Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON, Canada.
Research Computing Services, Carleton University, Ottawa, ON, Canada.
Commun Biol. 2024 Nov 6;7(1):1451. doi: 10.1038/s42003-024-07140-2.
Whole-genome sequencing studies of parent-offspring trios have provided valuable insights into the potential impact of de novo mutations (DNMs) on human health and disease. However, the molecular mechanisms that drive DNMs are unclear. Studies with multi-child families can provide important insight into the causes of inter-family variability in DNM rates but they are highly limited. We characterized 2479 de novo single nucleotide variants (SNVs) in 13 multi-child families of Mexican-American ethnicity. We observed a strong paternal age effect on validated de novo SNVs with extensive inter-family variability in the yearly rate of increase. Children of older fathers showed more C > T transitions at CpG sites than children from younger fathers. Validated SNVs were examined against one cancer (COSMIC) and two non-cancer (human germline and CRISPR-Cas 9 knockout of human DNA repair genes) mutational signature databases. These analyses suggest that inaccurate DNA mismatch repair during repair initiation and excision processes, along with DNA damage and replication errors, are major sources of human germline de novo SNVs. Our findings provide important information for understanding the potential sources of human germline de novo SNVs and the critical role of DNA mismatch repair in their genesis.
全基因组测序研究表明，新生突变（DNMs）可能会对人类健康和疾病产生影响。然而，导致 DNMs 的分子机制尚不清楚。多子女家庭的研究可以深入了解导致家族间 DNMs 率差异的原因，但此类研究非常有限。本研究分析了 13 个墨西哥裔美国家庭的 2479 个新生单核苷酸变异（SNVs），发现新生 SNVs 与父亲年龄有很强的相关性，且各家族间的年增长率存在显著差异。与年轻父亲的孩子相比，来自年长父亲的孩子的 CpG 位点的 C 到 T 转换更为频繁。研究人员对这些新生 SNVs 进行了癌症（COSMIC）和两种非癌症（人类种系和 CRISPR-Cas9 敲除人类 DNA 修复基因）突变特征数据库的验证，结果表明，在修复起始和切除过程中 DNA 错配修复不准确，加上 DNA 损伤和复制错误，是人类种系新生 SNVs 的主要来源。本研究为了解人类种系新生 SNVs 的潜在来源以及 DNA 错配修复在其产生过程中的关键作用提供了重要信息。
