The effects of amino acid substitution of spike protein and genomic recombination on the evolution of SARS-CoV-2

Abstract

Over three years' pandemic of 2019 novel coronavirus disease (COVID-19), multiple variants and novel subvariants have emerged successively, outcompeted earlier variants and become predominant. The sequential emergence of variants reflects the evolutionary process of mutation-selection-adaption of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Amino acid substitution/insertion/deletion in the spike protein causes altered viral antigenicity, transmissibility, and pathogenicity of SARS-CoV-2. Early in the pandemic, D614G mutation conferred virus with advantages over previous variants and increased transmissibility, and it also laid a conservative background for subsequent substantial mutations. The role of genomic recombination in the evolution of SARS-CoV-2 raised increasing concern with the occurrence of novel recombinants such as Deltacron, XBB.1.5, XBB.1.9.1, and XBB.1.16 in the late phase of pandemic. Co-circulation of different variants and co-infection in immunocompromised patients accelerate the emergence of recombinants. Surveillance for SARS-CoV-2 genomic variations, particularly spike protein mutation and recombination, is essential to identify ongoing changes in the viral genome and antigenic epitopes and thus leads to the development of new vaccine strategies and interventions.

Keywords: Omicron; SARS-CoV-2; amino acid substitution; evolution; recombination; spike protein.

Figure 1

Process of mutation-selection-adaptation in SARS-CoV-2 evolution.

Figure 2

Timeline, structure, and entry pathways of SARS-CoV-2. (A) The chronological order of the emergence of major SARS-CoV-2 variants. (B) There are two pathways for SARS-CoV-2 entering cells: endosome pathway and membrane pathway. ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane protease serine protease 2; S1, subunit 1 of the spike protein; FP, fusion peptide, responsible for membrane fusion; S1/S2, furin cleavage site between S1 and S2 subunit of the spike protein; S2’, another proteolytic site in the subunit 2 of the spike protein.

Figure 3

Illustration of RBD conformation of spike protein complexed with ACE2 receptors. There are two RBD conformations: “up” and “down,” and when the RBD is in “up” conformation, the spike protein is open to the ACE2 receptor. The trimeric spike protein is indicated by chain in three colors, purple, green, and blue, and three ACE2 receptors are indicated in yellow, gray, and pink. The complexes are obtained from RCSB.org (7KNE, 7KNH, 7KNI for 1 “up,” 2 “up,” 3 “up,” respectively).

Figure 4

Representation of the SARS-CoV-2 spike protein, showing amino acid mutations in VOCs Alpha, Beta, Gamma, Delta and Omicron. Amino acid mutations are colored in orange, Alpha; yellow, Beta; purple, Gamma; green, Delta; red, Omicron; blue, ≥ 2 VOCs. The spike protein structure complexed with ACE2 receptor is obtained from RCSB.org (7KNE). The mutations of VOCs are based on the data from covariants (https://covariants.org, 20I for Alpha, 20H for Beta, 20 J for Gamma, 21A for Delta, and 21 L for Omicron).

Figure 5

Illustration of recombination in co-infected cells and different recombination patterns. (A) When different variants co-infect an individual, there is possibility that recombinant variants emerge with altered properties. (B) BA.3 is putatively a recombinant of BA.1 and BA.2, and the breakpoint probably lies in the spike protein-coding gene. BA.4 is putatively a recombinant of BA.2 and BA.5, and the breakpoint probably lies in the M protein-coding gene. XD and XF are recombinants of Delta and BA.1, and the breakpoints lie in the spike protein-coding gene/ORF3a and NSP3 protein-coding gene, respectively. XE is a recombinant of BA.1 and BA.2, with breakpoint lying in the NSP6 protein-coding gene. XBB.1.5 is a recombinant od BJ.1 and BA.2.75, and the breakpoint probably lies in the S1 subunit of the spike protein-coding gene. M, membrane protein; ORF3a, open reading frame 3a; NSP, non-structural protein.