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

Published: 8 February 2022| Version 1 | DOI: 10.17632/6rfc2xrnyd.1
Serena Nik-Zainal


Human Induced Pluripotent Stem Cells (hiPSC) are an established patient-specific model system where opportunities are emerging for cell-based therapies. We compared and contrasted hiPSCs derived from different tissues in the same individual and across two large hiPSC cell repositories. We show extensive single-nucleotide mutagenesis in all hiPSC lines, although fibroblast-derived hiPSCs (F-hiPSCs) are particularly heavily mutagenized by ultraviolet (UV)-related damage. We analysed genome sequencing data on 454 F-hiPSCs, 101 blood-derived hiPSCs (B-hiPSCs) and 141 B-hiPSC derived subclones, as well as transcriptional data on 78 B-hiPSCs to gain further insights. Across 324 whole genome sequenced (WGS) F-hiPSCs derived by the Human Induced Pluripotent Stem Cell Initiative (HipSci), UV-related damage is present in ~72% of cell lines, sometimes resulting in substantial mutagenesis (range 0.25-15 per Mb). Furthermore, we find remarkable genomic heterogeneity between independent F-hiPSC clones derived during the same round of reprogramming, due to oligoclonal populations within fibroblasts. B-hiPSCs showed lower levels of genome-wide mutations (range 0.28-1.4 per Mb), no UV damage, but a strikingly high prevalence of acquired BCOR mutations in ~25% of lines. Genome-wide selection analysis revealed strong selection pressure for BCOR mutations in F-iPSCs and B-iPSCs. Directed differentiation experiments and RNA sequencing showed that BCOR mutations have functional consequences in affected B-hiPSCs. All hiPSCs had otherwise stable, diploid genomes on karyotypic pre-screening. Our work strongly suggests detailed nucleotide-resolution characterization is required prior to using hiPSCs for disease modelling or clinical applications.


Steps to reproduce

Please see Methods of the paper for details.


University of Cambridge


Induced Pluripotent Stem Cell, DNA Mutation