Researchers have revealed the presence of a mysterious gene in the SARS-CoV-2 coronavirus, a segment virtually hidden from view in the virus genome and until now overlooked.
The recently identified gene, called ORF3d, is an example of what is called overlapping gene: a gene whose expressible nucleotide sequence partially overlaps with the expressible nucleotide sequence of another gene.
“In terms of genome size, SARS-CoV-2 and its relatives are among the viruses with the most extensive RNA,” explains bioinformatician Chase Nelson of the American Museum of Natural History. “Therefore, they are more prone to ‘genomic deception’ than other RNA viruses.”
Overlapping genes are difficult to identify in genetic sequences, since they are sometimes ignored by scanning systems when analyzing strings of a code. This is because they are programmed to pick up individual genes, but not necessarily the arched instructions about the nucleotides shared between adjacent genes in a sequence.
In this context, for SARS-CoV-2 it could represent a fairly significant blind spot. Scientists have been racing to understand as much as possible about this devastating virus and, while some aspects of its genetic makeup have been elucidated, many remain unknown.
“Overlapping genes put us in danger of missing or underestimating important aspects of viral biology,” says Nelson. “It may be a way in which coronaviruses have evolved to replicate more efficiently, disrupt the host’s immunity, or improve its transmission speed.”
As for ORF3d, there is still a lot to learn about why it is there, swarming the genome and riding on other genes.
Searching genomic databases, researchers have found that this gene had been identified before, but only in a variant of the coronavirus that affects pangolins (found in Guangxi, China).
It has also previously been misclassified as another gene: ORF3b, which is present in other coronaviruses – including SARS-CoV – but is not the same.
“The two genes are not related and are encoded by entirely different proteins,” says Nelson.“ This means that the knowledge about SARS-CoV ORF3b should not be applied to SARS-CoV-2 ORF3d.
One thing we do know about this mysterious gene, based on blood draws from COVID-19 patients, is that it triggers a strong antibody response. Although there is no similar certainty as to whether it causes the same in T cells (a species of immune cell whose main purpose is to identify and kill invading pathogens or infected cells).
“We still do not know its function or if it is of clinical importance”, Nelson says.” But we predict that, in contrast to antibodies, this gene is unlikely to receive a response from T cells. And perhaps that has to do with how the gene is able to arise.”
One thing is for sure. In a virus that only has 15 known genes, the discovery of another – and on top of it overlapping – is a significant advance. How significant? It’s the next thing scientists will try to find out.
The findings have been published in eLife.