innovaTEbehaviour - How do transposons alter neuronal function and contribute to behavioural diversity?

innovaTEbehaviour - 转座子如何改变神经元功能并促进行为多样性？

• 批准号: EP/X038882/1
• 负责人: Christoph Treiber
• 金额: $ 164.39万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX038882%2F1
• 关键词: innovaTEbehaviour; How; do; transposons; alter

Transposons are mobile genetic elements that are highly pervasive in most animal genomes. Some transposons remain active in the human genome, and as a consequence, every person carries their own, unique combination of transposon insertions. Transposons within introns of genes can introduce new splice-donor and -acceptor sites and thereby alter host genes by forming chimeric mRNAs - a phenomenon known as transposon exonisation. Emerging evidence indicates that these chimeric mRNAs are highly abundant in somatic tissues, including the brain. This leads to an intriguing hypothesis: transposons might alter neuronal function and introduce behavioural variation within a population. I propose to combine the latest advances in high-throughput single-cell transcriptomics, new long-read sequencing tools, and a well-established behavioural paradigm in the fruit fly to test this hypothesis. I will pursue three main aims: 1. I will generate the first single-cell resolution atlas of genomic-locus specific transposon expression from an entire brain. Chimeric transposon-gene mRNA expression will be locliased to specific cells and brain regions. 2. Using this detailed information of neural transposon expression, I will test the impact of selected transposon insertions by removing them from the genomes of fly strains using CRISPR, and employing a range of physiological and behavioural tests on these genetically-edited flies. 3. I will next investigate the combinatorial effect of multiple transposon-induced changes in the brain and assess how the transposon landscape of individual flies contributes to behavioural variation within a population. Collectively, this research aims to create a new perspective on the impact of transposons in the brain, and on their role in diversifying behaviours.

转座子是移动的遗传元件，在大多数动物基因组中高度普遍存在。一些转座子在人类基因组中仍然活跃，因此，每个人都携带自己独特的转座子插入组合。基因内含子内的转座子可以引入新的剪接供体和剪接受体位点，从而通过形成嵌合mRNA来改变宿主基因-这种现象称为转座子外切。新出现的证据表明，这些嵌合mRNA在包括大脑在内的体细胞组织中非常丰富。这导致了一个有趣的假设：转座子可能会改变神经元功能，并在人群中引入行为变异。我建议结合联合收割机的最新进展，高通量单细胞转录组学，新的长读测序工具，以及一个完善的行为模式，在果蝇来测试这一假设。我将追求三个主要目标：1。我将从整个大脑中生成第一个基因组位点特异性转座子表达的单细胞分辨率图谱。嵌合转座子基因mRNA表达将定位于特定细胞和大脑区域。2.利用这些神经转座子表达的详细信息，我将通过使用CRISPR将它们从果蝇品系的基因组中移除来测试选定转座子插入的影响，并对这些基因编辑的果蝇进行一系列生理和行为测试。3.接下来，我将研究大脑中多种转座子诱导的变化的组合效应，并评估个体苍蝇的转座子景观如何影响种群内的行为变异。总的来说，这项研究旨在为转座子在大脑中的影响以及它们在多样化行为中的作用创造一个新的视角。