Epistasis not needed to explain low dN/dS

TL;DR

This paper demonstrates that the low dN/dS ratios observed in protein evolution can be explained without invoking epistasis, challenging previous claims that epistasis is pervasive in molecular evolution.

Contribution

The study shows that realistic models without epistasis can account for observed dN/dS ratios, relaxing previous assumptions of equal amino acid fitness.

Findings

Observed dN/dS values are consistent with non-epistatic models.

Equal fitness assumption is unrealistic and can bias interpretations.

Epistasis is not necessary to explain low dN/dS ratios in proteins.

Abstract

An important question in molecular evolution is whether an amino acid that occurs at a given position makes an independent contribution to fitness, or whether its effect depends on the state of other loci in the organism's genome, a phenomenon known as epistasis. In a recent letter to Nature, Breen et al. (2012) argued that epistasis must be "pervasive throughout protein evolution" because the observed ratio between the per-site rates of non-synonymous and synonymous substitutions (dN/dS) is much lower than would be expected in the absence of epistasis. However, when calculating the expected dN/dS ratio in the absence of epistasis, Breen et al. assumed that all amino acids observed in a protein alignment at any particular position have equal fitness. Here, we relax this unrealistic assumption and show that any dN/dS value can in principle be achieved at a site, without epistasis. Furthermore, for all nuclear and chloroplast genes in the Breen et al. dataset, we show that the observed dN/dS values and the observed patterns of amino acid diversity at each site are jointly consistent with a non-epistatic model of protein evolution.