How the indigenous Tibetan population evolved to live with so little oxygen has been a mystery. Now we are beginning to understand that another species may lie behind their survival.

Some time in the past, a family sat on the top of the world and gazed at the stars. They lived on the Tibetan Plateau, 4200m (14,100ft) above sea level, in a site now known as Chusang. They called it home. 

Although far from the comfort of more lowly climes, this location had its perks. Fuelled by the tectonic forces that raise and support the plateau, a hot spring at the surface provided a welcoming buffer against the chilled air. At night, the family lit fires in a hollow built into the slope, a lonely flicker against the peak of darkness. 

Their fire has long gone out, but the family still left a lasting impression on the world. As they walked and played, 19 hand and footprints were pressed into the clay-like mud that seeped from the spring and, as they dried, were preserved into the present. 

Judging by the size of the prints - and the hands and feet that made them - the family group contained six individuals, two of which were children. But who were they? And what brought them to such high altitudes? A foraging trip perhaps? Hunting? Or were they simply curious, always searching for lands untouched?

Their marks leave no answers to such questions. All that is known, as shown in a study from January 2017, is that the Chusang prints were made between 12,700 and 7,400 years ago, making it one of the oldest archaeological sites known on the Tibetan Plateau. 

But what makes the Chusang family special is their isolation, says Mark Aldenderfer, an anthropologist from the University of California at Merced and one of the study’s authors. Living at the centre of the plateau, they simply couldn’t migrate up and down the mountain with the seasons as other Tibetan people did during this period. They were here year-round, enduring the heavy snowfall, biting winds, and encroaching glaciers of winter.

Their survival is extraordinary. While the heat of fire could protect them from the cold, the family at Chusang couldn’t shelter from an obvious yet insurmountable obstacle of living on the plateau: the air becomes thinner with every step towards the sky. At more than 4,000m (13,000ft) above sea level, each breath contains around a third less oxygen than the same breath far below. But deep inside each of their bodies, within their blood and DNA, an ancient and unique trick to surviving at altitude protected them from the thin air in which they built their home.

Any mountain climber will be able to describe the shortness of breath that normally comes with altitude. It’s not that the air has a lower percentage of oxygen – it’s around 21% wherever you stand in the world. But air pressure decreases the further you walk or fly from the sea’s surface, allowing the gas molecules to spread out in all directions, and a lung can only stretch so far to compensate.

There are ways to deal with this change in pressure, however. Over many hundreds of generations, people living on the Andean altiplano that extends from Peru into Bolivia, have evolved barrel-shaped chests that increase the volume of each of their breaths. And since the late 1800s, scientists have known that their blood is pumped full of red blood cells and haemoglobin, the oxygen-carrying molecules, that they contain.

When the air is thin, the blood thickens to increase the amount of oxygen it can shepherd to cells around the body. This hematopoietic (literally, “blood” and “to make” in Greek) response is also found in anyone who decides to hike up a mountain. “Compared at altitude to Andean highlanders, we are pretty similar,” says Cynthia Beall, an anthropologist from Case Western Reserve University in Ohio. “Not completely, but the general response is the same.”

And since virtually all research on high-altitude populations was focused in the Andes, haematopoiesis was seen as a universal response to low oxygen levels for nearly two centuries. It was only in the late 1970s and early 80s, after hiking to seven villages in Nepal, that Beall started to find that Tibetans didn’t fit this theory. 

Firstly, they lacked the barrel-shaped chests, but seemed to breath at a faster rate than Andeans. And second, in the autumn of 1981 Beall and her colleagues found that Tibetans have surprisingly low haemoglobin levels, often within the range of what is normal for people who live at sea level. Although they live on the so-called “roof of the world”, their physiological state seemed surprisingly similar to those who had never left its floor.

“At first, this was anxiety inducing,” says Beall. “You think, ‘Oh gosh, did I measure the wrong people? Did I do the wrong measurements? Is there something I’m missing?’” But after returning to Tibet and Nepal many times since, collecting more data from more villages, she only found support for her initial results: at high altitude, low-oxygen environments, Tibetan people reduce the amount of oxygen their blood can carry.

How could this be? What at first appears to be highly paradoxical – not to mention potentially dangerous – actually makes a lot of sense, protecting Tibetan people from some of the nastier side effects of the high-life.

One benefit, for instance, is reduced wear and tear on their blood vessels. “If you have high levels of haemoglobin your blood tends to be more viscous, and that can have a lot of damaging effects,” says Tatum Simonson from the University of California in San Diego. “You’re basically pumping this very thick, concentrated blood throughout your system. Your heart is on overdrive.”

A possible outcome of this added stress on the entire circulatory system is chronic mountain sickness, or CMS. First described in 1925 by the Peruvian doctor Carlos Monge Medrano, CMS (also known as Monge’s disease) can afflict people who have lived happily at high altitude for years. “It’s not clear what triggers the onset,” says Beall. “But people become breathless, they become cyanotic [their lips and extremities turn blue], they can’t work, they can’t sleep well – they’re very ill.”

As with short-term altitude sickness, the remedy for CMS is a slow descent into thicker, more oxygenated air. But it is no cure. Fluid may have already built up in the lungs (a high altitude pulmonary oedema, or Hape) or in the brain (a high altitude cerebral oedema, or Hace), or the thick blood may be congested in other vital organs. The worst-case scenario is death.

