Emerging SARS-CoV-2 Variants: Genetic Variability and Clinical Implications

Abstract

The sudden rise in COVID-19 cases in 2020 and the incessant emergence of fast-spreading variants have created an alarming situation worldwide. Besides the continuous advancements in the design and development of vaccines to combat this deadly pandemic, new variants are frequently reported, possessing mutations that rapidly outcompeted an existing population of circulating variants. As concerns grow about the effects of mutations on the efficacy of vaccines, increased transmissibility, immune escape, and diagnostic failures are few other apprehensions liable for more deadly waves of COVID-19. Although the phenomenon of antigenic drift in new variants of SARS-CoV-2 is still not validated, it is conceived that the virus is acquiring new mutations as a fitness advantage for rapid transmission or to overcome immunological resistance of the host cell. Considerable evolution of SARS-CoV-2 has been observed since its first appearance in 2019, and despite the progress in sequencing efforts to characterize the mutations, their impacts in many variants have not been analyzed. The present article provides a substantial review of literature explaining the emerging variants of SARS-CoV-2 circulating globally, key mutations in viral genome, and the possible impacts of these new mutations on prevention and therapeutic strategies currently administered to combat this pandemic. Rising infections, mortalities, and hospitalizations can possibly be tackled through mass vaccination, social distancing, better management of available healthcare infrastructure, and by prioritizing genome sequencing for better serosurveillance studies and community tracking.

Fig. 1

Viral genome and functional domains in SARS-CoV-2. a Schematic annotation of SARS-CoV-2 genomic composition. Genome of SARS-CoV-2 is ~ 30 kb in length comprising 14 ORFs, responsible for producing structural and non-structural proteins (nsPs). b N-terminus region, spanning more than two-third portion of the viral genome, is translated to produce polyprotein of nsPs, which is proteolytically cleaved by main protease (nsP5) and papain-like protease (nsP3) to form the replicase-transcriptase complex for viral replication. c Schematic representation of domains of SARS-CoV-2 S protein. S1 subunit comprises N-terminal domain (NTD) and receptor-binding domain (RBD). Canonical location of S1/S2 (Furin site) and S2′ (TMPRSS2) cleavage sites are indicated in S protein

Fig. 2

a Cartoon representation of SARS-CoV-2 homotrimeric S protein interacting with human angiotensin converting enzyme2 (ACE2) via its receptor-binding domain (RBD). The three-dimensional complex structure of RBD and ACE2 was retrieved from the RCSB-Protein data bank (PDB ID: 7DF4). ACE2 has been shown in cyan while magenta, yellow and green cartoons represent the three S proteins linked together to form a homotrimer. b Key interactions of the receptor-binding domain (RBD) of S protein to human ACE2 (PDB ID: 6M0J) displayed using cartoon representation. Important RBD mutations circulating in emerging variants, c E484K, d E484Q, e K417T, f K417N, g N501Y, h Y453F, i N439K, j N440K, k L452R, and l S477N are represented in green sticks models. RBD is colored in magenta, ACE2 is colored in cyan, and the key residues at the RBD-ACE2 interface are shown as stick models (Color figure online)

Fig. 2

a Cartoon representation of SARS-CoV-2 homotrimeric S protein interacting with human angiotensin converting enzyme2 (ACE2) via its receptor-binding domain (RBD). The three-dimensional complex structure of RBD and ACE2 was retrieved from the RCSB-Protein data bank (PDB ID: 7DF4). ACE2 has been shown in cyan while magenta, yellow and green cartoons represent the three S proteins linked together to form a homotrimer. b Key interactions of the receptor-binding domain (RBD) of S protein to human ACE2 (PDB ID: 6M0J) displayed using cartoon representation. Important RBD mutations circulating in emerging variants, c E484K, d E484Q, e K417T, f K417N, g N501Y, h Y453F, i N439K, j N440K, k L452R, and l S477N are represented in green sticks models. RBD is colored in magenta, ACE2 is colored in cyan, and the key residues at the RBD-ACE2 interface are shown as stick models (Color figure online)

Fig. 3

a Cartoon representation of monomeric S protein of SARS-CoV-2 (PDB ID: 6XR8) depicting its different subunits where the S1 subunit is represented in blue, the RBD is shown in magenta, and the S2 is denoted in green color. b Cartoon representation of the S1 subunit (blue) and RBD (magenta) (PDB ID: 6XR8) with their key mutations depicted in the form of red sticks. Labeled and encircled residues represent the important mutations and their location in S1 protein of emerging variants of SARS-CoV-2. c Cartoon representation of the S2 subunit (green) (PDB ID: 6XR8) and its key mutations depicted as red sticks. Labeled and encircled residues represent the important mutations and their location in S2 protein of emerging variants of SARS-CoV-2 (Color figure online)

Fig. 4

Novel mutations in SARS-CoV-2 genome across different lineages. Sites of significant mutations in open-reading frames (ORFs), accessory proteins, nucleocapsid protein, membrane protein, envelope protein, and spike protein are marked in form of triangles (Δ). Color coded triangles are used to represent variants containing these mutations in their genomes (Color figure online)