Experiment
Linkage analysis was performed on 329 female (C57BL/6J x C3H/HeJ)F2 animals to identify QTLs associated with bone adaptive response to mechanical loading. Parental strain C57BL/6J is a good responder whereas C3H/HeJ is a poor responder. One hundred eleven microsatellite markers at an average spacing of 15 cM were used for the genome scan. Animals were subjected to mechanical loading using a four-point bending model at 10 weeks of age.
Significant linkage to mechanical loading-induced total volumetric bone mineral density (vBMD) mapped to 91.8 cM on mouse Chromosome 1 near D1Mit113 (LOD=3.4). This locus also shows suggestive linkage to cortical vBMD (LOD=2.3) and is named Brml1 (bone response to mechanical loading 1). Homozygosity for C57BL/6J-derived alleles at Brml1 confer a 5.6% increase in BMD compared to homozygosity for C3H/HeJ-derived alleles. Brml1 exhibits dominant inheritance.
Significant linkage to mechanical loading-induced total vBMD (LOD=4.2) and cortical thickness (LOD=3.6) mapped to 60.1 cM cM on mouse Chromosome 8 near D8Mit88. This locus is named Brml2 (bone response to mechanical loading 2). Homozygosity for C3H/HeJ-derived alleles at Brml2 confer a 5.8% increase in BMD compared to homozygosity for C57BL/6J-derived alleles. Brml2 exhibits recessive inheritance. Linkage to mechanical loading-induced periosteal circumference, Brml3, mapped more distally at 68.9 cM near D8Mit49 (LOD=3). Homozygosity for C57BL/6J-derived alleles at Brml3 confers a 10% increase in periosteal circumferencecompared to homozygosity for C3H/HeJ-derived alleles. Brml3 exhibits dominant inheritance.
Significant linkage to mechanical loading-induced cortical vBMD mapped to 50.3 cM on mouse Chromosome 3 near D3Mit320 (LOD=3.6). This locus is named Brml4 (bone response to mechanical loading 4).
Brml5 (bone response to mechanical loading 5) mapped to 13.1 cM on mouse Chromosome 9 near D9Mit2 (LOD=3). Suggestive linkage to mechanical loading-induced total vBMD, cortical vBMD, and periosteal circumference were alsoidentified at 33.9 cM (LOD=2.5 near D9Mit336), 49.2 cM (LOD=2.5 near D9Mit355), and 24 cM (LOD=2.2 near D9Mit97), respectively.
Brml6 (bone response to mechanical loading 6) mapped to 39.3 cM on mouse Chromosome 17 near D17Mit93 (LOD=3) in linkage to cortical thickness, and Brml7 mapped to 0 cM on mouse Chromosome 18 near D18Mit64 (LOD=3) in linkage to periosteal circumference.
Novel QTLs associated with non-loaded bone mineral density mapped to 35 cM on mouse Chromosome 3 (LOD=3.2 at D3Mit137), 62 cMon mouse Chromosome 10 (LOD=3.8 at D10Mit233), and 44 cM on mouse Chromosome 17 (LOD=5.9 at D17Mit93). These loci are named Bmd24 (bone mineral density 24), Bmd25, and Bmd26, respectively
Novel QTLs associated with non-loaded periosteal circumference mapped to 72 cM on mouse Chromosome 3 (LOD=4 at D3Mit320), 52 cM on mouse Chromosome 11 (LOD=4.3 at D11Mit285), 49 cM on mouse Chromosome 15 (LOD=3.1 at D15Mit107), 23 cM on mouse Chromosome 16 (LOD=3.1 at D16Mit60), and 44 cM on mouse Chromosome 17 (LOD=5.1 at D17Mit93). These loci are named Pstc1 (periosteal circumference 1), Pstc2, Pstc3, Pstc4, and Pstc5, respectively. Pstc1, Pstc4, and Pstc5 also exhibit significant linkage to cortical thickness.
Previously identified bone mineral density QTLs that were detected in this study include Bmd5 (83 cM, Chr1), Bmd7 (66.7 cM, Chr4), and Bmd15 (24 cM, Chr16).
Analysis Tools