Bone density is a highly heritable quantitative trait in humans, declines markedly with senescence, and is the major determinant of skeletal fragility in osteoporosis. The SAM/P-6 mouse displays an early-onset osteopenic phenotype featuring diminished peak bone mineral density, declining further after maturity, and markedly decreased numbers of osteoblast progenitors in bone marrow. This progressive osteopenia is also highly heritable, with about 60% of the variation in bone density in interstrain cross progeny attributable to genetic factors. It is proposed to identify genetic loci contributing to osteopenia and associated parameters, by standard gene-mapping procedures developed for quantitative trait loci, coupled to an improved technique for assessing bone mineral density in vivo. Crosses will be constructed between SAM/P-6 and a control line with normal-bone-density, SAM/R-1. The polygenic basis of osteopenia in P-6 mice, and the extent of its heritability, will be assessed for several indices of normal osteogenesis. Microsatellite- repeat markers which distinguish between the P-6 and R-1 genomes will be used to localize genes contributing to osteopenia, by maximum-likelihood analysis of genotype and bone-density data for the genetically variable F(2) progeny of a P-6 times R-1 cross. If several quantitative trait loci are identified which correlate with bone density, they will be tested for interactions in generating osteopenia. Endogenous retroviral integration sites will be probed to determine whether any co-localize with osteopenia loci, implying insertional mutation of the implicated genes and enabling their rapid isolation. To test the roles of individual osteopenia loci, and to allow their high-resolution mapping, congenic lines will be constructed which contain such loci in the genetic background of the contrasting-phenotype parent. Limited back-crossing strategies, and congenic strains based on tracking osteopenia-associated phenotypes and genotypes at the implicated loci, will also be employed to facilitate detailed mapping. The regions thus identified will be analyzed for previously-implicated """"""""candidate genes"""""""" and for sequence identity to transcripts in a cDNA library prepared from bone marrow cells. Aided by high-density genetic maps being constructed for human and mouse genomes, which are largely congruent, localization of osteopenia genes in SAMP/P-6 mice should expedite the search for human genes underlying osteoporosis.
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