Significance of population size on the fixation of nonsynonymous mutations in genes under varying levels of selection pressure.

Previous studies observed a higher ratio of divergences at nonsynonymous and synonymous sites (ω = dN/dS) in species with a small population size compared to that estimated for those with a large population size. Here we examined the theoretical relationship between ω, effective population size (Ne), and selection coefficient (s). Our analysis revealed that when purifying selection is high, ω of species with small Ne is much higher than that of species with large Ne. However the difference between the two ω reduces with the decline in selection pressure (s → 0). We examined this relationship using primate and rodent genes and found that the ω estimated for highly constrained genes of primates was up to 2.9 times higher than that obtained for their orthologous rodent genes. Conversely, for genes under weak purifying selection the ω of primates was only 17% higher than that of rodents. When tissue specificity was used as a proxy for selection pressure we found that the ω of broadly expressed genes of primates was up to 2.1-fold higher than that of their rodent counterparts and this difference was only 27% for tissue specific genes. Since most of the nonsynonymous mutations in constrained or broadly expressed genes are deleterious, fixation of these mutations is influenced by Ne. This results in a higher ω of these genes in primates compared to those from rodents. Conversely, the majority of nonsynonymous mutations in less-constrained or tissue-specific genes are neutral or nearly neutral and therefore fixation of them is largely independent of Ne, which leads to the similarity of ω in primates and rodents.