CN110157726A - 植物基因组定点替换的方法 - Google Patents
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Abstract
本发明提供了一种植物基因组定点替换的方法，具体地，本发明涉及一种核酸构建物，本发明采用特定结构的核酸构建物，首次在植物中成功实现了sgRNA引导的碱基定点突变(如T突变为C或A突变为G)。
Description
技术领域
本发明涉及生物技术领域，具体地，涉及植物基因组定点替换的方法。
背景技术
在真核生物中，用基因组进行单碱基分辨率的精确修饰主要是通过同源重组完成。然而，同源重组的固有的低效率和外源供体DNA模板的依赖性极大地限制了其在许多物种中的使用(Komor et al.，2017a)。目前由APOBEC/AID基因家族介导的C-T的碱基替换虽然高效，但是突变的形式比较单一，而且突变产物中往往会伴随的InDel的产生。由于插入或缺失突变常常会导致移码突变，因此造成基因编辑的风险上升。
因此，本领域迫切需要开发一种在植物细胞中可高效且精确地实现T-C(或者A-G)转化同时显著降低插入或缺失突变风险的方法。
发明内容
本发明的目的在于提供一种在植物细胞中可高效且精确地实现T-C转化的方法。
本发明第一方面提供了一种核酸构建物，所述核酸构建物具有5’-3’(5’至3’)的式I结构：
I1-Z1-Z2-I2(I)
式中，
I1为第一整合元件；
I2为第二整合元件；
Z1为第一表达盒；
Z2为第二表达盒；
并且，Z1和Z2中的一个表达盒具有Ia结构，而另一个表达盒具有式Ib结构：
P1-S1-X1-L1-X2-L2-X3(Ia)
P2-Y1(Ib)；
式中，
P1、S1、X1、L1、X2、L2、X3、P2、Y1分别为用于构成所述构建物的元件；
P1为第一启动子，所述第一启动子包括泛素启动子；
S1为无或信号肽的编码序列；
X1为腺嘌呤脱氨酶(如野生型和/或突变型TadA)的编码序列；
L1为无或第一连接肽的编码序列；
X2为Cas9核酸酶的编码序列，所述的Cas9核酸酶是无切割活性或单链切割活性的；
L2为无或第二连接肽的编码序列；
X3为核定位信号的编码序列，所述核定位信号为VirD2；
P2为第二启动子；
Y1为sgRNA的编码序列；
并且，各“-”为键或核苷酸连接序列。
在另一优选例中，所述泛素启动子包括玉米泛素启动子。
在另一优选例中，所述泛素启动子包括UBI启动子。
在另一优选例中，所述第二启动子包括U6启动子。
在另一优选例中，所述的“无切割活性或单链切割活性”指Cas9核酸酶对于靶位点T所在的单链无切割活性。
在另一优选例中，本发明的上述核苷酸元件是按阅读框(in-frame)连接的，从而表达氨基酸序列正确的融合蛋白。
在另一优选例中，所述的构建物具有式IIa或式IIb结构：
I1-P1-S1-X1-L1-X2-L2-X3-P2-Y1-I2(IIa)；
I1-P2-Y1-P1-S1-X1-L1-X2-L2-X3-I2(IIb)；
式中，各元件的定义如上所述。
在另一优选例中，所述的sgRNA的第5位-第10位对应于预定发生T→C定点突变的位置(即为T)。
在另一优选例中，所述的sgRNA的第6-14位对应于预定发生T→C定点突变的位置(即为T)。
在另一优选例中，所述的sgRNA的第12位、第13位和/或第14位对应于预定发生T→C定点突变的位置(即为T)。
在另一优选例中，所述的L1和L2的序列长度各自独立地为3-120nt,较佳地， 3-96nt，并且优选为3的倍数。
在另一优选例中，所述的核苷酸连接序列长度为1-300nt，较佳地1-100nt。
在另一优选例中，所述的第一表达盒和第二表达盒均具有终止子。
在另一优选例中，所述第一整合元件包括5’同源臂序列。
在另一优选例中，所述第一整合元件为RB序列。
在另一优选例中，所述RB序列如SEQ ID NO.:1(TAAACGCTCTTTTCTCTTAGGTTTAC)所示。
在另一优选例中，所述信号肽包括VirD2的核定位信号肽。
在另一优选例中，所述Cas9核酸酶选自下组：Cas9、Cas9n、或其组合。
在另一优选例中，所述Cas9核酸酶为突变的Cas9核酸酶。
在另一优选例中，所述X2元件中，突变位点在Cas9核酸酶(SEQ ID NO.:2) 的D10A位。
MDKKYSIGLAIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEATRLKRTARRR YTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQTYNQLFEENPINASGVDAKAILS ARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGD QYADLFLAAKNLSDAILLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQS KNGYAGYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQ EDFYPFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMTN FDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQLKEDY FKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTY AHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQK AQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVMGRHKPENIVIEMARENQTTQKGQKNSRERM KRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDSI DNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVE TRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVG TALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIET NGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGFDS PTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKLPKYSLFELE NGRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSK RVILADANLDKVLSAYNKHRDKPIREQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIH QSITGLYETRIDLSQLGGD(SEQ ID NO.:2)
在另一优选例中，所述X2元件中，Cas9核酸酶的氨基酸序列如SEQ ID NO.:69 所示。
在另一优选例中，所述X2元件的来源选自下组：酿脓链球菌(Streptococcuspyogenes)、葡萄球菌(Staphylococcus aureus)、或其组合。
在另一优选例中，所述连接序列包括XTEN。
在另一优选例中，所述连接序列如SEQ ID NO.:3(TCTGGAGGGTCCTCCGGCGGATCGTCCGGCAGCGAGACGCCAGGCACCTCCGAGAGCGCTACGCC TGAATCCTCCGGGGGATCTTCAGGAGGATCA)所示。
在另一优选例中，所述腺嘌呤脱氨酶包括TadA。
在另一优选例中，所述腺嘌呤脱氨酶包括野生型和突变型。
在另一优选例中，所述腺嘌呤脱氨酶的突变型包括TadA7-10。
在另一优选例中，所述腺嘌呤脱氨酶为串联型腺嘌呤脱氨酶，所述串联型腺嘌呤脱氨酶结构如式II所示：
Z8-L8-Z9(II)
其中，
Z8为野生型的腺嘌呤脱氨酶TadA的氨基酸序列；
L8为任选的连接肽序列；
Z9为突变型的腺嘌呤脱氨酶TadA7-10的氨基酸序列。
在另一优选例中，所述第一启动子来源于选自下组的一种或多种植物：玉米、水稻、大豆、拟南芥、番茄。
在另一优选例中，所述第二启动子来源于选自下组的一种或多种植物：水稻、玉米、大豆、拟南芥、番茄。
在另一优选例中，所述第二整合元件包括3’同源臂序列。
在另一优选例中，所述第二整合元件为LB序列。
在另一优选例中，所述LB序列如SEQ ID NO.:4(TGTTTACACCACAATATATCCTGCCA)所示。
在另一优选例中，所述核定位信号来源于农杆菌。
在另一优选例中，所述核酸构建物的长度为5000-10000bp，较佳地， 7500-8500bp。
在另一优选例中，在所述的I1和I2元件之间，还含有额外插入的一个或多个额外的表达盒。
在另一优选例中，所述的额外表达盒是独立于所述的第一表达盒和第二表达盒的。
在另一优选例中，所述的额外表达盒表达选自下组的物质：
(a1)标记基因；
(a2)与Y1编码的sgRNA不同的一种或多种sgRNA。
在另一优选例中，所述标记基因包括抗性基因(潮霉素基因)、荧光基因、或其组合。
本发明第二方面提供了一种载体，所述载体含有本发明第一方面所述的核酸构建物。
在另一优选例中，所述载体为植物表达载体。
在另一优选例中，所述的载体为可转染或转化植物细胞的表达载体。
在另一优选例中，所述的载体为农杆菌Ti载体。
在另一优选例中，所述的构建物整合到所述载体的T-DNA区。
在另一优选例中，所述载体是环状的或线性的。
