CN112449605A - 反式剪接分子 - Google Patents

反式剪接分子 Download PDF

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CN112449605A
CN112449605A CN201980040706.1A CN201980040706A CN112449605A CN 112449605 A CN112449605 A CN 112449605A CN 201980040706 A CN201980040706 A CN 201980040706A CN 112449605 A CN112449605 A CN 112449605A
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abca4
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菲利普·R·约翰逊
布鲁斯·C·施奈普
吉恩·贝内特
斯科特·J·杜利
克里希纳·贾瓦哈拉尔·费舍尔
孙军伟
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University of Pennsylvania Penn
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Abstract

本发明的特征在于能够校正ABCA4基因或CEP290基因中的一个或多个突变的核酸反式剪接分子(例如，前mRNA反式剪接分子(RTM))。此类分子可用于治疗与ABCA4突变相关的病症，例如Stargardt病(例如Stargardt病1)和与CEP290突变相关的病症，例如莱伯氏先天性黑蒙症10(LCA 10)。本文所述的发明还提供了使用核酸反式剪接分子来校正ABCA4和CEP290中的突变以及用于治疗与ABCA4和CEP290中的突变相关的病症例如Stargardt病和LCA 10的方法。

Description

反式剪接分子
相关申请的交叉引用
本申请要求享有美国临时申请序列号62/658,658和62/658,667的优先权的权益，这两个申请均于2018年4月17日提交，其全部内容通过引用整体并入本文。
序列表
本申请包含序列表，该序列表已经以ASCII格式电子提交，并且通过引用整体并入本文。所述ASCII副本于2019年3月17日创建，名为51219-016WO2_Sequence_Listing_04.16.19_ST25，大小为608,489字节。
技术领域
通常，本发明以ABCA4和CEP290反式剪接分子为特征。
背景技术
Stargardt病是一种进行性眼部疾病，其特征是中心视觉和色觉丧失，这种疾病可以迅速发生，也可以在数年内发生。外围视觉通常保持完整。沿着ABCA4基因的长度发生的各种突变都可能导致Stargardt病。目前正在为Stargardt病开发的治疗方法包括慢病毒递送ABCA4、维生素A的化学修饰变体和视网膜色素上皮细胞疗法。
莱伯氏先天性黑蒙症10(Leber congenital amourosis 10，LCA 10)是一种以婴儿期开始出现严重视力障碍为特征的状况。视力丧失与由于纤毛缺陷引起的光感受器细胞死亡相关。与LCA 10相关的最常见的已知突变是点突变，其中CEP290基因内含子26的核苷酸1655处的腺嘌呤被鸟嘌呤取代，这导致剪接缺陷，其中在第26和第27外显子之间剪接了隐性的终止密码子。这种常染色体隐性突变导致产生无功能的中心体蛋白，从而导致LCA10的失明特征。
腺相关病毒(Adeno-associated viral，AAV)运载体介导的基因治疗在人类中已证明具有安全性，是治疗多种遗传缺陷的有前途的方法。但是，AAV运载体可能具有病毒生物学所决定的局限性，例如包装尺寸限制，可能会阻碍大核酸分子的递送，例如替代ABCA4基因或CEP290基因所必需的核酸。因此，在该领域中需要用于校正ABCA4和CEP290中的突变的组合物和方法。
发明内容
本发明涉及核酸反式剪接分子，及其用于校正ABCA4基因或CEP290基因中的突变的方法。本文提供的组合物和方法可用于治疗或预防与ABCA4突变相关的疾病，例如Stargardt病(例如Stargardt病1)或CEP290突变，例如LCA(例如LCA10)。
ABCA4
在第一方面，本发明的特征在于ABCA4反式剪接分子。例如，本发明提供了一种核酸反式剪接分子，其包含以3'至5'方向或5'至3'方向可操作地连接：(a)结合结构域，其被配置为结合靶ABCA4内含子，该靶ABCA4内含子选自由内含子19、22、23或24组成的组；(b)被配置为介导反式剪接的剪接结构域；(c)包含功能性ABCA4外显子的编码结构域；其中所述核酸反式剪接分子被配置为将所述编码结构域反式剪接至与所述靶ABCA4内含子相邻的内源ABCA4外显子，从而用所述功能性ABCA4外显子替代所述内源ABCA4外显子并校正ABCA4中的突变。
在一些实施方案中，结合结构域与在突变3’端的靶ABCA4内含子结合，并且其中该突变在ABCA4外显子1-24或内含子1-24中的任何一个中。在一些实施方案中，靶ABCA4内含子是内含子19，突变是在ABCA4外显子1-19或内含子1-19中的任何一个中，并且编码结构域包含ABCA4外显子1-19。在一些实施方案中，结合结构域被配置为在结合位点结合内含子19，所述结合位点包含SEQ ID NO：25的核苷酸990至2174的任何一个或多个(例如，SEQ IDNO：25的核苷酸1670至2174的任何一个或多个，例如，SEQ ID NO：25的核苷酸1810至2000的任何一个或多个，例如，SEQ ID NO：25的核苷酸1870至2000的任何一个或多个，例如SEQ IDNO：25的核苷酸1920至2000的任何一个或多个)。
在一些实施方案中，靶ABCA4内含子是内含子23，该突变在ABCA4外显子1-23或内含子1-23中的任一个中，和/或编码结构域包含ABCA4外显子1-23。在一些实施方案中，结合结构域被配置为在结合位点结合内含子23，所述结合位点包含SEQ ID NO：29的核苷酸80至570或核苷酸720至1081中的任何一个或多个。
在一些实施方案中，结合结构域被配置为在结合位点结合ABCA4内含子23，所述结合位点包含SEQ ID NO：29的核苷酸261至410中的任一个或多个(例如，SEQ ID NO：29的核苷酸261至410之内或周围的结合位点的从1至200、从6至150、从12至100、或从20至80个核苷酸，例如SEQ ID NO：29的核苷酸261至410内或周围的结合位点的从1到6、从6到12、从12到18、从18到24、从24到50、从50到100、从100到150、或从150至200个核苷酸，例如，SEQ IDNO：29的核苷酸261至410之内或周围的结合位点的至少一个、至少两个、至少三个、至少四个、至少五个、至少六个、至少七个、至少八个、至少九个、至少10个、至少12个、至少15个、至少20个、至少25个、至少30个、至少40个、至少50个、至少60个、至少70个、至少80个、至少90个、至少100个、至少120个、至少150个或至少200个核苷酸)。例如，在特定的实施方案中，结合位点包含SEQ ID NO：29的核苷酸261至410中的六个或更多个。在一些实施方案中，结合结构域包含与结合位点的六个或更多个核苷酸互补(例如，反义)的六个或更多个连续的核酸残基。在一些实施方案中，结合结构域包含一组连续的核酸残基，其与具有SEQ ID NO：29的核苷酸261至410中的一个或多个核苷酸的ABCA4结合位点的对应的互补核苷酸的一组互补，其中结合结构域的连续核酸残基组的长度为从6至500个残基(例如，长度为从8至400、从12至300、从16至200、从24至280或从50至150个残基，例如，长度为从100到200、从6到10、从10到20、从20到30、从30到40、从40到50、从50到80、从80到100、从100到120、从120到150、从150至200或从200至300个残基，例如长度为6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、140、141、142、143、144、145、146、147、148、149、150、151、152、153、154、155、156、157、158、159、160或更多个残基)。
在一些实施方案中，结合结构域被配置为在结合位点结合ABCA4内含子23，所述结合位点包含SEQ ID NO：29的核苷酸801至950中的任一个或多个(例如，SEQ ID NO：29的核苷酸801至950之内或周围的结合位点的从1至200、从6至150、从12至100、或从20至80个核苷酸，例如SEQ ID NO：29的核苷酸801至950内或周围的结合位点的从1到6、从6到12、从12到18、从18到24、从24到50、从50到100、从100到150、或从150至200个核苷酸，例如，SEQ IDNO：29的核苷酸801至950之内或周围的结合位点的至少一个、至少两个、至少三个、至少四个、至少五个、至少六个、至少七个、至少八个、至少九个、至少10个、至少12个、至少15个、至少20个、至少25个、至少30个、至少40个、至少50个、至少60个、至少70个、至少80个、至少90个、至少100个、至少120个、至少150个或至少200个核苷酸)。例如，在特定的实施方案中，结合位点包含SEQ ID NO：29的核苷酸801至950中的六个或更多个。在一些实施方案中，结合结构域包含与结合位点的六个或更多个核苷酸互补(例如，反义)的六个或更多个连续的核酸残基。在一些实施方案中，结合结构域包含一组连续的核酸残基，其与具有SEQ ID NO：29的核苷酸801至950中的一个或多个核苷酸的ABCA4结合位点的对应的互补核苷酸的一组互补，其中结合结构域的连续核酸残基组的长度为从6至500个残基(例如，长度为从8至400、从12至300、从16至200、从24至280或从50至150个残基，例如，长度为从100到200、从6到10、从10到20、从20到30、从30到40、从40到50、从50到80、从80到100、从100到120、从120到150、从150至200或从200至300个残基，例如长度为6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、140、141、142、143、144、145、146、147、148、149、150、151、152、153、154、155、156、157、158、159、160或更多个残基)。
在一些实施方案中，结合结构域被配置为在结合位点结合ABCA4内含子23，所述结合位点包含SEQ ID NO：29的核苷酸841至990中的任一个或多个(例如，SEQ ID NO：29的核苷酸841至990之内或周围的结合位点的从1至200、从6至150、从12至100、或从20至80个核苷酸，例如SEQ ID NO：29的核苷酸841至990内或周围的结合位点的从1到6、从6到12、从12到18、从18到24、从24到50、从50到100、从100到150、或从150至200个核苷酸，例如，SEQ IDNO：29的核苷酸841至990之内或周围的结合位点的至少一个、至少两个、至少三个、至少四个、至少五个、至少六个、至少七个、至少八个、至少九个、至少10个、至少12个、至少15个、至少20、至少25、至少30、至少40、至少50、至少60、至少70、至少80、至少90、至少100、至少120、至少150或至少200个核苷酸)。例如，在特定的实施方案中，结合位点包含SEQ ID NO：29的核苷酸841至990中的六个或更多个。在一些实施方案中，结合结构域包含与结合位点的六个或更多个核苷酸互补(例如，反义)的六个或更多个连续的核酸残基。在一些实施方案中，结合结构域包含一组连续的核酸残基，其与具有SEQ ID NO：29的核苷酸841至990中的一个或多个核苷酸的ABCA4结合位点的对应的互补核苷酸的一组互补，其中结合结构域的连续核酸残基组的长度为从6至500个残基(例如，长度为从8至400、从12至300、从16至200、从24至280或从50至150个残基，例如，长度为从100到200、从6到10、从10到20、从20到30、从30到40、从40到50、从50到80、从80到100、从100到120、从120到150、从150至200或从200至300个残基，例如长度为6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、140、141、142、143、144、145、146、147、148、149、150、151、152、153、154、155、156、157、158、159、160或更多个残基)。
在其他实施方案中，靶ABCA4内含子是内含子24，突变是在ABCA4外显子1-24或内含子1-24中的任何一个中，并且编码结构域包含ABCA4外显子1-24。在一些实施方案中，结合结构域被配置为在结合位点结合内含子24，所述结合位点包含SEQ ID NO：30的核苷酸600至1250或核苷酸1490至2660中的任一个或多个。在其他实施方案中，结合位点包含SEQID NO：30的核苷酸1,000至1,200的任何一个或多个。
在一些实施方案中，结合结构域与在突变5’端的靶ABCA4内含子结合，并且其中该突变在ABCA4外显子23-50或内含子22-49的任何一个中。例如，在一些实施方案中，靶ABCA4内含子是内含子23，突变是在ABCA4外显子24-50或内含子23-49的任何一个中，并且编码结构域包含ABCA4外显子24-50。在一些实施方案中，结合结构域被配置为在结合位点结合内含子23，所述结合位点包含SEQ ID NO：29的核苷酸80至1081中的任一个或多个。在一些实施方案中，结合位点包含SEQ ID NO：29的核苷酸230至1081中的任一个或多个，例如SEQ IDNO：29的核苷酸250至400中的任何一个或多个，或SEQ ID NO：29的核苷酸690至850中的任何一个或多个。
在一些实施方案中，靶ABCA4内含子是内含子24，突变在ABCA4外显子25-50或内含子24-49中的任何一个中，并且编码结构域包含ABCA4外显子25-50。在一些实施方案中，结合结构域被配置为在结合位点结合内含子24，所述结合位点包含SEQ ID NO：30的核苷酸1至250，核苷酸300至2100或核苷酸2200至2692中的任一个或多个。在一些实施方案中，结合位点包含SEQ ID NO：30的核苷酸360至610中的任何一个或多个。在其他实施方案中，结合位点包含SEQ ID NO：30的核苷酸750至1110中的一个或多个。
在另一方面，本发明的特征在于一种核酸反式剪接分子，其包含以5'至3'方向可操作地连接的：(a)结合结构域，其被配置为在结合位点结合ABCA4内含子22，所述结合位点包含SEQ ID NO：28的核苷酸60至570、600至800或900至1350的任何一个或多个；(b)被配置为介导反式剪接的剪接结构域；(c)包含功能性ABCA4外显子23-50的编码结构域；其中所述核酸反式剪接分子被配置为将编码结构域反式剪接至内源ABCA4外显子22，从而用功能性ABCA4外显子23-50替代内源ABCA4外显子23-50。在一些实施方案中，结合位点包含SEQ IDNO：28的核苷酸70-250中的任何一个或多个。
在另一方面，本发明的特征在于一种核酸反式剪接分子，其包含以3'至5'方向可操作地连接的：(a)结合结构域，其被配置为在结合位点结合ABCA4内含子22，所述结合位点包含SEQ ID NO：28的核苷酸1至510或880至1350的任何一个或多个；(b)被配置为介导反式剪接的剪接结构域；(c)包含功能性ABCA4外显子1-22的编码结构域；其中所述核酸反式剪接分子被配置为将编码结构域反式剪接至内源ABCA4外显子23，从而用功能性ABCA4外显子1-22替代内源ABCA4外显子1-22。
在一些实施方案中，结合结构域被配置为在结合位点结合ABCA4内含子22，所述结合位点包含SEQ ID NO：28的核苷酸1041至1190中的任一个或多个(例如，SEQ ID NO：28的核苷酸1041至1190之内或周围的结合位点的从1至200、从6至150、从12至100、或从20至80个核苷酸，例如SEQ ID NO：28的核苷酸1041至1190内或周围的结合位点的从1到6、从6到12、从12到18、从18到24、从24到50、从50到100、从100到150、或从150至200个核苷酸，例如，SEQ ID NO：28的核苷酸1041至1190之内或周围的结合位点的至少一个、至少两个、至少三个、至少四个、至少五个、至少六个、至少七个、至少八个、至少九个、至少10个、至少12个、至少15个、至少20个、至少25个、至少30个、至少40个、至少50个、至少60个、至少70个、至少80个、至少90个、至少100个、至少120个、至少150个或至少200个核苷酸)。在特定的实施方案中，结合位点包含SEQ ID NO：28的核苷酸1041至1190中的六个或更多个。在一些实施方案中，结合结构域包含与结合位点的六个或更多个核苷酸互补(例如，反义)的六个或更多个连续的核酸残基。在一些实施方案中，结合结构域包含一组连续的核酸残基，其与具有SEQID NO：28的核苷酸1041至1190中的一个或多个核苷酸的ABCA4结合位点的对应的互补核苷酸的一组互补，其中结合结构域的连续核酸残基组的长度为从6至500个残基(例如，长度为从8至400、从12至300、从16至200、从24至280或从50至150个残基，例如，长度为从100到200、从6到10、从10到20、从20到30、从30到40、从40到50、从50到80、从80到100、从100到120、从120到150、从150至200或从200至300个残基，例如长度为6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、140、141、142、143、144、145、146、147、148、149、150、151、152、153、154、155、156、157、158、159、160或更多个残基)。
在一些实施方案中，结合结构域被配置为结合SEQ ID NO：28的核苷酸1171至1320中的任一个或多个(例如，SEQ ID NO：28的核苷酸1171至1320之内或周围的结合位点的从1至200、从6至150、从12至100、或从20至80个核苷酸，例如SEQ ID NO：28的核苷酸1171至1320内或周围的结合位点的从1到6、从6到12、从12到18、从18到24、从24到50、从50到100、从100到150、或从150至200个核苷酸，例如，SEQ ID NO：28的核苷酸1171至1320之内或周围的结合位点的至少一个、至少两个、至少三个、至少四个、至少五个、至少六个、至少七个、至少八个、至少九个、至少10个、至少12个、至少15个、至少20个、至少25个、至少30个、至少40个、至少50个、至少60个、至少70个、至少80个、至少90个、至少100个、至少120个、至少150个或至少200个核苷酸)。在特定的实施方案中，结合位点包含SEQ ID NO：28的核苷酸1171至1320中的六个或更多个。在一些实施方案中，结合结构域包含与结合位点的六个或更多个核苷酸互补(例如，反义)的六个或更多个连续的核酸残基。在一些实施方案中，结合结构域包含一组连续的核酸残基，其与具有SEQ ID NO：28的核苷酸1171至1320中的一个或多个核苷酸的ABCA4结合位点的对应的互补核苷酸的一组互补，其中结合结构域的连续核酸残基组的长度为从6至500个残基(例如，长度为从8至400、从12至300、从16至200、从24至280或从50至150个残基，例如，长度为从100到200、从6到10、从10到20、从20到30、从30到40、从40到50、从50到80、从80到100、从100到120、从120到150、从150至200或从200至300个残基，例如长度为6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、140、141、142、143、144、145、146、147、148、149、150、151、152、153、154、155、156、157、158、159、160或更多个残基)。
在一些实施方案中，结合结构域被配置为结合SEQ ID NO：28的核苷酸1201至1350中的任一个或多个(例如，SEQ ID NO：28的核苷酸1201至1350之内或周围的结合位点的从1至200、从6至150、从12至100、或从20至80个核苷酸，例如SEQ ID NO：28的核苷酸1201至1350内或周围的结合位点的从1到6、从6到12、从12到18、从18到24、从24到50、从50到100、从100到150、或从150至200个核苷酸，例如，SEQ ID NO：28的核苷酸1201至1350之内或周围的结合位点的至少一个、至少两个、至少三个、至少四个、至少五个、至少六个、至少七个、至少八个、至少九个、至少10个、至少12个、至少15个、至少20个、至少25个、至少30个、至少40个、至少50个、至少60个、至少70个、至少80个、至少90个、至少100个、至少120个、至少150个或至少200个核苷酸)。在特定的实施方案中，结合位点包含SEQ ID NO：28的核苷酸1201至1350中的六个或更多个。在一些实施方案中，结合结构域包含与结合位点的六个或更多个核苷酸互补(例如，反义)的六个或更多个连续的核酸残基。在一些实施方案中，结合结构域包含一组连续的核酸残基，其与具有SEQ ID NO：28的核苷酸1201至1350中的一个或多个核苷酸的ABCA4结合位点的对应的互补核苷酸的一组互补，其中结合结构域的连续核酸残基组的长度为从6至500个残基(例如，长度为从8至400、从12至300、从16至200、从24至280或从50至150个残基，例如，长度为从100到200、从6到10、从10到20、从20到30、从30到40、从40到50、从50到80、从80到100、从100到120、从120到150、从150至200或从200至300个残基，例如长度为6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、140、141、142、143、144、145、146、147、148、149、150、151、152、153、154、155、156、157、158、159、160或更多个残基)。
在任何前述实施方案中，结合结构域的长度可以为20-1,000个核苷酸(例如，长度为25-900个核苷酸，长度为30-800个核苷酸，长度为40-700个核苷酸，长度为50-600个核苷酸，长度为75-500个核苷酸，长度为100-400个核苷酸，长度为125-200个核苷酸，或长度为约150个核苷酸，例如，长度为20-30个核苷酸，长度为30-40个核苷酸，长度为40-50个核苷酸，长度为50-75个核苷酸，长度为75-100个核苷酸，长度为125-150个核苷酸，长度为150-175个核苷酸，长度为175-200个核苷酸，长度为200-250个核苷酸，长度为250-500个核苷酸，长度为500-750个核苷酸，或长度为750-1000个核苷酸)。
在一些实施方案中，编码结构域是cDNA序列。在一些实施方案中，编码结构域包含天然序列。在其他实施方案中，编码结构域包括密码子优化的序列。在一些实施方案中，反式剪接分子包括包含间隔子序列的人工内含子。
在任何前述方法的一些实施方案中，核酸反式剪接分子的长度为3,000至4,000个核苷酸(例如，长度为3,100-3,900个核苷酸，长度为3,200-3,800个核苷酸，长度为3,300-3,700个核苷酸，长度为3,400-3,600个核苷酸，或长度为约3500个核苷酸，例如，长度为3,000-3,100个核苷酸，长度为3,100-3,200个核苷酸，长度为3,200-3,300个核苷酸，长度为3,300-3,400个核苷酸，长度为3,400-3,500个核苷酸，长度为3,500-3,600个核苷酸，长度为3,600-3,700个核苷酸，长度为3,800-3,900个核苷酸或长度为3,900-4,000个核苷酸)。
在一些实施方案中，ABCA4基因中的突变与Stargardt病相关。在一些实施方案中，与Stargardt病相关的ABCA4基因中的突变在光感受器细胞中表达。
在另一方面，本文提供了一种核酸反式剪接分子，其包含在3'至5'方向上可操作地连接的：(a)结合结构域，其被配置为在结合位点结合ABCA4内含子23，所述结合位点包含SEQ ID NO：29的核苷酸261至410的六个或更多个，其中结合结构域包含六个或更多个连续核酸残基，所述连续核酸残基与结合位点的六个或更多个核苷酸互补；(b)包含剪接结构域的人工内含子；(c)包含功能性ABCA4外显子1-23的编码结构域；其中核酸反式剪接分子被配置为将编码结构域反式剪接至内源ABCA4外显子24，从而用功能性ABCA4外显子1-23替代内源ABCA4外显子1-23。
在另一方面，本发明提供了一种核酸反式剪接分子，其包含在3'至5'方向上可操作地连接的：(a)结合结构域，其被配置为在结合位点结合ABCA4内含子23，所述结合位点包含SEQ ID NO：29的核苷酸801至950的六个或更多个，其中结合结构域包含六个或更多个连续核酸残基，所述连续核酸残基与结合位点的六个或更多个核苷酸互补；(b)包含剪接结构域的人工内含子；(c)包含功能性ABCA4外显子1-23的编码结构域；其中核酸反式剪接分子被配置为将编码结构域反式剪接至内源ABCA4外显子24，从而用功能性ABCA4外显子1-23替代内源ABCA4外显子1-23。
在另一方面，本文提供了一种核酸反式剪接分子，其包含在3'至5'方向上可操作地连接的：(a)结合结构域，其被配置为在结合位点结合ABCA4内含子23，所述结合位点包含SEQ ID NO：29的核苷酸841至990的六个或更多个，其中结合结构域包含六个或更多个连续核酸残基，所述连续核酸残基与结合位点的六个或更多个核苷酸互补；(b)包含剪接结构域的人工内含子；(c)包含功能性ABCA4外显子1-23的编码结构域；其中核酸反式剪接分子被配置为将编码结构域反式剪接至内源ABCA4外显子24，从而用功能性ABCA4外显子1-23替代内源ABCA4外显子1-23。
在另一方面，本发明提供了一种核酸反式剪接分子，其包含在3'至5'方向上可操作地连接的：(a)结合结构域，其被配置为在结合位点结合ABCA4内含子22，所述结合位点包含SEQ ID NO：28的核苷酸1041至1190的六个或更多个，其中结合结构域包含六个或更多个连续核酸残基，所述连续核酸残基与结合位点的六个或更多个核苷酸互补；(b)包含剪接结构域的人工内含子；(c)包含功能性ABCA4外显子1-22的编码结构域；其中核酸反式剪接分子被配置为将编码结构域反式剪接至内源ABCA4外显子23，从而用功能性ABCA4外显子1-22替代内源ABCA4外显子1-22。
在另一方面，本发明的特征在于一种核酸反式剪接分子，其包含在3'至5'方向上可操作地连接的：(a)结合结构域，其被配置为在结合位点结合ABCA4内含子22，所述结合位点包含SEQ ID NO：28的核苷酸1171至1320的六个或更多个，其中结合结构域包含六个或更多个连续核酸残基，所述连续核酸残基与结合位点的六个或更多个核苷酸互补；(b)包含剪接结构域的人工内含子；(c)包含功能性ABCA4外显子1-22的编码结构域；其中核酸反式剪接分子被配置为将编码结构域反式剪接至内源ABCA4外显子23，从而用功能性ABCA4外显子1-22替代内源ABCA4外显子1-22。
在另一方面，本文提供了一种核酸反式剪接分子，其包含在3'至5'方向上可操作地连接的：(a)结合结构域，其被配置为在结合位点结合ABCA4内含子22，所述结合位点包含SEQ ID NO：28的核苷酸1201至1350的六个或更多个，其中结合结构域包含六个或更多个连续核酸残基，所述连续核酸残基与结合位点的六个或更多个核苷酸互补；(b)包含剪接结构域的人工内含子；(c)包含功能性ABCA4外显子1-22的编码结构域；其中核酸反式剪接分子被配置为将编码结构域反式剪接至内源ABCA4外显子23，从而用功能性ABCA4外显子1-22替代内源ABCA4外显子1-22。
在另一方面，本发明的特征在于前病毒质粒，其包括前述实施方案中任一项的核酸反式剪接分子。
在另一方面，本发明的特征在于一种腺相关病毒(AAV)，其包含前述实施方案中任一项的核酸分子。在一些实施方案中，AAV优先靶向光感受器细胞。在一些实施方案中，AAV包含AAV5衣壳蛋白，AAV8衣壳蛋白，AAV8(b)衣壳蛋白或AAV9衣壳蛋白。
在另一方面，本发明的特征在于一种药物组合物，其包含前述方面中任一项的核酸反式剪接分子、前病毒质粒或AAV。
在另一方面，本文提供了药物组合物，其具有任何前述实施方案的任何5'核酸反式剪接分子和任何前述实施方案的3'核酸反式剪接分子。
在另一方面，本发明的特征在于一种通过向受试者施用前述方面中任一项的药物组合物来校正受试者的靶细胞中的ABCA4基因中的突变的方法。
在另一方面，本文提供了一种通过向所述受试者施用具有前述实施例任何一种的核酸反式剪接分子的药物组合物来校正有此需要的受试者中的一个或多个ABCA4外显子1-24中的突变的方法。在特定的实施方案中，将被本发明的ABCA4反式剪接分子校正的突变的ABCA4外显子是外显子2。另外地或可替代地，将被本发明的ABCA4的反式剪接分子校正的突变的ABCA4外显子是外显子3。另外地或可替代地，将被本发明的ABCA4反式剪接分子校正的突变的ABCA4外显子是外显子4。
在另一方面，本发明包括通过向受试者施用包含前述实施例任何核酸反式剪接分子的药物组合物，在有此需要的受试者中校正一个或多个ABCA4外显子23-50中的突变的方法。
在另一方面，本发明的特征在于一种在有此需要的受试者中校正任一个ABCA4外显子1-24中的突变和任一个外显子23-50中的第二突变的方法，该方法包含向受试者施用药物组合物，其具有前述实施方案中任一项的5'核酸反式剪接分子和前述实施方案中任一项的3'核酸反式剪接分子。
在又一个实施方案中，本发明特征在于治疗患有与ABCA4中的突变相关的病症的受试者的方法，该方法包含向受试者施用任何前述药物组合物。在一些实施方案中，通过施用包含前述实施方案中任一项的核酸反式剪接分子的药物组合物来治疗患有与任一个或多个ABCA4外显子1-24或内含子1-24中的突变相关的病症的受试者。在一些实施方案中，通过施用包含前述实施方案中任一项的核酸反式剪接分子的药物组合物治疗患有与任何一个或多个ABCA4外显子23-50或内含子22-49中的突变相关的病症的受试者。
在另一方面，本发明的特征在于通过向受试者施用药物组合物来治疗患有与任何一个ABCA4外显子1-24中的第一突变和任何一个外显子23-50中的第二突变相关的病症的受试者的方法，该药物组合物具有前述实施方案中任一项的5'核酸反式剪接分子和前述实施方案中任一项的3'核酸反式剪接分子。
在任何前述方法中，受试者可以患有Stargardt病。在一些实施方案中，通过视网膜下注射、玻璃体内注射或静脉内注射来施用组合物。
在任何前述方法的一些实施方案中，所述受试者在施用后展现出ABCA4蛋白表达的至少1％的增加(例如，施用后ABCA4蛋白表达增加1-5％，增加5-10％，增加10-15％，增加15-20％，增加20-25％，增加25-50％或增加50-100％，例如，相对于同一受试者在施用前的ABCA4蛋白表达，或相对于参考样本、参考受试者或参考受试者组)。
CEP290
在另一方面，本发明的特征在于CEP290反式剪接分子。例如，本发明提供了一种核酸反式剪接分子，其包含以3'至5'方向可操作地连接的：(a)结合结构域，其被配置为在结合位点结合CEP290内含子26，所述结合位点包含SEQ ID NO：85的核苷酸4,800至5,838中任何一个或多个；(b)被配置为介导反式剪接的剪接结构域；(c)包含功能性CEP290外显子2-26的编码结构域；其中所述核酸反式剪接分子被配置为将所述编码结构域反式剪接至内源CEP290外显子27，从而用功能性CEP290外显子2-26替代内源CEP290外显子2-26并校正病原性点突变。在一些实施方案中，病原性点突变是SEQ ID NO：85的核苷酸1,655处的A至G突变。
在一些实施方案中，结合位点包含SEQ ID NO：85的核苷酸4,980至5,838的任一个或多个。在一些实施方案中，结合位点包含SEQ ID NO：85的核苷酸5,348至5,838的任一个或多个。在一些实施方案中，结合位点包含SEQ ID NO：85的核苷酸5,348至5,700的任何一个或多个。在一些实施方案中，结合位点包含SEQ ID NO：85的核苷酸5,400至5,600的任何一个或多个。在一些实施方案中，结合位点包含SEQ ID NO：85的核苷酸5,460至5,560中的任何一个或多个。在一些实施方案中，结合位点包含SEQ ID NO：85的核苷酸5,500。
在另一方面，本发明的特征在于一种核酸反式剪接分子，其包含以3'至5'方向可操作地连接：(a)被配置为在靶内含子27、28、29或30中的任何一个上结合CEP290的结合结构域；(b)被配置为介导反式剪接的剪接结构域；(c)编码结构域，其包含在靶内含子5'端的功能性CEP290外显子；其中所述核酸反式剪接分子被配置为将编码结构域反式剪接至内源CEP290，从而用功能性CEP290外显子替代在靶内含子5'端的内源CEP290外显子为并校正病原性点突变。在一些实施方案中，病原性点突变是SEQ ID NO：85的核苷酸1,655处的A至G突变。
在一些实施方案中，靶内含子是内含子27，编码结构域包含功能性CEP290外显子2-27，并且核酸反式剪接分子被配置为用功能性CEP290外显子2-27替代内源CEP290外显子2-27。在一些实施方案中，结合结构域被配置为在结合位点结合内含子27，所述结合位点包含SEQ ID NO：86的核苷酸120至680，核苷酸710至2,200或核苷酸2,670至2,910中的任一个或多个。在一些实施方案中，结合位点包含SEQ ID NO：86的核苷酸790至2,100的任何一个或多个，例如，SEQ ID NO：86的核苷酸1,020至1,630的任何一个或多个。在其他实施方案中，结合位点包含SEQ ID NO：86的核苷酸1,670至2,000的任何一个或多个。
在一些实施方案中，靶内含子是内含子28，编码结构域包含功能性CEP290外显子2-28，并且核酸反式剪接分子被配置为用功能性CEP290外显子2-28替代内源CEP290外显子2-28。在一些实施方案中，结合结构域被配置为在结合位点结合内含子28，所述结合位点包含SEQ ID NO：87的核苷酸1至390，核苷酸410至560或核苷酸730至937中的任一个或多个。在一些实施方案中，结合位点包含SEQ ID NO：87的核苷酸1至200中的任何一个或多个。在其他实施方案中，结合位点包含SEQ ID NO：87的核苷酸720至900中的任一个或多个。
在一些实施方案中，靶内含子是内含子29，编码结构域包含功能性CEP290外显子2-29，并且核酸反式剪接分子被配置为用功能性CEP290外显子2-29替代内源CEP290外显子2-29。在一些实施方案中，结合结构域被配置为在结合位点结合内含子28，所述结合位点包含SEQ ID NO：88的核苷酸1至600、核苷酸720至940或核苷酸1,370至1,790中的任一个或多个。
在一些实施方案中，靶内含子是内含子30，编码结构域包含功能性CEP290外显子2-30，并且核酸反式剪接分子被配置为用功能性CEP290外显子2-30替代内源CEP290外显子2-30。在一些实施方案中，结合结构域被配置为在结合位点结合内含子29，所述结合位点包含SEQ ID NO：89的核苷酸880至1,240中的任何一个或多个，例如SEQ ID NO：89的核苷酸950至1,240的任何一个或多个的，例如SEQ ID NO：89的核苷酸1,060至1,240中的任何一个或多个。
在任何前述实施方案中，结合结构域的长度为20-1,000个核苷酸(例如，长度为25-900个核苷酸，长度为30-800个核苷酸，长度为40-700个核苷酸，长度为50-600个核苷酸，长度为75-500个核苷酸，长度为100-400个核苷酸，长度为125-200个核苷酸或长度为约150个核苷酸，例如长度为20-30个核苷酸，长度为30-40个核苷酸，长度为40-50个核苷酸，长度为50-75个核苷酸，长度为75-100个核苷酸，长度为125-150个核苷酸，长度为150-175个核苷酸，长度为175-200个核苷酸，长度为200-250个核苷酸，长度为250-500个核苷酸，长度为500-750个核苷酸，或长度为750-1,000个核苷酸)。
在一些实施方案中，编码结构域是cDNA序列。在一些实施方案中，编码结构域是天然存在的序列。在其他实施方案中，编码结构域是密码子优化的序列。
在一些实施方案中，人工内含子包含人工内含子和间隔子序列。
在任何前述实施方案中，核酸反式剪接分子的长度可以是3,000至4,000个核苷酸。
在任何前述实施方案中，突变的CEP290外显子可以与LCA 10相关。在一些实施方案中，与LCA 10相关的突变的CEP290外显子在光感受器细胞中表达。
在本发明的另一方面，本文提供了一种前病毒质粒，其包含前述方面中任一项的核酸反式剪接分子。
在另一方面，本发明提供了一种腺相关病毒(AAV)，其包含前述方面中任一项的核酸分子。在一些实施方案中，AAV优先靶向光感受器细胞。在一些实施方案中，AAV包含AAV5衣壳蛋白、AAV8衣壳蛋白、AAV8(b)衣壳蛋白或AAV9衣壳蛋白。
在另一方面，本发明的特征在于一种药物组合物，其包含前述方面中任一项的核酸反式剪接分子、前病毒质粒或AAV。
在另一方面，本文的特征是在受试者的靶细胞中校正CEP290内含子26中的病原性点突变的方法，所述方法包含向受试者施用前述方面中任一项的所述核酸反式剪接分子、所述前病毒质粒、所述AAV或所述药物组合物。在一些实施方案中，受试者患有LCA 10。
在又一方面，本发明提供了一种治疗具有由CEP290内含子26中的病原性点突变引起的LCA 10的受试者的方法，该方法包含向该受试者施用前述方面中任一项的所述核酸反式剪接分子、所述前病毒质粒、所述AAV或所述药物组合物。
在任何前述方法中，病原性点突变可以是CEP290内含子26(SEQ ID NO：85)的核苷酸1655处的A至G突变。在一些实施方案中，通过视网膜下注射、玻璃体内注射或静脉内注射施用所述核酸反式剪接分子、所述前病毒质粒、所述AAV或所述药物组合物。
在另一方面，本发明提供了一种试剂盒，其包含上述核酸反式剪接分子、前病毒质粒、AAV或药物组合物中的任何一种或多种，其中该试剂盒进一步包括使用一种或多种核酸反式剪接分子、前病毒质粒、AAV或药物组合物校正受试者CEP290基因的突变(例如与病症相关的突变，例如LCA 10)的说明书。
附图说明
图1是用于用功能性ABCA4外显子校正突变的ABCA4外显子的几种示例性核酸反式剪接分子的示意图。深色阴影框表示天然ABCA4外显子。连接深色阴影框的虚线表示天然内含子。带有深色边框的浅色阴影框表示核酸反式剪接分子中的功能性ABCA4外显子。由曲线表示的剪接结构域附着于每个功能性ABCA4外显子的一端，并导向ABCA4前mRNA的内含子。
图2是显示使用5’反式剪接分子在十个核苷酸间隔内跨ABCA4内含子19(SEQ IDNO：25)的150聚体(150-mer)结合结构域赋予的反式剪接效率(相对倍数变化)的图。X轴标签表示从内含子5'末端开始的每个结合位点的数目(即内含子序列的第一个核苷酸)。
图3是显示使用5’反式剪接分子在十个核苷酸间隔内跨ABCA4内含子22(SEQ IDNO：28)的150聚体结合结构域赋予的反式剪接效率(相对倍数变化)的图。X轴标签表示从内含子5'末端开始的每个结合位点的数目(即内含子序列的第一个核苷酸)。
图4是显示使用3'反式剪接分子在十个核苷酸间隔内跨ABCA4内含子22(SEQ IDNO：28)的150聚体结合结构域赋予的反式剪接效率(相对倍数变化)的图。X轴标签表示从内含子5'末端开始的每个结合位点的数目(即内含子序列的第一个核苷酸)。
图5是显示使用5'反式剪接分子在十个核苷酸间隔内跨ABCA4内含子23(SEQ IDNO：29)的150聚体结合结构域赋予的反式剪接效率(相对倍数变化)的图。X轴标签表示从内含子5'末端开始的每个结合位点的数目(即内含子序列的第一个核苷酸)。
图6是显示使用3'反式剪接分子在十个核苷酸间隔内跨ABCA4内含子23(SEQ IDNO：29)的150聚体结合结构域赋予的反式剪接效率(相对倍数变化)的图。X轴标签表示从内含子5'末端开始的每个结合位点的数目(即内含子序列的第一个核苷酸)。
图7是显示使用5'反式剪接分子在十个核苷酸间隔内跨ABCA4内含子24(SEQ IDNO：30)的150聚体结合结构域赋予的反式剪接效率(相对倍数变化)的图。X轴标签表示从内含子5'末端开始的每个结合位点的数目(即内含子序列的第一个核苷酸)。
图8是显示使用3'反式剪接分子在十个核苷酸间隔内跨ABCA4内含子24(SEQ IDNO：30)的150聚体结合结构域赋予的反式剪接效率(相对倍数变化)的图。X轴标签表示从内含子5'末端开始的每个结合位点的数目(即内含子序列的第一个核苷酸)。
图9是显示TALEN蛋白的示意图，该TALEN蛋白由连接至转录激活结构域的DNA结合结构域组成。显示了VP64转录激活结构域。右侧面板显示了ABCA4的5'非翻译区域(5'-UTR)的一部分。显示了TATA框和推定的转录起始位点。还显示了TALEN的三个不同DNA结合结构域靶向的序列。如图所示，TALEN 1与第一个带下划线的序列结合，TALEN 2与第二个带下划线的序列结合，TALEN 3与第三个带下划线的序列结合。
图10是显示用设计为诱导内源ABCA4表达的TALEN构建体转染293T细胞的凝胶。将来自图9的所有三个TALENS稳定地引入293细胞，并挑出单细胞克隆并通过Western印迹进行分析。阳性对照(+)表示转染了表达ABCA4 cDNA质粒的细胞。转染后48小时制备细胞裂解液，并使用抗体ab72955(Abcam)检查膜级分的ABCA4表达。克隆ZT-22和ZT-48显示ABCA4蛋白表达。
图11是显示CAG启动子细胞系的示意图。
图12A和12B示出了位点特异性向导(图12A)，其被设计来使用同源臂(图12B)插入CAG启动子和嘌呤霉素选择标记。
图13是显示CAG启动子细胞系的示意图。
图14A和14B分别是图和凝胶图，其显示了来自选择用于进一步分析的几种克隆系的表达结果。图14A显示了RNA表达，图14B显示了细胞系的蛋白质表达。使用针对ABCA4的兔多克隆抗体(Abcam，ab72955)对指定细胞系的膜制剂进行ABCA4蛋白探测。曝光时间为23秒。293细胞是不表达ABCA4的亲代细胞。最高条带是所有细胞中都存在的非特异性背景。
图15是显示用于靶向外显子3和4的CRISPR向导RNA的示意图。
图16是显示RNA表达和凝胶的图，其显示了用CRISPR/Cas9处理后衍生的单细胞克隆的蛋白质谱，如图15所示。
图17A和17B是示意图，其显示了用于在cDNA上进行突变分析的PCR(图17A)和在cDNA上进行基因分型的PCR(图17B)，确认外显子3和4被靶向并中断。
图18是一组表，其显示来自图17A和17B的突变分析证实了外显子3和4在17+06和17+21细胞系的等位基因中被靶向并被中断。
图19A和19B是靶向ABCA4前mRNA的反式剪接分子的示意图。图19A显示了包括密码子优化的外显子(或外显子组)，与靶RNA杂交的结合结构域和人工内含子接头的通用反式剪接分子。图19B显示了靶向ABCA4的内含子22和23内的特定区域的各种反式剪接分子。
图20A-20D是凝胶(图20A和20C)和图(图20B和20D)，其显示了来自反式剪接反应的结果。图20A和20B分别显示内含子22反式剪接反应的蛋白质和RNA水平，图20C和20D分别显示内含子23反式剪接反应的蛋白质和RNA水平。
图21是以CEP290基因的功能性5'部分校正CEP290内含子26中的突变的几种示例性核酸反式剪接分子的示意图。深色阴影框代表天然CEP290外显子。连接深色阴影框的虚线表示天然内含子。带有深色边框的浅色阴影框表示核酸反式剪接分子中的功能性CEP290外显子。由曲线表示的剪接结构域附着于每个功能性CEP290外显子序列的一端，并导向CEP290前mRNA的内含子。
图22是显示在十个核苷酸间隔中跨CEP290内含子26(SEQ ID NO：85)的150聚体结合结构域赋予的反式剪接效率(相对倍数变化)的图。X轴标签表示从内含子5'末端开始的每个结合位点的数目的“基序号”(即内含子序列的第一个核苷酸)。
图23是显示在十个核苷酸间隔中跨CEP290内含子27(SEQ ID NO：86)的150聚体结合结构域赋予的反式剪接效率(相对倍数变化)的图。三行中的每行代表一个独立的实验。X轴标签表示从内含子5'末端开始的每个结合位点的数目的“基序号”(即内含子序列的第一个核苷酸)。
图24是显示在十个核苷酸间隔中跨CEP290内含子28(SEQ ID NO：87)的150聚体结合结构域赋予的反式剪接效率(相对倍数变化)的图。三行中的每行代表一个独立的实验。X轴标签表示从内含子5'末端开始的每个结合位点的数目的“基序号”(即内含子序列的第一个核苷酸)。
图25是显示在十个核苷酸间隔中跨CEP290内含子29(SEQ ID NO：88)的150聚体结合结构域赋予的反式剪接效率(相对倍数变化)的图。三行中的每行代表一个独立的实验。X轴标签表示从内含子5'末端开始的每个结合位点的数目的“基序号”(即内含子序列的第一个核苷酸)。
图26是显示在十个核苷酸间隔中跨CEP290内含子30(SEQ ID NO：89)的150聚体结合结构域赋予的反式剪接效率(相对倍数变化)的图。三行中的每行代表一个独立的实验。X轴标签表示从内含子5'末端开始的每个结合位点的数目的“基序号”(即内含子序列的第一个核苷酸)。
具体实施方式
本文所述的组合物和方法涉及用于治疗由ABCA4基因突变引起的疾病或病症的反式剪接分子(例如，腺相关病毒(AAV)递送的前mRNA剪接分子)。本文所述的方法和组合物采用前mRNA反式剪接作为基因疗法(例如，离体和体内基因疗法)，用于治疗由ABCA4突变引起的疾病，例如Stargardt病(例如，Stargardt病1)。
或者，本文所述的组合物和方法涉及用于治疗由CEP290基因突变引起的疾病或病症(例如LCA 10)的反式剪接分子(例如，由腺相关病毒(AAV)递送的前mRNA反式剪接分子)。这些方法采用前mRNA反式剪接作为基因疗法(例如离体和体内基因疗法)，用于治疗由CEP290突变引起的疾病，例如LCA 10。
本文举例说明的反式剪接分子及其使用方法提供了优于常规疗法的若干优点。首先，通过AAV的反式剪接分子递送的使用向光感受器提供了基因疗法的有效和特异性递送，同时克服了与AAV的包装极限有关的困难。其次，这些组合物和方法允许从源头校正遗传缺陷。另外，本文提供的组合物和方法可用于治疗ABCA4(或其他大cDNA/转基因盒)中的任何类型的突变。光感受器缺陷的校正为视网膜色素上皮细胞提供了二次拯救。此外，本方法和组合物通常在免疫学上是良性的。视网膜下递送和其他特征的使用使得效果特异于靶细胞(例如光感受器)，从而降低了脱靶剪接所致的毒性。此外，与核酸酶不同，反式剪接不需要基因组改变。最后，RNA修复不需要细胞分裂，而DNA修复方法(例如CRISPR-Cas9或锌指)需要细胞通过有丝分裂才能进行同源性定向修复，这在有丝分裂后的组织(像视网膜)中是不利的。
I.定义
除非另外定义，本文所用的技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义，并参考公开的文本，其为本领域技术人员提供了对本申请中所用的许多术语的一般性指导。如果本文所述的定义与参考出版物的定义有冲突，则以本文提供的定义为准。
“核酸反式剪接分子”或“反式剪接分子”具有三个主要元件：(a)通过将反式剪接分子与其靶基因(例如，前mRNA)栓系而赋予特异性的结合结构域；(b)剪接结构域(例如，具有3'或5'剪接位点的剪接结构域)；(c)被配置成可被反式剪接至靶基因上的编码序列，其可以替代靶基因中的一个或多个外显子(例如，一个或多个突变的外显子)。“前mRNA反式剪接分子”或“RTM”是指靶向前mRNA的核酸反式剪接分子。在一些实施方案中，反式剪接分子，例如RTM，可以包括cDNA，例如作为功能性外显子(例如，功能性ABCA4或CEP290外显子，例如，密码子优化的外显子)的一部分，用于替代或校正突变的ABCA4外显子或CEP290)。
“反式剪接”是指含有一个或多个外显子(例如，外源外显子，例如，作为反式剪接分子的编码结构域的一部分的外显子)的核酸分子与单独的RNA分子(例如，前mRNA分子，例如内源前mRNA分子)的第一部分的连接，通过剪接体介导的机制替代RNA分子的第二部分。
如本文所用，结合结构域和靶内含子之间的“结合”是指结合结构域和靶内含子之间的氢键结合的程度足以通过使反式剪接分子与靶基因(例如，前mRNA)缔合来介导反式剪接。在一些实施方案中，结合结构域和靶内含子之间的氢键在核苷酸碱基之间，所述核苷酸碱基彼此互补并且为反义方向(例如，彼此杂交)。
如本文所用，“人工内含子”是指将结合结构域与编码结构域直接或间接连接的核酸序列。人工内含子包括剪接结构域，并且可以进一步包括一个或多个间隔子序列和/或其他调控元件。
如本文所用，“剪接结构域”是指具有被剪接体识别并介导反式剪接的基序的核酸序列。剪接结构域包括剪接位点(例如，单个剪接位点，即一个和唯一一个剪接位点)，其可以是3'剪接位点或5'剪接位点。剪接结构域可以包括其他调控元件。例如，在一些实施方案中，剪接结构域包括剪接增强子(例如，外显子剪接增强子(ESE)或内含子剪接增强子(ISE))。在一些实施方案中，剪接结构域包括分支点(例如，强保守分支点)或分支位点序列和/或聚嘧啶束(PPT)。在一些实施方案中，5'反式剪接分子的剪接结构域不包含分支点或PPT，而是包含5'剪接受体或3'剪接供体。
如本文所用，“突变”是指引起缺陷蛋白质产物(例如，非功能性蛋白质产物，具有降低的功能的蛋白质产物，具有异常功能的蛋白质产物和/或产量低于正常或高于正常数量的蛋白质产物)的任何异常核酸序列。突变包括碱基对突变(例如，单核苷酸多态性)、错义突变、移码突变、缺失、插入和剪接突变。在一些实施方案中，突变是指核酸序列的一个或多个部分与相应的野生型核酸序列或其功能变体不同的核酸序列。在一些实施方案中，突变是指编码具有与相应的野生型蛋白或其功能变体不同的氨基酸序列的蛋白的核酸序列。“突变的外显子”(例如，突变的ABCA4外显子)是指含有在不同区域的突变或反映突变的外显子序列的外显子，例如由内含子中的突变产生的隐性外显子。
如本文所用，术语“ABCA4”是指编码视网膜特异性ATP结合盒转运蛋白的多核苷酸(例如，RNA(例如，前mRNA或mRNA)或DNA)。SEQ ID NO：6给出了功能性人ABCA4基因的示例性前mRNA序列。功能性(野生型)人ABCA4基因的示例性基因组DNA序列由NCBI参考序列：NG_009073给出。示例性ABCA4蛋白的氨基酸序列由蛋白登录号P78363给出。
本文标识的ABCA4的外显子和内含子如下表1所示，其可被映射到SEQ ID NO：6的ABCA4前mRNA分子上。ABCA4的每个外显子和内含子均根据第一列(左侧)中的参考编号在本文中进行标识。每个外显子和内含子的大小(碱基对；bp)在第二和第三列中指出。第四列表示相应的外显子的cDNA分子的长度，该外显子在相应的内含子编号的5'端。第五列表示相应的mRNA的cDNA分子的长度，该mRNA在相应的内含子编号的3'端。
表1.ABCA4外显子和内含子概要
Figure BDA0002841450420000291
Figure BDA0002841450420000301
Figure BDA0002841450420000311
如本文所用，“靶ABCA4内含子”是指上面表1中标识的49个ABCA4内含子之一。下表2中提供了每个ABCA4内含子序列的核酸序列标识符。应理解的是，术语“靶ABCA4内含子”的范围涵盖本文提供的ABCA4内含子的变体，例如与本文提供的序列具有90-100％同源性的内含子序列(例如与本文提供的序列具有90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％的同源性)，其中在ABCA4基因上的变体内含子的位置与本文提供的位置相对应(例如，相对于表1中列出的其相邻外显子)。
表2.ABCA4内含子序列
Figure BDA0002841450420000312
Figure BDA0002841450420000321
Figure BDA0002841450420000331
如本文所用，术语“CEP290”是指编码中心体蛋白290的多核苷酸(例如，RNA(例如，前mRNA或mRNA)或DNA)。SEQ ID NO：113给出了功能性人CEP290基因的示例性前mRNA序列。功能性(野生型)人CEP290基因的示例性基因组DNA序列由NCBI参考序列：NG_008417给出。示例性人中心体蛋白290蛋白的氨基酸序列由蛋白登录号O15078给出。
本文标识的CEP290外显子和内含子如下表3所示，可以映射到SEQ ID NO：112的CEP290前mRNA分子上。CEP290的每个外显子和内含子均根据第一列(左侧)中的参考编号在本文中进行标识。每个外显子和内含子的大小(碱基对；bp)在第二和第三列中指出。第四列表示相应的外显子的cDNA分子的长度，该外显子在相应的内含子编号的5'端。第五列表示相应的mRNA的cDNA分子的长度，该mRNA在相应的内含子编号的3'端。
表3.CEP290外显子和内含子概要
Figure BDA0002841450420000341
Figure BDA0002841450420000351
如本文所用，“靶CEP290内含子”是指以上表3中标识的53个CEP290内含子之一。下表4中提供了每个CEP290内含子序列的核酸序列标识符。应理解的是，术语“靶CEP290内含子”的范围涵盖本文提供的CEP290内含子的变体，例如与本文提供的序列具有90-100％同源性的内含子序列(例如与本文提供的序列具有90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％的同源性)，其中CEP290基因上的变异内含子的位置与本文提供的位置相对应(例如，相对于其在表3中列出的相邻外显子)。
表4.CEP290内含子序列
Figure BDA0002841450420000361
Figure BDA0002841450420000371
Figure BDA0002841450420000381
如本文所用，术语“受试者”包括需要这些治疗或预防方法的任何哺乳动物，包括人类。需要这种治疗或预防的其他哺乳动物包括狗、猫或其他家养动物、马、家畜、实验动物，包括非人类灵长类动物等。受试者可以是男性或女性。在一个实施方案中，受试者患有由ABCA4基因(例如Stargardt病，例如Stargardt病1)或CEP290基因(例如常染色体隐性遗传疾病，例如LCA 10)突变引起的疾病或病症。在另一个实施方案中，所述受试者处于发展由ABCA4基因或CEP290基因突变引起的疾病或病症的风险中。在另一个实施方案中，受试者已经显示出由ABCA4基因(例如Stargardt病)或CEP290基因(例如LCA 10)的突变引起的疾病或病症的临床体征。受试者可以是治疗或预防性治疗可能有益的任何年龄。例如，在某些实施例中，受试者为0-5岁、5-10岁、10-20岁、20-30岁、30-50岁、50-70岁或70岁以上年龄。在另一个实施方案中，所述受试者是12个月或更大，18个月或更大，2岁或更大，3岁或更大，4岁或更大，5岁或更大，6岁或更大，7岁或更大，8岁或更大，9岁或更大或10岁或更大。在另一个实施方案中，所述受试者具有存活的视网膜细胞。
如本文所用，术语“与突变相关的病症”或“与病症相关的突变”是指病症和突变之间的相关性。在一些实施方案中，已知或怀疑与突变相关的病症是由突变完全或部分或直接或间接引起的。例如，具有突变的受试者可能处于患病症的风险中，并且该风险可能另外取决于其他因素，例如其他(例如，独立的)突变(例如，相同或不同的基因)或环境因素。
如本文所用，术语“治疗”或其语法派生形式被定义为减少疾病的进展，降低疾病症状的严重性，延缓疾病症状的进展，消除疾病症状或延迟疾病发作。
如本文所用，术语“预防”病症或其语法派生形式被定义为降低疾病发作的风险，例如，对于有发展为与突变相关的病症的风险的受试者的预防性治疗。根据本领域已知的或本文所述的任何合适的方法，通过标识与病症相关的突变，可以将受试者表征为患该病症的“处于风险中”。在一些实施方案中，处于患病症风险中的受试者具有与该病症相关的一种或多种ABCA4或CEP290突变。另外地或可替代地，如果受试者具有家族病史，则可以将该受试者表征为“处于患病风险”。
可通过将反式剪接分子(例如在AAV运载体或AAV颗粒内)直接给受试者施用来治疗或预防受试者的病症。或者，可以将包含反式剪接分子的宿主细胞施用给受试者。
如本文所述的方法中所用的术语“施用”或其语法派生词是指将组合物或离体处理的细胞递送至有此需要的受试者，例如在靶基因中具有突变或缺陷的受试者。例如，在以眼细胞为靶的一个实施方案中，该方法涉及通过视网膜下注射将组合物递送至光感受器细胞或其他眼细胞。在另一个实施方案中，可以采用玻璃体内注射到眼细胞或通过睑静脉注射到眼细胞。在另一个实施方案中，该组合物静脉内施用。鉴于本公开，本领域技术人员可以选择其他施用方法。
密码子优化是指修饰核酸序列以改变单个核酸，而编码的氨基酸没有任何由此引起的改变。以这种方式修饰的序列在本文中称为“密码子优化的”。可以对本说明书中描述的任何序列执行该过程以增强表达或稳定性。密码子优化可以以例如在美国专利号7,561,972、7,561,973和7,888,112中描述的方式执行，其每一个均通过引用整体并入本文。可以根据已知方法将翻译起始位点周围的序列转化为共有Kozak序列。参见例如，Kozak等，Nucleic Acids Res.15(20):8125-8148，通过引用整体并入本文。
术语“同源的”是指两个核酸序列的序列之间的同一性程度。通过比较在最佳条件下比对的两个序列与待比较的序列来确定同源序列的同源性。本文中要比较的序列在两个序列的最佳比对中可以具有添加或缺失(例如，缺口等)。可以通过使用例如ClustalW算法(Nucleic Acid Res.,1994,22(22):4673 4680)创建比对来计算这样的序列同源性。也可以使用常用的序列分析软件，例如Vector NTI、GENETYX、BLAST或公共数据库提供的分析工具。
术语“药学上可接受的”是指对哺乳动物如人施用是安全的。在一些实施方案中，药学上可接受的组合物由联邦或州政府的监管机构批准或在美国药典或其他普遍认可的药典中列出用于动物，尤其是人类。
术语“载体”(“carrier”)是指与治疗分子(例如，本发明的反式剪接分子或包括运载体或细胞的反式剪接分子)一起施用的稀释剂、佐剂、赋形剂或媒介物。合适的药物载体的实例在《Remington's Pharmaceutical Sciences》Mack Publishing Co.，Easton，PA.，2005年第二版中描述。
术语“一个”是指“一个或多个”。例如，“一个基因”应理解为代表一个或多个这样的基因。这样，术语“一个”，“一个或多个中的一个或多个”和“一个(或一个或多个)中的至少一个”在本文中可互换使用。
如本文所用，除非另有说明，否则术语“约”是指与参考值相差±10％以内的值。
II.反式剪接分子
本文提供了ABCA4反式剪接分子和CEP290反式剪接分子。
ABCA4反式剪接分子
本发明的特征在于核酸反式剪接分子，其通过替代ABCA4基因中的一个或多个外显子(例如，具有突变的ABCA4外显子的ABCA4基因)，可用于治疗与ABCA4基因突变相关的疾病和病症。在一些实施方案中，核酸反式剪接分子是前RNA反式剪接分子(RTM)。反式剪接分子的设计允许用核酸序列(例如具有功能性(例如，正常)序列而没有突变的外显子)替代一个或多个前mRNA外显子的缺陷或突变部分。该功能性序列可以是野生型、天然存在的序列或具有一些其他修饰，例如密码子优化的校正序列。
在一个实施方案中，反式剪接分子被配置为校正位于ABCA4基因的3'部分上的一个或多个突变。在一个实施方案中，反式剪接分子被配置为校正位于ABCA4基因的5'部分上的一个或多个突变。本文提供的反式剪接分子的功能是通过替代有缺陷的前mRNA基因序列并去除靶前mRNA的有缺陷部分来修复受试者的靶细胞中的有缺陷基因，从而产生能够在细胞中转录功能性基因产物的功能性ABCA4基因。
本发明提供了具有配置为结合靶ABCA4内含子的结合结构域，配置为介导反式剪接的剪接结构域和具有一个或多个功能性ABCA4外显子的编码结构域的反式剪接分子。在5'反式剪接分子中，编码结构域、剪接位点和结合结构域在5'至3'方向上可操作地连接，使得反式剪接分子被配置为以编码结构域替代内源基因的5'末端，该编码结构域包括功能性ABCA4外显子，以替代突变的ABCA4外显子。相反，在3'反式剪接分子中，编码结构域，剪接位点和结合结构域在3'至5'方向可操作地连接，使得反式剪接分子被配置为以编码结构域替代内源基因的3'末端，该编码结构域包括功能性ABCA4外显子以替代突变的ABCA4外显子。在一些实施方案中，剪接结构域位于人工内含子内，该人工内含子将结合结构域连接至编码结构域。人工内含子可以包括其他元件，例如间隔子。
在一些实施方案中，反式剪接分子或其编码结构域的长度为至多4,700个核苷酸碱基(例如，长度为200至300个核苷酸碱基，长度为300至400个核苷酸碱基，长度为400至500个核苷酸碱基，长度为500至600个核苷酸碱基，长度为600至700个核苷酸碱基，长度为700至800个核苷酸碱基，长度为800至900个核苷酸碱基，长度为900至1,000个核苷酸碱基，长度为1,000至1,500个核苷酸碱基，长度为1,500至2,000个核苷酸碱基，长度为2,000至2500个核苷酸碱基，长度为2500至3,000个核苷酸碱基，或长度为3,000至4,000个核苷酸碱基，例如，长度为3,100至3,800个核苷酸碱基，长度为3,200至3,700个核苷酸碱基，或长度为3,300至3500个核苷酸碱基，例如，长度为3,000至3,100个核苷酸碱基，长度为3,100至3,200个核苷酸碱基，长度为3,200至3,300个核苷酸碱基，长度为3,300至3,400个核苷酸碱基，长度为3,400至3,500个核苷酸碱基，长度为3,500至3,600个核苷酸碱基，长度为3,600至3,700个核苷酸碱基，长度为3,700至3,800个核苷酸碱基，长度为3,800至3,900个核苷酸碱基，或长度为3,900至4,000个核苷酸碱基，例如，长度为大约2918个核苷酸碱基，长度为大约3328个核苷酸碱基，长度为大约3522个核苷酸碱基，长度为大约3607个核苷酸碱基，长度为大约3632个核苷酸碱基，长度为大约3494个核苷酸碱基或长度为大约3300个核苷酸碱基)。
由于ABCA4基因的大尺寸和AAV递送的大小限制，配置用于包装在AAV运载体中的单个反式剪接分子可能无法涵盖ABCA4基因中可能与病症相关的所有突变，因此可能不会沿着整个ABCA4基因的长度校正突变。因此，本发明的反式剪接分子可适于作为下述方法的一部分，以校正跨越ABCA4基因全长的多个突变。
本文所述的反式剪接分子靶向的ABCA4基因包含与一种或多种与疾病例如Stargardt病(例如Stargardt病1)相关(例如，引起或与其关连)的突变。功能性(野生型)人ABCA4基因的示例性DNA序列由NCBI参考序列：NG_009073给出。由ABCA4表达的示例性蛋白质视网膜特异性ATP结合盒转运蛋白的氨基酸序列由蛋白登录号P78363给出。
除这些公开的序列外，还包括后来获得的所有校正或在人类或其他哺乳动物群体中发生的天然存在的保守和非致病变体序列。还包括其他保守核苷酸替代或引起密码子优化的替代。由数据库登录号提供的序列也可用于在相同或另一哺乳动物生物中搜索同源序列。
预期ABCA4核酸序列和所得的蛋白质截短物或氨基酸片段可以在核酸水平上耐受某些较小的修饰，以包括例如对沉默的核苷酸碱基的修饰，例如偏好密码子。在其他实施方案中，预期改变氨基酸的核酸碱基修饰，例如以改善所得肽/蛋白质的表达(例如，密码子优化)。由于遗传密码的自然简并性引起的等位基因变异也包括作为可能的片段修饰。
ABCA4基因的修饰还包括本文提供的编码蛋白片段的类似物或修饰形式。通常，此类类似物与特异性标识的蛋白质仅相差一到四个密码子改变。保守替代是在氨基酸家族中发生的那些替代，与这些氨基酸的侧链和化学性质有关。
功能性ABCA4基因的核酸序列可以源自天然表达功能性视网膜特异性ATP结合盒转运蛋白或其同源物的任何哺乳动物。在其他实施方案中，对ABCA4基因序列进行某些修饰以增强在靶细胞中的表达。这样的修饰包括密码子优化。
在一些实施方案中，与ABCA4中的突变相关的病症是常染色体隐性遗传疾病，例如Stargardt病。在涉及患有常染色体隐性遗传病症的受试者的某些情况下，该受试者在两个等位基因上均具有ABCA4突变。不管突变在ABCA4基因中的位置如何，包含反式剪接分子的组合物都可以校正两个等位基因上的突变。例如，对于在第一等位基因上具有突变的ABCA4外显子1和在第二等位基因上具有突变的ABCA4外显子30的受试者，本文提供了具有5'反式剪接分子以替代突变的ABCA4外显子1和3'反式剪接分子以替代突变的ABCA4外显子30的组合物。在这样的实施方案中，两个反式剪接分子可以作为相同AAV运载体的一部分共同递送或在单独的AAV运载体中递送(例如，在两个反式剪接分子超出了AAV的包装限制的情况下)。
或者，在其中两个或更多个突变位于ABCA4基因的一部分上、该ABCA4基因的一部分可以被相同反式剪接分子替代的实施方案中，具有包含功能性ABCA4外显子的编码区的单个反式剪接分子可以替代一个或更多含有突变的外显子。特定ABCA4外显子中的突变也列于国际专利公开号WO 2017/087900中，其通过引用并入本文。
ABCA4编码结构域
在一些实施方案中，5'反式剪接分子的编码结构域包括所有ABCA4外显子(例如功能性ABCA4外显子)，所述ABCA4外显子在靶ABCA4内含子的5'端。例如，在5'反式剪接分子靶向ABCA4内含子19的实施方案中，编码结构域包括功能性ABCA4外显子1-19。在具有包括功能性ABCA4外显子1-19的编码结构域的5'反式剪接分子的此类实施方案中，该编码结构域的长度为约2918bp。在5'反式剪接分子靶向ABCA4内含子22的实施方案中，编码结构域包括功能性ABCA4外显子1-22。在具有包括功能性ABCA4外显子1-22的编码结构域的5'反式剪接分子的此类实施方案中，该编码结构域的长度为约3,328bp。在5'反式剪接分子靶向ABCA4内含子23的实施方案中，编码结构域包括功能性ABCA4外显子1-23。在具有包括功能性ABCA4外显子1-23的编码结构域的5'反式剪接分子的此类实施方案中，该编码结构域的长度为约3,522bp。在5'反式剪接分子靶向ABCA4内含子24的实施方案中，编码结构域包括功能性ABCA4外显子1-24。在具有包括功能性ABCA4外显子1-24的编码结构域的5'反式剪接分子的此类实施方案中，该编码结构域的长度为约3,607bp。靶向5'ABCA4的反式剪接分子的上述实施方案在图1的左下部分示出。
在一些实施方案中，3'反式剪接分子的编码结构域包括ABCA4外显子20-50中的任何一个或多个。例如，在3'反式剪接分子靶向ABCA4内含子22的实施方案中，编码结构域包括功能性ABCA4外显子23-50。在具有包括功能性ABCA4外显子23-50的编码结构域的3'反式剪接分子的此类实施方案中，该编码结构域的长度为约3,632bp。在3'反式剪接分子靶向ABCA4内含子23的实施方案中，编码结构域包括功能性ABCA4外显子24-50。在具有包括功能性ABCA4外显子24-50的编码结构域的3'反式剪接分子的此类实施方案中，该编码结构域的长度为约3,494bp。在3'反式剪接分子靶向ABCA4内含子24的实施方案中，编码结构域包括功能性ABCA4外显子25-50。在具有包括功能性ABCA4外显子25-50的编码结构域的3'反式剪接分子的此类实施方案中，该编码结构域的长度为约3,300bp。靶向3'ABCA4的反式剪接分子的上述实施方案在图1的右上部分示出。
在一些实施例中，编码结构域包括1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27或28个功能性ABCA4外显子。
在某些情况下，两种突变都发生在靶基因的5'部分，选择5'反式剪接分子来校正这两种突变。在一个实施方案中，结合结构域结合至内含子19，并且编码结构域包括功能性ABCA4外显子1-19。在一个实施方案中，结合结构域结合至内含子22，并且编码结构域包括功能性ABCA4外显子1-22。在一个实施方案中，结合结构域结合至内含子23，并且编码结构域包括功能性ABCA4外显子1-23。在一个实施方案中，结合结构域结合至内含子24，并且编码结构域包括功能性ABCA4外显子1-24。或者，在两个突变都发生在靶基因3'部分的情况下，选择3'反式剪接分子以校正两个突变。在一个实施方案中，结合结构域结合至内含子22，并且编码结构域包括功能性ABCA4外显子23-50。在一个实施方案中，结合结构域结合至内含子23，并且编码结构域包括功能性ABCA4外显子24-50。在一个实施方案中，结合结构域结合至内含子24，并且编码结构域包括功能性ABCA4外显子25-50。
作为一个实例，3'前mRNA ABCA4反式剪接分子的操作如下：嵌合mRNA是通过内源靶前mRNA的5'剪接位点与反式剪接分子的3'剪接位点之间的剪接体介导的反式剪接反应产生。反式剪接分子通过特异性碱基配对与内源靶前mRNA的靶ABCA4内含子结合，并用具有反式剪接分子的功能性ABCA4外显子序列的编码结构域替代靶内含子上游的内源ABCA4基因的整个3'序列。
3'反式剪接分子包括与在突变或缺陷5'端的靶ABCA4内含子结合的结合结构域、包含任选间隔子和3'剪接位点的人工内含子、以及编码眼的靶基因的所有外显子的编码结构域，所述靶基因在结合结构域与靶标结合的3'端。5'反式剪接分子包括与在突变或缺陷3'端的靶ABCA4内含子结合的结合结构域、5'剪接位点、任选的间隔子、以及编码眼的靶基因的所有外显子的编码结构域，所述靶基因在结合结构域与靶标结合的5'端。
在一些实施方案中，编码结构域包括互补DNA(cDNA)序列。例如，编码结构域内的一个或多个功能性ABCA4外显子可以是cDNA序列。在一些实施方案中，整个编码结构域是cDNA序列。另外地或可替代地，编码结构域的全部或一部分，或其一个或多个功能性ABCA4外显子可以是天然存在的序列(例如，与内源ABCA4外显子具有90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的序列)。
在一些实施方案中，全部或部分编码结构域或其一个或多个功能性ABCA4外显子是密码子优化的序列，其中核酸序列已被修饰，例如以增强表达或稳定性，而不会导致编码氨基酸的变化。可以以例如在美国专利号7,561,972、7,561,973和7,888,112中描述的方式执行密码子优化，其每一个均通过引用整体并入本文。为了通过重组AAV递送，如本文所述，在一个实施方案中，编码结构域可以是长度最高达4,000个核苷酸碱基的核酸序列(例如，长度为3,000至4,000个核苷酸碱基，长度为3,100至3,800个核苷酸碱基，长度为3,200至3,700个核苷酸碱基，或长度为3,300至3,500个核苷酸碱基，例如长度为3,000至3,100个核苷酸碱基，长度为3,100至3,200个核苷酸碱基，长度为3,200至3,300个核苷酸碱基，长度为3,300至3,400个核苷酸碱基，长度为3,400至3,500个核苷酸碱基，长度为3,500至3,600个核苷酸碱基，长度为3,600至3,700个核苷酸碱基，长度为从3,700至3,800核苷酸碱基，长度为从3,800至3,900核苷酸碱基，或长度为从3,900至4,000核苷酸碱基)。
ABCA4结合结构域
本发明的反式剪接分子特征在于结合结构域，其被配置为结合靶ABCA4内含子。在一个实施方案中，结合结构域是与靶ABCA4前mRNA(例如靶ABCA4内含子)的序列互补的核酸序列，以抑制内源靶顺式剪接，同时增强反式剪接分子与靶ABCA4前mRNA之间的反式剪接，例如以产生具有一部分内源ABCA4 mRNA和具有一个或多个功能性ABCA4外显子的编码结构域的嵌合分子。在一些实施方案中，结合结构域与靶ABCA4内含子的序列处于反义方向。
5'反式剪接分子通常结合在突变3'端的靶ABCA4内含子，同时3'反式剪接分子通常结合在突变5'端的靶ABCA4内含子。在一个实施方案中，结合结构域包含与靶ABCA4内含子互补的序列的一部分。在本文的一个实施方案中，结合结构域是与最接近(即，相邻)正被校正的外显子序列的内含子互补的核酸序列。
在另一个实施方案中，结合结构域靶向与靶内含子的3'或5'剪接信号非常接近的内含子序列。在又一个实施方案中，除了部分相邻的外显子外，结合结构域序列还可结合靶内含子。
因此，在某些情况下，结合结构域与突变的内源靶前mRNA特异性结合，以将反式剪接分子的编码结构域锚定至前mRNA，从而允许反式剪接发生在靶ABCA4基因的正确位置。然后，核的剪接体加工机器可以介导针对引起该疾病的突变外显子的校正外显子的成功反式剪接。
在某些实施方案中，反式剪接分子的特征在于结合结构域，其包含在靶前mRNA上一个以上位置结合的序列。结合结构域可包含稳定结合至靶前mRNA以允许与编码结构域发生反式剪接所必需的任何数量的核苷酸。在一个实施方案中，使用用于可接近的环(accessible loop)的mFOLD结构分析选择所述结合结构域(Zuker，Nucleic AcidsRes.2003,31(13):3406-3415)。
合适的靶结合结构域的长度可以是10至500个核苷酸。在一些实施方案中，结合结构域的长度为20至400个核苷酸。在一些实施方案中，结合结构域的长度为50至300个核苷酸。在一些实施方案中，结合结构域的长度为100至200个核苷酸。在一些实施方案中，结合结构域的长度为10-20个核苷酸(例如，长度为10、11、12、13、14、15、16、17、18、19或20个核苷酸)，长度为20-30个核苷酸(例如长度为20、21、22、23、24、25、26、27、28、29或30个核苷酸)，长度为30-40个核苷酸(例如长度为30、31、32、33、34、35、36、37、38、39或40个核苷酸)，长度为40-50个核苷酸(例如，长度为40、41、42、43、44、45、46、47、48、49、50个核苷酸)，长度为50-60个核苷酸(例如长度为50、51、52、53、54、55、56、57、58、59或60个核苷酸)，长度为60-70个核苷酸(例如，长度为60、61、62、63、64、65、66、67、68、69或70个核苷酸)，长度为70-80个核苷酸(例如，长度为70、71、72、73、74、75、76、77、78、79或80个核苷酸)，长度为80-90个核苷酸(例如长度为80、81、82、83、84、85、86、87、88、89或90个核苷酸)，长度为90-100个核苷酸(例如长度为90、91、92、93、94、95、96、97、98、99或100个核苷酸)，长度为100-110个核苷酸(例如长度为100、101、102、103、104、105、106、107、108、109或110个核苷酸)，长度为110-120个核苷酸(例如长度为110、111、112、113、114、115、116、117、118、119或120个核苷酸)，长度为120-130个核苷酸(例如长度为120、121、122、123、124、125、126、127、128、129或130个核苷酸)，长度为130-140个核苷酸(例如长度为130、131、132、133、134、135、136、137、138、139或140个核苷酸)，长度为140-150个核苷酸(例如长度为140、141、142、143、144、145、146、147、148、149或150个核苷酸)，长度为150-160个核苷酸(例如长度为150、151、152、153、154、155、156、157、158、159或160个核苷酸)，长度为160-170个核苷酸(例如长度为160、161、162、163、164、165、166、167、168、169或170个核苷酸)，长度为170-180个核苷酸(例如长度为170、171、172、173、174、175、176、177、178、179或180个核苷酸)，长度为180-190个核苷酸(例如长度为180、181、182、183、184、185、186、187、188、189或190个核苷酸)，长度为190-200个核苷酸(例如长度为190、191、192、193、194、195、196、197、198、199或200个核苷酸)，长度为200-210个核苷酸，长度为210-220个核苷酸，长度为220-230个核苷酸，长度为230-240个核苷酸，长度为240-250个核苷酸，长度为250-260个核苷酸，长度为260-270个核苷酸，长度为270-280个核苷酸，长度为280-290个核苷酸，长度为290-300个核苷酸，长度为300-350个核苷酸，长度为350-400个核苷酸，长度为400-450个核苷酸，或长度为450-500个核苷酸。在一些实施方案中，结合结构域的长度为约150个核苷酸。在另一个实施方案中，靶结合结构域可包括长度最高达750个核苷酸的核酸序列。在另一个实施方案中，靶结合结构域可以包括长度最多1000个核苷酸的核酸序列。在另一个实施方案中，靶结合结构域可包括长度高达2000个核苷酸或更多的核酸序列。
在一些实施方案中，可以通过增加靶结合结构域的长度来增加反式剪接分子的特异性。可以使用其他长度，这取决于反式剪接分子的其他组分的长度。
结合结构域可以与靶内含子80％至100％互补，以能够与靶内含子稳定杂交。例如，在一些实施方案中，结合结构域与靶内含子80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％互补。互补的程度由本领域技术人员根据需要保持反式剪接分子和含有用于表达的必需序列的核酸构建体以及包含在rAAV中在3,000或至多4,000个核苷酸碱基限制内而选择。该序列的选择和杂交强度取决于核酸的互补性和长度。
任何上述结合结构域可结合在内含子19(SEQ ID NO：25)，内含子22(SEQ ID NO：28)，内含子23(SEQ ID NO：29)或内含子24(SEQ ID NO：30)内的结合位点。
在本发明的某些情况下，反式剪接分子是5'反式剪接分子，其特征在于结合结构域与ABCA4的内含子19(SEQ ID NO：25)结合，并且包括具有功能性ABCA4外显子1-19的编码结构域。在一些实施方案中，结合位点包含SEQ ID NO：25的核苷酸990至2,174的任何一个或多个(例如，SEQ ID NO：25的核苷酸1,670至2,174中的任何一个或多个，SEQ ID NO：25的核苷酸1,810至2,000中的任何一个或多个，SEQ ID NO：25的核苷酸1,870至2,000中的任何一个或多个，或SEQ ID NO：25的核苷酸1,920至2,000个中的任何一个或多个)。
在一些实施方案中，反式剪接分子是5'反式剪接分子，其特征在于结合结构域，其结合ABCA4的内含子22(SEQ ID NO：28)，并包括具有功能性ABCA4外显子1-22的编码结构域。在一些实施方案中，结合位点包含SEQ ID NO：28的核苷酸60至570，核苷酸600至800或核苷酸900至1350中的任何一个或多个(例如，SEQ ID NO：28的核苷酸70至250中的任何一个或多个)。
可选择地，反式剪接分子可以是3'反式剪接分子，并且其特征在于与ABCA4的内含子22(SEQ ID NO：28)结合的结合结构域。该反式剪接分子可以包括具有功能性ABCA4外显子23-50的编码结构域。在一些实施方案中，结合位点包含SEQ ID NO：28的核苷酸1至510或880至1,350的任何一个或多个。
在其他实施方案中，反式剪接分子是5'反式剪接分子，其特征在于结合结构域，其结合ABCA4的内含子23(SEQ ID NO：29)，并且包括具有功能性ABCA4外显子1-23的编码结构域。在一些实施方案中，结合位点包含SEQ ID NO：29的核苷酸80至570或720至1,081中的任何一个或多个。
可选择地，反式剪接分子可以是3'反式剪接分子，并且其特征在于与ABCA4的内含子23(SEQ ID NO：29)结合的结合结构域和具有功能性ABCA4外显子24-50的编码结构域。在一些实施方案中，结合位点包含SEQ ID NO：29的核苷酸80至1081中的任何一个或多个(例如，SEQ ID NO：29的核苷酸230至1,081中的任何一个或多个，SEQ ID NO：29的核苷酸250至400中的任何一个或多个，或SEQ ID NO：29的核苷酸690至850中的任何一个或多个)。
在一些实施方案中，反式剪接分子是5'反式剪接分子，并且特征在于结合结构域，其结合ABCA4的内含子24(SEQ ID NO：30)，并且包括具有功能性ABCA4外显子1-24的编码结构域。在一些实施方案中，结合位点包含SEQ ID NO：30的核苷酸600至1,250或1,490至2,660的任何一个或多个(例如，SEQ ID NO：30的核苷酸1,000至1,200的任何一个或多个)。
在其他实施方案中，反式剪接分子是3'反式剪接分子，其特征在于结合结构域，所述结合结构域结合ABCA4的内含子24(SEQ ID NO：30)，并包括具有功能性ABCA4外显子25-50的编码结构域。在一些实施方案中，结合位点包含SEQ ID NO：30的核苷酸1至250，核苷酸300至2,100或核苷酸2,200至2,692中的任何一个或多个(例如，SEQ ID NO：30的核苷酸360至610中的任何一个或多个，或SEQ ID NO：30的核苷酸750至1110中的任何一个或多个)。
CEP290反式剪接分子
本发明的特征在于通过替代CEP290基因(例如，内含子26中有突变的CEP290基因)中的一个或多个外显子以可用于治疗与CEP290基因突变相关的疾病和病症的核酸反式剪接分子。在一些实施方案中，核酸反式剪接分子是前RNA反式剪接分子(RTM)。反式剪接分子的设计允许用核酸序列例如具有功能性(例如正常)序列的一个或多个外显子替代前mRNA的缺陷或突变部分而没有突变。功能性序列可以是野生型、天然存在的序列或具有一些其他修饰例如密码子优化的校正序列。
在一个实施方案中，反式剪接分子被配置为校正位于CEP290基因的5'部分上的一个或多个突变。本文提供的反式剪接分子通过替代缺陷的前mRNA基因序列来修复受试者靶细胞中的缺陷基因，从而产生能够在细胞中转录功能性基因产物的功能性CEP290基因。
本发明提供了具有配置为结合靶CEP290内含子的结合结构域，配置为介导反式剪接的剪接结构域和具有一个或多个功能性CEP290外显子的编码结构域的反式剪接分子。在5'反式剪接分子中，编码结构域、剪接位点和结合结构域在5'至3'方向上可操作地连接，使得反式剪接分子被配置为以编码结构域替代内源基因的5'末端，该编码结构域包括功能性CEP290外显子，以校正突变的CEP290前mRNA。在一些实施方案中，剪接结构域位于人工内含子内，该人工内含子将结合结构域连接至编码结构域。人工内含子可以包括其他元件，例如间隔子。
在一些实施方案中，反式剪接分子的长度为至多4,700个核苷酸碱基(例如，长度为3,000至4,000个核苷酸碱基，长度为3,100至3,800个核苷酸碱基，长度为3,200至3,700个核苷酸碱基，或长度为3,300至3,500个核苷酸碱基，例如长度为3,000至3,100个核苷酸碱基，长度为3,100至3,200个核苷酸碱基，长度为3,200至3,300个核苷酸碱基，长度为3,300至3,400个核苷酸碱基，长度为3,400至3,500个核苷酸碱基，长度为3,500至3,600个核苷酸碱基，长度为3,600至3,700个核苷酸碱基，长度为3,700至3,800个核苷酸碱基，长度为3,800至3,900个核苷酸碱基，或长度为3,900至4,000个核苷酸碱基，例如，长度为约2,991个核苷酸碱基，长度为约3,103个核苷酸碱基，长度为约3,309个核苷酸碱基，长度为约3,461个核苷酸碱基，或长度为约3,573个核苷酸碱基)。
本文所述的反式剪接分子靶向的CEP290基因包含一种或多种与疾病例如莱伯氏先天性黑蒙症(例如LCA 10)相关(例如，引起或与其关连)的突变。功能性(野生型)人CEP290基因的示例性DNA序列由NCBI参考序列：NG_008417给出。示例性中心体蛋白290的氨基酸序列由蛋白登录号O15078给出。
除这些公开的序列外，还包括后来获得的所有校正或在人类或其他哺乳动物群体中发生的自然产生的保守和非致病变体序列。还包括其他保守核苷酸替代或引起密码子优化的替代。由数据库登录号提供的序列也可用于在相同或另一哺乳动物生物中搜索同源序列。
预期CEP290核酸序列和所得的蛋白质截短物或氨基酸片段可以在核酸水平上耐受某些较小的修饰，以包括例如对沉默的核苷酸碱基的修饰，例如偏好密码子。在其他实施方案中，预期改变氨基酸的核酸碱基修饰，例如以改善所得肽/蛋白质的表达(例如，密码子优化)。由于遗传密码的自然简并性引起的等位基因变异也包括作为可能的片段修饰。
CEP290基因的修饰还包括本文提供的编码蛋白片段的类似物或修饰形式。通常，此类类似物与特异性标识的蛋白质仅相差一到四个密码子变化。保守替代是在氨基酸家族中发生的那些替代，与这些氨基酸的侧链和化学性质有关。
功能性CEP290基因的核酸序列可以源自天然表达功能性中心体蛋白290或其同源物的任何哺乳动物。在其他实施方案中，对CEP290基因序列进行某些修饰以增强在靶细胞中的表达。这样的修饰包括密码子优化。
CEP290突变可在CCHMC分子遗传学实验室突变数据库LOVD v.2.0中找到。特别是CEP290外显子的突变也列在国际专利公开号WO 2017/087900中，其通过引用并入本文。上面的表3提供了有关CEP290每个外显子和内含子的大小和位置的信息。
在一些实施方案中，与CEP290中的突变相关的病症是常染色体隐性遗传疾病，例如LCA 10。
编码结构域
在一些实施方案中，5'反式剪接分子的编码结构域包括在靶CEP290内含子5'端的所有CEP290外显子(例如功能性CEP290外显子)。例如，在5'反式剪接分子靶向CEP290内含子26的实施方案中，编码结构域包括功能性CEP290外显子2-26。在具有包括功能性CEP290外显子2-26的编码结构域的5'反式剪接分子的此类实施方案中，该编码结构域的长度为约2,991bp。在5'反式剪接分子靶向CEP290内含子27的实施方案中，编码结构域包括功能性CEP290外显子2-27。在具有包括功能性CEP290外显子2-27的编码结构域的5'反式剪接分子的此类实施方案中，该编码结构域的长度为约3,103bp。在5'反式剪接分子靶向CEP290内含子28的实施方案中，编码结构域包括功能性CEP290外显子2-28。在具有包括功能性CEP290外显子2-28的编码结构域的5'反式剪接分子的此类实施方案中，该编码结构域的长度为约3,309bp。在5'反式剪接分子靶向CEP290内含子29的实施方案中，编码结构域包括功能性CEP290外显子2-29。在具有包括功能性CEP290外显子2-29的编码结构域的5'反式剪接分子的此类实施方案中，该编码结构域的长度为约3,461bp。在5'反式剪接分子靶向CEP290内含子30的实施方案中，编码结构域包括功能性CEP290外显子2-30。在具有包括功能性CEP290外显子2-30的编码结构域的5'反式剪接分子的此类实施方案中，该编码结构域的长度为约3,573bp。靶向5'CEP290的反式剪接分子的前述实施方案在图21中示出。
在一些实施方案中，编码结构域包括25、26、27、28或29个功能性CEP290外显子。
在一些实施方案中，编码结构域包括互补DNA(cDNA)序列。例如，编码结构域内的一个或多个功能性CEP290外显子可以是cDNA序列。在一些实施方案中，整个编码结构域是cDNA序列。另外地或可替代地，全部或部分编码结构域或其一个或多个功能性CEP290外显子可以是天然存在的序列(例如，与内源CEP290外显子具有90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％序列同一性的序列)。
在一些实施方案中，全部或部分编码结构域或其一个或多个功能性CEP290外显子是密码子优化的序列，其中核酸序列已被修饰，例如以增强表达或稳定性，而不会导致编码氨基酸的变化。可以以例如在美国专利号7,561,972、7,561,973和7,888,112中描述的方式执行密码子优化，其每一个均通过引用整体并入本文。为了通过重组AAV递送，如本文所述，在一个实施方案中，编码结构域可以是长度最高达4,000个核苷酸碱基的核酸序列(例如，长度为3,000至4,000个核苷酸碱基，长度为3,100至3,800个核苷酸碱基，长度为3,200至3,700个核苷酸碱基，或长度为3,300至3,500个核苷酸碱基，例如长度为3,000至3,100个核苷酸碱基，长度为3,100至3,200个核苷酸碱基，长度为3,200至3,300个核苷酸碱基，长度为3,300至3,400个核苷酸碱基，长度为3,400至3,500个核苷酸碱基，长度为3,500至3,600个核苷酸碱基，长度为3,600至3,700个核苷酸碱基，长度为3,700至3,800个核苷酸碱基，长度为3,800至3,900个核苷酸碱基，或长度为3,900至4,000个核苷酸碱基，例如，长度为约3,108个核苷酸碱基，长度为约3,285个核苷酸碱基，长度为约3,375个核苷酸碱基，长度为约3,503个核苷酸碱基，长度为约3,630个核苷酸碱基，长度为约3,540个核苷酸碱基，长度为约3,363个核苷酸碱基，长度为约3,273个核苷酸碱基，长度为约3,145个核苷酸碱基，或长度为约3,018个核苷酸碱基)。
结合结构域
本发明的反式剪接分子的特征在于结合结构域，其被配置为结合靶CEP290内含子。在一个实施方案中，结合结构域是与靶CEP290前mRNA(例如，靶CEP290内含子)的序列互补的核酸序列，以抑制内源靶顺式剪接，同时增强反式剪接分子与靶CEP290前mRNA之间的反式剪接，例如以产生具有一部分内源CEP290 mRNA和具有一个或多个功能性CEP290外显子的编码结构域的嵌合分子。在一些实施方案中，结合结构域与靶CEP290内含子的序列处于反义方向。
5'反式剪接分子通常会与在突变3'端的靶CEP290内含子结合。在一个实施方案中，结合结构域包含与靶CEP290内含子互补的序列的一部分。
在另一个实施方案中，结合结构域靶向与靶内含子的3'或5'剪接信号非常接近的内含子序列。在又一个实施方案中，除了部分相邻的外显子外，结合结构域序列还可结合靶内含子。
因此，在某些情况下，结合结构域与突变的内源靶标前mRNA特异性结合，以将反式剪接分子的编码结构域锚定至前mRNA，从而允许反式剪接发生在靶CEP290基因的正确位置。然后，核的剪接体加工机器可以介导针对引起该疾病的突变外显子的校正外显子的成功反式剪接。
在某些实施方案中，反式剪接分子的特征在于结合结构域，其包含在靶前mRNA上一个以上位置结合的序列。结合结构域可包含稳定结合至靶前mRNA以允许与编码结构域发生反式剪接所必需的任何数量的核苷酸。在一个实施方案中，使用用于可接近的环的mFOLD结构分析选择结合结构域(Zuker，Nucleic Acids Res.2003,31(13):3406-3415)。
合适的靶结合结构域的长度可以是10至500个核苷酸。在一些实施方案中，结合结构域的长度为20至400个核苷酸。在一些实施方案中，结合结构域的长度为50至300个核苷酸。在一些实施方案中，结合结构域的长度为100至200个核苷酸。在一些实施方案中，结合结构域的长度为10-20个核苷酸(例如，长度为10、11、12、13、14、15、16、17、18、19或20个核苷酸)，长度为20-30个核苷酸(例如长度为20、21、22、23、24、25、26、27、28、29或30个核苷酸)，长度为30-40个核苷酸(例如长度为30、31、32、33、34、35、36、37、38、39或40个核苷酸)，长度为40-50个核苷酸(例如，长度为40、41、42、43、44、45、46、47、48、49、50个核苷酸)，长度为50-60个核苷酸(例如长度为50、51、52、53、54、55、56、57、58、59或60个核苷酸)，长度为60-70个核苷酸(例如，长度为60、61、62、63、64、65、66、67、68、69或70个核苷酸)，长度为70-80个核苷酸(例如，长度为70、71、72、73、74、75、76、77、78、79或80个核苷酸)，长度为80-90个核苷酸(例如长度为80、81、82、83、84、85、86、87、88、89或90个核苷酸)，长度为90-100个核苷酸(例如长度为90、91、92、93、94、95、96、97、98、99或100个核苷酸)，长度为100-110个核苷酸(例如长度为100、101、102、103、104、105、106、107、108、109或110个核苷酸)，长度为110-120个核苷酸(例如长度为110、111、112、113、114、115、116、117、118、119或120个核苷酸)，长度为120-130个核苷酸(例如长度为120、121、122、123、124、125、126、127、128、129或130个核苷酸)，长度为130-140个核苷酸(例如长度为130、131、132、133、134、135、136、137、138、139或140个核苷酸)，长度为140-150个核苷酸(例如长度为140、141、142、143、144、145、146、147、148、149或150个核苷酸)，长度为150-160个核苷酸(例如长度为150、151、152、153、154、155、156、157、158、159或160个核苷酸)，长度为160-170个核苷酸(例如长度为160、161、162、163、164、165、166、167、168、169或170个核苷酸)，长度为170-180个核苷酸(例如长度为170、171、172、173、174、175、176、177、178、179或180个核苷酸)，长度为180-190个核苷酸(例如长度为180、181、182、183、184、185、186、187、188、189或190个核苷酸)，长度为190-200个核苷酸(例如长度为190、191、192、193、194、195、196、197、198、199或200个核苷酸)，长度为200-210个核苷酸，长度为210-220个核苷酸，长度为220-230个核苷酸，长度为230-240个核苷酸，长度为240-250个核苷酸，长度为250-260个核苷酸，长度为260-270个核苷酸，长度为270-280个核苷酸，长度为280-290个核苷酸，长度为290-300个核苷酸，长度为300-350个核苷酸，长度为350-400个核苷酸，长度为400-450个核苷酸，或长度为450-500个核苷酸。在一些实施方案中，结合结构域的长度为约150个核苷酸。在另一个实施方案中，靶结合结构域可包括长度最高达750个核苷酸的核酸序列。在另一个实施方案中，靶结合结构域可以包括长度最多1000个核苷酸的核酸序列。在另一个实施方案中，靶结合结构域可包括长度高达2000个核苷酸或更多的核酸序列。
在一些实施方案中，可以通过增加靶结合结构域的长度来增加反式剪接分子的特异性。可以使用其他长度，这取决于反式剪接分子的其他组分的长度。
结合结构域可以与靶内含子80％至100％互补，以能够与靶内含子稳定杂交。例如，在一些实施方案中，结合结构域与靶内含子80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％互补。互补的程度由本领域技术人员根据需要保持反式剪接分子和含有用于表达的必需序列的核酸构建体以及包含在rAAV中在3,000或至多4,000个核苷酸碱基限制内而选择。该序列的选择和杂交强度取决于核酸的互补性和长度。
任何上述结合结构域可结合在内含子26(SEQ ID NO：85；例如，在突变处或在突变的3'端，例如，内含子26的核苷酸1,655处的替换突变)、内含子27(SEQ ID NO：86)、内含子28(SEQ ID NO：87)、内含子29(SEQ ID NO：88)或内含子30(SEQ ID NO：89)的结合位点。
在本发明的某些情况下，反式剪接分子的特征在于结合结构域，该结合结构域与CEP290的内含子26(SEQ ID NO：85)结合，并且包括具有功能性CEP290外显子2-26的编码结构域。在一些实施方案中，结合位点包含SEQ ID NO：85的核苷酸4,980至5,383的任一个或多个。在一个实施方案中，结合位点包含SEQ ID NO：85的核苷酸5,348至5,838的任一个或多个(例如，SEQ ID NO：85的核苷酸5,348至5,700中的任何一个或多个，例如SEQ ID NO：85的核苷酸5,400至5,600中的任何一个或多个，例如SEQ ID NO：85的核苷酸5,460至5,560的任何一个或多个，例如至少SEQ ID NO：85的核苷酸5,500)。
在其他实施方案中，反式剪接分子的特征在于结合结构域，其与CEP290的内含子27(SEQ ID NO：86)结合，并且包括具有功能性CEP290外显子2-27的编码结构域。在一些实施方案中，结合位点包含SEQ ID NO：86的核苷酸120至680、核苷酸710至2,200或核苷酸2,670至2,910中的任何一个或多个。在一些实施方案中，结合位点包含SEQ ID NO：86的核苷酸790至2,100中的任一个或多个，例如SEQ ID NO：86的核苷酸1,020至1,630中的任何一个或多个。在其他实施方案中，结合位点包含SEQ ID NO：86的核苷酸1,670至2,000中的任何一个或多个。
在一些实施方案中，反式剪接分子的特征在于结合结构域，该结合结构域与CEP290的内含子28(SEQ ID NO：87)结合，并且包括具有功能性CEP290外显子2-28的编码结构域。在一些实施方案中，结合位点包含SEQ ID NO：87的核苷酸1至390，核苷酸410至560或核苷酸730至937中的任何一个或多个。在一些实施方案中，结合位点包含SEQ ID NO：87的核苷酸1至200中的任一个或多个。在其他实施方案中，结合位点包含SEQ ID NO：87的核苷酸720至900中的任一个或多个。
在一些实施方案中，反式剪接分子的特征在于结合结构域，其结合CEP290的内含子29(SEQ ID NO：88)，并且包括具有功能性CEP290外显子2-29的编码结构域。在一些实施方案中，结合位点包含SEQ ID NO：88的核苷酸1至600、核苷酸720至940或核苷酸1370至1790中的任何一个或多个。
在其他实施方案中，反式剪接分子的特征在于结合结构域，其与CEP290的内含子30(SEQ ID NO：89)结合，并且包括具有功能性CEP290外显子2-30的编码结构域。在一些实施方案中，结合位点包含SEQ ID NO：89的核苷酸880至1,240中的任何一个或多个，例如SEQID NO：89的核苷酸950至1,240中的任何一个或多个，例如SEQ ID NO：89的核苷酸1,060至1,240中的任何一个或多个。
剪接结构域
以下剪接结构域可用于本发明的任何反式剪接分子(例如，本文所述的任何ABCA4反式剪接分子或CEP290反式剪接分子)。
剪接结构域可以包括剪接位点、分支点和/或PPT束以介导反式剪接。在一些实施方案中，剪接结构域具有单个剪接位点，这表示由于缺乏相应的剪接位点，该剪接位点能够进行反式剪接，但不能进行顺式剪接。在一些实施方案中，3'反式剪接分子的剪接结构域包括强保守分支点或分支位点序列、聚嘧啶束(PPT)和3'剪接受体(AG或YAG)位点和/或5'剪接供体位点。5'反式剪接分子的剪接结构域不含有分支点或PPT，但包含5'剪接受体/或3'剪接供体剪接位点。
剪接结构域可以由本领域技术人员根据已知方法和原理来选择。剪接结构域提供了剪接体识别的基本共有基序。分支点和PPT的使用遵循参与反式剪接的两个磷酸基转移反应进行所需的共有序列。在一个实施方案中，哺乳动物中的分支点共有序列是YNYURAC(Y＝嘧啶；N＝任何核苷酸)。聚嘧啶束位于分支点和剪接位点受体之间，对于不同的分支点利用和3'剪接位点识别非常重要。RNA剪接中使用的5'剪接供体位点和3'剪接区的共有序列在本领域中是众所周知的。另外，可以使用修饰的共有序列，其保持充当5'供体剪接位点和3'剪接区功能的能力。简而言之，在一个实施方案中，5'剪接位点共有序列是核酸序列AG/GURAGU(其中/表示剪接位点)。在另一个实施方案中，与邻近剪接位点的外显子相对应的内源剪接位点可用于维持任何剪接调控信号。
在一个实施方案中，具有间隔子的合适的5'剪接位点是：5'-GTA AGA GAG CTCGTT GCG ATA TTA T-3'(SEQ ID NO：1)。在一个实施方案中，合适的5'剪接位点是AGGT。
在一个实施方案中，合适的3'反式剪接分子分支位点是5'-TACTAAC-3'。在一个实施方案中，合适的3'剪接位点是：5'-TAC TAA CTG GTA CCT CTT CTT TTT TTT CTG CAG-3'(SEQ ID NO：2)或5'-CAGGT-3'。在一个实施方案中，合适的3'反式剪接分子PPT是：5'-TGGTAC CTC TTC TTT TTT TTC TG-3'(SEQ ID NO：3)。
附加元件或修饰
在本发明的任何反式剪接分子(例如，本文所述的任何ABCA4反式剪接分子或CEP290反式剪接分子)的一些实施方案中，剪接结构域作为人工内含子的一部分被包括在内，该人工内含子可以包括一个或多个附加元件。例如，在人工内含子内可包括间隔子区域，以将反式剪接分子中的剪接结构域与靶结合结构域分开。间隔子区域可以被设计成包括特征诸如(i)终止密码子，所述终止密码子起阻断任何未剪接的反式剪接分子的翻译的作用和/或(ii)增强与靶前mRNA的反式剪接的序列。所述间隔子可以在3至25个核苷酸之间或更多，这取决于反式剪接分子的其他组分的长度和rAAV的限制。在一个实施方案中，合适的5'反式剪接分子间隔子是AGA TCT CGT TGC GAT ATT AT(SEQ ID NO：4)。在一个实施方案中，合适的3'间隔子是：5'-GAG AAC ATT ATT ATA GCG TTG CTC GAG-3'(SEQ ID NO：5)。
反式剪接分子的其他任选元件(例如，作为人工内含子的一部分)包括将调控反式剪接的小型内含子，以及内含子或外显子的增强子(例如，内含子剪接增强子，例如下游内含子剪接增强子)或沉默子。
在另一个实施方案中，反式剪接分子进一步包含(例如，作为人工内含子的一部分)至少一个安全序列，其被并入间隔子、结合结构域或反式剪接分子中的其他地方以防止非特异性反式剪接。这是反式剪接分子的区域，其通过相对较弱的互补性覆盖了反式剪接分子的3'和/或5'剪接位点的元件，从而防止了非特异性的反式剪接。反式剪接分子的设计方式使得，在反式剪接分子的一个或多个结合/靶向部分杂交后，3'或5'剪接位点将被揭露并具有完全的活性。此类安全序列包含顺式序列的互补延伸(或可以是第二条分离的核酸链)，该序列与反式剪接分子分支点的一侧或两侧、嘧啶束、3'剪接位点和/或5'剪接位点(剪接元件)结合，或可与剪接元件本身的某些部分结合。安全序列的结合可被反式剪接分子的靶结合区与靶前mRNA的结合破坏，从而暴露并激活剪接元件(使其可用于反式剪接入靶前mRNA)。在另一个实施方案中，反式剪接分子具有添加到3'或5'末端的3'UTR序列或核酶序列。
在一个实施方案中，剪接增强子，例如被称为外显子剪接增强子的序列，也可以包括在人工内含子的结构中。可以向人工内含子添加其他特征，例如修饰RNA表达/稳定性的聚腺苷酸化信号，或增强剪接的5'剪接序列、附加结合区(additional binding region)、安全性自身互补区、附加剪接位点或保护基团，以调节分子的稳定性并防止降解。另外，终止密码子可包括在反式剪接分子(例如，作为人工内含子的一部分)中，以防止未剪接的反式剪接分子的翻译。可将其他元件(例如3'发夹结构、环化RNA、核苷酸碱基修饰或合成类似物)合并到反式剪接分子中，以促进或促成核定位和剪接体合并以及细胞内稳定性。
在一些实施方案中，反式剪接分子与靶前mRNA的结合通过互补性(即，基于核酸的碱基配对特征)、三螺旋的形成或蛋白质-核酸相互作用来介导(如本文引用的文件中所述)。在一个实施方案中，核酸反式剪接分子包括DNA、RNA或DNA/RNA杂合分子，其中DNA或RNA是单链或双链的。本文还包括RNA或DNA，它们可以与上述RNA或DNA之一杂交，优选在严格条件下，例如在60℃的2.5x SSC缓冲液中，并在37℃的较低缓冲液浓度下洗涤几次，例如0.5x SSC缓冲液。这些核酸可编码表现出脂质磷酸磷酸酶活性和/或与质膜结合的蛋白质。当在体外合成反式剪接分子时，可以在碱基部分、糖部分或磷酸骨架上修饰此类反式剪接分子，例如，以提高分子的稳定性，与靶mRNA杂交，转运到细胞中，细胞对酶促裂解的稳定性等。例如，修饰反式剪接分子以减少总电荷可以增强分子的细胞摄取。另外，可以进行修饰以降低对核酸酶或化学降解的敏感性。可以以与另一种分子例如肽、杂交触发的交联剂、转运剂、杂交触发的切割剂等缀合的方式合成核酸分子。
可以引入对核酸分子的各种其他众所周知的修饰，作为增加细胞内稳定性和半衰期的手段(也参见上文的寡核苷酸)。可能的修饰是本领域已知的。可以对合成反式剪接分子的结构进行的修饰包括骨架修饰。
III.重组AAV分子
任何合适的核酸运载体可以与本组合物和方法结合使用，以设计和组装反式剪接分子和重组腺相关病毒(AAV)的组分。在一个实施方案中，运载体是携带反式剪接分子并且由在受试者的选定细胞中表达反式剪接分子的启动子驱动的重组AAV。组装重组运载体的方法是本领域已知的。参见，例如，Ausubel等人，《Current Protocols in MolecularBiology》,John Wiley&Sons,New York,1989；Kay,M.A.等人，Nat.Medic,2001,7(l):33-40；以及Walther W.和Stein U.，Drugs 2000,60(2):249-71。
在本文所述的某些实施方案中，将携带ABCA4基因结合和编码结构域的反式剪接分子递送至需要借助AAV运载体治疗的所选细胞，例如光感受器细胞。有超过30种自然发生的AAV血清型可用。AAV衣壳中存在许多天然变体，可以标识和使用具有特别适合眼细胞特性的AAV。可以通过常规分子生物学技术对AAV病毒进行工程改造，从而可以优化这些颗粒用于反式剪接分子核酸序列的细胞特异性递送，用于最小化免疫原性，用于调节稳定性和颗粒寿命，用于高效降解，用于准确递送到细胞核等。
本文所述的反式剪接分子的表达可以通过重组工程AAV或含有编码所需反式剪接分子的序列的人工AAV的递送而在选定的细胞中实现。AAV的使用是DNA外源递送的一种常见方式，因为它相对无毒，可以提供有效的基因转移，并且可以很容易地针对特定目的进行优化。在从人或非人灵长类动物中分离出的特征明确的AAV血清型中，人类血清型2已广泛用于不同靶组织和动物模型中的有效基因转移实验。其他AAV血清型包括但不限于AAV1、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8和AAV9。除非另有说明，否则本文所述的AAV ITR和其他选择的AAV组分可以容易地选自任何AAV血清型，包括但不限于AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9或其他已知和未知的AAV血清型。在一个实施方案中，ITR来自AAV2。这些ITR或其他AAV组分可以使用本领域技术人员可用的技术容易地从AAV血清型中分离。可以从学术、商业或公共来源(例如，美国典型培养物保藏中心，马纳萨斯，VA)分离或获得这种AAV。可选择地，AAV序列可以通过合成的或其他合适的方法，参考文献或诸如例如GenBank，PubMed等数据库中的公开序列而获得。
用于组装成运载体的理想的AAV片段包括cap蛋白，包括vp1、vp2、vp3和高变区；rep蛋白，包括rep78、rep68、rep52和rep 40；以及编码这些蛋白的序列。这些片段可以容易地用于多种运载体系统和宿主细胞中。此类片段可以单独使用，与其他AAV血清型序列或片段结合使用，或与其他AAV或非AAV病毒序列的元件结合使用。如本文所用，人工AAV血清型包括但不限于具有非天然存在衣壳蛋白的AAV。可以通过任何合适的技术，使用选择的AAV序列(例如，vp1衣壳蛋白的片段)结合异源序列来产生这样的人工衣壳，所述异源序列可以获自不同的选定AAV血清型、相同AAV血清型的非连续部分，获自非AAV病毒来源，或获自非病毒来源。人工AAV血清型可以是但不限于假型AAV(pseudotyped AAV)、嵌合AAV衣壳、重组AAV衣壳或“人源化”AAV衣壳。假型运载体，其中一种AAV的衣壳与来自具有不同衣壳蛋白的AAV的ITR一起使用，可用于本发明。在一个实施例中，AAV是AAV2/5(即具有AAV2 ITR和AAV5衣壳的AAV)。在另一个实施方案中，AAV是AAV2/8(即具有AAV2 ITR和AAV8衣壳的AAV)。在一实施例中，AAV包括AAV8衣壳。这样的AAV8衣壳包括在NCBI参考序列：YP_077180.1(SEQ IDNO：56)下发现的氨基酸序列。在另一个实施方案中，AAV8衣壳包括由GenBank登录号：AF513852.1(SEQ ID NO：57)的核苷酸2121至4337编码的衣壳。
在一个实施方案中，AAV包括衍生自AAV8的衣壳序列。在一些实施方案中，衍生自AAV8的AAV是在美国专利号9,567,376中描述的AAV8(b)，其通过引用整体并入本文。与野生型AAV8相比，AAV(b)(SEQ ID NO：58)在氨基酸位置587-595处包含Pro-Glu-Arg-Thr-Ala-Met-Ser-Leu-Pro的氨基酸序列。在另一个实施方案中，AAV8(b)衣壳由SEQ ID NO：59编码。
在一个实施方案中，可用于本文所述的组合物和方法中的运载体至少包含编码选择的AAV血清型衣壳例如AAV2衣壳或其片段的序列。在另一个实施方案中，有用的运载体至少包含编码选择的AAV血清型rep蛋白例如AAV2 rep蛋白或其片段的序列。任选地，此类运载体可以同时包含AAV cap和rep蛋白。在同时提供了AAV rep和cap的运载体中，AAV rep和AAV cap序列都可以是一个血清型起源，例如，AAV2起源。
或者，可以使用其中rep序列来自AAV血清型的运载体，该AAV血清型不同于提供cap序列的血清型。在一个实施方案中，rep和cap序列从分开的来源(例如分开的运载体，或宿主细胞和运载体)表达。在另一个实施方案中，这些rep序列与不同AAV血清型的cap序列在框内(in frame)融合，以形成在美国专利号7,282,199中描述的嵌合AAV运载体，其通过引用并入本文。
通过培养宿主细胞产生合适的重组AAV(rAAV)，所述宿主细胞含有编码如本文定义的AAV血清型衣壳蛋白或其片段的核酸序列；功能性rep基因；由例如AAV ITR和反式剪接分子核酸序列组成的小基因；以及足够的辅助功能，以允许将小基因包装到AAV衣壳蛋白中。可将需要在宿主细胞中培养以将AAV小基因包装在AAV衣壳中的组分反式提供给宿主细胞。或者，可以由稳定的宿主细胞提供任何一种或多种所需组分(例如小基因、rep序列、cap序列和/或辅助功能)，所述稳定的宿主细胞已经使用本领域技术人员已知的方法被工程化为包含一种或多种所需组分。
在一个实施方案中，AAV包括启动子(或启动子的功能片段)。可以从多种组成型或诱导型启动子中选择在rAAV中使用的启动子，所述启动子可以在所需靶细胞中表达选择的转基因。参见例如国际专利公开号WO 2014/012482中标识的启动子列表，其通过引用并入本文。在一个实施方案中，启动子是细胞特异性的。术语“细胞特异性”是指为重组运载体选择的特定启动子，其可以指导所选转基因在特定细胞类型中的表达。在一个实施方案中，启动子对转基因在光感受器细胞中的表达是特异性的。在另一个实施方案中，启动子对于在视杆和/或视锥中表达是特异性的。在另一个实施方案中，启动子对于转基因在视网膜色素上皮(RPE)细胞中的表达是特异性的。在另一个实施方案中，启动子对于转基因在神经节细胞中的表达是特异性的。在另一个实施方案中，启动子对转基因在Mueller细胞中的表达是特异性的。在另一个实施方案中，启动子对于双极细胞中转基因的表达是特异性的。在另一个实施方案中，启动子对于转基因在水平细胞中的表达是特异性的。在另一个实施方案中，启动子对于转基因在无长突细胞中表达具有特异性。在另一个实施方案中，转基因在任何上述细胞中表达。
在另一个实施方案中，启动子是用于表达靶基因的天然启动子。有用的启动子包括但不限于视杆视蛋白启动子、红-绿视蛋白启动子、蓝视蛋白启动子、cGMP-磷酸二酯酶启动子、小鼠视蛋白启动子、视紫红质启动子、视锥细胞转导的α-亚基、β磷酸二酯酶(PDE)启动子、视网膜色素变性启动子(retinitis pigmentosa promoter)，NXNL2/NXNL 1启动子、RPE65启动子、慢性视网膜变性/外周蛋白2(Rds/perph2)启动子和VMD2启动子。
小基因或rAAV中包含的其他常规调控序列还公开于诸如WO2014/124282的文件中，并且其他文献通过引用并入本文。本领域技术人员可以在这些以及其他表达控制序列中进行选择，而不背离本文所述的范围。
AAV小基因可能包括本文所述的反式剪接分子及其调控序列，以及5'和3'AAVITR。在一个实施方案中，使用了AAV血清型2的ITR。在另一个实施方案中，使用AAV血清型5或8的ITR。但是，可以选择其他合适血清型的ITR。在一些实施方案中，将小基因包装到衣壳蛋白中并递送至选择的宿主细胞。
产生rAAV所需的小基因、rep序列、cap序列和辅助功能可以以任何遗传元件的形式递送给包装宿主细胞，所述遗传元件可以转移携带在其上的序列。选定的遗传元件可以通过任何合适的方法递送，包括本文所述的那些。用于构建本文所述的任何实施方案的方法是核酸操作技术人员已知的，并且包括基因工程、重组工程和合成技术。参见，例如，Sambrook等人，Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Press,Cold Spring Harbor,NY。类似地，产生rAAV病毒粒子的方法是众所周知的，并且选择合适的方法不是对本发明的限制。参见，例如，K.Fisher等人，J.Virol.,1993 70:520-532，以及美国专利5,478,745，其各自通过引用并入本文。
在另一个实施方案中，反式剪接分子小基因在前病毒质粒中制备，例如在国际专利公开号WO 2012/158757中公开的那些，在此通过引用并入本文。这样的前病毒质粒包含模块重组AAV基因组，其包含操作性连接，该基因组包含：野生型5'AAV2 ITR序列，其侧翼为允许立即去除或替代所述ITR的独特限制性位点；和包含在巨细胞病毒(CMV)-鸡β肌动蛋白序列上游的49个核酸的巨细胞病毒序列的启动子，或光感受器特异性启动子/增强子，该启动子的侧翼是独特的限制性位点，其可以方便地去除或替代整个启动子序列，上游序列的侧翼有独特的限制性位点，这些位点允许从启动子序列中仅去除或替代上游CMV或增强子序列。可以将本文所述的反式剪接分子插入多克隆多接头的位点，其中反式剪接分子与启动子可操作地连接并在其调控下。牛生长激素聚腺苷酸化序列的侧翼是独特的限制性位点，该限制性位点允许容易地去除或替代所述polyA序列；野生型3'AAV2 ITR序列，其两侧有独特的限制性位点，该限制性位点可以方便地去除或替代3'ITR；也是该质粒的一部分。质粒骨架包含在细菌细胞中复制所必需的元件，例如，卡那霉素抗性基因，并且其本身侧接转录终止子/绝缘子序列。
