Genetic Evidence for High-Altitude Adaptation in Tibet
The Genetics of High-Altitude Living. Call it Sherpa envy. Mountain climbers have long wished they could discover—and bottle in a drug—how Tibetans live and work high in the Himalayas without getting altitude sickness. Now researchers have discovered two new gene variants that help Tibetans use oxygen more efficiently than people who live at low altitudes; natural selection favored these variants in Tibetans, whose ancestors have lived at high altitude for thousands of years. Researchers have been mystified as to how Tibetans have thrived at altitudes over 4400 meters (14,435 feet). Some
high-altitude people, such as Andean highlanders, have an adaptation that adds more oxygen-rich hemoglobin to their blood. But many highland Tibetans, researchers have found, have less hemoglobin in their blood. That helps them avoid serious problems caused by too much hemoglobin, but Tibetans with this so-called decreased hemoglobin phenotype must somehow use small amounts of oxygen efficiently to get enough of it to their limbs while exercising at high altitude. Researchers have been unable to pinpoint the genes that are responsible for this remarkable balancing act in their blood. In a report published online today in Science, a team of Chinese and American researchers identified variants of two genes involved in oxygen processing that are found in most Tibetan highlanders. The researchers
used two methods to search for these genes. First, they scanned DNA registries for genes that might be involved in regulating oxygen in the blood and identified 247 candidate genes that vary in different populations. Then they analyzed segments of DNA that include those 247 genes in 31 unrelated Tibetans, 45 Chinese, and 45 Japanese lowland people whose DNA was genotyped in the HapMap Project. By identifying regions that had a characteristic signature of being strongly altered by natural selection, they were able to identify relatively new gene variants that had swept through highland Tibetans, but not Chinese or Japanese lowlanders. They finally homed in on 10 genes, including two, EGLN1 and PPARA, that were found at the highest frequency in Tibetans who had the least oxygen in their blood. The researchers found that people who have more copies of the gene variants (by inheriting a copy of each advantageous variant from both parents), had the least amount of oxygen in their blood and used it more efficiently than people without either variant, or only one copy from one parent.
“Tibetans with these genes appear to be much more efficient with the oxygen they have,” says senior author Lynn Jorde, a human geneticist at the University of Utah School of Medicine in Salt Lake City. The next step is to do functional studies to see how these gene variants actually regulate oxygen levels. “This is a groundbreaking paper,” says geneticist Anna Di Rienzo of the University of Chicago in Illinois. “These genes seem to have relatively large phenotypic effects.” But although these genes apparently lower the level of oxygen in the blood, they are responsible for only part of the story of the Tibetans’ adaptation and would not by themselves make a beneficial drug for climbers. “Just lowering your hemoglobin alone would make you less well adapted to high altitude,” points out Jorde. Researchers are still searching for the genes that orchestrate how Tibetans transport low levels of oxygen so efficiently to their tissues—a process that may involve using nitric oxide to boost their blood volume. news from sciencemag.org
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