ArticleMolecular biology and evolution2015
Epistasis constrains mutational pathways of hemoglobin adaptation in high-altitude pikas.
Article in Molecular biology and evolution, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.
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Who cites it
70 citing papers in PubMed, 141 citations in OpenAlex.
- Epistatic drift in protein evolution.Current opinion in genetics & development · 2025Review
- Evidence of Intraspecific Adaptive Variation in the American Pika (Ochotona princeps) on a Continental Scale Using a Target Enrichment and Mitochondrial Genome Skimming Approach.Molecular ecology · 2025Article
- Global Environmental Factors Impact the Evolution of Adult Hemoglobins in Squamata Reptiles (Lizards and Snakes) and Terrestrial Turtles.Genome biology and evolution · 2025Article
- Integrating Intermediate Traits in Phylogenetic Genotype-to-Phenotype Studies.Integrative and comparative biology · 2025Review
- Considerations in the search for epistasis.Genome biology · 2024Review
- 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
- Physiological and Genetic Basis of High-Altitude Indigenous Animals' Adaptation to Hypoxic Environments.Animals : an open access journal from MDPI · 2024Review
- Sampling Strategies for Experimentally Mapping Molecular Fitness Landscapes Using High-Throughput Methods.Journal of molecular evolution · 2024Article
- Ancestral Reconstruction and the Evolution of Protein Energy Landscapes.Annual review of biophysics · 2024Review
- Article
- Convergent High OAnimals : an open access journal from MDPI · 2024Article
- The Mutational Road not Taken: Using Ancestral Sequence Resurrection to Evaluate the Evolution of Plant Enzyme Substrate Preferences.Genome biology and evolution · 2024Article
- Evolution and molecular basis of a novel allosteric property of crocodilian hemoglobin.Current biology : CB · 2023Article
- Article
- Intragenic compensation through the lens of deep mutational scanning.Biophysical reviews · 2022Review
- Genetic variation in haemoglobin is associated with evolved changes in breathing in high-altitude deer mice.The Journal of experimental biology · 2022Article
- Time Domains of Hypoxia Responses and -Omics Insights.Frontiers in physiology · 2022Review
- 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
- Rheostat functional outcomes occur when substitutions are introduced at nonconserved positions that diverge with speciation.Protein science : a publication of the Protein Society · 2021Article
- High-Altitude Adaptation: Mechanistic Insights from Integrated Genomics and Physiology.Molecular biology and evolution · 2021Review
10 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 3 institutions in 2 countries.
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Abstract
A fundamental question in evolutionary genetics concerns the roles of mutational pleiotropy and epistasis in shaping trajectories of protein evolution. This question can be addressed most directly by using site-directed mutagenesis to explore the mutational landscape of protein function in experimentally defined regions of sequence space. Here, we evaluate how pleiotropic trade-offs and epistatic interactions influence the accessibility of alternative mutational pathways during the adaptive evolution of hemoglobin (Hb) function in high-altitude pikas (Mammalia: Lagomorpha). By combining ancestral protein resurrection with a combinatorial protein-engineering approach, we examined the functional effects of sequential mutational steps in all possible pathways that produced an increased Hb-O2 affinity. These experiments revealed that the effects of mutations on Hb-O2 affinity are highly dependent on the temporal order in which they occur: Each of three β-chain substitutions produced a significant increase in Hb-O2 affinity on the ancestral genetic background, but two of these substitutions produced opposite effects when they occurred as later steps in the pathway. The experiments revealed pervasive epistasis for Hb-O2 affinity, but affinity-altering mutations produced no significant pleiotropic trade-offs. These results provide insights into the properties of adaptive substitutions in naturally evolved proteins and suggest that the accessibility of alternative mutational pathways may be more strongly constrained by sign epistasis for positively selected biochemical phenotypes than by antagonistic pleiotropy.
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