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Tracking SARS-CoV-2 Omicron diverse spike gene mutations identifies multiple inter-variant recombination events

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The common mutations among Omicron (BA.1 and BA.2) and variants of concern (VOCs)

Circulating Omicron variant consists of two main subvariants, BA.1 and BA.2. BA.1 subvariant was more frequently detected than BA.2 during the early transmission phase. However, BA.2 is replacing BA.1 as the dominant epidemic subvariant in more and more countries over time.

Through scanning 52,563 high-quality completed Omicron spike gene sequences, most Omicron spike mutations appear stable (frequency >99%). 18 core mutations (frequency >99%) of BA.1 subvariant exist in NTD (A67V, del69-70, T95I, G142D, and del143-145), SD (underpinning subdomain) near the S1/S2 cleavage site (T547K, D614G, H655Y, N679K, and P681H), and S2 (D796Y, N856K, Q954H, N969K, and L981F) (Table 1). With regards to BA.2 subvariant, 27 core mutations were identified (Table 1).

Table 1 Comparison of Spike protein amino acid mutations between the Omicron subvariants and other VOCs and VOIs

BA.1 subvariant shares nine common amino acid mutations (del69-70, delY144, K417N, T478K, N501Y, D614G, H655Y, and P681H) in the spike protein with most VOCs, suggesting a possible origin of Omicron from these VOCs. Among these shared mutations, six common ones were found in Alpha variant (del69-70, delY144, N501Y, D614G, and P681H), to which the mutations of del69-70, delY144, and P681H are exclusive; three mutations were found in Beta variant (K417N, N501Y, and D614G), to which the mutation K417N is exclusive; three mutations found in Gamma (N501Y, D614G, and H655Y), to which the mutation H655Y is exclusive; two mutations found in Delta (T478K and D614G), to which the mutation T478K is exclusive (Fig. 1a and Table 1). The seven Omicron mutations exclusive to other four VOCs suggested a possible recombination origin of Omicron.

Fig. 1figure 1

Spike protein amino acid mutations of the Omicron subvariants (BA.1 and BA.2) compared with mutations from the other four variants of concern (VOCs). a Venn diagram noting mutations of Omicron (BA.1) and those of VOCs. b Venn diagram of Omicron (BA.2) mutations compared to ones of VOCs. c Venn diagram of mutations between Omicron (BA.1) and Omicron (BA.2). d Spike protein amino acid mutation counts of Omicron subvariants (BA.1 and BA.2) compared with mutations of VOCs

Compared to BA.1 subvariant, BA.2 shares only six amino acid mutations (K417N, T478K, N501Y, D614G, H655Y, and P681H) in the spike protein with most VOCs. Among these shared mutations, three mutations were found in Alpha variants (N501Y, D614G, and P681H); there were no del69-70 and delY144 mutations. The other three mutations in Beta, three mutations in Gamma, and two mutations in Delta were identical in the BA.2 and BA.1 genomes (Fig. 1b and Table 1).

BA.1 and BA.2 subvariants share 21 spike amino acid mutations: One in the N-terminal domain (NTD) (G142D), twelve in the receptor binding domain (RBD) (G339D, S373P, S375F, K417N, N440K, S477N, T478K, E484A, Q493R, Q498R, N501Y, and Y505H), four in SD (D614G, H655Y, N679K, and P681H), and four in S2 (N764K, D796Y, Q954H, and N969K) (Fig. 1c and Table 1).

In contrast to BA.2 subvariant, BA.1 share three additional amino acid deletions (del69-70, delY144) with the Alpha variants, suggesting a closer relationship between the BA.1 and Alpha variants (Fig. 1a, b and Table 1). Among the 21 shared mutations between BA.1 and BA.2 subvariants, 15 are specific to Omicron (G142D, G339D, S371L, S373P, S375F, N440K, S477N, Q493R, Q498R, Y505H, N679K, N764K, D796Y, Q954H, and N969K). Among these mutations, G142D in NTD, and G339D, S371L, S373P, S375F, N440K, S477N, Q493R, Q498R, and Y505H in RBD may contribute to the higher immune escape and transmissibility of Omicron variants (Table 1). As a whole, Omicron subvariants have a high number of amino acid mutations in the spike gene (40 in BA.1, and 31 in BA.2), of which some were found in other VOCs: Alpha (10x), Beta (11x), Gamma (12x), and Delta (9x). These mutations mainly occur in NTD and RBD (Fig. 1d and Table 1).

