CN110290814A - 用于治疗威尔逊病的基因疗法 - Google Patents
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Abstract
提供了可用于治疗威尔逊病的组合物和方案。所述组合物包含具有驱动人类ATP7B表达的甲状腺素运载蛋白增强子和启动子的重组腺相关病毒(rAAV)。
Description
以引用的方式并入以电子形式提交的材料
申请人在此将以引用的方式并入以电子形式提交的序列表材料。此文件标记为“UPN-16-7940PCT_ST25.txt”。
1.引言
本申请涉及可用于用以治疗威尔逊病的基因疗法的实施方案。
2.背景技术
本申请涉及可用于用以治疗威尔逊病的基因疗法的实施方案。威尔逊病是一种由于13号染色体上铜转运ATP酶2(ATP7B)基因的突变而导致的常染色体隐性遗传性病症铜贮存障碍。铜积累在表现为神经或精神症状的组织和通常在12至23岁之间观察到的肝病中。随着时间的推移,在没有适当治疗的情况下,高铜水平会导致危及生命的器官损害。
目前用于威尔逊病的治疗方法是每日口服螯合剂(青霉胺[Cuprimine]和***恩汀[Syprine])、锌(阻断肠上皮细胞吸收铜)和与循环中的白蛋白形成复合物的铜螯合剂四硫代钼酸盐(TM)的疗法,这需要患病个人一生服用药物。此外,这些治疗可能会引起副作用,诸如药物诱发的狼疮、肌无力、反常恶化,并且不能恢复正常的铜代谢。肝移植对威尔逊病有治疗作用,但移植受体需要保持恒定的免疫抑制方案以防止排斥。
3.发明内容
本文所述的实施方案涉及一种AAV基因疗法载体,其用于在静脉内(IV)施用所述载体后,将正常人类铜转运ATP酶2(ATP7B)递送至有需要的受试者,从而产生对威尔逊病(“WD”)的临床上有意义的长期校正,可能10年或更长时间。载体剂量旨在递送血液水平的ATP7B以将循环铜水平降低约25%或更多。在一个实施方案中,通过尿液中的铜***来评估循环铜的水平。在另一个实施方案中,评估血浆中的循环铜的水平。
在一个方面,本申请提供了复制缺陷型腺相关病毒(AAV)用于将人类铜转运ATP酶2(ATP7B)基因递送至诊断患有WD的患者(人类受试者)的肝细胞的用途。用于递送hATP7B基因(“rAAV.hATP7B”)的重组AAV载体(rAAV)应具有肝脏的趋向性(例如,携带AAV8衣壳的rAAV),并且hATP7B转基因应通过肝脏特异性表达控制元件来控制。在一个实施方案中,表达控制元件包括以下一种或多种:增强子;启动子;内含子;WPRE;以及polyA信号。这类元件在本文中进一步描述。由于hATP7B编码序列的大小,因此选择允许有效表达的控制元件是重要的。如果转基因的表达不充分,则校正缺陷所需的载体剂量将太高而不实用。因此,如本文所述,选择例如增强子、启动子和polyA是重要的。
在一个实施方案中,hATP7B编码序列示出于SEQ ID NO:1中。在一个实施方案中,ATP7B蛋白序列示出于SEQ ID NO:2中。在一个实施方案中,hATP7B的编码序列被密码子优化以在人类中表达。此类序列可以与天然hATP7B编码序列(SEQ ID NO:3)共享小于80%同一性。在一个实施方案中,hATP7B编码序列是示出于SEQ ID NO:1中的序列。
另一方面,本文提供了适用于向WD患者施用的水性悬浮液,其包含本文所述的rAAV。在一些实施方案中,悬浮液包含水性悬浮液体和约1x 1012至约lx1014个rAAV基因组拷贝(GC)/mL。在一个实施方案中,悬浮液适用于静脉内注射。在其他实施方案中,悬浮液还包含溶解在水性悬浮液体中的表面活性剂、防腐剂和/或缓冲液。
在另一个实施方案中,本文提供了一种用本文所述的rAAV治疗患有WD的患者的方法。在一个实施方案中,将约1x 1011至约3x 1013个rAAV基因组拷贝(GC)/kg患者体重以水性悬浮液递送至患者。
3.附图说明
图1是AAV8.En34.TBG-Sl.hATP7Bco.PA75载体的示意图。
图2A-2B表明在Atp7b KO小鼠中尿液和血清铜水平随时间增加。Atp7b KO小鼠中(A)尿液和(B)血清铜水平随时间变化(黑色)。杂合同窝仔(Het)用作对照(灰色)。在自然病史研究中每周收集样品,并进行电感耦合等离子体质谱法以评估铜水平。
图3A-3C表明了Atp7b KO小鼠中的尿液铜水平、血清铜水平和肝病评分。在雄性和雌性杂合(Het)和Atp7b KO小鼠(KO)中通过电感耦合等离子体质谱法评估随时间变化的(A)尿液和(B)血清铜水平。(C)在2、3、4、5、9、10和12个月大时对Atp7b KO小鼠进行尸检。收获肝脏,用H&E染色,并根据1-5评分***进行组织学评估。将数值表示为平均值±SEM。
图4表明了Atm7b KO小鼠中的Timm染色。对具有识别号1345的2个月大的Atp7b KO小鼠的肝脏中的铜进行的Timm染色的代表性结果。黑色沉积物指示铜的阳性染色。将具有识别号307的3.7个月大的野生型小鼠用作阴性对照。
图5表明Atp7b KO小鼠中肝病随时间发展。在2、3、4、5、9、10、和12个月大时对Atp7b KO小鼠进行尸检并收获肝脏以评价肝病。进行H&E、天狼星红(Sirius Red)和Timm染色,以用于肝脏病变(包括纤维化和铜积累)的组织病理学评估。*,12个月大的Atp7b KO小鼠肝脏内的再生区域。WT,来自野生型小鼠的切片作为铜积累的阴性对照,如通过Timm染色所见。
图6A-6C表明了8个月大的Atp7b KO小鼠的血清化学值。8个月大的Atp7b KO小鼠(KO)和杂合小鼠(Het)中的(A)ALT、(B)AST和(C)总胆红素水平。
图7表明了8个月大的Atp7b KO小鼠的肝病。在8个月大时对Atp7b KO和杂合(Het)小鼠进行尸检。收获肝脏,用H&E染色,并根据1-5评分***进行组织学评估。将数值表示为平均值±SEM。
图8A和8B表明了8个月大的Atp7b KO小鼠的肝纤维化和铜积累。在8个月大时对Atp7b KO(KO)和杂合(Het)小鼠进行尸检。收获肝脏,用Sirius Red和Timm染色剂进行染色,用以分别评估纤维化和铜积累。根据1-5评分***进行肝脏病变(包括(A)纤维化和(B)铜积累)的组织病理学评估。将数值表示为平均值±SEM。
图9表明了8个月大的Atp7b KO小鼠的肝铜水平。在8个月大时对Atp7b KO(KO)和杂合(Het)小鼠进行尸检。收获肝脏并通过电感耦合等离子体质谱法评估肝铜水平。将数值表示为平均值±SEM。
图10A-10C表明AAV8基因疗法可以恢复Atp7b KO小鼠的正常肝铜代谢。向雄性Atp7b KO小鼠静脉内注射1011GC/小鼠和1010GC/小鼠的AAV8.TTR.hATP7Bco,并向雌性Atp7b KO小鼠静脉内注射1011、1010和109GC/小鼠的相同载体。通过电感耦合等离子体质谱法评估(A)雄性和(B)雌性中的血清铜水平,并将其与来自年龄匹配的雄性和雌性杂合(het)和Atp7b KO小鼠的血清铜水平进行比较。在9个月大时对小鼠进行尸检并收获肝脏。(C)还通过电感耦合等离子体质谱法评估肝铜水平,并将其与年龄匹配的未注射的杂合(het)和Atp7b KO小鼠进行比较。数值表示为平均值土SEM。ns,不显著;**p<0.01,****p<0.0001。
图11表明高剂量AAV8基因疗法预防Atp7b KO小鼠中肝病的发展。向雄性Atp7b KO小鼠静脉内注射1011GC/小鼠和1010GC/小鼠的AAV8.TTR.hATP7Bco,并向雌性Atp7b KO小鼠静脉内注射1011、1010、和109GC/小鼠的相同载体。在9个月大时对小鼠进行尸检并收获肝脏以评估肝病。进行H&E、天狼星红和Timirfs染色,以用于评估肝脏(包括纤维化和铜积累)的组织病理学病变。包括来自年龄匹配的未注射的Atp7b KO小鼠的图像,以用于比较(也在图2中呈现)。WT,来自野生型(WT)小鼠的切片作为铜积累的阴性对照,如通过Timm染色所见。KO,来自两个月大的Atp7b KO小鼠的切片作为铜积累的阳性对照,如通过Timm染色所见。
图12A-12C表明了在Atp7b KO小鼠中高剂量AAV8基因疗法后预防肝病的定量。向雄性Atp7b KO小鼠静脉内注射1011GC/小鼠和1010GC/小鼠的AAV8.TTR.hATP7Bco,并向雌性Atp7b KO小鼠静脉内注射1011、1010和109GC/小鼠的相同载体。在9个月大时对小鼠进行尸检并收获肝脏用于组织学评估。(A)用H&E染色肝脏切片,并根据1-5评分***进行组织学评估。(B)用天狼星红染色肝脏切片并根据1-3评分***评估纤维化,并且(C)对肝脏切片进行Timm染色以根据1-5评分***评估铜积累。将表示为平均值±SEM的数值与年龄匹配的未注射的杂合(Het)和Atp7b KO小鼠进行比较,ns,不显著;*p<0.05,p<0.01,***p<0.001,****p<0.0001。
图13A-13C表明了AAV8基因疗法后Atp7b KO小鼠的血清化学水平。向雄性Atp7bKO小鼠静脉内注射1011GC/小鼠和1010GC/小鼠的AAV 8.TTR.h ATP 7B co,并向雌性Atp7bKO小鼠静脉内注射1011、1010和109GC/小鼠的相同载体。评估血清中的(A)ALT、(B)AST和(C)总胆红素水平。
图14表明了通过蛋白质印迹检测铜蓝蛋白。蛋白质印迹检测Atp7b KO小鼠中铜结合(Holo,下带)和非铜结合(Apo,上带)形式的铜蓝蛋白,所述Atp7b KO小鼠静脉内注射1010或1011GC/小鼠的AAV8.EnTTR.TTR.hATP7Bco.PA75。在施用后第21天收集血液样品。在中心泳道提供蛋白质标记物以用于比较。将未注射载体的Atp7b KO和杂合(het)同窝仔用作对照(1318,6个月大的het;1313,6个月大的Atp7b KO;388,Atp7b KO)。
图15A-15B表明了施用AAV8载体的雌性和雄性Atp7b KO小鼠中的血清铜水平。向Atp7b KO小鼠静脉内施用3x1012GC/kg的AAV 8载体,用于表达具有不同增强子/启动子组合的hATP7Bco(圆圈,EnTTR.TTR,AAV8.EnTTR.TTR.hATP7Bco.PA75;正方形,En34.TBG-Sl,AAV8.En34.TBG-Sl.hATP7Bco.PA75;直立三角形,En34.TTR,AAV8.En34.TTR.hATP7Bco.PA75;倒三角形,ABPS.TBG-S1,AAV8.ABPS.TBG-Sl.hATP7Bco.PA75;菱形,En34.mTTR,AAV8.En34.mTTR.hATP7Bco.PA75)。将未注射的Atp7bKO和杂合(Het)小鼠用作对照。在(A)雌性和(B)雄性Atp7b KO小鼠中通过电感耦合等离子体质谱法评估血清铜水平。将数值表示为平均值±SEM。
图16A-16C表明了施用AAV8载体的雌性和雄性Atp7b KO小鼠中的血清化学。向雌性和雄性Atp7b KO小鼠静脉内施用3x1012GC/kg的AAV8载体,用于表达具有不同增强子/启动子组合的hAT P7Bco(EnTTR.TTR,AAV8.EnTTR.TTR.hATP7Bco.PA75;En34.TBG-Sl,AAV8.En34.TBG-Sl.hATP7Bco.PA75;En34.TTR,AAV8.En34.TTR.hATP7Bco.PA75;ABPS.TBG-S1,AAV8.ABPS.TBG-Sl.hATP7Bco.PA75;En34.mTTR,AAV8.En34.mTTR.hATP7Bco.PA75)。将施用媒介物对照的Atp7b KO(PBS)小鼠用作对照。评估血清中的(A)ALT、(B)AST和(C)总胆红素水平。将数值表示为平均值±SEM。
图17表明了通过蛋白质印迹测定的肝脏ATP7Bco表达。向雌性和雄性Atp7b KO小鼠静脉内施用3x1012GC/kg的AAV8载体,以用于表达具有不同增强子/启动子组合的hATP7Bco(EnTTR TTR,AAV8.EnTTR.TTR.hATP7Bco.PA75;En34.TBG-Sl,AAV8.En34.TBG-Sl.hATP7Bco.PA75;En34.TTR,AAV8.En34.TTR.hATP7Bco.PA75;ABPS.TBG-S1,AAV8.ABPS.TBG-Sl.hATP7Bco.PA75;En34.mTTR,AAV8.En34.mTTR.hATP7Bco.PA75)并在6个月大时处死。通过带密度测定法定量检测Atp7b KO小鼠中的ATP7B的蛋白质印迹。将数值表示为平均值±SEM。
图18表明了施用AAV8载体的雌性和雄性Atp7b KO小鼠中的肝病。向雌性和雄性Atp7b KO小鼠静脉内施用3x1012GC/kg的AAV8载体,用于表达具有不同增强子/启动子组合的hATP7Bco(EnTT R.TTR,AAV8.EnTTR.TTR.hATP7Bco.PA75;En34.TBG-Sl,AAV8.En34.TBG-Sl.hATP7Bco.PA75;En34.TTR,AAV8.En34.TTR.hATP7Bco.PA75;ABPS.TBG-S1,AAV8.ABPS.TBG-Sl.hATP7Bco.PA75;En34.mTTR,AAV8.En34.mTTR.hATP7Bco.PA75)并在6个月大时处死。将施用媒介物对照的Atp7b KO(PBS)小鼠用作对照。用H&E染色肝脏切片,并根据1-5评分***进行组织学评估。将数值表示为平均值±SEM。
图19A-19B表明了施用AAV8载体的雌性和雄性Atp7b KO小鼠中的肝纤维化和铜积累。向雌性和雄性Atp7b KO小鼠静脉内施用3x1012GC/kg的AAV8载体,以用于表达具有不同增强子/启动子组合的hATP7Bco(EnTTRTTR,AAV8.EnTTR.TTR.hATP7Bco.PA75;En34.TBG-Sl,AAV8.En34.TBG-Sl.hATP7Bco.PA75;En34.TTR,AAV8.En34.TTR.hATP7Bco.PA75;ABPS.TBG-S1,AAV8.ABPS.TBG-Sl.hATP7Bco.PA75;En34.mTTR,AAV8.En34.mTTR.hATP7Bco.PA75)并在6个月大时处死。将施用媒介物对照的Atp7b KO(PBS)小鼠用作对照。(A)用天狼星红染色肝脏切片并根据1-3评分***评估纤维化,并且(B)对肝脏切片进行Timm染色,以根据1-5评分***评估铜积累。将表示为平均值±SEM的数值与年龄匹配的未注射的杂合(Het)和Atp7b KO(KO)小鼠进行比较。
图20表明了施用AAV8载体的雌性和雄性Atp7b KO小鼠中的肝铜水平。向雌性和雄性Atp7b KO小鼠静脉内施用3x1012GC/kg的AAV8载体,以用于表达具有不同增强子/启动子组合的hATP7Bco(EnTTR.TTR,AAV8.EnTTR.TTR.hATP7Bco.PA75;En34.TBG-Sl,AAV8.En34.TBG-Sl.hATP7Bco.PA75;En34.TTR,AAV8.En34.TTR.hATP7Bco.PA75;ABPS.TBG-S1,AAV8.ABPS.TBG-Sl.hATP7Bco.PA75;En34.mTTR,AAV8.En34.mTTR.hATP7Bco.PA75)并在6个月大时处死。将施用媒介物对照的Atp7b KO(PBS)小鼠用作对照。通过电感耦合等离子体质谱法评估肝铜水平,并与年龄匹配的未注射的杂合(het)和Atp7b KO(KO)小鼠进行比较。将数值表示为平均值±SEM。
图21表明了施用AAV8载体的雄性Atp7b KO小鼠中通过蛋白质印迹检测铜蓝蛋白。蛋白质印迹检测雄性Atp7b KO小鼠中铜结合(Holo,下带)和非铜结合(Apo,上带)形式的铜蓝蛋白,所述雄性Atp7b KO小鼠静脉内施用3x1012GC/kg的AAV8载体,以用于表达具有不同增强子/启动子组合的hATP7Bco(1,AAV8.EnTTR.TTR.hATP7Bco.PA75;2,AAV8.En34.TBG-Sl.hATP7Bco.PA75;3,AAV8.En34.TTR.hATP7Bco.PA75;4,AAV8.ABPS.TBG-Sl.hATP7Bco.PA75)。在施用后第21天收集血液样品。在中心泳道提供蛋白质标记物以用于比较。将未注射载体的Atp7b KO杂合(het)和野生型(WT)同窝仔用作对照(1313,6个月大的Atp7b KO;1318,6个月大的het;1345,2个月大的Atp7b KO;1945,WT)。
图22表明了施用AAV8截短的ATP7B载体的雄性Atp7b KO小鼠中的血清铜水平。向雄性Atp7b KO小鼠静脉内施用3x1012GC/kg的AAV8载体,以用于表达不同截短形式的hATP7Bco(MBDlDel,AAV8.En34.TBG-Sl.hATP7BcoMBDlDel.PA75;MBD2Del,AAV8.En34.TBG-Sl.hATP7BcoMBD2Del.PA75;MBD3Del,AAV8.En34.TBG-Sl.hATP7BcoMBD3Del.PA75;MBDl-2Del,AAV8.En34.TBG-Sl.hATP7BcoMBDl-2Del.PA75;MBDl-4Del,AAV8.En34.TBG-Sl.hATP7BcoMBDl-4Del.PA75;MBD1-5Del,AAV8.En34.TBG-Sl.hATP7BcoMBDl-5Del.PA75;TBG-MBDl-4Del,AAV8.TBG.hATP7BcoMBDl-4Del.PA75;TBG-MBDl-5Del,AAV8.TBG.hATP7BcoMBDl-5Del.PA75)。通过电感耦合等离子体质谱法评估血清铜水平,并随时间将其与杂合(Het)和Atp7b KO小鼠(KO)进行比较。将数值表示为平均值±SEM。
图23A-23C表明了施用AAV8截短的ATP7B载体的雄性Atp7bKO小鼠中的血清化学。向雄性Atp7b KO小鼠静脉内施用3x1012GC/kg的AAV8载体,以用于表达不同截短形式的hATP7Bco(MBDlDel,AAV8.En34.TBG-Sl.hATP7BcoMBDlDel.PA75;MBD2Del,AAV8.En34.TBG-Sl.hATP7BcoMBD2Del.PA75;MBD3Del,AAV8.En34.TBG-Sl.hATP7BcoMBD3Del.PA75;MBDl-2Del,AAV8.En34.TBG-Sl.hATP7BcoMBDl-2Del.PA75;MBDl-4Del,AAV8.En34.TBG-Sl.hATP7BcoMBDl-4Del.PA75;MBD1-5Del,AAV8.En34.TBG-Sl.hATP7BcoMBDl-5Del.PA75;TBG-MBDl-4Del,AAV8.TBG.hATP7BcoMBDl-4Del.PA75;TBG-MBDl-5Del,AAV8.TBG.hATP7BcoMBDl-5Del.PA75)。在6个月大时对小鼠进行尸检,并且评估血清中的(A)ALT、(B)AST和(C)总胆红素水平。将数值表示为平均值±SEM。
图24表明了施用AAV8截短的ATP7B载体的雄性Atp7b KO小鼠中通过蛋白质印迹测定的肝脏ATP7Bco表达。向雄性Atp7b KO小鼠静脉内施用3x1012GC/kg的AAV8载体,用于表达不同截短形式的hATP7Bco(MBDlDel,AAV8.En34.TBG-Sl.hATP7BcoMBDlDel.PA75;MBD2Del,AAV8.En34.TBG-Sl.hATP7BcoMBD2Del.PA75;MBD3Del,AAV8.En34.TBG-Sl.hATP7BcoMBD3Del.PA75;MBDl-2Del,AAV8.En34.TBG-Sl.hATP7BcoMBDl-2Del.PA75;MBDl-4Del,AAV8.En34.TBG-Sl.hATP7BcoMBDl-4Del.PA75;MBD1-5Del,AAV8.En34.TBG-Sl.hATP7BcoMBDl-5Del.PA75;TBG-MBDl-4Del,AAV8.TBG.hATP7BcoMBDl-4Del.PA75;TBG-MBDl-5Del,AAV8.TBG.hATP7BcoMBDl-5Del.PA75)。在6个月大时对小鼠进行尸检。通过带密度测定法定量检测Atp7b KO小鼠中的ATP7B的蛋白质印迹。将数值表示为平均值±SEM。
图25表明了施用AAV8截短的ATP7B载体的雄性Atp7b KO小鼠中的肝病。向雄性Atp7b KO小鼠静脉内施用3x1012GC/kg的AAV8载体,用于表达不同截短形式的hATP7Bco(MBDlDel,AAV8.En34.TBG-Sl.hATP7BcoMBDlDel.PA75;MBD2Del,AAV8.En34.TBG-Sl.hATP7BcoMBD2Del.PA75;MBD3Del,AAV8.En34.TBG-Sl.hATP7BcoMBD3Del.PA75;MBDl-2Del,AAV8.En34.TBG-Sl.hATP7BcoMBDl-2Del.PA75;MBDl-4Del,AAV8.En34.TBG-Sl.hATP7BcoMBDl-4Del.PA75;MBD1-5Del,AAV8.En34.TBG-Sl.hATP7BcoMBDl-5Del.PA75;TBG-MBDl-4Del,AAV8.TBG.hATP7BcoMBDl-5Del.PA75)。在6个月大时对小鼠进行尸检。将施用媒介物对照的Atp7b KO(PBS)小鼠用作对照。用H&E染色肝脏切片,并根据1-5评分***进行组织学评估。将数值表示为平均值±SEM。
图26A-26B表明了施用AAV8截短的ATP7B载体的雄性Atp7bKO小鼠中的肝纤维化和铜积累。向雄性Atp7b KO小鼠静脉内施用3x1012GC/kg的AAV8载体,以用于表达不同截短形式的hATP7Bco(MBDlDel,AAV8.En34.TBG-Sl.hATP7BcoMBDlDel.PA75;MBD2Del,AAV8.En34.TBG-Sl.hATP7BcoMBD2Del.PA75;MBD3Del,AAV8.En34.TBG-Sl.hATP7BcoMBD3Del.PA75;MBDl-2Del,AAV8.En34.TBG-Sl.hATP7BcoMBDl-2Del.PA75;MBDl-4Del,AAV8.En34.TBG-Sl.hATP7BcoMBDl-4Del.PA75;MBD1-5Del,AAV8.En34.TBG-Sl.hATP7BcoMBDl-5Del.PA75;TBG-MBDl-4Del,AAV8.TBG.hATP7BcoMBDl-4DeLPA75;TBG-MBDl-5Del,AAV8.TBG.hATP7BcoMBDl-5Del.PA75)。在6个月大时对小鼠进行尸检。将施用媒介物对照的Atp7b KO(PBS)小鼠用作对照。(A)用天狼星红染色肝脏切片并根据1-3评分***评估纤维化,并且(B)对肝脏切片进行Timm染色,以根据1-5评分***评估铜积累。将表示为平均值±SEM的数值与年龄匹配的未注射的杂合(Het)和Atp7b KO(KO)小鼠进行比较。
图27表明了施用AAV8截短的ATP7B载体的雄性Atp7b KO小鼠中的肝铜水平。向雄性Atp7b KO小鼠静脉内施用3x1012GC/kg的AAV8载体,以用于表达不同截短形式的hATP7Bco(MBDlDel,AAV8.En34.TBG-Sl.hATP7BcoMBDlDel.PA75;MBD2Del,AAV8.En34.TBG-Sl.hATP7BcoMBD2Del.PA75;MBD3Del,AAV8.En34.TBG-Sl.hATP7BcoMBD3Del.PA75;MBDl-2Del,AAV8.En34.TBG-Sl.hATP7BcoMBDl-2Del.PA75;MBDl-4Del,AAV8.En34.TBG-Sl.hATP7BcoMBDl-4Del.PA75;MBD1-5Del,AAV8.En34.TBG-Sl.hATP7BcoMBDl-5Del.PA75;TBG-MBDl-4Del,AAV8.TBG.hATP7BcoMBDl-4Del.PA75;TBG-MBDl-5Del,AAY8.TBG.hATP7BcoMBDl-5Del.PA75)。在6个月大时对小鼠进行尸检。
将施用媒介物对照的Atp7b KO(PBS)小鼠用作对照。通过电感耦合等离子体质谱法评估肝铜水平,并将其与年龄匹配的未注射的杂合(het)和Atp7b KO(KO)小鼠进行比较。将表示为平均值±SEM的数值与年龄匹配的未注射的杂合(Het)和Atp7b KO(KO)小鼠进行比较。
4.具体实施方式
本申请中描述的实施方案涉及复制缺陷型腺相关病毒(AAV)用于将人类铜转运ATP酶2(ATP7B)基因递送至诊断患有威尔逊病(WD)的患者(人类受试者)的肝细胞的用途。用于递送hATP7B基因(“rAAV.hATP7B”)的重组AAV载体(rAAV)应具有肝脏的趋向性(例如,携带AAV8衣壳的rAAV),并且hATP7B转基因应通过肝脏特异性表达控制元件来控制。在一个实施方案中,表达控制元件包括以下一种或多种:增强子;启动子;内含子;WPRE;以及polyA信号。这类元件在本文中进一步描述。
如本文所用,“AAV8衣壳”是指具有以下GenBank登录号的氨基酸序列的AAV8衣壳:YP_077180.1,SEQ ID NO:16,其以引用的方式并入本文。允许与此编码序列的一些变异,所述变异可以包括与YP_077180.1和WO 2003/052051(其以引用的方式并入本文中)中的参考氨基酸序列具有约99%同一性的序列(即,与所述参考序列的变异小于约1%)。已经描述了由其产生衣壳、编码序列的方法,以及产生rAAV病毒载体的方法。参见,例如,Gao等人,Proc.Natl.Acad.Sci.U.S.A.100(10),6081-6086(2003)和US 2015/0315612。
如本文所用,术语“NAb滴度”是产生多少中和抗体(例如,抗AAV Nab)的量度,所述中和抗体中和其靶向表位(例如,AAV)的生理效应。可如以下所述测量抗-AAV NAb滴度:例如Calcedo,R.等人,Worldwide Epidemiology of Neutralizing Antibodies to Adeno-Associated Viruses.Journal of Infectious Diseases,2009.199(3):第381-390页,其以引用的方式并入本文。
在氨基酸序列背景下,术语“百分比(%)同一性”、“序列同一性”、“百分比序列同一性”或“百分比相同”是指两个序列中的残基在对应地比对时相同。可以在蛋白质、多肽、约32个氨基酸、约330个氨基酸或其肽片段的全长或对应核酸序列编码测序仪上容易地确定氨基酸序列的百分比同一性。合适的氨基酸片段长度可以是至少约8个氨基酸,并且可以是至多约700个氨基酸。通常,当提及两个不同序列之间的“同一性”、“同源性”或“相似性”时,参考“比对”序列确定“同一性”、“同源性”或“相似性”。“比对”序列或“比对”是指多个核酸序列或蛋白质(氨基酸)序列,与参考序列相比,其通常含有缺失或额外的碱基或氨基酸的校正。使用多种公开或可商购获得的多序列比对程序中的任一种进行比对。对于氨基酸序列,可利用序列比对程序,例如“Clustal Omega”、“Clustal X”、“MAP”、“PIMA”、“MSA”、“BLOCKMAKER”、“MEME”和“Match-Box”程序。通常,这些程序中的任何程序都在默认设置下使用,但是本领域技术人员可以根据需要改变这些设置。或者,本领域的技术人员可以利用另一种算法或计算机程序,所述另一种算法或计算机程序至少提供由参考算法和程序提供的同一性或比对水平。参见,例如,J.D.Thomson等,Nucl.Acids.Res.,“A comprehensivecomparison of multiple sequence alignments”,27(13):2682-2690(1999)。
如本文所用,术语“可操作地连接”是指与目标基因邻接的表达控制序列和反式或远距离起作用以控制目标基因的表达控制序列。
“复制缺陷型病毒”或“病毒载体”是指合成或人工病毒粒子,其中含有目标基因的表达盒包装在病毒衣壳或包膜中,其中同样包装在病毒衣壳或包膜内的任何病毒基因组序列是复制缺陷的;即,它们不能产生子代病毒体,但保留感染靶细胞的能力。在一个实施方案中,病毒载体的基因组不包括编码复制所需酶的基因(基因组可以被工程化成“无肠的”-仅含有目标转基因,其侧接扩增和包装人工基因组所需的信号),但这些基因可以在生产期间供应。因此,认为用于基因疗法是安全的,因为除了存在复制所需的病毒酶之外,不会发生由子代病毒体引起的复制和感染。
应注意,术语“一个/种(a/an)”是指一个/种或多个/种。因此,术语“一个/种(a/an)”、“一个/种或多个/种”和“至少一个/种”在本文中可互换使用。
词语“包含(comprise/comprises/comprising)”应是包含在内而不是排他性地解释。单词“由...组成(consist/consisting)”及其变体应排他性地解释,而不是包含在内。虽然说明书中的各种实施方案是使用“包含”语言呈现的,但在其他情况下,相关实施方案也旨在使用“由...组成”或“基本上由......组成”语言来解释和描述。
除非另有说明,否则本文所用的术语“约”是指与给定参考值相差10%。
除非在本说明书中另有定义,否则本文使用的技术和科学术语具有与本领域普通技术人员并且参考公开的文本通常理解的含义相同的含义,其为本领域技术人员提供了对本申请中使用的许多术语的一般指导。
5.1基因疗法载体
一方面,提供携带人类ATP7B基因的重组腺相关病毒(rAAV)载体以用于基因疗法。rAAV.hATP7B载体应具有肝脏的趋向性(例如,携带AAV8衣壳的rAAV),并且hATP7B转基因应通过肝脏特异性表达控制元件来控制。将载体在适用于在人类受试者中输注的缓冲液/载剂中配制。缓冲液/载剂应包含防止rAAV粘附到输注管但不干扰体内rAAV结合活性的组分。
5.1.1.rAAV.hATP7B载体
5.1.1.1.hATP7B序列
威尔逊病是一种主要由编码铜转运P型ATP酶的ATP7B基因的突变引起的遗传性代谢障碍。ATP7B负责将铜从细胞内伴侣蛋白转运到分泌途径,既可以***到胆汁中,也可以掺入到载脂蛋白-铜蓝蛋白中,以用于合成功能性铜蓝蛋白。威尔逊病的发展是由于患病组织中铜的积累。参见EASL Clinical Practice Guidelines:Wilson’s disease,EASLJournal of Hepatology,2012,56(671-85),其以引用的方式并入本文。
威尔逊病的临床标志是凯塞-弗莱谢尔环(Kayser-Fleischer ring),其存在于95%具有神经症状的患者以及一半以上不具有神经症状的患者中。神经症状是可变的,最常见的是震颤、共济失调和肌张力障碍。患有威尔逊病的患者可能会遇到任何类型的肝病。临床上明显的肝病可能先于神经表现多达10年,并且大多数患有神经症状的患者在出现时会患有一定程度的肝病。出现肝病的症状可以是高度可变的,从仅有生化异常的无症状到具有其所有并发症的明显肝硬化。威尔逊病也可能表现为急性肝功能衰竭,有时与Coombs阴性溶血性贫血和急性肾功能衰竭有关。下表1提供了WD中的预后指数。(参见EASLClinical Practice Guidelines:Wilson’s disease,EASL Journal of Hepatology,2012,56(671-85),其以引用的方式并入本文。)
ATP7B具有形成穿过细胞膜用以铜易位的途径的八个跨膜结构域;和一个具有六个金属结合的大N端
*=得分点,AST的正常上限=20lU/ml(剑桥大学国王学院(King's College))。得分≥11与没有肝移植的高死亡概率相关。
ATP7B具有形成穿过细胞膜用以铜易位的途径的八个跨膜结构域;和具有六个金属结合结构域(MBD)的大N端,每个结合结构域包含约70个氨基酸和高度保守的金属结合基序GMxCxxC(其中x是任何氨基酸)。其他结构域包括铜穿过膜易位所需的膜内CPC基序、含有ATP结合位点的N-结构域、含有保守性天冬氨酸残基的P-结构域和包含磷酸酶结构域的A-结构域。存在于患有威尔逊病的一些或所有患者中的hATP7B基因和/或所得蛋白质中的各种突变是已知的。导致WB的已知突变的完整列表可以在http://www.uniprot.org/ uniprot/P35670中找到,其以引用的方式并入本文。此外,除了规范序列(也称为同种型a,其为最长同种型;NCBI参考序列:NP_000044.2)之外,四种其他同种型也是已知的:NCBI参考序列NP_001005918.1、NP_001230111.1、NP_001317507.1、NP_001317508.1,其各自以引用的方式并入本文。本文所述的组合物和方法可用于治疗具有引起疾病的任何ATP7B变体蛋白的受试者。
在一个实施方案中,hATP7B基因编码SEQ ID NO:2中所示的hATP7B蛋白。因此,在一个实施方案中,hATP7B转基因可包括但不限于在所附序列表中提供的SEQ ID NO:1或SEQID NO:3提供的序列,所述序列表以引用的方式并入本文。SEQ ID NO:3提供了天然人类ATP7B的cDNA。SEQ ID NO:1提供了人类ATP7B的工程化cDNA,其已被密码子优化以在人类中表达(本文有时称为hATP 7Bco)。应理解,在一些实施方案中,本文对hATP7B的提及是指hATP7B天然或密码子优化的序列或本文所述变体中的任一种。替代地或另外地,基于网络或可商购获得的计算机程序以及基于服务的公司可以用于将氨基酸序列反向翻译成核酸编码序列,包括RNA和/或cDNA。参见,例如,EMBOSS的backtranseq(www.ebi.ac.uk/Tool s/st/);Gene Infinity(www.geneinfmity.org/sms-/sms_backtranslation.html);ExPasy(www.expasy.org/tools/)。旨在涵盖编码所述hATP7B多肽序列的所有核酸,包括已被优化用于在所需目标受试者中表达(例如,通过密码子优化)的核酸序列。
ATP7B的天然编码序列超过4.3kb(SEQ ID NO:3;Genbank登录号XM_005266430),产生1465个氨基酸的蛋白质(SEQ ID NO:2)。在一些实施方案中,由于ATP7B的大小较大和病毒载体(包括AAV载体)的包装能力,因此期望缩短ATP7B编码序列。已经显示,前5个MBD的缺失显示所得蛋白质的催化磷酸化水平与野生型一致。参见Huster和Lutsenko,J.Biological Chem,2003年6月,其以引用的方式并入本文。因此,在一个实施方案中,通过缺失一个或多个MDB来缩短ATP7B编码序列。在一个实施方案中,ATP7B编码序列缺失MBD 1-2(例如,如SEQ ID NO:17以及SEQ ID NO:35的nt 403至nt4368所示)。在另一个实施方案中,ATP7B编码序列缺失MBD1-3。在另一个实施方案中,ATP7B编码序列缺失MBD1-4(例如,如SEQ ID NO:18、以及SEQ ID NO:34的nt 403至nt 3762和SEQ ID NO:29的nt 1059至nt4418所示)。在另一个实施方案中,ATP7B编码序列缺失MBD1-5(例如,如SEQ ID NO:19、SEQID NO:33的nt 403至nt3369和SEQ ID NO:28的nt 1059至nt 4025所示)。在另一个实施方案中,ATP7B编码序列缺失MBD1(例如,如SEQ ID NO:20以及SEQ ID NO:32的nt 403至nt4686所示)。在另一个实施方案中,ATP7B编码序列缺失MBD2(例如,如SEQ ID NO:21以及SEQID NO:31的nt 403至nt 4617所示)。在另一个实施方案中,ATP7B编码序列缺失MBD3(例如,如SEQ ID NO:22以及SEQ ID NO:30的nt 403至nt 4719所示)。在另一个实施方案中,ATP7B编码序列缺失MBD1-4和6(例如,如Cater等人,Biochem J.2004年6月15日;380(Pt 3);805-813所述,其以引用的方式并入本文)。还参见Gourdon等人,Biol Chem.2012年4月;393(4):205-16;Lutsenko,S.等人(2007)。"Function and regulation of human copper-transporting ATPases."Physiological reviews 87(3):1011-1046;Safaei,R.等人(2013)。"The role of metal binding and phosphorylation domains in theregulation of cisplatin-induced trafficking of ATP7B."Metallomics 5(8):964-972;以及美国专利公开号2015/0045284,所述文献各自以引用的方式并入文中。
在一个实施方案中,编码hATP7B的核酸序列与SEQ ID NO:3或SEQ ID NO:1的天然hATP7B编码序列或SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ IDNO:21、或SEQ ID NO:22中所示的任何变体共享至少95%同一性。在另一个实施方案中,编码hATP7B的核酸序列与SEQ ID NO:3或SEQ ID NO:1的天然hATP7B编码序列或SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、或SEQ ID NO:22中所示的任何变体共享至少90%、85%、80%、75%、70%或65%同一性。在一个实施方案中,编码hATP7B的核酸序列与SEQ ID NO:3或SEQ ID NO:1的天然hATP7B编码序列或SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21、或SEQ ID NO:22中所示的任何变体共享至少79%同一性。在一个实施方案中,编码hATP7B的核酸序列是SEQ ID NO:1。在另一个实施方案中,编码hATP7B的核酸序列是SEQ ID NO:17。在另一个实施方案中,编码hATP7B的核酸序列是SEQ ID NO:18。在另一个实施方案中,编码hATP7B的核酸序列是SEQID NO:19。在另一个实施方案中,编码hATP7B的核酸序列是SEQ ID NO:20。在另一个实施方案中,编码hATP7B的核酸序列是SEQ ID NO:21。在另一个实施方案中,编码hATP7B的核酸序列是SEQ ID NO:22。
密码子优化的编码区可以通过各种不同的方法设计。此优化可以使用可在线获得的方法(例如,GeneArt)、公开的方法或提供密码子优化服务的公司例如作为DNA2.0(MenloPark,CA)进行。密码子优化方法描述于例如国际专利公开号WO 2015/012924中,其以引用的方式并入本文,还参见例如美国专利公开号2014/0032186和美国专利公开号2006/0136184。适当地,改进产品的开放阅读框(ORF)的整个长度。然而,在一些实施方案中,可以仅改变ORF的片段。通过使用这些方法中的一种,可以将频率应用于任何给定的多肽序列,并产生编码多肽的密码子优化的编码区的核酸片段。
许多选项可用于对密码子进行实际改变或用于合成如本文所述设计的密码子优化的编码区。可以使用本领域普通技术人员熟知的标准和常规分子生物学操作进行这类修饰或合成。在一种方法中,通过标准方法合成一系列长度各自为80至90个核苷酸且跨越期望序列的长度的互补寡核苷酸对。合成这些寡核苷酸对,使得它们在退火时形成80至90个碱基对的含有粘性末端的双链片段,例如合成所述对中的每个寡核苷酸以延伸超出与所述对中的其他核苷酸互补的区域3、4、5、6、7、8、9、10或更多个碱基。设计每对寡核苷酸的单链末端以与另一对寡核苷酸的单链末端一起退火。使寡核苷酸对退火,然后使这些双链片段中的约5至6个通过粘性单链末端一起退火,然后将它们接合在一起并克隆到标准细菌克隆载体中,例如可从Thermo Fisher Scientific Inc.购得的载体。然后通过标准方法对构建体进行测序。制备这些构建体中的若干种,其由接合在一起的80至90个碱基对片段的5至6个片段(即约500个碱基对的片段)组成,使得整个所需序列在一系列质粒构建体中表示。然后用适当的限制酶切割这些质粒的***物并将其接合在一起以形成最终的构建体。然后将最终构建体克隆到标准细菌克隆载体中,并测序。其他方法对于技术人员来说是显而易见的。此外,基因合成在商业上很容易获得。
本文所述疗法的目标是提供功能性ATP7B酶,从而使得血清铜水平降低25%或更多。在一个实施方案中,期望每24小时***3-8μmol或更少的尿铜。
本文所述疗法的主要/次要目标包括但不限于:
·将血清非铜蓝蛋白结合铜(NCC)标准化(<150μg/L)
·将血清转氨酶标准化(肝脏生物化学,ALT/AST)
·将尿铜标准化(<40μg/24小时(0.6μmol/24小时)ULN)
·将血清铜蓝蛋白标准化(>200mg/L)[可能不一致]
·改善临床医生整体印象(CGI)量表[1:严重和2:整体改善]
·AE的发生率
探索:
·65Cu,可通过质谱检测的非放射性铜同位素
·IQ、神经认知和精神功能的改善(统一威尔逊病评定量表(Unified Wilson'sDisease Rating Scale,UWDRS)和简明国际神经精神访谈(Mini InternationalNeuropsychiatric Interview,MINI));以及
·PRO(EQ5D、MMAS-8、TSQM)
在一个实施方案中,“受试者”或“患者”是患有如上所述的WD的哺乳动物受试者。期望患有任何严重程度的WD的患者是预期受试者。
5.1.1.2.rAAV载体
因为ATP7B在肝脏中天然表达,所以期望使用显示肝脏趋向性的AAV。在一个实施方案中,供应衣壳的AAV是AAV8。在另一个实施方案中,供应衣壳的AAV是AAVrh.10。在又一个实施方案中,供应衣壳的AAV是分化体E AAV。这种AAV包括rh.2;rh.10;rh.25;bb.l、bb.2、pi.1、pi.2、pi.3、rh.38、rh.40、rh.43、rh.49、rh.50、rh.51、rh.52、rh.53、rh.57、rh.58、rh.61、rh.64、hu.6、hu.17、hu.37、hu.39、hu.40、hu.41、hu.42、hu.66和hu.67。此分化体还包括修饰的rh.2;修饰的rh.58;以及修饰的rh.64。参见WO 2005/033321,其以引用的方式并入本文。然而,可以使用许多具有肝脏趋向性的rAAV载体中的任一种。
在下文实施例中描述的具体实施方案中,基因疗法载体是在称为AAV8.En34.TBG-Sl.hATP7Bco.PA75的甲状腺素结合球蛋白(TBG-S1)启动子控制下表达hATP7B转基因的AAV8载体。外部AAV载体组分是血清型8。T=1二十面体衣壳,由3种1:1:10比率的AAV病毒蛋白VP1、VP2和VP3的60个拷贝组成。衣壳含有单链DNA rAAV载体基因组。
在一个实施方案中,rAAV.hATP7B基因组含有侧接两个AAV反向末端重复序列(ITR)的hATP7B转基因。在一个实施方案中,hATP7B转基因包含增强子、启动子、hATP7B编码序列和多腺苷酸化(polyA)信号中的一种或多种。这些控制序列与hATP7B基因序列“可操作地连接”。可以将包含这些序列的表达盒工程化到用于产生病毒载体的质粒上。
ITR是在载体生产期间负责基因组复制和包装的遗传元件,并且是产生rAAV所需的唯一病毒顺式元件。将表达盒包装到AAV病毒粒子中所需的最小序列是AAV 5'和3'ITR,其可以与衣壳具有相同的AAV来源,或者不同的AAV来源(以产生AAV假型)。在一个实施方案中,使用来自AAV2的ITR序列或其缺失版本(ΔITR)。然而,可以选择来自其他AAV源的ITR。当ITR的来源来自AAV2并且AAV衣壳来自另一个AAV来源时,所得载体可以称为假型。通常,AAV载体的表达盒包含AAV 5'ITR、hATP7B编码序列和任何调节序列以及AAV 3'ITR。然而,这些元件的其他构造可能是合适的。已经描述了缩短版本的5'ITR,称为ΔITR,其中缺失D-序列和终端分解位点(trs)。在其他实施方案中,使用全长AAV 5'和3'ITR。在一个实施方案中,5'ITR是示出于SEQ ID NO:14中的ITR。在一个实施方案中,3'ITR是示出于SEQ ID NO:15中的ITR。
在一个实施方案中,表达控制序列包括一种或多种增强子。在一个实施方案中,包括示出于SEQ ID NO:4中的En34增强子(来自人类载脂蛋白肝脏控制区的34bp核心增强子)。在另一个实施方案中,包括EnTTR(来自甲状腺素运载蛋白的100bp增强子序列)。此类序列示出于SEQ ID NO:5中。参见,Wu等人,Molecular Therapy,16(2):280-289,2008年2月,其以引用的方式并入本文。在又一实施方案中,包括α1-微球蛋白/尿抑胰酶素(bikunin)前体增强子。在又一个实施方案中,包括ABPS(来自α1-微球蛋白/尿抑胰酶素前体[ABP]的100bp远端增强子缩短成42bp的版本)增强子。此类序列示出于SEQ ID NO:6中。在又一个实施方案中,包括ApoE增强子。此类序列示出于SEQ ID NO:7中。在另一个实施方案中,存在多于一种的增强子。此类组合可以包括本文所述的任何增强子的多于一个拷贝和/或多于一种类型的增强子。
hATP7B编码序列的表达由肝特异性启动子驱动。由于ATP7B转基因的大小,因此期望使用大小相对小的启动子。本文描述的示例性质粒和载体使用修饰的甲状腺素结合球蛋白(TBG-S1)启动子(SEQ ID NO:8)。在另一个实施方案中,使用TBG启动子。TBG启动子序列示出于SEQ ID NO:9中。或者,可以使用其他肝特异性启动子,例如如SEQ ID NO:11中所示的甲状腺素运载蛋白启动子(TTR启动子)或如SEQ ID NO:11的nt 21至nt 190中所示的修饰的甲状腺素运载蛋白启动子(mTTR启动子)。另一种合适的启动子是α1抗胰蛋白酶(A1AT)或其修饰版本(其序列示出在SEQ ID NO:10中。在以下实施例中讨论了各种启动子和增强子组合。
其他合适的启动子包括人类白蛋白(Miyatake等人,J.Virol.,71:5124 32(1997))、humAlb;肝脏特异性启动子(LSP)和乙型肝炎病毒核心启动子(Sandig等人,GeneTher.,3:1002-9(1996)。参见,例如,The Liver Specific Gene Promoter Database,ColdSpring Harbor,http://rulai.schl.edu/LSPDrulai.schl.edu/LSPD,其以引用的方式并入。尽管不太理想,但可以使用的其他启动子,诸如病毒启动子、组成型启动子、可调节启动子【参见例如WO 2011/126808和WO 2013/04943】或可响应于生理信号的启动子,可以用于本文所述的载体中。
除启动子外,表达盒和/或载体还可以含有其他适当的转录起始、终止、增强子序列和高效的RNA加工信号。这类序列包括剪接和多腺苷酸化(polyA)信号;增强表达的调节元件(例如,WPRE);稳定细胞质mRNA的序列;增强翻译效率的序列(即,Kozak共有序列);增强蛋白质稳定性的序列;以及在期望时增强编码产物分泌的序列。在一个实施方案中,包括KOZAK序列。在一个实施方案中,包括介导hATP7B mRNA转录物终止的多腺苷酸化(polyA)信号。可用于本文的polyA信号是人工polyA,其大小为约75bp(PA75),如SEQ ID NO:13所示。其他合适的polyA序列的实例包括例如牛生长激素(SEQ ID NO:12)、SV40、兔β球蛋白和TKpolyA等。
在一个实施方案中,选择调节序列,使得总rAAV载体基因组的大小为约3.0千碱基至约5.5千碱基。在一个实施方案中,期望rAAV载体基因组接近天然AAV基因组的大小。因此,在一个实施方案中,选择调节序列使得总rAAV载体基因组的大小为约4.7kb。在另一个实施方案中,总rAAV载体基因组的大小小于5.2kb。在另一个实施方案中,总rAAV载体基因组的大小为约5.1kb或约5.0kb。可以基于调节序列的大小来操纵载体基因组的大小,所述调节序列包括启动子、增强子、内含子、poly A等。参见Wu等人,Mol Ther,Jan 2010 18(l):80-6,其以引用的方式并入本文。
在一个实施方案中,rAAV载体基因组包含SEQ ID NO:23的nt 1至nt 5134、SEQ IDNO:24的nt 1至nt 5056、SEQ ID NO:25的nt 1至nt 5064、SEQ ID NO:26的nt 1至nt 5068、SEQ ID NO:27的nt 1至nt 5048、SEQ ID NO:28的nt 1至nt 4284、SEQ ID NO:29的nt 1至nt 4677、SEQ ID NO:30的nt 1至nt 4978、SEQ ID NO:31的nt 1至nt 4876、SEQ ID NO:32的nt 1至nt 4945、SEQ ID NO:33的nt 1至nt 3628、SEQ ID NO:34的nt 1至nt 4021、或SEQID NO:35的nt 1至nt 4627。
用于产生rAAV的示例性生产质粒示出于SEQ ID NO:23、SEQ ID NO:24、SEQ IDNO:25、SEQ ID NO:26、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、SEQ ID NO:30、SEQ IDNO:31、SEQ ID NO:32、SEQ ID NO:33、SEQ ID NO:34和SEQ ID NO:35中。
5.1.2.组合物
在一个实施方案中,rAAV.hATP7B病毒以药物组合物形式提供,所述药物组合物包含水性载剂、赋形剂、稀释剂或缓冲剂。在一个实施方案中,所述缓冲剂为PBS。在一个具体实施方案中,rAAV.hATP7B制剂是含有有效量的rAAV.hATP7B载体的悬浮液,所述载体悬浮于含有TMN200(200mM氯化钠、1mM氯化镁、20mM Tris,pH 8.0)中的0.001%Pluronic F-68的水溶液中。然而,已知各种合适的溶液,包括包含以下一种或多种的溶液:缓冲盐水、表面活性剂和调节至等效于约100mM氯化钠(NaCl)至约250mM氯化钠的离子强度的生理学相容性盐或盐的混合物或调节至等效离子浓度的生理学相容盐。
例如,本文提供的悬浮液可以含有NaCl和KCl。pH可以在6.5至8.5、或7至8.5、或7.5至8的范围内。合适的表面活性剂或表面活性剂的组合可以选自泊洛沙姆(即由侧接两个聚氧乙烯(聚(环氧乙烷))亲水链的聚氧丙烯(聚(环氧丙烷))的中心疏水链组成的非离子三嵌段共聚物)、SOLUTOL HS 15(聚乙二醇-15羟基硬脂酸)、LABRASOL(聚氧辛酸甘油酯)、聚氧10油烯基醚、TWEEN(聚氧乙烯脱水山梨糖醇脂肪酸酯)、乙醇和聚乙二醇。在一个实施方案中,制剂含有泊洛沙姆。这些共聚物通常用字母“P”(对于泊洛沙姆)命名,后面跟三个数字:前两个数字x 100给出聚氧丙烯芯的近似分子量,最后一个数字x10给出聚氧乙烯含量百分比。在一个实施方案中,选择泊洛沙姆188。表面活性剂可以存在的量高达悬浮液的约0.0005%至约0.001%。在另一个实施方案中,将载体悬浮在pH 7.3的含有180mM氯化钠、10mM磷酸钠、0.001%泊洛沙姆188的水溶液中。
在一个实施方案中,所述制剂适用于在人类受试者中使用并且静脉内施用。在一个实施方案中,制剂通过推注注射经外周静脉递送。在一个实施方案中,制剂通过输注在约10分钟(±5分钟)内经外周静脉递送。在一个实施方案中,制剂通过输注在约20分钟(±5分钟)内经外周静脉递送。在一个实施方案中,制剂通过输注在约30分钟(±5分钟)内经外周静脉递送。在一个实施方案中,制剂通过输注在约60分钟(±5分钟)内经外周静脉递送。在一个实施方案中,制剂通过输注在约90分钟(±10分钟)内经外周静脉递送。然而,可以根据需要或期望调节此时间。可以使用任何合适的方法或途径来施用如本文所述的含有AAV的组合物,并且任选地与本文所述的hATP7B的AAV介导的递送结合来共同施用其他活性药物或疗法。施用途径包括例如全身、口服、吸入、鼻内、气管内、动脉内、眼内、静脉内、肌肉内、皮下、皮内和其他肠胃外施用途径。
在一个实施方案中,制剂可以含有例如约1.0x 1011个基因组拷贝/千克患者体重(GC/kg)至约1x 1014GC/kg、约5x 1011个基因组拷贝/千克患者体重(GC/kg)至约3x 1013GC/kg、或约1x 1012至约1x1014GC/kg,如通过oqPCR或数字液滴PCR(ddPCR)测量的,如例如M.Lock等人,Hum Gene Ther Methods.2014年4月;25(2):115-25.doi:10.1089/hgtb.2013.131.增刊2014年2月14日中所述的,所述文献以引用的方式并入本文。在一个实施方案中,rAAV.hATP7B制剂是含有至少lx1013个基因组拷贝(GC)/mL或更高的悬浮液,如通过oqPCR或数字液滴PCR(ddPCR)所测量,如例如M.Lock等人,同上所述的。
为了确保从向患者施用的AAV hATP7B剂量中除去空衣壳,在载体纯化过程期间,例如使用本文所讨论的方法,将空衣壳与载体粒子分离。在一个实施方案中,使用WO 2017/100676所述且题为“Scalable Purification Method for AAV8”的方法,从空衣壳中纯化含有包装基因组的载体粒子,所述专利以引用的方式并入本文中。简言之,描述了两步纯化方案,其从rAAV生产细胞培养物的澄清的浓缩上清液中选择性地捕获并分离含有基因组的rAAV载体粒子。所述方法利用在高盐浓度下进行的亲和捕获方法,然后在高pH下进行阴离子交换树脂方法,以提供基本上不含rAAV中间体的rAAV载体粒子。类似的纯化方法可用于具有其他衣壳的载体。
虽然可以使用任何常规的制造方法,但本文(以及WO 2017/100676)所述的方法产生载体制剂,其中50%至70%的粒子具有载体基因组,即50%至70%的全粒子。因此,对于1.6x1012GC/kg的示例性剂量,总粒子剂量将为2.3x1012至3x1012个粒子。在另一个实施方案中,所提出的剂量高出半对数,或为5x1012GC/kg,并且总粒子剂量将为7.6x1012个至l.lx1013个粒子。在一个实施方案中,制剂的特征在于rAAV原液的“空”与“全”的比率为1或更小,优选小于0.75,更优选0.5,优选小于0.3。
当原液中的rAAV8粒子是原液中的rAAV8的至少约75%至约100%、至少约80%、至少约85%、至少约90%、至少约95%、或至少99%,并且“空衣壳”是原液或制剂中的rAAV8的小于约1%、小于约5%、小于约10%、小于约15%时,rAAV8粒子(包装的基因组)的原液或制剂“基本上不含”AAV空衣壳(和其他中间体)。
通常,用于测定空衣壳和具有包装的基因组的AAV载体粒子的方法是本领域已知的。参见例如Grimm等人,Gene Therapy(1999)6:1322-1330;Sommer等人,Molec.Ther.(2003)7:122-128。为了测试变性衣壳,所述方法包括使处理的AAV原液经历SDS-聚丙烯酰胺凝胶电泳,所述电泳由能够分离三种衣壳蛋白的任何凝胶,例如在缓冲液中含有3-8%Tris-乙酸盐的梯度凝胶组成,然后运行凝胶直至样品材料分离,并将凝胶印迹到尼龙或硝酸纤维素膜(优选地尼龙)上。然后将抗AAV衣壳抗体用作结合变性衣壳蛋白的第一抗体,优选地抗AAV衣壳单克隆抗体,最优选地B1抗AAV-2单克隆抗体(Wobus等人,J.Virol.(2000)74:9281-9293)。然后使用第二抗体,其结合第一抗体并含有用于检测与第一抗体的结合的手段,更优选地含有与其共价键合的检测分子的抗IgG抗体,最优选地与辣根过氧化物酶共价连接的绵羊抗小鼠IgG抗体。用于检测结合的方法用于半定量测定第一抗体与第二抗体之间的结合,优选地能够检测放射性同位素发射、电磁辐射或比色变化的检测方法,最优选地化学发光检测试剂盒。例如,对于SDS-PAGE,可以从柱级分中取出样品并在含有还原剂(例如,DTT)的SDS-PAGE加载缓冲液中加热,并在预制梯度聚丙烯酰胺凝胶(例如,Novex)上解析衣壳蛋白。可以使用SilverXpress(Invitrogen,CA)根据制造商的说明书进行银染色。在一个实施方案中,可以通过定量实时PCR(Q-PCR)测量柱级分中AAV载体基因组(vg)的浓度。将样品稀释并用DNA酶I(或另一种合适的核酸酶)消化以除去外源DNA。在灭活核酸酶后,将样品进一步稀释并使用引物和对引物之间的DNA序列具有特异性的TaqManTM荧光探针扩增。在Applied Biosystems Prism 7700序列检测***上测量每个样品达到确定荧光水平所需的循环数(阈值循环,Ct)。使用含有与AAV载体中所含序列相同的序列的质粒DNA以在Q-PCR反应中产生标准曲线。从样品获得的循环阈值(Ct)值用于通过将其标准化为质粒标准曲线的Ct值来确定载体基因组滴度。也可以使用基于数字PCR的终点测定。
在一个方面,本文提供了优化的q-PCR方法,其使用广谱丝氨酸蛋白酶,例如蛋白酶K(诸如可从Qiagen商购获得)。更具体地讲,优化的qPCR基因组滴度测定与标准测定相似,除了在DNA酶I消化后,将样品用蛋白酶K缓冲液稀释并用蛋白酶K处理,然后加热灭活。适当地,用等于样品大小的蛋白酶K缓冲液稀释样品。蛋白酶K缓冲液可以浓缩至2倍或更高。通常,蛋白酶K处理为约0.2mg/mL,但可以在0.1mg/mL至约1mg/mL之间变化。处理步骤通常在约55℃下进行约15分钟,但可以在较低温度(例如,约37℃至约50℃)下进行较长时间(例如,约20分钟至约30分钟),或在较高温度(例如,高达约60℃)下进行较短时间(例如,约5分钟至10分钟)。类似地,热灭活通常在约95℃下持续约15分钟,但温度可以降低(例如,约70℃至约90℃)并且时间可以延长(例如,约20分钟至约30分钟)。然后将样品稀释(例如,1000倍)并如标准测定中所述进行TaqMan分析。
另外或替代地,可以使用液滴数字PCR(ddPCR)。例如,已经描述了通过ddPCR确定单链和自身互补AAV载体基因组滴度的方法。参见,例如,M.Lock等人,Hu Gene TherapyMethods,Hum Gene Ther Methods.2014年4月;25(2):115-25.doi:10.1089/ligtb.2013.131.Epub 2014年2月14日。
5.2患者人群
如上文所讨论,患有任何严重程度的WD的受试者是本文所述的组合物和方法的预期接受者。
可以允许受试者继续他们的标准护理治疗(例如,低铜饮食;用螯合剂诸如D-青霉胺和曲恩汀治疗)。其他药剂包括二巯基琥珀酸钠、二巯基琥珀酸、锌和四硫代钼酸盐),这些药剂在护理医师判定下在基因疗法治疗之前和同时施用。在替代方案中,医师可能更喜欢在施用基因疗法治疗之前停止标准护理疗法,并且任选地,在施用基因疗法后作为共同疗法恢复标准护理疗法。
基因疗法方案的期望终点将提供功能性ATP7B酶,从而使得血清铜水平降低25%或更多。在一个实施方案中,期望每24小时排出3-8μmol或更少的尿铜。
许多测试可用于研究可能患有威尔逊病的患者,包括非铜蓝蛋白结合铜(NCC;也称为“游离铜”或铜指数)、24小时尿铜、肝铜和基因突变测试。用于测量铜水平的方法是本领域已知的,例如McMillin等人,Am J Clin Pathol.2009;131(2):160-165所述,其以引用的方式并入本文。在一个实施方案中,患者在用rAAV.hATP7B单独治疗和/或与使用辅助治疗组合治疗后实现所需循环ATP7B水平。
5.3.施用的剂量和途径
在一个实施方案中,rAAV.hATP7B载体对每位患者以单剂量递送。在一个实施方案中,向受试者递送最小有效剂量(MED)(如通过本文实施例中描述的临床前研究确定)。如本文所用,MED是指提供功能性ATP7B酶使得血清铜水平降低25%或更多所需的rAAV.hATP7B剂量。
通常,载体滴度是基于载体制剂的DNA含量确定的。在一个实施方案中,如实施例中所述的定量PCR或优化的定量PCR用于确定rAAV.hATP7B载体制剂的DNA含量。在一个实施方案中,如上文所述的数字液滴PCR用于确定rAAV.hATP7B载体制剂的DNA含量。在一个实施方案中,剂量为约lx1011个基因组拷贝(GC)/kg体重至约lx1013GC/kg(包括端点)。在一个实施方案中,剂量为5x1011GC/kg。在另一个实施方案中,剂量为5x1012GC/kg。在具体的实施方案中,向患者施用的rAAV.hATP7B的剂量为至少5x 1011GC/kg、1x 1012GC/kg、1.5x 1012GC/kg、2.0x 1012GC/kg、2.5x 1012GC/kg、3.0x 1012GC/kg、3.5x 1012GC/kg、4.0x 1012GC/kg、4.5x 1012GC/kg、5.0x 1012GC/kg、5.5x1012GC/kg、6.0x 1012GC/kg、6.5x 1012GC/kg、7.0x1012GC/kg或7.5x 1012GC/kg。此外,复制缺陷型病毒组合物可以配制成剂量单位,以含有范围在约1.0x 109GC至约1.0x 1015GC内的量的复制缺陷型病毒。如本文所用,术语“剂量”可以是指在治疗过程中递送给受试者的总剂量,或者以单次(多次)施用递送的量。
