CN1048254C - 用于将预定的改变引入靶基因中的化合物 - Google Patents

用于将预定的改变引入靶基因中的化合物 Download PDF

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CN1048254C
CN1048254C CN94194935A CN94194935A CN1048254C CN 1048254 C CN1048254 C CN 1048254C CN 94194935 A CN94194935 A CN 94194935A CN 94194935 A CN94194935 A CN 94194935A CN 1048254 C CN1048254 C CN 1048254C
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Abstract

本发明涉及多核苷酸，它的第一链含有核糖核苷酸和脱氧核糖核苷酸两种，而第二链仅含有脱氧核糖核苷酸；其中链是沃森-克里克规则配对的并且通过寡核苷酸连接，如此该多核苷酸至多具有一个单一3′末端和一个单一5′末端。可将这些末端连接，这样多核苷酸就成为一个单一连续环状聚合物(single continuous circular polymer)。该多核苷酸可用于向靶基因中引入特定改变。

Description

用于将预定的改变引入靶基因中的化合物
本申请是于1993年12月9日递交的第08/164303号专利申请的后续申请，后者全文引入本文以供参考。
1.发明领域
本发明涉及分子遗传学领域。具体地说它涉及向活的、培养的真核细胞中引入特定基因改变的核酸化合物及其应用。更具体地说，它主要涉及基本上Watson-Crick配对的双链核酸，其中双链中的一条链的部分包含含2′-O或2′-OMe核糖的核苷酸，剩余部分包含脱氧核糖核苷酸。
2.发明背景
2.1.嵌合和/或杂种双链核酸
本发明领域涉及核酸。核酸是杂聚物，即不同亚单位的聚合物，亚单位是通过定向的磷酸二酯键或其衍生物连接形成聚合物。双链核酸是这样的核酸，按照尿嘧啶或胸腺嘧啶与腺嘌呤对应和胞嘧啶与鸟嘌呤对应的原则，双链中第一链的每一碱基对应于第二链的碱基。据说拥有这种对应性的逆平行双链是Watson-Crick配对的。双链核酸可有两种主要类型：核糖核酸和脱氧核糖核酸。每种核糖核苷酸都有相应的脱氧核糖核苷酸，例如，腺嘌呤和脱氧腺嘌呤，胞嘧啶和脱氧胞嘧啶，鸟嘌呤和脱氧鸟嘌呤，尿嘧啶和胸腺嘧啶。如本领域中所用的那样，在同一链中存在核糖核苷酸和脱氧核糖核苷酸的核酸被称为混合或嵌合(下文称“嵌合”)核酸。其中脱氧核糖核苷酸和核糖核苷酸相互对应的双链核酸被称为杂种双链(hybrid-duplex)。当两条链形成少于其全部碱基的双链核酸区时，所形成的分子被称为异形双链(heteroduplex)。
更经常地，双链核酸的两条链是非共价键合的，而仅通过Watson-Crick配对相连。然而，双链的两条链可通过寡核苷酸连接形成单一聚合物(single polymer)。连接寡核苷酸不是Watson-Crick配对的。其中第一链和第二链是单一聚合物的部分的异形双链被称为“发夹双链”或“柱和环”结构。本文采用前一种名称。
本文所用嵌合现象是核酸聚合物的一种特性，而杂种现象则是双链的一种特性。例如，mRNA及其模板形成杂种双链，但二者都是非嵌合的，然而例如嵌合的八核苷酸5′d(TTTT)-r(CCCC)3′和5′r(GGGG)-d(AAAA)3′相互形成沃森-克里克规则双链，但生成的双链是非杂种双链。下文称非杂种双链的双链核酸为“同质双链”(homo-duplex)。除非另外特别说明，同质双链仅指包含脱氧核苷酸的双链。最后，值得注意的是本领域中称沃森-克里克规则双链的形成为“杂交(hybridigation)”，即使其形成的是非杂种双链核酸。
