Comparative Genomics Reveals LINE-1 Recombination with Diverse RNAs

Long interspersed element-1 (LINE-1, L1) retrotransposons are the most abundant protein-coding transposable elements (TE) in mammalian genomes, and have shaped genome content over 170 million years of evolution. LINE-1 is self-propagating and mobilizes other sequences, including Alu elements. Occasionally, LINE-1 forms chimeric insertions with non-coding RNAs and mRNAs. U6 spliceosomal small nuclear RNA/LINE-1 chimeras are best known, though there are no comprehensive catalogs of LINE-1 chimeras. To address this, we developed TiMEstamp, a computational pipeline that leverages multiple sequence alignments (MSA) to estimate the age of LINE-1 insertions and identify candidate chimeric insertions where an adjacent sequence arrives contemporaneously. Candidates were refined by detecting hallmark features of L1 retrotransposition, such as target site duplication (TSD). Applying this pipeline to the human genome, we recovered all known species of LINE-1 chimeras and discovered new chimeric insertions involving small RNAs, Alu elements, and mRNA fragments. Some insertions are compatible with known mechanisms, such as RNA ligation. Other structures nominate novel mechanisms, such as trans-splicing. We also see evidence that LINE-1 loci with defunct promoters can acquire regulatory elements from nearby genes to restore retrotransposition activity. These discoveries highlight the recombinatory potential of LINE-1 RNA with implications for genome evolution and TE domestication.