For many diseases, however, there are too many candidates, such as seizure disorders in which hundreds of mutations are known
to produce epilepsy in mice. Alternatively, the gene associated with a particular disease may not have been identified yet
in any species. In these cases, alternative approaches are necessary.
Linkage mapping uses genetic markers to follow the inheritance of chromosomes within a family. The disease-causing gene will be in the vicinity
of some of these markers on a single chromosome. If a set of markers are consistently inherited in affected dogs, then those
markers are "linked" to the disease. Neonatal diseases are ideally suited for mapping studies because the entire family, except
maybe the sire, is available for DNA sampling at the time the disease is recognized.
Neonatal encephalopathy with seizures (NEWS) in standard poodles is characterized by developmental delay, ataxia, seizures
and death before weaning age. There is a linkage between markers on chromosome 36 and NEWS. Recombinations occur when a portion
of one chromosome is traded with its pair during meiosis. The resulting shuffle of markers allows more precise localization
of the portion of that chromosome where the disease gene resides. This area of a chromosome where the responsible gene is
located is called the locus. In NEWS, recombinations within the families studied further narrowed the locus to an area containing 26 genes. Of these,
three were clearly involved in central nervous system development and, thus, became the prime candidates to be sequenced.
A missense mutation in one of these genes was identified. DNA testing now allows standard poodle breeders to use wise breeding
strategies to avoid producing affected dogs while still being able to use carriers in their breeding program.
SNP association is similar to linkage mapping in that marker genes are used. In this case, the markers are single nucleotide polymorphisms,
or SNPs. SNPs are much more numerous than the type of markers used in linkage analysis, thus providing more dense coverage
of the genome. This increased density allows us to look for a statistical association between having a disease and having
a particular set of SNPs. The pattern of SNPs in dogs with the disease is compared with that of healthy dogs of the same breed.
Affected dogs will inherit the particular group of SNPs that reside close to the mutant gene more commonly than normal dogs
will. This approach can be done without having samples from the extended family. SNP association mapping has identified the
mutations responsible for exercise-induced collapse in Labrador retrievers and degenerative myelopathy in a number of breeds.
High-quality breeders understand the role genetic testing will play in their attempts to improve the health of their breed.
We, as veterinarians, should offer the diagnostic tests necessary to definitively diagnose a neonate with neurologic signs.
In some cases, we may find a treatable condition such as congenital hypothyroidism. We need to be aware of the genetic tests
already available and how to interpret them so that we can counsel owners and breeders appropriately. For other cases in which
a genetic disorder is suspected, diagnostic tests can provide the clues necessary to help identify the gene responsible for
the disease. Then, wise breeding strategies can ensure that affected dogs are not produced in the future and that the incidence
of the mutant allele in the population decreases over time.
Dr. Hoskins is owner of Docu-Tech Services. He is a diplomate of the American College of Veterinary Internal Medicine with specialities
in small animal pediatrics. He can be reached at (225) 955-3252, fax: (214) 242-2200 or e-mail: firstname.lastname@example.org