本发明第三方面提供了一种基因工程细胞，所述细胞含有本发明第一方面所述的核酸构建物，或其基因组整合有一个或多个本发明第一方面所述的核酸构建物。
在另一优选例中，所述的细胞为植物细胞。
在另一优选例中，所述的植物选自下组：禾本科植物、豆科植物、十字花科植物、或其组合。
在另一优选例中，所述的植物包括：拟南芥、小麦、大麦、燕麦、玉米、水稻、高粱、粟、大豆、花生、烟草、番茄、或其组合。
在另一优选例中，所述的基因工程细胞是用选自下组的方法将本发明第一方面所述的核酸构建物导入细胞的：农杆菌转化法、基因枪法、显微注射法、电击法、超声波法和聚乙二醇(PEG)介导法。
本发明第四方面提供了一种对植物进行基因编辑的方法，包括步骤：
(i)提供待编辑植物；和
(ii)将本发明第一方面所述的核酸构建物或本发明第二方面所述的载体导入所述待编辑植物的植物细胞，从而在所述植物细胞内进行基因编辑。
在另一优选例中，所述步骤(ii)和步骤(iii)中的植物细胞来自同一部位。
在另一优选例中，所述导入为通过农杆菌导入。
在另一优选例中，所述导入为通过基因枪导入。
在另一优选例中，所述的基因编辑为定点碱基替换(或突变)。
在另一优选例中，所述定点替换(或突变)包括将T突变为C和/或A突变为G。
在另一优选例中，所述的植物选自下组：禾本科植物、豆科植物、十字花科植物、或其组合。
在另一优选例中，所述的植物包括：拟南芥、小麦、大麦、燕麦、玉米、水稻、高粱、粟、大豆、花生、烟草、番茄、或其组合。
本发明第五方面提供了一种制备转基因植物细胞的方法，包括步骤：
(i)将本发明第一方面所述的核酸构建物、或本发明第二方面所述的载体转染植物细胞，使得所述核酸构建物与所述植物细胞中的染色体发生定点替换(或突变)，从而制得所述转基因植物细胞。
在另一优选例中，所述的转染采用农杆菌转化法或基因枪轰击法。
本发明第六方面提供了一种制备转基因植物细胞的方法，包括步骤：
(i)将本发明第一方面所述的核酸构建物、或本发明第二方面所述的载体转染植物细胞，使得所述植物细胞含有所述核酸构建物，从而制得所述转基因植物细胞。
本发明第七方面提供了一种制备转基因植物的方法，包括步骤：
将本发明第五方面或本发明第六方面所述方法制备的所述转基因植物细胞再生为植物体，从而获得所述转基因植物。
本发明第八方面提供了一种转基因植物，其特征在于，所述的植物是用本发明第七方面所述的方法制备的。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了水稻中A.T到G.C的高效碱基编辑。
其中，(A)两个水稻腺嘌呤碱基编辑载体pRABEsp-OsU6和pRABEsa-OsU6sa 的示意图。(B)OsSPL14基因中sgRNA1靶位点的示意图。OsmiR156与OsSPL14 结合的序列以红色突出显示。(C)两个代表性的OsSPL14编辑植株SG1-7和 SG1-15的测序峰图。(D)SLR1基因中sgRNA2靶位点的示意图。原间隔序列 (protospacer)区第6位的T-C替换可能导致TVHYNP基序中92位氨基酸V变为A。(E)两个SLR1编辑植株SG2-18和SG2-19的测序峰图。(F)设计的sgRNA4 同时靶向编辑OsSPL14和OsSPL17基因。OsSPL14和OsSPL17中的OsmiR156结合序列以红色突出显示。(G)OsSPL14和OsSPL17在两个转基因水稻系SG4-5和 SG4-25中都发生碱基编辑。两个株系两个靶位点的测序峰图如图所示。(H)本发明中使用不同sgRNA的碱基编辑效率的统计。水稻中的多位点碱基编辑分别由sgRNAs3-5引导。
图2显示了sgRNA1靶向OsSPL14基因的两个碱基编辑植株(SG1-7和 SG1-15)的TA克隆测序结果。随机选取每行20个克隆进行测序，显示了每个基因型的代表性测序峰图。
图3显示了pRABEsp-OsU6可用于水稻的多重碱基编辑。
其中，(A)sgRNA3被设计用于同时靶向编辑水稻基因组中的三个基因。三个基因中的OsmiR156结合核苷酸以红色突出显示。(B)提供了三个靶位点的代表性序列峰图。在SG3-11和SG3-12植株中，同时编辑OsSPL16和OsSPL18中的目标站点同时编辑，但LOC_Os02g24720的目标位点在这两个植株中为野生型。
图4显示了pRABEsa-OsU6sa在OsSPL16和OsSPL18上同时进行碱基编辑。
其中，(A)sgRNA5可同时靶向OsSPL16和OsSPL18两个位点。(B)代表性的三个转基因植株SG5-7，SG5-18，SG5-44在两个靶位点的测序峰图。这两个基因都是在三个选定的转基因植株中被同时编辑了。
图5显示了ABE-P1S对OsSPL14靶位点的编辑。
其中，A.ABE-P1S碱基编辑器的载体示意图.B.OsSPL14基因中sgRNA1 靶位点的示意图。OsmiR156与OsSPL14结合的序列以红色突出显示。C.两个代表性的株系Line 7和Line12在OsSPL14靶位点的测序峰图，黑色箭头指示了发生碱基替换的位点。D.ABE-P1S对OsSPL17位点的脱靶编辑，。OsmiR156 与OsSPL17结合的序列以红色突出显示，错配碱基字母小写，黑色箭头指示了发生碱基替换的位点。
图6显示了ABE-P2S对SPX2-MFS2位点的编辑。
其中，A.ABE-P2S碱基编辑器的载体示意图.B.SPX2-MFS2基因中sgRNA8 靶位点的示意图。OsmiR827与SPX2-MFS2结合的序列以红色突出显示。C.两个代表性的株系Line 38和Line 40在SPX2-MFS2靶位点的测序峰图，黑色箭头指示了发生碱基替换的位点。
图7显示了ABE-P5和ABE-P5S对OsSPL13位点的编辑。
其中，A.ABE-P5和ABE-P5S碱基编辑器的载体示意图.B.OsSPL13基因中sgRNA11靶位点的示意图。OsmiR156与OsSPL13结合的序列以蓝色突出显示， PAM序列由红色字母标出。C.代表性的株系Line3，Line 23和Line 27在OsSPL13 靶位点的测序峰图，黑色箭头指示了发生碱基替换的位点。
具体实施方式
本发明人经过广泛而深入地研究，通过大量筛选，筛选出驱动Cas9核酸酶与腺嘌呤脱氨酶、核定位信号VirD2构成的融合蛋白表达的特定启动子，以及驱动sgRNA转录的特定的启动子，并通过采用特定结构的核酸构建物，本发明首次在植物中成功实现了sgRNA引导的碱基定点突变(如T突变为C或A突变为 G)，并且突变效率非常高(可高达≥60％或更高)，并且申请人意外的发现，简化后的腺嘌呤碱基编辑器ABE-P1S具有更高的碱基编辑效率。并在此基础上完成了本发明。
术语
如本文所用，术语“同源臂”指打靶载体上待插入的外源序列两侧的与基因组序列完全一致的侧翼序列，用于识别并发生重组的区域。
如本文所用，术语“植物启动子”指能够在植物细胞中启动核酸转录的核酸序列。该植物启动子可以是来源于植物、微生物(如细菌、病毒)或动物等，或者是人工合成或改造过的启动子。
如本文所用，术语“碱基突变”指核苷酸序列的某一位置处发生碱基的替换(substitution)、插入(insertion)和/或缺失(deletion)。
如本文所用，术语“碱基替换”指核苷酸序列的某一位置处的碱基突变为另一不同的碱基，比如T突变为C。
如本文所用，术语“A.T到G.C”指在双链核酸序列(尤其是基因组序列) 中，某一位置上的A-T碱基对突变为或替换为G-C碱基对。
如本文所用，“筛选标记基因”指转基因过程中用来筛选转基因细胞或转基因动物的基因，可用于本申请的筛选标记基因没有特别限制，包括转基因领域常用的各种筛选标记基因，代表性例子包括(但并不限于)：潮霉素抗性基因 (Hyg)、卡那霉素抗性基因(NPTII)、新霉素基因、嘌呤霉素抗性基因、潮霉素的抗性基因(HYG)、G418和卡那霉素的抗性基因(NPTII)、Basta的抗性基因(BAR)、嘌呤霉素抗性基因(PAC)、和/或新霉素抗性基因(NEO)。
如本文所用，术语“Cas蛋白”指一种核酸酶。一种优选的Cas蛋白是Cas9 蛋白。典型的Cas9蛋白包括(但并不限于)：来源于酿脓链球菌 (Streptococcuspyogenes)的Cas9。在本发明中，Cas9蛋白为突变的Cas9蛋白，具体地，是无切割活性或只具有单链切割活性的突变的Cas9蛋白。
如本文所用，术语“Cas蛋白的编码序列”指编码Cas蛋白的核苷酸序列。在插入的多聚核苷酸序列被转录和翻译从而产生功能性Cas蛋白的情况下，技术人员会认识到，因为密码子的简并性，有大量多聚核苷酸序列可以编码相同的多肽。另外，技术人员也会认识到不同物种对于密码子具有一定的偏好性，可能会根据在不同物种中表达的需要，会对Cas蛋白的密码子进行优化，这些变异体都被术语“Cas蛋白的编码序列”所具体涵盖。此外，术语特定地包括了全长的、与Cas基因序列基本相同的序列，以及编码出保留Cas蛋白功能的蛋白质的序列。
在本发明中，核苷酸序列的描述是从5’至3’方向，除非特别注明。
腺嘌呤脱氨酶
如本文所用，术语“腺嘌呤脱氨酶”指TadA腺嘌呤脱氨酶，来源于大肠杆菌，原本作用于tRNA，能够对tRNA中的特定腺嘌呤进行脱氨反应。
在本发明中，适用的TadA既包含野生型的形式也包含其特定的突变形式 TadA7-10，也可包含野生型的形式和突变形式的组合。TadA7-10能够以DNA作为底物进行脱氨反应。
在另一优选例中，本发明的腺嘌呤脱氨酶的编码序列是对密码子进行优化的，从而能够更高效地在植物中表达。
本发明的构建物
本发明提供了一种核酸构建物，用于对植物进行基因编辑，所述的核酸构建物具有5’-3’的式I结构：
I1-Z1-Z2-I2(I)
其中，
I1为第一整合元件；
I2为第二整合元件；
Z1为第一表达盒；
Z2为第二表达盒；
并且，Z1和Z2中的一个表达盒具有Ia结构，而另一个表达盒具有式Ib结构：
