AIBSTRACTThe a-hemoglobin chains in adult deer mice are usually encoded by two tightly linked loci. Because of strong linkage disequilibrium, almost all a-globin haplotypes fall into just two classes. The a0co class predominates in highaltitude populations, whereas the aYcl class is generally fixed in low-altitude populations. Here we show that the a-globin genotype has effects at both the biochemical level [on blood oxygen affinity (P50)] and at the level of whole-anmal physiol- The deer mouse Peromyscus maniculatus provides an opportunity to assess the effects of a specific selective force (high-altitude hypoxia) on discrete genetic elements (a-chain hemoglobin haplotypes). The species inhabits one of the broadest altitudinal ranges of any North American mammal, from sea level to above 4300 m. At 4300 m, the partial pressure of oxygen (Po2) is only 55% of the sea-level value, and that may severely limit aerobic metabolism. Deer mice also exhibit one of the most complex and extensive polymorphisms for hemoglobin of any mammal (13-15). In most individuals, the adult a-chains of hemoglobin are encoded by two tightly linked loci, Hba and Hbc (15). At both loci, the multiple structural alleles can be classified into two groups (a0 versus a' and co versus c') on the basis of similarity of isoelectric points. There is very strong linkage disequilibrium between the two loci, such that a-globin haplotypes are almost always composed of alleles of like superscript (ref.16; un-published data). "Recombinant" haplotypes (i.e., either a c or a'co) are quite rare; their average population frequency is estimated at 0.015. In populations in western North America, there is a highly significant negative correlation between o'c' haplotype frequency and the altitude of the collection site (ref. 17; unpublished data). That distribution provides circumstantial evidence for evolutionary adaptation of a-globin polymorphisms to altitude, but other interpretations not involving natural selection-e.g., stochastic biogeographical processes-cannot be ruled out. To resolve those two possibilities, independent criteria are needed to assess whether the haplotype classes are in fact differentially adapted to altitude.Here we examine the effects of the common a-globin genotypes on the oxygen affinity (P50) of whole blood and also on an important parameter of whole-animal physiology, maximum rate of oxygen consumption (Vo2max), during both cold exposure and exercise. MATERIALS AND METHODSGenetic Strains and Population Samples. Strains of deer mice were developed that carried distinct a-globin haplotypes in identical-by-descent (IBD) condition, arrayed against contrasting a-globin haplotypes chosen at random from their original wild population. To develop an IBD strain for an aYc1 haplotype, a single alc'l/a'c heterozygote was mated to several unrelated aoco/aoco mice from the source population. Progeny carrying the alcl haplotype (all copies of which are identical, barring mutation) were mated to unrelated aoc0/aoc0 mice. After one or more genera...
Wild populations of deer mice (Peromyscus maniculatus) contain hemoglobin polymorphisms at both alpha-globin (Hba, Hbc) and beta-globin (Hbd) loci. Population gene frequencies of beta-globin variants (d and d haplotypes) are not correlated with altitude, whereas a c alpha-globin haplotypes are fixed in low-altitude populations, and a c haplotypes reach near fixation at high altitudes. We examined the effects of alpha- and beta-globin variants on blood oxygen affinity and on aerobic performance, measured as maximum oxygen consumption (V˙O2max). Exercise and cold exposure were used to elicit V˙O2max. Experiments were performed at low (340 m) and high (3,800 m) altitude to include the range of oxygen partial pressures encountered by wild deer mice. Beta-globin variants had little effect on blood oxygen affinity or V˙O2max. Oxygen-dissociation curves from a c and a c homozygotes and heterozygotes had similar shapes, but the P of a c homozygotes was significantly lower than that of other genotypes. Mice carrying a c /a c genotypes had the highest V˙O2max at low altitude, but mice with a c /a c genotypes had the highest V˙O2max at high altitude. Mice carrying rare recombinant alpha-globin haplotypes (a c ) had lower V˙O2max than nonrecombinant genotypes as a whole but in most cases were not significantly different from nonrecombinant heterozygotes (a c /a c ). We conclude that genetic adaptation to different altitudes was important in the evolution of deer mouse alpha-globin polymorphisms and in the maintenance of linkage disequilibrium in the alpha-globin loci but was not a significant factor in the evolution of beta-globin polymorphisms.
In deer mouse (Peromyscus maniculatus) populations in the western United States, alpha-globin haplotype frequency, beta-globin haplotype frequency, and base-line blood oxygen affinity (measured after acclimation to low altitude) show strong correlations with native altitude. The correlations improve when an average regional altitude is substituted for the local altitude at collection sites. This substitution roughly compensates for the effects of gene exchange between populations in areas of highly variable topography. When subspecific effects are removed with covariate analyses a significant (P < 0.05) relationship remains only for alpha-globin haplotype frequency and altitude. Thus, alpha-globin haplotype frequency, beta-globin haplotype frequency, and base-line blood oxygen affinity may be explained by either subspecific or altitudinal effects, but subspecific effects explain a larger proportion of the variance. Part of the subspecific effect may be attributable to an underlying relationship of subspecies with altitude. The analyses for the alpha-globins in conjunction with other data on the effects of alpha-globins on blood oxygen affinity and whole-animal physiological performance are consistent with the hypothesis that the frequency of the alpha-globins evolved in response to selection resulting from the stress of high-altitude hypoxia.
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