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Nature:冰岛学者揭示父母年龄与子女遗传突变关系

摘要 : 2017年9月28日,国际学术权威刊物自然出版集团《Nature》杂志在线发表了冰岛大学Kari Stefansson研究员的一篇研究论文,论文报告了迄今为止最大规模的人类自发性基因突变研究。

2017年9月28日,国际学术权威刊物自然出版集团《Nature》杂志在线发表了冰岛大学Kari Stefansson研究员的一篇研究论文,论文报告了迄今为止最大规模的人类自发性基因突变研究。该研究同时显示,父母年龄越大,尤其是父亲年龄越大,子女的自发性遗传突变(DNM)发生率越高。这项对人类基因组序列多样性突变过程的分析,对未来医学研究至关重要。

基因突变可以是自发的,也可以是诱发的,这两者之间其实并没有本质上的不同。通常自发性突变指家族当中首次出现的基因变化,由父母其中一方的卵子或精子突变导致。

为了解父母年龄和性别因素是如何引起自发性遗传突变差异的,研究人员对14688名冰岛人开展了全基因组序列分析,具体包括1548名个体及其父母,对于其中的225名个体,至少包含他们的一名子女。

在分析中,研究团队鉴定出108778个高质量自发性遗传突变,平均每个家庭70.3个。他们发现,来自母亲的自发性遗传突变数量,按年龄每年增加0.37个,而来自父亲的则按年龄每年增加1.51个,前者仅占后者的四分之一。研究团队还发现,簇状突变数量随母亲年龄增长的速度高于随父亲年龄增长的速度,而且母亲自发性遗传突变簇的基因组跨度大于父亲的。此外,来自母亲的自发性遗传突变类型会随着年龄发生显著变化。

研究人员表示,这项最新的分析帮助人们了解造成人类基因组序列多样性的突变过程,而这在医学、遗传学和演化学的研究中非常关键。

原文链接:

Parental influence on human germline de novomutations in 1,548 trios from Iceland

原文摘要:

The characterization of mutational processes that generate sequence diversity in the human genome is of paramount importance both to medical genetics1, 2 and to evolutionary studies3. To understand how the age and sex of transmitting parents affect de novo mutations, here we sequence 1,548 Icelanders, their parents, and, for a subset of 225, at least one child, to 35× genome-wide coverage. We find 108,778 de novo mutations, both single nucleotide polymorphisms and indels, and determine the parent of origin of 42,961. The number of de novo mutations from mothers increases by 0.37 per year of age (95% CI 0.32–0.43), a quarter of the 1.51 per year from fathers (95% CI 1.45–1.57). The number of clustered mutations increases faster with the mother’s age than with the father’s, and the genomic span of maternal de novo mutation clusters is greater than that of paternal ones. The types of de novo mutation from mothers change substantially with age, with a 0.26% (95% CI 0.19–0.33%) decrease in cytosine–phosphate–guanine to thymine–phosphate–guanine (CpG>TpG) de novo mutations and a 0.33% (95% CI 0.28–0.38%) increase in C>G de novo mutations per year, respectively. Remarkably, these age-related changes are not distributed uniformly across the genome. A striking example is a 20 megabase region on chromosome 8p, with a maternal C>G mutation rate that is up to 50-fold greater than the rest of the genome. The age-related accumulation of maternal non-crossover gene conversions also mostly occurs within these regions. Increased sequence diversity and linkage disequilibrium of C>G variants within regions affected by excess maternal mutations indicate that the underlying mutational process has persisted in humans for thousands of years. Moreover, the regional excess of C>G variation in humans is largely shared by chimpanzees, less by gorillas, and is almost absent from orangutans. This demonstrates that sequence diversity in humans results from evolving interactions between age, sex, mutation type, and genomic location.

来源: Nature 浏览次数:0

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