CN115232794A - 一种基因编辑系统及其在构建oca-1b型白化病模型猪核移植供体细胞中的应用 - Google Patents
一种基因编辑系统及其在构建oca-1b型白化病模型猪核移植供体细胞中的应用 Download PDFInfo
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Abstract
本发明公开了一种基因编辑系统及其在构建OCA‑1B型白化病模型猪核移植供体细胞中的应用。本发明提供的试剂盒,包括靶序列结合区如SEQ ID NO:18中第3‑22位核苷酸所示的TYR‑gRNA1、靶序列结合区如SEQ ID NO:19中第3‑22位核苷酸所示的TYR‑gRNA5、SEQ IDNO:20所示的TYR‑E4mut‑ss153和NCN蛋白;试剂盒的用途:制备重组细胞;制备白化病模型猪;制备白化病细胞模型或白化病组织模型或白化病器官模型。将所述重组细胞作为核移植供体细胞进行体细胞克隆,可以得到克隆猪,即为白化病模型猪。本发明对于白化病药物的研发及揭示该病的发病机制具有重大应用价值。
Description
技术领域
本发明属于生物技术领域,具体属于基因编辑技术领域,更具体基于CRISPR/Cas9系统及ssODN同源重组技术的一种基因编辑系统及其在构建OCA-1B型白化病模型猪核移植供体细胞中的应用。
背景技术
白化病(albinism)是由于黑色素合成减少或缺乏而导致的多种遗传性疾病的总称,主要表现为皮肤、毛发以及眼部的色素减退。多种基因的突变均可导致白化病的症状。根据色素缺失的部位以及有无其他系统异常,可将白化病分为非综合征性白化病和综合征性白化病两大类。非综合征白化病又可再分为只有眼部色素缺乏的眼白化病(OA)和皮肤、毛发、眼睛均有色素缺失(即具有全身症状)的眼及皮肤白化病(oculocutaneousalbinism,OCA)。
OCA是一组以眼、皮肤、毛发黑色素沉着减少或缺乏为主要临床表现的常染色体隐性遗传病。超过90%的白化病患者为OCA,一般是由黑色素合成或转运相关基因突变所引起的,主要临床表现为普遍色素沉着不足,眼部改变包括黄斑中心凹发育不良、屈光不正、视力低下、畏光、虹膜半透明、眼球震颤、眼底着色不足及视觉纤维通路异常等。近年来,OCA已根据发生突变的基因进行分类:酪氨酸酶基因(TYR)突变导致OCA1,OCA2基因(曾被命名为P基因)突变导致OCA2,酪氨酸酶相关蛋白-1基因(TYRP1)突变导致OCA3,SLC45A2基因(曾被命名为MATP或AIM1)突变导致OCA4。
OCA-1型约占OCA的40-50%,是TYR基因突变致使其编码的酪氨酸酶功能丧失引起的。已有研究结果表明,根据酪氨酸酶活性是否完全丧失,OCA-1可分为两型:OCA-1A和OCA-1B,两者在出生时无法区分。OCA-1A患者酪氨酸酶活性完全丧失,是最严重的类型,患者皮肤和眼睛色素完全缺失,视觉敏锐度下降至5%。OCA-1B患者体内酪氨酸酶活性明显下降,但尚未完全缺失,患者皮肤、头发和眼色素可以随年龄增长而增加,并可被晒黑。
研究由TYR突变导致OCA-1型的发生发展机制及研发相应的药物均需要在动物模型的基础上进行,目前常用的动物模型为小鼠模型,然而小鼠不论从体型、器官大小、生理、病理等方面都与人相差巨大,不能真实地模拟人类正常的生理、病理状态。而猪作为大动物,是人类长期以来主要的肉食供应动物,其体型大小和生理功能与人类近似,易于大规模繁殖饲养,而且在伦理道德及动物保护等方面要求较低,是理想的人类疾病模型动物。
基因编辑是近年来不断取得重大发展的一种生物技术,其包括从基于同源重组的基因编辑到基于核酸酶的ZFN、TALEN、CRISPR/Cas9等编辑技术,其中CRISPR/Cas9技术是当前最先进的基因编辑技术。目前,基因编辑技术被越来越多地应用到动物模型的制作上。
同源重组(HDR)是通过序列同源性交换DNA序列信息:即修复模板中包含所需插入片段,修复模板的两端则是与插入位点附近具有序列同源性的重组臂。过去通常使用双链DNA(dsDNA)作为修复模板,但最近的研究揭示了单链寡核苷酸脱氧核苷酸(ssODN)作为HDR供体模板的优越性。首先,ssODN作为供体模板比dsDNA模板的插入位点特异性高,dsDNA模板容易产生随机插入。其次,ssODN对同源重组臂的长度要求比dsDNA模板更短,单侧30-60个碱基的重组臂设计可以获得高效且稳定的HDR,相比类似的dsDNA模板,其提供的插入效率更高。第三,dsDNA容易被NHEJ修复途径合并,从而导致同源臂的复制或者dsDNA模板的部分整合,而ssODN就不易产生这种现象。另外,dsDNAs对培养的细胞是有害的,线型或者质粒dsDNAs的转染效率较低,并使细胞产生不良反应,而ssODN模板在这些方面就更有优势。
发明内容
本发明的目的是提供一种基因编辑系统及其在构建OCA-1B型白化病模型猪核移植供体细胞中的应用。
本发明提供了一种试剂盒,包括TYR-gRNA1、TYR-gRNA5、TYR-E4mut-ss153和NCN蛋白。
本发明还提供了一种试剂盒,包括TYR-gRNA1、TYR-gRNA5、TYR-E4mut-ss153和PRONCN蛋白。
本发明还提供了一种试剂盒,包括TYR-gRNA1、TYR-gRNA5、TYR-E4mut-ss153和特异质粒。
以上任一所述试剂盒还包括猪细胞。
本发明还提供了TYR-gRNA1、TYR-gRNA5、TYR-E4mut-ss153和NCN蛋白在制备试剂盒中的应用。
本发明还提供了TYR-gRNA1、TYR-gRNA5、TYR-E4mut-ss153和PRONCN蛋白在制备试剂盒中的应用。
本发明还提供了TYR-gRNA1、TYR-gRNA5、TYR-E4mut-ss153和特异质粒在制备试剂盒中的应用。
以上任一所述试剂盒的用途为如下(a)或(b)或(c):(a)制备重组细胞;(b)制备白化病模型猪;(c)制备白化病细胞模型或白化病组织模型或白化病器官模型。
本发明还提供了一种制备重组细胞的方法,包括如下步骤:用SEQ ID NO:20所示的DNA分子取代猪细胞的染色体DNA中SEQ ID NO:21所示的DNA分子,得到重组细胞。
用SEQ ID NO:20所示的DNA分子取代猪细胞的染色体DNA中SEQ ID NO:21所示的DNA分子的实现方式为:将TYR-gRNA1、TYR-gRNA5、TYR-E4mut-ss153和NCN蛋白共转染猪细胞。
所述共转染具体采用电击转染的方式。
电击转染的参数设置具体可为:1450V、10ms、3pulse。
所述共转染具体可采用哺乳动物核转染试剂盒(Neon kit,Thermofisher)与NeonTM transfection system电转仪。
TYR-gRNA1、TYR-gRNA5、TYR-E4mut-ss153和NCN蛋白的配比依次为:0.8-1.2μgTYR-gRNA1:0.8-1.2μg TYR-gRNA5:1.8-2.2μg TYR-E4mut-ss153:3-5μg NCN蛋白。
TYR-gRNA1、TYR-gRNA5、TYR-E4mut-ss153和NCN蛋白的配比依次为:1μg TYR-gRNA1:1μg TYR-gRNA5:2μg TYR-E4mut-ss153:4μg NCN蛋白。
猪细胞、TYR-gRNA1、TYR-gRNA5、TYR-E4mut-ss153和NCN蛋白的配比依次为:10万个猪细胞:0.8-1.2μg TYR-gRNA1:0.8-1.2μg TYR-gRNA5:1.8-2.2μg TYR-E4mut-ss153:3-5μg NCN蛋白。
猪细胞、TYR-gRNA1、TYR-gRNA5、TYR-E4mut-ss153和NCN蛋白的配比依次为:10万个猪细胞:1μg TYR-gRNA1:1μg TYR-gRNA5:2μg TYR-E4mut-ss153:4μg NCN蛋白。
以上任一所述TYR-gRNA1为sgRNA,其靶序列结合区如SEQ ID NO:18中第3-22位核苷酸所示。
以上任一所述TYR-gRNA5为sgRNA,其靶序列结合区如SEQ ID NO:19中第3-22位核苷酸所示。
以上任一所述TYR-E4mut-ss153为SEQ ID NO:20所示的单链DNA分子。
以上任一所述NCN蛋白为Cas9蛋白或具有Cas9蛋白的融合蛋白。
具体的,所述NCN蛋白如SEQ ID NO:3所示。
具体的,所述TYR-gRNA1如SEQ ID NO:18所示。
具体的,所述TYR-gRNA5如SEQ ID NO:19所示。
具体的,所述TYR-gRNA1如SEQ ID NO:10所示。
具体的,所述TYR-gRNA5如SEQ ID NO:14所示。
以上任一所述猪细胞为猪成纤维细胞。
以上任一所述猪细胞为猪原代成纤维细胞。
所述NCN蛋白的制备方法包括如下步骤:
(1)将质粒pKG-GE4导入大肠杆菌BL21(DE3),得到重组菌;
(2)采用液体培养基30℃培养所述重组菌,然后加入IPTG并进行25℃诱导培养,然后收集菌体;
(3)将收集的菌体进行菌体破碎,收集粗蛋白溶液;
(4)采用亲和层析从所述粗蛋白溶液中纯化具有His6标签的融合蛋白;
(5)采用具有His6标签的肠激酶酶切具有His6标签的融合蛋白,然后采用Ni-NTA树脂去除具有His6标签的蛋白,得到纯化的NCN蛋白;
质粒pKG-GE4中具有SEQ ID NO:1中第5209-9852位核苷酸所示的融合基因。
所述NCN蛋白的制备方法具体包括如下步骤:
(1)将质粒pKG-GE4导入大肠杆菌BL21(DE3),得到重组菌。
(2)将步骤(1)得到的重组菌接种至含氨苄青霉素的液体LB培养基,振荡培养;
(3)将步骤(2)得到的菌液接种至液体LB培养基,30℃、230rpm振荡培养至OD600nm值=1.0,然后加入IPTG并使其在体系中的浓度为0.5mM,然后25℃、230rpm振荡培养12小时,然后离心收集菌体;
(4)取步骤(3)得到的菌体,用PBS缓冲液洗涤;
(5)取步骤(4)得到的菌体,加入粗提缓冲液并悬浮菌体,然后进行菌体破碎,然后离心收集上清液,采用0.22μm孔径滤膜过滤,收集滤液;
(6)采用亲和层析从步骤(5)得到的滤液中纯化具有His6标签的融合蛋白(SEQ IDNO:2所示的融合蛋白);
(7)取步骤(6)收集的过柱后溶液,使用超滤管浓缩,然后用25mM Tris-HCl(pH8.0)稀释;
(8)将具有His6标签的重组牛肠激酶加入到步骤(7)得到的溶液中,酶切;
(9)将完成步骤(8)的溶液与Ni-NTA树脂混匀,孵育,然后离心收集上清液;
(10)取步骤(9)得到的上清液,使用超滤管浓缩,然后加入酶贮存液中,即为NCN蛋白溶液。
采用亲和层析从步骤(5)得到的滤液中纯化具有His6标签的融合蛋白的具体方法如下:
首先采用5个柱体积的平衡液平衡Ni-NTA琼脂糖柱(流速为1ml/min);然后上样50ml步骤(5)得到的滤液(流速为0.5-1ml/min);然后用5个柱体积的平衡液洗涤柱子(流速为1ml/min);然后用5个柱体积的缓冲液洗涤柱子(流速为1ml/min),以去除杂蛋白;然后用10个柱体积的洗脱液以0.5-1ml/min的流速洗脱,收集过柱后溶液(90-100ml)。
以上任一所述PRONCN蛋白自上游至下游依次包括如下元件:信号肽、分子伴侣蛋白、蛋白标签、蛋白酶酶切位点、核定位信号、Cas9蛋白、核定位信号。
所述信号肽的功能为促进蛋白分泌表达。所述信号肽可选自大肠杆菌碱性磷酸酶(phoA)信号肽、金黄色葡萄球菌蛋白A信号肽、大肠杆菌外膜蛋白(ompa)信号肽或任何其他原核基因的信号肽,优选为碱性磷酸酶信号肽(phoA signal peptide)。碱性磷酸酶信号肽用来引导目的蛋白分泌表达至细菌周质腔中,从而与细菌胞内蛋白分离,且分泌到细菌周质腔中的目的蛋白为可溶性表达,可被细菌周质腔中的信号肽酶裂解。
所述分子伴侣蛋白的功能为增加蛋白的可溶性。所述分子伴侣可为任何帮助形成二硫键的蛋白,优选为硫氧还原蛋白(TrxA蛋白)。硫氧还原蛋白,其能作为分子伴侣帮助所共表达的目的蛋白(例如Cas9蛋白)形成二硫键,提高蛋白的稳定性、折叠的正确性,增加目的蛋白的溶解性及活性。
所述蛋白标签的功能为用于蛋白纯化。所述标签可为His标签(His-Tag,His6蛋白标签)、GST标签、Flag标签、HA标签、c-Myc标签或其他任何蛋白标签,进一步优选为His标签。His标签能与Ni柱结合,可以通过一步法Ni柱亲和层析纯化目的蛋白,可极大地简化目的蛋白的纯化流程。
所述蛋白酶酶切位点的功能为纯化后用于切除非功能区段,以释放天然形式Cas9蛋白。所述蛋白酶可选自肠激酶(Enterokinase)、因子Xa(Factor Xa)、凝血酶(Thrombin)、TEV蛋白酶(TEV protease)、HRV 3C蛋白酶(HRV 3C protease)、WELQut蛋白酶或任何其他内切蛋白酶,进一步优选为肠激酶。EK为肠激酶酶切位点,便于使用肠激酶切除所融合的TrxA-His区段,得到天然形式的Cas9蛋白。本申请使用带His标签的商品肠激酶酶切融合蛋白后,可通过一次亲和层析除去TrxA-His区段及带His标签的肠激酶,得到天然形式的Cas9蛋白,避免了多次纯化透析对目的蛋白的伤害和损耗。
所述核定位信号可为任何核定位信号,优选为SV40核定位信号和/或nucleoplasmin核定位信号。NLS为核定位信号,在Cas9的N端及C端分别设计了一个NLS位点,使Cas9能更有效地进入细胞核进行基因编辑。
所述Cas9蛋白可为saCas9或spCas9,优选为spCas9蛋白。
PRONCN蛋白具体如SEQ ID NO:2所示。
以上任一所述特异质粒自上游至下游依次包括如下元件:启动子、操纵子、核糖体结合位点、PRONCN蛋白的编码基因、终止子。
所述启动子具体可为T7启动子。T7启动子为原核表达强启动子,能高效驱动外源基因的表达。
所述操纵子具体可为Lac操纵子。Lac操纵子为乳糖诱导表达的调控元件,可在细菌生长至一定数量后,再用IPTG在低温下诱导目的蛋白的表达,可避免目的蛋白过早表达对宿主菌生长的影响,低温下诱导表达也显著提高所表达的目的蛋白的可溶性。
所述核糖体结合位点是蛋白翻译时的核糖体结合位点,对蛋白质的翻译是必要的。
所述终止子具体可为T7终止子。T7终止子可在目的基因的末端有效终止基因转录,避免目的基因之外的其他下游序列得到转录和翻译。
对于spCas9蛋白的密码子,本申请对其密码子进行了优化,使之完全适应本申请所选用的大肠杆菌高效表达菌株E.coli BL21(DE3)的密码子偏好,从而提高Cas9蛋白的表达水平。
T7启动子如SEQ ID NO:1中第5121-5139位核苷酸所示。
Lac操纵子如SEQ ID NO:1中第5140-5164位核苷酸所示。
核糖体结合位点如SEQ ID NO:1中第5178-5201位核苷酸所示。
碱性磷酸酶信号肽的编码序列如SEQ ID NO:1中第5209-5271位核苷酸所示。
TrxA蛋白的编码序列如SEQ ID NO:1中第5272-5598位核苷酸所示。
His-Tag的编码序列如SEQ ID NO:1中第5620-5637位核苷酸所示。
肠激酶酶切位点的编码序列如SEQ ID NO:1中第5638-5652位核苷酸所示。
核定位信号的编码序列如SEQ ID NO:1中第5656-5670位核苷酸所示。
spCas9蛋白的编码序列如SEQ ID NO:1中第5701-9801位核苷酸所示。
核定位信号的编码序列如SEQ ID NO:1中第9802-9849位核苷酸所示。
T7终止子如SEQ ID NO:1中第9902-9949位核苷酸。
具体的,所述特异质粒为质粒pKG-GE4。
质粒pKG-GE4中具有SEQ ID NO:1中第5121-9949位核苷酸所示的DNA分子。
具体的,以上任一所述质粒pKG-GE4如SEQ ID NO:1所示。
本发明还保护以上任一所述方法制备得到的重组细胞。
本发明还保护所述重组细胞在制备白化病模型猪中的应用。
将所述重组细胞作为核移植供体细胞进行体细胞克隆,可以得到克隆猪,即为白化病模型猪。
本发明还保护利用所述重组细胞制备的模型猪的猪组织,即白化病组织模型。
本发明还保护利用所述重组细胞制备的模型猪的猪器官,即白化病器官模型。
本发明还保护利用所述重组细胞制备的模型猪的猪细胞,即白化病细胞模型。
本发明还保护所述重组细胞、所述白化病组织模型、所述白化病器官模型、所述白化病细胞模型或者所述白化病模型猪的应用,为如下(d1)或(d2)或(d3)或(d4):
(d1)筛选治疗白化病的药物;
(d2)进行白化病药物的药效评价;
(d3)进行白化病的基因治疗和/或细胞治疗的疗效评价;
(d4)研究白化病的发病机制。
以上任一所述猪具体可为从江香猪。
以上任一所述白化病可为OCA-1型白化病。
以上任一所述白化病可为OCA-1B型白化病。
OCA-1B型白化病是由TYR基因的如下突变引起的:TYR基因的H420R突变。
猪TYR基因信息:编码酪氨酸酶;位于9号染色体;GeneID为407745,Sus scrofa。猪TYR基因编码的氨基酸序列如SEQ ID NO:8所示。猪TYR基因具有SEQ ID NO:9所示的DNA区段。
与现有技术相比,本发明至少具有如下有益效果:
(1)本发明研究对象(猪)比其他动物(大小鼠、灵长类)具有更好的应用性。
大小鼠等啮齿类动物不论从体型、器官大小、生理、病理等方面都与人相差巨大,无法真实地模拟人类正常的生理、病理状态。研究表明,95%以上在大小鼠中验证有效的药物在人类临床试验中是无效的。就大动物而言,灵长类是与人亲缘关系最近的动物,但其体型小、性成熟晚(6-7岁开始交配),且为单胎动物,群体扩繁速度极慢,饲养成本很高。另外,灵长类动物克隆效率低、难度大、成本高。
而猪作为模型动物就没有上述缺点,猪是除灵长类外与人亲缘关系最近的动物,其体型、体重、器官大小等与人相近,在解剖学、生理学、免疫学、营养代谢、疾病发病机制等方面与人类极为相似。同时,猪的性成熟早(4-6个月),繁殖力高,一胎多仔,在2-3年内即可形成一个较大群体。另外,猪的克隆技术非常成熟,克隆及饲养成本也较灵长类低得多。因此猪是非常适合作为人类疾病模型的动物。