对X射线衍射和二维NMR分析嵌合和/或杂种核酸结构的研究感兴趣的人们已合成了用于此研究的嵌合核酸和杂种双链核酸。参见，例如Salazar，M.等，1994，J.Mol.Biol.241：440-55和Egli，M.等，1993，Biochemistry 32：3221-37(r3d7.d10形式的双链的嵌合杂种双链)；Ban，C.等，1994，J.Mol.Biol.236：275-85(d5r1d4形式的自身互补嵌合杂种双链)；Chou，S.H.，1991，Biochemistry 30：5248-57(d4r4d4形式的自身互补和非自身互补的嵌合杂种双链)。这些双链核酸的互补链彼此是非共价键合的；它们仅通过沃森-克里克规则配对相连。
合成了嵌合核酸的第二组科学家感兴趣于核糖酶(ribozyme)的研究和用途，核糖酶即自身切开或切开其它RNA的RNA分子。Perreault，J.P.等，1990，Nature 344：565；Taylor，N.R.等，1992，Neucleic Acids Research20：4559-65；Shimaya，T.，1993，Nrucleic Acids Research 21：2605。这些研究发现嵌合核糖酶具有活性，并且对核酸酶的消化比RNA核糖酶具有更强的耐受性。嵌合核糖酶是自身互补的，即沃森-克里克规则配对链是共价连接的。在嵌合核糖酶的研究期间合成的化合物不同于上面提到的杂种双链分子，它们被合成用于结构的研究，因为其中的嵌合核糖酶不包括稳定的杂种双链。因而，具有DNA结合臂的嵌合核糖酶与其底物结合，并形成杂种双链。Yang，G.H.等，1990，Biochemistry 29：11156-60。还参见Sawata，S.等，1993，Neucleic Acids Research 21：5656-60；Hendry，P.等，1992，Neucleic Acids Research 20：5737-41；Shimayama，T.，1993，Neucleic Acids Research 21：2605。核糖酶催化RNA底物的切开，杂种双链因此溶解。
2.2.真核细胞中定点遗传改变
分子生物学领域的技术人员知道不仅经常需要向靶真核细胞中引入新的多核酸序列，即新的基因，而且也需要对靶细胞中确定的预先存在的基因加以改变。靶细胞可在培养物中使用或者使用它建立转基因动物。
已经建立了许多向培养的真核细胞中引入DNA的技术。这些技术包括磷酸钙沉淀法，DEAE-葡聚糖介导的胞吞作用，电穿孔，脂质体介导的融合，使用复制缺损病毒的转导作用。然而，这些技术虽然十分普遍地用于向真核细胞中引入功能性基因，但它们不能轻而易举地完成对特定存在基因的改变(突变)。引入之后，外源性DNA通过异常重组在细胞基因组中随机位点上分离，而不是通过同源重组在特定位点上分离。
迄今为止，还没有一种令人普遍满意的向高级真核细胞，即哺乳动物或鸟类细胞中引入定点或特异位点的遗传改变(诱变)的方案。虽然在真核细胞中通过引入极长(＞1kb)的核酸可获得同源重组，但这些技术需要应用复杂的筛选技术，因为在高级真核细胞中异常重组率大大超过了同源重组率。Thomas，K.R.&Smithies，M.R.，1987，Cell 52：503。还参见Valancius，V.&Smithies，O.，1991，Mol.Cell.Biol.11：4389(比较真核细胞中线性化和超螺旋质粒的同源重组)。
一种完成优势定点诱变的方法是向细胞中直接引入单链寡脱氧核苷酸。这一技术被成功地用于酵母中，同源重组在啤酒酵母(Saccharomycescerevisiae)中的活性显著高于真核细胞。Moreschell，R.P.等，1988，Proc.Natl.Acad.Sci.85：524-28；Yamamoto，T.等，1992，Yeast 8：935-48。并且，至今也没有用单链寡核苷酸成功地转化哺乳动物或鸟类细胞的报道。
