ArticleeLife2024
Epistasis facilitates functional evolution in an ancient transcription factor.
Article in eLife, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- Evolutionary causes and consequences of gene duplication.Nature reviews. Genetics · 2026Review
- GaugeFixer: overcoming parameter non-identifiability in models of sequence-function relationships.bioRxiv : the preprint server for biology · 2026Article
- On learning functions over biological sequence space: relating Gaussian process priors, regularization, and gauge fixing.Journal of mathematical biology · 2026Article
- Predicting the topography of fitness landscapes from the structure of genotype-phenotype maps.Genetics · 2026Article
- Selective control of ligand binding through a distal mutation that alters the protein native ensemble.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Epistatic drift in protein evolution.Current opinion in genetics & development · 2025Review
- The structure of an ancient genotype-phenotype map shaped the functional evolution of a protein family.Nature ecology & evolution · 2025Article
- Importance of higher-order epistasis in protein sequence-function relationships.bioRxiv : the preprint server for biology · 2025Article
- The structure of an ancient genotype-phenotype map shaped the functional evolution of a protein family.bioRxiv : the preprint server for biology · 2025Article
- Stepwise neofunctionalization of the NF-κB family member Rel during vertebrate evolution.Nature immunology · 2025Article
- Epistatic hotspots organize antibody fitness landscape and boost evolvability.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Gauge fixing for sequence-function relationships.PLoS computational biology · 2025Article
- On the Analysis of Protein Genetic Architecture: Response to "Protein sequence landscapes are not so simple".bioRxiv : the preprint server for biology · 2024Article
- Specialization Restricts the Evolutionary Paths Available to Yeast Sugar Transporters.Molecular biology and evolution · 2024Article
- Article
- Higher-order epistasis within Pol II trigger loop haplotypes.bioRxiv : the preprint server for biology · 2024Article
- The simplicity of protein sequence-function relationships.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
- Specialization restricts the evolutionary paths available to yeast sugar transporters.bioRxiv : the preprint server for biology · 2024Article
- Gauge fixing for sequence-function relationships.bioRxiv : the preprint server for biology · 2024Article
Corrections and comments
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Authors and funding
4 authors.
Funding
Abstract
A protein's genetic architecture - the set of causal rules by which its sequence produces its functions - also determines its possible evolutionary trajectories. Prior research has proposed that the genetic architecture of proteins is very complex, with pervasive epistatic interactions that constrain evolution and make function difficult to predict from sequence. Most of this work has analyzed only the direct paths between two proteins of interest - excluding the vast majority of possible genotypes and evolutionary trajectories - and has considered only a single protein function, leaving unaddressed the genetic architecture of functional specificity and its impact on the evolution of new functions. Here, we develop a new method based on ordinal logistic regression to directly characterize the global genetic determinants of multiple protein functions from 20-state combinatorial deep mutational scanning (DMS) experiments. We use it to dissect the genetic architecture and evolution of a transcription factor's specificity for DNA, using data from a combinatorial DMS of an ancient steroid hormone receptor's capacity to activate transcription from two biologically relevant DNA elements. We show that the genetic architecture of DNA recognition consists of a dense set of main and pairwise effects that involve virtually every possible amino acid state in the protein-DNA interface, but higher-order epistasis plays only a tiny role. Pairwise interactions enlarge the set of functional sequences and are the primary determinants of specificity for different DNA elements. They also massively expand the number of opportunities for single-residue mutations to switch specificity from one DNA target to another. By bringing variants with different functions close together in sequence space, pairwise epistasis therefore facilitates rather than constrains the evolution of new functions.
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