Novel mutations and mutations with decreased frequency in the spike gene of Omicron BA.1 and BA.2

We investigated additional mutations among recently emerged BA.1 isolates and identified eight novel mutations in Omicron variant which were also found in other VOCs and VOIs (Table 2). For example, mutations R346K (33.90% of 49,609 BA.1 sequences) was found in Mu variants; A701V (5.50%) was found in Beta variants; L5F (0.37%) was found in Iota variants; and T76I (0.10%) was found in Lambda variants. Most notably, multiple representative amino acid mutations in the Delta spike protein were also identified in the recently emerged Omicron subvariants (del156-167, R158G, L452R, and P681R, at percentages of 0.14%, 0.14%, 1.81%, and 0.12%, respectively. This implied possible recombination events between the Omicron and Delta strains during the pandemic. The first “Deltacron”-like Omicron strain was isolated on November 11, 2021 in South Africa, followed on November 23 in Botswana. This indicates that the recombination between Omicron and Delta strains may occur during the early transmission phase. The other newly noted mutations (L141F, F643L, I1081V, S1147L, and P1162S) may have originated independently (Table 2).

Table 2 Novel mutations identified in the spike protein of the recently emerged Omicron subvariants (emerged before 15 January 2022; frequency > 50 sequences)

Several novel mutations were reported to be related to spike protein function, resulting in an enhancement of virus infectivity or in viral immune escape. Mutations that occurred in RBD, e.g., R346K, could result in a relatively weakened neutralizing antibody effect.29 A L452R mutation may provide evasion from cellular immunity and increased infectivity.5 The P681R as well as F643L and A701V mutations, near the S1/S2 cleavage site, may be associated with enhanced fusogenicity and pathogenicity of SARS-CoV-2 Delta variants.8 Additionally, mutations T76I, L141F, G142Y, 156–167 deletion, and R158G, located in the NTD region, were noted to affect antibody binding efficiencies and contribute to immune escape.30 These mutations sites are mapped and shown in Fig. 2a, b.

Fig. 2figure 2

Structure of the Spike protein with amino acid mutations detected in Omicron BA.1 subvariant. a Structure of human ACE2 receptor complexed with SARS-CoV-2 Omicron RBD, mapped with the recent mutations. b Structure of SARS-CoV-2 Omicron spike protein mapped with the novel mutations. Mutated residues in each domain of the spike protein are annotated in color (red: RBD; yellow: NTD; green: S1/S2; blue: S2) using with Pymol 2.0 software through SARS-CoV-2 Omicron model PDB:7WBL and 7QO7

Apparent revertant mutations are found in some dominant mutations (frequency >95%) in the BA.1 subvariant during the pandemic. Examples are the mutations in NTD (del211 and N212I) and RBD (G339D, S371L, S373P, S375F, K417N, 440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, and Y505H). The frequency of insertions of the amino acids EPE at site 214 in BA.1 decreased during the pandemic from more than 95% on 1 December 2021 to 89% on 15 January 2022. However, BA.2 spike protein remained constant (frequency >99%), with the exception of the three amino acid deletion (LPP) found at amino acids 24–26, which decreased from more than 95% frequency on 1 December 2021 to 85% on 15 January 2022 (Table 1). This may possibly be due to selection pressure on the circulating Omicron strains.

Diverse haplotypes of Omicron spike gene and full genome phylogenetic trees show multiple recombination events during the pandemic

The spike gene of Omicron subvariants consists of 49 representative haplotypes (each occurring in more than 50 sequences). BA.1, BA.2, R346K, L452R, and A701V, and a revertant type were identified in the phylogenetic network analysis (Fig. 3a). A large number of BA.1 spike mutations delineated haplotype 2, R346K, L452R, and A701V clusters and formed distinct subgroups (detailed mutations defining each haplotype are listed in Supplementary Table 1).

