BREAKING! COVID-19 Genomics: Harvard Led Study Identifies Specific SARS-CoV-2 Genomic Mutations Associated With Higher COVID-19 Deaths
: A new breakthrough research led by scientists from Harvard including researchers from the T.H. Chan School of Public Health, Harvard University-Boston, Massachusetts Institute of Technology-Cambridge, Harvard Medical School-Boston, Brigham and Women's Hospital-Boston, Boston Children’s Hospital and also experts from Dankook University-South Korea have identified specific SARS-CoV-2 genomic mutations that are linked with higher mortality rates upon infection.
SARS-CoV-2 mortality has been extensively studied in relationship to a patient's predisposition to the disease. However, how sequence variations in the SARS-CoV-2 genome affect mortality was not understood then. To address this issue, the study team used a whole-genome sequencing (WGS) association study to directly link death of SARS-CoV-2 patients with sequence variation in the viral genome.
Specifically, the study teamanalyzed 3,626 single stranded RNA-genomes of SARS-CoV-2 patients in the GISAID database with reported patient’s health status from COVID-19, i.e. deceased versus non-deceased. In total, evaluating 28,492 loci of the viral genome for association with patient/host mortality, two loci, 12,053bp and 25,088bp, achieved genome-wide significance (p-values of 1.24e-12, and 1.24e-26, respectively).
Mutations at 25,088bp occur in the S2 subunit of the SARS-CoV-2 spike protein, which plays a key role in viral entry of target host cells. Additionally, mutations at 12,053bp are within the ORF1ab gene, in a region encoding for the protein nsp7, which is necessary to form the RNA polymerase complex responsible for viral replication and transcription. Both mutations altered amino acid coding sequences, potentially imposing structural changes that could enhance viral infectivity and symptom severity, and may be important to consider as targets for therapeutic development.
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2020.11.17.386714v1
The SARS-CoV-2 coronavirus, the causative pathogen of COVID-19, is a single-stranded, positive-sense RNA virus with a genome size of around 30 kb. Since the emergence of the COVID-19 pandemic, many genomic studies have shown that the SARS-CoV-2 genome undergoes recurrent mutations, indicating a continuous viral adaptation process inside host cells. Some of these mutations, such as the D614G mutation in the viral spike protein, have been found to increase the infectivity and transmissibility of SARS-CoV-2. Thus, continuous monitoring of the viral genomic alterations would be vital to identify potential targets for drug or vaccine development.
The study team tried to find out the link between SARS-CoV-2 mutations and COVID-19 severity by analyzing a total of 3626 SARS-CoV-2 genomes available on the Global Initiative on Sharing All Influenza Data (GISAID) database.
The team conducted whole-genome sequence analysis to study the presence or absence of mutations on each genetic locus of SARS-CoV-2, as well as to evaluate the correlation between genetic mutations and patient mortality rates.
Simply by analyzing the genome sequences for possible confounding geographic factors, the scientists i
dentified distinct genome clusters that matched their respective geographic locations of origin.
Importantly and significantly, by conducting the whole-genome sequence analysis, the study team identified two genetic loci that reached genome-wide significance. These loci were positioned at 12053bp and 25088bp.
Also the study team observed that the Brazilian centers reported significantly higher numbers of deceased patients compared to other centers. The genomes of SARS-CoV-2 that bear at least one mutation at 12,053bp or 25,088bp were obtained predominantly from South America, Asia, and Europe.
Detailed analysis revealed that the mutations at these two loci increase the COVID-19 related mortality risk by 5-fold. The mutation at 25088bp occurred in the S2 subunit of the viral spike protein, which plays a vital role in virus-host membrane fusion and viral entry.
To date there is evidence indicating that mutations in the viral spike protein can increase the infectivity and virulence, which in turn can affect the COVID-19 severity and mortality.
The study team observed that most of the mutations at 25088bp were G to T missense mutations that cause a valine to phenylalanine amino acid substitution. Other mutations were G to A (valine to isoleucine) and G to C (valine to leucine) mutations.
As a result of significant biochemical and structural variations between valine and phenylalanine, a G to T mutation may alter the local structural architecture, facilitate secondary structure stabilization, or introduce preferential binding motifs. Thus, an induction in proteolytic cleavage in the S2 subunit due to specific mutations can potentially increase the infectivity and virulence.
The detailed study analysis shows that the mutation at 12053bp occurred within the open reading frame1ab (ORF1ab) gene. Specifically, the mutation occurred in non-structural protein 7 (NSP7), which mediates the formation of RNA polymerase complex necessary for viral replication and transcription.
The study team says that such a mutation may increase the activity of RNA polymerase, which in turn can increase virulence.
In conclusion, the study identifies two genetic variations in SARS-CoV-2 that can influence viral pathogenicity and increase the risk of COVID-19 related mortality.
While enhanced infectivity does not always cause higher fatality rate, more infectious viruses can lead to a higher viral load, which can impact symptom severity and mortality.
Thailand Medical News will be mapping out and identifying all existing strains and variants carrying these two mutations and listing them in a continuing article.
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