(2)发明所构建的载体,使用了能够高效表达目的蛋白的强启动子T7-lac来进行目的蛋白的表达,用细菌周质蛋白碱性磷酸酶(phoA)的信号肽来引导目的蛋白分泌表达至细菌周质腔中,从而与细菌胞内蛋白分离,且分泌到细菌周质腔中的目的蛋白为可溶性表达。同时还采用硫氧还原蛋白TrxA与Cas9蛋白融合表达,TrxA能帮助所共表达的目的蛋白形成二硫键,提高蛋白的稳定性、折叠的正确性,增加目的蛋白的溶解性及活性。为了方便目的蛋白的纯化,设计了His标签,可以通过一步法Ni柱亲和层析纯化目的蛋白,极大地简化了目的蛋白的纯化流程。同时在His标签后设计了一个肠激酶酶切位点,便于切除所融合的TrxA-His多肽片段,得到天然形式的Cas9蛋白。利用带His标签的肠激酶酶切融合蛋白后,可通过一次亲和层析除去TrxA-His多肽片段及带His标签的肠激酶,得到天然形式的Cas9蛋白,避免了多次纯化透析对目的蛋白的伤害和损耗。同时,本发明也在Cas9的N端及C端分别设计了一个NLS位点,使Cas9能更有效地进入细胞核进行基因编辑。另外,本发明选择了E.coli BL21(DE3)菌株为目的蛋白表达菌株,该菌株可高效表达克隆于含有噬菌体T7启动子的表达载体(如pET-32a)的外源基因。同时,对于Cas9蛋白的密码子,本发明进行了密码子优化,使之完全适应表达菌株的密码子偏好,从而提高目的蛋白的表达水平。另外,本发明在细菌生长至一定数量后,再用IPTG在低温下诱导目的蛋白的表达,可避免目的蛋白过早表达对宿主菌生长的影响,低温下诱导表达也显著提高所表达的目的蛋白的可溶性。经过上述各项优化设计及实验实施,所得到的Cas9蛋白活性比商品Cas9蛋白有了极显著的提高。
(3)采用本发明构建并表达的Cas9高效蛋白联合体外转录的gRNA进行基因编辑,并对Cas9和gRNA的最佳用量配比进行了优化,配合合成的ssODN作为Donor DNA,最终获得靶标位点点突变的单细胞克隆比率高达21.3%,远高于常规的点突变效率(<5%)。
(4)利用本发明所得到的靶基因点突变单细胞克隆株进行体细胞核移植动物克隆可直接得到含靶位点突变的克隆猪,并且该突变可稳定遗传。
在小鼠模型制作中采用的受精卵显微注射基因编辑材料后再进行胚胎移植的方法,因其直接获得点突变后代的概率非常低(低于1%),需要进行后代的杂交选育,这不太适用于妊娠期较长的大动物(如猪)模型制作。因此,本发明采用技术难度大、挑战性高的原代细胞体外编辑以及ssODN同源重组并筛选阳性编辑单细胞克隆的方法,后期再通过体细胞核移植动物克隆技术直接获得相应疾病模型猪,可大大缩短模型猪制作周期并节省人力、物力、财力。
本发明采用CRISPR/Cas9技术联合ssODN同源重组技术进行了TYR基因的定点突变,模拟OCA-1B型白化病的自然发病遗传特征,并获得了TYR基因点突变的单细胞克隆,为后期通过体细胞核移植动物克隆技术培育OCA-1B型白化病疾病模型猪奠定了基础。该模型猪将为研究OCA-1B型白化病的发病机制及药物研发提供有力的实验工具。
本发明为通过基因编辑手段获得TYR基因点突变的OCA-1B型白化病模型猪奠定了坚实的基础,将有助于研究并揭示TYR基因点突变导致OCA-1B型白化病的发病机制,也可用于进行药物筛选、药效检测、基因治疗及细胞治疗等研究,能够为进一步的临床应用提供有效的实验数据,进而为成功治疗人类OCA-1B型白化病提供有力的实验手段。本发明对于研发OCA-1B型白化病药物的研发及揭示该病的发病机制具有重大应用价值。
附图说明
图1为质粒pET-32a的结构示意图。
图2为质粒pKG-GE4的结构示意图。
图3为实施例3中gRNA与NCN蛋白用量配比优化的电泳图。
图4为实施例3中NCN蛋白与商品Cas9蛋白的基因编辑效率比较的电泳图。
图5为实施例4中用命名为1的猪的耳组织提取基因组作为模板采用不同引物对进行PCR扩增的电泳图。
图6为实施例4中分别以18只猪的基因组DNA为模板采用TYR-E4-JDF254和TYR-E4-JDR725组成的引物对进行PCR扩增的电泳图。
图7为实施例4中不同靶点的编辑效率比较的电泳图。
图8为实施例5中的电泳图。
图9为编号为4的单细胞克隆的正向和反向测序同时与靶标位点野生型序列的比对结果。
图10为编号为3的单细胞克隆的正向和反向测序同时与靶标位点野生型序列的比对结果。
图11为编号为9的单细胞克隆的正向和反向测序同时与靶标位点野生型序列的比对结果。
图12为编号为5的单细胞克隆的正向和反向测序同时与靶标位点野生型序列的比对结果。
图13为编号为14的单细胞克隆的正向和反向测序同时与靶标位点野生型序列的比对结果。
图14为编号为7的单细胞克隆的正向和反向测序同时与靶标位点野生型序列的比对结果。
具体实施方式
下面结合具体实施方式对本发明进行进一步的详细描述,给出的实施例仅为了阐明本发明,而不是为了限制本发明的范围。以下提供的实施例可作为本技术领域普通技术人员进行进一步改进的指南,并不以任何方式构成对本发明的限制。
下述实施例中的实验方法,如无特殊说明,均为常规方法,按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。实施例中构建的重组质粒,均已进行测序验证。商品Cas9-A蛋白为市售的效果好的Cas9蛋白。商品Cas9-B蛋白为市售的效果好的Cas9蛋白。完全培养液(%为体积比):15%胎牛血清(Gibco)+83%DMEM培养基(Gibco)+1%Penicillin-Streptomycin(Gibco)+1%HEPES(Solarbio)。细胞培养条件:37℃,5%CO2、5%O2的恒温培养箱。
实施例中采用的猪原代成纤维细胞均是用初生从江香猪耳组织制备得到的。制备猪原代成纤维细胞的方法:①取猪耳组织0.5g,去除毛发及骨组织,然后用75%酒精浸泡30-40s,然后用含5%(体积比)Penicillin-Streptomycin(Gibco)的PBS缓冲液洗涤5次,然后用PBS缓冲液洗涤一次;②用剪刀将组织剪碎,采用5mL 0.1%胶原酶溶液(Sigma),37℃消化1h,然后500g离心5min,弃上清;③将沉淀用1mL完全培养液重悬,然后铺入含10mL完全培养液并已用0.2%明胶(VWR)封盘的直径为10cm的细胞培养皿中,培养至细胞长满皿底60%左右;④完成步骤③后,采用胰蛋白酶消化并收集细胞,然后重悬于完全培养液。用于进行后续电转实验。
实施例1、原核Cas9高效表达载体的构建
质粒pET-32a的结构示意图见图1。
质粒pKG-GE4是以质粒pET-32a为出发质粒进行改造得到的。质粒pET32a-T7lac-phoA:SP-TrxA-His-EK-NLS-spCas9-NLS-T7ter(简称质粒pKG-GE4),如SEQ ID NO:1所示,为环形质粒,结构示意图见图2。
SEQ ID NO:1中,第5121-5139位核苷酸组成T7启动子,第5140-5164位核苷酸编码Lac操纵子(lac operator),第5178-5201位核苷酸组成核糖体结合位点(RBS),第5209-5271位核苷酸编码碱性磷酸酶信号肽(phoA signal peptide),第5272-5598位核苷酸编码TrxA蛋白,第5620-5637位核苷酸编码His-Tag,第5638-5652位核苷酸编码肠激酶酶切位点(EK酶切位点),第5656-5670位核苷酸编码核定位信号,第5701-9801位核苷酸编码spCas9蛋白,第9802-9849位核苷酸编码核定位信号,第9902-9949位核苷酸组成T7终止子。编码spCas9蛋白的核苷酸已进行针对大肠杆菌BL21(DE3)菌株的密码子优化。
质粒pKG-GE4的主要改造如下:①保留了TrxA蛋白的编码区域,TrxA蛋白可以帮助所表达的目的蛋白形成二硫键、增加目的蛋白的溶解性及活性;在TrxA蛋白的编码区域之前加入碱性磷酸酶信号肽的编码序列,碱性磷酸酶信号肽可以引导所表达的目的蛋白分泌至细菌的膜周质腔中并可被原核周质信号肽酶酶切;②在TrxA蛋白的编码序列之后增加His-Tag的编码序列,His-Tag可用于所表达的目的蛋白的富集;③在His-Tag的编码序列下游增加肠激酶酶切位点DDDDK(Asp-Asp-Asp-Asp-Lys)的编码序列,纯化出的蛋白将在肠激酶作用下去除His-Tag和上游所融合的TrxA蛋白;④插入密码子优化后的适宜大肠杆菌BL21(DE3)菌株表达的Cas9基因,同时在该基因的上游和下游均增加核定位信号编码序列,增加后期纯化出的Cas9蛋白的核定位能力。
质粒pKG-GE4中的融合基因如SEQ ID NO:1中第5209-9852位核苷酸所示,编码SEQID NO:2所示的融合蛋白(融合蛋白TrxA-His-EK-NLS-spCas9-NLS,简称为PRONCN蛋白)。由于碱性磷酸酶信号肽以及肠激酶酶切位点的存在,融合蛋白被肠激酶酶切后形成SEQ IDNO:3所示的蛋白质,将SEQ ID NO:3所示的蛋白质命名为NCN蛋白。
实施例2、NCN蛋白的制备和纯化
一、诱导表达
1、将质粒pKG-GE4导入大肠杆菌BL21(DE3),得到重组菌。
2、将步骤1得到的重组菌接种至含100μg/ml氨苄青霉素的液体LB培养基,37℃、200rpm振荡培养过夜。
3、将步骤2得到的菌液接种至液体LB培养基,30℃、230rpm振荡培养至OD600nm值=1.0,然后加入异丙基硫代半乳糖苷(IPTG)并使其在体系中的浓度为0.5mM,然后25℃、230rpm振荡培养12小时,然后4℃、10000g离心15分钟,收集菌体。
4、取步骤3得到的菌体,用PBS缓冲液洗涤。
二、融合蛋白TrxA-His-EK-NLS-spCas9-NLS的纯化
1、取步骤一得到的菌体,加入粗提缓冲液并悬浮菌体,然后采用均质机进行菌体破碎(1000par循环三次),然后4℃、15000g离心30min,收集上清液,上清液采用0.22μm孔径滤膜过滤,收集滤液。本步骤中,每g湿重的菌体配比10ml粗提缓冲液。
粗提缓冲液:含20mM Tris-HCl(pH8.0)、0.5M NaCl、5mM Imidazole、1mM PMSF,余量为ddH2O。
2、采用亲和层析纯化融合蛋白。
首先采用5个柱体积的平衡液平衡Ni-NTA琼脂糖柱(流速为1ml/min);然后上样50ml步骤1得到的滤液(流速为0.5-1ml/min);然后用5个柱体积的平衡液洗涤柱子(流速为1ml/min);然后用5个柱体积的缓冲液洗涤柱子(流速为1ml/min),以去除杂蛋白;然后用10个柱体积的洗脱液以0.5-1ml/min的流速洗脱,收集过柱后溶液(90-100ml)。
Ni-NTA琼脂糖柱:金斯瑞,L00250/L00250-C,填料为10ml。
平衡液:含20mM Tris-HCl(pH 8.0)、0.5M NaCl、5mM Imidazole,余量为ddH2O。
缓冲液:含20mM Tris-HCl(pH 8.0)、0.5M NaCl、50mM Imidazole,余量为ddH2O。
洗脱液:含20mM Tris-HCl(pH 8.0)、0.5M NaCl、500mM Imidazole,余量为ddH2O。
三、融合蛋白TrxA-His-EK-NLS-spCas9-NLS的酶切与NCN蛋白的纯化
1、取15ml步骤二收集的过柱后溶液,使用Amicon超滤管(Sigma,UFC9100,容量为15ml)将其浓缩至200μl,然后用25mM Tris-HCl(pH8.0)稀释至1ml。采用6个超滤管,共得到6ml。
2、将商品来源的具有His6标签的重组牛肠激酶(生工生物,C620031,重组牛肠激酶轻链,带His6标签,Recombinant Bovine Enterokinase Light Chain,His)加入到步骤1得到的溶液(约6ml)中,25℃酶切16小时。每50μg蛋白量配比加入2个单位的肠激酶。
3、取完成步骤2的溶液(约6ml),与480μl Ni-NTA树脂(金斯瑞,L00250/L00250-C)混匀,在室温下旋转混匀15min,然后7000g离心3min,收集上清液(4-5.5ml)。
4、取步骤3得到的上清液,使用Amicon超滤管(Sigma,UFC9100,容量为15ml)将其浓缩至200μl,然后加入酶贮存液中,调整蛋白浓度为5mg/ml,即为NCN蛋白溶液。
经测序,NCN蛋白溶液中的蛋白质,N端15个氨基酸残基如SEQ ID NO:3第1至15位所示,即NCN蛋白。
用于后续实施例的NCN蛋白均由NCN蛋白溶液提供。
酶贮存液(pH7.4):含10mM Tris,300mM NaCl,0.1mM EDTA,1mM DTT,50%(体积比)甘油,余量为ddH2O。
实施例3、NCN蛋白的性能
选择靶向TTN基因的2个gRNA靶点如下:
TTN-gRNA1:AGAGCACAGTCAGCCTGGCG;
TTN-gRNA2:CTTCCAGAATTGGATCTCCG。
用于鉴定包含TTN基因中gRNA的靶点片段的引物如下:
TTN-F55:TACGGAATTGGGGAGCCAGCGGA;
TTN-R560:CAAAGTTAACTCTCTGTGTCT。
一、制备gRNA
1、制备TTN-T7-gRNA1转录模板和TTN-T7-gRNA2转录模板
TTN-T7-gRNA1转录模板为双链DNA分子,如SEQ ID NO:4所示。
TTN-T7-gRNA2转录模板为双链DNA分子,如SEQ ID NO:5所示。
2、体外转录得到gRNA
取TTN-T7-gRNA1转录模板,采用Transcript Aid T7 High Yield TranscriptionKit(Fermentas,K0441)进行体外转录,然后用MEGA clearTM Transcription Clean-Up Kit(Thermo,AM1908)进行回收纯化,得到TTN-gRNA1。TTN-gRNA1为单链RNA,如SEQ ID NO:6所示。
取TTN-T7-gRNA2转录模板,采用Transcript Aid T7 High Yield TranscriptionKit(Fermentas,K0441)进行体外转录,然后用MEGA clearTM Transcription Clean-Up Kit(Thermo,AM1908)进行回收纯化,得到TTN-gRNA2。TTN-gRNA2为单链RNA,如SEQ ID NO:7所示。
二、gRNA与NCN蛋白用量配比优化
1、共转染猪原代成纤维细胞
第一组:将TTN-gRNA1、TTN-gRNA2和NCN蛋白共转染猪原代成纤维细胞。配比:约10万个猪原代成纤维细胞:0.5μg TTN-gRNA1:0.5μg TTN-gRNA2:4μg NCN蛋白。
第二组:将TTN-gRNA1、TTN-gRNA2和NCN蛋白共转染猪原代成纤维细胞。配比:约10万个猪原代成纤维细胞:0.75μg TTN-gRNA1:0.75μg TTN-gRNA2:4μg NCN蛋白。
第三组:将TTN-gRNA1、TTN-gRNA2和NCN蛋白共转染猪原代成纤维细胞。配比:约10万个猪原代成纤维细胞:1μg TTN-gRNA1:1μg TTN-gRNA2:4μg NCN蛋白。
第四组:将TTN-gRNA1、TTN-gRNA2和NCN蛋白共转染猪原代成纤维细胞。配比:约10万个猪原代成纤维细胞:1.25μg TTN-gRNA1:1.25μg TTN-gRNA2:4μg NCN蛋白。
第五组:将TTN-gRNA1和TTN-gRNA2共转染猪原代成纤维细胞。配比:约10万个猪原代成纤维细胞:1μg TTN-gRNA1:1μg TTN-gRNA2。
共转染采用电击转染的方式,采用哺乳动物核转染试剂盒(Neon kit,Thermofisher)与Neon TM transfection system电转仪(参数设置为:1450V、10ms、3pulse)。
2、完成步骤1后,采用完全培养液培养12-18小时,然后更换新的完全培养液进行培养。电转后培养总时间为48小时。
3、完成步骤2后,采用胰蛋白酶消化并收集细胞,提取基因组DNA,采用TTN-F55和TTN-R560组成的引物对进行PCR扩增,然后进行1%琼脂糖凝胶电泳。
电泳图见图3。505bp条带为野生型条带(WT),254bp左右(野生型条带505bp理论缺失251bp)为缺失突变条带(MT)。
基因缺失突变效率=(MT灰度/MT条带bp数)/(WT灰度/WT条带bp数+MT灰度/MT条带bp数)×100%。第一组基因缺失突变效率为19.9%,第二组基因缺失突变效率为39.9%,第三组基因缺失突变效率为79.9%,第四组基因缺失突变效率为44.3%。第五组未发生突变。
结果表明,当两个gRNA与NCN蛋白的质量配比为1:1:4,实际用量为1μg:1μg:4μg时基因编辑效率最高。因此,确定两个gRNA与NCN蛋白的最适用量为1μg:1μg:4μg。
三、NCN蛋白与商品Cas9蛋白的基因编辑效率比较
1、共转染猪原代成纤维细胞
Cas9-A组:将TTN-gRNA1、TTN-gRNA2和商品Cas9-A蛋白共转染猪原代成纤维细胞。配比:约10万个猪原代成纤维细胞:1μg TTN-gRNA1:1μg TTN-gRNA2:4μg Cas9-A蛋白。
pKG-GE4组:将TTN-gRNA1、TTN-gRNA2和NCN蛋白共转染猪原代成纤维细胞。配比:约10万个猪原代成纤维细胞:1μg TTN-gRNA1:1μg TTN-gRNA2:4μg NCN蛋白。
Cas9-B组:将TTN-gRNA1、TTN-gRNA2和商品Cas9-B蛋白共转染猪原代成纤维细胞。配比:约10万个猪原代成纤维细胞:1μg TTN-gRNA1:1μg TTN-gRNA2:4μg Cas9-B蛋白。
Control组:将TTN-gRNA1、TTN-gRNA2共转染猪原代成纤维细胞。配比:约10万个猪原代成纤维细胞:1μg TTN-gRNA1:1μg TTN-gRNA2。
