Copy number variation and selection during reprogramming to pluripotency

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 Trokovic, Michael Peitz, Oliver Brüstle, David P. Bazett-Jones, Kari Alitalo, Riitta Lahesmaa, Andras Nagy () and Timo Otonkoski ()
Additional contact information
Samer M. Hussein: Samuel Lunenfeld Research Institute, Toronto, Ontario M5T 3H7, Canada
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
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
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
Timo Otonkoski: Research Program Unit, Molecular Neurology, Biomedicum Stem Cell Center, University of Helsinki

Nature, 2011, vol. 471, issue 7336, 58-62

Abstract: 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.

Date: 2011
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DOI: 10.1038/nature09871

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