P1-S1-X1-L1-X2-L2-X3(Ia)
P2-Y1(Ib)；
I1、P1、S1、X1、L1、X2、L2、X3、L3、P2、Y1、I2分别为用于构成所述构建物的元件，其定义如本发明第一方面所述；
并且，各“-”为键或核苷酸连接序列。
在上述式I结构中，I1元件(或左侧整合元件)和I2元件(或右侧整合元件)可协同作用，从而将位于其间的元件(即从P1至Y1的核苷酸序列)整合到植物细胞的基因组中。
代表性的I1和I2是来自于农杆菌的Ti元件。当然，其他可起到类似整合作用的元件也可用于本发明。
本发明的构建物中所用的各种元件或者是本领域中已知的，或者可用本领域技术人员已知的方法制备。例如，可通过常规方法，如PCR方法、全人工化学合成法、酶切方法获得相应的元件，然后通过熟知的DNA连接技术连接在一起，就形成了本发明的构建物。
将本发明的构建物插入外源载体(尤其是适合转基因植物操作的载体)，就构成了本发明的载体。
将本发明的载体转化植物细胞从而介导本发明的载体对植物细胞染色体进行整合，制得转基因植物细胞。
将本发明的转基因植物细胞再生为植物体，从而获得转基因植物。
将本发明构建好的上述核酸构建物，通过常规的植物重组技术(例如农杆菌转让技术)，可以导入植物细胞，从而获得携带所述核酸构建物(或带有所述核酸构建物的载体)的植物细胞，或获得基因组中整合有所述核酸构建物的植物细胞。
载体构建
该载体的主要特征是将腺嘌呤脱氨基酶与CRISPR/Cas系统中的Cas蛋白以及核定位信号VirD2的编码序列连接在一起，从而形成融合蛋白的编码序列。当该编码序列所编码的融合蛋白在细胞质中表达后，所述的融合蛋白可以非常高效地被转移至细胞核内，并由式I构建物所编码的guide RNA引导至基因组中的靶点位置，从而在靶点位置进行A.T到G.C的碱基替换，并基本上避免或消除了发生插入/缺失的风险。
由于腺嘌呤脱氨基酶直接将T突变为C或A突变为G，并不需要Cas蛋白的DNA双链切割活性。因此，在本发明中Cas蛋白是无切割活性的突变的Cas 蛋白。在一优选实施方式中，本发明的Cas蛋白可以是SaKKH-Cas9(D10A)，其氨基酸序列如SEQ ID NO.:69所示。一般的，为了增加融合蛋白的活性，蛋白间一般通过一些柔性短肽连接，即Linker(连接肽序列)。优选的，该Linker 可以选用XTEN。
在本发明中，合适的启动子包括组成型和/或诱导型启动子。优选地，为了增加效率，可以选择适用于植物细胞的强启动子，代表性的例子包括(但并不限于)：CaMV 35S启动子或者UBI启动子或Actin启动子等。
选择适用于植物细胞的guide RNA的表达框，并将其与上述融合蛋白的开放表达框(ORF)构建在同一载体。
靶点设计
在本发明中，当腺嘌呤脱氨基酶通过CRISPR/Cas9系统引导至靶点位置后，脱氨基酶的作用区域就被固定的。
例如，将腺嘌呤脱氨基酶TadA或突变型的腺嘌呤脱氨基酶TadA7-10蛋白通过32个氨基酸的XTEN Linker连接至Cas9的N端后，通常，在人细胞系里面其脱氨基的作用区域为原间隔序列(protospacer)区的第4-7个碱基区域，本发明得到的实验结果表明，如果用SpCas9,碱基编辑窗口为原间隔序列 (protospacer)区第5-10位，如果用SaCas9,碱基编辑窗口为原间隔序列 (protospacer)区第6-14位。根据这一原则，在设计靶点时，需将待编辑的腺嘌呤处于“脱氨基窗口区”。
遗传转化
在本发明中，对于将本发明的式I构建物导入细胞或整合到基因组的方法，没有特别限制。可以用常规的方法进行，例如将式I构建物或相应的载体通过合适的方法导入到植物细胞中。代表性的导入方法包括但并不限于：农杆菌转染法、基因枪法、显微注射法、电击法、超声波法、和聚乙二醇(PEG)介导法等。
在本发明中，对于受体植物没有特别限制，其中包括各种不同的农作物植物(如禾本科植物)、林业植物、园艺植物(如花卉植物)等。代表性的例子包括但不限于：水稻、大豆、番茄、玉米、烟草、小麦、高粱等。
上述DNA载体或片段导入植物细胞后，使转化的植物细胞中的DNA表达该融合蛋白和gRNA。融合腺嘌呤脱氨基酶的Cas蛋白在相应gRNA的引导下，将靶点位置的T突变为C(进而使得互补链的A突变为G)。
对于用本发明方法进行植物基因组定点替换后的植物细胞或组织或器官，可以用常规方法再生获得相应的转基因植株。例如，通过组织培养，再生获得碱基替换后的植株。
应用
本发明可以用于植物基因工程领域，用于植物研究和育种，尤其是具有经济价值的农作物、林业作物或园艺植物的遗传改良。
本发明的主要优点包括：
(1)本发明首次提供了一种在植物中实现定点碱基突变(T→C或A→G)的高效方法，可以广泛的用于植物研究和育种。
(2)本发明的定点碱基突变的方法可高效地在植物细胞的特定位置进行碱基突变(如T→C或A→G)。
(3)用本发明的方法在植物细胞中进行碱基替换的效率非常高，可高达60％或更高。
(4)本发明能够同时对植物基因组中的多个位点同时进行编辑。
(5)本发明可以通过使用不同形式的Cas9，扩大植物基因组中可被定点编辑的位点。
(6)本发明可显著降低或基本上消除在靶位点发生插入和/或缺失的风险。
(7)本发明发现，sgRNA的第12位、第13位和/或第14位对应于预定发生T →C定点突变的位置(即为T)(从5’至3’)的碱基替换效率更高。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。本发明中所涉及的实验材料和试剂如无特殊说明均可从市售渠道获得。
通用方法
1.载体构建
用常规方法合成大肠杆菌野生型tRNA腺嘌呤脱氨基酶基因TadA(ecTadA) 和其突变体形式TadA7-10(ecTadA*7.10)。TadA和TadA7-10 3’端还各加有一段编码32个氨基酸残基的连接肽序列的96bp的接头编码序列。TadA-linker 和TadA7-10-linker两端分别加有AarI酶切位点。
通过对pCas9(OsU6)载体的改造，我们获得水稻腺嘌呤碱基编辑载体。
pCas9(OsU6)载体中Cas9基因由玉米泛素启动子驱动表达，sgRNA骨架由水稻U6启动子驱动表达。Cas9(D10A)切口酶和SaCas9(D10A)切口酶通过PCR 以pCas9(OsU6)和pX600(Addgene,#61592)为模板扩增获得。上游引物5’端含有两个AarI酶切位点，下游引物3’端加有VirD2核定位信号，扩增产物回收后用于替换pCas9(OsU6)中的Cas9基因。分别得到中间载体pRSp-OsU6and pRSa-OsU6。。TadA-linker和TadA7-10-l inker片段通过GoldenGate的方式连入pRSp-OsU6和pRSa-OsU6，分别获得pRABESp-OsU6和pRBESa-OsU6载体。
通过overlap PCR，将水稻U6启动子，两个BsaI酶切位点，和SaCas9的 sgRNA骨架连接在一起用于替换pRBESa-OsU6中OsU6-sgRNA片段，获得载体 pRABESa-OsU6Sa。
简化版腺嘌呤碱基编辑载体构建
为了构建简化版的腺嘌呤碱基编辑载体，我们首先对合成的ecTadA* (7.10)两端的AarI酶切位点接头进行了改造，然后通过金门克隆的方式将单个ecTadA*(7.10)连接到之前构建的pRSp-OsU6and pRSa-OsU6中间载体中，得到载体pRSABESp-OsU6和pRSABESa-OsU6。pRSABESp-OsU6即对应腺嘌呤碱基编辑器ABE-P1S。用HindIII和XmaI从之前构建的pRABESa-OsU6Sa 载体上切下OsU6-SasgRNA表达盒来替换掉pRSABESa-OsU6中 OsU6-SpsgRNA表达盒，获得pRSABESa-OsU6Sa载体，它对应腺嘌呤碱基编辑器ABE-P2S。我们用PCR从pRABEsa-SaKKH载体上扩增得到nSaKKH-Cas9 (D10A)缺口酶，用它替换pRSABESa-OsU6Sa载体中的nSaCas9(D10A)，得到pRSABEsa-SaKKH载体，它对应腺嘌呤碱基编辑器ABE-P5S。
pRABESp-OsU6和pRABESa-OsU6Sa载体骨架上含有潮霉素基因用于转基因植株的筛选。
人工合成sgRNA1至sgRNA5的序列。引物在PCR仪上退火后形成短的寡聚核苷酸接头，寡聚核苷酸接头插入到由BsaI酶切的pRABESp-OsU6， pRABESa-OsU6Sa载体中。
所有的载体都通过Sanger测序确认其准确性。
2.水稻转化
所有的双元载体通过冻融法转入常规的农杆菌EHA105之中。水稻转化受体为日本晴。具体的实验步骤按(Nishimura et al.,2007)等报道的进行。愈伤组织在农杆菌侵染两天以后转到含50mg/L潮霉素的筛选培养基上进行筛选。筛选2周以后，抗性愈伤组织直接转到分化培养基之中进行分化。待小苗长到 4-5cm长时，转到生根培养基中诱导生根。10天过后，打开生根盒炼苗3天后转到营养土中，放入温室生长，温室条件为28℃，光照12小时，22℃黑暗 12小时。
3.目标位点基因型检测
以CTAB法提取所有转基因水稻植株的叶片DNA。在靶标位点上下游各 250bp左右设计引物，通过PCR扩增出目标位点。PCR产物回收后直接送公司测序。测序结果有Sequencher软件分析。对于有些在目标位点发生编辑的植株，我们通过TA克隆进行了进一步的验证。具体为目标位点通过PCR扩增，纯化后连入p-EASY blunt Zero载体转化大肠杆菌。随机挑选20个克隆进行测序。碱基编辑的效率的计算由产生碱基编辑的植株数目除以总的转基因数目。
4.脱靶位点的检测