共转染采用电击转染的方式,采用哺乳动物核转染试剂盒(Neon kit,Thermofisher)与Neon TM transfection system电转仪(参数设置为:1450V、10ms、3pulse)。
2、完成步骤1后,采用完全培养液培养12-18小时,然后更换新的完全培养液进行培养。电转后培养总时间为48小时。
3、完成步骤2后,采用胰蛋白酶消化并收集细胞,提取基因组DNA,采用TTN-F55和TTN-R560组成的引物对进行PCR扩增,然后进行1%琼脂糖凝胶电泳。
电泳图见图4。采用商品Cas9-A蛋白的基因缺失突变效率为28.5%,采用NCN蛋白的基因缺失突变效率为85.6%,采用商品Cas9-B蛋白的基因缺失突变效率为16.6%。
结果表明,与采用商品的Cas9蛋白相比,采用本发明制备的NCN蛋白使得基因编辑效率显著提高。
实施例4、TYR基因高效gRNA靶点的筛选
猪TYR基因信息:编码酪氨酸酶;位于9号染色体;GeneID为407745,Sus scrofa。猪TYR基因编码的氨基酸序列如SEQ ID NO:8所示。基因组DNA中,猪TYR基因具有5个外显子。人类OCA-1B相关的TYR基因点突变为H420R突变。H420R突变对应于猪TYR基因第4外显子。猪基因组DNA中,TYR基因部分序列(含第4外显子及其上下游各400bp)如SEQ ID NO:9所示。
质粒pKG-GE3,为环形质粒,如专利申请202010084343.6中的SEQ ID NO:2所示。专利申请202010084343.6中的SEQ ID NO:2中,第395-680位核苷酸组成CMV增强子,第682-890位核苷酸组成EF1a启动子,第986-1006位核苷酸编码核定位信号(NLS),第1016-1036位核苷酸编码核定位信号(NLS),第1037-5161位核苷酸编码Cas9蛋白,第5162-5209位核苷酸编码核定位信号(NLS),第5219-5266位核苷酸编码核定位信号(NLS),第5276-5332位核苷酸编码自剪切多肽P2A(自剪切多肽P2A的氨基酸序列为“ATNFSLLKQAGDVEENPGP”,发生自剪切的断裂位置为C端开始第一个氨基酸残基和第二个氨基酸残基之间),第5333-6046位核苷酸编码EGFP蛋白,第6056-6109位核苷酸编码自裂解多肽T2A(自裂解多肽T2A的氨基酸序列为“EGRGSLLTCGDVEENPGP”,发生自裂解的断裂位置为C端开始第一个氨基酸残基和第二个氨基酸残基之间),第6110-6703位核苷酸编码Puromycin蛋白(简称Puro蛋白),第6722-7310位核苷酸组成WPRE序列元件,第7382-7615位核苷酸组成3’LTR序列元件,第7647-7871位核苷酸组成bGH poly(A)signal序列元件。专利申请202010084343.6中的SEQ ID NO:2中,第911-6706位核苷酸形成融合基因,表达融合蛋白。由于自剪切多肽P2A和自裂解多肽T2A的存在,融合蛋白自发形成如下三个蛋白:具有Cas9蛋白的蛋白、具有EGFP蛋白的蛋白和具有Puro蛋白的蛋白。
pKG-U6gRNA载体即质粒pKG-U6gRNA,为环形质粒,如专利申请202010084343.6中的SEQ ID NO:3所示。专利申请202010084343.6中的SEQ ID NO:3中,第2280-2539位核苷酸组成hU6启动子,第2558-2637位核苷酸用于转录形成gRNA骨架。使用时,将20bp左右的DNA分子(用于转录形成gRNA的靶序列结合区)插入质粒pKG-U6gRNA,形成重组质粒,在细胞中重组质粒转录得到gRNA。
一、TYR基因外显子4预设点突变位点及邻近基因组序列保守性分析
18只初生从江香猪,其中雌性10只(分别命名为1、2、3、4、5、6、7、8、9、10)、雄性8只(分别命名为A、B、C、D、E、F、G、H)。
TYR-E4-JDF253:ACACTTGTGCTGTGGCATTC;
TYR-E4-JDR722:AGGTAGCTGTAGTCATAGCCT;
TYR-E4-JDF254:CACTTGTGCTGTGGCATTCT;
TYR-E4-JDR725:TGTAGGTAGCTGTAGTCATAGCCT。
用命名为1的猪的耳组织提取基因组作为模板,采用不同引物对进行PCR扩增,然后进行1%琼脂糖凝胶电泳。电泳图见图5。图5中:组1:采用TYR-E4-JDF253和TYR-E4-JDR722组成的引物对;组2:采用TYR-E4-JDF253和TYR-E4-JDR725组成的引物对;组3:采用TYR-E4-JDF254和TYR-E4-JDR722组成的引物对;组4:采用TYR-E4-JDF254和TYR-E4-JDR725组成的引物对。结果表明,优选采用TYR-E4-JDF254和TYR-E4-JDR725组成的引物对进行目的片段扩增。
分别以18只猪的基因组DNA为模板,采用TYR-E4-JDF254和TYR-E4-JDR725组成的引物对进行PCR扩增,然后进行1%琼脂糖凝胶电泳。电泳图见图6。回收PCR扩增产物并进行测序,将测序结果与公共数据库中的TYR基因序列进行比对分析。选择18只猪中共有的保守区进行gRNA靶点的设计。
二、筛选靶点
通过筛选NGG(避开可能的突变位点)初步筛选到若干靶点,经过预实验进一步从中筛选到6个靶点。
6个靶点分别如下:
TYR-E4-gRNA1:TGCACCCATTGGACACAACC;
TYR-E4-gRNA2:CCGGAAGCCAATGCACCCAT;
TYR-E4-gRNA3:AGATTCCCGGTTGTGTCCAA;
TYR-E4-gRNA4:ATGCACCCATTGGACACAAC;
TYR-E4-gRNA5:CCGGATACACTTCAAGAAGA;
TYR-E4-gRNA6:GATACACTTCAAGAAGAGGG。
三、制备重组质粒
取质粒pKG-U6gRNA,用限制性内切酶BbsI进行酶切,回收载体骨架(约3kb的线性大片段)。
分别合成TYR-E4-gRNA1-S和TYR-E4-gRNA1-A,然后混合并进行退火,得到具有粘性末端的双链DNA分子。将具有粘性末端的双链DNA分子和载体骨架连接,得到质粒pKG-U6gRNA(TYR-E4-gRNA1)。质粒pKG-U6gRNA(TYR-E4-gRNA1)表达SEQ ID NO:10所示的sgRNATYR-E4-gRNA1。sgRNATYR-E4-gRNA1(SEQ ID NO:10):
UGCACCCAUUGGACACAACCguuuuagagcuagaaauagcaaguuaaaauaaggcuaguccguuaucaacuugaaaaaguggcaccgagucggugcuuuu。
分别合成TYR-E4-gRNA2-S和TYR-E4-gRNA2-A,然后混合并进行退火,得到具有粘性末端的双链DNA分子。将具有粘性末端的双链DNA分子和载体骨架连接,得到质粒pKG-U6gRNA(TYR-E4-gRNA2)。质粒pKG-U6gRNA(TYR-E4-gRNA2)表达SEQ ID NO:11所示的sgRNATYR-E4-gRNA2。sgRNATYR-E4-gRNA2(SEQ ID NO:11):
CCGGAAGCCAAUGCACCCAUguuuuagagcuagaaauagcaaguuaaaauaaggcuaguccguuaucaacuugaaaaaguggcaccgagucggugcuuuu。
分别合成TYR-E4-gRNA3-S和TYR-E4-gRNA3-A,然后混合并进行退火,得到具有粘性末端的双链DNA分子。将具有粘性末端的双链DNA分子和载体骨架连接,得到质粒pKG-U6gRNA(TYR-E4-gRNA3)。质粒pKG-U6gRNA(TYR-E4-gRNA3)表达SEQ ID NO:12所示的sgRNATYR-E4-gRNA3。sgRNATYR-E4-gRNA3(SEQ ID NO:12):
AGAUUCCCGGUUGUGUCCAAguuuuagagcuagaaauagcaaguuaaaauaaggcuaguccguuaucaacuugaaaaaguggcaccgagucggugcuuuu。
分别合成TYR-E4-gRNA4-S和TYR-E4-gRNA4-A,然后混合并进行退火,得到具有粘性末端的双链DNA分子。将具有粘性末端的双链DNA分子和载体骨架连接,得到质粒pKG-U6gRNA(TYR-E4-gRNA4)。质粒pKG-U6gRNA(TYR-E4-gRNA4)表达SEQ ID NO:13所示的sgRNATYR-E4-gRNA4。sgRNATYR-E4-gRNA4(SEQ ID NO:13):
AUGCACCCAUUGGACACAACguuuuagagcuagaaauagcaaguuaaaauaaggcuaguccguuaucaacuugaaaaaguggcaccgagucggugcuuuu。
分别合成TYR-E4-gRNA5-S和TYR-E4-gRNA5-A,然后混合并进行退火,得到具有粘性末端的双链DNA分子。将具有粘性末端的双链DNA分子和载体骨架连接,得到质粒pKG-U6gRNA(TYR-E4-gRNA5)。质粒pKG-U6gRNA(TYR-E4-gRNA5)表达SEQ ID NO:14所示的sgRNATYR-E4-gRNA5。sgRNATYR-E4-gRNA5(SEQ ID NO:14):
CCGGAUACACUUCAAGAAGAguuuuagagcuagaaauagcaaguuaaaauaaggcuaguccguuaucaacuugaaaaaguggcaccgagucggugcuuuu。
分别合成TYR-E4-gRNA6-S和TYR-E4-gRNA6-A,然后混合并进行退火,得到具有粘性末端的双链DNA分子。将具有粘性末端的双链DNA分子和载体骨架连接,得到质粒pKG-U6gRNA(TYR-E4-gRNA6)。质粒pKG-U6gRNA(TYR-E4-gRNA6)表达SEQ ID NO:15所示的sgRNATYR-E4-gRNA6。sgRNATYR-E4-gRNA6(SEQ ID NO:15):
GAUACACUUCAAGAAGAGGGguuuuagagcuagaaauagcaaguuaaaauaaggcuaguccguuaucaacuugaaaaaguggcaccgagucggugcuuuu。
TYR-E4-gRNA1-S:caccgTGCACCCATTGGACACAACC;
TYR-E4-gRNA1-A:aaacGGTTGTGTCCAATGGGTGCAc;
TYR-E4-gRNA2-S:caccgCCGGAAGCCAATGCACCCAT;
TYR-E4-gRNA2-A:aaacATGGGTGCATTGGCTTCCGGc;
TYR-E4-gRNA3-S:caccgAGATTCCCGGTTGTGTCCAA;
TYR-E4-gRNA3-A:aaacTTGGACACAACCGGGAATCTc;
TYR-E4-gRNA4-S:caccgATGCACCCATTGGACACAAC;
TYR-E4-gRNA4-A:aaacGTTGTGTCCAATGGGTGCATc;
TYR-E4-gRNA5-S:caccgCCGGATACACTTCAAGAAGA;
TYR-E4-gRNA5-A:aaacTCTTCTTGAAGTGTATCCGGc;
TYR-E4-gRNA6-S:caccGATACACTTCAAGAAGAGGG;
TYR-E4-gRNA6-A:aaacCCCTCTTCTTGAAGTGTATC。
TYR-E4-gRNA1-S、TYR-E4-gRNA1-A、TYR-E4-gRNA2-S、TYR-E4-gRNA2-A、TYR-E4-gRNA3-S、TYR-E4-gRNA3-A、TYR-E4-gRNA4-S、TYR-E4-gRNA4-A、TYR-E4-gRNA5-S、TYR-E4-gRNA5-A、TYR-E4-gRNA6-S、TYR-E4-gRNA6-A均为单链DNA分子。
四、不同靶点的编辑效率比较
1、共转染
第一组:将质粒pKG-U6gRNA(TYR-E4-gRNA1)、质粒pKG-GE3共转染猪原代成纤维细胞。配比:约20万个猪原代成纤维细胞:0.92μg质粒pKG-U6gRNA(TYR-E4-gRNA1):1.08μg质粒pKG-GE3。
第二组:将质粒pKG-U6gRNA(TYR-E4-gRNA2)、质粒pKG-GE3共转染猪原代成纤维细胞。配比:约20万个猪原代成纤维细胞:0.92μg质粒pKG-U6gRNA(TYR-E4-gRNA2):1.08μg质粒pKG-GE3。
第三组:将质粒pKG-U6gRNA(TYR-E4-gRNA3)、质粒pKG-GE3共转染猪原代成纤维细胞。配比:约20万个猪原代成纤维细胞:0.92μg质粒pKG-U6gRNA(TYR-E4-gRNA3):1.08μg质粒pKG-GE3。
第四组:将质粒pKG-U6gRNA(TYR-E4-gRNA4)、质粒pKG-GE3共转染猪原代成纤维细胞。配比:约20万个猪原代成纤维细胞:0.92μg质粒pKG-U6gRNA(TYR-E4-gRNA4):1.08μg质粒pKG-GE3。
第五组:将质粒pKG-U6gRNA(TYR-E4-gRNA5)、质粒pKG-GE3共转染猪原代成纤维细胞。配比:约20万个猪原代成纤维细胞:0.92μg质粒pKG-U6gRNA(TYR-E4-gRNA5):1.08μg质粒pKG-GE3。
第六组:将质粒pKG-U6gRNA(TYR-E4-gRNA6)、质粒pKG-GE3共转染猪原代成纤维细胞。配比:约20万个猪原代成纤维细胞:0.92μg质粒pKG-U6gRNA(TYR-E4-gRNA6):1.08μg质粒pKG-GE3。
第七组:猪原代成纤维细胞,同等电转参数不加质粒进行电转操作。
共转染采用电击转染的方式,采用哺乳动物核转染试剂盒(Neon kit,Thermofisher)与Neon TM transfection system电转仪(参数设置为:1450V、10ms、3pulse)。
2、完成步骤1后,采用完全培养液培养12-18小时,然后更换新的完全培养液进行培养。电转后培养总时间为48小时。
3、完成步骤2后,采用胰蛋白酶消化并收集细胞,裂解细胞,提取基因组DNA,采用TYR-E4-JDF254和TYR-E4-JDR725组成的引物对进行PCR扩增,然后进行1%琼脂糖凝胶电泳。检测细胞靶基因突变情况,电泳图见图7。
将目的产物切胶回收后送测序公司进行测序,然后将测序结果利用网页版Synthego ICE工具分析测序峰图得出不同靶点的基因编辑效率。第一组至第六组的基因编辑效率依次为55%、21%、12%、19%、44%、28%,第七组未发生基因编辑。结果表明,TYR-E4-gRNA1和TYR-E4-gRNA5编辑效率较高。
实施例5、利用体细胞克隆的方法制备TYR基因精确突变的单细胞克隆
选用实施例4中筛到的两个高效gRNA靶点(TYR-E4-gRNA1和TYR-E4-gRNA5)。
一、制备gRNA
1、制备TYR-T7-gRNA1转录模板和TYR-T7-gRNA5转录模板
TYR-T7-gRNA1转录模板为双链DNA分子,如SEQ ID NO:16所示。
TYR-T7-gRNA5转录模板为双链DNA分子,如SEQ ID NO:17所示。
2、体外转录得到gRNA
取TYR-T7-gRNA1转录模板,采用Transcript Aid T7 High Yield TranscriptionKit(Fermentas,K0441)进行体外转录,然后用MEGA clearTM Transcription Clean-Up Kit(Thermo,AM1908)进行回收纯化,得到TYR-gRNA1。TYR-gRNA1为单链RNA,如SEQ ID NO:18所示。
取TYR-T7-gRNA5转录模板,采用Transcript Aid T7 High Yield TranscriptionKit(Fermentas,K0441)进行体外转录,然后用MEGA clearTM Transcription Clean-Up Kit(Thermo,AM1908)进行回收纯化,得到TYR-gRNA5。TYR-gRNA5为单链RNA,如SEQ ID NO:19所示。
二、合成在TYR基因靶位点突变的单链Donor DNA
合成对应H420R突变的单链DNA作为Donor DNA,该单链DNA除靶位点突变外还含有TYR-E4-gRNA1和TYR-E4-gRNA5靶点PAM或邻近PAM的3’端序列同义突变。该单链Donor DNA命名为TYR-E4mut-ss153。
TYR-E4mut-ss153如SEQ ID NO:20所示。
三、转染猪原代成纤维细胞
1、将TYR-gRNA1、TYR-gRNA5、TYR-E4mut-ss153和NCN蛋白共转染猪原代成纤维细胞。配比:约10万个猪原代成纤维细胞:1μg TYR-gRNA1:1μg TYR-gRNA5:2μg TYR-E4mut-ss153:4μg NCN蛋白。共转染采用电击转染的方式,采用哺乳动物核转染试剂盒(Neon kit,Thermofisher)与Neon TM transfection system电转仪(参数设置为:1450V、10ms、3pulse)。
2、完成步骤1后,采用完全培养液培养16-18小时,然后更换新的完全培养液进行培养。电转后培养总时间为48小时。
3、完成步骤2后,采用胰蛋白酶消化并收集细胞,然后用完全培养液洗涤,然后用完全培养液重悬,然后分别挑取各个单克隆转移到96孔板中(每个孔1个细胞,每个孔中装有100μl完全培养液),培养2周(每2-3天更换新的完全培养液)。
4、完成步骤3后,采用胰蛋白酶消化并收集细胞(每孔得到的细胞,约2/3接种到装有完全培养液的6孔板中,剩余的1/3收集在1.5mL离心管中)。
5、取步骤4的6孔板,培养直至细胞长至80%汇合度,采用胰蛋白酶消化并收集细胞,使用细胞冻存液(90%完全培养基+10%DMSO,体积比)将细胞冻存。
