CN116410964A - 腺嘌呤脱氨酶及其应用 - Google Patents
腺嘌呤脱氨酶及其应用 Download PDFInfo
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- CN116410964A CN116410964A CN202111644450.0A CN202111644450A CN116410964A CN 116410964 A CN116410964 A CN 116410964A CN 202111644450 A CN202111644450 A CN 202111644450A CN 116410964 A CN116410964 A CN 116410964A
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Abstract
本发明公开了一种腺嘌呤脱氨酶及其应用。所述腺嘌呤脱氨酶相比于如SEQ ID NO:2所示的氨基酸序列具有氨基酸差异，所述氨基酸差异位于第46位。本发明的腺嘌呤脱氨酶完全避免了腺嘌呤编辑，并极大提高了对胞嘧啶的编辑，实现单个碱基C‑G到T‑A编辑。包含该腺嘌呤脱氨酶的碱基编辑器可高精度、高效、安全地介导胞嘧啶编辑，indels降低、体积更小，展示出较高的编辑活性和较低的脱靶事件，因此具备极高的安全性，将极大促进其在基因编辑领域的广泛应用。
Description
技术领域
本发明属于基因编辑领域，具体涉及一种腺嘌呤脱氨酶及其应用。
背景技术
人类遗传病发生的本质是由于基因突变，60％左右的遗传疾病由单个碱基突变引起，传统的利用基因组编辑技术介导的同源重组进行纠正这类遗传病非常低效(0.1％-5％)。基于CRISPR系统衍生出来的单碱基编辑器是近年来新兴的高效碱基编辑技术,因不产生DNA双链断裂、无须重组模板、高效编辑等优势使其在基础研究和临床疾病治疗展示了巨大的应用前景。
经典的碱基编辑器主要分为胞嘧啶碱基编辑器CBE和腺嘌呤碱基编辑器ABE，前者由活性受损的来源于酿脓链球菌(Streptococcus pyogenes)spCas9n、大鼠来源的胞嘧啶脱氨酶rAPOBEC1和尿嘧啶糖苷酶抑制剂组成，其中Cas9蛋白以NGG作为PAM识别并特异结合DNA，紧接着在脱氨酶以及DNA修复的作用下，最终在NGG(21-23位)上游靶向序列20bp范围实现C·G-T·A的替换，编辑窗口主要位于4-8位。然而致病的点突变事件中，往往需要精确地修正1个碱基，额外的碱基编辑(bystander突变，无法区别目标C和邻近C)反而会带来副作用，缺乏真正意义的精准，虽然YE1、YEE等胞嘧啶碱基编辑器一定程度缩窄靶向范围，但损失了靶向编辑效率，且多靶点不适用；eA3A-BE3、A3G-BE5.13等CBE依靠序列偏好性提高目标C的靶向性，但仍无法去除其他序列背景中C的编辑。
发明内容
本发明所要解决的技术问题是为了克服现有技术缺少同时具有高精度、高安全性、高效编辑的胞嘧啶碱基编辑器的不足，提供一种腺嘌呤脱氨酶及其应用。本发明包含该腺嘌呤脱氨酶的碱基编辑器完全避免了腺嘌呤编辑，并极大提高了对胞嘧啶的编辑；包含该腺嘌呤脱氨酶的碱基编辑器可精准、高效、安全地介导胞嘧啶编辑，展示出较高的编辑活性和较低的脱靶事件，因此具备极高的安全性，将极大促进其在基因编辑领域的广泛应用。
发明人基于上述难点，意外发现在腺嘌呤脱氨酶上的特定位点进行突变可以尝试在改造ABE转换为CGBE(C·G碱基编辑器)的载体(ADS-BE1)基础上融合2×UGI(尿嘧啶糖苷酶抑制剂)，基于结构导向设计开发不依赖于胞嘧啶脱氨酶的高活性碱基编辑器(baseeditor)，获得高效介导C到T突变的ADS-BE2系列，发现相对传统BE4max，ADS-BE2系列中ADS-BE2.5脱靶和indels降低、体积更小，并保持高效的C到T突变的能力；在高效进行靶向编辑的ADS-BE2.1和ADS-BE2.6上，通过结构导向设计和Linker改造双策略开发的胞嘧啶编辑编辑器eADS-BE2.1和eADS-BE2.6精度更高，可在C5/C6位引起精准的C-G到T-A碱基编辑，展示出较高的编辑活性和较低的脱靶事件，具备极高的安全性。
本发明通过以下技术方案解决上述技术问题：
本发明的第一方面提供一种腺嘌呤脱氨酶，所述腺嘌呤脱氨酶相比于如SEQ IDNO:2所示的氨基酸序列具有氨基酸差异，所述氨基酸差异位于第46位。
较佳地，所述差异还位于第27位、第29位和第48位中的一位或多位。
本发明一些实施方案中，所述氨基酸腺嘌呤脱氨酶相比于如SEQ ID NO:2所示的氨基酸序列具有以下氨基酸差异：第46位氨基酸残基N替换为L。
本发明一些实施方案中，所述氨基酸腺嘌呤脱氨酶相比于如SEQ ID NO:2所示的氨基酸序列具有以下氨基酸差异：第46位氨基酸残基N替换为L，并且第27位氨基酸残基E替换为R。
本发明一些实施方案中，所述氨基酸腺嘌呤脱氨酶相比于如SEQ ID NO:2所示的氨基酸序列具有以下氨基酸差异：第46位氨基酸残基N替换为L，并且第29位氨基酸残基P替换为A。
本发明一些实施方案中，所述氨基酸腺嘌呤脱氨酶相比于如SEQ ID NO:2所示的氨基酸序列具有以下氨基酸差异：第46位氨基酸残基N替换为L，并且第48位氨基酸残基A替换为M。
本发明的第二方面提供一种融合蛋白，所述融合蛋白包含如第一方面所述的腺嘌呤脱氨酶。
本发明一些实施方案中，所述融合蛋白还包括核定位信号序列，所述核定位信号序列位于所述腺嘌呤脱氨酶的N端和/或C端。
本发明一些实施方案中，所述核定位信号序列位于所述腺嘌呤脱氨酶的N端，其氨基酸序列优选如SEQ ID NO:1所示。
本发明中，所述融合蛋白还可融合其他功能蛋白，所述其他功能蛋白能够提高该融合蛋白的胞嘧啶编辑效率、调控编辑窗口或精准编辑效率。
本发明的第三方面提供一种胞嘧啶碱基编辑器，所述胞嘧啶碱基编辑器包括核酸酶和如第一方面所述的腺嘌呤脱氨酶。
本发明一些实施方案中，所述核酸酶为Cas蛋白及其变体。
本发明一些实施方案中，所述核酸酶和所述腺嘌呤脱氨酶通过连接子连接。
本发明一些实施方案中，所述胞嘧啶碱基编辑器还包括UGI片段，所述UGI片段优选连接在所述核酸酶的C端。
本发明一些实施方案中，所述Cas蛋白选自酿酒酵母来源的spCas9、金黄色葡萄球菌来源的SaCas9、毛螺菌科细菌来源的LbCas12a和酸胺球菌属细菌来源的enAsCas12a；所述Cas蛋白变体选自VQR-spCas9、VRER-spCas9、spRY、spNG、SaCas9-KKH和SaCas9-NG。
本发明一些实施方案中，所述连接子的氨基酸序列如SEQ ID NO:3、9或10任一项所示、或者所述连接子的氨基酸序列为PAP。
本发明一些实施方案中，所述核酸酶和所述UGI片段之间通过连接子连接，所述连接子优选为P2A片段，所述P2A的氨基酸序列例如如SEQ ID NO:7所示。
本发明一些实施方案中，所述UGI片段至少为一个拷贝，优选两个拷贝、三个拷贝或四个拷贝。
较佳地，所述拷贝之间通过氨基酸序列优选如SEQ ID NO:8所示的连接子相连。
本发明中，所述连接子的长度可根据本领域公知进行调整，以利于提高该融合蛋白的胞嘧啶编辑效率、调控编辑窗口或精准编辑效率。
本发明一些实施方案中，所述Cas蛋白为酿酒酵母来源的spCas9，所述spCas9的氨基酸序列如SEQ ID NO:4所示。
本发明一些实施方案中，所述核酸酶与所述P2A片段之间连有核定位信号序列，所述核定位信号序列的氨基酸序列优选如SEQ ID NO:1所示。
本发明一些实施方案中，所述UGI片段的C端还连接有核定位信号序列或polyA信号序列，所述核定位信号序列的氨基酸序列优选如SEQ ID NO:1所示，所述polyA信号序列优选为BGH polyA。
本发明中，所述polyA信号序列可为本领域常规来自真核细胞或原核细胞的多腺苷酸化信号序列。
所述BGH polyA为牛生长激素多腺苷酸化信号。
本发明的第四方面提供一种分离的核酸，所述核酸编码如第一方面所述的腺嘌呤脱氨酶、如第二方面所述的融合蛋白或者如第三方面所述的胞嘧啶碱基编辑器。
本发明的第五方面提供一种胞嘧啶碱基编辑系统，其包括：sgRNA和如第二方面所述的胞嘧啶碱基编辑器。
本发明中，sgRNA可为根据本领域常规技术设计并构建。
本发明一些实施方案中，所述sgRNA的靶序列具有如SEQ ID NO:11～24任一所示的核苷酸序列。
本发明的第六方面提供一种药物组合物，所述药物组合物包括如第一方面所述的腺嘌呤脱氨酶、如第二方面所述的融合蛋白、如第三方面所述的胞嘧啶碱基编辑器或者如第五方面所述的胞嘧啶碱基编辑系统。
本发明的第七方面提供一种非治疗目的的碱基编辑方法，所述碱基编辑方法包括：
在靶细胞中表达如第一方面所述的腺嘌呤脱氨酶、如第二方面所述的融合蛋白、如第三方面所述的胞嘧啶碱基编辑器、如第四方面所述的核酸或者如第五方面所述的胞嘧啶碱基编辑系统，使所述靶细胞发生碱基编辑。
本发明一些实施方案中，所述靶细胞的来源为分离的细胞系。
较佳地，所述分离的细胞系为293T细胞、HELA细胞、U2OS细胞、NIH3T3细胞或N2A细胞。
本发明中，所述非治疗目的的可为在构建疾病动物模型、作物育种等中进行碱基编辑，以及在体外进行基因表达调控研究。
在本发明一些实施方案中，所述靶细胞为真核细胞、原核细胞或古生物细胞。
本发明的第八方面提供如第一方面所述的腺嘌呤脱氨酶、如第二方面所述的融合蛋白、如第三方面所述的胞嘧啶碱基编辑器、如第四方面所述的核酸或者如第五方面所述的胞嘧啶碱基编辑系统在制备碱基编辑的药物、构建动物模型、农作物育种、制备基因治疗的药物或者制备碱基编辑工具中的应用。
本发明的第九方面提供一种基因表达盒，所述基因表达盒包括启动子元件和目的基因元件；
其中，所述目的基因元件选自编码如第一方面所述的腺嘌呤脱氨酶、如第二方面所述的融合蛋白或者如第三方面所述的胞嘧啶碱基编辑器的基因。
较佳地，所述启动子元件选自CMV、CAG、PGK、EF1α、Ctsk和Lp1。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：
本发明的腺嘌呤脱氨酶完全避免了腺嘌呤编辑，并极大提高了对胞嘧啶的编辑，实现单个碱基C-G到T-A编辑。包含该腺嘌呤脱氨酶的碱基编辑器可高精度、高效、安全地介导胞嘧啶编辑，indels降低、体积更小，展示出较高的编辑活性和较低的脱靶事件，因此具备极高的安全性，将极大促进其在基因编辑领域的广泛应用。
附图说明
