“I was with my colleague looking at our results when we found EPAS1,” says Emilia. “We didn’t know what it was, so we looked it up in the Human Genome Browser. When we saw it was involved in the response to hypoxia, we got really excited!” It was exactly the sort of gene they’d hoped to find. EPAS1 is a transcription factor — that is, it codes for a protein that helps control the expression of other genes. While the molecular details are still being investigated, EPAS1 seems to be expressed when oxygen levels fall and then goes on to regulate other genes involved in the response to low oxygen.
Emilia and her colleagues aren’t yet sure how the variant in EPAS1 that was favored among Tibetans works, but they do know that it makes a difference in altitude-related traits. The Chinese team studied the blood of Tibetan individuals carrying the most common mutation (called G in the table here) and found that people who carried that mutation tended to produce fewer red blood cells and to have lower hemoglobin concentrations.
C = allele most common among Han, G = allele most common among Tibetans.3
This observation fits with what was already known about Tibetans’ response to high altitudes. The extra production of red blood cells involves a tradeoff: additional red blood cells have hemoglobin that can carry more oxygen, but, in extreme cases, they can make the blood more viscous and actually decrease blood flow to organs. Tibetans don’t produce extra red blood cells, yet they somehow manage to get enough oxygen to their cells to do well at high altitudes. The Tibetan response to high altitudes is complex, but clearly works. Based on the results associating EPAS1 with red blood cell and hemoglobin levels, the gene seems to have something to do with this ability, although it will take a lot more research to figure out how all the puzzle pieces fit together and what other genes might be involved.
3 Adapted from Table S4 in Yi et al. (2010).