Nat Commun. 2015 Feb 18;6:6318. doi: 10.1038/ncomms7318.

Unique features of mutations revealed by sequentially reprogrammed induced pluripotent stem cells.

Gao S¹, Zheng C², Chang G³, Liu W⁴, Kou X⁴, Tan K⁵, Tao L⁵, Xu K⁴, Wang H⁴, Cai J², Tian J⁵, Gao S⁶.

Abstract

Although viable mice can be generated from induced pluripotent stem cells (iPSCs), the impact of accumulated mutations on the developmental potential of the resulting iPSCs remains to be determined. Here, we demonstrate that all-iPSC mice generated through tetraploid blastocysts complementation can tolerate the accumulation of somatic mutations for up to six generations using a Tet-on inducible reprogramming system. But, the viability of the all-iPS mice decreased with increasing generations. A whole-genome sequencing survey revealed that thousands of single-nucleotide variations (SNVs), including 44 non-synonymous ones, accumulated throughout the sequential reprogramming process. Subsequent analysis provides evidence that these accumulated SNVs account for the gradual reduction in viability of the resultant all-iPSC mice. Unexpectedly, our present reprogramming system revealed that pluripotent stem cells are heterogeneous in terms of possessing a set of copy-number alterations (CNAs). These CNAs are unique for pluripotent cells and subsequently disappear in the differentiating progenies.