图1为实施例3的nSaCas9-R-loop图谱。
图2为15个ADS-BE2系列和eADS-BE2在293T上FGF6-sg4位点实现的C到T碱基编辑对比示意图。
图3为2个ADS-BE2系列和2个eADS-BE2系列在293T上Site A和FGF6-sg4位点实现的C到T碱基编辑对比示意图。
图4为4个ADS-BE2系列、3个eADS-BE以及对照BE4max-PU、BE4max-YE1-PU，BE4max-YEE-PU、eA3A-PU、A3G5.13-PU在293T上8个内源位点实现C到T碱基编辑示意图。
图5为eADS-BE2.1、eADS-BE2.6、ADS-BE2.5和BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU、A3G5.13-PU不同位置平均C到T碱基编辑对比(统计8个内源位点)示意图。
图6为eADS-BE2.1、eADS-BE2.6、ADS-BE2.5和BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU、A3G5.13-PU产生的indels对比(统计8个内源位点)示意图。
图7为eADS-BE2.1、eADS-BE2.6、ADS-BE2.5和BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU、A3G5.13-PU在VEGFA site 2位点产生的非依赖性脱靶对比示意图。
图8为eADS-BE2.1、eADS-BE2.6、ADS-BE2.5和BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU、A3G5.13-PU在VEGFA site 2位点产生的C到T效率对比示意图。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例中使用的bNLS的氨基酸序列如下：
MKRTADGSEFESPKKKRKV(SEQ ID NO:1)；
TadA8e的氨基酸序列如下：
MSEVEFSHEYWMRHALTLAKRARDEREVPVGAVLVLNNRVIGEGWNRAIGLHDPTAHAEIMALRQGGLVMQNYRLIDATLYVTFEPCVMCAGAMIHSRIGRVVFGVRNSKRGAAGSLMNVLNYPGMNHRVEITEGILADECAALLCDFYRMPRQVFNAQKKAQSSIN(SEQ ID NO:2)。
连接子Linker1的氨基酸序列如下：
SGGSSGGSSGSETPGTSESATPESSGGSSGGS(SEQ ID NO:3)。
连接子Linker18的氨基酸序列为：PAP。
连接子Linker15的氨基酸序列为：PAPAPAP(SEQ ID NO:9)。
连接子Linker13的氨基酸序列为下：PAPAP(SEQ ID NO:10)。
spCas9n(D10A)的氨基酸序列如下：
MDKKYSIGLAIGTNSVGWAVITDEYKVPSKKFKVLGNTDRHSIKKNLIGALLFDSGETAEATRLKRTARRRYTRRKNRICYLQEIFSNEMAKVDDSFFHRLEESFLVEEDKKHERHPIFGNIVDEVAYHEKYPTIYHLRKKLVDSTDKADLRLIYLALAHMIKFRGHFLIEGDLNPDNSDVDKLFIQLVQTYNQLFEENPINASGVDAKAILSARLSKSRRLENLIAQLPGEKKNGLFGNLIALSLGLTPNFKSNFDLAEDAKLQLSKDTYDDDLDNLLAQIGDQYADLFLAAKNLSDAILLSDILRVNTEITKAPLSASMIKRYDEHHQDLTLLKALVRQQLPEKYKEIFFDQSKNGYAGYIDGGASQEEFYKFIKPILEKMDGTEELLVKLNREDLLRKQRTFDNGSIPHQIHLGELHAILRRQEDFYPFLKDNREKIEKILTFRIPYYVGPLARGNSRFAWMTRKSEETITPWNFEEVVDKGASAQSFIERMTNFDKNLPNEKVLPKHSLLYEYFTVYNELTKVKYVTEGMRKPAFLSGEQKKAIVDLLFKTNRKVTVKQLKEDYFKKIECFDSVEISGVEDRFNASLGTYHDLLKIIKDKDFLDNEENEDILEDIVLTLTLFEDREMIEERLKTYAHLFDDKVMKQLKRRRYTGWGRLSRKLINGIRDKQSGKTILDFLKSDGFANRNFMQLIHDDSLTFKEDIQKAQVSGQGDSLHEHIANLAGSPAIKKGILQTVKVVDELVKVMGRHKPENIVIEMARENQTTQKGQKNSRERMKRIEEGIKELGSQILKEHPVENTQLQNEKLYLYYLQNGRDMYVDQELDINRLSDYDVDHIVPQSFLKDDSIDNKVLTRSDKNRGKSDNVPSEEVVKKMKNYWRQLLNAKLITQRKFDNLTKAERGGLSELDKAGFIKRQLVETRQITKHVAQILDSRMNTKYDENDKLIREVKVITLKSKLVSDFRKDFQFYKVREINNYHHAHDAYLNAVVGTALIKKYPKLESEFVYGDYKVYDVRKMIAKSEQEIGKATAKYFFYSNIMNFFKTEITLANGEIRKRPLIETNGETGEIVWDKGRDFATVRKVLSMPQVNIVKKTEVQTGGFSKESILPKRNSDKLIARKKDWDPKKYGGFDSPTVAYSVLVVAKVEKGKSKKLKSVKELLGITIMERSSFEKNPIDFLEAKGYKEVKKDLIIKLPKYSLFELENGRKRMLASAGELQKGNELALPSKYVNFLYLASHYEKLKGSPEDNEQKQLFVEQHKHYLDEIIEQISEFSKRVILADANLDKVLSAYNKHRDKPIREQAENIIHLFTLTNLGAPAAFKYFDTTIDRKRYTSTKEVLDATLIHQSITGLYETRIDLSQLGGD(SEQ ID NO:4)。
UGI的氨基酸序列如下：
MTNLSDIIEKETGKQLVIQESILMLPEEVEEVIGNKPESDILVHTAYDESTDENVMLLTSDAPEYKPWALVIQDSNGENKIKML(SEQ ID NO:5)。
2×UGI的氨基酸序列如下：
MTNLSDIIEKETGKQLVIQESILMLPEEVEEVIGNKPESDILVHTAYDESTDENVMLLTSDAPEYKPWALVIQDSNGENKIKMLSGGSGGSGGSTNLSDIIEKETGKQLVIQESILMLPEEVEEVIGNKPESDILVHTAYDESTDENVMLLTSDAPEYKPWALVIQDSNGENKIKML(SEQ ID NO:6)。
2×UGI之间的连接子Linker0的氨基酸序列为：SGGSGGSGGS(SEQ ID NO:8)。
P2A的氨基酸序列为：MTNFSLLKQAGDVEENPGP(SEQ ID NO:7)。
实施例1结构导向设计和linker改造获得高精度的eADS-BE2系列以及宽窗口的ADS-BE2.5
根据TadA-8e结合底物DNA的晶体结构，推测8个氨基酸可能影响TadA-8e与底物DNA的非特异性结合，进而改变ADS-BE2的编辑窗口，通过改变氨基酸的疏水性或者极性得到11种构建，并改变Linker长度获得ADS-BE2-Linker18、ADS-BE2-Linker15、ADS-BE2-Linker13和eADS-BE2构建。
1.1质粒设计及构建
1.1.1根据ABE8e与底物DNA结合的晶体结构，设计了11个ADS-BE2系列突变体(如表1所示)，同时设计了1个来自于人的内源性靶点FANCF site1(如表2所示)。
1.1.2以BE4max(Addgene#112093)为模板，利用PCR仪(Veriti 96孔型梯度PCR仪，Applied Biosystems)和无缝克隆组装(试剂盒为Vazyme ClonExpress MultiS One StepCloning Kit，C113-01)将P2A-2×UGI引入到ADS-BE1载体中获得ADS-BE2，合成11个ADS-BE2系列突变序列，以ADS-BE2为载体进行无缝克隆组装，ADS-BE2-Linker18、ADS-BE2-Linker15、ADS-BE2-Linker13、eADS-BE2系列直接通过无缝克隆组装改变Linker长度获得。靶点即按表2进行合成两条oligo，正链加CACC，反链加上AAAC，连接至已经用BbsI酶切好的U6-sgRNA-EF1α-GFP上。
1.1.3将1.1.1与1.1.2中构建的质粒经sanger测序，确保完全正确，得到ADS-BE2系列。
表1 ADS-BE2系列组合突变序列
| 组合突变体 | 密码子 |
| N46L&A48M | ctg&atg |
| N46L&I49F | ctg&ttc |
| N46L&L51A | ctg&gcc |
| N46L&L51W | ctg&tgg |
| N46L&E27R | ctg&aga |
| N46L&P29A | ctg&gca |
| N46L&P29S | ctg&agc |
| N46L&G31S | ctg&agc |
| N46L&H57A | ctg&gca |
| N46L&H57S | ctg&agc |
| N46L&P86S | ctg&agc |
表2所用靶点及序列
表中，Oligo-up为正向引物，Oligo-dn为反向引物。
表3设计的碱基编辑器
1.2细胞转染
第1天用HEK293T(HEK293T细胞为ATCC CRL-3216细胞系)细胞铺种24孔板：
(1)消化HEK293T细胞，按照2×105cell/孔接种24孔板。
注：细胞复苏后，一般需传代2次后方可用于转染实验。
第2天转染：
(2)观察各孔细胞状态。
注：要求转染前细胞密度应为70％-90％，且状态正常。
(3)质粒转染如下：
使用上述步骤1中新构建的各个质粒：U6-sgRNA-EF1α-GFP＝750ng:250ng的质粒用量，转染试剂为PEI(每1μg质粒加3μL PEI)，共转染HEK293T宿主，以ADS-BE2或者ADS-BE2.1/2.6作为对照；设置n＝3孔/组。
1.3基因组提取及扩增子文库的准备
