ArticleNature2012
Epistasis as the primary factor in molecular evolution.
Article in Nature, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 212 papers.
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Who cites it
212 citing papers in PubMed.
- Enhancing prediction accuracy for enzyme activity engineering through sequence co-evolution and epistatic relationship modeling.Nucleic acids research · 2026Article
- How far can you go? Extrapolating values of catalytic activity from known protein landscapes in natural and directed evolution.Chemical Society reviews · 2026Review
- Multiple molecular and cellular properties jointly affect protein and site-specific evolutionary rates.bioRxiv : the preprint server for biology · 2026Article
- The Use of dN/dS Ratios to Investigate Types of Selection in Related Sexual and Asexual Lineages.Genome biology and evolution · 2026Review
- Growth of fatty acid vesicles coupled with amino acid sequences of peptides toward evolvable protocells.Communications chemistry · 2026Article
- Descent from a common ancestor restricts exploration of protein sequence space.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Deep homology and design of proteasome chaperone proteins in Candidozyma auris.Nature communications · 2026Article
- Evolutionary pathways in epistatic mechanical networks.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Sign Epistasis Can be Absent in Multi-peaked Landscapes With Neutral Mutations.Genome biology and evolution · 2026Article
- Phosphate ions modulate enzyme activity and epistatic effects in two clavulanic acid-resistant β-lactamase mutants.Protein science : a publication of the Protein Society · 2025Article
- Effect of Mutations on the Evolution of Extended Spectrum β-lactamases (ESBL).The protein journal · 2025Review
- Widespread epistasis shapes RNA polymerase II active site function and evolution.Nature communications · 2025Article
- Genome-wide association mapping and transcriptional analysis uncover genetic determinants of minor tocopherols in rice seeds.Scientific reports · 2025Article
- Article
- Higher-order epistasis drives evolutionary unpredictability toward novel antibiotic resistance.bioRxiv : the preprint server for biology · 2025Article
- The Constructive Neutral Evolution of Behaviour.Ecology and evolution · 2025Article
- Evolutionary-scale enzymology enables exploration of a rugged catalytic landscape.Science (New York, N.Y.) · 2025Article
- Robustness of Ancestral Sequence Reconstruction to Among-site and Among-lineage Evolutionary Heterogeneity.Molecular biology and evolution · 2025Article
- multistrap: boosting phylogenetic analyses with structural information.Nature communications · 2025Article
- A methodology for calculating the rarity of diverse proteins based on functional specificity and thermodynamic stability.PloS one · 2025Article
152 more citing papers are in PubMed but not listed here.
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5 authors.
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Abstract
The main forces directing long-term molecular evolution remain obscure. A sizable fraction of amino-acid substitutions seem to be fixed by positive selection, but it is unclear to what degree long-term protein evolution is constrained by epistasis, that is, instances when substitutions that are accepted in one genotype are deleterious in another. Here we obtain a quantitative estimate of the prevalence of epistasis in long-term protein evolution by relating data on amino-acid usage in 14 organelle proteins and 2 nuclear-encoded proteins to their rates of short-term evolution. We studied multiple alignments of at least 1,000 orthologues for each of these 16 proteins from species from a diverse phylogenetic background and found that an average site contained approximately eight different amino acids. Thus, without epistasis an average site should accept two-fifths of all possible amino acids, and the average rate of amino-acid substitutions should therefore be about three-fifths lower than the rate of neutral evolution. However, we found that the measured rate of amino-acid substitution in recent evolution is 20 times lower than the rate of neutral evolution and an order of magnitude lower than that expected in the absence of epistasis. These data indicate that epistasis is pervasive throughout protein evolution: about 90 per cent of all amino-acid substitutions have a neutral or beneficial impact only in the genetic backgrounds in which they occur, and must therefore be deleterious in a different background of other species. Our findings show that most amino-acid substitutions have different fitness effects in different species and that epistasis provides the primary conceptual framework to describe the tempo and mode of long-term protein evolution.
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