A SINE-VNTR-Alu at the LRIG2 locus is associated with proximal and distal gene expression in CRISPR and population models.

SINE-VNTR-Alu (SVA) retrotransposons represent mobile regulatory elements that have the potential to influence the surrounding genome when they insert into a locus. Evolutionarily recent mobilisation has resulted in loci in the human genome where a given retrotransposon might be observed to be present or absent, termed a retrotransposon insertion polymorphism (RIP). We previously observed that an SVA RIP ~ 2 kb upstream of LRIG2 on chromosome 1, the 'LRIG2 SVA', was associated with differences in local gene expression and methylation, and that the two were correlated. Here, we have used CRISPR-mediated deletion of the LRIG2 SVA in a cell line model to validate that presence of the retrotransposon is directly affecting local expression and provide evidence that is suggestive of a modest role for the SVA in modulating nearby methylation. Additionally, in leveraging an available Hi-C dataset we observed that the LRIG2 SVA was also involved in long-range chromatin interactions with a cluster of genes ~ 300 kb away, and that expression of these genes was to varying degrees associated with dosage of the SVA in both CRISPR cell line and population models. Altogether, these data support a regulatory role for SVAs in the modulation of gene expression, with the latter potentially involving chromatin looping, consistent with the model that RIPs may contribute to interpersonal differences in transcriptional networks.