Abstract
A pleiotropic quantitative trait locus (QTL) for bone geometry and mechanical performance in mice was mapped to distal chromosome 4 via an intercross of recombinant congenic mice HcB-8 and HcB-23. To study the QTL in isolation, we have generated C3H.B10-(rs6355453-rs13478087) (C.B.4.3) and C3H.B10-(rs6369860-D4Mit170) (C.B.4.2) congenic strains that harbor ~20 Mb and ~3 Mb, respectively, of chromosome 4 overlapping segments from C57BL/10ScSnA (B10) within the locus on a C3H/DiSnA (C3H) background. Using 3-point bend testing and standard beam equations, we phenotyped these mice for femoral mid-diaphyseal geometry and biomechanical performance. We analyzed the results via 2-way ANOVA, using sex and genotype as factors. In the C.B.4.3 strain, we found that homozygous B10/B10 male mice had smaller cross sectional area (CSA) and reduced total displacement than homozygous C3H/C3H mice. Sex by genotype interaction was also observed for maximum load and stiffness for C3H/C3H and B10/B10 mice, respectively. In C.B.4.2 strain, we found that homozygous B10/B10 mice had lower total displacement, post-yield displacement (PYD), stiffness, yield load and maximum load than mice harboring C3H allele. Sex by genotype interaction was observed in B10/B10 mice for perimeter, outer minor axis (OMA) and CSA. There were no significant differences in tissue level mechanical performance, which suggest that the QTL acts primarily on circumferential bone size. These data confirm the prior QTL mapping data and support other work demonstrating the importance of chromosome 4 QTL on bone modeling and bone responses to mechanical loading.
Highlights
Bone biomechanical performance encompasses a suite of functionally related complex traits [1,2,3,4]
We studied a total of 52 chromosome 4 long congenic segment (C3H x C.B.4.3) F2 mice including 9 C3H/C3H males, 8 C3H/C3H females, 8 C3H/backcrossing male C57BL/10ScSnA (B10) males, 9 C3H/B10 females, 10 B10/B10 males and 8 B10/B10 females
There was no significant difference in Bone Mineral Density (BMD) between the genotypes
Summary
Bone biomechanical performance encompasses a suite of functionally related complex traits [1,2,3,4]. Many quantitative trait loci (QTL) for bone phenotypes have been mapped in mice and humans [7,8,9]. The HcB recombinant congenic strains were constructed by backcrossing male C57BL/10ScSnA (B10) to female C3H/DiSnA (C3H) mice for 3 generations and inbreeding random offspring pairs to fixation. Twenty seven such strains were generated, each containing on average ~12.5% of alleles from B10, and the remaining alleles from C3H [15, 16]. We sought to identify the genomic regions mediating those differences by performing an intercross to map quantitative trait loci (QTLs) for bone biomechanical performance in these strains. We found a pleiotropic chromosome 4 QTL affecting bone shape, size and strength [10, 19,20,21]
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