Assessing determinants of exonic evolutionary rates in mammals

[[abstract]]From studies investigating the differences in evolutionary rates between genes, gene compactness and gene expression level have been identified as important determinants of gene-level protein evolutionary rate, as represented by nonsynonymous-to-synonymous substitution rate (dN/dS) ratio. However, the causes of exon-level variances in dN/dS are less understood. Here we use principal component regression to examine to what extent thirteen exon features explain the variance in dN, dS, and the dN/dS ratio of human-rhesus macaque or human-mouse orthologous exons. The exon features were grouped into six functional categories: expression features, mRNA splicing features, structural-functional features, compactness features, exon duplicability, and other features, including G+C content and exon length. Although expression features are important for determining dN and dN/dS between exons of different genes, structural-functional features and splicing features explained more of the variance for exons of the same genes. Furthermore, we show that compactness features can explain only a relatively small percentage of variance in exon-level dN or dN/dS in either between-gene or within-gene comparison. By contrast, dS yielded inconsistent results in the human-mouse comparison and the human-rhesus macaque comparison. This inconsistency may suggest rapid evolutionary changes of the mutation landscape in mammals. Our results suggest that between-gene and within-gene variation in dN/dS (and dN) are driven by different evolutionary forces, and that the role of mRNA splicing in causing the variation in evolutionary rates of coding sequences may be underappreciated