Dissecting cryptic genetic variation underlying complex traits in Drosophila

项目总结 确定复杂性状的遗传基础是一个重大挑战，这主要是由几个因素造成的。 首先，复杂性状涉及多种遗传变异、环境因素和错综复杂的相互作用 其中就有。其次，还有隐藏在基因内部的隐秘的遗传变异 并仅在非典型条件下表达。第三，存在缺失的连接 基因类型和表型之间的关系，如转录组学和分子表型 代谢组学，这代表了我们理解上的一个关键差距。为了应对这些挑战，我们 以果蝇为模式生物，利用丰富的自然变异，强大的 基因工具以及更好地控制环境因素的能力。我们的目标是揭示这个系统 用两种互补的方法敏化系统的隐秘遗传变异--高糖 饮食作为环境应激源，诱导性遗传缺陷作为遗传扰动。我们将使用 整合基因组学、转录组学和代谢组学的系统方法来剖析基因-基因 以及负责新陈代谢和发育的基因-环境相互作用。首先，我们将确定 高糖饮食诱导的代谢发育性状和基因的隐性遗传变异 使用我们与高级杂交群体创建的新作图资源进行交互 提高测绘能力和分辨率。其次，我们将使用代谢物作为中间体 分子表型，弥合已确定的遗传变异和生物表型之间的差距。 通过分析不同饮食条件下的更广泛的性状，我们将确定 与这些特征相关的变异和代谢物，并利用这些发现来构建复杂的基因组- 代谢组-物候组相互作用网络。最后，我们开发了一个诱导模型，该模型 在果蝇遗传的不同基因组背景中引入遗传缺陷基因 参考面板。这将使我们能够识别隐蔽的遗传修饰物和基因-基因相互作用 潜在的受影响的代谢和生理表型，我们也将描述转录组 进一步了解相关变异体的分子功能。总括而言，拟议的研究是 有望揭示隐蔽的遗传变异，揭示新的基因-基因和基因环境 相互作用，揭示新陈代谢和发育背后缺失的途径成员，并提供 研究复杂性状的新模型和新策略。

PROJECT SUMMARY Determining the genetic basis of complex traits is a significant challenge, largely due to several factors. Firstly, complex traits involve multiple genetic variants, environmental factors, and intricate interactions among them. Secondly, there is cryptic genetic variation that remains "hidden" within genetic backgrounds and only expresses under atypical conditions. Thirdly, there are missing connections between genotypes and phenotypes, such as molecular phenotypes like transcriptomics and metabolomics, which represent a critical gap in our understanding. To address these challenges, we use Drosophila as a model organism, taking advantage of the abundant natural variation, the powerful genetic tools, and the ability to better control environmental factors. Our goal is to reveal the system cryptic genetic variation by sensitizing the system using two complementary approaches – high sugar diet as environmental stressor and an inducible genetic defect as genetic perturbation. We will use a system approach by integrating genomics, transcriptomics, and metabolomics to dissect the gene-gene and gene-environment interactions responsible for metabolism and development. First, we will identify cryptic genetic variation in high sugar diet-induced metabolic and developmental traits and gene by diet interactions using a new mapping resource we have created with advanced intercross populations to enhance mapping power and resolution. Secondly, we will use the metabolome as an intermediate molecular phenotype to bridge the gap between identified genetic variants and organismal phenotypes. By analyzing a wider range of traits under different dietary conditions, we will identify the genetic variants and metabolites associated with these traits, and use these findings to build complex genome- metabolome-phenome interaction networks. Lastly, we have developed an inducible model that introduces a genetic defect genotype into various genomic backgrounds of the Drosophila Genetic Reference Panel. This will allow us to identify cryptic genetic modifiers and gene-gene interaction underlying affected metabolic and physiological phenotypes, and we will also profile the transcriptome to further understand the molecular functions of associated variants. Overall, the proposed study is expected to expose cryptic genetic variation, uncover novel gene-gene and gene-environment interactions, reveal missing pathway members underlying metabolism and development, and provide new models and strategies to investigate complex traits.