转染后72h，用天根细胞基因组提取试剂盒(DP304)提取细胞基因组DNA。之后用Hi-Tom Gene Editing Detection Kit(诺禾致源)操作流程，设计相对应的鉴定引物(如表4所示)，即在正向鉴定引物5`端加上搭桥序列5`-ggagtgagtacggtgtgc-3`(SEQ ID NO:53)，反向鉴定引物5`端加上搭桥序列5`-gagttggatgctggatgg-3`(SEQ ID NO:54)，即得到一轮PCR产物，之后利用一轮PCR产物作为模板，进行二轮PCR产物，后混在一起进行切胶回收纯化后进行送公司进行测序(测序的服务提供商为苏州金唯智生物科技有限公司)。
表4所用靶点的鉴定引物
表中，F为正向鉴定引物，R为反向鉴定引物。
1.4深度测序结果分析与统计
利用BE-analyzer网站(http://www.rgenome.net/be-analyzer/#！)分析深度测序结果，即统计C到T的比率，并用graphpad prism 9.1.0进行统计作图，如表5、表6和图2-3所示。
表5 15个ADS-BE2系列和eADS-BE2在293T上FGF6-sg4位点实现的C到T碱基编辑对比(单位，％)
表中，Rep.1、Rep.2和Rep.3为一式三份。
表6-1 2个ADS-BE2系列和2个eADS-BE2系列在293T上Site A位点实现的C到T碱基编辑对比(单位，％)
表6-2 2个ADS-BE2系列和2个eADS-BE2系列在293T上FGF6-sg4位点实现的C到T碱基编辑对比(单位，％)
表6中，Rep.1、Rep.2和Rep.3为一式三份。
根据二代测序结果发现，ADS-BE2编辑范围为C5、C6和C7，C7编辑效率为20％。而ADS-BE2.1和ADS-BE2.6编辑范围仅限于C5和C6，C7编辑效率分别为2.2％和1.4％，分别降低8.1倍和13.3倍，一定程度降低旁观者胞嘧啶。意外的是，ADS-BE2.5却极大的扩展了胞嘧啶的编辑范围，C7和C8位置的编辑效率分别是ADS-BE2的3.2倍和29.4倍。
实施例2 eADS-BE2.1、eADS-BE2.6和宽窗口ADS-BE2.5工作特性描述
2.1质粒设计及构建
2.1.1设计8个来自于人的内源性靶点EGFR-sg39、LAG3-sg4、PDCD1 site 2、HBG-sg14、VEGFAsite 2、FANCF-sg17、Site A、FGF6-sg4进行工作特性描述，构建方法同实施例1的1.1.2，对照组BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU、A3G5.13-PU分别以BE4max(Addgene#112093)、YE1-BE4max(#138155)、YE1-BE4max(#138155)、eA3A(Addgene#131315)、A3G5.13(#138155)为模板，将后者(SG2)3S-2×UGI更换为P2A-2×UGI作为公平对照，构建方法同1.1.2。
2.1.2将2.1.1中构建的质粒经sanger测序，确保完全正确。
2.2细胞转染
第1天用HEK293T(HEK293T细胞为ATCC CRL-3216细胞系)细胞铺种24孔板：
(1)消化HEK293T细胞，按照2×105cell/孔接种96孔板。
注：细胞复苏后，一般需传代2次后方可用于转染实验。
第2天转染：
(2)观察各孔细胞状态。
注：要求转染前细胞密度应为70％-90％，且状态正常。
(3)质粒转染量如下：
2.1中新构建的质粒：U6-sgRNA-EF1α-GFP＝750ng:250ng的质粒用量，转染试剂为PEI(每1μg质粒加3μL PEI)，共转染HEK293T宿主，以BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU和A3G5.13-PU作为对照；设置n＝3孔/组。
2.3基因组提取及扩增子文库的准备
转染后72h，用天根细胞基因组提取试剂盒(DP304)提取细胞基因组DNA。之后用Hi-Tom Gene Editing Detection Kit(诺禾致源)操作流程，设计相对应的鉴定引物(如表3所示)，即在正向鉴定引物5`端加上搭桥序列5`-ggagtgagtacggtgtgc-3`(SEQ ID NO:53)，反向鉴定引物5`端加上搭桥序列5`-gagttggatgctggatgg-3`(SEQ ID NO:54)，即得到一轮PCR产物，之后利用一轮PCR产物作为模板，进行二轮PCR产物，后混在一起进行切胶回收纯化后进行送公司进行测序(测序的服务提供商为苏州金唯智生物科技有限公司)。
2.4深度测序结果分析与统计
利用BE-analyzer网站进分析深度测序结果，即统计C到T、Indels的比率，并用graphpad prism 9.1.0进行统计作图，如表7～9和图4-6所示。
表7-1 4个ADS-BE2系列、3个eADS-BE以及对照BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU和A3G5.13-PU在293T上EGFR-sg39内源位点实现C到T碱基编辑(单位，％)
表7-2 4个ADS-BE2系列、3个eADS-BE以及对照BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU和A3G5.13-PU在293T上LAG3 sg4内源位点实现C
到T碱基编辑(单位，％)
表7-3 4个ADS-BE2系列、3个eADS-BE以及对照BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU和A3G5.13-PU在293T上HBG-sg14内源位点实现C
到T碱基编辑(单位，％)
表7-4 4个ADS-BE2系列、3个eADS-BE以及对照BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU和A3G5.13-PU在293T上FANCF-sg17内源位点实现C到T碱基编辑(单位，％)
表7-5 4个ADS-BE2系列、3个eADS-BE以及对照BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU和A3G5.13-PU在293T上VEGFA site 2内源位点实现C到T碱基编辑(单位，％)
表7-6 4个ADS-BE2系列、3个eADS-BE以及对照BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU和A3G5.13-PU在293T上Site A内源位点实现C到
T碱基编辑(单位，％)
表7-7 4个ADS-BE2系列、3个eADS-BE以及对照BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU和A3G5.13-PU在293T上FGF6-sg4内源位点实现C
到T碱基编辑(单位，％)
表7-8 4个ADS-BE2系列、3个eADS-BE以及对照BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU和A3G5.13-PU在293T上PDCD1 site 2内源位点实现C到T碱基编辑(单位，％)
表7中，Rep.1、Rep.2和Rep.3为一式三份。
表8 eADS-BE2.1、eADS-BE2.6、ADS-BE2.5和BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU、A3G5.13-PU不同位置平均C到T碱基编辑对比(统计8个内源位点)(单位，％)
表9 eADS-BE2.1、eADS-BE2.6、ADS-BE2.5和BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU、A3G5.13-PU产生的indels对比(统计8个内源位点)(单位，％)
由测序结果可知，ADS-BE2-Linker18、ADS-BE2-Linker15和ADS-BE2-Linker13也是一定程度降低了C7的编辑效率，而删除Linker的eADS-BE2不仅展现最低的C7编辑，还进一步降低C6的编辑，使得编辑更偏好于单个碱基C5。eADS-BE2.1和eADS-BE2.6在内源性测试靶点Site A和FGF6-sg4上的编辑位点更加集中在C5/C6，对于Site A靶点C5位置，eADS-BE2.1和eADS-BE2.6编辑效率分别是原来的1.7倍和2倍，对于FGF6-sg4靶点C6位置，编辑效率分别是原来的1.2倍和1.1倍，而邻近C7分别降低6.6倍和3.6倍，极大降低了旁观者胞嘧啶编辑，具备高精度的特性。
在12个内源性靶点上的再次验证表明，相对于对照BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU、3G5.13-PU，eADS-BE2.1和eADS-BE2.6依然展现精准编辑特性，偏好C5/C6位置产生C到T的编辑；而ADS-BE2.5则展示宽窗口高活性的特点，部分靶点(如HBG-sg14、FANCF-sg17、Site A)效率和效率甚至超过经典的BE4max-PU，根据12个靶点不同位置的平均C到T效率统计，以对照组中编辑表现相对较精准的BE4max-YEE-PU为对比，其主要编辑窗口C4、C5、C6、C7和C8的平均效率分别为10.7％、63.4％、57.2％、37.6％和11.2％，而eADS-BE2.1和eADS-BE2.6在C5位置轻微降低，平均效率为52.1％和52.7％，而C4位置平均效率分别为8.4％和9.3％，C6位置平均效率分别为24.4％和21.4％，C7位置平均效率分别为4％和5.4％，C8位置平均效率分别为0.3％和0.4％；ADS-BE2.5编辑范围为C2-C9，主要编辑活性窗口为C4-C8，这也与传统的BE4max保持一致。
实施例3 eADS-BE2.1，eADS-BE2.6和ADS-BE2.5安全性评价
3.1质粒设计及构建
3.1.1为了进一步描述eADS-BE2.1、eADS-BE2.6和ADS-BE2.5的安全性，再次以BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU、A3G5.13-PU为对照，目标位点为VEGFAsite 2，设计6个Cas9非依赖性脱靶检测靶点(如表2所示)，合成两条oligo，正链加CACC，反链加上AAAC，连接至已经用BbsI酶切好的nSaCas9-R-loop载体(如图1所示)上。
