Table 1 Comprehensive details of the included articles
Variants of COVID-19 | ||||||
|---|---|---|---|---|---|---|
ID | The first author (reference) | Type of study | Country | Study population | Genomic variants | Other |
1 | Alouane [21] | Research article | Morocco | SARS-CoV-2 genomes | ORF1, Receptor binding domain (RBD), D614G, Q57H, T265I | A total of 3206 variant sites were detected compared to the reference genome Wuhan-Hu-1/2019. For each cluster, we identified different clades: cluster one containing two main clades A1a and B1 harboring mainly strains from Asia, North America, and Asia Europe, respectively. However, cluster 2 harbored three clades: B2, A2, A2a without a specific pattern |
2 | Al-Tawfiq Jaffar [22] | Letter to the editor | USA | COVID-19 patients | There were three genomic variants, termed A, B, and C, based on amino acid changes | – |
3 | Armengaud [23] | Opinion | France | COVID-19 patients | – | As expected for any RNA virus, over time, individuals are infected with SARS-CoV-2 variants that typically display some degree of genetic drift, compared with the first isolates of the virus obtained in Wuhan. The study of viral evolution indicates that genetic drift, mainly derived from genomic deletions, will almost inevitably attenuate the pathogenicity of viruses given enough time. The only hint at attenuation comes from an observation in Singapore, where some SARS-CoV-2 isolates turned out to have a 382-nucleotide deletion in ORF8 of the viral genome. This finding is of particular interest because of the omission of 29 nucleotides in ORF8 during the early spreading of SARS-CoV-1 in 2003. This 29-nucleotide deletion was demonstrated to attenuate viral replication when introduced in an infectious clone generated by reverse genetics |
4 | Bajaj [24] | Scientific correspondence | India | COVID-19 patients | – | The initial studies identified two major types of virulent SARS-CoV-2 circulating among the Chinese population. The aggressive form’s prevalence decreased after early January 2020, and the milder type has become standard due to selective human intervention. Two genomes available from India showed clustering closer to the strains prevalent in China to date. However, a unique mutation 24351C (A930V (T)) in the spike surface glycoprotein of Indian SARS-CoV-2 genome is absent in other strains from Wuhan, Italy, USA, and Nepal is reported |
5 | Bhowmik [20] | Research article | India | COVID-19 patients | Two groups (A and B) and further subgrouping (C, D and E) of the significant group A | SARS-CoV-2 genome is around 29,903 nucleotides and organized in the following order from 5' to 3': ORF1ab (replicas), structural spike glycoprotein (S), ORF3a protein, a structural envelope protein (E), structural membrane glycoprotein (M), ORF6 protein, ORF7a protein, ORF7b protein, ORF8 protein, structural nucleocapsid-phosphoprotein (N) and ORF10 protein. Studies have revealed that the highly mutable spike (S) protein of the virus is associated with the elevated human-to-human transmission rate through interaction with the host's ACE2 receptor |
6 | Biswas [25] | Letter to the editor | Bangladesh | COIVD-19 patients | This study analyzed 95 SARS-CoV-2 complete genome sequences obtained from Gen Bank, found 156 variants in total and 116 unique variants | Another analysis of 86 genomic sequences obtained from the GISAID database (https://www.gisaid.org/) identified three deletions in the genomes of SARS-CoV-2 from Japan, USA, and Australia, and 93 mutations over the entire SARS-CoV-2 genomes [3]. Several of these mutations were located in the receptor-binding domain (RBD) of the spike surface glycoprotein |
7 | Biswas [26] | Letter to the editor | Bangladesh | SARS-CoV-2 genomes | Receptor binding domain (RBD), RNA-dependent RNA polymerase (RdRp) | Several studies have so far been conducted utilizing sequencing data of SARS-CoV-2 obtained from publicly available repositories. One such study, analyzed 95 SARS-CoV-2 complete genome sequences obtained from Gen Bank, found 156 variants in total and 116 unique variants |
8 | Blackstone [27] | Commentary | USA | COIVD-19 patients | – | If a pathogen strain replicates too rapidly, the transmission might not occur before the host is debilitated. Fast-replicating pathogen strains may thus face extinction. Slow-replicating strains that cause mild or inapparent disease may allow a longer transmission window and persist in the host population |
9 | Cao [28] | Research article | China | COIVD-19 patients | Types A and C were only found outside East Asia, i.e., Europe and America, whereas type B was the most common type in East Asia | Results showed that mainland China strains' genomes were mostly distributed in Clade B and Clade undefined in the phylogenetic tree, with only 3.47% (5/144) found in Clade A. Also, Clades A2 (one case) and A2a (112 instances) contained no mainland China cases. In these clades, all cases came from 16 regions, mainly the Netherlands (65 cases), Switzerland (13 cases, and UK 13 cases), with only one case reported from Taiwan. Further analysis demonstrated that amino acid variation of the S protein at 614 (QHD43416.1: p.614D > G), i.e., the substitution of glutamic acid (D) with glycine (G) in the mutant protein, was found in strains within Clades A2 and A2a |
