CN1882703B - 通过断裂双链脱氧核糖核酸进行多元核酸分析 - Google Patents
通过断裂双链脱氧核糖核酸进行多元核酸分析 Download PDFInfo
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Abstract
本发明公开了一种断裂双链DNA以进行核酸分析的方法，特别涉及多态性和突变的多元分析。本方法产生了标记的非互补的有义片段和反义片段的多样性，因此在适于多态性和/或突变的杂交分析(或俘获介导的延伸分析)条件下不会显著地重退火。这些片段的长度分布在期望或预测的范围内。可选择切割位点，从而片段短而又足够长以用于片段间的识别分析，以及从统计概率看，从而大部分片段至少含有一个标记核苷酸以便于检测。
Description
相关申请
本申请要求依据申请于2003年10月29日的美国临时申请No.60/515,413而享有优先权。
背景技术
常规的多元反向斑点杂交测定方案，用于检测样品中是否存在特定的等位基因，选择双链基因组DNA的位点时是首先使用多对正向引物和反向引物扩增，通过酶切或磁分离等技术分出每个双链扩增子的指定链。只有余下的链，最好是标记的，被与一组同源探针相接触，斑点杂交或放置在具有底物的硝酸纤维膜上，或者被置于在为杂交分析准备的编码微粒上。杂交是典型的基于与俘获靶或相应探针相关联的标记物的存在的检测。核酸测序允许通过被特定探针俘获的链的部分序列进行测定，因为这些俘获探针和这些部分序列是互补的。
除去指定链是为了通过消除链-链重退火过程以提高探针对于剩余链的俘获效率，该过程与同源俘获探针的退火相竞争，否则在反应过程中将不发生链选择和消除。
链能通过消化而除去，其中被选中的要除去的链先使其磷酸化，再用消化酶如λ-核酸内切酶，进行酶消化被磷酸化的链。链还可以通过磁分离被除去。不论消化还是磁分离都会增加测定方案的成本和工作量。更好的备选方案会从扩增子产生单链的片段，从而不必进行消化或磁分离。
已知一些方法能从双链DNA产生随机长度的单链片段。在传统的Maxam and Gilbert测序法(A.Maxam and W.Gilbert，PNAS 74，p.560，1977)中，双链DNA片段通过待排序的DNA种类的多元复制进行选择性的化学降解而产生。通过调节条件以产生所有可能长度的片段；就是说，长度差异仅仅是一个碱基的片段也可以被分离出来。排序时，这些组分的顺序 与它们各自的末端碱基代表了最初DNA种类的序列。
E.Southern等人也从双链DNA中生成了随机大小的单链片段，以便于将DNA从带有斑点印迹的琼脂糖凝胶膜上转移并通过DNA与寡核苷酸探针杂交而进行进一步分析，该法代表一种斑点印迹的形式。通过调节条件以产生足够小的片段来将其在凝胶中的缠结降至最小。
迄今为止，还没有使用扩增子片段而不进行为了用于反向斑点杂交分析方式的链消化和分离。因此，没有迹象表明，对于多态性的多元分析(MAP)来说，使用高度异源的靶片段的复杂混合物要优于使用单个，或不多于几个的靶序列。进一步地，对于在MAP中使用片段，除非条件被恰当调整，可以除去一些或全部多态位点，或误标记，但这些问题和它们的解决方法都未被提及。
一种标记扩增子的常规方法是扩增5’-端标记的引物使其产生末端标记的扩增子。这种末端标记方法需要标记保持完整无损的链，因为，在断裂后，只有一小部分含有5-端的片段能被标记。因此，当扩增子将被断裂时，需要不同的标记方法。
发明内容
