See Spot. See Spot run. Map Spot’s genome?
Spot, Rufus, Rhett. Dogs deliver the newspaper, collect scraps from the dinner table and entertain us at basketball games. And man’s best friend is now also at the forefront of genetic research in disease prevention and treatment.
For years, scientists have used mice to study just about every disease known to man, but a team at the Broad Institute of the Massachusetts Institute of Technology and Harvard set out to prove that using dogs is equally as ideal — and sometimes more efficient — in furthering genetic disease research.
DOGGIE DISCOVERY
“It’s easier to study dogs because their DNA travels in bigger chunks because they tend to be more inbred than people,” said assistant professor of oncology at Cummings School of Veterinary Medicine at Tufts University, Lisa Barber. “In people, the genetic material has commingled so extensively that we just don’t have breeds of people, thank goodness. Because of that vast variability it’s harder to study certain diseases in humans.”
These “chunks,” called haplotypes, which are roughly 100 times larger in dogs than humans, are passed directly from parent to offspring from one generation to the next without recombination, or mixing and reordering of genes from both parents. Recombination is prevalent in humans who have been producing offspring for thousands of years.
Kerstin Lindblad-Toh, co-director of the mammalian and vertebrate genome program at the Broad Institute, said large chunks of genomes travel together because of both the age and nature at which dogs are bred.
Lindblad-Toh said the closeness between humans and dogs makes dogs a better model than mice in genetic research, especially because dogs are naturally inflicted with many diseases. Mice typically have to be injected with specific diseases to study them.
“Dogs get cancer, diabetes, epilepsy and basically the vast majority of diseases humans get,” she said. “The environment is important in triggering it, but they mimic people really well.”
Erika Werne, director of canine research and education at the American Kennel Club’s Canine Health Foundation, said pooches are more like their owners than most think.
“We share 95 percent of our genomes,” she said. “The genes that make your eye look like an eye and see like an eye are the same. Dogs share our environment. They drink the same water we do. They walk across the same grass sprayed with herbicides, and whether we like it or not, they sometimes eat the same food.”
NEW TRICKS
Elinor Karlsson, a PhD student at the Boston University Bioinformatics Program, has been researching dogs at Broad since 2004, and published practical applications of research in a co-authored paper released in Nature Genetics in September.
The team mapped an entire genome of a Boxer and a Poodle in six months and published its work initially in the journal Nature in December 2005, but that was only the beginning. Since mapping the first two dogs, the researchers have been comparing the data and looking for single-nucleotide polymorphisms, often referred to as SNPs, which are sites in the genome where single changes frequently occur. From there, they were able to analyze both the genes for coat color in Boxers and a hair ridge in Rhodesian Ridgebacks.
Karlsson said these first two discoveries led them to confirm that certain physical traits are attached to disease.
“In the Rhodesians, often times the hair grows along the spine in the opposite direction and can create neural defects in development,” she said. “With white Boxers, there is a mutation where the pigment cells don’t migrate properly and five percent of them actually end up being deaf also. It is known that this gene is mutated in people as well and some deaf people have no pigment in their ear cells. It was a nice confirmation for us.”
Last year, in cooperation with science technology corporation Affymetrix, the team began marketing a chip to researchers studying canine diseases that quickly scans genomes to target chosen SNPs. By offering a glimpse of the entire canine genome, the chip can save researchers time.
“The SNP chip gives a snapshot for sequencing the genome without doing the whole thing,” Karlsson said.
BREED SPECIFIC
The researchers thought they were onto something, but were most surprised when all of their hypotheses actually checked out.
“We had so much power that we could do this with only a few dogs and just get absolute certainty, just no confusion at all,” Karlsson said. “You see how much trouble they have when doing these studies in people when pinpointing the exact gene. They also have thousands of people and controls. We thought we’d have this power, [and] it’s nice to find out that you were right.”
