Abstract

ObjecAves: RNA editing is an important post-transcriptional mechanism that may have crucial roles in introducing genetic variation and determining phenotypic differences among individuals and species. Although microRNA editing is known for years, its real biological relevance is still under debate. To better understand this issue we performed an exhaustive characterization of A-to-I site-specific editing patterns on mir-376a1, a mammalian microRNA for which RNA editing is involved in development and disease. Methods: Thorough a multidisciplinary approach based on high-throughput small RNA sequencing, Sanger sequencing and transition probability computer simulations we explored mir-376a1 editing in samples from various individuals and primate species including human placenta and macaque, gorilla, chimpanzee and human brain cortex. Results: We observed that mir-376a1 editing is a common phenomenon in the mature and primary microRNA molecules that is more frequently observed in brain than in placenta. Primary mir-376a1 is edited at three positions, -1, +4 and +44. Editing frequency estimations and in silico simulations revealed that certain mir-376a1 sites are more frequently edited than others and no epistatic effects could be observed among the three mir-376a1 editing sites. Particularly, the +4 site, located at the seed region of the mature miR-376a1-5p, reached the highest editing frequency in all tissues and species analysed. Furthermore, analysis of the secondary structure of the mir-376a1 hairpin revealed that editing at the +4 site conferred the highest stability to its hairpin molecule. Conclusion: Editing events conferring higher molecular stabilities and new functional regulatory roles in particular tissues and species could have been conserved along evolution, as it might be the case of mir-376a1.