Reduced intrinsic DNA curvature leads to increased mutation rate.
Reduced intrinsic DNA curvature leads to increased mutation rate.
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DOI：
10.1186/s13059-018-1525-y
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发表时间：
2018-09-14
期刊：
影响因子：
12.3
通讯作者：
Qian W
中科院分区：
文献类型：
--
作者：
Duan C;Huan Q;Chen X;Wu S;Carey LB;He X;Qian W
不同基因组的突变率各不相同。许多影响突变率的反式因子已经被确定，如在1-7-bp尺度上具有特定的序列基序，但顺式元件的特征仍然很差。缺乏对为什么不同序列具有不同突变率的理解，阻碍了我们识别进化中的正选择和识别肿瘤发生中的驱动突变的能力。在这里，我们使用合成基因和数千个分离酵母菌落序列的组合来表明内在DNA曲率是突变率的主要顺式决定因素。突变率与基因内DNA弯曲度呈负相关，弯曲度降低10%，突变率增加70%。始终如一，酵母和人类都在曲率较小的区域积累突变。我们进一步表明，这种影响是由于内在突变率的差异，可能是由于诱变剂敏感性的差异，而不是由于DNA修复的局部活性的差异。我们的研究为理解DNA序列在调节局部突变率中的顺式特性建立了一个框架，并确定了整个基因组中不均匀突变率的一个新的因果来源。本文的在线版本（10.1186/s13059-018-1525-y）包含补充内容，仅供授权用户使用。
Mutation rates vary across the genome. Many trans factors that influence mutation rates have been identified, as have specific sequence motifs at the 1–7-bp scale, but cis elements remain poorly characterized. The lack of understanding regarding why different sequences have different mutation rates hampers our ability to identify positive selection in evolution and to identify driver mutations in tumorigenesis. Here, we use a combination of synthetic genes and sequences of thousands of isolated yeast colonies to show that intrinsic DNA curvature is a major cis determinant of mutation rate. Mutation rate negatively correlates with DNA curvature within genes, and a 10% decrease in curvature results in a 70% increase in mutation rate. Consistently, both yeast and humans accumulate mutations in regions with small curvature. We further show that this effect is due to differences in the intrinsic mutation rate, likely due to differences in mutagen sensitivity and not due to differences in the local activity of DNA repair. Our study establishes a framework for understanding the cis properties of DNA sequence in modulating the local mutation rate and identifies a novel causal source of non-uniform mutation rates across the genome. The online version of this article (10.1186/s13059-018-1525-y) contains supplementary material, which is available to authorized users.
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