L1 retrotransposition in human neural progenitor cells (original) (raw)

Nature volume 460, pages 1127–1131 (2009)Cite this article

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Abstract

Long interspersed element 1 (LINE-1 or L1) retrotransposons have markedly affected the human genome. L1s must retrotranspose in the germ line or during early development to ensure their evolutionary success, yet the extent to which this process affects somatic cells is poorly understood. We previously demonstrated that engineered human L1s can retrotranspose in adult rat hippocampus progenitor cells in vitro and in the mouse brain in vivo1. Here we demonstrate that neural progenitor cells isolated from human fetal brain and derived from human embryonic stem cells support the retrotransposition of engineered human L1s in vitro. Furthermore, we developed a quantitative multiplex polymerase chain reaction that detected an increase in the copy number of endogenous L1s in the hippocampus, and in several regions of adult human brains, when compared to the copy number of endogenous L1s in heart or liver genomic DNAs from the same donor. These data suggest that de novo L1 retrotransposition events may occur in the human brain and, in principle, have the potential to contribute to individual somatic mosaicism.

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Change history

The position of the 'DAPI' label on Fig. 1f was altered on 27 August 2009.

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Acknowledgements

We thank J. Simon for excellent schematic drawings, M. L. Gage, J. Kim and H. Kopera for editorial comments, B. Miller and R. Keithley for cell culture assistance, C. T. Carson for hESC advice, D. Chambers and J. Barrie for flow cytometry assistance, L. Randolph-Moore for molecular advice, B. Aimone for statistics advice, T. Liang for microarray assistance, and Y. Lineu and J. Mosher for helpful comments. We also thank T. Fanning and M. Klymkowsky for the ORF1 protein and SOX3 antibodies, respectively. F.H.G. and N.G.C. are supported by the Picower Foundation, G. Harold and Leila Y. Mathers Charitable Foundation, Lookout Fund (MH082070), and the California Institute for Regenerative Medicine (CIRM). J.L.G.-P. is supported by Plan Estabilizacion Grupos SNS ENCYT 2015 (EMER07/56, Instituto de Salud Carlos III, Spain) and through the IRG-FP7-PEOPLE-2007 Marie Curie program. K.S.O. was supported by grants GM069985 and NS048187 from the National Institutes of Health (NIH). J.V.M. was supported by grants GM082970 and GM069985 from the NIH and by the Howard Hughes Medical Institute. Work in the laboratories of K.S.O. and J.V.M. only used NIH-approved stem cell lines.

Author Contributions N.G.C. and F.H.G. directed the project. J.V.M. and J.L.G.-P. directed aspects of the project conducted at Michigan. N.G.C., J.L.G.-P., J.V.M. and F.H.G. designed experiments and drafted the manuscript. N.G.C., F.H.G., J.L.G-P. and G.E.P. performed the experiments. G.W.Y. and M.T.L. carried out bioinformatics data analysis. Y.M. performed electrophysiology experiments. M.M. and K.S.O. provided hESC culture and NPC differentiation assistance. All authors commented on or contributed to the current manuscript.

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Author notes

  1. Gene W. Yeo & Michael T. Lovci
    Present address: Present address: Stem Cell Program, Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-5004, USA.,

Authors and Affiliations

  1. Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA ,
    Nicole G. Coufal, Grace E. Peng, Gene W. Yeo, Yangling Mu, Michael T. Lovci & Fred H. Gage
  2. Departments of Human Genetics and Internal Medicine, 1241 East Catherine Street, University of Michigan Medical School, Ann Arbor, Michigan 48109-5618, USA,
    José L. Garcia-Perez & John V. Moran
  3. Andalusian Stem Cell Bank, Center for Biomedical Research, Avda Conocimiento s/n, University of Granada, 18100, Spain ,
    José L. Garcia-Perez
  4. Department of Cell and Developmental Biology, 109 Zina Pitcher, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200, USA,
    Maria Morell & K. Sue O’Shea
  5. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, USA ,
    John V. Moran

Authors

  1. Nicole G. Coufal
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  2. José L. Garcia-Perez
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  3. Grace E. Peng
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  4. Gene W. Yeo
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  5. Yangling Mu
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  6. Michael T. Lovci
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  7. Maria Morell
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  8. K. Sue O’Shea
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  9. John V. Moran
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  10. Fred H. Gage
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Corresponding author

Correspondence toFred H. Gage.

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This file contains Supplementary Methods, Supplementary References, Supplementary Figures S1-S11 with Legends and Supplementary Tables S1-S5. (PDF 10345 kb)

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Coufal, N., Garcia-Perez, J., Peng, G. et al. L1 retrotransposition in human neural progenitor cells.Nature 460, 1127–1131 (2009). https://doi.org/10.1038/nature08248

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Editorial Summary

Shaping the individual brain

It is known that LINE-1 (long interspersed element-1) retrotransposons can move throughout the genomes of adult rat neural progenitor cells (NPCs) in vitro and in the mouse brain. Now it is shown that NPCs isolated from human fetal brain and derived from human embryonic stem cells also support the retrotransposition of engineered human LINE-1s in vitro. Interestingly, there is an increase in the copy number of endogenous LINE-1s in the hippocampus and elsewhere in adult human brains when compared to the copy number of endogenous LINE-1s in heart or liver genomic DNA from the same individual. This suggests that LINE-1 retrotransposition events may contribute to individual somatic mosaicism and heterogeneity of gene expression in the brain.

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