Search

Introduction: Knowledge of bone structure-function relationships in mice has been based on relatively small sample sets that limit generalizability. We sought to investigate structure-function relationships of long bones from a large population of genetically diverse mice. Therefore, we analyzed previously published data from the femur and radius of male and female mice from the F34 generation of the Large-by-Small advanced intercross line (LGXSM AI), which have over a two-fold continuous spread of bone and body sizes (Silva et al. 2019 JBMR). Methods: Morphological traits, mechanical properties, and estimated material properties were collected from the femur and radius from 1113 LGXSM AI adult mice (avg. age 25 wks). Males and females fed a low-fat or high-fat diet were evaluated to increase population variation. The data were analyzed using principal component analysis (PCA), Pearson's correlation, and multivariate linear regression. Results: Using PCA groupings and hierarchical clustering, we identified a reduced set of traits that span the population variation and are relatively independent of each other. These include three morphometry parameters (cortical area, medullary area, and length), two mechanical properties (ultimate force and post-yield displacement), and one material property (ultimate stress). When comparing traits of the femur to the radius, morphological traits are moderately well correlated (r2: 0.18–0.44) and independent of sex and diet. However, mechanical and material properties are weakly correlated or uncorrelated between the long bones. Ultimate force can be predicted from morphology with moderate accuracy for both long bones independent of variations due to genetics, sex, or diet; however, predictions miss up to 50 % of the variation in the population. Estimated material properties in the femur are moderately to strongly correlated with bone size parameters, while these correlations are very weak in the radius. Discussion: Our results indicate that variation in cortical bone phenotype in the F34 LGXSM AI mouse population can be adequately described by a reduced set of bone traits. These traits include cortical area, medullary area, bone length, ultimate force, post-yield displacement, and ultimate stress. The weak correlation of mechanical and material properties between the femur and radius indicates that the results from routine three-point bending tests of one long bone (e.g., femur) may not be generalizable to another long bone (e.g., radius). Additionally, these properties could not be fully predicted from bone morphology alone, confirming the importance of mechanical testing. Finally, material properties of the femur estimated based on beam theory equations showed a strong dependence on geometry that was not seen in the radius, suggesting that differences in femur size within a study may confound interpretation of estimated material properties.

Variation in serum cholesterol, free-fatty acids, and triglycerides is associated with cardiovascular disease (CVD) risk factors. There is great interest in characterizing the underlying genetic architecture of these risk factors, because they vary greatly within and among human populations and between the sexes. We present results of a genome-wide scan for quantitative trait loci (QTL) affecting serum cholesterol, free-fatty acids, and triglycerides in an F16 advanced intercross line of LG/J and SM/J (Wustl:LG,SM-G16). Half of the population was fed a high-fat diet and half was fed a relatively low-fat diet. Context-dependent genetic (additive and dominance) and epigenetic (imprinting) effects were characterized by partitioning animals into sex, diet, and sex-by-diet cohorts. Here we examine genetic, environmental, and genetic-by-environmental interactions of QTL overlapping previously identified loci associated with CVD risk factors, and we add to the serum lipid QTL landscape by identifying new loci.

We previously mapped Adip1, an obesity quantitative trait locus (QTL), to the central portion of murine chromosome 1 containing the calpain-10 (Capn10) gene. Human studies have associated calpain-10 (CAPN10) variants with type 2 diabetes and various metabolic traits. We performed a quantitative hybrid complementation test (QHCT) to determine whether differences attributed to Adip1 are the result of variant Capn10 alleles in LG/J and SM/J mice. We crossed LG/J and SM/J to wild-type (C57BL/6J) and Capn10 knockout (Capn10−/−) mice to form four F1 hybrid groups: LG/J by wild-type, LG/J by Capn10−/−, SM/J by wild-type, and SM/J by Capn10−/−. We performed a two-way ANOVA with the experimental strain, tester strain, and their interaction as the factors. Significant interaction indicates a quantitative failure to complement. We found failure to complement for fat, organ, and body weights, and leptin, female free fatty acid, and triglyceride levels. Capn10−/− resulted in heavier weights and higher serum levels in LG/J crosses but not in SM/J crosses. For glucose tolerance and insulin response tests, the Capn10−/− allele resulted in lower glucose levels in crosses with SM/J but had no effect in the LG/J crosses. Differences between the LG/J and SM/J Capn10 alleles are the likely source of some of the QTL effects mapped to Adip1 in the LG/J–by–SM/J cross. Capn10 plays an important role in regulating obesity and diabetes in mice.

Maternal effects on offspring phenotypes occur because mothers in many species provide an environment for their developing young. Although these factors are correctly “environmental” with respect to the offspring genome, their variance may have both a genetic and an environmental basis in the maternal generation. Here, reciprocal crosses between C57BL/6J and 10 LGXSM recombinant inbred (RI) strains were performed, and litters were divided at weaning into high-fat and low-fat dietary treatments. Differences between reciprocal litters were used to measure genetic maternal effects on offspring phenotypes. Nearly all traits, including weekly body weights and adult blood serum traits, show effects indicative of genetic variation in maternal effects across RI strains, allowing the quantitative trait loci involved to be mapped. Although much of the literature on maternal effects relates to early life traits, we detect strong and significant maternal effects on traits measured at adulthood (as much as 10% of the trait variance at 17 or more weeks after weaning).We also found an interaction affecting adult phenotype between the effects of maternal care between RI strain mothers and C57BL/6J mothers and a later environmental factor (dietary fat intake) for some age-specific weights.