本发明公开了一种断裂双链DNA以用于核酸分析，特别是多态性和突变的多元分析的方法。本方法产生了非互补的标记的有义片段和反义片段的多样性，因此在适合多样性和/或突变的杂交分析(或俘获介导的延伸分析(capture-mediated elongation analysis))的条件下并不显著地重退火。这些片段的长度分布在期望或预测的范围内。可选择切割位点，从而片段短而又足够长以用于片段间的识别分析，以及从统计概率看，从而大部分片段至少含有一个标记核苷酸以便于检测。也就是说，当条件被调整后，通过含有标记核苷酸，生成标记链的一种所选的线性密度的片段长度分布。在另一实施方案中，大部分片段的长度与同源俘获探针的长度相当。
双链DNA(或通过扩增从双链DNA得到的双链扩增子)在沿着链上随机分布的多个为了产生不完全互补的片段的位点被切割，而转化成 一组有义和反义片段。这可以通过每个链上的相同碱基的简单切割完成。这些片段接着在退火条件下，被置于和至少某些期望的片段完全互补的探针相接触。检测到杂交后，并基于这些结果，样品中特定寡核苷酸片段的存在或缺失能被确定。
本方法的优点是：
(i)取消了后PCR(post-PCR)链选择的步骤；
(ii)通过选择断裂位点的密度而提高靶的俘获效率，以产生具有最小二级结构的相对短的靶并表现出高效的亲和力，其详述于题为：“使用固定俘获探针进行基因表达分析的优化方法”(“Optimization of GeneExpression Analysis using Immobilized Capture Probes”)的同时待决的申请，申请于2004年10月28日，引作参考。
(iii)允许使用有义和反义俘获探针对两链上的多态位点询问。这是有益于多元分析的设计的一方面，因为它可以如期待的使用选择性的结合在有义或反义链上的特定探针，以避免与非同源靶的交叉杂交。见例如：美国申请序号10/847,046，申请于2004年5月17日的“杂交介导多态性分析(hMAP)”(“Hybridization-Mediated Analysis ofPolymorphisms(hMAP))”，引作参考。此外，包含反义探针与相应有义探针提高了俘获效率，因为反义探针从溶液中除掉了部分有义靶，因此进一步降低了溶液中链重退火的程度。
在产生扩增子的PCR扩增中，可结合能最终识别杂交靶的标记。此处需要注意的是在PCR中标记必须以足够大的机率被结合，以使得所有得到的片段有可能至少与某个标记结合。因此，当片段越短时，必然的，在每一片段上标记的机率必须越高。
作为可选的步骤，在样品中杂交靶的杂交和鉴定之后，可以使用俘获介导的和延伸分析来检验杂交结果的可靠性。在这一步骤中，设计了一套新的探针，它们中有些可能比用作杂交分析的最初的探针组短或与之互补。期望的靶上需要较短的探针，如果靶上沿着片段的长度，将有超过一个的多态性位点(或与多态性位点对应的子序列)。为了在俘获介导的延伸分析中得到一个可靠的结果，终端探针核苷酸必须与每个多 态性核苷酸对齐(″SNP″)。见于美国申请序号10/271,602，题为“通过并存询问和酶介导检测的多态性位点多元分析”(“Multiplexed Analysis ofPolymorphic Loci by Concurrent Interrogation and Enzyme-MediatedDetection”)，申请于2002年10月15日，引作参考。
另外，互补探针可被使用如果它有助于避免在组内靶间的交叉杂交。互补探针会与最初的探针组杂交的靶链的互补靶链(有义链或反义链)杂交。
俘获介导的延伸分析期望提高分析结果的可靠性，因为单独用杂交分析(只使用一组原始靶)，假阳性结果会在交叉杂交中产生。辅以俘获介导的延伸分析，其结果可与杂交介导分析相比较，因此大大提高了可靠性。最后的比较步骤可以通过程序和软件完成。
上述方法的有关附图描述如下。
附图说明
图1所示为基因组DNA的PCR产物染色结果，在紫外光照射下，于琼脂糖凝胶上可见。
图2所示为标记的组I和组II HLA PCR产物，它们已通过化学裂解和变性被处理成单链的DNA片段。
