Understanding the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the virus that causes the coronavirus disease 2019 (COVID-19) – is crucial for both vaccine and treatment development. Since the pandemic started in December 2019, many studies have explored the virus’s origins and how it infects humans. This way, scientists and clinicians have an idea of how to combat the infection.
A team of researchers from Germany, Taiwan, and the United States has identified and characterized a new hidden gene in SARS-CoV-2 that is also present in Guangxi pangolin coronaviruses – though, curiously, absent in closely related pangolin and bat coronaviruses.
What are overlapping genes?
The coronavirus pandemic raises urgent questions about the properties that allow viruses in animals to jump to humans. Called zoonosis, these types of diseases have impacted human life for years, including the AH1N1 virus, bovine tuberculosis, glanders, and bubonic plague, among others.
To further understand zoonotic diseases, it is essential to know more about viral genomes. One of the frequently overlooked sources is the evolution of novel overlapping genes (OLGs). In these genes, a single stretch of nucleotides encodes two different proteins in varying reading frames.
The SARS-CoV-2, in particular, has about 15 genes in total, and knowing more about them, including overlapping genes, is important.
“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,” Chase Nelson, a postdoctoral researcher at Academia Sinica in Taiwan and a visiting scientist at the American Museum of Natural History, explained.
“Knowing that overlapping genes exist and how they function may reveal new avenues for coronavirus control, for example, through antiviral drugs,” he added.
Gene repertoire and evolutionary relationships of Severe acute respiratory syndrome-related coronavirus species members. Only genes downstream of ORF1ab are shown, beginning with the Spike gene S. (A) Four types of genes and their relative positions in the SARS-CoV-2 Wuhan-Hu- 1 genome (NCBI: NC_045512.2). Genes are colored by type: novel overlapping genes (OLGs) (gold; ORF3d only); conserved OLGs (burgundy); accessory (green); and structural (blue). Note that ORF3b has been truncated relative to SARS-CoV genomes, whereas ORF8 remains intact (i.e. has not been split into ORF8a and ORF8b). (B) Genes with intact ORFs in each of 21 Severe acute respiratory syndrome-related coronavirus genomes. Gene positions are shown relative to each genome, i.e. homologous genes are not precisely aligned.
Identifying a new gene
In the current study, published in the journal eLife, the researchers identified ORF3d, a new overlapping gene in SARS-CoV2 that can potentially encode a protein that is longer than expected by chance alone. The researchers revealed that the gene is also present in previously discovered pangolin coronaviruses.
Further, the team found that the new gene has been shown to exhibit a strong antibody response in COVID-19 patients, indicating that the novel gene’s protein is produced during human infection.
“We don’t yet know its function or if there’s clinical significance. 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,” Nelson said.
It is challenging to detect overlapping genes since most high-end and scientific computers are not designed to find them. Nevertheless, these are common in coronaviruses since RNA viruses, like SARS-CoV-2, have a high mutation rate. Hence, viruses have developed a data compression system where one letter in the genome can influence two or three different genes.
Study implications
Studying the genome of viruses, particularly SARS-CoV-2, can help us gain a better understanding of its characteristics and its evolution. This becomes crucial in developing effective vaccines that can induce an adequate immune response to fight the infection.
COVID-19 continues to spread rapidly across the globe. In the past few weeks, many countries have reported a second wave of infections. Countries in Europe, which had reopened their businesses and schools just a couple of months ago, are now seeing a resurgence of cases. However, these clusters of new infections have triggered second lockdowns in many countries – including Belgium, the United Kingdom, and Italy – which could have potential social, economic, and psychological effects on the public.
The United States has the highest number of infections, reaching over 10.39 million cases and 240,918 deaths. India and Brazil follow with more than 8.63 million and 5.69 million cases, respectively.
France reports more than 1.91 million cases, followed by Russia, Spain, and Argentina, with over 1.82 million, 1.41 million, and 1.27 million cases, respectively.
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