实施方式中,所述重组或合成腺病毒包括衣壳突变,例如,六邻体蛋白中的突变(例如E451Q)。在一些实施方式中,所述重组或合成腺病毒包括来自天然地不感染、或基本上不感染特定细胞或组织类型的腺病毒的天然衣壳。在一些实施方式中,所述重组或合成腺病毒是肝脏去靶向和/或脾去靶向的。
E1A:腺病毒早期区域1A(E1A)基因和自该基因表达的多肽。所述E1A蛋白质通过驱动细胞进入细胞周期而在病毒基因组复制中发挥作用。如本文所用,术语“E1A蛋白质”是指自E1A基因表达的蛋白质,该术语包括任何腺病毒血清型产生的E1A蛋白质。
纤维:腺病毒纤维蛋白是介导与细胞表面受体结合的三聚蛋白质。纤维蛋白包括长的N-端轴和球形的C-端隆突。
融合蛋白:含有来自至少2种不同(异源性)蛋白质或肽的氨基酸片段的蛋白质。例如,通过自编码2种不同(异源性)蛋白质的至少一部分的核酸序列改造的核酸序列的表达,可以产生融合蛋白。为了产生融合蛋白,核酸序列必须位于相同阅读框中,并不含内部终止密码子。融合蛋白,特别是短的融合蛋白,也可以通过化学合成产生。
成胶质细胞瘤:快速生长的中枢神经系统肿瘤类型,其由脑和脊髓的神经胶质组织形成。成胶质细胞瘤通常在成人中发生,比起脊髓,更经常地感染大脑。成胶质细胞瘤是最常见、最具侵袭性的起始于大脑的癌症。成胶质细胞瘤也称作成胶质细胞瘤多形性细胞瘤(GBM)和IV级星形细胞瘤。
异源性:异源性蛋白质或基因是指蛋白质或基因源自不同的来源或物种。
六邻体:主要的腺病毒衣壳蛋白。来自Ad5的示例性六邻体序列在本文中描述为SEQID NO:3。包括E451Q置换的突变六邻体序列在本文中描述为SEQ ID NO:4。
分离:“分离的”生物组分(例如核酸分子、蛋白质、病毒或细胞)已经基本上与该组分天然存在的有机体的细胞或组织或者有机体自身中的其他生物组分(例如其他染色体或染色体外DNA和RNA、蛋白质和细胞)分离或从其中纯化。经“分离”的核酸分子和蛋白质包括通过标准纯化方法纯化的那些。该术语还包括通过在宿主细胞中重组表达制备的核酸分子和蛋白质以及化学合成的核酸分子和蛋白质。
微小RNA(miRNA或miR):调节植物、动物和病毒中基因表达的单链RNA分子。对编码微小RNA的基因进行转录,以形成初级转录物微小RNA(pri-miRNA),对其进行加工,以形成称作前体微小RNA(pre-miRNA)的短茎环分子,然后进行内切核苷酸切割,以形成成熟微小RNA。成熟微小RNA长度为大约21-23核苷酸,并且与一个或多个目标信使RNA(mRNA)的3'UTR部分互补。微小RNA通过促进靶mRNA的切割或者阻断细胞转录物的翻译来调节基因表达。在本公开的上下文中,“肝脏特异性微小RNA”是优先在肝脏中表达的微小RNA,例如仅在肝脏中表达的微小RNA,或者与其他器官或组织类型相比在肝脏中的表达显著更多的微小RNA。在一些实施方式中,所述微小RNA是miR-122。在本公开的上下文中,“脾特异性微小RNA”是优先在脾中表达的微小RNA,例如仅在脾中表达的微小RNA,或者与其他器官或组织类型相比在脾中的表达显著更多的微小RNA。在一些实施方式中,所述微小RNA是miR-142-3p。
修饰:核酸或蛋白质序列的序列改变。例如,氨基酸序列修饰包括,例如,置换、插入和缺失或其组合。插入包括氨基和/或羧基端融合以及单个或多个氨基酸残基的序列内插入。缺失特征在于自蛋白质序列移除一个或多个氨基酸残基。在本文的一些实施方式中,修饰(例如置换、插入或缺失)导致功能上的变化,例如蛋白质特定活性的降低或提高。如本文所用,“Δ”或“delta”是指缺失。置换修饰是其中至少一个残基被移除并在其位置中插入不同残基的修饰。氨基酸置换典型地是单个残基的,但也可以一次在若干个不同位置上发生。置换、缺失、插入或其任意组合可以结合起来,以获得最终的突变序列。这些修饰物可以通过修饰编码蛋白质的DNA中的核苷酸、从而产生编码该修饰的DNA而制备。在具有已知序列的DNA中的预定位置处进行插入、缺失和置换突变的技术是本领域公知的。“修饰的”蛋白质、核酸或病毒是具有上述一种或多种修饰者。
可操作连接:当第一核酸序列与第二核酸序列处于功能关系时,所述第一核酸序列和所述第二核酸序列可操作连接。例如,如果启动子影响编码序列的转录和表达,则所述启动子与所述编码序列可操作连接。通常,可操作连接的DNA序列是连续的,并且在必要时将两个蛋白质编码区结合在相同的阅读框中。
胰腺癌:在胰腺组织中开始的癌症。胰腺癌典型地迅速扩散,且极少在早期被检测到,导致大多数确诊患者的预后不良。最常见的胰腺癌类型是胰腺腺癌(pancreaticadenocarcinoma),其在胰腺癌病例中占大约85%。
药学可接受的载体:本公开中可用的药学可接受的载体(媒介物)是常规的。Remington’s Pharmaceutical Sciences(E.W.Martin,Mack Publishing Co.,Easton,PA,第15版(1975))描述了适用于一种或多种治疗性化合物、分子或药剂(例如本文公开的合成病毒)的药学递送的组合物和制剂。
通常,载体的性质取决于采用的具体施用方式。例如,肠胃外制剂通常包括可注射的流体作为载体,该流体包括药学和生理学可接受的流体,例如水、生理盐水、平衡盐溶液、含水葡萄糖、甘油等。对于固体组合物(例如,粉剂、丸剂、片剂或胶囊形式),常规的无毒固体载体可以包括,例如,药物级甘露醇、乳糖、淀粉或硬脂酸镁。除生物中性载体以外,待施用的药物组合物还可以含有微量的无毒辅剂,例如润湿或乳化剂、防腐剂和pH缓冲剂等,例如乙酸钠或去水山梨糖醇月桂酸酯。
多肽、肽或蛋白质:其中单体是通过酰胺键结合在一起的氨基酸残基的聚合物。当氨基酸是α-氨基酸时,可以使用L-光学异构体或D-光学异构体。术语“多肽”、“肽”和“蛋白质”在本文中可互换使用。这些术语适用于其中一个或多个氨基酸残基是相应天然氨基酸的人造化学模拟物的氨基酸聚合物,以及天然氨基酸聚合物和非天然氨基酸聚合物。术语“残基”或“氨基酸残基”包括指结合到蛋白质、多肽或肽中的氨基酸。
多肽中的保守置换是将蛋白质序列中的一氨基酸残基置换成具有相似生化特性的不同氨基酸残基。典型地,保守置换对产生的多肽的活性几乎没有或没有影响。例如,包括一个或多个保守置换(例如不多于1、2、3、4或5个置换)的蛋白质或肽保持野生型蛋白质或肽的结构和功能。通过使用例如标准方法如定点诱变或PCR操纵编码多肽的核苷酸序列,可以产生含有一个或多个保守置换的多肽。在一例子中,这些变体可以通过检验抗体交叉反应性或其诱导免疫反应的能力容易地选择。保守置换的例子显示如下。
保守置换通常保持(a)置换区中多肽骨架的结构,例如保持成折叠或螺旋构象,(b)目标位点处分子的电荷或疏水性,或(c)侧链的体积。
通常预期产生蛋白质特性极大改变的置换将是非保守的,例如,如下改变,其中(a)亲水性残基例如丝氨酰基或苏氨酰基置换成(为)疏水性残基例如亮氨酰基、异亮氨酰基、苯丙氨酰基、缬氨酰基或丙氨酰基;(b)半胱氨酸或脯氨酸置换成(为)其他残基;(c)具有电正性侧链的残基例如赖氨酰基、精氨酰基或组氨酰基置换成(为)电负性残基例如谷氨酰基或天冬氨酰基;或(d)具有大侧链的残基例如苯丙氨酸置换成(为)没有侧链的残基例如甘氨酸。
正电子发射断层成像术(PET):用于观察体内代谢过程的成像技术。PET检测在生物活性分子上引入至体内的正电子发射放射性核素直接发射的γ射线对。PET报道基因编码为PET探针提供靶标的分子(例如受体或酶),其然后可以通过成像得以检测。PET报道基因通常分成三类:(1)编码对特异性PET报道基因探针进行磷酸化的酶、导致其胞内捕获(intracellular entrapment)的报道基因;(2)编码可以被特异性PET报道基因探针结合的蛋白质受体的报道基因;和(3)编码将放射性核素报道基因转运到表达报道基因的细胞中的蛋白质转运体的报道基因(Yaghoubi et al.,Theranostics 2(4):374-391,2012)。如本文所用,“PET报道基因”包括任何编码蛋白质的基因,该蛋白质能够以允许探针通过分子成像得以检测的方式与PET报道基因探针相互作用。示例性的PET报道基因包括,但不限于,单纯性疱疹病毒(HSV)胸苷激酶(TK)及其突变形式、水痘-带状疱疹病毒(VSV)TK、人线粒体TK及其突变体、脱氧胞苷激酶的突变体、多巴胺2受体突变体、人雌激素受体α配体结合结构域(hERL)、人生长抑素受体亚型2(hSSTr2)、重组人癌胚抗原(CEA)、改造的抗体片段、人源化膜锚定抗-聚乙二醇(PEG)、钠碘同向转运体(NIS)和人去甲肾上腺素转运体(hNET)(参见Yaghoubiet al.(2012),PET报道基因和对应的报道基因探针的综述)。
预防、治疗或减轻疾病:“预防”疾病是指抑制疾病的完全进展。“治疗”是指在疾病或病理状态已经开始发展之后减轻其迹象或症状的治疗性干预。“减轻”是指降低疾病迹象或症状的数量或严重程度。
启动子:DNA指导/引发核酸(例如基因)转录的区域。启动子包括靠近转录起始位点的必需核酸序列。典型地,启动子位于其转录的基因附近。启动子还可以任选地包括远端增强子或阻遏子元件(repressor elements),其可以位于距离转录起始位点数千个碱基对处。“组成型启动子”是连续活性并不受外部信号或分子调节的启动子。与此相反,“诱导型启动子”的活性受外部信号或分子(例如转录因子或四环素)调节。“组织特异性启动子”是基本上仅在特定组织或多个组织中有活性的启动子。
蛋白质IX(pIX):腺病毒衣壳与六邻体蛋白缔合的次要组分。
纯化:术语“纯化”不要求绝对纯度;相反,它意在是相对术语。因此,例如,纯化的肽、蛋白质、病毒或其他化合物是整体上与天然结合的蛋白质和其他污染物全部或部分分离者。在某些实施方式中,术语“基本上纯化”是指肽、蛋白质、病毒或其他化合物已经自细胞、细胞培养基或其他粗制剂中分离出,并进行过分级(fractionation),以除去初始制剂中的各种组分,例如蛋白质、细胞碎片和其他组分。
重组:重组核酸分子、蛋白质或病毒是具有非天然序列或者具有通过将两个本分离的序列片段人工组合产生的序列的核酸分子、蛋白质或病毒。这种人工组合可以通过化学合成或者通过诸如基因改造技术的人工操纵分离的核酸分子片段来实现。术语“重组”还包括已单独地通过天然核酸分子、蛋白质或病毒的一部分的添加、置换或缺失而改变的核酸、蛋白质和病毒。
序列同一性:两个或更多个核酸序列或者两个或更多个氨基酸序列之间的同一性或相似性,其表示为序列之间的同一性或相似性。序列同一性可以测量为同一性百分比;百分比越高,序列越一致。序列相似性可以测量为相似性百分比(其考虑了保守氨基酸置换);百分比越高,序列越相似。当用标准方法比对时,核酸或氨基酸序列的同源物或直向同源物具备相对高度的序列同一性/相似性。与关系更远的物种相比(例如人和秀丽隐杆线虫(C.elegans)的序列),当直向同源性蛋白质或cDNA源自更加密切相关的物种时(例如人和小鼠的序列),这种同源性更加显著。
用于比较的序列比对方法是本领域公知的。各种程序和比对算法描述于:Smith&Waterman,Adv.Appl.Math.2:482,1981;Needleman&Wunsch,J.Mol.Biol.48:443,1970;Pearson&Lipman,Proc.Natl.Acad.Sci.USA 85:2444,1988;Higgins&Sharp,Gene,73:237-44,1988;Higgins&Sharp,CABIOS 5:151-3,1989;Corpet et al.,Nuc.Acids Res.16:10881-90,1988;Huang et al.Computer Appls.in the Biosciences 8,155-65,1992和Pearson et al.,Meth.Mol.Bio.24:307-31,1994。Altschul et al.,J.Mol.Biol.215:403-10,1990介绍了序列比对方法和同源性计算的详细考虑。
NCBI基础局部比对搜索工具(Basic Local Alignment Search Tool)(BLAST)(Altschul et al.,J.Mol.Biol.215:403-10,1990)可获自若干来源,包括美国生物信息中心(the National Center for Biological Information)(NCBI)和互联网,与序列分析程序blastp、blastn、blastx、tblastn和tblastx结合使用。其他信息可见于NCBI网站。
血清型:通过特征性抗原组区分的一类密切相关的微生物(例如病毒)。
基质:上皮器官或肿瘤的支持性组织,由结缔组织和血管组成。基质细胞是构成基质的细胞,主要是成纤维细胞和周细胞。肿瘤基质主要由成纤维细胞、细胞外基质、免疫细胞、血管和基膜构成(Bremnes et al.,J Thorac Oncol 6:209-217,2011)。肿瘤基质细胞已知在癌症的生长和进展中发挥重要作用。
受试者:活的多细胞脊椎动物有机体,包括人和非人哺乳动物的种类。
合成:通过人工方法在实验室中产生,例如,可以在实验室中化学合成的合成核酸或蛋白质。
治疗性药剂:适当地施用给受试者时能够诱导所需治疗性或预防性效果的化合物、小分子、重组病毒或其他组合物,例如反义化合物、抗体、肽或核酸分子。
治疗有效量:特定的药物或治疗药剂(例如重组病毒)足以在用该药剂治疗的受试者中或细胞中实现所需效果的量。药剂的有效量可以取决于若干因素,其包括但不限于,被治疗的受试者或细胞和治疗性组合物的施用方式。
转基因:被插入到不同有机体(例如病毒)的基因组中的基因。转基因也可以称作异源性基因。如本文所用,“诊断性转基因”是指编码可检测产物的任意转基因,上述可检测产物例如,但不限于,荧光蛋白、酶或PET报道基因。如本文所用,“治疗性转基因”是指编码具有治疗性应用的产物的任意转基因。在本公开的上下文中,治疗性转基因可以是,例如,抗癌药剂或者破坏或杀死肿瘤基质的药剂。
Uexon:位于早期E3区和纤维基因之间的l链(向左转录)上的开放阅读框(Tollefson et al.,J Virol 81(23):12918-12926)。
载体:允许外来核酸在不破坏载体在宿主细胞中复制和/或整合的能力的情况下插入的核酸分子。载体可以包括允许其在宿主细胞中复制的核酸序列,例如复制起点。载体还可以包括一个或多个选择标记基因和其他基因元件。表达载体是含有允许插入的一个或多个基因转录和翻译所必需的调控序列的载体。
III.若干实施方式总览
本文公开了表达具有Ad34隆突结构域的纤维蛋白的肝脏去靶向合成腺病毒能够归巢至肿瘤部位。所述合成腺病毒可以用于,例如,在肿瘤细胞(包括肿瘤基质细胞)中递送和表达诊断性或治疗性转基因。
本文提供在受试者肿瘤细胞中表达转基因的方法。在一些实施方式中,该方法包括给所述受试者施用合成腺病毒,所述合成腺病毒包括所述转基因,使合成腺病毒自肝脏去靶向的天然或修饰的衣壳,和Ad34纤维蛋白或包括Ad5轴结构域和Ad34隆突结构域的嵌合纤维蛋白。
在一些实施方式中,所述转基因是诊断性转基因。在一些例子中,所述诊断性转基因编码荧光蛋白,例如,但不限于,绿色荧光蛋白(GFP)、黄色荧光蛋白(YFP)、青色荧光蛋白(CFP)、红色荧光蛋白(RFP)、蓝色荧光蛋白(BFP)或橙色荧光蛋白(例如mOrange)。在其它例子中,所述诊断性转基因编码酶,例如荧光素酶。在其他的例子中,所述诊断性转基因包括正电子发射断层成像术(PET)报道基因。
在其它实施方式中,所述转基因是治疗性转基因。在一些例子中,所述治疗性转基因编码抗癌药剂。在具体例子中,所述抗癌药剂是促炎性分子或细胞因子,例如粒细胞巨噬细胞集落刺激因子(GM-CSF)、CD40配体(CD40L)、Fms-相关酪氨酸激酶3(FLT3)配体、白介素(IL)-1b、IL-2、IL-4、IL-6、IL-12、肿瘤坏死因子(TNF)-α、干扰素、趋化因子、B7-1、细胞间粘附分子(ICAM)-1、淋巴细胞功能相关抗原(LFA)-3、转化生长因子(TGF)-β、血小板源性生长因子(PDGF)或表皮生长因子(EGF)。在其他具体例子中,所述抗癌药剂是抗血管生成因子,例如血管内皮生长因子(VEGF)抑制剂。在其他具体例子中,所述抗癌药剂是KRas抑制剂(例如siRNA或shRNA抑制剂)。在其他具体例子中,所述抗癌药剂是细胞毒性T淋巴细胞相关分子(CTLA)-4、程序性细胞死亡蛋白质1(PD-1)、程序性死亡配体1(PD-L1)、癌胚抗原(CEA)或粘蛋白1(MUC1)的抑制剂。在一些例子中,所述治疗性转基因编码破坏或杀死肿瘤基质细胞的药剂。在具体例子中,所述药剂是Rexin-G、单纯性疱疹病毒(HSV)胸苷激酶(TK)、p53、TNF-α、Fas/FasL或白喉毒素A。
本文还提供诊断受试者患有肿瘤的方法。在一些实施方式中,该方法包括给所述受试者施用合成腺病毒,所述合成腺病毒包括诊断性转基因,使合成腺病毒自肝脏去靶向的天然或修饰的衣壳,和Ad34纤维蛋白或包括Ad5轴结构域和Ad34隆突结构域的嵌合纤维蛋白。
在一些实施方式中,所述诊断性转基因包括正电子发射断层成像术(PET)报道基因。在一些例子中,所述PET报道基因是病毒或人胸苷激酶(或其突变形式)、脱氧胞苷激酶的突变体、多巴胺2受体突变体、人雌激素受体α配体结合结构域(hERL)、人生长抑素受体亚型2(hSSTr2)、重组人CEA、改造的抗体片段、人源化膜锚定抗-聚乙二醇(PEG)、钠碘同向转运体(NIS)或人去甲肾上腺素转运体(hNET)。
在其他实施方式中,所述诊断性转基因编码荧光蛋白。在一些例子中,所述荧光蛋白包括GFP、YFP、CFP、RFP、BFP或橙色荧光蛋白。
在其他实施方式中,所述诊断性转基因编码酶。在一例子中,所述酶是荧光素酶。
本文还提供治疗受试者中肿瘤的方法。在一些实施方式中,该方法包括给所述受试者施用合成腺病毒,所述合成腺病毒包括治疗性转基因,使合成腺病毒自肝脏去靶向的天然或修饰的衣壳,和Ad34纤维蛋白或包括Ad5轴结构域和Ad34隆突结构域的嵌合纤维蛋白。
在一些实施方式中,所述治疗性转基因编码抗癌药剂。在一些例子中,所述抗癌药剂是促炎性分子或细胞因子,例如GM-CSF、CD40L、FLT3、IL-1b、IL-2、IL-4、IL-6、IL-12、TNF-α、干扰素、趋化因子、B7-1、ICAM-1、LFA-3、TGF-β、PDGF或EGF。在其他例子中,所述抗癌药剂是抗血管生成因子,例如VEGF抑制剂。在其它例子中,所述抗癌药剂是KRas抑制剂(例如siRNA或shRNA抑制剂)。在其他例子中,所述抗癌药剂是CTLA-4、PD-1、CEA或MUC1的抑制剂。在其他实施方式中,所述治疗性转基因编码破坏或杀死肿瘤基质细胞的药剂。在一些例子中,所述药剂是Rexin-G、HSV-TK、p53,TNF-α、Fas/FasL或白喉毒素A。
在本文公开的一些方法实施方式中,所述合成腺病毒包括使合成腺病毒自肝脏去靶向的修饰的衣壳。在一些例子中,所述合成腺病毒包括修饰的六邻体蛋白,例如E451Q突变(在本文中如SEQ ID NO:4所示)。在其它实施方式中,所述合成腺病毒具有使合成腺病毒自肝脏去靶向的天然(未修饰)衣壳(例如,来自天然地不感染肝脏的腺病毒血清型的衣壳)。
在本文公开的一些方法实施方式中,所述合成腺病毒还包括针对肝脏特异性微小RNA的一个或多个结合位点,例如2或3个结合位点。在一些例子中,所述肝脏特异性微小RNA是miR-122。在一些例子中,所述一个或多个结合位点位于转基因的3′UTR中。
在本文公开的一些方法实施方式中,所述合成腺病毒还包括针对脾特异性微小RNA的一个或多个结合位点,例如2或3个结合位点。在一些例子中,所述脾特异性微小RNA是miR142-3p。在一些例子中,所述一个或多个结合位点位于转基因的3′UTR中。
在本文公开的一些方法实施方式中,所述转基因受组织特异性启动子调节,例如,在胰腺或中枢神经系统细胞中有活性的启动子。在其他实施方式中,所述转基因受肿瘤特异性启动子调节。
在本文公开的一些方法实施方式中,所述合成腺病毒由Ad5载体基因组产生。在一些例子中,所述合成腺病毒包括Ad5衣壳蛋白和包括Ad5轴结构域和Ad34隆突结构域的嵌合纤维蛋白。
在本文公开的一些方法实施方式中,所述肿瘤是胰腺肿瘤。在其他实施方式中,所述肿瘤是成胶质细胞瘤。在其它实施方式中,所述肿瘤是乳腺癌、前列腺癌、胃肠癌、骨癌或黑色素瘤。
在本文公开的一些方法实施方式中,所述肿瘤的特征在于p53肿瘤抑制活性的丧失。在一些例子中,所述肿瘤在p53中表现出突变。在一些例子中,所述肿瘤表现出野生型p53等位基因的丧失。
在本文公开的一些方法实施方式中,所述肿瘤的特征在于Ras基因例如KRas、HRas或NRas中的突变。在本文公开的一些方法实施方式中,所述肿瘤的特征在于神经纤维瘤1型(NF1)、表皮生长因子受体(EGFR)、BRCA1、BRCA2或HER2中的改变或突变。
在本文公开的一些方法实施方式中,所述合成腺病毒的基因组包括与SEQ ID NO:2的同一性为至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%的核苷酸序列。在一些例子中,所述合成腺病毒的基因组包括SEQ ID NO:2的核苷酸序列或者由其组成。
在本文公开的其他方法实施方式中,所述合成腺病毒的基因组包括与SEQ ID NO:5的同一性为至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%的核苷酸序列。在一些例子中,所述合成腺病毒的基因组包括SEQ ID NO:5的核苷酸序列或者由其组成。
本文还提供与SEQ ID NO:2或SEQ ID NO:5的同一性为至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%的合成腺病毒基因组。在一些例子中,所述合成腺病毒的基因组包括SEQ ID NO:2或SEQ ID NO:5的核苷酸序列或者由其组成。
IV.合成腺病毒
Adsembly、AdSLICr和RapAD技术使得能够进行模块化设计并产生具有独特能力的腺病毒(参见PCT公开号WO2012/024351和WO2013/138505,将其全文通过引用并入本文)。设计具有新功能和特性的定制病毒的能力使得能够通过让宿主原位产生蛋白质而扩展腺病毒作为递送治疗性蛋白质的用途。这提供了将难以制造的人蛋白质用于治疗目的独特能力,并能够将几乎任何蛋白质灵活递送至疾病组织。
本文公开的具体修饰参考腺病毒5(Ad5)基因组序列加以描述,但也可以使用任意腺病毒血清型。腺病毒是天然的多基因表达载体。E1、E3和E4区在培养中对复制并非必要,或者可以用可用的细胞系进行补充。这些区中的每一个均具有独立的启动子元件,如果需要,该启动子元件可以被细胞启动子取代,以经由另外的剪接驱动多基因产物的表达。
如本文所公开,为了产生用于体内使用和转基因递送的Ad5表达载体,使E1A/E1B基因缺失,并用至少一个转基因代替。在一些实施方式中,所述转基因是EF1α驱动的荧光素酶-GFP融合物。
本文公开的合成腺病毒还可以包括使病毒自肝脏去靶向的修饰。Ad5六邻体可以在血液中与因子X结合,这会导致其在肝脏中被库普弗细胞(Kuppfer cell)吸收,其防止全身扩散和限制性炎症。为了克服这一点,将合成腺病毒改造成在E1中包括额外的基因组修饰,并包括防止肝脏中腺病毒摄入和转基因表达的核心模块,如下文中所进一步描述。
A.用于去靶向的Ad34纤维和嵌合纤维蛋白
尽管Ad5纤维蛋白和许多其他血清型已经显示出与柯萨奇腺病毒受体(CAR)结合用于细胞附着,其他血清型也显示使用CD46(Gaggar et al.,Nat Med 9:1408-1412,2003)、桥粒芯蛋白(desmoglein)2(Wang et al.,Nat Med 17:96-104,2011)、唾液酸(Nilsson et al.,Nat Med 17:105-109,2011)或其他(Arnberg,Trends Pharmacol Sci33:442-448,2012)。许多血清型的受体利用尚未深入考察,并且认为CD46在成熟小鼠中不表达。由于纤维蛋白C-端处的球形隆突通常负责受体结合,通过将Ad5纤维隆突用来自Ad34的纤维隆突取代,产生嵌合体(参见下文实施例1)。所述合成病毒包括含有E1A/E1B缺失的E1模块和由EF1α启动子驱动的荧光素酶-GFP融合物。所述合成腺病毒还在六邻体蛋白中包括肝脏去靶向修饰(E451Q),并在转基因的3′UTR中包括针对微小RNA的结合位点,上述微小RNA在肝脏中特异性表达(miR-122),以防止转基因的脱靶表达。
本文公开的数据说明了能够结合来自其他血清型的修饰部分以改善基于Ad5的载体。在该情形下,允许快速组装针对进入肿瘤细胞而优化的病毒。
B.肝脏去靶向修饰
天然Ad5载体将仅感染肺部(经由吸入)或肝脏(经由静脉内施用)。Ad5六邻体在血液中与因子X结合,这导致其在肝脏中被库普弗细胞吸收,防止全身扩散并诱导病毒限制性炎症。为了克服这一点并能够静脉内递送可全身行进至肿瘤部位的病毒,将合成腺病毒改造成在E1中包括额外的基因组修饰,并包括防止肝脏中的摄入和表达的核心模块。
为了防止病毒通过Ad5六邻体结合因子X在肝脏中摄入和隔离,将病毒改造成在六邻体中具有额外的防止肝脏摄入的突变(E451Q)。例如,AdSyn-CO171不在肝脏中累积,而是能够靶向其他器官例如脾和淋巴结。因此,在本文一些实施方式中,所述合成腺病毒包括具有E451Q置换的修饰的六邻体蛋白。
为了防止肝脏中的脱靶转基因表达,将病毒改造成在转基因的3′非翻译区(UTR)中包括针对微小RNA的结合位点,上述微小RNA在肝脏中特异性表达。在具体实施方式中,选择miR122作为肝脏特异性微小RNA,因为其表达和结合位点在人和小鼠肝细胞中都是保守的。在一些例子中,在转基因的3′UTR中插入针对肝脏特异性miR122的两个微小RNA结合位点,以防止肝脏中任何残余转基因表达。
本文公开了具有miR-122结合位点和六邻体突变的合成腺病毒不会在肝脏中积累,而是能够靶向肿瘤。在一些实施方式中,针对肝脏特异性微小RNA的一个或多个结合位点位于转基因的3′-UTR中。在一些例子中,所述肝脏特异性微小RNA是miR-122、miR-30或miR-192。
本文考虑了腺病毒六邻体基因的其他突变,以防止腺病毒在肝脏中积累。例如,通过将六邻体的9个高变区用来自不同血清型的高变区取代,可以使合成腺病毒自肝脏去靶向。
在一些例子中,所述重组腺病毒包括六邻体蛋白,该六邻体蛋白包括SEQ ID NO:3或SEQ ID NO:4的氨基酸序列或者由其组成。
C.用于避开中和抗体的衣壳交换
大多数人群体已经具有识别Ad5的抗体,Ad5是在研究和治疗应用中最常用的血清型。而且,一旦在患者中使用特定的腺病毒血清型,将会产生识别病毒衣壳的新抗体,使得重复施用相同的载体成为问题。因此,本公开还考虑开发天然的腺病毒模块,以产生能够避开现有中和抗体的嵌合病毒。例如,本文公开的重组腺病毒还可以包括完整的‘衣壳’模块交换(几乎60%的基因组),这使其对于现有的抗体“不可见”,能够重复接种。
在一些实施方式中,基因组的E1、E3和E4区源自第一腺病毒血清型,基因组的E2B、L1、L2、L3、E2A和L4区源自第二腺病毒血清型,例如Ad34。在一些例子中,第一腺病毒血清型的E1区被修饰成编码来自第二腺病毒血清型的pIX蛋白质;和/或第一腺病毒血清型的E3区被修饰成编码来自第二腺病毒血清型的Uexon和纤维蛋白。在具体例子中,所述第一腺病毒血清型是Ad5,且所述第二腺病毒血清型是Ad34。
D.用于诊断性和治疗性应用的转基因的表达
本文公开了包括具有Ad34隆突结构域和肝脏去靶向突变的嵌合纤维蛋白的重组腺病毒能够靶向肿瘤。还公开了所述重组腺病毒能够在肿瘤组织中例如在肿瘤基质细胞中表达转基因。在一例子中,所述转基因是报道基因,例如能够检测病毒转导细胞的荧光素酶-GFP报道基因。在另一例子中,所述转基因是治疗性转基因,例如抗癌分子。本公开提供包括用于诊断和治疗肿瘤的诊断性或治疗性转基因的合成腺病毒。
本文提供诊断受试者患有肿瘤的方法,通过给所述受试者施用合成腺病毒,所述合成腺病毒包括诊断性转基因,使合成腺病毒自肝脏去靶向的天然或修饰的衣壳,和Ad34纤维蛋白或包括Ad5轴结构域和Ad34隆突结构域的嵌合纤维蛋白。例如,所述诊断性转基因可以是PET报道基因、荧光蛋白或酶。
本文还提供治疗受试者中肿瘤的方法,通过给所述受试者施用合成腺病毒,所述合成腺病毒包括治疗性转基因,使合成腺病毒自肝脏去靶向的天然或修饰的衣壳,和Ad34纤维蛋白或包括Ad5轴结构域和Ad34隆突结构域的嵌合纤维蛋白。例如,所述治疗性转基因可以是抗癌药剂或者破坏或杀死肿瘤基质细胞的药剂。
在一些实施方式中,所述转基因插入E1到或E3区中。合适的转基因插入位点是本领域公知的(参见,例如,PCT公开号WO2012/024351)。
所述转基因例如编码荧光蛋白的基因与启动子可操作连接。在一些实施方式中,所述启动子是异源性启动子。在一些例子中,所述启动子是EF1α启动子。启动子的选择在本领域技术人员的能力范围之内。在一些情形中,所述启动子是诱导型启动子或组织特异性启动子。用于在胰腺组织中表达的示例性组织特异性启动子是Pdx1。
在一些情形中,使用单一启动子来调节多种基因的表达,其可以通过使用内部核糖体进入位点(IRES)或2A肽实现。
V.药物组合物及其施用
本文提供包括合成腺病毒(或者编码合成腺病毒的一种或多种核酸或载体)的组合物。任选地,所述组合物适合于在体内或体外配制和施用。任选地,所述组合物包括一种或多种重组腺病毒和药学可接受的载体。合适的载体及其制剂描述于以下文献中:Remington:The Science and Practice of Pharmacy,第22版,Loyd V.Allen et al.,editors,Pharmaceutical Press(2012)。药学可接受的载体包括在生物学上或其他方面并不是不合意的材料,即,将材料施用给受试者,而不会造成不合意的生物效果或者以有害的方式与包含其的药物组合物的其他组分相互作用。如果施用给受试者,任选地选择载体以使活性成分的降解最小化并使受试者中的有害副作用最小化。
根据已知方法施用重组病毒(或者编码重组腺病毒的一种或多种核酸或载体),例如静脉内施用,例如,作为推注(bolus)或者通过一段时间内连续输注,通过肌肉内、腹腔内、脑脊髓内、皮下、关节内、滑膜内、囊内、口服、局部、肿瘤内或吸入路径。所述施用可以是局部的或全身的。所述组合物可以经由若干施用路径中的任意者施用,其包括局部、口服、肠胃外、静脉内、关节内、腹腔内、肌肉内、皮下、腔内、经皮、肝内(intrahepatically)、颅内、雾化/吸入或通过经由支气管镜安装。因此,所述组合物以若干种方式施用,其取决于需要局部还是全身治疗,以及待治疗的区域。
在一些实施方式中,用于施用的组合物将包括溶解在药学可接受的载体、优选含水载体中的本文所述的重组腺病毒(或重组基因组)。可以使用许多种含水载体,例如,缓冲盐水等。这些溶液是无菌的,且通常不含不合意的物质。这些组合物可以通过常规的公知灭菌技术进行灭菌。所述组合物可以含有为接近生理条件所需的药学可接受的辅剂,,例如,pH调节和缓冲剂、毒性调节剂等,例如,乙酸钠、氯化钠、氯化钾、氯化钙、乳酸钠等。这些制剂中活性剂的浓度可以宽泛地变化,并将根据所选的具体施用方式和受试者的需求主要基于流体体积、粘度、体重等进行选择。
具体地,重组病毒的药物制剂可以通过将具有所需纯度的重组腺病毒(或编码重组腺病毒的一种或多种核酸)与任选的药学可接受的载体、赋形剂或稳定剂混合而制备。这些制剂可以是冻干制剂或水溶液。
可接受的载体、赋形剂或稳定剂在所用的剂量和浓度下对于接受者是无毒的。可接受的载体、赋形剂或稳定剂可以是乙酸盐、磷酸盐、柠檬酸盐和其他有机盐;抗氧化剂(例如抗坏血酸)防腐剂、低分子量多肽;蛋白质,例如血清白蛋白或明胶,或者亲水性聚合物例如聚乙烯吡洛烷酮;和氨基酸、单糖、二糖和其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂;和离子型和非离子型表面活性剂(例如聚山梨醇酯);成盐抗衡离子例如钠;金属复合物(例如Zn-蛋白质复合物);和/或非离子型表面活性剂。重组腺病毒(或编码重组腺病毒的一种或多种核酸)可以任意适当浓度的感染单位进行配制。
适合于口服施用的制剂可以由以下组成:(a)液体溶液,例如悬浮在稀释剂例如水、盐水或PEG 400中的有效量的重组腺病毒;(b)胶囊、小袋剂(sachets)或片剂,其每种均含有预订量的作为液体、固体、颗粒或明胶的活性成分;(c)适当液体中的悬液;和(d)适当的乳液。片剂形式可以包括一种或多种乳糖、蔗糖、甘露醇、山梨糖醇、磷酸钙、玉米淀粉、马铃薯淀粉、微晶纤维素、明胶、胶体二氧化硅、滑石、硬脂酸镁、硬脂酸和其他赋形剂、着色剂、填料、粘合剂、稀释剂、缓冲剂、润湿剂、防腐剂、芳香剂、染料、崩解剂和药学可接受的载体。锭剂形式可以在香料例如蔗糖中包括活性成分,以及在惰性基质中包括活性成分的软锭剂(pastilles),上述惰性基质例如明胶和甘油或蔗糖和阿拉伯胶乳液、凝胶等,其除活性成分以外还含有本领域已知的载体。
单独的或者与其他适当组分结合的重组腺病毒(或编码重组腺病毒的一种或多种核酸)可以制成气溶胶制剂(即,它们可被“雾化”),以经由吸入施用。气溶胶制剂可以置于加压的可接受推进剂中,例如,二氯二氟甲烷、丙烷、氮等。
适合于肠胃外施用(例如,诸如通过关节内(在关节中)、静脉内、肌肉内、肿瘤内、皮内、腹腔内和皮下路径)的制剂包括含水的或非水性的等渗无菌注射溶液,其可以含有抗氧化剂、缓冲剂、抑菌剂和使制剂与既定接受者的血液等渗的溶质;和含水的或非水性的无菌悬液,其可以含有悬浮剂、增溶剂、增稠剂、稳定剂和防腐剂。在提供的方法中,组合物可以通过,例如静脉内输注、口服、局部、腹腔内、膀胱内、肿瘤内或鞘内施用。肠胃外施用、肿瘤内施用和静脉内施用是优选的施用方法。化合物的制剂可以置于单位剂量或多剂量的密封容器中,例如安瓿或小瓶。
注射溶液和悬液可以由之前所述种类的无菌粉剂、颗粒剂和片剂制备。药物制剂优选为单位剂型。在该形式中,将制剂分成含有适量活性成份的单位剂量。因此,药物组合物可以根据施用方法以许多种单位剂型施用。例如,适合于口服施用的单位剂型包括,但不限于,粉剂、片剂、丸剂、胶囊和锭剂。
在一些实施方式中,所述组合物包括至少2种不同的重组腺病毒,例如编码不同转基因的重组腺病毒。在一些例子中,所述组合物包括2、3、4、5或6种不同的重组腺病毒。
在治疗性应用中,以有效的量或剂量给受试者施用重组腺病毒或其组合物。根据需要可以单一或多次施用组合物。“患者”或“受试者”包括人和其他动物,特别是哺乳动物。因此,这些方法可应用于人的疗法和兽医应用。
重组腺病毒的有效量基于个体确定,并且至少部分地基于所用的特定重组腺病毒;个体的大小、年龄、性别和总体健康。例如,对于人的施用,取决于所存在的增殖细胞或肿瘤的类型、大小和数量,使用至少103噬斑形成单位(PFU)的重组病毒,例如至少104、至少105、至少106、至少107、至少108、至少109、至少1010、至少1011或至少1012PFU,例如大约103至1012PFU的重组病毒。有效量可以是大约1.0pfu/kg体重至大约1015pfu/kg体重(例如,大约102pfu/kg体重至大约1013pfu/kg体重)。重组腺病毒以单一剂量或多剂量施用(例如,2、3、4、6或更多剂量)。多剂量可以同时或相继(例如在数天或数周时间内)施用。
在一些实施方式中,所提供的方法包括给受试者施用一种或多种治疗性药剂,例如一种或多种治疗癌症例如胰腺癌或成胶质细胞瘤的药剂。
本文所述的具有治疗性转基因的合成腺病毒的施用可以伴随着其他抗癌药剂或治疗性治疗(例如手术切除肿瘤)的施用。任何合适的抗癌药剂均可以与本文公开的重组病毒联合施用。示例性的抗癌药剂包括,但不限于,化疗药剂,例如,诸如有丝分裂抑制剂、烷基化药剂、抗代谢物、嵌入型抗生素、生长因子抑制剂、细胞周期抑制剂、酶、拓扑异构酶抑制剂、抗存活药剂、生物反应调节剂、抗激素(例如抗雄激素)、CDK抑制剂和抗血管生成药剂。其他抗癌治疗包括放疗和特异性靶向癌细胞的其他抗体(例如生物制剂)。
烷基化药剂的非限定性例子包括氮芥类(例如,氮芥、环磷酰胺、美法仑、尿嘧啶氮芥或苯丁酸氮芥)、烷基磺酸酯(例如白消安)、亚硝基脲(例如卡莫司汀、洛莫司汀、司莫司汀、链脲佐菌素或达卡巴嗪)。
抗代谢物的非限定性例子包括叶酸类似物(例如氨甲喋呤)、嘧啶类似物(例如5-FU或阿糖胞苷)和嘌呤类似物,例如巯嘌呤或硫鸟嘌呤。
天然产物的非限定性例子包括长春花生物碱(例如长春花碱、长春新碱或长春地辛)、表鬼臼毒素(例如依托泊苷或替尼泊苷)、抗生素(例如更生霉素、道诺霉素、阿霉素、博来霉素、普卡霉素或丝裂霉素C)和酶(例如L-天冬酰胺酶)。
其他药剂的非限定性例子包括铂配位化合物(例如顺式-二胺-二氯铂II,也称作顺铂)、取代的脲(例如羟基脲)、甲基肼衍生物(例如甲苄肼)和肾上腺皮质抑制剂(例如米托坦和氨鲁米特)。
激素和拮抗剂的非限定性例子包括肾上腺皮质激素类药(例如强的松)、孕酮(例如己酸羟孕酮、醋酸甲羟孕酮和醋酸甲地孕酮)、雌激素(例如己烯雌酚和乙炔雌二醇)、抗雌激素(例如他莫昔芬)和雄激素(例如丙酸睾酮和氟甲睾酮)。最常用的化疗药物的例子包括阿霉素、爱克兰、Ara-C、BiCNU、白消安、CCNU、卡铂、顺铂、环磷酰胺、道诺霉素、DTIC、5-FU、氟达拉滨、羟基脲、伊达比星、异环磷酰胺、氨甲喋呤、光神霉素、丝裂霉素、米托蒽醌、氮芥、紫杉醇(或其他紫杉烷,例如多西紫杉醇)、长春花碱、长春新碱、VP-16,而一些更新的药物包括吉西他滨(Gemzar)、赫赛汀、伊立替康(Camptosar,CPT-11)、Leustatin、长春瑞滨、Rituxan STI-571、Taxotere、拓扑替康(Hycamtin)、希罗达(卡培他滨)、Zevelin和骨化三醇。
可以使用的免疫调节剂的非限定性例子包括AS-101(Wyeth-Ayerst Labs.)、溴匹立明(bropirimine)(Upjohn)、γ干扰素(Genentech)、GM-CSF(粒细胞巨噬细胞集落刺激因子;Genetics Institute)、IL-2(Cetus或Hoffman-LaRoche)、人免疫球蛋白(CutterBiological)、IMREG(获自Imreg of New Orleans,La.)、SK&F 106528和TNF(肿瘤坏死因子;Genentech)。
另一种常用于一些类型癌症的治疗是手术治疗,例如,手术切除癌症或其一部分。治疗的另一例子是放疗,例如,向肿瘤部位施用放射性材料或能量(例如体外射线疗法),以帮助根除肿瘤或者在手术切除之前使其缩小。
CDK(周期蛋白依赖性激酶)抑制剂是抑制CDK功能的药剂。用于所提供方法的CDK抑制剂的非限定性例子包括AG-024322、AT7519、AZD5438、夫拉平度(flavopiridol)、吲地磺胺(indisulam)、P1446A-05、PD-0332991和P276-00(参见,例如,Lapenna et al.,NatureReviews,8:547-566,2009)。其他CDK抑制剂包括LY2835219、帕博西尼(Palbociclib)、LEE011(Novartis)、pan-CDK抑制剂AT7519、seliciclib、CYC065、丁内酯I、hymenialdisine、SU9516、CINK4、PD0183812或fascaplysin。
在一些例子中,所述CDK抑制剂是广谱抑制剂(例如夫拉平度、奥罗莫星(olomoucine)、罗可嘌呤(roscovitine)、kenpaullone、SNS-032、AT7519、AG-024322、(S)-罗可嘌呤或R547)。在其它例子中,所述CDK抑制剂是特异性抑制剂(例如fascaplysin、ryuvidine、purvalanol A、NU2058、BML-259、SU 9516、PD0332991或P-276–00)。
药剂和剂量的选择可以由本领域技术人员基于被治疗的指定疾病容易地确定。药剂和组合物的组合可以伴随地施用(例如,作为混合物),分别地但是同时施用(例如,经由分别的静脉导管),或者相继施用(例如,首先施用一种药剂,然后施用第二药剂)。因此,术语组合用于指两种或更多中药剂或组合物的伴随、同时或相继施用。
提供以下实施例,以说明某些具体特征和/或实施方式。这些实施例不应理解成将本公开限定于所描述的具体特征或实施方式。
实施例
实施例1:表达Ad5/Ad34嵌合纤维蛋白和肝脏去靶向修饰的合成腺病毒
尽管Ad5的纤维蛋白和许多其他血清型已经显示出与CAR结合用于细胞附着,其他血清型也显示使用CD46(Gaggar et al.,Nat Med 9:1408-1412,2003)、桥粒芯蛋白2(Wanget al.,Nat Med 17:96-104,2011)、唾液酸(Nilsson et al.,Nat Med 17:105-109,2011)或其他(Arnberg,Trends Pharmacol Sci 33:442-448,2012)。许多血清型的受体利用尚未深入考察,且认为CD46在成熟小鼠中不表达。
使用Adsembly/AdSLIC(参见PCT公开号WO 2012/024351,其通过引用并入本文)产生具有嵌合纤维蛋白的合成腺病毒。由于纤维蛋白C-端处的球形隆突通常负责受体结合,通过将Ad5纤维隆突用来自Ad34的纤维隆突取代,产生具有嵌合纤维蛋白的病毒(AdSyn-CO176)。对照病毒(AdSyn-CO171)含有Ad5纤维蛋白(即,轴和隆突结构域均来自Ad5)。两种病毒用相同的E1模块构建,该模块含有E1A/E1B缺失和由EF1α启动子驱动的荧光素酶-GFP融合物(表1)。所述重组病毒还包括肝脏去靶向修饰。天然Ad5载体仅感染肺部(经由吸入)或肝脏(经由静脉内施用)。Ad5六邻体在血液中与因子X结合,这导致其在肝脏中被库普弗细胞吸收,防止全身扩散并诱导病毒限制性炎症。为了克服这一点并允许对替代细胞类型的全身施用,将所述合成腺病毒改造成在E1中包括额外的基因组修饰,并包括防止肝脏中的摄入和表达的核心模块。具体地,两种病毒均在转基因的3′UTR中包括针对在肝脏中特异性表达的微小RNA(miR-122)的结合位点,并在六邻体中包括E451Q突变。
表1.具有嵌合纤维蛋白和肝脏去靶向修饰的腺病毒
实施例2:表达Ad34隆突结构域的合成腺病毒表现出对肿瘤基质的趋向性
该实施例说明了以下发现:表达具有Ad34隆突结构域的嵌合纤维蛋白的AdSyn-CO176特异性地运送至肿瘤基质。
胰腺肿瘤模型
图1A示出Cre-LoxP KrasG12D/p53胰腺肿瘤模型的示意性概况。命名为“Kras;p53/p53”的小鼠编码KrasG12D致癌基因,该致癌基因位于编码LoxP-终止密码子-LoxP的序列的下游。所述终止密码子在不存在Cre重组酶的情况下阻断突变体Kras(KrasG12D)的表达。但是,在Cre重组酶的存在下,所述终止密码子被除去,并允许KrasG12D致癌基因的表达。在这些相同的小鼠中,p53基因的两个等位基因的侧翼为LoxP位点(LoxP-p53-LoxP)。命名为“p53/p53;Cre”的小鼠也具有侧翼为LoxP的p53基因的两个等位基因(LoxP-p53-LoxP),并且它们在胰十二指肠同源盒1(Pdx1)启动子的驱动下表达Cre重组酶转基因。Pdx1是在胰腺细胞中特异性表达的基因,因此胰腺细胞中两个拷贝的p53缺失。株系之间的繁殖产生了这样的后代,其中Pdx1启动子驱动的Cre在胰腺细胞中介导肿瘤抑制基因p53的两个等位基因的缺失和突变体KrasG12D的激活。命名为“Kras;p53/p53;Cre”的纯合子小鼠在5-7周内发展为胰腺肿瘤。将AdSyn-CO176静脉注射至Kras;p53/p53和Kras;p53/p53;Cre小鼠中。注射病毒之后72小时,收集组织,与荧光素一起孵育5分钟,然后使用IVISTM成像系统扫描5分钟。如图1B所示,所述Kras;p53/p53小鼠具有正常的胰腺,且荧光素酶信号主要来自于脾。与此相反,所述Kras;p53/p53;Cre小鼠具有胰腺肿瘤,且信号主要来自胰腺肿瘤。
另一项研究在Cre-介导的基因操纵杂合模型中进行(图2A)。命名为“p53/+;Cre”的小鼠具有一个野生型p53等位基因和一个侧翼为LoxP位点的p53等位基因(LoxP-p53-LoxP)。Kras;p53/p53和p53/+;Cre株系之间的繁殖产生了这样的后代,其中Pdx1启动子驱动的Cre重组酶在胰腺细胞中介导肿瘤抑制基因p53的单个等位基因的缺失和突变体KrasG12D的激活。命名为“Kras;p53/+;Cre,”的这些杂合小鼠由于具有p53的一个野生型等位基因而在之后发展为肿瘤(4-9月龄时)。为使胰腺肿瘤发生,该野生型等位基因必须丧失或被突变。将AdSyn-CO176静脉注射至四个月大的p53/+;Cre和Kras;p53/+;Cre小鼠中。注射病毒之后72小时,收集组织,与荧光素一起孵育5分钟,然后使用IVISTM成像系统扫描1分钟。所述p53/+;Cre小鼠具有正常的胰腺,且信号主要来自于脾。与此相反,4月龄的Kras;p53/+;Cre小鼠具有胰腺肿瘤,且信号主要来自肿瘤和肝脏。
杂合Kras;p53/+;Cre小鼠在4-9个月内发展为胰腺肿瘤。为了检验AdSyn-CO176是否可以感染肿瘤发展极早期(肿瘤可见之前)的胰腺肿瘤,将AdSyn-CO176静脉注射至2月龄的Kras;p53/+;Cre小鼠中。注射病毒之后72小时,收集组织,与荧光素一起孵育5分钟,并使用IVISTM成像系统扫描4分钟。2月龄时Kras;p53/+;Cre小鼠的胰腺看起来是正常的,但是在该组织中发现了荧光素酶信号(图3A)。进行H&E染色,以评价用AdSyn-CO176感染之后胰腺的组织学。出于比较,图3B显示正常胰腺组织和胰腺肿瘤组织的典型组织学。来自2月龄Kras;p53/+;Cre小鼠的胰腺的H&E染色表明,小部分胰腺正在发展为肿瘤(图3C,通过多边形示出),而大多数胰腺组织看起来是正常的。该结果表明,AdSyn-CO176可以感染极早期胰腺肿瘤。
在胰腺肿瘤中,仅有10%的细胞是癌细胞;其余90%是基质细胞。为了确定AdSyn-CO176靶向哪种细胞类型,进行IHC和IF染色。CK19是肿瘤细胞标志物,而平滑肌肌动蛋白(SMA)是基质细胞标记物。用AdSyn-CO176感染的胰腺肿瘤的IHC染色表明,自AdSyn-CO176表达的GFP与SMA染色重叠,说明AdSyn-CO176靶向基质细胞(图4A)。被AdSyn-CO176感染的胰腺肿瘤的IF染色也表明GFP与SMA染色重叠(图4B),证实了AdSyn-CO176感染基质细胞。
成胶质细胞瘤模型
图5A显示Cre-介导的基因操纵成胶质细胞瘤模型的示意图。将慢病毒直接注射到GFAP-Cre小鼠的大脑中。胶质原纤维酸性蛋白(GFAP)启动子驱动的Cre重组酶将RFP自编码慢病毒的基因中切除,并诱导主要在星形细胞中的HRasV12和GFP的表达。编码慢病毒的U6-p53shRNA的表达敲低了摄入病毒的脑细胞中的p53表达。从注射之后1周起,HRasV12的表达和p53的敲低诱导大脑中的肿瘤发生。GFP信号用来指示成胶质细胞瘤的形成。将盐水、AdSyn-CO171或AdSyn-CO176经由静脉内(IV)施用注射到在4周前接受过肿瘤诱导慢病毒的GFAP-Cre小鼠中。注射病毒之后48小时,腹腔内注射荧光素之后,将小鼠用IVISTM成像系统扫描1分钟(图5B)。在注射AdSyn-CO176的小鼠中检测到荧光素酶信号,但在注射盐水或AdSyn-CO171的小鼠中没有检测到信号。
给野生型小鼠(正常大脑)和接受过肿瘤诱导慢病毒注射的GFAP-Cre小鼠注射AdSyn-CO171或AdSyn-CO176。注射合成腺病毒之后72小时收集脑组织,与荧光素一起孵育5分钟,并用IVISTM成像系统扫描5分钟(图5C)。仅有注射有肿瘤诱导慢病毒的GFAP-Cre小鼠显示出来自AdSyn-CO176的荧光素酶信号。这说明AdSyn-CO176仅在存在肿瘤时运送至脑组织。另外对脑组织进行GFP信号的扫描(图5D)。GFP信号用于识别成胶质细胞瘤。接受过肿瘤诱导慢病毒的两种GFAP-Cre小鼠均在大脑中具有GFP信号,而野生型小鼠中没有检测到GFP。在接受过肿瘤诱导慢病毒和AdSyn-CO176的GFAP-Cre小鼠中,GFP信号与荧光素酶信号完美地重合。
注射肿瘤诱导慢病毒在注射部位处引起暂时的脑损伤。尽管合成腺病毒(AdSyn-CO171和AdSyn-CO176)在最初注射慢病毒之后4周注射,但仍不明确AdSyn-CO176运送至成胶质细胞瘤是通过肿瘤还是通过注射部位损伤来驱动。为了回答该问题,在无注射、假注射或注射肿瘤诱导慢病毒之后4周,给GFAP-Cre小鼠注射合成腺病毒。给GFAP-Cre小鼠注射Hanks’平衡盐溶液(HBSS)或肿瘤诱导腺病毒。4周之后,静脉内注射AdSyn-CO171。如图6A所示,在任一组小鼠的脑中均没有来自AdSyn-CO171的荧光素酶信号。给GFAP-Cre小鼠注射HBSS或肿瘤诱导慢病毒,或者不接受注射。4周之后,给小鼠静脉内注射AdSyn-CO176。如图6B所示,仅在接受了肿瘤诱导慢病毒的小鼠的大脑中检测到荧光素酶信号,而接受HBSS或无注射的小鼠则不产生信号。这些结果说明,AdSyn-CO176的特异性是通过肿瘤驱动,而不是通过注射部位的损伤驱动。
实施例3:在异种移植模型中运送至人成胶质细胞瘤肿瘤的AdSyn-CO176
该实施例说明了以下发现:表达具有Ad34隆突结构域的嵌合纤维蛋白的合成腺病毒能够靶向人成胶质细胞瘤肿瘤。
U87-tdTomato细胞系是表达tdTomato荧光蛋白作为报道物以能够监测肿瘤生长的人成胶质细胞瘤细胞系。当U87-tdTomato细胞颅内注射到NSG小鼠中以产生成胶质细胞瘤肿瘤时,肿瘤发展通常需要4-8周(图7A)。使用该成胶质细胞瘤异种移植模型确定AdSyn-CO176是否可以运送至人成胶质细胞瘤肿瘤。小鼠接受U87-tdTomato细胞的颅内注射之后4周,将AdSyn-CO171(SEQ ID NO:1)和AdSyn-CO176(SEQ ID NO:2)通过尾静脉注射静脉内注射到NSG小鼠中。注射病毒之后48小时,收集肝脏、脾和脑组织,与荧光素一起孵育5分钟,然后使用IVISTM成像系统扫描1分钟。如图7B所示,仅有注射了AdSyn-CO176的小鼠在大脑中显示出荧光素酶信号,该信号与tdTomato表达完全重合。因此,这些结果说明,AdSyn-CO176可以运送至人成胶质细胞瘤肿瘤,而AdSyn-CO171则不能。
实施例4:靶向肿瘤基质并表达治疗性转基因的合成腺病毒在动物模型中降低肿瘤大小
该实施例说明:表达具有Ad34隆突结构域和治疗性负荷(payload)的嵌合纤维蛋白的合成腺病毒能够运送至肿瘤制剂,并降低肿瘤大小。
进行多项研究,以确定治疗性转基因是否可以被整合到AdSyn-CO176(SEQ ID NO:2)中以实现肿瘤治疗。为了进行该研究,使用KPCL(KrasG12D;p53敲除;Pdx1-Cre;萤火虫荧光素酶)小鼠模型(图8A)。KPCL小鼠与纯合的“Kras;p53/p53;Cre”小鼠类似,其在胰腺中特异性表达KrasG12D,并且仅在胰腺中敲除p53基因。但是,KPCL小鼠在胰腺中还特异性地表达萤火虫荧光素酶。KPCL小鼠中肿瘤的发展也类似于“Kras;p53/p53;Cre”小鼠。
产生两种其他的合成腺病毒–AdSyn-CO987(SEQ ID NO:5)和AdSyn-CO989(SEQ IDNO:6)。AdSyn-CO987是基于AdSyn-CO176的合成腺病毒。将单纯性疱疹病毒-1胸苷激酶(TK)/更昔洛韦(GCV)自杀基因克隆到AdSyn-CO176中,以代替萤火成荧光素酶/GFP基因。在AdSyn-CO176的基因组中在TK之后紧接着还插入海肾荧光素酶。通过将TK-P2A-海肾荧光素酶克隆到AdSyn-CO171中以代替原始的萤火虫荧光素酶/GFP基因,产生对照病毒AdSyn-CO989。
在5-6周龄时给KPCL小鼠经由尾部静脉静脉内注射1x106PFU AdSyn-CO987或AdSyn-CO989。2天之后,给小鼠i.p.或i.v.注射GCV。使用3个对照组:AdSyn-CO989+GCV;AdSyn-CO987之后注射盐水(AdSyn-CO987+盐水)和仅GCV注射(i.p.或i.v.)。图8B提供的表显示每个治疗组的KPCL小鼠的平均存活期。与对照相比,用AdSyn-CO987+GCV治疗延长了小鼠的存活。
治疗过程中对肿瘤表达的萤火虫荧光素酶信号进行分析,以监测肿瘤生长。结果显示于图8C。对于Z619R小鼠的治疗为AdSyn-CO987+盐水,将其用作对照。用AdSyn-CO987+GCV(i.p.)治疗小鼠Z601R和Z607R。尽管在对照小鼠Z619R中萤火虫荧光素酶信号的强度增加(表明肿瘤大小的增加),但在小鼠Z601R和Z607R中信号降低(表明肿瘤大小的降低)。
另外通过H&E染色对胰腺肿瘤的组织学进行了评价(图9A)。小鼠Z655、1806、Z619和Z621均为对照小鼠。小鼠Z655仅用i.p.注射的GCV治疗;小鼠1806仅用i.v.注射的GCV治疗;小鼠Z619用AdSyn-CO987+盐水治疗;小鼠Z621不接受治疗。小鼠Z656接受AdSyn-CO987+GCV i.v.的治疗。与对照相比,来自Z656的肿瘤具有更多的坏死区(图9B)。
鉴于可应用本公开原理的许多可能的实施方式,应当认识到,所示的实施方式仅仅是本发明的例子,不应当视作是对本发明的范围进行限定。相反,本发明的范围由所附权利要求限定。因此,我们要求保护落入这些权利要求的范围和精神以内的所有发明。
序列表
<110> 萨克生物研究学院
<120> 肿瘤靶向合成腺病毒及其用途
<130> 7158-96599-02
<150> US 62/433,140
<151> 2016-12-12
<160> 6
<170> PatentIn version 3.5
<210> 1
<211> 36913
<212> DNA
<213> 人工序列
<220>
<223> 合成腺病毒基因组 (AdSyn-CO171)
<400> 1
catcatcaat aatatacctt attttggatt gaagccaata tgataatgag ggggtggagt 60
ttgtgacgtg gcgcggggcg tgggaacggg gcgggtgacg tagtagtgtg gcggaagtgt 120
gatgttgcaa gtgtggcgga acacatgtaa gcgacggatg tggcaaaagt gacgtttttg 180
gtgtgcgccg gtgtacacag gaagtgacaa ttttcgcgcg gttttaggcg gatgttgtag 240
taaatttggg cgtaaccgag taagatttgg ccattttcgc gggaaaactg aataagagga 300
agtgaaatct gaataatttt gtgttactca tagcgcgtaa tatttgtcta gggccgcggg 360
gactttgacc gtttacgtgg agactcgccc aggtgttttt ctcaggtgtt ttccgcgttc 420
cgggtcaaag ttggcgtttt attattaaac cgtattaccg ccatgcattt aatggagtgc 480
ctcgtgaggc tccggtgccc gtcagtgggc agagcgcaca tcgcccacag tccccgagaa 540
gttgggggga ggggtcggca attgaaccgg tgcctagaga aggtggcgcg gggtaaactg 600
ggaaagtgat gtcgtgtact ggctccgcct ttttcccgag ggtgggggag aaccgtatat 660
aagtgcagta gtcgccgtga acgttctttt tcgcaacggg tttgccgcca gaacacaggt 720
aagtgccgtg tgtggttccc gcgggcctgg cctctttacg ggttatggcc cttgcgtgcc 780
ttgaattact tccacctggc tgcagtacgt gattcttgat cccgagcttc gggttggaag 840
tgggtgggag agttcgaggc cttgcgctta aggagcccct tcgcctcgtg cttgagttga 900
ggcctggcct gggcgctggg gccgccgcgt gcgaatctgg tggcaccttc gcgcctgtct 960
cgctgctttc gataagtctc tagccattta aaatttttga tgacctgctg cgacgctttt 1020
tttctggcaa gatagtcttg taaatgcggg ccaagatctg cacactggta tttcggtttt 1080
tggggccgcg ggcggcgacg gggcccgtgc gtcccagcgc acatgttcgg cgaggcgggg 1140
cctgcgagcg cggccaccga gaatcggacg ggggtagtct caagctggcc ggcctgctct 1200
ggtgcctggc ctcgcgccgc cgtgtatcgc cccgccctgg gcggcaaggc tggcccggtc 1260
ggcaccagtt gcgtgagcgg aaagatggcc gcttcccggc cctgctgcag ggagctcaaa 1320
atggaggacg cggcgctcgg gagagcgggc gggtgagtca cccacacaaa ggaaaagggc 1380
ctttccgtcc tcagccgtcg cttcatgtga ctccacggag taccgggcgc cgtccaggca 1440
cctcgattag ttctcgagct tttggagtac gtcgtcttta ggttgggggg aggggtttta 1500
tgcgatggag tttccccaca ctgagtgggt ggagactgaa gttaggccag cttggcactt 1560
gatgtaattc tccttggaat ttgccctttt tgagtttgga tcttggttca ttctcaagcc 1620
tcagacagtg gttcaaagtt tttttcttcc atttcaggtg tcgtgacgct agcgctaccg 1680
gactcagatc tcgagctcaa gcttcgaatt ctgcagtcga cggtaccgga tccatggaag 1740
acgccaaaaa cataaagaaa ggcccggcgc cattctatcc gctggaagat ggaaccgctg 1800
gagagcaact gcataaggct atgaagagat acgccctggt tcctggaaca attgctttta 1860
cagatgcaca tatcgaggtg gacatcactt acgctgagta cttcgaaatg tccgttcggt 1920
tggcagaagc tatgaaacga tatgggctga atacaaatca cagaatcgtc gtatgcagtg 1980
aaaactctct tcaattcttt atgccggtgt tgggcgcgtt atttatcgga gttgcagttg 2040
cgcccgcgaa cgacatttat aatgaacgtg aattgctcaa cagtatgggc atttcgcagc 2100
ctaccgtggt gttcgtttcc aaaaaggggt tgcaaaaaat tttgaacgtg caaaaaaagc 2160
tcccaatcat ccaaaaaatt attatcatgg attctaaaac ggattaccag ggatttcagt 2220
cgatgtacac gttcgtcaca tctcatctac ctcccggttt taatgaatac gattttgtgc 2280
cagagtcctt cgatagggac aagacaattg cactgatcat gaactcctct ggatctactg 2340
gtctgcctaa aggtgtcgct ctgcctcata gaactgcctg cgtgagattc tcgcatgcca 2400
gagatcctat ttttggcaat caaatcattc cggatactgc gattttaagt gttgttccat 2460
tccatcacgg ttttggaatg tttactacac tcggatattt gatatgtgga tttcgagtcg 2520
tcttaatgta tagatttgaa gaagagctgt ttctgaggag ccttcaggat tacaagattc 2580
aaagtgcgct gctggtgcca accctattct ccttcttcgc caaaagcact ctgattgaca 2640
aatacgattt atctaattta cacgaaattg cttctggtgg cgctcccctc tctaaggaag 2700
tcggggaagc ggttgccaag aggttccatc tgccaggtat caggcaagga tatgggctca 2760
ctgagactac atcagctatt ctgattacac ccgaggggga tgataaaccg ggcgcggtcg 2820
gtaaagttgt tccatttttt gaagcgaagg ttgtggatct ggataccggg aaaacgctgg 2880
gcgttaatca aagaggcgaa ctgtgtgtga gaggtcctat gattatgtcc ggttatgtaa 2940
acaatccgga agcgaccaac gccttgattg acaaggatgg atggctacat tctggagaca 3000
tagcttactg ggacgaagac gaacacttct tcatcgttga ccgcctgaag tctctgatta 3060
agtacaaagg ctatcaggtg gctcccgctg aattggaatc catcttgctc caacacccca 3120
acatcttcga cgcaggtgtc gcaggtcttc ccgacgatga cgccggtgaa cttcccgccg 3180
ccgttgttgt tttggagcac ggaaagacga tgacggaaaa agagatcgtg gattacgtcg 3240
ccagtcaagt aacaaccgcg aaaaagttgc gcggaggagt tgtgtttgtg gacgaagtac 3300
cgaaaggtct taccggaaaa ctcgacgcaa gaaaaatcag agagatcctc ataaaggcca 3360
agaagggcgg aaagatcgcc gtggcagccg cagccaccat ggtgagcaag ggcgaggagc 3420
tgttcaccgg ggtggtgccc atcctggtcg agctggacgg cgacgtaaac ggccacaagt 3480
tcagcgtgtc cggcgagggc gagggcgatg ccacctacgg caagctgacc ctgaagttca 3540
tctgcaccac cggcaagctg cccgtgccct ggcccaccct cgtgaccacc ctgacctacg 3600
gcgtgcagtg cttcagccgc taccccgacc acatgaagca gcacgacttc ttcaagtccg 3660
ccatgcccga aggctacgtc caggagcgca ccatcttctt caaggacgac ggcaactaca 3720
agacccgcgc cgaggtgaag ttcgagggcg acaccctggt gaaccgcatc gagctgaagg 3780
