CN114592040A - 基于Cas12i的核酸检测方法 - Google Patents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
基于Cas12i的核酸检测方法。本发明涉及基因工程和基因检测领域,是基于新的CRISPR系统开发的核酸检测方法,涉及在RNA的介导下由Cas12i蛋白以及其变体进行的靶向DNA、RNA检测方法的建立以及相关检测装置的开发,可应用于遗传诊断、检验检疫等方向。
Description
技术领域
本发明涉及基因工程和基因检测领域,具体而言涉及一种基于新的CRISPR系统开发的核酸检测方法,以及基于此检测方法的检测或诊断装置。
背景技术
2017年出现的CRISPR核酸检测技术兼具QPCR和恒温扩增技术的优点,在灵敏度、特异性、便携性上均具有突出优势,是新一代分子诊断技术,具有改变分子诊断领域格局的前景。Cas13由于具有 ssRNA反式切割活性已经被开发用于RNA检测。基于CRISPR-Cas13的RNA检测平台称为SHERLOCK,结合等温扩增技术可以检测寨卡病毒和登革热病毒、鉴定病原菌、SNP分析。2018 年,利用CRISPR核酸酶Cas13a、Cas12a、Csm6结合等温扩增技术建立了SHERLOCKv2,使核酸检测实现多重化、定量化和试纸化。将SHERLOCK和样品处理技术HUDSON相结合,能够灵敏地检测血清中的寨卡病毒和登革热病毒。同年,Cas12a与等温扩增相结合的DNA检测平台——DETECTR被建立,实现微生物的快速检测和人乳头瘤病毒分型。2019年,基于Cas12b的DNA检测工具——CDetection被开发,实现了第3类哺乳动物基因编辑工具在分子诊断上的应用,分析了CRISPR DNA检测过程中的脱靶效应,实现了细胞系SNP分型。
2019年初,Cas12i被报道,由于其蛋白小,且只需要crRNA就能介导其与靶序列的特异性识别和切割。在核酸检测领域具有更广泛的应用前景。
本发明提供一种基于Cas12i的核酸检测方法,能够特异性检测 DNA。基于其crRNA较短的特点,更容易添加化学修饰提高其稳定性,合成成本更低,具有广泛的应用前景。该技术能够提供快速简便的DNA或者RNA检测方法,适用于重大疾病筛查、基因检测、医药健康、农业、化工业等各领域应用。
发明内容
本申请在此提供了:
1.一种检测样品中靶核酸分子的存在和/或量的方法,所述方法包括以下步骤:
(a)使所述生物样品接触:i)Cas12i蛋白,ii)针对所述靶核酸分子中的靶序列的gRNA,和iii)被切割后产生可检测信号的DNA报告分子,从而形成反应混合物;
(b)检测所述反应混合物中产生的可检测信号的存在和/或水平,其中所述可检测信号的存在和/或水平代表所述靶核酸分子的存在和/或量,所述样品选自生物样品或环境样品。
2.项1的方法,其特征在于包括一个含向导RNA前体的阵列(CRISPR array),这个阵列中的向导RNA前体可以通过V型CRISPR/Cas蛋白加工成熟为向导RNA,因此至少包含一个向导RNA,优选所述向导RNA 是sgRNA,进一步优选,
(1)所述sgRNA包括由选自SEQ ID 6、SEQ ID7之一的核酸序列编码的支架序列,且所述sgRNA包括位于支架序列3’端的间隔区序列,其与靶序列或靶序列的互补序列特异性杂交,
或
(2)所述间隔区序列与靶序列具有至少一个核苷酸错配。
3.项1或2中的方法,所述Cas12i蛋白是来自Cas12i1或Cas12i2 或其突变体,所述突变体优选Cas12iVar1,Cas12iVar2,Cas12iVar3。
4.项1-4中的任一方法其中所述Cas12i蛋白包含
(1)与SEQ ID NO:1-5中任一序列具有至少80%、至少85%、至少 90%、至少95%、至少96%、至少97%、至少98%、至少99%序列相同性的氨基酸序列;
(2)相对于SEQ ID NO:1-5中任一序列具有一或多个氨基酸残基取代、缺失或添加的氨基酸序列;或
(3)SEQ ID NO:1-5中任一所示的氨基酸序列。
5.项1或2的方法,其中所述靶DNA为单链。
6.项1或2的方法,其中所述靶DNA为双链。
7.项1-4中的任何方法,靶DNA为病毒DNA。
8.项1-4中的任何方法,靶DNA为乳多泡病毒(papovavirus)、嗜肝DNA 病毒(hepadnavirus)、疱疹病毒(herpesvirus)、腺病毒(adenovirus)、痘病毒(poxvirus)或者是细小病毒(parvovirus)的DNA。
9.项1-8中的任何方法,样品包含细胞裂解物中的DNA分子。
10.项1-9中的任何方法,样品包括细胞。
11.项1-10中的任何方法,所述接触发生于生物体内、体外的细胞内部。
12.项11中所称方法,细胞是真核细胞。
13.项1-12所称方法,靶DNA可在低至1aM的浓度被检测到。
14.项1-13中的任何方法,包括对样品中存在的靶DNA进行定量。
15.项13中方法所述的检测包括:通过对可检测信号的测量得到检测结果;通过对参照样品或参照细胞生成的可检测信号进行测量得到检测结果;比较测量数据和参照数据来决定样品中靶DNA水平。
16.项1-15中的任何方法,测量可检测信号包括以下一种或多种方法:基于纳米颗粒的检测方法、荧光偏振、胶态相变、电化学检测或基于半导体的检测方法,所述纳米颗粒的检测方法,优选胶体金属,进一步优选胶体金或纳米金。
17.项1-16中的任何方法,单链DNA探针标记了荧光发射染料对。
18.项17所述方法,荧光发射染料对可以在单链探测DNA切割前产生一定量的可检测信号,在单链探测DNA切割后信号降低。
19.项18所述方法,单链DNA探针在被切割前产生第一个可检测信号并在被切割后产生第二个可检测信号。
20.项17-19中的任何方法,荧光发射染料对是一种荧光能量转移 (FRET)对。
21.项17中所述方法,可检测信号的量在单链探测DNA被切割后增加。
22.项17-21中所述方法,荧光发射染料对包括荧光基团和相应的淬灭基团。
23.项17-22中所述方法,单链探针DNA包括两对或多对荧光发射染料对。
24.项23中所述方法,所称两对或多对荧光发射染料对包括一种荧光能量转移对和荧光淬灭基团/荧光基团对。
25.项1-24所称任何方法中,单链探针DNA包括一种修饰的碱基,一种修饰的糖配基,和/或一种修饰的核酸连接键。
26.项1-25任一项的方法,其中所述单链探针长度为大约2个-大约 100个核苷酸。
27.项1-25任一项的方法,其中所述单链探针为聚腺苷酸、聚胞苷酸或聚胸苷酸。
28.项1-25中所述方法包括样品中的扩增的核酸分子。
29.项28所述方法中说的扩增包括等温扩增。
30.项29所述方法中的等温扩增包括但不限于重组酶聚合酶扩增。
31.项28-30中所述任何方法中所称的正在扩增起始于a步骤(接触) 之前。
32.项28-31中所述任何方法中所称的正在扩增和a步骤(接触)同时起始。
33.一种装置,其特征在于包含一个或多个基于项1-32的Cas12i核酸检测方法的核心检测单元,优选包含大于两个、大于三个、大于四个所述核心检测单元。
34.一种装置,其特征在于同时包含基于项1-32的Cas12i核酸检测方法的检测单元,以及基于其他CRISPR Cas核酸检测方法的检测单元,所述其他CRISPR Cas核酸检测方法选自Cas9、Cas13、除Cas12i之外的Cas12,中的一种或多种的突变体,进一步优选Cas12b或其突变体。
附图说明
图1 Cas12i1具有单链DNA反式切割能力。Cas12i1识别靶双链DNA (dsDNA)并非特异性切割单链DNA(ssDNA)。反应体系中缺少Cas12i1、crRNA、靶dsDNA时,反式ssDNA(ploy_T-FQ)不能被切割而释放荧光信号,说明检测到的荧光信号不是由ploy_T-FQ降解产生;反应体系中缺少crRNA和/或靶dsDNA时,反式ssDNA不能被切割,说明Cas12i只有在靶DNA存在和crRNA的指引下才会激活其对反式ssDNA的切割活性。误差棒表示平均值的标准误差(s.e.m.),n=3。RFU,相对荧光单位。
图2 Cas12i2具有单链DNA反式切割能力。Cas12i2识别靶双链DNA (dsDNA)并非特异性切割单链DNA(ssDNA)。反应体系中缺少 Cas12i2、crRNA、靶dsDNA时,反式ssDNA(ploy_T-FQ)不能被切割而释放荧光信号,说明检测到的荧光信号不是由ploy_T-FQ降解产生;反应体系中缺少crRNA和/或靶dsDNA时,反式ssDNA不能被切割,说明Cas12i只有在靶DNA存在和crRNA的指引下才会激活其对反式ssDNA的切割活性。误差棒表示平均值的标准误差(s.e.m.),n=3。RFU,相对荧光单位。
图3 Cas12i具有DNA反式切割能力。Cas12i在crRNA指引和靶DNA 的激活下,分别进行poly_T-FQ、poly_A-FQ、poly_G-FQ、poly_C-FQ 的切割实验,结果如图。
图4 Cas12i1具有RNA反式切割能力。Cas12i1在crRNA指引和靶 DNA的激活下,分别进行poly_rU-FQ、poly_rA-FQ、poly_rG-FQ、 poly_rC-FQ的切割实验,结果显示poly_rU能被Cas12i1非特异性切割。
图5 Cas12i2具有RNA反式切割能力。Cas12i2在crRNA指引和靶 DNA的激活下,分别进行poly_rU-FQ、poly_rA-FQ、poly_rG-FQ、 poly_rC-FQ的切割实验,结果显示poly_rU能被Cas12i2非特异性切割。
图6化学修饰的crRNA能提高Cas12i单链DNA反式切割效率。 crRNA5’和3’端的前3个碱基用甲氧基和硫代修饰后,Cas12i反式切割效率提高,表现在:荧光信号更强,释放速度更快。
图7 2’-OMe、2’-F的RNA核苷酸单体NTP合成的crRNA能提高Cas12i单链DNA反式切割效率。Cas12i在修饰过的NTP合成的 crRNA指引和靶DNA的激活下,Cas12i1反式切割效率提高,表现在:荧光信号更强,释放速度更快。
图8 Cas12i变体能提高单链DNA反式切割效率。三个Cas12i变体反式切割效率提高,表现在:荧光信号更强,释放速度更快。
图9 Cas12i及其变体反式切割碱基偏好性检测。Cas12i在crRNA指引和靶DNA的激活下,分别进行poly_T-FQ、poly_A-FQ、poly_G-FQ、 poly_C-FQ的切割实验,结果如图(9)。
图10 Cas12i及其变体最适检测温度范围。通过对Cas12i在37℃, 42℃,47℃,52℃,57℃,62℃对于单链DNA探针的检测,其最适温度范围在37℃~47℃。
图11 Cas12i与crRNA浓度比例优化能够提高检测信号。通过对 Cas12i及其变体在与crRNA比例2:6,4:6,6:6,2:10,4:10, 6:10对于单链DNA探针的检测,Cas12i与crRNA浓度比例经过优化能够提高检测信号。
图12 双链DNA激活子的长度能够影响检测信号。通过对Cas12i及其变体在与crRNA指引下对于带有靶点的 100bp,200bp,300bp,400bp,500bp,600bp,800bp双链DNA进行检测,说明双链DNA激活子的长度能够影响检测信号。
图13 crRNAspacer区域的长度能够影响检测信号。通过对Cas12i及其变体在与14nt,16nt,18nt,20nt,22nt,24nt,26nt的spacer长度的crRNA 的指引下对靶DNA进行检测,结果如图所示,crRNA spacer区域的长度能够影响检测信号。
图14 crRNA spacer区域单个碱基的mismatch能够影响检测信号。过对Cas12i及其变体在spacer上的单个碱基的mismatch合成的crRNA 的指引下对靶DNA进行检测,结果如图所示,crRNA spacer区域单个碱基的mismatch能够影响检测信号。crRNA spacer区域连续两个碱基的mismatch能够影响检测信号。过对Cas12i及其变体在spacer 上连续两个碱基的mismatch合成的crRNA的指引下对靶DNA进行检测,结果如图所示,crRNA spacer区域连续两个碱基的mismatch 能够影响检测信号。
图15 Cas12i及其变体在新型冠状病毒检测中的应用。a图为新型冠状病毒检测位点的筛选。b Cas12i及其变体在搭载等温扩增技术RPA 两步荧光检测后的灵敏度实验。结果表明,该检测方式能够达到亚渺摩尔级灵敏度,并且非常特异。灵敏度达到亚渺摩尔级。c图显示 Cas12i及其变体在搭载等温扩增技术RPA或RTRAA与侧向流结合试纸化。图为在检测体系中反应时间对于检测结果的影响。结果表明,与侧向流层析结合的检测方式能够达到亚渺摩尔级灵敏度。
具体实施方式
I.定义
在本发明中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且,本文中所用的蛋白质和核酸化学、分子生物学、细胞和组织培养、微生物学、免疫学相关术语和实验室操作步骤均为相应领域内广泛使用的术语和常规步骤。例如,本发明中使用的标准重组DNA和分子克隆技术为本领域技术人员熟知,并且在如下文献中有更全面的描述:Sambrook,J.,Fritsch, E.F.和Maniatis,T.,MolecularCloning:A Laboratory Manual;Cold Spring Harbor Laboratory Press: ColdSpringHarbor,1989(下文称为“Sambrook”)。同时,为了更好地理解本发明,下面提供相关术语的定义和解释。
II.核酸检测
本发明首次提出利用Cas12i或其突变体,优选Cas12i1,Cas12i2, Cas12iVar1,Cas12iVar2,Cas12iVar3,被目标DNA激活的随意切割非靶向双链或单链DNA(ssDNA)的功能检测核酸。当样品包括向导 RNA杂交的目标DNA(即,样品包括靶DNA)时,Cas12i或其突变体,优选Cas12i1,Cas12i2,Cas12iVar1,Cas12iVar2,Cas12iVar3,被向导RNA激活,该蛋白质就成为乱切ssdna(即,非靶ssDNAs,向导RNA的向导序列没有杂交的ssdna)。因此,当靶向DNA(双链或单链)存在于样品中时(例如,在某些情况下超过阈值量),结果是样品中SSDNA的断裂,可以使用任何方便的检测方法(例如,使用标记的双链或单链检测器DNA)检测。
本发明还提供用于检测靶DNA(双链或单链)的方法。在某些情况下,受试者方法包括:(a)使样品接触:(i)Cas12i或其突变体,优选Cas12i1,Cas12i2,Cas12iVar1,Cas12iVar2,Cas12iVar3; (ii)向导RNA(包括与Cas12i或其突变体,优选Cas12i1,Cas12i2, Cas12iVar1,Cas12iVar2,Cas12iVar3)结合的区域,以及与靶DNA 杂交的向导序列;以及 (iii)单链(即“单链检测器DNA”)且不与向导RNA的向导序列杂交的检测器DNA;以及(b)测量由单链检测器DNA的裂解(通过Cas12i 或其突变体,优选Cas12i1,Cas12i2,Cas12iVar1,Cas12iVar2, Cas12iVar3)产生的可检测信号。在某些情况下,目标DNA是病毒DNA(例如,巴氏病毒、肝炎病毒、疱疹病毒、腺病毒、痘病毒、细小病毒等)。
还提供了用于切割单链DNA的组合物和方法(ssDNAs)。在某些情况下,这种方法包括接触一组核酸,其中,所述群体包括一个靶 DNA和多个非靶向SSDNA,其中:(i)Cas12i(Cas12i1、Cas12i2、 Cas12iVar1、Cas12iVar2、Cas12iVar3);和(ii)一个向导RNA(包括与V型CRISPR/Cas效应蛋白结合的区域,以及与靶DNA杂交的向导序列),其中Cas12i(Cas12i1,Cas12i2,Cas12iVar1,Cas12iVar2, Cas12iVar3)蛋白质切割所述多个非靶向ssdna。在某些情况下,接触是在诸如真核细胞、植物细胞、哺乳动物细胞等的细胞内(例如,体外、体内)。
本发明还提供了一种装置,其特征在于包含一个或多个基于上述 Cas12i核酸检测方法的核心检测单元,优选包含大于两个、大于三个、大于四个所述核心检测单元。
本发明进一步提供一种装置,其特征在于同时包含基于上述Cas12i核酸检测方法的检测单元,以及基于其他CRISPR Cas核酸检测方法的检测单元,所述其他CRISPR Cas核酸检测方法选自Cas9、 Cas13、除Cas12i之外的Cas12,中的一种或多种的突变体,进一步优选Cas12b或其突变体。
所述装置优选为检测平台,进一步优选为便携型装置,包括但不限于可穿戴装置、检测试剂盒。
上述核酸检测方法以及装置,通过对向导RNA的设计,实现对一种或多种人类健康的检测和诊断。适用于的多种情形,包括例如病毒检测、菌株分型、灵敏基因分型和疾病相关的检测。
所述疾病可以是癌症、自身免疫疾病、由病毒、细菌、真菌、原生动物或寄生虫引起的感染。包括但不限于:疟疾检测和监测、生物标志检测、肿瘤检测、SNP检测和基因分型、表观遗传修饰的检测、产前筛选、癌症和癌症抗药性检测、免疫疗法应用、检测核酸标记。
对于由病毒引起的感染,其中所述病毒感染可以由DNA病毒引起,所述DNA病毒包含但不限于以下:肌病毒科、短尾病毒科、长尾病毒科、异疱疹病毒科、疱疹病毒科(包括人疱疹病毒和水痘带状疱疹病毒)、马洛疱疹病毒科、脂毛病毒科、小杆状病毒科、腺病毒科、瓶状病毒科、囊泡病毒科、非洲猪瘟病毒科(包括非洲猪瘟病毒)、杆状病毒科、西坎达病毒科、棒状病毒科、覆盖噬菌体科、小纺锤形噬菌体科、球状病毒科、滴状病毒科、唾液腺肥大病毒科、虹彩病毒科、马赛病毒科、拟菌病毒科、裸病毒科、线头病毒科、潘多拉病毒科、乳头瘤病毒科、藻类DNA病毒科、芽生噬菌体科、多DNA病毒、多瘤病毒科(包括猿猴病毒40、JC病毒、BK病毒)、痘病毒科(包括牛痘和天花)、球脂状病毒科、复层噬菌体科、图里病毒科、甲藻DNA 病毒、盐末端蛋白病毒、瑞兹病毒。其中所述病毒感染由双链RNA 病毒、正义RNA病毒、反义RNA病毒、逆转录病毒或它们的组合引起。所述病毒感染由冠状病毒科病毒、小RNA病毒科病毒、杯状病毒科病毒、黄病毒科病毒、披膜病毒科病毒、玻那病毒科、丝状病毒科、副粘病毒科、肺泡病毒科、弹状病毒科、沙粒病毒科、布尼亚病毒科、正粘病毒科或丁型病毒引起。所述病毒感染由冠状病毒、SARS、 SARS-CoV-2、脊髓灰质炎病毒、鼻病毒、甲型肝炎、诺瓦克病毒、黄热病病毒、西尼罗河病毒、丙型肝炎病毒、登革热病毒、寨卡病毒、风疹病毒、罗斯河病毒、辛德毕斯病毒、基孔肯雅病毒、博尔纳病病毒、埃博拉病毒、马尔堡病毒、麻疹病毒、腮腺炎病毒、尼帕病毒、亨德拉病毒、新城疫病毒、人呼吸道合胞病毒、狂犬病病毒、拉沙病毒、汉坦病毒、克里米亚-刚果出血热病毒、流感或丁型肝炎病毒引起。
其中所述病毒感染也可由登革热病毒引起。
对于由细菌引起的感染,其中引起所述细菌感染的细菌包含但不限于以下类别:不动杆菌属某种、放线杆菌属某种、放线菌目某种、放线菌属某种、气球菌属某种、气单胞菌属某种、红孢子虫属某种、产碱杆菌属某种、芽孢杆菌属某种、拟杆菌属某种、巴尔通体属某种、双歧杆菌属某种、博德特氏菌属某种、包柔氏螺旋体属某种、布鲁氏菌属某种、伯克氏菌属某种、弯曲杆菌属某种、嗜二氧化碳噬细胞菌属某种、衣原体属某种、柠檬酸杆菌属某种、柯克斯体属某种、棒状杆菌属某种、梭菌属某种、艾肯菌属某种、肠杆菌属某种、埃希氏菌属某种、肠球菌属某种、埃立克体属某种、表皮癣菌属某种、丹毒丝菌属某种、真杆菌属某种、弗朗西斯菌属某种、梭杆菌属某种、加德纳菌属某种、孪生球菌属某种、嗜血杆菌属某种、螺杆菌属某种、金氏菌属某种、克雷伯菌属某种、乳杆菌属某种、乳球菌属某种、李斯特菌属某种、钩端螺旋体属某种、军团菌属某种、钩端螺旋体属某种、明串珠菌属某种、曼氏杆菌属某种、小孢子菌属某种、微球菌属某种、莫拉菌属某种、摩根氏菌属某种、动弯杆菌属某种、微球菌属某种、分枝杆菌属某种、支原体属某种、诺卡氏菌属某种、奈瑟氏菌属某种、巴斯德菌属某种、片球菌属某种、消化链球菌属某种、糠疹癣菌属某种、邻单胞菌属某种、普雷沃菌属某种、卟啉单胞菌属某种、变形杆菌属某种、普罗威登斯菌属某种、假单胞菌属某种、丙酸杆菌属某种、红球菌属某种、立克次体属某种、红球菌属某种、沙雷氏菌属某种、寡养单胞菌属某种、沙门氏菌属某种、沙雷氏菌属某种、志贺氏菌属某种、葡萄球菌属某种、链球菌属某种、螺菌属某种、链杆菌属某种、密螺旋体属某种、养障体属某种、毛癣菌属某种、脲原体属某种、韦荣氏球菌属某种、弧菌属某种、耶尔森菌属某种、黄单胞菌属某种,或它们的组合。
对于由真菌引起的感染,其中所述真菌包含但不限于以下类别:曲霉属、芽生菌属、念珠菌属、球孢子菌属、新型隐球菌、格特隐球菌、某种组织胞浆菌属某种(如荚膜组织胞浆菌)、肺孢子菌属某种(如耶氏肺孢子菌)、葡萄穗霉属(如纸葡萄穗霉)、毛霉菌病、孢子丝菌属、真菌性眼睛感染癣、突脐蠕孢属、枝孢属、地霉属、酵母属、汉逊酵母属某种、假丝酵母属某种、克鲁维酵母属某种、德巴利酵母属某种、毕赤酵母属某种、毕青霉菌属某种、枝孢属某种、丝衣霉属某种,或它们的组合。
对于由原生动物引起的感染,其中所述原生动物包含但不限于以下类别:眼虫门、异叶足纲、双滴虫目、变形虫界、芽囊原虫属、顶复亚门,或它们的组合。
对于由寄生虫引起的感染,其中所述寄生虫包含但不限于以下类别:克氏锥虫(恰加斯病)、布氏冈比亚锥虫、布氏罗得西亚锥虫、巴西利什曼原虫、婴儿利什曼原虫、墨西哥利什曼原虫、硕大利什曼原虫、热带利什曼原虫、杜氏利什曼原虫、福氏耐格里变形虫、肠贾第虫(兰伯氏贾第虫、十二指肠贾第虫)、卡氏棘阿米巴虫、巴氏阿米巴原虫、溶组织内阿米巴、人芽囊原虫、田鼠巴贝虫、微小隐孢子虫、卡晏环孢子虫、恶性疟原虫、间日疟原虫、卵形疟原虫、三日疟原虫和刚地弓形虫,或它们的组合。
在某些情况下(例如,当与向导RNA和Cas12i(Cas12i1,Cas12i2, Cas12iVar1,Cas12iVar2,Cas12iVar3),则样品接触时间不超过2小时 (例如,1.5小时或更短、1小时或更短、40分钟或更短,30分钟或以下,20分钟或以下,10分钟或以下,或5分钟或以下,或1分钟或在测量步骤之前。例如,在某些情况下,与样品接触40测量步骤开始前不超过分钟。在某些情况下,样品接触20分钟或在测量步骤之前。在某些情况下,样品接触时间不超过10分钟在测量步骤之前。在某些情况下,在测量步骤。在某些情况下,在测量步骤。在某些情况下,样品的接触时间为50秒到60秒到测量步骤。在某些情况下,在测量步骤之前,样品接触时间为40秒到50秒。在某些情况下,在测量步骤之前,样品接触30秒到40秒。在某些情况下,在测量步骤之前,样品接触20 秒到30秒。在某些情况下,在测量步骤之前,样品接触10秒到20秒。
在某些情况下,核酸检测可在以下选择的温度下进行:25℃,26℃, 27℃,28℃,29℃,30℃,31℃,32℃,33℃,34℃,35℃,36℃,37℃, 38℃,39℃,40℃,41℃,42℃,43℃,44℃,45℃,46℃,47℃,48℃, 49℃,50℃,51℃,52℃,53℃,54℃,55℃,56℃,57℃,58℃,59℃, 60℃,61℃,62℃,63℃,64℃,65℃,66℃,67℃,68℃,69℃,70℃, 71℃,72℃,73℃,74℃,75℃.
