CN110577954A - 突变的肝细胞生长因子基因及其应用 - Google Patents
突变的肝细胞生长因子基因及其应用 Download PDFInfo
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Abstract
本申请涉及肝细胞生长因子(Hepatocyte growth factor,HGF)基因的突变的内含子4或其片段。本申请还涉及含有所述突变的内含子4或其片段的编码HGF蛋白的核酸分子，含有所述核酸分子的载体，含有所述核酸分子或载体的宿主细胞。本申请还涉及含有所述核酸分子的药物组合物，以及所述药物组合物的用途。
Description
技术领域
本申请涉及肝细胞生长因子(Hepatocyte growth factor,HGF)基因的突变的内含子4或其片段。本申请还涉及含有所述突变的内含子4或其片段的编码HGF蛋白的核酸分子，含有所述核酸分子的载体，含有所述核酸分子或载体的宿主细胞。本申请还涉及含有所述核酸分子的药物组合物，以及所述药物组合物的用途。
背景技术
肝细胞生长因子(HGF)最初从大鼠血浆和血小板中分离得到，是一种分泌型肝素亲和糖蛋白，又称为扩散因子(Scatter factor，SF)。HGF由间质细胞产生，能够与受体c-Met结合并激活该受体的酪氨酸激酶活性，促进肝细胞、上皮细胞、内皮细胞、黑色素细胞、造血细胞等多种类型细胞的生长、迁移和形态发生。HGF在胚肝和胎盘的发育中起重要作用，参与维持和更新肝、肺、肾等器官的细胞，并促进这些器官的再生和损伤后修复。此外，HGF对不同来源的肿瘤细胞具有促侵袭或者生长抑制的作用。
人类HGF基因位于第7号染色体长臂上，长度约为70Kb，由18个外显子和所间隔的17个内含子组成。HGF基因可转录出约6kb的转录本，并以此合成出一个由728个氨基酸组成的前体多肽HGF728。此外，HGF基因还可经历另一种剪切，并合成出由723个氨基酸组成的前体多肽HGF723。无活性的前体多肽经蛋白酶裂解及二硫键连接后，形成具有生物活性的成熟HGF蛋白。
由于HGF蛋白质的体内半衰期很短(HGF抗肾脏纤维化机制的研究进展，国外医学生理病理科学与临床分册，2005年，第25卷第3期)，因此，在使用HGF蛋白治疗疾病时，出现了反复给药和用药量过多等问题。为避免此类问题，研究人员开始尝试采用基因治疗的方法，将HGF基因直接应用到临床疾病的治疗中。
目前，临床上已有采用促血管生长因子基因来治疗缺血性疾病的案例，比如VEGF、FGF裸质粒(Theoretical base and investigational plan of the VIFCAD study-genetherapy for refractory coronary artery disease in no-option patients usingtransendocardial bicistronic VEGF/FGF plasmid injection.Post Kardiol Interw；2006,2：116-123)和HGF裸质粒。从已有的报道来看，采用HGF进行基因治疗的血管生成活性比VEGF和bFGF更强，安全性更高。因此，HGF基因在治疗血管缺血性疾病上有更好的应用前景。
另有研究发现，位于HGF基因外显子4和5中间的内含子4在体内起到了控制可变剪切的作用，使HGF基因可同时表达两种天然的HGF异构蛋白，HGF728和HGF723(Hepatocytegrowth factor and its variant with a deletion of five amino acids aredistinguishable in their biological activity and tertiary structure.BiochemBiophys Res Commun.1994 Apr 29；200:808-15)。中国专利ZL03806534.7报道，通过在天然HGF的cDNA的外显子4和5之间插入HGF基因组内含子4或其截短的序列，可产生能够同时表达HGF728和HGF723两种蛋白的杂合基因，这两种蛋白可发挥协同效应，对疾病的治疗产生积极的效果。
本领域仍然需要进一步提高HGF基因的表达水平。这至少对于增强使用HGF基因的基因治疗效果是特别有利的。
发明内容
本申请的发明人意外发现，可以对天然肝细胞生长因子基因(例如人HGF基因)的内含子4(例如，SEQ ID NO：1)或其片段进行突变，所产生的经突变的内含子4或其片段能够提高HGF基因的表达水平。
因此，在本申请的第一方面，提供了一种突变的肝细胞生长因子(HGF)基因的内含子4或其片段，其中，所述突变的内含子4在下述位点上包含突变：对应于SEQ ID NO：1的第3815位、第4774位和第4876位的位点；并且，所述片段包含所述突变的内含子4中对应于SEQID NO：1的第1至246位和第3686至4926位的核苷酸片段。在某些优选的实施方案中，所述片段还可以包含，用于连接核苷酸片段的接头序列。
在某些优选的实施方案中，所述片段进一步包含，所述突变的内含子4中对应于SEQ ID NO：1的第2686位至第3685位核苷酸片段。在某些优选的实施方案中，所述片段包含所述突变的内含子4中对应于SEQ ID NO：1的第1至246位和第2686至4926位的核苷酸片段。在某些优选的实施方案中，所述片段还可以包含，用于连接核苷酸片段的接头序列。
在某些优选的实施方案中，所述片段包含或者由下述组成：所述突变的内含子4中对应于SEQ ID NO：1的第1至246位的第一核苷酸片段，所述突变的内含子4中对应于SEQ IDNO：1的第3686至4926位的第二核苷酸片段，以及任选地，位于所述两个核苷酸片段之间的接头序列。在某些优选的实施方案中，所述片段包含或者由下述组成：所述突变的内含子4中对应于SEQ ID NO：1的第1至246位的第一核苷酸片段，和所述突变的内含子4中对应于SEQ ID NO：1的第3686至4926位的第二核苷酸片段，其中，所述第一核苷酸片段的3'端直接连接至所述第二核苷酸片段的5'端。在某些优选的实施方案中，所述片段包含或者由下述组成：所述突变的内含子4中对应于SEQ ID NO：1的第1至246位的第一核苷酸片段，和所述突变的内含子4中对应于SEQ ID NO：1的第3686至4926位的第二核苷酸片段，其中，所述第一核苷酸片段的3'端通过接头序列连接至所述第二核苷酸片段的5'端。可以使用本领域已知的各种接头序列。在某些优选的实施方案中，所述接头序列的长度为1-500个核苷酸，例如1-5个，5-10个，10-20个，20-30个，30-40个，40-50个，50-60个，60-70个，70-80个，80-90个，90-100个，100-200个，200-500个核苷酸。在某些优选的实施方案中，所述接头序列如SEQ ID NO:13所示。
在某些优选的实施方案中，所述片段包含或者由下述组成：所述突变的内含子4中对应于SEQ ID NO：1的第1至246位的第一核苷酸片段，所述突变的内含子4中对应于SEQ IDNO：1的第2686至4926位的第二核苷酸片段，以及任选地，位于所述两个核苷酸片段之间的接头序列。在某些优选的实施方案中，所述片段包含或者由下述组成：所述突变的内含子4中对应于SEQ ID NO：1的第1至246位的第一核苷酸片段，和所述突变的内含子4中对应于SEQ ID NO：1的第2686至4926位的第二核苷酸片段，其中，所述第一核苷酸片段的3'端直接连接至所述第二核苷酸片段的5'端。在某些优选的实施方案中，所述片段包含或者由下述组成：所述突变的内含子4中对应于SEQ ID NO：1的第1至246位的第一核苷酸片段，和所述突变的内含子4中对应于SEQ ID NO：1的第2686至4926位的第二核苷酸片段，其中，所述第一核苷酸片段的3'端通过接头序列连接至所述第二核苷酸片段的5'端。可以使用本领域已知的各种接头序列。在某些优选的实施方案中，所述接头序列的长度为1-500个核苷酸，例如1-5个，5-10个，10-20个，20-30个，30-40个，40-50个，50-60个，60-70个，70-80个，80-90个，90-100个，100-200个，200-500个核苷酸。在某些优选的实施方案中，所述接头序列如SEQ ID NO:13所示。
在某些优选的实施方案中，所述突变的内含子4包含选自下列的突变：在对应于SEQ ID NO：1的第3815位的位置上的核苷酸被突变为腺嘌呤核苷酸；在对应于SEQ ID NO：1的第4774位的位置上的核苷酸被突变为鸟嘌呤核苷酸；在对应于SEQ ID NO：1的第4876位的位置上的核苷酸被突变为鸟嘌呤核苷酸；以及，其任何组合。
在某些优选的实施方案中，所述突变的内含子4包含下述突变：在对应于SEQ IDNO：1的第3815位的位置上的核苷酸被突变为腺嘌呤核苷酸。在某些优选的实施方案中，所述突变的内含子4包含下述突变：在对应于SEQ ID NO：1的第4774位的位置上的核苷酸被突变为鸟嘌呤核苷酸。在某些优选的实施方案中，所述突变的内含子4包含下述突变：在对应于SEQ ID NO：1的第4876位的位置上的核苷酸被突变为鸟嘌呤核苷酸。
在某些优选的实施方案中，所述突变的内含子4包含下述突变：在对应于SEQ IDNO：1的第3815位的位置上的核苷酸被突变为腺嘌呤核苷酸；在对应于SEQ ID NO：1的第4774位的位置上的核苷酸被突变为鸟嘌呤核苷酸；以及，在对应于SEQ ID NO：1的第4876位的位置上的核苷酸被突变为鸟嘌呤核苷酸。
在某些优选的实施方案中，所述肝细胞生长因子为人肝细胞生长因子。在某些优选的实施方案中，所述人肝细胞生长因子具有如SEQ ID NO：12所示的氨基酸序列。在某些优选的实施方案中，所述人肝细胞生长因子基因具有如GenBank数据库登录号：NC_000007.14所示的核苷酸序列。
在某些优选的实施方案中，所述突变的内含子4具有如SEQ ID NO：9所示的核苷酸序列。在某些优选的实施方案中，所述片段具有选自SEQ ID NO：10和SEQ ID NO：11的核苷酸序列。
在本申请的另一方面，提供了一种编码肝细胞生长因子(HGF)的核酸分子，其包含HGF基因的外显子1-18，以及位于外显子4和5之间的根据本申请所述的突变的内含子4或其片段。
在某些优选的实施方案中，所述肝细胞生长因子为人肝细胞生长因子。在某些优选的实施方案中，所述人肝细胞生长因子具有如SEQ ID NO：12所示的氨基酸序列。在某些优选的实施方案中，所述外显子1-18编码如SEQ ID NO：12所示的氨基酸序列。在某些优选的实施方案中，所述人肝细胞生长因子基因具有如GenBank数据库登录号：NC_000007.14所示的核苷酸序列。
在某些优选的实施方案中，所述核酸分子具有选自SEQ ID NO：3，SEQ ID NO：4和SEQ ID NO：5的核苷酸序列。
在本申请的又一方面，提供了一种载体，其包含根据本申请所述的突变的内含子4或其片段。在某些优选的实施方案中，所述载体用于克隆所述突变的内含子4或其片段。
在本申请的又一方面，提供了一种载体，其包含根据本申请所述的核酸分子。在某些优选的实施方案中，所述载体选自质粒；噬菌粒；柯斯质粒；人工染色体，例如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1来源的人工染色体(PAC)；噬菌体如λ噬菌体或M13噬菌体；以及，病毒载体，例如逆转录酶病毒载体(例如慢病毒载体)、腺病毒载体、腺相关病毒载体、疱疹病毒载体(如单纯疱疹病毒载体)、痘病毒载体、杆状病毒载体、乳头瘤病毒载体、乳头多瘤空泡病毒载体。
在某些优选的实施方案中，所述载体用于表达(例如在受试者(例如哺乳动物，例如人)体内表达)所述HGF蛋白。在某些优选的实施方案中，所述载体是用于基因治疗的载体，例如质粒，腺病毒载体，腺相关病毒载体，和慢病毒载体。
在某些优选的实施方案中，所述载体具有选自SEQ ID NO:6，SEQ ID NO:7或SEQID NO:8的核苷酸序列。
在本申请的又一方面，提供了一种宿主细胞，其包含根据本申请所述的核酸分子或载体。在某些优选的实施方案中，所述宿主细胞选自原核细胞例如大肠杆菌细胞，以及真核细胞例如酵母细胞，昆虫细胞，植物细胞和动物细胞(如哺乳动物细胞，例如小鼠细胞、人细胞等)。在某些优选的实施方案中，所述宿主细胞是大肠杆菌细胞，例如大肠杆菌DH5α细胞。在某些优选的实施方案中，所述宿主细胞是293T细胞或人细胞。
在本申请的又一方面，提供了一种表达或产生HGF蛋白的方法，所述方法包括，使用根据本申请所述的突变的内含子4或其片段。在某些优选的实施方案中，所述方法包括，使用根据本申请所述的核酸分子或载体。在某些优选的实施方案中，所述方法包括，在允许蛋白表达的条件下，在宿主细胞中表达根据本申请所述的核酸分子或载体；以及任选地，回收宿主细胞中表达的HGF蛋白。
在本申请的又一方面，提供了根据本申请所述的突变的内含子4或其片段用于提高HGF蛋白的表达水平的用途。在某些优选的实施方案中，所述的突变的内含子4或其片段用于在体外提高HGF蛋白的表达水平。在某些优选的实施方案中，所述的突变的内含子4或其片段用于在细胞内提高HGF蛋白的表达水平。在某些优选的实施方案中，所述的突变的内含子4或其片段用于在体外、在细胞内提高HGF蛋白的表达水平。在某些优选的实施方案中，所述的突变的内含子4或其片段用于在体内提高HGF蛋白的表达水平。在某些优选的实施方案中，所述的突变的内含子4或其片段用于在患者(例如哺乳动物，例如人)体内提高HGF蛋白的表达水平。
在本申请的又一方面，提供了根据本申请所述的核酸分子或载体用于表达或产生HGF蛋白的用途。在某些优选的实施方案中，所述的核酸分子或载体用于在体外表达或产生HGF蛋白。在某些优选的实施方案中，所述的核酸分子或载体用于在细胞内表达或产生HGF蛋白。在某些优选的实施方案中，所述的核酸分子或载体用于在体外、在细胞内表达或产生HGF蛋白。在某些优选的实施方案中，所述的核酸分子或载体用于在体内表达或产生HGF蛋白。在某些优选的实施方案中，所述的核酸分子或载体用于在患者(例如哺乳动物，例如人)体内表达或产生HGF蛋白。
在本申请的又一方面，提供了一种药物组合物，其含有根据本申请所述的核酸分子或载体，以及任选地，药学上可接受的载体和/或赋形剂。
本申请所述的药物组合物可通过本领域公知的方法进行施用，例如但不限于通过注射进行施用。在某些优选的实施方案中，本申请所述的药物组合物为注射液或冻干粉剂。
在某些优选的实施方案中，所述核酸分子或载体以治疗有效量(例如治疗缺血性疾病有效量)存在。在某些优选的实施方案中，本申请所述的药物组合物以单位剂量形式存在。
在本申请的又一方面，提供了所述核酸分子或载体在制备药物组合物中的用途，所述药物组合物用于治疗受试者中可受益于天然HGF活性的疾病。在某些优选的实施方案中，所述疾病选自缺血性疾病(例如冠状动脉疾病(CAD)或外周动脉疾病(PAD)，例如心肌梗死或下肢动脉缺血)，代谢综合征，糖尿病及其并发症(例如糖尿病周围神经病变)，再狭窄(例如手术后再狭窄和灌注后再狭窄)，以及神经损伤(例如神经退行性疾病(例如肌萎缩性侧索硬化(ALS)，帕金森氏病，痴呆病)，创伤性神经损伤，周围神经病变(例如糖尿病周围神经病变))。在某些优选的实施方案中，所述受试者为哺乳动物，例如人。在某些优选的实施方案中，所述药物组合物通过注射来进行施用。在某些优选的实施方案中，所述药物组合物为注射液或冻干粉剂。
在本申请的又一方面，提供了一种在受试者中治疗可受益于天然HGF活性的疾病的方法，其包括，给由此需要的受试者施用治疗有效量的根据本申请所述的核酸分子或载体或药物组合物。在某些优选的实施方案中，所述疾病选自缺血性疾病(例如冠状动脉疾病(CAD)或外周动脉疾病(PAD)，例如心肌梗死或下肢动脉缺血)，代谢综合征，糖尿病及其并发症(例如糖尿病周围神经病变)，再狭窄(例如手术后再狭窄和灌注后再狭窄)，以及神经损伤(例如神经退行性疾病(例如肌萎缩性侧索硬化(ALS)，帕金森氏病，痴呆病)，创伤性神经损伤，周围神经病变(例如糖尿病周围神经病变))。在某些优选的实施方案中，所述受试者为哺乳动物，例如人。在某些优选的实施方案中，通过注射，将本申请所述的核酸分子或载体或药物组合物施用给所述受试者。
在本申请中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且，本文中所用的细胞培养、分子遗传学、核酸化学、免疫学实验室操作步骤均为相应领域内广泛使用的常规步骤。同时，为了更好地理解本申请，下面提供相关术语的定义和解释。
如本文中所使用的，术语“肝细胞生长因子”或“HGF”或“HGF蛋白”是指天然存在的、具有生物学活性的肝细胞生长因子(hepatocyte growth factor，HGF)，它们具有相同的含义，且可互换使用。如本文中所使用的，术语“人肝细胞生长因子”或“hHGF”或“hHGF蛋白”是指天然存在的、具有生物学活性的人肝细胞生长因子，它们具有相同的含义，且可互换使用。可方便地从各种公共数据库(例如，GenBank数据库)获得HGF蛋白或hHGF蛋白的氨基酸序列。例如，天然hHGF蛋白的氨基酸序列可见于GenBank数据库登录号：NP_000592.3。
如本文中所使用的，术语“肝细胞生长因子基因”或“HGF基因”是指，编码肝细胞生长因子的基因；术语“人肝细胞生长因子基因”或“hHGF基因”是指，编码人肝细胞生长因子的基因。通常而言，HGF基因/hHGF基因包含18个外显子和17个内含子。如本领域技术人员所理解的，在真核细胞中，编码结构蛋白的DNA一般被若干非编码性的间插序列(其不会被翻译成氨基酸序列)所间隔；此类非编码性的间插序列即被称为“内含子”，而被“内含子”间隔的每一段编码性的DNA序列(其将会被翻译成氨基酸序列)则称为外显子。因此，HGF基因/hHGF基因按顺序包含外显子1、内含子1、外显子2、内含子2、……、外显子17、内含子17和外显子18。在本申请的实施例中，所使用的hHGF外显子的核酸序列来自GenBank(gi：58533168)。然而，易于理解的是，还可以使用所述外显子序列的简并序列，而不影响或改变所表达的hHGF蛋白的氨基酸序列。因此，在本申请中，HGF基因/hHGF基因的外显子1-18不限于所使用的特定核苷酸序列，且可以是能够编码HGF蛋白/hHGF蛋白的任何核苷酸序列(包括所使用的特定核苷酸序列，以及其简并序列)。在一些优选的实施方案中，hHGF基因的外显子1-18编码具有如SEQ ID NO：12所示的氨基酸序列的hHGF蛋白。在本申请中，术语“内含子4”是指，位于外显子4和5之间的第四个内含子。在某些优选的实施方案中，所述hHGF基因具有如GenBank数据库登录号：NC_000007.14所示的核苷酸序列。在此情况下，可以通过BLAST或者利用hHGF蛋白的氨基酸序列，容易地确定hHGF基因中的外显子1-18和内含子1-17的核苷酸序列。在一些优选的实施方案中，hHGF基因的内含子4具有如SEQ ID NO:1所示的核苷酸序列。
如本文中所使用的，当提及hHGF基因时，参照GenBank数据库登录号：NC_000007.14所示的序列来进行描述；当提及hHGF基因的内含子4时，参照SEQ ID NO：1所示的序列来进行描述。然而，易于理解的是，天然hHGF基因及其内含子4可具有多种版本，它们具有基本上相同的核苷酸序列以及基本上相同的生物学功能，但是彼此之间在核苷酸序列上仍然可以存在微小差异。因此，在本申请中，hHGF基因并不局限于GenBank数据库登录号：NC_000007.14所示的核苷酸序列，并且，其内含子4也不局限于SEQ ID NO：1所示的核苷酸序列。本申请的hHGF基因意欲涵盖所有天然存在的、具有生物学功能的hHGF基因，包括GenBank数据库登录号：NC_000007.14所示的hHGF基因以及其天然存在的变体；并且相应地，其内含子4意欲涵盖所有此类hHGF基因所包含的内含子4，包括SEQ ID NO：1所示的hHGF基因内含子4以及其天然存在的变体。
根据本申请，表述“对应”是指，当对序列进行最优比对时，即当序列进行比对以获得最高百分数同一性时，进行比较的序列中位于等同位置的核苷酸位置或氨基酸位置。例如，表述“对应于SEQ ID NO:1的第3815位的位置”是指，当对某一序列与SEQ ID NO:1进行最优比对时，即当某一序列与SEQ ID NO:1进行比对以获得最高百分数同一性时，进行比较的该序列中位于与SEQ ID NO:1的第3815位等同位置的核苷酸位置。类似地，表述“对应于SEQ ID NO:1的第4774位的位置”和“对应于SEQ ID NO:1的第4876位的位置”也具有类似含义。
如本文中所使用的，术语“核苷酸”意欲包括核糖核苷酸和脱氧核糖核苷酸。例如，腺嘌呤核苷酸意欲包括腺嘌呤核糖核苷酸和腺嘌呤脱氧核糖核苷酸，并且可以根据实际需要进行选择。类似地，鸟嘌呤核苷酸意欲包括鸟嘌呤核糖核苷酸和鸟嘌呤脱氧核糖核苷酸，并且可以根据实际需要进行选择。在某些优选的实施方案中，核苷酸为脱氧核糖核苷酸。在某些优选的实施方案中，核苷酸为核糖核苷酸。在本申请中，所述核苷酸可以是经修饰的(例如，经化学修饰的)，也可以是未经修饰的。
如本文中所使用的，术语“核酸”意欲包括核糖核酸，脱氧核糖核酸，及其组合。因此，在本申请中，编码肝细胞生长因子(HGF)的核酸分子可以是RNA，DNA，或者RNA/DNA杂合体。在某些优选的实施方案中，所述核酸分子是RNA。在某些优选的实施方案中，所述核酸分子是DNA。在某些优选的实施方案中，所述核酸分子是RNA/DNA杂合体。在本申请中，所述核酸分子可以是经修饰的(例如，经化学修饰的)，也可以是未经修饰的。
如本文中所使用的，术语“载体(vector)”是指，可将多聚核苷酸插入其中的一种核酸运载工具。当载体能使插入的多核苷酸编码的蛋白获得表达时，载体称为表达载体。载体可以通过转化，转导或者转染导入宿主细胞，使其携带的遗传物质元件在宿主细胞中获得表达。载体是本领域技术人员公知的，包括但不限于：质粒；噬菌粒；柯斯质粒；人工染色体，例如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1来源的人工染色体(PAC)；噬菌体如λ噬菌体或M13噬菌体及病毒载体等。可用作载体的病毒包括但不限于，逆转录酶病毒(包括慢病毒)、腺病毒、腺相关病毒、疱疹病毒(如单纯疱疹病毒)、痘病毒、杆状病毒、乳头瘤病毒、乳头多瘤空泡病毒(如SV40)。一种载体可以含有多种控制表达的元件，包括但不限于，启动子序列、转录起始序列、增强子序列、选择元件及报告基因。另外，载体还可含有复制起始位点。
如本文中所使用的，术语“宿主细胞”是指，可用于扩增或表达外源基因(例如HGF基因)的细胞，其包括但不限于，如大肠杆菌或枯草菌等的原核细胞，如酵母细胞或曲霉菌等的真菌细胞，如S2果蝇细胞或Sf9等的昆虫细胞，或者如纤维原细胞，CHO细胞，COS细胞，NSO细胞，HeLa细胞，BHK细胞，HEK 293细胞，293T细胞或人细胞等的动物细胞。
如本文中所使用的，术语“药学上可接受的”意指，制药领域公认的可用于动物，特别是可用于人的。如本文中所使用的，术语“药学上可接受的载体和/或赋形剂”是指在药理学和/或生理学上与受试者和活性成分相容的载体和/或赋形剂，其是本领域公知的(参见例如Remington's Pharmaceutical Sciences.Edited by Gennaro AR,19thed.Pennsylvania:Mack Publishing Company,1995)，并且包括但不限于：pH调节剂(包括但不限于磷酸盐缓冲液)，表面活性剂(包括但不限于阳离子，阴离子或者非离子型表面活性剂，例如Tween-80)，佐剂，离子强度增强剂(包括但不限于氯化钠)，稀释剂，赋形剂，用于容纳或施用治疗剂的介质，以及其任何组合。
如本文中所使用的，药学上可接受的载体可以是无菌液体，诸如水和油，包括源自石油、动物、植物的或合成的油，诸如花生油、大豆油、矿物油、芝麻油等等。当静脉内施用药用组合物时，生理盐水是优选的载体。盐水溶液以及水性右旋糖和甘油溶液也可用作液态载体，特别是用于可注射溶液。
如本文中所使用的，药学上可接受的赋形剂可包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油、滑石、氯化钠、奶粉、甘油、丙烯、乙二醇、水、乙醇等等。如果需要，药物组合物还可以包含润湿剂，或乳化剂例如透明质酸钠，或pH缓冲剂。药物组合物可以采取溶液、悬浮液、乳状液、片剂、丸剂、胶囊、粉剂、缓释配方等形式。
如本文中所使用的，术语“受试者”是指哺乳动物，包括但不限于，人，啮齿类动物(小鼠，大鼠，豚鼠)，狗，马，牛，猫，猪，猴，黑猩猩等。优选地，受试者是人。
如本文中所使用的，术语“有效量”是指足以获得或至少部分获得期望的效果的量。例如，预防疾病有效量是指，足以预防，阻止，或延迟疾病的发生的量；治疗疾病有效量是指，足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。测定这样的有效量完全在本领域技术人员的能力范围之内。例如，对于治疗用途有效的量将取决于待治疗的疾病的严重度、患者自己的免疫系统的总体状态、患者的一般情况例如年龄，体重和性别，药物的施用方式，以及同时施用的其他治疗等等。
发明的有益效果
如之前所报道的，可使用HGF基因来进行基因治疗。在基因治疗过程中，在体内用质粒表达的HGF蛋白可具有多种生物学活性，包括但不限于以下的一种或多种活性：(1)促进内皮细胞生长和/或迁移；(2)促进血管(例如微小血管)发生；和/或，(3)促进神经损伤(例如周围神经病变，例如糖尿病周围神经病变)修复。因此，HGF基因治疗可在多个方面具有应用前景，包括但不限于：(1)促进内皮细胞生长和/或迁移；(2)促进血管(例如微小血管)发生；(3)治疗缺血性疾病，例如冠状动脉疾病(CAD)或外周动脉疾病(PAD)，例如下肢动脉缺血；(4)治疗代谢综合征和糖尿病及其并发症(例如，糖尿病周围神经病变)；(5)抑制再狭窄；和(6)促进神经损伤(例如，神经退行性疾病，创伤性神经损伤，周围神经病变)修复。
本申请的核酸分子和载体能够在细胞内以显著更高的水平表达HGF蛋白，因此，特别适合用于基因治疗，用于上述多个方面的应用场景中。
序列信息
本发明涉及的序列的信息提供于下面的表1中。
表1：SEQ ID NO:1-13的序列信息
下面将结合实施例对本申请的实施方案进行详细描述，但是本领域技术人员将理解，下列实施例仅用于说明本申请，而不是对本申请的范围的限定。根据优选实施方案的下列详细描述，本申请的各种目的和有利方面对于本领域技术人员来说将变得显然。
具体实施方式
现参照下列意在举例说明本申请(而非限定本申请)的实施例来描述本申请。
除非特别指明，本申请中所使用的分子生物学实验方法和免疫检测法，基本上参照J.Sambrook等人，分子克隆：实验室手册，第2版，冷泉港实验室出版社，1989，以及F.M.Ausubel等人，精编分子生物学实验指南，第3版，John Wiley&Sons,Inc.，1995中所述的方法进行；限制性内切酶的使用依照产品制造商推荐的条件。本领域技术人员知晓，实施例以举例方式描述本申请，且不意欲限制本申请所要求保护的范围。
实施例1：重组质粒的构建和制备
1.目的基因的获得
根据GenBank(NG_016274.2)的记载，获取hHGF基因的内含子4(YJG0)的序列(参见SEQ ID NO：1)。根据GenBank(gi：58533168)的记载，获取hHGF基因的外显子1-18的序列。应理解，此处外显子1-18的序列是示例性的，且可以使用不改变所编码的氨基酸序列的其他简并序列形式。
