Determining the factors driving selective effects of new nonsynonymous mutations

Huber Christian D.; Kim Bernard Y.; Marsden Clare D.Lohmueller Kirk E.

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Determining the factors driving selective effects of new nonsynonymous mutations

机译：Determining the factors driving selective effects of new nonsynonymous mutations

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The distribution of fitness effects (DFE) of new mutations plays a fundamental role in evolutionary genetics. However, the extent to which the DFE differs across species has yet to be systematically investigated. Furthermore, the biological mechanisms determining the DFE in natural populations remain unclear. Here, we show that theoretical models emphasizing different biological factors at determining the DFE, such as protein stability, back-mutations, species complexity, and mutational robustness make distinct predictions about how the DFE will differ between species. Analyzing amino acid-changing variants from natural populations in a comparative population genomic framework, we find that humans have a higher proportion of strongly deleterious mutations than Drosophila melanogaster. Furthermore, when comparing the DFE across yeast, Drosophila, mice, and humans, the average selection coefficient becomes more deleterious with increasing species complexity. Last, pleiotropic genes have a DFE that is less variable than that of nonpleiotropic genes. Comparing four categories of theoretical models, only Fisher's geometrical model (FGM) is consistent with our findings. FGM assumes that multiple phenotypes are under stabilizing selection, with the number of phenotypes defining the complexity of the organism. Our results suggest that long-term population size and cost of complexity drive the evolution of the DFE, with many implications for evolutionary and medical genomics.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2017年第17期|4465-4470|共6页
作者
Huber Christian D.; Kim Bernard Y.; Marsden Clare D.Lohmueller Kirk E.;
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Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
distribution of fitness effects; mutational robustness; protein stability; Fisher's geometrical model; Poisson random field;

Determining the factors driving selective effects of new nonsynonymous mutations

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