How Tibetans' Ancestors Adapted to High Altitudes

In response to low oxygen conditions, our body produces extra red blood cells in an attempt to get enough oxygen to our tissues. Although this is helpful in the short-term, it also makes the blood thicker, which impairs blood flow and can lead to long-term complications such as heart failure. Populations which live at high altitudes, like Tibetans and Andeans, don't suffer from this problem; their blood doesn't thicken in the hypoxic environments where they live. In a paper appearing in Nature Genetics, an international team of researchers has identified the mutation behind this difference, a key factor in enabling these populations to thrive where others fare poorly.

Earlier studies showed that variants of several genes are linked with the resilience of high-altitude populations, but they didn't demonstrate which of the mutations, if any, was actually responsible. To get to the bottom of the mystery, the team sequenced these candidate genes in 26 Tibetans living in the US. Two of the candidate genes were unaltered in these Tibetans, but the team found a consistent mutation in the third gene, with only 4 of the 26 individuals having the non-mutated version. All 26 individuals also had a second mutation at a different location in the same gene. An analysis showed that both mutations had undergone positive selection recently, and one of the mutations appeared only 8,000 years ago. Which of them was behind the low-oxygen tolerance of the Tibetans? Or were the two mutations — both in the same gene — jointly responsible?

The gene in question encodes a protein called PHD2 which controls the hypoxia response. At normal oxygen levels, PHD2 binds to a major hypoxia-response protein and marks it to be destroyed by the cell; this interaction doesn't happen at low oxygen levels, freeing the hypoxia response regulator to act without interference from PHD2. The team discovered that the two mutations don't knock out PHD2; instead, they seem to change the way it works. Neither of the mutations had an impact on its own, but the PHD2 variant with both mutations was more efficient at using oxygen to bind to the hypoxia response factor. In other words, it could still interact with the hypoxia-response regulator at low oxygen concentrations and tag it for destruction. The researchers double-checked their in vitro findings in cell cultures, confirming that cells with the doubly-mutated version of PHD2 have reduced levels of the hypoxia response protein at low oxygen levels. As a result, these cells don't over-proliferate in hypoxic conditions, and people with these mutations don't suffer from thick blood at high altitudes. Oddly enough, the mutant cells did grow more at "normal" oxygen levels, though the researchers don't know quite why.

Of course, adaptation to high-altitude conditions doesn't result from a single mutation; it takes a suite of changes acting in concert. Some of these may result from the mutations in PHD2, since the hypoxia-response protein it regulates also affects metabolism. Other factors (and other mutations) doubtless contribute, and it will take more research to find and understand them. In the meantime, we can benefit from an increased understanding of oxygen homeostasis, which is central to the functioning of our bodies.

Ref
Lorenzo, F.R. et al. A genetic mechanism for Tibetan high-altitude adaptation. Nature Genetics; advance online publication (2014). doi: 10.1038/ng.3067

Image credits
The image is by Felipe Lorenzo and is taken from a press release by the University of Utah.