随后，按照外显子1-4、完整天然内含子4、外显子5-18的顺序，合成了含有完整天然内含子4的、编码HGF蛋白的参照核酸1(HGF-YJG0，其序列如SEQ ID NO：2所示)。
进一步，将所述参照核酸1中的内含子4的第3815位碱基由脱氧鸟嘌呤G突变为脱氧腺嘌呤A(G→A)，第4774位碱基由脱氧腺嘌呤A突变为脱氧鸟嘌呤G(A→G)，第4876位碱基由脱氧腺嘌呤A突变为脱氧鸟嘌呤G(A→G)(以SEQ ID NO：1的序列位置为基准)，从而得到包含外显子1-4、突变的内含子4、外显子5-18的核酸突变体1(HGF-MUT0，其序列如SEQ IDNO：3所示)，其中，突变的内含子4(MUT0)的序列如SEQ ID NO：9所示。
此外，之前已报道，完整内含子4不是实现其功能所必须的；内含子4的截短序列也可以实现与完整内含子4类似的功能(参见例如中国专利ZL03806534.7)。因此，发明人还设计了2种天然内含子4的片段以及2种含有上述3个点突变的内含子4的片段：
YJG1，其由SEQ ID NO：1的第1-246位核苷酸、如SEQ ID NO:13所示的接头(GATCC)和SEQ ID NO：1的第3686-4926位核苷酸组成；
YJG2，其由SEQ ID NO：1的第1-246位核苷酸、如SEQ ID NO:13所示的接头(GATCC)和SEQ ID NO：1的第2686-4926位核苷酸组成；
MUT1(其序列如SEQ ID NO：10所示)，其由SEQ ID NO：1的第1-246位核苷酸、如SEQID NO:13所示的接头(GATCC)和SEQ ID NO：1的第3686-4926位核苷酸组成，且含有上述3个点突变；
MUT2(其序列如SEQ ID NO：11所示)，其由SEQ ID NO：1的第1-246位核苷酸、如SEQID NO:13所示的接头(GATCC)和SEQ ID NO：1的第2686-4926位核苷酸组成，且含有上述3个点突变。
在此基础上，合成了下述核酸分子：
包含外显子1-4、YJG1、外显子5-18的参照核酸2(HGF-YJG1)；
包含外显子1-4、YJG2、外显子5-18的参照核酸3(HGF-YJG2)；
包含外显子1-4、MUT1、外显子5-18的核酸突变体2(HGF-MUT1，其序列如SEQ IDNO：4所示)；以及
包含外显子1-4、MUT2、外显子5-18的核酸突变体3(HGF-MUT2，其序列如SEQ IDNO：5所示)。
2.重组质粒的构建
通过限制性内切酶的酶切和连接酶的连接，将合成的参照核酸1克隆入pYJC载体(自行构建，含有CMV启动子、卡那霉素抗性基因、大肠杆菌复制起点)，从而构建得到重组质粒pYJC-HGF-YJG0。将重组质粒pYJC-HGF-YJG0转化到大肠杆菌菌株DH5α(购自Invitrogen)中。将经转化的细菌涂板培养，然后挑取单克隆菌落，提取质粒并进行测序。经测序验证，获得含有参照核酸1的核苷酸序列的目的重组质粒。通过类似的方法，构建获得分别含有参照核酸2-3和核酸突变体1-3的另外5种重组质粒。
表2：6种重组质粒的表征
3.重组质粒的制备
用氯化钙法制备E.coli DH5α感受态细胞，然后用所构建的重组质粒进行转化，并进行扩大培养，直至OD600达到60以上。培养后，离心收集菌体，并提取质粒，获得含有重组质粒的原液。
实施例2:重组质粒的检测
1.质粒含量的测定
使用紫外分光光度计，测定所制备的各种原液中的质粒含量。测量结果如表3所示。结果显示，在所制备的各种含有重组质粒的原液中，质粒的含量均在2.0-2.2mg/mL范围内。
表3：重组质粒含量的测定
2.超螺旋比例的测定
取含有重组质粒的原液样品，用注射用水稀释至至质粒浓度为约0.1mg/ml。取稀释后的样品10μl，与10μl 2×上样缓冲液混合，并分别点样于1.0％琼脂糖凝胶的加样孔中。另外，取分子量标准6μl，用作对照。在70V恒压下进行电泳。电泳结束后，将凝胶放入凝胶成像仪中观察并拍照，计算重组质粒的超螺旋比例。测定结果如表4所示。结果显示，在所制备的各种原液样品中，重组质粒的超螺旋比例均大于90.0％。
表4：HGF质粒超螺旋比例测定结果
3.纯度检查
取含有重组质粒的原液样品，用注射用水稀释至质粒浓度约为30μg/ml，然后用HPLC检测纯度，所使用的检测条件如下：
所使用的色谱柱为阴离子交换HPLC分析柱DNA-NPR，其用20mM Tris-HCl，0.5MNaCl，pH8.8缓冲液进行平衡。平衡后，加载样品，进行检测。上样量为100μl，流速为0.5ml/min，检测波长为260nm。上样后，用20mM Tris-HCl，0.5M NaCl，pH8.8缓冲液进行平衡(5min)，然后进行线性梯度洗脱，条件如下：(1)由100％A溶液(A溶液为20mM Tris-HCl，0.5M NaCl，pH8.8)线性过渡至100％B溶液(B溶液为20mM Tris-HCl，0.8M NaCl)，洗脱30min；(2)然后用20mM Tris-HCl，0.8M NaCl，pH8.8缓冲液洗脱5min。检测结果如表5所示。结果显示，在所制备的各种原液样品中，质粒的HPLC纯度均大于95.0％。
表5：HGF质粒纯度的测定结果
实施例3.HGF蛋白表达量的检测
1.准备工作：
取待转染的293T细胞(购自ATCC)，接种于24孔细胞培养板(500μl/孔)，然后置于37℃、5％CO2的培养箱中过夜培养，直至细胞汇合率为90～95％。
2.质粒转染：
对于每孔细胞，使用100μl DMEM基础培养基稀释4μl Lipofectamine 2000；并且，使用100μl DMEM基础培养基稀释质粒。室温孵育5min后，将稀释后的质粒和稀释后的Lipofectamine 2000轻轻混匀，并在室温保温20min。实验组细胞用培养基+质粒+转染试剂(100μl/孔)进行转染。阴性对照组细胞用培养基+转染试剂(100μl/孔)进行转染。转染后，将细胞放入37℃、5％CO2的培养箱中培养48h，然后收集培养上清。
采用HGF检测试剂盒(R&D，货号DHG00B)，对培养上清中的HGF蛋白进行定量检测。测定结果如表3所示。从表3中可以看出，在使用突变的内含子4或其片段的情况下，HGF蛋白表达量显著提高(与使用未突变的内含子4或其片段的情况相比，HGF蛋白表达量提高至2.98-4.17倍)。
表6：HGF蛋白的定量检测
尽管本申请的具体实施方式已经得到详细的描述，但本领域技术人员将理解：根据已经公开的所有教导，可以对细节进行各种修改和变动，并且这些改变均在本申请的保护范围之内。本申请的全部范围由所附权利要求及其任何等同物给出。
序列表
<110> 北京万福来生物技术有限责任公司
<120> 突变的肝细胞生长因子基因及其应用
<160> 13
<170> SIPOSequenceListing 1.0
<210> 1
<211> 4926
<212> DNA
<213> 智人(Homo sapiens)
<400> 1
gtaagaacag tatgaagaaa agagatgaag cctctgtctt ttttacatgt taacagtctc 60
atattagtcc ttcagaataa ttctacaatc ctaaaataac ttagccaact tgctgaattg 120
tattacggca aggtttatat gaattcatga ctgatattta gcaaatgatt aattaatatg 180
ttaataaaat gtagccaaaa caatatctta ccttaatgcc tcaatttgta gatctcggta 240
tttgtgaaat aataacgtaa acttcgttta aaaggattct tcttcctgtc tttgagaaag 300
tacggcactg tgcaggggga gaggttgatt gtgaaaaatc agaggtagat gagaatctta 360
ctgagggctg agggttcttt aaccttggtg gatctcaaca ttggttgcac attaaaatca 420
cctgctgcaa gcccttgacg aatcttactt agaagatgac aacacagaac aattaaatca 480
gaatctctgg ggagaatagg gcaccagtat tttttgagct cccaccatga ttccaaagtg 540
cagccaaatt tgagaaccac tgctaaaagc tcaagcttca gattgaccag cttttccatc 600
tcacctatcg cctaaagacc aaattggata aatgtgttca ttacgacaga tgggtactat 660
ttaaagatga gtaaacacaa tatacttagg ctcgtcagac tgagagtttt aatcatcact 720
gaggaaaaac atagatatct aatactgact ggagtattag tcaaggctta tttcacacac 780
aattttatca gaaaccaaag tagtttaaaa cagctctccc cttattagta atgcattgga 840
gggtttactt taccatgtac cttgctgagc actgtacctt gttaatctca tttacttgta 900
atgagaacca cacagcgggt agttttattg gttctatttt acctacatga caaaactgaa 960
gcataaaaac acttagtaag ttttcagtgt catgcacaac taggaagtga catggccaga 1020
atataagccc agtcaccatc actctataac ctgcgctttt aacaacttca gggcatgaca 1080
catttggccg gtcagtagaa cccatgctgt gatttgtttt tgcagtggtg gtgatgactg 1140
ccttgttgaa tccacttttt attctattcc attttgggga cacaattctg caagatgatt 1200
cttcattagg aaacagagat gagttattga ccaacacaga aagaaaaaga gtttgttgct 1260
ccacactggg attaaaccta tgatcttggc ctaattaaca ctagctagta agtgtccaag 1320
ctgatcatct ctacaacatt tcaataacag aaaacaacaa ttttcaaaat tagttactta 1380
caattatgta gaaatgcctc taaaacacag tattttcctt atattacaaa aacaaaaatt 1440
ataattggtt ttgtcctctt ttgagagttt gcatggtgtt actccctgca tagtgaagaa 1500
aacattttat ttaagtagat ggatctaagt ttttcatgaa caaaggaatg acatttgaaa 1560
tcaatcctac cctagtccag gagaatgcat tagattaacc tagtagaggt cttatttcac 1620
cctgagtttt ctatgatcgt gattctctgc tggaggagta attgtgaaat agatctctct 1680
gggaactggc ttcctagtcc aatcagctct tttaccaatg aacacttcct tgtgatatag 1740
atgtttatgg ccgagaggat ccagtatatt aataaaatcc ctttttgtat tcaatgaggg 1800
aaacacataa ttttcatcaa ttagcagctt attggaatat ctgcatgatg gtttaacact 1860
tttaagtgtt gactaaagat taattttaca gaaaatagaa aaagaaatat gtttctgtct 1920
ggaggaatga tttattgttg acccctaaat tgaaatattt tactagtggc ttaatggaaa 1980
gatgatgaaa gatgatgaaa ttaatgtaga agcttaacta gaaaatcagg tgacctgata 2040
tctacatctg tatccttcat tggccaccca gcattcatta atgaatcaga tgatggaata 2100
gatcaagttt cctaggaaca cagtgaatat taaaagaaaa caaagggagc ctagcaccta 2160
gaagacctag tttatatttc aaagtatatt tggatgtaac ccaattttaa acatttcctc 2220
acttgtctct cttaaagcct tgccaacagc aaggacagag aaccaaaaat agtgtatata 2280
tgaataaatg cttattacag aatctgctga ctggcacatg ctttgtgtgt aatgggttct 2340
cataaacact tgttgaatga acacacataa gtgaaagagc atggctaggc ttcatccctt 2400
ggtcaaatat ggggtgctaa agaaaagcag gggaaataca ttgggacact aacaaaaaaa 2460
aacagttaat ttaggtaaaa gataaaatac accacagaat gaagaaaaga gatgacccag 2520
actgctcttt aaccttcatg tcctagagag gtttttgata tgaattgcat tcagaattgt 2580
ggaaaggagc ccatcttttc tcttcatttt gattttatta actccaatgg gggaatttta 2640
ttcgtgtttt ggccatatct acttttgatt tctacattat tctctcttcc tttctacctg 2700
tatttgtcct aataaattgt tgacttatta attcactact tcctcacagc ttttttttgg 2760
ctttacaaat ccactggaaa ggtatatggg tgtatcactt tgtgtatttc ggtgtgcatg 2820
tgtagagggg acaaaaatcc tctctcaaac tataaatatt gagtatttgt gtattgaaca 2880
tttgctataa ctactaggtt tcttaaataa tcttaatata taaaatgata tagaaaaagg 2940
gaaattatag ttcgtattat tcatctaagt gaagagatta aaacccaggg agtaaataaa 3000
ttgtctaagg actaaggttg tatactattt aggtgataga tatggggcaa ccgtatgggt 3060
tttatgatta acaaataaac ttctcaccac tctaccatat caacttttcc ataaaagaga 3120
gctatagtat tctttgctta aataaatttg attagtgcat gacttcttga aaacatataa 3180
agcaaaagtc acatttgatt ctatcagaaa agtgagtaag ccatggccca aacaaaagat 3240
gcattaaaat attctggaat gatggagcta aaagtaagaa aaatgacttt ttaaaaaagt 3300
ttactgttag gaattgtgaa attatgctga attttagttg cattataatt tttgtcagtc 3360
atacggtctg acaacctgtc ttatttctat ttccccatat gaggaatgct agttaagtat 3420
ggatattaac tattactact tagatgcatt gaagttgcat aatatggata atacttcact 3480
ggttccctga aaatgtttag ttagtaataa gtctcttaca ctatttgttt tgtccaataa 3540
tttatatttt ctgaagactt aactctagaa tacactcatg tcaaaatgaa agaatttcat 3600
tgcaaaatat tgcttggtac atgacgcata cctgtatttg ttttgtgtca caacatgaaa 3660
aatgatggtt tattagaagt ttcattgggt aggaaacaca tttgaatggt atttactaag 3720
atactaaaat ccttggactt cactctaatt ttagtgccat ttagaactca aggtctcagt 3780
aaaagtagaa ataaagcctg ttaacaaaac acaagctgaa tattaaaaat gtaactggat 3840
tttcaaagaa atgtttactg gtattacctg tagatgtata ttctttatta tgatcttttg 3900
tgtaaagtct ggcagacaaa tgcaatatct aattgttgag tccaatatca caagcagtac 3960
aaaagtataa aaaagacttg gccttttcta atgtgttaaa atactttatg ctggtaataa 4020
cactaagagt agggcactag aaattttaag tgaagataat gtgttgcagt tactgcactc 4080
aatggcttac tattataaac caaaactggg atcactaagc tccagtcagt caaaatgatc 4140
aaaattattg aagagaataa gcaattctgt tctttattag gacacagtag atacagacta 4200
caaagtggag tgtgcttaat aagaggtagc atttgttaag tgtcaattac tctattatcc 4260
cttggagctt ctcaaaataa ccatataagg tgtaagatgt taaaggttat ggttacactc 4320
agtgcacagg taagctaata ggctgagaga agctaaatta cttactgggg tctcacagta 4380
agaaagtgag ctgaagtttc agcccagatt taactggatt ctgggctctt tattcatgtt 4440
acttcatgaa tctgtttctc aattgtgcag aaaaaagggg gctatttata agaaaagcaa 4500
taaacaaaca agtaatgatc tcaaataagt aatgcaagaa atagtgagat ttcaaaatca 4560
gtggcagcga tttctcagtt ctgtcctaag tggccttgct caatcacctg ctatctttta 4620
gtggagcttt gaaattatgt ttcagacaac ttcgattcag ttctagaatg tttgactcag 4680
caaattcaca ggctcatctt tctaacttga tggtgaatat ggaaattcag ctaaatggat 4740
gttaataaaa ttcaaacgtt ttaaggacag atgaaaatga cagaatttta aggtaaaata 4800
tatgaaggaa tataagataa aggatttttc taccttcagc aaaaacatac ccactaatta 4860
gtaaaattaa taggcaaaaa aaagttgcat gctcttatac tgtaatgatt atcattttaa 4920
aactag 4926
<210> 2
<211> 7113
<212> DNA
<213> 智人(Homo sapiens)
<400> 2
atgtgggtga ccaaactcct gccagccctg ctgctgcagc atgtcctcct gcatctcctc 60
ctgctcccca tcgccatccc ctatgcagag ggacaaagga aaagaagaaa tacaattcat 120
gaattcaaaa aatcagcaaa gactacccta atcaaaatag atccagcact gaagataaaa 180
accaaaaaag tgaatactgc agaccaatgt gctaatagat gtactaggaa taaaggactt 240
ccattcactt gcaaggcttt tgtttttgat aaagcaagaa aacaatgcct ctggttcccc 300
ttcaatagca tgtcaagtgg agtgaaaaaa gaatttggcc atgaatttga cctctatgaa 360
aacaaagact acattagaaa ctgcatcatt ggtaaaggac gcagctacaa gggaacagta 420
tctatcacta agagtggcat caaatgtcag ccctggagtt ccatgatacc acacgaacac 480
aggtaagaac agtatgaaga aaagagatga agcctctgtc ttttttacat gttaacagtc 540
tcatattagt ccttcagaat aattctacaa tcctaaaata acttagccaa cttgctgaat 600
tgtattacgg caaggtttat atgaattcat gactgatatt tagcaaatga ttaattaata 660
tgttaataaa atgtagccaa aacaatatct taccttaatg cctcaatttg tagatctcgg 720
tatttgtgaa ataataacgt aaacttcgtt taaaaggatt cttcttcctg tctttgagaa 780
agtacggcac tgtgcagggg gagaggttga ttgtgaaaaa tcagaggtag atgagaatct 840
tactgagggc tgagggttct ttaaccttgg tggatctcaa cattggttgc acattaaaat 900
cacctgctgc aagcccttga cgaatcttac ttagaagatg acaacacaga acaattaaat 960
cagaatctct ggggagaata gggcaccagt attttttgag ctcccaccat gattccaaag 1020
tgcagccaaa tttgagaacc actgctaaaa gctcaagctt cagattgacc agcttttcca 1080
tctcacctat cgcctaaaga ccaaattgga taaatgtgtt cattacgaca gatgggtact 1140
atttaaagat gagtaaacac aatatactta ggctcgtcag actgagagtt ttaatcatca 1200
ctgaggaaaa acatagatat ctaatactga ctggagtatt agtcaaggct tatttcacac 1260
acaattttat cagaaaccaa agtagtttaa aacagctctc cccttattag taatgcattg 1320
gagggtttac tttaccatgt accttgctga gcactgtacc ttgttaatct catttacttg 1380
taatgagaac cacacagcgg gtagttttat tggttctatt ttacctacat gacaaaactg 1440
aagcataaaa acacttagta agttttcagt gtcatgcaca actaggaagt gacatggcca 1500
gaatataagc ccagtcacca tcactctata acctgcgctt ttaacaactt cagggcatga 1560
cacatttggc cggtcagtag aacccatgct gtgatttgtt tttgcagtgg tggtgatgac 1620
tgccttgttg aatccacttt ttattctatt ccattttggg gacacaattc tgcaagatga 1680
ttcttcatta ggaaacagag atgagttatt gaccaacaca gaaagaaaaa gagtttgttg 1740
ctccacactg ggattaaacc tatgatcttg gcctaattaa cactagctag taagtgtcca 1800
agctgatcat ctctacaaca tttcaataac agaaaacaac aattttcaaa attagttact 1860
tacaattatg tagaaatgcc tctaaaacac agtattttcc ttatattaca aaaacaaaaa 1920
ttataattgg ttttgtcctc ttttgagagt ttgcatggtg ttactccctg catagtgaag 1980
aaaacatttt atttaagtag atggatctaa gtttttcatg aacaaaggaa tgacatttga 2040
aatcaatcct accctagtcc aggagaatgc attagattaa cctagtagag gtcttatttc 2100
accctgagtt ttctatgatc gtgattctct gctggaggag taattgtgaa atagatctct 2160
ctgggaactg gcttcctagt ccaatcagct cttttaccaa tgaacacttc cttgtgatat 2220
agatgtttat ggccgagagg atccagtata ttaataaaat ccctttttgt attcaatgag 2280
ggaaacacat aattttcatc aattagcagc ttattggaat atctgcatga tggtttaaca 2340
cttttaagtg ttgactaaag attaatttta cagaaaatag aaaaagaaat atgtttctgt 2400
ctggaggaat gatttattgt tgacccctaa attgaaatat tttactagtg gcttaatgga 2460
aagatgatga aagatgatga aattaatgta gaagcttaac tagaaaatca ggtgacctga 2520