3.1.2将3.1.1中构建的质粒经sanger测序，确保完全正确。
3.2细胞转染
第1天用HEK293T(HEK293T细胞为ATCC CRL-3216细胞系)细胞铺种24孔板：
(1)消化HEK293T细胞，按照2×105cell/孔接种96孔板。
注：细胞复苏后，一般需传代2次后方可用于转染实验。
第2天转染：
(2)观察各孔细胞状态
注：要求转染前细胞密度应为70％-90％，且状态正常。
(3)质粒转染量如下：
BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU、A3G5.13-PU、eADS-BE2.1、eADS-BE2.6和ADS-BE2.5:3.1中新构建的质粒:VEGFA site 2靶点质粒＝400ng:300ng:300ng的质粒用量，转染试剂为PEI(每1μg质粒加3μL PEI)，共转染HEK293T宿主，设置n＝3孔/组。
3.3基因组提取及扩增子文库的准备
转染后72h，用天根细胞基因组提取试剂盒(DP304)提取细胞基因组DNA。之后用Hi-Tom Gene Editing Detection Kit(诺禾致源)操作流程，设计相对应的鉴定引物(如表3所示)，即在正向鉴定引物5`端加上搭桥序列5`-ggagtgagtacggtgtgc-3`(SEQ ID NO:53)，反向鉴定引物5`端加上搭桥序列5`-gagttggatgctggatgg-3`(SEQ ID NO:54)，即得到一轮PCR产物，之后利用一轮PCR产物作为模板，进行二轮PCR产物，后混在一起进行切胶回收纯化后进行送公司进行测序(测序的服务提供商为苏州金唯智生物科技有限公司)。
3.4深度测序结果分析与统计
利用BE-analyzer网站分析深度测序结果，即统计C到T比率，并用graphpadprism9.1.0进行统计作图。如表10～11和图7-8所示。
表10 eADS-BE2.1、eADS-BE2.6、ADS-BE2.5和BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU、A3G5.13-PU在VEGFA site2位点产生的非依赖性脱靶对比(单位，％)
表11 eADS-BE2.1、eADS-BE2.6、ADS-BE2.5和BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU、A3G5.13-PU在VEGFA site2位点产生的C到T效率对比(单位，％)
表10～11中，Rep.1、Rep.2和Rep.3为一式三份。
根据以上数据统计结果表明，对照组BE4max-PU、BE4max-YE1-PU、BE4max-YEE-PU、eA3A-PU和A3G5.13-PU产生indels平均效率分别为6.2％、3.4％、1.5％、4.5％和3.9％，ADS-BE2.5、eADS-BE2.1和eADS-BE2.6产生indels平均效率分别为4.6％、1.8％和1.2％，宽窗口ADS-BE2.5产生indels明显低于经典的BE4max-PU；eADS-BE2.1和eADS-BE2.6在保证高精度的同时也保持较低水平的indels。根据Cas9非依赖性脱靶评价，在6个R-loop位点检测发现，ADS-BE2.5产生的非依赖性脱靶事件也是低于传统的BE4max-PU，特别是在R-loop1和R-loop3位点降低幅度最大，而eADS-BE2.1和eADS-BE2.6引起极低的C到T编辑，微量的脱靶编辑事件和低水平的indel表明eADS-BE2.1和eADS-BE2.6同时兼容高精度和高安全性。
SEQUENCE LISTING
<110> 华东师范大学
上海邦耀生物科技有限公司
<120> 腺嘌呤脱氨酶及其应用
<130> P21018917C
<160> 82
<170> PatentIn version 3.5
<210> 1
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> bNLS
<400> 1
Met Lys Arg Thr Ala Asp Gly Ser Glu Phe Glu Ser Pro Lys Lys Lys
1 5 10 15
Arg Lys Val
<210> 2
<211> 167
<212> PRT
<213> Artificial Sequence
<220>
<223> TadA8e
<400> 2
Met Ser Glu Val Glu Phe Ser His Glu Tyr Trp Met Arg His Ala Leu
1 5 10 15
Thr Leu Ala Lys Arg Ala Arg Asp Glu Arg Glu Val Pro Val Gly Ala
20 25 30
Val Leu Val Leu Asn Asn Arg Val Ile Gly Glu Gly Trp Asn Arg Ala
35 40 45
Ile Gly Leu His Asp Pro Thr Ala His Ala Glu Ile Met Ala Leu Arg
50 55 60
Gln Gly Gly Leu Val Met Gln Asn Tyr Arg Leu Ile Asp Ala Thr Leu
65 70 75 80
Tyr Val Thr Phe Glu Pro Cys Val Met Cys Ala Gly Ala Met Ile His
85 90 95
Ser Arg Ile Gly Arg Val Val Phe Gly Val Arg Asn Ser Lys Arg Gly
100 105 110
Ala Ala Gly Ser Leu Met Asn Val Leu Asn Tyr Pro Gly Met Asn His
115 120 125
Arg Val Glu Ile Thr Glu Gly Ile Leu Ala Asp Glu Cys Ala Ala Leu
130 135 140
Leu Cys Asp Phe Tyr Arg Met Pro Arg Gln Val Phe Asn Ala Gln Lys
145 150 155 160
Lys Ala Gln Ser Ser Ile Asn
165
<210> 3
<211> 32
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker1
<400> 3
Ser Gly Gly Ser Ser Gly Gly Ser Ser Gly Ser Glu Thr Pro Gly Thr
1 5 10 15
Ser Glu Ser Ala Thr Pro Glu Ser Ser Gly Gly Ser Ser Gly Gly Ser
20 25 30
<210> 4
<211> 1368
<212> PRT
<213> Artificial Sequence
<220>
<223> spCas9n（D10A）
<400> 4
Met Asp Lys Lys Tyr Ser Ile Gly Leu Ala Ile Gly Thr Asn Ser Val
1 5 10 15
Gly Trp Ala Val Ile Thr Asp Glu Tyr Lys Val Pro Ser Lys Lys Phe
20 25 30
Lys Val Leu Gly Asn Thr Asp Arg His Ser Ile Lys Lys Asn Leu Ile
35 40 45
Gly Ala Leu Leu Phe Asp Ser Gly Glu Thr Ala Glu Ala Thr Arg Leu
50 55 60
Lys Arg Thr Ala Arg Arg Arg Tyr Thr Arg Arg Lys Asn Arg Ile Cys
65 70 75 80
Tyr Leu Gln Glu Ile Phe Ser Asn Glu Met Ala Lys Val Asp Asp Ser
85 90 95
Phe Phe His Arg Leu Glu Glu Ser Phe Leu Val Glu Glu Asp Lys Lys
100 105 110
His Glu Arg His Pro Ile Phe Gly Asn Ile Val Asp Glu Val Ala Tyr
115 120 125
His Glu Lys Tyr Pro Thr Ile Tyr His Leu Arg Lys Lys Leu Val Asp
130 135 140
Ser Thr Asp Lys Ala Asp Leu Arg Leu Ile Tyr Leu Ala Leu Ala His
145 150 155 160
Met Ile Lys Phe Arg Gly His Phe Leu Ile Glu Gly Asp Leu Asn Pro
165 170 175
Asp Asn Ser Asp Val Asp Lys Leu Phe Ile Gln Leu Val Gln Thr Tyr
180 185 190
Asn Gln Leu Phe Glu Glu Asn Pro Ile Asn Ala Ser Gly Val Asp Ala
195 200 205
Lys Ala Ile Leu Ser Ala Arg Leu Ser Lys Ser Arg Arg Leu Glu Asn
210 215 220
Leu Ile Ala Gln Leu Pro Gly Glu Lys Lys Asn Gly Leu Phe Gly Asn
225 230 235 240
Leu Ile Ala Leu Ser Leu Gly Leu Thr Pro Asn Phe Lys Ser Asn Phe
245 250 255
Asp Leu Ala Glu Asp Ala Lys Leu Gln Leu Ser Lys Asp Thr Tyr Asp
260 265 270
Asp Asp Leu Asp Asn Leu Leu Ala Gln Ile Gly Asp Gln Tyr Ala Asp
275 280 285
Leu Phe Leu Ala Ala Lys Asn Leu Ser Asp Ala Ile Leu Leu Ser Asp
