Unnatural Selection
In 2002, when dog researchers asked Lindblad-Toh about sequencing the animal's genome, she thought, "Oh, wow, this must be the ideal model." Human-directed breeding has produced wrinkly shar-peis, mohawked Rhodesian ridgebacks, and slender borzois with beautiful lines. "But when you enrich for specific desirable traits, you often unfortunately capture disease traits with them," says Lindblad-Toh. Along with its distinctive traits, each breed has distinctive genetic vulnerabilities: developmental defects, heart disease, hip problems, cancer. Dogs suffer from many of the same diseases as humans, so researchers can use their genome to identify genetic causes of the diseases in both species.

Lindblad-Toh and her collaborators at the National Human Genome Research Institute (part of NIH) first had to determine which breed to sequence. Humans have dramatically reduced the genetic diversity of some dogs by breeding, for example, only the most bowlegged bulldogs and the squarest-jawed boxers. Sequencing a breed with little genetic diversity is easier, because the two copies of each chromosome--one from the mother, one from the father--are similar to each other. So when a preliminary analysis suggested that boxers are among the least genetically diverse of all dog breeds, the researchers had their subject.

Even when genetic diversity is limited, drafting a genome is like putting together a very large, very difficult jigsaw ­puzzle whose pieces are scattered all over the house--wedged between sofa cushions or under a jar of mustard at the back of the fridge. First, researchers have to locate and identify all the pieces; then they face the formidable chore of assembling the puzzle. Lindblad-Toh and her collaborators spent six months sequencing segments of a female boxer's genome, and three or four times as long putting them together and analyzing them. They published the dog genome, along with an extensive analysis comparing it to the mouse and human genomes, in the journal Nature in December 2005.

Lindblad-Toh and her team also compared the boxer genome with the existing survey sequence of the poodle genome and partial sequences of nine other dog breeds' genomes that they had prepared for the purpose. As they expected, though each breed has its own distinctive traits and mutations, all breeds are still very similar to one another. (The domestic breeds haven't been around long enough for much diversity to creep in.) These similarities within and between dog breeds should make disease-related mutations easier to spot. Researchers at the Broad and elsewhere are currently uncovering disease genes in dogs with the help of the American Kennel Club/Canine Health Foundation and the Morris Animal Foundation. The researchers go to dog shows to collect blood samples and pedigrees, or they get samples from veterinarians. Using DNA microarrays, they then look for genetic differences between healthy dogs and those with diseases.

Lindblad-Toh says she and other Broad researchers have identified about 10 genes for simple traits like coat color and complex diseases like cancer; they're also looking into genes associated with cardiomyopathy and diabetes. "Of course, when you find a dog disease gene you look immediately in people with the same disease," she says. Dogs and humans are quite closely related and share versions of most of the same genes.