Increased genome instability in human DNA segments with self-chains: homology-induced structural variations via replicative mechanisms.
Increased genome instability in human DNA segments with self-chains: homology-induced structural variations via replicative mechanisms.
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DOI：
10.1093/hmg/ddt113
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发表时间：
2013-07
影响因子：
3.5
通讯作者：
Weichen Zhou;Feng Zhang;Xiaoli Chen;Yiping Shen;J. Lupski;Li Jin
中科院分区：
文献类型：
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作者：
Weichen Zhou;Feng Zhang;Xiaoli Chen;Yiping Shen;J. Lupski;Li Jin
众所周知，包括电离辐射和化学试剂在内的环境因素能够诱导 DNA 重排并导致基因组结构变异 (SV)；然而，人类基因组的内在特征（例如区域基因组结构）在 SV 形成中的作用以及基因组不稳定的潜在机制仍有待进一步阐明。最近，位点特异性观察表明，“自链”（SC）是人类基因组中一组短的低拷贝重复序列（LCR），可以诱导 MECP2 和 NRXN1 基因的自闭症相关 SV 突变。在这项研究中，我们进行了全基因组分析，以研究 SC 及其在基因组 SV 形成中的潜在作用。利用大量人类 SV 数据，我们观察到人类种系 SV 断点在 SC 区域的分布存在显着偏差。值得注意的是，SV 类型之间的断点分布模式在删除、重复、倒置和插入方面是不同的。我们的观察结果与 SC 诱导 DNA 复制错误的机制一致，而 SC 可能偶尔用作非等位基因同源重组 (NAHR) 的底物。我们对癌症基因组体细胞 SV 突变的一致发现进一步支持了这一论点，这表明了 SC 诱导人类生殖和体细胞基因组不稳定的一般机制。
Environmental factors including ionizing radiation and chemical agents have been known to be able to induce DNA rearrangements and cause genomic structural variations (SVs); however, the roles of intrinsic characteristics of the human genome, such as regional genome architecture, in SV formation and the potential mechanisms underlying genomic instability remain to be further elucidated. Recently, locus-specific observations showed that 'self-chain' (SC), a group of short low-copy repeats (LCRs) in the human genome, can induce autism-associated SV mutations of the MECP2 and NRXN1 genes. In this study, we conducted a genome-wide analysis to investigate SCs and their potential roles in genomic SV formation. Utilizing a vast amount of human SV data, we observed a significant biased distribution of human germline SV breakpoints to SC regions. Notably, the breakpoint distribution pattern is different between SV types across deletion, duplication, inversion and insertion. Our observations were coincident with a mechanism of SC-induced DNA replicative errors, whereas SC may sporadically be used as substrates of nonallelic homologous recombination (NAHR). This contention was further supported by our consistent findings in somatic SV mutations of cancer genomes, suggesting a general mechanism of SC-induced genome instability in human germ and somatic cells.