gcatcgactt caaggaggac ggcaacatcc tggggcacaa gctggagtac aactacaaca 3840
gccacaacgt ctatatcatg gccgacaagc agaagaacgg catcaaggtg aacttcaaga 3900
tccgccacaa catcgaggac ggcagcgtgc agctcgccga ccactaccag cagaacaccc 3960
ccatcggcga cggccccgtg ctgctgcccg acaaccacta cctgagcacc cagtccgccc 4020
tgagcaaaga ccccaacgag aagcgcgatc acatggtcct gctggagttc gtgaccgccg 4080
ccgggatcac tctcggcatg gacgagctgt acaagtaaag cgactctaga tcataatcag 4140
ccatacccaa acaccattgt cacactccaa tcgattcaaa caccattgtc acactccaac 4200
atttgtagag gttttacttg ctttaaaaaa cctcccacac ctccccctga acctgaaaca 4260
taaaatgaat gcaattgttg ttgttaactt gtttattgca gcttataatg gttacaaata 4320
aagcaatagc atcacaaatt tcacaaataa agcatttttt tcactgcatt ctagttgtgg 4380
tttgtccaaa ctcatcaatg taagtttaaa cggcgcgcct gaaatgtgtg ggcgtggctt 4440
aagggtggga aagaatatat aaggtggggg tcttatgtag ttttgtatct gttttgcagc 4500
agccgccgcc gccatgagca ccaactcgtt tgatggaagc attgtgagct catatttgac 4560
aacgcgcatg cccccatggg ccggggtgcg tcagaatgtg atgggctcca gcattgatgg 4620
tcgccccgtc ctgcccgcaa actctactac cttgacctac gagaccgtgt ctggaacgcc 4680
gttggagact gcagcctccg ccgccgcttc agccgctgca gccaccgccc gcgggattgt 4740
gactgacttt gctttcctga gcccgcttgc aagcagtgca gcttcccgtt catccgcccg 4800
cgatgacaag ttgacggctc ttttggcaca attggattct ttgacccggg aacttaatgt 4860
cgtttctcag cagctgttgg atctgcgcca gcaggtttct gccctgaagg cttcctcccc 4920
tcccaatgcg gtttaaaaca caacttttct atacaaagtt gtaaataaaa aaccagactc 4980
tgtttggatt tggatcaagc taagtgtctt gctgtcttta tttaggggtt ttgcgcgcgc 5040
ggtaggcccg ggaccagcgg tctcggtcgt tgagggtcct gtgtattttt tccaggacgt 5100
ggtaaaggtg actctggatg ttcagataca tgggcataag cccgtctctg gggtggaggt 5160
agcaccactg cagagcttca tgctgcgggg tggtgttgta gatgatccag tcgtagcagg 5220
agcgctgggc gtggtgccta aaaatgtctt tcagtagcaa gctgattgcc aggggcaggc 5280
ccttggtgta agtgtttaca aagcggttaa gctgggatgg gtgcatacgt ggggatatga 5340
gatgcatctt ggactgtatt tttaggttgg ctatgttccc agccatatcc ctccggggat 5400
tcatgttgtg cagaaccacc agcacagtgt atccggtgca cttgggaaat ttgtcatgta 5460
gcttagaagg aaatgcgtgg aagaacttgg agacgccctt gtgacctcca agattttcca 5520
tgcattcgtc cataatgatg gcaatgggcc cacgggcggc ggcctgggcg aagatatttc 5580
tgggatcact aacgtcatag ttgtgttcca ggatgagatc gtcataggcc atttttacaa 5640
agcgcgggcg gagggtgcca gactgcggta taatggttcc atccggccca ggggcgtagt 5700
taccctcaca gatttgcatt tcccacgctt tgagttcaga tggggggatc atgtctacct 5760
gcggggcgat gaagaaaacg gtttccgggg taggggagat cagctgggaa gaaagcaggt 5820
tcctgagcag ctgcgactta ccgcagccgg tgggcccgta aatcacacct attaccggct 5880
gcaactggta gttaagagag ctgcagctgc cgtcatccct gagcaggggg gccacttcgt 5940
taagcatgtc cctgactcgc atgttttccc tgaccaaatc cgccagaagg cgctcgccgc 6000
ccagcgatag cagttcttgc aaggaagcaa agtttttcaa cggtttgaga ccgtccgccg 6060
taggcatgct tttgagcgtt tgaccaagca gttccaggcg gtcccacagc tcggtcacct 6120
gctctacggc atctcgatcc agcatatctc ctcgtttcgc gggttggggc ggctttcgct 6180
gtacggcagt agtcggtgct cgtccagacg ggccagggtc atgtctttcc acgggcgcag 6240
ggtcctcgtc agcgtagtct gggtcacggt gaaggggtgc gctccgggct gcgcgctggc 6300
cagggtgcgc ttgaggctgg tcctgctggt gctgaagcgc tgccggtctt cgccctgcgc 6360
gtcggccagg tagcatttga ccatggtgtc atagtccagc ccctccgcgg cgtggccctt 6420
ggcgcgcagc ttgcccttgg aggaggcgcc gcacgagggg cagtgcagac ttttgagggc 6480
gtagagcttg ggcgcgagaa ataccgattc cggggagtag gcatccgcgc cgcaggcccc 6540
gcagacggtc tcgcattcca cgagccaggt gagctctggc cgttcggggt caaaaaccag 6600
gtttccccca tgctttttga tgcgtttctt acctctggtt tccatgagcc ggtgtccacg 6660
ctcggtgacg aaaaggctgt ccgtgtcccc gtatacagac ttgagaggcc tgtcctcgag 6720
cggtgttccg cggtcctcct cgtatagaaa ctcggaccac tctgagacaa aggctcgcgt 6780
ccaggccagc acgaaggagg ctaagtggga ggggtagcgg tcgttgtcca ctagggggtc 6840
cactcgctcc agggtgtgaa gacacatgtc gccctcttcg gcatcaagga aggtgattgg 6900
tttgtaggtg taggccacgt gaccgggtgt tcctgaaggg gggctataaa agggggtggg 6960
ggcgcgttcg tcctcactct cttccgcatc gctgtctgcg agggccagct gttggggtga 7020
gtactccctc tgaaaagcgg gcatgacttc tgcgctaaga ttgtcagttt ccaaaaacga 7080
ggaggatttg atattcacct ggcccgcggt gatgcctttg agggtggccg catccatctg 7140
gtcagaaaag acaatctttt tgttgtcaag cttggtggca aacgacccgt agagggcgtt 7200
ggacagcaac ttggcgatgg agcgcagggt ttggtttttg tcgcgatcgg cgcgctcctt 7260
ggccgcgatg tttagctgca cgtattcgcg cgcaacgcac cgccattcgg gaaagacggt 7320
ggtgcgctcg tcgggcacca ggtgcacgcg ccaaccgcgg ttgtgcaggg tgacaaggtc 7380
aacgctggtg gctacctctc cgcgtaggcg ctcgttggtc cagcagaggc ggccgccctt 7440
gcgcgagcag aatggcggta gggggtctag ctgcgtctcg tccggggggt ctgcgtccac 7500
ggtaaagacc ccgggcagca ggcgcgcgtc gaagtagtct atcttgcatc cttgcaagtc 7560
tagcgcctgc tgccatgcgc gggcggcaag cgcgcgctcg tatgggttga gtgggggacc 7620
ccatggcatg gggtgggtga gcgcggaggc gtacatgccg caaatgtcgt aaacgtagag 7680
gggctctctg agtattccaa gatatgtagg gtagcatctt ccaccgcgga tgctggcgcg 7740
cacgtaatcg tatagttcgt gcgagggagc gaggaggtcg ggaccgaggt tgctacgggc 7800
gggctgctct gctcggaaga ctatctgcct gaagatggca tgtgagttgg atgatatggt 7860
tggacgctgg aagacgttga agctggcgtc tgtgagacct accgcgtcac gcacgaagga 7920
ggcgtaggag tcgcgcagct tgttgaccag ctcggcggtg acctgcacgt ctagggcgca 7980
gtagtccagg gtttccttga tgatgtcata cttatcctgt cccttttttt tccacagctc 8040
gcggttgagg acaaactctt cgcggtcttt ccagtactct tggatcggaa acccgtcggc 8100
ctccgaacgg taagagccta gcatgtagaa ctggttgacg gcctggtagg cgcagcatcc 8160
cttttctacg ggtagcgcgt atgcctgcgc ggccttccgg agcgaggtgt gggtgagcgc 8220
aaaggtgtcc ctgaccatga ctttgaggta ctggtatttg aagtcagtgt cgtcgcatcc 8280
gccctgctcc cagagcaaaa agtccgtgcg ctttttggaa cgcggatttg gcagggcgaa 8340
ggtgacatcg ttgaagagta tctttcccgc gcgaggcata aagttgcgtg tgatgcggaa 8400
gggtcccggc acctcggaac ggttgttaat tacctgggcg gcgagcacga tctcgtcaaa 8460
gccgttgatg ttgtggccca caatgtaaag ttccaagaag cgcgggatgc ccttgatgga 8520
aggcaatttt ttaagttcct cgtaggtgag ctcttcaggg gagctgagcc cgtgctctga 8580
aagggcccag tctgcaagat gagggttgga agcgacgaat gagctccaca ggtcacgggc 8640
cattagcatt tgcaggtggt cgcgaaaggt cctaaactgg cgacctatgg ccattttttc 8700
tggggtgatg cagtagaagg taagcgggtc ttgttcccag cggtcccatc caaggttcgc 8760
ggctaggtct cgcgcggcag tcactagagg ctcatctccg ccgaacttca tgaccagcat 8820
gaagggcacg agctgcttcc caaaggcccc catccaagta taggtctcta catcgtaggt 8880
gacaaagaga cgctcggtgc gaggatgcga gccgatcggg aagaactgga tctcccgcca 8940
ccaattggag gagtggctat tgatgtggtg aaagtagaag tccctgcgac gggccgaaca 9000
ctcgtgctgg cttttgtaaa aacgtgcgca gtactggcag cggtgcacgg gctgtacatc 9060
ctgcacgagg ttgacctgac gaccgcgcac aaggaagcag agtgggaatt tgagcccctc 9120
gcctggcggg tttggctggt ggtcttctac ttcggctgct tgtccttgac cgtctggctg 9180
ctcgagggga gttacggtgg atcggaccac cacgccgcgc gagcccaaag tccagatgtc 9240
cgcgcgcggc ggtcggagct tgatgacaac atcgcgcaga tgggagctgt ccatggtctg 9300
gagctcccgc ggcgtcaggt caggcgggag ctcctgcagg tttacctcgc atagacgggt 9360
cagggcgcgg gctagatcca ggtgatacct aatttccagg ggctggttgg tggcggcgtc 9420
gatggcttgc aagaggccgc atccccgcgg cgcgactacg gtaccgcgcg gcgggcggtg 9480
ggccgcgggg gtgtccttgg atgatgcatc taaaagcggt gacgcgggcg agcccccgga 9540
ggtagggggg gctccggacc cgccgggaga gggggcaggg gcacgtcggc gccgcgcgcg 9600
ggcaggagct ggtgctgcgc gcgtaggttg ctggcgaacg cgacgacgcg gcggttgatc 9660
tcctgaatct ggcgcctctg cgtgaagacg acgggcccgg tgagcttgaa cctgaaagag 9720
agttcgacag aatcaatttc ggtgtcgttg acggcggcct ggcgcaaaat ctcctgcacg 9780
tctcctgagt tgtcttgata ggcgatctcg gccatgaact gctcgatctc ttcctcctgg 9840
agatctccgc gtccggctcg ctccacggtg gcggcgaggt cgttggaaat gcgggccatg 9900
agctgcgaga aggcgttgag gcctccctcg ttccagacgc ggctgtagac cacgccccct 9960
tcggcatcgc gggcgcgcat gaccacctgc gcgagattga gctccacgtg ccgggcgaag 10020
acggcgtagt ttcgcaggcg ctgaaagagg tagttgaggg tggtggcggt gtgttctgcc 10080
acgaagaagt acataaccca gcgtcgcaac gtggattcgt tgatatcccc caaggcctca 10140
aggcgctcca tggcctcgta gaagtccacg gcgaagttga aaaactggga gttgcgcgcc 10200
gacacggtta actcctcctc cagaagacgg atgagctcgg cgacagtgtc gcgcacctcg 10260
cgctcaaagg ctacaggggc ctcttcttct tcttcaatct cctcttccat aagggcctcc 10320
ccttcttctt cttctggcgg cggtggggga ggggggacac ggcggcgacg acggcgcacc 10380
gggaggcggt cgacaaagcg ctcgatcatc tccccgcggc gacggcgcat ggtctcggtg 10440
acggcgcggc cgttctcgcg ggggcgcagt tggaagacgc cgcccgtcat gtcccggtta 10500
tgggttggcg gggggctgcc atgcggcagg gatacggcgc taacgatgca tctcaacaat 10560
tgttgtgtag gtactccgcc gccgagggac ctgagcgagt ccgcatcgac cggatcggaa 10620
aacctctcga gaaaggcgtc taaccagtca cagtcgcaag gtaggctgag caccgtggcg 10680
ggcggcagcg ggcggcggtc ggggttgttt ctggcggagg tgctgctgat gatgtaatta 10740
aagtaggcgg tcttgagacg gcggatggtc gacagaagca ccatgtcctt gggtccggcc 10800
tgctgaatgc gcaggcggtc ggccatgccc caggcttcgt tttgacatcg gcgcaggtct 10860
ttgtagtagt cttgcatgag cctttctacc ggcacttctt cttctccttc ctcttgtcct 10920
gcatctcttg catctatcgc tgcggcggcg gcggagtttg gccgtaggtg gcgccctctt 10980
cctcccatgc gtgtgacccc gaagcccctc atcggctgaa gcagggctag gtcggcgaca 11040
acgcgctcgg ctaatatggc ctgctgcacc tgcgtgaggg tagactggaa gtcatccatg 11100
tccacaaagc ggtggtatgc gcccgtgttg atggtgtaag tgcagttggc cataacggac 11160
cagttaacgg tctggtgacc cggctgcgag agctcggtgt acctgagacg cgagtaagcc 11220
ctcgagtcaa atacgtagtc gttgcaagtc cgcaccaggt actggtatcc caccaaaaag 11280
tgcggcggcg gctggcggta gaggggccag cgtagggtgg ccggggctcc gggggcgaga 11340
tcttccaaca taaggcgatg atatccgtag atgtacctgg acatccaggt gatgccggcg 11400
gcggtggtgg aggcgcgcgg aaagtcgcgg acgcggttcc agatgttgcg cagcggcaaa 11460
aagtgctcca tggtcgggac gctctggccg gtcaggcgcg cgcaatcgtt gacgctctag 11520
accgtgcaaa aggagagcct gtaagcgggc actcttccgt ggtctggtgg ataaattcgc 11580
aagggtatca tggcggacga ccggggttcg agccccgtat ccggccgtcc gccgtgatcc 11640
atgcggttac cgcccgcgtg tcgaacccag gtgtgcgacg tcagacaacg ggggagtgct 11700
ccttttggct tccttccagg cgcggcggct gctgcgctag cttttttggc cactggccgc 11760
gcgcagcgta agcggttagg ctggaaagcg aaagcattaa gtggctcgct ccctgtagcc 11820
ggagggttat tttccaaggg ttgagtcgcg ggacccccgg ttcgagtctc ggaccggccg 11880
gactgcggcg aacgggggtt tgcctccccg tcatgcaaga ccccgcttgc aaattcctcc 11940
ggaaacaggg acgagcccct tttttgcttt tcccagatgc atccggtgct gcggcagatg 12000
cgcccccctc ctcagcagcg gcaagagcaa gagcagcggc agacatgcag ggcaccctcc 12060
cctcctccta ccgcgtcagg aggggcgaca tccgcggttg acgcggcagc agatggtgat 12120
tacgaacccc cgcggcgccg ggcccggcac tacctggact tggaggaggg cgagggcctg 12180
gcgcggctag gagcgccctc tcctgagcgg cacccaaggg tgcagctgaa gcgtgatacg 12240
cgtgaggcgt acgtgccgcg gcagaacctg tttcgcgacc gcgagggaga ggagcccgag 12300
gagatgcggg atcgaaagtt ccacgcaggg cgcgagctgc ggcatggcct gaatcgcgag 12360
cggttgctgc gcgaggagga ctttgagccc gacgcgcgaa ccgggattag tcccgcgcgc 12420
gcacacgtgg cggccgccga cctggtaacc gcatacgagc agacggtgaa ccaggagatt 12480
aactttcaaa aaagctttaa caaccacgtg cgtacgcttg tggcgcgcga ggaggtggct 12540
ataggactga tgcatctgtg ggactttgta agcgcgctgg agcaaaaccc aaatagcaag 12600
ccgctcatgg cgcagctgtt ccttatagtg cagcacagca gggacaacga ggcattcagg 12660
gatgcgctgc taaacatagt agagcccgag ggccgctggc tgctcgattt gataaacatc 12720
ctgcagagca tagtggtgca ggagcgcagc ttgagcctgg ctgacaaggt ggccgccatc 12780
aactattcca tgcttagcct gggcaagttt tacgcccgca agatatacca taccccttac 12840
gttcccatag acaaggaggt aaagatcgag gggttctaca tgcgcatggc gctgaaggtg 12900
cttaccttga gcgacgacct gggcgtttat cgcaacgagc gcatccacaa ggccgtgagc 12960
gtgagccggc ggcgcgagct cagcgaccgc gagctgatgc acagcctgca aagggccctg 13020
gctggcacgg gcagcggcga tagagaggcc gagtcctact ttgacgcggg cgctgacctg 13080
cgctgggccc caagccgacg cgccctggag gcagctgggg ccggacctgg gctggcggtg 13140
gcacccgcgc gcgctggcaa cgtcggcggc gtggaggaat atgacgagga cgatgagtac 13200
gagccagagg acggcgagta ctaagcggtg atgtttctga tcagatgatg caagacgcaa 13260
cggacccggc ggtgcgggcg gcgctgcaga gccagccgtc cggccttaac tccacggacg 13320
actggcgcca ggtcatggac cgcatcatgt cgctgactgc gcgcaatcct gacgcgttcc 13380
ggcagcagcc gcaggccaac cggctctccg caattctgga agcggtggtc ccggcgcgcg 13440
caaaccccac gcacgagaag gtgctggcga tcgtaaacgc gctggccgaa aacagggcca 13500
tccggcccga cgaggccggc ctggtctacg acgcgctgct tcagcgcgtg gctcgttaca 13560
acagcggcaa cgtgcagacc aacctggacc ggctggtggg ggatgtgcgc gaggccgtgg 13620
cgcagcgtga gcgcgcgcag cagcagggca acctgggctc catggttgca ctaaacgcct 13680
tcctgagtac acagcccgcc aacgtgccgc ggggacagga ggactacacc aactttgtga 13740
gcgcactgcg gctaatggtg actgagacac cgcaaagtga ggtgtaccag tctgggccag 13800
actatttttt ccagaccagt agacaaggcc tgcagaccgt aaacctgagc caggctttca 13860
aaaacttgca ggggctgtgg ggggtgcggg ctcccacagg cgaccgcgcg accgtgtcta 13920
gcttgctgac gcccaactcg cgcctgttgc tgctgctaat agcgcccttc acggacagtg 13980
gcagcgtgtc ccgggacaca tacctaggtc acttgctgac actgtaccgc gaggccatag 14040
gtcaggcgca tgtggacgag catactttcc aggagattac aagtgtcagc cgcgcgctgg 14100
ggcaggagga cacgggcagc ctggaggcaa ccctaaacta cctgctgacc aaccggcggc 14160
agaagatccc ctcgttgcac agtttaaaca gcgaggagga gcgcattttg cgctacgtgc 14220
agcagagcgt gagccttaac ctgatgcgcg acggggtaac gcccagcgtg gcgctggaca 14280
tgaccgcgcg caacatggaa ccgggcatgt atgcctcaaa ccggccgttt atcaaccgcc 14340
taatggacta cttgcatcgc gcggccgccg tgaaccccga gtatttcacc aatgccatct 14400
tgaacccgca ctggctaccg ccccctggtt tctacaccgg gggattcgag gtgcccgagg 14460
gtaacgatgg attcctctgg gacgacatag acgacagcgt gttttccccg caaccgcaga 14520
ccctgctaga gttgcaacag cgcgagcagg cagaggcggc gctgcgaaag gaaagcttcc 14580
gcaggccaag cagcttgtcc gatctaggcg ctgcggcccc gcggtcagat gctagtagcc 14640
catttccaag cttgataggg tctcttacca gcactcgcac cacccgcccg cgcctgctgg 14700
gcgaggagga gtacctaaac aactcgctgc tgcagccgca gcgcgaaaaa aacctgcctc 14760
cggcatttcc caacaacggg atagagagcc tagtggacaa gatgagtaga tggaagacgt 14820
acgcgcagga gcacagggac gtgccaggcc cgcgcccgcc cacccgtcgt caaaggcacg 14880
accgtcagcg gggtctggtg tgggaggacg atgactcggc agacgacagc agcgtcctgg 14940
atttgggagg gagtggcaac ccgtttgcgc accttcgccc caggctgggg agaatgtttt 15000
aaaaaaaaaa aaaaagcatg atgcaaaata aaaaactcac caaggccatg gcaccgagcg 15060
ttggttttct tgtattcccc ttagtatgcg gcgcgcggcg atgtatgagg aaggtcctcc 15120
tccctcctac gagagtgtgg tgagcgcggc gccagtggcg gcggcgctgg gttctccctt 15180
cgatgctccc ctggacccgc cgtttgtgcc tccgcggtac ctgcggccta ccggggggag 15240
aaacagcatc cgttactctg agttggcacc cctattcgac accacccgtg tgtacctggt 15300
ggacaacaag tcaacggatg tggcatccct gaactaccag aacgaccaca gcaactttct 15360
gaccacggtc attcaaaaca atgactacag cccgggggag gcaagcacac agaccatcaa 15420
tcttgacgac cggtcgcact ggggcggcga cctgaaaacc atcctgcata ccaacatgcc 15480
aaatgtgaac gagttcatgt ttaccaataa gtttaaggcg cgggtgatgg tgtcgcgctt 15540
gcctactaag gacaatcagg tggagctgaa atacgagtgg gtggagttca cgctgcccga 15600
gggcaactac tccgagacca tgaccataga ccttatgaac aacgcgatcg tggagcacta 15660
cttgaaagtg ggcagacaga acggggttct ggaaagcgac atcggggtaa agtttgacac 15720
ccgcaacttc agactggggt ttgaccccgt cactggtctt gtcatgcctg gggtatatac 15780
aaacgaagcc ttccatccag acatcatttt gctgccagga tgcggggtgg acttcaccca 15840
cagccgcctg agcaacttgt tgggcatccg caagcggcaa cccttccagg agggctttag 15900
gatcacctac gatgatctgg agggtggtaa cattcccgca ctgttggatg tggacgccta 15960
ccaggcgagc ttgaaagatg acaccgaaca gggcgggggt ggcgcaggcg gcagcaacag 16020
cagtggcagc ggcgcggaag agaactccaa cgcggcagcc gcggcaatgc agccggtgga 16080
ggacatgaac gatcatgcca ttcgcggcga cacctttgcc acacgggctg aggagaagcg 16140
cgctgaggcc gaagcagcgg ccgaagctgc cgcccccgct gcgcaacccg aggtcgagaa 16200
gcctcagaag aaaccggtga tcaaacccct gacagaggac agcaagaaac gcagttacaa 16260
cctaataagc aatgacagca ccttcaccca gtaccgcagc tggtaccttg catacaacta 16320
cggcgaccct cagaccggaa tccgctcatg gaccctgctt tgcactcctg acgtaacctg 16380
cggctcggag caggtctact ggtcgttgcc agacatgatg caagaccccg tgaccttccg 16440
ctccacgcgc cagatcagca actttccggt ggtgggcgcc gagctgttgc ccgtgcactc 16500
caagagcttc tacaacgacc aggccgtcta ctcccaactc atccgccagt ttacctctct 16560
gacccacgtg ttcaatcgct ttcccgagaa ccagattttg gcgcgcccgc cagcccccac 16620
catcaccacc gtcagtgaaa acgttcctgc tctcacagat cacgggacgc taccgctgcg 16680
caacagcatc ggaggagtcc agcgagtgac cattactgac gccagacgcc gcacctgccc 16740
ctacgtttac aaggccctgg gcatagtctc gccgcgcgtc ctatcgagcc gcactttttg 16800
agcaagcatg tccatcctta tatcgcccag caataacaca ggctggggcc tgcgcttccc 16860
aagcaagatg tttggcgggg ccaagaagcg ctccgaccaa cacccagtgc gcgtgcgcgg 16920
gcactaccgc gcgccctggg gcgcgcacaa acgcggccgc actgggcgca ccaccgtcga 16980
tgacgccatc gacgcggtgg tggaggaggc gcgcaactac acgcccacgc cgccaccagt 17040
gtccacagtg gacgcggcca ttcagaccgt ggtgcgcgga gcccggcgct atgctaaaat 17100
gaagagacgg cggaggcgcg tagcacgtcg ccaccgccgc cgacccggca ctgccgccca 17160
acgcgcggcg gcggccctgc ttaaccgcgc acgtcgcacc ggccgacggg cggccatgcg 17220
ggccgctcga aggctggccg cgggtattgt cactgtgccc cccaggtcca ggcgacgagc 17280
ggccgccgca gcagccgcgg ccattagtgc tatgactcag ggtcgcaggg gcaacgtgta 17340
ttgggtgcgc gactcggtta gcggcctgcg cgtgcccgtg cgcacccgcc ccccgcgcaa 17400
ctagattgca agaaaaaact acttagactc gtactgttgt atgtatccag cggcggcggc 17460
gcgcaacgaa gctatgtcca agcgcaaaat caaagaagag atgctccagg tcatcgcgcc 17520
ggagatctat ggccccccga agaaggaaga gcaggattac aagccccgaa agctaaagcg 17580
ggtcaaaaag aaaaagaaag atgatgatga tgaacttgac gacgaggtgg aactgctgca 17640
cgctaccgcg cccaggcgac gggtacagtg gaaaggtcga cgcgtaaaac gtgttttgcg 17700
acccggcacc accgtagtct ttacgcccgg tgagcgctcc acccgcacct acaagcgcgt 17760
gtatgatgag gtgtacggcg acgaggacct gcttgagcag gccaacgagc gcctcgggga 17820
gtttgcctac ggaaagcggc ataaggacat gctggcgttg ccgctggacg agggcaaccc 17880
aacacctagc ctaaagcccg taacactgca gcaggtgctg cccgcgcttg caccgtccga 17940
agaaaagcgc ggcctaaagc gcgagtctgg tgacttggca cccaccgtgc agctgatggt 18000
acccaagcgc cagcgactgg aagatgtctt ggaaaaaatg accgtggaac ctgggctgga 18060
gcccgaggtc cgcgtgcggc caatcaagca ggtggcgccg ggactgggcg tgcagaccgt 18120
ggacgttcag atacccacta ccagtagcac cagtattgcc accgccacag agggcatgga 18180
gacacaaacg tccccggttg cctcagcggt ggcggatgcc gcggtgcagg cggtcgctgc 18240
ggccgcgtcc aagacctcta cggaggtgca aacggacccg tggatgtttc gcgtttcagc 18300
cccccggcgc ccgcgccgtt cgaggaagta cggcgccgcc agcgcgctac tgcccgaata 18360
tgccctacat ccttccattg cgcctacccc cggctatcgt ggctacacct accgccccag 18420
aagacgagca actacccgac gccgaaccac cactggaacc cgccgccgcc gtcgccgtcg 18480
ccagcccgtg ctggccccga tttccgtgcg cagggtggct cgcgaaggag gcaggaccct 18540
ggtgctgcca acagcgcgct accaccccag catcgtttaa aagccggtct ttgtggttct 18600
tgcagatatg gccctcacct gccgcctccg tttcccggtg ccgggattcc gaggaagaat 18660
gcaccgtagg aggggcatgg ccggccacgg cctgacgggc ggcatgcgtc gtgcgcacca 18720
ccggcggcgg cgcgcgtcgc accgtcgcat gcgcggcggt atcctgcccc tccttattcc 18780
actgatcgcc gcggcgattg gcgccgtgcc cggaattgca tccgtggcct tgcaggcgca 18840
gagacactga ttaaaaacaa gttgcatgtg gaaaaatcaa aataaaaagt ctggactctc 18900
acgctcgctt ggtcctgtaa ctattttgta gaatggaaga catcaacttt gcgtctctgg 18960
ccccgcgaca cggctcgcgc ccgttcatgg gaaactggca agatatcggc accagcaata 19020
tgagcggtgg cgccttcagc tggggctcgc tgtggagcgg cattaaaaat ttcggttcca 19080
ccgttaagaa ctatggcagc aaggcctgga acagcagcac aggccagatg ctgagggata 19140
agttgaaaga gcaaaatttc caacaaaagg tggtagatgg cctggcctct ggcattagcg 19200
gggtggtgga cctggccaac caggcagtgc aaaataagat taacagtaag cttgatcccc 19260
gccctcccgt agaggagcct ccaccggccg tggagacagt gtctccagag gggcgtggcg 19320
aaaagcgtcc gcgccccgac agggaagaaa ctctggtgac gcaaatagac gagcctccct 19380
cgtacgagga ggcactaaag caaggcctgc ccaccacccg tcccatcgcg cccatggcta 19440
ccggagtgct gggccagcac acacccgtaa cgctggacct gcctcccccc gccgacaccc 19500
agcagaaacc tgtgctgcca ggcccgaccg ccgttgttgt aacccgtcct agccgcgcgt 19560
ccctgcgccg cgccgccagc ggtccgcgat cgttgcggcc cgtagccagt ggcaactggc 19620
aaagcacact gaacagcatc gtgggtctgg gggtgcaatc cctgaagcgc cgacgatgct 19680
tctgaatagc taacgtgtcg tatgtgtgtc atgtatgcgt ccatgtcgcc gccagaggag 19740
ctgctgagcc gccgcgcgcc cgctttccaa gatggctacc ccttcgatga tgccgcagtg 19800
gtcttacatg cacatctcgg gccaggacgc ctcggagtac ctgagccccg ggctggtgca 19860
gtttgcccgc gccaccgaga cgtacttcag cctgaataac aagtttagaa accccacggt 19920
ggcgcctacg cacgacgtga ccacagaccg gtcccagcgt ttgacgctgc ggttcatccc 19980
tgtggaccgt gaggatactg cgtactcgta caaggcgcgg ttcaccctag ctgtgggtga 20040
taaccgtgtg ctggacatgg cttccacgta ctttgacatc cgcggcgtgc tggacagggg 20100
ccctactttt aagccctact ctggcactgc ctacaacgcc ctggctccca agggtgcccc 20160
aaatccttgc gaatgggatg aagctgctac tgctcttgaa ataaacctag aagaagagga 20220
cgatgacaac gaagacgaag tagacgagca agctgagcag caaaaaactc acgtatttgg 20280
gcaggcgcct tattctggta taaatattac aaaggagggt attcaaatag gtgtcgaagg 20340
tcaaacacct aaatatgccg ataaaacatt tcaacctgaa cctcaaatag gagaatctca 20400
gtggtacgaa actgaaatta atcatgcagc tgggagagtc cttaaaaaga ctaccccaat 20460
gaaaccatgt tacggttcat atgcaaaacc cacaaatgaa aatggagggc aaggcattct 20520
tgtaaagcaa caaaatggaa agctagaaag tcaagtggaa atgcaatttt tctcaactac 20580
tgaggcgacc gcaggcaatg gtgataactt gactcctaaa gtggtattgt acagtgaaga 20640
tgtagatata gaaaccccag acactcatat ttcttacatg cccactatta aggaaggtaa 20700
ctcacgagaa ctaatgggcc aacaatctat gcccaacagg cctaattaca ttgcttttag 20760
ggacaatttt attggtctaa tgtattacaa cagcacgggt aatatgggtg ttctggcggg 20820
ccaagcatcg cagttgaatg ctgttgtaga tttgcaagac agaaacacag agctttcata 20880
ccagcttttg cttgattcca ttggtgatag aaccaggtac ttttctatgt ggaatcaggc 20940
tgttgacagc tatgatccag atgttagaat tattgaaaat catggaactg aagatgaact 21000
tccaaattac tgctttccac tgggaggtgt gattaataca gagactctta ccaaggtaaa 21060
acctaaaaca ggtcaggaaa atggatggga aaaagatgct acagaatttt cagataaaaa 21120
tcaaataaga gttggaaata attttgccat ggaaatcaat ctaaatgcca acctgtggag 21180
aaatttcctg tactccaaca tagcgctgta tttgcccgac aagctaaagt acagtccttc 21240
caacgtaaaa atttctgata acccaaacac ctacgactac atgaacaagc gagtggtggc 21300
tcccgggtta gtggactgct acattaacct tggagcacgc tggtcccttg actatatgga 21360
caacgtcaac ccatttaacc accaccgcaa tgctggcctg cgctaccgct caatgttgct 21420
gggcaatggt cgctatgtgc ccttccacat ccaggtgcct cagaagttct ttgccattaa 21480
aaacctcctt ctcctgccgg gctcatacac ctacgagtgg aacttcagga aggatgttaa 21540
catggttctg cagagctccc taggaaatga cctaagggtt gacggagcca gcattaagtt 21600
tgatagcatt tgcctttacg ccaccttctt ccccatggcc cacaacaccg cctccacgct 21660
tgaggccatg cttagaaacg acaccaacga ccagtccttt aacgactatc tctccgccgc 21720
caacatgctc taccctatac ccgccaacgc taccaacgtg cccatatcca tcccctcccg 21780
caactgggcg gctttccgcg gctgggcctt cacgcgcctt aagactaagg aaaccccatc 21840
actgggctcg ggctacgacc cttattacac ctactctggc tctataccct acctagatgg 21900
aaccttttac ctcaaccaca cctttaagaa ggtggccatt acctttgact cttctgtcag 21960
ctggcctggc aatgaccgcc tgcttacccc caacgagttt gaaattaagc gctcagttga 22020
cggggagggt tacaacgttg cccagtgtaa catgaccaaa gactggttcc tggtacaaat 22080
gctagctaac tacaacattg gctaccaggg cttctatatc ccagagagct acaaggaccg 22140
catgtactcc ttctttagaa acttccagcc catgagccgt caggtggtgg atgatactaa 22200
atacaaggac taccaacagg tgggcatcct acaccaacac aacaactctg gatttgttgg 22260
ctaccttgcc cccaccatgc gcgaaggaca ggcctaccct gctaacttcc cctatccgct 22320
tataggcaag accgcagttg acagcattac ccagaaaaag tttctttgcg atcgcaccct 22380
ttggcgcatc ccattctcca gtaactttat gtccatgggc gcactcacag acctgggcca 22440
aaaccttctc tacgccaact ccgcccacgc gctagacatg acttttgagg tggatcccat 22500
ggacgagccc acccttcttt atgttttgtt tgaagtcttt gacgtggtcc gtgtgcaccg 22560
gccgcaccgc ggcgtcatcg aaaccgtgta cctgcgcacg cccttctcgg ccggcaacgc 22620
cacaacataa agaagcaagc aacatcaaca acagctgccg ccatgggctc cagtgagcag 22680
gaactgaaag ccattgtcaa agatcttggt tgtgggccat attttttggg cacctatgac 22740
aagcgctttc caggctttgt ttctccacac aagctcgcct gcgccatagt caatacggcc 22800
ggtcgcgaga ctgggggcgt acactggatg gcctttgcct ggaacccgca ctcaaaaaca 22860
tgctacctct ttgagccctt tggcttttct gaccagcgac tcaagcaggt ttaccagttt 22920
gagtacgagt cactcctgcg ccgtagcgcc attgcttctt cccccgaccg ctgtataacg 22980
ctggaaaagt ccacccaaag cgtacagggg cccaactcgg ccgcctgtgg actattctgc 23040
tgcatgtttc tccacgcctt tgccaactgg ccccaaactc ccatggatca caaccccacc 23100
atgaacctta ttaccggggt acccaactcc atgctcaaca gtccccaggt acagcccacc 23160
ctgcgtcgca accaggaaca gctctacagc ttcctggagc gccactcgcc ctacttccgc 23220
agccacagtg cgcagattag gagcgccact tctttttgtc acttgaaaaa catgtaaaaa 23280
taatgtacta gagacacttt caataaaggc aaatgctttt atttgtacac tctcgggtga 23340
ttatttaccc ccacccttgc cgtctgcgcc gtttaaaaat caaaggggtt ctgccgcgca 23400
tcgctatgcg ccactggcag ggacacgttg cgatactggt gtttagtgct ccacttaaac 23460
tcaggcacaa ccatccgcgg cagctcggtg aagttttcac tccacaggct gcgcaccatc 23520
accaacgcgt ttagcaggtc gggcgccgat atcttgaagt cgcagttggg gcctccgccc 23580
tgcgcgcgcg agttgcgata cacagggttg cagcactgga acactatcag cgccgggtgg 23640
tgcacgctgg ccagcacgct cttgtcggag atcagatccg cgtccaggtc ctccgcgttg 23700
ctcagggcga acggagtcaa ctttggtagc tgccttccca aaaagggcgc gtgcccaggc 23760
tttgagttgc actcgcaccg tagtggcatc aaaaggtgac cgtgcccggt ctgggcgtta 23820
ggatacagcg cctgcataaa agccttgatc tgcttaaaag ccacctgagc ctttgcgcct 23880
tcagagaaga acatgccgca agacttgccg gaaaactgat tggccggaca ggccgcgtcg 23940
tgcacgcagc accttgcgtc ggtgttggag atctgcacca catttcggcc ccaccggttc 24000
ttcacgatct tggccttgct agactgctcc ttcagcgcgc gctgcccgtt ttcgctcgtc 24060
acatccattt caatcacgtg ctccttattt atcataatgc ttccgtgtag acacttaagc 24120
tcgccttcga tctcagcgca gcggtgcagc cacaacgcgc agcccgtggg ctcgtgatgc 24180
ttgtaggtca cctctgcaaa cgactgcagg tacgcctgca ggaatcgccc catcatcgtc 24240
acaaaggtct tgttgctggt gaaggtcagc tgcaacccgc ggtgctcctc gttcagccag 24300
gtcttgcata cggccgccag agcttccact tggtcaggca gtagtttgaa gttcgccttt 24360
agatcgttat ccacgtggta cttgtccatc agcgcgcgcg cagcctccat gcccttctcc 24420
cacgcagaca cgatcggcac actcagcggg ttcatcaccg taatttcact ttccgcttcg 24480
ctgggctctt cctcttcctc ttgcgtccgc ataccacgcg ccactgggtc gtcttcattc 24540
agccgccgca ctgtgcgctt acctcctttg ccatgcttga ttagcaccgg tgggttgctg 24600
aaacccacca tttgtagcgc cacatcttct ctttcttcct cgctgtccac gattacctct 24660
ggtgatggcg ggcgctcggg cttgggagaa gggcgcttct ttttcttctt gggcgcaatg 24720
gccaaatccg ccgccgaggt cgatggccgc gggctgggtg tgcgcggcac cagcgcgtct 24780
tgtgatgagt cttcctcgtc ctcggactcg atacgccgcc tcatccgctt ttttgggggc 24840
gcccggggag gcggcggcga cggggacggg gacgacacgt cctccatggt tgggggacgt 24900
cgcgccgcac cgcgtccgcg ctcgggggtg gtttcgcgct gctcctcttc ccgactggcc 24960
atttccttct cctataggca gaaaaagatc atggagtcag tcgagaagaa ggacagccta 25020
accgccccct ctgagttcgc caccaccgcc tccaccgatg ccgccaacgc gcctaccacc 25080
ttccccgtcg aggcaccccc gcttgaggag gaggaagtga ttatcgagca ggacccaggt 25140
tttgtaagcg aagacgacga ggaccgctca gtaccaacag aggataaaaa gcaagaccag 25200
gacaacgcag aggcaaacga ggaacaagtc gggcgggggg acgaaaggca tggcgactac 25260
ctagatgtgg gagacgacgt gctgttgaag catctgcagc gccagtgcgc cattatctgc 25320
gacgcgttgc aagagcgcag cgatgtgccc ctcgccatag cggatgtcag ccttgcctac 25380
gaacgccacc tattctcacc gcgcgtaccc cccaaacgcc aagaaaacgg cacatgcgag 25440
cccaacccgc gcctcaactt ctaccccgta tttgccgtgc cagaggtgct tgccacctat 25500
cacatctttt tccaaaactg caagataccc ctatcctgcc gtgccaaccg cagccgagcg 25560
gacaagcagc tggccttgcg gcagggcgct gtcatacctg atatcgcctc gctcaacgaa 25620
gtgccaaaaa tctttgaggg tcttggacgc gacgagaagc gcgcggcaaa cgctctgcaa 25680
caggaaaaca gcgaaaatga aagtcactct ggagtgttgg tggaactcga gggtgacaac 25740
gcgcgcctag ccgtactaaa acgcagcatc gaggtcaccc actttgccta cccggcactt 25800
aacctacccc ccaaggtcat gagcacagtc atgagtgagc tgatcgtgcg ccgtgcgcag 25860
cccctggaga gggatgcaaa tttgcaagaa caaacagagg agggcctacc cgcagttggc 25920
gacgagcagc tagcgcgctg gcttcaaacg cgcgagcctg ccgacttgga ggagcgacgc 25980
aaactaatga tggccgcagt gctcgttacc gtggagcttg agtgcatgca gcggttcttt 26040
gctgacccgg agatgcagcg caagctagag gaaacattgc actacacctt tcgacagggc 26100
tacgtacgcc aggcctgcaa gatctccaac gtggagctct gcaacctggt ctcctacctt 26160
ggaattttgc acgaaaaccg ccttgggcaa aacgtgcttc attccacgct caagggcgag 26220
gcgcgccgcg actacgtccg cgactgcgtt tacttatttc tatgctacac ctggcagacg 26280
gccatgggcg tttggcagca gtgcttggag gagtgcaacc tcaaggagct gcagaaactg 26340
ctaaagcaaa acttgaagga cctatggacg gccttcaacg agcgctccgt ggccgcgcac 26400
ctggcggaca tcattttccc cgaacgcctg cttaaaaccc tgcaacaggg tctgccagac 26460
ttcaccagtc aaagcatgtt gcagaacttt aggaacttta tcctagagcg ctcaggaatc 26520
ttgcccgcca cctgctgtgc acttcctagc gactttgtgc ccattaagta ccgcgaatgc 26580
cctccgccgc tttggggcca ctgctacctt ctgcagctag ccaactacct tgcctaccac 26640
tctgacataa tggaagacgt gagcggtgac ggtctactgg agtgtcactg tcgctgcaac 26700
ctatgcaccc cgcaccgctc cctggtttgc aattcgcagc tgcttaacga aagtcaaatt 26760
atcggtacct ttgagctgca gggtccctcg cctgacgaaa agtccgcggc tccggggttg 26820
aaactcactc cggggctgtg gacgtcggct taccttcgca aatttgtacc tgaggactac 26880
cacgcccacg agattaggtt ctacgaagac caatcccgcc cgccaaatgc ggagcttacc 26940
gcctgcgtca ttacccaggg ccacattctt ggccaattgc aagccatcaa caaagcccgc 27000
