Substantial somatic genomic variation and selection for BCOR mutations in human induced pluripotent stem cells
| Autor: | Rouhani, Foad J., Zou, Xueqing, Danecek, Petr, Badja, Cherif, Amarante, Tauanne Dias, Koh, Gene, Wu, Qianxin, Memari, Yasin, Durbin, Richard, Martincorena, Inigo, Bassett, Andrew R., Gaffney, Daniel, Nik-Zainal, Serena |
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| Přispěvatelé: | Rouhani, Foad J [0000-0002-2334-1305], Zou, Xueqing [0000-0003-1143-1028], Badja, Cherif [0000-0003-3736-672X], Martincorena, Inigo [0000-0003-1122-4416], Bassett, Andrew R [0000-0003-1632-9137], Gaffney, Daniel [0000-0002-1529-1862], Nik-Zainal, Serena [0000-0001-5054-1727], Apollo - University of Cambridge Repository, Rouhani, Foad J. [0000-0002-2334-1305], Bassett, Andrew R. [0000-0003-1632-9137] |
| Rok vydání: | 2022 |
| Předmět: | |
| Popis: | Funder: Dr Josef Steiner Cancer Research Award 2019, Medical Research Council (MRC) Grant-in-Aid to the MRC Cancer unit, CRUK Pioneer Award 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. |
| Databáze: | OpenAIRE |
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