6、取步骤4的离心管,取细胞,进行细胞裂解并提取基因组DNA,采用TYR-E4-JDF254和TYR-E4-JDR725组成的引物对进行PCR扩增,然后进行电泳。将猪原代成纤维细胞作为野生型对照(WT)。电泳图见图8。图8中的泳道编号与表1中的细胞编号一致。
7、完成步骤6后,回收PCR扩增产物并测序。
猪原代成纤维细胞的测序结果只有一种,其基因型为纯合野生型。如果某一单细胞克隆的测序结果有两种,一种与猪原代成纤维细胞的测序结果一致,另一种与猪原代成纤维细胞的测序结果相比发生了突变(突变包括一个或多个核苷酸的缺失、插入或替换),该单细胞克隆的基因型为杂合型;如果某一单细胞克隆的测序结果为两种,均与猪原代成纤维细胞的测序结果相比发生了突变(突变包括一个或多个核苷酸的缺失、插入或替换),该单细胞克隆的基因型为双等位基因不同突变型;如果某一单细胞克隆的测序结果为一种,且与猪原代成纤维细胞的测序结果相比发生了突变(突变包括一个或多个核苷酸的缺失、插入或替换),该单细胞克隆的基因型为双等位基因相同突变型;如果某一单细胞克隆的测序结果为一种,且与猪原代成纤维细胞的测序结果一致,该单细胞克隆的基因型为纯合野生型。
结果见表1。编号为4、6、20、25、27、43、46的单细胞克隆的基因型为纯合野生型。编号为1、3、8、11、14、16、18、22、23、24、31、33、35、37、38、47的单细胞克隆的基因型为杂合型。编号为2、9、13、17、26、28、30、32、39、40、41的单细胞克隆的基因型为双等位基因不同突变型。编号为5、7、10、12、15、19、21、29、34、36、42、44、45的单细胞克隆的基因型为双等位基因相同突变型。编号为14的单细胞克隆为靶标位点突变的杂合型(即两条同源染色体中的一条完成了单链Donor DNA的替换)。编号为2、17、26、28、32、39的单细胞克隆为靶位点突变的双等位基因不同突变型(即两条同源染色体中的一条完成了单链Donor DNA的替换)。编号为7、36、42的单细胞克隆为靶位点突变的双等位基因相同突变型(即两条同源染色体均完成了单链Donor DNA的替换)。得到TYR基因外显子4基因编辑单细胞克隆的比率为85%,得到靶位点突变的单细胞克隆(即编号为2、14、17、26、28、32、39、7、36、42的单细胞克隆)的比率为21.3%。
示例性的测序比对结果如图9至图14。图9是编号为4的单细胞克隆的正向测序和反向测序与靶标位点野生型序列的比对结果,为纯合野生型。图10是编号为3的单细胞克隆的正向测序和反向测序与靶标位点野生型序列的比对结果,为杂合型。图11是编号为9的单细胞克隆的正向测序和反向测序同时与靶标位点野生型序列的比对结果,为双等位基因不同突变型。图12是编号为5的单细胞克隆的正向测序和反向测序与靶标位点野生型序列的比对结果,为双等位基因相同突变型。图13是编号为14的单细胞克隆的正向测序和反向测序与靶标位点野生型序列的比对结果,为靶位点突变的双等位基因不同突变型。图14是编号为7的单细胞克隆的正向测序和反向测序与靶标位点野生型序列的比对结果,为靶位点突变的双等位基因相同突变型。
表1TYR基因外显子4点突变单细胞克隆的基因型测定结果
注:靶位点突变指的是完成了单链Donor DNA的替换;单链Donor DNA的替换即用SEQ ID NO:20所示的DNA分子取代了染色体DNA中SEQ ID NO:21所示的DNA分子。
编号为7、36、42的单细胞克隆为靶位点突变的双等位基因相同突变型(即两条同源染色体均完成了单链Donor DNA的替换)。
靶位点突变的双等位基因相同突变型细胞可用于进行后续的克隆猪生产。将细胞作为核移植供体细胞进行体细胞克隆,可以得到克隆猪,即为白化病模型猪。
以上对本发明进行了详述。对于本领域技术人员来说,在不脱离本发明的宗旨和范围,以及无需进行不必要的实验情况下,可在等同参数、浓度和条件下,在较宽范围内实施本发明。虽然本发明给出了特殊的实施例,应该理解为,可以对本发明作进一步的改进。总之,按本发明的原理,本申请欲包括任何变更、用途或对本发明的改进,包括脱离了本申请中已公开范围,而用本领域已知的常规技术进行的改变。按以下附带的权利要求的范围,可以进行一些基本特征的应用。
序列表
<110> 南京启真基因工程有限公司
<120> 一种基因编辑系统及其在构建OCA-1B型白化病模型猪核移植供体细胞中的应用
<130> GNCYX211950
<160> 21
<170> SIPOSequenceListing 1.0
<210> 1
<211> 9974
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 1
tggcgaatgg gacgcgccct gtagcggcgc attaagcgcg gcgggtgtgg tggttacgcg 60
cagcgtgacc gctacacttg ccagcgccct agcgcccgct cctttcgctt tcttcccttc 120
ctttctcgcc acgttcgccg gctttccccg tcaagctcta aatcgggggc tccctttagg 180
gttccgattt agtgctttac ggcacctcga ccccaaaaaa cttgattagg gtgatggttc 240
acgtagtggg ccatcgccct gatagacggt ttttcgccct ttgacgttgg agtccacgtt 300
ctttaatagt ggactcttgt tccaaactgg aacaacactc aaccctatct cggtctattc 360
ttttgattta taagggattt tgccgatttc ggcctattgg ttaaaaaatg agctgattta 420
acaaaaattt aacgcgaatt ttaacaaaat attaacgttt acaatttcag gtggcacttt 480
tcggggaaat gtgcgcggaa cccctatttg tttatttttc taaatacatt caaatatgta 540
tccgctcatg agacaataac cctgataaat gcttcaataa tattgaaaaa ggaagagtat 600
gagtattcaa catttccgtg tcgcccttat tccctttttt gcggcatttt gccttcctgt 660
ttttgctcac ccagaaacgc tggtgaaagt aaaagatgct gaagatcagt tgggtgcacg 720
agtgggttac atcgaactgg atctcaacag cggtaagatc cttgagagtt ttcgccccga 780
agaacgtttt ccaatgatga gcacttttaa agttctgcta tgtggcgcgg tattatcccg 840
tattgacgcc gggcaagagc aactcggtcg ccgcatacac tattctcaga atgacttggt 900
tgagtactca ccagtcacag aaaagcatct tacggatggc atgacagtaa gagaattatg 960
cagtgctgcc ataaccatga gtgataacac tgcggccaac ttacttctga caacgatcgg 1020
aggaccgaag gagctaaccg cttttttgca caacatgggg gatcatgtaa ctcgccttga 1080
tcgttgggaa ccggagctga atgaagccat accaaacgac gagcgtgaca ccacgatgcc 1140
tgcagcaatg gcaacaacgt tgcgcaaact attaactggc gaactactta ctctagcttc 1200
ccggcaacaa ttaatagact ggatggaggc ggataaagtt gcaggaccac ttctgcgctc 1260
ggcccttccg gctggctggt ttattgctga taaatctgga gccggtgagc gtgggtctcg 1320
cggtatcatt gcagcactgg ggccagatgg taagccctcc cgtatcgtag ttatctacac 1380
gacggggagt caggcaacta tggatgaacg aaatagacag atcgctgaga taggtgcctc 1440
actgattaag cattggtaac tgtcagacca agtttactca tatatacttt agattgattt 1500
aaaacttcat ttttaattta aaaggatcta ggtgaagatc ctttttgata atctcatgac 1560
caaaatccct taacgtgagt tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa 1620
aggatcttct tgagatcctt tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc 1680
accgctacca gcggtggttt gtttgccgga tcaagagcta ccaactcttt ttccgaaggt 1740
aactggcttc agcagagcgc agataccaaa tactgtcctt ctagtgtagc cgtagttagg 1800
ccaccacttc aagaactctg tagcaccgcc tacatacctc gctctgctaa tcctgttacc 1860
agtggctgct gccagtggcg ataagtcgtg tcttaccggg ttggactcaa gacgatagtt 1920
accggataag gcgcagcggt cgggctgaac ggggggttcg tgcacacagc ccagcttgga 1980
gcgaacgacc tacaccgaac tgagatacct acagcgtgag ctatgagaaa gcgccacgct 2040
tcccgaaggg agaaaggcgg acaggtatcc ggtaagcggc agggtcggaa caggagagcg 2100
cacgagggag cttccagggg gaaacgcctg gtatctttat agtcctgtcg ggtttcgcca 2160
cctctgactt gagcgtcgat ttttgtgatg ctcgtcaggg gggcggagcc tatggaaaaa 2220
cgccagcaac gcggcctttt tacggttcct ggccttttgc tggccttttg ctcacatgtt 2280
ctttcctgcg ttatcccctg attctgtgga taaccgtatt accgcctttg agtgagctga 2340
taccgctcgc cgcagccgaa cgaccgagcg cagcgagtca gtgagcgagg aagcggaaga 2400
gcgcctgatg cggtattttc tccttacgca tctgtgcggt atttcacacc gcatatatgg 2460
tgcactctca gtacaatctg ctctgatgcc gcatagttaa gccagtatac actccgctat 2520
cgctacgtga ctgggtcatg gctgcgcccc gacacccgcc aacacccgct gacgcgccct 2580
gacgggcttg tctgctcccg gcatccgctt acagacaagc tgtgaccgtc tccgggagct 2640
gcatgtgtca gaggttttca ccgtcatcac cgaaacgcgc gaggcagctg cggtaaagct 2700
catcagcgtg gtcgtgaagc gattcacaga tgtctgcctg ttcatccgcg tccagctcgt 2760
tgagtttctc cagaagcgtt aatgtctggc ttctgataaa gcgggccatg ttaagggcgg 2820
ttttttcctg tttggtcact gatgcctccg tgtaaggggg atttctgttc atgggggtaa 2880
tgataccgat gaaacgagag aggatgctca cgatacgggt tactgatgat gaacatgccc 2940
ggttactgga acgttgtgag ggtaaacaac tggcggtatg gatgcggcgg gaccagagaa 3000
aaatcactca gggtcaatgc cagcgcttcg ttaatacaga tgtaggtgtt ccacagggta 3060
gccagcagca tcctgcgatg cagatccgga acataatggt gcagggcgct gacttccgcg 3120
tttccagact ttacgaaaca cggaaaccga agaccattca tgttgttgct caggtcgcag 3180
acgttttgca gcagcagtcg cttcacgttc gctcgcgtat cggtgattca ttctgctaac 3240
cagtaaggca accccgccag cctagccggg tcctcaacga caggagcacg atcatgcgca 3300
cccgtggggc cgccatgccg gcgataatgg cctgcttctc gccgaaacgt ttggtggcgg 3360
gaccagtgac gaaggcttga gcgagggcgt gcaagattcc gaataccgca agcgacaggc 3420
cgatcatcgt cgcgctccag cgaaagcggt cctcgccgaa aatgacccag agcgctgccg 3480
gcacctgtcc tacgagttgc atgataaaga agacagtcat aagtgcggcg acgatagtca 3540
tgccccgcgc ccaccggaag gagctgactg ggttgaaggc tctcaagggc atcggtcgag 3600
atcccggtgc ctaatgagtg agctaactta cattaattgc gttgcgctca ctgcccgctt 3660
tccagtcggg aaacctgtcg tgccagctgc attaatgaat cggccaacgc gcggggagag 3720
gcggtttgcg tattgggcgc cagggtggtt tttcttttca ccagtgagac gggcaacagc 3780
tgattgccct tcaccgcctg gccctgagag agttgcagca agcggtccac gctggtttgc 3840
cccagcaggc gaaaatcctg tttgatggtg gttaacggcg ggatataaca tgagctgtct 3900
tcggtatcgt cgtatcccac taccgagatg tccgcaccaa cgcgcagccc ggactcggta 3960
atggcgcgca ttgcgcccag cgccatctga tcgttggcaa ccagcatcgc agtgggaacg 4020
atgccctcat tcagcatttg catggtttgt tgaaaaccgg acatggcact ccagtcgcct 4080
tcccgttccg ctatcggctg aatttgattg cgagtgagat atttatgcca gccagccaga 4140
cgcagacgcg ccgagacaga acttaatggg cccgctaaca gcgcgatttg ctggtgaccc 4200
aatgcgacca gatgctccac gcccagtcgc gtaccgtctt catgggagaa aataatactg 4260
ttgatgggtg tctggtcaga gacatcaaga aataacgccg gaacattagt gcaggcagct 4320
tccacagcaa tggcatcctg gtcatccagc ggatagttaa tgatcagccc actgacgcgt 4380
tgcgcgagaa gattgtgcac cgccgcttta caggcttcga cgccgcttcg ttctaccatc 4440
gacaccacca cgctggcacc cagttgatcg gcgcgagatt taatcgccgc gacaatttgc 4500
gacggcgcgt gcagggccag actggaggtg gcaacgccaa tcagcaacga ctgtttgccc 4560
gccagttgtt gtgccacgcg gttgggaatg taattcagct ccgccatcgc cgcttccact 4620
ttttcccgcg ttttcgcaga aacgtggctg gcctggttca ccacgcggga aacggtctga 4680
taagagacac cggcatactc tgcgacatcg tataacgtta ctggtttcac attcaccacc 4740
ctgaattgac tctcttccgg gcgctatcat gccataccgc gaaaggtttt gcgccattcg 4800
atggtgtccg ggatctcgac gctctccctt atgcgactcc tgcattagga agcagcccag 4860
