Researchers have identified genetic mutations that enable the Tibetan population to live in a low-oxygen environment without adverse side effects. The research believe these genes mutated about 2750 years ago, which would represent the fastest documented case of environmentally driven genetic adaptation.
The Tibetan population dwells in one of the highest regions of the world, on a plateau 13,000 feet about sea level at its lowest point. At such an elevation, oxygen levels are about 40% lower than those at sea level. Low-oxygen (hypoxic) environments can cause medical problems including fatigue, headache, low birth weight, and high infant mortality. Yet, Tibetans report no more of these problems than populations at sea level.
Jian Wang, a researcher at the Bejing Genomics Institute (BGI)–Shenzhen and avid mountain climber, was curious about what enabled these Tibetans to thrive at such high altitudes. “I have found that Tibetans are much better than all of us [Chinese] on the high mountain, and I wanted to know why,” Wang told BioTechniques. “How Tibetans adapted to extreme hypoxia is a very interesting evolutionary story; it may be the strongest instance of natural selection documented in the human population.”
Researchers from BGI, collaborating with a team from the University of California, Berkeley (UC Berkeley), found more than 30 genes with single nucleotide polymorphisms (SNPs) that were more prevalent in Tibetans than in Han Chinese, even though the two populations split fewer than three thousand years ago. Of the 30 genes, nearly half are linked to the way the body absorbs and uses oxygen.
One particular mutation, the endothelial Per-Arnt-Sim domain protein 1 gene, EPAS1, is found in fewer than 10% of Han Chinese but nearly 90% of Tibetans. EPAS1 is known as the “athlete gene” among geneticists because it has been found to correlate with increased athletic performance. EPAS1 codes for a protein involved in sensing oxygen levels and may play a role in balancing aerobic and anaerobic metabolism. Wang’s research revealed that many Tibetans actually have two copies of the EPAS1 gene, providing the population with an alternative mechanism to cope with low oxygen levels.
“One SNP in EPAS1 at a high-frequency gene in the Tibetan sample was associated with lower erythrocyte quantities, and correspondingly lower hemoglobin levels,” explained Wang. “Since elevated erythrocyte production is a common response to hypoxic stress, it may be that carriers of the ‘Tibetan allele’ of EPAS1 are able to maintain sufficient oxygenation of tissues at high altitude without the need for increased erythrocyte levels.”
Data gathered by the team from BGI included the DNA samples from 50 Tibetans living in the Tibet Autonomous Region of China, and 40 Han Chinese from Beijing. The Tibetans were from two villages located at elevations of 14,100 ft and 15,100 ft. The test subjects were selected from families that had lived in those locations for at least three generations. Blood samples from the participants were evaluated for oxygen saturation, red blood cell concentration, and hemoglobin levels.
The samples were then used to sequence the exons, regions of the genome that code for proteins, from each individual. The sequencing was done on Illumina’s Genome Analyzer II platform, at a depth of 18x, and was compared to the reference human genome from the National Center for Biotechnology Information.
The UC Berkeley team analyzed the data and approximated the evolutionary split between the Tibetans and Han Chinese by comparing the groups to a control population of 200 Danish individuals. Using the results from the analysis, the researchers concluded that the common ancestors of the Tibetans and Han Chinese split into two distinct populations 2750 years ago, with the larger of the groups moving up into the Tibetan plateau. The Han Chinese are now the dominant ethnic group in mainland China, while the Tibetans either merged with the people already occupying the plateau, or replaced them.
“The frequencies of the mutations in the two populations are extremely similar, indicating that the two populations are genetically very close to each other,” said Wang. “EPAS1 is the exception. In this one gene, there are mutations that are very common among Tibetans but rare among Hans.”
The study provides a fundamental genetic database for hypoxia and evolution research, according to Wang. The genes identified by this study play important roles not only in the survival and reproduction of the Tibetan population, but in general human fitness. The study highlights the role of oxygen in cellular response.
The sequenced genomes will be included in the data used for the 1000 Genomes project, an international effort to sequence 2500 human genomes by the end of 2011, and which recently announced that it is ready to get underway.
The paper, “Sequencing of 50 human exomes reveals adaptation to high altitude,” was published July 2 in Science.