Quantitative Genetic Analysis of Signal Transduction

描述(由申请人提供)：这是一项应用系统生物学方法来评估信号转导过程中的数量变化如何影响模式生物--果蝇的胚胎发生和翅膀模式形成的建议。我们将精确量化210个野生型品系和25个突变背景中参与受体介导信号传递的1000个基因的基因表达谱，并将25个关键基因中的SNP启动子多态性与转录丰度和表型变异联系起来。三个水平上的协方差模式(基因、基因表达和表型)，结合连接组件的生化网络的知识，将被用来生成预测模型，说明单个组件的差异如何被其他组件缓冲或将发育引导到特定的轨迹。然后将引入遗传和环境扰动来测试特定的预测，并在复杂的相互作用网络中区分因果关系和相关性。这一提议的生物医学意义在于，第一，产生了一个丰富的数据集，连接了果蝇发育中的大多数已知调控组件(该数据集将类似于目前计划用于各种复杂疾病研究的数据集)；第二，开发了统计方法，用于处理在基因组水平上评估关联的所谓“多维诅咒”；第三，利用可操纵的遗传系统，实际评估特定相互作用的功能意义。这项研究将分子定量遗传分析的重点从分离单个SNP效应转移到识别在复杂调控系统中产生动态平衡的调控控制点。

DESCRIPTION (provided by applicant): This is a proposal to apply systems biology approaches to evaluate how quantitative variation during signal transduction affects patterning during embryogenesis and wing patterning in the model organism, Drosophila. We will precisely quantify gene expression profiles for 1000 genes involved in receptor-mediated signaling during wing development in 210 wild-type lines and 25 mutant backgrounds, and associate SNP promoter polymorphism in 25 key genes with both transcript abundance and phenotypic variation. The patterns of covariance at the three levels (genotype, gene expression, and phenotype) in combination with knowledge of the biochemical networks connecting the components will be used to generate predictive models of how variation in individual components is either buffered by the other components or directs development into a particular trajectory. Genetic and environmental perturbations will then be introduced to test specific predictions, and to differentiate causality from correlation in the complex network of interactions. The biomedical significance of this proposal lies first in the generation of a rich data set connecting most of the known regulatory components in Drosophila development (this data set will be similar to data sets now planned for a wide variety of complex disease studies); second in the development of statistical methods for dealing with the so-called "curse of multidimensionality" in evaluating associations at the genome scale; and third in utilizing a manipulable genetic system to actually evaluate the functional significance of specific interactions. This research shifts the emphasis in molecular quantitative genetic analysis from isolation of individual SNP effects to identification of the regulatory control points that produce homeostasis in complex regulatory systems.