Fig. 3figure 3

Phylogenetic network and scanning of the spike gene from representative Omicron subvariant sequences. a Representative Omicron spike protein haplotypes (each consisting of at least 50 sequences) were constructed with PopART using the median-joining method. Nucleotide changes were notated with lines. The spike gene from Wuhan-Hu-1 strain was set as the root. The number of sequences in each haplotype were modified into different orders of magnitude, and subgroups based on the mutation types were delineated by color. b BootScan analysis of revertant and representative haplotypes of Omicron spike gene. Representative spike Omicron haplotypes (H3, H4, H7) sequences and selected reversion haplotypes (H18, H39, H44) sequences are included. Bootscan map was constructed by Simplot 3.5.1 (https://sray.med.som.jhmi.edu/SCRoftware/SimPlot/) using neighboring-joining method with 100 bootstrap replicates. Wuhan-Hu-1 spike sequences were set as references and reversion region was annotated. c Overview of possible evolution mechanism of reversion haplotypes and haplotypes with mutations from Delta and other variants

Multiple nucleotide mutations were detected in the haplotypes compared with BA.1, e.g., haplotype 19 and the revertant subgroup (H30, 32, and 43, etc.) and BA.2. The S:L452R subgroup (“Deltacron”-like Variants) consists of different haplotypes with multiple nucleotide substitutions, indicating a possibly separate origin of S:L452R haplotypes or prior recombination events. Haplotype 25 in S:L452R subgroup, with multiple nucleotide differences compared with BA.1, could have resulted through recombination between Omicron and Delta variants, gaining the mutation S:L452R from Delta and losing multiple mutations from Omicron (Fig. 3a). Some of these “Deltacron” -like haplotypes are being tracked by the UK Health Security Agency (https://www.gov.uk/government/publications/sars-cov-2-variants-of-public-health-interest/sars-cov-2-variants-of-public-health-interest-25-february-2022) and underway to confirm by Santé publique France (https://t.co/tVAKmHRYSy). The revertant subgroup consisted of Omicron haplotypes in which several BA.1 representative mutations were lost and appeared to have reverted to the bases of the Wuhan-Hu-1 strain. Multiple nucleotide differences in other haplotypes occurred, likely as multiple independent mutation events, or perhaps as recombination events among highly similar sequences. Bootscan analysis of Omicron spike sequences also indicated that the reversion haplotypes (H18, H39, and H44) were more similar to Delta variants when compared to typical Omicron haplotypes (Fig. 3b).

Furthermore, single nucleotide differences could also originate from recombination events among highly similar strains. Loops detected in phylogenetic networks also indicate possible recombination events among highly similar Omicron variants or subvariants (Fig. 3a, c). Multiple newly detected or recent mutations in the Omicron spike gene make it possible to trace a putative mutation origin from representative mutations in VOIs or VOCs, especially the Delta variant, which suggests possible recombination events between Omicron and Delta variants (Table 2).

For further investigating the geographic distribution and genome diversity of the “Deltacron”-like variants, 897 Omicron genomic sequences of high quality containing S:L452R mutation reported for the Delta variant were analyzed (Fig. 4a). “Deltacron”-like variants were mainly distributed in North America, Europe, and West Asia (Fig. 4a). Whole genome annotation of amino acid mutations and phylogenetic tree corroborated the diversity among these S:L452R containing “Deltacron”-like Omicron genomes, which consist Omicron Pango sublineages BA.1, BA.1.1 (with S:R346K), BA.1.15, and BA.1.17 (Fig. 4b, c). BA.1 and BA.1.15 are the two major sublineages that acquired S:L452R mutation. The mutation profiles among whole genomes of BA.1 are diverse, and the sequences branched to diverse clades by phylogenetic analyses.

Fig. 4figure 4

Geographic distribution and whole genome analyses of “Delatcron”-like BA.1 subvariants (with S:L452R mutations). a Geographic distribution of “Delatcron”-like BA.1 subvariants (with S:L452R), with the number of genome sequences noted. b Whole genome annotation of amino acid mutations highlighting the “Deltacron”-like BA.1 subvariants (with S:L452R). 897 full genome sequences of BA.1 with S:L452R mutation were shown with red circles. c Phylogenetic analysis of the “Deltacron”-like BA.1 subvariants (with S:L452R). Maximum likelihood tree was constructed using Iqtree2 with 1000 bootstrap replicates and TIM + F + R3 model. Low quality sequences were excluded. 897 SARS-CoV-2 BA.1 full genome sequences with S:L452R mutation submitted to the GISAID database before 15 January 2022 and reference sequences from VOCs were included. Pango sublineages BA.1, BA.1.1, BA.1.15, and BA.1.17 are marked in colors

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