图3A-3D图示为使用本发明方法进行杂交介导分析的步骤。
图4图示说明了与一些靶结合的强度与脱嘌呤时间的关系。
图5A-5D图示用本发明提出的方法进行俘获和延伸介导分析中包含的步骤。
图6说明滴定阈值与六种不同的有义探针的关系。
图7所示为Pcut值为5％的所选DNA链的片段累积大小分布。
图8所示为所选DNA链中两个不同长度，但可断裂键和不可断裂键比率相同的不同区域的存在概率。
具体实施方式
为实现上述方法，一个双链DNA样品，如：基因组DNA，被首先分 离出来。某些部分，代表目标位点，被通过PCR扩增。之后，互补的有义和反义链能被放置于允许退火的条件下，或者，它们被置于能使互补链保持分离的凝胶中。在任一情况下，它们最终被退火成双链DNA扩增子。在下一步骤中，两种互补链在非互补碱基对上裂解，以产生只能部分互补的有义和反义链。当将完全互补链置于退火条件下与探针阵列接触时，它们将相互退火，藉此与探针退火竞争并影响测定结果。
一个著名的在不互补的特定碱基上裂解有义和反义扩增子链的方法是用盐酸在扩增子上随机切割嘌呤碱基，从而对这些碱基脱嘌呤化。切割的双链DNA接着被在碱性溶液中加热变性，从而产生单链非互补的DNA片段。脱嘌呤的程度越大，脱嘌呤后得到的单链DNA片段的长度就越短。
作为双链DNA的PCR扩增的一个步骤，合并最后将用于鉴别与一组探针杂交的特定链的标记是必要的。完成这步的一个方法是在PCR反应混合物中加入标记的脱氧核苷酸(或双脱氧核苷酸)以在反应中标记每个扩增子链。另一方法是在PCR中加入生物素化的碱基，这些碱基通过与荧光标记的链霉抗生素蛋白偶联被标记。生物素化的胞嘧啶比腺嘌呤更优选，因为腺嘌呤碱基在脱嘌呤步骤中将被脱嘌呤化，从而导致标记的损失。如上所述，标记的频率必须足够高，以保证当想检测甚至是最短的片段时，都已被加入标记了。在PCR中标记是有利于通过断裂产生的单链DNA的，因为否则在后PCR加工步骤中每个链将被分别标记，这将是昂贵和费时的。
作为另一个步骤，杂交反应之后，如上所述，其结果能够被确认或推翻从而提高可靠性，如果俘获介导的延伸分析是在裂解的扩增子上完成的。如上所述，俘获介导的延伸反应可以用比最初的探针组短的或互补的探针完成。
下述实施例将进一步说明此处提出的方法。
实施例1：PCR扩增
在一个聚合酶链式反应(PCR)中，从人类组织和细胞分离出的基因 组DNA被用作模板。寡核苷酸旁侧HLA组I和组II被用作为了特定位点和特定基因节段的扩增的正向和反向引物。一对以上的引物能在PCR中被用于多位点的扩增。另外，引物可以包含在多态位点上引发基因组DNA的简并碱基。PCR依照一些众所周知的方法完成。
优选地，至少一种类型的配体标记的脱氧核苷酸被加入到PCR反应混合物中，以产生每个链都被标记的扩增子。配体可以是荧光染料或如生物素的分子，其能够在反应后与一个标记偶联。
PCR是通过使用一个程序化的温热循环器实现的。部分PCR产物和凝胶中作为标记的DNA梯度序列在琼脂糖凝胶或聚丙烯酰胺凝胶上一起电泳。凝胶中的DNA被用溴化乙锭染色，再显影于紫外透照仪(transluminator)，以检验PCR扩增子的完整性和产量。例如，位点A和B的外显子2和外显子3被用两组引物在多元PCR中扩增。DR位点的外显子2被用一组引物扩增。PCR产物按照扩增子的每20个碱基有一个以上的生物素酰核苷酸的密度被生物素酰化在各链上。PCR产物的各等分部分在琼脂糖凝胶上电泳，接着用溴化乙锭染色。被染色的PCR产物能在紫外照射下显色于琼脂糖凝胶上，见图1。
实施例2：后PCR样品处理
