Human endogenous retroviral elements promote genome instability via non-allelic homologous recombination.
Human endogenous retroviral elements promote genome instability via non-allelic homologous recombination.
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DOI：
10.1186/s12915-014-0074-4
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发表时间：
2014-09-23
期刊：
影响因子：
5.4
通讯作者：
Stankiewicz P
中科院分区：
文献类型：
--
作者：
Campbell IM;Gambin T;Dittwald P;Beck CR;Shuvarikov A;Hixson P;Patel A;Gambin A;Shaw CA;Rosenfeld JA;Stankiewicz P
导致疾病或变异的人类基因组的反复重排主要由低拷贝重复序列之间的非等位基因同源重组（NAHR）介导。然而，其他基因组结构，包括AT丰富的回文和逆转录病毒，也被报道为基础的经常性结构重排。值得注意的是，传递无精子症的Yq 12的复发性缺失以及非致病性相互重复是由人内源性逆转录病毒元件（HERVs）介导的。我们假设，HERV元件在整个基因组中可以作为基因组不稳定性的底物，并导致人类拷贝数变异（CNV）。我们开发的参数，以确定HERV元件类似于那些介导Yq 12重排以及复发性缺失3q13.2q13.31。我们使用这些参数来识别可能导致不稳定性的全基因组HERV对。我们的分析突出了170对，侧翼12.1%的基因组。我们交叉引用这些预测的易感区域与CNVs从我们的临床数据库潜在的HERV介导的重排，并确定了78 CNVs。随后，我们在分子水平上证实了10个个体中4个位点的重复和重复重排，包括2个位点的相互重排。断裂点测序揭示了在富含PRDM 9介导的重组热点基序的高序列同一性区域中的聚类。缺失和相互重复的存在表明NAHR是HERV介导的CNV的致病机制，即使HERV元件的长度和序列同源性低于目前认为NAHR所需的。我们认为，除了HERVs，其他重复元件，如长散布元件，也可能是通过NAHR形成复发性CNVs的原因。本文的在线版本（doi：10.1186/s12915-014-0074-4）包含补充材料，可供授权用户使用。
Recurrent rearrangements of the human genome resulting in disease or variation are mainly mediated by non-allelic homologous recombination (NAHR) between low-copy repeats. However, other genomic structures, including AT-rich palindromes and retroviruses, have also been reported to underlie recurrent structural rearrangements. Notably, recurrent deletions of Yq12 conveying azoospermia, as well as non-pathogenic reciprocal duplications, are mediated by human endogenous retroviral elements (HERVs). We hypothesized that HERV elements throughout the genome can serve as substrates for genomic instability and result in human copy-number variation (CNV). We developed parameters to identify HERV elements similar to those that mediate Yq12 rearrangements as well as recurrent deletions of 3q13.2q13.31. We used these parameters to identify HERV pairs genome-wide that may cause instability. Our analysis highlighted 170 pairs, flanking 12.1% of the genome. We cross-referenced these predicted susceptibility regions with CNVs from our clinical databases for potentially HERV-mediated rearrangements and identified 78 CNVs. We subsequently molecularly confirmed recurrent deletion and duplication rearrangements at four loci in ten individuals, including reciprocal rearrangements at two loci. Breakpoint sequencing revealed clustering in regions of high sequence identity enriched in PRDM9-mediated recombination hotspot motifs. The presence of deletions and reciprocal duplications suggests NAHR as the causative mechanism of HERV-mediated CNV, even though the length and the sequence homology of the HERV elements are less than currently thought to be required for NAHR. We propose that in addition to HERVs, other repetitive elements, such as long interspersed elements, may also be responsible for the formation of recurrent CNVs via NAHR. The online version of this article (doi:10.1186/s12915-014-0074-4) contains supplementary material, which is available to authorized users.
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DOI：
10.1146/annurev-genom-082509-141802
发表时间：
2011
影响因子：
8.7
作者：
Beck CR;Garcia-Perez JL;Badge RM;Moran JV
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