SRA

Haemoglobin (Hb)-O2 affinity has been a pervasive target of selection in many high-altitude taxa and is often presumed to safe-guard arterial O2 saturation in hypoxia, but the effect of genetic variation in globins on other aspects of respiratory physiology is poorly understood. We investigated the influence of the high-altitude variants in alpha- and beta-globins of North American deer mice (Peromyscus maniculatus) on control of breathing. We created a hybrid population of deer mice using a F2 intercross breeding design, which disrupts the linkages between loci that result from population genetic structure, so the effects of globin genotype on breathing, metabolism, and arterial O2 saturation during hypoxia could be compared on an admixed genetic background. Alpha-globin genotype had a significant influence on breathing pattern, with highland homozygotes breathing deeper but less frequently across a range of inspired O2. The ventilatory response to hypoxia was augmented in mice that were homozygous for highland beta-globin. These differences in breathing did not appear to be caused by genetically based differences in blood-O2 affinity, because treatment with efaproxiral to reduce Hb-O2 affinity had no effect on breathing in normoxia or hypoxia. Globins were not expressed in the brainstem, and globin genotype had little effect on gene expression in the medulla (assessed using RNA-Seq), so differences in control of breathing were not caused by non-erythroid expression of globins in these key sites of ventilatory control. Our findings suggest that the evolution of globin genes may have pervasive effects on multiple respiratory phenotypes, and may contribute to environmental adaptation via physiological mechanisms that are not commonly ascribed to this protein.