在一个实施方案中，前病毒质粒包含：(a)模块重组AAV基因组，其包含操作性连接，所述基因组包含：(i)野生型5'AAV2 ITR序列，其侧翼为允许立即去除或替代所述ITR的独特限制性位点；(ii)启动子，其包含(A)在CMV-鸡β肌动蛋白序列上游的49个核酸的CMV序列；(b)光感受器特异性启动子/增强子；或(c)神经元细胞特异性启动子/增强子。该启动子的侧翼是独特的限制性位点，其允许立即去除或替代整个启动子序列，而上游序列的侧翼是独特的限制性位点，其允许从启动子序列中仅立即去除或替代上游CMV或增强子序列。该前病毒质粒的一部分也是多克隆多接头序列，其允许插入反式剪接分子序列包括本文所述的任何序列，其中反式剪接分子与启动子可操作地连接并在该启动子调控下；牛生长激素聚腺苷酸化序列，其侧翼是独特的限制性位点，该限制性位点可以容易地去除或替代所述polyA序列；以及野生型3'AAV2 ITR序列，其侧翼有独特的限制性位点，该限制性位点可以方便地去除或替代3'ITR。前病毒质粒还包含质粒骨架，其包含在细菌细胞中复制所必需的元件，并且还包含卡那霉素抗性基因，所述质粒骨架的侧翼为转录终止子/绝缘子序列。本文所述的前病毒质粒还可在质粒骨架中含有非编码λ噬菌体5.1kb填充序列，以增加骨架长度并防止非功能性AAV基因组的反向包装。
在一些实施方案中，前病毒质粒含有反式剪接分子的多个拷贝。例如，本发明的特征在于反式剪接分子小于AAV的包装限制的一半，因此可以在单个前病毒质粒上重复一次、两次、三次、四次、五次、六次、七次、八次、九次、10次、11次、12次、13次、14次、15次、16次、17次、18次、19次、20次或更多。
在另一方面，修饰前病毒质粒的启动子以减小启动子的大小，以允许将较大的反式剪接分子序列插入rAAV。在一个实施方案中，如国际专利公开号WO 2017/087900中所述，将通常包括非编码外显子和总共约1,000个碱基对的内含子的CMV/CBA杂合启动子用130个碱基对的嵌合内含子替代，该专利通过引用将其全部内容并入本文。
然后将这些前病毒质粒用于目前常规的包装方法中，以产生表达前病毒质粒携带的反式剪接分子转基因的重组病毒。合适的生产细胞系是本领域技术人员容易选择的。例如，合适的宿主细胞可以选自任何生物，包括原核(例如细菌)细胞，以及真核细胞，包括昆虫细胞、酵母细胞和哺乳动物细胞。简而言之，将前病毒质粒转染到选定的包装细胞中，在其中它可能会瞬时存在。或者，带有侧翼ITR的小基因或基因表达盒可以通过染色体或作为附加体稳定地整合到宿主细胞的基因组中。合适的转染技术是已知的并且可以容易地用于将重组AAV基因组递送至宿主细胞。通常，前病毒质粒在表达cap和/或rep蛋白的宿主细胞中培养。在宿主细胞中，挽救由反式剪接分子和侧翼AAV ITR组成的小基因，并将其包装到衣壳蛋白或包膜蛋白中，形成感染性病毒颗粒。因此，通过在足够的病毒序列存在下培养携带前病毒质粒的包装细胞以允许基因表达盒病毒基因组包装到感染性AAV包膜或衣壳中来产生重组AAV感染性颗粒。
IV.药物组合物和试剂盒
本文提供了药物组合物，其包括核酸反式剪接分子、前病毒质粒或包含本文描述的核酸反式剪接分子的rAAV。在一些实施方案中，药物组合物包括本文所述的任何5'反式剪接分子。在其他实施方案中，药物组合物包括本文所述的任何3'反式剪接分子。在一些实施方案中，药物组合物包括5'反式剪接分子和3'反式剪接分子，例如，其中5'反式剪接分子和3'反式剪接分子一起含有功能性ABCA4外显子1-50并结合相同的靶ABCA4内含子。
可以通过常规方法评估本文所述的药物组合物的污染，然后配制成旨在用于合适的施用途径的药物组合物。含有反式剪接分子的其他组合物，例如裸露的DNA或作为蛋白质，可以与合适的载体类似地配制。这样的制剂涉及药物和/或生理学上可接受的媒介物或载体的使用，特别是针对靶细胞的施用。在一个实施方案中，适于施用于靶细胞的载体包括缓冲盐水、等渗氯化钠溶液或其他缓冲液，例如HEPES，以将pH维持在适当的生理水平，以及任选地，其他药物(medicinal agent)、药剂(pharmaceutical agent)、稳定剂、缓冲液、载体、佐剂、稀释剂等。
在一些实施方案中，载体是用于注射的液体。示例性的生理上可接受的载体包括无菌、无热原的水和无菌、无热原的磷酸盐缓冲盐水。在美国专利号7,629,322中提供了各种这样的已知载体，该专利在此引入作为参考。在一个实施方案中，载体是等渗氯化钠溶液。在另一个实施方案中，载体是平衡盐溶液。在一实施例中，载体包括吐温。如果病毒要长期保存，则可以在甘油或Tween20存在的情况下将其冷冻。
在其他实施方案中，含有本文所述的反式剪接分子的组合物包括表面活性剂。可以包括有用的表面活性剂，例如Pluronic F68(Poloxamer 188，也称为
Figure BDA0002841450420000731
)，因为它们可防止AAV粘附在惰性表面上，从而确保所需剂量的递送。作为一个实例，设计用于治疗本文所述的眼病的一种示例性组合物包含重组腺相关运载体(vector)和药学上可接受的载体(carrier)，所述重组腺相关运载体在调控序列的控制下携带编码本文所述的3'反式剪接分子的核酸序列，所述调控序列在哺乳动物受试者的眼细胞中表达所述反式剪接分子。所述载体是等渗氯化钠溶液，并包括表面活性剂Pluronic F68。在一个实施方案中，所述反式剪接分子是任何本文所述的那些。
在又一个示例性的实施方案中，所述组合物包含重组AAV2/5假型腺相关病毒，其携带用于ABCA4基因替代的3'或5'反式剪接分子，所述核酸序列在启动子的控制下指导在所述光感受器细胞中的反式剪接分子的表达，其中所述组合物与载体和适合于视网膜下注射的其他组分一起配制。在又一个实施方案中，用于生产或组装该组合物的组合物或组分，包括载体、rAAV颗粒、表面活性剂和/或用于产生rAAV的组分，以及用于制备该组合物的合适的实验室硬件，可以合并到试剂盒中。
在一些情况下，所述组合物包含携带用于CEP290基因替代的5'反式剪接分子的重组AAV2/5假型腺相关病毒，所述核酸序列在启动子的控制下指导在所述光感受器细胞中的反式剪接分子的表达，其中所述组合物与载体和适合于视网膜下注射的其他组分一起配制。在另一个实施方案中，用于生产或组装该组合物的组合物或组分，包括载体、rAAV颗粒、表面活性剂和/或用于产生rAAV的组分，以及用于制备该组合物的合适的实验室硬件，可以合并到试剂盒中。
本文还另外提供了试剂盒，其含有包含5'反式剪接分子的第一药物组合物和包含3'反式剪接分子的第二药物组合物，例如，其中5'反式剪接分子和3'反式剪接分子一起含有功能性ABCA4外显子1-50并结合相同的靶ABCA4内含子(例如，其中反式剪接分子包装在本文所述的任何AAV运载体中)。在一些实施方案中，试剂盒包括在施用前混合两种药物组合物的说明书。
本文还另外提供了含有第一药物组合物的试剂盒，所述第一药物组合物包含与靶CEP290内含子结合的5'反式剪接分子。
V.方法
上述涉及ABCA4反式剪接的组合物可用于治疗由ABCA4基因突变引起的疾病或病症的方法，例如Stargardt病(例如Stargardt病1)，该方法包括延迟或减轻与本文所述疾病相关的症状。这样的方法涉及在特定条件下使靶ABCA4基因(例如，ABCA4前mRNA)与本文所述的反式剪接分子(例如，本文所述的3'反式剪接分子、5'反式剪接分子或3'和5'反式剪接分子中的一个或多个)接触，所述特定条件中所述反式剪接分子的编码结构域可被剪接至靶ABCA4基因以用靶基因的功能性的(即健康的)、或正常的、或野生型或校正的mRNA替代带有一个或多个缺陷或突变的靶基因的一部分，以校正在靶细胞中的ABCA4表达。因此，该方法和组合物用于治疗与特定突变和/或基因表达相关的眼部疾病/病理。
在一个实施方案中，接触涉及直接施用给受影响的受试者。在另一个实施方案中，接触可以离体发生在培养的细胞中，并且将处理过的眼细胞再植入受试者中。在一个实施方案中，该方法涉及施用带有3'反式剪接分子的rAAV。在另一个实施方案中，该方法涉及施用携带5'反式剪接分子的rAAV。在又一个实施方案中，该方法涉及施用带有3'反式剪接分子的rAAV和带有5'反式剪接分子的rAAV的混合物。这些方法包含向有此需要的受试者施用有效浓度的本文所述的任何组合物。
在一些实施方案中，该方法包括选择一种或多种反式剪接分子以治疗患有与ABCA4的突变相关的病症的受试者，例如Stargardt病(例如Stargardt病1)。这样的选择可以基于受试者的基因型。在一些实施方案中，与ABCA4相关的病症可以是常染色体隐性遗传病症。在一些情况下，受试者对于ABCA4中的突变是纯合的或化合物杂合的。筛选和标识ABCA4中特定突变的方法是本领域已知的。
在其他情况下，上述涉及CEP290反式剪接的组合物可用于治疗由CEP290基因突变引起的疾病或病症的方法，例如莱伯氏先天性黑蒙症(如LCA 10)，该方法包括延迟或减轻与本文所述疾病相关的症状。这样的方法涉及在特定条件下使靶CEP290基因(例如，CEP290前mRNA)与本文所述的反式剪接分子(例如，5'反式剪接分子)接触，所述特定条件中所述反式剪接分子的编码结构域可被剪接至靶CEP290基因以用靶基因的功能性的(即健康的)、或正常的、或野生型或校正的mRNA替代带有一个或多个缺陷或突变的靶基因的一部分，以校正在靶细胞中的CEP290表达。因此，该方法和组合物用于治疗与特定突变和/或基因表达相关的眼部疾病/病理。本发明的方法包括通过施用5'反式剪接分子(例如本文所述的任何5'反式剪接分子)或其药物组合物来校正CEP290的内含子26(例如，内含子26的核苷酸1,655处)的病原性点突变。因此，本发明提供了通过施用本文所述的反式剪接分子治疗患有与CEP290中的突变相关的疾病或病症(例如，与CEP290的内含子26中的突变相关的疾病或病症，例如在内含子26的核苷酸1,655处)的受试者的方法。任何前述的反式剪接分子可以包括在药物组合物中(例如，包括两个分子的单一药物组合物，可以在施用之前预先制备或混合，例如作为试剂盒的一部分)。
在一个实施方案中，接触涉及直接施用给受影响的受试者。在另一个实施方案中，接触可以离体发生在培养的细胞中，并且将处理过的眼细胞再植入受试者中。在一个实施方案中，该方法涉及施用带有5'反式剪接分子的rAAV。这些方法包含向有此需要的受试者施用有效浓度的本文所述的任何组合物。
在一些实施方案中，该方法包括选择一种或多种反式剪接分子以治疗患有与CEP290中的突变相关的病症的受试者，例如LCA10。这种选择可以基于受试者的基因型。在一些实施方案中，与CEP290相关的病症可以是常染色体隐性遗传疾病。在一些情况下，受试者对于CEP290中的突变是纯合的或化合物杂合的。筛选和标识CEP290中特定突变的方法是本领域已知的。
用于校正单个突变的单个反式剪接分子
本发明的方法包括基于ABCA4中单个突变(例如，受试者的一个等位基因的突变)的位置选择单个反式剪接分子。在常染色体隐性突变的情况下，仅校正两个突变之一即可恢复功能性蛋白的活性，例如，其中第二个等位基因在ABCA4基因的另一部分具有一个突变，超出了配置为校正第一个突变的单个AAV递送的反式剪接分子的范围。
因此，在一些实施方案中，本发明的方法包括选择单个反式剪接分子以校正靶基因5'部分的单个突变，例如，不考虑突变在其他等位基因中的位置。在一个实施方案中，突变的外显子是外显子1，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1。在一个实施方案中，外显子1或外显子2被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1和2。在一个实施方案中，外显子1、2和3之一被突变，靶内含子是内含子19、22、23或24，并且编码结构域包含功能性ABCA4外显子1-3。在一个实施方案中，外显子1、2、3和4之一被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-4。在一个实施方案中，外显子1、2、3、4和5之一被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-5。在一个实施方案中，外显子1、2、3、4、5和6之一被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-6。在一个实施方案中，外显子1、2、3、4、5、6或7之一被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-7。在一个实施方案中，外显子1、2、3、4、5、6、7或8之一被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-8。在一个实施方案中，外显子1、2、3、4、5、6、7、8或9之一被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-9。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9或10之一被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-10。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10或11之一被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-11。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11或12之一被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-12。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12或13之一被突变，靶内含子是内含子19、22、23或24，编码结构域包括功能性ABCA4外显子1-13。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12或13之一被突变，靶内含子是内含子19、22、23或24，编码结构域包括功能性ABCA4外显子1-13。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13或14之一被突变，靶内含子是内含子19、22、23或24，编码结构域包括功能性ABCA4外显子1-14。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13、14或15之一被突变，靶内含子是内含子19、22、23或24，并且编码结构域包含功能性ABCA4外显子1-15。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13、14、15或16之一被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-16。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16或17之一被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-17。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18之一被突变，靶内含子为内含子19、22、23或24，编码结构域包括功能性ABCA4外显子1-18。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18或19之一被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-19。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20之一被突变，靶内含子是内含子22、23或24，编码结构域包括功能性ABCA4外显子1-20。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或21之一被突变，靶内含子是内含子22、23或24，编码结构域包括功能性ABCA4外显子1-21。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21或22之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子1-22。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22或23之一被突变，靶内含子是23或24内含子，编码结构域包括功能性ABCA4外显子1-23。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24之一被突变，靶内含子是内含子24，并且编码结构域包括功能性ABCA4外显子1-24。
或者，在其中突变位于靶基因的3'部分上的情况下，例如，不考虑突变在另一等位基因上的位置，选择3'反式剪接分子来校正突变。在一个实施方案中，外显子23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50之一被突变，靶内含子是内含子22，并且编码结构域包括功能性ABCA4外显子23-50。在一个实施方案中，外显子24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50之一被突变，靶内含子是内含子22或23，并且编码结构域包括功能性ABCA4外显子24-50。在一个实施方案中，外显子25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子25-50。在一个实施方案中，外显子26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子26-50。在一个实施方案中，外显子27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子27-50。在一个实施方案中，外显子28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子28-50。在一个实施方案中，外显子29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子29-50。在一个实施方案中，外显子30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子30-50。在一个实施方案中，外显子31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子31-50。在一个实施方案中，外显子32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子32-50。在一个实施方案中，外显子33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子33-50。在一个实施方案中，外显子34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子34-50。在一个实施方案中，外显子35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子35-50。在一个实施方案中，外显子36、37、38、39、40、41、42、43、44、45、46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子36-50。在一个实施方案中，外显子37、38、39、40、41、42、43、44、45、46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子37-50。在一个实施方案中，外显子38、39、40、41、42、43、44、45、46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子38-50。在一个实施方案中，外显子39、40、41、42、43、44、45、46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子39-50。在一个实施方案中，外显子40、41、42、43、44、45、46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子40-50。在一个实施方案中，外显子41、42、43、44、45、46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子41-50。在一个实施方案中，外显子42、43、44、45、46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子42-50。在一个实施方案中，外显子43、44、45、46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子43-50。在一个实施方案中，外显子44、45、46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子44-50。在一个实施方案中，外显子45、46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子45-50。在一个实施方案中，外显子46、47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子46-50。在一个实施方案中，外显子47、48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子47-50。在一个实施方案中，外显子48、49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子48-50。在一个实施方案中，外显子49或50之一被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子49或50。在一个实施方案中，外显子50被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子50。
用于校正多个突变的单个反式剪接分子
本发明的方法包括当两个突变位于基因的5'部分或基因的3'部分上时，基于受试者的每个等位基因中ABCA4中突变的位置来选择单个反式剪接分子，从而使得能够包装在AAV运载体中的单个反式剪接分子能够跨越两个突变，从而校正两个突变。
例如，在两个突变都发生在靶基因的5'部分上的情况下，选择5'反式剪接分子以校正两个突变。在一个实施方案中，突变的外显子是外显子1(即，两个突变都在外显子1中)，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1。在一个实施方案中，外显子1和/或外显子2被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1和2。在一个实施方案中，外显子1、2和3中的一个或两个被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-3。在一个实施方案中，外显子1、2、3和4中的一个或两个被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-4。在一个实施方案中，外显子1、2、3、4和5中的一个或两个被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-5。在一个实施方案中，外显子1、2、3、4、5和6中的一个或两个被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-6。在一个实施方案中，外显子1、2、3、4、5、6或7中的一个或两个被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-7。在一个实施方案中，外显子1、2、3、4、5、6、7或8中的一个或两个被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-8。在一个实施方案中，外显子1、2、3、4、5、6、7、8或9中的一个或两个被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-9。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9或10中的一个或两个被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-10。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10或11中的一个或两个被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-11。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11或12中的一个或两个被突变，靶内含子是内含子19、22、23或24，编码结构域包括功能性ABCA4外显子1-12。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12或13中的一个或两个被突变，靶内含子是内含子19、22、23或24，编码结构域包括功能性ABCA4外显子1-13。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12或13中的一个或两个被突变，靶内含子是内含子19、22、23或24，编码结构域包括功能性ABCA4外显子1-13。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13或14中的一个或两个被突变，靶内含子是内含子19、22、23或24，并且编码结构域包含功能性ABCA4外显子1-14。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13、14或15中的一个或两个被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-15。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13、14、15或16中的一个或两个被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-16。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16或17中的一个或两个被突变，靶内含子为内含子19、22、23或24，编码结构域包括功能性ABCA4外显子1-17。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18中的一个或两个被突变，靶内含子是内含子19、22、23或24，并且编码结构域包括功能性ABCA4外显子1-18。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18或19中的一个或两个被突变，靶内含子是内含子19、22、23或24，编码结构域包括功能性ABCA4外显子1-19。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20中的一个或两个是突变，靶内含子是内含子22、23或24，编码结构域包括功能性ABCA4外显子1-20。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或21中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子1-21。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21或22中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子1-22。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22或23中的一个或两个被突变，靶内含子是内含子23或24，并且编码结构域包括功能性ABCA4外显子1-23。在一个实施方案中，外显子1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24中的一个或两个被突变，靶内含子是内含子24，并且编码结构域包括功能性ABCA4外显子1-24。
另外，如果两个突变都发生在靶基因的3'部分，则选择3'反式剪接分子以校正两个突变。在一个实施方案中，外显子23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22，并且编码结构域包括功能性ABCA4外显子23-50。在一个实施方案中，外显子24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22或23，并且编码结构域包括功能性ABCA4外显子24-50。在一个实施方案中，外显子25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子25-50。在一个实施方案中，外显子26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子26-50。在一个实施方案中，外显子27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子27-50。在一个实施方案中，外显子28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50中的一个或两个是突变的，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子28-50。在一个实施方案中，外显子29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子29-50。在一个实施方案中，外显子30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子30-50。在一个实施方案中，外显子31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子31-50。在一个实施方案中，外显子32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子32-50。在一个实施方案中，外显子33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子33-50。在一个实施方案中，外显子34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子34-50。在一个实施方案中，外显子35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子35-50。在一个实施方案中，外显子36、37、38、39、40、41、42、43、44、45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子36-50。在一个实施方案中，外显子37、38、39、40、41、42、43、44、45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子37-50。在一个实施方案中，外显子38、39、40、41、42、43、44、45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子38-50。在一个实施方案中，外显子39、40、41、42、43、44、45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子39-50。在一个实施方案中，外显子40、41、42、43、44、45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子40-50。在一个实施方案中，外显子41、42、43、44、45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子41-50。在一个实施方案中，外显子42、43、44、45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子42-50。在一个实施方案中，外显子43、44、45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子43-50。在一个实施方案中，外显子44、45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子44-50。在一个实施方案中，外显子45、46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子45-50。在一个实施方案中，外显子46、47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子46-50。在一个实施方案中，外显子47、48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子47-50。在一个实施方案中，外显子48、49或50中的一个或两个被突变，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子48-50。在一个实施方案中，外显子49或50中的一个或两个是突变的，靶内含子是内含子22、23或24，并且编码结构域包括功能性ABCA4外显子49或50。在一个实施方案中，外显子50是突变的，靶内含子是内含子22、23或24，编码结构域包括功能性ABCA4外显子50。
用于校正多个突变的两个反式剪接分子
另外，本文提供了使用两个反式剪接分子(5'反式剪接分子和3'反式剪接分子)校正ABCA4基因内多个突变的方法。在一些实施方案中，整个ABCA4基因在两个反式剪接分子结合时被替代，例如，其中5'反式剪接分子和3'反式剪接分子结合相同的靶ABCA4内含子并分别替代位于靶内含子的上游和下游的外显子。
例如，在本发明的一些实施方案中，5'反式剪接分子和3'反式剪接分子各自结合靶ABCA4内含子22；5'反式剪接分子将内源外显子1-22替代为功能性外显子1-22；3'反式剪接分子用功能性外显子23-50替代了内源外显子23-50。在其他实施方案中，5'反式剪接分子和3'反式剪接分子各自结合靶ABCA4内含子23；5'反式剪接分子用功能性外显子1-23替代内源外显子1-23；而3'反式剪接分子则将内源外显子24-50替代为功能性外显子24-50。在其他实施方案中，5'反式剪接分子和3'反式剪接分子各自结合靶ABCA4内含子24；5'反式剪接分子用功能性外显子1-24替代内源外显子1-24；3'反式剪接分子用功能性外显子25-50替代了内源外显子25-50。5'和3'反式剪接分子的上述组合中的任何组合都可以包括在药物组合物中(例如，包括两种分子的单一药物组合物，可以在施用前预先制备或混合，例如作为试剂盒的一部分)。
剂量、监测和联合疗法
携带本文所述的反式剪接分子的重组腺相关病毒的有效浓度在每毫升约108至1013个运载体基因组之间(vg/mL)。所述rAAV感染单位按照McLaughlin等人J.Virol.1988,62:1963中的描述测量。在一个实施方案中，浓度范围为109-1013vg/mL。在另一个实施方案中，有效浓度为约1.5×1011vg/mL。在一实施方案中，有效浓度为约1.5×1010vg/mL。在另一个实施方案中，有效浓度为约2.8×1011vg/mL。在另一个实施方案中，有效浓度为约5×1011vg/mL。在另一个实施方案中，有效浓度为约1.5×1012vg/mL。在另一个实施方案中，有效浓度为约1.5×1013vg/mL。
希望使用病毒的最低有效剂量(递送的基因组总拷贝数)，以减少不良效果的风险，例如毒性以及与眼睛施用有关的其他问题，例如视网膜发育不良和脱离。携带本文所述的反式剪接分子的重组腺相关病毒的有效剂量为每剂量(即每次注射)约108至1013个运载体基因组(vg)。在一个实施方案中，剂量在109和1013vg之间。在另一个实施方案中，有效剂量为约1.5×1011vg。在另一个实施方案中，有效剂量为约5×1011vg。在一实施方案中，有效剂量为约1.5×1010vg。在另一个实施方案中，有效剂量为约2.8×1011vg。在另一个实施方案中，有效剂量为约1.5×1012vg。在另一个实施方案中，有效浓度为约1.5×1013vg。在这些范围内或以其它单位的其它剂量可由主治医师考虑所治疗的受试者的身体状态，包括受试者的年龄；所施用的组合物和特定病症；靶细胞和病症发展的程度(如果是进行性的)而选择。
所述组合物可以约50μL至约1mL的体积递送，包括该范围内的所有数目，这取决于待治疗区域的大小、所使用的病毒滴度、施用途径和该方法所期望的效果。在一实施方案中，体积为约50μL。在另一个实施方案中，体积为约70μL。在另一个实施方案中，体积为约100μL。在另一个实施方案中，体积为约125μL。在另一个实施方案中，体积为约150μL。在另一个实施方案中，体积为约175μL。在另一个实施方案中，体积为约200μL。在另一个实施方案中，体积为约250μL。在另一个实施方案中，体积为约300μL。在另一个实施方案中，体积为约350μL。在另一个实施方案中，体积为约400μL。在另一个实施方案中，体积为约450μL。在另一个实施方案中，体积为约500μL。在另一个实施方案中，体积为约600μL。在另一个实施方案中，体积为约750μL。在另一个实施方案中，体积为约850μL。在另一个实施方案中，体积为约1,000μL。
在一个实施方案中，选择rAAV组合物的体积和浓度，使得仅影响具有靶细胞的某些解剖区域。在另一个实施方案中，rAAV组合物的体积和/或浓度为较大量，以便到达眼睛的较大部分。类似地，调整剂量以施用于其他器官。
在另一个实施方案中，本发明提供了一种预防或阻止受试者的光感受器功能丧失或增加光感受器功能的方法。该组合物可以在疾病发作之前或之后施用。例如，可以使用本领域常规的功能研究，例如ERG或视野测量来评估光感受器功能。如本文所用，“光感受器功能丧失”是指与正常的、未患病的眼睛或同一只眼睛在较早的时间点相比，光感受器功能的降低。如本文所用，“增加光感受器功能”是指与患病的眼睛(患有相同的眼病)，同一只眼睛在较早的时间点，同一只眼睛的未治疗部分，或同一受试者的对侧眼睛相比，改善光感受器的功能或增加功能性光感受器的数量或百分比。
对于所描述的每种方法，该治疗可用于防止进一步损害的发生或挽救具有轻度或晚期疾病的组织。如本文所用，术语“挽救”是指预防疾病的进展，预防损伤扩散至未损伤的细胞或改善受损细胞的损伤。
因此，在一个实施方案中，在疾病发作之前施用组合物。在另一个实施方案中，在症状发展之前施用组合物。在另一个实施方案中，在症状发展后施用组合物。在又一个实施方案中，例如，与参考组织相比，当少于90％的靶细胞起作用或剩余时，施用组合物。在又一个实施方案中，例如，与参考组织相比，当多于10％的靶细胞起作用或剩余时，施用组合物。在另一个实施方案中，当超过20％的靶细胞起作用或剩余时施用组合物。在另一个实施方案中，当超过30％的靶细胞起作用或剩余时施用组合物。
在又一个实施方案中，任何上述方法与另一种或第二种疗法联合进行。该疗法可以是任何现在已知或尚未知道的疗法，其有助于预防、阻止或改善这些突变或缺陷或与之相关的任何效果。第二种疗法可以在上述反式剪接分子的施用之前、同时或之后施用。在一个实施方案中，第二种疗法涉及用于维持视网膜细胞健康的非特异性方法，例如神经营养因子、抗氧化剂、抗凋亡剂的施用。通过注射蛋白质、重组DNA、重组病毒运载体、干细胞、胎儿组织或基因改造的细胞可以实现非特异性方法。后者可以包括被封装的转基因改造的细胞。
在另一个实施方案中，该方法包括进行功能性和成像研究以确定治疗的功效。这些研究包括视网膜电图(ERG)和体内视网膜成像，如美国专利号8,147,823、国际专利公开号WO 2014/011210或WO2014/124282所描述，其通过引用并入本文。另外，可以进行视野研究、视野测量和微视野测量、移动测试、视敏度和/或色觉测试。
在某些实施方案中，期望进行非侵入性视网膜成像和功能性研究以标识保留的光感受器区域作为治疗靶标。在这些实施方案中，采用临床诊断测试来确定一种或多种视网膜下注射的一个或多个精确位置。这些测试可能包括ERG，视野测量，通过共聚焦扫描激光检眼镜(cSLO)和光学相干断层扫描(OCT)进行视网膜层的地形图绘制以及测量其各层的厚度，通过自适应光学器件(AO)对视锥密度进行地形图绘制，功能性眼部检查等。鉴于成像和功能性研究，在一些实施例中，在同一只眼睛中执行一次或多次注射，以便靶向保留的光感受器的不同区域。
为了在这些方法中使用，分别确定每次注射的体积和病毒滴度，并且可以与在同一只或对侧眼中进行的其他注射相同或不同。在另一个实施例中，进行一次较大体积的注射以便治疗整个眼睛。剂量、施用和方案可以由主治医师根据本公开的教导确定。
实施例
本发明至少部分地基于申请人的发现，即ABCA4的特定内含子以及这些内含子内的特定区域，为反式剪接分子的结合结构域提供了高效的结合位点，并有效地介导了反式剪接。申请人已经产生了一系列具有150聚体结合结构域的模拟反式剪接分子，这些结合结构域被设计为与以下内含子的相应系列的150碱基对结合位点序列杂交：(i)目的ABCA4内含子(内含子19和22-24)和(ii)目的CEP290内含子(内含子26-30)。ABCA4系列和CEP290系列中的每个结合结构域都设计为重叠140个核苷酸，从而可以在每个顺序测试结合结构域之间以10个核苷酸扫描每个内含子。对跨每个ABCA4内含子19和22-24和CEP290内含子26-30的每个结合结构域的反式剪接效率进行定量。实施例1中描述了ABCA4筛选，结果显示在图1-8中。实施例2描述了CEP290的筛选，结果示于图21-26。
实施例1.ABCA4
该实施例描述了ABCA4反式剪接分子的发展，例如，通过筛选特定ABCA4内含子内的有效结合位点，开发用于测试反式剪接分子的ABCA4细胞系，以及测试各种ABCA4反式剪接分子以恢复ABCA4蛋白表达。
结合位点筛选
被配置为在顺序结合位点结合ABCA4内含子19(SEQ ID NO：25)的一系列结合结构域的筛选，揭示了ABCA4内含子19的3'部分的区域，其在5'反式剪接分子的反式剪接中优先有效——内含子19的核苷酸990至2,174的区域(图2)。从1,670至2,174，从1,810至2,000，从1,870至2,000或从1,920至2,000的核苷酸范围内的结合位点，被揭示在介导内含子19的5'反式剪接方面特别高效。
类似地标识了内含子22内5'反式剪接分子的合适结合位点(图3)。相对于内含子的其余部分，内含子22的核苷酸1至150或核苷酸880至1,350的范围内的结合位点特别有效。
图4显示了针对3'反式剪接分子的ABCA4内含子22(SEQ ID NO：28)的类似筛选的结果。具有核苷酸60至570，核苷酸600至800或核苷酸900至1350的结合位点被标识为优先适合于3'反式剪接分子的反式剪接。特别地，靶向核苷酸70至250范围内的结合位点的结合结构域在3'反式剪接中非常有效。
在内含子23中，标识出5'反式剪接分子的相对有效的结合位点是在SEQ ID NO：29的核苷酸80至570或核苷酸720至1,081的范围内的那些结合位点(图5)。对于3'反式剪接分子，结合位点的效率特别好，包括SEQ ID NO：29的核苷酸80至1,081(例如，SEQ ID NO：29的核苷酸230至1,081，SEQ ID NO：29的核苷酸250至400或SEQ ID NO：29的核苷酸690至850)内的那些结合位点，如图6所示。
在ABCA4的内含子24(SEQ ID NO：30)上的类似筛选显示，核苷酸600至1,250或核苷酸1,490至2,660范围内的结合位点在5'反式剪接中是有效的(图7)。特别地，在核苷酸1,000至1,200范围内的结合位点表现出最大的5'反式剪接效率。图8显示了筛选3'反式剪接效率的结果，其揭示了在核苷酸1至250，核苷酸300至2,000，或核苷酸2,200至2,692的范围内的结合位点(特别是在核苷酸或核苷酸750至1,110范围内的结合位点)是最有效的。
ABCA4细胞系
首先，产生表达ABCA4的细胞系。已知ABCA4基因仅在视网膜中的活光感受器中表达，而全长ABCA4前mRNA和蛋白通常无法在体外培养的细胞中检测到。因此，为了测试ABCA4的反式剪接策略，对细胞进行了工程改造，使其从1号染色体(1p22.1)的天然基因组基因座表达ABCA4。采取两种策略。在第一种情况下，衍生出稳定的细胞系来表达与VP64病毒反式激活因子融合的位点特异性(ABCA4转录起始位点的上游)DNA结合TALEN。在第二种情况下，将组成型真核启动子直接插入(使用CRISPR/Cas9)到ABCA4转录起始位点紧接上游的基因组基因座中。在两种情况下的结果都是强力表达ABCA4前mRNA和蛋白质的稳定细胞系。
TALEN细胞系
设计靶向ABCA4转录起始位点上游特定结构域的TALEN，并将其与VP-64反式激活因子序列融合(图9)。将三种TALEN的这种组合转染到293细胞中，并获得了稳定的单细胞克隆。显示两个克隆指导ABCA4蛋白的表达(图10)。
CAG启动子细胞系
在图11-13中概述了用于获得CAG启动子细胞系的一般策略。设计位点特异性向导(图12A)以使用同源臂插入CAG启动子和嘌呤霉素选择标记(图12B)。克隆嘌呤霉素抗性细胞，并通过PCR分析所需的插入。选择了几个克隆系用于进一步分析。图14A和14B中示出了两种细胞系(B6和C3)的RNA和蛋白质表达。正如RNA和蛋白质分析所证实的，这两种细胞系均清楚地含有启动子插入。
ABCA4敲除细胞系
一旦在培养的细胞中建立了稳定的ABCA4表达，产生敲除ABCA4表达，以测试旨在恢复ABCA4蛋白表达的ABCA4反式剪接分子。通常，向导RNA和Cas9蛋白在B6细胞中共转染(将CAG启动子敲入ABCA4基因座并介导ABCA4表达)。9天后，用向导RNA和Cas9蛋白进行第二次转染。靶向外显子3和4的基本设计显示在图15中。通过有限稀释将单个细胞铺板，并且一旦生长，通过Western印迹评估ABCA4的蛋白质表达。
图16显示了用CRISPR/Cas9处理后得到的单细胞克隆的RNA和蛋白质谱，如图15所示。RNA和蛋白质的切除程度不同。选择克隆17+06和17+21，因为它们表现出完全的ABCA4蛋白敲除。突变分析(图17A-17B和18)证实外显子3和4被靶向并被打断。
ABCA4反式剪接介导的蛋白质修复
基于上述的高通量结合位点筛选，选择了八个反式剪接分子。这些研究的方法和结果描述如下
方法
对于Western印迹测定，在十二孔板的每个孔中以每孔106个细胞的密度播种17+06或17+21细胞。用1μg质粒(RTMx)转染各个孔。在48小时后，收集细胞，并根据制造商的说明，使用Mem-PER Plus膜蛋白提取试剂盒(Thermo Fisher 89842)，并添加1x HALTTM蛋白酶和磷酸酶抑制剂混合物(Thermo Fisher 78440)在所有缓冲液中，通过标准Western印迹法将膜制品进行处理，以进行分析。如下所述，还处理RNA用于分析。膜裂解液在室温下用4xLaemmli样品缓冲液(Biorad 161-0737)变性，该样品缓冲液包括10％还原剂TCEP 0.5M(Sigma 646547)，变性30分钟。在NuPage Precast 3-8％Tris-Acetate凝胶(ThermoFisher)上运行样品，并使用iBlot 2Mini PVDF Transfer Packs转移蛋白质–用iBlot 2在25V下运行10分钟。ABCA4的主要抗体是Abcam ab72955，兔多克隆(稀释度为1：2500)。二抗是抗兔抗体(稀释度为1：5000)。根据信号强度，印迹会暴露不同的时间。
对于用于RNA样品的qPCR，使用RNeasy Plus Mini试剂盒(Qiagen)，如上所述收获RNA用于qPCR分析。用SuperScript IV VILO Master Mix(Thermo 11756500；在水中以1：4稀释)在20μl反应中由400ng RNA合成cDNA。天然ABCA4(Thermo商业测定Hs00979594_m1)跨越外显子49-50。以管家基因作为对照，使用RNF20测定(Thermo商业测定Hs00219623_m1)。嵌合ABCA4密码子优化的外显子22-天然外显子23--qPCR引物和探针如下：
探针(FAM)063_ABCA4 co22n23_P1:
CGTGGACCCTTACAGCAGAAG
正向引物064_ABCA4 co22n23_F1:
GATCCTGGATGAGCCTAC
反向引物065_ABCA4 co22n23_R1:
GGACATGATGATGGTTCTG
具有RNF20测定的双链qPCR引物和探针如下：
探针(VIC)088_RNF20_P2:
CAGCGACTCAACCGACACTT
正向引物091_RNF20_F2:
GCAGTGGGATATTGACAA
反向引物099_RNF20_R5:
CGAGCATTGATAGTGATTG
使用QuantiFast 2x qPCR Mastermix进行PCT反应。
结果
测试了与内含子19、22、23和24结合的反式剪接分子。在与内含子19和24结合的反式剪接分子中未观察到蛋白质恢复(数据未显示)，但是与内含子22和23结合的反式剪接分子产生ABCA4蛋白和RNA表达的恢复(图19A和19B)，在下面讨论。
图20A是Western印迹，其显示ABCA4蛋白的表达归因于来自两个不同细胞系(17+06和17+21)的反式剪接反应，其中模拟GFP对照或5'A4In22拴系在五个不同的结合结构域上(无结合结构域(NBD)对照、92、99、105、118和121，编号对应于图3RTM#，其中结合结构域92结合内含子22的核苷酸911-1060，结合结构域99结合内含子22的核苷酸981-1130，结合结构域105结合内含子22的核苷酸1041-1190，结合结构域118结合内含子22的核苷酸1171-1320，以及结合结构域121结合内含子22的核苷酸1201-1350(遵循跨内含子22上150聚体的10个碱基移位间隔，如上所述))。这些与内含子22结合的构建体中的四个99、105、118和121产生蛋白质恢复，其中105、118和121显示出特别增强的恢复，而118显示在两个细胞系中表达的蛋白质量最大。mRNA表达谱显示出相似的模式，其中118构建体在两种细胞系中产生最高水平的ABCA4 mRNA(图20B)。单位是相对于RNF20管家基因的。
图20C是Western印迹，其显示了ABCA4蛋白表达，其归因于来自两个不同细胞系(17+06和17+21)的反式剪接反应，其中模拟GFP对照或5'A4In23被拴系到三个不同的结合结构域上(NBD对照、27、81和85，编号对应于图5RTM#，其中结合结构域27结合内含子23的核苷酸261-410，结合结构域81结合内含子23的801-950，以及结合结构域85结合内含子23的841-990(遵循跨内含子23上150聚体的10个碱基移位间隔，如上所述)。如在两个细胞系中表达的蛋白质的量所表明的，所有三个内含子23结合构建体均产生了反式剪接。mRNA表达谱产生相似的结果，所有三种构建体在两种细胞系中均产生稳健的ABCA4 mRNA表达(图20D)。单位是相对于RNF20管家基因的。
总而言之，对于结合内含子22和23的反式剪接分子获得的ABCA4蛋白和RNA表达数据与上述结合结构域筛选有关连。特别地，预测内含子22结合构建体105、118和121以及内含子23结合构建体27、81和85将高效结合(图3和5)，并且目前的ABCA4蛋白恢复数据表明包含这些构建体结合位点的ABCA4内含子区域适合与ABCA4反式剪接分子结合，从而赋予蛋白质和RNA还原能力。在本实施例中，恢复了10-20％的蛋白质表达，在结合内含子22和23的反式剪接分子之间该恢复是相当的。重要的是，由于与ABCA4有关的疾病(例如Stargardt病)是隐性的，因此该疾病的无症状携带者可能表达的水平低于正常ABCA4，并且不希望受到理论的束缚，如此处所示，部分蛋白质修复可能会赋予有意义的临床益处。
实施例2.CEP290
筛选被配置为在顺序结合位点结合CEP290内含子26(SEQ ID NO：85)的一系列结合结构域，其显示出CEP290内含子26的3'部分的区域优先适合于5'反式剪接分子的反式剪接-内含子26的核苷酸4,980至5,838的区域(图22)。揭示在核苷酸5,348-5,838、5,348-5,700、5,400-5,600、5,460-5,560或5,500的范围内的结合位点在介导反式剪接中特别有效。
图23显示了CEP290内含子27(SEQ ID NO：86)的相似筛选的结果。标识出具有核苷酸120至680、710至2,200、2,670至2,910的结合位点优先适合于5'反式剪接分子的反式剪接。特别地，靶向在核苷酸790至2,100，核苷酸1,020至1,630或核苷酸1,670至2,000的范围内的结合位点的结合结构域在反式剪接中是高效的。
在内含子27(SEQ ID NO：87)中，核苷酸1至390(例如核苷酸1至200)、核苷酸410至560或核苷酸720至937范围内的结合位点被标识为具有相对较高的反式剪接效率(图24)。
内含子28(SEQ ID NO：88)被类似地表征并且显示出在核苷酸1至600、核苷酸720至940或核苷酸1370至1790内具有相对有效的结合位点(图25)。
在内含子29(SEQ ID NO：89)中，相对于内含子的其余部分，内含子的3'部分在介导5'反式剪接方面效率更高(图26)。特别地，靶向核苷酸95至1,240范围内的结合位点的结合结构域，例如核苷酸1,060至1,240，表现出最大的反式剪接效率。
序列表
<110> 聚光灯生物有限公司
宾夕法尼亚大学理事会
<120> 反式剪接分子
<130> 51219-016WO2
<150> US 62/658,667
<151> 2018-04-17
<150> US 62/658,658
<151> 2018-04-17
<160> 113
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caacauccgu cugucucccc acuacaccgg gagcuugaga gaagaggcca ugucucuagc 14400
acccagcaca gggacuggca cacaugagau gcuccugcuu cuuaaaugcu gagaaugaag 14460
gaggacauca gaggggcccg ggccccuucc caaaaaggcc aacuccuagg ucugcauccu 14520
gcuuggucuc caugacuaau cccgucuugu ccucauuuuc uguuuuaaag gccauuuccc 14580
caacaaggcg augcccucag caggaaugcu gccguggcuc caggggaucu ucugcaaugu 14640
gaacaauccc uguuuucaaa gccccacccc aggagaaucu ccuggaauug ugucaaacua 14700
uaacaacucc auguaagugu ugagaucccu accaugcagg ggaggaaguu gcacaccccu 14760
ucacgugcug aaaugcacac gugcgugcac ggagcaugga gcacugagug uucuuguggc 14820
uuugcugagc cccuaaccuc uuaggagcag agcagguuuc cucucuggaa cauucuguua 14880
acugucaggg cacuugggga gaaaucucca agcuaaggcc acgugcacaa aauuucuugg 14940
uccuuauauc cccagaaugu gaccuggagu cugauggcag cccgcugcag agaugugucc 15000
acugccuucu ggucauugac cugcuugggu ggagugaauc auuguaggag aaaaacucag 15060
uucccucacc cugaucaacc uggacagauc ucucuuccuu uaaaagcuuu cuuggacauc 15120
uaagggcuag gaaaaauguc agggagcauu gggaagguaa augaagucag guuuacaaag 15180
ucaaguuuac uucuugggag aaaaauacaa uuuccaaauc cucuguuaua auugccaucg 15240
gcccccugga guggugagau cucggaauau ggcucgggug caguggcucu ucacuguggg 15300
ccugcaggcu auucugaaaa gcugaugaaa accaaugacc ccucuuccaa gaaaaauggc 15360
cacauaccaa acauuacacu guacaucuga uuucagggaa uuguagaugc cagguuagua 15420
gccucagguc uagggucaaa auucaagucg aaucccacag gaagaggguc ugccuucgga 15480
auucccuuuc agagcauugg gagaacauca ugggagcaua uucuagagac agaggcuuag 15540
gguguggaca gggccauccc ucacccacug ugcugaccuu aagcagcacc uugugcagcc 15600
cauaccugaa ggccaccagc aaaggccugu uggggagcag gcuuuacccg accuguauaa 15660
acaccaggcu aggugaaaac ugagauaccu gguuacuuua guuuuuuccu ugggggagcu 15720
caguaugauu cuuccaggag aagccugcuu uuagacuaaa aagaaaaaaa guuugauagg 15780
ucaaccuaau gauuggaggu ggccuucccc acugugaaca aacuauggcu gcaugugccc 15840
uacaauggca gaguugagua guugugauag agacuguaug aucuguaagc cuguaauuuu 15900
uauguuugcu gaccccugga uuaccagaug auagaagagg aaacaucugu cuuccuagca 15960
aagucaagga aguggcauuu agcaggacuc auauugcugc aagcacugcc uugcaguuuu 16020
aguuuacaac ugcacuuuca gcuuaagaaa caccugccca uccagagaga ucgugugggg 16080
ucacauggug ggaucaggga ggccugaaga cagcucagug gaggcugcau ggagcuuugg 16140
ugggaacggc ccuggcagug ucuauagaug uuauugcgga aaacugaggg gugggaguug 16200
gagaaggggg cuccagacuc uagcuguacu uggcauuuga acccggaaag uuggguuuca 16260
uguuuugcac ucacauuaug agugaaauau uggcuuauuc aagguucuuu ugcuugcaag 16320
gcacggaaac ccauucaagc aaucuuaaac cccagaagga aaucuaugau uuggauacua 16380
gacauucuca cagagccaag ggcagcaagg cggggcucag gagaggcagg ccaagaccug 16440
gagagcuguc aggagcugcu uccucaacuc ucuuccaucu gggccugcca gcccuggccu 16500
cuguaucuac uccauucacc ucucuccaug gaccagucuc cccugcuccu caaugccugg 16560
gcugccauug uucaugcaau ucacaauacc ucggccuggg caaucagaag cucaucucug 16620
aacaccaucc aaauuccugg gaacaaaucg gguugaccca gcuuuauucu cccuguccca 16680
ucagccuugg cagaggcgug caugugcaug cgugccaaug ugugugugca gggagguccu 16740
uguggaugaa gcauggcugu cagagccuac cugcgugaau ggguggaagg gcaggucuca 16800
gagaauuggg uaaaaacugg auaaacccuc cagugauauc caccaauguc acccuguuua 16860
aggcuucucu gggcaagaga cacacagagc augggaccga gaggcgagca gacccugcca 16920
aaacugggag acugaauaga ucgcucacca uccuugucag uuagccuaua uguacaagga 16980
aguaaaauua ucucuuucuc cugccuuggc aguauuguaa ggauacucaa uguaguagcu 17040
aggccagaca cauaguaucu uuaaauauag caugagaugg ccaagcacgg uggcucaugc 17100
cuguaauccc agcacuuugg gaggcugagg cggguggauc acgaggucag gagaucgaga 17160
ccauccuggc uaacacgaug aagccccguc ucuacuaaaa auauaaaaaa uuagcugggu 17220
gugguggcgg gcgccuguag ucccagcuac ucgggaggcu gaggcaggag aauagcguga 17280
acccgggggg cagagcuugc agugagccga gaucacgcca cugcacucca gccuggguga 17340
cagagcgaga uaaaaaaaaa aaauagcaug agauauuauu acuguuauaa aaauaacagc 17400
uauuuccuua uuaaugaggc uuuguccuua cagcuuggca aggguauauc gagauuuuca 17460
agaacuccuc augaaugcac cagagagcca gcaccuuggc cguauuugga cagagcuaca 17520
caucuugucc caauucaugg acacccuccg gacucacccg gagagaauug cagguaagca 17580
ugacugcagu gcucucaagc aucauuuccc ucaccuaugg agagacugaa gauauaggaa 17640
agaacaggga gaguugguga aaaauauacu agcggaggca ggaagggaug gggucuggag 17700
gcggcuugaa caucaccuug gugaagaugc cucuuccucc acagaagccu ggaagguagg 17760
aaguugggaa ggaaggcagg aaaggucuca uccacguuaa gucuagagac agaaagaaug 17820
cuaagagaga uggcacuaug ggaaguauga ggcuagguca agggcuagaa gcaggggaga 17880
cgaguuuaca gaguuucgua aagauauaga gcaacucuca cagaguucua gagcgagagc 17940
uaaccaggaa caugaagcag caaggccaac uaucauuaag gagccaggga ggucagagau 18000
cauguauuau caugacauaa auaugcauaa uuguacuauu ucucccagua auauuuagca 18060
cccaggcccc gaggcagagc aaguggagag ugggugaugc agggcugggg guguguaugg 18120
aggcaccaca gaaggucaac aggcagcggg cugaaggcag ggacuggacu acaugcauca 18180
aguccaggcu gcacgaggaa ggaugagaag gcagaugagc acggaaaugg acugggggaa 18240
augaagaggc aagggaauag aagucucagu gggugccaug acccuguuua agugauugag 18300
aaaaugaaca agaugaaaag guuaauggcu guggucagaa agugaaauau gugaauucag 18360
gauuucgaag guaggguggg ugaugacugg cccccagaug cggccauggu gaaguggggc 18420
aaaggugcag gugcauggug aggggaagga ggaaauggga ggugaugaug uuggccccac 18480
acggacacca cgguugugca ggaagauggc aggagcuggg caccagggug ggagccaccu 18540
ggagucagga agagugaaga gaaaggauga agaggcuccc ucuccugugu cucuccuccc 18600
caggagaaga acaagaaaca auccgaaagu aauaacacca augugccuuu acaaagugug 18660
aguggguguu gugugcuguc acguguguag uaggcuccuc uguggauggc uagagggacu 18720
ggacauggcc acuggauccc acuugcaaga gcagaggaaa agaguggucg ugaggaagua 18780
aagcccccca aaauccaggg guugcugcag cuuugggugu ggagcgugcc cucugaggaa 18840
aggcugcucu gggggagauu gcccaggaaa cggggcucag aggccacgaa agcagcuguu 18900
aggggcuucu gggagaugug ugcuccuagg auuagggagu ugacucuaag gaugaccuua 18960
gagguuaaca gggaugagaa aggggucacc aaggggucua ccaggggaau gggagaggcu 19020
guauugauag aacagcuucu gcugcagguu ccaaacaaga aaugugggag aaugguugaa 19080
aucagccccg ggggcaccuu cccgugcaug cgugcagcuc cuucaacauu cagucgaccu 19140
ucagugccuc cugugagcca ggcacugggc uagucucugg ggguggagag augagucagg 19200
caaaugccag cccucagagg gcucacaggg cagaagguga gagaugagug agcagaaaau 19260
gaccacagcg cguguggggc ccaguggagg gaaggagggg auucaggagc acaggagagu 19320
caacagggga aacuucuccg aggagaaucu gauccuccuc ccaucuggcc accuucugaa 19380
gcccucucuc cccauccaag ugagaaagga caggcguaug accagauugg uguaugaaga 19440
ugcugaauua cguucucauu guuucaaacu aguaaaccau agauuuuaug uaguaacuuc 19500
uacaaacugc auuacaaaca cuccauucuu uguugcccug gguagaaguu uauuuuagug 19560
agcccaaguu ugaggaaccu uauaugguau gaguacaauu accauuuuaa uaguaagaaa 19620
ucccccuucc ccuguguacc aaccagaagg uguuuuuuuc cuaauuuaaa caaacagaug 19680
cagacguggg cuguccagcu ccuggcggga ugacauaccu caugcaucca guggguuuga 19740
ugaugaggca gacauuucac uuaagugccu gaucaucaga uugaguccug cugggaggaa 19800
gugugaagga aguaauuuca aaccacaguu ucucuguggc uuuuacaaug uggauaugag 19860
aaccaaaauc acuacuucuu aaccccagag caggacugau uuugaauugg uaugcaggcg 19920
guuccuucug caggcuucgg gcugugagaa gucccuaaca gagcaaaucu ggggacaagg 19980
gcucaggaaa gguuggccac ggcccccuag gaaugggggc ucugcaagau cccuggccuu 20040
agaggcugug agagggaaca gggguccauc cccaaguaag ggacacgguc uuugaggaaa 20100
ucccaggcca gggccugaag ggcacuguca ggaacacagg cuguuucagu cuguugagau 20160
ucaccggggc gcugcucacu gugagcacgg acuccucagg ccaauguggc agaagagccc 20220
accuuugaaa gcgagcgggu ggggguggcg gggcuggugc uggugcgugc uucugcacag 20280
ccaccuggga agguaugccg cugguugacc caggcagagg uuuucuuuca uggcaaaccu 20340
gcaguacugc auucucagca gggaggauua augguaaaag accaggcaug gagcccccuu 20400
cccucucccu cgaagcaagc ucuguggucu cucaaucauc uuuaaaacac cuucuucccg 20460
ggagccuccu acauucuccu ggcuucccuc ccacccccac ccucagcucc uggggccuca 20520
gcagccccac ccccaagccu cuaaucuucc cagggaaggg aacaagaaga accacauuuu 20580
aaacgaaauu uauuuuucuu uccucaggcu cccaguucac auuucucccu caggagucua 20640
gggaagcuuc ugucugguau cggccuccuc uucaccuggg cccccgcccu ccucaggugu 20700
accagaagcc agcacacucc cccuuccccc ccagagccac agcagcccug ucuccugggu 20760
ggucuugugu gccaagccug ggcaacauca cucccagcuu uucuuguuuu gccccuucuc 20820
cccagcaaga uauuuguaug uaaggucagg ugagugaguu aaagaauaac gaagagauaa 20880
acagucaaau ggaguccuga cugucagguc aagacaacag uuauuuacug aaugccucau 20940
gucauucaac agacauuuau ugagacucug auuggauguc agucuuuaau gcuggguguc 21000
agagagaggu gacuucaagg gcuugcaucu gugcacccag cauugcuagg uacaaugagg 21060
aguauaauaa aagcaggagc cauagccccc aacucucaag agaucuccca uguguguaug 21120
ucugcauaug cgugcgugug caugugugcg caugugugca ugugugugug caugugugug 21180
caugcgugug ugugugcgug uguuggggau gguguuggug gagugagagu guacaaggcu 21240
guguaugaag ggguaauugg gaaaagaaca auggagcugg cacccaggga caggaggaaa 21300
agcaggaggg cuggguuugg aagacagccg gauuuauguu uuugaagagg gaagacuaga 21360
auauaaggga gcagcccuuc ucagagcccu ccuccucccu ucgggcccug uguccagcuu 21420
uccccaaagu ccuuggaucu uuccuaugca aaggggagug acagugggca ccacucucag 21480
ggaacccauu acugugagag aagccacugu gccacugugu ggucgaacuu caagaccggc 21540
uuccccugcc ccagcugcau ggacaggccu gugggguugg cgcaagaccc uuccagagga 21600
aacuagcugc aacauaaauc cggauauggu gcuguucagg gaaaggcaca accuggggau 21660
gagaagggug gcuguccagc acacaggggc aggccucuug gccacugggg gaggggagaa 21720
uuuggagagg aagaggaugg gaugccgugg aauugggacc aggaaagaau ggggacaugu 21780
gaugguuaaa gcuaguuaga gaagaacugg gagauaaaca gucacccaug ccccugaagc 21840
acucggggug aagagauugg cauuuucacg caccccagug cuuucccuuu guguugaagu 21900
cccuucguag acauccaggc ccauaaggcu cuucucuggc cagagccuca ugaacuauag 21960
cacuagcagg guugaggcca agcauuggcc cuggaagcca gccgaggagg agggugcuug 22020
ugugaaucuc ccaggagggg uaagaauuau auuaauucga ucauaauaag cauuuauuga 22080
gugcuguuuu gaggccuggg agcuaagcac uucacauucc uuaccccgca ucaacaaucc 22140
uaugagguag auguggaaaa ugcagacacg gggacaggcu caaucacuug ccccaagguc 22200
accuuaacug uuagguguuc uuuaugccuc cuuauaaaga aacccugcuu cccacaggug 22260
uugagaggag cuggagggag cuugacuagg gcucaucagg caagccccgg caugugccug 22320
gcucuccucu uucuaccugg agcuuuuccu gcccuuaaug gccccaacuc auuucucuua 22380
guccauguca gugcccugag caucucagcc caagcugaga ugauagaaac acccagaggg 22440
guccucuacc cugugacagc ugcggugugg gaagagcacg ugucuccucc aauccuagac 22500
cagaguuucu cagccucagc aucacugaca cuuggggcua gauaauccuu uguguggggg 22560
agggaggagu gucuugggcc uugcaggaug uuuagcagca ucucuggccu cuacccacca 22620
gcaccucccc aguugugaca cccagaaaug ucuuuagauc uugccaaaua uuuccaggag 22680
gaugaaauuc cccuguuuca guuccccagc cccaccucaa ugagaagcac uguccuagac 22740
caaccccaca aagcaucuga cacccccauc cagcccuggc uaacuuuuuc caccuucuua 22800
cuaaauuggg cccagcugcu ucagcaguca auguguuggg ggcagcccac uggcaagagc 22860
cucaccucua ggggcuccca gagaccccaa gaacagaacc uuccucugag aguugaguua 22920
caaguguuuc caaucgacuc uggcuguuuu ccuuuuuuug acccauuucc ccuucaacac 22980
ccuguucuuu cucuuauuca uauguaggaa gaggaauacg aauaagggau aucuugaaag 23040
augaagaaac acugacacua uuucucauua aaaacaucgg ccugucugac ucaguggucu 23100
accuucugau caacucucaa guccguccag agcagguagg gggaugucac uggccagugg 23160
ucccuggagg ggagggaagc acccagccug agaaaggcaa gaaauauauu ggcuuuuuuc 23220
uucuuucuuc cuuguguuca cauucagaau ccaucacuua augccuugua uuuagaaaaa 23280
aaccggggga ucacuugaga ucgugaucau uuucaacaua ggauucgaag cuguacacau 23340
ccuggugacc uuaaaacauc ucagguuuuu auaacuggaa ggaaccuuag agaucauggg 23400
gcacaaccuu cucuuuauag augaggaaac agaaaucuau ucauuuauua cucaaauauu 23460
uagggacagu uguagguacu agaacacagu gugaaccaga caggcaaaac cccaggccag 23520
ggagcuucca uuccaguggg gccacaggcg augcucaggu aagcagagac uccgcugugu 23580
gacuucuggc ugugaugggu gcugcaagga aaauccggua gagucgaggg uuagagaggg 23640
acggaggggc agguuuaagg gggaugcuca ggaaggccuu ccugaggagg ugguauuuga 23700
gcagaguugu cugucagcca cacaguaagu gagaggggag uuccgggcuu ggaagcugcc 23760
agcacagugc uggcaagugc ugggguggcg ucccgaggcu acagaaccug agaugcugca 23820
gaagagccca cuucugcuuu ccuggaccac uuccuucuca gcaccaggca aacuccuucu 23880
ucuauccccu ggcacauuuc ugaccugugu auacgccccc aauuuaucua accccuuuaa 23940
auaaucuccu cuauuuaugc agagcauucu uaccacuaac ucacgacuug cacaucccuu 24000
agcucccuua cuccucacaa caauccugag augggucaga gaaggaggcu ugcgcgucug 24060
gugauggggu gauuugugca caguuacagg gcuagaaauu gucagagcca gauggaaucc 24120
agguccucuc aauccuaauc caguguuucu uacuucaguc cuguggcucu caaagcccag 24180
agaccagcag caucagcgau gccugggagc uuguuaggaa ugcaaauuau cagggcccac 24240
uccaggugaa cuggguccaa agcccuggga uaaggccuag caaucugugc uucacaagcc 24300
cuccagguga uuccgcaggc ucagguguga gagcugcagc uguccucugg gccuucuggg 24360
cuccccgccc agcuucuuca gugugaugaa cacagcgaga augcuagauc ugcagcagcu 24420
gauaucccag acacccuccc gacucccucc uggcuggguc ugauccuccu ccagacucca 24480
ggagagaacg agacauaaac agaacuucag agccuguguu aacccugaga ucaaggucug 24540
cacagggugc ugucugaguc cagaggagug agggacccca ccccaccugg ucagcaccag 24600
cuccuggaag cagguucuca cacugguucc cugcacaaug aaggagcuca uaccugcuuu 24660
ucuggcuucu cagacccuga gguuuucacc gaaacuagac aaggggaacc uagggucagc 24720
cuggaggcag ggugagcuug gcgccugcag ugcccaggcc cuggguggug cggcuccggc 24780
caggcccugu uuagcuuccu cucccacccc cacagagggg gugcugucgg caccgauugc 24840
ucauuuuccc cuuugcuuuc ucuucagcuc guaaaacuca aguccugaca augccuugau 24900
gacuuccagu ugguaauaaa agggagauga agauaaggac aggaauuucg gggaaauuuc 24960
uuuccaguuc cuuacuaaug ugacauuuag aucucuagua cugugcuucu ggcaucagug 25020
ccaaggccuu ucauguugga gaauggaggc cggggucacc agguugugcc uuuauuucau 25080
guugcuggcu cugaugagcu gaugcucugc ugauuagcaa acgcugagcc aucugcgcuu 25140
cgcagaggca cguuccagcc aacccggccc ucccugccca cuucccagga ugcuuugccu 25200
ugugggcuca ccugucuucu agcuccugau cuguaucucc accuccaucc aguuccgggg 25260
cuccuuauca gcacuguucc cagaacuguc caucacgaug gcaacguucu cucugggcgc 25320
uguccaacau gggagcucgc cucuguguug ucacucaugc ucauugaaca uggauuugug 25380
uccuuuacca ucaggacugg auaccccucc ugguccuuuc ugccuggggu cuuagcacag 25440
cucagaagga accucaccau ucccucucuc caucuaggga auuagaagau gacaggggca 25500
caguucucug gcucaccccc agcccaguaa acuccuggac augcuucaag gcccagcuca 25560
gauguugccu ccucagugaa auaauuuaua aacccacccu ucuuuguccu gccuucuccc 25620
ucuucccuac ucacuggaga guuaacaggu gaugguuaag cucuggguuc aaaucucaca 25680
aggccacaca cuuagcuaug ugacuucagg caaguuaauu aaccacucug ugccucucgu 25740
uuccucauuu guaaaaugga aauaguaaaa gugccuacca gcauggcagu ugaaguuaaa 25800
agaaauaaua uaugugaaca cuuggaaggg cgccugacac auaguaaacu cucaguaaau 25860
acuagcugcu uuuaguggcu auucuuaaca cacccucuuc agugcucugg uuucacuaug 25920
uuuuaugggu cccugagauc gaaagugucc acaccgacuc auggucagcu guaaccugug 25980
ccucgugugg ggaccaggcu gccaugugua gucuggacag uguaggaggu ggcagagcuc 26040
aggccuguuc ugcccuccag cccagagagc cacgucguua gaugucaugg gagacugugg 26100
ugccccggga aucucacgaa uuugcccacg guacucagug ucuguccaau gcuaugggag 26160
uccaggacuc uaggagccag uuaaggugcu ggguggccac aggucccugg ccaaggucca 26220
ggccucuccc cugccaccug auccucgaga ggccaucacg aggguuguac uucaagaacc 26280
acuauccuug agcuaccuag gagcugcaga augugcacuc ugcagggcuu agggccugca 26340
gacaagauag augcagggug ucuaguuaaa uucgaacuuc agauaaacaa caaauaauuu 26400
uuucaaauaa uuguguucua uucggucccu auuugggaca uauuuguacu aaaaaguauu 26460
cauuuaucug aaauucagau ucgacugggc aucuggugcu uuuguuugcu aaauccaaga 26520
gcaaauuugu ucuagcuacu ucucaacccc accuucagag aggaagccuu gaugguacug 26580
uaacaucaug cuguaagaag gggaucccuu gaauuguaaa uggcacucug auaagaugag 26640
guauggggau uguauugguu uccuguugcu gcugucauaa auuaccacaa acuuaguggc 26700
uucaaacaac acagaugcau uaucuuacag uucuggaggu cacaagucug aaaguuaggg 26760
caucagcagg acugcauucc uuacugcgga guucuagaga aaaauccauu uuccugccuc 26820
cuucagccuc cagagacacg ccacauucuu uggcuagugg ucugcuucca ucuccaaggc 26880
cagugggggc uuaucaaguc uuucucacau cacaugacuc uguuucuucu gccucccucu 26940
ucuacauuua agggacccuu gugauuacac aggggcccac cuagaaaagc caaaauaauc 27000
uccuuauuuu aaaaucagcu aaucaguggc uuuaauccca ucugcgaucu uaauuccugu 27060
cgccauguaa cacaagguau ucccagguuc uguggguuag gacgugggug ucuuuccuac 27120
cacagggcag uuucuagugu ugccucuucu cccugcaguu cgcucaugga gucccggacc 27180
uggcgcugaa ggacaucgcc ugcagcgagg cccuccugga gcgcuucauc aucuucagcc 27240
agagacgcgg ggcaaagacg gugcgcuaug cccugugcuc ccucucccag ggcacccuac 27300
aguggauaga agacacucug uaugccaacg uggacuucuu caagcucuuc cgugugguaa 27360
gggagggguu uggcugcucg ccaauugcaa ggugauuccu gggguagcag agccucacga 27420
auugaccuug gggagggcgu gagccuggug uucuggacaa uccuugcaaa agcuccaggc 27480
ucccagggcu caaaaaauca caacugauag uauuucuaga acaguggccc agggacccag 27540
aagucacuau gagguucacc auuagguaug uggcuguggc auguuugugu ccacucuaaa 27600
uguggggaua auccccuuua ccuccucuaa cagaguggua aaggaaggag gaggccuggu 27660
uugacucccu gaccugcuau uuccuagcca ggugaucaug guaagauauu gaaccuuuuc 27720
uggucccagu acucaucuau aaaacaaaua uaauacuuua cagaguggua ggaauuauac 27780
aagaaaagua uacgcaaaac auuucauaaa uuuuaauaaa ugauggcccc augcuucuuc 27840
cucuggaaau ggucucaacc ucaaugguug guguuucuag agagaaaaaa cgacagagaa 27900
aguuucauag ucucaaaaau uuggaaagcc cugaucuagc ucaacccuuu guucuagaac 27960
ugcaucccag acagacugcu ugggaccuga aaauaucucc uccuuugcua gaaggauaag 28020
augagaagga auuagauaaa ggagguguag agcagagguu uucacacugc aaagugcaua 28080
aaaaccauca gagggccggg cgcaguggcu cacgccugua aucccagcac uuugggaggc 28140
cgaggcgggc ggaucaugag gucaggagau agagaccauc cuggcuaaca cggugaaacc 28200
ccgucucuac uaaaaaacac acacacacaa aaauuagcca gguguggugg cgggcgccug 28260
uaaucccagc uacugaggag gcugaggccg gagaauggcg ugaacccggg aggcggagcu 28320
ugcagugagc cgagauugcg ccacugcacu ccagccuggg ugacagagca agacuccguc 28380
ucaauaaaaa caaacaaaca aacaaaccaa aaaaacccau cagagaaguu gguaaaagau 28440
gcaagugcua aauccccacc cccaaucacu gugauucaga agaaccaggc caggcccaga 28500
aucuauccug uuaccuuagg cgauucugau gaagaccauu guaggccaca cuuucagaaa 28560
cacucaaaau uagaauccuu cagagaaggu ggcauauaua auauuucuag cauggaauua 28620
uguuuuuuuu cuuuugccua cauuuuaauu ucuagaacug uguuguaggg aaugucaguc 28680
acuaagaacu ugauugagga acuguguuuu gucuguuuca ugacugcucu cucaaguccc 28740
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caugaaauaa gacaccgcag uuucuggcac gguccacgcu uaauccccuu caauguguga 28860
cuuuccgugg aaaguuacuc uacgauuuuc ccagcucguc aggguggggc cccagaguga 28920
guaugaaggg ucagagccua gggaugccac caucagugag agcccaggac cccagaaaag 28980
gucucuuggc ucaccacacu guaggaaaaa uaaaaagcaa uguaguccaa augucucuau 29040
ccaaaguuuc aaaaagaacu ugauuuuaga cacgcuccuu gacuuguuuu cagaaucaga 29100
cagaagagug aggcaacaaa ggucccuuau uccaggcagc ugaauaccag cacagccagg 29160
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cuggguaccc agguucgugc aauccucucg ucaccaugaa gggagcagca ucauucuucc 29340
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aagaccaagu cuuuccuuac gucuucacau gcugccuugg caaaugcuag cauucacaaa 29580
cccugggcua ccuugaccug ucacccuugc agaccucaga cggguccugg gggcuugcuu 29640
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cagagacaag caaacaggac auuucacagc agugcagccu agaaagggcc aacaccagca 29820
gcauuugucc ccccgagcgg uagcuuuuag aagcuucccc agugauucaa uguguccuac 29880
aaaugccugg cccccacucc cagagauucu gagucagcug gccuagggug cagccuugac 29940
uucacugugu uaaaaagcuu cccagauaag uccaaugucc ggccaagauu gagaaucacu 30000
gaccuagagu uuaauuuacc accucagucu cuauagacca cgcauaauaa uaguacccca 30060
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ccgggagaug gcccagagga gaaagcucug ccguagucgg ccucaguuaa ccacggagca 30240
ccaccccuac cugcucuccu cucacuccug cuuccgucuc gguggagaaa gauccaaccg 30300
aagcaggaca caucuagucu ucuggugccu uuaaaaugua cuuuuccauu ugacaaaugg 30360
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ucaggcaggc agggguugcu ccggggccag ggaaggggcc ccgcugggac gcggcuguua 30600
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aaugaguucu cauuaacaaa gaaagaggga aaaucucagu aaaccaccgu gacggcaucu 30780
acccacuuug agucaggagc ugggggugug agugcaaccu ccgagacaag ggaaccugug 30840
gagcccagag aaucggaggg gggcgcuggg guuagcaccg acugagacca gcuguguuuu 30900
cucucgguuc cuuggagauc agaagugagu guugucaucu ucaaacaauc caaaggcagu 30960
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aauagccccu cuugguuuca ccugaaggag cuugucuuca ccugcggccu uugcaggcuu 31200
aacgccccca gcuugaaacc cagaagcuca gacuugggcc caagguauua uuagugccaa 31260
cacuaccuga aauguuucgc accucauaaa aauggugugu caguuucggg ugagagguug 31320
ggacgcuucc caucugauuu ggcccaaggc augcaugccc cuccuucucc uuccccuccu 31380
ccucccccuc uucccccuac cauccuuccu guuuucucuc caacucuggu gcacagcuuu 31440
gaaaucuugc ugagaagcaa aucugucccu ucugcuuuga auguuuauuu guggaaguuc 31500
ggcaggggaa ccgaggcggg ugccaagacc ugccaugcug cugggaaguc ugagucuccc 31560
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ccaaccacug cucuguuguc auuuuuacuu uucugauugc auuuuauccg ugucucuuug 31740
acuacggggu ggcuggacgu ugaguuccag gaagaaaagg gcccaaucuu gggguucuga 31800
cuacaugcgc ccaucaaugu ccuguuucau ucuuggcucu ggcucccuga auuccugagu 31860
cacuggggag aagcgugggu ggaccgcccc cuacccagug agaguugcca caguugcugc 31920
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gauauugcua cgucaagugu cugggaaagc ccccacagcu acaggauuuu acagugaggu 32040
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aaggguuuug ggaaggggag aagagaaagg agugauuccu gagugccagu accagggaac 32160
agcagggcug uugggaggaa acaaaacuaa aucaggaagg uuuuuguugu uguuuuuggg 32220
ggguuuuaug aaaauauuca agccacagca aauauauuug auuuauagca uuaguauuuu 32280
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gauuucaaca aagaagaaau aaaaaugaaa uagaagagag gccccuucgu gcacauugag 32400
ccuacuggcu ggauugucac uugccugccu ugaugucuuu ucagcuccag gcaggcagua 32460
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caaugugugc accaaugugu gaggcgucag guucucucca gggucaguug guuuuaagaa 32700
agguuuuggc uucugauaug uuuuaucucu acagaacagu agcucuuaac cuuucuuaug 32760
gguuaggauu accuucgaga aucugacuac agcucuagac cuguucccua aagaaaacua 32820
aguucacagg gacacacagg auggggcuca uggagcagcu gaagccagac cccagguuaa 32880
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cucaauauac accgauucuu ccuuaacucu guuuaugaag uauucagcau ccucccugcc 33000
cccuucagca uccucccugc cccugagcac aggauccaau ggcgugagga ccacaggccu 33060
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cugggagacu gcaugucucu gugaccuccu gguagagacc guuugacaug ucccccaacc 33600
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ccuccugguu gcccccucac cacugaagcc cgcuuccucc cuuuucauuu gaugcuuaac 33720
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cacacuucug uccacugcuu caacugcuuu ucaccucugg ucugcaugcc uucaagacug 33900
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gacacauuga accugaggcu acuuauuuac ccuuguguua gguauauccu caacuuagaa 34020
auuaauacug uuuccagauu gucuucuuug aaucacagaa aguaaaacaa caaaacauuc 34080
aaugcuuaag acauuucaug ugcgguuggg ugacaucugu uugaugaaca cauuugaucc 34140
aaagcaucag aaauacuaug ccaacaagac uuuuuaggag gugauaaaca ugucuguucu 34200
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cccaagcaga gaccucuuag ggccggaauc aucuuggcug cugccuagga ccuuauauca 34320
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cagaucccuu cacagccuua ucuuccuuag aggucuaguc ugaccuugaa cuucggcugg 34440
cagugcuguc aguugugaug ugugacaugg aagaguuauu uguuacuugg aaaauuaaga 34500
gaacuuauuu ggcauaggaa auugugugug ugugugugug ugugugugug ugugugugug 34560
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cucaguucca uuccaacuaa acuuacaguc ucuuccgguu cuuugacaga aacaauucau 34680
gugaauuuga acagauaaua gggaaggggg aaccaaaaga agaggagagc ccugggaaag 34740
uuauuuuaua auuuauggca accucaguca ggcaacugug aacagguaca uauggagggc 34800
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accauuccca cuaaaaagag cugggaagga aauuguagcu guagcaccag gcacguaacu 34920
ggagcuuagu aacuauuugg ugaaggaaua uuauuaaauu auuaacaaga uggaaaaaag 34980
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gauagauaca uuaaaaaaua acagcaaacc aaaauaaaag ugguaaauaa augcacugag 35520
aaagacagga auagcuagga ggggcaccua aucccuaggg aaggaaagcu ggaagagcau 35580
ggugaugggg gaagaaggcu uucuggagaa ggugagguag uuugaaauga guugacucug 35640
gccaguaggg guagagugag aaugggguga gacagggugg guuggucauu uugauccauu 35700
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gcccugagcu gcugggaugg aauccagcca cccaugacuc ugaacugaaa uaauugggug 36240
aauaauuauc uuacuuuuua auuaaucuuu gaaaauguau guauaguuca cauguauuuc 36300
aauauuuaau auuagaagua uuuuagucuu uauuuugaag uuuggugauu uauuguaacc 36360
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caccuguagu cccagcuacu uggguggcug aagcaggaga aucacuugaa cccgggaggc 36600
ggagcaguga gcagagaucg ugccacugca cucccaccua ggcgacagug ugacacucca 36660
ucucaaaaaa aaaaaaaaau agaaaagaaa gaaacuuaau ucugguuuau aucaauuagc 36720
cugugguaaa auugguuuca uuauagccau uucacuuagu ugaaguuucc aauaaccugu 36780
ggaugaauua agugaggauu uacuauauuc auaaaaucuu aaauuccaaa gccuguuugc 36840
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auaccagaua aaucauuaaa uaaguuguuc aaagucaaau aauuucauaa guaaaaauua 36960
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cagagugugc cuggggccug cagaaguaaa ggagagggga uggagagaag auuguccaca 37140
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gaagagaaaa uaaucaaaac ugaugggagc uugugacuga uuuacuuaug cgcagccucc 37260
cuggagacau gaguguggcu guuccuuagg uugugccucu gggcuccuac ccccucuuag 37320
augccuuccu auuaucuagg accugguugc uuuuugucug cauagcuucu uuggauucca 37380
gucuuugaug ccagcuuccu ccuaaaguag ccuuucagau gucccuuggu uacccucugc 37440
uaucuaaggg cucauccuac cccacacuca uucccagcac caauuucugg aucuccaggc 37500
uggagauuua gacaauggga ugggaagaac ccaugauggg ucccagacag aaaguggugc 37560
cagccacaga aagggcacac aggcacagaa guugguuugg gguaagacga uguggucagu 37620
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ucuggggaga ggucuagguu ggagguacag auuuagaagu caucaacaaa aagguagcag 37740
auuaaaugau aaaggaaaug agacuauccg gggagugugc agagugagag gagcaaggga 37800
ggcccuuggg aaccucagca cuucagggga agguagaggu acaguugcug gugggaaagg 37860
cagagaagua gcaaagcaaa ccaggcaaaa gcagugucac agacgaccag ggaggaaaag 37920
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gccuccucca gcacauccau guugcaggca gggaccaggc aaagggcaga ggggccuacu 38640
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ccuuguaaaa ccccagaaag ccagcuugcc gcuuccacca uaugaagaca cagagagaag 39120
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agcauagagu cuuacagggg agauagauga caaguaaaca ccagaauaau uaccaauggu 40140
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agaaguccac uguggcagca gagaagcagg agagaaggca agugagggag ccaggcacca 40440
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gagccaugga agauguuuga gcagggaaag cgacaugacu ggauuggccu guuggguaac 40560
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guccuuuuuc uaugccuauu uugaugaaau auucuagaag ggaagugaac aaagguaguc 40680
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auuuuugcau auacacuaaa accuuuuuua uuauuaaaac guuuuauugu aggaaaaaag 40800
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gucucuuuuc aucucuaaua aucucagggg agacaggagg gaggacgggc aggacuuggg 41220
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gugcucaggu caaagagggg agacgcuucu cagugaugug gugucaauag cagcuuaguu 41460
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uauucuagag uuucaggguc aaaaagaaua caaggaccuc ugcaucuaca gccaagagga 41640
gaggggcaaa gacacacagc uacaaaugag aaccuggcug gucaaagccu aacuccaccu 41700
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caaauaaaaa gcagaggcuu uuggucccca gauacuugga ugagaauuac aaguccagcu 41820
