Circular RNA repertoires are associated with evolutionarily young transposable elements
- University of Lausanne, Switzerland
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
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Suppl. Table 4. Mouse circRNA summary.Journal of Molecular and Cellular Cardiology, doi.org/10.1016/j.yjmcc.2016.07.007.
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Suppl. Table 5. Human circRNA summary.Journal of Molecular and Cellular Cardiology, doi.org/10.1016/j.yjmcc.2016.07.007.
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DNA replication time of the human genome G1 phase.Sequence Read Archive, SRA052697.
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Suppl. Table S2. Haploinsufficiency predictions without study bias.Nucleic Acids Research, https://doi.org/10.1093/nar/gkv474.
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The evolution of gene expression levels in mammalian organsNCBI Gene Expression Omnibus, GSE30352.
Article and author information
Author details
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.
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).
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.
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Circular RNA repertoires are associated with evolutionarily young transposable elements
eLife 10:e67991.
https://doi.org/10.7554/eLife.67991
Further reading
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- Evolutionary Biology
The majority of highly polymorphic genes are related to immune functions and with over 100 alleles within a population, genes of the major histocompatibility complex (MHC) are the most polymorphic loci in vertebrates. How such extraordinary polymorphism arose and is maintained is controversial. One possibility is heterozygote advantage (HA), which can in principle maintain any number of alleles, but biologically explicit models based on this mechanism have so far failed to reliably predict the coexistence of significantly more than 10 alleles. We here present an eco-evolutionary model showing that evolution can result in the emergence and maintenance of more than 100 alleles under HA if the following two assumptions are fulfilled: first, pathogens are lethal in the absence of an appropriate immune defence; second, the effect of pathogens depends on host condition, with hosts in poorer condition being affected more strongly. Thus, our results show that HA can be a more potent force in explaining the extraordinary polymorphism found at MHC loci than currently recognised.
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- Ecology
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Understanding the origins of novel, complex phenotypes is a major goal in evolutionary biology. Poison frogs of the family Dendrobatidae have evolved the novel ability to acquire alkaloids from their diet for chemical defense at least three times. However, taxon sampling for alkaloids has been biased towards colorful species, without similar attention paid to inconspicuous ones that are often assumed to be undefended. As a result, our understanding of how chemical defense evolved in this group is incomplete. Here, we provide new data showing that, in contrast to previous studies, species from each undefended poison frog clade have measurable yet low amounts of alkaloids. We confirm that undefended dendrobatids regularly consume mites and ants, which are known sources of alkaloids. Thus, our data suggest that diet is insufficient to explain the defended phenotype. Our data support the existence of a phenotypic intermediate between toxin consumption and sequestration — passive accumulation — that differs from sequestration in that it involves no derived forms of transport and storage mechanisms yet results in low levels of toxin accumulation. We discuss the concept of passive accumulation and its potential role in the origin of chemical defenses in poison frogs and other toxin-sequestering organisms. In light of ideas from pharmacokinetics, we incorporate new and old data from poison frogs into an evolutionary model that could help explain the origins of acquired chemical defenses in animals and provide insight into the molecular processes that govern the fate of ingested toxins.
