High in the Ecuadorian Andes, at altitudes thousands of meters above sea level, humans face environmental pressures very different from those at lower altitudes.
The human body can acclimatize, physiologically, to the lower levels of oxygen in the air at higher altitudes. Higher levels of ultraviolet radiation also present a challenge in high mountain environments.
Over millennia, these conditions can shape which genetic traits persist through the generations, with indigenous populations showing lasting differences to acclimatized newcomers.
The body's response to altitude can also affect how genes are regulated, as scientists have now observed in Indigenous Andean Kichwa communities. It's not evolution in the genetic sense, but part of the flexible, epigenetic toolkit our cells use to adjust to their environment using the genes they have.
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Whether these epigenetic changes are heritable in humans remains uncertain. It's not yet clear if these changes persist across generations, as the study only looked at people living today, not how populations have changed over time.
The world is a vast and varied place, and groups of humans living in specific conditions can develop adaptations suited to those conditions. Free divers in South Korea, for example, have genetic advantages linked to how their bodies store and release oxygen during long dives.
What intrigued a team led by anthropologists Yemko Pryor and John Lindo at Emory University in the US is that, while people on the Tibetan Plateau have a strong signal for evolutionary genetic changes associated with high altitude and inherited over generations, people living in the Andes at similar altitudes show different changes that may not be heritable – raising questions about how they adapted to altitudes above 2,500 meters (8,200 feet).
Rather than comb over the entire Andean genome again, the researchers took a different approach: the methylome.
If you think of DNA as the cookbook that contains all the recipes for biological actions required to keep the body functioning, the methylome is a set of little sticky tabs that can change the activity of DNA without altering the sequence. These are temporary modifications layered on top of the DNA that usually result in 'do less of this'.
The researchers collected blood samples from 39 Indigenous people living high up in the Ecuadorian Andes and in the Peruvian Amazon Basin: the Kichwa and Ashaninka communities, respectively. Then, they sequenced the entire methylome from each individual and compared the two sets.
"This is the first whole methylome data on these two populations," Pryor says. "Unlike many methylome studies that focus on just a few hundred thousand sites throughout the genome, we looked at all three [billion] base pairs to see what we would find."
The comparison revealed 779 differences between the high-altitude and the low-altitude populations, including specific changes related to high-altitude living conditions.
These results don't show heritable genetic changes, but shorter-term adaptations to life at high altitude.
In particular, two genes related to the body's response to hypoxia (low oxygen) are differentially methylated, with lower methylation levels for both genes observed in the high-altitude Kichwa communities.
This suggests a regulatory shift in how these genes might respond to low oxygen – consistent with long-term living in thin air, but not direct evidence of reduced emergency response.
Meanwhile, the follistatin gene – important for muscle, vein, and heart biology, as well as the body's response to oxygen stress – is hypermethylated, hinting at a possible connection to known Andean physiological traits, such as more muscular artery walls and higher blood viscosity.
This, the researchers suggested, may be linked to changes they found in the PI3K/AKT signaling pathway that plays a critical role in several cell processes, including metabolism and survival.
Finally, 39 genes related to skin pigmentation showed significant differences between lowland and highland populations, consistent with differing UV exposures at higher altitudes.
Taken together, these results suggest that heritable genetic changes may only constitute part of our adaptation toolkit, and that epigenetic adjustments to gene activity in a single lifetime could play another role.
"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 says. "Our findings suggest that epigenetics can contribute to adaptation in a longstanding way."
The research has been published in Environmental Epigenetics.