EMBRYONIC STEM CELLS/INDUCED PLURIPOTENT STEM CELLS Elevated Coding Mutation Rate During the Reprogramming of Human Somatic Cells into Induced Pluripotent Stem Cells

Mutations in human induced pluripotent stem cells (iPSCs) pose a risk for their clinical use due to preferential reprog-ramming of mutated founder cell and selection of mutations during maintenance of iPSCs in cell culture. It is unknown, however, if mutations in iPSCs are due to stress associated with oncogene expression during reprogramming. We per-formed whole exome sequencing of human foreskin fibro-blasts and their derived iPSCs at two different passages. We found that in vitro passaging contributed 7 % to the iPSC coding point mutation load, and ultradeep amplicon sequenc-ing revealed that 19 % of the mutations preexist as rare muta-tions in the parental fibroblasts suggesting that the remaining 74 % of the mutations were acquired during cellular reprog-ramming. Simulation suggests that the mutation intensity during reprogramming is ninefold higher than the back-ground mutation rate in culture. Thus the factor induced reprogramming stress contributes to a significant proportion of the mutation load of iPSCs. STEM CELLS 2012;30:435–440 Disclosure of potential conflicts of interest is found at the end of this article