High-Altitude Adaptation: Mechanistic Insights from Integrated Genomics and Physiology

Feedback Regulation ◽

Genomic Analyses ◽

Manipulative Experiments ◽

Altitude Adaptation ◽

Mechanisms Of Adaptation ◽

Physiological Pathways ◽

Underlying Mechanisms ◽

Integrated Genomics

AbstractPopulation genomic analyses of high-altitude humans and other vertebrates have identified numerous candidate genes for hypoxia adaptation, and the physiological pathways implicated by such analyses suggest testable hypotheses about underlying mechanisms. Studies of highland natives that integrate genomic data with experimental measures of physiological performance capacities and subordinate traits are revealing associations between genotypes (e.g., hypoxia-inducible factor gene variants) and hypoxia-responsive phenotypes. The subsequent search for causal mechanisms is complicated by the fact that observed genotypic associations with hypoxia-induced phenotypes may reflect second-order consequences of selection-mediated changes in other (unmeasured) traits that are coupled with the focal trait via feedback regulation. Manipulative experiments to decipher circuits of feedback control and patterns of phenotypic integration can help identify causal relationships that underlie observed genotype–phenotype associations. Such experiments are critical for correct inferences about phenotypic targets of selection and mechanisms of adaptation.

Genome-Wide Epigenetic Signatures of Adaptive Developmental Plasticity in the Andes

Genome Biology and Evolution ◽

10.1093/gbe/evaa239 ◽

2020 ◽

Author(s):

Ainash Childebayeva ◽

Jaclyn M Goodrich ◽

Fabiola Leon-Velarde ◽

Maria Rivera-Chira ◽

Melisa Kiyamu ◽

...

Keyword(s):

Dna Methylation ◽

Genetic Variation ◽

High Altitude ◽

Developmental Plasticity ◽

Adaptation To Hypoxia ◽

Altitude Adaptation ◽

Epigenetic Signatures ◽

Adaptive Developmental Plasticity

Abstract High-altitude adaptation is a classic example of natural selection operating on the human genome. Physiological and genetic adaptations have been documented in populations with a history of living at high altitude. However, the role of epigenetic gene regulation, including DNA methylation, in high-altitude adaptation is not well understood. We performed an epigenome-wide DNA methylation association study based on whole blood from 113 Peruvian Quechua with differential lifetime exposures to high altitude (>2,500) and recruited based on a migrant study design. We identified two significant differentially methylated positions (DMPs) and 62 differentially methylated regions (DMRs) associated with high-altitude developmental and lifelong exposure statuses. DMPs and DMRs were found in genes associated with hypoxia-inducible factor pathway, red blood cell production, blood pressure, and others. DMPs and DMRs associated with fractional exhaled Nitric Oxide (FeNO) also were identified. We found a significant association between EPAS1 methylation and EPAS1 SNP genotypes, suggesting that local genetic variation influences patterns of methylation. Our findings demonstrate that DNA methylation is associated with early developmental and lifelong high-altitude exposures among Peruvian Quechua as well as altitude-adaptive phenotypes. Together these findings suggest that epigenetic mechanisms might be involved in adaptive developmental plasticity to high altitude. Moreover, we show that local genetic variation is associated with DNA methylation levels, suggesting that methylation associated SNPs could be a potential avenue for research on genetic adaptation to hypoxia in Andeans.

Genetic variation in hypoxia-inducible factor 1α and its possible association with high altitude adaptation in Sherpas

Medical Hypotheses ◽

10.1016/s0306-9877(03)00178-6 ◽

2003 ◽

Vol 61 (3) ◽

pp. 385-389 ◽

Cited By ~ 38

Author(s):

K Suzuki ◽

T Kizaki ◽

Y Hitomi ◽

M Nukita ◽

K Kimoto ◽

...

Keyword(s):

Genetic Variation ◽

High Altitude ◽

Hypoxia Inducible Factor 1Α ◽

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 ◽

Human Populations ◽

The Tibetan Plateau ◽

Low Oxygen ◽

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.

