ReviewProtein science : a publication of the Protein Society2016
Epistasis in protein evolution.
Review in Protein science : a publication of the Protein Society, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 329 papers.
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Who cites it
329 citing papers in PubMed, 614 citations in OpenAlex.
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- A deep mutational scanning-informed protein language model predicts SARS-CoV-2 evolution dynamics with spatiotemporal resolution.Nature microbiology · 2026Article
- Molecular evolution in light of regulatory-coding epistasis.EMBO reports · 2026Review
- How far can you go? Extrapolating values of catalytic activity from known protein landscapes in natural and directed evolution.Chemical Society reviews · 2026Review
- Deep mutational scanning of recent SARS-CoV-2 variants highlights changing amino acid preferences within epistatic hotspot residues.PLoS pathogens · 2026Article
- Epistasis among clustered lineage-specific amino acid substitutions in the Drosophila Trio protein.PLoS genetics · 2026Article
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- Mount Fuji's stubby peak: the genotypic density of additive landscapes near maximal fitness.bioRxiv : the preprint server for biology · 2026Article
- Rapid directed evolution guided by protein language models and epistatic interactions.Science (New York, N.Y.) · 2026Article
269 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The structure, function, and evolution of proteins depend on physical and genetic interactions among amino acids. Recent studies have used new strategies to explore the prevalence, biochemical mechanisms, and evolutionary implications of these interactions-called epistasis-within proteins. Here we describe an emerging picture of pervasive epistasis in which the physical and biological effects of mutations change over the course of evolution in a lineage-specific fashion. Epistasis can restrict the trajectories available to an evolving protein or open new paths to sequences and functions that would otherwise have been inaccessible. We describe two broad classes of epistatic interactions, which arise from different physical mechanisms and have different effects on evolutionary processes. Specific epistasis-in which one mutation influences the phenotypic effect of few other mutations-is caused by direct and indirect physical interactions between mutations, which nonadditively change the protein's physical properties, such as conformation, stability, or affinity for ligands. In contrast, nonspecific epistasis describes mutations that modify the effect of many others; these typically behave additively with respect to the physical properties of a protein but exhibit epistasis because of a nonlinear relationship between the physical properties and their biological effects, such as function or fitness. Both types of interaction are rampant, but specific epistasis has stronger effects on the rate and outcomes of evolution, because it imposes stricter constraints and modulates evolutionary potential more dramatically; it therefore makes evolution more contingent on low-probability historical events and leaves stronger marks on the sequences, structures, and functions of protein families.
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Registered trials
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.