Integrating genomics, development and evolution to elucidate the genotype-phenotype map of Drosophila wing morphology

我的长期研究目标是了解自然表型变异的遗传，基因组和发育基础。具体来说，提供一个更广泛的定量遗传学框架，精确和长期的预测表型变化的目标，关键是需要一个更全面和详细的了解如何遗传和环境变化调节发展。我实验室的研究致力于解决有关野生型遗传背景中自然遗传变异功能的关键问题，以及这最终如何形成表型效应。我们的工作是在接口的发育和定量基因组学使用的遗传模式生物（果蝇）。我们的方法使我们能够解决有关等位基因效应对复杂表型的影响，以及遗传背景和环境如何修改这些问题。 目标1：最近，我们提出了一个假说来解释这种遗传背景效应在自然群体中何时（就遗传扰动的大小而言）可能普遍存在。根据我们的假设，我们预测中等严重程度的等位基因最可能对野生型遗传背景的影响敏感。我的研究计划的第一个目标是利用广泛的突变分布来测试这个预测。这项工作将结合联合收割机这两个标准的遗传工具与表型的方法，这些等位基因的影响，在一个大面板的野生型遗传背景的发展分析。 目标2：为什么突变对不同的个体有不同的影响？一种可能性是野生型菌株在关键发育事件的时间或功能方面有所不同。因此，突变可能只会干扰在一些野生型菌株中至关重要的发育事件，但在其他菌株中则不会。我建议使用机翼开发来测试这一点。 目的3：果蝇翅膀是一个完善的模型修饰筛选，以确定新的组件在信号通路。然而，目前还不清楚这些相同的基因是否在自然种群中表现出表型。我们的第二个计划目标是解决这个问题，确定自然的遗传变异，有助于作为大的影响突变的修饰符。使用人工选择，遗传作图和基因组方法的组合，我们将确定是否分离遗传变异修饰突变的大效应是一致的基因在传统的突变研究。 我们的工作将为基于实验室的发育研究结果与分离遗传变异提供重大进展。此外，测试我们的假设的遗传背景效应的性质可能会大大改变我们的理解异质性的等位基因效应的性质和复杂的性状，包括疾病的影响，这将有利于所有加拿大人。

My long term research goal is to understand the genetic, genomic and developmental basis of natural phenotypic variation. Specifically, the goal of providing a broader quantitative genetics framework for precise and long-term predictions of phenotypic change critically requires a more integrative and detailed understanding of how genetic and environmental variation modulates development. Research in my lab works to address critical issues regarding the function of natural genetic variants across wild type genetic backgrounds, and how this ultimately shapes phenotypic effects. Our work is at the interface of developmental and quantitative genomics using a genetic model organism (Drosophila). Our approach allows us to address questions about the influence of allelic effects on complex phenotypes, and how these are modified by both genetic background and the environment. Aim 1: Recently we have developed a hypothesis to explain when (in terms of magnitude of the genetic perturbations) such genetic background effects are likely to be prevalent in natural populations. From our hypothesis, we predict that alleles of intermediate severity are most likely to be sensitive to the influence of wild type genetic background. The first aim for my research program is to test this prediction utilizing a broad distributions of mutations. This work will combine both standard genetic tools with a phenomic approach to developmental analysis of these allelic effects across a large panel of wild type genetic backgrounds. Aim 2: Why does a mutation have different effects in different individuals? One possibility is that wild type strains vary with respect to the timing or function of critical developmental events. Thus mutations may only perturb development events that are critical in some wild type strains, but not in others . I propose to test this using wing development. Aim 3: The Drosophila wing is a well established model for modifier screens to identify novel components in signaling pathways. Yet, it is unclear whether these same genes contribute phenotypically in natural populations. Our second program aim addresses this question, identifying natural genetic variants that contribute as modifiers of mutations of large effect. Using a combination of artificial selection, genetic mapping and genomic approaches, we will determine whether segregating genetic variants modifing mutations of large effect are concordant with genes contributing in traditional mutational studies. Our work will provide significant progress relating the findings of lab based developmental studies with segregating genetic variation. Furthermore, testing our hypothesis on the nature of genetic background effects may substantially alter our understanding of the nature of heterogeneity in allelic effects and the influence on complex traits including disease, which will be of benefit to all Canadians.