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

Abstract

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, V̇O2max, 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 V̇O2max. Physiological experiments revealed that increases in Hb-O2 affinity of red blood cells improved blood oxygenation in hypoxia, but were not associated with an enhancements in V̇O2max. Sensitivity analyses performed using mathematical modeling showed that the influence of Hb-O2 affinity on V̇O2max 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.

Genetic variation in haemoglobin alters breathing in high-altitude deer mice

“…The effects of genetic variation in α-globin on arterial O 2 saturation were contingent upon acclimation environment, consistent with other recent findings (Wearing et al, 2020). Mice that were homozygous for highland α-globin (α HH ) maintained higher arterial O 2 saturation in hypoxia and had higher Hb-O 2 affinity than lowland homozygous mice (α LL ) when comparisons were made among normoxia-acclimated mice, but these differences were abolished after hypoxia acclimation.…”

“…Red blood cell O 2 affinity (P 50 , the PO 2 at which haemoglobin is 50% saturation with O 2 ) was calculated using Hemox Analytic Software (TCS Scientific). These measurements of blood Hb content, haematocrit, and P 50 have been previously published (Wearing et al, 2020) but are reported again here to provide insight into the measurements of acute hypoxia responses. In addition, the NO metabolites nitrite, S-nitrosothiols (SNO), and iron-nitrosyl and N-nitrosamine derivatives (FeNO + NNO) were measured by reductive chemiluminescence in plasma and red blood cells for a subset of hypoxia-acclimated mice following euthanasia, using a Sievers Nitric Oxide Analyzer (NOA model 280i, Boulder, CO, USA) and previously described protocols (Hansen and Jensen, 2010; Yang et al, 2003).…”

“…These F 2 hybrids (N=26) were raised to adulthood, a small volume of blood was obtained for genotyping (sampled from the facial vein and then stored at −80°C), and mice were then transported to McMaster for subsequent experiments (see below). These F 2 hybrid mice were also used for a distinct study on aerobic capacity (Wearing et al, 2020). The wild mice transported to McMaster were bred in captivity to produce first-generation (G 1 ) progeny within each population.…”

High-Altitude Adaptation: Mechanistic Insights from Integrated Genomics and Physiology

“…1988 ). To examine the physiological mechanisms by which increases in Hb-O 2 affinity affect whole-animal performance capacity in hypoxia, Wearing et al. (2020) created F 2 interpopulation hybrids between highland and lowland deer mice to randomize associations between allelic α- and β-globin variants on an admixed genetic background.…”

“…2017 , 2020 ). However, experimental results and mathematical modeling indicate that the increased arterial O 2 saturation only translates into an enhancement of hypoxic V O 2 max when accompanied by a corresponding increase in tissue O 2 diffusion capacity ( Wearing et al. 2020 ).…”