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Somatic coding mutations in human induced pluripotent stem cells

Author

Listed:
  • Athurva Gore

    (Institute for Genomic Medicine and Institute of Engineering in Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA)

  • Zhe Li

    (Institute for Genomic Medicine and Institute of Engineering in Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA)

  • Ho-Lim Fung

    (Institute for Genomic Medicine and Institute of Engineering in Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA)

  • Jessica E. Young

    (University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA)

  • Suneet Agarwal

    (Children’s Hospital Boston and Dana Farber Cancer Institute)

  • Jessica Antosiewicz-Bourget

    (University of Wisconsin-Madison)

  • Isabel Canto

    (University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA)

  • Alessandra Giorgetti

    (Center of Regenerative Medicine, 08003 Barcelona, Spain)

  • Mason A. Israel

    (University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA)

  • Evangelos Kiskinis

    (Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard University)

  • Je-Hyuk Lee

    (Harvard Medical School)

  • Yuin-Han Loh

    (Children’s Hospital Boston and Dana Farber Cancer Institute)

  • Philip D. Manos

    (Children’s Hospital Boston and Dana Farber Cancer Institute)

  • Nuria Montserrat

    (Center of Regenerative Medicine, 08003 Barcelona, Spain)

  • Athanasia D. Panopoulos

    (Salk Institute for Biological Studies)

  • Sergio Ruiz

    (Salk Institute for Biological Studies)

  • Melissa L. Wilbert

    (University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA)

  • Junying Yu

    (University of Wisconsin-Madison)

  • Ewen F. Kirkness

    (The J. Craig Venter Institute)

  • Juan Carlos Izpisua Belmonte

    (Center of Regenerative Medicine, 08003 Barcelona, Spain
    Salk Institute for Biological Studies)

  • Derrick J. Rossi

    (Immune Disease Institute, Children’s Hospital Boston)

  • James A. Thomson

    (University of Wisconsin-Madison)

  • Kevin Eggan

    (Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard University)

  • George Q. Daley

    (Children’s Hospital Boston and Dana Farber Cancer Institute)

  • Lawrence S. B. Goldstein

    (University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA)

  • Kun Zhang

    (Institute for Genomic Medicine and Institute of Engineering in Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA)

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.

Suggested Citation

  • Athurva Gore & Zhe Li & Ho-Lim Fung & Jessica E. Young & Suneet Agarwal & Jessica Antosiewicz-Bourget & Isabel Canto & Alessandra Giorgetti & Mason A. Israel & Evangelos Kiskinis & Je-Hyuk Lee & Yuin-, 2011. "Somatic coding mutations in human induced pluripotent stem cells," Nature, Nature, vol. 471(7336), pages 63-67, March.
  • Handle: RePEc:nat:nature:v:471:y:2011:i:7336:d:10.1038_nature09805
    DOI: 10.1038/nature09805
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    Cited by:

    1. Maria Arez & Melanie Eckersley-Maslin & Tajda Klobučar & João Gilsa Lopes & Felix Krueger & Annalisa Mupo & Ana Cláudia Raposo & David Oxley & Samantha Mancino & Anne-Valerie Gendrel & Bruno Bernardes, 2022. "Imprinting fidelity in mouse iPSCs depends on sex of donor cell and medium formulation," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    2. Patricia Gerdes & Sue Mei Lim & Adam D. Ewing & Michael R. Larcombe & Dorothy Chan & Francisco J. Sanchez-Luque & Lucinda Walker & Alexander L. Carleton & Cini James & Anja S. Knaupp & Patricia E. Car, 2022. "Retrotransposon instability dominates the acquired mutation landscape of mouse induced pluripotent stem cells," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. Ryoko Araki & Tomo Suga & Yuko Hoki & Kaori Imadome & Misato Sunayama & Satoshi Kamimura & Mayumi Fujita & Masumi Abe, 2024. "iPS cell generation-associated point mutations include many C > T substitutions via different cytosine modification mechanisms," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    4. Oliver J. Ziff & Jacob Neeves & Jamie Mitchell & Giulia Tyzack & Carlos Martinez-Ruiz & Raphaelle Luisier & Anob M. Chakrabarti & Nicholas McGranahan & Kevin Litchfield & Simon J. Boulton & Ammar Al-C, 2023. "Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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