tatctacatc tgtatccttc attggccacc cagcattcat taatgaatca gatgatggaa 2580
tagatcaagt ttcctaggaa cacagtgaat attaaaagaa aacaaaggga gcctagcacc 2640
tagaagacct agtttatatt tcaaagtata tttggatgta acccaatttt aaacatttcc 2700
tcacttgtct ctcttaaagc cttgccaaca gcaaggacag agaaccaaaa atagtgtata 2760
tatgaataaa tgcttattac agaatctgct gactggcaca tgctttgtgt gtaatgggtt 2820
ctcataaaca cttgttgaat gaacacacat aagtgaaaga gcatggctag gcttcatccc 2880
ttggtcaaat atggggtgct aaagaaaagc aggggaaata cattgggaca ctaacaaaaa 2940
aaaacagtta atttaggtaa aagataaaat acaccacaga atgaagaaaa gagatgaccc 3000
agactgctct ttaaccttca tgtcctagag aggtttttga tatgaattgc attcagaatt 3060
gtggaaagga gcccatcttt tctcttcatt ttgattttat taactccaat gggggaattt 3120
tattcgtgtt ttggccatat ctacttttga tttctacatt attctctctt cctttctacc 3180
tgtatttgtc ctaataaatt gttgacttat taattcacta cttcctcaca gctttttttt 3240
ggctttacaa atccactgga aaggtatatg ggtgtatcac tttgtgtatt tcggtgtgca 3300
tgtgtagagg ggacaaaaat cctctctcaa actataaata ttgagtattt gtgtattgaa 3360
catttgctat aactactagg tttcttaaat aatcttaata tataaaatga tatagaaaaa 3420
gggaaattat agttcgtatt attcatctaa gtgaagagat taaaacccag ggagtaaata 3480
aattgtctaa ggactaaggt tgtatactat ttaggtgata gatatggggc aaccgtatgg 3540
gttttatgat taacaaataa acttctcacc actctaccat atcaactttt ccataaaaga 3600
gagctatagt attctttgct taaataaatt tgattagtgc atgacttctt gaaaacatat 3660
aaagcaaaag tcacatttga ttctatcaga aaagtgagta agccatggcc caaacaaaag 3720
atgcattaaa atattctgga atgatggagc taaaagtaag aaaaatgact ttttaaaaaa 3780
gtttactgtt aggaattgtg aaattatgct gaattttagt tgcattataa tttttgtcag 3840
tcatacggtc tgacaacctg tcttatttct atttccccat atgaggaatg ctagttaagt 3900
atggatatta actattacta cttagatgca ttgaagttgc ataatatgga taatacttca 3960
ctggttccct gaaaatgttt agttagtaat aagtctctta cactatttgt tttgtccaat 4020
aatttatatt ttctgaagac ttaactctag aatacactca tgtcaaaatg aaagaatttc 4080
attgcaaaat attgcttggt acatgacgca tacctgtatt tgttttgtgt cacaacatga 4140
aaaatgatgg tttattagaa gtttcattgg gtaggaaaca catttgaatg gtatttacta 4200
agatactaaa atccttggac ttcactctaa ttttagtgcc atttagaact caaggtctca 4260
gtaaaagtag aaataaagcc tgttaacaaa acacaagctg aatattaaaa atgtaactgg 4320
attttcaaag aaatgtttac tggtattacc tgtagatgta tattctttat tatgatcttt 4380
tgtgtaaagt ctggcagaca aatgcaatat ctaattgttg agtccaatat cacaagcagt 4440
acaaaagtat aaaaaagact tggccttttc taatgtgtta aaatacttta tgctggtaat 4500
aacactaaga gtagggcact agaaatttta agtgaagata atgtgttgca gttactgcac 4560
tcaatggctt actattataa accaaaactg ggatcactaa gctccagtca gtcaaaatga 4620
tcaaaattat tgaagagaat aagcaattct gttctttatt aggacacagt agatacagac 4680
tacaaagtgg agtgtgctta ataagaggta gcatttgtta agtgtcaatt actctattat 4740
cccttggagc ttctcaaaat aaccatataa ggtgtaagat gttaaaggtt atggttacac 4800
tcagtgcaca ggtaagctaa taggctgaga gaagctaaat tacttactgg ggtctcacag 4860
taagaaagtg agctgaagtt tcagcccaga tttaactgga ttctgggctc tttattcatg 4920
ttacttcatg aatctgtttc tcaattgtgc agaaaaaagg gggctattta taagaaaagc 4980
aataaacaaa caagtaatga tctcaaataa gtaatgcaag aaatagtgag atttcaaaat 5040
cagtggcagc gatttctcag ttctgtccta agtggccttg ctcaatcacc tgctatcttt 5100
tagtggagct ttgaaattat gtttcagaca acttcgattc agttctagaa tgtttgactc 5160
agcaaattca caggctcatc tttctaactt gatggtgaat atggaaattc agctaaatgg 5220
atgttaataa aattcaaacg ttttaaggac agatgaaaat gacagaattt taaggtaaaa 5280
tatatgaagg aatataagat aaaggatttt tctaccttca gcaaaaacat acccactaat 5340
tagtaaaatt aataggcaaa aaaaagttgc atgctcttat actgtaatga ttatcatttt 5400
aaaactagct ttttgccttc gagctatcgg ggtaaagacc tacaggaaaa ctactgtcga 5460
aatcctcgag gggaagaagg gggaccctgg tgtttcacaa gcaatccaga ggtacgctac 5520
gaagtctgtg acattcctca gtgttcagaa gttgaatgca tgacctgcaa tggggagagt 5580
tatcgaggtc tcatggatca tacagaatca ggcaagattt gtcagcgctg ggatcatcag 5640
acaccacacc ggcacaaatt cttgcctgaa agatatcccg acaagggctt tgatgataat 5700
tattgccgca atcccgatgg ccagccgagg ccatggtgct atactcttga ccctcacacc 5760
cgctgggagt actgtgcaat taaaacatgc gctgacaata ctatgaatga cactgatgtt 5820
cctttggaaa caactgaatg catccaaggt caaggagaag gctacagggg cactgtcaat 5880
accatttgga atggaattcc atgtcagcgt tgggattctc agtatcctca cgagcatgac 5940
atgactcctg aaaatttcaa gtgcaaggac ctacgagaaa attactgccg aaatccagat 6000
gggtctgaat caccctggtg ttttaccact gatccaaaca tccgagttgg ctactgctcc 6060
caaattccaa actgtgatat gtcacatgga caagattgtt atcgtgggaa tggcaaaaat 6120
tatatgggca acttatccca aacaagatct ggactaacat gttcaatgtg ggacaagaac 6180
atggaagact tacatcgtca tatcttctgg gaaccagatg caagtaagct gaatgagaat 6240
tactgccgaa atccagatga tgatgctcat ggaccctggt gctacacggg aaatccactc 6300
attccttggg attattgccc tatttctcgt tgtgaaggtg ataccacacc tacaatagtc 6360
aatttagacc atcccgtaat atcttgtgcc aaaacgaaac aattgcgagt tgtaaatggg 6420
attccaacac gaacaaacat aggatggatg gttagtttga gatacagaaa taaacatatc 6480
tgcggaggat cattgataaa ggagagttgg gttcttactg cacgacagtg tttcccttct 6540
cgagacttga aagattatga agcttggctt ggaattcatg atgtccacgg aagaggagat 6600
gagaaatgca aacaggttct caatgtttcc cagctggtat atggccctga aggatcagat 6660
ctggttttaa tgaagcttgc caggcctgct gtcctggatg attttgttag tacgattgat 6720
ttacctaatt atggatgcac aattcctgaa aagaccagtt gcagtgttta tggctggggc 6780
tacactggat tgatcaacta tgatggccta ttacgagtgg cacatctcta tataatggga 6840
aatgagaaat gcagccagca tcatcgaggg aaggtgactc tgaatgagtc tgaaatatgt 6900
gctggggctg aaaagattgg atcaggacca tgtgaggggg attatggtgg cccacttgtt 6960
tgtgagcaac ataaaatgag aatggttctt ggtgtcattg ttcctggtcg tggatgtgcc 7020
attccaaatc gtcctggtat ttttgtccga gtagcatatt atgcaaaatg gatacacaaa 7080
attattttaa catataaggt accacagtca tag 7113
<210> 3
<211> 7113
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 3
atgtgggtga ccaaactcct gccagccctg ctgctgcagc atgtcctcct gcatctcctc 60
ctgctcccca tcgccatccc ctatgcagag ggacaaagga aaagaagaaa tacaattcat 120
gaattcaaaa aatcagcaaa gactacccta atcaaaatag atccagcact gaagataaaa 180
accaaaaaag tgaatactgc agaccaatgt gctaatagat gtactaggaa taaaggactt 240
ccattcactt gcaaggcttt tgtttttgat aaagcaagaa aacaatgcct ctggttcccc 300
ttcaatagca tgtcaagtgg agtgaaaaaa gaatttggcc atgaatttga cctctatgaa 360
aacaaagact acattagaaa ctgcatcatt ggtaaaggac gcagctacaa gggaacagta 420
tctatcacta agagtggcat caaatgtcag ccctggagtt ccatgatacc acacgaacac 480
aggtaagaac agtatgaaga aaagagatga agcctctgtc ttttttacat gttaacagtc 540
tcatattagt ccttcagaat aattctacaa tcctaaaata acttagccaa cttgctgaat 600
tgtattacgg caaggtttat atgaattcat gactgatatt tagcaaatga ttaattaata 660
tgttaataaa atgtagccaa aacaatatct taccttaatg cctcaatttg tagatctcgg 720
tatttgtgaa ataataacgt aaacttcgtt taaaaggatt cttcttcctg tctttgagaa 780
agtacggcac tgtgcagggg gagaggttga ttgtgaaaaa tcagaggtag atgagaatct 840
tactgagggc tgagggttct ttaaccttgg tggatctcaa cattggttgc acattaaaat 900
cacctgctgc aagcccttga cgaatcttac ttagaagatg acaacacaga acaattaaat 960
cagaatctct ggggagaata gggcaccagt attttttgag ctcccaccat gattccaaag 1020
tgcagccaaa tttgagaacc actgctaaaa gctcaagctt cagattgacc agcttttcca 1080
tctcacctat cgcctaaaga ccaaattgga taaatgtgtt cattacgaca gatgggtact 1140
atttaaagat gagtaaacac aatatactta ggctcgtcag actgagagtt ttaatcatca 1200
ctgaggaaaa acatagatat ctaatactga ctggagtatt agtcaaggct tatttcacac 1260
acaattttat cagaaaccaa agtagtttaa aacagctctc cccttattag taatgcattg 1320
gagggtttac tttaccatgt accttgctga gcactgtacc ttgttaatct catttacttg 1380
taatgagaac cacacagcgg gtagttttat tggttctatt ttacctacat gacaaaactg 1440
aagcataaaa acacttagta agttttcagt gtcatgcaca actaggaagt gacatggcca 1500
gaatataagc ccagtcacca tcactctata acctgcgctt ttaacaactt cagggcatga 1560
cacatttggc cggtcagtag aacccatgct gtgatttgtt tttgcagtgg tggtgatgac 1620
tgccttgttg aatccacttt ttattctatt ccattttggg gacacaattc tgcaagatga 1680
ttcttcatta ggaaacagag atgagttatt gaccaacaca gaaagaaaaa gagtttgttg 1740
ctccacactg ggattaaacc tatgatcttg gcctaattaa cactagctag taagtgtcca 1800
agctgatcat ctctacaaca tttcaataac agaaaacaac aattttcaaa attagttact 1860
tacaattatg tagaaatgcc tctaaaacac agtattttcc ttatattaca aaaacaaaaa 1920
ttataattgg ttttgtcctc ttttgagagt ttgcatggtg ttactccctg catagtgaag 1980
aaaacatttt atttaagtag atggatctaa gtttttcatg aacaaaggaa tgacatttga 2040
aatcaatcct accctagtcc aggagaatgc attagattaa cctagtagag gtcttatttc 2100
accctgagtt ttctatgatc gtgattctct gctggaggag taattgtgaa atagatctct 2160
ctgggaactg gcttcctagt ccaatcagct cttttaccaa tgaacacttc cttgtgatat 2220
agatgtttat ggccgagagg atccagtata ttaataaaat ccctttttgt attcaatgag 2280
ggaaacacat aattttcatc aattagcagc ttattggaat atctgcatga tggtttaaca 2340
cttttaagtg ttgactaaag attaatttta cagaaaatag aaaaagaaat atgtttctgt 2400
ctggaggaat gatttattgt tgacccctaa attgaaatat tttactagtg gcttaatgga 2460
aagatgatga aagatgatga aattaatgta gaagcttaac tagaaaatca ggtgacctga 2520
tatctacatc tgtatccttc attggccacc cagcattcat taatgaatca gatgatggaa 2580
tagatcaagt ttcctaggaa cacagtgaat attaaaagaa aacaaaggga gcctagcacc 2640
tagaagacct agtttatatt tcaaagtata tttggatgta acccaatttt aaacatttcc 2700
tcacttgtct ctcttaaagc cttgccaaca gcaaggacag agaaccaaaa atagtgtata 2760
tatgaataaa tgcttattac agaatctgct gactggcaca tgctttgtgt gtaatgggtt 2820
ctcataaaca cttgttgaat gaacacacat aagtgaaaga gcatggctag gcttcatccc 2880
ttggtcaaat atggggtgct aaagaaaagc aggggaaata cattgggaca ctaacaaaaa 2940
aaaacagtta atttaggtaa aagataaaat acaccacaga atgaagaaaa gagatgaccc 3000
agactgctct ttaaccttca tgtcctagag aggtttttga tatgaattgc attcagaatt 3060
gtggaaagga gcccatcttt tctcttcatt ttgattttat taactccaat gggggaattt 3120
tattcgtgtt ttggccatat ctacttttga tttctacatt attctctctt cctttctacc 3180
tgtatttgtc ctaataaatt gttgacttat taattcacta cttcctcaca gctttttttt 3240
ggctttacaa atccactgga aaggtatatg ggtgtatcac tttgtgtatt tcggtgtgca 3300
tgtgtagagg ggacaaaaat cctctctcaa actataaata ttgagtattt gtgtattgaa 3360
catttgctat aactactagg tttcttaaat aatcttaata tataaaatga tatagaaaaa 3420
gggaaattat agttcgtatt attcatctaa gtgaagagat taaaacccag ggagtaaata 3480
aattgtctaa ggactaaggt tgtatactat ttaggtgata gatatggggc aaccgtatgg 3540
gttttatgat taacaaataa acttctcacc actctaccat atcaactttt ccataaaaga 3600
gagctatagt attctttgct taaataaatt tgattagtgc atgacttctt gaaaacatat 3660
aaagcaaaag tcacatttga ttctatcaga aaagtgagta agccatggcc caaacaaaag 3720
atgcattaaa atattctgga atgatggagc taaaagtaag aaaaatgact ttttaaaaaa 3780
gtttactgtt aggaattgtg aaattatgct gaattttagt tgcattataa tttttgtcag 3840
tcatacggtc tgacaacctg tcttatttct atttccccat atgaggaatg ctagttaagt 3900
atggatatta actattacta cttagatgca ttgaagttgc ataatatgga taatacttca 3960
ctggttccct gaaaatgttt agttagtaat aagtctctta cactatttgt tttgtccaat 4020
aatttatatt ttctgaagac ttaactctag aatacactca tgtcaaaatg aaagaatttc 4080
attgcaaaat attgcttggt acatgacgca tacctgtatt tgttttgtgt cacaacatga 4140
aaaatgatgg tttattagaa gtttcattgg gtaggaaaca catttgaatg gtatttacta 4200
agatactaaa atccttggac ttcactctaa ttttagtgcc atttagaact caaggtctca 4260
gtaaaagtag aaataaagcc tgttaacaaa acacaaactg aatattaaaa atgtaactgg 4320
attttcaaag aaatgtttac tggtattacc tgtagatgta tattctttat tatgatcttt 4380
tgtgtaaagt ctggcagaca aatgcaatat ctaattgttg agtccaatat cacaagcagt 4440
acaaaagtat aaaaaagact tggccttttc taatgtgtta aaatacttta tgctggtaat 4500
aacactaaga gtagggcact agaaatttta agtgaagata atgtgttgca gttactgcac 4560
tcaatggctt actattataa accaaaactg ggatcactaa gctccagtca gtcaaaatga 4620
tcaaaattat tgaagagaat aagcaattct gttctttatt aggacacagt agatacagac 4680
tacaaagtgg agtgtgctta ataagaggta gcatttgtta agtgtcaatt actctattat 4740
cccttggagc ttctcaaaat aaccatataa ggtgtaagat gttaaaggtt atggttacac 4800
tcagtgcaca ggtaagctaa taggctgaga gaagctaaat tacttactgg ggtctcacag 4860
taagaaagtg agctgaagtt tcagcccaga tttaactgga ttctgggctc tttattcatg 4920
ttacttcatg aatctgtttc tcaattgtgc agaaaaaagg gggctattta taagaaaagc 4980
aataaacaaa caagtaatga tctcaaataa gtaatgcaag aaatagtgag atttcaaaat 5040
cagtggcagc gatttctcag ttctgtccta agtggccttg ctcaatcacc tgctatcttt 5100
tagtggagct ttgaaattat gtttcagaca acttcgattc agttctagaa tgtttgactc 5160
agcaaattca caggctcatc tttctaactt gatggtgaat atggaaattc agctaaatgg 5220
atgttaataa aattcaaacg ttttaaggac agatggaaat gacagaattt taaggtaaaa 5280
tatatgaagg aatataagat aaaggatttt tctaccttca gcaaaaacat acccactaat 5340
