Retrotransposons are mobile genetic elements that use a germline ‘copy-and-paste’ mechanism to spread throughout metazoan genomes1. At least 50 per cent of the human genome is derived from retrotransposons, with three active families (L1, Alu and SVA) associated with insertional mutagenesis and disease2,3. Epigenetic and post-transcriptional suppression block retrotransposition in somatic cells4,5, excluding early embryo development and some malignancies6,7. Recent reports of L1 expression8,9 and copy number variation10,11 in the human brain suggest that L1 mobilization may also occur during later development. However, the corresponding integration sites have not been mapped. Here we apply a high-throughput method to identify numerous L1, Alu and SVA germline mutations, as well as 7,743 putative somatic L1 insertions, in the hippocampus and caudate nucleus of three individuals. Surprisingly, we also found 13,692 somatic Alu insertions and 1,350 SVA insertions. Our results demonstrate that retrotransposons mobilize to protein-coding genes differentially expressed and active in the brain. Thus, somatic genome mosaicism driven by retrotransposition may reshape the genetic circuitry that underpins normal and abnormal neurobiological processes.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Kazazian, H. H., Jr Mobile elements: drivers of genome evolution. Science 303, 1626–1632 (2004)
Cordaux, R. & Batzer, M. A. The impact of retrotransposons on human genome evolution. Nature Rev. Genet. 10, 691–703 (2009)
Xing, J. et al. Mobile elements create structural variation: analysis of a complete human genome. Genome Res. 19, 1516–1526 (2009)
Garcia-Perez, J. L. et al. Epigenetic silencing of engineered L1 retrotransposition events in human embryonic carcinoma cells. Nature 466, 769–773 (2010)
Yang, N. & Kazazian, H. H., Jr L1 retrotransposition is suppressed by endogenously encoded small interfering RNAs in human cultured cells. Nature Struct. Mol. Biol. 13, 763–771 (2006)
Iskow, R. C. et al. Natural mutagenesis of human genomes by endogenous retrotransposons. Cell 141, 1253–1261 (2010)
Kano, H. et al. L1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicism. Genes Dev. 23, 1303–1312 (2009)
Belancio, V. P., Roy-Engel, A. M., Pochampally, R. R. & Deininger, P. Somatic expression of LINE-1 elements in human tissues. Nucl. Acids Res. 38, 3909–3922 (2010)
Faulkner, G. J. et al. The regulated retrotransposon transcriptome of mammalian cells. Nature Genet. 41, 563–571 (2009)
Coufal, N. G. et al. L1 retrotransposition in human neural progenitor cells. Nature 460, 1127–1131 (2009)
Muotri, A. R. et al. L1 retrotransposition in neurons is modulated by MeCP2. Nature 468, 443–446 (2010)
Muotri, A. R. et al. Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature 435, 903–910 (2005)
Eriksson, P. S. et al. Neurogenesis in the adult human hippocampus. Nature Med. 4, 1313–1317 (1998)
Singer, T., McConnell, M. J., Marchetto, M. C., Coufal, N. G. & Gage, F. H. LINE-1 retrotransposons: mediators of somatic variation in neuronal genomes? Trends Neurosci. 33, 345–354 (2010)
Cost, G. J., Golding, A., Schlissel, M. S. & Boeke, J. D. Target DNA chromatinization modulates nicking by L1 endonuclease. Nucleic Acids Res. 29, 573–577 (2001)
Ewing, A. D. & Kazazian, H. H., Jr High-throughput sequencing reveals extensive variation in human-specific L1 content in individual human genomes. Genome Res. 20, 1262–1270 (2010)
Wang, J. et al. dbRIP: a highly integrated database of retrotransposon insertion polymorphisms in humans. Hum. Mutat. 27, 323–329 (2006)
Morrish, T. A. et al. DNA repair mediated by endonuclease-independent LINE-1 retrotransposition. Nature Genet. 31, 159–165 (2002)
