Using Deep Learning to Characterize Somatic Mobile Element Insertions in Neurodevelopmental Disorders

Mobile elements (MEs) are segments of DNA that can change genomic positions, leading to profound impacts on the structure and function of the host genome. Active MEs in the human genome can undergo retrotransposition to create novel mobile elementinsertion (MEI) mutations in both germline and somatic tissues. Somatic retrotransposition of active L1 elements occurs during human brain development and is hypothesized to contribute to neurodevelopmental disorders (NDDs) by affecting theexpression level or the coding sequences of disease-associated genes. I previously developed a machine learning-based approach (RetroSom), that allowed, for the first time, to detect somatic L1 and Alu retrotransposition with standard whole-genomesequencing. When applied to brain tissues from two schizophrenia-controls pairs, I identified two L1 insertions in known schizophrenia-associated genes that likely occurred in fetal brain development. However, RetroSom has limited sensitivity towardlow-frequency MEIs due to the limited training data. Furthermore, the retrotransposition rate in normal and NDD brains is still unknown due to the small number of subjects. Finally, the somatic MEIs were discovered in the adult brain, and their functional consequences on fetal brain development are poorly understood. This project aims to investigate the detection, quantitation, and functional perturbation of somatic MEIs. We will first improve the analytical software by utilizing state-of-art deep learning techniques and 60 times more training data. We will then evaluate thebrain somatic MEIs in a cohort of 130 donors, including 9 Schizophrenia, 19 Tourette Syndrome, 59 Autism Spectrum Disorder, and 43 Healthy controls. Finally, we will model likely pathogenic MEIs in isogenic induced pluripotent cell lines (iPSCs) by genomeediting, and study the molecular and biochemical phenotypes in early development by inducing the iPSCs to brain organoids. This project will enhance and disseminate the analytic tools for detecting somatic MEIs. It will also provide direct evidence for thehypothetical mobile element activation in patients with NDDs, and illustrate the mechanisms and functional consequences of the MEIs in early brain development.