Somatic retrotransposition alters the genetic landscape of the human brain


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.

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Figure 1: Overall RC-seq methodology.
Figure 2: Multiplex quantitative PCR confirms L1 CNV in the human brain.
Figure 3: Characterization of non-reference genome insertions.
Figure 4: Discovery of somatic insertions in HDAC1 and RAI1.

Accession codes

Primary accessions

Sequence Read Archive

Data deposits

RC-seq FASTA sequences for brain and blood have been deposited in the NCBI Sequence Read Archive under accession number SRA024401.


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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.

Author information




J.K.B., M.W.B., K.R.U., D.J.G., P.R., S.S., P.C. and G.J.F. designed and performed the experiments. J.K.B., T.A.R., F.D.S. and M.F. conducted the computational analyses. P.B., R.T.T., T.C.F., D.A.H., P.H., P.C., J.A.J. and G.J.F. provided resources. S.G. and J.S.M. contributed to the discussion. J.A.J. and G.J.F. invented RC-seq. G.J.F. directed the study, led the bioinformatic analysis and wrote the manuscript. All authors commented on or contributed to the final manuscript.

Corresponding author

Correspondence to Geoffrey J. Faulkner.

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Competing interests

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.

Supplementary information

Supplementary Information

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)

Supplementary Table 2

This table shows RC-seq coverage and characteristics of retrotransposons targeted by sequence capture. (XLS 1491 kb)

Supplementary Table 3

This table shows overall RC-seq mapping statistics. (XLS 33 kb)

Supplementary Table 4

This table shows non-reference genome retrotransposon insertions in RC-seq brain libraries. (XLS 23089 kb)

Supplementary Table 5

This table shows non-reference genome retrotransposon insertions in RC-seq pooled blood library (XLS 3807 kb)

Supplementary Table 6

The table shows germ line insertions validated by PCR and capillary sequencing. (XLS 627 kb)

Supplementary Table 7

The table shows somatic insertions validated by nested PCR and capillary sequencing. (XLS 62 kb)

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Baillie, J., Barnett, M., Upton, K. et al. Somatic retrotransposition alters the genetic landscape of the human brain. Nature 479, 534–537 (2011).

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