The role of continuous phenotypic variation in structural defects of the face

 描述（由申请人提供）：了解基因型和表型之间的关系对于将基因组信息用于个性化或预测性医学至关重要。我们工作的长期目标是了解产生表型变异的机制，以促进我们对颅面复合体结构性出生缺陷的理解。形态发生是一种新出现的发育特性，它使基因型和表型之间的关系变得复杂。在本申请中，我们将扩展我们在第一轮融资期间所做的工作，并将扩大我们的工作范围，以在面部形态发生期间对基因型-表型关系产生更全面的理解。之前，我们证明了Sonic hedgehog（Shh）信号和面部形状变化之间存在非线性关系，SHH信号的微小变化会产生大的表型变化。我们的初步数据表明，这是信号系统的基本属性。此外，我们已经确定基因表达结构域的形状与形态学变化高度相关，并且对于特定基因型，表现出一系列表型结果的倾向存在遗传变异。这些初步的数据使我们的假设，面部形态的变化出现，部分，从分子信号传导机制，调制，不仅信号的大小，而且信号的变化和信号中心的空间组织。我们将测试这个假设， 三个目标。首先，我们将使用FGF 8等位基因系列的小鼠来产生基于FGF 8信号传导水平的表型变异，并且我们将把表型结果与通路活性和细胞行为的水平相关联。其次，我们将改变鸟类面部额鼻外胚层区（FEZ）的形状，因为FEZ调节上颌的形态发生。然后，我们将直接涉及的FEZ的形状，分子，细胞和形态的结果。第三，我们将在一大组重组近交系小鼠品系中测试目标1和2中研究的机制的基因组水平的含义。在这个目标中，我们测试的遗传基础的调制表型方差，我们探讨的假设，即形态的遗传学是加性比通常假设的基因组的影响。非加性遗传变异是目前复杂性状基因组学研究的一个主要挑战。我们相信，我们的工作结果将作出重大贡献，了解基因型和表型之间的关系，在生产结构性疾病的颅面复合体。

 DESCRIPTION (provided by applicant): Understanding the relationship between genotype and phenotype is essential to use genomic information for personalized or predictive medicine. The long-term goal of our work is to understand mechanisms that generate phenotypic variation in order to advance our understanding of structural birth defects of the craniofacial complex. Morphogenesis is an emergent property of development that makes the relationship between genotype and phenotype complex. In this application we will expand on work that we performed during our first round of funding, and we will broaden the scope of our work to generate a more global understanding of genotype-phenotype relationship during morphogenesis of the face. Previously, we demonstrated that a non-linear relationship between Sonic hedgehog (Shh) signaling and facial shape variation exists, whereby small changes in SHH signaling produce large phenotypic changes. Our preliminary data suggests that this is a fundamental property of signaling systems. In addition, we have determined that the shape of gene expression domains is highly associated with changes in morphology, and that there is genetic variation in the propensity to exhibit a range of phenotypic outcomes for a particular genotype. These preliminary data have led us to the hypothesis that variation in facial morphology emerges, in part, from molecular signaling mechanisms that modulate, not only signal magnitude, but also signal variation and the spatial organization of signaling centers. We will test this hypothesis in three Aims. First, we will use the Fgf8 allelic series of mice to generate phenotypic variation based on levels of FGF8 signaling and we will relate phenotypic outcomes with levels of pathway activity and cellular behaviors. Second, we will alter the shape of the Frontonasal Ectodermal Zone (FEZ) in the avian face, because the FEZ regulates morphogenesis of the upper jaw. We will then directly relate the shape of the FEZ to molecular, cellular, and morphological outcomes. Third, we will test genomic-level implications of the mechanisms investigated in aims 1 and 2 in a large group of recombinant inbred mouse strains. In this aim, we test the genetic basis for the modulation of phenotypic variance and we explore the genomic implications of the hypothesis that the genetics of morphology is less additive than is commonly assumed. Non-additive genetic variation is a major challenge to current genomic approaches to complex traits. We believe that the results of our work will make a significant contribution to understanding the relationship between genotype and phenotype in the production structural diseases of the craniofacial complex.