title: Genetic adaptation to high altitude in the Ethiopian highlands.
abstract: BACKGROUND
  Genomic analysis of high-altitude populations residing in the Andes and Tibet has revealed several candidate loci for involvement in high-altitude adaptation, a subset of which have also been shown to be associated with hemoglobin levels, including EPAS1, EGLN1, and PPARA, which play a role in the HIF-1 pathway. Here, we have extended this work to high- and low-altitude populations living in Ethiopia, for which we have measured hemoglobin levels. We genotyped the Illumina 1M SNP array and employed several genome-wide scans for selection and targeted association with hemoglobin levels to identify genes that play a role in adaptation to high altitude.
  
  
  RESULTS
  We have identified a set of candidate genes for positive selection in our high-altitude population sample, demonstrated significantly different hemoglobin levels between high- and low-altitude Ethiopians and have identified a subset of candidate genes for selection, several of which also show suggestive associations with hemoglobin levels.
  
  
  CONCLUSIONS
  We highlight several candidate genes for involvement in high-altitude adaptation in Ethiopia, including CBARA1, VAV3, ARNT2 and THRB. Although most of these genes have not been identified in previous studies of high-altitude Tibetan or Andean population samples, two of these genes (THRB and ARNT2) play a role in the HIF-1 pathway, a pathway implicated in previous work reported in Tibetan and Andean studies. These combined results suggest that adaptation to high altitude arose independently due to convergent evolution in high-altitude Amhara populations in Ethiopia.
authors.affiliation: Department of Genetics, University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Scheinfeldt
authors.forename: Sameer
authors.initials: S
authors.lastname: Soi
authors.forename: Simon
authors.initials: S
authors.lastname: Thompson
authors.forename: Alessia
authors.initials: A
authors.lastname: Ranciaro
authors.forename: Dawit
authors.initials: D
authors.lastname: Woldemeskel
authors.forename: William
authors.initials: W
authors.lastname: Beggs
authors.forename: Charla
authors.initials: C
authors.lastname: Lambert
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Jarvis
authors.forename: Dawit
authors.initials: D
authors.lastname: Abate
authors.forename: Gurja
authors.initials: G
authors.lastname: Belay
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Tishkoff
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics*; D000531:Altitude; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics; D005002:Ethiopia; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006454:Hemoglobins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics; D037042:Thyroid Hormone Receptors beta / Q000235:genetics
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins; D006454:Hemoglobins; D033681:Mitochondrial Membrane Transport Proteins; D051567:Proto-Oncogene Proteins c-vav; D037042:Thyroid Hormone Receptors beta; C490989:ARNT2 protein, human; C116241:MICU1 protein, human; C496621:VAV3 protein, human