The population structure of the world's 400 dog breeds is a powerful tool for dissecting the genetics of complex traits like skeletal size. The dog acquired skeletal size diversity early in its history and on a very short evolutionary timescale of a few thousand years. But the nature of the functional genomic sequences that made this possible is not known. This lack of knowledge is an important problem for the field because without it we cannot fully exploit the dog's genomic and population structure to maximize power in mapping genes for disease and morphology. Heritable diseases of both man and dog are caused by retrotransposon insertions that disrupt genes. While retrotransposons segregate for insertion and non-insertion at many loci in the dog genome, this is rare in the human genome. Our long-term goal is to understand the mechanisms for rapid trait diversification during dog evolution. The objective here is to identify the pattern of short interspersed element (SINE) retrotransposon insertions in the dog genome and identify SINEs contributing to size variation. Our central hypothesis is that an explosion of SINE retrotranspositions during domestication provided functional sequence variation that enabled rapid diversification of traits under selection, such as body size. The rationale for the proposed research is that the dog's long history of intense selection under domestication, population structure and naturally occurring genetic diseases make the species a vital resource for understanding complex traits in man. Therefore, an improved understanding of retrotransposition within the dog genome will increase the dog's value as a model for human health, growth and development. With supportive preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Identify the genome-wide pattern of SINE retrotranspositions in the dog;and 2) Identify SINE insertions contributing to body size differences. A method for massively parallel sequencing genomic DNA that flanks SINEs has been developed and established as feasible in the applicant's hands. SINEs discovered in small and giant purebred dogs will be tested for association with size and genotyped in a large panel of purebred dogs to identify loci contributing to size variation. SINEs that disrupt gene expression and splicing will also be identified and a SINE-based breed phylogeny will be built. The approach is innovative because it utilizes a novel cloning method to characterize an underappreciated functional sequence variant in a non-traditional but increasingly valuable mammal model. This contribution is significant because it is the first step along a research trajectory expected to further unlock the intrinsic value of the domestic dog's evolution, population structure, size variation and genetic disease burden in an effort to better understand complex traits in man.
The proposed research is relevant to public health because a genetic understanding of growth and body size in the dog will serve as a model for the genetics of complex traits in man. Furthermore, the discovery and characterization of thousands of retrotransposons in the dog genome will ultimately lead to an improved understanding of how they cause heritable diseases in man.