gguuaaaagg cacaugccca gugcucacuu cacaccuacu caggaagcac acuugaguug 41880
gaaaaccacu gucuuuacac uuagaacuca guccuacaug acuccucuag gaucagugau 41940
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aaccagaugu ucacaucagu cucuggagcu uggaggcagc acaccugggg acuuccacau 42060
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aacacugcug gcaauuggag aaucugcaag ggaacuucuc cgacuccuac cagcagcugc 42180
uuuaaaauaa aggugaugua gcuggucaaa uccuccauga gagagcagug uugaauggag 42240
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cgguaaaacc ccgauaaaga auacacagca gaggcgagga aaaggcucua agcacugcag 77340
agggccagag caaaacaucu cauggcaagg guggaaagaa gccuaggaaa cugacucucu 77400
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gcacagcccc ugggcucugc cugacagggc aggagagggu cuggccuuua ucccuccagc 78000
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gacugcagua caccaugccu cuggcaagau ccuccuccca caguggaaag ucuaagccaa 78120
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aagaaacagu ggacuuuuuc ccccuaggga aagaaaugcu uagagcuaca guauuaagau 78240
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uuauguuuac aucauguuca uuuuuuuucc uccaagacuc cuucuuugaa cgugagcauc 79080
cagggugggu uccuggggua ugcgugaaga aucugguaaa gauuuuugag cccuguggcc 79140
ggccagcugu ggaccgucug aacaucaccu ucuacgagaa ccagaucacc gcauuccugg 79200
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gcucacugca accuccgccu cccaggauca agcgauucuc ccaccucagc cucccaagua 79800
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cucaggugau cugcccgccu cagcuuccca aagugcuggg auuacaggcg ugagcgaccg 79980
caccaggccg aguccugcua uuuucaagga acauuccuuu uccuaccaau cauuaggcag 80040
gcuucaacau cagcugauga ggguuagugg ucguucugga gaaagugaaa aaagaaucag 80100
ucucuagagg ggcuugugga guaaccgccu gguaacagaa ggucagggca gggaaggcaa 80160
aggggcucug cgcggaucuc ucagcuccgc aggcgcccca cucuccucca agggacccga 80220
gcgccaucug cugagaggag aacacggccc gccaugguuu cccaaggagc agcagacacg 80280
gaccucgcag ggggcagcga acccacguga cacagucuuc aaguccuuug gagagcccca 80340
ggaaggaaca acagcgugua cacccuguga uggaauguuc ucuagggcgg uucaguguga 80400
auggaaugug gggccggugc cauucuaauu gguucuguuu cccucuagug guugaucgcg 80460
gagauuucgg cuucuccauc aggacaaguu cagauagccu gagaugguau cagaacucag 80520
ggacagagcu ggguguggcg gcccugcauc caucugcuuu cucuccaugc uaacugauau 80580
ggucagagag cuggaagcaa auuccaggac cccagggcuc cgcaaaggca aacacauuac 80640
uucaucggcu gcugacaugc aacuuccccc agggguuaaa acaauguuua auacuaacag 80700
uaauaauauu uuugaguuuu acuuuaugcu ggcgcuguuc uaauguugua aguguauuaa 80760
cucauuuaag ccuuacaaca accuaaggac augggaguca uaguucccau uuaaaaaaaa 80820
aaaaaaaaaa agcccaccau ugcucugagg cuuuuuaugu uuuggaucca aagcuaauau 80880
uggugguggu aauucccaug ccuggcuucg aucaauuaau cagcaaaugc cuaggacugc 80940
uuaggguucu ggccuucauc aagaccuuac ccgggcuuua ugaugaugac accuggcuuu 81000
ucaauagcca ugacugcuca cccaggaggc aacgccucga gucaugcacc gaacaccuuu 81060
uauugauccu cuccaacacc aggcuccgug auggcugagc uggggacacc ugugacugca 81120
cgugaacauu uugaggcugg gaaucccaaa ggcccucggc guuggccugg gagcaccaug 81180
aaacaaguag aagcagagaa ggauggcaga gguggcccuc ugcauuaggg ccuggaugua 81240
uacacuggug cuaagggggc cccacagcua auagggguuu gaguuugacu gacagcccca 81300
ggcaggaauc ugugagaguu cucacugaac cugguguggg gguggcccuc cuaaggcaug 81360
uugcuaaagg ccaucucuuc ugccacugac gccuguguuc ugcaggucca uccugacggg 81420
ucuguugcca ccaaccucug ggacugugcu cguuggggga agggacauug aaaccagccu 81480
ggaugcaguc cggcagagcc uuggcaugug uccacagcac aacauccugu uccaccagua 81540
agcgacacag gaacugagac cgccccaucc ccucuccuca ccucugcccc cagcacacuu 81600
cucuagagcc cagcucaggg gugccaggcc ugggcacagg cagagauaca gacucuuauu 81660
ugguuucccc uauguuuaaa guccuuuguc cuacuugcag ugagaauugu cccugagaau 81720
augggacucu gccucugcug cucagagcug agggcuccuc ccucagaagg gugaggcugc 81780
cuucgcucug acagagcagc ugaucgaucc ccgagccccu ugugcagccc ugaaguacuu 81840
ccucucuggg accaaagaca ggagaaccau uguuccuuuu uccuguugaa gccacggccu 81900
gaaaggcaaa cuuuucaggg ggcuuuucag uuacuuuuuu uccccaauaa gauaucuuuu 81960
auuucuuauc uaagaagcua cgcauaguca uugugaaaga aaaaaaagga agggaggaag 82020
gaagggagga aggaaggaag gaaggaagga aggaaagaag ggagggaggg aggggagaag 82080
gaagcgaggg agggagggag gggagaagga agggaacagg agggaggaaa agggaagggg 82140
aaggaggaag gaaagggaag gagggaggaa guaaauauag guaaacaaaa aauugaaaau 82200
aaaagucacc uguaauuuca cuacucagag auaaccgcug aguuauaaca uugguauaua 82260
auuuuuuaga acuuucuccu auacauguau agauagauaa acacauauac uucaaaauga 82320
uaaagaauag uaaaacuaug cauacaauuu uauaaccuga cuuuuuuuuc aaaaaaaagg 82380
auugcuuuuu uaaacauaag auaucaggaa caucuuucau gucauuacau auucuucuau 82440
aaaauaauau uuaauguuua cagauuauuc cauuguaugc augaacuaug uaagccaucc 82500
ucuuauuaga uauuuaagca gggucugcua uuuuuguauu guaucauaaa caccaccaca 82560
gugagcaucu ugauugccaa aucaagaaua cuuguccuca auuauuucug uaagaucagc 82620
ugcuggaagu ggaagugcua agccacugcu uuucucguug ucccauccuc cuagccucac 82680
gguggcugag cacaugcugu ucuaugccca gcugaaagga aagucccagg aggaggccca 82740
gcuggagaug gaagccaugu uggaggacac aggccuccac cacaagcgga augaagaggc 82800
ucaggaccua ucaggugcuc agagcuggau ggagacaggg ccacagaugg caaauccaug 82860
gcuccccagu gcacccagga ggcaggggag gcuuggagca ggagagcuuc uaaggguggg 82920
aacaccucug ugaaguuaca ccaaaaaucu aagagcagcc cccagaucau uuucccugca 82980
gagcacuguc ucacagcagc cuggguuuua uuuguccuga gauugaugug cuugaacagu 83040
cuucaaaggg ucugauccga ggaggugagg guugcccuuu cugcauuuac aaagccugaa 83100
caguauuagg gcuuugaacg cuauaaacau cuaagaggca gcaccaaacc acugcugggu 83160
uaagguaccc ccacaaugcc acuugcccug ggccuuucuc uuccucaccc uccacagccc 83220
cuuaacucuc ccguccuucu ugugccucca gguggcaugc agagaaagcu gucgguugcc 83280
auugccuuug ugggagaugc caagguggug auucuggacg aacccaccuc ugggguggac 83340
ccuuacucga gacgcucaau cugggaucug cuccugaagu aucgcucagg uaacagcugc 83400
ugcucagucu ccugggcugg gcucucacug cagcccuagc uguggucccc acucucucac 83460
cugccauuuu guagcugagu acaggaacca caaugacuac acucagaagg ggguuuauca 83520
gugacuuggu gaaucuaagu uccagcuaaa gccuccugag guuuuuacaa auauaaacag 83580
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cagcugggcu uugcugaccc aggcuagagu gggagguguu gcaggcugga gaacccuccu 111180
augaauugua cagggcuuug uaguuuacag aguauauaca cagcuagcag cccauuugcu 111240
ccucacaaaa ccccaugaag uggucaaggc aggcaucauu aucuccauuu aaaguugagg 111300
cacagagacc aacaaaugga guaucucucu gguccccugg gacucuggcc aguucacaca 111360
caucaccuca gguguaaggg gagugcauua uauccagacg uauuguaggu ggaauggaau 111420
guggaacucc aucacucuga guugucucau uucacacaga ugggcgguca uucccaugau 111480
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uguuggucga gcagagccag gggcaagcau cguacaugua gcagcuguau gcggaugagu 111720
gccacuuucu uccucccuac ccccgacccu gccuccuuuc cuuccuuccu uccucccauc 111780
cuuccuuccu cuuuccuucu ucuccucccu ccucccuccu ucccccgucc cuccuuccuu 111840
ccuuuuucau ugcuuccuuc cuuccuucgu cccuccuucc cuuccucuuu ccuucugccc 111900
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cagaaagguu uucucaggga cuuugggugu uggguuuuac acacacacac aucaauacau 112140
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accccuguuu cccacucaug caguucucuu cuccagaggc aaacucuuac uugaguuucc 112260
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aaauuguaac acucugacau auacuauucc uugggcaagu uaaucuugau gaagagacug 112380
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ccugaccucc cccuguccag agacagaugg ccaaacugaa ucauaaaaag agggggaaaa 112500
aaagaaggca gucgcugcag ggcugucuuu acuccacacu ccacacuccc aguccccacc 112560
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uccccaggcg ccucaaccuu uccucuccuc auuagcucuu cccaguucag agggugggac 112680
cggccagcac aucugcacug cugcccugcc acacccaccu ccaccugccu cugggcccca 112740
cuggggaaca caggacaaau cugugcggag gccccaccau gaaccgccca gacccgugga 112800
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aagccucauc ugucccauga augauaagaa auucagcaug ucagagucag acucuggaaa 112920
ggcgggggga uaagaacaca gccccagcag auggccagag cacccaggug acugaaagug 112980
cugcuuugca gagcuguguu ugccacaggc ucacagccca cuaagucuua agacaguuuu 113040
ccuucagaau aauuaaauag ccagcuuaaa gcaacucaga acauuuuccc cucugaggcu 113100
gcacccauuu agccaacauu ugcuaagcac ccgccuucaa aaaccuggua uuuucaugua 113160
aauuauccga uacacagcug cuauggaaac ccccaguauc ccacaggaag cuccccagcu 113220
cccagcagcu gccggcccgu gugagaucag gaggucuuua ccagcugaac accacgugcc 113280
gggugugugc ugauauaaac aagcguggcc cacucguccu gcccuccaga ggcucccguu 113340
ccagucggaa aaggaccugc ccacgaaguu ugcaacgaua uaagccacag uguaugaucc 113400
uccauaauac agcgugugac agagcagcag aggagcgagg cagauaacau gcugcaggcc 113460
agaggcagcg ggaagagcca ggcugcaggg gcugggggag ccguggugga ggaaguucaa 113520
uuucagccug uagauuucua uuagcccauu uaauaaauaa ugaagugccu acucugagcu 113580
aaucauugug cagguauuua ggaaggacaa aaaaauaauu aggacucagu gcccacccuc 113640
caggggccca cugacuagua gagaaaguag gcagauuuuu aaaaaauuaa ucaugggaau 113700
gugauaagug cugggagaga ggaauggaua cuuucucaug ggaaucuugg aaggcuugua 113760
agggaaggca cucucugagc cagcugucua aagaagaaca ggaaucuuua agaaagcaga 113820
agggaaaaga gcauucuuuc cugcuuggag caauagguaa cagccugcac augcccaggc 113880
cuagaggcca aagagcacag ugauuccaga aagagugggg agaaagggua ggcagggaag 113940
gaugagguaa ugugggcgca gguguggagg cuggagaggg aggagguugu gggacuggga 114000
ggagccagau ggaauggaca gcaguggccc agccaggagc uaugcuggcc ucguacgccu 114060
cgaugucccu ucuauuuucu caggggaggc ucugcccaac augccaaguc cgaccacuug 114120
aaaacaaguc ccuggcuuaa cacagacccc agagagaguc uccaacccuc cucucccuag 114180
acaaugguag uugcccugug aggggcugaa aagcagagcu ggagauggcu cagggccugg 114240
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uaaguggaca gcaggagggc ugcagcuucu cugcacauuc cugcugucac ccccagaguc 114360
accuagggga gggguaagga caguaaugca gguuccucac aguuagccuc ggugcccaca 114420
ugguacugag cauaguaaau guuuagaaga ugcugccugg cuagacaaag gggaagcucc 114480
cgcccacuag aaacuugcag ggagccccag uccuugauug gucauuuaau ugauuagcuc 114540
cuuggccugg ccuugaggca cugcuuguaa guacuucaug accuccauug caaacccaug 114600
augcucugcu ggacaaaucc cuccaguggc cagucuggcu gcaaggacuc ucugucugca 114660
ggccuugccc ugugcugucc ugugagagca ucugggcccc accugcugaa gagagggggg 114720
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uugaccuugc acugagccag gcugugacag augucuaugc ccgguuuggu gggugguagc 114900
cgaggcccau ggagcauggg cccugggucc aaagcuggga ggguuaccgg gggggcuccu 114960
gcaucagacu guggcagggg cuggugcuag gaggggaccu uguugggcug gagguguccu 115020
gccagcugga gaggauuagg gugccucugu uuccauggcu ggggagccac aggagggaug 115080
gagggcagcc cuuaugaggc ggguguuugg cucuugcuca guucccacau aaggccuggu 115140
cuagugggcc cugugcugug gccaggucug uggggugagc uggggcggcu gaaguggacu 115200
caauuccugu ugaugcccag gugaggagca cucugcaaau ccguuccacu gggaccugau 115260
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gcagcucagg gcauccagaa cuggaccuua uacccacaug gucauuucuu uccucaggag 115440
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aauguguauu uugauuagau gauaguauug caaauaacaa ugguuacagg guauccaaag 115680
uacuaggaaa uagacuaaug uauuuaugag agaaaggaca cagcaggccc cuuugcuaau 115740
uagagauuug ggagcauggg aguaauaugg gagccaugug gaggggugcg ggcagugauc 115800
acgacccccc acuccuggag gaaggugggu agcugccaac ccugacuuuu gaccagggcu 115860
ucucaaaugc cagguuagcu ggcaauugcc auucuuccgc aggcucuucc ugaagcuggg 115920
ugggccccug ccucacuccc cucugcaauc caguccuacc uuuauugucc ucacccaggg 115980
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ggacugugag aggugaauga gaucacaggu gucaacacac gccugaugaa acaggauaca 116220
caagcaguuc uaguuauggg agacaguguc aggaauuguu guccuuggca cccucagccc 116280
cugcagaccc uuucugcagc cuuggccaua ccuuuuagag gcuuuugugu gggagagagc 116340
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gauuccauuu gguggggcag gaggaggaga acauugaggg acuggaaaca caugcggagg 116580
cugggagacg ggaaugacca auaggacugg gaaccagggg gagaugccaa uugcugacag 116640
aggaguuagu gcaagaggua agugagaagg guaggugggg cuggauugca gggcuguaac 116700
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cugaguucau cuucagcaca auccuaugag acagguauug uuacccuccu ccucaucaca 117000
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ggacuggaac ccaaggcuga cucuggacau gagcaccuga ccucucuacc uaaugccuaa 117120
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gaagcagaag caaggaagug gaagagaggu cccauggaaa ggacagugcc aaggacacug 117240
uacagccagc ccaauccuga ccccuuuucu ucaucuagga uugccgagcc cacuaaggag 117300
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aauaaaacug acaucuuaag gcuacaugaa cuaaccaagg uaagggaaug gguaugaguu 117420
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cacugacaca gggccucagu gagaaucacu ccagcugagc aucauucccu uuucuguguu 117660
cuguuucugc agagcauggg ucagccucga gaugucucag uacucaccac accucugugc 117720
cugcccaugu caauauguaa ccuccuagug cugguaguuu ucuccuaaac cauccuuugc 117780
ucuuuguucc cucuuccccu ccuugcucuc acccugucuc aguucucagu ccgguuucuu 117840
cguaucuugc agauuuaucc aggcaccucc agcccagcag uggacaggcu gugugucgga 117900
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ucuugugccu gccucuccuc cccauaaggc agagcuauuc aauaggaaca uaaugccaua 118020
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aauagguaaa auuaauuuca uuaguauuuu uuauuuuacu caauauaacc aaaauauuau 118140
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uuaagucuuu gaaucuuuac acucagggcc cgugucaacu gggacuuaga uguguuucaa 118260
gugcuuagua gccacauaug gcucguggcc ucugauggca gcccaggucu aaaauuccuc 118320
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ggccaggcua gcucuguguu uucuccuagu gcuuuggccu ccugggagug aauggugccg 118440
gcaaaacaac cacauucaag augcucacug gggacaccac agugaccuca ggggaugcca 118500
ccguagcagg caagagguga guauccugcu ccuccugucu cagggagucu cucacagguc 118560
cugugagaag aauaggaagg gugaucauca gacccuauag uaggguggcu cugaggcccu 118620
gaaagaucug uacagagaag gaggccuccc agagagcaug gcccaaaaag cccaacacau 118680
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accuuuuaag caucugauga auauuuguag ccuauuccua uaaaaaugca ccauugcuuc 118860
ccauuaccuc ccuccacaca uuuuuacaaa acguuucagg gaguuuacug agccccaggu 118920
cacauuuaug auccugcagg agcucuugaa ucccagguua agaaccccug ugaugaauga 118980
agaauccuuc cucuggguug aguuucuaga uaggggcuca ugcaugggcc uuugggguag 119040
ccuaaccugc auuggcuauu uguaggcuga uauuuggcuu ugccagacca aggagcauag 119100
agggaaaacu ggcgugugcc cuuggauucu ggagggugac ugcugcucuc uguaauaaaa 119160
uguguuuaaa cagacugguc cccuaugggc aggacagaga ggaugagcuc ucacucaucu 119220
gccucuuucc uggcugcagg aaaagcuuga acaguaaaac uucagcacac acaauagagg 119280
ugcccagagg aagccucugc ccugguuuau aaguggaguu aggugcugcu gacaucuguc 119340
cagcaucugc uugacugggg ccucuuccuc ucuccugaaa gccauccuca gcauggccca 119400
augcccagug ggcaggacga guccugagca cgcuucacug gcucagacag gaugaauuug 119460
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agccagguca uggcugaguc caucucaaca gauccagcuu caccugcaag ugaccacgca 119580
ggugacuucc ucauggugac aaaaggaguc auggcagggu agagauauca uaccauggca 119640
ggggaaagau aucauagaau uuuccaugag cacauuuaug agacaucaag uuacaacugu 119700
guccaaguga ggcacagucu gacauccaga agguaaaacu gagcuggacg cuagaaagaa 119760
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aacguacccu acuugcuucc cugaguaguu uuaauuggcc cagccaugcc uuugguggcu 119880
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uucauagacc cuaagcuaua agaagaaaag gaugagauua gacuaaaugu cuauguauag 120000
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ucugacuggc uccucuuuca uugcuaucuu ugccaauaaa uacagauaga gaaguuuacu 120180
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aucaugaauc auuuucuuaa accugaucuu cccucuguuu uuaaacucac augugaggug 120300
aucugaucca aaaugaaagc ugacuuuugg cguaacaggg auucaauuaa uccuagacau 120360
ggaaacaugg aagaaucuga caggauucag uuucuaaccg aagggccccu guuuugauuc 120420
ccaaauaucc caugcauuuc ugaagccaaa uaggagaaga gaagaagcag cuuccuuuuc 120480
ccguuggcag aagcuucucc agcccuagcu cuauggucau cccuccacuc cuugaaggau 120540
acucaguaau ugcuuuuuuu cuugcaguau uuuaaccaau auuucugaag uccaucaaaa 120600
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uuaccuuuau gcccggcuuc gagguguacc agcagaagaa aucgaaaagg ugaaaaaugu 120720
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cuuggagaug agaaacugaa gcgugcuauu cauucauuca uuccaacaaa uguuuacuau 120840
gugucuacug ugugccaagu acuguucuag aaaccaggag uauagcagug aacaagacag 120900
acaaaaaaaa auccccacuc ucauaucuaa caaaauguug uaugcauuua uccucugacu 120960
cagcaaucac acgucuaaga guuuauccug aagaugcauc ucccacagug caaaaugaau 121020
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agucauugua gauuggcuga auaauuuaug guacagacac acaauaaagu cuuacgcaac 121140
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aaggauaaac cagaaaacaa ugaauuuggu gaucaacaag aagaaaaugg gaagaaagaa 121380
aaaugggagg aaacaguacu ucuggggaua uauuuuugua uaguuuuaau uuuuggaagc 121440
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aacaaaaaga aaaccuaaca cugacagcaa acuaaauaaa guaacccaau uuuauuucaa 121560
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uuuagaugug uuacaggauu aaauaaauua auaaauguuu ugauguuauu gggacccaga 121800
auucucaccg uggaagaagg gacuuacaaa uauggaaaag ggaaaagcaa gaaagaacug 121860
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ccaugagcac acuuagcacu caggcuuuug ucuuaauaac auuccccacu aaaaguaacc 122100
cugauuccuc caauaaauga uaaguuccag ggcuggaaug gcauagguau aaaaugaacc 122160
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gcccaggagu uccagauuag ccugugcaac auagggagac ccugucucua caaaaaauua 122340
gcaaacaaau uagcugggcc ugguggugca cgccuauagu cccagcuacu cagguggcug 122400
aggugggagg aaugcuugag cccaggaggu ugaggcugca gugagcugug aucaagccac 122460
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aauuuuacaa uggagaaauu agacagcacc uuaacugggu gaucaaaauu aaccauaagg 122640
ggcagaugga caucucaugc cccgagaugu gauacccugu gaaggacaca auuucacuua 122700
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agagucauaa aagacaaaga aagagcuaug gaaauaucuc ugaucgcagg aggcuaaaca 122880
ggcauaauga cugaauagca gacaauagac uacaucuugu gcagaagaga aaaaaaauga 122940
uagaaggaua uuauuggacc aacugacaaa acugaacuau gaacaguaga uuagguaaau 123000
guaucauaac auuaaguuua cugacauuga uaauguacug ugguuaugua agagaagauc 123060
ucuauucuua ggaaauaugc ccugaaguau uuaggaguga agggcuguga ugaguaauuu 123120
acccucaaau gggucacaaa aaauugugug ugagagagag aaggguuuua uuaguuaaua 123180
auucuaugaa cuauuuuuau uccuauaugu uugugugagu uugaaacuau uuccaaauaa 123240
aaaguuaaaa auggagauua cauucuagug ggagggauag acgaucugua gauaaauagg 123300
uaaaauaucc aguacauuag agagugaaaa guccucaggg aaaaguaacg cagggaggaa 123360
cugcuggggc aggguuugca uuuugaggua ggguggccca gggagagccu gcagaggaga 123420
gaaccugaau gaagaacuag aggugagaga aggagccacg ugcacaccua gggaggaaca 123480
uuccaggcac gggggacuag uauagaaggc agaagcaugg ugagcuuguc uccaguggcu 123540
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acagcacugu cacgaucugc caguauucug uuuauuuuga cugccaccuc cccgcagucu 123660
gaggauagca gcaauggcug uguucacauu guucuccagu gccugguuca gugccuggcg 123720
uauggucagu gcuccauagg uaugugucgg augcacaagg cuuugggugu aacccucuug 123780
acggguggga ucaacagguc ugggacucac caucuucuca aacagagccu uccuccucca 123840
cugcuagcca ugguccagga cgcugggcga gacccacugu cuugcucuuu guaaggcuga 123900
aguccauuuc ccaggcggcu acacccaaca gaugcugagc aggcugggcc acccugggau 123960
ccaagacaca gagagaaaga gccccugucu ggcgccugaa gcacaugcca gaggacagga 124020
gccagcagga gccuguuuca gccuagcugg ggauuucauu cuggaggcgu gagaucuggg 124080
agcccaaggc uuugaacugg gggagguuug ggguguuugc uugucuucuc caaauggcau 124140
uucuuucucu ucccuagguu gcaaacugga guauuaagag ccugggccug acugucuacg 124200
ccgacugccu ggcuggcacg uacagugggg gcaacaagcg gaaacucucc acagccaucg 124260
cacucauugg cugcccaccg cuggugcugc ugguaacugc gggcuugggc cgcaccaagg 124320
gcuuaaacca agugcugggu cucuuggguu ggggaaauag guucuggguc ggcagauuua 124380
gaaacugcag caguuuggcu uuagucugga cuguuuccug uguugcucau uuugagcgau 124440
cagcccagug uuugguucac acagcuccgg agaaaaacaa gucacggcac agccuugacu 124500
ugggacugcg cacauccugc guucccagga ugucuccugu ggggccaucg gcucacagcc 124560
gggaaguuca gcccacucug cggccugucg gugucugguc cccauacagg agcacugagc 124620
ugggucaaag gcuccugagc ugagccaggc caggccugag gccaugccca cgcagcccaa 124680
ggaucaugag ggcacaggac auagcgggaa ccaaggaagu gaccugagug accucccugc 124740
cuucugacaa auguauuugc aggauuuucu uuuuuugagg agaauucugu cauugccuua 124800
auccacuuua auccccucgu gggcugaaau gggcccagga uggacgccac gcuucuuuac 124860
ucuuggaucc accuccugcc uucccuaccc uacaccaggg uaccccuguc uugcucaagu 124920
gaggggagug acugugugcg ccuucuguca gcucauccuc cacaggggag ccagcccagg 124980
gggaagcagu aaucagaagg gccagcuccc agccugugcc cccaaccuuc ucuccacccc 125040
ccaggaugag cccaccacag ggauggaccc ccaggcacgc cgcaugcugu ggaacgucau 125100
cgugagcauc aucagagaag ggagggcugu gguccucaca ucccacaggc aagagauucc 125160
cagggcuggg gaaggugggu gggaauccuc uccugcucac cuccucucuc cugccccaca 125220
gcauggaaga augugaggca cuguguaccc ggcuggccau caugguaaag ggcgccuuuc 125280
gauguauggg caccauucag caucucaagu ccaaguaagc agaugguggg gcgugccccu 125340
uguugccuuc uguggaucca ccuggauccu guguucucca uugacacuug gaagaguccu 125400
gcugcuccgu cauccccugg ggcagaggca ggugguggcu gggccucauu cuccagcagc 125460
agauggagaa ggccaucaug cugauaagaa acuccucuau auuggccuaa uuuccugugg 125520
ucgaagacuc gcccaagucu cuggaugggg caucugauca ggaugcaugc agagccuggc 125580
ugggaugagg gagggcugcu accacugccu caauauuuca ccacuuaucu caacagaucc 125640
gggaccugug gccuauuuac uaagagucca cuccaaugua ggaaugguua ggagaccaac 125700
ugacuugagg acccaucuuu guuuuuagaa uauuguaugc uuuugaguuu gaaaaaagac 125760
cauauguuau augacaaacc aacaauggca guaaucuuga auaggauuau ccuuauccug 125820
uacccacaca uuguaaacua uuguagauaa uuccuuauua uuaagaguuu gcaugccaaa 125880
gcuaacaguu uaagauuauc agcauauugc cgugcucauu cacguucuga uaugcuuuau 125940
aaccuagaaa agagcagagu uacaauuacu cauuuauuua acaaacacuu auuaagagcu 126000
cagaauauaa gucacuaagc ugguuggugg gaggaacagc acauaaccca ccuuaucuau 126060
gcugaggugc auaauccuga ugcacccaca ggaggguguu acacagaaga ugucauccuu 126120
ucauaugugu cagagcagau aaauaauuga gagaaagguc uaauagauua gcugcuugug 126180
gcaaguggac guuugaccca ugauuuauug agcaacuaca acuuggacac ugcauagaua 126240
ucuauagaaa uagcagcaug ucaggucacc agaccugugu cagcaacuuc cuguguccaa 126300
cugcuggaga aagggaaguc uccuauuccu uucccuccag cuccuuaaua ucuccaugau 126360
agagggggug agaggggagu guucccugug uggagggaug gugaguuuuc uggagcugaa 126420
agguaaacag ccuuucuccu cugcaucuua cugcagagga gaacagcccu agacugugga 126480
ggaagcuuug gagucaguua ugacugacac aggauaccag ggcauagggu acugacaccc 126540
gcuagccgug cacacacucu cugguggacc aucacucauc caagagaggg uaaccagcca 126600
uccugcugaa ggagaaagaa agcaccaaug gcccaagccc uagcagcucc auuguuucag 126660
gaagcuuccu cagggaagug cugccuuccc gagccuuugc ucccaccugg cccaucagcc 126720
cuuaccacca cucaguaugc acugguccac gugucuuuau gggcagucuu gggaucccca 126780
cacugggcua aaacuaccuu ugacggccag gugcaguggc uuacaccugu aauccuauca 126840
cuuugggaag cugaggcagg uggaucacuu gaggucagga guucgagacc agccuggcca 126900
acacggugaa acccugucuc uacuaaaaau acaaaaauua gaugggcaug gugguaugca 126960
ccuguaaucc caccuacucg ggaaacugag gcacaagaau ugcuugaacu cagaaggcag 127020
agguugcagu gaaucgagau cacaccacug cacuccagcc ugggugaaac agcaagacuc 127080
ugucucaaaa aauaaaauag gcugggcgug guggcucaug ccuguaaucc cagcacuuug 127140
ggaggccaag gcgggcggau cacuugaggu caggaguuua agaccagccu ggccaacaua 127200
gugaaacccu gucucuacua aaaauacaaa aaaaaaaaaa aaaauuagcc gaguguggug 127260
gcaggugccu guaguuccag ccucucagga gacugaggca ggagaauugc uugaacccag 127320
gaggcggagg uugcagugag ccaagaucau gccacuguac uccagccugg gcaacgguga 127380
gacugucuca aauaaaauaa aauaaaauaa aauaaaauaa aauaaaauaa aauaaauaaa 127440
auaaaauaaa uaaaacuacc uuugacuuca gcaaguacga uuaucccaca uuaccaugca 127500
gacauuugau cucuaaaaac ugguaucaaa ugauuucucc agggacuacc augguuuuuc 127560
ucuccuaguu uucaguaugu acacaggucu augguauggg ccuuuaaucc ccaguauuuc 127620
uuuuuuuguu guucuuguuu ggguuuguuu cuuguuuuuc gguuuuuuug agacaggguc 127680
ucacucuguc acccaggcug gagugcagug gcaugaucau ggcucacugu agccuugacc 127740
uccuaugcuc aagugauccu cccgccucag ccucccaagu agcugggacc acaggcaugu 127800
gccaccaugc ccugcuaauu uucguagaga cagggucuuu cuuguugccc aggcuuaucu 127860
uacauuccug agcucaagug auccucccac cucuaccucc caaauugcug ggauuucagg 127920
ugugagccac caagcugagc uuaaucccca aaauuucuga ugagucuacu ccuuauuuug 127980
ggauuaccuu aggcccaacc acuaacagag gccuguccug cacugugugc auccccuaga 128040
uuuggagaug gcuauaucgu cacaaugaag aucaaauccc cgaaggacga ccugcuuccu 128100
gaccugaacc cuguggagca guucuuccag gggaacuucc caggcagugu gcagagggag 128160
aggcacuaca acaugcucca guuccagguc uccuccuccu cccuggcgag gaucuuccag 128220
cuccuccucu cccacaagga cagccugcuc aucgaggagu acucagucac acagaccaca 128280
cuggaccagg caaguuggcc cuggggcacc gagagcugag caaagacugg uccagaacac 128340
ccaguguggg uuggaauugc cauaagaggg aggcauaaca uucccgauuu uuaacaaacu 128400
cuugcccucu guuuauuggg guaaaagcug auauaucaga aauuguuuuc uaacaauauu 128460
uuuuagucau caggaaacuu cauugauucu uuuuuuuaca uuuuccuucc cugugaugcu 128520
augguguguu auuucauucu ugcucguuug uggugguggu uuuuccuuca aaucagcuuu 128580
auugaugugu aauuaacaua cgaugaaaca cagguucuuu gggaggccaa ggcaggagga 128640
ucacuugagc ccaggaguuu aagacaggcc cauguaacaa agugagacuu ugucucuaca 128700
gaaaaaaaaa aaaaaaauca gaaaauuagc caggcguggu ggugcaugcc ugugguccca 128760
ucuacauggg agguugagga aggaagauug cuggagccca ggaggucaag gcugcaauga 128820
gcuguguuca uaccacugca cucuagucug ggugacagag caagccccug ucucaaaaaa 128880
gcaaaacaaa acaaaaacac cuauuuuaaa uguacaguuu agugaguuuu gauaaacgug 128940
cauuccaugu gugguuuuua aaaauguaau cacauuuuuu auugcgguaa aauauaauaa 129000
cauaaaauug accaugccaa ccauguuuaa gugcacagug caguggcacu aaguacauuu 129060
acauuguugu gcaaccguua ccaccauccc cgauagaacu cuuucaucuu gcuucaguga 129120
aaaucugugc ccauuaaaca cuaacucacc acuuacugcc ccccucgccc uuggcaacua 129180
cuguucuacu uucugucucu aaggcucuga cuacuauaga uaccucauau aaguggaauc 129240
auacaguguu uguccuuuug ugucuggcuu auuaugcgag gacuuagcau aauguccuca 129300
agguucaucc guguuguauc augugccaga auuuccuucc uuuuucaggc cgaauaauau 129360
uccuuuguac guauaugugc uacauuuugu ucauccaucu auucauucau ugauagacau 129420
uuggguuguu ucuggguuuu guguuuuuau auauguuuuu uuaaaaauaa acaucuuuag 129480
agacaguuca guaaagcagu ggaaacaggg aagucuccau uuaaccccug aggaucuggc 129540
ucaccugcac cuucucauca gcauuaagca gagggaggca cgagcaggag ccaccugcac 129600
acucaaugag gagcugaaca gggaucaauu accuuuuuuu uuaguuauua ggaugcugcu 129660
agcugagaau cugccuugcc uugauuaccc caaugucugg ugcccaaguc ccuugagucc 129720
uccagcagga acuccugugg caucacucag gagucuaguc uaagaagcua gcucugacca 129780
gggcaguggu ggccaggcuu cugugagugg gccagccucc cccggguagg acacaagcca 129840
uaccagcagg gcuguaugug aacuguggaa aauagagagc aaagugggua ggugggugua 129900
gggugcuguu uuccuggaaa uaucuaccua aucucgcucu ucucuuaccu cuagguguuu 129960
guaaauuuug cuaaacagca gacugaaagu caugaccucc cucugcaccc ucgagcugcu 130020
ggagccaguc gacaagccca gguaccccug cugcuuaugc aguccacagc uugaggcagu 130080
uccuuggcuc agagcccagc ugguucacug ggcuugaguu gcuccaaggc ucagauaugc 130140
cuccuacaga gagccccacc cacaccacgg ucccuaccaa guccccacca cauccucauc 130200
acauccuugc uaagucccug ccacugugug uucugugcug aagaacuuuu cauucaguag 130260
uuguaggggu uccuauugua aucaggaaac caucuggaua gcaugggaga gcauuuuuga 130320
aaagaacuuu cccauguuuu ugcuuacagc aaaaaagcuu ggauuugggg aauaaggagc 130380
agagaaggua auagagaaua uuagaauguu uugggugcuu gacaucuaug ucuggacaug 130440
uguuugaguu ucaagggaag ggacuuaacu ggcacaucau uucaguguca gacacauuug 130500
guuagaucaa ggaauagcau cuguuguagg aagagggcuc uuuguucuuu auaaaaauua 130560
caagaagaug gagaaagaag caauaggagg uaugucuccu ggcuugugau aacucuugga 130620
auaggugcuu guagguuccu gcccuggcac agugccccau guaaggagca caccacccaa 130680
gaaggagaga gcuagagcaa guacuggagg aggcaccagc aucccaaugc cuuggcuuaa 130740
gccugggauu guagagggau gaauuagcca cucucuucug acuuaccugg agaguaaauc 130800
aaaucaaauc aagaagcaag gauaugcaaa aaccuuauuu ccccauaaag uuuuuauucu 130860
gcccaguuuc uggauugcaa gaaaaaccaa auacagcuaa ugauugaaac acugcugucu 130920
aaagcagugc uugugaugaa uuuuuucccu uccucuugac cagcagagac cuaauggcua 130980
cuuggcaaaa cugacuuugu cuucccaccc cuuaccugcc agagggccca gaaaugccua 131040
aggcuccuuu aguuacagaa aguuugcuuu uacugagauc uuccagccac ugauucccau 131100
uuauagaucu ggugauugcu guugacauca guugaaaauu auuuuuaaaa accacuugca 131160
guugcaaauc cuuuuuauaa cucuguaacu cagaauauag aauuggguag caaaauuguu 131220
ucccagaauu accaaugguc uccccacccc ugccuggcau guucccucuu aaaggacuaa 131280
ucccaccaca ucaccucugg gccaggcaga acaucagggg ugcugauguu cugugaucua 131340
cagcaguuaa uuccaaacuu uucucccuua uuggaugaga ucauuuuucu auuguguuuu 131400
uuacauuuuu guucacaaag auuagaaaac cugcaacaca cuuauuggca uauuuuucug 131460
auaauuuuca uccaaaaccu aauucugacu uuacaacaua cuaucuuuac aaagguuugc 131520
aaaaauucuu ucauauagca uuguauaugu cugucaugaa auaauaguaa guauauuauu 131580
guuuacauua uaccacuuca aaauaauuuc cuuuaaagua uucuucaaac aagaaaaagg 131640
caauuucucu caagaaguuu uagagagaau uuacaacuug cuccuaagca aaugugagaa 131700
cuucaggagg uucaucuggc cauuggcuuu acaacuccaa auugugagcc aggaccacac 131760
agauauuucu cuagaaauca gcguuugcuu accaagaaca uuuuuacucu ccaaaggacu 131820
ccauccugga aaacauguuu ugggauaagg ucuuaugcaa ucuuauacuc uguuauuaaa 131880
accagugagg gucaaggugu uaauagauua aguagugaca gaugaucaga caacuuagaa 131940
acauccuaaa uagguuaaua auuaugugac caucgcaugu gcauucccaa auuaggaaca 132000
acucagauca auuucuaauc cuuauucuua cacuguucca guucccccau auaacucgua 132060
ucuuuguguu aguuucagaa guuucugaag uacccucagc cuugaugggg auccucgcac 132120
caccucaaau ccuguucuca gcccuaagaa cuguguuagu cauccucuua agaggaugug 132180
ugauuuuaaa ucagauaaug ggauaaacca cauuucgucu agacugguca ggccuuuguc 132240
caguccccuc cucgcccaca cuaccccagc uccacagcgg gcauugguuc aggaauucaa 132300
cccacacuuu auaacuggag acaguaucuc uccaguuaaa aaggucaccu ugguguccgc 132360
uucucaagga acauggacau cuuuauuaau caaagcccaa gcuuugaucu ggagccuaau 132420
auccugcacu ccagcucuca ucucuccccu cccccaguca cacuuucaug cuucccagag 132480
ccaccccuac aggaaguggu caagggaauu cuauaccuca gggcugaccu aaauuaggau 132540
uucuuggcuu uuaagauaau gguaacuuuc uuaagcuaaa aaagccccaa aagacccugu 132600
aagagcccuu ggaaacagca ccaugggugu agcuuccccc caggauguaa gcauguaugc 132660
acacaucucg uauguguguc uuuguaacaa augccuggau cuuaguacca gggagaccug 132720
auucauagau uucauagaga aggagagaaa gauggcccau aaccugggug aucugacaga 132780
aucacagugc ccucagcuga gugcccuuca gaaauugauu gacaacuguu uagcuuuuga 132840
aaucuaaaag uaguacagca ucucagaaaa ccaagaugac gcgaguccau gugaucuccu 132900
uccacaggac ugaucuuuca caccgcucgu uccugcagcc agaaaggaac ucugggcagc 132960
uggaggcgca ggagccugug cccauauggu cauccaaaug gacuggccag cguaaaugac 133020
cccacugcag cagaaaacaa acacacgagg agcaugcagc gaauucagaa agaggucuuu 133080
cagaaggaaa ccgaaacuga cuugcucacc uggaacaccu gauggugaaa ccaaacaaau 133140
acaaaauccu ucuccagacc ccagaacuag aaaccccggg ccaucccacu agcagcuuug 133200
gccuccauau ugcucucauu ucaagcagau cugcuuuucu gcauguuugu cugugugucu 133260
gcguugugug ugauuuucau ggaaaaauaa aaugcaaaug cacucaucac aaacuauccu 133320
aauucacagu cucccuggug ugcaccaccu aguauaguuu uagacauucu uuagaugggu 133380
gcauagcucc uugucagucc caugcacuuc ugugaguguu acugccucag gacugcucgu 133440
ucuggcaaga uucugcaaca cuagguugga agugaaugga cuagucuuaa uguuccaugu 133500
caagucuuug uagaguuuga agaaaacacc caacuaguaa ugccuguaaa cauuauccau 133560
ugucagcugg guauuacuga cuuuaaguuu cgugucuguu ugcccagcuu auuugagugu 133620
uuaccucaca aguguaauua ggacaggaga caaagaggca ugcacaggcg agaguugguc 133680
cuugguugga cgugagaccc gacaggacuu uguaaccauu ugaagagguc aggaccucau 133740
ucucaugcug cugugccuuu ucugcagugc uaccaugugc aucuucugca gugguguuag 133800
aagggaauga aggccgggcg caguagcuca cgccuguaau cccagcacuu ugggagccug 133860
aggugggcag aucacaagau cagaagauca agaccauccu gacuaacaca gugagacccc 133920
gugucuacua aaacuaugaa aaauuagcug agcauggugg cacaugccug uagucccagc 133980
uacucaggag gcugaggcag gagaaucgcu ugaacccagg aggcagaggu ugcagugagc 134040
ugagauugug ccacugcaca ccagccuggc gacagagcaa gacuccaucu aaaaauaaau 134100
aaauaaauaa aaaggaauga agauggacau cuaguucaca uaaaugcuca ucaagauuca 134160
gaaaauaaua auuuuaaacc aaacauuucc agagacugug gaugaggaga acaagugggu 134220
uuccuuguca gggcagucuc cccuccauga ccuagagaug ggcuucgucg uaaacaugcu 134280
uucauuauac ugaggauaga cuccagaguc ggggugaggc aagaggaaaa ggggagagau 134340
gcugaggccc aggaacuguu gcugagaaga ggaugagaaa gaaagugagc acaaggugcu 134400
aaaauuuuug uuucagcugu gcuuguuuag aggcagacag agggcaaggg cuacacaacu 134460
uuaaguccug cacaccuccu ggcuugccac uuugcaccuu cuagaugcua ggcaaacaac 134520
ugcccauaga gacuauaaaa cuacuuuggu aaccccgcag cuucaucugg uguugacuuu 134580
uucuuuuaag uuaccaagga ccaaaacugu aagaccauuu uagcuagggc uaggauagag 134640
guugggaaag cccagcacac ugcuugcauc acacugcugc acccuggcug guuucauaau 134700
uuaaauuagc aacugcaaua ucacaggaaa gaagacuaca cucuucgggg cugcuuagga 134760
aaagaaaacu aaaaaaagac uauguagggg aggugguuua gcagccauuc uguuuggcug 134820
ugaggguuuc ggaaaggcau caugaacugg gaagagucga ugcagguaaa aucugcacac 134880
ccccuuaagg aaaaaucuca guuuaccuuu ugucuccacu acaccugagg ucugugucuu 134940
uucauccugu uuuuuccagc uccuggcaca cagaaaaugu ucaacuaaua cccaccaaac 135000
ugaaaaccca gcaaacuaug aaaacucagc aagaaaaaua gacagaaaag aagugggucc 135060
aagaaaauga ugccuccaaa aagcagcaaa gggcaagugg agcaggagga ugccgugcuu 135120
uaaaaacagc cacaggccgg gugugguggc ucacgucuaa uccuagcacu uugggaggcc 135180
gaggcgggcg gauugccuga gcucaggagu ucgagaccag cuggccaaug uggugaaagc 135240
ccgucucuau uaaaauacaa aaaaaaaaaa aagaaagaaa gaaaauuagc caggcguggu 135300
ggugggugcc ugu 135313
<210> 7
<211> 7913
<212> RNA
<213> 智人
<400> 7
guaacaguua cugucugugg uuuaaaaaug agguguggag caaauaaaca gguuggaagu 60
gugggguggg gugguggggu aggguggugg ggcagggugg gggguuguga gcagucagug 120
ggcuugucgc cgauuagcac ugaagcagug uuuagcugga cggccuuucu gugggccccu 180
cugacagugc ccuucccagg aagauguguu ucucuguccu cagccacaug aaaaucuuuu 240
gccuaccgug ccugucaauc cauugccugc ccgccccucc cccacccccc guuuuacacc 300
ugccugucca gucuaccgcu cucuagggca uccacgcuga gcagugggaa gaacuuuaag 360
cccugaagag caggccaaag gcaagcaaga acccccucga acagcuuccc agcuuaguga 420
ggccuuauuu cauugauucu cugaggcaca uuguuuuuuc acauguuagc auuucugaaa 480
uugggaugca gcucacgauc aagucacagu uuaacuggac acauuauuuu ucuuucuuag 540
uggugcagaa aaguaacagu gugucuuaca auugacugcg uccuagauuc ugugagaugc 600
aauacguuau uaaccaucac gcacauuucc ugaacucuuu caaugagcag acaccagccu 660
ggguuagacu ggagcccuaa aagcacgaca cagauuccac ccuggacugg cuucuguucu 720
gccugggaaa acccaaagua cguuuggaga ccaagagcaa cauaaaguag cauaggugga 780
auaguccaug agaagugcga gcaaaaggug ccggagauca gagaacacca agacuguacu 840
uguaaaugac aacuggcuuu gugcaauuuu uucugggaaa ggauaaggag ugacuauaga 900
acuguaaaga aagaaugcac uuugcuacag ccuugcagag uugugcaaau gccgaugacu 960
aaaggagcug aaagaggaag gaggggauaa gggauggggg cuggguaggg gugagauuag 1020
gacccuggga gcugcaagcc acuggagaga ucaggaggaa agggagggag accugcuuua 1080
ggcgagaaga gaacaguauu uguuccaaau cucgguucag aauaaguuca uguaggugau 1140
ggggccaacu ggaacaggug aaggccuaug aaugaguguc ucaguuaggg ucuccuuaga 1200
guuuaauaug aaaagguguu agcuaaguac agagcuggua ccugagagag uaaaaggaaa 1260
cucuaaggua ucauggaggu agcaauugca ggacacagcu cccaccccua gggcugagag 1320
aaccaaggga agagacagga auuauuaaga cuuggagcau agaugagagg ucuguggagc 1380
ugacauuagg acuugggagg aaggcgugca uggaggcugc ugcuggaucu cugaaccuga 1440
ccucgggucu ggaccccuga ggagaaagcc cuggcagguu ggugcaugug gggccgaggg 1500
acaauagcuu aacaaccagc auaaaagaga gcagcauggg acacgcuuca accaugcgca 1560
uggauggcuc caaaaccugu guguggcugg cccaggacgc agggaggcug cagggggaag 1620
agacaaguua aaccugacuu gucugggaag caccauuguc cucaggucac uuuccucugu 1680
caagccuggu gcugaaguua ucuguugucu ccaggggcca aguauuaaga guaaucagaa 1740
acucaguccu uucuucuagg agcuucccuu cuugcaugaa aauccugaua aaacuggaaa 1800
aaaaaaccuc augauuaaau uuuuucaugu auucauucuu uccuucuauc aaaaaauaau 1860
cuccaggcac cgugcuaggu ucauugguau acaauggcaa caagaccucc cagccccugc 1920
cuaugugagg caucugugga cugcggagga aaauccaaua ugccauuguu cucucuuucc 1980
cauaagaaau uacaauucuc aguucauuuu auucucacug ugcucuuugu gacccucaaa 2040
gggggucaca ugauaacagg acuguagcug cuggccuaaa augagcccau uccuguggcg 2100
cucaugucgc ugugacagag aauaacccug uuuucagaau gcucuggugc ccucccucuc 2160
aaucuggccu uucgcuggca ugggugggcg acuccugcuc agggacucug ccuucuccac 2220
agugugcucc cagggagaug gagccacucg ggcugagggc cuuggccagg gcaccuccca 2280
gggcugggcc uggucugggc uggcguucac uggaugccau ccugauggcc uggaaauuga 2340
gauuucuguc uggcacgccu cccgauggcu ccccaccugc uaccacauuc caggagcuuc 2400
caggaugucu ggguaagaca gaggcacccc caacagauuc aguagcucug agagggaucu 2460
guggcuccuu ccuaagcuug cgguucuucu ggaaacuucu gccucuagaa gauggucccu 2520
cuaagaaaag uacaaccacc cagcccauaa uucagcuccc agguuuuccc ucaaaccucc 2580
augucuccug uaagcagagc aagaguaaaa ucagauacca aauuuccuca uuccucagcu 2640
cccaaucccu aagggcauaa gaugaaaauc uucagaucuc ugcuuuccuc ccucuuuuuu 2700
ucuuccucug uuaacauuug ucaaguguua cuaagugucu ggcacuguac uaagugcauc 2760
accucccuga acucuccgaa caguuccacg agagaggccu cucugugauc cccccgguac 2820
ugaugagguc acugaggcuc cagagaagga uuaguaacug gugggguugg accugggauu 2880
cacacccaug cugcgugacc caggacaggc aggcauggcc guuacaccac acugaccccc 2940
guggaucgag aucuauccaa uagucugguc acugauauca cuaagauaga guggccauau 3000
aauuuaucau ccaaucaggg caguuuugca agugaaaggg agcacuauua auaauugcac 3060
ugggacaaua aauguaaacc aacacuggac cuggaaaacu gggacgugug uuugcccuau 3120
accaagguaa gcuagacaca gccacugccu ucauggaguu cagaaccagg caggggcggc 3180
ucccacguau aauuacugug cagcacaacg uggagaccgu ggaguagaag gaaacacgga 3240
ugggagguga ggaggagguc ugugagcuca gaggaggcac cggggcugga gagggugaga 3300
gaagacuucc caaggaguuc auccugauaa cgugcauucc caaugacgag cgcucucucc 3360
acugcacaag acaaguauac aucugcccgu guuggcugug gaccuggcgc ugugucaggg 3420
aggguuuaug aagaucacua ggugggucuc uuggugucau cccuucaucc cagcuucugg 3480
guuaggaugg auaucugugg gggggccuga ggacucauga aaguggggcg cuaaucaugu 3540
uuuggacacc acacccugga gcaccuggga cagcuguggc cuuuguccug gguucagcau 3600
caagccgagg auguggcaag uaaagagagg cugggcacca acuccagugu acccaggcuc 3660
cgggucaugu uuguccaggc uaagaauucu guccugguuc ucagugcaga aggaagaauc 3720
auggggcuca uuuuaggccu uggcugccuu cuguuaaauu gaaaacagag caggaaggaa 3780
gaaaauuuaa caggcucagu ucuaaaacaa caagcacaac ugugcccuug ccagaaaccc 3840
cuccucccca uguugauuga augguaaaga gaggagggga ggugagaggg agagagagag 3900
agaggaagag agagagaaag gaaagaaagg aaagaagaag aaagaaagaa aaggaaagaa 3960
agaaagaaag aaagaaagaa agaaagaaag aaagaaagaa agaaagaaag agaaagaaag 4020
aaaggaggga gggagggaag gggaaaagaa aagaaaagaa aaagaaaaaa agaaggaaau 4080
accaguuugg gaaaaaagaa uuuuccacca gcccuucuga gccuuggcug ggcuuaauua 4140
aaguuacaga cauguguaaa gggcagggua gggggagucu gagcugcuga gaaaacaugu 4200
uuuuaauuau acuguggaau uucucccugg gguaugccug uacgcaguua agcgucaagg 4260
acagggaugc cgcucugggg aggggaagcu gagcaugauu uuggaagccg gcagaagagg 4320
cuauugugaa aaccagaccu gucaggcuag gaaaagaaug gcuggugguc uuugaccagg 4380
gagugacgcg ugaaaugcag caaccgcccc cgccccccgc caaaaacaaa cacacucuca 4440
cagaguuaga acaacaguga ccucucaaca aauauuuuuc aaagauuacc aaccaaccau 4500
uaccuagagc agcgguucuc aaccuuggcu gcacggugga acuaccugag acguguuaaa 4560
aagaagaacc cugauguccc augccccaag auucugaugu aguugaucug ggguaugauc 4620
ugagaccccg gcauguuuuc agccugcagc cacaugagaa gugcugaccu aaucaacagg 4680
ggugaugauu ugaggggcgg ggacuauagg caaaaaaaaa cagccuaauu caaggaugag 4740
aagagggcac aggugaggug ggaacagucc uagggccaga caaagaagga agggagaaag 4800
gaggugcuga ucccuccccu acuccugaga ggaggccuuu aagucaccgu gccuugugga 4860
gaccagauuc uucaaaaaua caagaaugag ugagugaggg agugggugga ugccaggaga 4920
gugcgugaca agccuugcaa gggaggauga caaugcacua gcuugguuug gaaauuuuac 4980
cccuggaaca ggcaggccaa gcuggcuggu ccccucccug auacacagcc cucccucuuu 5040
auauauggag caggggacgg uguguggcug guuucuuagc aagcaccaug guuccaaguu 5100
ggcaacuggg gaguucugaa uccaaaaagg agggagauga acguaagugg agggcaggcc 5160
uacaagguug cagauaagcu uaauucuguc uccuuacucu ucugccuuug caacaacccu 5220
gugaucuugc gacaacccug uaaggcaaua acaaauggcu cauguuuauu gaguguuacc 5280
ucaugccaua uugugcuuuc guguuuaaca caauugucuc auuucacccu cacgacugcu 5340
cugggaggua gguccuggua ucacauccau uucacagaug agaccauuug gcacggaaga 5400
guugaguggg cugcccaagg ucacauagcu aagauggaac aggcuggaua ggaaccccag 5460
uaacuugacc ucagaguaac cuucucuuaa cccugagugu acacuguagg aaaaaugagc 5520
agucccauuu cagagaggac aaaacugaga cucagagguu aagcaagccc caaagugguu 5580
guuaacccag aucuucccac uaacucccaa aucagcauca guguuuaacg uaccagaccu 5640
cucccagaua gauguugccg cauggaagac agccgaucua cgugauagaa agccaauauu 5700
gcaagcaguc gucuaaagga gucaaaugug uuggauuuga acuggauguc ucauuucuuu 5760
ggugaagaca cuggaaacaa cuuccagguu ucaucaauug cuccuaucac ucaacguugc 5820
uaucuuacug aacuuguucc ccagccuuac ccacugaugg aaugauccag aauggaagac 5880
aagacaccaa uguacaugac ccugggggag gcuguuucuu aaaucuacag acuguuggug 5940
accugagccc caugucacca aaggcuuucc uggagaagcc uccuagacca gucuugacaa 6000
aggcucacuc auuccgugga uauuuauugg gcaccuauua ugaguucugc cccauguggg 6060
gugcuggaau cacaguagug acaacgacag augagguucc uguccucagg aagcuuacug 6120
cccuugaggg cuucacuuac uuggaggagu gaugaaccug aagugcggug uguguuaaga 6180
agcggaaguc cagggccagg cgcgguggcu cacgccugua aucccagcac uuugggaggc 6240
ugaggcaggc ggaucaccag gucaggagau cgagaccauc cuggcuaaca uggugaaacc 6300
ccgucucuac uaaaaauaca aaaaaauuag ccgggcaugg uggugggcac cugcaguccc 6360
agcuacucag gaggcugagg caggagagug gcgugaaccu gggaggcaga gcuugcagug 6420
agccaagauc gugccacugc acuccagccu gggcaacaga gugagacucc gucucaaaaa 6480
gaaaaaaaaa agugccucac ggagagucua uucuuuucuu cccauauugu gugugugugu 6540
gcgcgcuucc uccaacacau ccucccuaua uauauuuuga guaaaacauc uuguaaaaag 6600
uuacagcuac auaaucacca ccugucccua aauaguuuuu gcuuuuucuu ucuucaaugc 6660
acgaucauuu ucccccauca auuuauuuuu uaguuucuua uaaucuuguu gccaguaggc 6720
uguuuuuuaa aaagcagaac augguuuguu cuuacuagca ggaaaggagc auuuauugag 6780
ccucugcuau ggugucuuuu auuuugcuga gagccuauuu acauuucuuu gagaggaaaa 6840
caacaaaggg uuacaugaaa gaccauguga auagccccua gcugaucuau uaaacuugcu 6900
auuccccggc cagcugcuuc agaucuccuu cagaucuuau guguuuccuu ccuaaggucc 6960
cuggaguaag gguugcauag accuauucua cucuccaacu cacauguccc ucucccucuu 7020
ccucuccaua auuccacauc uccaaccccc accccuaugu gcaaugccac agggugugga 7080
cugccacagc cacuggaucu gcuuuuggaa ucaagagucc uuaagcucca aauggaaccg 7140
aaauuuaaau accaacuuuc aaccauaugu uaacaucagc agccucuucc aauguaaaaa 7200
cccauggcag ugugcccugc uuuguuucuu uaagcaauag aaacuugaag gaagcauguu 7260
gguaggccag auuuuuguug gcuuugcaau ggaucacagu cauuuauuca cucauucauu 7320
cacugauuca uuaaaugacc acauuugcaa gggcaaggua auggggaggg ccagaaagga 7380
cacuggcccc agaaacagga ggcuggauuu ugguucugau gcugccacug cugaugugac 7440
acugcacagg ucaccugccu ccucugagcc ucuuuccuua acugcagagu gaguggcuac 7500
agagaaaucu uuacuaccug uuagaucagc auuaccuggg agcuuguuag aaaugcaagc 7560
ucuggugggg ccauacugaa cccaaaucug cauucaugug cauagugaca gcuaaaaugc 7620
acugaagcag augaucuuga ugauccuuua ugaaagucuc augcuaaugc aguuuucuaa 7680
aauagaggca gaguggaacc cagauggaca caaaaucugg uugauauaau aaaacaaggu 7740
agagggugua ugguggggag gggguaaagg aaggaaacug uuuagguaaa gauaccacaa 7800
ccaaaguccu acugcacaca ugggaucuga ggagggcugu gucugcucug guuacguuuu 7860
cuauaaucuc uuagcaccac ugaacuuucu cucuuuuugu uuuguuuuuc cag 7913
<210> 8
<211> 1393
<212> RNA
<213> 智人
<400> 8
guaagcauag caggguagcu ugggcaagcc cugaagagac uuuggucugg gccuuuuguc 60
uagaaagauc uugggguggg agugugggga ucagaucugc uuaucaucau uucaugucua 120
ugaugcaugu aacagauuua ucaauguuac acaaauuaua auuuuuaaaa agucuuuaga 180
gacagggucu cacucuguug ccgaggcugg aguacagugu uaggaccaug gcacacugca 240
gcuucuaucu cuugggcuca agugauccuc cugccugggc uuccaaagug cuggaauuau 300
aggcaugagc cacugcuccc agcuaauuuu uuuguuuuuu guggagacag agucacuaca 360
uugcccgggc uggucuugaa cuccuggccu caagugaucc ucccaccuca gcguucuaaa 420
gcacugggau uacaagcaug agccaccuug uccagcccaa auuuucaugu uuuaauccua 480
cacauucuaa gcaaauacuu guguguaguu acuaagggac ugugcacuua uuuuuguuug 540
cuuuguuguu gcuaguuuuu auuuuuuuau accuaaacuc ucucguuuua aagagaacag 600
auuuguagau gaguucucga aaauauuuca ggaaucaaua uagagaauau guuauacaug 660
gugccagaga aaaaugagga caagagaugc uauacaaucg uacugaagaa aaauuuuauu 720
ucuuggaccc cugagguguc ugcagaccug aaaggaaccu agugagagcc ucuuuuacac 780
ucugccccug ugggaaagcc uucaccuggu uuccggcccu cuauguggug aauguggaag 840
ccucaagcgu uaugcaaauc ugcccagucc ucuauucuug aucuucaccu ucucguucau 900
gaguuucagg ccccaguucu gaaucagccu ccuguccauc agacucuucu uuaccucucc 960
ccgaggagcc cauaaccugc agcccuacug caugcuuggg guaggugcuc aguucaccgu 1020
gguugaagga auagacgagc gucugcucaa gcagcagcag caacugcgug gagucuucuu 1080
gaacuaacac uccuaugccc cucucggcac aaaaugacgu guccccccuu gcuuccccuu 1140
cacauuucca cccaugccua uuacaacauc cgucugucuc cccacuacac cgggagcuug 1200
agagaagagg ccaugucucu agcacccagc acagggacug gcacacauga gaugcuccug 1260
cuucuuaaau gcugagaaug aaggaggaca ucagaggggc ccgggccccu ucccaaaaag 1320
gccaacuccu aggucugcau ccugcuuggu cuccaugacu aaucccgucu uguccucauu 1380
uucuguuuua aag 1393
<210> 9
<211> 2721
<212> RNA
<213> 智人
<400> 9
guaaguguug agaucccuac caugcagggg aggaaguugc acaccccuuc acgugcugaa 60
augcacacgu gcgugcacgg agcauggagc acugaguguu cuuguggcuu ugcugagccc 120
cuaaccucuu aggagcagag cagguuuccu cucuggaaca uucuguuaac ugucagggca 180
cuuggggaga aaucuccaag cuaaggccac gugcacaaaa uuucuugguc cuuauauccc 240
cagaauguga ccuggagucu gauggcagcc cgcugcagag auguguccac ugccuucugg 300
ucauugaccu gcuugggugg agugaaucau uguaggagaa aaacucaguu cccucacccu 360
gaucaaccug gacagaucuc ucuuccuuua aaagcuuucu uggacaucua agggcuagga 420
aaaaugucag ggagcauugg gaagguaaau gaagucaggu uuacaaaguc aaguuuacuu 480
cuugggagaa aaauacaauu uccaaauccu cuguuauaau ugccaucggc ccccuggagu 540
ggugagaucu cggaauaugg cucgggugca guggcucuuc acugugggcc ugcaggcuau 600
ucugaaaagc ugaugaaaac caaugacccc ucuuccaaga aaaauggcca cauaccaaac 660
auuacacugu acaucugauu ucagggaauu guagaugcca gguuaguagc cucaggucua 720
gggucaaaau ucaagucgaa ucccacagga agagggucug ccuucggaau ucccuuucag 780
agcauuggga gaacaucaug ggagcauauu cuagagacag aggcuuaggg uguggacagg 840
gccaucccuc acccacugug cugaccuuaa gcagcaccuu gugcagccca uaccugaagg 900
ccaccagcaa aggccuguug gggagcaggc uuuacccgac cuguauaaac accaggcuag 960
gugaaaacug agauaccugg uuacuuuagu uuuuuccuug ggggagcuca guaugauucu 1020
uccaggagaa gccugcuuuu agacuaaaaa gaaaaaaagu uugauagguc aaccuaauga 1080
uuggaggugg ccuuccccac ugugaacaaa cuauggcugc augugcccua caauggcaga 1140
guugaguagu ugugauagag acuguaugau cuguaagccu guaauuuuua uguuugcuga 1200
ccccuggauu accagaugau agaagaggaa acaucugucu uccuagcaaa gucaaggaag 1260
uggcauuuag caggacucau auugcugcaa gcacugccuu gcaguuuuag uuuacaacug 1320
cacuuucagc uuaagaaaca ccugcccauc cagagagauc gugugggguc acaugguggg 1380
aucagggagg ccugaagaca gcucagugga ggcugcaugg agcuuuggug ggaacggccc 1440
uggcaguguc uauagauguu auugcggaaa acugaggggu gggaguugga gaagggggcu 1500
ccagacucua gcuguacuug gcauuugaac ccggaaaguu ggguuucaug uuuugcacuc 1560
acauuaugag ugaaauauug gcuuauucaa gguucuuuug cuugcaaggc acggaaaccc 1620
auucaagcaa ucuuaaaccc cagaaggaaa ucuaugauuu ggauacuaga cauucucaca 1680
gagccaaggg cagcaaggcg gggcucagga gaggcaggcc aagaccugga gagcugucag 1740
gagcugcuuc cucaacucuc uuccaucugg gccugccagc ccuggccucu guaucuacuc 1800
cauucaccuc ucuccaugga ccagucuccc cugcuccuca augccugggc ugccauuguu 1860
caugcaauuc acaauaccuc ggccugggca aucagaagcu caucucugaa caccauccaa 1920
auuccuggga acaaaucggg uugacccagc uuuauucucc cugucccauc agccuuggca 1980
gaggcgugca ugugcaugcg ugccaaugug ugugugcagg gagguccuug uggaugaagc 2040
auggcuguca gagccuaccu gcgugaaugg guggaagggc aggucucaga gaauugggua 2100
aaaacuggau aaacccucca gugauaucca ccaaugucac ccuguuuaag gcuucucugg 2160
gcaagagaca cacagagcau gggaccgaga ggcgagcaga cccugccaaa acugggagac 2220
ugaauagauc gcucaccauc cuugucaguu agccuauaug uacaaggaag uaaaauuauc 2280
ucuuucuccu gccuuggcag uauuguaagg auacucaaug uaguagcuag gccagacaca 2340
uaguaucuuu aaauauagca ugagauggcc aagcacggug gcucaugccu guaaucccag 2400
cacuuuggga ggcugaggcg gguggaucac gaggucagga gaucgagacc auccuggcua 2460
acacgaugaa gccccgucuc uacuaaaaau auaaaaaauu agcugggugu gguggcgggc 2520
gccuguaguc ccagcuacuc gggaggcuga ggcaggagaa uagcgugaac ccggggggca 2580
gagcuugcag ugagccgaga ucacgccacu gcacuccagc cugggugaca gagcgagaua 2640
aaaaaaaaaa auagcaugag auauuauuac uguuauaaaa auaacagcua uuuccuuauu 2700
aaugaggcuu uguccuuaca g 2721
<210> 10
<211> 5434
<212> RNA
<213> 智人
<400> 10
guaagcauga cugcagugcu cucaagcauc auuucccuca ccuauggaga gacugaagau 60
auaggaaaga acagggagag uuggugaaaa auauacuagc ggaggcagga agggaugggg 120
ucuggaggcg gcuugaacau caccuuggug aagaugccuc uuccuccaca gaagccugga 180
agguaggaag uugggaagga aggcaggaaa ggucucaucc acguuaaguc uagagacaga 240
aagaaugcua agagagaugg cacuauggga aguaugaggc uaggucaagg gcuagaagca 300
ggggagacga guuuacagag uuucguaaag auauagagca acucucacag aguucuagag 360
cgagagcuaa ccaggaacau gaagcagcaa ggccaacuau cauuaaggag ccagggaggu 420
cagagaucau guauuaucau gacauaaaua ugcauaauug uacuauuucu cccaguaaua 480
uuuagcaccc aggccccgag gcagagcaag uggagagugg gugaugcagg gcugggggug 540
uguauggagg caccacagaa ggucaacagg cagcgggcug aaggcaggga cuggacuaca 600
ugcaucaagu ccaggcugca cgaggaagga ugagaaggca gaugagcacg gaaauggacu 660
gggggaaaug aagaggcaag ggaauagaag ucucaguggg ugccaugacc cuguuuaagu 720
gauugagaaa augaacaaga ugaaaagguu aauggcugug gucagaaagu gaaauaugug 780
aauucaggau uucgaaggua ggguggguga ugacuggccc ccagaugcgg ccauggugaa 840
guggggcaaa ggugcaggug cauggugagg ggaaggagga aaugggaggu gaugauguug 900
gccccacacg gacaccacgg uugugcagga agauggcagg agcugggcac caggguggga 960
gccaccugga gucaggaaga gugaagagaa aggaugaaga ggcucccucu ccugugucuc 1020
uccuccccag gagaagaaca agaaacaauc cgaaaguaau aacaccaaug ugccuuuaca 1080
aagugugagu ggguguugug ugcugucacg uguguaguag gcuccucugu ggauggcuag 1140
agggacugga cauggccacu ggaucccacu ugcaagagca gaggaaaaga guggucguga 1200
ggaaguaaag ccccccaaaa uccagggguu gcugcagcuu ugggugugga gcgugcccuc 1260
ugaggaaagg cugcucuggg ggagauugcc caggaaacgg ggcucagagg ccacgaaagc 1320
agcuguuagg ggcuucuggg agaugugugc uccuaggauu agggaguuga cucuaaggau 1380
gaccuuagag guuaacaggg augagaaagg ggucaccaag gggucuacca ggggaauggg 1440
agaggcugua uugauagaac agcuucugcu gcagguucca aacaagaaau gugggagaau 1500
gguugaaauc agccccgggg gcaccuuccc gugcaugcgu gcagcuccuu caacauucag 1560
ucgaccuuca gugccuccug ugagccaggc acugggcuag ucucuggggg uggagagaug 1620
agucaggcaa augccagccc ucagagggcu cacagggcag aaggugagag augagugagc 1680
agaaaaugac cacagcgcgu guggggccca guggagggaa ggaggggauu caggagcaca 1740
ggagagucaa caggggaaac uucuccgagg agaaucugau ccuccuccca ucuggccacc 1800
uucugaagcc cucucucccc auccaaguga gaaaggacag gcguaugacc agauuggugu 1860
augaagaugc ugaauuacgu ucucauuguu ucaaacuagu aaaccauaga uuuuauguag 1920
uaacuucuac aaacugcauu acaaacacuc cauucuuugu ugcccugggu agaaguuuau 1980
uuuagugagc ccaaguuuga ggaaccuuau augguaugag uacaauuacc auuuuaauag 2040
uaagaaaucc cccuuccccu guguaccaac cagaaggugu uuuuuuccua auuuaaacaa 2100
acagaugcag acgugggcug uccagcuccu ggcgggauga cauaccucau gcauccagug 2160
gguuugauga ugaggcagac auuucacuua agugccugau caucagauug aguccugcug 2220
ggaggaagug ugaaggaagu aauuucaaac cacaguuucu cuguggcuuu uacaaugugg 2280
auaugagaac caaaaucacu acuucuuaac cccagagcag gacugauuuu gaauugguau 2340
gcaggcgguu ccuucugcag gcuucgggcu gugagaaguc ccuaacagag caaaucuggg 2400
gacaagggcu caggaaaggu uggccacggc ccccuaggaa ugggggcucu gcaagauccc 2460
uggccuuaga ggcugugaga gggaacaggg guccaucccc aaguaaggga cacggucuuu 2520
gaggaaaucc caggccaggg ccugaagggc acugucagga acacaggcug uuucagucug 2580
uugagauuca ccggggcgcu gcucacugug agcacggacu ccucaggcca auguggcaga 2640
agagcccacc uuugaaagcg agcggguggg gguggcgggg cuggugcugg ugcgugcuuc 2700
ugcacagcca ccugggaagg uaugccgcug guugacccag gcagagguuu ucuuucaugg 2760
caaaccugca guacugcauu cucagcaggg aggauuaaug guaaaagacc aggcauggag 2820
cccccuuccc ucucccucga agcaagcucu guggucucuc aaucaucuuu aaaacaccuu 2880