caagagtttc tgctacgaaa gggacggggg gtttacttgg acccccagtc cggcgaggag 27060
ctcaacccaa tccccccgcc gccgcagccc tatcagcagc agccgcgggc ccttgcttcc 27120
caggatggca cccaaaaaga agctgcagct gccgccgcca cccacggacg aggaggaata 27180
ctgggacagt caggcagagg aggttttgga cgaggaggag gaggacatga tggaagactg 27240
ggagagccta gacgaggaag cttccgaggt cgaagaggtg tcagacgaaa caccgtcacc 27300
ctcggtcgca ttcccctcgc cggcgcccca gaaatcggca accggttcca gcatggctac 27360
aacctccgct cctcaggcgc cgccggcact gcccgttcgc cgacccaacc gtagatggga 27420
caccactgga accagggccg gtaagtccaa gcagccgccg ccgttagccc aagagcaaca 27480
acagcgccaa ggctaccgct catggcgcgg gcacaagaac gccatagttg cttgcttgca 27540
agactgtggg ggcaacatct ccttcgcccg ccgctttctt ctctaccatc acggcgtggc 27600
cttcccccgt aacatcctgc attactaccg tcatctctac agcccatact gcaccggcgg 27660
cagcggcagc ggcagcaaca gcagcggcca cacagaagca aaggcgaccg gatagcaaga 27720
ctctgacaaa gcccaagaaa tccacagcgg cggcagcagc aggaggagga gcgctgcgtc 27780
tggcgcccaa cgaacccgta tcgacccgcg agcttagaaa caggattttt cccactctgt 27840
atgctatatt tcaacagagc aggggccaag aacaagagct gaaaataaaa aacaggtctc 27900
tgcgatccct cacccgcagc tgcctgtatc acaaaagcga agatcagctt cggcgcacgc 27960
tggaagacgc ggaggctctc ttcagtaaat actgcgcgct gactcttaag gactagtttc 28020
gcgccctttc tcaaatttaa gcgcgaaaac tacgtcatct ccagcggcca cacccggcgc 28080
cagcacctgt cgtcagcgcc atttcaactt tgtatacaaa agttgtgatg agcaaggaaa 28140
ttcccacgcc ctacatgtgg agttaccagc cacaaatggg acttgcggct ggagctgccc 28200
aagactactc aacccgaata aactacatga gcgcgggacc ccacatgata tcccgggtca 28260
acggaatacg cgcccaccga aaccgaattc tcctggaaca ggcggctatt accaccacac 28320
ctcgtaataa ccttaatccc cgtagttggc ccgctgccct ggtgtaccag gaaagtcccg 28380
ctcccaccac tgtggtactt cccagagacg cccaggccga agttcagatg actaactcag 28440
gggcgcagct tgcgggcggc tttcgtcaca gggtgcggtc gcccgggcag ggtataactc 28500
acctgacaat cagagggcga ggtattcagc tcaacgacga gtcggtgagc tcctcgcttg 28560
gtctccgtcc ggacgggaca tttcagatcg gcggcgccgg ccgctcttca ttcacgcctc 28620
gtcaggcaat cctaactctg cagacctcgt cctctgagcc gcgctctgga ggcattggaa 28680
ctctgcaatt tattgaggag tttgtgccat cggtctactt taaccccttc tcgggacctc 28740
ccggccacta tccggatcaa tttattccta actttgacgc ggtaaaggac tcggcggacg 28800
gctacgactg aatgttaagt ggagaggcag agcaactgcg cctgaaacac ctggtccact 28860
gtcgccgcca caagtgcttt gcccgcgact ccggtgagtt ttgctacttt gaattgcccg 28920
aggatcatat cgagggcccg gcgcacggcg tccggcttac cgcccaggga gagcttgccc 28980
gtagcctgat tcgggagttt acccagcgcc ccctgctagt tgagcgggac aggggaccct 29040
gtgttctcac tgtgatttgc aactgtccta accctggatt acatcaagat ctttgttgcc 29100
atctctgtgc tgagtataat aaatacagaa attaaaatat actggggctc ctatcgccat 29160
cctgtaaacg ccaccgtctt cacccgccca agcaaaccaa ggcgaacctt acctggtact 29220
tttaacatct ctccctctgt gatttacaac agtttcaacc cagacggagt gagtctacga 29280
gagaacctct ccgagctcag ctactccatc agaaaaaaca ccaccctcct tacctgccgg 29340
gaacgtacga gtgcgtcacc ggccgctgca ccacacctac cgcctgaccg taaaccagac 29400
tttttccgga cagacctcaa taactctgtt taccagaaca ggaggtgagc ttagaaaacc 29460
cttagggtat taggccaaag gcgcagctac tgtggggttt atgaacaatt caagcaactc 29520
tacgggctat tctaattcag gtttctctag aatcggggtt ggggttattc tctgtcttgt 29580
gattctcttt attcttatac taacgcttct ctgcctaagg ctcgccgcct gctgtgtgca 29640
catttgcatt tattgtcagc tttttaaacg ctggggtcgc cacccaagat gattaggtac 29700
ataatcctag gtttactcac ccttgcgtca gcccacggta ccacccaaaa ggtggatttt 29760
aaggagccag cctgtaatgt tacattcgca gctgaagcta atgagtgcac cactcttata 29820
aaatgcacca cagaacatga aaagctgctt attcgccaca aaaacaaaat tggcaagtat 29880
gctgtttatg ctatttggca gccaggtgac actacagagt ataatgttac agttttccag 29940
ggtaaaagtc ataaaacttt tatgtatact tttccatttt atgaaatgtg cgacattacc 30000
atgtacatga gcaaacagta taagttgtgg cccccacaaa attgtgtgga aaacactggc 30060
actttctgct gcactgctat gctaattaca gtgctcgctt tggtctgtac cctactctat 30120
attaaataca aaagcagacg cagctttatt gaggaaaaga aaatgcctta atttactaag 30180
ttacaaagct aatgtcacca ctaactgctt tactcgctgc ttgcaaaaca aattcaaaaa 30240
gttagcatta taattagaat aggatttaaa ccccccggtc atttcctgct caataccatt 30300
cccctgaaca attgactcta tgtgggatat gctccagcgc tacaaccttg aagtcaggct 30360
tcctggatgt cagcatctga ctttggccag cacctgtccc gcggatttgt tccagtccaa 30420
ctacagcgac ccaccctaac agagatgacc aacacaacca acgcggccgc cgctaccgga 30480
cttacatcta ccacaaatac accccaagtt tctgcctttg tcaataactg ggataacttg 30540
ggcatgtggt ggttctccat agcgcttatg tttgtatgcc ttattattat gtggctcatc 30600
tgctgcctaa agcgcaaacg cgcccgacca cccatctata gtcccatcat tgtgctacac 30660
ccaaacaatg atggaatcca tagattggac ggactgaaac acatgttctt ttctcttaca 30720
gtatgattaa atgagacatg attcctcgag tttttatatt actgaccctt gttgcgcttt 30780
tttgtgcgtg ctccacattg gctgcggttt ctcacatcga agtagactgc attccagcct 30840
tcacagtcta tttgctttac ggatttgtca ccctcacgct catctgcagc ctcatcactg 30900
tggtcatcgc ctttatccag tgcattgact gggtctgtgt gcgctttgca tatctcagac 30960
accatcccca gtacagggac aggactatag ctgagcttct tagaattctt taattatgaa 31020
atttactgtg acttttctgc tgattatttg caccctatct gcgttttgtt ccccgacctc 31080
caagcctcaa agacatatat catgcagatt cactcgtata tggaatattc caagttgcta 31140
caatgaaaaa agcgatcttt ccgaagcctg gttatatgca atcatctctg ttatggtgtt 31200
ctgcagtacc atcttagccc tagctatata tccctacctt gacattggct ggaacgcaat 31260
agatgccatg aaccacccaa ctttccccgc gcccgctatg cttccactgc aacaagttgt 31320
tgccggcggc tttgtcccag ccaatcagcc tcgcccacct tctcccaccc ccactgaaat 31380
cagctacttt aatctaacag gaggagatga ctgacaccct agatctagaa atggacggaa 31440
ttattacaga gcagcgcctg ctagaaagac gcagggcagc ggccgagcaa cagcgcatga 31500
atcaagagct ccaagacatg gttaacttgc accagtgcaa aaggggtatc ttttgtctgg 31560
taaagcaggc caaagtcacc tacgacagta ataccaccgg acaccgcctt agctacaagt 31620
tgccaaccaa gcgtcagaaa ttggtggtca tggtgggaga aaagcccatt accataactc 31680
agcactcggt agaaaccgaa ggctgcattc actcaccttg tcaaggacct gaggatctct 31740
gcacccttat taagaccctg tgcggtctca aagatcttat tccctttaac taataaaaaa 31800
aaataataaa gcatcactta cttaaaatca gttagcaaat ttctgtccag tttattcagc 31860
agcacctcct tgccctcctc ccagctctgg tattgcagct tcctcctggc tgcaaacttt 31920
ctccacaatc taaatggaat gtcagtttcc tcctgttcct gtccatccgc acccactatc 31980
ttcatgttgt tgcagatgaa gcgcgcaaga ccgtctgaag ataccttcaa ccccgtgtat 32040
ccatatgaca cggaaaccgg tcctccaact gtgccttttc ttactcctcc ctttgtatcc 32100
cccaatgggt ttcaagagag tccccctggg gtactctctt tgcgcctatc cgaacctcta 32160
gttacctcca atggcatgct tgcgctcaaa atgggcaacg gcctctctct ggacgaggcc 32220
ggcaacctta cctcccaaaa tgtaaccact gtgagcccac ctctcaaaaa aaccaagtca 32280
aacataaacc tggaaatatc tgcacccctc acagttacct cagaagccct aactgtggct 32340
gccgccgcac ctctaatggt cgcgggcaac acactcacca tgcaatcaca ggccccgcta 32400
accgtgcacg actccaaact tagcattgcc acccaaggac ccctcacagt gtcagaagga 32460
aagctagccc tgcaaacatc aggccccctc accaccaccg atagcagtac ccttactatc 32520
actgcctcac cccctctaac tactgccact ggtagcttgg gcattgactt gaaagagccc 32580
atttatacac aaaatggaaa actaggacta aagtacgggg ctcctttgca tgtaacagac 32640
gacctaaaca ctttgaccgt agcaactggt ccaggtgtga ctattaataa tacttccttg 32700
caaactaaag ttactggagc cttgggtttt gattcacaag gcaatatgca acttaatgta 32760
gcaggaggac taaggattga ttctcaaaac agacgcctta tacttgatgt tagttatccg 32820
tttgatgctc aaaaccaact aaatctaaga ctaggacagg gccctctttt tataaactca 32880
gcccacaact tggatattaa ctacaacaaa ggcctttact tgtttacagc ttcaaacaat 32940
tccaaaaagc ttgaggttaa cctaagcact gccaaggggt tgatgtttga cgctacagcc 33000
atagccatta atgcaggaga tgggcttgaa tttggttcac ctaatgcacc aaacacaaat 33060
cccctcaaaa caaaaattgg ccatggccta gaatttgatt caaacaaggc tatggttcct 33120
aaactaggaa ctggccttag ttttgacagc acaggtgcca ttacagtagg aaacaaaaat 33180
aatgataagc taactttgtg gaccacacca gctccatctc ctaactgtag actaaatgca 33240
gagaaagatg ctaaactcac tttggtctta acaaaatgtg gcagtcaaat acttgctaca 33300
gtttcagttt tggctgttaa aggcagtttg gctccaatat ctggaacagt tcaaagtgct 33360
catcttatta taagatttga cgaaaatgga gtgctactaa acaattcctt cctggaccca 33420
gaatattgga actttagaaa tggagatctt actgaaggca cagcctatac aaacgctgtt 33480
ggatttatgc ctaacctatc agcttatcca aaatctcacg gtaaaactgc caaaagtaac 33540
attgtcagtc aagtttactt aaacggagac aaaactaaac ctgtaacact aaccattaca 33600
ctaaacggta cacaggaaac aggagacaca actccaagtg catactctat gtcattttca 33660
tgggactggt ctggccacaa ctacattaat gaaatatttg ccacatcctc ttacactttt 33720
tcatacattg cccaagaata aagaatcgtt tgtgttatgt ttcaacgtgt ttatttttca 33780
attgcagaaa atttcaagtc atttttcatt cagtagtata gccccaccac cacatagctt 33840
atacagatca ccgtacctca actttgtata ataaagttgt aatcaaactc acagaaccct 33900
agtattcaac ctgccacctc cctcccaaca cacagagtac acagtccttt ctccccggct 33960
ggccttaaaa agcatcatat catgggtaac agacatattc ttaggtgtta tattccacac 34020
ggtttcctgt cgagccaaac gctcatcagt gatattaata aactccccgg gcagctcact 34080
taagttcatg tcgctgtcca gctgctgagc cacaggctgc tgtccaactt gcggttgctt 34140
aacgggcggc gaaggagaag tccacgccta catgggggta gagtcataat cgtgcatcag 34200
gatagggcgg tggtgctgca gcagcgcgcg aataaactgc tgccgccgcc gctccgtcct 34260
gcaggaatac aacatggcag tggtctcctc agcgatgatt cgcaccgccc gcagcataag 34320
gcgccttgtc ctccgggcac agcagcgcac cctgatctca cttaaatcag cacagtaact 34380
gcagcacagc accacaatat tgttcaaaat cccacagtgc aaggcgctgt atccaaagct 34440
catggcgggg accacagaac ccacgtggcc atcataccac aagcgcaggt agattaagtg 34500
gcgacccctc ataaacacgc tggacataaa cattacctct tttggcatgt tgtaattcac 34560
cacctcccgg taccatataa acctctgatt aaacatggcg ccatccacca ccatcctaaa 34620
ccagctggcc aaaacctgcc cgccggctat acactgcagg gaaccgggac tggaacaatg 34680
acagtggaga gcccaggact cgtaaccatg gatcatcatg ctcgtcatga tatcaatgtt 34740
ggcacaacac aggcacacgt gcatacactt cctcaggatt acaagctcct cccgcgttag 34800
aaccatatcc cagggaacaa cccattcctg aatcagcgta aatcccacac tgcagggaag 34860
acctcgcacg taactcacgt tgtgcattgt caaagtgtta cattcgggca gcagcggatg 34920
atcctccagt atggtagcgc gggtttctgt ctcaaaagga ggtagacgat ccctactgta 34980
cggagtgcgc cgagacaacc gagatcgtgt tggtcgtagt gtcatgccaa atggaacgcc 35040
ggacgtagtc atatttcctg aagcaaaacc aggtgcgggc gtgacaaaca gatctgcgtc 35100
tccggtctcg ccgcttagat cgctctgtgt agtagttgta gtatatccac tctctcaaag 35160
catccaggcg ccccctggct tcgggttcta tgtaaactcc ttcatgcgcc gctgccctga 35220
taacatccac caccgcagaa taagccacac ccagccaacc tacacattcg ttctgcgagt 35280
cacacacggg aggagcggga agagctggaa gaaccatgtt ttttttttta ttccaaaaga 35340
ttatccaaaa cctcaaaatg aagatctatt aagtgaacgc gctcccctcc ggtggcgtgg 35400
tcaaactcta cagccaaaga acagataatg gcatttgtaa gatgttgcac aatggcttcc 35460
aaaaggcaaa cggccctcac gtccaagtgg acgtaaaggc taaacccttc agggtgaatc 35520
tcctctataa acattccagc accttcaacc atgcccaaat aattctcatc tcgccacctt 35580
ctcaatatat ctctaagcaa atcccgaata ttaagtccgg ccattgtaaa aatctgctcc 35640
agagcgccct ccaccttcag cctcaagcag cgaatcatga ttgcaaaaat tcaggttcct 35700
cacagacctg tataagattc aaaagcggaa cattaacaaa aataccgcga tcccgtaggt 35760
cccttcgcag ggccagctga acataatcgt gcaggtctgc acggaccagc gcggccactt 35820
ccccgccagg aaccatgaca aaagaaccca cactgattat gacacgcata ctcggagcta 35880
tgctaaccag cgtagccccg atgtaagctt gttgcatggg cggcgatata aaatgcaagg 35940
tgctgctcaa aaaatcaggc aaagcctcgc gcaaaaaaga aagcacatcg tagtcatgct 36000
catgcagata aaggcaggta agctccggaa ccaccacaga aaaagacacc atttttctct 36060
caaacatgtc tgcgggtttc tgcataaaca caaaataaaa taacaaaaaa acatttaaac 36120
attagaagcc tgtcttacaa caggaaaaac aacccttata agcataagac ggactacggc 36180
catgccggcg tgaccgtaaa aaaactggtc accgtgatta aaaagcacca ccgacagctc 36240
ctcggtcatg tccggagtca taatgtaaga ctcggtaaac acatcaggtt gattcacatc 36300
ggtcagtgct aaaaagcgac cgaaatagcc cgggggaata catacccgca ggcgtagaga 36360
caacattaca gcccccatag gaggtataac aaaattaata ggagagaaaa acacataaac 36420
acctgaaaaa ccctcctgcc taggcaaaat agcaccctcc cgctccagaa caacatacag 36480
cgcttccaca gcggcagcca taacagtcag ccttaccagt aaaaaagaaa acctattaaa 36540
aaaacaccac tcgacacggc accagctcaa tcagtcacag tgtaaaaaag ggccaagtgc 36600
agagcgagta tatataggac taaaaaatga cgtaacggtt aaagtccaca aaaaacaccc 36660
agaaaaccgc acgcgaacct acgcccagaa acgaaagcca aaaaacccac aacttcctca 36720
aatcgtcact tccgttttcc cacgttacgt cacttcccat tttaagaaaa ctacaattcc 36780
caacacatac aagttactcc gccctaaaac ctacgtcacc cgccccgttc ccacgccccg 36840
cgccacgtca caaactccac cccctcatta tcatattggc ttcaatccaa aataaggtat 36900
attattgatg atg 36913
<210> 2
<211> 36943
<212> DNA
<213> 人工序列
<220>
<223> 合成腺病毒基因组 (AdSyn-CO176)
<400> 2
catcatcaat aatatacctt attttggatt gaagccaata tgataatgag ggggtggagt 60
ttgtgacgtg gcgcggggcg tgggaacggg gcgggtgacg tagtagtgtg gcggaagtgt 120
gatgttgcaa gtgtggcgga acacatgtaa gcgacggatg tggcaaaagt gacgtttttg 180
gtgtgcgccg gtgtacacag gaagtgacaa ttttcgcgcg gttttaggcg gatgttgtag 240
taaatttggg cgtaaccgag taagatttgg ccattttcgc gggaaaactg aataagagga 300
agtgaaatct gaataatttt gtgttactca tagcgcgtaa tatttgtcta gggccgcggg 360
gactttgacc gtttacgtgg agactcgccc aggtgttttt ctcaggtgtt ttccgcgttc 420
cgggtcaaag ttggcgtttt attattaaac cgtattaccg ccatgcattt aatggagtgc 480
ctcgtgaggc tccggtgccc gtcagtgggc agagcgcaca tcgcccacag tccccgagaa 540
gttgggggga ggggtcggca attgaaccgg tgcctagaga aggtggcgcg gggtaaactg 600
ggaaagtgat gtcgtgtact ggctccgcct ttttcccgag ggtgggggag aaccgtatat 660
aagtgcagta gtcgccgtga acgttctttt tcgcaacggg tttgccgcca gaacacaggt 720
aagtgccgtg tgtggttccc gcgggcctgg cctctttacg ggttatggcc cttgcgtgcc 780
ttgaattact tccacctggc tgcagtacgt gattcttgat cccgagcttc gggttggaag 840
tgggtgggag agttcgaggc cttgcgctta aggagcccct tcgcctcgtg cttgagttga 900
ggcctggcct gggcgctggg gccgccgcgt gcgaatctgg tggcaccttc gcgcctgtct 960
cgctgctttc gataagtctc tagccattta aaatttttga tgacctgctg cgacgctttt 1020
tttctggcaa gatagtcttg taaatgcggg ccaagatctg cacactggta tttcggtttt 1080
tggggccgcg ggcggcgacg gggcccgtgc gtcccagcgc acatgttcgg cgaggcgggg 1140
cctgcgagcg cggccaccga gaatcggacg ggggtagtct caagctggcc ggcctgctct 1200
ggtgcctggc ctcgcgccgc cgtgtatcgc cccgccctgg gcggcaaggc tggcccggtc 1260
ggcaccagtt gcgtgagcgg aaagatggcc gcttcccggc cctgctgcag ggagctcaaa 1320
atggaggacg cggcgctcgg gagagcgggc gggtgagtca cccacacaaa ggaaaagggc 1380
ctttccgtcc tcagccgtcg cttcatgtga ctccacggag taccgggcgc cgtccaggca 1440
cctcgattag ttctcgagct tttggagtac gtcgtcttta ggttgggggg aggggtttta 1500
tgcgatggag tttccccaca ctgagtgggt ggagactgaa gttaggccag cttggcactt 1560
gatgtaattc tccttggaat ttgccctttt tgagtttgga tcttggttca ttctcaagcc 1620
tcagacagtg gttcaaagtt tttttcttcc atttcaggtg tcgtgacgct agcgctaccg 1680
gactcagatc tcgagctcaa gcttcgaatt ctgcagtcga cggtaccgga tccatggaag 1740
acgccaaaaa cataaagaaa ggcccggcgc cattctatcc gctggaagat ggaaccgctg 1800
gagagcaact gcataaggct atgaagagat acgccctggt tcctggaaca attgctttta 1860
cagatgcaca tatcgaggtg gacatcactt acgctgagta cttcgaaatg tccgttcggt 1920
tggcagaagc tatgaaacga tatgggctga atacaaatca cagaatcgtc gtatgcagtg 1980
aaaactctct tcaattcttt atgccggtgt tgggcgcgtt atttatcgga gttgcagttg 2040
cgcccgcgaa cgacatttat aatgaacgtg aattgctcaa cagtatgggc atttcgcagc 2100
ctaccgtggt gttcgtttcc aaaaaggggt tgcaaaaaat tttgaacgtg caaaaaaagc 2160
tcccaatcat ccaaaaaatt attatcatgg attctaaaac ggattaccag ggatttcagt 2220
cgatgtacac gttcgtcaca tctcatctac ctcccggttt taatgaatac gattttgtgc 2280
cagagtcctt cgatagggac aagacaattg cactgatcat gaactcctct ggatctactg 2340
gtctgcctaa aggtgtcgct ctgcctcata gaactgcctg cgtgagattc tcgcatgcca 2400
gagatcctat ttttggcaat caaatcattc cggatactgc gattttaagt gttgttccat 2460
tccatcacgg ttttggaatg tttactacac tcggatattt gatatgtgga tttcgagtcg 2520
tcttaatgta tagatttgaa gaagagctgt ttctgaggag ccttcaggat tacaagattc 2580
aaagtgcgct gctggtgcca accctattct ccttcttcgc caaaagcact ctgattgaca 2640
aatacgattt atctaattta cacgaaattg cttctggtgg cgctcccctc tctaaggaag 2700
tcggggaagc ggttgccaag aggttccatc tgccaggtat caggcaagga tatgggctca 2760
ctgagactac atcagctatt ctgattacac ccgaggggga tgataaaccg ggcgcggtcg 2820
gtaaagttgt tccatttttt gaagcgaagg ttgtggatct ggataccggg aaaacgctgg 2880
gcgttaatca aagaggcgaa ctgtgtgtga gaggtcctat gattatgtcc ggttatgtaa 2940
acaatccgga agcgaccaac gccttgattg acaaggatgg atggctacat tctggagaca 3000
tagcttactg ggacgaagac gaacacttct tcatcgttga ccgcctgaag tctctgatta 3060
agtacaaagg ctatcaggtg gctcccgctg aattggaatc catcttgctc caacacccca 3120
acatcttcga cgcaggtgtc gcaggtcttc ccgacgatga cgccggtgaa cttcccgccg 3180
ccgttgttgt tttggagcac ggaaagacga tgacggaaaa agagatcgtg gattacgtcg 3240
ccagtcaagt aacaaccgcg aaaaagttgc gcggaggagt tgtgtttgtg gacgaagtac 3300
cgaaaggtct taccggaaaa ctcgacgcaa gaaaaatcag agagatcctc ataaaggcca 3360
agaagggcgg aaagatcgcc gtggcagccg cagccaccat ggtgagcaag ggcgaggagc 3420
tgttcaccgg ggtggtgccc atcctggtcg agctggacgg cgacgtaaac ggccacaagt 3480
tcagcgtgtc cggcgagggc gagggcgatg ccacctacgg caagctgacc ctgaagttca 3540
tctgcaccac cggcaagctg cccgtgccct ggcccaccct cgtgaccacc ctgacctacg 3600
gcgtgcagtg cttcagccgc taccccgacc acatgaagca gcacgacttc ttcaagtccg 3660
ccatgcccga aggctacgtc caggagcgca ccatcttctt caaggacgac ggcaactaca 3720
agacccgcgc cgaggtgaag ttcgagggcg acaccctggt gaaccgcatc gagctgaagg 3780
gcatcgactt caaggaggac ggcaacatcc tggggcacaa gctggagtac aactacaaca 3840
gccacaacgt ctatatcatg gccgacaagc agaagaacgg catcaaggtg aacttcaaga 3900
tccgccacaa catcgaggac ggcagcgtgc agctcgccga ccactaccag cagaacaccc 3960
ccatcggcga cggccccgtg ctgctgcccg acaaccacta cctgagcacc cagtccgccc 4020
tgagcaaaga ccccaacgag aagcgcgatc acatggtcct gctggagttc gtgaccgccg 4080
ccgggatcac tctcggcatg gacgagctgt acaagtaaag cgactctaga tcataatcag 4140
ccatacccaa acaccattgt cacactccaa tcgattcaaa caccattgtc acactccaac 4200
atttgtagag gttttacttg ctttaaaaaa cctcccacac ctccccctga acctgaaaca 4260
taaaatgaat gcaattgttg ttgttaactt gtttattgca gcttataatg gttacaaata 4320
aagcaatagc atcacaaatt tcacaaataa agcatttttt tcactgcatt ctagttgtgg 4380
tttgtccaaa ctcatcaatg taagtttaaa cggcgcgcct gaaatgtgtg ggcgtggctt 4440
aagggtggga aagaatatat aaggtggggg tcttatgtag ttttgtatct gttttgcagc 4500
agccgccgcc gccatgagca ccaactcgtt tgatggaagc attgtgagct catatttgac 4560
aacgcgcatg cccccatggg ccggggtgcg tcagaatgtg atgggctcca gcattgatgg 4620
tcgccccgtc ctgcccgcaa actctactac cttgacctac gagaccgtgt ctggaacgcc 4680
gttggagact gcagcctccg ccgccgcttc agccgctgca gccaccgccc gcgggattgt 4740
gactgacttt gctttcctga gcccgcttgc aagcagtgca gcttcccgtt catccgcccg 4800
cgatgacaag ttgacggctc ttttggcaca attggattct ttgacccggg aacttaatgt 4860
cgtttctcag cagctgttgg atctgcgcca gcaggtttct gccctgaagg cttcctcccc 4920
tcccaatgcg gtttaaaaca caacttttct atacaaagtt gtaaataaaa aaccagactc 4980
tgtttggatt tggatcaagc taagtgtctt gctgtcttta tttaggggtt ttgcgcgcgc 5040
ggtaggcccg ggaccagcgg tctcggtcgt tgagggtcct gtgtattttt tccaggacgt 5100
ggtaaaggtg actctggatg ttcagataca tgggcataag cccgtctctg gggtggaggt 5160
agcaccactg cagagcttca tgctgcgggg tggtgttgta gatgatccag tcgtagcagg 5220
agcgctgggc gtggtgccta aaaatgtctt tcagtagcaa gctgattgcc aggggcaggc 5280
ccttggtgta agtgtttaca aagcggttaa gctgggatgg gtgcatacgt ggggatatga 5340
gatgcatctt ggactgtatt tttaggttgg ctatgttccc agccatatcc ctccggggat 5400
tcatgttgtg cagaaccacc agcacagtgt atccggtgca cttgggaaat ttgtcatgta 5460
gcttagaagg aaatgcgtgg aagaacttgg agacgccctt gtgacctcca agattttcca 5520
tgcattcgtc cataatgatg gcaatgggcc cacgggcggc ggcctgggcg aagatatttc 5580
tgggatcact aacgtcatag ttgtgttcca ggatgagatc gtcataggcc atttttacaa 5640
agcgcgggcg gagggtgcca gactgcggta taatggttcc atccggccca ggggcgtagt 5700
taccctcaca gatttgcatt tcccacgctt tgagttcaga tggggggatc atgtctacct 5760
gcggggcgat gaagaaaacg gtttccgggg taggggagat cagctgggaa gaaagcaggt 5820
tcctgagcag ctgcgactta ccgcagccgg tgggcccgta aatcacacct attaccggct 5880
gcaactggta gttaagagag ctgcagctgc cgtcatccct gagcaggggg gccacttcgt 5940
taagcatgtc cctgactcgc atgttttccc tgaccaaatc cgccagaagg cgctcgccgc 6000
ccagcgatag cagttcttgc aaggaagcaa agtttttcaa cggtttgaga ccgtccgccg 6060
taggcatgct tttgagcgtt tgaccaagca gttccaggcg gtcccacagc tcggtcacct 6120
gctctacggc atctcgatcc agcatatctc ctcgtttcgc gggttggggc ggctttcgct 6180
gtacggcagt agtcggtgct cgtccagacg ggccagggtc atgtctttcc acgggcgcag 6240
ggtcctcgtc agcgtagtct gggtcacggt gaaggggtgc gctccgggct gcgcgctggc 6300
cagggtgcgc ttgaggctgg tcctgctggt gctgaagcgc tgccggtctt cgccctgcgc 6360
gtcggccagg tagcatttga ccatggtgtc atagtccagc ccctccgcgg cgtggccctt 6420
ggcgcgcagc ttgcccttgg aggaggcgcc gcacgagggg cagtgcagac ttttgagggc 6480
gtagagcttg ggcgcgagaa ataccgattc cggggagtag gcatccgcgc cgcaggcccc 6540
gcagacggtc tcgcattcca cgagccaggt gagctctggc cgttcggggt caaaaaccag 6600
gtttccccca tgctttttga tgcgtttctt acctctggtt tccatgagcc ggtgtccacg 6660
ctcggtgacg aaaaggctgt ccgtgtcccc gtatacagac ttgagaggcc tgtcctcgag 6720
cggtgttccg cggtcctcct cgtatagaaa ctcggaccac tctgagacaa aggctcgcgt 6780
ccaggccagc acgaaggagg ctaagtggga ggggtagcgg tcgttgtcca ctagggggtc 6840
cactcgctcc agggtgtgaa gacacatgtc gccctcttcg gcatcaagga aggtgattgg 6900
tttgtaggtg taggccacgt gaccgggtgt tcctgaaggg gggctataaa agggggtggg 6960
ggcgcgttcg tcctcactct cttccgcatc gctgtctgcg agggccagct gttggggtga 7020
gtactccctc tgaaaagcgg gcatgacttc tgcgctaaga ttgtcagttt ccaaaaacga 7080
ggaggatttg atattcacct ggcccgcggt gatgcctttg agggtggccg catccatctg 7140
gtcagaaaag acaatctttt tgttgtcaag cttggtggca aacgacccgt agagggcgtt 7200
ggacagcaac ttggcgatgg agcgcagggt ttggtttttg tcgcgatcgg cgcgctcctt 7260
ggccgcgatg tttagctgca cgtattcgcg cgcaacgcac cgccattcgg gaaagacggt 7320
ggtgcgctcg tcgggcacca ggtgcacgcg ccaaccgcgg ttgtgcaggg tgacaaggtc 7380
aacgctggtg gctacctctc cgcgtaggcg ctcgttggtc cagcagaggc ggccgccctt 7440
gcgcgagcag aatggcggta gggggtctag ctgcgtctcg tccggggggt ctgcgtccac 7500
ggtaaagacc ccgggcagca ggcgcgcgtc gaagtagtct atcttgcatc cttgcaagtc 7560
tagcgcctgc tgccatgcgc gggcggcaag cgcgcgctcg tatgggttga gtgggggacc 7620
ccatggcatg gggtgggtga gcgcggaggc gtacatgccg caaatgtcgt aaacgtagag 7680
gggctctctg agtattccaa gatatgtagg gtagcatctt ccaccgcgga tgctggcgcg 7740
cacgtaatcg tatagttcgt gcgagggagc gaggaggtcg ggaccgaggt tgctacgggc 7800
gggctgctct gctcggaaga ctatctgcct gaagatggca tgtgagttgg atgatatggt 7860
tggacgctgg aagacgttga agctggcgtc tgtgagacct accgcgtcac gcacgaagga 7920
ggcgtaggag tcgcgcagct tgttgaccag ctcggcggtg acctgcacgt ctagggcgca 7980
gtagtccagg gtttccttga tgatgtcata cttatcctgt cccttttttt tccacagctc 8040
gcggttgagg acaaactctt cgcggtcttt ccagtactct tggatcggaa acccgtcggc 8100
ctccgaacgg taagagccta gcatgtagaa ctggttgacg gcctggtagg cgcagcatcc 8160
cttttctacg ggtagcgcgt atgcctgcgc ggccttccgg agcgaggtgt gggtgagcgc 8220
aaaggtgtcc ctgaccatga ctttgaggta ctggtatttg aagtcagtgt cgtcgcatcc 8280
gccctgctcc cagagcaaaa agtccgtgcg ctttttggaa cgcggatttg gcagggcgaa 8340
ggtgacatcg ttgaagagta tctttcccgc gcgaggcata aagttgcgtg tgatgcggaa 8400
gggtcccggc acctcggaac ggttgttaat tacctgggcg gcgagcacga tctcgtcaaa 8460
gccgttgatg ttgtggccca caatgtaaag ttccaagaag cgcgggatgc ccttgatgga 8520
aggcaatttt ttaagttcct cgtaggtgag ctcttcaggg gagctgagcc cgtgctctga 8580
aagggcccag tctgcaagat gagggttgga agcgacgaat gagctccaca ggtcacgggc 8640
cattagcatt tgcaggtggt cgcgaaaggt cctaaactgg cgacctatgg ccattttttc 8700
tggggtgatg cagtagaagg taagcgggtc ttgttcccag cggtcccatc caaggttcgc 8760
ggctaggtct cgcgcggcag tcactagagg ctcatctccg ccgaacttca tgaccagcat 8820
gaagggcacg agctgcttcc caaaggcccc catccaagta taggtctcta catcgtaggt 8880
gacaaagaga cgctcggtgc gaggatgcga gccgatcggg aagaactgga tctcccgcca 8940
ccaattggag gagtggctat tgatgtggtg aaagtagaag tccctgcgac gggccgaaca 9000
ctcgtgctgg cttttgtaaa aacgtgcgca gtactggcag cggtgcacgg gctgtacatc 9060
ctgcacgagg ttgacctgac gaccgcgcac aaggaagcag agtgggaatt tgagcccctc 9120
gcctggcggg tttggctggt ggtcttctac ttcggctgct tgtccttgac cgtctggctg 9180
ctcgagggga gttacggtgg atcggaccac cacgccgcgc gagcccaaag tccagatgtc 9240
cgcgcgcggc ggtcggagct tgatgacaac atcgcgcaga tgggagctgt ccatggtctg 9300
gagctcccgc ggcgtcaggt caggcgggag ctcctgcagg tttacctcgc atagacgggt 9360
cagggcgcgg gctagatcca ggtgatacct aatttccagg ggctggttgg tggcggcgtc 9420
gatggcttgc aagaggccgc atccccgcgg cgcgactacg gtaccgcgcg gcgggcggtg 9480
ggccgcgggg gtgtccttgg atgatgcatc taaaagcggt gacgcgggcg agcccccgga 9540
ggtagggggg gctccggacc cgccgggaga gggggcaggg gcacgtcggc gccgcgcgcg 9600
ggcaggagct ggtgctgcgc gcgtaggttg ctggcgaacg cgacgacgcg gcggttgatc 9660
tcctgaatct ggcgcctctg cgtgaagacg acgggcccgg tgagcttgaa cctgaaagag 9720
agttcgacag aatcaatttc ggtgtcgttg acggcggcct ggcgcaaaat ctcctgcacg 9780
tctcctgagt tgtcttgata ggcgatctcg gccatgaact gctcgatctc ttcctcctgg 9840
agatctccgc gtccggctcg ctccacggtg gcggcgaggt cgttggaaat gcgggccatg 9900
agctgcgaga aggcgttgag gcctccctcg ttccagacgc ggctgtagac cacgccccct 9960
tcggcatcgc gggcgcgcat gaccacctgc gcgagattga gctccacgtg ccgggcgaag 10020
acggcgtagt ttcgcaggcg ctgaaagagg tagttgaggg tggtggcggt gtgttctgcc 10080
acgaagaagt acataaccca gcgtcgcaac gtggattcgt tgatatcccc caaggcctca 10140
aggcgctcca tggcctcgta gaagtccacg gcgaagttga aaaactggga gttgcgcgcc 10200
gacacggtta actcctcctc cagaagacgg atgagctcgg cgacagtgtc gcgcacctcg 10260
cgctcaaagg ctacaggggc ctcttcttct tcttcaatct cctcttccat aagggcctcc 10320
ccttcttctt cttctggcgg cggtggggga ggggggacac ggcggcgacg acggcgcacc 10380
gggaggcggt cgacaaagcg ctcgatcatc tccccgcggc gacggcgcat ggtctcggtg 10440
acggcgcggc cgttctcgcg ggggcgcagt tggaagacgc cgcccgtcat gtcccggtta 10500
tgggttggcg gggggctgcc atgcggcagg gatacggcgc taacgatgca tctcaacaat 10560
tgttgtgtag gtactccgcc gccgagggac ctgagcgagt ccgcatcgac cggatcggaa 10620
aacctctcga gaaaggcgtc taaccagtca cagtcgcaag gtaggctgag caccgtggcg 10680
ggcggcagcg ggcggcggtc ggggttgttt ctggcggagg tgctgctgat gatgtaatta 10740
aagtaggcgg tcttgagacg gcggatggtc gacagaagca ccatgtcctt gggtccggcc 10800
tgctgaatgc gcaggcggtc ggccatgccc caggcttcgt tttgacatcg gcgcaggtct 10860
ttgtagtagt cttgcatgag cctttctacc ggcacttctt cttctccttc ctcttgtcct 10920
gcatctcttg catctatcgc tgcggcggcg gcggagtttg gccgtaggtg gcgccctctt 10980
cctcccatgc gtgtgacccc gaagcccctc atcggctgaa gcagggctag gtcggcgaca 11040
acgcgctcgg ctaatatggc ctgctgcacc tgcgtgaggg tagactggaa gtcatccatg 11100
tccacaaagc ggtggtatgc gcccgtgttg atggtgtaag tgcagttggc cataacggac 11160
cagttaacgg tctggtgacc cggctgcgag agctcggtgt acctgagacg cgagtaagcc 11220
ctcgagtcaa atacgtagtc gttgcaagtc cgcaccaggt actggtatcc caccaaaaag 11280
tgcggcggcg gctggcggta gaggggccag cgtagggtgg ccggggctcc gggggcgaga 11340
tcttccaaca taaggcgatg atatccgtag atgtacctgg acatccaggt gatgccggcg 11400
gcggtggtgg aggcgcgcgg aaagtcgcgg acgcggttcc agatgttgcg cagcggcaaa 11460
aagtgctcca tggtcgggac gctctggccg gtcaggcgcg cgcaatcgtt gacgctctag 11520
accgtgcaaa aggagagcct gtaagcgggc actcttccgt ggtctggtgg ataaattcgc 11580
aagggtatca tggcggacga ccggggttcg agccccgtat ccggccgtcc gccgtgatcc 11640
atgcggttac cgcccgcgtg tcgaacccag gtgtgcgacg tcagacaacg ggggagtgct 11700
ccttttggct tccttccagg cgcggcggct gctgcgctag cttttttggc cactggccgc 11760
gcgcagcgta agcggttagg ctggaaagcg aaagcattaa gtggctcgct ccctgtagcc 11820
ggagggttat tttccaaggg ttgagtcgcg ggacccccgg ttcgagtctc ggaccggccg 11880
gactgcggcg aacgggggtt tgcctccccg tcatgcaaga ccccgcttgc aaattcctcc 11940
ggaaacaggg acgagcccct tttttgcttt tcccagatgc atccggtgct gcggcagatg 12000
cgcccccctc ctcagcagcg gcaagagcaa gagcagcggc agacatgcag ggcaccctcc 12060
cctcctccta ccgcgtcagg aggggcgaca tccgcggttg acgcggcagc agatggtgat 12120
tacgaacccc cgcggcgccg ggcccggcac tacctggact tggaggaggg cgagggcctg 12180
gcgcggctag gagcgccctc tcctgagcgg cacccaaggg tgcagctgaa gcgtgatacg 12240
cgtgaggcgt acgtgccgcg gcagaacctg tttcgcgacc gcgagggaga ggagcccgag 12300
gagatgcggg atcgaaagtt ccacgcaggg cgcgagctgc ggcatggcct gaatcgcgag 12360
cggttgctgc gcgaggagga ctttgagccc gacgcgcgaa ccgggattag tcccgcgcgc 12420
gcacacgtgg cggccgccga cctggtaacc gcatacgagc agacggtgaa ccaggagatt 12480
aactttcaaa aaagctttaa caaccacgtg cgtacgcttg tggcgcgcga ggaggtggct 12540
ataggactga tgcatctgtg ggactttgta agcgcgctgg agcaaaaccc aaatagcaag 12600
ccgctcatgg cgcagctgtt ccttatagtg cagcacagca gggacaacga ggcattcagg 12660
gatgcgctgc taaacatagt agagcccgag ggccgctggc tgctcgattt gataaacatc 12720
ctgcagagca tagtggtgca ggagcgcagc ttgagcctgg ctgacaaggt ggccgccatc 12780
aactattcca tgcttagcct gggcaagttt tacgcccgca agatatacca taccccttac 12840
gttcccatag acaaggaggt aaagatcgag gggttctaca tgcgcatggc gctgaaggtg 12900
cttaccttga gcgacgacct gggcgtttat cgcaacgagc gcatccacaa ggccgtgagc 12960
gtgagccggc ggcgcgagct cagcgaccgc gagctgatgc acagcctgca aagggccctg 13020
gctggcacgg gcagcggcga tagagaggcc gagtcctact ttgacgcggg cgctgacctg 13080
cgctgggccc caagccgacg cgccctggag gcagctgggg ccggacctgg gctggcggtg 13140
gcacccgcgc gcgctggcaa cgtcggcggc gtggaggaat atgacgagga cgatgagtac 13200
gagccagagg acggcgagta ctaagcggtg atgtttctga tcagatgatg caagacgcaa 13260
