Dogged Research Spots Gene Behind Pooches' Size

Discovery also gives insight into canine, human disease, experts say

Dogged Research Spots Gene Behind Pooches' Size

THURSDAY, April 5, 2007 (HealthDay News) -- Variation in just one gene turns a toy poodle into a standard and helps separate tiny Chihuahuas from massive Great Danes, new research shows.

"It's a gene called IGF1, for 'insulin growth factor 1'. We found a particular signature or pattern of variation for that gene in all small dogs, and we see a different pattern of variation in that gene when we look at the large breeds -- the St. Bernards and the Great Danes and Newfoundlands," said the study's senior researcher, Elaine Ostrander, chief of the cancer genetics branch at the U.S. National Human Genome Research Institute.

While dog lovers may be most interested in how the gene determines their pet's size, scientists like Ostrander say the discovery has much broader implications.

"Understanding the genetics of growth and regulation is key to understanding many disease processes that we see in both animals and humans, whether that's cancer, diseases of skeletal growth, hip dysplasia -- any of those things where cell division has gone awry," she said.

Other dog -- and medical -- experts agreed. "We're very excited about these findings, both with regard to the canine community and the implications for human research as well," said A. Duane Butherus, grants chairman of the American Kennel Club's Canine Health Foundation.

"The compact breeding cycles and well-documented pedigrees of purebred dogs are helpful tools in the search for genetic markers," he said. "The markers we find in canine research are often the candidate genes for human research as well, so 'man's best friend' is truly becoming man's best friend in the fight against disease," Butherus said.

The findings, based on a collaboration involving the National Human Genome Research Institute and a number of academic centers, are published in the April 6 issue of the journal Science.

According to Ostrander, dogs are ideal subjects for research into the genetics of cell growth. "Dogs differ in body mass by about 40-fold, and nowhere else among the land mammals do we see that amazing diversity and variation," she said.

Most of that variation is man-made, she added. As humans moved to a more settled, agrarian society more than 15,000 years age, they began domesticating young wolves to help protect them and to help them herd and hunt. That meant rapid specialization of canines.

"We strongly selected different breeds of dogs to have different features that would suit our lifestyle," Ostrander said. That produced everything from large, fleet-footed dogs (to help bring down game) to much smaller "ratters" for digging out ground-dwelling mammals, she said.

But why selectively breed dogs and not cats or pigs? According to Ostrander, Canis familiaris may have a distinct genetic advantage over other species.

Although it hasn't been proven yet, many scientists believe that "there is some kind of 'fast-forward' evolutionary mechanism in dogs that constantly throws up new (gene) variants much more quickly than in other species," she said.

The IGF1 gene seems particularly pliable in that regard. The research into this bit of DNA began with the Portuguese Water Dog, a shaggy, highly pedigreed breed that varies widely in size, from tiny toys to waist-high variants.

Study co-author K. Gordon Lark, professor emeritus of biology at the University of Utah, is a geneticist and owner of Mopsa, a Portuguese water dog. His team had previously scanned this breeds' genome and found a suspected locus for a "size gene" on chromosome 15.

Reaching out to other Portuguese water dog owners nationwide, the team also obtained blood samples from more than 1,000 dogs and took X-rays of 600 more.

Mopsa was "'dog number zero'" in this effort, Lark said. "She had the prototype X-rays and such so that we could see what we wanted done."

Based on the Utah findings, Ostrander and others expanded the research to include DNA from more than 3,000 dogs and 143 breeds. They finally honed in on the IGF1 gene, which appears to be regulated differently depending on a dog's size.

"This gene makes this hormone, insulin growth factor 1, that is necessary for growth," Lark explained. "The regulatory sequence determines how much of that hormone will be made and put into the dog's blood system to control the growth rate. It's like a dimmer switch for growth."

The pattern quickly became clear, Ostrander said. "Small dogs had one signature, larger breeds had another," she said.

Exceptions arose, however. For example, Rottweilers carry both the small- and big-dog signatures, although the big-body variant seems to win out, Ostrander said. Mastiffs carry both gene signatures, as well.

"That tells us that there are other genes out there that are interacting with this master-regulator, IGF1," Ostrander said.

For that reason, simply tweaking the IGF1 gene probably wouldn't lead to super-sized Chihuahuas or teacup German Shepherds.

"No, it's going to take other genes to do that," Ostrander said. "But now we know the master regulator, and we know what other kinds of genes to go after. That's what we are in the process of doing now."

More information

There's more on research into dog genetics at the Canine Health Information Center.

SOURCES: Elaine Ostrander, Ph.D., chief, cancer genetics branch, U.S. National Human Genome Research Institute, Bethesda, Md; K. Gordon Lark, Ph.D., distinguished professor emeritus, biology, University of Utah, Salt Lake City; A. Duane Butherus, Ph.D., grants chairman, Canine Health Foundation, American Kennel Club; April 6, 2007, Science
Consumer News