Somatic coding mutations in human induced pluripotent stem cells

被引:917
作者
Gore, Athurva [3 ,4 ]
Li, Zhe [3 ,4 ]
Fung, Ho-Lim [3 ,4 ]
Young, Jessica E. [1 ,2 ]
Agarwal, Suneet [5 ,6 ]
Antosiewicz-Bourget, Jessica [7 ]
Canto, Isabel [1 ,2 ]
Giorgetti, Alessandra [8 ]
Israel, Mason A. [1 ,2 ]
Kiskinis, Evangelos [9 ]
Lee, Je-Hyuk [10 ]
Loh, Yuin-Han [5 ,6 ]
Manos, Philip D. [5 ,6 ]
Montserrat, Nuria [8 ]
Panopoulos, Athanasia D. [11 ]
Ruiz, Sergio [11 ]
Wilbert, Melissa L. [1 ,2 ]
Yu, Junying [7 ]
Kirkness, Ewen F. [12 ]
Izpisua Belmonte, Juan Carlos [8 ,11 ]
Rossi, Derrick J. [13 ]
Thomson, James A. [7 ]
Eggan, Kevin [9 ]
Daley, George Q. [5 ,6 ]
Goldstein, Lawrence S. B. [1 ,2 ]
Zhang, Kun [3 ,4 ]
机构
[1] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Howard Hughes Med Inst, La Jolla, CA 92093 USA
[3] Univ Calif San Diego, Inst Genom Med, Dept Bioengn, La Jolla, CA 92093 USA
[4] Univ Calif San Diego, Inst Engn Med, La Jolla, CA 92093 USA
[5] Childrens Hosp Boston, Div Pediat Hematol Oncol, Boston, MA 02115 USA
[6] Dana Farber Canc Inst, Boston, MA 02115 USA
[7] Univ Wisconsin, Dept Anat, Madison, WI 53705 USA
[8] Ctr Regenerat Med, Barcelona 08003, Spain
[9] Harvard Univ, Howard Hughes Med Inst, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA
[10] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02135 USA
[11] Salk Inst Biol Studies, La Jolla, CA 92037 USA
[12] J Craig Venter Inst, Rockville, MD 20850 USA
[13] Childrens Hosp Boston, Immune Dis Inst, Boston, MA 02115 USA
关键词
FIBROBLASTS; GENERATION; EFFICIENT; VARIANTS;
D O I
10.1038/nature09805
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:63 / U76
页数:9
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