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Abstract Protein sequence evolution in the presence of epistasis makes many previously acceptable amino acid residues at a site unfavorable over time. This phenomenon of entrenchment has also been observed with neutral substitutions using Potts Hamiltonian models. Here, we show that simulations using these models often evolve non-neutral proteins. We introduce a Neutral-with-Epistasis (N×E) model that incorporates purifying selection to conserve fitness, a requirement of neutral evolution. N×E protein evolution revealed a surprising lack of entrenchment, with site-specific amino-acid preferences remaining remarkably conserved, in biologically realistic time frames despite extensive residue coupling. Moreover, we found that the overdispersion of the molecular clock is caused by rate variation across sites introduced by epistasis in individual lineages, rather than by historical contingency. Therefore, substitutional entrenchment and rate contingency may indicate that adaptive and other non-neutral evolutionary processes were at play during protein evolution.
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The effectiveness of selection in a species affects the direction of amino acid frequency evolution
Nearly neutral theory predicts that species with higher effective population size (N_e) are better at purging slightly deleterious mutations. We compare evolution in high N_e vs. low-N_e vertebrates to reveal subtle selective preferences among amino acids. We take three complementary approaches. First, we fit non-stationary substitution models using maximum likelihood, comparing the high-N_e clade of rodents and lagomorphs to its low-N_e sister clade of primates and colugos. Second, we compared evolutionary outcomes across a wider range of vertebrates, via correlations between amino acid frequencies and N_e. Third, we dissected which amino acids substitutions occurred in human, chimpanzee, mouse, and rat, as scored by parsimony – this also enabled comparison to a historical paper. All methods agree on amino acid preference under more effective selection. Preferred amino acids are less costly to synthesize and use GC-rich codons, which are hard to maintain under AT-biased mutation. These factors explain 85% of the variance in amino acid preferences. Parsimony-induced bias in the historical study produces an apparent reduction in structural disorder, perhaps driven by slightly deleterious substitutions in rapidly evolving regions. Within highly exchangeable pairs of amino acids, arginine is strongly preferred over lysine, aspartate over glutamate, and valine over isoleucine, consistent with more effective selection preferring a marginally larger free energy of folding. Two of these preferences (K→R and I→V), but not a third (E→D) match differences between thermophiles and mesophilic relatives. These results reveal the biophysical consequences of mutation-selection-drift balance, and demonstrate the utility of nearly neutral theory for understanding protein evolution.
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- Award ID(s):
- 2333243
- PAR ID:
- 10621344
- Publisher / Repository:
- bioRxiv
- Date Published:
- Format(s):
- Medium: X
- Institution:
- bioRxiv
- Sponsoring Org:
- National Science Foundation
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Accepted Manuscript1.0
- Posted Content:
- https://doi.org/10.1101/2023.02.01.526552
