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PreprintCC BY-NC-NDbioRxiv

The biochemical composition of coronavirus Nucleocapsid proteins drives the bicistronic properties of their sub-genomic mRNAs

  • F. De Angelis
  • H. W. Chook
  • T. Apaa
  • A. Seekings
  • L. McElhinney
  • R. Rademan
  • M. Geldenhuys
  • W. Markotter
  • R. M. Pinto
  • E. R. Gaunt
  • L. R. Lu
  • S. J. Lycett
1 more authors
  • P. Digard1
  1. 1University of Edinburgh
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Abstract

The nucleocapsid (N) gene of coronaviruses (CoVs) encodes a structural RNA-binding protein required for viral assembly. In SARS- and MERS-CoV viruses, reading frame 2 of N contains an overlapping open reading frame (ORF) encoding an innate immune antagonist accessory protein. However, the extent of this dual coding capacity across the CoV family, and the genetic features driving overlapping ORF formation, remain unexamined. Here, we developed an in-silico tool (ORFan) to screen structural gene sub-genomic mRNA sequences from 152 species of coronavirus for the presence of overlapping accessory gene candidates. We found that frame 2 of the N gene in Alpha-, Beta- and Delta-CoVs frequently contains a potential accessory ORF (AcORF), conserved at the subgenus level, unlike the spike, envelope and membrane genes. We also show that CoV nucleotide biases in conjunction with codon biases integral to N protein function drive the relatively high abundances of start codons in frame two and stop codons in frame three, explaining the tendency towards frame 2 AcORFs. We further suggest that viral nucleotide biases and the codon composition required for RNA-binding function facilitate overlapping ORF formation in other virus families

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Cite

BibTeXRIS
BibTeX
@misc{angelis2026biochemical,
  title = {{The biochemical composition of coronavirus Nucleocapsid proteins drives the bicistronic properties of their sub-genomic mRNAs}},
  author = {F. De Angelis and H. W. Chook and T. Apaa and A. Seekings and L. McElhinney and R. Rademan and M. Geldenhuys and W. Markotter and R. M. Pinto and E. R. Gaunt and L. R. Lu and S. J. Lycett and P. Digard},
  howpublished = {bioRxiv},
  year = {2026},
  month = nov,
  doi = {10.64898/2026.11.04.764307},
  url = {https://www.biorxiv.org/content/10.64898/2026.11.04.764307v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - The biochemical composition of coronavirus Nucleocapsid proteins drives the bicistronic properties of their sub-genomic mRNAs
AU  - F. De Angelis
AU  - H. W. Chook
AU  - T. Apaa
AU  - A. Seekings
AU  - L. McElhinney
AU  - R. Rademan
AU  - M. Geldenhuys
AU  - W. Markotter
AU  - R. M. Pinto
AU  - E. R. Gaunt
AU  - L. R. Lu
AU  - S. J. Lycett
AU  - P. Digard
PY  - 2026
DA  - 2026/11/04
PB  - bioRxiv
DO  - 10.64898/2026.11.04.764307
UR  - https://www.biorxiv.org/content/10.64898/2026.11.04.764307v1
AB  - The nucleocapsid (N) gene of coronaviruses (CoVs) encodes a structural RNA-binding protein required for viral assembly. In SARS- and MERS-CoV viruses, reading frame 2 of N contains an overlapping open reading frame (ORF) encoding an innate immune antagonist accessory protein. However, the extent of this dual coding capacity across the CoV family, and the genetic features driving overlapping ORF formation, remain unexamined. Here, we developed an in-silico tool (ORFan) to screen structural gene sub-genomic mRNA sequences from 152 species of coronavirus for the presence of overlapping accessory gene candidates. We found that frame 2 of the N gene in Alpha-, Beta- and Delta-CoVs frequently contains a potential accessory ORF (AcORF), conserved at the subgenus level, unlike the spike, envelope and membrane genes. We also show that CoV nucleotide biases in conjunction with codon biases integral to N protein function drive the relatively high abundances of start codons in frame two and stop codons in frame three, explaining the tendency towards frame 2 AcORFs. We further suggest that viral nucleotide biases and the codon composition required for RNA-binding function facilitate overlapping ORF formation in other virus families
ER  -