Abstract
Circular RNAs (circRNAs) are found across eukaryotes and can function in post-transcriptional gene regulation. Their biogenesis through a circle-forming backsplicing reaction is facilitated by reverse-complementary repetitive sequences promoting pre-mRNA folding. Orthologous genes from which circRNAs arise, overall contain more strongly conserved splice sites and exons than other genes, yet it remains unclear to what extent this conservation reflects purifying selection acting on the circRNAs themselves. Our analyses of circRNA repertoires from five species representing three mammalian lineages (marsupials, eutherians: rodents, primates) reveal that surprisingly few circRNAs arise from orthologous exonic loci across all species. Even the circRNAs from orthologous loci are associated with young, recently active and species-specific transposable elements, rather than with common, ancient transposon integration events. These observations suggest that many circRNAs emerged convergently during evolution - as a byproduct of splicing in orthologs prone to transposon insertion. Overall, our findings argue against widespread functional circRNA conservation.
Highlights
First described more than forty years ago, circular RNAs were originally perceived as a curiosity of gene expression, yet they have gained significant prominence over the last decade (reviewed in Kristensen et al (2019); Patop et al (2019))
Using a custom pipeline that took into account RNase R enrichment and other factors to remove likely false-positives and low expression noise, we identified circRNAs from backsplice junction (BSJ) reads, estimated circRNA steady-state abundances, and reconstructed their isoforms
We have investigated this topic through the analysis of novel, dedicated cross-species datasets
Summary
First described more than forty years ago, circular RNAs (circRNAs) were originally perceived as a curiosity of gene expression, yet they have gained significant prominence over the last decade (reviewed in Kristensen et al (2019); Patop et al (2019)). It has been reported that circRNAs are frequently generated from orthologous genomic regions across species such as mouse, pig and human (Rybak-Wolf et al, 2015; Venøet al., 2015), and that their splice sites have elevated conservation scores (You et al, 2015). In these studies, circRNA coordinates were transferred between species to identify “conserved” circRNAs. the analyses did not distinguish between potential selective constraints acting on the circRNAs themselves, from those preserving canonical splicing features of genes in which they are formed (termed “parental genes” in the following). Our work suggests that most circRNAs - even when occurring in orthologs of multiple species and comprising the same exons - may not trace back to common ancestral circRNAs but have rather emerged 75 convergently during evolution, facilitated by independent TE insertion events
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