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Replication stress associated genome instability in the pathogenesis of autism

Abstract

The association between macrocephaly and autism spectrum disorder (ASD) suggests that the mechanisms underlying excessive neural growth could contribute to the pathogenesis of the disorder. Neural progenitor cells (NPCs) derived from induced pluripotent stem cells of ASD individuals with early developmental brain enlargement are inherently more proliferative than control NPCs. Here, we demonstrate that NPCs derived from ASD patients with macrocephaly display an altered DNA replication program and increased DNA damage. When compared to the control NPCs, high throughput genome-wide translocation sequencing demonstrates that ASD-derived NPCs harbored elevated DNA double-strand breaks in replication stress-susceptible genes, some of which are associated with the pathogenesis of ASD. Our results identify a mechanism linking hyperproliferation of NPCs with the pathogenesis of ASD by disrupting long neural genes involved in cell-cell adhesion and migration.

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