ArticleProceedings of the National Academy of Sciences of the United States of America2015
Contingency and entrenchment in protein evolution under purifying selection.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 107 papers.
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107 citing papers in PubMed, 209 citations in OpenAlex.
- Epistasis plays a limited role in driving entrenchment during neutral protein evolution.Genome biology · 2026Article
- Deep mutational scanning of recent SARS-CoV-2 variants highlights changing amino acid preferences within epistatic hotspot residues.PLoS pathogens · 2026Article
- Entrenchment of germline amino-acid differences in antibody affinity maturation.bioRxiv : the preprint server for biology · 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
- Pleiotropic mutational effects on function and stability constrain the antigenic evolution of influenza haemagglutinin.Nature ecology & evolution · 2026Article
- Free energy perturbations in enzyme kinetic models reveal cryptic epistasis.PLoS computational biology · 2026Article
- D81 Mutants Reveal Hidden EF-Tu Diversity while Natural Sequences Preserve Aspartate.Computational and structural biotechnology journal · 2026Article
- Adversarial Sequence Mutations in AlphaFold and ESMFold Reveal Nonphysical Structural Invariance, Confidence Failures, and Concerns for Protein Design.Computational and structural biotechnology journal · 2026Article
- Epistatic drift in protein evolution.Current opinion in genetics & development · 2025Review
- Exploring evolutionary trajectories of drug resistance.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Accurate prediction of substitution rates at protein sites with a mutation-selection model.Scientific reports · 2025Article
- Pleiotropic mutational effects on function and stability constrain the antigenic evolution of influenza hemagglutinin.bioRxiv : the preprint server for biology · 2025Article
- SURFS and AlphaFold Reveal Ribosome Footprint Shift Caused by EF-Tu D81 Mutation.bioRxiv : the preprint server for biology · 2025Article
- Intramolecular epistasis correlates with divergence of specificity in promiscuous and bifunctional NSAR/OSBS enzymes.Protein science : a publication of the Protein Society · 2025Article
- Characterization of the Complete Mitochondrial Genome ofAnimals : an open access journal from MDPI · 2025Article
- Specialization Restricts the Evolutionary Paths Available to Yeast Sugar Transporters.Molecular biology and evolution · 2024Article
- Understanding epistatic networks in the B1 β-lactamases through coevolutionary statistical modeling and deep mutational scanning.Nature communications · 2024Article
- Addressing epistasis in the design of protein function.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Alternate conformational trajectories in ribosome translocation.PLoS computational biology · 2024Article
47 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The phenotypic effect of an allele at one genetic site may depend on alleles at other sites, a phenomenon known as epistasis. Epistasis can profoundly influence the process of evolution in populations and shape the patterns of protein divergence across species. Whereas epistasis between adaptive substitutions has been studied extensively, relatively little is known about epistasis under purifying selection. Here we use computational models of thermodynamic stability in a ligand-binding protein to explore the structure of epistasis in simulations of protein sequence evolution. Even though the predicted effects on stability of random mutations are almost completely additive, the mutations that fix under purifying selection are enriched for epistasis. In particular, the mutations that fix are contingent on previous substitutions: Although nearly neutral at their time of fixation, these mutations would be deleterious in the absence of preceding substitutions. Conversely, substitutions under purifying selection are subsequently entrenched by epistasis with later substitutions: They become increasingly deleterious to revert over time. Our results imply that, even under purifying selection, protein sequence evolution is often contingent on history and so it cannot be predicted by the phenotypic effects of mutations assayed in the ancestral background.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.