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Am J Hum Genet. 2017 Nov 2;101(5):752-767. doi: 10.1016/j.ajhg.2017.09.023.

Natural Selection on Genes Related to Cardiovascular Health in High-Altitude Adapted Andeans.

Author information

1
Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94702, USA.
2
Director, Cell Biology Unit, Medical School, San Andres University, La Paz, Bolivia.
3
Department of Medicine, University of Utah Health Center and Veterans Affairs Medical Center, Salt Lake City, UT, 84123, USA.
4
Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
5
Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94702, USA; Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Oster Voldgade 5-7, Copenhagen 1350, Denmark.
6
Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90502, USA.
7
Department of Cardiology, Johns Hopkins University, 600 North Wolfe Street, Baltimore, MD 21205, USA.
8
Department of Obstetrics and Gynecology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA.
9
Department of Medicine, University of Utah Health Center and Veterans Affairs Medical Center, Salt Lake City, UT, 84123, USA. Electronic address: josef.prchal@hsc.utah.edu.
10
Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94702, USA; Museum of Natural History, University of Copenhagen, Øster Voldgade 5-7, 1350 Copenhagen, Denmark; Department of Statistics, University of California, Berkeley, Berkeley, CA 94702, USA. Electronic address: rasmus_nielsen@berkeley.edu.

Abstract

The increase in red blood cell mass (polycythemia) due to the reduced oxygen availability (hypoxia) of residence at high altitude or other conditions is generally thought to be beneficial in terms of increasing tissue oxygen supply. However, the extreme polycythemia and accompanying increased mortality due to heart failure in chronic mountain sickness most likely reduces fitness. Tibetan highlanders have adapted to high altitude, possibly in part via the selection of genetic variants associated with reduced polycythemic response to hypoxia. In contrast, high-altitude-adapted Quechua- and Aymara-speaking inhabitants of the Andean Altiplano are not protected from high-altitude polycythemia in the same way, yet they exhibit other adaptive features for which the genetic underpinnings remain obscure. Here, we used whole-genome sequencing to scan high-altitude Andeans for signals of selection. The genes showing the strongest evidence of selection-including BRINP3, NOS2, and TBX5-are associated with cardiovascular development and function but are not in the response-to-hypoxia pathway. Using association mapping, we demonstrated that the haplotypes under selection are associated with phenotypic variations related to cardiovascular health. We hypothesize that selection in response to hypoxia in Andeans could have vascular effects and could serve to mitigate the deleterious effects of polycythemia rather than reduce polycythemia itself.

KEYWORDS:

Andean; Aymara; adaptation; high altitude; hypoxia; natural selection

PMID:
29100088
PMCID:
PMC5673686
DOI:
10.1016/j.ajhg.2017.09.023
[Indexed for MEDLINE]
Free PMC Article

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