Mechanisms of disease-associated SINE-VNTR-Alus

Abstract

SINE-VNTR-Alus (SVAs) are the youngest retrotransposon family in the human genome. Their ongoing mobilization has generated genetic variation within the human population. At least 24 insertions to date, detailed in this review, have been associated with disease. The predominant mechanisms through which this occurs are alterations to normal splicing patterns, exonic insertions causing loss-of-function mutations, and large genomic deletions. Dissecting the functional impact of these SVAs and the mechanism through which they cause disease provides insight into the consequences of their presence in the genome and how these elements could influence phenotypes. Many of these disease-associated SVAs have been difficult to characterize and would not have been identified through routine analyses. However, the number identified has increased in recent years as DNA and RNA sequencing data became more widely available. Therefore, as the search for complex structural variation in disease continues, it is likely to yield further disease-causing SVA insertions.

Keywords: SINE-VNTR-Alu; disease; genetic variation; mobile DNA; retrotransposon; splicing.

Figure 1.

SVA structure and mechanisms through which they are associated with disease. (a) A complete SVA consists of a hexamer repeat (CCCTCT) variable in length, an Alu-like sequence on the antisense strand, a variable number tandem repeat (VNTR), a SINE-R domain, a poly A-tail and are usually flanked by target site duplications (TSDs). (b) An SVA F1 consists of the VNTR, SINE-R, and poly A-tail but is lacking the CCCTCT domain and the majority of the Alu-like sequence. At the 5′ end is sequence from the MAST2 exon 1 that can vary in size. (c) An example of a genomic deletion upon SVA insertion where a region of ~36.8 kb is deleted that includes exons 7-9 of the FBN1 gene. (d) Exon skipping induced by the insertion of an SVA into exon 5 of the SPTA1 gene resulting in an inframe deletion and the production of an abnormal protein. This was associated with hereditary elliptocytosis and hereditary pyropoikilocytosis. (e) Exonization of an intronic SVA insertion that introduced a premature stop codon in the BRCA1 gene in a family with early onset breast cancer. (f) An SVA insertion into an intron of the MFSD8 gene that activates existing cryptic splice sites causing missplicing and the introduction of a premature stop codon in the transcript. This was associated with neuronal ceroid lipofuscinosis 7. (A color version of this figure is available in the online journal.)