Beall C, Cavalleri G, Deng L, Elston R, Gao Y, Knight J et al.. Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders. Proc Natl Acad Sci USA 107: 11459-11464

Department of Anthropology, Case Western Reserve University, Cleveland, OH 44106-7125, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2010; 107(25):11459-64. DOI: 10.1073/pnas.1002443107
Source: PubMed


By impairing both function and survival, the severe reduction in oxygen availability associated with high-altitude environments is likely to act as an agent of natural selection. We used genomic and candidate gene approaches to search for evidence of such genetic selection. First, a genome-wide allelic differentiation scan (GWADS) comparing indigenous highlanders of the Tibetan Plateau (3,200-3,500 m) with closely related lowland Han revealed a genome-wide significant divergence across eight SNPs located near EPAS1. This gene encodes the transcription factor HIF2alpha, which stimulates production of red blood cells and thus increases the concentration of hemoglobin in blood. Second, in a separate cohort of Tibetans residing at 4,200 m, we identified 31 EPAS1 SNPs in high linkage disequilibrium that correlated significantly with hemoglobin concentration. The sex-adjusted hemoglobin concentration was, on average, 0.8 g/dL lower in the major allele homozygotes compared with the heterozygotes. These findings were replicated in a third cohort of Tibetans residing at 4,300 m. The alleles associating with lower hemoglobin concentrations were correlated with the signal from the GWADS study and were observed at greatly elevated frequencies in the Tibetan cohorts compared with the Han. High hemoglobin concentrations are a cardinal feature of chronic mountain sickness offering one plausible mechanism for selection. Alternatively, as EPAS1 is pleiotropic in its effects, selection may have operated on some other aspect of the phenotype. Whichever of these explanations is correct, the evidence for genetic selection at the EPAS1 locus from the GWADS study is supported by the replicated studies associating function with the allelic variants.

