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Open Access Research article

Genome-wide CNV analysis in mouse induced pluripotent stem cells reveals dosage effect of pluripotent factors on genome integrity

Yulin Chen1, Lin Guo2, Jiekai Chen2, Xiangjie Zhao2, Weichen Zhou1, Cheng Zhang1, Jiucun Wang1, Li Jin13*, Duanqing Pei2* and Feng Zhang13*

Author Affiliations

1 State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, China

2 Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China

3 Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China

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BMC Genomics 2014, 15:79  doi:10.1186/1471-2164-15-79

Published: 28 January 2014

Abstract

Background

Induced pluripotent stem cells (iPSCs) derived from somatic cells have enormous potential for clinical applications. Notably, it was recently reported that reprogramming from somatic cells to iPSCs can induce genomic copy number variation (CNV), which is one of the major genetic causes of human diseases. However it was unclear if this genome instability is dependent on reprogramming methods and/or the genetic background of donor cells. Furthermore, genome-wide CNV analysis is technically challenging and CNV data need to be interpreted with care.

Results

In order to carefully investigate the possible CNV instability during somatic reprogramming, we performed genome-wide CNV analyses with 41 mouse iPSC lines generated from the same parental donor; therefore, the donor’s genetic background can be controlled. Different reprogramming factor combinations and dosages were used for investigating potential method-dependent effects on genome integrity. We detected 63 iPSC CNVs using high-resolution comparative genomic hybridization. Intriguingly, CNV rates were negatively associated with the dosages of classic factor(s). Furthermore, the use of high-performance engineered factors led to less CNVs than the classic factor(s) of the same dosage.

Conclusion

Our observations suggest that sufficient reprogramming force can protect the genome from CNV instability during the reprogramming process.

Keywords:
CNV; Genome integrity; Induced pluripotent stem cell; Reprogramming factor; Reprogramming kinetics