II.核酸检测体系和零件
Cas12i蛋白和其突变体
在某些情况下,V型CRISPR/Cas12i效应子与Cas12i包含具有 20%或更高的氨基酸序列同一性(例如30%或更高,40%或更高, 50%或以上,60%或以上,70%或以上,80%或以上,85%或更高, 90%或更高,95%或更高,97%或更高,98%或更高,99%或更高或100%序列同一性)。在某些情况下,V型CRISPR/Cas效应子蛋白质与Cas12i蛋白包含具有50%的氨基酸序列或更高的序列同一性(例如60%或更高,70%或更高,80%或以上,85%或以上,90%或以上,95%或以上,97%或更高,98%或更高,99%或更高,或100%序列同一性)。在某些情况下,V型CRISPR/Cas效应蛋白与Cas12i 蛋白包含氨基酸序列80%或更高的序列同一性(例如85%或更高, 90%或更高,95%或更高,97%或更高,98%或更高,99%或更多,或100%序列同一性)。在某些情况下V型CRISPR/Cas效应蛋白与Cas12i包含具有90%或更高序列同一性的氨基酸序列(例如,95%或以上,97%或以上,98%或以上,99%或以上或100%序列同一性。
在某些情况下,V型CRISPR/Cas12i1效应子与Cas12i1包含具有20%或更高的氨基酸序列同一性(例如30%或更高,40%或更高, 50%或以上,60%或以上,70%或以上,80%或以上,85%或更高, 90%或更高,95%或更高,97%或更高,98%或更高,99%或更高或100%序列同一性)。在某些情况下,V型CRISPR/Cas效应子蛋白质与Cas12i1蛋白包含具有50%的氨基酸序列或更高的序列同一性 (例如60%或更高,70%或更高,80%或以上,85%或以上,90%或以上,95%或以上,97%或更高,98%或更高,99%或更高,或 100%序列同一性)。在某些情况下,V型CRISPR/Cas效应蛋白与 Cas12i1蛋白包含氨基酸序列80%或更高的序列同一性(例如85%或更高,90%或更高,95%或更高,97%或更高,98%或更高,99%或更多,或100%序列同一性)。在某些情况下V型CRISPR/Cas效应蛋白与Cas12i1包含具有90%或更高序列同一性的氨基酸序列(例如,95%或以上,97%或以上,98%或以上,99%或以上,或100%序列同一性。在某些情况下,V型CRISPR/Cas效应子蛋白包含 Cas12i1氨基酸序列如SEQID No:1中所示。
在某些情况下,V型CRISPR/Cas12i效应子与Cas12i2包含具有 20%或更高的氨基酸序列同一性(例如30%或更高,40%或更高, 50%或以上,60%或以上,70%或以上,80%或以上,85%或更高, 90%或更高,95%或更高,97%或更高,98%或更高,99%或更高或100%序列同一性)。在某些情况下,V型CRISPR/Cas效应子蛋白质与Cas12i2蛋白包含具有50%的氨基酸序列或更高的序列同一性 (例如60%或更高,70%或更高,80%或以上,85%或以上,90%或以上,95%或以上,97%或更高,98%或更高,99%或更高,或 100%序列同一性)。在某些情况下,V型CRISPR/Cas效应蛋白与 Cas12i2蛋白包含氨基酸序列80%或更高的序列同一性(例如85%或更高,90%或更高,95%或更高,97%或更高,98%或更高,99%或更多,或100%序列同一性)。在某些情况下V型CRISPR/Cas效应蛋白与Cas12i2包含具有90%或更高序列同一性的氨基酸序列(例如,95%或以上,97%或以上,98%或以上,99%或以上,或100%序列同一性。在某些情况下,V型CRISPR/Cas效应子蛋白包含 Cas12i2氨基酸序列如SEQ ID No 2中所示。
在某些情况下,V型CRISPR/Cas12i效应子与Cas12i Var1包含具有20%或更高的氨基酸序列同一性(例如30%或更高,40%或更高,50%或以上,60%或以上,70%或以上,80%或以上,85%或更高,90%或更高,95%或更高,97%或更高,98%或更高,99%或更高或100%序列同一性)。在某些情况下,V型CRISPR/Cas效应子蛋白质与Cas12iVar1蛋白包含具有50%的氨基酸序列或更高的序列同一性(例如60%或更高,70%或更高,80%或以上,85%或以上, 90%或以上,95%或以上,97%或更高,98%或更高,99%或更高,或100%序列同一性)。在某些情况下,V型CRISPR/Cas效应蛋白与Cas12iVar1蛋白包含氨基酸序列80%或更高的序列同一性(例如 85%或更高,90%或更高,95%或更高,97%或更高,98%或更高, 99%或更多,或100%序列同一性)。在某些情况下V型CRISPR/Cas 效应蛋白与Cas12iVar1包含具有90%或更高序列同一性的氨基酸序列(例如,95%或以上,97%或以上,98%或以上,99%或以上,或 100%序列同一性。在某些情况下,V型CRISPR/Cas效应子蛋白包含Cas12iVar1氨基酸序列如SEQ ID No:3中所示。
在某些情况下,V型CRISPR/Cas12i效应子与Cas12iVar2包含具有20%或更高的氨基酸序列同一性(例如30%或更高,40%或更高,50%或以上,60%或以上,70%或以上,80%或以上,85%或更高,90%或更高,95%或更高,97%或更高,98%或更高,99%或更高或100%序列同一性)。在某些情况下,V型CRISPR/Cas效应子蛋白质与Cas12iVar2蛋白包含具有50%的氨基酸序列或更高的序列同一性(例如60%或更高,70%或更高,80%或以上,85%或以上, 90%或以上,95%或以上,97%或更高,98%或更高,99%或更高,或100%序列同一性)。在某些情况下,V型CRISPR/Cas效应蛋白与Cas12iVar2蛋白包含氨基酸序列80%或更高的序列同一性(例如 85%或更高,90%或更高,95%或更高,97%或更高,98%或更高, 99%或更多,或100%序列同一性)。在某些情况下V型CRISPR/Cas 效应蛋白与Cas12iVar2包含具有90%或更高序列同一性的氨基酸序列(例如,95%或以上,97%或以上,98%或以上,99%或以上,或 100%序列同一性。在某些情况下,V型CRISPR/Cas效应子蛋白包含Cas12iVar2氨基酸序列如SEQ ID NO:4中所示。
在某些情况下,V型CRISPR/Cas12i效应子与Cas12i2Var3包含具有20%或更高的氨基酸序列同一性(例如30%或更高,40%或更高,50%或以上,60%或以上,70%或以上,80%或以上,85%或更高,90%或更高,95%或更高,97%或更高,98%或更高,99%或更高或100%序列同一性)。在某些情况下,V型CRISPR/Cas效应子蛋白质与Cas12iVar3蛋白包含具有50%的氨基酸序列或更高的序列同一性(例如60%或更高,70%或更高,80%或以上,85%或以上,90%或以上,95%或以上,97%或更高,98%或更高,99%或更高,或100%序列同一性)。在某些情况下,V型CRISPR/Cas效应蛋白与Cas12iVar3蛋白包含氨基酸序列80%或更高的序列同一性(例如85%或更高,90%或更高,95%或更高,97%或更高,98%或更高,99%或更多,或100%序列同一性)。在某些情况下V型CRISPR /Cas效应蛋白与Cas12iVar3包含具有90%或更高序列同一性的氨基酸序列(例如,95%或以上,97%或以上,98%或以上,99%或以上,或100%序列同一性。在某些情况下,V型CRISPR/Cas效应子蛋白包含Cas12iVar3氨基酸序列如SEQ ID No:5中所示。
PAM V型CRISPR/Cas效应蛋白结合于靶向DNA的特定序列—DNA靶向性RNA和靶DNA的互补区域。与许多CRISPR/Cas内切酶相似,特异性结合(和/或切割)的位点由两个因素决定:(i) 向导RNA和靶DNA之间的碱基对互补性;和(ii)靶DNA中包含的一个短的基序(PAM)序列。
在某些情况下,用于Cas12i或其突变体,优选Cas12i1,Cas12i2, Cas12iVar1,Cas12iVar2,Cas12iVar3,效应蛋白的PAM紧接靶序列的5'端(例如,靶DNA的非互补链或互补链与向导RNA杂交而非互补链不与向导RNA杂交并且是非互补链的反向互补)。一些情况下,(例如,此处所述的Cas12i或其突变体,优选Cas12i1, Cas12i2,Cas12iVar1,Cas12iVar2,Cas12iVar3),优选的PAM序列为5'-TTN-3'。在某些情况下,PAM序列为5'-TTTN-3。
在某些情况下,不同的V型CRISPR/Cas效应蛋白(如来自不同物种的V型CRISPR/Cas效应蛋白在不同应用场景下可能更有优势(例如,不同V型CRISPR/Cas效应蛋白具有不同特性)。不同物种来源的V型CRISPR/Cas效应蛋白可能需要靶DNA中包含有不同的PAM序列。因此,对于特定的CRISPR/Cas12i,PAM序列的需求可能与上述5'-TTN-3'或5'-TTTN-3'序列不同。各种方法(包括silico 方法和/或wet lab方法)确定合适的PAM序列是本领域已知并且常规方法,也可以使用任何便捷的方法。
向导RNA
可与V型CRISPR/Cas12i效应蛋白形成核糖核蛋白复合物 (RNP)并将复合物靶向到靶向DNA中特定的靶序列的核酸分子(如天然存在的crRNA)在这里被称为“向导RNA”。可以理解为,在某些情况下,杂交的DNA/RNA复合物可以
一个向导RNA包含DNA碱基,但“向导RNA”的术语仍被使用以包括这种杂交分子在内。常见的向导RNA包括与靶DNA中靶序列杂交的向导序列(spacer)和一个恒定序列(constant region)。恒定序列可被认为是蛋白结合区。在一些情况下,例如,对于Cas12i来说,恒定序列为向导序列的5’端。
向导序列
向导序列与靶DNA中的靶序列互补(与之杂交)。在一些情况下,向导序列的长度为15-28个核苷酸(nt)(如,15-26,15-24,15-22, 15-20,15-18,16-28,16-26,16-24,16-22,16-20,16-18,17-26, 17-24,17-22,17-20,17-18,18-26,18-24,或18-22nt)。在一些情况下,向导序列的长度为18-24个核苷酸。在一些情况下,向导序列的长度至少为15nt(如,至少16,18,20或22nt)。在一些情况下,向导序列至少有17nt。在一些情况下,向导序列至少有18nt。在一些情况下,向导序列至少有20nt。
在一些情况下,向导序列与靶DNA的靶序列具有80%或更高(例如85%或更高,90%或更高,95%或更高或100%)的互补性。在某些情况下,向导序列与靶DNA的靶序列100%互补。在某些情况下,靶DNA中至少包含15个核苷与向导RNA的序列互补。
“针对靶核酸分子的靶序列的crRNA”指的是crRNA能够特异性识别所述靶序列。例如,在一些实施方案中(靶核酸分子是双链 DNA),所述crRNA包含能够与靶序列的互补序列特异性DNA-RNA 杂交的间隔区序列(spacer)。在一些实施方案中,所述Cas12i1的 crRNA由以下的核酸序列编码: 5’-ATTTTTGTGCCCATCGTTGGCACNx-3’。在一些实施方案中,所述Cas12i2的crRNA由以下的核酸序列编码: 5’-AGAAATCCGTCTTTCATTGACGGNx-3’,其中Nx表示X个连续的核苷酸组成的核苷酸序列(spacer序列),N各自独立地选自A、 G、C和T;X为18≤X≤35的整数。优选地,X=20。在一些实施方案中,序列Nx是能够与靶序列的互补序列特异性杂交的间隔区序列(靶核酸分子是双链DNA)。
所述crRNA中除Nx之外的序列为crRNA的支架(scaffold)序列。
在本发明的一些实施方案中,所述向导RNA是crRNA。在一些实施方案中,所述crRNA由5’端的支架序列和3’端的间隔区序列组成。间隔区序列可以与靶序列或靶序列的互补序列特异性杂交。间隔区序列通常长度为18至35个核苷酸,优选20个核苷酸。在一些实施方案中,所述crRNA可以通过体外转录产生。在一些实施方案中,所述crRNA通过化学合成产生,其中一些在5’端和3’端添加了化学修饰,例如在crRNA 5’端和3’端的前3个碱基(这些碱基可以独立地选自A、U、C、G)引入甲氧基修饰和硫代修饰。合适的RNA 修饰包括但不限于甲氧基修饰和硫代修饰。
恒定序列(Constant Region)
可用于CRISPR/Cas12i(Cas12i1,Cas12i2,Cas12iVar1,Cas12i Var2,Cas12iVar3)的向导RNA序列的恒定序列的示例如本文所示。
在一些情况下,向导RNA包括与crRNA重复序列 5’-AGAAATCCGTCTTTCATTGACGGNx-3’或者其他序列具有70% 或更多(例如80%或更高,85%或更高,90%或更高,95%或更高, 98%或更高,99%或更高,或100%)同源性的核苷酸序列。在某些 情况下,向导RNA包括与本文中所示的crRNA重复序列中任一序列 具有90%或更多(例如95%或更高,98%或更高,99%或更高,或 100%)同源性的核苷酸序列。在某些情况下,向导RNA包括如本文 所示的crRNA核苷酸序列。
在某些情况下,向导RNA包括一个双链RNA复合体(dsRNA duplex)。在某些情况下,向导RNA包括长度为2至12bp(例如2 至10bp,2至8bp,2至6bp,2至5bp,2到4bp,3到12bp,3到10bp,3到8bp,3到6bp,3至5bp,3至4bp,4至12bp,4 至10bp,4至8bp,4至6bp或4至5bp)的dsRNA双链体。在某些情况下,向导RNA的长度为2bp或更多(例如3或更多, 4个或更多,5个或更多,6个或更多,或7个或更多bp的长度)。在某些情况下,向导RNA包含一个比相应野生的dsRNA双链体更短的dsRNA双链体。
在某些情况下,指导RNA的恒定序列是15个或更多核苷酸(nt) 的长度(例如18个或更多,20个或更多,21或更多,22或更多, 23或更多,24或更多,25或更多,26或更多,27或更多,28或更多,29或更多,30或更多,31或更多nt,32或更多,33或更多, 34或长度大于或等于35nt)。在某些情况下,向导RNA的恒定序列长度为18nt或更多。
在某些情况下,向导RNA的恒定序列长度范围为12到100nt(例如,从12至90、12至80、12至70、12至60、12至50、12至40、 15至100、15至90、15至80、15至70、15至60、15至50、15至 40、20至100、20至90、20至80、20至70、20至60、20至50、 20至40、25至100、25至90、25至80、25至70、25至60、25至 50、25至40、28至100、28至90、28至80、28至70、28至60、 28至50、28至40、29至100、29至90、29至80,29至70、29至 60、29至50或29至40nt)。在某些情况下,向导RNA的恒定序列的长度在一定范围内从28到100nt。在某些情况下,向导RNA的区域为向导序列5'端,长度在从28到40nt的范围内。
在某些情况下,向导RNA的恒定序列较对应的野生型向导RNA 的区域被截短。在在某些情况下,向导RNA的恒定序列较对应的野生型向导RNA的区域被延长(更长)。在某些情况下,向导RNA 的长度为30个或更多核苷酸(例如34或以上,40或以上,45或以上,50或以上,55或以上,60或更多,65或更多,70或更多或80 或更多)。在某些情况下,向导RNA的长度在35nt或更长。
探针修饰
在某些情况下,一个被标记的探测ssDNA(和/或向导RNA)包含一种或多种修饰,例如,一种碱基修饰,一种骨架修饰,一种糖基修饰等,以为核酸提供新的或增强功能(例如改进稳定性)。众所周知,核苷是一种糖基结合物。基础的核苷部分通常是杂环碱基。这种杂环碱基的两种最常见的类别是嘌呤和嘧啶。核苷酸是核苷进一步通过共价键与糖部分连接。对于那些包括戊呋喃糖基糖的核苷,磷酸基团可与糖基的2',3'或5'羟基连接。在形成寡核苷酸时,磷酸基团将相邻的核苷共价连接形成线性聚合物。反过来,该线性聚合化合物的各个末端可以进一步连接从而形成环状化合物。但线性聚合物合物通常是合适的。另外,线性聚合物可能具有内部核苷酸碱基互补性,因此可能会折叠产生完全或部分双链的化合物。寡核苷酸内,磷酸基通常被认为是寡核苷酸核苷间的骨架结构。通常情况下RNA和DNA 的连接骨架是3'-5'磷酸二酯键。
适当修饰的例子包括修饰的核酸骨架和非天然的核苷复合物。具有修饰骨架的核酸包括在主链上保留有磷原子的那些和在骨架上没有磷原子的那些。适当修饰的核苷酸骨架具有一个磷原子,因此包括,如,硫代磷酸酯,手性硫代磷酸酯,磷酸二硫代酸酯,磷酸三酯,氨基烷基磷酸三酯,甲基和其他烷基膦酸酯,包括3'-亚烷基膦酸酯,5'-亚烷基膦酸酯和手性磷酸酯酸酯,次膦酸酯,包括3'-氨基的氨基磷酸酯;氨基磷酸酯和氨基烷基磷酰胺酸酯苯二酰胺,硫代膦酸酯,硫代烷基膦酸酯,硫代烷基磷酸三酸酯,具有正常3'-5'键的硒磷酸酯和硼酸磷酸盐,它们的2'-5'链接类似物,以及具有反向极性的其中一个或多个核苷酸间键为3'至3',5'至5'或2'至2'连接。合适的具有反极性的寡核苷酸包含一个3'到3'的单键。如各种盐(例如钾或钠),混合盐和游离酸形式也包括在内。
在某些情况下,带有标记的探测ssDNA(和/或向导RNA)包含一种或多种硫代磷酸酯和/或杂原子核苷间键,特别是-CH2-NH-0-CH2-, -CH2-N(CH3)-0-CH2–(亚甲基(甲基亚氨基)或MMI主链),-CH2-0-N(CH3)-CH2-,-CH2-N(CH3)-N(CH3)-CH2-和 O-N(CH3)-CH2-CH2-(其中磷酸二酯核苷酸间键表示为-0P(=O)(OH) -0-CH2-)。MMI型核苷连接被美国专利No.5,489,677披露。适当的的酰胺核苷间键被美国专利No.5,602,240披露。
具有吗啉代骨架结构的核酸(如美国专利5,034,506)也是适合的。例如,在一些情况下,探测ssDNA(和/或向导RNA)包含6个组分的吗啉环代替核糖环。在一些情况下,二氨基磷酰胺或其他非磷酸二酯核苷键取代了磷酸二酯键。
不包含磷原子的具有被合适修饰的多核苷酸骨架因而具有由短链烷基或环烷基核苷键,混合杂原子与烷基或环烷基核苷间键,或一个或多个短链杂原子或杂环间核苷键的骨架。这些包括具有吗啉代键的那些(部分由来自核苷的糖部分形成);硅氧烷骨架;硫化物,亚砜和砜骨架;甲酰和硫甲乙酰骨架;亚甲基形式十六烷基和硫甲酰基骨架;核糖乙酰骨架;含烯烃的骨架;氨基磺酸盐骨架;甲基乙烯亚胺基和甲基肼基骨架;磺酸盐和磺胺骨架;酰胺骨架;以及其他混有N,O, S和CH2的组成部分的骨架。
模拟物
标记的检测ssDNA(和/或向导RNA)可以是核酸模拟物。术语“模拟”指应用于多核苷酸意在包括多核其中仅呋喃糖环或两个呋喃糖的核苷酸环和核苷酸间键被取代为非呋喃糖基团,仅呋喃糖环的取代在本领域中也称为糖代品。杂环碱基部分或修饰的杂环碱基被保留以与正确的靶核苷酸发生杂交。一种这样的核苷酸模拟物已被证明具有出色杂交效果,被称为肽核酸(PNA)。在PNA中,多核苷酸的糖骨架被含酰胺的骨架替代,特别是氨基乙基甘氨酸主链。核苷酸被保留并且直接或间接与骨架中酰胺部分的氮杂氮原子结合。
已经报道了一种多核苷酸模拟物—肽核酸(PNA),具有出色的杂交特性。PNA化合物的骨架是两个或多个连接的氨基乙基甘氨酸单元,这赋予PNA一种含酰胺的骨架。杂环碱基部分直接或间接与骨架中酰胺部分氮杂氮原子结合。代表性的描述PNA复合物准备过程的美国专利包括但不限于美国专利5,539,082;5,714,331;和5,719,262。
另一类已被研究的多核苷酸模拟物基于连接的带有连接于吗啉代环上的杂环碱基的吗啉代单元(吗啉代核酸)。许多在吗啉代核酸中连接吗啉单体的连接组分已被报道。一类连接组已被选作加上一个非离子型的寡聚化合物。基于非离子吗啉代的寡聚化合物较少可能与细胞中的蛋白发生不良相互作用。基于吗啉代多核苷酸是寡核苷酸的非离子模拟物,不太可能与细胞蛋白发生不良的相互作用(Dwaine A. Braasch and David R.Corey,Biochemistry,2002,41(14),4503-4510)。基于吗啉代的多核苷酸披露于美国专利No.5,034,506。许多吗啉代类的多核苷酸化合物已被制备,它们具有各种不同的连接基团来连接单分子亚基。
另一类多核苷酸模拟物为环己烯基核酸(CENA)。通常存在于DNA /RNA分子中的呋喃糖环被环己烯基环取代。被CENA DMT保护的亚磷酰胺单体已被制备并用于依照经典亚磷酰胺化学方法合成低聚化合物。在特定位置被CeNA修饰的寡聚化合物和寡核苷酸已被制备和研究(见Wang et al.,J.Am.Chem.Soc.,2000,122,8595-8602)。通常情况下,在DNA链中引入CeNA单元能够提升DNA/RNA杂交物的稳定性。CeNA寡腺苷酸与RNA和DNA形成的复合物与天然复合物相较更为稳定。NMR和将CeNA结构引入天然的核酸结构由 NMR和环形二色性所证明易于构象适应。
进一步的修改包括锁定核苷酸(LNAs,其中)2'-羟基连接至糖环的 4'碳原子从而形成一个2’-C,4'-C-甲醛连接键,由此一个双环糖部分。连接处可以是亚甲基(-CH2-),桥接2'氧原子和4'碳原子的基团,其中n为1或2(Singh et al.,Chem.Commun.,1998,4,455-456)。 LNA和LNA类似物与互补的DNA和RNA显示出非常高的二聚体热稳定性(Tm=+3至+10℃),对3'-核酸外降解稳定性及良好的溶解性。含有LNA的有效且无毒性的寡核苷酸已被描述(Wahlestedt et al., Proc.Natl.Acad.Sci.U.S.A.,2000,97,5633-5638)。