对于sgRNA1和sgRNA4的脱靶位点进行预测分析。水稻基因组中与sgRNA1 和sgRNA4序列错配低于5个碱基以下的位点被认为是潜在的脱靶位点。在所有潜在脱靶位点上下游各250bp左右设计引物，PCR扩增出这些潜在脱靶位点， PCR产物纯化后直接送公司进行测序。测序结果有Sequencher软件分析。
实施例1测试ABE7-10在水稻中的编辑效果
在本实施例中，根据通用方法，本发明合成了野生型ecTadA及其突变体形式ecTadA*7.10的编码序列。然后通过使用编码32个氨基酸残基的接头编码序列将它们连接在一起。接下来，将该重组蛋白的编码序列与具有相同接头的Cas9(D10A)切口酶编码序列的N-末端融合。最后将VirD2核定位信号的编码序列连接到Cas9(D10A)切口酶的C端，以形成ABE7-10。然后将ABE7-10 克隆到玉米泛素启动子控制下的双元载体中，并且通过水稻U6启动子驱动 sgRNA，形成载体pRABEsp-OsU6(图1A)。
为了测试ABE7-10在水稻中的编辑效果，我们选择调节水稻理想株型的 IPA1(OsSPL14)作为靶基因(图1B)。
本发明设计了一个sgRNA(sgRNA1)靶向OsSPL14的OsmiR156结合位点序列(图1B)，sgRNA1载体构建所对应的引物为表3中的sgRNA1F和sgRNA1R。该双元载体以冻融法转化农杆菌，然后以农杆菌侵染水稻日本晴的愈伤组织，获得了23个独立的转基因系。然后，通过PCR扩增目标区域，并通过Sanger测序进行基因型鉴定,扩增引物为表3中SPL14-seq-F和SPL14-seq-R。
表3本发明用到的引物
根据测序结果，在23株转基因植株中有6株在目标位点显示了预期的T-C 替换，碱基编辑效率高达26％(6/23)(图1H)。在这6个株系中，两个株系 (SG1-11，SG1-21)在protospacer的第5位具有T-C替换(将PAM位点定为 21-23)，两个株系(SG1-10，SG1-15)protospacer的5和7位具有T-C替换，而其余两株(SG1-7，SG1-23)在protospacer的5和10具有T-C置换(图1C)。
本发明发现两个转基因植株(SG1-7和SG1-10)在protospacer的第10位发生编辑(图1C)。为了进一步确认Sanger测序结果，选择了SG1-7和SG1-15 进行TA克隆，随机挑选了20个克隆进行测序。有趣的是，本发明发现来自SG1-7 的11个克隆在protospacer第5位具有T-C替换，9个克隆在protospacer 的第10位具有T-C取代，表明这株转基因是bi-allele(图2)。然而，SG1-15 株系只有15％的克隆(3/20)在protospacer的5和7位有T-C替换，表明该转基因植株是嵌合型的(图2)。
为了评估ABE7-10在水稻中的特异性，通过在线工具CRISPR-GE预测了 sgRNA1在水稻基因组中的潜在脱靶位点。对九个潜在脱靶位点的测序未发现任何碱基编辑事件。九个脱靶位点的信息见表1，对九个潜在脱靶位点扩增所用的引物见表3。
表1.sgRNA1潜在脱靶位点的编辑效率
注：PAM序列的核苷酸以粗体书写，潜在脱靶的错配碱基以小写字母显示。
测序结果表明，腺嘌呤碱基编辑在水稻中是高度特异的。
实施例2测试水稻中腺嘌呤碱基编辑系统的编辑能力
为了进一步测试水稻中腺嘌呤碱基编辑系统的编辑能力，对SLR1基因座做进一步实验。SLR1编码水稻中的DELLA蛋白，其作为GA信号传导途径中的阻遏物。
本发明设计了针对SLR1的TVHYNP结构域的sgRNA(sgRNA2)。sgRNA2载体构建所对应的引物为表3中的sgRNA2F和sgRNA2R。Protospacer第6位的T-C 碱基替换可导致TVHYNP基序中的V92A替换(图1D)。
从获得的40个转基因株系中，5个株系在protospacer的6位具有预期的 T-C替换(图1E，1H)。目标区域扩增引物为表3中SLR-seq-F和SLR-seq-R由于在SLR1的碱基编辑窗口中只有一个可编辑的T，因此在目标基因座中没有发现任何其他的突变形式。这些结果证实了水稻中腺嘌呤碱基编辑系统的高特异性。
实施例3检测本发明的碱基编辑系统是否可以同时编辑水稻基因组中的两个或多个位点
为了检测本发明的碱基编辑系统是否可以同时编辑水稻基因组中的两个或多个位点，同时设计了第三个sgRNA(sgRNAs3)，同时靶向OsSPL16和OsSPL18 的OsmiR156结合位点(图3，A和B)。sgRNA3载体构建所对应的引物为表3中的sgRNA3F和sgRNA3R。另外，在LOC_Os02g24720基因的内含子中发现了一个与sgRNA3序列100％匹配的脱靶位点(图3，A和B)。因此，sgRNA3可以同时靶向水稻基因组中的三个位点。本发明对21个转基因株系中的这三个靶位点进行了基因型鉴定。各有四个转基因株系在OsSPL16和OsSPL18靶向区域中显示T-C替换。然而，在LOC_Os02g24720中只有一个株系含有T-C取代(图1H和图3)。三个目标位点的扩增引物为表3中 SPL16-seq-F/SPL16-seq-R,SPL18-seq-F/SPL18-seq-R,02G-seq-F/02G-seq-R 。有趣的是，在SG3-11，SG3-12两个转基因株系中，OsSPL16和OsSPL18能够被同时编辑，这表明本发明的碱基编辑系统可以在水稻中同时靶向多个基因 (图3，A和B)。
利用pRABEsp-OsU6载体进行碱基编辑需要在protospacer下游含有NGG的 PAM序列。这一要求显着限制了水稻基因组中可被pRABEsp-OsU6编辑的位点数目。为了进一步增加水稻腺嘌呤碱基编辑器在水稻基因组中可编辑的目标，我们用SaCas9(D10A)切口酶和SaCas9的骨架sgRNA替换了pRABEsp-OsU6载体中的Cas9(D10A)切口酶及其sgRNA骨架。最终构建成的载体pRABEsa-OsU6sa可以识别不同的PAM序列NNGRRT(图1A)。
实施例4测试该载体的可行性和效率
为了测试该载体的可行性和效率，我们设计了第四个sgRNA(sgRNA4)，同时靶向OsSPL14和OsSPL17的OsmiR156结合位点(图1F)。sgRNA4载体构建所对应的引物为表3中的sgRNA4F和sgRNA4R。值得注意的是，尽管PAM序列不同，但sgRNA4识别的protospacer序列与sgRNA2识别的protospacer序列重叠(图1F和1B)。从我们基因鉴定的31个转基因株系中，我们发现14个株系在OsSPL14目标位点具有T-C替换，而在OsSPL17目标位点有19个株系发生了T-C的替换。目标位点的扩增引物为表3中 SPL14-seq-F/SPL14-seq-R,SPL17-seq-F/SPL17-seq-R,因此，在OsSPL14和 OsSPL17靶位点处pRABEsa-OsU6sa的碱基编辑效率分别为45.2％和61.3％，远高于sgRNA2靶向的pRABEsp-OsU6(图1H)。更重要的是，在这两个靶位点有13 个株系(41.9％)被同时编辑。
此外，SaCas9(D10A)切口酶的碱基编辑窗口比Cas9(D10A)切口酶更宽，这可能是由于在由SaCas9(D10A)在诱导形成R-环复合物形成期间有更多的单链暴露于腺嘌呤脱氨酶。出乎意料的是，甚至在protospacer第12和14位的T 在两个靶位点都被编辑了，具体的ABE-P1的碱基编辑窗口口如表4和表5所示。
表4.ABE-P1的碱基编辑窗口
注意：从PAM远端计算碱基编辑位置，将PAM记录为位置21-23(Note:Base editingposition was counted from the PAM-distal end,scoring the PAM as position 21-23.)。
表5.ABE-P2的碱基编辑窗口
注意：从PAM远端计算碱基编辑位置，将PAM记录为位置22-27(Note:Base editingposition was counted from the PAM-distal end,scoring the PAM as position 22-27.)。
为了评估pRABEsa-OsU6sa的脱靶编辑，用在线工具CRISPR-GE预测了 sgRNA4在水稻基因组中的潜在脱靶位点。对sgRNA4的潜在脱靶位点进行了测序，发现这些位点没有发生任何形式的突变，表明pRABEsa-OsU6sa在水稻中也是高度特异的。sgRNA4的潜在脱靶位点信息见表2，扩增sgRNA4潜在脱靶位点的引物见表3。
表2sgRNA4潜在脱靶位点的编辑效率
注：PAM序列的核苷酸以粗体书写，潜在脱靶的错配碱基以小写字母显示。
实施例5测试pRABEsa-OsU6sa是否可以用于水稻的多位点碱基编辑
本发明还设计了另一个同时靶向OsSPL16和OsSPL18的OsmiR156结合位点的sgRNA(sgRNA5)(图4)。sgRNA5载体构建所对应的引物为表3中的sgRNA5F 和sgRNA5R。然而，sgRNA5的编辑效率远远低于sgRNA4。在OsSPL16目标位点只有17％(8/47)的株系具有T-C替换，在OsSPL18位点有23.4％(11/47)株系发生了编辑(图4，A和B)。目标位点的扩增引物为表3中 SPL16-seq-F/SPL16-seq-R,SPL18-seq-F/SPL18-seq-R。值得注意的是，有 14.6％(6/47)的株系在这两个位点同时发生了T-C的替换，进一步证实 pRABEsa-OsU6sa也可以用于水稻的多位点碱基编辑。
实施例6测试简化后的腺嘌呤碱基载体pRSABESp-OsU6在水稻中的编辑效果
本发明为进一步提高水稻中腺嘌呤碱基编辑的效率，对原有的碱基编辑载体pRABEsp-OsU6(称为腺嘌呤碱基编辑器ABE-P1)进行了简化，得到新的腺嘌呤碱基载体pRSABESp-OsU6(称为腺嘌呤碱基编辑器ABE-P1S)(图5A)。与pRABEsp-OsU6 相比较，在载体pRSABESp-OsU6中，我们只把ecTadA*7.10通过编码32个氨基酸残基的接头连接到SpCas9(D10A)切口酶编码序列的N-末端，其它序列没有任何改变。