10 | Castillo [29] | Research article | Chile | Chilean COVID-19 patients | Three variants: S variant, G variant, V variant | According to prevalent SNPs, all genomes have been classified by amino acid changes in specific ORFs. The first three cases (20–1891820–1930320–19305) are classified as "S" type for the Chilean strains. Meanwhile, the fourth case (20–19731) is a "G" type, according to nucleotide substitutions in the positions 28 144 and 23 403 |
11 | Everett [30] | Research article | USA | COIVD-19 patients | D614G, RNA-dependent RNA polymerase (RdRp) located on ORF1b | The D614G substitution has been proposed to promote infection of human cells, and this variant has spread globally at the expense of other genotypes |
12 | Forni [31] | Original article | Italy | SARS-CoV-2 genomes | D614G | Recent studies have indicated that the D614G variant, which is now prevalent worldwide, enhances viral infectivity |
13 | Forster [32] | Research article | Germany | COVID-19 patients | Three central variants: A variant B variant C variant | Node B is derived from A by two mutations: the synonymous mutation T8782C and the non-synonymous mutation C28144T changing a leucine to a serine. Type C differs from its parent type B by the non-synonymous mutation G26144T, which changes a glycine to a valine |
14 | Gómez-Carballa [33] | Research article | Spain | SARS-CoV-2 genomes | C8782T, C18060T, T28144C, C29095T | Sub-haplogroup A2 most likely originated in Europe from an Asian ancestor and gave rise to sub-clade A2a, which represents the major non-Asian outbreak, especially in Africa and Europe |
15 | Goren [34] | Letter to the editor | USA | COIVD-19 patients | TMPRSS2 | Both SARS-CoV-2 and influenza are dependent on TMPRSS2 for infectivity, it is likely that SARS-CoV-2 will have a similar seasonal cycle; thus, the fall and winter are likely to see an increase in COVID-19 cases |
16 | Graudenzi [35] | Research article | Italy | COIVD-19 patients | – | Several mutations linked to low-rate mutational processes appear to transit to clonality in the population, eventually leading to the definition of new viral genotypes and to an increase of overall genomic diversity |
17 | Islam [36] | Original article | Bangladesh | COVID-19 patients | Three central variants A variant B variant C variant Clade S Clade V Clade G | – |
18 | Jain [37] | Research article | India | COIVD-19 patients | – | SARS-CoV-2 variants impact RT-PCR efficiency in detection. A total of 29 global SARS-CoV-2 genetic variants had a frequency ≥ 1%. The thermodynamic stability of the virus–primers complex gets perturbed. A number of recommended primer or probe sequences had high variant frequency |
19 | Jay [8] | Research article | France | COVID-19 patients | Genomic diversity of SARS-CoV-2 by next-generation sequencing (NGS) | For the first time, minority viral populations represented up to 1% during SARS-CoV-2 infection. Subspecies were different from one day to the next and between anatomical sites, suggesting that in vivo, this new coronavirus appears as a complex and dynamic distribution of variants |
20 | Joshi [38] | Research article | India | COVID-19 patients | C28854T and G25563T | From missense mutations found from Gujarat SARS-CoV-2 genomes, C28854T, deleterious mutation in the nucleocapsid (N) gene was significantly associated with mortality in patients. The other significant deleterious variant (G25563T) is found in patients located in Orf3a and has a potential role in viral pathogenesis. SARS-CoV-2 genomes from Gujarat are forming distinct clusters under the GH clade of GISAID |
21 | Junejo [39] | Review article | Pakistan | COVID-19 patients | ACE2, IL-10, TNF, VEGF | Elevated levels of cytokines and chemokines in COVID-19 patients including IL1 β, IL1RA, IL7, IL8, IL9, IL10, basic FGF2, GCSF, GMCSF, IFN γ, IP10, MCP1, MIP1 α, MIP1 β, PDGFB, TNF α, and VEGFA were observed. The increased pro-inflammatory cytokines, including IL2, IL7, IL10, GCSF, IP10, MCP1, MIP1 α, and TNF α, were responsible for disease severity. Many candidate genes, i.e., ACE2, IL-10, TNF, VEGF, are believed to be associated with ARDS development or outcome. In addition, the increased levels of IL-6 and IL-8 were confirmed to be associated with ARDS. Data collected on genetic evolution, receptor-binding, and pathogenesis have shown that bats most likely cause SARS-CoV by sequential recombination of bat SARS-CoVs |
22 | Korber [11] | Research article | USA | COVID-19 patients | D614G | An A-to-G nucleotide mutation causes the Spike D614G amino acid change at position 23,403 in the Wuhan reference strain. Three other mutations almost always accompany the D614G change: a C-to-T mutation in the 5′ UTR (position 241 relative to the Wuhan reference sequence), a silent C-to-T mutation at position 3,037, and a C-to-T mutation at position 14,408 that results in an amino acid change in RNA-dependent RNA polymerase (RdRp P323L). The haplotype comprising these four genetically linked mutations is now the globally dominant form |
