Identification of Genes Regulating Bone Matrix Composition and Quality
The overarching goal of this application is to find the genes that control bone tissue mechanical integrity, with a focus on the genetic regulation of bone composition and quality. The secondary goal of this application is to determine the contribution of genetic factors to the maintenance of bone quality with aging. It is well understood that the incidence of fragility fracture increases with age, and that the quality of bone tissue decreases with age, but the involvement of genetics in either slowing or speeding this decline is largely undefined. In Aim 1 of this application, we will use the Heterogeneous Stock Rat (HS Rat) to identify genes and genetic loci that regulate bone matrix composition and mechanical integrity (collectively defining bone quality), as well as their integration with bone size and shape to account for the overall strength of a bone. Previous studies have demonstrated that bone size and shape vary in the HS progenitor population, and that long bone strength is genetically regulated in the HS Rat population. In combination with the aforementioned genetic structure of the HS Rat, these preliminary data indicate that this population is ideal for genetic mapping of bone composition and quality. In Aim 2, we will use inbred rat strains to ascertain how bone matrix composition and mechanical integrity change with age, and how genetic background contributes to these changes. These studies will yield novel genetic loci and genes that contribute to the genetic regulation of bone strength, and will help to elucidate the genetic role of age-related decline in bone quality.
Methods for genotype
Low-coverage WGS based on Riptide library preparation (pulication in progress)
Methods for Phenotypes
Methods for Omics