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According to the law of natural selection, genetic mutations that make people sick would ordinarily get suppressed in the human genome during the course of evolution. But the opposite can happen if that genetic variant occurs on the genome close to one that carries big advantages, as new University of Utah-led research shows.

A team of scientists has concluded that a genetic variant implicated in Crohn's disease, a painful chronic bowel disorder, "thumbed a ride" with the same genetic adaptation that allowed humans to nourish themselves on the world's first food crops thousands of years ago.

Researchers believe the genes responsible for Crohn's were swept along with variants that helped humans adjust to agricultural diets after eons of hunting and gathering wild foods, according to results published Thursday online in the journal Molecular Biology and Evolution.

Senior author Stephen Guthery, a U. associate professor of pediatrics, initiated the study to explore the intriguing association between this helpful variant to the gene OCTN and Crohn's disease. He hypothesized that genes in IBD5, the same region of the genome where OCTN is parked, predispose people to the condition.

"We focused on a single genetic risk factor for Crohn's disease," Guthery said, quoted in a U. news release. "This risk factor contains several genes, and it is unclear which of these genes cause Crohn's disease. Our work suggests that one genetic mutation in this region became common in Europeans because it was beneficial, and that neighboring disease-causing genetic changes hitchhiked and became more common."

Agriculture gained a foothold in an area known as the Fertile Crescent, centered around modern day Iraq's Tigris and Euphrates rivers. Some of the first domesticated foods, such as milk, lentils and peas, are devoid of ergothioneine, an amino acid and antioxidant common in meat and fungi.

Along with the spread of agriculture, a genetic variant to the OCTN gene enabled humans to quadruple their absorption of ergothioneine, according to lead author Chad Huff, a U. postdoctoral research fellow in human genetics. It swept through European populations because it gave those with the variant a "2 percent selective advantage," Huff said, meaning carriers would produce 2 percent more offspring than non-carriers.

"We tend to think of adaptive evolution as something that is always beneficial. But rapid adaptation can be inefficient and sometimes even detrimental," he said. "In this case, we think an adaptation to a transient change in diet around 12,000 years ago resulted in a genetic predisposition to Crohn's disease that is present in about half of all Europeans today."

Only a fraction of a percent of those with this genetic predisposition actually develop symptoms, a lifelong inflammation of the bowels, that afflict an estimated 700,000 Americans.

The team used a genetic association study, a technique that compares the genomes of many unrelated Crohn's patients to those without the disease.

They discovered that the OCTN mutation was associated with Crohn's only when it was paired with changes to a nearby gene called IRF1. To confirm their suspicion that IRF was a genetic culprit, the team studied gastrointestinal biopsies of Crohn's patients and found a 72 percent increase in IRF gene expression compared to those without the disease. Meanwhile, there was no increase in OCTN gene expression.

"We are trying to identify the actual variants that cause Crohn's. This puts us closer to identifying genetic risks," Huff said. "We can also apply this technique to other regions of the genome for other diseases." Crohn's disease

Scientists suspect genetics predispose people to this inflammatory bowel disorder, suffered by 700,000 Americans, but have yet to pinpoint risk factors and or identify a cause. Typical cases include ulcers in the intestines and symptoms of abdominal pain and diarrhea. New University of Utah research implicates a gene variant that "hitched a ride" with a beneficial mutation that allowed humans to adapt to agricultural diets.

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