Leading the way: canine models of genomics and disease

Abstract

In recent years Canis familiaris, the domestic dog, has drawn considerable attention as a system in which to investigate the genetics of disease susceptibility, morphology and behavior. Because dogs show remarkable intrabreed homogeneity, coupled with striking interbreed heterogeneity, the dog offers unique opportunities to understand the genetic underpinnings of natural variation in mammals, a portion of which is disease susceptibility. In this review, we highlight the unique features of the dog, such as population diversity and breed structure, that make it particularly amenable to genetic studies. We highlight recent advances in understanding the architecture of the dog genome, which propel the system to the forefront of consideration when selecting a system for disease gene studies. The most notable benefit of using the dog for genetic studies is that dogs get many of the same diseases as humans, with a similar frequency, and the same genetic factors are often involved. We discuss two approaches for localizing disease genes in the dog and provide examples of ongoing studies.

Fig. 1.

Genome-wide association study (GWAS) versus linkage-based study. A GWAS study compares a dense set of genotypes from animals that have a particular trait (cases) with unrelated controls, in order to ascertain alleles that are associated with the trait. Specific corrections need to be applied to account for factors such as population stratification. By comparison, a linkage study analyzes a genome-wide distribution of markers through multiple generations of a pedigree. Statistical methods are used to find a marker whose alleles segregate with disease status more often then would be expected by chance. Both types of approaches can be successful in identifying a disease locus. Fine mapping with more markers is used to identify a shared pattern of alleles from adjacent markers (haplotype). Sequencing is used to ultimately identify the disease mutation. The red cross symbol indicates an individual that is affected with the disease. The polymorphic markers that are used most frequently for linkage-based studies include SNPs and microsatellites, whereas GWAS studies use SNPs exclusively.

Fig. 2.

Example of a linkage pedigree. The GSD pedigrees segregating RCND; this is an example of a powerful canine linkage study that was used to identify a cancer locus (Jónasdóttir et al., 2000). Several highly linked microsatellite markers established CFA5 as the location (Jónasdóttir et al., 2000), which was subsequently identified as a mutation in exon 7 of the folliculin gene (Lingaas et al., 2003). Figure reproduced from Jónasdóttir et al. (Jónasdóttir et al., 2000). Copyright (2000) National Academy of Sciences, USA.