Screening for a canine model of choroideremia exclusively identifies nonpathogenic CHM variants.

Choroideremia is an X-linked, progressive photoreceptor degeneration disorder due to mutations in CHM. In addition to an atrophy of the outer retina, affected individuals present with a characteristic atrophy of the choroid. To search for a canine model, we screened the CHM gene of 37 dogs (22 breeds) with various forms of retinal dystrophies. We found 21 variations in 13 breeds (17 detected in only one breed and 4 shared by two or more) with 43% segregating in the same pedigree, a Great Dane female and a female offspring. Of particular interest were an exonic missense variation and a 3-bp intronic deletion near a splice acceptor site. However, although not detected in unrelated healthy Great Danes, these variants were nonpathogenic since they did not segregate with the disease phenotype in the pedigree. These results suggest that a CHM dog model may not be viable, as is the case for mouse and zebrafish.

Canine population structure: assessment and impact of intra-breed stratification on SNP-based association studies.

BACKGROUND: In canine genetics, the impact of population structure on whole genome association studies is typically addressed by sampling approximately equal numbers of cases and controls from dogs of a single breed, usually from the same country or geographic area. However one way to increase the power of genetic studies is to sample individuals of the same breed but from different geographic areas, with the expectation that independent meiotic events will have shortened the presumed ancestral haplotype around the mutation differently. Little is known, however, about genetic variation among dogs of the same breed collected from different geographic regions. METHODOLOGY/PRINCIPAL FINDINGS: In this report, we address the magnitude and impact of genetic diversity among common breeds sampled in the U.S. and Europe. The breeds selected, including the Rottweiler, Bernese mountain dog, flat-coated retriever, and golden retriever, share susceptibility to a class of soft tissue cancers typified by malignant histiocytosis in the Bernese mountain dog. We genotyped 722 SNPs at four unlinked loci (between 95 and 271 per locus) on canine chromosome 1 (CFA1). We showed that each population is characterized by distinct genetic diversity that can be correlated with breed history. When the breed studied has a reduced intra-breed diversity, the combination of dogs from international locations does not increase the rate of false positives and potentially increases the power of association studies. However, over-sampling cases from one geographic location is more likely to lead to false positive results in breeds with significant genetic diversity. CONCLUSIONS: These data provide new guidelines for association studies using purebred dogs that take into account population structure.