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Researchers Identify Gene That Plays Key Role in Size of Dogs -- and Probably in Humans

An international team of scientists, including researchers from Cornell University, has found a mutation in a single gene that plays a key role in determining// body-size differences within and among dog breeds and probably is important in determining the size of humans as well.

The research, published in the April 6 issue of the journal Science, "is one of the first demonstrations that if you look at different dog breeds that share the same trait (such as large or small size or short legs or scrunched-up faces) due to human-directed selection, you will find genes that are likely to affect the same traits in humans," said co-author Carlos Bustamante, assistant professor of biological statistics and computational biology at Cornell.

The researchers began by comparing the DNA of individuals within a single dog breed that shows great variation in skeletal size -- Portuguese water dogs -- and identifying regions of the genome that differ between small and large individuals.

One of these regions included a gene that codes for a protein hormone called insulin-like growth factor 1 (IGF1), which is known to play an important role in growth, body size and longevity in mice and in body size in humans. The researchers then analyzed this region in hundreds of dogs from 14 small dog breeds, such as Chihuahuas, toy fox terriers and Pomeranians, and nine large dog breeds, including Irish wolfhounds, Saint Bernards and Great Danes.

Surprisingly, almost all of the dogs from the small breed shared a stretch of DNA that was identical to that found in small Portuguese water dogs, but different from that found in large breeds, large Portuguese water dogs, wolves and other wild members of the dog family, such as jackals.

Researchers suspect a single mutation early in the domestication history of dogs created a "small dog" version (or allele) of IGF1. This mutation became fixed in small dog breeds through human breeding of the dogs. The results suggest that IGF1 plays a similar role in differentiating small from large dogs within breeds, small from large breeds within dogs, and likely size differences among species.

Cornell's role in the research was in part to show the statistical significance of the pattern of variation found near the IGF1 gene and to demonstrate that selection by humans likely was responsible for the differences in IGF1 between small and large dog breeds using a sample of more than 3,000 dogs from 143 breeds.

"It is staggering to think that so many of the small dog breeds came about through selection on the same mutation in the same gene. These results suggest that while there are invariably differences among breeds (even in genes for size), IGF1 has played an important role in the evolution of many small breeds by being a gene that consistently affects body size," said Bustamante. "The research points to the utility of the domestic dog model system to identify genes that have a large effect."

Because small dog breeds are only distantly related to each other, the researchers believe the gene variation for small dogs probably first appeared early in the history of dogs. As a result of selective breeding of dogs by humans over many generations, dogs today exhibit the greatest diversity in body size of any mammal.

The study's lead author was Nathan Sutter and senior author Elaine A. Ostrander, both of the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health. The study included close collaboration between NHGRI, Cornell, University of Southern California, University of Utah in Salt Lake City, University of California-Los Angeles, University of Missouri in Columbia, the Waltham Centre for Pet Nutrition in Leicestershire, England, and the Nestle Research Center in St. Louis.

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