The Genetic Architecture of Adaptations to High Altitude in Ethiopia

Abstract

Although hypoxia is a major stress on physiological processes, several human populations have survived for millennia at high altitudes, suggesting that they have adapted to hypoxic conditions. This hypothesis was recently corroborated by studies of Tibetan highlanders, which showed that polymorphisms in candidate genes show signatures of natural selection as well as well-replicated association signals for variation in hemoglobin levels. We extended genomic analysis to two Ethiopian ethnic groups: Amhara and Oromo. For each ethnic group, we sampled low and high altitude residents, thus allowing genetic and phenotypic comparisons across altitudes and across ethnic groups. Genome-wide SNP genotype data were collected in these samples by using Illumina arrays. We find that variants associated with hemoglobin variation among Tibetans or other variants at the same loci do not influence the trait in Ethiopians. However, in the Amhara, SNP rs10803083 is associated with hemoglobin levels at genome-wide levels of significance. No significant genotype association was observed for oxygen saturation levels in either ethnic group. Approaches based on allele frequency divergence did not detect outliers in candidate hypoxia genes, but the most differentiated variants between high- and lowlanders have a clear role in pathogen defense. Interestingly, a significant excess of allele frequency divergence was consistently detected for genes involved in cell cycle control and DNA damage and repair, thus pointing to new pathways for high altitude adaptations. Finally, a comparison of CpG methylation levels between high- and lowlanders found several significant signals at individual genes in the Oromo. Although hypoxia is a major stress on physiological processes, several human populations have survived for millennia at high altitudes, suggesting that they have adapted to hypoxic conditions. Consistent with this idea, previous studies have identified genetic variants in Tibetan highlanders associated with reduction in hemoglobin levels, an advantageous phenotype at high altitude. To compare the genetic bases of adaptations to high altitude, we collected genetic and epigenetic data in Ethiopians living at high and low altitude, respectively. We find that variants associated with hemoglobin variation among Tibetans or other variants at the same loci do not influence the trait in Ethiopians. However, we find a different variant that is significantly associated with hemoglobin levels in Ethiopians. Approaches based on the difference in allele frequency between high- and lowlanders detected strong signals in genes with a clear role in defense from pathogens, consistent with known differences in pathogens between altitudes. Finally, we found a few genome-wide significant epigenetic differences between altitudes. These results taken together imply that Ethiopian and Tibetan highlanders adapted to the same environmental stress through different variants and genetic loci.