PT - JOURNAL ARTICLE AU - Christian D. Huber AU - Bernard Kim AU - Clare D. Marsden AU - Kirk E. Lohmueller TI - Determining the factors driving selective effects of new nonsynonymous mutations AID - 10.1101/071209 DP - 2016 Jan 01 TA - bioRxiv PG - 071209 4099 - http://biorxiv.org/content/early/2016/08/23/071209.short 4100 - http://biorxiv.org/content/early/2016/08/23/071209.full AB - The distribution of fitness effects (DFE) of new mutations is a fundamental parameter in evolutionary genetics1–3. While theoretical models have emphasized the importance of distinct biological factors, such as protein folding4, back mutations5, species complexity6,7, and mutational robustness8 at determining the DFE, it remains unclear which of these models can describe the DFE in natural populations. Here, we show that the theoretical models make distinct predictions about how the DFE will differ between species. We further show that humans have a higher proportion of strongly deleterious mutations than Drosophila melanogaster. Comparing four categories of theoretical models, only Fisher’s Geometrical Model (FGM) is consistent with our data. FGM assumes that multiple phenotypes are under stabilizing selection, with the number of phenotypes defining a complexity of the organism. It suggests that long-term population size and cost of complexity drive the evolution of the DFE, with many implications for evolutionary and medical genomics.