23 | Kouriba [40] | Research article | Africa | COIVD-19 patients | M002593 and M002659 | Analysis shows that both the early A (19B) and the later observed B (20A/C) clade are present in Mali, indicating multiple and independent introductions of SARS-CoV-2 to the Sahel region |
24 | Koyama [41] | Research article | USA | COVID-19 patients | D614G, L84S, L3606F, D448del and G392D | Several variants of the SARS-CoV-2 genome exist, and that the D614G clade has become the most common variant since December 2019. The authors identified six significant clades (that is, basal, D614G, L84S, L3606F, D448del, and G392D) and 14 subclades. Regarding the base changes, the C > T mutation was the most common distinct variants |
25 | Kozlovskaya [42] | Research article | Russia | COVID-19 patients | Amino acid substitutions | A specific set of seven nucleotide mutations using amino acid substitutions in spike protein S and nucleoprotein N, possibly affecting their properties |
26 | Laha [25] | Research article | India | COVID-19 patients | Nucleotide and amino acid sequences of ORF1ab, ORF3a, ORF6, ORF7a, ORF8, ORF10, envelop (E), membrane (M), nucleocapsid (N), and surface glycoprotein (S) | The surface glycoprotein, nucleocapsid, ORF1ab, and ORF8 showed frequent mutations, while envelope, membrane, ORF6, ORF7a, and ORF7b showed conservation in terms of amino acid substitutions. Some of the mutations across different proteins showed co-occurrences, suggesting their structural and/or functional interaction among different SARS-COV-2 proteins and their involvement in adaptability and viral transmission. Analysis of protein structure stability of surface glycoprotein mutants indicated the viability of specific variants and are more prone to be temporally and spatially distributed across the globe |
27 | Latini [43] | Research article | Italy | COVID-19 patients | ACE2, TMPRSS2, PCSK3, DPP4, and BSG genes | It is known that ACE2 acts as a receptor for this pathogen, but the viral entry into the target cell also depends on other proteins. In the PCSK3 gene, we observed a missense variant (c.893G > A) statistically more frequent compared to the EUR GnomAD reference population and a missense mutation (c.1906A > G) not found in the GnomAD database. In the TMPRSS2 gene, the authors observed a significant difference in c.331G > A, c.23G > T, and c.589G > A variant alleles in COVID-19 patients, compared to the corresponding allelic frequency in GnomAD. Genetic variants in these genes could influence the entry of the SARS-CoV-2. These data also support the hypothesis that host genetic variability may contribute to the variability in infection susceptibility and severity |
28 | Lau [44] | Research article | China | COVID-19 patients | Vero-E6 cells | The presence of a distinct motif in the S1/S2 junction region suggests the possible acquisition of the cleavage site(s) in the spike protein that promoted cross-species transmission. Through plaque purification of Vero-E6 cultured SARS-CoV-2, we found a series of variants that contain 15–30-bp deletions (Del–mut) or point mutations, respectively, at the S1/S2 junction. The unique cleavage motif promoting SARS-CoV-2 infection in humans may be under intense selective pressure, given that replication in permissive Vero-E6 cells leads to the loss of this adaptive function |
29 | Lee [45] | Research article | Japan | COIVD-19 patients | ACE2, TMPRSS2, TLR7 | Genome‐wide association studies have identified genetic risk factors for severe COVID‐19 cases in a segment of chromosome 3 that involves six genes encoding three immune‐regulatory chemokine receptors and another three molecules. The risk haplotype seemed to be inherited from Neanderthals, suggesting genetic adaptation against pathogens in modern human evolution. Therefore, SARS‐CoV‐2 uses highly conserved molecules as its virion interaction, whereas its immune‐response appears to be genetically biased in individuals to some extent |
30 | Liu [46] | Research article | USA | COVID-19 patients | Single-nucleotide variants (SNVs) | Four signature groups of frequently occurred single-nucleotide variants (SNVs) were identified in over twenty-eight thousand high-quality and high-coverage SARS-CoV-2 complete genome sequences, representing different viral strains. Interestingly nucleotide substitutions among SARS-CoV-2 genomes tended to switch between bat RaTG13 coronavirus sequence and Wuhan-Hu-1 genome, indicating the higher genetic instability or tolerance of mutations on those sites or suggesting that major viral strains might exist between Wuhan-Hu-1 and RaTG13 coronavirus |
31 | Lokman [47] | Research article | Bangladesh | COVID-19 patients | N-terminal domain (NTD) and receptor-binding domain (RBD) and angiotensin-converting enzyme 2 (ACE2) | Spike glycoprotein is one of the major targets to be explored because of its role during coronaviruses' entry into host cells. Variations located at the N-terminal domain (NTD) and the receptor-binding domain (RBD) might alter the interaction of S protein with the host receptor angiotensin-converting enzyme 2 (ACE2) |
