Researchers from leading institutions, including Academia Sinica, have identified a previously overlooked "overlapping gene" in the SARS-CoV-2 genome. This discovery, published in the prestigious journal eLife, sheds light on the virus's unique biology and its potential role in the ongoing pandemic.
Dubbed ORF3d, this gene exemplifies an "overlapping gene," where one segment of genetic code produces multiple proteins. Such features are challenging for standard genome-scanning tools to detect, as they aren't designed to identify these nested structures.
RNA viruses like SARS-CoV-2 frequently evolve overlapping genes due to their rapid mutation rates. This allows them to maintain a compact genome—around 15 genes total—acting like a biological data compression system where a single sequence can encode multiple functions.
With so few genes, pinpointing structures like ORF3d is crucial for developing targeted therapies against COVID-19.
"Overlapping genes may be one of the many ways coronaviruses have evolved to efficiently replicate, thwart host immunity, or transmit," explains lead author Chase Nelson, a virologist at Academia Sinica in Taiwan. "Knowing that these genes exist and how they work may reveal new pathways for coronavirus control, such as through antiviral drugs."
Much remains to be discovered about ORF3d's function or clinical relevance, Nelson notes: "We don't yet know its function or if there is any clinical significance." Genomic database analysis revealed it in a pangolin coronavirus variant from Guangxi, China, but it was mistakenly classified as the unrelated ORF3b gene found in other coronaviruses, including SARS-CoV-2.
"ORF3d and ORF3b are unrelated and encode entirely different proteins," Nelson clarifies. "This means that our knowledge of SARS-CoV ORF3b should not be applied to SARS-CoV-2 ORF3d."
Notably, blood samples from COVID-19 patients show a strong antibody response to ORF3d, confirming the protein is produced during human infection.
Ongoing research aims to fully map SARS-CoV-2's genomic architecture, paving the way for innovative protections against this pathogen.
