Evolution of amino acid propensities under stability-mediated epistasis

Mol Biol Evol. 2022 Feb 4:msac030. doi: 10.1093/molbev/msac030. Online ahead of print.


Site-specific amino acid preferences are influenced by the genetic background of the protein. The preferences for resident amino acids are expected to, on average, increase over time because of replacements at other sites – a nonadaptive phenomenon referred to as the ‘evolutionary Stokes shift’. Alternatively, decreases in resident amino acid propensity have recently been viewed as evidence of adaptations to external environmental changes. Using population genetics theory and thermodynamic stability-constraints, we show that nonadaptive evolution can lead to both positive and negative shifts in propensities following the fixation of an amino acid, emphasizing that the detection of negative shifts is not conclusive evidence of adaptation. Considering shifts in propensities over windows between substitutions at a focal site, we find that following ≈ 50% of substitutions the propensity for the new resident amino acid decreases over time, and both positive and negative shifts were comparable in magnitude. Preferences were often conserved via a significant negative autocorrelation in propensity changes-increases in propensities often followed by decreases, and vice versa. Lastly, we explore the underlying mechanisms that lead propensities to fluctuate. We observe that stabilizing replacements increase the mutational tolerance at a site and in doing so decrease the propensity for the resident amino acid. In contrast, destabilizing substitutions result in more rugged fitness landscapes that tend to favor the resident amino acid. In summary, our results characterize propensity trajectories under nonadaptive stability-constrained evolution against which evidence of adaptations should be calibrated.

PMID:35134997 | DOI:10.1093/molbev/msac030