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

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Foad Rouhani Xueqing Zou Petr Danecek Cherif Badja Tauanne Dias Amarante Gene Koh Qianxin Wu Yasin Memari Richard Durbin Inigo Martincorena Andrew R Bassett Daniel Gaffney Serena Nik-Zainal
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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.

Journal details

Journal Nature Genetics
Volume 54
Issue number 9
Pages 1406-1416
Available online
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Publisher website (DOI) 10.1038/s41588-022-01147-3
Europe PubMed Central 35953586
Pubmed 35953586

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