tagtaggttg aggccgttga gcaccgccgc cgcaaggaat ggtgcatgca aggagatggc 4920
gcccaacagt cccccggcca cggggcctgc caccataccc acgccgaaac aagcgctcat 4980
gagcccgaag tggcgagccc gatcttcccc atcggtgatg tcggcgatat aggcgccagc 5040
aaccgcacct gtggcgccgg tgatgccggc cacgatgcgt ccggcgtaga ggatcgagat 5100
cgatctcgat cccgcgaaat taatacgact cactataggg gaattgtgag cggataacaa 5160
ttcccctcta gaaataattt tgtttaactt taagaaggag atatacatat gaaacaaagc 5220
actattgcac tggcactctt accgttactg tttacccctg tgacaaaagc catgagcgat 5280
aaaattattc acctgactga cgacagtttt gacacggatg tactcaaagc ggacggggcg 5340
atcctcgtcg atttctgggc agagtggtgc ggtccgtgca aaatgatcgc cccgattctg 5400
gatgaaatcg ctgacgaata tcagggcaaa ctgaccgttg caaaactgaa catcgatcaa 5460
aaccctggca ctgcgccgaa atatggcatc cgtggtatcc cgactctgct gctgttcaaa 5520
aacggtgaag tggcggcaac caaagtgggt gcactgtcta aaggtcagtt gaaagagttc 5580
ctcgacgcta acctggccgg ttctggttct ggccatatgc accatcatca tcatcatgac 5640
gatgacgata agatgcccaa aaagaaacga aaggtgggta tccacggagt cccagcagcc 5700
gacaaaaaat atagcatcgg cctggacatc ggtaccaaca gcgttggctg ggcagtgatc 5760
actgatgaat acaaagttcc atccaaaaaa tttaaagtac tgggcaacac cgaccgtcac 5820
tctatcaaaa aaaacctgat tggtgctctg ctgtttgaca gcggcgaaac tgctgaggct 5880
acccgtctga aacgtacggc tcgccgtcgc tacactcgtc gtaaaaaccg catctgttat 5940
ctgcaggaaa ttttctctaa cgaaatggca aaagttgatg atagcttctt tcatcgtctg 6000
gaagagagct tcctggtgga agaagataaa aaacacgaac gtcacccgat tttcggtaac 6060
attgtggatg aggttgccta ccacgagaaa tatccgacca tctaccatct gcgtaaaaaa 6120
ctggttgata gcactgacaa agcggatctg cgtctgatct acctggctct ggcacacatg 6180
atcaaattcc gtggtcactt cctgatcgaa ggtgatctga accctgataa ctccgacgtg 6240
gacaaactgt tcattcagct ggttcagacc tataaccagc tgttcgaaga aaacccgatc 6300
aacgcgtccg gtgtagacgc taaggcaatt ctgtctgcgc gtctgtctaa gtctcgtcgt 6360
ctggaaaacc tgattgcgca actgccaggt gaaaagaaaa acggcctgtt cggcaatctg 6420
atcgccctgt ccctgggtct gactccgaac tttaaatcca actttgacct ggcggaagat 6480
gccaagctgc agctgagcaa agatacctat gacgatgacc tggataacct gctggcacag 6540
atcggtgatc agtatgccga tctgttcctg gccgcgaaaa acctgtctga tgcgattctg 6600
ctgtctgata tcctgcgcgt taacactgaa attactaaag cgccgctgag cgcatccatg 6660
attaaacgtt acgatgaaca ccaccaggat ctgaccctgc tgaaagcgct ggtgcgtcag 6720
cagctgccgg aaaaatacaa ggagatcttc ttcgaccaga gcaaaaacgg ttacgcgggc 6780
tacattgatg gtggtgcatc tcaggaggaa ttctacaaat tcattaaacc gatcctggaa 6840
aaaatggatg gtactgaaga gctgctggtt aaactgaatc gtgaagatct gctgcgcaaa 6900
cagcgtacct tcgataacgg ttccatcccg catcagattc atctgggcga actgcacgct 6960
atcctgcgcc gtcaggaaga cttttatccg ttcctgaaag acaaccgtga gaaaattgaa 7020
aaaatcctga ccttccgtat tccgtactat gtaggtccgc tggcgcgtgg taactcccgt 7080
ttcgcttgga tgacccgcaa aagcgaagaa accatcaccc cgtggaattt cgaagaagtc 7140
gttgacaaag gcgcgtccgc gcagtctttc atcgaacgca tgacgaactt cgacaaaaac 7200
ctgccgaacg agaaagtgct gccgaaacac tctctgctgt acgagtactt cactgtgtac 7260
aacgaactga ccaaagtgaa atacgtcacc gaaggtatgc gtaaaccggc attcctgtcc 7320
ggtgagcaaa aaaaagcaat cgtggatctg ctgttcaaaa ccaaccgtaa agtaaccgtg 7380
aaacagctga aggaagacta tttcaagaaa atcgaatgtt ttgattctgt tgaaatctcc 7440
ggcgtggaag atcgcttcaa tgcgtccctg ggtacgtatc acgacctgct gaaaattatc 7500
aaagacaaag attttctgga caacgaggaa aacgaagaca tcctggagga tattgtactg 7560
accctgaccc tgttcgaaga ccgtgagatg atcgaagaac gcctgaaaac ctacgcccac 7620
ctgttcgatg acaaggtaat gaagcagctg aaacgtcgtc gttataccgg ctggggtcgt 7680
ctgtcccgta aactgatcaa tggcatccgt gataaacagt ctggcaaaac catcctggac 7740
ttcctgaaat ccgacggttt cgcgaatcgt aacttcatgc aactgattca tgacgattct 7800
ctgactttca aagaagacat ccagaaagca caggtttccg gccagggtga ctctctgcac 7860
gagcacattg ccaatctggc tggttctccg gctattaaaa agggtattct gcagactgtg 7920
aaagtagttg atgagctggt caaagtaatg ggccgtcaca agccggaaaa cattgtgatc 7980
gaaatggcac gtgaaaacca gacgacccag aaaggtcaga aaaactctcg tgaacgcatg 8040
aaacgtatcg aagaaggcat caaagaactg ggctctcaga tcctgaagga acaccctgta 8100
gaaaataccc agctgcagaa cgaaaagctg tatctgtatt acctgcagaa cggccgcgat 8160
atgtatgtgg accaggaact ggatatcaac cgcctgtccg attacgatgt agatcacatc 8220
gtgccgcaaa gcttcctgaa agacgacagc attgacaaca aagtactgac ccgttctgat 8280
aagaaccgtg gcaaatccga taacgtcccg tctgaagaag ttgttaaaaa aatgaaaaac 8340
tattggcgtc agctgctgaa cgcgaaactg atcacccagc gtaagttcga caatctgact 8400
aaagctgagc gcggtggtct gtccgaactg gataaagcgg gttttatcaa acgccagctg 8460
gttgaaaccc gtcagatcac gaagcacgtt gcgcagattc tggactctcg tatgaacacc 8520
aaatacgacg aaaacgacaa actgatccgc gaggttaagg ttatcaccct gaaaagcaaa 8580
ctggtatccg attttcgtaa agactttcag ttctacaaag tgcgcgaaat taacaactat 8640
caccacgctc acgatgcata tctgaatgca gttgttggca cggcgctgat caaaaagtat 8700
ccgaaactgg aatctgaatt cgtatacggc gattacaaag tgtatgacgt tcgtaagatg 8760
atcgcaaaat ccgagcagga aattggtaag gcgacggcga aatacttctt ttattccaat 8820
attatgaact ttttcaaaac cgaaatcacc ctggcgaatg gtgaaattcg taaacgcccg 8880
ctgatcgaaa ccaacggtga aactggtgaa atcgtttggg acaaaggccg cgacttcgcg 8940
accgtgcgta aagttctgtc tatgccgcaa gtgaacatcg tcaagaagac cgaagtacaa 9000
accggcggtt ttagcaaaga gagcattctg ccaaaacgta actccgacaa actgatcgcg 9060
cgcaagaaag actgggatcc gaaaaaatac ggtggtttcg attctccaac cgttgcttat 9120
tccgttctgg tggtagccaa agttgagaaa ggtaaaagca aaaaactgaa atccgtaaag 9180
gaactgctgg gtattactat catggagcgt agctccttcg aaaaaaaccc gatcgatttt 9240
ctggaagcga aaggctataa agaagtcaaa aaggacctga tcatcaaact gccaaaatac 9300
agcctgttcg agctggaaaa cggccgtaaa cgtatgctgg catctgcggg cgaactgcag 9360
aaaggcaacg agctggctct gccgtccaaa tacgtgaact ttctgtacct ggcctctcac 9420
tacgaaaaac tgaaaggttc cccggaagac aacgaacaga aacagctgtt cgtagagcag 9480
cacaaacact acctggacga gatcatcgaa cagatttctg aattttctaa acgtgtgatt 9540
ctggctgatg cgaatctgga taaagttctg tctgcctata acaagcatcg tgacaaaccg 9600
atccgcgaac aggctgagaa catcatccac ctgttcactc tgactaacct gggcgcgcca 9660
gcggctttca agtactttga taccaccatt gaccgcaagc gttacacctc cactaaagaa 9720
gtgctggacg cgactctgat ccaccagtcc atcaccggtc tgtacgagac ccgtatcgat 9780
ctgagccagc tgggcggtga caaaaggccg gcggccacga aaaaggccgg ccaggcaaaa 9840
aagaaaaagt gacaaagccc gaaaggaagc tgagttggct gctgccaccg ctgagcaata 9900
actagcataa ccccttgggg cctctaaacg ggtcttgagg ggttttttgc tgaaaggagg 9960
aactatatcc ggat 9974
<210> 2
<211> 1547
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Met Lys Gln Ser Thr Ile Ala Leu Ala Leu Leu Pro Leu Leu Phe Thr
1 5 10 15
Pro Val Thr Lys Ala Met Ser Asp Lys Ile Ile His Leu Thr Asp Asp
20 25 30
Ser Phe Asp Thr Asp Val Leu Lys Ala Asp Gly Ala Ile Leu Val Asp
35 40 45
Phe Trp Ala Glu Trp Cys Gly Pro Cys Lys Met Ile Ala Pro Ile Leu
50 55 60
Asp Glu Ile Ala Asp Glu Tyr Gln Gly Lys Leu Thr Val Ala Lys Leu
65 70 75 80
Asn Ile Asp Gln Asn Pro Gly Thr Ala Pro Lys Tyr Gly Ile Arg Gly
85 90 95
Ile Pro Thr Leu Leu Leu Phe Lys Asn Gly Glu Val Ala Ala Thr Lys
100 105 110
Val Gly Ala Leu Ser Lys Gly Gln Leu Lys Glu Phe Leu Asp Ala Asn
115 120 125
Leu Ala Gly Ser Gly Ser Gly His Met His His His His His His Asp
130 135 140
Asp Asp Asp Lys Met Pro Lys Lys Lys Arg Lys Val Gly Ile His Gly
145 150 155 160
Val Pro Ala Ala Asp Lys Lys Tyr Ser Ile Gly Leu Asp Ile Gly Thr
165 170 175
Asn Ser Val Gly Trp Ala Val Ile Thr Asp Glu Tyr Lys Val Pro Ser
180 185 190
Lys Lys Phe Lys Val Leu Gly Asn Thr Asp Arg His Ser Ile Lys Lys
195 200 205
Asn Leu Ile Gly Ala Leu Leu Phe Asp Ser Gly Glu Thr Ala Glu Ala
210 215 220
Thr Arg Leu Lys Arg Thr Ala Arg Arg Arg Tyr Thr Arg Arg Lys Asn
225 230 235 240
Arg Ile Cys Tyr Leu Gln Glu Ile Phe Ser Asn Glu Met Ala Lys Val
245 250 255
Asp Asp Ser Phe Phe His Arg Leu Glu Glu Ser Phe Leu Val Glu Glu
260 265 270
Asp Lys Lys His Glu Arg His Pro Ile Phe Gly Asn Ile Val Asp Glu
275 280 285
Val Ala Tyr His Glu Lys Tyr Pro Thr Ile Tyr His Leu Arg Lys Lys
290 295 300
Leu Val Asp Ser Thr Asp Lys Ala Asp Leu Arg Leu Ile Tyr Leu Ala
305 310 315 320
Leu Ala His Met Ile Lys Phe Arg Gly His Phe Leu Ile Glu Gly Asp
