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.

Keywords: Cardiovascular response; Chronic mountain sickness; Genomics; High-altitude adaptation; Polycythemic response.

Fig. 1

Representative genetic interactions (as deciphered by IPA analysis) regulating biological processes and physiological functions that are involved in human adaption to high altitude. The central figure shows the complexity of the pathology linked to chronic mountain sickness. It involves various physiological responses such as erythrocyte differentiation, immune response, and response to hypoxia. Network 1 shows the gene interactions regulating post-translational modification, cell-to-cell signaling and interaction, and nervous system development and function. Network 2 shows the genetic network regulating hematological system development and function, immunological disease, and lymphoid tissue structure and development. Network 3 depicts the genetic interactions regulating cell death and survival, gene expression, and cell cycle particularly during hematopoiesis. Network 4 shows the genetic network regulating cardiovascular system development and function, tissue development, and organismal development. Color code: yellow—genes identified in Andean population, blue—genes identified in Ethiopian population, green—genes identified in Tibetan population, and red—genes identified in both Andean and Tibetan populations

Fig. 2

Convergence at the genetic level. Insert is the Venn diagram depicting the common genes shared between three HA populations. We used Genemania v3.4.1 app on Cytospace v3.4.0. The network is based on the common gene (n = 64) that are shared at least in two populations. We restrict our analysis to Homo sapiens and options restricted to finding top 20 related genes with automatic weighting process. The color in each node depict the HA population from which the particular gene is reportedly found associated

Fig. 3

Convergence in the major biological processes. Anticipating the predominant role of biological processes involved in hypoxia response, e.g., circulatory system (GO: 0003013), angiogenesis (GO: 0001525), erythrocyte homeostasis (GO: 0034101), and O₂ transport (GO: 0015671), the HA selected genes involved in these specific GO classes were picked for network analysis from Gene Ontology Consortium (geneontology.org). The Venn diagram (except “oxygen transport” (GO: 0005344) because there were only 13 genes in this GO category and 5 were common) depicts the common gene(s) shared between HA candidate genes and the respective GO category’s gene list. The probability of gene enrichment at HA for these GO categories was significant (Fisher’s exact test P < 0.001). We used Genemania v3.4.1 app on Cytospace v3.4.0. Each network is restricted to Homo sapiens with weighting process only related to GO biological process-based

Fig. 4

Convergence at erythropoietic response and cardiovascular system. a Genes that were mined from high-altitude studies that have been involved in erythropoiesis. There is regulation at multiple time points of erythroid maturation and differentiation by various genes shown in the figure. The genes found in various populations are color-coded. Blue—Tibetan, red—Andean, orange—genes found in both Andean and Tibetan, and purple—Ethiopian population. b Cardiovascular homeostasis at HA primarily depends on the vasoconstriction and vasodilation response to hypoxia. Important genes from RAAS (ACE, AGT, and AGTR1), endothelin pathway (EDN1, EDNRA, and EDNRB), and the three NOS isoforms (NOS1, NOS2, and NOS3) involved in NO signaling pathway are all reported in different HA population studies