290 295 300
Ile Leu Arg Val Asn Thr Glu Ile Thr Lys Ala Pro Leu Ser Ala Ser
305 310 315 320
Met Ile Lys Arg Tyr Asp Glu His His Gln Asp Leu Thr Leu Leu Lys
325 330 335
Ala Leu Val Arg Gln Gln Leu Pro Glu Lys Tyr Lys Glu Ile Phe Phe
340 345 350
Asp Gln Ser Lys Asn Gly Tyr Ala Gly Tyr Ile Asp Gly Gly Ala Ser
355 360 365
Gln Glu Glu Phe Tyr Lys Phe Ile Lys Pro Ile Leu Glu Lys Met Asp
370 375 380
Gly Thr Glu Glu Leu Leu Val Lys Leu Asn Arg Glu Asp Leu Leu Arg
385 390 395 400
Lys Gln Arg Thr Phe Asp Asn Gly Ser Ile Pro His Gln Ile His Leu
405 410 415
Gly Glu Leu His Ala Ile Leu Arg Arg Gln Glu Asp Phe Tyr Pro Phe
420 425 430
Leu Lys Asp Asn Arg Glu Lys Ile Glu Lys Ile Leu Thr Phe Arg Ile
435 440 445
Pro Tyr Tyr Val Gly Pro Leu Ala Arg Gly Asn Ser Arg Phe Ala Trp
450 455 460
Met Thr Arg Lys Ser Glu Glu Thr Ile Thr Pro Trp Asn Phe Glu Glu
465 470 475 480
Val Val Asp Lys Gly Ala Ser Ala Gln Ser Phe Ile Glu Arg Met Thr
485 490 495
Asn Phe Asp Lys Asn Leu Pro Asn Glu Lys Val Leu Pro Lys His Ser
500 505 510
Leu Leu Tyr Glu Tyr Phe Thr Val Tyr Asn Glu Leu Thr Lys Val Lys
515 520 525
Tyr Val Thr Glu Gly Met Arg Lys Pro Ala Phe Leu Ser Gly Glu Gln
530 535 540
Lys Lys Ala Ile Val Asp Leu Leu Phe Lys Thr Asn Arg Lys Val Thr
545 550 555 560
Val Lys Gln Leu Lys Glu Asp Tyr Phe Lys Lys Ile Glu Cys Phe Asp
565 570 575
Ser Val Glu Ile Ser Gly Val Glu Asp Arg Phe Asn Ala Ser Leu Gly
580 585 590
Thr Tyr His Asp Leu Leu Lys Ile Ile Lys Asp Lys Asp Phe Leu Asp
595 600 605
Asn Glu Glu Asn Glu Asp Ile Leu Glu Asp Ile Val Leu Thr Leu Thr
610 615 620
Leu Phe Glu Asp Arg Glu Met Ile Glu Glu Arg Leu Lys Thr Tyr Ala
625 630 635 640
His Leu Phe Asp Asp Lys Val Met Lys Gln Leu Lys Arg Arg Arg Tyr
645 650 655
Thr Gly Trp Gly Arg Leu Ser Arg Lys Leu Ile Asn Gly Ile Arg Asp
660 665 670
Lys Gln Ser Gly Lys Thr Ile Leu Asp Phe Leu Lys Ser Asp Gly Phe
675 680 685
Ala Asn Arg Asn Phe Met Gln Leu Ile His Asp Asp Ser Leu Thr Phe
690 695 700
Lys Glu Asp Ile Gln Lys Ala Gln Val Ser Gly Gln Gly Asp Ser Leu
705 710 715 720
His Glu His Ile Ala Asn Leu Ala Gly Ser Pro Ala Ile Lys Lys Gly
725 730 735
Ile Leu Gln Thr Val Lys Val Val Asp Glu Leu Val Lys Val Met Gly
740 745 750
Arg His Lys Pro Glu Asn Ile Val Ile Glu Met Ala Arg Glu Asn Gln
755 760 765
Thr Thr Gln Lys Gly Gln Lys Asn Ser Arg Glu Arg Met Lys Arg Ile
770 775 780
Glu Glu Gly Ile Lys Glu Leu Gly Ser Gln Ile Leu Lys Glu His Pro
785 790 795 800
Val Glu Asn Thr Gln Leu Gln Asn Glu Lys Leu Tyr Leu Tyr Tyr Leu
805 810 815
Gln Asn Gly Arg Asp Met Tyr Val Asp Gln Glu Leu Asp Ile Asn Arg
820 825 830
Leu Ser Asp Tyr Asp Val Asp His Ile Val Pro Gln Ser Phe Leu Lys
835 840 845
Asp Asp Ser Ile Asp Asn Lys Val Leu Thr Arg Ser Asp Lys Asn Arg
850 855 860
Gly Lys Ser Asp Asn Val Pro Ser Glu Glu Val Val Lys Lys Met Lys
865 870 875 880
Asn Tyr Trp Arg Gln Leu Leu Asn Ala Lys Leu Ile Thr Gln Arg Lys
885 890 895
Phe Asp Asn Leu Thr Lys Ala Glu Arg Gly Gly Leu Ser Glu Leu Asp
900 905 910
Lys Ala Gly Phe Ile Lys Arg Gln Leu Val Glu Thr Arg Gln Ile Thr
915 920 925
Lys His Val Ala Gln Ile Leu Asp Ser Arg Met Asn Thr Lys Tyr Asp
930 935 940
Glu Asn Asp Lys Leu Ile Arg Glu Val Lys Val Ile Thr Leu Lys Ser
945 950 955 960
Lys Leu Val Ser Asp Phe Arg Lys Asp Phe Gln Phe Tyr Lys Val Arg
965 970 975
Glu Ile Asn Asn Tyr His His Ala His Asp Ala Tyr Leu Asn Ala Val
980 985 990
Val Gly Thr Ala Leu Ile Lys Lys Tyr Pro Lys Leu Glu Ser Glu Phe
995 1000 1005
Val Tyr Gly Asp Tyr Lys Val Tyr Asp Val Arg Lys Met Ile Ala
1010 1015 1020
Lys Ser Glu Gln Glu Ile Gly Lys Ala Thr Ala Lys Tyr Phe Phe
1025 1030 1035
Tyr Ser Asn Ile Met Asn Phe Phe Lys Thr Glu Ile Thr Leu Ala
1040 1045 1050
Asn Gly Glu Ile Arg Lys Arg Pro Leu Ile Glu Thr Asn Gly Glu
1055 1060 1065
Thr Gly Glu Ile Val Trp Asp Lys Gly Arg Asp Phe Ala Thr Val
1070 1075 1080
Arg Lys Val Leu Ser Met Pro Gln Val Asn Ile Val Lys Lys Thr
1085 1090 1095
Glu Val Gln Thr Gly Gly Phe Ser Lys Glu Ser Ile Leu Pro Lys
1100 1105 1110
Arg Asn Ser Asp Lys Leu Ile Ala Arg Lys Lys Asp Trp Asp Pro
1115 1120 1125
Lys Lys Tyr Gly Gly Phe Asp Ser Pro Thr Val Ala Tyr Ser Val
1130 1135 1140
Leu Val Val Ala Lys Val Glu Lys Gly Lys Ser Lys Lys Leu Lys
1145 1150 1155
Ser Val Lys Glu Leu Leu Gly Ile Thr Ile Met Glu Arg Ser Ser
1160 1165 1170
Phe Glu Lys Asn Pro Ile Asp Phe Leu Glu Ala Lys Gly Tyr Lys
1175 1180 1185
Glu Val Lys Lys Asp Leu Ile Ile Lys Leu Pro Lys Tyr Ser Leu
1190 1195 1200
Phe Glu Leu Glu Asn Gly Arg Lys Arg Met Leu Ala Ser Ala Gly
1205 1210 1215