325 330 335
Leu Asn Pro Asp Asn Ser Asp Val Asp Lys Leu Phe Ile Gln Leu Val
340 345 350
Gln Thr Tyr Asn Gln Leu Phe Glu Glu Asn Pro Ile Asn Ala Ser Gly
355 360 365
Val Asp Ala Lys Ala Ile Leu Ser Ala Arg Leu Ser Lys Ser Arg Arg
370 375 380
Leu Glu Asn Leu Ile Ala Gln Leu Pro Gly Glu Lys Lys Asn Gly Leu
385 390 395 400
Phe Gly Asn Leu Ile Ala Leu Ser Leu Gly Leu Thr Pro Asn Phe Lys
405 410 415
Ser Asn Phe Asp Leu Ala Glu Asp Ala Lys Leu Gln Leu Ser Lys Asp
420 425 430
Thr Tyr Asp Asp Asp Leu Asp Asn Leu Leu Ala Gln Ile Gly Asp Gln
435 440 445
Tyr Ala Asp Leu Phe Leu Ala Ala Lys Asn Leu Ser Asp Ala Ile Leu
450 455 460
Leu Ser Asp Ile Leu Arg Val Asn Thr Glu Ile Thr Lys Ala Pro Leu
465 470 475 480
Ser Ala Ser Met Ile Lys Arg Tyr Asp Glu His His Gln Asp Leu Thr
485 490 495
Leu Leu Lys Ala Leu Val Arg Gln Gln Leu Pro Glu Lys Tyr Lys Glu
500 505 510
Ile Phe Phe Asp Gln Ser Lys Asn Gly Tyr Ala Gly Tyr Ile Asp Gly
515 520 525
Gly Ala Ser Gln Glu Glu Phe Tyr Lys Phe Ile Lys Pro Ile Leu Glu
530 535 540
Lys Met Asp Gly Thr Glu Glu Leu Leu Val Lys Leu Asn Arg Glu Asp
545 550 555 560
Leu Leu Arg Lys Gln Arg Thr Phe Asp Asn Gly Ser Ile Pro His Gln
565 570 575
Ile His Leu Gly Glu Leu His Ala Ile Leu Arg Arg Gln Glu Asp Phe
580 585 590
Tyr Pro Phe Leu Lys Asp Asn Arg Glu Lys Ile Glu Lys Ile Leu Thr
595 600 605
Phe Arg Ile Pro Tyr Tyr Val Gly Pro Leu Ala Arg Gly Asn Ser Arg
610 615 620
Phe Ala Trp Met Thr Arg Lys Ser Glu Glu Thr Ile Thr Pro Trp Asn
625 630 635 640
Phe Glu Glu Val Val Asp Lys Gly Ala Ser Ala Gln Ser Phe Ile Glu
645 650 655
Arg Met Thr Asn Phe Asp Lys Asn Leu Pro Asn Glu Lys Val Leu Pro
660 665 670
Lys His Ser Leu Leu Tyr Glu Tyr Phe Thr Val Tyr Asn Glu Leu Thr
675 680 685
Lys Val Lys Tyr Val Thr Glu Gly Met Arg Lys Pro Ala Phe Leu Ser
690 695 700
Gly Glu Gln Lys Lys Ala Ile Val Asp Leu Leu Phe Lys Thr Asn Arg
705 710 715 720
Lys Val Thr Val Lys Gln Leu Lys Glu Asp Tyr Phe Lys Lys Ile Glu
725 730 735
Cys Phe Asp Ser Val Glu Ile Ser Gly Val Glu Asp Arg Phe Asn Ala
740 745 750
Ser Leu Gly Thr Tyr His Asp Leu Leu Lys Ile Ile Lys Asp Lys Asp
755 760 765
Phe Leu Asp Asn Glu Glu Asn Glu Asp Ile Leu Glu Asp Ile Val Leu
770 775 780
Thr Leu Thr Leu Phe Glu Asp Arg Glu Met Ile Glu Glu Arg Leu Lys
785 790 795 800
Thr Tyr Ala His Leu Phe Asp Asp Lys Val Met Lys Gln Leu Lys Arg
805 810 815
Arg Arg Tyr Thr Gly Trp Gly Arg Leu Ser Arg Lys Leu Ile Asn Gly
820 825 830
Ile Arg Asp Lys Gln Ser Gly Lys Thr Ile Leu Asp Phe Leu Lys Ser
835 840 845
Asp Gly Phe Ala Asn Arg Asn Phe Met Gln Leu Ile His Asp Asp Ser
850 855 860
Leu Thr Phe Lys Glu Asp Ile Gln Lys Ala Gln Val Ser Gly Gln Gly
865 870 875 880
Asp Ser Leu His Glu His Ile Ala Asn Leu Ala Gly Ser Pro Ala Ile
885 890 895
Lys Lys Gly Ile Leu Gln Thr Val Lys Val Val Asp Glu Leu Val Lys
900 905 910
Val Met Gly Arg His Lys Pro Glu Asn Ile Val Ile Glu Met Ala Arg
915 920 925
Glu Asn Gln Thr Thr Gln Lys Gly Gln Lys Asn Ser Arg Glu Arg Met
930 935 940
Lys Arg Ile Glu Glu Gly Ile Lys Glu Leu Gly Ser Gln Ile Leu Lys
945 950 955 960
Glu His Pro Val Glu Asn Thr Gln Leu Gln Asn Glu Lys Leu Tyr Leu
965 970 975
Tyr Tyr Leu Gln Asn Gly Arg Asp Met Tyr Val Asp Gln Glu Leu Asp
980 985 990
Ile Asn Arg Leu Ser Asp Tyr Asp Val Asp His Ile Val Pro Gln Ser
995 1000 1005
Phe Leu Lys Asp Asp Ser Ile Asp Asn Lys Val Leu Thr Arg Ser Asp
1010 1015 1020
Lys Asn Arg Gly Lys Ser Asp Asn Val Pro Ser Glu Glu Val Val Lys
1025 1030 1035 1040
Lys Met Lys Asn Tyr Trp Arg Gln Leu Leu Asn Ala Lys Leu Ile Thr
1045 1050 1055
Gln Arg Lys Phe Asp Asn Leu Thr Lys Ala Glu Arg Gly Gly Leu Ser
1060 1065 1070
Glu Leu Asp Lys Ala Gly Phe Ile Lys Arg Gln Leu Val Glu Thr Arg
1075 1080 1085
Gln Ile Thr Lys His Val Ala Gln Ile Leu Asp Ser Arg Met Asn Thr
1090 1095 1100
Lys Tyr Asp Glu Asn Asp Lys Leu Ile Arg Glu Val Lys Val Ile Thr
1105 1110 1115 1120
Leu Lys Ser Lys Leu Val Ser Asp Phe Arg Lys Asp Phe Gln Phe Tyr
1125 1130 1135
Lys Val Arg Glu Ile Asn Asn Tyr His His Ala His Asp Ala Tyr Leu
1140 1145 1150
Asn Ala Val Val Gly Thr Ala Leu Ile Lys Lys Tyr Pro Lys Leu Glu
1155 1160 1165
Ser Glu Phe Val Tyr Gly Asp Tyr Lys Val Tyr Asp Val Arg Lys Met
1170 1175 1180
Ile Ala Lys Ser Glu Gln Glu Ile Gly Lys Ala Thr Ala Lys Tyr Phe
1185 1190 1195 1200
Phe Tyr Ser Asn Ile Met Asn Phe Phe Lys Thr Glu Ile Thr Leu Ala
1205 1210 1215
Asn Gly Glu Ile Arg Lys Arg Pro Leu Ile Glu Thr Asn Gly Glu Thr
1220 1225 1230
Gly Glu Ile Val Trp Asp Lys Gly Arg Asp Phe Ala Thr Val Arg Lys
1235 1240 1245
Val Leu Ser Met Pro Gln Val Asn Ile Val Lys Lys Thr Glu Val Gln
1250 1255 1260
Thr Gly Gly Phe Ser Lys Glu Ser Ile Leu Pro Lys Arg Asn Ser Asp
1265 1270 1275 1280
Lys Leu Ile Ala Arg Lys Lys Asp Trp Asp Pro Lys Lys Tyr Gly Gly
1285 1290 1295
Phe Asp Ser Pro Thr Val Ala Tyr Ser Val Leu Val Val Ala Lys Val
1300 1305 1310
Glu Lys Gly Lys Ser Lys Lys Leu Lys Ser Val Lys Glu Leu Leu Gly
1315 1320 1325
Ile Thr Ile Met Glu Arg Ser Ser Phe Glu Lys Asn Pro Ile Asp Phe
1330 1335 1340
Leu Glu Ala Lys Gly Tyr Lys Glu Val Lys Lys Asp Leu Ile Ile Lys
1345 1350 1355 1360
Leu Pro Lys Tyr Ser Leu Phe Glu Leu Glu Asn Gly Arg Lys Arg Met
1365 1370 1375
Leu Ala Ser Ala Gly Glu Leu Gln Lys Gly Asn Glu Leu Ala Leu Pro
1380 1385 1390
Ser Lys Tyr Val Asn Phe Leu Tyr Leu Ala Ser His Tyr Glu Lys Leu
1395 1400 1405
Lys Gly Ser Pro Glu Asp Asn Glu Gln Lys Gln Leu Phe Val Glu Gln
1410 1415 1420
His Lys His Tyr Leu Asp Glu Ile Ile Glu Gln Ile Ser Glu Phe Ser
1425 1430 1435 1440
Lys Arg Val Ile Leu Ala Asp Ala Asn Leu Asp Lys Val Leu Ser Ala
1445 1450 1455
Tyr Asn Lys His Arg Asp Lys Pro Ile Arg Glu Gln Ala Glu Asn Ile
1460 1465 1470
Ile His Leu Phe Thr Leu Thr Asn Leu Gly Ala Pro Ala Ala Phe Lys
1475 1480 1485
Tyr Phe Asp Thr Thr Ile Asp Arg Lys Arg Tyr Thr Ser Thr Lys Glu
1490 1495 1500
Val Leu Asp Ala Thr Leu Ile His Gln Ser Ile Thr Gly Leu Tyr Glu
1505 1510 1515 1520
Thr Arg Ile Asp Leu Ser Gln Leu Gly Gly Asp Lys Arg Pro Ala Ala
1525 1530 1535
Thr Lys Lys Ala Gly Gln Ala Lys Lys Lys Lys
1540 1545
<210> 3
<211> 1399
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Met Pro Lys Lys Lys Arg Lys Val Gly Ile His Gly Val Pro Ala Ala
1 5 10 15
Asp Lys Lys Tyr Ser Ile Gly Leu Asp Ile Gly Thr Asn Ser Val Gly
20 25 30
Trp Ala Val Ile Thr Asp Glu Tyr Lys Val Pro Ser Lys Lys Phe Lys
35 40 45
Val Leu Gly Asn Thr Asp Arg His Ser Ile Lys Lys Asn Leu Ile Gly
50 55 60
Ala Leu Leu Phe Asp Ser Gly Glu Thr Ala Glu Ala Thr Arg Leu Lys
65 70 75 80
Arg Thr Ala Arg Arg Arg Tyr Thr Arg Arg Lys Asn Arg Ile Cys Tyr
85 90 95
Leu Gln Glu Ile Phe Ser Asn Glu Met Ala Lys Val Asp Asp Ser Phe
100 105 110
Phe His Arg Leu Glu Glu Ser Phe Leu Val Glu Glu Asp Lys Lys His
115 120 125
Glu Arg His Pro Ile Phe Gly Asn Ile Val Asp Glu Val Ala Tyr His
130 135 140
Glu Lys Tyr Pro Thr Ile Tyr His Leu Arg Lys Lys Leu Val Asp Ser
145 150 155 160
Thr Asp Lys Ala Asp Leu Arg Leu Ile Tyr Leu Ala Leu Ala His Met
165 170 175
Ile Lys Phe Arg Gly His Phe Leu Ile Glu Gly Asp Leu Asn Pro Asp
180 185 190
Asn Ser Asp Val Asp Lys Leu Phe Ile Gln Leu Val Gln Thr Tyr Asn
195 200 205
Gln Leu Phe Glu Glu Asn Pro Ile Asn Ala Ser Gly Val Asp Ala Lys
210 215 220
Ala Ile Leu Ser Ala Arg Leu Ser Lys Ser Arg Arg Leu Glu Asn Leu
225 230 235 240
Ile Ala Gln Leu Pro Gly Glu Lys Lys Asn Gly Leu Phe Gly Asn Leu
245 250 255
Ile Ala Leu Ser Leu Gly Leu Thr Pro Asn Phe Lys Ser Asn Phe Asp
260 265 270
Leu Ala Glu Asp Ala Lys Leu Gln Leu Ser Lys Asp Thr Tyr Asp Asp
275 280 285
Asp Leu Asp Asn Leu Leu Ala Gln Ile Gly Asp Gln Tyr Ala Asp Leu
290 295 300
Phe Leu Ala Ala Lys Asn Leu Ser Asp Ala Ile Leu Leu Ser Asp Ile
305 310 315 320
Leu Arg Val Asn Thr Glu Ile Thr Lys Ala Pro Leu Ser Ala Ser Met
325 330 335
Ile Lys Arg Tyr Asp Glu His His Gln Asp Leu Thr Leu Leu Lys Ala
340 345 350
Leu Val Arg Gln Gln Leu Pro Glu Lys Tyr Lys Glu Ile Phe Phe Asp
