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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.
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