Overview of the International Workshop on Canine Genetics

Overview of the International Workshop on Canine Genetics G. D. Aguirre, K. Ray, and G. M. Acland

Photograph of Great Dane by C. H. Brown. From the Center for Canine Genetics and Reproduction, the James A. Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853. q 1999 The American Genetic Association 90:1–2

On July 12–13, 1997, the James A. Baker Institute for Animal Health, College of Veterinary Medicine at Cornell University hosted an International Workshop on Canine Genetics. The workshop, centered on the evolving canine genome map, focused on the map, the genes, and the diseases. Over 100 scientists representing 13 countries attended the 2 day workshop. This watershed event marked a turning point for canine genetics, denoting a transition from classical investigations to studies based on molecular approaches pioneered in mammalian genetics by studies of human and mouse. It became clear during the workshop that the genomic revolution that is energizing all of modern biology is now finding ready application to problems that interest scientists working on the dog. Scientists attending the meeting reported construction of a low-resolution framework map of the dog genome and further tools, such as canine-rodent somatic cell hybrids, radiation hybrid cells, and a BAC library, necessary for further development of the evolving map. It was gratifying to observe that these efforts are already paying dividends. Markers linked to two different inherited diseases were reported in the meeting. The numerous small and acrocentric chromosomes of dog have created a particular challenge for karyotypic studies. The excellent results obtained by fluorescence in situ hybridization (FISH) and chromosome painting, as presented at this meeting and in this issue of the Journal of Heredity, promise to overcome the long-standing limitation of advancement of studies in this area. The dog has an amazing repertoire of breed-specific characteristics. The consistent and predictable suite of phenotypes associated with each breed, including for example, coat color, morphologic appearance, behavioral characteristics, and, in some cases, breed-specific diseases, attests to the heritability of these traits. However, until recently, molecular characterization of these

interesting heritable traits was hampered by a paucity of the necessary resources. Development of the appropriate tools for such investigations in the dog has, until now, lagged behind the rapid progress of the human genome project, and burgeoning studies on other species which gained financial support either for their merit as a less expensive and better studied animal models, or as species of agro-economic importance. As a result, the dog remained a “map-poor” species. Efforts toward building a map for the canine genome have particularly benefited from the knowledge accumulated from comparative mapping of mammalian species. A notable advance using this approach is described by Werner et al. in this issue of the Journal and illustrated in this introductory editorial. They observed that a large segment of canine chromosome 9 (CFA 9) has syntenic homology to human chromosome 17q, and gene order is maintained although the entire region is inverted in relation to the centromere. More recent studies have mapped additional genes and markers to this region, and the first inherited autosomal disease of dogs has been mapped to this chromosome using a comparative mapping approach (Acland et al., PNAS USA 1998;95: 3048; Gu et al., Mamm Genome 1998;9:740). Thus canine chromosome 9 has become the best characterized of all canine autosomes, and some of the genes identified, for example, PDEG and BRCA1, will likely play an important role in our future understanding of inherited breast cancer susceptibility (BRCA1) and retinal photoreceptor dysfunction and disease (PDEG). Each different breed of dog displays a characteristic phenotypic uniformity indicative of a high degree of genetic homogeneity. In their excellent review (“What man’s best friend can teach us about human biology and disease,” Am J Hum Genet 1997;61: 475), Ostrander and Giniger emphasized that a diverse array of phenotypically dis-

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tinct and stable breeds has been created in only a few generations, implying that only a small number of key genes and loci are responsible for the characteristic features that define particular breeds. The great and consistent discrepancy in size between different dog breeds, for example, the Chihuahua and the Irish wolfhound, is unique in the animal kingdom. In no other species is the spread of the size continuum so great, both in terms of standard height and weight. Since these phenotypic traits are passed on to the progeny, and segregate in a predictable manner in backcross generations, the genes and loci that define body size and weight in dog are amenable to identification using a combination of linkage and comparative mapping approaches. Such genes may provide key information about the morphology of humans. Similarly, dogs show a unique repertoire of breed-specific behavior. In many, these characteristics define a breed and are appreciated as desirable behaviors. For the most part the various breeds of pointers point, the retrievers retrieve, and herding dogs such as border collies have an obsessive desire to herd sheep and even two-legged humans. On the other hand, aberrant or undesirable behavior, such as nervousness, aggression, or shyness, is also common, often in a breed-specific manner. These behavioral traits can be identified naturally or bred into study populations, measured reliably, mapped, and the responsible genes cloned (Ostrander and Giniger, Am J Hum Genet 1997;61:475). Such studies are difficult in humans, not only because of the difficulties in separating genetic from environmental influences, but also because they raise

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moral and ethical questions regarding the study subjects. In this respect the dog is ideally suited to molecular approaches to study complex behavior. From a biomedical perspective, the dog is an excellent model for studies of human diseases. Over 300 inherited diseases of dogs are presently being cataloged (Patterson D, unpublished data). A web page has been established [Online Mendelian Inheritance in Animals (OMIA), http://www.angis.org.au/Databases/BIRX/ omia/] that references many of these disorders and is at least conceptually similar to Online Mendelian Inheritance in Man (OMIM). Many of these inherited diseases represent, at least clinically or biochemically, homologs of disorders affecting humans and other species. In a few cases, for example, achromatopsia and Xlinked inherited retinal degeneration, the dog is the only known animal counterpart of the human disorder. Some canine diseases thus far identified are true homologs of human diseases caused by defects in the same gene. Hemophilia B was the first canine disorder for which a mutation was identified in 1989. The gene and mutation responsible for two other X-linked disorders, proteolipid protein deficiency and muscular dystrophy, were identified by 1992. As of 1998, three more canine Xlinked diseases have been characterized, including the locus homolog for another human disease, retinitis pigmentosa 3. In contrast, the first autosomal gene defect (protein 4.1 gene), causing hereditary elliptocytosis, was recognized in 1991. The rapid progress in canine genetics is evident by the fact that of the 12 molecularly

characterized diseases or locus homologues, 7 have been identified since 1996. We hope that the enthusiasm among scientists, fueled by recent advances in canine genetics, will further accelerate the progress in the study of dogs. In the near future, dog breeders will breed healthier dogs, ongoing studies on gene therapy using the dog will be further improved, and provocative and probing questions regarding the wide variation of morphology and behavior of dogs will be answered. Once again, the dog will prove to be man’s best friend. It has been our pleasure to organize the International Workshop on Canine Genetics held at Cornell University, July 12–13, 1997, and to work with the editorial staff of the Journal of Heredity to assemble this special issue. The publications included reflect the very active endeavors of a large number of dedicated scientists who are joining forces to make sure that the unique qualities that dogs offer for genetic studies are used to their maximum potential. We are also grateful to those individuals and organizations, listed below, who supported the workshop and publication. Gustavo D. Aguirre, Kunal Ray, Gregory M. Acland Ithaca, NY September 24, 1998 Sponsors of the International Workshop on Canine Genetics James A. Baker Institute College of Veterinary Medicine, Cornell University Eugene V. & Clare E. Thaw Charitable Trust American Genetic Association American Kennel Club-Canine Health Foundation Amersham Life Sciences, Inc. Dad’s Products Company, Inc. ICOS Corporation Kal Kan Foods, Inc. Orthopedic Foundation for Animals, Inc. PE Zoogen The Foundation Fighting Blindness The Wellcome Trust