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Substantial somatic genomic variation and selection for BCOR mutations in human induced pluripotent stem cells
- Publication Year :
- 2022
- Publisher :
- Springer Science and Business Media LLC, 2022.
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Abstract
- Funder: Dr Josef Steiner Cancer Research Award 2019, Medical Research Council (MRC) Grant-in-Aid to the MRC Cancer unit, CRUK Pioneer Award<br />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.
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....f11de0e70f379fc9231097abd5674f6b