Small deletion variants have stable breakpoints commonly associated with alu elements.
Small deletion variants have stable breakpoints commonly associated with alu elements.
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DOI：
10.1371/journal.pone.0003104
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发表时间：
2008-08-29
期刊：
影响因子：
3.7
通讯作者：
Blakemore, Alexandra I. F.
中科院分区：
文献类型：
--
作者：
de Smith, Adam J.;Walters, Robin G.;Coin, Lachlan J. M.;Steinfeld, Israel;Yakhini, Zohar;Sladek, Rob;Froguel, Philippe;Blakemore, Alexandra I. F.
拷贝数变异（CNVs）对人类基因组变异有重要贡献，据报道有超过5000个位点，覆盖了18%以上的人类常染色质基因组。然而，对于不同大小和复杂程度的变异的起源和稳定性，我们所知甚少。我们使用安捷伦微阵列，在50名健康的法国高加索受试者中研究了20个小的、常见的缺失的断点，这些缺失代表了最初由CGH阵列识别的一个子集。通过使用设计用于跨越缺失区域的引物扩增的PCR产物测序，我们确定了所有受影响样品中缺失的确切大小和基因组位置。对于所研究的每个缺失，所有携带该缺失的个体在序列水平上具有相同的上游和下游断点，这表明该缺失事件仅发生一次，后来在群体中变得普遍。这一结论得到了链接不平衡（LD）分析的支持，该分析显示，所研究的大多数缺失是中等至强的LD，具有周围的snp，并且具有保守的远程单倍型。对缺失断点两侧序列的分析显示，在断点连接处微同源性丰富。更重要的是，我们发现了Alu重复元件的富集，其中绝大多数在其poly-A尾部相交的缺失断点。与其他报告不同，我们没有发现LINE元素的富集或片段重复。序列分析显示，在缺失断点周围的序列中富集了一个保守基序，尽管该基序是否在某些缺失的形成中具有任何机制作用尚未确定。考虑到更复杂的遗传变异区域的现有信息，以及与自闭症相关的新生变异的报告，这些数据支持基因组中CNV的不同亚群的存在，这些亚群可能通过不同的机制起源。
Copy number variants (CNVs) contribute significantly to human genomic variation, with over 5000 loci reported, covering more than 18% of the euchromatic human genome. Little is known, however, about the origin and stability of variants of different size and complexity. We investigated the breakpoints of 20 small, common deletions, representing a subset of those originally identified by array CGH, using Agilent microarrays, in 50 healthy French Caucasian subjects. By sequencing PCR products amplified using primers designed to span the deleted regions, we determined the exact size and genomic position of the deletions in all affected samples. For each deletion studied, all individuals carrying the deletion share identical upstream and downstream breakpoints at the sequence level, suggesting that the deletion event occurred just once and later became common in the population. This is supported by linkage disequilibrium (LD) analysis, which has revealed that most of the deletions studied are in moderate to strong LD with surrounding SNPs, and have conserved long-range haplotypes. Analysis of the sequences flanking the deletion breakpoints revealed an enrichment of microhomology at the breakpoint junctions. More significantly, we found an enrichment of Alu repeat elements, the overwhelming majority of which intersected deletion breakpoints at their poly-A tails. We found no enrichment of LINE elements or segmental duplications, in contrast to other reports. Sequence analysis revealed enrichment of a conserved motif in the sequences surrounding the deletion breakpoints, although whether this motif has any mechanistic role in the formation of some deletions has yet to be determined. Considered together with existing information on more complex inherited variant regions, and reports of de novo variants associated with autism, these data support the presence of different subgroups of CNV in the genome which may have originated through different mechanisms.
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