Cat Genome Project: Why the Cat

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THE DEVELOPMENT OF THE DOMESTIC CAT, Felis catus, AS A MODEL FOR GENETIC ANALYSIS

The publication of the first genetic map of the Drosophila X-chromosome in 1913 by Sturtevant ushered in the century of genomics. Advancements in technology have resulted in progression from the first maps, constructed of visible mutant phenotypes in Drosophila and corn, to resolution on the nucleotide level and the sequencing of whole genomes.

Spearheaded by the human genome initiative, enormous interest and resources have recently been directed towards the development of gene maps in other species. Traditional models of genetic analysis, which have been key to elucidating basic biological mechanisms (Escherichia coli, Drosophila, Caenorhabditis, yeast, Arabidopsis, and mouse) have been the target of large genome sequencing initiatives with complete nucleotide sequences recently reported for E. coli, C. elegans and Drosophila. Additionally, significant gene maps have been published for over 30 mammalian species. These comprehensive gene maps will have two general uses: first as a resource for elucidating gene action in all fields of human biology including development, aging, cancer, heritable disease, immune defenses and quantitative traits, and secondly for approaching an understanding of the evolutionary heritage of mankind and whether there is any adaptive rationale underlying mammalian genome organization.

We decided to build a gene map for the domestic cat, Felis catus as an attempt to develop this species as a suitable model for genetic analysis. The cat was an attractive candidate for comparative gene mapping for several reasons .

1. The cat as an animal model for human hereditary disease:

Clinical emphasis on pet cats in the veterinary specialties has resulted in the identification of over 200 heritable genetic defects (http://www.angis.org.au/Databases/BIRX/omia/), many of which are homologous to human inborn errors. Specific metabolic defects have been identified underlying many of these feline diseases and derived cat strains homozygous for many of these mutations are maintained in veterinary clinical centers for development of model therapy. However, whereas genes associated with some feline disorders have been characterized, and even corrective gene therapy strategies have been examined for some disorders, the genes associated with the majority of feline disorders have yet to be identified.

Model animal systems serve to elucidate molecular mechanisms underlying pathology, and ultimately provide a whole animal system for trial of potential treatments, drug or gene therapy interventions. Mouse and rat have been powerful models to examine molecular mechanisms of human hereditary disorders. We believe that there are cogent rationales for development of a carnivore animal model. (i) Multiple animal models from diverse evolutionary backgrounds may be required to fully characterize many molecular pathologies. As an example, lack of dystrophin in muscular dystrophic human, mouse, cat and dog elicit very different clinical phenotypes ; (ii) Murine models may prove inadequate for analysis of some quantitative characters, as generations of inbreeding may have eliminated multigenic diversity at crucial modifying loci; (iii) Spontaneously generated models will continue to have value in animal models, particularly for pathologies that are rare in humans and hence poor candidates for traditional mapping strategies; (iv) The cat is frequently used as an animal in laboratory experimentation ranging from gastroenterology to ophthalmology. This wealth of information can be capitalized on in elucidating molecular pathologies for inherited conditions. As an example, in the field of vision research, a vast amount of knowledge has been gained through elaborate investigations including physiological and morphological aspects of the cat retina contributing to the value of the cat as a model for retinitis pigmentosa.

2. The cat as an animal model for infectious disease:

Domestic cats are subject to epidemics of two viruses, FeLV and FIV, that cause immunodeficiencies and neoplasias, providing a powerful animal model for leukemia and AIDS. These viruses and other feline pathogens provide a good opportunity to investigate the interaction of host immune response and fatal infectious disease through studies of the major histocompatibility complex, T-cell receptor loci, immunoglobulin genes and other loci that participate in immune response.

3. The cat as a model for the evolution of genome organization:

Our studies have revealed a high degree of linkage conservation between the cat and human genomes (3 to 4 times more conserved than mouse vs. human), permitting a reconstruction of primitive mammalian genome organization. Increased understanding of genomic organization of the cat will contribute to our understanding of mammalian genome evolution and whether there is adaptive rationale to genomic organization as has been observed in the MHC, HOX and globin complexes. Additionally, the high degree of conserved synteny between human and cat leads to powerful comparative inference in gene mapping exercises.

4. The cat as model of structure, function and regulation of coat color genes:

A number of morphological loci (coat color, pattern, hair length, texture) have been described which are abundantly polymorphic in cat populations and which are homozygous, but in different combinations, in over 33 registered domestic cat breeds (Cat Fancier’s Association, Manasquan, NJ). Several of the genes involved in the production and distribution of pigment in the mouse have been shown to be part of diverse cellular, developmental and physiological processes, and also to be implicated in pathologies such as anemia, sterility and neurological disorders.

The domestic cat is one of thirty-seven species of the family Felidae. Nearly all of these species are maintained in zoos and wildlife preserves where they can be available for comparative research initiatives. The LGD has collected biological specimens from individuals sampled across the range of each species. These have been used to study genome and species evolution during Felidae emergence and evolution.