Circular RNA repertoires are associated with evolutionarily young transposable elements

  1. Franziska Gruhl
  2. Peggy Janich
  3. Henrik Kaessmann  Is a corresponding author
  4. David Gatfield  Is a corresponding author
  1. University of Lausanne, Switzerland
  2. Center for Molecular Biology of Heidelberg University, Germany

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.

Data availability

Sequencing data have been deposited in GEO under accession code GSE162152

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Franziska Gruhl

    Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  2. Peggy Janich

    Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Henrik Kaessmann

    Center for Molecular Biology of Heidelberg University, Heidelberg, Germany
    For correspondence
    h.kaessmann@zmbh.uni-heidelberg.de
    Competing interests
    The authors declare that no competing interests exist.
  4. David Gatfield

    Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
    For correspondence
    david.gatfield@unil.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5114-2824

Funding

Swiss Institute of Bioinformatics (SIB PhD Fellowship)

  • Franziska Gruhl

Human Frontiers Science Program (LT000158/2013-L)

  • Peggy Janich

European Research Council (242597,SexGenTransEvolution)

  • Henrik Kaessmann

European Research Council (615253,OntoTransEvol)

  • Henrik Kaessmann

Swiss National Science Foundation (NCCR RNA & Disease (141735,182880))

  • David Gatfield

Swiss National Science Foundation (individual grant 179190)

  • David Gatfield

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Juan Valcárcel, Centre de Regulació Genòmica (CRG), Spain

Ethics

Animal experimentation: Mouse samples were collected by the Kaessmann lab at the Center for Integrative Genomics in Lausanne. Rat samples were kindly provided by Carmen Sandi, EPFL, Lausanne. Opossum samples were kindly provided by Peter Giere, Museum für Naturkunde, Berlin. All animal procedures were performed in compliance with national and international ethical guidelines and regulations for the care and use of laboratory animals and were approved by the local animal welfare authorities (Vaud Cantonal Veterinary office, Berlin State Office of Health and Social Affairs). The rhesus macaque samples were provided by the Suzhou Experimental Animal Center (China); the Biomedical Research Ethics Committee of Shanghai Institutes for Biological Sciences reviewed the use and care of the animals in the research project (approval ID: ER-SIBS-260802P). All rhesus macaques used in this study suffered sudden deaths for reasons other than their participation in this study and without any relation to the organ sampled. The use of all samples for the work described in this study was approved by an ERC Ethics Screening panel (associated with H.K.'s ERC Consolidator Grant 615253, OntoTransEvol).

Human subjects: The human post-mortem samples were provided by the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland (USA). They originated from individuals with diverse causes of death that, given the information available, were not associated with the organ sampled. Written consent for the use of human tissues for research was obtained from all donors or their next of kin by this tissue bank. The use of these samples was approved by an ERC Ethics Screening panel (associated with H.K.'s ERC Consolidator Grant 615253, OntoTransEvol), and, in addition, by the local ethics committee in Lausanne (authorization 504/12).

Version history

  1. Preprint posted: March 1, 2021 (view preprint)
  2. Received: March 1, 2021
  3. Accepted: September 19, 2021
  4. Accepted Manuscript published: September 20, 2021 (version 1)
  5. Accepted Manuscript updated: September 22, 2021 (version 2)
  6. Accepted Manuscript updated: September 28, 2021 (version 3)
  7. Version of Record published: October 14, 2021 (version 4)

Copyright

© 2021, Gruhl et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,479
    views
  • 331
    downloads
  • 16
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Franziska Gruhl
  2. Peggy Janich
  3. Henrik Kaessmann
  4. David Gatfield
(2021)
Circular RNA repertoires are associated with evolutionarily young transposable elements
eLife 10:e67991.
https://doi.org/10.7554/eLife.67991

Share this article

https://doi.org/10.7554/eLife.67991

Further reading

    1. Evolutionary Biology
    Raphael Aguillon, Mieka Rinsky ... Oren Levy
    Research Article

    The circadian clock enables anticipation of the day/night cycle in animals ranging from cnidarians to mammals. Circadian rhythms are generated through a transcription-translation feedback loop (TTFL or pacemaker) with CLOCK as a conserved positive factor in animals. However, CLOCK’s functional evolutionary origin and mechanism of action in basal animals are unknown. In the cnidarian Nematostella vectensis, pacemaker gene transcript levels, including NvClk (the Clock ortholog), appear arrhythmic under constant darkness, questioning the role of NvCLK. Utilizing CRISPR/Cas9, we generated a NvClk allele mutant (NvClkΔ), revealing circadian behavior loss under constant dark (DD) or light (LL), while maintaining a 24 hr rhythm under light-dark condition (LD). Transcriptomics analysis revealed distinct rhythmic genes in wild-type (WT) polypsunder LD compared to DD conditions. In LD, NvClkΔ/Δ polyps exhibited comparable numbers of rhythmic genes, but were reduced in DD. Furthermore, under LD, the NvClkΔ/Δ polyps showed alterations in temporal pacemaker gene expression, impacting their potential interactions. Additionally, differential expression of non-rhythmic genes associated with cell division and neuronal differentiation was observed. These findings revealed that a light-responsive pathway can partially compensate for circadian clock disruption, and that the Clock gene has evolved in cnidarians to synchronize rhythmic physiology and behavior with the diel rhythm of the earth’s biosphere.

    1. Computational and Systems Biology
    2. Evolutionary Biology
    Ryan T Bell, Harutyun Sahakyan ... Eugene V Koonin
    Research Article

    A comprehensive census of McrBC systems, among the most common forms of prokaryotic Type IV restriction systems, followed by phylogenetic analysis, reveals their enormous abundance in diverse prokaryotes and a plethora of genomic associations. We focus on a previously uncharacterized branch, which we denote coiled-coil nuclease tandems (CoCoNuTs) for their salient features: the presence of extensive coiled-coil structures and tandem nucleases. The CoCoNuTs alone show extraordinary variety, with three distinct types and multiple subtypes. All CoCoNuTs contain domains predicted to interact with translation system components, such as OB-folds resembling the SmpB protein that binds bacterial transfer-messenger RNA (tmRNA), YTH-like domains that might recognize methylated tmRNA, tRNA, or rRNA, and RNA-binding Hsp70 chaperone homologs, along with RNases, such as HEPN domains, all suggesting that the CoCoNuTs target RNA. Many CoCoNuTs might additionally target DNA, via McrC nuclease homologs. Additional restriction systems, such as Type I RM, BREX, and Druantia Type III, are frequently encoded in the same predicted superoperons. In many of these superoperons, CoCoNuTs are likely regulated by cyclic nucleotides, possibly, RNA fragments with cyclic termini, that bind associated CARF (CRISPR-Associated Rossmann Fold) domains. We hypothesize that the CoCoNuTs, together with the ancillary restriction factors, employ an echeloned defense strategy analogous to that of Type III CRISPR-Cas systems, in which an immune response eliminating virus DNA and/or RNA is launched first, but then, if it fails, an abortive infection response leading to PCD/dormancy via host RNA cleavage takes over.