As its goal, this project seeks to decipher the genetic architecture underlying the mammalian skeletal system. We use a population of Portuguese Water (PW) Dogs, descended from a few founders and characterized by frequent inbreeding events. This unstructured pedigreed population is similar to human isolates such as the Hutterites or larger well documented populations such as the Mormons. Dogs are genotyped using microsatellite markers and phenotyped from five x-rays comprising the skull, fore- and hind limbs and pelvis. From this information it has been possible to identify QTLs (haplotypes of Quantitative Trait Loci) that inform the skeleton. During the first 2+ years of the project, we have used Principal Component Analysis to define groupings of skeletal metrics that represent functional trade-offs between adaptations for power or speed (e.g. skull vs. post cranial body, limb width vs. length, pelvis size vs. limb width) and have identified genetic loci that regulate these groupings. Loci also have been identified that regulate variation in the right vs. the left hip joints (bilateral asymmetry); and an interaction between QTLs affecting size has been identified that, in part, explains sexual dimorphism. In continuing this project we shall (i) complete the analysis of the canine genome; (ii) analyze several QTLs in detail; and (iii) attempt to transfer specific canine genetic information to the mouse, (i) Missing genotypic information (gaps in genome markers) will be supplied using the canine genomic sequence as a source of new markers to identify QTLs in the approximately 30% of the genome that remains to be analyzed, (ii) In a collaborative effort with Dr. Elaine Ostrander, four unlinked QTLs will be examined in detail that regulate: a) limb bone length vs. limb width; b) skull length vs. limb width; c) overall size; and d) size differences between males and females (sexual dimorphism). This detailed analysis will utilize the emerging sequence of the canine genome, analyzing each QTL haplotype with a high density of markers (SSR and then SNP) to pinpoint the informative region of sequence. Linkage disequilibrium analysis within the PWD population as well as between PW dogs and other breeds will be a powerful tool, (iii) Emerging murine transgenic technology suggests that it will be possible for canine genes to be transferred to, and function in, the mouse. In a collaborative effort with Dr. Capecchi, we shall carry out such a transfer.
Dogs and humans have several hundred genetic diseases in common; share commonenvironments that may trigger these diseases and utilize similar aspects of serumchemistry and serum biomarkers as diagnostic tools. The availability of more than 200pure-bred dog breeds; each a genetic isolate with different morphological andphysiological characteristics as well as differences in life span and the incidence ofspecific genetic diseases facilitates the analysis of corresponding genetic diseasesfound in humans. This study will enhance our understanding of the genetic changes thatcause disease and shorten life span as well as improve the interpretation of diagnostictools used to characterize human genetic disease.
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