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    • "Identifying the genes and signalling pathways involved in protecting native highlanders presents a novel means for addressing the mechanisms by which intrauterine hypoxia influences fetal growth. Several gene regions have been acted upon by natural selection in long-resident populations (Bigham et al. 2009, 2010; Beall et al. 2010; Simonson et al. 2010; Yi et al. 2010; Alkorta-Aranburu et al. 2012). In Andeans prominent among these are single nucleotide polymorphisms (SNPs) near adenosine monophosphate-activated protein kinase α1 (PRKAA1) (Bigham et al. 2009, 2010). "
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    ABSTRACT: Genes near PRKAA1 (adenosine monophosphate-activated protein kinase [AMPK] alpha-1) have been implicated in the greater uterine artery (UtA) blood flow and relative protection from fetal growth restriction seen in altitude-adapted, Andean populations. AMPK activation vasodilates multiple vessels but whether AMPK is present in UtA or placental tissue and influences UtA vasoreactivity during normal or hypoxic pregnancy remains unknown. We studied isolated UtA and placenta from near-term C57BL/6 J mice housed in normoxia (n = 8) or hypoxia (10% Fi O2 , n = 7-9) from day 14-19, and placentas from non-labouring sea level (n = 3) or 3100 m (n = 3) women. Hypoxia increased AMPK immunostaining in near-term murine UtA and placental tissue. RT-PCR products for AMPK alpha-1 and alpha-2 isoforms and LKB1 (the upstream kinase activating AMPK) were present in murine and human placenta, and hypoxia increased LKB1, AMPK alpha-1 and alpha-2 expression in the high- compared with low-altitude human placentas. Pharmacological AMPK activation by A769662 caused phenylephrine pre-constricted UtA from normoxic or hypoxic pregnant mice to dilate and this dilatation was partially reversed by the NOS inhibitor L-NAME. Hypoxic pregnancy sufficient to restrict fetal growth markedly augmented the UtA vasodilator effect of AMPK activation in opposition to PE constriction as the result of both NO-dependent and NO-independent mechanisms. We concluded that AMPK is activated during hypoxic pregnancy and that AMPK activation vasodilates the UtA, especially in hypoxic pregnancy. AMPK activation may be playing an adaptive role by limiting cellular energy depletion and helping to maintain utero-placental blood flow in hypoxic pregnancy. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jun 2015 · The Journal of Physiology
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    • "[Reprinted from (18) with permission: Natural selection on EPAS1 (HIF2␣) associated with low hemoglobin concentration in Tibetan highlanders. Beall CM, et al., Proc Natl Acad Sci USA 107: 11,459-11,464, 2010]. "
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    ABSTRACT: Whole-animal physiological performance is highly polygenic and highly plastic, and the same is generally true for the many subordinate traits that underlie performance capacities. Quantitative genetics therefore provides an appropriate framework for the analysis of physiological phenotypes and can be used to infer the microevolutionary processes that have shaped patterns of trait variation within and among species. When specific genes are known to contribute to variation in physiological traits, analyses of intraspecific polymorphism and interspecific divergence can reveal molecular mechanisms of functional evolution and can provide insights into the possible adaptive significance of observed sequence changes. Here we explain how the tools and theory of quantitative genetics, population genetics, and molecular evolution can inform our understanding of mechanism and process in physiological evolution. For example, lab-based studies of polygenic inheritance can be integrated with field-based studies of trait variation and survivorship to measure selection in the wild, thereby providing direct insights into the adaptive significance of physiological variation. Analyses of quantitative genetic variation in selection experiments can be used to probe interrelationships among traits and the genetic basis of physiological trade-offs and constraints. We review approaches for characterizing the genetic architecture of physiological traits, including linkage mapping and association mapping, and systems approaches for dissecting intermediary steps in the chain of causation between genotype and phenotype. We also discuss the promise and limitations of population genomic approaches for inferring adaptation at specific loci. We end by highlighting the role of organismal physiology in the functional synthesis of evolutionary biology. Copyright © 2015, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology.
    Full-text · Article · Jun 2015 · AJP Regulatory Integrative and Comparative Physiology
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    • "expression in kidneys in response to hypoxia (Kapitsinou et al., 2010). A mutation in this gene was previously associated with polycytosis (Percy et al., 2008) and, interestingly , several gene variants in this gene were found to be associated with lower hemoglobin levels amongst Tibetans adapted to living at high altitude (Beall et al., 2010). This suggests that Tibetans have evolved a blunted erythropoietic response to hypoxia. "
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    ABSTRACT: Given the high inter-individual variability in the sensitivity to high altitude, we hypothesize the presence of underlying genetic factors. The aim of this study was to construct a genetic predisposition score based on previously identified high-altitude gene variants to explain the inter-individual variation in the reduced maximal O 2 uptake (DVo 2max) in response to acute hypoxia. Ninety-six healthy young male Belgian lowlanders were included. In both normobaric normoxia (Fio 2 = 20.9%) and acute normobaric hypoxia (Fio 2 = 10.7%–12.5%) Vo 2max was measured. Forty-one SNPs in 21 genes were genotyped. A stepwise regression analysis was applied to detect a subset of SNPs to be associated with DVo 2max. This subset of SNPs was included in the genetic predisposition score. A general linear model and regression analysis with age, weight, height, hypoxic protocol group, and Vo 2max in normoxia as covariates were used to test the explained variance of the genetic predisposition score. A ROC analysis was performed to discriminate between the low-and high DVo 2max subgroups. A stepwise regression analysis revealed a subset of SNPs [rs833070 (VEGFA), rs4253778 (PPARA), rs6735530 (EPAS1), rs4341 (ACE), rs1042713 (ADRB2), and rs1042714 (ADRB2)] to be associated with DVo 2max. The genetic predisposition score was found to be an independent predictive variable with a partial explained variance of 23% (p < 0.0001). A ROC analysis showed significant discriminating accuracy (AUC = 0.78, 95% confidence interval = 0.64–0.91) between the low-and high DVo 2max subgroups. This six-SNP based genetic predisposition score showed a significantly predictive value for DVo 2max .
    Full-text · Article · Mar 2015 · High Altitude Medicine & Biology
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