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Mapping of Craniofacial Traits in Outbred Mice Identifies Major Developmental Genes Involved in Shape Determination.

Pallares LF, Carbonetto P, Gopalakrishnan S, Parker CC, Ackert-Bicknell CL, Palmer AA, Tautz D - PLoS Genet. (2015)

Bottom Line: Candidate genes within the associated loci have known roles in craniofacial development; this includes 6 transcription factors and several regulators of bone developmental pathways.One gene, Mn1, has an unusually large effect on shape variation in our study.Our study shows that it is possible to identify important developmental genes through genome-wide mapping of high-dimensional shape features in an outbred population.

View Article: PubMed Central - PubMed

Affiliation: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Biology, Plön, Germany.

ABSTRACT
The vertebrate cranium is a prime example of the high evolvability of complex traits. While evidence of genes and developmental pathways underlying craniofacial shape determination is accumulating, we are still far from understanding how such variation at the genetic level is translated into craniofacial shape variation. Here we used 3D geometric morphometrics to map genes involved in shape determination in a population of outbred mice (Carworth Farms White, or CFW). We defined shape traits via principal component analysis of 3D skull and mandible measurements. We mapped genetic loci associated with shape traits at ~80,000 candidate single nucleotide polymorphisms in ~700 male mice. We found that craniofacial shape and size are highly heritable, polygenic traits. Despite the polygenic nature of the traits, we identified 17 loci that explain variation in skull shape, and 8 loci associated with variation in mandible shape. Together, the associated variants account for 11.4% of skull and 4.4% of mandible shape variation, however, the total additive genetic variance associated with phenotypic variation was estimated in ~45%. Candidate genes within the associated loci have known roles in craniofacial development; this includes 6 transcription factors and several regulators of bone developmental pathways. One gene, Mn1, has an unusually large effect on shape variation in our study. A knockout of this gene was previously shown to affect negatively the development of membranous bones of the cranial skeleton, and evolutionary analysis shows that the gene has arisen at the base of the bony vertebrates (Eutelostomi), where the ossified head first appeared. Therefore, Mn1 emerges as a key gene for both skull formation and within-population shape variation. Our study shows that it is possible to identify important developmental genes through genome-wide mapping of high-dimensional shape features in an outbred population.

No MeSH data available.


Related in: MedlinePlus

Changes in mandible (a-c) and skull (d-g) shape associated with the SNPs of largest effect.SNP rs33702397 explains 2% of skull shape variation, and rs33614268 explains 1.4% of mandible shape variation. The sample mean shape is depicted in grey (dotted line). In orange (continuous line) is the mean shape associated to the SNP effect, scaled 10x. For mandible, (a) lateral, (b) frontal, and (c) dorsal views are shown. For skull, (d) dorsal, (e) frontal, (f) lateral, and (g) ventral views are shown. Dots and numbers represent relevant landmarks for each view.
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pgen.1005607.g004: Changes in mandible (a-c) and skull (d-g) shape associated with the SNPs of largest effect.SNP rs33702397 explains 2% of skull shape variation, and rs33614268 explains 1.4% of mandible shape variation. The sample mean shape is depicted in grey (dotted line). In orange (continuous line) is the mean shape associated to the SNP effect, scaled 10x. For mandible, (a) lateral, (b) frontal, and (c) dorsal views are shown. For skull, (d) dorsal, (e) frontal, (f) lateral, and (g) ventral views are shown. Dots and numbers represent relevant landmarks for each view.

Mentions: Out of the 22 PCs used to map skull shape, 12 PCs had at least one significant QTL; and out of the 20 PCs used in the mapping of mandible shape, 7 PCs had a significant QTL (see Fig 3 and Tables 1 and 2). 17 QTLs were identified for skull shape variation (Table 1), and eight QTLs for mandible shape variation (Table 2). One QTL was associated with mandible centroid size, and no QTLs were identified for skull centroid size. The shape traits associated with the “peak SNPs” (SNPs with lowest p-value) are depicted in Figs 4 and S4–S8.