在一些实施方案中,rAAV.hATP7B与一种或多种用于治疗WD的疗法组合施用,所述疗法例如低铜饮食或施用D-青霉胺、曲恩汀、二巯基琥珀酸钠、二巯基琥珀酸、锌和/或四硫代钼酸盐。
5.4.测量临床目标
可以通过如由ATP7B活性和或非铜蓝蛋白结合铜(NCC;也称为“游离铜”或铜指数)、24小时尿铜或肝铜水平确定的转基因表达和活性测量治疗功效的测量值。可以通过临床评估膳食铜耐受性来确定对功效的进一步评估。
如本文所用,当患者表达足够水平的ATP7B以实现ATP7B活性时,rAAV.hATP7B载体在本文中用活性ATP7B“功能性地替代”或“功能性补充”缺陷型ATP7B患者,使得非铜蓝蛋白结合铜、24小时尿铜和/或肝铜降低25%或更多。
以下实施例仅是说明性的,并不意图限制本发明。
实施例
以下实施例仅是说明性的,并不意图限制本发明。
实施例1含有hATP7B的AAV载体(AAV.hATP7Bco)
在TBG-S1启动子和En34增强子控制下通过携带密码子优化的人类hATP7B cDNA(hATP7Bco)的AAV8载体构建示例性基因疗法载体AAV8.En34.TBG-Sl.hATP7Bco.PA75(图1)。ATP7B表达盒侧接AAV2衍生的反向末端重复序列(ITR),并且还包括Kozak共有序列和PA75poly(A)信号。AAV8.En34.TBG-Sl.hATP7Bco.PA75基因组的序列示出于SEQ ID NO:24的nt 1至nt 5056中。
如上文所述构建具有肝细胞特异性TTR启动子而非TBG-S1的载体AAV8.En34.TTR.hATP7Bco.PA75。AAV8.En34.TTR.hATP7Bco.PA75序列示出于SEQ ID NO:26的nt 1至nt 5068中。
利用具有示出为SEQ ID NO:11的nt 21至nt 190的修饰的TTR启动子而非TBG-S1来构建载体AAV.En34.mTTR.hATP7Bco.PA75。AAV.En34.mTTR.hATP7Bco.PA75的序列示出于SEQ ID NO:27的nt 1至nt 5048中。
AAV8.EnTTR.TTR.hATP7Bco.PA75载体的ATP7B表达盒由EnTTR增强子和TTR启动子利用Kozak共有序列和PA75poly(A)信号驱动。AAV8.EnTTR.TTR.hATP7Bco.PA75的序列示出于SEQ ID NO:23的nt 1至nt 5134中。
AAV8.EnABPS.TBG-Sl.hATP7Bco.PA75载体在ABP-S2(ABPS增强子)增强子和TBG-S1启动子控制下利用Kozak共有序列和PA75 poly(A)信号编码密码子优化的人类ATP7BcDNA(hATP7Bco)。AAV8.ABPS.TBG-Sl.hATP7Bco.PA75的序列示出于SEQ ID NO:25的nt 1至nt 5064中。
另外,截短的hATP7Bco载体,包括AAV8.En34.TBG-S1.hAT P7Bco(MBD 1Del).PA75(如SEQ ID NO:32的nt 1至nt 4945所示)、AAV8.En34.TBG-Sl.hATP7Bco(MBD2Del).PA75(如SEQ ID NO:31的nt 1至nt 4876所示)、AAV8.En34.TBG-Sl.hATP7Bco(MBD3Del).PA75(SEQ ID NO:30的nt 1至nt 4978)、AAV8.En34.TBG-Sl.hATP7Bco(MBDl-2Del).PA75(SEQID NO:35的nt 1至nt 4627)、AAV8.En34.TBG-Sl.hATP7Bco(MBDl-4Del).PA75(SEQ ID NO:34的nt 1至nt 4021)、AAV8.En34.TBG-Sl.hATP7Bco(MBDl-5Del).PA75(SEQ ID NO:33的nt1至nt 3628)、AAV8.TBG.hATP7Bco(MBDl-4Del).PA75(SEQ ID NO:29的nt 1至nt 4677)和AAV8.TBG.hATP7Bco(MBDl-5Del).PA75(SEQ ID NO:28的nt 1至nt 4284),利用Kozak共有序列、PA75Ploy(A)信号和如表2所示的启动子和增强子设计、构建并产生为所指示的截短的hATP7Bco。
简言之,将由大小减小的甲状腺素运载蛋白增强子和启动子表达密码子优化形式的hATP7B(hATP7Bco)的质粒用AAV8病毒衣壳包装。
使用常规三重转染技术在293细胞中制备载体,如例如Mizukami、Hiroaki等人,AProtocol for AAV vector production and purification.Diss.Division of GeneticTherapeutics,Center for MolecularMedicine,1998.所述,其以引用的方式并入本文。所有载体均由宾夕法尼亚大学(University of Pennsylvania)的载体中心(Vector Core)产生,如先前所述[Lock,M.等人,Hum Gene Ther,21:1259-1271(2010)]。
表2
实施例2威尔逊病的小鼠模型
在开发用于治疗威尔逊病的基因治疗方法之前,必须充分表征疾病表型的动物模型。本文所述的研究是tx1小鼠品系以及从出生开始养育所有Atp7b KO小鼠之后铜代谢和疾病病理学的评估的首次详细表征。在不存在由于在患病母亲的乳腺中缺乏Atp7b而在断奶前提供的冲突性铜缺乏时,准确地确定了疾病进展的时间线。Atp7b KO小鼠从出生时就在肝脏中积累铜,两个月大时铜积累严重,并发肝病。
影响单个器官的单基因疾病是基因治疗方法的有吸引力的目标,尤其是在相关组织学病变相对较少时。然而,对于影响肝脏的代谢障碍,由于所述疾病通常可能会对肝实质造成严重损害。其中一个典型实例是威尔逊病,一种由威尔逊病蛋白(铜转运P型ATP酶,Atp7b)突变引起的常染色体隐性疾病。缺乏功能性Atp7b导致铜在肝脏和其他组织中积累,这表现为具有神经或精神症状的肝病。可以通过使用螯合疗法减少铜吸收或从体内去除多余铜来治疗威尔逊病,但是,对于许多其他代谢障碍而言,肝移植既可以纠正与疾病相关的遗传缺陷,也可以替代功能失调的器官。
威尔逊病影响1:30,000名具有不同疾病症状和进展的人。为了开发螯合和肝移植的新治疗替代方案,必须充分表征此疾病的可靠动物模型。先前报道了若干威尔逊病的大鼠和小鼠动物模型,包括Long-Evans Cinnamon(LEC)大鼠和各种转基因小鼠品系(1-6)。为了评估小鼠模型中的威尔逊病表型,我们选择了可从Jackson实验室获得的有毒乳鼠(txj)(2)。这些小鼠在Atp7b基因中具有Gly712Asp错义突变,其位于编码蛋白的第二个推定的跨膜结构域中并且产生功能失调的Atp7b蛋白。
此品系的原始名称,即有毒乳鼠,是Atp7b除了肝脏外还在***组织中表达的结果。因此,此模型中有毒乳表型的“自发产生”是威尔逊病的直接结果(7)。由于缺乏Atp7b蛋白,铜不能从母体转运到母乳中(8)。从患病母亲那里吮吸的患病幼崽会出现威尔逊病(铜缺乏症)的逆转形式,因为它们在饮食中不能接受任何铜,直到它们断奶并消耗正常的小鼠口粮。这种威尔逊病的逆转形式也解释了先前描述的白色毛色和精神缺陷(9)。在这里,由于功能失调的Atp7b蛋白以及这些研究中使用的所有小鼠在出生后72小时内寄养到Balb/c养育母亲处以减轻有毒乳问题的这个事实,因此我们更喜欢将此小鼠模型描述为Atp7b敲除(KO),而不是txj。因此,此处描述的威尔逊病表型的表征已与断奶前与铜缺乏相关的任何潜在问题分开。
所有动物程序均根据宾夕法尼亚大学的机构动物护理和使用委员会(Institutional Animal Care and Use Committee,IACUC)批准的方案进行。
ATP7B KO小鼠不表达功能性铜转运ATP酶(Lutsenko等人,Function andRegulation of Human Copper-Transporting ATPases,Physiological Reviews,87(3):1011-46(2007年7月),因此用作威尔逊病的小鼠模型。进行自然病史研究以评估ATP7B KO小鼠中的威尔逊病进展。所述研究分2个阶段进行。首先,
在不同年龄对小鼠进行尸检以评估肝病。在第二阶段,跟踪小鼠至9个月大,以评估若干生物标记物。
从2个月大开始,每周和每两周分别评估Atp7b杂合和KO小鼠的尿液和血清铜水平,持续7个月(图3A和3B)。肝脏中的Atp7b将铜输出到胆汁以便以粪便***(7)。在不存在Atp7b的情况下,将通过泌尿道***铜。在所研究的两种基因型中,尿铜水平最初是相似的,但是在3个月大时,与杂合动物相比,Atp7b KO小鼠的尿液中的铜水平开始增加(图3A)。在研究完成时,尿铜水平在杂合小鼠中平均为0.18μg/g,在Atp7b KO小鼠中为1.08μg/g。与0.47μg/g相比,2个月大的Atp7b KO小鼠的血清铜水平与0.07μg/g的杂合动物显著不同(通过学生t检验,p<0.0001,图3B)。在3-4个月大时,Atp7b KO小鼠的血清铜水平开始上升,达到与杂合小鼠的血清铜水平相当的水平。雄性或雌性小鼠的尿液或血清铜水平几乎没有差异。第一阶段的结果表明,从出生开始就观察到肝脏中的铜积累。当Atp7b KO小鼠达到2个月大时,Timm铜染色显示肝脏中存在严重铜积累(图4)。
影响肝脏代谢的单基因疾病可分为两个亚类,即具有肝脏病变的亚类和不具有肝脏病变的亚类。威尔逊病患者确实表现出中度至重度肝病,通常表现为肝硬化(13,14)。因此,我们想要评估这种威尔逊病小鼠模型中肝脏病理学发展的时间进程。在2、3、4、5、9、10和12个月时对Atp7b KO小鼠进行尸检,以评估随时间变化的肝脏病变(图5)。用H&E染色肝脏切片,并根据1-5评分***评估组织病理学(图3C)。Atp7b KO小鼠从2个月大开始就存在最小肝细胞肥大和变性以及单细胞坏死和炎症。肝细胞肥大、变性和坏死的严重程度在6个月大时最高,并且此后保持一致。评估的其他参数在从2-3个月大到7个月大的时间内有所增加,所述其他参数包括炎症、胆管增生和卵圆细胞增生。肝转氨酶ALT和AST存在同时升高,ALT和AST从2个月时的正常值分别升至10个月大时的199U/l和381U/l(表3)。在血清总胆红素水平突然增加到2.5mg/dl时,从这些水平还明显看出10个月大的肝损伤程度。除了肝脏病变之外,在此小鼠模型中从6个月大开始肝脏结节再生区域就是明显的(由图5中的星号示出一个实例)。由于肝病的严重程度,因此这可能并不令人惊讶。表3
还分别通过天狼星红和Timm染色评估肝脏切片的纤维化和铜积累(图5)。在Atp7bKO小鼠3个月大时观察到局灶性或多灶性门静脉周纤维化。到7个月大时,迅速进展到扩散桥接纤维化,伴有结构破坏。肝脏病变的发展可能是由于肝脏中积累了大量铜,如通过Timm染色所见(图5)。从两个月大时,Atp7b KO小鼠的肝脏就已经饱含有铜,如通过黑色染色所示。由于在不存在功能性Atp7b的情况下铜到胆汁的输出受到破坏,因此发生肝脏中的铜积累。肝脏中的铜水平随时间降低,这可能是由于肝细胞损伤并将铜释放到血清中。这一点先前已经显示,其中铜值在亚大量或大量坏死的情况下显著降低,并且在再生和纤维化的情况下甚至进一步降低(1,15-17)。纤维***和再生肝细胞不含过量的铜浓度(18)。
还监测ATP7B KO小鼠尿液中的铜水平。在自然病史研究中每周收集样品,然后进行电感耦合等离子体质谱法以评估铜浓度。结果表明,虽然杂合同窝仔维持低铜水平,但Atp7b KO小鼠在约第三周开始出现铜溢入尿液,随后在观察期间尿液铜浓度稳定增长(图2A,图3A),这表现为在威尔逊病患者中观察到的高尿铜***率。
每两周收集Atp7b KO小鼠的血清,以通过电感耦合等离子体质谱法评估铜浓度。结果显示与杂合同窝仔相比,直至2个月大的血清铜水平非常低,这表明在Atp7b KO小鼠中将铜从组织提取到血液中的能力受损。当Atp7b KO小鼠3至4个月大时,铜的血清浓度显著增加并达到杂合同窝仔的水平(图2B,3B)。
在此Atp7b KO小鼠模型中,疾病的进展如下:在2个月大时通过Timm铜染色观察到肝脏中的严重铜积累,但随时间的推进而减少,类似于先前其他人所描述的情况(1,15-17)。由于幼崽的养育,铜可能从出生就在Atp7b KO小鼠的肝脏中积累并在2-3个月大时达到饱和水平。在2个月大时肝病发展之后,铜可能会释放到血清中,从而使得肝细胞中的积累明显减少并且到3-4个月大时血清铜水平升高。血清铜水平从最初的低水平到与杂合小鼠类似的水平的这种升高不同于先前对于另一种威尔逊病小鼠模型报道的升高(17),其中Atp7b-/-品系中的血清铜水平在6周大时类似于野生型小鼠中观察到的水平并且在44周大时随着时间的推移而增加至野生型小鼠的2至3倍。
我们观察到在约3个月大时铜开始溢入尿液中,这同样可能是由于肝细胞坏死和积累的铜的随后释放。已提出通过肾脏***铜的替代机制,包括肾脏中缺乏Atp7b活性导致***增加(23-25),或肝脏中的铜积累导致肝铜转运蛋白的下调、Ctrl和通过小铜载体进行尿***(26)。同样,尿铜***的时间进程在此小鼠模型中不同于先前报道的时间进程。这里,尿铜***在杂合和Atp7b KO小鼠中最初是类似的,但在研究过程中在KO小鼠中增加。相比之下,Atp7b-/-品系在6周大时,尿铜水平比野生型小鼠大3倍,增加直至14-20周大,然后在20周大时显著下降(26)。
肝细胞肥大、变性和坏死在6月大时达到峰值,可能从这个年龄开始同时观察到肝结节再生区域。已报道了其他威尔逊病小鼠模型的这种再生进展(17)。然而,与其他小鼠模型不同,此处中描述的Atp7bKO小鼠中没有胆管癌的证据。3个月大时可见纤维化区域,到7个月大时,其严重程度随时间迅速增加,并且伴有结构破坏。虽然3-4个月大时血清转氨酶显著增加,但血清总胆红素水平仅在9个月大时开始增加,这表明晚期肝病。
在自然病史研究的第二阶段,在8个月大时处死Atp7b KO和杂合同窝仔。获得ALT、AST和总胆红素水平。图6A-6C.进行H&E染色并且然后由病理学家根据评分方案评估组织病理学,其示出于图7中。通过Timm染色进行的纤维化评分和铜染色评分分别示出于图8A和8B中。肝脏中的铜水平示出于图9中。
实施例3:威尔逊病模型中的AAV8.hATP7Bco载体
向雄性Atp7b KO小鼠静脉内注射1010GC/小鼠和1011GC/小鼠的AAV8.TTR.hATP7Bco,并向雌性Atp7b KO小鼠静脉内注射109、1010和1011GC/小鼠的相同载体。在载体注射后监测血清铜水平(图10A和10B)。在雄性Atp7b KO小鼠中施用1010或1011GC/小鼠,在载体施用后两周,使血清铜水平从平均值0.11μg/g分别增加至0.52μg/g和0.34μg/g(图10A)。然而,在雌性小鼠中的作用较小(图10B)。在约9个月大时在施用载体后7个月处死小鼠,并收获肝脏以用于评估肝铜水平。杂合和Atp7b KO小鼠中的肝铜水平分别平均为6μg/g和222μg/g(图10C)。与年龄匹配的未注射的Atp7b KO小鼠相比,以剂量>109GC/小鼠施用AAV8载体导致肝铜水平显著降低。然而,在施用109GC/小鼠的雌性小鼠和对照Atp7b KO小鼠的肝铜水平之间没有显著差异。对于此测量,由于肝铜水平与杂合小鼠没有显著差异,因此在雌性小鼠中高载体剂量具有更强的作用(图10C)。
在9月大时对施用AAV8载体的小鼠进行尸检,并通过Timm染色在组织学上评估肝脏的酮相关肝病(包括纤维化和铜水平)的参数(图11)。用H&E染色肝脏切片,并根据1-5评分***进行组织学评估(图12A)。与对于肝铜水平可见的情况相似,在年龄匹配的未注射的Atp7b KO小鼠和施用109GC/小鼠的AAV8载体的雌性小鼠之间,肝脏病变没有显著差异。注射1011GC/小鼠的雄性小鼠中肝脏病变呈剂量依赖性减少,观察到所述病变仅有轻度核巨大细胞(karyocytomegaly)(表示肝细胞肥大和变性)、轻度炎症和局灶性或多灶性门静脉周卵圆细胞增生。与年龄匹配的未注射的Atp7b KO小鼠相比,在施用1010和1011GC/小鼠的小鼠中肝细胞肥大、变性/坏死以及胆管增生显著减少(p<0.05)。对于炎症和卵圆细胞增生,与年龄匹配的未注射的Atp7b KO小鼠相比,仅在1011GC/小鼠的剂量下观察到显著降低(p<0.05)。当将组织病理学参数合并并使用Fisher's组合概率测试评估时,与年龄匹配的未注射的Atp7b KO小鼠相比,在施用1010和1011GC/小鼠之后存在显著差异(p<0.0001)。
接受最高载体剂量的雄性小鼠也没有纤维化,这使用天狼星红染色来评估(图11和12B)。对于所有其他施用载体的小鼠,与年龄匹配的未注射的Atp7b KO小鼠相比,纤维化没有显著差异(图12B)。然而,在施用1011GC/小鼠的雌性小鼠中观察到的纤维化减少足以使得在这些小鼠和雌性Atp7b杂合小鼠的肝纤维化评分之间也没有显著差异。对肝脏中的铜积累的Timm染色表明与由通过电感耦合等离子体质谱法测定的定量肝铜水平所见的结果类似的结果(图12C)。在年龄匹配的未注射的Atp7b KO小鼠与任何施用载体的组之间,Timm染色得分没有显著差异。为了评估AAV8.hATP7Bco载体的功效,Atp7b Ko小鼠接受以3x1012GC/kg静脉内施用的各种基因疗法载体,包括AAV8.EnTTR.TTR.hATP7Bco.PA75(图21,组1)、AAV8.En34.TBG-Sl.hATP7Bco.PA75(图21,组2)、AAV8.En34.TTR.hATP7Bco.PA75(图21,组3)和AAV8.EnABPS.TBG-Sl.hATP7Bco.PA75(图21,组4)。将杂合和野生型同窝仔和未处理的Atp7b KO小鼠用作对照。每周收集血液样品以通过蛋白质印迹评估铜结合形式和非铜结合形式的铜蓝蛋白的水平。在施用后第21天,在用AAV8.En34.TBG-Sl.hATP7Bco.PA75处理的Atp7b KO小鼠中观察到铜结合的铜蓝蛋白的出现,这表明促进铜提取到血液中(图21,第2组)。然而,在上文所述实验设置下,其他三种测试载体未显示铜结合的铜蓝蛋白的增加(图21)。
为了评估注射本文所述的AAV8.hATP7Bco载体的ATP7B KO小鼠肝脏中的铜积累,对其肝脏切片进行Timm铜染色。黑色沉积物表明铜积累。结果示出于图19B中。与来自未处理或仅PBS处理的小鼠的样品相比,向雄性Atp7b KO小鼠注射所有五种载体导致肝脏切片的黑色沉积物减少,而AAV8.EnTTR.TTR.hATP7Bco.PA75载体显示最少黑色沉积物和类似于野生型的图案(图19B)。与雄性Atp7b KO小鼠相比,雌性Atp7b KO小鼠(图19B)在肝脏中显示更多的铜沉积物,这表明存在性别差异。还与未处理的小鼠相比,雌性Atp7b KO小鼠在肝脏中显示更少的铜沉积物。正在研究在注射本文所述的AAV.hATP7Bco载体的雄性和雌性Atp7b KO小鼠中针对人类ATP7B蛋白的抗体的产生。
同时,收集血清样品并如实施例2中所述评估铜浓度。在图15A和15B中分别绘制雌性和雄性小鼠的数据。结果表明,本文所述的3x 1012GC/kg的AAV8.hATP7Bco载体的治疗成功地增加了Atp7b KO小鼠中的血清铜水平(图15A和15B)。
如下进行进一步测试:
随时间变化的血清铜水平示出于图15A和15B中。获得ALT、AST和总胆红素水平。图16A-C。相对ATP7B表达示出于图17中。进行H&E染色并且然后由病理学家根据评分方案评估组织病理学,其示出于图18中。通过Timm染色进行的纤维化评分和铜染色评分分别示出于图19A和19B中。
实施例4:注射AAV.hATP7Bco载体的威尔逊病模型中铜蓝蛋白的氧化酶活性
铜是一种潜在有毒金属,但它是许多生理功能所必需的,可作为多种酶的辅助因子。在肠道吸收后,铜被转运到肝细胞,在所述肝细胞中它与位于高尔基体外侧网络(TGN)膜中的ATP7B结合。这种大跨膜蛋白负责将金属转移到铜依赖性酶。将铜加载到铜蓝蛋白中是此酶的亚铁氧化酶活性所必需的,并且构成金属的重要分泌途径,因为健康个体的血浆中存在的95%铜与铜蓝蛋白结合。请参见例如Murillo,Oihana等人"Long-term metaboliccorrection of Wilson’s disease m a murine model by gene therapy"Journal ofHepatology 64.2(2016):419-426,其以引用的方式并入本文。
为了测量氧化酶活性,使用Sigma Ceruloplasmin活性比色试剂盒(MAK177)或BioVision Ceruloplasmin活性比色试剂盒遵循其对应产品信息中所示的方案处理20μl血清,所述产品信息以引用的方式并入本文。也根据以下所示的方案进行氧化酶活性测定:Schosinsky等人,"Measurement of ceruloplasmin from its oxidase activity inserum by use of o-dianisidine dihydrochloride"Clinical Chemistry 20.12(1974):1556-1563和Murillo等人"Long-term metabolic correction of Wilson’s disease ina murine model by gene therapy"Journal of Hepatol ogy 64.2(2016):419-426,其以引用的方式并入本文。
使用上文所述四种测定法测量Atp7b KO小鼠的血清铜蓝蛋白的氧化酶活性。将来自野生型和杂合小鼠的样品用作对照。在野生型与Atp7b KO小鼠之间未检测到差异。
此外,用硫酸铵处理或不用硫酸铵处理Atp7b KO小鼠。提供野生型小鼠作为对照。使用Schosinsky等人,"Measurement of ceruloplasmin from its oxidase activity inserum by use of o-dianisidine dihydrochloride"Clinical Chemistry 20.12(1974):1556-1563所示的方案,在野生型或Atp7b KO小鼠之间未检测到铜蓝蛋白氧化酶活性测定的差异。
在另一个实验中,用硫酸铜处理或不用硫酸铜处理Atp7b KO小鼠。提供野生型小鼠作为对照。进行铜蓝蛋白氧化酶活性测定以使用上文所述的四种方法检测用硫酸铜处理或不用硫酸铜处理的小鼠之间的差异。还收集本文所述小鼠的肝匀浆物,并使用上文所述四种方法测试铜蓝蛋白的氧化酶活性。将硫酸铜进一步加入肝匀浆物中并用作阳性对照。
实施例5:进一步测试AAV8.TTR.hATP7Bco载体
为了确定AAV8.EnTTR.TTR.hATP7Bco.PA75载体的剂量依赖性效应和最小有效剂量(MED),向2个月大的雄性和雌性ATP7B KO小鼠静脉内注射1x 109、1x 1010或1x 1011GC/小鼠的载体。铜蓝蛋白的蛋白质印迹显示在接受1x 1011GC的AAV8.EnTTR.TTR.hATP7Bco.PA75的四只测试小鼠中有三只的血清中出现铜结合的铜蓝蛋白,这表明铜提取增加(图14)。在用1x 1010GC的相同载体治疗时,五只测试小鼠中有一只在血液中显示铜结合的铜蓝蛋白(图14)。这些日期确认在威尔逊病小鼠模型中以每只小鼠1x 1011GC的剂量单次静脉内注射AAV8.EnTTR.TTR.hATP7Bco.PA75成功地促进了铜提取。
实施例6:截短的载体
单基因疾病是使用AAV载体的基因替代疗法方法的优秀候选疾病。然而,可以包装在AAV载体衣壳内的cDNA的大小是有限的。野生型AAV基因组是4,700bp,并且要求包装更大基因组可能减小包封在AAV衣壳内的DNA序列的完整性(19)。先前,已经进行了广泛的研究以研究减小给定转基因的大小和表达所需的转录和polyA控制序列的方式。成功完成此操作的一个实例是开发用于治疗A型血友病的基因疗法载体,其涉及产生长度为4,374bp的人类凝血因子VIII的B结构域缺失的转基因序列(19-21)。对于威尔逊病的治疗,因为ATP7BcDNA为4,395bp,所以问题增加。因此,与75bp合成polyA序列(PA75)组合,我们选择使用大小减小的甲状腺素运载蛋白增强子和启动子(TTR)序列来表达人类ATP7B转基因的密码子优化形式(19)。所得AAV基因组为5.1kb并包装在AAV8衣壳内。
另外,设计、产生截短的hATP7Bco载体并以3x1012GC/kg的剂量静脉内注射到ATP7BKO小鼠中,所述载体包括AAV8.En34.TBG-Sl.hATP7Bco(MBDlDel).PA75、AAV8.En34.TBG-Sl.hATP7Bco(MBD2Del).PA75、AAV8.En34.TBG-Sl.hATP7Bco(MBD3Del).PA75、AAV8.En34.TBG-Sl.hATP7Bco(MBDl-2Del).PA75、AAV8.En34.TBG-Sl.hATP7Bco(MBDl-4Del).PA75、AAV8.En34.TBG-Sl.hATP7Bco(MBDl-5Del).PA75、AAV8.TBG.PI.hATP7Bco(MBDl-4Del).PA75、和AAV8.TBG.PI.hATP7Bco(MBDl-5Del).PA75。
研究用上文所述的各种截短的载体治疗的Atp7b KO小鼠以及杂合同窝仔,并在6个月大时处死。随时间变化的血清铜水平是出于图22中。获得ALT、AST和总胆红素水平。图23。相对ATP7B表达示出于图24中。进行H&E染色并且然后由病理学家根据评分方案评估组织病理学,其示出于图25中。通过Timm染色进行的纤维化评分和铜染色评分示出于图26中。尸检时的肝铜水平示出于图27中。
实施例7:用于以上实验的材料和方法
A.AAV载体生产
所有AAV载体均由宾夕法尼亚大学的佩恩载体中心(Penn Vector Core)产生,如先前所述(10)。简言之,用AAV8病毒衣壳包装由大小减小的甲状腺素运载蛋白增强子和启动子表达密码子优化形式的hATP7B(hATP7Bco)的质粒。
B.小鼠
杂合Atp7b+/-小鼠育种对从The Jackson Laboratory(Bar Harbor,ME,USA)获得,并且在宾夕法尼亚大学中小鼠群体保持在特定无病原体条件下。所有动物程序和方案均由宾夕法尼亚大学的机构动物护理和使用委员会(IACUC)批准。产生Atp7b KO并将其用于随后的育种。由Atp7b KO交配对产生的所有幼崽均在出生后72小时内寄养到Balb/c养育母亲处。通过尾静脉向两个月大的雄性和雌性Atp7b KO小鼠静脉内注射109-1011个基因组拷贝(GC)/小鼠的AAV8.TTR.hATP7Bco(n=5/性别/组)。
C.血清分析
在指定时间点将血液收集在血清分离管中,使其凝结,并通过在室温下以3,500xg离心5分钟来分离血清。通过Antech Diagnostics(Irvine,CA,USA)分析血清的丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)和总胆红素水平。还通过Exova(Edinburgh,UK)分析血清和尿液的铜水平。
D.肝铜分析
通过Exova(Edinburgh,UK)分析在尸检时采集的肝样品的铜水平。
E.组织病理学
将***固定的石蜡包埋的组织样品切片并根据标准方案进行苏木精和曙红(H&E)染色。为了检测肝纤维化,对石蜡切片进行天狼星红染色。将切片脱石蜡并在0.1%(w/v)直接红(Direct Red)(Sigma)、4%(w/v)苦味酸(Sigma)的溶液中染色90分钟,用0.01N HCl洗涤(2x1分钟),通过乙醇和二甲苯系列脱水,并应用盖玻片。
F.Timm铜染色
将***固定的石蜡包埋的肝脏切片脱蜡,依次在0.5%硫化铵(5分钟)、去离子水(1分钟冲洗),0.1N HCl(2-3分钟)、去离子水(2-3分钟冲洗)和显影剂(1份5%硝酸银、5份2%(w/v)氢醌/5%(w/v)柠檬酸,约10分钟)中孵育。在每次运行中包括来自对照动物(野生型和ATP7B KO)的肝脏切片并监测一致的染色强度。最后在水中洗涤切片,用核固红(Nuclear Fast Red)复染,脱水,并施加盖玻片。
G.组织病理学评分
基于以下标准对组织病理学病变进行评分。肝细胞肥大和变性:0,无明显病变;1,最小核巨大细胞(很少至偶尔,小叶内1-2个肝细胞),2,轻度核巨大细胞(小叶内<10%的肝细胞);3,中度核巨大细胞(小叶内10-50%肝细胞)伴有肝细胞解离和少见单细胞坏死;4,严重的核巨大细胞(小叶内51-90%肝细胞)伴有广泛的肝细胞解离和频繁的单细胞坏死;维持相对正常的肝脏结构;5,明显的核巨大细胞(小叶内>90%肝细胞)伴有小叶塌陷和许多单细胞坏死。炎症0,没有炎症;1,门静脉区域内轻度-少量聚集体,而实质内的罕见病灶;认为处于正常范围内;2,中度-延伸到周围的门静脉周肝细胞或实质内多灶性;3,明显-桥接或解剖肝细胞或在实质内多灶性至聚结。胆管增生:0,没有胆管增生;1,门静脉区域内的局灶性或多灶性;2,门静脉周区域的解剖肝细胞;3,桥接或解剖肝细胞伴有结构破坏。卵圆细胞增生:0,没有卵圆细胞增生;1,局灶性或多灶性(门静脉周);2,桥接或解剖肝细胞;3,桥接或解剖肝细胞伴有结构破坏。结节再生:0,不存在;1,存在。
基于天狼星红染色的纤维化分级方案来源于文献报道的那些(11):0,没有纤维化;1,局灶性或多灶性;2,桥接;3,桥接伴有结构破坏,具有关于分布是小叶中心、中间区、门静脉周围或弥漫的符号。
H.基于Timm染色的铜积累分级方案与先前文献(12)中描述的相同:1,偶尔肝细胞的细胞质中不含或含有少量含铜颗粒;认为处于正常范围内;2,在一些小叶中心肝细胞中含有明显的含铜颗粒;认为处于正常范围内;3,轻度-大多数小叶中心肝细胞中的大量颗粒(每个小叶的三分之一);4,中度-在所有小叶中心和中间区肝细胞中存在大量颗粒(所有小叶中约三分之二的肝细胞);5,明显-在所有小叶中超过三分之二的肝细胞中含有丰富的颗粒。统计分析
对于所有数据,计算并报道组平均值和均值标准误差(SEM)。进行学生t检验以比较两组并且在各组之间进行单因素方差分析(AVOVA)与Tukey多重比较检验并按性别分层。在载体施用中分析了五种病理学参数,并将其与年龄匹配的未注射的Atp7b KO小鼠中的参数进行比较。使用R程序(版本3.3.1;https//cran.r-project.org)内的威尔科克森(Wilcoxon)秩和检验进行比较。还使用“metap”包中的函数“sumlog”,使用R程序内的Fisher组合概率测试,与年龄匹配的未注射的ATP7B KO小鼠相比,评估每个剂量组的组合病理学参数的差异。p值0.05被认为是显著的。
实施例8:讨论
在小鼠疾病模型可用于评估治疗方法对临床的可翻译性(translatability)之前,必须对模型进行充分表征。虽然已对其他威尔逊病小鼠模型进行了表征(1,15,17),但这项研究是对txJ小鼠品系以及从出生开始养育所有Atp7b KO小鼠后铜代谢和肝病的评估的首次详细表征。在不存在由于在患病母亲的乳腺中缺乏Atp7b而在断奶前出现的冲突性铜缺乏的情况下,通过确保疾病表型与断奶前与铜缺乏相关的任何潜在问题分离,可以更准确地确定这些小鼠的疾病进展时间线。在此小鼠模型中肝病和结节性再生的发展类似于先前已针对其他人开发的Atp7b+/-品系所报道的发展(1,17)。然而,此小鼠品系的时间线略有增加,这可能是由于从出生开始养育幼崽,从而导致连续供应铜。
在这个Atp7b KO小鼠模型中,疾病的进展如下:在2个月大时通过Timm铜染色观察到肝脏中的严重铜积累,但随时间减少,这类似于其他人先前所述的情况(1,15-17)。由于幼崽的养育,铜可能从出生开始在Atp7b KO小鼠的肝脏中积累并在2-3个月大时达到饱和水平。在2个月大时肝病发展之后,铜可能会释放到血清中,从而使得在肝细胞中的积累明显减少并且到3-4个月大时血清铜水平升高。血清铜水平从最初的低水平到与杂合小鼠类似的水平的这种升高不同于先前对于另一种威尔逊病小鼠模型报道的升高(17),其中Atp7b-/-品系中的血清铜水平在6周大时类似于野生型小鼠中观察到的水平并且在44周大时随着时间的推移而增加至野生型小鼠的2至3倍。
我们观察到铜在约3个月大时开始溢入尿液中,这同样可能是由于肝细胞坏死和积累的铜的随后释放。已提出通过肾脏***铜的替代机制,包括肾脏中缺乏Atp7b活性导致***增加(23-25),或肝脏中的铜积累导致肝铜转运蛋白的下调、Ctrl和通过小铜载体进行尿***(26)。同样,尿铜***的时间进程在此小鼠模型中不同于先前报道的时间进程。这里,尿铜***在杂合和Atp7b KO小鼠中最初是类似的,但在研究过程中在KO小鼠中增加。相比之下,Atp7b-/-品系在6周大时,尿铜水平比野生型小鼠大3倍,增加直至14-20周大,然后在20周大时显著下降(26)。
肝细胞肥大、变性和坏死在6月大时达到峰值,可能从这个年龄开始同时观察到肝结节再生区域。已报道了其他威尔逊病小鼠模型的这种再生进展(17)。然而,与其他小鼠模型不同,此处中描述的Atp7b KO小鼠中没有胆管癌的证据。3个月大时可见纤维化区域,到7个月大时,其严重程度随时间迅速增加,并且伴有结构破坏。虽然3-4个月大时血清转氨酶显著增加,但血清总胆红素水平仅在9个月大时开始增加,这表明晚期肝病。
在对此Atp7b KO小鼠模型进行表征后,我们开发了一种用于治疗威尔逊病的基因治疗方法。在两个月大时将表达密码子优化形式的人类ATP7B转基因的AAV8载体静脉内施用到Atp7b KO小鼠中,导致血清铜水平在施用载体后两周增加。与年龄匹配的未注射的Atp7b KO小鼠相比,此处评估的更高剂量的载体(>109GC/小鼠)导致肝铜水平显著降低。肝脏病变中存在显著的剂量依赖性降低,注射1011GC/小鼠的雄性小鼠中仅存在轻微的组织病理学发现并完全缺乏肝纤维化。因此,在威尔逊病小鼠模型中在疾病发作的早期阶段施用基因治疗方法防止肝损伤并且校正铜代谢。
本说明书中引用的所有出版物以及美国临时专利公布号62/440,659和62/473,656均以引用的方式并入本文。类似地,本文引用并出现在所附序列表中的SEQ ID NO以引用的方式并入本文。虽然已经参考特定实施方案描述了本发明,但是应理解,可以在不脱离本发明的精神的情况下进行修改。这些修改旨在落入所附权利要求的范围内。
序列表自由文本
Seq ID
NO 自由文本
参考文献
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序列表
<110> 宾夕法尼亚州立大学托管会
<120> 用于治疗威尔逊病的基因疗法
<130> UPN-16-7940PCT
<150> US 62/440,659
<151> 2016-12-30
<150> US 62/473,656
<151> 2017-03-20
<160> 35
<170> PatentIn 3.5版
<210> 1
<211> 4395
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 1
atgcccgagc aggaaagaca gatcaccgcc agagagggcg ccagccggaa gatcctgagc 60
aagctgagcc tgcccaccag agcctgggag cccgccatga agaagtcctt cgccttcgac 120
aacgtgggct acgagggcgg cctggacgga ctgggaccat cttctcaggt ggccacaagc 180
accgtgcgca tcctgggcat gacctgccag agctgcgtga agtccatcga ggaccggatc 240
agcaacctga agggcatcat cagcatgaag gtgtccctgg aacagggcag cgccaccgtg 300
aaatacgtgc cctctgtcgt gtgcctgcag caggtgtgcc accagatcgg cgacatgggc 360
ttcgaggcct ctatcgccga gggaaaggcc gcctcttggc cctctagaag cctgcctgct 420
caggaagccg tcgtgaagct gcgggtggaa gggatgacct gtcagtcctg cgtgtccagc 480
atcgagggca aagtgcggaa gctgcagggc gtggtgcgcg tgaaagtgtc tctgagcaac 540
caggaagctg tgatcaccta ccagccctac ctgatccagc ccgaggacct gagggaccac 600
gtgaacgata tgggatttga ggccgccatc aagagcaagg tggcccctct gtctctgggc 660
cccatcgaca tcgagagact gcagagcacc aaccccaagc ggcctctgag cagcgccaac 720
cagaacttca acaacagcga gacactgggc caccagggca gccacgtcgt gacactgcag 780
ctgcggatcg acggaatgca ctgcaagagc tgtgtgctga acatcgagga aaacatcggc 840
cagctgctgg gagtgcagag catccaggtg tcactggaaa acaagaccgc ccaggtgaag 900
tacgacccca gctgcacaag ccccgtggcc ctgcagagag ccattgaagc tctgccccct 960
ggcaacttca aagtgtccct gcctgacgga gccgagggct ccggaacaga tcacagaagc 1020
agcagcagcc acagccctgg cagcccccct agaaatcagg tgcagggcac ctgtagcacc 1080
accctgatcg ccattgccgg catgacatgc gccagctgcg tgcactctat tgagggcatg 1140
atctcccagc tggaaggcgt gcagcagatc agtgtgtctc tggccgaggg caccgccaca 1200
gtgctgtaca accctagcgt gatcagcccc gaagaactga gagccgccat tgaggacatg 1260
ggattcgaag ccagcgtggt gtccgagagc tgctccacca accctctggg caatcacagc 1320
gccggcaaca gcatggtgca gaccaccgac ggcaccccca ccagcgtgca ggaagtggcc 1380
ccacatacag gcagactgcc cgccaatcac gcccccgata tcctggccaa gagcccccag 1440
agtacaagag ccgtggcccc ccagaagtgc ttcctgcaga tcaagggcat gacttgtgcc 1500
tcttgtgtgt ccaatatcga gcggaacctg cagaaagagg ccggcgtgct gtctgtgctg 1560
gtggctctga tggccggcaa ggccgagatc aaatacgacc ccgaagtgat tcagcccctg 1620
gaaatcgccc agtttatcca ggacctgggc tttgaagccg ccgtgatgga agattacgcc 1680
ggctccgacg gcaacatcga gctgaccatc accggaatga cctgcgcctc ctgtgtgcac 1740
aacattgagt ccaagctgac ccggaccaac ggcatcacct acgcctctgt ggctctggcc 1800
acctccaagg ccctcgtgaa gttcgatccc gagatcatcg gccccaggga catcatcaag 1860
atcatcgaag agatcggctt ccacgccagc ctggcccaga ggaaccctaa cgcccaccac 1920
ctggaccaca agatggaaat caagcagtgg aagaaaagct tcctgtgcag cctggtgttc 1980
ggcatccccg tgatggccct gatgatctac atgctgatcc ccagcaacga gccccaccag 2040
tccatggtgc tggatcacaa catcatcccc ggcctgtcta tcctgaacct gatcttcttc 2100
atcctgtgca ccttcgtgca gctgctgggc ggctggtact tctacgtgca ggcctacaag 2160
tccctgcggc acagatccgc caacatggac gtgctgatcg tgctggccac atctatcgcc 2220
tacgtgtact ccctcgtgat cctggtggtg gccgtggccg agaaagccga gagaagccct 2280
gtgaccttct tcgacacccc ccctatgctg ttcgtgttta tcgccctggg ccggtggctg 2340
gaacacctgg ccaaaagcaa gaccagcgag gccctggcta agctgatgag tctgcaggcc 2400
accgaggcca cagtcgtgac cctgggcgag gacaacctga tcatccgcga ggaacaggtg 2460
ccaatggaac tggtgcagcg gggcgacatc gtgaaggtgg tgcctggcgg caagttcccc 2520
gtggacggaa aagtgctgga agggaatacc atggccgacg agagcctgat cacaggcgag 2580
gccatgcccg tgaccaagaa acctggcagc acagtgatcg ccggcagcat caatgcccac 2640
ggcagcgtgc tgattaaggc cacacacgtg ggcaacgata ccaccctggc tcagattgtg 2700
aagctggtgg aagaggccca gatgagcaag gcccccattc agcagctggc tgaccggttc 2760
agcggctact tcgtgccctt tatcatcatc atgagcaccc tgacactggt cgtgtggatc 2820
gtgatcggct ttatcgactt cggagtggtg cagagatact tccccaaccc taacaagcac 2880
atcagccaga cagaagtgat catcagattc gcctttcaga ccagcatcac cgtgctgtgt 2940
atcgcctgcc cctgtagcct gggactggcc acacctaccg ctgtgatggt gggaacaggc 3000
gtggccgctc agaacggcat cctgatcaag gggggcaagc ctctggaaat ggctcacaag 3060
atcaagaccg tgatgttcga caagaccggc accatcaccc acggcgtgcc cagagtgatg 3120
agagtgctgc tgctggggga tgtggccacc ctgcctctga gaaaggtgct ggctgtcgtg 3180
ggcacagccg aggctagctc tgaacaccca ctgggagtgg ccgtgacaaa gtactgcaaa 3240
gaggaactgg gcaccgaaac cctgggctac tgcaccgact ttcaggccgt gcctggctgt 3300
ggcatcggct gcaaggtgtc caacgtggaa ggcatcctgg cccacagcga gaggccactg 3360
tctgcccctg ccagccacct gaacgaggcc ggatctctgc ccgccgaaaa ggacgctgtg 3420
ccccagacct tctctgtgct gattggcaac agagagtggc tgcggcggaa cggcctgacc 3480
atctcctccg atgtgtccga cgccatgacc gaccacgaga tgaagggcca gaccgccatt 3540
ctggtggcca ttgacggggt gctgtgcggc atgatcgcaa tcgccgatgc cgtgaaacag 3600
gaagcagcac tggccgtgca caccctgcag tctatgggag tggatgtggt gctgatcacc 3660
ggcgacaaca gaaagaccgc cagggccatt gccacccagg tgggcatcaa caaggtgttc 3720
gccgaggtgc tgcccagcca caaagtggcc aaggtgcagg aactgcagaa caaaggcaaa 3780
aaggtggcca tggtgggaga tggcgtgaac gactctcctg ctctggccca ggcagatatg 3840
ggcgtggcca tcggcacagg caccgacgtg gcaattgagg ctgctgacgt ggtgctgatt 3900
cggaacgacc tgctggacgt ggtggcctcc atccacctgt ccaagagaac cgtgcggcgg 3960
atcagaatca acctggtgct ggcactgatc tataacctcg tgggcatccc tatcgccgct 4020
ggcgtgttca tgcctatcgg aatcgtgctg cagccctgga tgggctctgc cgccatggct 4080
gcaagctccg tgtctgtggt gctgtccagc ctgcagctga agtgctacaa gaagcccgac 4140
ctggaaagat acgaggccca ggcccacgga cacatgaagc ctctgacagc ctcccaggtg 4200
tccgtgcaca tcggcatgga cgacagatgg cgggacagcc ctagagccac cccttgggat 4260
caggtgtcat acgtgtcaca ggtgtccctg agcagcctga ccagcgacaa gcccagcaga 4320
catagcgccg ctgccgacga cgatggggac aagtggtccc tgctgctgaa cggccgggat 4380
gaggaacagt acatc 4395
<210> 2
<211> 1465
<212> PRT
<213> 智人(Homo sapiens)
<400> 2
Met Pro Glu Gln Glu Arg Gln Ile Thr Ala Arg Glu Gly Ala Ser Arg
1 5 10 15
Lys Ile Leu Ser Lys Leu Ser Leu Pro Thr Arg Ala Trp Glu Pro Ala
20 25 30
Met Lys Lys Ser Phe Ala Phe Asp Asn Val Gly Tyr Glu Gly Gly Leu
35 40 45
Asp Gly Leu Gly Pro Ser Ser Gln Val Ala Thr Ser Thr Val Arg Ile
50 55 60
Leu Gly Met Thr Cys Gln Ser Cys Val Lys Ser Ile Glu Asp Arg Ile
65 70 75 80
Ser Asn Leu Lys Gly Ile Ile Ser Met Lys Val Ser Leu Glu Gln Gly
85 90 95
Ser Ala Thr Val Lys Tyr Val Pro Ser Val Val Cys Leu Gln Gln Val
100 105 110
Cys His Gln Ile Gly Asp Met Gly Phe Glu Ala Ser Ile Ala Glu Gly
115 120 125
Lys Ala Ala Ser Trp Pro Ser Arg Ser Leu Pro Ala Gln Glu Ala Val
130 135 140
Val Lys Leu Arg Val Glu Gly Met Thr Cys Gln Ser Cys Val Ser Ser
145 150 155 160
Ile Glu Gly Lys Val Arg Lys Leu Gln Gly Val Val Arg Val Lys Val
165 170 175
Ser Leu Ser Asn Gln Glu Ala Val Ile Thr Tyr Gln Pro Tyr Leu Ile
180 185 190
Gln Pro Glu Asp Leu Arg Asp His Val Asn Asp Met Gly Phe Glu Ala
195 200 205
Ala Ile Lys Ser Lys Val Ala Pro Leu Ser Leu Gly Pro Ile Asp Ile
210 215 220
Glu Arg Leu Gln Ser Thr Asn Pro Lys Arg Pro Leu Ser Ser Ala Asn
225 230 235 240
Gln Asn Phe Asn Asn Ser Glu Thr Leu Gly His Gln Gly Ser His Val
245 250 255
Val Thr Leu Gln Leu Arg Ile Asp Gly Met His Cys Lys Ser Cys Val
260 265 270
Leu Asn Ile Glu Glu Asn Ile Gly Gln Leu Leu Gly Val Gln Ser Ile
275 280 285
Gln Val Ser Leu Glu Asn Lys Thr Ala Gln Val Lys Tyr Asp Pro Ser
290 295 300
Cys Thr Ser Pro Val Ala Leu Gln Arg Ala Ile Glu Ala Leu Pro Pro
305 310 315 320
Gly Asn Phe Lys Val Ser Leu Pro Asp Gly Ala Glu Gly Ser Gly Thr
325 330 335
Asp His Arg Ser Ser Ser Ser His Ser Pro Gly Ser Pro Pro Arg Asn
340 345 350
Gln Val Gln Gly Thr Cys Ser Thr Thr Leu Ile Ala Ile Ala Gly Met
355 360 365
Thr Cys Ala Ser Cys Val His Ser Ile Glu Gly Met Ile Ser Gln Leu
370 375 380
Glu Gly Val Gln Gln Ile Ser Val Ser Leu Ala Glu Gly Thr Ala Thr
385 390 395 400
Val Leu Tyr Asn Pro Ser Val Ile Ser Pro Glu Glu Leu Arg Ala Ala
405 410 415
Ile Glu Asp Met Gly Phe Glu Ala Ser Val Val Ser Glu Ser Cys Ser
420 425 430
Thr Asn Pro Leu Gly Asn His Ser Ala Gly Asn Ser Met Val Gln Thr
435 440 445
Thr Asp Gly Thr Pro Thr Ser Val Gln Glu Val Ala Pro His Thr Gly
450 455 460
Arg Leu Pro Ala Asn His Ala Pro Asp Ile Leu Ala Lys Ser Pro Gln
465 470 475 480
Ser Thr Arg Ala Val Ala Pro Gln Lys Cys Phe Leu Gln Ile Lys Gly
485 490 495
Met Thr Cys Ala Ser Cys Val Ser Asn Ile Glu Arg Asn Leu Gln Lys
500 505 510
Glu Ala Gly Val Leu Ser Val Leu Val Ala Leu Met Ala Gly Lys Ala
515 520 525
Glu Ile Lys Tyr Asp Pro Glu Val Ile Gln Pro Leu Glu Ile Ala Gln
530 535 540
Phe Ile Gln Asp Leu Gly Phe Glu Ala Ala Val Met Glu Asp Tyr Ala
545 550 555 560
Gly Ser Asp Gly Asn Ile Glu Leu Thr Ile Thr Gly Met Thr Cys Ala
565 570 575
Ser Cys Val His Asn Ile Glu Ser Lys Leu Thr Arg Thr Asn Gly Ile
580 585 590
Thr Tyr Ala Ser Val Ala Leu Ala Thr Ser Lys Ala Leu Val Lys Phe
595 600 605
Asp Pro Glu Ile Ile Gly Pro Arg Asp Ile Ile Lys Ile Ile Glu Glu
610 615 620
Ile Gly Phe His Ala Ser Leu Ala Gln Arg Asn Pro Asn Ala His His
625 630 635 640
Leu Asp His Lys Met Glu Ile Lys Gln Trp Lys Lys Ser Phe Leu Cys
645 650 655
Ser Leu Val Phe Gly Ile Pro Val Met Ala Leu Met Ile Tyr Met Leu
660 665 670
Ile Pro Ser Asn Glu Pro His Gln Ser Met Val Leu Asp His Asn Ile
675 680 685
Ile Pro Gly Leu Ser Ile Leu Asn Leu Ile Phe Phe Ile Leu Cys Thr
690 695 700
Phe Val Gln Leu Leu Gly Gly Trp Tyr Phe Tyr Val Gln Ala Tyr Lys
705 710 715 720
Ser Leu Arg His Arg Ser Ala Asn Met Asp Val Leu Ile Val Leu Ala
725 730 735
Thr Ser Ile Ala Tyr Val Tyr Ser Leu Val Ile Leu Val Val Ala Val
740 745 750
Ala Glu Lys Ala Glu Arg Ser Pro Val Thr Phe Phe Asp Thr Pro Pro
755 760 765
Met Leu Phe Val Phe Ile Ala Leu Gly Arg Trp Leu Glu His Leu Ala
770 775 780
Lys Ser Lys Thr Ser Glu Ala Leu Ala Lys Leu Met Ser Leu Gln Ala
785 790 795 800
Thr Glu Ala Thr Val Val Thr Leu Gly Glu Asp Asn Leu Ile Ile Arg
805 810 815
Glu Glu Gln Val Pro Met Glu Leu Val Gln Arg Gly Asp Ile Val Lys
820 825 830
Val Val Pro Gly Gly Lys Phe Pro Val Asp Gly Lys Val Leu Glu Gly
835 840 845
Asn Thr Met Ala Asp Glu Ser Leu Ile Thr Gly Glu Ala Met Pro Val
850 855 860
Thr Lys Lys Pro Gly Ser Thr Val Ile Ala Gly Ser Ile Asn Ala His
865 870 875 880
Gly Ser Val Leu Ile Lys Ala Thr His Val Gly Asn Asp Thr Thr Leu
885 890 895
Ala Gln Ile Val Lys Leu Val Glu Glu Ala Gln Met Ser Lys Ala Pro
900 905 910
Ile Gln Gln Leu Ala Asp Arg Phe Ser Gly Tyr Phe Val Pro Phe Ile
915 920 925
Ile Ile Met Ser Thr Leu Thr Leu Val Val Trp Ile Val Ile Gly Phe
930 935 940
Ile Asp Phe Gly Val Val Gln Arg Tyr Phe Pro Asn Pro Asn Lys His
945 950 955 960
Ile Ser Gln Thr Glu Val Ile Ile Arg Phe Ala Phe Gln Thr Ser Ile
965 970 975
Thr Val Leu Cys Ile Ala Cys Pro Cys Ser Leu Gly Leu Ala Thr Pro
980 985 990
Thr Ala Val Met Val Gly Thr Gly Val Ala Ala Gln Asn Gly Ile Leu
995 1000 1005
Ile Lys Gly Gly Lys Pro Leu Glu Met Ala His Lys Ile Lys Thr
1010 1015 1020
Val Met Phe Asp Lys Thr Gly Thr Ile Thr His Gly Val Pro Arg
1025 1030 1035
Val Met Arg Val Leu Leu Leu Gly Asp Val Ala Thr Leu Pro Leu
1040 1045 1050
Arg Lys Val Leu Ala Val Val Gly Thr Ala Glu Ala Ser Ser Glu
1055 1060 1065
His Pro Leu Gly Val Ala Val Thr Lys Tyr Cys Lys Glu Glu Leu
1070 1075 1080
Gly Thr Glu Thr Leu Gly Tyr Cys Thr Asp Phe Gln Ala Val Pro
1085 1090 1095
Gly Cys Gly Ile Gly Cys Lys Val Ser Asn Val Glu Gly Ile Leu
1100 1105 1110
Ala His Ser Glu Arg Pro Leu Ser Ala Pro Ala Ser His Leu Asn
1115 1120 1125
Glu Ala Gly Ser Leu Pro Ala Glu Lys Asp Ala Val Pro Gln Thr
1130 1135 1140
Phe Ser Val Leu Ile Gly Asn Arg Glu Trp Leu Arg Arg Asn Gly
1145 1150 1155
Leu Thr Ile Ser Ser Asp Val Ser Asp Ala Met Thr Asp His Glu
1160 1165 1170
Met Lys Gly Gln Thr Ala Ile Leu Val Ala Ile Asp Gly Val Leu
1175 1180 1185
Cys Gly Met Ile Ala Ile Ala Asp Ala Val Lys Gln Glu Ala Ala
1190 1195 1200
Leu Ala Val His Thr Leu Gln Ser Met Gly Val Asp Val Val Leu
1205 1210 1215
Ile Thr Gly Asp Asn Arg Lys Thr Ala Arg Ala Ile Ala Thr Gln
