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May 21, 2019

Adaptation, the gift of the Denisovans

Filed under: Adaptation,Denisovans,geenetics,Tibet — Razib Khan @ 10:57 pm
The Tibetan Plateau

The city of Lhasa, the capital of the Tibetan Autonomous Region, is at ~12,000 feet above sea level. For comparison, Denver, Colorado, is on average close to ~5,500 feet above sea level. The “Mile High” city has nothing on Lhasa! But believe it or not, Lhasa is in a valley. The average elevation of the Tibetan Plateau as a whole is ~14,500 feet above sea level.

It is not for nothing that Tibet is sometimes called the “roof of the world.”
Potala Palace

The stark and austere beauty of this region has long attracted romantics and inspired legends of lost civilizations and ancient wisdom. Tibetans are known for a unique culture and a hardy people. Over 1,000 years ago a vast region of Central Asia was dominated by the Tibetan Empire. But the Tibetan Plateau itself has rarely been invaded.

Perhaps one reason is a matter of biology: Tibetans are better adapted to high altitudes than their neighbors to the north, south, west, and east. Of course, most people can adapt physiologically in the short-term to a higher elevation, but altitude sickness is the normal response to spending too much time too high up for most humans. In contrast, Tibetans can flourish when others tend to suffer discomfort. Importantly, Tibetan women seem to give birth to healthier and heavier infants at higher elevations than non-Tibetans.

Tibetan Mastiff

Over the past ten years, the genetic basis of Tibetan adaptation to high altitude has been elucidated, and one gene that has come to be as important is EPAS1. One of the names for the protein generated by EPAS1 is “hypoxia-inducible factor-2alpha.” Though most scientific jargon is quite impenetrable, the term “hypoxia” should jump out at you, as that’s the term for oxygen deprivation.

And EPAS1 is not only of interest in the case of adaptation for Tibetans humans. Tibetan Mastiff dogs seem to be adapted to high elevation to due to a mutation in EPAS1 which they absorbed from interbreeding with Tibetan wolves. It turns out that only is the mutation in EPAS1 in these dogs different from other breeds, but the region in the genome in the mutation looks a lot more like Tibetan wolf than dog.

Haplotype network showing Tibetan EPAS1 as distinct

Several years before this, researchers found something similar for EPAS1 in humans in Tibetan when it comes to high altitude adaptation. The paper was titled Altitude adaptation in Tibet caused by introgression of Denisovan-like DNA, and that gives the game away.

Scientists had already known for several years that the EPAS1 region in Tibetans was strange. Far different from other human populations. Where Tibetans and Han Chinese were much more similar to each other genetically than they were to Europeans overall, around EPAS1 Han Chinese and Europeans were much more similar to each other than either were to Tibetans!

In fact, the whole area around the EPAS1 mutation was defined by a set of very distinct markers different from anything researchers saw in other human populations. On a lark, they checked ancient genomes from prehistoric populations, Neanderthals and Denisovans. To their surprise, they found that the Tibetan EPAS1 mutation was surrounded by a region of the genome that matched that from the Altai Denisovans!

The implication from this is that the Tibetans who are adapted to the highlands of their homeland carry a mutation which has very deep roots in this part of Eurasia, as Denisovans occupied it for hundreds of thousands of years. As the first modern humans mixed with these ancient people ~50,000 years ago, they picked up this variation of EPAS1, and modern Tibetans, though descended from migrants from lower elevations within the last 10,000 years, found it fortuitous as they adapted to a high altitude lifestyle.

It turns out that the legacy of the first human people of Eurasia remains with us today, and that legacy can be quite useful. It is one of their gifts to us, their descendents.

Adaptation, the gift of the Denisovans was originally published in Insitome on Medium, where people are continuing the conversation by highlighting and responding to this story.

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