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Copy number variation and selection during reprogramming to pluripotency

Author

Listed:
  • Samer M. Hussein

    (Samuel Lunenfeld Research Institute, Toronto, Ontario M5T 3H7, Canada
    Research Program Unit, Molecular Neurology, Biomedicum Stem Cell Center, University of Helsinki)

  • Nizar N. Batada

    (Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada)

  • Sanna Vuoristo

    (Research Program Unit, Molecular Neurology, Biomedicum Stem Cell Center, University of Helsinki)

  • Reagan W. Ching

    (The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada)

  • Reija Autio

    (Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku 20520, Finland
    Tampere University of Technology, Tampere 33101, Finland)

  • Elisa Närvä

    (Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku 20520, Finland)

  • Siemon Ng

    (Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada)

  • Michel Sourour

    (Samuel Lunenfeld Research Institute, Toronto, Ontario M5T 3H7, Canada)

  • Riikka Hämäläinen

    (Samuel Lunenfeld Research Institute, Toronto, Ontario M5T 3H7, Canada
    Research Program Unit, Molecular Neurology, Biomedicum Stem Cell Center, University of Helsinki)

  • Cia Olsson

    (Research Program Unit, Molecular Neurology, Biomedicum Stem Cell Center, University of Helsinki)

  • Karolina Lundin

    (Research Program Unit, Molecular Neurology, Biomedicum Stem Cell Center, University of Helsinki)

  • Milla Mikkola

    (Research Program Unit, Molecular Neurology, Biomedicum Stem Cell Center, University of Helsinki)

  • Ras Trokovic

    (Research Program Unit, Molecular Neurology, Biomedicum Stem Cell Center, University of Helsinki)

  • Michael Peitz

    (Institute of Reconstructive Neurobiology, Life and Brain Center, University of Bonn and Hertie Foundation)

  • Oliver Brüstle

    (Institute of Reconstructive Neurobiology, Life and Brain Center, University of Bonn and Hertie Foundation)

  • David P. Bazett-Jones

    (The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada)

  • Kari Alitalo

    (Molecular Cancer Biology Laboratory, University of Helsinki and Helsinki University Central Hospital, Helsinki FI-00014, Finland)

  • Riitta Lahesmaa

    (Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku 20520, Finland)

  • Andras Nagy

    (Samuel Lunenfeld Research Institute, Toronto, Ontario M5T 3H7, Canada
    University of Toronto, Toronto, Ontario M5S 1A8, Canada)

  • Timo Otonkoski

    (Research Program Unit, Molecular Neurology, Biomedicum Stem Cell Center, University of Helsinki
    Children’s Hospital, University of Helsinki, Helsinki FI-00029, Finland)

Abstract

The mechanisms underlying the low efficiency of reprogramming somatic cells into induced pluripotent stem (iPS) cells are poorly understood. There is a clear need to study whether the reprogramming process itself compromises genomic integrity and, through this, the efficiency of iPS cell establishment. Using a high-resolution single nucleotide polymorphism array, we compared copy number variations (CNVs) of different passages of human iPS cells with their fibroblast cell origins and with human embryonic stem (ES) cells. Here we show that significantly more CNVs are present in early-passage human iPS cells than intermediate passage human iPS cells, fibroblasts or human ES cells. Most CNVs are formed de novo and generate genetic mosaicism in early-passage human iPS cells. Most of these novel CNVs rendered the affected cells at a selective disadvantage. Remarkably, expansion of human iPS cells in culture selects rapidly against mutated cells, driving the lines towards a genetic state resembling human ES cells.

Suggested Citation

  • Samer M. Hussein & Nizar N. Batada & Sanna Vuoristo & Reagan W. Ching & Reija Autio & Elisa Närvä & Siemon Ng & Michel Sourour & Riikka Hämäläinen & Cia Olsson & Karolina Lundin & Milla Mikkola & Ras , 2011. "Copy number variation and selection during reprogramming to pluripotency," Nature, Nature, vol. 471(7336), pages 58-62, March.
    • Handle: RePEc:nat:nature:v:471:y:2011:i:7336:d:10.1038_nature09871
    DOI: 10.1038/nature09871
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    Cited by:

    1. 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.
    2. 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.
    3. Kai Kammers & Margaret A Taub & Ingo Ruczinski & Joshua Martin & Lisa R Yanek & Alyssa Frazee & Yongxing Gao & Dixie Hoyle & Nauder Faraday & Diane M Becker & Linzhao Cheng & Zack Z Wang & Jeff T Leek, 2017. "Integrity of Induced Pluripotent Stem Cell (iPSC) Derived Megakaryocytes as Assessed by Genetic and Transcriptomic Analysis," PLOS ONE, Public Library of Science, vol. 12(1), pages 1-16, January.

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