1. Neuroscience
  2. Stem Cells and Regenerative Medicine
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16p11.2 microdeletion imparts transcriptional alterations in human iPSC-derived models of early neural development

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Cite this article as: eLife 2020;9:e58178 doi: 10.7554/eLife.58178

Abstract

Microdeletions and microduplications of the 16p11.2 chromosomal locus are associated with syndromic neurodevelopmental disorders and reciprocal physiological conditions such as macro/microcephaly and high/low body mass index. To facilitate cellular and molecular investigations into these phenotypes, 65 clones of human induced pluripotent stem cells (hiPSCs) were generated from 13 individuals with 16p11.2 copy number variations (CNVs). To ensure these cell lines were suitable for downstream mechanistic investigations, a customizable bioinformatic strategy for the detection of random integration and expression of reprogramming vectors was developed and leveraged towards identifying a subset of 'footprint'-free hiPSC clones. Transcriptomic profiling of cortical neural progenitor cells derived from these hiPSCs identified alterations in gene expression patterns which precede morphological abnormalities reported at later neurodevelopmental stages. Interpreting clinical information—available with the cell lines by request from the Simons Foundation Autism Research Initiative—with this transcriptional data revealed disruptions in gene programs related to both nervous system function and cellular metabolism. As demonstrated by these analyses, this publicly available resource has the potential to serve as a powerful medium for probing the etiology of developmental disorders associated with 16p11.2 CNVs.

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Author details

  1. Julien G Roth

    Department of Neurosurgery and The Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7560-3258
  2. Kristin L Muench

    Department of Neurosurgery, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Aditya Asokan

    Department of Neurosurgery, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Victoria M Mallett

    Department of Neurosurgery, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Hui Gai

    Department of Neurosurgery and The Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Yogendra Verma

    Department of Neurosurgery and The Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Stephen Weber

    Department of Neurosurgery, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Carol Charlton

    Department of Neurosurgery, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Jonas L Fowler

    Department of Neurosurgery and The Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Kyle M Loh

    Department of Neurosurgery and The Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Ricardo E Dolmetsch

    Department of Neurobiology, Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2738-8338
  12. Theo D Palmer

    Department of Neurosurgery, Stanford University School of Medicine, Stanford, United States
    For correspondence
    tpalmer@stanford.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6266-1862

Funding

National Institute of Mental Health (1R01MH108660)

  • Theo D Palmer

Simons Foundation SFARI (SFARI Research Contract)

  • Ricardo E Dolmetsch

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Lee L Rubin, Harvard Stem Cell Institute, Harvard University, United States

Publication history

  1. Received: April 22, 2020
  2. Accepted: November 9, 2020
  3. Accepted Manuscript published: November 10, 2020 (version 1)

Copyright

? 2020, Roth et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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