Mining the canine genome

Man’s best friend, the dog, is proving that it has one more way to lend a helping paw. The identification of canine genes is not only improving the health of dogs, but is also helping researchers identify genes controlling human diseases and develop treatments. Dr. Dennis O’Brien, a professor of neurology at the University of Missouri’s College of Veterinary Medicine and an expert on neurodegenerative diseases, says he is thrilled about the recent identification of genes that cause two types of rare epilepsy in dogs and humans. “It’s very exciting. I think it shows the power of canine genomics to (be able) to start answering some of these questions,” Dr. O’Brien said.

Berge Minassian, MD, and other scientists at the Hospital for Sick Children in Toronto, turned to the dog in their hunt for genes that cause Lafora disease in humans. With Lafora, seizures begin in the teenage years and increase in frequency until they cause death, usually within five years after the onset of the first symptoms. The researchers had identified one gene in humans but knew there was at least a second gene, because some families couldn’t be linked to the first gene. “I knew that Lafora is, relatively, frequently reported in dogs,” Dr. Minassian said. “I thought perhaps if we found families of dogs (that) have this disease, it may help us find the gene and, from there, the human gene.”

Dogs with Lafora have myoclonic seizures, which are characterized by brief short jerks of a muscle or a group of muscles. Animals develop signs between the ages of six and nine, and death follows within three years. After learning that five percent of purebred miniature wirehaired Dachshunds in the United Kingdom suffered from Lafora, the Canadian researchers began collaborating with veterinary neurologists Dr. Clare Rusbridge at The Stone Lion Veterinary Centre in London and Dr. Sue Fitzmaurice at Wey Referrals in Surrey, England. Veterinarians from the United States and France also contributed.

In the Jan. 7, 2005, issue of Science, the investigators report that affected dogs carry two copies of a gene with an expansion mutation. These “stutters” or repetitions of base pairs have also been implicated in other neurodegenerative diseases, such as Huntington’s disease.
Scientists have developed a test so that breeders can identify dogs that carry the gene. Canadian researchers had continued their efforts to map the gene responsible for Lafora in humans and actually finished mapping the gene in dogs and humans at the same time. Nevertheless, the identification of the gene in dogs will greatly benefit human medicine. Mice don’t make good models for Lafora, in part, because their lives are too short. “The dog models the disease almost perfectly,” Dr. Minassian said. “In terms of when we start developing treatments, it is going to be great to have the dogs to treat first, before we try (a treatment) in humans. This applies not only to any kind of medication-type treatment, but if and when we are ready to do gene therapy.”

The canine genome also recently proved valuable in identifying a gene that causes neuronal ceroid-lipofuscinosis in humans, otherwise known as Batten’s disease. Over time, children with this disease suffer mental impairment, worsening seizures, and progressive loss of sight and motor skills. The disease is usually fatal in the late teens or 20s. In the 1950s, a Norwegian veterinarian identified an NCL-like disease in a group of related English Setters. Affected English Setters develop signs similar to Batten’s and die at approximately two years of age from intractable seizures. The canine disorder most closely resembles the juvenile form of Batten’s disease.

This past February, researchers at the University of Missouri-Columbia and Indiana University-Indianapolis announced in the journal Biochemical and Biophysical Research Communications that they had identified the gene involved in this type of epilepsy. The canine model will help scientists study the disease in humans; the genetic test will help breeders. “When the American Kennel Club surveys dog breeders about what diseases they consider the most pressing problems, epilepsy is always in the top five,” Dr. O’Brien said. “We hope these kind of genetic mapping studies will ultimately lead us to find the genes that are responsible for the more common forms of epilepsy.”

The two epilepsy genes are only the most recent success stories involving the canine genome. Scientists have identified genes for conditions including vision disorders, heritable kidney cancer, narcolepsy, severe combined immunodeficiency (often called bubble boy disease), cystinuria, and bleeding disorders. The narcolepsy gene is one example of how identifying a gene for a rare condition can uncover the molecular biology of common cellular processes. In 1999, researchers showed that a mutation in the HCRT2 gene caused narcolepsy in Doberman Pinschers.
This gene was found to affect hypocretin, a protein neuropeptide. Since then, further studies have proved that hypocretin deficiency is associated with most cases of narcolepsy in humans, and that hypocretin might have a key role in circadian clock-dependent alertness and in regulating metabolic rate, appetite, mood, and sleep.
Targeting hypocretin could lead to therapies for narcolepsy and more common sleep disorders.

According to Dr. Gustavo Aguirre, a professor of medical genetics and ophthalmology at the University of Pennsylvania School of Veterinary Medicine, almost half of the roughly 30 genes identified for diseases in dogs are for vision disorders. Scientists have even successfully used gene therapy to cure two of them, one being Leber congenital amaurosis. In humans, this condition causes vision loss starting in infancy. “We treated dogs, restored vision, and that (treatment) will be used to treat human patients, if that continues to be successful,” says Dr. Aguirre, who was involved in the study. He anticipates that phase I clinical trials for humans could begin at the end of 2005 or early 2006.

So why are researchers having such success? It is often easier to find a gene in a dog than in another mammal, because of breeding. Dog breeds are similar to geographically isolated human populations, which offers an advantage when tracking down genes. Nearly half of genetic diseases reported in dogs occur predominantly, or exclusively, in one or a few breeds. When genes are identified, the development of genetic tests allows dog breeders to reduce the incidence of disease. The first such test was developed in 1995 for progressive renal atrophy in Irish Setters. For some time, canine geneticists have understood the promise of the pooch to help human health.
The top 10 diseases of greatest concern in purebred dogs include several that are of concern to human health, among them, cancer, epilepsy, autoimmune diseases, heart disease, and diseases causing cataracts.

Elaine Ostrander, PhD, chief of the cancer genetics branch of the National Human Genome Research Institute, believes canine genome research could be particularly useful in studying cancer. “By using dogs as an animal model and comparing what we learn in them to what we know about human cancer, we are slowly but surely putting together the basic vocabulary of cancer susceptibility,” Dr. Ostrander says. She and others believe that we are seeing only a small hint of what is to come. Drafts of the canine genome, the first of which was published in 2003, will help researchers identify genes more quickly. “With the canine genome, we know what the normal sequence is in a normal dog, so it makes it much easier to then see (whether a) dog with a disease has the normal kind of gene or if there is something different,” Dr. O’Brien said. Subsequent drafts of the genome will provide more information.

Dr. Ostrander believes that, in the future, canine geneticists will turn their attention even to genes involved in behavior, such as obsessive-compulsive tail chasing seen in Bull Terriers, which could provide clues to human behavior. Other possibilities are separation anxiety, impulse control disorders, and even aggression. She cautions, however, that with this latter behavior, legal and social implications come into play.

Source: Kate O’Rourke

March 29, 2005

Original web page at JAVMA