Genetic research across multiple studies now points to a clear pattern: populations living in the Andes highlands for thousands of years carry distinct DNA variants that help their bodies cope with thin air, low oxygen, and intense ultraviolet radiation. The evidence spans changes in single genes, shifts across entire biological pathways, and even chemical modifications layered on top of DNA itself. Together, these findings reshape how scientists understand human adaptation to extreme environments and raise new questions about why some highlanders still develop dangerous altitude-related illness.
An EPAS1 Variant Tied to Blood Oxygen Transport
At the center of recent attention is a missense variant in the EPAS1 gene, also called HIF2A, designated rs570553380. This variant, known as H194R, is enriched in Andean populations and has been associated with hematocrit, the proportion of red blood cells in blood. Hematocrit matters because at high altitude the body often produces extra red blood cells to compensate for low oxygen, thickening the blood and straining the heart and lungs. A variant that moderates that response could protect against cardiovascular complications.
Research published in Science Advances found that this Andean-enriched EPAS1 missense variant is associated with hematocrit levels in highland populations, with evidence consistent with positive selection around the H194R site. Experimental work using a knock-in mouse model showed the variant affects hypoxia responses and relates to pulmonary hypertension-related transcriptional changes, according to a separate analysis in Molecular Biology and Evolution. The mouse results suggest the allele acts as a hypomorphic variant, dialing down rather than eliminating the gene’s activity, which could explain why Andean highlanders avoid some of the worst effects of chronic oxygen deprivation.
Adaptation Runs Deeper Than a Single Gene
While EPAS1 draws the most attention, the genetic architecture behind altitude adaptation in the Andes is far more distributed. A genome-wide study comparing Andean and Himalayan populations, with Andean sampling conducted at altitudes of roughly 3,800 to 4,200 meters, found that adaptation is polygenic and operates at the pathway level. Signals of selection cluster in genes governing angiogenesis and vascular development, as well as placental and embryonic growth, not just oxygen-sensing genes. That finding matters because it means natural selection did not simply flip one genetic switch. Instead, it tuned an entire network of biological processes to help people grow, reproduce, and sustain blood flow in oxygen-poor conditions.
Separate genome-wide scans have identified candidate regions that extend well beyond classic HIF pathway genes. One study pinpointed the FAM213A locus and nearby regulatory elements affecting gene expression as a novel candidate region for genetic adaptation in Andean populations. These regulatory regions can alter how much protein a gene produces without changing the protein itself, adding another layer of fine-tuning to the body’s altitude response. The Andean highlands are the second-largest high-altitude plateau in the world, and the breadth of genetic signals detected there reflects the scale of the selective pressure involved.
Ancient DNA Reveals a Long Timeline
How long have these adaptations been accumulating? Ancient DNA evidence covering roughly 7,000 years of Andean history shows that highland and lowland populations diverged genetically over that span, with selection signals detectable across multiple time points. According to that work, long-term residence at altitude left clear marks on genes involved in cardiovascular and pulmonary function, consistent with the physiological demands of life above 3,000 meters.
Other lines of evidence highlight that adaptation did not unfold along a single timeline. Some traits tied to hypoxia tolerance likely faced strong selective pressure soon after people began occupying the high plateau, while metabolic traits responded later to shifts in subsistence. Ancient genome analysis, for example, revealed that one of the strongest signals in highland populations involves MGAM, an intestinal enzyme important to the digestion of starch. Andean settlers consumed a high-starch diet after they started to farm, yet their genomes did not develop additional copies of amylase genes, the route taken by other starch-dependent populations. Instead, selection acted on a different digestive enzyme, illustrating that evolution can solve the same problem through entirely different genetic paths.
These time-staggered signatures underscore that Andean highlanders are the product of overlapping episodes of natural selection. Oxygen transport, blood flow, and lung function appear to have been shaped over millennia of exposure to hypobaric hypoxia, while diet-related genes responded more recently to the rise of agriculture and new staple crops such as potatoes and maize. The result is a mosaic of adaptations layered onto a shared ancestral background.