tagtaaaatt aataggcgaa aaaaagttgc atgctcttat actgtaatga ttatcatttt 5400
aaaactagct ttttgccttc gagctatcgg ggtaaagacc tacaggaaaa ctactgtcga 5460
aatcctcgag gggaagaagg gggaccctgg tgtttcacaa gcaatccaga ggtacgctac 5520
gaagtctgtg acattcctca gtgttcagaa gttgaatgca tgacctgcaa tggggagagt 5580
tatcgaggtc tcatggatca tacagaatca ggcaagattt gtcagcgctg ggatcatcag 5640
acaccacacc ggcacaaatt cttgcctgaa agatatcccg acaagggctt tgatgataat 5700
tattgccgca atcccgatgg ccagccgagg ccatggtgct atactcttga ccctcacacc 5760
cgctgggagt actgtgcaat taaaacatgc gctgacaata ctatgaatga cactgatgtt 5820
cctttggaaa caactgaatg catccaaggt caaggagaag gctacagggg cactgtcaat 5880
accatttgga atggaattcc atgtcagcgt tgggattctc agtatcctca cgagcatgac 5940
atgactcctg aaaatttcaa gtgcaaggac ctacgagaaa attactgccg aaatccagat 6000
gggtctgaat caccctggtg ttttaccact gatccaaaca tccgagttgg ctactgctcc 6060
caaattccaa actgtgatat gtcacatgga caagattgtt atcgtgggaa tggcaaaaat 6120
tatatgggca acttatccca aacaagatct ggactaacat gttcaatgtg ggacaagaac 6180
atggaagact tacatcgtca tatcttctgg gaaccagatg caagtaagct gaatgagaat 6240
tactgccgaa atccagatga tgatgctcat ggaccctggt gctacacggg aaatccactc 6300
attccttggg attattgccc tatttctcgt tgtgaaggtg ataccacacc tacaatagtc 6360
aatttagacc atcccgtaat atcttgtgcc aaaacgaaac aattgcgagt tgtaaatggg 6420
attccaacac gaacaaacat aggatggatg gttagtttga gatacagaaa taaacatatc 6480
tgcggaggat cattgataaa ggagagttgg gttcttactg cacgacagtg tttcccttct 6540
cgagacttga aagattatga agcttggctt ggaattcatg atgtccacgg aagaggagat 6600
gagaaatgca aacaggttct caatgtttcc cagctggtat atggccctga aggatcagat 6660
ctggttttaa tgaagcttgc caggcctgct gtcctggatg attttgttag tacgattgat 6720
ttacctaatt atggatgcac aattcctgaa aagaccagtt gcagtgttta tggctggggc 6780
tacactggat tgatcaacta tgatggccta ttacgagtgg cacatctcta tataatggga 6840
aatgagaaat gcagccagca tcatcgaggg aaggtgactc tgaatgagtc tgaaatatgt 6900
gctggggctg aaaagattgg atcaggacca tgtgaggggg attatggtgg cccacttgtt 6960
tgtgagcaac ataaaatgag aatggttctt ggtgtcattg ttcctggtcg tggatgtgcc 7020
attccaaatc gtcctggtat ttttgtccga gtagcatatt atgcaaaatg gatacacaaa 7080
attattttaa catataaggt accacagtca tag 7113
<210> 4
<211> 3679
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 4
atgtgggtga ccaaactcct gccagccctg ctgctgcagc atgtcctcct gcatctcctc 60
ctgctcccca tcgccatccc ctatgcagag ggacaaagga aaagaagaaa tacaattcat 120
gaattcaaaa aatcagcaaa gactacccta atcaaaatag atccagcact gaagataaaa 180
accaaaaaag tgaatactgc agaccaatgt gctaatagat gtactaggaa taaaggactt 240
ccattcactt gcaaggcttt tgtttttgat aaagcaagaa aacaatgcct ctggttcccc 300
ttcaatagca tgtcaagtgg agtgaaaaaa gaatttggcc atgaatttga cctctatgaa 360
aacaaagact acattagaaa ctgcatcatt ggtaaaggac gcagctacaa gggaacagta 420
tctatcacta agagtggcat caaatgtcag ccctggagtt ccatgatacc acacgaacac 480
aggtaagaac agtatgaaga aaagagatga agcctctgtc ttttttacat gttaacagtc 540
tcatattagt ccttcagaat aattctacaa tcctaaaata acttagccaa cttgctgaat 600
tgtattacgg caaggtttat atgaattcat gactgatatt tagcaaatga ttaattaata 660
tgttaataaa atgtagccaa aacaatatct taccttaatg cctcaatttg tagatctcgg 720
tatttgtgga tcctgggtag gaaacacatt tgaatggtat ttactaagat actaaaatcc 780
ttggacttca ctctaatttt agtgccattt agaactcaag gtctcagtaa aagtagaaat 840
aaagcctgtt aacaaaacac aaactgaata ttaaaaatgt aactggattt tcaaagaaat 900
gtttactggt attacctgta gatgtatatt ctttattatg atcttttgtg taaagtctgg 960
cagacaaatg caatatctaa ttgttgagtc caatatcaca agcagtacaa aagtataaaa 1020
aagacttggc cttttctaat gtgttaaaat actttatgct ggtaataaca ctaagagtag 1080
ggcactagaa attttaagtg aagataatgt gttgcagtta ctgcactcaa tggcttacta 1140
ttataaacca aaactgggat cactaagctc cagtcagtca aaatgatcaa aattattgaa 1200
gagaataagc aattctgttc tttattagga cacagtagat acagactaca aagtggagtg 1260
tgcttaataa gaggtagcat ttgttaagtg tcaattactc tattatccct tggagcttct 1320
caaaataacc atataaggtg taagatgtta aaggttatgg ttacactcag tgcacaggta 1380
agctaatagg ctgagagaag ctaaattact tactggggtc tcacagtaag aaagtgagct 1440
gaagtttcag cccagattta actggattct gggctcttta ttcatgttac ttcatgaatc 1500
tgtttctcaa ttgtgcagaa aaaagggggc tatttataag aaaagcaata aacaaacaag 1560
taatgatctc aaataagtaa tgcaagaaat agtgagattt caaaatcagt ggcagcgatt 1620
tctcagttct gtcctaagtg gccttgctca atcacctgct atcttttagt ggagctttga 1680
aattatgttt cagacaactt cgattcagtt ctagaatgtt tgactcagca aattcacagg 1740
ctcatctttc taacttgatg gtgaatatgg aaattcagct aaatggatgt taataaaatt 1800
caaacgtttt aaggacagat ggaaatgaca gaattttaag gtaaaatata tgaaggaata 1860
taagataaag gatttttcta ccttcagcaa aaacataccc actaattagt aaaattaata 1920
ggcgaaaaaa agttgcatgc tcttatactg taatgattat cattttaaaa ctagcttttt 1980
gccttcgagc tatcggggta aagacctaca ggaaaactac tgtcgaaatc ctcgagggga 2040
agaaggggga ccctggtgtt tcacaagcaa tccagaggta cgctacgaag tctgtgacat 2100
tcctcagtgt tcagaagttg aatgcatgac ctgcaatggg gagagttatc gaggtctcat 2160
ggatcataca gaatcaggca agatttgtca gcgctgggat catcagacac cacaccggca 2220
caaattcttg cctgaaagat atcccgacaa gggctttgat gataattatt gccgcaatcc 2280
cgatggccag ccgaggccat ggtgctatac tcttgaccct cacacccgct gggagtactg 2340
tgcaattaaa acatgcgctg acaatactat gaatgacact gatgttcctt tggaaacaac 2400
tgaatgcatc caaggtcaag gagaaggcta caggggcact gtcaatacca tttggaatgg 2460
aattccatgt cagcgttggg attctcagta tcctcacgag catgacatga ctcctgaaaa 2520
tttcaagtgc aaggacctac gagaaaatta ctgccgaaat ccagatgggt ctgaatcacc 2580
ctggtgtttt accactgatc caaacatccg agttggctac tgctcccaaa ttccaaactg 2640
tgatatgtca catggacaag attgttatcg tgggaatggc aaaaattata tgggcaactt 2700
atcccaaaca agatctggac taacatgttc aatgtgggac aagaacatgg aagacttaca 2760
tcgtcatatc ttctgggaac cagatgcaag taagctgaat gagaattact gccgaaatcc 2820
agatgatgat gctcatggac cctggtgcta cacgggaaat ccactcattc cttgggatta 2880
ttgccctatt tctcgttgtg aaggtgatac cacacctaca atagtcaatt tagaccatcc 2940
cgtaatatct tgtgccaaaa cgaaacaatt gcgagttgta aatgggattc caacacgaac 3000
aaacatagga tggatggtta gtttgagata cagaaataaa catatctgcg gaggatcatt 3060
gataaaggag agttgggttc ttactgcacg acagtgtttc ccttctcgag acttgaaaga 3120
ttatgaagct tggcttggaa ttcatgatgt ccacggaaga ggagatgaga aatgcaaaca 3180
ggttctcaat gtttcccagc tggtatatgg ccctgaagga tcagatctgg ttttaatgaa 3240
gcttgccagg cctgctgtcc tggatgattt tgttagtacg attgatttac ctaattatgg 3300
atgcacaatt cctgaaaaga ccagttgcag tgtttatggc tggggctaca ctggattgat 3360
caactatgat ggcctattac gagtggcaca tctctatata atgggaaatg agaaatgcag 3420
ccagcatcat cgagggaagg tgactctgaa tgagtctgaa atatgtgctg gggctgaaaa 3480
gattggatca ggaccatgtg agggggatta tggtggccca cttgtttgtg agcaacataa 3540
aatgagaatg gttcttggtg tcattgttcc tggtcgtgga tgtgccattc caaatcgtcc 3600
tggtattttt gtccgagtag catattatgc aaaatggata cacaaaatta ttttaacata 3660
taaggtacca cagtcatag 3679
<210> 5
<211> 4679
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 5
atgtgggtga ccaaactcct gccagccctg ctgctgcagc atgtcctcct gcatctcctc 60
ctgctcccca tcgccatccc ctatgcagag ggacaaagga aaagaagaaa tacaattcat 120
gaattcaaaa aatcagcaaa gactacccta atcaaaatag atccagcact gaagataaaa 180
accaaaaaag tgaatactgc agaccaatgt gctaatagat gtactaggaa taaaggactt 240
ccattcactt gcaaggcttt tgtttttgat aaagcaagaa aacaatgcct ctggttcccc 300
ttcaatagca tgtcaagtgg agtgaaaaaa gaatttggcc atgaatttga cctctatgaa 360
aacaaagact acattagaaa ctgcatcatt ggtaaaggac gcagctacaa gggaacagta 420
tctatcacta agagtggcat caaatgtcag ccctggagtt ccatgatacc acacgaacac 480
aggtaagaac agtatgaaga aaagagatga agcctctgtc ttttttacat gttaacagtc 540
tcatattagt ccttcagaat aattctacaa tcctaaaata acttagccaa cttgctgaat 600
tgtattacgg caaggtttat atgaattcat gactgatatt tagcaaatga ttaattaata 660
tgttaataaa atgtagccaa aacaatatct taccttaatg cctcaatttg tagatctcgg 720
tatttgtgga tcccttcctt tctacctgta tttgtcctaa taaattgttg acttattaat 780
tcactacttc ctcacagctt ttttttggct ttacaaatcc actggaaagg tatatgggtg 840
tatcactttg tgtatttcgg tgtgcatgtg tagaggggac aaaaatcctc tctcaaacta 900
taaatattga gtatttgtgt attgaacatt tgctataact actaggtttc ttaaataatc 960
ttaatatata aaatgatata gaaaaaggga aattatagtt cgtattattc atctaagtga 1020
agagattaaa acccagggag taaataaatt gtctaaggac taaggttgta tactatttag 1080
gtgatagata tggggcaacc gtatgggttt tatgattaac aaataaactt ctcaccactc 1140
taccatatca acttttccat aaaagagagc tatagtattc tttgcttaaa taaatttgat 1200
tagtgcatga cttcttgaaa acatataaag caaaagtcac atttgattct atcagaaaag 1260
tgagtaagcc atggcccaaa caaaagatgc attaaaatat tctggaatga tggagctaaa 1320
agtaagaaaa atgacttttt aaaaaagttt actgttagga attgtgaaat tatgctgaat 1380
tttagttgca ttataatttt tgtcagtcat acggtctgac aacctgtctt atttctattt 1440
ccccatatga ggaatgctag ttaagtatgg atattaacta ttactactta gatgcattga 1500
agttgcataa tatggataat acttcactgg ttccctgaaa atgtttagtt agtaataagt 1560
ctcttacact atttgttttg tccaataatt tatattttct gaagacttaa ctctagaata 1620
cactcatgtc aaaatgaaag aatttcattg caaaatattg cttggtacat gacgcatacc 1680
tgtatttgtt ttgtgtcaca acatgaaaaa tgatggttta ttagaagttt cattgggtag 1740
gaaacacatt tgaatggtat ttactaagat actaaaatcc ttggacttca ctctaatttt 1800
agtgccattt agaactcaag gtctcagtaa aagtagaaat aaagcctgtt aacaaaacac 1860
aaactgaata ttaaaaatgt aactggattt tcaaagaaat gtttactggt attacctgta 1920
gatgtatatt ctttattatg atcttttgtg taaagtctgg cagacaaatg caatatctaa 1980
ttgttgagtc caatatcaca agcagtacaa aagtataaaa aagacttggc cttttctaat 2040
gtgttaaaat actttatgct ggtaataaca ctaagagtag ggcactagaa attttaagtg 2100
aagataatgt gttgcagtta ctgcactcaa tggcttacta ttataaacca aaactgggat 2160
cactaagctc cagtcagtca aaatgatcaa aattattgaa gagaataagc aattctgttc 2220
tttattagga cacagtagat acagactaca aagtggagtg tgcttaataa gaggtagcat 2280
ttgttaagtg tcaattactc tattatccct tggagcttct caaaataacc atataaggtg 2340
taagatgtta aaggttatgg ttacactcag tgcacaggta agctaatagg ctgagagaag 2400
ctaaattact tactggggtc tcacagtaag aaagtgagct gaagtttcag cccagattta 2460
actggattct gggctcttta ttcatgttac ttcatgaatc tgtttctcaa ttgtgcagaa 2520
aaaagggggc tatttataag aaaagcaata aacaaacaag taatgatctc aaataagtaa 2580
tgcaagaaat agtgagattt caaaatcagt ggcagcgatt tctcagttct gtcctaagtg 2640
gccttgctca atcacctgct atcttttagt ggagctttga aattatgttt cagacaactt 2700
cgattcagtt ctagaatgtt tgactcagca aattcacagg ctcatctttc taacttgatg 2760
gtgaatatgg aaattcagct aaatggatgt taataaaatt caaacgtttt aaggacagat 2820
ggaaatgaca gaattttaag gtaaaatata tgaaggaata taagataaag gatttttcta 2880
ccttcagcaa aaacataccc actaattagt aaaattaata ggcgaaaaaa agttgcatgc 2940
tcttatactg taatgattat cattttaaaa ctagcttttt gccttcgagc tatcggggta 3000
aagacctaca ggaaaactac tgtcgaaatc ctcgagggga agaaggggga ccctggtgtt 3060
tcacaagcaa tccagaggta cgctacgaag tctgtgacat tcctcagtgt tcagaagttg 3120
aatgcatgac ctgcaatggg gagagttatc gaggtctcat ggatcataca gaatcaggca 3180
agatttgtca gcgctgggat catcagacac cacaccggca caaattcttg cctgaaagat 3240
atcccgacaa gggctttgat gataattatt gccgcaatcc cgatggccag ccgaggccat 3300
ggtgctatac tcttgaccct cacacccgct gggagtactg tgcaattaaa acatgcgctg 3360
acaatactat gaatgacact gatgttcctt tggaaacaac tgaatgcatc caaggtcaag 3420
gagaaggcta caggggcact gtcaatacca tttggaatgg aattccatgt cagcgttggg 3480
attctcagta tcctcacgag catgacatga ctcctgaaaa tttcaagtgc aaggacctac 3540
gagaaaatta ctgccgaaat ccagatgggt ctgaatcacc ctggtgtttt accactgatc 3600
caaacatccg agttggctac tgctcccaaa ttccaaactg tgatatgtca catggacaag 3660
attgttatcg tgggaatggc aaaaattata tgggcaactt atcccaaaca agatctggac 3720
taacatgttc aatgtgggac aagaacatgg aagacttaca tcgtcatatc ttctgggaac 3780
cagatgcaag taagctgaat gagaattact gccgaaatcc agatgatgat gctcatggac 3840
cctggtgcta cacgggaaat ccactcattc cttgggatta ttgccctatt tctcgttgtg 3900
aaggtgatac cacacctaca atagtcaatt tagaccatcc cgtaatatct tgtgccaaaa 3960
cgaaacaatt gcgagttgta aatgggattc caacacgaac aaacatagga tggatggtta 4020
gtttgagata cagaaataaa catatctgcg gaggatcatt gataaaggag agttgggttc 4080
ttactgcacg acagtgtttc ccttctcgag acttgaaaga ttatgaagct tggcttggaa 4140
ttcatgatgt ccacggaaga ggagatgaga aatgcaaaca ggttctcaat gtttcccagc 4200
tggtatatgg ccctgaagga tcagatctgg ttttaatgaa gcttgccagg cctgctgtcc 4260
tggatgattt tgttagtacg attgatttac ctaattatgg atgcacaatt cctgaaaaga 4320
ccagttgcag tgtttatggc tggggctaca ctggattgat caactatgat ggcctattac 4380
gagtggcaca tctctatata atgggaaatg agaaatgcag ccagcatcat cgagggaagg 4440
tgactctgaa tgagtctgaa atatgtgctg gggctgaaaa gattggatca ggaccatgtg 4500
