Evolution of Canalizing Mechanisms in Gene Expression

基因表达中渠道机制的演变

• 批准号: 7892947
• 负责人: Martin E KREITMAN
• 金额: $ 35.45万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892947
• 关键词: Adverse effects; Affect; Anterior; Buffers; Cells; Cephalic; Development; Diffusion; Disease susceptibility; Dorsal; Drosophila genus; Drug resistance; Embryo; Embryonic Development; Enhancers; Event; Evolution; Financial compensation; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Head; Human; Human Development; Individual; Knock-out; Knowledge; Lead; Length; Location; Measures; Mediating; Molecular; Morphology; Noise; Pathway interactions; Pattern; Pattern Formation; Positioning Attribute; Principal Investigator; Process; Regulator Genes; Regulatory Element; Research; Shapes; Site; Site-Directed Mutagenesis; System; Temperature; Testing; Variant; base; egg; morphogens; pressure; research study; response; trait

DESCRIPTION (provided by applicant): Drosophila embryogenesis is characterized by a highly orchestrated set of events directed by a regulatory gene cascade that creates a coordinate system along the anterior-posterior and dorsal-ventral axes of the embryo. This process must be highly canalized to suppress developmental noise introduced by environmental and mutational variation. But prior to cellularization, the steps in creating morphogenetic landmarks are diffusion mediated and are expected to be sensitive to initial morphogen concentrations, egg morphology, and environmental conditions (such as temperature). These factors vary extensively within and between species. The general aim of the proposal is to investigate the extent and mechanisms by which genetic and environmental variation is suppressed during patterning of the anterior-posterior axis in Drosophila development, and how these canalizing mechanisms respond to evolutionary changes in the coordinate system between species. Experiments will be carried out to: Test the hypothesis that ds-regulatory elements are building blocks of canalization Measure the sensitivity of the anterior-posterior patterning pathway to modulation of expression levels and positioning of its constituent genes Investigate genetic variation in pattern formation among isogenic strains differing in egg size and in development rate. Compare closely related species of Drosophila for the same traits to investigate the evolution of canalization of anterior-posterior patterning. Similar mechanisms to suppress environmental and genetic variation are expected to be acting in human development. The proposed research may lead to a better understanding of concealed gene polymorphism in humans, which when expressed may contribute to individual variation in disease susceptibility or resistance, drug response and side effects, as well as other medically relevant traits.

描述(申请人提供)：果蝇胚胎发生的特征是一系列高度协调的事件，由调控基因级联指导，沿着胚胎的前后轴和背腹轴创建一个坐标系。这一过程必须高度通道化，以抑制环境和突变变异带来的发育噪音。但在细胞化之前，创建形态发生标志的步骤是扩散介导的，预计会对初始形态原浓度、卵子形态和环境条件(如温度)敏感。这些因素在物种内和物种之间差异很大。该提案的总体目标是研究在果蝇发育的前后轴模式期间，遗传和环境变异被抑制的程度和机制，以及这些管化机制如何响应物种间坐标系的进化变化。将进行以下实验：验证DS调节元件是管化的构建块的假设，测量前后模式通路对其组成基因的表达水平和位置调节的敏感性，调查不同卵子大小和发育速度的同源菌株之间模式形成的遗传差异。比较近缘种果蝇的相同特征，以探讨前后方纹路的进化。类似的抑制环境和遗传变异的机制预计将在人类发育过程中发挥作用。这项拟议的研究可能有助于更好地理解人类隐藏的基因多态性，当这些基因表达时，可能会导致疾病易感性或耐药性、药物反应和副作用以及其他医学相关特征的个体差异。

项目成果

A Drosophila model of the neurodegenerative disease SCA17 reveals a role of RBP-J/Su(H) in modulating the pathological outcome.

• DOI: 10.1093/hmg/ddr251
• 发表时间: 2011-09
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Jie Ren;A. Jegga;Minlu Zhang;Jingyuan Deng;Junbo Liu;Christopher B. Gordon;B. Aronow;L. Lu;Bo Zhang;Jun Ma

Evolution and inheritance of early embryonic patterning in Drosophila simulans and D. sechellia.

• DOI: 10.1111/j.1558-5646.2010.01206.x
• 发表时间: 2011-05
• 期刊: Evolution; international journal of organic evolution
• 作者: Lott SE;Ludwig MZ;Kreitman M
• 通讯作者: Kreitman M

A multiscale investigation of bicoid-dependent transcriptional events in Drosophila embryos.

• DOI: 10.1371/journal.pone.0019122
• 发表时间: 2011-04-22
• 期刊: PloS one
• 影响因子: 3.7
• 作者: He F;Ren J;Wang W;Ma J
• 通讯作者: Ma J

Does positive selection drive transcription factor binding site turnover? A test with Drosophila cis-regulatory modules.

• DOI: 10.1371/journal.pgen.1002053
• 发表时间: 2011-04
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: He BZ;Holloway AK;Maerkl SJ;Kreitman M
• 通讯作者: Kreitman M

A two-dimensional simulation model of the bicoid gradient in Drosophila.

• DOI: 10.1371/journal.pone.0010275
• 发表时间: 2010-04-21
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Deng J;Wang W;Lu LJ;Ma J
• 通讯作者: Ma J