TY - JOUR
T1 - The heterogeneous landscape and early evolution of pathogen-associated CpG dinucleotides in SARS-CoV-2
AU - Di Gioacchino, Andrea
AU - Sulc, Petr
AU - Komarova, Anastassia V.
AU - Greenbaum, Benjamin D.
AU - Monasson, Remi
AU - Cocco, Simona
N1 - Funding Information:
We thank Nicolas Vabret for discussions and reading of the manuscript, Eddie Holmes and Marta Łuksza for helpful exchanges. We gratefully acknowledge the authors, originating and submitting laboratories of the sequences from GISAIDs EpiCoV(TM) Database on which this research is based. This work was partially supported by the ANR-19 Decrypted CE30-0021-01 Grant and by the Fondation de la Recherche Medicale (FRM) (ANR-Flash Covid, project SARS-Cov-2immunRNAs). B.G. was supported by National Institutes of Health (Grant Nos. 7R01AI081848-04, 1R01CA240924-01), a Stand Up to Cancer Lustgarten Foundation Convergence Dream Team Grant, and the Pershing Square Sohn Prize Mark Foundation Fellow supported by funding from the Mark Foundation for Cancer Research.
Publisher Copyright:
© The Author(s) 2021.
PY - 2021/6/1
Y1 - 2021/6/1
N2 - COVID-19 can lead to acute respiratory syndrome, which can be due to dysregulated immune signaling. We analyze the distribution of CpG dinucleotides, a pathogen-associated molecular pattern, in the SARS-CoV-2 genome. We characterize CpG content by a CpG force that accounts for statistical constraints acting on the genome at the nucleotidic and amino acid levels. The CpG force, as the CpG content, is overall low compared with other pathogenic betacoronaviruses; however, it widely fluctuates along the genome, with a particularly low value, comparable with the circulating seasonal HKU1, in the spike coding region and a greater value, comparable with SARS and MERS, in the highly expressed nucleocapside coding region (N ORF), whose transcripts are relatively abundant in the cytoplasm of infected cells and present in the 30UTRs of all subgenomic RNA. This dual nature of CpG content could confer to SARS-CoV-2 the ability to avoid triggering pattern recognition receptors upon entry, while eliciting a stronger response during replication. We then investigate the evolution of synonymous mutations since the outbreak of the COVID-19 pandemic, finding a signature of CpG loss in regions with a greater CpG force. Sequence motifs preceding the CpG-loss-associated loci in the N ORF match recently identified binding patterns of the zinc finger antiviral protein. Using a model of the viral gene evolution under human host pressure, we find that synonymous mutations seem driven in the SARS-CoV-2 genome, and particularly in the N ORF, by the viral codon bias, the transition–transversion bias, and the pressure to lower CpG content.
AB - COVID-19 can lead to acute respiratory syndrome, which can be due to dysregulated immune signaling. We analyze the distribution of CpG dinucleotides, a pathogen-associated molecular pattern, in the SARS-CoV-2 genome. We characterize CpG content by a CpG force that accounts for statistical constraints acting on the genome at the nucleotidic and amino acid levels. The CpG force, as the CpG content, is overall low compared with other pathogenic betacoronaviruses; however, it widely fluctuates along the genome, with a particularly low value, comparable with the circulating seasonal HKU1, in the spike coding region and a greater value, comparable with SARS and MERS, in the highly expressed nucleocapside coding region (N ORF), whose transcripts are relatively abundant in the cytoplasm of infected cells and present in the 30UTRs of all subgenomic RNA. This dual nature of CpG content could confer to SARS-CoV-2 the ability to avoid triggering pattern recognition receptors upon entry, while eliciting a stronger response during replication. We then investigate the evolution of synonymous mutations since the outbreak of the COVID-19 pandemic, finding a signature of CpG loss in regions with a greater CpG force. Sequence motifs preceding the CpG-loss-associated loci in the N ORF match recently identified binding patterns of the zinc finger antiviral protein. Using a model of the viral gene evolution under human host pressure, we find that synonymous mutations seem driven in the SARS-CoV-2 genome, and particularly in the N ORF, by the viral codon bias, the transition–transversion bias, and the pressure to lower CpG content.
KW - CpG motifs
KW - Evolution of synonymous mutations
KW - Pathogen-associated molecular patterns
KW - Pattern recognition receptors
KW - SARS-CoV-2
KW - SsRNA viruses
KW - Viral host mimicry
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U2 - 10.1093/molbev/msab036
DO - 10.1093/molbev/msab036
M3 - Article
C2 - 33555346
AN - SCOPUS:85107086989
VL - 38
SP - 2428
EP - 2445
JO - Molecular Biology and Evolution
JF - Molecular Biology and Evolution
SN - 0737-4038
IS - 6
ER -