Detecting past and ongoing natural selection among ethnically Tibetan women at high altitude in Nepal

Jeong, Choongwon; Witonsky, David B.; Basnyat, Buddha; Neupane, Maniraj; Childs, Geoff; Craig, Sienna R.; Novembre, John; Rienzo, Anna Di

doi:10.1371/journal.pgen.1007650

Cited by 56 publications

(55 citation statements)

References 95 publications

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“…While some coding-region changes have been identified in Tibetan humans [9,16] and goats [31] and Andean humans [41], the majority of SNPs have been identified in non-coding regions, suggesting that gene regulation is affected. Additionally, few studies have attempted to identify genome-wide associations between genotype and phenotype [3,10] and only a handful of physiological studies have been conducted in domesticated populations, making it challenging to show convergence in genetic changes and their effects across species. It is also possible that selection is not acting on the physiological traits being measured (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…3000–4500 m), Tibetans have a high resting ventilation but low arterial oxygen content and low oxygen saturation—of the three populations who have lived at high altitudes for generations, they are the most hypoxic [2]. There is a correlation in women between higher levels of oxygen saturation and an increased number of surviving children, and alleles undergoing positive selection are associated with more positive pregnancy outcomes in Tibetan women [3], suggesting that selection is still acting on this population. Some Tibetans show an increase in haemoglobin concentration, but only at altitudes higher than 4000 m [2].…”

Section: High-altitude Adaptationsmentioning

confidence: 99%

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Convergent evolution in human and domesticate adaptation to high-altitude environments

Witt

Huerta‐Sánchez

2019

Phil. Trans. R. Soc. B

116

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Humans and their domestic animals have lived and thrived in high-altitude environments worldwide for thousands of years. These populations have developed a number of adaptations to survive in a hypoxic environment, and several genomic studies have been conducted to identify the genes that drive these adaptations. Here, we discuss the various adaptations and genetic variants that have been identified as adaptive in human and domestic animal populations and the ways in which convergent evolution has occurred as these populations have adapted to high-altitude environments. We found that human and domesticate populations have adapted to hypoxic environments in similar ways. Specific genes and biological pathways have been involved in high-altitude adaptation for multiple populations, although the specific variants differ between populations. Additionally, we found that the gene EPAS1 is often a target of selection in hypoxic environments and has been involved in multiple adaptive introgression events. High-altitude environments exert strong selective pressures, and human and animal populations have evolved in convergent ways to cope with a chronic lack of oxygen. This article is part of the theme issue ‘Convergent evolution in the genomics era: new insights and directions'.

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Section: Discussionmentioning

confidence: 99%

Section: High-altitude Adaptationsmentioning

confidence: 99%

Convergent evolution in human and domesticate adaptation to high-altitude environments

Witt

Huerta‐Sánchez

2019

Phil. Trans. R. Soc. B

116

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“…Genome scans of polymorphisms have detected strong selective sweep signals in Tibetans at 2 loci, EGLIN1 and EPAS 1 (4, 5). However, a recent study of Tibetans found no clear evidence for polygenic adaptation for low hemoglobin concentration (2), questioning whether hemoglobin concentration is truly the target of selection, or merely a consequence or component of the true adaptive trait, as proposed previously (6). The study of Jeong et al (2) found polygenic adaptation for a lower heart rate in Tibetan females that was also associated with greater reproductive success (2).…”

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confidence: 89%

“…Hemoglobin concentration is a defining feature in the differential manifestations of adaptation between high-altitude Andeans and Tibetans (1). Tibetans demonstrate a hemoglobin concentration that would be comparable to sea level residents (1); the lower concentration is associated with greater reproductive success (2) and exercise capacity (3). Genome scans of polymorphisms have detected strong selective sweep signals in Tibetans at 2 loci, EGLIN1 and EPAS 1 (4, 5).…”

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confidence: 99%

The overlooked significance of plasma volume for successful adaptation to high altitude in Sherpa and Andean natives

Stembridge

Williams

Gasho

et al. 2019

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

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In contrast to Andean natives, high-altitude Tibetans present with a lower hemoglobin concentration that correlates with reproductive success and exercise capacity. Decades of physiological and genomic research have assumed that the lower hemoglobin concentration in Himalayan natives results from a blunted erythropoietic response to hypoxia (i.e., no increase in total hemoglobin mass). In contrast, herein we test the hypothesis that the lower hemoglobin concentration is the result of greater plasma volume, rather than an absence of increased hemoglobin production. We assessed hemoglobin mass, plasma volume and blood volume in lowlanders at sea level, lowlanders acclimatized to high altitude, Himalayan Sherpa, and Andean Quechua, and explored the functional relevance of volumetric hematological measures to exercise capacity. Hemoglobin mass was highest in Andeans, but also was elevated in Sherpa compared with lowlanders. Sherpa demonstrated a larger plasma volume than Andeans, resulting in a comparable total blood volume at a lower hemoglobin concentration. Hemoglobin mass was positively related to exercise capacity in lowlanders at sea level and in Sherpa at high altitude, but not in Andean natives. Collectively, our findings demonstrate a unique adaptation in Sherpa that reorientates attention away from hemoglobin concentration and toward a paradigm where hemoglobin mass and plasma volume may represent phenotypes with adaptive significance at high altitude.

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“…2010 ; Hernandez et al. 2011 ; Schrider and Kern 2017 ), as well as in high-altitude adaptation of Himalayan populations ( Jeong and Di Rienzo 2014 ; Jeong et al. 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Evidence of polygenic adaptation to high altitude from Tibetan and Sherpa genomes

Gnecchi‐Ruscone

Abondio

Fanti

et al. 2018

Genome Biology and Evolution

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Although Tibetans and Sherpa present several physiological adjustments evolved to cope with selective pressures imposed by the high-altitude environment, especially hypobaric hypoxia, few selective sweeps at a limited number of hypoxia related genes were confirmed by multiple genomic studies. Nevertheless, variants at these loci were found to be associated only with downregulation of the erythropoietic cascade, which represents an indirect aspect of the considered adaptive phenotype. Accordingly, the genetic basis of Tibetan/Sherpa adaptive traits remains to be fully elucidated, in part due to limitations of selection scans implemented so far and mostly relying on the hard sweep model.In order to overcome this issue, we used whole-genome sequence data and several selection statistics as input for gene network analyses aimed at testing for the occurrence of polygenic adaptation in these high-altitude Himalayan populations. Being able to detect also subtle genomic signatures ascribable to weak positive selection at multiple genes of the same functional subnetwork, this approach allowed us to infer adaptive evolution at loci individually showing small effect sizes, but belonging to highly interconnected biological pathways overall involved in angiogenetic processes.Therefore, these findings pinpointed a series of selective events neglected so far, which likely contributed to the augmented tissue blood perfusion observed in Tibetans and Sherpa, thus uncovering the genetic determinants of a key biological mechanism that underlies their adaptation to high altitude.

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Detecting past and ongoing natural selection among ethnically Tibetan women at high altitude in Nepal

Cited by 56 publications

References 95 publications

Convergent evolution in human and domesticate adaptation to high-altitude environments

Convergent evolution in human and domesticate adaptation to high-altitude environments

The overlooked significance of plasma volume for successful adaptation to high altitude in Sherpa and Andean natives

Evidence of polygenic adaptation to high altitude from Tibetan and Sherpa genomes

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