ArticleCell systems2024
Rugged fitness landscapes minimize promiscuity in the evolution of transcriptional repressors.
Article in Cell systems, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Graph-based representations in modern protein science.The Biochemical journal · 2026Review
- How far can you go? Extrapolating values of catalytic activity from known protein landscapes in natural and directed evolution.Chemical Society reviews · 2026Review
- MicroRNA target gene prediction model based on input-feature dependency and sample data expansion technique.PLoS computational biology · 2026Article
- D-LIM: A neural network for interpretable gene-gene interactions.PLoS computational biology · 2026Article
- Low-N Protein Activity Optimization with FolDE.ArXiv · 2025Article
- Investigating the determinants of performance in machine learning for protein fitness prediction.Protein science : a publication of the Protein Society · 2025Article
- Ancestral reconstruction of polyethylene terephthalate degrading cutinases reveals a rugged and unexplored sequence-fitness landscape.Science advances · 2025Article
- Specialization Restricts the Evolutionary Paths Available to Yeast Sugar Transporters.Molecular biology and evolution · 2024Article
- Specialization restricts the evolutionary paths available to yeast sugar transporters.bioRxiv : the preprint server for biology · 2024Article
Corrections and comments
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Authors and funding
7 authors.
Funding
Abstract
How a protein's function influences the shape of its fitness landscape, smooth or rugged, is a fundamental question in evolutionary biochemistry. Smooth landscapes arise when incremental mutational steps lead to a progressive change in function, as commonly seen in enzymes and binding proteins. On the other hand, rugged landscapes are poorly understood because of the inherent unpredictability of how sequence changes affect function. Here, we experimentally characterize the entire sequence phylogeny, comprising 1,158 extant and ancestral sequences, of the DNA-binding domain (DBD) of the LacI/GalR transcriptional repressor family. Our analysis revealed an extremely rugged landscape with rapid switching of specificity, even between adjacent nodes. Further, the ruggedness arises due to the necessity of the repressor to simultaneously evolve specificity for asymmetric operators and disfavors potentially adverse regulatory crosstalk. Our study provides fundamental insight into evolutionary, molecular, and biophysical rules of genetic regulation through the lens of fitness landscapes.
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Registered trials
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