研究表明改变的嘌呤和嘧啶碱基区，即〔d(TG)30·d(AC)30〕显示显示了令人喜悦的重组率，由此可推知哺乳动物中靶DNA结构和同源重组率之间的关系。对培养的哺乳动物细胞的非复制质粒的研究证实了这些效果。Wahls，W.P.等，1990，Mol.Cell.Biol.10：785-93。这些实验没有进而表明外源性核酸和细胞基因组之间的重组。
曾尝试使用RecA，一种促进细菌(大肠杆菌)中同源重组的蛋白质来促进真核细胞中的同源重组。但是，这些尝试显然未获得成功。例如，W.Bertling的美国专利4950599公开了在真核细胞中使用RecA导致极低的定向位点突变率，并且同源重组率也未增高。D.Zarling和E.Sane的专利申请WO93/22443及D.C.Gruenert和Z.Kunzelmann的申请94/04032都旨在校正培养的涉及囊纤维变性的细胞系中的基因缺损。这些出版物公开了证实原理的原始实验数据而非涉及操作方法实施例的数据。为将多核苷酸/RecA复合物引入到核中，Zarling和Gruenert使用膜是通透性的细胞，尽管这类细胞不能进一步生长。另外，即使这些出版物宣称在完整细胞中发生了RecA促进同源重组，它们也未给出对其频率的定量评价。因此，还没有证据可令人信服地表明在任何活的真核细胞中，使用原核RecA导致的同源重组率明显高于自发性同源重组率。
3.发明概述
本发明涉及单一共价连接的双链寡核苷酸，它与所研究的基因同源，且具有脱氧核糖核苷酸和核糖核苷酸。为了产生遗传改变，在同源区内，有一对或多对非对应(下文称“异源”或“突变基因”)碱基对。通常，细胞原有的同源重组过程导致突变基因核苷酸插入靶基因组位置。可使用本发明的双链寡核苷酸(下文称“嵌合载体”)向基因中引入异源碱基对，特定地改变所研究的基因。异源碱基对可能是不同于所研究的基因的碱基对，或者可能是所研究基因中存在的碱基对之外那些碱基对(插入)，或者异源碱基对还可能是不存在于所研究基因中的碱基对(缺失)。本发明部分地是基于下述发现，即载体中包含杂种双链核酸的约15-50个碱基对区大大提高所研究基因的改变率。当异源碱基对区是1-50个碱基对时，异源碱基对可以同质或杂种双链存在于本发明的载体中。当异源碱基对长度大于50个碱基对时，它优选以同质双链存在。
可采用任何已知的向真核细胞中引入核酸的方法向靶细胞中引入载体。虽然就理论而言没有限定，但据信嵌合载体是通过靶细胞的重组/修复机制来参与的，并且经基因转化或同源重组指导靶基因改变。
4.附图的简要说明
图1显示图表表示的两种嵌合载体。特定标记如下：1，第一链；2，第二链；3，异源区；4，同质区；5，连接物；6，连接位点。
图1的符号图解
图1A是R-D-R形式的连接的嵌合载体。
图1B是R-D-R形式的具有单一3′和5′末端的发夹式嵌合载体。
5.发明详述
5.1.本发明嵌合载体的描述
本发明包括含有含脱氧核糖和核糖的碱基双链核酸。因此它们包括DNA和RNA区，故而被称为“嵌合载体”。嵌合载体的核糖核苷酸的2′-O可以是甲基化的。任何磷酸二酯都可被硫代磷酸二酯或甲基磷酸二酯替代。
本发明的嵌合载体是单一核酸聚合物。因此本发明的嵌合载体须至少包括1个碱基至更通常的3或4个碱基，这些碱基不是沃森-克里克规则配对的。这些未配对碱基区连接两条沃森-克里克规则配对的碱基链。与其它合成的具有未配对核苷酸的嵌合核苷酸相反嵌合载体没有酶活性，即它们不催化化学反应或者在没有生物能源，如ATP存在下它们自身进行化学反应。
优选实施方案中的连接区碱基是脱氧核糖核苷酸。可构建具有两个连接区的嵌合载体，以使聚合物的3′和5′末端与相邻的互补链核苷酸呈沃森-克里克规则配对。它们易于连接使嵌合载体形成单一连续环状核酸聚合物。
基本上，嵌合载体的所有其余碱基都是沃森-克里克规则配对的。本文所描述的碱基是沃森-克里克规则配对的或它们形成双链核酸应被理解为在适当的温度和盐的条件下，它们可形成碱基对或双链核酸。应该知道在某些少盐和/或升高的温度条件下，沃森-克里克规则碱基对会失去热力学稳定性而使得双链核酸熔解掉或变性。还应知道一或两对碱基对失配并不影响本发明的可操作性。
