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

Abstract

ABSTRACT:Introduction: 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. Materials and Methods: We use interval mapping and quantitative trait locus (QTL) mapping techniques in the combined F 2 -F 3 populations (n ‫ס‬ 2111) of an LG/J × SM/J mouse intercross to detect QTLs associated with the lengths of the humerus, ulna, femur, and tibia. Results: 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 sexspecific 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. Conclusions: 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.

Directionality of Epistasis in a Murine Intercross Population

“…The epistatic effects considered here are thus different from the classical epistasis components reported in the original studies Norgard et al 2008). All models were fitted using the NOIA framework (AlvarezCastro et al 2008), as operationalized in the R package noia (Le Rouzic 2008, Le Rouzic and.…”

“…Nonetheless, previous mapping studies have shown that the alleles from the LG/J line generally cause increased size relative to SM/J alleles in the intercross of these two lines (Cheverud et al , 2001(Cheverud et al , 2004. For details on the population, husbandry, experimental design, and mapping see , Vaughn et al (1999), Fawcett et al (2008), and Norgard et al (2008).…”

“…Given the large number of loci across the genome, and to make the study of directionality feasible, we preselected the loci to be included in the current study from the results of previous mapping studies of epistatic QTLs in the same population Norgard et al 2008). The population (N ¼ 2060) was genotyped at 351 approximately evenly distributed single-nucleotide polymorphisms (SNPs), located on 19 chromosomes (excluding the sex chromosome).…”

“…The criterion for QTL detection was based on significance thresholds controlling for multiple comparisons and the family structure (for detailed description of threshold-generating technique see Pavlicev et al 2008) to avoid false positives (type I error). Here we used a subset of loci reported in Fawcett et al (2008) and Norgard et al (2008) as having significant marginal and/or epistatic effects for each trait (see supporting information, Table S1, for data and for the list of QTL; see File S1 and File S2 for genotypic and phenotypic data). We calculated the interaction directionality separately for each trait.…”

Pleiotropic Patterns of Quantitative Trait Loci for 70 Murine Skeletal Traits

“…We expect that there are sizable epistatic effects as well, given that in studies of a more limited number of skeletal traits (femur, tibia, humerus, and ulna lengths), Cheverud and colleagues found extensive epistasis Norgard et al 2008). While multiple individual-trait QTL may underlie the pleiotropic loci due to the level of resolution of an F 2 intercross study (Kenney-Hunt et al 2006;Christians and Senger 2007), pleiotropy was found to be widespread with most traits affected by multiple loci of small individual effect.…”