The Canine Genome and Molecular Mechanisms of Disease
- Canine Genomics and Genetics: Running with the Pack

Among the most well-studied elements of the canine genome sequence are the short interspersed nuclear elements (SINEs) [2527]. These retrotransposons are implicated in genome evolution and include several families of well-recognized repeats, such as the Alu sequences in humans [18,19,28]. In dogs, the major family of SINEs is derived from a tRNA-Lys, and is distributed throughout the genome at about 126 kilobase spacing [26,29,30]. The frequency of bimorphic SINE elements is 10- to 100-fold higher than what is observed in humans, largely because of the expansion of a single subfamily, termed SINEC-Cf in the canine lineage [11].

As with human Alu repeats, a surprising number of SINEs seem to be located in positions that affect gene expression. A perfect example is the often cited SINEC-Cf element inserted into intron 3 of the gene encoding the hypocretin receptor, resulting in narcolepsy in the Doberman pinscher [31]. These data were the first to link the hypocretin gene family to sleep disorders, and a large body of work on molecular biology of sleep has evolved from these initial studies. Likewise, insertion of a SINE into the canine PTPLA gene leads to multiple splicing defects, causing an autosomal recessive centronuclear myopathy in the Labrador retriever [32].

By studying SINEs in the dog, genome researchers have learned about important disease mechanisms that have not been appreciated from the study of human families. Analysis of other canine diseases demonstrates this as well. For example, analysis of miniature wire-haired dachshunds in the United Kingdom revealed that recessive progressive myeloclonic epilepsy is due to expansion of a dodecamer repeat in the Epm2b gene [33]. Normal dogs carry two sequential copies of the repeat and a third slightly variant copy, while affected individuals carry up to 26 repeats, resulting in dramatic reduction of mRNA by about 900-fold. While simple mutations in the same gene cause Lafora disease in humans, this is the only report of a dodecamer repeat expansion associated with any mammalian disease.

Over 360 genetic disorders found in humans have been described in the dog [3,34], with 46% occurring largely in either one or a few breeds ( It has been said that the “low hanging fruit” of canine genetics is rapidly being plucked. That is, the genes that can be mapped using easily obtainable pedigrees or those caused by highly penetrant alleles are rapidly being identified. To some degree this is true. Loci have been mapped, and in some cases mutations found, for a multitude of common canine diseases (reviewed in [3,22,35,36]). In some cases, the biology of the underlying mutations has been helpful in understanding a comparable human disorder. In other cases, such as the identification of the CNGB3 gene for cone degeneration [37] or the folliculin gene for renal cystadenocarcinoma and nodular dermatofibrosis [38], the work has served primarily to highlight the power of canine genetics for dissecting genetic diseases common to humans and dogs.

Particularly challenging will be the identification of genes associated with complex diseases such as hip dysplasia, a common disease in dogs, affecting up to 50% of the large breeds. The disease is recognized radiographically as subluxation of the femoral head from the acetabulum of the hip joint [39,40], and is likely caused by a mixture of genetic [4145] and environmental factors [4448]. Two approaches have been used to try to identify causative genes.

Investigators at the University of Utah have looked for a genetic association in a population of well-characterized and densely genotyped Portuguese water dogs (PWD) using the Norberg angle, a highly heritable and quantitative radiographic measure of joint laxity. They report the presence of two unlinked quantitative trait loci (QTLs) on CFA1, located more than100 megabases apart, which demonstrated statistically significant associations [49]. A third locus on a different chromosome was found to be associated with osteoarthritis [50].

By comparison, Todhunter and colleagues have developed a large outcrossed pedigree of affected Labrador retrievers crossed with unaffected greyhounds [45,51,52]. A variety of measures, including age at detection of femoral capital epiphyseal ossification, distraction index, hip joint dorsolateral subluxation score, and hip joint osteoarthritis, are being used in a genome-wide scan for classical linkage [51]. While no gene has yet been found, pedigree analysis suggests that loci controlling these traits act additively, and that the distraction index may be controlled by a single major locus [45,53].

These studies represent two distinct methods for approaching a complex problem. Both highlight different advantages of using the canine system for genetic analysis. The first makes use of the availability of large controlled populations with limited genetic diversity. The second demonstrates the ability to cross populations showing extremes of phenotype in order to map genes. Each has the potential for success, and comparison of the two methods will improve the design of future studies.

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