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Nature:与复制相关的基因组变异

摘要 : 决定突变在基因组中非随机分布的机制仍有待确定。在这篇论文中,Andrew Jackson及同事报告, “Okazaki片段” (复制过程中在DNA的拖后链上合成的DNA短片段)的5′端核苷酸替代水平增高。

 决定突变在基因组中非随机分布的机制仍有待确定。在这篇论文中,Andrew Jackson及同事报告, “Okazaki片段” (复制过程中在DNA的拖后链上合成的DNA短片段)的5′端核苷酸替代水平增高。

在用来跟踪聚合酶活性的一个新研究出的被称为 “emRiboSeq”的方法帮助下,他们发现,尽管存在“Okazaki片段”处理现象,但由 “易出错的聚合酶-α”(Pol-α)合成的DNA在活体中被保留了下来,占基因组的约1.5%。

这些发现将Pol-α确定为造成基因组变化的一个重要原因,并为核苷酸取代率的点特异性差异提供了一个机制。 调控性序列上的突变热点因而是染色质和调控性蛋白结合所付出的一个突变代价。

原文链接:

Lagging-strand replication shapes the mutational landscape of the genome

The origin of mutations is central to understanding evolution and of key relevance to health. Variation occurs non-randomly across the genome, and mechanisms for this remain to be defined. Here we report that the 5′ ends of Okazaki fragments have significantly increased levels of nucleotide substitution, indicating a replicative origin for such mutations. Using a novel method, emRiboSeq, we map the genome-wide contribution of polymerases, and show that despite Okazaki fragment processing, DNA synthesized by error-prone polymerase-α (Pol-α) is retained in vivo, comprising approximately 1.5% of the mature genome. We propose that DNA-binding proteins that rapidly re-associate post-replication act as partial barriers to Pol-δ-mediated displacement of Pol-α-synthesized DNA, resulting in incorporation of such Pol-α tracts and increased mutation rates at specific sites. We observe a mutational cost to chromatin and regulatory protein binding, resulting in mutation hotspots at regulatory elements, with signatures of this process detectable in both yeast and humans.

对应Nature杂志: 2015年02月26日Nature杂志精选

来源: Nature 浏览次数:90

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