Abstract
Mobile element insertions (MEIs) are a diverse and poorly understood source of genetic variation in humans.
These insertions occur when retrotransposons integrate into the genome. Recent advancements in genomics
technologies in large populations have revealed over 100,000 polymorphic MEIs, making them a very prevalent
class of genetic variation. MEIs have been shown to significantly impact gene function and contribute to human
diseases. In many cases, specific noncoding MEIs have been linked to neurologic disease. In particular, my
training lab has discovered that the cause of the neurodegenerative disease X-linked Dystonia Parkinsonism is
an intronic insertion of a SINE-VNTR-Alu (SVA) element, which causes a distinct expression and alternative
splicing signature. However, our understanding of the broader effects of MEIs on gene regulation, particularly
alternative splicing, remains limited. This fellowship aims to leverage large-scale genetic datasets and cutting-
edge analytical methods to characterize MEIs, explore their functional implications for gene expression and
splicing, and investigate their association with neurological diseases. I will also specifically dissect the role of
SVA elements, which are hominid specific and display unique patterns of internal variation. I will assemble a
dataset of over 2000 matched short-read whole genome sequencing and bulk RNA-seq data, including multi-
tissue expression data from the Genotype-Tissue Expression Project and brain sequencing data from the
CommonMind Consortium, which includes neuropsychiatric cases and controls. Using this data, I will look at
broad patterns of transcriptomic effects from MEIs (Aim 1) and identify specific MEIs associated with splicing
changes in the brain (Aim 2). Finally, I will perform MEI discovery in long-read whole genome sequencing data
from 10,000 individuals from the NIH All of Us initiative. I will harness this large dataset to comprehensively
characterize MEIs and identify SVA elements associated with neurological disease (Aim 3). In parallel with these
research aims, an exceptional team of mentors and advisors across multiple disciplines, career stages, and
institutions will provide didactic training, hands-on research support, regular opportunities for presentation in
seminars and conferences, and a variety of soft skill development sessions that directly align with my career
objectives during my PhD training. Collectively, the aims outlined in this proposal will take advantage of unique
tools and resources to yield novel insights into mobile element insertions and their relationship to neurological
disease and will serve as an outstanding training opportunity for me in computational, statistical, and functional
disease genomics.
