Hominid retrotransposons as a modulator of genomic function

Transposable elements constitute 45% of the human genome contributing to our evolution, creating new exons, structural variation and influencing the regulation of transcription. SINE-VNTR-Alus (SVAs) are a hominid specific retrotransposon that are still actively retrotransposing in the human genome today. The structure and sequence of SVAs, in particular their variable number tandem repeat (VNTR) domain, suggest their potential for influencing the regulation of gene expression through binding of transcription factors, differential methylation patterns and formation of secondary structures along with potential for genetic variation between individuals. This project has identified novel regulatory domains and genetic variation within elements belonging to a hominid specific group of retrotransposons. A global analysis undertaken of their distribution identified their preference for genic regions over gene deserts and their insertion into functional regions of the genome such as promoters and introns. An in depth analysis of two SVA insertions, one upstream of the FUS gene and another upstream of the PARK7 gene, demonstrated the ability of SVAs to affect reporter expression in vitro and in vivo. Both of these SVAs were identified as polymorphic in their central VNTR regions and the PARK7 SVA also demonstrated different copy numbers of repeats it its 5’ CCCTCT domain. Analysis of the PARK7 SVA insertion and gene in cell lines indicated the SVA is not epigenetically silenced, as dogma might suggest to suppress retrotransposition, but present in a transcriptionally active region of the genome. There is increasing evidence for loss of silencing of retrotransposons including within the human brain which would allow for greater influence of potential transcriptional properties embedded within SVAs impacting on genomic function