The adaptive benefit of evolved increases in hemoglobin-O2affinity is contingent on tissue O2diffusing capacity in high-altitude deer mice

Background 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 O 2 consumption, V◻O 2 max, during acute cold exposure) in high-altitude deer mice ( Peromyscus maniculatus ). We crossed highland and lowland deer mice to produce F 2 inter-population hybrids, which expressed genetically based variation in hemoglobin (Hb) O 2 affinity on a mixed genetic background. We then combined physiological experiments and mathematical modeling of the O 2 transport pathway to examine links between cardiorespiratory traits and V◻O 2 max. Results Physiological experiments revealed that increases in Hb-O 2 affinity of red blood cells improved blood oxygenation in hypoxia, but were not associated with an enhancement in V◻O 2 max. Sensitivity analyses performed using mathematical modeling showed that the influence of Hb-O 2 affinity on V◻O 2 max in hypoxia was contingent on the capacity for O 2 diffusion in active tissues. Conclusions These results suggest that increases in Hb-O 2 affinity would only have adaptive value in hypoxic conditions if concurrent with or preceded by increases in tissue O 2 diffusing capacity. In high-altitude deer mice, the adaptive benefit of increasing Hb-O 2 affinity is contingent on the capacity to extract O 2 from the blood, which helps resolve controversies about the general role of hemoglobin function in hypoxia tolerance.