Genetic signatures of high-altitude adaptation in Tibetans

Indigenous Tibetan people have lived on the Tibetan Plateau for millennia. There is a long-standing question about the genetic basis of high-altitude adaptation in Tibetans. We conduct a genome-wide study of 7.3 million genotyped and imputed SNPs of 3,008 Tibetans and 7,287 non-Tibetan individuals of Eastern Asian ancestry. Using this large dataset, we detect signals of high-altitude adaptation at nine genomic loci, of which seven are unique. The alleles under natural selection at two of these loci [methylenetetrahydrofolate reductase (MTHFR) and EPAS1] are strongly associated with blood-related phenotypes, such as hemoglobin, homocysteine, and folate in Tibetans. The folate-increasing allele of rs1801133 at the MTHFR locus has an increased frequency in Tibetans more than expected under a drift model, which is probably a consequence of adaptation to high UV radiation. These findings provide important insights into understanding the genomic consequences of high-altitude adaptation in Tibetans.

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A Genome-Wide Search for Signals of High-Altitude Adaptation in Tibetans

Molecular Biology and Evolution ◽

10.1093/molbev/msq277 ◽

2010 ◽

Vol 28 (2) ◽

pp. 1003-1011 ◽

Cited By ~ 195

Author(s):

S. Xu ◽

S. Li ◽

Y. Yang ◽

J. Tan ◽

H. Lou ◽

...

Keyword(s):

High Altitude ◽

High Altitude Adaptation ◽

Genome Wide ◽

A Genome ◽

Genome Wide Search ◽

Altitude Adaptation

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Altitude-wise analysis of co-occurrence networks of mitochondrial genome in Asian population

10.1101/2019.12.21.885905 ◽

2019 ◽

Author(s):

Rahul K Verma ◽

Cristina Giuliani ◽

Alena Kalyakuina ◽

Ajay Deep Kachhvah ◽

Mikhail Ivanchenko ◽

...

Keyword(s):

Mitochondrial Genome ◽

High Altitude ◽

Dna Sequences ◽

Group Analysis ◽

Asian Population ◽

The Tibetan Plateau ◽

Mt Dna ◽

High Altitude Adaptation ◽

Altitude Adaptation ◽

The Impact

ABSTRACTFinding mechanisms behind high altitude adaptation in humans at the Tibetan plateau has been a subject of evolutionary research. Mitochondrial DNA (mt-DNA) variations have been established as one of the key players in understanding the biological mechanisms at the basis of adaptation to these extreme conditions. To explore cumulative effects and dynamics of the variations in mitochondrial genome at varying altitudes, we investigated human mt-DNA sequences from NCBI database at different altitudes by employing co-occurrence motifs framework. We constructed co-occurrence motifs by taking into account variable sites for each altitude group. Analysis of the co-occurrence motifs using similarity clustering revealed a clear distinction between a lower and a higher altitude region. In addition, the previously known high altitude markers 3394 and 7697 (which are definitive sites of haplogroup M9a1a1c1b) were found to co-occur within their own gene complexes indicating the impact of intra-genic constraint on co-evolution of nucleotides. Furthermore, an ancestral marker 10398 was found to co-occur only at higher altitudes supporting the fact that a separate root of colonization at these altitudes might have taken place. Overall, our analysis revealed the presence of co-occurrence motifs at a whole mitochondrial genome level. This study, combined with the classical haplogroups analysis is useful in understanding role of co-occurrence of mitochondrial variations in high altitude adaptation.

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High altitude adaptation mitigates anemia risk associated with diabetes among the Mosuo of Southwest China

10.1101/406579 ◽

2018 ◽

Cited By ~ 1

Author(s):

M Su ◽

K Wander ◽

MK Shenk ◽

T Blumenfield ◽

H Li ◽

...

Keyword(s):

Tibetan Plateau ◽

High Altitude ◽

Market Integration ◽

Hypoxia Inducible Factor ◽

Human Populations ◽

The Tibetan Plateau ◽

Low Oxygen ◽

High Altitude Adaptation ◽

Altitude Adaptation ◽

Hb Concentration

AbstractHuman populations native to high altitude regions (≥2500 m) exhibit numerous adaptations to hypoxic stress. On the Tibetan Plateau, these include modifications of the hypoxia inducible factor (HIF) pathway to essentially uncouple erythropoiesis (red blood cell production) and blood hemoglobin (Hb) concentration—which normally increase in response to low oxygen—from hypoxia. Uncoupling of erythropoiesis and hypoxia is also observed among people with diabetes due to damage to kidney tissues. This is hypothesized to result in elevated risk for anemia among diabetics, which increases risk for cardiovascular disease and death. We tested the hypothesis that the independence of erythropoiesis from HIF among high-altitude adapted populations of the Tibetan Plateau may protect against diabetes-associated anemia. We investigated this hypothesis among the Mosuo, a population living in Yunnan Province, China (at ~2800 m altitude) that is undergoing rapid market integration and lifestyle change, with concomitant increase in risk for type 2 diabetes. We found that, although diabetes (glycated hemoglobin, HbA1c ≥6.5%) is associated with anemia (females: Hb<12g/dl; males: Hb<13g/dl) among the Chinese population as a whole (N: 5,606; OR: 1.48; p: 0.008), this is not the case among the Mosuo (N: 316; OR: 1.36; p: 0.532). Both pathways uncoupling hypoxia from erythropoiesis (diabetic disease and high altitude adaptation) are incompletely understood; their intersection in protecting Mosuo with diabetes from anemia may provide insight into the mechanisms underlying each. Further, these findings point to the importance of understanding how high-altitude adaptations interact with chronic disease processes, as populations like the Mosuo experience rapid market integration.

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