High-altitude environments provide ideal testing grounds for investigations of mechanism and process in physiological adaptation. In vertebrates, much of our understanding of the acclimatization response to high-altitude hypoxia derives from studies of animal species that are native to lowland environments. Such studies can indicate whether phenotypic plasticity will generally facilitate or impede adaptation to high altitude. Here, we review general mechanisms of physiological acclimatization and genetic adaptation to high-altitude hypoxia in birds and mammals. We evaluate whether the acclimatization response to environmental hypoxia can be regarded generally as a mechanism of adaptive phenotypic plasticity, or whether it might sometimes represent a misdirected response that acts as a hindrance to genetic adaptation. In cases in which the acclimatization response to hypoxia is maladaptive, selection will favor an attenuation of the induced phenotypic change. This can result in a form of cryptic adaptive evolution in which phenotypic similarity between high- and low-altitude populations is attributable to directional selection on genetically based trait variation that offsets environmentally induced changes. The blunted erythropoietic and pulmonary vasoconstriction responses to hypoxia in Tibetan humans and numerous high-altitude birds and mammals provide possible examples of this phenomenon. When lowland animals colonize high-altitude environments, adaptive phenotypic plasticity can mitigate the costs of selection, thereby enhancing prospects for population establishment and persistence. By contrast, maladaptive plasticity has the opposite effect. Thus, insights into the acclimatization response of lowland animals to high-altitude hypoxia can provide a basis for predicting how altitudinal range limits might shift in response to climate change.

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Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates

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 α-globin paralogs on chromosome 8 and two β-globin paralogs on chromosome 1. Differences in O2-binding affinity of the alternative β-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 β-globin haplotype that predominates at high altitude is associated with suppressed DPG-sensitivity (and hence, increased hemoglobin-O2 affinity), which enhances pulmonary O2 loading under hypoxia. The discovery that allelic differences in DPG-sensitivity contribute to adaptive variation in hemoglobin–O2 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 β-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 O2-binding properties corroborated the tests of selection by demonstrating a functional difference between the products of alternative alleles.

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

SUMMARY In high-altitude vertebrates, adaptive changes in blood–O 2 affinity may be mediated by modifications of hemoglobin (Hb) structure that affect intrinsic O 2 affinity and/or responsiveness to allosteric effectors that modulate Hb–O 2 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–O 2 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. O 2 equilibrium experiments revealed that the Hbs of highland mice exhibit slightly higher intrinsic O 2 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 O 2 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–O 2 affinity.

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Genetic differences in hemoglobin function between highland and lowland deer mice

Understanding the biochemical mechanisms that enable high-altitude animals to survive and function under conditions of hypoxic stress can provide important insights into the nature of physiological adaptation. Evidence from a number of high-altitude vertebrates indicates that modifications of hemoglobin function typically play a key role in mediating an adaptive response to chronic hypoxia. Because much is known about structure‐ function relationships of mammalian hemoglobins and their physiological role in oxygen transport, the study of hemoglobin variation in high-altitude mammals holds much promise for understanding the nature of adaptation to hypoxia from the level of blood biochemistry to the level of whole-organism physiology. In this review I 1st discuss basic biochemical principles of hemoglobin function and the nature of physiological adaptation to highaltitude hypoxia in mammals. I then discuss a case study involving a complex hemoglobin polymorphism in North American deer mice (Peromyscus maniculatus) that illustrates how integrative studies of protein function and fitness-related physiological performance can be used to obtain evolutionary insights into genetic mechanisms of adaptation.

/pdf/hemoglobin-function-and-physiological-adaptation-to-hypoxia-2xa2o1g4cc.pdf

Hemoglobin function and physiological adaptation to hypoxia in high-altitude mammals

An important goal of population genetics is to elucidate the effects of natural selection on patterns of DNA sequence variation. Here we report results of a study to assess the joint effects of selection, recombination, and gene flow in shaping patterns of nucleotide variation at genes involved in local adaptation. We first describe a new summary statistic, Zg, that measures the between-sample component of linkage disequilibrium (LD). We then report results of a multilocus survey of nucleotide diversity and LD between high- and low-altitude populations of deer mice, Peromyscus maniculatus. The multilocus survey included two closely linked α-globin genes, HBA-T1 and HBA-T2, that underlie adaptation to different elevational zones. The primary goals were to assess whether the α-globin genes exhibit the hallmarks of spatially varying selection that are predicted by theory (i.e., sharply defined peaks in the between-population components of nucleotide diversity and LD) and to assess whether peaks in diversity and LD may be useful for identifying specific sites that distinguish selectively maintained alleles. Consistent with theoretical expectations, HBA-T1 and HBA-T2 were characterized by highly elevated levels of diversity between populations and between allele classes. Simulation and empirical results indicate that sliding-window analyses of Zg between allele classes may provide an effective means of pinpointing causal substitutions.

https://www.genetics.org/content/genetics/early/2008/08/20/genetics.108.088732.full.pdf

Effects of Spatially Varying Selection on Nucleotide Diversity and Linkage Disequilibrium: Insights From Deer Mouse Globin Genes

We have studied pulsed ruby laser and furnace annealing of high‐dose (D>1017 N/cm2) 50‐keV nitrogen‐implanted silicon Using Rutherford backscattering and channeling, transmission electron microscopy, and infrared transmission spectroscopy, we have compared liquid and solid phase regrowth, diffusion, impurity segregation, and nitride formation As has been previously reported, during furnace annealing at or above 1200 °C nitrogen redistributes and forms a polycrystalline silicon nitride (Si3N4) layer In contrast, pulsed laser melting produces a buried amorphous layer containing silicon and nitrogen with only very small amounts of polycrystalline silicon nitride below a layer of polycrystalline silicon

P. J. Stiles

Papers

Comparison of pulsed laser and furnace annealing of nitrogen‐implanted silicon