为了测试新的腺嘌呤碱基器ABE-P1S在水稻中的编辑效果，我们同样选择 sgRNA1靶向OsSPL14的OsmiR156结合位点序列(图5B)，sgRNA1载体构建所对应的引物为表6中的sgRNA1F和sgRNA1R。该双元载体以冻融法转化农杆菌，然后以农杆菌侵染水稻日本晴的愈伤组织，获得了17个独立的转基因系。然后，通过PCR 扩增目标区域，并通过Sanger测序进行基因型鉴定,扩增引物为表10中SPL14-seq-F和SPL14-seq-R。
表10扩增靶位点及测序所用的引物
根据测序结果，在17株转基因植株中有12株在目标位点显示了预期的T-C 替换，碱基编辑效率高达70.6％(12/17)。是pRABEsp-OsU6在此位点编辑效率的2.7 倍(对比表7和图1H)。对所有发生碱基替换的位置进行统计后我们发现 pRSABESp-OsU6可以对OsSPL14protospacer区第1，3，5，7，10，12位的腺嘌呤进行编辑，碱基编辑窗口较pRABEsp-OsU6有了一定的扩展(图5C显示出代表性结果)。
此外，我们还设计了其它的sgRNAs靶向水稻基因组不同位点，同时选择了不同的水稻品种(日本晴和kittake)作为转基因受体材料。结果表明除了OsDEP1 靶位点以外，简化后的腺嘌呤碱基编辑器ABE-P1S比原来的腺嘌呤碱基编辑器 ABE-P1有更高的碱基编辑效率(表7)。
表7ABE-P1和ABE-P1S在不同靶位点编辑效率的统计
为了评估pRSABESp-OsU6在水稻中的特异性，我们对sgRNA1的九个潜在脱靶位点进行了测序，测序结果表明有一个株系在OsSPL17基因内的脱靶位点发生了碱基替换，该脱靶位点和sgRNA1在PAM上游第5位存在1个碱基的错配(图5D)。在其它潜在脱靶位点我们没有检测到任何形式的突变。九个脱靶位点的信息见表 1，对九个潜在脱靶位点扩增所用的引物见表3。
实施例7测试简化后的腺嘌呤碱基载体pRSABESa-OsU6Sa在水稻中的编辑效果
腺嘌呤碱基编辑载体pRABEsa-OsU6sa(称为腺嘌呤碱基编辑器ABE-P2)使用了SaCas9(D10A)切口酶，它可以识别不同的PAM序列NNGRRT,这可以扩展水稻腺嘌呤碱基编辑器在水稻基因组中可编辑的目标。
本发明为进一步提高腺嘌呤碱基编辑器ABE-P2的编辑效率，对 pRSABESa-OsU6Sa载体也进行了简化，得到新的腺嘌呤碱基载体pRSABESa-OsU6Sa (称为腺嘌呤碱基编辑器ABE-P2S)(图6A)。与pRABEsa-OsU6Sa相比较，在载体pRSABESa-OsU6Sa中，我们只把ecTadA*7.10通过编码32个氨基酸残基的接头连接到SaCas9(D10A)切口酶编码序列的N-末端，其它序列没有任何改变。
为了比较新的腺嘌呤碱基器ABE-P2S与ABE-P2在水稻中的编辑效果，我们同样选择sgRNA8靶向水稻SPX-MFS2的OsmiR827结合位点(图6B)，sgRNA8所对应的引物为表6中的sgRNA8F和sgRNA8R。将sgRNA8分别装入pRABEsa-OsU6Sa 和pRSABEsa-OsU6Sa，将双元载体以冻融法转化农杆菌，然后以农杆菌侵染水稻日本晴的愈伤组织。对于pRABEsa-OsU6Sa，我们得到了41株转基因阳性苗。通过PCR扩增目标区域，并通过Sanger测序进行基因型鉴定,扩增引物为表10中 SPX-MFS2-F和SPX-MFS2-R。经鉴定发现有4株在靶位点发生了单个碱基A-G 的替换，编辑效率为9.8％(表8)。发生碱基替换的位点为protospacer区第1， 9或15位腺嘌呤，但没有株系表现为纯合替换。对于pRSABEsa-OsU6Sa，我们获得47株转基因阳性苗，其中7株在靶位点发生了A-G的替换，编辑效率为 14.9％(表8)，是pRABEsa-OsU6Sa在此位点编辑效率的1.5倍。除株系Line 40 外，其它株系均在protosapcer区的3，6，9，15位发生了单个碱基A-G替换，其中株系Line 38在protospacer第6位表现为纯合替换(图6C)。
表8ABE-P2和ABE-P2S在不同靶位点碱基编辑效率的统计
此外，我们还设计了其它的sgRNAs靶向水稻基因组不同位点。结果表明除了OsSPL17靶位点以外，简化后的腺嘌呤碱基编辑器ABE-P2S比原来的腺嘌呤碱基编辑器ABE-P2有更高的碱基编辑效率(对比表8与图1H)。
实施例8对含Cas9蛋白变体的腺嘌呤碱基器ABE-P5进行简化后观测其在水稻中的编辑效果
腺嘌呤碱基编辑器ABE-P5使用了SaKKH-Cas9(D10A)切口酶(图7A)， SaKKH-Cas9(D10A)是在SaCas9(D10A)中引入了E782K/N968K/R1015H三个突变，它可以识别不同的PAM序列NNNRRT。
本发明为进一步提高腺嘌呤碱基编辑器ABE-P5的编辑效率，对其进行了简化，得到新的腺嘌呤碱基编辑器ABE-P5S(图7A)。与ABE-P5相比较，在载体ABE-P5S 中，我们只把ecTadA*7.10通过编码32个氨基酸残基的接头连接到 SaKKH-Cas9(D10A)切口酶编码序列的N-末端，其它序列没有任何改变。
为了比较ABE-P5和ABE-P5S的编辑效率，我们设计了sgRNA11靶向 OsSPL13的OsmiR156结合位点(图7B)。sgRNA11所对应的引物为表6中的 sgRNA11-F和sgRNA11-R。将sgRNA11分别装入ABE-P5和ABE-P5S，将双元载体以冻融法转化农杆菌，然后以农杆菌侵染水稻日本晴的愈伤组织。对于ABE-P5，我们共获得46株转基因苗。通过扩增引物OsSPL13-F和OsSPL13-R(表10)对靶位点扩增测序后只发现1株转基因苗Line 3在protospacer第11位发生了A-G 的替换，编辑效率仅为2.2％(表9)。而且从Sanger测序峰图可以看出这个株系可能只有极少部分细胞在protospacer第11位发生了A-G的替换(图7C)。对于ABE-P5S，我们共获得了33株转基因苗，其中有2株在靶位点发生了A-G替换，编辑效率为6.1％(表9)。Line23在protospacer第7位发生了 A-G的替换，而Line 27在protospacer第9位发生了A-G的替换(图7C)。因此在sgRNA11靶位点，ABE-P5S的效率是ABE-P5的2.8倍。
此外，我们还设计了其它的sgRNA12靶向水稻基因组的SNB基因。结果表明简化后的腺嘌呤碱基编辑器ABE-P5S(33.9％)的编辑效率是ABE-P5(6.5％)的5.2 倍(表9)。
表9ABE-P5和ABE-P5S在不同靶位点碱基编辑效率的统计
对比例1
方法同实施例1，区别在于，用水稻Actin启动子驱动Cas9核酸酶、核定位信号VirD2和腺嘌呤脱氨酶的表达，用依赖于II型RNA聚合酶的启动子或者U3 启动子驱动sgRNA的转录。
结果表明，在水稻中的编辑效率(即定点替换效率)仅为实施例1的50％。
对比例2
方法同实施例1，区别在于，用SV40核定位信号替换VirD2。
结果表明，在水稻中的编辑效率(即定点替换效率)仅为实施例1的约50％-70％。
参考文献
1.Komor,A.C.,Badran,A.H.,and Liu,D.R.(2017a).Editing the GenomeWithout Double-Stranded DNA Breaks.ACS Chem Biol.Advance Access publishedSeptember 28,2017,doi:10.1021/acschembio.7b00710.
2.Nishimura,A.,Aichi,I.,and Matsuoka,M.(2007).A protocol forAgrobacterium-mediated transformation in rice.Nat.Protoc.1:2796-2802.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
序列表
<110> 中国科学院上海生命科学研究院
<120> 植物基因组定点替换的方法
<130> P2018-2359
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<151> 2018-02-11
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<213> 人工序列(artificial sequence)
<400> 53
agagagagca cagctcgagt cgg 23
<210> 54
<211> 23
<212> DNA
<213> 人工序列(artificial sequence)
<400> 54
agagagagca cagctggagt cgg 23
<210> 55
<211> 23
<212> DNA
<213> 人工序列(artificial sequence)
<400> 55
tgatcgggca cagctcgcgt cgg 23
<210> 56
<211> 23
<212> DNA
<213> 人工序列(artificial sequence)
<400> 56
agaaagagca tgggtcgagt cgg 23
<210> 57
<211> 23
<212> DNA
<213> 人工序列(artificial sequence)
<400> 57
agagtgagca cagcgggaga cgg 23
<210> 58
<211> 23
