Aberrant firing of replication origins potentially explains intragenic nonrecurrent rearrangements within genes, including the human DMD gene
Aberrant firing of replication origins potentially explains intragenic nonrecurrent rearrangements within genes, including the human DMD gene
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DOI：
10.1101/gr.123463.111
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发表时间：
2012-01-01
期刊：
影响因子：
7
通讯作者：
Hegde, Madhuri R.
中科院分区：
文献类型：
--
作者：
Ankala, Arunkanth;Kohn, Jordan N.;Hegde, Madhuri R.
非等位基因同源重组（NAHR）、非同源末端连接（NHEJ）和微同源介导复制依赖重组（MMRDR）都被提出作为解释基因组疾病相关DNA重排的机制。然而，人类的许多非复发性重排仍然无法解释。为了进一步研究这些拷贝数变异（cnv）的突变机制，我们对62例基因内缺失的人类DMD基因（50例）和其他已知致病基因（1例PCCB、1例IVD、1例DBT、3例PAH、1例STK11、1例HEXB、3例DBT、1例HRPT1和1例EMD）的临床病例进行了断点定位分析。虽然重复元件仅在4例病例中发现，其中3例涉及DMD和1例HEXB基因，但在56%的断点连接处观察到微同源性（210 bp），在62例病例中有16例发现插入范围在1至48 bp之间。在这些插入中，我们观察到在6例DMD病例中，参考序列在断点附近的短片段（5- 20bp）串联重复的证据（1例6次重复，3例4次重复，1例2次重复，1例1次重复），强烈表明复制机制试图超越停滞的复制叉。我们提供了一个新的模板滑移事件的证据，在复制抢救。随着最近的研究对复杂的复制过程及其在起源失败期间的挽救有了更深入的了解，我们提出了一个基于复制起源异常触发的假设来解释基因内非复发性重排，包括DMD基因。
Non-allelic homologous recombination (NAHR), non-homologous end joining (NHEJ), and microhomology-mediated replication-dependent recombination (MMRDR) have all been put forward as mechanisms to explain DNA rearrangements associated with genomic disorders. However, many nonrecurrent rearrangements in humans remain unexplained. To further investigate the mutation mechanisms of these copy number variations (CNVs), we performed breakpoint mapping analysis for 62 clinical cases with intragenic deletions in the human DMD gene (50 cases) and other known disease-causing genes (one PCCB, one IVD, one DBT, three PAH, one STK11, one HEXB, three DBT, one HRPT1, and one EMD cases). While repetitive elements were found in only four individual cases, three involving DMD and one HEXB gene, microhomologies (210 bp) were observed at breakpoint junctions in 56% and insertions ranging from 1 to 48 bp were seen in 16 of the total 62 cases. Among these insertions, we observed evidence for tandem repetitions of short segments (5-20 bp) of reference sequence proximal to the breakpoints in six individual DMD cases (six repeats in one, four repeats in three, two repeats in one, and one repeat in one case), strongly indicating attempts by the replication machinery to surpass the stalled replication fork. We provide evidence of a novel template slippage event during replication rescue. With a deeper insight into the complex process of replication and its rescue during origin failure, brought forward by recent studies, we propose a hypothesis based on aberrant firing of replication origins to explain intragenic nonrecurrent rearrangements within genes, including the DMD gene.