355 360 365
Gln Ser Lys Asn Gly Tyr Ala Gly Tyr Ile Asp Gly Gly Ala Ser Gln
370 375 380
Glu Glu Phe Tyr Lys Phe Ile Lys Pro Ile Leu Glu Lys Met Asp Gly
385 390 395 400
Thr Glu Glu Leu Leu Val Lys Leu Asn Arg Glu Asp Leu Leu Arg Lys
405 410 415
Gln Arg Thr Phe Asp Asn Gly Ser Ile Pro His Gln Ile His Leu Gly
420 425 430
Glu Leu His Ala Ile Leu Arg Arg Gln Glu Asp Phe Tyr Pro Phe Leu
435 440 445
Lys Asp Asn Arg Glu Lys Ile Glu Lys Ile Leu Thr Phe Arg Ile Pro
450 455 460
Tyr Tyr Val Gly Pro Leu Ala Arg Gly Asn Ser Arg Phe Ala Trp Met
465 470 475 480
Thr Arg Lys Ser Glu Glu Thr Ile Thr Pro Trp Asn Phe Glu Glu Val
485 490 495
Val Asp Lys Gly Ala Ser Ala Gln Ser Phe Ile Glu Arg Met Thr Asn
500 505 510
Phe Asp Lys Asn Leu Pro Asn Glu Lys Val Leu Pro Lys His Ser Leu
515 520 525
Leu Tyr Glu Tyr Phe Thr Val Tyr Asn Glu Leu Thr Lys Val Lys Tyr
530 535 540
Val Thr Glu Gly Met Arg Lys Pro Ala Phe Leu Ser Gly Glu Gln Lys
545 550 555 560
Lys Ala Ile Val Asp Leu Leu Phe Lys Thr Asn Arg Lys Val Thr Val
565 570 575
Lys Gln Leu Lys Glu Asp Tyr Phe Lys Lys Ile Glu Cys Phe Asp Ser
580 585 590
Val Glu Ile Ser Gly Val Glu Asp Arg Phe Asn Ala Ser Leu Gly Thr
595 600 605
Tyr His Asp Leu Leu Lys Ile Ile Lys Asp Lys Asp Phe Leu Asp Asn
610 615 620
Glu Glu Asn Glu Asp Ile Leu Glu Asp Ile Val Leu Thr Leu Thr Leu
625 630 635 640
Phe Glu Asp Arg Glu Met Ile Glu Glu Arg Leu Lys Thr Tyr Ala His
645 650 655
Leu Phe Asp Asp Lys Val Met Lys Gln Leu Lys Arg Arg Arg Tyr Thr
660 665 670
Gly Trp Gly Arg Leu Ser Arg Lys Leu Ile Asn Gly Ile Arg Asp Lys
675 680 685
Gln Ser Gly Lys Thr Ile Leu Asp Phe Leu Lys Ser Asp Gly Phe Ala
690 695 700
Asn Arg Asn Phe Met Gln Leu Ile His Asp Asp Ser Leu Thr Phe Lys
705 710 715 720
Glu Asp Ile Gln Lys Ala Gln Val Ser Gly Gln Gly Asp Ser Leu His
725 730 735
Glu His Ile Ala Asn Leu Ala Gly Ser Pro Ala Ile Lys Lys Gly Ile
740 745 750
Leu Gln Thr Val Lys Val Val Asp Glu Leu Val Lys Val Met Gly Arg
755 760 765
His Lys Pro Glu Asn Ile Val Ile Glu Met Ala Arg Glu Asn Gln Thr
770 775 780
Thr Gln Lys Gly Gln Lys Asn Ser Arg Glu Arg Met Lys Arg Ile Glu
785 790 795 800
Glu Gly Ile Lys Glu Leu Gly Ser Gln Ile Leu Lys Glu His Pro Val
805 810 815
Glu Asn Thr Gln Leu Gln Asn Glu Lys Leu Tyr Leu Tyr Tyr Leu Gln
820 825 830
Asn Gly Arg Asp Met Tyr Val Asp Gln Glu Leu Asp Ile Asn Arg Leu
835 840 845
Ser Asp Tyr Asp Val Asp His Ile Val Pro Gln Ser Phe Leu Lys Asp
850 855 860
Asp Ser Ile Asp Asn Lys Val Leu Thr Arg Ser Asp Lys Asn Arg Gly
865 870 875 880
Lys Ser Asp Asn Val Pro Ser Glu Glu Val Val Lys Lys Met Lys Asn
885 890 895
Tyr Trp Arg Gln Leu Leu Asn Ala Lys Leu Ile Thr Gln Arg Lys Phe
900 905 910
Asp Asn Leu Thr Lys Ala Glu Arg Gly Gly Leu Ser Glu Leu Asp Lys
915 920 925
Ala Gly Phe Ile Lys Arg Gln Leu Val Glu Thr Arg Gln Ile Thr Lys
930 935 940
His Val Ala Gln Ile Leu Asp Ser Arg Met Asn Thr Lys Tyr Asp Glu
945 950 955 960
Asn Asp Lys Leu Ile Arg Glu Val Lys Val Ile Thr Leu Lys Ser Lys
965 970 975
Leu Val Ser Asp Phe Arg Lys Asp Phe Gln Phe Tyr Lys Val Arg Glu
980 985 990
Ile Asn Asn Tyr His His Ala His Asp Ala Tyr Leu Asn Ala Val Val
995 1000 1005
Gly Thr Ala Leu Ile Lys Lys Tyr Pro Lys Leu Glu Ser Glu Phe Val
1010 1015 1020
Tyr Gly Asp Tyr Lys Val Tyr Asp Val Arg Lys Met Ile Ala Lys Ser
1025 1030 1035 1040
Glu Gln Glu Ile Gly Lys Ala Thr Ala Lys Tyr Phe Phe Tyr Ser Asn
1045 1050 1055
Ile Met Asn Phe Phe Lys Thr Glu Ile Thr Leu Ala Asn Gly Glu Ile
1060 1065 1070
Arg Lys Arg Pro Leu Ile Glu Thr Asn Gly Glu Thr Gly Glu Ile Val
1075 1080 1085
Trp Asp Lys Gly Arg Asp Phe Ala Thr Val Arg Lys Val Leu Ser Met
1090 1095 1100
Pro Gln Val Asn Ile Val Lys Lys Thr Glu Val Gln Thr Gly Gly Phe
1105 1110 1115 1120
Ser Lys Glu Ser Ile Leu Pro Lys Arg Asn Ser Asp Lys Leu Ile Ala
1125 1130 1135
Arg Lys Lys Asp Trp Asp Pro Lys Lys Tyr Gly Gly Phe Asp Ser Pro
1140 1145 1150
Thr Val Ala Tyr Ser Val Leu Val Val Ala Lys Val Glu Lys Gly Lys
1155 1160 1165
Ser Lys Lys Leu Lys Ser Val Lys Glu Leu Leu Gly Ile Thr Ile Met
1170 1175 1180
Glu Arg Ser Ser Phe Glu Lys Asn Pro Ile Asp Phe Leu Glu Ala Lys
1185 1190 1195 1200
Gly Tyr Lys Glu Val Lys Lys Asp Leu Ile Ile Lys Leu Pro Lys Tyr
1205 1210 1215
Ser Leu Phe Glu Leu Glu Asn Gly Arg Lys Arg Met Leu Ala Ser Ala
1220 1225 1230
Gly Glu Leu Gln Lys Gly Asn Glu Leu Ala Leu Pro Ser Lys Tyr Val
1235 1240 1245
Asn Phe Leu Tyr Leu Ala Ser His Tyr Glu Lys Leu Lys Gly Ser Pro
1250 1255 1260
Glu Asp Asn Glu Gln Lys Gln Leu Phe Val Glu Gln His Lys His Tyr
1265 1270 1275 1280
Leu Asp Glu Ile Ile Glu Gln Ile Ser Glu Phe Ser Lys Arg Val Ile
1285 1290 1295
Leu Ala Asp Ala Asn Leu Asp Lys Val Leu Ser Ala Tyr Asn Lys His
1300 1305 1310
Arg Asp Lys Pro Ile Arg Glu Gln Ala Glu Asn Ile Ile His Leu Phe
1315 1320 1325
Thr Leu Thr Asn Leu Gly Ala Pro Ala Ala Phe Lys Tyr Phe Asp Thr
1330 1335 1340
Thr Ile Asp Arg Lys Arg Tyr Thr Ser Thr Lys Glu Val Leu Asp Ala
1345 1350 1355 1360
Thr Leu Ile His Gln Ser Ile Thr Gly Leu Tyr Glu Thr Arg Ile Asp
1365 1370 1375
Leu Ser Gln Leu Gly Gly Asp Lys Arg Pro Ala Ala Thr Lys Lys Ala
1380 1385 1390
Gly Gln Ala Lys Lys Lys Lys
1395
<210> 4
<211> 225
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 4
ggcttgtcgg actcttcgct attacgccag ctggcgaagg gggatgtgct gcaaggcgat 60
taagttgggt aacgccaggg ttttcccagt cacgacgtta ggaaattaat acgactcact 120
ataggagagc acagtcagcc tggcggtttt agagctagaa atagcaagtt aaaataaggc 180
tagtccgtta tcaacttgaa aaagtggcac cgagtcggtg ctttt 225
<210> 5
<211> 225
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 5
ggcttgtcgg actcttcgct attacgccag ctggcgaagg gggatgtgct gcaaggcgat 60
taagttgggt aacgccaggg ttttcccagt cacgacgtta ggaaattaat acgactcact 120
ataggcttcc agaattggat ctccggtttt agagctagaa atagcaagtt aaaataaggc 180
tagtccgtta tcaacttgaa aaagtggcac cgagtcggtg ctttt 225
<210> 6
<211> 102
<212> RNA
<213> 人工序列(Artificial Sequence)
<400> 6
ggagagcaca gucagccugg cgguuuuaga gcuagaaaua gcaaguuaaa auaaggcuag 60
uccguuauca acuugaaaaa guggcaccga gucggugcuu uu 102
<210> 7
<211> 102
<212> RNA
<213> 人工序列(Artificial Sequence)
<400> 7
ggcuuccaga auuggaucuc cgguuuuaga gcuagaaaua gcaaguuaaa auaaggcuag 60
uccguuauca acuugaaaaa guggcaccga gucggugcuu uu 102
<210> 8
<211> 531
<212> PRT
<213> Sus scrofa
<400> 8
Met Leu Leu Ala Ala Leu Tyr Cys Leu Leu Trp Thr Phe Gln Thr Ser
1 5 10 15
Ala Gly His Phe Pro Arg Ala Cys Ala Ser Ser Lys Asn Leu Met Glu
20 25 30
Lys Glu Cys Cys Pro Pro Trp Gly Gly Asp Gly Ser Pro Cys Gly Gln
35 40 45
Leu Ser Gly Arg Gly Ser Cys Gln Asp Ile Ile Leu Ser Lys Ala Pro
50 55 60
Leu Gly Pro Gln Phe Pro Phe Thr Gly Val Asp Glu Arg Glu Ser Trp
65 70 75 80
Pro Ser Val Phe Tyr Asn Arg Thr Cys Gln Cys Phe Gly Asn Phe Met
85 90 95
Gly Phe Asn Cys Gly Ser Cys Lys Phe Gly Phe Gln Gly Pro Asn Cys
100 105 110
Thr Glu Arg Arg Leu Leu Val Arg Arg Asn Ile Phe Asp Leu Ser Val
115 120 125
Pro Glu Lys Asn Lys Phe Leu Ala Tyr Leu Thr Leu Ala Lys His Thr
130 135 140
Thr Ser Pro Asp Phe Val Ile Pro Thr Gly Thr Tyr Gly Gln Met Asn
145 150 155 160
Asn Gly Ser Thr Pro Met Phe Ser Asp Ile Asn Ile Tyr Asp Leu Phe
165 170 175
Val Trp Met His Tyr Tyr Val Ser Arg Asp Thr Leu Leu Gly Gly Ser
180 185 190
Glu Ile Trp Arg Asp Ile Asp Phe Ala His Glu Ala Pro Gly Phe Leu
195 200 205
Pro Trp His Arg Leu Phe Leu Leu Val Trp Glu Gln Glu Ile Gln Lys
210 215 220
Leu Thr Gly Asp Glu Asn Phe Thr Ile Pro Tyr Trp Asp Trp Arg Asp
225 230 235 240
Ala Glu Asn Cys Asp Ile Cys Thr Asp Glu Tyr Met Gly Gly Arg Asn
245 250 255
Pro Ala Asn Pro Asn Leu Leu Ser Pro Ala Ser Phe Phe Ser Ser Trp
260 265 270
Gln Ile Ile Cys Ser Arg Leu Glu Glu Tyr Asn Ser Arg Gln Ala Leu
275 280 285
Cys Asn Gly Thr Pro Glu Gly Pro Leu Leu Arg Asn Pro Gly Asn His
290 295 300
Asp Lys Ser Arg Thr Pro Arg Leu Pro Ser Ser Ala Asp Val Glu Phe
305 310 315 320
Cys Leu Ser Leu Thr Gln Tyr Glu Ser Gly Ser Met Asp Lys Ser Ala
