An expanded repertoire of brain microexons is directly impacted by autism-associated genetic variation

ABSTRACT: A major challenge in understanding autism spectrum disorder (ASD) is to establish the underlying convergent genetic and molecular mechanisms. Neuronal microexons represent a highly conserved class of alternative splicing event and are enriched in genes with diverse and critical functions in nervous system biology. Previous studies have provided evidence that microexon splicing is disrupted in the brains of approximately one-third of ASD individuals, in part as a consequence of altered neuronal activity. Moreover, mice with microexon splicing deficiencies display multiple ASD-like phenotypes. However, the full landscape of microexons is not known, and whether these exons are directly impacted human genetic variation has not been previously investigated. Through extensive profiling of brain RNA-Seq data, we have discovered several hundred new neuronal microexons, including many that have highly specific neuronal subtype-specific splicing patterns, and others with the potential to control gene expression by activating nonsense-mediated mRNA decay. By developing a machine learning model that predicts neuronally-spliced microexons from genome sequence, we have defined critical regulatory elements surrounding the expanded repertoire of microexons. Using this model, we identify rare and common variants that are predicted to alter microexon splicing patterns in approximately 30% of ASD-affected individuals, relative to their unaffected siblings, with rare variants having the strongest impact. These variants are mostly detected in idiopathic individuals and converge on a subset of microexons concentrated in synaptic and additional ASD-linked genes, but also in genes not previously linked to autism. Our results collectively define an expanded repertoire of neuronal microexons, delineate their regulatory code, and pinpoint genetic variants that impact their splicing, with implications for the disruption of functions central to neuronal biology and brain disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE268269 | GEO | 2026/08/11

REPOSITORIES: GEO