Sherpas Resist Altitude Sickness With a Gene From an Extinct Human

In 2010, geneticists pulled DNA from a sliver of a girl’s little finger bone, dug out of a cave in the Altai Mountains of southern Siberia, and found that it belonged to no human and no Neanderthal anyone knew. They named the owner the Denisovans, after Denisova Cave. For years there was almost nothing of them to look at: that finger bone, a few teeth, a scrap of skull, a jaw found later on the Tibetan Plateau. They were a people known essentially by their genome — a lineage reconstructed from chemistry rather than bones, a population that left more of itself inside us than in the ground.

Four years later, a piece of that vanished species turned up in the blood of people climbing Everest.

Two ways to fail at altitude

Take a lowlander to the Tibetan Plateau, 4,000 meters up, where the air holds about 40 percent less oxygen than at sea level, and their body does the obvious thing. It reads the shortage and starts manufacturing red blood cells, the tiny carriers that ferry oxygen from lungs to tissue. More carriers, more oxygen delivered. It is a sensible response, and over weeks and months the blood grows steadily thicker with them.

It is also how you get sick. Pack too many cells into the blood and it thickens, sludges, strains the heart, and clots. The chronic version, called high-altitude polycythemia, brings headaches, fatigue, swollen fingers, and in the long run heart failure. The body’s intuitive fix for thin air is, past a point, a slow poison.

Tibetans and Sherpas, who have lived on the roof of the world for generations, largely escape it. They live at altitudes that wreck visitors, climb without bottled oxygen, bear healthy babies where outsiders miscarry. Faced with thin air, their bodies make less blood than a lowlander would, not more.

The difference traces to a single gene. It is called EPAS1, and it codes for a protein that acts as one of the body’s oxygen sensors — when oxygen runs low, EPAS1 helps switch on the emergency response, including the order to crank out red blood cells. In most people, that order runs loud at altitude.

The Tibetan version keeps it quiet. Carriers mount a blunted response: their oxygen sensor is turned down, so the red-cell factory never goes into overdrive. Their hemoglobin stays close to sea-level normal even miles up. At the same altitude, a Tibetan’s hemoglobin runs anywhere from one to three and a half grams per deciliter below an Andean highlander’s — and the Andeans, who adapted to the high Andes by a different route, do build up thicker blood and pay for it with more mountain sickness. The Tibetan body solves the oxygen problem some other way — more efficient breathing, wider blood vessels, better delivery per cell — without the dangerous thickening.

EPAS1 carries the most extreme fingerprint of natural selection in the Tibetan genome. When a team sequenced fifty Tibetan exomes in 2010, the gap between Tibetans and Han at this one gene was the fastest change in allele frequency yet observed at any human gene. Something pushed hard to spread this one variant across the plateau. The question was where the variant came from.

A haplotype too strange to be ours

In 2014, a team led by the population geneticist Emilia Huerta-Sánchez, working with Rasmus Nielsen at Berkeley, sequenced the stretch of DNA around EPAS1 in 40 Tibetans and 40 Han Chinese. The Han are the Tibetans’ closest large relatives; the two populations split only thousands of years ago. If the altitude variant were a normal Tibetan mutation, it should look like ordinary Tibetan DNA with a few recent changes.

It did not. The Tibetan version carried a long, unbroken block of linked mutations — a haplotype — that matched nothing else in the human gene pool. It was too distinct, and too long, to have arisen quietly within the human lineage and survived intact. A stretch that unusual almost always means the DNA came from somewhere else, recently enough that recombination had not yet chopped it up.

So the team went looking for a match outside living humans, and they found one. The Tibetan haplotype lined up, almost perfectly, with a genome that had been published only a few years earlier — that of the Denisovans. The fit was so exact that Nielsen would say there was no other way of explaining the data: this version of the gene had come from Denisovans.

How the gene crossed over

The two threads meet tens of thousands of years ago. Modern humans, moving across Asia, met Denisovans and had children with them. Those children’s descendants carry scraps of Denisovan DNA, and one of those scraps was the EPAS1 variant — already shaped, by whatever pressures the Denisovans had faced, into a version that handled thin air without flooding the blood.

The variant sits in roughly 87 percent of Tibetans today and in only about 9 percent of Han Chinese. The timing is the strange part. An ancestral population picked up the Denisovan version of EPAS1 by interbreeding — best estimates put that crossing at around 48,000 years ago. Then nothing happened for some forty thousand years. Down at ordinary elevations the variant was worth nothing in particular, and it simply drifted, neither favored nor purged. Only around 9,000 years ago does selection appear to grip it — roughly when people were settling the high plateau in earnest. There, the carriers survived and bred while the others sickened and lost children, and within a few hundred generations a piece of DNA from an extinct species had swept through nearly an entire living population.

The Denisovans themselves are gone, absorbed or outcompeted. It took until 2025 for anyone to put a face to them: a heavy-browed skull pulled from a riverbank in Harbin, in northeast China, back in 1933, then hidden down a well for most of a century, was matched to the Denisovan line by ancient proteins and by DNA recovered from the plaque on its teeth. The part of them that let a body live on thin air had never needed finding. It crossed into our line tens of thousands of years earlier, sat unremarkable in a scattering of carriers, and turned out to be exactly the thing a people needed when they climbed higher than humans were built to live. The Sherpa guiding a climber up Everest without an oxygen tank is running, in part, on instructions written by a vanished kind of human.