Blood oxygen affinity in high- and low-altitude populations of the deer mouse

Snyder, Lee R. G.; Born, Stephen M.; Lechner, Andrew J.

doi:10.1016/0034-5687(82)90052-4

Cited by 65 publications

(73 citation statements)

References 25 publications

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“…The suppressed DPG-sensitivity of mice with the d 1 d 1 /d 1 d 1 genotype helps to maintain an elevated Hb-O 2 affinity (reduced P 50 ) in the presence of RBC cofactors, which enhances pulmonary O 2 -loading under hypoxia. It thus appears that allelic differences in DPG-sensitivity make a significant contribution to the welldocumented differences in blood-O 2 affinity between high-and low-altitude deer mice (10,11,14). Interestingly, the effect of Cl Ϫ on Hb-O 2 affinity is much greater than that of DPG in both highand low-altitude mice (Fig.…”

Section: Tests Of Spatially Varying Selection Between High-and Low-almentioning

confidence: 86%

“…In deer mice that are native to different elevational zones, the divergent fine-tuning of Hb-O 2 affinity appears to be attributable to the independent or joint effects of 5 amino acid mutations in the ␣-chain subunits and 4 amino acid mutations in the ␤-chain subunits. Although altitudinal variation in blood-O 2 affinity has been well documented in deer mice (10,11,14), the functional (and adaptive) significance of the HBB polymorphism was previously unappreciated. The discovery that allelic differences in DPG-sensitivity contribute to adaptive variation in Hb-O 2 affinity illustrates the value of integrating evolutionary analyses of sequence variation with mechanistic appraisals of protein function (25).…”

Section: Discussionmentioning

confidence: 99%

“…This rank order of phenotypic effects appears to be attributable to the fact that the possession of high-affinity Hb facilitates pulmonary O 2 loading under hypoxia, but hinders O 2 delivery to aerobically metabolizing tissues under normoxic conditions. These tradeoffs in O 2 -transport efficiency at different O 2 partial pressures (PO 2 's) suggest that the highaffinity ␣-globin genotype may confer highest fitness in highaltitude environments, whereas the low-affinity genotype may confer highest fitness in low-altitude environments (10)(11)(12)(13)(14). Consistent with this hypothesis, survivorship studies of freeranging deer mice demonstrated that aerobic performance is subject to strong directional selection at high-altitude (15) and electrophoretic surveys of ␣-globin polymorphism in deer mice from western North America revealed striking altitudinal patterns of allele frequency variation that are consistent with the predicted rank-order of genotypic fitnesses across environments: The high-affinity ␣-globin electromorph is present at high frequency in high-altitude populations (Ͼ2,750 m), whereas the low-affinity electromorph is either fixed or nearly fixed in low-altitude populations [Ͻ1,750 m; (16)].…”

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confidence: 99%

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Evolutionary and functional insights into the mechanism underlying high-altitude adaptation of deer mouse hemoglobin

Storz

Runck

Sabatino

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

191

217

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Adaptive modifications of heteromeric proteins may involve genetically based changes in single subunit polypeptides or parallel changes in multiple genes that encode distinct, interacting subunits. Here we investigate these possibilities by conducting a combined evolutionary and functional analysis of duplicated globin genes in natural populations of deer mice (Peromyscus maniculatus) that are adapted to different elevational zones. A multilocus analysis of nucleotide polymorphism and linkage disequilibrium revealed that high-altitude adaptation of deer mouse hemoglobin involves parallel functional differentiation at multiple unlinked gene duplicates: two ␣-globin paralogs on chromosome 8 and two ␤-globin paralogs on chromosome 1. Differences in O 2-binding affinity of the alternative ␤-chain hemoglobin isoforms were entirely attributable to allelic differences in sensitivity to 2,3-diphosphoglycerate (DPG), an allosteric cofactor that stabilizes the low-affinity, deoxygenated conformation of the hemoglobin tetramer. The two-locus ␤-globin haplotype that predominates at high altitude is associated with suppressed DPGsensitivity (and hence, increased hemoglobin-O 2 affinity), which enhances pulmonary O2 loading under hypoxia. The discovery that allelic differences in DPG-sensitivity contribute to adaptive variation in hemoglobin-O 2 affinity illustrates the value of integrating evolutionary analyses of sequence variation with mechanistic appraisals of protein function. Investigation into the functional significance of the deer mouse ␤-globin polymorphism was motivated by the results of population genetic analyses which revealed evidence for a history of divergent selection between elevational zones. The experimental measures of O 2-binding properties corroborated the tests of selection by demonstrating a functional difference between the products of alternative alleles.A daptive modifications of heteromeric proteins may involve genetically based changes in single subunit polypeptides or parallel changes in multiple genes that encode distinct, interacting subunits. The tetrameric hemoglobin (Hb) protein, which transports O 2 from the respiratory surfaces to metabolizing tissues, is an ideal molecule for addressing questions about the functional evolution of allosteric, multimeric proteins. In jawed vertebrates, Hb is a heterotetramer, consisting of two ␣-chain subunits and two ␤-chain subunits that form two semirigid ␣␤ dimers (␣ 1 ␤ 1 and ␣ 2 ␤ 2 ). A mutual rotation of the two ␣␤ dimers occurs during the oxygenation-linked transition in quaternary structure between the deoxy-and oxyHb conformations that is basic to cooperativity (1). Because modifications of Hb function are often implicated in adaptation to environmental hypoxia, and because much is known about structure-function relationships of vertebrate Hbs and their role in blood-O 2 transport (2, 3), the study of Hb function in vertebrate species that are native to hypoxic environments provides an opportunity to elucidate detailed molecular mechanisms of p...