agggggatta tggtggccca cttgtttgtg agcaacataa aatgagaatg gttcttggtg 4560
tcattgttcc tggtcgtgga tgtgccattc caaatcgtcc tggtattttt gtccgagtag 4620
catattatgc aaaatggata cacaaaatta ttttaacata taaggtacca cagtcatag 4679
<210> 6
<211> 10811
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 6
cgcgttgaca ttgattattg actagttatt aatagtaatc aattacgggg tcattagttc 60
atagcccata tatggagttc cgcgttacat aacttacggt aaatggcccg cctggctgac 120
cgcccaacga cccccgccca ttgacgtcaa taatgacgta tgttcccata gtaacgccaa 180
tagggacttt ccattgacgt caatgggtgg agtatttacg gtaaactgcc cacttggcag 240
tacatcaagt gtatcatatg ccaagtccgc cccctattga cgtcaatgac ggtaaatggc 300
ccgcctggca ttatgcccag tacatgacct tacgggactt tcctacttgg cagtacatct 360
acgtattagt catcgctatt accatggtga tgcggttttg gcagtacacc aatgggcgtg 420
gatagcggtt tgactcacgg ggatttccaa gtctccaccc cattgacgtc aatgggagtt 480
tgttttggca ccaaaatcaa cgggactttc caaaatgtcg taataacccc gccccgttga 540
cgcaaatggg cggtaggcgt gtacggtggg aggtctatat aagcagagct cgtttagtga 600
accgtcagat cgcctggaga cgccatccac gctgttttga cctccataga agacaccggg 660
accgatccag cctccgcggc cgggaacggt gcattggaac gcggattccc cgtgccaaga 720
gtgacgtaag taccgcctat agactctata ggcacacccc tttggctctt atgcatgcta 780
tactgttttt ggcttggggc ctatacaccc ccgcttcctt atgctatagg tgatggtata 840
gcttagccta taggtgtggg ttattgacca ttattgacca ctcccctatt ggtgacgata 900
ctttccatta ctaatccata acatggctct ttgccacaac tatctctatt ggctatatgc 960
caatactctg tccttcagag actgacacgg actctgtatt tttacaggat ggggtcccat 1020
ttattattta caaattcaca tatacaacaa cgccgtcccc cgtgcccgca gtttttatta 1080
aacatagcgt gggatctcca cgcgaatctc gggtacgtgt tccggacatg ggctcttctc 1140
cggtagcggc ggagcttcca catccgagcc ctggtcccat gcctccagcg gctcatggtc 1200
gctcggcagc tccttgctcc taacagtgga ggccagactt aggcacagca caatgcccac 1260
caccaccagt gtgccgcaca aggccgtggc ggtagggtat gtgtctgaaa atgagctcgg 1320
agattgggct cgcaccgctg acgcagatgg aagacttaag gcagcggcag aagaagatgc 1380
aggcagctga gttgttgtat tctgataaga gtcagaggta actcccgttg cggtgctgtt 1440
aacggtggag ggcagtgtag tctgagcagt actcgttgct gccgcgcgcg ccaccagaca 1500
taatagctga cagactaaca gactgttcct ttccatgggt cttttctgca gtcaccgtcc 1560
ttgacacgaa gcttgctagc accatgtggg tgaccaaact cctgccagcc ctgctgctgc 1620
agcatgtcct cctgcatctc ctcctgctcc ccatcgccat cccctatgca gagggacaaa 1680
ggaaaagaag aaatacaatt catgaattca aaaaatcagc aaagactacc ctaatcaaaa 1740
tagatccagc actgaagata aaaaccaaaa aagtgaatac tgcagaccaa tgtgctaata 1800
gatgtactag gaataaagga cttccattca cttgcaaggc ttttgttttt gataaagcaa 1860
gaaaacaatg cctctggttc cccttcaata gcatgtcaag tggagtgaaa aaagaatttg 1920
gccatgaatt tgacctctat gaaaacaaag actacattag aaactgcatc attggtaaag 1980
gacgcagcta caagggaaca gtatctatca ctaagagtgg catcaaatgt cagccctgga 2040
gttccatgat accacacgaa cacaggtaag aacagtatga agaaaagaga tgaagcctct 2100
gtctttttta catgttaaca gtctcatatt agtccttcag aataattcta caatcctaaa 2160
ataacttagc caacttgctg aattgtatta cggcaaggtt tatatgaatt catgactgat 2220
atttagcaaa tgattaatta atatgttaat aaaatgtagc caaaacaata tcttacctta 2280
atgcctcaat ttgtagatct cggtatttgt gaaataataa cgtaaacttc gtttaaaagg 2340
attcttcttc ctgtctttga gaaagtacgg cactgtgcag ggggagaggt tgattgtgaa 2400
aaatcagagg tagatgagaa tcttactgag ggctgagggt tctttaacct tggtggatct 2460
caacattggt tgcacattaa aatcacctgc tgcaagccct tgacgaatct tacttagaag 2520
atgacaacac agaacaatta aatcagaatc tctggggaga atagggcacc agtatttttt 2580
gagctcccac catgattcca aagtgcagcc aaatttgaga accactgcta aaagctcaag 2640
cttcagattg accagctttt ccatctcacc tatcgcctaa agaccaaatt ggataaatgt 2700
gttcattacg acagatgggt actatttaaa gatgagtaaa cacaatatac ttaggctcgt 2760
cagactgaga gttttaatca tcactgagga aaaacataga tatctaatac tgactggagt 2820
attagtcaag gcttatttca cacacaattt tatcagaaac caaagtagtt taaaacagct 2880
ctccccttat tagtaatgca ttggagggtt tactttacca tgtaccttgc tgagcactgt 2940
accttgttaa tctcatttac ttgtaatgag aaccacacag cgggtagttt tattggttct 3000
attttaccta catgacaaaa ctgaagcata aaaacactta gtaagttttc agtgtcatgc 3060
acaactagga agtgacatgg ccagaatata agcccagtca ccatcactct ataacctgcg 3120
cttttaacaa cttcagggca tgacacattt ggccggtcag tagaacccat gctgtgattt 3180
gtttttgcag tggtggtgat gactgccttg ttgaatccac tttttattct attccatttt 3240
ggggacacaa ttctgcaaga tgattcttca ttaggaaaca gagatgagtt attgaccaac 3300
acagaaagaa aaagagtttg ttgctccaca ctgggattaa acctatgatc ttggcctaat 3360
taacactagc tagtaagtgt ccaagctgat catctctaca acatttcaat aacagaaaac 3420
aacaattttc aaaattagtt acttacaatt atgtagaaat gcctctaaaa cacagtattt 3480
tccttatatt acaaaaacaa aaattataat tggttttgtc ctcttttgag agtttgcatg 3540
gtgttactcc ctgcatagtg aagaaaacat tttatttaag tagatggatc taagtttttc 3600
atgaacaaag gaatgacatt tgaaatcaat cctaccctag tccaggagaa tgcattagat 3660
taacctagta gaggtcttat ttcaccctga gttttctatg atcgtgattc tctgctggag 3720
gagtaattgt gaaatagatc tctctgggaa ctggcttcct agtccaatca gctcttttac 3780
caatgaacac ttccttgtga tatagatgtt tatggccgag aggatccagt atattaataa 3840
aatccctttt tgtattcaat gagggaaaca cataattttc atcaattagc agcttattgg 3900
aatatctgca tgatggttta acacttttaa gtgttgacta aagattaatt ttacagaaaa 3960
tagaaaaaga aatatgtttc tgtctggagg aatgatttat tgttgacccc taaattgaaa 4020
tattttacta gtggcttaat ggaaagatga tgaaagatga tgaaattaat gtagaagctt 4080
aactagaaaa tcaggtgacc tgatatctac atctgtatcc ttcattggcc acccagcatt 4140
cattaatgaa tcagatgatg gaatagatca agtttcctag gaacacagtg aatattaaaa 4200
gaaaacaaag ggagcctagc acctagaaga cctagtttat atttcaaagt atatttggat 4260
gtaacccaat tttaaacatt tcctcacttg tctctcttaa agccttgcca acagcaagga 4320
cagagaacca aaaatagtgt atatatgaat aaatgcttat tacagaatct gctgactggc 4380
acatgctttg tgtgtaatgg gttctcataa acacttgttg aatgaacaca cataagtgaa 4440
agagcatggc taggcttcat cccttggtca aatatggggt gctaaagaaa agcaggggaa 4500
atacattggg acactaacaa aaaaaaacag ttaatttagg taaaagataa aatacaccac 4560
agaatgaaga aaagagatga cccagactgc tctttaacct tcatgtccta gagaggtttt 4620
tgatatgaat tgcattcaga attgtggaaa ggagcccatc ttttctcttc attttgattt 4680
tattaactcc aatgggggaa ttttattcgt gttttggcca tatctacttt tgatttctac 4740
attattctct cttcctttct acctgtattt gtcctaataa attgttgact tattaattca 4800
ctacttcctc acagcttttt tttggcttta caaatccact ggaaaggtat atgggtgtat 4860
cactttgtgt atttcggtgt gcatgtgtag aggggacaaa aatcctctct caaactataa 4920
atattgagta tttgtgtatt gaacatttgc tataactact aggtttctta aataatctta 4980
atatataaaa tgatatagaa aaagggaaat tatagttcgt attattcatc taagtgaaga 5040
gattaaaacc cagggagtaa ataaattgtc taaggactaa ggttgtatac tatttaggtg 5100
atagatatgg ggcaaccgta tgggttttat gattaacaaa taaacttctc accactctac 5160
catatcaact tttccataaa agagagctat agtattcttt gcttaaataa atttgattag 5220
tgcatgactt cttgaaaaca tataaagcaa aagtcacatt tgattctatc agaaaagtga 5280
gtaagccatg gcccaaacaa aagatgcatt aaaatattct ggaatgatgg agctaaaagt 5340
aagaaaaatg actttttaaa aaagtttact gttaggaatt gtgaaattat gctgaatttt 5400
agttgcatta taatttttgt cagtcatacg gtctgacaac ctgtcttatt tctatttccc 5460
catatgagga atgctagtta agtatggata ttaactatta ctacttagat gcattgaagt 5520
tgcataatat ggataatact tcactggttc cctgaaaatg tttagttagt aataagtctc 5580
ttacactatt tgttttgtcc aataatttat attttctgaa gacttaactc tagaatacac 5640
tcatgtcaaa atgaaagaat ttcattgcaa aatattgctt ggtacatgac gcatacctgt 5700
atttgttttg tgtcacaaca tgaaaaatga tggtttatta gaagtttcat tgggtaggaa 5760
acacatttga atggtattta ctaagatact aaaatccttg gacttcactc taattttagt 5820
gccatttaga actcaaggtc tcagtaaaag tagaaataaa gcctgttaac aaaacacaaa 5880
ctgaatatta aaaatgtaac tggattttca aagaaatgtt tactggtatt acctgtagat 5940
gtatattctt tattatgatc ttttgtgtaa agtctggcag acaaatgcaa tatctaattg 6000
ttgagtccaa tatcacaagc agtacaaaag tataaaaaag acttggcctt ttctaatgtg 6060
ttaaaatact ttatgctggt aataacacta agagtagggc actagaaatt ttaagtgaag 6120
ataatgtgtt gcagttactg cactcaatgg cttactatta taaaccaaaa ctgggatcac 6180
taagctccag tcagtcaaaa tgatcaaaat tattgaagag aataagcaat tctgttcttt 6240
attaggacac agtagataca gactacaaag tggagtgtgc ttaataagag gtagcatttg 6300
ttaagtgtca attactctat tatcccttgg agcttctcaa aataaccata taaggtgtaa 6360
gatgttaaag gttatggtta cactcagtgc acaggtaagc taataggctg agagaagcta 6420
aattacttac tggggtctca cagtaagaaa gtgagctgaa gtttcagccc agatttaact 6480
ggattctggg ctctttattc atgttacttc atgaatctgt ttctcaattg tgcagaaaaa 6540
agggggctat ttataagaaa agcaataaac aaacaagtaa tgatctcaaa taagtaatgc 6600
aagaaatagt gagatttcaa aatcagtggc agcgatttct cagttctgtc ctaagtggcc 6660
ttgctcaatc acctgctatc ttttagtgga gctttgaaat tatgtttcag acaacttcga 6720
ttcagttcta gaatgtttga ctcagcaaat tcacaggctc atctttctaa cttgatggtg 6780
aatatggaaa ttcagctaaa tggatgttaa taaaattcaa acgttttaag gacagatgga 6840
aatgacagaa ttttaaggta aaatatatga aggaatataa gataaaggat ttttctacct 6900
tcagcaaaaa catacccact aattagtaaa attaataggc gaaaaaaagt tgcatgctct 6960
tatactgtaa tgattatcat tttaaaacta gctttttgcc ttcgagctat cggggtaaag 7020
acctacagga aaactactgt cgaaatcctc gaggggaaga agggggaccc tggtgtttca 7080
caagcaatcc agaggtacgc tacgaagtct gtgacattcc tcagtgttca gaagttgaat 7140
gcatgacctg caatggggag agttatcgag gtctcatgga tcatacagaa tcaggcaaga 7200
tttgtcagcg ctgggatcat cagacaccac accggcacaa attcttgcct gaaagatatc 7260
ccgacaaggg ctttgatgat aattattgcc gcaatcccga tggccagccg aggccatggt 7320
gctatactct tgaccctcac acccgctggg agtactgtgc aattaaaaca tgcgctgaca 7380
atactatgaa tgacactgat gttcctttgg aaacaactga atgcatccaa ggtcaaggag 7440
aaggctacag gggcactgtc aataccattt ggaatggaat tccatgtcag cgttgggatt 7500
ctcagtatcc tcacgagcat gacatgactc ctgaaaattt caagtgcaag gacctacgag 7560
aaaattactg ccgaaatcca gatgggtctg aatcaccctg gtgttttacc actgatccaa 7620
acatccgagt tggctactgc tcccaaattc caaactgtga tatgtcacat ggacaagatt 7680
gttatcgtgg gaatggcaaa aattatatgg gcaacttatc ccaaacaaga tctggactaa 7740
catgttcaat gtgggacaag aacatggaag acttacatcg tcatatcttc tgggaaccag 7800
atgcaagtaa gctgaatgag aattactgcc gaaatccaga tgatgatgct catggaccct 7860
ggtgctacac gggaaatcca ctcattcctt gggattattg ccctatttct cgttgtgaag 7920
gtgataccac acctacaata gtcaatttag accatcccgt aatatcttgt gccaaaacga 7980
aacaattgcg agttgtaaat gggattccaa cacgaacaaa cataggatgg atggttagtt 8040
tgagatacag aaataaacat atctgcggag gatcattgat aaaggagagt tgggttctta 8100
ctgcacgaca gtgtttccct tctcgagact tgaaagatta tgaagcttgg cttggaattc 8160
atgatgtcca cggaagagga gatgagaaat gcaaacaggt tctcaatgtt tcccagctgg 8220
tatatggccc tgaaggatca gatctggttt taatgaagct tgccaggcct gctgtcctgg 8280
atgattttgt tagtacgatt gatttaccta attatggatg cacaattcct gaaaagacca 8340
gttgcagtgt ttatggctgg ggctacactg gattgatcaa ctatgatggc ctattacgag 8400
tggcacatct ctatataatg ggaaatgaga aatgcagcca gcatcatcga gggaaggtga 8460
ctctgaatga gtctgaaata tgtgctgggg ctgaaaagat tggatcagga ccatgtgagg 8520
gggattatgg tggcccactt gtttgtgagc aacataaaat gagaatggtt cttggtgtca 8580
ttgttcctgg tcgtggatgt gccattccaa atcgtcctgg tatttttgtc cgagtagcat 8640
attatgcaaa atggatacac aaaattattt taacatataa ggtaccacag tcatagcggc 8700
cgctctagag ggcccgttta aacccgctga tcagcctcga ctgtgccttc tagttgccag 8760
ccatctgttg tttgcccctc ccccgtgcct tccttgaccc tggaaggtgc cactcccact 8820
gtcctttcct aataaaatga ggaaattgca tcgcattgtc tgagtaggtg tcattctatt 8880
ctggggggtg gggtggggca ggacagcaag ggggaggatt gggaagacaa tagcaggcat 8940
gctggggagt cgaaattcag aagaactcgt caagaaggcg atagaaggcg atgcgctgcg 9000
aatcgggagc ggcgataccg taaagcacga ggaagcggtc agcccattcg ccgccaagct 9060
cttcagcaat atcacgggta gccaacgcta tgtcctgata gcggtccgcc acacccagcc 9120
ggccacagtc gatgaatcca gaaaagcggc cattttccac catgatattc ggcaagcagg 9180
catcgccatg ggtcacgacg agatcctcgc cgtcgggcat gctcgccttg agcctggcga 9240
acagttcggc tggcgcgagc ccctgatgct cttcgtccag atcatcctga tcgacaagac 9300
cggcttccat ccgagtacgt gctcgctcga tgcgatgttt cgcttggtgg tcgaatgggc 9360
aggtagccgg atcaagcgta tgcagccgcc gcattgcatc agccatgatg gatactttct 9420
cggcaggagc aaggtgagat gacaggagat cctgccccgg cacttcgccc aatagcagcc 9480
agtcccttcc cgcttcagtg acaacgtcga gcacagctgc gcaaggaacg cccgtcgtgg 9540
ccagccacga tagccgcgct gcctcgtctt gcagttcatt cagggcaccg gacaggtcgg 9600
tcttgacaaa aagaaccggg cgcccctgcg ctgacagccg gaacacggcg gcatcagagc 9660
agccgattgt ctgttgtgcc cagtcatagc cgaatagcct ctccacccaa gcggccggag 9720
aacctgcgtg caatccatct tgttcaatca tgcgaaacga tcctcatcct gtctcttgat 9780
