A Chromosomal Inversion within a Quantitative Trait Locus Has a Major Effect on Adipogenesis and Osteoblastogenesis
- 1 November 2007
- journal article
- Published by Wiley in Annals of the New York Academy of Sciences
- Vol. 1116 (1), 291-305
- https://doi.org/10.1196/annals.1402.010
Abstract
We mapped a quantitative trait locus (QTL) for BMD to mid-distal chromosome (Chr) 6 in a cross between C57BL/6J (B6) and C3H/HeJ (C3H). The B6.C3H-6T (6T) congenic was developed to map candidate genes in this QTL. Recently, a 25 cM paracentric inversion was discovered on Chr 6 in C3H/HeJ; we found 6T also carries this inversion. Microarrays from the liver of B6 and 6T uncovered two narrow bands of decreased gene expression in close proximity to the predicted locations of the inversion breakpoints. Changes in specific gene expression in 6T were consistent with its phenotype of low trabecular bone volume and marrow adipogenesis. The BXH recombinant inbred (RI) strains do not carry the C3H/HeJ inversion. To test if the inversion, or allelic effects, were responsible for the 6T phenotype, we made a new congenic, B.H-6, developed by introgressing a 30 Mb region of C3H genomic sequence from BXH6 onto a B6 background. While genetically identical to 6T, this new congenic had a distinct metabolic and skeletal phenotype, with more body fat and greater trabecular BV/TV compared to B6 or 6T. We conclude that the phenotype of 6Tcannot be explained by simple allelic differences in one or more genes from C3H. Rather, 6T demonstrates that disordered regulation of gene expression by genomic rearrangement can have a profound effect on a complex trait, such as BMD, and that genomic rearrangement can supersede the effects of various alleles.Keywords
This publication has 18 references indexed in Scilit:
- Genetic regulation of bone mass and susceptibility to osteoporosisGenes & Development, 2006
- Chromosomal inversion discovered in C3H/HeJ miceGenomics, 2006
- Long-Range Control of Gene Expression: Emerging Mechanisms and Disruption in DiseaseAmerican Journal of Human Genetics, 2005
- Congenic mice with low serum IGF-I have increased body fat, reduced bone mineral density, and an altered osteoblast differentiation programBone, 2004
- The evolutionary dynamics of eukaryotic gene orderNature Reviews Genetics, 2004
- Meta-Analysis of Molecular Association Studies: Vitamin D Receptor Gene Polymorphisms and BMD as a Case StudyJournal of Bone and Mineral Research, 2004
- Generation of a New Congenic Mouse Strain to Test the Relationships Among Serum Insulin-like Growth Factor I, Bone Mineral Density, and Skeletal Morphology In VivoJournal of Bone and Mineral Research, 2002
- Quantitative Trait Loci for Femoral and Lumbar Vertebral Bone Mineral Density in C57BL/6J and C3H/HeJ Inbred Strains of MiceJournal of Bone and Mineral Research, 2001
- Mapping quantitative trait loci for serum insulin-like growth factor-1 levels in miceBone, 2000
- Genetic variability in adult bone density among inbred strains of miceBone, 1996