cggacccggc ggtgcgggcg gcgctgcaga gccagccgtc cggccttaac tccacggacg 13320
actggcgcca ggtcatggac cgcatcatgt cgctgactgc gcgcaatcct gacgcgttcc 13380
ggcagcagcc gcaggccaac cggctctccg caattctgga agcggtggtc ccggcgcgcg 13440
caaaccccac gcacgagaag gtgctggcga tcgtaaacgc gctggccgaa aacagggcca 13500
tccggcccga cgaggccggc ctggtctacg acgcgctgct tcagcgcgtg gctcgttaca 13560
acagcggcaa cgtgcagacc aacctggacc ggctggtggg ggatgtgcgc gaggccgtgg 13620
cgcagcgtga gcgcgcgcag cagcagggca acctgggctc catggttgca ctaaacgcct 13680
tcctgagtac acagcccgcc aacgtgccgc ggggacagga ggactacacc aactttgtga 13740
gcgcactgcg gctaatggtg actgagacac cgcaaagtga ggtgtaccag tctgggccag 13800
actatttttt ccagaccagt agacaaggcc tgcagaccgt aaacctgagc caggctttca 13860
aaaacttgca ggggctgtgg ggggtgcggg ctcccacagg cgaccgcgcg accgtgtcta 13920
gcttgctgac gcccaactcg cgcctgttgc tgctgctaat agcgcccttc acggacagtg 13980
gcagcgtgtc ccgggacaca tacctaggtc acttgctgac actgtaccgc gaggccatag 14040
gtcaggcgca tgtggacgag catactttcc aggagattac aagtgtcagc cgcgcgctgg 14100
ggcaggagga cacgggcagc ctggaggcaa ccctaaacta cctgctgacc aaccggcggc 14160
agaagatccc ctcgttgcac agtttaaaca gcgaggagga gcgcattttg cgctacgtgc 14220
agcagagcgt gagccttaac ctgatgcgcg acggggtaac gcccagcgtg gcgctggaca 14280
tgaccgcgcg caacatggaa ccgggcatgt atgcctcaaa ccggccgttt atcaaccgcc 14340
taatggacta cttgcatcgc gcggccgccg tgaaccccga gtatttcacc aatgccatct 14400
tgaacccgca ctggctaccg ccccctggtt tctacaccgg gggattcgag gtgcccgagg 14460
gtaacgatgg attcctctgg gacgacatag acgacagcgt gttttccccg caaccgcaga 14520
ccctgctaga gttgcaacag cgcgagcagg cagaggcggc gctgcgaaag gaaagcttcc 14580
gcaggccaag cagcttgtcc gatctaggcg ctgcggcccc gcggtcagat gctagtagcc 14640
catttccaag cttgataggg tctcttacca gcactcgcac cacccgcccg cgcctgctgg 14700
gcgaggagga gtacctaaac aactcgctgc tgcagccgca gcgcgaaaaa aacctgcctc 14760
cggcatttcc caacaacggg atagagagcc tagtggacaa gatgagtaga tggaagacgt 14820
acgcgcagga gcacagggac gtgccaggcc cgcgcccgcc cacccgtcgt caaaggcacg 14880
accgtcagcg gggtctggtg tgggaggacg atgactcggc agacgacagc agcgtcctgg 14940
atttgggagg gagtggcaac ccgtttgcgc accttcgccc caggctgggg agaatgtttt 15000
aaaaaaaaaa aaaaagcatg atgcaaaata aaaaactcac caaggccatg gcaccgagcg 15060
ttggttttct tgtattcccc ttagtatgcg gcgcgcggcg atgtatgagg aaggtcctcc 15120
tccctcctac gagagtgtgg tgagcgcggc gccagtggcg gcggcgctgg gttctccctt 15180
cgatgctccc ctggacccgc cgtttgtgcc tccgcggtac ctgcggccta ccggggggag 15240
aaacagcatc cgttactctg agttggcacc cctattcgac accacccgtg tgtacctggt 15300
ggacaacaag tcaacggatg tggcatccct gaactaccag aacgaccaca gcaactttct 15360
gaccacggtc attcaaaaca atgactacag cccgggggag gcaagcacac agaccatcaa 15420
tcttgacgac cggtcgcact ggggcggcga cctgaaaacc atcctgcata ccaacatgcc 15480
aaatgtgaac gagttcatgt ttaccaataa gtttaaggcg cgggtgatgg tgtcgcgctt 15540
gcctactaag gacaatcagg tggagctgaa atacgagtgg gtggagttca cgctgcccga 15600
gggcaactac tccgagacca tgaccataga ccttatgaac aacgcgatcg tggagcacta 15660
cttgaaagtg ggcagacaga acggggttct ggaaagcgac atcggggtaa agtttgacac 15720
ccgcaacttc agactggggt ttgaccccgt cactggtctt gtcatgcctg gggtatatac 15780
aaacgaagcc ttccatccag acatcatttt gctgccagga tgcggggtgg acttcaccca 15840
cagccgcctg agcaacttgt tgggcatccg caagcggcaa cccttccagg agggctttag 15900
gatcacctac gatgatctgg agggtggtaa cattcccgca ctgttggatg tggacgccta 15960
ccaggcgagc ttgaaagatg acaccgaaca gggcgggggt ggcgcaggcg gcagcaacag 16020
cagtggcagc ggcgcggaag agaactccaa cgcggcagcc gcggcaatgc agccggtgga 16080
ggacatgaac gatcatgcca ttcgcggcga cacctttgcc acacgggctg aggagaagcg 16140
cgctgaggcc gaagcagcgg ccgaagctgc cgcccccgct gcgcaacccg aggtcgagaa 16200
gcctcagaag aaaccggtga tcaaacccct gacagaggac agcaagaaac gcagttacaa 16260
cctaataagc aatgacagca ccttcaccca gtaccgcagc tggtaccttg catacaacta 16320
cggcgaccct cagaccggaa tccgctcatg gaccctgctt tgcactcctg acgtaacctg 16380
cggctcggag caggtctact ggtcgttgcc agacatgatg caagaccccg tgaccttccg 16440
ctccacgcgc cagatcagca actttccggt ggtgggcgcc gagctgttgc ccgtgcactc 16500
caagagcttc tacaacgacc aggccgtcta ctcccaactc atccgccagt ttacctctct 16560
gacccacgtg ttcaatcgct ttcccgagaa ccagattttg gcgcgcccgc cagcccccac 16620
catcaccacc gtcagtgaaa acgttcctgc tctcacagat cacgggacgc taccgctgcg 16680
caacagcatc ggaggagtcc agcgagtgac cattactgac gccagacgcc gcacctgccc 16740
ctacgtttac aaggccctgg gcatagtctc gccgcgcgtc ctatcgagcc gcactttttg 16800
agcaagcatg tccatcctta tatcgcccag caataacaca ggctggggcc tgcgcttccc 16860
aagcaagatg tttggcgggg ccaagaagcg ctccgaccaa cacccagtgc gcgtgcgcgg 16920
gcactaccgc gcgccctggg gcgcgcacaa acgcggccgc actgggcgca ccaccgtcga 16980
tgacgccatc gacgcggtgg tggaggaggc gcgcaactac acgcccacgc cgccaccagt 17040
gtccacagtg gacgcggcca ttcagaccgt ggtgcgcgga gcccggcgct atgctaaaat 17100
gaagagacgg cggaggcgcg tagcacgtcg ccaccgccgc cgacccggca ctgccgccca 17160
acgcgcggcg gcggccctgc ttaaccgcgc acgtcgcacc ggccgacggg cggccatgcg 17220
ggccgctcga aggctggccg cgggtattgt cactgtgccc cccaggtcca ggcgacgagc 17280
ggccgccgca gcagccgcgg ccattagtgc tatgactcag ggtcgcaggg gcaacgtgta 17340
ttgggtgcgc gactcggtta gcggcctgcg cgtgcccgtg cgcacccgcc ccccgcgcaa 17400
ctagattgca agaaaaaact acttagactc gtactgttgt atgtatccag cggcggcggc 17460
gcgcaacgaa gctatgtcca agcgcaaaat caaagaagag atgctccagg tcatcgcgcc 17520
ggagatctat ggccccccga agaaggaaga gcaggattac aagccccgaa agctaaagcg 17580
ggtcaaaaag aaaaagaaag atgatgatga tgaacttgac gacgaggtgg aactgctgca 17640
cgctaccgcg cccaggcgac gggtacagtg gaaaggtcga cgcgtaaaac gtgttttgcg 17700
acccggcacc accgtagtct ttacgcccgg tgagcgctcc acccgcacct acaagcgcgt 17760
gtatgatgag gtgtacggcg acgaggacct gcttgagcag gccaacgagc gcctcgggga 17820
gtttgcctac ggaaagcggc ataaggacat gctggcgttg ccgctggacg agggcaaccc 17880
aacacctagc ctaaagcccg taacactgca gcaggtgctg cccgcgcttg caccgtccga 17940
agaaaagcgc ggcctaaagc gcgagtctgg tgacttggca cccaccgtgc agctgatggt 18000
acccaagcgc cagcgactgg aagatgtctt ggaaaaaatg accgtggaac ctgggctgga 18060
gcccgaggtc cgcgtgcggc caatcaagca ggtggcgccg ggactgggcg tgcagaccgt 18120
ggacgttcag atacccacta ccagtagcac cagtattgcc accgccacag agggcatgga 18180
gacacaaacg tccccggttg cctcagcggt ggcggatgcc gcggtgcagg cggtcgctgc 18240
ggccgcgtcc aagacctcta cggaggtgca aacggacccg tggatgtttc gcgtttcagc 18300
cccccggcgc ccgcgccgtt cgaggaagta cggcgccgcc agcgcgctac tgcccgaata 18360
tgccctacat ccttccattg cgcctacccc cggctatcgt ggctacacct accgccccag 18420
aagacgagca actacccgac gccgaaccac cactggaacc cgccgccgcc gtcgccgtcg 18480
ccagcccgtg ctggccccga tttccgtgcg cagggtggct cgcgaaggag gcaggaccct 18540
ggtgctgcca acagcgcgct accaccccag catcgtttaa aagccggtct ttgtggttct 18600
tgcagatatg gccctcacct gccgcctccg tttcccggtg ccgggattcc gaggaagaat 18660
gcaccgtagg aggggcatgg ccggccacgg cctgacgggc ggcatgcgtc gtgcgcacca 18720
ccggcggcgg cgcgcgtcgc accgtcgcat gcgcggcggt atcctgcccc tccttattcc 18780
actgatcgcc gcggcgattg gcgccgtgcc cggaattgca tccgtggcct tgcaggcgca 18840
gagacactga ttaaaaacaa gttgcatgtg gaaaaatcaa aataaaaagt ctggactctc 18900
acgctcgctt ggtcctgtaa ctattttgta gaatggaaga catcaacttt gcgtctctgg 18960
ccccgcgaca cggctcgcgc ccgttcatgg gaaactggca agatatcggc accagcaata 19020
tgagcggtgg cgccttcagc tggggctcgc tgtggagcgg cattaaaaat ttcggttcca 19080
ccgttaagaa ctatggcagc aaggcctgga acagcagcac aggccagatg ctgagggata 19140
agttgaaaga gcaaaatttc caacaaaagg tggtagatgg cctggcctct ggcattagcg 19200
gggtggtgga cctggccaac caggcagtgc aaaataagat taacagtaag cttgatcccc 19260
gccctcccgt agaggagcct ccaccggccg tggagacagt gtctccagag gggcgtggcg 19320
aaaagcgtcc gcgccccgac agggaagaaa ctctggtgac gcaaatagac gagcctccct 19380
cgtacgagga ggcactaaag caaggcctgc ccaccacccg tcccatcgcg cccatggcta 19440
ccggagtgct gggccagcac acacccgtaa cgctggacct gcctcccccc gccgacaccc 19500
agcagaaacc tgtgctgcca ggcccgaccg ccgttgttgt aacccgtcct agccgcgcgt 19560
ccctgcgccg cgccgccagc ggtccgcgat cgttgcggcc cgtagccagt ggcaactggc 19620
aaagcacact gaacagcatc gtgggtctgg gggtgcaatc cctgaagcgc cgacgatgct 19680
tctgaatagc taacgtgtcg tatgtgtgtc atgtatgcgt ccatgtcgcc gccagaggag 19740
ctgctgagcc gccgcgcgcc cgctttccaa gatggctacc ccttcgatga tgccgcagtg 19800
gtcttacatg cacatctcgg gccaggacgc ctcggagtac ctgagccccg ggctggtgca 19860
gtttgcccgc gccaccgaga cgtacttcag cctgaataac aagtttagaa accccacggt 19920
ggcgcctacg cacgacgtga ccacagaccg gtcccagcgt ttgacgctgc ggttcatccc 19980
tgtggaccgt gaggatactg cgtactcgta caaggcgcgg ttcaccctag ctgtgggtga 20040
taaccgtgtg ctggacatgg cttccacgta ctttgacatc cgcggcgtgc tggacagggg 20100
ccctactttt aagccctact ctggcactgc ctacaacgcc ctggctccca agggtgcccc 20160
aaatccttgc gaatgggatg aagctgctac tgctcttgaa ataaacctag aagaagagga 20220
cgatgacaac gaagacgaag tagacgagca agctgagcag caaaaaactc acgtatttgg 20280
gcaggcgcct tattctggta taaatattac aaaggagggt attcaaatag gtgtcgaagg 20340
tcaaacacct aaatatgccg ataaaacatt tcaacctgaa cctcaaatag gagaatctca 20400
gtggtacgaa actgaaatta atcatgcagc tgggagagtc cttaaaaaga ctaccccaat 20460
gaaaccatgt tacggttcat atgcaaaacc cacaaatgaa aatggagggc aaggcattct 20520
tgtaaagcaa caaaatggaa agctagaaag tcaagtggaa atgcaatttt tctcaactac 20580
tgaggcgacc gcaggcaatg gtgataactt gactcctaaa gtggtattgt acagtgaaga 20640
tgtagatata gaaaccccag acactcatat ttcttacatg cccactatta aggaaggtaa 20700
ctcacgagaa ctaatgggcc aacaatctat gcccaacagg cctaattaca ttgcttttag 20760
ggacaatttt attggtctaa tgtattacaa cagcacgggt aatatgggtg ttctggcggg 20820
ccaagcatcg cagttgaatg ctgttgtaga tttgcaagac agaaacacag agctttcata 20880
ccagcttttg cttgattcca ttggtgatag aaccaggtac ttttctatgt ggaatcaggc 20940
tgttgacagc tatgatccag atgttagaat tattgaaaat catggaactg aagatgaact 21000
tccaaattac tgctttccac tgggaggtgt gattaataca gagactctta ccaaggtaaa 21060
acctaaaaca ggtcaggaaa atggatggga aaaagatgct acagaatttt cagataaaaa 21120
tcaaataaga gttggaaata attttgccat ggaaatcaat ctaaatgcca acctgtggag 21180
aaatttcctg tactccaaca tagcgctgta tttgcccgac aagctaaagt acagtccttc 21240
caacgtaaaa atttctgata acccaaacac ctacgactac atgaacaagc gagtggtggc 21300
tcccgggtta gtggactgct acattaacct tggagcacgc tggtcccttg actatatgga 21360
caacgtcaac ccatttaacc accaccgcaa tgctggcctg cgctaccgct caatgttgct 21420
gggcaatggt cgctatgtgc ccttccacat ccaggtgcct cagaagttct ttgccattaa 21480
aaacctcctt ctcctgccgg gctcatacac ctacgagtgg aacttcagga aggatgttaa 21540
catggttctg cagagctccc taggaaatga cctaagggtt gacggagcca gcattaagtt 21600
tgatagcatt tgcctttacg ccaccttctt ccccatggcc cacaacaccg cctccacgct 21660
tgaggccatg cttagaaacg acaccaacga ccagtccttt aacgactatc tctccgccgc 21720
caacatgctc taccctatac ccgccaacgc taccaacgtg cccatatcca tcccctcccg 21780
caactgggcg gctttccgcg gctgggcctt cacgcgcctt aagactaagg aaaccccatc 21840
actgggctcg ggctacgacc cttattacac ctactctggc tctataccct acctagatgg 21900
aaccttttac ctcaaccaca cctttaagaa ggtggccatt acctttgact cttctgtcag 21960
ctggcctggc aatgaccgcc tgcttacccc caacgagttt gaaattaagc gctcagttga 22020
cggggagggt tacaacgttg cccagtgtaa catgaccaaa gactggttcc tggtacaaat 22080
gctagctaac tacaacattg gctaccaggg cttctatatc ccagagagct acaaggaccg 22140
catgtactcc ttctttagaa acttccagcc catgagccgt caggtggtgg atgatactaa 22200
atacaaggac taccaacagg tgggcatcct acaccaacac aacaactctg gatttgttgg 22260
ctaccttgcc cccaccatgc gcgaaggaca ggcctaccct gctaacttcc cctatccgct 22320
tataggcaag accgcagttg acagcattac ccagaaaaag tttctttgcg atcgcaccct 22380
ttggcgcatc ccattctcca gtaactttat gtccatgggc gcactcacag acctgggcca 22440
aaaccttctc tacgccaact ccgcccacgc gctagacatg acttttgagg tggatcccat 22500
ggacgagccc acccttcttt atgttttgtt tgaagtcttt gacgtggtcc gtgtgcaccg 22560
gccgcaccgc ggcgtcatcg aaaccgtgta cctgcgcacg cccttctcgg ccggcaacgc 22620
cacaacataa agaagcaagc aacatcaaca acagctgccg ccatgggctc cagtgagcag 22680
gaactgaaag ccattgtcaa agatcttggt tgtgggccat attttttggg cacctatgac 22740
aagcgctttc caggctttgt ttctccacac aagctcgcct gcgccatagt caatacggcc 22800
ggtcgcgaga ctgggggcgt acactggatg gcctttgcct ggaacccgca ctcaaaaaca 22860
tgctacctct ttgagccctt tggcttttct gaccagcgac tcaagcaggt ttaccagttt 22920
gagtacgagt cactcctgcg ccgtagcgcc attgcttctt cccccgaccg ctgtataacg 22980
ctggaaaagt ccacccaaag cgtacagggg cccaactcgg ccgcctgtgg actattctgc 23040
tgcatgtttc tccacgcctt tgccaactgg ccccaaactc ccatggatca caaccccacc 23100
atgaacctta ttaccggggt acccaactcc atgctcaaca gtccccaggt acagcccacc 23160
ctgcgtcgca accaggaaca gctctacagc ttcctggagc gccactcgcc ctacttccgc 23220
agccacagtg cgcagattag gagcgccact tctttttgtc acttgaaaaa catgtaaaaa 23280
taatgtacta gagacacttt caataaaggc aaatgctttt atttgtacac tctcgggtga 23340
ttatttaccc ccacccttgc cgtctgcgcc gtttaaaaat caaaggggtt ctgccgcgca 23400
tcgctatgcg ccactggcag ggacacgttg cgatactggt gtttagtgct ccacttaaac 23460
tcaggcacaa ccatccgcgg cagctcggtg aagttttcac tccacaggct gcgcaccatc 23520
accaacgcgt ttagcaggtc gggcgccgat atcttgaagt cgcagttggg gcctccgccc 23580
tgcgcgcgcg agttgcgata cacagggttg cagcactgga acactatcag cgccgggtgg 23640
tgcacgctgg ccagcacgct cttgtcggag atcagatccg cgtccaggtc ctccgcgttg 23700
ctcagggcga acggagtcaa ctttggtagc tgccttccca aaaagggcgc gtgcccaggc 23760
tttgagttgc actcgcaccg tagtggcatc aaaaggtgac cgtgcccggt ctgggcgtta 23820
ggatacagcg cctgcataaa agccttgatc tgcttaaaag ccacctgagc ctttgcgcct 23880
tcagagaaga acatgccgca agacttgccg gaaaactgat tggccggaca ggccgcgtcg 23940
tgcacgcagc accttgcgtc ggtgttggag atctgcacca catttcggcc ccaccggttc 24000
ttcacgatct tggccttgct agactgctcc ttcagcgcgc gctgcccgtt ttcgctcgtc 24060
acatccattt caatcacgtg ctccttattt atcataatgc ttccgtgtag acacttaagc 24120
tcgccttcga tctcagcgca gcggtgcagc cacaacgcgc agcccgtggg ctcgtgatgc 24180
ttgtaggtca cctctgcaaa cgactgcagg tacgcctgca ggaatcgccc catcatcgtc 24240
acaaaggtct tgttgctggt gaaggtcagc tgcaacccgc ggtgctcctc gttcagccag 24300
gtcttgcata cggccgccag agcttccact tggtcaggca gtagtttgaa gttcgccttt 24360
agatcgttat ccacgtggta cttgtccatc agcgcgcgcg cagcctccat gcccttctcc 24420
cacgcagaca cgatcggcac actcagcggg ttcatcaccg taatttcact ttccgcttcg 24480
ctgggctctt cctcttcctc ttgcgtccgc ataccacgcg ccactgggtc gtcttcattc 24540
agccgccgca ctgtgcgctt acctcctttg ccatgcttga ttagcaccgg tgggttgctg 24600
aaacccacca tttgtagcgc cacatcttct ctttcttcct cgctgtccac gattacctct 24660
ggtgatggcg ggcgctcggg cttgggagaa gggcgcttct ttttcttctt gggcgcaatg 24720
gccaaatccg ccgccgaggt cgatggccgc gggctgggtg tgcgcggcac cagcgcgtct 24780
tgtgatgagt cttcctcgtc ctcggactcg atacgccgcc tcatccgctt ttttgggggc 24840
gcccggggag gcggcggcga cggggacggg gacgacacgt cctccatggt tgggggacgt 24900
cgcgccgcac cgcgtccgcg ctcgggggtg gtttcgcgct gctcctcttc ccgactggcc 24960
atttccttct cctataggca gaaaaagatc atggagtcag tcgagaagaa ggacagccta 25020
accgccccct ctgagttcgc caccaccgcc tccaccgatg ccgccaacgc gcctaccacc 25080
ttccccgtcg aggcaccccc gcttgaggag gaggaagtga ttatcgagca ggacccaggt 25140
tttgtaagcg aagacgacga ggaccgctca gtaccaacag aggataaaaa gcaagaccag 25200
gacaacgcag aggcaaacga ggaacaagtc gggcgggggg acgaaaggca tggcgactac 25260
ctagatgtgg gagacgacgt gctgttgaag catctgcagc gccagtgcgc cattatctgc 25320
gacgcgttgc aagagcgcag cgatgtgccc ctcgccatag cggatgtcag ccttgcctac 25380
gaacgccacc tattctcacc gcgcgtaccc cccaaacgcc aagaaaacgg cacatgcgag 25440
cccaacccgc gcctcaactt ctaccccgta tttgccgtgc cagaggtgct tgccacctat 25500
cacatctttt tccaaaactg caagataccc ctatcctgcc gtgccaaccg cagccgagcg 25560
gacaagcagc tggccttgcg gcagggcgct gtcatacctg atatcgcctc gctcaacgaa 25620
gtgccaaaaa tctttgaggg tcttggacgc gacgagaagc gcgcggcaaa cgctctgcaa 25680
caggaaaaca gcgaaaatga aagtcactct ggagtgttgg tggaactcga gggtgacaac 25740
gcgcgcctag ccgtactaaa acgcagcatc gaggtcaccc actttgccta cccggcactt 25800
aacctacccc ccaaggtcat gagcacagtc atgagtgagc tgatcgtgcg ccgtgcgcag 25860
cccctggaga gggatgcaaa tttgcaagaa caaacagagg agggcctacc cgcagttggc 25920
gacgagcagc tagcgcgctg gcttcaaacg cgcgagcctg ccgacttgga ggagcgacgc 25980
aaactaatga tggccgcagt gctcgttacc gtggagcttg agtgcatgca gcggttcttt 26040
gctgacccgg agatgcagcg caagctagag gaaacattgc actacacctt tcgacagggc 26100
tacgtacgcc aggcctgcaa gatctccaac gtggagctct gcaacctggt ctcctacctt 26160
ggaattttgc acgaaaaccg ccttgggcaa aacgtgcttc attccacgct caagggcgag 26220
gcgcgccgcg actacgtccg cgactgcgtt tacttatttc tatgctacac ctggcagacg 26280
gccatgggcg tttggcagca gtgcttggag gagtgcaacc tcaaggagct gcagaaactg 26340
ctaaagcaaa acttgaagga cctatggacg gccttcaacg agcgctccgt ggccgcgcac 26400
ctggcggaca tcattttccc cgaacgcctg cttaaaaccc tgcaacaggg tctgccagac 26460
ttcaccagtc aaagcatgtt gcagaacttt aggaacttta tcctagagcg ctcaggaatc 26520
ttgcccgcca cctgctgtgc acttcctagc gactttgtgc ccattaagta ccgcgaatgc 26580
cctccgccgc tttggggcca ctgctacctt ctgcagctag ccaactacct tgcctaccac 26640
tctgacataa tggaagacgt gagcggtgac ggtctactgg agtgtcactg tcgctgcaac 26700
ctatgcaccc cgcaccgctc cctggtttgc aattcgcagc tgcttaacga aagtcaaatt 26760
atcggtacct ttgagctgca gggtccctcg cctgacgaaa agtccgcggc tccggggttg 26820
aaactcactc cggggctgtg gacgtcggct taccttcgca aatttgtacc tgaggactac 26880
cacgcccacg agattaggtt ctacgaagac caatcccgcc cgccaaatgc ggagcttacc 26940
gcctgcgtca ttacccaggg ccacattctt ggccaattgc aagccatcaa caaagcccgc 27000
caagagtttc tgctacgaaa gggacggggg gtttacttgg acccccagtc cggcgaggag 27060
ctcaacccaa tccccccgcc gccgcagccc tatcagcagc agccgcgggc ccttgcttcc 27120
caggatggca cccaaaaaga agctgcagct gccgccgcca cccacggacg aggaggaata 27180
ctgggacagt caggcagagg aggttttgga cgaggaggag gaggacatga tggaagactg 27240
ggagagccta gacgaggaag cttccgaggt cgaagaggtg tcagacgaaa caccgtcacc 27300
ctcggtcgca ttcccctcgc cggcgcccca gaaatcggca accggttcca gcatggctac 27360
aacctccgct cctcaggcgc cgccggcact gcccgttcgc cgacccaacc gtagatggga 27420
caccactgga accagggccg gtaagtccaa gcagccgccg ccgttagccc aagagcaaca 27480
acagcgccaa ggctaccgct catggcgcgg gcacaagaac gccatagttg cttgcttgca 27540
agactgtggg ggcaacatct ccttcgcccg ccgctttctt ctctaccatc acggcgtggc 27600
cttcccccgt aacatcctgc attactaccg tcatctctac agcccatact gcaccggcgg 27660
cagcggcagc ggcagcaaca gcagcggcca cacagaagca aaggcgaccg gatagcaaga 27720
ctctgacaaa gcccaagaaa tccacagcgg cggcagcagc aggaggagga gcgctgcgtc 27780
tggcgcccaa cgaacccgta tcgacccgcg agcttagaaa caggattttt cccactctgt 27840
atgctatatt tcaacagagc aggggccaag aacaagagct gaaaataaaa aacaggtctc 27900
tgcgatccct cacccgcagc tgcctgtatc acaaaagcga agatcagctt cggcgcacgc 27960
tggaagacgc ggaggctctc ttcagtaaat actgcgcgct gactcttaag gactagtttc 28020
gcgccctttc tcaaatttaa gcgcgaaaac tacgtcatct ccagcggcca cacccggcgc 28080
cagcacctgt cgtcagcgcc atttcaactt tgtatacaaa agttgtgatg agcaaggaaa 28140
ttcccacgcc ctacatgtgg agttaccagc cacaaatggg acttgcggct ggagctgccc 28200
aagactactc aacccgaata aactacatga gcgcgggacc ccacatgata tcccgggtca 28260
acggaatacg cgcccaccga aaccgaattc tcctggaaca ggcggctatt accaccacac 28320
ctcgtaataa ccttaatccc cgtagttggc ccgctgccct ggtgtaccag gaaagtcccg 28380
ctcccaccac tgtggtactt cccagagacg cccaggccga agttcagatg actaactcag 28440
gggcgcagct tgcgggcggc tttcgtcaca gggtgcggtc gcccgggcag ggtataactc 28500
acctgacaat cagagggcga ggtattcagc tcaacgacga gtcggtgagc tcctcgcttg 28560
gtctccgtcc ggacgggaca tttcagatcg gcggcgccgg ccgctcttca ttcacgcctc 28620
gtcaggcaat cctaactctg cagacctcgt cctctgagcc gcgctctgga ggcattggaa 28680
ctctgcaatt tattgaggag tttgtgccat cggtctactt taaccccttc tcgggacctc 28740
ccggccacta tccggatcaa tttattccta actttgacgc ggtaaaggac tcggcggacg 28800
gctacgactg aatgttaagt ggagaggcag agcaactgcg cctgaaacac ctggtccact 28860
gtcgccgcca caagtgcttt gcccgcgact ccggtgagtt ttgctacttt gaattgcccg 28920
aggatcatat cgagggcccg gcgcacggcg tccggcttac cgcccaggga gagcttgccc 28980
gtagcctgat tcgggagttt acccagcgcc ccctgctagt tgagcgggac aggggaccct 29040
gtgttctcac tgtgatttgc aactgtccta accctggatt acatcaagat ctttgttgcc 29100
atctctgtgc tgagtataat aaatacagaa attaaaatat actggggctc ctatcgccat 29160
cctgtaaacg ccaccgtctt cacccgccca agcaaaccaa ggcgaacctt acctggtact 29220
tttaacatct ctccctctgt gatttacaac agtttcaacc cagacggagt gagtctacga 29280
gagaacctct ccgagctcag ctactccatc agaaaaaaca ccaccctcct tacctgccgg 29340
gaacgtacga gtgcgtcacc ggccgctgca ccacacctac cgcctgaccg taaaccagac 29400
tttttccgga cagacctcaa taactctgtt taccagaaca ggaggtgagc ttagaaaacc 29460
cttagggtat taggccaaag gcgcagctac tgtggggttt atgaacaatt caagcaactc 29520
tacgggctat tctaattcag gtttctctag aatcggggtt ggggttattc tctgtcttgt 29580
gattctcttt attcttatac taacgcttct ctgcctaagg ctcgccgcct gctgtgtgca 29640
catttgcatt tattgtcagc tttttaaacg ctggggtcgc cacccaagat gattaggtac 29700
ataatcctag gtttactcac ccttgcgtca gcccacggta ccacccaaaa ggtggatttt 29760
aaggagccag cctgtaatgt tacattcgca gctgaagcta atgagtgcac cactcttata 29820
aaatgcacca cagaacatga aaagctgctt attcgccaca aaaacaaaat tggcaagtat 29880
gctgtttatg ctatttggca gccaggtgac actacagagt ataatgttac agttttccag 29940
ggtaaaagtc ataaaacttt tatgtatact tttccatttt atgaaatgtg cgacattacc 30000
atgtacatga gcaaacagta taagttgtgg cccccacaaa attgtgtgga aaacactggc 30060
actttctgct gcactgctat gctaattaca gtgctcgctt tggtctgtac cctactctat 30120
attaaataca aaagcagacg cagctttatt gaggaaaaga aaatgcctta atttactaag 30180
ttacaaagct aatgtcacca ctaactgctt tactcgctgc ttgcaaaaca aattcaaaaa 30240
gttagcatta taattagaat aggatttaaa ccccccggtc atttcctgct caataccatt 30300
cccctgaaca attgactcta tgtgggatat gctccagcgc tacaaccttg aagtcaggct 30360
tcctggatgt cagcatctga ctttggccag cacctgtccc gcggatttgt tccagtccaa 30420
ctacagcgac ccaccctaac agagatgacc aacacaacca acgcggccgc cgctaccgga 30480
cttacatcta ccacaaatac accccaagtt tctgcctttg tcaataactg ggataacttg 30540
ggcatgtggt ggttctccat agcgcttatg tttgtatgcc ttattattat gtggctcatc 30600
tgctgcctaa agcgcaaacg cgcccgacca cccatctata gtcccatcat tgtgctacac 30660
ccaaacaatg atggaatcca tagattggac ggactgaaac acatgttctt ttctcttaca 30720
gtatgattaa atgagacatg attcctcgag tttttatatt actgaccctt gttgcgcttt 30780
tttgtgcgtg ctccacattg gctgcggttt ctcacatcga agtagactgc attccagcct 30840
tcacagtcta tttgctttac ggatttgtca ccctcacgct catctgcagc ctcatcactg 30900
tggtcatcgc ctttatccag tgcattgact gggtctgtgt gcgctttgca tatctcagac 30960
accatcccca gtacagggac aggactatag ctgagcttct tagaattctt taattatgaa 31020
atttactgtg acttttctgc tgattatttg caccctatct gcgttttgtt ccccgacctc 31080
caagcctcaa agacatatat catgcagatt cactcgtata tggaatattc caagttgcta 31140
caatgaaaaa agcgatcttt ccgaagcctg gttatatgca atcatctctg ttatggtgtt 31200
ctgcagtacc atcttagccc tagctatata tccctacctt gacattggct ggaacgcaat 31260
agatgccatg aaccacccaa ctttccccgc gcccgctatg cttccactgc aacaagttgt 31320
tgccggcggc tttgtcccag ccaatcagcc tcgcccacct tctcccaccc ccactgaaat 31380
cagctacttt aatctaacag gaggagatga ctgacaccct agatctagaa atggacggaa 31440
ttattacaga gcagcgcctg ctagaaagac gcagggcagc ggccgagcaa cagcgcatga 31500
atcaagagct ccaagacatg gttaacttgc accagtgcaa aaggggtatc ttttgtctgg 31560
taaagcaggc caaagtcacc tacgacagta ataccaccgg acaccgcctt agctacaagt 31620
tgccaaccaa gcgtcagaaa ttggtggtca tggtgggaga aaagcccatt accataactc 31680
agcactcggt agaaaccgaa ggctgcattc actcaccttg tcaaggacct gaggatctct 31740
gcacccttat taagaccctg tgcggtctca aagatcttat tccctttaac taataaaaaa 31800
aaataataaa gcatcactta cttaaaatca gttagcaaat ttctgtccag tttattcagc 31860
agcacctcct tgccctcctc ccagctctgg tattgcagct tcctcctggc tgcaaacttt 31920
ctccacaatc taaatggaat gtcagtttcc tcctgttcct gtccatccgc acccactatc 31980
ttcatgttgt tgcagatgaa gcgcgcaaga ccgtctgaag ataccttcaa ccccgtgtat 32040
ccatatgaca cggaaaccgg tcctccaact gtgccttttc ttactcctcc ctttgtatcc 32100
cccaatgggt ttcaagagag tccccctggg gtactctctt tgcgcctatc cgaacctcta 32160
gttacctcca atggcatgct tgcgctcaaa atgggcaacg gcctctctct ggacgaggcc 32220
ggcaacctta cctcccaaaa tgtaaccact gtgagcccac ctctcaaaaa aaccaagtca 32280
aacataaacc tggaaatatc tgcacccctc acagttacct cagaagccct aactgtggct 32340
gccgccgcac ctctaatggt cgcgggcaac acactcacca tgcaatcaca ggccccgcta 32400
accgtgcacg actccaaact tagcattgcc acccaaggac ccctcacagt gtcagaagga 32460
aagctagccc tgcaaacatc aggccccctc accaccaccg atagcagtac ccttactatc 32520
actgcctcac cccctctaac tactgccact ggtagcttgg gcattgactt gaaagagccc 32580
atttatacac aaaatggaaa actaggacta aagtacgggg ctcctttgca tgtaacagac 32640
gacctaaaca ctttgaccgt agcaactggt ccaggtgtga ctattaataa tacttccttg 32700
caaactaaag ttactggagc cttgggtttt gattcacaag gcaatatgca acttaatgta 32760
gcaggaggac taaggattga ttctcaaaac agacgcctta tacttgatgt tagttatccg 32820
tttgatgctc aaaaccaact aaatctaaga ctaggacagg gccctctttt tataaactca 32880
gcccacaact tggatattaa ctacaacaaa ggcctttact tgtttacagc ttcaaacaat 32940
tccaaaaagc ttgaggttaa cctaagcact gccaaggggt tgatgtttga cgctacagcc 33000
atagccatta atgcaggaga tgggcttgaa tttggttcac ctaatgcacc aaacacaaat 33060
cccctcaaaa caaaaattgg ccatggccta gaatttgatt caaacaaggc tatggttcct 33120
aaactaggaa ctggccttag ttttgacagc acaggtgcca ttacagtagg aaacaaaaat 33180
aatgataagc taactttatg gactggaata aaccctccac ctaactgtca aattgtggaa 33240
aacactaata caaatgatgg caaacttact ttagtattag taaaaaacgg agggcttgtt 33300
aatggctacg tgtctctagt tggtgtatca gacactgtga accaaatgtt cacacaaaag 33360
acagcaaaca tccaattaag attatatttt gactcttctg gaaatctatt aactgatgaa 33420
tcagacttaa aaattccact taaaaataaa tcttctacag cgaccagtga aactgtagcc 33480
agcagcaaag cctttatgcc aagtactaca gcttatccct tcaacaccac tactagggat 33540
agtgaaaact acattcatgg aatatgttac tacatgacta gttatgatag aagtctattt 33600
cccttgaaca tttctataat gctaaacagc cgtatgattt cttccaatgt tgcctatgcc 33660
atacaatttg aatggaatct aaatgcaagt gaatctccag aaagcaacat agctacgctg 33720
accacatccc cctttttctt ttcttacatt acagaagacg acaactaata aagaatcgtt 33780
tgtgttatgt ttcaacgtgt ttatttttca attgcagaaa atttcaagtc atttttcatt 33840
cagtagtata gccccaccac cacatagctt atacagatca ccgtacctca actttgtata 33900
ataaagttgt aatcaaactc acagaaccct agtattcaac ctgccacctc cctcccaaca 33960
cacagagtac acagtccttt ctccccggct ggccttaaaa agcatcatat catgggtaac 34020
agacatattc ttaggtgtta tattccacac ggtttcctgt cgagccaaac gctcatcagt 34080
gatattaata aactccccgg gcagctcact taagttcatg tcgctgtcca gctgctgagc 34140
cacaggctgc tgtccaactt gcggttgctt aacgggcggc gaaggagaag tccacgccta 34200
catgggggta gagtcataat cgtgcatcag gatagggcgg tggtgctgca gcagcgcgcg 34260
aataaactgc tgccgccgcc gctccgtcct gcaggaatac aacatggcag tggtctcctc 34320
agcgatgatt cgcaccgccc gcagcataag gcgccttgtc ctccgggcac agcagcgcac 34380
cctgatctca cttaaatcag cacagtaact gcagcacagc accacaatat tgttcaaaat 34440
cccacagtgc aaggcgctgt atccaaagct catggcgggg accacagaac ccacgtggcc 34500
atcataccac aagcgcaggt agattaagtg gcgacccctc ataaacacgc tggacataaa 34560
cattacctct tttggcatgt tgtaattcac cacctcccgg taccatataa acctctgatt 34620
aaacatggcg ccatccacca ccatcctaaa ccagctggcc aaaacctgcc cgccggctat 34680
acactgcagg gaaccgggac tggaacaatg acagtggaga gcccaggact cgtaaccatg 34740
gatcatcatg ctcgtcatga tatcaatgtt ggcacaacac aggcacacgt gcatacactt 34800
cctcaggatt acaagctcct cccgcgttag aaccatatcc cagggaacaa cccattcctg 34860
aatcagcgta aatcccacac tgcagggaag acctcgcacg taactcacgt tgtgcattgt 34920
caaagtgtta cattcgggca gcagcggatg atcctccagt atggtagcgc gggtttctgt 34980
ctcaaaagga ggtagacgat ccctactgta cggagtgcgc cgagacaacc gagatcgtgt 35040
tggtcgtagt gtcatgccaa atggaacgcc ggacgtagtc atatttcctg aagcaaaacc 35100
aggtgcgggc gtgacaaaca gatctgcgtc tccggtctcg ccgcttagat cgctctgtgt 35160
agtagttgta gtatatccac tctctcaaag catccaggcg ccccctggct tcgggttcta 35220
tgtaaactcc ttcatgcgcc gctgccctga taacatccac caccgcagaa taagccacac 35280
ccagccaacc tacacattcg ttctgcgagt cacacacggg aggagcggga agagctggaa 35340
gaaccatgtt ttttttttta ttccaaaaga ttatccaaaa cctcaaaatg aagatctatt 35400
aagtgaacgc gctcccctcc ggtggcgtgg tcaaactcta cagccaaaga acagataatg 35460
gcatttgtaa gatgttgcac aatggcttcc aaaaggcaaa cggccctcac gtccaagtgg 35520
acgtaaaggc taaacccttc agggtgaatc tcctctataa acattccagc accttcaacc 35580
atgcccaaat aattctcatc tcgccacctt ctcaatatat ctctaagcaa atcccgaata 35640
ttaagtccgg ccattgtaaa aatctgctcc agagcgccct ccaccttcag cctcaagcag 35700
cgaatcatga ttgcaaaaat tcaggttcct cacagacctg tataagattc aaaagcggaa 35760
cattaacaaa aataccgcga tcccgtaggt cccttcgcag ggccagctga acataatcgt 35820
gcaggtctgc acggaccagc gcggccactt ccccgccagg aaccatgaca aaagaaccca 35880
cactgattat gacacgcata ctcggagcta tgctaaccag cgtagccccg atgtaagctt 35940
gttgcatggg cggcgatata aaatgcaagg tgctgctcaa aaaatcaggc aaagcctcgc 36000
gcaaaaaaga aagcacatcg tagtcatgct catgcagata aaggcaggta agctccggaa 36060
ccaccacaga aaaagacacc atttttctct caaacatgtc tgcgggtttc tgcataaaca 36120
caaaataaaa taacaaaaaa acatttaaac attagaagcc tgtcttacaa caggaaaaac 36180
aacccttata agcataagac ggactacggc catgccggcg tgaccgtaaa aaaactggtc 36240
accgtgatta aaaagcacca ccgacagctc ctcggtcatg tccggagtca taatgtaaga 36300