cagatcttga tcccctgcgc catcagatcc ttggcggcaa gaaagccatc cagtttactt 9840
tgcagggctt cccaacctta ccagagggcg ccccagctgg caattccggt tcgcttgctg 9900
tccataaaac cgcccagtct agctatcgcc atgtaagccc actgcaagct acctgctttc 9960
tctttgcgct tgcgttttcc cttgtccaga tagcccagta gctgacattc atccggggtc 10020
agcaccgttt ctgcggactg gctttctacg tgaaaaggat ctaggtgaag atcctttttg 10080
ataatctcat gaccaaaatc ccttaacgtg agttttcgtt ccactgagcg tcagaccccg 10140
tagaaaagat caaaggatct tcttgagatc ctttttttct gcgcgtaatc tgctgcttgc 10200
aaacaaaaaa accaccgcta ccagcggtgg tttgtttgcc ggatcaagag ctaccaactc 10260
tttttccgaa ggtaactggc ttcagcagag cgcagatacc aaatactgtt cttctagtgt 10320
agccgtagtt aggccaccac ttcaagaact ctgtagcacc gcctacatac ctcgctctgc 10380
taatcctgtt accagtggct gctgccagtg gcgataagtc gtgtcttacc gggttggact 10440
caagacgata gttaccggat aaggcgcagc ggtcgggctg aacggggggt tcgtgcacac 10500
agcccagctt ggagcgaacg acctacaccg aactgagata cctacagcgt gagctatgag 10560
aaagcgccac gcttcccgaa gggagaaagg cggacaggta tccggtaagc ggcagggtcg 10620
gaacaggaga gcgcacgagg gagcttccag ggggaaacgc ctggtatctt tatagtcctg 10680
tcgggtttcg ccacctctga cttgagcgtc gatttttgtg atgctcgtca ggggggcgga 10740
gcctatggaa aaacgccagc aacgcggcct ttttacggtt cctggccttt tgctggcctt 10800
ttgctcacat g 10811
<210> 7
<211> 7377
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 7
cgcgttgaca ttgattattg actagttatt aatagtaatc aattacgggg tcattagttc 60
atagcccata tatggagttc cgcgttacat aacttacggt aaatggcccg cctggctgac 120
cgcccaacga cccccgccca ttgacgtcaa taatgacgta tgttcccata gtaacgccaa 180
tagggacttt ccattgacgt caatgggtgg agtatttacg gtaaactgcc cacttggcag 240
tacatcaagt gtatcatatg ccaagtccgc cccctattga cgtcaatgac ggtaaatggc 300
ccgcctggca ttatgcccag tacatgacct tacgggactt tcctacttgg cagtacatct 360
acgtattagt catcgctatt accatggtga tgcggttttg gcagtacacc aatgggcgtg 420
gatagcggtt tgactcacgg ggatttccaa gtctccaccc cattgacgtc aatgggagtt 480
tgttttggca ccaaaatcaa cgggactttc caaaatgtcg taataacccc gccccgttga 540
cgcaaatggg cggtaggcgt gtacggtggg aggtctatat aagcagagct cgtttagtga 600
accgtcagat cgcctggaga cgccatccac gctgttttga cctccataga agacaccggg 660
accgatccag cctccgcggc cgggaacggt gcattggaac gcggattccc cgtgccaaga 720
gtgacgtaag taccgcctat agactctata ggcacacccc tttggctctt atgcatgcta 780
tactgttttt ggcttggggc ctatacaccc ccgcttcctt atgctatagg tgatggtata 840
gcttagccta taggtgtggg ttattgacca ttattgacca ctcccctatt ggtgacgata 900
ctttccatta ctaatccata acatggctct ttgccacaac tatctctatt ggctatatgc 960
caatactctg tccttcagag actgacacgg actctgtatt tttacaggat ggggtcccat 1020
ttattattta caaattcaca tatacaacaa cgccgtcccc cgtgcccgca gtttttatta 1080
aacatagcgt gggatctcca cgcgaatctc gggtacgtgt tccggacatg ggctcttctc 1140
cggtagcggc ggagcttcca catccgagcc ctggtcccat gcctccagcg gctcatggtc 1200
gctcggcagc tccttgctcc taacagtgga ggccagactt aggcacagca caatgcccac 1260
caccaccagt gtgccgcaca aggccgtggc ggtagggtat gtgtctgaaa atgagctcgg 1320
agattgggct cgcaccgctg acgcagatgg aagacttaag gcagcggcag aagaagatgc 1380
aggcagctga gttgttgtat tctgataaga gtcagaggta actcccgttg cggtgctgtt 1440
aacggtggag ggcagtgtag tctgagcagt actcgttgct gccgcgcgcg ccaccagaca 1500
taatagctga cagactaaca gactgttcct ttccatgggt cttttctgca gtcaccgtcc 1560
ttgacacgaa gcttgctagc accatgtggg tgaccaaact cctgccagcc ctgctgctgc 1620
agcatgtcct cctgcatctc ctcctgctcc ccatcgccat cccctatgca gagggacaaa 1680
ggaaaagaag aaatacaatt catgaattca aaaaatcagc aaagactacc ctaatcaaaa 1740
tagatccagc actgaagata aaaaccaaaa aagtgaatac tgcagaccaa tgtgctaata 1800
gatgtactag gaataaagga cttccattca cttgcaaggc ttttgttttt gataaagcaa 1860
gaaaacaatg cctctggttc cccttcaata gcatgtcaag tggagtgaaa aaagaatttg 1920
gccatgaatt tgacctctat gaaaacaaag actacattag aaactgcatc attggtaaag 1980
gacgcagcta caagggaaca gtatctatca ctaagagtgg catcaaatgt cagccctgga 2040
gttccatgat accacacgaa cacaggtaag aacagtatga agaaaagaga tgaagcctct 2100
gtctttttta catgttaaca gtctcatatt agtccttcag aataattcta caatcctaaa 2160
ataacttagc caacttgctg aattgtatta cggcaaggtt tatatgaatt catgactgat 2220
atttagcaaa tgattaatta atatgttaat aaaatgtagc caaaacaata tcttacctta 2280
atgcctcaat ttgtagatct cggtatttgt ggatcctggg taggaaacac atttgaatgg 2340
tatttactaa gatactaaaa tccttggact tcactctaat tttagtgcca tttagaactc 2400
aaggtctcag taaaagtaga aataaagcct gttaacaaaa cacaaactga atattaaaaa 2460
tgtaactgga ttttcaaaga aatgtttact ggtattacct gtagatgtat attctttatt 2520
atgatctttt gtgtaaagtc tggcagacaa atgcaatatc taattgttga gtccaatatc 2580
acaagcagta caaaagtata aaaaagactt ggccttttct aatgtgttaa aatactttat 2640
gctggtaata acactaagag tagggcacta gaaattttaa gtgaagataa tgtgttgcag 2700
ttactgcact caatggctta ctattataaa ccaaaactgg gatcactaag ctccagtcag 2760
tcaaaatgat caaaattatt gaagagaata agcaattctg ttctttatta ggacacagta 2820
gatacagact acaaagtgga gtgtgcttaa taagaggtag catttgttaa gtgtcaatta 2880
ctctattatc ccttggagct tctcaaaata accatataag gtgtaagatg ttaaaggtta 2940
tggttacact cagtgcacag gtaagctaat aggctgagag aagctaaatt acttactggg 3000
gtctcacagt aagaaagtga gctgaagttt cagcccagat ttaactggat tctgggctct 3060
ttattcatgt tacttcatga atctgtttct caattgtgca gaaaaaaggg ggctatttat 3120
aagaaaagca ataaacaaac aagtaatgat ctcaaataag taatgcaaga aatagtgaga 3180
tttcaaaatc agtggcagcg atttctcagt tctgtcctaa gtggccttgc tcaatcacct 3240
gctatctttt agtggagctt tgaaattatg tttcagacaa cttcgattca gttctagaat 3300
gtttgactca gcaaattcac aggctcatct ttctaacttg atggtgaata tggaaattca 3360
gctaaatgga tgttaataaa attcaaacgt tttaaggaca gatggaaatg acagaatttt 3420
aaggtaaaat atatgaagga atataagata aaggattttt ctaccttcag caaaaacata 3480
cccactaatt agtaaaatta ataggcgaaa aaaagttgca tgctcttata ctgtaatgat 3540
tatcatttta aaactagctt tttgccttcg agctatcggg gtaaagacct acaggaaaac 3600
tactgtcgaa atcctcgagg ggaagaaggg ggaccctggt gtttcacaag caatccagag 3660
gtacgctacg aagtctgtga cattcctcag tgttcagaag ttgaatgcat gacctgcaat 3720
ggggagagtt atcgaggtct catggatcat acagaatcag gcaagatttg tcagcgctgg 3780
gatcatcaga caccacaccg gcacaaattc ttgcctgaaa gatatcccga caagggcttt 3840
gatgataatt attgccgcaa tcccgatggc cagccgaggc catggtgcta tactcttgac 3900
cctcacaccc gctgggagta ctgtgcaatt aaaacatgcg ctgacaatac tatgaatgac 3960
actgatgttc ctttggaaac aactgaatgc atccaaggtc aaggagaagg ctacaggggc 4020
actgtcaata ccatttggaa tggaattcca tgtcagcgtt gggattctca gtatcctcac 4080
gagcatgaca tgactcctga aaatttcaag tgcaaggacc tacgagaaaa ttactgccga 4140
aatccagatg ggtctgaatc accctggtgt tttaccactg atccaaacat ccgagttggc 4200
tactgctccc aaattccaaa ctgtgatatg tcacatggac aagattgtta tcgtgggaat 4260
ggcaaaaatt atatgggcaa cttatcccaa acaagatctg gactaacatg ttcaatgtgg 4320
gacaagaaca tggaagactt acatcgtcat atcttctggg aaccagatgc aagtaagctg 4380
aatgagaatt actgccgaaa tccagatgat gatgctcatg gaccctggtg ctacacggga 4440
aatccactca ttccttggga ttattgccct atttctcgtt gtgaaggtga taccacacct 4500
acaatagtca atttagacca tcccgtaata tcttgtgcca aaacgaaaca attgcgagtt 4560
gtaaatggga ttccaacacg aacaaacata ggatggatgg ttagtttgag atacagaaat 4620
aaacatatct gcggaggatc attgataaag gagagttggg ttcttactgc acgacagtgt 4680
ttcccttctc gagacttgaa agattatgaa gcttggcttg gaattcatga tgtccacgga 4740
agaggagatg agaaatgcaa acaggttctc aatgtttccc agctggtata tggccctgaa 4800
ggatcagatc tggttttaat gaagcttgcc aggcctgctg tcctggatga ttttgttagt 4860
acgattgatt tacctaatta tggatgcaca attcctgaaa agaccagttg cagtgtttat 4920
ggctggggct acactggatt gatcaactat gatggcctat tacgagtggc acatctctat 4980
ataatgggaa atgagaaatg cagccagcat catcgaggga aggtgactct gaatgagtct 5040
gaaatatgtg ctggggctga aaagattgga tcaggaccat gtgaggggga ttatggtggc 5100
ccacttgttt gtgagcaaca taaaatgaga atggttcttg gtgtcattgt tcctggtcgt 5160
ggatgtgcca ttccaaatcg tcctggtatt tttgtccgag tagcatatta tgcaaaatgg 5220
atacacaaaa ttattttaac atataaggta ccacagtcat agcggccgct ctagagggcc 5280
cgtttaaacc cgctgatcag cctcgactgt gccttctagt tgccagccat ctgttgtttg 5340
cccctccccc gtgccttcct tgaccctgga aggtgccact cccactgtcc tttcctaata 5400
aaatgaggaa attgcatcgc attgtctgag taggtgtcat tctattctgg ggggtggggt 5460
ggggcaggac agcaaggggg aggattggga agacaatagc aggcatgctg gggagtcgaa 5520
attcagaaga actcgtcaag aaggcgatag aaggcgatgc gctgcgaatc gggagcggcg 5580
ataccgtaaa gcacgaggaa gcggtcagcc cattcgccgc caagctcttc agcaatatca 5640
cgggtagcca acgctatgtc ctgatagcgg tccgccacac ccagccggcc acagtcgatg 5700
aatccagaaa agcggccatt ttccaccatg atattcggca agcaggcatc gccatgggtc 5760
acgacgagat cctcgccgtc gggcatgctc gccttgagcc tggcgaacag ttcggctggc 5820
gcgagcccct gatgctcttc gtccagatca tcctgatcga caagaccggc ttccatccga 5880
gtacgtgctc gctcgatgcg atgtttcgct tggtggtcga atgggcaggt agccggatca 5940
agcgtatgca gccgccgcat tgcatcagcc atgatggata ctttctcggc aggagcaagg 6000
tgagatgaca ggagatcctg ccccggcact tcgcccaata gcagccagtc ccttcccgct 6060
tcagtgacaa cgtcgagcac agctgcgcaa ggaacgcccg tcgtggccag ccacgatagc 6120
cgcgctgcct cgtcttgcag ttcattcagg gcaccggaca ggtcggtctt gacaaaaaga 6180
accgggcgcc cctgcgctga cagccggaac acggcggcat cagagcagcc gattgtctgt 6240
tgtgcccagt catagccgaa tagcctctcc acccaagcgg ccggagaacc tgcgtgcaat 6300
ccatcttgtt caatcatgcg aaacgatcct catcctgtct cttgatcaga tcttgatccc 6360
ctgcgccatc agatccttgg cggcaagaaa gccatccagt ttactttgca gggcttccca 6420
accttaccag agggcgcccc agctggcaat tccggttcgc ttgctgtcca taaaaccgcc 6480
cagtctagct atcgccatgt aagcccactg caagctacct gctttctctt tgcgcttgcg 6540
ttttcccttg tccagatagc ccagtagctg acattcatcc ggggtcagca ccgtttctgc 6600
ggactggctt tctacgtgaa aaggatctag gtgaagatcc tttttgataa tctcatgacc 6660
aaaatccctt aacgtgagtt ttcgttccac tgagcgtcag accccgtaga aaagatcaaa 6720
ggatcttctt gagatccttt ttttctgcgc gtaatctgct gcttgcaaac aaaaaaacca 6780
ccgctaccag cggtggtttg tttgccggat caagagctac caactctttt tccgaaggta 6840
actggcttca gcagagcgca gataccaaat actgttcttc tagtgtagcc gtagttaggc 6900
caccacttca agaactctgt agcaccgcct acatacctcg ctctgctaat cctgttacca 6960
gtggctgctg ccagtggcga taagtcgtgt cttaccgggt tggactcaag acgatagtta 7020
ccggataagg cgcagcggtc gggctgaacg gggggttcgt gcacacagcc cagcttggag 7080
cgaacgacct acaccgaact gagataccta cagcgtgagc tatgagaaag cgccacgctt 7140
cccgaaggga gaaaggcgga caggtatccg gtaagcggca gggtcggaac aggagagcgc 7200
acgagggagc ttccaggggg aaacgcctgg tatctttata gtcctgtcgg gtttcgccac 7260
ctctgacttg agcgtcgatt tttgtgatgc tcgtcagggg ggcggagcct atggaaaaac 7320
gccagcaacg cggccttttt acggttcctg gccttttgct ggccttttgc tcacatg 7377
<210> 8
<211> 8377
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
cgcgttgaca ttgattattg actagttatt aatagtaatc aattacgggg tcattagttc 60
atagcccata tatggagttc cgcgttacat aacttacggt aaatggcccg cctggctgac 120
cgcccaacga cccccgccca ttgacgtcaa taatgacgta tgttcccata gtaacgccaa 180
tagggacttt ccattgacgt caatgggtgg agtatttacg gtaaactgcc cacttggcag 240
tacatcaagt gtatcatatg ccaagtccgc cccctattga cgtcaatgac ggtaaatggc 300
ccgcctggca ttatgcccag tacatgacct tacgggactt tcctacttgg cagtacatct 360
acgtattagt catcgctatt accatggtga tgcggttttg gcagtacacc aatgggcgtg 420
gatagcggtt tgactcacgg ggatttccaa gtctccaccc cattgacgtc aatgggagtt 480
tgttttggca ccaaaatcaa cgggactttc caaaatgtcg taataacccc gccccgttga 540
cgcaaatggg cggtaggcgt gtacggtggg aggtctatat aagcagagct cgtttagtga 600
accgtcagat cgcctggaga cgccatccac gctgttttga cctccataga agacaccggg 660
accgatccag cctccgcggc cgggaacggt gcattggaac gcggattccc cgtgccaaga 720
gtgacgtaag taccgcctat agactctata ggcacacccc tttggctctt atgcatgcta 780
tactgttttt ggcttggggc ctatacaccc ccgcttcctt atgctatagg tgatggtata 840
gcttagccta taggtgtggg ttattgacca ttattgacca ctcccctatt ggtgacgata 900
ctttccatta ctaatccata acatggctct ttgccacaac tatctctatt ggctatatgc 960
caatactctg tccttcagag actgacacgg actctgtatt tttacaggat ggggtcccat 1020
ttattattta caaattcaca tatacaacaa cgccgtcccc cgtgcccgca gtttttatta 1080
aacatagcgt gggatctcca cgcgaatctc gggtacgtgt tccggacatg ggctcttctc 1140
cggtagcggc ggagcttcca catccgagcc ctggtcccat gcctccagcg gctcatggtc 1200
gctcggcagc tccttgctcc taacagtgga ggccagactt aggcacagca caatgcccac 1260
caccaccagt gtgccgcaca aggccgtggc ggtagggtat gtgtctgaaa atgagctcgg 1320
agattgggct cgcaccgctg acgcagatgg aagacttaag gcagcggcag aagaagatgc 1380
aggcagctga gttgttgtat tctgataaga gtcagaggta actcccgttg cggtgctgtt 1440
aacggtggag ggcagtgtag tctgagcagt actcgttgct gccgcgcgcg ccaccagaca 1500
