No mammal on Earth comes in such a variety of sizes as man's best friend.
Yet from a genetic standpoint, dogs are 99.8 percent identical to each other - about the same as humans.
So why do they come in packages as small as a 3-pound Chihuahua and as large as a 150-pound Great Dane?
Breeding techniques play a major role in determining why one dog can be 30 to 50 times larger than another. But scientists are beginning to better understand the role played by nature.
Researchers in Bethesda and other places, working with DNA from more than 3,200 dogs, reported in a study published today that all small dogs share a specific sequence of DNA nearly absent from larger breeds.
Moreover, the sequence lies along the same piece of real estate in the small dog genomes - near a gene known as IGF-1 - which produces a protein that promotes growth.
Somehow the DNA sequence, or genetic variant, is restricting the size of small dogs, while its absence is spurring growth among larger ones, the researchers say. It's common among dogs weighing less than 20 pounds, but not in larger ones.
"There's an enormous role being played by this one gene sequence," said Nathan Sutter, the first author and a molecular geneticist at the National Human Genome Research Institute. The findings were published in the journal Science.
Of course, other genes play a role in determining dog sizes. "You can't put this gene in a Great Dane and expect to have a 10-pound Great Dane. There are other factors going on," said co-author Carlos D. Bustamante, an assistant professor of biological statistics and computational biology at Cornell University.
Modern dogs diverged from the gray wolf more than 15,000 years ago, and in the centuries since, selective breeding has played a major role in determining why they are so diverse, experts say.
Their range of shapes, sizes and abilities have probably made many an owner wonder why some dogs are intelligent enough to round up sheep, while others are so stubborn they won't move when called for dinner.
"Humans have had lots and lots of opportunities to produce the dogs they wanted," Sutter said.
For the study, researchers took blood and saliva samples from 3,200 dogs comprised of 143 breeds to compile DNA profiles. Samples were mailed in by kennel clubs and collected by researchers at dog shows around the world over several years.
Biologists at the University of Utah also X-rayed 463 Portuguese water dogs, a breed known for its variety of sizes. From the X-rays, researchers took 92 different measurements of each water dog's anatomy, then used the measurements, and others like them, to document the variety of sizes.
Experts not involved in the study say the work sheds light on how dogs have evolved.
"It's striking and remarkable to think that all small dogs have this mutation, and that at one point, this mutation was something that developed in a single dog," said Mark Neff, who is studying the genetics behind dog pointing behavior at the University of California, Davis.
But the results are not surprising, Neff said. The IGF-1 gene also has been shown to play a role in growth rates among mice and humans.
"It's a well-done study, but it's really part of an ongoing story and there's still a lot to be learned," Neff said.
A sophisticated map of the dog's genome, published by another team of scientists in 2005, showed dogs have about 19,300 genes, compared with about 20,000 for humans, said Kerstin Lindblad-Toh, a researcher at the Broad Institute in Boston who helped sequence the dog genome.
Humans began breeding dogs centuries ago, Sutter said.
Remains of dogs as big as Great Danes have been found in 15,000-year-old settlements in eastern Russia, and bones from terrier-sized mutts have been dug up at archaeological sites inhabited 12,000 years ago in the Middle East and Europe, the researchers say.
The newly discovered genetic variant appeared sometime after dogs split from wolves and its presence in so many breeds means it apparently arrived early on as dogs evolved, Sutter said. It isn't found in wolves, or in their cousins, the jackal, they said.
"Our findings are consistent with the idea that first dogs were large and that when they were domesticated, they were bred early on to get smaller," Sutter said.
The earliest breeders may have preferred small dogs because they were better-adapted to the confines of village life, the authors say.
Sutter says the findings, along with other studies focused on dogs, also could lead to better understanding of the roles specific genes play in the estimated 200 to 300 genetically based diseases shared by humans and dogs.
Dogs can get cardiovascular disease, autoimmune diseases and cancers, such as melanomas and skin cancers, the researchers say.
"Dogs are wonderful models where multiple genes play a role in diseases that may also have some environmental component," said K. Gordon Lark, a co-author and geneticist from the University of Utah.
Lark has been looking into canine genetics since 1986, when his Portuguese water dog, Georgie, died of an autoimmune 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. The water dogs turned out to be useful study subjects because the breeding standard allows for a wide range of sizes - from about 25 pounds to about 80 pounds, Lark says.
"At that point, little was known about how you would approach complex genetic traits, like height or a behavior," Lark said.
In an unrelated project, the National Human Genome Research Institute is developing a family tree that shows how hundreds of breeds are genetically related. One goal is to identify diseases associated with different breeds, so that the responsible genes can be identified and eventually eliminated, Sutter said.
"We think we can make healthier and longer-living breeds of dogs and have an impact on human health as well," said Sutter, who owns a chocolate Labrador retriever named Maggie.
About the study
Researchers found that small dogs share a specific sequence of DNA absent from larger breeds. They believe the sequence is a major factor in limiting the size of small dogs.
Dogs with the DNA sequence include: bichon frise, Chihuahua, Maltese, Pomeranian, toy poodle, pug and Pekingese.
Dogs without the DNA sequence include: St. Bernard, Newfoundland, mastiff, Great Dane, Irish wolfhound and standard poodle.
-- Dogs diverged from the gray wolf 15,000 years ago.
-- They have the widest range of sizes of any living mammal.
-- The smallest is the Chihuahua, which breeding experts say should not weigh more than 6 pounds.
-- The tallest is the Irish wolfhound, which should have a minimum shoulder height of 32 inches.
-- In terms of weight, the largest breeds include mastiffs, Neapolitan mastiffs, Great Danes, St. Bernards and Newfoundlands, which all can reach 150 pounds. The American Kennel Club says individual size often depend on how a dog is fed.
-- Humans and dogs share up to 300 diseases, including arthritis, heart disease and many cancers.
-- There are approximately 400 breeds listed with international registry organizations. The American Kennel Club recognizes 155 breeds.
SOURCES: The American Kennel Club and the Unviersity of California, Davis