Mutational signature analyses in multi-child families reveal sources of age-related increases in human germline mutations.

IF 5.2 1区 生物学 Q1 BIOLOGY Communications Biology Pub Date : 2024-11-06 DOI:10.1038/s42003-024-07140-2
Habiballah Shojaeisaadi, Andrew Schoenrock, Matthew J Meier, Andrew Williams, Jill M Norris, Nicholette D Palmer, Carole L Yauk, Francesco Marchetti
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Abstract

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.

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多子女家庭的突变特征分析揭示了与年龄相关的人类种系突变增加的来源。
对父母-后代三人组进行的全基因组测序研究为了解新发突变(DNMs)对人类健康和疾病的潜在影响提供了宝贵的信息。然而,驱动 DNMs 的分子机制尚不清楚。针对多子女家庭的研究可以为了解家庭间 DNM 变异率的原因提供重要见解,但这些研究非常有限。我们对 13 个墨西哥裔美国人多子女家庭中的 2479 个从头单核苷酸变异(SNV)进行了特征分析。我们观察到,父亲的年龄对已验证的从头单核苷酸变异有强烈的影响,而且家庭间的年增长率存在很大差异。与父亲年龄较小的孩子相比,父亲年龄较大的孩子在 CpG 位点上表现出更多的 C > T 转变。根据一个癌症(COSMIC)和两个非癌症(人类种系和 CRISPR-Cas 9 基因敲除人类 DNA 修复基因)突变特征数据库对经过验证的 SNV 进行了检查。这些分析表明,在修复启动和切除过程中不准确的DNA错配修复以及DNA损伤和复制错误是人类种系新生SNV的主要来源。我们的研究结果为了解人类种系新生SNV的潜在来源以及DNA错配修复在其发生过程中的关键作用提供了重要信息。
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来源期刊
Communications Biology
Communications Biology Medicine-Medicine (miscellaneous)
CiteScore
8.60
自引率
1.70%
发文量
1233
审稿时长
13 weeks
期刊介绍: Communications Biology is an open access journal from Nature Research publishing high-quality research, reviews and commentary in all areas of the biological sciences. Research papers published by the journal represent significant advances bringing new biological insight to a specialized area of research.
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