ctcggtaaac acatcaggtt gattcacatc ggtcagtgct aaaaagcgac cgaaatagcc 36360
cgggggaata catacccgca ggcgtagaga caacattaca gcccccatag gaggtataac 36420
aaaattaata ggagagaaaa acacataaac acctgaaaaa ccctcctgcc taggcaaaat 36480
agcaccctcc cgctccagaa caacatacag cgcttccaca gcggcagcca taacagtcag 36540
ccttaccagt aaaaaagaaa acctattaaa aaaacaccac tcgacacggc accagctcaa 36600
tcagtcacag tgtaaaaaag ggccaagtgc agagcgagta tatataggac taaaaaatga 36660
cgtaacggtt aaagtccaca aaaaacaccc agaaaaccgc acgcgaacct acgcccagaa 36720
acgaaagcca aaaaacccac aacttcctca aatcgtcact tccgttttcc cacgttacgt 36780
cacttcccat tttaagaaaa ctacaattcc caacacatac aagttactcc gccctaaaac 36840
ctacgtcacc cgccccgttc ccacgccccg cgccacgtca caaactccac cccctcatta 36900
tcatattggc ttcaatccaa aataaggtat attattgatg atg 36943
<210> 3
<211> 952
<212> PRT
<213> 腺病毒5型
<400> 3
Met Ala Thr Pro Ser Met Met Pro Gln Trp Ser Tyr Met His Ile Ser
1 5 10 15
Gly Gln Asp Ala Ser Glu Tyr Leu Ser Pro Gly Leu Val Gln Phe Ala
20 25 30
Arg Ala Thr Glu Thr Tyr Phe Ser Leu Asn Asn Lys Phe Arg Asn Pro
35 40 45
Thr Val Ala Pro Thr His Asp Val Thr Thr Asp Arg Ser Gln Arg Leu
50 55 60
Thr Leu Arg Phe Ile Pro Val Asp Arg Glu Asp Thr Ala Tyr Ser Tyr
65 70 75 80
Lys Ala Arg Phe Thr Leu Ala Val Gly Asp Asn Arg Val Leu Asp Met
85 90 95
Ala Ser Thr Tyr Phe Asp Ile Arg Gly Val Leu Asp Arg Gly Pro Thr
100 105 110
Phe Lys Pro Tyr Ser Gly Thr Ala Tyr Asn Ala Leu Ala Pro Lys Gly
115 120 125
Ala Pro Asn Pro Cys Glu Trp Asp Glu Ala Ala Thr Ala Leu Glu Ile
130 135 140
Asn Leu Glu Glu Glu Asp Asp Asp Asn Glu Asp Glu Val Asp Glu Gln
145 150 155 160
Ala Glu Gln Gln Lys Thr His Val Phe Gly Gln Ala Pro Tyr Ser Gly
165 170 175
Ile Asn Ile Thr Lys Glu Gly Ile Gln Ile Gly Val Glu Gly Gln Thr
180 185 190
Pro Lys Tyr Ala Asp Lys Thr Phe Gln Pro Glu Pro Gln Ile Gly Glu
195 200 205
Ser Gln Trp Tyr Glu Thr Glu Ile Asn His Ala Ala Gly Arg Val Leu
210 215 220
Lys Lys Thr Thr Pro Met Lys Pro Cys Tyr Gly Ser Tyr Ala Lys Pro
225 230 235 240
Thr Asn Glu Asn Gly Gly Gln Gly Ile Leu Val Lys Gln Gln Asn Gly
245 250 255
Lys Leu Glu Ser Gln Val Glu Met Gln Phe Phe Ser Thr Thr Glu Ala
260 265 270
Thr Ala Gly Asn Gly Asp Asn Leu Thr Pro Lys Val Val Leu Tyr Ser
275 280 285
Glu Asp Val Asp Ile Glu Thr Pro Asp Thr His Ile Ser Tyr Met Pro
290 295 300
Thr Ile Lys Glu Gly Asn Ser Arg Glu Leu Met Gly Gln Gln Ser Met
305 310 315 320
Pro Asn Arg Pro Asn Tyr Ile Ala Phe Arg Asp Asn Phe Ile Gly Leu
325 330 335
Met Tyr Tyr Asn Ser Thr Gly Asn Met Gly Val Leu Ala Gly Gln Ala
340 345 350
Ser Gln Leu Asn Ala Val Val Asp Leu Gln Asp Arg Asn Thr Glu Leu
355 360 365
Ser Tyr Gln Leu Leu Leu Asp Ser Ile Gly Asp Arg Thr Arg Tyr Phe
370 375 380
Ser Met Trp Asn Gln Ala Val Asp Ser Tyr Asp Pro Asp Val Arg Ile
385 390 395 400
Ile Glu Asn His Gly Thr Glu Asp Glu Leu Pro Asn Tyr Cys Phe Pro
405 410 415
Leu Gly Gly Val Ile Asn Thr Glu Thr Leu Thr Lys Val Lys Pro Lys
420 425 430
Thr Gly Gln Glu Asn Gly Trp Glu Lys Asp Ala Thr Glu Phe Ser Asp
435 440 445
Lys Asn Glu Ile Arg Val Gly Asn Asn Phe Ala Met Glu Ile Asn Leu
450 455 460
Asn Ala Asn Leu Trp Arg Asn Phe Leu Tyr Ser Asn Ile Ala Leu Tyr
465 470 475 480
Leu Pro Asp Lys Leu Lys Tyr Ser Pro Ser Asn Val Lys Ile Ser Asp
485 490 495
Asn Pro Asn Thr Tyr Asp Tyr Met Asn Lys Arg Val Val Ala Pro Gly
500 505 510
Leu Val Asp Cys Tyr Ile Asn Leu Gly Ala Arg Trp Ser Leu Asp Tyr
515 520 525
Met Asp Asn Val Asn Pro Phe Asn His His Arg Asn Ala Gly Leu Arg
530 535 540
Tyr Arg Ser Met Leu Leu Gly Asn Gly Arg Tyr Val Pro Phe His Ile
545 550 555 560
Gln Val Pro Gln Lys Phe Phe Ala Ile Lys Asn Leu Leu Leu Leu Pro
565 570 575
Gly Ser Tyr Thr Tyr Glu Trp Asn Phe Arg Lys Asp Val Asn Met Val
580 585 590
Leu Gln Ser Ser Leu Gly Asn Asp Leu Arg Val Asp Gly Ala Ser Ile
595 600 605
Lys Phe Asp Ser Ile Cys Leu Tyr Ala Thr Phe Phe Pro Met Ala His
610 615 620
Asn Thr Ala Ser Thr Leu Glu Ala Met Leu Arg Asn Asp Thr Asn Asp
625 630 635 640
Gln Ser Phe Asn Asp Tyr Leu Ser Ala Ala Asn Met Leu Tyr Pro Ile
645 650 655
Pro Ala Asn Ala Thr Asn Val Pro Ile Ser Ile Pro Ser Arg Asn Trp
660 665 670
Ala Ala Phe Arg Gly Trp Ala Phe Thr Arg Leu Lys Thr Lys Glu Thr
675 680 685
Pro Ser Leu Gly Ser Gly Tyr Asp Pro Tyr Tyr Thr Tyr Ser Gly Ser
690 695 700
Ile Pro Tyr Leu Asp Gly Thr Phe Tyr Leu Asn His Thr Phe Lys Lys
705 710 715 720
Val Ala Ile Thr Phe Asp Ser Ser Val Ser Trp Pro Gly Asn Asp Arg
725 730 735
Leu Leu Thr Pro Asn Glu Phe Glu Ile Lys Arg Ser Val Asp Gly Glu
740 745 750
Gly Tyr Asn Val Ala Gln Cys Asn Met Thr Lys Asp Trp Phe Leu Val
755 760 765
Gln Met Leu Ala Asn Tyr Asn Ile Gly Tyr Gln Gly Phe Tyr Ile Pro
770 775 780
Glu Ser Tyr Lys Asp Arg Met Tyr Ser Phe Phe Arg Asn Phe Gln Pro
785 790 795 800
Met Ser Arg Gln Val Val Asp Asp Thr Lys Tyr Lys Asp Tyr Gln Gln
805 810 815
Val Gly Ile Leu His Gln His Asn Asn Ser Gly Phe Val Gly Tyr Leu
820 825 830
Ala Pro Thr Met Arg Glu Gly Gln Ala Tyr Pro Ala Asn Phe Pro Tyr
835 840 845
Pro Leu Ile Gly Lys Thr Ala Val Asp Ser Ile Thr Gln Lys Lys Phe
850 855 860
Leu Cys Asp Arg Thr Leu Trp Arg Ile Pro Phe Ser Ser Asn Phe Met
865 870 875 880
Ser Met Gly Ala Leu Thr Asp Leu Gly Gln Asn Leu Leu Tyr Ala Asn
885 890 895
Ser Ala His Ala Leu Asp Met Thr Phe Glu Val Asp Pro Met Asp Glu
900 905 910
Pro Thr Leu Leu Tyr Val Leu Phe Glu Val Phe Asp Val Val Arg Val
915 920 925
His Arg Pro His Arg Gly Val Ile Glu Thr Val Tyr Leu Arg Thr Pro
930 935 940
Phe Ser Ala Gly Asn Ala Thr Thr
945 950
<210> 4
<211> 952
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 4
Met Ala Thr Pro Ser Met Met Pro Gln Trp Ser Tyr Met His Ile Ser
1 5 10 15
Gly Gln Asp Ala Ser Glu Tyr Leu Ser Pro Gly Leu Val Gln Phe Ala
20 25 30
Arg Ala Thr Glu Thr Tyr Phe Ser Leu Asn Asn Lys Phe Arg Asn Pro
35 40 45
Thr Val Ala Pro Thr His Asp Val Thr Thr Asp Arg Ser Gln Arg Leu
50 55 60
Thr Leu Arg Phe Ile Pro Val Asp Arg Glu Asp Thr Ala Tyr Ser Tyr
65 70 75 80
Lys Ala Arg Phe Thr Leu Ala Val Gly Asp Asn Arg Val Leu Asp Met
85 90 95
Ala Ser Thr Tyr Phe Asp Ile Arg Gly Val Leu Asp Arg Gly Pro Thr
100 105 110
Phe Lys Pro Tyr Ser Gly Thr Ala Tyr Asn Ala Leu Ala Pro Lys Gly
115 120 125
Ala Pro Asn Pro Cys Glu Trp Asp Glu Ala Ala Thr Ala Leu Glu Ile
130 135 140
Asn Leu Glu Glu Glu Asp Asp Asp Asn Glu Asp Glu Val Asp Glu Gln
145 150 155 160
Ala Glu Gln Gln Lys Thr His Val Phe Gly Gln Ala Pro Tyr Ser Gly
165 170 175
Ile Asn Ile Thr Lys Glu Gly Ile Gln Ile Gly Val Glu Gly Gln Thr
180 185 190
Pro Lys Tyr Ala Asp Lys Thr Phe Gln Pro Glu Pro Gln Ile Gly Glu
195 200 205
Ser Gln Trp Tyr Glu Thr Glu Ile Asn His Ala Ala Gly Arg Val Leu
210 215 220
Lys Lys Thr Thr Pro Met Lys Pro Cys Tyr Gly Ser Tyr Ala Lys Pro
225 230 235 240
Thr Asn Glu Asn Gly Gly Gln Gly Ile Leu Val Lys Gln Gln Asn Gly
245 250 255
Lys Leu Glu Ser Gln Val Glu Met Gln Phe Phe Ser Thr Thr Glu Ala
260 265 270
Thr Ala Gly Asn Gly Asp Asn Leu Thr Pro Lys Val Val Leu Tyr Ser
275 280 285
Glu Asp Val Asp Ile Glu Thr Pro Asp Thr His Ile Ser Tyr Met Pro
290 295 300
Thr Ile Lys Glu Gly Asn Ser Arg Glu Leu Met Gly Gln Gln Ser Met
305 310 315 320
Pro Asn Arg Pro Asn Tyr Ile Ala Phe Arg Asp Asn Phe Ile Gly Leu
325 330 335
Met Tyr Tyr Asn Ser Thr Gly Asn Met Gly Val Leu Ala Gly Gln Ala
340 345 350
Ser Gln Leu Asn Ala Val Val Asp Leu Gln Asp Arg Asn Thr Glu Leu
355 360 365
Ser Tyr Gln Leu Leu Leu Asp Ser Ile Gly Asp Arg Thr Arg Tyr Phe
370 375 380
Ser Met Trp Asn Gln Ala Val Asp Ser Tyr Asp Pro Asp Val Arg Ile
385 390 395 400
Ile Glu Asn His Gly Thr Glu Asp Glu Leu Pro Asn Tyr Cys Phe Pro
405 410 415
Leu Gly Gly Val Ile Asn Thr Glu Thr Leu Thr Lys Val Lys Pro Lys
420 425 430
Thr Gly Gln Glu Asn Gly Trp Glu Lys Asp Ala Thr Glu Phe Ser Asp
435 440 445
Lys Asn Gln Ile Arg Val Gly Asn Asn Phe Ala Met Glu Ile Asn Leu
450 455 460
Asn Ala Asn Leu Trp Arg Asn Phe Leu Tyr Ser Asn Ile Ala Leu Tyr
465 470 475 480
Leu Pro Asp Lys Leu Lys Tyr Ser Pro Ser Asn Val Lys Ile Ser Asp
485 490 495
Asn Pro Asn Thr Tyr Asp Tyr Met Asn Lys Arg Val Val Ala Pro Gly
500 505 510
Leu Val Asp Cys Tyr Ile Asn Leu Gly Ala Arg Trp Ser Leu Asp Tyr
515 520 525
Met Asp Asn Val Asn Pro Phe Asn His His Arg Asn Ala Gly Leu Arg
530 535 540
Tyr Arg Ser Met Leu Leu Gly Asn Gly Arg Tyr Val Pro Phe His Ile
545 550 555 560
Gln Val Pro Gln Lys Phe Phe Ala Ile Lys Asn Leu Leu Leu Leu Pro
565 570 575
Gly Ser Tyr Thr Tyr Glu Trp Asn Phe Arg Lys Asp Val Asn Met Val
580 585 590
Leu Gln Ser Ser Leu Gly Asn Asp Leu Arg Val Asp Gly Ala Ser Ile
595 600 605
Lys Phe Asp Ser Ile Cys Leu Tyr Ala Thr Phe Phe Pro Met Ala His
610 615 620
Asn Thr Ala Ser Thr Leu Glu Ala Met Leu Arg Asn Asp Thr Asn Asp
625 630 635 640
Gln Ser Phe Asn Asp Tyr Leu Ser Ala Ala Asn Met Leu Tyr Pro Ile
645 650 655
Pro Ala Asn Ala Thr Asn Val Pro Ile Ser Ile Pro Ser Arg Asn Trp
660 665 670
Ala Ala Phe Arg Gly Trp Ala Phe Thr Arg Leu Lys Thr Lys Glu Thr
675 680 685
Pro Ser Leu Gly Ser Gly Tyr Asp Pro Tyr Tyr Thr Tyr Ser Gly Ser
690 695 700
Ile Pro Tyr Leu Asp Gly Thr Phe Tyr Leu Asn His Thr Phe Lys Lys
705 710 715 720
Val Ala Ile Thr Phe Asp Ser Ser Val Ser Trp Pro Gly Asn Asp Arg
725 730 735
Leu Leu Thr Pro Asn Glu Phe Glu Ile Lys Arg Ser Val Asp Gly Glu
740 745 750
Gly Tyr Asn Val Ala Gln Cys Asn Met Thr Lys Asp Trp Phe Leu Val
755 760 765
Gln Met Leu Ala Asn Tyr Asn Ile Gly Tyr Gln Gly Phe Tyr Ile Pro
770 775 780
Glu Ser Tyr Lys Asp Arg Met Tyr Ser Phe Phe Arg Asn Phe Gln Pro
785 790 795 800
Met Ser Arg Gln Val Val Asp Asp Thr Lys Tyr Lys Asp Tyr Gln Gln
805 810 815
Val Gly Ile Leu His Gln His Asn Asn Ser Gly Phe Val Gly Tyr Leu
820 825 830
Ala Pro Thr Met Arg Glu Gly Gln Ala Tyr Pro Ala Asn Phe Pro Tyr
835 840 845
Pro Leu Ile Gly Lys Thr Ala Val Asp Ser Ile Thr Gln Lys Lys Phe
850 855 860
Leu Cys Asp Arg Thr Leu Trp Arg Ile Pro Phe Ser Ser Asn Phe Met
865 870 875 880
Ser Met Gly Ala Leu Thr Asp Leu Gly Gln Asn Leu Leu Tyr Ala Asn
885 890 895
Ser Ala His Ala Leu Asp Met Thr Phe Glu Val Asp Pro Met Asp Glu
900 905 910
Pro Thr Leu Leu Tyr Val Leu Phe Glu Val Phe Asp Val Val Arg Val
915 920 925
His Arg Pro His Arg Gly Val Ile Glu Thr Val Tyr Leu Arg Thr Pro
930 935 940
Phe Ser Ala Gly Asn Ala Thr Thr
945 950
<210> 5
<211> 41258
<212> DNA
<213> 人工序列
<220>
<223> 合成腺病毒基因组 (AdSyn-CO987)
<400> 5
gttccactga gcgtcagacc ccttaataag atgatcttct tgagatcgtt ttggtctgcg 60
cgtaatctct tgctctgaaa acgaaaaaac cgccttgcag ggcggttttt cgaaggttct 120
ctgagctacc aactctttga accgaggtaa ctggcttgga ggagcgcagt caccaaaact 180
tgtcctttca gtttagcctt aaccggcgca tgacttcaag actaactcct ctaaatcaat 240
taccagtggc tgctgccagt ggtgcttttg catgtctttc cgggttggac tcaagacgat 300
agttaccgga taaggcgcag cggtcggact gaacgggggg ttcgtgcata cagtccagct 360
tggagcgaac tgcctacccg gaactgagtg tcaggcgtgg aatgagacaa acgcggccat 420
aacagcggaa tgacaccggt aaaccgaaag gcaggaacag gagagcgcac gagggagccg 480
ccaggggaaa cgcctggtat ctttatagtc ctgtcgggtt tcgccaccac tgatttgagc 540
gtcagatttc gtgatgcttg tcaggggggc ggagcctatg gaaaaacggc tttgccgcgg 600
ccctctcact tccctgttaa gtatcttcct ggcatcttcc aggaaatctc cgccccgttc 660
gtaagccatt tccgctcgcc gcagtcgaac gaccgagcgt agcgagtcag tgagcgagga 720
agcggaatat atcctgtatc acatattctg ctgacgcacc ggtgcagcct tttttctcct 780
gccacatgaa gcacttcact gacaccctca tcagtgccaa catagtaagc cagtatacac 840
tccgctagcg ctgaggtctg cctcgtgaag aaggtgttgc tgactcatac caggcctgaa 900
tcgccccatc atccagccag aaagtgaggg agccacggtt gatgagagct ttgttgtagg 960
tggaccagtt ggtgattttg aacttttgct ttgccacgga acggtctgcg ttgtcgggaa 1020
gatgcgtgat ctgatccttc aactcagcaa aagttcgatt tattcaacaa agccacgttg 1080
tgtctcaaaa tctctgatgt tacattgcac aagataaaaa tatatcatca tgaacaataa 1140
aactgtctgc ttacataaac agtaatacaa ggggtgttga tactctcagt acaatctgct 1200
ctgatgccgc atagttaagc cagtatctgc tccctgcttg tgtgttggag gtcgctgagt 1260
agtgcgcgag caaaatttaa gctacaacaa ggcaaggctt gaccgacaat tgcatgaaga 1320
atctgcttag ggttaggcgt tttgcgctgc ttcgcgatgt acgggccaga tatacgcgta 1380
tctgagggga ctagggtgtg tttaggcgaa aagcggggct tcggttgtac gcggttagga 1440
gtcccctcag gatatagtag tttcgctttt gcatagggag ggggaaatgt agtcttatgc 1500
aatactcttg tagtcttgca acatggtaac gatgagttag caacatgcct tacaaggaga 1560
gaaaaagcac cgtgcatgcc gattggtgga agtaaggtgg tacgatcgtg ccttattagg 1620
aaggcaacag acgggtctga catggattgg acgaaccact gaattccgca ttgcagagat 1680
attgtattta agtgcctagc tcgatacaat aaacgccatt tgaccattca ccacattggt 1740
gtgcacctcc aagctgggta cggatccggc cttgccggcc tcgagcggcc gctagcgccg 1800
ccactatggg atcaagatcg ccaaaaaaga agagaaaggt gccgaagaag catgcagcac 1860
caccaaaaaa aaaacgaaaa gtagaagacc cacgatttat gtacccatac gatgttcctg 1920
actatgcggg tatgaaaaac atcaaaaaaa accaggtaat gaacctgggt ccgaactcta 1980
aactgctgaa agaatacaaa tcccagctga tcgaactgaa catcgaacag ttcgaagcag 2040
gtatcggtct gatcctgggt gatgcttaca tccgttctcg tgatgaaggt aaaacctact 2100
gtatgcagtt cgagtggaaa aacaaagcat acatggacca cgtatgtctg ctgtacgatc 2160
agtgggtact gtccccgccg cacaaaaaag aacgtgttaa ccacctgggt aacctggtaa 2220
tcacctgggg cgcccagact ttcaaacacc aagctttcaa caaactggct aacctgttca 2280
tcgttaacaa caaaaaaacc atcccgaaca acctggttga aaactacctg accccgatgt 2340
ctctggcata ctggttcatg gatgatggtg gtaaatggga ttacaacaaa aactctacca 2400
acaaatcgat cgtactgaac acccagtctt tcactttcga agaagtagaa tacctggtta 2460
agggtctgcg taacaaattc caactgaact gttacgtaaa aatcaacaaa aacaaaccga 2520
tcatctacat cgattctatg tcttacctga tcttctacaa cctgatcaaa ccgtacctga 2580
tcccgcagat gatgtacaaa ctgccgaaca ctatctcctc cgaaactttc ctgaaataag 2640
gtaccgatcc agacatgata agatacattg atgagtttgg acaaaccaca actagaatgc 2700
agtgaaaaaa atgctttatt tgtgaaattt gtgatgctat tgctttattt gtaaccatta 2760
taagctgcaa taaacaagtt aacaacaaca attgcattca ttttatgttt caggttcagg 2820
gggaggtgtg ggaggttttt taaagcaagt aaaacctcta caaatgtggt atggctgatt 2880
atgatcatcg taaacttggt ctgacagtta ccaatgctta atcagtgagg cacctatctc 2940
agcgatctgt ctatttcgtt catccatagt tgcctgactc cccgtcgtgt agataactac 3000
gatacgggag ggcttaccat ctggccccag tgctgcaatg ataccgcgag acccacgctc 3060
accggctcca gatttatcag caataaacca gccagccgga agggccgagc gcagaagtgg 3120
tcctgcaact ttatccgcct ccatccagtc tattaattgt tgccgggaag ctagagtaag 3180
tagttcgcca gttaatagtt tgcgcaacgt tgttgccatt gctacaggca tcgtggtgtc 3240
acgctcgtcg tttggtatgg cttcattcag ctccggttcc caacgatcaa ggcgagttac 3300
atgatccccc atgttgtgca aaaaagcggt tagctccttc ggtcctccga tcgttgtcag 3360
aagtaagttg gccgcagtgt tatcactcat ggttatggca gcactgcata attctcttac 3420
tgtcatgcca tccgtaagat gcttttctgt gactggtgag tactcaacca agtcattctg 3480
agaatagtgt atgcggcgac cgagttgctc ttgcccggcg tcaatacggg ataataccgc 3540
gccacatagc agaactttaa aagtgctcat cattggaaaa cgttcttcgg ggcgaaaact 3600
ctcaaggatc ttaccgctgt tgagatccag ttcgatgtaa cccactcgtg cacccaactg 3660
atcttcagca tcttttactt tcaccagcgt ttctgggtga gcaaaaacag gaaggcaaaa 3720
tgccgcaaaa aagggaataa gggcgacacg gaaatgttga atactcatac tcttcctttt 3780
tcaatattat tgaagcattt atcagggtta ttgtctcatg agcggataca tatttgaatg 3840
tatttagaaa aataaacaaa taggggttcc gcgcacattt ccccgaaaag tgccacctga 3900
cgtctaagaa accattatta tcatgacatt aacctataaa aataggcgta tcacgaggcc 3960
ctttcgtctc gcgcgtttcg gtgatgacgg tgaaaacctc tgacacatgc agctcccgga 4020
gacggtcaca gcttgtctgt aagcggatgc cgggagcaga caagcccgtc agggcgcgtc 4080
agcgggtgtt ggcgggtgtc ggggctggct taactatgcg gcatcagagc agattgtact 4140
gagagtgcac catatgcggt gtgaaatacc gcacagatgc gtaaggagaa aataccgcat 4200
caggcgccat tcgccattca ggctgcgcaa ctgttgggaa gggcgatcgg tgcgggcctc 4260
ttcgctatta cgccagctgg cgaaaggggg atgtgctgca aggcgattaa gttgggtaac 4320
gccagggttt tcccagtcac gacgttgtaa aacgacggcc agtgaattac aactttgtac 4380
aaaaaagcag attaccctgt tatccctaca tcatcaataa tataccttat tttggattga 4440
agccaatatg ataatgaggg ggtggagttt gtgacgtggc gcggggcgtg ggaacggggc 4500
gggtgacgta gtagtgtggc ggaagtgtga tgttgcaagt gtggcggaac acatgtaagc 4560
gacggatgtg gcaaaagtga cgtttttggt gtgcgccggt gtacacagga agtgacaatt 4620
ttcgcgcggt tttaggcgga tgttgtagta aatttgggcg taaccgagta agatttggcc 4680
attttcgcgg gaaaactgaa taagaggaag tgaaatctga ataattttgt gttactcata 4740
gcgcgtaata tttgtctagg gccgcgggga ctttgaccgt ttacgtggag actcgcccag 4800
gtgtttttct caggtgtttt ccgcgttccg ggtcaaagtt ggcgttttat tattaaaccg 4860
tattaccgcc atgcatttaa tggagtgcct cgtgaggctc cggtgcccgt cagtgggcag 4920
agcgcacatc gcccacagtc cccgagaagt tggggggagg ggtcggcaat tgaaccggtg 4980
cctagagaag gtggcgcggg gtaaactggg aaagtgatgt cgtgtactgg ctccgccttt 5040
ttcccgaggg tgggggagaa ccgtatataa gtgcagtagt cgccgtgaac gttctttttc 5100
gcaacgggtt tgccgccaga acacaggtaa gtgccgtgtg tggttcccgc gggcctggcc 5160
tctttacggg ttatggccct tgcgtgcctt gaattacttc cacctggctg cagtacgtga 5220
ttcttgatcc cgagcttcgg gttggaagtg ggtgggagag ttcgaggcct tgcgcttaag 5280
gagccccttc gcctcgtgct tgagttgagg cctggcctgg gcgctggggc cgccgcgtgc 5340
gaatctggtg gcaccttcgc gcctgtctcg ctgctttcga taagtctcta gccatttaaa 5400
atttttgatg acctgctgcg acgctttttt tctggcaaga tagtcttgta aatgcgggcc 5460
aagatctgca cactggtatt tcggtttttg gggccgcggg cggcgacggg gcccgtgcgt 5520
cccagcgcac atgttcggcg aggcggggcc tgcgagcgcg gccaccgaga atcggacggg 5580
ggtagtctca agctggccgg cctgctctgg tgcctggcct cgcgccgccg tgtatcgccc 5640
cgccctgggc ggcaaggctg gcccggtcgg caccagttgc gtgagcggaa agatggccgc 5700
ttcccggccc tgctgcaggg agctcaaaat ggaggacgcg gcgctcggga gagcgggcgg 5760
gtgagtcacc cacacaaagg aaaagggcct ttccgtcctc agccgtcgct tcatgtgact 5820
ccacggagta ccgggcgccg tccaggcacc tcgattagtt ctcgagcttt tggagtacgt 5880
cgtctttagg ttggggggag gggttttatg cgatggagtt tccccacact gagtgggtgg 5940
agactgaagt taggccagct tggcacttga tgtaattctc cttggaattt gccctttttg 6000
agtttggatc ttggttcatt ctcaagcctc agacagtggt tcaaagtttt tttcttccat 6060
ttcaggtgtc gtgacgctag cgctaccgga ctcagatctc gagctcaagc ttcgaattct 6120
gcagcaccat ggactataaa gatgacgacg acaaggcttc gtaccccggc catcagcacg 6180
cgtctgcgtt cgaccaggct gcgcgttctc gcggccatag caaccgacgt acggcgttgc 6240
gccctcgccg gcagcaagaa gccacggaag tccgcccgga gcagaaaatg cccacgctac 6300
tgcgggttta tatagacggt ccccacggga tggggaaaac caccaccacg caactgctgg 6360
tggccctggg ttcgcgcgac gatatcgtct acgtacccga gccgatgact tactggcggg 6420
tgctgggggc ttccgagaca atcgcgaaca tctacaccac acaacaccgc cttgaccagg 6480
gtgagatatc ggccggggac gcggcggtgg taatgacaag cgcccagata acaatgggca 6540
tgccttatgc cgtgaccgac gccgttctgg ctcctcatat cgggggggag gctgggagct 6600
cacatgcccc gcccccggcc ctcaccctca tcttcgaccg ccatcccatc gccgccctcc 6660
tgtgctaccc ggccgcgcga taccttatgg gcagcatgac cccccaggcc gtgctggcgt 6720
tcgtggccct catcccgccg accttgcccg gcacaaacat cgtgttgggg gcccttccgg 6780
aggacagaca catcgaccgc ctggccaaac gccagcgccc cggcgagcgg cttgacctgg 6840
ctatgctggc cgcgattcgc cgcgtttacg ggctgcttgc caatacggtg cggtatctgc 6900
agggcggcgg gtcgtggcgg gaggattggg gacagctttc ggggacggcc gtgccgcccc 6960
agggtgccga gccccagagc aacgcgggcc cacgacccca tatcggggac acgttattta 7020
ccctgtttcg ggcccccgag ttgctggccc ccaacggcga cctgtacaac gtgtttgcct 7080
gggccttgga cgtcttggcc aaacgcctcc gtcccatgca cgtctttatc ctggattacg 7140
accaatcgcc cgccggctgc cgggacgccc tgctgcaact tacctccggg atgatccaga 7200
cccacgtcac caccccaggc tccataccga cgatctgcga cctggcgcgc acgtttgccc 7260
gggagatggg ggaggctaac ggaagcggag ctactaactt cagcctgctg aagcaggctg 7320
gtgacgtcga ggagaatcct ggcccaatga cttcgaaagt ttatgatcca gaacaaagga 7380
aacggatgat aactggtccg cagtggtggg ccagatgtaa acaaatgaat gttcttgatt 7440
catttattaa ttattatgat tcagaaaaac atgcagaaaa tgctgttatt tttttacatg 7500
gtaacgcggc ctcttcttat ttatggcgac atgttgtgcc acatattgag ccagtagcgc 7560
ggtgtattat accagacctt attggtatgg gcaaatcagg caaatctggt aatggttctt 7620
ataggttact tgatcattac aaatatctta ctgcatggtt tgaacttctt aatttaccaa 7680
agaagatcat ttttgtcggc catgattggg gtgcttgttt ggcatttcat tatagctatg 7740
agcatcaaga taagatcaaa gcaatagttc acgctgaaag tgtagtagat gtgattgaat 7800
catgggatga atggcctgat attgaagaag atattgcgtt gatcaaatct gaagaaggag 7860
aaaaaatggt tttggagaat aacttcttcg tggaaaccat gttgccatca aaaatcatga 7920
gaaagttaga accagaagaa tttgcagcat atcttgaacc attcaaagag aaaggtgaag 7980
ttcgtcgtcc aacattatca tggcctcgtg aaatcccgtt agtaaaaggt ggtaaacctg 8040
acgttgtaca aattgttagg aattataatg cttatctacg tgcaagtgat gatttaccaa 8100
aaatgtttat tgaatcggac ccaggattct tttccaatgc tattgttgaa ggtgccaaga 8160
agtttcctaa tactgaattt gtcaaagtaa aaggtcttca tttttcgcaa gaagatgcac 8220
ctgatgaaat gggaaaatat atcaaatcgt tcgttgagcg agttctcaaa aatgaacaat 8280
aaggagcgac tctagatcat aatcagccat accacatttg tagaggtttt acttgcttta 8340
aaaaacctcc cacacctccc cctgaacctg aaacataaaa tgaatgcaat tgttgttgtt 8400
aacttgttta ttgcagctta taatggttac aaataaagca atagcatcac aaatttcaca 8460
aataaagcat ttttttcact gcattctagt tgtggtttgt ccaaactcat caatgtaagt 8520
ttaaacggcg cgcctgaaat gtgtgggcgt ggcttaaggg tgggaaagaa tatataaggt 8580
gggggtctta tgtagttttg tatctgtttt gcagcagccg ccgccgccat gagcaccaac 8640
tcgtttgatg gaagcattgt gagctcatat ttgacaacgc gcatgccccc atgggccggg 8700
gtgcgtcaga atgtgatggg ctccagcatt gatggtcgcc ccgtcctgcc cgcaaactct 8760
actaccttga cctacgagac cgtgtctgga acgccgttgg agactgcagc ctccgccgcc 8820
gcttcagccg ctgcagccac cgcccgcggg attgtgactg actttgcttt cctgagcccg 8880
cttgcaagca gtgcagcttc ccgttcatcc gcccgcgatg acaagttgac ggctcttttg 8940
gcacaattgg attctttgac ccgggaactt aatgtcgttt ctcagcagct gttggatctg 9000
cgccagcagg tttctgccct gaaggcttcc tcccctccca atgcggttta aaacacaact 9060
tttctataca aagttgtaaa taaaaaacca gactctgttt ggatttggat caagctaagt 9120
gtcttgctgt ctttatttag gggttttgcg cgcgcggtag gcccgggacc agcggtctcg 9180
gtcgttgagg gtcctgtgta ttttttccag gacgtggtaa aggtgactct ggatgttcag 9240
atacatgggc ataagcccgt ctctggggtg gaggtagcac cactgcagag cttcatgctg 9300
cggggtggtg ttgtagatga tccagtcgta gcaggagcgc tgggcgtggt gcctaaaaat 9360
gtctttcagt agcaagctga ttgccagggg caggcccttg gtgtaagtgt ttacaaagcg 9420
gttaagctgg gatgggtgca tacgtgggga tatgagatgc atcttggact gtatttttag 9480
gttggctatg ttcccagcca tatccctccg gggattcatg ttgtgcagaa ccaccagcac 9540
agtgtatccg gtgcacttgg gaaatttgtc atgtagctta gaaggaaatg cgtggaagaa 9600
cttggagacg cccttgtgac ctccaagatt ttccatgcat tcgtccataa tgatggcaat 9660
gggcccacgg gcggcggcct gggcgaagat atttctggga tcactaacgt catagttgtg 9720
ttccaggatg agatcgtcat aggccatttt tacaaagcgc gggcggaggg tgccagactg 9780
cggtataatg gttccatccg gcccaggggc gtagttaccc tcacagattt gcatttccca 9840
cgctttgagt tcagatgggg ggatcatgtc tacctgcggg gcgatgaaga aaacggtttc 9900
cggggtaggg gagatcagct gggaagaaag caggttcctg agcagctgcg acttaccgca 9960
gccggtgggc ccgtaaatca cacctattac cggctgcaac tggtagttaa gagagctgca 10020
gctgccgtca tccctgagca ggggggccac ttcgttaagc atgtccctga ctcgcatgtt 10080
ttccctgacc aaatccgcca gaaggcgctc gccgcccagc gatagcagtt cttgcaagga 10140
agcaaagttt ttcaacggtt tgagaccgtc cgccgtaggc atgcttttga gcgtttgacc 10200
aagcagttcc aggcggtccc acagctcggt cacctgctct acggcatctc gatccagcat 10260
atctcctcgt ttcgcgggtt ggggcggctt tcgctgtacg gcagtagtcg gtgctcgtcc 10320
agacgggcca gggtcatgtc tttccacggg cgcagggtcc tcgtcagcgt agtctgggtc 10380
acggtgaagg ggtgcgctcc gggctgcgcg ctggccaggg tgcgcttgag gctggtcctg 10440
ctggtgctga agcgctgccg gtcttcgccc tgcgcgtcgg ccaggtagca tttgaccatg 10500
gtgtcatagt ccagcccctc cgcggcgtgg cccttggcgc gcagcttgcc cttggaggag 10560
gcgccgcacg aggggcagtg cagacttttg agggcgtaga gcttgggcgc gagaaatacc 10620
gattccgggg agtaggcatc cgcgccgcag gccccgcaga cggtctcgca ttccacgagc 10680
caggtgagct ctggccgttc ggggtcaaaa accaggtttc ccccatgctt tttgatgcgt 10740
ttcttacctc tggtttccat gagccggtgt ccacgctcgg tgacgaaaag gctgtccgtg 10800
tccccgtata cagacttgag aggcctgtcc tcgagcggtg ttccgcggtc ctcctcgtat 10860
agaaactcgg accactctga gacaaaggct cgcgtccagg ccagcacgaa ggaggctaag 10920
tgggaggggt agcggtcgtt gtccactagg gggtccactc gctccagggt gtgaagacac 10980
atgtcgccct cttcggcatc aaggaaggtg attggtttgt aggtgtaggc cacgtgaccg 11040
ggtgttcctg aaggggggct ataaaagggg gtgggggcgc gttcgtcctc actctcttcc 11100
gcatcgctgt ctgcgagggc cagctgttgg ggtgagtact ccctctgaaa agcgggcatg 11160
acttctgcgc taagattgtc agtttccaaa aacgaggagg atttgatatt cacctggccc 11220
gcggtgatgc ctttgagggt ggccgcatcc atctggtcag aaaagacaat ctttttgttg 11280
tcaagcttgg tggcaaacga cccgtagagg gcgttggaca gcaacttggc gatggagcgc 11340
agggtttggt ttttgtcgcg atcggcgcgc tccttggccg cgatgtttag ctgcacgtat 11400
tcgcgcgcaa cgcaccgcca ttcgggaaag acggtggtgc gctcgtcggg caccaggtgc 11460
acgcgccaac cgcggttgtg cagggtgaca aggtcaacgc tggtggctac ctctccgcgt 11520
aggcgctcgt tggtccagca gaggcggccg cccttgcgcg agcagaatgg cggtaggggg 11580
tctagctgcg tctcgtccgg ggggtctgcg tccacggtaa agaccccggg cagcaggcgc 11640
gcgtcgaagt agtctatctt gcatccttgc aagtctagcg cctgctgcca tgcgcgggcg 11700
gcaagcgcgc gctcgtatgg gttgagtggg ggaccccatg gcatggggtg ggtgagcgcg 11760
gaggcgtaca tgccgcaaat gtcgtaaacg tagaggggct ctctgagtat tccaagatat 11820
gtagggtagc atcttccacc gcggatgctg gcgcgcacgt aatcgtatag ttcgtgcgag 11880
ggagcgagga ggtcgggacc gaggttgcta cgggcgggct gctctgctcg gaagactatc 11940
tgcctgaaga tggcatgtga gttggatgat atggttggac gctggaagac gttgaagctg 12000
gcgtctgtga gacctaccgc gtcacgcacg aaggaggcgt aggagtcgcg cagcttgttg 12060
accagctcgg cggtgacctg cacgtctagg gcgcagtagt ccagggtttc cttgatgatg 12120
tcatacttat cctgtccctt ttttttccac agctcgcggt tgaggacaaa ctcttcgcgg 12180
tctttccagt actcttggat cggaaacccg tcggcctccg aacggtaaga gcctagcatg 12240
tagaactggt tgacggcctg gtaggcgcag catccctttt ctacgggtag cgcgtatgcc 12300
tgcgcggcct tccggagcga ggtgtgggtg agcgcaaagg tgtccctgac catgactttg 12360
aggtactggt atttgaagtc agtgtcgtcg catccgccct gctcccagag caaaaagtcc 12420
gtgcgctttt tggaacgcgg atttggcagg gcgaaggtga catcgttgaa gagtatcttt 12480
cccgcgcgag gcataaagtt gcgtgtgatg cggaagggtc ccggcacctc ggaacggttg 12540
ttaattacct gggcggcgag cacgatctcg tcaaagccgt tgatgttgtg gcccacaatg 12600
taaagttcca agaagcgcgg gatgcccttg atggaaggca attttttaag ttcctcgtag 12660
gtgagctctt caggggagct gagcccgtgc tctgaaaggg cccagtctgc aagatgaggg 12720
ttggaagcga cgaatgagct ccacaggtca cgggccatta gcatttgcag gtggtcgcga 12780
aaggtcctaa actggcgacc tatggccatt ttttctgggg tgatgcagta gaaggtaagc 12840
gggtcttgtt cccagcggtc ccatccaagg ttcgcggcta ggtctcgcgc ggcagtcact 12900
agaggctcat ctccgccgaa cttcatgacc agcatgaagg gcacgagctg cttcccaaag 12960
gcccccatcc aagtataggt ctctacatcg taggtgacaa agagacgctc ggtgcgagga 13020
tgcgagccga tcgggaagaa ctggatctcc cgccaccaat tggaggagtg gctattgatg 13080
tggtgaaagt agaagtccct gcgacgggcc gaacactcgt gctggctttt gtaaaaacgt 13140
gcgcagtact ggcagcggtg cacgggctgt acatcctgca cgaggttgac ctgacgaccg 13200
cgcacaagga agcagagtgg gaatttgagc ccctcgcctg gcgggtttgg ctggtggtct 13260
tctacttcgg ctgcttgtcc ttgaccgtct ggctgctcga ggggagttac ggtggatcgg 13320
accaccacgc cgcgcgagcc caaagtccag atgtccgcgc gcggcggtcg gagcttgatg 13380
acaacatcgc gcagatggga gctgtccatg gtctggagct cccgcggcgt caggtcaggc 13440
gggagctcct gcaggtttac ctcgcataga cgggtcaggg cgcgggctag atccaggtga 13500
tacctaattt ccaggggctg gttggtggcg gcgtcgatgg cttgcaagag gccgcatccc 13560
cgcggcgcga ctacggtacc gcgcggcggg cggtgggccg cgggggtgtc cttggatgat 13620
gcatctaaaa gcggtgacgc gggcgagccc ccggaggtag ggggggctcc ggacccgccg 13680
ggagaggggg caggggcacg tcggcgccgc gcgcgggcag gagctggtgc tgcgcgcgta 13740
ggttgctggc gaacgcgacg acgcggcggt tgatctcctg aatctggcgc ctctgcgtga 13800
agacgacggg cccggtgagc ttgaacctga aagagagttc gacagaatca atttcggtgt 13860
cgttgacggc ggcctggcgc aaaatctcct gcacgtctcc tgagttgtct tgataggcga 13920
tctcggccat gaactgctcg atctcttcct cctggagatc tccgcgtccg gctcgctcca 13980
cggtggcggc gaggtcgttg gaaatgcggg ccatgagctg cgagaaggcg ttgaggcctc 14040
cctcgttcca gacgcggctg tagaccacgc ccccttcggc atcgcgggcg cgcatgacca 14100
cctgcgcgag attgagctcc acgtgccggg cgaagacggc gtagtttcgc aggcgctgaa 14160
agaggtagtt gagggtggtg gcggtgtgtt ctgccacgaa gaagtacata acccagcgtc 14220
gcaacgtgga ttcgttgata tcccccaagg cctcaaggcg ctccatggcc tcgtagaagt 14280
ccacggcgaa gttgaaaaac tgggagttgc gcgccgacac ggttaactcc tcctccagaa 14340
gacggatgag ctcggcgaca gtgtcgcgca cctcgcgctc aaaggctaca ggggcctctt 14400
cttcttcttc aatctcctct tccataaggg cctccccttc ttcttcttct ggcggcggtg 14460
ggggaggggg gacacggcgg cgacgacggc gcaccgggag gcggtcgaca aagcgctcga 14520
tcatctcccc gcggcgacgg cgcatggtct cggtgacggc gcggccgttc tcgcgggggc 14580
gcagttggaa gacgccgccc gtcatgtccc ggttatgggt tggcgggggg ctgccatgcg 14640
gcagggatac ggcgctaacg atgcatctca acaattgttg tgtaggtact ccgccgccga 14700
gggacctgag cgagtccgca tcgaccggat cggaaaacct ctcgagaaag gcgtctaacc 14760
agtcacagtc gcaaggtagg ctgagcaccg tggcgggcgg cagcgggcgg cggtcggggt 14820
tgtttctggc ggaggtgctg ctgatgatgt aattaaagta ggcggtcttg agacggcgga 14880
