Natural History and Functional Evolutionary Studies of A-to-I pre-mRNA Editing

A-to-I mRNA 前体编辑的自然历史和功能进化研究

• 批准号: 0091142
• 负责人: Robert Reenan
• 金额: $ 33万
• 依托单位: University of Connecticut Health Center
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0091142&HistoricalAwards=false
• 关键词: Natural; History; Functional; Evolutionary; Studies

0091142 Robert ReenanAdenosine-to-inosine (A-to-I) pre-mRNA editing hydrolytically deaminates A-to-I in target messenger RNA through the action of adenosine deaminases that act on RNA (ADARs). Inosine is interpreted as guanosine during translation, and the resulting non-templated recoding of the genetic information can introduce single amino acid changes that have dramatic effects on protein function. The process of A-to-I pre-mRNA editing itself has been demonstrated in both invertebrates and vertebrates, primarily in transcripts encoding voltage- and ligand-gated ion channels and receptors of the nervous system. It is the goal of this project to utilize Drosophila and other insect genera to create a natural history of RNA editing. Such a record will be used to directly address three important areas of this evolutionarily conserved but mysterious process. First, DNA sequence data from different species will be compared to identify the most highly conserved sequence elements necessary to form an ADAR substrate in a pre-mRNA and to determine the distribution of editing sites among species. Secondly, because each editing site is modified at a different frequency, levels of editing for given sites between species will be quantitated, and editing efficiency will be correlated with structural elements. Lastly, these data will be employed to genetically modify editing of particular sites or subsets of sites in vivo. Such experiments will address how the modification of individual editing sites affects organismal behavior and nervous system function. The project summarized here will not only provide molecular systematic data of a novel kind, but promises to deliver a deeper understanding of the process and purpose of RNA editing. Also, a detailed phylogenetic study of RNA editing such as this may also provide ammunition for new population genetic and molecular biogeographic studies into the distribution of variation in the editing process. Moreover, such advances will serve to assist in developing methods that would apply not only to Drosophila, but also in identifying and studying RNA editing sites in humans.

0091142 Robert ReenanAdenosine-to-inosine（A-to-I）pre-mRNA编辑通过作用于RNA的腺苷脱氨酶（ADAR）的作用水解靶信使RNA中的A-to-I。 肌苷在翻译过程中被解释为鸟苷，并且由此产生的遗传信息的非模板化重新编码可以引入对蛋白质功能具有显著影响的单个氨基酸变化。 A-to-I前mRNA编辑过程本身已在无脊椎动物和脊椎动物中得到证实，主要是在编码电压和配体门控离子通道和神经系统受体的转录物中。 该项目的目标是利用果蝇和其他昆虫属来创建RNA编辑的自然历史。 这样的记录将被用来直接解决这个进化上保守但神秘的过程中的三个重要领域。 首先，将比较来自不同物种的DNA序列数据，以鉴定在前体mRNA中形成阿达尔底物所必需的最高度保守的序列元件，并确定编辑位点在物种中的分布。 其次，由于每个编辑位点以不同的频率被修改，因此物种之间给定位点的编辑水平将被量化，并且编辑效率将与结构元素相关。 最后，这些数据将用于体内特定位点或位点子集的遗传修饰编辑。 这些实验将解决个体编辑位点的修改如何影响生物体行为和神经系统功能。 这里总结的项目不仅将提供一种新的分子系统数据，而且有望更深入地了解RNA编辑的过程和目的。 此外，诸如此类的RNA编辑的详细系统发育研究也可能为编辑过程中变异分布的新种群遗传学和分子生物地理学研究提供弹药。 此外，这些进展将有助于开发不仅适用于果蝇，而且适用于识别和研究人类RNA编辑位点的方法。