Mouse U3‐RNA‐processed pseudogenes are nonrandomly integrated into genomic DNA

Abstract

We have characterized three mouse U3-RNA-processed pseudogenes. Together with previous analyses of mouse functional genes and of rat genes and pseudogenes, these data provide some insights into the processes of U3 retrogene formation during the evolution of rodents. All the mouse retrogenes correspond to a full-length U3B-coding sequence with a 3'-poly(A) tail and are precisely flanked by a pair of direct repeats, in agreement with formation through an RNA intermediate followed by insertion at staggered nicks in the genome. All the rodents U3 retrogenes identified so far are produced from a U3B-RNA form, with two of them (one for each rodent) formed from a 3'-elongated U3-RNA precursor, pointing to the particular susceptibility of RNA precursors forms to serve as templates for retrogene formation. Rodent full-length U3 retrogenes are not inserted randomly in the genome but are systematically found in a context of simple sequences, prone to slipped-strand mispairings and likely to favour the appearance of single-stranded DNA. Moreover their flanking repeats share not only the same size (15 bp) but also common sequence features (which extend to vicinal upstream nucleotides) suggesting that common mechanisms, specific to this class of retrogenes, have been involved in their formation. For the first time, a model accounting for the generation of full-length cDNA copies from nonpolyadenylated RNA templates is proposed. Rodent U3 retrogenes appear to be of rather recent origin (posterior to the mouse/ rat divergence) and some of them could have undergone subsequent genetic exchanges with the functional genes.The reverse flow of genetic information from RNA into DNA has played a substantial part in the evolution of eukaryotic genomes, particularly in mammals [l, 21. The generation of the transposed information through reverse transcription appears to apply either to proretroviral-like or to nonviral elements [I -41. Members of the first class of retroposons have been identified in a variety of eukaryotes [5 -81. As for the nonviral family, it comprises three major groups: the processed genes, corresponding to cDNA copies of mRNAs, the 'Alu-like' families of dispersed repeats and a subset of the small-nuclear RNA pseudogenes [3, 41. These nonviral retrogenes share characteristic structural features, i.e. sequence boundaries precisely congruent with an RNA species (with possible truncations, mostly at the 3' side), presence of a repetitive poly(A)-rich 3' tail and of a pair of direct repeats (usually of 8 -19 bp) which flank the homologous poly(A)-tailed RNA sequence. The biological processes involved in creation of these remain speculative. However, the potential role of retroviral intermediates has been recently suggested: mutant retroviruses defective in their ability to encapsulate viral genomic RNA can indeed package and reverse transcribe cellular RNAs devoid to retroviral cis-acting sequences and can integrate the newly formed cDNAs into the cellular genome [9 -121. The molecular mechanisms inCorrespondence to J. ...

Structure of the differentially expressed mouse U3A gene

“…The preferential formation of U3B retrogenes in rodents could merely result from the higher relative cellular abundance of the U3B RNA variant. Alternatively, it could also reflect a higher intrinsic propensity of U3B RNA to serve as a template for cDNA synthesis, due either to specific features of its sequence [42]. snRNP organization or subcellular compartmentalization.…”