Correlation between frequency of non-allelic homologous recombination and homology properties: evidence from homology-mediated CNV mutations in the human genome
Correlation between frequency of non-allelic homologous recombination and homology properties: evidence from homology-mediated CNV mutations in the human genome
复制标题
非等位基因同源重组频率与同源特性之间的相关性：来自人类基因组中同源介导的 CNV 突变的证据
DOI：
10.1093/hmg/ddu533
复制
发表时间：
2015-03-01
影响因子：
3.5
通讯作者：
Zhang, Feng
中科院分区：
文献类型：
--
作者：
Peng, Zhen;Zhou, Weichen;Zhang, Feng
非等位基因同源重组（NAHR）是DNA重排的重要机制之一。直接同源重复序列之间的NAHR可以产生基因组拷贝数变异（CNV），并对基因组进化和人类疾病（如癌症）做出重要贡献。有趣的是，以前对某些基因组疾病位点的罕见CNV的观察表明，NAHR频率可能依赖于同源性。然而，这种相关性在其他NAHR介导的CNV基因座，特别是在人群中常见的CNV仍然不清楚。与基因组疾病相关的罕见CNV不同，在常见CNV基因座鉴定从头NAHR事件具有挑战性。因此，我们先前提出的统计量M用于估计人群中NAHR介导的CNV的相对突变率。利用广义回归神经网络和主成分分析方法，对3个HapMap群体中的4330个CNVs进行了研究，发现了NAHR介导的配对片段重复（SD）之间的CNVs，并进一步揭示了SD特性与NAHR概率之间的相关性。SD长度和SD间距离被证明是NAHR发生的主要贡献，而染色体位置和配对SD的序列相似性也参与NAHR。SD属性对NAHR频率的综合影响被揭示为人类群体中常见的CNVs。这些观察结果可以很好地解释了异位突触NAHR连同我们提出的模型的染色体压缩/延伸/循环（CCEL）的同源性错配。我们的研究结果表明SDs在NAHR和人类基因组进化中的重要作用。
Non-allelic homologous recombination (NAHR) is one of the key mechanisms of DNA rearrangement. NAHR occurring between direct homologous repeats can generate genomic copy number variation (CNV) and make significant contributions to both genome evolution and human diseases such as cancer. Intriguingly, previous observations on the rare CNVs at certain genomic disorder loci suggested that NAHR frequency could be dependent on homology properties. However, such a correlation remains unclear at the other NAHR-mediated CNV loci, especially the common CNVs in human populations. Different from the rare CNVs associated with genomic disorders, it is challenging to identify de novo NAHR events at common CNV loci. Therefore, our previously proposed statistic M was employed in estimating relative mutation rate for the NAHR-mediated CNVs in human populations. By utilizing generalized regression neural network and principal component analysis in studying 4330 CNVs ascertained in 3 HapMap populations, we identified the CNVs mediated by NAHR between paired segmental duplications (SDs) and further revealed the correlations between SD properties and NAHR probability. SD length and inter-SD distance were shown to make major contributions to the occurrence of NAHR, whereas chromosomal position and sequence similarity of paired SDs are also involved in NAHR. An integrated effect of SD properties on NAHR frequency was revealed for the common CNVs in human populations. These observations can be well explained by ectopic synapsis in NAHR together with our proposed model of chromosomal compression/extension/looping (CCEL) for homology mis-pairing. Our findings showed the important roles of SDs in NAHR and human genomic evolution.