Commentary on “Poor evidence for host-dependent regular RNA editing in the transcriptome of SARS-CoV-2”

Martignano, Filippo; Giorgio, Salvatore Di; Mattiuz, Giorgio; Conticello, Silvestro G.

doi:10.1007/s13353-022-00688-x

Cited by 17 publications

(17 citation statements)

References 65 publications

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“…We should state that our analysis did not distinguish the source of the mutation. Mutations in SARS-CoV-2 come from either replication errors or RNA modifications [ 33–40 ]. However, the selection force acting on the mutations is irrelevant to their origins.…”

Section: Discussionmentioning

confidence: 99%

Evidence for selection on SARS-CoV-2 RNA translation revealed by the evolutionary dynamics of mutations in UTRs and CDSs

et al. 2022

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RNA translation is the rate-limiting step when cells synthesize proteins. Elevating translation efficiency (TE) is intuitively beneficial. Particularly, when viruses invade host cells, how to compete with endogenous RNAs for efficient translation is a major issue to be resolved. We collected millions of worldwide SARS-CoV-2 sequences during the past year and traced the dynamics of allele frequency of every mutation. We defined adaptive and deleterious mutations according to the rise and fall of their frequencies along time. For 5ʹUTR and synonymous mutations in SARS-CoV-2, the selection on TE is evident near start codons. Adaptive mutations generally decrease GC content while deleterious mutations increase GC content. This trend fades away with increasing distance to start codons. Mutations decreasing GC content near start codons would unravel the complex RNA structure and facilitate translation initiation, which are beneficial to SARS-CoV-2, and vice versa. During this evolutionary arms race between human and virus, SARS-CoV-2 tries to improve its cis elements to compete with host RNAs for rapid translation.

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Section: Discussionmentioning

confidence: 99%

Evidence for selection on SARS-CoV-2 RNA translation revealed by the evolutionary dynamics of mutations in UTRs and CDSs

et al. 2022

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“…The ssRNA-preferring APOBEC proteins drive the C-to-U(T) deamination in the viral RNAs (Yin et al 2013), while the dsRNA-preferring ADAR proteins mediate the A-to-I(G) deamination in the viral RNAs (Bass 2002;Picardi et al 2021). These deamination events, especially the C-to-U alterations, are far more prevalent than the traditional (or natural) mutation resource (the replication errors) as inferred from the enzyme accessibility to the viral RNA (Martignano et al 2022;Zong et al 2022). Although there is a report on the prevalence of A-to-I deamination in SARS-CoV-2 transcriptome (Di Giorgio et al 2020), it was soon proven to contain false positive sites (Simmonds 2020;Picardi et al 2021;Simmonds and Ansari 2021;Martignano et al 2022;Song et al 2022;Zong et al 2022).…”

Section: Fast Evolution Of Sars-cov-2 Might Be Driven By Rna Deaminat...mentioning

confidence: 99%

“…These deamination events, especially the C-to-U alterations, are far more prevalent than the traditional (or natural) mutation resource (the replication errors) as inferred from the enzyme accessibility to the viral RNA (Martignano et al 2022;Zong et al 2022). Although there is a report on the prevalence of A-to-I deamination in SARS-CoV-2 transcriptome (Di Giorgio et al 2020), it was soon proven to contain false positive sites (Simmonds 2020;Picardi et al 2021;Simmonds and Ansari 2021;Martignano et al 2022;Song et al 2022;Zong et al 2022). Therefore, C-to-U deamination is likely to be the most prevalent mutation type in the viral transcriptome, indicating a host-driven model of SARS-CoV-2 evolution.…”

Section: Fast Evolution Of Sars-cov-2 Might Be Driven By Rna Deaminat...mentioning

confidence: 99%

Rampant C-to-U deamination accounts for the intrinsically high mutation rate in SARS-CoV-2 spike gene

