The Transposon Toolkit for Immune Isoform Diversity in Evolution and Disease

Transposable elements (TEs) occupy roughly half of the genomic content across mammals and have long been recognized for their contributions to immune gene regulation as co-opted enhancers and promoters. Less appreciated is their role in diversifying the immune transcriptome itself. TE sequences embedded in introns and gene-flanking regions can provide alternative splice sites, transcription start sites, and polyadenylation signals that generate structurally distinct isoforms of host immune genes. Here we review the mechanisms by which TEs contribute to alternative transcription and the cases with experimental evidence that TE-derived isoforms introduce alternative regulation or function to immune signaling pathways. We give particular attention to the species-specific nature of these events, as each vertebrate lineage carries a distinct TE repertoire and elements shared between species are not always used in the same way, making TE exonization a source of immune regulatory variation both across and within species. These events also contribute to cancer, where epigenetic dysregulation can aberrantly activate TE-derived transcripts with potential as biomarkers and therapeutic targets. Finally, we discuss how advances in long-read sequencing, bioinformatic tools, and proteomics are enabling more systematic characterization of TE-derived isoforms, and outline priorities for cataloguing the full scope of TE contributions to immune transcript diversity.