Genetic differences in hemoglobin function between highland and lowland deer mice

Abstract

SUMMARY In high-altitude vertebrates, adaptive changes in blood–O2 affinity may be mediated by modifications of hemoglobin (Hb) structure that affect intrinsic O2 affinity and/or responsiveness to allosteric effectors that modulate Hb–O2 affinity. This mode of genotypic specialization is considered typical of mammalian species that are high-altitude natives. Here we investigated genetically based differences in Hb–O2 affinity between highland and lowland populations of the deer mouse (Peromyscus maniculatus), a generalist species that has the broadest altitudinal distribution of any North American mammal. The results of a combined genetic and proteomic analysis revealed that deer mice harbor a high level of Hb isoform diversity that is attributable to allelic polymorphism at two tandemly duplicated α-globin genes and two tandemly duplicated β-globin genes. This high level of isoHb diversity translates into a correspondingly high level of interindividual variation in Hb functional properties. O2 equilibrium experiments revealed that the Hbs of highland mice exhibit slightly higher intrinsic O2 affinities and significantly lower Cl– sensitivities relative to the Hbs of lowland mice. The experiments also revealed distinct biochemical properties of deer mouse Hb related to the anion-dependent allosteric regulation of O2 affinity. In conjunction with previous findings, our results demonstrate that modifications of Hb structure that alter allosteric anion sensitivity play an important role in the adaptive fine-tuning of blood–O2 affinity.

Regulatory changes contribute to the adaptive enhancement of thermogenic capacity in high-altitude deer mice

“…Under conditions of chronic O 2 deprivation at high altitude, a similar enhancement in fatty-acid oxidation capacity could promote thermogenic endurance, but would require additional physiological changes to ensure adequate O 2 flux through oxidative pathways. The elevated blood-O 2 affinity of highland deer mice helps to preserve an adequate level of tissue-O 2 delivery despite hypoxia (20,(27)(28)(29)(30)61) and may help to power an enhanced capacity for lipid oxidation. Thus, adaptation to hypoxic cold stress in deer mice seems to involve changes in both the functional properties and expression levels of proteins that interact in hierarchical pathways, a situation that is likely to be common in the evolution of complex physiological traits (62).…”

“…Because of this broad altitudinal distribution, deer mice have long been used as a model to study physiological mechanisms of acclimatization and adaptation to high-altitude hypoxia (3)(4)(5)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). The wellestablished connections between thermogenic capacity and fitness (3) make P. maniculatus an especially ideal study animal for investigating the mechanistic underpinnings of metabolic adaptation to high-altitude environments.…”

Genomic insights into adaptation to high-altitude environments

“…In P. maniculatus, two tandemly duplicated genes encode the a-chain (HBA-T1 and HBA-T2) and b-chain (HBB-T1 and HBB-T2) subunits of the tetrameric adult Hb (Snyder, 1978;Storz et al, 2007Storz et al, , 2009Storz et al, , 2010a. Altitudinal patterns of nucleotide diversity and linkage disequilibrium are indicative of local adaptation of a-and b-globin genes to different altitudinal zones, and Hb genotypes differ in oxygen affinity and aerobic performance (measured by VO 2 max) (Chappell and Snyder, 1984;Chappell et al, 1988;Snyder et al, 1988;Storz et al, 2007Storz et al, , 2010aStorz et al, , 2009Storz and Kelly, 2008). The rank order of performance depends on the altitude at which the genotypes are tested, and is also consistent with local adaptation, with high-altitude a-globin genotypes outperforming low-altitude genotypes at 3800 m and vice versa at 340 m (Chappell and Snyder, 1984;Chappell et al, 1988).…”

“…Much of what is known about the genetic basis of high-altitude adaptation in natural populations comes from studies that have taken a 'candidate gene' approach, and many of these studies have focused on sequence variation in hemoglobin genes. Several of these have become well-known case studies of the genetics of adaptation (Snyder, 1978(Snyder, , 1985Snyder et al, 1982Snyder et al, , 1988Chappell and Snyder, 1984;Jessen et al, 1991;Weber et al, 2002;Storz et al, 2007Storz et al, , 2009Storz et al, , 2010a, but many other physiological traits may be as important as blood oxygen affinity in determining lifetime reproductive success in high-altitude environments. These physiological parameters are often complex traits with a polygenic basis.…”

Relaxed functional constraints on triplicate α-globin gene in the bank vole suggest a different evolutionary history from other rodents

“…Intriguingly, a recent study of Storz et al (2010) assessing the transcriptional activity of the Peromyscus HBA genes by using reverse transcription-PCR (RT-PCR) did not detect transcripts matching the HBA-T3 gene in the definitive erythrocytes of adult deer mice, suggesting the gene might be transcriptionally inactive although it has a complete open reading frame .…”