1220 1225 1230
Val Gly Ile Asn Lys Val Phe Ala Glu Val Leu Pro Ser His Lys
1235 1240 1245
Val Ala Lys Val Gln Glu Leu Gln Asn Lys Gly Lys Lys Val Ala
1250 1255 1260
Met Val Gly Asp Gly Val Asn Asp Ser Pro Ala Leu Ala Gln Ala
1265 1270 1275
Asp Met Gly Val Ala Ile Gly Thr Gly Thr Asp Val Ala Ile Glu
1280 1285 1290
Ala Ala Asp Val Val Leu Ile Arg Asn Asp Leu Leu Asp Val Val
1295 1300 1305
Ala Ser Ile His Leu Ser Lys Arg Thr Val Arg Arg Ile Arg Ile
1310 1315 1320
Asn Leu Val Leu Ala Leu Ile Tyr Asn Leu Val Gly Ile Pro Ile
1325 1330 1335
Ala Ala Gly Val Phe Met Pro Ile Gly Ile Val Leu Gln Pro Trp
1340 1345 1350
Met Gly Ser Ala Ala Met Ala Ala Ser Ser Val Ser Val Val Leu
1355 1360 1365
Ser Ser Leu Gln Leu Lys Cys Tyr Lys Lys Pro Asp Leu Glu Arg
1370 1375 1380
Tyr Glu Ala Gln Ala His Gly His Met Lys Pro Leu Thr Ala Ser
1385 1390 1395
Gln Val Ser Val His Ile Gly Met Asp Asp Arg Trp Arg Asp Ser
1400 1405 1410
Pro Arg Ala Thr Pro Trp Asp Gln Val Ser Tyr Val Ser Gln Val
1415 1420 1425
Ser Leu Ser Ser Leu Thr Ser Asp Lys Pro Ser Arg His Ser Ala
1430 1435 1440
Ala Ala Asp Asp Asp Gly Asp Lys Trp Ser Leu Leu Leu Asn Gly
1445 1450 1455
Arg Asp Glu Glu Gln Tyr Ile
1460 1465
<210> 3
<211> 4395
<212> DNA
<213> 智人(Homo sapiens)
<400> 3
atgcctgagc aggagagaca gatcacagcc agagaagggg ccagtcggaa aatcttatct 60
aagctttctt tgcctacccg tgcctgggaa ccagcaatga agaagagttt tgcttttgac 120
aatgttggct atgaaggtgg tctggatggc ctgggccctt cttctcaggt ggccaccagc 180
acagtcagga tcttgggcat gacttgccag tcatgtgtga agtccattga ggacaggatt 240
tccaatttga aaggcatcat cagcatgaag gtttccctgg aacaaggcag tgccactgtg 300
aaatatgtgc catcggttgt gtgcctgcaa caggtttgcc atcaaattgg ggacatgggc 360
ttcgaggcca gcattgcaga aggaaaggca gcctcctggc cctcaaggtc cttgcctgcc 420
caggaggctg tggtcaagct ccgggtggag ggcatgacct gccagtcctg tgtcagctcc 480
attgaaggca aggtccggaa actgcaagga gtagtgagag tcaaagtctc actcagcaac 540
caagaggccg tcatcactta tcagccttat ctcattcagc ccgaagacct cagggaccat 600
gtaaatgaca tgggatttga agctgccatc aagagcaaag tggctccctt aagcctggga 660
ccaattgata ttgagcggtt acaaagcact aacccaaaga gacctttatc ttctgctaac 720
cagaatttta ataattctga gaccttgggg caccaaggaa gccatgtggt caccctccaa 780
ctgagaatag atggaatgca ttgtaagtct tgcgtcttga atattgaaga aaatattggc 840
cagctcctag gggttcaaag tattcaagtg tccttggaga acaaaactgc ccaagtaaag 900
tatgaccctt cttgtaccag cccagtggct ctgcagaggg ctatcgaggc acttccacct 960
gggaatttta aagtttctct tcctgatgga gccgaaggga gtgggacaga tcacaggtct 1020
tccagttctc attcccctgg ctccccaccg agaaaccagg tccagggcac atgcagtacc 1080
actctgattg ccattgccgg catgacctgt gcatcctgtg tccattccat tgaaggcatg 1140
atctcccaac tggaaggggt gcagcaaata tcggtgtctt tggccgaagg gactgcaaca 1200
gttctttata atccctctgt aattagccca gaagaactca gagctgctat agaagacatg 1260
ggatttgagg cttcagtcgt ttctgaaagc tgttctacta accctcttgg aaaccacagt 1320
gctgggaatt ccatggtgca aactacagat ggtacaccta catctgtgca ggaagtggct 1380
ccccacactg ggaggctccc tgcaaaccat gccccggaca tcttggcaaa gtccccacaa 1440
tcaaccagag cagtggcacc gcagaagtgc ttcttacaga tcaaaggcat gacctgtgca 1500
tcctgtgtgt ctaacataga aaggaatctg cagaaagaag ctggtgttct ctccgtgttg 1560
gttgccttga tggcaggaaa ggcagagatc aagtatgacc cagaggtcat ccagcccctc 1620
gagatagctc agttcatcca ggacctgggt tttgaggcag cagtcatgga ggactacgca 1680
ggctccgatg gcaacattga gctgacaatc acagggatga cctgcgcgtc ctgtgtccac 1740
aacatagagt ccaaactcac gaggacaaat ggcatcactt atgcctccgt tgcccttgcc 1800
accagcaaag cccttgttaa gtttgacccg gaaattatcg gtccacggga tattatcaaa 1860
attattgagg aaattggctt tcatgcttcc ctggcccaga gaaaccccaa cgctcatcac 1920
ttggaccaca agatggaaat aaagcagtgg aagaagtctt tcctgtgcag cctggtgttt 1980
ggcatccctg tcatggcctt aatgatctat atgctgatac ccagcaacga gccccaccag 2040
tccatggtcc tggaccacaa catcattcca ggactgtcca ttctaaatct catcttcttt 2100
atcttgtgta cctttgtcca gctcctcggt gggtggtact tctacgttca ggcctacaaa 2160
tctctgagac acaggtcagc caacatggac gtgctcatcg tcctggccac aagcattgct 2220
tatgtttatt ctctggtcat cctggtggtt gctgtggctg agaaggcgga gaggagccct 2280
gtgacattct tcgacacgcc ccccatgctc tttgtgttca ttgccctggg ccggtggctg 2340
gaacacttgg caaagagcaa aacctcagaa gccctggcta aactcatgtc tctccaagcc 2400
acagaagcca ccgttgtgac ccttggtgag gacaatttaa tcatcaggga ggagcaagtc 2460
cccatggagc tggtgcagcg gggcgatatc gtcaaggtgg tccctggggg aaagtttcca 2520
gtggatggga aagtcctgga aggcaatacc atggctgatg agtccctcat cacaggagaa 2580
gccatgccag tcactaagaa acccggaagc actgtaattg cggggtctat aaatgcacat 2640
ggctctgtgc tcattaaagc tacccacgtg ggcaatgaca ccactttggc tcagattgtg 2700
aaactggtgg aagaggctca gatgtcaaag gcacccattc agcagctggc tgaccggttt 2760
agtggatatt ttgtcccatt tatcatcatc atgtcaactt tgacgttggt ggtatggatt 2820
gtaatcggtt ttatcgattt tggtgttgtt cagagatact ttcctaaccc caacaagcac 2880
atctcccaga cagaggtgat catccggttt gctttccaga cgtccatcac ggtgctgtgc 2940
attgcctgcc cctgctccct ggggctggcc acgcccacgg ctgtcatggt gggcaccggg 3000
gtggccgcgc agaacggcat cctcatcaag ggaggcaagc ccctggagat ggcgcacaag 3060
ataaagactg tgatgtttga caagactggc accattaccc atggcgtccc cagggtcatg 3120
cgggtgctcc tgctggggga tgtggccaca ctgcccctca ggaaggttct ggctgtggtg 3180
gggactgcgg aggccagcag tgaacacccc ttgggcgtgg cagtcaccaa atactgtaaa 3240
gaggaacttg gaacagagac cttgggatac tgcacggact tccaggcagt gccaggctgt 3300
ggaattgggt gcaaagtcag caacgtggaa ggcatcctgg cccacagtga gcgccctttg 3360
agtgcaccgg ccagtcacct gaatgaggct ggcagccttc ccgcagaaaa agatgcagtc 3420
ccccagacct tctctgtgct gattggaaac cgtgagtggc tgaggcgcaa cggtttaacc 3480
atttctagcg atgtcagtga cgctatgaca gaccacgaga tgaaaggaca gacagccatc 3540
ctggtggcta ttgacggtgt gctctgtggg atgatcgcaa tcgcagacgc tgtcaagcag 3600
gaggctgccc tggctgtgca cacgctgcag agcatgggtg tggacgtggt tctgatcacg 3660
ggggacaacc ggaagacagc cagagctatt gccacccagg ttggcatcaa caaagtcttt 3720
gcagaggtgc tgccttcgca caaggtggcc aaggtccagg agctccagaa taaagggaag 3780
aaagtcgcca tggtggggga tggggtcaat gactccccgg ccttggccca ggcagacatg 3840
ggtgtggcca ttggcaccgg cacggatgtg gccatcgagg cagccgacgt cgtccttatc 3900
agaaatgatt tgctggatgt ggtggctagc attcaccttt ccaagaggac tgtccgaagg 3960
atacgcatca acctggtcct ggcactgatt tataacctgg ttgggatacc cattgcagca 4020
ggtgtcttca tgcccatcgg cattgtgctg cagccctgga tgggctcagc ggccatggca 4080
gcctcctctg tgtctgtggt gctctcatcc ctgcagctca agtgctataa gaagcctgac 4140
ctggagaggt atgaggcaca ggcgcatggc cacatgaagc ccctgacggc atcccaggtc 4200
agtgtgcaca taggcatgga tgacaggtgg cgggactccc ccagggccac accatgggac 4260
caggtcagct atgtcagcca ggtgtcgctg tcctccctga cgtccgacaa gccatctcgg 4320
cacagcgctg cagcagacga tgatggggac aagtggtctc tgctcctgaa tggcagggat 4380
gaggagcagt acatc 4395
<210> 4
<211> 34
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 4
tgtttgctgc ttgcaatgtt tgcccatttt aggg 34
<210> 5
<211> 100
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 5
ctacctcgtg atcgcccggc ccctgttcaa acatgtccta atactctgtc tctgcaaggg 60
tcatcagtag ttttccatct tactcaacat cctcccagtg 100
<210> 6
<211> 42
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 6
aggttaattt ttaaactgtt tgctctggtt aataatctca gg 42
<210> 7
<211> 322
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 7
aaggctcaga ggcacacagg agtttctggg ctcaccctgc ccccttccaa cccctcagtt 60
cccatcctcc agcagctgtt tgtgtgctgc ctctgaagtc cacactgaac aaacttcagc 120
ctactcatgt ccctaaaatg ggcaaacatt gcaagcagca aacagcaaac acacagccct 180
ccctgcctgc tgaccttgga gctggggcag aggtcagaga cctctctggg cccatgccac 240
ctccaacatc cactcgaccc cttggaattt cggtggagag gagcagaggt tgtcctggcg 300
tggtttaggt agtgtgagag gg 322
<210> 8
<211> 178
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 8
actcaaagtt caaaccttat cattttttgc tttgttcctc ttggccttgg ttttgtacat 60
cagctttgaa aataccatcc cagggttaat gctggggtta atttataact aagagtgctc 120
tagttttgca atacaggaca tgctataaaa atggaaagat gttgctttct gagagaca 178
<210> 9
<211> 477
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 9
agggctggaa gctacctttg acatcatttc ctctgcgaat gcatgtataa tttctacaga 60
acctattaga aaggatcacc cagcctctgc ttttgtacaa ctttccctta aaaaactgcc 120
aattccactg ctgtttggcc caatagtgag aactttttcc tgctgcctct tggtgctttt 180
gcctatggcc cctattctgc ctgctgaaga cactcttgcc agcatggact taaacccctc 240
cagctctgac aatcctcttt ctcttttgtt ttacatgaag ggtctggcag ccaaagcaat 300
cactcaaagt tcaaacctta tcattttttg ctttgttcct cttggccttg gttttgtaca 360
tcagctttga aaataccatc ccagggttaa tgctggggtt aatttataac taagagtgct 420
ctagttttgc aatacaggac atgctataaa aatggaaaga tgttgctttc tgagaga 477
<210> 10
<211> 218
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 10
tggacacagg acgctgtggt ttctgagcca gggggcgact cagatcccag ccagtggact 60
tagcccctgt ttgctcctcc gataactggg gtgaccttgg ttaatattca ccagcagcct 120
cccccgttgc ccctctggat ccactgctta aatacggacg aggacagggc cctgtctcct 180
cagcttcagg caccaccact gacctgggac agtgaata 218
<210> 11
<211> 190
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 11
atttcataga acgaatgttc cgatgctcta atctctctag acaaggttca tatttgtatg 60
ggttacttat tctctctttg ttgactaagt caataatcag aatcagcagg tttgcagtca 120
gattggcagg gataagcagc ctagctcagg agaagtgagt ataaaagccc caggctggga 180
gcagccatca 190
<210> 12
<211> 215
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 12
gcctcgactg tgccttctag ttgccagcca tctgttgttt gcccctcccc cgtgccttcc 60
ttgaccctgg aaggtgccac tcccactgtc ctttcctaat aaaatgagga aattgcatcg 120
cattgtctga gtaggtgtca ttctattctg gggggtgggg tggggcagga cagcaagggg 180
gaggattggg aagacaatag caggcatgct gggga 215
<210> 13
<211> 75
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 13
aataaagtct gagtgggcgg cagcctgtgt gtgcctgggt tctctctgtc ccggaatgtg 60
caaacaatgg aggtg 75
<210> 14
<211> 168
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 14
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctacg 168
<210> 15
<211> 168
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 15
cgtagataag tagcatggcg ggttaatcat taactacaag gaacccctag tgatggagtt 60
ggccactccc tctctgcgcg ctcgctcgct cactgaggcc gggcgaccaa aggtcgcccg 120
acgcccgggc tttgcccggg cggcctcagt gagcgagcga gcgcgcag 168
<210> 16
<211> 738
<212> PRT
<213> 腺相关病毒8 (adeno-associated virus 8)
<400> 16
Met Ala Ala Asp Gly Tyr Leu Pro Asp Trp Leu Glu Asp Asn Leu Ser
1 5 10 15
Glu Gly Ile Arg Glu Trp Trp Ala Leu Lys Pro Gly Ala Pro Lys Pro
20 25 30
Lys Ala Asn Gln Gln Lys Gln Asp Asp Gly Arg Gly Leu Val Leu Pro
35 40 45
Gly Tyr Lys Tyr Leu Gly Pro Phe Asn Gly Leu Asp Lys Gly Glu Pro
50 55 60
Val Asn Ala Ala Asp Ala Ala Ala Leu Glu His Asp Lys Ala Tyr Asp
65 70 75 80
Gln Gln Leu Gln Ala Gly Asp Asn Pro Tyr Leu Arg Tyr Asn His Ala
85 90 95
Asp Ala Glu Phe Gln Glu Arg Leu Gln Glu Asp Thr Ser Phe Gly Gly
100 105 110
Asn Leu Gly Arg Ala Val Phe Gln Ala Lys Lys Arg Val Leu Glu Pro
115 120 125
Leu Gly Leu Val Glu Glu Gly Ala Lys Thr Ala Pro Gly Lys Lys Arg
130 135 140
Pro Val Glu Pro Ser Pro Gln Arg Ser Pro Asp Ser Ser Thr Gly Ile
145 150 155 160
Gly Lys Lys Gly Gln Gln Pro Ala Arg Lys Arg Leu Asn Phe Gly Gln
165 170 175
Thr Gly Asp Ser Glu Ser Val Pro Asp Pro Gln Pro Leu Gly Glu Pro
180 185 190
Pro Ala Ala Pro Ser Gly Val Gly Pro Asn Thr Met Ala Ala Gly Gly
195 200 205
Gly Ala Pro Met Ala Asp Asn Asn Glu Gly Ala Asp Gly Val Gly Ser
210 215 220
Ser Ser Gly Asn Trp His Cys Asp Ser Thr Trp Leu Gly Asp Arg Val
225 230 235 240
Ile Thr Thr Ser Thr Arg Thr Trp Ala Leu Pro Thr Tyr Asn Asn His
245 250 255
Leu Tyr Lys Gln Ile Ser Asn Gly Thr Ser Gly Gly Ala Thr Asn Asp
260 265 270
Asn Thr Tyr Phe Gly Tyr Ser Thr Pro Trp Gly Tyr Phe Asp Phe Asn
275 280 285
Arg Phe His Cys His Phe Ser Pro Arg Asp Trp Gln Arg Leu Ile Asn
290 295 300
Asn Asn Trp Gly Phe Arg Pro Lys Arg Leu Ser Phe Lys Leu Phe Asn
305 310 315 320
Ile Gln Val Lys Glu Val Thr Gln Asn Glu Gly Thr Lys Thr Ile Ala
325 330 335
Asn Asn Leu Thr Ser Thr Ile Gln Val Phe Thr Asp Ser Glu Tyr Gln
340 345 350
Leu Pro Tyr Val Leu Gly Ser Ala His Gln Gly Cys Leu Pro Pro Phe
355 360 365
Pro Ala Asp Val Phe Met Ile Pro Gln Tyr Gly Tyr Leu Thr Leu Asn
370 375 380
Asn Gly Ser Gln Ala Val Gly Arg Ser Ser Phe Tyr Cys Leu Glu Tyr
385 390 395 400
Phe Pro Ser Gln Met Leu Arg Thr Gly Asn Asn Phe Gln Phe Thr Tyr
405 410 415
Thr Phe Glu Asp Val Pro Phe His Ser Ser Tyr Ala His Ser Gln Ser
420 425 430
Leu Asp Arg Leu Met Asn Pro Leu Ile Asp Gln Tyr Leu Tyr Tyr Leu
435 440 445
Ser Arg Thr Gln Thr Thr Gly Gly Thr Ala Asn Thr Gln Thr Leu Gly
450 455 460
Phe Ser Gln Gly Gly Pro Asn Thr Met Ala Asn Gln Ala Lys Asn Trp
465 470 475 480
Leu Pro Gly Pro Cys Tyr Arg Gln Gln Arg Val Ser Thr Thr Thr Gly
485 490 495
Gln Asn Asn Asn Ser Asn Phe Ala Trp Thr Ala Gly Thr Lys Tyr His
500 505 510
Leu Asn Gly Arg Asn Ser Leu Ala Asn Pro Gly Ile Ala Met Ala Thr
515 520 525
His Lys Asp Asp Glu Glu Arg Phe Phe Pro Ser Asn Gly Ile Leu Ile
530 535 540
Phe Gly Lys Gln Asn Ala Ala Arg Asp Asn Ala Asp Tyr Ser Asp Val
545 550 555 560
Met Leu Thr Ser Glu Glu Glu Ile Lys Thr Thr Asn Pro Val Ala Thr
565 570 575
Glu Glu Tyr Gly Ile Val Ala Asp Asn Leu Gln Gln Gln Asn Thr Ala
580 585 590
Pro Gln Ile Gly Thr Val Asn Ser Gln Gly Ala Leu Pro Gly Met Val
595 600 605
Trp Gln Asn Arg Asp Val Tyr Leu Gln Gly Pro Ile Trp Ala Lys Ile
610 615 620
Pro His Thr Asp Gly Asn Phe His Pro Ser Pro Leu Met Gly Gly Phe
625 630 635 640
Gly Leu Lys His Pro Pro Pro Gln Ile Leu Ile Lys Asn Thr Pro Val
645 650 655
Pro Ala Asp Pro Pro Thr Thr Phe Asn Gln Ser Lys Leu Asn Ser Phe
660 665 670
Ile Thr Gln Tyr Ser Thr Gly Gln Val Ser Val Glu Ile Glu Trp Glu
675 680 685
Leu Gln Lys Glu Asn Ser Lys Arg Trp Asn Pro Glu Ile Gln Tyr Thr
690 695 700
Ser Asn Tyr Tyr Lys Ser Thr Ser Val Asp Phe Ala Val Asn Thr Glu
705 710 715 720
Gly Val Tyr Ser Glu Pro Arg Pro Ile Gly Thr Arg Tyr Leu Thr Arg
725 730 735
Asn Leu
<210> 17
<211> 3966
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 17
atgcccgagc aggaaagaca gatcaccgcc agagagggcg ccagccggaa gatcctgagc 60
aagctgagcc tgcccaccag agcctgggag cccgccatga agaagtcctt cgccttcgac 120
aacgtgggct acgagggcgg cctggacgga ctgggaccat cttctcaggt ggccacaagc 180
accgtgcgcg aggccgccat caagagcaag gtggcccctc tgtctctggg ccccatcgac 240
atcgagagac tgcagagcac caaccccaag cggcctctga gcagcgccaa ccagaacttc 300
aacaacagcg agacactggg ccaccagggc agccacgtcg tgacactgca gctgcggatc 360
gacggaatgc actgcaagag ctgtgtgctg aacatcgagg aaaacatcgg ccagctgctg 420
ggagtgcaga gcatccaggt gtcactggaa aacaagaccg cccaggtgaa gtacgacccc 480
agctgcacaa gccccgtggc cctgcagaga gccattgaag ctctgccccc tggcaacttc 540
aaagtgtccc tgcctgacgg agccgagggc tccggaacag atcacagaag cagcagcagc 600
cacagccctg gcagcccccc tagaaatcag gtgcagggca cctgtagcac caccctgatc 660
gccattgccg gcatgacatg cgccagctgc gtgcactcta ttgagggcat gatctcccag 720
ctggaaggcg tgcagcagat cagtgtgtct ctggccgagg gcaccgccac agtgctgtac 780
aaccctagcg tgatcagccc cgaagaactg agagccgcca ttgaggacat gggattcgaa 840
gccagcgtgg tgtccgagag ctgctccacc aaccctctgg gcaatcacag cgccggcaac 900
agcatggtgc agaccaccga cggcaccccc accagcgtgc aggaagtggc cccacataca 960
ggcagactgc ccgccaatca cgcccccgat atcctggcca agagccccca gagtacaaga 1020
gccgtggccc cccagaagtg cttcctgcag atcaagggca tgacttgtgc ctcttgtgtg 1080
tccaatatcg agcggaacct gcagaaagag gccggcgtgc tgtctgtgct ggtggctctg 1140
atggccggca aggccgagat caaatacgac cccgaagtga ttcagcccct ggaaatcgcc 1200
cagtttatcc aggacctggg ctttgaagcc gccgtgatgg aagattacgc cggctccgac 1260
ggcaacatcg agctgaccat caccggaatg acctgcgcct cctgtgtgca caacattgag 1320
tccaagctga cccggaccaa cggcatcacc tacgcctctg tggctctggc cacctccaag 1380
gccctcgtga agttcgatcc cgagatcatc ggccccaggg acatcatcaa gatcatcgaa 1440
gagatcggct tccacgccag cctggcccag aggaacccta acgcccacca cctggaccac 1500
aagatggaaa tcaagcagtg gaagaaaagc ttcctgtgca gcctggtgtt cggcatcccc 1560
gtgatggccc tgatgatcta catgctgatc cccagcaacg agccccacca gtccatggtg 1620
ctggatcaca acatcatccc cggcctgtct atcctgaacc tgatcttctt catcctgtgc 1680
accttcgtgc agctgctggg cggctggtac ttctacgtgc aggcctacaa gtccctgcgg 1740
cacagatccg ccaacatgga cgtgctgatc gtgctggcca catctatcgc ctacgtgtac 1800
tccctcgtga tcctggtggt ggccgtggcc gagaaagccg agagaagccc tgtgaccttc 1860
ttcgacaccc cccctatgct gttcgtgttt atcgccctgg gccggtggct ggaacacctg 1920
gccaaaagca agaccagcga ggccctggct aagctgatga gtctgcaggc caccgaggcc 1980
acagtcgtga ccctgggcga ggacaacctg atcatccgcg aggaacaggt gccaatggaa 2040
ctggtgcagc ggggcgacat cgtgaaggtg gtgcctggcg gcaagttccc cgtggacgga 2100
aaagtgctgg aagggaatac catggccgac gagagcctga tcacaggcga ggccatgccc 2160
gtgaccaaga aacctggcag cacagtgatc gccggcagca tcaatgccca cggcagcgtg 2220
ctgattaagg ccacacacgt gggcaacgat accaccctgg ctcagattgt gaagctggtg 2280
gaagaggccc agatgagcaa ggcccccatt cagcagctgg ctgaccggtt cagcggctac 2340
ttcgtgccct ttatcatcat catgagcacc ctgacactgg tcgtgtggat cgtgatcggc 2400
tttatcgact tcggagtggt gcagagatac ttccccaacc ctaacaagca catcagccag 2460
acagaagtga tcatcagatt cgcctttcag accagcatca ccgtgctgtg tatcgcctgc 2520
ccctgtagcc tgggactggc cacacctacc gctgtgatgg tgggaacagg cgtggccgct 2580
cagaacggca tcctgatcaa ggggggcaag cctctggaaa tggctcacaa gatcaagacc 2640
gtgatgttcg acaagaccgg caccatcacc cacggcgtgc ccagagtgat gagagtgctg 2700
ctgctggggg atgtggccac cctgcctctg agaaaggtgc tggctgtcgt gggcacagcc 2760
gaggctagct ctgaacaccc actgggagtg gccgtgacaa agtactgcaa agaggaactg 2820
ggcaccgaaa ccctgggcta ctgcaccgac tttcaggccg tgcctggctg tggcatcggc 2880
tgcaaggtgt ccaacgtgga aggcatcctg gcccacagcg agaggccact gtctgcccct 2940
gccagccacc tgaacgaggc cggatctctg cccgccgaaa aggacgctgt gccccagacc 3000
ttctctgtgc tgattggcaa cagagagtgg ctgcggcgga acggcctgac catctcctcc 3060
gatgtgtccg acgccatgac cgaccacgag atgaagggcc agaccgccat tctggtggcc 3120
attgacgggg tgctgtgcgg catgatcgca atcgccgatg ccgtgaaaca ggaagcagca 3180
ctggccgtgc acaccctgca gtctatggga gtggatgtgg tgctgatcac cggcgacaac 3240
agaaagaccg ccagggccat tgccacccag gtgggcatca acaaggtgtt cgccgaggtg 3300
ctgcccagcc acaaagtggc caaggtgcag gaactgcaga acaaaggcaa aaaggtggcc 3360
atggtgggag atggcgtgaa cgactctcct gctctggccc aggcagatat gggcgtggcc 3420
atcggcacag gcaccgacgt ggcaattgag gctgctgacg tggtgctgat tcggaacgac 3480
ctgctggacg tggtggcctc catccacctg tccaagagaa ccgtgcggcg gatcagaatc 3540
aacctggtgc tggcactgat ctataacctc gtgggcatcc ctatcgccgc tggcgtgttc 3600
atgcctatcg gaatcgtgct gcagccctgg atgggctctg ccgccatggc tgcaagctcc 3660
gtgtctgtgg tgctgtccag cctgcagctg aagtgctaca agaagcccga cctggaaaga 3720
tacgaggccc aggcccacgg acacatgaag cctctgacag cctcccaggt gtccgtgcac 3780
atcggcatgg acgacagatg gcgggacagc cctagagcca ccccttggga tcaggtgtca 3840
tacgtgtcac aggtgtccct gagcagcctg accagcgaca agcccagcag acatagcgcc 3900
gctgccgacg acgatgggga caagtggtcc ctgctgctga acggccggga tgaggaacag 3960
tacatc 3966
<210> 18
<211> 3360
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 18
atgcccgagc aggaaagaca gatcaccgcc agagagggcg ccagccggaa gatcctgagc 60
aagctgagcc tgcccaccag agcctgggag cccgccatga agaagtcctt cgccttcgac 120
aacgtgggct acgagggcgg cctggacgga ctgggaccat cttctcaggt ggccacaagc 180
accgtgcgca gccccgaaga actgagagcc gccattgagg acatgggatt cgaagccagc 240
gtggtgtccg agagctgctc caccaaccct ctgggcaatc acagcgccgg caacagcatg 300
gtgcagacca ccgacggcac ccccaccagc gtgcaggaag tggccccaca tacaggcaga 360
ctgcccgcca atcacgcccc cgatatcctg gccaagagcc cccagagtac aagagccgtg 420
gccccccaga agtgcttcct gcagatcaag ggcatgactt gtgcctcttg tgtgtccaat 480
atcgagcgga acctgcagaa agaggccggc gtgctgtctg tgctggtggc tctgatggcc 540
ggcaaggccg agatcaaata cgaccccgaa gtgattcagc ccctggaaat cgcccagttt 600
atccaggacc tgggctttga agccgccgtg atggaagatt acgccggctc cgacggcaac 660
atcgagctga ccatcaccgg aatgacctgc gcctcctgtg tgcacaacat tgagtccaag 720
ctgacccgga ccaacggcat cacctacgcc tctgtggctc tggccacctc caaggccctc 780
gtgaagttcg atcccgagat catcggcccc agggacatca tcaagatcat cgaagagatc 840
ggcttccacg ccagcctggc ccagaggaac cctaacgccc accacctgga ccacaagatg 900
gaaatcaagc agtggaagaa aagcttcctg tgcagcctgg tgttcggcat ccccgtgatg 960
gccctgatga tctacatgct gatccccagc aacgagcccc accagtccat ggtgctggat 1020
cacaacatca tccccggcct gtctatcctg aacctgatct tcttcatcct gtgcaccttc 1080
gtgcagctgc tgggcggctg gtacttctac gtgcaggcct acaagtccct gcggcacaga 1140
tccgccaaca tggacgtgct gatcgtgctg gccacatcta tcgcctacgt gtactccctc 1200
gtgatcctgg tggtggccgt ggccgagaaa gccgagagaa gccctgtgac cttcttcgac 1260
acccccccta tgctgttcgt gtttatcgcc ctgggccggt ggctggaaca cctggccaaa 1320
agcaagacca gcgaggccct ggctaagctg atgagtctgc aggccaccga ggccacagtc 1380
gtgaccctgg gcgaggacaa cctgatcatc cgcgaggaac aggtgccaat ggaactggtg 1440
cagcggggcg acatcgtgaa ggtggtgcct ggcggcaagt tccccgtgga cggaaaagtg 1500
ctggaaggga ataccatggc cgacgagagc ctgatcacag gcgaggccat gcccgtgacc 1560
aagaaacctg gcagcacagt gatcgccggc agcatcaatg cccacggcag cgtgctgatt 1620
aaggccacac acgtgggcaa cgataccacc ctggctcaga ttgtgaagct ggtggaagag 1680
gcccagatga gcaaggcccc cattcagcag ctggctgacc ggttcagcgg ctacttcgtg 1740
ccctttatca tcatcatgag caccctgaca ctggtcgtgt ggatcgtgat cggctttatc 1800
gacttcggag tggtgcagag atacttcccc aaccctaaca agcacatcag ccagacagaa 1860
gtgatcatca gattcgcctt tcagaccagc atcaccgtgc tgtgtatcgc ctgcccctgt 1920
agcctgggac tggccacacc taccgctgtg atggtgggaa caggcgtggc cgctcagaac 1980
ggcatcctga tcaagggggg caagcctctg gaaatggctc acaagatcaa gaccgtgatg 2040
ttcgacaaga ccggcaccat cacccacggc gtgcccagag tgatgagagt gctgctgctg 2100
ggggatgtgg ccaccctgcc tctgagaaag gtgctggctg tcgtgggcac agccgaggct 2160
agctctgaac acccactggg agtggccgtg acaaagtact gcaaagagga actgggcacc 2220
gaaaccctgg gctactgcac cgactttcag gccgtgcctg gctgtggcat cggctgcaag 2280
gtgtccaacg tggaaggcat cctggcccac agcgagaggc cactgtctgc ccctgccagc 2340
cacctgaacg aggccggatc tctgcccgcc gaaaaggacg ctgtgcccca gaccttctct 2400
gtgctgattg gcaacagaga gtggctgcgg cggaacggcc tgaccatctc ctccgatgtg 2460
tccgacgcca tgaccgacca cgagatgaag ggccagaccg ccattctggt ggccattgac 2520
ggggtgctgt gcggcatgat cgcaatcgcc gatgccgtga aacaggaagc agcactggcc 2580
gtgcacaccc tgcagtctat gggagtggat gtggtgctga tcaccggcga caacagaaag 2640
accgccaggg ccattgccac ccaggtgggc atcaacaagg tgttcgccga ggtgctgccc 2700
agccacaaag tggccaaggt gcaggaactg cagaacaaag gcaaaaaggt ggccatggtg 2760
ggagatggcg tgaacgactc tcctgctctg gcccaggcag atatgggcgt ggccatcggc 2820
acaggcaccg acgtggcaat tgaggctgct gacgtggtgc tgattcggaa cgacctgctg 2880
gacgtggtgg cctccatcca cctgtccaag agaaccgtgc ggcggatcag aatcaacctg 2940
gtgctggcac tgatctataa cctcgtgggc atccctatcg ccgctggcgt gttcatgcct 3000
atcggaatcg tgctgcagcc ctggatgggc tctgccgcca tggctgcaag ctccgtgtct 3060
gtggtgctgt ccagcctgca gctgaagtgc tacaagaagc ccgacctgga aagatacgag 3120
gcccaggccc acggacacat gaagcctctg acagcctccc aggtgtccgt gcacatcggc 3180
atggacgaca gatggcggga cagccctaga gccacccctt gggatcaggt gtcatacgtg 3240
tcacaggtgt ccctgagcag cctgaccagc gacaagccca gcagacatag cgccgctgcc 3300
gacgacgatg gggacaagtg gtccctgctg ctgaacggcc gggatgagga acagtacatc 3360
<210> 19
<211> 2967
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 19
atgcccgagc aggaaagaca gatcaccgcc agagagggcg ccagccggaa gatcctgagc 60
aagctgagcc tgcccaccag agcctgggag cccgccatga agaagtcctt cgccttcgac 120
aacgtgggct acgagggcgg cctggacgga ctgggaccat cttctcaggt ggccacaagc 180
accgtgcgcc tggaaatcgc ccagtttatc caggacctgg gctttgaagc cgccgtgatg 240
gaagattacg ccggctccga cggcaacatc gagctgacca tcaccggaat gacctgcgcc 300
tcctgtgtgc acaacattga gtccaagctg acccggacca acggcatcac ctacgcctct 360
gtggctctgg ccacctccaa ggccctcgtg aagttcgatc ccgagatcat cggccccagg 420
gacatcatca agatcatcga agagatcggc ttccacgcca gcctggccca gaggaaccct 480
aacgcccacc acctggacca caagatggaa atcaagcagt ggaagaaaag cttcctgtgc 540
agcctggtgt tcggcatccc cgtgatggcc ctgatgatct acatgctgat ccccagcaac 600
gagccccacc agtccatggt gctggatcac aacatcatcc ccggcctgtc tatcctgaac 660
ctgatcttct tcatcctgtg caccttcgtg cagctgctgg gcggctggta cttctacgtg 720
caggcctaca agtccctgcg gcacagatcc gccaacatgg acgtgctgat cgtgctggcc 780
acatctatcg cctacgtgta ctccctcgtg atcctggtgg tggccgtggc cgagaaagcc 840
gagagaagcc ctgtgacctt cttcgacacc ccccctatgc tgttcgtgtt tatcgccctg 900
ggccggtggc tggaacacct ggccaaaagc aagaccagcg aggccctggc taagctgatg 960
agtctgcagg ccaccgaggc cacagtcgtg accctgggcg aggacaacct gatcatccgc 1020
gaggaacagg tgccaatgga actggtgcag cggggcgaca tcgtgaaggt ggtgcctggc 1080
ggcaagttcc ccgtggacgg aaaagtgctg gaagggaata ccatggccga cgagagcctg 1140
atcacaggcg aggccatgcc cgtgaccaag aaacctggca gcacagtgat cgccggcagc 1200
atcaatgccc acggcagcgt gctgattaag gccacacacg tgggcaacga taccaccctg 1260
gctcagattg tgaagctggt ggaagaggcc cagatgagca aggcccccat tcagcagctg 1320
gctgaccggt tcagcggcta cttcgtgccc tttatcatca tcatgagcac cctgacactg 1380
gtcgtgtgga tcgtgatcgg ctttatcgac ttcggagtgg tgcagagata cttccccaac 1440
cctaacaagc acatcagcca gacagaagtg atcatcagat tcgcctttca gaccagcatc 1500
accgtgctgt gtatcgcctg cccctgtagc ctgggactgg ccacacctac cgctgtgatg 1560
gtgggaacag gcgtggccgc tcagaacggc atcctgatca aggggggcaa gcctctggaa 1620
atggctcaca agatcaagac cgtgatgttc gacaagaccg gcaccatcac ccacggcgtg 1680
cccagagtga tgagagtgct gctgctgggg gatgtggcca ccctgcctct gagaaaggtg 1740
ctggctgtcg tgggcacagc cgaggctagc tctgaacacc cactgggagt ggccgtgaca 1800
aagtactgca aagaggaact gggcaccgaa accctgggct actgcaccga ctttcaggcc 1860
gtgcctggct gtggcatcgg ctgcaaggtg tccaacgtgg aaggcatcct ggcccacagc 1920
gagaggccac tgtctgcccc tgccagccac ctgaacgagg ccggatctct gcccgccgaa 1980
aaggacgctg tgccccagac cttctctgtg ctgattggca acagagagtg gctgcggcgg 2040
aacggcctga ccatctcctc cgatgtgtcc gacgccatga ccgaccacga gatgaagggc 2100
cagaccgcca ttctggtggc cattgacggg gtgctgtgcg gcatgatcgc aatcgccgat 2160
gccgtgaaac aggaagcagc actggccgtg cacaccctgc agtctatggg agtggatgtg 2220
gtgctgatca ccggcgacaa cagaaagacc gccagggcca ttgccaccca ggtgggcatc 2280
aacaaggtgt tcgccgaggt gctgcccagc cacaaagtgg ccaaggtgca ggaactgcag 2340
aacaaaggca aaaaggtggc catggtggga gatggcgtga acgactctcc tgctctggcc 2400
caggcagata tgggcgtggc catcggcaca ggcaccgacg tggcaattga ggctgctgac 2460
gtggtgctga ttcggaacga cctgctggac gtggtggcct ccatccacct gtccaagaga 2520
accgtgcggc ggatcagaat caacctggtg ctggcactga tctataacct cgtgggcatc 2580
cctatcgccg ctggcgtgtt catgcctatc ggaatcgtgc tgcagccctg gatgggctct 2640
gccgccatgg ctgcaagctc cgtgtctgtg gtgctgtcca gcctgcagct gaagtgctac 2700
aagaagcccg acctggaaag atacgaggcc caggcccacg gacacatgaa gcctctgaca 2760
gcctcccagg tgtccgtgca catcggcatg gacgacagat ggcgggacag ccctagagcc 2820
accccttggg atcaggtgtc atacgtgtca caggtgtccc tgagcagcct gaccagcgac 2880
aagcccagca gacatagcgc cgctgccgac gacgatgggg acaagtggtc cctgctgctg 2940
aacggccggg atgaggaaca gtacatc 2967
<210> 20
<211> 4284
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 20
atgcccgagc aggaaagaca gatcaccgcc agagagggcg ccagccggaa gatcctgagc 60
aagctgagcc tgcccaccag agcctgggag cccgccatga agaagtcctt cgccttcgac 120
aacgtgggct acgagggcgg cctggacgga ctgggaccat cttctcaggt ggccacaagc 180
accgtgcgca aatacgtgcc ctctgtcgtg tgcctgcagc aggtgtgcca ccagatcggc 240
gacatgggct tcgaggcctc tatcgccgag ggaaaggccg cctcttggcc ctctagaagc 300
ctgcctgctc aggaagccgt cgtgaagctg cgggtggaag ggatgacctg tcagtcctgc 360
gtgtccagca tcgagggcaa agtgcggaag ctgcagggcg tggtgcgcgt gaaagtgtct 420
ctgagcaacc aggaagctgt gatcacctac cagccctacc tgatccagcc cgaggacctg 480
agggaccacg tgaacgatat gggatttgag gccgccatca agagcaaggt ggcccctctg 540