32 | Muhammad Ansari [48] | Research article | Indonesia | COVID-19 patients | SARS-CoV-2 spike glycoprotein gene sequences | Therefore, the coronavirus spike glycoprotein mediates membrane fusion and viral entry into host cells and is the primary target for many neutralizing antibodies. The spike glycoprotein has two domains, S1 and S2, where S1 is responsible for binding the virion to ACE2 on the host cell membrane 21. Several antiviral drugs and vaccines have been developed which target the spike glycoprotein. There was no significant difference between the SARS-CoV-2 spike glycoprotein gene sequences found in Indonesia and the Wuhan-Hu-1 isolate from China |
33 | Mukherjee [49] | Research article | India | COVID-19 patients | SARS-CoV-2 genome sequence | This study suggested a possible cross-talk between host RBPs-miRNAs and viral UTR variants in SARS-Cov-2 infection. The variations in the UTR regions and binding of host RBP to them remain mostly unaltered, which further influenced specific miRNAs’ functioning |
34 | Pachetti [50] | Review article | Italy | COVID-19 patients | SARS-CoV-2 genome sequence, RdRp gene | The virus is evolving, and European, North American, and Asian strains might coexist, each of them characterized by a different mutation pattern. The contribution of the mutated RdRp to this phenomenon needs to be investigated. To date, several drugs targeting RdRp enzymes are being employed for SARS-CoV-2 infection treatment. Some of them have a predicted binding moiety in a SARS-CoV-2 RdRp hydrophobic cleft adjacent to the 14,408 mutations we identified. Consequently, it is important to study and characterize SARS-CoV-2 RdRp mutation to assess possible drug-resistance viral phenotypes. It is also important to recognize whether the presence of some mutations might correlate with different SARS-CoV-2 mortality rates |
35 | Panchin [51] | Research article | Russia | COVID-19 patients | Single-nucleotide variations | Mutation patterns of SARS-CoV-2 have changed after transmission to humans. There are two remarkable observations regarding the excess of G–U transversions in SARS-CoV-2. One is the change in SARS-CoV-2 mutation rates after zoonotic transfer to humans since the proportion of G–U substitutions measured between the SARS-CoV-2 and the bat coronavirus RaTG13 is unremarkable. The second remarkable feature is that this excess of mutations is asymmetric: there is no similar effect for C–A mutations |
36 | Pardo-Seco [52] | Letter to the editor | Spain | COIVD-19 patients | C8782T–T28144C | Barcodes based on worldwide databases inevitably prioritize variants located at the basal nodes of the phylogeny, such that most representative genomes in these ancestral nodes are no longer in circulation. Consequently, coronavirus phylodynamics cannot be properly captured by universal genomic barcodes because most SARS-CoV-2 variation is generated in geographically restricted areas by the continuous introduction of domestic variants |
37 | Parlikar [53] | Research article | India | COIVD-19 patients | – | SARS-CoV-2 strains form a monophyletic clade distinct from SARS-CoV and Pangolin CoV that they are closest to the Bat CoV RaTG13 strain followed by Pangolin CoV, suggesting that SARS-CoV-2 evolved from a common ancestor putatively residing in bat or pangolin hosts. 44 protein-coding regions constitute the pan-genome for nineteen genus Betacoronavirus strains. Moreover, their pan-genome is open, highlighting the wide diversity provided by newly identified novel strains. Even members of subgenus Sarbecovirus are diverse relative to each other due to the relative presence of unique protein-coding regions orf3b, orf7b, orf8 and orf9b and orf10 |
38 | Peñarrubia [54] | Research article | Spain | COVID-19 patients | The annotated single-nucleotide variations | Given that genetic variability in the SARS-CoV-2 genome is expected to increase based on the natural viral mutation and recombination rates, our results show that the combination of more than one assay target in real-time RT-PCR SARS-CoV-2 panels can mitigate the risk of loss of sensitivity or specificity |
39 | Peñarrubia [55] | Research article | Spain | SARS-CoV-2 genomes | Genomic variants detected in complementary binding regions of earliest available SARS-CoV-2 RT-PCR assays | Combination of more than one assay target in real-time RT-PCR SARS-CoV-2 panels can mitigate the risk of loss of sensitivity or specificity. In this regard, continuous monitoring of genomic variations is essential to provide a rapid response in case assay re-design is needed |
40 | Portelli [56] | Commentary | Australia | structural distribution of genetic variation in SARS-CoV-2 obtained from GISAID and COG-UK | SARS-CoV-2 spike protein's ACE2-receptor-binding domains (QHD43416 p). Asp614Gly), SARS-CoV-2 main proteinase domains (QHD43415_5) | That study developed a comprehensive online resource, COVID-3D, to enable the analysis and interpretation of variants detected in more than 125,000 SARS-CoV-2 genomic sequences. The SARS-CoV-2 spike protein binds h-ACE2, which mediates cell entry. Subsequently, the spike protein’s ACE2-receptor-binding domain has been the main target of most vaccine programs. Measures of selective pressure suggest that the spike protein is one of the viral proteins most tolerant of introducing mutations. Closer inspection indicates that substantial variation can be seen across the protein surface, including in predicted epitope regions in the receptor-binding domain. Of these variants, QHD43416 p.Asp614Gly is present in two-thirds of the sequenced strains, although its actual importance remains unclear, despite initial suggestions that it may increase transmissibility. It is identified several genes under strong purifying selection. These include the genes encoding helicase, RNA polymerase, NSP4, NSP9, and ExoN, which may serve as novel, promising drug targets with few circulating variants seen near the druggable pockets |