taatagctga cagactaaca gactgttcct ttccatgggt cttttctgca gtcaccgtcc 1560
ttgacacgaa gcttgctagc accatgtggg tgaccaaact cctgccagcc ctgctgctgc 1620
agcatgtcct cctgcatctc ctcctgctcc ccatcgccat cccctatgca gagggacaaa 1680
ggaaaagaag aaatacaatt catgaattca aaaaatcagc aaagactacc ctaatcaaaa 1740
tagatccagc actgaagata aaaaccaaaa aagtgaatac tgcagaccaa tgtgctaata 1800
gatgtactag gaataaagga cttccattca cttgcaaggc ttttgttttt gataaagcaa 1860
gaaaacaatg cctctggttc cccttcaata gcatgtcaag tggagtgaaa aaagaatttg 1920
gccatgaatt tgacctctat gaaaacaaag actacattag aaactgcatc attggtaaag 1980
gacgcagcta caagggaaca gtatctatca ctaagagtgg catcaaatgt cagccctgga 2040
gttccatgat accacacgaa cacaggtaag aacagtatga agaaaagaga tgaagcctct 2100
gtctttttta catgttaaca gtctcatatt agtccttcag aataattcta caatcctaaa 2160
ataacttagc caacttgctg aattgtatta cggcaaggtt tatatgaatt catgactgat 2220
atttagcaaa tgattaatta atatgttaat aaaatgtagc caaaacaata tcttacctta 2280
atgcctcaat ttgtagatct cggtatttgt ggatcccttc ctttctacct gtatttgtcc 2340
taataaattg ttgacttatt aattcactac ttcctcacag cttttttttg gctttacaaa 2400
tccactggaa aggtatatgg gtgtatcact ttgtgtattt cggtgtgcat gtgtagaggg 2460
gacaaaaatc ctctctcaaa ctataaatat tgagtatttg tgtattgaac atttgctata 2520
actactaggt ttcttaaata atcttaatat ataaaatgat atagaaaaag ggaaattata 2580
gttcgtatta ttcatctaag tgaagagatt aaaacccagg gagtaaataa attgtctaag 2640
gactaaggtt gtatactatt taggtgatag atatggggca accgtatggg ttttatgatt 2700
aacaaataaa cttctcacca ctctaccata tcaacttttc cataaaagag agctatagta 2760
ttctttgctt aaataaattt gattagtgca tgacttcttg aaaacatata aagcaaaagt 2820
cacatttgat tctatcagaa aagtgagtaa gccatggccc aaacaaaaga tgcattaaaa 2880
tattctggaa tgatggagct aaaagtaaga aaaatgactt tttaaaaaag tttactgtta 2940
ggaattgtga aattatgctg aattttagtt gcattataat ttttgtcagt catacggtct 3000
gacaacctgt cttatttcta tttccccata tgaggaatgc tagttaagta tggatattaa 3060
ctattactac ttagatgcat tgaagttgca taatatggat aatacttcac tggttccctg 3120
aaaatgttta gttagtaata agtctcttac actatttgtt ttgtccaata atttatattt 3180
tctgaagact taactctaga atacactcat gtcaaaatga aagaatttca ttgcaaaata 3240
ttgcttggta catgacgcat acctgtattt gttttgtgtc acaacatgaa aaatgatggt 3300
ttattagaag tttcattggg taggaaacac atttgaatgg tatttactaa gatactaaaa 3360
tccttggact tcactctaat tttagtgcca tttagaactc aaggtctcag taaaagtaga 3420
aataaagcct gttaacaaaa cacaaactga atattaaaaa tgtaactgga ttttcaaaga 3480
aatgtttact ggtattacct gtagatgtat attctttatt atgatctttt gtgtaaagtc 3540
tggcagacaa atgcaatatc taattgttga gtccaatatc acaagcagta caaaagtata 3600
aaaaagactt ggccttttct aatgtgttaa aatactttat gctggtaata acactaagag 3660
tagggcacta gaaattttaa gtgaagataa tgtgttgcag ttactgcact caatggctta 3720
ctattataaa ccaaaactgg gatcactaag ctccagtcag tcaaaatgat caaaattatt 3780
gaagagaata agcaattctg ttctttatta ggacacagta gatacagact acaaagtgga 3840
gtgtgcttaa taagaggtag catttgttaa gtgtcaatta ctctattatc ccttggagct 3900
tctcaaaata accatataag gtgtaagatg ttaaaggtta tggttacact cagtgcacag 3960
gtaagctaat aggctgagag aagctaaatt acttactggg gtctcacagt aagaaagtga 4020
gctgaagttt cagcccagat ttaactggat tctgggctct ttattcatgt tacttcatga 4080
atctgtttct caattgtgca gaaaaaaggg ggctatttat aagaaaagca ataaacaaac 4140
aagtaatgat ctcaaataag taatgcaaga aatagtgaga tttcaaaatc agtggcagcg 4200
atttctcagt tctgtcctaa gtggccttgc tcaatcacct gctatctttt agtggagctt 4260
tgaaattatg tttcagacaa cttcgattca gttctagaat gtttgactca gcaaattcac 4320
aggctcatct ttctaacttg atggtgaata tggaaattca gctaaatgga tgttaataaa 4380
attcaaacgt tttaaggaca gatggaaatg acagaatttt aaggtaaaat atatgaagga 4440
atataagata aaggattttt ctaccttcag caaaaacata cccactaatt agtaaaatta 4500
ataggcgaaa aaaagttgca tgctcttata ctgtaatgat tatcatttta aaactagctt 4560
tttgccttcg agctatcggg gtaaagacct acaggaaaac tactgtcgaa atcctcgagg 4620
ggaagaaggg ggaccctggt gtttcacaag caatccagag gtacgctacg aagtctgtga 4680
cattcctcag tgttcagaag ttgaatgcat gacctgcaat ggggagagtt atcgaggtct 4740
catggatcat acagaatcag gcaagatttg tcagcgctgg gatcatcaga caccacaccg 4800
gcacaaattc ttgcctgaaa gatatcccga caagggcttt gatgataatt attgccgcaa 4860
tcccgatggc cagccgaggc catggtgcta tactcttgac cctcacaccc gctgggagta 4920
ctgtgcaatt aaaacatgcg ctgacaatac tatgaatgac actgatgttc ctttggaaac 4980
aactgaatgc atccaaggtc aaggagaagg ctacaggggc actgtcaata ccatttggaa 5040
tggaattcca tgtcagcgtt gggattctca gtatcctcac gagcatgaca tgactcctga 5100
aaatttcaag tgcaaggacc tacgagaaaa ttactgccga aatccagatg ggtctgaatc 5160
accctggtgt tttaccactg atccaaacat ccgagttggc tactgctccc aaattccaaa 5220
ctgtgatatg tcacatggac aagattgtta tcgtgggaat ggcaaaaatt atatgggcaa 5280
cttatcccaa acaagatctg gactaacatg ttcaatgtgg gacaagaaca tggaagactt 5340
acatcgtcat atcttctggg aaccagatgc aagtaagctg aatgagaatt actgccgaaa 5400
tccagatgat gatgctcatg gaccctggtg ctacacggga aatccactca ttccttggga 5460
ttattgccct atttctcgtt gtgaaggtga taccacacct acaatagtca atttagacca 5520
tcccgtaata tcttgtgcca aaacgaaaca attgcgagtt gtaaatggga ttccaacacg 5580
aacaaacata ggatggatgg ttagtttgag atacagaaat aaacatatct gcggaggatc 5640
attgataaag gagagttggg ttcttactgc acgacagtgt ttcccttctc gagacttgaa 5700
agattatgaa gcttggcttg gaattcatga tgtccacgga agaggagatg agaaatgcaa 5760
acaggttctc aatgtttccc agctggtata tggccctgaa ggatcagatc tggttttaat 5820
gaagcttgcc aggcctgctg tcctggatga ttttgttagt acgattgatt tacctaatta 5880
tggatgcaca attcctgaaa agaccagttg cagtgtttat ggctggggct acactggatt 5940
gatcaactat gatggcctat tacgagtggc acatctctat ataatgggaa atgagaaatg 6000
cagccagcat catcgaggga aggtgactct gaatgagtct gaaatatgtg ctggggctga 6060
aaagattgga tcaggaccat gtgaggggga ttatggtggc ccacttgttt gtgagcaaca 6120
taaaatgaga atggttcttg gtgtcattgt tcctggtcgt ggatgtgcca ttccaaatcg 6180
tcctggtatt tttgtccgag tagcatatta tgcaaaatgg atacacaaaa ttattttaac 6240
atataaggta ccacagtcat agcggccgct ctagagggcc cgtttaaacc cgctgatcag 6300
cctcgactgt gccttctagt tgccagccat ctgttgtttg cccctccccc gtgccttcct 6360
tgaccctgga aggtgccact cccactgtcc tttcctaata aaatgaggaa attgcatcgc 6420
attgtctgag taggtgtcat tctattctgg ggggtggggt ggggcaggac agcaaggggg 6480
aggattggga agacaatagc aggcatgctg gggagtcgaa attcagaaga actcgtcaag 6540
aaggcgatag aaggcgatgc gctgcgaatc gggagcggcg ataccgtaaa gcacgaggaa 6600
gcggtcagcc cattcgccgc caagctcttc agcaatatca cgggtagcca acgctatgtc 6660
ctgatagcgg tccgccacac ccagccggcc acagtcgatg aatccagaaa agcggccatt 6720
ttccaccatg atattcggca agcaggcatc gccatgggtc acgacgagat cctcgccgtc 6780
gggcatgctc gccttgagcc tggcgaacag ttcggctggc gcgagcccct gatgctcttc 6840
gtccagatca tcctgatcga caagaccggc ttccatccga gtacgtgctc gctcgatgcg 6900
atgtttcgct tggtggtcga atgggcaggt agccggatca agcgtatgca gccgccgcat 6960
tgcatcagcc atgatggata ctttctcggc aggagcaagg tgagatgaca ggagatcctg 7020
ccccggcact tcgcccaata gcagccagtc ccttcccgct tcagtgacaa cgtcgagcac 7080
agctgcgcaa ggaacgcccg tcgtggccag ccacgatagc cgcgctgcct cgtcttgcag 7140
ttcattcagg gcaccggaca ggtcggtctt gacaaaaaga accgggcgcc cctgcgctga 7200
cagccggaac acggcggcat cagagcagcc gattgtctgt tgtgcccagt catagccgaa 7260
tagcctctcc acccaagcgg ccggagaacc tgcgtgcaat ccatcttgtt caatcatgcg 7320
aaacgatcct catcctgtct cttgatcaga tcttgatccc ctgcgccatc agatccttgg 7380
cggcaagaaa gccatccagt ttactttgca gggcttccca accttaccag agggcgcccc 7440
agctggcaat tccggttcgc ttgctgtcca taaaaccgcc cagtctagct atcgccatgt 7500
aagcccactg caagctacct gctttctctt tgcgcttgcg ttttcccttg tccagatagc 7560
ccagtagctg acattcatcc ggggtcagca ccgtttctgc ggactggctt tctacgtgaa 7620
aaggatctag gtgaagatcc tttttgataa tctcatgacc aaaatccctt aacgtgagtt 7680
ttcgttccac tgagcgtcag accccgtaga aaagatcaaa ggatcttctt gagatccttt 7740
ttttctgcgc gtaatctgct gcttgcaaac aaaaaaacca ccgctaccag cggtggtttg 7800
tttgccggat caagagctac caactctttt tccgaaggta actggcttca gcagagcgca 7860
gataccaaat actgttcttc tagtgtagcc gtagttaggc caccacttca agaactctgt 7920
agcaccgcct acatacctcg ctctgctaat cctgttacca gtggctgctg ccagtggcga 7980
taagtcgtgt cttaccgggt tggactcaag acgatagtta ccggataagg cgcagcggtc 8040
gggctgaacg gggggttcgt gcacacagcc cagcttggag cgaacgacct acaccgaact 8100
gagataccta cagcgtgagc tatgagaaag cgccacgctt cccgaaggga gaaaggcgga 8160
caggtatccg gtaagcggca gggtcggaac aggagagcgc acgagggagc ttccaggggg 8220
aaacgcctgg tatctttata gtcctgtcgg gtttcgccac ctctgacttg agcgtcgatt 8280
tttgtgatgc tcgtcagggg ggcggagcct atggaaaaac gccagcaacg cggccttttt 8340
acggttcctg gccttttgct ggccttttgc tcacatg 8377
<210> 9
<211> 4926
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
gtaagaacag tatgaagaaa agagatgaag cctctgtctt ttttacatgt taacagtctc 60
atattagtcc ttcagaataa ttctacaatc ctaaaataac ttagccaact tgctgaattg 120
tattacggca aggtttatat gaattcatga ctgatattta gcaaatgatt aattaatatg 180
ttaataaaat gtagccaaaa caatatctta ccttaatgcc tcaatttgta gatctcggta 240
tttgtgaaat aataacgtaa acttcgttta aaaggattct tcttcctgtc tttgagaaag 300
tacggcactg tgcaggggga gaggttgatt gtgaaaaatc agaggtagat gagaatctta 360
ctgagggctg agggttcttt aaccttggtg gatctcaaca ttggttgcac attaaaatca 420
cctgctgcaa gcccttgacg aatcttactt agaagatgac aacacagaac aattaaatca 480
gaatctctgg ggagaatagg gcaccagtat tttttgagct cccaccatga ttccaaagtg 540
cagccaaatt tgagaaccac tgctaaaagc tcaagcttca gattgaccag cttttccatc 600
tcacctatcg cctaaagacc aaattggata aatgtgttca ttacgacaga tgggtactat 660
ttaaagatga gtaaacacaa tatacttagg ctcgtcagac tgagagtttt aatcatcact 720
gaggaaaaac atagatatct aatactgact ggagtattag tcaaggctta tttcacacac 780
aattttatca gaaaccaaag tagtttaaaa cagctctccc cttattagta atgcattgga 840
gggtttactt taccatgtac cttgctgagc actgtacctt gttaatctca tttacttgta 900
atgagaacca cacagcgggt agttttattg gttctatttt acctacatga caaaactgaa 960
gcataaaaac acttagtaag ttttcagtgt catgcacaac taggaagtga catggccaga 1020
atataagccc agtcaccatc actctataac ctgcgctttt aacaacttca gggcatgaca 1080
catttggccg gtcagtagaa cccatgctgt gatttgtttt tgcagtggtg gtgatgactg 1140
ccttgttgaa tccacttttt attctattcc attttgggga cacaattctg caagatgatt 1200
cttcattagg aaacagagat gagttattga ccaacacaga aagaaaaaga gtttgttgct 1260
ccacactggg attaaaccta tgatcttggc ctaattaaca ctagctagta agtgtccaag 1320
ctgatcatct ctacaacatt tcaataacag aaaacaacaa ttttcaaaat tagttactta 1380
caattatgta gaaatgcctc taaaacacag tattttcctt atattacaaa aacaaaaatt 1440
ataattggtt ttgtcctctt ttgagagttt gcatggtgtt actccctgca tagtgaagaa 1500
aacattttat ttaagtagat ggatctaagt ttttcatgaa caaaggaatg acatttgaaa 1560
tcaatcctac cctagtccag gagaatgcat tagattaacc tagtagaggt cttatttcac 1620
cctgagtttt ctatgatcgt gattctctgc tggaggagta attgtgaaat agatctctct 1680
gggaactggc ttcctagtcc aatcagctct tttaccaatg aacacttcct tgtgatatag 1740
atgtttatgg ccgagaggat ccagtatatt aataaaatcc ctttttgtat tcaatgaggg 1800
aaacacataa ttttcatcaa ttagcagctt attggaatat ctgcatgatg gtttaacact 1860
tttaagtgtt gactaaagat taattttaca gaaaatagaa aaagaaatat gtttctgtct 1920
ggaggaatga tttattgttg acccctaaat tgaaatattt tactagtggc ttaatggaaa 1980
gatgatgaaa gatgatgaaa ttaatgtaga agcttaacta gaaaatcagg tgacctgata 2040
tctacatctg tatccttcat tggccaccca gcattcatta atgaatcaga tgatggaata 2100
gatcaagttt cctaggaaca cagtgaatat taaaagaaaa caaagggagc ctagcaccta 2160
gaagacctag tttatatttc aaagtatatt tggatgtaac ccaattttaa acatttcctc 2220
acttgtctct cttaaagcct tgccaacagc aaggacagag aaccaaaaat agtgtatata 2280
tgaataaatg cttattacag aatctgctga ctggcacatg ctttgtgtgt aatgggttct 2340
cataaacact tgttgaatga acacacataa gtgaaagagc atggctaggc ttcatccctt 2400
ggtcaaatat ggggtgctaa agaaaagcag gggaaataca ttgggacact aacaaaaaaa 2460
aacagttaat ttaggtaaaa gataaaatac accacagaat gaagaaaaga gatgacccag 2520
actgctcttt aaccttcatg tcctagagag gtttttgata tgaattgcat tcagaattgt 2580
ggaaaggagc ccatcttttc tcttcatttt gattttatta actccaatgg gggaatttta 2640
ttcgtgtttt ggccatatct acttttgatt tctacattat tctctcttcc tttctacctg 2700
tatttgtcct aataaattgt tgacttatta attcactact tcctcacagc ttttttttgg 2760
ctttacaaat ccactggaaa ggtatatggg tgtatcactt tgtgtatttc ggtgtgcatg 2820
tgtagagggg acaaaaatcc tctctcaaac tataaatatt gagtatttgt gtattgaaca 2880
tttgctataa ctactaggtt tcttaaataa tcttaatata taaaatgata tagaaaaagg 2940
gaaattatag ttcgtattat tcatctaagt gaagagatta aaacccaggg agtaaataaa 3000
ttgtctaagg actaaggttg tatactattt aggtgataga tatggggcaa ccgtatgggt 3060
