Oxygen transport in Tibetan women during pregnancy at 3,658 m

Moore, Lorna G.; Zamudio, Stacy; Zhuang, Jianguo; Sun, Shinfu; Droma, Tarshi

doi:10.1002/1096-8644(200101)114:1<42::aid-ajpa1004>3.0.co;2-b

Cited by 116 publications

(72 citation statements)

References 31 publications

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“…If this pattern were to continue over time, then the frequency of the allele for high oxygen saturation would increase. These data do not distinguish whether the higher infant survival of the high oxygen saturation genotype mothers results from characteristics of the newborn, such as birth weight, that are substantially influenced by maternal characteristics (10) or the infant's ability to withstand postnatal stress that might be more influenced by his or her own genotype.…”

Section: Discussionmentioning

confidence: 89%

Higher offspring survival among Tibetan women with high oxygen saturation genotypes residing at 4,000 m

Beall

Song

Elston

et al. 2004

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

105

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Here we test the hypothesis that high-altitude native resident Tibetan women with genotypes for high oxygen saturation of hemoglobin, and thus less physiological hypoxic stress, have higher Darwinian fitness than women with low oxygen saturation genotypes. Oxygen saturation and genealogical data were collected from residents of 905 households in 14 villages at altitudes of 3,800 -4,200 m in the Tibet Autonomous Region along with fertility histories from 1,749 women. Segregation analysis confirmed a major gene locus with an autosomal dominant mode of inheritance for high oxygen saturation levels, associated with a 10% higher mean. Oxygen saturation genotypic probability estimators were then used to calculate the effect of the inferred oxygen saturation locus on measures of fertility, in a subsample of 691 women (20 -59 years of age and still married to their first husbands, those with the highest exposure to the risk of pregnancy). The genotypic probability estimators were not significantly associated with the number of pregnancies or live births. The high oxygen saturation genotypic mean offspring mortality was significantly lower, at 0.48 deaths compared with 2.53 for the low oxygen saturation homozygote, because of lower infant mortality. Tibetan women with a high likelihood of possessing one to two alleles for high oxygen saturation had more surviving children. These findings suggest that high-altitude hypoxia is acting as an agent of natural selection on the locus for oxygen saturation of hemoglobin by the mechanism of higher infant survival of Tibetan women with high oxygen saturation genotypes.H igh-altitude native populations are exposed to lifelong ambient hypoxia that stresses the oxygen delivery system and elicits adaptations. The genetic bases and thus the evolutionary interpretation of the adaptive traits of high-altitude populations are generally unknown, with the exception of oxygen saturation of hemoglobin among high-altitude native Tibetans. Tibetans at a given high altitude vary widely in percent oxygen saturation of hemoglobin despite uniform ambient hypoxic stress. A putative major gene (an inferred locus) with a recognizable quantitative effect having an autosomal dominant mode of inheritance that is associated with Ϸ6% higher oxygen saturation has been detected in two areas of the Tibet Autonomous Region (1, 2). The high oxygen saturation genotypes may have greater Darwinian fitness because they are less physiologically stressed, in the sense of having higher arterial oxygen content and less departure from the internal milieu that evolved at sea level. Here, we test the hypotheses that Tibetan women with high oxygen saturation genotypes have higher fertility or lower offspring mortality than women with low oxygen saturation genotypes. Because the oxygen saturation locus is unknown, the approach is to assign to each person genotypic probability estimators for oxygen saturation, and therefore calculate genotypic mean values of demographic traits. 3 for details of data collection in 13 villages...

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Section: Discussionmentioning

confidence: 89%

Higher offspring survival among Tibetan women with high oxygen saturation genotypes residing at 4,000 m

Beall

Song

Elston

et al. 2004

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

105

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“…Pointing to a genetic basis for this trait, the Andean HVR has been associated with Quechua ancestry (Brutsaert et al 2005), thus suggesting an evolutionary origin. Tibetans maintain equal or higher resting ventilation compared with other acclimatized Asian and European populations measured at the same altitude Ge et al 1994;Beall et al 1997a;Moore et al 2001b), and, notably, their resting ventilation is 1.5 times higher than that observed among the Andean Aymara (Beall et al 1997a). Furthermore, Tibetan HVR is in line with acclimatized newcomers and low-altitude populations acutely exposed to hypoxia ).…”

Section: Human Populations Adapted To High Altitude and Physiologic Rmentioning

confidence: 85%

Human high-altitude adaptation: forward genetics meets the HIF pathway

2014

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Humans have adapted to the chronic hypoxia of high altitude in several locations, and recent genome-wide studies have indicated a genetic basis. In some populations, genetic signatures have been identified in the hypoxia-inducible factor (HIF) pathway, which orchestrates the transcriptional response to hypoxia. In Tibetans, they have been found in the HIF2A (EPAS1) gene, which encodes for HIF-2α, and the prolyl hydroxylase domain protein 2 (PHD2, also known as EGLN1) gene, which encodes for one of its key regulators, PHD2. High-altitude adaptation may be due to multiple genes that act in concert with one another. Unraveling their mechanism of action can offer new therapeutic approaches toward treating common human diseases characterized by chronic hypoxia.

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“…For example, pre-and postnatal mortality are threefold higher in the Han than in the Tibetans, and birth weight is significantly lower (56). This may relate in part to the presence of greater uterine arterial blood flow and lower hemoglobin concentration in the Tibetans (9,57). As such, natural selection on EPAS1 may also have operated via effects during pregnancy that affect both pre-and postnatal mortality.…”

Section: Discussionmentioning

confidence: 99%

“…The low partial pressure of oxygen resulting from the extreme altitude would have presented a formidable biological challenge to such colonists. Individuals from low-altitude populations (European and Han) who move to live at high altitude suffer from a number of potentially lethal diseases specifically related to the low levels of oxygen (3)(4)(5) and struggle to reproduce at these altitudes (6)(7)(8)(9). The hypoxia of altitude (hypobaric hypoxia) would thus have exerted substantial evolutionary selection pressure.…”

mentioning

confidence: 99%

Natural selection on EPAS1 ( HIF2α ) associated with low hemoglobin concentration in Tibetan highlanders

Beall

Cavalleri

Deng

et al. 2010

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

731

770

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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 HIF2α, 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.chronic mountain sickness | high altitude | human genome variation | hypoxia | hypoxia-inducible factor

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Oxygen transport in Tibetan women during pregnancy at 3,658 m

Cited by 116 publications

References 31 publications

Higher offspring survival among Tibetan women with high oxygen saturation genotypes residing at 4,000 m

Higher offspring survival among Tibetan women with high oxygen saturation genotypes residing at 4,000 m

Human high-altitude adaptation: forward genetics meets the HIF pathway

Natural selection on EPAS1 ( HIF2α ) associated with low hemoglobin concentration in Tibetan highlanders

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