The Francis Crick Institute, London, NW1 1AT, UK.
School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.
Nat Commun. 2020 Mar 13;11(1):1363. doi: 10.1038/s41467-020-15185-0.
Nucleosome organization has been suggested to affect local mutation rates in the genome. However, the lack of de novo mutation and high-resolution nucleosome data has limited the investigation of this hypothesis. Additionally, analyses using indirect mutation rate measurements have yielded contradictory and potentially confounding results. Here, we combine data on >300,000 human de novo mutations with high-resolution nucleosome maps and find substantially elevated mutation rates around translationally stable ('strong') nucleosomes. We show that the mutational mechanisms affected by strong nucleosomes are low-fidelity replication, insufficient mismatch repair and increased double-strand breaks. Strong nucleosomes preferentially locate within young SINE/LINE transposons, suggesting that when subject to increased mutation rates, transposons are then more rapidly inactivated. Depletion of strong nucleosomes in older transposons suggests frequent positioning changes during evolution. The findings have important implications for human genetics and genome evolution.
核小体组织被认为会影响基因组中的局部突变率。然而，由于缺乏新的突变和高分辨率核小体数据，限制了对这一假设的研究。此外，使用间接突变率测量方法的分析得出了相互矛盾且可能存在混淆的结果。在这里，我们将超过 30 万个人类新突变的数据与高分辨率核小体图谱相结合，发现翻译稳定（“强”）核小体周围的突变率显著升高。我们表明，受强核小体影响的突变机制包括低保真度复制、不充分的错配修复和增加的双链断裂。强核小体优先定位于年轻的 SINE/LINE 转座子内，这表明当受到更高的突变率影响时，转座子会更快地失活。在较老的转座子中耗尽强核小体表明，在进化过程中经常发生位置变化。这些发现对人类遗传学和基因组进化具有重要意义。
