Hotspots of De Novo Point Mutations in Induced Pluripotent Stem Cells

Abstract

Summary: Induced pluripotent stem cells (iPSCs) are generated by direct reprogramming of somatic cells and hold great promise for novel therapies. However, several studies have reported genetic variations in iPSC genomes. Here, we investigated point mutations identified by whole-genome sequencing in mouse and human iPSCs in the context of epigenetic status. In contrast to disease-causing single-nucleotide polymorphisms, de novo point mutations introduced during reprogramming were underrepresented in protein-coding genes and in open chromatin regions, including transcription factor binding sites. Instead, these mutations occurred preferentially in structurally condensed lamina-associated heterochromatic domains, suggesting that chromatin organization is a factor that can bias the regional mutation rate in iPSC genomes. Mutation signature analysis implicated oxidative stress associated with reprogramming as a likely cause of point mutations. Altogether, our study provides deeper understanding of the mutational landscape of iPSC genomes, paving an important way toward the translation of iPSC-based cell therapy. : Yoshihara et al. show that de novo point mutations introduced during iPSC reprogramming preferentially occur in structurally condensed lamina-associated heterochromatic domains and exhibit an oxidative stress-induced DNA damage mutation signature. This study provides better characterization of iPSC mutations at the whole-genome level and accelerates the translation of iPSC-based cell therapies. Keywords: iPSCs, genomics, point mutation, epigenetics, heterochromatin, lamina-associated domains, iPSC-based cell therapy