Human adaptation to the hypoxia of high altitude: the Tibetan paradigm from the pregenomic to the postgenomic era

Journal of Applied Physiology ◽

10.1152/japplphysiol.00605.2013 ◽

2014 ◽

Vol 116 (7) ◽

pp. 875-884 ◽

Cited By ~ 59

Author(s):

Nayia Petousi ◽

Peter A. Robbins

Keyword(s):

Natural Selection ◽

High Altitude ◽

Hemoglobin Concentration ◽

Phenotypic Traits ◽

The Tibetan Plateau ◽

Oxygen Homeostasis ◽

Functional Variants ◽

Hypoxic Environment ◽

Underlying Mechanisms

The Tibetan Plateau is one of the highest regions on Earth. Tibetan highlanders are adapted to life and reproduction in a hypoxic environment and possess a suite of distinctive physiological traits. Recent studies have identified genomic loci that have undergone natural selection in Tibetans. Two of these loci, EGLN1 and EPAS1, encode major components of the hypoxia-inducible factor transcriptional system, which has a central role in oxygen sensing and coordinating an organism's response to hypoxia, as evidenced by studies in humans and mice. An association between genetic variants within these genes and hemoglobin concentration in Tibetans at high altitude was demonstrated in some of the studies ( 8 , 80 , 96 ). Nevertheless, the functional variants within these genes and the underlying mechanisms of action are still not known. Furthermore, there are a number of other possible phenotypic traits, besides hemoglobin concentration, upon which natural selection may have acted. Integration of studies at the genomic level with functional molecular studies and studies in systems physiology has the potential to provide further understanding of human evolution in response to high-altitude hypoxia. The Tibetan paradigm provides further insight on the role of the hypoxia-inducible factor system in humans in relation to oxygen homeostasis.

Faculty Opinions recommendation of The molecular basis of high-altitude adaptation in deer mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1079774.532691 ◽

2007 ◽

Author(s):

Ary Hoffmann

Keyword(s):

High Altitude ◽

Molecular Basis ◽

Deer Mice ◽

Faculty Opinions recommendation of Evolutionary and functional insights into the mechanism underlying high-altitude adaptation of deer mouse hemoglobin.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1163704.625482 ◽

2009 ◽

Author(s):

Anthony Zera

Keyword(s):

High Altitude ◽

Deer Mouse ◽

Whole-genome sequence data suggests environmental adaptation of Ethiopian sheep populations

Genome Biology and Evolution ◽

10.1093/gbe/evab014 ◽

2021 ◽

Author(s):

Pamela Wiener ◽

Christelle Robert ◽

Abulgasim Ahbara ◽

Mazdak Salavati ◽

Ayele Abebe ◽

...

Keyword(s):

High Altitude ◽

Environmental Variables ◽

Large Scale ◽

Sequence Data ◽

Strong Association ◽

Environmental Adaptation ◽

Whole Genome Sequence ◽

Single Nucleotide Variants ◽

Abstract Great progress has been made over recent years in the identification of selection signatures in the genomes of livestock species. This work has primarily been carried out in commercial breeds for which the dominant selection pressures, are associated with artificial selection. As agriculture and food security are likely to be strongly affected by climate change, a better understanding of environment-imposed selection on agricultural species is warranted. Ethiopia is an ideal setting to investigate environmental adaptation in livestock due to its wide variation in geo-climatic characteristics and the extensive genetic and phenotypic variation of its livestock. Here, we identified over three million single nucleotide variants across 12 Ethiopian sheep populations and applied landscape genomics approaches to investigate the association between these variants and environmental variables. Our results suggest that environmental adaptation for precipitation-related variables is stronger than that related to altitude or temperature, consistent with large-scale meta-analyses of selection pressure across species. The set of genes showing association with environmental variables was enriched for genes highly expressed in human blood and nerve tissues. There was also evidence of enrichment for genes associated with high-altitude adaptation although no strong association was identified with hypoxia-inducible-factor (HIF) genes. One of the strongest altitude-related signals was for a collagen gene, consistent with previous studies of high-altitude adaptation. Several altitude-associated genes also showed evidence of adaptation with temperature, suggesting a relationship between responses to these environmental factors. These results provide a foundation to investigate further the effects of climatic variables on small ruminant populations.