title: Quantitative trait loci affecting the 3D skull shape and size in mouse and prioritization of candidate genes in-silico.
abstract: We describe the first application of high-resolution 3D micro-computed tomography, together with 3D landmarks and geometric morphometrics, to map QTL responsible for variation in skull shape and size using a backcross between C57BL/6J and A/J inbred strains. Using 433 animals, 53 3D landmarks, and 882 SNPs from autosomes, we identified seven QTL responsible for the skull size (SCS.qtl) and 30 QTL responsible for the skull shape (SSH.qtl). Size, sex, and direction-of-cross were all significant factors and included in the analysis as covariates. All autosomes harbored at least one SSH.qtl, sometimes up to three. Effect sizes of SSH.qtl appeared to be small, rarely exceeding 1% of the overall shape variation. However, they account for significant amount of variation in some specific directions of the shape space. Many QTL have stronger effect on the neurocranium than expected from a random vector that will parcellate uniformly across the four cranial regions. On the contrary, most of QTL have an effect on the palate weaker than expected. Combined interval length of 30 SSH.qtl was about 315 MB and contained 2476 known protein coding genes. We used a bioinformatics approach to filter these candidate genes and identified 16 high-priority candidates that are likely to play a role in the craniofacial development and disorders. Thus, coupling the QTL mapping approach in model organisms with candidate gene enrichment approaches appears to be a feasible way to identify high-priority candidates genes related to the structure or tissue of interest.
authors: Division of Craniofacial Medicine, Department of Pediatrics, University of Washington Seattle, WA, USA ; Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute Seattle, WA, USA.
authors: A Murat
authors: AM
authors: Maga
authors: Laboratoire PALEVO, Ecole Pratique des Hautes Etudes Dijon, France ; UMR uB/CNRS 6282 - Biogéosciences, Université de Bourgogne Dijon, France.
authors: Nicolas
authors: N
authors: Navarro
authors: Division of Craniofacial Medicine, Department of Pediatrics, University of Washington Seattle, WA, USA ; Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute Seattle, WA, USA.
authors: Michael L
authors: ML
authors: Cunningham
authors: Division of Craniofacial Medicine, Department of Pediatrics, University of Washington Seattle, WA, USA ; Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute Seattle, WA, USA ; Department of Anatomy and Developmental Biology, Monash University Clayton, VIC, Australia.
authors: Timothy C
authors: TC
authors: Cox
keywords: 3D imaging; candidate gene enrichment; geometric morphometrics; multivariate QTL mapping; skull shape