Retrotransposons as Drivers of Mammalian Brain Evolution

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.

HERV-K(HML7) Integrations in the Human Genome: Comprehensive Characterization and Comparative Analysis in Non-Human Primates

“…The possible impact of HERVs on the host genome depends not only on their chromosomal position but also on the surrounding genic environment. Accordingly, we evaluated each HML7 locus context of integration, since proviral insertions in the vicinity or within human genes are potentially capable of modifying their expression (especially if they are in the same orientation) [7]. For example, HERV LTRs can provide alternative regulatory signals including promoters, enhancers, transcription factor binding sites and splicing donors/acceptors.…”

“…Far from being only "junk DNA," HERV sequences are progressively revealing their contribution to the host physiology. Besides the known cooption of (H)ERV envelope proteins to serve placenta development and homeostasis in eutherian mammals [1][2][3][4], growing evidence indicates that HERV integrations are important drivers of genomic innovation and had a pivotal role in the evolution and shaping of entire transcriptional networks, including major innate immunity pathways [5][6][7]. Such an impact on the host biology prompted also the investigation of HERV contribution to diverse diseased conditions, trying to link the various HERV groups' expression to human pathogenesis.…”

Non-codon Optimized PiggyBac Transposase Induces Developmental Brain Aberrations: A Call for in vivo Analysis

“…While it is not immediately evident why the transposition would cause an increase in BPs, it is intriguing to consider that the naturally occurring transposition by recently integrated endogenous retroviruses (ERVs) may play a similar role, as their proportion hugely increases in the mammalian and especially the primate genome, correlating to cortex size and gyrification ( Linker et al, 2017 ). Indeed, ERVs can regulate the expression of neighboring genes ( Fasching et al, 2015 ; Brattas et al, 2017 ; Jonsson et al, 2019 , 2020 ; Petri et al, 2019 ) and may thus have evolved as a novel gene regulatory machinery involved in enlarging and folding brain regions ( Ferrari et al, 2021 ).…”

“…An important consideration in the use of integrating constructs is the similarity to endogenous transposable elements (TE), which play an important role in development. In humans, these make up the majority of the genome, with up to 69% suggested to be TE ( de Koning et al, 2011 ; Ferrari et al, 2021 ). In the developing brain, the mobilization and (re-)integration of TE, especially of the endogenous retroviral LINE-1 elements, is linked to the development of neuronal subtype diversity and genomic mosaicism, and dysregulation may lead to developmental abnormalities (see e.g., Bodea et al, 2018 ; Misiak et al, 2019 ).…”

An RNA Polymerase III General Transcription Factor Engages in Cell Type-Specific Chromatin Looping

“…In this context, one of our recent works has unveiled a crucial role of a Pol III GTF, namely transcription factor C (TFIIIC), in structurally and functionally tuning Pol II transcription via chromatin looping and histone acetylation in human breast cancer cells [19]. TFIIIC recognizes the so-called A-and B-boxes of Pol III genes internal promoters [20]; these regulatory elements are also spread out in mammalian genomes within repetitive sequences (REs) such as Short INterspersed Elements (SINEs) Alu elements (AE) and Mammalian-wide Interspersed Repeats (MIRs) [21,22]. Many of these REs have cell-type specific expression [23,24] and participate in 3D genome folding [9,25,26]; therefore, it is tempting to speculate that TFIIIC might have the potential role to serve as a genome organizer in a cell type-specific fashion (like the CTFs) by virtue of its ability to bind these REs.…”