tggtcgacag aagcaccatg tccttgggtc cggcctgctg aatgcgcagg cggtcggcca 14940
tgccccaggc ttcgttttga catcggcgca ggtctttgta gtagtcttgc atgagccttt 15000
ctaccggcac ttcttcttct ccttcctctt gtcctgcatc tcttgcatct atcgctgcgg 15060
cggcggcgga gtttggccgt aggtggcgcc ctcttcctcc catgcgtgtg accccgaagc 15120
ccctcatcgg ctgaagcagg gctaggtcgg cgacaacgcg ctcggctaat atggcctgct 15180
gcacctgcgt gagggtagac tggaagtcat ccatgtccac aaagcggtgg tatgcgcccg 15240
tgttgatggt gtaagtgcag ttggccataa cggaccagtt aacggtctgg tgacccggct 15300
gcgagagctc ggtgtacctg agacgcgagt aagccctcga gtcaaatacg tagtcgttgc 15360
aagtccgcac caggtactgg tatcccacca aaaagtgcgg cggcggctgg cggtagaggg 15420
gccagcgtag ggtggccggg gctccggggg cgagatcttc caacataagg cgatgatatc 15480
cgtagatgta cctggacatc caggtgatgc cggcggcggt ggtggaggcg cgcggaaagt 15540
cgcggacgcg gttccagatg ttgcgcagcg gcaaaaagtg ctccatggtc gggacgctct 15600
ggccggtcag gcgcgcgcaa tcgttgacgc tctagaccgt gcaaaaggag agcctgtaag 15660
cgggcactct tccgtggtct ggtggataaa ttcgcaaggg tatcatggcg gacgaccggg 15720
gttcgagccc cgtatccggc cgtccgccgt gatccatgcg gttaccgccc gcgtgtcgaa 15780
cccaggtgtg cgacgtcaga caacggggga gtgctccttt tggcttcctt ccaggcgcgg 15840
cggctgctgc gctagctttt ttggccactg gccgcgcgca gcgtaagcgg ttaggctgga 15900
aagcgaaagc attaagtggc tcgctccctg tagccggagg gttattttcc aagggttgag 15960
tcgcgggacc cccggttcga gtctcggacc ggccggactg cggcgaacgg gggtttgcct 16020
ccccgtcatg caagaccccg cttgcaaatt cctccggaaa cagggacgag cccctttttt 16080
gcttttccca gatgcatccg gtgctgcggc agatgcgccc ccctcctcag cagcggcaag 16140
agcaagagca gcggcagaca tgcagggcac cctcccctcc tcctaccgcg tcaggagggg 16200
cgacatccgc ggttgacgcg gcagcagatg gtgattacga acccccgcgg cgccgggccc 16260
ggcactacct ggacttggag gagggcgagg gcctggcgcg gctaggagcg ccctctcctg 16320
agcggcaccc aagggtgcag ctgaagcgtg atacgcgtga ggcgtacgtg ccgcggcaga 16380
acctgtttcg cgaccgcgag ggagaggagc ccgaggagat gcgggatcga aagttccacg 16440
cagggcgcga gctgcggcat ggcctgaatc gcgagcggtt gctgcgcgag gaggactttg 16500
agcccgacgc gcgaaccggg attagtcccg cgcgcgcaca cgtggcggcc gccgacctgg 16560
taaccgcata cgagcagacg gtgaaccagg agattaactt tcaaaaaagc tttaacaacc 16620
acgtgcgtac gcttgtggcg cgcgaggagg tggctatagg actgatgcat ctgtgggact 16680
ttgtaagcgc gctggagcaa aacccaaata gcaagccgct catggcgcag ctgttcctta 16740
tagtgcagca cagcagggac aacgaggcat tcagggatgc gctgctaaac atagtagagc 16800
ccgagggccg ctggctgctc gatttgataa acatcctgca gagcatagtg gtgcaggagc 16860
gcagcttgag cctggctgac aaggtggccg ccatcaacta ttccatgctt agcctgggca 16920
agttttacgc ccgcaagata taccataccc cttacgttcc catagacaag gaggtaaaga 16980
tcgaggggtt ctacatgcgc atggcgctga aggtgcttac cttgagcgac gacctgggcg 17040
tttatcgcaa cgagcgcatc cacaaggccg tgagcgtgag ccggcggcgc gagctcagcg 17100
accgcgagct gatgcacagc ctgcaaaggg ccctggctgg cacgggcagc ggcgatagag 17160
aggccgagtc ctactttgac gcgggcgctg acctgcgctg ggccccaagc cgacgcgccc 17220
tggaggcagc tggggccgga cctgggctgg cggtggcacc cgcgcgcgct ggcaacgtcg 17280
gcggcgtgga ggaatatgac gaggacgatg agtacgagcc agaggacggc gagtactaag 17340
cggtgatgtt tctgatcaga tgatgcaaga cgcaacggac ccggcggtgc gggcggcgct 17400
gcagagccag ccgtccggcc ttaactccac ggacgactgg cgccaggtca tggaccgcat 17460
catgtcgctg actgcgcgca atcctgacgc gttccggcag cagccgcagg ccaaccggct 17520
ctccgcaatt ctggaagcgg tggtcccggc gcgcgcaaac cccacgcacg agaaggtgct 17580
ggcgatcgta aacgcgctgg ccgaaaacag ggccatccgg cccgacgagg ccggcctggt 17640
ctacgacgcg ctgcttcagc gcgtggctcg ttacaacagc ggcaacgtgc agaccaacct 17700
ggaccggctg gtgggggatg tgcgcgaggc cgtggcgcag cgtgagcgcg cgcagcagca 17760
gggcaacctg ggctccatgg ttgcactaaa cgccttcctg agtacacagc ccgccaacgt 17820
gccgcgggga caggaggact acaccaactt tgtgagcgca ctgcggctaa tggtgactga 17880
gacaccgcaa agtgaggtgt accagtctgg gccagactat tttttccaga ccagtagaca 17940
aggcctgcag accgtaaacc tgagccaggc tttcaaaaac ttgcaggggc tgtggggggt 18000
gcgggctccc acaggcgacc gcgcgaccgt gtctagcttg ctgacgccca actcgcgcct 18060
gttgctgctg ctaatagcgc ccttcacgga cagtggcagc gtgtcccggg acacatacct 18120
aggtcacttg ctgacactgt accgcgaggc cataggtcag gcgcatgtgg acgagcatac 18180
tttccaggag attacaagtg tcagccgcgc gctggggcag gaggacacgg gcagcctgga 18240
ggcaacccta aactacctgc tgaccaaccg gcggcagaag atcccctcgt tgcacagttt 18300
aaacagcgag gaggagcgca ttttgcgcta cgtgcagcag agcgtgagcc ttaacctgat 18360
gcgcgacggg gtaacgccca gcgtggcgct ggacatgacc gcgcgcaaca tggaaccggg 18420
catgtatgcc tcaaaccggc cgtttatcaa ccgcctaatg gactacttgc atcgcgcggc 18480
cgccgtgaac cccgagtatt tcaccaatgc catcttgaac ccgcactggc taccgccccc 18540
tggtttctac accgggggat tcgaggtgcc cgagggtaac gatggattcc tctgggacga 18600
catagacgac agcgtgtttt ccccgcaacc gcagaccctg ctagagttgc aacagcgcga 18660
gcaggcagag gcggcgctgc gaaaggaaag cttccgcagg ccaagcagct tgtccgatct 18720
aggcgctgcg gccccgcggt cagatgctag tagcccattt ccaagcttga tagggtctct 18780
taccagcact cgcaccaccc gcccgcgcct gctgggcgag gaggagtacc taaacaactc 18840
gctgctgcag ccgcagcgcg aaaaaaacct gcctccggca tttcccaaca acgggataga 18900
gagcctagtg gacaagatga gtagatggaa gacgtacgcg caggagcaca gggacgtgcc 18960
aggcccgcgc ccgcccaccc gtcgtcaaag gcacgaccgt cagcggggtc tggtgtggga 19020
ggacgatgac tcggcagacg acagcagcgt cctggatttg ggagggagtg gcaacccgtt 19080
tgcgcacctt cgccccaggc tggggagaat gttttaaaaa aaaaaaaaaa gcatgatgca 19140
aaataaaaaa ctcaccaagg ccatggcacc gagcgttggt tttcttgtat tccccttagt 19200
atgcggcgcg cggcgatgta tgaggaaggt cctcctccct cctacgagag tgtggtgagc 19260
gcggcgccag tggcggcggc gctgggttct cccttcgatg ctcccctgga cccgccgttt 19320
gtgcctccgc ggtacctgcg gcctaccggg gggagaaaca gcatccgtta ctctgagttg 19380
gcacccctat tcgacaccac ccgtgtgtac ctggtggaca acaagtcaac ggatgtggca 19440
tccctgaact accagaacga ccacagcaac tttctgacca cggtcattca aaacaatgac 19500
tacagcccgg gggaggcaag cacacagacc atcaatcttg acgaccggtc gcactggggc 19560
ggcgacctga aaaccatcct gcataccaac atgccaaatg tgaacgagtt catgtttacc 19620
aataagttta aggcgcgggt gatggtgtcg cgcttgccta ctaaggacaa tcaggtggag 19680
ctgaaatacg agtgggtgga gttcacgctg cccgagggca actactccga gaccatgacc 19740
atagacctta tgaacaacgc gatcgtggag cactacttga aagtgggcag acagaacggg 19800
gttctggaaa gcgacatcgg ggtaaagttt gacacccgca acttcagact ggggtttgac 19860
cccgtcactg gtcttgtcat gcctggggta tatacaaacg aagccttcca tccagacatc 19920
attttgctgc caggatgcgg ggtggacttc acccacagcc gcctgagcaa cttgttgggc 19980
atccgcaagc ggcaaccctt ccaggagggc tttaggatca cctacgatga tctggagggt 20040
ggtaacattc ccgcactgtt ggatgtggac gcctaccagg cgagcttgaa agatgacacc 20100
gaacagggcg ggggtggcgc aggcggcagc aacagcagtg gcagcggcgc ggaagagaac 20160
tccaacgcgg cagccgcggc aatgcagccg gtggaggaca tgaacgatca tgccattcgc 20220
ggcgacacct ttgccacacg ggctgaggag aagcgcgctg aggccgaagc agcggccgaa 20280
gctgccgccc ccgctgcgca acccgaggtc gagaagcctc agaagaaacc ggtgatcaaa 20340
cccctgacag aggacagcaa gaaacgcagt tacaacctaa taagcaatga cagcaccttc 20400
acccagtacc gcagctggta ccttgcatac aactacggcg accctcagac cggaatccgc 20460
tcatggaccc tgctttgcac tcctgacgta acctgcggct cggagcaggt ctactggtcg 20520
ttgccagaca tgatgcaaga ccccgtgacc ttccgctcca cgcgccagat cagcaacttt 20580
ccggtggtgg gcgccgagct gttgcccgtg cactccaaga gcttctacaa cgaccaggcc 20640
gtctactccc aactcatccg ccagtttacc tctctgaccc acgtgttcaa tcgctttccc 20700
gagaaccaga ttttggcgcg cccgccagcc cccaccatca ccaccgtcag tgaaaacgtt 20760
cctgctctca cagatcacgg gacgctaccg ctgcgcaaca gcatcggagg agtccagcga 20820
gtgaccatta ctgacgccag acgccgcacc tgcccctacg tttacaaggc cctgggcata 20880
gtctcgccgc gcgtcctatc gagccgcact ttttgagcaa gcatgtccat ccttatatcg 20940
cccagcaata acacaggctg gggcctgcgc ttcccaagca agatgtttgg cggggccaag 21000
aagcgctccg accaacaccc agtgcgcgtg cgcgggcact accgcgcgcc ctggggcgcg 21060
cacaaacgcg gccgcactgg gcgcaccacc gtcgatgacg ccatcgacgc ggtggtggag 21120
gaggcgcgca actacacgcc cacgccgcca ccagtgtcca cagtggacgc ggccattcag 21180
accgtggtgc gcggagcccg gcgctatgct aaaatgaaga gacggcggag gcgcgtagca 21240
cgtcgccacc gccgccgacc cggcactgcc gcccaacgcg cggcggcggc cctgcttaac 21300
cgcgcacgtc gcaccggccg acgggcggcc atgcgggccg ctcgaaggct ggccgcgggt 21360
attgtcactg tgccccccag gtccaggcga cgagcggccg ccgcagcagc cgcggccatt 21420
agtgctatga ctcagggtcg caggggcaac gtgtattggg tgcgcgactc ggttagcggc 21480
ctgcgcgtgc ccgtgcgcac ccgccccccg cgcaactaga ttgcaagaaa aaactactta 21540
gactcgtact gttgtatgta tccagcggcg gcggcgcgca acgaagctat gtccaagcgc 21600
aaaatcaaag aagagatgct ccaggtcatc gcgccggaga tctatggccc cccgaagaag 21660
gaagagcagg attacaagcc ccgaaagcta aagcgggtca aaaagaaaaa gaaagatgat 21720
gatgatgaac ttgacgacga ggtggaactg ctgcacgcta ccgcgcccag gcgacgggta 21780
cagtggaaag gtcgacgcgt aaaacgtgtt ttgcgacccg gcaccaccgt agtctttacg 21840
cccggtgagc gctccacccg cacctacaag cgcgtgtatg atgaggtgta cggcgacgag 21900
gacctgcttg agcaggccaa cgagcgcctc ggggagtttg cctacggaaa gcggcataag 21960
gacatgctgg cgttgccgct ggacgagggc aacccaacac ctagcctaaa gcccgtaaca 22020
ctgcagcagg tgctgcccgc gcttgcaccg tccgaagaaa agcgcggcct aaagcgcgag 22080
tctggtgact tggcacccac cgtgcagctg atggtaccca agcgccagcg actggaagat 22140
gtcttggaaa aaatgaccgt ggaacctggg ctggagcccg aggtccgcgt gcggccaatc 22200
aagcaggtgg cgccgggact gggcgtgcag accgtggacg ttcagatacc cactaccagt 22260
agcaccagta ttgccaccgc cacagagggc atggagacac aaacgtcccc ggttgcctca 22320
gcggtggcgg atgccgcggt gcaggcggtc gctgcggccg cgtccaagac ctctacggag 22380
gtgcaaacgg acccgtggat gtttcgcgtt tcagcccccc ggcgcccgcg ccgttcgagg 22440
aagtacggcg ccgccagcgc gctactgccc gaatatgccc tacatccttc cattgcgcct 22500
acccccggct atcgtggcta cacctaccgc cccagaagac gagcaactac ccgacgccga 22560
accaccactg gaacccgccg ccgccgtcgc cgtcgccagc ccgtgctggc cccgatttcc 22620
gtgcgcaggg tggctcgcga aggaggcagg accctggtgc tgccaacagc gcgctaccac 22680
cccagcatcg tttaaaagcc ggtctttgtg gttcttgcag atatggccct cacctgccgc 22740
ctccgtttcc cggtgccggg attccgagga agaatgcacc gtaggagggg catggccggc 22800
cacggcctga cgggcggcat gcgtcgtgcg caccaccggc ggcggcgcgc gtcgcaccgt 22860
cgcatgcgcg gcggtatcct gcccctcctt attccactga tcgccgcggc gattggcgcc 22920
gtgcccggaa ttgcatccgt ggccttgcag gcgcagagac actgattaaa aacaagttgc 22980
atgtggaaaa atcaaaataa aaagtctgga ctctcacgct cgcttggtcc tgtaactatt 23040
ttgtagaatg gaagacatca actttgcgtc tctggccccg cgacacggct cgcgcccgtt 23100
catgggaaac tggcaagata tcggcaccag caatatgagc ggtggcgcct tcagctgggg 23160
ctcgctgtgg agcggcatta aaaatttcgg ttccaccgtt aagaactatg gcagcaaggc 23220
ctggaacagc agcacaggcc agatgctgag ggataagttg aaagagcaaa atttccaaca 23280
aaaggtggta gatggcctgg cctctggcat tagcggggtg gtggacctgg ccaaccaggc 23340
agtgcaaaat aagattaaca gtaagcttga tccccgccct cccgtagagg agcctccacc 23400
ggccgtggag acagtgtctc cagaggggcg tggcgaaaag cgtccgcgcc ccgacaggga 23460
agaaactctg gtgacgcaaa tagacgagcc tccctcgtac gaggaggcac taaagcaagg 23520
cctgcccacc acccgtccca tcgcgcccat ggctaccgga gtgctgggcc agcacacacc 23580
cgtaacgctg gacctgcctc cccccgccga cacccagcag aaacctgtgc tgccaggccc 23640
gaccgccgtt gttgtaaccc gtcctagccg cgcgtccctg cgccgcgccg ccagcggtcc 23700
gcgatcgttg cggcccgtag ccagtggcaa ctggcaaagc acactgaaca gcatcgtggg 23760
tctgggggtg caatccctga agcgccgacg atgcttctga atagctaacg tgtcgtatgt 23820
gtgtcatgta tgcgtccatg tcgccgccag aggagctgct gagccgccgc gcgcccgctt 23880
tccaagatgg ctaccccttc gatgatgccg cagtggtctt acatgcacat ctcgggccag 23940
gacgcctcgg agtacctgag ccccgggctg gtgcagtttg cccgcgccac cgagacgtac 24000
ttcagcctga ataacaagtt tagaaacccc acggtggcgc ctacgcacga cgtgaccaca 24060
gaccggtccc agcgtttgac gctgcggttc atccctgtgg accgtgagga tactgcgtac 24120
tcgtacaagg cgcggttcac cctagctgtg ggtgataacc gtgtgctgga catggcttcc 24180
acgtactttg acatccgcgg cgtgctggac aggggcccta cttttaagcc ctactctggc 24240
actgcctaca acgccctggc tcccaagggt gccccaaatc cttgcgaatg ggatgaagct 24300
gctactgctc ttgaaataaa cctagaagaa gaggacgatg acaacgaaga cgaagtagac 24360
gagcaagctg agcagcaaaa aactcacgta tttgggcagg cgccttattc tggtataaat 24420
attacaaagg agggtattca aataggtgtc gaaggtcaaa cacctaaata tgccgataaa 24480
acatttcaac ctgaacctca aataggagaa tctcagtggt acgaaactga aattaatcat 24540
gcagctggga gagtccttaa aaagactacc ccaatgaaac catgttacgg ttcatatgca 24600
aaacccacaa atgaaaatgg agggcaaggc attcttgtaa agcaacaaaa tggaaagcta 24660
gaaagtcaag tggaaatgca atttttctca actactgagg cgaccgcagg caatggtgat 24720
aacttgactc ctaaagtggt attgtacagt gaagatgtag atatagaaac cccagacact 24780
catatttctt acatgcccac tattaaggaa ggtaactcac gagaactaat gggccaacaa 24840
tctatgccca acaggcctaa ttacattgct tttagggaca attttattgg tctaatgtat 24900
tacaacagca cgggtaatat gggtgttctg gcgggccaag catcgcagtt gaatgctgtt 24960
gtagatttgc aagacagaaa cacagagctt tcataccagc ttttgcttga ttccattggt 25020
gatagaacca ggtacttttc tatgtggaat caggctgttg acagctatga tccagatgtt 25080
agaattattg aaaatcatgg aactgaagat gaacttccaa attactgctt tccactggga 25140
ggtgtgatta atacagagac tcttaccaag gtaaaaccta aaacaggtca ggaaaatgga 25200
tgggaaaaag atgctacaga attttcagat aaaaatcaaa taagagttgg aaataatttt 25260
gccatggaaa tcaatctaaa tgccaacctg tggagaaatt tcctgtactc caacatagcg 25320
ctgtatttgc ccgacaagct aaagtacagt ccttccaacg taaaaatttc tgataaccca 25380
aacacctacg actacatgaa caagcgagtg gtggctcccg ggttagtgga ctgctacatt 25440
aaccttggag cacgctggtc ccttgactat atggacaacg tcaacccatt taaccaccac 25500
cgcaatgctg gcctgcgcta ccgctcaatg ttgctgggca atggtcgcta tgtgcccttc 25560
cacatccagg tgcctcagaa gttctttgcc attaaaaacc tccttctcct gccgggctca 25620
tacacctacg agtggaactt caggaaggat gttaacatgg ttctgcagag ctccctagga 25680
aatgacctaa gggttgacgg agccagcatt aagtttgata gcatttgcct ttacgccacc 25740
ttcttcccca tggcccacaa caccgcctcc acgcttgagg ccatgcttag aaacgacacc 25800
aacgaccagt cctttaacga ctatctctcc gccgccaaca tgctctaccc tatacccgcc 25860
aacgctacca acgtgcccat atccatcccc tcccgcaact gggcggcttt ccgcggctgg 25920
gccttcacgc gccttaagac taaggaaacc ccatcactgg gctcgggcta cgacccttat 25980
tacacctact ctggctctat accctaccta gatggaacct tttacctcaa ccacaccttt 26040
aagaaggtgg ccattacctt tgactcttct gtcagctggc ctggcaatga ccgcctgctt 26100
acccccaacg agtttgaaat taagcgctca gttgacgggg agggttacaa cgttgcccag 26160
tgtaacatga ccaaagactg gttcctggta caaatgctag ctaactacaa cattggctac 26220
cagggcttct atatcccaga gagctacaag gaccgcatgt actccttctt tagaaacttc 26280
cagcccatga gccgtcaggt ggtggatgat actaaataca aggactacca acaggtgggc 26340
atcctacacc aacacaacaa ctctggattt gttggctacc ttgcccccac catgcgcgaa 26400
ggacaggcct accctgctaa cttcccctat ccgcttatag gcaagaccgc agttgacagc 26460
attacccaga aaaagtttct ttgcgatcgc accctttggc gcatcccatt ctccagtaac 26520
tttatgtcca tgggcgcact cacagacctg ggccaaaacc ttctctacgc caactccgcc 26580
cacgcgctag acatgacttt tgaggtggat cccatggacg agcccaccct tctttatgtt 26640
ttgtttgaag tctttgacgt ggtccgtgtg caccggccgc accgcggcgt catcgaaacc 26700
gtgtacctgc gcacgccctt ctcggccggc aacgccacaa cataaagaag caagcaacat 26760
caacaacagc tgccgccatg ggctccagtg agcaggaact gaaagccatt gtcaaagatc 26820
ttggttgtgg gccatatttt ttgggcacct atgacaagcg ctttccaggc tttgtttctc 26880
cacacaagct cgcctgcgcc atagtcaata cggccggtcg cgagactggg ggcgtacact 26940
ggatggcctt tgcctggaac ccgcactcaa aaacatgcta cctctttgag ccctttggct 27000
tttctgacca gcgactcaag caggtttacc agtttgagta cgagtcactc ctgcgccgta 27060
gcgccattgc ttcttccccc gaccgctgta taacgctgga aaagtccacc caaagcgtac 27120
aggggcccaa ctcggccgcc tgtggactat tctgctgcat gtttctccac gcctttgcca 27180
actggcccca aactcccatg gatcacaacc ccaccatgaa ccttattacc ggggtaccca 27240
actccatgct caacagtccc caggtacagc ccaccctgcg tcgcaaccag gaacagctct 27300
acagcttcct ggagcgccac tcgccctact tccgcagcca cagtgcgcag attaggagcg 27360
ccacttcttt ttgtcacttg aaaaacatgt aaaaataatg tactagagac actttcaata 27420
aaggcaaatg cttttatttg tacactctcg ggtgattatt tacccccacc cttgccgtct 27480
gcgccgttta aaaatcaaag gggttctgcc gcgcatcgct atgcgccact ggcagggaca 27540
cgttgcgata ctggtgttta gtgctccact taaactcagg cacaaccatc cgcggcagct 27600
cggtgaagtt ttcactccac aggctgcgca ccatcaccaa cgcgtttagc aggtcgggcg 27660
ccgatatctt gaagtcgcag ttggggcctc cgccctgcgc gcgcgagttg cgatacacag 27720
ggttgcagca ctggaacact atcagcgccg ggtggtgcac gctggccagc acgctcttgt 27780
cggagatcag atccgcgtcc aggtcctccg cgttgctcag ggcgaacgga gtcaactttg 27840
gtagctgcct tcccaaaaag ggcgcgtgcc caggctttga gttgcactcg caccgtagtg 27900
gcatcaaaag gtgaccgtgc ccggtctggg cgttaggata cagcgcctgc ataaaagcct 27960
tgatctgctt aaaagccacc tgagcctttg cgccttcaga gaagaacatg ccgcaagact 28020
tgccggaaaa ctgattggcc ggacaggccg cgtcgtgcac gcagcacctt gcgtcggtgt 28080
tggagatctg caccacattt cggccccacc ggttcttcac gatcttggcc ttgctagact 28140
gctccttcag cgcgcgctgc ccgttttcgc tcgtcacatc catttcaatc acgtgctcct 28200
tatttatcat aatgcttccg tgtagacact taagctcgcc ttcgatctca gcgcagcggt 28260
gcagccacaa cgcgcagccc gtgggctcgt gatgcttgta ggtcacctct gcaaacgact 28320
gcaggtacgc ctgcaggaat cgccccatca tcgtcacaaa ggtcttgttg ctggtgaagg 28380
tcagctgcaa cccgcggtgc tcctcgttca gccaggtctt gcatacggcc gccagagctt 28440
ccacttggtc aggcagtagt ttgaagttcg cctttagatc gttatccacg tggtacttgt 28500
ccatcagcgc gcgcgcagcc tccatgccct tctcccacgc agacacgatc ggcacactca 28560
gcgggttcat caccgtaatt tcactttccg cttcgctggg ctcttcctct tcctcttgcg 28620
tccgcatacc acgcgccact gggtcgtctt cattcagccg ccgcactgtg cgcttacctc 28680
ctttgccatg cttgattagc accggtgggt tgctgaaacc caccatttgt agcgccacat 28740
cttctctttc ttcctcgctg tccacgatta cctctggtga tggcgggcgc tcgggcttgg 28800
gagaagggcg cttctttttc ttcttgggcg caatggccaa atccgccgcc gaggtcgatg 28860
gccgcgggct gggtgtgcgc ggcaccagcg cgtcttgtga tgagtcttcc tcgtcctcgg 28920
actcgatacg ccgcctcatc cgcttttttg ggggcgcccg gggaggcggc ggcgacgggg 28980
acggggacga cacgtcctcc atggttgggg gacgtcgcgc cgcaccgcgt ccgcgctcgg 29040
gggtggtttc gcgctgctcc tcttcccgac tggccatttc cttctcctat aggcagaaaa 29100
agatcatgga gtcagtcgag aagaaggaca gcctaaccgc cccctctgag ttcgccacca 29160
ccgcctccac cgatgccgcc aacgcgccta ccaccttccc cgtcgaggca cccccgcttg 29220
aggaggagga agtgattatc gagcaggacc caggttttgt aagcgaagac gacgaggacc 29280
gctcagtacc aacagaggat aaaaagcaag accaggacaa cgcagaggca aacgaggaac 29340
aagtcgggcg gggggacgaa aggcatggcg actacctaga tgtgggagac gacgtgctgt 29400
tgaagcatct gcagcgccag tgcgccatta tctgcgacgc gttgcaagag cgcagcgatg 29460
tgcccctcgc catagcggat gtcagccttg cctacgaacg ccacctattc tcaccgcgcg 29520
taccccccaa acgccaagaa aacggcacat gcgagcccaa cccgcgcctc aacttctacc 29580
ccgtatttgc cgtgccagag gtgcttgcca cctatcacat ctttttccaa aactgcaaga 29640
tacccctatc ctgccgtgcc aaccgcagcc gagcggacaa gcagctggcc ttgcggcagg 29700
gcgctgtcat acctgatatc gcctcgctca acgaagtgcc aaaaatcttt gagggtcttg 29760
gacgcgacga gaagcgcgcg gcaaacgctc tgcaacagga aaacagcgaa aatgaaagtc 29820
actctggagt gttggtggaa ctcgagggtg acaacgcgcg cctagccgta ctaaaacgca 29880
gcatcgaggt cacccacttt gcctacccgg cacttaacct accccccaag gtcatgagca 29940
cagtcatgag tgagctgatc gtgcgccgtg cgcagcccct ggagagggat gcaaatttgc 30000
aagaacaaac agaggagggc ctacccgcag ttggcgacga gcagctagcg cgctggcttc 30060
aaacgcgcga gcctgccgac ttggaggagc gacgcaaact aatgatggcc gcagtgctcg 30120
ttaccgtgga gcttgagtgc atgcagcggt tctttgctga cccggagatg cagcgcaagc 30180
tagaggaaac attgcactac acctttcgac agggctacgt acgccaggcc tgcaagatct 30240
ccaacgtgga gctctgcaac ctggtctcct accttggaat tttgcacgaa aaccgccttg 30300
ggcaaaacgt gcttcattcc acgctcaagg gcgaggcgcg ccgcgactac gtccgcgact 30360
gcgtttactt atttctatgc tacacctggc agacggccat gggcgtttgg cagcagtgct 30420
tggaggagtg caacctcaag gagctgcaga aactgctaaa gcaaaacttg aaggacctat 30480
ggacggcctt caacgagcgc tccgtggccg cgcacctggc ggacatcatt ttccccgaac 30540
gcctgcttaa aaccctgcaa cagggtctgc cagacttcac cagtcaaagc atgttgcaga 30600
actttaggaa ctttatccta gagcgctcag gaatcttgcc cgccacctgc tgtgcacttc 30660
ctagcgactt tgtgcccatt aagtaccgcg aatgccctcc gccgctttgg ggccactgct 30720
accttctgca gctagccaac taccttgcct accactctga cataatggaa gacgtgagcg 30780
gtgacggtct actggagtgt cactgtcgct gcaacctatg caccccgcac cgctccctgg 30840
tttgcaattc gcagctgctt aacgaaagtc aaattatcgg tacctttgag ctgcagggtc 30900
cctcgcctga cgaaaagtcc gcggctccgg ggttgaaact cactccgggg ctgtggacgt 30960
cggcttacct tcgcaaattt gtacctgagg actaccacgc ccacgagatt aggttctacg 31020
aagaccaatc ccgcccgcca aatgcggagc ttaccgcctg cgtcattacc cagggccaca 31080
ttcttggcca attgcaagcc atcaacaaag cccgccaaga gtttctgcta cgaaagggac 31140
ggggggttta cttggacccc cagtccggcg aggagctcaa cccaatcccc ccgccgccgc 31200
agccctatca gcagcagccg cgggcccttg cttcccagga tggcacccaa aaagaagctg 31260
cagctgccgc cgccacccac ggacgaggag gaatactggg acagtcaggc agaggaggtt 31320
ttggacgagg aggaggagga catgatggaa gactgggaga gcctagacga ggaagcttcc 31380
gaggtcgaag aggtgtcaga cgaaacaccg tcaccctcgg tcgcattccc ctcgccggcg 31440
ccccagaaat cggcaaccgg ttccagcatg gctacaacct ccgctcctca ggcgccgccg 31500
gcactgcccg ttcgccgacc caaccgtaga tgggacacca ctggaaccag ggccggtaag 31560
tccaagcagc cgccgccgtt agcccaagag caacaacagc gccaaggcta ccgctcatgg 31620
cgcgggcaca agaacgccat agttgcttgc ttgcaagact gtgggggcaa catctccttc 31680
gcccgccgct ttcttctcta ccatcacggc gtggccttcc cccgtaacat cctgcattac 31740
taccgtcatc tctacagccc atactgcacc ggcggcagcg gcagcggcag caacagcagc 31800
ggccacacag aagcaaaggc gaccggatag caagactctg acaaagccca agaaatccac 31860
agcggcggca gcagcaggag gaggagcgct gcgtctggcg cccaacgaac ccgtatcgac 31920
ccgcgagctt agaaacagga tttttcccac tctgtatgct atatttcaac agagcagggg 31980
ccaagaacaa gagctgaaaa taaaaaacag gtctctgcga tccctcaccc gcagctgcct 32040
gtatcacaaa agcgaagatc agcttcggcg cacgctggaa gacgcggagg ctctcttcag 32100
taaatactgc gcgctgactc ttaaggacta gtttcgcgcc ctttctcaaa tttaagcgcg 32160
aaaactacgt catctccagc ggccacaccc ggcgccagca cctgtcgtca gcgccatttc 32220
aactttgtat acaaaagttg tgatgagcaa ggaaattccc acgccctaca tgtggagtta 32280
ccagccacaa atgggacttg cggctggagc tgcccaagac tactcaaccc gaataaacta 32340
catgagcgcg ggaccccaca tgatatcccg ggtcaacgga atacgcgccc accgaaaccg 32400
aattctcctg gaacaggcgg ctattaccac cacacctcgt aataacctta atccccgtag 32460
ttggcccgct gccctggtgt accaggaaag tcccgctccc accactgtgg tacttcccag 32520
agacgcccag gccgaagttc agatgactaa ctcaggggcg cagcttgcgg gcggctttcg 32580
tcacagggtg cggtcgcccg ggcagggtat aactcacctg acaatcagag ggcgaggtat 32640
tcagctcaac gacgagtcgg tgagctcctc gcttggtctc cgtccggacg ggacatttca 32700
gatcggcggc gccggccgct cttcattcac gcctcgtcag gcaatcctaa ctctgcagac 32760
ctcgtcctct gagccgcgct ctggaggcat tggaactctg caatttattg aggagtttgt 32820
gccatcggtc tactttaacc ccttctcggg acctcccggc cactatccgg atcaatttat 32880
tcctaacttt gacgcggtaa aggactcggc ggacggctac gactgaatgt taagtggaga 32940
ggcagagcaa ctgcgcctga aacacctggt ccactgtcgc cgccacaagt gctttgcccg 33000
cgactccggt gagttttgct actttgaatt gcccgaggat catatcgagg gcccggcgca 33060
cggcgtccgg cttaccgccc agggagagct tgcccgtagc ctgattcggg agtttaccca 33120
gcgccccctg ctagttgagc gggacagggg accctgtgtt ctcactgtga tttgcaactg 33180
tcctaaccct ggattacatc aagatctttg ttgccatctc tgtgctgagt ataataaata 33240
cagaaattaa aatatactgg ggctcctatc gccatcctgt aaacgccacc gtcttcaccc 33300
gcccaagcaa accaaggcga accttacctg gtacttttaa catctctccc tctgtgattt 33360
acaacagttt caacccagac ggagtgagtc tacgagagaa cctctccgag ctcagctact 33420
ccatcagaaa aaacaccacc ctccttacct gccgggaacg tacgagtgcg tcaccggccg 33480
ctgcaccaca cctaccgcct gaccgtaaac cagacttttt ccggacagac ctcaataact 33540
ctgtttacca gaacaggagg tgagcttaga aaacccttag ggtattaggc caaaggcgca 33600
gctactgtgg ggtttatgaa caattcaagc aactctacgg gctattctaa ttcaggtttc 33660
tctagaatcg gggttggggt tattctctgt cttgtgattc tctttattct tatactaacg 33720
cttctctgcc taaggctcgc cgcctgctgt gtgcacattt gcatttattg tcagcttttt 33780
aaacgctggg gtcgccaccc aagatgatta ggtacataat cctaggttta ctcacccttg 33840
cgtcagccca cggtaccacc caaaaggtgg attttaagga gccagcctgt aatgttacat 33900
tcgcagctga agctaatgag tgcaccactc ttataaaatg caccacagaa catgaaaagc 33960
tgcttattcg ccacaaaaac aaaattggca agtatgctgt ttatgctatt tggcagccag 34020
gtgacactac agagtataat gttacagttt tccagggtaa aagtcataaa acttttatgt 34080
atacttttcc attttatgaa atgtgcgaca ttaccatgta catgagcaaa cagtataagt 34140
tgtggccccc acaaaattgt gtggaaaaca ctggcacttt ctgctgcact gctatgctaa 34200
ttacagtgct cgctttggtc tgtaccctac tctatattaa atacaaaagc agacgcagct 34260
ttattgagga aaagaaaatg ccttaattta ctaagttaca aagctaatgt caccactaac 34320
tgctttactc gctgcttgca aaacaaattc aaaaagttag cattataatt agaataggat 34380
ttaaaccccc cggtcatttc ctgctcaata ccattcccct gaacaattga ctctatgtgg 34440
gatatgctcc agcgctacaa ccttgaagtc aggcttcctg gatgtcagca tctgactttg 34500
gccagcacct gtcccgcgga tttgttccag tccaactaca gcgacccacc ctaacagaga 34560
tgaccaacac aaccaacgcg gccgccgcta ccggacttac atctaccaca aatacacccc 34620
aagtttctgc ctttgtcaat aactgggata acttgggcat gtggtggttc tccatagcgc 34680
ttatgtttgt atgccttatt attatgtggc tcatctgctg cctaaagcgc aaacgcgccc 34740
gaccacccat ctatagtccc atcattgtgc tacacccaaa caatgatgga atccatagat 34800
tggacggact gaaacacatg ttcttttctc ttacagtatg attaaatgag acatgattcc 34860
tcgagttttt atattactga cccttgttgc gcttttttgt gcgtgctcca cattggctgc 34920
ggtttctcac atcgaagtag actgcattcc agccttcaca gtctatttgc tttacggatt 34980
tgtcaccctc acgctcatct gcagcctcat cactgtggtc atcgccttta tccagtgcat 35040
tgactgggtc tgtgtgcgct ttgcatatct cagacaccat ccccagtaca gggacaggac 35100
tatagctgag cttcttagaa ttctttaatt atgaaattta ctgtgacttt tctgctgatt 35160
atttgcaccc tatctgcgtt ttgttccccg acctccaagc ctcaaagaca tatatcatgc 35220
agattcactc gtatatggaa tattccaagt tgctacaatg aaaaaagcga tctttccgaa 35280
gcctggttat atgcaatcat ctctgttatg gtgttctgca gtaccatctt agccctagct 35340
atatatccct accttgacat tggctggaac gcaatagatg ccatgaacca cccaactttc 35400
cccgcgcccg ctatgcttcc actgcaacaa gttgttgccg gcggctttgt cccagccaat 35460
cagcctcgcc caccttctcc cacccccact gaaatcagct actttaatct aacaggagga 35520
gatgactgac accctagatc tagaaatgga cggaattatt acagagcagc gcctgctaga 35580
aagacgcagg gcagcggccg agcaacagcg catgaatcaa gagctccaag acatggttaa 35640
cttgcaccag tgcaaaaggg gtatcttttg tctggtaaag caggccaaag tcacctacga 35700
cagtaatacc accggacacc gccttagcta caagttgcca accaagcgtc agaaattggt 35760
ggtcatggtg ggagaaaagc ccattaccat aactcagcac tcggtagaaa ccgaaggctg 35820
cattcactca ccttgtcaag gacctgagga tctctgcacc cttattaaga ccctgtgcgg 35880
tctcaaagat cttattccct ttaactaata aaaaaaaata ataaagcatc acttacttaa 35940
aatcagttag caaatttctg tccagtttat tcagcagcac ctccttgccc tcctcccagc 36000
tctggtattg cagcttcctc ctggctgcaa actttctcca caatctaaat ggaatgtcag 36060
tttcctcctg ttcctgtcca tccgcaccca ctatcttcat gttgttgcag atgaagcgcg 36120
caagaccgtc tgaagatacc ttcaaccccg tgtatccata tgacacggaa accggtcctc 36180
caactgtgcc ttttcttact cctccctttg tatcccccaa tgggtttcaa gagagtcccc 36240
ctggggtact ctctttgcgc ctatccgaac ctctagttac ctccaatggc atgcttgcgc 36300
tcaaaatggg caacggcctc tctctggacg aggccggcaa ccttacctcc caaaatgtaa 36360
ccactgtgag cccacctctc aaaaaaacca agtcaaacat aaacctggaa atatctgcac 36420
ccctcacagt tacctcagaa gccctaactg tggctgccgc cgcacctcta atggtcgcgg 36480
gcaacacact caccatgcaa tcacaggccc cgctaaccgt gcacgactcc aaacttagca 36540
ttgccaccca aggacccctc acagtgtcag aaggaaagct agccctgcaa acatcaggcc 36600
ccctcaccac caccgatagc agtaccctta ctatcactgc ctcaccccct ctaactactg 36660
ccactggtag cttgggcatt gacttgaaag agcccattta tacacaaaat ggaaaactag 36720
gactaaagta cggggctcct ttgcatgtaa cagacgacct aaacactttg accgtagcaa 36780
ctggtccagg tgtgactatt aataatactt ccttgcaaac taaagttact ggagccttgg 36840
gttttgattc acaaggcaat atgcaactta atgtagcagg aggactaagg attgattctc 36900
aaaacagacg ccttatactt gatgttagtt atccgtttga tgctcaaaac caactaaatc 36960
taagactagg acagggccct ctttttataa actcagccca caacttggat attaactaca 37020
acaaaggcct ttacttgttt acagcttcaa acaattccaa aaagcttgag gttaacctaa 37080
gcactgccaa ggggttgatg tttgacgcta cagccatagc cattaatgca ggagatgggc 37140
ttgaatttgg ttcacctaat gcaccaaaca caaatcccct caaaacaaaa attggccatg 37200
gcctagaatt tgattcaaac aaggctatgg ttcctaaact aggaactggc cttagttttg 37260
acagcacagg tgccattaca gtaggaaaca aaaataatga taagctaact ttatggactg 37320
gaataaaccc tccacctaac tgtcaaattg tggaaaacac taatacaaat gatggcaaac 37380
ttactttagt attagtaaaa aacggagggc ttgttaatgg ctacgtgtct ctagttggtg 37440
tatcagacac tgtgaaccaa atgttcacac aaaagacagc aaacatccaa ttaagattat 37500
attttgactc ttctggaaat ctattaactg atgaatcaga cttaaaaatt ccacttaaaa 37560
ataaatcttc tacagcgacc agtgaaactg tagccagcag caaagccttt atgccaagta 37620
ctacagctta tcccttcaac accactacta gggatagtga aaactacatt catggaatat 37680
gttactacat gactagttat gatagaagtc tatttccctt gaacatttct ataatgctaa 37740
acagccgtat gatttcttcc aatgttgcct atgccataca atttgaatgg aatctaaatg 37800
caagtgaatc tccagaaagc aacatagcta cgctgaccac atcccccttt ttcttttctt 37860
acattacaga agacgacaac taataaagaa tcgtttgtgt tatgtttcaa cgtgtttatt 37920
tttcaattgc agaaaatttc aagtcatttt tcattcagta gtatagcccc accaccacat 37980