LNA单体腺嘌呤,胞嘧啶,鸟嘌呤,5-甲基胞嘧啶,胸腺嘧啶和尿嘧啶的合成和制备,以及它们的低聚反应和核酸识别特性都已被描述 (Koshkin et al.,Tetrahedron,1998,54,3607-3630)。LNA及其制备也被描述于WO98/39352和WO99/14226。
标记的探测ssDNA(和/或向导RNA)也可以包括一个或多个取代的糖部分。合适的多核苷酸包含选自以下的糖取代基:OH;F;O,S- 或N-烷基;O-,S-或N-烯基;O,S-或N-炔基;或O-烷基-O-烷基,其中烷基,烯基和炔基可以被取代或未取代的C1至C10烷基或C2 至C10烯基和炔基。部分合适的有O((CH2)nO)mCH3,O(CH2)nNH2, O(CH2)nCH3,O(CH2)nONH2,和O(CH2)nON((CH2)nCH3)2,其中n和m 为1至10左右。其他合适的多核苷酸包含选自以下的糖取代基:C1 至C10低级烷基,取代的低级烷基,烯基,炔基,烷芳基,芳烷基, O-烷芳基或O-芳烷基,SH,SCH3,OCN,Cl,Br,CN,CF 3,OCF 3,SOCH3,SO2CH3,ONO2,NO2,N3,NH2,杂环烷基,杂环烷芳基,氨基烷基氨基,聚烷基氨基,取代的甲硅烷基,RNA切割基团,报告基团,插层基,用于改善寡核苷酸的药代动力学性质的基团,或用于改善寡核苷酸和具有类似性质的其他取代基的药效性质的基团。合适的修饰包括2'-甲氧基乙氧基(2'-0-CH2CH2OCH3,也称为2'-O- (2-甲氧基乙基)或2'-MOE)(Martin et al.,Helv.Chim.Acta,1995, 78,486-504)。另一合适的修饰包括2’-二甲基氨基氧基乙氧基,如 O(CH2)2ON(CH3)2基团,也称为2'-DMAOE,和2'-二甲基氨基乙氧基乙氧基(本领域中也称为2'-O-二甲基-氨基乙氧基-乙基或 2'-DMAEOE),即2'-O-CH2-O-CH2-N(CH3)2。
其他合适的糖取代基包括甲氧基(-O-CH3),氨基丙氧基 (-OCH2CH2CH2NH2),烯丙基(-CH2-CH=CH2),-O-烯丙基 (-O-CH2CH=CH2)和氟(F)。2′-糖取代基可以位于阿拉伯糖(上) 位置或核糖(下)位置。合适的2'-阿拉伯糖基修饰是2'-F。还可以在寡聚化合物的其他位置,特别是在3'末端核苷上或2'-5'连接的寡核苷酸中糖的3'位置和5'末端核苷酸的5'位置进行类似的修饰。寡聚化合物还可具有糖模拟物,例如环丁基部分代替戊呋喃糖基糖。
信号测量
在某些情况下,主题方法包括测量步骤(例如,测量Cas12i(Cas12i1, Cas12i2,Cas12iVar1,Cas12iVar2,Cas12iVar3)的可检测信号。因为 Cas12i(Cas12i1,Cas12i2,Cas12iVar1,Cas12iVar2,Cas12iVar3)一旦被激活,就会切割非靶向的ssDNA,这发生在向导RNA在Cas12i (Cas12i1,Cas12i2,Cas12iVar1,Cas12iVar2,Cas12iVar3)存在下与靶DNA杂交,可检测到的信号可以是任何当ssDNA被切割时产生的信号。例如,在某些情况下测量可以包括一个或多个:基于金纳米粒子的检测(例如,Xu et al.,Angew Chem Int Ed,2007;46(19): 3468-70;和Xia et al.,Proc Natl Acad Sci U S A.2010年6月15日;107(24):10837-41),荧光偏振,胶体相变/分散(例如,Baksh et al., Nature,2004年1月8日;427(6970):139-41),电化学检测,半导体传感(例如,Rothberg et al.,Nature,2011年7月20日;475(7356): 348-52;例如,人们可以通过将2'-3'环磷酸盐和无机磷酸盐释放到溶液中,使用磷酸酶在ssDNA裂解反应后产生pH值变化,并检测标记检测器ssDNA(更多详细信息,请参阅本文其他部分)。这种检测方法的读出可以是任何方便的读出。可能读数的示例包括但不限于:可检测荧光信号的测量量;凝胶上条带的目视分析(例如,代表裂解产物与未清洁基板的带),基于视觉或传感器的颜色存在或缺失检测(即颜色检测方法),以及电信号的存在或不存在(或定量分析)。
在某些情况下,测量可以是定量的,例如,在某种意义上检测到的信号可以用来确定样品中存在的靶DNA的数量。这个在某些情况下,测量可以是定性的,例如,在某种意义上可检测信号可以指示靶向 DNA(如病毒、SNP等)的存在与否。在在某些情况下,不存在可检测信号(例如,高于给定的阈值水平),除非靶向DNA(如病毒、SNP等)高于特定的阈值浓度。在在某些情况下,可以通过修改Cas12i (Cas12i1,Cas12i2,Cas12iVar1,Cas12iVar2,Cas12iVar3)的含量来滴定检测阈值、向导RNA、样品量和/或检测器ssDNA(如果使用)。因此,为了例如,如本领域普通技术人员所理解的,如果需要的话可以进一步设置多个控件,以便设置一个或多个反应,每个反应都设置为检测不同的阈值目标DNA的水平,因此这一系列反应可以用来确定样品中的靶DNA(例如,可以通过一系列反应来确定目标DNA以“至少X”的浓度存在于样品中。而不局限于本发明所描述的那些的组合物及其方法,应用/用途。该图描绘了样品的核酸被放大的实施例。在与Casl2蛋白接触之前,但相同的应用/用途(例如,SNP检测、癌症筛查、细菌感染检测、抗生素耐药性检测、病毒感染检测等)可应用于不包括扩增步骤的实施例。本发明的组合物和方法可用于检测任何DNA靶点。例如,任何将核酸材料整合到基因组中的病毒都可以被检测到,因为受试者样品可以包括细胞基因组DNA,而向导RNA 可以设计成检测整合的核苷酸序列。
在一些情况下,可以使用本发明的方法来量化样品发明中的目标 DNA(例如,包含目标DNA和多个目标DNA)。确定样品中目标DNA 的数量可以包括比较从从参考样品中的测试样品产生的可检测信号量与可检测信号量之比。确定样品中目标DNA的数量包括:测量可检测信号以产生测试测量;测量由参考样品产生的可检测信号,以产生参考测量值;以及将测试测量值与参考测量值进行比较,以确定样品中存在的目标DNA量。
例如,在某些情况下,本发明的一种确定样品中靶DNA的量包括:a) 接触样品(例如样品包含靶DNA和多个非靶DNA)和:(i)一个向导RNA与靶DNA杂交,(ii)Cas12i(Cas12i1,Cas12i2,Cas12iVar1, Cas12iVar2,Cas12iVar3),可切割存在于样品,和(iii)检测器ssDNA; b)测量Cas12i(Cas12i1,Cas12i2,Cas12iVar1,Cas12iVar2,Cas12iVar3) 介导的ssDNA裂解(例如,检测器ssDNA的裂解),产生测试测量; c)测量参考样品产生的可检测信号,以产生参考测量值;以及d)将试验测量值与参考测量值进行比较确定样品中存在的目标DNA量。作为另一示例,在某些情况下,本发明的一种用于确定样品中靶DNA 的量包括:a)接触样品(例如样品包含靶DNA和多个非靶DNA),具有:i)包含两个或多个导向RNAs的前体导向RNAarray,其中每一个具有不同的向导序列;(ii)Cas12i或其突变体,优选Cas12i1,Cas12i2,Cas12iVar1,Cas12iVar2,Cas12iVar3,将前体向导RNA阵列切割成单个的向导RNA,并切割样品的RNA;和(iii)检测器ssDNA; b)测量Cas12i或其突变体,优选Cas12i1,Cas12i2,Cas12iVar1, Cas12iVar2,Cas12iVar3,介导的ssDNA裂解(例如,裂解检测器ssDNA),产生测试测量值;c)测量两个或多个参考样品中每个样品产生的可检测信号,以生成两个或多个参考测量值;以及d)将测试测量值与参考测量值进行比较,以确定样品中存在的目标DNA量。
核酸扩增
在一些实施例中,被测物组合物和/或方法的灵敏度(例如,对于检测靶DNA(如病毒DNA或SNP,在细胞基因组DNA中的存在)可以通过结合检测和核酸扩增来提高。在某些情况下,样品中的核酸在与 Cas12i或其突变体,优选Cas12i1,Cas12i2,Cas12iVar1,Cas12iVar2, Cas12iVar3,效应器接触前被放大裂解ssDNA的Cas12i或其突变体,优选Cas12i1,Cas12i2,Cas12iVar1,Cas12iVar2,Cas12iVar3,(例如,核酸在样品可在接触Cas12i或其突变体,优选Cas12i1,Cas12i2, Cas12iVar1,Cas12iVar2,Cas12iVar3,效应蛋白之前开始。在某些情况下,样品中的核酸在与Cas12i或其突变体,优选Cas12i1,Cas12i2,Cas12iVar1,Cas12iVar2,Cas12iVar3,效应蛋白接触的同时被扩增。例如,在某些情况下,受试方法包括在将扩增的样品与V型 CRISPR/Cas效应蛋白(例如,Casl2蛋白)接触之前,对样品的核酸进行扩增(例如,通过使样品与扩增组分接触)。在某些情况下,受试方法包括在样品与V型CRISPR/Cas效应蛋白(例如Casl2蛋白)接触的同时(同时)接触扩增组分。如果同时添加所有组分(扩增组分和检测组分,如Cas12i或其突变体,优选Cas12i1,Cas12i2,Cas12iVar1, Cas12iVar2,Cas12iVar3,、向导RNA和检测器DNA),则Cas12i或其突变体,优选Cas12i1,Cas12i2,Cas12iVar1,Cas12iVar2, Cas12iVar3,的反式切割活性可能是,在核酸进行扩增的同时开始降解样品中的核酸。然而,即使是这样,与不进行放大的方法相比,同时放大和检测仍然可以提高灵敏度。
在某些情况下,特定序列(例如,病毒序列,包括感兴趣的SNP)从样品中扩增,例如使用引物。因此,可以对向导RNA杂交的序列进行扩增,以提高受试者检测方法的灵敏度——这可以实现对所需序列的有偏扩增,以增加样品中存在的感兴趣序列相对于样品中存在的其他序列的拷贝数。作为一个说明性示例,如果正在使用受试方法来确定给定样品是否包括特定病毒(或特定SNP),则可以扩增所需的病毒序列区域(或非病毒基因组序列),并且所扩增的区域将包括在病毒序列(或SNP)确实存在于样品中。
如前所述,在某些情况下,核酸被放大(例如,通过与扩增组分)在将扩增的核酸与V型病毒接触之前Cas12i或其突变体,优选Cas12i1, Cas12i2,Cas12iVar1,Cas12iVar2,Cas12iVar3。在某些情况下,放大倍数为10秒或更长时间(例如30秒或更长时间、45秒或更长时间、 1分钟或更长时间、2分钟或更长时间
在接触活性Cas12i或其突变体,优选Cas12i1,Cas12i2,Cas12iVar1,Cas12iVar2,Cas12iVar3,之前,超过3分钟或更长时间、4分钟或更长时间、5分钟或更长时间、7.5分钟或更长时间、10分钟或更长时间等)。在某些情况下,在与活性Cas12i或其突变体,优选Cas12i1, Cas12i2,Cas12iVar1,Cas12iVar2,Cas12iVar3接触之前,扩增发生2 分钟或更长时间(例如,3分钟或更长时间、4分钟或更长时间、5分钟或更长时间、7.5分钟或更长时间、10分钟或更长时间等)。在某些情况下,放大发生的时间范围为10秒到60分钟(例如,10秒到40 分钟,10秒到30分钟,10秒到20分钟,10秒到15分钟,10秒到10分钟, 10秒到5分钟,30秒到40分钟,30秒到30分钟,30秒到20分钟,30秒到15分钟,30秒到10分钟,30秒到5分钟,1分钟到40分钟,1分钟到 30分钟,1分钟到20分钟,1分钟到15分钟,1分钟到10分钟,1分钟到 5分钟,2分钟到40分钟,2分钟到30分钟,2分钟到20分钟,2分钟到15分钟,2分钟到10分钟,2分钟到5分钟,5分钟到40分钟,5分钟到 30分钟,5分钟到20分钟,5分钟到15分钟,或者5分钟到10分钟。在某些情况下,样品与放大元件同时接触Cas12i或其突变体,优选Cas12i1,Cas12i2,Cas12iVar1,Cas12iVar2,Cas12iVar3。在某些情况下,Cas12i或其突变体,优选Cas12i1,Cas12i2,Cas12iVar1, Cas12iVar2,Cas12iVar3或其他CRISPR体系的零件在接触时处于不活跃状态,并被激活一次样品中的核酸已被扩增。在某些情况下,Cas 效应蛋白或其他零件仍然保持活性,并且通过调节pH值、盐浓度或添加添加剂(例如但不限于有机化合物、盐、聚乙二醇聚合物)来调节缓冲条件以确保CRISPR组分和扩增组分之间的相容性,非聚乙二醇聚合物,洗涤剂,脂肪酸。
各种扩增方法和组件将为普通技术人员所熟知可以使用该技术和任何方便的方法(见Zanoli and Spoto,Biosensors(Basel).2013Mar;3(1): 18-43;Gill and Ghaemi,Nucleosides,Nucleotides,and Nucleic Acids, 2008,27:224-243;Craw andBalachandrana,Lab Chip,2012,12, 2469-2486)。核酸扩增可以包括聚合酶链式反应(PCR)、反转录 PCR(RT-PCR)、定量PCR(qPCR)、反向转录qPCR(RT-qPCR)、套式PCR、多重PCR、不对称PCR、触地PCR,随机引物PCR,半巢式PCR,聚合酶循环组装(PCA),菌落PCR,连接酶链反应(LCR)、数字PCR、甲基化特异性PCR(MSP)、共扩增低温变性PCR (COLD-PCR),等位基因特异性PCR,序列间特异性PCR,PCR (ISS-PCR)、全基因组扩增(WGA)、反向PCR和热不对称交错PCR (TAIL-PCR)。
在某些情况下,放大是等温放大。术语“等温扩增”指核酸(如DNA) 扩增的一种方法(例如,使用酶链式反应),可以使用一个温度孵化,从而避免了热循环的需要。等温扩增是核酸扩增的一种形式,在扩增反应中不依赖目标核酸的热变性,因此可能不需要多次快速的温度变化。因此,恒温核酸扩增方法可以在实验室环境内外进行。通过结合逆转录步骤,这些扩增方法可用于等温扩增RNA。
等温扩增方法的例子包括但不限于:环介导等温扩增(LAMP)、解旋酶依赖性扩增(HDA),重组酶聚合酶扩增(RPA)、重组酶介导核酸扩增(RAA)、链替代扩增技术(SDA)、依赖核酸序列的扩增技术(NASBA)、转录介导扩增(TMA)、切割酶扩增反应(NEAR)、滚圈扩增(RCA)、多重置换扩增(MDA)、网状分支扩增(RAM),环螺旋酶依赖性扩增(cHDA)、单引物等温扩增(SPIA)、信号介导RNA扩增技术(SMART)、再生式序列复制反应(3SR)、基因组指数扩增反应(GEAR)和等温多位移扩增(IMDA)。
在某些情况下,扩增是重组酶聚合酶扩增(RPA)重组酶聚合酶扩增 (RPA)使用两个相反的引物(很像PCR)并使用三种酶-重组酶、单链DNA结合蛋白(SSB)和链置换聚合酶。重组酶将双链DNA中具有同源序列的寡核苷酸引物配对,SSB与移位的DNA链结合以防止引物移位,链置换聚合酶在引物与靶DNA结合处开始DNA合成。在RPA 反应中加入逆转录酶可以促进RNA和DNA的检测,而不需要单独的步骤来产生cDNA。在转录介导扩增(TMA)中,RNA聚合酶用于一个启动子的RNA在引物区进行工程化,然后是一个逆转录酶从引物合成cDNA。第三种酶,例如Rnase H,可用于降解cDNA中的RNA靶点,而无需热变性步骤。这种扩增技术类似于再生式序列复制反应 (3SR)和依赖核酸序列的扩增技术(NASBA),但酶的使用有所不同。再举个例子,解旋酶依赖性扩增(HDA)利用一个热稳定的解旋酶(Tte-UvrD)而不是通过加热来解开dsDNA,从而产生可用于杂交和聚合酶扩增引物的单链。再举一个例子,环介导扩增(LAMP) 使用一种具有链置换能力的热稳定聚合酶和一组四个或更多个特定设计的引物。每种底漆都设计有发夹状的末端移位,卡入发夹以促进自启动和进一步的聚合酶扩增。在LAMP反应,虽然反应是在等温条件下进行的,但它是一种初始热双链靶需要变性步骤。此外,放大后产生各种长度产品的梯形图。还有一个例子,链替代扩增技术(SDA) 结合了限制性内切酶的能力,以阻断目的DNA的未修饰链和一个外切酶缺失的DNA聚合酶延伸3'末端在缺口处,取代下游的DNA链。
本发明公开的方法可以包括扩增试剂。扩增试剂可以包括缓冲液,所述缓冲液选自下组的一种或任意几种缓冲液:Tris缓冲液,ACES缓冲液、PIPES缓冲液、PBS缓冲液、MOPAS缓冲液、MOPSO缓冲液、 Bis-Tris Propane缓冲液、BES缓冲液、MOPS缓冲液、TES缓冲液、 HEPES缓冲液、DIPSO缓冲液、MOBS缓冲液、TAPSO缓冲液、Trizma 缓冲液、HEPPSO缓冲液、POPSO缓冲液、TEA缓冲液、EPPS缓冲液、 Tricine缓冲液、Gly-Gly缓冲液、Bicine缓冲液、HEPES缓冲液、TAPS 缓冲液、AMPD缓冲液、TABS缓冲液、AMPSO缓冲液、CHES缓冲液。上述缓冲液可以在适于所需应用或用途的任何浓度下使用,例如包括但不限于1mM、2mM、3mM、4mM、5mM、6mM、7mM、8mM、 9mM、10mM、11mM、12mM、13mM、14mM、15mM、25mM、50mM、 75mM、1M等浓度。本领域技术人员将能够确定用于本发明的缓冲液 (例如Tris)的适当浓度。
检测探针
在一些情况下,主题方法包括接触样品(例如,样品包括一个靶DNA 和多个非靶ssdna),具有:i)Cas12i或其突变体,优选Cas12i1,Cas12i2, Cas12iVar1,Cas12iVar2,Cas12iVar3;ii)向导RNA(或前体向导 RNA阵列);以及iii)一种单链的检测DNA不能与向导RNA的向导序列杂交。例如,在Casl2i的情况下,用Casl2i标记的单链DNA检测器/双链DNA检测器(Casl2i)包括标记为Casl2i的单链DNA检测器/ 双链DNA检测器(在向导RNA与靶DNA杂交的背景下,通过与向导 RNA结合);并且测量的可检测信号由荧光发射染料对产生。例如,在某些情况下,对象方法包括将样品与标记检测器ssDNA接触,所述检测器ssDNA包括荧光共振能量转移(FRET)对或猝灭剂/氟对,或两者。在某些情况下,主体方法包括将样品与包含FRET对的标记检测器ssDNA接触。在某些情况下,主体方法包括将样品与包含荧光/ 猝灭剂对的标记检测器ssDNA接触。
荧光发射染料对包括FRET对或猝灭剂/荧光对。两者兼而有之在 FRET对和猝灭剂/荧光对的情况下,其中一种染料的发射光谱重叠了另一种染料的吸收光谱的一个区域。如本文所用,术语“荧光发射染料对”是用于包括“荧光共振能量转移(FRET)对”和“猝灭剂/荧光对”两者的通用术语,下文将更详细地讨论这两个术语。术语“荧光发射染料对”与短语“FRET对和/或猝灭剂/荧光对”互换使用。
在某些情况下(例如,当检测器单链DNA包括一个FRET对时),被标记的检测器ssDNA在被切割之前产生可检测信号量,并且当被标记检测器单链DNA被切割时,所测量的可检测信号量减少。在某些情况下,标记检测器单链DNA在被切割之前产生第一可检测信号(例如,来自FRET对),并且当标记检测器单链DNA被切割时产生第二可检测信号(例如,来自猝灭剂/氟对)。因此,在某些情况下,标记检测器单链DNA包括一个FRET对和一个猝灭剂/氟对。
在某些情况下,标记检测器ssDNA包含一对FRET。FRET是一个过程从激发态荧光团到第二荧光团的无辐射能量转移发色团近距离的。能量转移的范围是限制在大约10纳米(100埃),并且传输效率对荧光团之间的分离距离非常敏感。因此,如本文所用术语“FRET”(“荧光共振能量转移”;也称为“Forster共振”能量转移”)指的是一种涉及施主荧光团和匹配的物理现象选择受体荧光团,使施主的发射光谱与激发光谱重叠光谱中的受主,并进一步选择使施主和受主接近彼此接近(通常为10nm或更小),施主的激发将导致以及从受体发射,当一些能量通过量子耦合效应。因此,FRET信号用作供体和受体;只有当它们彼此靠近时才产生信号。FRET供体部分(例如供体荧光团) 和FRET受体部分(例如受体荧光团)这里统称为“一对”。
所述供体-受体对(FRET供体部分和FRET受体部分)在这里称为“FRET对”或“signal FRET pair”。因此,在某些情况下,被标记为检测器ssDNA包括两个信号伙伴(信号对),其中一个信号伙伴是FRET 供体部分,另一个信号伙伴是FRET受体部分或具有淬灭作用。受试者标记的检测器ssDNA包括这样一个FRET对(FRET供体部分和 FRET受体部分),因此当信号伙伴非常接近时(例如,在同一RNA 分子上),将显示可检测信号(FRET信号),但当伙伴分离时,信号将减少(或消失)(例如,通过Cas12i效应蛋白(例如,Cas12i(Cas12i1,Cas12i2,Cas12iVar1,Cas12iVar2,Cas12iVar3))切割RNA分子后。
FRET供体和受体部分(FRET对)将为本领域普通技术人员所知和任何可用的FRET对(例如,任何方便的供体和受体部分对)可以使用。合适的FRET组合可见::Bajar et al.,Sensors(Basel).2016Sep 14; 16(9);and Abraham et al.PLoS One.2015Aug 3;l0(8):e0l34436.
