From the comparative study of a circRNA originating from an mammalian ATXN2L intron to understanding the genesis of intron lariat-derived circRNAs.

Circular intronic RNAs (ciRNAs) are still unexplored regarding mechanisms for their emergence. We considered the ATXN2L intron lariat-derived circular RNA (ciRNA-ATXN2L) as an opportunity to conduct a cross-species examination of ciRNA genesis. To this end, we investigated 207 datasets from 4 tissues and from 13 mammalian species. While in eight species, ciRNA-ATXN2L was never detected, in pigs and rabbits, ciRNA-ATXN2L was expressed in all tissues and sometimes at very high levels. Bovine tissues were an intermediate case and in macaques and cats, only ciRNA-ATXN2L traces were detected. The pattern of ciRNA-ATXN2L restricted to only five species is not related to a particular evolution of intronic sequences. To empower our analysis, we considered 221 additional introns including 80 introns where a lariat-derived ciRNA was previously described. The primary driver of micro-ciRNA genesis (< 155 nt as ciRNA-ATXN2L) appears to be the absence of a canonical "A" (i.e. a "tnA" located in the usual branching region) to build the lariat around this adenosine. The balance between available "non canonical-A" (no ciRNA genesis) and "non-A" (ciRNA genesis) for use as a branch point to build the lariat could modify the expression level of ciRNA-ATXN2L. In addition, the rare localization of the 2'-5' bond in an open RNA secondary structure could also negatively affect the lifetime of ciRNAs (macaque ciRNA-ATXN2L). Our analyses suggest that ciRNA-ATXN2L is likely a functionless splice remnant. This study provides a better understanding of the ciRNAs origin, especially drivers for micro ciRNA genesis.