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Genetic signatures reveal high-altitude adaptation in a set of ethiopian populations.

ABSTRACT: The Tibetan and Andean Plateaus and Ethiopian highlands are the largest regions to have long-term high-altitude residents. Such populations are exposed to lower barometric pressures and hence atmospheric partial pressures of oxygen. Such "hypobaric hypoxia" may limit physical functional capacity, reproductive health, and even survival. As such, selection of genetic variants advantageous to hypoxic adaptation is likely to have occurred. Identifying signatures of such selection is likely to help understanding of hypoxic adaptive processes. Here, we seek evidence of such positive selection using five Ethiopian populations, three of which are from high-altitude areas in Ethiopia. As these populations may have been recipients of Eurasian gene flow, we correct for this admixture. Using single-nucleotide polymorphism genotype data from multiple populations, we find the strongest signal of selection in BHLHE41 (also known as DEC2 or SHARP1). Remarkably, a major role of this gene is regulation of the same hypoxia response pathway on which selection has most strikingly been observed in both Tibetan and Andean populations. Because it is also an important player in the circadian rhythm pathway, BHLHE41 might also provide insights into the mechanisms underlying the recognized impacts of hypoxia on the circadian clock. These results support the view that Ethiopian, Andean, and Tibetan populations living at high altitude have adapted to hypoxia differently, with convergent evolution affecting different genes from the same pathway.

SUBMITTER: Huerta-Sanchez E

PROVIDER: S-EPMC3708501 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Genetic signatures reveal high-altitude adaptation in a set of ethiopian populations.

Huerta-Sánchez Emilia E Degiorgio Michael M Pagani Luca L Tarekegn Ayele A Ekong Rosemary R Antao Tiago T Cardona Alexia A Montgomery Hugh E HE Cavalleri Gianpiero L GL Robbins Peter A PA Weale Michael E ME Bradman Neil N Bekele Endashaw E Kivisild Toomas T Tyler-Smith Chris C Nielsen Rasmus R

Molecular biology and evolution 20130510 8

The Tibetan and Andean Plateaus and Ethiopian highlands are the largest regions to have long-term high-altitude residents. Such populations are exposed to lower barometric pressures and hence atmospheric partial pressures of oxygen. Such "hypobaric hypoxia" may limit physical functional capacity, reproductive health, and even survival. As such, selection of genetic variants advantageous to hypoxic adaptation is likely to have occurred. Identifying signatures of such selection is likely to help u ...[more]

PMID: 23666210

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Project description:Humans living at high altitude (≥ 2,500 meters above sea level) have acquired unique abilities to survive the associated extreme environmental conditions, including hypoxia, cold temperature, limited food availability and high levels of free radicals and oxidants. Long-term inhabitants of the most elevated regions of the world have undergone extensive physiological and/or genetic changes, particularly in the regulation of respiration and circulation, when compared to lowland populations. Genome scans have identified candidate genes involved in altitude adaption in the Tibetan Plateau and the Ethiopian highlands, in contrast to populations from the Andes, which have not been as intensively investigated. In the present study, we focused on three indigenous populations from Bolivia: two groups of Andean natives, Aymara and Quechua, and the low-altitude control group of Guarani from the Gran Chaco lowlands. Using pooled samples, we identified a number of SNPs exhibiting large allele frequency differences over 900,000 genotyped SNPs. A region in chromosome 10 (within the cytogenetic bands q22.3 and q23.1) was significantly differentiated between highland and lowland groups. We resequenced ~1.5 Mb surrounding the candidate region and identified strong signals of positive selection in the highland populations. A composite of multiple signals like test localized the signal to FAM213A and a related enhancer; the product of this gene acts as an antioxidant to lower oxidative stress and may help to maintain bone mass. The results suggest that positive selection on the enhancer might increase the expression of this antioxidant, and thereby prevent oxidative damage. In addition, the most significant signal in a relative extended haplotype homozygosity analysis was localized to the SFTPD gene, which encodes a surfactant pulmonary-associated protein involved in normal respiration and innate host defense. Our study thus identifies two novel candidate genes and associated pathways that may be involved in high-altitude adaptation in Andean populations.

Project description:BackgroundTibetans have lived at very high altitudes for thousands of years, and have a distinctive suite of physiological traits that enable them to tolerate environmental hypoxia. Expanding awareness and knowledge of the differences in hematology, hypoxia-associated genes, immune system of people living at different altitudes and from different ethnic groups may provide evidence for the prevention of mountain sickness.MethodNinety-five Han people at mid-altitude, ninety-five Tibetan people at high-altitude and ninety-eight Han people at high-altitude were recruited. Red blood cell parameters, immune cells, the contents of cytokines, hypoxia-associated gene single nucleotide polymorphisms (SNPs) were measured.ResultsThe values of Hematocrit (HCT), Mean cell volume (MCV) and Mean cell hemoglobin (MCH) in red blood cell, immune cell CD19+ B cell number, the levels of cytokines Erb-B2 receptor tyrosine kinase 3 (ErbB3) and Tumor necrosis factor receptor II (TNF-RII) and the levels of hypoxia-associated factors Hypoxia inducible factor-1α (HIF-1α), Hypoxia inducible factor-2α (HIF-2α) and HIF prolyl 4-hydroxylase 2 (PHD2) were decreased, while the frequencies of SNPs in twenty-six Endothelial PAS domain protein 1 (EPAS1) and Egl-9 family hypoxia inducible factor 1 (EGLN1) were increased in Tibetan people at high-altitude compared with that of Han peoples at high-altitude. Furthermore, compared with mid-altitude individuals, high-altitude individuals showed lower blood cell parameters including Hemoglobin concentration (HGB), HCT, MCV and MCH, higher Mean cell hemoglobin concentration (MCHC), lower immune cells including CD19+ B cells, CD4+ T cells and CD4/CD8 ratio, higher immune cells containing CD8+ T cells and CD16/56NK cells, decreased Growth regulated oncogene alpha (GROa), Macrophage inflammatory protein 1 beta (MIP-1b), Interleukin-8 (IL-8), and increased Thrombomodulin, downregulated hypoxia-associated factors including HIF1α, HIF2α and PHD2, and higher frequency of EGLN1 rs2275279.ConclusionsThese results indicated that biological adaption to hypoxia at high altitude might have been mediated by changes in immune cells, cytokines, and hypoxia-associated genes during the evolutionary history of Tibetan populations. Furthermore, different responses to high altitude were observed in different ethnic groups, which may provide a useful knowledge to improve the protection of high-altitude populations from mountain sickness.

Dataset Information

Genetic signatures reveal high-altitude adaptation in a set of ethiopian populations.

Publications

Genetic signatures reveal high-altitude adaptation in a set of ethiopian populations.

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