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Thumbing a Ride with Evolution: 'Hitchhiking' Gene Tied to Crohn's Disease

(SALT LAKE CITY)—Evolution isn’t always neat.

New research led by the University of Utah School of Medicine proposes that when a particular genetic change evolved as a dietary adaptation in humans who grew the first food crops, the process swept along less desirable changes in another gene that contribute to a painful bowel disorder affecting an estimated 700,000 people in the United States – Crohn’s disease.

In the Thursday, Aug. 4, 2011 online edition of the British journal Molecular Biology and Evolution, researchers from the U and nine other institutions state that about 12,000 years ago a genetic mutation evolved to compensate for a dietary substance in short supply in the first domesticated crops. When that happened, the genetic mutation increased in frequency. But other mutations were pulled along in the genetic whirlwind and in a process known as “genetic hitchhiking” increased in frequency, too

Genetic hitchhiking can be thought of as beads on string. Each bead represents a genetic change.  If one lays the string on a table, then pushes up on a single bead, other beads also move.  The pushed bead represents a genetic mutation that is increasing in frequency, and the other beads are the genetic hitchhikers.

“There are many genetic risk factors for Crohn’s disease, but for many of these risk factors, how they cause disease is not known,” says Stephen L. Guthery, M.D., the study’s senior author, associate professor of pediatrics at the University of Utah, and a physician at Primary Children’s Medical Center in Salt Lake City. “We focused on a single genetic risk factor for Crohn disease.  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.”

The story unfolded in the Fertile Crescent, the large swath of land that today comprises parts of Iraq, Iran, Israel, and other areas in the Middle East where humans grew the first food crops. Guthery, lead author Chad D. Huff, Ph.D., a postdoctoral fellow in human genetics at the U, and their colleagues hypothesize that early crops grown, such as lentils, peas, wheat, and barley, were low in ergothioneine, an amino acid and antioxidant.  In response, a gene variant in OCTN1, which transports or allows ergothioneine to enter into cells, was “selected” to evolve and increase in frequency.
“We tend to think of adaptive evolution as something that is always beneficial.  But rapid adaptation can be inefficient and sometimes even detrimental,” says Huff.  “In this case, we think that 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.”
Crohn’s disease is a lifelong inflammatory bowel disease in which parts of the digestive system get swollen and have ulcers. It is usually found in the small or large intestine, but it can develop anywhere in the digestive system. Common symptoms include abdominal pain, diarrhea, and weight loss. Less common symptoms include mouth sores and intestinal blockages.
The causes of Crohn’s disease are not known. It is thought to be caused by an inappropriate inflammatory response to intestinal microbes in genetically susceptible individuals.
Approximately 70 regions in the genome contribute to Crohn’s disease, though in many cases, the precise gene that causes disease is unknown.  The researchers focused on one region, called IBD5, which contains several genes, including OCTN1 and IRF1.  IBD5 contains many genetic changes, most of which have different frequencies in Crohn’s disease compared to healthy controls. As a result, it has been difficult to identify the precise gene in IBD5 that is causing Crohn’s disease.
A number of studies have linked OCTN1 to Crohn’s disease. But this new study suggests that many genetic changes in IBD5 were swept along for the ride when OCTN1 was selected. The authors speculate that it is the variants in IRF1, not OCTN1, that predispose to Crohn’s.Using a genetic association study, a technique that compares the genomes of many people with a particular disease to those of a control group without the disease, the researchers looked at the genes of 1,868 Crohn’s disease cases and a control group of 5,550 non-Crohn’s cases. Their analysis examined two classes of chromosomes, those with both the OCTN1 mutation and genetic hitchhikers near IRF1, and those with the OCTN1 mutation but with no genetic hitchhikers.  They found that the OCTN1 mutation was only associated with Crohn’s disease when it was paired with IRF1 hitchhikers, suggesting that the increased risk for Crohn’s disease is not due to the OCTN1 mutation itself, but is instead due to genetic hitchhikers in IRF1.
To verify their results, Guthery, Huff, and colleagues obtained gastrointestinal biopsy samples from both healthy people and Crohn’s disease patients and found a 72 percent increase in IRF1gene expression in the samples from people with the disorder and no significant increase in OCTN1 gene expression.

Other institutions involved in the research are:  Cincinnati Children’s Hospital; University of Cincinnati College of Medicine; Emory University School of Medicine; Children’s Health Care of Atlanta (Ga.); Children’s Hospital of Pennsylvania; Children’s Hospital of Philadelphia; University of Washington School of Medicine; and Vavilov Institute of General Genetics, Moscow, Russia.