Empirical Validation of the Nearly Neutral Theory at Divergence and Population-Genomic Scales Using 144 Placental Mammal Genomes

By limiting the efficacy of selection, random drift is expected to play a major role in genome evolution. Formalizing this idea, the nearly-neutral theory predicts that the ratio of non-synonymous over synonymous polymorphism (πN/πS) within populations, and divergence (dN/dS) between species, should both correlate negatively with Ne. This has previously been tested in mammals and other groups. However, most studies have focused on either dN/dS or on πN/πS, thus not addressing the problem across evolutionary scales. In addition, many studies at the macro scale have used life-history traits (LHT) as a proxy of Ne, assuming that large-bodied organisms have lower Ne than small-bodied species. However, this assumption itself has rarely been validated against more objective measures of Ne, such as genetic diversity πS=4Neμ, in part because πS estimates are scarce. Here we propose an integrative test of the nearly-neutral predictions on 150 mammalian species, using 6000 orthologous genes, spanning the macro and the micro-evolutionary scale, using for the latter a measure of heterozygosity on each of the assembled diploid genomes. At the micro scale, we observe, for the first time in mammalian nuclear genomes, a relationship between πN/πS and πS. At the macro scale, we confirm the positive correlation between dN/dS and LHT but, more importantly, establish that LHT and dN/dS are correlated with πS, although weakly so. Together, these results provide the first global test of the nearly-neutral theory in mammals across time scales, suggesting all variables are correlated with a single hidden variable: Ne.