在某些情况下,当被标记的检测器ssDNA被切割时产生可检测的信号(例如,在某些情况下,标记检测器ssDNA包括一对猝灭剂/氟对)。信号猝灭对的一个信号伙伴产生可检测信号,另一个信号伙伴是猝灭第一信号伙伴的可检测信号的猝灭器部分(即。,猝灭器部分对信号部分的信号进行猝灭,使得当信号伙伴彼此接近时(例如,当信号对的信号伙伴非常接近时),来自信号部分的信号被减少(猝灭)。
例如,在某些情况下,当标记探测器ssDNA被切割。例如,在某些情况下,由一个信号显示的信号伙伴(信号部分)被另一个信号伙伴(猝灭信号部分)猝灭,例如,在Cas12i或其突变体,优选Cas12i1,Cas12i2, Cas12iVar1,Cas12iVar2,Cas12iVar3,裂解之前,二者均存在于同一ssDNA分子上。这种信号对在这里被称为“猝灭器/荧光对”、“猝灭对”或“信号猝灭对”。例如,在某些情况下,一个信号伙伴(例如,第一信号伙伴)是产生由第二信号伙伴(例如,猝灭器部分)猝灭的可检测信号的信号部分。这样的猝灭剂/氟对的信号伴侣因此在伴侣被分离时(例如,在检测器ssDNA被Cas12i或其突变体,优选Cas12i1, Cas12i2,Cas12iVar1,Cas12iVar2,Cas12iVar3)切割后产生可检测的信号,但当伙伴靠近时,信号将被猝灭(例如,Cas12i或其突变体,优选Cas12i1,Cas12i2,Cas12iVar1,Cas12iVar2,Cas12iVar3,裂解检测器ssDNA之前)。
猝灭器部分可以使来自信号部分的信号猝灭(例如Cas12i或其突变体,优选Cas12i1,Cas12i2,Cas12iVar1,Cas12iVar2,Cas12iVar3) 在不同程度上。在某些情况下,淬火剂部分对来自信号部分的信号进行猝灭,其中在猝灭器部分存在时(当信号伙伴彼此接近时)检测到的信号是在没有猝灭器部分的情况下检测到的信号的95%或更少(当信号伙伴是分离)。例如,在某些情况下,在猝灭器存在时检测到的信号部分可为90%或以下、80%或以下、70%或以下、60%或以下、 50%或以下、40%或以下、30%或更少,20%或更少,15%或更少, 10%或更少,或在缺失时检测到的信号的5%或更少淬火部分。
在某些情况下,在没有猝灭剂部分的情况下检测到的信号(当信号伙伴分离)至少大1.2倍(例如,至少1.3倍,至少1.5倍,在至少1.7倍,至少2倍,至少2.5倍,至少3倍,至少3.5倍,至少4倍、至少5倍、至少7倍、至少10倍、至少20倍或至少50倍)在猝灭器部分存在时检测到的信号(当信号伙伴靠近时彼此之间)。
在某些情况下,信号部分是荧光标签。在某些情况下,淬火剂部分使来自荧光标签的信号(光信号)猝灭(例如,通过吸收标签发射光谱中的能量)。因此,当猝灭器部分不靠近信号部分时,由于信号没有被猝灭部分吸收,所以可以检测来自荧光标签的发射(信号)。可以使用任何方便的施主-受体对(信号部分/猝灭部分对),并且本领域已知许多合适的对。在某些情况下,猝灭器部分从信号部分吸收能量 (也可参考在此作为“可检测标签”),然后发射信号(例如,不同波长的光)。因此,在某些情况下,猝灭器部分本身是信号部分(例如,信号部分可以是6-羧荧光素,而猝灭部分可以是6-羧基四甲基罗丹明),并且在一些这样的情况下,这对也可能是一对。在某些情况下,淬火部分是黑暗的淬火剂。暗猝灭剂可以吸收激发能量并在不同的方式(例如,加热)。因此,暗猝灭剂本身几乎没有荧光发射荧光)。暗猝灭剂例子请看美国专利号8,822,673and 8,586,718;20140378330, 20140349295,and20140194611;and国际专利申请:W0200142505 and WO200186001。
荧光标记例子如下:an Alexadye,an ATTO dye(e.g.,ATTO 390,ATTO425,ATTO 465,ATTO 488,ATTO 495,ATTO 514,ATTO 520,ATTO 532,ATTO Rho6G,ATTO542,ATTO 550,ATTO 565, ATTO Rho3B,ATTO Rholl,ATTO Rhol2,ATTO Thiol 2,ATTORholOl,ATTO 590,ATTO 594,ATTO Rhol3,ATTO 610,ATTO 620, ATTO Rhol4,ATTO 633,ATTO 647,ATTO 647N,ATTO655,ATTO Oxal2,ATTO 665,ATTO 680,ATTO 700,ATTO 725,ATTO 740),a DyLight dye,a cyanine dye(e.g.,Cy2,Cy3,Cy3.5,Cy3b,Cy5,Cy5.5, Cy7,Cy7.5),a FluoProbes dye,a Sulfo Cy dye,a Seta dye,an IRIS Dye, a SeTau dye,anSRfluor dye,a Square dye,fluorescein isothiocyanate (FITC),tetramethylrhodamine(TRITC),德克萨斯红,俄勒冈州绿,太平洋蓝,太平洋绿,太平洋橙,量子点,和一种栓系荧光蛋白.AlexaFluor荧光标记如下但不限于:Alexa350,Alexa 405,Alexa430,Alexa488,Alexa500, Alexa514,Alexa532,Alexa546,Alexa 555,Alexa568,Alexa594,Alexa610,Alexa 633,Alexa635,Alexa647,Alexa660, Alexa680,Alexa700,Alexa750,Alexa 790,and the like.
淬灭剂标记物如下但不限于:a dark quencher,a BlackHole (e.g.,BHQ-0,BHQ-1,BHQ-2,BHQ-3),a Qxl淬灭剂,an ATTO淬灭剂(e.g.,ATTO540Q,ATTO 580Q,and ATTO 612Q),二甲氨基偶氮苯磺酸(Dabsyl),Iowa Black RQ,IowaBlack FQ,IRDye QC-1,a QSY dye(e.g.,QSY 7,QSY 9,QSY 21),AbsoluteQuencher,Eclipse,and metal clusters such as gold nanoparticles,and the like. 在一些实施案例中,淬灭剂选于:a dark quencher,a Black Hole (e.g.,BHQ-0,BHQ-1,BHQ-2,BHQ-3),a Qxl quencher,an ATTO淬灭剂(e.g.,ATTO 540Q,ATTO580Q,and ATTO 612Q),dimethylaminoazobenzenesulfonic acid(Dabsyl),Iowa BlackRQ, Iowa Black FQ,IRDye QC-1,a QSY dye(e.g.,QSY 7,QSY 9,QSY 21),AbsoluteQuencher,Eclipse,and a metal cluster.ATTO淬灭剂例子如下但不限于:ATTO540Q,ATTO580Q,and ATTO 612Q.Examples of a Black Hole包括但不限于:BHQ-0(493nm), BHQ-1(534nm),BHQ-2(579nm)and BHQ-3(672nm).
在某些情况下,标记检测器ssDNA的断裂可以通过测量比色读数。例如,荧光团的释放(例如,从FRET对的释放、从猝灭剂/荧光对的释放等)可导致可检测信号的波长偏移(并且由此产生颜色偏移)。因此,在某些情况下,受试者标记的检测器ssDNA的断裂可以通过色差来检测。这种偏移可以表示为一种颜色(波长)的信号量的损失、另一种颜色的量的增加、一种颜色与另一种颜色的比例的变化等。
试纸条方案(胶体金)
在某些情况中,本发明提供一种层析法,其包含底物。底物的一端,其中包括样品装载部分。所述第一端还包括第一区域,所述第一区域装载Cas12i(Cas12i1、Cas12i2、Cas12iVar1、Cas12iVar2、Cas12iVar3)、检测ssDNA、包括包含生物素配体的第一测试带和包含用于所述可检测配体的捕获分子的第二测试带。检测探针可以包括单链DNA,在第一端具有第一分子,在第二端具有第二分子。
所述层析装置还可以包括可切割的探针,所述探针包括由RNA或 DNA两端分别连接第一分子和第二分子。在一些实施例中,第一分子可以是FITC,第二分子可以是生物素,反之亦然。层析装置可进一步包括第一捕捉区,在一些实施例中,该第一捕捉区可以是穿过该装置的第一水平线。在具体实施例中,第一捕获区域与样品装载部分接近且位于侧流基板的同一端,并且可以包括第一结合剂,该第一结合剂具体结合探针一端的第一分子。在一些实施例中,第一结合剂可以是抗体,例如抗FITC抗体,其被固定或以其他方式固定到第一捕捉区域。层析装置还可包括第二捕捉区,在一些实施例中,该第二捕捉区位于从第一结合区朝向侧流底物的另一端。在具体实施例中,第二捕捉区域可包含第二结合剂,该第二结合剂具体结合报告者结构之第二分子。在一些实施例中,第二结合剂可以是抗体,例如抗生物素抗体,其固定或以其他方式固定到第二捕捉区域。
在某些示例实施例中,层析装置包括侧流底物,所述侧流底物包括用于施加样品的第一端。第一区域装载可检测的配体,例如本文所公开的配体,例如纳米金。纳米金可以链接第一抗体,例如抗FITC抗体。第一区域还包括探针。在一个示例实施例中,如本文所揭示的,DNA 探针和基于Cas12i的CRISPR效应器系统。在一个示例实施例中,并且为了进一步说明的目的,探针的一端是FAM分子和第二端链接生物素。从横向流动底物的第一端向上游流动的溶液是第一个测试带。测试带可包含生物素配体。因此,当探针呈现其初始状态时,即在没有靶点的情况下,第一端的FAM分子将与金纳米粒子上的抗 FITC抗体结合,探针第二端的生物素会结合生物素配体,让可检测的配体在第一次测试时积累,产生可检测的信号。在第一条带上产生可检测的信号表明目标配体的缺失。在靶向DNA存在的情况下,CRISPR效应器复合物形成,Cas12i(Cas12i1,Cas12i2,Cas12iVar1, Cas12iVar2,Cas12iVar3)蛋白被激活,导致探针被切割。在没有完整的探针的情况下,胶体金将流向第二条带。横向流动装置可包括第一带上游的第二带。第二条带可以包括能够结合抗体标记的胶体金分子的分子,例如将兔抗FTIC抗体结合到胶体金上的兔抗抗体。因此,在存在一个或多个靶点的情况下,可检测的配体将聚集在第二个带上,表明样品中存在一个或多个靶点在一些实施例中,可检测配体可为胶体金,其连接第一抗体。在特定实施例中,第一抗体可为抗FITC 抗体。
在一些实施例中,底物可以是柔性材料基板,例如纸张底物或基于柔性聚合物的底物。
III.样品
核酸浓度
在某些情况下,检测阈值,用于检测目标DNA的主体方法在样品中,为10nM或更小。这里使用术语“检测阈值”来描述为了进行检测,样品中必须存在的最小数量的目标DNA。因此,作为说明性示例,当检测阈值为10nm时,则信号可以是当目标DNA以10纳米或更高的浓度存在于样品中时检测。在在某些情况下,本发明的一种方法的检测阈值为5nm或更小。在在某些情况下,本发明的方法的检测阈值为1nm 或更小。在某些情况下,本发明的方法的检测阈值为0.5nm或更小。在某些情况下,本发明的方法具有0.1nm或更小的检测阈值。在某些情况下,本发明的方法的检测阈值为0.05nM或更小。在某些情况下,本发明的方法的检测阈值为0.01nm或更小。在某些情况下,本发明的方法具有0.005nM或更小的检测阈值。在本发明的一些情况下,nM 或本发明的检测阈值为0.001nM更少。在某些情况下,本发明的方法的检测阈值为0.0005nM或者更少。在某些情况下,本发明的一种方法的检测阈值为0.0001nM或更小。在某些情况下,本发明的方法具有检测阈值0.00005nM或更小。在某些情况下,本发明的一种方法的阈值为检测0.00001nM或更小。在某些情况下,本发明的一种方法具有检测阈值为10pM或更小。在某些情况下,本发明的一种方法具有检测阈值为1pm或更小。在某些情况下,本发明的一种方法具有检测阈值为500fM或更小。在某些情况下,本发明的一种方法具有检测阈值为250fM或更低。在某些情况下,本发明的一种方法具有检测阈值为100fM或更小。在某些情况下,本发明的一种方法具有检测阈值为50fM或更小。在某些情况下,本发明的一种方法具有检测阈值为500aM(阿耳摩尔)或更低。在某些情况下,当前的一种方法本发明的检测阈值为250aM或更低。在某些情况下,当前的一种方法公开具有100aM或更小的检测阈值。在某些情况下,当前的一种方法公开的检测阈值为50aM或更少。在某些情况下,当前的一种方法公开的检测阈值为上午10点或更少。在某些情况下,当前的一种方法公开的检测阈值为上午1点或更少.
在某些情况下,检测核酸浓度阈值(用于检测受试者的目标DNA方法)的范围为500fM到1nM(例如,从500fM到500pM,从500fM 到200pM,从500fM到100pM,从500fM到10pM,从500fM 到1pM,从800fM到1nM,从800fM到500pM,从800fM到200 pM,从800fM到100pM,从800fM到100pM,从800fM到10pM,从800fM到1pM,从1pM到1nM,从1pM到500pM,从1pM到200pM,从1pM到100pM,或从1pM到10pM)(其中浓度指目标DNA浓度的阈值)。在某些情况下,本发明的一种方法具有800fM 到100范围内的检测阈值1pM。在一些情况下,本发明的一种方法具有在以下范围内的检测阈值:1pM到10pM。在某些情况下,本发明的一种方法的阈值在10fM到500fM的范围内检测,例如从10 fM到50fM,从50fM到100fM,从100fM到250fM,或者从250fM 到500fM。
在某些情况下,样品中可检测目标DNA浓度介于500fM到1nM (譬如.,500fM到500pM,500fM到200pM,500fM到100pM, 500fM到10pM,500fM到1pM,800fM到1nM,800fM到500pM,800fM到200pM,800fM到100pM,800fM到10pM,800 fM到1pM,1pM到1nM,1pM到500pM,1pM到200pM,1 pM到100pM,or 1pM到10pM).
在某些情况下,核酸检测浓度阈值介于1aM到1nM(e.g.,从1 aM到500pM,从1aM到200pM,从1aM到100pM,从1aM 到10pM,从1aM到1pM,从100aM到1nM,从100aM到 500pM,从100aM到200pM,从100aM到100pM,从100aM 到10pM,从100aM到1pM,从250aM到1nM,从250aM到500pM,从250aM到200pM,从250aM到100pM,从250 aM到10pM,从250aM到1pM,从500aM到1nM,从500 aM到500pM,从500aM到200pM,从500aM到100pM,从 500aM到10pM,从500aM到1pM,从750aM到1nM,从 750aM到500pM,从750aM到200pM,从750aM到100pM, 从750aM到10pM,从750aM到1pM,从1fM到1nM,从1 fM到500pM,从1fM到200pM,从1fM到100pM,从1fM 到10pM,从1fM到1pM,从500fM到500pM,从500fM到200pM,从500fM到100pM,从500fM到10pM,从500fM 到1pM,从800fM到1nM,从800fM到500pM,从800fM 到200pM,从800fM到100pM,从800fM到10pM,从800 fM到1pM,从1pM到1nM,从1pM到500pM,从1pM到 200pM,从1pM到100pM,或从1pM到10pM)(核酸检测浓度阈值指的是样品中能检测出最低的核酸浓度).在某些情况下,核酸检测浓度阈值介于50aM到500fM.
在某些情况下,核酸检测浓度阈值介于1aM到1nM(e.g.,1aM到 500pM,1aM到200pM,1aM到100pM,1aM到10pM,1aM 到1pM,100aM到1nM,100aM到500pM,100aM到200 pM,100aM到100pM,100aM到10pM,100aM到1pM, 250aM到1nM,250aM到500pM,250aM到200pM,250aM到100pM,250aM到10pM,250aM到1pM,500aM 到1nM,500aM到500pM,500aM到200pM,500aM到 100pM,500aM到10pM,500aM到1pM,750aM到1nM, 750aM到500pM,750aM到200pM,750aM到100pM, 750aM到10pM,750aM到1pM,1fM到1nM,1fM到 500pM,1fM到200pM,1fM到100pM,1fM到10pM, 1fM到1pM,500fM到500pM,500fM到200pM,500fM到 100pM,500fM到10pM,500fM到1pM,800fM到1nM, 800fM到500pM,800fM到200pM,800fM到100pM,800 fM到10pM,800fM到1pM,1pM到1nM,1pM到500pM, 1pM到200pM,1pM到100pM,or 1pM到10pM).在某些情况下,核酸检测浓度阈值介于1aM到500pM.在某些情况下,能检测到最低的核酸浓度介于100aM到500pM.
