A Method for Inferring the Rate of Occurrence and Fitness Effects of Advantageous Mutations

The distribution of fitness effects (DFE) of new mutations is of fundamental importance in evolutionary genetics. Recently, methods have been developed for inferring the DFE that use information from the allele frequency distributions of putatively neutral and selected nucleotide polymorphic variants in a population sample. Here, we extend an existing maximum-likelihood method that estimates the DFE under the assumption that mutational effects are unconditionally deleterious, by including a fraction of positively selected mutations. We allow one or more classes of positive selection coefficients in the model and estimate both the fraction of mutations that are advantageous and the strength of selection acting on them. We show by simulations that the method is capable of recovering the parameters of the DFE under a range of conditions. We apply the method to two data sets on multiple protein-coding genes from African populations of Drosophila melanogaster. We use a probabilistic reconstruction of the ancestral states of the polymorphic sites to distinguish between derived and ancestral states at polymorphic nucleotide sites. In both data sets, we see a significant improvement in the fit when a category of positively selected amino acid mutations is included, but no further improvement if additional categories are added. We estimate that between 1% and 2% of new nonsynonymous mutations in D. melanogaster are positively selected, with a scaled selection coefficient representing the product of the effective population size, N-e, and the strength of selection on heterozygous carriers of similar to 2.5.