ArticleScience (New York, N.Y.)2022
Epistatic drift causes gradual decay of predictability in protein evolution.
Article in Science (New York, N.Y.), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Who cites it
64 citing papers in PubMed, 120 citations in OpenAlex.
- Evolutionary causes and consequences of gene duplication.Nature reviews. Genetics · 2026Review
- How far can you go? Extrapolating values of catalytic activity from known protein landscapes in natural and directed evolution.Chemical Society reviews · 2026Review
- Seven complete comparative maps of allosteric mutations in a protein family.Nature communications · 2026Article
- Article
- Influenza hemagglutinin subtypes have different sequence constraints despite sharing extremely similar structures.bioRxiv : the preprint server for biology · 2026Article
- Origins and breadth of pairwise epistasis in an α-helix of β-lactamase TEM-1.Nature communications · 2026Article
- Influenza hemagglutinin subtypes have different sequence constraints despite sharing extremely similar structures.Virus evolution · 2026Article
- Bacterial mutation dynamics emerging insights into virulence evolution and drug resistance. A review study.Frontiers in medicine · 2026Review
- Epistatic drift in protein evolution.Current opinion in genetics & development · 2025Review
- Systematic design and evaluation of artificial COSynthetic and systems biotechnology · 2025Article
- Changes in flexibility but not in compactness underlie the thermal adaptation of prokaryotic adenylate kinases.Evolution letters · 2025Article
- Favorable epistasis in ancestral diterpene synthases promoted convergent evolution of a resin acid precursor in conifers.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Article
- AlphaFold 3 accurately models natural variants ofMicrobiology spectrum · 2025Article
- The structure of an ancient genotype-phenotype map shaped the functional evolution of a protein family.Nature ecology & evolution · 2025Article
- Widespread epistasis shapes RNA polymerase II active site function and evolution.Nature communications · 2025Article
- Learning sequence-function relationships with scalable, interpretable Gaussian processes.bioRxiv : the preprint server for biology · 2025Article
- Article
- Dissecting the effects of single amino acid substitutions in SARS-CoV-2 Mpro.Protein science : a publication of the Protein Society · 2025Article
- The structure of an ancient genotype-phenotype map shaped the functional evolution of a protein family.bioRxiv : the preprint server for biology · 2025Article
4 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Epistatic interactions can make the outcomes of evolution unpredictable, but no comprehensive data are available on the extent and temporal dynamics of changes in the effects of mutations as protein sequences evolve. Here, we use phylogenetic deep mutational scanning to measure the functional effect of every possible amino acid mutation in a series of ancestral and extant steroid receptor DNA binding domains. Across 700 million years of evolution, epistatic interactions caused the effects of most mutations to become decorrelated from their initial effects and their windows of evolutionary accessibility to open and close transiently. Most effects changed gradually and without bias at rates that were largely constant across time, indicating a neutral process caused by many weak epistatic interactions. Our findings show that protein sequences drift inexorably into contingency and unpredictability, but that the process is statistically predictable, given sufficient phylogenetic and experimental data.
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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.