Liu

Zhou

et al. 2022

RNA

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The high mutation rate of SARS-CoV-2 largely complicates our control of the pandemic. Particularly, it is currently unclear why the spike (S) gene has extraordinarily high mutation rate among all SARS-CoV-2 genes. By analyzing the occurrence of fixed synonymous mutations between SARS-CoV-2 and RaTG13, and profiling the DAF (derived allele frequency) of polymorphic synonymous sites among millions of world-wide SARS-CoV-2 strains, we found that both fixed and polymorphic mutations show higher mutation rates in S gene than other genes. The majority of mutation is C-to-T, representing the APOBEC-mediated C-to-U deamination instead of the previously-proposed A-to-I deamination. Both in silico and in vivo evidences indicated that S gene is more likely to be single-stranded compared to other SARS-CoV-2 genes, agreeing with the APOBEC preference on ssRNA. We conclude that the single-stranded property of S gene makes itself a favorable target for C-to-U deamination, leading to its excessively high mutation rate compared to other non-S genes. In conclusion, APOBEC, rather than ADAR, is the “editor-in-chief” of SARS-CoV-2 RNAs. This work helps us understand the molecular mechanism underlying the mutation and evolution of SARS-CoV-2, and is believed to contribute to the control of the pandemic.

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“…We obtained the population SNP data from multiple species. These SNP data include the human 1000 genome (Kuehn, 2008 ), Drosophila genetic reference panel (Mackay et al, 2012 ), 1000 genome project of Arabidopsis thaliana (Alonso-Blanco et al, 2016 ; Chu and Wei, 2021a ; Wei, 2020 ), and the SNPs called from millions of global SARS-CoV-2 sequences available in GISAID or relevant literatures (Cai et al, 2022 ; Li et al, 2020b ; Liu et al, 2022 ; Martignano et al, 2022 ; Shu and McCauley, 2017 ; Wei, 2022 ; Zhao et al, 2022 ; Zhu et al, 2022 ; Zong et al, 2022 ). We utilized these SNP data to test whether the mutations that abolish uORFs are most deleterious.…”

Section: Resultsmentioning

confidence: 99%

uORF-Mediated Translational Regulation of ATF4 Serves as an Evolutionarily Conserved Mechanism Contributing to Non-Small-Cell Lung Cancer (NSCLC) and Stress Response

Xiao

Sun

et al. 2022

J Mol Evol

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Diseases and environmental stresses are two distinct challenges for virtually all living organisms. In light of evolution, cellular responses to diseases and stresses might share similar molecular mechanisms, but the detailed regulation pathway is not reported yet. We obtained the transcriptomes and translatomes from several NSCLC (non-small-cell lung cancer) patients as well as from different species under normal or stress conditions. We found that the translation level of gene ATF4 is remarkably enhanced in NSCLC due to the reduced number of ribosomes binding to its upstream open reading frames (uORFs). We also showed the evolutionary conservation of this uORF- ATF4 regulation in the stress response of other species. Molecular experiments showed that knockdown of ATF4 reduced the cell growth rate while overexpression of ATF4 enhanced cell growth, especially for the ATF4 allele with mutated uORFs. Population genetics analyses in multiple species verified that the mutations that abolish uATGs (start codon of uORFs) are highly deleterious, suggesting the functional importance of uORFs. Our study proposes an evolutionarily conserved pattern that enhances the ATF4 translation by uORFs upon stress or disease. We generalized the concept of cellular response to diseases and stresses. These two biological processes may share similar molecular mechanisms.

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Commentary on “Poor evidence for host-dependent regular RNA editing in the transcriptome of SARS-CoV-2”

Cited by 17 publications

References 65 publications

Evidence for selection on SARS-CoV-2 RNA translation revealed by the evolutionary dynamics of mutations in UTRs and CDSs

Evidence for selection on SARS-CoV-2 RNA translation revealed by the evolutionary dynamics of mutations in UTRs and CDSs

Rampant C-to-U deamination accounts for the intrinsically high mutation rate in SARS-CoV-2 spike gene

uORF-Mediated Translational Regulation of ATF4 Serves as an Evolutionarily Conserved Mechanism Contributing to Non-Small-Cell Lung Cancer (NSCLC) and Stress Response

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