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 this and other overlapping genes—or “genes within genes”—could have a
significant impact on how we combat the virus. The new gene is described today
in the journal eLife.
“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 lead author Chase Nelson, a
postdoctoral researcher at Academia Sinica in Taiwan and a visiting
scientist at the American Museum of Natural History. “Knowing that
overlapping genes exist and how they function may reveal new avenues 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, perhaps reflecting repeated loss or gain of
this gene during the evolution of SARS-CoV-2 and related viruses. In
addition, ORF3d has been independently identified and shown to elicit a
strong antibody response in COVID-19 patients, demonstrating that the new
gene’s protein is manufactured during human infection.
“We don’t yet know its function or if there’s clinical significance,” Nelson
said. “But we predict this gene is relatively unlikely to be detected by a
T-cell response, in contrast to the antibody response. And maybe that has
something to do with how the gene was able to arise.”
At first glance, genes can seem like written language in that they are made
of strings of letters (in RNA viruses, the nucleotides A, U, G, and C) that
convey information. But 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 hard to spot, and most scientific computer programs
are not designed to find them. However, they are common in viruses. This is
partly because RNA viruses have a high mutation rate, so they tend to keep
their gene count low to prevent a large number of mutations. As a result,
viruses have evolved a sort of data compression system in which one letter
in its genome can contribute to two or even three different genes.
“Missing overlapping genes puts us in peril of overlooking important aspects
of viral biology,” said Nelson. “In terms of genome size, SARS-CoV-2 and its
relatives are among the longest RNA viruses that exist. They are thus
perhaps more prone to ‘genomic trickery’ than other RNA viruses.”
Prior to the pandemic, while working at the Museum as a Gerstner Scholar in
Bioinformatics and Computational Biology, Nelson developed a computer
program that screens genomes for patterns of genetic change that are unique
to overlapping genes. For this study, Nelson teamed up with colleagues from
institutions including the Technical University of Munich and the University
of California, Berkeley, to apply this software and other methods to the
wealth of new sequence data available for SARS-CoV-2. The group is hopeful
that other scientists will investigate the gene they discovered in the lab
to define its function and possibly determine what role it might have played
in the emergence of the pandemic virus.
Reference:
Nelson CW, Ardern Z, Goldberg TL, et al. Dynamically evolving novel
overlapping gene as a factor in the SARS-CoV-2 pandemic. eLife. 2020. doi:
10.7554/eLife.59633
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