In the Peruvian Andes, up to 18% of the population develop CMS at some point in their lives. But on the Tibetan Plateau that number is rarely above 1%.

Certainly thin blood helps reduce CMS risk, but it’s certainly not the only reason Tibetan people can live happily at such extremes. In 2005, for instance, Beall and her colleagues found that Tibetans exhale more nitric oxide compared to people living in the Andes and at sea level. Originally described as a relaxation factor, this gas leads to a widening of blood vessels in the lung and around the body, known as vasodilation. With more space, blood flow – and oxygen transport – can increase.

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And, as Simonson suggests, what if Tibetans simply don’t require as much oxygen as other people? What if their muscles are just more efficient with their usage, for instance? “Perhaps they are already so well tuned that they don’t need more red blood cells and haemoglobin to bind more oxygen,” she says. Her work is now exploring this possibility.

Although she has visited the Tibetan Plateau several times for her research, Simonson surveys the history of this region back in her laboratory. As a geneticist, she can scour the genomes (the entire DNA sequence of an individual) of Tibetan people to find what underlies their unique adaptations to the high life.

In 2010, by comparing the genomes of 30 Tibetan people to those from a Han Chinese population living in Beijing, Simonson could identify those genes that were associated with living at high-altitude. This is easier than it sounds. Since the two populations are closely related but only one has lived at altitude for thousands of years, any major differences between the genomes are likely to underlie adaptations to this change in environment, such as an atmosphere thin on oxygen.

Simonson’s lab wasn’t the only one attempting this. In the space of two weeks in 2010, a total of three research groups each published a study that found a handful of genes that were markedly different between the two populations. Of note, two genes called EPAS1 and EGLN1 stood out from the crowd, and, importantly, were already known to modulate the haemoglobin levels in blood. 

“The really wonderful part was everyone finding the same thing,” says Beall, who was involved in one of the three studies. “In genomic studies, there are so many instances where one study found an association [between a trait and a gene] and it wasn’t possible to replicate it,” says Beall. “And in this case, right off the bat, we had replication. It’s real.”

The field of human genomics is made easier by the nature of our species as a whole: at the level of DNA, of genomes, we are very similar. “On average, there aren’t big differences between different populations,” says Rasmus Nielsen from University of California in Berkeley. “The genetic variants that are most different between different groups are variants that code for things like hair colour and eye colour and skin colour.”

Our differences are slight and are held at the surface. Under the skin, deep in our DNA, we are nearly identical. From this sea of similarity, important genetic changes between populations can be seen as small but steep islands breaking the surface of the genome. But after looking more closely at the EPAS1 gene from the Tibetan genomes, Nielsen not only found it was a steep change, but it was a unique one too. After searching through the aptly named 1,000 Genomes Project, he couldn’t find anything quite like it elsewhere. “The DNA sequence that we saw in Tibetans was simply too different,” Nielsen says.

It was as if Tibetans had inherited the gene from another species. And, in fact, that’s exactly what had happened.

Before its publication in 2010, Nielsen had worked on the Neanderthal genome project with the doyen of ancient DNA Svante Paabo, a geneticist from the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. He knew our species had bred with these close evolutionary cousins, and scoured their DNA for the source of the Tibetan-specific EPAS1 gene. No match.

Although disappointing, it wasn’t all that surprising. Neanderthals are only known to have mated with the ancestors of modern-day Europeans, leaving a legacy of 1-5% Neanderthal DNA in their genomes. For people of Asian ancestry Nielsen instead looked to Denisovans, another branch of the human family tree.

Discovered in the Altai Mountains in Siberia, they are known only from two teeth, a tiny finger bone, from which Paabo and his colleagues published a rough genome in 2012. The results demonstrated that populations from Papua New Guinea, Australia, and a few regions of southeast Asia had inherited between 1-6% of their genomes from Denisovans.

It was a case of third time lucky. “There was a complete match,” he says. “It’s so hard to believe that it could possibly be true. But it is.” Between 50,000 and 30,000 years ago, some Denisovans and the ancient ancestors of Tibetan and Han Chinese people had sex, merged their genomes, shuffled the genes like a deck of cards, and produced children who would grow up to have offspring of their own.

Over the next tens of thousands of years, this gene seems to have conferred little benefit to Han Chinese people and is only found in roughly 1% of the population today. But for all those intrepid groups that moved up onto the Tibetan Plateau, including the Chusang family, it helped make every breath easier, every heartbeat less dangerous. On the Tibetan Plateau, 78% of the population has this version of EPAS1, a gene that separates them from those far below, but connects them to the past.

Over 50,000 years in the making, this story still doesn’t have an ending. Although its origin is known, those areas that make EPAS1 in Tibetans unique are still largely unchartered. The specific change (or changes) that leads to a reduction in haemoglobin content is still unknown. “All the geneticists say it’s in an area that’s very hard to sequence,” says Beall. The new explorers, those of mountains of data and genomes, still have a long journey ahead of them.

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Alex Riley is a writer based in Berlin, Germany. He tweets as @riley__alex.

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