title: Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data.
abstract: High-altitude hypoxia (reduced inspired oxygen tension due to decreased barometric pressure) exerts severe physiological stress on the human body. Two high-altitude regions where humans have lived for millennia are the Andean Altiplano and the Tibetan Plateau. Populations living in these regions exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. Although these responses have been well characterized physiologically, their underlying genetic basis remains unknown. We performed a genome scan to identify genes showing evidence of adaptation to hypoxia. We looked across each chromosome to identify genomic regions with previously unknown function with respect to altitude phenotypes. In addition, groups of genes functioning in oxygen metabolism and sensing were examined to test the hypothesis that particular pathways have been involved in genetic adaptation to altitude. Applying four population genetic statistics commonly used for detecting signatures of natural selection, we identified selection-nominated candidate genes and gene regions in these two populations (Andeans and Tibetans) separately. The Tibetan and Andean patterns of genetic adaptation are largely distinct from one another, with both populations showing evidence of positive natural selection in different genes or gene regions. Interestingly, one gene previously known to be important in cellular oxygen sensing, EGLN1 (also known as PHD2), shows evidence of positive selection in both Tibetans and Andeans. However, the pattern of variation for this gene differs between the two populations. Our results indicate that several key HIF-regulatory and targeted genes are responsible for adaptation to high altitude in Andeans and Tibetans, and several different chromosomal regions are implicated in the putative response to selection. These data suggest a genetic role in high-altitude adaption and provide a basis for future genotype/phenotype association studies necessary to confirm the role of selection-nominated candidate genes and gene regions in adaptation to altitude.
authors.affiliation: Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania, United States of America. awb150@u.washington.edu
authors.forename: Abigail
authors.initials: A
authors.lastname: Bigham
authors.forename: Marc
authors.initials: M
authors.lastname: Bauchet
authors.forename: Dalila
authors.initials: D
authors.lastname: Pinto
authors.forename: Xianyun
authors.initials: X
authors.lastname: Mao
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Akey
authors.forename: Rui
authors.initials: R
authors.lastname: Mei
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.forename: Colleen G
authors.initials: CG
authors.lastname: Julian
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Wilson
authors.forename: David
authors.initials: D
authors.lastname: López Herráez
authors.forename: Tom
authors.initials: T
authors.lastname: Brutsaert
authors.forename: Esteban J
authors.initials: EJ
authors.lastname: Parra
authors.forename: Lorna G
authors.initials: LG
authors.lastname: Moore
authors.forename: Mark D
authors.initials: MD
authors.lastname: Shriver
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D000531:Altitude; D056915:DNA Copy Number Variations / Q000235:genetics; D030541:Databases, Genetic; D020869:Gene Expression Profiling; D005828:Genetics, Population; D015894:Genome, Human / Q000235:genetics*; D005843:Geography; D005914:Globins / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics; D012641:Selection, Genetic; D013020:South America; D018609:Tibet
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D005914:Globins; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases