High-altitude adaptation in humans: from genomics to integrative physiology

Abstract

About 1.2 to 33% of high-altitude populations suffer from Monge's disease or chronic mountain sickness (CMS). Number of factors such as age, sex, and population of origin (older, male, Andean) contribute to the percentage reported from a variety of samples. It is estimated that there are around 83 million people who live at altitudes > 2500 m worldwide and are at risk for CMS. In this review, we focus on a human "experiment in nature" in various high-altitude locations in the world-namely, Andean, Tibetan, and Ethiopian populations that have lived under chronic hypoxia conditions for thousands of years. We discuss the adaptive as well as mal-adaptive changes at the genomic and physiological levels. Although different genes seem to be involved in adaptation in the three populations, we can observe convergence at genetic and signaling, as well as physiological levels. What is important is that we and others have shown that lessons learned from the genes mined at high altitude can be helpful in better understanding and treating diseases that occur at sea level. We discuss two such examples: EDNRB and SENP1 and their role in cardiac tolerance and in the polycythemic response, respectively.

Mitochondrial dysfunction in iPSC-derived neurons of subjects with chronic mountain sickness

“…Over the past two decades, CMS research has shifted from physiology to genetics with the development of new technologies such as microarrays and genome sequencing. Although genetic signature of highaltitude adaptation has been demonstrated through many studies (2,28), our understanding of CMS pathology at the cellular level is still lagging behind because of the lack of human samples and study techniques. The availability of induced pluripotent stem cell technology can now help to overcome these limitations.…”

“…And 3) are the changes observed in CMS cells as a result of hypoxia, inherent properties of the cells, or other types of stresses of high altitude? To address such questions, we should highlight the context and background of the research that we have undertaken for the past several years (2,3,18,29,32,36,37,42,48,50,51). In particular, we have done a large number of whole genome sequencing on high-altitude dwellers to investigate genetic differences between CMS and non-CMS (32,51).…”

Novel insight into the genetic basis of high-altitude pulmonary hypertension in Kyrgyz highlanders

“…When describing 'adaptation/mal-adaptation to HA' in Kyrgyz highlanders, it is important to distinguish this unique population from the rest of the HA populations, i.e., Ethiopians, Tibetans and Andeans. Studies conducted on the other three HA populations successfully identified different physiological and genetic modes of adaptation, some common across populations [12] and others exclusive to one population [6]. However, very few studies have been conducted on Kyrgyz highlanders where the studies are either focused on single gene/single variant, i.e., Angiotensin-Converting Enzyme Insertion/Deletion polymorphism [3], or on using whole-exome sequencing [13].…”

Natural Climbers: Insights from Avian Physiology at High Altitude

“…First, those that are fixed as the result of generations of adaptation (the process of selection pressures increasing the expression of genes that alter physical or behavioral features at a species or population level) (Willmer et al, 2005). For example, some human populations have adapted to life at high altitude, and these adaptations vary with respect to geographical origin (e.g., Tibetan vs. Andean people, see reviews elsewhere; Beall, 2007;Azad et al, 2017). Second, short-term phenotypically plastic responses (referred to as ''acute hypoxia responses'' from now on), which are almost instantaneous responses to hypoxia exposure, but are usually temporary and reversible (Piersma and van Gils, 2011).…”