cuucccggga gccuccuaca uucuccuggc uucccuccca cccccacccu cagcuccugg 2940
ggccucagca gccccacccc caagccucua aucuucccag ggaagggaac aagaagaacc 3000
acauuuuaaa cgaaauuuau uuuucuuucc ucaggcuccc aguucacauu ucucccucag 3060
gagucuaggg aagcuucugu cugguaucgg ccuccucuuc accugggccc ccgcccuccu 3120
cagguguacc agaagccagc acacuccccc uuccccccca gagccacagc agcccugucu 3180
ccuggguggu cuugugugcc aagccugggc aacaucacuc ccagcuuuuc uuguuuugcc 3240
ccuucucccc agcaagauau uuguauguaa ggucagguga gugaguuaaa gaauaacgaa 3300
gagauaaaca gucaaaugga guccugacug ucaggucaag acaacaguua uuuacugaau 3360
gccucauguc auucaacaga cauuuauuga gacucugauu ggaugucagu cuuuaaugcu 3420
gggugucaga gagaggugac uucaagggcu ugcaucugug cacccagcau ugcuagguac 3480
aaugaggagu auaauaaaag caggagccau agcccccaac ucucaagaga ucucccaugu 3540
guguaugucu gcauaugcgu gcgugugcau gugugcgcau gugugcaugu gugugugcau 3600
gugugugcau gcgugugugu gugcgugugu uggggauggu guugguggag ugagagugua 3660
caaggcugug uaugaagggg uaauugggaa aagaacaaug gagcuggcac ccagggacag 3720
gaggaaaagc aggagggcug gguuuggaag acagccggau uuauguuuuu gaagagggaa 3780
gacuagaaua uaagggagca gcccuucuca gagcccuccu ccucccuucg ggcccugugu 3840
ccagcuuucc ccaaaguccu uggaucuuuc cuaugcaaag gggagugaca gugggcacca 3900
cucucaggga acccauuacu gugagagaag ccacugugcc acuguguggu cgaacuucaa 3960
gaccggcuuc cccugcccca gcugcaugga caggccugug ggguuggcgc aagacccuuc 4020
cagaggaaac uagcugcaac auaaauccgg auauggugcu guucagggaa aggcacaacc 4080
uggggaugag aaggguggcu guccagcaca caggggcagg ccucuuggcc acugggggag 4140
gggagaauuu ggagaggaag aggaugggau gccguggaau ugggaccagg aaagaauggg 4200
gacaugugau gguuaaagcu aguuagagaa gaacugggag auaaacaguc acccaugccc 4260
cugaagcacu cggggugaag agauuggcau uuucacgcac cccagugcuu ucccuuugug 4320
uugaaguccc uucguagaca uccaggccca uaaggcucuu cucuggccag agccucauga 4380
acuauagcac uagcaggguu gaggccaagc auuggcccug gaagccagcc gaggaggagg 4440
gugcuugugu gaaucuccca ggagggguaa gaauuauauu aauucgauca uaauaagcau 4500
uuauugagug cuguuuugag gccugggagc uaagcacuuc acauuccuua ccccgcauca 4560
acaauccuau gagguagaug uggaaaaugc agacacgggg acaggcucaa ucacuugccc 4620
caaggucacc uuaacuguua gguguucuuu augccuccuu auaaagaaac ccugcuuccc 4680
acagguguug agaggagcug gagggagcuu gacuagggcu caucaggcaa gccccggcau 4740
gugccuggcu cuccucuuuc uaccuggagc uuuuccugcc cuuaauggcc ccaacucauu 4800
ucucuuaguc caugucagug cccugagcau cucagcccaa gcugagauga uagaaacacc 4860
cagagggguc cucuacccug ugacagcugc ggugugggaa gagcacgugu cuccuccaau 4920
ccuagaccag aguuucucag ccucagcauc acugacacuu ggggcuagau aauccuuugu 4980
gugggggagg gaggaguguc uugggccuug caggauguuu agcagcaucu cuggccucua 5040
cccaccagca ccuccccagu ugugacaccc agaaaugucu uuagaucuug ccaaauauuu 5100
ccaggaggau gaaauucccc uguuucaguu ccccagcccc accucaauga gaagcacugu 5160
ccuagaccaa ccccacaaag caucugacac ccccauccag cccuggcuaa cuuuuuccac 5220
cuucuuacua aauugggccc agcugcuuca gcagucaaug uguugggggc agcccacugg 5280
caagagccuc accucuaggg gcucccagag accccaagaa cagaaccuuc cucugagagu 5340
ugaguuacaa guguuuccaa ucgacucugg cuguuuuccu uuuuuugacc cauuuccccu 5400
ucaacacccu guucuuucuc uuauucauau guag 5434
<210> 11
<211> 4023
<212> RNA
<213> 智人
<400> 11
guagggggau gucacuggcc aguggucccu ggaggggagg gaagcaccca gccugagaaa 60
ggcaagaaau auauuggcuu uuuucuucuu ucuuccuugu guucacauuc agaauccauc 120
acuuaaugcc uuguauuuag aaaaaaaccg ggggaucacu ugagaucgug aucauuuuca 180
acauaggauu cgaagcugua cacauccugg ugaccuuaaa acaucucagg uuuuuauaac 240
uggaaggaac cuuagagauc auggggcaca accuucucuu uauagaugag gaaacagaaa 300
ucuauucauu uauuacucaa auauuuaggg acaguuguag guacuagaac acagugugaa 360
ccagacaggc aaaaccccag gccagggagc uuccauucca guggggccac aggcgaugcu 420
cagguaagca gagacuccgc ugugugacuu cuggcuguga ugggugcugc aaggaaaauc 480
cgguagaguc gaggguuaga gagggacgga ggggcagguu uaagggggau gcucaggaag 540
gccuuccuga ggagguggua uuugagcaga guugucuguc agccacacag uaagugagag 600
gggaguuccg ggcuuggaag cugccagcac agugcuggca agugcugggg uggcgucccg 660
aggcuacaga accugagaug cugcagaaga gcccacuucu gcuuuccugg accacuuccu 720
ucucagcacc aggcaaacuc cuucuucuau ccccuggcac auuucugacc uguguauacg 780
cccccaauuu aucuaacccc uuuaaauaau cuccucuauu uaugcagagc auucuuacca 840
cuaacucacg acuugcacau cccuuagcuc ccuuacuccu cacaacaauc cugagauggg 900
ucagagaagg aggcuugcgc gucuggugau ggggugauuu gugcacaguu acagggcuag 960
aaauugucag agccagaugg aauccagguc cucucaaucc uaauccagug uuucuuacuu 1020
caguccugug gcucucaaag cccagagacc agcagcauca gcgaugccug ggagcuuguu 1080
aggaaugcaa auuaucaggg cccacuccag gugaacuggg uccaaagccc ugggauaagg 1140
ccuagcaauc ugugcuucac aagcccucca ggugauuccg caggcucagg ugugagagcu 1200
gcagcugucc ucugggccuu cugggcuccc cgcccagcuu cuucagugug augaacacag 1260
cgagaaugcu agaucugcag cagcugauau cccagacacc cucccgacuc ccuccuggcu 1320
gggucugauc cuccuccaga cuccaggaga gaacgagaca uaaacagaac uucagagccu 1380
guguuaaccc ugagaucaag gucugcacag ggugcugucu gaguccagag gagugaggga 1440
ccccacccca ccuggucagc accagcuccu ggaagcaggu ucucacacug guucccugca 1500
caaugaagga gcucauaccu gcuuuucugg cuucucagac ccugagguuu ucaccgaaac 1560
uagacaaggg gaaccuaggg ucagccugga ggcaggguga gcuuggcgcc ugcagugccc 1620
aggcccuggg uggugcggcu ccggccaggc ccuguuuagc uuccucuccc acccccacag 1680
agggggugcu gucggcaccg auugcucauu uuccccuuug cuuucucuuc agcucguaaa 1740
acucaagucc ugacaaugcc uugaugacuu ccaguuggua auaaaaggga gaugaagaua 1800
aggacaggaa uuucggggaa auuucuuucc aguuccuuac uaaugugaca uuuagaucuc 1860
uaguacugug cuucuggcau cagugccaag gccuuucaug uuggagaaug gaggccgggg 1920
ucaccagguu gugccuuuau uucauguugc uggcucugau gagcugaugc ucugcugauu 1980
agcaaacgcu gagccaucug cgcuucgcag aggcacguuc cagccaaccc ggcccucccu 2040
gcccacuucc caggaugcuu ugccuugugg gcucaccugu cuucuagcuc cugaucugua 2100
ucuccaccuc cauccaguuc cggggcuccu uaucagcacu guucccagaa cuguccauca 2160
cgauggcaac guucucucug ggcgcugucc aacaugggag cucgccucug uguugucacu 2220
caugcucauu gaacauggau uuguguccuu uaccaucagg acuggauacc ccuccugguc 2280
cuuucugccu ggggucuuag cacagcucag aaggaaccuc accauucccu cucuccaucu 2340
agggaauuag aagaugacag gggcacaguu cucuggcuca cccccagccc aguaaacucc 2400
uggacaugcu ucaaggccca gcucagaugu ugccuccuca gugaaauaau uuauaaaccc 2460
acccuucuuu guccugccuu cucccucuuc ccuacucacu ggagaguuaa caggugaugg 2520
uuaagcucug gguucaaauc ucacaaggcc acacacuuag cuaugugacu ucaggcaagu 2580
uaauuaacca cucugugccu cucguuuccu cauuuguaaa auggaaauag uaaaagugcc 2640
uaccagcaug gcaguugaag uuaaaagaaa uaauauaugu gaacacuugg aagggcgccu 2700
gacacauagu aaacucucag uaaauacuag cugcuuuuag uggcuauucu uaacacaccc 2760
ucuucagugc ucugguuuca cuauguuuua ugggucccug agaucgaaag uguccacacc 2820
gacucauggu cagcuguaac cugugccucg uguggggacc aggcugccau guguagucug 2880
gacaguguag gagguggcag agcucaggcc uguucugccc uccagcccag agagccacgu 2940
cguuagaugu caugggagac uguggugccc cgggaaucuc acgaauuugc ccacgguacu 3000
cagugucugu ccaaugcuau gggaguccag gacucuagga gccaguuaag gugcugggug 3060
gccacagguc ccuggccaag guccaggccu cuccccugcc accugauccu cgagaggcca 3120
ucacgagggu uguacuucaa gaaccacuau ccuugagcua ccuaggagcu gcagaaugug 3180
cacucugcag ggcuuagggc cugcagacaa gauagaugca gggugucuag uuaaauucga 3240
acuucagaua aacaacaaau aauuuuuuca aauaauugug uucuauucgg ucccuauuug 3300
ggacauauuu guacuaaaaa guauucauuu aucugaaauu cagauucgac ugggcaucug 3360
gugcuuuugu uugcuaaauc caagagcaaa uuuguucuag cuacuucuca accccaccuu 3420
cagagaggaa gccuugaugg uacuguaaca ucaugcugua agaaggggau cccuugaauu 3480
guaaauggca cucugauaag augagguaug gggauuguau ugguuuccug uugcugcugu 3540
cauaaauuac cacaaacuua guggcuucaa acaacacaga ugcauuaucu uacaguucug 3600
gaggucacaa gucugaaagu uagggcauca gcaggacugc auuccuuacu gcggaguucu 3660
agagaaaaau ccauuuuccu gccuccuuca gccuccagag acacgccaca uucuuuggcu 3720
aguggucugc uuccaucucc aaggccagug ggggcuuauc aagucuuucu cacaucacau 3780
gacucuguuu cuucugccuc ccucuucuac auuuaaggga cccuugugau uacacagggg 3840
cccaccuaga aaagccaaaa uaaucuccuu auuuuaaaau cagcuaauca guggcuuuaa 3900
ucccaucugc gaucuuaauu ccugucgcca uguaacacaa gguauuccca gguucugugg 3960
guuaggacgu gggugucuuu ccuaccacag ggcaguuucu aguguugccu cuucucccug 4020
cag 4023
<210> 12
<211> 15352
<212> RNA
<213> 智人
<400> 12
guaagggagg gguuuggcug cucgccaauu gcaaggugau uccuggggua gcagagccuc 60
acgaauugac cuuggggagg gcgugagccu gguguucugg acaauccuug caaaagcucc 120
aggcucccag ggcucaaaaa aucacaacug auaguauuuc uagaacagug gcccagggac 180
ccagaaguca cuaugagguu caccauuagg uauguggcug uggcauguuu guguccacuc 240
uaaauguggg gauaaucccc uuuaccuccu cuaacagagu gguaaaggaa ggaggaggcc 300
ugguuugacu cccugaccug cuauuuccua gccaggugau caugguaaga uauugaaccu 360
uuucuggucc caguacucau cuauaaaaca aauauaauac uuuacagagu gguaggaauu 420
auacaagaaa aguauacgca aaacauuuca uaaauuuuaa uaaaugaugg ccccaugcuu 480
cuuccucugg aaauggucuc aaccucaaug guugguguuu cuagagagaa aaaacgacag 540
agaaaguuuc auagucucaa aaauuuggaa agcccugauc uagcucaacc cuuuguucua 600
gaacugcauc ccagacagac ugcuugggac cugaaaauau cuccuccuuu gcuagaagga 660
uaagaugaga aggaauuaga uaaaggaggu guagagcaga gguuuucaca cugcaaagug 720
cauaaaaacc aucagagggc cgggcgcagu ggcucacgcc uguaauccca gcacuuuggg 780
aggccgaggc gggcggauca ugaggucagg agauagagac cauccuggcu aacacgguga 840
aaccccgucu cuacuaaaaa acacacacac acaaaaauua gccaggugug guggcgggcg 900
ccuguaaucc cagcuacuga ggaggcugag gccggagaau ggcgugaacc cgggaggcgg 960
agcuugcagu gagccgagau ugcgccacug cacuccagcc ugggugacag agcaagacuc 1020
cgucucaaua aaaacaaaca aacaaacaaa ccaaaaaaac ccaucagaga aguugguaaa 1080
agaugcaagu gcuaaauccc cacccccaau cacugugauu cagaagaacc aggccaggcc 1140
cagaaucuau ccuguuaccu uaggcgauuc ugaugaagac cauuguaggc cacacuuuca 1200
gaaacacuca aaauuagaau ccuucagaga agguggcaua uauaauauuu cuagcaugga 1260
auuauguuuu uuuucuuuug ccuacauuuu aauuucuaga acuguguugu agggaauguc 1320
agucacuaag aacuugauug aggaacugug uuuugucugu uucaugacug cucucucaag 1380
ucccaggaaa cucacuuuca gcuugucuua aaaagcaagc ugaaggcuuu uaaaaaugaa 1440
gcaacaugaa auaagacacc gcaguuucug gcacggucca cgcuuaaucc ccuucaaugu 1500
gugacuuucc guggaaaguu acucuacgau uuucccagcu cgucagggug gggccccaga 1560
gugaguauga agggucagag ccuagggaug ccaccaucag ugagagccca ggaccccaga 1620
aaaggucucu uggcucacca cacuguagga aaaauaaaaa gcaauguagu ccaaaugucu 1680
cuauccaaag uuucaaaaag aacuugauuu uagacacgcu ccuugacuug uuuucagaau 1740
cagacagaag agugaggcaa caaagguccc uuauuccagg cagcugaaua ccagcacagc 1800
caggagucca gugcuggugu uugcagagcc accagaggcu cccucucagg uguccagggc 1860
ccgcaugcuu uguagaaugg gcagaaugag caaugucugu gcaccugggc uuugcaggca 1920
gggccugggu acccagguuc gugcaauccu cucgucacca ugaagggagc agcaucauuc 1980
uucccuucuu gaagcaccuu ggccaccagu auagguaaau uuaccuccca ggacaugacc 2040
auugauucug ggaugucaau gccagagaua guaggguaaa ucggcaccug gguaaaacuu 2100
uccauuggag acuagaacca aaacucagga cacuggcuuc caaauguuuc uuuaucagac 2160
aagaaagacc aagucuuucc uuacgucuuc acaugcugcc uuggcaaaug cuagcauuca 2220
caaacccugg gcuaccuuga ccugucaccc uugcagaccu cagacggguc cugggggcuu 2280
gcuuucucgg uuucuguaug caggcacuca aaccugcauc aggcaccugu gaagggccgg 2340
gcacugugcu gaggccaagg cuccaaaugu gaaccuucca cccucacuga acucacagcc 2400
agaccagaga caagcaaaca ggacauuuca cagcagugca gccuagaaag ggccaacacc 2460
agcagcauuu guccccccga gcgguagcuu uuagaagcuu ccccagugau ucaauguguc 2520
cuacaaaugc cuggccccca cucccagaga uucugaguca gcuggccuag ggugcagccu 2580
ugacuucacu guguuaaaaa gcuucccaga uaaguccaau guccggccaa gauugagaau 2640
cacugaccua gaguuuaauu uaccaccuca gucucuauag accacgcaua auaauaguac 2700
cccacacacc ucugaggguc caaagaacuu ucauuugauc acccaugaga ccaccguggu 2760
guggagaugc uuucucucuc cuguucucuu aacaaagcug gugagcgaca gagccugcag 2820
uggaccggga gauggcccag aggagaaagc ucugccguag ucggccucag uuaaccacgg 2880
agcaccaccc cuaccugcuc uccucucacu ccugcuuccg ucucggugga gaaagaucca 2940
accgaagcag gacacaucua gucuucuggu gccuuuaaaa uguacuuuuc cauuugacaa 3000
auggauuaca cuaaaaacaa aaauuuacaa aaaaaaaaaa aaaaccugaa agaaauugca 3060
ggcauuaaaa ugggacuuug ccuuuauugc uccugggccc auccuauuug gguuuuuaga 3120
aaaacaagcc ugaggcaggc ccagaaaggc ucagggcaga cccuccgauc cucugaaagg 3180
agcaucaggc aggcaggggu ugcuccgggg ccagggaagg ggccccgcug ggacgcggcu 3240
guuauugcag cugguuggcg cgcagccaug cuuagcugca gugcgggaau gcugggccuu 3300
cuguucuggg cuguuucuca uacgcacgua ggccagugua uaaauaaggu uuuauuaaau 3360
gccaaaugag uucucauuaa caaagaaaga gggaaaaucu caguaaacca ccgugacggc 3420
aucuacccac uuugagucag gagcuggggg ugugagugca accuccgaga caagggaacc 3480
uguggagccc agagaaucgg aggggggcgc ugggguuagc accgacugag accagcugug 3540
uuuucucucg guuccuugga gaucagaagu gaguguuguc aucuucaaac aauccaaagg 3600
caguacccau ggccuuacua caucccuccc acaccauccc acccaucccc gcgcguacac 3660
ucacacgcuc auuugcacac uaucgcacac gcucacuugc gugcgcacac acagauuggu 3720
gaccuaggug gacugggaga gaaauaagag ccaaaugacu ggauuuucuc caaggaaauu 3780
uauuaauagc cccucuuggu uucaccugaa ggagcuuguc uucaccugcg gccuuugcag 3840
gcuuaacgcc cccagcuuga aacccagaag cucagacuug ggcccaaggu auuauuagug 3900
ccaacacuac cugaaauguu ucgcaccuca uaaaaauggu gugucaguuu cgggugagag 3960
guugggacgc uucccaucug auuuggccca aggcaugcau gccccuccuu cuccuucccc 4020
uccuccuccc ccucuucccc cuaccauccu uccuguuuuc ucuccaacuc uggugcacag 4080
cuuugaaauc uugcugagaa gcaaaucugu cccuucugcu uugaauguuu auuuguggaa 4140
guucggcagg ggaaccgagg cgggugccaa gaccugccau gcugcuggga agucugaguc 4200
ucccucccuu cccccuccua aaugcuuguu gauagagaaa agucagccuc cucggcauuu 4260
gggcucacgg uuuuccuuug aaaaugcuuc caguguggca ugauucagcu uucuuuucug 4320
ucccccaacc acugcucugu ugucauuuuu acuuuucuga uugcauuuua uccgugucuc 4380
uuugacuacg ggguggcugg acguugaguu ccaggaagaa aagggcccaa ucuugggguu 4440
cugacuacau gcgcccauca auguccuguu ucauucuugg cucuggcucc cugaauuccu 4500
gagucacugg ggagaagcgu ggguggaccg cccccuaccc agugagaguu gccacaguug 4560
cugcucuccu gggucauugg uugcagauug uuaaacuuca ccuaugcauu ucaacuuucg 4620
gguggauauu gcuacgucaa gugucuggga aagcccccac agcuacagga uuuuacagug 4680
aggucccacu aaugacuuga ugucaugacu uccucauucu uuccaauuuc ucccacuucu 4740
ccauaagggu uuugggaagg ggagaagaga aaggagugau uccugagugc caguaccagg 4800
gaacagcagg gcuguuggga ggaaacaaaa cuaaaucagg aagguuuuug uuguuguuuu 4860
ugggggguuu uaugaaaaua uucaagccac agcaaauaua uuugauuuau agcauuagua 4920
uuuuuucugc cugcaucuac aaaaaucuuu accuauuacc aucaaaauau ccucugggug 4980
aauggauuuc aacaaagaag aaauaaaaau gaaauagaag agaggccccu ucgugcacau 5040
ugagccuacu ggcuggauug ucacuugccu gccuugaugu cuuuucagcu ccaggcaggc 5100
aguaggccag ggcuuauuuu caugacagau cagauguucu uuuauggauu uacaaagaaa 5160
gaaauacuga gaagucaaaa cugaagucac uuaagacaag agcaggcccc ugggaaggcu 5220
gccauugagg auaaugaguc cugggguccu ggccuuuguu caguaaauac gcacuaggcg 5280
ccuacaaugu gugcaccaau gugugaggcg ucagguucuc uccaggguca guugguuuua 5340
agaaagguuu uggcuucuga uauguuuuau cucuacagaa caguagcucu uaaccuuucu 5400
uauggguuag gauuaccuuc gagaaucuga cuacagcucu agaccuguuc ccuaaagaaa 5460
acuaaguuca cagggacaca caggaugggg cucauggagc agcugaagcc agaccccagg 5520
uuaauagccu uuacauuaaa auguuuuucu accuaccacu aauaugcauu cuuuaguaag 5580
cggucucaau auacaccgau ucuuccuuaa cucuguuuau gaaguauuca gcauccuccc 5640
ugcccccuuc agcauccucc cugccccuga gcacaggauc caauggcgug aggaccacag 5700
gccugggcag cugcuggggc auacaggcau cucuuagugg cugagagacu gggcccuggc 5760
ucuauguugg cuccuaacuu gcugccauuu aaaggaaauc uuagccuccc auccguaaaa 5820
ucgagaaaau aagacuuguc cuacacagcu caugaaauag uaaugaaauu cacauuagag 5880
aagagaugga aaaacacuuu gaacaaaaag cauuuugcuc uuauaaaagc acagccucuu 5940
uugagaggcc cuuugcuccc cauuucuccu ucuucagacc cccccagacu aggagaaggu 6000
cugucucaug gagugaccuu uuggcugccu cuagauucca agcucaguuu ugcuuucauu 6060
aaccacagau acugggacgg acagaaaaag accuaguuuc uguugagcca aagagucuca 6120
uaacuugucu guucacauac ccaagagccc acccucuagu ugagacacuc aguucccucu 6180
cauucuggga gacugcaugu cucugugacc uccugguaga gaccguuuga cauguccccc 6240
aaccccccag ugauugaguc ugaauucucc acugaugacg cauuuccuag cacucagggu 6300
guccccuccu gguugccccc ucaccacuga agcccgcuuc cucccuuuuc auuugaugcu 6360
uaacaacugu caguuugcaa gaaacaugcu ucaaauccac auucucccag uugccuagca 6420
acaacuuccc ucccggauaa auguggguuu ccuguagcuc agcccaggac ugaacacagc 6480
agcacacacu ucuguccacu gcuucaacug cuuuucaccu cuggucugca ugccuucaag 6540
acugcagcuc aucccucccu ucagaaccuu ccauagccug cagaggccau gucugcccca 6600
aaaagacaca uugaaccuga ggcuacuuau uuacccuugu guuagguaua uccucaacuu 6660
agaaauuaau acuguuucca gauugucuuc uuugaaucac agaaaguaaa acaacaaaac 6720
auucaaugcu uaagacauuu caugugcggu ugggugacau cuguuugaug aacacauuug 6780
auccaaagca ucagaaauac uaugccaaca agacuuuuua ggaggugaua aacaugucug 6840
uucuaccuua agaaaaaaau auuacacagu cccaagggag agacaugguu uugaucccag 6900
acaacccaag cagagaccuc uuagggccgg aaucaucuug gcugcugccu aggaccuuau 6960
aucaauuucu uaagcacagg aucaaggccu aaaggccccu uagacugacc ucaguuagua 7020
gaggcagauc ccuucacagc cuuaucuucc uuagaggucu agucugaccu ugaacuucgg 7080
cuggcagugc ugucaguugu gaugugugac auggaagagu uauuuguuac uuggaaaauu 7140
aagagaacuu auuuggcaua ggaaauugug ugugugugug ugugugugug ugugugugug 7200
ugugugugug ugugagauga uguuugccau uuugaucugu gacuuuuuuu uccagaaaua 7260
guuucucagu uccauuccaa cuaaacuuac agucucuucc gguucuuuga cagaaacaau 7320
ucaugugaau uugaacagau aauagggaag ggggaaccaa aagaagagga gagcccuggg 7380
aaaguuauuu uauaauuuau ggcaaccuca gucaggcaac ugugaacagg uacauaugga 7440
gggcucccuc gggacuaggc aguauucaga gauguaaggu gugaggaccg gacccucauc 7500
auuuaccauu cccacuaaaa agagcuggga aggaaauugu agcuguagca ccaggcacgu 7560
aacuggagcu uaguaacuau uuggugaagg aauauuauua aauuauuaac aagauggaaa 7620
aaaggguauu aaccacacaa aaauacaucu caagcuauug uuucucuguu cccuuucccc 7680
caaauuccua gucuugcucu uaucuggcug ucucucuagu cacucuuucu ugcugacucu 7740
cuucacguuc cuuucuccac cuggaauucc ugggcccucc ccuuuuacug acagacacug 7800
uccucacucu cacagucauc aguuugucuc uuuacaaacc ucagcucaag ugucacuucc 7860
ccguccccag gugaaacuga cugcucccuc ccuguaaguc accaugauga cugcuauaua 7920
uagcccucau ggaaccuaaa accucaacag acacagucuc uuuccuacuc uguuauaguu 7980
uauuuacuca uuaauuacca caacacguau uauugagcac cuacugugua ccaugcccag 8040
aagauaaaag acaaacaaaa uaaaaccuau uccuaugcuu aaugaguuua cagucuagug 8100
gagagauaga uacauuaaaa aauaacagca aaccaaaaua aaagugguaa auaaaugcac 8160
ugagaaagac aggaauagcu aggaggggca ccuaaucccu agggaaggaa agcuggaaga 8220
gcauggugau gggggaagaa ggcuuucugg agaaggugag guaguuugaa augaguugac 8280
ucuggccagu agggguagag ugagaauggg gugagacagg guggguuggu cauuuugauc 8340
cauuaguccu caaagugaua ggacuagugg cuaaggacug caggcuuuac agaagccuac 8400
aaaacuauuu gagauuugaa guuuuuuuuu uuuuuuaauu ggcuccaaaa gaaaaugaaa 8460
aaacuuuaga auuauaauga augaauauua aaugaauauu uaaggaaggu aauuuuauuc 8520
aacuucauug uuaaauuuag uuaaaacaag cccuugaguu ucauucaaca cuguuuuauc 8580
auaccguuga ugagagaaaa caaaacugau uccuggccag ggccacuguc agcguggggu 8640
uugcacaucu uucccauguc ugcuuggguu agcuccaggu acuccuguuu cccccacauc 8700
cccaagaugu gcccauuagu ggaaacggug ugucugcaug auuccaacgu gagugagugu 8760
ggguguggga gugagugccc cugccauggg agggcauccu guccagguua gauuccuacc 8820
uugugcccug agcugcuggg auggaaucca gccacccaug acucugaacu gaaauaauug 8880
ggugaauaau uaucuuacuu uuuaauuaau cuuugaaaau guauguauag uucacaugua 8940
uuucaauauu uaauauuaga aguauuuuag ucuuuauuuu gaaguuuggu gauuuauugu 9000
aaccagaaac aagcuauaga aacuuaauuu ugggccaagu gcaguggcuc acaccuauaa 9060
ucccagcauu uugggaggcc gaggcagacg caucacuuga gguccggagu ucaagaucag 9120
ccuggccaac augguaaaac ccugucucua cuaaaaaaua caaaaauuag ccagaugugg 9180
ugggcaccug uagucccagc uacuugggug gcugaagcag gagaaucacu ugaacccggg 9240
aggcggagca gugagcagag aucgugccac ugcacuccca ccuaggcgac agugugacac 9300
uccaucucaa aaaaaaaaaa aaauagaaaa gaaagaaacu uaauucuggu uuauaucaau 9360
uagccugugg uaaaauuggu uucauuauag ccauuucacu uaguugaagu uuccaauaac 9420
cuguggauga auuaagugag gauuuacuau auucauaaaa ucuuaaauuc caaagccugu 9480
uugcaguuca gguuuuucca cuuuacaaac acuucuaagu auucacaaug auugcuuaaa 9540
auucauacca gauaaaucau uaaauaaguu guucaaaguc aaauaauuuc auaaguaaaa 9600
auuaggagcu uuuagaaaac uauaccuaca uagaccuaga ccuauagaua gacagagauc 9660
ugaauagaua uggacacaga ugcuuuccaa aguguucaug ugaugugugg uggaguuuca 9720
agaccagagu gugccugggg ccugcagaag uaaaggagag gggauggaga gaagauuguc 9780
cacauggcca ugggcaaucu cccacccaca cucaagugag gaagacagga aacaaauuca 9840
gaaagaagag aaaauaauca aaacugaugg gagcuuguga cugauuuacu uaugcgcagc 9900
cucccuggag acaugagugu ggcuguuccu uagguugugc cucugggcuc cuacccccuc 9960
uuagaugccu uccuauuauc uaggaccugg uugcuuuuug ucugcauagc uucuuuggau 10020
uccagucuuu gaugccagcu uccuccuaaa guagccuuuc agaugucccu ugguuacccu 10080
cugcuaucua agggcucauc cuaccccaca cucauuccca gcaccaauuu cuggaucucc 10140
aggcuggaga uuuagacaau gggaugggaa gaacccauga ugggucccag acagaaagug 10200
gugccagcca cagaaagggc acacaggcac agaaguuggu uugggguaag acgauguggu 10260
caguucagaa cacgcuggau cuaggcagau gcccagcaga caguuggaua uguaagucug 10320
aagcucuggg gagaggucua gguuggaggu acagauuuag aagucaucaa caaaaaggua 10380
gcagauuaaa ugauaaagga aaugagacua uccggggagu gugcagagug agaggagcaa 10440
gggaggcccu ugggaaccuc agcacuucag gggaagguag agguacaguu gcugguggga 10500
aaggcagaga aguagcaaag caaaccaggc aaaagcagug ucacagacga ccagggagga 10560
aaaggacaug aucaaaaugu ugagaaaagc agagagguuu gaaaauacaa gaagcaaaaa 10620
uguccacuag acuuaaaaac caggagaaaa cugggggguu cuugauaaag caucuuagua 10680
ggauggugag gguagaagcc agggaagugu uggugaggaa gugaagucac ugauuacgga 10740
cuaugcuuaa aagaaugugg gaaugaaggg uggaagagag aaauuagacu guagcuaggg 10800
agacauaagc gaucagaggu agauucuuuc ucuccugugg gagaaucuug cacguauaca 10860
cagcaugacg acagugaugg aagggcuggc gaagccucag ggagacucuu ggagguaaac 10920
cccaugaagg gaggacuuug uuucauucac ugccgugucc ccagcaccug gcacaauagc 10980
agacacucaa uacauauuug ucaaaugugg gauuuuauca uuuagaaacu gcaccuggcu 11040
gugaguaaca aaagucagag aaaccguggg uuucauuuuu cuccccaggc agagucugga 11100
gcuggguccu ccaagagggg uuuggagcac cacagguuuc cucaagaccc ccaggcugcc 11160
cuguguuucc cuccuucauc cccagcauau gccugucauc uggugaccuc caaacaccug 11220
ugcugccucc uccagcacau ccauguugca ggcagggacc aggcaaaggg cagaggggcc 11280
uacuucaaaa gaccauuucc agaaacccca uccuaugacu ucuccuggug ucuugguuac 11340
cauugugcca uaggcucacc cuguaugcau gggaggcugg gccaggcauu augacuuuua 11400
gcaauauugc auagauaagc aucaaucuuu gucacuguga cgaagccuag ucacucagug 11460
cuaggcaagg uuaauggaau ggguuggugu gugcauuauu cuugaggucu uucuuaugcu 11520
ucauguuaua cauuuauuag gacguuuagg caacaggggg auaaaaauga agaggagaug 11580
caugcuauga ucugaauguu ugcauccucc ccaaaauuca uauguugaaa ucuucauccc 11640
caagaugaug gcauuaggag guggggccuu ucggaggcaa uuaggucaug acugggauua 11700
gugcccuugu aaaaccccag aaagccagcu ugccgcuucc accauaugaa gacacagaga 11760
gaagaugcca ucuacgaauc aggaaaugag cccgcaccau gcaauaaacc ugcuggagcc 11820
uugaucuuag acuucccagc ugccagaucu gugggaaaua gauuucuguu guuuacccag 11880
cuuaugguau uuuguuguag cagccagagu gaacuaagac agugcugauc ucguauucuu 11940
ggagggaacc cuuagucuuu agggaaagca aagccaccau uuggggcagg guguucucca 12000
agugcugcca cauaugcuga ugugguuaaa cugcaaacua ugguaaaaau guggaggucu 12060
guggaauugu caaucaggaa aaagauauaa aaagaaguua aagucuucgu gcuucuggaa 12120
ggauaugugc caaauuguua acauugauua uccuugggua gagauguggg gaaguuugca 12180
gagacaguuu ugccuuguac uuuauauaag uaaacagcua cuacuucguu gucuuaaaaa 12240
aaaaaaacag ccuaugugcu cuucauguga cucagaacua ccuaggcaau acgauuaauu 12300
gaauuaguaa aauugaguga uuaugaauuu ucaggaaguc auuaauuuac cacuucuuua 12360
uuacauccac uucuaacagg acuucaauau aggggaauuu gacuucaaga uaaaaagacc 12420
aaauuuauuu acccuuuuaa aaaaagacaa cuuaaaagca gacuugucuu acagaaccuu 12480
ccuuaguugg acaucgauga guguacagaa aaugcaaugg auaaaaagcu uggugauaca 12540
aagauaaaaa gugggguccu guccuuaaug aacauaccau uucauggagu aucaggugua 12600
uaaacaauua uaaucaaucu gcuuguuauu cugauaagau cauuuacuca cacaucaaau 12660
acugagugcc caccacaugc ccagcauacc uagaagucau ccaguaugau uucugucuac 12720
auggagcaua gagucuuaca ggggagauag augacaagua aacaccagaa uaauuaccaa 12780
uggugaagag cacaaggaag gaaacagaac uccuaaagag agcguggcug ggcaggggug 12840
agcaagaggc auagaaaaag gggcaucuaa aucuacuugg gaggaagcug uuucucacau 12900
aggucaucau guuaggaaug agacuugagg gaugaguaga aguuugccag gcaaagaagg 12960
aauggggggg aauagagagc agagcuaggg gcaggagaca gcugacgugu gagcagacau 13020
aaaaagaagu ccacuguggc agcagagaag caggagagaa ggcaagugag ggagccaggc 13080
accagcucac agaggucaug ugugucaaaa cguaguaaug gccuucucuu cuggagacag 13140
uagggagcca uggaagaugu uugagcaggg aaagcgacau gacuggauug gccuguuggg 13200
uaacucagac cacaaugcau uggaagggag ggggcuagag gcaaggggac uggcaagaag 13260
gccaguccuu uuucuaugcc uauuuugaug aaauauucua gaagggaagu gaacaaaggu 13320
aguccuagag aggaagaaca aaacagauag gauacuuccu uaguauuugc ucauucgaca 13380
auuuauuuuu gcauauacac uaaaaccuuu uuuauuauua aaacguuuua uuguaggaaa 13440
aaaguaugaa aguagaguga auaauaaaau gagcucccau ggaucuauca cccagcuuca 13500
acuauuauca auauuuggcu guucuuguuu uaacuguucu ccaccuuuuu uuccugaagu 13560
uuuuuugaag caaaucacag acaacauauc auuucaccau auguacuucc cucuguaucu 13620
cuaacaugua agaacuuguu uuaacaaaau caccaugcua ugaucauacc caacaaaauu 13680
uaucauaaug ucuuaauaau accuaauacc cauuucaugu ccacuuuccc ccaauugcua 13740
cagcugguuu guucagauca gaaucaaaau ccaccugugg ccauuuuacu gcuaugucuc 13800
ucaggucucu uuucaucucu aauaaucuca ggggagacag gagggaggac gggcaggacu 13860
uggggcuaac uugcuuaucg acacacaguu uugccuacuu gcuuccuccc uucacaccca 13920
cucuucuucu cagccccacc cuuguaugga aaaaacagaa auuaaagugc uuugcccagc 13980
acccacugaa gcuauuucga aggaguuuga agaguacucc cggcaagaca aaugccucgg 14040
uccagugcuc aggucaaaga ggggagacgc uucucaguga ugugguguca auagcagcuu 14100
aguuguucuu uccucuggaa aauucuaccc aucugcuuug uaacucccau accuaacaag 14160
gccuuuuauu ucacaauuag aaaauaagcc ugaaauauga augcugccug aguguaccua 14220
cauuuauucu agaguuucag ggucaaaaag aauacaagga ccucugcauc uacagccaag 14280
aggagagggg caaagacaca cagcuacaaa ugagaaccug gcuggucaaa gccuaacucc 14340
accuguuugu cagcacugau gcaaguuagg ucagcccaau gaucauuuag gagaacugug 14400
cuggcaaaua aaaagcagag gcuuuugguc cccagauacu uggaugagaa uuacaagucc 14460
agcugguuaa aaggcacaug cccagugcuc acuucacacc uacucaggaa gcacacuuga 14520
guuggaaaac cacugucuuu acacuuagaa cucaguccua caugacuccu cuaggaucag 14580
ugauuccauc aguuuugaaa caugaagcau gaagucaaac aggacaugac cuugguuucc 14640
agaaaaccag auguucacau cagucucugg agcuuggagg cagcacaccu ggggacuucc 14700
acauccccug ccgagguggc aaaagcagga gcagugguga guucacaugg gcugggguuu 14760
ccugaacacu gcuggcaauu ggagaaucug caagggaacu ucuccgacuc cuaccagcag 14820
cugcuuuaaa auaaagguga uguagcuggu caaauccucc augagagagc aguguugaau 14880
ggaggaagag acacaaccug ucugaaaaug gcacaaagga agaaagaugu aaacaaugac 14940
gagaagacug cagugucuac aaagcuccga ggugaacaga ugggcacccc aggcccgcag 15000
cacuuccuuc agucucugcc agcugcacuc uguuuuccuu ccuccaggaa ucuuguuugg 15060
ugucacuaaa acagcaauua gaaucacuuu gaaauaguga uaguauuuaa uauaacuaug 15120
aaacuaucug ugauugacaa gugcagcaag gagucuugga augagagccu uuauuuuuuc 15180
aauuaaauaa aagaguuuuu uguuucuaaa aguaaucuug cagaaaagau ccugcgauca 15240
gaaagaagga gggggggagu uuucaaacau auaggagauc agacugugcc uaugugugua 15300
uauaccuaca aacauauaua uauuuaaaaa auuguuuuac ugucaauuac ag 15352
<210> 13
<211> 2633
<212> RNA
<213> 智人
<400> 13
gugaguagcc ugaugguagu aauuauaauu ucauuauguc uuuccaccau uuaccccacu 60
uaugucaaau aauuuaauug uauuucaaac cuguucaagg aaaaguacau uugaucuuuc 120
caucuagcaa uuucaaagca ccuguucaca ucccaaauua ucugugcucu uaaguaagag 180
gcagaaagaa aggaaccacc cuucugauuu cacaucaaaa aagaaaugcc acuggcaaua 240
agcaacuugc cugguguggc auaaaucauc agaagacuua caguugaauc uaagucuuuu 300
caguacugag gugguucauu auucuguuac agucuuaaaa uucacauaaa uauauacugc 360
caauaauaau agcauacacc uuuauagcuu acaggcacuc uucuucuaag uguuuuaccu 420
auguuggcuu auuucaucau aaagaaaaca auggacuuuu guguuguuuu guaaaaagau 480
gcgcacauuu uaauuaacau cugauugcac aagucuccuc ccauauagaa auggauucuu 540
ccacgcaaua gauaagaggu gcuggggaua ugaugaugaa cacacagauu uggucaugac 600
ccugugggaa agagagaugg gaaaaaaaca auucucuuca agugugauga guguuacgaa 660
agggagggaa aaguugaaac agguuuuuuu ccaaacuuuu cucccuccau uauucgcagc 720
ugacuugggc uccaccaacc uggaaaacug caugguugga aucugucuuu auaaaacgca 780
ucucaaccug ggccgaguau gcacacugau gugggaaagu uagagaagag cccauuguac 840
uaaugcucac cugcuacagu gggagucucu guuaaacagu cuuuucuuca uagcauuaaa 900
aaaauuuaua ucacuacaau aagguugaaa uugauagaga auguacaaac aauccccaaa 960
guauaucaac acucuuaguu cugaguagaa guuccagaag gcuucuugac ugucuagaua 1020
gcaagucuaa ucauuuguga acuaaguuaa agcagaaggc ccaguuuaua ugaauuggua 1080
uuacaccauu ugaccugaga acagccccuu caucucugag ugcuuugacu aaaugagcaa 1140
cauaauaaua guaauaaccc cuuacaagau gucauaagac ucacuguugu ugaagcaauu 1200
ugagauuuug acuuuauuga agcauagaug gugauuauag gcaugacuca cuguguggau 1260
ucucccuggg cucaucaguu ucagagggca aguguuggca uguggacaaa gagagggaug 1320
acacguaaac auggcuuauu gcaaugggga aauauuuuca gucucacuga uugaauccua 1380
augguuuuau aaauucccca guaccacuga aagcaaagca aguaaucagg uguguuuuag 1440
gaauaaaagc agcauuauuu uaauuucgua uuuuccccua aagcaaagcc aaauggcauu 1500
augggagcca agcuacuggc agcuccacca gccuucuccu gaguucucgg cauuacagau 1560
cuacccucaa aggaugaggc cagcaagcac cacagggugc ccacauggag aagagaaggc 1620
caccaaccuc cucuuagcug gcacagaauu gaaaaagugu uuuuccagga auggauacuu 1680
caucuguucu guauuugcua gaauuuuaaa acgcacacac agacacacac aggcgugcac 1740
acacacacgc acacacacac gagaaaacca caaaccacac auuucaagga aauggaagaa 1800
uucauuggua aaauuaagcu aauaagauua uuuuccaaau auaagaaacu aaauuuuaga 1860
cuauuuagcc aaagaaauuu gcucugaucu ugcuuuucua caacagaauc auuccccaau 1920
cauuuuauuu cccucuuuuu cuccccagua uccccaucuu ggugggacaa cagaacccaa 1980
gaacuggcuu aacaguaaaa uauuuucugc auuugcccaa ggacacauuc ccaacgaauu 2040
caaauaaagg agacuagaag aagagaggcu auacuacagu gcucuagggg ucacucugug 2100
auuuguuguu guuguuguug uuguuuugag acggaguauu gcucagucgc ccaggcugga 2160
gugcaguggc acgaugucua cucacuguaa gcucugcccc ccagguucac gccauucucc 2220
ugccucagcc ucccgaauag cugggaguac aggggcccgc caccaugucc ggcuaauuuu 2280
uuuguauuuu uaauagagac gggguuucac cauguucgcc aggauggucu cgaucuccug 2340
accucgugau ccgcccgccu cggccuccca aagugcuagg auuacaggca ugagccacug 2400
cgcccggcca cucugugauu uucuuuaagg cucauccuag uauucuccua gucccuaagu 2460
agauggcagu agguuuuguu uuuuguuuuu cgcagcugga uuaaggauug cugagaauau 2520
auggauguuu ucuuuuaaau guggaaguca aaccaaacgu uggagcauug gccucacagc 2580
agauuaugac ucuagcugcc uuaaaauaac cugaagacuu ugccuugccc uag 2633
<210> 14
<211> 1016
<212> RNA
<213> 智人
<400> 14
guaaguuuuc ugaguccugc uuauaaauug gccucucaug uugguuaagu ugaugguuua 60
acacuucuag gugaaaccaa accugggguu gcaucugucu ugucuugcug aguggccuua 120
gguaaagaga cuucucccag aaaguccacu uccccuugca gaaagggggc auugcuuaua 180
agcaauucug gacaugaacc acagaaagaa cugaggccca cuuggaaagg gaacagaggg 240
gccauuuccc acugauguaa uugaacuagg gcuaaguuca agaggaagag aaugauccgc 300
aaggaagcaa cccagaguuc caggugaagc ucaggucaga agggcccugg caaguaaaca 360
cggcuguggg augcuuuuac aaacacaaua ucgugaaaau cuaugugugu aguacugaau 420
uacauuccaa auggcaaauu ccuggcaaau caucuucccc accuuucacu auuuuuuuuu 480
uuuuggucuu cuauggggua aaggaggaug ggguggggaa gaaauguaac uggcugcccc 540
ucuaguuaaa aacugaaaag aggcagcaag ggacaugcca aaaguaguug gacucuaaga 600
uagcuacaca caacaaagca gcuaagcagc uaauugaagg gaaauuacug aggcucaagc 660
ugagauucca agcgggggcc uuguuuggcc ucucaguccc uuucaucuga gaaaggccuc 720
aguuccuagc aguaaucaga ggcaggcuuc ucagccuccu ucuccuaaag cagaauaaac 780
cacagggcaa gucgcauccu uuguuucucu gaugaggcca uuacugagag ucacuguggc 840
auuuugcuac uaaugaugag cuuguuauug gugggguaca gccuauuaau uuagguuauu 900
caucaaaucc uccagcaugg aguugaauga gacaugugau guggauacac uaaugacuau 960
auugaguuac aagcaauggg gaguuucugu aaaaucuguc ccuugucucc uggcag 1016
<210> 15
<211> 615
<212> RNA
<213> 智人
<400> 15
guaagauccc agcugggcuu gccuugugua cccuggaccu cccagaagug ugugugugug 60
ugugugugug ugagagagau gugccuuccu gguagcacau cucauguuug uuuuuugcua 120
aguggacucu ugcguuuccu cccccaucca cagucaucac uggaaugcuu ugcuucagug 180
ccccugccug ggcccucccc ucucuacugc agccuacaau gagguuuucu uucccauugc 240
uugaauuaua ucccuaaugg aaggguucac aauucucuga auccuggcua cucagauaaa 300
gacagggagg aagggaggaa ggguauuuuc ucccaggggg uccaaaucua gcuuuaacga 360
gggagguucu gagaaaauaa uaucaucaau auuacaugga cuucugagau acuaagaaau 420
uagauucugu cagcccagga aguugggaga uggugaauug uucugggaaa uagcaauaga 480
cugagaaaau aaaaacacuu ccuugaaaag ccuuucccua acacuaagug auaggggcag 540
aaaagacaca accaaaaguu cucucucacu uuucucucug uucgugucuc ugucuugauc 600
ucugucuggu uuuag 615
<210> 16
<211> 702
<212> RNA
<213> 智人
<400> 16
guaagggggg uuggaggaug gggaggggag gggaggagga agcggugggg gcaagaaagu 60
uccacuuguu uccuuuuccc aggaaagagu uaaucgcuau uggaguuaga ucaaaauaca 120
acaagcaggc cccaaaggcc uucauuccaa gcagucacca agugggguca cugacuuugg 180
augagaaaua uguuucuuga auucugggag aagucuaaaa gcugccacaa gaccaguggc 240
uuccuggagu uuccuacuuu uaugaauuca cucaagggcc ucaaauucaa agaggcaucu 300
ccccaagggg ccagcucugu aacuccaaag augguggaau guguuugucu ggucucauuu 360
ucagcuuugc aaaaugaaga caagaguucu auauaucagg gacacucaaa agaaaacaaa 420
aauauccaua agcaaaagaa agcuuuuuau acaccauauu caaugacccc caucuggccc 480
cuccuuugcc ccuacacauc uucccucuau ucuagagacc cauggacuug gggaaauggg 540
auauagauag guauguuuca uaguggaaca agcucaccag cucuucaggg agccuuagca 600
ucucuauccu caaucacuaa aaauuagaaa uggcugaaga acaagaccaa agauccuaug 660
gaauuucuaa gcagagcagu gacuguauuu cuucuuccca ag 702
<210> 17
<211> 14372
<212> RNA
<213> 智人
<400> 17
guaaggggcu gcaagcccca cagugggccc cuugaagaua gccccaugag uggggccaga 60
gcucccuuag caagucaagu ggucuugaau uuaagcuuuc auuuucccca cugaagaaac 120
aagaaucccu acauccccug uacaguucuc auucucuaac agcuuaucca uacuuaaaac 180
uuaucuaugc ugaaaacggu uuccucuuca caucuccuac uucucaugcu gggcaccucc 240
uccuguagcc cccuuuaagc aucugugucu guccucaacc cucuucuguc ugacauugcu 300
ugaguggcca ucuauggcca guguccccuc aaccccacag uccauugcuu gcuggacacu 360
ccugcccuca aguucuacaa gcacaucagc cucaacaugu ccccuccaaa aacuguaugu 420
ucuccuugcc cauagaacau auccuucucc uauauuuccu auccuaauua acguccucag 480
cauuugcccg aauucucaag ugagggauuu cagggucauc ccuaauuuuc cuucuucacc 540
cuccacacag uagcugucac uuacugagug uuacuuuaug ccaaguacug ugccaacugc 600
uuuuacacac auaugcuuca uuuaauucuc acagcuccau gaggcuugca ccauuaucau 660
ugccaauuug cagaugagaa gccagggcuu aaagagguua aauaagaucc cacgcaugac 720
cauuaagagg agcgaacagg auccagcucu gggggugccu gaguucagag ccugccuuuc 780
ugauuucucu uaccaagcuu ugucuccucu cccuccuaaa uaucucucaa cucugccucu 840
ugcauuccag gcucucugag gacuagaggc cuugucaucu cugcgccagc ccauuccaag 900
ggcuuccuuc cuggaaucca ggguccagcc ucuguuggcc caggcauuuc ucuacacugg 960
caccagaguu acauuccgca caccugcuua cguugcucuc ucacuuaaaa ucuuaaugac 1020
ucgaccccca aauaacacag gucccuucca aaucuguccu accccaccuu cccagcccuu 1080
gcucaacucu gcuaccuggc ccuuucacgc cuacaggcau ucccauucca ugaccucuug 1140
ggauucuacc cuuugcaaau gcuguuuuca uugcccauuu auuagagcgc uuuuggucac 1200
aagcuuuuug cuuaaccaaa aagaaagcau uuauuggugg acauaaauaa ugaaguucag 1260
gaggauccaa gaguuggaag ccaccaugag accccugugu ccuuccaccu cacuuuucua 1320
cucgccucug cucagcuuca ucucuggcca ggcccucucc ucugcugaug cccuagcugc 1380
uuacagcccu uagcagucau cuauacacca aaaaucccuu ucccauagca gaagcaaugc 1440
uccuagagag uuucccuguu ggucuggcuc cuguacccac cccuguguac ucugauuggg 1500
aggccugggu cagcugccca ccauggggcc auuucuauga gcaggauuac ugugaagugg 1560
aggaagaugu uuccccaaaa gaagaaacac aagguagaaa aguguauguc caccaaugcc 1620
ugaaaugacu gucccuuucc ucaucugcug agcuucuacu cauucauucu uugagacuca 1680
gcacucagcu cuuaaauguc acuucugcuu ugauggaggu uuagucauuc acuccucugu 1740
gcuuccuggc ccucucuuca caccucucuc agaccccucu cccagauaga uuagaguugg 1800
cuguugacau guccaucucu ggcugggcag cuaaacugga guuauuuaga aucagggagc 1860
acaugucagu cauuuucaaa uucucaaccu cauacuccca guaaaugacu ccaucuaagg 1920
guggaccacu cuugcccaug ggccaggucu gggucugugu caucuagaac uguuggaagg 1980
uaggggcuuc ugugagcagu aggagaggga auaaacucga gggcccucgg gagcaugccc 2040
ucuugucuca gacuugugag uccugaggau aacaaacuag ugaagaaaag ccucguucua 2100
ucugucaccu ggugcucuug aggacuuucu guugcccugg ugccaccaca auuuuccaga 2160
gugugugacc cucgcucucc aaacucugga aguggcagcc gaggcucccc aguggccuuu 2220
cagaaggugc cagucaugac agcagcacca aacugcaggc aacuacuaag cgaucaccaa 2280
cuugucugaa gauaagaaug accuugaaug cauuuuauaa aacaggauuu uuuuuuuaau 2340
uuuuagauuu ucuuucuuua uuuuaccuua aguucuggga uacaagugca gaauguguag 2400
guuuguuaca uagguauaug ugugccaugg ugguuugcug cacuugucaa cccaucaucu 2460
agguuuuaag ccccacaugc auuagcuauu uguccuaaug cucucccucg ccucgccccu 2520
accccacccc aacaggcucc ggugugugau guuccccucc cuguguccau guguucucau 2580
uguucagcuu ccacuuacaa gugagaacau gugguguuua guuuucuguu ccuguguuag 2640
uuugcugagg augauggcuu ccagcuucuu ccaugucccu gcaaaggaca ugaucucauu 2700
ccuuuuuaug gcugcauagu auucuauggu guauauguac cauauuuucc uuauccagcc 2760
uaucacugau gggcauuugg auugguucca ugucuuugca auuguaaaca uacaugugca 2820
uguauuuuua uaguagaaug auuuauauuc cuuugguuau auacccagua augggauugc 2880
cuggucaaau uguauuucug guucuagauc cuugaggaau cacacuaucu uccacaaugg 2940
uugaacuaau uuacauuccc accaacagug uaaaagccuu ccuauuucuc aacagccuca 3000
ccagcaucua uuguuucuug acauuuuaau aaucaccauu cugacuggca ugagaugaua 3060
gauacccauu ugucagaugg guagauuaca aaaauuuucu cucauucugc agguugccug 3120
uucacgcuaa ugauaguuuc uuuugcugug cagaagcucu uuagccuaau uagauccauu 3180
uuucaauuuu ggcuuuuguu gcaauugcuu uugguguuuu agucaugaag ucuuugccca 3240
ugcguauguc cugaguggua uugccuaggc uuucuucuag uuuucaugau uuuagauuuu 3300
acauuuaagu cuuuaaucca gcuugaguua auuuuuguau aagguguaag gaagggaucc 3360
aguuuaaguu uucuacauau ggcuagccag uuuucccaac accauuuauu aaauagggaa 3420
uccuuucccc auugcuugug ugugucaggu uuggcaaaga ucaggugguu guagaugugu 3480
ggugcuauuu cugaagccuc uguucuguuc cauuggucua ugugucuguu uacaaaacag 3540
auucuuaagc aucaacccag aucgacuggc ucagaauuuc cagggaagag gccugguuau 3600
cugcauguuu acagaccuau uagauuugug ggaccugcag uucccuugua caguuaguua 3660
cucaauuaac aucucccucc ucucauggug ccucuaccug cuaagcccuu auucccagcc 3720
aggcccacca ccauccaccc acugcuguua uaacauaagc aggaccugug cgagggggug 3780
uggacggagg agagaggcuc uguugcuuca uuugugcagc auggaguuca gugguucuca 3840
caauguuuuu gcaaaguaua uaaagaauac uccuugucua cuugacauuc guaucgugac 3900
auaaaugucu uguuuuccag aaggauuauu uuuuccaagc agcuuguucc uaaugcagcc 3960
ccaggcacca aacagauacu uaaaauauau uaauugcuua aaugguuaag aauucagucu 4020
cuggacccac acugccuggg uucaaauucc uauuaucugu gcccaguuuc caagucuaua 4080
aaauagggau auuaauagca cuuaccuaau aggcucguua ugagaauuaa augagcuaau 4140
ucaugcaaag cacugacaua uaguaagcac uuaauaaaua uuagcuuuuu aacaaaauac 4200
aagccaaaaa acacugcuua ggagaggaaa ugauguuagu gccuccugua aauaggccca 4260
gccuccaagc uggugcuccu cuaggaauca caacgcugca aaucacaucc uccggggccg 4320
ccaggacuuc acgagggccu cugagcagag ggguaugaug ggagcagaag cccagcagcu 4380
gugaugaugu gguuucugau cuuccugccc uugggguggg ggaggaggaa agcaaggggc 4440
aaugaacaga aaggagaaga uagcggggag gaaaugugug aggaagaaac acaucacugu 4500
ggcuuguccu ggauuuuucu gcuucuguuc ucguguuuug ggaagucugg aggagacuug 4560
aaaaucauuc auguccccac ccugaggaug gcuuaguagc agagaggcca ugaaaacucu 4620
uugcugaugg cucugaaagc aaggauguug cuucacuggg cugcugaagg ccugccuggg 4680
gguucugagc agagaguaca ggccccuccc aggagggcgg ccuaaccacc augcuggcau 4740
uucuguggac cauggucugc ugucucagac ccccuccaca auagggucug caaucucauu 4800
caccccauaa auacauucug ucuuuccucu gauccccucc cauuagcagg gggaaauaaa 4860
uggaagucag acggcccagu uagaaggcag gcaguggagu aggaaaauag augauggugg 4920
uuuggggagc cucacaucac ucauggggag acauucauuc ccaugggccu uccaaucacc 4980
cuuuucucca aaucuaagga cacaggacaa auggguccuc auacaggcaa auaucuuaaa 5040
cugguaugug uauucauuua uaguucuaau uuauaugugu cuuuauucac auauauuuug 5100
cuucuggaga aaagcucaau uagaaaaauu aauacauuau ucuucuuauu gcccuucagc 5160
uaaaacaagc auacacaccc cuccccuuug gauuuuuugu uuagcaaaag guuaggccug 5220
gcacagauga aauacuauuc agaguucaca guguauuuuc auuucauaau auauuugauu 5280
uucaggucuu gaauuucaca ucaggaagcu gauauaggaa gcugaauuca gccagauuuu 5340
aauacgaaaa uaccucugau caaggcauaa aauuguacuu uaaccaguaa ccacuguauu 5400
ucucuaagcu gugaaaaaac augcauucau uaacugcuuu uuccucugcu gucaacacag 5460
ucaauacaug ugcauaacuc cuuauugucu acauggugau uaucuugcug augaauucuc 5520
aaaggccaga gauuuggacu auuuuuucuc uguaaccuug cauguuccug gccacaugcc 5580
accaccaccc aaacagaaug uacgcaggga auguauuuuu caggauaacc uaagaaaaaa 5640
uaggauuaag aagauaaagc ugcugaucau guaauguacu uuagacucag auauauaaau 5700
auuugugaau uaucuguccu auuucuuucu ucuauuaauu cauugacucu agaugugcau 5760
uggaaggcua gggagaaauc aggggaucgu gagaaagagc acagaagucu gcaucacaca 5820
aacaauauua uuucaagagc caugaacuag auccuaagca acucauaggc aaugaccuca 5880
uuucauaccu cuagucucua agaaacauau aacuggccug aggaaggaaa augugggcaa 5940
gggguagacc ggggucaugg guggaggucc aaauaguaau caauggagcu cauagggugg 6000
acugauauug aagcugcuau gagccagcca caugcugggc acuguuacau gucaucucau 6060
gcaauacucc caauuaccug ccuaguaagc auaauuguca uuuuauagaa uuaaaaacag 6120
acucaaagag guugacaguc uaauguaaca caacagcuaa augggggauc uggaauuaua 6180
auccagagcu gccuggcucu gaugagaaag cucuuucugc ugucauaugc agcccacauu 6240
aauagggggc ucagaaagua uucucuggau aaauuauaua augaauccaa ugaaggaaga 6300
cauuauuuua uaauaugcag cauaauaggc acuauuauga uuggauuuuc cugcuugaaa 6360
guagcuagau uagaguagga aaccaaaaag augugaauuc auucagucau ucaugcauuu 6420
gcauggauug agcuaccuac auuugaauaa augcuguuaa ucccugauuc cuuggaagcu 6480
cacauuggag agauaagcau gucauuaaau aaugccauaa uagugguauc ucagaggacu 6540
agcagaacau aauucaaucu gacagaguag aaacagauug uacaaaucca auucaaaaca 6600
ucauaaaucc ucuaagcacu gucaauucuu ccuccaaauu aucucugaaa uuccuccuuc 6660
uuucccauuu auggccucca uuuacagaag cguguacugu cucucuuagc uguuugccag 6720
gccgccaguc ucuugcuguu cagcucucaa cugcuuccag caagaucuuu cuaaaauccc 6780
aggcuugcca agacuuagcg cccacagcuc cacagugacu ccucauugcu guuaagguaa 6840
aggccuuccc agucuagccc uucaugcuuc uuccauguuc uaugggacug ccccaggcuu 6900
cccaccuggu accacugagc cuuuccaucc uucccccacu cgacugccag gucaacaccc 6960
acacccacgc uucaggacuc agguccuaug uuucgggccu ucuucugugc accauucccu 7020
ucccuguagc ccuugaucau gauuuguuua uacgccuccg caccuucaug gcccugaacc 7080
ccucaagggc cgaaacugcc uuacuuuucu uuuugacuuc ccaacuuacc uuaguggagc 7140
uguagucaca uagaauagac gcucauaaau gcuucucugg gcuguaaagg uugaauuuuc 7200
cagcuaagca aggaagaaag acaauuucag gcaggaggaa gggcauaagc aaagugcaga 7260
gaugugaagc ucaagagaaa uggaugggcu gggcagaggu guggcugcag caucagggga 7320
gaagaaguag ugccuggagu cagcaggcac ggcuugcaaa agcuucaccu auaggugaaa 7380
ggacaccauc ucuugcacca auaggcucug ugauuggagg caacuuugcu guuuuacugc 7440
cagaaaacug aggaugauaa cccaaacugc aguucaagug gcauucacug guguggcuga 7500
aauggguguu uguggccaga auguggucug auuggucagu gcccagcucu guugauuagc 7560
agauguuuug aauauaguag cauccaugug cccaaguugu ugggaugauu caacaagaaa 7620
cuuuaagagc ucaagugccc ugcaguuguc agccagguga uucucuuccu uuggacccag 7680
uuagacgcag gcauuaccuc guggcuuugc cccaguguga aucuuugucc uccaacuuga 7740
ucuuuuuauu uguuucauua uuguauuuaa guuguuuauu uuagagacag acauuuuuua 7800
acagcugugc auuuccuguc ccuuuguuuu ccagucguca uguguuuccu uacucucugu 7860
gggugaacgu uucagauguc uguuugcggu gcccagcgug caagauaaaa uuuauugcag 7920
ugccuucggc cucuaacuca ccauuccaac caauucagau agcccaaggc uguuuuaucc 7980
aguggauuuu uccauguagu gggaaauaaa ucuugaaugu uacuguuuag auuagccagg 8040
aaacucauuc ugggauguuu gcccacaucc auuggcauuu cucaaaagga accccaggug 8100
ucuaccuuga caccagcagg gccacuugag cccuccgcug gcauucaucg cccgcuuugu 8160
ucucagccug aguuuaggag uuacagaugu gagaggcggg auuauacagc caacaucucu 8220
aagcgggcag uggcucccuu acccucgaag accucacucc uagcacgucc uggauguauu 8280
cgucaaaaua uguccucuua ugccacguca gcacaggguu gcuccccacu uugaucauca 8340
aguuuaaaca aaaggaaaga uuuucuuucu uucucugccu cuacuggaca ucauuuccca 8400
ccuaacagau aauuuaaugu aucuguuacu gaauguguuu gaauuacaga cagagagguc 8460
acaguuaaag aaggaagccu gcugcuacug cagcuugucc ucccaaggag guguuugauu 8520
uagcugugua aacaaaugac ugcauucucc agagguccug aacacagcug ccugcgcugg 8580
agagggcuca aaccucuucc gccaggguga acucugcuuc cuggugagug ccagcaaaac 8640
aaccaacaaa gagcuguagg acuugugugg acuucaaaug gugguggucc ugccacuugg 8700
gcucagccac agcaguuagg aaacuaaagg ggaggaggaa agcccuuucc uugcuuuauu 8760
gucauuggcu gucauagggc auuacaaugg uucucuuuga gauucugagc uccggcuaua 8820
acauuugccc agaaucugcc ucugaggccu uaagacacug uguuuuuauu cagcaaagau 8880
gcccuuugac uccuuuuccc acuaguggug cuagguuuga gcaccuuaca cuggccccuu 8940
acaauagcca guucuugucu accuacauuc uucccuaaca uucaugauug cauaguuacu 9000
cuuaguguag aagcagacag cuuuuacaca uagacuccau ggccguagcc ucauagaacc 9060
uacuauauuc uaacuugcaa gcuaaucaga ccaaauauau caaaaucaaa aaccucugcu 9120
gagaguuuau ucauucaucu cugucuccca aacguacuua uguacauacg ugcacuaaua 9180
uacaugucca uuagccaaga uuuugauuuc agggaucaaa gcaaguacca auagggaaug 9240
aggucacuug cugcauggca gguggcuucc ccaugagaau gcaaggccac cucaugacuc 9300
auacuucaga gggugaccca ggaacuucug auucaugucc aaagcagcuu cuacaauugc 9360
ucuaccuuga ucuagggaag auguggggag gaugacauuc gggauuagcu uuauaaggcc 9420
uuccuguggg cagaguuguc ugacuuucac cuagugauca acaagcagcu agcaagcauc 9480
agugugugag gccccacgcc cucucagcuc cccuacugcc caccugggac augggcuuug 9540
gcaucugucc auagcauugu ucuaaccaaa ugagguguua uggaucagcu caggauggga 9600
uauguuccca gacauauuau uuaaagaaaa uagcucccuu ccuccccuga uaaacagcug 9660
ccauggcuaa aagguaaccu ggcuggggcu uaaaagucug uugacuuuca agauauuuug 9720
caaaaacagu cauaaaaaug guauuuauca gauccuaacu auuugugaga cgguuuggua 9780
uaccauagug guuaaaaaca caggcucuuu ccagaggagg uuuacuuugc uuagucgugu 9840
cuccuaagug aacuuggacc ucauaagguu guugugagaa ugaaaugggu gaauaugagu 9900
aaaguccuug gaccaguuuu ggccguauag uaagccuuca gcaagcaucu gcuuuuauuc 9960
cuacagggag gcaauuguaa gcccuucaca aacagcgucu aaugugaucc uuagaacaaa 10020
ccuaugagau agggcauauc ucaauuuugu agguagggaa acagaagcca cacaauuagg 10080
aaauggcaac agaucuguua gacucuuaaa cacuaugcua caccaauuug caaggcaagg 10140
aagacaaagc accuuugaaa augggucaga uguuuuaggg uaaaugaacg uuugagaauc 10200
uuuuaaguuu uuuuuccccc agagauuauc aagguaucau uguaggggga ugcaucagga 10260
aacaugacua ugaaucagcu gccugauaaa ccagccagga uggagcccac gucaucacag 10320
cagucagcaa ugccacugaa aaacaucagc ugcuuauucc cguauagauu uccccuuaag 10380
acaugaaaag ggaguucaaa gagaaugggc cagauaucuc ugagagucau auuacuaaaa 10440
uauauuuauu uuuacuagcu uuuuuguuuu aagagguaua cugucauuag cacuguagca 10500
aaaauucacg uuuuauuaau uucuccuagu uuaucaugug auucuagggu aggaugcaga 10560
guuauauuca aaauacacaa aucaacucaa cucaguaaac auauaucgag gcccuaucau 10620
gacaaaaugc uauucuagag accacggcga acaagccacg gccccagccu caaagaaugu 10680
acuaucuuug gaacugugcu ggccaauaca guaaccagca gccacgcagg gcuauuuaaa 10740
uuuaaauuaa uuaaaaguaa aaacacaaug ccucagaugc auuagccaca uuuuaagugu 10800
ucaauagaua uuuguggcuc cugccugcca uauuggacag ggcagauaua gaacaauucc 10860
aucacugcag aaaguucuac ugaacaaugc ugcucuggag cagaagaucu ucuuguucag 10920
ggauguuaca cccccgcuug uggcuagagu guggcuuauc cucagagcaa ggauagggga 10980
accauggcac ucugcaggcu cagcacugaa gacacggaug caggcucugc uucugaccua 11040
gauugaccuu gggcaaggcc cuuugcuccu cugaucccaa uuucuucacc agccaaguaa 11100
gaacaucaga ccacaagccc ucuagggcuc uguccaaaug ccccaugacu gagugaacug 11160
guagaacauu cuaugugugu gucacaacau gaagagcaaa gacuuucauc uccccaaaua 11220
auuuuguuuu ucguuuuagg aauuaaauuu cagauucacu cuaauugcca auacuaaaau 11280
ucucuauaug caguucuaaa cuugacaaac caauaaaaaa agauuauuug acuacuuauc 11340
uuuguacaac auugaggucu cccuaaagca aauuuaaaug cauauuuuaa aaauguauuc 11400
uagcaguuca guucagaagc ccccuggccc aagcaucaca cugucaaucc uuuguccuca 11460
agcagcaugg uugggugggu uaaguacuga caaacacugg gugucaggcc cauggucagg 11520
gacugugcua acagucuaca uauuagaugc caccuacccc cacccucaac agacccaaac 11580
uauuuaucca auagcaaacc uugcauuauu ucuguccaga agaaacaaac auuuauugac 11640
aacuuuuggu gugugaccug uuuaaguccu acaucucauu uaaggacugg ucaauguuag 11700
gcuaggcaau gccuguuugu gagagaauca cugccuaaag aaaauucucc auuucccuua 11760
gcucuauggu gggugacuac acauacuggu auuucuuaaa gaaauaccaa uuccauuucc 11820
uuuuaacaua auuauuaaua ucucauuagc auggugucac ugaagccugg gcccaaagaa 11880
auaccaauuc cauaucauuu uaagaucauu auuaauaucu caucagcgug gugucacuua 11940
agccugggcc cuuuagaauu uuucauguac cuguguuccu cugcccauau cagcuggaac 12000
acuaauaguu uucuuccuuu uuaucuagaa gacugagaac auuacauggg accugccccc 12060
agggcaugga ggcugaggug ggacaguuua guucaggagg cccaagaagu guugggugug 12120
cagccccuug uucaaacaca gccucugaau cgccagaggc uuccggugca uacucugagg 12180
cgcagguggg acucgggagu gagagguuuc ggcgaaugaa uugggauugc cuacuucuuc 12240
ccagugcagu ggagcuuggu ucugugguca gguccuuacg cccugucugc cuuucucguu 12300
ucuuuauuuc ucggguagua guuguggaau caaaugaccu gggguuugau accuacucua 12360
ccacgccucu gggggaguca cucagacucg uugaaccuaa guuccggggc ugccaaguga 12420
ggauaaguag uaauugcuga uccaccuacu ugacaagaua guagugaggg cccugagcgc 12480
caggcugugg auccagccuu ucccacgguu ccuggugugg caggaagaac ucuaggccug 12540
aaggugaaau uggggaggga gucccagcuc ugccacuguc ucucugggug accucaggca 12600
ggucuccuca aaaaaauaag auacuuuaua aagcucaguu uccucuucag uaaaaugagg 12660
auuccaggua acucacagau aguuuguggg gaugaaucug uuccuuaaag ccugcaguac 12720
aucaauaacc cagucuuccu gcuugcuuuc cccccucucc acuaccagug aucauagucu 12780
gaucccauag gugauauccc agcucaaaac ccuacauuag cuucuguggc uguuuaaggc 12840
cugcccagaa cuccccuggu cuuagcacug aaagcacgug uccggggaag cccugcauug 12900
gucguucaua cuacugaguc ccgcagggca aaccguccgg ucccacccuc cuuucuagug 12960
cugcugucac acucaccucc cuucacccua cacucccuuc ugugccuugc aauuaccuag 13020
ggaguuuuuu acaagauaug gaugcccugg cccugccacu agagauucug auuuaauugc 13080
uugggguagg gccuggcaua gguaucuuuu aaagcuccgc agugguucua aagcacagcc 13140
acagauggga accacugauc uauucuugua gguccccaga uaccucaugu gcuguucccu 13200
gugccugagc ugaccuuucc cccacuuucc ucuccucggc uaauuccugc uuauccuccu 13260
acucaggagg cucuuccucc aggcagccuu cccugauccc uccaggaaga cuuagcugcg 13320
ucccuccgcu gggcuucccc aauacacugg gcuugcuuuc auuagaaccu gauccuucca 13380
cauuaugguu guugguuugc uccaauccuc ucccucauua gcucucaacu uucuuucagg 13440
aagagauguu uaucuuuccu ucuuguauuc cuagagucga ccaggcucug gcacauugca 13500
gauucucagu augcauucag ggaacaacuu aaucaagaca agaccaucug acuucuugug 13560
aguuacaugc uaagaaagaa augucgacac caauagcccu cacaaugaua ggaacaggag 13620
guuaaagaaa aggaaauaga ugcaaauagc aauauaagug cuuuaacaaa ucuauacagg 13680
aggacaacca ucauauucaa auuuucaaac auucuuaguu cugcucuuuu guggguaaug 13740
guuuuuuuuu uuccucuucc aggagaagaa aagaggcaua uuauagaaau uccuccuccc 13800
ccagcauuac uugucacaga auuguaauug gaagugauuu cccugacuaa guuauuuugg 13860
cugucuguua uuuucucucu uccuccuugc ucuucccuca gcuggccauc cuguguguuu 13920
ggagagagcc agaaagguuc aaggcuagga auguuucucu cucucuuuaa agcucuuuaa 13980
ucgucaggcu uucugaucuu caaagcaggc uguagccagu gugaccccac ucccucgccu 14040
ccccaugcug gagaguaaaa gccuggagua uuuuugucau uuugaagacu ugcauauuug 14100
gacagccuug gacaucugga aagugugguc cucacuagcu cugcagggau aagagcacgu 14160
cagcacuucc aagcucucug gcgccccuac aucuggacac guugaaaaau uaacaccaga 14220
cucuggaguu aagcaaacau uaaguuuaua ggccuccuug cauuugacca uuuccuggga 14280
cagcagcccu uauccuguga cuuucugugu guagaguuga gucuuugcag uugguccucc 14340
ucacacucuc ucaacuuugu gacucucugc ag 14372
<210> 18
<211> 358
<212> RNA
<213> 智人
<400> 18
gugauguuuc aggaagggcu cgcugcauuu cuccaaaguc agugggaaau uacauuuggu 60
agagagaaag ggauugagac uggacucaua aaucaauaaa auuaaguuaa auaagaaaaa 120
auaagauauu uuauaaagcu caacaaagag uccuugaaug aaagcaauua cagagucaca 180
uuguggcuaa uauucaaaac ugagauuuaa acugaggacu aggaaauaga auuggauccu 240
uuugaagcgu uuaggagaaa gauuuuaaga gaaugaguuc cgagucaccc uguggucggg 300
aggugugagu gagcuaucca agcccguucc cauccuuugu cccucugugu cuucucag 358
<210> 19
<211> 1817
<212> RNA
<213> 智人
<400> 19
gugagucuga aguucgcgau ccuccuccau gacacgcuaa ugggggugcu ggagugggcu 60
ggggugggcu gggggugccc ucaaggcuuc caugucuuua gagagagccc cagggaccag 120
agccaaauug gagagcaugg agcucugacu gaggaaccug cuucucccaa gcuccaggca 180
ggcacagaug agucagugca guggugggaa agggaaaaga guugauguug uagcuggaaa 240
agggaagggg aaaauuaaag caaggaaagu gaggcugggg gaggggacaa auuccccacu 300
auguaguaug uuugguaugu ggaaggguuc uggucagaau guuugcccaa ugauugccac 360
aucagcauuc auuuuggacu cuguauggcc aguaggucug guuccuggga gcccuggaau 420
aaugcagccc cuucccuaac uaacauuucc augauguaug cucaaugaca aggcagagga 480
