Hot on the Trail of Little Dogs

Dog size

The Utah researchers played a key role in the new study, which began with their research on Portuguese water dogs, a breed with sizes ranging from small to large.

"Lark and Chase were instrumental in the success of this study," says Ostrander, the study's senior author and chief of cancer genetics at the National Human Genome Research Institute. "Their approach was very clever. They enlisted the help of hundreds of pet dog owners across America to provide DNA samples and body-size measurements in the form of X-rays from over 500 Portuguese water dogs. That allowed a careful analysis of all the dog's chromosomes and the eventual identification of a region on canine chromosome 15 where a gene critical for controlling body size was likely to lie."

"Dogs have the biggest range of sizes of any mammal in existence," says Lark. "One of the big questions has always been, where does this range of sizes come from? By studying the Portuguese water dog, which has three-fold range of sizes - from 25 pounds to 75 pounds - we realized that IGF1 was a big player."

A scan of the dog genome at the University of Utah found a long stretch of DNA (called a quantitative trait locus) on chromosome 15 that strongly correlated with size in Portuguese water dogs. IGF1 was within that stretch of DNA, but so were about 100 other genes.

Chase and Lark suspected IGF1 was involved in keeping small dogs small for several reasons: It produces a growth factor. Another study showed poodles are larger if they have more of the growth factor in their blood. And a disabled version of the gene was known to produce small mice and was linked to an unusual case of a tiny person.

But to turn suspicion into fact, many more breeds had to be examined. So the study eventually expanded the genetic analysis to 3,241 dogs from 143 breeds, ranging from small ones like bichon frise, Chihuahua, Maltese, Pomeranian, toy poodle, pug and Pekingese to large breeds such as Saint Bernard, Newfoundland, mastiff, Great Dane, Irish wolfhound, and standard poodle.

Ostrander, Sutter and colleagues traveled to dog shows across the country to collect blood or cells. Their analyses confirmed that the location of genetic instructions for keeping dogs small was near the IGF1 gene.

"All dogs under 20 pounds have this - all of them," Lark says. "That's extraordinary."

Oddly, so do Rottweilers, which are large. But even though they have the small-dog haplotype, other yet-unidentified genetic factors make them big, Chase says.

Researchers plan to breed mice with the small-dog haplotype - the IGF1 gene and nearby DNA - to see how mouse size is affected and pinpoint the exact mutation responsible for small size. Chase says one or more of six mutations in the short DNA regulatory sequence are suspected of reducing activity of the growth factor gene.