Monkey Genomes Offer Clues to Survival at High Altitudes

Thursday, July 28, 2016
David Irwin headshot
Professor David Irwin

Scientists in China recently discovered changes in gene function that partly explain how snub-nosed monkeys have adapted to life in Asia's remote mountains. The findings could help conserve the endangered primates and may shed light on altitude sickness in humans.

David Irwin was a co-author on the study, which Nature Genetics published last month. Irwin is a professor in the Departments of Laboratory Medicine and Pathobiology, and Ecology and Evolutionary Biology, and he has studied changes in gene function for more than three decades. Irwin spoke with Faculty of Medicine writer Jim Oldfield about the recent findings, his collaborations in China and what genomics is revealing about evolution.

What did this study find?

The researchers uncovered six genes involved in adaptation to high altitudes, and which appear to play a role in lung function, DNA repair and angiogenesis (new blood vessel growth). There are five species of snub-nosed monkey, and this study compared two groups of those species that moved to higher altitudes independently of one another. That was a strength of the study — the distinct geographical separation but short evolutionary time between the two groups meant the researchers could be confident the adaptive changes they found were related to high altitude and not just a coincidence.

What was your role in this study?

I didn't play a big role. I've been working with this group for several years, and they keep posing interesting research questions. I've given them some suggestions on different ways to handle their data or make it more publishable. I've encouraged them to move into more functional analysis, not just bioinformatics analysis of data. Important changes in gene function appear in the order of chemical bases in a DNA or RNA sequence, but also in the abundance or expression of the gene's products. So the addition of RNAseq data, which showed increased expression of many genes involved in energy metabolism in high altitude species, begins to address this important issue.

How did you come to work with this group?

About a decade ago my wife got a three-year position with Bayer Pharmaceuticals in Beijing. I planned to travel there and at the time, Ya-Ping Zhang (the principal investigator on the Nature Genetics paper) was probably the most famous molecular evolutionist in China, so I contacted him and asked to meet. He said yes and we struck up a relationship, which has been very productive. I've met several very bright and hard working students through collaborations with his and other groups, and I've since come to work with Li Yu, the first author on the current study. My wife stayed in China and now leads research and development at Takeda in Shanghai, so I look for good reasons to go there. 

Why study these monkeys and evolutionary changes in gene function?

Well, all species of snub-nosed monkey are endangered. They're unusual in that they've adapted to life at varying, and in some cases extremely high, altitudes. Anything we can figure out about their biology and genetics should be helpful in trying to conserve them. For breeding programs, for example, you need extensive knowledge of each species. One effort to conserve orangutans didn't work because the mates weren't the same species. As for the value of this work in human health, high-altitude sickness is a problem, both for travelers and populations that live in mountainous regions. It causes headaches, nausea and fatigue, and it can be fatal. Part of the goal with this kind of research is to discover physiological processes that we might modify so that humans can better function and survive at high altitudes.

When did you first take an interest in changes in gene function?

I did my postdoctoral work at the University of California, Berkeley, where I developed an interest in the evolution of gene function while studying lysozyme. Lysozyme is an enzyme that in humans occurs naturally in saliva, tears and other bodily fluids, and it acts as an anti-septic by helping to break down bacterial cell walls. But in cows and other ruminants, it's expressed in stomach. The recruitment and adaptation of lysozyme to function in the stomach allows ruminants to break open and digest the contents of bacterial cells (which, after fermentation in the foregut, contain essential nutrients). After studying lysozyme, I began looking for other examples where genes changed function and play a key role in survival, health and disease.

What have we learned about how genes change function?

Both natural selection and neutral evolution (random genetic changes unrelated to a species' survival) contribute to changes in gene function. Natural selection can either remove alleles (gene variants) that are not useful or drive the spread of alleles that have benefits. Neutral evolution typically provides minor changes that species can use to explore new environments. We've learned that as species move into new environments, natural selection commonly drives adaptive evolution — changes that help them thrive in a particular environment. Surprisingly, loss of genes can increase the diversity of traits that allow species to adapt. With the increased number of genome sequences from different species and individuals, we're getting a clearer picture of how genes change as species adapt, and of how pathways and networks adapt. In my lab we're now using these genomes to explore the evolution of genes in pathways that regulate glucose metabolism, especially in the liver. A better understanding of changes in those genes could help improve treatments for diabetes and other diseases.