Increased Neural Progenitor Proliferation in a hiPSC Model of Autism Induces Replication Stress-Associated Genome Instability

The association between macrocephaly and autism spectrum disorder (ASD) suggests that the mechanisms underlying excessive neural growth could contribute to ASD pathogenesis. Consistently, neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSCs) of ASD individuals with early developmental brain enlargement are inherently more proliferative than control NPCs. Here, we show that hiPSC-derived NPCs from ASD individuals with macrocephaly display an altered DNA replication program and increased DNA damage. When compared with the control NPCs, high-throughput genome-wide translocation sequencing (HTGTS) demonstrates that ASD-derived NPCs harbored elevated DNA double-strand breaks in replication stress-susceptible genes, some of which are associated with ASD pathogenesis. Our results provide a mechanism linking hyperproliferation of NPCs with the pathogenesis of ASD by disrupting long neural genes involved in cell-cell adhesion and migration. [Display omitted] •NPCs derived from macrocephalic ASD patients exhibit replication stress•Replication stress induces replication-transcription conflicts•Replication stress induces DSB hotspots in genes in human NPCs•ASD-derived NPCs show aberrant adherens junctions, apical polarity, and migration Replication stress poses threats to genome stability. Wang et al. show that macrocephalic ASD patient-specific neural progenitor cells display increased DNA damage in a group of long neural genes vulnerable to replication stress, some of which are associated with the pathogenesis of ASD.