auguguugga ugagcucagg accugccucc cuggacacuc ccaucccagg ccuguauauc 540
uguugaccag gaauaagcca agcaagcagc cuacuguuug acugaauaug gauuuggggg 600
gugguagaga aagggccggg guggaggguu gggaggcuca uuugucauua uagauggggu 660
cagacacacu accaaaacag cagcagagau cuacaauuga guucaccuaa aacucagugu 720
ggacacagga aacccucuuu uaauaacugu ccaauggguu uuccagccuc agcucuacag 780
aaaacuugag auaacagugg ccagucugca guuaguuugg guucggacaa uaggcagagc 840
ugggaaaugg agccaggggc gaaagcccag guccacuuua ggaucaggac gggaguggcu 900
gguggggaag ugaggugggu guggggaggc aauagggagc ugggucauuu gguaugggag 960
aguccucugg uggcuagucc cagaagugca ugcuuuacga acauaugcuu cucucccuag 1020
ggccaccuug agugaaaccc ucccaugcug gaauugggcc cuuucaguga caacacacaa 1080
caguuuucaa uagauaauaa ucccaagggc uuuacuagca caugaaacac agggaaaacg 1140
uguaaaguuc acaagaaagu cguuccagug uaucaaaucu auccuguuug ccagguggau 1200
auaccagggu cuccuccacc ugugcauggc uggugguggg uccaguggcu guuggauaac 1260
ugauguauug auggaucauu cgccuucuga aagugccaaa cugauuaguu auuuugugug 1320
ucuuuuugug uaacuagggu uugaccuucc agggcagacu gugcuggggc ggcugacccc 1380
uuggggagcc aaguuauugc ucuuaccacc accacuugcc cuugucaguc cuccacccuc 1440
uuggguuuca gugucagcau guagcugucu acucagaucc cauccacauc aucaagucug 1500
caguuuuuuc cuugcaaggc cuuacaggga agaucuuuga cauagaggau auaauuuuau 1560
ugacacauuu uacuugcaga gcauucaccc gggcuaacca gaaagccagc acucugcuau 1620
aaacaaaaaa uaaugcuuca gggcuaacau ggaauguguu aaaagauucc agcccauuaa 1680
auguccaggg gagguuuucc uguuuuccuu ucccuccauc ugggcuuugu ucucaacaca 1740
uucauucaac aaacauuuau ucugccucua ccagguacag agcacucuac uauucugcuu 1800
cucuccuuuu gcuuuag 1817
<210> 20
<211> 3714
<212> RNA
<213> 智人
<400> 20
guaagccaaa uggagaaggc ccagaaaauc uugaauacuu ugguuccuuu ccccuuuccu 60
ccuguucaug ugccuggauu agucaugugg ccaccaagga gagcgugaca ucuagcuucc 120
cagcccuucc uuuuagccaa cgugggagac acucaaagag acgaaaucuc cugaaggagc 180
cacuguauca cagcauccuc ccaucuccca cuuccugccc agggguccau gguccacaca 240
gacuucccag ucccauuccg ugaccaucug gagaagcugc uauuagcaga gcccugcaca 300
gggugauagu guaauuaaag uggucuucuc uuuccaaaca cagaaaaaau caguucaggg 360
aguguuuucc ugggcuuaca auuuuaacua cuggcuagag uugaaauggg gaaagccuuu 420
ugccuuuuca guagcaguag gggaggagau cuggauuauu uacuuaucau caucaugguc 480
accuccuaca uggcuucacc aaaaaacauu cugcugccug aaaaagcucc aacaccucuc 540
ucucuuuuaa aggauggaau uuggagucca uccuuccuca gugauaagga guuuuuauag 600
ccacaggcag caucuauugg ucuguccucu gcaaacuugc aacuccucug agagcuagac 660
uuggaaauga aacauuauuu ugcaaugcgc ugcuauccuu cauuuuuagc uccuccaccg 720
uagaugauag uuuguacuug uuaaaugaua aggauauaaa uuuaggucau uuuuuauauu 780
uuauugggug gaauuuggua uaauuuuuag acuucaggcu uuacaggcuc cugagaugga 840
cugauugagc uuguucuacu ucuuccccau caugauagga agugcuguac cacacuaggc 900
agugugugua gugaccacag acuggcugag ugucucccau cccaugcugg cccauaucug 960
guacccaccu gauccacaaa uguuccauca gauccuguuc aaacaacaca ucuccaguua 1020
agccaaaucu ugcccuuucu ccuuacggua aaauguacua aaucugaagg uuuugucuuu 1080
uuaauguugc uccaugaucc agugaucugu ggccuugguu augcucugug cuagaguccu 1140
aacaagacaa augcuaaggu agaggucauu cugcucaaac aaccugaccc caccuggaug 1200
ugggcuuaca uuugcaaagg gcaccaaagu ucuaagagau gaggggagga gcugagcccc 1260
uuguccuuau cuagguuucc cuuguucuuu cccaucccuc agucugcuuc uuuucccagu 1320
accaacaugu uuguguccuc agaauuaaag gaguaaaaau guguaaacau cugacuagca 1380
acagccauga gauuuugccu ggcuuguuga uaagcagcau ugagaucugc ccuccuaaga 1440
augggccauu aggucuucaa agcuuuuacg augugaggua aagaauguuc accaggaguu 1500
ucaugcacaa aaggguuucu cuuuguggga acuagaacau uguuccagug augacggaaa 1560
cagggcuuuc cauaccaaaa caggguuuuc cuuugaauga cucucccacc uuucccuugu 1620
cucuuccucc ccaccucaac aacacaggaa agaagcugga agcagggaca augggaaggu 1680
cccuuuguua cucgagcuau uagaaacaaa aagaaaagug gccaucugag gaagccacag 1740
cuggugaaac uguaggguca cagagugaau uacaccucug gcuuaaguca gugaaaaguc 1800
cuagaaguuu gugguccuag aaguccuaaa aguuuauggg acuuuguuuu gagcaaggau 1860
aagaaauuga uuucaggcug ggcguggugg cucacgccug uaacccuaau acuuugggag 1920
acagaggcag guggaucacu ucaggucagg aguuccagag cagucuggcc aacauggcga 1980
aacccugccu cuccuaaaaa uacaaaaauu agccaggugc gguggcacau gccuguaguc 2040
ccggcuacuc aggagacuga gcaaggagaa ucccuugaac ccaggaggug gaggucucag 2100
ugagcugaua ucauaucacu gcacucuagc cugggcaaca gagcaagacu cugucuaaaa 2160
aaauaaauaa auaaaaaaga aauugauuuc auucuucuga gaacugcaac aacuaccuua 2220
aagugauucc auccaaaacc cacauguuca gccauggacu ugcuuuuaug gagcugcgug 2280
ugggugacac acaaaaucag gagcucugag uccuaauuua gacuuuuauu uagauuuccu 2340
caaauuuggg uuccaguuaa gcgugggucu cuucugugcc ccgcuccccu uugccauuug 2400
uuuuaucugu ucuucagucu guucugucag uacccacagg caggagagca gaaaggagaa 2460
auggcagcca cagcagacaa auggcacauu cguuccacuc agcucucgca ugcccaucac 2520
agauacagcu cauuggucuc uuuucuauga gaggaagcca gagcuccagg gaacuacugc 2580
caacugauca gaacucauuu aggacaugga ccuauuuguu ccuuuauguu ccugggaaga 2640
gcacaggaug aauucuaugu acucauuuac guguucagag aguaaagugc cucauaggau 2700
gccuccagca aaagauaacc aagaaggucu aauaccuuug acaaucucag uuuauccuau 2760
aguguaauug gauagcaguu ccccuagcaa aaguugcuag uuugguccua uuuucuacau 2820
agccaaagug auugauucau ugguuaaugu gaaaguuacu gaguacugcc agcagguucu 2880
aggaaauaua uuugugugau auucauggau ggggaggauc aauccacuuc caagugauuu 2940
ggauuaauua cugguauuuu caccugugug gguagcaaac cucagaaaau caaguauaga 3000
ugacggcaua ggacaggcca ggccccaggc aaaauguuga agcuccucug gaguucccuc 3060
ccaucucccu cuuuuguuuu ccauauaccu gguuuaucca gggcccugga gaugcuccaa 3120
gacccccuac ccaggucuuc cucccuuguc ccagcuauau uucuccauau uaccacucuu 3180
cucaccgagg auuugcuuac uuaacacaua auaaauacua uuaaaagaga aacuuaggca 3240
cauuaaaaug uuagaguuga uuccagcaaa cagugauuca caggaggcuc cagaucacaa 3300
gugguucagg gccccacuga gggguaggga agcaagacaa agaaaaacaa agcaaauauu 3360
ugauugguuc aaguggaaag ucccugauua cagguuagug ggcaguuugu gauuaguuaa 3420
guuucucuaa guuggguuuu gguuugcuga uguaggaaca cagaaugcug gggccguuuc 3480
aaccuaaugg ucucccaauu aauuuuuuua acauuacuga ugacuguuag gagucuaaug 3540
ugcuacuccu cccagggaaa auggcauucc uaggauuaaa ggaacucagc acauggagug 3600
ugcguagaaa uuuagacacu aacugcaggc uggugggaga gagcccuuua gggcagaaug 3660
agaaggcguc cggccaaggg caggaguuac ugacgcaugg ccucuugguu ucag 3714
<210> 21
<211> 1285
<212> RNA
<213> 智人
<400> 21
gugaggcccu ugggcuggcc ccuguccuac aacacguuuc cuuggaaggg uccguagcag 60
uccuggaggc ccagccugcc cucugagggg guccacuuug ccuuugaccu aagguuaaaa 120
aguucacgug aggcuaaaau guacaggggc aaaaguggga gcaguccuca ccccgagcga 180
ugcaacagug acuccucacc acgccugcuu gauucaucug cccuggaaag ucauuaaaaa 240
accaguucaa cucauggguc ccuuuauuua cucacaagag agagccagca gcccauuuca 300
cuaguuuucc uuuccuacuc uuugagaaga aucagaaggg agggagcuug ccacuuuacu 360
aucugucuaa agagauguuu ccauuaauua aagguuuuug uuuugcuuca aaaaaacuug 420
aauuggagua uuuccacaag uaucuuuaac augcucuacc aauguuugca gaaagaagug 480
cagaaaugag acuguccaca gagucaggcu cgcuggccag gagaggacuc ccgaagcuga 540
cuucugaugg ccugagaaac uuccuaguuc acaauuccca gacccagaca aagagcacug 600
ucuuuucucu aauuguuuuc aaaugggcca uuuccacccu cuaaucagcc ucuggcccug 660
gagggugcag uuccccuugu ccuccggagu cucccugucu cugugcugua gagucaagaa 720
gggacaacca ccugcccuca cugggaaaag acagaaaguc ugacuuguuc ucacgacuca 780
cacuuauuag gcuccagagg ugucagggca ucugccuuuc auuucuuagg uuaaauaaga 840
aaucaauugc ugccauuugu aguacccaau uuucuaaaau gaucacaaug gauaaguggc 900
aagaaauccu uaugacucau cugugggcag aguugggcua uuuugguaau ccuugaguag 960
gcagauggaa uuugaggcca ucuucuuggg uacauagauc acuaggaagc uauaggucua 1020
gcaacugugg auuagggcug ggcugagaau uguuucaugu uuuuugugac uguauagcua 1080
gagacucucu uguuugcaga gagacacucu gaacuccccc uggccgucaa gggaaagacu 1140
gccuucaccc uccugagcug accuuacacu gagagacaau ggggacccuc uuuuggcccu 1200
ccccucuacc ucgagggcau cugggugcug uugcauugga uaaaaggcac ugcucuuuuu 1260
cugugcccuc uccgccucac ugcag 1285
<210> 22
<211> 3412
<212> RNA
<213> 智人
<400> 22
guaagcaucc uccucuauag gguaaaggua auugaguucu ucagaucccc agcccucucc 60
auucaucuag uuuaaauuuc auuucuucca agcucuuugu cagaaccagc auuugaaguu 120
uaaaucuaga aguuaaaaau ccaccagcaa auccuacugg cucuacuuga gaaacaaauc 180
cagaaucuga ucucuuguca ccaccuccac cacaaccuuc ccaaugccag ucucuuccuu 240
ccacuaccac cucccaucag uccauucugc acacuguauu cagggagauc cuuucagaau 300
caaggucaug uggugucagc ccucucuguc aaaugcuugc acuggcuuuu ccucucuuuc 360
agaguaaaac ccagugucuc aacccuggcc uccaagcugc uucauuaucc ggccuccaac 420
ucucuucuuc aucuuacgau uuucccuacu ccuccauguu ccucugcucc agccacgucg 480
gccuccuuac ugacuguuua auacaccgag cgcauuuccu cuucagggcc uuuccaccug 540
cuguucucau gccagaagca cauuucucuc cccacaaccu gcaacccgcc ccucauaucu 600
gcaggcuugc uuccuuacuu uguuaagguc ucuguucaaa ugucccauua ucacagggau 660
cuuuccagac ugaagagauc uacauaacua uggcucugua aacaacauuc cuccaggguu 720
ccuguccccu uacccuacuu uauuuugggg aacauucuuc accaucugau acaaugaugu 780
aucuuaugca uguauuuacu gacucucugc ccuuaguaga auaugagccc agagagcaug 840
cauguggucu auuuuguuaa cugugacagu cccagugccc agaauagugc cugaccuuug 900
gugggcacug aauaaauauc uaaguaaucu guagcaugga aaaucagcuu cugaaaauug 960
gcuguuugca cggucgugua uuugcuuggu agaaaaucaa auuuuccuuc aaauuagcau 1020
uuucugguaa cuagagcugc cccaucuucc ucugaguggu cuccaaguca gccaauagcc 1080
uugugcugug gcagccaugc cuggcucuug augcuguagc caaaagcagg caggggaugg 1140
ugaggcuggu ccaguccaug gggagggaca aacucacagc ucucagauca ucucagggca 1200
gccuuuguug gcagaaauag guaggcagcc acccugaaua ggaggaaggc uucuagacug 1260
ggucaggagg ccuggguuug cauccuagug gcaagcgugc auucauuuac uagggcugcc 1320
auaacaaaau accacuaacu gggcagcuua gacaacagcc auuuauaucu cacagcucug 1380
aaggcuggaa guccaaaauc aagguguugg cagggccaug cucccucuga aaccuguagg 1440
ugcuugggca cuccuugacu uguagaugcu uccugcugau ccuucgucug cacauggcau 1500
ucugccuguc uuacauggcc aucuuauaag gauaccaacu ggauuggauu aggugccuac 1560
cuugcuccca ugugaccuca ucucaacuaa ucacaucugc aaugacccug uuccuaaaca 1620
aggccacauu augagguacc ugggguuagc acucugguau cuuuuuucuu gacagcacuu 1680
cugacaccaa auguguguuu ugguuuuuug uuguuguugu uuuggcacca accaauucuc 1740
cuauauuaau ggguugucca agaauucaau ugaauucuga cacuauccag aauucacaca 1800
gacuccacgg guucaguccc acaaggcuuc cccgucuuca gaugccagcu ggaaaugugg 1860
ugcccaggcu acccacacuu uugccaaaau ccuguacuua caaucacagc uuuaaaauga 1920
aggaugcagc ucaggaacug ccacauggaa gagaagcaca guaugggguc gggggaagag 1980
uuucuaugcu cucucuagac gcaccacucu cccagcaccu caaaguguuc agcaacccaa 2040
aagcucucca aaucuuguug uucgagaguu uuuauaaccc uaucuccagc uccauacucc 2100
cccauuggag guugaggguu gggacugaaa guuccauucu ucacaugugu gguguuucug 2160
gugaccaguc cccagaaacu gcagcuaucu uggggcucua cccugaguca caucauuagc 2220
auaaacucag augugguaga ggaaggggcu uauuaugaau aaaaaaagac acuccuuucu 2280
gccaggaaau uccaaggguu uuaggagauc ugugcccugc acaggagcug gggacaaaga 2340
ccaaguauau uuuguguuau gccacagacc ccaacauguc uuuuuggagg gagaccaaau 2400
ucaacccaug acagugacuu ugaacaagac auuugaacuu agucuguuuu uucuauccua 2460
cuagauuguu ggaaacagau auaauagaug aaaauuaguu gauuaaaauu gaaauuugug 2520
cauaauucaa aaguuuuauu uuagccaagc uaaagcuuuc auuuauucaa cagcuauuua 2580
cugagcagca ccugugcaug aggcucagca gggccagguu cugggaacag agcgguggag 2640
auaaagaucc agaccugccc cgaggaauag acaguccagu ggcagcaaag gccaugaaac 2700
auacggcaac ucuuaaaaaa agccgagacc augauuuuac aaaaucaaca uuuuguaggg 2760
agcagaacuu ucaaagagaa cuggacuaga aauuugggag ucuuuuucuu ggaacccugg 2820
uagauccagu agaaugaggg augggggugu aggguuaaaa acacugacau uagaacugga 2880
uuaccugugu uggaauuccu acauuucugu uucacuaucu gugacggggg gcagauggcu 2940
gaaucucagu gugccucugu uuccuuucuc acaagaauaa uauuacuacc uaucuccugg 3000
gguuguuuug agguuuagau uauuuaacac auggaaagca cucacagcaa ugccugccac 3060
agaaagaaua uccaguacau cuuagugaug aucaccauua uuauuaucug acuccuggaa 3120
aaggacuuga uuuaauucuc ucaugaaacg uuuucuugga aaacugaugu caaccaagau 3180
uauuggucuu gcuguugcuu auaacacccc aaaaacauga cuguguggau aaaaauaugu 3240
uggaaggggu agucuuucug ggagccugag aauagccaug uaauaauaac ugcaaauauc 3300
uauaguuaca auuugagguu cagguaaaua aacucuagau cuuauagaac ugcgguaagg 3360
uaggauaggg agacuccuuc gacuuucucu guuuauuugu cucuauuuuu ag 3412
<210> 23
<211> 2675
<212> RNA
<213> 智人
<400> 23
gugaguccuu uaaaacacaa aucuuaaugu uugaaaucaa cuccuugggc ucugugcaag 60
auguauaugg aucacagagg uggcccucua uguaaacggu gugauuccug augagucagc 120
ugccuccugg ggcucugccc cuugaugggc auugcagcgu cugggggacc accuuucaca 180
aguugcuggg cccuguguga ucaugaaugg cugaucaugg augaagcccu ggguccugua 240
caccuugucc aguagacuaa auugcccuau uuaaaaaagg ccaagccacu ucaggguuca 300
aagaacuuuu gcagcuuuuc aguauaaagc agaaauccag ggaaucauga aggaaccuuu 360
gcauucaucu cccauugccu uccuugugcc uuuuuauucu ucucugccuu uucaaaauau 420
aaauuaguuu auucucccaa gaugaagacu ccuccugggg cugaggcaga gcuguuaucu 480
ucagggcaau accucagauu cuccuggugu ugaucuuucu uagggguggg gaaaaaggcu 540
gaaagggcau uugcccacaa cacaucuuag guaaaaggca ccuuuacuac ugaaccaaac 600
aggaggccua gcuagagaaa guucuagaag cagggaaaag cacagacucu uuugugaggu 660
cugagaaagc aaagaaauuc cagggugaaa gcgggggacu ccccuagagc ugaaguacuc 720
ucccaucugu uuguugcuca ccuaccuauu cuuuacuuug uauuauuggg ccugggccag 780
gacuuauccu gcaagcacug agauggaugu uuguuuucuc ugggggauua gucuuuuuuu 840
uucuuuuuuu cuuuuguuuu uugcuuuugu uuucacuggg ucaaacaaac aacacuuuaa 900
cagcucagga uuuuuucauu guauugacuu gucuaccugu aaacuuguua auuuuuuacu 960
auaauaaaau uaucauauaa uaaaugaaaa auuucaacac agggcuugug ggcauuuuau 1020
uuuucucuac aaucccaaca gauacucugc cucuuaagaa aaaaagaaau cauaaggaaa 1080
auaugcuccu ucaaaaguga aucacaaaua uguuugccaa cggaaggcaa auauuuuuca 1140
ccugucucau aggcuggacu gaaauggauu ucuaaaacuc ucuaaaacca gaaaagagcu 1200
gagugucucc acccaaccuc ccuccuuuca cagauuaaaa aauaaaaaau ggagcccagg 1260
agacauccag uaucuucccc uauuggucac cugggacaaa aucuggaaca ugcacaugca 1320
uugccuggca ggaacucauu ccagugauua aacucuucag gaggauguuu ccucuugcua 1380
uuucauuacc uauuugugca guuugauagc uaguaaagug aucaaaggaa cuguggggca 1440
uagauucaaa aguccuucag gaagcagaaa uagaagaaca guacuagagg cagcaggucc 1500
cugaccagca ggcccacuac cugcugcucc agcacacauc cugcacauuu ucagagggug 1560
ggggacagag gggcccuggg uggcuguugc auugagaaau cucgcccugc uccuguaugu 1620
gcacuugagg ccgagagccc uuggaugccu ggugacagug guuuccuccu gccccugccu 1680
uccucucugg cagacugacu ggcccuucug cuccucuucc ccuuccagga uguccugaua 1740
ucuuuuuaaa ccaaaugcca aguuugccaa aaagugucug uuugugugug ugugugugug 1800
uguguucaau gcguguguuu auaccacacu ucacaauuug uccaggcuug uauuaauacc 1860
aucaccaggc ucaacccugg uguuaauucc aagauacuua aaugcccauc uaggugaauu 1920
ucucagguaa accauauauu caagcuguag uuuaagcugg cugcccguca uagcacuuug 1980
aauagacuuu guuuuuguuu uuguuuuuug agacagaguc ucacucuguc ggccaggcug 2040
gagugcagug gcacuaucuc ggcucacugc aaccuccgcc ucccggguuc aagcgauucu 2100
ccugccucag ccuccuaagu agcugggauu acaggugagc gccaccccac ccggcuaauu 2160
uuuguauuuu uaguagauac gggguuucac cauguugguc agacuggucu cgaacuccug 2220
accucaugau acgccuacau uggccuccca aagugcuggg auuacaggcg ugagccacca 2280
cauccggccc cugaauagac uuuuacucaa gguucaccau gacuuucaca uguuuuguau 2340
uggaguaaaa ugugccagug gugggcuaaa gaaaauuaac ucauuucaaa uucaaaccug 2400
guuuucuuaa uuuuuuuaaa aucacaguuu cugaaacugu gggcuccuca uggcacauug 2460
agaggaggag gugaaacucu ccaagucuga agcuccuguu auaaaucuuc cucuggcaaa 2520
gauuguguga ucaggcuuga guaccucaca guccuagagc aggucaaagg cuggcuagga 2580
aacucauuug cucccuguac cucuccccuc cuuuccugcc uuugcucguu cucagcuccc 2640
ggugguagag uaacacuggc uucugauugg ugcag 2675
<210> 24
<211> 1774
<212> RNA
<213> 智人
<400> 24
guaaaacccc gauaaagaau acacagcaga ggcgaggaaa aggcucuaag cacugcagag 60
ggccagagca aaacaucuca uggcaagggu ggaaagaagc cuaggaaacu gacucucucu 120
guggacaagu guuaaaccag aucccuucuc agagguccau cugcaugugu guggaaugaa 180
ugguucagcc cagacauuag cgcauauuuc cuggagaaag caaauaccaa cuauguagug 240
ugccugugcc cuuguuaggc aaaucccaag ugaguugcac aaaugugcug acuuccgagg 300
auuuagcaag aacaauaacu uuggucacug ggacuuaaag cggauaugag cuauaaggaa 360
agacaaaaau aaaugcuucu guguccaggg ggaaagagac uccaggggag cugacuacac 420
uucacuuacg gcuuacaaau cuagaaggcc auucauugaa accaucagaa gccuuuccug 480
acaguggaag uuaccuaaua aucccuaaac ugacgaccca gauuuacaag uuuuguuuuc 540
cuggcuuuug cugcccucau cuucucucuu aaacuaguuc uguauuucuc ccaaggcuuu 600
ucauucccua agcauacgca uuucucugug gccaaaaugc ucuggguuua gacaggcagc 660
acagccccug ggcucugccu gacagggcag gagagggucu ggccuuuauc ccuccagccc 720
accccagggg ccauuucaua aaacuaaagc cagagaccug cagccccucc cagaguuaga 780
cugcaguaca ccaugccucu ggcaagaucc uccucccaca guggaaaguc uaagccaaau 840
caggaggcug gggacugguu ccaccucagu ugcaggcaag gccaggaggc acggauagaa 900
gaaacagugg acuuuuuccc ccuagggaaa gaaaugcuua gagcuacagu auuaagauga 960
caaauuaagc ugugccauau agggugaaau gaagcaggga uagaugggag gucagggaga 1020
agugagagca cucggugagg gucugcacug gagggggcau gggaggaaga aggaggggag 1080
ugggguuuga gggaugguga ugaggaagcg uggacugccc uacccaccua uuggaaaacc 1140
ugggaguucu gaggagcaag aagccuuagu caaagucaac ucaaagauuc aagccaaggu 1200
gacuaagaga auggcggucc agaaaagguc augggagaau cugaaggcag auguuguuuu 1260
gggaagauga agaaccuaag ccgcuuccag aaauucauga ggaaaugccc cguggacugu 1320
uggcaaugag ggccuaggac caagguugag cuuggggcca acucucccua uagacaguga 1380
gugcauucug acaagcaugg gcucuggguu caaaucccaa cucugccacu caugccuaug 1440
uguccuuaau aggacgcuug augucucugu gucuaagguu uccuggacua uggaaaugag 1500
ccuaauaaau gucuaccccu uaggaccauu guaagaguac auugagguaa uuuguguaaa 1560
gcagucgaag cagugccugg cauauaggag gugcuguaua aacguuugau gcuaguauua 1620
cuauuauuau ucuggagucu uccuugcaac ggugauagcc gaagccacag gggcagguga 1680
cguuauaggc agaauacaag ggccuggaga cagagcccug gggccaugua auuaggcauu 1740
auguuuacau cauguucauu uuuuuuccuc caag 1774
<210> 25
<211> 2174
<212> RNA
<213> 智人
<400> 25
gugagucuuc cagcagagaa gcuggcugcc augcuagccu gucauuuccu ggcuuagucu 60
uucccuauca gcggcugucu acucuuuccc acaaauuuua gugacaaaua uuugcggccc 120
caaaaaugug uaaaagcuuu cugcaguauu caaagaucac uaauauguau ucucuugaug 180
gggagguaga auacguuuau ugccccuuuu gugugccggg gaaguggaca uucauucaga 240
gaguugaagu gacuuuccug aagccaccaa guugucaugg cucagcgggg gcaaaagcca 300
ggcaccacag uugccucuug uuucucacac cuugagucuu uccccccauc ucaacagucc 360
auggugguga ucaagucaug gccacuguca ucaugugcau ggaagcuaua gaguccuccu 420
auuuccuuuc ucuuuucuuu ucuuuuuuuu uuuuuuuuuu uuugagauag uaaccauuac 480
ccaugcugga gggcaguggu gcgaucuugg cucacugcaa ccuccgccuc ccaggaucaa 540
gcgauucucc caccucagcc ucccaaguag gugggacuac aggugcauac caccaugccc 600
agcuaauuuu uguauuuuuu uuuuuuuuuu uuuuuuuuag uacagacagg guuucaccau 660
guuggccagg cuggucucga acuccugacc ucaggugauc ugcccgccuc agcuucccaa 720
agugcuggga uuacaggcgu gagcgaccgc accaggccga guccugcuau uuucaaggaa 780
cauuccuuuu ccuaccaauc auuaggcagg cuucaacauc agcugaugag gguuaguggu 840
cguucuggag aaagugaaaa aagaaucagu cucuagaggg gcuuguggag uaaccgccug 900
guaacagaag gucagggcag ggaaggcaaa ggggcucugc gcggaucucu cagcuccgca 960
ggcgccccac ucuccuccaa gggacccgag cgccaucugc ugagaggaga acacggcccg 1020
ccaugguuuc ccaaggagca gcagacacgg accucgcagg gggcagcgaa cccacgugac 1080
acagucuuca aguccuuugg agagccccag gaaggaacaa cagcguguac acccugugau 1140
ggaauguucu cuagggcggu ucagugugaa uggaaugugg ggccggugcc auucuaauug 1200
guucuguuuc ccucuagugg uugaucgcgg agauuucggc uucuccauca ggacaaguuc 1260
agauagccug agaugguauc agaacucagg gacagagcug gguguggcgg cccugcaucc 1320
aucugcuuuc ucuccaugcu aacugauaug gucagagagc uggaagcaaa uuccaggacc 1380
ccagggcucc gcaaaggcaa acacauuacu ucaucggcug cugacaugca acuuccccca 1440
gggguuaaaa caauguuuaa uacuaacagu aauaauauuu uugaguuuua cuuuaugcug 1500
gcgcuguucu aauguuguaa guguauuaac ucauuuaagc cuuacaacaa ccuaaggaca 1560
ugggagucau aguucccauu uaaaaaaaaa aaaaaaaaaa gcccaccauu gcucugaggc 1620
uuuuuauguu uuggauccaa agcuaauauu ggugguggua auucccaugc cuggcuucga 1680
ucaauuaauc agcaaaugcc uaggacugcu uaggguucug gccuucauca agaccuuacc 1740
cgggcuuuau gaugaugaca ccuggcuuuu caauagccau gacugcucac ccaggaggca 1800
acgccucgag ucaugcaccg aacaccuuuu auugauccuc uccaacacca ggcuccguga 1860
uggcugagcu ggggacaccu gugacugcac gugaacauuu ugaggcuggg aaucccaaag 1920
gcccucggcg uuggccuggg agcaccauga aacaaguaga agcagagaag gauggcagag 1980
guggcccucu gcauuagggc cuggauguau acacuggugc uaagggggcc ccacagcuaa 2040
uagggguuug aguuugacug acagccccag gcaggaaucu gugagaguuc ucacugaacc 2100
uggugugggg guggcccucc uaaggcaugu ugcuaaaggc caucucuucu gccacugacg 2160
ccuguguucu gcag 2174
<210> 26
<211> 1137
<212> RNA
<213> 智人
<400> 26
guaagcgaca caggaacuga gaccgcccca uccccucucc ucaccucugc ccccagcaca 60
cuucucuaga gcccagcuca ggggugccag gccugggcac aggcagagau acagacucuu 120
auuugguuuc cccuauguuu aaaguccuuu guccuacuug cagugagaau ugucccugag 180
aauaugggac ucugccucug cugcucagag cugagggcuc cucccucaga agggugaggc 240
ugccuucgcu cugacagagc agcugaucga uccccgagcc ccuugugcag cccugaagua 300
cuuccucucu gggaccaaag acaggagaac cauuguuccu uuuuccuguu gaagccacgg 360
ccugaaaggc aaacuuuuca gggggcuuuu caguuacuuu uuuuccccaa uaagauaucu 420
uuuauuucuu aucuaagaag cuacgcauag ucauugugaa agaaaaaaaa ggaagggagg 480
aaggaaggga ggaaggaagg aaggaaggaa ggaaggaaag aagggaggga gggaggggag 540
aaggaagcga gggagggagg gaggggagaa ggaagggaac aggagggagg aaaagggaag 600
gggaaggagg aaggaaaggg aaggagggag gaaguaaaua uagguaaaca aaaaauugaa 660
aauaaaaguc accuguaauu ucacuacuca gagauaaccg cugaguuaua acauugguau 720
auaauuuuuu agaacuuucu ccuauacaug uauagauaga uaaacacaua uacuucaaaa 780
ugauaaagaa uaguaaaacu augcauacaa uuuuauaacc ugacuuuuuu uucaaaaaaa 840
aggauugcuu uuuuaaacau aagauaucag gaacaucuuu caugucauua cauauucuuc 900
uauaaaauaa uauuuaaugu uuacagauua uuccauugua ugcaugaacu auguaagcca 960
uccucuuauu agauauuuaa gcagggucug cuauuuuugu auuguaucau aaacaccacc 1020
acagugagca ucuugauugc caaaucaaga auacuugucc ucaauuauuu cuguaagauc 1080
agcugcugga aguggaagug cuaagccacu gcuuuucucg uugucccauc cuccuag 1137
<210> 27
<211> 437
<212> RNA
<213> 智人
<400> 27
gugcucagag cuggauggag acagggccac agauggcaaa uccauggcuc cccagugcac 60
ccaggaggca ggggaggcuu ggagcaggag agcuucuaag ggugggaaca ccucugugaa 120
guuacaccaa aaaucuaaga gcagccccca gaucauuuuc ccugcagagc acugucucac 180
agcagccugg guuuuauuug uccugagauu gaugugcuug aacagucuuc aaagggucug 240
auccgaggag gugaggguug cccuuucugc auuuacaaag ccugaacagu auuagggcuu 300
ugaacgcuau aaacaucuaa gaggcagcac caaaccacug cuggguuaag guacccccac 360
aaugccacuu gcccugggcc uuucucuucc ucacccucca cagccccuua acucucccgu 420
ccuucuugug ccuccag 437
<210> 28
<211> 1358
<212> RNA
<213> 智人
<400> 28
guaacagcug cugcucaguc uccugggcug ggcucucacu gcagcccuag cugugguccc 60
cacucucuca ccugccauuu uguagcugag uacaggaacc acaaugacua cacucagaag 120
gggguuuauc agugacuugg ugaaucuaag uuccagcuaa agccuccuga gguuuuuaca 180
aauauaaaca gagaaucacu gaugaugcaa ccuacuuccc aaaauauuuu agaaaauucu 240
cuugaccugc agcccuucug ucuggaauaa uggaugcuac ucuaggugaa ugucuucucu 300
gaccaugggg acccagguca ccugcaaaca uaccuagaag cuccauagcu gucagaugac 360
cacucaggac cagugugagg gugaccugcu gggcauucag ugcuccagag gguggccaca 420
gauggaagug gcuccucugu cauggcaccu cucagacaag gggcucagau cagaagagac 480
agcaagcaga gcugagugcc cauagaggua acagcacggu ucaaccccgu ggucaagcca 540
gagcuuuccc ccuugcucua cucacacagc guugccccgu gccuuucucu gaggguuugu 600
cauccugaaa uccucauugc uauuuucuuu cuuucuuuuc uuuuuuuuuu uuuuuuuuuu 660
uugagacaga aucucgcucu gucgcgcagg cuggagugca guggcgcaau cuccacucac 720
ugcaagcucc gccuccuggg uucgagccau ucuccugccu cagccuccug aguagcuggg 780
acuacaggug cccgccacca cgccuagcua auuguuuuug uauuuuuagu agagacgggg 840
uuucaccgug uuagccagga uggucucgau cucccgaccu caggugaucc ucccgccuug 900
uccucccaaa gugcugggau uacaggcaug agccaccgug cccggccugc uguuuucugu 960
uaaugacauc uccaguuagu gagaguaugc acgugugugu ucuuuaugaa gaguauaaau 1020
ccagagcuua augauccaga aaauguacau augaaacucc cuagaugcug accauaauac 1080
augagccccu aauauagaga uuuauuugaa ucagauccua ugcuggauac agagacacug 1140
uguguggcaa ugcuuuacag uauguaggaa gcuaugaaau guuaguuauu auuguccuaa 1200
uaugcuggaa uuugcugcug aauuaguucc cuuggguuuu uuuuuuuagu uaacuccuga 1260
uuuuugcaac uauauagcca ggaaauugcu guacacccuu uaccaacaau gcccaaccca 1320
gggcaggccu ggugauugcc cuggccccua ccuugcag 1358
<210> 29
<211> 1081
<212> RNA
<213> 智人
<400> 29
guaggugucu gcccagggaa ggacccuggc cugggugaga aggagcacac agcacggggc 60
ugccacucca gacauggcua cucacacagg cucucgccac cagaaucagu gucuuuguuc 120
ugggaccauu ugcagaagau uucgaugaac acauucugaa gccuccuccu acagagaugc 180
uuuagccaaa augaaacaac uagcuuuaaa uggucugcaa guauuacaug ccagauuaca 240
caccaguuug gugcgguuug gugcaacaua gaagugagug ucuuauucug uaagguuagg 300
cuguuuuaag agcaauuggu ugagcuucau uucaacauua auauucccua auuaaaccug 360
aauuucagug guaagugaaa acuaagaaga ggccuccuug ggugcuauaa cauaaaaaug 420
augaaggcaa aaaguaccaa ccagcagaga ccacuucagc acaucaggag acccaguuuu 480
augucugugc ugcgaaguga acaaacugug ucauccuagg caaauuauuu aauuccuccu 540
uuuuuuuagu auuuuuuucu ucuucacaug gaacaugaag cuaaugaccu cugcuucuau 600
uucuuaggga ugugaagaua agugagauaa aguauuauaa augugcucug ggcuucuuaa 660
gaacaggcau ugcucacauu caaaugguca ugauuaugau auggcagcau uauuuaugcc 720
ucugguuuaa gugucuggcu gccgcugggg uuuccuaugu ccauccacgg ggagggaggc 780
acagaauguc ucccacaggc agaaccuaca gcugccacau aauugaugac aagccaaagg 840
gacccuugga gguucugcuc cucucugugu gugacucaca cacucucuag gauaaaauca 900
agcgacuaca cccucaaaau gcucagauga auuaacagau uaaacaguga agaaaaaaau 960
guguugacua cacuuggcag ugagaaauaa auaaagcggg cggugacagc agcuggcauc 1020
agggagaggc ugucauggaa gggaugugca ucuugucagu caucccaucc aucuguugca 1080
g 1081
<210> 30
<211> 2692
<212> RNA
<213> 智人
<400> 30
guaaggacug gacgggccau acuuggguuc cgucuggcag ccaucuccca guauugcugg 60
guguguccug uugugaugca uuuuaauggg agcaaagaga acacugggua cuucugcagg 120
ucacacaguu guucuuuugc uuugagcuuc uuucuccucu uccuucuucc uucauuccca 180
aagggauuuu aaaagucaug caccuaaagg cccucucccu uuaaugagga auacacucug 240
ugcucuuacc cuuaguaagc caucauuccu gggguccccc ugcccuggcu ccaggccaca 300
uuccuuagug ucuggggaga gcuucuucua caugugugcc guggcgcccu cuaguggaag 360
cauggugaug cacggcucuu ccagugaauu cguggaguca gagauugcac auguggaugg 420
caagucugga aauagcauac accccuguua uacuccugau ucuccccuca gcuucccaau 480
uucccaguga uucucccuuu aauuaggaug cacugaagcu cucaggggug cccccaucuc 540
caaggagcug caguggagag gcuauccccu cucuauguga gagaaugugu gagaagcgua 600
uucccacaca ggagcaaaac uaaacuuacg uacugaugca gguuaaugaa uggggaaagu 660
aucugcuuau caaagaaaag gcauauuuuu cuauuuagca caaacuuuuu caaauguuaa 720
gaauuuacua acugaaaucu ggugaagcaa gagaaccggg caauauuugc guugucugau 780
cauuacaacu ggagggaaca ugcucagaga ggcaucauca cuguucaugc accugcccuc 840
ucuuuacacu gagagacccu gugaugaaca gaaaacaucu uuuuaggaug acaucucugg 900
gucuuucucc uagccugccu ugcugugggu accuaucucc cugcucucug aaccuugguc 960
aagaaguuua uauuuguuuu aaauugauac uaauauguua aguuacugug auuugccaaa 1020
aucagauugg aaacagggcc ugcauggcug aaugauucuu uuuuuuaaau uacuuuauuu 1080
cuaaauaaag guuuucuuug uauagaaucg ggaugcugug aaugguggga aaugcacuaa 1140
auaguuaugc cccaaauaag aaagggaaaa ucauuugaau ccccaguuag cuccuugaaa 1200
gucuuuucac uuaaacacac ccacauacca cacacacacu cacagaccuc ccucccagau 1260
gcccaaagcc cugcugaccu acagagcuac uucuggaaag gcugacacau gccuaagaca 1320
caauuccugg gaauccagca gcuuuggguu caauuuccuu ccuaaaagaa caaugaauau 1380
gaccccugga gagcuauuag ggcagagcug cuuccuuaac guaaaggacu cuccagccuc 1440
cguaugaagu caucucagag cuaaagacaa ucaaguccaa cuugcagauu ugacauaaag 1500
caagacuucc aauccggcua ggcagaagga uuuugguuga aaaccaugaa aucccuucau 1560
auggaucauu uuuuaaacaa caaaaaaaga aaagaaccua cugggugucc acaacucuga 1620
gagcugcuuu cugaagaguc auguuuugag uccuggaauc ccucucccuu ugaccugccu 1680
cucaagacaa ugugcgagag aacucucucu ucaagugcau gcaagugagg uuuucacagu 1740
uagauuuuua auuuuaaagu aauacacauu uguacauaaa auucaauucu gacuguauac 1800
augugucaga uaaacaguug auaccugaca cuuguucaca gucuaugaua cgcaccgcau 1860
auccuacccu cucccccagc cucucuccau ggcuucucaa cccccccucu gcauuuccug 1920
ugaccugagg auucaguuuu guuuguggag gcaggugcaa ucccaagaga aacugugcaa 1980
ucuucugaga aguuagagua ggcaugugug ugugauuuag ggaagguacu ucucacucag 2040
cuuggucacc gguuccaggu uugugucuug ggcaaguccc ccauagcugg ugacagacca 2100
gaaaaaugaa aacaacuuug acuuagcccu caaguuuuca gugaaugaga augaaaaaca 2160
accaugagua agagauuucu uaccgagaug auguaaagga uaauaauagc agccagcacu 2220
caccuaugug ccagguauuu cucuaacugc uuuguguagu uugacucauc caguccucaa 2280
aaacaacaau gaaguggaua ccaguauuuu ccccuuuuca cagaugagga aagucuaaug 2340
ugacccaccc aacauaacau aguuugaggg gacagagcau uucguugaac agaggaggaa 2400
cuggcacagg aaaguugcau gaccccccca ccaaccuccg cccccagguu gcacagcuag 2460
cuagucggga ggacuuugcu uccguuuccc ucugccucuc aaugaugauc ucagggccaa 2520
cuaagcuaaa agcagacuug auggagcauc aguccucuga aagagucacu gccgagauac 2580
aaaauaccuc uucuucaaag gggaagugga gagaaguagg aaaucugggu aaccucacag 2640
ucuuccaguu ucuggaaaac agagcuggca ucagucuuuu uucuuguccu ag 2692
<210> 31
<211> 356
<212> RNA
<213> 智人
<400> 31
guaaaguaga gauuccagcu gguuucuguc aagugccaga aguggcgguu cuuugaaaaa 60
gucuaacauu agagcaaagu uuuguaaaag caaaaagcca ucguucccca cccaagcaua 120
gcaacuaucu uuauuuuugg cauaguuccc ccaucucugc augcauacaa auuuuaugua 180
cuugugguua cugugugcuu acguuuuugu auuuauagaa gaugauguuc ucagauagag 240
ucguaaugga uuuucuuccc auuaugaagc aauacccaac aaaacagagc uuggguuaga 300
uuuuucugag aauaagaaug acuaaacaaa auucucucuu uuuuucuucu ugacag 356
<210> 32
<211> 4696
<212> RNA
<213> 智人
<400> 32
guauggugcu ggagccagug gcuuguuccc uuccuugccu cccucccaag uuccaucucg 60
aaagucuaag gggcugggca caguggcuca ugccuguaau cccagcaauu ugggaggcca 120
aggcagaugg accaccugag uucgagacca gccuggccaa cauggugaaa ccccaucugu 180
acuaaaaaua caaaaauuag cuaggugugg uggcgcgcac cuguaauucc agcuacucgg 240
gaggcugagg caggagaauc acuugaaccu gggaggcaga gguugcagug agcagagauu 300
gugccacugc acugcagccu gagcgacaag agcaaaaucc aucucaaaaa aaaaaaaaag 360
ucuaaggaaa aagucaugaa acaacaaagc aggcaaauac uccuccauag uaucugacuc 420
cccaguagua ggcauuuugc auccuagaug gcuuugagug acaaaggaau aacagacuga 480
guuaggucua gauggggaca cuuuggauga augaggauuc uuacggaggu cagguuggua 540
gcuucauccc ucagcuccuc augcuguauc cccagucucu cggccugcca ugucaucauc 600
cucaucuccu ccugucaucu ccaccaggcc ucugauccau cucugucugc augagugaca 660
gcuggcagag uccuuaaugu uuaucaaaua caacucagac gucagucucc uggccccuuu 720
gagaucaaca uaaaaucauu uugaacccuu auuuaguggu cuaugggcuu ugaaaacaug 780
gggaccaaaa uuccugugga uucuagaagu cucucuucua caugugucag ccugggcacc 840
aacuagcucc uuccaugaac uuuuaucaaa cccacagcca cacaaagcau gugugagugu 900
agcagaguuu acagcagagg guggagggug gggagauaga uguguggaag gguuaccugc 960
cacacaaaca gaaaccacuu cugauagaac acgagguguc cacccacacu guaaaauccu 1020
cuccugguac aggcaaagcu uugcagcgau ucuccuuugc ugccccuggg cuccuaacac 1080
cuccuaaacc accaguuacc uccuucuuuc caguguggca uauuucagug uuuuccuguu 1140
ggaguguuuc cuuucuaugu ggauucugga aucagcucuu aagauaacuu gguuuucauc 1200
uuucuucaua augaucccaa acaucuaucu acuaugccua gaacuaccaa uggacacaua 1260
uaccagccca gauaugcuuc agcccauccc aguacaucgc auggugacca aaagauguag 1320
ucguccuggc acagugggug uggggcagga agcaguccuc uccaggggac agcagcaauu 1380
caccacagaa cccaaguuuc uuucaagcuc ugcugacaca gaaauugaau aaucucagcu 1440
cacccaaugu caaagacuca uauuaaccaa gaccagaaug aaaauaugcu aauuuauauc 1500
agaagcuuug cuggauucaa gaguuagggc cuuuuaccug ugcagaauau uccuucuuga 1560
uaaauaggcc cucucaggag aauaaauuac acaucagagg acuguuuagu cagcauaggc 1620
auagaacagg auguuccaaa gauacaguca aggggagugg guaagagugu agccucugga 1680
gugaggccga ccaaauauca aaccugagcu ucauaauuug caaacuaacu ggcuuugggu 1740
aaguacauag ccucuuugua ccuguuuccc caucugcaaa auggagauaa uaauagcauc 1800
uaccuguagc auuguugaga gaauuaagug aguuaaugcu ugccgacuua uaacacagua 1860
uacgaucacu gauuaagacu uagcaacucu aaacuaaaug uuuacaaacc aucucuuacc 1920
ucaaagcacu uaacauccau ugucuuauuu gauuaucacu guaaucuuau gaagcaggca 1980
gggcaggggu cugccccauc uggggggaac ugagcucaca gagguuggag gguuugccua 2040
aagucaccca ggccacuggg ucucacucuc uggucuuagc ucuguaaucu aggaugcuca 2100
augccacacu cucagccacu uuucagaugg cuaaguacau uuguuuugag uuagcucagu 2160
cucagaggau gacauuuucu gaucuugucu ccaguguuua aaugaaccug uagcugugca 2220
uuggggucac acaaugcgug gcauggagag ggucuguggc ugacugccac gguuacuacg 2280
ugaaaccauc auuacagcag uuacuacugu uacugccuga gaacaucauu acaagacuga 2340
acgaagggau caacauggaa augauaacaa aaaaaccaaa guaacuguuu uaaggaaagg 2400
cuagcaucgg gaagaagaag agagaagaag agaagaagaa aagggcuccc ugcuucuaau 2460
gaguaaaggc agcucccuaa gcuucugcag cccuucauua uuuauugggu aacaggagga 2520
aggagcagga gguaaugauu gggucagcug cuuaaaugau cacggguuca uguuguuacu 2580
gacagauuuc aauuaugccu aaucauaaga aacauuugug cagccuccaa caagggucaa 2640
ugccacuucu gaagggguga cucauaguca guaacuagaa agcagcagau agcuagggac 2700
aaacuggcga uucugaauag gccuggaacc cuuagcucug gccaggucag ugggcuccag 2760
ucaggaugga gccuucaggg agagaucaaa gcucagaggu uugagaugau aucagccagc 2820
aaagaggagg ggcaguaggg auccucccag agggagggcc agccauagaa gacaucaaau 2880
cugagcccgg aucaggagaa ggagccugca gaacuggggc ucuggcaccg agaaccugca 2940
gaacuucgcc ccucugagug caggugccag ggcuggggcu gccacccagc cuucgcaucc 3000
caggccuggc acgucauagg uaaauguagu ugaaaggaug acugagcuga uccaauuccc 3060
uuuacaacug uccuuguccu gggggacuug aggaggguua agaaagcagc uggggaccaa 3120
ccaacagucc ucuaggcucu ccauguccag caauaguugu ucagcaaaug agcauuaauc 3180
agugacuaua aacuguagcu ucaacauaac cgacaacuug caaugguuuc uagagcaugc 3240
ucccaugugu uaucucauuu aaauuuccaa accaauccug ugaaauguuc uuuuuuuuuu 3300
ucuuuuuuuu uuuuuugaga uagaguuuug cucugucacc caggcuggaa uacagcggcu 3360
cgaucauagc ucacugcagc cuugaccucc ugggcccaag ggguccuccc accucagccu 3420
cccaaguagc ugggacuaca ggcacacgcc accgugccug gcuaauuucu uuucuaguug 3480
uuuguagaga cagggucucc cuauguugua caggcugauc ugaaacuccu ggggucaauc 3540
aauccuccug gcuuggccuc ccaaagugcu gggauuacag gcaugagcca ccaugccuuc 3600
auuuuacaga uaagaagucu gagaaaacuc agauuuaggc agauugaguc acuuccccaa 3660
auuuauguau cuuguaagaa uccauauuca aaccucaguc cccuaacucu uaguucauua 3720
cuuuuucuac cacuucucag uauccucuaa gaauucagaa agaaccacau cgacucugau 3780
uuuucauuug uuuaaguaca cagguaauag gugaauguau uuuguuguuu aaaaauucau 3840
auaauacaca aaaggcuaaa gucucgcuuc ccacuuccuc uccccuuucu acccaacucu 3900
gccuccccag ggagagcuuc ugcugacagu cgguggacau ucuuucagag uuuuacaauu 3960
augugugugu guguacauaa gaugucaguu uuucuuugug uaggauacau gaacaugaau 4020
uuuaaacaua aaugugagug uauuacacau auugaccagc accuuaguuu uuuuguuugu 4080
uuguuugguu uucuuugugc uguuugagaa ggagucuugc ucugucaccc aggcuggagu 4140
gcagucuugc aaucucggcu uacgcaaccu ccaccuccug gguucaagug auucuccugc 4200
cucagccucc cgaguaguug ggauuacagg ugccugccac caugccuggc uaauuuuugu 4260
auuuuuguag agaggggguu ucacuaugua ggucaagcug gucucaaacu gcugaccuca 4320
aaugauccau ccaccucagc cucccaaagu gcugagauga caggcgugag ccuccgugcc 4380
cagccaguuu uguuuuuuua uuaaccaagu uacguauuuu aaacuucucc augucaaugc 4440
uuuuagagcu auuuuguucu cuuuaauguu aauagagaau uuuaaggcaa uuucagguga 4500
aucuauacaa uuucucugua uaaguaauuu acacuagaaa uagauuuuua uaaagaugau 4560
uaagcuacca gccugguauu ucauugcuga cuuaaaugaa gaggaaaauc aaugcuguaa 4620
gggaaaaaaa aaauggcauu agagauccag accuuauagg cauuuuccaa auuauuaauu 4680
caaucucuca aaacag 4696
<210> 33
<211> 657
<212> RNA
<213> 智人
<400> 33
guacuauugu cggucggugu uuagcugagc ucaguggcuc cucucccagc cuuccccucc 60
ucuccugagu guuccuucag gcauggguua uaacucagca aggagcaccc ucuuuagauu 120
cugcugguuu uguuuccugc uuuccaaacc cuuaucuuga uucuugguaa caugaaucuu 180
cuuuguaagu uggaccuccc cuagcaaaga aaauagaaua auagugaaaa uguuaauauu 240
guuuuuauuu uuacagugag ggauaaaguc auguuuucau ucauuuuugc agugacccua 300
cauaucaaaa ucauugcccu cuuuuuucuu uuaauguugu uuaauuuaga aaaagaagcu 360
cugguuuaaa gaacagugag ucacgugacu ugcucuuuga aaugcccuuu gaagucuggc 420
ugaacacugg gcugcauuca gauucuucag uggccaccag aacauucugu uuucuucugc 480
acaucuuacc uuugcacacc cugcuuauua uguuccccca gaagcccaac ccucuccacc 540
aggggcugau uaggaggcug caggauaaau guuuaaaaga augaagaugu gugugcacgc 600
gcacguguga caucuccaug ccacagucau guuuauucca cgucuauucu cccacag 657
<210> 34
<211> 469
<212> RNA
<213> 智人
<400> 34
gugcgcggac ucggggucac cauucuccuc uguggguuug gggcaccugg gucacaugcu 60
gcuuagaagg gcccugaccu ucccacuuca cugggaccuu caccaaugag agaggggagg 120
ggucuuuggg cugccugcag aaaggaacuu aauguaucug ccacugcuug gaaaggcgau 180
ccuaguggac aggcaggacu gcuugggaag gccgaauggg gaaaggaaug caaagcuuag 240
gugaaugggu ugaagcgcca ucuuuuugag gcauagguga caugccauca gaccacugcg 300
aguguucagg cagccuaccg cacucccagg agagcuagcg ccaucccaag gcagcauucg 360
gugccuccaa uacauaccug gcacacagca gcuauccagu aaaggcucug aguugcauga 420
uguuggcacg cgccugcucu gucccaguca caugucucac ucugucuag 469
<210> 35
<211> 796
<212> RNA
<213> 智人
<400> 35
guaagugccu acgcgccccu guccuaagaa gacuagcucc ccugggagga cccaacggug 60
gguucaagau ggcaggcguu ggggaggccc cacucaaucc ugcucugcug gucacuucca 120
ugucucugac cagcacuccc ccaaccucuc cuuccacacu ugugugcagg gacauucacu 180
accuccuagg aagcccccac accacuggac agcucuauau uucucagcau agaaguucua 240
uguugaguug acagaugauu ccccauaacu uauuugaaag gccucugagc agggagggag 300
ggaaauaggg uuaugcuauu gugugauugg gccuugaaug gcgugaguga cacaguggcc 360
aguacuuugu gauaguugug agucuggaga agggaguuag cgaaggccau ugacauccac 420
caggaauccu aaaaguucaa uauaauuuua acuuuucucc cucagucuuu uucaaagcug 480
ucaauaagga ccaaaacaga cuaauuucaa auuccucuuc ugguugcugu gucucucaac 540
agcuagagcu gcuaggaaua aaaagggaga caaaacgauc cacaagcuag agaugguuau 600
uccccagccc cacaccuagu cagucacaaa acccuaguuu ugauauugcu ugagcagaaa 660
ccagccucca agagaauaag aagaaagggc cugggucuaa agaggaggag gaaaggguug 720
ggcacaauuu cuuaugccua gggauuuguc agcaacuuug aggcugauua uggaauauuu 780
ucuugucuuc caugag 796
<210> 36
<211> 4396
<212> RNA
<213> 智人
<400> 36
guaccugacc uccaaacaac ggggccccag gucugccugc cacagaggga cuaggggagu 60
cccugguauc uccugagucu cucacaaacu aacauuucaa acuggcaguu gaguagggga 120
cuaaaccaaa cucccugcac ccucugggag gggcucccca cagggcgcug uggcugccaa 180
cuggaggaag ccacucacca aaagcuucau uuuccaccag auacuuccua uuugaucuag 240
uagaaaaaau guguuuaagc acuaaaaaaa auuaagucau augugcucau uauagaaaaa 300
uuagaaaaca cagguaaguc agaaggaaaa aaaaucaucg cuuggauaua aacacagaua 360
auguuugguu ugcagccacc caaacagauu auauuccaaa uauugucuua aaaucugauu 420
uacugcauaa uuuacuagga acaugcaucc augucaauaa auagacaucu gcaucacuuu 480
uaauaucugu auauuauccc auuguuugaa uuucuuuuuu uuuuuuuuuu uuuuuuuuga 540
gacagagucu cucucuguca cccagguugg agugcagcgg ugugaucucg gcucacugca 600
accucugccu cccagguuca auucuugugc cucagccccc ccgaguagug gggauuacag 660
gcaugcacca ucaugcccgc cuaauuuuuu ugguaguuuu aguacagaug ggguuuuacc 720
auguuggcca ggcugguguu gaacuccugg ccucaaguga ucuacccacu ucugccuacc 780
agagugcuag gauuacaagc gucagccacu gcuccuggcc uaaaguuacu uuaaauuaac 840
ugaucuccca uuauucgcca cuuagguuuu uuaguuuuca ccauuauaag caaugcuaug 900
auguacauuc aaauggaaau guguuuacac acuuauuaac agucuuaauu aagaagcucu 960
ccaugugcug ugucucuaac aucugcaggu auguacacaa auacaugcac agccagcauc 1020
caucuuuugc agggacauua augaucuugg cucugagcag cacccugucc ugggaguucu 1080
aaaguccaga acagauuaca gugagcaucu ccugggggau uuagagacau caaagaaggc 1140
uguguccgug guugauaaug ggccucccag cugacuugcc agggcugggc cuuagacagc 1200
ccuguccaau gauuugucaa ugaauaaacu guucccaaac aggcuaugca guucaguggg 1260
aaagcacagg uaugggacac ggagagcccc agguggacua cuugaccucu cugagccuua 1320
auuuuaucac cugugaauug ggaauaacug cuuauuucau aauauuauua ugaggauuua 1380
augaaaucau gugggcaagg aauuauuuag aauuagauuc aacucaagug augacaaccc 1440
caaacuaaca gcagauaaaa caagacacaa cuuguuucuc acucaucuaa aagucuacgu 1500
ggguggugca cgauguucua uucucuuucu ccuccacacu aaacaggccu cagccucauc 1560
agccaauaag gcaggagcug ccuuccaggc agcggaaugg aagaaggaug aagcaaaaca 1620
gagggcagag ugugcacaug ugcuauguuu agggaagguu uucugaaguu cccacauagu 1680
acuuccacuu acaaacccaa caaaaaaggc uauggcuaag gcagcaggga ggagcaaaua 1740
augggagcaa cuagauuuug ccacagcacc uaucacaguc ugguuuauaa augguucuag 1800
gccaagaaca cccgaucccu gcucuuuuuu auauucuaaa gcauguaucu uuauauuucu 1860
caagcaauau uuucucucuu ugaaucacag cucaucugcu gcaucauagg gaucccaaaa 1920
gaaggaccca aggaacuugu cucaguccuc ugugccccaa gaggaagcuu ugcuuguuug 1980
cuuugcuguc aaugcugagg gcuccugugg cugccuccac ucaaaacccu ccagcaucag 2040
gacgucaagg cugugauacu guacccugag cucuuggcca gggcgaggga ggggaggcca 2100
agccuaccua caugguguuu cauuuccuaa acgaacccuu acuuccacgc ggucugucca 2160
gcuuagaaac uuauuuucag uaguguuggu ccuugguccc uggacaaaau guaacagcca 2220
aaguccuaga aaaaggcaag ccaguuccug ccauuuucuu ucacuucugc auuuccucac 2280
uauuauacgu gccuuccauu ggagcaaaac ugaaugccac gcauaugcac aggagcugug 2340
cgcgcucugu cucucucacu cacucuuuuu cucucucucu cuuucucucu caaucucucu 2400
gucucuaucu aucucuuacu cuuuaucucu cacucucuca cucuuucuca cucuuucucu 2460
caaucucuuu cucauucucu cucuaucuuu cucucucucu cucuuucuca cacacacaca 2520
cucacaaacc cacacucuua uucacaucug cucacccuag ccacucaaac acaaucccuc 2580
auucagccug gaauaagucc agagggcgug ggccugauuc agagacaauc aguuguucuc 2640
aucugggaaa uggggcaaug uggucaucuc uagggacccu cccugcucua acauucuuug 2700
aauguggugg guccugaggu ggaagcacuc ugucccugac uucuaguaua uguggagaua 2760
ggguuacaca aauauuuuau ugggcagaac uuuuauaaaa caauuuauca uaagcuaucg 2820
cagccagcag caauuuuucc aaccuggauu ccaccagggg agcuuggccg gugucugagu 2880
gccacuuuca gcuugagaag caggugacuc agugaaaaga gcaaggagga gacagaggca 2940
gauucaguuc cuaggcccug ggccacccac cugcaaguuu gcagcccagu cagugcaagu 3000
cagcuaacug uucugaaccu caguuucucu gucuguaaau uaagcuaaaa auucuucuuu 3060
caaagagugu caggaugaag ugagaucgug uauguagggc auuuaacaua gugcccgaca 3120
cacagggagc auucgguagg ugccagcucu ccuccuggca ggagagagag aaacaaggug 3180
aaaagaguga auuaaagaag aggaaaguca aaugggaaaa cagggggagg agauagaaag 3240
uguaugaaaa ggaaagaaug gugcgcaaua acggcggugu aaugccacca aaauccccuc 3300
aacuacuucu gggcagcacc cuugacagag ugaaugcuuu uaugagaaug uaagcggaau 3360
guguucccag auuugcagua auauugccac cugguggaca aacccaugca ccuuugaauu 3420
uuccaaaaua uuucgaugaa cuagcuucca guccuagaug uauuuugaaa gugauuugua 3480
aauuguaagg aacuauucaa auucuuucau uaaugucaca aaucaacugu gucaucugua 3540
ugccacccac uauucugggu gcuggggaca caacagcuca caaaucaggc aaagucccug 3600
cucucaccaa aaugauaucc uacgggggau uacagauaca aauacguaaa cagauccauc 3660
gggaggaaac ucucagaugg aaaugagagc uaugaagaua acacaacagu acaugacaau 3720
acagagugac uggaaccagg aacauuucuc cgaggaauaa aauuugaagc gagccaugag 3780
agggucuaca gguagaguuc ccaggcagag ugaacagcca agcacaaagc ugcaccagga 3840
gagagaggug cucgccgaga gacagggagg ggaguguggc aggugagcuc agagaggggc 3900
agggccacac acaucggcca caugggccuu gguagugagu cgagauuuga ucccaggguu 3960
uauuggagug gauaaguaag caaggugacu gaggugcucg gguuuacauu uuuauaguuc 4020
aagcuggcug cuggguggaa aacggaaguu ggcagaccaa ggacagaauc aggcagaccc 4080
auguggaagu uucucuagug gucuaggugg uggcuugggu agcguggcag uauuggagcu 4140
ggagaaacgc agauggauug gagauuuguu uuggagugac gccauucugu cuugucaaug 4200
gauuggcgaa aaaagaggca ucaaagauga guuacacauc auugaaguga gaacuaggga 4260
gaugccagua cuuuauuuag uauuuucuca gcagcucaau ccauaaauaa uuuuuggaag 4320
acaacaagca guuucacaaa cuacuuauaa guccucaagu uccaagguaa uuaacguggg 4380
ugucucauug ccucag 4396
<210> 37
<211> 1535
<212> RNA
<213> 智人
<400> 37
guaagaagaa auccuuuuau gcuuuuuauc cuggcucccu guagaagaua uuaacuaggg 60
acagaagaua auuuucucuc ucaauuuaug uaugaucagg gcaguagauu uuuuucuuuu 120
uuaucugauu ugagggcccc auucaacaua aaaagcaauu gaggcacaua caaguaaaau 180
guaacuuaag auuaauucuu uuuuuguugu uuguuuguuu guuuuuacau uuagggcaag 240
cagucuuaaa uuuuaaccca cguauuauua aaaguuauau cagaagacca uagaaguuau 300
ucaaaaaugc agccacauau uuuaacuagu uaaaagagag aguaaaaauu uggagggagg 360
uggaggagua uaggggaaaa gguagaagaa aaagagaaaa uaaguaagug gcaaaaaaga 420
gaaaggaaaa agauagggug ggaaagaggc agcgggacag ugucugaguc cagcacacgc 480
cagggcgagc caggucaacu gcagcuguca uauucuaacu gugaauuauc aucuuugauc 540
acugcccuuu gagaugccaa ugaacuuuuc aagaaauauc uaguucucuu ggcucuccag 600
cuguucuuau cagccccauc caggauggaa cagcuuuggc agcccguauc agaacaagca 660
gcuugacagg ggcaugccau gccaggagag aggauccuaa ggaagcgugg uccaguccgc 720
acaggcucug gggcuuuaag auaaaaccuc cugucuaacu uuaguaggac uuucuguugc 780
uucaccugcc agagcccuga acgagggaua aauugacuua auuaacuaga acacacugca 840
aauggugaaa gcauuuagca aaacaaagaa ugccauccaa gccccaaaau aaaagcagaa 900
uaaauagaau gcaauaaaca gcaaccaucc caaacugagu ucucagcagc aaaucuccag 960
uaugaaauuu uggauuuugu gcgugugugc uuaaaggugg augacaauga caguucaugg 1020
gauugagcuc ugggguccag aguuggcauc uguucauuuc ccauuuuguc auuuuacccu 1080
ugauugacug aaugucagug ccuuaacuuu gggcugugga gugagucgga acucccccga 1140
ggugugcagg ugguuguuag agucucauuu uugcagggug gaagacagga gggcugcagc 1200
cuucauucca cacugacaug gucauugccg uguguucugg guccagauca ggcauauuga 1260
ccugacauau gaccugacaa caggaccacu cagaaagucc agcaugcggg auaugauuug 1320
gagagccagu gggggaaauc auagguccuu ucucugcaug uguauucagg caauguccca 1380
gggcugggcg gcuuccgcau ugcuuggaua ucggaaaaug caaaaaugcc ccugaagacu 1440
gagacuucag ucuucaaaau gaauguuugg gaaagaaagu uaacggcacu gcuguacuug 1500
ugguauucau ugcauuauuu uauuuuggcu uucag 1535
<210> 38
<211> 1434
<212> RNA
<213> 智人
<400> 38
guaagaaacu auuuuuauca gaauuaaaau cucagauuga uucauuguug aaauaauugc 60
acacuuuuaa aaggcacacc ucacagccau gaggaggggc uguucuguag gugcucagga 120
agucacaaga cacguccuga agaauaugug gcuagggaca ucccagacuc agaagacacu 180
caguggugcc ucuucuugga ggacauaagu ggggguggca uucccugaug uggcguuuca 240
gagcauucuc acccaaaaaa agcuucuaaa accuccaagu auauaacagu uuauaauacu 300
ccaacaagag ggccuuguag ccuaaacccg ggacacuccu uggcccauuc cuuuuaagcu 360
ucagggagug ugggccagcc ccagacucac cccauuccug aggcauccug gagguugaaa 420
uauuuccaga gguuuagaac cucaccaagu gggacucuag gagccugcug ccucccagcc 480
ucccucagga acugcaccuc cagaacaggu gcggggcuga cauguaugug cuuuccuggg 540
cagauucuag accguacaca ugaaaucugg cuuucaggau ugcucuccag agggaccugu 600
ggggccucgg cugagacaga gaguaggagu gaggcaguga uucaaggccc ugagaaagag 660
cuccuccucu gcuugguaua accagcuaau ucauucuguu cuguugacuu uggcuucugc 720
ccugccuuug aaggguuuga ggccagggag ugaugcacuc agacuggugu uuccacacag 780
ucacuucaga cuuccagggc aguacaggag auagauccca gggccaguga agaagcagag 840
cacaagucca ggcaggagag gcuaagggcc ucccugaaca ggugugaggc acagaagccc 900
cgagagguag ggaugacagg augaagaugg guccugugcu gcuagaagua ccugcaaagc 960
acagaggugg cacagaaaag gaguccuugg cugggauggg aggagaugac augugacaug 1020
ugaaagagga ccuggaguug gcucgaugcu cccaaaaggg aaaggugccg aggggagcua 1080
gcagccaugc aaaggcagag acaugcaggc agucugggcc augaggagcu cuggaaguga 1140
cucgauaugu ccagaauagg ccacuccagg gaagggcuga ggaaggauga aguuggagag 1200
gggcacagac cagaugcaga agggccucag aggccaggau gaggguuugg acuccuuccu 1260
ggaggcagca gcagugggaa aagaguuaaa agcugguuug uaaaguggag ccauguugcu 1320
cgcuggucca ggcaauuccc ccgaaaguuc auguuucccu acaaaacccg agagagcuac 1380
uaguaggcgu gaaguucgug gcccuggucu gaggauuucc uguuuccuug ucag 1434
<210> 39
<211> 131
<212> RNA
<213> 智人
<400> 39
guauguaaac agacuggaga uuugaguagg auuuuugacu ugcuuaacua ccaugaauga 60
gaaacucuca ugagugauaa caggaaaaaa aaauuaaaac cgucuuguuu guuuguuuac 120
augguuuuua g 131
<210> 40
<211> 230
<212> RNA
<213> 智人
<400> 40
guacuugacc uauguauaau cugcucugga gcuaaaaauu uaccugagcu gguuauuuua 60
uuuuuacuuu ccuaccuuca uuaaauucca ucccuccucc ugcugaaauc uagcaaggaa 120
ugucuuccag cuaccaaacc cuuccugcuu cucaaauuuc cuuuccuuca cugauuucug 180
cuuuaacuag cuguuagugc agcgucucag auguccucuc cacccucuag 230
<210> 41
<211> 1480
<212> RNA
<213> 智人
<400> 41
guaagccacc acagccccag ccucaccacu uucuugucac cuucuccacu cuuugaacau 60
ccugagagga uucucaccac cgcgaagugc ugauuuggau gguaaugcug uuuagucagg 120
cacauaugaa cauccgacuu ucaaauaagu gccucacacu ucacauacca gaccucuugg 180
ucauucuuuc uccccaacau uuauguggca aguaaguuua cauuugguuc cauucccuuu 240
uggcuuuuga uagcaaguug cuccuggagc uuauacaauu auuaucuuug cuaugugcaa 300
agcagcugcc aggaacuggc aaaguucagu aaaccuuuca gcucccucgg aguaauuauc 360
uuagauucca ggaauuuccu cagaagagca uacuuuggag augucgacag agcuuugcua 420
cccucaagcu gaggcucuuc uugcacaguu ucagccagug gagacagugg ccuugugcgu 480
uuuguaguau guucacucua uuugaggccu acauggagga gggguuggua ggagcaccuu 540
uguuagugca aacuucagca acguuguggg guccugauuu uacuauccua gcacacgcug 600
agugccagug aacaugccca gggucaucca cuaaaaccug ggccuuggcu ccuugguguc 660
uuccucugga cacccuaggg cccuagacug uccucuguua auucucacuc agccacacuu 720
ucgugugucu ccuuccaguc auuuguucua agcuuacuac guguauggau gauaugaucu 780
guaguuuuau caagguagug acuaccacau aggauaccuu uguggaaauu aguaaaaaug 840
cucuuuucug cagguggaca cugucccaug ccagggguua uggcuuguac auaaaguuca 900
ggcuggcuuu agccccaacu uaccccucag ccagaugccu ucuauuuguc cgaggaaaga 960
auaaauagag ccaagucccu guacaacuug ccugcccucu uuucacuuaa auuuacauca 1020
ugaacauuuc cuuguguuac gauguacuuc uugaaaaugu gauuuaacaa gaugauuauu 1080
aacaaaagau aaaucucaca gaccguaugu cugucaacau agaaaauuca agagacucua 1140
uagacagauu auuagagcua augagagcau ugcaguacau aagauuaaua uaaacaucua 1200
uuucuauaca ccauaaaaau aauuagagaa uauaauaaaa agaaagguug ucuagaaaua 1260
uucacaugaa auagaaaggc aacccgcaaa uacccauuua accuuggucc auauggauua 1320
agacaguuua guggagugac agcuucaagg uagagaagag gaaccuggag gccacaccug 1380
ggcgggugua aggccuuccc aaagccugac uuuguaucuu cuccuccuuc ugcucuuccc 1440
ucuucaucgc ccucucccug ugucucuggc ccugcugcag 1480
<210> 42
<211> 3727
<212> RNA
<213> 智人
<400> 42
guaaguguca guuuacagcg ccucccuccc cuccgugggc ccaaggugga gcuugugugu 60
gcucugaagg accagaccaa gaggggaggg guucucacgg ugccagggcu gcugaaaggc 120
acugggccaa gggccuugug uaucugcugu cccuugacau cuucucagaa aggcacagaa 180
cuaggagccc gaagcuagga aaggcugugg ggugcagcuu aacaacuggu gaacgggggc 240
ucucuauguc cugcacugag gggucuucug acccaucaaa uaaucacugc accgcaggca 300
ugagucuggc cuuccuggca ucagucuggc gcugagaagg uaauaugaag gggucuuuca 360
ccccaagucc ccuucucaaa uccugcccca ccuucaaaag gguaaaggua aaacuuuccc 420
ugugguaggg ucaccagaua aauacaggac acccaguuaa auuuaauuuc agaugaugaa 480
uaauuuuuag uauaagcaua ugcuacuuca aauauugcac aggacauauc uacacuaaaa 540
aaaaaaaaaa aaaaaaaaaa aaccugguug uuuaucugaa acucaaauuu cacuaggcau 600
ccuagauuuu uauuugccaa aucuggcaac cccagccagu ggccaaaaua auaagaccuu 660
cacuuauuag auuaaccacc gcuacaggga aaaaugaaga aaaaauauuu auuaaaucaa 720
uagcacacua ccaccuuccu gacaaccaag guuggugggg guagggaggg gucaggauag 780
cguacccuau uacaggcugc agggucaaag gaauugguag uaaaggccua guuauaaugu 840
aacagggauc auuaugacau caaccccaau uuauucuagg ugucuugagu aguaaaaucu 900
caacauuuua agaccaacau gagccuccau uucaugugau gauaagauau accaacugau 960
ggagaccaac acaaaugacc uucucaucca ugguuuuuua aaaugauggu gaauauugga 1020
auuccugaag auaugauuuc uaucuuacuc agcuuaguaa gcagcuauca cuuaacaaua 1080
caaaaccaga gauuaucagu agcaacuaaa uuauuuccuc ucucuucugu cuacacgagg 1140
aaacacucau aaaugcacgg ggaggagguc agaaccugaa agccuuucuu uggauaagag 1200
caucaacugc agguaccaca uuggcccugu gaugcuaaua uaaaaggagc uaggcccacc 1260
gguaccgaaa aguuacuuag aaaagugcgg aggcuuuuaa uuuuacuuuu uuuaaaagau 1320
aagaaauaga auuuacacac uuggggcugg cccacguguu ucugugugug uguaugugug 1380
cacgcacgcg cgugugcgcu uacagggauc ucugagccua uggagagaga uguagcuagg 1440
auagagugga caucugaggu gggaggugau acuagcuggc aguccaauga agggguagaa 1500
gaugguaggc aucauguuag caggcuuucu gaugcuccag aauuuuaaag cuggccugga 1560
aucucaccuc cgcgauccau cauuuuggaa cuuaggacca ccauuagcca guggcaaaaa 1620
aaaaguugaa ugaaggaaca aacaauuauu gcuuauguaa uucacuuagc acauauauga 1680
uguuuuaaau ucuuauaugu gucaucuauu uuucuuuacu uuaaaauuuu gcaacaguua 1740
cagacuuaug gaaaagucac aaguacaguu gaaaccuuuu uuucuuaguc auuugaaagu 1800
aacuucucag caagaugccc cuucucauuu auuucucucu uccugucucu cucucucaca 1860
ccccucagca cguccgaugu auacuuccua caaacgagga uacaccccau acaaccacaa 1920
cacaaacugu caacaugagg aaaccagcac ugauguguca ucaccaccua auccucacac 1980
cccacuccuc uuucgcccau ugccccagug augucuuuca gaaaaaagga ucuagcucag 2040
aaucaugcau gacauuugau ugugcuguuu cuuuagucuc guucagccug gaagaguucc 2100
acagucuuuu guuaacacuc auggucuuga cacuuugagg acugcaggcu gguuauuuug 2160
cagaaugucc cuuggucuga gcuugucuga gguuuccucu ugcccagguu gagggugugc 2220
aucuuggcag caguaucagc aaacagaugc uguguucuca cugcauccua ucagguggcu 2280
ucugauuuca auuugcucug uuacugauga uguucaauuc ggucacuuaa gaaggugucu 2340
gcugagcuuc uucacuguaa aauuacucuu uuccccuuua uaauaaauac aaauuucagg 2400
uagaggcacu ucaaagauau auaaauaucc uauucauuau acaauuuucc auuuauucau 2460
ccauuuauuu aucucuguau gcagucaugg uucauguguu aaucaaugga cuaugaucca 2520
agacuaucau uauuuauuuu gauauucaca uuauccccac uguggucagu ggggggccgu 2580
ugaagcuggc uucuguaucg ucuugacuug gguccucaug ccccuggacc uccuccaugc 2640
