Somatic coding mutations in human induced pluripotent stem cells

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-Han Loh, Philip D. Manos, Nuria Montserrat, Athanasia D. Panopoulos, Sergio Ruiz, Melissa L. Wilbert, Junying Yu, Ewen F. Kirkness, Juan Carlos Izpisua Belmonte, Derrick J. Rossi, James A. Thomson, Kevin Eggan, George Q. Daley, Lawrence S. B. Goldstein () and Kun Zhang ()
Additional contact information
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
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

Nature, 2011, vol. 471, issue 7336, 63-67

Abstract: 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.

Date: 2011
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DOI: 10.1038/nature09805

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