Study reveals why tiny dogs are tiny

WASHINGTON -- From the towering Great Dane to the feisty little Chihuahua, all dogs are brothers under the skin. Researchers now have uncovered a reason why the animals wearing that skin vary so much in size.

Dogs have the largest variation in body size of any land animal, so researchers led by Elaine Ostrander of the National Human Genome Research Institute decided to look into the reasons why.

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

"All dogs under 20 pounds have this -- all of them," said University of Utah biologist K. Gordon Lark, one of the researchers. "That's extraordinary."

The discovery helps explain the great diversity in size among dog breeds, but it also may have implications for humans.

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

Learning how growth is controlled can improve the understanding of cancer and other diseases caused by growth gone awry, Ostrander said. And the research adds to the basic study of variations, perhaps improving knowledge about the differences between people, she added.

Lark noted that dogs have 200 to 300 diseases in common with people, including high blood pressure, autoimmune diseases and cancer. "They also share our environment, so if there is an environmental influence that can trigger disease," dogs will be going through the same process, he said.

"So, if we can solve this in dogs, that's a fantastic jump ahead," Lark said.

Lark has been looking into canine genetics since 1986, when his Portuguese water dog, Georgie, died of an auto-immune disease. He wanted another Portuguese water dog because of their lovable personalities.

When he found a breeder who had some, she coaxed him into shifting his genetic research from soybeans to dogs.

Lark and one of his colleagues, biologist Kevin Chase, soon realized that 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 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 -- funded by the National Human Genome Research Institute, National Science Foundation, National Institute of General Medical Sciences, Judith Chiara Charitable Trust, Mars Inc. and Nestle Purina -- then was expanded to look at other dogs. Ostrander and colleagues traveled to dog shows across the United States, collecting DNA samples from various breeds.

"People desperately wanted to be part of the study," she said. "We had no trouble acquiring thousands of DNA samples."

They eventually accumulated and analyzed genetic samples from 3,241 dogs from 143 breeds. All 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 the whole story isn't IGF-1. There are other genes that interact, and we are going after them right now."

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

Dogs are descended from wolves, having been domesticated 12,000 to 15,000 years ago. Selective breeding has produced the many breeds of dogs that exist today.

Judging from ancient artwork, small breeds were developed quite early, Lark said.

A study of several hundred modern wolves didn't find any with the small-dog marker, he said, but it is possible there were small wolves in ancient times.

"If you're a primitive man you would adopt the small wolf, not the big one," he said. And for a small wolf, life would have been easier hanging around people looking for scraps than competing with larger wolves in the wild.

And, he added, unlike today when dogs are mainly companions, there was plenty of work for small dogs to do in the past -- they hunted rats and other vermin, did some herding and could be excellent watchdogs.

Compiled from The Associated Press, Los Angeles Times and The Baltimore Sun