Every person carries a unique set of mobile DNA snippets—called transposons—that can insert themselves into genes and create hybrid molecules, and this project will test whether those genetic hitchhikers alter how brain cells work and why individuals behave differently. These jumping genetic elements are not rare: they make up nearly half of the human genome, and some remain active. Scientists have recently found that the hybrid RNA molecules they create are abundant in brain tissue, but no one knows whether they actually change how neurons fire or whether they contribute to the natural variation in behaviour seen within a population. This project will fill that gap. The researcher will map every transposon insertion in the entire brain of a fruit fly at single-cell resolution, then use CRISPR to delete specific insertions and test the flies’ behaviour and neural activity. If successful, this work will show that transposons are not just genomic junk but active modifiers of brain function. This is fundamental science: it will not produce a medical treatment or a commercial product tomorrow. But understanding how genetic variation—even from parasitic DNA—shapes neural circuits could eventually inform why people respond differently to drugs, stress, or learning, and may reveal hidden sources of neurological diversity that current genetics overlooks.
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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.
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