ArticleNature communications2024
The highly rugged yet navigable regulatory landscape of the bacterial transcription factor TetR.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Graph-based representations in modern protein science.The Biochemical journal · 2026Review
- Emergence Biases in Molecular Evolution.Genome biology and evolution · 2026Review
- The adaptive landscapes of three globaleLife · 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
- Predicting the topography of fitness landscapes from the structure of genotype-phenotype maps.Genetics · 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
- Article
- Inference and visualization of complex genotype-phenotype maps withbioRxiv : the preprint server for biology · 2025Article
- annATAC: automatic cell type annotation for scATAC-seq data based on language model.BMC biology · 2025Article
- Engineering a Novel Probiotic Toolkit inACS synthetic biology · 2024Article
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Authors and funding
3 authors.
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Abstract
Transcription factor binding sites (TFBSs) are important sources of evolutionary innovations. Understanding how evolution navigates the sequence space of such sites can be achieved by mapping TFBS adaptive landscapes. In such a landscape, an individual location corresponds to a TFBS bound by a transcription factor. The elevation at that location corresponds to the strength of transcriptional regulation conveyed by the sequence. Here, we develop an in vivo massively parallel reporter assay to map the landscape of bacterial TFBSs. We apply this assay to the TetR repressor, for which few TFBSs are known. We quantify the strength of transcriptional repression for 17,765 TFBSs and show that the resulting landscape is highly rugged, with 2092 peaks. Only a few peaks convey stronger repression than the wild type. Non-additive (epistatic) interactions between mutations are frequent. Despite these hallmarks of ruggedness, most high peaks are evolutionarily accessible. They have large basins of attraction and are reached by around 20% of populations evolving on the landscape. Which high peak is reached during evolution is unpredictable and contingent on the mutational path taken. This in-depth analysis of a prokaryotic gene regulator reveals a landscape that is navigable but much more rugged than the landscapes of eukaryotic regulators.
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