Glu Leu Gln Lys Gly Asn Glu Leu Ala Leu Pro Ser Lys Tyr Val
1220 1225 1230
Asn Phe Leu Tyr Leu Ala Ser His Tyr Glu Lys Leu Lys Gly Ser
1235 1240 1245
Pro Glu Asp Asn Glu Gln Lys Gln Leu Phe Val Glu Gln His Lys
1250 1255 1260
His Tyr Leu Asp Glu Ile Ile Glu Gln Ile Ser Glu Phe Ser Lys
1265 1270 1275
Arg Val Ile Leu Ala Asp Ala Asn Leu Asp Lys Val Leu Ser Ala
1280 1285 1290
Tyr Asn Lys His Arg Asp Lys Pro Ile Arg Glu Gln Ala Glu Asn
1295 1300 1305
Ile Ile His Leu Phe Thr Leu Thr Asn Leu Gly Ala Pro Ala Ala
1310 1315 1320
Phe Lys Tyr Phe Asp Thr Thr Ile Asp Arg Lys Arg Tyr Thr Ser
1325 1330 1335
Thr Lys Glu Val Leu Asp Ala Thr Leu Ile His Gln Ser Ile Thr
1340 1345 1350
Gly Leu Tyr Glu Thr Arg Ile Asp Leu Ser Gln Leu Gly Gly Asp
1355 1360 1365
<210> 5
<211> 84
<212> PRT
<213> Artificial Sequence
<220>
<223> UGI
<400> 5
Met Thr Asn Leu Ser Asp Ile Ile Glu Lys Glu Thr Gly Lys Gln Leu
1 5 10 15
Val Ile Gln Glu Ser Ile Leu Met Leu Pro Glu Glu Val Glu Glu Val
20 25 30
Ile Gly Asn Lys Pro Glu Ser Asp Ile Leu Val His Thr Ala Tyr Asp
35 40 45
Glu Ser Thr Asp Glu Asn Val Met Leu Leu Thr Ser Asp Ala Pro Glu
50 55 60
Tyr Lys Pro Trp Ala Leu Val Ile Gln Asp Ser Asn Gly Glu Asn Lys
65 70 75 80
Ile Lys Met Leu
<210> 6
<211> 177
<212> PRT
<213> Artificial Sequence
<220>
<223> 2×UGI
<400> 6
Met Thr Asn Leu Ser Asp Ile Ile Glu Lys Glu Thr Gly Lys Gln Leu
1 5 10 15
Val Ile Gln Glu Ser Ile Leu Met Leu Pro Glu Glu Val Glu Glu Val
20 25 30
Ile Gly Asn Lys Pro Glu Ser Asp Ile Leu Val His Thr Ala Tyr Asp
35 40 45
Glu Ser Thr Asp Glu Asn Val Met Leu Leu Thr Ser Asp Ala Pro Glu
50 55 60
Tyr Lys Pro Trp Ala Leu Val Ile Gln Asp Ser Asn Gly Glu Asn Lys
65 70 75 80
Ile Lys Met Leu Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Thr Asn
85 90 95
Leu Ser Asp Ile Ile Glu Lys Glu Thr Gly Lys Gln Leu Val Ile Gln
100 105 110
Glu Ser Ile Leu Met Leu Pro Glu Glu Val Glu Glu Val Ile Gly Asn
115 120 125
Lys Pro Glu Ser Asp Ile Leu Val His Thr Ala Tyr Asp Glu Ser Thr
130 135 140
Asp Glu Asn Val Met Leu Leu Thr Ser Asp Ala Pro Glu Tyr Lys Pro
145 150 155 160
Trp Ala Leu Val Ile Gln Asp Ser Asn Gly Glu Asn Lys Ile Lys Met
165 170 175
Leu
<210> 7
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> P2A
<400> 7
Met Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn
1 5 10 15
Pro Gly Pro
<210> 8
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker0
<400> 8
Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser
1 5 10
<210> 9
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker15
<400> 9
Pro Ala Pro Ala Pro Ala Pro
1 5
<210> 10
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Linker13
<400> 10
Pro Ala Pro Ala Pro
1 5
<210> 11
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> LAG3-sg4
<400> 11
tgacccctgc tcttcgcaga 20
<210> 12
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> HBG-sg14
<400> 12
agctcctagt ccagacgcca 20
<210> 13
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> FANCF-sg17
<400> 13
gcgatccagg tgctgcagaa 20
<210> 14
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> VEGFA site 2
<400> 14
gaccccctcc accccgcctc 20
<210> 15
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> Site A
<400> 15
tgcccctccc tccctggccc 20
<210> 16
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> FGF6-sg4
<400> 16
ataagcccct gccgccatgc 20
<210> 17
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> PDCD1 site 2
<400> 17
acttccacat gagcgtggtc 20
<210> 18
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> EGFR-sg39
<400> 18
tagtccagga ggcagccgaa 20
<210> 19
<211> 22
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 1
<400> 19
gtggtagaca gcatgtgtcc ta 22
<210> 20
<211> 22
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 2
<400> 20
atttacagcc tggcctttgg gg 22
<210> 21
<211> 22
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 3
<400> 21
gtgtcaggta atgtgctaaa ca 22
<210> 22
<211> 22
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 4
<400> 22
ggtggaggag ggtgcatggg gt 22
<210> 23
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 5
<400> 23
tctgcttctc cagccctggc 20
<210> 24
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 6
<400> 24
gatgttccaa tcagtacgca 20
<210> 25
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> LAG3-sg4 Oligo-up
<400> 25
caccgtgacc cctgctcttc gcaga 25
<210> 26
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> LAG3-sg4 Oligo-dn
<400> 26
aaactctgcg aagagcaggg gtcac 25
<210> 27
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> HBG-sg14 Oligo-up
<400> 27
caccgagctc ctagtccaga cgcca 25
