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Hotspots of De Novo Point Mutations in Induced Pluripotent Stem Cells.

Abstract

Induced pluripotent stem cells (iPSCs) are generated by direct reprogramming of somatic cells and hold great promise for novel therapies. However, several studies have reported genetic variations in iPSC genomes. Here, we investigated point mutations identified by whole-genome sequencing in mouse and human iPSCs in the context of epigenetic status. In contrast to disease-causing single-nucleotide polymorphisms, de novo point mutations introduced during reprogramming were underrepresented in protein-coding genes and in open chromatin regions, including transcription factor binding sites. Instead, these mutations occurred preferentially in structurally condensed lamina-associated heterochromatic domains, suggesting that chromatin organization is a factor that can bias the regional mutation rate in iPSC genomes. Mutation signature analysis implicated oxidative stress associated with reprogramming as a likely cause of point mutations. Altogether, our study provides deeper understanding of the mutational landscape of iPSC genomes, paving an important way toward the translation of iPSC-based cell therapy.

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  • Authors+Show Affiliations

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    Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan; Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.

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    Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.

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    Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.

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    Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.

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    Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.

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    Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.

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    Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan; RIKEN Preventive Medicine and Diagnosis Innovation Program, Yokohama, Kanagawa 230-0045, Japan; Preventive Medicine and Applied Genomics Unit, RIKEN Advanced Center for Computing and Communication, Yokohama, Kanagawa 230-0045, Japan.

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    RIKEN Preventive Medicine and Diagnosis Innovation Program, Yokohama, Kanagawa 230-0045, Japan.

    Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan; RIKEN Preventive Medicine and Diagnosis Innovation Program, Yokohama, Kanagawa 230-0045, Japan. Electronic address: yasuhiro.murakawa@riken.jp.

    Source

    Cell reports 21:2 2017 Oct 10 pg 308-315

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    29020618