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High-altitude adaptation of Tibetans represents a remarkable case of natural selection during recent human evolution. Previous genome-wide scans found many non-coding variants under selection, suggesting a pressing need to understand the functional role of non-coding regulatory elements (REs). Here, we generate time courses of paired ATAC-seq and RNA-seq data on cultured HUVECs under hypoxic and normoxic conditions. We further develop a variant interpretation methodology (vPECA) to identify active selected REs (ASREs) and associated regulatory network. We discover three causal SNPs of EPAS1, the key adaptive gene for Tibetans. These SNPs decrease the accessibility of ASREs with weakened binding strength of relevant TFs, and cooperatively down-regulate EPAS1 expression. We further construct the downstream network of EPAS1, elucidating its roles in hypoxic response and angiogenesis. Collectively, we provide a systematic approach to interpret phenotype-associated noncoding variants in proper cell types and relevant dynamic conditions, to model their impact on gene regulation.

The cardiopulmonary system is a physiological cornerstone in the adaptive response to hypobaric hypoxia. Portable devices make it feasible nowadays to precisely assess the response to high altitude (HA) expeditions. In this study, we investigated breathing and arterial blood pressure responses during a Himalayan trek from 665 m to 4,780 m altitude in a white European (Italian) sojourner and a native Nepali (Tamang) guide, both healthy males. Resting diurnal and nocturnal data were acquired by means of ambulatory blood pressure monitoring (ABPM) and sleep apnea monitoring. We found an increase in the mean diurnal arterial blood pressure. Nocturnal blood pressure dipping was confirmed at all altitudes. Oxygen saturation decreased at altitude, with its additional nocturnal fall. Sleep apneic episodes, present in the Italian only, increased with altitude. We conclude that the nocturnal, more than diurnal, cardiorespiratory function is affected by HA hypoxia. Further studies should address the role of ethnicity, medications, and sociodemographic factors in the cardiorespiratory responses to hypobaric hypoxia., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Medical problems occur at high altitude because of the low inspired Po(2), which is caused by the reduced barometric pressure. The classical physiological responses to high altitude include hyperventilation, polycythemia, hypoxic pulmonary vasoconstriction-increased intracellular oxidative enzymes, and increased capillary density in muscle. However, with the discovery of hypoxia-inducible factors (HIFs), it is apparent that there is a multitude of responses to cellular hypoxia. HIFs constitute a master switch determining the general response of the body to oxygen deprivation. The recent discovery of genetic changes in Tibetans has opened up an exciting area of research. The two major human populations that have adapted well to high altitude, the Tibetans and Andeans, have strikingly different phenotypes. Diseases of lowlanders going to high altitude include acute mountain sickness, high-altitude pulmonary edema, and high-altitude cerebral edema. Diseases affecting permanent residents or highlanders include chronic mountain sickness and high-altitude pulmonary hypertension. Important recent advances have been made on mitigation of the effects of the hypoxic environment. Oxygen enrichment of room air is very powerful. Every 1% increase in oxygen concentration reduces the equivalent altitude by about 300 m. This procedure is used in numerous facilities at high altitude and in a Chinese train to Lhasa. An alternative strategy is to increase the barometric pressure as in aircraft cabins. A hybrid approach combining both strategies shows promise but has never been used. Mines that are being developed at increasingly high altitudes pose great medical problems.

About 30 million people live above 2500 m in the Andean Mountains of South America. Among them are 5.5 million Aymaras, an ethnic group with its own language, living on the altiplano of Bolivia, Peru, and northern Chile at altitudes of up to 4400 m. In this high altitude region traces of human population go back for more than 2000 years with constant evolutionary pressure on its residents for genetic adaptation to high altitude. Aymaras as the assumed direct descendents of the ancient cultures living in this region were the focus of much research interest during the last decades and several distinctive adaptation patterns to life at high altitude have been described in this ethnic group. The aim of this article was to review the physiology and pathophysiology of circulatory adaptation and maladaptation to longtime altitude exposure in Aymaras and Caucasians.

