ArticleMolecular biology and evolution2017
Robustness of Reconstructed Ancestral Protein Functions to Statistical Uncertainty.
Article in Molecular biology and evolution, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers.
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69 citing papers in PubMed.
- Structural and functional characterisation of a reconstructed ancestral strigolactone receptor.The Plant journal : for cell and molecular biology · 2026Article
- Phylogenetic investigation of the 100 kDa hexokinase enzyme family with the topiary ancestral sequence reconstruction pipeline.Protein science : a publication of the Protein Society · 2026Article
- Functional conservation with mechanistic drift: AMP activation in the evolution of archaeal sugar kinases.Molecular biology and evolution · 2026Article
- From transporter to motor: Evolutionary and structural insights into the emergence of prestin's area-motor activity in mammals.Protein science : a publication of the Protein Society · 2026Article
- Comparative phenotypic analysis of rhodopsin supports stepwise evolution of dim-light vision in early vertebrates.Molecular biology and evolution · 2026Article
- AI-Enhanced Adaptive Virtual Screening Platform Enabling Exploration of 69 Billion Molecules Discovers Structurally Validated FSP1 Inhibitors.bioRxiv : the preprint server for biology · 2026Article
- Studying the evolutionary potential of ancestral aryl sulfatases in the alkaline phosphatase family with droplet microfluidics.The Analyst · 2026Article
- Evolutionary analysis reveals the origin of sodium coupling in glutamate transporters.Nature structural & molecular biology · 2025Article
- 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
- Stochastic Character Mapping: An Under-Exploited Approach to the Study of Molecular Evolution.Journal of molecular evolution · 2025Article
- Multiple transitions to high l-DOPA 4,5-dioxygenase activity reveal molecular pathways to convergent betalain pigmentation in Caryophyllales.The New phytologist · 2025Article
- Ancestral reconstruction of polyethylene terephthalate degrading cutinases reveals a rugged and unexplored sequence-fitness landscape.Science advances · 2025Article
- Reconstruction of Ancestral Protein Sequences Using Autoregressive Generative Models.Molecular biology and evolution · 2025Article
- Robustness of Ancestral Sequence Reconstruction to Among-site and Among-lineage Evolutionary Heterogeneity.Molecular biology and evolution · 2025Article
- Genomic and phenotypic evidence support visual and olfactory shifts in primate evolution.Nature ecology & evolution · 2025Article
- Evolutionary insights into the stereoselectivity of imine reductases based on ancestral sequence reconstruction.Nature communications · 2024Article
- Applications of ancestral sequence reconstruction for understanding the evolution of plant specialized metabolism.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2024Review
- Stable monomers in the ancestral sequence reconstruction of the last opisthokont common ancestor of dimeric triosephosphate isomerase.Protein science : a publication of the Protein Society · 2024Article
- Rugged fitness landscapes minimize promiscuity in the evolution of transcriptional repressors.Cell systems · 2024Article
- Extant Sequence Reconstruction: The Accuracy of Ancestral Sequence Reconstructions Evaluated by Extant Sequence Cross-Validation.Journal of molecular evolution · 2024Article
9 more citing papers are in PubMed but not listed here.
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5 authors.
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Abstract
Hypotheses about the functions of ancient proteins and the effects of historical mutations on them are often tested using ancestral protein reconstruction (APR)-phylogenetic inference of ancestral sequences followed by synthesis and experimental characterization. Usually, some sequence sites are ambiguously reconstructed, with two or more statistically plausible states. The extent to which the inferred functions and mutational effects are robust to uncertainty about the ancestral sequence has not been studied systematically. To address this issue, we reconstructed ancestral proteins in three domain families that have different functions, architectures, and degrees of uncertainty; we then experimentally characterized the functional robustness of these proteins when uncertainty was incorporated using several approaches, including sampling amino acid states from the posterior distribution at each site and incorporating the alternative amino acid state at every ambiguous site in the sequence into a single "worst plausible case" protein. In every case, qualitative conclusions about the ancestral proteins' functions and the effects of key historical mutations were robust to sequence uncertainty, with similar functions observed even when scores of alternate amino acids were incorporated. There was some variation in quantitative descriptors of function among plausible sequences, suggesting that experimentally characterizing robustness is particularly important when quantitative estimates of ancient biochemical parameters are desired. The worst plausible case method appears to provide an efficient strategy for characterizing the functional robustness of ancestral proteins to large amounts of sequence uncertainty. Sampling from the posterior distribution sometimes produced artifactually nonfunctional proteins for sequences reconstructed with substantial ambiguity.
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