The Evolution and Biology of SARS-CoV-2 Variants

Abstract

Our understanding of the still unfolding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic would have been extremely limited without the study of the genetics and evolution of this new human coronavirus. Large-scale genome-sequencing efforts have provided close to real-time tracking of the global spread and diversification of SARS-CoV-2 since its entry into the human population in late 2019. These data have underpinned analysis of its origins, epidemiology, and adaptations to the human population: principally immune evasion and increasing transmissibility. SARS-CoV-2, despite being a new human pathogen, was highly capable of human-to-human transmission. During its rapid spread in humans, SARS-CoV-2 has evolved independent new forms, the so-called "variants of concern," that are better optimized for human-to-human transmission. The most important adaptation of the bat coronavirus progenitor of both SARS-CoV-1 and SARS-CoV-2 for human infection (and other mammals) is the use of the angiotensin-converting enzyme 2 (ACE2) receptor. Relaxed structural constraints provide plasticity to SARS-related coronavirus spike protein permitting it to accommodate significant amino acid replacements of antigenic consequence without compromising the ability to bind to ACE2. Although the bulk of research has justifiably concentrated on the viral spike protein as the main determinant of antigenic evolution and changes in transmissibility, there is accumulating evidence for the contribution of other regions of the viral proteome to virus-host interaction. Whereas levels of community transmission of recombinants compromising genetically distinct variants are at present low, when divergent variants cocirculate, recombination between SARS-CoV-2 clades is being detected, increasing the risk that viruses with new properties emerge. Applying computational and machine learning methods to genome sequence data sets to generate experimentally verifiable predictions will serve as an early warning system for novel variant surveillance and will be important in future vaccine planning. Omicron, the latest SARS-CoV-2 variant of concern, has focused attention on step change antigenic events, "shift," as opposed to incremental "drift" changes in antigenicity. Both an increase in transmissibility and antigenic shift in Omicron led to it readily causing infections in the fully vaccinated and/or previously infected. Omicron's virulence, while reduced relative to the variant of concern it replaced, Delta, is very much premised on the past immune exposure of individuals with a clear signal that boosted vaccination protects from severe disease. Currently, SARS-CoV-2 has proven itself to be a dangerous new human respiratory pathogen with an unpredictable evolutionary capacity, leading to a risk of future variants too great not to ensure all regions of the world are screened by viral genome sequencing, protected through available and affordable vaccines, and have non-punitive strategies in place for detecting and responding to novel variants of concern.

Figure 1.

Phylogenetic tree showing severe acute respiratory syndrome coronavirus 1 and 2 (SARS-CoV-1 and -2) emerging from divergent SARS-related coronavirus lineages. The Sarbecovirus subgenus includes, in addition to the SARS-CoV-2 clade, related SARS-like viruses sampled from horseshoe bats, pangolins, civets, and the first SARS-virus clade, SARS-CoV-1 (see key). The tree-branching structure depicts most recent common ancestry relative to the genome sequences at the tips on the right (colored by host species). The scale bar shows nucleotide substitutions per site and refers to the horizontal branch lengths. Placing of some of these relationships is approximate owing to recombination in the evolutionary history of these viruses (Boni et al. 2020). (Analysis and images reprinted from Nextstrain.org [nextstrain.org/groups/blab/sars-like-cov] under an Attribution 4.0 International (CC-BY-4.0) license.)

Figure 2.

The evolutionary and temporal relationships of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clades. Since its emergence in late 2019, SARS-CoV-2's two initial lineages (A,B) have continued to diversify, forming novel genetic variants with a subset of “variants of concern” dominating at different times in the pandemic. (A) Unrooted phylogenetic tree showing the main SARS-CoV-2 clades, which are defined by different nomenclature conventions (see Box 2). The tree-branching structure depicts most recent common ancestry relative to the genome sequences at internal nodes or the tips of each branch (colored by Nextstrain and WHO clade designations with Omicron also labeled with its Pango sublineages; see key). Branch lengths correspond to genetic change. (B) Frequencies of SARS-CoV-2 variants colored by clade (see key) from late March 2021 to March 2022. A subset of variants of concern have dominated in the pandemic (Alpha, Delta, and Omicron) with Omicron clades constituting the majority of infections as of March 2022. This visualization is based on a subsample of available full genome data (∼600 genomes per continental region with ∼400 from the previous 4 mo and ∼200 from before this). This subsampling results in a more equitable global sequence distribution. (Analysis and images reprinted from Nextstrain.org [nextstrain.org/ncov/gisaid/global] under an Attribution 4.0 International (CC-BY-4.0) license.)

Figure 3.

Dynamics of replacement of variants of concern (VOCs) during the first 2 years of the pandemic. Data are based on over eight million sequences from GISAID EpiCoV 2022_02_22. The emergence of D614G is included for completeness. BA.1 (orange) and BA.2 (dark orange) are subvariants of Omicron (dark blue) and are highlighted individually for completeness.

Figure 4.

Variant fitness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Shown is “mutational”/variant-level fitness measured by the increase in average transmission for different SARS-CoV-2 variants colored by clade relative to an early 2020 genotype: Wuhan-Hu-1 (Obermeyer et al. 2021). (Analysis and image reprinted from Nextstrain.org [nextstrain.org/ncov/gisaid/global] under an Attribution 4.0 International (CC-BY-4.0) license.)

Figure 5.

Conservation of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. 180 of 1273 (14%) amino acid positions of the SARS-CoV-2 spike protein are identified as moderately variant or common sites of variation, while 86% remain conserved or highly conserved. Data from analysis of over nine million sequences from GISAID on March 2022.