Since the beginning of the Himalayan climbing era, the anecdotal extraordinary physical performance at high altitude of Sherpas and Tibetans has intrigued scientists interested in altitude adaptation. These ethnic groups may have been living at high altitude for longer than any other population, and the hypothesis of a possible evolutionary genetic adaptation to altitude makes sense. Reviewed here is the evidence as to whether Tibetans are indeed better adapted for life and work at high altitude as compared to other populations and, if so, whether this better adaptation might be inborn. Tibetans, compared to lowlanders, maintain higher arterial oxygen saturation at rest and during exercise and show less loss of aerobic performance with increasing altitude. Tibetans have greater hypoxic and hypercapnic ventilatory responsiveness, larger lungs, better lung function, and greater lung diffusing capacity than lowlanders. Blood hemoglobin concentration is lower in Tibetans than in lowlanders or Andeans living at similar altitudes. Tibetans develop only minimal hypoxic pulmonary hypertension and have higher levels of exhaled nitric oxide than lowlanders or Andeans. Tibetans' sleep quality at altitude is better and they desaturate less at night. Several of these findings are also found in Tibetans born at low altitude when exposed for the first time to high altitude once adult. In conclusion, Tibetans indeed seem better adapted to life and work at high altitude, and this superior adaptation may very well be inborn, even though its exact genetic basis remains to be elucidated.

Background and Purpose: Andean highlanders, unlike Ethiopians, develop chronic mountain sickness (CMS), a maladaptation to their native land. Ambient hypoxia induces NO-mediated vasodilatation. Fitness for life at altitude might be revealed by cerebrovascular responses to NO., Methods: Nine altitude-native men were examined at 3622 and 794 m in Ethiopia and compared with 9 altitude-native Andean men tested at 4338 and 150 m in Peru. We assessed CMS scores, hematocrits, end-tidal pressure of carbon dioxide (P(ET)co2), oxygen saturations, and cerebral blood flow velocity (CBV). We evaluated fitness for life at altitude from the cerebrovascular response to an exogenous NO donor., Results: At high altitude, CMS scores and hematocrits were higher in Andeans, and they had lower oxygen saturations. Ethiopians had higher P(ET)co2 at all study sites. At low altitude, saturations were similar in both groups. Responsiveness of the cerebral circulation to NO was minimal in Ethiopians at low altitude, whereas Andeans had a large response. In contrast, at high altitude, Ethiopians showed large responses, and Peruvians had minimal responses., Conclusions: By our measure, high altitude-native Peruvians were well-adapted lowlanders, whereas Ethiopian highlanders were well adapted to altitude life. Environmental pressures were sufficient for human adaptation to chronic hypoxia in Africa but not South America. The mechanisms underlying these differences are unknown, although studies of neurovascular diseases suggest that this may be related to a NO receptor polymorphism.

For the male inhabitants of La Paz, Bolivia (3200-4100 m), and other high altitude regions in America and Asia, chronic mountain sickness (CMS) is a major health problem. Since CMS was first described by Carlos Monge in the Peruvian Andes in 1925, numerous research papers have been devoted to this topic, but many unanswered questions still exist with respect to the beginning of the disease and its cause(s). The experience with CMS has shown that an excessively high hemoglobin concentration is not favorable for high altitude acclimatization, and the hypothesis of theoretically "optimal" hematocrit and "optimal" hemoglobin has been made. The calculated optimal hemoglobin concentration of 14.7 g/dL for resting men in the Andes is discussed as theoretical and not applicable in real life. The most frequent congenital and acquired heart diseases are discussed, such as patent ductus, atrial septum defect, ventricle septum defect among congenital heart diseases and the still very frequent rheumatic valve cardiopathies and Chagas disease as acquired cardiopathies. Among the typical acquired heart diseases of the high altitude dweller, special attention is given to chronic cor pulmonale as a consequence of severe CMS with pulmonary hypertension.

Highland population (HA) from the Andes, living above 3000 m, have a blunted ventilatory response to increasing hypoxia, breathe less compared to acclimatized newcomers, but more, compared to sea-level natives at sea level. Subjects with chronic mountain sickness (CMS) breathe like sea-level natives and have excessive erythrocytosis (EE). The respiratory stimulation that arises through the peripheral chemoreflex is modestly less in the CMS group when compared with the HA group at the same P(ET(O2)). With regard to CO(2) sensitivity, CMS subjects seem to have reset their central CO(2) chemoreceptors to operate around the sea-level resting P(ET(CO2)). Acetazolamide, an acidifying drug that increases the chemosensitivity of regions in the brain stem that contain CO(2)/H(+) sensitive neurons, partially reverses this phenomenon, thus, providing CMS subjects with the possibility to have high CO(2) changes, despite small changes in ventilation. However, the same type of adjustments of the breathing pattern established for Andeans has not been found necessarily in Asian humans and/or domestic animals nor in the various high altitude species studied. The differing time frames of exposure to hypoxia among the populations, as well as the reversibility of the different components of the respiratory process at sea level, provide key concepts concerning the importance of time at high altitude in the evolution of an appropriate breathing pattern.