本发明的嵌合载体旨在将改变(突变)特定地引入靶基因。通过选择具有与靶位点序列相同(同源)序列的嵌合载体部分(下文称之为同源区)确定遗传改变位点。嵌合载体序列和靶基因之间的不同区被称为异源区。应注意到嵌合载体与靶基因虽是异源的，但在该载体区中并不是异形双链。根据本发明的优选实施方案，每个嵌合载体有两个同源区，它们位于插入的异源区侧翼，所有这三个区都以单一连续双链核酸形式存在。再有，依据本发明，每个同源区包括杂种双链核酸部分。每个杂种双链至少是4对碱基对，优选为8对碱基对，更优选为约20-30对碱基对。嵌合载体的作用并不受到杂种双链区内同质双链的二核苷酸碱基对的影响，置入嵌合载体使3′和5′末端彼此连接。两个同源区的长度至少为20对碱基对，优选在40-60对碱基对之间。
依据本发明，可将同质双链核酸区排列在载体的杂种双链/同源区之间。被插入的同质双链区可包括异源区。当异源区少于约50对碱基对，优选地少于约20对碱基对时，可存在或不存在被插入的同质双链区。当异源区超过约20对碱基对时，包含异源区的被插入同质双链是优选的。
5.2.本发明的嵌合载体的构建
可使用任意方法合成本发明的嵌合载体。使用经改进的用于DNA固相合成的技术可最简便地合成嵌合载体。参见Caruthers，M.H.，1985，Science 230：281-85；Itakura，K.等，1984，Ann.Rev.Biochem.53：523-56。可合成RNA和嵌合核酸的改进方法公开于Scaringe，S.A.等，1990，NucleicAcids Research 18：5433-41；Usman，N.等，1992，Nucleic Acids Research20：6695-99；和Swiderski，P.M.等，1994，Anal.Biochem.216：83-88，上述文献均全文引入本文以供参考。有关嵌合核酸合成的新近进展综述于Usman，N.&Cedergren，R.，1992，Trends Bioch.Sci.17：334-9。
插入两个杂种双链区之间的包含同质双链区的嵌合载体可使用半合成技术来建立。构建两种合成的具发夹构象的嵌合多聚核酸。使用与两种不同限制酶的消化产物的重叠部分互补的重叠交叉末端，构建两种嵌合核酸的游离3′和5′末端。得到与限制酶消化末端互补的同质双链区。可采用本领域技术人员熟知的技术来完成限制酶位点与克隆DNA片段末端的加成，所述技术例如，但不限于使用伸展引物的PCR扩增和包含限制位点的连接体的平整末端连接。可使用常规的酶促技术连接两种嵌合核苷酸和同质双链区。通过在Tris Borate EDTA缓冲液中的6％聚丙烯酰胺电泳从不完全反应的底物中分离两个末端连接的嵌合寡核苷酸。该线性加帽的分子是压缩的并且在这一条件下的电泳更缓慢。
仅含有天然产生的核苷酸的嵌合载体也可用于本发明。据发现包含约20个核糖核苷酸的杂种双链区的嵌合载体在体外是RNAse H抗性的。可通过用2′-O甲基化核糖核苷酸替代核糖核苷酸获得对酶促降解的抗性。另外或者可选择性地，核酸的磷酸二酯键可被硫代磷酸二酯键替代。Shimayama，T.等，1993，Nucleic Acids Research 21：2605.也可以使用含阿拉伯糖的核苷酸。本文所用术语核酸意指包括带有这些修饰的核酸。
5.3.本发明的嵌合载体的应用
本发明的嵌合载体可用于靶细胞基因组的特定位置上的突变。采用其核酸序列定义靶位的特定位置，下文中称此核酸序列为靶序。依据本发明构建嵌合载体，其中除存在某些杂种双链区外，同源区与靶序列一致。异源区编码被引入的变化。变化可是序列的一个或多个碱基变化或者是一个或多个碱基的加成。当靶序列的变化是少于约20个碱基的加成时，可采用一或二个杂种双链区实现本发明。当靶序列的变化是多于约50个碱基的加成时，则优选采用被包括在同质双链区内的异源区。
本发明的实现要求向靶细胞核中引入嵌合载体。任何导致这种引入的方法均可使用。这类方法包括电穿孔法，DEAE葡聚糖法，磷酸钙沉淀法，脂质体介导的融合法(LIPOFECTIN)和直接注射法。电穿孔法是特别适合的。
