期刊
STEM CELLS
卷 32, 期 10, 页码 2657-2667出版社
WILEY-BLACKWELL
DOI: 10.1002/stem.1779
关键词
DNA copy number variations; Chromosomal aberrations; Induced pluripotent stem cells; Neural stem cells; DNA replication
资金
- Israel Science Foundation [47/10, 322/13]
- Minerva foundation
- Federal German Ministry for Education and Research
- Chief Scientist Office at the Israeli Ministry of Health, under the frame of ERA-Net NEURON (DISCover) [IMOS 3-00000-6785]
- Benoziyo Center for Neurological diseases
- Kekst Family Center for Medical Genetics
- David and Fela Shapell Family Center for Genetic Disorders Research
- National Institute of Neurological Disorders and Stroke (National Institutes of Health) [R01NS058529]
- Texas Children's Hospital General Clinical Research Center [M01RR00188]
- Intellectual and Developmental Disabilities Research Centers [P30HD024064]
- New York Stem Cell Foundation Robertson Innovator grant
- ERC [StG-281906]
Emergence of genomic instability is a practical issue in preparing neural stem cells (NSCs) and induced pluripotent stem cells (iPSCs). However, it is still not fully understood what the origins and mechanisms for formation are for the genomic alternations observed. Here, we studied the extent of genomic variation on the scale of individual cells originating from the same animal. We used mouse NSCs grown from embryonic cells and iPSCs generated from embryonic brain cells, B cells or fibroblasts, and performed comparative analysis with cultures of fibroblasts from the same mouse. In the first passage of these cell lines, aneuploidies were only observed for chromosomes 6, 11, 12, 19, and Y, which is overall at a rate lower than previously reported; de novo copy number variations (CNVs) were observed in 4.3% of neural iPSCs, 29% of B cell iPSCs, 10% of fibroblast iPSCs, and 1.3% of neurospheres. In contrast, propagation of these first passage cells to a later passage induced additional aneuploidies and CNVs. Breakpoint sequencing analysis suggested that the majority of the detected CNVs arose by replicative mechanisms. Interestingly, we detected identical de novo CNVs in different single cell colonies that appeared to have arisen independently from each other, which suggests a novel CNV formation mechanism in these cells. Our findings provide insights into mechanisms of CNV formation during reprogramming and suggest that replicative mechanisms for CNV formation accompany mitotic divisions.
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