While often ignored in analysis, repetitive regions of the genome and their association with disease is becoming more apparent in recent years. Part of the resurgence of interest in these regions is the availability of new tech- nologies to sequence them and accurately map their location. Indeed, classes of transposable elements have been shown to be polymorphic in the population indicating both their continued activity in shaping our genomes and their propensity to be genetic drivers of phenotype. This has been especially true in neurologic disorders, where transposable elements are not only polymorphic but actively moving in somatic cells and has driven parts of projects such as the Brain Somatic Mosaicism Network. However, a major roadblock in identifying these ele- ments remains as their inherent repetitive nature makes them difficult to place on a genome. In this proposal, we will develop a technology to capture a set of actively moving transposable elements: L1Hs, AluYa5/8, AluYb8/9, and SVAs. These represent the vast majority of active transposable elements and thus will allow us to measure the genetic diversity of polymorphic insertions of these elements. After capture, we will use nanopore long-read sequencing to capture both the entire insertion as well as thousands of bases of surrounding sequence which will allow for accurate mapping of these elements to the genome. We will apply this new technology to a set of three diverse trios that have been well-studied and characterized to allow for follow-up analysis of the effect of polymorphic insertions of transposable elements.
This project seeks to develop assays to capture and map repetitive elements in the human genome. Accurate mapping of these elements will allow for study into genetic mechanisms driven by actively moving transposable elements in the genome. Improved understanding of these regions will provide a better mechanism for interpretation of element function and suggest new targets to approach incorrect regulation leading to disease.