在本发明的一个实施方案中嵌合载体用于建立转基因动物。按照文献描述方法，采用直接注射法向卵细胞的原核中引入嵌合载体，所述文献是Brinster R.L.等，1989，PROC.NATL.ACAD.SCI.86：7087；还有T.E.Wagner和P.C.Hoppe的美国专利4,873,191，二者都全文引入本文以供参考。另外，可向胚胎干细胞中引入嵌合载体，可用正常胚泡细胞聚集胚胎干细胞从而产生嵌合动物，以嵌合动物的后代可重新获得转基因动物，该方法参见Capccchi，M.R.，1989，Science 244：1288，该文献全文引入本文以供参考。
采用电穿孔法，每10,000个被处理细胞就有一个细胞在靶序列上发生特异性突变(下文称“转化”)。因此，本发明的实践包括从大量未突变细胞中选择转化细胞的方法的使用。在另一个实施方案中，转化细胞的优点增多。这些增多的优点的非限制性实例包括抗药性，生长调节的改变和利用代谢物能力的改变。在另一个实施例中，选择方法是负选择法，使用该方法在所选择条件下使得被转化细胞不能生长，并且通过使其暴露在选择性破坏增殖细胞的条件下而除去未被转化的细胞。
另外，被转化的细胞可具有改变的细胞表面抗原表型，它可通过免疫荧光进行检测，采用荧光激活细胞分离器进行选择。
当向细胞中引入嵌合载体的方法是直接注射法时，例如当采用原核注射法建立转基因动物时，每10,000个细胞的转化率可高于1个细胞。因此，大大降低了选择的需要。
采用电穿孔法转化的嵌合载体的典型用量是每百万个培养细胞在10-1000ng之间。
6.实施例
6.1.实施例1：对黑粉菌属真菌的体内活性
野生型黑粉菌具有功能性的尿嘧啶(ura)-3基因，其产物是尿嘧啶生物合成途径中的一部分。当野生型黑粉菌生长于5′-fluororotic acid(5FOA)培养基中时，细胞由于该酸加入到上述途径中而死亡。假如尿嘧啶-3发生突变，则不会产生尿嘧啶-3 mRNA，细胞就得以在5FOA培养基中存活。
内源性尿嘧啶-3基因序列是本领域中已知的。在一组实验中，该序列的碱基358由腺嘌呤变为胸腺嘧啶，这一突变导致功能障碍蛋白的产生。
嵌合载体的合成如下：
碱基358突变的载体：(358 RNA载体)
5′TGCCGATCGGCAACTTTTGUUGCCGAUCGGCAAATTT 3′(SEQ ID：1)
该358载体采用发夹构象。划线碱基表示核糖核酸残基。黑体字母表示突变基因(异型区)。斜体″T″表示未配对碱基。
建立具有相同序列但不包含核糖核酸的载体作为对照。在该载体中胸腺嘧啶被尿嘧啶替代。
对照载体在碱基358进行突变：(DNA 358载体)
5′TGCCGATCGGCAACTTTTGTTGCCGATCGGCAAATTT 3′
(SEQ ID：2)也采用发夹构象。再者，黑体残基是突变基因。
进行体内转化实验，按照本领域所熟知的方法，将U.maydis细胞制成回收率为50ul转化缓冲液中106个细胞的原生质体，并使用不同量的嵌合载体进行转染或者将同源(仅DNA)载体与原生质体在37℃混合。然后，将细胞铺于所选择的培养基上，计数存活菌落(转化细胞)的数目。结果以下面的表格形式表示：
    转染数量(ug)   载体-358类型   存活菌落数
       0.1     DNA     0
       0.1     嵌合的     13
       0.25     DNA     1
       0.25     嵌合的     49
       0.75     DNA     12
       0.75     嵌合的     131
       1.0     DNA     19
       1.0     嵌合的     573
这些数据表明使用RNA 358载体的细胞转染与使用相应DNA载体的转染相比，极大地提高了细胞的存活率。
6.2.实施例2：NIH 3T3细胞的转化
