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Genetic background drives transcriptional variation in human induced pluripotent stem cells.

Published version
Peer-reviewed

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Type

Article

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Authors

Kumasaka, Natsuhiko 
de Brito, Miguel Cardoso 

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.

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Keywords

Adult, Base Sequence, Cell Differentiation, Cells, Cultured, Embryonic Stem Cells, Endothelial Cells, Epigenomics, Female, Fibroblasts, Humans, Induced Pluripotent Stem Cells, Keratinocytes, Male, Sequence Alignment, Sequence Analysis, RNA, Transcription, Genetic

Journal Title

PLoS Genet

Conference Name

Journal ISSN

1553-7390
1553-7404

Volume Title

10

Publisher

Public Library of Science (PLoS)
Sponsorship
Engineering and Physical Sciences Research Council (TS/H001220/1)