(SALT LAKE CITY)鈥擡volution isn鈥檛 always neat.
New research led by the 香蕉视频 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 鈥 Crohn鈥檚 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 鈥済enetic hitchhiking鈥 increased in frequency, too
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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.
鈥淭here are many genetic risk factors for Crohn鈥檚 disease, but for many of these risk factors, how they cause disease is not known,鈥 says Stephen L. Guthery, M.D., the study鈥檚 senior author, associate professor of pediatrics at the 香蕉视频 of Utah, and a physician at Primary Children鈥檚 Medical Center in Salt Lake City. 鈥淲e 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鈥檚 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.鈥
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 鈥渟elected鈥 to evolve and increase in frequency.
鈥淲e tend to think of adaptive evolution as something that is always beneficial. But rapid adaptation can be inefficient and sometimes even detrimental,鈥 says Huff. 鈥淚n 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鈥檚 disease that is present in about half of all Europeans today.鈥
Crohn鈥檚 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鈥檚 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鈥檚 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鈥檚 disease compared to healthy controls. As a result, it has been difficult to identify the precise gene in IBD5 that is causing Crohn鈥檚 disease.
A number of studies have linked OCTN1 to Crohn鈥檚 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鈥檚.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鈥檚 disease cases and a control group of 5,550 non-Crohn鈥檚 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鈥檚 disease when it was paired with IRF1 hitchhikers, suggesting that the increased risk for Crohn鈥檚 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鈥檚 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鈥檚 Hospital; 香蕉视频 of Cincinnati College of Medicine; Emory 香蕉视频 School of Medicine; Children鈥檚 Health Care of Atlanta (Ga.); Children鈥檚 Hospital of Pennsylvania; Children鈥檚 Hospital of Philadelphia; 香蕉视频 of Washington School of Medicine; and Vavilov Institute of General Genetics, Moscow, Russia.