Transposable Elements in Health and Disease

Abstract

Transposable elements are DNA sequences that can move within the genome. They play a pivotal role in genomic variability in humans and can cause diseases. Their repetitive nature requires specific computational algorithms to detect new retrotransposon insertions with high sensitivity. Therefore, they are often overlooked in clinical testing and basic research. This thesis intends to systematically determine the impact of transposable elements in certain neurological disorders and the healthy brain. The first main aim of this work was to identify the role of retrotransposons in autism spectrum disorder (ASD). We analyzed whole-genome sequencing data from 2,288 families with an individual with ASD. This large cohort provided the opportunity to study the frequency of retrotransposons in healthy parental individuals as well. We detected 86,154 polymorphic retrotransposon insertions, most of which were novel, and 158 de novo insertions. We obtained precise estimates of 1 de novo insertion per 29, 104, and 192 births for Alu, L1, and SVA, respectively. As expected, rates of de novo retrotransposition were similar between individuals with ASD and their unaffected siblings. The main finding from this analysis was that ASD cases showed more de novo L1 insertions in ASD genes. Here, we identified a candidate causal de novo insertion and exonic insertions in loss-of-function genes. Our second main aim was to study the rates of somatic retrotransposition in healthy aging brain cells and neurodegeneration. Rates of somatic retrotransposition in the brain have been controversial. The work presented here supports the argument that somatic retrotransposition is rare in the brain in healthy individuals and the neurological disorders studied here. We hoped that this research will clarify previous conflicting data, despite technical issues that still prevent us from detecting retrotransposons in a sensitive and precise manner in single cells. This work offers important insights into germline and somatic retrotransposition. Although retrotransposition rates are modest, their impact can be substantial. This work highlights the importance of using high-throughput computational tools to study rare variants, including transposable element insertions.