High-Altitude Living Rewires Gene Regulation: Whole-Methylome Study of Andean Highlanders

High in the Ecuadorian Andes, thousands of meters above sea level, people face a unique combination of environmental stresses: thinner air, lower oxygen availability and stronger ultraviolet radiation. New research shows these conditions are associated with widespread changes in how genes are regulated — not by altering DNA sequence, but by modifying chemical marks that control gene activity.

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What the Study Did

Researchers led by Yemko Pryor and John Lindo at Emory University sequenced the whole methylome — the full set of DNA methylation marks across the genome — in Indigenous Andean Kichwa highlanders and Ashaninka lowlanders from the Peruvian Amazon. The team analyzed blood samples from 78 participants (39 Kichwa highlanders and 39 Ashaninka lowlanders) and compared methylation patterns across the entire three billion base pairs of the human genome.

Cotopaxi Volcano in the Ecuadorian Andes. (Fabricio Burbano/iStock/Getty Images Plus)

Main Findings

The analysis identified 779 sites or regions with significant methylation differences between highland and lowland groups. Key results include:

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• Two genes involved in the hypoxia (low-oxygen) response showed lower methylation in the Kichwa highlanders, a change that could alter how these genes are regulated under chronic altitude stress.
• The follistatin gene, linked to muscle, vascular and heart biology and to responses to oxygen stress, was hypermethylated in the high-altitude group — a pattern that may relate to known Andean traits like thicker arterial walls and higher blood viscosity.
• Changes were observed in the PI3K/AKT signaling pathway, which coordinates cellular metabolism and survival and is relevant to oxygen stress responses.
• Methylation differences were also found in 39 genes tied to skin pigmentation, consistent with adaptation to higher ultraviolet (UV) exposure at elevation.

Interpretation and Limits

These results point to substantial epigenetic (methylation) variation associated with long-term residence at altitude. Epigenetic marks can change gene activity without altering DNA sequence and may provide a flexible layer of adaptation within a lifetime. However, the study does not demonstrate that these methylation patterns are inherited across generations; it analyzed people living today and cannot resolve transgenerational transmission.

"The Kichwa population that participated in our study did not just arrive in the Andean highlands — their ancestors had been living there for nearly 10,000 years," Lindo said. "Our findings suggest that epigenetics can contribute to adaptation in a longstanding way."

Why It Matters

Comparative work among high-altitude populations has shown different solutions to similar environmental challenges: Tibetans display clear inherited genetic signals for altitude adaptation, while Andean populations may rely more on physiological and regulatory adjustments. This study adds whole-methylome evidence that epigenetic regulation complements inherited changes and highlights pathways worth exploring for their roles in oxygen handling and vascular biology.

Next steps include larger multi-generational studies and functional work to test whether the observed methylation changes alter gene expression and physiology, and whether any marks are passed reliably between generations.

Study published in Environmental Epigenetics.