Genomic alterations in cultured human embryonic stem cells (original) (raw)

• Letter
• Published: 04 September 2005
• Dan E Arking1 na1,
• Narayan Shivapurkar4,
• Morna Ikeda1,
• Victor Stastny4,
• Keyaunoosh Kassauei2,
• Guoping Sui2,
• David J Cutler1,
• Ying Liu5,
• Sandii N Brimble6,
• Karin Noaksson7,
• Johan Hyllner7,
• Thomas C Schulz6,
• Xianmin Zeng8,
• William J Freed8,
• Jeremy Crook9,
• Suman Abraham9,
• Alan Colman9,
• Peter Sartipy7,
• Sei-Ichi Matsui10,
• Melissa Carpenter11,
• Adi F Gazdar4,
• Mahendra Rao5 &
• …
• Aravinda Chakravarti1

Nature Genetics volume 37, pages 1099–1103 (2005)Cite this article

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Abstract

Cultured human embryonic stem cell (hESC) lines are an invaluable resource because they provide a uniform and stable genetic system for functional analyses and therapeutic applications. Nevertheless, these dividing cells, like other cells, probably undergo spontaneous mutation at a rate of 10−9 per nucleotide. Because each mutant has only a few progeny, the overall biological properties of the cell culture are not altered unless a mutation provides a survival or growth advantage. Clonal evolution that leads to emergence of a dominant mutant genotype may potentially affect cellular phenotype as well. We assessed the genomic fidelity of paired early- and late-passage hESC lines in the course of tissue culture. Relative to early-passage lines, eight of nine late-passage hESC lines had one or more genomic alterations commonly observed in human cancers, including aberrations in copy number (45%), mitochondrial DNA sequence (22%) and gene promoter methylation (90%), although the latter was essentially restricted to 2 of 14 promoters examined. The observation that hESC lines maintained in vitro develop genetic and epigenetic alterations implies that periodic monitoring of these lines will be required before they are used in in vivo applications and that some late-passage hESC lines may be unusable for therapeutic purposes.

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Acknowledgements

We thank J. Gearhart and C. Dang for comments and suggestions and J. LaDuca for carrying out FISH analysis. A.C. is supported by the Henry J. Knott Professorship in Genetic Medicine. A.M. is supported by the Sol Goldman Pancreatic Cancer Research Center at Johns Hopkins and a grant from the Maryland Cigarette Restitution Fund. A.C. and D.E.A. are supported by the Donald W. Reynolds Foundation Clinical Cardiovascular Research Center grant to Johns Hopkins University. A.F.G. is supported by the National Cancer Institute Early Detection and Research Network. The work related to lines BG01, 02 and 03 was partially supported by a grant from the US National Institutes of Health to BresaGen. The work related to lines SA001 and SA002/2.5 was partially supported by a grant from the US National Institutes of Health to Cellartis AB. A.C. is a paid member of the Affymetrix Scientific Advisory Board. The terms of this arrangement are being managed by Johns Hopkins University in accordance with its conflict of interest policies.

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Author notes

1. Anirban Maitra and Dan E Arking: These authors contributed equally to this work.

Authors and Affiliations

1. McKusick-Nathans Institute of Genetic Medicine, The Sol Goldman Pancreatic Cancer Research Center, 733 N. Broadway Research Bldg., Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA
   Anirban Maitra, Dan E Arking, Morna Ikeda, David J Cutler & Aravinda Chakravarti
2. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, 733 N. Broadway Research Bldg., Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA
   Anirban Maitra, Keyaunoosh Kassauei & Guoping Sui
3. Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, 733 N. Broadway Research Bldg., Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA
   Anirban Maitra
4. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA
   Narayan Shivapurkar, Victor Stastny & Adi F Gazdar
5. Laboratory of Neurosciences, National Institute on Aging, 333 Cassell Drive, Triad Bldg., Baltimore, 21224, Maryland, USA
   Ying Liu & Mahendra Rao
6. BresaGen, Inc., Athens, Georgia, USA
   Sandii N Brimble & Thomas C Schulz
7. Cellartis AB, Goteborg, Sweden
   Karin Noaksson, Johan Hyllner & Peter Sartipy
8. Cellular Neurobiology Branch, National Institute on Drug Abuse, Baltimore, Maryland, USA
   Xianmin Zeng & William J Freed
9. ES Cell International, Singapore
   Jeremy Crook, Suman Abraham & Alan Colman
10. Roswell Park Cancer Institute, State University of New York at Buffalo, Buffalo, New York, USA
    Sei-Ichi Matsui
11. Robarts Research Institute, Ontario, Canada
    Melissa Carpenter

Authors

1. Anirban Maitra
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2. Dan E Arking
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3. Narayan Shivapurkar
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4. Morna Ikeda
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5. Victor Stastny
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6. Keyaunoosh Kassauei
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7. Guoping Sui
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8. David J Cutler
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9. Ying Liu
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10. Sandii N Brimble
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11. Karin Noaksson
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12. Johan Hyllner
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13. Thomas C Schulz
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14. Xianmin Zeng
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15. William J Freed
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16. Jeremy Crook
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17. Suman Abraham
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18. Alan Colman
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19. Peter Sartipy
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20. Sei-Ichi Matsui
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21. Melissa Carpenter
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22. Adi F Gazdar
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23. Mahendra Rao
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24. Aravinda Chakravarti
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Corresponding authors

Correspondence toMahendra Rao or Aravinda Chakravarti.

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Competing interests

T.C.S. and S.N.B. are employed by BresaGen; their research is partially funded by BresaGen; and they may own stock options in BresaGen. J.C., S.A. and A. Colman are employed by ES Cell International; their research is partially funded by ES Cell International; and they may own stock options in ES Cell International.

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Maitra, A., Arking, D., Shivapurkar, N. et al. Genomic alterations in cultured human embryonic stem cells.Nat Genet 37, 1099–1103 (2005). https://doi.org/10.1038/ng1631

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• Received: 06 June 2005
• Accepted: 25 July 2005
• Published: 04 September 2005
• Issue Date: 01 October 2005
• DOI: https://doi.org/10.1038/ng1631

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