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Putting their best paw forward
Scientists make the case for sequencing the dog genome
By Kate Dalke

Featured Article.

The US National Institutes of Health are holding a competition for the next genome to be sequenced. With humans and mice nearly wrapped up, the Human Genome Project is looking for a fresh batch of organisms to enter the "sequencing pipeline."

Some scientists would like to see the dog join the ranks of sequenced species. They say the dog genome will greatly inform human health by helping find human disease genes and illuminating basic biology. To make their case, these scientists have entered a competition to strut their canine stuff.

Leonberger, Standard Poodle and Doberman Pinscher are in the running.

The National Human Genome Research Institute (NHGRI)—an arm of the NIH in Bethesda, Maryland—has adopted a competitive submission process to decide which organisms to sequence next. Members of the scientific community have been invited to submit proposals championing their favorite species.

Proposals are reviewed and ranked by a scientific research committee and ratified by the National Advisory Council for Human Genome Research. The government-supported sequencing centers can then choose from these organisms based on their available sequencing capacity.

NHGRI has already ranked the first group of high-priority organisms: the chicken, honeybee, chimpanzee, sea urchin, a protozoan, and 15 fungal species. The next round of organisms will be announced after the council's September 8th meeting.

The dog is one of the creatures currently under consideration for sequencing. It is expected that other large mammals such as cow, pig and cat will be judged alongside the dog. The bovine genome was deferred from the first round so it could be evaluated with other large-size genomes.

The proposal—a 10-page white paper—outlines how a genome sequence can be used to improve our understanding of human health and disease and basic biology. Other considerations include the size of the genome, the demand for new sequence data and how suitable an organism may be for experiments in the lab.

Another key point, says Jane Peterson, program director for large-scale sequencing at NHGRI, is that the research community that studies the organism be "enthusiastic and prepared to use the sequence."

Top: An English Mastiff. Bottom: Retinal thinning in dogs with eye disease. View full

The dog research community says they are more than ready to use the canine genome sequence. "Dogs have a pretty strong case," says Elaine Ostrander, who heads the Dog Genome Project at the Fred Hutchinson Cancer Research Center in Seattle, Washington.

"We have a strong, collaborative research community. We have a long history of pulling together to get things done," Ostrander adds. She is one of three authors of the dog genome white paper.

Eric Lander and Kerstin Lindblad-Toh, both of the Whitehead Center/MIT Center for Genome Research in Cambridge, Massachusetts, are the other two authors. They hope the dog genome will be sequenced at the Whitehead, one of the government-funded sequencing centers.

Dog researchers argue that sequencing the canine genome would help find genes that cause disease in humans and dogs. The top 10 diseases affecting purebred dogs are also major health concerns for humans—including cancer, epilepsy, allergy, and heart disease.

"Dogs get all the same diseases as humans and the clinical presentations are similar," says Ostrander. Cancer is a good example. The dog offers a naturally occurring model for studying the disease, whereas mice and rats usually do not.

Researchers at Cornell University in Ithaca, New York, have been searching for genes that cause retinal disease in humans and dogs. Gregory Acland and colleagues discovered that mutations in the same genes that cause vision loss for individuals with the disease retinitis pigmentosa also occur in the English Mastiff. The researchers are using these dogs to study how the disease develops in both humans and animals.

The well-preserved lineages and medical records of purebred dogs are also reasons to sequence man's best friend.

"You can track the history or ancestry of dogs that have a disease in ways that you cannot in humans," says W. Richard McCombie of Cold Spring Harbor Laboratory in New York. McCombie is developing a database of canine genome sequences that will help fill in gaps and order sequences of the dog genome.

Purebred dogs receive "enormously good medical care and records," so scientists know "the history of diseases," says McCombie, noting that his fascination with dogs is purely professional. He owns cats.

Dogs are also being used to understand how skeletons in mammals develop. Finding regulatory genes in dogs could benefit research on osteoporosis, osteoarthritis, and hip dysplasia.

K. Gordon Lark of the University of Utah in Salt Lake City has worked with the Portuguese Water Dog to study how genes affect the development of bones. Portuguese Water Dogs have extremely well preserved lineages arising from only a few founding ancestors. This has helped Lark trace the inheritance of skeletal genes.

