Although the genome of SARS-CoV-2 was sequenced early in the outbreak (see BioNews 1033), scientists in Taiwan, Germany and the US have recently identified a gene hidden within another gene. Genes within other genes are known as overlapping genes (OLGs); they are common in viruses, and easily overlooked, despite their pathogenic potential.
'Overlapping genes may be one of an arsenal of ways in which coronaviruses have evolved to replicate efficiently, thwart host immunity, or get themselves transmitted,' said Dr Chase Nelson from Taiwan's Academia Sinica, lead author of the study published in eLife.
To identify OLGs, Dr Nelson and colleagues used a method to screen genomes for open reading frames (ORFs). ORFs are sections of DNA that contain no stop codons – signals that stop the genetic sequence being translated into protein. The longer the ORF, the more likely a gene is translated and a protein expressed.
The team applied this method to SARS-CoV-2 DNA sequence data, and identified one unexpectedly long ORF, ORF3d, inside another gene, ORF3a. ORF3d is actually longer than some other SARS-CoV-2 genes. ORF3d encodes a novel protein that is not expressed in other 'severe acute respiratory syndrome'-related coronavirus genomes, such as the SARS viruses of 2002-2004. In contrast, ORF3d was found in pangolin coronaviruses native to the Guangxi province of southern China, although, this does not conclusively determine the animal source of the virus.
T cells, a type of immune cell, failed to react to ORF3d, suggesting that it evades the immune system. However, other groups have reported that ORF3d elicits a strong antibody response in COVID-19 patients, demonstrating that the ORF3d protein is assembled during infection.
According to Dr Nelson, 'Missing overlapping genes puts us in peril of overlooking important aspects of viral biology... Knowing that overlapping genes exist and how they function may reveal new avenues for coronavirus control, for example through antiviral drugs.'