Overlooked roles of DNA damage and maternal age in generating human germline mutations
Overlooked roles of DNA damage and maternal age in generating human germline mutations
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DOI：
10.1073/pnas.1901259116
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发表时间：
2019-05-07
影响因子：
11.1
通讯作者：
Przeworski, Molly
中科院分区：
文献类型：
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作者：
Gao, Ziyue;Moorjani, Priya;Przeworski, Molly
教科书上的观点认为，哺乳动物中的大多数生殖系突变是由复制错误引起的，这一观点得到了以下事实的间接支持：雄性生殖系中的突变和细胞分裂都比雌性生殖系中的多。在分析人类的大型从头突变数据集时，我们发现了多条证据，对这一观点提出了质疑。值得注意的是，尽管在精子发生开始后，男性与女性生殖细胞分裂的比例急剧增加，但即使是年轻的父亲也比年轻的母亲贡献了三倍多的突变，而且这个比例几乎没有随着父母年龄的增加而增加。这一令人惊讶的发现指出了损伤诱导突变的重大贡献。事实上，C-to-G颠换和CpG转换，它们共同构成了超过四分之一的所有碱基置换突变，显示基因组分布和性别特异性年龄依赖性，分别指示双链断裂修复和甲基化相关损伤。此外，我们发现的证据表明，母亲怀孕的年龄影响突变率，因为卵母细胞中的损伤的积累，并可能通过对胚胎中的合子后突变的数量的影响。这些发现揭示了DNA损伤和母亲年龄在人类生殖系突变发生中未被充分认识的作用。
The textbook view that most germline mutations in mammals arise from replication errors is indirectly supported by the fact that there are both more mutations and more cell divisions in the male than in the female germline. When analyzing large de novo mutation datasets in humans, we find multiple lines of evidence that call that view into question. Notably, despite the drastic increase in the ratio of male to female germ cell divisions after the onset of spermatogenesis, even young fathers contribute three times more mutations than young mothers, and this ratio barely increases with parental age. This surprising finding points to a substantial contribution of damage-induced mutations. Indeed, C-to-G transversions and CpG transitions, which together constitute over one-fourth of all base substitution mutations, show genomic distributions and sex-specific age dependencies indicative of double-strand break repair and methylation-associated damage, respectively. Moreover, we find evidence that maternal age at conception influences the mutation rate both because of the accumulation of damage in oocytes and potentially through an influence on the number of postzygotic mutations in the embryo. These findings reveal underappreciated roles of DNA damage and maternal age in the genesis of human germline mutations.