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

转座子是一种在大多数动物基因组中高度普遍存在的可移动遗传元件。一些转座子在人类基因组中保持活跃，因此，每个人都携带着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受体位点，从而通过形成嵌合mrna改变宿主基因，这种现象被称为转座子外显子。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。这就引出了一个有趣的假设：转座子可能会改变神经元功能，并在种群中引入行为变异。我建议结合高通量单细胞转录组学的最新进展，新的长读测序工具，以及果蝇中成熟的行为范式来验证这一假设。我将追求三个主要目标：1。我将生成首个单细胞分辨率的基因组位点特异性转座子表达图谱从整个大脑中提取。嵌合转座子基因mRNA的表达将定位于特定的细胞和大脑区域。2. 利用这些神经转座子表达的详细信息，我将测试选定的转座子插入的影响，方法是使用CRISPR将它们从果蝇菌株的基因组中移除，并对这些基因编辑过的果蝇进行一系列生理和行为测试。3. 接下来，我将研究多个转座子诱导的大脑变化的组合效应，并评估单个苍蝇的转座子景观如何影响种群内的行为变化。总的来说，这项研究旨在为转座子在大脑中的影响及其在多样化行为中的作用创造一个新的视角。

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.