title: Genetic background drives transcriptional variation in human induced pluripotent stem cells.
abstract: Human iPS cells have been generated using a diverse range of tissues from a variety of donors using different reprogramming vectors. However, these cell lines are heterogeneous, which presents a limitation for their use in disease modeling and personalized medicine. To explore the basis of this heterogeneity we generated 25 iPS cell lines under normalised conditions from the same set of somatic tissues across a number of donors. RNA-seq data sets from each cell line were compared to identify the majority contributors to transcriptional heterogeneity. We found that genetic differences between individual donors were the major cause of transcriptional variation between lines. In contrast, residual signatures from the somatic cell of origin, so called epigenetic memory, contributed relatively little to transcriptional variation. Thus, underlying genetic background variation is responsible for most heterogeneity between human iPS cell lines. We conclude that epigenetic effects in hIPSCs are minimal, and that hIPSCs are a stable, robust and powerful platform for large-scale studies of the function of genetic differences between individuals. Our data also suggest that future studies using hIPSCs as a model system should focus most effort on collection of large numbers of donors, rather than generating large numbers of lines from the same donor.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Foad
authors.initials: F
authors.lastname: Rouhani
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Natsuhiko
authors.initials: N
authors.lastname: Kumasaka
authors.affiliation: University of Cambridge, Cambridge, Cambridge, United Kingdom.
authors.forename: Miguel Cardoso
authors.initials: MC
authors.lastname: de Brito
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Allan
authors.initials: A
authors.lastname: Bradley
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; University of Cambridge, Cambridge, Cambridge, United Kingdom.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Vallier
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gaffney
mesh_terms: D000328:Adult; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology*; D042783:Endothelial Cells / Q000166:cytology; D057890:Epigenomics; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D015603:Keratinocytes / Q000166:cytology; D008297:Male; D016415:Sequence Alignment; D017423:Sequence Analysis, RNA; D014158:Transcription, Genetic / Q000235:genetics*