Identification of Quantitative Trait Loci Affecting Murine Long Bone Length in a Two-Generation Intercross of LG/J and SM/J Mice

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Abstract
Study of mutations with large phenotypic effects has allowed the identification of key players in skeletal development. However, the molecular nature of variation in large, phenotypically normal populations tends to be characterized by smaller phenotypic effects that remain undefined. We use interval mapping and quantitative trait locus (QTL) mapping techniques in the combined F2-F3 populations (n = 2111) of an LG/J x SM/J mouse intercross to detect QTLs associated with the lengths of the humerus, ulna, femur, and tibia. Seventy individual trait QTLs affecting long bone lengths were detected, with several chromosomes harboring multiple QTLs. The genetic architecture suggests mainly small, additive effects on long bone length, with roughly one third of the QTLs displaying dominance. Sex interactions were common, and four sex-specific QTLs were observed. Pleiotropy could not be rejected for most of the QTLs identified. Thirty-one epistatic interactions were detected, almost all affecting regions including or immediately adjacent to QTLs. A complex regulatory network with many gene interactions modulates bone growth, possibly with integrated skeletal modules that allow fine-tuning of developmental processes present. Candidate genes in the QTL CIs include many genes known to affect endochondral bone growth and genes that have not yet been associated with bone growth or body size but have a strong potential to influence these traits.