tctctgggcc ccatcgacat cgagagactg cagagcacca accccaagcg gcctctgagc 600
agcgccaacc agaacttcaa caacagcgag acactgggcc accagggcag ccacgtcgtg 660
acactgcagc tgcggatcga cggaatgcac tgcaagagct gtgtgctgaa catcgaggaa 720
aacatcggcc agctgctggg agtgcagagc atccaggtgt cactggaaaa caagaccgcc 780
caggtgaagt acgaccccag ctgcacaagc cccgtggccc tgcagagagc cattgaagct 840
ctgccccctg gcaacttcaa agtgtccctg cctgacggag ccgagggctc cggaacagat 900
cacagaagca gcagcagcca cagccctggc agccccccta gaaatcaggt gcagggcacc 960
tgtagcacca ccctgatcgc cattgccggc atgacatgcg ccagctgcgt gcactctatt 1020
gagggcatga tctcccagct ggaaggcgtg cagcagatca gtgtgtctct ggccgagggc 1080
accgccacag tgctgtacaa ccctagcgtg atcagccccg aagaactgag agccgccatt 1140
gaggacatgg gattcgaagc cagcgtggtg tccgagagct gctccaccaa ccctctgggc 1200
aatcacagcg ccggcaacag catggtgcag accaccgacg gcacccccac cagcgtgcag 1260
gaagtggccc cacatacagg cagactgccc gccaatcacg cccccgatat cctggccaag 1320
agcccccaga gtacaagagc cgtggccccc cagaagtgct tcctgcagat caagggcatg 1380
acttgtgcct cttgtgtgtc caatatcgag cggaacctgc agaaagaggc cggcgtgctg 1440
tctgtgctgg tggctctgat ggccggcaag gccgagatca aatacgaccc cgaagtgatt 1500
cagcccctgg aaatcgccca gtttatccag gacctgggct ttgaagccgc cgtgatggaa 1560
gattacgccg gctccgacgg caacatcgag ctgaccatca ccggaatgac ctgcgcctcc 1620
tgtgtgcaca acattgagtc caagctgacc cggaccaacg gcatcaccta cgcctctgtg 1680
gctctggcca cctccaaggc cctcgtgaag ttcgatcccg agatcatcgg ccccagggac 1740
atcatcaaga tcatcgaaga gatcggcttc cacgccagcc tggcccagag gaaccctaac 1800
gcccaccacc tggaccacaa gatggaaatc aagcagtgga agaaaagctt cctgtgcagc 1860
ctggtgttcg gcatccccgt gatggccctg atgatctaca tgctgatccc cagcaacgag 1920
ccccaccagt ccatggtgct ggatcacaac atcatccccg gcctgtctat cctgaacctg 1980
atcttcttca tcctgtgcac cttcgtgcag ctgctgggcg gctggtactt ctacgtgcag 2040
gcctacaagt ccctgcggca cagatccgcc aacatggacg tgctgatcgt gctggccaca 2100
tctatcgcct acgtgtactc cctcgtgatc ctggtggtgg ccgtggccga gaaagccgag 2160
agaagccctg tgaccttctt cgacaccccc cctatgctgt tcgtgtttat cgccctgggc 2220
cggtggctgg aacacctggc caaaagcaag accagcgagg ccctggctaa gctgatgagt 2280
ctgcaggcca ccgaggccac agtcgtgacc ctgggcgagg acaacctgat catccgcgag 2340
gaacaggtgc caatggaact ggtgcagcgg ggcgacatcg tgaaggtggt gcctggcggc 2400
aagttccccg tggacggaaa agtgctggaa gggaatacca tggccgacga gagcctgatc 2460
acaggcgagg ccatgcccgt gaccaagaaa cctggcagca cagtgatcgc cggcagcatc 2520
aatgcccacg gcagcgtgct gattaaggcc acacacgtgg gcaacgatac caccctggct 2580
cagattgtga agctggtgga agaggcccag atgagcaagg cccccattca gcagctggct 2640
gaccggttca gcggctactt cgtgcccttt atcatcatca tgagcaccct gacactggtc 2700
gtgtggatcg tgatcggctt tatcgacttc ggagtggtgc agagatactt ccccaaccct 2760
aacaagcaca tcagccagac agaagtgatc atcagattcg cctttcagac cagcatcacc 2820
gtgctgtgta tcgcctgccc ctgtagcctg ggactggcca cacctaccgc tgtgatggtg 2880
ggaacaggcg tggccgctca gaacggcatc ctgatcaagg ggggcaagcc tctggaaatg 2940
gctcacaaga tcaagaccgt gatgttcgac aagaccggca ccatcaccca cggcgtgccc 3000
agagtgatga gagtgctgct gctgggggat gtggccaccc tgcctctgag aaaggtgctg 3060
gctgtcgtgg gcacagccga ggctagctct gaacacccac tgggagtggc cgtgacaaag 3120
tactgcaaag aggaactggg caccgaaacc ctgggctact gcaccgactt tcaggccgtg 3180
cctggctgtg gcatcggctg caaggtgtcc aacgtggaag gcatcctggc ccacagcgag 3240
aggccactgt ctgcccctgc cagccacctg aacgaggccg gatctctgcc cgccgaaaag 3300
gacgctgtgc cccagacctt ctctgtgctg attggcaaca gagagtggct gcggcggaac 3360
ggcctgacca tctcctccga tgtgtccgac gccatgaccg accacgagat gaagggccag 3420
accgccattc tggtggccat tgacggggtg ctgtgcggca tgatcgcaat cgccgatgcc 3480
gtgaaacagg aagcagcact ggccgtgcac accctgcagt ctatgggagt ggatgtggtg 3540
ctgatcaccg gcgacaacag aaagaccgcc agggccattg ccacccaggt gggcatcaac 3600
aaggtgttcg ccgaggtgct gcccagccac aaagtggcca aggtgcagga actgcagaac 3660
aaaggcaaaa aggtggccat ggtgggagat ggcgtgaacg actctcctgc tctggcccag 3720
gcagatatgg gcgtggccat cggcacaggc accgacgtgg caattgaggc tgctgacgtg 3780
gtgctgattc ggaacgacct gctggacgtg gtggcctcca tccacctgtc caagagaacc 3840
gtgcggcgga tcagaatcaa cctggtgctg gcactgatct ataacctcgt gggcatccct 3900
atcgccgctg gcgtgttcat gcctatcgga atcgtgctgc agccctggat gggctctgcc 3960
gccatggctg caagctccgt gtctgtggtg ctgtccagcc tgcagctgaa gtgctacaag 4020
aagcccgacc tggaaagata cgaggcccag gcccacggac acatgaagcc tctgacagcc 4080
tcccaggtgt ccgtgcacat cggcatggac gacagatggc gggacagccc tagagccacc 4140
ccttgggatc aggtgtcata cgtgtcacag gtgtccctga gcagcctgac cagcgacaag 4200
cccagcagac atagcgccgc tgccgacgac gatggggaca agtggtccct gctgctgaac 4260
ggccgggatg aggaacagta catc 4284
<210> 21
<211> 4215
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 21
atgcccgagc aggaaagaca gatcaccgcc agagagggcg ccagccggaa gatcctgagc 60
aagctgagcc tgcccaccag agcctgggag cccgccatga agaagtcctt cgccttcgac 120
aacgtgggct acgagggcgg cctggacgga ctgggaccat cttctcaggt ggccacaagc 180
accgtgcgca tcctgggcat gacctgccag agctgcgtga agtccatcga ggaccggatc 240
agcaacctga agggcatcat cagcatgaag gtgtccctgg aacagggcag cgccaccgtg 300
aaatacgtgc cctctgtcgt gtgcctgcag caggtgtgcc accagatcgg cgacatgggc 360
ttcgaggcct ctatcgccga gggaaaggcc gcctcttggc cctctagaag cctgcctgct 420
caggaagccg tcgtgaagga ggccgccatc aagagcaagg tggcccctct gtctctgggc 480
cccatcgaca tcgagagact gcagagcacc aaccccaagc ggcctctgag cagcgccaac 540
cagaacttca acaacagcga gacactgggc caccagggca gccacgtcgt gacactgcag 600
ctgcggatcg acggaatgca ctgcaagagc tgtgtgctga acatcgagga aaacatcggc 660
cagctgctgg gagtgcagag catccaggtg tcactggaaa acaagaccgc ccaggtgaag 720
tacgacccca gctgcacaag ccccgtggcc ctgcagagag ccattgaagc tctgccccct 780
ggcaacttca aagtgtccct gcctgacgga gccgagggct ccggaacaga tcacagaagc 840
agcagcagcc acagccctgg cagcccccct agaaatcagg tgcagggcac ctgtagcacc 900
accctgatcg ccattgccgg catgacatgc gccagctgcg tgcactctat tgagggcatg 960
atctcccagc tggaaggcgt gcagcagatc agtgtgtctc tggccgaggg caccgccaca 1020
gtgctgtaca accctagcgt gatcagcccc gaagaactga gagccgccat tgaggacatg 1080
ggattcgaag ccagcgtggt gtccgagagc tgctccacca accctctggg caatcacagc 1140
gccggcaaca gcatggtgca gaccaccgac ggcaccccca ccagcgtgca ggaagtggcc 1200
ccacatacag gcagactgcc cgccaatcac gcccccgata tcctggccaa gagcccccag 1260
agtacaagag ccgtggcccc ccagaagtgc ttcctgcaga tcaagggcat gacttgtgcc 1320
tcttgtgtgt ccaatatcga gcggaacctg cagaaagagg ccggcgtgct gtctgtgctg 1380
gtggctctga tggccggcaa ggccgagatc aaatacgacc ccgaagtgat tcagcccctg 1440
gaaatcgccc agtttatcca ggacctgggc tttgaagccg ccgtgatgga agattacgcc 1500
ggctccgacg gcaacatcga gctgaccatc accggaatga cctgcgcctc ctgtgtgcac 1560
aacattgagt ccaagctgac ccggaccaac ggcatcacct acgcctctgt ggctctggcc 1620
acctccaagg ccctcgtgaa gttcgatccc gagatcatcg gccccaggga catcatcaag 1680
atcatcgaag agatcggctt ccacgccagc ctggcccaga ggaaccctaa cgcccaccac 1740
ctggaccaca agatggaaat caagcagtgg aagaaaagct tcctgtgcag cctggtgttc 1800
ggcatccccg tgatggccct gatgatctac atgctgatcc ccagcaacga gccccaccag 1860
tccatggtgc tggatcacaa catcatcccc ggcctgtcta tcctgaacct gatcttcttc 1920
atcctgtgca ccttcgtgca gctgctgggc ggctggtact tctacgtgca ggcctacaag 1980
tccctgcggc acagatccgc caacatggac gtgctgatcg tgctggccac atctatcgcc 2040
tacgtgtact ccctcgtgat cctggtggtg gccgtggccg agaaagccga gagaagccct 2100
gtgaccttct tcgacacccc ccctatgctg ttcgtgttta tcgccctggg ccggtggctg 2160
gaacacctgg ccaaaagcaa gaccagcgag gccctggcta agctgatgag tctgcaggcc 2220
accgaggcca cagtcgtgac cctgggcgag gacaacctga tcatccgcga ggaacaggtg 2280
ccaatggaac tggtgcagcg gggcgacatc gtgaaggtgg tgcctggcgg caagttcccc 2340
gtggacggaa aagtgctgga agggaatacc atggccgacg agagcctgat cacaggcgag 2400
gccatgcccg tgaccaagaa acctggcagc acagtgatcg ccggcagcat caatgcccac 2460
ggcagcgtgc tgattaaggc cacacacgtg ggcaacgata ccaccctggc tcagattgtg 2520
aagctggtgg aagaggccca gatgagcaag gcccccattc agcagctggc tgaccggttc 2580
agcggctact tcgtgccctt tatcatcatc atgagcaccc tgacactggt cgtgtggatc 2640
gtgatcggct ttatcgactt cggagtggtg cagagatact tccccaaccc taacaagcac 2700
atcagccaga cagaagtgat catcagattc gcctttcaga ccagcatcac cgtgctgtgt 2760
atcgcctgcc cctgtagcct gggactggcc acacctaccg ctgtgatggt gggaacaggc 2820
gtggccgctc agaacggcat cctgatcaag gggggcaagc ctctggaaat ggctcacaag 2880
atcaagaccg tgatgttcga caagaccggc accatcaccc acggcgtgcc cagagtgatg 2940
agagtgctgc tgctggggga tgtggccacc ctgcctctga gaaaggtgct ggctgtcgtg 3000
ggcacagccg aggctagctc tgaacaccca ctgggagtgg ccgtgacaaa gtactgcaaa 3060
gaggaactgg gcaccgaaac cctgggctac tgcaccgact ttcaggccgt gcctggctgt 3120
ggcatcggct gcaaggtgtc caacgtggaa ggcatcctgg cccacagcga gaggccactg 3180
tctgcccctg ccagccacct gaacgaggcc ggatctctgc ccgccgaaaa ggacgctgtg 3240
ccccagacct tctctgtgct gattggcaac agagagtggc tgcggcggaa cggcctgacc 3300
atctcctccg atgtgtccga cgccatgacc gaccacgaga tgaagggcca gaccgccatt 3360
ctggtggcca ttgacggggt gctgtgcggc atgatcgcaa tcgccgatgc cgtgaaacag 3420
gaagcagcac tggccgtgca caccctgcag tctatgggag tggatgtggt gctgatcacc 3480
ggcgacaaca gaaagaccgc cagggccatt gccacccagg tgggcatcaa caaggtgttc 3540
gccgaggtgc tgcccagcca caaagtggcc aaggtgcagg aactgcagaa caaaggcaaa 3600
aaggtggcca tggtgggaga tggcgtgaac gactctcctg ctctggccca ggcagatatg 3660
ggcgtggcca tcggcacagg caccgacgtg gcaattgagg ctgctgacgt ggtgctgatt 3720
cggaacgacc tgctggacgt ggtggcctcc atccacctgt ccaagagaac cgtgcggcgg 3780
atcagaatca acctggtgct ggcactgatc tataacctcg tgggcatccc tatcgccgct 3840
ggcgtgttca tgcctatcgg aatcgtgctg cagccctgga tgggctctgc cgccatggct 3900
gcaagctccg tgtctgtggt gctgtccagc ctgcagctga agtgctacaa gaagcccgac 3960
ctggaaagat acgaggccca ggcccacgga cacatgaagc ctctgacagc ctcccaggtg 4020
tccgtgcaca tcggcatgga cgacagatgg cgggacagcc ctagagccac cccttgggat 4080
caggtgtcat acgtgtcaca ggtgtccctg agcagcctga ccagcgacaa gcccagcaga 4140
catagcgccg ctgccgacga cgatggggac aagtggtccc tgctgctgaa cggccgggat 4200
gaggaacagt acatc 4215
<210> 22
<211> 4317
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 22
atgcccgagc aggaaagaca gatcaccgcc agagagggcg ccagccggaa gatcctgagc 60
aagctgagcc tgcccaccag agcctgggag cccgccatga agaagtcctt cgccttcgac 120
aacgtgggct acgagggcgg cctggacgga ctgggaccat cttctcaggt ggccacaagc 180
accgtgcgca tcctgggcat gacctgccag agctgcgtga agtccatcga ggaccggatc 240
agcaacctga agggcatcat cagcatgaag gtgtccctgg aacagggcag cgccaccgtg 300
aaatacgtgc cctctgtcgt gtgcctgcag caggtgtgcc accagatcgg cgacatgggc 360
ttcgaggcct ctatcgccga gggaaaggcc gcctcttggc cctctagaag cctgcctgct 420
caggaagccg tcgtgaagct gcgggtggaa gggatgacct gtcagtcctg cgtgtccagc 480
atcgagggca aagtgcggaa gctgcagggc gtggtgcgcg tgaaagtgtc tctgagcaac 540
caggaagctg tgatcaccta ccagccctac ctgatccagc ccgaggacct gagggaccac 600
gtgaacgata tgggatttga ggccgccatc aagagcaagg tggcccctct gtctctgggc 660
cccatcgaca tcgagagact gcagagcacc aaccccaagc ggcctctgag cagcgccaac 720
cagaacttca acaacagcga gacactgggc caccagggca gccacgtcgt gacactgcag 780
agcatccagg tgtcactgga aaacaagacc gcccaggtga agtacgaccc cagctgcaca 840
agccccgtgg ccctgcagag agccattgaa gctctgcccc ctggcaactt caaagtgtcc 900
ctgcctgacg gagccgaggg ctccggaaca gatcacagaa gcagcagcag ccacagccct 960
ggcagccccc ctagaaatca ggtgcagggc acctgtagca ccaccctgat cgccattgcc 1020
ggcatgacat gcgccagctg cgtgcactct attgagggca tgatctccca gctggaaggc 1080
gtgcagcaga tcagtgtgtc tctggccgag ggcaccgcca cagtgctgta caaccctagc 1140
gtgatcagcc ccgaagaact gagagccgcc attgaggaca tgggattcga agccagcgtg 1200
gtgtccgaga gctgctccac caaccctctg ggcaatcaca gcgccggcaa cagcatggtg 1260
cagaccaccg acggcacccc caccagcgtg caggaagtgg ccccacatac aggcagactg 1320
cccgccaatc acgcccccga tatcctggcc aagagccccc agagtacaag agccgtggcc 1380
ccccagaagt gcttcctgca gatcaagggc atgacttgtg cctcttgtgt gtccaatatc 1440
gagcggaacc tgcagaaaga ggccggcgtg ctgtctgtgc tggtggctct gatggccggc 1500
aaggccgaga tcaaatacga ccccgaagtg attcagcccc tggaaatcgc ccagtttatc 1560
caggacctgg gctttgaagc cgccgtgatg gaagattacg ccggctccga cggcaacatc 1620
gagctgacca tcaccggaat gacctgcgcc tcctgtgtgc acaacattga gtccaagctg 1680
acccggacca acggcatcac ctacgcctct gtggctctgg ccacctccaa ggccctcgtg 1740
aagttcgatc ccgagatcat cggccccagg gacatcatca agatcatcga agagatcggc 1800
ttccacgcca gcctggccca gaggaaccct aacgcccacc acctggacca caagatggaa 1860
atcaagcagt ggaagaaaag cttcctgtgc agcctggtgt tcggcatccc cgtgatggcc 1920
ctgatgatct acatgctgat ccccagcaac gagccccacc agtccatggt gctggatcac 1980
aacatcatcc ccggcctgtc tatcctgaac ctgatcttct tcatcctgtg caccttcgtg 2040
cagctgctgg gcggctggta cttctacgtg caggcctaca agtccctgcg gcacagatcc 2100
gccaacatgg acgtgctgat cgtgctggcc acatctatcg cctacgtgta ctccctcgtg 2160
atcctggtgg tggccgtggc cgagaaagcc gagagaagcc ctgtgacctt cttcgacacc 2220
ccccctatgc tgttcgtgtt tatcgccctg ggccggtggc tggaacacct ggccaaaagc 2280
aagaccagcg aggccctggc taagctgatg agtctgcagg ccaccgaggc cacagtcgtg 2340
accctgggcg aggacaacct gatcatccgc gaggaacagg tgccaatgga actggtgcag 2400
cggggcgaca tcgtgaaggt ggtgcctggc ggcaagttcc ccgtggacgg aaaagtgctg 2460
gaagggaata ccatggccga cgagagcctg atcacaggcg aggccatgcc cgtgaccaag 2520
aaacctggca gcacagtgat cgccggcagc atcaatgccc acggcagcgt gctgattaag 2580
gccacacacg tgggcaacga taccaccctg gctcagattg tgaagctggt ggaagaggcc 2640
cagatgagca aggcccccat tcagcagctg gctgaccggt tcagcggcta cttcgtgccc 2700
tttatcatca tcatgagcac cctgacactg gtcgtgtgga tcgtgatcgg ctttatcgac 2760
ttcggagtgg tgcagagata cttccccaac cctaacaagc acatcagcca gacagaagtg 2820
atcatcagat tcgcctttca gaccagcatc accgtgctgt gtatcgcctg cccctgtagc 2880
ctgggactgg ccacacctac cgctgtgatg gtgggaacag gcgtggccgc tcagaacggc 2940
atcctgatca aggggggcaa gcctctggaa atggctcaca agatcaagac cgtgatgttc 3000
gacaagaccg gcaccatcac ccacggcgtg cccagagtga tgagagtgct gctgctgggg 3060
gatgtggcca ccctgcctct gagaaaggtg ctggctgtcg tgggcacagc cgaggctagc 3120
tctgaacacc cactgggagt ggccgtgaca aagtactgca aagaggaact gggcaccgaa 3180
accctgggct actgcaccga ctttcaggcc gtgcctggct gtggcatcgg ctgcaaggtg 3240
tccaacgtgg aaggcatcct ggcccacagc gagaggccac tgtctgcccc tgccagccac 3300
ctgaacgagg ccggatctct gcccgccgaa aaggacgctg tgccccagac cttctctgtg 3360
ctgattggca acagagagtg gctgcggcgg aacggcctga ccatctcctc cgatgtgtcc 3420
gacgccatga ccgaccacga gatgaagggc cagaccgcca ttctggtggc cattgacggg 3480
gtgctgtgcg gcatgatcgc aatcgccgat gccgtgaaac aggaagcagc actggccgtg 3540
cacaccctgc agtctatggg agtggatgtg gtgctgatca ccggcgacaa cagaaagacc 3600
gccagggcca ttgccaccca ggtgggcatc aacaaggtgt tcgccgaggt gctgcccagc 3660
cacaaagtgg ccaaggtgca ggaactgcag aacaaaggca aaaaggtggc catggtggga 3720
gatggcgtga acgactctcc tgctctggcc caggcagata tgggcgtggc catcggcaca 3780
ggcaccgacg tggcaattga ggctgctgac gtggtgctga ttcggaacga cctgctggac 3840
gtggtggcct ccatccacct gtccaagaga accgtgcggc ggatcagaat caacctggtg 3900
ctggcactga tctataacct cgtgggcatc cctatcgccg ctggcgtgtt catgcctatc 3960
ggaatcgtgc tgcagccctg gatgggctct gccgccatgg ctgcaagctc cgtgtctgtg 4020
gtgctgtcca gcctgcagct gaagtgctac aagaagcccg acctggaaag atacgaggcc 4080
caggcccacg gacacatgaa gcctctgaca gcctcccagg tgtccgtgca catcggcatg 4140
gacgacagat ggcgggacag ccctagagcc accccttggg atcaggtgtc atacgtgtca 4200
caggtgtccc tgagcagcct gaccagcgac aagcccagca gacatagcgc cgctgccgac 4260
gacgatgggg acaagtggtc cctgctgctg aacggccggg atgaggaaca gtacatc 4317
<210> 23
<211> 7944
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 23
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctactta agctacctcg 180
tgatcgcccg gcccctgttc aaacatgtcc taatactctg tctctgcaag ggtcatcagt 240
agttttccat cttactcaac atcctcccag tggaattcat ttcatagaac gaatgttccg 300
atgctctaat ctctctagac aaggttcata tttgtatggg ttacttattc tctctttgtt 360
gactaagtca ataatcagaa tcagcaggtt tgcagtcaga ttggcaggga taagcagcct 420
agctcaggag aagtgagtat aaaagcccca ggctgggagc agccatcagc ggccgccacc 480
atgcccgagc aggaaagaca gatcaccgcc agagagggcg ccagccggaa gatcctgagc 540
aagctgagcc tgcccaccag agcctgggag cccgccatga agaagtcctt cgccttcgac 600
aacgtgggct acgagggcgg cctggatgga ctgggaccat cttctcaggt ggccacaagc 660
accgtgcgca tcctgggcat gacctgccag agctgcgtga agtccatcga ggaccggatc 720
agcaacctga agggcatcat cagcatgaag gtgtccctgg aacagggcag cgccaccgtg 780
aaatacgtgc cctctgtcgt gtgcctgcag caagtgtgcc accagatcgg cgacatgggc 840
ttcgaggcct ctatcgccga gggaaaggcc gcctcttggc cctctagaag cctgcctgct 900
caggaagccg tcgtgaagct gcgggtggaa gggatgacct gtcagtcctg cgtgtccagc 960
atcgagggca aagtgcggaa gctgcagggc gtggtgcgcg tgaaagtgtc tctgagcaac 1020
caggaagctg tgatcaccta ccagccctac ctgatccagc ccgaggacct gagggaccac 1080
gtgaacgata tgggatttga ggccgccatc aagagcaagg tggcccctct gtctctgggc 1140
cccatcgaca tcgagagact gcagagcacc aaccccaagc ggcctctgag cagcgccaac 1200
cagaacttca acaacagcga gacactgggc caccagggca gccacgtcgt gacactgcag 1260
ctgcggatcg acggaatgca ctgcaagagc tgtgtgctga acatcgagga aaacatcggc 1320
cagctgctgg gagtgcagag catccaggtg tcactggaaa acaagaccgc ccaagtgaag 1380
tacgacccca gctgcacaag ccccgtggcc ctgcagagag ccattgaagc tctgccccct 1440
ggcaacttca aagtgtccct gcctgatggc gccgagggct ccggaacaga tcacagaagc 1500
agcagcagcc acagccctgg cagcccccct agaaatcagg tgcagggcac ctgtagcacc 1560
accctgatcg ccattgccgg catgacatgc gccagctgcg tgcactctat tgagggcatg 1620
atctcccagc tggaaggcgt gcagcagatc agtgtgtctc tggccgaggg caccgccaca 1680
gtgctgtaca accctagcgt gatcagcccc gaagaactga gagccgccat tgaggacatg 1740
ggattcgaag ccagcgtggt gtccgagagc tgctccacca accctctggg caatcacagc 1800
gccggcaaca gcatggtgca gaccaccgat ggcaccccca ccagcgtgca ggaagtggcc 1860
ccacatacag gcagactgcc cgccaatcac gcccccgata tcctggccaa gagcccccag 1920
agtacaagag ccgtggcccc ccagaagtgc ttcctgcaga tcaagggcat gacttgtgcc 1980
tcttgtgtgt ccaatatcga gcggaacctg cagaaagagg ccggcgtgct gtctgtgctg 2040
gtggctctga tggccggcaa ggccgagatc aaatacgacc ccgaagtgat tcagcccctg 2100
gaaatcgccc agtttatcca ggacctgggc tttgaagccg ccgtgatgga agattacgcc 2160
ggctccgacg gcaacatcga gctgaccatc accggaatga cctgcgcctc ctgtgtgcac 2220
aacattgagt ccaagctgac ccggaccaac ggcatcacct acgcctctgt ggctctggcc 2280
acctccaagg ccctcgtgaa gttcgatccc gagatcatcg gccccaggga catcatcaag 2340
atcatcgaag agatcggctt ccacgccagc ctggcccaga ggaaccctaa tgcccaccac 2400
ctggaccaca agatggaaat caagcagtgg aagaaaagct tcctgtgcag cctggtgttc 2460
ggcatccccg tgatggccct gatgatctac atgctgatcc ccagcaacga gccccaccag 2520
tccatggtgc tggatcacaa catcatcccc ggcctgtcta tcctgaacct gatcttcttc 2580
atcctgtgca ccttcgtgca gctgctgggc ggctggtact tctatgtgca agcctacaag 2640
tccctgcggc acagatccgc caacatggac gtgctgatcg tgctggccac atctatcgcc 2700
tacgtgtact ccctcgtgat cctggtggtg gccgtggccg agaaagccga gagaagccct 2760
gtgaccttct tcgacacccc ccctatgctg ttcgtgttta tcgccctggg ccggtggctg 2820
gaacacctgg ccaaaagcaa gaccagcgag gccctggcta agctgatgag tctgcaggcc 2880
accgaggcca cagtcgtgac cctgggcgag gacaacctga tcatccgcga ggaacaggtg 2940
ccaatggaac tggtgcagcg gggcgacatc gtgaaggtgg tgcctggcgg caagttcccc 3000
gtggacggaa aagtgctgga agggaatacc atggccgacg agagcctgat cacaggcgag 3060
gccatgcccg tgaccaagaa acctggcagc acagtgatcg ccggcagcat caatgcccac 3120
ggcagcgtgc tgattaaggc cacacacgtg ggcaacgata ccaccctggc tcagattgtg 3180
aagctggtgg aagaggccca gatgagcaag gcccccattc agcagctggc tgaccggttc 3240
agcggctact tcgtgccctt tatcatcatc atgagcaccc tgacactggt cgtgtggatc 3300
gtgatcggct ttatcgactt cggagtggtg cagagatact tccccaaccc taacaagcac 3360
atcagccaga cagaagtgat catcagattc gcctttcaga ccagcatcac cgtgctgtgt 3420
atcgcctgcc cctgtagcct gggactggcc acacctaccg ctgtgatggt gggaacaggc 3480
gtggccgctc agaacggcat cctgatcaag gggggcaagc ctctggaaat ggctcacaag 3540
atcaagaccg tgatgttcga caagaccggc accatcaccc acggcgtgcc cagagtgatg 3600
agagtgctgc tgctggggga tgtggccacc ctgcctctga gaaaggtgct ggctgtcgtg 3660
ggcacagccg aggctagctc tgaacaccca ctgggagtgg ccgtgacaaa gtactgcaaa 3720
gaggaactgg gcaccgaaac cctgggctac tgcaccgact ttcaggccgt gcctggctgt 3780
ggcatcggct gcaaggtgtc caacgtggaa ggcatcctgg cccacagcga gaggccactg 3840
tctgcccctg ccagccacct gaatgaggcc ggatctctgc ccgccgaaaa ggacgctgtg 3900
ccccagacct tctctgtgct gattggcaac agagagtggc tgcggcggaa cggcctgacc 3960
atctcctccg atgtgtccga cgccatgacc gaccacgaga tgaagggcca gaccgccatt 4020
ctggtggcca ttgacggggt gctgtgcggc atgatcgcaa tcgccgatgc cgtgaaacag 4080
gaagcagcac tggccgtgca caccctgcag tctatgggag tggatgtggt gctgatcacc 4140
ggcgacaaca gaaagaccgc cagggccatt gccacccaag tgggcatcaa caaggtgttc 4200
gccgaggtgc tgcccagcca caaagtggcc aaggtgcagg aactgcagaa caaaggcaaa 4260
aaggtggcca tggtgggaga tggcgtgaac gactctcctg ctctggccca ggcagatatg 4320
ggcgtggcca tcggcacagg caccgacgtg gcaattgagg ctgctgacgt ggtgctgatt 4380
cggaacgacc tgctggacgt ggtggcctcc atccacctgt ccaagagaac cgtgcggcgg 4440
atcagaatca acctggtgct ggcactgatc tataacctcg tgggcatccc tatcgccgct 4500
ggcgtgttca tgcctatcgg aatcgtgctg cagccctgga tgggctctgc cgccatggct 4560
gcaagctccg tgtctgtggt gctgtccagc ctgcagctga agtgctacaa gaagcccgac 4620
ctggaaagat acgaggccca ggcccacgga cacatgaagc ctctgacagc ctcccaggtg 4680
tccgtgcaca tcggcatgga cgacagatgg cgggacagcc ctagagccac cccttgggat 4740
caggtgtcat acgtgtcaca ggtgtccctg agcagcctga ccagcgacaa gcccagcaga 4800
catagcgccg ctgccgacga cgatggggac aaatggtccc tgctgctgaa cggccgggat 4860
gaggaacagt acatctgata agcatgcaat aaagtctgag tgggcggcag cctgtgtgtg 4920
cctgggttct ctctgtcccg gaatgtgcaa acaatggagg tgctcgagta gataagtagc 4980
atggcgggtt aatcattaac tacaaggaac ccctagtgat ggagttggcc actccctctc 5040
tgcgcgctcg ctcgctcact gaggccgggc gaccaaaggt cgcccgacgc ccgggctttg 5100
cccgggcggc ctcagtgagc gagcgagcgc gcagccttaa ttaacctaat tcactggccg 5160
tcgttttaca acgtcgtgac tgggaaaacc ctggcgttac ccaacttaat cgccttgcag 5220
cacatccccc tttcgccagc tggcgtaata gcgaagaggc ccgcaccgat cgcccttccc 5280
aacagttgcg cagcctgaat ggcgaatggg acgcgccctg tagcggcgca ttaagcgcgg 5340
cgggtgtggt ggttacgcgc agcgtgaccg ctacacttgc cagcgcccta gcgcccgctc 5400
ctttcgcttt cttcccttcc tttctcgcca cgttcgccgg ctttccccgt caagctctaa 5460
atcgggggct ccctttaggg ttccgattta gtgctttacg gcacctcgac cccaaaaaac 5520
ttgattaggg tgatggttca cgtagtgggc catcgccctg atagacggtt tttcgccctt 5580
tgacgttgga gtccacgttc tttaatagtg gactcttgtt ccaaactgga acaacactca 5640
accctatctc ggtctattct tttgatttat aagggatttt gccgatttcg gcctattggt 5700
taaaaaatga gctgatttaa caaaaattta acgcgaattt taacaaaata ttaacgctta 5760
caatttaggt ggcacttttc ggggaaatgt gcgcggaacc cctatttgtt tatttttcta 5820
aatacattca aatatgtatc cgctcatgag acaataaccc tgataaatgc ttcaataata 5880
ttgaaaaagg aagagtatga gtattcaaca tttccgtgtc gcccttattc ccttttttgc 5940
ggcattttgc cttcctgttt ttgctcaccc agaaacgctg gtgaaagtaa aagatgctga 6000
agatcagttg ggtgcacgag tgggttacat cgaactggat ctcaacagcg gtaagatcct 6060
tgagagtttt cgccccgaag aacgttttcc aatgatgagc acttttaaag ttctgctatg 6120
tggcgcggta ttatcccgta ttgacgccgg gcaagagcaa ctcggtcgcc gcatacacta 6180
ttctcagaat gacttggttg agtactcacc agtcacagaa aagcatctta cggatggcat 6240
gacagtaaga gaattatgca gtgctgccat aaccatgagt gataacactg cggccaactt 6300
acttctgaca acgatcggag gaccgaagga gctaaccgct tttttgcaca acatggggga 6360
tcatgtaact cgccttgatc gttgggaacc ggagctgaat gaagccatac caaacgacga 6420
gcgtgacacc acgatgcctg tagcaatggc aacaacgttg cgcaaactat taactggcga 6480
actacttact ctagcttccc ggcaacaatt aatagactgg atggaggcgg ataaagttgc 6540
aggaccactt ctgcgctcgg cccttccggc tggctggttt attgctgata aatctggagc 6600
cggtgagcgt gggtctcgcg gtatcattgc agcactgggg ccagatggta agccctcccg 6660
tatcgtagtt atctacacga cggggagtca ggcaactatg gatgaacgaa atagacagat 6720
cgctgagata ggtgcctcac tgattaagca ttggtaactg tcagaccaag tttactcata 6780
tatactttag attgatttaa aacttcattt ttaatttaaa aggatctagg tgaagatcct 6840
ttttgataat ctcatgacca aaatccctta acgtgagttt tcgttccact gagcgtcaga 6900
ccccgtagaa aagatcaaag gatcttcttg agatcctttt tttctgcgcg taatctgctg 6960
cttgcaaaca aaaaaaccac cgctaccagc ggtggtttgt ttgccggatc aagagctacc 7020
aactcttttt ccgaaggtaa ctggcttcag cagagcgcag ataccaaata ctgttcttct 7080
agtgtagccg tagttaggcc accacttcaa gaactctgta gcaccgccta catacctcgc 7140
tctgctaatc ctgttaccag tggctgctgc cagtggcgat aagtcgtgtc ttaccgggtt 7200
ggactcaaga cgatagttac cggataaggc gcagcggtcg ggctgaacgg ggggttcgtg 7260
cacacagccc agcttggagc gaacgaccta caccgaactg agatacctac agcgtgagct 7320
atgagaaagc gccacgcttc ccgaagggag aaaggcggac aggtatccgg taagcggcag 7380
ggtcggaaca ggagagcgca cgagggagct tccaggggga aacgcctggt atctttatag 7440
tcctgtcggg tttcgccacc tctgacttga gcgtcgattt ttgtgatgct cgtcaggggg 7500
gcggagccta tggaaaaacg ccagcaacgc ggccttttta cggttcctgg ccttttgctg 7560
gccttttgct cacatgttct ttcctgcgtt atcccctgat tctgtggata accgtattac 7620
cgcctttgag tgagctgata ccgctcgccg cagccgaacg accgagcgca gcgagtcagt 7680
gagcgaggaa gcggaagagc gcccaatacg caaaccgcct ctccccgcgc gttggccgat 7740
tcattaatgc agctggcacg acaggtttcc cgactggaaa gcgggcagtg agcgcaacgc 7800
aattaatgtg agttagctca ctcattaggc accccaggct ttacacttta tgcttccggc 7860
tcgtatgttg tgtggaattg tgagcggata acaatttcac acaggaaaca gctatgacca 7920
tgattacgcc agatttaatt aagg 7944
<210> 24
<211> 7866
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 24
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctactta agtgtttgct 180
gcttgcaatg tttgcccatt ttaggggaat tcactcaaag ttcaaacctt atcatttttt 240
gctttgttcc tcttggcctt ggttttgtac atcagctttg aaaataccat cccagggtta 300
atgctggggt taatttataa ctaagagtgc tctagttttg caatacagga catgctataa 360
aaatggaaag atgttgcttt ctgagagaca gcggccgcca ccatgcccga gcaggaaaga 420
cagatcaccg ccagagaggg cgccagccgg aagatcctga gcaagctgag cctgcccacc 480
agagcctggg agcccgccat gaagaagtcc ttcgccttcg acaacgtggg ctacgagggc 540
ggcctggacg gactgggacc atcttctcag gtggccacaa gcaccgtgcg catcctgggc 600
atgacctgcc agagctgcgt gaagtccatc gaggaccgga tcagcaacct gaagggcatc 660
atcagcatga aggtgtccct ggaacagggc agcgccaccg tgaaatacgt gccctctgtc 720
gtgtgcctgc agcaggtgtg ccaccagatc ggcgacatgg gcttcgaggc ctctatcgcc 780
gagggaaagg ccgcctcttg gccctctaga agcctgcctg ctcaggaagc cgtcgtgaag 840
ctgcgggtgg aagggatgac ctgtcagtcc tgcgtgtcca gcatcgaggg caaagtgcgg 900
aagctgcagg gcgtggtgcg cgtgaaagtg tctctgagca accaggaagc tgtgatcacc 960
taccagccct acctgatcca gcccgaggac ctgagggacc acgtgaacga tatgggattt 1020
gaggccgcca tcaagagcaa ggtggcccct ctgtctctgg gccccatcga catcgagaga 1080
ctgcagagca ccaaccccaa gcggcctctg agcagcgcca accagaactt caacaacagc 1140
gagacactgg gccaccaggg cagccacgtc gtgacactgc agctgcggat cgacggaatg 1200
cactgcaaga gctgtgtgct gaacatcgag gaaaacatcg gccagctgct gggagtgcag 1260
agcatccagg tgtcactgga aaacaagacc gcccaggtga agtacgaccc cagctgcaca 1320
agccccgtgg ccctgcagag agccattgaa gctctgcccc ctggcaactt caaagtgtcc 1380
ctgcctgacg gagccgaggg ctccggaaca gatcacagaa gcagcagcag ccacagccct 1440
ggcagccccc ctagaaatca ggtgcagggc acctgtagca ccaccctgat cgccattgcc 1500
ggcatgacat gcgccagctg cgtgcactct attgagggca tgatctccca gctggaaggc 1560
gtgcagcaga tcagtgtgtc tctggccgag ggcaccgcca cagtgctgta caaccctagc 1620
gtgatcagcc ccgaagaact gagagccgcc attgaggaca tgggattcga agccagcgtg 1680
gtgtccgaga gctgctccac caaccctctg ggcaatcaca gcgccggcaa cagcatggtg 1740
cagaccaccg acggcacccc caccagcgtg caggaagtgg ccccacatac aggcagactg 1800
cccgccaatc acgcccccga tatcctggcc aagagccccc agagtacaag agccgtggcc 1860
ccccagaagt gcttcctgca gatcaagggc atgacttgtg cctcttgtgt gtccaatatc 1920
gagcggaacc tgcagaaaga ggccggcgtg ctgtctgtgc tggtggctct gatggccggc 1980
aaggccgaga tcaaatacga ccccgaagtg attcagcccc tggaaatcgc ccagtttatc 2040
caggacctgg gctttgaagc cgccgtgatg gaagattacg ccggctccga cggcaacatc 2100
gagctgacca tcaccggaat gacctgcgcc tcctgtgtgc acaacattga gtccaagctg 2160
