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。具体地说，为精确和长期预测表型变化提供更广泛的数量遗传学框架的目标，关键是需要对遗传和环境变异如何调节发育有更全面和详细的理解。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的功能以及这最终如何形成表型效应的关键问题。我们的工作是利用遗传模式生物(果蝇)进行发育基因组学和数量基因组学的交界处。我们的方法使我们能够解决等位基因效应对复杂表型的影响，以及这些影响如何被遗传背景和环境改变的问题。 目的1：最近，我们提出了一个假说来解释这种遗传背景效应何时可能在自然种群中流行(根据遗传扰动的程度)。根据我们的假设，我们预测中等严重程度的等位基因最有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一预测。这项工作将结合标准遗传工具和表现学方法，对大量野生型遗传背景的这些等位基因效应进行发展分析。 目标2：为什么一种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存在差异。因此，突变可能只会扰乱在某些野生型菌株中至关重要的发育事件，而在其他类型的菌株中则不会。我建议使用机翼开发来测试这一点。 目的3：果蝇的翅膀是一个成熟的模型，用于修饰筛选以识别信号通路中的新成分。然而，目前还不清楚这些相同的基因是否会影响自然种群的表型。我们的第二个程序目标是解决这个问题，识别作为大效应突变修饰物的自然遗传变异。利用人工选择、遗传作图和基因组学方法相结合的方法，我们将确定改变大效应突变的分离遗传变异是否与传统突变研究中的基因一致。 我们的工作将提供重大进展，将基于实验室的发育研究结果与分离的遗传变异联系起来。此外，测试我们关于遗传背景效应性质的假设可能会极大地改变我们对等位基因效应异质性的性质以及对包括疾病在内的复杂性状的影响的理解，这将对所有加拿大人有利。

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.