The Genetic Architecture and Developmental Bases for Long Bone Length Quantitative Trait Loci in Mice

The analysis of mutant growth phenotypes with Mendelian properties has been successful at identifying key genetic and environmental contributors to bone development, but the molecular basis of normal bone length variation remains unknown. A quantitative genetics approach can identify genomic elements (quantitative trait loci; QTL) with complex genetic properties that play smaller, modulatory roles in development. Individuals from the F2-3, F9-10, and F34 generations (n ~ 5000) of the LG,SM advanced intercross were SNP-genotyped and QTL for humerus, ulna, femur, and tibia lengths were mapped using standard quantitative genetics techniques, resulting in the identification of ~40 pleiotropic QTL with complex genetic architectural elements, including epistasis as well as diet- and sex-specific QTL. Developmental differences between LG/J and SM/J parental strains were characterized by examining bone lengths and stained sections of the proximal tibia from just prior to birth through 6 weeks of age, revealing that bone length variation between LG/J and SM/J occurs postnatally and results from changes in the rate at which elongation slows as the mice age. Finally, QTL positional candidate genes were evaluated by assessing mRNA expression levels in the growth plate and analyzing coding region sequence differences between LG/J and SM/J. The presence of relatively few nonsynonymous changes in protein sequence and increased expression of some candidate genes suggests that more variation in bone length may be explained by mutations in genetic regulatory elements than mutations in coding regions. Future work will focus on understanding how individual mutations interact with other genomic elements and the environment to produce variation in adult bone lengths

P-Cable high-resolution seismic

Quantitative trait locus (QTL) studies of a skeletal trait or a few related skeletal components are becoming commonplace, but as yet there has been no investigation of pleiotropic patterns throughout the skeleton. We present a comprehensive survey of pleiotropic patterns affecting mouse skeletal morphology in an intercross of LG/J and SM/J inbred strains (N = 1040), using QTL analysis on 70 skeletal traits. We identify 798 single-trait QTL, coalescing to 105 loci that affect on average 7–8 traits each. The number of traits affected per locus ranges from only 1 trait to 30 traits. Individual traits average 11 QTL each, ranging from 4 to 20. Skeletal traits are affected by many, small-effect loci. Significant additive genotypic values average 0.23 standard deviation (SD) units. Fifty percent of loci show codominance with heterozygotes having intermediate phenotypic values. When dominance does occur, the LG/J allele tends to be dominant to the SM/J allele (30% vs. 8%). Over- and underdominance are relatively rare (12%). Approximately one-fifth of QTL are sex specific, including many for pelvic traits. Evaluating the pleiotropic relationships of skeletal traits is important in understanding the role of genetic variation in the growth and development of the skeleton

Calpain-10 is a component of the obesity-related quantitative trait locus Adip1

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