<212> DNA
<213> 人工序列(artificial sequence)
<400> 58
ggagagcgcg cggctcgagg cgg 23
<210> 59
<211> 23
<212> DNA
<213> 人工序列(artificial sequence)
<400> 59
agagtgtgca gagttcgagt cgg 23
<210> 60
<211> 23
<212> DNA
<213> 人工序列(artificial sequence)
<400> 60
agagagagct cggctcggct cgg 23
<210> 61
<211> 23
<212> DNA
<213> 人工序列(artificial sequence)
<400> 61
agagagatct cagatcgagg cgg 23
<210> 62
<211> 23
<212> DNA
<213> 人工序列(artificial sequence)
<400> 62
agacagagca cagcaagaat cgg 23
<210> 63
<211> 27
<212> DNA
<213> 人工序列(artificial sequence)
<400> 63
acagaagaga gagagcacag ctcgagt 27
<210> 64
<211> 27
<212> DNA
<213> 人工序列(artificial sequence)
<400> 64
acagaagaga gagagcacag ctggagt 27
<210> 65
<211> 27
<212> DNA
<213> 人工序列(artificial sequence)
<400> 65
acagaagaga gagagcacaa tcggagt 27
<210> 66
<211> 27
<212> DNA
<213> 人工序列(artificial sequence)
<400> 66
acagaagaga gagagcacac tccgggt 27
<210> 67
<211> 27
<212> DNA
<213> 人工序列(artificial sequence)
<400> 67
acagaagaga gagagcacac tccgggt 27
<210> 68
<211> 27
<212> DNA
<213> 人工序列(artificial sequence)
<400> 68
acggaagaga aagagcatgg gtcgagt 27
<210> 69
<211> 1053
<212> PRT
<213> 人工序列(artificial sequence)
<400> 69
Met Lys Arg Asn Tyr Ile Leu Gly Leu Asp Ile Gly Ile Thr Ser Val
1 5 10 15
Gly Tyr Gly Ile Ile Asp Tyr Glu Thr Arg Asp Val Ile Asp Ala Gly
20 25 30
Val Arg Leu Phe Lys Glu Ala Asn Val Glu Asn Asn Glu Gly Arg Arg
35 40 45
Ser Lys Arg Gly Ala Arg Arg Leu Lys Arg Arg Arg Arg His Arg Ile
50 55 60
Gln Arg Val Lys Lys Leu Leu Phe Asp Tyr Asn Leu Leu Thr Asp His
65 70 75 80
Ser Glu Leu Ser Gly Ile Asn Pro Tyr Glu Ala Arg Val Lys Gly Leu
85 90 95
Ser Gln Lys Leu Ser Glu Glu Glu Phe Ser Ala Ala Leu Leu His Leu
100 105 110
Ala Lys Arg Arg Gly Val His Asn Val Asn Glu Val Glu Glu Asp Thr
115 120 125
Gly Asn Glu Leu Ser Thr Lys Glu Gln Ile Ser Arg Asn Ser Lys Ala
130 135 140
Leu Glu Glu Lys Tyr Val Ala Glu Leu Gln Leu Glu Arg Leu Lys Lys
145 150 155 160
Asp Gly Glu Val Arg Gly Ser Ile Asn Arg Phe Lys Thr Ser Asp Tyr
165 170 175
Val Lys Glu Ala Lys Gln Leu Leu Lys Val Gln Lys Ala Tyr His Gln
180 185 190
Leu Asp Gln Ser Phe Ile Asp Thr Tyr Ile Asp Leu Leu Glu Thr Arg
195 200 205
Arg Thr Tyr Tyr Glu Gly Pro Gly Glu Gly Ser Pro Phe Gly Trp Lys
210 215 220
Asp Ile Lys Glu Trp Tyr Glu Met Leu Met Gly His Cys Thr Tyr Phe
225 230 235 240
Pro Glu Glu Leu Arg Ser Val Lys Tyr Ala Tyr Asn Ala Asp Leu Tyr
245 250 255
Asn Ala Leu Asn Asp Leu Asn Asn Leu Val Ile Thr Arg Asp Glu Asn
260 265 270
Glu Lys Leu Glu Tyr Tyr Glu Lys Phe Gln Ile Ile Glu Asn Val Phe
275 280 285
Lys Gln Lys Lys Lys Pro Thr Leu Lys Gln Ile Ala Lys Glu Ile Leu
290 295 300
Val Asn Glu Glu Asp Ile Lys Gly Tyr Arg Val Thr Ser Thr Gly Lys
305 310 315 320
Pro Glu Phe Thr Asn Leu Lys Val Tyr His Asp Ile Lys Asp Ile Thr
325 330 335
Ala Arg Lys Glu Ile Ile Glu Asn Ala Glu Leu Leu Asp Gln Ile Ala
340 345 350
Lys Ile Leu Thr Ile Tyr Gln Ser Ser Glu Asp Ile Gln Glu Glu Leu
355 360 365
Thr Asn Leu Asn Ser Glu Leu Thr Gln Glu Glu Ile Glu Gln Ile Ser
370 375 380
Asn Leu Lys Gly Tyr Thr Gly Thr His Asn Leu Ser Leu Lys Ala Ile
385 390 395 400
Asn Leu Ile Leu Asp Glu Leu Trp His Thr Asn Asp Asn Gln Ile Ala
405 410 415
Ile Phe Asn Arg Leu Lys Leu Val Pro Lys Lys Val Asp Leu Ser Gln
420 425 430
Gln Lys Glu Ile Pro Thr Thr Leu Val Asp Asp Phe Ile Leu Ser Pro
435 440 445
Val Val Lys Arg Ser Phe Ile Gln Ser Ile Lys Val Ile Asn Ala Ile
450 455 460
Ile Lys Lys Tyr Gly Leu Pro Asn Asp Ile Ile Ile Glu Leu Ala Arg
465 470 475 480
Glu Lys Asn Ser Lys Asp Ala Gln Lys Met Ile Asn Glu Met Gln Lys
485 490 495
Arg Asn Arg Gln Thr Asn Glu Arg Ile Glu Glu Ile Ile Arg Thr Thr
500 505 510
Gly Lys Glu Asn Ala Lys Tyr Leu Ile Glu Lys Ile Lys Leu His Asp
515 520 525
Met Gln Glu Gly Lys Cys Leu Tyr Ser Leu Glu Ala Ile Pro Leu Glu
530 535 540
Asp Leu Leu Asn Asn Pro Phe Asn Tyr Glu Val Asp His Ile Ile Pro
545 550 555 560
Arg Ser Val Ser Phe Asp Asn Ser Phe Asn Asn Lys Val Leu Val Lys
565 570 575
Gln Glu Glu Asn Ser Lys Lys Gly Asn Arg Thr Pro Phe Gln Tyr Leu
580 585 590
Ser Ser Ser Asp Ser Lys Ile Ser Tyr Glu Thr Phe Lys Lys His Ile
595 600 605
Leu Asn Leu Ala Lys Gly Lys Gly Arg Ile Ser Lys Thr Lys Lys Glu
610 615 620
Tyr Leu Leu Glu Glu Arg Asp Ile Asn Arg Phe Ser Val Gln Lys Asp
