Intrachromosomal serial replication slippage in trans gives rise to diverse genomic rearrangements involving inversions
Intrachromosomal serial replication slippage in trans gives rise to diverse genomic rearrangements involving inversions
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DOI：
10.1002/humu.20230
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发表时间：
2005-10-01
期刊：
影响因子：
3.9
通讯作者：
Cooper, DN
中科院分区：
文献类型：
--
作者：
Chen, JM;Chuzhanova, N;Cooper, DN
顺式序列复制滑移（SRScis）为人类遗传疾病背后的许多复杂基因组重排提供了一个合理的解释。这一概念，再加上解释准同源性纠正引起的突变的分子内和分子间链开关模型，表明由短反向重复介导的反式染色体内SRS （SRStrans）也可能引起一系列复杂的基因组重排。如果是这样的话，这种重新安排必然会产生倒置。为了验证这个想法，我们整理了所有涉及到的信息突变！通过筛选人类基因突变数据库（HGMD; www.hgmd.org）并进行广泛的文献检索。在21个产生的突变中，只有两个（碰巧都包含未模板化的添加物）被发现与SRStrans模型不相容。其余19个突变中的18个（1个简单反转，6个反转涉及上游或下游序列的序列替换，5个反转涉及被移除序列的部分重新插入，6个反转发生在更复杂的背景下）被发现与染色体内SRStrans的两个步骤或顺式染色体内SRStrans的复制滑移的组合一致。剩余的病变是一个31 kb的片段重复，与SLC3A I基因的一个小反转相关，可以用一个改进的SRS模型来解释，该模型整合了“断裂诱导复制”的概念。因此，这项研究为我们的假设提供了广泛的支持，即染色体内SRStrans可以解释涉及倒位的各种复杂的基因重排。
Serial replication slippage in cis (SRScis) provides a plausible explanation for many complex genomic rearrangements that underlie human genetic disease. This concept, taken together with the intra- and intermolecular strand switch models that account for mutations that arise via quasipalindrome correction, suggest that intrachromosomal SRS in trans (SRStrans) mediated by short inverted repeats may also give rise to a diverse series of complex genomic rearrangements. If this were to be so, such rearrangements would invariably generate inversions. To test this idea, we collated all informative mutations involving inversions of ! 5 bp but < I kb by screening the Human Gene Mutation Database (HGMD; www.hgmd.org) and conducting an extensive literature search. Of the 21 resulting mutations, only two (both of which coincidentally contain untemplated additions) were found to be incompatible with the SRStrans model. Eighteen (one simple inversion, six inversions involving sequence replacement by upstream or downstream sequence, five inversions involving the partial reinsertion of removed sequence, and six inversions that occurred in a more complicated context) of the remaining 19 mutations were found to be consistent with either two steps of intrachromosomal SRStrans or a combination of replication slippage in cis plus intrachromosomal SRStrans. The remaining lesion, a 31-kb segmental duplication associated with a small inversion in the SLC3A I gene, is explicable in terms of a modified SRS model that integrates the concept of "break-induced replication." This study therefore lends broad support to our postulate that intrachromosomal SRStrans can account for a variety of complex gene rearrangements that involve inversions.