Determining the factors driving selective effects of new nonsynonymous mutations

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 Fishers