<210> 28
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> HBG-sg14 Oligo-dn
<400> 28
aaactggcgt ctggactagg agctc 25
<210> 29
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> FANCF-sg17 Oligo-up
<400> 29
caccggcgat ccaggtgctg cagaa 25
<210> 30
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> FANCF-sg17 Oligo-dn
<400> 30
aaacttctgc agcacctgga tcgcc 25
<210> 31
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> VEGFA site 2 Oligo-up
<400> 31
caccgacccc ctccaccccg cctc 24
<210> 32
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> VEGFA site 2 Oligo-dn
<400> 32
aaacgaggcg gggtggaggg ggtc 24
<210> 33
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> Site A Oligo-up
<400> 33
caccgtgccc ctccctccct ggccc 25
<210> 34
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> Site A Oligo-dn
<400> 34
aaacgggcca gggagggagg ggcac 25
<210> 35
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> FGF6-sg4 Oligo-up
<400> 35
caccgataag cccctgccgc catgc 25
<210> 36
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> FGF6-sg4 Oligo-dn
<400> 36
aaacgcatgg cggcaggggc ttatc 25
<210> 37
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> PDCD1 site 2 Oligo-up
<400> 37
caccgacttc cacatgagcg tggtc 25
<210> 38
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> PDCD1 site 2 Oligo-dn
<400> 38
aaacgaccac gctcatgtgg aagtc 25
<210> 39
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> EGFR-sg39 Oligo-up
<400> 39
caccgtagtc caggaggcag ccgaa 25
<210> 40
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> EGFR-sg39 Oligo-dn
<400> 40
aaacttcggc tgcctcctgg actac 25
<210> 41
<211> 26
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 1 Oligo-up
<400> 41
caccgtggta gacagcatgt gtccta 26
<210> 42
<211> 26
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 1 Oligo-dn
<400> 42
aaactaggac acatgctgtc taccac 26
<210> 43
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 2 Oligo-up
<400> 43
caccgattta cagcctggcc tttgggg 27
<210> 44
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 2 Oligo-dn
<400> 44
aaacccccaa aggccaggct gtaaatc 27
<210> 45
<211> 26
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 3 Oligo-up
<400> 45
caccgtgtca ggtaatgtgc taaaca 26
<210> 46
<211> 26
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 3 Oligo-dn
<400> 46
aaactgttta gcacattacc tgacac 26
<210> 47
<211> 26
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 4 Oligo-up
<400> 47
caccggtgga ggagggtgca tggggt 26
<210> 48
<211> 26
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 4 Oligo-dn
<400> 48
aaacacccca tgcaccctcc tccacc 26
<210> 49
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 5 Oligo-up
<400> 49
caccgtctgc ttctccagcc ctggc 25
<210> 50
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 5 Oligo-dn
<400> 50
aaacgccagg gctggagaag cagac 25
<210> 51
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 6 Oligo-up
<400> 51
caccgatgtt ccaatcagta cgca 24
<210> 52
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 6 Oligo-dn
<400> 52
aaactgcgta ctgattggaa catc 24
<210> 53
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> 正向鉴定引物搭桥序列
<400> 53
ggagtgagta cggtgtgc 18
<210> 54
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> 反向鉴定引物搭桥序列
<400> 54
gagttggatg ctggatgg 18
<210> 55
<211> 39
<212> DNA
<213> Artificial Sequence
<220>
<223> LAG3-sg4-F
<400> 55
ggagtgagta cggtgtgctt tgctcaccta gtgaagcct 39
<210> 56
<211> 38
<212> DNA
<213> Artificial Sequence
<220>
<223> LAG3-sg4-R
<400> 56
gagttggatg ctggatggag tttggggtgc atacctgt 38
<210> 57
<211> 43
<212> DNA
<213> Artificial Sequence
<220>
<223> HBG-sg14-F
<400> 57
ggagtgagta cggtgtgctt agagtatcca gtgaggccag ggg 43
<210> 58
<211> 43
<212> DNA
<213> Artificial Sequence
<220>
<223> HBG-sg14-R
<400> 58
gagttggatg ctggatggtt gccccacagg cttgtgatag tag 43
<210> 59
<211> 40
<212> DNA
<213> Artificial Sequence
<220>
<223> FANCF-sg17-F
<400> 59
ggagtgagta cggtgtgcga ccaaagcgcc gatggatgtg 40
<210> 60
<211> 43
<212> DNA
<213> Artificial Sequence
<220>
<223> FANCF-sg17-R
<400> 60
gagttggatg ctggatggct ccaaggtgaa agcggaagta ggg 43
<210> 61
<211> 40
<212> DNA
<213> Artificial Sequence
<220>
<223> VEGFA site 2-F
<400> 61
ggagtgagta cggtgtgcga cagacagaca gacaccgccc 40
<210> 62
<211> 43
<212> DNA
<213> Artificial Sequence
<220>
<223> VEGFA site 2-R
<400> 62
gagttggatg ctggatggac agcccagaag ttggacgaaa agt 43
<210> 63
<211> 41
<212> DNA
<213> Artificial Sequence
<220>
<223> Site A-F
<400> 63
ggagtgagta cggtgtgcga gtgttgaggc cccagtggct g 41
<210> 64