ucaauggcac agcaagauau uccaggcuca uccuuccauu auccccauuc cuacccucuc 2700
cccaagaagc ccugguuccu gccaguggga aguggcccuc agaagccaag gucugagugc 2760
uagauauguu cauugccucu ggagcaccau uggucccagg ccuucucagu gauagaacua 2820
gggaagauau ggauguacac acacagguau gcacacaccu cuaucuauag uucucuaucu 2880
accuauacag ugaacacuau gagcucucca aaaccaacuc cacagggcuc auucuaguuu 2940
uuuuucuuuc cacaucugua acucccuucu ccaacaguga gacgcuggcu ucucucacuc 3000
ccaacucauu uaucuaccgg accuauacac cugaacagug cccaacucug ccaccauccc 3060
cuccccaugu ggaugccguc cucucccugc uccagcugcc ucugcugcau gcagguccuc 3120
cucguucugc ucuggcucug auacccugca ccagaucagc cuccuguaag gauaucuuuc 3180
ucaucccguu gaggccucca caccccacgg cagguugccc ccugaggaag cccgucucug 3240
guucuugccc ugcuccugau caccauggcu ccuccccuaa ccccacuguu gccguccccu 3300
uucugugccc aguauagugg cuguaggacu aaauuguuua aaaaggguau cauuauuuau 3360
uugagcuuug ugaagccaag aacuaggcuu uaaguuuuuc ugaauucuga agacaugcuu 3420
agaaagaaga aucaacaaaa cuuuaugacc aaauagaaag agugagagac caggcagaau 3480
uuuguaauug auccuuucaa aagauacaaa cuaaagguuc ccuuggcagg gagguagggc 3540
augggguggg guaggaggac uagugacagc uuaacauaug uuugccaacc aagaacuguu 3600
uaaaaagcaa gucgaaucag aaucccagac ccuacgagcu ggaggagccu ggccccaccc 3660
cucauuuugc agagcuggca gcaggucuga gagguuaagu gacuugcucu ccucuucucu 3720
uuccgag 3727
<210> 43
<211> 1048
<212> RNA
<213> 智人
<400> 43
guaagccguu ugggccauua gcuaaugccu cugaagagaa gccugguggu gggggugggg 60
gaucaucucc ugacagaaaa ccugggcugu ccuguggugg uagcacccac aaguuuagcu 120
uccggcccca gguagggucu gaagcugaua accagggauc ugucuggcuu cugauucuga 180
cuccacugac agagguaucu cugaggccug guccugucag ugacaaugag agaaguccca 240
caugaucuga aucuccuacu caaacugagg ccuugaccaa agccuggggg cagccauucc 300
ccaaccccuc acccagcucu gacucucacu caucuguggc caaucugucc accucagugu 360
ccccauguga acuggccaag aguuaccgcc cacaguagaa gacuccggcc aaaaagcucc 420
uccugaguca gggacagagg augacacagg gguuacauca gcagaguuac agggcccagc 480
augcaacuuu cuuucccacg uguguaaauu ugaaugagua auucauccau cucggccuca 540
guuuccucau cuguaaaaga aaauagugau ccugguccuu ccucuguggg ccaguagagc 600
cuugccaaag cauuguucuc cacaucuuuc ucuuggaaau agagaauuug ggaaccaacc 660
ugacuauaag cugugaagau gagcucacug ggcucaucug agaugaccuc agcugggcuu 720
ugcugaccca ggcuagagug ggagguguug caggcuggag aacccuccua ugaauuguac 780
agggcuuugu aguuuacaga guauauacac agcuagcagc ccauuugcuc cucacaaaac 840
cccaugaagu ggucaaggca ggcaucauua ucuccauuua aaguugaggc acagagacca 900
acaaauggag uaucucucug guccccuggg acucuggcca guucacacac aucaccucag 960
guguaagggg agugcauuau auccagacgu auuguaggug gaauggaaug uggaacucca 1020
ucacucugag uugucucauu ucacacag 1048
<210> 44
<211> 3157
<212> RNA
<213> 智人
<400> 44
gugagcauaa cuuucuuggc uuuuuuguuu gauuaguagg auaguagagu auguguuggu 60
cgagcagagc caggggcaag caucguacau guagcagcug uaugcggaug agugccacuu 120
ucuuccuccc uacccccgac ccugccuccu uuccuuccuu ccuuccuccc auccuuccuu 180
ccucuuuccu ucuucuccuc ccuccucccu ccuucccccg ucccuccuuc cuuccuuuuu 240
cauugcuucc uuccuuccuu cgucccuccu ucccuuccuc uuuccuucug cccucucucc 300
cuuuuuccuu ucauccuccc uccaucccuc ccuccauccu uccuucuuuc uuccuucuuu 360
ccuuccuaua agcaccuuuu ucauuucugu gcucugaaug aaaugguuuu cuguguuuau 420
ucugcaagca aaacuugauu cuugcaauaa acuuuaagcu uugcuuacuc uuucagaaag 480
guuuucucag ggacuuuggg uguuggguuu uacacacaca cacaucaaua cauuugggua 540
auuucaaaau cuaaaaggaa caaaaaggca uacaaugaaa aaaucuccuu ccuaccccug 600
uuucccacuc augcaguucu cuucuccaga ggcaaacucu uacuugaguu uccugugugc 660
ucuggagaca caucagcaga ucccuauacg gucuuucucc cgcuuucuua uggaaauugu 720
aacacucuga cauauacuau uccuugggca aguuaaucuu gaugaagaga cuggguguuc 780
uccaugcuga augccucacu uuuaugagcu gccaagccca guugucccuu ccaccugacc 840
ucccccuguc cagagacaga uggccaaacu gaaucauaaa aagaggggga aaaaaagaag 900
gcagucgcug cagggcuguc uuuacuccac acuccacacu cccagucccc accgcugugu 960
cugaguccug gcuguggcug uccuuggaac auuugccuca ccacgugccu guguccccag 1020
gcgccucaac cuuuccucuc cucauuagcu cuucccaguu cagagggugg gaccggccag 1080
cacaucugca cugcugcccu gccacaccca ccuccaccug ccucugggcc ccacugggga 1140
acacaggaca aaucugugcg gaggccccac caugaaccgc ccagacccgu ggaccccuga 1200
gacugacucu uuccagaucu uguuaggguu ucguggcugc uaggcaagua acgaagccuc 1260
aucuguccca ugaaugauaa gaaauucagc augucagagu cagacucugg aaaggcgggg 1320
ggauaagaac acagccccag cagauggcca gagcacccag gugacugaaa gugcugcuuu 1380
gcagagcugu guuugccaca ggcucacagc ccacuaaguc uuaagacagu uuuccuucag 1440
aauaauuaaa uagccagcuu aaagcaacuc agaacauuuu ccccucugag gcugcaccca 1500
uuuagccaac auuugcuaag cacccgccuu caaaaaccug guauuuucau guaaauuauc 1560
cgauacacag cugcuaugga aacccccagu aucccacagg aagcucccca gcucccagca 1620
gcugccggcc cgugugagau caggaggucu uuaccagcug aacaccacgu gccgggugug 1680
ugcugauaua aacaagcgug gcccacucgu ccugcccucc agaggcuccc guuccagucg 1740
gaaaaggacc ugcccacgaa guuugcaacg auauaagcca caguguauga uccuccauaa 1800
uacagcgugu gacagagcag cagaggagcg aggcagauaa caugcugcag gccagaggca 1860
gcgggaagag ccaggcugca ggggcugggg gagccguggu ggaggaaguu caauuucagc 1920
cuguagauuu cuauuagccc auuuaauaaa uaaugaagug ccuacucuga gcuaaucauu 1980
gugcagguau uuaggaagga caaaaaaaua auuaggacuc agugcccacc cuccaggggc 2040
ccacugacua guagagaaag uaggcagauu uuuaaaaaau uaaucauggg aaugugauaa 2100
gugcugggag agaggaaugg auacuuucuc augggaaucu uggaaggcuu guaagggaag 2160
gcacucucug agccagcugu cuaaagaaga acaggaaucu uuaagaaagc agaagggaaa 2220
agagcauucu uuccugcuug gagcaauagg uaacagccug cacaugccca ggccuagagg 2280
ccaaagagca cagugauucc agaaagagug gggagaaagg guaggcaggg aaggaugagg 2340
uaaugugggc gcaggugugg aggcuggaga gggaggaggu ugugggacug ggaggagcca 2400
gauggaaugg acagcagugg cccagccagg agcuaugcug gccucguacg ccucgauguc 2460
ccuucuauuu ucucagggga ggcucugccc aacaugccaa guccgaccac uugaaaacaa 2520
gucccuggcu uaacacagac cccagagaga gucuccaacc cuccucuccc uagacaaugg 2580
uaguugcccu gugaggggcu gaaaagcaga gcuggagaug gcucagggcc ugguguuaac 2640
aaaugccuug agggcuccug uuguuucaaa gugagucugc agggagagcu cccuaagugg 2700
acagcaggag ggcugcagcu ucucugcaca uuccugcugu cacccccaga gucaccuagg 2760
ggagggguaa ggacaguaau gcagguuccu cacaguuagc cucggugccc acaugguacu 2820
gagcauagua aauguuuaga agaugcugcc uggcuagaca aaggggaagc ucccgcccac 2880
uagaaacuug cagggagccc caguccuuga uuggucauuu aauugauuag cuccuuggcc 2940
uggccuugag gcacugcuug uaaguacuuc augaccucca uugcaaaccc augaugcucu 3000
gcuggacaaa ucccuccagu ggccagucug gcugcaagga cucucugucu gcaggccuug 3060
cccugugcug uccugugaga gcaucugggc cccaccugcu gaagagaggg gggguggggu 3120
uugccccguu uccaacaguc cuacuucucu guuucag 3157
<210> 45
<211> 332
<212> RNA
<213> 智人
<400> 45
guggguggua gccgaggccc auggagcaug ggcccugggu ccaaagcugg gaggguuacc 60
gggggggcuc cugcaucaga cuguggcagg ggcuggugcu aggaggggac cuuguugggc 120
uggagguguc cugccagcug gagaggauua gggugccucu guuuccaugg cuggggagcc 180
acaggaggga uggagggcag cccuuaugag gcggguguuu ggcucuugcu caguucccac 240
auaaggccug gucuaguggg cccugugcug uggccagguc ugugggguga gcuggggcgg 300
cugaagugga cucaauuccu guugaugccc ag 332
<210> 46
<211> 1928
<212> RNA
<213> 智人
<400> 46
guacguccau gccacacccu gggccagugg gcagcucagg gcauccagaa cuggaccuua 60
uacccacaug gucauuucuu uccucaggag ccccacucca caauguuuuu ucuacauucu 120
caaagccugg cuuuucucca auaauacaag uagaggaucg gguuaaaaua ggcacauuca 180
aauaugugaa gagcauccac uuuaaaauau uuaaaaugca gugcuauuaa uuucaauugc 240
ugauauuuaa uccuucucau uuaauuacca aauguguauu uugauuagau gauaguauug 300
caaauaacaa ugguuacagg guauccaaag uacuaggaaa uagacuaaug uauuuaugag 360
agaaaggaca cagcaggccc cuuugcuaau uagagauuug ggagcauggg aguaauaugg 420
gagccaugug gaggggugcg ggcagugauc acgacccccc acuccuggag gaaggugggu 480
agcugccaac ccugacuuuu gaccagggcu ucucaaaugc cagguuagcu ggcaauugcc 540
auucuuccgc aggcucuucc ugaagcuggg ugggccccug ccucacuccc cucugcaauc 600
caguccuacc uuuauugucc ucacccaggg gccugaauug ccaagcagca gcccuuccua 660
gcaagcuuuc cccaauagug uuuuguuucu uaacuuuucc uccucucagg cugagugugg 720
ucaccuguaa auagauucca aggacuuggu uuuauguuuu gauccacagg gaauugauuu 780
auuggaaaug aaucugccuu ucuacucaca ggacugugag aggugaauga gaucacaggu 840
gucaacacac gccugaugaa acaggauaca caagcaguuc uaguuauggg agacaguguc 900
aggaauuguu guccuuggca cccucagccc cugcagaccc uuucugcagc cuuggccaua 960
ccuuuuagag gcuuuugugu gggagagagc aggucaggag guugacuacc caaauugacu 1020
cauuagcuuc aaacucugau gucaacacau uugaaugagu ccugccugcu uuagggccua 1080
aagaggacca gagaaguaca ccauaguccc uggcuuccag aaggucaggg aggguuucaa 1140
agaagaggcu gugucuuuaa gaauggggaa gauuccauuu gguggggcag gaggaggaga 1200
acauugaggg acuggaaaca caugcggagg cugggagacg ggaaugacca auaggacugg 1260
gaaccagggg gagaugccaa uugcugacag aggaguuagu gcaagaggua agugagaagg 1320
guaggugggg cuggauugca gggcuguaac uacagcugca gagggagggc uucaaccuac 1380
agcugauggg gaacaacaga agguuuugag gcaugaggug gccugaugac aacucuguuu 1440
uggaaaggug gaguuggcag ggcagacugg aggaaguggg aggcucggag guuaguaacu 1500
accccuuacu gagugcuugc uguagaggaa gcauuuuagu ccugacggug aucccaggcc 1560
cugagucuuu acucugugcc aggcacugug cugaguucau cuucagcaca auccuaugag 1620
acagguauug uuacccuccu ccucaucaca ugguugaagu aggcaagguu cagagagguc 1680
caaugcccaa gaucacacau gaggaggcca ggacuggaac ccaaggcuga cucuggacau 1740
gagcaccuga ccucucuacc uaaugccuaa ugccucuccu gcugggagcc cuuuuuagaa 1800
uuuaagucuu aaaggaugga agcccagaag gaagcagaag caaggaagug gaagagaggu 1860
cccauggaaa ggacagugcc aaggacacug uacagccagc ccaauccuga ccccuuuucu 1920
ucaucuag 1928
<210> 47
<211> 453
<212> RNA
<213> 智人
<400> 47
guaagggaau ggguaugagu uuggaggugc ugguuagauc cacaguuggc augauguugc 60
cauuuuccuu cuauagaaca auugauaugc uuaugcaagc aauuugguuc ccaguuuuau 120
guagggucau caucccugug uuauaacucg ucuuccaaga gcaucuaauu ccaaugugug 180
uucccugcua uucaucucgg gcacugacac agggccucag ugagaaucac uccagcugag 240
caucauuccc uuuucugugu ucuguuucug cagagcaugg gucagccucg agaugucuca 300
guacucacca caccucugug ccugcccaug ucaauaugua accuccuagu gcugguaguu 360
uucuccuaaa ccauccuuug cucuuuguuc ccucuucccc uccuugcucu cacccugucu 420
caguucucag uccgguuucu ucguaucuug cag 453
<210> 48
<211> 494
<212> RNA
<213> 智人
<400> 48
guggguacuc ugcagaccac gugugaaagg cuuccgaaca ucagcucuug ugccugccuc 60
uccuccccau aaggcagagc uauucaauag gaacauaaug ccauaaugca agucacauau 120
guaauuuuaa aucuuccacu agccacauga gaaaaguaaa aagaaaauag guaaaauuaa 180
uuucauuagu auuuuuuauu uuacucaaua uaaccaaaau auuauuucaa aauguaauua 240
auagaaaacc uuauuaauga aauauuugac aauuucucgu uguuuuuaag ucuuugaauc 300
uuuacacuca gggcccgugu caacugggac uuagaugugu uucaagugcu uaguagccac 360
auauggcucg uggccucuga uggcagccca ggucuaaaau uccuccccca gcucacacac 420
acacuuaccc uggggccuga cauuuuagac cuucuugauc ucuagggcca ggcuagcucu 480
guguuuucuc cuag 494
<210> 49
<211> 2051
<212> RNA
<213> 智人
<400> 49
gugaguaucc ugcuccuccu gucucaggga gucucucaca gguccuguga gaagaauagg 60
aagggugauc aucagacccu auaguagggu ggcucugagg cccugaaaga ucuguacaga 120
gaaggaggcc ucccagagag cauggcccaa aaagcccaac acauagaccc aauggaaaag 180
ugaacugaau ugugauaguu aagagauucc ucuguuggga uggauucuug gaaagaccug 240
ggaagcacua aguguguggu ucuuaaucuc uuagagguca cggaaccuuu uaagcaucug 300
augaauauuu guagccuauu ccuauaaaaa ugcaccauug cuucccauua ccucccucca 360
cacauuuuua caaaacguuu cagggaguuu acugagcccc aggucacauu uaugauccug 420
caggagcucu ugaaucccag guuaagaacc ccugugauga augaagaauc cuuccucugg 480
guugaguuuc uagauagggg cucaugcaug ggccuuuggg guagccuaac cugcauuggc 540
uauuuguagg cugauauuug gcuuugccag accaaggagc auagagggaa aacuggcgug 600
ugcccuugga uucuggaggg ugacugcugc ucucuguaau aaaauguguu uaaacagacu 660
gguccccuau gggcaggaca gagaggauga gcucucacuc aucugccucu uuccuggcug 720
caggaaaagc uugaacagua aaacuucagc acacacaaua gaggugccca gaggaagccu 780
cugcccuggu uuauaagugg aguuaggugc ugcugacauc uguccagcau cugcuugacu 840
ggggccucuu ccucucuccu gaaagccauc cucagcaugg cccaaugccc agugggcagg 900
acgaguccug agcacgcuuc acuggcucag acaggaugaa uuugauucuu uggccuccau 960
agccagcccu acuggguuua cagaaaaggg acaggcaggg gugaagccag gucauggcug 1020
aguccaucuc aacagaucca gcuucaccug caagugacca cgcaggugac uuccucaugg 1080
ugacaaaagg agucauggca ggguagagau aucauaccau ggcaggggaa agauaucaua 1140
gaauuuucca ugagcacauu uaugagacau caaguuacaa cuguguccaa gugaggcaca 1200
gucugacauc cagaagguaa aacugagcug gacgcuagaa agaaacuaua ggcuuaagac 1260
acagaauugg gauuauaugg uaggguagcu cccacuaauu uggaaacgua cccuacuugc 1320
uucccugagu aguuuuaauu ggcccagcca ugccuuuggu ggcuuuuguc auugugggga 1380
acuguaaugg ucucucugua ccauccuaua ucauccaucc uuuauucaua gacccuaagc 1440
uauaagaaga aaaggaugag auuagacuaa augucuaugu auaguuuauu uuccaucuug 1500
gcaauauauu uuuuaguggg ggugaauaua uuagccaaag ggaguuggug gaacccaacu 1560
cacucuaccc cugcucccug caggccucuc gcugugggua guuaucugac uggcuccucu 1620
uucauugcua ucuuugccaa uaaauacaga uagagaaguu uacuuccauc gggacacaug 1680
caucuuuucu aguuacuucc caaaugucug aaaauuauug auaaaucaug aaucauuuuc 1740
uuaaaccuga ucuucccucu guuuuuaaac ucacauguga ggugaucuga uccaaaauga 1800
aagcugacuu uuggcguaac agggauucaa uuaauccuag acauggaaac auggaagaau 1860
cugacaggau ucaguuucua accgaagggc cccuguuuug auucccaaau aucccaugca 1920
uuucugaagc caaauaggag aagagaagaa gcagcuuccu uuucccguug gcagaagcuu 1980
cuccagcccu agcucuaugg ucaucccucc acuccuugaa ggauacucag uaauugcuuu 2040
uuuucuugca g 2051
<210> 50
<211> 3448
<212> RNA
<213> 智人
<400> 50
gugaaaaaug uuuuguugug gccacauagg agucugguua auuacaagcc uguuucauga 60
gagugcauuc ucuuggagau gagaaacuga agcgugcuau ucauucauuc auuccaacaa 120
auguuuacua ugugucuacu gugugccaag uacuguucua gaaaccagga guauagcagu 180
gaacaagaca gacaaaaaaa aauccccacu cucauaucua acaaaauguu guaugcauuu 240
auccucugac ucagcaauca cacgucuaag aguuuauccu gaagaugcau cucccacagu 300
gcaaaaugaa uauguauaag gugauccauu gcauuuguaa uugcaaaaug cuggaaguua 360
ccuaaauguu uagucauugu agauuggcug aauaauuuau gguacagaca cacaauaaag 420
ucuuacgcaa cuauaaaaaa gaagaagaaa agucucagua aacugauaug gagauauuuc 480
caguaaauac uguuaaauga uaaaaagcaa aguggaaaac agaacauaga gaacgcuacu 540
uuguauguaa gaaagaagga aaaacaagaa aguaaacgua ugucugcuua ccuuugcaaa 600
uagaacguag aaaggauaaa ccagaaaaca augaauuugg ugaucaacaa gaagaaaaug 660
ggaagaaaga aaaaugggag gaaacaguac uucuggggau auauuuuugu auaguuuuaa 720
uuuuuggaag cauguuaaug uuccacauau ucaaaaaaaa ucaguaagaa ugggaaguag 780
gcaaaaauga aaacaaaaag aaaaccuaac acugacagca aacuaaauaa aguaacccaa 840
uuuuauuuca aauaaauauc auaaucuugc aaaaggggga uagagcuaac acaaacaacu 900
gcugaacaca guguuugacu cuauauccuc auucuugggc aggguggagc gggggagaag 960
aacuacaaau aauuucugag uucuuuuuag uuuguuuuuu auagugguau aggcaaagug 1020
auucugaaaa uuuuagaugu guuacaggau uaaauaaauu aauaaauguu uugauguuau 1080
ugggacccag aauucucacc guggaagaag ggacuuacaa auauggaaaa gggaaaagca 1140
agaaagaacu gugaggucau ggauaggaac cggagguagc acugggaauu caggaauauu 1200
uauaugcuug uguuuguggg ugcaugcaga uguguucaug uuucaugcac auaggcaugu 1260
auauauagac auauauuugc auguguguau cugucuuccg aaaggcucaa gaagcaaaaa 1320
caccccagua gccaugagca cacuuagcac ucaggcuuuu gucuuaauaa cauuccccac 1380
uaaaaguaac ccugauuccu ccaauaaaug auaaguucca gggcuggaau ggcauaggua 1440
uaaaaugaac cuggaauauc uuaugccaga aaguaaggaa gugcuuuuaa aaaaaaaaua 1500
aggggcuggg caugguggcu cacaccugua aucgcagcac uuugggaggc caagguagga 1560
agaucgcuug agcccaggag uuccagauua gccugugcaa cauagggaga cccugucucu 1620
acaaaaaauu agcaaacaaa uuagcugggc cugguggugc acgccuauag ucccagcuac 1680
ucagguggcu gaggugggag gaaugcuuga gcccaggagg uugaggcugc agugagcugu 1740
gaucaagcca cugcucucca gccugggaaa cagagcaaga cucugucucu uaaaauaaua 1800
auaauauaau uuuaaagaaa uaaaaguaac ucuguacaga uugcuuauug guuacauggg 1860
agaaacauaa uaauuuuaca auggagaaau uagacagcac cuuaacuggg ugaucaaaau 1920
uaaccauaag gggcagaugg acaucucaug ccccgagaug ugauacccug ugaaggacac 1980
aauuucacuu auguagaauc cagauuggag auauguaacc ugaaucuuau caugaggaaa 2040
caucugacaa gcuccaaaga aggaauauuc cuuaaaaaaa aaaaaaggag acuguauucu 2100
ucaaaaacau aagagucaua aaagacaaag aaagagcuau ggaaauaucu cugaucgcag 2160
gaggcuaaac aggcauaaug acugaauagc agacaauaga cuacaucuug ugcagaagag 2220
aaaaaaaaug auagaaggau auuauuggac caacugacaa aacugaacua ugaacaguag 2280
auuagguaaa uguaucauaa cauuaaguuu acugacauug auaauguacu gugguuaugu 2340
aagagaagau cucuauucuu aggaaauaug cccugaagua uuuaggagug aagggcugug 2400
augaguaauu uacccucaaa ugggucacaa aaaauugugu gugagagaga gaaggguuuu 2460
auuaguuaau aauucuauga acuauuuuua uuccuauaug uuugugugag uuugaaacua 2520
uuuccaaaua aaaaguuaaa aauggagauu acauucuagu gggagggaua gacgaucugu 2580
agauaaauag guaaaauauc caguacauua gagagugaaa aguccucagg gaaaaguaac 2640
gcagggagga acugcugggg caggguuugc auuuugaggu aggguggccc agggagagcc 2700
ugcagaggag agaaccugaa ugaagaacua gaggugagag aaggagccac gugcacaccu 2760
agggaggaac auuccaggca cgggggacua guauagaagg cagaagcaug gugagcuugu 2820
cuccaguggc uucccuagau ccccuccugc gcaugugcac acacaccugg ugucucuguc 2880
aucguucccu cacagcacug ucacgaucug ccaguauucu guuuauuuug acugccaccu 2940
ccccgcaguc ugaggauagc agcaauggcu guguucacau uguucuccag ugccugguuc 3000
agugccuggc guauggucag ugcuccauag guaugugucg gaugcacaag gcuuugggug 3060
uaacccucuu gacggguggg aucaacaggu cugggacuca ccaucuucuc aaacagagcc 3120
uuccuccucc acugcuagcc augguccagg acgcugggcg agacccacug ucuugcucuu 3180
uguaaggcug aaguccauuu cccaggcggc uacacccaac agaugcugag caggcugggc 3240
cacccuggga uccaagacac agagagaaag agccccuguc uggcgccuga agcacaugcc 3300
agaggacagg agccagcagg agccuguuuc agccuagcug gggauuucau ucuggaggcg 3360
ugagaucugg gagcccaagg cuuugaacug ggggagguuu gggguguuug cuugucuucu 3420
ccaaauggca uuucuuucuc uucccuag 3448
<210> 51
<211> 752
<212> RNA
<213> 智人
<400> 51
guaacugcgg gcuugggccg caccaagggc uuaaaccaag ugcugggucu cuuggguugg 60
ggaaauaggu ucugggucgg cagauuuaga aacugcagca guuuggcuuu agucuggacu 120
guuuccugug uugcucauuu ugagcgauca gcccaguguu ugguucacac agcuccggag 180
aaaaacaagu cacggcacag ccuugacuug ggacugcgca cauccugcgu ucccaggaug 240
ucuccugugg ggccaucggc ucacagccgg gaaguucagc ccacucugcg gccugucggu 300
gucugguccc cauacaggag cacugagcug ggucaaaggc uccugagcug agccaggcca 360
ggccugaggc caugcccacg cagcccaagg aucaugaggg cacaggacau agcgggaacc 420
aaggaaguga ccugagugac cucccugccu ucugacaaau guauuugcag gauuuucuuu 480
uuuugaggag aauucuguca uugccuuaau ccacuuuaau ccccucgugg gcugaaaugg 540
gcccaggaug gacgccacgc uucuuuacuc uuggauccac cuccugccuu cccuacccua 600
caccagggua ccccugucuu gcucaaguga ggggagugac ugugugcgcc uucugucagc 660
ucauccucca caggggagcc agcccagggg gaagcaguaa ucagaagggc cagcucccag 720
ccugugcccc caaccuucuc uccacccccc ag 752
<210> 52
<211> 73
<212> RNA
<213> 智人
<400> 52
gcaagagauu cccagggcug gggaaggugg gugggaaucc ucuccugcuc accuccucuc 60
uccugcccca cag 73
<210> 53
<211> 2725
<212> RNA
<213> 智人
<400> 53
guaagcagau gguggggcgu gccccuuguu gccuucugug gauccaccug gauccugugu 60
ucuccauuga cacuuggaag aguccugcug cuccgucauc cccuggggca gaggcaggug 120
guggcugggc cucauucucc agcagcagau ggagaaggcc aucaugcuga uaagaaacuc 180
cucuauauug gccuaauuuc cuguggucga agacucgccc aagucucugg auggggcauc 240
ugaucaggau gcaugcagag ccuggcuggg augagggagg gcugcuacca cugccucaau 300
auuucaccac uuaucucaac agauccggga ccuguggccu auuuacuaag aguccacucc 360
aauguaggaa ugguuaggag accaacugac uugaggaccc aucuuuguuu uuagaauauu 420
guaugcuuuu gaguuugaaa aaagaccaua uguuauauga caaaccaaca auggcaguaa 480
ucuugaauag gauuauccuu auccuguacc cacacauugu aaacuauugu agauaauucc 540
uuauuauuaa gaguuugcau gccaaagcua acaguuuaag auuaucagca uauugccgug 600
cucauucacg uucugauaug cuuuauaacc uagaaaagag cagaguuaca auuacucauu 660
uauuuaacaa acacuuauua agagcucaga auauaaguca cuaagcuggu uggugggagg 720
aacagcacau aacccaccuu aucuaugcug aggugcauaa uccugaugca cccacaggag 780
gguguuacac agaagauguc auccuuucau augugucaga gcagauaaau aauugagaga 840
aaggucuaau agauuagcug cuuguggcaa guggacguuu gacccaugau uuauugagca 900
acuacaacuu ggacacugca uagauaucua uagaaauagc agcaugucag gucaccagac 960
cugugucagc aacuuccugu guccaacugc uggagaaagg gaagucuccu auuccuuucc 1020
cuccagcucc uuaauaucuc caugauagag ggggugagag gggaguguuc ccugugugga 1080
gggaugguga guuuucugga gcugaaaggu aaacagccuu ucuccucugc aucuuacugc 1140
agaggagaac agcccuagac uguggaggaa gcuuuggagu caguuaugac ugacacagga 1200
uaccagggca uaggguacug acacccgcua gccgugcaca cacucucugg uggaccauca 1260
cucauccaag agaggguaac cagccauccu gcugaaggag aaagaaagca ccaauggccc 1320
aagcccuagc agcuccauug uuucaggaag cuuccucagg gaagugcugc cuucccgagc 1380
cuuugcuccc accuggccca ucagcccuua ccaccacuca guaugcacug guccacgugu 1440
cuuuaugggc agucuuggga uccccacacu gggcuaaaac uaccuuugac ggccaggugc 1500
aguggcuuac accuguaauc cuaucacuuu gggaagcuga ggcaggugga ucacuugagg 1560
ucaggaguuc gagaccagcc uggccaacac ggugaaaccc ugucucuacu aaaaauacaa 1620
aaauuagaug ggcauggugg uaugcaccug uaaucccacc uacucgggaa acugaggcac 1680
aagaauugcu ugaacucaga aggcagaggu ugcagugaau cgagaucaca ccacugcacu 1740
ccagccuggg ugaaacagca agacucuguc ucaaaaaaua aaauaggcug ggcguggugg 1800
cucaugccug uaaucccagc acuuugggag gccaaggcgg gcggaucacu ugaggucagg 1860
aguuuaagac cagccuggcc aacauaguga aacccugucu cuacuaaaaa uacaaaaaaa 1920
aaaaaaaaaa uuagccgagu gugguggcag gugccuguag uuccagccuc ucaggagacu 1980
gaggcaggag aauugcuuga acccaggagg cggagguugc agugagccaa gaucaugcca 2040
cuguacucca gccugggcaa cggugagacu gucucaaaua aaauaaaaua aaauaaaaua 2100
aaauaaaaua aaauaaaaua aauaaaauaa aauaaauaaa acuaccuuug acuucagcaa 2160
guacgauuau cccacauuac caugcagaca uuugaucucu aaaaacuggu aucaaaugau 2220
uucuccaggg acuaccaugg uuuuucucuc cuaguuuuca guauguacac aggucuaugg 2280
uaugggccuu uaauccccag uauuucuuuu uuuguuguuc uuguuugggu uuguuucuug 2340
uuuuucgguu uuuuugagac agggucucac ucugucaccc aggcuggagu gcaguggcau 2400
gaucauggcu cacuguagcc uugaccuccu augcucaagu gauccucccg ccucagccuc 2460
ccaaguagcu gggaccacag gcaugugcca ccaugcccug cuaauuuucg uagagacagg 2520
gucuuucuug uugcccaggc uuaucuuaca uuccugagcu caagugaucc ucccaccucu 2580
accucccaaa uugcugggau uucaggugug agccaccaag cugagcuuaa uccccaaaau 2640
uucugaugag ucuacuccuu auuuugggau uaccuuaggc ccaaccacua acagaggccu 2700
guccugcacu gugugcaucc ccuag 2725
<210> 54
<211> 1665
<212> RNA
<213> 智人
<400> 54
gcaaguuggc ccuggggcac cgagagcuga gcaaagacug guccagaaca cccagugugg 60
guuggaauug ccauaagagg gaggcauaac auucccgauu uuuaacaaac ucuugcccuc 120
uguuuauugg gguaaaagcu gauauaucag aaauuguuuu cuaacaauau uuuuuaguca 180
ucaggaaacu ucauugauuc uuuuuuuuac auuuuccuuc ccugugaugc uauggugugu 240
uauuucauuc uugcucguuu gugguggugg uuuuuccuuc aaaucagcuu uauugaugug 300
uaauuaacau acgaugaaac acagguucuu ugggaggcca aggcaggagg aucacuugag 360
cccaggaguu uaagacaggc ccauguaaca aagugagacu uugucucuac agaaaaaaaa 420
aaaaaaaauc agaaaauuag ccaggcgugg uggugcaugc cugugguccc aucuacaugg 480
gagguugagg aaggaagauu gcuggagccc aggaggucaa ggcugcaaug agcuguguuc 540
auaccacugc acucuagucu gggugacaga gcaagccccu gucucaaaaa agcaaaacaa 600
aacaaaaaca ccuauuuuaa auguacaguu uagugaguuu ugauaaacgu gcauuccaug 660
ugugguuuuu aaaaauguaa ucacauuuuu uauugcggua aaauauaaua acauaaaauu 720
gaccaugcca accauguuua agugcacagu gcaguggcac uaaguacauu uacauuguug 780
ugcaaccguu accaccaucc ccgauagaac ucuuucaucu ugcuucagug aaaaucugug 840
cccauuaaac acuaacucac cacuuacugc cccccucgcc cuuggcaacu acuguucuac 900
uuucugucuc uaaggcucug acuacuauag auaccucaua uaaguggaau cauacagugu 960
uuguccuuuu gugucuggcu uauuaugcga ggacuuagca uaauguccuc aagguucauc 1020
cguguuguau caugugccag aauuuccuuc cuuuuucagg ccgaauaaua uuccuuugua 1080
cguauaugug cuacauuuug uucauccauc uauucauuca uugauagaca uuuggguugu 1140
uucuggguuu uguguuuuua uauauguuuu uuuaaaaaua aacaucuuua gagacaguuc 1200
aguaaagcag uggaaacagg gaagucucca uuuaaccccu gaggaucugg cucaccugca 1260
ccuucucauc agcauuaagc agagggaggc acgagcagga gccaccugca cacucaauga 1320
ggagcugaac agggaucaau uaccuuuuuu uuuaguuauu aggaugcugc uagcugagaa 1380
ucugccuugc cuugauuacc ccaaugucug gugcccaagu cccuugaguc cuccagcagg 1440
aacuccugug gcaucacuca ggagucuagu cuaagaagcu agcucugacc agggcagugg 1500
uggccaggcu ucugugagug ggccagccuc ccccggguag gacacaagcc auaccagcag 1560
ggcuguaugu gaacugugga aaauagagag caaagugggu aggugggugu agggugcugu 1620
uuuccuggaa auaucuaccu aaucucgcuc uucucuuacc ucuag 1665
<210> 55
<211> 2866
<212> RNA
<213> 智人
<400> 55
guaccccugc ugcuuaugca guccacagcu ugaggcaguu ccuuggcuca gagcccagcu 60
gguucacugg gcuugaguug cuccaaggcu cagauaugcc uccuacagag agccccaccc 120
acaccacggu cccuaccaag uccccaccac auccucauca cauccuugcu aagucccugc 180
cacugugugu ucugugcuga agaacuuuuc auucaguagu uguagggguu ccuauuguaa 240
ucaggaaacc aucuggauag caugggagag cauuuuugaa aagaacuuuc ccauguuuuu 300
gcuuacagca aaaaagcuug gauuugggga auaaggagca gagaagguaa uagagaauau 360
uagaauguuu ugggugcuug acaucuaugu cuggacaugu guuugaguuu caagggaagg 420
gacuuaacug gcacaucauu ucagugucag acacauuugg uuagaucaag gaauagcauc 480
uguuguagga agagggcucu uuguucuuua uaaaaauuac aagaagaugg agaaagaagc 540
aauaggaggu augucuccug gcuugugaua acucuuggaa uaggugcuug uagguuccug 600
cccuggcaca gugccccaug uaaggagcac accacccaag aaggagagag cuagagcaag 660
uacuggagga ggcaccagca ucccaaugcc uuggcuuaag ccugggauug uagagggaug 720
aauuagccac ucucuucuga cuuaccugga gaguaaauca aaucaaauca agaagcaagg 780
auaugcaaaa accuuauuuc cccauaaagu uuuuauucug cccaguuucu ggauugcaag 840
aaaaaccaaa uacagcuaau gauugaaaca cugcugucua aagcagugcu ugugaugaau 900
uuuuucccuu ccucuugacc agcagagacc uaauggcuac uuggcaaaac ugacuuuguc 960
uucccacccc uuaccugcca gagggcccag aaaugccuaa ggcuccuuua guuacagaaa 1020
guuugcuuuu acugagaucu uccagccacu gauucccauu uauagaucug gugauugcug 1080
uugacaucag uugaaaauua uuuuuaaaaa ccacuugcag uugcaaaucc uuuuuauaac 1140
ucuguaacuc agaauauaga auuggguagc aaaauuguuu cccagaauua ccaauggucu 1200
ccccaccccu gccuggcaug uucccucuua aaggacuaau cccaccacau caccucuggg 1260
ccaggcagaa caucaggggu gcugauguuc ugugaucuac agcaguuaau uccaaacuuu 1320
ucucccuuau uggaugagau cauuuuucua uuguguuuuu uacauuuuug uucacaaaga 1380
uuagaaaacc ugcaacacac uuauuggcau auuuuucuga uaauuuucau ccaaaaccua 1440
auucugacuu uacaacauac uaucuuuaca aagguuugca aaaauucuuu cauauagcau 1500
uguauauguc ugucaugaaa uaauaguaag uauauuauug uuuacauuau accacuucaa 1560
aauaauuucc uuuaaaguau ucuucaaaca agaaaaaggc aauuucucuc aagaaguuuu 1620
agagagaauu uacaacuugc uccuaagcaa augugagaac uucaggaggu ucaucuggcc 1680
auuggcuuua caacuccaaa uugugagcca ggaccacaca gauauuucuc uagaaaucag 1740
cguuugcuua ccaagaacau uuuuacucuc caaaggacuc cauccuggaa aacauguuuu 1800
gggauaaggu cuuaugcaau cuuauacucu guuauuaaaa ccagugaggg ucaagguguu 1860
aauagauuaa guagugacag augaucagac aacuuagaaa cauccuaaau agguuaauaa 1920
uuaugugacc aucgcaugug cauucccaaa uuaggaacaa cucagaucaa uuucuaaucc 1980
uuauucuuac acuguuccag uucccccaua uaacucguau cuuuguguua guuucagaag 2040
uuucugaagu acccucagcc uugaugggga uccucgcacc accucaaauc cuguucucag 2100
cccuaagaac uguguuaguc auccucuuaa gaggaugugu gauuuuaaau cagauaaugg 2160
gauaaaccac auuucgucua gacuggucag gccuuugucc aguccccucc ucgcccacac 2220
uaccccagcu ccacagcggg cauugguuca ggaauucaac ccacacuuua uaacuggaga 2280
caguaucucu ccaguuaaaa aggucaccuu gguguccgcu ucucaaggaa cauggacauc 2340
uuuauuaauc aaagcccaag cuuugaucug gagccuaaua uccugcacuc cagcucucau 2400
cucuccccuc ccccagucac acuuucaugc uucccagagc caccccuaca ggaagugguc 2460
aagggaauuc uauaccucag ggcugaccua aauuaggauu ucuuggcuuu uaagauaaug 2520
guaacuuucu uaagcuaaaa aagccccaaa agacccugua agagcccuug gaaacagcac 2580
caugggugua gcuucccccc aggauguaag cauguaugca cacaucucgu augugugucu 2640
uuguaacaaa ugccuggauc uuaguaccag ggagaccuga uucauagauu ucauagagaa 2700
ggagagaaag auggcccaua accuggguga ucugacagaa ucacagugcc cucagcugag 2760
ugcccuucag aaauugauug acaacuguuu agcuuuugaa aucuaaaagu aguacagcau 2820
cucagaaaac caagaugacg cgaguccaug ugaucuccuu ccacag 2866
<210> 56
<211> 738
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 56
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> 57
<211> 4393
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<400> 57
cagagaggga gtggccaact ccatcactag gggtagcgcg aagcgcctcc cacgctgccg 60
cgtcagcgct gacgtaaatt acgtcatagg ggagtggtcc tgtattagct gtcacgtgag 120
tgcttttgcg gcattttgcg acaccacgtg gccatttgag gtatatatgg ccgagtgagc 180
gagcaggatc tccattttga ccgcgaaatt tgaacgagca gcagccatgc cgggcttcta 240
cgagatcgtg atcaaggtgc cgagcgacct ggacgagcac ctgccgggca tttctgactc 300
gtttgtgaac tgggtggccg agaaggaatg ggagctgccc ccggattctg acatggatcg 360
gaatctgatc gagcaggcac ccctgaccgt ggccgagaag ctgcagcgcg acttcctggt 420
ccaatggcgc cgcgtgagta aggccccgga ggccctcttc tttgttcagt tcgagaaggg 480
cgagagctac tttcacctgc acgttctggt cgagaccacg ggggtcaagt ccatggtgct 540
aggccgcttc ctgagtcaga ttcgggaaaa gcttggtcca gaccatctac ccgcggggtc 600
gagccccacc ttgcccaact ggttcgcggt gaccaaagac gcggtaatgg cgccggcggg 660
ggggaacaag gtggtggacg agtgctacat ccccaactac ctcctgccca agactcagcc 720
cgagctgcag tgggcgtgga ctaacatgga ggagtatata agcgcgtgct tgaacctggc 780
cgagcgcaaa cggctcgtgg cgcagcacct gacccacgtc agccagacgc aggagcagaa 840
caaggagaat ctgaacccca attctgacgc gcccgtgatc aggtcaaaaa cctccgcgcg 900
ctatatggag ctggtcgggt ggctggtgga ccggggcatc acctccgaga agcagtggat 960
ccaggaggac caggcctcgt acatctcctt caacgccgcc tccaactcgc ggtcccagat 1020
caaggccgcg ctggacaatg ccggcaagat catggcgctg accaaatccg cgcccgacta 1080
cctggtgggg ccctcgctgc ccgcggacat tacccagaac cgcatctacc gcatcctcgc 1140
tctcaacggc tacgaccctg cctacgccgg ctccgtcttt ctcggctggg ctcagaaaaa 1200
gttcgggaaa cgcaacacca tctggctgtt tggacccgcc accaccggca agaccaacat 1260
tgcggaagcc atcgcccacg ccgtgccctt ctacggctgc gtcaactgga ccaatgagaa 1320
ctttcccttc aatgattgcg tcgacaagat ggtgatctgg tgggaggagg gcaagatgac 1380
ggccaaggtc gtggagtccg ccaaggccat tctcggcggc agcaaggtgc gcgtggacca 1440
aaagtgcaag tcgtccgccc agatcgaccc cacccccgtg atcgtcacct ccaacaccaa 1500
catgtgcgcc gtgattgacg ggaacagcac caccttcgag caccagcagc ctctccagga 1560
ccggatgttt aagttcgaac tcacccgccg tctggagcac gactttggca aggtgacaaa 1620
gcaggaagtc aaagagttct tccgctgggc cagtgatcac gtgaccgagg tggcgcatga 1680
gttttacgtc agaaagggcg gagccagcaa aagacccgcc cccgatgacg cggataaaag 1740
cgagcccaag cgggcctgcc cctcagtcgc ggatccatcg acgtcagacg cggaaggagc 1800
tccggtggac tttgccgaca ggtaccaaaa caaatgttct cgtcacgcgg gcatgcttca 1860
gatgctgttt ccctgcaaaa cgtgcgagag aatgaatcag aatttcaaca tttgcttcac 1920
acacggggtc agagactgct cagagtgttt ccccggcgtg tcagaatctc aaccggtcgt 1980
cagaaagagg acgtatcgga aactctgtgc gattcatcat ctgctggggc gggctcccga 2040
gattgcttgc tcggcctgcg atctggtcaa cgtggacctg gatgactgtg tttctgagca 2100
ataaatgact taaaccaggt atggctgccg atggttatct tccagattgg ctcgaggaca 2160
acctctctga gggcattcgc gagtggtggg cgctgaaacc tggagccccg aagcccaaag 2220
ccaaccagca aaagcaggac gacggccggg gtctggtgct tcctggctac aagtacctcg 2280
gacccttcaa cggactcgac aagggggagc ccgtcaacgc ggcggacgca gcggccctcg 2340
agcacgacaa ggcctacgac cagcagctgc aggcgggtga caatccgtac ctgcggtata 2400
accacgccga cgccgagttt caggagcgtc tgcaagaaga tacgtctttt gggggcaacc 2460
tcgggcgagc agtcttccag gccaagaagc gggttctcga acctctcggt ctggttgagg 2520
aaggcgctaa gacggctcct ggaaagaaga gaccggtaga gccatcaccc cagcgttctc 2580
cagactcctc tacgggcatc ggcaagaaag gccaacagcc cgccagaaaa agactcaatt 2640
ttggtcagac tggcgactca gagtcagttc cagaccctca acctctcgga gaacctccag 2700
cagcgccctc tggtgtggga cctaatacaa tggctgcagg cggtggcgca ccaatggcag 2760
acaataacga aggcgccgac ggagtgggta gttcctcggg aaattggcat tgcgattcca 2820
catggctggg cgacagagtc atcaccacca gcacccgaac ctgggccctg cccacctaca 2880
acaaccacct ctacaagcaa atctccaacg ggacatcggg aggagccacc aacgacaaca 2940
cctacttcgg ctacagcacc ccctgggggt attttgactt taacagattc cactgccact 3000
tttcaccacg tgactggcag cgactcatca acaacaactg gggattccgg cccaagagac 3060
tcagcttcaa gctcttcaac atccaggtca aggaggtcac gcagaatgaa ggcaccaaga 3120
ccatcgccaa taacctcacc agcaccatcc aggtgtttac ggactcggag taccagctgc 3180
cgtacgttct cggctctgcc caccagggct gcctgcctcc gttcccggcg gacgtgttca 3240
tgattcccca gtacggctac ctaacactca acaacggtag tcaggccgtg ggacgctcct 3300
ccttctactg cctggaatac tttccttcgc agatgctgag aaccggcaac aacttccagt 3360
ttacttacac cttcgaggac gtgcctttcc acagcagcta cgcccacagc cagagcttgg 3420
accggctgat gaatcctctg attgaccagt acctgtacta cttgtctcgg actcaaacaa 3480
caggaggcac ggcaaatacg cagactctgg gcttcagcca aggtgggcct aatacaatgg 3540
ccaatcaggc aaagaactgg ctgccaggac cctgttaccg ccaacaacgc gtctcaacga 3600
caaccgggca aaacaacaat agcaactttg cctggactgc tgggaccaaa taccatctga 3660
atggaagaaa ttcattggct aatcctggca tcgctatggc aacacacaaa gacgacgagg 3720
agcgtttttt tcccagtaac gggatcctga tttttggcaa acaaaatgct gccagagaca 3780
atgcggatta cagcgatgtc atgctcacca gcgaggaaga aatcaaaacc actaaccctg 3840
tggctacaga ggaatacggt atcgtggcag ataacttgca gcagcaaaac acggctcctc 3900
aaattggaac tgtcaacagc cagggggcct tacccggtat ggtctggcag aaccgggacg 3960
tgtacctgca gggtcccatc tgggccaaga ttcctcacac ggacggcaac ttccacccgt 4020
ctccgctgat gggcggcttt ggcctgaaac atcctccgcc tcagatcctg atcaagaaca 4080
cgcctgtacc tgcggatcct ccgaccacct tcaaccagtc aaagctgaac tctttcatca 4140
cgcaatacag caccggacag gtcagcgtgg aaattgaatg ggagctgcag aaggaaaaca 4200
gcaagcgctg gaaccccgag atccagtaca cctccaacta ctacaaatct acaagtgtgg 4260
actttgctgt taatacagaa ggcgtgtact ctgaaccccg ccccattggc acccgttacc 4320
tcacccgtaa tctgtaattg cctgttaatc aataaaccgg ttgattcgtt tcagttgaac 4380
tttggtctct gcg 4393
<210> 58
<211> 738
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 58
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 Pro Glu Arg Thr Ala Met
580 585 590
Ser Leu Pro 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> 59
<211> 2214
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<400> 59
atggctgccg atggttatct tccagattgg ctcgaggaca acctctctga gggcattcgc 60
gagtggtggg cgctgaaacc tggagccccg aagcccaaag ccaaccagca aaagcaggac 120
gacggccggg gtctggtgct tcctggctac aagtacctcg gacccttcaa cggactcgac 180
aagggggagc ccgtcaacgc ggcggacgca gcggccctcg agcacgacaa ggcctacgac 240
cagcagctgc aggcgggtga caatccgtac ctgcggtata accacgccga cgccgagttt 300
caggagcgtc tgcaagaaga tacgtctttt gggggcaacc tcgggcgagc agtcttccag 360
gccaagaagc gggttctcga acctctcggt ctggttgagg aaggcgctaa gacggctcct 420
ggaaagaaga gaccggtaga gccatcaccc cagcgttctc cagactcctc tacgggcatc 480
ggcaagaaag gccaacagcc cgccagaaaa agactcaatt ttggtcagac tggcgactca 540
gagtcagttc cagaccctca acctctcgga gaacctccag cagcgccctc tggtgtggga 600
cctaatacaa tggctgcagg cggtggcgca ccaatggcag acaataacga aggcgccgac 660
ggagtgggta gttcctcggg aaattggcat tgcgattcca catggctggg cgacagagtc 720
atcaccacca gcacccgaac ctgggccctg cccacctaca acaaccacct ctacaagcaa 780
atctccaacg ggacatcggg aggagccacc aacgacaaca cctacttcgg ctacagcacc 840
ccctgggggt attttgactt taacagattc cactgccact tttcaccacg tgactggcag 900
cgactcatca acaacaactg gggattccgg cccaagagac tcagcttcaa gctcttcaac 960
atccaggtca aggaggtcac gcagaatgaa ggcaccaaga ccatcgccaa taacctcacc 1020
agcaccatcc aggtgtttac ggactcggag taccagctgc cgtacgttct cggctctgcc 1080
caccagggct gcctgcctcc gttcccggcg gacgtgttca tgattcccca gtacggctac 1140
ctaacactca acaacggtag tcaggccgtg ggacgctcct ccttctactg cctggaatac 1200
tttccttcgc agatgctgag aaccggcaac aacttccagt ttacttacac cttcgaggac 1260
gtgcctttcc acagcagcta cgcccacagc cagagcttgg accggctgat gaatcctctg 1320
attgaccagt acctgtacta cttgtctcgg actcaaacaa caggaggcac ggcaaatacg 1380
cagactctgg gcttcagcca aggtgggcct aatacaatgg ccaatcaggc aaagaactgg 1440
ctgccaggac cctgttaccg ccaacaacgc gtctcaacga caaccgggca aaacaacaat 1500
agcaactttg cctggactgc tgggaccaaa taccatctga atggaagaaa ttcattggct 1560
aatcctggca tcgctatggc aacacacaaa gacgacgagg agcgtttttt tcccagtaac 1620
gggatcctga tttttggcaa acaaaatgct gccagagaca atgcggatta cagcgatgtc 1680
atgctcacca gcgaggaaga aatcaaaacc actaaccctg tggctacaga ggaatacggt 1740
atcgtggcag ataacttgcc tgagcggacg gcgatgagtc ttccgggaac tgtcaacagc 1800
cagggggcct tacccggtat ggtctggcag aaccgggacg tgtacctgca gggtcccatc 1860
tgggccaaga ttcctcacac ggacggcaac ttccacccgt ctccgctgat gggcggcttt 1920
ggcctgaaac atcctccgcc tcagatcctg atcaagaaca cgcctgtacc tgcggatcct 1980
ccgaccacct tcaaccagtc aaagctgaac tctttcatca cgcaatacag caccggacag 2040
gtcagcgtgg aaattgaatg ggagctgcag aaggaaaaca gcaagcgctg gaaccccgag 2100
atccagtaca cctccaacta ctacaaatct acaagtgtgg actttgctgt taatacagaa 2160
ggcgtgtact ctgaaccccg ccccattggc acccgttacc tcacccgtaa tctg 2214
<210> 60
<211> 565
<212> RNA
<213> 智人
<400> 60
guggguggau ccuuguaagc aggauuagcg agucacucca cgcucagguu cuuuagccug 60
agggcccgug ugccacagca uagcuacccc gcccuuccag ccucgggucc cuaauacugc 120
cuugcuucgg uuccaguuuc cgccgcacaa cuucacucau uccaaauguu aauuucugcg 180
uuuuuuuuca gccccaauuc uguuucucca aaucagggau gauugucggc cuuccacaga 240
cccucgcgcu ugccaggauu aggguguucg cgcgcauugu ggguaggggu guggaggaag 300
ggauccagaa aucuuaagua uuaacuuaga uuaguguuag caaggaagcc gucacauuuu 360
auuuagccgg gacacucuga caguuugugc cgacugcuau uuuugaucaa ggcuauuuug 420
cccacuuguc uauuuugugg cccaauuguc uguuuugcua acaucagaaa guuauaauga 480
aauaaucugc aaaaaaugua aggugcuaga aaaccaauaa uacuguguac cuugaaaaug 540
cuaauauaca ccuguuuugu uacag 565
<210> 61
<211> 172
<212> RNA
<213> 智人
<400> 61
gugcuuaauu ggucaauaau aauagauaua uacauuaacu uaugauuaau uuauuaauaa 60
aauaugaauu uauuuuuuuc agggacaacu auaauuguca caaucuggaa guguucuuau 120
auuuugcuug aagguuauaa aauauaaaac aguugcuuuu cuguuuacuu ag 172
<210> 62
<211> 1391
<212> RNA
<213> 智人
<400> 62
guuuguaugu aguagguuuu aacuauaggu uuggcuauua guggaacuau aaaaaucugu 60
ucuuauauaa gguaaucuuu gugaaaauac cugguaauau cuacaucacc acuaaaaaau 120
gcaauauauu uaaaugugaa uuaaguauuu uaguguauaa aacauugcua guuucuacuu 180
aaaguuucua aaagggugug uaggggaaau agaaugagua uguugaaaag uaacauaagg 240
aaauauaucu ugagguccaa augacaaaug cagacaauga cugcuauagg gauuuguuaa 300
gaggggaaau gauuuaagag augucagaag acuucacaaa ggaucaauac ugaggaguag 360
uguuagauaa guggaaggca augcaguggu aagauaguaa gggaauucua gagcuguugg 420
uuaccauaaa uaaauacuga gaacaggaaa uauguuuauu cuuuauauuu gaggaaacaa 480
ggugcagcaa guuuguagca gacuguagag aaaacaaauc uuggguaagu acuuugagau 540
agguuguuga gggccuuaaa gguguauuuu augcuaucag caauugagaa ggcaguaaag 600
guuuucgaaa cacaauugau agguacaaaa auacaccuua agaaggcaaa acugaguaua 660
uuauguagga caaacugaag gaaauuggag cuuuguagac aucacauuau agcggaguuu 720
aaaccugaaa uuauggauua gaauaauagc aauuggaaca gaaaaaaagu aguggaaaga 780
cauuacaaag ggagauguug cauuacugga uauaagacuu gaggacuuga gguaaaaagg 840
agaaucaaaa auguuucaug cuauuaaaaa ucuagaaauu guagucuuaa guaagaaaau 900
ugccuggcau gguggcucac gucuguaauc ccagcacuuu gggaggccaa ggcaggagga 960
uugcuugagc cugggaguuc aagacuagcc uggauaauau agugaguccu ugccuguacg 1020
aaaaaauuug ccgagcauga uggcacacca agcaugaugg cacgccaagc augauggcau 1080
gcaccuguag ucccagcuac ucaggagacu gagaugggaa gauugcuuga gcccaggagg 1140
caggagguug cagugagcug agauugugcc acugcacucc agccugggug acaaagugag 1200
gcccuaucuc aaaagcaaaa aaaacaaaaa caaaaaccaa aaacuauuua uucagcaaau 1260
auuuacugaa cgucuccaug ugccagccau ugcuggcacu aaggaucaua acaaauaaaa 1320
cagaauuuuu auuuucagug cuuacauucc aguauaaagg cauauugaaa uaaccuuuuu 1380
uuaauguuua g 1391
<210> 63
<211> 303
<212> RNA
<213> 智人
<400> 63
guaagcaccu uggaaaaagu uuauuauggu auuaaauaau gaauuccauu uguucauuaa 60
acuguagaaa auuaaauuau auucuauaaa auauauauau ucaguuuauu uuuaauauau 120
aacauuuaau aauaaauauu ucuagacucc uauuuuaugg aucugccaua uaauacuuuu 180
uguuaccuua uaaucaugau ggacucuuuu aaaagaauua auuuuguuau ugaaauuuau 240
uuaaaaguuu guuuuguggu aacuaaucaa uuaaaacguu uuucuuuuuu uuuaaaaaaa 300
uag 303
<210> 64
<211> 2358
<212> RNA
<213> 智人
<400> 64
guaugucuuu uuguauuccc uaggauguaa uugucauuaa uuuuauuuug aauuguuuuc 60
aaauuuuaaa auuauuguug gcuggaaaaa uuauaaggau gauuguaauc augguuauuu 120
guuuauucug uauauguucu acaugccuau uaugugccuu auauaguacu aaggacugag 180
cauaugguug ugaacaaaau aagaaguuaa cugcuggaug gagcuuauag ucuugggaaa 240
uauacagaaa gauuacuagu aacugaggug gagggugggu ggggauuuga ggaauaguga 300
cgaaagggug uuauagaagu aauuuuugac aaagcugaag gcuaaaauau gaauguauug 360
uugaagaaca aaauacauug agauuccuga gaagguagga augugauaca aauggaucag 420
ccuuugaaag gaggaauacc cuuuuccuuu guguuaggag aggaggauga guggaugagc 480
gugggaagag uggaugugua uagaggcuuu uauguuugua ggcauaaugc uuggaaguug 540
agggguuggu gaugacaucu ucuguuaaaa agagugggaa augguguggu cacauuuuaa 600
ggaaauuagg uaaaauuuga aauauauugg agacaggacu ggagaguugg ggaucuggag 660
ucagacagau uugaguucua guccugauuc uucuacucgu uaacucucug aacuuggaug 720
accuauuguu uuugauugua uauccagcuc cugggaaaau gccaagcacu uucaauaaau 780
acuaaaugaa uuauggaguu ggaucaguuc uguguuagug uuuagcuagg uagcugcugu 840
agaauagaag gguagcacag uugaagauau ugguaggaaa gugguugaag ugaugauuau 900
gaagucuuaa cugaauagau aaaaucaaga uugggguugg gugggcagaa ggguagggau 960
auggagggag aagaugaggg guuagagugu ccugugaggu cgaaggacag gcauaguggg 1020
aauaauugaa agaauguucu gguuggacaa ggaucugaug uggguguggg agugagagac 1080
uauagugaau ucaagaaaaa aauagacuag aacaaaaguu auguggagau ugcuuagugg 1140
gcauuugaua gacaucugug ggccacaugc uuaaauuccc agugcauuuu gcggaguuac 1200
uggaagguug guggcuuguu ucuaccauga guagguaaag auggagagca ggauauuuug 1260
ugagaaagca gcugaaguuu cuauaggaug auggaggaau gauaggaaug aucaccugaa 1320
guugcagggu gggguaaacc uagaagcacc aacaccuucu ucugacccuc auguauuugg 1380
aaucugaaag aaugagcacc uuccaauuga aagaguucca agggcauuag uauacuaaag 1440
gauccaaauu gcagcuaagc caaggagaug gaaaggagga uucaguaaag aaucugagga 1500
ugugaaauau uaauuuaucu uggaagagaa uuuuagagag cacaauggaa ugcuuuuugg 1560
aggagagaaa gaguaagaac aauuugguua agguagagga auaacagaac uauaagguga 1620
agaaaugaau gugagacaca uuagaugacc aaaugauuug auguucuugg ccaugaccug 1680
aauuaacaag acugugaggu aaaauggauu uaaucggcua caaaucuuaa gauaaccaaa 1740
accugagcug uuuaauaugg uagcacuagc acuaaccacu uguagcuauu uauauuuaca 1800
uugguuaaaa uuaaaaugaa aaauuuaguu cuucaguugc acuagccaca cuucaaaugc 1860
ccgaacauag cuacauguag cgaguggcua uugaacugga cagcacugac agcaugucca 1920
uuaugcuaga aaguccuaug ggacagcacu ggucuaaaca gugcauggua ugagagaaag 1980
ggcagguuaa ggcacucagc uucacugacu gggguggaga uucugauggu uuguacucag 2040
guuccagauc ccugaggcuc aggaaccuuu gcaguuuagu cugguuaccu guggcccagu 2100
gguuacaaca gaaugauuaa cagucaauuc uuugcaucuc uggguggcuc aggaaaaauu 2160
uaaggaguua uuagcuguga acuaaccuua aguaaguuaa auuaaaaaaa aaaaaguucu 2220
uaagcuaaua ugauuuuaaa uaucugcacu gaaguauaau gcaaauuuaa auucagcaua 2280
auuauuugcu uguuguugac ucauuugaac cucaaaauau aaugggauua auuuauacuu 2340
uggguuuauu acuuuaag 2358
<210> 65
<211> 5424
<212> RNA
<213> 智人
<400> 65
guaaagcacu uuuuuuuucc augaaucuuc acuguucaag uuaccuggcu uuuuauuauu 60
auugguaaca auaucaauuu uuauauugua uguuauauuu gaaaaaugau guacacuuau 120
cucuaagguu uuauaucacu guucauuuug ucaucaccaa uuuuaaaaua uaaugguacu 180
ucuagugaau augacuugaa gauuaauucu uuauauuugg aaguacauuu uucucaggac 240
aucaaacuug uuaccuaaaa uuaaugcuuu ugucuggaag auugguauca aguaacuaau 300
agauuuucau aaagaaguga ucuuucuagu gccauaguuu auuuugggua aaaguuauau 360
uuguucauuu caauguauuu auaugauuag uagauucgca aaugaaucuu ucgauauauu 420
caauaauggu uaauuaaaua ucuuguuuuu gguuguaccu uauuuuaugu gagauauaua 480
uauauaugua uaguuuuuga aaaguugugu ucaugucagc aguuuauaaa ucacauauuu 540
aaaauaacau uuuuaaugca uaguuuuuau uaccucguua uuccuuguua uaaacuaaua 600
auucuugcag uguucacuug aauuuaguuu uaggaaaaaa guuuuuugca gaucaacuug 660
uauuuccugg aagaaaauuu ccuauuuuac cucagcuucc uauuuaaugu auuauuuauu 720
uauuuacuua acauuuauuu guuuuuuauu ucaccugaac uguuaguaaa cuuaguaaaa 780
uuuggugccu acauguggua acuguccugu cccuuauacu cagaaacguu uuccaccuuu 840
guguccuuua ggucauuguu guguuauauu ccauuuauuu uauuuugucc auuguucucu 900
cagaaauuga gggucauaca uuuuaagaaa acaaugauau gcuauuuaag agaauguauc 960
auaaauugau uuguaaggaa aaguaucccc auucuucaug uauguauuuu acucuaaaau 1020
guugaagaau cauauagaag uuagcuauga aaacaaugug guagagaaag uauggaucga 1080
ugccacuuaa auguuaggaa gaagcucuua gagcauuauc uguuuagcua acugcaaaac 1140
auagcagaca uguggauuuu uuaauaguca ucaaggaucu aacuuauaau auacacuggu 1200
agaauugcuu agggggaugu cugugguuuu cuggacuuuu guucuucuau auagaccugu 1260
aucaguugac uuaucauuca uaccacacac ccuuagcuaa ucagaacuac cuuguccauu 1320
uauaucuuag acuauugucu uuuuucauag ucacacacag agaaaacuug aauauauggc 1380
cuguguuccu uuuuggcugc ucaauuccuu gagaugaaau auggguaugg guugcuuugg 1440
caauuacuuc uuugccguua accagucauu caguuuuauu gagucuuuac agcauaccag 1500
aggcugcuag uuacuaguga uauagugggc aacuauguuc ugguucucaa gaauauucau 1560
agucaauaau aagcauaaca uagugauaau augauacuua gggagauaca uaaggucaua 1620
uucuggcaua cucuggagag agauaccgua aucagccuug aggugcagga ugugaucugu 1680
aaacugagac cugaaguaua guuagacugg uaagaggaau gaggauauau auggugguua 1740
auaaaagaac auucugggua gaagauauag cauuugcuaa gaccuagagg uaagagaugu 1800
uauggaguau uuaggaaacu acaguuauuc auuuugacug aaauauaagu gaaaauagcu 1860
uucauagagu ccuuacuaug ugccaggcac uucauaugca uuaauucauu auugcuuauu 1920
ugauacuugu cauaugagau aguugucauu ucugccauga uacagaugaa gaaauggaga 1980
cacagaaaga guaauugccc augguugcac agcuuauaaa ugguaaaggu aggauuugaa 2040
aacagucuua cucaagaguc ugugcuaucu ugccuuccca guuuuauuuu uuaugauccu 2100
cuggagagau aagcaagggc caguuccuaa ugaauuuggu ucuuuuccug aaaggagcca 2160
gugaagaguu uugagcacag gauaucauga ucagaucuau acuuuaaaag uuuacuguac 2220
uuuguagaga guggauugaa aagggccaag acuaguaagg aaacauuugu guuaauucag 2280
ggaagugcua augauggcau uugccugaga aagacaagug ugagagaagu agauguaauu 2340
ggauguggug aauguaauug guuguuggag gagagggagg auggagaguc ugccuaauuu 2400
uguggguugg gccacuaaau agguagauag ugccauucau uaaggaggaa cacaagagga 2460
auuuggaaag cuugagauua uuucaguuuu guagauguug aguuugaggu ucuucugggc 2520
auauucaaaa aggguaucug uggauaugga auucacaaga gacccuguac agaugaugag 2580
gauuuaugaa ucaucaaugu agacauuauu gaagccagag aagugauugu aaggcacguc 2640
ucugagaaau gucuaauaaa gcaaugaaau aggaagagug cuucaaggaa aagcucaaga 2700
aaggagaaac agagugugau guuugagaag acaagggaaa aaaacauuaa uagcauuaaa 2760
ugcuuuagca uuaaguucuu ggcuucucuu cuuguaaaaa uuucccaauu cagaacacag 2820
ugggauuauu aacuuucaau ugauaauaau aaugauaggc aaacuucuaa aauuuguauu 2880
guaguuugca uuuuauuaua aacuuucuuu aaauuuuuau uuugaaaaau gucauaucuu 2940
cauaaagauu guaagaaaca cacuguuggu guuaauguaa auuaguucaa ccauuguggg 3000
agacagugug gcaauuccuc gaagaucuag aagcagaaau accacuugac ccagcaaucc 3060
cauuacuggg uauauaccca aaagaauaua aaucauuuuc uuauaaagau acuugcacac 3120
auauguucau ugcagcacua uucacaauag caaagacaug gaaucaaccc aaaugcucau 3180
caaugauaga cuggauaaug aaaaugugga acauauacau cauagaauac uaugcagcca 3240
ucaaaagaga augagagguc aagcguggug acucaugccu acagucccag cacuuuggga 3300
ggccgaggca ggcagaucac uugaggucag gaguucaaga ccagccuggc caguauggug 3360
aaaccccauc ucuacaaaaa caaaacaaaa caaacaaaaa uuaacugguc augguacugu 3420
augccugcag ucccagcuac uugggaggcu gaggcaggag aaugacuuga acccagaagg 3480
cagagguugc agugagcuga gaucgcacca cuggacucua gccuuagcaa caaaacuaga 3540
guuugucuca aaaaaaaaaa aaaaaaaaaa ccggaacaag aucauguccu uugcagggac 3600
augggaugga gguggaagcc auuauccuca gcaaacucac acaggaacag aaaaccaaac 3660
acugcauguu cucacuuaua agugggagcu gaacaaugag aacacaugga cacauggugg 3720
ggaacaacac acacugggac ccgucaaggg gucggggugg gagaacauca ggaagaauag 3780
cuaauggaug cugggcuuaa uaucuagguu auggguugau cugugcagca agccaccauu 3840
guacacauuu accuaaguaa caaaccugca caucuuacac auguacccca gaacuuaaaa 3900
guugauggga aaaagaaaaa caauaaccac ccacauaccc uucauauaga uucaccaguu 3960
cuuaauguug ugccaacuuu gcuuuaucuu uuugucagua uuuuuacaca cacauguauu 4020
ucucugucuc uuguuuguuc aaucacauuu uuugcugagu cauuuaagag cuaauugcag 4080
auaugauacu uugcacuuaa auauuucagc uugucuguuu gaaaaagaaa gauguucucc 4140
uacaaugaac acaauauaau ugucaugcuc aggaauuuua auauugauuc aacaccauua 4200
ucuaguccau aaugagauuu cuucuaaugg cccaauaaua uccuucaguc uccccaccuc 4260
caauauccaa aguucuguca aggaucacau acuacauuug guucuuuauu auagacuuuu 4320
uaaauaucgu uguauaccau ugugauucua ucgucuccuu uaauaaagag gagaaccaga 4380
aaaaugaaag gucauaagag gaaugagguu uggagaauag gugaaaaaag gcaucauaau 4440
guuuauaaua auguuugccu guucagagaa acaagaauca cagauaaagu cacuuauaug 4500
uagauaagag aaugcuguau uacuuuuugc uauucuauuc acugaucauu uuucuaagaa 4560
cucuguaugc uucuuguuua acucuuaugu cagcauguau gagaaaacug aguuaaagag 4620
auguuaagua acucauucau gcuuuacuag aaauugguug augagggaca uaaaccuagg 4680
ccggugugau uuuagauugc uucuuuuaac cauuguguug uauugccuua uauuucuaag 4740
uaauuuaugu ucacugagag caaauaauag ucuagcuaug acuuagaaaa guaaaauaaa 4800
gauguugggc agaaaaccau uuuauuaggg guuuuuuugg aggagcagau uaauuuguuu 4860
cuguauucuu ugguuaguuu gugugugugu ucuuuuuaau ucuuuaaaau gaaacuguuu 4920
aauccuuaaa uccuuaaguu uugaaaauuu uggccuauua uuuauguguu agguugauau 4980
uaaauccuua auagcuuuaa cauuuucuac uuuguuagag aggauuuaaa auuuaaguag 5040
auaagcugaa uaucuggcuu uauauuaaau uacugcugau ggccaggcac aguggcucau 5100
gucugaaauc cuagcacuuu gggagguuga ggcagaugga ucacuugagg ccaggaguuc 5160
aagaccagcc uggcuaacac agugaaaccc cgucucuacu aaaaauacaa aaauuagcca 5220
guuaugguaa ugcaugccag uaauuccagc uacucgguag gcugaggugg gagaauugcu 5280
ugaaccggga ggcagagguu gcagugagcc gagaucgcac cacuguacuc cagccuaggc 5340
gacaaagacu uugucucaaa aaaaaaaaaa auuacugcug aauuuuaucu ucuucuuauu 5400
uauuuuuuuu uuuuacuauu uuag 5424
<210> 66
<211> 599
<212> RNA
<213> 智人
<400> 66
guaaaaaauu uuaguaguug uggugguuca acaaagguac uuauuaaaau aaguaccuaa 60
guuuacauaa auuuauauuu uaaccaggac uggagucuuc uaaguaacug auguuuucag 120
acugauuuua ugguaugacu uugucucagg gaaauagaaa acaaagcaaa augugaggcc 180
auuaaguauu acauucaucu caggucuaug cggguaaauc uuuuuuuguu guuuuauaag 240
ccauucuuug cuaguuuucu aauugaauag augacuggau uucuauucuu auuucucuua 300
cccagaaucc uuuaaaauuu uuuguuacuu guggaaucuu auaaauucug auuaucauuu 360
gguucuacug agccaaauaa uguuuguaca uuguuuauuc ugauagaagu ucuuaaguuu 420
cuaacauaau ugaaauauua uuuguuuugg uagauaauua guauucuuuc uuugguuauu 480
caagauaaua ugcaucauuu ucccaaaauu uuuuuguuuu cuuuaguuuc ugauuauuau 540
uuuuaauuau guauuaccuu ucucauuucu aauuaccguu uuccuguccu uuucuguag 599
<210> 67
<211> 124
<212> RNA
<213> 智人
<400> 67
gugaggcuuu aaguguggug aaaucuuggg aauuuaaaau auguugugag agcacuauuu 60
agaggauaug auuuuguuau ucugaauagu uuuguaauug aauguugugu uugguuaccu 120
ucag 124
<210> 68
<211> 391
<212> RNA
<213> 智人
<400> 68
guaaaauggc uagaagucaa uucagagcaa ugguuccuaa aaacuuuaau uucauuacaa 60
uguaaauaua auauuuagcc cuacauguaa auucccuggu auaaaucugu cacuauguac 120
uuguaaaaug ugaaauaaau uacaucuuug aaguugcaac uuuuuagcca uuuuuauauu 180
ugccugucuu ggucauuaag aacaauugag guccuuaugu acuauuuucu ugauucaauu 240
ugauuuaauu ggucaaugcc aauuaguaaa ggucuauaaa gaauucucuu uuuuucuaga 300
ggacacuuau ggcugcguuu aauuuuaauu ugguuuaaau uucaguuuuu uuaaaauuac 360
uuuuuaauua uagugucuuu aacuuuuuua g 391
<210> 69
<211> 658
<212> RNA
<213> 智人
<400> 69
guaagaauua cuuuuagaau aacuuauuua uucagacuuc auauuaucuc auuacuauuu 60
auuugacacu agaaaguacu uuuucuagga ugugaauuuu ugucugucuu uuuaauagug 120
uaauaucuug ucauguuggu auauuugucc auauguguuu cuccaaucac cucacaaaca 180
cuaauuuuug caauuuagga uauauaaaug auacuugaau gaauguguag auagcaguca 240
uuaugggguu uucuauaaaa gacuacugaa aauccugugg aucauaacau uucauuuuau 300
cuuaaaauaa auacauuaua aauguauuag aaaccaauac auuguucagu auuuaugugg 360
auuaaauuug uuuaaaaggu agaauaaugu uuaaaaauaa aauuuucuag uaaugaaaga 420
uaauuaugca auuauaagau gcagaaacua uuaaauguca ccuauaauuc caggaugacu 480
ucaaugauaa auacacauau guaauguaau guauccguau guauguguau auaaguauga 540
auacguaugu guguguaugu agauauauuu auauauauaa uguauaugua aauaugcaca 600
gguguaaaua uauguuacau caguuugcaa caacucuuga aauaacuuug ucuuuuag 658
<210> 70
<211> 2507
<212> RNA
<213> 智人
<400> 70
guauuuuuuu ucaauugaca uaauaacuuu uucuuuuugu auuuuagauu uaaauuuuag 60
ucuuauuuuu cuuuaaaugu cuuauacugg uuuauaacac guuuauuagg guuuuuaaac 120
auaaguuuau uuuauuuauu gguuagaaaa gcucuagaac uguccuuuuu gaucucuagc 180
uaauuuguua uugaaugacc ucuuucacau caaugaguuu aacuuuaaac uuuuugauag 240
aagucuaacu ccaaaauaua uuuggcaucu aaaauauaua auucgaaaua uaauuuaaau 300
uuuuuuacuu aacucauagu uaccuuauau acauuaguua aauaguugca gguuuaauuu 360
uaguuuuucu aacuaaaugu cagguucauc agugggaaug ggaauaagca aagggaucag 420
aauaacuugg gaagccuuuu caaaauacac uuuucuuccu caccaccacu cuccaaccuu 480
aaccaaauug ucaggccuua ccauauuaga agcugggauu augaugguug uauacuugaa 540
aaacaucaga gauuauucug aaugaauaau ucuaauuuua aaaacuauca cuucuagagu 600
cauugcuuuc uaguaugguu cacauaaauc uugugggcag uuuggaacug guuagcaucu 660
