Hussein, SM, Batada, NN, Vuoristo, S, Ching, RW, Autio, R, Närvä, E et al.. Copy number variation and selection during reprogramming to pluripotency. Nature 471: 58-62

Samuel Lunenfeld Research Institute, Toronto, Ontario M5T 3H7, Canada.
Nature (Impact Factor: 41.46). 03/2011; 471(7336):58-62. DOI: 10.1038/nature09871
Source: PubMed


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.

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    • "However, recent reports imply that genetic and epigenetic aberrations occur during the derivation and reprogramming processes (Liang and Zhang, 2013; Pera, 2011; Lund et al., 2012). These range from chromosomal abnormalities (Laurent et al., 2011),''de novo'' copy number variations (CNVs) (Hussein et al., 2011), and point mutations in protein-coding regions (Gore et al., 2011). Such changes may complicate their use for regenerative medicine purposes (Bayart and Cohen-Haguenauer, 2013). "
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    • "Several research groups have found that those proclaimed induced stem cells had more abnormal chromosomes [7] , more protein-coding point mutations [8] , more abnormal epigenomic reprogramming and DNA methylation [9] [10] [11] , and more copy number variations [12] [13] than normal somatic cells or embryonic stem cells; those supposed induced pluripotent stem cells had more chances to develop tumors, and they could form tumors more rapidly than human embryonic stem cells [14] . "
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    • "[96] of transcriptome data (Illumina HT-12v4 array) and by the capacity to form embryoid bodies that spontaneously differentiate into the three germ layers (ectoderm, endoderm, and mesoderm) (Fig. 2B). More extensive characterization includes aberrant genetic/epigenetic modification [97] , reprogramming-induced point mutations [98] and CNVs [99] , Fig. 2 "
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