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Whole genome sequencing of Ethiopian highlanders reveals conserved hypoxia tolerance genes

Nitin Udpa1, Roy Ronen1, Dan Zhou2, Junbin Liang3, Tsering Stobdan2, Otto Appenzeller4, Ye Yin5, Yuanping Du5, Lixia Guo3, Rui Cao3, Yu Wang5, Xin Jin3, Chen Huang5, Wenlong Jia3, Dandan Cao3, Guangwu Guo3, Victoria E Claydon6, Roger Hainsworth7, Jorge L Gamboa8, Mehila Zibenigus9, Guta Zenebe9, Jin Xue2, Siqi Liu10, Kelly A Frazer11, Yingrui Li5, Vineet Bafna12 and Gabriel G Haddad13142*

  • * Corresponding author: Gabriel G Haddad

  • † Equal contributors

Author Affiliations

1 Bioinformatics & Systems Biology Graduate Program, University of California San Diego, La Jolla, California 92093, USA

2 Department of Pediatrics, Division of Respiratory Medicine, University of California San Diego, La Jolla, California 92093, USA

3 BGI-Americas, Cambridge, Massachusetts 02142, USA

4 Department of Neurology, New Mexico Health Enhancement and Marathon Clinics Research Foundation, Albuquerque, New Mexico 87122, USA

5 BGI-Shenzhen, Shenzhen 518083, China

6 Department of Biomedical Physiology and Kinesiology, Faculty of Science, Simon Fraser University, British Columbia, Canada V5A 16S

7 Division of Cardiovascular and Neuronal Remodeling, Faculty of Medicine, University of Leeds, Leeds LS2 9JT, UK

8 Division of Clinical Pharmacology/Department of Medicine, Vanderbilt University Medical Center, Tennessee 37232, USA

9 Department of Medicine, Yehuleshet Higher clinic, University of Addis Ababa, Addis Ababa 1176, Ethiopia

10 Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100029, China

11 Department of Pediatrics, Division of Genome Information Science, University of California San Diego, La Jolla, California 92093, USA

12 Department of Computer Science and Engineering, University of California San Diego, La Jolla, California 92093, USA

13 Department of Neurosciences, University of California San Diego, La Jolla, California 92093, USA

14 Rady Children’s Hospital, San Diego, California 92123, USA

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Genome Biology 2014, 15:R36  doi:10.1186/gb-2014-15-2-r36

Published: 20 February 2014



Although 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.


We 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.


Our 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.