ArticleNature2017
Alternative evolutionary histories in the sequence space of an ancient protein.
Article in Nature, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 120 papers.
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Who cites it
120 citing papers in PubMed.
- Retracing the origin and evolution of a cryptic antimicrobial peptide within mammalian lactoferrin.PLoS biology · 2026Article
- Evolutionary causes and consequences of gene duplication.Nature reviews. Genetics · 2026Review
- 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
- CountESS: a flexible, graphical pipeline tool for deep mutational scanning analysis.bioRxiv : the preprint server for biology · 2026Article
- Retracing and rewriting the evolutionary trajectories of mammalian developmental enhancers.bioRxiv : the preprint server for biology · 2026Article
- Deep homology and design of proteasome chaperone proteins in Candidozyma auris.Nature communications · 2026Article
- Structural and evolutionary constraints of organophosphate resistance in dipteran carboxylesterases.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Functional bottlenecks can emerge from non-epistatic underlying traits.PLoS computational biology · 2026Article
- Free energy perturbations in enzyme kinetic models reveal cryptic epistasis.PLoS computational biology · 2026Article
- Deep models of protein evolution in time generate realistic evolutionary trajectories and functional proteins.bioRxiv : the preprint server for biology · 2026Article
- Inference and Visualization of Complex Genotype-Phenotype Maps.Molecular biology and evolution · 2026Article
- TF paralogs-Natural experiments in DNA binding.Current opinion in structural biology · 2025Review
- Epistatic drift in protein evolution.Current opinion in genetics & development · 2025Review
- BTK autoinhibition analyzed by high-throughput swaps of SH2 domains.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Variant scoring tools for deep mutational scanning.Molecular systems biology · 2025Review
- 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
- The structure of an ancient genotype-phenotype map shaped the functional evolution of a protein family.Nature ecology & evolution · 2025Article
- Inference and visualization of complex genotype-phenotype maps withbioRxiv : the preprint server for biology · 2025Article
- Learning sequence-function relationships with scalable, interpretable Gaussian processes.bioRxiv : the preprint server for biology · 2025Article
60 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors.
Funding
Abstract
To understand why molecular evolution turned out as it did, we must characterize not only the path that evolution followed across the space of possible molecular sequences but also the many alternative trajectories that could have been taken but were not. A large-scale comparison of real and possible histories would establish whether the outcome of evolution represents an optimal state driven by natural selection or the contingent product of historical chance events; it would also reveal how the underlying distribution of functions across sequence space shaped historical evolution. Here we combine ancestral protein reconstruction with deep mutational scanning to characterize alternative histories in the sequence space around an ancient transcription factor, which evolved a novel biological function through well-characterized mechanisms. We find hundreds of alternative protein sequences that use diverse biochemical mechanisms to perform the derived function at least as well as the historical outcome. These alternatives all require prior permissive substitutions that do not enhance the derived function, but not all require the same permissive changes that occurred during history. We find that if evolution had begun from a different starting point within the network of sequences encoding the ancestral function, outcomes with different genetic and biochemical forms would probably have resulted; this contingency arises from the distribution of functional variants in sequence space and epistasis between residues. Our results illuminate the topology of the vast space of possibilities from which history sampled one path, highlighting how the outcome of evolution depends on a serial chain of compounding chance events.
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