Dean H. Lang

Quantitative Trait Loci Analysis of Structural and Material Skeletal Phenotypes in C57BL/6J and DBA/2 Second-Generation and Recombinant Inbred Mice

QTL analyses identified several chromosomal regions influencing skeletal phenotypes of the femur and tibia in BXD F2 and BXD RI populations of mice. QTLs for skeletal traits co‐located with each other and with correlated traits such as body weight and length, adipose mass, and serum alkaline phosphatase.

Adjusting data to body size : A comparison of methods as applied to quantitative trait loci analysis of musculoskeletal phenotypes

The aim of this study was to compare three methods of adjusting skeletal data for body size and examine their use in QTL analyses. It was found that dividing skeletal phenotypes by body mass index induced erroneous QTL results. The preferred method of body size adjustment was multiple regression.

QTL analysis of trabecular bone in BXD F2 and RI mice.

A sample of 693 mice was used to identify regions of the mouse genome associated with trabecular bone architecture as measured using μCT. QTLs for bone in the proximal tibial metaphysis were identified on several chromosomes indicating regions containing genes that regulate properties of trabecular bone.

Strontium Administration in Young Chickens Improves Bone Volume and Architecture but Does not Enhance Bone Structural and Material Strength

Genetic selection for rapid body growth in broiler chickens has resulted in adverse effects on the skeletal system exemplified by a higher rate of cortical fractures in leg bones. Strontium (Sr) has been reported to have beneficial effects on bone formation and strength. We supplemented the diet of 300-day-old chicks with increasing dosages of Sr (0%, 0.12%, or 0.24%) to study the capacity of the element to improve bone quality and mechanical integrity. Treatment with Sr increased cortical bone volume and reduced bone porosity as measured by micro-computed tomography. The higher level of Sr significantly reduced bone Ca content (34.7%) relative to controls (37.2%), suggesting that Sr replaced some of the Ca in bone. Material properties determined by the three-point bending test showed that bone in the Sr-treated groups withstood greater deformation prior to fracture. Load to failure and ultimate stress were similar across groups. Our results indicate that Sr treatment in rapidly growing chickens induced positive effects on bone volume but did not improve the breaking strength of long bones.

Quantitative Trait Loci (QTL) analysis of longevity in C57BL/6J by DBA/2J (BXD) recombinant inbred mice

Background and aims: Genes associated with longevity have been identified using both single gene and genome-wide approaches in a variety of species. The aim of this study was to identify quantitative trait loci (QTLs) that influence longevity in male and female mice from twenty-three C57BL/6J by DBA/2J (BXD) recombinant inbred (RI) strains. Methods: Approximately 12 animals of each sex for each RI strain were maintained under standard conditions until natural death or moribundity criteria were met. Results: A number of life span-relevant loci previously reported on chromosomes (Chrs) 7,8, 10 and 11 were confirmed. In addition, 5 previously unre-ported QTLs for mouse life span on Chrs 1,2,6,11, and X were identified as significant and 3 QTLs on Chrs 5, 8, and 16 were suggestive. Conclusions: Several QTLs were coincident in males and females although the modest correlation between male and female median lifespans and the identification of sex specific QTLs provide evidence that the genetic architecture underlying longevity in the sexes may differ substantially. The identification of multiple QTLs for longevity will provide valuable resources for both reductionist and integrationist research into mechanisms of life span determination.

Bone, muscle, and physical activity: structural equation modeling of relationships and genetic influence with age

Correlations among bone strength, muscle mass, and physical activity suggest that these traits may be modulated by each other and/or by common genetic and/or environmental mechanisms. This study used structural equation modeling (SEM) to explore the extent to which select genetic loci manifest their pleiotropic effects through functional adaptations commonly referred to as Wolffs law. Quantitative trait locus (QTL) analysis was used to identify regions of chromosomes that simultaneously influenced skeletal mechanics, muscle mass, and/or activity‐related behaviors in young and aged B6×D2 second‐generation (F2) mice of both sexes. SEM was used to further study relationships among select QTLs, bone mechanics, muscle mass, and measures of activity. The SEM approach provided the means to numerically decouple the musculoskeletal effects of mechanical loading from the effects of other physiological processes involved in locomotion and physical activity. It was found that muscle mass was a better predictor of bone mechanics in young females, whereas mechanical loading was a better predictor of bone mechanics in older females. An activity‐induced loading factor positively predicted the mechanical behavior of hindlimb bones in older males; contrarily, load‐free locomotion (i.e., the remaining effects after removing the effects of loading) negatively predicted bone performance. QTLs on chromosomes 4, 7, and 9 seem to exert some of their influence on bone through actions consistent with Wolffs Law. Further exploration of these and other mechanisms through which genes function will aid in development of individualized interventions able to exploit the numerous complex pathways contributing to skeletal health.

Genes in context: probing the genetics of fracture resistance.

Fracture resistance is a complex trait dictated by bone volume, shape, internal architecture, and material performance of the calcified tissue itself, all of which may be influenced by a large number of different genetic and environmental processes. Quantitative Trait Loci analyses provide a sobering picture of this system and illustrate the importance of considering genes in context.

Genetic architecture for hole‐board behaviors across substantial time intervals in young, middle‐aged and old mice

A quantitative trait locus (QTL) analysis of behaviors across the life span was conducted in F2 mice from a C57BL/6J × DBA/2J cross and 22 BXD recombinant inbred (RI) strains. Mice of three age groups were tested in a hole‐board apparatus for 3 min on three occasions ∼1 month apart (average age at test 150, 450 and 750 days, ∼400 mice per group, divided equally by sex). Quantitative trait loci with small effect size were found on 11 chromosomes for hole‐board activity (Hbact) and hole‐board rearing (Hbrear). Analysis of 22 RI strains tested at 150 and 450 days of age found only suggestive linkage, with four QTL for Hbact overlapping with those from the F2 analysis. There was a significant phenotypic correlation between Hbact and Hbrear (∼0.55–0.69) and substantial commonality among QTL for the two behaviors. QTL analyses of head‐pokes (HP) and fecal boli (FB) only identified QTL at the suggestive level of significance. Age accounted for ∼15% of the phenotypic variance (sex ∼3%), and there were genotype by age interactions at ∼25% of the Hbact and Hbrear QTL. Quantitative trait loci for Hbrear were relatively stable across the three measurement occasions (those for Hbact somewhat less so), although mean levels of each index declined markedly comparing the first to subsequent trials. Considered as a whole, the polygenic system influencing exploratory behaviors accounts for approximately the same amount of phenotypic variance as age (within the range studied), is stable across substantial periods of time, and acts, for the most part, independently of age and sex.