Empirical validation of the nearly neutral theory at divergence and population genomic scale across 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 ({pi}N /{pi}S) 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{pi} N /{pi}S, 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{pi} S = 4Ne{micro}, in part because{pi} S 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{pi} N /{pi}S and{pi} S. 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{pi} S, 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. Significance StatementNatural selection eliminates large-effect deleterious mutations but has limited efficacy for purging mutations of small effects. The effective population size (called Ne) is what determines the cutoff below which selection is inefficient. Since Ne varies between species, the prediction is that more mutations of intermediate effect should segregate and reach fixation in species with small populations. This has been widely studied both between species (macro-evolution) and within species (micro-evolution), although never in a fully integrated manner. Here, we analysed 144 genomes of placental mammals and 6002 orthologous genes, using the original sequence reads produced for genome assembly to estimate within-species genetic diversity based on the heterozygosity of the diploid individual whose genome has been sequenced. We show consistent relationships between genetic diversity within species, life-history traits such as body mass or longevity and selection efficacy simultaneously at the micro- and macro-evolutionary levels. Our analysis provides a globally consistent picture confirming the role of effective population size in tuning selection efficacy in placental mammals.