Epigenetic Marks Add Another Dimension
Beyond changes in DNA sequence, differences in how genes are chemically regulated also distinguish high-altitude from low-altitude Andean populations. A whole-methylome comparison between Indigenous Andean groups at different elevations identified methylation differences in hypoxia-response and pigmentation genes. Methylation is a chemical tag that can silence or activate genes without altering the underlying code, and these tags can shift in response to environmental conditions over generations.
The second strongest epigenetic signal detected in that study related to adaptation to strong ultraviolet radiation, a constant threat at high elevation where the atmosphere filters less sunlight. These methylation patterns affected genes involved in skin pigmentation and DNA repair, hinting at a dynamic regulatory response to intense solar exposure. Because epigenetic marks can be sensitive to both inherited factors and lifetime exposures, they may help explain why individuals with similar genetic backgrounds can still differ in their vulnerability to altitude-related illness or skin damage.
Importantly, scientists have not found a single dominant “high-altitude gene” in the genomes of Indigenous people living in the Andes. Instead, the picture that emerges is one of modest shifts across many loci, complemented by environment-responsive epigenetic changes. In this context, the methylation differences observed between highland and lowland groups are not mere biochemical curiosities; they represent another axis along which natural selection and local conditions can shape physiology.
Diverse Strategies Among Highland Populations
Comparisons across the world’s major highland regions reveal that Andean adaptation is distinctive rather than universal. Research on Tibetan highlanders, for example, has emphasized variants in EPAS1 and EGLN1 that strongly influence hemoglobin levels, while some Ethiopian highlanders show minimal elevation in hemoglobin despite living at similar altitudes. A review of human high-altitude responses highlights these contrasts and suggests that different populations have taken partially independent genetic routes to solve the shared problem of chronic hypoxia.
Andeans, in particular, tend to exhibit relatively high hemoglobin concentrations compared with Tibetans, yet not as extreme as what is seen in lowlanders who rapidly ascend to altitude. The Andean-enriched EPAS1 variant tied to hematocrit appears to moderate, rather than abolish, this response. Polygenic changes in vascular and developmental pathways further refine how blood is distributed and how organs grow in a low-oxygen environment. Together, these features may reduce the risk of acute altitude sickness while still supporting adequate oxygen delivery.
At the same time, Andean populations experience a notable burden of chronic mountain sickness and pulmonary hypertension, especially in older adults. The very traits that help sustain life at altitude, such as increased red blood cell mass, can become liabilities later in life when compounded by other health factors. This tension between short-term benefits and long-term costs is a recurring theme in evolutionary medicine and underscores why no adaptation is perfect.
Unanswered Questions and Future Directions
The emerging picture of Andean high-altitude biology is rich but incomplete. Key questions remain about how specific variants, such as the EPAS1 H194R allele, interact with other loci across the genome and with epigenetic marks to shape real-world health outcomes. Large-scale studies that integrate whole-genome sequencing, methylation profiling, and detailed clinical data could clarify why some individuals develop chronic mountain sickness or pregnancy complications at altitude while their neighbors do not.
Another open area involves developmental timing. Many Andean highlanders are exposed to hypoxia from conception onward, and there is evidence that prenatal and early-life conditions can leave lasting marks on cardiovascular structure and function. Disentangling which features reflect inherited genetic differences and which arise from developmental plasticity will require longitudinal research that spans generations.
Finally, as climate change and migration alter where and how people live in mountain regions, the relevance of these adaptations may shift. Urbanization in highland cities introduces new stressors such as air pollution and changing diets, potentially interacting with altitude-adapted genotypes in unexpected ways. Understanding the full spectrum of Andean high-altitude adaptation is therefore not only a matter of reconstructing the past; it is also essential for anticipating future health challenges in some of the world’s highest communities.
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*This article was researched with the help of AI, with human editors creating the final content.
