DEX: a consensus-based amino acid exchangeability measure for improved codon substitution modelling

Physicochemically similar amino acids undergo more frequent substitutions compared to dissimilar amino acid pairs. Despite their clear potential, amino acid similarity matrices remain underused in molecular evolution, partially due to the high number of proposed amino acid distance measures and the lack of agreement on which are most accurate. In this study, we assessed the performance of 30 amino acid distance measures, including a new amino acid distance measure we developed based on recent deep mutational scanning data. We compared these measures across codon substitution models fit to alignments spanning Streptococcus, Drosophila, and mammalian lineages, as well as segregating variants across Escherichia coli strains and human genotypes. We further constructed consensus measures from combinations of top-performing measures in this analysis using the DISTATIS approach and retested these matrices. Our results show that experimentally-derived measures, particularly our new measure and the existing experimental exchangeability (EX) measure, best fit codon substitution patterns across diverse lineages. We found that a consensus measure based on these two approaches, which we named DEX, performed best overall. In addition, although site-specific variant effect predictors are intended to identify deleterious mutations, the representative tools we tested did not outperform amino acid distance measures for predicting mean substitution frequencies. They were however substantially more informative for identifying individual highly deleterious mutations. Overall, we provide a systematic comparison of the performance of existing measures, and we introduce an improved general-purpose amino acid distance measure for molecular evolution models.