An Ethiopian pattern of human adaptation to high-altitude hypoxia

Beall, Cynthia M.; Decker, Michael J.; Brittenham, Gary M.; Kushner, Irving; Gebremedhin, Amha; Strohl, Kingman P.

doi:10.1073/pnas.252649199

Cited by 224 publications

(204 citation statements)

References 16 publications

(7 reference statements)

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“…For example, because of exposure during growth and development, Andean high-altitude natives function normally under hypoxic conditions, but adult migrants from sea level rarely do as well even after substantial physiological adjustments to the stress of hypoxia (33,34). The FRM argues that, in like manner, in a given set of environmental conditions, the reproductive system is under selection to function normally.…”

Section: Figmentioning

confidence: 99%

Interpopulational differences in progesterone levels during conception and implantation in humans

Vitzthum

Spielvogel

Thornburg

2004

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

100

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Clinical studies of women from the United States demonstrate a sensitivity of the ovarian system to energetic stress. Even moderate exercise or caloric restriction can lead to lower progesterone levels and failure to ovulate. Yet women in many nonindustrial populations experience as many as a dozen pregnancies in a lifetime despite poor nutritional resources, heavy workloads, and typical progesterone levels only about two-thirds of those of U.S. women. Previous cross-sectional studies of progesterone may, however, suffer from inadvertent selection bias. In a noncontracepting population, the most fecund women, who might be expected to have the highest progesterone, are more likely to be pregnant or breastfeeding and hence unavailable for a crosssectional study of the ovarian cycle. The present longitudinal study was designed to ascertain whether lower progesterone also characterizes conception, implantation, and gestation in women from nonindustrialized populations. We compared rural Bolivian Aymara women (n ‫؍‬ 191) to women from Chicago (n ‫؍‬ 29) and found that mean-peak-luteal progesterone in the ovulatory cycles of Bolivian women averaged Ϸ71% that of the women from Chicago. In conception cycles, progesterone levels in Bolivian women during the periovulatory period were Ϸ63%, and during the peri-implantation period were Ϸ50%, those of the U.S. women. These observations argue that lower progesterone levels typically characterize the reproductive process in Bolivian women and perhaps others from nonindustrialized populations. We discuss the possible proximate and evolutionary explanations for this variation and note the implications for developing suitable hormonal contraceptives and elucidating the etiology of cancers of the breast and reproductive tract.I n an evaluation of demographic data from populations worldwide, Bongaarts (1) concluded that, except in cases of famine, nutritional factors play a relatively minor role in determining human fecundity (capacity to conceive) or fertility (number of live births). Despite characteristically marginal nutritional status and the demands of arduous activities, women in less developed countries often average seven to eight pregnancies, some having 12 or more during a lifetime. Differences among populations, or reductions from a theoretical maximum, appear fully attributable to a limited set of behavioral and physiological proximate fertility determinants apparently little affected by nutritional factors. If neither fecundity nor fertility is thus significantly influenced, neither is fecundability (the monthly probability of conception). Yet clinical studies of women from the United States indicate a sensitivity of ovarian function to both relatively low energy intake and͞or high energy expenditure. The most extreme response, failure to ovulate, may occur in the face of only moderate energetic stress (2-4) and, of course, reduces fecundity and fecundability to 0. Short of anovulation, milder disruptions of ovarian function may also reduce fecundability. Why should o...

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Section: Figmentioning

confidence: 99%

Interpopulational differences in progesterone levels during conception and implantation in humans

Vitzthum

Spielvogel

Thornburg

2004

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

100

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“…Several lines of evidence suggest that Himalayan populations are genetically adapted to hypobaric hypoxia (Moore et al 2000;Beall et al 2002Beall et al , 2004Beall, 2003). Genetic adaptation to hypoxia could result from few oligogenes (Maniatis et al 2004;Morton, 2005).…”

Section: Introductionmentioning

confidence: 99%

Association Between Human Polymorphic DNA Markers and Hypoxia Adaptation in Sherpa Detected by a Preliminary Genome Scan

