Project Summary. Human LINE-1 (L1) elements are autonomous retrotransposons that continue to produce new “offspring” L1 insertions in human genomes. Until recently, L1 elements were thought to be mobilized primarily in the germline and then silenced in somatic cells throughout adulthood. However, several recent reports have shown that L1 elements are active in at least some adult somatic tissues, including the brain and epithelial somatic tumors. These observations have led to the suggestion that L1 might play a role in initiating human cancers by mutating specific tumor suppressor genes and oncogenes in somatic cells. In the three aims of this proposal, we will further explore this hypothesis with an emphasis on studying the expression, regulation, and mobilization of the full-length L1 source elements that generate new L1 insertions. In Specific Aim 1, we will generate a comprehensive resource of full-length, human-specific L1 (FL-L1Hs) source elements that will be used throughout this proposal (Aims 1-3) to study the role of L1 mobilization in human tissues and tumors. In Specific Aim 2, we will examine the expression and regulation of FL-L1Hs elements that can evade somatic repression and will study the mechanism(s) whereby these elements manage to do this. Finally, in Specific Aim 3, we will examine the mobilization capacities of FL-L1Hs elements. Combined with the data generated in Aims 1 and 2, these data will allow us to better understand the expression, regulation, and mobilization of the FL-L1Hs elements that mutagenize the human genome. The successful completion of the three Aims of this study will transform our understanding of how mobile elements impact human diseases, including cancers.