Abstract
BackgroundAlthough it has long been proposed that genetic factors contribute to adaptation to high altitude, such factors remain largely unverified. Recent advances in high-throughput sequencing have made it feasible to analyze genome-wide patterns of genetic variation in human populations. Since traditionally such studies surveyed only a small fraction of the genome, interpretation of the results was limited.ResultsWe report here the results of the first whole genome resequencing-based analysis identifying genes that likely modulate high altitude adaptation in native Ethiopians residing at 3,500 m above sea level on Bale Plateau or Chennek field in Ethiopia. Using cross-population tests of selection, we identify regions with a significant loss of diversity, indicative of a selective sweep. We focus on a 208 kbp gene-rich region on chromosome 19, which is significant in both of the Ethiopian subpopulations sampled. This region contains eight protein-coding genes and spans 135 SNPs. To elucidate its potential role in hypoxia tolerance, we experimentally tested whether individual genes from the region affect hypoxia tolerance in Drosophila. Three genes significantly impact survival rates in low oxygen: cic, an ortholog of human CIC, Hsl, an ortholog of human LIPE, and Paf-AHα, an ortholog of human PAFAH1B3.ConclusionsOur study reveals evolutionarily conserved genes that modulate hypoxia tolerance. In addition, we show that many of our results would likely be unattainable using data from exome sequencing or microarray studies. This highlights the importance of whole genome sequencing for investigating adaptation by natural selection.
Highlights
It has long been proposed that genetic factors contribute to adaptation to high altitude, such factors remain largely unverified
It has been suggested that the Ethiopians are better adapted to these conditions, as they show the least evidence of chronic mountain sickness (CMS), a high altitude syndrome that exists in other populations, especially the Andeans [5]
Our study identifies a number of candidate genes for hypoxia tolerance that were not previously reported
Summary
It has long been proposed that genetic factors contribute to adaptation to high altitude, such factors remain largely unverified. Recent advances in high-throughput sequencing have made it feasible to analyze genome-wide patterns of genetic variation in human populations. Since traditionally such studies surveyed only a small fraction of the genome, interpretation of the results was limited. Previous studies suggest that the three large high altitude populations (that is, Andeans, Himalayans, and Ethiopians) have each adapted uniquely to cope with their inhospitable hypoxic environments [3,4]. Recent advances in high-throughput sequencing technologies have made it feasible to analyze patterns of genetic variation in human populations across the entire genome. Several genomic scans for natural selection have been performed in high altitude populations (for instance, [8,9,10,11,12,13,14,15]); as these studies either focused on a priori candidate genes, or assayed small portions of the genome (exons or a subset of genotyped SNPs), there is likely much yet to be deciphered
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