The Role of SINE-VNTR-Alu (SVA) Retrotransposons in Shaping the Human Genome

Abstract

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.

CRISPR Deletion of a SVA Retrotransposon Demonstrates Function as a cis-Regulatory Element at the TRPV1/TRPV3 Intergenic Region

“…Nevertheless, co-expression of TRPV1 and TRPV3 is found in many human tissues, which is not true of mouse tissues (e.g., DRG) which have been shown to express TRPV1 but not TRPV3 ( Figure 2 C). These functional data lend support to the hypothesis that SVAs serve as newly evolved CREs in primate genomes and contribute to gene regulation in primate species [ 13 , 14 , 17 , 26 ]. When we compared the ratio of TRPV1:TRPV3 expression between unedited and homozygous ΔSVA clones, a greater decrease in TRPV3 expression compared to TRPV1 was observed.…”

“…We and others have previously demonstrated that SVAs preferentially insert into gene dense regions and several regions across the human genome are enriched for SVA insertions [ 17 ]. One such region previously identified was a 1 Mb region (chr17:3000001–4000000, hg19) on chromosome 17 (chr17p13.2), which contained six SVA insertions ( Figure 1 B).…”

“…These insertions were SVA subclass D, which is a subclass that shares some insertions with gorilla and chimpanzee but the majority (67.5%) are human specific [ 3 ]. Furthermore, SVA D comprises 44.4% of all SVAs in the human genome [ 17 ], highlighting this subclass as particularly active throughout human evolution. It has been established that there is a strong bias of human specific SVAs inserting into regions already containing SVAs [ 11 , 12 , 17 ].…”

“…Furthermore, SVA D comprises 44.4% of all SVAs in the human genome [ 17 ], highlighting this subclass as particularly active throughout human evolution. It has been established that there is a strong bias of human specific SVAs inserting into regions already containing SVAs [ 11 , 12 , 17 ]. All SVAs at chr17p13.2 were subclass SVA D ( Figure 1 C), with 5 out of 6 being full length and human-specific ( Figure 1 B), highlighting chr17p13.2 as an area of the genome that has been tolerant to multiple SVA insertions throughout recent human evolution and an area of the genome where human-specific gene regulation via SVA-mediated activity may have evolved.…”

Host Gene Regulation by Transposable Elements: The New, the Old and the Ugly

“…SVAs harbour a variable number of tandem repeats (VNTRs) and hijack L1 retrotransposition machinery for their mobilisation. With the youngest SVA family (SVA_F), around three million years old (myo), SVA elements represent the youngest TE in the human genome [ 14 ]. In contrast, the mouse genome appears to contain cohorts of ERVs and L1s capable of retrotransposition [ 15 , 16 ].…”