‘Fat gene’ stands falsely accused, offers lesson in gene-gene interactions

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For little more than a half-decade, a gene called FTO has been touted as a ‘fat gene’ — now it seems like it was falsely accused. The connection between FTO and body weight is real, but the way it influences metabolism and eating behavior is more complicated than the one-to-one relationship implied by the phrase ‘fat gene’.

It seems a gene called IRX3 is the actual ‘fat gene’ researchers have been looking for, according to a study published yesterday in Nature. FTO, it seems, only affects weight by influencing IRX3. More than simply advancing our knowledge of weight and metabolism in mammals, the story of how researchers spent so long focused on the wrong gene offers a lesson in the physical complexity of the genome and the importance of gene-gene interactions.

The revelation that FTO is not the true culprit in this particular crime has been a long time coming. Nature news summarizes some of the red flags that had been bothering geneticists, including Marcelo Nóbrega at the University of Chicago, lead author of the new study:

The mutations were located in non-coding portions of FTO involved in regulating gene expression. But when Nóbrega looked closer, he found that something was amiss. These regulatory regions contained some elements that are specific for the lungs, one of the few tissues in which FTO is not expressed. “This made us pause,” he says. “Why are there regulatory elements that presumably regulate FTO in the tissue where it isn’t expressed?”

There should have been some identifiable link between the mutated version of FTO, obesity, and the expression of FTO in obese animals. Attempts to find this link had been a “miserable failure”, Nóbrega told Nature news.

The puzzle facing Nóbrega and his collegues: a mutation in FTO is observably connected to obesity. But this mutation is not in the coding part of the FTO gene, rather in the non-coding portions that serve to regulate the expression of the FTO gene. But no one can link the expression of FTO to obesity either.

So, Nature explains, Nóbrega and his began looking around in the genetic “neighborhood” of FTO for promising candidates. They found IRX3: a gene that codes for a protein that regulates the expression of other genes and is highly expressed in the brain, which would make it consistent with a role in metabolism and eating behavior.

After a gamut of tests in lab mice to see what happens when IRX3 is turned off, the researchers confirmed that it not only had the effect on weight they were looking for, but that it was more powerful than the one observed from messing with FTO.

Though the two genes are in the same ‘neighborhood,’ they’re still about half a million base pairs away — how could FTO be interacting with IRX3 to influence obesity?

Science journalist Ed Yong explains:

Remember that the genome isn’t just a string of As, Gs, Cs, and Ts on a page—it’s a physical thing. It is made of DNA that twists and loops into three-dimensional spaghetti-like whorl, turning distant bits into close neighbours.

The team found that one such long-range connection between the obesity-related part of FTO and the region that switches on IRX3. The two regions were linked in mice, in zebrafish, and in human cells, which shows that the they have been interacting for at least 400 million years.

So those bits of non-coding DNA in the FTO gene that should have been influencing the expression of FTO? They were influencing the expression of IRX3 due to its close proximity.

The moral of the story? Just because we’ve identified a link between a particular effect like weight gain and a particular gene doesn’t necessarily tell us anything about what genes are directly involved, or how. The physical structure of our DNA is not linear, and the spatial arrangement of our genes means that sometimes seemingly distant and unrelated genes can influence one another.

Nóbrega told Nature that he sees a lesson for his peers in his latest study:

Geneticists should keep in mind this example of unexpected interactions between distant genes when dealing with genetic association studies. “There may be many other cases where people are studying the wrong gene,” he says. “We might be chasing ghosts.”

Kenrick Vezina is Gene-ius Editor for the Genetic Literacy Project and a freelance science writer, educator, and amateur naturalist based in the Greater Boston area.


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