在某些情况下,受试者组合物或方法表现出亚渺摩尔(aM)检测灵敏度。在某些情况下,受试者的构图或方法表现出费托摩尔(fM) 的检测灵敏度。在某些情况下,受试者的构图或方法表现出微微摩尔 (pM)的探测灵敏度。在某些情况下,受试物组合物或方法表现出纳米摩尔(nM)的检测灵敏度。
受试者样品包括核酸(例如,多个核酸分子)。术语“多个”在本文中用于表示两个或更多个。因此,在某些情况下,样品包含两个或更多 (例如3个或更多,5个或更多,10个或更多,20个或更多,50个或更多,100个或更多,500个或更多,1,000个或更多,或5,000个或更多)核酸分子(如DNA分子)。常见方法可以用作检测样品中存在的目标DNA(例如,在复杂的核酸混合物中的目标DNA)的非常灵敏的方法。在某些情况下,样品包含5个或更多DNA(顺序上彼此不同)(例如10个或更多,20个或更多,50个或更多,100个或更多,500个或更多,1,000个或更多,或5,000个或更多的DNA 分子)。在某些情况下,样品包含10个或更多,20个或更多,50个或更多,100个或更多,500个或更多,1,000个或更多,5X103个或更多,104个或更多,5X104个或更多,105个或更多,5X105个或更多,106个或更多,5X106个或更多,107个或更多,或多于107个DNA。在一些情况下,样品包含10-20个,50-100个,100-500个,500-103个,103-5X103个,5X103-104个,104-5X104个,5X104-105个,105-5X105个,5X105-106个,106-5X106个,或5X106-107个,或多于107个DNA 分子。在一些情况下,样品包含5-107个DNA分子(序列各不相同)。在某些情况下,样品包含20或更多序列各不相同的DNA分子。在某些情况下,样品中包含细胞裂解液(例如,真核细胞裂解液,哺乳动物细胞裂解液,人细胞裂解液,原核细胞裂解液,植物细胞裂解液等)。例如,在某些情况下,样品包括来自诸如真核细胞等细胞的DNA,例如,如人类细胞的哺乳动物细胞。
本文使用的术语“样品”是指包括DNA的任何样品(例如,为了确定 DNA群体中是否存在目标DNA)。样品可以来自任何来源,例如,样品可以是纯化DNA的合成组合;样品可以是细胞裂解物,富含 DNA的细胞裂解物,或从细胞裂解物中分离和/或纯化的DNA。样品可以来自患者(例如,出于诊断目的)。样品可以来自透性化细胞。样品可以来自交联的细胞。样品可以在组织切片中。样品可以来自通过交联并在随后做脱脂和调节以形成均匀折射率而制备的组织。通过交联并在随后做脱脂和调节以形成均匀折射率而制备的组织的实例已有文献记载,如。
“样品”可以包含靶标(目标)DNA和多个非靶标DNA。在某些情况下,样品中每10个拷贝非目标DNA中包含1个目标DNA,每10 个拷贝非目标DNA中包含1个目标DNA,每20个拷贝非目标DNA 中包含1个目标DNA,每25个拷贝非目标DNA中包含1个目标 DNA,每50个拷贝非目标DNA中包含1个目标DNA,每100个拷贝非目标DNA中包含1个目标DNA,每500个拷贝非目标DNA中包含1个目标DNA,每103个拷贝非目标DNA中包含1个目标DNA,每5X103个拷贝非目标DNA中包含1个目标DNA,每104个拷贝非目标DNA中包含1个目标DNA,每5X104个拷贝非目标DNA中包含1个目标DNA,每105个拷贝非目标DNA中包含1个目标DNA,每5X105个拷贝非目标DNA中包含1个目标DNA,每106个拷贝非目标DNA中包含1个目标DNA,或低于每106个拷贝非目标DNA 中包含1个目标DNA。在某些情况下,样品中目标DNA/非目标DNA 拷贝数比为:从1/10到1/20,从1/20到1/50,从1/50到1/100,从 1/100到1/500,从1/500到1/103,从1/103到1/5X103,从1/5X103到1/104,从1/104到1/105,从1/105到1/106,从1/106到1/107。
合适的样品包括但不限于唾液,血液,血清,血浆,尿液,抽吸物和活检样品。因此,关于患者的术语“样品”包括血液和生物学来源的其他液体样品,诸如活检样品或组织培养物或源自其的细胞的固体组织样品及其后代。该定义还包括采购后以任何方式处理的样品,例如通过试剂处理;洗净;或富集某些细胞群体,如癌细胞。该定义还包括已经针对特定类型的分子进行富集的样品,例如,DNAs。术语“样品”包括生物样品,例如临床样品,例如血液,血浆,血清,抽吸物,脑脊髓液(CSF),还包括通过手术切除获得的组织,通过活检获得的组织,培养中的细胞,细胞上清液细胞裂解物,组织样品,器官,骨髓等。“生物样品”包括从那里衍生的生物流体(例如癌细胞,感染的细胞等),例如含有从这些细胞获得的DNA的样品(例如细胞裂解物或其他含有DNA的细胞提取物)。
样品可以包含多种细胞,组织,器官或无细胞液中的任何一种,或可以从中获得。合适的样品来源包括真核细胞,细菌细胞和古细菌细胞。合适的样品来源包括单细胞生物和多细胞生物。
适合样品来源包括单细胞真核生物;植物或植物细胞;藻细胞,如 Botryococcusbraunii,Chlamydomonas reinhardtii,Nannochloropsis gaditana,Chlorellapyrenoidosa,Sargassum patens,C.agardh等;真菌细胞(如酵母细胞);动物细胞,组织或器官;无脊椎动物的细胞,组织或器官(例如果蝇,刺胞动物,棘皮动物,线虫,昆虫,蜘蛛纲动物等);来自脊椎动物(如鱼,两栖动物,爬行动物,鸟类,哺乳动物)的细胞,组织,液体或器官;哺乳动物(例如人类,非人类灵长类动物,有蹄类动物,猫类,动物类)的细胞,组织,液体或器官。合适的样品来源包括线虫,原生动物等。合适的样品来源包括寄生虫,例如蠕虫,疟原虫等。
合适的样品来源包括自然界(如细菌(如真细菌);古细菌类;原生生物;真菌;植物界;和动物界)中的任何一种细胞、组织或生物体。合适的样品来源包括原植物界的类植物,包括但不限于藻类(如绿藻、红藻、蓝藻、蓝藻类);原生体类真菌的成员,如黏菌、水霉菌等;类动物原生体成员,如鞭毛虫(尤格莱属)、阿米巴原虫(尤指阿米巴)、孢子虫(尤指顶复动物亚门、粘虫、微孢子虫)和纤毛虫(尤指草履虫)。合适的样品来源包括真菌的成员,包括但不限于蘑菇属,牛肝菌属、蛤蟆菌属,鸡油菌属等任何成员。子囊菌属(例如酿酒酵母菌等);真菌(例如地衣);接合菌(例如接合真菌);和半知菌门。合适的样品来源包括:植物家族的成员,包括但不限于以下任何门:苔藓植物门(如苔藓)藓门(例如,角苔纲),苔纲(例如,苔类),石松门(例如,石松类)、楔叶(例如,木贼类),裸蕨植物门(如搅拌蕨类),水蕨科(例如,蕨类植物),苏铁纲,,松柏门,买麻藤纲,被子植物门(例如,开花植物)。合适的样品来源包括动物界的成员,包括但不限于下列任一门的成员:多孔类(海绵类);丝盘虫;海洋无脊椎动物的寄生虫;菱叶草属发育完全的个体;刺胞动物(珊瑚、海葵、水母、海栏、三色堇、海黄蜂);栉水母(栉水母);扁虫(扁形虫);带状蠕虫;舌虫;腹毛;轮虫纲;动吻动物门;兜甲形动物门;棘头纲;内肛动物;环口动物门,蜕皮动物超门,线形动物门;软体动物;花生虫;环节虫(节段虫);水熊;丝绒蠕虫。节肢动物(包括螯鳃亚门)多足纲、六足纲和甲壳纲,鳞甲纲包括蛛形纲、纲口纲和足纲纲,而多足纲包括爪足纲(蜈蚣类),二足纲(千足纲),副足纲和合生纲。六足类包括昆虫,甲壳类包括虾、磷虾、藤壶等;帚虫动物门;苔藓动物;腕足类;棘皮类(例如海星、海雏菊、羽毛星、海胆、海参、海蛇尾、篮子蛇尾等);毛毛虫(箭虫);半种子(橡子虫);和脊索动物。脊索动物的适宜成员包括以下亚门的任何成员:尾脊索动物(海鞘,包括海鞘,和尾海鞘纲;头脊索(盲鳗)以及脊椎动物,其中包括七鳃鳗,软骨鱼、光鳍鱼(如鳐鳍鱼)、光鳍鱼(例如空腔鱼)、肺鱼、鳞蜥(爬行动物,如蛇、短吻鳄、鳄鱼、蜥蜴)。
适合的样品来源包括取自生物体的细胞、液体、组织或器官;来自生物体分离的特定细胞或细胞群,例如,如果生物是植物,适合的来源包括木质部、韧皮部、形成层、叶子、根等。如果生物是动物,适合的来源包括特定的组织(例如,肺、肝、心脏、肾、脑、脾、皮肤、胎儿组织等)或特定细胞类型(例如神经元细胞、上皮细胞、内皮细胞、星形细胞、巨噬细胞、神经胶质细胞、胰岛细胞、T淋巴细胞、 B淋巴细胞等)。
在某些情况下,样品的来源是(或疑似患者的细胞、液体、组织或器官)。在某些情况下,样品的来源是一个正常的(未患病的)细胞、液体、组织或器官。在某些情况下,样品的来源是(或被怀疑是病原体感染的细胞、组织或器官)。例如,样品的来源可以是一个可能被感染也可能没有被感染的个人——样品可以是任何生物样品(如血液、唾液、活检、血浆、血清、支气管肺泡灌洗液,痰,大便样品,脑脊液,拭子样品 (例如,口腔拭子、宫颈拭子、鼻拭子),组织液,滑液,鼻涕,眼泪,黏膜样例, 从个体上收集的上皮细胞样品(例如上皮细胞碎片)等。在某些情况下,样品是无细胞的液体样品。
在某些情况下,样品是含有细胞的液体样品。病原体包括病毒、真菌、蠕虫、原生动物、疟原虫寄生虫、弓形虫寄生虫、丝裂体寄生虫等。“蠕虫”包括圆虫、心虫和植食线虫(线虫纲),吸虫纲,棘形虫和绦虫纲。原生动物感染包括鞭毛虫感染、滴虫属感染、非洲锥虫病、阿米巴痢疾、巴贝斯病、痢疾、Chaga氏病、球虫病、疟疾和弓形虫病。病原体包括但不限于:Plasmodium falciparum,Plasmodium vivax, Trypanosoma cruzi和Toxoplasma gondii。真菌病原体包括但不限于:Cryptococcus neoformans,Histoplasma capsulatum,Coccidioides immitis,Blastomyces dermatitidis,Chlamydia trachomatis和Candidaalbicans。病毒可以是DNA病毒、RNA病毒或逆转录病毒。适用于本发明的病毒的非限制性实例包括但不限于免疫机能丧失病毒(例如艾滋病毒);流行性感冒病毒,登革热;西尼罗河病毒;疱疹病毒;黄热病病毒;丙型肝炎病毒;甲型肝炎病毒;乙型肝炎病毒;乳头瘤病毒;诸如此类。致病性病毒包括DNA病毒,如:乳头瘤病毒(如人类乳头瘤病毒 (HPV)、多瘤病毒);肝病毒(如乙型肝炎病毒),疱疹病毒(如:sim疱疹病毒(HSV)、水痘带状疱疹病毒(VZV)、eb病毒(EBV)、巨细胞病毒 (CMV)、嗜淋巴性疱疹病毒、罗西糠疹病、卡波西肉瘤相关疱疹病毒);腺病毒(如:禽类腺病毒,鸟类腺病毒,美洲白豚腺病毒);痘病毒(如天花、牛痘病毒、牛痘病毒、猴痘病毒、orf病毒、假痘病毒、牛丘疹性口炎病毒);特纳河痘病毒,亚巴猴肿瘤病毒;传染性软体病毒 (MCV);细小病毒(如腺相关病毒(AAV)、细小病毒B19、人类博卡病毒、布法病毒)丝状噬菌体科;微小噬菌体科;藻类脱氧核糖核酸病毒科;诸如此类:结核分枝杆菌(Mycobacterium tuberculosis),无乳链球菌(Streptococcus agalactiae),methicillin-resistant,金黄色葡萄球菌(Staphylococcus aureus),嗜肺军团菌(Legionella pneumophila), Streptococcuspyogenes,Escherichia coli,淋病奈瑟氏菌Neisseria gonorrhoeae,脑膜炎奈瑟氏菌(Neisseria meningitidis),Pneumococcus,Cryptococcus neoformans,Histoplasma capsulatum,Hemophilus influenzae B,Treponema pallidum,Lyme disease spirochetes, Pseudomonas aeruginosa,Mycobacterium leprae,Brucella abortus,狂犬病毒、流感病毒、巨细胞病毒、疱疹病毒,单纯疱疹病毒,人类血清细小病毒、呼吸道合胞病毒、水痘-带状疱疹病毒、乙型肝炎病毒、丙型肝炎病毒、麻疹病毒、人类T-细胞白血病病毒,爱泼斯坦-巴尔病毒小鼠白血病病毒、腮腺炎病毒、疱疹性口炎病毒,辛德毕斯病毒,淋巴细胞性脉络丛脑膜炎病毒疣病毒、蓝舌病毒、仙台病毒,猫白血病病毒,呼肠孤病毒,小儿麻痹症病毒,猴病毒40,小鼠玛丽肿瘤病毒,登革热,Plasmodium falciparum,Plasmodium vivax,Toxoplasma gondii,Trypanosomarangeli,Trypanosoma cruzi,Trypanosoma rhodesiense,Trypanosoma brucei,Schistosoma mansoni,Schistosoma japonicum,Babesia bovis,Eimeria tenella,Onchocerca volvulus, Leishmania tropica,Mycobacterium tuberculosis,Trichinella spiralis, Theileriaparva,Taenia hydatigena,Taenia ovis,Taeniasaginata,Echinococcus granulosus,Mesocestoides corti,Mycoplasma arthritidis,M.hyorhinis,M.orale,M.arginini,Acholeplasma laidlawii, M.salivarium andM.pneumoniae。适用于本发明的病毒的非限制性实例包括但不限于埃博拉、麻疹、SARS、SARS-CoV-2、基孔肯雅、肝炎、马尔堡、黄热病、MERS、登革、拉沙、流感、棒状病毒或HIV。肝炎病毒可以包括甲型肝炎、乙型肝炎或丙型肝炎。流感病毒可以包括例如甲型流感或乙型流感。HIV可以包括HIV 1或HIV 2。在某些示例性实施方案中,病毒序列可以是人呼吸道合胞病毒、苏丹埃博拉病毒(Sudan ebola virus)、本迪布焦病毒(Bundibugyo virus)、大森林埃博拉病毒(TaiForest ebola virus)、雷斯顿埃博拉病毒(Reston ebola virus)、阿基莫塔(Achimota)、伊蚊黄病毒、艾顾凯特病毒(Aguacate virus)、阿卡班病毒(Akabanevirus)、阿德非德瑞塔沙粒病毒(Alethinophid reptarena virus)、阿帕华约哺乳类沙粒病毒 (Allpahuayomammarena virus)、阿马帕里沙粒病毒(Amapari mmarena virus)、安第斯病毒(Andes virus)、阿波依病毒(Apoi virus)、阿拉万病毒(Aravan virus)、阿罗阿病毒(Aroavirus)、阿莫瓦病毒(Arumwot virus)、大西洋鲑鱼副粘病毒(Atlanticsalmonparamyoxivirus)、澳洲蝙蝠狂犬病病毒(Australian bat lyssavirus)、禽波纳病毒(Avian bornavirus)、禽偏肺病毒(Avian metapneumovirus)、禽副粘病毒(Avianparamyoxvirus)、企鹅或福克兰群岛病毒(penguin or Falkland Islandsvirus)、BK多瘤病毒、巴加扎病毒(Bagaza virus)、版纳病毒 (Banna virus)、蝙蝠戊型肝炎病毒(Bathepevirus)、蝙蝠札幌病毒(Bat sapovirus)、熊佳农哺乳类沙粒病毒(BearCanonmammarenavirus)、北龙病毒(Beilong virus)、贝塔康诺病毒(Betacoronoavirus)、贝塔乳头瘤病毒1-6(Betapapillomavirus 1-6)、班杰病毒(Bhanja virus)、博克洛蝙蝠狂犬病病毒(Bokeloh bat lyssavirus)、博尔纳病病毒、波本病毒 (Bourbonvirus)、牛丙型肝炎病毒(Bovine hepacivirus)、牛副流感病毒 3、牛呼吸道合胞病毒、巴宗病毒(Brazoranvirus)、本雅威病毒 (Bunyamwere virus)、杯状病毒科病毒、加利福尼亚脑炎病毒(California encephalitis virus)、坎迪鲁病毒(Candiru virus)、犬瘟热病毒(Caninedistemper virus)、犬肺病毒(Canaine pneumovirus)、松湾病毒 (Cedarvirus)、细胞融合因子病毒(Cell fusing agent virus)、鲸麻疹病毒(Cetacean morbillivirus)、金迪普拉病毒(Chandipura virus)、朝阳病毒(Chaoyang virus)、查帕雷哺乳类沙粒病毒(Chaparemammarena virus)、基孔肯雅病毒、疣猴乳头瘤病毒(Colobus monkey papillomavirus)、科罗拉多蜱传热病毒(Colorado tick fevervirus)、牛痘病毒、克里米亚-刚果出血热病毒、库蚊黄病毒、库皮科斯哺乳类沙粒病毒 (Cupixi mammarenavirus)、登革病毒、多布拉瓦-贝尔格莱德病毒 (Dobrava-Belgrade virus)、东港病毒(Donggang virus)、杜贝病毒(Dugbe virus)、杜文海格病毒(Duvenhage virus)、东方马脑炎病毒(Easternequineencephalitis virus)、恩德培蝙蝠病毒(Entebbe bat virus)、肠病毒 A-D、欧洲蝙蝠狂犬病病毒1-2、依埃契病毒(Eyach virus)、猫麻疹病毒(Feline morbillivirus)、矛头蛇副粘病毒(Fer-de-Lance paramyxo virus)、费茨罗伊河病毒(Fitzroy Rivervirus)、黄病毒科病毒、弗萊克索哺乳类沙粒病毒(Flexal mammarenavirus)、GB病毒C、加伊若病毒(Gairovirus)、戈麦环状病毒(Gemycircularvirus)、鹅副粘病毒SF02、大岛病毒(GreatIslandvirus)、瓜纳瑞托哺乳类沙粒病毒(Guanarito mammarenavirus)、汉坦病毒(Hantaanvirus)、汉坦病毒Z10、哈特兰德病毒(Heartlandvirus)、亨德拉病毒、甲型/乙型/丙型/戊型肝炎、丁型肝炎病毒(Hepatitis delta virus)、人博卡病毒(Humanbocavirus)、人冠状病毒、人内源逆转录病毒K、人肠道冠状病毒、人生殖器相关环状DNA病毒-1、人疱疹病毒1-8、人免疫缺陷病毒1/2、人哺乳动物腺病毒A-G(Huan mastadenovirusA-G)、人乳头瘤病毒、人副流感病毒1-4、人副肠孤病毒(Humanparaechovirus)、人小双节RNA病毒 (Humanpicobirnavirus)、人斯马可病毒(Human smacovirus)、艾克马狂犬病病毒(Ikomalyssavirus)、伊列乌斯病毒(Ilheus virus)、甲型-丙型流感、伊皮哺乳类沙粒病毒(Ippymammarenavirus)、伊尔库特病毒(Irkut virus)、J-病毒、JC多瘤病毒、日本脑炎病毒、胡宁哺乳类沙粒病毒 (Junin mammarenavirus)、KI多瘤病毒、卡迪皮罗病毒(Kadipirovirus)、卡密河病毒(Kamiti River virus)、凯杜古病毒(Kedougou virus)、库贾德病毒(Khujandvirus)、科科贝拉病毒(Kokobera virus)、科萨努尔森林病病毒(Kyasanurforestdisease virus)、拉各斯蝙蝠病毒(Lagos bat virus)、兰加特病毒(Langatvirus)、拉沙哺乳类沙粒病毒(Lassa mammarenavirus)、拉丁哺乳类沙粒病毒(Latinomammarenavirus)、罗帕德山病毒(Leopards Hill virus)、辽宁病毒(Liao ningvirus)、永安河病毒(Ljungan virus)、拉洛维病毒(Lloviu virus)、跳跃病病毒(Loupingillvirus)、卢约哺乳类沙粒病毒(Lujo mammarenavirus)、卢纳哺乳类沙粒病毒(Lunamammarenavirus)、伦卡病毒(Lunk virus)、淋巴细胞性脉络丛脑膜炎哺乳类沙粒病毒(Lymphocytic choriomeningitis mammarenavirus)、欧泽诺尔狂犬病病毒(LyssavirusOzernoe)、MSSI2\.225病毒、马丘波哺乳类沙粒病毒(Machupomammarenavirus)、哺乳动物星状病毒1(Mamastrovirus 1)、曼萨尼亚病毒(Manzanillavirus)、马普埃拉病毒(Mapuera virus)、马尔堡病毒、马雅罗病毒(Mayaro virus)、麻疹病毒、梅南高病毒(Menangle virus)、摩西卡迪病毒 (Mercadeo virus)、梅克尔细胞多瘤病毒(Merkel cellpolyomavirus)、中东呼吸综合征冠状病毒、莫巴拉哺乳类沙粒病毒(Mobalamammarenavirus)、摩多克病毒(Modoc virus)、莫江病毒(Moijang virus)、莫科洛病毒(Mokolo virus)、猴痘病毒、蒙大拿鼠耳蝙蝠脑白质炎病毒(Montanamyotisleukoenchalitis virus)、莫佩亚拉沙病毒重排体 29(Mopeia lassavirusreassortant29)、莫佩亚哺乳类沙粒病毒 (Mopeia mammarenavirus)、莫罗戈罗病毒(Morogoro virus)、莫斯曼病毒(Mossman virus)、腮腺炎病毒、鼠类肺炎病毒、墨累山谷脑炎病毒(Murray Valley encephalitis virus)、纳里瓦病毒 (Nariva virus)、新城疫病毒、尼帕病毒、诺瓦克病毒、挪威鼠丙型肝炎病毒(Norway rat hepacivirus)、恩塔亚病毒(Ntaya virus)、奥尼昂-尼昂病毒(O'nyong-nyong virus)、奥利韦罗斯哺乳类沙粒病毒(Oliveros mammarenavirus)、鄂木斯克出血热病毒(Omsk hemorrhagic fever virus)、奥罗普切病毒(Oropouche virus)、副流感病毒5、巴拉那哺乳类沙粒病毒(Paranamammarenavirus)、帕拉马塔河病毒(Parramatta River virus)、小型反刍动物瘟疫病毒(Peste-des-petits-ruminants virus)、毕赤德哺乳类沙粒病毒(Pichandemammarenavirus)、小RNA病毒科病毒、皮里陶哺乳类沙粒病毒(Piritalmammarenavirus)、鱼戊型肝炎病毒A(Piscihepevirus A)、猪副流感病毒1、猪腮腺炎病毒(porcinerubulavirus)、波瓦桑病毒(Powassan virus)、灵长类动物T-嗜淋巴细胞病毒1-2、灵长类动物红系细小病毒1(Primate erythroparvovirus 1)、庞塔托鲁病毒(PuntaTorovirus)、普马拉病毒(Puumala virus)、广平病毒(Quang Binh virus)、狂犬病病毒、拉兹丹病毒(Razdan virus)、爬行动物博尔纳病毒(Reptile bornavirus 1)、鼻病毒A-B、里夫特山谷热病毒(Rift Valley fevervirus)、牛瘟病毒、热伯维病毒(Rio Bravo virus)、啮齿动物细环病毒(Rodent Torque Teno virus)、啮齿动物丙型肝炎病毒(Rodenthepacivirus)、罗斯河病毒、轮状病毒A-I、皇家农场病毒(Royal Farm virus)、风疹病毒、萨比亚哺乳类沙粒病毒(Sabia mammarenavirus)、塞勒姆病毒(Salem virus)、那不勒斯白蛉热病毒(Sandfly fever Naples virus)、西西里白蛉热病毒(Sandfly feverSicilianvirus)、札幌病毒(Sapporo virus)、萨苏伯里病毒 (Sathuperi virus)、海豹指环病毒(Seal anellovirus)、塞姆利基森林病毒(Semliki Forest virus)、仙台病毒(Sendaivirus)、汉城病毒 (Seoul virus)、塞皮克病毒(Sepik virus)、严重急性呼吸综合征相关冠状病毒、严重发热伴血小板减少综合征病毒、沙门达病毒(Shamonda virus)、希莫尼蝙蝠病毒 (Shimoni bat virus)、舒尼病毒(Shuni virus)、西姆布病毒(Simbu virus)、猿猴细环病毒(Simian torque teno virus)、猿猴病毒 40-41、辛诺柏病毒(Sin Nombrevirus)、辛德毕斯病毒、小指环病毒(Small anellovirus)、索素佳病毒(Sosuga virus)、西班牙山羊脑炎病毒(Spanish goat encephalitis virus)、斯庞德温尼病毒(Spondwenivirus)、圣路易斯脑炎病毒 (St.Louis encephalitis virus)、森夏恩病毒(Sunshinevirus)、 TTV样微小病毒(TTV-like mini virus)、塔卡里伯哺乳类沙粒病毒(Tacaribemammarenavirus)、台依病毒(Taila virus)、塔玛纳蝙蝠病毒(Tamana batvirus)、塔米埃米哺乳类沙粒病毒(Tamiami mammarenavirus)、坦布苏病毒(Tembusuvirus)、托高土病毒(Thogoto virus)、索托帕拉雅病毒(Thottapalayam virus)、蜱传脑炎病毒(Tick-borneencephalitis virus)、刁曼病毒(Tioman virus)、披膜病毒科病毒、犬细环病毒 (Torqueteno canis virus)、夜猴细环病毒(Torque teno douroucouli virus)、猫细环病毒(Torque teno felis virus)、中细环病毒(Torque teno midi virus)、猪细环病毒(Torque teno sus virus)、狨猴细环病毒(Torque teno tamarin virus)、细环病毒(Torque teno virus)、海狮细环病毒(Torque teno zalophus virus)、吐霍克病毒(Tuhoko virus)、图拉病毒(Tula virus)、树鼩副粘病毒、乌苏图病毒(Usutu virus)、尤库尼米病毒 (Uukuniemi virus)、痘苗病毒、天花病毒、委内瑞拉马脑炎病毒(Venezuelanequine encephalitis virus)、印第安纳水泡性口炎病毒(VesicularstomatitisIndiana virus)、WU多瘤病毒、韦塞尔斯布朗病毒(Wesselsbron virus)、西高加索蝙蝠病毒 (West Caucasian bat virus)、西尼罗河病毒、西方马脑炎病毒 (Westernequineencephalitis virus)、怀特沃特阿罗约哺乳类沙粒病毒(WhitewaterArroyomammarenavirus)、黄热病病毒、横须贺病毒(Yokose virus)、尤格波格丹诺夫奇病毒 (YugBogdanovac virus)、扎伊尔埃博拉病毒(Zaire ebolavirus)、寨卡病毒或拜氏接合酵母病毒Z病毒序列 (Zygosaccharomyces bailii virus Z viral sequence)。可以检测的 RNA病毒的实例包括以下一种或多种(或其任何组合):冠状病毒科病毒、小RNA病毒科病毒、杯状病毒科病毒、黄病毒科病毒、披膜病毒科病毒、玻那病毒科、丝状病毒科、副粘病毒科、肺泡病毒科、弹状病毒科、沙粒病毒科、布尼亚病毒科、正粘病毒科或丁型病毒。在某些示例性实施方案中,病毒是冠状病毒、SARS、SARS-CoV-2、脊髓灰质炎病毒、鼻病毒、甲型肝炎、诺瓦克病毒、黄热病病毒、西尼罗河病毒、丙型肝炎病毒、登革热病毒、寨卡病毒、风疹病毒、罗斯河病毒、辛德毕斯病毒、基孔肯雅病毒、博尔纳病病毒、埃博拉病毒、马尔堡病毒、麻疹病毒、腮腺炎病毒、尼帕病毒、亨德拉病毒、新城疫病毒、人呼吸道合胞病毒、狂犬病病毒、拉沙病毒、汉坦病毒、克里米亚-刚果出血热病毒、流感或丁型肝炎病毒。
在某些示例性实施方案中,病毒可以是逆转录病毒。可以使用本文所公开的实施方案检测的示例性逆转录病毒包括以下病毒中的一种或多种或任何组合:α逆转录病毒属、β逆转录病毒属、γ逆转录病毒属、δ逆转录病毒属、ε逆转录病毒属、慢病毒属、泡沫病毒属(Spumavirus),或转座病毒科 (Metaviridae)、假病毒科(Pseudoviridae)和逆转录病毒科(Retroviridae)(包括HIV)、嗜肝DNA病毒科 (Hepadnaviridae)(包括乙型肝炎病毒)和花椰菜花叶病毒科(Caulimoviridae)(包括花椰菜花叶病毒)。
