Genetics of Adaptation to High Altitude


From the initial observation of Monge on the Andeans in the 1920s, polycythaemia and elevated haemoglobin (Hb) were considered the universal response to life at high altitude. However, this response is maladaptive, as excessive polycythaemia leads to the potentially lethal ‘chronic mountain sickness’. Highlanders in Tibet and Ethiopia revealed different phenotypes with Hb levels similar to those of sea‐level populations. Genome‐wide search for gene selection in these highlanders pointed on candidate genes encoding proteins belonging or closely related to the hypoxia‐inducible transcription factors (HIF) pathway. However, each population exhibits distinct sets of candidate genes suggesting convergent evolution on a candidate pathway rather than candidate genes. Complexity of the candidate genes in each population suggests that altering the HIF pathway globally needs to be balanced by other changes rescuing essential hypoxia‐regulated downstream processes. These observations open new avenues of investigations to uncover the molecular bases of adaptation to hypoxia that could also improve our understanding of common hypoxia‐induced maladies in lowlanders.

Key Concepts:

  • Moving out of Africa, man has colonised a very diverse array of environments including high altitude.

  • The three most dramatic examples of long‐term high‐altitude residence are populations of the Andean Altiplano, the Tibetan plateau and the Ethiopian highlands.

  • Highland populations have to cope with hypobaric hypoxia and cold and still maintain exercise, energetic metabolism and reproductive success.

  • Based on the pioneer observation of Dr Carlos Monge on the Andean populations, polycythaemia and increased haemoglobin level have been considered the universal adaptive response to high‐altitude hypoxia for more than half a century.

  • Tibetan and Ethiopian highlanders exhibit haemoglobin level comparable to sea‐level residents; thus elevated haemoglobin is not the universal response to hypoxia.

  • Genome‐wide search for adaptive genes in the three paradigmal highland populations identified largely distinct patterns in each population, but converging towards the hypoxia‐inducible transcription factors (HIF) pathway.

  • Analysis of genetic adaptation to high altitude in man expands the concept of converging evolution from candidate genes to candidate pathways.

  • Complexity of the candidate genes in each highland population suggests that altering the central HIF‐mediated hypoxic signalling pathway globally may need to be balanced by other changes rescuing essential hypoxia‐regulated downstream processes.

Keywords: high altitude; genetics; hypoxia‐inducible factor; evolution

Figure 1.

World map showing the regions of extensive land area >2500 m (shaded). Red areas are regions >3500 m where the populations have been studied for their adaptation to high altitude. The phenotypic pattern of adaptation clearly varies in these different population groups.

Figure 2.

Hypoxia‐inducible factors pathway. HIFs are O2‐sensitive transcriptional activators composed of two α‐ and β‐subunits. HIF function is primarily regulated by the α subunits. Under normoxic conditions, these subunits are hydroxylated by PHDs, combine with the von Hippel–Lindau (VHL) complex and are targeted to the proteasome for degradation via the ubiquitin (Ub)‐mediated pathway. Alternatively, they can be hydroxylated by an asparagyl hydroxylase, the factor inhibiting HIF‐1 (FIH‐1) in its transactivation domain, leading to its inactivation. Both PDHs and FIH‐1 are oxygen‐dependent ferrous ion (Fe+2) deoxygenases and function as oxygen‐sensing enzymes. Under hypoxic conditions, the α and β HIF subunits assemble, bind to (HRE), recruit members of the CBP/p300 transcriptional co‐activator family, and activate the transcription of about a large number of target genes, including that encoding erythropoietin.



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Further Reading

Cheviron ZA and Brumfield RT (2012) Genomic insights into adaptation to high‐altitude environments. Heredity (Edinb) 108(4): 354–361.

MacInnis MJ and Rupert JL (2011) ‘ome on the range: altitude adaptation, positive selection, and Himalayan genomics. High Altitude Medical Biology 12(2): 133–139.

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Labie, Dominique, and Elion, Jacques(Jun 2012) Genetics of Adaptation to High Altitude. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023850]