Many facets of human behaviour are likely to have developed in part due to evolutionary changes in the regulation of neuropeptide and other brain-related genes. This has allowed species-specific expression patterns and unique epigenetic modulation in response to our environment, regulating response not only at the molecular level, but also contributing to differences in behaviour between individuals. As such, genetic variants or epigenetic changes that may alter neuropeptide gene expression are predicted to play a role in behavioural conditions and psychiatric illness. It is therefore of interest to identify regulatory elements that have the potential to drive differential gene expression. Retrotransposons are mobile genetic elements that are known to be drivers of genomic diversity, with the ability to alter expression of nearby genes. In particular, the SINE-VNTR-Alu (SVA) class of retrotransposons is specific to hominids, and its appearance and expansion across the genome has been associated with the evolution of numerous behavioural traits, presumably through their ability to confer unique regulatory properties at the site of their insertion. We review the evidence for SVAs as regulatory elements, exploring how polymorphic variation within these repetitive sequences can drive allele specific gene expression, which would be associated with changes in behaviour and disease risk through the alteration of molecular pathways that are central to healthy brain function.

Retrotransposons can alter the regulation of genes both transcriptionally and post-transcriptionally, through mechanisms such as binding transcription factors and alternative splicing of transcripts. SINE-VNTR-Alu (SVA) retrotransposons are the most recently evolved class of retrotransposable elements, found solely in primates, including humans. SVAs are preferentially found at genic, high GC loci, and have been termed “mobile CpG islands”. We hypothesise that the ability of SVAs to mobilise, and their non-random distribution across the genome, may result in differential regulation of certain pathways. We analysed SVA distribution patterns across the human reference genome and identified over-representation of SVAs at zinc finger gene clusters. Zinc finger proteins are able to bind to and repress SVA function through transcriptional and epigenetic mechanisms, and the interplay between SVAs and zinc fingers has been proposed as a major feature of genome evolution. We describe observations relating to the clustering patterns of both reference SVAs and polymorphic SVA insertions at zinc finger gene loci, suggesting that the evolution of this network may be ongoing in humans. Further, we propose a mechanism to direct future research and validation efforts, in which the interplay between zinc fingers and their epigenetic modulation of SVAs may regulate a network of zinc finger genes, with the potential for wider transcriptional consequences.

Genomic wide association studies identified the CACNA1C locus as genetically associated with both schizophrenia and bipolar affective disorder. CACNA1C encodes Cav1.2, one of four subunits of L-type voltage gated calcium channels. Variation resides in non-coding regions of CACNA1C which interact with the promoter and are validated expression quantitative trait loci. Using reporter gene constructs we demonstrate the CACNA1C promoter is a major mediator of inducible regulation of CACNA1C activity in the SH-SY5Y neuroblastoma cell line. Exposure of SH-SY5Y cells to lithium and cocaine modulated both the endogenous CACNA1C gene and the promoter in reporter gene constructs. Deletion analysis of the promoter demonstrated the actions of both lithium and cocaine were mediated by the proximal promoter. Initial interrogation of ENCODE ChIP-seq data over the CACNA1C promoter indicated binding of the transcription factor ‘Enhancer of zeste homolog 2’ (EZH2), which was consistent with our data that overexpression of EZH2 repressed CACNA1C promoter reporter gene expression. Array data from the Human Brain Transcriptome demonstrated that EZH2 was highly expressed across the developing brain, but subsequently maintained at low levels after birth and adulthood. RNA-seq data obtained from PD_NGSAtlas, a reference database for epigenomic and transcriptomic data for psychiatric disorders, demonstrated a 3-fold increase in EZH2 expression in the anterior cingulate cortex of individuals with schizophrenia compared to controls. We propose that EZH2 may contribute to schizophrenia risk at two distinct time points either through disruption in development leading to neurodevelopmental changes, or through anomalous reactivation of expression in the adult brain.