Abstract
Neural progenitor cells undergo somatic retrotransposition events, mainly involving L1 elements, which can be potentially deleterious. Here, we analyze the whole genomes of 20 brain samples and 80 non-brain samples, and characterized the retrotransposition landscape of patients affected by a variety of neurodevelopmental disorders including Rett syndrome, tuberous sclerosis, ataxia-telangiectasia and autism. We report that the number of retrotranspositions in brain tissues is higher than that observed in non-brain samples and even higher in pathologic vs normal brains. The majority of somatic brain retrotransposons integrate into pre-existing repetitive elements, preferentially A/T rich L1 sequences, resulting in nested insertions. Our findings document the fingerprints of encoded endonuclease independent mechanisms in the majority of L1 brain insertion events. The insertions are “non-classical” in that they are truncated at both ends, integrate in the same orientation as the host element, and their target sequences are enriched with a CCATT motif in contrast to the classical endonuclease motif of most other retrotranspositions. We show that L1Hs elements integrate preferentially into genes associated with neural functions and diseases. We propose that pre-existing retrotransposons act as “lightning rods” for novel insertions, which may give fine modulation of gene expression while safeguarding from deleterious events. Overwhelmingly uncontrolled retrotransposition may breach this safeguard mechanism and increase the risk of harmful mutagenesis in neurodevelopmental disorders.
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Acknowledgements
We thank the Kahn Family Foundation for their continuous support. This work was supported in part by grants from the Flight Attendant Medical Research Institute (FAMRI), and by the I-CORE Program of the Planning and Budgeting Committee and the Israel Science Foundation (Grant numbers 41/11 and 1796/12). GR is a member of the Sagol Neuroscience Network and holds the Djerassi Chair in Oncology at the Sackler Faculty of Medicine, Tel Aviv University. Human brain tissues were obtained from the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD. This work was performed in partial fulfilment of the requirements for a PhD degree to JJ-H and BK, The Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University.
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Supplementary information
Supplementary information, Figure S1
Detection and Characterization of MEI Events. (PDF 234 kb)
Supplementary information, Figure S2
Overall study workflow. (PDF 207 kb)
Supplementary information, Figure S3
Verification and characterization of L1Hs insertion events using PCR and Sanger sequencing. (PDF 401 kb)
Supplementary information, Figure S4
Verification of L1Hs insertions that were detected by CG sequencing using the Pacific Biosciences technology. (PDF 276 kb)
Supplementary information, Figure S5
Somatic L1Hs and AluY event identification. (PDF 179 kb)
Supplementary information, Figure S6
Chromosomal distribution of somatic L1Hs insertions. (PDF 107 kb)
Supplementary information, Figure S7
L1Hs events validated by 3′ Illumina targeted sequencing. (PDF 68 kb)
Supplementary information, Figure S8
Preferred insertion of L1Hs into the most homologous and not the most prevalent L1 family host sequence. (PDF 128 kb)
Supplementary information, Figure S9
Stringent analysis of L1Hs insertion truncation in brain samples. (PDF 112 kb)
Supplementary information, Figure S10
L1Hs insertion length in the AT samples compared to the NB samples. (PDF 88 kb)
Supplementary information, Figure S11
Insertion of somatic L1Hs in long non-coding RNA. (PDF 82 kb)
Supplementary information, Figure S12
Enriched functional groups of genes with non-nested L1Hs insertions. (PDF 110 kb)
Supplementary information Tables
Supplementary information, Table S1a–S1b (PDF 212 kb)
Supplementary information, Table S2
Verification and characterization of L1Hs insertion events. (PDF 58 kb)
Supplementary information, Tables
Supplementary information, Table S3a–S3b (PDF 244 kb)
Supplementary information, Table S4
Examples of nested L1Hs insertions that are truncated at the 3′ end, that were detected by whole genome sequencing by Pacific Biosciences. (PDF 63 kb)
Supplementary information, Table S5
Selected neural genes with somatic L1Hs insertions. (PDF 321 kb)
Supplementary information, Datas S1
Supplementary information, Datas S1–S5 (PDF 351 kb)
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Jacob-Hirsch, J., Eyal, E., Knisbacher, B. et al. Whole-genome sequencing reveals principles of brain retrotransposition in neurodevelopmental disorders. Cell Res 28, 187–203 (2018). https://doi.org/10.1038/cr.2018.8
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DOI: https://doi.org/10.1038/cr.2018.8
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