Mapping of Craniofacial Traits in Outbred Mice Identifies Major Developmental Genes Involved in Shape Determination.

Pallares LF, Carbonetto P, Gopalakrishnan S, Parker CC, Ackert-Bicknell CL, Palmer AA, Tautz D - PLoS Genet. (2015)

Changes in mandible (a-c) and skull (d-g) shape associated with the SNPs of largest effect.SNP rs33702397 explains 2% of skull shape variation, and rs33614268 explains 1.4% of mandible shape variation. The sample mean shape is depicted in grey (dotted line). In orange (continuous line) is the mean shape associated to the SNP effect, scaled 10x. For mandible, (a) lateral, (b) frontal, and (c) dorsal views are shown. For skull, (d) dorsal, (e) frontal, (f) lateral, and (g) ventral views are shown. Dots and numbers represent relevant landmarks for each view.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4629907&req=5

pgen.1005607.g004: Changes in mandible (a-c) and skull (d-g) shape associated with the SNPs of largest effect.SNP rs33702397 explains 2% of skull shape variation, and rs33614268 explains 1.4% of mandible shape variation. The sample mean shape is depicted in grey (dotted line). In orange (continuous line) is the mean shape associated to the SNP effect, scaled 10x. For mandible, (a) lateral, (b) frontal, and (c) dorsal views are shown. For skull, (d) dorsal, (e) frontal, (f) lateral, and (g) ventral views are shown. Dots and numbers represent relevant landmarks for each view.
Mentions: Out of the 22 PCs used to map skull shape, 12 PCs had at least one significant QTL; and out of the 20 PCs used in the mapping of mandible shape, 7 PCs had a significant QTL (see Fig 3 and Tables 1 and 2). 17 QTLs were identified for skull shape variation (Table 1), and eight QTLs for mandible shape variation (Table 2). One QTL was associated with mandible centroid size, and no QTLs were identified for skull centroid size. The shape traits associated with the “peak SNPs” (SNPs with lowest p-value) are depicted in Figs 4 and S4–S8.

Bottom Line: Candidate genes within the associated loci have known roles in craniofacial development; this includes 6 transcription factors and several regulators of bone developmental pathways.One gene, Mn1, has an unusually large effect on shape variation in our study.Our study shows that it is possible to identify important developmental genes through genome-wide mapping of high-dimensional shape features in an outbred population.

View Article: PubMed Central - PubMed

Affiliation: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Biology, Plön, Germany.

ABSTRACT
The vertebrate cranium is a prime example of the high evolvability of complex traits. While evidence of genes and developmental pathways underlying craniofacial shape determination is accumulating, we are still far from understanding how such variation at the genetic level is translated into craniofacial shape variation. Here we used 3D geometric morphometrics to map genes involved in shape determination in a population of outbred mice (Carworth Farms White, or CFW). We defined shape traits via principal component analysis of 3D skull and mandible measurements. We mapped genetic loci associated with shape traits at ~80,000 candidate single nucleotide polymorphisms in ~700 male mice. We found that craniofacial shape and size are highly heritable, polygenic traits. Despite the polygenic nature of the traits, we identified 17 loci that explain variation in skull shape, and 8 loci associated with variation in mandible shape. Together, the associated variants account for 11.4% of skull and 4.4% of mandible shape variation, however, the total additive genetic variance associated with phenotypic variation was estimated in ~45%. Candidate genes within the associated loci have known roles in craniofacial development; this includes 6 transcription factors and several regulators of bone developmental pathways. One gene, Mn1, has an unusually large effect on shape variation in our study. A knockout of this gene was previously shown to affect negatively the development of membranous bones of the cranial skeleton, and evolutionary analysis shows that the gene has arisen at the base of the bony vertebrates (Eutelostomi), where the ossified head first appeared. Therefore, Mn1 emerges as a key gene for both skull formation and within-population shape variation. Our study shows that it is possible to identify important developmental genes through genome-wide mapping of high-dimensional shape features in an outbred population.

No MeSH data available.


Related in: MedlinePlus