School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia
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A geneticist's best friend

Dogs are leading the pack in the hunt for the causes of inherited diseases, reports science writer Leigh Dayton

September 19, 2009

Article from: The Australian <http://www.theaustralian.news.com.au/> .

Canine lab assistant: Alan Wilton of the University of New South Wales takes a sample from Ned.

Picture: Amos Alkman

PEDIGREE dogs such as Ned don't just chase balls, wag their tail and pose perfectly in the judging ring. Increasingly, they're teaming up with scientists such as Alan Wilton in the search for genes behind inherited diseases, human and canine.
       Right now, Ned and Wilton -- a dog geneticist with the University of NSW -- are tracking genes that cause a specific type of deafness in people and Australian cattle dogs. If they can locate the genetic source of the problem, that will be good news for pooches and people. ``We want to identify the genes responsible for the condition in dogs to better understand the biology of the disorder to help humans,'' Wilton explains. ``We also want to develop genetic tests that detect carriers in dogs so breeders can eliminate the problem. With a test, we could stop this disease being present in future generations.''

      It took decades of work by dedicated pioneers such as Elaine Ostrander -- with the US National Institutes of Health in Bethesda, Maryland -- to prove what's now obvious to researchers worldwide: dogs are a geneticist's best friend. For starters, humans have a penchant for sharing genes indiscriminately. Purebred dogs don't. Their reproductive activities are controlled by breeders seeking to inbreed specific traits.

      According to University of Sydney geneticist Peter Williamson, that simplifies the job of identifying the genes that produce those traits, from physical characteristics such as coat colour to propensity for inherited diseases. ``The breed structure has scientific power because in humans the populations are complex and the genetics all scrambled,'' says Williamson, leader of the Canine Biobank Project in the faculty of veterinary sciences. In other words, there are far fewer variations in target genes in purebreds such as Ned -- Warrukadli Rebellion on his birth certificate -- than among people. That means it's necessary to trawl through the entire genetic complement, the genome, of far fewer dogs than people to get a hit, Williamson says.

      For example, if a disorder is caused by a single mutation at one spot on a gene, it could be identified in as few as 10 pedigree dogs, but would require genetic material from thousands of people. ``In complex disorders like diabetes, the numbers go up to 100 to 200 dogs but that's instead of 10,000 to 20,000 humans,'' Williamson adds.

      There's another reason pedigree dogs are rapidly becoming the model animal of choice. As Wilton says, ``people love their dogs''. They take them to the vet, who keeps records, and breeders document genealogies. Having such detailed health and genetic records helps speed up the search for mutations that cause serious diseases, for dog and human alike.

      According to data complied by University of Sydney emeritus professor Frank Nicholas -- creator of the Online Mendelian Inheritance in Animals, hosted by the NIH -- about 440 inherited disorders have been identified in dogs and 6000 in people. Most are so-called single gene disorders. Many affect both species. Researchers suspect that many complex diseases are also likely to be shared. In fact, the top 10 diseases affecting dogs include diseases that affect millions of people across the world: cancer, epilepsy, allergy and heart disease. Moreover, Williamson notes that dogs and people share the same environment: ``For instance, as humans get fatter, so do their pets. Somebody has to hand them the food.''

      The pudgy pet-pudgy person connection holds promise for unravelling the underlying mechanisms of adult onset, type 2 diabetes. ``Dogs don't seem to get type 2 diabetes even if they're obese. It's over-represented in humans,'' Williamson says.

      Clearly there must be a genetic component to the difference. If geneticists can find what that is in dogs, it may well reveal details of the human version of the disorder, which accounts for up to 90 per cent of all cases of diabetes. Such insights could suggest directions for new treatments, possibly gene therapy though which defective biochemical processes and pathways are corrected.

      While the potential for humans of dog genetics is ``quite profound'', as Williamson puts it, the field is in its infancy. As suggested by Nicholas's OMIA data, most of the inherited diseases of Canis familiaris domesticus and Homo sapiens that have been traced to their genetic foundations are caused by mutations in a single gene. Little wonder, then, that the genes for human diseases found by detecting them first in dogs are the cause of very rare disorders. ``There are two well-known cases,'' says Wilton, pointing to the Hcrtr2 gene that causes a form of narcolepsy in dachshunds, labrador retrievers, doberman pinschers and people. Animal and human sufferers are prone to the sudden onset of sleep during waking hours.

      The second landmark case was the discovery of the genetic defect causing a form of blindness called progressive rod-cone degeneration. ``It's the cause of blindness in humans, but only in a small number of cases,'' Wilton says. ``Gene therapy can probably be developed to restore the sight of blind dogs,'' he adds, noting that, if so, human trials could soon follow. After all, the treatment would have been tested first in an animal model, a prerequisite for trials with people.

      Wilton and his colleagues have already tracked down the genes behind a deadly disease affecting puppies and babies. They've patented a genetic test for the dog version -- neuronal ceroid lipofuscinose disease -- which strikes about one in 1800 purebred border collies, as well as english setters, some cats and ferrets.

      The human form, Batten disease, hits about three in every 100,000 children. There's no cure or treatment for the neurodegenerative disorder. So while Wilton says testing will completely eliminate the dog form in time, he hopes the findings will be applied to people.

      Wilton and co have other projects on the go, among them the search for the gene defect causing ataxia -- shaky movements and unsteady gait -- in kelpie dogs and probably in people. They're also working with border collies to pinpoint the mutations behind the eye disorder glaucoma, which affects mostly older people.

      At the University of Sydney, Williamson and his colleagues Rosanne Taylor and Claire Wade are also tackling a range of immune, allergic and neurological disorders affecting people and dogs. It's all part of what Williamson calls ``one medicine'', the use of powerful new genetic technology that enables scientists to compare and contrast the genomes of people and pedigree pooches. Such advances help them search, sequence and screen samples of genetic material; they also have plenty of data. Four years after international scientists completed the human genome project in 2001, another international consortium, led by geneticist Kerstin Lindblad-Toh with the Broad Institute of Harvard and the Massachusetts Institute of Technology, laid out and ordered the dog genome. As Wilton said at the time: ``The genome is like an encyclopedia. It's an awfully good resource for future work.'' Scientists worldwide are adding entries to the encyclopedia through projects such as Williamson's Canine Biobank, which began taking doggie DNA deposits early this year.

      The Sydney Biobank is but a pup compared with the Lupa consortium, named after the wolf that, legend says, suckled the founders of Rome. Scientists from 20 European institutions plan to obtain DNA samples from and genealogical and health records on 8000 dogs. ``It's still early in the piece, but we're already seeing a marked upswing in this kind of work,'' claims Williamson. Like Wilton and all the international teams working on dog genetics, he predicts results for both species soon. Rightly so.

      As Lindblad-Toh said when her group published details of the dog genome: ``For millennia, dogs have accompanied humans on their travels. It is only fitting the dog should be a valued companion on our journeys of scientific discovery.''