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Researchers have discovered a mysterious gene in the genetic code of the SARS-CoV-2 coronavirus – a segment virtually hidden in the virus’s genome, and largely neglected until now.
The newly identified gene – called ORF3d – is an example of what is called an overlapping gene: a kind of “gene within a gene” that is effectively concealed in a chain of nucleotides, due to the way it overlaps with the encoded sequences of other genes .
“In terms of genome size, SARS-CoV-2 and its parents are among the longest RNA viruses that exist,” says bioinformatician Chase Nelson of the American Museum of Natural History.
“So they are perhaps more prone to ‘genomic deception’ than other RNA viruses.”
Viruses are actually quite prone to harboring overlapping genes, so it’s not really a shocking finding. Whether ORF3d truly represents a genomic trickery remains to be seen, but in any case, it is certainly difficult to see.
Overlapping genes are difficult to identify in genetic sequences, as genomic scanning systems can often miss them when traversing strings of genetic code: programmed to capture individual genes, but not necessarily seeing the overall instructions shared between the nucleotides of adjacent genes in a sequence.
Against the background of viruses like SARS-CoV-2, this could create a serious blind spot. Scientists have been trying to understand as much as possible about this devastating virus since the start of this year, and although some aspects of its genetic makeup have been elucidated (including the strong consensus that it was not ‘made in laboratory ”), a lot remains that we just don’t know yet.
“The lack of overlapping genes puts us at risk of overlooking important aspects of viral biology,” Nelson says.
“Overlapping genes may be one of the many ways in which coronaviruses have evolved to replicate efficiently, thwart host immunity, or be transmitted.”
As for ORF3d, there is still a lot to learn about why it is there, hidden in the genome and overlapping other genes.
Browsing through genomic databases, the researchers found that the gene had already been identified, but only in a variant of the coronavirus that affects pangolins (found in Guangxi, China).
It was also previously incorrectly classified as an unrelated gene, ORF3b – which is present in other coronaviruses, including SARS-CoV – but it’s not actually the same.
“The two genes are not linked and code for totally different proteins”, Nelson says. “This means that knowledge about SARS-CoV ORF3b should not be applied to SARS-CoV-2 ORF3d. “
One thing we do know about the mysterious gene, based on previous blood tests with human COVID-19 patients, is that ORF3d elicits a strong antibody response.
As to whether T cells would also be triggered – or for what other viral purposes the overlap ORF3d might have – we’re still in the dark. It could be relatively benign. It might not be.
“We don’t yet know its function or if there is clinical significance,” Nelson says.
“But we predict that this gene is relatively unlikely to be detected by a T cell response, unlike the antibody response. And maybe that has something to do with how the gene may have appeared.”
One thing is certain. In a virus that has only about 15 known genes, the discovery of another – not to mention an overlapping gene – is an important development. How scientists will now try to find out.
The results are reported in eLife.
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