The purpose of the proposed research project is to elucidate the molecular basis of physiological adaptation to high-altitude hypoxia, a condition resulting from a reduced supply of oxygen to the cells of respiring tissues. Specifically, the proposed research will involve a structural and functional analysis of hemoglobin variation that is associated with adaptive variation in the blood biochemistry and aerobic metabolism of high-altitude deer mice (Peromyscus maniculatus). Insights into the molecular mechanisms that allow high-altitude animals to survive and function under conditions of chronic hypoxia can aid our understanding and management of disease processes in humans that compromise the oxygen transport system. By identifying the molecular underpinnings of hypoxia tolerance, it may be possible to replicate the mechanism with novel drug-based therapy, gene therapy, and hemoglobin-based blood substitutes. This highly interdisciplinary study will integrate the tools and theory of molecular population genetics, molecular evolution, structural biology, and protein biochemistry.
The specific aims of this research project are (1) To identify the specific amino acid mutations that are responsible for hemoglobin adaptation to hypoxia;(2) To assess whether modifications of hemoglobin structure are also associated with regulatory adjustments in the composition stoichiometry of different hemoglobin isoforms in circulating red blood cells;and (3) To assess the functional consequences of the observed structural and regulatory changes. After first conducting a population-level survey of DNA sequence variation to identify naturally occurring mutations in the globin genes of high-altitude deer mice, this study will involve a population-genetic analysis to infer which of the observed amino-acid changes may be attributable to positive Darwinian selection, an analysis of regulatory variation at the mRNA and protein levels, an 'in silico'computational analysis to predict effects on hemoglobin-oxygen affinity, and an 'in vitro'experimental analysis to assess how the identified structural and regulatory changes influence intrinsic oxygen affinity, as well as sensitivities to temperature, protons (Bohr effect), allosteric effectors, and metabolism of reactive oxygen species and nitric oxide. By identifying mechanisms of hemoglobin adaptation that have evolved in natural populations of high-altitude rodents, the proposed research project should provide novel insights into the molecular basis of hypoxia tolerance.

Public Health Relevance

The goal of the proposed research project is to identify the specific changes in hemoglobin function that have evolved in mice that are native to high-altitude environments. By identifying the specific molecular mechanisms that have enabled high-altitude animals to survive and function under low oxygen conditions, it may be possible to replicate the mechanism in therapeutic treatments of human diseases that compromise the oxygen transport system.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVS-A (50))
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Luksenburg, Harvey
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University of Nebraska Lincoln
Schools of Arts and Sciences
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Storz, Jay F (2016) Gene Duplication and Evolutionary Innovations in Hemoglobin-Oxygen Transport. Physiology (Bethesda) 31:223-32
Storz, Jay F (2016) Causes of molecular convergence and parallelism in protein evolution. Nat Rev Genet 17:239-50
Jensen, Birgitte; Storz, Jay F; Fago, Angela (2016) Bohr effect and temperature sensitivity of hemoglobins from highland and lowland deer mice. Comp Biochem Physiol A Mol Integr Physiol 195:10-4
Storz, Jay F (2016) Hemoglobin-oxygen affinity in high-altitude vertebrates: is there evidence for an adaptive trend? J Exp Biol 219:3190-3203
Galen, Spencer C; Natarajan, Chandrasekhar; Moriyama, Hideaki et al. (2015) Contribution of a mutational hot spot to hemoglobin adaptation in high-altitude Andean house wrens. Proc Natl Acad Sci U S A 112:13958-63
Storz, Jay F; Natarajan, Chandrasekhar; Moriyama, Hideaki et al. (2015) Oxygenation properties and isoform diversity of snake hemoglobins. Am J Physiol Regul Integr Comp Physiol 309:R1178-91
Natarajan, Chandrasekhar; Hoffmann, Federico G; Lanier, Hayley C et al. (2015) Intraspecific polymorphism, interspecific divergence, and the origins of function-altering mutations in deer mouse hemoglobin. Mol Biol Evol 32:978-97
Storz, Jay F; Bridgham, Jamie T; Kelly, Scott A et al. (2015) Genetic approaches in comparative and evolutionary physiology. Am J Physiol Regul Integr Comp Physiol 309:R197-214
Lui, Mikaela A; Mahalingam, Sajeni; Patel, Paras et al. (2015) High-altitude ancestry and hypoxia acclimation have distinct effects on exercise capacity and muscle phenotype in deer mice. Am J Physiol Regul Integr Comp Physiol 308:R779-91
Scott, Graham R; Elogio, Todd S; Lui, Mikaela A et al. (2015) Adaptive Modifications of Muscle Phenotype in High-Altitude Deer Mice Are Associated with Evolved Changes in Gene Regulation. Mol Biol Evol 32:1962-76

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