Combinatorial Conflicting Homozygosity (CCH) analysis enables the rapid identification of shared genomic regions in the presence of multiple phenocopies.
Combinatorial Conflicting Homozygosity (CCH) analysis enables the rapid identification of shared genomic regions in the presence of multiple phenocopies.
复制标题
DOI：
10.1186/s12864-015-1360-4
复制
发表时间：
2015-03-10
期刊：
影响因子：
4.4
通讯作者：
Gale DP
中科院分区：
文献类型：
--
作者：
Levine AP;Connor TM;Oygar DD;Neild GH;Segal AW;Maxwell PH;Gale DP
随着高通量测序技术的广泛应用，鉴定一个或多个家族中遗传有显性性状的基因组区域的能力变得越来越有价值。虽然存在许多方法用于在近亲家庭中与隐性性状分离的纯合变体的作图，但显性条件通常通过连锁分析来分析，这需要从标记基因型进行计算上苛刻的单倍型重建，并且即使使用先进的平行近似实现，也可能花费大量时间，特别是对于大谱系。此外，连锁分析在表型复制（共享性状但不负责遗传变异的个体）的存在下缺乏敏感性。组合标记纯合性（CCH）分析使用高密度双等位基因单核苷酸多态性（SNP）标记基因型来鉴定其中连续标记对于不同等位基因不是纯合的遗传基因座。这允许在相关或不相关个体的集合或子集中推断单倍型的血统相同（IBD）遗传。单个全基因组冲突纯合性分析需要<3秒，并且并行化允许快速分析个体子集的多个组合。对无关个体的分析表明，在不存在IBD遗传的情况下，没有观察到CH超过4 cM的运行。在该阈值下，CCH对超过该长度的谱系内的IBD区域的敏感性和特异性>97%，并且能够鉴定负责土族塞浦路斯家庭中的显性遗传性肾病的基因座，其中17个受影响个体中有6个是表型复制。它还揭示了来自两个不同塞浦路斯人口的受影响个体在疾病相关位点的共同祖先。CCH不需要计算上苛刻的单倍型重建，并且可以直接从SNP基因型数据检测相关或不相关个体的子集之间的单倍型的共享遗传区域。与允许表型复制的参数连锁相反，CCH直接提供共享每个位点的个体的确切数量和身份。CCH还可以在表面上不相关的共享特征的个体中识别共享祖先的区域。CCH是用Python实现的，可以从http://sourceforge.net/projects/cchsnp/免费获得（作为源代码）。本文的在线版本（doi：10.1186/s12864-015-1360-4）包含补充材料，可供授权用户使用。
The ability to identify regions of the genome inherited with a dominant trait in one or more families has become increasingly valuable with the wide availability of high throughput sequencing technology. While a number of methods exist for mapping of homozygous variants segregating with recessive traits in consanguineous families, dominant conditions are conventionally analysed by linkage analysis, which requires computationally demanding haplotype reconstruction from marker genotypes and, even using advanced parallel approximation implementations, can take substantial time, particularly for large pedigrees. In addition, linkage analysis lacks sensitivity in the presence of phenocopies (individuals sharing the trait but not the genetic variant responsible). Combinatorial Conflicting Homozygosity (CCH) analysis uses high density biallelic single nucleotide polymorphism (SNP) marker genotypes to identify genetic loci within which consecutive markers are not homozygous for different alleles. This allows inference of identical by descent (IBD) inheritance of a haplotype among a set or subsets of related or unrelated individuals. A single genome-wide conflicting homozygosity analysis takes <3 seconds and parallelisation permits multiple combinations of subsets of individuals to be analysed quickly. Analysis of unrelated individuals demonstrated that in the absence of IBD inheritance, runs of no CH exceeding 4 cM are not observed. At this threshold, CCH is >97% sensitive and specific for IBD regions within a pedigree exceeding this length and was able to identify the locus responsible for a dominantly inherited kidney disease in a Turkish Cypriot family in which six out 17 affected individuals were phenocopies. It also revealed shared ancestry at the disease-linked locus among affected individuals from two different Cypriot populations. CCH does not require computationally demanding haplotype reconstruction and can detect regions of shared inheritance of a haplotype among subsets of related or unrelated individuals directly from SNP genotype data. In contrast to parametric linkage allowing for phenocopies, CCH directly provides the exact number and identity of individuals sharing each locus. CCH can also identify regions of shared ancestry among ostensibly unrelated individuals who share a trait. CCH is implemented in Python and is freely available (as source code) from http://sourceforge.net/projects/cchsnp/. The online version of this article (doi:10.1186/s12864-015-1360-4) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
5.3
作者：
Wijsman EM
通讯作者：
Wijsman EM
影响因子：
1.9
作者：
CLERGETDARPOUX, F;BONAITIPELLIE, C;HOCHEZ, J
通讯作者：
HOCHEZ, J
影响因子：
14.9
作者：
Seelow, Dominik;Schuelke, Markus
通讯作者：
Schuelke, Markus
影响因子：
1.8
作者：
Tong, Liping;Thompson, Elizabeth
通讯作者：
Thompson, Elizabeth
影响因子：
30.8
作者：
Abecasis, GR;Cherny, SS;Cardon, LR
通讯作者：
Cardon, LR