41 | Poterico [57] | Research article | Peru | 691 SARS-CoV-2 complete viral genomes worldwide, including 30 genomes from South American countries in the GISAID database | ORF1a (G392D in nsp1, T708I in nsp2, A876T and A1043V in nsp3, N2894D and F3071Y in nsp4, G3334S in nsp5, L3606F in nsp6), ORF1b (P314L in nsp12), Spike protein (D614G, E1207V), ORF3a (Q57H, G196V, G251V), Membrane gene (T175M), ORF8 (L84S), N gene (D103Y, R191C, S197L, G238C, R203K, G204R) | Our results portray circulating SARS‐CoV‐2 South American strains coming from Europe, North America, and Oceania; and mostly belongs to Clade G. Infectivity and pathogenicity of SARS‐CoV‐2 is related to S protein, mainly due to the h‐ACE2 binding ridge structural changes of the RBD domain, on residues 482 to 485: Gly, Val, Glu, and Gly. Our report highlights two strains with novel variants on the S region, with no amino acid change in nt24022 (E1207E), whereas another non-synonymous alteration in nt25182 (E1207V), for Peru (EPI_ISL_415787) and Ecuador (EPI_ISL_417482), respectively. However, these changes seem far away from the critical region of S protein for h‐ACE2 affinity. Due to its prevalence, Clade G strains could be more contagious than other subtypes due to nucleotide changes in ORF1ab (nt8750) and N (nt29063) genes that enhance viral replication. We found 8 (8/30) variations in both of nt8782 and nt28144 positions. Conversely, other regions seem to be hotspots in South American strains, with 11(36.67%) of these portraying changes at 5′UTR (nt241), nsp3 (nt3037), nsp12 (nt14408), and N/ORF9 (nt28881, nt28882, and nt28883) regions. This is paramount because changes in nsp1, nsp3, and nsp5 could be related to some functions of the viral incubation period and immune response evasion of SARS‐CoV‐2. Amino acid alterations in both of these regions, such as G392D (nsp1), A876T, A1043 (nsp3), and nsp5 (G3334S); and should be tested in further studies. Strikingly, we identified four changes—nt15324 in ORF1ab (RdRp), nt26144 in E gene, nt28580, and nt28657 in the nucleocapsid gene—in the suggested regions for primer annealing for SARS‐CoV‐2 specific fragments identification, according to real-time RT‐PCR recommendations from the WHO. Moreover, viral genomes with alterations on 14 408 and 23 403 positions have been correlated with more mutations (3–4 per genome) than their counterparts without it. All South American viruses of Clade G analyzed in this report have mutations concomitantly on 14 408 and 23 403 nucleotidic positions |
42 | Romero [58] | Commentary | Peru | South American SARS‐CoV‐2 genome sequences in the SRA database | mutation N2894D in nsp4, non-synonymous mutation E1207E in the S gene | The de novo reassembly and mapped reads provided independent evidence to validate Poterico and Mestanza’s mutations based on the Peruvian SARS‐CoV‐2 genome. First, mutation N2894D in nsp4 (Table 1 in ref. 1) corresponding to a change from A to G in the nucleotide position 8945 occurs only in few reads (4 out of 33 mapped reads). It is not considered in the consensus sequence in the de novo reassembly. Thus, we should be cautious in considering this mutation as a real variant. Second, the authors reported a non-synonymous mutation E1207E in the S gene; this corresponds to T to C in the nucleotide position 24,022. Again, this mutation occurred only in 4 of 29 mapped reads, and it is not present in the consensus sequence. This evidence supports the necessity of using original sequence reads to verify if the previously described mutations in SARS‐CoV‐2 genomes are accurate, assembly artifacts, or sequencing errors |
43 | Sapoval [59] | Research article | USA | 6928 SARS-CoV-2, 42 SARS-CoV-1, and 53 MERS genome datasets in addition to RNA-seq datasets from 151 COVID-19 positive patients | Intra-host single-nucleotide variants (iSNVs), consensus-level single-nucleotide polymorphisms (SNPs) and structural variants (SVs) in three clades V, S and G | Though RNA viruses mutate more rapidly than DNA viruses, there are a relatively small number of SNPs that differentiate the main SARS-CoV-2 clades that have spread throughout the world. First, the mutational profile of SARS-CoV-2 highlights iSNV and SNP similarity, albeit with high variability in C > T changes. Genes NSP6 and NSP10 are particularly enriched for T > C mutations, while NSP7 has an enrichment of A > C SNVs. Second, iSNV and SNP patterns in SARS-CoV-2 are more similar to MERS-CoV than SARS-CoV-1; except for significantly larger proportion of G > T changes in both iSNVs and SNPs. Third, a significant fraction of small indels fuel the genetic diversity of SARS-CoV-2. Fourth, the mutational spectra of the SNPs and iSNVs indicate that there is a complex interplay between endogenous