Retroelements in human disease

Retroelements are an abundant class of noncoding DNAs present in about half of the human genome. Among them, L1, Alu and SVA are currently active. They “jump” by retrotransposition, shuffle genomic regions by 5′ and 3′ transduction, and promote or inhibit gene transcription by providing alternative promoters or generating antisense and/or regulatory noncoding RNAs. Recent data also suggest that retroelement insertions into exons and introns of genes induce different types of genetic disease, including cancer. Retroelements interfere with the expression of genes by inducing alternative splicing via exon skipping and exonization using cryptic splice sites, and by providing polyadenylation signals. Here we summarize our current understanding of the molecular mechanisms of retroelement-induced mutagenesis which causes fifty different types of human disease. We categorize these mutagenic effects according to eleven different mechanisms and show that most of them may be explained either by traditional exon definition or transcriptional interference, a previously unrecognized molecular mechanism. In summary, this review gives an overview of retroelement insertions in genes that cause significant changes in their transcription and cotranscriptional splicing and show a remarkable level of complexity.

► Human retroelements L1, Alu and SVA are currently active.
► They influence gene expression via various (non)coding and regulatory RNAs.
► Eighty five human genetic diseases are caused by transposing retroelements.
► We summarize their insertion effects on the transcription and splicing of genes.