ArticlePLoS genetics2019
An experimental assay of the interactions of amino acids from orthologous sequences shaping a complex fitness landscape.
Article in PLoS genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed, 138 citations in OpenAlex.
- Predicting Enzyme Turnover Numbers and Enabling Rational Enzyme Evolution.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Inference of fitness landscapes with heterogeneous patterns of epistasis across sites.bioRxiv : the preprint server for biology · 2026Article
- How far can you go? Extrapolating values of catalytic activity from known protein landscapes in natural and directed evolution.Chemical Society reviews · 2026Review
- A simple model captures key characteristics of biological non-deterministic genotype-phenotype maps.PLoS computational 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
- Sign Epistasis Can be Absent in Multi-peaked Landscapes With Neutral Mutations.Genome biology and evolution · 2026Article
- Enhancing kCommunications biology · 2026Article
- Experimental evolution in an era of molecular manipulation.Nature reviews. Genetics · 2026Review
- Distinguishing direct interactions from global epistasis using rank statistics.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- PRO-LDM: A Conditional Latent Diffusion Model for Protein Sequence Design and Functional Optimization.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Learning sequence-function relationships with scalable, interpretable Gaussian processes.bioRxiv : the preprint server for biology · 2025Article
- A Cyanobacterial Screening Platform for Rubisco Mutant Variants.ACS synthetic biology · 2025Article
- Pervasive Divergence in Protein Thermostability is Mediated by Both Structural Changes and Cellular Environments.Molecular biology and evolution · 2025Article
- Importance of higher-order epistasis in protein sequence-function relationships.bioRxiv : the preprint server for biology · 2025Article
- PRESCOTT: a population aware, epistatic, and structural model accurately predicts missense effects.Genome biology · 2025Article
- MMRT: MultiMut Recursive Tree for predicting functional effects of high-order protein variants from low-order variants.Computational and structural biotechnology journal · 2025Article
- Protein stability models fail to capture epistatic interactions of double point mutations.Protein science : a publication of the Protein Society · 2025Article
- MoCHI: neural networks to fit interpretable models and quantify energies, energetic couplings, epistasis, and allostery from deep mutational scanning data.Genome biology · 2024Article
- Specialization Restricts the Evolutionary Paths Available to Yeast Sugar Transporters.Molecular biology and evolution · 2024Article
- Article
1 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 5 institutions in 6 countries.
Funding
Abstract
Characterizing the fitness landscape, a representation of fitness for a large set of genotypes, is key to understanding how genetic information is interpreted to create functional organisms. Here we determined the evolutionarily-relevant segment of the fitness landscape of His3, a gene coding for an enzyme in the histidine synthesis pathway, focusing on combinations of amino acid states found at orthologous sites of extant species. Just 15% of amino acids found in yeast His3 orthologues were always neutral while the impact on fitness of the remaining 85% depended on the genetic background. Furthermore, at 67% of sites, amino acid replacements were under sign epistasis, having both strongly positive and negative effect in different genetic backgrounds. 46% of sites were under reciprocal sign epistasis. The fitness impact of amino acid replacements was influenced by only a few genetic backgrounds but involved interaction of multiple sites, shaping a rugged fitness landscape in which many of the shortest paths between highly fit genotypes are inaccessible.
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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.