Comparison of Greyhound and Pit Bull (left). X-rays of a Portuguese Water Dog skull and pelvis (right). View full

"Our research is not targeted toward any specific disease, but rather toward a basic understanding of the genetics of the musculoskeletal system in mammals," says Lark.

Understanding the genetics and "regulation of this system" could help design therapies for "diseases that result in skeletal malformation," Lark adds.

Bone marrow transplantation is another area of medical research where dogs have made a tremendous contribution. Dogs have similar tissue to humans and therefore can be models for investigating immune response to transplants.

Thirty years of research on dogs have led to successful bone marrow transplantation in humans, researchers say. Many of the biomedical principles and therapies developed in the dog "have been directly translated into the clinic," according to the white paper.

The breed or breeds of dog to be sequenced remains undecided. Some researchers argue it would be easier to assemble the genome of a particularly inbred breed. Possibilities include the Ibizan Hound, Samoyed, Saluki, Maltese, or Leonburger.

The greatest amount of biomedical research has been done on the Beagle and therefore some think it should be sequenced. A huge library of genetic sequences and information has been collected on a Doberman Pinscher so enthusiasm for sequencing this genome is also high.

A Standard Poodle is also in the running because the only large-scale sequencing to date has been done on a poodle by Celera Genomics and The Institute for Genomic Research (TIGR), both in Rockville, Maryland.

The initial poodle sequence is now being used to identify and map canine genes. Ewen Kirkness of TIGR, Francis Galibert of the University of Rennes, France, and Ostrander are working on a map of 10,000 dog genes. They are using human genes to find the equivalent genes in dogs and then map those along the canine sequence. They began the project this month and plan to complete the map over the next three years.

"The [1x] sequence is much more useful than I initially thought it would be," says Kirkness. Although the sequence is not complete, it has allowed researchers to find genetic markers and create more refined maps of the dog genome, he says.

Whether the poodle or another breed is selected, a comparison between different breeds would benefit all dog researchers, says Kirkness, who recently became the proud parent of a mixed-breed puppy from the pound.

A Canine Genome Leadership Group—made up of scientists from various universities and centers—has been designated to work with the sequencing centers to determine what breeds would eventually be sequenced.

Whatever the breed, a dog genome sequence would add value to the human, mouse, and rat sequences, say researchers. They emphasize the importance of having a third (non-rodent) mammalian species for comparative studies.

"I think it will be important to find out what parts of the genome are important and therefore preserved in all three organisms," says Lindblad-Toh of the Whitehead Institute.

Scientists working with dogs say that many of their accomplishments have been accelerated by access to the dog genome map, which was published in October 2001. A complete genome sequence would further advance research currently underway and be "the vital step forward" for canine researchers.

But first they must win the competition. The backers of the cow, honeybee and other species are all gunning for their favorite genome. Even so, the competitors have remained friendly.

"Dog researchers are friends with cow genome people, who are then both friends with the cat genome people," says Ostrander.

"Even if the dog doesn't come out on top, I will still feel like it was a fair process," Ostrander adds. "The white paper is a chance for members of the mammalian community to stand up and speak for themselves about what is important."

Beagle puppies from Bayou Oaks Beagles in Lake Charles, Lousiana.

James Womack, a geneticist at Texas A & M University in College Station who authored the cow genome white paper, agrees.

"Of course I have my biases," Womack says. "Yet, dogs, cats, pigs, or cows all represent an important evolutionary category that is neither primate nor rodent. Each has its own contribution to human health."

See related GNN article
»Mapping the Dog: What the human genome sequence can do for dogs. And vice versa.

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Chase, K. et al. Genetic basis for systems of skeletal quantitative traits: Principal component analysis of the canid skeleton. Proc Natl Acad Sci USA 99, 9930-9935 (July 23, 2002).

Kijas, J.W. et al. Naturally occurring rhodopsin mutation in the dog causes retinal dysfunction and degeneration mimicking human dominant retinitis pigmentosa. Proc Natl Acad Sci USA 99, 6328-6333 (April 30, 2002).

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