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Exome Sequencing Study Uncovers High Altitude Adaptations in Tibetans

By Andrea Anderson

NEW YORK (GenomeWeb News) – By sequencing and analyzing the exomes of dozens of Tibetan individuals, an international research team has identified genetic hints about how this population thrives in high altitudes and low oxygen environments.

The researchers sequenced the exomes of 50 individuals from Tibet and subsequently compared them with 40 Han Chinese genomes and 200 Danish exomes. In the process, they not only gained insights into when Tibetan and Chinese populations diverged, but also tracked down genes, including a transcription factor gene called EPAS1, that apparently contribute to high altitude adaptation in Tibetan populations.

The study, which appears online today in Science, also highlights the potential of using evolutionary clues to find functionally important genes, co-corresponding author Rasmus Nielsen, a researcher affiliated with the University of California at Berkeley, BGI-Shenzhen, and the University of Copenhagen, told GenomeWeb Daily News. "By doing that we found the very gene that seems to explain the functional differences," he said.

Although oxygen levels on the Tibetan Plateau are just 40 percent or so of those at sea level, the researchers explained, previous studies have shown that Tibetans and other high altitude populations such as Andeans have adapted to these diminished oxygen levels.

At low altitudes, for example, Tibetan and Han Chinese birth weights are comparable. But at higher altitudes Tibetan birth weights are usually higher, Nielsen noted. In addition, past studies have found that Tibetans tend to have lower levels of the oxygen-carrying compound hemoglobin in their blood when living at higher altitudes.

In an effort to better understand the genetic bases of such adaptation, Nielsen and his co-workers sequenced the exomes of 50 Tibetan individuals from two villages in the Tibet Autonomous Region and compared them with genome sequences for 40 Han Chinese individuals from Beijing sequenced to about four times coverage through the 1000 Genomes Project.

The Tibetan exome sequences, which represented some 92 percent of human genes at a mean of about 18 times coverage, were generated at BGI-Shenzhen using the NimbleGen 2.1M exon capture array and the Illumina Genome Analyzer II. Tibetans involved in the study belonged to families living between 14,100 and 15,100 feet above sea level for several generations.

Based on Tibetan and Chinese sequence data, the researchers estimate that the two populations diverged relatively recently — only about 2,750 years ago. Given the strong correlation between allele frequencies in the Han Chinese and Tibetans, Nielsen explained, "it's quite clear that the divergence time must be quite small."

After tossing in exome sequence data for about 200 Danish individuals sequenced for another study, the team used an evolutionary approach to hunt for changes related to Tibetan altitude adaptation, looking for population-specific changes in allele frequency.

In the process, the researchers found several candidate genes, including 34 low oxygen response genes. Indeed, they noted, the strongest Tibetan-specific signal of selection fell in EPAS1 — a HIF-family transcription factor-coding gene previously linked to everything from response to low oxygen conditions and red blood cell production to athletic prowess.

The Tibetan exomes also contained potential altitude-related signals of selection in and around genes coding for fetal and adult versions of hemoglobin itself as well as genes implicated in red blood cell production, maintenance, and shape, and more.

Consistent with past physiological studies, when the team looked at hemoglobin levels in the blood of 200 Tibetan individuals, they found that the potentially adaptive EPAS1 allele — present in roughly 87 percent of Tibetans but just 9 percent of Han Chinese — was associated with lower hemoglobin levels.

Even so, the oxygen saturation levels did not seem to be affected by these hemoglobin changes — a finding that researchers speculate may reflect a possible role for EPAS1 in regulating how reliant an individual's metabolism is on oxygen.

"One possibility is perhaps that Tibetans switch more easily to anaerobic metabolism without the use of oxygen," Nielsen said. Still, he added, more research is needed to determine whether that is the case.

And, researchers noted, the estimated divergence time of less than 3,000 years between Tibetan and Han Chinese populations points to unusually fast genetic adaptation. "EPAS1 may … represent the strongest instance of natural selection documented in a human population," they concluded, "and variation at this gene appears to have had important consequences for human survival and/or reproduction in the Tibetan region."

"It remains to be seen whether hemoglobin concentration represents the direct phenotypic target of selection in Tibetans, or whether changes in hemoglobin concentration represent an ancillary effect of selection on some other physiological trait," University of Nebraska evolutionary biologist Jay Storz noted in a perspectives article appearing in the same issue of Science.

"These results should motivate detailed functional studies that will hopefully reveal the mechanistic basis of fitness variation among alternative genotypes at EPAS1 and other HIF-related candidate genes fro high-altitude adaptation," Storz added.

Indeed, Nielsen said he hopes his team's study will motivate such physiological studies. For their part, he and his team are planning additional genetic studies involving the Tibetan individuals already sampled as well as other individuals from high altitude locales — work that they hope will uncover key causal variants in altitude adaptation.

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