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

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.

Craniofacial shape transition across the house mouse hybrid zone: implications for the genetic architecture and evolution of between-species differences

“…In this study, using a phenotype-focused approach, we find patterns that support a highly polygenic basis for between-subspecies differences. Different experimental approaches (GWAS, congenic lines, consomic panels) using different type of mice (inbred, outbred, wild) have found a positive correlation between the length of genomic fragments and the magnitude of their effect on craniofacial shape (Burgio et al 2009(Burgio et al , 2012Pallares et al 2014Pallares et al , 2015. Here we also find a strong positive correlation between genomic distance and phenotypic distance.…”

“…Using a GWAS approach, we have previously shown that the genetic architecture of within-population craniofacial shape variation in the mouse is highly polygenic (Pallares et al 2015). In this study, using a phenotype-focused approach, we find patterns that support a highly polygenic basis for between-subspecies differences.…”

“…Results from QTL studies in fish, and dog breeds suggest that few loci of large effect explain most of the craniofacial differences between species/breeds (Albertson et al 2003b;Kimmel et al 2005;Boyko et al 2010;Roberts et al 2011;Schoenebeck et al 2012). In contrast, studies of withinspecies variation in mice have shown the opposite picture, craniofacial variation is associated with many loci of small effect (Pallares et al 2015). A discrepancy regarding the genetic architecture of within-and between-species variation has been reported for other traits (Orr 2001;Stern and Orgogozo 2008).…”

Exploring the Underlying Genetics of Craniofacial Morphology through Various Sources of Knowledge

“…In humans, loss of ALX1 is causing frontonasal dysplasia (OMIM #136760) [18]. In a recently published study, Pallares and colleagues were able to map within population variance of craniofacial shape of inbred mice [19]. Furthermore, they identified 17 loci responsible for variation in skull shape and eight loci responsible for variation in mandible shape of these mice, with Mn1 as a key gene in skull formation and within population shape variation.…”

Size and shape—integration of morphometrics, mathematical modelling, developmental and evolutionary biology

“…During this early phase, shape was still mainly described by multiple linear measurements and distances and the major problem of capturing the geometry or overall shape of a complex structure persisted. In the 1980s, advances in the development of statistical analytic tools and their combination with outline and landmark data revolutionized the field of geometric morphometrics (Zelditch et al 2012;Rohlf and Marcus 1993;Adams et al 2004;Mitteroecker and Gunz 2009;Adams et al 2013) and sparked studies in facial expression (Adams et al 2013), shape-to-body size correlation (allometry) (Sidlauskas et al 2011), symmetry (Klingenberg et al 2002), quantitative genetics (Klingenberg and Leamy 2001;Boell et al 2011;Pallares et al 2015) and evolutionary-developmental biology (Klingenberg 2010;Salazar-Ciudad and Jernvall 2010) to name but a few.…”