标记组I和组II的PCR产物通过化学裂解和变性处理成单链的DNA片段。简单的说，正如众所周知的，PCR产物被用盐酸处理以脱嘌呤(例见：M.H.Caruthers等人，基因工程中的规则和方法(in Genetic Engineering：Principle and Methods)，J.K.Setlow等人，编者(纽约：Plenum出版社，1982))。双链DNA在盐酸存在下随机的在嘌呤碱基，即：腺嘌呤和鸟嘌呤上被切割。在碱性溶液中，带切口的双链DNA被在94℃加热变性，致使生成单链DNA片段。脱嘌呤的程度直接关系到单链DNA片段的长度。
组I和组II基因的PCR扩增子的脱嘌呤作用被优化以产生小的单链DNA片段，基于概率，这些片段一般包含至少一个生物素化核苷酸。分散在聚丙烯酰胺凝胶上的裂解产物的长度分布显示，大多数的单链DNA 片段有大约75个碱基长。因此，根据实施例1描述的情况，每个DNA片段应该包含大约两个生物素化核苷酸。
进行了时程(time course)实验以优化脱嘌呤条件。B位点上外显子2和3的生物素化的PCR产物用特定量的盐酸培养并以增加的时间阶段温育在水浴中，接着加入氢氧化钠并加热变性。化学裂解的PCR产物用8％尿素电泳测序以分离消化产物，接着用溴化乙锭染色。裂解产物在紫外透照仪(transluminator)上显影，其指示了随着脱嘌呤时间的增加，小的裂解产物的量也增加(图2)。
实施例3：在芯片上的杂交分析
按实施例2中所述制备加工的PCR产物被加热变性以得到大量的单链DNA片段。在变性后，样品被在冰上进行快速冷冻以保持DNA片段处于单链状态。DNA样品接着与杂交缓冲液混合以在芯片上杂交出互补的寡核苷酸探针，这些不同的探针类型各自被固定在不同的编码微粒上，而编码微粒被排列在固体基质阵列上(“BeadChipTM”微珠芯片)。见于美国申请序号10/204,799：“使用专用随机粒子阵列的多分析物分析”(“Multianalyte Molecular Analysis Using Application-Specific RandomParticle Arrays”)，申请于2002年8月23日，引作参考。
杂交条件和缓冲溶液的离子强度是技术上常规的。优选地，为了具有快速有效的反应动力学，芯片杂交在一个温度和湿度控制的培养箱中进行。见于美国专利申请：“用于生物样品的光学检验的可控蒸发，温度控制和包装”(“Controlled Evaporation，Temperature Control and Packaging forOptical Inspection of Biological Samples”)，序号10/870,213，申请于2004年6月17日。
杂交之后，未结合的标记的DNA被通过充分洗涤除去。寡核苷酸与配体，如生物素结合，而不是结合于荧光染料时，分析芯片用含有与配体具有高亲和力的荧光标记分子的染色液培养。例如，可使用荧光标记的链霉抗生素蛋白结合生物素化的DNA片段。
如果存在显著的交叉杂交，标记的DNA靶可被超过一类的探针俘获，并与微珠芯片上一类以上的编码微粒联合。
如图3所示，一个典型的hMAP微珠芯片分析有如下四个步骤：步骤1，在标记的dNTPs，如生物素化的dATP和生物素化的dCTP，存在下的基因组DNA的PCR扩增。PCR产物的每个链都在PCR反应中被标记。步骤2，标记的PCR产物在盐酸存在下脱嘌呤，接着在碱性溶液中加热变性。步骤3，断裂的单链DNA靶被用作微珠芯片分析的靶。步骤4，微珠上的俘获靶被检测到，通过用与标记有高亲和力的荧光标记的配体培养，如用于检测生物素化靶的Cy3轭合的链霉抗生素蛋白，接着被READ检出(图3)。
