ArticleMolecular biology and evolution2017
Stability-Mediated Epistasis Restricts Accessible Mutational Pathways in the Functional Evolution of Avian Hemoglobin.
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 28 papers.
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Who cites it
28 citing papers in PubMed, 61 citations in OpenAlex.
- Evolutionary rewiring of the dynamic network underpinning allosteric epistasis in NS1 of the influenza A virus.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Ancestral Reconstruction and the Evolution of Protein Energy Landscapes.Annual review of biophysics · 2024Review
- Article
- Evolution and molecular basis of a novel allosteric property of crocodilian hemoglobin.Current biology : CB · 2023Article
- Intragenic compensation through the lens of deep mutational scanning.Biophysical reviews · 2022Review
- Energy landscape reshaped by strain-specific mutations underlies epistasis in NS1 evolution of influenza A virus.Nature communications · 2022Article
- Article
- Comparison of hematological traits and oxygenation properties of hemoglobins from highland and lowland Asiatic toad (Bufo gargarizans).Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology · 2021Review
- Article
- High-Altitude Adaptation: Mechanistic Insights from Integrated Genomics and Physiology.Molecular biology and evolution · 2021Review
- Evolved increases in hemoglobin-oxygen affinity and the Bohr effect coincided with the aquatic specialization of penguins.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Introgressive Hybridization and Hypoxia Adaptation in High-Altitude Vertebrates.Frontiers in genetics · 2021Review
- Physiological and genetic convergence supports hypoxia resistance in high-altitude songbirds.PLoS genetics · 2020Article
- Lateral Gene Transfer Acts As an Evolutionary Shortcut to Efficient C4 Biochemistry.Molecular biology and evolution · 2020Article
- Effect of NH2-terminal acetylation on the oxygenation properties of vertebrate haemoglobin.The Biochemical journal · 2020Article
- Synthesis of Recombinant Human Hemoglobin With NHCurrent protocols in protein science · 2020Article
- Genotype networks of 80 quantitative Arabidopsis thaliana phenotypes reveal phenotypic evolvability despite pervasive epistasis.PLoS computational biology · 2020Article
- Limits to Compensatory Mutations: Insights from Temperature-Sensitive Alleles.Molecular biology and evolution · 2019Article
- Adaptive substitutions underlying cardiac glycoside insensitivity in insects exhibit epistasis in vivo.eLife · 2019Article
- The role of mutation bias in adaptive molecular evolution: insights from convergent changes in protein function.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2019Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
If the fitness effects of amino acid mutations are conditional on genetic background, then mutations can have different effects depending on the sequential order in which they occur during evolutionary transitions in protein function. A key question concerns the fraction of possible mutational pathways connecting alternative functional states that involve transient reductions in fitness. Here we examine the functional effects of multiple amino acid substitutions that contributed to an evolutionary transition in the oxygenation properties of avian hemoglobin (Hb). The set of causative changes included mutations at intradimer interfaces of the Hb tetramer. Replacements at such sites may be especially likely to have epistatic effects on Hb function since residues at intersubunit interfaces are enmeshed in networks of salt bridges and hydrogen bonds between like and unlike subunits; mutational reconfigurations of these atomic contacts can affect allosteric transitions in quaternary structure and the propensity for tetramer-dimer dissociation. We used ancestral protein resurrection in conjunction with a combinatorial protein engineering approach to synthesize genotypes representing the complete set of mutational intermediates in all possible forward pathways that connect functionally distinct ancestral and descendent genotypes. The experiments revealed that 1/2 of all possible forward pathways included mutational intermediates with aberrant functional properties because particular combinations of mutations promoted tetramer-dimer dissociation. The subset of mutational pathways with unstable intermediates may be selectively inaccessible, representing evolutionary roads not taken. The experimental results also demonstrate how epistasis for particular functional properties of proteins may be mediated indirectly by mutational effects on quaternary structural stability.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.