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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。






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


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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