实施例2中描述的裂解DNA产品被用于微珠芯片hMAP分析。简要地说，每一个脱嘌呤处理的产物，即：那些从0，10，13，15，17，20，25和＞25分钟脱嘌呤得到的结果，被用作hMAP微珠芯片分析中的一个靶。分析了各靶对于一系列序列特异的探针的杂交强度。如图4所示，对探针A和探针C的强度随着脱嘌呤时间的增加而减少，这提示了脱嘌呤作用中，从长DNA靶到小片段的裂解增加。然而，对探针B，D，E和F的强度首先在部分脱嘌呤中增加，接着在进一步脱嘌呤中降低，提示了部***解导致某些靶序列的释放，它们是在长链DNA中因为其他因素，如靶的二级结构无法得到的(图4)。
实施例4：定制微珠芯片的制备
用于杂交介导分析的DNA寡核苷酸探针可以包含一个末端反应基团，一个内部的间隔区分子，和与目标靶DNA互补的一段核苷酸序列。寡核苷酸探针可以与DNA分子的有义链或反义链互补。总有一个链被选择以降低交叉杂交。
当DNA寡核苷酸偶联到颜色编码的微粒上后，不同寡核苷酸官能化的微粒被组合进一个小管，其用于装配排列在硅晶片(或微珠芯片)上的随机平面排列的微珠阵列。在HLA分子分型中，每个微珠芯片应该包含用于组I和组II分子的特定位点的多个有义和反义探针。不同的位点的微 珠芯片可被固定在一个用于杂交反应的公共槽(common chamber)中。
实施例5：俘获介导的延伸分析
如上所讨论的，杂交介导分析之后，其结果能用俘获介导的延伸反应确定或推翻。如图5所示，一个用化学裂解的DNA靶的典型eMAP微珠芯片分析应该有如下四个步骤：步骤1，基因组DNA的PCR扩增。步骤2，PCR产品在盐酸存在下脱嘌呤，接着在碱性溶液中加热变性。步骤3，断裂的单链DNA被作为靶用于杂交到序列特异的探针上，接着在荧光标记的dNTPs，如Cy3标记的dATP和dCTP存在下进行延伸反应。步骤4，靶模板被通过充分洗涤除去，继之以延伸探针的READ测定(图5)。
实施例6：有义探针和反义探针的多元hMAP分析
本发明描述的化学裂解的DNA靶能杂交于一系列多元分析格式的多个寡核苷酸探针，如，可分析此格式的HLA基因。在这样一个多元分析中，寡核苷酸探针可以包含与靶HLA子序列的有义链或反义链互补的俘获序列。当这种分析被用于筛选一组已知基因型的人类DNA样品时，探针信号与阳性对照信号的比率(“信号率”)能被在样品中被探针组的各个探针所确定。信号率的阈值可被任意设定，以识别探针和靶之间的“真正匹配”和“错配”。通过与靶DNA的互补链结合，在平板上加入反义探针能够提高多元hMAP分析中有义探针的俘获效率。根据实验，表现出在多元hMAP分析中加入反义探针没有降低任何有义探针的俘获效率，并且事实上当反义探针被加入时，俘获效率被提高了(结果未列出)。仅有义探针的分析被示于图6。
实施例7：DNA断裂模型
在本实施例中，DNA断裂过程的两个不同方面的模型被提出，即：单链DNA(结构已知的)的片段大小分布和在断裂后链中DNA的特定序列的存在概率。此分析的价值是双重的。第一，它鉴别片段大小怎样成为断裂百分数的一个函数。第二，通过模拟片段大小分布，提供了一种独特 的方法，以估计在目标DNA链中的靶区的存在概率。这有与俘获探针的设计有关的重要意义，因为只有当片段的成分包含完整无损的目标子序列，或者那些片段使得探针-靶大量重叠时，能够成功的退火到俘获探针。具有小的相互重叠区的片段在发生检测或延伸前变性。并且，因为片段大小分布和含有目标未切区的链的百分数都是实验可以得到的量，此方法提供了一种独特的手段，用于匹配实验和模拟结果，并有可能定量模型中的重要参数。
为了模拟的目的，假设如上概括的断裂实验过程产生随机分布的多核苷酸片段。随机断裂意味着每个可裂解的核苷酸-核苷酸键有相等的被断裂的概率，Pcut。此假设是合理的，因为断裂过程是基本公平的对于所有使用的A和G的片段，而不依赖于序列。另一假设是键的断裂是独立的，因此片段产生的顺序不影响它们出现的概率。这些模拟由一个单链HLA B外显子2扩增子完成，其有268个碱基长。序列被示于下(序列标识号1)。
