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

描述（由申请人提供）：口面裂，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发生率约为1/700至1/1000，约70%为散发性孤立异常。这种“非综合征”的口面裂表现为复杂的特征，涉及多个基因和环境风险因素。到目前为止，传统的遗传作图方法已经确定了只有少数几个主要的非综合征性口面裂的易感基因与肯定。因此，显然需要采取新的办法。有相当多的证据表明，口面畸形可以发生在极端的正常范围内的表型变异面中部的大小和形状。在这里，我们提出了一种新的方法来确定基因调控面中部的形状在小鼠和人类。我们假设，基因是正常的口面大小和形状的主要贡献者也将在口面裂的发生中发挥重要作用。为了识别这些基因，我们将在创新的小鼠品系以及在选定的人群中进行详细的面中部形状差异的形态测定分析，将这些研究与遗传分析相结合，以识别控制面中部形态测定的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方面具有遗传差异。我们将利用我们开发的一种有价值的新资源，小鼠“协作杂交”（CC），将CC的8个创始品系之间的面部形状的遗传差异与选择的重组近交系和重组互交（RIX）以及这些小鼠的详细遗传图谱数据沿着。这种方法将使数量性状基因座（QTL），这些形态差异的基础鉴定。我们将通过对人类的类似分析来补充我们的小鼠研究，研究对口面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确定人类面部中部形状的基因。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，这些研究应提供一个基础，了解人类面部形态和易感性orofacial裂缝之间的关系，并启动这些基因的功能在动物模型中的研究与人类orofacial发展。

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.