在某些示例性的实施方案中,病毒是DNA病毒。可以使用本文所公开的实施方案检测的示例性DNA病毒尤其包括来自以下科的病毒中的一种或多种(或其任何组合):肌病毒科(Myoviridae)、短尾病毒科(Podoviridae)、长尾病毒科(Siphoviridae)、异疱疹病毒科(Alloherpesviridae)、疱疹病毒科(Herpesviridae)(包括人疱疹病毒和水痘带状疱疹病毒)、马洛疱疹病毒科 (Malocoherpesviridae)、脂毛病毒科(Lipothrixviridae)、小杆状病毒科(Rudiviridae)、腺病毒科(Adenoviridae)、瓶状病毒科 (Ampullaviridae)、囊泡病毒科(Ascoviridae)、非洲猪瘟病毒科 (Asfarviridae)(包括非洲猪瘟病毒)、杆状病毒科(Baculoviridae)、西坎达病毒科(Cicaudaviridae)、棒状病毒科 (Clavaviridae)、覆盖噬菌体科(Corticoviridae)、微小纺锤形病毒科(Fuselloviridae)、球状病毒科(Globuloviridae)、滴状病毒科(Guttaviridae)、肥大唾腺炎病毒科(Hytrosaviridae)、虹彩病毒科(Iridoviridae)、马赛病毒科(Maseilleviridae)、拟菌病毒科(Mimiviridae)、裸病毒科(Nudiviridae)、线形病毒科 (Nimaviridae)、潘多拉病毒科(Pandoraviridae)、乳头瘤病毒科 (Papillomaviridae)、藻类DNA病毒科(Phycodnaviridae)、原质病毒科(Plasmaviridae)、多DNA病毒(Polydnavirus)、多瘤病毒科(Polyomaviridae)(包括猿猴病毒40、JC病毒、BK病毒)、痘病毒科(Poxviridae)(包括牛痘和天花)、球脂状病毒科(Sphaerolipoviridae)、复层病毒科(Tectiviridae)、图里病毒科 (Turriviridae)、地诺DNA病毒(Dinodnavirus)、盐末端蛋白病毒(Salterprovirus)、瑞兹病毒(Rhizidovirus)。在一些实施方案中,一种诊断疑似具有细菌感染的受试者中的种类特异性细菌感染的方法被描述为从受试者获得包含细菌核糖体核糖核酸的样品;使样品与所描述的探针中的一个或多个接触;以及检测样品中存在的细菌核糖体核糖核酸序列与探针之间的杂交,其中杂交的检测指示受试者受以下细菌感染:大肠杆菌、肺炎克雷伯菌、绿脓假单胞菌、金黄色葡萄球菌、鲍曼不动杆菌(Acinetobacter baumannii)、白色念珠菌、阴沟肠杆菌、粪肠球菌、屎肠球菌、奇异变形杆菌、无乳葡萄球菌(Staphylococcus agalactiae)或嗜麦芽葡萄球菌(Staphylococcus maltophilia)或它们的组合。
所述的用于检测的样品不仅局限于生物样品,还可以是环境样品。所述环境样品获自食物样品、纸表面、织物、金属表面、木材表面、塑料表面、土壤样品、淡水样品、废水样品、盐水样品,或它们的组合。用于本发明的样品可以是生物或环境样品,例如食物样品(新鲜水果或蔬菜、肉)、饮料样品、纸表面、织物表面、金属表面、木材表面、塑料表面、土壤样品、淡水样品、废水样品、盐水样品、暴露于大气或其他气体样品,或它们的组合。举例来说,可以拭抹由包括但不限于金属、木材、塑料、橡胶等的任何材料制成的家用/商业/工业表面并测试污染物。可以针对病原性细菌或寄生虫或者其他微生物的存在测试土壤样品,用于环境目的和/或用于人、动物或植物疾病测试。可以评估例如淡水样品、废水样品或盐水样品的水样品的清洁度和安全性和/或可饮用性,以检测例如微小隐孢子虫(Cryptosporidiumparvum)、蓝氏贾第鞭毛虫(Giardia lamblia)或其他微生物污染的存在。在一些特定实施方案中,环境样品或生物样品可以是粗样品和/或在应用方法之前一种或多种靶分子可能未从样品纯化或扩增。微生物的鉴别可以适用于许多应用和/或为许多应用所需,并且因此可以根据本发明使用本领域技术人员认为适当的来自任何来源的任何类型的样品。
实施例
实验材料和方法
蛋白表达和纯化
根据之前的报道纯化Cas12i。简言之,BPK2014-Cas12i-His10 蛋白在大肠杆菌菌株BL21(λDE3)中表达,用0.5mM IPTG在16℃诱导表达16小时。收获细胞沉淀并裂解,使用His60 Ni Superflow Resin(Thermo Fisher)纯化。将纯化的Cas12i蛋白透析,浓缩定量。
核酸制备
DNA寡核苷酸和经化学合成修饰的RNA经商购获得 (GenScript)。双链DNA激活物通过PCR扩增获得并使用Oligo Clean&Concentrator Kit(ZYMO Research)纯化。crRNA使用 HiScribeTM T7 High Yield RNA Synthesis Kit(NEB)体外转录并用 Oligo Clean&Concentrator Kit(ZYMO Research)纯化,Qubit定量。荧光团猝灭剂(FQ)-标记的报告测定
用一定浓度Cas12i、crRNA、激活物、定制合成的均聚物 ssDNA/ssRNA FQ报告基因和反应buffer(除非另有说明)在Corning 384-孔聚苯乙烯NBS微孔板/Axygene八连管中进行20μl反应检测测定。将反应物在37℃下孵育以在荧光板读数器(BioTek Synergy4) 中指示时间,每5分钟测量荧光动力学(λex=485nm;λem=528nm,透射增益=61)。或者在Applied Biosystems公司real-time PCR系统 (Thermo Fisher)中在一定温度孵育30分钟,每分钟测量一次荧光动力学。通过SigmaPlot 14.0软件分析荧光/ΔRn结果。
重组酶聚合酶扩增(RPA)反应
根据制造商的方案,使用TwistAmp Basic(TwistDx)进行重组酶聚合酶扩增(R反应。将含有不同DNA输入量的50μl RPA反应系统在 37℃下孵育10分钟。如上所述,将5μlRPA产物直接转移至55μl检测荧光团猝灭剂(FQ)-标记的报告系统试验。
环介导等温扩增(LAMP)实验
根据制造商的方案,使用Bst2.0DNA聚合酶、Bst3.0DNA聚合酶、热启动RTx逆转录酶,混合对应扩增引物。将含有不同DNA输入量的50μl LAMP反应系统在65℃下孵育40-60分钟。如上所述,将5μlLAMP产物直接转移至55μl检测荧光团猝灭剂(FQ)-标记的报告系统试验。
一步检测系统将待测样品加入到CRISPR/Cas12i与等温扩增的酶混合后在一定温度下敷育,将产物可用于在AppliedBiosystems公司real-time PCR系统(Thermo Fisher)中在一定温度孵育30分钟,每分钟测量一次荧光动力学,通过SigmaPlot 14.0软件分析荧光/ΔRn结果。或者通过 ssDNA/ssRNAFB报告基因在侧向流层析上判读结果。
侧向流层析判读系统
将用Cas12i、crRNA、激活物、定制合成的均聚物ssDNA/ssRNA FB报告基因和反应buffer(除非另有说明)扩增后产物存在的检测体系中敷育,将产物与稀释液按说明书稀释后,插入试纸条(Milenia HybriDetect Dipstick)判读结果。
将采集到的图像用photoshop转换为8位灰度,导入ImageLab 软件(BioRadImageLab software)。图像被反转。在同一幅图像中,各条带之间的条带宽度和背景调整保持不变。计算方法是将顶部(测试) 带的强度除以底部(对照)带的强度。
假病毒的制备
利用lenti-CRISPR-V2构建lenti-target,连同psPAX2和pMD2.G 通过脂质体试剂(Life Technology)共转染HEK293T细胞。转染48和 72小时后,收集培养基,用Ultra-15离心过滤器(Millipore) 过滤浓缩。用QPCR法计算滴定。
假病毒核酸提取
为了模拟实际的病毒检测,将咽拭子加入病毒转运培养基(友康) 中稀释慢病毒,制成样品。病毒RNA提取试剂盒。采用QIAamp病毒RNA迷你试剂盒(QIAGEN)按照厂家方案进行。对于裂解液,使用与慢病毒混合热灭活(95℃,5分钟)混合。对于磁珠处理是将商用磁珠(Beckman Coulter,B23317)的磁珠与慢病毒混合热灭活(95℃,5 分钟)混合。快速DNA提取液按说明书添加。混合物在室温下5分钟,然后转移到磁力架上。磁珠用1毫升70%的乙醇清洗,然后晾干5 分钟。检测体系直接加入到微珠中,反应混合物在适宜温度下孵育 1-2小时。在有些执行方案中,以上概述的洗涤和干燥步骤被跳过,并使用了使用不含KCl的改良1X等温扩增缓冲液(20mM Tris-HCl, 10mM(NH4)2SO4,2mM MgSO4,0.1%Tween 20,pH 8.8)来替代上述缓冲液。
实施例1、Cas12i的反式ssDNA切割活性的表征
CRISPR-Cas12i1(氨基酸序列示于SEQ ID NO:1),Cas12i2核酸酶 (氨基酸序列示于SEQ ID NO:2)因为其具有经典的dsDNA靶向切割能力。为了表征Cas12i的非经典反式旁路切割活性,Cas12i识别靶双链DNA(dsDNA)并非特异性切割单链DNA(ssDNA)。反应体系中缺少Cas12i、crRNA、靶dsDNA时,反式ssDNA(ploy_T-FQ) 不能被切割而释放荧光信号,说明检测到的荧光信号不是由 ploy_T-FQ降解产生;反应体系中缺少crRNA和/或靶dsDNA时,反式ssDNA不能被切割,说明Cas12i只有在靶DNA存在和crRNA的指引下才会激活其对反式ssDNA的切割活性(图1、图2)。结果表明 Cas12i-crRNA复合物一旦被与向导序列互补的DNA触发,就可以获得非特异性ssDNA反式切割活性。
实施例2、开发Cas12i介导的DNA检测系统
为了开发Cas12i介导的DNA检测系统,首先分析了 Cas12i-crRNA复合物对荧光团-猝灭剂(FQ)标记的同聚物报告分子的切割偏好。发现Cas12i偏好多聚胸苷酸(ployT)以及多聚腺苷酸(polyA) 和多聚胞苷酸(poly C),而多聚鸟苷酸(poly G)基本上不被切割(图3)。同时,进行poly_rU-FQ、poly_rA-FQ、poly_rG-FQ、poly_rC-FQ的切割偏好实验,结果显示poly_rU能被Cas12i非特异性切割(图4、 5)。为了能够提高切割效率,我们对crRNA进行了化学修饰,在5’和3’端的前3个碱基用甲氧基和硫代修饰后,Cas12i2反式切割效率提高,表现在:荧光信号更强,释放速度更快。化学修饰的crRNA 能提高Cas12i2单链DNA反式切割效率。同时也利用2’-OMe、2’-F 以及2’-锁型结构的RNA核苷酸单体NTP合成的crRNA,Cas12i在修饰过的NTP合成的crRNA指引和靶DNA的激活下,Cas12i反式切割效率提高,表现在:荧光信号更强,释放速度更快。说明修饰过的NTP合成的crRNA能提高Cas12i单链DNA反式切割效率(图6、 7)。
实施例3、开发Cas12i变体介导的DNA检测系统
为了进一步提高反式切割的效率,我们获得了Cas12i的3种变体A,B,C(氨基酸序列示于SEQ ID NO:3,4,5。检测证明变体存在反式切割效率的提高(图8),随后进行了Cas12i及其变体反式切割碱基偏好性检测。Cas12i在crRNA指引和靶DNA的激活下,分别进行 poly_T-FQ、poly_A-FQ、poly_G-FQ、poly_C-FQ的切割实验的报告分子的切割偏好性(图9)。同时进行了Cas12i及其变体反式切割 ssDNA长度偏好性检测,Cas12i在crRNA指引和靶DNA的激活下,分别进行荧光基团修饰的ssDNA长度为 4nt,5nt,7nt,12nt,17nt,22nt,27nt的切割实验(图10)。
为了进一步探究Cas12i及其变体的性质,检测了最适检测温度范围。通过对Cas12i在37度,42度,47度,52度,57度,62度, 67度对于单链DNA探针的检测,其最适温度范围在37度~47度(图11)。进行Cas12i与crRNA浓度比例优化能够提高检测信号。通过对Cas12i及其变体在与crRNA比例2:6,4:6,6:6,2:10,4:10, 6:10对于单链DNA探针的检测,发现Cas12i与crRNA浓度比例经过优化能够提高检测信号(图12)。
为了测试双链DNA激活子的长度对于反式切割效率的影响,通过对Cas12i及其变体在与crRNA指引下对于带有检测靶点的 100bp,200bp,300bp,400bp,500bp,600bp,800bp双链DNA进行检测(图 13)。同时液通过对Cas12i及其变体在与 14nt,16nt,18nt,20nt,22nt,24nt,26nt的spacer长度的crRNA的指引下对靶DNA进行检测(图14)。
实施例4、优化Cas12i变体介导的DNA检测系统
为了验证这一系统的特异性,通过对Cas12i及其变体在spacer 上的单个碱基的mismatch合成的crRNA的指引下对靶DNA进行检测,结果如图所示,crRNA spacer区域单个碱基和连续两个碱基的mismatch合成的crRNA的指引下对靶DNA进行检测,结果如图(图14).并且基于上述现象引入tsgRNA的设计,在spacer提前引入一个点突变,能够提高本系统对相似程度很高的位点(只相差一个碱基) 的识别特异性。
实施例5、比较Cas12i变体介导的DNA检测系统的灵敏度与特异性
由SARS-CoV-2(severe acute respiratory syndrome coronavirus-2) 引起的新型冠状病毒肺炎COVID-19正在全球范围内引发大规模流行,威胁全球公共卫生系统安全。在此次新冠肺炎疫情中,核酸检测在疾病的早期诊断中发挥了重要作用。到目前为止,已经发表了多种基于CRISPR的SARS-CoV-2检测方案。于是在新型冠状病毒基因组的N、E、S基因中进行检测位点的筛选(图15a),使用Cas12i Variant 可以筛选出多个荧光信号强的病毒检测位点(表2)。随后为了提高检测灵敏度,将Cas12i及其变体搭载等温扩增技术RPA两步荧光检测进行灵敏度与特异性实验。结果表明,该检测方式能够达到亚渺摩尔级灵敏度,并且无其他交叉反应(图15b)。
实施例6、Cas12i变体介导的DNA检测系统与侧向流层析结合
为了更好地结合POCT,尝试将Cas12i及其变体在搭载等温扩增技术RPA、LAMP与侧向流结合试纸化。我们使用了FAM和生物素修饰的探针:5’FAM-TTTTTTT-Biotin3’作为切割探针进行检测,从横向流动底物的第一端向上游流动的溶液是第一个测试带。测试带可包含生物素配体。因此,当探针呈现其初始状态时,即在没有靶点的情况下,第一端的FAM分子将与金纳米粒子上的抗FITC抗体结合,探针第二端的生物素会结合生物素配体,让可检测的配体在第一次测试时积累,产生可检测的信号。在第一条带上产生可检测的信号表明目标配体的缺失。在靶向DNA存在的情况下,CRISPR效应器复合物形成,Cas12i(Cas12i1,Cas12i2,Cas12iVar1,Cas12iVar2,Cas12iVar3) 蛋白被激活,导致探针被切割。在没有完整的探针的情况下,胶体金将流向第二条带。横向流动装置可包括第一带上游的第二带。第二条带可以包括能够结合抗体标记的胶体金分子的分子,例如将兔抗 FTIC抗体结合到胶体金上的兔抗抗体。因此,在存在一个或多个靶点的情况下,可检测的配体将聚集在第二个带上,表明样品中存在一个或多个靶点在一些实施例中,可检测配体可为胶体金,其连接第一抗体。在特定实施例中,第一抗体可为抗FITC抗体。浓度为125nM, 更换掉荧光检测中的荧光探针,并结合等温扩增RPA扩增新冠病毒基因组核酸,随后用扩增产物加入监测体系中切割试纸反应探针,切割产物按照商品化试纸说明书操作,检测结果在侧向流上的结果如图所示(图15c),检测结果可以在试纸上直接判读。结果表明,与侧向流层析结合的检测方式能够达到亚渺摩尔级灵敏度100000拷贝每毫升,并且无其他交叉反应。
序列表
表1.本申请涉及的氨基酸序列表
表2.实施例中涉及的引物序列
序列表
<110> 北京干细胞与再生医学研究院
中国科学院动物研究所
<120> 基于Cas12i的核酸检测方法
<130> PE01980
<141> 2021-12-07
<150> CN202011417683.2
<151> 2020-12-07
<160> 45
<170> SIPOSequenceListing 1.0
<210> 1
<211> 1093
<212> PRT
<213> Artificial Sequence
<220>
<223> CAS12i1
<400> 1
Met Ser Asn Lys Glu Lys Asn Ala Ser Glu Thr Arg Lys Ala Tyr Thr
1 5 10 15
Thr Lys Met Ile Pro Arg Ser His Asp Arg Met Lys Leu Leu Gly Asn
20 25 30
Phe Met Asp Tyr Leu Met Asp Gly Thr Pro Ile Phe Phe Glu Leu Trp
35 40 45
Asn Gln Phe Gly Gly Gly Ile Asp Arg Asp Ile Ile Ser Gly Thr Ala
50 55 60
Asn Lys Asp Lys Ile Ser Asp Asp Leu Leu Leu Ala Val Asn Trp Phe
65 70 75 80
Lys Val Met Pro Ile Asn Ser Lys Pro Gln Gly Val Ser Pro Ser Asn
85 90 95
Leu Ala Asn Leu Phe Gln Gln Tyr Ser Gly Ser Glu Pro Asp Ile Gln
100 105 110
Ala Gln Glu Tyr Phe Ala Ser Asn Phe Asp Thr Glu Lys His Gln Trp
115 120 125
Lys Asp Met Arg Val Glu Tyr Glu Arg Leu Leu Ala Glu Leu Gln Leu
130 135 140
Ser Arg Ser Asp Met His His Asp Leu Lys Leu Met Tyr Lys Glu Lys
145 150 155 160
Cys Ile Gly Leu Ser Leu Ser Thr Ala His Tyr Ile Thr Ser Val Met
165 170 175
Phe Gly Thr Gly Ala Lys Asn Asn Arg Gln Thr Lys His Gln Phe Tyr
180 185 190
Ser Lys Val Ile Gln Leu Leu Glu Glu Ser Thr Gln Ile Asn Ser Val
195 200 205
Glu Gln Leu Ala Ser Ile Ile Leu Lys Ala Gly Asp Cys Asp Ser Tyr
210 215 220
Arg Lys Leu Arg Ile Arg Cys Ser Arg Lys Gly Ala Thr Pro Ser Ile
225 230 235 240
Leu Lys Ile Val Gln Asp Tyr Glu Leu Gly Thr Asn His Asp Asp Glu
245 250 255
Val Asn Val Pro Ser Leu Ile Ala Asn Leu Lys Glu Lys Leu Gly Arg
260 265 270
Phe Glu Tyr Glu Cys Glu Trp Lys Cys Met Glu Lys Ile Lys Ala Phe
275 280 285
Leu Ala Ser Lys Val Gly Pro Tyr Tyr Leu Gly Ser Tyr Ser Ala Met
290 295 300
Leu Glu Asn Ala Leu Ser Pro Ile Lys Gly Met Thr Thr Lys Asn Cys
305 310 315 320
Lys Phe Val Leu Lys Gln Ile Asp Ala Lys Asn Asp Ile Lys Tyr Glu
325 330 335
Asn Glu Pro Phe Gly Lys Ile Val Glu Gly Phe Phe Asp Ser Pro Tyr
340 345 350
Phe Glu Ser Asp Thr Asn Val Lys Trp Val Leu His Pro His His Ile
355 360 365
Gly Glu Ser Asn Ile Lys Thr Leu Trp Glu Asp Leu Asn Ala Ile His
370 375 380
Ser Lys Tyr Glu Glu Asp Ile Ala Ser Leu Ser Glu Asp Lys Lys Glu
385 390 395 400
Lys Arg Ile Lys Val Tyr Gln Gly Asp Val Cys Gln Thr Ile Asn Thr
405 410 415
Tyr Cys Glu Glu Val Gly Lys Glu Ala Lys Thr Pro Leu Val Gln Leu
420 425 430
Leu Arg Tyr Leu Tyr Ser Arg Lys Asp Asp Ile Ala Val Asp Lys Ile
435 440 445
Ile Asp Gly Ile Thr Phe Leu Ser Lys Lys His Lys Val Glu Lys Gln
450 455 460
Lys Ile Asn Pro Val Ile Gln Lys Tyr Pro Ser Phe Asn Phe Gly Asn
465 470 475 480
Asn Ser Lys Leu Leu Gly Lys Ile Ile Ser Pro Lys Asp Lys Leu Lys
485 490 495
His Asn Leu Lys Cys Asn Arg Asn Gln Val Asp Asn Tyr Ile Trp Ile
500 505 510
Glu Ile Lys Val Leu Asn Thr Lys Thr Met Arg Trp Glu Lys His His
515 520 525
Tyr Ala Leu Ser Ser Thr Arg Phe Leu Glu Glu Val Tyr Tyr Pro Ala
530 535 540
Thr Ser Glu Asn Pro Pro Asp Ala Leu Ala Ala Arg Phe Arg Thr Lys
545 550 555 560
Thr Asn Gly Tyr Glu Gly Lys Pro Ala Leu Ser Ala Glu Gln Ile Glu
565 570 575
Gln Ile Arg Ser Ala Pro Val Gly Leu Arg Lys Val Lys Lys Arg Gln
580 585 590
Met Arg Leu Glu Ala Ala Arg Gln Gln Asn Leu Leu Pro Arg Tyr Thr
595 600 605
Trp Gly Lys Asp Phe Asn Ile Asn Ile Cys Lys Arg Gly Asn Asn Phe
610 615 620
Glu Val Thr Leu Ala Thr Lys Val Lys Lys Lys Lys Glu Lys Asn Tyr
625 630 635 640
Lys Val Val Leu Gly Tyr Asp Ala Asn Ile Val Arg Lys Asn Thr Tyr
645 650 655
Ala Ala Ile Glu Ala His Ala Asn Gly Asp Gly Val Ile Asp Tyr Asn
660 665 670
Asp Leu Pro Val Lys Pro Ile Glu Ser Gly Phe Val Thr Val Glu Ser
675 680 685
Gln Val Arg Asp Lys Ser Tyr Asp Gln Leu Ser Tyr Asn Gly Val Lys
690 695 700
Leu Leu Tyr Cys Lys Pro His Val Glu Ser Arg Arg Ser Phe Leu Glu
705 710 715 720
Lys Tyr Arg Asn Gly Thr Met Lys Asp Asn Arg Gly Asn Asn Ile Gln
725 730 735
Ile Asp Phe Met Lys Asp Phe Glu Ala Ile Ala Asp Asp Glu Thr Ser
740 745 750
Leu Tyr Tyr Phe Asn Met Lys Tyr Cys Lys Leu Leu Gln Ser Ser Ile
755 760 765
Arg Asn His Ser Ser Gln Ala Lys Glu Tyr Arg Glu Glu Ile Phe Glu
770 775 780
Leu Leu Arg Asp Gly Lys Leu Ser Val Leu Lys Leu Ser Ser Leu Ser
785 790 795 800
Asn Leu Ser Phe Val Met Phe Lys Val Ala Lys Ser Leu Ile Gly Thr
805 810 815
Tyr Phe Gly His Leu Leu Lys Lys Pro Lys Asn Ser Lys Ser Asp Val
820 825 830
Lys Ala Pro Pro Ile Thr Asp Glu Asp Lys Gln Lys Ala Asp Pro Glu
835 840 845
Met Phe Ala Leu Arg Leu Ala Leu Glu Glu Lys Arg Leu Asn Lys Val
850 855 860
Lys Ser Lys Lys Glu Val Ile Ala Asn Lys Ile Val Ala Lys Ala Leu
865 870 875 880
Glu Leu Arg Asp Lys Tyr Gly Pro Val Leu Ile Lys Gly Glu Asn Ile
885 890 895
Ser Asp Thr Thr Lys Lys Gly Lys Lys Ser Ser Thr Asn Ser Phe Leu
900 905 910
Met Asp Trp Leu Ala Arg Gly Val Ala Asn Lys Val Lys Glu Met Val
915 920 925
Met Met His Gln Gly Leu Glu Phe Val Glu Val Asn Pro Asn Phe Thr
930 935 940
Ser His Gln Asp Pro Phe Val His Lys Asn Pro Glu Asn Thr Phe Arg
945 950 955 960
Ala Arg Tyr Ser Arg Cys Thr Pro Ser Glu Leu Thr Glu Lys Asn Arg
965 970 975
Lys Glu Ile Leu Ser Phe Leu Ser Asp Lys Pro Ser Lys Arg Pro Thr
980 985 990
Asn Ala Tyr Tyr Asn Glu Gly Ala Met Ala Phe Leu Ala Thr Tyr Gly
995 1000 1005
Leu Lys Lys Asn Asp Val Leu Gly Val Ser Leu Glu Lys Phe Lys Gln
1010 1015 1020
Ile Met Ala Asn Ile Leu His Gln Arg Ser Glu Asp Gln Leu Leu Phe
1025 1030 1035 1040
Pro Ser Arg Gly Gly Met Phe Tyr Leu Ala Thr Tyr Lys Leu Asp Ala
1045 1050 1055
Asp Ala Thr Ser Val Asn Trp Asn Gly Lys Gln Phe Trp Val Cys Asn
1060 1065 1070
Ala Asp Leu Val Ala Ala Tyr Asn Val Gly Leu Val Asp Ile Gln Lys
1075 1080 1085
Asp Phe Lys Lys Lys
1090
<210> 2
<211> 1054
<212> PRT
<213> Artificial Sequence
<220>
<223> CAS12i2
<400> 2
Met Ser Ser Ala Ile Lys Ser Tyr Lys Ser Val Leu Arg Pro Asn Glu
1 5 10 15
Arg Lys Asn Gln Leu Leu Lys Ser Thr Ile Gln Cys Leu Glu Asp Gly
20 25 30
Ser Ala Phe Phe Phe Lys Met Leu Gln Gly Leu Phe Gly Gly Ile Thr
35 40 45
Pro Glu Ile Val Arg Phe Ser Thr Glu Gln Glu Lys Gln Gln Gln Asp
50 55 60
Ile Ala Leu Trp Cys Ala Val Asn Trp Phe Arg Pro Val Ser Gln Asp
65 70 75 80
Ser Leu Thr His Thr Ile Ala Ser Asp Asn Leu Val Glu Lys Phe Glu
85 90 95
Glu Tyr Tyr Gly Gly Thr Ala Ser Asp Ala Ile Lys Gln Tyr Phe Ser
100 105 110
Ala Ser Ile Gly Glu Ser Tyr Tyr Trp Asn Asp Cys Arg Gln Gln Tyr
115 120 125
Tyr Asp Leu Cys Arg Glu Leu Gly Val Glu Val Ser Asp Leu Thr His
130 135 140
Asp Leu Glu Ile Leu Cys Arg Glu Lys Cys Leu Ala Val Ala Thr Glu
145 150 155 160
Ser Asn Gln Asn Asn Ser Ile Ile Ser Val Leu Phe Gly Thr Gly Glu
165 170 175
