Genetic Determinants of Orofacial Shape and Relationship to Cleft Lip/Palate

描述（由申请人提供）：唇腭裂，主要是唇裂（CL），腭裂（CP）和唇腭裂（CLP），是最常见的主要出生缺陷之一，在世界各地的各种人群中，约有1/700至1/1000的活产婴儿发生，约70%为零星的，孤立的异常。这种“非综合征性”的口面裂隙是一种复杂的特征，涉及多种基因和环境风险因素。迄今为止，传统的遗传作图方法已经确定只有少数主要的易感基因的非综合征口面裂。因此，显然需要新的方法。有相当多的证据表明，口面部畸形可以发生在极端的正常范围的表型变异的中面大小和形状。在这里，我们提出了一种新的方法来识别调节小鼠和人类中面部形状的基因。我们推测，对正常的口面大小和形状起主要作用的基因也会在口面裂的发生中起重要作用。为了确定这些基因，我们将对创新小鼠品系和选定人群的中面部形状差异进行详细的形态计量分析，并将这些研究与遗传分析相结合，以确定控制中面部形态计量主要决定因素的基因。我们的研究表明，特定的近交系小鼠在面部形状的可测量参数上具有遗传差异。我们将利用我们开发的宝贵的新资源——小鼠“协作杂交”（CC），将CC的8个创始菌株之间的面部形状遗传差异与选择的重组自交系和重组交叉（RIX）联系起来，并提供这些小鼠的详细遗传作图数据。这种方法将能够识别这些形态差异背后的数量性状位点（qtl）。我们将用对人类的类似分析来补充我们的小鼠研究，研究对唇腭裂具有不同易感性的特定人群。这些比较研究将使我们能够识别人类中面部形状的基因。最后，我们将进行功能研究，以评估我们已经确定的基因如何影响面部形状。总之，这些研究应该为理解人类面部形态发生与口面裂易感性之间的关系提供基础，并为在与人类口面发育相关的动物模型中启动这些基因的功能研究提供基础。

DESCRIPTION (provided by applicant): 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.