PT  - JOURNAL ARTICLE
AU  - Oliver H. Wearing
AU  - Catherine M. Ivy
AU  - Natalia Gutiérrez-Pinto
AU  - Jonathan P. Velotta
AU  - Shane C. Campbell-Staton
AU  - Chandrasekhar Natarajan
AU  - Zachary A. Cheviron
AU  - Jay F. Storz
AU  - Graham R. Scott
TI  - The adaptive benefit of increases in hemoglobin-O<sub>2</sub> affinity is contingent on tissue O<sub>2</sub> diffusing capacity in high-altitude deer mice
AID  - 10.1101/2020.10.29.357665
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.10.29.357665
4099  - http://biorxiv.org/content/early/2020/10/29/2020.10.29.357665.short
4100  - http://biorxiv.org/content/early/2020/10/29/2020.10.29.357665.full
AB  - Complex organismal traits are often the result of multiple interacting genes and sub-organismal phenotypes, but how these interactions shape the evolutionary trajectories of adaptive traits is poorly understood. We examined how functional interactions between cardiorespiratory traits contribute to adaptive increases in the capacity for aerobic thermogenesis (maximal O2 consumption, , during acute cold exposure) in high-altitude deer mice (Peromyscus maniculatus). We crossed highland and lowland deer mice to produce F2 inter-population hybrids, which expressed genetically based variation in hemoglobin (Hb) O2 affinity on a mixed genetic background. We then combined physiological experiments and mathematical modeling of the O2 transport pathway to examine links between cardiorespiratory traits and . Physiological experiments revealed that increases in Hb-O2 affinity of red blood cells improved blood oxygenation in hypoxia, but were not associated with enhancements in . Sensitivity analyses performed using mathematical modeling showed that the influence of Hb-O2 affinity on in hypoxia was contingent on the capacity for O2 diffusion in active tissues. These results suggest that increases in Hb-O2 affinity would only have adaptive value in hypoxic conditions if concurrent with or preceded by increases in tissue O2 diffusing capacity. In high-altitude deer mice, the adaptive benefit of increasing Hb-O2 affinity is contingent on the capacity to extract O2 from the blood, which helps resolve controversies about the general role of hemoglobin function in hypoxia tolerance.Significance Statement Complex organismal traits are often the result of multiple interacting genes and phenotypes, but the role of these interactions in shaping adaptive traits is poorly understood. We combined physiological experiments and modeling to examine how functional interactions between cardiorespiratory traits underlie high-altitude adaptation in deer mice. We show that adaptive increases in thermogenic capacity result from a functional interaction between blood hemoglobin and active tissues, in which the adaptive benefit of increasing hemoglobin O2 affinity is contingent on the capacity for O2 diffusion from the blood. This helps reconcile controversy about the general role of hemoglobin in hypoxia tolerance, and provides insight into physiological mechanisms of high-altitude adaptation.Competing Interest StatementThe authors have declared no competing interest.