A SINE-VNTR-Alu in the LRIG2 Promoter Is Associated with Gene Expression at the Locus

Abstract

The hominid SINE-VNTR-Alu (SVA) retrotransposons represent a repertoire of genomic variation which could have significant effects on genome function. A human-specific SVA in the promoter region of the gene leucine-rich repeats and immunoglobulin-like domains 2 (LRIG2), which we termed SVA_LRIG2, is a common retrotransposon insertion polymorphism (RIP), defined as an element which is polymorphic for its presence or absence in the genome. We hypothesised that this RIP might be associated with differential levels of expression of LRIG2. The RIP genotype of SVA_LRIG2 was determined in a subset of frontal cortex DNA samples from the North American Brain Expression Consortium (NABEC) cohort and was imputed for a larger set of that cohort. Utilising available frontal cortex total RNA-seq and CpG methylation data for this cohort, we observed that increased allele dosage of SVA_LRIG2 was non-significantly associated with a decrease in transcription from the region and significantly associated with increased methylation of the CpG probe nearest to SVA_LRIG2, i.e., SVA_LRIG2 is a significant methylation quantitative trait loci (mQTL) at the LRIG2 locus. These data are consistent with SVA_LRIG2 being a transcriptional regulator, which in part may involve epigenetic modulation.

Targeted Long-Read Sequencing Identifies a Retrotransposon Insertion as a Cause of Altered GNAS Exon A/B Methylation in a Family With Autosomal Dominant Pseudohypoparathyroidism Type 1b (PHP1B)

“…SVA retrotransposons are known to be active in the human genome, are frequently associated with disease, ( 35,36 ) and have been shown to alter local methylation patterns. ( 37 ) A similar insertion at this position was not found in public genome databases or after analysis of nearly 14,000 whole short‐read genomes of unrelated individuals.…”

Characterisation of the Function of a SINE-VNTR-Alu Retrotransposon to Modulate Isoform Expression at the MAPT Locus

“…However, intron retention is not operating at the MAPT locus as the SVA is intergenic in nature ( Figure 1 ). To date, studies have focused predominantly on differential gene expression analyses, however, these approaches are limited as they do not account for isoform diversity ( Makino et al, 2007 ; Hancks and Kazazian, 2010 ; Gianfrancesco et al, 2017 ; Hall et al, 2020 ). Many of the genes at this locus have been associated with CNS functional parameters ( Caillet-Boudin et al, 2015 ; McEwan et al, 2015 ; Moreno-Igoa et al, 2015 ; de la Tremblaye et al, 2017 ) and encode more than one isoform which are generated, for instance, through mechanisms such as alternative splicing or alternative usage of transcription start sites ( Elkon et al, 2013 ).…”

SEQSIM – A novel bioinformatics tool for comparisons of upstream gene regions – a case study of calcium binding protein spermatid associated 1 (CABS1)

“…Similarly, the small nuclear RNA U4atac Pseudogene 9 (RNU4ATAC9P) may be involved in minor spliceosome function. Traditionally thought to be non-functional, recent studies have suggested that pseudogenes, and types of pseudogenes like retrotransposons, may play a regulatory role in gene expression (34,35). The similarity of the CABS1 UGR to these other UGRs could provide clues to how CABS1 is regulated in the body and perhaps some of its functions.…”