Fitness conferred by replaced amino acids declines with time

Abstract

The fitness landscape of a locus, the array of fitnesses conferred by its alleles, can be affected by allele replacements at other loci, in the presence of epistatic interactions between loci. In a pair of diverging homologous proteins, the initially high probability that an amino acid replacement in one of them will make it more similar to the other declines with time, implying that the fitness landscapes of homologous sites diverge. Here, we use data on within-population non-synonymous polymorphisms and on amino acid replacements between species to study the dynamics, after an amino acid replacement, of the fitness of the ancestral amino acid, and show that selection against its restoration increases with time. This effect can be owing to increase of fitness conferred by the new amino acid occupying the site, and/or to decline of fitness conferred by the replaced amino acid. We show that the fitness conferred by the replaced amino acid rapidly declines, reaching a new lower steady-state level after approximately 20 per cent of amino acids in the protein get replaced. Therefore, amino acid replacements in evolving proteins are routinely involved in negative epistatic interactions with currently absent amino acids, and chisel off the unused parts of the fitness landscape.

Contingency and entrenchment in protein evolution under purifying selection

“…In particular, we find that each mutation that fixes is typically permitted to fix by the presence of preceding substitutions-that is, most substitutions would be too deleterious to fix were it not for epistasis with preceding substitutions. Conversely, we also find that mutations that fix typically become entrenched over time by epistasis-so that a substitution that was nearly neutral when it fixed becomes increasingly deleterious to revert as subsequent substitutions accumulate (18,39). These results imply an important role for epistasis in shaping the course of sequence evolution in a protein under selection to maintain thermodynamic stability.…”

“…Naumenko et al (39) studied the rate of reversion and found that the longer an amino acid had been present at a site, the lower the reversion rate to the ancestral amino acid. This is precisely what would be expected if the entrenchment observed in our simulations occurs in nature.…”

“…In the absence of epistasis, a mutation has the same effect regardless of its context and therefore regardless of any prior history or subsequent evolution. By contrast, in the presence of epistasis, each substitution may be contingent on the entire prior history of the protein, and it may constrain all subsequent evolution.The potential for epistasis to play an important role in evolution, including protein evolution, has not been overlooked by researchers (1, 8, 25-34), nor have the concepts of contingency (3,4,9,12,(35)(36)(37)(38) and, more recently, entrenchment (18,39,40). However, most studies have addressed the role of epistasis in the context of adaptive evolution (1-9, 27, 30, 31, 36, 38), whereas the consequences of epistasis under purifying selection have received less attention (18,(41)(42)(43)(44).…”

Epistasis and the Dynamics of Reversion in Molecular Evolution

“…This issue has been especially important recently, due to ongoing debate in the field of protein evolution about how position-specific preferences for amino acids may change over time (Naumenko et al 2012;Pollock et al 2012;Ashenberg et al 2013;Pollock and Goldstein 2014;Bazykin 2015;Doud et al 2015;Goldstein et al 2015;Risso et al 2015;Shah et al 2015;Usmanova et al 2015). Specifically, several groups have suggested that once an amino acid substitution occurs at a particular position, epistatic interactions with subsequent substitutions at other positions should tend to increase the selective preference for the derived amino acid relative to the ancestral state (Naumenko et al 2012;Pollock et al 2012;Shah et al 2015; cf. Fisher 1930, p. 95), a phenomenon known as entrenchment .…”

“…In addition, there are a variety of practical problems with inferring substitution histories such as apparent homoplastic substitutions due to incomplete lineage sorting (Mendes and Hahn 2016) and the fact that substitution histories are typically inferred using site-independent models even when there is substantial evidence for epistasis (e.g., Goldstein et al 2015). Nonetheless, multiple studies in this broader literature (Rogozin et al 2008;Naumenko et al 2012;Soylemez and Kondrashov 2012;Goldstein et al 2015;Zou and Zhang 2015) support our qualitative prediction that reversions and parallel substitutions should occur either very rapidly or only after a long waiting time. …”