The specificity of dog breeds gives researchers the opportunity to hone in on certain traits. Some breeders may question the effect of such research on canines, but Karlsson said it’s for their own good. “Once they see we’ll be able to help them, they should be more open to it,” she said. “We’ll actually be able to help the dogs as well.”
“Nobody wants to hear that their breed of dogs has a certain mutation because then people could stop getting puppies from that breeder and that’s their livelihood. Rather than saying ‘don’t breed this dog,’ we’d like to say ‘if you breed these two dogs together, its not a good idea, but its okay to breed this dog with this other dog.’ We’re not saying there’s anything fundamentally wrong with a breed, its just understanding it better,” Karlsson said.
CANINE CAPTIVATION
Modern dog breeds have a relatively short history compared to humans, dating back only about 200 years. In that time spectrum, humans took control of the changes previously slowly played out by natural selection and began choosing desired traits like short noses in Pugs and black and white spots in Dalmatians.
Barber sees the research at Broad contributing to the ultimate eradication of disease.
“If we can understand the disease we can have abilities to intervene with prevention and treatment, not just in dogs, but in humans or other species too,” she said. “We all want to enjoy good health for ourselves as well as the animals we love.”
Barber explained that often the gene for a certain physical trait is connected with a mutation leading to some disease. Humans, by continued breeding for certain traits, have failed to recognize that certain diseases are more common in certain breeds.
“We’ve selected for certain genetic traits, that’s how we have breeds,” Barber said. “Dog breeds are fairly homogeneous populations in which we can look for genes in common that are in some way risk factors for disease because they’re mutated. We know there is a gene found both in Rottweilers and Wolfhounds that gives them osteosarcoma, cancer of the bones.”
TREAT WITH CARE
Cirilla Logan, who breeds American Staffordshire Terriers at Fairlawn Farm in Ipswich, Mass., said dogs shouldn’t be used for research. “I don’t see injecting things in ten dogs in a kennel,” she said. But, Logan said, as long as the dogs being used are already sick, “it is not a problem.”
It is important to be clear on motives behind canine research, Logan said.
“There’s not really a whole lot of controversy, but in the dog world when investigators are looking for samples, they sometimes have a hard time because people don’t want to admit that their breed line carries a certain disease. Especially if the dog is producing cute puppies and winning awards,” Werne said. “There can be a lot of secrecy we’ve been working to overcome. A healthy dog is the most important thing. It’s important to produce healthy puppies.”
BRED TO PLEASE
The original funding for the canine genome mapping project came from the Morris Animal Foundation and the AKC in 1994, said Werne. At $10,000, a small study was planned until the Canine Health Foundation was formed in 1995 and dedicated $2.2 million toward the project. The Broad Institute, then the Whitehead Institute/MIT Center for Genome Research, signed on in 2002 when Elaine Ostrander, who worked on the project from the start, and her colleagues wrote a white paper on their proposed research to the National Institutes of Health and were granted $50 million to continue the study.
“When Elaine Ostrander contacted me, it was quite clear that the dog breed structure should be very advantageous,” Lindblad-Toh said.
By that time, Ostrander had already done a cluster-analysis to visualize relatedness between breeds, and the team at the Broad began sampling breeds from the entire spectrum. The blood was collected from healthy purebred dogs mainly through breeders and dog shows, and veterinarians participated in the collection of blood samples from diseased dogs. Purebreds were targeted for their lack of “background noise” and “long haplotype locks,” when looking at genetic traits as opposed to mixed-breeds, said Lindblad-Toh.
“We predicted that, because of the inbred nature of the dog’s genome, we would only need samples from a hundred sick dogs and a hundred healthy dogs,” she said. “If we were to do the same research in humans, we would need thousands of people to participate.”
Lindblad-Toh said she would like to eventually transition her research to study disease in humans.
“I hope to take these findings and look in human patients so that in long terms we can diagnose at the genetic level before any symptoms show,” she said. “If we can prevent and detect these diseases early and figure out which treatments are best based on the mutation, we can have personalized medicine and we can tailor treat individuals.”