BREAKING! COVID-19 Genomics: Scientist Uncover Hidden Novel Overlapping Gene ORF3d In SARS-CoV-2 Genome That Might Not Be Detectable By T-Cells
: Scientists and genomic specialists from the Academia Sinica-Taiwan, the Institute for Comparative Genomics-U.S, Technical University of Munich-Germany, University of Wisconsin-Madison, SUNY Downstate Health Sciences University-U.S, University of California-Berkeley and University of California-Los Angeles have in a new study discovered a hidden novel overlapping gene that the international research community had overlooked till now. This gene known as the ORF3d gene could also be undetectable by T-cell response and more studies are needed to understand its role and functions.
Typically understanding the emergence of novel viruses requires an accurate and comprehensive annotation of their genomes. Overlapping genes (OLGs) are common in viruses and have been associated with pandemics but are still widely overlooked.
The study team discovered and characterized ORF3d, a novel OLG in SARS-CoV-2 that is also present in Guangxi pangolin-CoVs but not other closely related pangolin-CoVs or bat-CoVs.
The team then documented evidence of ORF3d translation, characterized its protein sequence, and conducted an evolutionary analysis at three levels: between taxa (21 members of Severe acute respiratory syndrome-related coronavirus), between human hosts (3978 SARS-CoV-2 consensus sequences), and within human hosts (401 deeply sequenced SARS-CoV-2 samples).
ORF3d has been independently identified and shown to elicit a strong antibody response in COVID-19 patients. However, it has been misclassified as the unrelated gene ORF3b, leading to confusion. The study findings liken ORF3d to other accessory genes in emerging viruses and highlight the importance of OLGs.
The study results were published in the peer reviewed journal: eLife https://elifesciences.org/articles/59633
Totally understanding the SARS-CoV-2 coronavirus that causes the COVID-19 disease 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.
The study team from Germany, Taiwan, and America 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.
The COVID-19 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.
In order 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.
Importantly the SARS-CoV-2, in particular, has about 15
genes in total, and knowing more about them, including overlapping genes, is important.
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.
Dr Chase Nelson, a postdoctoral researcher at Academia Sinica in Taiwan and a visiting scientist at the American Museum of Natural History, explained to Thailand Medical News, “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. Knowing that overlapping genes exist and how they function may reveal new avenues for coronavirus control, for example, through antiviral drugs.”
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 study team revealed that the gene is also present in previously discovered pangolin coronaviruses.
Interestingly 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.
Dr Nelson added, “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.”
Normally 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.
Detailed studies of 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.
In conclusion, OLGs are an important part of viral biology and deserve more attention. We document several lines of evidence for the expression and functionality of a novel OLG in SARS-CoV-2, ORF3d, and compare it to other hypothesized OLG candidates in ORF3a. Finally, as a resource for future studies, we provide a detailed annotation of the SARS-CoV-2 genome and highlight mutations of potential relevance to the within- and between-host evolution of SARS-CoV-2.
Thailand Medical News strongly recommends all genomic, genetic, immunology and drug researchers to carefully peruse through the study results and discussions and also attached references as the are many key interesting and useful points.
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