ArticlePLoS computational biology2017
High-order epistasis shapes evolutionary trajectories.
Article in PLoS computational biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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66 citing papers in PubMed, 146 citations in OpenAlex.
- How far can you go? Extrapolating values of catalytic activity from known protein landscapes in natural and directed evolution.Chemical Society reviews · 2026Review
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- Epistasis and background dependence in the evolution of Omicron variants of the SARS-CoV-2 spike protein.Molecular biology and evolution · 2026Article
- Gene duplication is associated with gene diversification and potential neofunctionalization in lung cancer evolution.Genome research · 2026Article
- Pleiotropic mutational effects on function and stability constrain the antigenic evolution of influenza haemagglutinin.Nature ecology & evolution · 2026Article
- Functional bottlenecks can emerge from non-epistatic underlying traits.PLoS computational biology · 2026Article
- Inference and Visualization of Complex Genotype-Phenotype Maps.Molecular biology and evolution · 2026Article
- Factors controlling protein evolvability-at the molecular scale.European biophysics journal : EBJ · 2026Article
- Epistatic drift in protein evolution.Current opinion in genetics & development · 2025Review
- Epistasis and background dependence in the evolution of Omicron variants of the SARS-CoV-2 Spike protein.bioRxiv : the preprint server for biology · 2025Article
- Graph attention with structural features improves the generalizability of identifying functional sequences at a protein interface.bioRxiv : the preprint server for biology · 2025Article
- Pleiotropic mutational effects on function and stability constrain the antigenic evolution of influenza hemagglutinin.bioRxiv : the preprint server for biology · 2025Article
- Distinguishing direct interactions from global epistasis using rank statistics.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
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- Inference and visualization of complex genotype-phenotype maps withbioRxiv : the preprint server for biology · 2025Article
- Learning sequence-function relationships with scalable, interpretable Gaussian processes.bioRxiv : the preprint server for biology · 2025Article
- Article
- Protein stability models fail to capture epistatic interactions of double point mutations.Protein science : a publication of the Protein Society · 2025Article
- Evolutionary insights into the stereoselectivity of imine reductases based on ancestral sequence reconstruction.Nature communications · 2024Article
- The origin of mutational epistasis.European biophysics journal : EBJ · 2024Article
6 more citing papers are in PubMed but not listed here.
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2 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
High-order epistasis-where the effect of a mutation is determined by interactions with two or more other mutations-makes small, but detectable, contributions to genotype-fitness maps. While epistasis between pairs of mutations is known to be an important determinant of evolutionary trajectories, the evolutionary consequences of high-order epistasis remain poorly understood. To determine the effect of high-order epistasis on evolutionary trajectories, we computationally removed high-order epistasis from experimental genotype-fitness maps containing all binary combinations of five mutations. We then compared trajectories through maps both with and without high-order epistasis. We found that high-order epistasis strongly shapes the accessibility and probability of evolutionary trajectories. A closer analysis revealed that the magnitude of epistasis, not its order, predicts is effects on evolutionary trajectories. We further find that high-order epistasis makes it impossible to predict evolutionary trajectories from the individual and paired effects of mutations. We therefore conclude that high-order epistasis profoundly shapes evolutionary trajectories through genotype-fitness maps.
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