NIH 3T3细胞是具有良性(可控制的)生长特性的人细胞。恶性(无控制的)生长特性是由致癌基因H→ras中的单位点突变给予的，所谓突变是由Thr替代Gly12。这样，G→T12导致生长特性的易于选择的变化。Taparowsky，E.等，1982，Nature 300：762；Sukumar S.等，1983，Nature306：658。
建立下述序列以指导发生G→T12突变的嵌合载体：5′-CACACCGACGGCGCCCACCACTTTGTGGTGGGCGCCGTCGGTGTGGGTTTGCC-3′(SEQ ID：3)
该序列以常规单字母代码表示，其它特点是未划线的表示RNA，未配对碱基是斜体，突变体碱基是黑体。需要注意的是，环化之后通过两个三胸腺嘧啶序列将嵌合载体分为两条基本上互补的链，并且所有含核糖的核苷酸仅存在于两条链中的一条。
使用2′-OMe核糖碱基合成两种形式的嵌合载体，它们分别具有一个(″R″)和两个(″R-D-R″)的翼侧有四个脱氧核糖残基的杂种双链区。R-D-R形式如上SEQ ID：3所示，R形式除碱基6-9是脱氧核苷酸外是相同的。值得注意的是，5′和3′末端是脱氧核苷酸。采用如在重组DNA中常用的相同DNA连接酶法，在合成之后环化嵌合载体。连接之后，通过两次重复的制备性D600凝胶(AT Biochem，Malvern，PA)电泳从底物中分离环化嵌合载体。
对照载体是：1)没有杂种双链的相同序列(“同质双链”
所示数据)；2)具有5′-GCCCACACCGACGGCGCCACCAC-3′(SEQ ID 4)序列的未配对DNA(“sDNA”所示数据)；3)没有异源区的嵌合载体，因而是没有突变基因的核苷酸(未显示数据)。
采用电穿孔法通过转化NIH 3T3细胞(1×106个细胞)进行实验。电穿孔法之后，将细胞以4×103个接种密度铺于培养基中并使其生长14天。用结晶紫染色灶形成细胞使转化细胞可见。使用编码T12形式的H ras的质粒pT24作为阳性对照。该对照用于测定转染的NIH 3T3细胞中的异常重组水平。该实验重复5次，下表表示其概括性结果。除下面所示结果外，使用没有突变基因密码子的嵌合载体的对照实验未显示出NIH 3T3细胞转化灶。
    载体类型      转染量(每106个细胞)     转化细胞每106个细胞(14天)
  pT24(阳性对照)     10ug         57
  sDNA     1ug         2
  sDNA     10ug         13
  同质双链     1ug         0
  同质双链     10ug         2
  嵌合的     50ng     R-D-R    R19       12
  嵌合的     200ng     55       43
  嵌合的     1ug     139      103
这些结果表明嵌合载体通过同源重组引入特定突变以转化哺乳动物细胞。该实验中的转化率大大高于通过异常重组的转化率，这是由使用包含完全突变的H-ras基因的pT24阳性对照载体进行转染观察到的。因此，在哺乳动物细胞中使用嵌合载体的同源重组率远远高于异常重组率。
                    序列表(1)普通信息：(i)申请者：Kmiec，Eric(ii)发明题目：用于真核细胞中定点突变的化合物和方法(iii)序列数：4(iv)通讯地址：(A)收信人：Pennie & Edmonds(B)街道：1155 Avenue of the Americas(C)城市：New York(D)国家：NY(F)邮政编码：10036-2731(v)可读计算机源：(A)媒介类型：软盘(B)计算机：IBM PC兼容机(C)操作系统：PC-DOS/MS-DOS(D)软件：PatentIn Release #1.0，Version #1.25(vi)当前申请资料：(A)申请号：US(B)递交日：(C)分类：(viii)律师/代理人信息：(A)姓名：Friebel，Thomas E.