<211> 41
<212> DNA
<213> Artificial Sequence
<220>
<223> Site A-R
<400> 64
gagttggatg ctggatggat gcgccaccgg ttgatgtgat g 41
<210> 65
<211> 43
<212> DNA
<213> Artificial Sequence
<220>
<223> FGF6-sg4-F
<400> 65
ggagtgagta cggtgtgcat gtcagcagcc ttcatctgcc ttc 43
<210> 66
<211> 43
<212> DNA
<213> Artificial Sequence
<220>
<223> FGF6-sg4-R
<400> 66
gagttggatg ctggatggct gctccccggg acatagtgat gaa 43
<210> 67
<211> 40
<212> DNA
<213> Artificial Sequence
<220>
<223> PDCD1 site 2-F
<400> 67
ggagtgagta cggtgtgcct ctgcccgcag gctctctttg 40
<210> 68
<211> 37
<212> DNA
<213> Artificial Sequence
<220>
<223> PDCD1 site 2-R
<400> 68
gagttggatg ctggatggct tccccgagga ccgcagc 37
<210> 69
<211> 38
<212> DNA
<213> Artificial Sequence
<220>
<223> EGFR-sg39-F
<400> 69
ggagtgagta cggtgtgccg atctgcacac accagttg 38
<210> 70
<211> 38
<212> DNA
<213> Artificial Sequence
<220>
<223> EGFR-sg39-R
<400> 70
gagttggatg ctggatggcc tccaggaagc ctacgtga 38
<210> 71
<211> 44
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 1-F
<400> 71
ggagtgagta cggtgtgcgg ttagaaggac ccctgtattt ttgc 44
<210> 72
<211> 43
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 1-R
<400> 72
gagttggatg ctggatggct gtaccaacat acatgcccct ttg 43
<210> 73
<211> 43
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 2-F
<400> 73
ggagtgagta cggtgtgcaa aggacatttc caccgcaaaa tgg 43
<210> 74
<211> 41
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 2-R
<400> 74
gagttggatg ctggatggga atggggagaa gggcaggttc c 41
<210> 75
<211> 43
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 3-F
<400> 75
ggagtgagta cggtgtgctc tttgctccag atttcccttc ata 43
<210> 76
<211> 43
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 3-R
<400> 76
gagttggatg ctggatggcc ttaagtgttc agctgctttt ctt 43
<210> 77
<211> 43
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 4-F
<400> 77
ggagtgagta cggtgtgcac agaaatgtga gcccatcagg tat 43
<210> 78
<211> 43
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 4-R
<400> 78
gagttggatg ctggatggga atcctggaca aggtttgaag gac 43
<210> 79
<211> 43
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 5-F
<400> 79
ggagtgagta cggtgtgcag tctatttctg ctgcaagtaa gca 43
<210> 80
<211> 43
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 5-R
<400> 80
gagttggatg ctggatggac atactagccc ctgtctagga aaa 43
<210> 81
<211> 39
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 6-F
<400> 81
ggagtgagta cggtgtgcga acacggataa agacgctgg 39
<210> 82
<211> 39
<212> DNA
<213> Artificial Sequence
<220>
<223> R-loop 6-R
<400> 82
gagttggatg ctggatgggc agaagggatt ccatgaggt 39
Claims (10)
1.一种腺嘌呤脱氨酶，其特征在于，所述腺嘌呤脱氨酶相比于如SEQ ID NO:2所示的氨基酸序列具有氨基酸差异，所述氨基酸差异位于第46位；
较佳地，所述差异还位于第27位、第29位和第48位中的一位或多位。
2.如权利要求1所述的腺嘌呤脱氨酶，其特征在于，所述氨基酸腺嘌呤脱氨酶相比于如SEQ ID NO:2所示的氨基酸序列具有如下氨基酸差异：
第46位氨基酸残基N替换为L；或，
第46位氨基酸残基N替换为L，并且第27位氨基酸残基E替换为R；或，
第46位氨基酸残基N替换为L，并且第29位氨基酸残基P替换为A；或，
第46位氨基酸残基N替换为L，并且第48位氨基酸残基A替换为M。
3.一种融合蛋白，其特征在于，所述融合蛋白包含如权利要求1或2所述的腺嘌呤脱氨酶；
较佳地，所述融合蛋白还包括核定位信号序列，所述核定位信号序列位于所述腺嘌呤脱氨酶的N端和/或C端；
更佳地，所述核定位信号序列位于所述腺嘌呤脱氨酶的N端，其氨基酸序列优选如SEQID NO:1所示。
4.一种胞嘧啶碱基编辑器，其特征在于，所述胞嘧啶碱基编辑器包括核酸酶和如权利要求1或2所述的腺嘌呤脱氨酶；
较佳地，所述核酸酶为Cas蛋白及其变体；和/或，所述核酸酶和所述腺嘌呤脱氨酶通过连接子连接；和/或，所述胞嘧啶碱基编辑器还包括UGI片段，所述UGI片段优选连接在所述核酸酶的C端；
更佳地，所述Cas蛋白选自酿酒酵母来源的spCas9、金黄色葡萄球菌来源的SaCas9、毛螺菌科细菌来源的LbCas12a和酸胺球菌属细菌来源的enAsCas12a；所述Cas蛋白变体选自VQR-spCas9、VRER-spCas9、spRY、spNG、SaCas9-KKH和SaCas9-NG；和/或，所述连接子的氨基酸序列如SEQ ID NO:3、9或10任一项所示、或者所述连接子的氨基酸序列为PAP；和/或，所述核酸酶和所述UGI片段之间通过连接子连接，所述连接子优选为P2A片段，例如氨基酸序列如SEQ ID NO:7所示的P2A片段；和/或，所述UGI片段至少为一个拷贝，优选两个拷贝、三个拷贝或四个拷贝；优选地，所述拷贝之间通过氨基酸序列例如SEQ ID NO:8所示的连接子相连；
进一步更佳地，所述Cas蛋白为酿酒酵母来源的spCas9，所述spCas9的氨基酸序列如SEQ ID NO:4所示；和/或，所述核酸酶与所述P2A片段之间连有核定位信号序列；和/或，所述UGI片段的C端还连接有核定位信号序列或polyA信号序列，所述核定位信号序列的氨基酸序列优选如SEQ ID NO:1所示，所述polyA信号序列优选为BGH polyA。
5.一种分离的核酸，其特征在于，所述核酸编码如权利要求1或2所述的腺嘌呤脱氨酶、如权利要求3所述的融合蛋白或者如权利要求4所述的胞嘧啶碱基编辑器。
6.一种胞嘧啶碱基编辑系统，其特征在于，其包括：sgRNA和如权利要求3所述的胞嘧啶碱基编辑器；
较佳地，所述sgRNA的靶序列具有如SEQ ID NO:11～24任一所示的核苷酸序列。
7.一种药物组合物，其特征在于，所述药物组合物包括如权利要求1或2所述的腺嘌呤脱氨酶、如权利要求3所述的融合蛋白、如权利要求4所述的胞嘧啶碱基编辑器或者如权利要求6所述的胞嘧啶碱基编辑系统。
8.一种非治疗目的的碱基编辑方法，其特征在于，所述碱基编辑方法包括：
在靶细胞中表达如权利要求1或2所述的腺嘌呤脱氨酶、如权利要求3所述的融合蛋白、如权利要求4所述的胞嘧啶碱基编辑器、如权利要求5所述的核酸或者如权利要求6所述的胞嘧啶碱基编辑系统，使所述靶细胞发生碱基编辑；
较佳地，所述靶细胞的来源为分离的细胞系；
更佳地，所述分离的细胞系为293T细胞、HELA细胞、U2OS细胞、NIH3T3细胞或N2A细胞。
9.如权利要求1或2所述的腺嘌呤脱氨酶、如权利要求3所述的胞嘧啶碱基编辑器、如权利要求4所述的融合蛋白、如权利要求5所述的核酸或者如权利要求6所述的胞嘧啶碱基编辑系统在制备碱基编辑的药物、构建动物模型、农作物育种、制备基因治疗的药物或者制备碱基编辑工具中的应用。
10.一种基因表达盒，其特征在于，所述基因表达盒包括启动子元件和目的基因元件；
其中，所述目的基因元件选自编码如权利要求1或2所述的腺嘌呤脱氨酶、如权利要求3所述的胞嘧啶碱基编辑器或者如权利要求4所述的融合蛋白的基因；
较佳地，所述启动子元件选自CMV、CAG、PGK、EF1α、Ctsk和Lp1。
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