625 630 635 640
Phe Ile Asn Arg Asn Leu Val Asp Thr Arg Tyr Ala Thr Arg Gly Leu
645 650 655
Met Asn Leu Leu Arg Ser Tyr Phe Arg Val Asn Asn Leu Asp Val Lys
660 665 670
Val Lys Ser Ile Asn Gly Gly Phe Thr Ser Phe Leu Arg Arg Lys Trp
675 680 685
Lys Phe Lys Lys Glu Arg Asn Lys Gly Tyr Lys His His Ala Glu Asp
690 695 700
Ala Leu Ile Ile Ala Asn Ala Asp Phe Ile Phe Lys Glu Trp Lys Lys
705 710 715 720
Leu Asp Lys Ala Lys Lys Val Met Glu Asn Gln Met Phe Glu Glu Lys
725 730 735
Gln Ala Glu Ser Met Pro Glu Ile Glu Thr Glu Gln Glu Tyr Lys Glu
740 745 750
Ile Phe Ile Thr Pro His Gln Ile Lys His Ile Lys Asp Phe Lys Asp
755 760 765
Tyr Lys Tyr Ser His Arg Val Asp Lys Lys Pro Asn Arg Lys Leu Ile
770 775 780
Asn Asp Thr Leu Tyr Ser Thr Arg Lys Asp Asp Lys Gly Asn Thr Leu
785 790 795 800
Ile Val Asn Asn Leu Asn Gly Leu Tyr Asp Lys Asp Asn Asp Lys Leu
805 810 815
Lys Lys Leu Ile Asn Lys Ser Pro Glu Lys Leu Leu Met Tyr His His
820 825 830
Asp Pro Gln Thr Tyr Gln Lys Leu Lys Leu Ile Met Glu Gln Tyr Gly
835 840 845
Asp Glu Lys Asn Pro Leu Tyr Lys Tyr Tyr Glu Glu Thr Gly Asn Tyr
850 855 860
Leu Thr Lys Tyr Ser Lys Lys Asp Asn Gly Pro Val Ile Lys Lys Ile
865 870 875 880
Lys Tyr Tyr Gly Asn Lys Leu Asn Ala His Leu Asp Ile Thr Asp Asp
885 890 895
Tyr Pro Asn Ser Arg Asn Lys Val Val Lys Leu Ser Leu Lys Pro Tyr
900 905 910
Arg Phe Asp Val Tyr Leu Asp Asn Gly Val Tyr Lys Phe Val Thr Val
915 920 925
Lys Asn Leu Asp Val Ile Lys Lys Glu Asn Tyr Tyr Glu Val Asn Ser
930 935 940
Lys Cys Tyr Glu Glu Ala Lys Lys Leu Lys Lys Ile Ser Asn Gln Ala
945 950 955 960
Glu Phe Ile Ala Ser Phe Tyr Lys Asn Asp Leu Ile Lys Ile Asn Gly
965 970 975
Glu Leu Tyr Arg Val Ile Gly Val Asn Asn Asp Leu Leu Asn Arg Ile
980 985 990
Glu Val Asn Met Ile Asp Ile Thr Tyr Arg Glu Tyr Leu Glu Asn Met
995 1000 1005
Asn Asp Lys Arg Pro Pro His Ile Ile Lys Thr Ile Ala Ser Lys Thr
1010 1015 1020
Gln Ser Ile Lys Lys Tyr Ser Thr Asp Ile Leu Gly Asn Leu Tyr Glu
1025 1030 1035 1040
Val Lys Ser Lys Lys His Pro Gln Ile Ile Lys Lys Gly
1045 1050
<210> 70
<211> 22
<212> DNA
<213> 人工序列(artificial sequence)
<400> 70
agggttccaa gcagcgtaag ga 22
<210> 71
<211> 22
<212> DNA
<213> 人工序列(artificial sequence)
<400> 71
tggtgctggg gctggaccgt tc 22
<210> 72
<211> 23
<212> DNA
<213> 人工序列(artificial sequence)
<400> 72
tctccggtgg tatccagtgg cac 23
<210> 73
<211> 23
<212> DNA
<213> 人工序列(artificial sequence)
<400> 73
gcgcaattat tactagctat agc 23
<210> 74
<211> 23
<212> DNA
<213> 人工序列(artificial sequence)
<400> 74
agccgtcgcc accaccggta agg 23
<210> 75
<211> 19
<212> DNA
<213> 人工序列(artificial sequence)
<400> 75
cgtcgacgag ctgctggcg 19
<210> 76
<211> 19
<212> DNA
<213> 人工序列(artificial sequence)
<400> 76
ccatctgcac gcatgactt 19
<210> 77
<211> 24
<212> DNA
<213> 人工序列(artificial sequence)
<400> 77
agagttgtac gtacaataca gcag 24
<210> 78
<211> 19
<212> DNA
<213> 人工序列(artificial sequence)
<400> 78
gcttcgtgga gcatgaggt 19
<210> 79
<211> 20
<212> DNA
<213> 人工序列(artificial sequence)
<400> 79
tgccgtcgta ccggcagtcg 20
<210> 80
<211> 22
<212> DNA
<213> 人工序列(artificial sequence)
<400> 80
cacgaggcct ccgacatgat gc 22
<210> 81
<211> 22
<212> DNA
<213> 人工序列(artificial sequence)
<400> 81
ctccatgccg ctctgcgtgc tg 22
<210> 82
<211> 23
<212> DNA
<213> 人工序列(artificial sequence)
<400> 82
gggagttcat gattggaggc acg 23
<210> 83
<211> 24
<212> DNA
<213> 人工序列(artificial sequence)
<400> 83
gtgctacctc gcccagtgct catc 24
<210> 84
<211> 21
<212> DNA
<213> 人工序列(artificial sequence)
<400> 84
ctgtgacatt tgcaaccaca c 21
<210> 85
<211> 23
<212> DNA
<213> 人工序列(artificial sequence)
<400> 85
gcaatctgtt cctcgtgctg gac 23
<210> 86
<211> 24
<212> DNA
<213> 人工序列(artificial sequence)
<400> 86
cttgaagcga ttttgtgtca gcac 24
<210> 87
<211> 21
<212> DNA
<213> 人工序列(artificial sequence)
<400> 87
ggcattgctg gacttcaacc g 21
<210> 88
<211> 22
<212> DNA
<213> 人工序列(artificial sequence)
<400> 88
ctctttcaca ctcgctcgct cg 22
<210> 89
<211> 22
<212> DNA
<213> 人工序列(artificial sequence)
<400> 89
agcacagcac agtgtcaaga ac 22
<210> 90
<211> 20
<212> DNA
<213> 人工序列(artificial sequence)
<400> 90
aggagatccg attcgccgcg 20
<210> 91
<211> 21
<212> DNA
<213> 人工序列(artificial sequence)
<400> 91
agcacacaca cagacagtgt c 21
<210> 92
<211> 22
<212> DNA
<213> 人工序列(artificial sequence)
<400> 92
