@article{fd887be389a940618493bfd64c514f20,
title = "Natural Selection on Genes Related to Cardiovascular Health in High-Altitude Adapted Andeans",
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",
author = "Crawford, {Jacob E.} and Ricardo Amaru and Jihyun Song and Julian, {Colleen G.} and Fernando Racimo and Cheng, {Jade Yu} and Xiuqing Guo and Jie Yao and Bharath Ambale-Venkatesh and Lima, {Jo{\~a}o A.} and Rotter, {Jerome I.} and Josef Stehlik and Moore, {Lorna G.} and Prchal, {Josef T.} and Rasmus Nielsen",
note = "Funding Information: For the Colorado cohort, we thank the Instituto Boliviano de Biologia de Altura investigators and the local physicians and other health-care personnel who helped with the study, the many subjects who generously participated, and grant support from the NIH ( HLBI 079647 and TW 001188 ). The Multi-Ethnic Study of Atherosclerosis (MESA) is supported by NIH contracts HHSN2682015000031 , N01-HC-95159 , N01-HC-95160 , N01-HC-95161 , N01-HC-95162 , N01-HC-95163 , N01-HC-95164 , N01-HC-95165 , N01-HC-95166 , N01-HC-95167 , N01-HC-95168 , and N01-HC-95169 and by grants UL1-TR-000040 , UL1-TR-001079 , and UL1-RR-025005 from the National Center for Research Resources . Funding for MESA SHARe genotyping was provided by NHLBI contract N02-HL-6-4278 . The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences , the Clinical and Translational Science Institute (grant UL1TR000124 ), and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (grant DK063491 to the Southern California Diabetes Endocrinology Research Center). We also thank two anonymous reviewers for their comments, which helped to improve the manuscript. Publisher Copyright: {\textcopyright} 2017",
year = "2017",
month = nov,
day = "2",
doi = "10.1016/j.ajhg.2017.09.023",
language = "English (US)",
volume = "101",
pages = "752--767",
journal = "American journal of human genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "5",
}