acccggacca acggcatcac ctacgcctct gtggctctgg ccacctccaa ggccctcgtg 2220
aagttcgatc ccgagatcat cggccccagg gacatcatca agatcatcga agagatcggc 2280
ttccacgcca gcctggccca gaggaaccct aacgcccacc acctggacca caagatggaa 2340
atcaagcagt ggaagaaaag cttcctgtgc agcctggtgt tcggcatccc cgtgatggcc 2400
ctgatgatct acatgctgat ccccagcaac gagccccacc agtccatggt gctggatcac 2460
aacatcatcc ccggcctgtc tatcctgaac ctgatcttct tcatcctgtg caccttcgtg 2520
cagctgctgg gcggctggta cttctacgtg caggcctaca agtccctgcg gcacagatcc 2580
gccaacatgg acgtgctgat cgtgctggcc acatctatcg cctacgtgta ctccctcgtg 2640
atcctggtgg tggccgtggc cgagaaagcc gagagaagcc ctgtgacctt cttcgacacc 2700
ccccctatgc tgttcgtgtt tatcgccctg ggccggtggc tggaacacct ggccaaaagc 2760
aagaccagcg aggccctggc taagctgatg agtctgcagg ccaccgaggc cacagtcgtg 2820
accctgggcg aggacaacct gatcatccgc gaggaacagg tgccaatgga actggtgcag 2880
cggggcgaca tcgtgaaggt ggtgcctggc ggcaagttcc ccgtggacgg aaaagtgctg 2940
gaagggaata ccatggccga cgagagcctg atcacaggcg aggccatgcc cgtgaccaag 3000
aaacctggca gcacagtgat cgccggcagc atcaatgccc acggcagcgt gctgattaag 3060
gccacacacg tgggcaacga taccaccctg gctcagattg tgaagctggt ggaagaggcc 3120
cagatgagca aggcccccat tcagcagctg gctgaccggt tcagcggcta cttcgtgccc 3180
tttatcatca tcatgagcac cctgacactg gtcgtgtgga tcgtgatcgg ctttatcgac 3240
ttcggagtgg tgcagagata cttccccaac cctaacaagc acatcagcca gacagaagtg 3300
atcatcagat tcgcctttca gaccagcatc accgtgctgt gtatcgcctg cccctgtagc 3360
ctgggactgg ccacacctac cgctgtgatg gtgggaacag gcgtggccgc tcagaacggc 3420
atcctgatca aggggggcaa gcctctggaa atggctcaca agatcaagac cgtgatgttc 3480
gacaagaccg gcaccatcac ccacggcgtg cccagagtga tgagagtgct gctgctgggg 3540
gatgtggcca ccctgcctct gagaaaggtg ctggctgtcg tgggcacagc cgaggctagc 3600
tctgaacacc cactgggagt ggccgtgaca aagtactgca aagaggaact gggcaccgaa 3660
accctgggct actgcaccga ctttcaggcc gtgcctggct gtggcatcgg ctgcaaggtg 3720
tccaacgtgg aaggcatcct ggcccacagc gagaggccac tgtctgcccc tgccagccac 3780
ctgaacgagg ccggatctct gcccgccgaa aaggacgctg tgccccagac cttctctgtg 3840
ctgattggca acagagagtg gctgcggcgg aacggcctga ccatctcctc cgatgtgtcc 3900
gacgccatga ccgaccacga gatgaagggc cagaccgcca ttctggtggc cattgacggg 3960
gtgctgtgcg gcatgatcgc aatcgccgat gccgtgaaac aggaagcagc actggccgtg 4020
cacaccctgc agtctatggg agtggatgtg gtgctgatca ccggcgacaa cagaaagacc 4080
gccagggcca ttgccaccca ggtgggcatc aacaaggtgt tcgccgaggt gctgcccagc 4140
cacaaagtgg ccaaggtgca ggaactgcag aacaaaggca aaaaggtggc catggtggga 4200
gatggcgtga acgactctcc tgctctggcc caggcagata tgggcgtggc catcggcaca 4260
ggcaccgacg tggcaattga ggctgctgac gtggtgctga ttcggaacga cctgctggac 4320
gtggtggcct ccatccacct gtccaagaga accgtgcggc ggatcagaat caacctggtg 4380
ctggcactga tctataacct cgtgggcatc cctatcgccg ctggcgtgtt catgcctatc 4440
ggaatcgtgc tgcagccctg gatgggctct gccgccatgg ctgcaagctc cgtgtctgtg 4500
gtgctgtcca gcctgcagct gaagtgctac aagaagcccg acctggaaag atacgaggcc 4560
caggcccacg gacacatgaa gcctctgaca gcctcccagg tgtccgtgca catcggcatg 4620
gacgacagat ggcgggacag ccctagagcc accccttggg atcaggtgtc atacgtgtca 4680
caggtgtccc tgagcagcct gaccagcgac aagcccagca gacatagcgc cgctgccgac 4740
gacgatgggg acaagtggtc cctgctgctg aacggccggg atgaggaaca gtacatctga 4800
taagcatgca ataaagtctg agtgggcggc agcctgtgtg tgcctgggtt ctctctgtcc 4860
cggaatgtgc aaacaatgga ggtgctcgag tagataagta gcatggcggg ttaatcatta 4920
actacaagga acccctagtg atggagttgg ccactccctc tctgcgcgct cgctcgctca 4980
ctgaggccgg gcgaccaaag gtcgcccgac gcccgggctt tgcccgggcg gcctcagtga 5040
gcgagcgagc gcgcagcctt aattaaccta attcactggc cgtcgtttta caacgtcgtg 5100
actgggaaaa ccctggcgtt acccaactta atcgccttgc agcacatccc cctttcgcca 5160
gctggcgtaa tagcgaagag gcccgcaccg atcgcccttc ccaacagttg cgcagcctga 5220
atggcgaatg ggacgcgccc tgtagcggcg cattaagcgc ggcgggtgtg gtggttacgc 5280
gcagcgtgac cgctacactt gccagcgccc tagcgcccgc tcctttcgct ttcttccctt 5340
cctttctcgc cacgttcgcc ggctttcccc gtcaagctct aaatcggggg ctccctttag 5400
ggttccgatt tagtgcttta cggcacctcg accccaaaaa acttgattag ggtgatggtt 5460
cacgtagtgg gccatcgccc tgatagacgg tttttcgccc tttgacgttg gagtccacgt 5520
tctttaatag tggactcttg ttccaaactg gaacaacact caaccctatc tcggtctatt 5580
cttttgattt ataagggatt ttgccgattt cggcctattg gttaaaaaat gagctgattt 5640
aacaaaaatt taacgcgaat tttaacaaaa tattaacgct tacaatttag gtggcacttt 5700
tcggggaaat gtgcgcggaa cccctatttg tttatttttc taaatacatt caaatatgta 5760
tccgctcatg agacaataac cctgataaat gcttcaataa tattgaaaaa ggaagagtat 5820
gagtattcaa catttccgtg tcgcccttat tccctttttt gcggcatttt gccttcctgt 5880
ttttgctcac ccagaaacgc tggtgaaagt aaaagatgct gaagatcagt tgggtgcacg 5940
agtgggttac atcgaactgg atctcaacag cggtaagatc cttgagagtt ttcgccccga 6000
agaacgtttt ccaatgatga gcacttttaa agttctgcta tgtggcgcgg tattatcccg 6060
tattgacgcc gggcaagagc aactcggtcg ccgcatacac tattctcaga atgacttggt 6120
tgagtactca ccagtcacag aaaagcatct tacggatggc atgacagtaa gagaattatg 6180
cagtgctgcc ataaccatga gtgataacac tgcggccaac ttacttctga caacgatcgg 6240
aggaccgaag gagctaaccg cttttttgca caacatgggg gatcatgtaa ctcgccttga 6300
tcgttgggaa ccggagctga atgaagccat accaaacgac gagcgtgaca ccacgatgcc 6360
tgtagcaatg gcaacaacgt tgcgcaaact attaactggc gaactactta ctctagcttc 6420
ccggcaacaa ttaatagact ggatggaggc ggataaagtt gcaggaccac ttctgcgctc 6480
ggcccttccg gctggctggt ttattgctga taaatctgga gccggtgagc gtgggtctcg 6540
cggtatcatt gcagcactgg ggccagatgg taagccctcc cgtatcgtag ttatctacac 6600
gacggggagt caggcaacta tggatgaacg aaatagacag atcgctgaga taggtgcctc 6660
actgattaag cattggtaac tgtcagacca agtttactca tatatacttt agattgattt 6720
aaaacttcat ttttaattta aaaggatcta ggtgaagatc ctttttgata atctcatgac 6780
caaaatccct taacgtgagt tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa 6840
aggatcttct tgagatcctt tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc 6900
accgctacca gcggtggttt gtttgccgga tcaagagcta ccaactcttt ttccgaaggt 6960
aactggcttc agcagagcgc agataccaaa tactgttctt ctagtgtagc cgtagttagg 7020
ccaccacttc aagaactctg tagcaccgcc tacatacctc gctctgctaa tcctgttacc 7080
agtggctgct gccagtggcg ataagtcgtg tcttaccggg ttggactcaa gacgatagtt 7140
accggataag gcgcagcggt cgggctgaac ggggggttcg tgcacacagc ccagcttgga 7200
gcgaacgacc tacaccgaac tgagatacct acagcgtgag ctatgagaaa gcgccacgct 7260
tcccgaaggg agaaaggcgg acaggtatcc ggtaagcggc agggtcggaa caggagagcg 7320
cacgagggag cttccagggg gaaacgcctg gtatctttat agtcctgtcg ggtttcgcca 7380
cctctgactt gagcgtcgat ttttgtgatg ctcgtcaggg gggcggagcc tatggaaaaa 7440
cgccagcaac gcggcctttt tacggttcct ggccttttgc tggccttttg ctcacatgtt 7500
ctttcctgcg ttatcccctg attctgtgga taaccgtatt accgcctttg agtgagctga 7560
taccgctcgc cgcagccgaa cgaccgagcg cagcgagtca gtgagcgagg aagcggaaga 7620
gcgcccaata cgcaaaccgc ctctccccgc gcgttggccg attcattaat gcagctggca 7680
cgacaggttt cccgactgga aagcgggcag tgagcgcaac gcaattaatg tgagttagct 7740
cactcattag gcaccccagg ctttacactt tatgcttccg gctcgtatgt tgtgtggaat 7800
tgtgagcgga taacaatttc acacaggaaa cagctatgac catgattacg ccagatttaa 7860
ttaagg 7866
<210> 25
<211> 7874
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 25
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctactta agaggttaat 180
ttttaaactg tttgctctgg ttaataatct cagggaattc actcaaagtt caaaccttat 240
cattttttgc tttgttcctc ttggccttgg ttttgtacat cagctttgaa aataccatcc 300
cagggttaat gctggggtta atttataact aagagtgctc tagttttgca atacaggaca 360
tgctataaaa atggaaagat gttgctttct gagagacagc ggccgccacc atgcccgagc 420
aggaaagaca gatcaccgcc agagagggcg ccagccggaa gatcctgagc aagctgagcc 480
tgcccaccag agcctgggag cccgccatga agaagtcctt cgccttcgac aacgtgggct 540
acgagggcgg cctggacgga ctgggaccat cttctcaggt ggccacaagc accgtgcgca 600
tcctgggcat gacctgccag agctgcgtga agtccatcga ggaccggatc agcaacctga 660
agggcatcat cagcatgaag gtgtccctgg aacagggcag cgccaccgtg aaatacgtgc 720
cctctgtcgt gtgcctgcag caggtgtgcc accagatcgg cgacatgggc ttcgaggcct 780
ctatcgccga gggaaaggcc gcctcttggc cctctagaag cctgcctgct caggaagccg 840
tcgtgaagct gcgggtggaa gggatgacct gtcagtcctg cgtgtccagc atcgagggca 900
aagtgcggaa gctgcagggc gtggtgcgcg tgaaagtgtc tctgagcaac caggaagctg 960
tgatcaccta ccagccctac ctgatccagc ccgaggacct gagggaccac gtgaacgata 1020
tgggatttga ggccgccatc aagagcaagg tggcccctct gtctctgggc cccatcgaca 1080
tcgagagact gcagagcacc aaccccaagc ggcctctgag cagcgccaac cagaacttca 1140
acaacagcga gacactgggc caccagggca gccacgtcgt gacactgcag ctgcggatcg 1200
acggaatgca ctgcaagagc tgtgtgctga acatcgagga aaacatcggc cagctgctgg 1260
gagtgcagag catccaggtg tcactggaaa acaagaccgc ccaggtgaag tacgacccca 1320
gctgcacaag ccccgtggcc ctgcagagag ccattgaagc tctgccccct ggcaacttca 1380
aagtgtccct gcctgacgga gccgagggct ccggaacaga tcacagaagc agcagcagcc 1440
acagccctgg cagcccccct agaaatcagg tgcagggcac ctgtagcacc accctgatcg 1500
ccattgccgg catgacatgc gccagctgcg tgcactctat tgagggcatg atctcccagc 1560
tggaaggcgt gcagcagatc agtgtgtctc tggccgaggg caccgccaca gtgctgtaca 1620
accctagcgt gatcagcccc gaagaactga gagccgccat tgaggacatg ggattcgaag 1680
ccagcgtggt gtccgagagc tgctccacca accctctggg caatcacagc gccggcaaca 1740
gcatggtgca gaccaccgac ggcaccccca ccagcgtgca ggaagtggcc ccacatacag 1800
gcagactgcc cgccaatcac gcccccgata tcctggccaa gagcccccag agtacaagag 1860
ccgtggcccc ccagaagtgc ttcctgcaga tcaagggcat gacttgtgcc tcttgtgtgt 1920
ccaatatcga gcggaacctg cagaaagagg ccggcgtgct gtctgtgctg gtggctctga 1980
tggccggcaa ggccgagatc aaatacgacc ccgaagtgat tcagcccctg gaaatcgccc 2040
agtttatcca ggacctgggc tttgaagccg ccgtgatgga agattacgcc ggctccgacg 2100
gcaacatcga gctgaccatc accggaatga cctgcgcctc ctgtgtgcac aacattgagt 2160
ccaagctgac ccggaccaac ggcatcacct acgcctctgt ggctctggcc acctccaagg 2220
ccctcgtgaa gttcgatccc gagatcatcg gccccaggga catcatcaag atcatcgaag 2280
agatcggctt ccacgccagc ctggcccaga ggaaccctaa cgcccaccac ctggaccaca 2340
agatggaaat caagcagtgg aagaaaagct tcctgtgcag cctggtgttc ggcatccccg 2400
tgatggccct gatgatctac atgctgatcc ccagcaacga gccccaccag tccatggtgc 2460
tggatcacaa catcatcccc ggcctgtcta tcctgaacct gatcttcttc atcctgtgca 2520
ccttcgtgca gctgctgggc ggctggtact tctacgtgca ggcctacaag tccctgcggc 2580
acagatccgc caacatggac gtgctgatcg tgctggccac atctatcgcc tacgtgtact 2640
ccctcgtgat cctggtggtg gccgtggccg agaaagccga gagaagccct gtgaccttct 2700
tcgacacccc ccctatgctg ttcgtgttta tcgccctggg ccggtggctg gaacacctgg 2760
ccaaaagcaa gaccagcgag gccctggcta agctgatgag tctgcaggcc accgaggcca 2820
cagtcgtgac cctgggcgag gacaacctga tcatccgcga ggaacaggtg ccaatggaac 2880
tggtgcagcg gggcgacatc gtgaaggtgg tgcctggcgg caagttcccc gtggacggaa 2940
aagtgctgga agggaatacc atggccgacg agagcctgat cacaggcgag gccatgcccg 3000
tgaccaagaa acctggcagc acagtgatcg ccggcagcat caatgcccac ggcagcgtgc 3060
tgattaaggc cacacacgtg ggcaacgata ccaccctggc tcagattgtg aagctggtgg 3120
aagaggccca gatgagcaag gcccccattc agcagctggc tgaccggttc agcggctact 3180
tcgtgccctt tatcatcatc atgagcaccc tgacactggt cgtgtggatc gtgatcggct 3240
ttatcgactt cggagtggtg cagagatact tccccaaccc taacaagcac atcagccaga 3300
cagaagtgat catcagattc gcctttcaga ccagcatcac cgtgctgtgt atcgcctgcc 3360
cctgtagcct gggactggcc acacctaccg ctgtgatggt gggaacaggc gtggccgctc 3420
agaacggcat cctgatcaag gggggcaagc ctctggaaat ggctcacaag atcaagaccg 3480
tgatgttcga caagaccggc accatcaccc acggcgtgcc cagagtgatg agagtgctgc 3540
tgctggggga tgtggccacc ctgcctctga gaaaggtgct ggctgtcgtg ggcacagccg 3600
aggctagctc tgaacaccca ctgggagtgg ccgtgacaaa gtactgcaaa gaggaactgg 3660
gcaccgaaac cctgggctac tgcaccgact ttcaggccgt gcctggctgt ggcatcggct 3720
gcaaggtgtc caacgtggaa ggcatcctgg cccacagcga gaggccactg tctgcccctg 3780
ccagccacct gaacgaggcc ggatctctgc ccgccgaaaa ggacgctgtg ccccagacct 3840
tctctgtgct gattggcaac agagagtggc tgcggcggaa cggcctgacc atctcctccg 3900
atgtgtccga cgccatgacc gaccacgaga tgaagggcca gaccgccatt ctggtggcca 3960
ttgacggggt gctgtgcggc atgatcgcaa tcgccgatgc cgtgaaacag gaagcagcac 4020
tggccgtgca caccctgcag tctatgggag tggatgtggt gctgatcacc ggcgacaaca 4080
gaaagaccgc cagggccatt gccacccagg tgggcatcaa caaggtgttc gccgaggtgc 4140
tgcccagcca caaagtggcc aaggtgcagg aactgcagaa caaaggcaaa aaggtggcca 4200
tggtgggaga tggcgtgaac gactctcctg ctctggccca ggcagatatg ggcgtggcca 4260
tcggcacagg caccgacgtg gcaattgagg ctgctgacgt ggtgctgatt cggaacgacc 4320
tgctggacgt ggtggcctcc atccacctgt ccaagagaac cgtgcggcgg atcagaatca 4380
acctggtgct ggcactgatc tataacctcg tgggcatccc tatcgccgct ggcgtgttca 4440
tgcctatcgg aatcgtgctg cagccctgga tgggctctgc cgccatggct gcaagctccg 4500
tgtctgtggt gctgtccagc ctgcagctga agtgctacaa gaagcccgac ctggaaagat 4560
acgaggccca ggcccacgga cacatgaagc ctctgacagc ctcccaggtg tccgtgcaca 4620
tcggcatgga cgacagatgg cgggacagcc ctagagccac cccttgggat caggtgtcat 4680
acgtgtcaca ggtgtccctg agcagcctga ccagcgacaa gcccagcaga catagcgccg 4740
ctgccgacga cgatggggac aagtggtccc tgctgctgaa cggccgggat gaggaacagt 4800
acatctgata agcatgcaat aaagtctgag tgggcggcag cctgtgtgtg cctgggttct 4860
ctctgtcccg gaatgtgcaa acaatggagg tgctcgagta gataagtagc atggcgggtt 4920
aatcattaac tacaaggaac ccctagtgat ggagttggcc actccctctc tgcgcgctcg 4980
ctcgctcact gaggccgggc gaccaaaggt cgcccgacgc ccgggctttg cccgggcggc 5040
ctcagtgagc gagcgagcgc gcagccttaa ttaacctaat tcactggccg tcgttttaca 5100
acgtcgtgac tgggaaaacc ctggcgttac ccaacttaat cgccttgcag cacatccccc 5160
tttcgccagc tggcgtaata gcgaagaggc ccgcaccgat cgcccttccc aacagttgcg 5220
cagcctgaat ggcgaatggg acgcgccctg tagcggcgca ttaagcgcgg cgggtgtggt 5280
ggttacgcgc agcgtgaccg ctacacttgc cagcgcccta gcgcccgctc ctttcgcttt 5340
cttcccttcc tttctcgcca cgttcgccgg ctttccccgt caagctctaa atcgggggct 5400
ccctttaggg ttccgattta gtgctttacg gcacctcgac cccaaaaaac ttgattaggg 5460
tgatggttca cgtagtgggc catcgccctg atagacggtt tttcgccctt tgacgttgga 5520
gtccacgttc tttaatagtg gactcttgtt ccaaactgga acaacactca accctatctc 5580
ggtctattct tttgatttat aagggatttt gccgatttcg gcctattggt taaaaaatga 5640
gctgatttaa caaaaattta acgcgaattt taacaaaata ttaacgctta caatttaggt 5700
ggcacttttc ggggaaatgt gcgcggaacc cctatttgtt tatttttcta aatacattca 5760
aatatgtatc cgctcatgag acaataaccc tgataaatgc ttcaataata ttgaaaaagg 5820
aagagtatga gtattcaaca tttccgtgtc gcccttattc ccttttttgc ggcattttgc 5880
cttcctgttt ttgctcaccc agaaacgctg gtgaaagtaa aagatgctga agatcagttg 5940
ggtgcacgag tgggttacat cgaactggat ctcaacagcg gtaagatcct tgagagtttt 6000
cgccccgaag aacgttttcc aatgatgagc acttttaaag ttctgctatg tggcgcggta 6060
ttatcccgta ttgacgccgg gcaagagcaa ctcggtcgcc gcatacacta ttctcagaat 6120
gacttggttg agtactcacc agtcacagaa aagcatctta cggatggcat gacagtaaga 6180
gaattatgca gtgctgccat aaccatgagt gataacactg cggccaactt acttctgaca 6240
acgatcggag gaccgaagga gctaaccgct tttttgcaca acatggggga tcatgtaact 6300
cgccttgatc gttgggaacc ggagctgaat gaagccatac caaacgacga gcgtgacacc 6360
acgatgcctg tagcaatggc aacaacgttg cgcaaactat taactggcga actacttact 6420
ctagcttccc ggcaacaatt aatagactgg atggaggcgg ataaagttgc aggaccactt 6480
ctgcgctcgg cccttccggc tggctggttt attgctgata aatctggagc cggtgagcgt 6540
gggtctcgcg gtatcattgc agcactgggg ccagatggta agccctcccg tatcgtagtt 6600
atctacacga cggggagtca ggcaactatg gatgaacgaa atagacagat cgctgagata 6660
ggtgcctcac tgattaagca ttggtaactg tcagaccaag tttactcata tatactttag 6720
attgatttaa aacttcattt ttaatttaaa aggatctagg tgaagatcct ttttgataat 6780
ctcatgacca aaatccctta acgtgagttt tcgttccact gagcgtcaga ccccgtagaa 6840
aagatcaaag gatcttcttg agatcctttt tttctgcgcg taatctgctg cttgcaaaca 6900
aaaaaaccac cgctaccagc ggtggtttgt ttgccggatc aagagctacc aactcttttt 6960
ccgaaggtaa ctggcttcag cagagcgcag ataccaaata ctgttcttct agtgtagccg 7020
tagttaggcc accacttcaa gaactctgta gcaccgccta catacctcgc tctgctaatc 7080
ctgttaccag tggctgctgc cagtggcgat aagtcgtgtc ttaccgggtt ggactcaaga 7140
cgatagttac cggataaggc gcagcggtcg ggctgaacgg ggggttcgtg cacacagccc 7200
agcttggagc gaacgaccta caccgaactg agatacctac agcgtgagct atgagaaagc 7260
gccacgcttc ccgaagggag aaaggcggac aggtatccgg taagcggcag ggtcggaaca 7320
ggagagcgca cgagggagct tccaggggga aacgcctggt atctttatag tcctgtcggg 7380
tttcgccacc tctgacttga gcgtcgattt ttgtgatgct cgtcaggggg gcggagccta 7440
tggaaaaacg ccagcaacgc ggccttttta cggttcctgg ccttttgctg gccttttgct 7500
cacatgttct ttcctgcgtt atcccctgat tctgtggata accgtattac cgcctttgag 7560
tgagctgata ccgctcgccg cagccgaacg accgagcgca gcgagtcagt gagcgaggaa 7620
gcggaagagc gcccaatacg caaaccgcct ctccccgcgc gttggccgat tcattaatgc 7680
agctggcacg acaggtttcc cgactggaaa gcgggcagtg agcgcaacgc aattaatgtg 7740
agttagctca ctcattaggc accccaggct ttacacttta tgcttccggc tcgtatgttg 7800
tgtggaattg tgagcggata acaatttcac acaggaaaca gctatgacca tgattacgcc 7860
agatttaatt aagg 7874
<210> 26
<211> 7878
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 26
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctactta agtgtttgct 180
gcttgcaatg tttgcccatt ttaggggaat tcatttcata gaacgaatgt tccgatgctc 240
taatctctct agacaaggtt catatttgta tgggttactt attctctctt tgttgactaa 300
gtcaataatc agaatcagca ggtttgcagt cagattggca gggataagca gcctagctca 360
ggagaagtga gtataaaagc cccaggctgg gagcagccat cagcggccgc caccatgccc 420
gagcaggaaa gacagatcac cgccagagag ggcgccagcc ggaagatcct gagcaagctg 480
agcctgccca ccagagcctg ggagcccgcc atgaagaagt ccttcgcctt cgacaacgtg 540
ggctacgagg gcggcctgga cggactggga ccatcttctc aggtggccac aagcaccgtg 600
cgcatcctgg gcatgacctg ccagagctgc gtgaagtcca tcgaggaccg gatcagcaac 660
ctgaagggca tcatcagcat gaaggtgtcc ctggaacagg gcagcgccac cgtgaaatac 720
gtgccctctg tcgtgtgcct gcagcaggtg tgccaccaga tcggcgacat gggcttcgag 780
gcctctatcg ccgagggaaa ggccgcctct tggccctcta gaagcctgcc tgctcaggaa 840
gccgtcgtga agctgcgggt ggaagggatg acctgtcagt cctgcgtgtc cagcatcgag 900
ggcaaagtgc ggaagctgca gggcgtggtg cgcgtgaaag tgtctctgag caaccaggaa 960
gctgtgatca cctaccagcc ctacctgatc cagcccgagg acctgaggga ccacgtgaac 1020
gatatgggat ttgaggccgc catcaagagc aaggtggccc ctctgtctct gggccccatc 1080
gacatcgaga gactgcagag caccaacccc aagcggcctc tgagcagcgc caaccagaac 1140
ttcaacaaca gcgagacact gggccaccag ggcagccacg tcgtgacact gcagctgcgg 1200
atcgacggaa tgcactgcaa gagctgtgtg ctgaacatcg aggaaaacat cggccagctg 1260
ctgggagtgc agagcatcca ggtgtcactg gaaaacaaga ccgcccaggt gaagtacgac 1320
cccagctgca caagccccgt ggccctgcag agagccattg aagctctgcc ccctggcaac 1380
ttcaaagtgt ccctgcctga cggagccgag ggctccggaa cagatcacag aagcagcagc 1440
agccacagcc ctggcagccc ccctagaaat caggtgcagg gcacctgtag caccaccctg 1500
atcgccattg ccggcatgac atgcgccagc tgcgtgcact ctattgaggg catgatctcc 1560
cagctggaag gcgtgcagca gatcagtgtg tctctggccg agggcaccgc cacagtgctg 1620
tacaacccta gcgtgatcag ccccgaagaa ctgagagccg ccattgagga catgggattc 1680
gaagccagcg tggtgtccga gagctgctcc accaaccctc tgggcaatca cagcgccggc 1740
aacagcatgg tgcagaccac cgacggcacc cccaccagcg tgcaggaagt ggccccacat 1800
acaggcagac tgcccgccaa tcacgccccc gatatcctgg ccaagagccc ccagagtaca 1860
agagccgtgg ccccccagaa gtgcttcctg cagatcaagg gcatgacttg tgcctcttgt 1920
gtgtccaata tcgagcggaa cctgcagaaa gaggccggcg tgctgtctgt gctggtggct 1980
ctgatggccg gcaaggccga gatcaaatac gaccccgaag tgattcagcc cctggaaatc 2040
gcccagttta tccaggacct gggctttgaa gccgccgtga tggaagatta cgccggctcc 2100
gacggcaaca tcgagctgac catcaccgga atgacctgcg cctcctgtgt gcacaacatt 2160
gagtccaagc tgacccggac caacggcatc acctacgcct ctgtggctct ggccacctcc 2220
aaggccctcg tgaagttcga tcccgagatc atcggcccca gggacatcat caagatcatc 2280
gaagagatcg gcttccacgc cagcctggcc cagaggaacc ctaacgccca ccacctggac 2340
cacaagatgg aaatcaagca gtggaagaaa agcttcctgt gcagcctggt gttcggcatc 2400
cccgtgatgg ccctgatgat ctacatgctg atccccagca acgagcccca ccagtccatg 2460
gtgctggatc acaacatcat ccccggcctg tctatcctga acctgatctt cttcatcctg 2520
tgcaccttcg tgcagctgct gggcggctgg tacttctacg tgcaggccta caagtccctg 2580
cggcacagat ccgccaacat ggacgtgctg atcgtgctgg ccacatctat cgcctacgtg 2640
tactccctcg tgatcctggt ggtggccgtg gccgagaaag ccgagagaag ccctgtgacc 2700
ttcttcgaca ccccccctat gctgttcgtg tttatcgccc tgggccggtg gctggaacac 2760
ctggccaaaa gcaagaccag cgaggccctg gctaagctga tgagtctgca ggccaccgag 2820
gccacagtcg tgaccctggg cgaggacaac ctgatcatcc gcgaggaaca ggtgccaatg 2880
gaactggtgc agcggggcga catcgtgaag gtggtgcctg gcggcaagtt ccccgtggac 2940
ggaaaagtgc tggaagggaa taccatggcc gacgagagcc tgatcacagg cgaggccatg 3000
cccgtgacca agaaacctgg cagcacagtg atcgccggca gcatcaatgc ccacggcagc 3060
gtgctgatta aggccacaca cgtgggcaac gataccaccc tggctcagat tgtgaagctg 3120
gtggaagagg cccagatgag caaggccccc attcagcagc tggctgaccg gttcagcggc 3180
tacttcgtgc cctttatcat catcatgagc accctgacac tggtcgtgtg gatcgtgatc 3240
ggctttatcg acttcggagt ggtgcagaga tacttcccca accctaacaa gcacatcagc 3300
cagacagaag tgatcatcag attcgccttt cagaccagca tcaccgtgct gtgtatcgcc 3360
tgcccctgta gcctgggact ggccacacct accgctgtga tggtgggaac aggcgtggcc 3420
gctcagaacg gcatcctgat caaggggggc aagcctctgg aaatggctca caagatcaag 3480
accgtgatgt tcgacaagac cggcaccatc acccacggcg tgcccagagt gatgagagtg 3540
ctgctgctgg gggatgtggc caccctgcct ctgagaaagg tgctggctgt cgtgggcaca 3600
gccgaggcta gctctgaaca cccactggga gtggccgtga caaagtactg caaagaggaa 3660
ctgggcaccg aaaccctggg ctactgcacc gactttcagg ccgtgcctgg ctgtggcatc 3720
ggctgcaagg tgtccaacgt ggaaggcatc ctggcccaca gcgagaggcc actgtctgcc 3780
cctgccagcc acctgaacga ggccggatct ctgcccgccg aaaaggacgc tgtgccccag 3840
accttctctg tgctgattgg caacagagag tggctgcggc ggaacggcct gaccatctcc 3900
tccgatgtgt ccgacgccat gaccgaccac gagatgaagg gccagaccgc cattctggtg 3960
gccattgacg gggtgctgtg cggcatgatc gcaatcgccg atgccgtgaa acaggaagca 4020
gcactggccg tgcacaccct gcagtctatg ggagtggatg tggtgctgat caccggcgac 4080
aacagaaaga ccgccagggc cattgccacc caggtgggca tcaacaaggt gttcgccgag 4140
gtgctgccca gccacaaagt ggccaaggtg caggaactgc agaacaaagg caaaaaggtg 4200
gccatggtgg gagatggcgt gaacgactct cctgctctgg cccaggcaga tatgggcgtg 4260
gccatcggca caggcaccga cgtggcaatt gaggctgctg acgtggtgct gattcggaac 4320
gacctgctgg acgtggtggc ctccatccac ctgtccaaga gaaccgtgcg gcggatcaga 4380
atcaacctgg tgctggcact gatctataac ctcgtgggca tccctatcgc cgctggcgtg 4440
ttcatgccta tcggaatcgt gctgcagccc tggatgggct ctgccgccat ggctgcaagc 4500
tccgtgtctg tggtgctgtc cagcctgcag ctgaagtgct acaagaagcc cgacctggaa 4560
agatacgagg cccaggccca cggacacatg aagcctctga cagcctccca ggtgtccgtg 4620
cacatcggca tggacgacag atggcgggac agccctagag ccaccccttg ggatcaggtg 4680
tcatacgtgt cacaggtgtc cctgagcagc ctgaccagcg acaagcccag cagacatagc 4740
gccgctgccg acgacgatgg ggacaagtgg tccctgctgc tgaacggccg ggatgaggaa 4800
cagtacatct gataagcatg caataaagtc tgagtgggcg gcagcctgtg tgtgcctggg 4860
ttctctctgt cccggaatgt gcaaacaatg gaggtgctcg agtagataag tagcatggcg 4920
ggttaatcat taactacaag gaacccctag tgatggagtt ggccactccc tctctgcgcg 4980
ctcgctcgct cactgaggcc gggcgaccaa aggtcgcccg acgcccgggc tttgcccggg 5040
cggcctcagt gagcgagcga gcgcgcagcc ttaattaacc taattcactg gccgtcgttt 5100
tacaacgtcg tgactgggaa aaccctggcg ttacccaact taatcgcctt gcagcacatc 5160
cccctttcgc cagctggcgt aatagcgaag aggcccgcac cgatcgccct tcccaacagt 5220
tgcgcagcct gaatggcgaa tgggacgcgc cctgtagcgg cgcattaagc gcggcgggtg 5280
tggtggttac gcgcagcgtg accgctacac ttgccagcgc cctagcgccc gctcctttcg 5340
ctttcttccc ttcctttctc gccacgttcg ccggctttcc ccgtcaagct ctaaatcggg 5400
ggctcccttt agggttccga tttagtgctt tacggcacct cgaccccaaa aaacttgatt 5460
agggtgatgg ttcacgtagt gggccatcgc cctgatagac ggtttttcgc cctttgacgt 5520
tggagtccac gttctttaat agtggactct tgttccaaac tggaacaaca ctcaacccta 5580
tctcggtcta ttcttttgat ttataaggga ttttgccgat ttcggcctat tggttaaaaa 5640
atgagctgat ttaacaaaaa tttaacgcga attttaacaa aatattaacg cttacaattt 5700
aggtggcact tttcggggaa atgtgcgcgg aacccctatt tgtttatttt tctaaataca 5760
ttcaaatatg tatccgctca tgagacaata accctgataa atgcttcaat aatattgaaa 5820
aaggaagagt atgagtattc aacatttccg tgtcgccctt attccctttt ttgcggcatt 5880
ttgccttcct gtttttgctc acccagaaac gctggtgaaa gtaaaagatg ctgaagatca 5940
gttgggtgca cgagtgggtt acatcgaact ggatctcaac agcggtaaga tccttgagag 6000
ttttcgcccc gaagaacgtt ttccaatgat gagcactttt aaagttctgc tatgtggcgc 6060
ggtattatcc cgtattgacg ccgggcaaga gcaactcggt cgccgcatac actattctca 6120
gaatgacttg gttgagtact caccagtcac agaaaagcat cttacggatg gcatgacagt 6180
aagagaatta tgcagtgctg ccataaccat gagtgataac actgcggcca acttacttct 6240
gacaacgatc ggaggaccga aggagctaac cgcttttttg cacaacatgg gggatcatgt 6300
aactcgcctt gatcgttggg aaccggagct gaatgaagcc ataccaaacg acgagcgtga 6360
caccacgatg cctgtagcaa tggcaacaac gttgcgcaaa ctattaactg gcgaactact 6420
tactctagct tcccggcaac aattaataga ctggatggag gcggataaag ttgcaggacc 6480
acttctgcgc tcggcccttc cggctggctg gtttattgct gataaatctg gagccggtga 6540
gcgtgggtct cgcggtatca ttgcagcact ggggccagat ggtaagccct cccgtatcgt 6600
agttatctac acgacgggga gtcaggcaac tatggatgaa cgaaatagac agatcgctga 6660
gataggtgcc tcactgatta agcattggta actgtcagac caagtttact catatatact 6720
ttagattgat ttaaaacttc atttttaatt taaaaggatc taggtgaaga tcctttttga 6780
taatctcatg accaaaatcc cttaacgtga gttttcgttc cactgagcgt cagaccccgt 6840
agaaaagatc aaaggatctt cttgagatcc tttttttctg cgcgtaatct gctgcttgca 6900
aacaaaaaaa ccaccgctac cagcggtggt ttgtttgccg gatcaagagc taccaactct 6960
ttttccgaag gtaactggct tcagcagagc gcagatacca aatactgttc ttctagtgta 7020
gccgtagtta ggccaccact tcaagaactc tgtagcaccg cctacatacc tcgctctgct 7080
aatcctgtta ccagtggctg ctgccagtgg cgataagtcg tgtcttaccg ggttggactc 7140
aagacgatag ttaccggata aggcgcagcg gtcgggctga acggggggtt cgtgcacaca 7200
gcccagcttg gagcgaacga cctacaccga actgagatac ctacagcgtg agctatgaga 7260
aagcgccacg cttcccgaag ggagaaaggc ggacaggtat ccggtaagcg gcagggtcgg 7320
aacaggagag cgcacgaggg agcttccagg gggaaacgcc tggtatcttt atagtcctgt 7380
cgggtttcgc cacctctgac ttgagcgtcg atttttgtga tgctcgtcag gggggcggag 7440
cctatggaaa aacgccagca acgcggcctt tttacggttc ctggcctttt gctggccttt 7500
tgctcacatg ttctttcctg cgttatcccc tgattctgtg gataaccgta ttaccgcctt 7560
tgagtgagct gataccgctc gccgcagccg aacgaccgag cgcagcgagt cagtgagcga 7620
ggaagcggaa gagcgcccaa tacgcaaacc gcctctcccc gcgcgttggc cgattcatta 7680
atgcagctgg cacgacaggt ttcccgactg gaaagcgggc agtgagcgca acgcaattaa 7740
tgtgagttag ctcactcatt aggcacccca ggctttacac tttatgcttc cggctcgtat 7800
gttgtgtgga attgtgagcg gataacaatt tcacacagga aacagctatg accatgatta 7860
cgccagattt aattaagg 7878
<210> 27
<211> 7858
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 27
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctactta agtgtttgct 180
gcttgcaatg tttgcccatt ttaggggaat tccgatgctc taatctctct agacaaggtt 240
catatttgta tgggttactt attctctctt tgttgactaa gtcaataatc agaatcagca 300
ggtttgcagt cagattggca gggataagca gcctagctca ggagaagtga gtataaaagc 360
cccaggctgg gagcagccat cagcggccgc caccatgccc gagcaggaaa gacagatcac 420
cgccagagag ggcgccagcc ggaagatcct gagcaagctg agcctgccca ccagagcctg 480
ggagcccgcc atgaagaagt ccttcgcctt cgacaacgtg ggctacgagg gcggcctgga 540
cggactggga ccatcttctc aggtggccac aagcaccgtg cgcatcctgg gcatgacctg 600
ccagagctgc gtgaagtcca tcgaggaccg gatcagcaac ctgaagggca tcatcagcat 660
gaaggtgtcc ctggaacagg gcagcgccac cgtgaaatac gtgccctctg tcgtgtgcct 720
gcagcaggtg tgccaccaga tcggcgacat gggcttcgag gcctctatcg ccgagggaaa 780
ggccgcctct tggccctcta gaagcctgcc tgctcaggaa gccgtcgtga agctgcgggt 840
ggaagggatg acctgtcagt cctgcgtgtc cagcatcgag ggcaaagtgc ggaagctgca 900
gggcgtggtg cgcgtgaaag tgtctctgag caaccaggaa gctgtgatca cctaccagcc 960
ctacctgatc cagcccgagg acctgaggga ccacgtgaac gatatgggat ttgaggccgc 1020
catcaagagc aaggtggccc ctctgtctct gggccccatc gacatcgaga gactgcagag 1080
