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Researchers find gene that determines dog size

Canines' regulatory DNA could have human corollary

Thomas H. Maugh II, Los Angeles Times (Friday, April 6, 2007)

Researchers have finally solved one of the great canine mysteries: Why are small dogs small?

As it turns out, small dogs all bear a tiny piece of regulatory DNA that shuts off the gene that produces a powerful growth factor.

The gene regulator was probably inherited from a miniature wolf about 15,000 years ago a -- though it has since disappeared from the wolf population -- and has spread rapidly throughout the dog world by human intervention.

"All dogs under 20 pounds have this -- all of them," said biologist K. Gordon Lark of the University of Utah, one of the authors of the paper published today in the journal Science. "That's extraordinary."

The discovery helps explain the great diversity in size among dog breeds, the greatest diversity among any mammalian species. It also may have implications for humans.

"By learning how genes control body size in dogs, we are apt to learn something about how skeletal size is genetically programmed in humans," said geneticist Elaine Ostrander of the National Human Genome Research Institute, who led the study.

The gene in question, IGF-1, is the blueprint for a protein called insulinlike growth factor, which not only plays a role in human growth but also is implicated in cancer and certain skeletal diseases.

Learning how it is controlled will have many applications in humans, said Jeff Sossamon of the American Kennel Club's Canine Health Foundation, who was not involved in the research. "The canine model is perfect for human research, because we share 85 percent of our genetic makeup with dogs," he said. "And we share 300 common diseases."

The study was triggered by Lark, who began studying the genetics of soybeans. Along the way, he adopted a stray dog called Georgie, who turned out to be a Portuguese water dog. When Georgie died in 1996, Lark contacted Karen Miller, a breeder in New York state, for a replacement.

When she found out Lark studied genetics, she began pestering him to study dog genetics and sent him an expensive Portuguese water dog -- Mopsa, who is now 10 years old. Within three months, she also sent him 5,000 pedigrees -- the genetic histories of individual dogs.

Lark and his colleague, biologist Kevin Chase, soon realized that the Portuguese water dogs were ideal for genetic studies because they all descended from a small number of "founders." They also are permitted an unusually large range of sizes for a purebred dog, ranging from 25 to 75 pounds.

Lark and Chase began collecting X-rays -- to document body size -- and DNA samples from owners of other Portuguese water dogs, eventually accumulating more than 500 samples. They initially concluded that a segment of chromosome 15 containing IGF-1 and about 100 other genes was strongly correlated with size in the animals.

They focused on IGF-1 because a defective form of the gene previously had been associated with small mice and an unusual case of a tiny person. The gene itself was fine, but they found genetic changes in a regulatory sequence sitting next to it.

The study was then expanded to look at other dogs. Ostrander and colleagues traveled to dog shows around the United States, collecting DNA samples from various breeds.

Eventually, they accumulated and analyzed genetic samples from 3,241 dogs from 143 breeds. All the small dogs had the same altered regulatory sequence.

So, too, did the occasional big dog, such as a Rottweiler and a mastiff.

"There is something funny going on with Rottweilers," Ostrander said. "That told us right away that that the whole story isn't IGF-1. There are other genes that interact, and we are going after them right now."

The team also is looking for the genes that control leg length and width.

Because the regulatory variant is found in small dogs that are only distantly related and in widely dispersed locales, the team concluded that the variant must have originated about the time wolves were domesticated by humans.

Lark speculated that small dogs arose because "a small wolf couldn't survive in nature, but it could survive in company with humans," or because an early human "wanted to domesticate a wolf and they didn't want to adopt a big sucker."

~ Photo and article from San Francisco Chronicle.

(Photo depicts Gibson, a Great Dane who is the world's tallest dog at 7'2", standing with his friend Zoie, a 7.5" tall Chihuahua.)