Hunting for Beneficial Mutations: Conditioning on SIFT Scores When Estimating the Distribution of Fitness Effect of New Mutations

Abstract

The distribution of fitness effects (DFE) of new mutations is a key parameter of molecular evolution. The DFE can in principle be estimated by comparing the site frequency spectra (SFS) of putatively neutral and functional polymorphisms. Unfortunately, the DFE is intrinsically hard to estimate, especially for beneficial mutations because these tend to be exceedingly rare. There is therefore a strong incentive to find out whether conditioning on properties of mutations that are independent of the SFS could provide additional information. In the present study, we developed a new measure based on SIFT scores. SIFT scores are assigned to nucleotide sites based on their level of conservation across a multispecies alignment: the more conserved a site, the more likely mutations occurring at this site are deleterious, and the lower the SIFT score. If one knows the ancestral state at a given site, one can assign a value to new mutations occurring at the site based on the change of SIFT score associated with the mutation. We called this new measure d. We show that properties of the DFE as well as the flux of beneficial mutations across classes covary with d and, hence, that SIFT scores are informative when estimating the fitness effect of new mutations. In particular, conditioning on SIFT scores can help to characterize beneficial mutations.