ABSTRACT
Previous work indicated that the nucleocapsid 203 mutation increase the virulence and transmission of the SARS-CoV-2 Alpha variant. However, Delta later outcompeted Alpha and other lineages, promoting a new wave of infections. Delta also possesses a nucleocapsid 203 mutation, R203M. Large-scale epidemiological analyses suggest a synergistic effect of the 203 mutation and the spike L452R mutation, associated with Delta expansion. Viral competition experiments demonstrate the synergistic effect in fitness and infectivity. More importantly, we found that the combination of R203M and L452R brings in a 3.2-fold decrease in neutralizing titers to the neutralizing serum relative to L452R-only virus. R203M/L452R show an increased fitness after the initiation of global vaccination programmes, possibly associated with the enhanced immune evasion. Another rapidly emerging variant Omicron also bears the 203 mutation. Thus, we proposed that nucleocapsid mutations play an essential role for the rise and predominance of variants in concern.
Subject(s)
SeizuresABSTRACT
In this study, cooccurring mutations R203K/G204R in the nucleocapsid protein are demonstrated adaptive and associated with the emergence of a high-transmissibility SARS-CoV-2 lineage B.1.1.7. Through comparing a R203K/G204R mutant virus, created based on the USA-WA1/2020 SARS-CoV-2 strain, with the native virus in competition experiments, we found that the 203K/204R variants possess a replication advantage over the preceding R203/G204 variants, possibly related to ribonucleocapsid (RNP) assembly during virus replication. Moreover, the 203K/204R virus showed increased infectivity in a human lung cell line and induced increased damage to blood vessels in infected hamster lungs. Accordingly, we observed a positive association between increased COVID-19 severity and the incidence frequency of 203K/204R. Our work suggested a contribution of the 203K/204R mutations to the increased transmission and virulence of SARS-CoV-2. In addition to mutations in the spike protein, the mutations in the nucleocapsid protein are important for viral spreading during the pandemic.Funding Information: This work was supported by grants from the National Natural Science Foundation of China, SGC's Rapid Response Funding for COVID-19 (C-0002), the National Key Research and Development Program (2019YFC1604600), the National Natural Science Foundation of China (81970008 and 31200941), the Fundamental Research Funds for the Central Universities (2021CDJYGRH-009), the Youth Innovative Talents Training Project of Chongqing (CY210102) and the National Natural Science Foundation of HeBei province (19226631D).Declaration of Interests: The authors declare no competing interests.
Subject(s)
COVID-19ABSTRACT
In addition to the mutations on the spike protein (S), co-occurring mutations on nucleocapsid (N) protein are also emerging in SARS-CoV-2 world widely. Mutations R203K/G204R on N, carried by high transmissibility SARS-CoV-2 lineages including B.1.1.7 and P.1, has a rapid spread in the pandemic during the past year. In this study, we performed comprehensive population genomic analyses and virology experiment concerning on the evolution, causation and virology consequence of R203K/G204R mutations. The global incidence frequency (IF) of 203K/204R has rose up from nearly zero to 76% to date with a shrinking from August to November in 2020 but bounced later. Our results show that the emergence of B.1.1.7 is associated with the second growth of R203K/G204R mutants. We identified positive selection evidences that support the adaptiveness of 203K/204R variants. The R203K/G204R mutant virus was created and compared with the native virus. The virus competition experiments show that 203K/204R variants possess a replication advantage over the preceding R203/G204 variants, possibly in relation to the ribonucleocapsid (RNP) assemble during the virus replication. Moreover, the 203K/204R virus increased the infectivity in a human lung cell line and induced an enhanced damage to blood vessel of infected hamsters' lungs. In consistence, we observed a positive association between the increased severity of COVID-19 and the IF of 203K/204R from in silicon analysis of global clinical and epidemic data. In combination with the informatics and virology experiment, our work suggested the contribution of 203K/204R to the increased transmission and virulence of the SARS-CoV-2. In addition to mutations on the S protein, the mutations on the N protein are also important to virus spread during the pandemic.
Subject(s)
COVID-19 , SeizuresABSTRACT
The novel coronavirus (COVID-19) has become a pandemic and is threatening human health globally. Here, we report 14 newly evolved COVID-19 single nucleotide polymorphism (SNP) alleles those underwent a rapid increase (12 cases) or decrease (2 cases) in their frequency from between 10% and 50% in the last three months. The 14 SNPs are mostly (13/14) located in the coding region and are mainly (9/14) nonsynonymous substitutions. Out of the 14 SNPs, 12 SNPs showed a complete linkage in SNP pairs and clustered into 4 linkage groups, named LG_1 to LG_4. SNPs located in 514 and 27046 are independent events. Analyses in population genetics show that the increases in the new alleles result from genetic differentiation between Europe and America. We found that the mutants in LG_1 are driven by balancing selection and arose rapidly in Europe but not in America. The mutants in LG_2 and LG_3, also driven by balancing selection, arose rapidly in American but not in European strains. Based on analysis of geographic COVID-19 cases worldwide, we found that the mutants in LG_1 positively correlate the fatality rate of COVID-19 while those in LG_2 and LG_3 negatively correlate with the fatality rate. The correlations are statistically significant, suggesting that the virus strains possessing mutants in LG_1 are more aggressive, while those in LG_2 and LG_3 are in opposite. Further analysis revealed that mutants in LG_1 have been identified more frequently in European strains than in American strains, while mutants in LG_2 and LG_3 have been found more frequently in American strains. This may partially explain the higher fatality rates of COVID-19 infection in Italy, England and France, compared with the United States. These findings should be instructive for epidemiological surveys and disease control of COVID-19 in the future.
Subject(s)
COVID-19ABSTRACT
To trace the evolution of coronavirus and reveal the possible origination of the novel pneumonia coronavirus (2019-nCoV), we collected and thoroughly analyzed 2966 publicly available coronavirus genomes, including 182 2019-nCoVs strains. We observed 3 independent recombination events with statistical significance between some isolates from bats and pangolins. In consistence with previous records, we also detected the putative recombination between Bat-CoV-RaTG13 and Pangolin-CoV-2019 covering the receptor bind domain (RBD) of the spike glycoprotein (S protein), which may lead to the origination of 2019-nCoV. Population genetic analyses give estimations indicating that the recombinant region around RBD is possibly undergoing directional evolution. This may result to the adaption of the virus to be infectious in hosts. Not surprisingly, we find that the S protein of coronavirus keeps high diversity among bat isolates, which may provide a genetic pool for the origination of 2019-nCoV.
Subject(s)
Coronavirus InfectionsABSTRACT
The recent outbreak of a new zoonotic origin Coronavirus has ring the bell for the potential spread of epidemic Coronavirus crossing the species. With the urgent needs to assist the control of the Coronavirus spread and to provide valuable scientific information, we developed a coronavirus database (CoVdb), an online genomics and proteomics analysis platform. Based on public available coronavirus genomic information, the database annotates the genome of every strain and identifies 780 possible ORFs of all strains available in Genebank. In addition, the comprehensive evaluation of all the published genomes of Coronavirus strains, including population genetics analysis, functional analysis and structural analysis on a historical and global scale were presented in the CoVdb. In the database, the researcher can easily obtain the basic information of a Coronavirus gene with the distribution of the gene among strains, conserved or high mutation regions, possible subcellular location and topology of the gene. Moreover, sliding windows for population genetics analysis results is provided, thereby facilitating genetics and evolutional analysis at the genomic level. CoVdb can be accessed freely at http://covdb.popgenetics.net.