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

2014 ◽  
Vol 116 (7) ◽  
pp. 875-884 ◽  
Author(s):  
Nayia Petousi ◽  
Peter A. Robbins
Keyword(s):  
Natural Selection ◽  
High Altitude ◽  
Hypoxia Inducible Factor ◽  
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.

scholarly journals Tibetans living at sea level have a hyporesponsive hypoxia-inducible factor system and blunted physiological responses to hypoxia

2014 ◽  
Vol 116 (7) ◽  
pp. 893-904 ◽  
Author(s):  
Nayia Petousi ◽  
Quentin P. P. Croft ◽  
Gianpiero L. Cavalleri ◽  
Hung-Yuan Cheng ◽  
Federico Formenti ◽  
...  
Keyword(s):  
Natural Selection ◽  
Sea Level ◽  
Pulmonary Ventilation ◽  
Hypoxia Inducible Factor ◽  
Hemoglobin Concentration ◽  
Peripheral Blood Lymphocytes ◽  
Cellular Level ◽  
Han Chinese ◽  
The Tibetan Plateau ◽  
Integrative Physiology

Tibetan natives have lived on the Tibetan plateau (altitude ∼4,000 m) for at least 25,000 years, and as such they are adapted to life and reproduction in a hypoxic environment. Recent studies have identified two genetic loci, EGLN1 and EPAS1, that have undergone natural selection in Tibetans, and further demonstrated an association of EGLN1/ EPAS1 genotype with hemoglobin concentration. Both genes encode major components of the hypoxia-inducible factor (HIF) transcriptional pathway, which coordinates an organism's response to hypoxia. Patients living at sea level with genetic disease of the HIF pathway have characteristic phenotypes at both the integrative-physiology and cellular level. We sought to test the hypothesis that natural selection to hypoxia within Tibetans results in related phenotypic differences. We compared Tibetans living at sea level with Han Chinese, who are Tibetans' most closely related major ethnic group. We found that Tibetans had a lower hemoglobin concentration, a higher pulmonary ventilation relative to metabolism, and blunted pulmonary vascular responses to both acute (minutes) and sustained (8 h) hypoxia. At the cellular level, the relative expression and hypoxic induction of HIF-regulated genes were significantly lower in peripheral blood lymphocytes from Tibetans compared with Han Chinese. Within the Tibetans, we found a significant correlation between both EPAS1 and EGLN1 genotype and the induction of erythropoietin by hypoxia. In conclusion, this study provides further evidence that Tibetans respond less vigorously to hypoxic challenge. This is evident at sea level and, at least in part, appears to arise from a hyporesponsive HIF transcriptional system.

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

2021 ◽  
Author(s):  
Jay F Storz
Keyword(s):  
High Altitude ◽  
Hypoxia Inducible Factor ◽  
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.

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

2018 ◽  
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.

scholarly journals EPAS 1, congenital heart disease, and high altitude: disclosures by genetics, bioinformatics, and experimental embryology

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Consolato Sergi
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
High Altitude ◽  
Congenital Heart ◽  
Hypoxia Inducible Factor ◽  
Gene Mutations ◽  
Epidemiologic Studies ◽  
The Tibetan Plateau ◽  
Low Oxygen ◽  
Downstream Target

Abstract The high-altitude environment is a challenge for human settlement. Low oxygen concentrations, extreme cold, and a harsh arid climate are doubtlessly challenges for the colonization of the Tibetan plateau. I am delighted to comment on the article of Pan et al. (2018) on mutations in endothelial PAS domain-containing protein 1 (EPAS1) in congenital heart disease in Tibetans. In humans, the EPAS1 gene is responsible for coding EPAS1 protein, an alias of which is HIF2α, an acronym for hypoxia-inducible factor 2 alpha. EPAS1 is a type of hypoxia-inducible factors, which are collected as a group of transcription factors involved in body response to oxygen level. EPAS1 gene is active under hypoxic conditions and plays an essential role in the development of the heart and in the management of the catecholamine balance, mutations of which have been identified in neuroendocrine tumors. In this article, Pan et al. investigated Tibetan patients with and without non-syndromic congenital heart disease. They identified two novel EPAS1 gene mutations, of which N203H mutation significantly affected the transcription activity of the vascular endothelial growth factor (VEGF) promoter, particularly in situations of hypoxia. VEGF is a downstream target of HIF-2 (other than HIF-1), and the expression levels of either HIF-1α or HIF-2α correlate positively to VEGF expression. Pan et al.’s data may be of incitement to further evaluate protein–protein interaction and using experimental animal models. Moreover, it may also be a stimulus for setting up genetic epidemiologic studies for other populations living at high altitudes.

scholarly journals Gastric Mucosal Lesions in Tibetans with High-Altitude Polycythemia Show Increased HIF-1A Expression and ROS Production

