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

 描述(由申请人提供)：了解基因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。形态发生是一种突现的发育特性，使得基因型和表型之间的关系变得复杂。在这项申请中，我们将扩展我们在第一轮资助中所做的工作，并将扩大我们的工作范围，以产生对面部形态形成过程中的基因型-表型关系的更全面的理解。以前，我们证明了Sonic hedgehog(Shh)信号与脸型变化之间存在非线性关系，因此SHH信号的微小变化会产生较大的表型变化。我们的初步数据表明，这是信令系统的一个基本属性。此外，我们已经确定，基因表达结构域的形状与形态的变化高度相关，并且在呈现特定基因的一系列表型结果的倾向上存在遗传差异。这些初步数据让我们提出假设，面部形态的变异部分来自分子信号机制，这些机制不仅调节信号大小，还调节信号变异和信号中心的空间组织。我们将在以下方面测试这一假设 三个目标。首先，我们将使用Fgf8等位基因系列小鼠来产生基于FGF8信号水平的表型变异，并将表型结果与途径活动水平和细胞行为联系起来。其次，我们将改变鸟类面部的额鼻外胚层带(FEZ)的形状，因为FEZ调节上颌的形态发生。然后，我们将直接将FeZ的形状与分子、细胞和形态结果相关联。第三，我们将在一大群重组近交系小鼠身上测试AIMS 1和AIMS 2中研究的机制在基因组水平上的意义。在这一目标中，我们测试了表型变异调节的遗传基础，并探索了形态遗传学的加性比通常假设的要少的假设的基因组含义。非加性遗传变异是当前基因组方法处理复杂性状的主要挑战。我们相信，我们的工作结果将对了解在颅面复合体的生产型结构性疾病中基因型和表型之间的关系做出重要贡献。

 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.