Lys Glu Asp Arg Ser Val Lys Leu Arg Ile Thr Lys Lys Ile Leu Glu
180 185 190
Ala Ile Ser Asn Leu Lys Glu Ile Pro Lys Asn Val Ala Pro Ile Gln
195 200 205
Glu Ile Ile Leu Asn Val Ala Lys Ala Thr Lys Glu Thr Phe Arg Gln
210 215 220
Val Tyr Ala Gly Asn Leu Gly Ala Pro Ser Thr Leu Glu Lys Phe Ile
225 230 235 240
Ala Lys Asp Gly Gln Lys Glu Phe Asp Leu Lys Lys Leu Gln Thr Asp
245 250 255
Leu Lys Lys Val Ile Arg Gly Lys Ser Lys Glu Arg Asp Trp Cys Cys
260 265 270
Gln Glu Glu Leu Arg Ser Tyr Val Glu Gln Asn Thr Ile Gln Tyr Asp
275 280 285
Leu Trp Ala Trp Gly Glu Met Phe Asn Lys Ala His Thr Ala Leu Lys
290 295 300
Ile Lys Ser Thr Arg Asn Tyr Asn Phe Ala Lys Gln Arg Leu Glu Gln
305 310 315 320
Phe Lys Glu Ile Gln Ser Leu Asn Asn Leu Leu Val Val Lys Lys Leu
325 330 335
Asn Asp Phe Phe Asp Ser Glu Phe Phe Ser Gly Glu Glu Thr Tyr Thr
340 345 350
Ile Cys Val His His Leu Gly Gly Lys Asp Leu Ser Lys Leu Tyr Lys
355 360 365
Ala Trp Glu Asp Asp Pro Ala Asp Pro Glu Asn Ala Ile Val Val Leu
370 375 380
Cys Asp Asp Leu Lys Asn Asn Phe Lys Lys Glu Pro Ile Arg Asn Ile
385 390 395 400
Leu Arg Tyr Ile Phe Thr Ile Arg Gln Glu Cys Ser Ala Gln Asp Ile
405 410 415
Leu Ala Ala Ala Lys Tyr Asn Gln Gln Leu Asp Arg Tyr Lys Ser Gln
420 425 430
Lys Ala Asn Pro Ser Val Leu Gly Asn Gln Gly Phe Thr Trp Thr Asn
435 440 445
Ala Val Ile Leu Pro Glu Lys Ala Gln Arg Asn Asp Arg Pro Asn Ser
450 455 460
Leu Asp Leu Arg Ile Trp Leu Tyr Leu Lys Leu Arg His Pro Asp Gly
465 470 475 480
Arg Trp Lys Lys His His Ile Pro Phe Tyr Asp Thr Arg Phe Phe Gln
485 490 495
Glu Ile Tyr Ala Ala Gly Asn Ser Pro Val Asp Thr Cys Gln Phe Arg
500 505 510
Thr Pro Arg Phe Gly Tyr His Leu Pro Lys Leu Thr Asp Gln Thr Ala
515 520 525
Ile Arg Val Asn Lys Lys His Val Lys Ala Ala Lys Thr Glu Ala Arg
530 535 540
Ile Arg Leu Ala Ile Gln Gln Gly Thr Leu Pro Val Ser Asn Leu Lys
545 550 555 560
Ile Thr Glu Ile Ser Ala Thr Ile Asn Ser Lys Gly Gln Val Arg Ile
565 570 575
Pro Val Lys Phe Asp Val Gly Arg Gln Lys Gly Thr Leu Gln Ile Gly
580 585 590
Asp Arg Phe Cys Gly Tyr Asp Gln Asn Gln Thr Ala Ser His Ala Tyr
595 600 605
Ser Leu Trp Glu Val Val Lys Glu Gly Gln Tyr His Lys Glu Leu Gly
610 615 620
Cys Phe Val Arg Phe Ile Ser Ser Gly Asp Ile Val Ser Ile Thr Glu
625 630 635 640
Asn Arg Gly Asn Gln Phe Asp Gln Leu Ser Tyr Glu Gly Leu Ala Tyr
645 650 655
Pro Gln Tyr Ala Asp Trp Arg Lys Lys Ala Ser Lys Phe Val Ser Leu
660 665 670
Trp Gln Ile Thr Lys Lys Asn Lys Lys Lys Glu Ile Val Thr Val Glu
675 680 685
Ala Lys Glu Lys Phe Asp Ala Ile Cys Lys Tyr Gln Pro Arg Leu Tyr
690 695 700
Lys Phe Asn Lys Glu Tyr Ala Tyr Leu Leu Arg Asp Ile Val Arg Gly
705 710 715 720
Lys Ser Leu Val Glu Leu Gln Gln Ile Arg Gln Glu Ile Phe Arg Phe
725 730 735
Ile Glu Gln Asp Cys Gly Val Thr Arg Leu Gly Ser Leu Ser Leu Ser
740 745 750
Thr Leu Glu Thr Val Lys Ala Val Lys Gly Ile Ile Tyr Ser Tyr Phe
755 760 765
Ser Thr Ala Leu Asn Ala Ser Lys Asn Asn Pro Ile Ser Asp Glu Gln
770 775 780
Arg Lys Glu Phe Asp Pro Glu Leu Phe Ala Leu Leu Glu Lys Leu Glu
785 790 795 800
Leu Ile Arg Thr Arg Lys Lys Lys Gln Lys Val Glu Arg Ile Ala Asn
805 810 815
Ser Leu Ile Gln Thr Cys Leu Glu Asn Asn Ile Lys Phe Ile Arg Gly
820 825 830
Glu Gly Asp Leu Ser Thr Thr Asn Asn Ala Thr Lys Lys Lys Ala Asn
835 840 845
Ser Arg Ser Met Asp Trp Leu Ala Arg Gly Val Phe Asn Lys Ile Arg
850 855 860
Gln Leu Ala Pro Met His Asn Ile Thr Leu Phe Gly Cys Gly Ser Leu
865 870 875 880
Tyr Thr Ser His Gln Asp Pro Leu Val His Arg Asn Pro Asp Lys Ala
885 890 895
Met Lys Cys Arg Trp Ala Ala Ile Pro Val Lys Asp Ile Gly Asp Trp
900 905 910
Val Leu Arg Lys Leu Ser Gln Asn Leu Arg Ala Lys Asn Ile Gly Thr
915 920 925
Gly Glu Tyr Tyr His Gln Gly Val Lys Glu Phe Leu Ser His Tyr Glu
930 935 940
Leu Gln Asp Leu Glu Glu Glu Leu Leu Lys Trp Arg Ser Asp Arg Lys
945 950 955 960
Ser Asn Ile Pro Cys Trp Val Leu Gln Asn Arg Leu Ala Glu Lys Leu
965 970 975
Gly Asn Lys Glu Ala Val Val Tyr Ile Pro Val Arg Gly Gly Arg Ile
980 985 990
Tyr Phe Ala Thr His Lys Val Ala Thr Gly Ala Val Ser Ile Val Phe
995 1000 1005
Asp Gln Lys Gln Val Trp Val Cys Asn Ala Asp His Val Ala Ala Ala
1010 1015 1020
Asn Ile Ala Leu Thr Val Lys Gly Ile Gly Glu Gln Ser Ser Asp Glu
1025 1030 1035 1040
Glu Asn Pro Asp Gly Ser Arg Ile Lys Leu Gln Leu Thr Ser
1045 1050
<210> 3
<211> 1056
<212> PRT
<213> Artificial Sequence
<220>
<223> Cas12iVar1
<400> 3
Met Ser Ser Ala Ile Lys Ser Tyr Lys Ser Val Leu Arg Pro Asn Glu
1 5 10 15
Arg Lys Asn Gln Leu Leu Lys Ser Thr Ile Gln Cys Leu Glu Asp Gly
20 25 30
Ser Ala Phe Phe Phe Lys Met Leu Gln Gly Leu Phe Gly Gly Ile Thr
35 40 45
Pro Glu Ile Val Arg Phe Ser Thr Glu Gln Glu Lys Gln Gln Gln Asp
50 55 60
Ile Ala Leu Trp Cys Ala Val Asn Trp Phe Arg Pro Val Ser Gln Asp
65 70 75 80
Ser Leu Thr His Thr Ile Ala Ser Asp Asn Leu Val Glu Lys Phe Glu
85 90 95
Glu Tyr Tyr Gly Gly Thr Ala Ser Asp Ala Ile Lys Gln Tyr Phe Ser
100 105 110
Ala Ser Ile Gly Glu Ser Tyr Tyr Trp Asn Asp Cys Arg Gln Gln Tyr
115 120 125
Tyr Asp Leu Cys Arg Glu Leu Gly Val Glu Val Ser Asp Leu Thr His
130 135 140
Asp Leu Glu Ile Leu Cys Arg Glu Lys Cys Leu Ala Val Ala Thr Glu
145 150 155 160
Ser Asn Gln Asn Asn Ser Ile Ile Ser Val Leu Phe Gly Thr Gly Glu
165 170 175
Lys Glu Asp Arg Ser Val Lys Leu Arg Ile Thr Lys Lys Ile Leu Glu
180 185 190
Ala Ile Ser Asn Leu Lys Glu Ile Pro Lys Asn Val Ala Pro Ile Gln
195 200 205
Glu Ile Ile Leu Asn Val Ala Lys Ala Thr Lys Glu Thr Phe Arg Gln
210 215 220
Val Tyr Ala Gly Asn Leu Gly Ala Pro Ser Thr Leu Glu Lys Phe Ile
225 230 235 240
Ala Lys Asp Gly Gln Lys Glu Phe Asp Leu Lys Lys Leu Gln Thr Asp
245 250 255
Leu Lys Lys Val Ile Arg Gly Lys Ser Lys Glu Arg Asp Trp Cys Cys
260 265 270
Gln Glu Glu Leu Arg Ser Tyr Val Glu Gln Asn Thr Ile Gln Tyr Asp
275 280 285
Leu Trp Ala Trp Gly Glu Met Phe Asn Lys Ala His Thr Ala Leu Lys
290 295 300
Ile Lys Ser Thr Arg Asn Tyr Asn Phe Ala Lys Gln Arg Leu Glu Gln
305 310 315 320
Phe Lys Glu Ile Gln Ser Leu Asn Asn Leu Leu Val Val Lys Lys Leu
325 330 335
Asn Asp Phe Phe Asp Ser Glu Phe Phe Ser Gly Glu Glu Thr Tyr Thr
340 345 350
Ile Cys Val His His Leu Gly Gly Lys Asp Leu Ser Lys Leu Tyr Lys
355 360 365
Ala Trp Glu Asp Asp Pro Ala Asp Pro Glu Asn Ala Ile Val Val Leu
370 375 380
Cys Asp Asp Leu Lys Asn Asn Phe Lys Lys Glu Pro Ile Arg Asn Ile
385 390 395 400
Leu Arg Tyr Ile Phe Thr Ile Arg Gln Glu Cys Ser Ala Gln Asp Ile
405 410 415
Leu Ala Ala Ala Lys Tyr Asn Gln Gln Leu Asp Arg Tyr Lys Ser Gln
420 425 430
Lys Ala Asn Pro Ser Val Leu Gly Gly Gly Asn Gln Gly Phe Thr Trp
435 440 445
Thr Asn Ala Val Ile Leu Pro Glu Lys Ala Gln Arg Asn Asp Arg Pro
450 455 460
Asn Ser Leu Asp Leu Arg Ile Trp Leu Tyr Leu Lys Leu Arg His Pro
465 470 475 480
Asp Gly Arg Trp Lys Lys His His Ile Pro Phe Tyr Asp Thr Arg Phe
485 490 495
Phe Gln Glu Ile Tyr Ala Ala Gly Asn Ser Pro Val Asp Thr Cys Gln
500 505 510
Phe Arg Thr Pro Arg Phe Gly Tyr His Leu Pro Lys Leu Thr Asp Gln
515 520 525
Thr Ala Ile Arg Val Asn Lys Lys His Val Lys Ala Ala Lys Thr Glu
530 535 540
Ala Arg Ile Arg Leu Ala Ile Gln Gln Gly Thr Leu Pro Val Ser Asn
545 550 555 560
Leu Lys Ile Thr Glu Ile Ser Ala Thr Ile Asn Ser Lys Gly Gln Val
565 570 575
Arg Ile Pro Val Lys Phe Asp Val Gly Arg Gln Lys Gly Thr Leu Gln
580 585 590
Ile Gly Asp Arg Phe Cys Gly Tyr Asp Gln Asn Gln Thr Ala Ser His
595 600 605
Ala Tyr Ser Leu Trp Glu Val Val Lys Glu Gly Gln Tyr His Lys Glu
610 615 620
Leu Gly Cys Phe Val Arg Phe Ile Ser Ser Gly Asp Ile Val Ser Ile
625 630 635 640
Thr Glu Asn Arg Gly Asn Gln Phe Asp Gln Leu Ser Tyr Glu Gly Leu
645 650 655
Ala Tyr Pro Gln Tyr Ala Asp Trp Arg Lys Lys Ala Ser Lys Phe Val
660 665 670
Ser Leu Trp Gln Ile Thr Lys Lys Asn Lys Lys Lys Glu Ile Val Thr
675 680 685
Val Glu Ala Lys Glu Lys Phe Asp Ala Ile Cys Lys Tyr Gln Pro Arg
690 695 700
Leu Tyr Lys Phe Asn Lys Glu Tyr Ala Tyr Leu Leu Arg Asp Ile Val
705 710 715 720
Arg Gly Lys Ser Leu Val Glu Leu Gln Gln Ile Arg Gln Glu Ile Phe
725 730 735
Arg Phe Ile Glu Gln Asp Cys Gly Val Thr Arg Leu Gly Ser Leu Ser
740 745 750
Leu Ser Thr Leu Glu Thr Val Lys Ala Val Lys Gly Ile Ile Tyr Ser
755 760 765
Tyr Phe Ser Thr Ala Leu Asn Ala Ser Lys Asn Asn Pro Ile Ser Asp
770 775 780
Glu Gln Arg Lys Glu Phe Asp Pro Glu Leu Phe Ala Leu Leu Glu Lys
785 790 795 800
Leu Glu Leu Ile Arg Thr Arg Lys Lys Lys Gln Lys Val Glu Arg Ile
805 810 815
Ala Asn Ser Leu Ile Gln Thr Cys Leu Glu Asn Asn Ile Lys Phe Ile
820 825 830
Arg Gly Glu Gly Asp Leu Ser Thr Thr Asn Asn Ala Thr Lys Lys Lys
835 840 845
Ala Asn Ser Arg Ser Met Asp Trp Leu Ala Arg Gly Val Phe Asn Lys
850 855 860
Ile Arg Gln Leu Ala Pro Met His Asn Ile Thr Leu Phe Gly Cys Gly
865 870 875 880
Ser Leu Tyr Thr Ser His Gln Asp Pro Leu Val His Arg Asn Pro Asp
885 890 895
Lys Ala Met Lys Cys Arg Trp Ala Ala Ile Pro Val Lys Asp Ile Gly
900 905 910
Asp Trp Val Leu Arg Lys Leu Ser Gln Asn Leu Arg Ala Lys Asn Ile
915 920 925
Gly Thr Gly Glu Tyr Tyr His Gln Gly Val Lys Glu Phe Leu Ser His
930 935 940
Tyr Glu Leu Gln Asp Leu Glu Glu Glu Leu Leu Lys Trp Arg Ser Asp
945 950 955 960
Arg Lys Ser Asn Ile Pro Cys Trp Val Leu Gln Asn Arg Leu Ala Glu
965 970 975
Lys Leu Gly Asn Lys Glu Ala Val Val Tyr Ile Pro Val Arg Gly Gly
980 985 990
Arg Ile Tyr Phe Ala Thr His Lys Val Ala Thr Gly Ala Val Ser Ile
995 1000 1005
Val Phe Asp Gln Lys Gln Val Trp Val Cys Asn Ala Asp His Val Ala
1010 1015 1020
Ala Ala Asn Ile Ala Leu Thr Val Lys Gly Ile Gly Glu Gln Ser Ser
1025 1030 1035 1040
Asp Glu Glu Asn Pro Asp Gly Ser Arg Ile Lys Leu Gln Leu Thr Ser
1045 1050 1055
<210> 4
<211> 1054
<212> PRT
<213> Artificial Sequence
<220>
<223> Cas12iVar2
<400> 4
Met Ser Ser Ala Ile Lys Ser Tyr Lys Ser Val Leu Arg Pro Asn Glu
1 5 10 15
Arg Lys Asn Gln Leu Leu Lys Ser Thr Ile Gln Cys Leu Glu Asp Gly
20 25 30
Ser Ala Phe Phe Phe Lys Met Leu Gln Gly Leu Phe Gly Gly Ile Thr
35 40 45
Pro Glu Ile Val Arg Phe Ser Thr Glu Gln Glu Lys Gln Gln Gln Asp
50 55 60
Ile Ala Leu Trp Cys Ala Val Asn Trp Phe Arg Pro Val Ser Gln Asp
65 70 75 80
Ser Leu Thr His Thr Ile Ala Ser Asp Asn Leu Val Glu Lys Phe Glu
85 90 95
Glu Tyr Tyr Gly Gly Thr Ala Ser Asp Ala Ile Lys Gln Tyr Phe Ser
100 105 110
Ala Ser Ile Gly Glu Ser Tyr Tyr Trp Asn Asp Cys Arg Gln Gln Tyr
115 120 125
Tyr Asp Leu Cys Arg Glu Leu Gly Val Glu Val Ser Asp Leu Thr His
130 135 140
Asp Leu Glu Ile Leu Cys Arg Glu Lys Cys Leu Ala Val Ala Thr Glu
145 150 155 160
Ser Asn Gln Asn Asn Ser Ile Ile Ser Val Leu Phe Gly Thr Gly Glu
165 170 175
Lys Glu Asp Arg Ser Val Lys Leu Arg Ile Thr Lys Lys Ile Leu Glu
180 185 190
Ala Ile Ser Asn Leu Lys Glu Ile Pro Lys Asn Val Ala Pro Ile Gln
195 200 205
Glu Ile Ile Leu Asn Val Ala Lys Ala Thr Lys Glu Thr Phe Arg Gln
210 215 220
Val Tyr Ala Gly Asn Leu Gly Ala Pro Ser Thr Leu Glu Lys Phe Ile
225 230 235 240
Ala Lys Asp Gly Gln Lys Glu Phe Asp Leu Lys Lys Leu Gln Thr Asp
245 250 255
Leu Lys Lys Val Ile Arg Gly Lys Ser Lys Glu Arg Asp Trp Cys Cys
260 265 270
Gln Glu Glu Leu Arg Ser Tyr Val Glu Gln Asn Thr Ile Gln Tyr Asp
275 280 285
Leu Trp Ala Trp Gly Glu Met Phe Asn Lys Ala His Thr Ala Leu Lys
290 295 300
Ile Lys Ser Thr Arg Asn Tyr Asn Phe Ala Lys Gln Arg Leu Glu Gln
305 310 315 320
Phe Lys Glu Ile Gln Ser Leu Asn Asn Leu Leu Val Val Lys Lys Leu
325 330 335
Asn Asp Phe Phe Asp Ser Glu Phe Phe Ser Gly Glu Glu Thr Tyr Thr
340 345 350
Ile Cys Val His His Leu Gly Gly Lys Asp Leu Ser Lys Leu Tyr Lys
355 360 365
Ala Trp Glu Asp Asp Pro Ala Asp Pro Glu Asn Ala Ile Val Val Leu
370 375 380
Cys Asp Asp Leu Lys Asn Asn Phe Lys Lys Glu Pro Ile Arg Asn Ile
385 390 395 400
Leu Arg Tyr Ile Phe Thr Ile Arg Gln Glu Cys Ser Ala Gln Asp Ile
405 410 415
Leu Ala Ala Ala Lys Tyr Asn Gln Gln Leu Asp Arg Tyr Lys Ser Gln
420 425 430
Lys Ala Asn Pro Ser Val Leu Gly Asn Gln Gly Phe Thr Trp Thr Asn
435 440 445
Ala Val Ile Leu Pro Glu Lys Ala Gln Arg Asn Asp Arg Pro Asn Ser
450 455 460
Leu Asp Leu Arg Ile Trp Leu Tyr Leu Lys Leu Arg His Pro Asp Gly
465 470 475 480
Arg Trp Lys Lys His His Ile Pro Phe Tyr Asp Thr Arg Phe Phe Gln
485 490 495
Glu Ile Tyr Ala Ala Gly Asn Ser Pro Val Asp Thr Cys Gln Phe Arg
500 505 510
Thr Pro Arg Phe Gly Tyr His Leu Pro Lys Leu Thr Asp Gln Thr Ala
515 520 525
Ile Arg Val Asn Lys Lys His Val Lys Ala Ala Lys Thr Glu Ala Arg
530 535 540
Ile Arg Leu Ala Ile Gln Gln Gly Thr Leu Pro Val Ser Asn Leu Lys
545 550 555 560
Ile Thr Glu Ile Ser Ala Thr Ile Asn Ser Lys Gly Gln Val Arg Ile
565 570 575
Pro Val Lys Phe Asp Val Gly Arg Gln Lys Gly Thr Leu Gln Ile Gly
580 585 590
Asp Arg Phe Cys Gly Tyr Asp Gln Asn Gln Thr Ala Ser His Ala Tyr
595 600 605
Ser Leu Trp Glu Val Val Lys Glu Gly Gln Tyr His Lys Glu Leu Gly
610 615 620
Cys Phe Val Arg Phe Ile Ser Ser Gly Asp Ile Val Ser Ile Thr Glu
625 630 635 640
Asn Arg Gly Asn Gln Phe Asp Gln Leu Ser Tyr Glu Gly Leu Ala Tyr
645 650 655
Pro Gln Tyr Ala Asp Trp Arg Lys Lys Ala Ser Lys Phe Val Ser Leu
660 665 670
Trp Gln Ile Thr Lys Lys Asn Lys Lys Lys Glu Ile Val Thr Val Glu
675 680 685
Ala Lys Glu Lys Phe Asp Ala Ile Cys Lys Tyr Gln Pro Arg Leu Tyr
690 695 700
Lys Phe Asn Lys Glu Tyr Ala Tyr Leu Leu Arg Asp Ile Val Arg Gly
705 710 715 720
Lys Ser Leu Val Glu Leu Gln Gln Ile Arg Gln Glu Ile Phe Arg Phe
725 730 735
Ile Glu Gln Asp Cys Gly Val Thr Arg Leu Gly Ser Leu Ser Leu Ser
740 745 750