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Kang Li ◽  
Chaohui He
Keyword(s):  
Gastric Mucosa ◽  
High Altitude ◽  
Healthy Subjects ◽  
Hypoxia Inducible Factor ◽  
Average Diameter ◽  
Low Oxygen ◽  
Gastric Mucosal Lesions ◽  
Oxygen Homeostasis ◽  
Mucosal Lesions ◽  
High Level

Background. Living at a high plateau in a very hostile environment and low oxygen levels often leads to the development of high-altitude polycythemia (HAPC) and gastric mucosal lesions caused by high-level reactive oxygen species (ROS). Hypoxia-inducible factor-1A (HIF-1A) helps maintain oxygen homeostasis by promoting the transcription of various genes and can be affected by ROS levels. To evaluate the molecular mechanism by which HAPC causes the gastric mucosal lesions, the expression of HIF-1A was measured in Tibetans with HAPC and in healthy subjects. Ultrastructural, histopathological, and immunohistochemical analyses were performed in the gastric tissues of both groups, and the expression of HIF-1A in the gastric mucosa was detected using qPCR and Western Blot.Results. The microvessel density and average diameter of gastric mucosal vessels were significantly greater in the HAPC patients than in the healthy subjects (p< 0.05). The number of red blood cells in the gastric mucosa was also significantly higher in the HAPC group than in the healthy subjects (p< 0.05). In addition, the density of the mitochondrial vacuoles and endoplasmic reticulum and pathological apoptosis were significantly increased in the gastric cells from HAPC patients compared to those from the healthy subjects. The levels of ROS and HIF-1A in the gastric mucosa were increased in HAPC patients compared to those in controls (p< 0.05).Conclusions. An increased level of HIF-1A was associated with HAPC development in the stomach of Tibetans living at a high altitude. ROS upregulated the levels of HIF-1A. Thus, ROS-mediated HIF-1A signaling transduction may be the mechanism associated with HAPC-induced gastric lesions.

scholarly journals Spleen contraction elevates hemoglobin concentration at high altitude during rest and exercise

2020 ◽  
Vol 120 (12) ◽  
pp. 2693-2704
Author(s):  
Erika Schagatay ◽  
Alexander Lunde ◽  
Simon Nilsson ◽  
Oscar Palm ◽  
Angelica Lodin-Sundström
Keyword(s):  
High Altitude ◽  
Acute Hypoxia ◽  
Arterial Oxygen Saturation ◽  
Hemoglobin Concentration ◽  
Step Test ◽  
Arterial Oxygen ◽  
Spleen Volume ◽  
Spleen Contraction ◽  
Response To Exercise ◽  
Rest And Exercise

Abstract Purpose Hypoxia and exercise are known to separately trigger spleen contraction, leading to release of stored erythrocytes. We studied spleen volume and hemoglobin concentration (Hb) during rest and exercise at three altitudes. Methods Eleven healthy lowlanders did a 5-min modified Harvard step test at 1370, 3700 and 4200 m altitude. Spleen volume was measured via ultrasonic imaging and capillary Hb with Hemocue during rest and after the step test, and arterial oxygen saturation (SaO2), heart rate (HR), expiratory CO2 (ETCO2) and respiratory rate (RR) across the test. Results Resting spleen volume was reduced with increasing altitude and further reduced with exercise at all altitudes. Mean (SE) baseline spleen volume at 1370 m was 252 (20) mL and after exercise, it was 199 (15) mL (P < 0.01). At 3700 m, baseline spleen volume was 231 (22) mL and after exercise 166 (12) mL (P < 0.05). At 4200 m baseline volume was 210 (23) mL and after exercise 172 (20) mL (P < 0.05). After 10 min, spleen volume increased to baseline at all altitudes (NS). Baseline Hb increased with altitude from 138.9 (6.1) g/L at 1370 m, to 141.2 (4.1) at 3700 m and 152.4 (4.0) at 4200 m (P < 0.01). At all altitudes Hb increased from baseline during exercise to 146.8 (5.7) g/L at 1370 m, 150.4 (3.8) g/L at 3700 m and 157.3 (3.8) g/L at 4200 m (all P < 0.05 from baseline). Hb had returned to baseline after 10 min rest at all altitudes (NS). The spleen-derived Hb elevation during exercise was smaller at 4200 m compared to 3700 m (P < 0.05). Cardiorespiratory variables were also affected by altitude during both rest and exercise. Conclusions The spleen contracts and mobilizes stored red blood cells during rest at high altitude and contracts further during exercise, to increase oxygen delivery to tissues during acute hypoxia. The attenuated Hb response to exercise at the highest altitude is likely due to the greater recruitment of the spleen reserve during rest, and that maximal spleen contraction is reached with exercise.

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