Dissecting cryptic genetic variation underlying complex traits in Drosophila

剖析果蝇复杂性状背后的神秘遗传变异

• 批准号: 10796086
• 负责人: Xuan Zhuang
• 金额: $ 43.63万
• 依托单位: UNIVERSITY OF ARKANSAS AT FAYETTEVILLE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-11 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10796086
• 关键词: Ablation; Address; Affect; Animal Model; Cells; Complex; Complex Genetic Trait; Development; Diet; Dietary Sugars; Disease; Drosophila genus; Environmental Risk Factor; Evolution; Exposure to; Frequencies; Genes; Genetic; Genetic Models; Genetic Polymorphism; Genetic Variation; Genome; Genomics; Genotype; Goals; Health; Heritability; Human; Investigation; Link; Longevity; Maps; Medicine; Metabolic; Metabolic Pathway; Metabolism; Methods; Modeling; Molecular; Mutation; Pathway interactions; Penetrance; Phenotype; Physiological; Population; Quantitative Trait Loci; Reproduction; Research; Resolution; Resources; Role; Signal Transduction; Stress; System; Systems Biology; Variant; candidate validation; cost effective; dietary; environmental change; environmental stressor; fly; gene environment interaction; gene interaction; genetic architecture; genetic variant; improved; innovation; insight; insulin-like peptide; life history; member; metabolome; metabolomics; model organism; molecular phenotype; multiple omics; new therapeutic target; novel; phenome; precision medicine; programs; rare variant; sugar; tool; trait; transcriptome; transcriptomic profiling; transcriptomics

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.

项目摘要 确定复杂性状的遗传基础是一个重大挑战，主要是由于几个因素。 首先，复杂性状涉及多种遗传变异、环境因素和复杂的相互作用 其中。第二，有一种神秘的遗传变异仍然“隐藏”在遗传物质中， 背景，只在非典型条件下表达。第三，缺乏联系 基因型和表型之间，如转录组学等分子表型， 代谢组学，这代表了我们理解的一个关键差距。为了应对这些挑战，我们 利用果蝇作为模式生物，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 通过使用两种互补方法-高糖-敏化系统来隐藏遗传变异 饮食作为环境应激源，可诱导的遗传缺陷作为遗传干扰。我们将使用一个 通过整合基因组学、转录组学和代谢组学来剖析基因-基因的系统方法 基因与环境的相互作用决定了新陈代谢和发育。首先，我们将确定 高糖饮食诱导的代谢和发育性状的隐性遗传变异及饮食基因 利用我们用先进的杂交种群创建的新的映射资源， 增强映射能力和分辨率。其次，我们将使用代谢组作为中间体 分子表型，以弥合所鉴定的遗传变体和生物体表型之间的差距。 通过分析不同饮食条件下更广泛的性状，我们将确定遗传 与这些性状相关的变异体和代谢物，并利用这些发现来构建复杂的基因组- 代谢组-表型组相互作用网络。最后，我们开发了一个诱导模型， 将遗传缺陷基因型引入果蝇遗传学的各种基因组背景中， 参考面板。这将使我们能够识别隐藏的遗传修饰剂和基因-基因相互作用 潜在的受影响的代谢和生理表型，我们还将分析转录组， 以进一步了解相关变体的分子功能。总体而言，拟议的研究是 揭示隐藏的遗传变异，揭示新的基因-基因和基因-环境 相互作用，揭示了代谢和发育过程中缺失的途径成员， 研究复杂性状的新模型和策略。