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ORF3c is a gene found in coronaviruses of the subgenus Sarbecovirus, including SARS-CoV and SARS-CoV-2. It was first identified in the SARS-CoV-2 genome and encodes a 41 amino acid non-structural protein of unknown function. It is also present in the SARS-CoV genome, but was not recognized until the identification of the SARS-CoV-2 homolog.

Nomenclature

There has been significant confusion in the scientific literature around the nomenclature used for the accessory proteins of SARS-CoV-2, especially several overlapping genes with ORF3a. The predicted protein product of the ORF3c gene has at least once been referred to as "3b protein", but it is not to be confused with the non-homologous gene ORF3b. It has also been described under the names ORF3h and ORF3a.iORF1. The recommended nomenclature for SARS-CoV-2 uses the term ORF3c for this gene.

Comparative genomics

ORF3c is an overlapping gene whose open reading frame overlaps both ORF3a and ORF3d in the SARS-CoV-2 genome. This potentially represents a rare example of all three possible reading frames of the same sequence region encoding functional proteins.

Bioinformatics analyses of Sarbecovirus sequences suggest that the sequence and length of ORF3c are well conserved, indicating that it is likely to encode a functional protein. It appears to be subject to purifying selection.

Properties

Ribosome profiling experiments confirm that the ORF3c gene expresses a protein product. The relatively short 41-residue protein is predicted to contain a transmembrane domain and has features suggestive of a viroporin.

References

1. ^ Firth AE (October 2020). "A putative new SARS-CoV protein, 3c, encoded in an ORF overlapping ORF3a". The Journal of General Virology. 101 (10): 1085–1089. doi:10.1099/jgv.0.001469. PMC 7660454. PMID 32667280.
2. ^ Cagliani R, Forni D, Clerici M, Sironi M (September 2020). "Coding potential and sequence conservation of SARS-CoV-2 and related animal viruses". Infection, Genetics and Evolution. 83: 104353. doi:10.1016/j.meegid.2020.104353. PMC 7199688. PMID 32387562.
3. ^ Jungreis I, Sealfon R, Kellis M (May 2021). "SARS-CoV-2 gene content and COVID-19 mutation impact by comparing 44 Sarbecovirus genomes". Nature Communications. 12 (1): 2642. doi:10.1038/s41467-021-22905-7. hdl:1721.1/130581. PMC 8113528. PMID 33976134.
4. ^ Jungreis I, Nelson CW, Ardern Z, Finkel Y, Krogan NJ, Sato K, et al. (June 2021). "Conflicting and ambiguous names of overlapping ORFs in the SARS-CoV-2 genome: A homology-based resolution". Virology. 558: 145–151. doi:10.1016/j.virol.2021.02.013. hdl:1721.1/130363. PMC 7967279. PMID 33774510.
5. Pavesi A (July 2020). "New insights into the evolutionary features of viral overlapping genes by discriminant analysis". Virology. 546: 51–66. doi:10.1016/j.virol.2020.03.007. PMC 7157939. PMID 32452417.
6. ^ Finkel Y, Mizrahi O, Nachshon A, Weingarten-Gabbay S, Morgenstern D, Yahalom-Ronen Y, et al. (January 2021). "The coding capacity of SARS-CoV-2". Nature. 589 (7840): 125–130. doi:10.1038/s41586-020-2739-1. PMID 32906143.
7. ^ Nelson CW, Ardern Z, Goldberg TL, Meng C, Kuo CH, Ludwig C, et al. (October 2020). "Dynamically evolving novel overlapping gene as a factor in the SARS-CoV-2 pandemic". eLife. 9: e59633. doi:10.7554/eLife.59633. PMC 7655111. PMID 33001029.

v t e Coronavirus genomes
Viral structural protein	spike protein (S) envelope protein (E) membrane protein (M) nucleocapsid protein (N)
Viral nonstructural protein (expressed from ORF1ab)	nonstructural protein 1 nonstructural protein 2 papain-like protease (nsp3) nonstructural protein 4 3C-like protease (nsp5) nonstructural protein 6 nonstructural protein 7 nonstructural protein 8 nonstructural protein 9 nonstructural protein 10 nonstructural protein 11 nonstructural protein 12 nonstructural protein 13 nonstructural protein 14 nonstructural protein 15 nonstructural protein 16
Viral accessory protein	ORF3a ORF3b ORF3c ORF3d ORF6 ORF7a ORF7b ORF8 ORF9b ORF9c ORF10
RNA	Coronavirus 5′ UTR Coronavirus 3′ UTR Coronavirus 3′ UTR pseudoknot Coronavirus 3′ stem-loop II-like motif (s2m) Coronavirus packaging signal Coronavirus frameshifting stimulation element Human identical sequence

• Coronavirus proteins
• Viral nonstructural proteins