Orofacial clefts, principally cleft lip (CL), cleft palate (CP), and cleft lip and palate (CLP), are among the most common major birth defects, occurring in ~1/700 to 1/1000 live births in various populations around the world, ~70% as a sporadic, isolated abnormality. Such """"""""non-syndromic"""""""" orofacial clefts act as complex traits, involving multiple genes and environmental risk factors. To date traditional genetic mapping approaches have identified only a few major susceptibility genes for non-syndromic orofacial clefts with certainty. Therefore, new approaches are clearly required. There is considerable evidence that orofacial malformations can occur at the extremes of the normal ranges of phenotypic variation of midfacial size and shape. Here we propose a novel approach to identify genes that regulate midfacial shape in mouse and human. We hypothesize that genes that are major contributors to normal orofacial size and shape will also have important roles in the occurrence of orofacial clefts. To identify such genes, we will perform detailed morphometric analysis of midfacial shape differences in innovative mouse strains as well as in select human populations, combining these studies with genetic analyses to identify genes that control major determinants of midfacial morphometries. Our studies have shown that specific inbred strains of mice have heritable differences in measurable parameters of facial shape. We will take advantage of a valuable new resource we have developed, the mouse """"""""Collaborative Cross"""""""" (CC), to correlate heritable differences in facial shape among the 8 founder strains of the CC, along with select Recombinant Inbred lines and Recombinant Intercross (RIX), with detailed genetic mapping data for these mice. This approach will enable identification of quantitative trait loci (QTLs) that underlie these morphometric differences. We will complement our mouse studies with a similar analysis of humans, studying specific populations with different susceptibilities to orofacial clefts. These comparative studies will allow us to identify genes that underlie midfacial shape in humans. Finally, we will perform functional studies to assess how the genes we have identified can influence facial shape. Together, these studies should provide a basis for understanding the relationship between human facial morphogenesis and susceptibility to orofacial clefts, and for initiating studies of the functions of these genes in animal models relevant to human orofacial development.
This proposal is submitted in specific response to an RFA to develop projects to advance our understanding of normal craniofacial development and the genetic and environmental perturbations that lead to diseases and disorders. This proposal will study the genetic determinants of normal orofacial development in mouse and human, with the specific intent of investigating relationship of these genes to human orofacial clefts.
|Percival, Christopher J; Liberton, Denise K; Pardo-Manuel de Villena, Fernando et al. (2016) Genetics of murine craniofacial morphology: diallel analysis of the eight founders of the Collaborative Cross. J Anat 228:96-112|
|Gonzalez, P N; Pavlicev, M; Mitteroecker, P et al. (2016) Genetic structure of phenotypic robustness in the collaborative cross mouse diallel panel. J Evol Biol 29:1737-51|
|Cole, Joanne B; Manyama, Mange; Kimwaga, Emmanuel et al. (2016) Genomewide Association Study of African Children Identifies Association of SCHIP1 and PDE8A with Facial Size and Shape. PLoS Genet 12:e1006174|
|Hallgrimsson, Benedikt; Percival, Christopher J; Green, Rebecca et al. (2015) Morphometrics, 3D Imaging, and Craniofacial Development. Curr Top Dev Biol 115:561-97|
|Hallgrimsson, Benedikt; Mio, Washington; Marcucio, Ralph S et al. (2014) Let's face it--complex traits are just not that simple. PLoS Genet 10:e1004724|
|Manyama, Mange; Larson, Jacinda R; Liberton, Denise K et al. (2014) Facial morphometrics of children with non-syndromic orofacial clefts in Tanzania. BMC Oral Health 14:93|
|Gonzalez, Paula N; Kristensen, Erika; Morck, Douglas W et al. (2013) Effects of growth hormone on the ontogenetic allometry of craniofacial bones. Evol Dev 15:133-45|
|Attanasio, Catia; Nord, Alex S; Zhu, Yiwen et al. (2013) Fine tuning of craniofacial morphology by distant-acting enhancers. Science 342:1241006|
|Hochheiser, Harry; Aronow, Bruce J; Artinger, Kristin et al. (2011) The FaceBase Consortium: a comprehensive program to facilitate craniofacial research. Dev Biol 355:175-82|
|Parsons, Trish E; Schmidt, Eric J; Boughner, Julia C et al. (2011) Epigenetic integration of the developing brain and face. Dev Dyn 240:2233-44|