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Cell Stem Cell. 2020 Feb 6;26(2):221-233.e6. doi: 10.1016/j.stem.2019.12.013. Epub 2020 Jan 30.

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

Author information

1
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA 92037, USA; Neurobiology Section, Division of Biological Sciences, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA.
2
Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Genetics and Pediatrics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
3
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
4
Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
5
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA 92037, USA; Neurobiology Section, Division of Biological Sciences, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA. Electronic address: gage@salk.edu.

Abstract

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.

KEYWORDS:

DNA double-strand breaks; autism spectrum disorder; cell-cell adhesion; genome instability; high-throughput genome-wide translocation sequencing; migration; neural progenitor cells; replication stress; replication-transcription conflicts

PMID:
32004479
DOI:
10.1016/j.stem.2019.12.013

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