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Managing Genetic Disorders

Practical Genetics for Bull Terrier Breeders and Owners

Health Seminar presented to the Bull Terrier Club of America, October 10, 2002

Jerold S Bell, DVM, Tufts University School of Veterinary Medicine

Along with the new tools of genetic tests, there is a new philosophy for managing genetic disorders. Recognizing that breeders own dogs that they favor; recommendations to eliminate their dogs from breeding and use other dogs is counterproductive. There are breeding recommendations that both preserve breeding lines, and manage genetic disorders.

Management recommendations for genetic disorders will vary due to many factors. These include the mode of inheritance, the availability of genetic tests, the size of the breed gene pool and itís diversity, and the spread of the defective gene(s) causing the disorder. With disorders caused by simple dominant genes, everyone with the gene is affected, so these should be easier to manage. You want to replace affected dogs in your breeding program with normal siblings, the normal parent, or prior born offspring. Ideally you do not want to breed affected dogs and produce more affected individuals. If the disorder shows incomplete penetrance, where a dog may have the gene, but not the disorder, selection is more difficult. You should follow the recommendations for recessive genes without tests for carriers.

Managing simple recessive disorders is straightforward if there is a test for carriers: Breed carriers to genetically normal mates, and replace the carrier parent with a genetically normal offspring that equals or surpasses it in quality. For a testable disorder, with a quality dog you are planning on breeding, a carrier test result should not alter your breeding decision. The worse thing breeders can do is to not breed quality dogs due to a single testable defective gene that can be eliminated in one generation. With tens of thousands of genes present in each dog, such a practice will narrow the genetic diversity of the breed gene pool, possibly increasing the frequency of other deleterious genes in the population. As additional genetic tests are developed, the chance of identifying a deleterious gene in all dogs increases. On the other hand, with quality carrier offspring, you do not want to breed more carrier offspring than the carrier parent that you are eliminating, as this will act to increase the frequency of the gene in the breeding population.

A problem with recessive genes and disorders is the spread of unapparent carriers. On average, two-thirds of clinically normal sibs of affected dogs will be carriers, half of the sibs of the parents of affected dogs will be carriers, two grandparents of affected dogs, plus half of their sibs will be carriers, etc. The only matings that produce dogs affected with a simple autosomal recessive disorder are those where both parents are either carriers or affected. Unfortunately, the vast majority of matings involving a carrier are those bred to genetically normal mates. These matings will not produce affected dogs, but will multiply and propagate the defective gene in carrier offspring.

To combat the spread of genetic disorders, many researchers are working to identify the defective genes that cause them. There are two methods of identifying defective genes. The candidate gene approach looks at genes that have been identified to be involved in the affected body system in dogs or even other species. If an abnormality is found in both copies of the candidate gene in all recessively affected dogs, one is abnormal in all known carriers, and all genetically normal dogs have two normal copies of the gene, then the candidate gene is the cause of the disorder. With this knowledge, a direct gene test can be made that can unequivocally identify affected, carrier, and genetically normal dogs.

If there are no candidate genes, or none prove to be involved in the genetic disorder, then a linkage analysis approach may be fruitful. There are genetic markers spread across all of the chromosomes of the dog. If a marker is found to be present twice in affected dogs, once in carrier dogs, and none in normal dogs, then the marker may be linked to the defective gene. With a linked marker, the defective gene has not been identified, but a marker that lies close to it on the chromosome has. With a linkage-based test, there can be false positive and false negative test results, depending on whether a chromosome crossover between the marker and the defective gene has occurred. If this occurs, then the linkage test will not be able to accurately test for the defective gene in the dogís descendents.

Understanding the types of genetic tests that are available will allow breeders to use them properly. Are there tests available that identify the dogís genotype (affected, carrier, normal), or just itís phenotype (affected or not affected)? What is the minimum age necessary for an accurate test of the phenotype (such as hip radiographs, eye examinations, thyroid autoantibodies, etc.)? For linkage-based tests, what is the predicted frequency of false results?

If there is a direct gene test, then you as a breeder only have to know the results of your breeding dog, and that of the proposed mates. For a phenotypic test, linkage test, or if there is no test for carriers, then knowledge of the test results or carrier or affected status of relatives is important. Especially important is full-sibling information for prospective mates and their parents.

Without tests for carriers of recessive disorders, relative risk pedigree analysis can be used to compute risk factors for producing carrier and affected offspring. If a researcher determines the average risk of being a carrier of a specific defective gene for the breed, then breeders should attempt matings below this average. Breeders can compare the carrier risk of prospective mates, and factor this into their breeding decisions.

Relative risk analysis requires openness between both breeders and owners about confirmed affected and carrier dogs, and works best with an open health registry. It allows breeders with higher risk breeding dogs to lower their risk, and provides an objective comparison of dogs. The downside of this analysis is that it applies risk to whole families, and not to just the individuals who may be a carrier. Therefore, itís use selects against both carrier and normal dogs. However, without a test for carriers, it is the only objective tool available to assist breeders with high carrier-risk dogs.

The Canine Health Information Center (CHIC) has been established by the AKC Canine Health Foundation, and the Orthopedic Foundation for Animals. The Bull Terrier Club of America was one of the first breed clubs to participate. Each parent breed club determines the testable disorders for the breed, in an open, or semi-open on-line registry. The beauty of the CHIC program is that for a dog to get CHIC certification, it only has to complete all the required genetic tests - not pass all of them. CHIC certification is a statement of health consciousness, not perfection. Breeders can search online for the test results of prospective mates that are compatible with their own dogs www.caninehealthinfo.org .

04062006 Reprint for www.btca.com