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Review
, 8 (7)

Retrotransposon-induced Mosaicism in the Neural Genome

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Review

Retrotransposon-induced Mosaicism in the Neural Genome

Gabriela O Bodea et al. Open Biol.

Abstract

Over the past decade, major discoveries in retrotransposon biology have depicted the neural genome as a dynamic structure during life. In particular, the retrotransposon LINE-1 (L1) has been shown to be transcribed and mobilized in the brain. Retrotransposition in the developing brain, as well as during adult neurogenesis, provides a milieu in which neural diversity can arise. Dysregulation of retrotransposon activity may also contribute to neurological disease. Here, we review recent reports of retrotransposon activity in the brain, and discuss the temporal nature of retrotransposition and its regulation in neural cells in response to stimuli. We also put forward hypotheses regarding the significance of retrotransposons for brain development and neurological function, and consider the potential implications of this phenomenon for neuropsychiatric and neurodegenerative conditions.

Keywords: LINE-1; mosaicism; neurogenesis; neuron; retrotransposon.

Conflict of interest statement

We declare we have no competing interests.

Figures

Figure 1.
Figure 1.
Human retrotransposon families and mobilization mechanism. (a) Types of retrotransposons, their mobilization capacity, size and number of copies in the human genome. HERV, human endogenous retroviruses consisting of two LTRs; gag, group-specific antigen; pol, polymerase; env, envelope gene; long interspersed element-1 (L1) structure: 5′ untranslated region (UTR) with open reading frame (ORF)0 and promoter activity; ORF1 and ORF2; 3′ UTR and poly(A) tail; SVA structure: CCCTCT hexamer repeats (HR), Alu sequence in reverse orientation (Alu-like); VNTR, variable number of tandem repeats; SINE-R, a short interspersed element of HERV origin; An, poly(A) tail; Alu structure: a left monomer with internal RNA polymerase III promoter binding sites (A, B boxes); AAA, adenosine-rich linker; right monomer ending in poly(A) tail (An); processed pseudogene: sequence derived from cellular messenger RNA, which has been reverse transcribed into DNA and has no introns; target side duplications are shown as white triangles. (b) L1 retrotransposition mechanism as an example of retrotransposon mobilization. A full-length, retrotransposition-competent L1 is present at one genomic locus (blue box in the left grey chromosome). The L1 encodes two proteins essential for its mobility, ORF1p (with nucleic acid chaperone activity [31,32]) and ORF2p (with endonuclease [33] and reverse transcriptase [34] activity), as well as an unusual antisense ORF0 that may facilitate retrotransposition [35]. L1 transcription results in a bicistronic, polyadenylated mRNA (blue rectangle), which is transported to the cytoplasm for translation. Upon translation, ORF1p and ORF2p (blue spheres) bind to their encoding L1 mRNA in cis and form an RNP complex. Note that the L1 proteins can retrotranspose cellular mRNAs to generate processed pseudogenes, as well as SVA and Alu retrotransposons (purple, red and yellow wavy lines). Once the RNP is formed, it enters the nucleus through a still poorly understood process, where a new L1 insertion occurs by target-site primed reverse transcription (TPRT) [36,37]. During TPRT, the ORF2p endonuclease makes a first and second cleavage (red arrows) in the genomic DNA at the consensus sequence 5'-TTTT/AA [33], and releases a 3' hydroxyl (OH) group from which the ORF2p reverse transcriptase initiates reverse transcription of the attached L1 mRNA (indicated by the red dashed line arrow). The DNA fragment between the two cleavages is highlighted in green to indicate the formation of TSDs. The black dashed arrow indicates completing synthesis across the second strand of cDNA, resulting in a new L1 copy, and the TSDs, which flank the new L1 copy.
Figure 2.
Figure 2.
Timeline of retrotransposition activity in the brain. (a) Retrotransposition can occur in the germline, during embryogenesis, as well as during nervous system development, and can involve neural stem cells (NSCs), NPCs and post-mitotic neurons. Retrotransposition events could accumulate over time and also, potentially, take place later in life as a consequence of the ageing process. (b) Depending on its timing and cell type, a single retrotransposition event can become clonally expanded in the neural cells of the adult brain, with potentially significant effects on brain physiology. When retrotransposition occurs later in brain development, or even in post-mitotic neural cells, new insertions are restricted to one cell, which can in turn be selected against during development or maintained in adults but with a lesser probability of affecting overall brain function.

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