tttatgatta acaaataaac ttctcaccac tctaccatat caacttttcc ataaaagaga 3120
gctatagtat tctttgctta aataaatttg attagtgcat gacttcttga aaacatataa 3180
agcaaaagtc acatttgatt ctatcagaaa agtgagtaag ccatggccca aacaaaagat 3240
gcattaaaat attctggaat gatggagcta aaagtaagaa aaatgacttt ttaaaaaagt 3300
ttactgttag gaattgtgaa attatgctga attttagttg cattataatt tttgtcagtc 3360
atacggtctg acaacctgtc ttatttctat ttccccatat gaggaatgct agttaagtat 3420
ggatattaac tattactact tagatgcatt gaagttgcat aatatggata atacttcact 3480
ggttccctga aaatgtttag ttagtaataa gtctcttaca ctatttgttt tgtccaataa 3540
tttatatttt ctgaagactt aactctagaa tacactcatg tcaaaatgaa agaatttcat 3600
tgcaaaatat tgcttggtac atgacgcata cctgtatttg ttttgtgtca caacatgaaa 3660
aatgatggtt tattagaagt ttcattgggt aggaaacaca tttgaatggt atttactaag 3720
atactaaaat ccttggactt cactctaatt ttagtgccat ttagaactca aggtctcagt 3780
aaaagtagaa ataaagcctg ttaacaaaac acaaactgaa tattaaaaat gtaactggat 3840
tttcaaagaa atgtttactg gtattacctg tagatgtata ttctttatta tgatcttttg 3900
tgtaaagtct ggcagacaaa tgcaatatct aattgttgag tccaatatca caagcagtac 3960
aaaagtataa aaaagacttg gccttttcta atgtgttaaa atactttatg ctggtaataa 4020
cactaagagt agggcactag aaattttaag tgaagataat gtgttgcagt tactgcactc 4080
aatggcttac tattataaac caaaactggg atcactaagc tccagtcagt caaaatgatc 4140
aaaattattg aagagaataa gcaattctgt tctttattag gacacagtag atacagacta 4200
caaagtggag tgtgcttaat aagaggtagc atttgttaag tgtcaattac tctattatcc 4260
cttggagctt ctcaaaataa ccatataagg tgtaagatgt taaaggttat ggttacactc 4320
agtgcacagg taagctaata ggctgagaga agctaaatta cttactgggg tctcacagta 4380
agaaagtgag ctgaagtttc agcccagatt taactggatt ctgggctctt tattcatgtt 4440
acttcatgaa tctgtttctc aattgtgcag aaaaaagggg gctatttata agaaaagcaa 4500
taaacaaaca agtaatgatc tcaaataagt aatgcaagaa atagtgagat ttcaaaatca 4560
gtggcagcga tttctcagtt ctgtcctaag tggccttgct caatcacctg ctatctttta 4620
gtggagcttt gaaattatgt ttcagacaac ttcgattcag ttctagaatg tttgactcag 4680
caaattcaca ggctcatctt tctaacttga tggtgaatat ggaaattcag ctaaatggat 4740
gttaataaaa ttcaaacgtt ttaaggacag atggaaatga cagaatttta aggtaaaata 4800
tatgaaggaa tataagataa aggatttttc taccttcagc aaaaacatac ccactaatta 4860
gtaaaattaa taggcgaaaa aaagttgcat gctcttatac tgtaatgatt atcattttaa 4920
aactag 4926
<210> 10
<211> 1492
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
gtaagaacag tatgaagaaa agagatgaag cctctgtctt ttttacatgt taacagtctc 60
atattagtcc ttcagaataa ttctacaatc ctaaaataac ttagccaact tgctgaattg 120
tattacggca aggtttatat gaattcatga ctgatattta gcaaatgatt aattaatatg 180
ttaataaaat gtagccaaaa caatatctta ccttaatgcc tcaatttgta gatctcggta 240
tttgtggatc ctgggtagga aacacatttg aatggtattt actaagatac taaaatcctt 300
ggacttcact ctaattttag tgccatttag aactcaaggt ctcagtaaaa gtagaaataa 360
agcctgttaa caaaacacaa actgaatatt aaaaatgtaa ctggattttc aaagaaatgt 420
ttactggtat tacctgtaga tgtatattct ttattatgat cttttgtgta aagtctggca 480
gacaaatgca atatctaatt gttgagtcca atatcacaag cagtacaaaa gtataaaaaa 540
gacttggcct tttctaatgt gttaaaatac tttatgctgg taataacact aagagtaggg 600
cactagaaat tttaagtgaa gataatgtgt tgcagttact gcactcaatg gcttactatt 660
ataaaccaaa actgggatca ctaagctcca gtcagtcaaa atgatcaaaa ttattgaaga 720
gaataagcaa ttctgttctt tattaggaca cagtagatac agactacaaa gtggagtgtg 780
cttaataaga ggtagcattt gttaagtgtc aattactcta ttatcccttg gagcttctca 840
aaataaccat ataaggtgta agatgttaaa ggttatggtt acactcagtg cacaggtaag 900
ctaataggct gagagaagct aaattactta ctggggtctc acagtaagaa agtgagctga 960
agtttcagcc cagatttaac tggattctgg gctctttatt catgttactt catgaatctg 1020
tttctcaatt gtgcagaaaa aagggggcta tttataagaa aagcaataaa caaacaagta 1080
atgatctcaa ataagtaatg caagaaatag tgagatttca aaatcagtgg cagcgatttc 1140
tcagttctgt cctaagtggc cttgctcaat cacctgctat cttttagtgg agctttgaaa 1200
ttatgtttca gacaacttcg attcagttct agaatgtttg actcagcaaa ttcacaggct 1260
catctttcta acttgatggt gaatatggaa attcagctaa atggatgtta ataaaattca 1320
aacgttttaa ggacagatgg aaatgacaga attttaaggt aaaatatatg aaggaatata 1380
agataaagga tttttctacc ttcagcaaaa acatacccac taattagtaa aattaatagg 1440
cgaaaaaaag ttgcatgctc ttatactgta atgattatca ttttaaaact ag 1492
<210> 11
<211> 2492
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 11
gtaagaacag tatgaagaaa agagatgaag cctctgtctt ttttacatgt taacagtctc 60
atattagtcc ttcagaataa ttctacaatc ctaaaataac ttagccaact tgctgaattg 120
tattacggca aggtttatat gaattcatga ctgatattta gcaaatgatt aattaatatg 180
ttaataaaat gtagccaaaa caatatctta ccttaatgcc tcaatttgta gatctcggta 240
tttgtggatc ccttcctttc tacctgtatt tgtcctaata aattgttgac ttattaattc 300
actacttcct cacagctttt ttttggcttt acaaatccac tggaaaggta tatgggtgta 360
tcactttgtg tatttcggtg tgcatgtgta gaggggacaa aaatcctctc tcaaactata 420
aatattgagt atttgtgtat tgaacatttg ctataactac taggtttctt aaataatctt 480
aatatataaa atgatataga aaaagggaaa ttatagttcg tattattcat ctaagtgaag 540
agattaaaac ccagggagta aataaattgt ctaaggacta aggttgtata ctatttaggt 600
gatagatatg gggcaaccgt atgggtttta tgattaacaa ataaacttct caccactcta 660
ccatatcaac ttttccataa aagagagcta tagtattctt tgcttaaata aatttgatta 720
gtgcatgact tcttgaaaac atataaagca aaagtcacat ttgattctat cagaaaagtg 780
agtaagccat ggcccaaaca aaagatgcat taaaatattc tggaatgatg gagctaaaag 840
taagaaaaat gactttttaa aaaagtttac tgttaggaat tgtgaaatta tgctgaattt 900
tagttgcatt ataatttttg tcagtcatac ggtctgacaa cctgtcttat ttctatttcc 960
ccatatgagg aatgctagtt aagtatggat attaactatt actacttaga tgcattgaag 1020
ttgcataata tggataatac ttcactggtt ccctgaaaat gtttagttag taataagtct 1080
cttacactat ttgttttgtc caataattta tattttctga agacttaact ctagaataca 1140
ctcatgtcaa aatgaaagaa tttcattgca aaatattgct tggtacatga cgcatacctg 1200
tatttgtttt gtgtcacaac atgaaaaatg atggtttatt agaagtttca ttgggtagga 1260
aacacatttg aatggtattt actaagatac taaaatcctt ggacttcact ctaattttag 1320
tgccatttag aactcaaggt ctcagtaaaa gtagaaataa agcctgttaa caaaacacaa 1380
actgaatatt aaaaatgtaa ctggattttc aaagaaatgt ttactggtat tacctgtaga 1440
tgtatattct ttattatgat cttttgtgta aagtctggca gacaaatgca atatctaatt 1500
gttgagtcca atatcacaag cagtacaaaa gtataaaaaa gacttggcct tttctaatgt 1560
gttaaaatac tttatgctgg taataacact aagagtaggg cactagaaat tttaagtgaa 1620
gataatgtgt tgcagttact gcactcaatg gcttactatt ataaaccaaa actgggatca 1680
ctaagctcca gtcagtcaaa atgatcaaaa ttattgaaga gaataagcaa ttctgttctt 1740
tattaggaca cagtagatac agactacaaa gtggagtgtg cttaataaga ggtagcattt 1800
gttaagtgtc aattactcta ttatcccttg gagcttctca aaataaccat ataaggtgta 1860
agatgttaaa ggttatggtt acactcagtg cacaggtaag ctaataggct gagagaagct 1920
aaattactta ctggggtctc acagtaagaa agtgagctga agtttcagcc cagatttaac 1980
tggattctgg gctctttatt catgttactt catgaatctg tttctcaatt gtgcagaaaa 2040
aagggggcta tttataagaa aagcaataaa caaacaagta atgatctcaa ataagtaatg 2100
caagaaatag tgagatttca aaatcagtgg cagcgatttc tcagttctgt cctaagtggc 2160
cttgctcaat cacctgctat cttttagtgg agctttgaaa ttatgtttca gacaacttcg 2220
attcagttct agaatgtttg actcagcaaa ttcacaggct catctttcta acttgatggt 2280
gaatatggaa attcagctaa atggatgtta ataaaattca aacgttttaa ggacagatgg 2340
aaatgacaga attttaaggt aaaatatatg aaggaatata agataaagga tttttctacc 2400
ttcagcaaaa acatacccac taattagtaa aattaatagg cgaaaaaaag ttgcatgctc 2460
ttatactgta atgattatca ttttaaaact ag 2492
<210> 12
<211> 728
<212> PRT
<213> 智人(Homo sapiens)
<400> 12
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln
20 25 30
Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Lys Lys Val
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Asn Lys Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Gln Cys
85 90 95
Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asn Cys
115 120 125
Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr Val Ser Ile Thr Lys
130 135 140
Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp Leu Gln Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Phe Thr Ser
180 185 190
Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 13
<211> 5
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 13
gatcc 5
Claims (13)
1.一种突变的肝细胞生长因子(HGF)基因的内含子4或其片段，其中，所述突变的内含子4在下述位点上包含突变：对应于SEQ ID NO：1的第3815位、第4774位和第4876位的位点；并且，所述片段包含所述突变的内含子4中对应于SEQ ID NO：1的第1至246位和第3686至4926位的核苷酸片段；
优选地，所述片段还包含，所述突变的内含子4中对应于SEQ ID NO：1的第2686位至第3685位核苷酸片段；
优选地，所述片段还包含，用于连接核苷酸片段的接头序列；优选地，所述接头序列的长度为1-5个，5-10个，10-20个，20-30个，30-40个，40-50个，50-60个，60-70个，70-80个，80-90个，90-100个，100-200个，或200-500个核苷酸；例如，所述接头序列如SEQ ID NO:13所示。
2.权利要求1的突变的内含子4或其片段，其中，所述片段包含或者由下述组成：
(1)所述突变的内含子4中对应于SEQ ID NO：1的第1至246位的第一核苷酸片段，所述突变的内含子4中对应于SEQ ID NO：1的第3686至4926位的第二核苷酸片段，以及任选地，位于所述两个核苷酸片段之间的接头序列；
(2)所述突变的内含子4中对应于SEQ ID NO：1的第1至246位的第一核苷酸片段，和所述突变的内含子4中对应于SEQ ID NO：1的第3686至4926位的第二核苷酸片段，其中，所述第一核苷酸片段的3'端直接连接至所述第二核苷酸片段的5'端；
(3)所述突变的内含子4中对应于SEQ ID NO：1的第1至246位的第一核苷酸片段，和所述突变的内含子4中对应于SEQ ID NO：1的第3686至4926位的第二核苷酸片段，其中，所述第一核苷酸片段的3'端通过接头序列连接至所述第二核苷酸片段的5'端；
(4)所述突变的内含子4中对应于SEQ ID NO：1的第1至246位的第一核苷酸片段，所述突变的内含子4中对应于SEQ ID NO：1的第2686至4926位的第二核苷酸片段，以及任选地，位于所述两个核苷酸片段之间的接头序列；
(5)所述突变的内含子4中对应于SEQ ID NO：1的第1至246位的第一核苷酸片段，和所述突变的内含子4中对应于SEQ ID NO：1的第2686至4926位的第二核苷酸片段，其中，所述第一核苷酸片段的3'端直接连接至所述第二核苷酸片段的5'端；或
(6)所述突变的内含子4中对应于SEQ ID NO：1的第1至246位的第一核苷酸片段，和所述突变的内含子4中对应于SEQ ID NO：1的第2686至4926位的第二核苷酸片段，其中，所述第一核苷酸片段的3'端通过接头序列连接至所述第二核苷酸片段的5'端。
3.权利要求1或2的突变的内含子4或其片段，其中，所述突变的内含子4包含选自下列的突变：在对应于SEQ ID NO：1的第3815位的位置上的核苷酸被突变为腺嘌呤核苷酸；在对应于SEQ ID NO：1的第4774位的位置上的核苷酸被突变为鸟嘌呤核苷酸；在对应于SEQ IDNO：1的第4876位的位置上的核苷酸被突变为鸟嘌呤核苷酸；以及，其任何组合；
优选地，所述突变的内含子4包含下述突变：在对应于SEQ ID NO：1的第3815位的位置上的核苷酸被突变为腺嘌呤核苷酸；在对应于SEQ ID NO：1的第4774位的位置上的核苷酸被突变为鸟嘌呤核苷酸；以及，在对应于SEQ ID NO：1的第4876位的位置上的核苷酸被突变为鸟嘌呤核苷酸。
4.权利要求1-3任一项的突变的内含子4或其片段，所述肝细胞生长因子为人肝细胞生长因子；
优选地，所述人肝细胞生长因子具有如SEQ ID NO：12所示的氨基酸序列；
优选地，所述人肝细胞生长因子基因具有如GenBank数据库登录号：NC_000007.14所示的核苷酸序列；
优选地，所述突变的内含子4具有如SEQ ID NO：9所示的核苷酸序列，或者，所述片段具有选自SEQ ID NO：10和SEQ ID NO：11的核苷酸序列。
5.一种编码肝细胞生长因子(HGF)的核酸分子，其包含HGF基因的外显子1-18，以及位于外显子4和5之间的根据权利要求1-4任一项所述的突变的内含子4或其片段；
优选地，所述肝细胞生长因子为人肝细胞生长因子；
优选地，所述人肝细胞生长因子具有如SEQ ID NO：12所示的氨基酸序列；
优选地，所述外显子1-18编码如SEQ ID NO：12所示的氨基酸序列；
优选地，所述人肝细胞生长因子基因具有如GenBank数据库登录号：NC_000007.14所示的核苷酸序列；
优选地，所述核酸分子具有选自SEQ ID NO：3，SEQ ID NO：4和SEQ ID NO：5的核苷酸序列。
6.一种载体，其包含根据权利要求1-4任一项所述的突变的内含子4或其片段；优选地，所述载体用于克隆所述突变的内含子4或其片段。
7.一种载体，其包含根据权利要求5所述的核酸分子；
优选地，所述载体选自质粒；噬菌粒；柯斯质粒；人工染色体，例如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1来源的人工染色体(PAC)；噬菌体如λ噬菌体或M13噬菌体；以及，病毒载体，例如逆转录酶病毒载体(例如慢病毒载体)、腺病毒载体、腺相关病毒载体、疱疹病毒载体(如单纯疱疹病毒载体)、痘病毒载体、杆状病毒载体、乳头瘤病毒载体、乳头多瘤空泡病毒载体；
优选地，所述载体用于表达(例如在受试者(例如哺乳动物，例如人)体内表达)所述HGF蛋白；
优选地，所述载体是用于基因治疗的载体，例如质粒，腺病毒载体，腺相关病毒载体，和慢病毒载体；
优选地，所述载体具有选自SEQ ID NO:6，SEQ ID NO:7或SEQ ID NO:8的核苷酸序列。
8.一种宿主细胞，其包含根据权利要求5所述的核酸分子或根据权利要求6或7所述的载体；
优选地，所述宿主细胞选自原核细胞例如大肠杆菌细胞，以及真核细胞例如酵母细胞，昆虫细胞，植物细胞和动物细胞(如哺乳动物细胞，例如小鼠细胞、人细胞等)；
优选地，所述宿主细胞是大肠杆菌细胞，例如大肠杆菌DH5α细胞；或者所述宿主细胞是293T细胞或人细胞。
9.一种表达或产生HGF蛋白的方法，所述方法包括，使用根据权利要求1-4任一项所述的突变的内含子4或其片段；
优选地，所述方法包括，使用根据权利要求5所述的核酸分子或根据权利要求7所述的载体；
优选地，所述方法包括，在允许蛋白表达的条件下，在宿主细胞中表达根据权利要求5所述的核酸分子或根据权利要求7所述的载体；以及任选地，回收宿主细胞中表达的HGF蛋白。
10.根据权利要求1-4任一项所述的突变的内含子4或其片段用于提高HGF蛋白的表达水平的用途；
例如，所述的突变的内含子4或其片段用于在体外提高HGF蛋白的表达水平；
例如，所述的突变的内含子4或其片段用于在细胞内提高HGF蛋白的表达水平；
例如，所述的突变的内含子4或其片段用于在体外、在细胞内提高HGF蛋白的表达水平；
例如，所述的突变的内含子4或其片段用于在体内提高HGF蛋白的表达水平；
例如，所述的突变的内含子4或其片段用于在患者(例如哺乳动物，例如人)体内提高HGF蛋白的表达水平。
11.根据权利要求5所述的核酸分子或根据权利要求7所述的载体用于表达或产生HGF蛋白的用途；
例如，所述的核酸分子或载体用于在体外表达或产生HGF蛋白；
例如，所述的核酸分子或载体用于在细胞内表达或产生HGF蛋白；
例如，所述的核酸分子或载体用于在体外、在细胞内表达或产生HGF蛋白；
例如，所述的核酸分子或载体用于在体内表达或产生HGF蛋白；
例如，所述的核酸分子或载体用于在患者(例如哺乳动物，例如人)体内表达或产生HGF蛋白。
12.一种药物组合物，其含有根据权利要求5所述的核酸分子或根据权利要求7所述的载体，以及任选地，药学上可接受的载体和/或赋形剂；
优选地，所述药物组合物通过注射进行施用；
优选地，所述药物组合物为注射液或冻干粉剂；
优选地，所述核酸分子或载体以治疗有效量(例如治疗缺血性疾病有效量)存在；
优选地，所述的药物组合物以单位剂量形式存在。
13.根据权利要求5所述的核酸分子或根据权利要求7所述的载体在制备药物组合物中的用途，所述药物组合物用于治疗受试者中可受益于天然HGF活性的疾病；
优选地，所述疾病选自缺血性疾病(例如冠状动脉疾病(CAD)或外周动脉疾病(PAD)，例如心肌梗死或下肢动脉缺血)，代谢综合征，糖尿病及其并发症(例如糖尿病周围神经病变)，再狭窄(例如手术后再狭窄和灌注后再狭窄)，以及神经损伤(例如神经退行性疾病(例如肌萎缩性侧索硬化(ALS)，帕金森氏病，痴呆病)，创伤性神经损伤，周围神经病变(例如糖尿病周围神经病变))；
优选地，所述受试者为哺乳动物，例如人；
优选地，所述药物组合物通过注射来进行施用；
优选地，所述药物组合物为注射液或冻干粉剂。
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| US20190111154A1 (en) * | 2017-10-18 | 2019-04-18 | Viromed Co., Ltd. | Treatment of neuropathy with dna construct expressing hgf isoforms with reduced interference from gabapentinoids |
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