BREAKING! Most Of The New Aggressive SARS-CoV-2 Strains In America And Europe Contain Three Mutations D614G, P323L and C241U On A Single Strain!

SARS-CoV-2 Strains: A new study led by researchers from University of Missouri along with scientists from University of Nebraska and Karolinska Institute-Sweden have alarmingly discovered that most of the new prevailing SARS-CoV-2 coronavirus strains in the United States and Europe are not just strains containing the D61G mutation on them but they also have two other mutations on them ie P323L and C241U.


 
The study findings were published in the peer reviewed Journal of Neuroimmune Pharmacology. https://link.springer.com/article/10.1007/s11481-020-09954-3
 
The study team from University of Missouri wanted to initially identify the mutations in virus causing COVID-19 and they analyzed protein sequences for COVID-19 samples from all over the world.
 
The team identified 3 specific mutations, D614G, P323L and C241U, that were co-existing in every single case of COVID-19 in the United States, which could suggest why the virus seems to be so infectious in the United States.
 
The new research findings also indicate that resurgent COVID-19 viruses in European countries also have all three of the identified mutations in nearly all European cases.
 
The new findings define the dynamics of COVID-19 evolution, and they can be useful for developers of COVID-19 treatments or vaccines to help them consider which mutations in the virus are necessary to target.
 
Dr Kamlendra Singh, Project Supervisor and Professor, University of Missouri-Columbia College of Veterinary Medicine told Thailand Medical News, “Simply by detailing a more complete picture of what mutations are occurring in the virus, we can provide specific information to assist those developing treatments and vaccines for the disease. Our overall objective is to better understand what is causing the virus to be spreading so rapidly and efficiently, and our research has shown there may be multiple mutations involved that need to be considered when developing antiviral drugs or vaccines."
 
Dr Singh is also the Bond Life Sciences Center investigator, and assistant director of the Molecular Interactions Core.
 
Dr Singh mentored co-researchers Kannan and Spratt by allowing these students to use their computer programming skills to advance scientific research aimed at addressing the challenges of the COVID-19 pandemic.
 
By identifying patterns in the various sequences of COVID-19 virus samples from all over the world, the students were able to paint a clearer picture of co-evolving mutations occurring inside the virus that is causing it to spread.
 
Spratt said, "The antiviral drugs that are currently being made to treat COVID-19 are developed based off the current model for the virus.But as these mutations are co-evolving and causing the virus' structure to change, the model becomes less accurate and so the current antiviral drugs may become less effective on the mutated versions of the virus. Therefore, by getting a clearer picture of how the virus' structure is evolving, we can create better models of the virus so better antiviral drugs and vaccines can be developed."
 
As anticipated, SARS-CoV-2 evo lution is most likely through selection, perhaps conferring enhanced fitness and/or infectivity. Numerous reports detail the molecular identification of D614G mutation in Spike protein (S-protein). Regardless of how D614G arose, it is clear that this variant has a distinct phenotype. With the report of D614G, it was hypothesized that viruses containing G614 were more infectious than D614 viruses. However, a report from COVID-19 Genomics UK Consortium(Report #9 - 25th June 2020) showed G614 virus has grown 1.22 times faster than the D614, but the statistical significance was low, indicating the role of other factors such as mutations in other genes. https://www.cogconsortium.uk/wp-content/uploads/2020/07/25th-June-2020-Report-COVID-19-Genomics-UK-COG-UK-Consortium.pdf
 
In order to gain insight into the distribution of mutations in SARS-CoV-2 nonstructural proteins (nsps) and structural proteins, the study team  analyzed protein sequences (n = 7232) from the United States (n = 6302), Europe (n = 420), China (n = 104), and India (n = 406), and determined the mutations with respect to Wuhan-Hu-1 isolate (NCBI Reference Sequence: NC_045512.2).
 
A Circos diagram showing non-synonymous mutations in select viral proteins (nsp8, nsp12, nsp13, nsp14, and S-protein) in SARS-CoV-2 has evolved by developing mutations in different viral proteins. Mutations in other viral proteins were also identified in this analysis. The data also revealed that some mutations were widespread, while other mutations appeared to be restricted geographically. Most strikingly, mutation P323L in nsp12 (an RNA-dependent RNA polymerase or RdRp) and D614G in S-protein co-evolved throughout the world. Other mutations, such as P504L and Y541C in nsp13 (helicase) were more prevalent in the USA .
 
To further analyze the coevolution of P323L and D614G, the team determined the mutation frequency of P323L and D614G in SARS-CoV-2 nucleotide sequences from the United States (n = 7233) over a six-month period (January, 2020 - June, 2020). The results of the temporal analysis of the mutation frequency of P323L (nsp12), C241U (5’UTR) and D614G (S-protein) show that P323L was consistently present in the viruses that had D614G mutation and C241U started co-evolving with D614G sometime late January 2020.
 
Additionally, there were mutations in other nsps that varied with time. For example, two mutations in nsp13 (P504L and Y541C) coexisted with almost the same frequency over time and these mutations were prevalent up to ~54% by Feb. 2020 before gradually decreasing to ~10% by the end of June 2020.Mutations in nsp7 and nsp8 also emerged over time albeit at low frequency.
 
Reported experimental data show that D614G mutation enhances the infectivity of SARS-CoV-2 virus. However, it is highly unlikely that a seemingly high infection rate of SARS-CoV-2 is solely the result of this mutation. A near 100% coexistence of P323L (nsp12) and C241U (5’-UTR) with D614G likely contributes to the viral replication, infectivity, or a combination of attributes that are complex and interplay with the host machinery. P323 is located in the Interface domain (residues 251–398) of nsp12. However, in the cryoEM structure of replication-transcription complex (RTC), consisting of nsp7, nsp8, nsp12 and nsp13, the Interface domain is packed against nsp8. The role of nsp7 and nsp8 in the context of the RTC is not known, but they can serve as the processivity factor using the replicating complex of nsp12/nsp7/nsp8/RNA similar to that of thioredoxin in the replicating structure of T7 DNA polymerase. P323 is located at the interface of nsp12 and nsp8 and mutation P323L is expected to position the leucine side chain within interacting distance to F396, which mediates hydrophobic interactions involving L122 an N118 (Cβ) of nsp8 and T323 (Cγ2) and L270 of nsp12. Enhanced interaction between nsp12 and nsp8 would further improve the processivity of nsp12 and thereby help in the viral replication. C241 is located in the 5’UTR of the viral RNA.
 
However, from the coexistence of several mutations with relatively high frequency suggest that the infectivity of G614 virus mutation is not solely dependent on the entry. Remarkably, COVID-19 presents with a wide variety of symptoms, including neuropathology, delayed onset symptoms, and anosmia.
 
While these coevolving mutations could impact viral fitness, the breadth and complexity of the clinical symptoms may also be associated with new mutations and adaptations. While there has been an unprecedented eruption of COVID-19 mutation studies, clearly we have much to learn going forward.
 
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