Replicative mechanisms of CNV formation preferentially occur as intrachromosomal events: evidence from Potocki-Lupski duplication syndrome.
Replicative mechanisms of CNV formation preferentially occur as intrachromosomal events: evidence from Potocki-Lupski duplication syndrome.
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DOI：
10.1093/hmg/dds482
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发表时间：
2013-02
影响因子：
3.5
通讯作者：
Zhe Sun;Pengfei Liu;Xueyuan Jia;Marjorie A. Withers;L. Jin;J. Lupski;Feng Zhang
中科院分区：
文献类型：
--
作者：
Zhe Sun;Pengfei Liu;Xueyuan Jia;Marjorie A. Withers;L. Jin;J. Lupski;Feng Zhang
人类基因组中的拷贝数变异（CNVs）对疾病有重要影响。新生CNV突变是通过基因组重排产生的，这种重排可能发生在“反式”，即通过染色体间事件，也可能发生在“顺式”，即通过染色体内事件。然而，染色体之间与染色单体之间或染色单体内部发生的分子机制尚未得到系统的研究。我们假设基于其内在特性的不同CNV突变机制可能以染色体内与染色体间的偏倚方式发生。在这里，我们研究了与散发性Potocki-Lupski综合征（PTLS）相关的62个基因组重复，其中多种突变机制似乎起作用。有趣的是，在非等位基因同源重组介导的复发性PTLS重复中，染色体间事件多于染色体内事件，而在复制机制和非同源末端连接中发现了互反分布，这可能反映了在不同突变过程中同源染色体的空间接近性差异。
Copy number variations (CNVs) in the human genome contribute significantly to disease. De novo CNV mutations arise via genomic rearrangements, which can occur in 'trans', i.e. via interchromosomal events, or in 'cis', i.e. via intrachromosomal events. However, what molecular mechanisms occur between chromosomes versus between or within chromatids has not been systematically investigated. We hypothesized that distinct CNV mutational mechanisms, based on their intrinsic properties, may occur in a biased intrachromosomal versus interchromosomal manner. Here, we studied 62 genomic duplications observed in association with sporadic Potocki-Lupski syndrome (PTLS), in which multiple mutational mechanisms appear to be operative. Intriguingly, more interchromosomal than intrachromosomal events were identified in recurrent PTLS duplications mediated by non-allelic homologous recombination, whereas the reciprocal distribution was found for replicative mechanisms and non-homologous end-joining, likely reflecting the differences in spacial proximity of homologous chromosomes during different mutational processes.