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Researchers have discovered a mysterious gene in the genetic code of the SARS-CoV-2 coronavirus, a segment virtually hidden from view in the virus genome and largely overlooked 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 actually hidden in a string of nucleotides, due to the way it overlaps the encoded sequences of other genes.
“In terms of genome size, SARS-CoV-2 and its relatives are among the longest RNA viruses in existence,” explains bioinformatician Chase Nelson of the American Museum of Natural History.
“They are therefore perhaps more prone to” genomic deceptions “than other RNA viruses.”
Viruses are actually quite prone to harboring overlapping genes, so that’s not exactly a shocking finding. Self ORF3d truly represents a genomic deception 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 collect individual genes, but not necessarily by seeing general instructions shared between the nucleotides of adjacent genes in a sequence .
In the context of viruses such as SARS-CoV-2, this could be a serious blind spot. Scientists have been trying to understand as much as possible about this devastating virus since the beginning of this year, and while some aspects of its genetic make-up have been elucidated (including the firm consensus that it was not “ lab-produced ”), much remains what we do not yet know.
“The lack of overlapping genes puts us in danger of neglecting important aspects of viral biology,” says Nelson.
“Overlapping genes may be one of an arsenal of ways coronaviruses have evolved to replicate efficiently, counter host immunity, or be transmitted.”
As for ORF3d, there is still much to learn about why it is there, lurking in the genome and straddling other genes.
By analyzing genomic databases, the researchers found that the gene had previously been identified, but only in a variant of the coronavirus that affects pangolins (found in Guangxi, China).
It was also previously misclassified as an unrelated gene, ORF3b – which is present in other coronaviruses, including SARS-CoV – but they are not actually the same.
“The two genes are unrelated and encode completely different proteins”, Nelson says. “This means that the knowledge of SARS-CoV ORF3b it 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 this ORF3d causes a strong antibody response.
As to whether the T lymphocytes would also be triggered – or what other viral purposes the overlap ORF3d might have – we’re still in the dark. It could be relatively benign. It may not be.
“We don’t yet know its function or if there is any clinical significance,” Nelson says.
“But we anticipate that it is relatively unlikely that this gene will be detected by a T cell response, as opposed to the antibody response. And perhaps this has something to do with how the gene was able to arise.”
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 a significant development. How significant that is, scientists will now try to find out.
The results are reported in eLife.
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