Adapting to life at high altitudes depends on more than genes alone

Geneticists have long wondered why Andean highlanders show no strong “high-altitude gene” signature. Tibetans clearly do. Yet both groups have lived for millennia in thin air and intense UV.

A new study led by anthropologists at Emory University offers a compelling answer. The Andean adaptation may be written less in the “letters” of DNA than in its “punctuation marks” – epigenetic tags that tune genes up or down.

“This is the first whole methylome dataset on these two populations,” said Yemko Pryor, who led the project as an Emory Ph.D. student.

“Unlike many methylome studies that focus on just a few hundred thousand sites throughout the genome, we looked at all three million base pairs to see what we would find.”

Andean gene control emerges

Classic scans for natural selection comb the genome for hard-coded mutations that spread because they help people survive. That’s the story in the Himalayas, where a distinctive variant boosts oxygen delivery.

But the Emory team took a different route. Rather than look for mutations, the team mapped DNA methylation – the regulatory tags that govern gene expression – across whole genomes. They compared the Kichwa of the Andean highlands with the Ashaninka of the Amazon Basin.

Methylation acts like a dimmer switch for genes. It doesn’t alter the letters of DNA. Environmental pressures often reshape how cells read those letters.

By surveying methylation at the whole-genome scale, the researchers could ask whether life above 2,500 meters (8,200 feet) leaves a regulatory imprint.

Such conditions – low oxygen, cold, and intense sunlight – might shape regulation even without dramatic genetic changes.

Altitude reshapes vessel pathways

The contrasts were striking. The team found strong methylation differences between high- and low-altitude participants in PSMA8, a gene tied to vascular regulation. They detected differences in FST, a gene that regulates cardiac and skeletal muscle.

The researchers also detected a pronounced signal across genes in the PI3K/AKT pathway, a master regulator of muscle growth and blood vessel formation.

Taken together, these epigenetic shifts outline a plausible physiological strategy. Altitude-tuned gene regulation could reinforce thicker arteriole walls, more muscularized small arteries, and higher blood viscosity.

The authors note that low oxygen activates PI3K/AKT to induce arteriole wall thickening in animal models and human cells. This dovetails with elevated rates of pulmonary hypertension documented in Andean populations.

UV stress alters Andean genes

Oxygen isn’t the only stressor at altitude. UV radiation is punishing at Andean elevations, and the methylation data reflected that as well.

The team identified robust differences across 39 pigmentation-related genes, consistent with an adaptive response to higher UV exposure. In other words, both the air you breathe and the sunlight that hits your skin may be shaping how Andean genomes are read.

“The findings are particularly interesting because we’re not seeing these strong signals in the genome but when we look at the methylome, we are seeing these changes,” said John Lindo, an associate professor of anthropology at Emory and senior author of the study.

Long-term living, flexible genes

Gene selection theory holds that adaptations enduring across many generations typically appear as inherited DNA variants.

Epigenetic changes, by contrast, are often cast as flexible, responsive, and sometimes reversible. They are useful for short-term plasticity but less central to deep evolutionary change. The Andean case challenges that neat division.

“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 long-standing way.”

That doesn’t mean the DNA sequence is irrelevant in the Andes. Rather, it suggests that durable population-level adjustments can also arise through stable shifts in gene regulation. Culture, environment, and possibly heritable epigenetic mechanisms may maintain these shifts.

Rethinking how humans adapt

By shifting the spotlight from genetic variants to genome regulation, the study widens the lens on how humans meet extreme environments.

The Tibetan path – hard-wired changes that alter oxygen physiology – isn’t the only route. In the Andes, a regulatory toolkit appears to recalibrate vascular and pigmentation systems to the demands of altitude and UV.

That perspective carries practical implications. Population-specific regulatory profiles may drive health risks such as pulmonary hypertension. These patterns – not just fixed DNA changes – are reshaping how clinicians think about screening and treatment in highland communities.

The study is published in the journal Environmental Epigenetics.

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