agcttataca gatcaccgta cctcaacttt gtataataaa gttgtaatca aactcacaga 38040
accctagtat tcaacctgcc acctccctcc caacacacag agtacacagt cctttctccc 38100
cggctggcct taaaaagcat catatcatgg gtaacagaca tattcttagg tgttatattc 38160
cacacggttt cctgtcgagc caaacgctca tcagtgatat taataaactc cccgggcagc 38220
tcacttaagt tcatgtcgct gtccagctgc tgagccacag gctgctgtcc aacttgcggt 38280
tgcttaacgg gcggcgaagg agaagtccac gcctacatgg gggtagagtc ataatcgtgc 38340
atcaggatag ggcggtggtg ctgcagcagc gcgcgaataa actgctgccg ccgccgctcc 38400
gtcctgcagg aatacaacat ggcagtggtc tcctcagcga tgattcgcac cgcccgcagc 38460
ataaggcgcc ttgtcctccg ggcacagcag cgcaccctga tctcacttaa atcagcacag 38520
taactgcagc acagcaccac aatattgttc aaaatcccac agtgcaaggc gctgtatcca 38580
aagctcatgg cggggaccac agaacccacg tggccatcat accacaagcg caggtagatt 38640
aagtggcgac ccctcataaa cacgctggac ataaacatta cctcttttgg catgttgtaa 38700
ttcaccacct cccggtacca tataaacctc tgattaaaca tggcgccatc caccaccatc 38760
ctaaaccagc tggccaaaac ctgcccgccg gctatacact gcagggaacc gggactggaa 38820
caatgacagt ggagagccca ggactcgtaa ccatggatca tcatgctcgt catgatatca 38880
atgttggcac aacacaggca cacgtgcata cacttcctca ggattacaag ctcctcccgc 38940
gttagaacca tatcccaggg aacaacccat tcctgaatca gcgtaaatcc cacactgcag 39000
ggaagacctc gcacgtaact cacgttgtgc attgtcaaag tgttacattc gggcagcagc 39060
ggatgatcct ccagtatggt agcgcgggtt tctgtctcaa aaggaggtag acgatcccta 39120
ctgtacggag tgcgccgaga caaccgagat cgtgttggtc gtagtgtcat gccaaatgga 39180
acgccggacg tagtcatatt tcctgaagca aaaccaggtg cgggcgtgac aaacagatct 39240
gcgtctccgg tctcgccgct tagatcgctc tgtgtagtag ttgtagtata tccactctct 39300
caaagcatcc aggcgccccc tggcttcggg ttctatgtaa actccttcat gcgccgctgc 39360
cctgataaca tccaccaccg cagaataagc cacacccagc caacctacac attcgttctg 39420
cgagtcacac acgggaggag cgggaagagc tggaagaacc atgttttttt ttttattcca 39480
aaagattatc caaaacctca aaatgaagat ctattaagtg aacgcgctcc cctccggtgg 39540
cgtggtcaaa ctctacagcc aaagaacaga taatggcatt tgtaagatgt tgcacaatgg 39600
cttccaaaag gcaaacggcc ctcacgtcca agtggacgta aaggctaaac ccttcagggt 39660
gaatctcctc tataaacatt ccagcacctt caaccatgcc caaataattc tcatctcgcc 39720
accttctcaa tatatctcta agcaaatccc gaatattaag tccggccatt gtaaaaatct 39780
gctccagagc gccctccacc ttcagcctca agcagcgaat catgattgca aaaattcagg 39840
ttcctcacag acctgtataa gattcaaaag cggaacatta acaaaaatac cgcgatcccg 39900
taggtccctt cgcagggcca gctgaacata atcgtgcagg tctgcacgga ccagcgcggc 39960
cacttccccg ccaggaacca tgacaaaaga acccacactg attatgacac gcatactcgg 40020
agctatgcta accagcgtag ccccgatgta agcttgttgc atgggcggcg atataaaatg 40080
caaggtgctg ctcaaaaaat caggcaaagc ctcgcgcaaa aaagaaagca catcgtagtc 40140
atgctcatgc agataaaggc aggtaagctc cggaaccacc acagaaaaag acaccatttt 40200
tctctcaaac atgtctgcgg gtttctgcat aaacacaaaa taaaataaca aaaaaacatt 40260
taaacattag aagcctgtct tacaacagga aaaacaaccc ttataagcat aagacggact 40320
acggccatgc cggcgtgacc gtaaaaaaac tggtcaccgt gattaaaaag caccaccgac 40380
agctcctcgg tcatgtccgg agtcataatg taagactcgg taaacacatc aggttgattc 40440
acatcggtca gtgctaaaaa gcgaccgaaa tagcccgggg gaatacatac ccgcaggcgt 40500
agagacaaca ttacagcccc cataggaggt ataacaaaat taataggaga gaaaaacaca 40560
taaacacctg aaaaaccctc ctgcctaggc aaaatagcac cctcccgctc cagaacaaca 40620
tacagcgctt ccacagcggc agccataaca gtcagcctta ccagtaaaaa agaaaaccta 40680
ttaaaaaaac accactcgac acggcaccag ctcaatcagt cacagtgtaa aaaagggcca 40740
agtgcagagc gagtatatat aggactaaaa aatgacgtaa cggttaaagt ccacaaaaaa 40800
cacccagaaa accgcacgcg aacctacgcc cagaaacgaa agccaaaaaa cccacaactt 40860
cctcaaatcg tcacttccgt tttcccacgt tacgtcactt cccattttaa gaaaactaca 40920
attcccaaca catacaagtt actccgccct aaaacctacg tcacccgccc cgttcccacg 40980
ccccgcgcca cgtcacaaac tccaccccct cattatcata ttggcttcaa tccaaaataa 41040
ggtatattat tgatgatgta gggataacag ggtaatcagc tttcttgtac aaagttgaaa 41100
tccggggatc ctctagagtc gacctgcagg catgcaagct tggcgtaatc atggtcatag 41160
ctgtttcctg tgtgaaattg ttatccgctc acaattccac acaacatacg agccggaagc 41220
ataaagtgta aagcctgggg tgcctaatga gtgagcta 41258
<210> 6
<211> 41228
<212> DNA
<213> 人工序列
<220>
<223> 合成腺病毒基因组 (AdSyn-CO989)
<400> 6
gttccactga gcgtcagacc ccttaataag atgatcttct tgagatcgtt ttggtctgcg 60
cgtaatctct tgctctgaaa acgaaaaaac cgccttgcag ggcggttttt cgaaggttct 120
ctgagctacc aactctttga accgaggtaa ctggcttgga ggagcgcagt caccaaaact 180
tgtcctttca gtttagcctt aaccggcgca tgacttcaag actaactcct ctaaatcaat 240
taccagtggc tgctgccagt ggtgcttttg catgtctttc cgggttggac tcaagacgat 300
agttaccgga taaggcgcag cggtcggact gaacgggggg ttcgtgcata cagtccagct 360
tggagcgaac tgcctacccg gaactgagtg tcaggcgtgg aatgagacaa acgcggccat 420
aacagcggaa tgacaccggt aaaccgaaag gcaggaacag gagagcgcac gagggagccg 480
ccaggggaaa cgcctggtat ctttatagtc ctgtcgggtt tcgccaccac tgatttgagc 540
gtcagatttc gtgatgcttg tcaggggggc ggagcctatg gaaaaacggc tttgccgcgg 600
ccctctcact tccctgttaa gtatcttcct ggcatcttcc aggaaatctc cgccccgttc 660
gtaagccatt tccgctcgcc gcagtcgaac gaccgagcgt agcgagtcag tgagcgagga 720
agcggaatat atcctgtatc acatattctg ctgacgcacc ggtgcagcct tttttctcct 780
gccacatgaa gcacttcact gacaccctca tcagtgccaa catagtaagc cagtatacac 840
tccgctagcg ctgaggtctg cctcgtgaag aaggtgttgc tgactcatac caggcctgaa 900
tcgccccatc atccagccag aaagtgaggg agccacggtt gatgagagct ttgttgtagg 960
tggaccagtt ggtgattttg aacttttgct ttgccacgga acggtctgcg ttgtcgggaa 1020
gatgcgtgat ctgatccttc aactcagcaa aagttcgatt tattcaacaa agccacgttg 1080
tgtctcaaaa tctctgatgt tacattgcac aagataaaaa tatatcatca tgaacaataa 1140
aactgtctgc ttacataaac agtaatacaa ggggtgttga tactctcagt acaatctgct 1200
ctgatgccgc atagttaagc cagtatctgc tccctgcttg tgtgttggag gtcgctgagt 1260
agtgcgcgag caaaatttaa gctacaacaa ggcaaggctt gaccgacaat tgcatgaaga 1320
atctgcttag ggttaggcgt tttgcgctgc ttcgcgatgt acgggccaga tatacgcgta 1380
tctgagggga ctagggtgtg tttaggcgaa aagcggggct tcggttgtac gcggttagga 1440
gtcccctcag gatatagtag tttcgctttt gcatagggag ggggaaatgt agtcttatgc 1500
aatactcttg tagtcttgca acatggtaac gatgagttag caacatgcct tacaaggaga 1560
gaaaaagcac cgtgcatgcc gattggtgga agtaaggtgg tacgatcgtg ccttattagg 1620
aaggcaacag acgggtctga catggattgg acgaaccact gaattccgca ttgcagagat 1680
attgtattta agtgcctagc tcgatacaat aaacgccatt tgaccattca ccacattggt 1740
gtgcacctcc aagctgggta cggatccggc cttgccggcc tcgagcggcc gctagcgccg 1800
ccactatggg atcaagatcg ccaaaaaaga agagaaaggt gccgaagaag catgcagcac 1860
caccaaaaaa aaaacgaaaa gtagaagacc cacgatttat gtacccatac gatgttcctg 1920
actatgcggg tatgaaaaac atcaaaaaaa accaggtaat gaacctgggt ccgaactcta 1980
aactgctgaa agaatacaaa tcccagctga tcgaactgaa catcgaacag ttcgaagcag 2040
gtatcggtct gatcctgggt gatgcttaca tccgttctcg tgatgaaggt aaaacctact 2100
gtatgcagtt cgagtggaaa aacaaagcat acatggacca cgtatgtctg ctgtacgatc 2160
agtgggtact gtccccgccg cacaaaaaag aacgtgttaa ccacctgggt aacctggtaa 2220
tcacctgggg cgcccagact ttcaaacacc aagctttcaa caaactggct aacctgttca 2280
tcgttaacaa caaaaaaacc atcccgaaca acctggttga aaactacctg accccgatgt 2340
ctctggcata ctggttcatg gatgatggtg gtaaatggga ttacaacaaa aactctacca 2400
acaaatcgat cgtactgaac acccagtctt tcactttcga agaagtagaa tacctggtta 2460
agggtctgcg taacaaattc caactgaact gttacgtaaa aatcaacaaa aacaaaccga 2520
tcatctacat cgattctatg tcttacctga tcttctacaa cctgatcaaa ccgtacctga 2580
tcccgcagat gatgtacaaa ctgccgaaca ctatctcctc cgaaactttc ctgaaataag 2640
gtaccgatcc agacatgata agatacattg atgagtttgg acaaaccaca actagaatgc 2700
agtgaaaaaa atgctttatt tgtgaaattt gtgatgctat tgctttattt gtaaccatta 2760
taagctgcaa taaacaagtt aacaacaaca attgcattca ttttatgttt caggttcagg 2820
gggaggtgtg ggaggttttt taaagcaagt aaaacctcta caaatgtggt atggctgatt 2880
atgatcatcg taaacttggt ctgacagtta ccaatgctta atcagtgagg cacctatctc 2940
agcgatctgt ctatttcgtt catccatagt tgcctgactc cccgtcgtgt agataactac 3000
gatacgggag ggcttaccat ctggccccag tgctgcaatg ataccgcgag acccacgctc 3060
accggctcca gatttatcag caataaacca gccagccgga agggccgagc gcagaagtgg 3120
tcctgcaact ttatccgcct ccatccagtc tattaattgt tgccgggaag ctagagtaag 3180
tagttcgcca gttaatagtt tgcgcaacgt tgttgccatt gctacaggca tcgtggtgtc 3240
acgctcgtcg tttggtatgg cttcattcag ctccggttcc caacgatcaa ggcgagttac 3300
atgatccccc atgttgtgca aaaaagcggt tagctccttc ggtcctccga tcgttgtcag 3360
aagtaagttg gccgcagtgt tatcactcat ggttatggca gcactgcata attctcttac 3420
tgtcatgcca tccgtaagat gcttttctgt gactggtgag tactcaacca agtcattctg 3480
agaatagtgt atgcggcgac cgagttgctc ttgcccggcg tcaatacggg ataataccgc 3540
gccacatagc agaactttaa aagtgctcat cattggaaaa cgttcttcgg ggcgaaaact 3600
ctcaaggatc ttaccgctgt tgagatccag ttcgatgtaa cccactcgtg cacccaactg 3660
atcttcagca tcttttactt tcaccagcgt ttctgggtga gcaaaaacag gaaggcaaaa 3720
tgccgcaaaa aagggaataa gggcgacacg gaaatgttga atactcatac tcttcctttt 3780
tcaatattat tgaagcattt atcagggtta ttgtctcatg agcggataca tatttgaatg 3840
tatttagaaa aataaacaaa taggggttcc gcgcacattt ccccgaaaag tgccacctga 3900
cgtctaagaa accattatta tcatgacatt aacctataaa aataggcgta tcacgaggcc 3960
ctttcgtctc gcgcgtttcg gtgatgacgg tgaaaacctc tgacacatgc agctcccgga 4020
gacggtcaca gcttgtctgt aagcggatgc cgggagcaga caagcccgtc agggcgcgtc 4080
agcgggtgtt ggcgggtgtc ggggctggct taactatgcg gcatcagagc agattgtact 4140
gagagtgcac catatgcggt gtgaaatacc gcacagatgc gtaaggagaa aataccgcat 4200
caggcgccat tcgccattca ggctgcgcaa ctgttgggaa gggcgatcgg tgcgggcctc 4260
ttcgctatta cgccagctgg cgaaaggggg atgtgctgca aggcgattaa gttgggtaac 4320
gccagggttt tcccagtcac gacgttgtaa aacgacggcc agtgaattac aactttgtac 4380
aaaaaagcag attaccctgt tatccctaca tcatcaataa tataccttat tttggattga 4440
agccaatatg ataatgaggg ggtggagttt gtgacgtggc gcggggcgtg ggaacggggc 4500
gggtgacgta gtagtgtggc ggaagtgtga tgttgcaagt gtggcggaac acatgtaagc 4560
gacggatgtg gcaaaagtga cgtttttggt gtgcgccggt gtacacagga agtgacaatt 4620
ttcgcgcggt tttaggcgga tgttgtagta aatttgggcg taaccgagta agatttggcc 4680
attttcgcgg gaaaactgaa taagaggaag tgaaatctga ataattttgt gttactcata 4740
gcgcgtaata tttgtctagg gccgcgggga ctttgaccgt ttacgtggag actcgcccag 4800
gtgtttttct caggtgtttt ccgcgttccg ggtcaaagtt ggcgttttat tattaaaccg 4860
tattaccgcc atgcatttaa tggagtgcct cgtgaggctc cggtgcccgt cagtgggcag 4920
agcgcacatc gcccacagtc cccgagaagt tggggggagg ggtcggcaat tgaaccggtg 4980
cctagagaag gtggcgcggg gtaaactggg aaagtgatgt cgtgtactgg ctccgccttt 5040
ttcccgaggg tgggggagaa ccgtatataa gtgcagtagt cgccgtgaac gttctttttc 5100
gcaacgggtt tgccgccaga acacaggtaa gtgccgtgtg tggttcccgc gggcctggcc 5160
tctttacggg ttatggccct tgcgtgcctt gaattacttc cacctggctg cagtacgtga 5220
ttcttgatcc cgagcttcgg gttggaagtg ggtgggagag ttcgaggcct tgcgcttaag 5280
gagccccttc gcctcgtgct tgagttgagg cctggcctgg gcgctggggc cgccgcgtgc 5340
gaatctggtg gcaccttcgc gcctgtctcg ctgctttcga taagtctcta gccatttaaa 5400
atttttgatg acctgctgcg acgctttttt tctggcaaga tagtcttgta aatgcgggcc 5460
aagatctgca cactggtatt tcggtttttg gggccgcggg cggcgacggg gcccgtgcgt 5520
cccagcgcac atgttcggcg aggcggggcc tgcgagcgcg gccaccgaga atcggacggg 5580
ggtagtctca agctggccgg cctgctctgg tgcctggcct cgcgccgccg tgtatcgccc 5640
cgccctgggc ggcaaggctg gcccggtcgg caccagttgc gtgagcggaa agatggccgc 5700
ttcccggccc tgctgcaggg agctcaaaat ggaggacgcg gcgctcggga gagcgggcgg 5760
gtgagtcacc cacacaaagg aaaagggcct ttccgtcctc agccgtcgct tcatgtgact 5820
ccacggagta ccgggcgccg tccaggcacc tcgattagtt ctcgagcttt tggagtacgt 5880
cgtctttagg ttggggggag gggttttatg cgatggagtt tccccacact gagtgggtgg 5940
agactgaagt taggccagct tggcacttga tgtaattctc cttggaattt gccctttttg 6000
agtttggatc ttggttcatt ctcaagcctc agacagtggt tcaaagtttt tttcttccat 6060
ttcaggtgtc gtgacgctag cgctaccgga ctcagatctc gagctcaagc ttcgaattct 6120
gcagcaccat ggactataaa gatgacgacg acaaggcttc gtaccccggc catcagcacg 6180
cgtctgcgtt cgaccaggct gcgcgttctc gcggccatag caaccgacgt acggcgttgc 6240
gccctcgccg gcagcaagaa gccacggaag tccgcccgga gcagaaaatg cccacgctac 6300
tgcgggttta tatagacggt ccccacggga tggggaaaac caccaccacg caactgctgg 6360
tggccctggg ttcgcgcgac gatatcgtct acgtacccga gccgatgact tactggcggg 6420
tgctgggggc ttccgagaca atcgcgaaca tctacaccac acaacaccgc cttgaccagg 6480
gtgagatatc ggccggggac gcggcggtgg taatgacaag cgcccagata acaatgggca 6540
tgccttatgc cgtgaccgac gccgttctgg ctcctcatat cgggggggag gctgggagct 6600
cacatgcccc gcccccggcc ctcaccctca tcttcgaccg ccatcccatc gccgccctcc 6660
tgtgctaccc ggccgcgcga taccttatgg gcagcatgac cccccaggcc gtgctggcgt 6720
tcgtggccct catcccgccg accttgcccg gcacaaacat cgtgttgggg gcccttccgg 6780
aggacagaca catcgaccgc ctggccaaac gccagcgccc cggcgagcgg cttgacctgg 6840
ctatgctggc cgcgattcgc cgcgtttacg ggctgcttgc caatacggtg cggtatctgc 6900
agggcggcgg gtcgtggcgg gaggattggg gacagctttc ggggacggcc gtgccgcccc 6960
agggtgccga gccccagagc aacgcgggcc cacgacccca tatcggggac acgttattta 7020
ccctgtttcg ggcccccgag ttgctggccc ccaacggcga cctgtacaac gtgtttgcct 7080
gggccttgga cgtcttggcc aaacgcctcc gtcccatgca cgtctttatc ctggattacg 7140
accaatcgcc cgccggctgc cgggacgccc tgctgcaact tacctccggg atgatccaga 7200
cccacgtcac caccccaggc tccataccga cgatctgcga cctggcgcgc acgtttgccc 7260
gggagatggg ggaggctaac ggaagcggag ctactaactt cagcctgctg aagcaggctg 7320
gtgacgtcga ggagaatcct ggcccaatga cttcgaaagt ttatgatcca gaacaaagga 7380
aacggatgat aactggtccg cagtggtggg ccagatgtaa acaaatgaat gttcttgatt 7440
catttattaa ttattatgat tcagaaaaac atgcagaaaa tgctgttatt tttttacatg 7500
gtaacgcggc ctcttcttat ttatggcgac atgttgtgcc acatattgag ccagtagcgc 7560
ggtgtattat accagacctt attggtatgg gcaaatcagg caaatctggt aatggttctt 7620
ataggttact tgatcattac aaatatctta ctgcatggtt tgaacttctt aatttaccaa 7680
agaagatcat ttttgtcggc catgattggg gtgcttgttt ggcatttcat tatagctatg 7740
agcatcaaga taagatcaaa gcaatagttc acgctgaaag tgtagtagat gtgattgaat 7800
catgggatga atggcctgat attgaagaag atattgcgtt gatcaaatct gaagaaggag 7860
aaaaaatggt tttggagaat aacttcttcg tggaaaccat gttgccatca aaaatcatga 7920
gaaagttaga accagaagaa tttgcagcat atcttgaacc attcaaagag aaaggtgaag 7980
ttcgtcgtcc aacattatca tggcctcgtg aaatcccgtt agtaaaaggt ggtaaacctg 8040
acgttgtaca aattgttagg aattataatg cttatctacg tgcaagtgat gatttaccaa 8100
aaatgtttat tgaatcggac ccaggattct tttccaatgc tattgttgaa ggtgccaaga 8160
agtttcctaa tactgaattt gtcaaagtaa aaggtcttca tttttcgcaa gaagatgcac 8220
ctgatgaaat gggaaaatat atcaaatcgt tcgttgagcg agttctcaaa aatgaacaat 8280
aaggagcgac tctagatcat aatcagccat accacatttg tagaggtttt acttgcttta 8340
aaaaacctcc cacacctccc cctgaacctg aaacataaaa tgaatgcaat tgttgttgtt 8400
aacttgttta ttgcagctta taatggttac aaataaagca atagcatcac aaatttcaca 8460
aataaagcat ttttttcact gcattctagt tgtggtttgt ccaaactcat caatgtaagt 8520
ttaaacggcg cgcctgaaat gtgtgggcgt ggcttaaggg tgggaaagaa tatataaggt 8580
gggggtctta tgtagttttg tatctgtttt gcagcagccg ccgccgccat gagcaccaac 8640
tcgtttgatg gaagcattgt gagctcatat ttgacaacgc gcatgccccc atgggccggg 8700
gtgcgtcaga atgtgatggg ctccagcatt gatggtcgcc ccgtcctgcc cgcaaactct 8760
actaccttga cctacgagac cgtgtctgga acgccgttgg agactgcagc ctccgccgcc 8820
gcttcagccg ctgcagccac cgcccgcggg attgtgactg actttgcttt cctgagcccg 8880
cttgcaagca gtgcagcttc ccgttcatcc gcccgcgatg acaagttgac ggctcttttg 8940
gcacaattgg attctttgac ccgggaactt aatgtcgttt ctcagcagct gttggatctg 9000
cgccagcagg tttctgccct gaaggcttcc tcccctccca atgcggttta aaacacaact 9060
tttctataca aagttgtaaa taaaaaacca gactctgttt ggatttggat caagctaagt 9120
gtcttgctgt ctttatttag gggttttgcg cgcgcggtag gcccgggacc agcggtctcg 9180
gtcgttgagg gtcctgtgta ttttttccag gacgtggtaa aggtgactct ggatgttcag 9240
atacatgggc ataagcccgt ctctggggtg gaggtagcac cactgcagag cttcatgctg 9300
cggggtggtg ttgtagatga tccagtcgta gcaggagcgc tgggcgtggt gcctaaaaat 9360
gtctttcagt agcaagctga ttgccagggg caggcccttg gtgtaagtgt ttacaaagcg 9420
gttaagctgg gatgggtgca tacgtgggga tatgagatgc atcttggact gtatttttag 9480
gttggctatg ttcccagcca tatccctccg gggattcatg ttgtgcagaa ccaccagcac 9540
agtgtatccg gtgcacttgg gaaatttgtc atgtagctta gaaggaaatg cgtggaagaa 9600
cttggagacg cccttgtgac ctccaagatt ttccatgcat tcgtccataa tgatggcaat 9660
gggcccacgg gcggcggcct gggcgaagat atttctggga tcactaacgt catagttgtg 9720
ttccaggatg agatcgtcat aggccatttt tacaaagcgc gggcggaggg tgccagactg 9780
cggtataatg gttccatccg gcccaggggc gtagttaccc tcacagattt gcatttccca 9840
cgctttgagt tcagatgggg ggatcatgtc tacctgcggg gcgatgaaga aaacggtttc 9900
cggggtaggg gagatcagct gggaagaaag caggttcctg agcagctgcg acttaccgca 9960
gccggtgggc ccgtaaatca cacctattac cggctgcaac tggtagttaa gagagctgca 10020
gctgccgtca tccctgagca ggggggccac ttcgttaagc atgtccctga ctcgcatgtt 10080
ttccctgacc aaatccgcca gaaggcgctc gccgcccagc gatagcagtt cttgcaagga 10140
agcaaagttt ttcaacggtt tgagaccgtc cgccgtaggc atgcttttga gcgtttgacc 10200
aagcagttcc aggcggtccc acagctcggt cacctgctct acggcatctc gatccagcat 10260
atctcctcgt ttcgcgggtt ggggcggctt tcgctgtacg gcagtagtcg gtgctcgtcc 10320
agacgggcca gggtcatgtc tttccacggg cgcagggtcc tcgtcagcgt agtctgggtc 10380
acggtgaagg ggtgcgctcc gggctgcgcg ctggccaggg tgcgcttgag gctggtcctg 10440
ctggtgctga agcgctgccg gtcttcgccc tgcgcgtcgg ccaggtagca tttgaccatg 10500
gtgtcatagt ccagcccctc cgcggcgtgg cccttggcgc gcagcttgcc cttggaggag 10560
gcgccgcacg aggggcagtg cagacttttg agggcgtaga gcttgggcgc gagaaatacc 10620
gattccgggg agtaggcatc cgcgccgcag gccccgcaga cggtctcgca ttccacgagc 10680
caggtgagct ctggccgttc ggggtcaaaa accaggtttc ccccatgctt tttgatgcgt 10740
ttcttacctc tggtttccat gagccggtgt ccacgctcgg tgacgaaaag gctgtccgtg 10800
tccccgtata cagacttgag aggcctgtcc tcgagcggtg ttccgcggtc ctcctcgtat 10860
agaaactcgg accactctga gacaaaggct cgcgtccagg ccagcacgaa ggaggctaag 10920
tgggaggggt agcggtcgtt gtccactagg gggtccactc gctccagggt gtgaagacac 10980
atgtcgccct cttcggcatc aaggaaggtg attggtttgt aggtgtaggc cacgtgaccg 11040
ggtgttcctg aaggggggct ataaaagggg gtgggggcgc gttcgtcctc actctcttcc 11100
gcatcgctgt ctgcgagggc cagctgttgg ggtgagtact ccctctgaaa agcgggcatg 11160
acttctgcgc taagattgtc agtttccaaa aacgaggagg atttgatatt cacctggccc 11220
gcggtgatgc ctttgagggt ggccgcatcc atctggtcag aaaagacaat ctttttgttg 11280
tcaagcttgg tggcaaacga cccgtagagg gcgttggaca gcaacttggc gatggagcgc 11340
agggtttggt ttttgtcgcg atcggcgcgc tccttggccg cgatgtttag ctgcacgtat 11400
tcgcgcgcaa cgcaccgcca ttcgggaaag acggtggtgc gctcgtcggg caccaggtgc 11460
acgcgccaac cgcggttgtg cagggtgaca aggtcaacgc tggtggctac ctctccgcgt 11520
aggcgctcgt tggtccagca gaggcggccg cccttgcgcg agcagaatgg cggtaggggg 11580
tctagctgcg tctcgtccgg ggggtctgcg tccacggtaa agaccccggg cagcaggcgc 11640
gcgtcgaagt agtctatctt gcatccttgc aagtctagcg cctgctgcca tgcgcgggcg 11700
gcaagcgcgc gctcgtatgg gttgagtggg ggaccccatg gcatggggtg ggtgagcgcg 11760
gaggcgtaca tgccgcaaat gtcgtaaacg tagaggggct ctctgagtat tccaagatat 11820
gtagggtagc atcttccacc gcggatgctg gcgcgcacgt aatcgtatag ttcgtgcgag 11880
ggagcgagga ggtcgggacc gaggttgcta cgggcgggct gctctgctcg gaagactatc 11940
tgcctgaaga tggcatgtga gttggatgat atggttggac gctggaagac gttgaagctg 12000
gcgtctgtga gacctaccgc gtcacgcacg aaggaggcgt aggagtcgcg cagcttgttg 12060
accagctcgg cggtgacctg cacgtctagg gcgcagtagt ccagggtttc cttgatgatg 12120
tcatacttat cctgtccctt ttttttccac agctcgcggt tgaggacaaa ctcttcgcgg 12180
tctttccagt actcttggat cggaaacccg tcggcctccg aacggtaaga gcctagcatg 12240
tagaactggt tgacggcctg gtaggcgcag catccctttt ctacgggtag cgcgtatgcc 12300
tgcgcggcct tccggagcga ggtgtgggtg agcgcaaagg tgtccctgac catgactttg 12360
aggtactggt atttgaagtc agtgtcgtcg catccgccct gctcccagag caaaaagtcc 12420
gtgcgctttt tggaacgcgg atttggcagg gcgaaggtga catcgttgaa gagtatcttt 12480
cccgcgcgag gcataaagtt gcgtgtgatg cggaagggtc ccggcacctc ggaacggttg 12540
ttaattacct gggcggcgag cacgatctcg tcaaagccgt tgatgttgtg gcccacaatg 12600
taaagttcca agaagcgcgg gatgcccttg atggaaggca attttttaag ttcctcgtag 12660
gtgagctctt caggggagct gagcccgtgc tctgaaaggg cccagtctgc aagatgaggg 12720
ttggaagcga cgaatgagct ccacaggtca cgggccatta gcatttgcag gtggtcgcga 12780
aaggtcctaa actggcgacc tatggccatt ttttctgggg tgatgcagta gaaggtaagc 12840
gggtcttgtt cccagcggtc ccatccaagg ttcgcggcta ggtctcgcgc ggcagtcact 12900
agaggctcat ctccgccgaa cttcatgacc agcatgaagg gcacgagctg cttcccaaag 12960
gcccccatcc aagtataggt ctctacatcg taggtgacaa agagacgctc ggtgcgagga 13020
tgcgagccga tcgggaagaa ctggatctcc cgccaccaat tggaggagtg gctattgatg 13080
tggtgaaagt agaagtccct gcgacgggcc gaacactcgt gctggctttt gtaaaaacgt 13140
gcgcagtact ggcagcggtg cacgggctgt acatcctgca cgaggttgac ctgacgaccg 13200
cgcacaagga agcagagtgg gaatttgagc ccctcgcctg gcgggtttgg ctggtggtct 13260
tctacttcgg ctgcttgtcc ttgaccgtct ggctgctcga ggggagttac ggtggatcgg 13320
accaccacgc cgcgcgagcc caaagtccag atgtccgcgc gcggcggtcg gagcttgatg 13380
acaacatcgc gcagatggga gctgtccatg gtctggagct cccgcggcgt caggtcaggc 13440
gggagctcct gcaggtttac ctcgcataga cgggtcaggg cgcgggctag atccaggtga 13500
tacctaattt ccaggggctg gttggtggcg gcgtcgatgg cttgcaagag gccgcatccc 13560
cgcggcgcga ctacggtacc gcgcggcggg cggtgggccg cgggggtgtc cttggatgat 13620
gcatctaaaa gcggtgacgc gggcgagccc ccggaggtag ggggggctcc ggacccgccg 13680
ggagaggggg caggggcacg tcggcgccgc gcgcgggcag gagctggtgc tgcgcgcgta 13740
ggttgctggc gaacgcgacg acgcggcggt tgatctcctg aatctggcgc ctctgcgtga 13800
agacgacggg cccggtgagc ttgaacctga aagagagttc gacagaatca atttcggtgt 13860
cgttgacggc ggcctggcgc aaaatctcct gcacgtctcc tgagttgtct tgataggcga 13920
tctcggccat gaactgctcg atctcttcct cctggagatc tccgcgtccg gctcgctcca 13980
cggtggcggc gaggtcgttg gaaatgcggg ccatgagctg cgagaaggcg ttgaggcctc 14040
cctcgttcca gacgcggctg tagaccacgc ccccttcggc atcgcgggcg cgcatgacca 14100
cctgcgcgag attgagctcc acgtgccggg cgaagacggc gtagtttcgc aggcgctgaa 14160
agaggtagtt gagggtggtg gcggtgtgtt ctgccacgaa gaagtacata acccagcgtc 14220
gcaacgtgga ttcgttgata tcccccaagg cctcaaggcg ctccatggcc tcgtagaagt 14280
ccacggcgaa gttgaaaaac tgggagttgc gcgccgacac ggttaactcc tcctccagaa 14340
gacggatgag ctcggcgaca gtgtcgcgca cctcgcgctc aaaggctaca ggggcctctt 14400
cttcttcttc aatctcctct tccataaggg cctccccttc ttcttcttct ggcggcggtg 14460
ggggaggggg gacacggcgg cgacgacggc gcaccgggag gcggtcgaca aagcgctcga 14520
tcatctcccc gcggcgacgg cgcatggtct cggtgacggc gcggccgttc tcgcgggggc 14580
gcagttggaa gacgccgccc gtcatgtccc ggttatgggt tggcgggggg ctgccatgcg 14640
gcagggatac ggcgctaacg atgcatctca acaattgttg tgtaggtact ccgccgccga 14700
gggacctgag cgagtccgca tcgaccggat cggaaaacct ctcgagaaag gcgtctaacc 14760
agtcacagtc gcaaggtagg ctgagcaccg tggcgggcgg cagcgggcgg cggtcggggt 14820
tgtttctggc ggaggtgctg ctgatgatgt aattaaagta ggcggtcttg agacggcgga 14880
tggtcgacag aagcaccatg tccttgggtc cggcctgctg aatgcgcagg cggtcggcca 14940
tgccccaggc ttcgttttga catcggcgca ggtctttgta gtagtcttgc atgagccttt 15000
ctaccggcac ttcttcttct ccttcctctt gtcctgcatc tcttgcatct atcgctgcgg 15060
cggcggcgga gtttggccgt aggtggcgcc ctcttcctcc catgcgtgtg accccgaagc 15120
ccctcatcgg ctgaagcagg gctaggtcgg cgacaacgcg ctcggctaat atggcctgct 15180
gcacctgcgt gagggtagac tggaagtcat ccatgtccac aaagcggtgg tatgcgcccg 15240
tgttgatggt gtaagtgcag ttggccataa cggaccagtt aacggtctgg tgacccggct 15300
gcgagagctc ggtgtacctg agacgcgagt aagccctcga gtcaaatacg tagtcgttgc 15360
aagtccgcac caggtactgg tatcccacca aaaagtgcgg cggcggctgg cggtagaggg 15420
gccagcgtag ggtggccggg gctccggggg cgagatcttc caacataagg cgatgatatc 15480
cgtagatgta cctggacatc caggtgatgc cggcggcggt ggtggaggcg cgcggaaagt 15540
cgcggacgcg gttccagatg ttgcgcagcg gcaaaaagtg ctccatggtc gggacgctct 15600
ggccggtcag gcgcgcgcaa tcgttgacgc tctagaccgt gcaaaaggag agcctgtaag 15660
cgggcactct tccgtggtct ggtggataaa ttcgcaaggg tatcatggcg gacgaccggg 15720
gttcgagccc cgtatccggc cgtccgccgt gatccatgcg gttaccgccc gcgtgtcgaa 15780
cccaggtgtg cgacgtcaga caacggggga gtgctccttt tggcttcctt ccaggcgcgg 15840
cggctgctgc gctagctttt ttggccactg gccgcgcgca gcgtaagcgg ttaggctgga 15900
aagcgaaagc attaagtggc tcgctccctg tagccggagg gttattttcc aagggttgag 15960
tcgcgggacc cccggttcga gtctcggacc ggccggactg cggcgaacgg gggtttgcct 16020
ccccgtcatg caagaccccg cttgcaaatt cctccggaaa cagggacgag cccctttttt 16080
gcttttccca gatgcatccg gtgctgcggc agatgcgccc ccctcctcag cagcggcaag 16140
agcaagagca gcggcagaca tgcagggcac cctcccctcc tcctaccgcg tcaggagggg 16200
cgacatccgc ggttgacgcg gcagcagatg gtgattacga acccccgcgg cgccgggccc 16260
ggcactacct ggacttggag gagggcgagg gcctggcgcg gctaggagcg ccctctcctg 16320
agcggcaccc aagggtgcag ctgaagcgtg atacgcgtga ggcgtacgtg ccgcggcaga 16380
acctgtttcg cgaccgcgag ggagaggagc ccgaggagat gcgggatcga aagttccacg 16440
cagggcgcga gctgcggcat ggcctgaatc gcgagcggtt gctgcgcgag gaggactttg 16500
agcccgacgc gcgaaccggg attagtcccg cgcgcgcaca cgtggcggcc gccgacctgg 16560
taaccgcata cgagcagacg gtgaaccagg agattaactt tcaaaaaagc tttaacaacc 16620
acgtgcgtac gcttgtggcg cgcgaggagg tggctatagg actgatgcat ctgtgggact 16680
ttgtaagcgc gctggagcaa aacccaaata gcaagccgct catggcgcag ctgttcctta 16740
tagtgcagca cagcagggac aacgaggcat tcagggatgc gctgctaaac atagtagagc 16800
ccgagggccg ctggctgctc gatttgataa acatcctgca gagcatagtg gtgcaggagc 16860
gcagcttgag cctggctgac aaggtggccg ccatcaacta ttccatgctt agcctgggca 16920
agttttacgc ccgcaagata taccataccc cttacgttcc catagacaag gaggtaaaga 16980
tcgaggggtt ctacatgcgc atggcgctga aggtgcttac cttgagcgac gacctgggcg 17040
tttatcgcaa cgagcgcatc cacaaggccg tgagcgtgag ccggcggcgc gagctcagcg 17100
accgcgagct gatgcacagc ctgcaaaggg ccctggctgg cacgggcagc ggcgatagag 17160
aggccgagtc ctactttgac gcgggcgctg acctgcgctg ggccccaagc cgacgcgccc 17220
tggaggcagc tggggccgga cctgggctgg cggtggcacc cgcgcgcgct ggcaacgtcg 17280
gcggcgtgga ggaatatgac gaggacgatg agtacgagcc agaggacggc gagtactaag 17340
cggtgatgtt tctgatcaga tgatgcaaga cgcaacggac ccggcggtgc gggcggcgct 17400
gcagagccag ccgtccggcc ttaactccac ggacgactgg cgccaggtca tggaccgcat 17460
catgtcgctg actgcgcgca atcctgacgc gttccggcag cagccgcagg ccaaccggct 17520
ctccgcaatt ctggaagcgg tggtcccggc gcgcgcaaac cccacgcacg agaaggtgct 17580
ggcgatcgta aacgcgctgg ccgaaaacag ggccatccgg cccgacgagg ccggcctggt 17640
ctacgacgcg ctgcttcagc gcgtggctcg ttacaacagc ggcaacgtgc agaccaacct 17700
ggaccggctg gtgggggatg tgcgcgaggc cgtggcgcag cgtgagcgcg cgcagcagca 17760
gggcaacctg ggctccatgg ttgcactaaa cgccttcctg agtacacagc ccgccaacgt 17820
gccgcgggga caggaggact acaccaactt tgtgagcgca ctgcggctaa tggtgactga 17880
gacaccgcaa agtgaggtgt accagtctgg gccagactat tttttccaga ccagtagaca 17940
aggcctgcag accgtaaacc tgagccaggc tttcaaaaac ttgcaggggc tgtggggggt 18000
gcgggctccc acaggcgacc gcgcgaccgt gtctagcttg ctgacgccca actcgcgcct 18060
gttgctgctg ctaatagcgc ccttcacgga cagtggcagc gtgtcccggg acacatacct 18120
aggtcacttg ctgacactgt accgcgaggc cataggtcag gcgcatgtgg acgagcatac 18180
tttccaggag attacaagtg tcagccgcgc gctggggcag gaggacacgg gcagcctgga 18240
ggcaacccta aactacctgc tgaccaaccg gcggcagaag atcccctcgt tgcacagttt 18300
aaacagcgag gaggagcgca ttttgcgcta cgtgcagcag agcgtgagcc ttaacctgat 18360
gcgcgacggg gtaacgccca gcgtggcgct ggacatgacc gcgcgcaaca tggaaccggg 18420
catgtatgcc tcaaaccggc cgtttatcaa ccgcctaatg gactacttgc atcgcgcggc 18480
cgccgtgaac cccgagtatt tcaccaatgc catcttgaac ccgcactggc taccgccccc 18540
tggtttctac accgggggat tcgaggtgcc cgagggtaac gatggattcc tctgggacga 18600
catagacgac agcgtgtttt ccccgcaacc gcagaccctg ctagagttgc aacagcgcga 18660
gcaggcagag gcggcgctgc gaaaggaaag cttccgcagg ccaagcagct tgtccgatct 18720
aggcgctgcg gccccgcggt cagatgctag tagcccattt ccaagcttga tagggtctct 18780
taccagcact cgcaccaccc gcccgcgcct gctgggcgag gaggagtacc taaacaactc 18840
gctgctgcag ccgcagcgcg aaaaaaacct gcctccggca tttcccaaca acgggataga 18900
gagcctagtg gacaagatga gtagatggaa gacgtacgcg caggagcaca gggacgtgcc 18960
aggcccgcgc ccgcccaccc gtcgtcaaag gcacgaccgt cagcggggtc tggtgtggga 19020
ggacgatgac tcggcagacg acagcagcgt cctggatttg ggagggagtg gcaacccgtt 19080
tgcgcacctt cgccccaggc tggggagaat gttttaaaaa aaaaaaaaaa gcatgatgca 19140
aaataaaaaa ctcaccaagg ccatggcacc gagcgttggt tttcttgtat tccccttagt 19200
atgcggcgcg cggcgatgta tgaggaaggt cctcctccct cctacgagag tgtggtgagc 19260
gcggcgccag tggcggcggc gctgggttct cccttcgatg ctcccctgga cccgccgttt 19320
gtgcctccgc ggtacctgcg gcctaccggg gggagaaaca gcatccgtta ctctgagttg 19380
gcacccctat tcgacaccac ccgtgtgtac ctggtggaca acaagtcaac ggatgtggca 19440
tccctgaact accagaacga ccacagcaac tttctgacca cggtcattca aaacaatgac 19500
tacagcccgg gggaggcaag cacacagacc atcaatcttg acgaccggtc gcactggggc 19560
ggcgacctga aaaccatcct gcataccaac atgccaaatg tgaacgagtt catgtttacc 19620
aataagttta aggcgcgggt gatggtgtcg cgcttgccta ctaaggacaa tcaggtggag 19680
ctgaaatacg agtgggtgga gttcacgctg cccgagggca actactccga gaccatgacc 19740
atagacctta tgaacaacgc gatcgtggag cactacttga aagtgggcag acagaacggg 19800
gttctggaaa gcgacatcgg ggtaaagttt gacacccgca acttcagact ggggtttgac 19860