SARS-CoV-2 mutational processes and host-dependent RNA editing. This observation is in line with several recent studies that propose APOBEC and ADAR deaminase activity as a likely driver of the C > T changes in the SARS-CoV-2 genomes. The study showed high sequence conservation within the NSP3 region, a region that is one of the most diverged from SARS-CoV-1 and MERS-CoV. The lower NSP3 mutations are due to its essential functional implications in viral replication, thus promising NSP3 as a good target for drug development. A number of convergent findings suggest de-mono-ADP-ribosylation of STAT1 by the SARS-CoV-2NSP3 as a putative cause of the cytokine storm observed in the most severe cases of COVID-19. Also, one deletion (at 28245 bp) was present in 10 samples (AF: 6%) in ORF8, a potentially important gene for viral adaptation to humans |
44 | Sarkar [60] | Research article | India | 837 Indian SARS-CoV-2 strains | 33 different mutations; 18 of which these were unique to India: S glycoprotein (L54F, K77M, R78M, D294D, E583D, Q677H), NSP3 (G716I, T749I, A994D, D1121G, S1197R), RdRP (A97V, L329I, G571S, V880I), NSP2 (S301F, G339S), and N (S194L) | Non-synonymous mutations were found to be 3.07 times more prevalent than synonymous mutations. The A2a clade was found to be dominant in India (71.34%), followed by A3 (23.29%) and B (5.36%), but a heterogeneous distribution was observed among various geographical regions. The A2a clade was highly predominant in East India, Western India, and Central India, whereas the A2a and A3 clades were nearly equal in prevalence in South and North India. D614G/S, a characteristic mutation of the A2 clade that was first reported in Germany, has been found to correlate strongly with high infectivity |
45 | Shen [61] | Research article | China | Bronchoalveolar lavage fluid samples from 8 patients with SARS-CoV-2, and 25 patients with community-acquired pneumonia (CAP), and 20 healthy controls for comparison | ORF1a, ORF1b, S, ORF3a, E, M, ORF6, ORF7a, ORF8, N, ORF10 mutations | The median number of intra-host variants was 1–4 in SARS-CoV-2-infected patients, ranged from 0 to 51 in different samples, suggesting a high evolution rate of the virus. The distribution of variants on genes was similar to those observed in the population data. However, very few intra-host variants were observed in the population as polymorphisms, implying either a bottleneck or purifying selection involved in the transmission of the virus or a consequence of the limited diversity represented in the current polymorphism data. Although recent evidence did not support the transmission of intra-host variants in a possible person-to-person spread, the risk should not be overlooked. Microbiota in SARS-CoV-2-infected patients were similar to those in CAP, either dominated by the pathogens or with elevated levels of oral and upper respiratory commensal bacteria. SARS-CoV-2 evolves in vivo after infection, affecting its virulence, infectivity, and transmissibility |
46 | Singh [62] | Research article | India | 1,325 complete draft genomic sequences of SARS-CoV-2 and additional 279 CDS having partial genomes coding spike protein from NCBI database | RBD (A348V, V367F, A419S, T323I, A344S, R408I, G476S, V483A, H519Q, A520S, A522S, K529E, T323I, A344S, V367F, A419S, A522S, and K529E) | The significant variations in the predicted epitopes showing high antigenicity were A348V, V367F, and A419S in the receptor-binding domain (RBD). Other mutations observed within RBD exhibiting low antigenicity were T323I, A344S, R408I, G476S, V483A, H519Q, A520S, A522S, and K529E. The RBD T323I, A344S, V367F, A419S, A522S, and K529E are novel mutations reported for the first time in this study. Moreover, A930V and D936Y mutations were observed in the heptad repeat domain, and one mutation, D1168H, was noted in heptad repeat domain 2. S protein is the primary target for vaccine development, but several mutations were predicted in S protein's antigenic epitopes across all genomes available globally. The emergence of various mutations within a short period might result in conformational changes in the protein structure, suggesting that developing a universal vaccine may be a challenging task |
47 | Taboada [63] | Research article | Mexico | Covid-19 patients | present the full genome sequence for 17 SARS-CoV-2 isolates corresponding to the earliest sampled cases in Mexico | The authors reported that the initial virus strains introduced in Mexico came from Europe and the United States. The virus was circulating locally in the country as early as mid-March. They also found evidence for early local transmission of strains with an H49Y mutation in the Spike protein, which could be further used as a molecular marker to follow viral spread within the country and the region |
