Limits...
Quantitative trait loci affecting the 3D skull shape and size in mouse and prioritization of candidate genes in-silico.

Maga AM, Navarro N, Cunningham ML, Cox TC - Front Physiol (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

No MeSH data available.


Visualizations of the main effects of skull size, gender and directionality of the cross on skull shape. The model is the shape resulting from the addition of the effect to the mean shape. Color map of 3D model corresponds to the deformation distance between this shape and the mean shape. Warm colors indicate shrinkage, cold colors indicate expansion with respect to the mean shape. Heatmaps are NOT to the same scale, as each effect scaled different. Dynamic visualizations of these effects can be found in the Supplemental Animations 1–3. (A) Skull centroid size: Increases in skull size expands the anterior brain case both vertically and laterally. (B) Sex: Sexual dimorphism is low and appears to map mainly on the basicranium. (C) Direction-of-cross: This effect shows offspring born to F1 hybrid mothers as having a higher neurocranium than those produced from pure A/J dams.
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Figure 4: Visualizations of the main effects of skull size, gender and directionality of the cross on skull shape. The model is the shape resulting from the addition of the effect to the mean shape. Color map of 3D model corresponds to the deformation distance between this shape and the mean shape. Warm colors indicate shrinkage, cold colors indicate expansion with respect to the mean shape. Heatmaps are NOT to the same scale, as each effect scaled different. Dynamic visualizations of these effects can be found in the Supplemental Animations 1–3. (A) Skull centroid size: Increases in skull size expands the anterior brain case both vertically and laterally. (B) Sex: Sexual dimorphism is low and appears to map mainly on the basicranium. (C) Direction-of-cross: This effect shows offspring born to F1 hybrid mothers as having a higher neurocranium than those produced from pure A/J dams.

Mentions: Principal component analysis of the symmetric component of the full tangent coordinates resulted in 80 PCs with non-zero eigenvalues. The amount of variation explained by each PC is shown on Figure 3. No single PC explained more than 12% of the phenotypic variation. The main effects of skull size, gender and directionality of the cross on skull shape were found to be significant (p < 0.0001) and explained about 1–4% of the total Procrustes variance. No significant interactions among them were found, therefore only the main effects were included in following genetic analyses as additive covariates. Increases in skull size expand the anterior brain case both vertically and laterally (Figure 4A). Sexual dimorphism is low and appears to map mainly on the basicranium (Figure 4B). The direction-of-cross effect shows offspring from F1 dams as having a higher neurocranium than those produced from A/J dams (Figure 4C). Dynamic visualizations of effects of these covariates on skull shape are provided with online Supplemental Data. To reduce the computation time, we opted to use 80 non-zero PCs in our QTL mapping instead of using 159 tangent coordinates. Since the PCA is simply a rotation along orthogonal axes, no variation is lost and PC scores can be back converted to tangent coordinates without loss of variation.


Quantitative trait loci affecting the 3D skull shape and size in mouse and prioritization of candidate genes in-silico.

Maga AM, Navarro N, Cunningham ML, Cox TC - Front Physiol (2015)

Visualizations of the main effects of skull size, gender and directionality of the cross on skull shape. The model is the shape resulting from the addition of the effect to the mean shape. Color map of 3D model corresponds to the deformation distance between this shape and the mean shape. Warm colors indicate shrinkage, cold colors indicate expansion with respect to the mean shape. Heatmaps are NOT to the same scale, as each effect scaled different. Dynamic visualizations of these effects can be found in the Supplemental Animations 1–3. (A) Skull centroid size: Increases in skull size expands the anterior brain case both vertically and laterally. (B) Sex: Sexual dimorphism is low and appears to map mainly on the basicranium. (C) Direction-of-cross: This effect shows offspring born to F1 hybrid mothers as having a higher neurocranium than those produced from pure A/J dams.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4374467&req=5

Figure 4: Visualizations of the main effects of skull size, gender and directionality of the cross on skull shape. The model is the shape resulting from the addition of the effect to the mean shape. Color map of 3D model corresponds to the deformation distance between this shape and the mean shape. Warm colors indicate shrinkage, cold colors indicate expansion with respect to the mean shape. Heatmaps are NOT to the same scale, as each effect scaled different. Dynamic visualizations of these effects can be found in the Supplemental Animations 1–3. (A) Skull centroid size: Increases in skull size expands the anterior brain case both vertically and laterally. (B) Sex: Sexual dimorphism is low and appears to map mainly on the basicranium. (C) Direction-of-cross: This effect shows offspring born to F1 hybrid mothers as having a higher neurocranium than those produced from pure A/J dams.
Mentions: Principal component analysis of the symmetric component of the full tangent coordinates resulted in 80 PCs with non-zero eigenvalues. The amount of variation explained by each PC is shown on Figure 3. No single PC explained more than 12% of the phenotypic variation. The main effects of skull size, gender and directionality of the cross on skull shape were found to be significant (p < 0.0001) and explained about 1–4% of the total Procrustes variance. No significant interactions among them were found, therefore only the main effects were included in following genetic analyses as additive covariates. Increases in skull size expand the anterior brain case both vertically and laterally (Figure 4A). Sexual dimorphism is low and appears to map mainly on the basicranium (Figure 4B). The direction-of-cross effect shows offspring from F1 dams as having a higher neurocranium than those produced from A/J dams (Figure 4C). Dynamic visualizations of effects of these covariates on skull shape are provided with online Supplemental Data. To reduce the computation time, we opted to use 80 non-zero PCs in our QTL mapping instead of using 159 tangent coordinates. Since the PCA is simply a rotation along orthogonal axes, no variation is lost and PC scores can be back converted to tangent coordinates without loss of variation.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

No MeSH data available.