|Genetic Testing for Dogs|
|By Sharon Guynup
July 21, 2000
In 1975 when Trista, Sandy Novacin's six-month-old Irish setter puppy, began walking into things in semi-darkness, Novacin knew she had a problem. The pup was exhibiting early symptoms of progressive retinal atrophy (PRA), an inherited disease that causes blindness in many types of dogs. When Trista matured, she was put in a "test breeding program," used by Novacin and others to identify male carriers in attempt to stem the spread of the disease.
Finally in 1995, a blood test for PRA in Irish setters became availablethe first canine DNA test for a genetic disease. Now there are 17 tests. "These molecular tests could effectively eliminate specific genetic diseases in a breed in one or two generations," says Urs Giger, of the Section of Medical Genetics at the University of Pennsylvania's School of Veterinary Medicine.
Scientists in the US and Europe are making progress in identifying the genetic mutations that cause inherited illnesses, developing tests for themand mapping the dog genome. Canine genetics research is beginning to make important contributions to the understanding of human genetic disorders. In 1999, Stanford University researcher Emmanuel Mignot located the gene and mutations that cause narcolepsy in dachshunds, Labrador retrievers, and Doberman pinschers. Mignot says the discovery will help researchers probe the mystery of narcolepsy in humans and devise new treatments.
But compared with the human genome project, the canine effort is miniscule, funded by a few grants totaling only a few million dollars a year, largely contributed by the American Kennel Club's Canine Health Foundation and 60 different breed clubs. Elaine Ostrander, of the human genetics program at the Fred Hutchinson Cancer Research Center in Seattle, coordinates the Dog Genome Project: a group of about 15 American and European researchers.
Experts estimate that as many as one quarter of the approximately 20 million purebred dogs living in US households may have or carry a serious genetic disease. (A one-percent disease rate in humans is considered high-risk.) These maladies, which can be debilitating and even fatal, include epilepsy in collies, skeletal malformations such as hip dysplasia in many breeds, and hemophilia-like bleeding disorders in Shetland sheepdogs.
Dogs are plagued by the greatest number of documented, naturally occurring genetic disorders of any non-human species. Donald Patterson, professor of medical genetics at the University of Pennsylvania, has maintained the Canine Genetic Disease Information System for the past 20 years, amassing a database that has grown to include over 370 genetic diseases in 200 dog breeds, with 5 to 10 new disorders added each year.
Since 1989, researchers have traced 21 hereditary illnesses to their disease-causing gene, with more than half of them identified since 1996. Many of these afflictions are breed-specific, spread widely by selective breeding practices intended to produce puppies with particular desirable traitswhich have sometimes paired brother to sister and father to daughter. "When you select for something, say exceptional scenting ability, you may also be breeding for lack of a tumor-suppressing gene or some other serious problem without knowing it," says Deborah Lynch, of the American Kennel Club Canine Health Foundation.
This practice increases the odds that two carriers will matethe necessary recipe for transmission. Two-thirds of canine genetic disorders are recessive. When both parents carry the faulty gene, half of their puppies usually carry the mutation, while one quarter inherits a normal gene, and another quarter develops the disease.
The problem is exacerbated by what is known as "popular sire effect," when frequently bred championship sires carry a mutant gene, spreading it far and wide. Some diseases have reached epidemic proportions. For example, of 10,000 Doberman pinschers tested for von Willebrand's disease, a bleeding disorder, nearly 50 percent proved to be carriers, with 30 percent affected by the disease, according to John Duffendack, of VetGen.
Testing is slowly becoming more commonplace among breeders. In the past, when an animal developed one of these diseases, owners put the animal down or took it out of the breeding program. But geneticists know this causes other problems. "It's not good to say, 'All right, everybody out of the pool that tests positive for this,'" says Lynch. "You'd be throwing out at least 25 percent of the gene pool." Now breeders can have much more control over genetic planning.
There are early success stories. In the years that followed the development of the PRA test for Irish setters, the dogs were bred very carefully to avoid conjoining two carriers. Last year when the Irish Setter Club of America did a health survey, they found no blind setters. Patterson feels that the diagnosis and control of genetic diseases will become an increasingly important part of veterinary practice. Presently, most vets have little knowledge of genetic diseases. But, later this year, Patterson's database will be published as a CD-ROM with a companion book outlining their diagnosis and control.
Most tests only identify a specific gene defect in a particular breed. So although a disease may plague many breeds, the affected gene must be isolated and a test created for each of them. For example, Gustavo Aguirre, professor of opthamology at Cornell's Baker Institute, found that PRA, which afflicts not only Irish setters, but Labrador retrievers, poodles, American and English cocker spaniels and others, may be caused by a mutation to any one of at least seven different genes.
Of the diseases where the gene is known, Giger predicts that the DNA defect will be known within the next decade. "Technology is moving so fast that we can do in months what used to take years," he says. During the mid-1990s, it took several years' work to identify an immune disorder in Basset hounds called severe combined immunodeficiency (SCID). But a few years later, the disorder was identified in the Welsh corgi breed within months.
For this genetic detective work on SCID, researchers used a human "candidate gene,"a gene that correlates to a like disease in another species. Up until now, benefits from studies on the genetics of disease have flowed mainly from human to dog because of the mammoth research efforts in human genetics. But the dog is also a good model to help researchers characterize human illnesses. Dogs and people share about 85 percent of their genetic code; over half of all canine genetic disorders mirror a human genetic disease, including deafness, blindness, kidney failure, congenital heart disease, skeletal malformations, and cancer.
But mapping of genetic diseases in purebred dogs is much easier than in humans because each breed is a genetic isolate, much like a human population that inhabits a remote island, and pedigrees can be traced for many generations.
Researchers at Cornell University began sequencing the dog genome in 1990. It is estimated that the canine genome has 100,000 genes, distributed over 78 chromosomesabout two-thirds of which have been identified. In order to track inherited traits and pinpoint corresponding genes, scientists are currently charting the location of hundreds of markersgenes and microsatellites, or repetitive strands of genetic codewhich must then be assigned to chromosomes. Once they have sleuthed out the defective gene, they can create a DNA test for it. "The goal is to recognize and control these diseases in future generations," says Giger.
Diseases like PRA are caused by a mutation in a single gene. But dogs also suffer from polygenic conditions, which involve multiple genes. Eradicating these diseases will take longer. "We've learned that our dogs don't have to be the victims of disease," says Deborah Lynch. "We're going to see diseases fall that we wouldn't have believed we could make progress against."
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