Abstract
BackgroundGenomic 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.ResultsWe 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.ConclusionsWe 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.
Highlights
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 been shown to be associated with hemoglobin levels, including EPAS1, EGLN1, and PPARA, which play a role in the hypoxia inducible factor (HIF)-1 pathway
Genome-wide tests of neutrality We were interested in identifying the subset of single nucleotide polymorphism (SNP) that were highly differentiated between the Amhara and Omotic population samples, because these SNPs are likely to be enriched for variants (or to be in linkage disequilibrium (LD) with variants) that have been subjected to regionally restricted positive selection
While PPARA was identified as a target of selection in our Ethiopian population sample, we have identified several additional candidate genes for involvement in high-altitude adaptation in the Amhara, two of which play a role in the HIF-1 pathway
Summary
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 been shown to be associated with hemoglobin levels, including EPAS1, EGLN1, and PPARA, which play a role in the HIF-1 pathway. 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. Concentrations of hemoglobin are elevated in highaltitude Andean populations relative to high-altitude Asian and African populations as well as low-altitude populations, and oxygen saturation is reduced in high-altitude Andeans as well as in Tibetans (who do not have increased hemoglobin levels) [4]. Physiological traits that reduce hypoxic stress, and the underlying genetic factors influencing these traits, are likely to be common in long-term high-altitude residents
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