Activities and diversity of natural L1 retrotransposon copies in human genomes – ActiveLINE

L1 retrotransposon sequences form 20% of the human genome, and L1 mobilization drives germline and somatic genome mutations in health, aging and disease. Only one L1 subfamily, L1HS, is functional in humans, and only a few L1HS loci are active in each cell-type. Two hypotheses can explain locus- and cell-type-dependent activity: i) sequence variation within each L1 copy; ii) regulation by the genomic position. Here, we will systematically test these hypotheses in 12 human cell lines from distinct individuals and tissues. We will use massively parallel assays to measure the intrinsic transcriptional and mobilization capabilities of each L1HS copy, including those absent from the reference genome. In parallel, we will evaluate how the genomic context can repress or activate L1s, by perturbing repressive chromatin and by systematically deleting putative enhancers near active copies. Together, these studies will extend our knowledge of a potent endogenous mutagen of the human genome.