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Cited by 1,273Pluripotent Stem Cells ResearchCRISPR and Genetic EngineeringEpigenetics and DNA Methylation

Somatic coding mutations in human induced pluripotent stem cells

Open access
Gore, Athurva, Li, Zhe, Fung, Ho-Lim, Young, Jessica E., Agarwal, Suneet, Antosiewicz-Bourget, Jessica, Canto, Isabel, Giorgetti, Alessandra +18 more·2011·Nature
DOI 10.1038/nature09805PMC PMC3074107
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Abstract

Defined transcription factors can induce epigenetic reprogramming of adult mammalian cells into induced pluripotent stem cells. Although DNA factors are integrated during some reprogramming methods, it is unknown whether the genome remains unchanged at the single nucleotide level. Here we show that 22 human induced pluripotent stem (hiPS) cell lines reprogrammed using five different methods each contained an average of five protein-coding point mutations in the regions sampled (an estimated six protein-coding point mutations per exome). The majority of these mutations were non-synonymous, nonsense or splice variants, and were enriched in genes mutated or having causative effects in cancers. At least half of these reprogramming-associated mutations pre-existed in fibroblast progenitors at low frequencies, whereas the rest occurred during or after reprogramming. Thus, hiPS cells acquire genetic modifications in addition to epigenetic modifications. Extensive genetic screening should become a standard procedure to ensure hiPS cell safety before clinical use.

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  • Reprogramming and genetic engineering have been implicated in increasing genomic variation.

    “To further complicate this issue, reprogramming and genetic engineering itself have also been implicated in increasing genomic variation.169–171”

    From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [169]

    The Abstract reports coding mutations in reprogrammed human iPS cells, and the Discussion says that pre-existing and new mutations contribute to their high mutational load. The Discussion also cautions that the data do not establish reprogramming itself as mutagenic; it points to selection, colony-picking, and culture as possible contributors. The paper does not establish the separate claim that genetic engineering increases genomic variation. (LLM, conf=0.85)

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References 41 · Cited by 1,273

Research works printed but not linked: 30

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Authors
Gore, A., Li, Z., Fung, H.-L., Young, J. E., Agarwal, S., Antosiewicz-Bourget, J., Canto, I., Giorgetti, A., Israel, M. A., Kiskinis, E., Lee, J.-H., Loh, Y.-H., Manos, P. D., Montserrat, N., Panopoulos, A. D., Ruiz, S., Wilbert, M. L., Yu, J., Kirkness, E. F., Belmonte, J. C. I., Rossi, D. J., Thomson, J. A., Eggan, K., Daley, G. Q., Goldstein, L. S. B., & Zhang, K.
Affiliations
  • University of California San Diego (US)
  • Howard Hughes Medical Institute (US)
  • Boston Children's Hospital (US)
  • Center of Regenerative Medicine in Barcelona (ES)
  • Harvard University (US)
  • Salk Institute for Biological Studies (US)
  • University of Wisconsin–Madison (US)
  • J. Craig Venter Institute (US)
Corresponding author
  • Goldstein, Lawrence S. B.
  • Zhang, Kun
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2011-03
Volume
471
Issue
7336
Pages
63-67
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature09805
PMC
PMC3074107
OpenAlex
W2059378220
Cited by
1,273
References
41
Citations by year
2026: 20 · 2025: 23 · 2024: 30 · 2023: 29 · 2022: 36 · 2021: 59 · 2020: 58 · 2019: 45 · 2018: 54 · 2017: 81 · 2016: 87 · 2015: 101 · 2014: 130 · 2013: 147 · 2012: 207
FWCI
84.09
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
Funders
  • Howard Hughes Medical Institute
  • National Heart, Lung, and Blood Institute (U01HL100001, K08HL089150, R01HL094963)
  • National Institute of General Medical Sciences (T32GM008666)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
induced pluripotent stem cells, somatic mutations, point mutations, nonsense mutation, splice variants, cancer genes, epigenetic reprogramming, mutational burden, copy number variation, DNA methylation, somatic cell reprogramming
MeSH terms
Cells, Cultured, DNA Mutational Analysis, Epistasis, Genetic, Fibroblasts, Humans, Male, Middle Aged, Models, Genetic, Mutagenesis, Open Reading Frames, Point Mutation, Induced Pluripotent Stem Cells, Cellular Reprogramming

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