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How replication and recombination contribute to the emergence of SARS-CoV-2 mutants

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The pandemic of coronavirus disease 2019 (COVID-19) was caused by the rapid outbreak of a new coronavirus, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). SARS-CoV-2 was first reported in Wuhan, China in late December 2019. Since then, the virus has already killed more than 4.3 million people worldwide.

The vaccine against SARS-CoV-2 was developed in record time thanks to the rapid sharing of information among researchers. However, the virus is evolving as it spreads.

SARS-CoV-2 is an RNA virus belonging to the family Coronaviridae. Like all RNA viruses, this virus has an error-prone replication process that causes mutations and new SARS-CoV-2 variants.

Researchers say that increased selection pressure is widespread among circulating SARS-CoV-2 strains. Only strains that can avoid natural infections and vaccine-induced immunity affect the selection of viral variants.

New research published in the journal Microbiology TrendsHas focused on the contribution of two processes, replication and recombination, to the production of current and future SARS-CoV-2 mutants.

Genome error during replication process

SARS-CoV-2, like other coronaviruses, requires RNA-dependent RNA polymerase (RdRp) for replication. RdRp is error-prone by nature and helps the virus evolve through replication-related changes. Due to the virus-encoded 3’exonuclease calibration process, the mutation rate is low. For SARS-CoV-2, calibration is performed by nsp14. However, calibration alone cannot prevent the virus from undergoing genetic alterations or mutations. This is very important for the emergence of SARS-CoV-2 mutants.

Scientists believe that understanding the molecules and other extrinsic factors involved in the production of SARS-CoV-2 mutants is important for containment of the pandemic.

The basic analysis is the reservoirs (bats, etc.) of zoonotic diseases in which most of the changes in virus adaptation occur. The true diversity of this virus can be determined by studying the accumulation rate of replication-induced errors in the genomes of SARS-CoV-2 or SARS-CoV-2 related viruses of other mammalian species.

It is still unclear whether viral adaptation within bats has produced a more diverse population of quasi-mutant salvecoviruses than other mammalian species.

Different cell types from different hosts have their own biochemical pathways. For example, the catalytic reaction of a viral polymerase requires a specific substrate, and its characteristics (quality and quantity) can vary depending on the cell type of the host. therefore, coronavirus The degree of error depends on the host and cell type.

In addition, other host factors, such as enzymes, influence the evolution of viral variants. For example, the coding sequence of an enzyme called TMPRSS2 differs between distantly related mammalian species.

During zoonoses spillover, the virus infects mammalian species with different orthologs of TMPRSS2. NS Spike protein The proportion of SARS-CoV-2 varies sufficiently to gain invasion of new species. Therefore, there is a high risk that the viral population within the cell line containing the orthologous enzyme will evolve and be selected as the more infectious mutant.

Previous studies have emphasized that genomes with random mutations associated with replication accumulate in the same cell, where heterogeneous mixing of viral proteins occurs. This casts doubt on the true diversity of proteins on the surface of individual virions and the subsequent development of SARS-CoV-2 and its variants at the tissue level.

However, it is unclear if there is a more ordered molecular-level process that regulates the uniform distribution of peplomer mutants on individual virions.

Recombination-related mutations

Recombination, unlike replication, can result in even more important modifications to the viral genome. These changes can result in significant changes in the SARS-CoV-2 phenotype. In addition, discontinuous transcription of the coronavirus genome allows recombination in cells infected with multiple coronavirus species, leading to the formation of subgenomic RNAs and proteins that affect the fate of infected cells.

Homologous recombination also occurs in the SARS-CoV-2 genome. In this type of recombination, RNA molecules recombine through regions of high similarity. Recombination is very common with betacoronavirus, especially in bats. In addition, recombinant events are also found in human coronavirus.

Recent studies have identified eight possible recombination events between the SARS-CoV-2 genome. Four originated within the structural gene and two were found within the spike gene. However, these recombination events were not present in all subsampled datasets. There are also gaps in studies related to the frequency of SARS-CoV-2 recombination and the factors that enable it. Such studies will help us understand the evolutionary trajectory of SARS-CoV-2 in an ongoing pandemic and will help us to make long-term predictions. Effectiveness of Immunity from vaccines and natural infections.

Future research

Scientists explain that receptor distribution and cell orientation are important determinants of coinfection with two closely related coronaviruses and are prone to recombination. However, it is unclear which viruses and host factors have a strong effect on recombination. It is also necessary to evaluate the characteristics of the replication mechanism of SARS-CoV-2. These studies will help determine if SARS-CoV-2 is replication-induced error or recombination-prone.

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