Dataset Information

Genetic factors and diet affect long-bone length in the F34 LG,SM advanced intercross.

ABSTRACT: Previous studies on the LG,SM advanced intercross line have identified approximately 40 quantitative trait loci (QTL) for long -bone (humerus, ulna, femur, and tibia) lengths. In this study, long-bone-length QTL were fine-mapped in the F(34) generation (n = 1424) of the LG,SM advanced intercross. Environmental effects were assessed by dividing the population by sex between high-fat and low-fat diets, producing eight sex/diet cohorts. We identified 145 individual bone-length QTL comprising 45 pleiotropic QTL; 69 replicated QTL from previous studies, 35 were new traits significant at previously identified loci, and 41 were novel QTL. Many QTL affected only a subset of the population based on sex and/or diet. Eight of ten known skeletal growth genes were upregulated in 3-week-old LG/J male proximal tibial growth plates relative to SM/J. The sequences of parental strains LG/J and SM/J indicated the presence of over half a million polymorphisms in the confidence intervals of these 45 QTL. We examined 526 polymorphisms and found that 97 represented radical changes to amino acid composition while 40 were predicted to be deleterious to protein function. Additional experimentation is required to understand how changes in gene regulation or protein function can alter the genetic architecture and interact with the environment to produce phenotypic variation.

SUBMITTER: Norgard EA

PROVIDER: S-EPMC3648211 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Genetic factors and diet affect long-bone length in the F34 LG,SM advanced intercross.

Norgard Elizabeth A EA Lawson Heather A HA Pletscher L Susan LS Wang Bing B Brooks Victoria R VR Wolf Jason B JB Cheverud James M JM

Mammalian genome : official journal of the International Mammalian Genome Society 20101219 3-4

Previous studies on the LG,SM advanced intercross line have identified approximately 40 quantitative trait loci (QTL) for long -bone (humerus, ulna, femur, and tibia) lengths. In this study, long-bone-length QTL were fine-mapped in the F(34) generation (n = 1424) of the LG,SM advanced intercross. Environmental effects were assessed by dividing the population by sex between high-fat and low-fat diets, producing eight sex/diet cohorts. We identified 145 individual bone-length QTL comprising 45 ple ...[more]

PMID: 21170743

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Project description:Ectopic calcification in synovial tissues is devastating to diarthrodial joints. While some forms of synovial ectopic calcification have genetically simple basis, most cases manifest as complex traits with environmental and multigenic components. The location of causal loci or the physiological processes affected by allelic variants is poorly understood. Here, we report on genetic susceptibility to ectopic calcification in the LG/J and SM/J advanced intercross mice. Using 347 mice in 98 full-sibships, destabilization of medial meniscus was performed to induce joint injury. We performed quantitative trait locus (QTL) analysis to map calcification phenotypes to discrete genomic locations. To validate the functional significance of the selected QTL candidate genes, we compared mRNA expression between parental LG/J and SM/J inbred strains. Our findings showed that joint destabilization instigated ectopic calcifications as detected and quantified by micro-CT. Overall, we detected 20 QTLs affecting synovial and meniscus calcification phenotypes with 11 QTLs linked to synovial calcification. Functional and bioinformatic analyses of single nucleotide polymorphism identified functional classifications relevant to angiogenesis (Myo1e, Kif26b, Nprl3, Stab2, Fam105b), bone metabolism/calcification (Tle3, Tgfb2, Lipc, Nfe2l1, Ank, Fam105b), arthritis (Stab2, Tbx21, Map4k4, Hoxb9, Larp6, Col1a2, Adam10, Timp3, Nfe2l1, Trpm3), and ankylosing-spondylitis (Ank, Pon1, Il1r2, Tbkbp1) indicating that ectopic calcification involves multiple mechanisms. Furthermore, the expression of 11 candidate genes was significantly different between LG/J and SM/J. Correlation analysis showed that Aff3, Fam81a, Syn3, and Ank were correlated with synovial calcification. Our findings of multiple genetic loci affecting the phenotype suggest the involvement of multiple genes contributing to its pathogenesis. We collected tissue lysates from the formalin-fixed paraffin-embedded sections from mouse knee joints and analyzed the expression of several genes by Affymetrix QuantiGene Plex assay.

Dataset Information

Genetic factors and diet affect long-bone length in the F34 LG,SM advanced intercross.

Publications

Genetic factors and diet affect long-bone length in the F34 LG,SM advanced intercross.

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