Canines Our canine studies canine studies focus on finding genes important in disease susceptibility and growth regulation. This work is accomplished by collaboration with dog owners, breeders and kennel clubs and not by breeding or housing any dogs on site. Several high profile papers have resulted from these efforts to date. Domestic dogs exhibit tremendous phenotypic diversity. In a recent paper we generated a high density map of canine genetic variation by genotyping 915 dogs from 80 domestic dog breeds, 83 wild canids, and 10 outbred African dogs across 60,968 single-nucleotide polymorphisms (SNPs) (Boyko et al., PLoS Biology, 2010). Coupling this genomic resource with external measurements from breed standards and individuals as well as skeletal measurements from museum specimens, we identify 51 regions of the dog genome associated with phenotypic variation among breeds in 57 traits. Building on this data and fine mapping, we have found and published on genes controlling body size, leg length and width, among others. We are currently expanding our studies of body size to try and identify all major genes that contribute to the continuum of skeletal size (Hoopes et al., Mamm Genome, 2012), and in doing so, we identify genes that are candidates for human disorders of the skeleton. In contrast to humans we find that for across dog breeds a small number of quantitative trait loci (less or = 3) explain the majority of phenotypic variation for most of the traits we studied. In addition, many genomic regions show signatures of recent selection, with most of the highly differentiated regions being associated with breed-defining traits such as body size, coat characteristics, and ear floppiness. Our results demonstrate the efficacy of mapping multiple traits in the domestic dog using a database of genotyped individuals and highlight the important role human-directed selection has played in altering the genetic architecture of key traits in this important species. A new set of studies focuses on genes that affect skull shape (Schoenebeck et al., PLoS Genetics, 2012). Using intrabreed association mapping with 51 measurements captured using an Immersion MicroScribe Digitizer on museum specimens, we show that skull shape is regulated by at least five quantitative trait loci (QTLs). Specifically, we show that at least five genetic loci are responsible for the cranioskeletal differences that differentiate dolichocephalic and brachycephalic dog breeds. Our detailed analysis using whole-genome sequencing uncovers a missense mutation in the BMP3 gene. Validation studies in zebrafish show that Bmp3 function in cranial development is ancient. Microdeletions in humans that include or flank BMP3 are described. Although craniofacial abnormalities associated with these microdeletions were attributed to loss of PRKG2, a nearby gene, our results suggest that haploinsufficiency for BMP3 might also contribute to the clinical features of 4q21 syndrome. Furthermore, we propose that isolated BMP3 dysfunction could be the basis of human cephalic conditions whose genetic etiologies remain unknown. We are also continuing our series of GWAS aimed at finding loci for cancer susceptibility in the dog. Ongoing studies include mapping loci for transitional cell carcinoma (TCC) of the bladder in the Scottish terrier and West Highland White terrier and very recently the Sheltie. We have also continued our work on squamous cell carcinoma of the digit, completing two genome wide association studies (GWAS). We have also recently advanced our studies of histiocytic carcinoma. We coupled a GWAS with genetic fine mapping to identify cancer- associated, non-coding sequence variants spanning the CDKN2A multiple tumor suppressor locus in Bernese Mountain Dogs (BMD) (Shearin et al., Cancer Epidemiol Bio and Prev 2012), who suffer from a 15-25% incidence of malignant histiocytosis. Histiocytic precursor cells from dogs carrying case-associated sequence variants expanded more readily in vitro and expressed less p16 than cells from control dogs. A novel linkage of several cancer- associating sequence variants in BMD show how lower penetrance non-coding sequence variants may combine to deregulate a tumor suppressor locus to cause a high penetrance, distinctive multiple cancer syndrome. In summary, our work is aimed at understanding the role of genetic variation in regulating phenotypes contributing to both morphology and disease susceptibility. As a result, the past year has been defined by significant progress on all fronts and resulted in the publication of multiple papers.
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