Evolutionary dynamics of collateral gene silencing by piRNA

piRNA 附带基因沉默的进化动力学

• 批准号: 1413532
• 负责人: Justin Blumenstiel
• 金额: $ 59.32万
• 依托单位: University of Kansas Center for Research Inc
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1413532&HistoricalAwards=false
• 关键词: Evolutionary; dynamics; collateral; gene; silencing

Transposable elements (TE) are DNA sequences that can change their position in the genome and thereby produce a variety of harmful mutations. Animals, including fruit flies, have evolved a defense mechanism to guard against TE movement whereby small RNAs, called piRNAs, can destroy essential RNA intermediates produced by the TEs. Exactly how piRNAs work is not well understood, and the overall aim of this project is to study how piRNAs specifically target TE RNAs without destroying beneficial RNAs. The research has the potential to provide valuable insights into prevention of harmful mutations that could cause genetic defects or death. The project will have broader impacts for undergraduates, graduate students and a postdoctoral researcher, who will receive training in genetics, evolution and bioinformatics. Added benefit will derive from production of internet videos that will serve as general tools for education about various topics in genetics and evolution. piRNAs play a critical role in genome defense by destroying TE RNAs. This research will determine how the piRNA defense mechanism is constrained by the harm that occurs when piRNAs mistakenly target RNAs from normal genes and thus result in off-target, or collateral, gene silencing. Using different species of Drosophila as a model, the work will test the hypothesis that species with high TE content are more affected by these collateral effects. One series of experiments will determine whether species with higher TE content have less variation in expression of the piRNA machinery, increased silencing by piRNA, and stronger maternal effects on gene expression. Other experiments, in which piRNA expression is artificially increased, will reveal whether there is a functional tradeoff between genome defense and off-target effects. This work will provide important information about how the mechanisms that protect the genome are governed by the harmful effects of collateral gene silencing, which can be considered to be a form of "genomic autoimmunity".

转座因子（TE）是可以改变其在基因组中的位置并由此产生各种有害突变的DNA序列。包括果蝇在内的动物已经进化出一种防御机制来防止TE运动，由此称为piRNA的小RNA可以破坏TE产生的必需RNA中间体。piRNA的确切工作原理尚不清楚，该项目的总体目标是研究piRNA如何特异性靶向TE RNA而不破坏有益RNA。这项研究有可能为预防可能导致遗传缺陷或死亡的有害突变提供有价值的见解。 该项目将对本科生、研究生和博士后研究人员产生更广泛的影响，他们将接受遗传学、进化和生物信息学方面的培训。更多的好处将来自制作互联网视频，这些视频将作为遗传学和进化方面各种主题教育的一般工具。 piRNA通过破坏TE RNA在基因组防御中发挥关键作用。 这项研究将确定皮尔纳防御机制如何受到piRNA错误地靶向来自正常基因的RNA从而导致脱靶或附带基因沉默时发生的伤害的限制。使用不同种类的果蝇作为模型，这项工作将测试这一假设，即TE含量高的物种更容易受到这些附带效应的影响。 一系列实验将确定具有较高TE含量的物种是否在皮尔纳机制的表达中具有较小的变化、皮尔纳沉默的增加以及对基因表达的更强的母体效应。人工增加皮尔纳表达的其他实验将揭示基因组防御和脱靶效应之间是否存在功能权衡。 这项工作将提供重要的信息，如何保护基因组的机制是由附属基因沉默的有害影响，这可以被认为是一种形式的“基因组自身免疫”。