caccaacccc aagcggcctc tgagcagcgc caaccagaac ttcaacaaca gcgagacact 1140
gggccaccag ggcagccacg tcgtgacact gcagctgcgg atcgacggaa tgcactgcaa 1200
gagctgtgtg ctgaacatcg aggaaaacat cggccagctg ctgggagtgc agagcatcca 1260
ggtgtcactg gaaaacaaga ccgcccaggt gaagtacgac cccagctgca caagccccgt 1320
ggccctgcag agagccattg aagctctgcc ccctggcaac ttcaaagtgt ccctgcctga 1380
cggagccgag ggctccggaa cagatcacag aagcagcagc agccacagcc ctggcagccc 1440
ccctagaaat caggtgcagg gcacctgtag caccaccctg atcgccattg ccggcatgac 1500
atgcgccagc tgcgtgcact ctattgaggg catgatctcc cagctggaag gcgtgcagca 1560
gatcagtgtg tctctggccg agggcaccgc cacagtgctg tacaacccta gcgtgatcag 1620
ccccgaagaa ctgagagccg ccattgagga catgggattc gaagccagcg tggtgtccga 1680
gagctgctcc accaaccctc tgggcaatca cagcgccggc aacagcatgg tgcagaccac 1740
cgacggcacc cccaccagcg tgcaggaagt ggccccacat acaggcagac tgcccgccaa 1800
tcacgccccc gatatcctgg ccaagagccc ccagagtaca agagccgtgg ccccccagaa 1860
gtgcttcctg cagatcaagg gcatgacttg tgcctcttgt gtgtccaata tcgagcggaa 1920
cctgcagaaa gaggccggcg tgctgtctgt gctggtggct ctgatggccg gcaaggccga 1980
gatcaaatac gaccccgaag tgattcagcc cctggaaatc gcccagttta tccaggacct 2040
gggctttgaa gccgccgtga tggaagatta cgccggctcc gacggcaaca tcgagctgac 2100
catcaccgga atgacctgcg cctcctgtgt gcacaacatt gagtccaagc tgacccggac 2160
caacggcatc acctacgcct ctgtggctct ggccacctcc aaggccctcg tgaagttcga 2220
tcccgagatc atcggcccca gggacatcat caagatcatc gaagagatcg gcttccacgc 2280
cagcctggcc cagaggaacc ctaacgccca ccacctggac cacaagatgg aaatcaagca 2340
gtggaagaaa agcttcctgt gcagcctggt gttcggcatc cccgtgatgg ccctgatgat 2400
ctacatgctg atccccagca acgagcccca ccagtccatg gtgctggatc acaacatcat 2460
ccccggcctg tctatcctga acctgatctt cttcatcctg tgcaccttcg tgcagctgct 2520
gggcggctgg tacttctacg tgcaggccta caagtccctg cggcacagat ccgccaacat 2580
ggacgtgctg atcgtgctgg ccacatctat cgcctacgtg tactccctcg tgatcctggt 2640
ggtggccgtg gccgagaaag ccgagagaag ccctgtgacc ttcttcgaca ccccccctat 2700
gctgttcgtg tttatcgccc tgggccggtg gctggaacac ctggccaaaa gcaagaccag 2760
cgaggccctg gctaagctga tgagtctgca ggccaccgag gccacagtcg tgaccctggg 2820
cgaggacaac ctgatcatcc gcgaggaaca ggtgccaatg gaactggtgc agcggggcga 2880
catcgtgaag gtggtgcctg gcggcaagtt ccccgtggac ggaaaagtgc tggaagggaa 2940
taccatggcc gacgagagcc tgatcacagg cgaggccatg cccgtgacca agaaacctgg 3000
cagcacagtg atcgccggca gcatcaatgc ccacggcagc gtgctgatta aggccacaca 3060
cgtgggcaac gataccaccc tggctcagat tgtgaagctg gtggaagagg cccagatgag 3120
caaggccccc attcagcagc tggctgaccg gttcagcggc tacttcgtgc cctttatcat 3180
catcatgagc accctgacac tggtcgtgtg gatcgtgatc ggctttatcg acttcggagt 3240
ggtgcagaga tacttcccca accctaacaa gcacatcagc cagacagaag tgatcatcag 3300
attcgccttt cagaccagca tcaccgtgct gtgtatcgcc tgcccctgta gcctgggact 3360
ggccacacct accgctgtga tggtgggaac aggcgtggcc gctcagaacg gcatcctgat 3420
caaggggggc aagcctctgg aaatggctca caagatcaag accgtgatgt tcgacaagac 3480
cggcaccatc acccacggcg tgcccagagt gatgagagtg ctgctgctgg gggatgtggc 3540
caccctgcct ctgagaaagg tgctggctgt cgtgggcaca gccgaggcta gctctgaaca 3600
cccactggga gtggccgtga caaagtactg caaagaggaa ctgggcaccg aaaccctggg 3660
ctactgcacc gactttcagg ccgtgcctgg ctgtggcatc ggctgcaagg tgtccaacgt 3720
ggaaggcatc ctggcccaca gcgagaggcc actgtctgcc cctgccagcc acctgaacga 3780
ggccggatct ctgcccgccg aaaaggacgc tgtgccccag accttctctg tgctgattgg 3840
caacagagag tggctgcggc ggaacggcct gaccatctcc tccgatgtgt ccgacgccat 3900
gaccgaccac gagatgaagg gccagaccgc cattctggtg gccattgacg gggtgctgtg 3960
cggcatgatc gcaatcgccg atgccgtgaa acaggaagca gcactggccg tgcacaccct 4020
gcagtctatg ggagtggatg tggtgctgat caccggcgac aacagaaaga ccgccagggc 4080
cattgccacc caggtgggca tcaacaaggt gttcgccgag gtgctgccca gccacaaagt 4140
ggccaaggtg caggaactgc agaacaaagg caaaaaggtg gccatggtgg gagatggcgt 4200
gaacgactct cctgctctgg cccaggcaga tatgggcgtg gccatcggca caggcaccga 4260
cgtggcaatt gaggctgctg acgtggtgct gattcggaac gacctgctgg acgtggtggc 4320
ctccatccac ctgtccaaga gaaccgtgcg gcggatcaga atcaacctgg tgctggcact 4380
gatctataac ctcgtgggca tccctatcgc cgctggcgtg ttcatgccta tcggaatcgt 4440
gctgcagccc tggatgggct ctgccgccat ggctgcaagc tccgtgtctg tggtgctgtc 4500
cagcctgcag ctgaagtgct acaagaagcc cgacctggaa agatacgagg cccaggccca 4560
cggacacatg aagcctctga cagcctccca ggtgtccgtg cacatcggca tggacgacag 4620
atggcgggac agccctagag ccaccccttg ggatcaggtg tcatacgtgt cacaggtgtc 4680
cctgagcagc ctgaccagcg acaagcccag cagacatagc gccgctgccg acgacgatgg 4740
ggacaagtgg tccctgctgc tgaacggccg ggatgaggaa cagtacatct gataagcatg 4800
caataaagtc tgagtgggcg gcagcctgtg tgtgcctggg ttctctctgt cccggaatgt 4860
gcaaacaatg gaggtgctcg agtagataag tagcatggcg ggttaatcat taactacaag 4920
gaacccctag tgatggagtt ggccactccc tctctgcgcg ctcgctcgct cactgaggcc 4980
gggcgaccaa aggtcgcccg acgcccgggc tttgcccggg cggcctcagt gagcgagcga 5040
gcgcgcagcc ttaattaacc taattcactg gccgtcgttt tacaacgtcg tgactgggaa 5100
aaccctggcg ttacccaact taatcgcctt gcagcacatc cccctttcgc cagctggcgt 5160
aatagcgaag aggcccgcac cgatcgccct tcccaacagt tgcgcagcct gaatggcgaa 5220
tgggacgcgc cctgtagcgg cgcattaagc gcggcgggtg tggtggttac gcgcagcgtg 5280
accgctacac ttgccagcgc cctagcgccc gctcctttcg ctttcttccc ttcctttctc 5340
gccacgttcg ccggctttcc ccgtcaagct ctaaatcggg ggctcccttt agggttccga 5400
tttagtgctt tacggcacct cgaccccaaa aaacttgatt agggtgatgg ttcacgtagt 5460
gggccatcgc cctgatagac ggtttttcgc cctttgacgt tggagtccac gttctttaat 5520
agtggactct tgttccaaac tggaacaaca ctcaacccta tctcggtcta ttcttttgat 5580
ttataaggga ttttgccgat ttcggcctat tggttaaaaa atgagctgat ttaacaaaaa 5640
tttaacgcga attttaacaa aatattaacg cttacaattt aggtggcact tttcggggaa 5700
atgtgcgcgg aacccctatt tgtttatttt tctaaataca ttcaaatatg tatccgctca 5760
tgagacaata accctgataa atgcttcaat aatattgaaa aaggaagagt atgagtattc 5820
aacatttccg tgtcgccctt attccctttt ttgcggcatt ttgccttcct gtttttgctc 5880
acccagaaac gctggtgaaa gtaaaagatg ctgaagatca gttgggtgca cgagtgggtt 5940
acatcgaact ggatctcaac agcggtaaga tccttgagag ttttcgcccc gaagaacgtt 6000
ttccaatgat gagcactttt aaagttctgc tatgtggcgc ggtattatcc cgtattgacg 6060
ccgggcaaga gcaactcggt cgccgcatac actattctca gaatgacttg gttgagtact 6120
caccagtcac agaaaagcat cttacggatg gcatgacagt aagagaatta tgcagtgctg 6180
ccataaccat gagtgataac actgcggcca acttacttct gacaacgatc ggaggaccga 6240
aggagctaac cgcttttttg cacaacatgg gggatcatgt aactcgcctt gatcgttggg 6300
aaccggagct gaatgaagcc ataccaaacg acgagcgtga caccacgatg cctgtagcaa 6360
tggcaacaac gttgcgcaaa ctattaactg gcgaactact tactctagct tcccggcaac 6420
aattaataga ctggatggag gcggataaag ttgcaggacc acttctgcgc tcggcccttc 6480
cggctggctg gtttattgct gataaatctg gagccggtga gcgtgggtct cgcggtatca 6540
ttgcagcact ggggccagat ggtaagccct cccgtatcgt agttatctac acgacgggga 6600
gtcaggcaac tatggatgaa cgaaatagac agatcgctga gataggtgcc tcactgatta 6660
agcattggta actgtcagac caagtttact catatatact ttagattgat ttaaaacttc 6720
atttttaatt taaaaggatc taggtgaaga tcctttttga taatctcatg accaaaatcc 6780
cttaacgtga gttttcgttc cactgagcgt cagaccccgt agaaaagatc aaaggatctt 6840
cttgagatcc tttttttctg cgcgtaatct gctgcttgca aacaaaaaaa ccaccgctac 6900
cagcggtggt ttgtttgccg gatcaagagc taccaactct ttttccgaag gtaactggct 6960
tcagcagagc gcagatacca aatactgttc ttctagtgta gccgtagtta ggccaccact 7020
tcaagaactc tgtagcaccg cctacatacc tcgctctgct aatcctgtta ccagtggctg 7080
ctgccagtgg cgataagtcg tgtcttaccg ggttggactc aagacgatag ttaccggata 7140
aggcgcagcg gtcgggctga acggggggtt cgtgcacaca gcccagcttg gagcgaacga 7200
cctacaccga actgagatac ctacagcgtg agctatgaga aagcgccacg cttcccgaag 7260
ggagaaaggc ggacaggtat ccggtaagcg gcagggtcgg aacaggagag cgcacgaggg 7320
agcttccagg gggaaacgcc tggtatcttt atagtcctgt cgggtttcgc cacctctgac 7380
ttgagcgtcg atttttgtga tgctcgtcag gggggcggag cctatggaaa aacgccagca 7440
acgcggcctt tttacggttc ctggcctttt gctggccttt tgctcacatg ttctttcctg 7500
cgttatcccc tgattctgtg gataaccgta ttaccgcctt tgagtgagct gataccgctc 7560
gccgcagccg aacgaccgag cgcagcgagt cagtgagcga ggaagcggaa gagcgcccaa 7620
tacgcaaacc gcctctcccc gcgcgttggc cgattcatta atgcagctgg cacgacaggt 7680
ttcccgactg gaaagcgggc agtgagcgca acgcaattaa tgtgagttag ctcactcatt 7740
aggcacccca ggctttacac tttatgcttc cggctcgtat gttgtgtgga attgtgagcg 7800
gataacaatt tcacacagga aacagctatg accatgatta cgccagattt aattaagg 7858
<210> 28
<211> 7094
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 28
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctactta agctagcagg 180
ttaattttta aaaagcagtc aaaagtccaa gtggcccttg gcagcattta ctctctctgt 240
ttgctctggt taataatctc aggagcacaa acattccaga tccaggttaa tttttaaaaa 300
gcagtcaaaa gtccaagtgg cccttggcag catttactct ctctgtttgc tctggttaat 360
aatctcagga gcacaaacat tccagatccg gcgcgccagg gctggaagct acctttgaca 420
tcatttcctc tgcgaatgca tgtataattt ctacagaacc tattagaaag gatcacccag 480
cctctgcttt tgtacaactt tcccttaaaa aactgccaat tccactgctg tttggcccaa 540
tagtgagaac tttttcctgc tgcctcttgg tgcttttgcc tatggcccct attctgcctg 600
ctgaagacac tcttgccagc atggacttaa acccctccag ctctgacaat cctctttctc 660
ttttgtttta catgaagggt ctggcagcca aagcaatcac tcaaagttca aaccttatca 720
ttttttgctt tgttcctctt ggccttggtt ttgtacatca gctttgaaaa taccatccca 780
gggttaatgc tggggttaat ttataactaa gagtgctcta gttttgcaat acaggacatg 840
ctataaaaat ggaaagatgt tgctttctga gagactgcag aagttggtcg tgaggcactg 900
ggcaggtaag tatcaaggtt acaagacagg tttaaggaga ccaatagaaa ctgggcttgt 960
cgagacagag aagactcttg cgtttctgat aggcacctat tggtcttact gacatccact 1020
ttgcctttct ctccacaggt gtccaggcgg ccgccaccat gcccgagcag gaaagacaga 1080
tcaccgccag agagggcgcc agccggaaga tcctgagcaa gctgagcctg cccaccagag 1140
cctgggagcc cgccatgaag aagtccttcg ccttcgacaa cgtgggctac gagggcggcc 1200
tggacggact gggaccatct tctcaggtgg ccacaagcac cgtgcgcctg gaaatcgccc 1260
agtttatcca ggacctgggc tttgaagccg ccgtgatgga agattacgcc ggctccgacg 1320
gcaacatcga gctgaccatc accggaatga cctgcgcctc ctgtgtgcac aacattgagt 1380
ccaagctgac ccggaccaac ggcatcacct acgcctctgt ggctctggcc acctccaagg 1440
ccctcgtgaa gttcgatccc gagatcatcg gccccaggga catcatcaag atcatcgaag 1500
agatcggctt ccacgccagc ctggcccaga ggaaccctaa cgcccaccac ctggaccaca 1560
agatggaaat caagcagtgg aagaaaagct tcctgtgcag cctggtgttc ggcatccccg 1620
tgatggccct gatgatctac atgctgatcc ccagcaacga gccccaccag tccatggtgc 1680
tggatcacaa catcatcccc ggcctgtcta tcctgaacct gatcttcttc atcctgtgca 1740
ccttcgtgca gctgctgggc ggctggtact tctacgtgca ggcctacaag tccctgcggc 1800
acagatccgc caacatggac gtgctgatcg tgctggccac atctatcgcc tacgtgtact 1860
ccctcgtgat cctggtggtg gccgtggccg agaaagccga gagaagccct gtgaccttct 1920
tcgacacccc ccctatgctg ttcgtgttta tcgccctggg ccggtggctg gaacacctgg 1980
ccaaaagcaa gaccagcgag gccctggcta agctgatgag tctgcaggcc accgaggcca 2040
cagtcgtgac cctgggcgag gacaacctga tcatccgcga ggaacaggtg ccaatggaac 2100
tggtgcagcg gggcgacatc gtgaaggtgg tgcctggcgg caagttcccc gtggacggaa 2160
aagtgctgga agggaatacc atggccgacg agagcctgat cacaggcgag gccatgcccg 2220
tgaccaagaa acctggcagc acagtgatcg ccggcagcat caatgcccac ggcagcgtgc 2280
tgattaaggc cacacacgtg ggcaacgata ccaccctggc tcagattgtg aagctggtgg 2340
aagaggccca gatgagcaag gcccccattc agcagctggc tgaccggttc agcggctact 2400
tcgtgccctt tatcatcatc atgagcaccc tgacactggt cgtgtggatc gtgatcggct 2460
ttatcgactt cggagtggtg cagagatact tccccaaccc taacaagcac atcagccaga 2520
cagaagtgat catcagattc gcctttcaga ccagcatcac cgtgctgtgt atcgcctgcc 2580
cctgtagcct gggactggcc acacctaccg ctgtgatggt gggaacaggc gtggccgctc 2640
agaacggcat cctgatcaag gggggcaagc ctctggaaat ggctcacaag atcaagaccg 2700
tgatgttcga caagaccggc accatcaccc acggcgtgcc cagagtgatg agagtgctgc 2760
tgctggggga tgtggccacc ctgcctctga gaaaggtgct ggctgtcgtg ggcacagccg 2820
aggctagctc tgaacaccca ctgggagtgg ccgtgacaaa gtactgcaaa gaggaactgg 2880
gcaccgaaac cctgggctac tgcaccgact ttcaggccgt gcctggctgt ggcatcggct 2940
gcaaggtgtc caacgtggaa ggcatcctgg cccacagcga gaggccactg tctgcccctg 3000
ccagccacct gaacgaggcc ggatctctgc ccgccgaaaa ggacgctgtg ccccagacct 3060
tctctgtgct gattggcaac agagagtggc tgcggcggaa cggcctgacc atctcctccg 3120
atgtgtccga cgccatgacc gaccacgaga tgaagggcca gaccgccatt ctggtggcca 3180
ttgacggggt gctgtgcggc atgatcgcaa tcgccgatgc cgtgaaacag gaagcagcac 3240
tggccgtgca caccctgcag tctatgggag tggatgtggt gctgatcacc ggcgacaaca 3300
gaaagaccgc cagggccatt gccacccagg tgggcatcaa caaggtgttc gccgaggtgc 3360
tgcccagcca caaagtggcc aaggtgcagg aactgcagaa caaaggcaaa aaggtggcca 3420
tggtgggaga tggcgtgaac gactctcctg ctctggccca ggcagatatg ggcgtggcca 3480
tcggcacagg caccgacgtg gcaattgagg ctgctgacgt ggtgctgatt cggaacgacc 3540
tgctggacgt ggtggcctcc atccacctgt ccaagagaac cgtgcggcgg atcagaatca 3600
acctggtgct ggcactgatc tataacctcg tgggcatccc tatcgccgct ggcgtgttca 3660
tgcctatcgg aatcgtgctg cagccctgga tgggctctgc cgccatggct gcaagctccg 3720
tgtctgtggt gctgtccagc ctgcagctga agtgctacaa gaagcccgac ctggaaagat 3780
acgaggccca ggcccacgga cacatgaagc ctctgacagc ctcccaggtg tccgtgcaca 3840
tcggcatgga cgacagatgg cgggacagcc ctagagccac cccttgggat caggtgtcat 3900
acgtgtcaca ggtgtccctg agcagcctga ccagcgacaa gcccagcaga catagcgccg 3960
ctgccgacga cgatggggac aagtggtccc tgctgctgaa cggccgggat gaggaacagt 4020
acatctgata agcatgcaat aaagtctgag tgggcggcag cctgtgtgtg cctgggttct 4080
ctctgtcccg gaatgtgcaa acaatggagg tgctcgagta gataagtagc atggcgggtt 4140
aatcattaac tacaaggaac ccctagtgat ggagttggcc actccctctc tgcgcgctcg 4200
ctcgctcact gaggccgggc gaccaaaggt cgcccgacgc ccgggctttg cccgggcggc 4260
ctcagtgagc gagcgagcgc gcagccttaa ttaacctaat tcactggccg tcgttttaca 4320
acgtcgtgac tgggaaaacc ctggcgttac ccaacttaat cgccttgcag cacatccccc 4380
tttcgccagc tggcgtaata gcgaagaggc ccgcaccgat cgcccttccc aacagttgcg 4440
cagcctgaat ggcgaatggg acgcgccctg tagcggcgca ttaagcgcgg cgggtgtggt 4500
ggttacgcgc agcgtgaccg ctacacttgc cagcgcccta gcgcccgctc ctttcgcttt 4560
cttcccttcc tttctcgcca cgttcgccgg ctttccccgt caagctctaa atcgggggct 4620
ccctttaggg ttccgattta gtgctttacg gcacctcgac cccaaaaaac ttgattaggg 4680
tgatggttca cgtagtgggc catcgccctg atagacggtt tttcgccctt tgacgttgga 4740
gtccacgttc tttaatagtg gactcttgtt ccaaactgga acaacactca accctatctc 4800
ggtctattct tttgatttat aagggatttt gccgatttcg gcctattggt taaaaaatga 4860
gctgatttaa caaaaattta acgcgaattt taacaaaata ttaacgctta caatttaggt 4920
ggcacttttc ggggaaatgt gcgcggaacc cctatttgtt tatttttcta aatacattca 4980
aatatgtatc cgctcatgag acaataaccc tgataaatgc ttcaataata ttgaaaaagg 5040
aagagtatga gtattcaaca tttccgtgtc gcccttattc ccttttttgc ggcattttgc 5100
cttcctgttt ttgctcaccc agaaacgctg gtgaaagtaa aagatgctga agatcagttg 5160
ggtgcacgag tgggttacat cgaactggat ctcaacagcg gtaagatcct tgagagtttt 5220
cgccccgaag aacgttttcc aatgatgagc acttttaaag ttctgctatg tggcgcggta 5280
ttatcccgta ttgacgccgg gcaagagcaa ctcggtcgcc gcatacacta ttctcagaat 5340
gacttggttg agtactcacc agtcacagaa aagcatctta cggatggcat gacagtaaga 5400
gaattatgca gtgctgccat aaccatgagt gataacactg cggccaactt acttctgaca 5460
acgatcggag gaccgaagga gctaaccgct tttttgcaca acatggggga tcatgtaact 5520
cgccttgatc gttgggaacc ggagctgaat gaagccatac caaacgacga gcgtgacacc 5580
acgatgcctg tagcaatggc aacaacgttg cgcaaactat taactggcga actacttact 5640
ctagcttccc ggcaacaatt aatagactgg atggaggcgg ataaagttgc aggaccactt 5700
ctgcgctcgg cccttccggc tggctggttt attgctgata aatctggagc cggtgagcgt 5760
gggtctcgcg gtatcattgc agcactgggg ccagatggta agccctcccg tatcgtagtt 5820
atctacacga cggggagtca ggcaactatg gatgaacgaa atagacagat cgctgagata 5880
ggtgcctcac tgattaagca ttggtaactg tcagaccaag tttactcata tatactttag 5940
attgatttaa aacttcattt ttaatttaaa aggatctagg tgaagatcct ttttgataat 6000
ctcatgacca aaatccctta acgtgagttt tcgttccact gagcgtcaga ccccgtagaa 6060
aagatcaaag gatcttcttg agatcctttt tttctgcgcg taatctgctg cttgcaaaca 6120
aaaaaaccac cgctaccagc ggtggtttgt ttgccggatc aagagctacc aactcttttt 6180
ccgaaggtaa ctggcttcag cagagcgcag ataccaaata ctgttcttct agtgtagccg 6240
tagttaggcc accacttcaa gaactctgta gcaccgccta catacctcgc tctgctaatc 6300
ctgttaccag tggctgctgc cagtggcgat aagtcgtgtc ttaccgggtt ggactcaaga 6360
cgatagttac cggataaggc gcagcggtcg ggctgaacgg ggggttcgtg cacacagccc 6420
agcttggagc gaacgaccta caccgaactg agatacctac agcgtgagct atgagaaagc 6480
gccacgcttc ccgaagggag aaaggcggac aggtatccgg taagcggcag ggtcggaaca 6540
ggagagcgca cgagggagct tccaggggga aacgcctggt atctttatag tcctgtcggg 6600
tttcgccacc tctgacttga gcgtcgattt ttgtgatgct cgtcaggggg gcggagccta 6660
tggaaaaacg ccagcaacgc ggccttttta cggttcctgg ccttttgctg gccttttgct 6720
cacatgttct ttcctgcgtt atcccctgat tctgtggata accgtattac cgcctttgag 6780
tgagctgata ccgctcgccg cagccgaacg accgagcgca gcgagtcagt gagcgaggaa 6840
gcggaagagc gcccaatacg caaaccgcct ctccccgcgc gttggccgat tcattaatgc 6900
agctggcacg acaggtttcc cgactggaaa gcgggcagtg agcgcaacgc aattaatgtg 6960
agttagctca ctcattaggc accccaggct ttacacttta tgcttccggc tcgtatgttg 7020
tgtggaattg tgagcggata acaatttcac acaggaaaca gctatgacca tgattacgcc 7080
agatttaatt aagg 7094
<210> 29
<211> 7487
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 29
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctactta agctagcagg 180
ttaattttta aaaagcagtc aaaagtccaa gtggcccttg gcagcattta ctctctctgt 240
ttgctctggt taataatctc aggagcacaa acattccaga tccaggttaa tttttaaaaa 300
gcagtcaaaa gtccaagtgg cccttggcag catttactct ctctgtttgc tctggttaat 360
aatctcagga gcacaaacat tccagatccg gcgcgccagg gctggaagct acctttgaca 420
tcatttcctc tgcgaatgca tgtataattt ctacagaacc tattagaaag gatcacccag 480
cctctgcttt tgtacaactt tcccttaaaa aactgccaat tccactgctg tttggcccaa 540
tagtgagaac tttttcctgc tgcctcttgg tgcttttgcc tatggcccct attctgcctg 600
ctgaagacac tcttgccagc atggacttaa acccctccag ctctgacaat cctctttctc 660
ttttgtttta catgaagggt ctggcagcca aagcaatcac tcaaagttca aaccttatca 720
ttttttgctt tgttcctctt ggccttggtt ttgtacatca gctttgaaaa taccatccca 780
gggttaatgc tggggttaat ttataactaa gagtgctcta gttttgcaat acaggacatg 840
ctataaaaat ggaaagatgt tgctttctga gagactgcag aagttggtcg tgaggcactg 900
ggcaggtaag tatcaaggtt acaagacagg tttaaggaga ccaatagaaa ctgggcttgt 960
cgagacagag aagactcttg cgtttctgat aggcacctat tggtcttact gacatccact 1020
ttgcctttct ctccacaggt gtccaggcgg ccgccaccat gcccgagcag gaaagacaga 1080
tcaccgccag agagggcgcc agccggaaga tcctgagcaa gctgagcctg cccaccagag 1140
cctgggagcc cgccatgaag aagtccttcg ccttcgacaa cgtgggctac gagggcggcc 1200
tggacggact gggaccatct tctcaggtgg ccacaagcac cgtgcgcagc cccgaagaac 1260
tgagagccgc cattgaggac atgggattcg aagccagcgt ggtgtccgag agctgctcca 1320
ccaaccctct gggcaatcac agcgccggca acagcatggt gcagaccacc gacggcaccc 1380
ccaccagcgt gcaggaagtg gccccacata caggcagact gcccgccaat cacgcccccg 1440
atatcctggc caagagcccc cagagtacaa gagccgtggc cccccagaag tgcttcctgc 1500
agatcaaggg catgacttgt gcctcttgtg tgtccaatat cgagcggaac ctgcagaaag 1560
aggccggcgt gctgtctgtg ctggtggctc tgatggccgg caaggccgag atcaaatacg 1620
accccgaagt gattcagccc ctggaaatcg cccagtttat ccaggacctg ggctttgaag 1680
ccgccgtgat ggaagattac gccggctccg acggcaacat cgagctgacc atcaccggaa 1740
tgacctgcgc ctcctgtgtg cacaacattg agtccaagct gacccggacc aacggcatca 1800
cctacgcctc tgtggctctg gccacctcca aggccctcgt gaagttcgat cccgagatca 1860
tcggccccag ggacatcatc aagatcatcg aagagatcgg cttccacgcc agcctggccc 1920
agaggaaccc taacgcccac cacctggacc acaagatgga aatcaagcag tggaagaaaa 1980
gcttcctgtg cagcctggtg ttcggcatcc ccgtgatggc cctgatgatc tacatgctga 2040
tccccagcaa cgagccccac cagtccatgg tgctggatca caacatcatc cccggcctgt 2100
ctatcctgaa cctgatcttc ttcatcctgt gcaccttcgt gcagctgctg ggcggctggt 2160
acttctacgt gcaggcctac aagtccctgc ggcacagatc cgccaacatg gacgtgctga 2220
tcgtgctggc cacatctatc gcctacgtgt actccctcgt gatcctggtg gtggccgtgg 2280
ccgagaaagc cgagagaagc cctgtgacct tcttcgacac cccccctatg ctgttcgtgt 2340
ttatcgccct gggccggtgg ctggaacacc tggccaaaag caagaccagc gaggccctgg 2400
ctaagctgat gagtctgcag gccaccgagg ccacagtcgt gaccctgggc gaggacaacc 2460
tgatcatccg cgaggaacag gtgccaatgg aactggtgca gcggggcgac atcgtgaagg 2520
tggtgcctgg cggcaagttc cccgtggacg gaaaagtgct ggaagggaat accatggccg 2580
acgagagcct gatcacaggc gaggccatgc ccgtgaccaa gaaacctggc agcacagtga 2640
tcgccggcag catcaatgcc cacggcagcg tgctgattaa ggccacacac gtgggcaacg 2700
ataccaccct ggctcagatt gtgaagctgg tggaagaggc ccagatgagc aaggccccca 2760
ttcagcagct ggctgaccgg ttcagcggct acttcgtgcc ctttatcatc atcatgagca 2820
ccctgacact ggtcgtgtgg atcgtgatcg gctttatcga cttcggagtg gtgcagagat 2880
acttccccaa ccctaacaag cacatcagcc agacagaagt gatcatcaga ttcgcctttc 2940
agaccagcat caccgtgctg tgtatcgcct gcccctgtag cctgggactg gccacaccta 3000
ccgctgtgat ggtgggaaca ggcgtggccg ctcagaacgg catcctgatc aaggggggca 3060
agcctctgga aatggctcac aagatcaaga ccgtgatgtt cgacaagacc ggcaccatca 3120
cccacggcgt gcccagagtg atgagagtgc tgctgctggg ggatgtggcc accctgcctc 3180
tgagaaaggt gctggctgtc gtgggcacag ccgaggctag ctctgaacac ccactgggag 3240
tggccgtgac aaagtactgc aaagaggaac tgggcaccga aaccctgggc tactgcaccg 3300
actttcaggc cgtgcctggc tgtggcatcg gctgcaaggt gtccaacgtg gaaggcatcc 3360
tggcccacag cgagaggcca ctgtctgccc ctgccagcca cctgaacgag gccggatctc 3420
tgcccgccga aaaggacgct gtgccccaga ccttctctgt gctgattggc aacagagagt 3480
ggctgcggcg gaacggcctg accatctcct ccgatgtgtc cgacgccatg accgaccacg 3540
agatgaaggg ccagaccgcc attctggtgg ccattgacgg ggtgctgtgc ggcatgatcg 3600
caatcgccga tgccgtgaaa caggaagcag cactggccgt gcacaccctg cagtctatgg 3660
gagtggatgt ggtgctgatc accggcgaca acagaaagac cgccagggcc attgccaccc 3720
aggtgggcat caacaaggtg ttcgccgagg tgctgcccag ccacaaagtg gccaaggtgc 3780
aggaactgca gaacaaaggc aaaaaggtgg ccatggtggg agatggcgtg aacgactctc 3840
ctgctctggc ccaggcagat atgggcgtgg ccatcggcac aggcaccgac gtggcaattg 3900
aggctgctga cgtggtgctg attcggaacg acctgctgga cgtggtggcc tccatccacc 3960
tgtccaagag aaccgtgcgg cggatcagaa tcaacctggt gctggcactg atctataacc 4020
tcgtgggcat ccctatcgcc gctggcgtgt tcatgcctat cggaatcgtg ctgcagccct 4080
ggatgggctc tgccgccatg gctgcaagct ccgtgtctgt ggtgctgtcc agcctgcagc 4140
tgaagtgcta caagaagccc gacctggaaa gatacgaggc ccaggcccac ggacacatga 4200
agcctctgac agcctcccag gtgtccgtgc acatcggcat ggacgacaga tggcgggaca 4260
gccctagagc caccccttgg gatcaggtgt catacgtgtc acaggtgtcc ctgagcagcc 4320
tgaccagcga caagcccagc agacatagcg ccgctgccga cgacgatggg gacaagtggt 4380
ccctgctgct gaacggccgg gatgaggaac agtacatctg ataagcatgc aataaagtct 4440
gagtgggcgg cagcctgtgt gtgcctgggt tctctctgtc ccggaatgtg caaacaatgg 4500
aggtgctcga gtagataagt agcatggcgg gttaatcatt aactacaagg aacccctagt 4560
gatggagttg gccactccct ctctgcgcgc tcgctcgctc actgaggccg ggcgaccaaa 4620
ggtcgcccga cgcccgggct ttgcccgggc ggcctcagtg agcgagcgag cgcgcagcct 4680
taattaacct aattcactgg ccgtcgtttt acaacgtcgt gactgggaaa accctggcgt 4740
tacccaactt aatcgccttg cagcacatcc ccctttcgcc agctggcgta atagcgaaga 4800
ggcccgcacc gatcgccctt cccaacagtt gcgcagcctg aatggcgaat gggacgcgcc 4860
ctgtagcggc gcattaagcg cggcgggtgt ggtggttacg cgcagcgtga ccgctacact 4920
tgccagcgcc ctagcgcccg ctcctttcgc tttcttccct tcctttctcg ccacgttcgc 4980
cggctttccc cgtcaagctc taaatcgggg gctcccttta gggttccgat ttagtgcttt 5040
acggcacctc gaccccaaaa aacttgatta gggtgatggt tcacgtagtg ggccatcgcc 5100
ctgatagacg gtttttcgcc ctttgacgtt ggagtccacg ttctttaata gtggactctt 5160
gttccaaact ggaacaacac tcaaccctat ctcggtctat tcttttgatt tataagggat 5220
tttgccgatt tcggcctatt ggttaaaaaa tgagctgatt taacaaaaat ttaacgcgaa 5280
ttttaacaaa atattaacgc ttacaattta ggtggcactt ttcggggaaa tgtgcgcgga 5340
acccctattt gtttattttt ctaaatacat tcaaatatgt atccgctcat gagacaataa 5400
ccctgataaa tgcttcaata atattgaaaa aggaagagta tgagtattca acatttccgt 5460
gtcgccctta ttcccttttt tgcggcattt tgccttcctg tttttgctca cccagaaacg 5520
ctggtgaaag taaaagatgc tgaagatcag ttgggtgcac gagtgggtta catcgaactg 5580
gatctcaaca gcggtaagat ccttgagagt tttcgccccg aagaacgttt tccaatgatg 5640
agcactttta aagttctgct atgtggcgcg gtattatccc gtattgacgc cgggcaagag 5700
caactcggtc gccgcataca ctattctcag aatgacttgg ttgagtactc accagtcaca 5760
gaaaagcatc ttacggatgg catgacagta agagaattat gcagtgctgc cataaccatg 5820
agtgataaca ctgcggccaa cttacttctg acaacgatcg gaggaccgaa ggagctaacc 5880
gcttttttgc acaacatggg ggatcatgta actcgccttg atcgttggga accggagctg 5940
aatgaagcca taccaaacga cgagcgtgac accacgatgc ctgtagcaat ggcaacaacg 6000
ttgcgcaaac tattaactgg cgaactactt actctagctt cccggcaaca attaatagac 6060
tggatggagg cggataaagt tgcaggacca cttctgcgct cggcccttcc ggctggctgg 6120
tttattgctg ataaatctgg agccggtgag cgtgggtctc gcggtatcat tgcagcactg 6180
gggccagatg gtaagccctc ccgtatcgta gttatctaca cgacggggag tcaggcaact 6240
atggatgaac gaaatagaca gatcgctgag ataggtgcct cactgattaa gcattggtaa 6300
ctgtcagacc aagtttactc atatatactt tagattgatt taaaacttca tttttaattt 6360
aaaaggatct aggtgaagat cctttttgat aatctcatga ccaaaatccc ttaacgtgag 6420
ttttcgttcc actgagcgtc agaccccgta gaaaagatca aaggatcttc ttgagatcct 6480
ttttttctgc gcgtaatctg ctgcttgcaa acaaaaaaac caccgctacc agcggtggtt 6540
tgtttgccgg atcaagagct accaactctt tttccgaagg taactggctt cagcagagcg 6600
cagataccaa atactgttct tctagtgtag ccgtagttag gccaccactt caagaactct 6660
gtagcaccgc ctacatacct cgctctgcta atcctgttac cagtggctgc tgccagtggc 6720
gataagtcgt gtcttaccgg gttggactca agacgatagt taccggataa ggcgcagcgg 6780
tcgggctgaa cggggggttc gtgcacacag cccagcttgg agcgaacgac ctacaccgaa 6840
ctgagatacc tacagcgtga gctatgagaa agcgccacgc ttcccgaagg gagaaaggcg 6900
gacaggtatc cggtaagcgg cagggtcgga acaggagagc gcacgaggga gcttccaggg 6960
ggaaacgcct ggtatcttta tagtcctgtc gggtttcgcc acctctgact tgagcgtcga 7020
tttttgtgat gctcgtcagg ggggcggagc ctatggaaaa acgccagcaa cgcggccttt 7080
ttacggttcc tggccttttg ctggcctttt gctcacatgt tctttcctgc gttatcccct 7140
gattctgtgg ataaccgtat taccgccttt gagtgagctg ataccgctcg ccgcagccga 7200
acgaccgagc gcagcgagtc agtgagcgag gaagcggaag agcgcccaat acgcaaaccg 7260
cctctccccg cgcgttggcc gattcattaa tgcagctggc acgacaggtt tcccgactgg 7320
aaagcgggca gtgagcgcaa cgcaattaat gtgagttagc tcactcatta ggcaccccag 7380
gctttacact ttatgcttcc ggctcgtatg ttgtgtggaa ttgtgagcgg ataacaattt 7440
cacacaggaa acagctatga ccatgattac gccagattta attaagg 7487
<210> 30
<211> 7788
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 30
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctactta agtgtttgct 180
gcttgcaatg tttgcccatt ttaggggaat tcactcaaag ttcaaacctt atcatttttt 240
gctttgttcc tcttggcctt ggttttgtac atcagctttg aaaataccat cccagggtta 300
atgctggggt taatttataa ctaagagtgc tctagttttg caatacagga catgctataa 360
aaatggaaag atgttgcttt ctgagagaca gcggccgcca ccatgcccga gcaggaaaga 420
cagatcaccg ccagagaggg cgccagccgg aagatcctga gcaagctgag cctgcccacc 480
agagcctggg agcccgccat gaagaagtcc ttcgccttcg acaacgtggg ctacgagggc 540
ggcctggacg gactgggacc atcttctcag gtggccacaa gcaccgtgcg catcctgggc 600
atgacctgcc agagctgcgt gaagtccatc gaggaccgga tcagcaacct gaagggcatc 660
atcagcatga aggtgtccct ggaacagggc agcgccaccg tgaaatacgt gccctctgtc 720
gtgtgcctgc agcaggtgtg ccaccagatc ggcgacatgg gcttcgaggc ctctatcgcc 780
gagggaaagg ccgcctcttg gccctctaga agcctgcctg ctcaggaagc cgtcgtgaag 840
ctgcgggtgg aagggatgac ctgtcagtcc tgcgtgtcca gcatcgaggg caaagtgcgg 900
aagctgcagg gcgtggtgcg cgtgaaagtg tctctgagca accaggaagc tgtgatcacc 960
taccagccct acctgatcca gcccgaggac ctgagggacc acgtgaacga tatgggattt 1020
gaggccgcca tcaagagcaa ggtggcccct ctgtctctgg gccccatcga catcgagaga 1080
ctgcagagca ccaaccccaa gcggcctctg agcagcgcca accagaactt caacaacagc 1140
