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Delayed DNA replication in haploid human embryonic stem cells

View ORCID ProfileMatthew M. Edwards, Michael V. Zuccaro, Ido Sagi, Qiliang Ding, Dan Vershkov, Nissim Benvenisty, Dieter Egli, Amnon Koren
doi: https://doi.org/10.1101/2021.05.11.443666
Matthew M. Edwards
1Department of Molecular Biology and Genetics, Cornell University, Ithaca NY 14853, USA
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Michael V. Zuccaro
2Department of Pediatrics and Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA; Columbia University Stem Cell Initiative, New York, NY 10032, USA
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Ido Sagi
3The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem 91904, Israel
4Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
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Qiliang Ding
1Department of Molecular Biology and Genetics, Cornell University, Ithaca NY 14853, USA
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Dan Vershkov
3The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem 91904, Israel
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Nissim Benvenisty
3The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem 91904, Israel
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Dieter Egli
2Department of Pediatrics and Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA; Columbia University Stem Cell Initiative, New York, NY 10032, USA
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Amnon Koren
1Department of Molecular Biology and Genetics, Cornell University, Ithaca NY 14853, USA
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  • For correspondence: koren@cornell.edu
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Abstract

Haploid human embryonic stem cells (ESCs) provide a powerful genetic system but diploidize at high rates. We hypothesized that diploidization results from aberrant DNA replication. To test this, we profiled DNA replication timing in isogenic haploid and diploid ESCs. The greatest difference was the earlier replication of the X chromosome in haploids, consistent with the lack of X chromosome inactivation. Surprisingly, we also identified 21 autosomal regions that had dramatically delayed replication in haploids, extending beyond the normal S phase and into G2/M. Haploid-delays comprised a unique set of quiescent genomic regions that are also under-replicated in polyploid placental cells. The same delays were observed in female ESCs with two active X chromosomes, suggesting that increased X chromosome dosage may cause delayed autosomal replication. We propose that incomplete replication at the onset of mitosis could prevent cell division and result in re-entry into the cell cycle and whole genome duplication.

  • DNA replication timing of haploid ESCs profiled by WGS

  • Extreme replication timing delays in haploid ESCs at unique genomic regions

  • Replication delays associate with X-chromosome dosage in multiple systems

  • Replication delayed regions correspond to underreplication in mouse polyploid cells

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted May 12, 2021.
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Delayed DNA replication in haploid human embryonic stem cells
Matthew M. Edwards, Michael V. Zuccaro, Ido Sagi, Qiliang Ding, Dan Vershkov, Nissim Benvenisty, Dieter Egli, Amnon Koren
bioRxiv 2021.05.11.443666; doi: https://doi.org/10.1101/2021.05.11.443666
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Delayed DNA replication in haploid human embryonic stem cells
Matthew M. Edwards, Michael V. Zuccaro, Ido Sagi, Qiliang Ding, Dan Vershkov, Nissim Benvenisty, Dieter Egli, Amnon Koren
bioRxiv 2021.05.11.443666; doi: https://doi.org/10.1101/2021.05.11.443666

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