The Distribution of Genomic Variations in Human iPSCs Is Related to Replication-Timing Reorganization during Reprogramming

• Reprogramming results in extensive replication-timing reorganization
• Distinct effects on copy-number gains and losses in early versus late replicating domains
• iPSC gains enriched in regions that change to earlier replication during reprogramming

SummaryCell-fate change involves significant genome reorganization, including changes in replication timing, but how these changes are related to genetic variation has not been examined. To study how a change in replication timing that occurs during reprogramming impacts the copy-number variation (CNV) landscape, we generated genome-wide replication-timing profiles of induced pluripotent stem cells (iPSCs) and their parental fibroblasts. A significant portion of the genome changes replication timing as a result of reprogramming, indicative of overall genome reorganization. We found that early- and late-replicating domains in iPSCs are differentially affected by copy-number gains and losses and that in particular, CNV gains accumulate in regions of the genome that change to earlier replication during the reprogramming process. This differential relationship was present irrespective of reprogramming method. Overall, our findings reveal a functional association between reorganization of replication timing and the CNV landscape that emerges during reprogramming.

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