Transposable element polymorphisms and human genome regulation

Abstract

Transposable elements (TEs) are DNA sequences that are capable of moving from one genomic location to another. A large proportion of the human genome is derived from TEs, and TE-derived sequences have been shown to contribute to genome regulation in a variety of ways. There are several active families of human TEs, primarily the Alu, LINE-1 (L1), and SVA retrotransposons, which generate structural variations that segregate as polymorphisms within and between human populations. Given the known regulatory properties of human TEs, considered together with the fact that TE insertion activity is a source of population genetic variation, I hypothesized that TE polymorphisms can lead to gene regulatory differences among human individuals with health related phenotypic consequences. I evaluated this hypothesis via a series of genome-wide association screens aimed at assessing: (1) how the human genome regulates TE activity, and (2) how TE activity impacts human genome regulation and health related phenotypes. Expression quantitative trait loci (eQTL) analysis was used to discover a number of novel genetic modifiers of L1 element expression, including genes encoding for transcription factors and chromatin associated proteins. Human TE polymorphisms were shown to participate in population-specific gene regulation, with the potential to coordinately modify transcriptional networks. The regulatory effects of human TE polymorphisms were linked to immune system function, and related diseases, via insertions into cell type-specific enhancers. Results from my novel genome-wide approach to the study of human TE activity underscore the ability of TEs to effect health related phenotypes by virtue of changes to the regulatory landscape of the genome.