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Review
. 2021 Apr 22;11(5):376.
doi: 10.3390/life11050376.

Retrotransposons as Drivers of Mammalian Brain Evolution

Roberto Ferrari  1 , Nicole Grandi  2 , Enzo Tramontano  2   3 , Giorgio Dieci  1
Affiliations
Review

Retrotransposons as Drivers of Mammalian Brain Evolution

Roberto Ferrari et al. Life (Basel). .

Abstract

Retrotransposons, a large and diverse class of transposable elements that are still active in humans, represent a remarkable force of genomic innovation underlying mammalian evolution. Among the features distinguishing mammals from all other vertebrates, the presence of a neocortex with a peculiar neuronal organization, composition and connectivity is perhaps the one that, by affecting the cognitive abilities of mammals, contributed mostly to their evolutionary success. Among mammals, hominids and especially humans display an extraordinarily expanded cortical volume, an enrichment of the repertoire of neural cell types and more elaborate patterns of neuronal connectivity. Retrotransposon-derived sequences have recently been implicated in multiple layers of gene regulation in the brain, from transcriptional and post-transcriptional control to both local and large-scale three-dimensional chromatin organization. Accordingly, an increasing variety of neurodevelopmental and neurodegenerative conditions are being recognized to be associated with retrotransposon dysregulation. We review here a large body of recent studies lending support to the idea that retrotransposon-dependent evolutionary novelties were crucial for the emergence of mammalian, primate and human peculiarities of brain morphology and function.

Keywords: ERV; LINE-1; SINE; enhancer; exaptation; neocortex; neuron; noncoding RNA; transposable elements.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic view of retrotransposons. Retrotransposons are divided into two main classes depending on the presence of long terminal repeat (LTR) regions. (A) LTR retrotransposons are also generally referred to as endogenous retroviruses (ERVs). Their full-length sequence (top) is schematically composed of a 5’-LTR (orange arrow) containing the RNA polymerase II (Pol II) promoter, from which the entire unit is transcribed. The coding region of the transcribed ERV spans three main genes, such as Gag, Pol and Env, represented by the blue, purple and yellow boxes, respectively. The coding region is followed by the 3’-LTR sequence (orange arrow); 5’ and 3’ LTRs are formed from viral RNA ends during reverse transcription and are identical at the time of integration. Intact LTR retrotransposons are autonomous, as they encode for the protein machinery required for their reverse transcription and integration. Many LTR retrotransposons are incomplete, however. In extreme cases (bottom), the recombination between 5’ and 3’ LTRs of the same provirus can reduce ERV sequences to a solitary LTR only, from which transcripts can originate by virtue of the Pol II promoter embedded within the LTR (orange arrow). (B) Non-LTR retrotransposons include both autonomous (LINE) and non-autonomous (SINE, SVA) classes, illustrated in the upper and lower parts of the panel, respectively. LINEs, predominantly represented by the LINE-1 (L1) group in humans, harbor a 5’-UTR, containing the Pol II promoter from which they are transcribed (curved arrow). The coding region of the transcribed LINE-1 is composed of two main open-reading frames, ORF1 and ORF2, coding for the homonymous proteins (green and pink boxes). The 3’-UTR of the LINE-1 contains a poly(A) tract (An). SINEs are further divided into three main groups or clades: SINE1/7SL, SINE2/tRNA and SINE3/5S, depending on the type of ancestral sequence from which they originated, specifically the 7SL RNA, the tRNA and the 5S RNA sequence. Consistent with their origin, SINEs contain internal Pol III promoters. Alu elements, the most numerous SINEs in humans, belong to the SINE1/7SL group as they contain two 7SL-related moieties (gray boxes). The upstream 7SL-related moiety harbors A- and B-box internal control elements, recognized by the Pol III-specific transcription factor TFIIIC (yellow boxes) in their left 7SL-related moiety. The two moieties are also separated by an A-rich tract (An). Another poly(A) tract is found at the end of the SINE. SINEs of the SINE2/tRNA group harbor A- and B-boxes in their tRNA-related upstream moiety (yellow boxes), followed by sequences of diverse origins. A noteworthy example of this group is represented by the mammalian-wide interspersed repeat (MIR) elements. SINE3/5S elements are exemplified in the Figure by AmnSINE1, formed by an upstream 5S-derived moiety (red box), containing the 5S-specific A- and C-box internal promoter elements, followed by a tRNA-related fragment (yellow). Represented in the bottom part of the panel is the structure of an SVA element, consisting of (from the 5’ to 3’ end) a hexameric repeat region, an Alu-related region, a variable number tandem repeat (VNTR) region, and a SINE-R sequence sharing homology with human endogenous retrovirus HERV-K10.
Figure 2
Figure 2
Transcriptional and 3D genome effects of retrotransposons. Retrotransposons (or retroelements, RE) are responsible for a wide range of possible effects on both transcription control and 3D genome organization. (A) Schematic representation of some of the predominant effects of REs on transcription. REs (purple box) can be inserted within the coding region between two exons (gray boxes), providing new transcription start sites (TSS, dark gray arrow) for both sense and antisense transcription. REs can also provide new cis-regulatory sequences (such as enhancers or insulators) which can in turn activate (green arrow) and repress (red arrow) transcription of the associated gene. REs could also alter the epigenetic state of a given gene, leading to its transcriptional repression, by increasing the DNA methylation (yellow circles) within the promoter region of the transcription unit and directly or indirectly recruiting repressive complexes (red box). (B) REs can impact the 3D genome organization of the chromatin within the nuclei. REs (especially Alu elements) are found to be enriched at topologically associating domain (TAD) boundaries. Represented in the Figure is a putative case in which two TADs, one active (blue) and one inactive (red), are separated by a TAD boundary. This boundary limits the action of a brain enhancer region (yellow box) within the active TAD towards a gene (white box) within the inactive TAD, thereby impeding the ectopic brain expression of the gene. As a result of an RE insertion event within the inactive TAD, the 3D genome organization is altered, and a new active TAD is formed due to the boundary effect of the RE. This leads to the spreading of the active TAD over the gene, which allows the brain enhancer region (yellow) to now induce gene activation and therefore its ectopic expression within the brain (yellow area).
Figure 3
Figure 3
Summary of retrotransposon exaptations involved in brain evolution. Schematically recapitulated in the Figure are five major types of genomic novelty provided by RE exaptation that have been recognized to strongly affect brain evolution. Going clockwise from the left upper sector: REs can be a source of novel retrotransposon-derived ncRNAs (e.g., SINE-derived BC200 RNA); REs can be the source of novel proteins derived from retrotransposon (especially ERV) coding sequences; exonization of retrotransposon sequences (resulting in mRNAs or lncRNAs with embedded RE-derived sequences) can lead, for example, to the appearance of a new regulatory site (green box) within mRNA sequences, which can recruit miRNA, thereby affecting mRNA translation/stability; REs can provide new transcription TF binding sites, contributing to the birth of novel enhancers and altering the transcription of specific brain genes; REs can play a major role as 3D genome organizers, thereby strongly influencing the expression of brain-specific genes via changes in the 3D nuclear chromatin folding.
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