325 330 335
Asn Phe Ser Phe Arg Asn Thr Leu Glu Gly Phe Ala Ser Pro Leu Thr
340 345 350
Gly Ile Ala Asp Ala Ser Gln Ser Ser Met His Asn Ala Leu His Ile
355 360 365
Tyr Met Asn Gly Thr Met Ser Gln Val Gln Gly Ser Ala Asn Asp Pro
370 375 380
Ile Phe Leu Leu His His Ala Phe Val Asp Ser Ile Phe Glu Gln Trp
385 390 395 400
Leu Arg Lys His His Pro Leu Leu Glu Val Tyr Pro Glu Ala Asn Ala
405 410 415
Pro Ile Gly His Asn Arg Glu Ser Tyr Met Val Pro Phe Ile Pro Leu
420 425 430
Tyr Arg Asn Gly Asp Phe Phe Ile Ser Ser Arg Asp Leu Gly Tyr Asp
435 440 445
Tyr Ser Tyr Leu Gln Asp Ser Glu Pro Asp Phe Phe Gln Asp Tyr Ile
450 455 460
Lys Pro Tyr Leu Glu Gln Ala Ser Arg Ile Trp Pro Trp Leu Leu Gly
465 470 475 480
Ala Ala Val Val Gly Ser Val Leu Thr Ala Val Leu Gly Gly Ile Thr
485 490 495
Arg Arg Leu Cys Cys Arg Arg Lys Arg Lys Arg Leu Pro Glu Glu Lys
500 505 510
Gln Pro Leu Leu Met Glu Lys Glu Asp Tyr Asp Ser Leu Leu Tyr Gln
515 520 525
Ser His Leu
530
<210> 9
<211> 982
<212> DNA
<213> Sus scrofa
<400> 9
atttagtttt acatgttctt tctttgggtg aactttcttt gagatgagaa acatatttaa 60
tttacagctg tgtctcagtt gtcactcaac caataattat tacacttgtg ctgtggcatt 120
ctgaagcatc taaacttgtc atgtaagttt catttatctt ttaagaaatt ctttttttca 180
gagttatcct ctaatatgta tctcaagtaa gtgagctttg tcagggcctg acagcatgaa 240
ctggtacttt atgaaatatt ttcaaagcat gaaaactata tttggcatct ttacatggct 300
tgagatatta agatatgcct tgttatttta agttgagagg tccacatttt ttctttacaa 360
acaatacgtt tctgactctg aatattcctt tcctctgcag tatttttgaa cagtggcttc 420
gaaagcacca ccctcttctt gaagtgtatc cggaagccaa tgcacccatt ggacacaacc 480
gggaatctta catggttcca tttatacctc tctacagaaa tggtgacttc tttatttcat 540
ccagagatct aggctatgac tacagctacc tacaagattc aggtaaagtt cagtttcttt 600
catcacaatt gctgagtctc atgtgaccag attcttttga gagagcacaa aaccctaggt 660
ttttacagtg ttatccccaa attccctaaa ttggggaagt gcattgcaac cattagctca 720
tcactgattt attattacat ggaccaggag ttcccgtcgt ggcgcagtgg ttaacgaatc 780
cgactaggaa ccatgaggtt gcgggttcgg tccctgccct tgctcagtgg gttaacgatc 840
cggcgttgcc gtgagctgtg gtgtaggttg cagacgcggc tcggatcctg cgttgctgtg 900
gctctggtgt aggccagtgg ctacagctcc gattcgaccc ctagcctggg aacctccata 960
ggccacagga gtggcccaaa ga 982
<210> 10
<211> 100
<212> RNA
<213> 人工序列(Artificial Sequence)
<400> 10
ugcacccauu ggacacaacc guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 11
<211> 100
<212> RNA
<213> 人工序列(Artificial Sequence)
<400> 11
ccggaagcca augcacccau guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 12
<211> 100
<212> RNA
<213> 人工序列(Artificial Sequence)
<400> 12
agauucccgg uuguguccaa guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 13
<211> 100
<212> RNA
<213> 人工序列(Artificial Sequence)
<400> 13
augcacccau uggacacaac guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 14
<211> 100
<212> RNA
<213> 人工序列(Artificial Sequence)
<400> 14
ccggauacac uucaagaaga guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 15
<211> 100
<212> RNA
<213> 人工序列(Artificial Sequence)
<400> 15
gauacacuuc aagaagaggg guuuuagagc uagaaauagc aaguuaaaau aaggcuaguc 60
cguuaucaac uugaaaaagu ggcaccgagu cggugcuuuu 100
<210> 16
<211> 225
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 16
ggcttgtcgg actcttcgct attacgccag ctggcgaagg gggatgtgct gcaaggcgat 60
taagttgggt aacgccaggg ttttcccagt cacgacgtta ggaaattaat acgactcact 120
ataggtgcac ccattggaca caaccgtttt agagctagaa atagcaagtt aaaataaggc 180
tagtccgtta tcaacttgaa aaagtggcac cgagtcggtg ctttt 225
<210> 17
<211> 225
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 17
ggcttgtcgg actcttcgct attacgccag ctggcgaagg gggatgtgct gcaaggcgat 60
taagttgggt aacgccaggg ttttcccagt cacgacgtta ggaaattaat acgactcact 120
ataggccgga tacacttcaa gaagagtttt agagctagaa atagcaagtt aaaataaggc 180
tagtccgtta tcaacttgaa aaagtggcac cgagtcggtg ctttt 225
<210> 18
<211> 102
<212> RNA
<213> 人工序列(Artificial Sequence)
<400> 18
ggugcaccca uuggacacaa ccguuuuaga gcuagaaaua gcaaguuaaa auaaggcuag 60
uccguuauca acuugaaaaa guggcaccga gucggugcuu uu 102
<210> 19
<211> 102
<212> RNA
<213> 人工序列(Artificial Sequence)
<400> 19
ggccggauac acuucaagaa gaguuuuaga gcuagaaaua gcaaguuaaa auaaggcuag 60
uccguuauca acuugaaaaa guggcaccga gucggugcuu uu 102
<210> 20
<211> 153
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 20
aatattcctt tcctctgcag tatttttgaa cagtggcttc gaaagcacca tcctcttctt 60
gaagtgtatc cggaagccaa tgcacccatt ggacgcaacc gagaatctta catggttcca 120
tttatacctc tctacagaaa tggtgacttc ttt 153
<210> 21
<211> 153
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 21
aatattcctt tcctctgcag tatttttgaa cagtggcttc gaaagcacca ccctcttctt 60
gaagtgtatc cggaagccaa tgcacccatt ggacacaacc gggaatctta catggttcca 120
tttatacctc tctacagaaa tggtgacttc ttt 153
Claims (15)
1.一种试剂盒,包括TYR-gRNA1、TYR-gRNA5、TYR-E4mut-ss153和NCN蛋白;
所述TYR-gRNA1为sgRNA,其靶序列结合区如SEQ ID NO:18中第3-22位核苷酸所示;所述TYR-gRNA5为sgRNA,其靶序列结合区如SEQ ID NO:19中第3-22位核苷酸所示;所述TYR-E4mut-ss153为SEQ ID NO:20所示的单链DNA分子;所述NCN蛋白为Cas9蛋白或具有Cas9蛋白的融合蛋白;
所述试剂盒的用途为如下(a)或(b)或(c):(a)制备重组细胞;(b)制备白化病模型猪;(c)制备白化病细胞模型或白化病组织模型或白化病器官模型。
2.一种试剂盒,包括TYR-gRNA1、TYR-gRNA5、TYR-E4mut-ss153和PRONCN蛋白;
TYR-gRNA1为权利要求1中所述的TYR-gRNA1;TYR-gRNA5为权利要求1中所述的TYR-gRNA5;TYR-E4mut-ss153为权利要求1中所述的TYR-E4mut-ss153;
所述PRONCN蛋白自上游至下游依次包括如下元件:信号肽、分子伴侣蛋白、蛋白标签、蛋白酶酶切位点、核定位信号、Cas9蛋白、核定位信号;
所述试剂盒的用途为如下(a)或(b)或(c):(a)制备重组细胞;(b)制备白化病模型猪;(c)制备白化病细胞模型或白化病组织模型或白化病器官模型。
3.一种试剂盒,包括TYR-gRNA1、TYR-gRNA5、TYR-E4mut-ss153和特异质粒;
TYR-gRNA1为权利要求1中所述的TYR-gRNA1;TYR-gRNA5为权利要求1中所述的TYR-gRNA5;TYR-E4mut-ss153为权利要求1中所述的TYR-E4mut-ss153;
所述特异质粒自上游至下游依次包括如下元件:启动子、操纵子、核糖体结合位点、PRONCN蛋白的编码基因、终止子;所述PRONCN蛋白自上游至下游依次包括如下元件:信号肽、分子伴侣蛋白、蛋白标签、蛋白酶酶切位点、核定位信号、Cas9蛋白、核定位信号;
所述试剂盒的用途为如下(a)或(b)或(c):(a)制备重组细胞;(b)制备白化病模型猪;(c)制备白化病细胞模型或白化病组织模型或白化病器官模型。
4.TYR-gRNA1、TYR-gRNA5、TYR-E4mut-ss153和NCN蛋白在制备试剂盒中的应用;
TYR-gRNA1为权利要求1中所述的TYR-gRNA1;TYR-gRNA5为权利要求1中所述的TYR-gRNA5;TYR-E4mut-ss153为权利要求1中所述的TYR-E4mut-ss153;NCN蛋白为权利要求1中所述的NCN蛋白;
所述试剂盒的用途为如下(a)或(b)或(c):(a)制备重组细胞;(b)制备白化病模型猪;(c)制备白化病细胞模型或白化病组织模型或白化病器官模型。
5.TYR-gRNA1、TYR-gRNA5、TYR-E4mut-ss153和PRONCN蛋白在制备试剂盒中的应用;
TYR-gRNA1为权利要求1中所述的TYR-gRNA1;TYR-gRNA5为权利要求1中所述的TYR-gRNA5;TYR-E4mut-ss153为权利要求1中所述的TYR-E4mut-ss153;
所述PRONCN蛋白自上游至下游依次包括如下元件:信号肽、分子伴侣蛋白、蛋白标签、蛋白酶酶切位点、核定位信号、Cas9蛋白、核定位信号;
所述试剂盒的用途为如下(a)或(b)或(c):(a)制备重组细胞;(b)制备白化病模型猪;(c)制备白化病细胞模型或白化病组织模型或白化病器官模型。
6.TYR-gRNA1、TYR-gRNA5、TYR-E4mut-ss153和特异质粒在制备试剂盒中的应用;
TYR-gRNA1为权利要求1中所述的TYR-gRNA1;TYR-gRNA5为权利要求1中所述的TYR-gRNA5;TYR-E4mut-ss153为权利要求1中所述的TYR-E4mut-ss153;
所述特异质粒自上游至下游依次包括如下元件:启动子、操纵子、核糖体结合位点、PRONCN蛋白的编码基因、终止子;所述PRONCN蛋白自上游至下游依次包括如下元件:信号肽、分子伴侣蛋白、蛋白标签、蛋白酶酶切位点、核定位信号、Cas9蛋白、核定位信号;
所述试剂盒的用途为如下(a)或(b)或(c):(a)制备重组细胞;(b)制备白化病模型猪;(c)制备白化病细胞模型或白化病组织模型或白化病器官模型。
7.一种制备重组细胞的方法,包括如下步骤:用SEQ ID NO:20所示的DNA分子取代猪细胞的染色体DNA中SEQ ID NO:21所示的DNA分子,得到重组细胞。
8.如权利要求7所述的方法,其特征在于:用SEQ ID NO:20所示的DNA分子取代猪细胞的染色体DNA中SEQ ID NO:21所示的DNA分子的实现方式为:将TYR-gRNA1、TYR-gRNA5、TYR-E4mut-ss153和NCN蛋白共转染猪细胞;TYR-gRNA1为权利要求1中所述的TYR-gRNA1;TYR-gRNA5为权利要求1中所述的TYR-gRNA5;TYR-E4mut-ss153为权利要求1中所述的TYR-E4mut-ss153;NCN蛋白为权利要求1中所述的NCN蛋白。
9.如权利要求8所述的方法,其特征在于:猪细胞、TYR-gRNA1、TYR-gRNA5、TYR-E4mut-ss153和NCN蛋白的配比依次为:10万个猪细胞:0.8-1.2μg TYR-gRNA1:0.8-1.2μg TYR-gRNA5:1.8-2.2μg TYR-E4mut-ss153:3-5μg NCN蛋白。
10.如权利要求1至3中任一所述的试剂盒或如权利要求4至6中任一所述的应用或如权利要求7至9中任一所述的方法,其特征在于:所述NCN蛋白如SEQ ID NO:3所示。
11.如权利要求10所述的试剂盒或应用或方法,其特征在于:
所述NCN蛋白的制备方法包括如下步骤:
(1)将质粒pKG-GE4导入大肠杆菌BL21(DE3),得到重组菌;
(2)采用液体培养基30℃培养所述重组菌,然后加入IPTG并25℃诱导培养,然后收集菌体;
(3)将收集的菌体进行菌体破碎,收集粗蛋白溶液;
(4)采用亲和层析从所述粗蛋白溶液中纯化具有His6标签的融合蛋白;
(5)采用具有His6标签的肠激酶酶切具有His6标签的融合蛋白,然后采用Ni-NTA树脂去除具有His6标签的蛋白,得到纯化的NCN蛋白;
质粒pKG-GE4中具有SEQ ID NO:1中第5209-9852位核苷酸所示的融合基因。
12.权利要求7至11中任一所述方法制备得到的重组细胞。
13.权利要求12所述重组细胞在制备白化病模型猪中的应用。
14.利用权利要求12所述重组细胞所制备的白化病模型猪的猪组织、猪器官或猪细胞。
15.权利要求12所述重组细胞、权利要求14所述猪组织、权利要求14所述猪器官、权利要求14所述猪细胞或者利用权利要求12所述重组细胞所制备的白化病模型猪的应用,为如下(d1)或(d2)或(d3)或(d4):
(d1)筛选治疗白化病的药物;
(d2)进行白化病药物的药效评价;
(d3)进行白化病的基因治疗和/或细胞治疗的疗效评价;
(d4)研究白化病的发病机制。
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