1 GCTCCCACTC CATGAGGTAT TTCTACACCT CCGTGTCCCG GCCCGGCCGC
51 GGGGAGCCCC GCTTCATCTC AGTGGGCTAC GTGGACGACA CCCAGTTCGT
101 GAGGTTCGAC AGCGACGCCG CGAGTCCGAG AGAGGAGCCG CGGGCGCCGT
151 GGATAGAGCA GGAGGGGCCG GAGTATTGGG CCGGAACACA CAGATCTACA
201 AGGCCCAGGC ACAGACTGAC CGAGAGAGCC TGCGGAACCT GCGCGGCTAC
251 TACAACCAGA GCGAGGCC
方法：
1)给定参数(Pcut＝断裂％)和链序列。
2)根据通过实验可被断裂和不可断裂的键将序列分成微小的区域。可断裂的键的总数用nF表示。邻近的不可断裂的键作为可断裂键旁侧的不可断裂区被集中起来。
3)创建一个N个序列的集合，每个包括nF个区域(可断裂的)。典型的N＝1000。
4)在0和1之间，产生均匀的随机数的2矢量，R1和R2，每个的大小Ncut＝(nF*Pcut*N)/100，其中Ncut代表了集合中将要断裂的键的总数。第一个矢量，确定在一个序列中发生切割的随机点。这样，对于矢量R1，切割部位由求(nF*R1)的值计算。从第二个矢量，在被切割的集合中的特殊的复制由如下(N*R2)决定。因而，对于每个在序列上将要***作的切口i，产生两个一组的数字(fi，ni)，其中ni表示将要产生的切口的复制数目，fi表示将要切割的复制中的可断裂键。然而，产生的每组(fi，ni)可能不是唯一的。因此，在实际操作中，某一特定复制中的特定的键可能被再次选中(revisit)。一旦一个给定的键被指定为断裂的，定义该键位置的重复组(fi，ni)即被排除，无论是否遇到它。因此，事实上，在实验中，键断裂的总数是ncut≤Ncut。
5)通过给定的片段大小的分布计算出断裂的键或序列末端旁侧的碱基(连接大量的可断裂区和非断裂区)数目。
图7表明选出的具有5％的Pcut值DNA链得到的片段的累积大小分布。该图说明了小的片段比大片段更普遍的存在(最终的片段混合物的50％由长度小于～20个碱基的片段组成)。图8表明在选出的DNA链中，两种长度不同但具有相同的可断裂与不可断裂键的机率的不同区域的存在概率。
应该理解为，此处使用的术语，表示式和实施例仅作示范，而非限制本发明的范围，本发明的范围仅在接着的权利要求书中被确定，并且包含权利要求的主题的所有等效表达。权利要求中的程序和方法的步骤可按任何顺序进行，包括权利要求书中采用的顺序，在权利要求书中另有说明的除外。
Claims (18)
1.一种检出双链寡核苷酸样品中的特定核苷酸序列的方法，包括：
扩增所述样品的区段以产生双链扩增子；
在所述扩增子链间没有匹配的位置切割所述双链扩增子，藉此产生不完全互补的有义和反义片段；
将所述片段与一组单链寡核苷酸共同退火，其中，所述组中的单链寡核苷酸与所述片段或所述片段的子序列互补；并
检出所述单链寡核苷酸和所述片段间的杂交。
2.根据权利要求1所述的方法，其中所述单链寡核苷酸为DNA。
3.根据权利要求1所述的方法，其中所述双链寡核苷酸样品为基因组DNA。
4.根据权利要求1所述的方法，其中所述双链寡核苷酸样品包括目标基因位点。
5.根据权利要求1所述的方法，其中所述切割通过其链上的嘌呤碱基与盐酸随机反应脱嘌呤，并且热变性产生单链DNA片段。
6.根据权利要求5所述的方法，其中所述切割位点的选择由控制盐酸的pH、与盐酸接触的时间及反应温度来控制。
7.根据权利要求1所述的方法，其中标记物在扩增过程中被***所述扩增子中。
