Somatic retrotransposition alters the genetic landscape of the human brain

Division of Genetics and Genomics, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Edinburgh EH25 9RG, UK.
Nature (Impact Factor: 42.35). 11/2011; 479(7374):534-7. DOI: 10.1038/nature10531
Source: PubMed

ABSTRACT Retrotransposons are mobile genetic elements that use a germline 'copy-and-paste' mechanism to spread throughout metazoan genomes. 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 disease. Epigenetic and post-transcriptional suppression block retrotransposition in somatic cells, excluding early embryo development and some malignancies. Recent reports of L1 expression and copy number variation 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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Available from: Piero Carninci, Jul 07, 2015
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    • "The neuropsychiatric-related research on LINEs has mainly focused on the identification of active retrotranspositions in early and later brain development, potentially revealing signatures of expression . In their high-throughput study of somatic retrotransposition of the brain, Baillie and colleagues found that protein-coding loci are disproportionally affected by TEs, with over-representation of L1s in introns and Alus in exons [Baillie et al., 2011]. In particular, somatic L1 insertions affected genes detected in neuroblastoma and glioma (i.e., CAMTA1), dopamine receptors (DRD3), and several neurotransmitter transporters such as SLC6A5, -A6 and -A9. "
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    • "That is, one assumes that a subset of the genome is evolving neutrally and is therefore indicative of the rate of unconstrained divergence, then finds that most of the rest of the genome is behaving similarly, which is therefore concluded to also be non-functional. If the first assumption is incorrect, and increasing evidence suggests that it may be (Oldmeadow et al. 2010; Faulkner et al. 2009; Baillie et al. 2011) (although this is disputed in Graur et al. 2013), the derived conclusion of nonfunctionality of the rest of the genome is also incorrect (Pheasant and Mattick 2007). "
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    • "As was noted above (sect. 4.1), Baillie et al. (2011) found an elevated number of retrotransposition events in the human brain relative to other regions, which is consistent with increased retrotransposition during neurogenesis in adult humans. Muotri et al. (2009) also reported an increase in L1 retrotransposition not only in neurogenic areas but also in non-neurogenic areas, such as the cerebellum. "
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