agggagcuca gauaaccuau auuuuaaaca aaagcauuag caauggaaau aaggccuaua 720
gaaucaguca ugucuccaua aacuuuauau aaagggccag acagugaaua uuuuagacca 780
ccuggucucu gcuauaacua aacucugcuu auagcaugaa agcagccauu gacaauacgu 840
aaaugaguga gcaagguggu uuuccgguaa aauuuuauuu acaaaagcag augggaggcc 900
agauuugacc uuugggccau agucuaccaa ccccuggaaa aaacaguugu cuuuaccaga 960
uugaauguug gcaggguaaa uggugacaug uuauauguau ucuguacuuu guuuugacuu 1020
aauaccauuu cauaauuauu uuauaucagu acguauagua uugcuguucu uuuuaaaggc 1080
uauguaauuu uucuuuuuau acagguguua auuugauaau uugugaaguu uaugaaguuu 1140
ccaauuuugg gguuguaaac uguuuuaaug aauauccuua uauauguuau uuugcaaaug 1200
uacaaguaua ucuguggaau aaauugcugc aaguguugua auugucaugu auguugcaaa 1260
uacauucuaa caguuuguca cuuuuuuugc uuuauggcau uuuuugcugu gaaauauuuc 1320
uuuuuaugcu uaguuaaauu uauuauuuuu uaaugacuuu ugacauuugu uauaaugaga 1380
aaggcuucug aguauaaacu uguuuucuca ucuuuucucc uaauaucuug uuuuguuuuu 1440
guuuuuguuu uuguuuuuga gacagagucu cacucaguug cuuaggcugg agugcaaugg 1500
uacaaucuca gcucacugca aaugccaccu ccuggguuca ggugguucuu gugccucagc 1560
cuccugagua gcugggauua caggcaugug ccgccaugcg cagcuaauuu uuguaguuuu 1620
aguagacaug gggucacacu guguuggcca ggcuggucuu gaaccccugg ccucaaguga 1680
uccuccugcc ugggccuccc aaagugcugg aauuacaggu gugacucugc cuggccuuuu 1740
uuuacauuua aaucuucgaa acauauaauu cauuuugaug uaaggaguau cauguggauu 1800
caacagagcu acucuguugu ccaaacaucu uuuauugauu auuucaucuu uuauugaauu 1860
gauugaucua uuuucuagca guguauacuu guuuuaauuu guguauguuu uaauaucuaa 1920
aaacguuauu auuuuucugc uuuuagacuu cuuuaugaau auuuuuaaug ugaauuauag 1980
aacuggcuug uccaguucuu aaaaaauauc uuguggauuu uuauugggua uguguuaaag 2040
uuauaaauug uuuuauagau ugauuuagga uaaaccuuuu uauguuauuu gguccuucua 2100
gcuaaagaac acaagauacc uuuucuuuca uucauucaag auauuuuaug ccucuugguu 2160
gcauuuuaau gcauacuuca uaaagaucaa uuguauaaaa cuuuucacag uuguauggaa 2220
guacuucuug uuuauaaaug aguuuugaaa gguugaaaua uuuuuaaaga uugaauuaua 2280
aaaaaagaaa auucgguaua uauuuuaaaa ucauuuucua uuugaauuuc agguuguaua 2340
uacaaaagga acagagauua ugccaguagu ugcucauacu uucucauuuc aaauaauuuu 2400
uauuuucugu aucauaaauc uacuaacggu guuuauuauu uaugauaaug aagaauguuu 2460
uauuaacuuu ccuuuugcau aacagauucu auuguguuua uuucuag 2507
<210> 71
<211> 946
<212> RNA
<213> 智人
<400> 71
guaaaaucuu aacagaauuu uguuuaucaa ccaguuuuau uacaguugga acucugaacg 60
augucuuuua uuuauuauau caucagugcc uaguguagcg gcugguacua ccaaguguau 120
aauaaugucu uuugaaauuu cuucuaccac cuggucccaa uaaaaaauua gaauuaaguu 180
uagaucacgg auuagacuua gaacuagagu uacuguguuu auuuuucuau guuuaugugg 240
auaguacaca cauuguuuug guuagaaauu auuuaacaag aaaugauuaa aaacuuuuag 300
aaauuuaaaa uaauuuuaua cucuuuuaag guuuauuuua cuguaucuua guccuaacau 360
acccuauaca augugaaaua agcuaaaagc augguuauaa uuugacugug cuaccuauuu 420
uauuuuuagu gaaaauaacc caaauaaaag gaaguaauac uuuuauuauu ugugcuguag 480
uuauagucca caaguaagaa gaugauuuga aaaguguaug cugaauaaga acaauuacag 540
gggacaacau uuuuuaauaa aguacgaaag gggaaaaagc uaaguugaau aaaagagaaa 600
gcacagagca aaacagaaac auacaaaaug guaaaaaggu ggaauugaau ggaggaugag 660
gaaaguaaca uauaaggaag uauagaagcc auaaacauua gggaguucug gaaauccuau 720
uuuccagagu guuagccauu auauccaucu uucaguauug gaguaacagc aguguaccua 780
ucauugugua uuacaguuga aguguacaaa augguaaaag gcauacuugu acccacaaga 840
aaauauguuc uacagucuug uugaaaaaaa ucagacguac uuuuuuccuu accuuuuuag 900
guuaauauuc augaagggau auauauuguu uuaaaauauu uuauag 946
<210> 72
<211> 4079
<212> RNA
<213> 智人
<400> 72
guauuuuuau aaauauauag uuauuuuaua uacaauuaug uuuuuaacga cuuuauuuuu 60
auuaaaauaa aaugucaagu caauauugag uuuucuccau uugaauuuua uauuuucaaa 120
aaauuguaca agauauuuau uauuauacuu auauuacuag ugcuuacauu uguaaaugau 180
ggaugcauuu ucuauuauuu uucuccucug gugaaaauua cauuaacguu uauuaccagg 240
ucacugguau gaaagaaaug aaaaauugug auacaauuau uuuuauuuaa cuuuuuauaa 300
uuaacaaaga auggaagaua auaaaauuuu gaccagugua acagcauugc agauaguuuu 360
cagagguaau uucacauuaa ucuuacccaa auuaauguuu caucauauuc uccuuacccu 420
gagccauauu accuuuuuua acacaucaaa uucuaugaau auaaguucuu acaauaucug 480
uguuguuaua uuuccauagc acuacauacu auaguuaugc cagggcacac uagugcgaac 540
uguucauggg aaauucaugg acauguuuau uauaauuggu gacuauguau auauguauac 600
acuacauuua uacacacgcg cauggaauca cuauuucuuc uucaugucau auauauauac 660
auauauacac auauauauac augucauaug ugugugugua uauauauaua uuuguauaua 720
ugacaugaag aagaaauagu gauuccgugc acauaugugu guguaagugu agugaugugu 780
uugcagguac gguuguaauu ucaaaaauga agcaaaagcc uugcucagga gauaauugaa 840
ccaauacuua aaggaaguaa aggagugaaa caugcagaug gcucuaagca gugggaauaa 900
guucaaaggc aguaaagcag gaguguacca aucaugucug agaacaacaa agaagucuuu 960
uuggcuggag uagagucagc aagugaggca gugauaagac cagagaggua aacagaggcc 1020
auaucauaug gggccuuaua guucauugug cagacuuggc uuuuaaguga gaagggacac 1080
cggggaaagu uucugaagau agaaaugaua uaauuugacu uaggcugugu uugcaguaga 1140
cuguaggagu gguaaauaag aaucagggag accuguuaga agacuauugc aauaaucugg 1200
agaaaaguga uggugguuug gggcauggug guagcagugg aguuacugga ugcagcaguu 1260
cuggauguau uuugaaagug auaaaaaugg aauuugcuaa cagaucagau guaggaugug 1320
agagagagag aacucuuggu cugaaccaaa aguuuugguc augguggggu ugugggaaga 1380
gcagguugag agauaaucag guacuuaauu uuagacaugu uagguuugag augcuuauua 1440
gacauucaag ugaagguguu aaguaggcac uuguauauaa aaguuuaagg uuuaggacaa 1500
caaucuaggc uaaagauaug uuugguaacu gucucuguaa aaguaauuga aauaaugagg 1560
cuggcuaaga ucaccaaggg aguaaaugua gguuaagaag aaaaaucuaa agagcuucua 1620
cuuuagcagc uggggagaua aaaaggagcu accaaaggag acugaaaagg aaagcccaga 1680
gagcuaggag gaaaagcagg aguauggaga gcccugaaaa ccacaugagg aauguaacca 1740
aggaagaaga aacaacugcu uucagagcug uguucauugc ugcugauagg ucaagaugau 1800
cacuaaaagu ugacuauugg acuuagcaau ggucauuuuu gguucaagag aaaaugggua 1860
gagaggaaau guaauaaaga aauauaggaa cccuuuucca ggacuguuuc uauaaagaga 1920
aggagaaaac aaggugguag cuugagggga aagagggauu aagaaaacau uuuucucuuu 1980
aagauggaag aaauaacuca ugauuuuagg uuaauaggag agcuccauua aagaagaaac 2040
auuaaugaau caaugaagug gagagagaga acuucuggaa caauaauauu uuuaagaaug 2100
caaugggaug ggauccuagu gugccaguga agagguuggc cuuaacuagg aacacagagu 2160
ucauccauaa uuguagaaaa gaagguagag uguauagaua ucgauguagg uggcuuggua 2220
gacauccugg uaaugggaau uuguggaagu ucuaaacugg uugcugcuuu uuucucagug 2280
aacaagggag caagguucuu agcugaaggu gaggauagga gaagauguuu cauaaguuug 2340
aggagaaaga agagaaguga aaguauaaaa uggucaucug aaagauugaa gacguggaga 2400
augugguaug acuguugagu aacuucaaga gcccacgaua uauauaugua uuucuauuua 2460
uguguuuauu auauuuguau cagaacacuu ugaaaguagu uuaaacugcu uuaaaaggau 2520
gacuaauagu auggauugug cguauucuaa uuacuaggag aaaaaguggc aauugaucuc 2580
ugcugucaaa uaaggaaaag gacuuaucug auaacacuuu agucaguccg uaguuauaua 2640
aucccuaaag cucacagaag guguguguac uagacuguac ucuacaucuu gaacuuaacu 2700
uguaaaacgu aauggcuaau gguauucuuc cuucauaaga uuaggauuag guuuaguuau 2760
caggaacaga gagcugaaga auaauggcaa aaucaagaua gacauuuauu ucucaucuau 2820
guaauggccu agaauuaagc auuccagggu guugccuuca ucugccccau ccaaaaugga 2880
uggaaugcag cuuuaucuca ugucuguguc ccaaacagca agacagagga agaggggcaa 2940
gaguuaaaag caugugcuga aggauaggca gguaaauaua guguuuauug uguagggcca 3000
uguggaagaa ugauaggaga auagauaugu ggauggaagg gagaauagau acugggggac 3060
aacucagccu gugucauguu ccacagcuua gauguuagcu ccagacagcu gugcucauuu 3120
cuuaaaaacu uuugugaucu caaacguacu aguuuuaugc cuaaguccaa uauuaaauau 3180
auaaccuaua uauuaguaaa ugcuuauaau gaaugagugu gagaaugauc ugucaaucaa 3240
uuuuggaaug auagcaauau uauguuuugg ucuuuuaaca auuuaguaag auauuacaag 3300
uaggcauuua ggaaguuuuu agcuuaguuu ggauuaaauu uagcugcaag ugacagaaaa 3360
aucaagcaua auacaauaau uuaaacaaga uagaaauuua uuucucuaua auauagacaa 3420
aguugaagca acuagggcag gauuugugug acagaugcuc aaauaucccc uaucaggaac 3480
ccugucucuu guugcugugc cuaucucaac augugguuuc uaacucaugu gaaguugcca 3540
cccucauauc cauguggauu ucagcuagca ggaaggagga aagagaagag agauuacucc 3600
uuuauuuuaa aaacauuuuu uuuuuuuuuu uugaaauuca cauaugaacu uugcguuuau 3660
auuccauuac ugacaugacc acacauagcu gcuugugugu aaguggaaau uuaguucuuu 3720
auuucaaaug gccacguguc aagcuaaaaa uccauaguuu uaguacagug gacaaaaggg 3780
agguuaaaua uuaggaacag cuagcagucu guaucacaau gaucauuuuu uguaaagcag 3840
uauuuugcaa ccuuuuaaaa uccauacccc uucagcuaag aagguuuuac ugaacuucag 3900
uuuuuuagua aauuguauua guaaaaccaa aacaaaacuu ucaucuuaca aauauaaaau 3960
gacaacuuua aaggauuuuu uuuuaauggc auaccacuuu ucuugccacc auguugggau 4020
cacugauuug aaggaauaag uagucaauuc aauucaugau uuuuguuuuu acucuguag 4079
<210> 73
<211> 720
<212> RNA
<213> 智人
<400> 73
guauguauuu uuaucuuguc auucaaggag cuuagaauua uucuugccau ucacagacua 60
uucugugcua uuuacugcau accauuuaaa aaacauucca uaaguaucuu uugauaaaga 120
uuauccucau uaauuuauac uaaacuauug aaaccuuuga gcauuuacuu uuugccagaa 180
uuguuuucaa acuuuugauc acagugauuu guccaaauaa ucaguuuugg ugaagcagca 240
ggauuacuuu uuuuuauuau cuguguucau ugggccacca uguagaugug acaccacugg 300
ccaauuugac agaauuuaug acaggaacau acugugucaa uacaaccugc ucuccacuuu 360
uuauacuuuu ucauugguua caacuaauuc aagcaacuaa ugacuuacuu auucuacugg 420
uauugcugau uugcuuuuac uaauucuuuu aguauuuugg uaaguguuuu uuauauguaa 480
ugcauauuca gagucacuuu gccuuuagga uauuauacug gaaaguuuua acuguugcau 540
auuacaucau uauuauuacu ggauuugguu uauaaaagca caauaaaaaa ccaguguaau 600
gauauaaauu auaggcauau guacauuuuc cuuuagacuu aguaaaaaaa aaaucaugaa 660
cuugauaaau uuauucaagu aaaccauguu auauuuuaaa uuaaauugga uauuuuucag 720
<210> 74
<211> 1370
<212> RNA
<213> 智人
<400> 74
guaagccaug uuuuaaguua cauaguuugc gcaaccugau uuacaagucu uuuuuuuuaa 60
uuuaaauuuu guuuauuauu auuuauuaag uaguuuaaug cuuuuuucaa augcuuuuau 120
aaaacauuua auacaaauaa aaguggagcu aaccugauug aaguggaauc agauuuuaug 180
ggguuggagu gguggguggg cagggcugga acauugcuuu auuuggucua gcaucuccuc 240
aguaauagcu gcuuguuuaa aaagaugaaa guuuauuaau accacauauc agagauuaac 300
cuuuuuuuuu cccaacaaaa guagggucug uauuacccau guuuguuugc aaaaugcucu 360
uguaacagau gagauauuua aacuucuugc ucuguguugu gauucuccug ccucugccuc 420
cugaguagcu gggauuacag gugugcacca cuaugcccgg cuaauuuuug uauuuuuggu 480
agagauggga uuucaccaug uuggcuaggc uggucuccaa cuccugaccu uaagugaucc 540
acccgccuug gccucccaaa gugcugggau aauaggcaug agccaccgcg ccuggccugu 600
uaaaaucuuu uaaagauuuu uaaguacuug auuuuuauaa uuuagacuac uuacguuuua 660
cuuuguucga guauuuuaag gaguaauuag uaauauagcu ugagaguuua uauauuuauu 720
uuaauaaaua gccuauuagu uaauauuacu aauuugagug uuaugauagu gcagacuaag 780
uugcugcuuu aaaaugaaaa uaaauaucua aauaucaauu ucauuauugc uaaauuucau 840
uuaaugcuuu cuuaguuaaa aaugaucauu uguaaaaacu auuaucuaaa gaaaagacaa 900
auagacaaau aaguauuuua uacagauaua uaugugugaa aaguaucuaa cuuggauccg 960
uaguugugcu aggaccccaa auuagacuuc ugaucaacuu ggacuaucag aucacagccu 1020
ucugaucaac uuggacuauc agaucacagc caagaaucug gaaguuccua aagaugacuu 1080
cuggcccguc uagguagcug ucauagacau cauauuuucu gugcuuaaaa agcuccaaau 1140
cuugguuuau aauuucauuu agguuuuugu uaggauuucc auuaauaauu gugauaaaau 1200
uuuaacuugg guuacaguuu aaauaucugg aaaauucuuu cacagaaagu uaccucauuc 1260
uucagugaua cuggcuaagu gaauuauaac caguugcuug augguauaug acauuuuugc 1320
agcuuauuug aauguuuuua aguuuuuaau uauauugcuu ucuauuguag 1370
<210> 75
<211> 72
<212> RNA
<213> 智人
<400> 75
gcaagugugg uagucaguug auuauuuucu uggcugaacu auagagaaau acuaauaauu 60
uauacuuugc ag 72
<210> 76
<211> 1337
<212> RNA
<213> 智人
<400> 76
guauacucag uuauucuaaa ccuuuaaaaa gaauuauuga uaagugaguu gucuggauau 60
gaaauuauuu gugucuuagc uguuuuugcu guucuauugu ggaucugcua caaauuuaau 120
aaaugacaau aauaaccuga aggagauaag ugagugucag uggguucagu ccugaaucug 180
aaauagacaa aaacaaaaca aaacaaaaua acaaaaacca agcaaacaaa aaagaaaaaa 240
accuuagaau uauggaauuu uugaaaaguu uuauaguaua guauuuuaau uucuagacag 300
caccaauaug uuguuauuaa uaauaauaaa acuuaguagu uuuuauguua auauauguua 360
cucaacauuu ucccuuuccu uaaggacuau gcauugaaaa gcuuuucuug uaaguuauua 420
uuauuauuau uauuauuaau auuugagaug gagucugucu uguucuauug cccaggcugg 480
agugcacugg ugcgaucuug cucauugcaa ccuccgccuc ccggguucua gugauucuug 540
ugcuucagcc uccugaguag uugagacuac aggcgugagc caccacgccu gacuuauuuu 600
uguauuuuua guagaaacag gguuucacca uguuggccca ggcuggucuu gaacuccuga 660
ccucaaguga uccauccacu uuggcucccc aaagugcugg aauuauaggc gugagccacc 720
augccuggcc uuaaauuauu cuuuucuaag ugaaaguaau guuuuauuga auauaaauua 780
acaucuuucu uggguuuauu uuacuugagc uaaagagaac aguugguuaa guuuuauaau 840
agccauugca gugcuuuuuu guaagaagac cacacagaag gacugucuuu uucacuugcc 900
ccaaaucccc aagcacguau augaguaaua gcagaguggu ucuuuuuagc auuaugauuu 960
cuauaauaca uccaaaacuu ucucaagaaa aaacuucaug auuuauuagu acaauaauca 1020
guuuacucau uacucaucau uuauauuuac uuuauauguc uuuuaacugg ugcuuauuaa 1080
guagcacuuu aauauagaau aggcaaagaa ugguagagaa gaugaaauuc aaaaauuagg 1140
uucucacauu auuaauaguu cauuaaaagu gagcuaaaug agaagcuugu auuggcuaug 1200
uagaauuuug gagggauuuu ggaaacaauu auucuaccuu ugcauuaaaa cuugauugua 1260
gguuuuaaga auuaaagugu uggaauagua ggaggguuau uuuaauguuu uuaguuuguu 1320
aauucucuua uauauag 1337
<210> 77
<211> 1850
<212> RNA
<213> 智人
<400> 77
guaauaguaa aguauugcaa agagaguaaa ggaaaauauu uuuuuuuuuu uuuuuuuuug 60
agacggaguc ucgcucuguc ucccaggcug gagugcagug gcgcgaucuc ggcucacugc 120
aagcuccgcc ucccggguuc augccauucu ccugccucag ccucccaagu agcugggacu 180
acaggcgccc gccaccacgc ccggcuaauu uuuuguauuu uuaguagaga cgggguuuca 240
ccguuuuagc cgggaugguc ucgaucuucu gaccucguga uccgcccgcc ucggccuccc 300
aaagugcugg gauuacaggc gugagccacc gcgcccggcc aggaaaauau uuuuauugug 360
uuuucauuuc uucccccuuu aucucauucu ugaacaucua aucuuauuau uguuguuaaa 420
uaaguagagg gaaauauuug cuuauuuaac cuguugauuc aaagauugau uaaugagaca 480
uuauuuacuc ugaauacaga uuaggaguuc agauaaagca gagcugcugc auaggagauc 540
aucauucaau accccacagu cagaucagaa ugagacagaa gagaauauga ccauaggauc 600
auuaucaaga auguuaucug aaauucacca uaguguagaa aguggaaugc auccuuuugu 660
cccuuuaacu agacuuucuu cauccaugca aguuaaagag aauucaacuc cagaaacuau 720
uacaauaaga gagauuuuua aagcaccaug ucugcagucu ucaagaaauc uagaaucguu 780
agucagcacc uuuaguaggg aaagccauga agaaauaaau gacauaugcc uuuuuucuga 840
ugacuguaug aagaaggugu caagaagcca ucaagcacua gagaagacua guuuuguaca 900
aaaaagcaau ucaucuuuuc auggcuuauc aacagcuuca gacauaaugc agaaguuauc 960
acuuaggcaa aaaucugcaa uauuuuguca acaaauucau gaaaauagag cugacaugga 1020
uaaaucacaa guagcaacau uagaagaaga acagguucau ucccaaguaa aguaugcuga 1080
uaucaauuug aaagaagaua uaauaaaaag ugaaguaccc uuacagacag agauauugaa 1140
aaauaagcuu aagguuaauc uuccagaccc ugugucuauu acugcacaau caaaauuauc 1200
ucagauaaau ucucuugaaa aucuuauaga acaguuacgg agagagcuag uauuucuuag 1260
aucucaggug aguuuuucuc caaauuauau uucugugguu guucuuuuau gacgucucua 1320
acaaaguucu guaacaauua uaguuagaau auuuuuguuu gcacuuuaac aucaguuaua 1380
cacauuguac uuuuuaaaau cuaaaaugca guacauugau augaacucau ugacuugucu 1440
aauuuauuaa auuuuucuuu agaaugaaau cauagcacag gaauucuuga ucaaagaagc 1500
agaguguaga aaugcagaua uagagcuuga acaucacaga agccaggcag aacagguagu 1560
guaaaggcag aacauuaaaa gagaugauug ugguacuaaa gacaaaaacc guuauaucuu 1620
uuugccucuu accauggaug uugggagagg gagaaagugg gauuaagauc accaucugcu 1680
uuacuguuua gauuuuaguu uauuuuuaug auugcugcua ugucuucaua gcucguuuuu 1740
uuuguuuugu uuuguuauac uuaauugauc aaacuuuucu uaacuugaaa auuauagacu 1800
ugugauauuu uguugaaaaa aaucaauuuu auucucucug cuuuuuucag 1850
<210> 78
<211> 535
<212> RNA
<213> 智人
<400> 78
guaaguuaca auuaucuuuu acuuuucugu ucuuauuuuu ccuauacuua aaaucauggg 60
ccuaaaaggg cguuaacaca uucucuguuu ucuaaucugc uuuacuccua auuaccucug 120
uacuguauau acuucagucu gucacuaucc aguugauuug ccuugcuguu uucauuguga 180
gagaauguua cuaauaugaa uuuuuuguga gaauauauaa cuccuuuuuc uuguguguuc 240
uucaaucaaa augaaguuag aacaccaaau uuaaaauacu uuaauauaaa gcauaguuua 300
aguuaaggca gaaguaugcc uuauauacgu guguauaugc acgugauaua aauaggucug 360
ucauuuaacu caacuauuca cguuggauuu auaguugaau uuuuuuguau guuuauuuac 420
auuuggauuu uuccaaugau gucuuuggua uaugugaaau auuugucauc uguauagcau 480
aguguaaauu gugaaaaaga ucugaucauc caaugagaaa acuguguaau uacag 535
<210> 79
<211> 2561
<212> RNA
<213> 智人
<400> 79
guaaguuauu uuuuucaugu uaauguuuuu ccccuaucac uuuagagaga uuuucugcug 60
uguacagauc uccauaguuu cugaugagau auuuuuaguc auuugaauca uuguuucccu 120
guauguaaag uguaguuuuu cuugagcugc uuucaauacu uuucuucuac caauuggaua 180
auuguuauua aucugucuuc aaguucacug acauuuuccu cuuuaucugu guucuuuugg 240
uucaaggguc agcuugagac cuugaggagu uuuuuacacc gacuuuggag cucguuuuug 300
cugacucuuu ucuuauuggg auuuuccuuu cacuuauccc auggcuuugg gcuguauccu 360
gugguuuucu agaugagaaa gaugauagau cucugcaauu gcacccugcc cuaugacuaa 420
aucuuuaaaa auggcaaagu caaucuuugc ugguccuguc uuccguauuu gagggguuuu 480
uucccaaaau cugcuugcuu uuguucauuu ucuagaacau cuagguaguu uuuuuucauu 540
cauuuuuuau uuaugggagu guagaucucu uaggaacuua ugccaucaga aguauuauga 600
aauggcuuua uucuaaaugu uuaaagauuu acucauugcu acaagaaaga uuuagccauc 660
acuaauauuc uauauauauu uaccauauag ggacuugaga auuucacagg auucaguauc 720
uguauauaaa cuugaauaau auacacauuu uagauuguua auauuuaagu auaugucauu 780
uauguuaucu gaacauauuu agcguacauu gucauauuau uucccaaauu ugugcuugau 840
uucaaauggg aaaaaaauuc uuauuauuua uugaauuguu uuuuuaaaaa aaucaugauu 900
aaucaguaau uggauacuuu uuaaaauaac acuauaauug uuaacagaga augagaguga 960
uacugguaug uuaaaaacuu ccugaggcaa gaaaauaauu ugauucccau uauaucuuuc 1020
ucauacugac uuuccuucuc ugauugguga uuuuguuuug ccucugccac uuugaauguc 1080
uaaaaugauu cuuuaugcuu uuuuuaugug aacaucuuuu guccgugaug augcccacua 1140
cugauacugu gucccagauc aaacuuaauu uuccaagggc agcucuacuu agugaccaaa 1200
ugaaaacaca gugaauagcc caagaaaucc uaacuucuau uuauguugac aaucucugga 1260
ccuuccugaa gccacuguuu gcauagacuu cauuuacuuu uauccgggau ugucauuguu 1320
uuuucagauu cauaggcccu aucugaaauu cacaaaucac cuagcaauac uucucuaaga 1380
aaucuucaga auccaugaca auuuagacca gacaaugcug gauuaugcac uucaguucac 1440
uuuuuguuac uacaagguau uuuucagugc ccccaacagc uaucuuaacu cauucucauu 1500
uuaccaaagu ccauguagac acggcacuau uccucaauga gacaacuaac uagaccaccu 1560
uguugucagu cagaguaccu uccucuaccu acuuuuaucu uccuuauauc cucuuugagu 1620
uaguauaagu uauuacucug caugaccugc ucuaaucucc uucaggggaa ggcuuuuaca 1680
aaucuacuac cuagaguuaa accccagauc accuuccuga guaggagauu gcauuugguu 1740
cuauucauuu uaccuuauuu ggcuucuacc uucacuuuuu aagacuuacu uugccuuuaa 1800
caguuuuuuc cauacaguuc aucuaaaguc caaauauauu uauuagaugu gugcauugug 1860
uguauauacu uagauaugcc acuguuggag auuucgggcc agugaugcca cucugauaau 1920
auuuuaauau uugacauauu auuuuugcuu acucauuauu cuuagauaau aucauguuau 1980
gauaccuugc cuuuauuuuu auuuaugcuu caacuaugug gagaggaagc acugaaaaau 2040
ucacuuaauu gaauguugua uugaucaauu guucaauauu guauuccauu ccuuugcgca 2100
ugcuuugaau gcaggugcua uauaauuuca gagaaaaaua ccucauuuug acuguacaaa 2160
aaccccaugu agggagcaga gcucacauug uuuuccccuu uuagagacaa gaaaacuaag 2220
auacagagaa uuuaagucac uugcccagcu guuaagugac ugauuaaaau uugaacccug 2280
gucaucuuau ucccgucugg uuguuuuucu agucuaccag ucuauuaaga uuagcuaggu 2340
guuuuuuaau uguuuuaaug aaguaauuac uaugcuuggu aauguaaaug aaaguuuuau 2400
agauucauaa auaagaauuu gaauuggcau acuuuauuau caugcuuggc aaugaaaaua 2460
ggaaaaugcu uaaaugucca uuuuauuuaa agacagacug uuuuuuacua ugauuuuacu 2520
guuuuucucc acauuucuaa uauauaauau aaauuugcua g 2561
<210> 80
<211> 342
<212> RNA
<213> 智人
<400> 80
gugagaauuu uauuaaauaa aagaaaaugc uaaacauaag aauguagauu uaauaggaaa 60
uuuuuaauuu uuuaaaaaga augcuuuaug agaaaaugcc ccuugaauua auucuuucaa 120
uauuaagaaa cuggauuucu cuuauaaaau uauaagugga aaauaagugc cuuauaagau 180
ugaaaagaau acaaaaauuc uaaaucucau accuaggcau uucuaagcag aaacugaagu 240
augguugagg uaaaauuccu ggcagggcau ucacauaucu gucaauuugu cuuucuuugg 300
guguaagagu ugugauucuc auugcuggau uuuuuuuucc ag 342
<210> 81
<211> 2020
<212> RNA
<213> 智人
<400> 81
guauugaaaa uuuuguuaca gguauugaaa auuuuacaug ugaauaacaa aaaucauugg 60
uaguauguuu cuuuauguuu uuauuuuuau uuuacuuuau uuuaauuuuu ccaucaccaa 120
agcaugcaga uaguacuuuu cucaauauuu agucuucaug uauuccugag uucucaaaau 180
aguaacagug aaauauauuu uuuauggauu uugauguuag auggauuaua aauaaaagca 240
auuuauacca uucauuccau ucaucugcau gagcagcaug uucauacauc uuguucgcac 300
accugucauu caugugaaau auaugguuca caagcagaac aacaagcagc uauuauaaag 360
caguguuaag uaaaugagca cuuuuauuuc uugcugggug gaaaacaaaa gaauaaaguc 420
ugucaaggcu uuuuaguguc augauagaau uguuccccuu uuugcauuca caaguaaaaa 480
cuacuuuuuu uuugagacag agccucacuc ugucacucag gcuggagugc aguugcgcua 540
ucuuggcuca cugcaacuuc caccuccuga guuuaaguga uucucaugcc ucagccuccu 600
gaguagcugg gacuacaggc augcaucccu ggcuaauuuu uguauuuuuu uuuaguagag 660
augguguguc gucauauugg ccaggcuggu cucaaacucc uggucucaag ugauucgccu 720
gccuuggccu cccaaggugc uaggguuaca gacgugagcc acugcacaca gccauaagca 780
aaaacuucua aaccaaauua uucuucaucu uugucuuccc uuuacgcaau aaaauguuaa 840
ucuaccacca aagaggaaag gguacucuac uauacuaccu gcccuggguu ucucaguuuu 900
gcugucuaua uaauggucgu uaugaauguc cuaaugacag auccuuuuca uuauuuuauu 960
ugaaauuuga cuaucuauaa caucacauac auuauaaaua uaauuacaaa uauauguuca 1020
gaaucaauga aaauauauuu uugauuauau gggccacuau uucucucugc uaggugaucc 1080
auuugugagu auacuugagu uauaauuauu aaguacucau uuuuauuuug gaaauuacag 1140
uaauucaucu uuuucucaau auugggauuu uuauuauuau uuuauguugu cuaaggacag 1200
ccuuaacuac uuauuagaau auugcuuugu augugauauu auuauuuuua aauguauaau 1260
uuuaacauua uuauuucucu uauuuaccug agguauagga acacuaucag caaauauugg 1320
uaguauggca uugucguauu uuuugagaua aaauucauga uuuuuaaucu uuguauaaga 1380
aauauaucag aaguuuguag uagauuagag aguaccaacu gggagucuga aaagcugucc 1440
aaaguggcaa aacagguacu uagacucuca auccuaaggc uguauagagc uauaaacgug 1500
gcaagaccuu uggagucaga cagacccaaa cucaaauguu ggauccaugu auauggaaag 1560
caccugacaa caagccuagc auauguacuu gguaaaaaug auugccaagu guaguguuaa 1620
ugaguuuuug gauauugagu aaguuauuua aauuucaauu ucaucuuuaa aaugaaauaa 1680
uuggaaagga uaauuugagu gaggguauga aauuaugugu ucauaagaga ggguaugugg 1740
ccgagugacu agaggcgagu uuauaacuau ucuaucuaau aaaacuuugu aaucugguaa 1800
uuugugugcu aaaaauaacu uuaccuguug uauaguacuc uuuuuuuaug ccuuaaacua 1860
aaguguucaa aauaucaugg aaaaaugauc uguguugcuu acagauuugg ugacuuuuaa 1920
cuuuccuaua auguugucag aauaugaauu uauacuuuca aauucagcau uuauucuauu 1980
guguuuuuuu uugcauucuu auuucuaaac cacuuuucag 2020
<210> 82
<211> 1967
<212> RNA
<213> 智人
<400> 82
guauagguau uagcaaaacu auaaauauaa uugcaguaua uucuuguuaa uugugaaagu 60
aacguaagaa uaauuuaugu uuuguucuuc ccuucuucuu cuuccuuugc aauuguauuu 120
uuuuuuacuc ugguaacuac uguuaggaac uuauuuaugg agacagugua gcuuaaugau 180
uacauuaagc cugggauuau ccugccuggg uuugagucau uuaacguuug cuuuuuguaa 240
gagcuugagc aagucaucuu accuaucugu gucucaguuu ccuuaucugu aaguuacuuu 300
guaaguaaua cccuuuucau aggauuauug uaaaacguaa augaauuauu agaugaaaau 360
gcucggacua guguguggca cauaugaaca guuuguaaau guuagcuguu guuagcauca 420
uucaucauca ucacaaucau cauuguucau auauguuuau agggaacuaa cauauuucuc 480
cuuauuucug ucaucucauc uaaaucaaua gaaugauuuc cuuaauagga auuagaauac 540
cuaaucaaag gugauuuaaa cacuaagaau aauuauuauc ugaccuaacc agaaccacaa 600
agcuaguugu agggcagguc auauuugaag guuguuguua ucgccuauga ugguuguaaa 660
auagcugcau gaauucaaga aagaugaugu gcccauugaa gaagaggagc auuuuuuucu 720
acauagcuuu uauuuuuaaa uaaacauuuu uuucugguga uaccuggcag acauugacuc 780
cgaucucauu ugcuagaauu ggaucacaug uccaagucug aaccauucag uugcaaagag 840
aaugauaccg cuauacuggg uuuaugccaa gaacauuaca cauguuugug gaaugcucau 900
guguagacaa cagugucuua cacaacuuca aaaaaauaau uuauauauaa auauguuuua 960
aauuacuuuu uaaauucaca agaauuuaug guauacaaca ugguguucua uauauguaua 1020
uacuaugcua uacaacaugg uguucuauau auguauauac uaugcuauac aacauggugu 1080
ucuauauaug uauauacugu ggaauggcua aaucaagcua cuuaacauau guauuaccuc 1140
gcauacuuuu uuuuuuuuuu ccuugagaca gagucuugcu cugucaccca ggcuggagug 1200
caguggcgcu aucuuggcuc acugcaaccu cugccuccug gguccaaguu auuuucuugc 1260
cucagccucc caaguagcug agauuacagg caugugccac cacgccuggc uaauuuuugu 1320
auuuuuggua aagacggagu uuugccauau uguccacgcu agucucaaaa uuccuagccu 1380
caagcaaucu gcccaccuug gccucccaaa gugcugggau uacagcauac uucuucuuau 1440
uuuuuuuuuu uuuugcacua agaacacuua aaauuuacuc ucuuagcaau uuuaaaguau 1500
auaauauacu guuauuaacu uuggucacua uuuuaauuag acuuaagaug uguuuguauu 1560
caaauuauuu uguaagcauu uaacacccaa auuugagagu ggggucagaa uguuggaauu 1620
ugauuucuag aauuaguaua ggguauuauu uuccuacuuu uuuucugugu ucaauaaaau 1680
guuuauaaga uucagcuuca auuauauuau aacccauuua guggugaauc agggaagaau 1740
gaaaauaauu ugauaacuuu guugccuugc auuuauuuaa aaaauuuuua auucuaggcu 1800
aaacccuuuu uaaaugaaag uuuaacuucu uguguuuuca gauacugaau agcuaugaua 1860
ccucuugugu ugagaaaacu uuaaauuugc auaaucugaa guuaucuuuu cuuauaaaca 1920
uuuuauuagg uuuacaguau ugucuuuuug uuuuguuuug uuuuuag 1967
<210> 83
<211> 90
<212> RNA
<213> 智人
<400> 83
guaaguaaaa cauuuuuaac auuaguaugc aauauuguac aaaguaggau agcuagauuc 60
aacaaguaau auggaugugu cuuugugcag 90
<210> 84
<211> 3663
<212> RNA
<213> 智人
<400> 84
guacaucuga uucuuauuuu gcuuuuucug acuaugaaaa auuucaaaua ugcagaagau 60
aggaugguau caauaaugcu caucaccuga auuaauaguu aacauuuauu aacauuuugu 120
cauaauugcu ucuucugauu uuugugggau guuugaauug cagacauucc uccccuaaau 180
auuuaaugua cccuuuugaa aaaggcuuuu uucuuuaacu aaccauagua acuuuauuau 240
accuaacaaa augacaguaa uuuucuaaua ucgccuaaua cccugauuau agucacauuu 300
uuuacauuuu uugaucaaag aauaagcauu uggauguuac aucucauaaa ucuuuuuaau 360
auagaauccc cuugguuuuc uuuuucucca aaaaauguuu gaagauguau cuaacuuuug 420
uguguguguc auuuuacuug uuccuguguc ccuuguauua cuaaaaguua ggucagaacc 480
cuaaguuaca uucagguuua aacauuuuug gcaagaauac uucauaagua guguucuaua 540
cuuuauauug caucacuuca agaguaucug guuguuccau guuuuguaau ugauuacucu 600
guuaaggaaa agacaagcag accaaguaug guggcucaug ccuauaauuc caacauuuug 660
gaaggcccag gcaggaaaau uuccugagcc cagaccagcc uaggcaauau agugagacuc 720
cgucucuaca aaaaauguuu uuuuuuuugu uuguuuguuu uuaauuagcu ugguguagug 780
gcacaugcuu guaaucccag cuaccuggga cauugaggug ggaggaucgc uugagcccag 840
gaaguugggg gcugcaguga gcugugauca ugugccacug aucuccagcc uaugugccug 900
uauaacagag cgagucucuc ucuuaaaaga aaaaaagaag aagaagaaga agaaaagaua 960
accauauacc uccauuauua agcaauuuag cuaacuggug auauuuuggu accauacaaa 1020
uaacaaauua uuugucaguc cuaaugauuu uagcaucugc ugaugauugu ugccuaaccc 1080
aauuauuaaa aguugcaaac aucauaauuu ucuaguuaua uuaugcacuu acauuuauua 1140
acagacaugc uuuuguaaaa uaaauagcgu uuccucauua gcccaggcua uuuguuuauc 1200
uugaaguuua gcuccuacua caaaggcaag auaaaugcuu uucucuuuaa uuaccaguuu 1260
ucagaauaca cacuuggugu acucugcacu accugcuuuu uuuguccccu ccgcuuucuc 1320
uuuuuuaagu aucagauuag acucacagau uuuuaaauau uccauguguu uuaguuggag 1380
ucauauucuu uugucucaac uuuagccaaa gagaguccuu uaaaguugac ucuuauauug 1440
ucuugacaaa aauucauuag ucuuuugaac gaagccucaa agcuugacuu guuuucuagc 1500
auaagauguc uuagacuuac cuacauacuu caugcccaua cuuggaauaa accauuucuu 1560
uaaagagccc agguuccuuu uaguggggaa ggcauuuaga uaccaaaaac uggccacugg 1620
gcaucauugc ucucagagua ucauugccac uagucucuca guagacaagu uagaaaaaua 1680
uguauauauu uaaaccauga guucauauug uuauuuccag uuuaauuaua acauuauggg 1740
guaaguaaau aguaucggau uuuuacuaag cuucuuugau uuugcacuug uauuuuuuuc 1800
uuacauagaa aaccuuuauu auuaacauua aaauauuugu uuuauccuac aauauacaua 1860
caauaauuug aaaaauaaua cuugaauuga uauuaauagu aacaacaaca gcacugcugc 1920
caaacauagu uuaaaguuuu auuucagguc uuauuuucuu cagaauauau cuugcugaga 1980
auguauaggc aaaguauucu acacuuacuu gaaauaauug ucuucaugcg guuauguuau 2040
acauuugaua uauaguuagg cucauuuguu uuucauuuuu uuuauuuuag ggauuuuuuu 2100
ccuuuauuga auuuuaauau auacaauauu uauauaugca aaauauuuaa ucagagaaau 2160
cuuaauucug gucuuacgcc uuucauauua uucugcucca cccucuguag guaacuuauu 2220
aucuuucuca uguuuccuuu uuggaaacau aaacaaagac aagacagguu acaugacaug 2280
uauacccuuc ugcaccuagu uuuauaccuu accuuguagu uuauuuuuaa gcauguaaau 2340
guucaauguu caugacuaaa uuuggacagg aucauaggaa cacagaauuc aaagugaaau 2400
uaaaaugggc uuggguucuu uacuuuccac uuuaaagguu guaaugggug augucaggcu 2460
aauaaaccua uuuucagcuu gaucuaaagc uuaauacuga gcaucaagaa auucuuuaau 2520
aaauauaagu gauauuuauu cagacaugua auaaggaaau guucaugucu uauuuuugug 2580
uuagauuuuu uuagaaucua cuuuuguuag aguuuuauaa auacaguuag uguuugagau 2640
agaaagagaa aagaauuagu uuucuuccuc uucuaccugc ucaugaacuu gauuuuuuuc 2700
ucccaacaau ugaagagcca agaaaaaggg agauucuuaa gagaugggaa auagaaucuc 2760
aucuaccccu guuuccccca gaacagugaa acugaaucuu aaggguaaga uagaauagug 2820
uguacuuaac uuagauggag aagaaaggcu gccaaaauga gaucugaagc gcuauuacaa 2880
auauuuccau cguuacugua cuucagaaug aauuacaacc guaaguuuuu uuacuuccuc 2940
auucauaaau uugauuauuc cuuauaccac uucucagcuu ucaucauucu uuauuguacu 3000
uuucuaugua auguuugccu auuauacagc aacuuaagag aacuguaagu uuggacauuu 3060
cauuuuggug uugauaauag aauaucuuug aauaguucua uaguugauga guagaaccau 3120
gaaccaagua acuuaaaguc cuugauguua uuuauuacag agaacuauaa uagaagcucu 3180
cccgcuaaug uuuccaucau guguacaaaa aguuuucuug uuauuaaagc uaguccguuu 3240
aacuuacaau aagcauaaau agcuaagcug ugaaaguuac cugugauaau gcuaauuuuc 3300
ccauuuauua aaaggcaagu uguuuuccga ucauaagaaa uuuagaaaag ccauccaaag 3360
auaaauuccg agugauauau uccugcuguu uguuauguuu ucucaaauua auugaguuuu 3420
auuuuacaau gacaggaguu auuaaaguau uuuauuuuua uuaugauuaa gauuuucaaa 3480
guaacauuuc uuauaugaaa gaaauuaugu uaaugcaugu uuuucuuaca ugggaaauca 3540
uauauuuuaa aaaugauuuu aaaauucguu uuacuuuaag uuguauuauc uuucucaaaa 3600
guggcuagug cuugaccaga aaaaaagaca ccagcauaac ucaguguauc uuuauuuaca 3660
uag 3663
<210> 85
<211> 5838
<212> RNA
<213> 智人
<400> 85
guaaguuugu gugauucuug aaccuuguga aauuagccau uuuucuucaa uauuuuugug 60
uuugggggga uuuggcagau uuuaauuaaa guuugccugc auuuauauaa auuuaacaga 120
gauauaauua uccauauuau ucauucaguu uaguuauaaa uauuuuguuc ccacauaaca 180
cacacacaca cacacaauau auuaucuauu uauaguggcu gaaugacuuc ugaaugauua 240
ucuagaucau ucuccuuagg ucacuugcau gauuuagcug aaucaaaccu cuuuuaacca 300
gacaucuaag agaaaaagga gcaugaaaca gguagaauau uguaaucaaa ggagggaagc 360
acucauuaag ugcccauccc uuucucuuac cccuguaccc agaacaaacu auucucccau 420
ggucccuggc uuuuguuccu uggaauggau guagccaaca guagcugaaa uauuaagggc 480
ucuuccugga ccauggaugc acucuguaaa uucucaucau uuuuuauugu agaauaaaug 540
uagaauuuua auguagaaua aauuuauuua auguagaaua aaaaauaaaa aaacuagagu 600
agaauaucau aaguuacaau cugugaauau ggaccagacc cuuuguaguu aucuuacagc 660
cacuugaacu cuauaccuuu uacugaggac agaacaagcu ccugauuugu ucaucuuccu 720
caucagaaau agaggcuuau ggauuuugga uuauucuuau cuaagauccu uucacaggag 780
uagaauaaga ucuaauucua uuagcucaaa agcuuuugcu ggcucauaga gacacauuca 840
guaaaugaaa acguuguucu gaguagcuuu caggauuccu acuaaauuau gagucauguu 900
uaucaauauu auuuagaagu aaucauaauc aguuugcuuu cugcugcuuu ugccaaagag 960
aggugauuau guuacuuuuu auagaaaauu augccuauuu agugugguga uaauuuauuu 1020
uuuuccauuc uccauguccu cuguccuauc cucuccagca uuagaaaguc cuaggcaaga 1080
gacaucuugu ggauaaugua ucaaugagug auguuuaacg uuaucauuuu cccaaagagu 1140
auuuuucauc uuuccuaaag auuuuuuuuu uuuuuuuuug agauggaguu ucauucuguc 1200
acccaggcug agugcagugg cacgaucucg gcuuaacgcu uacugcaucc ucugccuccc 1260
agauucaagc aguucuccug ccucagccuc ugaguagcug ggauuacagg ugugcaccac 1320
cacaccagcu aauuuuuuuu uuuuuuuuuu uuuuuuugag gcagagucuc gcucugucac 1380
ccaggcugga gugcaguggc gccaucuugg cucacugcaa gcuccaccuc ccggguucag 1440
gccguucucc ugccucagcc uccugaguag cugguaccac aggcacccac caucaugccc 1500
ggcuaauuuu uuguauuuuu aguagagaug ggguuucacc uuguuagcca ggaugguguc 1560
gaucuccuga acucgugauc cacccgccuc ggccuccuaa agugcuggga uuacagaugu 1620
gagccaccgc accuggcccc aguuguaauu gugaauaucu cauaccuauc ccuauuggca 1680
gugucuuagu uuuauuuuuu auuaucuuua uuguggcagc cauuauuccu gucucuaucu 1740
ccagucuuac auccuccuua cugccacaag aaugaucauu cuaaacauga auccuacccu 1800
gugacuccca ugugacuccc cgccuuaaaa acugucaaaa gcuaccgguu accugaaggg 1860
uaaaagucaa guccccuacu uaccucaugu caucuagagc aagagaugaa cuagcugagu 1920
uuucugacca caguguucuu ucuuauguau guucuuuugu acgugcucuu uucuauauau 1980
agggaaccau uucucucuuc caguuguuuu gcucagugaa uuucuauucc uguuucaaaa 2040
cuuguucagg cauuaccuuu uuuuucuuaa gcauacuuuu uuuaauggaa caaagucacu 2100
ccugucuaca cuaguucugc aucuuauaca uagguuuugu acauaguaca uauuuauauc 2160
acaucaaauu auauguguuu acauaucugu cuuccuuaau ggaauauaag ucuuuugaua 2220
uaaggaacua uuuaauuugu uucugugugu ugaguaucuc cuguuuggca cagaguucaa 2280
gcuaauacau gagagugauu agugguggag agccacagug cauguggugu caaauauggu 2340
gcuuaggaaa uuauuguugc uuuuugagag guaaagguuc augagacuag aggucacgaa 2400
aaucagauuu caugugugaa gaauggaaua gauaauaagg aaauacaaaa acuggauggg 2460
uaauaaagca aaagaaaaac uugaaauuug auaguagaag aaaaaagaaa uagauguaga 2520
uugagguaga aucaagaaga ggauucuuuu uuuguuguuu uuuuuuuuga aacagagucu 2580
cacuguguug cccaggcugg agugcagugg agugaucuug gcuuacugca accucugccu 2640
cccagguuca agcgauucuu cugcuucagu cucccgagua gcuggaauua caggugccca 2700
ccagcacggc cggcuaauuu aguagagaca ggguuuugcc auguuggccg ggcuggucuc 2760
aaacuuugga ucucagguaa uccgccagcc ucaacuuccc aaagugcugg gauuacaggc 2820
augagccacu gugcccagcc uguuuuuuuu uuuuuaaagg agaccaguga aguuucagga 2880
ggagggaaag aaaauuuaga guuacuaggg agagagugau gaagauaaga gaugaaagug 2940
guaauaaggg aaauagcaaa auaucagggu aggugggaga aaaagagauu uguaacaaac 3000
aauaggauua uccugugaaa aaggaugaaa ggaagaaaaa aauggauaga aagauauuua 3060
aaacacccuc agccuccugu uuucccuccu guguauucau aguauauaaa acuauaauua 3120
uguacuuuac uuaaaaaaua uauuauuauu accuuaucgu gcuuauuuaa ucauagcaug 3180
uccucuuuuu agucucauua cccuguuugu auuauucuuc auaacacuua auaccugaca 3240
uuguauuaua uauuggcuua uuuuccaggu acuccacuca aauauaaguu cuaggauaua 3300
auuuauuuau cacugaaauc cauugcuuag aguaccuggc auguaguaaa uaggcauucu 3360
guuuuuucaa auaaaaaaua aaggaacuua agauauauau uuauguuaua ucgccagccu 3420
uuuuccucac agcucuauuc uguuguacag aauuaccuac uuuacaauuc cuguguuuca 3480
aggggaucuc aaauuuaacg uguccacaau gaacuccuga uuucuguuuc ucuccuaguc 3540
auucuuauuu caauauaugu ucaguuaccu aaccagcuag ucaaggcaga uacuuuagag 3600
uuauucugua gucauucuuu uucccuacca uuuuuguuuu ccaaauguaa uuuaugugug 3660
ucuucuucau ccucgcagcu cuaacccuug uccaaaccag caucaucacu caucuggagu 3720
uccacaaugu cuuucuggcu aguuucccug auuucucuau ugaccccuuu auucuccaca 3780
gugcagccag aaugauuguu uaaaacuucc uccuuaaaau cuuuaaauug uuuucuuuua 3840
uacguuaagu uaaauuccag uuccuugucu uggcaugcca ugcccugccu gguguggccc 3900
cugauggucu cuccaacuuc auguuuuacu acuauugacu cuuauuuuug cuuacucugc 3960
uugggugcuc caguccucca aaucauuucc ugcuccaauc auuucaauca uuuuuuccuc 4020
ucagaucuua uaguauucca aaugcuuucu uccuuuggag caucuggguu uacuaauaaa 4080
uacuucguac cucacaguuc agcuuaaaua ucaauuauuu ggugguuaag acauccuuca 4140
accgcucuau cuaaauguuc cuuucuauua uucacuggcu caguacucug uuuuuauuuu 4200
cuuucuaaau gucaacuuuu uuuuuuuuga gucagggucu cacuguugcc caggcucgag 4260
ugcaguugca caaucauagc ucauugcagc cuugcccucc ugggaucaag uaauucuccc 4320
accucagccu ccaaaauagc ugggauuaca gguaugcauc accaugcuca gcuaauuuuu 4380
uguguuuuuu uguagagaug aggucucacu uuguugccca ggcuggucuc aaacuccugg 4440
acucaaguga uucucccacc ucagccuccc aaagugcugg gguuacaggu gugagccacu 4500
gcaccugguc gauacugacu uuuuuuuuuu uuugagaugg aguuuugcuc uguugcccag 4560
gcuagagcgc agugguguga ucucagcuca cugcaaccuc caccucccag guuaaaggga 4620
uucuucugcc ucagucuccu gaguagcugg gauuacaggc aagugccauc augacuggcu 4680
aauuuuugua uuuuuagcac uauguuuagu acuguguugg ccaggcuugu cucgaacucc 4740
ugaccucaag ugauccaccc accucagccu cccaaagugc ugggauuaca ggugugagcc 4800
accguaaucg gccaacauug acauuuuuag uagacuuuuu guuuguuuac uugcuuauua 4860
ucugcugccu uccacacucu ggcgaaaucc ugccacccac ccacacacac auaggcacug 4920
aaugggcaga acucugaagg ccagaauuuu auauuucuuu ucacuguaaa caucaucauc 4980
ugucacugau ggcacacuag gaugcucagc aacugugugc augaaggaag uaagcacuag 5040
uuugugaagg cugcaaaacu cuugaguauu cuaagaguuu uggccaaaau gaauguacag 5100
cuuuaguggc agaagcuaau acucagaaau ugaggccgua uauuggauaa cacaggauuu 5160
ggaugauuau uuuaaaauaa uauuuuacau uguauauaug ugugugugug ugugugugug 5220
uguguguaug ugugugugug uguauauaua uauguaugua uguguauuag uccguucuca 5280
ugcugcuaug aagaaauacc ugagacuggg uaauuuauaa aggaaagagg uuuaauugac 5340
ucacaguucc acagagcugg ggaggccuca gaaaacuuaa caguuauggc agaaggggaa 5400
gcaaacacau uuuucuucac augguggccg gaauuagaag aaugugagcc gagcaaaggg 5460
gaaagccccu uauaaaacca ucagacaucg ugagaacuua cuauuaugag aauagcgugg 5520
gggaaaccac ccccacgauu caauuaccuc ccaccaaauc ccucccauga cauaugagga 5580
uuaugggaac uaugauucaa gaugagauuu ggguagggac acagccaaac cauaucagua 5640
uguauaugua uacaaguauu auauauauau guauguguuu guaugcauac auguauuaua 5700
uauggaggaa auucuaauuu uguaaaaaac uggauuguga guuuuaagga gauguuauau 5760
aaaguuaaga caaugucauu uugugguauu ggucugaauu acaauguagu uucuuaguga 5820
uauuuuuccu uuauucag 5838
<210> 86
<211> 2912
<212> RNA
<213> 智人
<400> 86
guaaguuuua ugacucugau aauauaaaau gauuaacauc uaauaaugaa uauuucuuau 60
uuaaaguucc uuuuuuaugc uagauuaaaa ggaaguauuu ugacuaaaaa aagaaagaac 120
uuucugccua auaauuuaac uuaggcagau gaauaauccu guacuuaacc ccaccaaagu 180
uuaguuuuca guccuuaagu uagauuuguu ucuaaugaaa ucauauaugu uaaaaauuua 240
ugacuaagua uuagcuacuu ugaaccguuu aacaauuaaa acugaugaua uuuuauuaau 300
gguauuauga guucuuucac ugagugcaag uuauauuagu uauauaucac uugauauuuu 360
uaaauuaaaa gauaccagga aacagcaaag aaaaugugaa aagaaguugu auuucucaua 420
guuuuacuac uauauuacug uauauuuuug cuccuauaug cuuacauauu uuauauauuu 480
uaaauuauua uaaacauggu uuuauacugu auuuagauag uaauaucaaa aauauuuuua 540
uggccggcgc aguggcucac accuguaauu ccagcacuug ggaggcugag gagagcagau 600
ccccuggggu caggaguucg agaccagccu ggccaacaug gcaaaacccc aucucuacua 660
aaaguacaaa aauuagccag gcgugguggc aguugccugu aauuccaucu acucaggagg 720
cugaggcagg agaauugcuu gaaccuagga gucagagguu gcagugagcc aagaucauac 780
cacagcacuc cagccuaggc gauaagagug agacuccguc ucaaaaaaaa aaaaaaauuu 840
guuuuauuca ucauacuuau aaauacuuau acaauagccu aauguguuug agugauuaaa 900
ucacuagcuu uuuauauuuu ugcuauugcu uauagugcca cagugaacau uuucauguau 960
aucuaacaga gauauuacug ucucagaagg uauugaaauc uuuguugcuc ucauuagagu 1020
uuuccauauu aauuuuucaa acaguuauau aguuuauaag auuuucauaa uuuuaucuca 1080
uauauugugc uucauaauuu ucaaauaaau uugcugcuuu cgauaaugua uuuucaugua 1140
uuuguuuccu agacguuaga gcuauucaag guuuuuauua cuaaauagag cuguucucuu 1200
aaauugguaa ugagauacuu gguuuagaga agccuaacac ugggaaaucu uacauaagcu 1260
acuuuuagaa auguaauuuu uagcucaaua agagauuaaa uaugaauuga cuuuugugua 1320
guauuugcau ggaagaaggu accauuuaaa ugaagacaug agaguauuac guacaauuuu 1380
aguagguucu uuuuauuuua ucaucuuuau uuuuaauaaa ugcugaauuc ccuacagaaa 1440
uucuuuaauu uuuacauauc uugaucucuu ucauauaugg auuuauauca ccgaaguuuu 1500
aagaguguuu cccuauuccc uguugcccuu auaucuuugu uuaaaaaugu cacaucauua 1560
gcuuuuuuuc aucuaggaau uuguuagugu ugggcuguug ugcucuaccc ucucuuuaag 1620
aaaacuccaa acccaaaaac auacaagaug gcuagucugc uucagccuuu gugaugugcu 1680
uuucucuucu aaucagaguu uagcacaaua cagaauggag aaggacuccu uuauauauug 1740
guauuuauug caguauuuuu cuacauggug ccuaagguua cuugaaugag ucuuuauucc 1800
auaaugaacu gauuuacuaa ugcuuuuagc accuguuagu gauccauuau uguuaguuac 1860
uugauuacug cuugccacag cuauucuaaa auaauacauu uuaaagauaa auacagaaca 1920
uaaugaagua cuuuuuaaaa cugagauaga gaccaauuuu uuuuucagga aauguauauu 1980
acuuugagaa aacucaguua uaaaacuuga acuuaugaag cuggaaaaac aggagggggc 2040
auuauuggua uuguaaaagg cuguuuacaa agugaguugc ugcuuaguuc cuuuaaguaa 2100
uuggcuaccc uaaacacauc aguuuuaagu ugcugaaaag caaaacacuc uaccaaauuu 2160
uguuuuuuuu cuagaccaug uuuacaaagc aaaaguaugu uuucuucccc cccccucaaa 2220
aaaugacuaa ugacacuccu augcgaugcc uuuuuauggu aaauugaggc uuuuaguucu 2280
cuuuccauuu agccacagac uuuugugucc aaagacaagc ugcguaacug cauauauaag 2340
guuaaggcau aacuacuaau aaaagaaugu aaaauauuug auauuagguc uguacaaaga 2400
ccaaauaaua cucaugauua gacaagauua uauuugguag aaucuaucca ucauauggcu 2460
ucagauuuua cuuuucagcu uggcuuugug agacuuuaaa aaucaaguca uugcacuuau 2520
auucacaaag ucacauugcu uuacugcauu gcuucucaua caguuuaucu ccuuucagua 2580
aaauguuuac uugccauuuu uaaaauuucu uauaugugac acuucuacac uaaguccuuu 2640
auguuguuag uuccacaauu cugugaggaa uagguuuuuu uuuuuaauca uuugauugau 2700
gaagaacauu aaguuccaca gagauuaaau gguacaggca ucacacaggc aggaaguaac 2760
agagcuaaga uuagagucca ggucugaugg aauucagaaa gcuaaugugc uuuccaugga 2820
acuauaaugc uuucuaauau acagcaucua aaauaucuga gguaauuuua auauaaacag 2880
caugagauug acuuaaauau uauugcaugu ag 2912
<210> 87
<211> 937
<212> RNA
<213> 智人
<400> 87
guuugauauu auaaguuuua ucauacaauu auagaauaaa gaauuaguuu ugguagacau 60
uguauuauug uuaagugguu ugucuggauc ucugaaauau cuuauuaaua uagugccuau 120
guuuugugua auaaauaaau aaaagauuua aaucugaauu guuuaaaagg aaagcagaua 180
uuucuguaag uuuuucucac caauguuaua uuauuagauu uaauuuauga aauguuauuu 240
acuaaacaau ggaauugccu uucaccacca ucccuucauu uaacaaauau uuauucauug 300
ccuauuacau gucagacccu guguugggac uggcaguaua gcaagaaaca aaauagacaa 360
uaaucucuac uuucagggac uuuacauucu aauugguggu uuuauauauu uuugaugugg 420
ucagaaucau uaaacugugu ggcaguaaau auaguuugca aguauuuaac aauuuaugau 480
uaaacacaac ucuuacagug uuugcuuacc uugagauuua auauauuuuc aaagcauuua 540
uaucauuuuu guuuuaacua ugucacuaaa ucuauaugag uaagauuuua uuaacucauu 600
uggauuuauu uauagaugau acaauugaag uaaaauauaa ugagcagauu gcauucuaag 660
caaaguaaga auauugcaag uucagauauu auuagauaau gaguugccua auaaaaauga 720
cuuuuggugg auuggaauau aaccagaguu uccauaguuu guuucugauu cuuucauauu 780
uuuuacccuc cuucagucug uucuuaacac uucacacuua auauaauaug ugaacuaagg 840
ccaaguaaag aggauugcag uacuuuaaaa gcuaaauuac aaagaaaacc ucaccaaaaa 900
uugauguauc ugaacauuuu uuguuacauu uccuuag 937
<210> 88
<211> 1841
<212> RNA
<213> 智人
<400> 88
guaagugcau auaagcauuu uagccauuug acuagaugua ucuucuuuaa uuugucuuua 60
agaaacccaa uuacagguau acaauucuua guaguaauug auacugauuu cuuuuuauaa 120
gaacaggauu aaguaauauu aagaucgguu uuaacagggu uaaauaauaa uauugacgag 180
aauaauauug uuaaagagga agugaccucu caagauuugc auuuuuuaga guucaggaau 240
auuauugcag aaagguccag uuccuccaca uauugauuuu uuggggaagg ggugauggag 300
gaggaauggu uguuuauugu auuuaaacuu aaguuucuuc auuuuaauaa gggaguaaua 360
guaccucuuc uaccuguuuc auaagguugc uguaagaaua uaauaaaaaa uucagauuuu 420
gauuuaguuu acauuuaucg ggcaucuacu auguacuagu cacggugcaa gguauuaaac 480
auauauugac uuguacaauu auacuuaacc uugagguuau auuuuuguuu ucauuuuaca 540
ugaagaaaua ugcccagcua guuuagaaca caaaauauau auaaggagua aauacugcgu 600
gcuggcuggg cguggugaca ugugccugua gccccagcua cucgggaggc agaggcagga 660
gaaucgcuug aucccgggag guggagguug cagugagccg agaucgcgcc acugcacucc 720
ugccugguga cagagcgaga cucugucaaa caaacaaaca aacaaagaaa aacaaaacaa 780
aaaaaccgug ugccagcuau augcuguauu uucauucucu uuuguaauua ggugauauuu 840
caguagaaaa guauaaggag cacuuaguua aucugucaag cauaaauagu aaaaauauuu 900
uauggccuac ucauaaaaau auaaccauuc cuuuggagcc uugauaguuc ucuugggaau 960
aucaguuuuu gacaucuuuu ucacuaugaa agacccuuuu uuuuaaaaaa auugauccuu 1020
ucuucucaug gaccucuuuu gauauaaacu aacuuauaau aguucauuuu aaucauauuu 1080
uguuaaucau gcaacuggca augagagccu cucaucagua ugaggaaacc ugccuuaucu 1140
auaauacuga acuaaaauua uucuaaccca aagcaaagaa acuuuacauu uugcuuugcc 1200
uguauuagcu uaucacagua uucaugaggg aauuugaagg acuuauuacc auuaggcuau 1260
cucuuuuuuu uuuuuuuugu aauuuuauua aaugcauguu uuguuucuuu ucacauuacu 1320
gauaacuugu agauuaaaac aaaucaaaac augcauuaau ccaucuaagg auccuagaaa 1380
uuuuacauuu cuguguucuu aacuguguga uggucuuaga uaaauguacu aaauaccuua 1440
uccuagcaua uuccaaauua ugacaauaaa uguuuuaugg aaaaaaguau gggaacagaa 1500
guucuuuggc uauauacauu uggaaaauac uauauaguaa guaugauuug agauaauuau 1560
auaugauaga accucuggga gcacugaaua uauguuagga auauucaaga gggaggaggg 1620
auguugagaa ugaaguuuuu uuuauauagc aaacaugaua accucugaug gaauuauguu 1680
ucaugaaaca guuuaggaaa uccuguuuua auauuucaua caaagaagag auagaugcug 1740
aaaacgaaug gcuuuuugaa aaagggucua gaaauuuuga auuuuggcau uuacuuagaa 1800
aguguacuua auuguuccug aaauaccuua ucauuuccua g 1841
<210> 89
<211> 1240
<212> RNA
<213> 智人
<400> 89
guaugugcag uauuggcucu ucuacauaga auccacuuuu uucccuaaau uuacauuaga 60
uguugggagu gggauauguu auacuuuuug uuuguuucga gauagggucu cauucuguug 120
cccagggugg agugcagugg uacauucaag gcucauugca gccuucacca ccuggguuca 180
ggugauccuc ccaccucagc cucuuagaca gcugggacua caggcacgug ccaccacacc 240
uaauuuuuuu gcauuuuuug uagagacagg guuucaccau guugccuagg cuggucccaa 300
acuccugggu uaaaaugauc ugcccaccuu gacuucccag aaugcuggga uuacagguau 360
gagccaccau gcugggccau uguuacauuu uuaaucaaaa gauauaccaa ccagaggcug 420
uuauucuugu uaguuggaac cugauuagaa agcucuuuaa uuugaaauau uguucaguaa 480
uccaguacag cauuuaaaug ccuauagaug aauuaugcug cugaucaaaa uuaggacacu 540
gagaauugua guuaguaaau cuuuaauaac aauauuuucu cuuguauuua uauguaacuu 600
uuuacauauu cuuacguuau auauguuggg aauuauaaaa acauacacau uguccugauc 660
aguauuaugu uacuugcaau ggagguuaaa aaaaaacugu aacagucagg caugguggcu 720
cacgccugua aucccagcac ucugggaggc cgaggcaggc ggaucacgag gucaggaguu 780
cgagaccagc cugaccaaua uggugaaacc ccgucccuac uaaaaauaca aaaguuagcc 840
aggcguggug gcaugugccu guaaucccag cuacccagga ggcugaggca ggagaauugc 900
uugaacccgg gagguggagg uugcagugag ccaaaaucac gccauugcac uccagcuugg 960
gugacagagu gaaacucugu cucaaaaaaa aaaaaaaaaa acaccaguaa cauacccacu 1020
guuauucagu uacauuugga uuuuaaguuu guuugauucu agguuuuuuc uuuuacaguu 1080
cuuugguaau uauuuguauu aaagcaaagu uacauuuuug uagaucucau gugccacugu 1140
guuaaaacuu ugcuuaguaa auugugaauu uuaaaucugu gauaacuuuc acuggaaaaa 1200
uuugaaacuu acuacaaaua uauauuuuuu uuaauaucag 1240
<210> 90
<211> 1087
<212> RNA
<213> 智人
<400> 90
guaaacauuu aaacuugauu uuuuuuuuua agagacagua ucuugaucug uuucccaggc 60
uggaguucag uggugcaaac auagcuggaa cuccugggcu caagggacuc ucuagccuca 120
gccuccugag uaguuguagc uggcaguaca ggugcacacc accauaccua ccuaauuuuu 180
uaaaauuuuu aaauuuuuuu guagagacaa ggucucacuu ugucacccag gcuggccuug 240
aacuccuggc uucaaguaau ccuccugcuu uggucucuca aaagugcuga gauuacaggc 300
augagccacu gugcccagcc aauuuuaaau ucauuaucuu caaaagaguu acaugauaau 360
uucuuaauau augccuauau gaaaaaugcu uaagauacaa auuccaauua ugauucauua 420
auuuagauuu uauaacuuag caguguuggc uauuugaaug ucuauuauac guaaaaauaa 480
aauuaggcuu uucuaaccaa agauuuuagu gggaauguuc agauuguaua auagcaaaga 540
auuuuaauua cuauaggaaa auuuauauua auuaaacacu aauuauuaua uuuaaacauu 600
guaguaguua ucaguugauu ucuacuguuc auaauuaucu uugaucuaca aguagugggc 660
ccacauuuac uuuuaauaug guuuaaucuu cauuuagaaa gaauuaaaug aaaaauaauu 720
aucuugcaac uacauccugu ucucuaggcu agaaacauuu aggauuucug uuuuugaaag 780
uaauaccaaa guuccaauga ccugcuuaua gucaguguuc aauaaacgua uaacaaauga 840
aagugaauau uagugauguc cauuccaaca uaauuugaag auuuuuauug uaaaauccca 900
cauauuugua gaaaagucua uggaaauccu aaauaagauu uugucaugua guuugacaaa 960
agauaacauu gugucuuauu uuauuuuaga auggccauua cuuucaauua aaaucauuau 1020
caucaaugga ggaauguuau uuguuaauau agcauuuaua uuuguguaua uaaauuguaa 1080
aucuuag 1087
<210> 91
<211> 1281
<212> RNA
<213> 智人
<400> 91
guuuuauuuu auauuuauuu cauuuuuuuc ccuaaguuuu uuuuuuuuuu uuuuuuuuuu 60
gagauggagu cucacucugu cgcccagacu ggagugcagu ggcgugaucu cggcucacug 120
caagcucugc cucccggguu caugccauuc uccugccuca gccucccaag uagcugggac 180
uacaggcacc cgccaccgug ccuggcuaau uuuuuguauu uuuaguagag acgggguuuc 240
accauauuag ccaggauggu cuugaucucc ugaccucaug auccgcccgc cucggccucc 300
caaagugcug ggauuacagg cgugagcccc uaagauuuua aacaagaaua uugcacaaau 360
gacuauguua uccuucuaau uaagugcacc uuccauuacu aauugauuau auaauaauuu 420
guuuuuuauu uucuaaacua uucuaaaaau ucauauuuau uuagcuuuua uaacaguagu 480
cuuaaucuua aaaacggcaa uacauaagca accucauuug guaaguuaau uuuuauuuug 540
auauugguua uuugacuuuu cacaguucca cguuucuacu ggcucucacu gauagaguaa 600
gaagucagcu ucuuauagaa uaaaguauau acuucagaga cagaugaaau ucgucaaaca 660
uaugacuguc ucagagauug uucccccugc uuaaauuguu cuuacccuag auaccuuugg 720
uauuuacacu gucagugccu gcaggucuua gcucaaaugu cuuaccuuau caguguaucc 780
uucaccagcc accuaauaua caacaguaaa uccuacuauc cagauuccua aauagagauu 840
aauuaacuua auuuuucucc aaagugcuug uaaccuucug acguauuaca uacuuacugg 900
uuuauuauug acugucuuuc cuucgccaga augcaaguuc cguggugaca cggacuuggu 960
uuuguuuacu gccauguuug uauuuccuag aaugaugcuu ggcacauaau auaugucauc 1020
aaauaucuuu cguauagcug aacggaugga uggauggaug gauggaugga uggauagacu 1080
gaaauccuua cuucacaucu gccuuuguga ucuuacacaa guuacuucac cucucugagu 1140
uuguauuuuu uuccauaaaa ggaaaauaau uacaguuucu ucaauguguu gugaggauua 1200
gauaagaaaa uauauauaaa augccuguua ugugccugau gucuucgugu augugucuga 1260
cacaaauugu ccuuuuuuua g 1281
<210> 92
<211> 217
<212> RNA
<213> 智人
<400> 92
guaugaauga uuaaucuugu uuguuacucu guagcauagu cuagaguguu aacucacaga 60
aauauuuccu guaucagaug uaauuuuaau ugauguuaua uuguauauuu aaaauauaag 120
agggguuuaa ucuauguuuu aucauacagc uguaaaaauu aauaguuacu cucaaugcug 180
caacugcuuu uuuaaaaaac auacuauuuc uuaauag 217
<210> 93
<211> 1186
<212> RNA
<213> 智人
<400> 93
guaauuagaa gaauuugcau uuugauuagu guauuauuug guauguuugg ggggcuuucu 60
aaauaauauu ucuuuaugag ggcaaugcau agaaugauga aucuauugcu aauuucacua 120
uuuuucuauu cuccuauaau guuucuaaua gccaauaaug aacagcagau auaguuaauu 180
ugaauucacu auuuaauuau uaguugguac cuuucgguac acugaauaug aaaggaaaua 240
aaaagcauuu aauuguaguu cuaugagcaa uauauucucu uauaugaucu cuuuauucuu 300
acuuuuuugg uuuuauuuug aagugcaugu uacauaaucu augaaucaau uuucaguuca 360
uugccuuuaa ugcaugguua aaggguugaa gguaaauuag aaauuacuuu cuguuuuaac 420
cuagaucuug aauuugauua guaggugauc aaaucuguca ucuucauuaa auuauucaga 480
aaauaaugua aacugaaugu guuuucauuu uaguuuucau cuaaauaaac ugcaaauaca 540
uuuaaaauau acauaaagaa guuuuucaag uaaaacugua cauuuuuaau cauuucagga 600
aacguagauu uucuucagua auuuuaagau uugucauuua ugugaauugc cauugaauua 660
cuuaauuuaa aauacucacc uuaauccucu ugaagaguaa aaauuuuucu guuuuuuucu 720
cuuuguuuua auaagcugcg gauuuuauau ucguaauuua uugaguuggg ccucuaaaau 780
uccaguuuug uacuuaacug acuuauagau uagucuccua augcucugcu agucaaugga 840
ccaaaauaaa agaaauaauu uauuacauau ucuuccuaaa ucuaguacca ccauacaugu 900
auaauucuaa acuguaauau cucaauaaag uaccuuaauu aaauuuuaug uucaucauaa 960
caaugaaguu ucuagcauau guaauagucu uauaaauaag caugcaaaua acugcuguca 1020
auuagaauua gucaguuuaa ccuuauuaag uaucaaaugg cuauuguaca uaugauguga 1080
aaaauaaagu gaauuuuuuu uggcuaauaa cuaaucuaaa auucagauga agcauuuuaa 1140
agggaaaaag auacuuuaau gauuuauuau aauuuaauca uugcag 1186
<210> 94
<211> 631
<212> RNA
<213> 智人
<400> 94
guauuuuauu auauuaugag uuaugcuguu auccauuagu uuuuuuaagc aaaugcuaaa 60
uauuauuuua cccuaaagug guauuucuuu ucuugcuuuc aaaugauucu auuuaagaau 120
uguuacuugc augugauugg auuacaccuc ugucaguaaa acuggaaguu uguguacaug 180
uaucuuucua uuauacacug acuaaaccac gaguagcuau cauggugaaa ucauaugauu 240
uugaaaaaua uuuuaauuga guuuauaggu gaggauugag gcaauagggu ggaaugaaau 300
auaucacacc gguaaucagu agaaaucaga uuuguuagaa cuucgugggg gaaagcuaac 360
auuuaauuuu uucuagaagu aaguuaaaag augauagaua caugucauuc uaauguuaag 420
aauaaauuau gaacugaggc ugggcuuguc aacuugaaca uugucugagg ggacaugcau 480
accagucuag auacauacau auauggagau acuguuucuu ccucaucuca aaggaauuuu 540
agaagauuga agagaaaaua uauaaggucu ucaaaaugug aauuuguuuu aaucacaauu 600
uaagauauag uuucgauuuu cuguaaaaca g 631
<210> 95
<211> 616
<212> RNA
<213> 智人
<400> 95
guaagauucu aagaacuuug uuccauucuu uauugauuuu ugugaccaug uaaauuaaaa 60
uucagcucuc uucuuuuuug gaauggaagu uacccuuuuu guugccaaaa uaaucuucug 120
aaaacauagc ucugaucauu cuuccuccug uagcucaccg cuguucacaa aauuauauuu 180
auaauucuua gccauguacu caaucugcua ugaaccuacc ugccuuucuu uucaaauucu 240
acucacugug aguuuagcua uaucuaacuu ccagaauuca gcucauauuu gccucuuuug 300
accauucugu uccauaugua ugaaaugaca ugucuuucau cuuuuaaugu guaaccuuag 360
cauauuugag cauuaccucg uuaauucggu caacacuuau ugaucuccug cuacgugcag 420
acauuuugcu agcuauugua aauacaaaua auaaagucug cauuuccugu cuucuuuaag 480
ccuucauugc cuauuaaauc auuacauuuu agauuagaua uuauauuuug aucauuugag 540
gaaccaaauu aaaaauaugg aauaaguaug gcauugaauu auacaugccu auugcuaaua 600
uauucauauu uuauag 616
<210> 96
<211> 2635
<212> RNA
<213> 智人
<400> 96
guaagucuuc gaaauguauu guaaaaauag gcaaaugaua agugauauaa ugaagauaaa 60
cauaaguguu ugcuaugcca ggcacuguuc uaagacuuuu aaguauauug ucucauuuuu 120
auccucagga cugcugguua cauauguuau cauuuucccc auuuuaaaga gaggauaugg 180
ccucaggaau gcuuaauagc augucugggg guagauggga aagccauaau uugaaacuag 240
ucagucugac ucaaaagcca auacaaauuc uuuuccagaa ucucauuuuu accuucuuug 300
agccucaguu ucaucuuauu uauuuauuuu uauuuuugag acaaggucug gcucuauuuc 360
cuaggcugga gugcagugac auaaucucag cucacugcaa ccuugaccuu ccaggcucaa 420
accaucuucc caccucagcc ugcagaguag cuggcacuac aggcaggugc caccacaccu 480
ggguaguuuu uuuguauuuu uguagagaca agguuucucc auguugccca ggcuggucuu 540
gaacucguga gcucaaguga uccgcccacu ucggccuccc aaagugcugg gauuacaggc 600
