16p11.2 microdeletion imparts transcriptional alterations in human iPSC-derived models of early neural development
- Stanford University School of Medicine, United States
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.
Article and author information
Author details
Ricardo E Dolmetsch
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
- Lee L Rubin, Harvard Stem Cell Institute, Harvard University, United States
Publication history
- Received: April 22, 2020
- Accepted: November 9, 2020
- 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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