How People Living at Earth's Extremes Reveal the Genome's Best Tricks

Evolution has sculpted the human genome to cope with Earth’s toughest climates, inadvertently pointing geneticists towards medically important genes.

If I ate an Inuit diet, extremely low in plants and high in fats from oily fish and blubbery mammals, my blood vessels would soon be screaming out for mercy. The Inuit themselves have no such problem. They have long since adapted to their distinctive diet, and have several unusually common variants in genes that metabolize fatty acids. And Rasmus Nielsen from the University of California, Berkeley, who identified these variants, showed that they also strongly influence height and weight, not just in the Inuit, but in Europeans too.

Nielsen's study was notable not just for its results, but for the vanishingly small number of people it took to get those results. Height, weight, and other traits like intelligence and schizophrenia risk are influenced by hundreds or thousands of genetic variants, each of which only has a small effect. In the early years of human genetics, when researchers searched for these variants by running small studies, they ended up with reams of unreliable results. So, studies got bigger and more collaborative.

For example, the aptly named GIANT consortium recently found 700 genetic variants that collectively explain just 20 percent of the variation in heights between people—and it took them 253,000 volunteers to do so. Nielsen's team, by comparison, initially worked with just 191 Inuit volunteers.

They got away with it because natural selection had already done a lot of the hard work for them. Over millennia, it had identified genes that help the Inuit to cope with their extremely fatty diets and sculpted them accordingly. All Nielsen had to do was to look for the signatures of this sculpting—for example, regions of the genome with variants that are more common in Inuits than in other populations. He then analyzed these regions in a larger group of 4,500 Inuit volunteers, to see if the genes within affected traits like height or weight.

That's the opposite way round to how many other geneticists work. They often start with the trait and try to find relevant genes. Nielsen, however, started by finding genes that evolution had already flagged as being important, and then worked out what traits those genes influence. “First, we find the bit of the haystack where the needle might be,” he explains. And his team did the same thing in Tibet and Ethiopia, identifying genes that help local people cope with air that has 40 percent less oxygen than what most of us inhale.

The field of genetics needs more studies like this. Humanity isn't just restricted to the cities of Europe, North America and East Asia, where most participants in genetic studies hail from. We are a species of extremes. We have spread far and wide, and evolution has sculpted our genomes to meet the toughest challenges Earth has to offer: scorching heat, freezing cold, mountains with thin air and intense sunlight, and regions where debilitating diseases are everyday threats. And by looking at the genomes of people who live in such environments, we stand a better chance of finding genetic variants that are broadly relevant to human health.

For example, the variants that Nielsen identified are found in one in every six East Asians, and probably also influence their health, height, or weight. They’re much rarer in Europe, but Europeans have other variants in the same genes, which might affect their health. So the Inuit study gives us clues about human biology that will ripple globally. “Nature has produced a way for them to adapt to high-fat diet,” says Sarah Tishkoff at the University of Pennsylvania. “If you base a therapeutic on that, it could affect all populations.”

There is precedent for this. By studying African Americans with astonishingly low levels of cholesterol, scientists at University of Texas Southwestern Medical Center identified rare mutations in a gene called PCKS9, which reduce the risk of heart disease. That discovery led to a new class of cholesterol-busting drugs that target PCKS9.

Similar important variants are probably sitting in the genomes of ethnically diverse groups from all corners of the world, who have adapted to the harshest challenges that the planet has to offer. And yet most genetic studies have focused on the same recurring populations: Europeans, North Americans, and East Asians. To Nielsen, this makes no sense. “We want to know about variants that affect, say, Alzheimer's risk in Europeans to know more about what causes Alzheimer’s, not for the sake of knowledge in that particular group,” he says. “So why do we keep on focusing on Europeans? There are many other populations in the world.”

Africa is particularly full of genetic treasure. “Based on our evolutionary history, all non-Africans are a subset of Africans,” says Tishkoff. “Africa has the greatest amount of genetic diversity in the world so you're likely to find something novel there.” She has worked with West African pygmies to identify genes involved in (short) height, and she’s interested in the Fulani, a West African group who “have an innate resistance to malaria, which no one understands.”

Groups like these are still underrepresented in genetic research, partly because the same harsh environments that have sculpted their genomes can scupper genomicists. “When we were working in Cameroon, I had to get two landcruisers and bring liquid nitrogen, a generator, and our own portable lab. Four members of my team got malaria. One got extremely ill,” says Tishkoff. And in other parts of Africa, “we’ve had car crashes and near-electrocutions. People can't imagine how hard it is.”

Even when researchers successfully run this gauntlet, they still face the hardest obstacle of all: peer review. “It takes hundreds of thousands of dollars to get 1,300 samples, and for that amount of money, you could get tens of thousands of Europeans,” says Tishkoff. “So when we try to publish, you'll get people who are used to studying these giant urban populations scoffing at our sample size.”

“So, what, we should ignore all these people? Not include them?” she adds. “It's not fair to them because they’re not benefiting from the knowledge that's gained, and the potential diagnostics and therapeutics that could come out of this. We lose out, and they lose out.”

But these scientific goals must be balanced against the cultural beliefs of indigenous groups, and well-founded fears over exploitation, as Rose Eveleth discussed in the Atlantic earlier this year. “We geneticists need to change our mindset,” adds Nielsen. “Instead of studying a population, you're working with that population. One objective is always to improve health care in the communities.”

For example, one of his collaborators on the Inuit project has been working to improve public health in Greenland for years. Similarly, Nielsen and fellow geneticist Eske Willerslev have been talking to Aboriginal Australian communities about research goals that are relevant to them. “They have a very high rate of type 2 diabetes, and they want to know why they get that more than Australians of European descent,” says Nielsen.

Implicitly, working with a population involves ensuring that they hear about the results of research that they were a part of. “We go back,” says Tishkoff. “We translate results to layman's terms and local languages. And let me tell you, they really, really appreciate that.”

She remembers recently working with Sandawe hunter-gatherers, when one man asked if she was from the same group that visited them in 1954. “They knew the exact date these people had come, and they had been waiting for over 50 years to get the results from the study. One of them had this pamphlet with a double helix on it. And he pointed to it and said: This is what you're studying, right? He clearly got it. And when I showed them the results, he said: We’re important.”