cugagccauu gcacccagcc ucaucaucuu uaaaauggaa auaauaauac uuacccuggc 660
ccuuucaggg ugguuauaug aaggucaaau uauaccgugu augaaaguaa uuugaaaacu 720
guaaaauaac auacagauag aaaacuuuug auuacacacu uauaagagug ucugucauau 780
aauagagauu cuaaacauug uucaaccacu uuaucagaac guagauuuua aacucaaaau 840
agguuuauag uuagguaguu ucuaaucauu auaauauuau cucuaugggc cuaaauuuua 900
uuaucugaaa aaacaugaga aaauugaacu gcuugacuua uaauuccauu ucagcucuca 960
agccccugcu agagucuuug auucuuuacu cacuuauuca aaugccucug acagaauuaa 1020
cacuauuuuu gcuuugcuaa ggagcugcca cuguuaagaa auuacucucu aaaagaaaga 1080
aaauuggcaa cagcauaugu guauuuucag ucucuuuucc ucacucuauu aaauuuugua 1140
caagagaugu uauuuuuggu cuaguaaauu ucugucaugu uuuggaguau aaaauuacuu 1200
gugcuuuugc aucuaauuug uggguguaga aaaucauaau cuuuugaaau accuuauaua 1260
auacauuuuu uugccacagg aaauacuuga aguuauuguu guguaccuua cgucauuuua 1320
guccaaaauu auacuugugu ucucugugug cauauuuuga uauguauuag gagauuaugg 1380
aucuguguga uuucuuaagu aaauccugau auuuucacaa uuugaugaug acucuuuaaa 1440
guuagacuua aguuuugcca aaagcaagaa gccucaaaga guaacauuug uucaugucuu 1500
aacacuaucu cccucuuauu ggucagaauc ucaguaugga ugcagugucc auaugcacaa 1560
caauauauua auucaguuua acagacuuaa ugcugaauaa gcaauaagau uaauugaauu 1620
aacuaaaucu uuugauagua uccacuucca uauauauagu uauagauaua augcuaguga 1680
auuugaacca uaaacaaauu aauaauacau gugauuucug ugaaaauuua uauuagucuu 1740
uucaauaugu caauauaggg caguauuucu caaauauaga ggaucaguuu uucaccauug 1800
ucccucuugg ggacauuugg cgaugucugg agacauuuuu gauugucaug gcucgggggu 1860
gcuacuggua uccagugggu agaaucaaaa gaugcugcua aacauccuau caugcacaag 1920
gcagccccac caccaacaaa gaauuaucca gucaaaaaug uuacuaguag uaugguuagg 1980
aaacuaucau auagaggaag caaucacauu uuacaagagc cauaauauuu aaaaugccuu 2040
uuuguucauu cucuguauau uugacuagag ucacaaaaua acuugauaag auuguugcca 2100
aaaauauuag aaacuagaag aaaaaugugu uguuaagucu aagaguaguu aaaugaaaua 2160
aagaauuauu cuucuuugga uuuggaugcc ugcaucaaga uuuagauugu aaggauacuu 2220
aggacugaac auuugcucua uaugaaauuu guauuaauca agguaugaau ugcagcaacc 2280
acucuauuaa uuacauaugu uuggccaggu gugguggcuc acaccuguaa ucccagcaau 2340
uugggaugcc aaagcgggcu uaucaccuga ggucaugcgu ucaaacuggc cuggccaaca 2400
uggugaaacc ccaucucuac uaaaaauaca aaaauuagcu gggccugaug gugcacgccc 2460
guagucccag cuacucagga aguugaggca aaaaaaucac uugaaucugg gaggcagagg 2520
uugcagucag ccgagauugc gcugcugcac uccagccugg gugacagagu gagacugggu 2580
cucaaaaaaa uuaaaaauua aaaaacacac acacacauau guuuauuuac aucag 2635
<210> 97
<211> 952
<212> RNA
<213> 智人
<400> 97
guaaguaaca acagaaaauu aucaacauuu aggaaaaaua ugugguagau ugcuuuuaga 60
gaagauuugu aaauuuauaa aagaugguag uauaaaucuc cguguuguaa uaaaaaguau 120
gagcuuuauc uuaugcuguu aaacaaggua uuuuagacaa ugcuguuuuu gugggcagau 180
auaguccaau uuaucuuuuu auguuuucgu caaucugauu ugugaauuau cuauaugaag 240
uuaggaaaaa ucuuaaugua cauuacaaaa auauaauaua uauuacauug uauuuucuuu 300
uuuucuacug gaauuuuaug cuacugaggc uauuuuuaac aaaugaacaa uuuugaacaa 360
uuugagggau ugagggaagu augauaauga caaaaaggga ugaaaaaagg gggucauaga 420
gauguuuuug ugagaaggag uuggucagug uauucugauu uauuaggguu uuuuuuaguu 480
uaucucagau uugaucuauu uaaauuguuu uagaagaugc ugguguuuuu cugugcuagc 540
uaugaaauuu auggguaaac uuuaagccuu uccuaguccu uuuguugucu accuaaauuc 600
aauuaauuuc auauggaagg auguaguaag ugaguaauau aaauaucuaa aauuggaugu 660
uugaaaacaa aacauaccug uuuuuuguaa uagcuugauu uaaugcugag uucucaaaau 720
cauuauuaag auuuugaacu uucacauuca auguggaaag aauugagugu aauuacaaaa 780
gauuuauuug aaaaaguuga guuguuaauu ugugaaauau guuccauuaa acucauaaua 840
uuuuagaaaa auaguaggaa guaauaaagc uuguuuauuu uuuauaucau auauucauau 900
aaaaugucag uuuuccuuua aaaauuacau uuuuuuuuug guuaauuuuu ag 952
<210> 98
<211> 1173
<212> RNA
<213> 智人
<400> 98
gugaacauca acacguguua auguaacaaa auuucugaua auuccuauug gaagagaauu 60
cacuaugaua uauaguaauu uuguugauga auagggaauu uauaaugcac uguugguggc 120
uagacauaga cacacacaug cauuuuucaa caauaagucu cuuuaugaua cucauuuacu 180
gauuaucauc uuggggauua ggaaaggaua ggccauuaug aacuacuguu ucuaaugaaa 240
uuaaauuuaa gaaauauuuu acuuaggauu uuuuuuaaga cuuuauuauu uuuuuagagc 300
aauuuuaggu ucacagcaaa auugagagga agguacagag auuuccugua uaucuccuac 360
ccugaaagug guacauuugu uaaaauugau gaaccuauau ugauacauca uaaucaccca 420
aaguccaagu uuaccucuau uuuagcucuu gguauuuuac acucugugug uuuagacaaa 480
uguauaauga uauguaucca ucauuauagu auuauacagg guauuuucac ugcccuaaaa 540
aucuucugug ccucucuucu ucauuccuuc cucugcaccu caccaaaccc cuggcaacca 600
gugaucuuuu uacugucucc auaguuucac cuuuuccaga auauguuaua gauggaaaca 660
uacagugugu ccccaucauu cucaccauag gacagcuagg aacuccuuuc uaguggcaua 720
cauauugucu aguauuguaa guuacccuuu uauaucuuau cuuuguaaac uagguuagaa 780
auuacuucaa gucagagauu uguucuguac uacucuuaug cuucauagug uuuaaaacgu 840
ugucauauau auuguuauau acuuguuugu uuaauuaauu cagccaaaau gaaacgugca 900
uauuugauaa aauuuuguuu guggguguuu guugaagaug aauugcuuua cacuaguuuu 960
uuuuuuuuuu cucaaagucg acuuuuuucc ucaagguaga cuugacauga auauggaaaa 1020
auauauguag uuugugguua uuuuuuuucu cuuguguacu uaaaaauuca gacugaauuu 1080
uucuuauaau gguauauuuu cuguuuuaug uuccuuuuau cauugauacu ucuugaagag 1140
ucaugaauaa uaccuuucuu uuucucuuau uag 1173
<210> 99
<211> 352
<212> RNA
<213> 智人
<400> 99
guaauuuuau auuuaacucu gauaaugucu gauuuacaau auagagguag uaguuuauuu 60
cuacuuuauc auuuuaucua ugguauuugu uaaaacugac uuucaaauca cuuugauuaa 120
uguaauuaau uucuuuugug acuucuauug uguuuauagu ucuagaguag cauauuagua 180
uguuguauua aaaugcagaa gcagcuacca gauuaucuua uguauuaagu gucauuuaga 240
aaguaugguc agugauagcu ucagaaaguu gcuauuauau aauugaaaua uuuacugucu 300
auuuuguuuu acauuuauuu guaaaaauau aaaguuacau uuuauuuuuu ag 352
<210> 100
<211> 5295
<212> RNA
<213> 智人
<400> 100
guaugugaag aaacauacug acuuauaugc uuaagguagu gacagaguaa guuaaauaca 60
uagcugauua acaguuaaua uacugccuua auuugaugac cuggcuguau uaauucugua 120
uuaauuuuga ggacuauaag caguauugaa uaacguagaa aagucuaagu uucuguucug 180
uaggaauuua gagucuacuu gaggagauac cuauaaugua acucuuauuu ggaaauuacu 240
acaucaauuu cauucaucuu ucugacauua gaguaccucu gaaguuccuu cacaccuuaa 300
cauauucaac uguguaucau uucucuccaa aguaaucauu uacacagguu ggugcuuuug 360
acuuuuggga cagaaagaua gacauuuuaa gauaccccac uuugacccaa auagguccuu 420
uuuaauccuu caggagacua ggcuguuauu ucagauagca aaguuauuug gaauaucuuc 480
aguauuugca guaauaauca guaaccaauc ugcucauaga uuaauucugu gggagaaauu 540
gcuuaaaauu uuauaguuca uaguaaacug uuuuguaaua aaaauuacug auugaaauaa 600
ccccaaaaaa aacuaaaauu ggcuaaaaug cguguaauua aauuuguuau ggacaauaaa 660
uuggagauaa cuuguuggua acauucaaaa uaucgaaagu gaacugggaa auguugaugu 720
uagcaguaau auuugccauu gaagaaaauc aguauggagg agcuaugguu aggaaaauuu 780
uuauuauaaa auuuacccag aaaauauuua augucuauaa aauaauuuca aucacaugaa 840
aauggaaaag aaaauucugu cuuuaaaggc auugaauaga aaauagguaa uggaauucaa 900
auuucuuaau agaguaugcu cccaaaauua uuuucuauga aaauucauua augucagugu 960
aauuuauuga cacuauuugc guggagucac aacaugcuug cugucagaag cuuugcuggu 1020
gaaaacugua agaucaaagu guccuuaauc uuuuggauuu ccaucuuucu aacucccuaa 1080
uuggggauag gccugaucuu aucccuaaau ggggauaggu uagaaacugg uauguuuguu 1140
ccuaacuggu guguuucuau accaguuucu aaccugauuc cuaucagaau guuuuaagag 1200
ccuuguggcu uugccuggac ucuucuaugc uacaguuuau uuaguuuauu uauucaguuu 1260
auuccuccuu aaagugggaa uaauacuauc uguauugcca guuucucagg auuauuuuac 1320
auaaaaugau augauaugcg gaagucuuuu guaagccauc acauccauag caguauaaga 1380
uauuacuacu aacuagaaag agaaaacagg ggucuaugcc caguauuaaa auuggcauuc 1440
aggaaucuag ugagaauauu uuuucagguu cauugcuugg gcauuucuaa uuuauacuca 1500
agaaaugcuu ucauauuguu uggaaauuuu aguacccuuu ucucuguaaa cagaauuugu 1560
agucuaccua uguaacaaaa cccaccccug ugccuugcau uucauucucc uuagcauuua 1620
uuacuaucuu aacauacuag acauguacuu gucuuuuguu caucuuuuuu uuuucuuuuu 1680
uuauuagacc auaaacuuug auggcaggaa cuuugccuau uuuauuuauu auuguauucc 1740
cagcaccuag aacaaucgcu ggcacauagu agaugcucag uauuuguuga augaauauaa 1800
auuuuuaaau guuauaauaa uauuauucug aaaucuaugc auacgaagcu uuugguacag 1860
aaaacaugaa aagagaacua cugccuuauc auccagucuu cuucccucuu cucauucagu 1920
cuagaacaua accuguuuug gaaaaaguuc ucaaaccaua uguuuaucuu gcccucaaac 1980
cauaacaaca aucaaugcaa aagacuucug ugacccccag aauauguggg gauuucucca 2040
caucagcaag caagcaguug guuuuguagc agacaccaac ugggugucgu ccaauucaau 2100
ucaucaucua ccuggagaua gugucagauc ccacagauau cuuacuucga ucaaaucaca 2160
aguccaggcc uccgugacuu ccgaaguucc cacaucccca gcccccagcu uuggguuuga 2220
uuaauuuccu ggaguggcuc acagaacuca gggaaacauu uacuuacauu uaccaguuua 2280
uaauaaaggu uauuacaaag gauacagguu aagagaugug uaagaagaga uaugggggaa 2340
ggggugugga ccuuccaugc cuuucugggg ugccaccuuc cucuagaaac cuccacaugu 2400
ucaguucucc agaaccucuc ugaacccagu ccucuugguu uuuagggaag cuucaugaca 2460
ucaguauuuc uucuccuagg guauggggca ggacccccuc guauuagggu uuuaagaccc 2520
acagucagaa aggcagggga agauuacagu ccugccuuag ggcaggugaa aggaggaugg 2580
gagaagguca gagagacucu uuucugaggu gugcucggaa ggccuaacac acucaauauu 2640
auaacuaaag augaggacaa gggcuaugag aguuauaagc caggaaccau ggaaaaaagc 2700
cuauauguaa uaacaccaca auacccaugg uaccauucac guuuguuguu uuucuguuuu 2760
ucaauuguuc uuucagucuu gguucccuua aucuuaauuu agcaaguaau gccagguggg 2820
auaaaauugc ccaaacccaa caaaguacug ugugcugcag gauuauuuaa ugacauaccu 2880
uauguccccc acuaguauuu acauuucugg gaguacagaa aaauucuugu acauauuuca 2940
gaaaaaauga aauuaauaac uaucaaccac uuagugaagu uuuuacuuuu uuuuuugaga 3000
uggaguuuua uucuugucac ccaggcugga gugcaauggc gcaaucucag cucacugcaa 3060
ccuccgccuc cuggguucaa gugauucucc ugcaucaacc ucccaaguag cugggauuac 3120
aggugccugg caccacgacu ggcuaauuuu ugaauuuuua guaaagaugg gguuucacca 3180
uguuggccag gcuagucuca aacuccugac cucaggugau cugcccgccu uggcccccca 3240
aagugcugga uuacagguau gagccaccac acccagacug aaguuuuuac auuuuuuaaa 3300
gggcacuuau uagcugaauu aaauaaggua aaaaauugac uaguauuaga gacaagaauu 3360
ggagaauaua guucucuagu auucgagaaa gucguuuuga uaggacaacu aaucuuagug 3420
agaauuuggc uuuauuucau auuuuuuuaa uuuuuugaga ugacgucuua cuauguugcc 3480
cuggcugguc uuugaacucu gggcucaaac aaucuuccug ccucggccuc ccaaagugcu 3540
gagauuauaa gcaugagcca ucuccccagg aauuugacuu uaaaccaugg uucucaaccc 3600
uuucagauuc aacauucccu uuaauaaaaa auauaauguu ucauaauuuc cccuuuacua 3660
uuauaauuga aaugcauagu uaacauaaac ucuaccuacu uacauaauuu caaaaauguc 3720
auuaugaaug uccuaaauga aauauauagg gggaacauaa aaggaauauu cauauuucaa 3780
cauguaaaug cuuuggcaug acuccauugg aaaauauaau gaacuaguca ugugcuugca 3840
ccuucauuaa ugugaguuca aagcuacgau ugcagacuga cacaaaugug uucuauuggc 3900
aacugauggg ucaugauggu auugccauuu guaauuugau uuccaaaaug guaaacaaau 3960
uguuggugca guucucagca aaacaauguc uauaaucuua ccuuuuauaa gacuguugua 4020
uuccuagaaa acuuagugua uaguaaaacc auuaaaaaau uacuuagugu gaauauguua 4080
guuggagaua aauucuuagc ucagaccagu guaagcagaa uuuuuuacug uauuaauauc 4140
caguagaaca uuugaaaguu guucagugca ugagacuauu cugcauugga uaggcuuucu 4200
uuggcuccuu uaucauaguu auaauaaacc augacaccua ccccugaaau gcccuaauuc 4260
ccuuccguuu cuuuuucuuu uuucuuuuua gcacuuaaaa cuagcuaacu uacuacaaaa 4320
uagauuuaga uuuauuucuu guuuuguuau cuguaucguu ugcucccuuc uccccaaucu 4380
aucuaaccaa cuaguauaaa cuagauagua agauucauga agauacacuu uuuuaucuga 4440
uuuuauucau uuguucuauu ccuauugccu cuagaguagu acuuggcaca ugguuagcac 4500
uaaauaagua ccugucaaau gagugaagua augugcauug aagacuugaa ggggcucuga 4560
ugcuaggaaa uugucauggg auaauagaug agguuggucg uuuguacaga ggauucuugu 4620
uagaagcuua cucuagucau gauuguauua gaaucuucau uuaaaggcuc cugaagggug 4680
uuggcauuag ucagaacugu cucccagaau uuuauuuguc uugugauaga auaaagcaua 4740
guuagccuaa agagcaguuu uccuaauagc ucggcaugcc caaagauucu aggaguuaua 4800
cagguugaac aucuaaucca aaaaucugaa augcuccaag auacaaaauu uuuugagcac 4860
caauaugaug ccacaagugg aaaauucuga ugugaccuca uaugaugagu cacagucaaa 4920
acacagucaa aacuuuguuu cauguacaaa auuauuaaaa aauauuguau aauacuaccu 4980
ccaagcuaug uguagaaggu guaugugaaa cauaagugaa uuuuguguuu ggacuuggga 5040
cccaucccua agauaucuca uuauguauau gcaaauauuc caaaaauauu uuuuaaaaaa 5100
auccaaauuc uaaaacacgg cugguuccaa gcguuucgua agggauacuc aaccuguaua 5160
gcaaaaugaa cauauuuaca uauucucuag gaaauauuag uuuacaauuu uucuaggcaa 5220
auuauaauug auaaaucaua aagaaaauuu aaaauaacac ugguaauuuu ccuaccuccu 5280
ucguuauugu uacag 5295
<210> 101
<211> 331
<212> RNA
<213> 智人
<400> 101
gugaguuuaa auaucauuau aaaacuaauu auguguaaaa uccuuuagug accuggaaau 60
uauauagcuu uaucauaguu gauaauauga gaaauggucu aguuuaaaug aucauuuauu 120
aucuaugauu uacuuacuuu uuauuuucuu uaaaaucugu uuuaaauaua uuguaacaau 180
uauagaugga uuuuccugug aucucguugu aaauuagcuu augacaaaua uaggguguua 240
caauuauugu aauuugguuu gguaaugagu augcaauuga aaagccaaac acugaauggu 300
auauuucaug auucuauauu aaauuccaca g 331
<210> 102
<211> 2648
<212> RNA
<213> 智人
<400> 102
guaagcuauu auguggaaau gugccaccca uuguaaugaa aaacugguug accccuagaa 60
auugaaauaa uaaaugugug uugucuuaag cuuggguuau guuuucuuuu cccaugugaa 120
uugagauauu ccugguucuu cauaugccac auaauuuugg uguauuuuug aucuuuugaa 180
uauuauauug ugagacucug guucuuguuu aaauucuaug ggaaaaugua gauacuuuug 240
uuuuagcaug caaucggucu aauuagguuc aggccacaag uuccaaccuc auuucuuggg 300
cugugguucc auuuuucaaa gccuuuucaa uacucuucag aucuguccug ccuguguacc 360
ucacaauagg ugaucuggua ugugagcuau guaccauuag uucaguucuu agaaacuuug 420
guauucugau uaggaucgau ccauacauuu gcagcucaag agugagccca gaaguucaua 480
aacaacuuua uagggucccu uucuugagcu ccucccucuu ugccaucucu cugauacuuu 540
guuucccuag ggauuuccau uuggggcuuu aguuacccag ugaugccaug uacuucagga 600
auugcacacu ucugcagcca agcaagcaag aggagaguag aaagaggaag aaaaaaacga 660
cuuuuaccuu acccucuuag uaucauagcu cuaccaauug gagauuuccc ucccaaaaaa 720
uauuagcuuc ugugaguucc cauugcagcc ucuauuacca cugcuauggg auggcuuaag 780
gguuggggca ugaaagaaca gauagaagaa aaaaaaagug agguguuuuc auauugucuc 840
uugaguguua aaagauuccc uuucucuuua cucgagcuag aauuagaagg uuuaccugga 900
gcucucucug ucagugcaga cacccaucuu cagguuucaa auaauguugu cuucagggca 960
ggcaguaaca gaauaaaaga aaagguaaau ucaucaccug uuugcugcua cuuuaagucc 1020
ugguauucua uuguaaucug ccuucuacuc cuuugcaaag uccucaaaug guugcuccau 1080
gcauuuagga gagagaagau ugaauguauu uacuccauug uaccuggaac cagaugcccu 1140
ugcccugcau caccccaugu cauuucuuag cagagccuuu gagauuuuug ugugugugug 1200
cuuuacaauc ucuuuccaag uuauaucuuc ugauacaguc auggucguga aaagcaaaau 1260
aaaaucaugu guuaacauuu aaaacuuuuu aauuuuauuc ugacaacagc uaaaacuauu 1320
uaaucuucug uuucgcucau uucuuccaag guaaacuuca guugguuuua cgugauuugc 1380
uauuucuucu ucuuugcauu uacaaaugau cugugaucau auuacugauc uuuguaaagg 1440
gcuaauaucu accugcaaca uuuggauaug acaguauuua cccuuuguaa auacacauuu 1500
ucuauuuauc uucaaaaauu accauucauu agucuguguu aaugucuguu uacuauugug 1560
ucauuaugaa ugugauguga acauacgaag uugaacuuau uuaaacgaac acucucauga 1620
gcuucuaauc cacauuccuu ccuuuuccuu cuaaguuacc auuucuuaaa aaucuuuuag 1680
aaguuuccuu gauagggaaa acacaaauua uugaggaauu uuucuuucuc uugacaucug 1740
uuuauaguua cucucuuguu ccagcagugg auauuucccc uccauguuuu ucuuugucua 1800
aacauauguu caaaacaaaa cacuuuuauu cuucuuugca gguuuuacaa ggaucaacuu 1860
uuaguuuuga aaccugcuau uacuuuuaga ggccauuuuu uuuuucucua auaaugugag 1920
uucaugcggg cugaaguaau uggaauacuu uauagaaaag auugaauuug ucuucucucu 1980
gaacucuagu uugaauuucu aaauuuuaug aaucaucuag auauuaaaga ggaggggcau 2040
aucaaagagg agaacccuag cagagauaag aggcaagagu aaauguuuca uguaugggua 2100
agaguggauu uguauuuacc uaaguaaagg uagacccugg acaauaaggu uggauagaug 2160
uggagguggc aaaccaugga gggucuugua ggucaagugg auguuuuuag acuugaagug 2220
uuaaauuauu aucugaaauc auuaagaguc uuuuuagauc cuugagcuuc uugagaagac 2280
cauggauauu augcaguuau uauauaaugu uuuaaaauag uaaguauuuu aguuuaacug 2340
ucuuauguaa uuccauauaa auggaugcau guucuuuaaa aauguuaaug uauuucagua 2400
aaucaaaaua uacuuuuuga cucaucauuu aaaggaggcc uucagugaau gcucuguaga 2460
ggauuauuuu auaauacuaa uuuugauauc cuaauuuauu uguuauaaag uuuagaaggu 2520
uugaagaauu uaaaauauag uguuaauaaa cacacugaac uuuucuuuuu uuaucuugua 2580
uuuuuauaua guacaacaga aaaaagauga aaugugaaua guaaagaguc ugugauuguu 2640
guucauag 2648
<210> 103
<211> 4406
<212> RNA
<213> 智人
<400> 103
guaaguguau aucuuuuauu auuuuuuucu uuuuuccaug uuaaaaugca ugaaagugaa 60
aucaacuucu uucuuaaucu ggccaaaagc auuacaucuu ucucauuaau aguaauacag 120
uaaauucaac uuuuauuuuu aacagguagu gauguguaau aauuuauuua auccuuuuua 180
acauaauaac aguaaacuua agauucuuaa gcuuuucaua aagcucauaa augauuucua 240
gaaauuuuaa auauguaguu aucauuaugu auuuugcugu agcagcagua uacaguuaaa 300
uaaaauagga aaacauguuc caagacuguu uucauucaaa uauuuaugcu auauuuuuag 360
cuuauaaaaa cucauuaauc auuaauguaa aauuauuugu uggauuuuuu aaauauuuag 420
uguauuauuu uuguuucuuu uuucuuucca uguuucuuca uucuuccacc uuaagcagaa 480
ucaggugugu gacacaacua uguuuucuau ccuuguuacc auuauuaaua aauacaaggg 540
caugauauuu uucacaaaag aaacacuuug uucagaacca aaaaagauca uggcaacagu 600
cagaauuaaa aaugguaaaa gacuaggugc caaagaugac uuacauaauu ggguaccuag 660
aaauauucua ugguauuaca guaaugauga aaaauacaaa uuagaacaca uuuuagaucc 720
uauugaguua aauaaaucag agucaagacc aaacaauaaa uaaagucaau uuacgucaac 780
aaaugguaag uuggcagauu uuaacucccu uuuugaaaau gaaccaugau ccuaagguug 840
guaaaauuaa ucaagaaugu ugucaaaaug auaaagauaa aaaugaggaa gagaauaaga 900
uaggcaagag ugagaaagga aagagacaca uagcugaaaa ugugagucac aacaacuaca 960
uagauccgua gaaucugcua uggaggacug ugauuaugug acaguugcug augccguggc 1020
uuagugagcu gagggugaug cacaggcagg cgauguaacu gaugcgucag uccagccaag 1080
aaaggacgcg ucccugguuu ggcuacgugg ccguccuuua uuucuuuguu aacugaauuu 1140
ucuuauagua aguagcuuac guacauauau agugcaaaug ggaaagugug uaagauuuag 1200
aaaaagcauu aacuauuagu aaacuuuauc uuaagcucua acuuuugauu aguuccuaca 1260
aaaauuagug aauaugcauu uucuaauuua gugcuuuuuu uuuuuuuaca auugguguuc 1320
acuuaauguu auauuagaua aaugaauagc aaaaauaagg uacuuuagag uugauuguuu 1380
ugccuuacaa acuucuaauc cauccagcug uauuuagaag uaagaucuca cuacagcgaa 1440
uuauaucagu aaaauuuugu uacaguguug ugcagugucc uaagauguau acuaaguucc 1500
uucaguggcu uuuuuugcca uguuuuauaa cagauaauuu uguuauaaug agaaaaggaa 1560
acuuggaugu guugcugucu auauuguguu aggcucaggc aggaugcugu ggcuuacuca 1620
uuuaaucacu uugggaggca ggggcaggaa gauugcuuga ggccaagagu uugagaucag 1680
cuugggcagc auagccagac ccugucucua caaaaaauuu agacagaugu gguggaacac 1740
auuuguaguc cuagcuauua gggaggcugu ggugggagga ucauuugagc ccaggaguuu 1800
gauguuacau ugcccuauug cacuccagac ugggcaacag agugagaccu gucucuaaaa 1860
uaauaauaau gauaaugaua aaugguguua ggcucugugc cuaaguauau uuuucacaua 1920
ggcuggguaa aguggcucau gccugcaauc ccagcacuuu gggaggccaa ggcagcagga 1980
gcauuugagg ccaggaguca aagaccagcc uugagagacc ccaucucuac cagaaaaaaa 2040
aaaaaaaaga aacaauuagc ugggugugau ugugcacacc uguaguccua gcuacucggg 2100
aggcagaggu gggcagauca cuugagccca ggaguuugag guuauaguga gcuaagauug 2160
ugccacugca cuccagacug ggcaacagag caagacuguc ucaaacaaaa acaaacaaac 2220
aaaaagcacu uugcagaaua ucagucuaac ucuacaguuu auggacuuuu uauguacgua 2280
cuacuuuugg cuagcuuaca uugagauaca gaauaaaagu uuguucauag cauuuaucgu 2340
uuuuuucuuu auacugucca ccugagauau uccagucacc uaagucaugg aaacaucaac 2400
uaaaauuaaa uaucuauguu aagagaaaau ggcugaaagu gauuuaauuc auaacacuuu 2460
uuuucacaug cuaauaaaua agaguuugag acuuccacua ggcauuaucu cuaacuccua 2520
uccacuaaga auuugauuuu aaguaguuga uggcuuuuaa ccggauuauu cuucuguaag 2580
aguuuggaag ucucgugaag uucguuauac aagaauucug uuuacaagag agcauuacau 2640
uagaauuugu uuuucagaaa uuuggacuau cucaacgaau accuuuaguu uuauuauuuc 2700
aaaaugcaag ggaaaaaaug agccauaauc acuaauagua acugcaucau auuuuaguga 2760
gaaauguguu aaaaauaucc ucaugugaga ucuuccuuag auagaauuac ccucuacucu 2820
aauauuuaau auauuuuaua ucuaccaauc agugauauua auagguguuu aucauuugcu 2880
gaaucaaaua gguacaacag aagacaggaa guuugggaga uagaagagcu cagggacagg 2940
aaaucacaga uguccauauc ugaaauaacc uuaaaaguua uccugucuaa ugccuucacu 3000
uauaaacugu agugguagaa uuugccuagu auuaaccuaa uagugguaga uuugaaugua 3060
uacuugggcu uucuuauuaa guggaaaugu auuccuguga uuuacauaua ucaacaaaaa 3120
uguuugucuu cuuuuuuuug cuacgacaua ugugcaugug cacacacauc uccucaaaca 3180
aaaaucagau ggacacaugc agucauugga ucuaaaagau guuauaaagu uguguauaau 3240
agguauuuua uaauaauaua uuuuaagacc cauaaugucg guggaguaac ugacuuuaca 3300
gcccaucaag ccaauagaga gagaaaggag aaaaaaauga aaguugugcu gaauaauuaa 3360
aaaaaauuau uuccuaugau gcuuauaaca guccuaugag guagguggua uucuaauuua 3420
uagaaaaaau gcauagaaaa auauaauuaa gcacaguuaa aaaaaauaaa guuuagaaug 3480
agaaguaaca acauaaauaa ugacccaaug uagauucagg ucaaaagaaa ugaaaauaua 3540
auauuaaugg uuuucaaaga gggaaccauu acuuuagcuc aaagaaugaa ggagggcuuu 3600
ccgaaggagu aaagaauuau ggcaguucuu uuguagccua guguauucau uugcuaaggu 3660
ggcuguaaca gacuacuaca gauuuggugg cuuaaacaau agaaauuuau ggucuuaguu 3720
cuggagaccu agaaguccaa aaucaagaca ucagcagggu ugauuuccuc ugcacaauca 3780
gagggaaaga ucuuucccaa uccucucucc uuggcuuaua aauguccaug uuuucccugu 3840
uucuuuuuau caucuuccuu cuguacaugu cucugugucu aaauccccaa auuuucucuu 3900
uucauaagga uaccagucac agucgaauag gguuuacccu gaaaucucau uuuaacuuga 3960
auaccucugu aaagacccag ucuccaaaua aagucacauu cugagguacu ggaaauuaug 4020
acuuuaauau auaaaugugg aggguaaggg gaacacaguu caacccauaa cgguuagaua 4080
acaaucgugc uuuauuuugg acuaguaaaa ccaccauaga ucaguuuaac cauuaugaaa 4140
uuauacauga aggcauuaua uguauggaca uuauuaaguc auacuugcuu ugcuuccauu 4200
guaauuaaaa caaaccauac uaccuuuguu cugcaaguuu uguauucuaa cuuauuuauu 4260
uuuggcuuuc accagaacac uccgauuuuc ucauauuccu uugaggaaaa aaaguuaccu 4320
uuugacagua uuuucuuauc caguaugucu uuuauggcuu uuauuuauua aacuuuaaaa 4380
auauuccuaa uuucauuucc cugaag 4406
<210> 104
<211> 1202
<212> RNA
<213> 智人
<400> 104
gugaauuuaa uguuuuuuau uaggaaaucu aaugccuaaa acuccuuccu uaguuguuau 60
guuuacuuuu auuagcuuau uaagaaguca aaaaugcaua uuccuaauau aucaugguga 120
ugguauacuu uauacauuug cucuuuagca uuuauuuguu gaaggccuac uuuauauuaa 180
acacuccucc agaugcuggg aaacagcagu caaaaaauuc cuuauacuca uaggacuuac 240
guucuagugg agaagacuga caauaaacaa gucacuaaau aguaugucau cugauguuag 300
ugcuaaggag agaaauaaag caugauuggu guaaagagua uggggagaga gaaggggugu 360
aacugaaaau agaguaguaa gggaggucuu ccuuaauaag augauauaug aacagagagc 420
uaaggagggg uaaaggaagu gagucauaca gauacuagaa aaauaauuac agacaacaga 480
aauagcaagu ucagaugucc uaagguggga ggaugcgugg uauauuucau uaaaaauuau 540
cacacuguaa aauauaagaa uaauuuguuu cuuuuagaaa uuuuacuuua uucugauauu 600
aauaaugauu uuuuaaucuu ugguuuucca agucuuaccc uauuuauggg aaucuuuuuu 660
uucuuuuggc uagcuaauug cuucaguuuu guuuucuaau cuagaauguu agcaaucugu 720
uaauuccacu gguaaugaua uaguuaagcu augucuugcu ucucacacuu uauuuauuua 780
uuuacucagg gcacuaaucu gccauuuuuu cgcacuuuuu uuccuuuuuu uuuuuuuugg 840
uacugcuucu uauucugguu uuuacauuga uagaaccaau guuagacguu cauuugccuu 900
uugcugugua uauuugggua aggaucuaua ugugcaauau augggacagu uaaaaucaga 960
auucuaaauu uguauuauug caucaggcaa uaauguggga aauaccuuga cauuucauau 1020
acacaauauu cuuguauuaa uuuaacgucu uaguucaaaa ucuuccuugu uaauauagag 1080
acccuauuau uugguuuggc aauacaguug aagagauuga ugguucuuau gaauuguuug 1140
ccuuuucuuu ucaauggcug uagcuauguu aaauuauuac auguuugcuu guuaucuuuc 1200
ag 1202
<210> 105
<211> 1697
<212> RNA
<213> 智人
<400> 105
guaugugaga auuuaccaua cauuuguuuu gguuucagca gugauaagcc agaaaugaaa 60
aguuuagaua uguuguaaaa guacugauau gccucuacaa gugcccugua guuucagugu 120
uuauucugca ucuguaauau aaaacaguaa gcauuucuau gugucucaaa guauuuuauc 180
aucuguuaua ccuuacauac uuucaucucu cuuuuuauug aauaugccuc cauaccuuga 240
aaacauuuaa cuuccaggaa uccuuuuguu uauggaggua acugcuaacu gguccuuggu 300
ccaaugcugc cauuuuguaa ccauuuguua ugauaucuuc ccagcuuggu auaauguuuu 360
auaauuacau uguuccuccc ccucuuuuuu uguguucuug uaauuuucuc ccuauguuau 420
uuuguauuca uuuuauauaa ugaauaaaug uugcuuauga ggucaaggcc aaagacuuaa 480
gcuccuguug auuucauguu gcugaguguc auaaauggaa gcaaucauaa ugcagaguca 540
uucugguagu aauauuaaau auaugaugga uucagugaaa auauuaugug uuauuagaaa 600
aauauucaga acaggccggg ggcaguggcu cacaccugua aucccagcaa uuugggaggc 660
cgaggcgggc agaucacugg aagucaggag uucaagacca gccuggccga cauggugaaa 720
ccccaucucu acuaaaaaua ugaaaauuag cugggcaugg uggcucaugc cuguaauccu 780
agcuacucag gagguugagg caggagaauu gcuugaaccu ggcaggcgga gguuacagug 840
agccaugguc acacaacugu acuccagccu gggcgacaga gcgagacucc aucuuuuaaa 900
acaaaaaaaa aaaaggaaaa auauucagaa caguaucuug cuggcagcaa cauuuguuuc 960
aucaaugaaa auauguguua auuugaccuu uucuaucuaa guuaauuaug aaagugcaua 1020
cuaaaaugau guaaaaguuu auauuucagg auuauucuua uucauggaug auuaacuaaa 1080
augcaaaaag aaauuaagca uacuguuugg cuaaacuguu aaaaauuauu uuuauuuuaa 1140
augauaagca guuaaacuua uuaagugaug acucaucucu gcugauauau uuaugcaagg 1200
uuuuuuauuu cagauaacuc uucuauuuau auuaaacaga aacuguauuu cuaagcaaua 1260
gcauuucuua gagaaaauug ccucuauuau guugcaauua aaauuuaauu acucaugagc 1320
ucuuuaaaga cacaauuucu cuuguguggu uuuauuucau auaaagaaaa acucugauau 1380
acuggagaga acauuagcua aauagacuau uuagacuuaa ucauuuugau cagacaucaa 1440
ggcuagacua uuuaagcugu uacuuauuag cugcaugauu uuaggaaugu caaauuuccu 1500
aagucuuggu uuucuuguau uuaaaaugga aauuauaauu ccuaucucau agaauuguuu 1560
uaaggaugaa uugaauuaau acaguuuuga cuucaaauau uaggaauuau ugaguauaau 1620
aagccuguug uauuguuggu acuucguauu auacuuacua aaauauuuga uuaaagauuu 1680
aacauauucu uucguag 1697
<210> 106
<211> 809
<212> RNA
<213> 智人
<400> 106
guaauuuuuu uuaaugugau cauuuuuagg ggaauauuuu acguuuuguu acuauuuagg 60
aaaauuucaa auaugcucau uacuauauaa aauggcuuua augaauacaa uacauauuuu 120
auaaauauag aaaaaaacuu augagaggca aggcuaaggg uuauagagua ggucuaccug 180
aucuuucuug uuauuucaag accaauacuu uucacuuuuc ucucugacag cauagauuaa 240
uuaccugugu cucucuuuuu uuuuucuuuu gagauggagu acugcuuugu cacccaggcu 300
ggaaugcagu ggugcaaucu ugacucacug caagcucugc cucccggguu caugccauuc 360
uccugccuca gccuccccca guagcuggga cuacaggugc ccaccaccac gccuggcuaa 420
cuuuucguau uuuuaguaga gaugggguuu caccauguua accaggacug ucucgaucuc 480
cugaccucgu gauccgccca cugcggccuc ugugucucuu ugugaaaaua cagaugccca 540
agcucccauc ccugaaauug auuuaauuau uuuagggugg guccugacac agauauguau 600
guuguuguua uuuuaaguca ucaauuuauu cuaauaugua gccaacguug ggaacuucgu 660
ucucacuaau auucaaauga agacuuuaau ucuaaucaua ucaaauaugg uuucuaaaac 720
uacuuugaag auuuaugagu uuauaagauu aucuuuuauu uccuuguuuu gauaauguau 780
acuuuuuauu uuguuuguuu uuuuacuag 809
<210> 107
<211> 877
<212> RNA
<213> 智人
<400> 107
guaugacuuu uaugacugau uauaacuuuu gauuuuuauu uuacuuaaua ccucuuggaa 60
aaacuggaag uagauccuug augagagugu cuguaaaggu agauauuaag agauugagga 120
auuguguuuc uaugccugcu gucaucacau uccaccauga aaaacauuga uaauaaaagu 180
uaauacauuu aggcugggca cgguggcuca cgccuguaau cccagcacuu ugggaggcca 240
aggcgggugg aucacgaggu caggagaucg agaccauccu ggcuaacacg gugaaacccc 300
gucucuacua aaaauacaaa aaauuagccg ggcguggugg cgggcgccug uagucccagc 360
uacucgggaa gcugaggcag gagaaucgcu ugaacccggg aggcagaggu ugcagugagc 420
cgagaucgca ccacuacacu ccagccuggg caacagagcg agacuccauc ucaaacaaac 480
aaaaaaaaga aaugaucuac guugcuuaca cauaccuuau gcuuauagcu aggucucgua 540
agcauuagga agucaaaaca aagaaucuuu uacaugugua aagguauaaa cuaucccauu 600
uuucuaaaaa uauagaggaa caaaguguca aauuuaaagu aaucacuagu aacuaaauau 660
auuccucuga ccucauuuuc gugaucuguu guucuaauua uuauuggcca uauugcugcu 720
uuaaaggaga gauguugaau uuguugaaau uuuaaucagc auuuagagcc ccagguuauu 780
uuuguuuucc aauuuguaau gauaauuuug aauacacuga aucuaugaga acaguauuau 840
guuuucucau aaaauacuaa uuagcauuua augauag 877
<210> 108
<211> 3130
<212> RNA
<213> 智人
<400> 108
guaggaacag aguuuuaaac uuguacaaag uuuaaucauu ucaaauuuug gcauuguuuu 60
aaaagacaac acuauucugg auaaccuggu uucuuccuga ugaacaguuu guuugguugu 120
uguuuuaaca uaauacuuuu uuucuguugu aguauuguug gagacuuuuu cuuccuugaa 180
auguuuaacu uguuuaaccu uguuugggug gcagggcaug gaacagugua gagcuggggc 240
ugggcgaagg aguuggagcu gugugugcgu caugaagcug ucaucagcua ugagccuggg 300
cugaggcugc ucagcuucuc cugggugcua uuuuucucca acugcagcuu cagcuucuug 360
auuguauaau uugcuuccuc aaguaugagc caggaauaau ugagcugucu ugucacaaug 420
uguggcauac uggaucuagg cugugcugca augcuuuuag aguuauaucc ugggcaacuu 480
ucucuucaga uagccccaag agaugaauuc agcaccagcu uugauguuuu acuagcuucu 540
gcuuucuggu acuugauuuu cucccacccc gaacacaugg gauuccaacc ugugaaacua 600
auuuuugugg cuaugaaaga gguaguggua guuuaugagu aaacauucag ucuguugcca 660
cuaucaucau gugugguuca ucaugacugu gaugaguagg uaaaaggcuc uuugugucau 720
ucucauuucc aauuuuaagc agcugcuuca aggagucugg aagucauuga ccagugggau 780
ccugccugug ucuuuuccca uuaaagccau ccuguaugaa gugguauccu uuaccaucua 840
gcacaucugc cgcccccauu ucaaaaggca uacucaucuu uaucucaaca uucucauaca 900
guuccuuaug uccaugcacc uccaaugucc ccuuugaugu cuuugagguu uucaucuucc 960
augucugcua uuuggaaugg ucuugauggg aggcaagaua gugaucacua caacuaggau 1020
gggagucuua guaccgugag gcuacagcaa gucccacaga gggccugcug cacuguacuu 1080
gccucuguca accaagucua aggagaaaga uuaagcaggc auauuaaagg acagcccaga 1140
uggacaugaa guccuggagg aggccuuggu uccuguccua auacuaaacc uagaguaccc 1200
agaauccaca cuucuccacu cuagcucuca cuuuucccau cuacacacug ggaaaaauua 1260
uucugucaga aagccagugu caaggugaga acaaauaaca aaugugauga uauggagugg 1320
gagaaggggu cucuucuacu gucuuauugg acccuagcag uggcucugag ccagcagucc 1380
ugucaguuga uuucuugguc guuccuuugu uuucuucuau aaucacaugu ggacucagaa 1440
ugaauuuuga guuacucuga aaucuauuua uucaacagau auuuacuuag uaccuccuau 1500
ugccagacuc ugcuuuaugu uggauauuau uuuuuaaaag cccaccuugc cuagauuucc 1560
ucaaaggacc agguggcuuc ccugguuuug aaagacccua auucuuacua ugaucuuaag 1620
uaaauuauau ccuuucugug ggcucaaguu cuuucuaaga gggcucuuug gggcuacaaa 1680
agaaauuguu agugcaaaaa gaguuuauaa gguuuauaaa ugguuaguag aggugaugau 1740
gauauuuaac cauaauugaa gaugacuuug cauuuuagau cauauacgug uuuuucgucu 1800
gagaacgaua caggucacug agcauaccau aagccuucag uaaaucauuu gcagaagaca 1860
uugcagaaga cauaagucua aguagaaauc ucuugacaga gagaaggcuc guuuugaucc 1920
uugaccucaa auuuagguuc ccuaaaucca uuaaaaaaga gaaagaaaaa gaaaaaaagu 1980
uacuaaaguu uaaaucuggg aggauuauau acccuucuca auaaagcagu uuagagagau 2040
cucuuuuggg acccaugaca caggucuugc ucaugcugac aucuuuauag uugcuuuauu 2100
auuuauucaa caaacuuagu aacacguauu cuaugucagg ccuuuuccug acuacuggga 2160
caaaccaggg ugaugugggg gcuguuuuag auagggugau cagaggaggc cucucuguuu 2220
ggguggcuuu ugaauagaaa auuagaugaa gugaaggagu aagcuucuga uauuucacug 2280
uuuacuugug guagaucugu gauaaucucu gucagguuaa aaacauuccc uucuaaucua 2340
aguuucuaag aucuaucaaa agcuguuuga auauauuuag acaaucauaa uuuuccuuuc 2400
uuguauuauc cuagcagauu uuguugccaa agcuauacug gccauuuuaa cuuagaaugc 2460
agucuuucua uucauuucuc uggaaaaguu uggauauugu aagcauuauu uuucuuuagg 2520
uaugaugaac cugcagaacu guuugguuca auuaugaauu uuuuuuuucu ggagucugua 2580
uuuuuuugaa cuauuaauca uuucuuuaau gauuauaaau cuauucagau uuuuacaagc 2640
uuuaucccuc ucccaucaua cacuauuuuu cuuacccaug cuuuugcaca auuuuuuccu 2700
cucccuuagu guuuuccuac cuagauaccu ccuaugugug ucuguguaug ugagaaaagc 2760
uuuuuauuug ccaucuuuau auuucuaaga auaucuagua auacagaauu uuauauucug 2820
aagaauuuua cuuugcauuu ucuuauuuug ugauugaaaa aagguauuaa uuuuaaaaug 2880
gucaaaucag gcuccauccu uggaaaauac ccaaauccuu uauuuugauu gggccaucug 2940
uuaauuaggg auaccuuauc ucuugccacc acuuuuuaau gcuaaauaaa uauguagcua 3000
aaacuuugac uagaagaaac aguaaaauaa gauauucuug cuuauuuuua guacaguuau 3060
uugaacugac uuuuaaauca gugacauaaa uuauuugcca ugucuauacu uuuuuuccuu 3120
auacuuuuag 3130
<210> 109
<211> 1162
<212> RNA
<213> 智人
<400> 109
guaaguaacg uaauuuuucu uuacaugaua aaauaaugca uaauaucgca agauguuccu 60
ugcauugucu uauauagaua aaaauggacu cuauuaagaa gacccaucua acugaagggc 120
accccauuca cccauuugcu uaagccagaa acuuuggauc aucaacgacu ucauucuuuu 180
cauucuccac auuuucuauc auuaaaucau gucagcucua uuuucaaacu auauccuaaa 240
uaugaccacu ucuugguauc uugagacauc acuaccaguc uuguccaagc uauuguuuua 300
uaccugaaua acugcaauaa uuuccaagcu gguaucucag cuuccacucu uggauuauuu 360
cacccuauuu cuauuucugg gcugucucca cacaguugcc agguaacccu uuuaaaacau 420
aaagcacauc acaaagcaca aaguccuauc cucagaaucu uccagugguu cuccaucacc 480
cuaaaauaaa acuuaaaagu ucuuuucaua ucccaaaaca acauaugagg ucuggcaccc 540
aguuuucuuc ccaaucucau cuucuacuac uuuucccuuc auuucauuca caauguuuua 600
accacaguaa ccuucuuuca guacuuuaaa caauccaaac ucguuuaagc gucaaguccu 660
uauacuuguu uccuuuguuu agaauacugu ucacccaaau auucucauag cuugcuccca 720
gacuucaugu cucugcugaa auagaggcuc cuuagagaga ccuucccuaa cccuaacccu 780
aacccuauac uacuugccau cacucuuuau ccucuuaccc uggauuauuu uuucuugaua 840
gcucuuccua ccaucuggca cuauauuaca ucauaucaua uuaaacacac auucuuugug 900
cuuccccacu aaacaaggac caugcaagau ggaacauugc cauuuuguuc acugcuguua 960
gccucugugc cuaggacaau gccaguuaug caguaguuac ucaauacuug uugaaugaau 1020
ggugaauaga acauagaaau uugccuaugc gugcuuuuga aaaccauauu uuaauauuac 1080
gcuuuguuaa aaauguguau cuuuauaaau ccucauauuu ccauggcaaa ccuuaucuuc 1140
uaacuuuuca uuguccucaa ag 1162
<210> 110
<211> 593
<212> RNA
<213> 智人
<400> 110
guacaucaug uauucauaug acuacuuugu uuuuuucuuu aaaaaaaaaa uuauuaguuu 60
uuauauacuc cgaauugcua caacuagaga caagcauuuu ucgacuuuac ugccuaacag 120
gcuuauuagg uccuuauuuc uucccucuaa ugcuaaucac ucuuuuucau aauacacacu 180
agaaaaaaag gauaaaccca acucuaaguu uccaguuugu aauuuaguuu aaacuuuucu 240
aagagcauag aaugaguuaa accuuagcuu cccagaggaa aauacuaaug aaagagaaca 300
aguaauuuuu uuacuuucag gggucucugu agccugcuuu cauuaagcuc cucuuauaac 360
gaaaccacac uugcaaaugc caucagguca gauauuaaga aaaacgugaa ggcuuuugua 420
uuccaggcuu uuuguuugag aauggugaca uuguagcauu gagaguaaau guuuacuucg 480
auaaaggcua gcuuguucug auuacuguac aucacuaguu cauaagaaau gcccauauau 540
uuuaugaagc aauaucugcu uuauuuuuuu aacacauuau cauuguguuc uag 593
<210> 111
<211> 3218
<212> RNA
<213> 智人
<400> 111
guaauguauu uuaaaaaaca uguuagcuac ccccaaguuu uugaauuugg guuugccuuu 60
uuuuuuuuuu uuuggcucag auuucugauc auugucuccc uguaaaaucg aauuccugau 120
aagcuuuggg ucuuuugucu cucugugcua uuaauauaaa aauauuccca uuuuucucuu 180
uguguuguuu auacuauaga guagcaagua cccaaguguu cuucucuuug uucuccaucu 240
ggguguuaca gauuuaauca caauacagug cuaagcaaug aauacuaaau cuguugcuuc 300
caguuucuaa guauaggcuc uuucaagucc ucugaacauu uuuaaaaacu gcaaauaagu 360
aaauacugcc uauauuuuuu uccguuuaca aaguaaaaag aaaaucuuuc ugcucccuuc 420
cauucccauu caaaagugau uacuaaucau uccucauucc ugcauauaca uacacacaua 480
uuuuguauac auauauauca cacauaugca uacauguguu uguauguuca uauguacaau 540
guacauaucc ucauuauuug uggauucugu auuuucuaaa ucaccuccuc acuaaagugu 600
guauguaauc ccaaaucaac acucgcagca cauuugcaaa cauccacaga gccuuggaaa 660
guuugaauaa uccaaccuac auguccccag cagaagucca acaaggcagu gcucaguauc 720
cucauuucag uuuucauaga gaaaugagca gaggauggag acaguagagg gcagcacagc 780
auagugcaag aagcuguggc ucuggggccu gguggaaggg auuugaaucc caauucugag 840
gcuuguuacu gcucuagccu uaggagaguc auguaacacu ucugaaucuu guuuucuuau 900
guaaauaaau agaauuuacc aggaugaguu aucuuuagga uuuaagauua ucaucugugu 960
gagauaugua gguguaugua uauauaugcg uguauguaua uauaugcgug uauguauaua 1020
uaugcauguc uguacauauu ucccguagca gcagugguuu gauauucacu aauugggcua 1080
acuuuauaga ccaaaacuac uauggauaga gaauacuuug uuugcauuua cguauauaua 1140
uuuucuuggc aaguaacaua aaauugaacu aauacuauac acauuucuag cauauuugcc 1200
uuuaacaguu uaucauggac aucuuuugag gucuguucau aaauuaucuc auccauuuaa 1260
uaauuccaua guguauuauu gcauguauaa gcacaucgaa ccauuuaugu uuugauggau 1320
auuuaguuug cuuccaaguu ucugcuucua uaaaauauga uuaaucuauu gaccuaauua 1380
ugccauugug auaggaugau agagaugcca uucucuccaa aggauuauac caauuuauau 1440
cugaacuauc uuugacuauc ucuuguagcu uuuucaguau gcuauguagu ccuauuacua 1500
auuuguaaua aaagccauca ugugugaguu guacuagaca cuaugcuaau ugccuuacaa 1560
gcauucuaua uuuacaacca uauaugauag guauuacugu cuccauuuua ugugauaaac 1620
aaauucaaag ugguuaagua accauucccu aagccagcua ggaaauagag gcaggauuaa 1680
aaucuaaaug uaugaaacuc cacagcuccu uggcauuccu aguccuuaac ccgcuaugcu 1740
augcuacguc uugguaacua aaaguacaua uuaaauacuc ucaaaauaug ucucauagca 1800
gccagcuugg uauguacacu agacacagua uuaaugcugu ugaugugagg aaaauuuuau 1860
aauuuuccuu ccauccauau acuaaccagg cccaacagug cuuagcuucu gagaucagag 1920
aucaggugca ugugcauuaa gggucauaug gccauagaua guucucuaau cuuuccauuc 1980
cucaguuucu uaagggaauu ucugaacccu caaaauuccu uauuuccuaa guagacagau 2040
uaccugucau uuuucaaaga uuaaggcuua agaucaaacc agaacuguuu uggaaauucu 2100
aaaucacugu cuauauaaau ggcaagauaa cuuuuaagau auuuauacca agcccaguac 2160
aguagcacac cacaccugua aucccagcac uuugggaggc ugaagugggu ggaucacaug 2220
aggucaggag uucgagacca cucuggccaa cauggugaaa cccugucucu acuaaaaaua 2280
uaaaaauuag ccaggcaugg uggcacuugc cuguuauccc agcuacaagg gaggcuaagg 2340
caggagaauc gcuuuaaccu gggaggcagu gguuguugca gugagccaag auugcaccac 2400
ugcacucuag ccugggcgac agagugagac ugucucaaaa aaaaaaaaaa aaaaaaagau 2460
acuuguccca gccaugaaaa uguuugcugc cccuuacuuu cgcaaacuuu uaguauuuua 2520
uuauuuuuca auggcuguaa aauaugacuu auuaaaugua guauaauaua aagaaaagag 2580
auaucuagca aagauagcau uaaagcaaaa auccuauuug ccugcugaua aaguuagagg 2640
uguuaacuug gagggugaau ccaauaaauu agaacuuuug ugcuauauuu ggagacuuuu 2700
guuuuccuac caaaguauca gggcuauguc uuacuuaucu uuguauuaca cagccugcau 2760
gacacguuuu gcacauagua auugcacagu aaauguguaa uaaccuacau ggaauagcca 2820
guguuguguu ggauagcggg agcauuuggc uagcuuaugg uuauaguccc uuacccaaca 2880
gucugcuuuu cuucuguugu acuuuuagua ccuaacaagu uucccuggcu uuaggauuuu 2940
uuccauguaa aauuucuauc augugaagaa aaaauaacuu ggccuacacu ucuaauaccu 3000
agcacauacc ucuuucugcc ugcuaugaaa uuauaauacu ugauggaggg aggcagcauu 3060
aaguguuuac auccugaagu auuucagcca uaacauccag uguuuuccag guucuagguu 3120
ucauaaaaug uaucucuguu cucuagaaca aauccauuac cuugaacuca uucguagugg 3180
gaaaaagcug agucuaauuu guaugacuuu uucaacag 3218
<210> 112
<211> 939
<212> RNA
<213> 智人
<400> 112
guaauauuua auuauauuuu aguaucguuu ugugaaaaca gcuguugaaa acuauuuuca 60
uuaccaucuu uaacuacgua uccuaaaaaa uucaguaaua acaucuuaua uuugaccuuu 120
auauugcaaa guuaauuaug uucaucugac uauuccuaac auauuagagu uaacaaaaaa 180
uucagacuca acauaggauu aaguaguaaa uuuauuuuuu aauuguaaca aauauaugcc 240
auuaguaugu ucuuaaguuu ugggucacau uggcaacagu gucuuuauuu uuuuuuugaa 300
auucuuuuca ggaauccuaa gguuauaguu cccuuaaaaa aauauuugcu guuuuaccuc 360
uuuuaagacu guaaacagga caaaaaggca uggauaugag aauuagcuag ugaucacugg 420
cuauucuaaa uagucacuaa ggcuugaauu gucucuucac cagaugccug ucagaagucc 480
caaagguuuc ccugaucaua uuaauaacuu uauaaaaaau ugaucauuau ucauuaaaua 540
uuagauauua guaaggaaaa uauaaaugaa gucuaaacca aaacucuuaa ccagacuaac 600
uucaauguua ugaaucacaa aaucuuuuug auugauugcu cuauugacaa gcucuuauau 660
gcuuuuagag aaagauuaag ucccauuaua agagaugaua aauuuuaguc aaagacuaga 720
acacaacuua cagaauacau aacuggacuu gacaguuaac aacuuaguua uuuacacugu 780
acaauggaac aaagaaaaau cuuaauucuu cugccuuuau ugcuguauuu gaccauucag 840
gaauacuuug gcuuucauau uuacaauuaa aucuccuugu ucaaacguaa aauauguaua 900
uuuccuauau gcaacuuuua aagauaaugu uuccauuag 939
<210> 113
<211> 100204
<212> RNA
<213> 智人
<400> 113
auacuuggga acaacuuaug uaucuaauuu uuagaguacu ugcaauguuu aagagaaucu 60
aacauccugg agacuugaua cauuagcugu uaaauuauug uuaaauuaaa uaauuuaaaa 120
uaaauuaaau aauuuaaaaa uauauaaaaa uauacaauaa uaugcauaau aaacaauauu 180
aaauuaugca ucugauuuuu uagaguaacu gcaaccuuua agagaaucug acauccugga 240
gacuuugaua uauuagcugc auaacuauaa uuuuaaaaua uacaauaaua cguauaauaa 300
acauauuaaa cauaauaaac auauuaaacu acugacuaug uaguuucugg auucacaacu 360
auaguugaaa aguauaauaa uuagcuaaau acacaaauag uauuggaauu uuuauaagaa 420
cuugggauuu gcuauaguuu caaguuuuau uuccuaaauu uaaucaguua uuuaaguacu 480
gagaaaguuu ucuuuguuaa guuaggcauc ugaaguacuu aaaaaugaau acauucaaaa 540
uaauucaauu cuucaauaua ucuuuauuuu acauauauau acauauauau guauauauau 600
auauacacac acacacacac acacaaauau auagguaugu auaugguucu ucuguuaguu 660
gugccugggg ucacucaugu gcuuauaguu auccaguggc uugauuaggg cuggauggcu 720
uuuaaagggu agauuucuca gcuuugaaaa cuagucucug cuacuuauua acacauccuc 780
uaauagguua ucuuaggcuu cuuaaaugau gaucucagga caacaggagg gcaagguuca 840
augcacaagc ucuuuauaag gcucuauuua gugcguauuu uaaaaauuau uauucaagca 900
agguacaucc ugaaucaaug gggaagaagu uauaaaaggg ccaagauaac agaauuuuua 960
agauucccca agggagcaua guaugagaga aagggagaga gagcauguua cgagcucagu 1020
uguggaguca ucuuagguua cuuccaagag ccaccugcaa aguagagguu gcagggaagg 1080
gacagauuua cacaaaggca uaggcagacg gggaccugac ucacuggggg ccauuauugc 1140
aaacauguaa cacacuauuc uuguuaguug ugagaacuuc uaauuuuucc uaggcacaga 1200
agcagacuua cagaugcagu uuaaguggau gggaugacug auuucuguuu gcuuacaaaa 1260
augggguguu acuauauaug ugcacaaaau ccaagugcaa uuggaaaugu gaaaggaaaa 1320
uaaaacuugg gaucucaauu cauuaugucu auaagaaaaa auuaggguga aagcugaguc 1380
augcaagaaa cugcucuccu uuuguucuua gcagacagcu acacaucaaa uguuaaauau 1440
cuccacaggu agcuacuuua ggacauucau cuuaucucac guaaagugcu gauuuaccac 1500
cccacgugaa uacauaauau cuauuucccu cucugcucuu uuucucuugc aacacauaga 1560
uuaccauauc uacccuuuuu cucuuccaau ggauuuuucc ccuuuaaaua cugaagcccu 1620
caaaaucauc uuagagaaag gaagagacua cagacuguuu cugugauuca guguuuauuu 1680
cuuuucggca ugucccuaac cuuggcaaaa uaaacuucua aauugauuga gacccgucuu 1740
agacacuuuu ugguucacaa agacuucuca ugagcuacau uauagauaua caaaacuaaa 1800
uacaaucccu ucaauaaaac uguaaauugu auuaaggcaa auuguuuugc cuuaauuuca 1860
uggacaagaa ugagugugca gcaagcagau acuugucuuc cuucaacaug aggaaacugg 1920
aaagaucagu agggagucag ugugaauuaa gccauuaacc auggcuuaau uugccaugaa 1980
gauaaggcaa aacaaaaugu uuaggacaca caauggauac aaaauggcca ugcuuuguuu 2040
uagagaucgg agaaguaagc uacuaugacu uuucuuggua agucagcaaa aaggaacuag 2100
aaguaacauc caaggaauau aaauucauug cuacagagaa caaagguaag caauaauaaa 2160
aggugaggcc uucuugugaa gugauuuugg ucagauaaaa cuguucacaa aagccuaggg 2220
cagaaagaag gcagguccag acaaguguuc uuauaacaag gccacuuaca acauugucac 2280
auaaguccca uuucuugaug aaaacugaca ggugcagaaa aucugacgaa aaauaauagu 2340
uuugccaauu uuccucaaaa auauacagug aguuauugaa cuagaaccug aguuaaauuu 2400
ccugacucac acuuagguac agacgacaau gcauaaaaac uuaguugacu uguucaagcc 2460
agagcugacu uguucacugc uguaucccca gugccuagca caggaaacag gauaaaaaau 2520
acuguuagaa ugaguuaaag aauaaaauuu agguaagauu uugcuuuuag uuacaauugu 2580
cacugagauc uagguuacaa ucuuagcuuc aucaauuauu acuuaacuuc uaugaacuug 2640
uucucacuuc ugaaaaauua gaauaaaauu uaccauuaga gaccaggcac cuugaguuua 2700
ugaaugugag caagagggug guggcagaag gguagaaaag aguaauacag acaaacgaaa 2760
cuuguaagug aauacauaaa aauaaguuau aacgaaugaa aaaaaaaaca gaagaaaagg 2820
uguuagagaa aacagacuuc uauuaugaaa acaaacacgc aguagucagc auaguguaug 2880
acauaacaug ugcucaguaa cuauuaaauu ucauuccuac cauugucaga gguauuugaa 2940
ucacaacaac uccaucuuga auaggggcug gguaaaauaa gggugagacc uacugggcug 3000
cauucucagg augucuguca gucauucuaa gucacaggau gagauaggag gugggcacaa 3060
gauacugauc auaaagacuu ugcugauaaa acagcaugca guaaagaagc cagccaaauc 3120
ccaccaaauc caagauggcg agaaaggugg gacgucugcu cguucucacu gcucauuaua 3180
cacuaauuau aaugcauuag cauccuaaaa gacacuccca ccagugcuau gacaguuuac 3240
agaugccaug gcaaugugaa gaaguuacuc uauauagucu aaaaagggga ggaacacuca 3300
gaucuaggaa uggccuaccc ucuucccaga aaacucauga auaacccacc ccuuguuuag 3360
cauauaauca agaaauaacu auaacaaucc uuagucuacc accuccaaug gggguguaug 3420
caccuccaau ucuuucuugg cgagauccag gagcccucuc cuggggucca gaucagaaca 3480
ccuuuccaga aacaccaucc cauguuaaau uaugaauuaa gaacacugaa caugaagaau 3540
guuuaauuca aauuauugag uaaacacuua caaaauuaaa auauaacauu uaauaaaaau 3600
agcaagauug aggaacaagc acuucacaaa uauugguuuc ccagaauguc ugaggaggug 3660
uauagaaguu aagaauaugu ccuccagcca gagagaucug uguucaauca cacuauuuaa 3720
guuacuuagc uucuccaagc cucaguuucu uaacucagau ggaaaaugag gacaauguaa 3780
gcaccuauuu cacuggauug uaaggaagaa uaaacaagau aaugaauagu auuuggcaua 3840
uaaucuuuca gaaaaguagu aaaauuguca uuccuauaaa ucuaacuaau gucuuuaaaa 3900
uucaucucac aaaaucagua ucuuuuuauu uuguacugag cuacuuauuu uacccaaauu 3960
ggggguuuaa aaagaaacuc auuacuuauu uucgaaagga aaauuuacug ucaaguacag 4020
uaauuuuuuu uuuaaagcag cguuuaaaaa aaaaaaaaga caaagcacug guccagauag 4080
uuggaaaugu cauuuagauu uaagucuaca gcuucuuagg aaaguuaggu agagauguau 4140
cauacuccag caugauugug agcagacgag caggaugagc aaaacuugca cgaguaagag 4200
ugguaaacac cagagaaggc gcuuucaugg aagggcaccc uagguaacca agcaaguggc 4260
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agggaacaaa guauaagaua auucauucug uauauaucaa cugcuaccuu ggcacucuuu 99900
uuacucaaca gauucuacac ucaagucugg gagaugcuga guuaaguuag uacaagaugu 99960
cucugagagc acuacugugc aacaugaauu uccacgcagg ggauauauag uuaucacuuu 100020
aauucugaag cacaccuguu augaucgaug ccccacacaa uacacacugg gaagcacugu 100080
uuuaccucuu aaaaaauggu gguacauggg augagaaaau uaaauuucuu uacugcaaau 100140
aagaauugcu gccauuugua gagagaauuu uagugucacu ucuacucuau uguaggaaua 100200
uaag 100204

Claims (72)

1.一种核酸反式剪接分子，其包含以3'至5'方向或5'至3'方向可操作地连接的：
(a)结合结构域，其被配置为结合选自由内含子19、23或24组成的组的靶ABCA4内含子；
(b)被配置为介导反式剪接的剪接结构域；和
(c)包含功能性ABCA4外显子的编码结构域；
其中所述核酸反式剪接分子被配置为将所述编码结构域反式剪接至与靶ABCA4内含子相邻的内源ABCA4外显子，从而用功能性ABCA4外显子替代内源ABCA4外显子并校正ABCA4中的突变。
2.根据权利要求1所述的核酸反式剪接分子，其中所述结合结构域与在所述突变3'端的靶ABCA4内含子结合，并且其中所述突变在ABCA4外显子1-24或内含子1-24中的任何一个中。
3.根据权利要求2所述的核酸反式剪接分子，其中所述靶ABCA4内含子是内含子19，所述突变在ABCA4外显子1-19或内含子1-19中的任一个中，并且所述编码结构域包含ABCA4外显子1-19。
4.根据权利要求3所述的核酸反式剪接分子，其中所述结合结构域被配置为在结合位点结合内含子19，所述结合位点包含SEQ ID NO：25的核苷酸990至2174的任一个或多个。
5.根据权利要求4所述的核酸反式剪接分子，其中所述结合位点包含SEQ ID NO：25的核苷酸1670至2174中的任何一个或多个。
6.根据权利要求5所述的核酸反式剪接分子，其中所述结合位点包含SEQ ID NO：25的核苷酸1810至2000中的任何一个或多个。
7.根据权利要求6所述的核酸反式剪接分子，其中所述结合位点包含SEQ ID NO：25的核苷酸1870至2000中的任何一个或多个。
8.根据权利要求7所述的核酸反式剪接分子，其中所述结合位点包含SEQ ID NO：25的核苷酸1920至2000中的任何一个或多个。
9.根据权利要求2所述的核酸反式剪接分子，其中所述靶ABCA4内含子是内含子23，并且所述突变是在ABCA4外显子1-23或内含子1-23中的任何一个或多个中。
10.根据权利要求9所述的核酸反式剪接分子，其中所述编码结构域包含功能性ABCA4外显子1-23。
11.根据权利要求10所述的核酸反式剪接分子，其中所述结合结构域被配置为在结合位点结合内含子23，所述结合位点包含SEQ ID NO：29的核苷酸80至570或核苷酸720至1081中的任一个或多个。
12.根据权利要求11所述的核酸反式剪接分子，其中所述结合结构域被配置为在结合位点结合ABCA4内含子23，所述结合位点包含：
(a)SEQ ID NO：29的核苷酸261至410中的任何一个或多个；
(b)SEQ ID NO：29的核苷酸801至950中的任何一个或多个；或者
(c)SEQ ID NO：29的核苷酸841至990中的任何一个或多个。
13.根据权利要求12所述的核酸反式剪接分子，其中所述结合位点包含：
(a)SEQ ID NO：29的核苷酸261至410中的六个或更多个；
(b)SEQ ID NO：29的核苷酸801至950的六个或更多个核苷酸；或者
(c)SEQ ID NO：29的核苷酸841至990的六个或更多个核苷酸。
14.根据权利要求13所述的核酸反式剪接分子，其中所述结合结构域包含与结合位点的六个或更多个核苷酸互补的六个或更多个连续的核酸残基。
15.根据权利要求2所述的核酸反式剪接分子，其中所述靶ABCA4内含子是内含子24，所述突变是在ABCA4外显子1-24或内含子1-24中的任一个中，并且所述编码结构域包含ABCA4外显子1-24。
16.根据权利要求11所述的核酸反式剪接分子，其中所述结合结构域被配置为在结合位点结合内含子24，所述结合位点包含SEQ ID NO：30的核苷酸600至1250或核苷酸1490至2660中的任一个或多个。
17.根据权利要求12所述的核酸反式剪接分子，其中所述结合位点包含SEQ ID NO：30的核苷酸1000至1200中的任何一个或多个。
18.根据权利要求1所述的核酸反式剪接分子，其中所述结合结构域与在所述突变5'端的靶ABCA4内含子结合，并且其中所述突变在ABCA4外显子23-50或内含子22-49的任何一个中。
19.根据权利要求14所述的核酸反式剪接分子，其中所述靶ABCA4内含子是内含子23，所述突变在ABCA4外显子24-50或内含子23-49中的任一个中，并且所述编码结构域包含ABCA4外显子24-50。
20.根据权利要求15所述的核酸反式剪接分子，其中所述结合结构域被配置为在结合位点结合内含子23，所述结合位点包含SEQ ID NO：29的核苷酸80至1081中的任一个或多个。
21.根据权利要求16所述的核酸反式剪接分子，其中所述结合位点包含SEQ ID NO：29的核苷酸230至1081中的任何一个或多个。
22.根据权利要求17所述的核酸反式剪接分子，其中所述结合位点包含SEQ ID NO：29的核苷酸250至400中的任何一个或多个。
23.根据权利要求17所述的核酸反式剪接分子，其中所述结合位点包含SEQ ID NO：29的核苷酸690至850中的任何一个或多个。
24.根据权利要求14所述的核酸反式剪接分子，其中所述靶ABCA4内含子是内含子24，所述突变在ABCA4外显子25-50或内含子24-49中的任何一个中，并且所述编码结构域包含ABCA4外显子25-50。
25.根据权利要求20所述的核酸反式剪接分子，其中所述结合结构域被配置为在结合位点结合内含子24，所述结合位点包含SEQ ID NO：30的核苷酸1至250，核苷酸300至2100或核苷酸2200至2692中的任一个或多个。
26.根据权利要求21所述的核酸反式剪接分子，其中所述结合位点包含SEQ ID NO：30的核苷酸360至610中的任何一个或多个。
27.根据权利要求21所述的核酸反式剪接分子，其中所述结合位点包含SEQ ID NO：30的核苷酸750至1110中的任何一个或多个。
28.一种核酸反式剪接分子，其包含以5'至3'方向可操作地连接的：
(a)结合结构域，其被配置为在结合位点结合ABCA4内含子22，所述结合位点包含SEQID NO：28的核苷酸60至570、600至800或900至1350中的任一个或多个；
(b)被配置为介导反式剪接的剪接结构域；和
(c)包含功能性ABCA4外显子23-50的编码结构域；
其中所述核酸反式剪接分子被配置为将编码结构域反式剪接至内源ABCA4外显子22，从而用功能性ABCA4外显子23-50替代内源ABCA4外显子23-50。
29.根据权利要求24所述的核酸反式剪接分子，其中所述结合位点包含SEQ ID NO：28的核苷酸70-250中的任何一个或多个。
30.一种核酸反式剪接分子，其包含以3'至5'方向可操作地连接的：
(a)结合结构域，其被配置为在结合位点结合ABCA4内含子22，所述结合位点包含SEQID NO：28的核苷酸1至510或880至1350的任一个或多个；
(b)被配置为介导反式剪接的剪接结构域；和
(c)包含功能性ABCA4外显子1-22的编码结构域；
其中所述核酸反式剪接分子被配置为将编码结构域反式剪接至内源ABCA4外显子23，从而用功能性ABCA4外显子1-22替代内源ABCA4外显子1-22。
31.根据权利要求30所述的核酸反式剪接分子，其中所述结合结构域被配置为在结合位点结合ABCA4内含子22，所述结合位点包含：
(a)SEQ ID NO：28的核苷酸1041至1190中的任何一个或多个；
(b)SEQ ID NO：28的核苷酸1171至1320中的任何一个或多个；
(c)SEQ ID NO：28的核苷酸1201至1350中的任何一个或多个。
32.根据权利要求31所述的核酸反式剪接分子，其中所述结合位点包含：
(a)SEQ ID NO：28的核苷酸1041至1190中的六个或更多个；
(b)SEQ ID NO：28的核苷酸1171至1320中的六个或更多个；
(c)SEQ ID NO：28的核苷酸1201至1350中的六个或更多个。
33.根据权利要求32所述的核酸反式剪接分子，其中所述结合结构域包含与所述结合位点的六个或更多个核苷酸互补的六个或更多个连续核酸残基。
34.根据权利要求1-33中任一项所述的核酸反式剪接分子，其中所述结合结构域的长度为100-200个核苷酸。
35.根据权利要求1-34中任一项所述的核酸反式剪接分子，其中所述编码结构域是cDNA序列。
36.根据权利要求1-34中任一项所述的核酸反式剪接分子，其中所述编码结构域包含天然存在的序列。
37.根据权利要求1-34中任一项所述的核酸反式剪接分子，其中所述编码结构域包含密码子优化的序列。
38.根据权利要求1-37中任一项所述的核酸反式剪接分子，其中人工内含子包含间隔子序列。
39.根据权利要求1-38中任一项所述的核酸反式剪接分子，其长度为3000至4000个核苷酸。
40.根据权利要求1-39中任一项所述的核酸反式剪接分子，其中ABCA4基因中的突变与Stargardt病相关。
41.根据权利要求40所述的核酸反式剪接分子，其中与Stargardt病相关的ABCA4基因中的突变在光感受器细胞中表达。
42.一种核酸反式剪接分子，其包含以3'至5'方向可操作地连接的：
(a)结合结构域，其被配置为在结合位点结合ABCA4内含子23，所述结合位点包含SEQID NO：29的核苷酸261至410的六个或更多个，其中所述结合结构域包含与所述结合位点的六个或更多个核苷酸互补的六个或更多个连续核酸残基；
(b)包含剪接结构域的人工内含子；和
(c)包含功能性ABCA4外显子1-23的编码结构域；
其中核酸反式剪接分子被配置为将编码结构域反式剪接至内源ABCA4外显子24，从而用功能性ABCA4外显子1-23替代内源ABCA4外显子1-23。
43.一种核酸反式剪接分子，其包含以3'至5'方向可操作地连接的：
(a)结合结构域，其被配置为在结合位点结合ABCA4内含子23，所述结合位点包含SEQID NO：29的核苷酸801至950的六个或更多个，其中所述结合结构域包含与所述结合位点的六个或更多个核苷酸互补的六个或更多个连续核酸残基；
(b)包含剪接结构域的人工内含子；和
(c)包含功能性ABCA4外显子1-23的编码结构域；
其中核酸反式剪接分子被配置为将编码结构域反式剪接至内源ABCA4外显子24，从而用功能性ABCA4外显子1-23替代内源ABCA4外显子1-23。
44.一种核酸反式剪接分子，其包含以3'至5'方向可操作地连接的：
(a)结合结构域，其被配置为在结合位点结合ABCA4内含子23，所述结合位点包含SEQID NO：29的核苷酸841至990的六个或更多个，其中所述结合结构域包含与所述结合位点的六个或更多个核苷酸互补的六个或更多个连续核酸残基；
(b)包含剪接结构域的人工内含子；和
(c)包含功能性ABCA4外显子1-23的编码结构域；
其中核酸反式剪接分子被配置为将编码结构域反式剪接至内源ABCA4外显子24，从而用功能性ABCA4外显子1-23替代内源ABCA4外显子1-23。
45.一种核酸反式剪接分子，其包含以3'至5'方向可操作地连接的：
(a)结合结构域，其被配置为在结合位点结合ABCA4内含子22，所述结合位点包含SEQID NO：28的核苷酸1041至1190的六个或更多个，其中所述结合结构域包含与所述结合位点的六个或更多个核苷酸互补的六个或更多个连续核酸残基；
(b)包含剪接结构域的人工内含子；和
(c)包含功能性ABCA4外显子1-22的编码结构域；
其中所述核酸反式剪接分子被配置为将编码结构域反式剪接至内源ABCA4外显子23，从而用功能性ABCA4外显子1-22替代内源ABCA4外显子1-22。
46.一种核酸反式剪接分子，其包含以3'至5'方向可操作地连接的：
(a)结合结构域，其被配置为在结合位点结合ABCA4内含子22，所述结合位点包含SEQID NO：28的核苷酸1171至1320的六个或更多个，其中所述结合结构域包含与所述结合位点的六个或更多个核苷酸互补的六个或更多个连续核酸残基；
(b)包含剪接结构域的人工内含子；和
(c)包含功能性ABCA4外显子1-22的编码结构域；
其中所述核酸反式剪接分子被配置为将编码结构域反式剪接至内源ABCA4外显子23，从而用功能性ABCA4外显子1-22替代内源ABCA4外显子1-22。
47.一种核酸反式剪接分子，其包含以3'至5'方向可操作地连接的：
(a)结合结构域，其被配置为在结合位点结合ABCA4内含子22，所述结合位点包含SEQID NO：28的核苷酸1201至1350的六个或更多个，其中所述结合结构域包含与所述结合位点的六个或更多个核苷酸互补的六个或更多个连续核酸残基；
(b)包含剪接结构域的人工内含子；和
(c)包含功能性ABCA4外显子1-22的编码结构域；
其中所述核酸反式剪接分子被配置为将编码结构域反式剪接至内源ABCA4外显子23，从而用功能性ABCA4外显子1-22替代内源ABCA4外显子1-22。
48.一种前病毒质粒，其包含权利要求1-47中任一项的核酸反式剪接分子。
49.一种腺相关病毒AAV，其包含权利要求1-48中任一项的核酸分子。
50.根据权利要求49所述的AAV，其中所述AAV优先靶向光感受器细胞。
51.根据权利要求49或50所述的AAV，其中所述AAV包含AAV5衣壳蛋白、AAV8衣壳蛋白、AAV8(b)衣壳蛋白或AAV9衣壳蛋白。
52.一种药物组合物，其包含权利要求1-47中任一项的核酸反式剪接分子、权利要求48的前病毒质粒或权利要求49-51中任一项的AAV。
53.一种药物组合物，其包含5'核酸反式剪接分子和3'核酸反式剪接分子，其中所述5'核酸反式剪接分子是权利要求2-13或30-47中任一项的核酸反式剪接分子，并且3'核酸反式剪接分子是权利要求14-25中任一项的核酸反式剪接分子。
54.一种校正受试者的靶细胞中ABCA4基因突变的方法，所述方法包含向受试者施用权利要求52或53的药物组合物。
55.一种在有此需要的受试者中校正ABCA4外显子1-24中任何一个或多个突变的方法，所述方法包含向所述受试者施用包含权利要求2-13或30-47中任一项的核酸反式剪接分子的药物组合物。
56.一种在有此需要的受试者中校正ABCA4外显子23-50中的任何一个或多个突变的方法，所述方法包含向所述受试者施用包含权利要求14-25中任一项的核酸反式剪接分子的药物组合物。
57.一种在有此需要的受试者中校正任一个ABCA4外显子1-24中的突变和在外显子23-50中的任何一个中的第二突变的方法，所述方法包含向所述受试者施用权利要求53的药物组合物。
58.一种治疗患有与ABCA4中的突变相关的病症的受试者的方法，所述方法包含向所述受试者施用权利要求52或53的药物组合物。
59.一种治疗患有与任一个或多个ABCA4外显子1-24或内含子1-24中的突变相关的病症的受试者的方法，所述方法包含向所述受试者施用包含根据权利要求2-13或30-47中任一项所述的核酸反式剪接分子的药物组合物。
60.一种治疗受试者的方法，所述受试者患有与ABCA4外显子23-50或内含子22-49中的任何一个或多个中的突变相关的病症，所述方法包含向所述受试者施用包含根据权利要求14-25中任一项所述的核酸反式剪接分子的药物组合物。
61.一种治疗受试者的方法，所述受试者患有与ABCA4外显子1-24中的任一个的第一突变和外显子23-50中的任一个的第二突变相关的病症，所述方法包含向所述受试者施用权利要求53的药物组合物。
62.根据权利要求54-61中任一项所述的方法，其中所述受试者患有Stargardt病。
63.根据权利要求54-62中任一项所述的方法，其中所述组合物通过视网膜下注射、玻璃体内注射或静脉内注射施用。
64.一种腺相关病毒AAV，其包含组装的衣壳，所述衣壳中包装了包含AAV 5'ITR，在调控序列的操作控制下的权利要求1-47中任一项的核酸分子和AAV 3'ITR的运载体基因组。
65.根据权利要求54-63中任一项所述的方法，其中所述受试者在施用后表现出ABCA4蛋白表达增加至少10％。
66.一种核酸反式剪接分子，其包含以3'至5'方向可操作地连接的：
(a)结合结构域，其被配置为在结合位点结合CEP290内含子26，所述结合位点包含SEQID NO：32的核苷酸4800至5838的任一个或多个；
(b)被配置为介导反式剪接的剪接结构域；和
(c)包含功能性CEP290外显子2-26的编码结构域；
其中所述核酸反式剪接分子被配置为将所述编码结构域反式剪接至内源CEP290外显子27，从而用功能性CEP290外显子2-26替代内源CEP290外显子2-26并校正病原性点突变。
67.一种核酸反式剪接分子，其包含以3'至5'方向可操作地连接的：
(a)被配置为在靶内含子27、28、29或30中的任一个上结合CEP290的结合结构域；
(b)被配置为介导反式剪接的剪接结构域；和
(c)编码结构域，其包含在靶内含子5'端的功能性CEP290外显子；
其中所述核酸反式剪接分子被配置为将编码结构域反式剪接至内源CEP290，从而用功能性CEP290外显子替代在靶内含子5'端的内源CEP290外显子并校正病原性点突变。
68.一种前病毒质粒，其包含权利要求66或67的核酸反式剪接分子。
69.一种AAV，其包含权利要求66-68中任一项的核酸分子。
70.一种药物组合物，其包含权利要求66或67的核酸反式剪接分子，权利要求68的前病毒质粒或权利要求69的AAV。
71.一种校正受试者的靶细胞中CEP290内含子26中的病原性点突变的方法，所述方法包含向所述受试者施用权利要求66或67的核酸反式剪接分子、权利要求68的前病毒质粒、权利要求69的AAV或权利要求70的药物组合物。
72.一种治疗具有由CEP290内含子26中的病原性点突变引起的LCA 10的受试者的方法，所述方法包含向所述受试者施用权利要求66或67的核酸反式剪接分子、权利要求68的前病毒质粒、权利要求69的AAV或权利要求70的药物组合物。
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