(B)注册号：29,258(C)文献/摘要号：7991-009(ix)通讯信息：(A)电话：(212)790-9090(B)传真：(212)869-8864/009(2)第一序列(SEQ ID：1)信息：(i)序列特征：(A)长度：37对碱基对(B)类型：核酸(C)链合方式：自身互补(D)拓扑结构：线性(ii)分子类型：DNA/RNA(ix)特点：(A)名称/检索表：-(B)位点：19..32(D)其它信息：/标记＝a/注＝″RNA″(xi)序列描述：第一序列描述：TGCCGATCGG CAACTTTTGU UGCCGAUCGG CAAATTT                  37(2)第二序列(SEQ ID：2)信息：(i)序列特征：(A)长度：37对碱基对(B)类型：核酸(C)链合方式：自身互补(D)拓扑结构：线性(ii)分子类型：DNA(xi)序列描述：第二序列描述：TGCCGATCGG CAACTTTTGT TGCCGATCGG CAAATTT                  37(2)第三序列(SEQ ID：3)信息：(i)序列特征：(A)长度：53对碱基对(B)类型：核酸(C)链合方式：自身互补(D)拓扑结构：线性(ii)分子类型：DNA/RNA(ix)特点：  (A)名称/检索表：-(B)位点：2..5(D)其它信息：/标记＝b/注＝″RNA″(ix)特点：(A)名称/检索表：(B)位点：10..21(D)其它信息：/标记＝d/注＝“RNA”
(ix)特点：(A)名称/检索表：(B)位点：51..52(D)其它信息：/标记＝f/注＝“RNA”(xi)序列描述：第三序列描述：CACACCGACG GCGCCCACCA CTTTGTGGTG GGCGCCGTCG GTGTGGGTTT GCC        53(2)第四序列(SEQ ID：4)信息：(i)序列特征：(A)长度：23对碱基对(B)类型：核酸(C)链合方式：自身互补(D)拓扑结构：线性(ii)分子类型：DNA(xi)序列描述：第四序列描述：GCCCACACCG ACGGCGCCAC CAC                                         23

Claims (27)

1.一种用于将预定的改变引入靶基因中的化合物，该化合物是具有至多一个3′末端和一个5′末端的混合的核糖-脱氧核糖核酸，所述核酸还包含：
a)至少一段邻接的未配对碱基的区域，该未配对区域将核酸分成第一链和第二链，所述第一链和第二链是由所述邻接的未配对碱基区域连接起来的；
b)至少一段长度至少为15个碱基对的沃森-克里克规则配对的核酸区域，其中第一链的碱基对应于第二链的碱基；并且其中
c)第一链含有至少三个邻接的核糖核苷酸的区域，该区域在沃森-克里克规则配对的核酸区域内形成杂种双链。
2.权利要求1的核酸，其中至少三个邻接的核苷酸是核糖核酸酶H抗性的。
3.权利要求2的核酸，其中第二链不含有由2′-OMe或2′-O核糖组成的核苷酸，第一链不含有由2′-O核糖组成的核苷酸。
4.权利要求1-3中任一权项的核酸，该核酸包含杂种双链的15-50个碱基对。
5.权利要求1-3中任一权项的核酸，其中5′和3′末端在沃森-克里克规则配对的核酸区域内与互补链的相邻碱基形成沃森-克里克规则配对。
6.权利要求4的核酸，其中5′和3′末端在沃森-克里克规则配对的核酸区域内与互补链的相邻碱基形成沃森-克里克规则配对。
7.权利要求1-3中任一权项的核酸，该核酸还含有邻接的未配对碱基的第二区域，该未配对区域将核酸分成第一链和第二链，所述第一链和第二链是由所述邻接的未配对碱基的第二区域连接起来的。
8.权利要求1-3中任一权项的核酸，其中第一链含有两个核糖核酸酶抗性核糖核苷酸的区域，所述区域形成两个杂种双链区域，每个杂种双链区域的长度至少为8个碱基对，并且具有一段处于杂种双链区之间的同质双链的至少4个碱基对形成的插入区。
9.权利要求8的核酸，其中同质双链的插入区由4-50个2′-脱氧核糖碱基对组成。