Dewannieux, M., Esnault, C. & Heidmann, T. LINE-mediated retrotransposition of marked Alu sequences. Nature Genet. 35, 41–48 (2003)
Han, J. S., Szak, S. T. & Boeke, J. D. Transcriptional disruption by the L1 retrotransposon and implications for mammalian transcriptomes. Nature 429, 268–274 (2004)
Feschotte, C. Transposable elements and the evolution of regulatory networks. Nature Rev. Genet. 9, 397–405 (2008)
Morgan, H. D., Sutherland, H. G., Martin, D. I. & Whitelaw, E. Epigenetic inheritance at the agouti locus in the mouse. Nature Genet. 23, 314–318 (1999)
Beck, C. R. et al. LINE-1 retrotransposition activity in human genomes. Cell 141, 1159–1170 (2010)
Huang, C. R. et al. Mobile interspersed repeats are major structural variants in the human genome. Cell 141, 1171–1182 (2010)
Nan, X. et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386–389 (1998)
Kazantsev, A. G. & Thompson, L. M. Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nature Rev. Drug Discov. 7, 854–868 (2008)
Slager, R. E., Newton, T. L., Vlangos, C. N., Finucane, B. & Elsea, S. H. Mutations in RAI1 associated with Smith–Magenis syndrome. Nature Genet. 33, 466–468 (2003)
Mattick, J. S. RNA as the substrate for epigenome-environment interactions: RNA guidance of epigenetic processes and the expansion of RNA editing in animals underpins development, phenotypic plasticity, learning, and cognition. Bioessays 32, 548–552 (2010)
Miki, Y. et al. Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer. Cancer Res. 52, 643–645 (1992)
Chahrour, M. & Zoghbi, H. Y. The story of Rett syndrome: from clinic to neurobiology. Neuron 56, 422–437 (2007)
J.K.B. is supported by a Wellcome Trust Clinical Fellowship (090385/Z/09/Z) through the Edinburgh Clinical Academic Track. G.J.F. is funded by an Institute Strategic Programme Grant and a New Investigator Award from the British BBSRC (BB/H005935/1) and a C. J. Martin Overseas Based Biomedical Fellowship from the Australian NHMRC (575585). Human brain tissues were provided by the Netherlands Brain Bank to P.H. with ethical consent for them to be used as described in the study.
D.J.G., T.A.R. and J.A.J. are employed by Roche NimbleGen, Inc., and Roche NimbleGen capture arrays and reagents were used in the study.
The file contains Supplementary Results, Supplementary Discussion, Supplementary Methods, Supplementary Figures 1-5 with legends, Supplementary Tables 1,8 9, 10,11 (see separate files for Supplementary Tables 2-7), and additional references. (PDF 854 kb)
This table shows RC-seq coverage and characteristics of retrotransposons targeted by sequence capture. (XLS 1491 kb)
This table shows overall RC-seq mapping statistics. (XLS 33 kb)
This table shows non-reference genome retrotransposon insertions in RC-seq brain libraries. (XLS 23089 kb)
This table shows non-reference genome retrotransposon insertions in RC-seq pooled blood library (XLS 3807 kb)
The table shows germ line insertions validated by PCR and capillary sequencing. (XLS 627 kb)
The table shows somatic insertions validated by nested PCR and capillary sequencing. (XLS 62 kb)
About this article
Cite this article
Baillie, J., Barnett, M., Upton, K. et al. Somatic retrotransposition alters the genetic landscape of the human brain. Nature 479, 534–537 (2011). https://doi.org/10.1038/nature10531
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics (2020)
Fusion transcripts in normal human cortex increase with age and show distinct genomic features for single cells and tissues
Scientific Reports (2020)
Aberrantly High Levels of Somatic LINE-1 Expression and Retrotransposition in Human Neurological Disorders
Frontiers in Genetics (2020)
Prion protein PrP nucleic acid binding and mobilization implicates retroelements as the replicative component of transmissible spongiform encephalopathy
Archives of Virology (2020)