Amino acid exchangeabilities vary across the tree of life.

Different amino acid pairs have drastically different relative exchangeabilities (REs), and accounting for this variation is an important and common practice in inferring phylogenies, testing selection, and predicting mutational effects, among other analyses. In all such endeavors, REs have been generally considered invariant among species; this assumption, however, has not been scrutinized. Using maximum likelihood to analyze 180 genome sequences, we estimated REs from 90 clades representing all three domains of life, and found numerous instances of substantial between-clade differences in REs. REs show more differences between orthologous proteins of different clades than unrelated proteins of the same clade, suggesting that REs are genome-wide, clade-specific features, probably a result of proteome-wide evolutionary changes in the physicochemical environments of amino acid residues. The discovery of among-clade RE variations cautions against assuming constant REs in various analyses and demonstrates a higher-than-expected complexity in mechanisms of proteome evolution.