Scientific Use of the Canine Genome Map Greg Acland, BVSc  Cornell University

Summary:

Recent progress in development of the canine genome map has been very rewarding, both for the scientists concerned with canine genetics research, and for the broader community of dog breeders, owners and lovers. Although further refinement will yield valuable increases in the map's power, the currently available map is already proving to be a major asset. This map is not a single instrument but a set of connected, interacting tools.

The primary component is the linkage map, which basically establishes an ordered array of genetic markers, sorted into linkage groups, that are vital for linkage mapping studies. This tool has rapidly matured since the first linkage map of the dog was published, and is currently in its third generation, with linkage groups covering almost the entire canine genome, and in many cases identified with the specific corresponding canine chromosome. This has enabled linkage studies to be undertaken, mapping the genetic loci for a range of canine genetic disorders, and establishes that such mapping efforts can now be undertaken with a very high expectation of success, given a well defined single gene train, and adequate pedigrees for the mapping effort. As specific examples, we now know the precise map position for two forms of Progressive Retinal Atrophy: progressive rod-cone degeneration (prcd) and early retinal degeneration (erd); and for dayblindness/cone degeneration (cd). For breeders of purebred dogs, this means that marker tests can now be developed to help in strategic breeding plans to eliminate undesirable traits in their breeds.

The radiation hybrid map is the second crucial tool; this too has progressed at an astounding rate. By ordering both the marker loci from the linkage map, and additional gene specific markers, onto a much higher resolution map, it is possible and in fact becomes obvious, to determine how the various canine linkage groups correspond to the maps of other species, in particular those of humans and mice. The combination of the linkage map and the radiation hybrid map is termed the integrated map. Because genes are common to different species, the integrated map tells you to which human or mouse map position your mapped trait corresponds. For example, we now know that prcd is on canine chromosome 9, which corresponds to human 17 q, and thus prcd in dogs is probably the direct equivalent of retinitis pigmentosa type 17 (RP17) in humans. This allow two very important questions to be asked: 1) which, if any, train previously known in humans or other species, corresponds to this canine trait? This is critical because many traits appear similar but are caused by very different genes; and 2) are there any genes known on the corresponding region of the human or mouse map, that might determine the canine trait? This is important because many more genes have been placed on the human and mouse map than will, likely, ever be mapped in the dog - in fact it will not be long until every single gene is identified on the human map.

The third crucial tool that has been developed is the canine BAC library. This tool allows investigators access to the genomic sequence, that is the actual DNA, corresponding to regions identified by the integrated mapping studies. This is essential because in many cases even when the 'gene is mapped, that does not automatically tell us which gene really causes the disease, particularly if the gene has not previously been known at all. Already, investigators are making great progress in searching the BAC library to identify novel genes in the regions where trait loci have been mapped, and this should rapidly lead to the identification of an increasing number of the genes and mutations responsible for these single gene traits. A specific example of how valuable and successful this approach can be is the recent identification of the gene for canine narcolepsy. Once Dr. Mignot's research group had successfully mapped this disease to a small enough region, they were able to construct a physical and sequence map of the region, and identify a unique gene that proved to be the cause of the disease.

A harder problem, however, is the search for genes controlling complex disorders; unfortunately many of the genetic problems, and the desirable characteristics, of dogs are inherited in a complex manner, involving multiple genes that may interact with each other, and with nongenetic effects in determining expression of the trait. As the power of our map improves, and new tools evolve, we can expect to start making progress on these problems as well.

Biographical Profile

Gregory M. Acland is a veterinary ophthalmologist at the James A. Baker Institute for Animal Health, in the College of Veterinary Medicine of Cornell University. His research is undertaken as part of the Center for Canine Genetics and Reproduction directed by Dr. Gustavo Aguirre. Current projects include collaborative efforts to identify the genes for PRA in multiple breeds, for cone degeneration in Alaskan Malamutes, Collie Eye Anomaly, and several forms of cataract; and to evaluated potential therapies for inherited retinal degenerations. Dr. Acland is funded by the American Border Collie Association, the AKC Canine Health Foundation, the Baker Institute PRA/CEA Fund, The Foundation Fighting Blindness, and the National Eye Institute (Grant EY06855).