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Section: Tests Of Spatially Varying Selection Between High-and Low-almentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Evolutionary and functional insights into the mechanism underlying high-altitude adaptation of deer mouse hemoglobin

Storz

Runck

Sabatino

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

191

217

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“…Similarly, the P 50 of bar-headed geese, which fly over the Himalayas during migration, is more than 10 mmHg lower than that of closely-related birds from moderate altitudes (Black & Tenney, 1980). The degree of the change in affinity seems to be related to the degree of hypoxia, as determined from the case of deer mice (Snyder et al, 1982;Snyder, 1985).…”

Section: What Type Of Shift Is Beneficial At Altitude?mentioning

confidence: 88%

The in-vivo oxyhaemoglobin dissociation curve at sea level and high altitude

Balaban

Duffin

Preiss

et al. 2013

Respiratory Physiology & Neurobiology

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Some animals have adapted to hypoxia by increasing their haemoglobin affinity for oxygen, but in vitro studies have not shown any change of haemoglobin affinity for oxygen in human high altitude natives or lowlanders acutely acclimatized to high altitude. We conducted the first in vivo study of the oxyhaemoglobin dissociation curve by progressively reducing arterial PO 2 while maintaining normocapnia in lowlanders at sea level, lowlanders sojourning at 3600m for two weeks and native Andeans at the same altitude. We found that the in vivo PO 2 at which haemoglobin is half-saturated (P 50 ) is higher in lowlanders at sea level (32 mmHg) than that measured in vitro (27 mmHg) and that lowlanders and highlanders do significantly increase the in vivo affinity of their haemoglobin for oxygen with exposure to high altitude. These results indicate the value of an in vivo approach for studying the oxyhaemoglobin dissociation curve.iii

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“…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.…”

Section: Introductionmentioning

confidence: 99%

Genomic insights into adaptation to high-altitude environments

2011

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Elucidating the molecular genetic basis of adaptive traits is a central goal of evolutionary genetics. The cold, hypoxic conditions of high-altitude habitats impose severe metabolic demands on endothermic vertebrates, and understanding how high-altitude endotherms cope with the combined effects of hypoxia and cold can provide important insights into the process of adaptive evolution. The physiological responses to high-altitude stress have been the subject of over a century of research, and recent advances in genomic technologies have opened up exciting opportunities to explore the molecular genetic basis of adaptive physiological traits. Here, we review recent literature on the use of genomic approaches to study adaptation to high-altitude hypoxia in terrestrial vertebrates, and explore opportunities provided by newly developed technologies to address unanswered questions in high-altitude adaptation at a genomic scale.

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Blood oxygen affinity in high- and low-altitude populations of the deer mouse

Cited by 65 publications

References 25 publications

Evolutionary and functional insights into the mechanism underlying high-altitude adaptation of deer mouse hemoglobin

Evolutionary and functional insights into the mechanism underlying high-altitude adaptation of deer mouse hemoglobin

The in-vivo oxyhaemoglobin dissociation curve at sea level and high altitude

Genomic insights into adaptation to high-altitude environments

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