Analysis of the Inverse Effect in Drosophila

果蝇逆效应分析

• 批准号: 9807802
• 负责人: James Birchler
• 金额: $ 14.5万
• 依托单位: University of Missouri-Columbia
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9807802&HistoricalAwards=false
• 关键词: Analysis; Inverse; Effect; Drosophila

Birchler9807802The long range goal of the proposed work is to understand the nature and mechanism of transacting regulatory genes that affect the expression of structural genes in a dosage sensitive manner, utilizing the white eye color locus of Drosophila melanogaster as a model system. It is believed that this type of regulatory effect is involved in the developmental expression of most types of structural genes in multicellular eukaryotes. Aneuploidy, or the change of individual chromosome number in an otherwise euploid genome, is associated with certain phenotypic consequences and it is thought that the dosage regulators play a significant role in the molecular basis of these syndromes. Previous work has identified several genes that produce a dosage sensitive modifying effect on white expression. Cloning, or other means of identifying these genes, revealed them to be various types of transcriptional factors and chromatin components. The major type of dosage effect is an inverse correlation between the copy number of the regulator and the expression of the target locus. If the regulator and the target are varied together, the effects cancel to produce dosage compensation. In the proposed work, a study of the interactions of 20 molecularly defined regulatory genes that are effective on white will establish what types of regulatory genes predominate in establishing the overall level of gene expression when several regulators are varied together as would occur in large aneuploids. This information will be of value for understanding regulatory gene circuitry, aneuploid syndromes, dosage compensation mechanisms and involvement of regulatory genes in the control of quantitative traits. The second major direction will be to analyze a newly discovered global regulatory complex that appears to exist throughout multicellular eukaryotes. The orthologous complex acts in yeast as a global negative regulatory system, but there are significant differences in the predicted protein sequences and action in Drosophila. The functional tests proposed will begin work on how these genes produce their effect on gene expression in multicellular species. Lastly, evidence was found in the previous funding period for nucleation sites for the association of the male specific lethal (MSL) complex on the male X chromosome. The hypothesized nucleation site will be isolated and the mechanism by which it conditions binding to the X will be studied. These experiments will address how the MSL proteins act to modify the action of the dosage sensitive regulatory genes. The proposed project will contribute to an understanding of inverse dosage regulation and address whether there is a connection between the responsible regulatory genes and the biological effects associated with chromosomal dosage such as compensation, quantitative traits, aneuploid syndromes and position effect variegation.A genome is more than a series of individual genes. It is a unit whose control of cell and organismal function is the result of complex interactions of those individual genes in a precise and patterned choreography. This work will give greater insight into some of those interactions and how they affect the regulation of individual target loci.

Birchler9807802拟议工作的长期目标是利用果蝇的白色眼色基因作为模型系统，以剂量敏感的方式了解影响结构基因表达的调控基因的性质和机制。人们认为这种类型的调控作用参与了多细胞真核生物中大多数类型结构基因的发育表达。非整倍体或整倍体基因组中个体染色体数目的变化与某些表型后果有关，剂量调节剂在这些综合征的分子基础上发挥着重要作用。以前的工作已经确定了几个基因，它们对白色表达产生剂量敏感的修饰效应。克隆或其他识别这些基因的方法揭示了它们是各种类型的转录因子和染色质成分。剂量效应的主要类型是调控基因的拷贝数与靶基因表达之间的负相关。如果调节剂和靶点一起变化，效果就会抵消，从而产生剂量补偿。在这项拟议的工作中，一项对20个分子定义的对白色有效的调控基因相互作用的研究将确定当几个调控基因一起变化时，什么类型的调控基因在确定基因表达的总体水平方面占主导地位，就像在大型非整倍体中会发生的那样。这些信息将有助于理解调控基因回路、非整倍体综合征、剂量补偿机制以及调控基因参与数量性状的控制。第二个主要方向将是分析新发现的似乎存在于多细胞真核生物中的全球调控复合体。这个同源复合体在酵母中作为一个全球负调控系统发挥作用，但在果蝇中预测的蛋白质序列和作用有显著差异。拟议的功能测试将开始研究这些基因如何在多细胞物种中对基因表达产生影响。最后，在前一个资助时期发现了与男性X染色体上的男性特定致死(MSL)复合体相关的成核地点的证据。假想的成核点将被分离，并将研究其与X结合的机制。这些实验将解决MSL蛋白如何作用于改变剂量敏感调控基因的作用。这项拟议的项目将有助于理解反向剂量调控，并解决负责的调控基因与与染色体剂量相关的生物效应之间是否存在联系，如补偿、数量性状、非整倍体综合征和位置效应变异。基因组不仅仅是一系列单个基因。它是一个单位，它对细胞和有机体功能的控制是这些单独基因在精确和有模式的编排中复杂相互作用的结果。这项工作将更深入地了解其中一些相互作用，以及它们如何影响单个靶基因的调节。