Molecular Determinants of SARS-CoV-2 Variants

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution is expected, given the nature of virus replication. Selection and establishment of variants in the human population depend on viral fitness and on molecular and immunological selection pressures. Here we discuss how mechanisms of replication and recombination may contribute to the emergence of current and future variants of SARS-CoV-2.

Keywords: COVID-19; SARS-CoV-2; recombination; replication; variants.

Figure 1

Replication-Associated Generation of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants. Replication-associated mutations and intrinsic selection factors play a critical role in the evolution and subsequent emergence of SARS-CoV-2 variants from infected cells. SARS-CoV-2 genome [positive (+) sense single stranded (ss)RNA] is released into the cytoplasm after virus binding to the angiotensin-converting enzyme 2 (ACE2) receptor and entry (A; red strand). The viral replicase complex transcribes the genome into negative (–) sense ssRNA (B; green strand) which acts as a template for subsequent synthesis of full-length +sense ssRNA genome copies (C). During replication, errors introduce mutations within the SARS-CoV-2 genome (D), which lead to mutations within viral proteins (E). While one copy of the genome is packaged into each SARS-CoV-2 virion (F), the heterogeneity of spike proteins on the surface of each virion (represented by different colors) remains unknown. Finally, SARS-CoV-2 variants carrying +sense ssRNA genomes with a varying number of mutations are released from the infected cell following egress (G).

Figure 2

Recombination-Induced Variants. (A) Strand switching. Discontinuous transcription facilitates the generation of potential chimeric subgenomic RNA (sgmRNA) in cells that are infected with more than one species or variant of Coronavirus (CoV). A CoV (CoV 1) entering (a) an already-infected cell will release its genomic RNA in the cytoplasm (b), which will undergo discontinuous transcription (c) to generate sgmRNA (d). During discontinuous transcription, the viral RNA-dependent RNA polymerase (RdRp) may inadvertently switch strands and jump (e) onto a template from a second CoV (CoV 2), leading to the synthesis of chimeric sgmRNA (CoV1+CoV2) (f). (B) Homologous recombination. Similar to recombination between homologous DNA sequences, regions of homology between two CoV genomes (CoV1 and CoV2) may facilitate breakage and rejoining of genomes to form chimeric genomes (CoV1+CoV 2).