Genetic Dissection of a QTL Affecting Bone Geometry

Parameters of bone geometry such as width, length, and cross-sectional area are major determinants of bone strength. Though these traits are highly heritable, few genes influencing bone geometry have been identified. Here, we dissect a major quantitative trait locus (QTL) influencing femur size. This QTL was originally identified in an F2 cross between the C57BL/6J-hg/hg (HG) and CAST/EiJ strains and was referred to as femur length in high growth mice 2 (Feml2). Feml2 was located on Chromosome (Chr.) 9 at ~20 cM. Here, we show that the HG.CAST-(D9Mit249-D9Mit133)/Ucd congenic strain captures Feml2. In an F2 congenic cross, we fine-mapped the location of Feml2 to an ~6 Mbp region extending from 57.3 to 63.3 Mbp on Chr. 9. We have identified candidates by mining the complete genome sequence of CAST/EiJ and through allele specific expression analysis of growth plates in C57BL/6J x CAST/EiJ F1 hybrids. Interestingly, we also find that the refined location of Feml2 overlaps a cluster of six independent genome-wide associations for human height. This work provides the foundation to identify novel genes affecting bone geometry.

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