gagacactgg gccaccaggg cagccacgtc gtgacactgc agagcatcca ggtgtcactg 1200
gaaaacaaga ccgcccaggt gaagtacgac cccagctgca caagccccgt ggccctgcag 1260
agagccattg aagctctgcc ccctggcaac ttcaaagtgt ccctgcctga cggagccgag 1320
ggctccggaa cagatcacag aagcagcagc agccacagcc ctggcagccc ccctagaaat 1380
caggtgcagg gcacctgtag caccaccctg atcgccattg ccggcatgac atgcgccagc 1440
tgcgtgcact ctattgaggg catgatctcc cagctggaag gcgtgcagca gatcagtgtg 1500
tctctggccg agggcaccgc cacagtgctg tacaacccta gcgtgatcag ccccgaagaa 1560
ctgagagccg ccattgagga catgggattc gaagccagcg tggtgtccga gagctgctcc 1620
accaaccctc tgggcaatca cagcgccggc aacagcatgg tgcagaccac cgacggcacc 1680
cccaccagcg tgcaggaagt ggccccacat acaggcagac tgcccgccaa tcacgccccc 1740
gatatcctgg ccaagagccc ccagagtaca agagccgtgg ccccccagaa gtgcttcctg 1800
cagatcaagg gcatgacttg tgcctcttgt gtgtccaata tcgagcggaa cctgcagaaa 1860
gaggccggcg tgctgtctgt gctggtggct ctgatggccg gcaaggccga gatcaaatac 1920
gaccccgaag tgattcagcc cctggaaatc gcccagttta tccaggacct gggctttgaa 1980
gccgccgtga tggaagatta cgccggctcc gacggcaaca tcgagctgac catcaccgga 2040
atgacctgcg cctcctgtgt gcacaacatt gagtccaagc tgacccggac caacggcatc 2100
acctacgcct ctgtggctct ggccacctcc aaggccctcg tgaagttcga tcccgagatc 2160
atcggcccca gggacatcat caagatcatc gaagagatcg gcttccacgc cagcctggcc 2220
cagaggaacc ctaacgccca ccacctggac cacaagatgg aaatcaagca gtggaagaaa 2280
agcttcctgt gcagcctggt gttcggcatc cccgtgatgg ccctgatgat ctacatgctg 2340
atccccagca acgagcccca ccagtccatg gtgctggatc acaacatcat ccccggcctg 2400
tctatcctga acctgatctt cttcatcctg tgcaccttcg tgcagctgct gggcggctgg 2460
tacttctacg tgcaggccta caagtccctg cggcacagat ccgccaacat ggacgtgctg 2520
atcgtgctgg ccacatctat cgcctacgtg tactccctcg tgatcctggt ggtggccgtg 2580
gccgagaaag ccgagagaag ccctgtgacc ttcttcgaca ccccccctat gctgttcgtg 2640
tttatcgccc tgggccggtg gctggaacac ctggccaaaa gcaagaccag cgaggccctg 2700
gctaagctga tgagtctgca ggccaccgag gccacagtcg tgaccctggg cgaggacaac 2760
ctgatcatcc gcgaggaaca ggtgccaatg gaactggtgc agcggggcga catcgtgaag 2820
gtggtgcctg gcggcaagtt ccccgtggac ggaaaagtgc tggaagggaa taccatggcc 2880
gacgagagcc tgatcacagg cgaggccatg cccgtgacca agaaacctgg cagcacagtg 2940
atcgccggca gcatcaatgc ccacggcagc gtgctgatta aggccacaca cgtgggcaac 3000
gataccaccc tggctcagat tgtgaagctg gtggaagagg cccagatgag caaggccccc 3060
attcagcagc tggctgaccg gttcagcggc tacttcgtgc cctttatcat catcatgagc 3120
accctgacac tggtcgtgtg gatcgtgatc ggctttatcg acttcggagt ggtgcagaga 3180
tacttcccca accctaacaa gcacatcagc cagacagaag tgatcatcag attcgccttt 3240
cagaccagca tcaccgtgct gtgtatcgcc tgcccctgta gcctgggact ggccacacct 3300
accgctgtga tggtgggaac aggcgtggcc gctcagaacg gcatcctgat caaggggggc 3360
aagcctctgg aaatggctca caagatcaag accgtgatgt tcgacaagac cggcaccatc 3420
acccacggcg tgcccagagt gatgagagtg ctgctgctgg gggatgtggc caccctgcct 3480
ctgagaaagg tgctggctgt cgtgggcaca gccgaggcta gctctgaaca cccactggga 3540
gtggccgtga caaagtactg caaagaggaa ctgggcaccg aaaccctggg ctactgcacc 3600
gactttcagg ccgtgcctgg ctgtggcatc ggctgcaagg tgtccaacgt ggaaggcatc 3660
ctggcccaca gcgagaggcc actgtctgcc cctgccagcc acctgaacga ggccggatct 3720
ctgcccgccg aaaaggacgc tgtgccccag accttctctg tgctgattgg caacagagag 3780
tggctgcggc ggaacggcct gaccatctcc tccgatgtgt ccgacgccat gaccgaccac 3840
gagatgaagg gccagaccgc cattctggtg gccattgacg gggtgctgtg cggcatgatc 3900
gcaatcgccg atgccgtgaa acaggaagca gcactggccg tgcacaccct gcagtctatg 3960
ggagtggatg tggtgctgat caccggcgac aacagaaaga ccgccagggc cattgccacc 4020
caggtgggca tcaacaaggt gttcgccgag gtgctgccca gccacaaagt ggccaaggtg 4080
caggaactgc agaacaaagg caaaaaggtg gccatggtgg gagatggcgt gaacgactct 4140
cctgctctgg cccaggcaga tatgggcgtg gccatcggca caggcaccga cgtggcaatt 4200
gaggctgctg acgtggtgct gattcggaac gacctgctgg acgtggtggc ctccatccac 4260
ctgtccaaga gaaccgtgcg gcggatcaga atcaacctgg tgctggcact gatctataac 4320
ctcgtgggca tccctatcgc cgctggcgtg ttcatgccta tcggaatcgt gctgcagccc 4380
tggatgggct ctgccgccat ggctgcaagc tccgtgtctg tggtgctgtc cagcctgcag 4440
ctgaagtgct acaagaagcc cgacctggaa agatacgagg cccaggccca cggacacatg 4500
aagcctctga cagcctccca ggtgtccgtg cacatcggca tggacgacag atggcgggac 4560
agccctagag ccaccccttg ggatcaggtg tcatacgtgt cacaggtgtc cctgagcagc 4620
ctgaccagcg acaagcccag cagacatagc gccgctgccg acgacgatgg ggacaagtgg 4680
tccctgctgc tgaacggccg ggatgaggaa cagtacatct gataagcatg caataaagtc 4740
tgagtgggcg gcagcctgtg tgtgcctggg ttctctctgt cccggaatgt gcaaacaatg 4800
gaggtgctcg agtagataag tagcatggcg ggttaatcat taactacaag gaacccctag 4860
tgatggagtt ggccactccc tctctgcgcg ctcgctcgct cactgaggcc gggcgaccaa 4920
aggtcgcccg acgcccgggc tttgcccggg cggcctcagt gagcgagcga gcgcgcagcc 4980
ttaattaacc taattcactg gccgtcgttt tacaacgtcg tgactgggaa aaccctggcg 5040
ttacccaact taatcgcctt gcagcacatc cccctttcgc cagctggcgt aatagcgaag 5100
aggcccgcac cgatcgccct tcccaacagt tgcgcagcct gaatggcgaa tgggacgcgc 5160
cctgtagcgg cgcattaagc gcggcgggtg tggtggttac gcgcagcgtg accgctacac 5220
ttgccagcgc cctagcgccc gctcctttcg ctttcttccc ttcctttctc gccacgttcg 5280
ccggctttcc ccgtcaagct ctaaatcggg ggctcccttt agggttccga tttagtgctt 5340
tacggcacct cgaccccaaa aaacttgatt agggtgatgg ttcacgtagt gggccatcgc 5400
cctgatagac ggtttttcgc cctttgacgt tggagtccac gttctttaat agtggactct 5460
tgttccaaac tggaacaaca ctcaacccta tctcggtcta ttcttttgat ttataaggga 5520
ttttgccgat ttcggcctat tggttaaaaa atgagctgat ttaacaaaaa tttaacgcga 5580
attttaacaa aatattaacg cttacaattt aggtggcact tttcggggaa atgtgcgcgg 5640
aacccctatt tgtttatttt tctaaataca ttcaaatatg tatccgctca tgagacaata 5700
accctgataa atgcttcaat aatattgaaa aaggaagagt atgagtattc aacatttccg 5760
tgtcgccctt attccctttt ttgcggcatt ttgccttcct gtttttgctc acccagaaac 5820
gctggtgaaa gtaaaagatg ctgaagatca gttgggtgca cgagtgggtt acatcgaact 5880
ggatctcaac agcggtaaga tccttgagag ttttcgcccc gaagaacgtt ttccaatgat 5940
gagcactttt aaagttctgc tatgtggcgc ggtattatcc cgtattgacg ccgggcaaga 6000
gcaactcggt cgccgcatac actattctca gaatgacttg gttgagtact caccagtcac 6060
agaaaagcat cttacggatg gcatgacagt aagagaatta tgcagtgctg ccataaccat 6120
gagtgataac actgcggcca acttacttct gacaacgatc ggaggaccga aggagctaac 6180
cgcttttttg cacaacatgg gggatcatgt aactcgcctt gatcgttggg aaccggagct 6240
gaatgaagcc ataccaaacg acgagcgtga caccacgatg cctgtagcaa tggcaacaac 6300
gttgcgcaaa ctattaactg gcgaactact tactctagct tcccggcaac aattaataga 6360
ctggatggag gcggataaag ttgcaggacc acttctgcgc tcggcccttc cggctggctg 6420
gtttattgct gataaatctg gagccggtga gcgtgggtct cgcggtatca ttgcagcact 6480
ggggccagat ggtaagccct cccgtatcgt agttatctac acgacgggga gtcaggcaac 6540
tatggatgaa cgaaatagac agatcgctga gataggtgcc tcactgatta agcattggta 6600
actgtcagac caagtttact catatatact ttagattgat ttaaaacttc atttttaatt 6660
taaaaggatc taggtgaaga tcctttttga taatctcatg accaaaatcc cttaacgtga 6720
gttttcgttc cactgagcgt cagaccccgt agaaaagatc aaaggatctt cttgagatcc 6780
tttttttctg cgcgtaatct gctgcttgca aacaaaaaaa ccaccgctac cagcggtggt 6840
ttgtttgccg gatcaagagc taccaactct ttttccgaag gtaactggct tcagcagagc 6900
gcagatacca aatactgttc ttctagtgta gccgtagtta ggccaccact tcaagaactc 6960
tgtagcaccg cctacatacc tcgctctgct aatcctgtta ccagtggctg ctgccagtgg 7020
cgataagtcg tgtcttaccg ggttggactc aagacgatag ttaccggata aggcgcagcg 7080
gtcgggctga acggggggtt cgtgcacaca gcccagcttg gagcgaacga cctacaccga 7140
actgagatac ctacagcgtg agctatgaga aagcgccacg cttcccgaag ggagaaaggc 7200
ggacaggtat ccggtaagcg gcagggtcgg aacaggagag cgcacgaggg agcttccagg 7260
gggaaacgcc tggtatcttt atagtcctgt cgggtttcgc cacctctgac ttgagcgtcg 7320
atttttgtga tgctcgtcag gggggcggag cctatggaaa aacgccagca acgcggcctt 7380
tttacggttc ctggcctttt gctggccttt tgctcacatg ttctttcctg cgttatcccc 7440
tgattctgtg gataaccgta ttaccgcctt tgagtgagct gataccgctc gccgcagccg 7500
aacgaccgag cgcagcgagt cagtgagcga ggaagcggaa gagcgcccaa tacgcaaacc 7560
gcctctcccc gcgcgttggc cgattcatta atgcagctgg cacgacaggt ttcccgactg 7620
gaaagcgggc agtgagcgca acgcaattaa tgtgagttag ctcactcatt aggcacccca 7680
ggctttacac tttatgcttc cggctcgtat gttgtgtgga attgtgagcg gataacaatt 7740
tcacacagga aacagctatg accatgatta cgccagattt aattaagg 7788
<210> 31
<211> 7686
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 31
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctactta agtgtttgct 180
gcttgcaatg tttgcccatt ttaggggaat tcactcaaag ttcaaacctt atcatttttt 240
gctttgttcc tcttggcctt ggttttgtac atcagctttg aaaataccat cccagggtta 300
atgctggggt taatttataa ctaagagtgc tctagttttg caatacagga catgctataa 360
aaatggaaag atgttgcttt ctgagagaca gcggccgcca ccatgcccga gcaggaaaga 420
cagatcaccg ccagagaggg cgccagccgg aagatcctga gcaagctgag cctgcccacc 480
agagcctggg agcccgccat gaagaagtcc ttcgccttcg acaacgtggg ctacgagggc 540
ggcctggacg gactgggacc atcttctcag gtggccacaa gcaccgtgcg catcctgggc 600
atgacctgcc agagctgcgt gaagtccatc gaggaccgga tcagcaacct gaagggcatc 660
atcagcatga aggtgtccct ggaacagggc agcgccaccg tgaaatacgt gccctctgtc 720
gtgtgcctgc agcaggtgtg ccaccagatc ggcgacatgg gcttcgaggc ctctatcgcc 780
gagggaaagg ccgcctcttg gccctctaga agcctgcctg ctcaggaagc cgtcgtgaag 840
gaggccgcca tcaagagcaa ggtggcccct ctgtctctgg gccccatcga catcgagaga 900
ctgcagagca ccaaccccaa gcggcctctg agcagcgcca accagaactt caacaacagc 960
gagacactgg gccaccaggg cagccacgtc gtgacactgc agctgcggat cgacggaatg 1020
cactgcaaga gctgtgtgct gaacatcgag gaaaacatcg gccagctgct gggagtgcag 1080
agcatccagg tgtcactgga aaacaagacc gcccaggtga agtacgaccc cagctgcaca 1140
agccccgtgg ccctgcagag agccattgaa gctctgcccc ctggcaactt caaagtgtcc 1200
ctgcctgacg gagccgaggg ctccggaaca gatcacagaa gcagcagcag ccacagccct 1260
ggcagccccc ctagaaatca ggtgcagggc acctgtagca ccaccctgat cgccattgcc 1320
ggcatgacat gcgccagctg cgtgcactct attgagggca tgatctccca gctggaaggc 1380
gtgcagcaga tcagtgtgtc tctggccgag ggcaccgcca cagtgctgta caaccctagc 1440
gtgatcagcc ccgaagaact gagagccgcc attgaggaca tgggattcga agccagcgtg 1500
gtgtccgaga gctgctccac caaccctctg ggcaatcaca gcgccggcaa cagcatggtg 1560
cagaccaccg acggcacccc caccagcgtg caggaagtgg ccccacatac aggcagactg 1620
cccgccaatc acgcccccga tatcctggcc aagagccccc agagtacaag agccgtggcc 1680
ccccagaagt gcttcctgca gatcaagggc atgacttgtg cctcttgtgt gtccaatatc 1740
gagcggaacc tgcagaaaga ggccggcgtg ctgtctgtgc tggtggctct gatggccggc 1800
aaggccgaga tcaaatacga ccccgaagtg attcagcccc tggaaatcgc ccagtttatc 1860
caggacctgg gctttgaagc cgccgtgatg gaagattacg ccggctccga cggcaacatc 1920
gagctgacca tcaccggaat gacctgcgcc tcctgtgtgc acaacattga gtccaagctg 1980
acccggacca acggcatcac ctacgcctct gtggctctgg ccacctccaa ggccctcgtg 2040
aagttcgatc ccgagatcat cggccccagg gacatcatca agatcatcga agagatcggc 2100
ttccacgcca gcctggccca gaggaaccct aacgcccacc acctggacca caagatggaa 2160
atcaagcagt ggaagaaaag cttcctgtgc agcctggtgt tcggcatccc cgtgatggcc 2220
ctgatgatct acatgctgat ccccagcaac gagccccacc agtccatggt gctggatcac 2280
aacatcatcc ccggcctgtc tatcctgaac ctgatcttct tcatcctgtg caccttcgtg 2340
cagctgctgg gcggctggta cttctacgtg caggcctaca agtccctgcg gcacagatcc 2400
gccaacatgg acgtgctgat cgtgctggcc acatctatcg cctacgtgta ctccctcgtg 2460
atcctggtgg tggccgtggc cgagaaagcc gagagaagcc ctgtgacctt cttcgacacc 2520
ccccctatgc tgttcgtgtt tatcgccctg ggccggtggc tggaacacct ggccaaaagc 2580
aagaccagcg aggccctggc taagctgatg agtctgcagg ccaccgaggc cacagtcgtg 2640
accctgggcg aggacaacct gatcatccgc gaggaacagg tgccaatgga actggtgcag 2700
cggggcgaca tcgtgaaggt ggtgcctggc ggcaagttcc ccgtggacgg aaaagtgctg 2760
gaagggaata ccatggccga cgagagcctg atcacaggcg aggccatgcc cgtgaccaag 2820
aaacctggca gcacagtgat cgccggcagc atcaatgccc acggcagcgt gctgattaag 2880
gccacacacg tgggcaacga taccaccctg gctcagattg tgaagctggt ggaagaggcc 2940
cagatgagca aggcccccat tcagcagctg gctgaccggt tcagcggcta cttcgtgccc 3000
tttatcatca tcatgagcac cctgacactg gtcgtgtgga tcgtgatcgg ctttatcgac 3060
ttcggagtgg tgcagagata cttccccaac cctaacaagc acatcagcca gacagaagtg 3120
atcatcagat tcgcctttca gaccagcatc accgtgctgt gtatcgcctg cccctgtagc 3180
ctgggactgg ccacacctac cgctgtgatg gtgggaacag gcgtggccgc tcagaacggc 3240
atcctgatca aggggggcaa gcctctggaa atggctcaca agatcaagac cgtgatgttc 3300
gacaagaccg gcaccatcac ccacggcgtg cccagagtga tgagagtgct gctgctgggg 3360
gatgtggcca ccctgcctct gagaaaggtg ctggctgtcg tgggcacagc cgaggctagc 3420
tctgaacacc cactgggagt ggccgtgaca aagtactgca aagaggaact gggcaccgaa 3480
accctgggct actgcaccga ctttcaggcc gtgcctggct gtggcatcgg ctgcaaggtg 3540
tccaacgtgg aaggcatcct ggcccacagc gagaggccac tgtctgcccc tgccagccac 3600
ctgaacgagg ccggatctct gcccgccgaa aaggacgctg tgccccagac cttctctgtg 3660
ctgattggca acagagagtg gctgcggcgg aacggcctga ccatctcctc cgatgtgtcc 3720
gacgccatga ccgaccacga gatgaagggc cagaccgcca ttctggtggc cattgacggg 3780
gtgctgtgcg gcatgatcgc aatcgccgat gccgtgaaac aggaagcagc actggccgtg 3840
cacaccctgc agtctatggg agtggatgtg gtgctgatca ccggcgacaa cagaaagacc 3900
gccagggcca ttgccaccca ggtgggcatc aacaaggtgt tcgccgaggt gctgcccagc 3960
cacaaagtgg ccaaggtgca ggaactgcag aacaaaggca aaaaggtggc catggtggga 4020
gatggcgtga acgactctcc tgctctggcc caggcagata tgggcgtggc catcggcaca 4080
ggcaccgacg tggcaattga ggctgctgac gtggtgctga ttcggaacga cctgctggac 4140
gtggtggcct ccatccacct gtccaagaga accgtgcggc ggatcagaat caacctggtg 4200
ctggcactga tctataacct cgtgggcatc cctatcgccg ctggcgtgtt catgcctatc 4260
ggaatcgtgc tgcagccctg gatgggctct gccgccatgg ctgcaagctc cgtgtctgtg 4320
gtgctgtcca gcctgcagct gaagtgctac aagaagcccg acctggaaag atacgaggcc 4380
caggcccacg gacacatgaa gcctctgaca gcctcccagg tgtccgtgca catcggcatg 4440
gacgacagat ggcgggacag ccctagagcc accccttggg atcaggtgtc atacgtgtca 4500
caggtgtccc tgagcagcct gaccagcgac aagcccagca gacatagcgc cgctgccgac 4560
gacgatgggg acaagtggtc cctgctgctg aacggccggg atgaggaaca gtacatctga 4620
taagcatgca ataaagtctg agtgggcggc agcctgtgtg tgcctgggtt ctctctgtcc 4680
cggaatgtgc aaacaatgga ggtgctcgag tagataagta gcatggcggg ttaatcatta 4740
actacaagga acccctagtg atggagttgg ccactccctc tctgcgcgct cgctcgctca 4800
ctgaggccgg gcgaccaaag gtcgcccgac gcccgggctt tgcccgggcg gcctcagtga 4860
gcgagcgagc gcgcagcctt aattaaccta attcactggc cgtcgtttta caacgtcgtg 4920
actgggaaaa ccctggcgtt acccaactta atcgccttgc agcacatccc cctttcgcca 4980
gctggcgtaa tagcgaagag gcccgcaccg atcgcccttc ccaacagttg cgcagcctga 5040
atggcgaatg ggacgcgccc tgtagcggcg cattaagcgc ggcgggtgtg gtggttacgc 5100
gcagcgtgac cgctacactt gccagcgccc tagcgcccgc tcctttcgct ttcttccctt 5160
cctttctcgc cacgttcgcc ggctttcccc gtcaagctct aaatcggggg ctccctttag 5220
ggttccgatt tagtgcttta cggcacctcg accccaaaaa acttgattag ggtgatggtt 5280
cacgtagtgg gccatcgccc tgatagacgg tttttcgccc tttgacgttg gagtccacgt 5340
tctttaatag tggactcttg ttccaaactg gaacaacact caaccctatc tcggtctatt 5400
cttttgattt ataagggatt ttgccgattt cggcctattg gttaaaaaat gagctgattt 5460
aacaaaaatt taacgcgaat tttaacaaaa tattaacgct tacaatttag gtggcacttt 5520
tcggggaaat gtgcgcggaa cccctatttg tttatttttc taaatacatt caaatatgta 5580
tccgctcatg agacaataac cctgataaat gcttcaataa tattgaaaaa ggaagagtat 5640
gagtattcaa catttccgtg tcgcccttat tccctttttt gcggcatttt gccttcctgt 5700
ttttgctcac ccagaaacgc tggtgaaagt aaaagatgct gaagatcagt tgggtgcacg 5760
agtgggttac atcgaactgg atctcaacag cggtaagatc cttgagagtt ttcgccccga 5820
agaacgtttt ccaatgatga gcacttttaa agttctgcta tgtggcgcgg tattatcccg 5880
tattgacgcc gggcaagagc aactcggtcg ccgcatacac tattctcaga atgacttggt 5940
tgagtactca ccagtcacag aaaagcatct tacggatggc atgacagtaa gagaattatg 6000
cagtgctgcc ataaccatga gtgataacac tgcggccaac ttacttctga caacgatcgg 6060
aggaccgaag gagctaaccg cttttttgca caacatgggg gatcatgtaa ctcgccttga 6120
tcgttgggaa ccggagctga atgaagccat accaaacgac gagcgtgaca ccacgatgcc 6180
tgtagcaatg gcaacaacgt tgcgcaaact attaactggc gaactactta ctctagcttc 6240
ccggcaacaa ttaatagact ggatggaggc ggataaagtt gcaggaccac ttctgcgctc 6300
ggcccttccg gctggctggt ttattgctga taaatctgga gccggtgagc gtgggtctcg 6360
cggtatcatt gcagcactgg ggccagatgg taagccctcc cgtatcgtag ttatctacac 6420
gacggggagt caggcaacta tggatgaacg aaatagacag atcgctgaga taggtgcctc 6480
actgattaag cattggtaac tgtcagacca agtttactca tatatacttt agattgattt 6540
aaaacttcat ttttaattta aaaggatcta ggtgaagatc ctttttgata atctcatgac 6600
caaaatccct taacgtgagt tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa 6660
aggatcttct tgagatcctt tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc 6720
accgctacca gcggtggttt gtttgccgga tcaagagcta ccaactcttt ttccgaaggt 6780
aactggcttc agcagagcgc agataccaaa tactgttctt ctagtgtagc cgtagttagg 6840
ccaccacttc aagaactctg tagcaccgcc tacatacctc gctctgctaa tcctgttacc 6900
agtggctgct gccagtggcg ataagtcgtg tcttaccggg ttggactcaa gacgatagtt 6960
accggataag gcgcagcggt cgggctgaac ggggggttcg tgcacacagc ccagcttgga 7020
gcgaacgacc tacaccgaac tgagatacct acagcgtgag ctatgagaaa gcgccacgct 7080
tcccgaaggg agaaaggcgg acaggtatcc ggtaagcggc agggtcggaa caggagagcg 7140
cacgagggag cttccagggg gaaacgcctg gtatctttat agtcctgtcg ggtttcgcca 7200
cctctgactt gagcgtcgat ttttgtgatg ctcgtcaggg gggcggagcc tatggaaaaa 7260
cgccagcaac gcggcctttt tacggttcct ggccttttgc tggccttttg ctcacatgtt 7320
ctttcctgcg ttatcccctg attctgtgga taaccgtatt accgcctttg agtgagctga 7380
taccgctcgc cgcagccgaa cgaccgagcg cagcgagtca gtgagcgagg aagcggaaga 7440
gcgcccaata cgcaaaccgc ctctccccgc gcgttggccg attcattaat gcagctggca 7500
cgacaggttt cccgactgga aagcgggcag tgagcgcaac gcaattaatg tgagttagct 7560
cactcattag gcaccccagg ctttacactt tatgcttccg gctcgtatgt tgtgtggaat 7620
tgtgagcgga taacaatttc acacaggaaa cagctatgac catgattacg ccagatttaa 7680
ttaagg 7686
<210> 32
<211> 7755
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 32
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctactta agtgtttgct 180
gcttgcaatg tttgcccatt ttaggggaat tcactcaaag ttcaaacctt atcatttttt 240
gctttgttcc tcttggcctt ggttttgtac atcagctttg aaaataccat cccagggtta 300
atgctggggt taatttataa ctaagagtgc tctagttttg caatacagga catgctataa 360
aaatggaaag atgttgcttt ctgagagaca gcggccgcca ccatgcccga gcaggaaaga 420
cagatcaccg ccagagaggg cgccagccgg aagatcctga gcaagctgag cctgcccacc 480
agagcctggg agcccgccat gaagaagtcc ttcgccttcg acaacgtggg ctacgagggc 540
ggcctggacg gactgggacc atcttctcag gtggccacaa gcaccgtgcg caaatacgtg 600
ccctctgtcg tgtgcctgca gcaggtgtgc caccagatcg gcgacatggg cttcgaggcc 660
tctatcgccg agggaaaggc cgcctcttgg ccctctagaa gcctgcctgc tcaggaagcc 720
gtcgtgaagc tgcgggtgga agggatgacc tgtcagtcct gcgtgtccag catcgagggc 780
aaagtgcgga agctgcaggg cgtggtgcgc gtgaaagtgt ctctgagcaa ccaggaagct 840
gtgatcacct accagcccta cctgatccag cccgaggacc tgagggacca cgtgaacgat 900
atgggatttg aggccgccat caagagcaag gtggcccctc tgtctctggg ccccatcgac 960
atcgagagac tgcagagcac caaccccaag cggcctctga gcagcgccaa ccagaacttc 1020
aacaacagcg agacactggg ccaccagggc agccacgtcg tgacactgca gctgcggatc 1080
gacggaatgc actgcaagag ctgtgtgctg aacatcgagg aaaacatcgg ccagctgctg 1140
ggagtgcaga gcatccaggt gtcactggaa aacaagaccg cccaggtgaa gtacgacccc 1200
agctgcacaa gccccgtggc cctgcagaga gccattgaag ctctgccccc tggcaacttc 1260
aaagtgtccc tgcctgacgg agccgagggc tccggaacag atcacagaag cagcagcagc 1320
cacagccctg gcagcccccc tagaaatcag gtgcagggca cctgtagcac caccctgatc 1380
gccattgccg gcatgacatg cgccagctgc gtgcactcta ttgagggcat gatctcccag 1440
ctggaaggcg tgcagcagat cagtgtgtct ctggccgagg gcaccgccac agtgctgtac 1500
aaccctagcg tgatcagccc cgaagaactg agagccgcca ttgaggacat gggattcgaa 1560
gccagcgtgg tgtccgagag ctgctccacc aaccctctgg gcaatcacag cgccggcaac 1620
agcatggtgc agaccaccga cggcaccccc accagcgtgc aggaagtggc cccacataca 1680
ggcagactgc ccgccaatca cgcccccgat atcctggcca agagccccca gagtacaaga 1740
gccgtggccc cccagaagtg cttcctgcag atcaagggca tgacttgtgc ctcttgtgtg 1800
tccaatatcg agcggaacct gcagaaagag gccggcgtgc tgtctgtgct ggtggctctg 1860
atggccggca aggccgagat caaatacgac cccgaagtga ttcagcccct ggaaatcgcc 1920
cagtttatcc aggacctggg ctttgaagcc gccgtgatgg aagattacgc cggctccgac 1980
ggcaacatcg agctgaccat caccggaatg acctgcgcct cctgtgtgca caacattgag 2040
tccaagctga cccggaccaa cggcatcacc tacgcctctg tggctctggc cacctccaag 2100
gccctcgtga agttcgatcc cgagatcatc ggccccaggg acatcatcaa gatcatcgaa 2160
gagatcggct tccacgccag cctggcccag aggaacccta acgcccacca cctggaccac 2220
aagatggaaa tcaagcagtg gaagaaaagc ttcctgtgca gcctggtgtt cggcatcccc 2280
gtgatggccc tgatgatcta catgctgatc cccagcaacg agccccacca gtccatggtg 2340
ctggatcaca acatcatccc cggcctgtct atcctgaacc tgatcttctt catcctgtgc 2400
accttcgtgc agctgctggg cggctggtac ttctacgtgc aggcctacaa gtccctgcgg 2460
cacagatccg ccaacatgga cgtgctgatc gtgctggcca catctatcgc ctacgtgtac 2520
tccctcgtga tcctggtggt ggccgtggcc gagaaagccg agagaagccc tgtgaccttc 2580
ttcgacaccc cccctatgct gttcgtgttt atcgccctgg gccggtggct ggaacacctg 2640
gccaaaagca agaccagcga ggccctggct aagctgatga gtctgcaggc caccgaggcc 2700
acagtcgtga ccctgggcga ggacaacctg atcatccgcg aggaacaggt gccaatggaa 2760
ctggtgcagc ggggcgacat cgtgaaggtg gtgcctggcg gcaagttccc cgtggacgga 2820
aaagtgctgg aagggaatac catggccgac gagagcctga tcacaggcga ggccatgccc 2880
gtgaccaaga aacctggcag cacagtgatc gccggcagca tcaatgccca cggcagcgtg 2940
ctgattaagg ccacacacgt gggcaacgat accaccctgg ctcagattgt gaagctggtg 3000
gaagaggccc agatgagcaa ggcccccatt cagcagctgg ctgaccggtt cagcggctac 3060
ttcgtgccct ttatcatcat catgagcacc ctgacactgg tcgtgtggat cgtgatcggc 3120
tttatcgact tcggagtggt gcagagatac ttccccaacc ctaacaagca catcagccag 3180
acagaagtga tcatcagatt cgcctttcag accagcatca ccgtgctgtg tatcgcctgc 3240
ccctgtagcc tgggactggc cacacctacc gctgtgatgg tgggaacagg cgtggccgct 3300
cagaacggca tcctgatcaa ggggggcaag cctctggaaa tggctcacaa gatcaagacc 3360
gtgatgttcg acaagaccgg caccatcacc cacggcgtgc ccagagtgat gagagtgctg 3420
ctgctggggg atgtggccac cctgcctctg agaaaggtgc tggctgtcgt gggcacagcc 3480
gaggctagct ctgaacaccc actgggagtg gccgtgacaa agtactgcaa agaggaactg 3540
ggcaccgaaa ccctgggcta ctgcaccgac tttcaggccg tgcctggctg tggcatcggc 3600
tgcaaggtgt ccaacgtgga aggcatcctg gcccacagcg agaggccact gtctgcccct 3660
gccagccacc tgaacgaggc cggatctctg cccgccgaaa aggacgctgt gccccagacc 3720
ttctctgtgc tgattggcaa cagagagtgg ctgcggcgga acggcctgac catctcctcc 3780
gatgtgtccg acgccatgac cgaccacgag atgaagggcc agaccgccat tctggtggcc 3840
attgacgggg tgctgtgcgg catgatcgca atcgccgatg ccgtgaaaca ggaagcagca 3900
ctggccgtgc acaccctgca gtctatggga gtggatgtgg tgctgatcac cggcgacaac 3960
agaaagaccg ccagggccat tgccacccag gtgggcatca acaaggtgtt cgccgaggtg 4020
ctgcccagcc acaaagtggc caaggtgcag gaactgcaga acaaaggcaa aaaggtggcc 4080
atggtgggag atggcgtgaa cgactctcct gctctggccc aggcagatat gggcgtggcc 4140
atcggcacag gcaccgacgt ggcaattgag gctgctgacg tggtgctgat tcggaacgac 4200
ctgctggacg tggtggcctc catccacctg tccaagagaa ccgtgcggcg gatcagaatc 4260
aacctggtgc tggcactgat ctataacctc gtgggcatcc ctatcgccgc tggcgtgttc 4320
atgcctatcg gaatcgtgct gcagccctgg atgggctctg ccgccatggc tgcaagctcc 4380
gtgtctgtgg tgctgtccag cctgcagctg aagtgctaca agaagcccga cctggaaaga 4440
tacgaggccc aggcccacgg acacatgaag cctctgacag cctcccaggt gtccgtgcac 4500
atcggcatgg acgacagatg gcgggacagc cctagagcca ccccttggga tcaggtgtca 4560
tacgtgtcac aggtgtccct gagcagcctg accagcgaca agcccagcag acatagcgcc 4620
gctgccgacg acgatgggga caagtggtcc ctgctgctga acggccggga tgaggaacag 4680
tacatctgat aagcatgcaa taaagtctga gtgggcggca gcctgtgtgt gcctgggttc 4740
tctctgtccc ggaatgtgca aacaatggag gtgctcgagt agataagtag catggcgggt 4800
taatcattaa ctacaaggaa cccctagtga tggagttggc cactccctct ctgcgcgctc 4860
gctcgctcac tgaggccggg cgaccaaagg tcgcccgacg cccgggcttt gcccgggcgg 4920
cctcagtgag cgagcgagcg cgcagcctta attaacctaa ttcactggcc gtcgttttac 4980
aacgtcgtga ctgggaaaac cctggcgtta cccaacttaa tcgccttgca gcacatcccc 5040
ctttcgccag ctggcgtaat agcgaagagg cccgcaccga tcgcccttcc caacagttgc 5100
gcagcctgaa tggcgaatgg gacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg 5160
tggttacgcg cagcgtgacc gctacacttg ccagcgccct agcgcccgct cctttcgctt 5220
tcttcccttc ctttctcgcc acgttcgccg gctttccccg tcaagctcta aatcgggggc 5280
tccctttagg gttccgattt agtgctttac ggcacctcga ccccaaaaaa cttgattagg 5340
gtgatggttc acgtagtggg ccatcgccct gatagacggt ttttcgccct ttgacgttgg 5400
agtccacgtt ctttaatagt ggactcttgt tccaaactgg aacaacactc aaccctatct 5460
cggtctattc ttttgattta taagggattt tgccgatttc ggcctattgg ttaaaaaatg 5520
agctgattta acaaaaattt aacgcgaatt ttaacaaaat attaacgctt acaatttagg 5580
tggcactttt cggggaaatg tgcgcggaac ccctatttgt ttatttttct aaatacattc 5640
aaatatgtat ccgctcatga gacaataacc ctgataaatg cttcaataat attgaaaaag 5700
gaagagtatg agtattcaac atttccgtgt cgcccttatt cccttttttg cggcattttg 5760
ccttcctgtt tttgctcacc cagaaacgct ggtgaaagta aaagatgctg aagatcagtt 5820
gggtgcacga gtgggttaca tcgaactgga tctcaacagc ggtaagatcc ttgagagttt 5880
tcgccccgaa gaacgttttc caatgatgag cacttttaaa gttctgctat gtggcgcggt 5940
attatcccgt attgacgccg ggcaagagca actcggtcgc cgcatacact attctcagaa 6000
tgacttggtt gagtactcac cagtcacaga aaagcatctt acggatggca tgacagtaag 6060
agaattatgc agtgctgcca taaccatgag tgataacact gcggccaact tacttctgac 6120
aacgatcgga ggaccgaagg agctaaccgc ttttttgcac aacatggggg atcatgtaac 6180
tcgccttgat cgttgggaac cggagctgaa tgaagccata ccaaacgacg agcgtgacac 6240
cacgatgcct gtagcaatgg caacaacgtt gcgcaaacta ttaactggcg aactacttac 6300
tctagcttcc cggcaacaat taatagactg gatggaggcg gataaagttg caggaccact 6360
tctgcgctcg gcccttccgg ctggctggtt tattgctgat aaatctggag ccggtgagcg 6420
tgggtctcgc ggtatcattg cagcactggg gccagatggt aagccctccc gtatcgtagt 6480
tatctacacg acggggagtc aggcaactat ggatgaacga aatagacaga tcgctgagat 6540
aggtgcctca ctgattaagc attggtaact gtcagaccaa gtttactcat atatacttta 6600
gattgattta aaacttcatt tttaatttaa aaggatctag gtgaagatcc tttttgataa 6660
tctcatgacc aaaatccctt aacgtgagtt ttcgttccac tgagcgtcag accccgtaga 6720
aaagatcaaa ggatcttctt gagatccttt ttttctgcgc gtaatctgct gcttgcaaac 6780
aaaaaaacca ccgctaccag cggtggtttg tttgccggat caagagctac caactctttt 6840
tccgaaggta actggcttca gcagagcgca gataccaaat actgttcttc tagtgtagcc 6900
gtagttaggc caccacttca agaactctgt agcaccgcct acatacctcg ctctgctaat 6960
cctgttacca gtggctgctg ccagtggcga taagtcgtgt cttaccgggt tggactcaag 7020
acgatagtta ccggataagg cgcagcggtc gggctgaacg gggggttcgt gcacacagcc 7080
cagcttggag cgaacgacct acaccgaact gagataccta cagcgtgagc tatgagaaag 7140
cgccacgctt cccgaaggga gaaaggcgga caggtatccg gtaagcggca gggtcggaac 7200
aggagagcgc acgagggagc ttccaggggg aaacgcctgg tatctttata gtcctgtcgg 7260
gtttcgccac ctctgacttg agcgtcgatt tttgtgatgc tcgtcagggg ggcggagcct 7320
atggaaaaac gccagcaacg cggccttttt acggttcctg gccttttgct ggccttttgc 7380
tcacatgttc tttcctgcgt tatcccctga ttctgtggat aaccgtatta ccgcctttga 7440
gtgagctgat accgctcgcc gcagccgaac gaccgagcgc agcgagtcag tgagcgagga 7500
agcggaagag cgcccaatac gcaaaccgcc tctccccgcg cgttggccga ttcattaatg 7560
cagctggcac gacaggtttc ccgactggaa agcgggcagt gagcgcaacg caattaatgt 7620
gagttagctc actcattagg caccccaggc tttacacttt atgcttccgg ctcgtatgtt 7680
gtgtggaatt gtgagcggat aacaatttca cacaggaaac agctatgacc atgattacgc 7740
cagatttaat taagg 7755
<210> 33
<211> 6438
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 33
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctactta agtgtttgct 180
gcttgcaatg tttgcccatt ttaggggaat tcactcaaag ttcaaacctt atcatttttt 240
gctttgttcc tcttggcctt ggttttgtac atcagctttg aaaataccat cccagggtta 300
atgctggggt taatttataa ctaagagtgc tctagttttg caatacagga catgctataa 360
aaatggaaag atgttgcttt ctgagagaca gcggccgcca ccatgcccga gcaggaaaga 420
