Study identifies new gene ‘hidden’ in COVID-19 virus

Researchers have discovered a new “hidden” gene in SARS-CoV-2 – the virus that causes COVID-19 – that may have contributed to its unique biology and pandemic potential. In a virus that only has about 15 genes in total, knowing more about it and other overlapping genes – or “genes in genes” – could have a significant impact on how we fight it. virus. The new gene is described today in the journal eLife.

“Overlapping genes may be one of the many ways in which coronaviruses have evolved to replicate efficiently, thwart host immunity, or transmit themselves,” said lead author Chase Nelson, postdoctoral researcher at the Academia Sinica in Taiwan and visiting scholar at the American Museum of Natural History. “Knowing that there are overlapping genes and how they work may reveal new pathways for coronavirus control, for example through antiviral drugs.”

The research team identified ORF3d, a new overlapping gene in SARS-CoV-2 that has the potential to encode a protein that is longer than expected by chance alone. They found that this gene is also present in a previously discovered pangolin coronavirus, possibly reflecting a repeated loss or gain of this gene during the course of SARS-CoV-2 and related viruses. Furthermore, ORF3d has been independently identified and shown to induce a strong antibody response in COVID-19 patients, demonstrating that the new gene protein is made during human infection.

“We don’t yet know its function or if there is clinical significance,” Nelson said. “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.”

At first glance, genes can look like written language in that they are made up of strings of letters (in RNA viruses, nucleotides A, U, G, and C) that carry information. But while the units of language (words) are discrete and don’t overlap, genes can overlap and be multifunctional, with information encrypted depending on where you start to “read.” Overlapping genes are difficult to spot, and most scientific computer programs are not designed to find them. However, they are common in viruses. This is partly due to the fact that RNA viruses have a high mutation rate, so they tend to keep their gene count low to avoid a large number of mutations. As a result, viruses have developed a kind of data compression system in which one letter in its genome can contribute to two or even three different genes.

“The lack of overlapping genes puts us at risk of overlooking important aspects of viral biology,” Nelson said. “In terms of genome size, SARS-CoV-2 and its parents are among the longest RNA viruses in existence. They are therefore perhaps more prone to ‘genomic trickery’ than other RNA viruses. “

Before the pandemic, while working at the Museum as a Gerstner Fellow in Bioinformatics and Computational Biology, Nelson developed a computer program that analyzes genomes for patterns of genetic change unique to overlapping genes. For this study, Nelson partnered with colleagues from institutions such as the Technical University of Munich and the University of California at Berkeley, to apply this software and other methods to the wealth of new sequence data available. for SARS-CoV-2. The group hopes other scientists will study the gene discovered in the lab to define its function and possibly determine what role it may have played in the emergence of the pandemic virus.