Mobile Element Discovery and Activity in Human Populations and Diseases

Abstract

Approximately 45% of the human genome is occupied by Mobile genetic Elements (MEs). Small subsets of these are still active and belong to three different families: L1, Alu, and SVA. These active families can generate new copies known as Mobile Element Insertions (MEIs), which can be polymorphic in humans. There remain several open- ended questions as to which MEs are generating the vast majority of new MEIs, and if they are in fact active prior to, and can initiate, tumorigenesis. To investigate active MEs in these two scenarios, I designed a computational algorithm to find polymorphic MEIs in human whole genome sequencing (WGS) data: the Mobile Element Locator Tool (MELT). As part of the 1000 Genomes Project (1KGP), I used MELT to discover over 22,500 polymorphic MEIs. Using this data in combination with Neanderthal, Denisovan, and Chimp WGS, I investigated the population dynamics of ME activity in the great ape lineage. To evaluate the possibility of L1 playing a dynamic role in cancer tumorigenesis, we screened ten colorectal cancer cases for somatic L1 activity. In one of these cases, we discovered a somatic L1 insertion into the tumor suppressor gene APC, causing this particular cancer case. Follow-up studies revealed that a population-specific L1 element was responsible for the generation of this insertion, and was active in the normal soma. Overall, through the development of new computational and sequencing tools, my work demonstrates that distinct families of MEs are generating the majority of new MEIs in human genomes, that a subset of these elements are stratified by population, and that somatically active L1s can initiate cancer.