Autism spectrum disorder (ASD) has a complex genetic architecture, yet a significant fraction of cases remain unexplained. Repetitive elements are an underexplored source of genetic and regulatory variation with potential relevance to ASD. Among these, Alu elements, primate-specific transposable elements, have recently emerged as active regulators of gene expression. Preliminary work on the current project shows that neurodevelopmental and psychiatric disorder risk variants with validated enhancer activity are strongly and selectively enriched in Alu repeats, suggesting a novel class of regulatory elements contributing to disease risk. Complementing this, evidence from fragile X syndrome highlights how repeat-induced epigenetic misregulation and genome instability can directly drive neurodevelopmental pathology.

Building on these findings, Hyejung Won and Hungoo Lee propose an Alu-centric analysis to uncover novel genetic risk factors for ASD. They will identify de novo rare and common non-coding ASD variants within Alu elements to test whether these variants disrupt key regulatory motifs of Alu elements. They will also quantify enrichment of repetitive elements, including Alu repeats, in ASD genomes compared to unaffected family members, using whole-genome sequencing data from the SFARI base. Furthermore, they will map ASD-associated Alu variants to target genes using enhancer-promoter RNA and chromatin interaction profiles, thereby assessing whether these variants alter the regulation of genes implicated in ASD and other neurodevelopmental disorders. Genes associated with repetitive-element mediated variation will be cross-examined with transcriptomic data from matched ASD cohorts to pinpoint biologically relevant pathways.

This project introduces repetitive elements as a previously overlooked but potentially critical contributor to ASD pathogenesis. By identifying a new class of regulatory variants embedded within Alu and other repeat elements, Won and Lee will shed light on the unexplored genetic architecture underlying ASD, reveal key neurodevelopmental pathways disrupted by repeat-associated variants and lay the groundwork for improved patient stratification and the discovery of novel therapeutic targets.