Abstract

Human Induced Pluripotent Stem Cells (hiPSC) are an established patient-specific model system where opportunities are emerging for cell-based therapies. We studied the mutational landscape of hiPSCs derived from different tissues, at single-nucleotide resolution, across hundreds of cell lines including sub-clones. The majority of fibroblast derived hiPSC (72%) were heavily mutagenized with UV-related damage and there was evidence of genomic heterogeneity amongst hiPSCs derived in the same reprogramming experiment, due to oligoclonal fibroblast populations. Whilst blood derived hiPSCs had a lower mutational burden, we found frequent recurrent mutations in BCOR (26.9% of lines) which our findings suggested were acquired by hiPSCs during in vitro culture. We explored the functional consequences of BCOR mutated hiPSCs and demonstrated global transcriptional changes and impaired differentiation into neural lineages. Our work highlights the importance of comprehensive and high resolution genomic characterisation of hiPSC lines prior to research or clinical use.