cccgtcactg gtcttgtcat gcctggggta tatacaaacg aagccttcca tccagacatc 19920
attttgctgc caggatgcgg ggtggacttc acccacagcc gcctgagcaa cttgttgggc 19980
atccgcaagc ggcaaccctt ccaggagggc tttaggatca cctacgatga tctggagggt 20040
ggtaacattc ccgcactgtt ggatgtggac gcctaccagg cgagcttgaa agatgacacc 20100
gaacagggcg ggggtggcgc aggcggcagc aacagcagtg gcagcggcgc ggaagagaac 20160
tccaacgcgg cagccgcggc aatgcagccg gtggaggaca tgaacgatca tgccattcgc 20220
ggcgacacct ttgccacacg ggctgaggag aagcgcgctg aggccgaagc agcggccgaa 20280
gctgccgccc ccgctgcgca acccgaggtc gagaagcctc agaagaaacc ggtgatcaaa 20340
cccctgacag aggacagcaa gaaacgcagt tacaacctaa taagcaatga cagcaccttc 20400
acccagtacc gcagctggta ccttgcatac aactacggcg accctcagac cggaatccgc 20460
tcatggaccc tgctttgcac tcctgacgta acctgcggct cggagcaggt ctactggtcg 20520
ttgccagaca tgatgcaaga ccccgtgacc ttccgctcca cgcgccagat cagcaacttt 20580
ccggtggtgg gcgccgagct gttgcccgtg cactccaaga gcttctacaa cgaccaggcc 20640
gtctactccc aactcatccg ccagtttacc tctctgaccc acgtgttcaa tcgctttccc 20700
gagaaccaga ttttggcgcg cccgccagcc cccaccatca ccaccgtcag tgaaaacgtt 20760
cctgctctca cagatcacgg gacgctaccg ctgcgcaaca gcatcggagg agtccagcga 20820
gtgaccatta ctgacgccag acgccgcacc tgcccctacg tttacaaggc cctgggcata 20880
gtctcgccgc gcgtcctatc gagccgcact ttttgagcaa gcatgtccat ccttatatcg 20940
cccagcaata acacaggctg gggcctgcgc ttcccaagca agatgtttgg cggggccaag 21000
aagcgctccg accaacaccc agtgcgcgtg cgcgggcact accgcgcgcc ctggggcgcg 21060
cacaaacgcg gccgcactgg gcgcaccacc gtcgatgacg ccatcgacgc ggtggtggag 21120
gaggcgcgca actacacgcc cacgccgcca ccagtgtcca cagtggacgc ggccattcag 21180
accgtggtgc gcggagcccg gcgctatgct aaaatgaaga gacggcggag gcgcgtagca 21240
cgtcgccacc gccgccgacc cggcactgcc gcccaacgcg cggcggcggc cctgcttaac 21300
cgcgcacgtc gcaccggccg acgggcggcc atgcgggccg ctcgaaggct ggccgcgggt 21360
attgtcactg tgccccccag gtccaggcga cgagcggccg ccgcagcagc cgcggccatt 21420
agtgctatga ctcagggtcg caggggcaac gtgtattggg tgcgcgactc ggttagcggc 21480
ctgcgcgtgc ccgtgcgcac ccgccccccg cgcaactaga ttgcaagaaa aaactactta 21540
gactcgtact gttgtatgta tccagcggcg gcggcgcgca acgaagctat gtccaagcgc 21600
aaaatcaaag aagagatgct ccaggtcatc gcgccggaga tctatggccc cccgaagaag 21660
gaagagcagg attacaagcc ccgaaagcta aagcgggtca aaaagaaaaa gaaagatgat 21720
gatgatgaac ttgacgacga ggtggaactg ctgcacgcta ccgcgcccag gcgacgggta 21780
cagtggaaag gtcgacgcgt aaaacgtgtt ttgcgacccg gcaccaccgt agtctttacg 21840
cccggtgagc gctccacccg cacctacaag cgcgtgtatg atgaggtgta cggcgacgag 21900
gacctgcttg agcaggccaa cgagcgcctc ggggagtttg cctacggaaa gcggcataag 21960
gacatgctgg cgttgccgct ggacgagggc aacccaacac ctagcctaaa gcccgtaaca 22020
ctgcagcagg tgctgcccgc gcttgcaccg tccgaagaaa agcgcggcct aaagcgcgag 22080
tctggtgact tggcacccac cgtgcagctg atggtaccca agcgccagcg actggaagat 22140
gtcttggaaa aaatgaccgt ggaacctggg ctggagcccg aggtccgcgt gcggccaatc 22200
aagcaggtgg cgccgggact gggcgtgcag accgtggacg ttcagatacc cactaccagt 22260
agcaccagta ttgccaccgc cacagagggc atggagacac aaacgtcccc ggttgcctca 22320
gcggtggcgg atgccgcggt gcaggcggtc gctgcggccg cgtccaagac ctctacggag 22380
gtgcaaacgg acccgtggat gtttcgcgtt tcagcccccc ggcgcccgcg ccgttcgagg 22440
aagtacggcg ccgccagcgc gctactgccc gaatatgccc tacatccttc cattgcgcct 22500
acccccggct atcgtggcta cacctaccgc cccagaagac gagcaactac ccgacgccga 22560
accaccactg gaacccgccg ccgccgtcgc cgtcgccagc ccgtgctggc cccgatttcc 22620
gtgcgcaggg tggctcgcga aggaggcagg accctggtgc tgccaacagc gcgctaccac 22680
cccagcatcg tttaaaagcc ggtctttgtg gttcttgcag atatggccct cacctgccgc 22740
ctccgtttcc cggtgccggg attccgagga agaatgcacc gtaggagggg catggccggc 22800
cacggcctga cgggcggcat gcgtcgtgcg caccaccggc ggcggcgcgc gtcgcaccgt 22860
cgcatgcgcg gcggtatcct gcccctcctt attccactga tcgccgcggc gattggcgcc 22920
gtgcccggaa ttgcatccgt ggccttgcag gcgcagagac actgattaaa aacaagttgc 22980
atgtggaaaa atcaaaataa aaagtctgga ctctcacgct cgcttggtcc tgtaactatt 23040
ttgtagaatg gaagacatca actttgcgtc tctggccccg cgacacggct cgcgcccgtt 23100
catgggaaac tggcaagata tcggcaccag caatatgagc ggtggcgcct tcagctgggg 23160
ctcgctgtgg agcggcatta aaaatttcgg ttccaccgtt aagaactatg gcagcaaggc 23220
ctggaacagc agcacaggcc agatgctgag ggataagttg aaagagcaaa atttccaaca 23280
aaaggtggta gatggcctgg cctctggcat tagcggggtg gtggacctgg ccaaccaggc 23340
agtgcaaaat aagattaaca gtaagcttga tccccgccct cccgtagagg agcctccacc 23400
ggccgtggag acagtgtctc cagaggggcg tggcgaaaag cgtccgcgcc ccgacaggga 23460
agaaactctg gtgacgcaaa tagacgagcc tccctcgtac gaggaggcac taaagcaagg 23520
cctgcccacc acccgtccca tcgcgcccat ggctaccgga gtgctgggcc agcacacacc 23580
cgtaacgctg gacctgcctc cccccgccga cacccagcag aaacctgtgc tgccaggccc 23640
gaccgccgtt gttgtaaccc gtcctagccg cgcgtccctg cgccgcgccg ccagcggtcc 23700
gcgatcgttg cggcccgtag ccagtggcaa ctggcaaagc acactgaaca gcatcgtggg 23760
tctgggggtg caatccctga agcgccgacg atgcttctga atagctaacg tgtcgtatgt 23820
gtgtcatgta tgcgtccatg tcgccgccag aggagctgct gagccgccgc gcgcccgctt 23880
tccaagatgg ctaccccttc gatgatgccg cagtggtctt acatgcacat ctcgggccag 23940
gacgcctcgg agtacctgag ccccgggctg gtgcagtttg cccgcgccac cgagacgtac 24000
ttcagcctga ataacaagtt tagaaacccc acggtggcgc ctacgcacga cgtgaccaca 24060
gaccggtccc agcgtttgac gctgcggttc atccctgtgg accgtgagga tactgcgtac 24120
tcgtacaagg cgcggttcac cctagctgtg ggtgataacc gtgtgctgga catggcttcc 24180
acgtactttg acatccgcgg cgtgctggac aggggcccta cttttaagcc ctactctggc 24240
actgcctaca acgccctggc tcccaagggt gccccaaatc cttgcgaatg ggatgaagct 24300
gctactgctc ttgaaataaa cctagaagaa gaggacgatg acaacgaaga cgaagtagac 24360
gagcaagctg agcagcaaaa aactcacgta tttgggcagg cgccttattc tggtataaat 24420
attacaaagg agggtattca aataggtgtc gaaggtcaaa cacctaaata tgccgataaa 24480
acatttcaac ctgaacctca aataggagaa tctcagtggt acgaaactga aattaatcat 24540
gcagctggga gagtccttaa aaagactacc ccaatgaaac catgttacgg ttcatatgca 24600
aaacccacaa atgaaaatgg agggcaaggc attcttgtaa agcaacaaaa tggaaagcta 24660
gaaagtcaag tggaaatgca atttttctca actactgagg cgaccgcagg caatggtgat 24720
aacttgactc ctaaagtggt attgtacagt gaagatgtag atatagaaac cccagacact 24780
catatttctt acatgcccac tattaaggaa ggtaactcac gagaactaat gggccaacaa 24840
tctatgccca acaggcctaa ttacattgct tttagggaca attttattgg tctaatgtat 24900
tacaacagca cgggtaatat gggtgttctg gcgggccaag catcgcagtt gaatgctgtt 24960
gtagatttgc aagacagaaa cacagagctt tcataccagc ttttgcttga ttccattggt 25020
gatagaacca ggtacttttc tatgtggaat caggctgttg acagctatga tccagatgtt 25080
agaattattg aaaatcatgg aactgaagat gaacttccaa attactgctt tccactggga 25140
ggtgtgatta atacagagac tcttaccaag gtaaaaccta aaacaggtca ggaaaatgga 25200
tgggaaaaag atgctacaga attttcagat aaaaatcaaa taagagttgg aaataatttt 25260
gccatggaaa tcaatctaaa tgccaacctg tggagaaatt tcctgtactc caacatagcg 25320
ctgtatttgc ccgacaagct aaagtacagt ccttccaacg taaaaatttc tgataaccca 25380
aacacctacg actacatgaa caagcgagtg gtggctcccg ggttagtgga ctgctacatt 25440
aaccttggag cacgctggtc ccttgactat atggacaacg tcaacccatt taaccaccac 25500
cgcaatgctg gcctgcgcta ccgctcaatg ttgctgggca atggtcgcta tgtgcccttc 25560
cacatccagg tgcctcagaa gttctttgcc attaaaaacc tccttctcct gccgggctca 25620
tacacctacg agtggaactt caggaaggat gttaacatgg ttctgcagag ctccctagga 25680
aatgacctaa gggttgacgg agccagcatt aagtttgata gcatttgcct ttacgccacc 25740
ttcttcccca tggcccacaa caccgcctcc acgcttgagg ccatgcttag aaacgacacc 25800
aacgaccagt cctttaacga ctatctctcc gccgccaaca tgctctaccc tatacccgcc 25860
aacgctacca acgtgcccat atccatcccc tcccgcaact gggcggcttt ccgcggctgg 25920
gccttcacgc gccttaagac taaggaaacc ccatcactgg gctcgggcta cgacccttat 25980
tacacctact ctggctctat accctaccta gatggaacct tttacctcaa ccacaccttt 26040
aagaaggtgg ccattacctt tgactcttct gtcagctggc ctggcaatga ccgcctgctt 26100
acccccaacg agtttgaaat taagcgctca gttgacgggg agggttacaa cgttgcccag 26160
tgtaacatga ccaaagactg gttcctggta caaatgctag ctaactacaa cattggctac 26220
cagggcttct atatcccaga gagctacaag gaccgcatgt actccttctt tagaaacttc 26280
cagcccatga gccgtcaggt ggtggatgat actaaataca aggactacca acaggtgggc 26340
atcctacacc aacacaacaa ctctggattt gttggctacc ttgcccccac catgcgcgaa 26400
ggacaggcct accctgctaa cttcccctat ccgcttatag gcaagaccgc agttgacagc 26460
attacccaga aaaagtttct ttgcgatcgc accctttggc gcatcccatt ctccagtaac 26520
tttatgtcca tgggcgcact cacagacctg ggccaaaacc ttctctacgc caactccgcc 26580
cacgcgctag acatgacttt tgaggtggat cccatggacg agcccaccct tctttatgtt 26640
ttgtttgaag tctttgacgt ggtccgtgtg caccggccgc accgcggcgt catcgaaacc 26700
gtgtacctgc gcacgccctt ctcggccggc aacgccacaa cataaagaag caagcaacat 26760
caacaacagc tgccgccatg ggctccagtg agcaggaact gaaagccatt gtcaaagatc 26820
ttggttgtgg gccatatttt ttgggcacct atgacaagcg ctttccaggc tttgtttctc 26880
cacacaagct cgcctgcgcc atagtcaata cggccggtcg cgagactggg ggcgtacact 26940
ggatggcctt tgcctggaac ccgcactcaa aaacatgcta cctctttgag ccctttggct 27000
tttctgacca gcgactcaag caggtttacc agtttgagta cgagtcactc ctgcgccgta 27060
gcgccattgc ttcttccccc gaccgctgta taacgctgga aaagtccacc caaagcgtac 27120
aggggcccaa ctcggccgcc tgtggactat tctgctgcat gtttctccac gcctttgcca 27180
actggcccca aactcccatg gatcacaacc ccaccatgaa ccttattacc ggggtaccca 27240
actccatgct caacagtccc caggtacagc ccaccctgcg tcgcaaccag gaacagctct 27300
acagcttcct ggagcgccac tcgccctact tccgcagcca cagtgcgcag attaggagcg 27360
ccacttcttt ttgtcacttg aaaaacatgt aaaaataatg tactagagac actttcaata 27420
aaggcaaatg cttttatttg tacactctcg ggtgattatt tacccccacc cttgccgtct 27480
gcgccgttta aaaatcaaag gggttctgcc gcgcatcgct atgcgccact ggcagggaca 27540
cgttgcgata ctggtgttta gtgctccact taaactcagg cacaaccatc cgcggcagct 27600
cggtgaagtt ttcactccac aggctgcgca ccatcaccaa cgcgtttagc aggtcgggcg 27660
ccgatatctt gaagtcgcag ttggggcctc cgccctgcgc gcgcgagttg cgatacacag 27720
ggttgcagca ctggaacact atcagcgccg ggtggtgcac gctggccagc acgctcttgt 27780
cggagatcag atccgcgtcc aggtcctccg cgttgctcag ggcgaacgga gtcaactttg 27840
gtagctgcct tcccaaaaag ggcgcgtgcc caggctttga gttgcactcg caccgtagtg 27900
gcatcaaaag gtgaccgtgc ccggtctggg cgttaggata cagcgcctgc ataaaagcct 27960
tgatctgctt aaaagccacc tgagcctttg cgccttcaga gaagaacatg ccgcaagact 28020
tgccggaaaa ctgattggcc ggacaggccg cgtcgtgcac gcagcacctt gcgtcggtgt 28080
tggagatctg caccacattt cggccccacc ggttcttcac gatcttggcc ttgctagact 28140
gctccttcag cgcgcgctgc ccgttttcgc tcgtcacatc catttcaatc acgtgctcct 28200
tatttatcat aatgcttccg tgtagacact taagctcgcc ttcgatctca gcgcagcggt 28260
gcagccacaa cgcgcagccc gtgggctcgt gatgcttgta ggtcacctct gcaaacgact 28320
gcaggtacgc ctgcaggaat cgccccatca tcgtcacaaa ggtcttgttg ctggtgaagg 28380
tcagctgcaa cccgcggtgc tcctcgttca gccaggtctt gcatacggcc gccagagctt 28440
ccacttggtc aggcagtagt ttgaagttcg cctttagatc gttatccacg tggtacttgt 28500
ccatcagcgc gcgcgcagcc tccatgccct tctcccacgc agacacgatc ggcacactca 28560
gcgggttcat caccgtaatt tcactttccg cttcgctggg ctcttcctct tcctcttgcg 28620
tccgcatacc acgcgccact gggtcgtctt cattcagccg ccgcactgtg cgcttacctc 28680
ctttgccatg cttgattagc accggtgggt tgctgaaacc caccatttgt agcgccacat 28740
cttctctttc ttcctcgctg tccacgatta cctctggtga tggcgggcgc tcgggcttgg 28800
gagaagggcg cttctttttc ttcttgggcg caatggccaa atccgccgcc gaggtcgatg 28860
gccgcgggct gggtgtgcgc ggcaccagcg cgtcttgtga tgagtcttcc tcgtcctcgg 28920
actcgatacg ccgcctcatc cgcttttttg ggggcgcccg gggaggcggc ggcgacgggg 28980
acggggacga cacgtcctcc atggttgggg gacgtcgcgc cgcaccgcgt ccgcgctcgg 29040
gggtggtttc gcgctgctcc tcttcccgac tggccatttc cttctcctat aggcagaaaa 29100
agatcatgga gtcagtcgag aagaaggaca gcctaaccgc cccctctgag ttcgccacca 29160
ccgcctccac cgatgccgcc aacgcgccta ccaccttccc cgtcgaggca cccccgcttg 29220
aggaggagga agtgattatc gagcaggacc caggttttgt aagcgaagac gacgaggacc 29280
gctcagtacc aacagaggat aaaaagcaag accaggacaa cgcagaggca aacgaggaac 29340
aagtcgggcg gggggacgaa aggcatggcg actacctaga tgtgggagac gacgtgctgt 29400
tgaagcatct gcagcgccag tgcgccatta tctgcgacgc gttgcaagag cgcagcgatg 29460
tgcccctcgc catagcggat gtcagccttg cctacgaacg ccacctattc tcaccgcgcg 29520
taccccccaa acgccaagaa aacggcacat gcgagcccaa cccgcgcctc aacttctacc 29580
ccgtatttgc cgtgccagag gtgcttgcca cctatcacat ctttttccaa aactgcaaga 29640
tacccctatc ctgccgtgcc aaccgcagcc gagcggacaa gcagctggcc ttgcggcagg 29700
gcgctgtcat acctgatatc gcctcgctca acgaagtgcc aaaaatcttt gagggtcttg 29760
gacgcgacga gaagcgcgcg gcaaacgctc tgcaacagga aaacagcgaa aatgaaagtc 29820
actctggagt gttggtggaa ctcgagggtg acaacgcgcg cctagccgta ctaaaacgca 29880
gcatcgaggt cacccacttt gcctacccgg cacttaacct accccccaag gtcatgagca 29940
cagtcatgag tgagctgatc gtgcgccgtg cgcagcccct ggagagggat gcaaatttgc 30000
aagaacaaac agaggagggc ctacccgcag ttggcgacga gcagctagcg cgctggcttc 30060
aaacgcgcga gcctgccgac ttggaggagc gacgcaaact aatgatggcc gcagtgctcg 30120
ttaccgtgga gcttgagtgc atgcagcggt tctttgctga cccggagatg cagcgcaagc 30180
tagaggaaac attgcactac acctttcgac agggctacgt acgccaggcc tgcaagatct 30240
ccaacgtgga gctctgcaac ctggtctcct accttggaat tttgcacgaa aaccgccttg 30300
ggcaaaacgt gcttcattcc acgctcaagg gcgaggcgcg ccgcgactac gtccgcgact 30360
gcgtttactt atttctatgc tacacctggc agacggccat gggcgtttgg cagcagtgct 30420
tggaggagtg caacctcaag gagctgcaga aactgctaaa gcaaaacttg aaggacctat 30480
ggacggcctt caacgagcgc tccgtggccg cgcacctggc ggacatcatt ttccccgaac 30540
gcctgcttaa aaccctgcaa cagggtctgc cagacttcac cagtcaaagc atgttgcaga 30600
actttaggaa ctttatccta gagcgctcag gaatcttgcc cgccacctgc tgtgcacttc 30660
ctagcgactt tgtgcccatt aagtaccgcg aatgccctcc gccgctttgg ggccactgct 30720
accttctgca gctagccaac taccttgcct accactctga cataatggaa gacgtgagcg 30780
gtgacggtct actggagtgt cactgtcgct gcaacctatg caccccgcac cgctccctgg 30840
tttgcaattc gcagctgctt aacgaaagtc aaattatcgg tacctttgag ctgcagggtc 30900
cctcgcctga cgaaaagtcc gcggctccgg ggttgaaact cactccgggg ctgtggacgt 30960
cggcttacct tcgcaaattt gtacctgagg actaccacgc ccacgagatt aggttctacg 31020
aagaccaatc ccgcccgcca aatgcggagc ttaccgcctg cgtcattacc cagggccaca 31080
ttcttggcca attgcaagcc atcaacaaag cccgccaaga gtttctgcta cgaaagggac 31140
ggggggttta cttggacccc cagtccggcg aggagctcaa cccaatcccc ccgccgccgc 31200
agccctatca gcagcagccg cgggcccttg cttcccagga tggcacccaa aaagaagctg 31260
cagctgccgc cgccacccac ggacgaggag gaatactggg acagtcaggc agaggaggtt 31320
ttggacgagg aggaggagga catgatggaa gactgggaga gcctagacga ggaagcttcc 31380
gaggtcgaag aggtgtcaga cgaaacaccg tcaccctcgg tcgcattccc ctcgccggcg 31440
ccccagaaat cggcaaccgg ttccagcatg gctacaacct ccgctcctca ggcgccgccg 31500
gcactgcccg ttcgccgacc caaccgtaga tgggacacca ctggaaccag ggccggtaag 31560
tccaagcagc cgccgccgtt agcccaagag caacaacagc gccaaggcta ccgctcatgg 31620
cgcgggcaca agaacgccat agttgcttgc ttgcaagact gtgggggcaa catctccttc 31680
gcccgccgct ttcttctcta ccatcacggc gtggccttcc cccgtaacat cctgcattac 31740
taccgtcatc tctacagccc atactgcacc ggcggcagcg gcagcggcag caacagcagc 31800
ggccacacag aagcaaaggc gaccggatag caagactctg acaaagccca agaaatccac 31860
agcggcggca gcagcaggag gaggagcgct gcgtctggcg cccaacgaac ccgtatcgac 31920
ccgcgagctt agaaacagga tttttcccac tctgtatgct atatttcaac agagcagggg 31980
ccaagaacaa gagctgaaaa taaaaaacag gtctctgcga tccctcaccc gcagctgcct 32040
gtatcacaaa agcgaagatc agcttcggcg cacgctggaa gacgcggagg ctctcttcag 32100
taaatactgc gcgctgactc ttaaggacta gtttcgcgcc ctttctcaaa tttaagcgcg 32160
aaaactacgt catctccagc ggccacaccc ggcgccagca cctgtcgtca gcgccatttc 32220
aactttgtat acaaaagttg tgatgagcaa ggaaattccc acgccctaca tgtggagtta 32280
ccagccacaa atgggacttg cggctggagc tgcccaagac tactcaaccc gaataaacta 32340
catgagcgcg ggaccccaca tgatatcccg ggtcaacgga atacgcgccc accgaaaccg 32400
aattctcctg gaacaggcgg ctattaccac cacacctcgt aataacctta atccccgtag 32460
ttggcccgct gccctggtgt accaggaaag tcccgctccc accactgtgg tacttcccag 32520
agacgcccag gccgaagttc agatgactaa ctcaggggcg cagcttgcgg gcggctttcg 32580
tcacagggtg cggtcgcccg ggcagggtat aactcacctg acaatcagag ggcgaggtat 32640
tcagctcaac gacgagtcgg tgagctcctc gcttggtctc cgtccggacg ggacatttca 32700
gatcggcggc gccggccgct cttcattcac gcctcgtcag gcaatcctaa ctctgcagac 32760
ctcgtcctct gagccgcgct ctggaggcat tggaactctg caatttattg aggagtttgt 32820
gccatcggtc tactttaacc ccttctcggg acctcccggc cactatccgg atcaatttat 32880
tcctaacttt gacgcggtaa aggactcggc ggacggctac gactgaatgt taagtggaga 32940
ggcagagcaa ctgcgcctga aacacctggt ccactgtcgc cgccacaagt gctttgcccg 33000
cgactccggt gagttttgct actttgaatt gcccgaggat catatcgagg gcccggcgca 33060
cggcgtccgg cttaccgccc agggagagct tgcccgtagc ctgattcggg agtttaccca 33120
gcgccccctg ctagttgagc gggacagggg accctgtgtt ctcactgtga tttgcaactg 33180
tcctaaccct ggattacatc aagatctttg ttgccatctc tgtgctgagt ataataaata 33240
cagaaattaa aatatactgg ggctcctatc gccatcctgt aaacgccacc gtcttcaccc 33300
gcccaagcaa accaaggcga accttacctg gtacttttaa catctctccc tctgtgattt 33360
acaacagttt caacccagac ggagtgagtc tacgagagaa cctctccgag ctcagctact 33420
ccatcagaaa aaacaccacc ctccttacct gccgggaacg tacgagtgcg tcaccggccg 33480
ctgcaccaca cctaccgcct gaccgtaaac cagacttttt ccggacagac ctcaataact 33540
ctgtttacca gaacaggagg tgagcttaga aaacccttag ggtattaggc caaaggcgca 33600
gctactgtgg ggtttatgaa caattcaagc aactctacgg gctattctaa ttcaggtttc 33660
tctagaatcg gggttggggt tattctctgt cttgtgattc tctttattct tatactaacg 33720
cttctctgcc taaggctcgc cgcctgctgt gtgcacattt gcatttattg tcagcttttt 33780
aaacgctggg gtcgccaccc aagatgatta ggtacataat cctaggttta ctcacccttg 33840
cgtcagccca cggtaccacc caaaaggtgg attttaagga gccagcctgt aatgttacat 33900
tcgcagctga agctaatgag tgcaccactc ttataaaatg caccacagaa catgaaaagc 33960
tgcttattcg ccacaaaaac aaaattggca agtatgctgt ttatgctatt tggcagccag 34020
gtgacactac agagtataat gttacagttt tccagggtaa aagtcataaa acttttatgt 34080
atacttttcc attttatgaa atgtgcgaca ttaccatgta catgagcaaa cagtataagt 34140
tgtggccccc acaaaattgt gtggaaaaca ctggcacttt ctgctgcact gctatgctaa 34200
ttacagtgct cgctttggtc tgtaccctac tctatattaa atacaaaagc agacgcagct 34260
ttattgagga aaagaaaatg ccttaattta ctaagttaca aagctaatgt caccactaac 34320
tgctttactc gctgcttgca aaacaaattc aaaaagttag cattataatt agaataggat 34380
ttaaaccccc cggtcatttc ctgctcaata ccattcccct gaacaattga ctctatgtgg 34440
gatatgctcc agcgctacaa ccttgaagtc aggcttcctg gatgtcagca tctgactttg 34500
gccagcacct gtcccgcgga tttgttccag tccaactaca gcgacccacc ctaacagaga 34560
tgaccaacac aaccaacgcg gccgccgcta ccggacttac atctaccaca aatacacccc 34620
aagtttctgc ctttgtcaat aactgggata acttgggcat gtggtggttc tccatagcgc 34680
ttatgtttgt atgccttatt attatgtggc tcatctgctg cctaaagcgc aaacgcgccc 34740
gaccacccat ctatagtccc atcattgtgc tacacccaaa caatgatgga atccatagat 34800
tggacggact gaaacacatg ttcttttctc ttacagtatg attaaatgag acatgattcc 34860
tcgagttttt atattactga cccttgttgc gcttttttgt gcgtgctcca cattggctgc 34920
ggtttctcac atcgaagtag actgcattcc agccttcaca gtctatttgc tttacggatt 34980
tgtcaccctc acgctcatct gcagcctcat cactgtggtc atcgccttta tccagtgcat 35040
tgactgggtc tgtgtgcgct ttgcatatct cagacaccat ccccagtaca gggacaggac 35100
tatagctgag cttcttagaa ttctttaatt atgaaattta ctgtgacttt tctgctgatt 35160
atttgcaccc tatctgcgtt ttgttccccg acctccaagc ctcaaagaca tatatcatgc 35220
agattcactc gtatatggaa tattccaagt tgctacaatg aaaaaagcga tctttccgaa 35280
gcctggttat atgcaatcat ctctgttatg gtgttctgca gtaccatctt agccctagct 35340
atatatccct accttgacat tggctggaac gcaatagatg ccatgaacca cccaactttc 35400
cccgcgcccg ctatgcttcc actgcaacaa gttgttgccg gcggctttgt cccagccaat 35460
cagcctcgcc caccttctcc cacccccact gaaatcagct actttaatct aacaggagga 35520
gatgactgac accctagatc tagaaatgga cggaattatt acagagcagc gcctgctaga 35580
aagacgcagg gcagcggccg agcaacagcg catgaatcaa gagctccaag acatggttaa 35640
cttgcaccag tgcaaaaggg gtatcttttg tctggtaaag caggccaaag tcacctacga 35700
cagtaatacc accggacacc gccttagcta caagttgcca accaagcgtc agaaattggt 35760
ggtcatggtg ggagaaaagc ccattaccat aactcagcac tcggtagaaa ccgaaggctg 35820
cattcactca ccttgtcaag gacctgagga tctctgcacc cttattaaga ccctgtgcgg 35880
tctcaaagat cttattccct ttaactaata aaaaaaaata ataaagcatc acttacttaa 35940
aatcagttag caaatttctg tccagtttat tcagcagcac ctccttgccc tcctcccagc 36000
tctggtattg cagcttcctc ctggctgcaa actttctcca caatctaaat ggaatgtcag 36060
tttcctcctg ttcctgtcca tccgcaccca ctatcttcat gttgttgcag atgaagcgcg 36120
caagaccgtc tgaagatacc ttcaaccccg tgtatccata tgacacggaa accggtcctc 36180
caactgtgcc ttttcttact cctccctttg tatcccccaa tgggtttcaa gagagtcccc 36240
ctggggtact ctctttgcgc ctatccgaac ctctagttac ctccaatggc atgcttgcgc 36300
tcaaaatggg caacggcctc tctctggacg aggccggcaa ccttacctcc caaaatgtaa 36360
ccactgtgag cccacctctc aaaaaaacca agtcaaacat aaacctggaa atatctgcac 36420
ccctcacagt tacctcagaa gccctaactg tggctgccgc cgcacctcta atggtcgcgg 36480
gcaacacact caccatgcaa tcacaggccc cgctaaccgt gcacgactcc aaacttagca 36540
ttgccaccca aggacccctc acagtgtcag aaggaaagct agccctgcaa acatcaggcc 36600
ccctcaccac caccgatagc agtaccctta ctatcactgc ctcaccccct ctaactactg 36660
ccactggtag cttgggcatt gacttgaaag agcccattta tacacaaaat ggaaaactag 36720
gactaaagta cggggctcct ttgcatgtaa cagacgacct aaacactttg accgtagcaa 36780
ctggtccagg tgtgactatt aataatactt ccttgcaaac taaagttact ggagccttgg 36840
gttttgattc acaaggcaat atgcaactta atgtagcagg aggactaagg attgattctc 36900
aaaacagacg ccttatactt gatgttagtt atccgtttga tgctcaaaac caactaaatc 36960
taagactagg acagggccct ctttttataa actcagccca caacttggat attaactaca 37020
acaaaggcct ttacttgttt acagcttcaa acaattccaa aaagcttgag gttaacctaa 37080
gcactgccaa ggggttgatg tttgacgcta cagccatagc cattaatgca ggagatgggc 37140
ttgaatttgg ttcacctaat gcaccaaaca caaatcccct caaaacaaaa attggccatg 37200
gcctagaatt tgattcaaac aaggctatgg ttcctaaact aggaactggc cttagttttg 37260
acagcacagg tgccattaca gtaggaaaca aaaataatga taagctaact ttgtggacca 37320
caccagctcc atctcctaac tgtagactaa atgcagagaa agatgctaaa ctcactttgg 37380
tcttaacaaa atgtggcagt caaatacttg ctacagtttc agttttggct gttaaaggca 37440
gtttggctcc aatatctgga acagttcaaa gtgctcatct tattataaga tttgacgaaa 37500
atggagtgct actaaacaat tccttcctgg acccagaata ttggaacttt agaaatggag 37560
atcttactga aggcacagcc tatacaaacg ctgttggatt tatgcctaac ctatcagctt 37620
atccaaaatc tcacggtaaa actgccaaaa gtaacattgt cagtcaagtt tacttaaacg 37680
gagacaaaac taaacctgta acactaacca ttacactaaa cggtacacag gaaacaggag 37740
acacaactcc aagtgcatac tctatgtcat tttcatggga ctggtctggc cacaactaca 37800
ttaatgaaat atttgccaca tcctcttaca ctttttcata cattgcccaa gaataaagaa 37860
tcgtttgtgt tatgtttcaa cgtgtttatt tttcaattgc agaaaatttc gaatcatttt 37920
tcattcagta gtatagcccc accaccacat agcttataca gatcaccgta cctcaacttt 37980
gtataataaa gttgtaatca aactcacaga accctagtat tcaacctgcc acctccctcc 38040
caacacacag agtacacagt cctttctccc cggctggcct taaaaagcat catatcatgg 38100
gtaacagaca tattcttagg tgttatattc cacacggttt cctgtcgagc caaacgctca 38160
tcagtgatat taataaactc cccgggcagc tcacttaagt tcatgtcgct gtccagctgc 38220
tgagccacag gctgctgtcc aacttgcggt tgcttaacgg gcggcgaagg agaagtccac 38280
gcctacatgg gggtagagtc ataatcgtgc atcaggatag ggcggtggtg ctgcagcagc 38340
gcgcgaataa actgctgccg ccgccgctcc gtcctgcagg aatacaacat ggcagtggtc 38400
tcctcagcga tgattcgcac cgcccgcagc ataaggcgcc ttgtcctccg ggcacagcag 38460
cgcaccctga tctcacttaa atcagcacag taactgcagc acagcaccac aatattgttc 38520
aaaatcccac agtgcaaggc gctgtatcca aagctcatgg cggggaccac agaacccacg 38580
tggccatcat accacaagcg caggtagatt aagtggcgac ccctcataaa cacgctggac 38640
ataaacatta cctcttttgg catgttgtaa ttcaccacct cccggtacca tataaacctc 38700
tgattaaaca tggcgccatc caccaccatc ctaaaccagc tggccaaaac ctgcccgccg 38760
gctatacact gcagggaacc gggactggaa caatgacagt ggagagccca ggactcgtaa 38820
ccatggatca tcatgctcgt catgatatca atgttggcac aacacaggca cacgtgcata 38880
cacttcctca ggattacaag ctcctcccgc gttagaacca tatcccaggg aacaacccat 38940
tcctgaatca gcgtaaatcc cacactgcag ggaagacctc gcacgtaact cacgttgtgc 39000
attgtcaaag tgttacattc gggcagcagc ggatgatcct ccagtatggt agcgcgggtt 39060
tctgtctcaa aaggaggtag acgatcccta ctgtacggag tgcgccgaga caaccgagat 39120
cgtgttggtc gtagtgtcat gccaaatgga acgccggacg tagtcatatt tcctgaagca 39180
aaaccaggtg cgggcgtgac aaacagatct gcgtctccgg tctcgccgct tagatcgctc 39240
tgtgtagtag ttgtagtata tccactctct caaagcatcc aggcgccccc tggcttcggg 39300
ttctatgtaa actccttcat gcgccgctgc cctgataaca tccaccaccg cagaataagc 39360
cacacccagc caacctacac attcgttctg cgagtcacac acgggaggag cgggaagagc 39420
tggaagaacc atgttttttt ttttattcca aaagattatc caaaacctca aaatgaagat 39480
ctattaagtg aacgcgctcc cctccggtgg cgtggtcaaa ctctacagcc aaagaacaga 39540
taatggcatt tgtaagatgt tgcacaatgg cttccaaaag gcaaacggcc ctcacgtcca 39600
agtggacgta aaggctaaac ccttcagggt gaatctcctc tataaacatt ccagcacctt 39660
caaccatgcc caaataattc tcatctcgcc accttctcaa tatatctcta agcaaatccc 39720
gaatattaag tccggccatt gtaaaaatct gctccagagc gccctccacc ttcagcctca 39780
agcagcgaat catgattgca aaaattcagg ttcctcacag acctgtataa gattcaaaag 39840
cggaacatta acaaaaatac cgcgatcccg taggtccctt cgcagggcca gctgaacata 39900
atcgtgcagg tctgcacgga ccagcgcggc cacttccccg ccaggaacca tgacaaaaga 39960
acccacactg attatgacac gcatactcgg agctatgcta accagcgtag ccccgatgta 40020
agcttgttgc atgggcggcg atataaaatg caaggtgctg ctcaaaaaat caggcaaagc 40080
ctcgcgcaaa aaagaaagca catcgtagtc atgctcatgc agataaaggc aggtaagctc 40140
cggaaccacc acagaaaaag acaccatttt tctctcaaac atgtctgcgg gtttctgcat 40200
aaacacaaaa taaaataaca aaaaaacatt taaacattag aagcctgtct tacaacagga 40260
aaaacaaccc ttataagcat aagacggact acggccatgc cggcgtgacc gtaaaaaaac 40320
tggtcaccgt gattaaaaag caccaccgac agctcctcgg tcatgtccgg agtcataatg 40380
taagactcgg taaacacatc aggttgattc acatcggtca gtgctaaaaa gcgaccgaaa 40440
tagcccgggg gaatacatac ccgcaggcgt agagacaaca ttacagcccc cataggaggt 40500
ataacaaaat taataggaga gaaaaacaca taaacacctg aaaaaccctc ctgcctaggc 40560
aaaatagcac cctcccgctc cagaacaaca tacagcgctt ccacagcggc agccataaca 40620
gtcagcctta ccagtaaaaa agaaaaccta ttaaaaaaac accactcgac acggcaccag 40680
ctcaatcagt cacagtgtaa aaaagggcca agtgcagagc gagtatatat aggactaaaa 40740
aatgacgtaa cggttaaagt ccacaaaaaa cacccagaaa accgcacgcg aacctacgcc 40800
cagaaacgaa agccaaaaaa cccacaactt cctcaaatcg tcacttccgt tttcccacgt 40860
tacgtcactt cccattttaa gaaaactaca attcccaaca catacaagtt actccgccct 40920
aaaacctacg tcacccgccc cgttcccacg ccccgcgcca cgtcacaaac tccaccccct 40980
cattatcata ttggcttcaa tccaaaataa ggtatattat tgatgatgta gggataacag 41040
ggtaatcagc tttcttgtac aaagttgaaa tccggggatc ctctagagtc gacctgcagg 41100
catgcaagct tggcgtaatc atggtcatag ctgtttcctg tgtgaaattg ttatccgctc 41160
acaattccac acaacatacg agccggaagc ataaagtgta aagcctgggg tgcctaatga 41220
gtgagcta 41228
Claims (37)
1.在受试者肿瘤细胞中表达转基因的方法,其包括给所述受试者施用合成腺病毒,所述合成腺病毒包括:
所述转基因;
使所述合成腺病毒自肝脏去靶向的天然或修饰的衣壳;和
腺病毒34型(Ad34)纤维蛋白或者包括腺病毒5型(Ad5)轴结构域和Ad34隆突结构域的嵌合纤维蛋白。
2.根据权利要求1所述的方法,其中所述转基因是诊断性转基因。
3.根据权利要求2所述的方法,其中所述诊断性转基因编码荧光蛋白。
4.根据权利要求3所述的方法,其中所述荧光蛋白包括绿色荧光蛋白(GFP)、黄色荧光蛋白(YFP)、青色荧光蛋白(CFP)、红色荧光蛋白(RFP)、蓝色荧光蛋白(BFP)或橙色荧光蛋白。
5.根据权利要求2所述的方法,其中所述诊断性转基因编码酶。
6.根据权利要求5所述的方法,其中所述酶是荧光素酶。
7.根据权利要求2所述的方法,其中所述诊断性转基因包括正电子发射断层成像术(PET)报道基因。
8.根据权利要求1所述的方法,其中所述转基因是治疗性转基因。
9.根据权利要求8所述的方法,其中所述治疗性转基因编码抗癌药剂。
10.根据权利要求8所述的方法,其中所述治疗性转基因编码破坏或杀死肿瘤基质细胞的药剂。
11.诊断受试者患有肿瘤的方法,其包括给所述受试者施用合成腺病毒,所述合成腺病毒包括:
诊断性转基因;
使所述合成腺病毒自肝脏去靶向的天然或修饰的衣壳;和
腺病毒34型(Ad34)纤维蛋白或者包括腺病毒5型(Ad5)轴结构域和Ad34隆突结构域的嵌合纤维蛋白。
12.根据权利要求11所述的方法,其中所述诊断性转基因包括正电子发射断层成像术(PET)报道基因。
13.根据权利要求11所述的方法,其中所述诊断性转基因编码荧光蛋白。
14.根据权利要求13所述的方法,其中所述荧光蛋白包括绿色荧光蛋白(GFP)、黄色荧光蛋白(YFP)、青色荧光蛋白(CFP)、红色荧光蛋白(RFP)、蓝色荧光蛋白(BFP)或橙色荧光蛋白。
15.根据权利要求11所述的方法,其中所述诊断性转基因编码酶。
16.根据权利要求15所述的方法,其中所述酶是荧光素酶。
17.治疗受试者中肿瘤的方法,其包括给所述受试者施用合成腺病毒,所述合成腺病毒包括:
治疗性转基因;
使所述合成腺病毒自肝脏去靶向的天然或修饰的衣壳;和
腺病毒34型(Ad34)纤维蛋白或者包括腺病毒5型(Ad5)轴结构域和Ad34隆突结构域的嵌合纤维蛋白。
18.根据权利要求17所述的方法,其中所述治疗性转基因编码抗癌药剂。
19.根据权利要求17所述的方法,其中所述治疗性转基因编码破坏或杀死肿瘤基质细胞的药剂。
20.根据权利要求1-19中任一项所述的方法,其中所述合成腺病毒包括使所述合成腺病毒自肝脏去靶向的修饰的衣壳。
21.根据权利要求20所述的方法,其中所述合成腺病毒包括修饰的六邻体蛋白。
22.根据权利要求21所述的方法,其中所述修饰的六邻体蛋白包括E451Q突变。
23.根据权利要求1-22中任一项所述的方法,其中所述合成腺病毒还包括针对肝脏特异性微小RNA的一个或多个结合位点。
24.根据权利要求23所述的方法,其中所述肝脏特异性微小RNA是miR-122。
25.根据权利要求23或24所述的方法,其中所述一个或多个结合位点位于所述转基因的3′UTR中。
26.根据权利要求1-25中任一项所述的方法,其中所述合成腺病毒还包括针对脾特异性微小RNA的一个或多个结合位点。
27.根据权利要求26所述的方法,其中所述脾特异性微小RNA是miR142-3p。
28.根据权利要求26或27所述的方法,其中所述一个或多个结合位点位于所述转基因的3′UTR中。
29.根据权利要求1-28中任一项所述的方法,其中所述转基因的表达受组织特异性启动子调节。
30.根据权利要求1-29中任一项所述的方法,其中所述合成腺病毒由Ad5载体基因组产生。
31.根据权利要求30所述的方法,其中所述合成腺病毒包括Ad5衣壳蛋白和包括Ad5轴结构域和Ad34隆突结构域的嵌合纤维蛋白。
32.根据权利要求1-31中任一项所述的方法,其中所述肿瘤是胰腺肿瘤。
33.根据权利要求1-31中任一项所述的方法,其中所述肿瘤是成胶质细胞瘤。
34.根据权利要求1-33中任一项所述的方法,其中所述合成腺病毒的基因组包括与SEQID NO:2或SEQ ID NO:5的同一性为至少95%的核苷酸序列。
35.根据权利要求34所述的方法,其中所述合成腺病毒的基因组包括SEQ ID NO:2或SEQ ID NO:5的核苷酸序列。
36.合成腺病毒基因组,其包括与SEQ ID NO:2或SEQ ID NO:5的同一性为至少95%的核苷酸序列。
37.根据权利要求36所述的合成腺病毒基因组,其包括SEQ ID NO:2或SEQ ID NO:5。
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