10.权利要求1的核酸，其还含有：
i.第一和第二同源区，它们共同的长度是从20到60个核苷酸，该区域与靶基因同源；
ii.一段异源区域，它处于第一和第二同源区之间，长度为1到20个核苷酸，它与靶基因是异源的，并含有预定的改变，其中
靶基因是非酵母或真菌的真核细胞的基因。
11.权利要求10的核酸，其中第一和第二同源区共同含有20-60个核糖核酸酶H抗性核糖核苷酸。
12.权利要求10的核酸，其中一个核糖核苷酸被2′-O-甲基化。
13.权利要求10的核酸，其中每个核糖核苷酸被2′-O-甲基化。
14.权利要求10-13中任一权项的核酸，其中异源区由脱氧核糖核苷酸组成。
15.权利要求10-13中任一权项的核酸，其中异源区的长度是一个核苷酸。
16.权利要求10-13中任一权项的核酸，其中异源区含有靶基因的一个插入或缺失。
17.权利要求1的核酸，其中
第二链含有一段至少九个脱氧核糖核苷酸的区域，该区域与第
一链的核苷酸形成杂种双链；
5′和3′末端与沃森-克里克规则配对核酸的互补链的相邻碱基
形成沃森-克里克规则配对。
18.权利要求17的核酸，其中第一链含有一个核糖核酸酶H抗性核糖核苷酸。
19.权利要求17的核酸，该核酸含有杂种双链的至少九个邻接的碱基对。
20.权利要求17-19中任一权项的核酸，其中第二链包含5′和3′末端。
21.权利要求17-19中任一权项的核酸，它含有杂种双链的至少15个碱基对。
22.权利要求20核酸，它含有杂种双链的至少15个碱基对。
23.权利要求17-19中任一权项的核酸，其中第一链含有两个邻接的核苷酸的区域，它们形成两个杂种双链区，每个杂种双链区的长度至少是4个碱基对，在杂种双链区之间有一个由同质双链的至少一个碱基对形成的插入区。
24.权利要求23的核酸，其中第二链含有5′和3′末端。
25.权利要求23的核酸，它含有杂种双链的至少15个碱基对。
26.权利要求1-25中任一权项的核酸在向真核细胞引入遗传改变中的应用。
27.权利要求1-25中任一权项的核酸在向非酵母或真菌的真核细胞引入遗传改变中的应用。
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GR3034988T3 (en) 2001-03-30
KR960706500A (ko) 1996-12-09
US5565350A (en) 1996-10-15
US5756325A (en) 1998-05-26
PT733059E (pt) 2001-03-30
ES2149962T3 (es) 2000-11-16
AU1399595A (en) 1995-06-27
KR100386337B1 (ko) 2004-03-24
DE69425903T2 (de) 2001-02-15
EP0733059A4 (en) 1997-05-21
DE69425903D1 (de) 2000-10-19
JPH09506511A (ja) 1997-06-30
EP0733059A1 (en) 1996-09-25
DK0733059T3 (da) 2000-10-16
US5871984A (en) 1999-02-16
ATE196311T1 (de) 2000-09-15
DE733059T1 (de) 1997-08-28
WO1995015972A1 (en) 1995-06-15
CN1142829A (zh) 1997-02-12
NZ278490A (en) 1998-03-25
AU691550B2 (en) 1998-05-21
CA2178729A1 (en) 1995-06-15
JP3585238B2 (ja) 2004-11-04
CN1117866C (zh) 2003-08-13
CN1215755A (zh) 1999-05-05

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