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

转座子是一种可移动的遗传元件，广泛存在于大多数动物基因组中。一些转座子在人类基因组中仍然活跃，因此，每个人都携带着自己独特的转座子插入组合。基因内含子中的转座子可以引入新的剪接供体和受体位点，从而通过形成嵌合的mRNAs来改变宿主基因--这一现象被称为转座子外显子。新出现的证据表明，这些嵌合的mRNAs在包括大脑在内的躯体组织中含量非常丰富。这导致了一个有趣的假设：转座子可能会改变神经元功能，并在种群中引入行为变化。我建议结合高通量单细胞转录学的最新进展，新的长读测序工具，以及在果蝇中建立的成熟的行为范式来检验这一假设。我将追求三个主要目标：1.我将从整个大脑中产生第一个单细胞分辨率的基因组位点特异性转座子表达图谱。嵌合转座子基因的mRNA表达将定位于特定的细胞和大脑区域。2.利用神经转座子表达的这些详细信息，我将使用CRISPR从果蝇品系的基因组中移除它们，并对这些经过基因编辑的果蝇进行一系列生理和行为测试，以测试选择的转座子插入的影响。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，并评估单个果蝇的转座子环境如何对种群内的行为变化做出贡献。总而言之，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。

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.