Oral Presentation 6th Annual Meeting for Australasian Society for Stem Cell Research 2013

Endogenous LINE-1 insertional mutagenesis is a feature of human iPSC reprogramming (#5)

Geoffrey J Faulkner 1
  1. Mater Medical Research Institute, Woolloongabba, QLD, Australia

Human induced pluripotent stem cells (hiPSCs) show major promise as a tool for regenerative medicine and as in vitro models of disease. However, genetic abnormalities seen previously in hiPSCs, as well as other unexplored mutation types, may be an obstacle to their therapeutic use. In this talk, I will present data based on retrotransposon capture sequencing (RC-seq) applied to 10 diverse hiPSC lines demonstrating that reprogramming frequently enables LINE-1 retrotransposition. Of the 12 validated de novo LINE-1 insertions detected, 7 were full-length (6kb), suggesting that epigenetic and host factor suppression of LINE-1 mobility is at least partially abrogated during reprogramming. 5/12 de novo LINE-1 insertions impacted genes highly expressed in hiPSCs or committed lineages, including examples of strong positive selection of mutated hiPSCs upon extended culture. Alu retrotransposons were also found to be active, including mutation of PTPN9 and other tumour suppressors. These experiments reveal endogenous retrotransposition as a novel source of mutagenesis in hiPSCs.