cagatcaccg ccagagaggg cgccagccgg aagatcctga gcaagctgag cctgcccacc 480
agagcctggg agcccgccat gaagaagtcc ttcgccttcg acaacgtggg ctacgagggc 540
ggcctggacg gactgggacc atcttctcag gtggccacaa gcaccgtgcg cctggaaatc 600
gcccagttta tccaggacct gggctttgaa gccgccgtga tggaagatta cgccggctcc 660
gacggcaaca tcgagctgac catcaccgga atgacctgcg cctcctgtgt gcacaacatt 720
gagtccaagc tgacccggac caacggcatc acctacgcct ctgtggctct ggccacctcc 780
aaggccctcg tgaagttcga tcccgagatc atcggcccca gggacatcat caagatcatc 840
gaagagatcg gcttccacgc cagcctggcc cagaggaacc ctaacgccca ccacctggac 900
cacaagatgg aaatcaagca gtggaagaaa agcttcctgt gcagcctggt gttcggcatc 960
cccgtgatgg ccctgatgat ctacatgctg atccccagca acgagcccca ccagtccatg 1020
gtgctggatc acaacatcat ccccggcctg tctatcctga acctgatctt cttcatcctg 1080
tgcaccttcg tgcagctgct gggcggctgg tacttctacg tgcaggccta caagtccctg 1140
cggcacagat ccgccaacat ggacgtgctg atcgtgctgg ccacatctat cgcctacgtg 1200
tactccctcg tgatcctggt ggtggccgtg gccgagaaag ccgagagaag ccctgtgacc 1260
ttcttcgaca ccccccctat gctgttcgtg tttatcgccc tgggccggtg gctggaacac 1320
ctggccaaaa gcaagaccag cgaggccctg gctaagctga tgagtctgca ggccaccgag 1380
gccacagtcg tgaccctggg cgaggacaac ctgatcatcc gcgaggaaca ggtgccaatg 1440
gaactggtgc agcggggcga catcgtgaag gtggtgcctg gcggcaagtt ccccgtggac 1500
ggaaaagtgc tggaagggaa taccatggcc gacgagagcc tgatcacagg cgaggccatg 1560
cccgtgacca agaaacctgg cagcacagtg atcgccggca gcatcaatgc ccacggcagc 1620
gtgctgatta aggccacaca cgtgggcaac gataccaccc tggctcagat tgtgaagctg 1680
gtggaagagg cccagatgag caaggccccc attcagcagc tggctgaccg gttcagcggc 1740
tacttcgtgc cctttatcat catcatgagc accctgacac tggtcgtgtg gatcgtgatc 1800
ggctttatcg acttcggagt ggtgcagaga tacttcccca accctaacaa gcacatcagc 1860
cagacagaag tgatcatcag attcgccttt cagaccagca tcaccgtgct gtgtatcgcc 1920
tgcccctgta gcctgggact ggccacacct accgctgtga tggtgggaac aggcgtggcc 1980
gctcagaacg gcatcctgat caaggggggc aagcctctgg aaatggctca caagatcaag 2040
accgtgatgt tcgacaagac cggcaccatc acccacggcg tgcccagagt gatgagagtg 2100
ctgctgctgg gggatgtggc caccctgcct ctgagaaagg tgctggctgt cgtgggcaca 2160
gccgaggcta gctctgaaca cccactggga gtggccgtga caaagtactg caaagaggaa 2220
ctgggcaccg aaaccctggg ctactgcacc gactttcagg ccgtgcctgg ctgtggcatc 2280
ggctgcaagg tgtccaacgt ggaaggcatc ctggcccaca gcgagaggcc actgtctgcc 2340
cctgccagcc acctgaacga ggccggatct ctgcccgccg aaaaggacgc tgtgccccag 2400
accttctctg tgctgattgg caacagagag tggctgcggc ggaacggcct gaccatctcc 2460
tccgatgtgt ccgacgccat gaccgaccac gagatgaagg gccagaccgc cattctggtg 2520
gccattgacg gggtgctgtg cggcatgatc gcaatcgccg atgccgtgaa acaggaagca 2580
gcactggccg tgcacaccct gcagtctatg ggagtggatg tggtgctgat caccggcgac 2640
aacagaaaga ccgccagggc cattgccacc caggtgggca tcaacaaggt gttcgccgag 2700
gtgctgccca gccacaaagt ggccaaggtg caggaactgc agaacaaagg caaaaaggtg 2760
gccatggtgg gagatggcgt gaacgactct cctgctctgg cccaggcaga tatgggcgtg 2820
gccatcggca caggcaccga cgtggcaatt gaggctgctg acgtggtgct gattcggaac 2880
gacctgctgg acgtggtggc ctccatccac ctgtccaaga gaaccgtgcg gcggatcaga 2940
atcaacctgg tgctggcact gatctataac ctcgtgggca tccctatcgc cgctggcgtg 3000
ttcatgccta tcggaatcgt gctgcagccc tggatgggct ctgccgccat ggctgcaagc 3060
tccgtgtctg tggtgctgtc cagcctgcag ctgaagtgct acaagaagcc cgacctggaa 3120
agatacgagg cccaggccca cggacacatg aagcctctga cagcctccca ggtgtccgtg 3180
cacatcggca tggacgacag atggcgggac agccctagag ccaccccttg ggatcaggtg 3240
tcatacgtgt cacaggtgtc cctgagcagc ctgaccagcg acaagcccag cagacatagc 3300
gccgctgccg acgacgatgg ggacaagtgg tccctgctgc tgaacggccg ggatgaggaa 3360
cagtacatct gataagcatg caataaagtc tgagtgggcg gcagcctgtg tgtgcctggg 3420
ttctctctgt cccggaatgt gcaaacaatg gaggtgctcg agtagataag tagcatggcg 3480
ggttaatcat taactacaag gaacccctag tgatggagtt ggccactccc tctctgcgcg 3540
ctcgctcgct cactgaggcc gggcgaccaa aggtcgcccg acgcccgggc tttgcccggg 3600
cggcctcagt gagcgagcga gcgcgcagcc ttaattaacc taattcactg gccgtcgttt 3660
tacaacgtcg tgactgggaa aaccctggcg ttacccaact taatcgcctt gcagcacatc 3720
cccctttcgc cagctggcgt aatagcgaag aggcccgcac cgatcgccct tcccaacagt 3780
tgcgcagcct gaatggcgaa tgggacgcgc cctgtagcgg cgcattaagc gcggcgggtg 3840
tggtggttac gcgcagcgtg accgctacac ttgccagcgc cctagcgccc gctcctttcg 3900
ctttcttccc ttcctttctc gccacgttcg ccggctttcc ccgtcaagct ctaaatcggg 3960
ggctcccttt agggttccga tttagtgctt tacggcacct cgaccccaaa aaacttgatt 4020
agggtgatgg ttcacgtagt gggccatcgc cctgatagac ggtttttcgc cctttgacgt 4080
tggagtccac gttctttaat agtggactct tgttccaaac tggaacaaca ctcaacccta 4140
tctcggtcta ttcttttgat ttataaggga ttttgccgat ttcggcctat tggttaaaaa 4200
atgagctgat ttaacaaaaa tttaacgcga attttaacaa aatattaacg cttacaattt 4260
aggtggcact tttcggggaa atgtgcgcgg aacccctatt tgtttatttt tctaaataca 4320
ttcaaatatg tatccgctca tgagacaata accctgataa atgcttcaat aatattgaaa 4380
aaggaagagt atgagtattc aacatttccg tgtcgccctt attccctttt ttgcggcatt 4440
ttgccttcct gtttttgctc acccagaaac gctggtgaaa gtaaaagatg ctgaagatca 4500
gttgggtgca cgagtgggtt acatcgaact ggatctcaac agcggtaaga tccttgagag 4560
ttttcgcccc gaagaacgtt ttccaatgat gagcactttt aaagttctgc tatgtggcgc 4620
ggtattatcc cgtattgacg ccgggcaaga gcaactcggt cgccgcatac actattctca 4680
gaatgacttg gttgagtact caccagtcac agaaaagcat cttacggatg gcatgacagt 4740
aagagaatta tgcagtgctg ccataaccat gagtgataac actgcggcca acttacttct 4800
gacaacgatc ggaggaccga aggagctaac cgcttttttg cacaacatgg gggatcatgt 4860
aactcgcctt gatcgttggg aaccggagct gaatgaagcc ataccaaacg acgagcgtga 4920
caccacgatg cctgtagcaa tggcaacaac gttgcgcaaa ctattaactg gcgaactact 4980
tactctagct tcccggcaac aattaataga ctggatggag gcggataaag ttgcaggacc 5040
acttctgcgc tcggcccttc cggctggctg gtttattgct gataaatctg gagccggtga 5100
gcgtgggtct cgcggtatca ttgcagcact ggggccagat ggtaagccct cccgtatcgt 5160
agttatctac acgacgggga gtcaggcaac tatggatgaa cgaaatagac agatcgctga 5220
gataggtgcc tcactgatta agcattggta actgtcagac caagtttact catatatact 5280
ttagattgat ttaaaacttc atttttaatt taaaaggatc taggtgaaga tcctttttga 5340
taatctcatg accaaaatcc cttaacgtga gttttcgttc cactgagcgt cagaccccgt 5400
agaaaagatc aaaggatctt cttgagatcc tttttttctg cgcgtaatct gctgcttgca 5460
aacaaaaaaa ccaccgctac cagcggtggt ttgtttgccg gatcaagagc taccaactct 5520
ttttccgaag gtaactggct tcagcagagc gcagatacca aatactgttc ttctagtgta 5580
gccgtagtta ggccaccact tcaagaactc tgtagcaccg cctacatacc tcgctctgct 5640
aatcctgtta ccagtggctg ctgccagtgg cgataagtcg tgtcttaccg ggttggactc 5700
aagacgatag ttaccggata aggcgcagcg gtcgggctga acggggggtt cgtgcacaca 5760
gcccagcttg gagcgaacga cctacaccga actgagatac ctacagcgtg agctatgaga 5820
aagcgccacg cttcccgaag ggagaaaggc ggacaggtat ccggtaagcg gcagggtcgg 5880
aacaggagag cgcacgaggg agcttccagg gggaaacgcc tggtatcttt atagtcctgt 5940
cgggtttcgc cacctctgac ttgagcgtcg atttttgtga tgctcgtcag gggggcggag 6000
cctatggaaa aacgccagca acgcggcctt tttacggttc ctggcctttt gctggccttt 6060
tgctcacatg ttctttcctg cgttatcccc tgattctgtg gataaccgta ttaccgcctt 6120
tgagtgagct gataccgctc gccgcagccg aacgaccgag cgcagcgagt cagtgagcga 6180
ggaagcggaa gagcgcccaa tacgcaaacc gcctctcccc gcgcgttggc cgattcatta 6240
atgcagctgg cacgacaggt ttcccgactg gaaagcgggc agtgagcgca acgcaattaa 6300
tgtgagttag ctcactcatt aggcacccca ggctttacac tttatgcttc cggctcgtat 6360
gttgtgtgga attgtgagcg gataacaatt tcacacagga aacagctatg accatgatta 6420
cgccagattt aattaagg 6438
<210> 34
<211> 6831
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 34
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctactta agtgtttgct 180
gcttgcaatg tttgcccatt ttaggggaat tcactcaaag ttcaaacctt atcatttttt 240
gctttgttcc tcttggcctt ggttttgtac atcagctttg aaaataccat cccagggtta 300
atgctggggt taatttataa ctaagagtgc tctagttttg caatacagga catgctataa 360
aaatggaaag atgttgcttt ctgagagaca gcggccgcca ccatgcccga gcaggaaaga 420
cagatcaccg ccagagaggg cgccagccgg aagatcctga gcaagctgag cctgcccacc 480
agagcctggg agcccgccat gaagaagtcc ttcgccttcg acaacgtggg ctacgagggc 540
ggcctggacg gactgggacc atcttctcag gtggccacaa gcaccgtgcg cagccccgaa 600
gaactgagag ccgccattga ggacatggga ttcgaagcca gcgtggtgtc cgagagctgc 660
tccaccaacc ctctgggcaa tcacagcgcc ggcaacagca tggtgcagac caccgacggc 720
acccccacca gcgtgcagga agtggcccca catacaggca gactgcccgc caatcacgcc 780
cccgatatcc tggccaagag cccccagagt acaagagccg tggcccccca gaagtgcttc 840
ctgcagatca agggcatgac ttgtgcctct tgtgtgtcca atatcgagcg gaacctgcag 900
aaagaggccg gcgtgctgtc tgtgctggtg gctctgatgg ccggcaaggc cgagatcaaa 960
tacgaccccg aagtgattca gcccctggaa atcgcccagt ttatccagga cctgggcttt 1020
gaagccgccg tgatggaaga ttacgccggc tccgacggca acatcgagct gaccatcacc 1080
ggaatgacct gcgcctcctg tgtgcacaac attgagtcca agctgacccg gaccaacggc 1140
atcacctacg cctctgtggc tctggccacc tccaaggccc tcgtgaagtt cgatcccgag 1200
atcatcggcc ccagggacat catcaagatc atcgaagaga tcggcttcca cgccagcctg 1260
gcccagagga accctaacgc ccaccacctg gaccacaaga tggaaatcaa gcagtggaag 1320
aaaagcttcc tgtgcagcct ggtgttcggc atccccgtga tggccctgat gatctacatg 1380
ctgatcccca gcaacgagcc ccaccagtcc atggtgctgg atcacaacat catccccggc 1440
ctgtctatcc tgaacctgat cttcttcatc ctgtgcacct tcgtgcagct gctgggcggc 1500
tggtacttct acgtgcaggc ctacaagtcc ctgcggcaca gatccgccaa catggacgtg 1560
ctgatcgtgc tggccacatc tatcgcctac gtgtactccc tcgtgatcct ggtggtggcc 1620
gtggccgaga aagccgagag aagccctgtg accttcttcg acaccccccc tatgctgttc 1680
gtgtttatcg ccctgggccg gtggctggaa cacctggcca aaagcaagac cagcgaggcc 1740
ctggctaagc tgatgagtct gcaggccacc gaggccacag tcgtgaccct gggcgaggac 1800
aacctgatca tccgcgagga acaggtgcca atggaactgg tgcagcgggg cgacatcgtg 1860
aaggtggtgc ctggcggcaa gttccccgtg gacggaaaag tgctggaagg gaataccatg 1920
gccgacgaga gcctgatcac aggcgaggcc atgcccgtga ccaagaaacc tggcagcaca 1980
gtgatcgccg gcagcatcaa tgcccacggc agcgtgctga ttaaggccac acacgtgggc 2040
aacgatacca ccctggctca gattgtgaag ctggtggaag aggcccagat gagcaaggcc 2100
cccattcagc agctggctga ccggttcagc ggctacttcg tgccctttat catcatcatg 2160
agcaccctga cactggtcgt gtggatcgtg atcggcttta tcgacttcgg agtggtgcag 2220
agatacttcc ccaaccctaa caagcacatc agccagacag aagtgatcat cagattcgcc 2280
tttcagacca gcatcaccgt gctgtgtatc gcctgcccct gtagcctggg actggccaca 2340
cctaccgctg tgatggtggg aacaggcgtg gccgctcaga acggcatcct gatcaagggg 2400
ggcaagcctc tggaaatggc tcacaagatc aagaccgtga tgttcgacaa gaccggcacc 2460
atcacccacg gcgtgcccag agtgatgaga gtgctgctgc tgggggatgt ggccaccctg 2520
cctctgagaa aggtgctggc tgtcgtgggc acagccgagg ctagctctga acacccactg 2580
ggagtggccg tgacaaagta ctgcaaagag gaactgggca ccgaaaccct gggctactgc 2640
accgactttc aggccgtgcc tggctgtggc atcggctgca aggtgtccaa cgtggaaggc 2700
atcctggccc acagcgagag gccactgtct gcccctgcca gccacctgaa cgaggccgga 2760
tctctgcccg ccgaaaagga cgctgtgccc cagaccttct ctgtgctgat tggcaacaga 2820
gagtggctgc ggcggaacgg cctgaccatc tcctccgatg tgtccgacgc catgaccgac 2880
cacgagatga agggccagac cgccattctg gtggccattg acggggtgct gtgcggcatg 2940
atcgcaatcg ccgatgccgt gaaacaggaa gcagcactgg ccgtgcacac cctgcagtct 3000
atgggagtgg atgtggtgct gatcaccggc gacaacagaa agaccgccag ggccattgcc 3060
acccaggtgg gcatcaacaa ggtgttcgcc gaggtgctgc ccagccacaa agtggccaag 3120
gtgcaggaac tgcagaacaa aggcaaaaag gtggccatgg tgggagatgg cgtgaacgac 3180
tctcctgctc tggcccaggc agatatgggc gtggccatcg gcacaggcac cgacgtggca 3240
attgaggctg ctgacgtggt gctgattcgg aacgacctgc tggacgtggt ggcctccatc 3300
cacctgtcca agagaaccgt gcggcggatc agaatcaacc tggtgctggc actgatctat 3360
aacctcgtgg gcatccctat cgccgctggc gtgttcatgc ctatcggaat cgtgctgcag 3420
ccctggatgg gctctgccgc catggctgca agctccgtgt ctgtggtgct gtccagcctg 3480
cagctgaagt gctacaagaa gcccgacctg gaaagatacg aggcccaggc ccacggacac 3540
atgaagcctc tgacagcctc ccaggtgtcc gtgcacatcg gcatggacga cagatggcgg 3600
gacagcccta gagccacccc ttgggatcag gtgtcatacg tgtcacaggt gtccctgagc 3660
agcctgacca gcgacaagcc cagcagacat agcgccgctg ccgacgacga tggggacaag 3720
tggtccctgc tgctgaacgg ccgggatgag gaacagtaca tctgataagc atgcaataaa 3780
gtctgagtgg gcggcagcct gtgtgtgcct gggttctctc tgtcccggaa tgtgcaaaca 3840
atggaggtgc tcgagtagat aagtagcatg gcgggttaat cattaactac aaggaacccc 3900
tagtgatgga gttggccact ccctctctgc gcgctcgctc gctcactgag gccgggcgac 3960
caaaggtcgc ccgacgcccg ggctttgccc gggcggcctc agtgagcgag cgagcgcgca 4020
gccttaatta acctaattca ctggccgtcg ttttacaacg tcgtgactgg gaaaaccctg 4080
gcgttaccca acttaatcgc cttgcagcac atcccccttt cgccagctgg cgtaatagcg 4140
aagaggcccg caccgatcgc ccttcccaac agttgcgcag cctgaatggc gaatgggacg 4200
cgccctgtag cggcgcatta agcgcggcgg gtgtggtggt tacgcgcagc gtgaccgcta 4260
cacttgccag cgccctagcg cccgctcctt tcgctttctt cccttccttt ctcgccacgt 4320
tcgccggctt tccccgtcaa gctctaaatc gggggctccc tttagggttc cgatttagtg 4380
ctttacggca cctcgacccc aaaaaacttg attagggtga tggttcacgt agtgggccat 4440
cgccctgata gacggttttt cgccctttga cgttggagtc cacgttcttt aatagtggac 4500
tcttgttcca aactggaaca acactcaacc ctatctcggt ctattctttt gatttataag 4560
ggattttgcc gatttcggcc tattggttaa aaaatgagct gatttaacaa aaatttaacg 4620
cgaattttaa caaaatatta acgcttacaa tttaggtggc acttttcggg gaaatgtgcg 4680
cggaacccct atttgtttat ttttctaaat acattcaaat atgtatccgc tcatgagaca 4740
ataaccctga taaatgcttc aataatattg aaaaaggaag agtatgagta ttcaacattt 4800
ccgtgtcgcc cttattccct tttttgcggc attttgcctt cctgtttttg ctcacccaga 4860
aacgctggtg aaagtaaaag atgctgaaga tcagttgggt gcacgagtgg gttacatcga 4920
actggatctc aacagcggta agatccttga gagttttcgc cccgaagaac gttttccaat 4980
gatgagcact tttaaagttc tgctatgtgg cgcggtatta tcccgtattg acgccgggca 5040
agagcaactc ggtcgccgca tacactattc tcagaatgac ttggttgagt actcaccagt 5100
cacagaaaag catcttacgg atggcatgac agtaagagaa ttatgcagtg ctgccataac 5160
catgagtgat aacactgcgg ccaacttact tctgacaacg atcggaggac cgaaggagct 5220
aaccgctttt ttgcacaaca tgggggatca tgtaactcgc cttgatcgtt gggaaccgga 5280
gctgaatgaa gccataccaa acgacgagcg tgacaccacg atgcctgtag caatggcaac 5340
aacgttgcgc aaactattaa ctggcgaact acttactcta gcttcccggc aacaattaat 5400
agactggatg gaggcggata aagttgcagg accacttctg cgctcggccc ttccggctgg 5460
ctggtttatt gctgataaat ctggagccgg tgagcgtggg tctcgcggta tcattgcagc 5520
actggggcca gatggtaagc cctcccgtat cgtagttatc tacacgacgg ggagtcaggc 5580
aactatggat gaacgaaata gacagatcgc tgagataggt gcctcactga ttaagcattg 5640
gtaactgtca gaccaagttt actcatatat actttagatt gatttaaaac ttcattttta 5700
atttaaaagg atctaggtga agatcctttt tgataatctc atgaccaaaa tcccttaacg 5760
tgagttttcg ttccactgag cgtcagaccc cgtagaaaag atcaaaggat cttcttgaga 5820
tccttttttt ctgcgcgtaa tctgctgctt gcaaacaaaa aaaccaccgc taccagcggt 5880
ggtttgtttg ccggatcaag agctaccaac tctttttccg aaggtaactg gcttcagcag 5940
agcgcagata ccaaatactg ttcttctagt gtagccgtag ttaggccacc acttcaagaa 6000
ctctgtagca ccgcctacat acctcgctct gctaatcctg ttaccagtgg ctgctgccag 6060
tggcgataag tcgtgtctta ccgggttgga ctcaagacga tagttaccgg ataaggcgca 6120
gcggtcgggc tgaacggggg gttcgtgcac acagcccagc ttggagcgaa cgacctacac 6180
cgaactgaga tacctacagc gtgagctatg agaaagcgcc acgcttcccg aagggagaaa 6240
ggcggacagg tatccggtaa gcggcagggt cggaacagga gagcgcacga gggagcttcc 6300
agggggaaac gcctggtatc tttatagtcc tgtcgggttt cgccacctct gacttgagcg 6360
tcgatttttg tgatgctcgt caggggggcg gagcctatgg aaaaacgcca gcaacgcggc 6420
ctttttacgg ttcctggcct tttgctggcc ttttgctcac atgttctttc ctgcgttatc 6480
ccctgattct gtggataacc gtattaccgc ctttgagtga gctgataccg ctcgccgcag 6540
ccgaacgacc gagcgcagcg agtcagtgag cgaggaagcg gaagagcgcc caatacgcaa 6600
accgcctctc cccgcgcgtt ggccgattca ttaatgcagc tggcacgaca ggtttcccga 6660
ctggaaagcg ggcagtgagc gcaacgcaat taatgtgagt tagctcactc attaggcacc 6720
ccaggcttta cactttatgc ttccggctcg tatgttgtgt ggaattgtga gcggataaca 6780
atttcacaca ggaaacagct atgaccatga ttacgccaga tttaattaag g 6831
<210> 35
<211> 7437
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 构建序列
<400> 35
ctgcgcgctc gctcgctcac tgaggccgcc cgggcaaagc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct tgtagttaat gattaacccg ccatgctact tatctactta agtgtttgct 180
gcttgcaatg tttgcccatt ttaggggaat tcactcaaag ttcaaacctt atcatttttt 240
gctttgttcc tcttggcctt ggttttgtac atcagctttg aaaataccat cccagggtta 300
atgctggggt taatttataa ctaagagtgc tctagttttg caatacagga catgctataa 360
aaatggaaag atgttgcttt ctgagagaca gcggccgcca ccatgcccga gcaggaaaga 420
cagatcaccg ccagagaggg cgccagccgg aagatcctga gcaagctgag cctgcccacc 480
agagcctggg agcccgccat gaagaagtcc ttcgccttcg acaacgtggg ctacgagggc 540
ggcctggacg gactgggacc atcttctcag gtggccacaa gcaccgtgcg cgaggccgcc 600
atcaagagca aggtggcccc tctgtctctg ggccccatcg acatcgagag actgcagagc 660
accaacccca agcggcctct gagcagcgcc aaccagaact tcaacaacag cgagacactg 720
ggccaccagg gcagccacgt cgtgacactg cagctgcgga tcgacggaat gcactgcaag 780
agctgtgtgc tgaacatcga ggaaaacatc ggccagctgc tgggagtgca gagcatccag 840
gtgtcactgg aaaacaagac cgcccaggtg aagtacgacc ccagctgcac aagccccgtg 900
gccctgcaga gagccattga agctctgccc cctggcaact tcaaagtgtc cctgcctgac 960
ggagccgagg gctccggaac agatcacaga agcagcagca gccacagccc tggcagcccc 1020
cctagaaatc aggtgcaggg cacctgtagc accaccctga tcgccattgc cggcatgaca 1080
tgcgccagct gcgtgcactc tattgagggc atgatctccc agctggaagg cgtgcagcag 1140
atcagtgtgt ctctggccga gggcaccgcc acagtgctgt acaaccctag cgtgatcagc 1200
cccgaagaac tgagagccgc cattgaggac atgggattcg aagccagcgt ggtgtccgag 1260
agctgctcca ccaaccctct gggcaatcac agcgccggca acagcatggt gcagaccacc 1320
gacggcaccc ccaccagcgt gcaggaagtg gccccacata caggcagact gcccgccaat 1380
cacgcccccg atatcctggc caagagcccc cagagtacaa gagccgtggc cccccagaag 1440
tgcttcctgc agatcaaggg catgacttgt gcctcttgtg tgtccaatat cgagcggaac 1500
ctgcagaaag aggccggcgt gctgtctgtg ctggtggctc tgatggccgg caaggccgag 1560
atcaaatacg accccgaagt gattcagccc ctggaaatcg cccagtttat ccaggacctg 1620
ggctttgaag ccgccgtgat ggaagattac gccggctccg acggcaacat cgagctgacc 1680
atcaccggaa tgacctgcgc ctcctgtgtg cacaacattg agtccaagct gacccggacc 1740
aacggcatca cctacgcctc tgtggctctg gccacctcca aggccctcgt gaagttcgat 1800
cccgagatca tcggccccag ggacatcatc aagatcatcg aagagatcgg cttccacgcc 1860
agcctggccc agaggaaccc taacgcccac cacctggacc acaagatgga aatcaagcag 1920
tggaagaaaa gcttcctgtg cagcctggtg ttcggcatcc ccgtgatggc cctgatgatc 1980
tacatgctga tccccagcaa cgagccccac cagtccatgg tgctggatca caacatcatc 2040
cccggcctgt ctatcctgaa cctgatcttc ttcatcctgt gcaccttcgt gcagctgctg 2100
ggcggctggt acttctacgt gcaggcctac aagtccctgc ggcacagatc cgccaacatg 2160
gacgtgctga tcgtgctggc cacatctatc gcctacgtgt actccctcgt gatcctggtg 2220
gtggccgtgg ccgagaaagc cgagagaagc cctgtgacct tcttcgacac cccccctatg 2280
ctgttcgtgt ttatcgccct gggccggtgg ctggaacacc tggccaaaag caagaccagc 2340
gaggccctgg ctaagctgat gagtctgcag gccaccgagg ccacagtcgt gaccctgggc 2400
gaggacaacc tgatcatccg cgaggaacag gtgccaatgg aactggtgca gcggggcgac 2460
atcgtgaagg tggtgcctgg cggcaagttc cccgtggacg gaaaagtgct ggaagggaat 2520
accatggccg acgagagcct gatcacaggc gaggccatgc ccgtgaccaa gaaacctggc 2580
agcacagtga tcgccggcag catcaatgcc cacggcagcg tgctgattaa ggccacacac 2640
gtgggcaacg ataccaccct ggctcagatt gtgaagctgg tggaagaggc ccagatgagc 2700
aaggccccca ttcagcagct ggctgaccgg ttcagcggct acttcgtgcc ctttatcatc 2760
atcatgagca ccctgacact ggtcgtgtgg atcgtgatcg gctttatcga cttcggagtg 2820
gtgcagagat acttccccaa ccctaacaag cacatcagcc agacagaagt gatcatcaga 2880
ttcgcctttc agaccagcat caccgtgctg tgtatcgcct gcccctgtag cctgggactg 2940
gccacaccta ccgctgtgat ggtgggaaca ggcgtggccg ctcagaacgg catcctgatc 3000
aaggggggca agcctctgga aatggctcac aagatcaaga ccgtgatgtt cgacaagacc 3060
ggcaccatca cccacggcgt gcccagagtg atgagagtgc tgctgctggg ggatgtggcc 3120
accctgcctc tgagaaaggt gctggctgtc gtgggcacag ccgaggctag ctctgaacac 3180
ccactgggag tggccgtgac aaagtactgc aaagaggaac tgggcaccga aaccctgggc 3240
tactgcaccg actttcaggc cgtgcctggc tgtggcatcg gctgcaaggt gtccaacgtg 3300
gaaggcatcc tggcccacag cgagaggcca ctgtctgccc ctgccagcca cctgaacgag 3360
gccggatctc tgcccgccga aaaggacgct gtgccccaga ccttctctgt gctgattggc 3420
aacagagagt ggctgcggcg gaacggcctg accatctcct ccgatgtgtc cgacgccatg 3480
accgaccacg agatgaaggg ccagaccgcc attctggtgg ccattgacgg ggtgctgtgc 3540
ggcatgatcg caatcgccga tgccgtgaaa caggaagcag cactggccgt gcacaccctg 3600
cagtctatgg gagtggatgt ggtgctgatc accggcgaca acagaaagac cgccagggcc 3660
attgccaccc aggtgggcat caacaaggtg ttcgccgagg tgctgcccag ccacaaagtg 3720
gccaaggtgc aggaactgca gaacaaaggc aaaaaggtgg ccatggtggg agatggcgtg 3780
aacgactctc ctgctctggc ccaggcagat atgggcgtgg ccatcggcac aggcaccgac 3840
gtggcaattg aggctgctga cgtggtgctg attcggaacg acctgctgga cgtggtggcc 3900
tccatccacc tgtccaagag aaccgtgcgg cggatcagaa tcaacctggt gctggcactg 3960
atctataacc tcgtgggcat ccctatcgcc gctggcgtgt tcatgcctat cggaatcgtg 4020
ctgcagccct ggatgggctc tgccgccatg gctgcaagct ccgtgtctgt ggtgctgtcc 4080
agcctgcagc tgaagtgcta caagaagccc gacctggaaa gatacgaggc ccaggcccac 4140
ggacacatga agcctctgac agcctcccag gtgtccgtgc acatcggcat ggacgacaga 4200
tggcgggaca gccctagagc caccccttgg gatcaggtgt catacgtgtc acaggtgtcc 4260
ctgagcagcc tgaccagcga caagcccagc agacatagcg ccgctgccga cgacgatggg 4320
gacaagtggt ccctgctgct gaacggccgg gatgaggaac agtacatctg ataagcatgc 4380
aataaagtct gagtgggcgg cagcctgtgt gtgcctgggt tctctctgtc ccggaatgtg 4440
caaacaatgg aggtgctcga gtagataagt agcatggcgg gttaatcatt aactacaagg 4500
aacccctagt gatggagttg gccactccct ctctgcgcgc tcgctcgctc actgaggccg 4560
ggcgaccaaa ggtcgcccga cgcccgggct ttgcccgggc ggcctcagtg agcgagcgag 4620
cgcgcagcct taattaacct aattcactgg ccgtcgtttt acaacgtcgt gactgggaaa 4680
accctggcgt tacccaactt aatcgccttg cagcacatcc ccctttcgcc agctggcgta 4740
atagcgaaga ggcccgcacc gatcgccctt cccaacagtt gcgcagcctg aatggcgaat 4800
gggacgcgcc ctgtagcggc gcattaagcg cggcgggtgt ggtggttacg cgcagcgtga 4860
ccgctacact tgccagcgcc ctagcgcccg ctcctttcgc tttcttccct tcctttctcg 4920
ccacgttcgc cggctttccc cgtcaagctc taaatcgggg gctcccttta gggttccgat 4980
ttagtgcttt acggcacctc gaccccaaaa aacttgatta gggtgatggt tcacgtagtg 5040
ggccatcgcc ctgatagacg gtttttcgcc ctttgacgtt ggagtccacg ttctttaata 5100
gtggactctt gttccaaact ggaacaacac tcaaccctat ctcggtctat tcttttgatt 5160
tataagggat tttgccgatt tcggcctatt ggttaaaaaa tgagctgatt taacaaaaat 5220
ttaacgcgaa ttttaacaaa atattaacgc ttacaattta ggtggcactt ttcggggaaa 5280
tgtgcgcgga acccctattt gtttattttt ctaaatacat tcaaatatgt atccgctcat 5340
gagacaataa ccctgataaa tgcttcaata atattgaaaa aggaagagta tgagtattca 5400
acatttccgt gtcgccctta ttcccttttt tgcggcattt tgccttcctg tttttgctca 5460
cccagaaacg ctggtgaaag taaaagatgc tgaagatcag ttgggtgcac gagtgggtta 5520
catcgaactg gatctcaaca gcggtaagat ccttgagagt tttcgccccg aagaacgttt 5580
tccaatgatg agcactttta aagttctgct atgtggcgcg gtattatccc gtattgacgc 5640
cgggcaagag caactcggtc gccgcataca ctattctcag aatgacttgg ttgagtactc 5700
accagtcaca gaaaagcatc ttacggatgg catgacagta agagaattat gcagtgctgc 5760
cataaccatg agtgataaca ctgcggccaa cttacttctg acaacgatcg gaggaccgaa 5820
ggagctaacc gcttttttgc acaacatggg ggatcatgta actcgccttg atcgttggga 5880
accggagctg aatgaagcca taccaaacga cgagcgtgac accacgatgc ctgtagcaat 5940
ggcaacaacg ttgcgcaaac tattaactgg cgaactactt actctagctt cccggcaaca 6000
attaatagac tggatggagg cggataaagt tgcaggacca cttctgcgct cggcccttcc 6060
ggctggctgg tttattgctg ataaatctgg agccggtgag cgtgggtctc gcggtatcat 6120
tgcagcactg gggccagatg gtaagccctc ccgtatcgta gttatctaca cgacggggag 6180
tcaggcaact atggatgaac gaaatagaca gatcgctgag ataggtgcct cactgattaa 6240
gcattggtaa ctgtcagacc aagtttactc atatatactt tagattgatt taaaacttca 6300
tttttaattt aaaaggatct aggtgaagat cctttttgat aatctcatga ccaaaatccc 6360
ttaacgtgag ttttcgttcc actgagcgtc agaccccgta gaaaagatca aaggatcttc 6420
ttgagatcct ttttttctgc gcgtaatctg ctgcttgcaa acaaaaaaac caccgctacc 6480
agcggtggtt tgtttgccgg atcaagagct accaactctt tttccgaagg taactggctt 6540
cagcagagcg cagataccaa atactgttct tctagtgtag ccgtagttag gccaccactt 6600
caagaactct gtagcaccgc ctacatacct cgctctgcta atcctgttac cagtggctgc 6660
tgccagtggc gataagtcgt gtcttaccgg gttggactca agacgatagt taccggataa 6720
ggcgcagcgg tcgggctgaa cggggggttc gtgcacacag cccagcttgg agcgaacgac 6780
ctacaccgaa ctgagatacc tacagcgtga gctatgagaa agcgccacgc ttcccgaagg 6840
gagaaaggcg gacaggtatc cggtaagcgg cagggtcgga acaggagagc gcacgaggga 6900
gcttccaggg ggaaacgcct ggtatcttta tagtcctgtc gggtttcgcc acctctgact 6960
tgagcgtcga tttttgtgat gctcgtcagg ggggcggagc ctatggaaaa acgccagcaa 7020
cgcggccttt ttacggttcc tggccttttg ctggcctttt gctcacatgt tctttcctgc 7080
gttatcccct gattctgtgg ataaccgtat taccgccttt gagtgagctg ataccgctcg 7140
ccgcagccga acgaccgagc gcagcgagtc agtgagcgag gaagcggaag agcgcccaat 7200
acgcaaaccg cctctccccg cgcgttggcc gattcattaa tgcagctggc acgacaggtt 7260
tcccgactgg aaagcgggca gtgagcgcaa cgcaattaat gtgagttagc tcactcatta 7320
ggcaccccag gctttacact ttatgcttcc ggctcgtatg ttgtgtggaa ttgtgagcgg 7380
ataacaattt cacacaggaa acagctatga ccatgattac gccagattta attaagg 7437
Claims (23)
1.一种可用作威尔逊病(WD)的肝脏定向治疗剂的重组腺相关病毒(rAAV),所述rAAV包含AAV衣壳和包装在其中的载体基因组,所述载体基因组包含:
(a)AAV 5'反向末端重复(ITR)序列;
(b)启动子;
(c)编码人类铜转运ATP酶2(ATP7B)的编码序列;
(d)AAV 3'ITR。
2.根据权利要求1所述的rAAV,其中(c)的所述编码序列为SEQ ID NO:1。
3.根据权利要求1或2所述的rAAV,其中所述rAAV衣壳是AAV8衣壳或其变体。
4.根据任一前述权利要求所述的rAAV,其中所述启动子是TBG启动子或TBG-S1启动子。
5.根据任一前述权利要求所述的rAAV,其中所述启动子是TTR启动子。
6.根据任一前述权利要求所述的rAAV,其中所述启动子是修饰的TTR启动子。
7.根据任一前述权利要求所述的rAAV,其中所述AAV 5'ITR和/或AAV3'ITR来自AAV2。
8.根据任一前述权利要求所述的rAAV,其中所述载体基因组还包含poly A。
9.根据任一前述权利要求所述的rAAV,其中所述poly A的长度为约75aa。
10.根据任一前述权利要求所述的rAAV,还包含WPRE。
11.根据任一前述权利要求所述的rAAV,还包含内含子。
12.根据任一前述权利要求所述的rAAV,其中所述内含子来自人类β珠蛋白IVS2或SV40。
13.根据任一前述权利要求所述的rAAV,还包含增强子。
14.根据任一前述权利要求所述的rAAV,其中所述增强子是APB增强子、ABPS增强子、αmic/bik增强子、TTR增强子、en34或ApoE增强子。
15.根据任一前述权利要求所述的rAAV,其中所述载体基因组的大小为约3千碱基至约5.5千碱基。
16.一种适用于向威尔逊病患者施用的水性悬浮液,所述悬浮液包含水性悬浮液体和约1x1012GC/mL至约1x1014GC/mL的可用作威尔逊病的肝脏定向治疗剂的重组腺相关病毒(rAAV),所述rAAV具有AAV衣壳并且具有包装在其中的载体基因组,所述载体基因组包含:
(a)AAV 5'反向末端重复(ITR)序列;
(b)启动子;
(c)编码人类铜转运ATP酶2(ATP7B)的编码序列;以及
(d)AAV 3'ITR。
17.根据权利要求17所述的悬浮液,其中所述悬浮液适用于静脉内注射。
18.根据权利要求17或18所述的悬浮液,其中所述悬浮液还包含溶解在所述水性悬浮液体中的表面活性剂、防腐剂和/或缓冲液。
19.一种用根据权利要求1所述的rAAV治疗患有威尔逊病的患者的方法,其中所述rAAV以在水性悬浮液中的约1x 1012至约1x 1014个基因组拷贝(GC)/kg进行递送,其中所述GC如基于oqPCR或ddPCR所确定的那样计算。
20.根据权利要求1所述的rAAV,其中所述载体基因组包含SEQ ID NO:23、SEQ ID NO:24、SEQ ID NO:25、SEQ ID NO:26或SEQ ID NO:27。
21.根据权利要求17所述的悬浮液,其中所述rAAV衣壳为AAV8衣壳。
22.根据权利要求1所述的rAAV,其包含En34.TBG-S1增强子/启动子。
23.根据权利要求1-16中任一项所述的rAAV用于治疗有需要的受试者中的威尔逊病的用途。
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PCT/US2017/068919 WO2018126116A1 (en) | 2016-12-30 | 2017-12-29 | Gene therapy for treating wilson's disease |
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CN115216481A (zh) * | 2021-04-21 | 2022-10-21 | 四川至善唯新生物科技有限公司 | 一种表达量提高的截短型atp7b基因及其应用 |
CN115216533A (zh) * | 2022-06-30 | 2022-10-21 | 湖南家辉生物技术有限公司 | 一种用于诊断威尔逊病的生物标志物、扩增引物组、检测试剂及应用 |
CN117947035A (zh) * | 2024-03-25 | 2024-04-30 | 上海凌医生物科技有限公司 | 一种增强基因表达的启动子 |
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KR20230160411A (ko) | 2023-11-23 |
US11473106B2 (en) | 2022-10-18 |
KR102604096B1 (ko) | 2023-11-23 |
JP2020514286A (ja) | 2020-05-21 |
US20190338310A1 (en) | 2019-11-07 |
MX2019007873A (es) | 2019-11-18 |
EP4361277A2 (en) | 2024-05-01 |
WO2018126116A1 (en) | 2018-07-05 |
KR20190101410A (ko) | 2019-08-30 |
EP3562514A4 (en) | 2020-08-05 |
EP3562514A1 (en) | 2019-11-06 |
CA3048044A1 (en) | 2018-07-05 |
BR112019013245A2 (pt) | 2020-02-11 |
EP4361277A3 (en) | 2024-07-31 |
US20220389455A1 (en) | 2022-12-08 |
JP7128190B2 (ja) | 2022-08-30 |
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