On Genes and Time

You’d be forgiven for calling FTO the “fat gene.” There are two variants of the gene, and in study after study, one of those variants, known as rs993609, is associated with more weight, as well as a much higher risk of obesity. The comparison holds up in different countries, and in different ethnic groups. The link is so clear that it might seem like saying FTO can make you fat is as true as saying two plus two equals four.

Now try to imagine discovering that before World War II two plus two equaled zero.

That’s the gist of a new study on FTO’s effects over time. As I explain in my new “Matter” column for the New York Times, scientists have looked at the link between FTO and body-mass index in a long-term study of thousands of people over many decades. They found that people born before 1942 show no link. None. The link is strong in people born afterwards, and gets stronger with time.

I find this study interesting because it provides a twist on the old debate about nature versus nurture. Take two people with identical genes and put them in different environments, and some of their genes may respond in different ways. That’s long been a good counterargument against genetic hyper-determinism. Here’s a case where the entire environment–the world in which we live, work, and eat–has changed. As a result, a gene that would have gone overlooked if scientists looked for it a couple generations ago now leaps out as a clear factor in one of the world’s most pressing medical problems.

It’s possible that other genes will show patterns of their own over time. Putting a time axis on how genes affect our health may make studying the matter far more challenging–as well as using that information to guide medicine. What proves true now may not be true a few years from now.

PS– There’s a fascinating side-story about FTO that I didn’t have space to get into, which University of Chicago geneticist Vincent Lynch raised on Twitter. Ever since FTO’s effect was discovered in 2007, scientists have been puzzling over how that effect comes about. They’ve discovered that the FTO protein does all sorts of interesting things, including affecting the brain biochemistry involved in appetite. But a study that came out in March suggests the risk variant may have nothing to do with the FTO protein at all.

“Wha….?” you say? Well, here’s the thing. A gene like FTO is made up of two different kinds of pieces of DNA, called introns and exons. Cells make FTO proteins by only reading the exons of the FTO gene, essentially ignoring the introns. Packing genes with unread DNA may not sound smart, but evolution doesn’t build life the way you might.

It turns out that the rs993609 mutation sits in an intron in the FTO gene. So it doesn’t appear to change the FTO protein. Instead, scientists suspect that the rs993609 mutation sits in a little stretch of DNA in that intron, called an enhancer. They speculate that this enhancer can somehow coax our cells to make copies of another gene that lies elsewhere in our DNA. The rs993609 mutation changes how the enhancer acts on that other gene.

So rs993609 is “in” the FTO gene–in a geographical sense–and yet the FTO gene itself may not make post-war folks fat.

This molecular mystery doesn’t affect the patterns in the new study I wrote about in my column. But it will be important to understanding the biology of obesity. And it serves as a good lesson in how tricky it can be to talk about genes.