One gene, a million small dogs - fighting human disease

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One gene, a million small dogs

Scientists identify the switch that leads to size variation among

breeds. Learning more about it could help fight human disease.

http://www.latimes.com/news/science/la-sci-

smalldogs6apr06,1,5498377.story

By H. Maugh II, Times Staff Writer

April 6, 2007

As it turns out, small dogs all bear a single 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 — although it has since disappeared from the

wolf population — and has spread rapidly through 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 Friday in the journal Science. " That's

extraordinary. "

The discovery helps explain the great diversity in size among dog

breeds, the greatest among any mammalian species. It might also 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 A. Ostrander of the National Human

Genome Research Institute, who led the study.

The gene in question, IGF1, 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 it is controlled would have many applications for

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% of our

genetic makeup with dogs, " he said. " And we share 300 common

diseases. "

The study was triggered by Lark, who began his career studying the

genetics of soybeans. Along the way, he adopted a stray dog named

Georgie, who turned out to be a Portuguese water dog. When Georgie

died in 1996, Lark contacted , a breeder in New York,

about getting a new dog.

When she found out Lark studied genetics, began pestering him

to investigate dog genetics. She sent him another Portuguese water

dog — Mopsa, who is now 10. Within three months, she also sent him

5,000 pedigrees — the genetic histories of individual dogs.

Lark, working with biologist Chase, soon realized that

Portuguese water dogs were ideal for genetic studies because they

all descend from a small number of " founders. " They also have an

unusually large size range for a purebred dog, from 25 to 75 pounds.

Lark and Chase began collecting X-rays — to document body size — and

DNA from owners of other Portuguese water dogs, eventually

accumulating more than 500 samples. They initially concluded that a

segment of chromosome 15 containing IGF1 and about 100 other genes

was strongly correlated with size in the animals.

They focused on IGF1 because a defective form of the gene had

previously been associated with small mice and one unusual case of a

tiny person. The gene itself was fine in the dogs, but they found

genetic changes in a regulatory sequence sitting next to it.

With their coworkers, they expanded the study to look at other dogs.

Ostrander and her colleagues traveled to dog shows around the

country, 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. "

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, including 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 IGF1.

There are other genes that interact, and we are going after them

right now. "

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

width.

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 that

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. "

They spread rapidly because people liked them.

" Tiny dogs are not particularly functional, " Chase said. " They don't

hunt with you. They don't protect your house. They don't pull carts.

" They're just small and sweet, " he said.