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Duck-Tolling Retrievers Yield Genetic Clues to Autoimmune Disease

Genome-wide association studies (GWAS) of DNA from Nova Scotia duck-tolling retrievers (NSDTRs) have identified five genetic loci that predispose this breed to an autoimmune disease similar to systemic lupus erythematosis (SLE) in humans. "We know that SLE in humans is caused by many genes and were therefore not surprised to find several risk factors that contribute to the disease in dogs," said Maria Wilbe, a doctoral candidate at the Swedish University of Agricultural Sciences in Uppsala and lead author of the article. The results provide clues as to where researchers might look for corresponding SLE-related disease genes in humans. The results also demonstrate why dogs can serve as highly useful and efficient models for identifying genes for multigenic diseases and related pathways in humans. "Our results indicate that the homogeneity of strong genetic risk factors within dog breeds allows multigenic disorders to be mapped with fewer than 100 cases and 100 controls, making dogs an excellent model in which to identify pathways involved in human complex diseases," said Dr. Hannes Lohi, of the University of Helsinki and Folkhälsan Research Center in Finland, a co-leader of the project. As the result of two genetic bottlenecks—domestication from the wolf and breed formation--the members of any particular dog breed tend to share much longer stretches of DNA with each other than do members of heterogeneous human populations or even members of relatively homogeneous human sub-populations. Many breeds also tend to exhibit elevated incidences of certain specific genetic diseases within their populations—indicating that a few risk factors might have accumulated through genetic drift or selective breeding.

Taken together, these facts imply that many fewer SNPs are necessary to perform statistically significant GWAS to identify complex disease genes in dogs than in humans. It has been estimated that an effective GWAS study in a dog breed can be carried out with at least 15,000 SNPs and at least 200 dogs, whereas similar studies in a general human population would require approximately 500,000 SNPs and many, many more than 200 individuals—resulting in much costlier, more time-consuming, and more difficult studies.

NSDTRs are strongly predisposed to many immune-mediated diseases, including an SLE-related disease complex consisting of an immune-mediated rheumatic disease (IMRD) and a steroid-responsive meningitis-arteritis (SRMA). The NSDTR breed was developed in the Yarmouth region of Nova Scotia in the early 1800s as a hunting and retrieving dog. The breed descended from a very small population of dogs that survived two devastating outbreaks of canine distemper virus in 1908 and 1912. One hypothesis for the abnormally high rates of autoimmune diseases in modern NSDTRs worldwide is that dogs with particularly strong or reactive immune systems were much more likely to survive these outbreaks.

Pedigree analysis of the SLE disease complex in NSDTRs has indicated that it involves multigenic inheritance, as do most autoimmune diseases in humans. The IMRD disease complex includes chronic musculoskeletal signs with a clinical picture indicative of immune-mediated non-erosive polyarthritis. Many of the clinical features of the canine IMRD complex are similar to those of human SLE.

"In this study, we have identified five loci that predispose to an SLE-related disease in NSDTRs. The study highlights the strength of disease mapping in dogs, where a canine breed may carry a few disease loci, each with a strong effect, that together are sufficient to predispose to a complex disease," Dr. Lohi stated. Some types of genetic risk factor will be more easily traced in dogs than in humans, and the dog studies might be a valuable complement to human studies for identifying new genes and pathways that are important in disease pathogenesis.

"Although we plan to identify and characterize the functions of the canine mutations, this study opens the door for further studies of specific T-cell activation pathways in human populations. In the more long term, the development of clinical treatment regimens based on a dog's particular risk genotype might be possible. For instance, the effect of calcineurin inhibitors could be studied in dogs as a complement or alternative to traditional corticosteroid therapy. Such studies might also lead to better treatment options for human rheumatic diseases and SLE," Dr. Lohi said.

Interestingly, members of the NSDTR breed exhibit a remarkable behavior called “tolling” (luring). The dog plays near the shore to lure curious ducks and geese into range for hunters shooting from land. The quintessential example of tolling is exhibited by the red fox. One fox plays along the shoreline ignoring ducks in the water, but arousing their curiosity and drawing them closer, while the fox’s mate hides near the shore. At an opportune moment, the mate leaps from its hiding place and pounces on a curious, but unfortunate, nearby duck. Tolling is said to be an innate behavior that cannot be learned.

The senior author of the article was Dr. Kerstin Lindblad-Toh of the Broad Institute of Harvard and MIT in the United States, and Uppsala University in Sweden. "It's extremely interesting and feels fantastic that we can so readily find genes even for complex diseases in dogs. The study also provides entirely new avenues for studying SLE in humans," said Dr. Lindblad-Toh.

The research results were reported online on January 31, 2010 in Nature Genetics.
[Press release 1] [Press release 2] [Nature Genetics abstract]