Determining the factors driving selective effects of new nonsynonymous mutations

Significance 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.