The long (and winding) road to gene discovery for canine hip dysplasia

Abstract

Hip dysplasia is a common inherited trait of dogs that results in secondary osteoarthritis. In this article the methods used to uncover the mutations contributing to this condition are reviewed, beginning with hip phenotyping. Coarse, genome-wide, microsatellite-based screens of pedigrees of greyhounds and dysplastic Labrador retrievers were used to identify linked quantitative trait loci (QTL). Fine-mapping across two chromosomes (CFA11 and 29) was employed using single nucleotide polymorphism (SNP) genotyping. Power analyses and preferential selection of dogs for ongoing SNP-based genotyping is described with the aim of refining the QTL intervals to 1-2 megabases on these and several additional chromosomes prior to candidate gene screening. The review considers how a mutation or a genetic marker such as a SNP or haplotype of SNPs might be combined with pedigree and phenotype information to create a 'breeding value' that could improve the accuracy of predicting a dog's hip conformation.

Monitoring Hip and Elbow Dysplasia Achieved Modest Genetic Improvement of 74 Dog Breeds over 40 Years in USA

“…The complex inheritance patterns of both ED and HD have been extensively investigated [1], [3]–[7], which supports the argument that in order to reduce the incidence of HD and ED, selection for breeding should be based on estimated breeding values (EBVs) and not simply the phenotype of antecedent generations [3]. The genotype of a dog with a complex trait cannot be revealed from its phenotype.…”

“…There is an estimated 60–70 million pet dog population in USA households. The prevalence of HD, as estimated by the Orthopedic Foundation for Animals (OFA), varied widely from 1 to 75 percent [1], while the incidence of ED ranged from 1.2 to 47.9 percent in 78 breeds (http://www.offa.org/pdf/elbowarticle.pdf). Because osteoarthritis caused by HD and ED is incurable and progressive, it is increasingly important to improve hip and elbow joint conformation and thus reduce the incidence of osteoarthritis in these joints through selective breeding.…”

Trends in the phenotypic hip status of selected breeds of dog as measured by the New Zealand Veterinary Association Hip Dysplasia scheme (1990–2008)

“…Some authors have proposed that a selection index based on breeding values jointly estimated from a hip-extended measurement and distraction radiography would most rapidly influence genetic trend . A combination of a genetic test for a major gene locus, in combination with phenotypic scoring, would represent an important development in CHD screening, and is the subject of ongoing research (Zhu et al 2009). …”

“…Due to the difficulty in objectively quantifying clinical CHD, radiological methods have been developed in an attempt to allow dog breeders to select stock for breeding that are less phenotypically affected (Lawson 1963;Smith et al 1990;Smith 1997;Fluckiger et al 1999;Lust et al 2001). CHD has a quantitative mode of inheritance, so a simple genetic screening test is not available nor is likely to be in the foreseeable future (Clements et al 2006;Zhu et al 2009). …”

Genetic Studies: The Linear Mixed Models in Genome-wide Association Studies

“…In this process, Q as the fixed effect measures population structure that is calculated by package Structure [11], K as the random effect detects the relative kinship matrix that empirically measures the genetical similarity across individuals from markers or SNPs and computed by SPAGeDi [40]. It is known that K is superior to the co-ancestry matrix (G) in absence of pedigree information or under biases from genetic drift [41,42]. Additionally, this unified linear mixed-model is flexible to be adopted in population data including both stratification and familial relatedness and family based data containing family structure alone [23].…”