Mechanisms for human genomic rearrangements.
Mechanisms for human genomic rearrangements.
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DOI：
10.1186/1755-8417-1-4
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发表时间：
2008-11-03
期刊：
影响因子：
--
通讯作者：
Lupski JR
中科院分区：
文献类型：
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作者：
Gu W;Zhang F;Lupski JR
基因组重排描述了大小从几百个碱基对（平均外显子的大小）到兆碱基（Mb）的总DNA变化。当大于3至5 Mb时，这种变化通常通过染色体研究在显微镜下可见。由基因组重排引起的人类疾病被称为基因组疾病。人类基因组中的基因组重排有三种主要机制。非等位基因同源重组（NAHR）主要由低拷贝重复序列（LCR）介导，具有重组热点、基因转换和表观最小有效加工片段。NAHR解释了大多数的复发性重排：那些有共同大小，显示断点聚集，并在多个个体中复发的重排。非复发性重排在每个患者中具有不同的大小，但可以共享最小的重叠区域，其拷贝数的变化可以导致不同患者之间共享的临床特征。LCR不介导，但可能刺激非复发性事件。一些罕见的NAHR也可以由高度同源的重复序列（例如，Alu，LINE）介导;这些NAHR解释了一些非复发性重排。其他非重复性重排可以通过非同源末端连接（NHEJ）和Fork Stalling and Template Switching（FoSTeS）模型来解释。这些机制既发生在生殖细胞中，其中重排可能与基因组疾病相关，也发生在体细胞中，其中这种基因组重排可能导致疾病，如癌症。NAHR，NHEJ和FoSTeS可能占我们基因组中基因组重排的大部分，并且在给定基因座处这三个基因的频率分布可能部分地反映了该基因座附近的基因组结构。我们提供了一个审查目前的理解这三种模式。
Genomic rearrangements describe gross DNA changes of the size ranging from a couple of hundred base pairs, the size of an average exon, to megabases (Mb). When greater than 3 to 5 Mb, such changes are usually visible microscopically by chromosome studies. Human diseases that result from genomic rearrangements have been called genomic disorders. Three major mechanisms have been proposed for genomic rearrangements in the human genome. Non-allelic homologous recombination (NAHR) is mostly mediated by low-copy repeats (LCRs) with recombination hotspots, gene conversion and apparent minimal efficient processing segments. NAHR accounts for most of the recurrent rearrangements: those that share a common size, show clustering of breakpoints, and recur in multiple individuals. Non-recurrent rearrangements are of different sizes in each patient, but may share a smallest region of overlap whose change in copy number may result in shared clinical features among different patients. LCRs do not mediate, but may stimulate non-recurrent events. Some rare NAHRs can also be mediated by highly homologous repetitive sequences (for example, Alu, LINE); these NAHRs account for some of the non-recurrent rearrangements. Other non-recurrent rearrangements can be explained by non-homologous end-joining (NHEJ) and the Fork Stalling and Template Switching (FoSTeS) models. These mechanisms occur both in germ cells, where the rearrangements can be associated with genomic disorders, and in somatic cells in which such genomic rearrangements can cause disorders such as cancer. NAHR, NHEJ and FoSTeS probably account for the majority of genomic rearrangements in our genome and the frequency distribution of the three at a given locus may partially reflect the genomic architecture in proximity to that locus. We provide a review of the current understanding of these three models.