International Mammalian Genome Society

F19 Fine Mapping of the Osteopetrotic Grey-Lethal Locus on Mouse Chromosome 10

Nader Chalhoub, Hugues Bernard and Jean Vacher. Clinical Research Institute of Montreal, 110 des Pins West Avenue, Montreal (Quebec), Canada

The grey-lethal (gl) mouse represents the best animal model to study recessive osteopetrosis, a genetic disorder characterized by either a failure of osteoclast formation or function resulting in the persistence of unresorbed osteocartilaginous matrix in marrow cavities. Osteoclasts are multinucleated cells from the mononuclear phagocyte lineage that have the unique property to resorb bone matrix and mineral during development, but also all along the life of vertebrates in order to maintain bone homeostasis. Homozygous gl animals die at approximately three weeks of age displaying growth retardation, poor development of the medullary cavity and no teeth eruption. In addition, pleiotropic effect of the mutation is evidenced by the development of a grey coat color in gl homozygous mice instead of agouti as in their heterozygous littermates. The gl locus was previously mapped to mouse chromosome 10, and to further refine the location of the gl locus, two novel backcross panels between the gl mutant strain GL/Le dl^J +/+ gl and either Mus spretus or Mus m. molossinus have been generated and allowed us to establish the genetic map of the region that includes the gl locus. On the genetic map, we were able to localize the gl locus within a 1 cM genetic interval and we have eliminated all the five genes previously mapped to this region (Braf-rs1, Fyn, Cd24a, Ros1 and Gja1) as candidate for the gl locus. The genetic map served as a starting point for the construction of the physical map for this poorly defined region of mouse chromosome 10. Markers localized within the 1cM interval were used to screen four different yeast artificial chromosome (YAC) libraries that allowed us to generate a 2 Mb contig including the gl locus. These genetic and physical data delineate the gl locus within a 700 kb physical interval. The establishment of a BAC contig is presently in progress and novel STS markers have been isolated and mapped in this interval.