8.根据权利要求7所述的方法，其中加入标记物为***生物素，生物素接着与标记的链霉抗生素蛋白偶联。
9.根据权利要求8所述的方法，其中所述生物素与被***的dNTPs联合。
10.根据权利要求1所述的方法，其中荧光标记的dNTPs或ddNTPs被***所述扩增子中。
11.根据权利要求7所述的方法，其中标记频率根据预计的片段长度调整，从而在预计切割后片段较短的位置，标记的频率增加。
12.根据权利要求1所述的方法，其中对所述片段长度进行调整以产生与所述单链寡核苷酸长度接近的片段。
13.根据权利要求1所述的方法，其进一步包括提供适于延伸所述单链寡核苷酸的条件，并检出所述单链寡核苷酸的延伸的步骤。
14.根据权利要求13所述的方法，其中检出特定的单链寡核苷酸和片段的杂交是基于是否所述的特定单链寡核苷酸存在延伸。
15.根据权利要求1所述的方法，其进一步包括提供一组单链寡核苷酸探针的步骤，其中一些探针比所述单链寡核苷酸短或与之互补。
16.根据权利要求15所述的方法，其进一步包括提供适于延伸所述单链寡核苷酸探针的条件，并检出所述单链寡核苷酸探针的延伸的步骤。
17.根据权利要求16所述的方法，其进一步包括比较所述单链寡核苷酸探针的延伸结果和所述单链寡核苷酸的延伸结果的步骤。
18.根据权利要求17所述的方法，其中所述比较是使用一个软件程序自动完成的。
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| WO2018001258A1 (zh) * | 2016-06-30 | 2018-01-04 | 厦门艾德生物医药科技股份有限公司 | 一种用于核酸富集捕获的探针及设计方法 |
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| NZ547495A (en) | 2008-05-30 |
| WO2005045060A3 (en) | 2005-07-21 |
| CA2544202C (en) | 2012-07-24 |
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| US20120015836A1 (en) | 2012-01-19 |
| PT1694859E (pt) | 2015-04-13 |
| EP1694859A2 (en) | 2006-08-30 |
| US7790380B2 (en) | 2010-09-07 |
| US20050095635A1 (en) | 2005-05-05 |
| US20070178481A1 (en) | 2007-08-02 |
| CN1882703A (zh) | 2006-12-20 |
| EP1694859A4 (en) | 2007-08-08 |
| US8563247B2 (en) | 2013-10-22 |
| CA2544202A1 (en) | 2005-05-19 |
| AU2004287069B2 (en) | 2009-07-16 |
| EP1694859B1 (en) | 2015-01-07 |
| TW200519214A (en) | 2005-06-16 |
| ES2533876T3 (es) | 2015-04-15 |
| AU2004287069A1 (en) | 2005-05-19 |
| US7049077B2 (en) | 2006-05-23 |
| IL175185A0 (en) | 2006-09-05 |
| WO2005045060A2 (en) | 2005-05-19 |
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