Malacrida

Katsuyama

Droma

et al. 2007

Annals of Human Genetics

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SummaryGenetic determinants of resistance to hypobaric hypoxia in the Sherpa are still unknown. Since adaptive gene variants must still be subjected to positive selection, linkage disequilibrium between such variants and specific alleles of flanking DNA markers is expected. Following this line of reasoning, we performed a human genome scan using 998 polymorphic DNA markers in 7 unrelated Sherpa porters living in the Solu-Khumbu area. This minimalist approach succeeded in detecting 8 DNA markers showing homozygosity for the same shared allele. Analysis of additional DNA samples from 2 more Sherpa porters focused our attention on three polymorphic DNA markers (D6S1697, D14S274, D17S1795) showing homozygosity for the same shared allele in 8 out 9 tested individuals. Analysis of DNA samples from Sherpa and non-Sherpa populations of Nepal proved HW equilibrium in both populations for markers D14S274 and D17S1795, while an excess of heterozygotes was observed in the Sherpa population for marker D6S1697. A significant difference in allele frequencies for D14S274 and D17S1795 between the two populations was observed. These findings exclude the possibility that homozygosity for 3 specific loci in 8 unrelated individuals might be ascribed to inbreeding or recent genetic drift. We therefore conclude that the chromosomal segments detected by such DNA markers may include genes involved in adaptation to hypobaric hypoxia.

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“…Although there is still debate about the mechanisms of adaptation in HA populations, especially in relation to those populations that are beststudied (9), the Ethiopians are considered to be the best-adapted because the prevalence of chronic mountain sickness, a maladaptation syndrome to HA, has never been reported (10,11). In our recent effort to understand the basis for adaptation to HA in humans, we analyzed the whole genome for genetic variation in HA Ethiopians (4).…”

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confidence: 99%

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

Stobdan

Zhou

Ao-Ieong

et al. 2015

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

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To better understand human adaptation to stress, and in particular to hypoxia, we took advantage of one of nature's experiments at high altitude (HA) and studied Ethiopians, a population that is well-adapted to HA hypoxic stress. Using whole-genome sequencing, we discovered that EDNRB (Endothelin receptor type B) is a candidate gene involved in HA adaptation. To test whether EDNRB plays a critical role in hypoxia tolerance and adaptation, we generated EdnrB knockout mice and found that when EdnrB −/+ heterozygote mice are treated with lower levels of oxygen (O 2 ), they tolerate various levels of hypoxia (even extreme hypoxia, e.g., 5% O 2 ) very well. For example, they maintain ejection fraction, cardiac contractility, and cardiac output in severe hypoxia. Furthermore, O 2 delivery to vital organs was significantly higher and blood lactate was lower in EdnrB −/+ compared with wild type in hypoxia. Tissue hypoxia in brain, heart, and kidney was lower in EdnrB −/+ mice as well. These data demonstrate that a lower level of EDNRB significantly improves cardiac performance and tissue perfusion under various levels of hypoxia. Transcriptomic profiling of left ventricles revealed three specific genes [natriuretic peptide type A (Nppa), sarcolipin (Sln), and myosin light polypeptide 4 (Myl4)] that were oppositely expressed (q < 0.05) between EdnrB −/+ and wild type. Functions related to these gene networks were consistent with a better cardiac contractility and performance. We conclude that EDNRB plays a key role in hypoxia tolerance and that a lower level of EDNRB contributes, at least in part, to HA adaptation in humans.is often referred to as a biosignature, a chemical marker in the atmosphere closely associated with life, and in a complex organism, such as humans, various physiological systems have evolved to maintain an optimal O 2 homeostasis. Arguably, humans living at high altitude (HA) for thousands of years ought to have undergone a significant level of natural selection to adjust to the challenging hypoxic condition. Human adaptation to HA hypoxia, which can be protective to tissues, can potentially be harnessed for better therapeutic modalities for sea-level diseases that involve hypoxia and ischemia in their pathogenesis. Indeed, lessons from such an "experiment in nature" can be derived from HA adaptation and can advance lowaltitude medicine (1). With the advent of newer technology including next-generation sequencing (seq), this idea has recently led to intensive efforts, and a number of publications have appeared on studies of human populations living at HA (2-4). These studies also draw added significance not only to sea-level human diseases but also to more than 140 million people living at an altitude above 2,500 m, where the hypoxic condition presents a major challenge for survival (5). Although a number of laboratory methods that mimic hypoxia adaptation using model organisms (6) have been used as tools to identify causative genetic pathways (7,8), studies in human populations living at different H...

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An Ethiopian pattern of human adaptation to high-altitude hypoxia

Cited by 224 publications

References 16 publications

Interpopulational differences in progesterone levels during conception and implantation in humans

Interpopulational differences in progesterone levels during conception and implantation in humans

Association Between Human Polymorphic DNA Markers and Hypoxia Adaptation in Sherpa Detected by a Preliminary Genome Scan

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

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