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Deconstructing the Gene Pool

Mark Neff: The study of how individuals respond differently to medicines due to their genetic makeup is called pharmacogenetics, and it’s an intense area of investigation in human genetics. Probably all of us are aware of instances where one person responds positively to a medicine and is cured, while another person responds negatively or not at all. These differences are often tied to variation in genes. If we knew the genes that were responsible for side effects, we could identify the individuals at risk and prescribe the medicine that avoids a reaction and still provides relief. The same opportunity exists for dogs. Not all Collies have the mutation; those that don’t can be treated with ivermectin, which is an effective drug for its purpose. The Collies who do have the mutation can be treated with a different medicine.

JB: In dogs with the mutation, what happens?

MN: The normal product of this gene is a protein pump that can eliminate toxic chemicals from the central nervous system, thereby protecting the brain. The mutation causes the pump to be defective. If both copies of the gene are mutated, no functional pump is produced at all, which is the worst scenario. When the dogs are given a drug like ivermectin, which is toxic to neurons in high doses, the drug accumulates in the central nervous system, killing nerve cells. However, dose-sensitivity is an important issue. The smaller dose of ivermectin used to prevent canine heartworm infection, for instance, does not appear to be a problem for these dogs regardless of the mutation, but the higher dose used to treat mange can be fatal in a dog with two defective genes. The dose sensitivity varies by drug as well, so there’s still a lot to be sorted out.

JB: You’ve said that you think there is currently a disconnect between canine genetic research and the application of genetic knowledge. What do you mean?

MN: Breeders and owners are beginning to be inundated with DNA test results, which will only increase in the next few years. There’s an unmet need of genetic counseling that ideally would accompany DNA test results. In addition, we as researchers typically don’t have all the information we need to advise breeders on integrating test results with their breeding strategies. For example, based on our data, we think that both copies of the gene need to be mutated to acquire supersensitivity to ivermectin, but this may pertain to only some of the breeds with the mutation. Sighthounds have very different physiologies from Collies, for instance, and this could alter the effects of the mutation. Science always involves uncertainty, and it’s difficult to convey the ambiguity that remains. Katrina Mealey, our collaborator at Washington State, is continuing the research and adding a lot more detail to this particular story.

JB: In the research article, you advise re-examining how a breed is defined genetically. Would you elaborate?

MN: This is a statement more for academic geneticists than for breeders and owners. There’s a lot of scientific work going on now that neglects the fundamental fact that dog breeds are not natural species, but rather, have evolved through selective breeding and intentional outcrossing to produce new combinations of traits and hence new breeds. Most studies describing breed relationships use statistical and computational tools that were developed to describe relationships between species with distinct lineages. These tools are inappropriate for analyzing breeds of dog. Our paper showed that an identical mutation existed in two very different types of dog, two sighthounds and seven herding breeds. Conventional tools would have almost certainly missed the relatedness of these breeds.

JB: Your research identified seven affected herding breeds, which were mostly developed after the mid-19th century, and provided evidence that these breeds are in fact closely related. How did you draw those conclusions?

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