ARG-walker: inference of individual specific strengths of meiotic recombination hotspots by population genomics analysis.
ARG-walker: inference of individual specific strengths of meiotic recombination hotspots by population genomics analysis.
复制标题
Arg-Walker：通过人群基因组学分析来推论减数分裂重组热点的单个特定优势。
DOI：
10.1186/1471-2164-16-s12-s1
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发表时间：
2015
期刊：
影响因子：
4.4
通讯作者：
Zheng J
中科院分区：
文献类型：
--
作者：
Chen H;Yang P;Guo J;Kwoh CK;Przytycka TM;Zheng J
减数分裂重组热点在基因组学的各个方面发挥着重要作用，但重组热点的位置和强度调控机制尚未完全揭示。尽管有证据表明个体之间的重组率存在异质性，但大多数现有的从序列多态性数据估计重组率的算法只能输出群体的平均重组率。对于重组热点的全基因组关联研究（GWAS），迫切需要一种有效的算法来估计重组热点的个体化强度。在这项工作中，我们提出了一种新的基于祖先重组图（ARG）随机行走的ARG-walker图挖掘算法来估计个体特异性重组热点强度。大量的模拟结果表明，ARG-walker能够区分重组热点的热等位基因和冷等位基因。结合ARG-walker的输出，我们对中国人和日本人（JPT+CHB）的HapMap亚洲人群样本的22条常染色体的分阶段单倍型数据进行了GWAS。我们检测到显著的顺式调控信号，这被PRDM9蛋白著名的13-mer基序CCNCCNTNNCCNC的富集所证实。此外，在显著相关的snp（单核苷酸多态性）的侧翼区域发现了两个新的DNA基序，它们可能是人类基因组减数分裂重组热点的新的顺式调控元件。我们在模拟和真实数据上的结果表明，ARG-walker是一种很有前途的估计个体重组变化的新方法。在未来，它可用于揭示重组调控机制和与重组热点相关的人类疾病。
Meiotic recombination hotspots play important roles in various aspects of genomics, but the underlying mechanisms for regulating the locations and strengths of recombination hotspots are not yet fully revealed. Most existing algorithms for estimating recombination rates from sequence polymorphism data can only output average recombination rates of a population, although there is evidence for the heterogeneity in recombination rates among individuals. For genome-wide association studies (GWAS) of recombination hotspots, an efficient algorithm that estimates the individualized strengths of recombination hotspots is highly desirable. In this work, we propose a novel graph mining algorithm named ARG-walker, based on random walks on ancestral recombination graphs (ARG), to estimate individual-specific recombination hotspot strengths. Extensive simulations demonstrate that ARG-walker is able to distinguish the hot allele of a recombination hotspot from the cold allele. Integrated with output of ARG-walker, we performed GWAS on the phased haplotype data of the 22 autosome chromosomes of the HapMap Asian population samples of Chinese and Japanese (JPT+CHB). Significant cis-regulatory signals have been detected, which is corroborated by the enrichment of the well-known 13-mer motif CCNCCNTNNCCNC of PRDM9 protein. Moreover, two new DNA motifs have been identified in the flanking regions of the significantly associated SNPs (single nucleotide polymorphisms), which are likely to be new cis-regulatory elements of meiotic recombination hotspots of the human genome. Our results on both simulated and real data suggest that ARG-walker is a promising new method for estimating the individual recombination variations. In the future, it could be used to uncover the mechanisms of recombination regulation and human diseases related with recombination hotspots.