Crossovers are associated with mutation and biased gene conversion at recombination hotspots
Crossovers are associated with mutation and biased gene conversion at recombination hotspots
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DOI：
10.1073/pnas.1416622112
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发表时间：
2015-02-17
影响因子：
11.1
通讯作者：
Tiemann-Boege, Irene
中科院分区：
文献类型：
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作者：
Arbeithuber, Barbara;Betancourt, Andrea J.;Tiemann-Boege, Irene
减数分裂是种系突变的潜在重要来源，因为减数分裂重组位点经历反复的双链断裂（DSB）。然而，来自群体序列数据的重组的局部致突变效应的证据一直是模棱两可的，可能是因为突变只是形成序列变异的几种力量之一。通过对从人类精子中获得的两个重组热点的大量单交叉分子进行测序，我们发现了重组具有致突变性的直接证据：交叉分子比针对相同供体和热点分析的非重组DNA分子携带更多的从头突变。观察到的突变主要是CG到TA的转换，在CpG位点的转换频率高于非CpG位点。在热点的CpG位点处的突变的这种富集可以在涉及作为DSB修复的一部分的频繁单链DNA加工的甲基化区域中占主导地位。此外，我们的数据集提供的证据表明，GC等位基因在交叉过程中优先传输，反对突变，并显示GC偏向基因转换（gBGC）在热点序列进化中占主导地位的突变。这些发现与gBGC可能是抵消重组突变负荷的适应的想法一致。
Meiosis is a potentially important source of germline mutations, as sites of meiotic recombination experience recurrent double-strand breaks (DSBs). However, evidence for a local mutagenic effect of recombination from population sequence data has been equivocal, likely because mutation is only one of several forces shaping sequence variation. By sequencing large numbers of single crossover molecules obtained from human sperm for two recombination hotspots, we find direct evidence that recombination is mutagenic: Crossovers carry more de novo mutations than nonrecombinant DNA molecules analyzed for the same donors and hotspots. The observed mutations were primarily CG to TA transitions, with a higher frequency of transitions at CpG than non-CpGs sites. This enrichment of mutations at CpG sites at hotspots could predominate in methylated regions involving frequent single-stranded DNA processing as part of DSB repair. In addition, our data set provides evidence that GC alleles are preferentially transmitted during crossing over, opposing mutation, and shows that GC-biased gene conversion (gBGC) predominates over mutation in the sequence evolution of hotspots. These findings are consistent with the idea that gBGC could be an adaptation to counteract the mutational load of recombination.