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Cell Rep. 2014 Apr 10;7(1):70-8. doi: 10.1016/j.celrep.2014.03.007. Epub 2014 Mar 27.

The distribution of genomic variations in human iPSCs is related to replication-timing reorganization during reprogramming.

Author information

1
Department of Pediatric Newborn Medicine and Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02115, USA.
2
Center for Individualized Medicine, Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
3
Department of Statistics, Harvard University, Cambridge, MA 02138, USA.
4
Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
5
Howard Hughes Medical Institute, Department of Biomedical Engineering and Center of Synthetic Biology, Boston University, Boston, MA 02215, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
6
Department of Pediatric Newborn Medicine and Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02115, USA. Electronic address: plerou@partners.org.

Abstract

Cell-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.

PMID:
24685138
PMCID:
PMC4133748
DOI:
10.1016/j.celrep.2014.03.007
[Indexed for MEDLINE]
Free PMC Article
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