UC San Diego

Associations between genetic factors and physical characteristics of populations living more than 3500 m above sea level have been of long-standing interest in studies of high-altitude adaptation. Many present-day highlanders whose ancestors occupied Andean Altiplano have adapted to challenging environmental conditions over many generations, and yet some lack adaptation to this harsh environment. Those who lack adaptations to the hypoxic conditions caused by high-altitude may suffer with health conditions such as chronic mountain sickness (CMS). Recent technological and analytical advancements have pushed forward efforts to identify the molecular mechanisms that dictate the human’s ability to adapt to high-altitude environments, and recent studies suggest the ability to adapt to high-altitude, at least in part, may be due to epigenetic modifications. Epigenetics is the study of heritable changes acquired through lifestyle and environmental factors that play a role in gene expression without altering DNA sequence. DNA methylation is a type of epigenetic modification that involves the attachment of a methyl group to a part of the DNA molecule. The EPAS1 and EGLN1 genes both play key roles in modulating oxygen levels in the hypoxia inducible factor (HIF) pathway and are reported as top targets of selection in both Tibetan and Andean populations, and epigenetic modifications are known to impact the regulation of these genes. Genome-wide epigenetic profiling and targeted bisulfite methylation studies are techniques recently implemented in studies aimed at identifying DNA methylation markers that might explain the differences in altitude-adapted and -maladapted highlanders involving these and other genes.