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

Yulin Chen,Feng Zhang,Li Jin,Jiucun Wang,Jiekai Chen,Duanqing Pei,Cheng Zhang,Lin Guo,Xiangjie Zhao,Weichen Zhou

doi:10.1186/1471-2164-15-79

Abstract

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

Highlights

Induced pluripotent stem cells derived from somatic cells have enormous potential for clinical applications
The rates of Mouse iPSCs (miPSCs) copy number variation (CNV) between these two reprogramming methods are obviously different, suggesting that the strength of the Induced pluripotent stem cells (iPSCs) reprogramming has an effect on genome integrity
We screened the genomes of 41 miPSC lines and identified 63 CNVs across 24 genomic loci of the mouse genome (Figure 2 and Additional file 2)

Summary

Introduction

Induced pluripotent stem cells (iPSCs) derived from somatic cells have enormous potential for clinical applications. 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 It was unclear if this genome instability is dependent on reprogramming methods and/or the genetic background of donor cells. Previous CNV calls in iPSCs cannot readily distinguish between reprogramming-associated CNVs (either de novo CNV or selected mosaic CNV) [10,13] and pre-existing germ-line CNVs in parental cells It is still unknown whether the reported CNV instability is dependent on reprogramming methods or due to the genetic backgrounds of parental cells [6,14], which can potentially cause method-specific or donor-specific genome instability

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Results

Discussion

Conclusion