Confirmation and fine mapping of chromosomal regions influencing peak bonemass in mice

Bone mineral density (BMD) is determined by both environmental influences a nd polygenic inheritance. The extreme difficulty of dissecting out environm ental factors from genetic ones in humans has motivated the investigation o f animal models. Previously, we used quantitative trait locus (QTL) analysi s to examine peak BMD in 24 recombinant inbred (RI) mouse strains, derived from a cross between C57BL/6 (B6) and DBA/2 (D2) progenitors (RI-BXD). The distribution of BMD values among these strains indicated strong genetic inf luences and a number of chromosomal sites linked to BMD were identified pro visionally. Using three additional independent mapping populations derived from the same progenitors, we have confirmed loci on chromosomes 1, 2, and 4, and 11 that contain genes that influence peak BMD. Using a novel fine-ma pping approach (RI segregation testing [RIST]), we have substantially narro wed two of the BMD-related chromosomal regions and in the process eliminate d a number of candidate genes. The homologous regions in the human genome f or each of these murine QTLs have been identified in recent human genetic s tudies. In light of this, we believe that findings in mice should aid in th e identification of specific candidate genes for study in humans.