Identification of Copy Number Variation Hotspots in Human Populations
Identification of Copy Number Variation Hotspots in Human Populations
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人群中拷贝数变异热点的鉴定
DOI：
10.1016/j.ajhg.2010.09.006
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发表时间：
2010-10-08
影响因子：
9.8
通讯作者：
Jin, Li
中科院分区：
文献类型：
--
作者：
Fu, Wenqing;Zhang, Feng;Jin, Li
人类基因组中的拷贝数变异(CNV)在进化过程中对孟德尔和复杂的性状以及基因组的可塑性都有贡献。研究CNV的突变率对于了解基因组的不稳定性和拷贝数变异(CNV)相关性状的病因至关重要，然而，在基因组水平上评估CNV的突变率是一个难以克服的实际挑战，需要大量样本和准确的分型。在这项研究中，我们表明，通过使用侧翼SNPs的系统发育信息可以实现对CNV突变率的近似估计，这使得使用大量的SNP基因分型数据可以在全基因组范围内比较CNV之间的突变率。本研究对HapMap人群中已发现的4187个CNV区(CNV)进行了调查。结果表明，大多数CNV的突变率为每代10(-5)数量级，与个别基因座的实验观察结果一致。值得注意的是，104个(2.5%)CNV的突变率估计为每代10(-3)数量级，因此它们被确定为潜在的热点。进一步的分析表明，CNV基因座的基因组结构在激发人类基因组的突变热点方面具有潜在的作用。有趣的是，49个(47%)CNV热点包括人类基因，其中一些是已知的功能性CNV基因座(例如，引起自身免疫性疾病的C4和β-防御素的CNV，以及与大脑皮层大小控制有关的HYDIN的CNV)，暗示CNV在人类健康和进化中的重要作用，特别是在常见和复杂的疾病中
Copy number variants (CNVs) in the human genome contribute to both Mendelian and complex traits as well as to genomic plasticity in evolution The investigation of mutational rates of CNVs is critical to understanding genomic instability and the etiology of the copy number variation (CNV)-related traits However, the evaluation of the CNV mutation rate at the genome level poses an insurmountable practical challenge that requires large samples and accurate typing. In this study, we show that an approximate estimation of the CNV mutation rate could be achieved by using the phylogeny information of flanking SNPs This allows a genome-wide comparison of mutation rates between CNVs with the use of vast, readily available data of SNP genotyping. A total of 4187 CNV regions (CNVRs) previously identified in HapMap populations were investigated in this study We showed that the mutation rates for the majority of these CNVRs are at the order of 10(-5) per generation, consistent with experimental observations at individual loci Notably, the mutation rates of 104 (2 5%) CNVRs were estimated at the order of 10(-3) per generation, therefore, they were identified as potential hotspots. Additional analyses revealed that genome architecture at CNV loci has a potential role in inciting mutational hotspots in the human genome. Interestingly, 49 (47%) CNV hotspots include human genes, some of which are known to be functional CNV loci (e g, CNVs of C4 and beta-defensin causing autoimmune diseases and CNVs of HYDIN with implication in control of cerebral cortex size), implicating the important role of CNV in human health and evolution, especially in common and complex diseases