The gene regulatory basis of the genotype-phenotype map

基因型-表型图谱的基因调控基础

• 批准号: 10621949
• 负责人: Mark J Rebeiz
• 金额: $ 40.3万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621949
• 关键词: 3-Dimensional; Affect; Anatomy; Animals; Area; Body Patterning; Cell physiology; Development; Drosophila genus; Drosophila melanogaster; Evolution; Gene Expression Regulation; Genes; Genetic; Genome; Genotype; Homeobox Genes; Human; Human Development; Individual; Instruction; Life; Maps; Modeling; Molecular; Morphogenesis; Morphology; Mutation; Nature; Organism; Pattern; Phenotype; Pigmentation physiologic function; Population; Process; Regulator Genes; Research; Research Project Summaries; Shapes; Structure; System; Tissues; Variant; Work; behavior influence; cell behavior; fly; gene function; gene regulatory network; human disease; programs; trait; transcription factor

PROJECT SUMMARY This research program seeks to reveal how morphological traits are genetically encoded during development and modified during evolution. Gene regulatory networks are key to generating the physical features of an organism, as they govern the spatial and temporal expression of each gene during its development. It is now well accepted that phenotypic differences between species and within populations, including the human population, are often caused by changes to regulatory networks which alter expression levels or timing. Despite much progress in this field, our understanding of network function and evolution is lacking in several major areas: (1) how do new traits emerge from changes to networks? (2) how do networks influence the behavior of cells in developing tissues? (3) how do mutations that affect gene regulation permeate networks and populations to cause traits? This research will leverage the highly tractable Drosophila melanogaster model to answer these questions. The first theme of this program will address a gene regulatory network controlling a rapidly evolving three- dimensional anatomical structure in Drosophila. The network which patterns this structure will be dissected to determine how individual components became integrated into the network. In parallel, the proposed studies will trace the connections between these networks and the cellular processes that drive morphogenesis. Finally, genetic changes which alter the three-dimensional shape of these structures will be identified. Performing these studies will provide an unprecedented view of how gene regulatory networks are assembled and modified to generate physical differences in tissue structure and produce elaborate morphologies. The second theme comprises studies on Drosophila pigmentation traits that differ among populations and between species. Most traits involve multiple loci, and much of this polygenic variation will be derived from standing variants that persist in populations without phenotypic consequences. The accumulation of multiple genetic changes will be traced and connected to a putatively adaptive pigmentation trait in Drosophila melanogaster. The pigmentation trait under study is controlled by Hox transcription factors, which are highly conserved body-patterning genes shared between flies and humans. This project will examine Hox gene function and evolution in populations and between species to determine how the gene regulatory network for this trait arose and diversified. This work will provide a deep molecular understanding of how phenotypes are generated, informing the nature of these processes in less tractable systems, including humans.

项目概要 该研究项目旨在揭示形态特征在发育过程中如何进行遗传编码 并在进化过程中进行了修改。基因调控网络是产生生物体物理特征的关键 有机体，因为它们在发育过程中控制每个基因的空间和时间表达。现在是 人们普遍认为，物种之间和群体内部（包括人类）的表型差异 群体，通常是由改变表达水平或时间的调节网络的变化引起的。 尽管该领域取得了很大进展，但我们对网络功能和演化的理解在几个方面仍然缺乏 主要领域：（1）网络变化如何产生新特征？ (2) 网络如何影响 发育组织中细胞的行为？ (3)影响基因调控的突变如何渗透网络 和人群造成的特征？这项研究将利用高度易驯化的黑腹果蝇 模型来回答这些问题。 该计划的第一个主题将解决控制快速发展的三体的基因调控网络 果蝇的三维解剖结构。构建该结构的网络将被剖析为 确定各个组件如何集成到网络中。与此同时，拟议的研究将 追踪这些网络和驱动形态发生的细胞过程之间的联系。最后， 改变这些结构的三维形状的遗传变化将被识别。表演 这些研究将为基因调控网络如何组装和形成提供前所未有的视角。 进行修改以产生组织结构的物理差异并产生复杂的形态。 第二个主题包括对果蝇色素沉着特征的研究，这些特征在种群和群体之间存在差异。 物种之间。大多数性状涉及多个基因座，并且大部分多基因变异将源自 在群体中持续存在且没有表型后果的常设变异。多重积累 将追踪果蝇的遗传变化并将其与假定的适应性色素沉着特征联系起来 黑腹果蝇。所研究的色素沉着特征由 Hox 转录因子控制，该因子高度 果蝇和人类共享的保守身体模式基因。该项目将检查Hox基因 种群和物种之间的功能和进化，以确定基因调控网络如何 这种特征出现并多样化。这项工作将为表型如何产生提供深入的分子理解 生成，告知难以处理的系统（包括人类）中这些过程的性质。