Tibetans adapted to live at high altitudes where oxygen is scarce; study suggests ancient interbreeding with an extinct human population may have given their ancestors a genetic advantage to survive in one of planet’s harshest environments

At around 4,000 meters above sea level on the Tibetan Plateau, the air contains significantly less oxygen than at sea level. For most lowlanders, spending a long time at such elevations can put the body under considerable stress. The natural response is to make more red blood cells and increase hemoglobin, the protein that carries oxygen through the blood.

But Tibetans appear to have found another way. A 2010 study led by American anthropologist Cynthia M. Beall and other researchers published in the Proceedings of the National Academy of Sciences (PNAS) found evidence that genetic changes near a gene called EPAS1 are associated with unusually low hemoglobin levels in Tibetan highlanders. The findings offer a glimpse into how humans can gradually adapt to some of the planet’s most extreme environments.

When more blood is not necessarily better

At first glance, producing more hemoglobin sounds like an obvious solution to living in oxygen-poor air. And that is exactly what happens when people from low altitudes travel to high mountains.

The body senses the shortage of oxygen and responds by producing more red blood cells. More red blood cells mean more hemoglobin, allowing the blood to carry more oxygen. But there is a downside.

If hemoglobin levels remain too high for too long, the blood can thicken. This is associated with chronic mountain sickness, a condition that can cause serious health problems.

Tibetans, however, tend to show a different pattern. Despite living for generations at elevations where oxygen is scarce, they generally do not respond by dramatically increasing their hemoglobin levels. The PNAS study provides an important genetic clue for why.

A gene that changes the body's response

Researchers compared indigenous Tibetan highlanders living at elevations of 3,200–3,500 meters above sea level with closely related Han Chinese populations living at lower elevations.

They found a strong signal of genetic difference around EPAS1, a gene involved in the body's response to low oxygen. The gene produces a protein known as HIF-2α, which helps regulate processes including the production of red blood cells.

The researchers then looked at Tibetans living even higher, around 4,200 meters. They identified 31 genetic variants near EPAS1 that were strongly associated with hemoglobin concentration. People carrying particular versions of these variants tended to have lower hemoglobin levels. On average, one group had hemoglobin concentrations about 0.8 grams per decilitre lower than another group. The relationship was subsequently replicated in another Tibetan group living at around 4,300 meters.

In simple terms, the study suggests that Tibetans have inherited genetic variants that appear to turn down the body's usual response to oxygen shortage.

That may sound counterintuitive. But in an environment where low oxygen is permanent, avoiding an excessive increase in red blood cells could actually be beneficial.

Evolution's unusual solution

The striking part of the discovery is not simply that Tibetans have a different version of a gene. It is that the difference appears to have been shaped by natural selection.

The variants linked with lower hemoglobin were found at much higher frequencies among the Tibetan populations studied than among the Han populations. The researchers interpreted the pattern as evidence that natural selection had acted on or near EPAS1 in Tibetan highlanders.

For simplification, imagine two people arriving at a mountain where oxygen is scarce. One body responds by saying: Make more red blood cells.

The other, shaped by generations of life at high altitude, appears to respond more cautiously: Don't overreact.

That difference may have helped Tibetan populations survive and reproduce in an environment that is challenging for people who have not evolved there.

The researchers were careful, however, not to claim that EPAS1 explains everything. Because the gene affects several biological processes, natural selection may have acted on another trait connected to EPAS1 rather than hemoglobin alone. The study also noted that the exact causal genetic variant still needed to be identified.

The gene may have come from an ancient human relative

But where did this unusual genetic adaptation come from in the first place? A 2014 study published in Nature offered a remarkable answer: part of the genetic toolkit that helps Tibetans live at high altitude may have come from Denisovans, an extinct group of ancient humans.

Researchers examined the region around EPAS1 in 40 Tibetan and 40 Han Chinese individuals. They found that the Tibetan version had an unusual pattern of DNA, a long stretch of genetic material that was strikingly similar to DNA found in Denisovans, the extinct species of archaic human that ranged across Asia during the Middle to Late Pleistocene, approximately 200,000–32,000 years ago, but was rare or absent in most other modern human populations.

The researchers concluded that the pattern was best explained by introgression, in simple terms, ancient interbreeding between modern humans and Denisovan-like people, followed by the inherited DNA being passed down through generations.

But Tibetans are not Denisovans

This also does not mean Tibetans are “part Denisovan” in any simple sense. Rather, a small piece of DNA inherited from an ancient human relative appears to have proved useful in a particular environment. Once modern humans carrying that variant lived on the Tibetan Plateau, natural selection could favor it because it helped them cope with the chronic shortage of oxygen.

The sequence was found at high frequency among Tibetans, while it was found only at very low frequency among Han Chinese in the researchers' comparisons. The unusual length and structure of the shared DNA also made ordinary inheritance from a much older common ancestor an unlikely explanation.

In other words, the story of Tibetan adaptation may not have started entirely with a new mutation appearing among modern Tibetans. It may have begun with a genetic gift from another human lineage.

That makes the EPAS1 story particularly striking. The 2010 PNAS research showed that genetic variation around EPAS1 was associated with the unusually low hemoglobin levels seen in Tibetan highlanders. Four years later, the Nature study suggested that the very DNA region involved in this adaptation had an even older history, reaching back to Denisovans.

The Denisovans themselves are known from a relatively small number of fossil and genetic discoveries, including remains from Denisova Cave in Siberia. Yet their genetic legacy survives in some modern human populations.

Tibetans carry an ancient DNA that helped them to survive at high altitude

The Tibetan Plateau provides one of the clearest examples of what natural selection may have done. For thousands of years, humans living at extreme altitude faced the same basic problem: there simply was not enough oxygen in the air. Instead of relying solely on the usual response of producing more hemoglobin, some populations appear to have inherited genetic variants that altered how their bodies responded to low oxygen. Natural selection then eventually helped preserve those variants.