Thr Leu Glu Thr Val Lys Ala Val Lys Gly Ile Ile Tyr Ser Tyr Phe
755 760 765
Ser Thr Ala Leu Asn Ala Ser Lys Asn Asn Pro Ile Ser Asp Glu Gln
770 775 780
Arg Lys Glu Phe Asp Pro Glu Leu Phe Ala Leu Leu Glu Lys Leu Glu
785 790 795 800
Leu Ile Arg Thr Arg Lys Lys Lys Gln Lys Val Glu Arg Ile Ala Asn
805 810 815
Ser Leu Ile Gln Thr Cys Leu Glu Asn Asn Ile Lys Phe Ile Arg Gly
820 825 830
Glu Gly Asp Leu Ser Thr Thr Asn Asn Ala Thr Lys Lys Lys Ala Asn
835 840 845
Ser Arg Ser Met Asp Trp Leu Ala Arg Gly Val Phe Asn Lys Ile Arg
850 855 860
Gln Leu Ala Pro Met His Asn Ile Thr Leu Phe Gly Cys Gly Ser Leu
865 870 875 880
Tyr Thr Ser His Gln Asp Pro Leu Val His Arg Asn Pro Asp Lys Ala
885 890 895
Met Lys Cys Arg Trp Ala Ala Ile Pro Val Lys Asp Ile Gly Asp Trp
900 905 910
Val Leu Arg Lys Leu Ser Gln Asn Leu Arg Ala Lys Asn Gly Gly Thr
915 920 925
Gly Glu Tyr Tyr His Gln Gly Val Lys Glu Phe Leu Ser His Tyr Glu
930 935 940
Leu Gln Asp Leu Glu Glu Glu Leu Leu Lys Trp Arg Ser Asp Arg Lys
945 950 955 960
Ser Asn Ile Pro Cys Trp Val Leu Gln Asn Arg Leu Ala Glu Lys Leu
965 970 975
Gly Asn Lys Glu Ala Val Val Tyr Ile Pro Val Arg Gly Gly Arg Ile
980 985 990
Tyr Phe Ala Thr His Lys Val Ala Thr Gly Ala Val Ser Ile Val Phe
995 1000 1005
Asp Gln Lys Gln Val Trp Val Cys Asn Ala Asp His Val Ala Ala Ala
1010 1015 1020
Asn Ile Ala Leu Thr Val Lys Gly Ile Gly Glu Gln Ser Ser Asp Glu
1025 1030 1035 1040
Glu Asn Pro Asp Gly Ser Arg Ile Lys Leu Gln Leu Thr Ser
1045 1050
<210> 5
<211> 1056
<212> PRT
<213> Artificial Sequence
<220>
<223> Cas12iVar3
<400> 5
Met Ser Ser Ala Ile Lys Ser Tyr Lys Ser Val Leu Arg Pro Asn Glu
1 5 10 15
Arg Lys Asn Gln Leu Leu Lys Ser Thr Ile Gln Cys Leu Glu Asp Gly
20 25 30
Ser Ala Phe Phe Phe Lys Met Leu Gln Gly Leu Phe Gly Gly Ile Thr
35 40 45
Pro Glu Ile Val Arg Phe Ser Thr Glu Gln Glu Lys Gln Gln Gln Asp
50 55 60
Ile Ala Leu Trp Cys Ala Val Asn Trp Phe Arg Pro Val Ser Gln Asp
65 70 75 80
Ser Leu Thr His Thr Ile Ala Ser Asp Asn Leu Val Glu Lys Phe Glu
85 90 95
Glu Tyr Tyr Gly Gly Thr Ala Ser Asp Ala Ile Lys Gln Tyr Phe Ser
100 105 110
Ala Ser Ile Gly Glu Ser Tyr Tyr Trp Asn Asp Cys Arg Gln Gln Tyr
115 120 125
Tyr Asp Leu Cys Arg Glu Leu Gly Val Glu Val Ser Asp Leu Thr His
130 135 140
Asp Leu Glu Ile Leu Cys Arg Glu Lys Cys Leu Ala Val Ala Thr Glu
145 150 155 160
Ser Asn Gln Asn Asn Ser Ile Ile Ser Val Leu Phe Gly Thr Gly Glu
165 170 175
Lys Glu Asp Arg Ser Val Lys Leu Arg Ile Thr Lys Lys Ile Leu Glu
180 185 190
Ala Ile Ser Asn Leu Lys Glu Ile Pro Lys Asn Val Ala Pro Ile Gln
195 200 205
Glu Ile Ile Leu Asn Val Ala Lys Ala Thr Lys Glu Thr Phe Arg Gln
210 215 220
Val Tyr Ala Gly Asn Leu Gly Ala Pro Ser Thr Leu Glu Lys Phe Ile
225 230 235 240
Ala Lys Asp Gly Gln Lys Glu Phe Asp Leu Lys Lys Leu Gln Thr Asp
245 250 255
Leu Lys Lys Val Ile Arg Gly Lys Ser Lys Glu Arg Asp Trp Cys Cys
260 265 270
Gln Glu Glu Leu Arg Ser Tyr Val Glu Gln Asn Thr Ile Gln Tyr Asp
275 280 285
Leu Trp Ala Trp Gly Glu Met Phe Asn Lys Ala His Thr Ala Leu Lys
290 295 300
Ile Lys Ser Thr Arg Asn Tyr Asn Phe Ala Lys Gln Arg Leu Glu Gln
305 310 315 320
Phe Lys Glu Ile Gln Ser Leu Asn Asn Leu Leu Val Val Lys Lys Leu
325 330 335
Asn Asp Phe Phe Asp Ser Glu Phe Phe Ser Gly Glu Glu Thr Tyr Thr
340 345 350
Ile Cys Val His His Leu Gly Gly Lys Asp Leu Ser Lys Leu Tyr Lys
355 360 365
Ala Trp Glu Asp Asp Pro Ala Asp Pro Glu Asn Ala Ile Val Val Leu
370 375 380
Cys Asp Asp Leu Lys Asn Asn Phe Lys Lys Glu Pro Ile Arg Asn Ile
385 390 395 400
Leu Arg Tyr Ile Phe Thr Ile Arg Gln Glu Cys Ser Ala Gln Asp Ile
405 410 415
Leu Ala Ala Ala Lys Tyr Asn Gln Gln Leu Asp Arg Tyr Lys Ser Gln
420 425 430
Lys Ala Asn Pro Ser Val Leu Gly Gly Gly Asn Gln Gly Phe Thr Trp
435 440 445
Thr Asn Ala Val Ile Leu Pro Glu Lys Ala Gln Arg Asn Asp Arg Pro
450 455 460
Asn Ser Leu Asp Leu Arg Ile Trp Leu Tyr Leu Lys Leu Arg His Pro
465 470 475 480
Asp Gly Arg Trp Lys Lys His His Ile Pro Phe Tyr Asp Thr Arg Phe
485 490 495
Phe Gln Glu Ile Tyr Ala Ala Gly Asn Ser Pro Val Asp Thr Cys Gln
500 505 510
Phe Arg Thr Pro Arg Phe Gly Tyr His Leu Pro Lys Leu Thr Asp Gln
515 520 525
Thr Ala Ile Arg Val Asn Lys Lys His Val Lys Ala Ala Lys Thr Glu
530 535 540
Ala Arg Ile Arg Leu Ala Ile Gln Gln Gly Thr Leu Pro Val Ser Asn
545 550 555 560
Leu Lys Ile Thr Glu Ile Ser Ala Thr Ile Asn Ser Lys Gly Gln Val
565 570 575
Arg Ile Pro Val Lys Phe Asp Val Gly Arg Gln Lys Gly Thr Leu Gln
580 585 590
Ile Gly Asp Arg Phe Cys Gly Tyr Asp Gln Asn Gln Thr Ala Ser His
595 600 605
Ala Tyr Ser Leu Trp Glu Val Val Lys Glu Gly Gln Tyr His Lys Glu
610 615 620
Leu Gly Cys Phe Val Arg Phe Ile Ser Ser Gly Asp Ile Val Ser Ile
625 630 635 640
Thr Glu Asn Arg Gly Asn Gln Phe Asp Gln Leu Ser Tyr Glu Gly Leu
645 650 655
Ala Tyr Pro Gln Tyr Ala Asp Trp Arg Lys Lys Ala Ser Lys Phe Val
660 665 670
Ser Leu Trp Gln Ile Thr Lys Lys Asn Lys Lys Lys Glu Ile Val Thr
675 680 685
Val Glu Ala Lys Glu Lys Phe Asp Ala Ile Cys Lys Tyr Gln Pro Arg
690 695 700
Leu Tyr Lys Phe Asn Lys Glu Tyr Ala Tyr Leu Leu Arg Asp Ile Val
705 710 715 720
Arg Gly Lys Ser Leu Val Glu Leu Gln Gln Ile Arg Gln Glu Ile Phe
725 730 735
Arg Phe Ile Glu Gln Asp Cys Gly Val Thr Arg Leu Gly Ser Leu Ser
740 745 750
Leu Ser Thr Leu Glu Thr Val Lys Ala Val Lys Gly Ile Ile Tyr Ser
755 760 765
Tyr Phe Ser Thr Ala Leu Asn Ala Ser Lys Asn Asn Pro Ile Ser Asp
770 775 780
Glu Gln Arg Lys Glu Phe Asp Pro Glu Leu Phe Ala Leu Leu Glu Lys
785 790 795 800
Leu Glu Leu Ile Arg Thr Arg Lys Lys Lys Gln Lys Val Glu Arg Ile
805 810 815
Ala Asn Ser Leu Ile Gln Thr Cys Leu Glu Asn Asn Ile Lys Phe Ile
820 825 830
Arg Gly Glu Gly Asp Leu Ser Thr Thr Asn Asn Ala Thr Lys Lys Lys
835 840 845
Ala Asn Ser Arg Ser Met Asp Trp Leu Ala Arg Gly Val Phe Asn Lys
850 855 860
Ile Arg Gln Leu Ala Pro Met His Asn Ile Thr Leu Phe Gly Cys Gly
865 870 875 880
Ser Leu Tyr Thr Ser His Gln Asp Pro Leu Val His Arg Asn Pro Asp
885 890 895
Lys Ala Met Lys Cys Arg Trp Ala Ala Ile Pro Val Lys Asp Ile Gly
900 905 910
Asp Trp Val Leu Arg Lys Leu Ser Gln Asn Leu Arg Ala Lys Asn Gly
915 920 925
Gly Thr Gly Glu Tyr Tyr His Gln Gly Val Lys Glu Phe Leu Ser His
930 935 940
Tyr Glu Leu Gln Asp Leu Glu Glu Glu Leu Leu Lys Trp Arg Ser Asp
945 950 955 960
Arg Lys Ser Asn Ile Pro Cys Trp Val Leu Gln Asn Arg Leu Ala Glu
965 970 975
Lys Leu Gly Asn Lys Glu Ala Val Val Tyr Ile Pro Val Arg Gly Gly
980 985 990
Arg Ile Tyr Phe Ala Thr His Lys Val Ala Thr Gly Ala Val Ser Ile
995 1000 1005
Val Phe Asp Gln Lys Gln Val Trp Val Cys Asn Ala Asp His Val Ala
1010 1015 1020
Ala Ala Asn Ile Ala Leu Thr Val Lys Gly Ile Gly Glu Gln Ser Ser
1025 1030 1035 1040
Asp Glu Glu Asn Pro Asp Gly Ser Arg Ile Lys Leu Gln Leu Thr Ser
1045 1050 1055
<210> 6
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> S-sg1
<400> 6
tacatgcacc agcaactgtt 20
<210> 7
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> S-sg2
<400> 7
caacttcaat ggtttaacag 20
<210> 8
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> S-sg3
<400> 8
actgcacaga agtccctgtt 20
<210> 9
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> S-sg4
<400> 9
ctgacactac tgatgctgtc 20
<210> 10
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> S-sg5
<400> 10
caccatgttc ttttggtggt 20
<210> 11
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> S-sg6
<400> 11
ggtggtgtca gtgttataac 20
<210> 12
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> S-sg7
<400> 12
taacaccagg aacaaatact 20
<210> 13
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> S-sg8
<400> 13
atcaggatgt taactgcaca 20
<210> 14
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N-sg21
<400> 14
caaacattgg ccgcaaattg 20
<210> 15
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N-sg22
<400> 15
gccgcaaatt gcacaatttg 20
<210> 16
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N-sg23
<400> 16
cacaatttgc ccccagcgct 20
<210> 17
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N-sg24
<400> 17
ccgaaggtgt gacttccatg 20
<210> 18
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N-sg25
<400> 18
gcatggaagt cacaccttcg 20
<210> 19
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N-sg26
<400> 19
gggaacgtgg ttgacctaca 20
<210> 20
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N-sg27
<400> 20
gatgacaaag atccaaattt 20
<210> 21
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N-sg28
<400> 21
aaagatcaag tcattttgct 20
<210> 22
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N-sg29
<400> 22
atctttgaaa tttggatctt 20
<210> 23
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N-sg30
<400> 23
tttttaggct ctgttggtgg 20
<210> 24
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N-sg31
<400> 24
tgtctctgcg gtaaggcttg 20
<210> 25
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N-sg32
<400> 25
tatgcgtcaa tatgcttatt 20
<210> 26
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N-sg33
<400> 26
atggcacctg tgtaggtcaa 20
<210> 27
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N-sg34
<400> 27
gtgggaatgt tttgtatgcg 20
<210> 28
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N1-1
<400> 28
gtctggtagc tcttcggtag 20
<210> 29
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N1-9
<400> 29
ctaggtagta gaaataccat 20
<210> 30
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N2-11
<400> 30
cgaagaacgc tgaagcgctg 20
<210> 31
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N2-5
<400> 31
taatcagttc cttgtctgat 20
<210> 32
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N2-9
<400> 32
tgcaatttgc ggccaatgtt 20
<210> 33
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N2-6
<400> 33
ggaatgtcgc gcattggcat 20
<210> 34
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N2-15
<400> 34
agcgttcttc ggaatgtcgc 20
<210> 35
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> N2-17
<400> 35
ggaatgtcgc gcattggcat 20
<210> 36
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> T7-E-nCoV-sg1
<400> 36
taagcacaag ctgatgagta 20
<210> 37
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> T7-E-nCoV-sg2
<400> 37
atgatgaacc gacgacgact 20
<210> 38
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> T7-E-nCoV-sg3
<400> 38
ggaagagaca ggtacgttaa 20
<210> 39
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> T7-E-nCoV-sg4
<400> 39
ttatgtactc attcgtttcg 20
<210> 40
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> T7-E-nCoV-sg5
<400> 40
cgactactag cgtgcctttg 20
<210> 41
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> T7-E-nCoV-sg6
<400> 41
cgattgtgtg cgtactgctg 20
<210> 42
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> T7-E-nCoV-sg7
<400> 42
tggtctaaac gaactaaata 20
<210> 43
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> T7-E-nCoV-sg8
<400> 43
gagttcctga tcttctggtc 20
<210> 44
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> T7-E-nCoV-sg9
<400> 44
ttttacgttt actctcgtgt 20
<210> 45
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> T7-E-nCoV-sg10
<400> 45
tgtgcgtact gctgcaatat 20
Claims (34)
1.一种检测样品中靶核酸分子的存在和/或量的方法,所述方法包括以下步骤:
(a)使所述生物样品接触:i)Cas12i蛋白,ii)针对所述靶核酸分子中的靶序列的gRNA,和iii)被切割后产生可检测信号的DNA报告分子,从而形成反应混合物;
(b)检测所述反应混合物中产生的可检测信号的存在和/或水平,其中所述可检测信号的存在和/或水平代表所述靶核酸分子的存在和/或量,所述样品选自生物样品或环境样品。
2.权利要求1的方法,其特征在于包括一个含向导RNA前体的阵列(CRISPR array),这个阵列中的向导RNA前体可以通过V型CRISPR/Cas蛋白加工成熟为向导RNA,因此至少包含一个向导RNA,优选所述向导RNA是sgRNA。
3.权利要求1或2中的方法,所述Cas12i蛋白是来自Cas12i1或Cas12i2或其突变体,所述突变体优选Cas12i2Var1,Cas12i2Var2,Cas12i2Var3。
4.权利要求1-4中的任一方法其中所述Cas12i蛋白包含
(1)与SEQ ID NO:1-5中任一序列具有至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%、至少99%序列相同性的氨基酸序列;
(2)相对于SEQ ID NO:1-5中任一序列具有一或多个氨基酸残基取代、缺失或添加的氨基酸序列;或
(3)SEQ ID NO:1-5中任一所示的氨基酸序列。
5.权利要求1或2的方法,其中所述靶DNA为单链。
6.权利要求1或2的方法,其中所述靶DNA为双链。
7.权利要求1-4中的任何方法,靶DNA为病毒DNA。
8.权利要求1-4中的任何方法,靶DNA为乳多泡病毒(papovavirus)、嗜肝DNA病毒(hepadnavirus)、疱疹病毒(herpesvirus)、腺病毒(adenovirus)、痘病毒(poxvirus)或者是细小病毒(parvovirus)的DNA。
9.权利要求1-8中的任何方法,样品包含细胞裂解物中的DNA分子。
10.权利要求1-9中的任何方法,样品包括细胞。
11.权利要求1-10中的任何方法,所述接触发生于生物体内、体外的细胞内部。
12.权利要求11中所称方法,细胞是真核细胞。
13.权利要求1-12所称方法,靶DNA可在低至1aM的浓度被检测到。
14.权利要求1-13中的任何方法,包括对样品中存在的靶DNA进行定量。
15.权利要求13中方法所述的检测包括:通过对可检测信号的测量得到检测结果;通过对参照样品或参照细胞生成的可检测信号进行测量得到检测结果;比较测量数据和参照数据来决定样品中靶DNA水平。
16.权利要求1-15中的任何方法,测量可检测信号包括以下一种或多种方法:基于纳米颗粒的检测方法、荧光偏振、胶态相变、电化学检测或基于半导体的检测方法,所述纳米颗粒的检测方法,优选胶体金属,进一步优选胶体金或纳米金。
17.权利要求1-16中的任何方法,单链DNA探针标记了荧光发射染料对。
18.权利要求17所述方法,荧光发射染料对可以在单链探测DNA切割前产生一定量的可检测信号,在单链探测DNA切割后信号降低。
19.权利要求18所述方法,单链DNA探针在被切割前产生第一个可检测信号并在被切割后产生第二个可检测信号。
20.权利要求17-19中的任何方法,荧光发射染料对是一种荧光能量转移(FRET)对。
21.权利要求17中所述方法,可检测信号的量在单链探测DNA被切割后增加。
22.权利要求17-21中所述方法,荧光发射染料对包括荧光基团和相应的淬灭基团。
23.权利要求17-22中所述方法,单链探针DNA包括两对或多对荧光发射染料对。
24.权利要求23中所述方法,所称两对或多对荧光发射染料对包括一种荧光能量转移对和荧光淬灭基团/荧光基团对。
25.权利要求1-24所称任何方法中,单链探针DNA包括一种修饰的碱基,一种修饰的糖配基,和/或一种修饰的核酸连接键。
26.权利要求1-25任一项的方法,其中所述单链探针长度为大约2个-大约100个核苷酸。
27.权利要求1-25任一项的方法,其中所述单链探针为聚腺苷酸、聚胞苷酸或聚胸苷酸。
28.权利要求1-25中所述方法包括样品中的扩增的核酸分子。
29.权利要求28所述方法中说的扩增包括等温扩增。
30.权利要求29所述方法中的等温扩增包括但不限于重组酶聚合酶扩增。
31.权利要求28-30中所述任何方法中所称的正在扩增起始于a步骤(接触)之前。
32.权利要求28-31中所述任何方法中所称的正在扩增和a步骤(接触)同时起始。
33.一种装置,其特征在于包含一个或多个基于权利要求1-32的Cas12i核酸检测方法的核心检测单元,优选包含大于两个、大于三个、大于四个所述核心检测单元。
34.一种装置,其特征在于同时包含基于权利要求1-32的Cas12i核酸检测方法的检测单元,以及基于其他CRISPR Cas核酸检测方法的检测单元,所述其他CRISPR Cas核酸检测方法选自Cas9、Cas13、除Cas12i之外的Cas12,中的一种或多种的突变体,进一步优选Cas12b或其突变体。
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