ggcaacttag gttggcattg cc 22
<210> 93
<211> 22
<212> DNA
<213> 人工序列(artificial sequence)
<400> 93
cgctgcatgc atgcaggcgc gt 22
<210> 94
<211> 22
<212> DNA
<213> 人工序列(artificial sequence)
<400> 94
gggttccaag cagtgtgagg ga 22
<210> 95
<211> 21
<212> DNA
<213> 人工序列(artificial sequence)
<400> 95
ggacctcgtt cagcacaacc c 21
<210> 96
<211> 22
<212> DNA
<213> 人工序列(artificial sequence)
<400> 96
atgaactcca tcctcaccgc ag 22
<210> 97
<211> 23
<212> DNA
<213> 人工序列(artificial sequence)
<400> 97
ttggcatcag cagcaggcag cag 23
<210> 98
<211> 25
<212> DNA
<213> 人工序列(artificial sequence)
<400> 98
agagacgacg acgtgccatc cgatg 25
<210> 99
<211> 25
<212> DNA
<213> 人工序列(artificial sequence)
<400> 99
cagctgctgc tgctgcttca gtgtg 25
<210> 100
<211> 22
<212> DNA
<213> 人工序列(artificial sequence)
<400> 100
tgggatcatc aaatccgagg ag 22
<210> 101
<211> 21
<212> DNA
<213> 人工序列(artificial sequence)
<400> 101
ctgtccatgc tcgggcaggc g 21
<210> 102
<211> 22
<212> DNA
<213> 人工序列(artificial sequence)
<400> 102
cctccatgag ggcgatcaga ta 22
<210> 103
<211> 23
<212> DNA
<213> 人工序列(artificial sequence)
<400> 103
atttgacaag agtgcattat gca 23
<210> 104
<211> 24
<212> DNA
<213> 人工序列(artificial sequence)
<400> 104
agcactgcat atatgtagca gcag 24
<210> 105
<211> 20
<212> DNA
<213> 人工序列(artificial sequence)
<400> 105
gcttcatcat catcttgtcc 20
<210> 106
<211> 21
<212> DNA
<213> 人工序列(artificial sequence)
<400> 106
ggttagaatc atccattcat g 21
<210> 107
<211> 22
<212> DNA
<213> 人工序列(artificial sequence)
<400> 107
ccagctttag tgcccactgt tc 22
<210> 108
<211> 22
<212> DNA
<213> 人工序列(artificial sequence)
<400> 108
ctggtagcac ggtcacgatt cg 22
Claims (14)
1.一种核酸构建物，其特征在于，所述核酸构建物具有5’-3’(5’至3’)的式I结构：
I1-Z1-Z2-I2 (I)
式中，
I1为第一整合元件；
I2为第二整合元件；
Z1为第一表达盒；
Z2为第二表达盒；
并且，Z1和Z2中的一个表达盒具有Ia结构，而另一个表达盒具有式Ib结构：
P1-S1-X1-L1-X2-L2-X3 (Ia)
P2-Y1 (Ib)；
式中，
P1、S1、X1、L1、X2、L2、X3、P2、Y1分别为用于构成所述构建物的元件；
P1为第一启动子，所述第一启动子包括泛素启动子；
S1为无或信号肽的编码序列；
X1为腺嘌呤脱氨酶(如野生型和/或突变型TadA)的编码序列；
L1为无或第一连接肽的编码序列；
X2为Cas9核酸酶的编码序列，所述的Cas9核酸酶是无切割活性或单链切割活性的；
L2为无或第二连接肽的编码序列；
X3为核定位信号的编码序列，所述核定位信号为VirD2；
P2为第二启动子；
Y1为sgRNA的编码序列；
并且，各“-”为键或核苷酸连接序列。
2.如权利要求1所述的核酸构建物，其特征在于，所述泛素启动子包括玉米泛素启动子。
3.如权利要求1所述的核酸构建物，其特征在于，所述第二启动子包括U6启动子。
4.如权利要求1所述的核酸构建物，其特征在于，所述的sgRNA的第5位-第10位对应于预定发生T→C定点突变的位置(即为T)。
5.如权利要求1所述的核酸构建物，其特征在于，所述的sgRNA的第6-14位对应于预定发生T→C定点突变的位置(即为T)。
6.如权利要求1所述的核酸构建物，其特征在于，所述信号肽包括VirD2的核定位信号肽。
7.如权利要求1所述的核酸构建物，其特征在于，所述第一启动子来源于选自下组的一种或多种植物：玉米、水稻、大豆、拟南芥、番茄。
8.如权利要求1所述的核酸构建物，其特征在于，所述第二启动子来源于选自下组的一种或多种植物：水稻、玉米、大豆、拟南芥、番茄。
9.一种载体，其特征在于，所述载体含有权利要求1所述的核酸构建物。
10.一种基因工程细胞，其特征在于，所述细胞含有权利要求1所述的核酸构建物，或其基因组整合有一个或多个权利要求1所述的核酸构建物。
11.一种对植物进行基因编辑的方法，其特征在于，包括步骤：
(i)提供待编辑植物；和
(ii)将权利要求1所述的核酸构建物或权利要求9所述的载体导入所述待编辑植物的植物细胞，从而在所述植物细胞内进行基因编辑。
12.一种制备转基因植物细胞的方法，其特征在于，包括步骤：
(i)将权利要求1所述的核酸构建物、或权利要求9所述的载体转染植物细胞，使得所述核酸构建物与所述植物细胞中的染色体发生定点替换，从而制得所述转基因植物细胞。
13.一种制备转基因植物细胞的方法，其特征在于，包括步骤：
(i)将权利要求1所述的核酸构建物、或权利要求9所述的载体转染植物细胞，使得所述植物细胞含有所述核酸构建物，从而制得所述转基因植物细胞。
14.一种制备转基因植物的方法，其特征在于，包括步骤：
将权利要求12或权利要求13所述方法制备的所述转基因植物细胞再生为植物体，从而获得所述转基因植物。
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| CN110526993A (zh) * | 2019-03-06 | 2019-12-03 | 山东舜丰生物科技有限公司 | 一种用于基因编辑的核酸构建物 |
| CN110527695A (zh) * | 2019-03-07 | 2019-12-03 | 山东舜丰生物科技有限公司 | 一种用于基因定点突变的核酸构建物 |
| CN110878305A (zh) * | 2019-12-09 | 2020-03-13 | 安徽省农业科学院水稻研究所 | 一种高效的宽窗口单碱基编辑基因及其应用和育种方法 |
| CN111508558A (zh) * | 2020-03-23 | 2020-08-07 | 广州赛业百沐生物科技有限公司 | 一种基于CRISPR-Cas9技术设计点突变模型的方法及系统 |
| WO2020177751A1 (zh) * | 2019-03-06 | 2020-09-10 | 山东舜丰生物科技有限公司 | 一种用于基因编辑的核酸构建物 |
| CN112553246A (zh) * | 2020-12-08 | 2021-03-26 | 安徽省农业科学院水稻研究所 | 一种基于CRISPR-SaCas9系统的高效基因组编辑载体及其应用 |
| CN112725348A (zh) * | 2019-10-28 | 2021-04-30 | 安徽省农业科学院水稻研究所 | 一种提高水稻单碱基编辑效率的基因、方法及应用 |
| WO2021233442A1 (zh) * | 2020-05-22 | 2021-11-25 | 山东舜丰生物科技有限公司 | 一种核酸表达的方法 |
| CN113717961A (zh) * | 2021-09-10 | 2021-11-30 | 四川大学 | 一种融合蛋白及其多核苷酸、碱基编辑器及其在药物制备中的应用 |
| CN115667528A (zh) * | 2020-03-04 | 2023-01-31 | 苏州齐禾生科生物科技有限公司 | 多重基因组编辑方法和系统 |
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| WO2020177751A1 (zh) * | 2019-03-06 | 2020-09-10 | 山东舜丰生物科技有限公司 | 一种用于基因编辑的核酸构建物 |
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| CN113717961A (zh) * | 2021-09-10 | 2021-11-30 | 四川大学 | 一种融合蛋白及其多核苷酸、碱基编辑器及其在药物制备中的应用 |
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