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|Title:||Determining the factors driving selective effects of new nonsynonymous mutations|
|Citation:||Proceedings of the National Academy of Sciences, 2017; 114(17):4465-4470|
|Publisher:||National Academy of Sciences|
|Christian D. Huber, Bernard Y. Kim, Clare D. Marsden and Kirk E. Lohmueller|
|Abstract:||Our study addresses two fundamental questions regarding the effect of random mutations on fitness: First, do fitness effects differ between species when controlling for demographic effects? Second, what are the responsible biological factors? We show that amino acid-changing mutations in humans are, on average, more deleterious than mutations in Drosophila. We demonstrate that the only theoretical model that is fully consistent with our results is Fisher’s geometrical model. This result indicates that species complexity, as well as distance of the population to the fitness optimum, modulated by long-term population size, are the key drivers of the fitness effects of new amino acid mutations. Other factors, like protein stability and mutational robustness, do not play a dominant role.|
|Keywords:||Distribution of fitness effects; mutational robustness; protein stability; Fisher’s geometrical model; poisson random field|
|Rights:||Freely available online through the PNAS open access option. The author(s) retains copyright to individual PNAS articles, and the National Academy of Sciences of the United States of America (NAS) holds copyright to the collective work and retains an exclusive License to Publish these articles, except for open access articles submitted beginning September 2017. For such open access articles, NAS retains a nonexclusive License to Publish, and these articles are distributed under either a CC BY-NC-ND or CC BY license.|
|Appears in Collections:||Physiology publications|
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