48 | Thielen [64] | Research article | USA | 620 samples from the Johns Hopkins Health System collected between March 11–31, 2020; 143 of which was sequenced, generating 114 complete viral genomes | Identified a total of 153 unique, unambiguous single-nucleotide variants across all sequences (54 synonymous variants, 91 non- synonymous variants, 8 noncoding variants) compared to the Wuhan-Hu-1 SARS-CoV-2 reference genome | These genomes belong to all five major Next strain-defined clades, suggesting multiple introductions into the region and underscoring the diversity of the regional epidemic. We also found that clinically severe cases had genomes belonging to all of these clades. We found no clear correlation, but were limited by sample size. Similarly, patient phenotypes including sex, race, recent travel, symptoms, and comorbidities were represented across all five major phylogenetic clades, suggesting that susceptibility was independent of clade. The widely examined mutation in the viral spike protein (D614G) 28–30 is one of the key mutations differentiating the 19 and 20 clades. Notably, we see severe cases in both of these clades, though our dataset is underpowered to show significant correlations between viral genome mutations and disease severity. The diversity of virus genetics, clinical symptoms, and patient outcomes suggests that viral mutations are not the main driver of clinical presentation |
49 | Toyoshima [65] | Research article | Japan | Covid-19 patients | One thousand two hundred thirty-four mutations by comparing with the reference SARS-CoV-2 sequence | All replicating viruses, including coronavirus, continuously accumulate genomic mutations that persist due to natural selections. These mutations contribute to the enhancement of the ability of viral proliferation and infection and an escape from host immune attack |
50 | Ugurel [66] | Research article | Turkey | Covid-19 patients | Variations in SARS-CoV-2 genome | Despite some variations being in low-frequency rate in some continents, C14408T and A23403G variations on Nsp12 and S protein, respectively, were observed to be the most prominent variations all over the world, in general, and both cause missense mutations. It is also notable that most isolates carry C14408T and A23403 variations simultaneously, and also nearly all isolates carrying the G25563T variation on ORF3a, also carry C14408T and A23403 variations, although their location distributions are not similar |
51 | van Dorp [67] | Research article | UK | 7710 SARS-CoV-2 assemblies flagged as “complete (> 29,000 bp)”, “high coverage only”, “low coverage excl” were downloaded from the GISAID Initiative EpiCoV platform as of April 19 2020 | Identified 198 homoplasy positions in the SARS-CoV-2 genome alignment (0.67% of all sites) which was associated with 290 amino acid changes across all genomes; 232 non-synonymous and 58 synonymous mutations. Two non-synonymous mutations involved the introduction or removal of stop codons were found (*13402Y, *26152G) | One of the strongest homoplasies lies at site 11,083 in the SARS-CoV-2 genomes in a region of Orf1a encoding Nsp6. This site passed our stringent filtering criteria and was also present in our analysis of the SRA dataset. Interestingly, this region overlaps a putative immunogenic peptide predicted to result in both CD4+ and CD8+ T cell reactivity. More minor homoplasies among our top candidates, identified within Orf3a, also map to a predicted CD4 T cell epitope of note, we also identify a strong recurrent mutation in nucleotide position 21,575, corresponding to the SARS-CoV-2 spike protein (codon 5). While the spike protein is the known mediator of host cell entry, our detected homoplasy falls outside of the N-terminal and receptor-binding domains |
52 | Wang [68] | Research article | China | Covid-19 patients | Analyzed sequence variations along the SARS-CoV-2 genome | There may be selective mutations in SARS-COV-2, and it is necessary to avoid certain regions when designing primers and probes. The establishment of the reference sequence for SARS-CoV-2 could benefit not only the biological study of this virus but also diagnosis, clinical monitoring, and intervention of SARS-CoV-2 infection in the future |
53 | Xiao [69] | Research article | China | Clinical specimens (including throat swab, nasal swab, an anal swab, and sputum) obtained from confirmed COVID-19 cases at the First Affiliated Hospital of Guangzhou Medical University | SARS-CoV-2 genome sequences | This work offers practical guidance for genome sequencing and analyses of SARS-CoV-2 and other emerging viruses. We demonstrated that both amplicon and capture methods efficiently enriched SARS-CoV-2 content from clinical samples, while the enrichment efficiency of amplicon outran that of capture in more challenging samples |
54 | Yap [70] | Research article | Southeast Asia countries | 142 complete sequences of SARS-CoV-2 from six of the SEA countries, including Cambodia (n = 1), Malaysia (n = 16), the Philippines/Philippines (n = 12), Singapore (n = 74), Thailand (n = 31) and Vietnam (n = 8) | ORF1a, ORF1b, S, M, E, ORF3a, ORF6, ORF7a, ORF8, ORF10 | The authors focused on mutations that have emerged multiple times and identified 22 recurrent mutations in the SEA SARS-CoV-2 genomes. They also note that nearly 75% of the hits also overlap with candidate mutations, which may affect the phenotype of SARS-CoV-2 identified by Van Dorp et al. The current genomes studied showed phylogenetic relation with common recurrent mutations. Cluster I exhibited common recurrent mutation at 8782C > T in ORF1ab (n = 35). Forster et al. observed that the