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.

项目摘要 该研究计划旨在揭示形态学特征在开发过程中的遗传编码方式 并在进化过程中进行了修改。基因调节网络是生成物理特征的关键 生物体在其发育过程中控制每个基因的空间和时间表达时。现在 人们接受了物种和人群之间的表型差异，包括人类 人口通常是由改变表达水平或时机的监管网络的变化引起的。 尽管在这一领域取得了很大进展，但我们对网络功能和进化的理解缺乏几个 主要领域：（1）新特征如何从网络变化中出现？ （2）网络如何影响 细胞在发育组织中的行为？ （3）如何影响基因调节的突变渗透网络 和人群引起特质？这项研究将利用高度可触犯的果蝇Melanogaster 回答这些问题的模型。 该程序的第一个主题将介绍一个控制迅速发展的基因调节网络。 果蝇的尺寸解剖结构。该结构将剖析的网络 确定单个组件如何集成到网络中。同时，拟议的研究将 追踪这些网络与驱动形态发生的细胞过程之间的连接。最后， 将确定改变这些结构的三维形状的遗传变化。表演 这些研究将提供前所未有的观点，说明基因调节网络的组装方式以及 修改以产生组织结构的物理差异并产生精致的形态。 第二个主题包括对种群不同和人群不同的果蝇色素沉着性状的研究 物种之间。大多数特征涉及多个基因座，大部分多基因变异将从 持续存在没有表型后果的人群中的常规变体。多重的积累 遗传变化将被追踪并连接到果蝇中推测的自适应色素沉着性状 Melanogaster。研究所研究的色素沉着性状由HOX转录因子控制，这是高度的 苍蝇和人之间共享的保守的身体造成基因。该项目将检查HOX基因 种群和物种之间的功能和进化，以确定基因调节网络如何用于 这种特征出现和多样化。这项工作将对表型的深入分子理解 生成的，在包括人类在内的较低的系统中为这些过程的性质提供了信息。