Researchers have discovered a new “hidden” gene in SARS-CoV-2 – the virus that causes COVID-19 – that could have contributed to its unique biology and pandemic potential. For a virus with only about 15 genes in total, knowing about this and other overlapping genes – or “genes within genes” – could have a significant impact on how we fight the virus. The new gene is described in the journal today eLife.
“Overlapping genes may be one of the ways coronaviruses have evolved to replicate efficiently, thwart host immunity, or transmit themselves,” said lead author Chase Nelson, a postdoctoral fellow at Academia Sinica in Taiwan and visiting researcher at the American Museum of Natural History. “Knowing that overlapping genes exist and how they work can open new avenues for coronavirus control, such as 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. They found that this gene is also present in a previously discovered pangolin coronavirus, possibly due to the repeated loss or gain of this gene during the development of SARS-CoV-2 and related viruses. Additionally, ORF3d has been independently identified and shown to elicit a strong antibody response in COVID-19 patients, showing that the protein of the new gene is made during infection in humans.
“We don’t yet know what its function is or if it has any clinical significance,” said Nelson. “However, we assume that, in contrast to the antibody response, it is relatively unlikely that this gene will be detected by a T cell response. And maybe that has something to do with how the gene came about. ”
At first glance, genes can appear like a written language, as they consist of strings of letters (in RNA Viruses that carry nucleotides A, U, G and C) that convey information. While the units of language (words) are discrete and non-overlapping, genes can be overlapping and multifunctional, with information cryptically encoded depending on where you start “reading”. Overlapping genes are difficult to spot, and most scientific computer programs are not designed to find them. However, they are common with viruses. This is partly due to the fact that RNA viruses have a high mutation rate and therefore tend to keep their gene counts low in order to prevent a large number of mutations. As a result, viruses have developed a type of data compression system where a letter in its genome can contribute to two or even three different genes.
“The lack of overlapping genes puts us at risk of missing important aspects of viral biology,” said Nelson. “In terms of genome size, SARS-CoV-2 and its relatives are among the longest existing RNA viruses. They are therefore possibly more prone to “genomic tricks” than other RNA viruses. ”
Before the pandemic, Nelson, as a Gerstner fellow in bioinformatics and computational biology, developed a computer program at the museum that examines genomes for patterns of genetic changes that only apply to overlapping genes. For this study, Nelson worked with colleagues from institutions such as the Technical University of Munich and the University of California, Berkeleyto apply this software and other methods to the plethora of new sequence data available for SARS-CoV-2. The group hopes that other scientists will study the gene discovered in the laboratory to define its function and possibly determine what role it may have played in causing the pandemic virus.
Reference: “Dynamically evolving novel overlapping genes as a factor in the SARS-CoV-2 pandemic” by Chase W. Nelson, Zachary Ardern, Tony L. Goldberg, Chen Meng, Chen-Hao Kuo, Christina Ludwig, Sergios-Orestis Kolokotronis and Xinzhu Wei, October 1st, 2020 eLife.
DOI: 10.7554 / eLife.59633
Funding for this work was provided in part by the Academia Sinica, the Bavarian state government and the 12 National Philanthropic Trust, the US National Science Foundation (grant numbers 1755370 and 1758800) and the University of Wisconsin-Madison.
