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Substantial somatic genomic variation and selection for BCOR mutations in human induced pluripotent stem cells.

Accepted version
Peer-reviewed

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Abstract

We explored human induced pluripotent stem cells (hiPSCs) derived from different tissues to gain insights into genomic integrity at single-nucleotide resolution. We used genome sequencing data from two large hiPSC repositories involving 696 hiPSCs and daughter subclones. We find ultraviolet light (UV)-related damage in ~72% of skin fibroblast-derived hiPSCs (F-hiPSCs), occasionally resulting in substantial mutagenesis (up to 15 mutations per megabase). We demonstrate remarkable genomic heterogeneity between independent F-hiPSC clones derived during the same round of reprogramming due to oligoclonal fibroblast populations. In contrast, blood-derived hiPSCs (B-hiPSCs) had fewer mutations and no UV damage but a high prevalence of acquired BCOR mutations (26.9% of lines). We reveal strong selection pressure for BCOR mutations in F-hiPSCs and B-hiPSCs and provide evidence that they arise in vitro. Directed differentiation of hiPSCs and RNA sequencing showed that BCOR mutations have functional consequences. Our work strongly suggests that detailed nucleotide-resolution characterization is essential before using hiPSCs.

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Journal Title

Nat Genet

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Journal ISSN

1061-4036
1546-1718

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Publisher

Springer Science and Business Media LLC

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Except where otherwised noted, this item's license is described as All Rights Reserved
Sponsorship
Cancer Research UK (23916)
Cancer Research UK (23433)
Medical Research Council (MR/R015724/1)
Dr. Josef Steiner Cancer Foundation (Award 2019)
Wellcome Trust (109915_A_15_Z)
This work was funded by Cancer Research UK (CRUK) Advanced Clinician Scientist Award (C60100/A23916), Dr Josef Steiner Cancer Research Award 2019, Medical Research Council (MRC) Grant-in-Aid to the MRC Cancer unit, CRUK Pioneer Award and Wellcome Intermediate Clinical Fellowship (WT100183) and supported by NIHR-BRC Cambridge core grant (BRC-125-20014) and UK Regenerative Medicine Platform (MR/R015724/1). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.