H: Similarity of synonymous substitution rates across mammalian genomes

Abstract Given that a gene has a high (or low) synony-mous substitution rate in one mammalian species, will it also have a high (or low) synonymous substitution rate in another mammalian species? Such similarities in the rate of synonymous substitution can reveal both selective pres-sures and neutral processes acting on mammalian gene sequences; however, the existence of such an effect has been a matter of disagreement. We resolve whether such synonymous substitution rate similarities exist using 7462 ortholog triplets aligned across rat, mouse, and human, a dataset two orders of magnitude larger than previous studies. We find that a gene’s synonymous substitution rate in the rat-mouse branch of the phylogeny is correlated with its rate in the branch connecting human and the rat-mouse ancestor. We confirm this for several different measures of synonymous substitution rate, including corrections for base composition and CpG dinucleotides, and we verify the results in the larger mouse-human-rat-dog phylogeny. This similarity of rates is most apparent for genes in which synonymous sites are well conserved across species, sug-gesting that a significant component of the effect is due to purifying selection. We observe rate correlations at a res-olution as fine as a few hundred kilobases, and the genes with the most similar synonymous substitution rates are enriched for regulatory functions. Genes with above-aver-age substitution rates also exhibit significant, though somewhat weaker, rate correlations, suggesting that some neutral processes may have persisted in the phylogeny as well