Circular RNAs (circRNAs) are produced from precursor mRNA (pre-mRNA) back-splicing of thousands of genes in eukaryotes. Although circRNAs are generally expressed at low levels, recent findings have shed new light on their cell type-specific and tissue-specific expression and on the regulation of their biogenesis. Furthermore, the data indicate that circRNAs shape gene expression by titrating microRNAs, regulating transcription and interfering with splicing, thus effectively expanding the diversity and complexity of eukaryotic transcriptomes.

The biogenesis and emerging roles of circular RNAs

Accurate estimates of virus mutation rates are important to understand the evolution of the viruses and to combat them. However, methods of estimation are varied and often complex. Here, we critically review over 40 original studies and establish criteria to facilitate comparative analyses. The mutation rates of 23 viruses are presented as substitutions per nucleotide per cell infection (s/n/c) and corrected for selection bias where necessary, using a new statistical method. The resulting rates range from 10 8 to10 6 s/n/c for DNA viruses and from 10 6 to 10 4 s/n/c for RNA viruses. Similar to what has been shown previously for DNA viruses, there appears to be a negative correlation between mutation rate and genome size among RNA viruses, but this result requires further experimental testing. Contrary to some suggestions, the mutation rate of retroviruses is not lower than that of other RNA viruses. We also show that nucleotide substitutions are on average four times more common than insertions/deletions (indels). Finally, we provide estimates of the mutation rate per nucleotide per strand copying, which tends to be lower than that per cell infection because some viruses undergo several rounds of copying per cell, particularly double-stranded DNA viruses. A regularly updated virus mutation rate data set will be available at www.uv.es/rsanjuan/virmut.

https://www.uv.es/rasanve2/Sanjuan%20JVirol%202010.pdf

Viral mutation rates.

It is now clear that there is a diversity of circular RNAs in biological systems. Circular RNAs can be produced by the direct ligation of 5′ and 3′ ends of linear RNAs, as intermediates in RNA processing reactions, or by “backsplicing,” wherein a downstream 5′ splice site (splice donor) is joined to an upstream 3′ splice site (splice acceptor). Circular RNAs have unique properties including the potential for rolling circle amplification of RNA, the ability to rearrange the order of genomic information, protection from exonucleases, and constraints on RNA folding. Circular RNAs can function as templates for viroid and viral replication, as intermediates in RNA processing reactions, as regulators of transcription in cis, as snoRNAs, and as miRNA sponges. Herein, we review the breadth of circular RNAs, their biogenesis and metabolism, and their known and anticipated functions.

/pdf/circular-rnas-diversity-of-form-and-function-ghxg4z3np0.pdf

Circular RNAs: diversity of form and function

Kepa Ruiz-Mirazo,†,∥ Carlos Briones,‡,∥ and Andreś de la Escosura* †Biophysics Unit (CSIC-UPV/EHU), Leioa, and Department of Logic and Philosophy of Science, University of the Basque Country, Avenida de Tolosa 70, 20080 Donostia−San Sebastiań, Spain ‡Department of Molecular Evolution, Centro de Astrobiología (CSIC−INTA, associated to the NASA Astrobiology Institute), Carretera de Ajalvir, Km 4, 28850 Torrejoń de Ardoz, Madrid, Spain Organic Chemistry Department, Universidad Autońoma de Madrid, Cantoblanco, 28049 Madrid, Spain

Prebiotic systems chemistry: new perspectives for the origins of life.

RNA silencing is a central regulator of gene expression in most eukaryotes and acts both at the transcriptional level through DNA methylation and at the post-transcriptional level through direct mRNA interference mediated by small RNAs. In plants and invertebrates, the same pathways also function directly in host defence against viruses by targeting viral RNA for degradation. Successful viruses have consequently evolved diverse mechanisms to avoid silencing, most notably through the expression of viral suppressors of RNA silencing. RNA silencing suppressors have also been recently identified in plant pathogenic bacteria and oomycetes, suggesting that disruption of host silencing is a general virulence strategy across several kingdoms of plant pathogens. There is also increasing evidence that plants have evolved specific defences against RNA-silencing suppression by pathogens, providing yet another illustration of the never-ending molecular arms race between plant pathogens and their hosts.

RNA silencing suppression by plant pathogens: defence, counter-defence and counter-counter-defence

Natural hammerhead ribozymes are mostly found in some viroid and viroid-like RNAs and catalyze their cis cleavage during replication. Hammerheads have been manipulated to act in trans and assumed to have a similar catalytic behavior in this artificial context. However, we show here that two natural cis-acting hammerheads self-cleave much faster than trans-acting derivatives and other reported artificial hammerheads. Moreover, modifications of the peripheral loops 1 and 2 of one of these natural hammerheads induced a >100-fold reduction of the self-cleavage constant, whereas engineering a trans-acting artificial hammerhead into a cis derivative by introducing a loop 1 had no effect. These data show that regions external to the central conserved core of natural hammerheads play a role in catalysis, and suggest the existence of tertiary interactions between these peripheral regions. The interactions, determined by the sequence and size of loops 1 and 2 and most likely of helices I and II, must result from natural selection and should be studied in order to better understand the hammerhead requirements in vivo.

https://www.embopress.org/doi/pdf/10.1093/emboj/cdg530

Peripheral regions of natural hammerhead ribozymes greatly increase their self-cleavage activity

The mutation rates of viroids, plant pathogens with minimal non-protein-coding RNA genomes, are unknown. Their replication is mediated by host RNA polymerases and, in some cases, by hammerhead ribozymes, small self-cleaving motifs embedded in the viroid. By using the principle that the population frequency of nonviable genotypes equals the mutation rate, we screened for changes that inactivated the hammerheads of Chrysanthemum chlorotic mottle viroid. We obtained a mutation rate of 1/400 per site, the highest reported for any biological entity. Such error-prone replication can only be tolerated by extremely simple genomes such as those of viroids and, presumably, the primitive replicons of the RNA world. Our results suggest that the emergence of replication fidelity was critical for the evolution of complexity in the early history of life.

http://personales.upv.es/sfelena/Science-mutrateCChMVd.pdf

Extremely high mutation rate of a hammerhead viroid

Viroids and viroid-like satellite RNAs from plants, and the human hepatitis delta virus (HDV) RNA share some properties that include small size, circularity and replication through a rolling-circle...

/pdf/rolling-circle-replication-of-viroids-viroid-like-satellite-5gisaxro1v.pdf

Rolling-circle replication of viroids, viroid-like satellite RNAs and hepatitis delta virus: variations on a theme.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/j.febslet.2004.03.118

Viroids: the minimal non-coding RNAs with autonomous replication

https://www.ipb-halle.de/uploads/tx_avonisintranet/pdf/Double-stranded%20RNA%20interferes%20in%20a%20sequence-specific%20manner%20with%20the.pdf

Selma Gago

Papers

Peripheral regions of natural hammerhead ribozymes greatly increase their self-cleavage activity

Extremely high mutation rate of a hammerhead viroid

Rolling-circle replication of viroids, viroid-like satellite RNAs and hepatitis delta virus: variations on a theme.

Viroids: the minimal non-coding RNAs with autonomous replication

Double-stranded RNA interferes in a sequence-specific manner with the infection of representative members of the two viroid families.