Gene mutation helps Andean highlanders thrive at altitude, and 'living fossil' fish live deep underwater

Living at high altitudes for long periods can be detrimental to most people's health — however, over thousands of years, some populations in the Andes and mountains of Tibet have adapted to the low-oxygen environments with genetic changes that allow them to thrive. 

The same adaptation can also be seen in a deep-sea-dwelling fish. 

In a new study published Friday (Feb. 9) in the journal Science Advances, researchers identified a genetic mutation in the gene EPAS1 in a group of Indigenous Quechua people in the Peruvian Andes. The mutation lowers the amount of hemoglobin — the body's key oxygen-carrying molecule — in the blood.

Mutations in this same gene have been previously tied to lower hemoglobin levels in certain Tibetan highlander populations. The new study highlights the importance of EPAS1 in regulating how human cells react to low oxygen levels, and it also presents a novel example of convergent evolution in humans, in which different populations independently evolve similar traits.

"It is a daunting prospect to identify the causal variant, physiologic trait, and underlying mechanism that underlies a signature of natural selection in humans, like described here," Benjamin Voight, a professor of pharmacology at the University of Pennsylvania who was not involved in the study, told Live Science in an email. The study accomplishes a feat by connecting a specific gene variant and its function to an observable trait in people.

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Revealing gene variation in an Indigenous community

Lengthy exposure to high-altitude, low-oxygen environments can cause excessive production of red blood cells in a disease called chronic mountain sickness (CMS). Previously, the Tibetan highlander community was shown to have naturally lower red blood cell levels than people in other communities, as measured by their hemoglobin levels. This both prevents CMS and improves people's ability to exercise at high altitudes.

Some individuals in the Andean highlander population show a similar ability to thrive at high elevations, while others experience the cardiovascular complications that come with high-altitude living, such as pulmonary hypertension and heart failure.

Tatum Simonson, an associate professor of medicine at the University of California, San Diego, and her longtime collaborator Francisco Villafuerte, a professor of physiology at the University of Peru, went to Cerro de Pasco, a village in Peru with an altitude of 2.7 miles (4.3 kilometers). There, they discussed health concerns with the local Andean community and sequenced the genomes of 40 volunteers.

In the genomic data, they found a stretch of DNA associated with low-oxygen tolerance in the Andeans that overlapped with another they had found in the Tibetan population. This region included a version of the gene EPAS1 that often appeared in Andeans with lower hemoglobin levels who could tolerate low-oxygen conditions.

"People [who can't tolerate low-oxygen conditions] could go to lower altitude, but it is very clear they do not want to do that. This is their home, which is understandable, completely, and they are not going to leave," Simonson told Live Science. "So, anything we can do to mitigate some of these negative outcomes is interesting to those involved."

The researchers went on to show that both the Andean and Tibetan mutations in EPAS1 limit its activity and alter the production of proteins related to hypoxia, which is when the body is deprived of oxygen. This means these changes in EPAS1 activity could be protective against pulmonary hypertension and thickening of the heart's tissues.

"Thinking about how people do well in response to low oxygen, and also how people maybe don't do as well, I think is really important in a clinical context," Simonson said, "because we know there are people who suffer from lung disease or cardiopulmonary or cardiorespiratory diseases that respond differently to that pathological stress." 

By looking at the consequences of EPAS1 variants, researchers may get a glimpse into why people fare differently when faced with respiratory disorders, such as chronic obstructive pulmonary disease or sleep apnea.

Related: Scientists finally solve mystery of why Europeans have less Neanderthal DNA than East Asians

What does this tell us about evolution?

Investigating the variants also gives a glimpse into human evolution. The EPAS1 variants found in Andean and Tibetan populations have entirely different origins, the researchers found. The Tibetans likely inherited their EPAS1 gene from a Denisovan ancestor more than 48,000 years ago. However, the variant found in the Andean population popped up more recently in the community, approximately 10,000 years ago.

The variants are found at a high frequency in Tibetans but a low frequency in Andeans. Since the Andean variant is "younger," the researchers hypothesize it is still under early-stage genetic selection.

"There are only a handful of plausible examples of potential convergent evolution across human populations," such as some people retaining the ability to digest lactose, Voight said. "Thus, this work helps to further 'elevate' adaptation to high altitude environments into this collection of human traits."

Simonson and her team also found that, while variants in the human gene EPAS1 are unique to highlander populations, the Andean variant can also be found in other animals. These animals include the coelacanth, a deep-sea-dwelling fish that thrives in low-oxygen environments and diverged from humans on the evolutionary tree of life 400 million years ago.

Considered a living fossil, this fish nonetheless shows some adaptive traits found in people.

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