Adaptation to High Altitude: Does It Teach Us about the Pathobiology of Hypoxia at Sea Level?

Adaptation to High Altitude: Does it Teach us About the Pathobiology of Hypoxia at Sea Level?

 

Gabriel G. Haddad, MD. University of California, San Diego and Rady Children’s Hospital, San Diego

 

BACKGROUND: Chronic mountain sickness (CMS) is a disease that affects many high-altitude dwellers, particularly in the Andean Mountains in South America. The hallmark symptom of CMS is polycythemia, which causes increased risk of pulmonary hypertension and stroke (among other symptoms). A prevailing hypothesis in high-altitude medicine is that CMS results from a population-specific "maladaptation" to the hypoxic conditions at high altitude. In contrast, the prevalence of CMS is very low in other high-altitude populations (e.g., Tibetans and Ethiopians), which are seemingly well adapted to hypoxia. In recent years, concurrent with the advent of genomic technologies, several studies have investigated the genetic basis of adaptation to altitude. These studies have identified several candidate genes that may underlie the adaptation, or maladaptation. 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.

RESULTS:  We report here the results of the first whole genome re-sequencing-based analysis identifying genes that likely modulate high altitude adaptation in native Ethiopians residing at 3,500 m above sea level. 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. It 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 and mice.

CONCLUSIONS: Our study reveals evolutionarily conserved genes that modulate hypoxia tolerance. In addition, we show that genes that are important at high altitude are also important at sea level presumably in conditions that have hypoxia as part of their pathophysiologic etiology.