ancestral S variant with these two mutations at 8782C > T and 28144 T > C was predominantly identified in East Asia. Still, this variant outside of Asia was observed with striking, long mutational branch lengths. The G variant was rarely sampled in Asia but corresponded to the most frequent variant in Europe. In this study, G variants were identified in strains predominantly from Thailand, followed by Singapore and Vietnam. Cluster III belonged to clades outside the reported S, G, and V shared mutations distinguished clades, and at 6312C > A, 11083G > T, 13730C > T, and 19524C > T in ORF1ab, 23929C > T in spike, and 28311C > T in the N protein (n = 38). This variant was observed in strains from Malaysia, the Philippines, and Singapore from mid-March onwards. On April 19, 2020, a new cluster emerged from students returning to Malaysia from Indonesia |
55 | Zhang [18] | Research article | China | 97 complete genomes of COVID-19 samples from GISAID | Three type-specific variants correspond to the genomic positions 8750, 28112, and 29063, respectively; the coordinates are referred to as the sequence MN938384.1 | COVID-19 strains form two well-supported clades (genotype I, or Type I, and Type II). The two types' genomes mainly differ at three sites, which are 875028112 and 29063, based on MN938384.1's genome coordinates. Specifically, the nucleotides at the three areas are T, C, and T/C in Type I, and C, T, and C in Type II, respectively. Based on the nucleotide at the site 29063, the Type I strains can be further divided into Type IA and IB. The number of genomes belonging to type IA, IB, and is 10 18 and 69. Type II strains were likely evolved from Type I and are more prevalent than Type I among infected patients (68 Type II strains vs. 29 Type I strains in total). The outbreak of type II COVID-19 likely occurred in the Huanan market, while the initial transmission of the type I virus to humans probably happened at a different location in Wuhan. By analyzing the three genomic sites distinguishing Type I and Type II strains, they found that the synonymous changes at two of the three sites confer higher protein translational efficiencies in Type II strains than in Type I strains, which might explain why Type II strains are more prevalent, implying that Type II is more contagious (transmissible) than Type I |
56 | Zhu [71] | Research article | China | 27,388 full-length COVID-19 genomes (collected from December, 2019 to May, 2020 from GISAID, NCBI, CoVdb and Viral Zone | 9 new mutations; SNP-241 C > T, SNP-3037 C > T, SNP-8782 C > T, SNP-14408 C > T, SNP-23403 A > G, SNP-28144 T > C, SNP-28881 G > A, SNP-28882 G > A and SNP-28883 G > C; where the genome of the strain MN908947 is used as the reference | The 9 newly evolved SARS-CoV-2 single-nucleotide polymorphism (SNP) alleles reported, underwent a rapid increase(7 cases) 0 or decrease (2 cases) in their frequency for 30–80% in the initial four months, which are further confirmed by intra-host single-nucleotide variation (iSNV) analysis using raw sequence data including 8217 samples. The 9 SNPs are mostly (8/9) located in the coding region and are mainly (6/9) non-synonymous substitutions. They show a complete linkage in SNP pairs and belong to 3 different linkage groups, named LG_1–LG_3. Analyses in population genetics show signatures of adaptive selection toward the mutants in LG_1, but no signal of selection for LG_2. Population genetic analysis results on LG_3 show geological differentiation. Analyses on geographic COVID-19 cases and published clinical data provide evidence that the mutants in LG_1 and LG_3 benefit virus replication and those in LG_1 have a positive correlation with the disease severity in COVID-19-infected patients. The mutants in LG_2 show a bias toward mildness of the disease based on available public clinical data |
Novazzi [72] | Case report | Italy | 66-year-old Italian male who tested positive for B.1.351. After returning from Malawi (Africa) | B.1.351 in PANGOLIN phylogeny or 20H/501Y.V2 in NextStrain phylogeny | Despite significant resistance to convalescent plasma and several mAbs, sera from human subjects vaccinated with mRNA-1273 led to 2.7 and a 6.4-fold geometric mean reduction in neutralization (but still 1:190) against K417N + E484K + N501Y + D614G or full B.1.351 Spike pseudovirus, respectively, when compared to the D614G VSV pseudovirus. Similarly, sera from human subjects vaccinated with BNT162b2 led to 0.81- to a 1.46-fold geometric mean reduction in neutralization against an E484K + N501Y + D614G spike pseudovirus finally, sera from persons vaccinated with one of 2 Chinese vaccines (BBIBP-CorV or recombinant dimeric RBD vaccine ZF2001) largely preserved neutralizing titres, with a slight reduction, against 501Y.V2 authentic virus | |
Faria [73] | Reports | Brazil | Covid-19 patients | P.1 | Lineage P.1, acquired 17 mutations, including a trio in the spike protein (K417T, E484K, and N501Y) associated with increased binding to the human ACE2 receptor | |
Ferreira [74] | Research article | UK, India | Covid-19 patients | B.1.617 | The defining mutations in B.1.617.1 spike are L452R and E484Q in the RBD that interacts with ACE2 and is the target of neutralizing antibodies | |