Contrary to the conventional wisdom that the majority of healthy cells in an individual have identical genomes, endogenous L1 retrotransposons are now known to 'jump'during neurogenesis and change neuronal genomes. The diversity and prevalence of unique genomes is unknown, but these are essential data for understanding how mobile element-mediated genetic diversity affects neural circuits. Genetic diversity in a population cannot be measured using typical bulk analysis of a million or so cells;therefore, we propose to develop single cell methods to analyze retrotransposition in individual neuronal genomes. To understand how the diversity and prevalence (i.e. the mosaic composition) of de novo mobile element insertions alters neuron function, we propose three experiments. In one experiment, we will examine the mosaic composition of specific neural circuits in behavioral outliers. A second experiment will test the expectation that new mobile element insertions differentially alter the transcriptome of individual neurons. In a third experiment, we will generate mouse lines with little or no retrotransposition to determine if mobile element insertions are both necessary and sufficient for specific aspects of neuron function. Taken together, the application of single cell genomic approaches to understand neuronal diversity promises to challenge basic assumptions about the genetics of behavior and the origin of human neurodevelopmental disorders.
Our overall objective is to develop single-cell approaches to measure mobile element-mediated genetic diversity in neural circuits. These tools promise to reveal new factors that bring about discordant behavioral phenotypes in monozygotic twins and contribute to polygenic neuropsychiatric diseases such as schizophrenia and autism.
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