Evolutionary Tracking of SARS-CoV-2 Genetic Variants Highlights an Intricate Balance of Stabilizing and Destabilizing Mutations

Abstract

The currently ongoing COVID-19 pandemic caused by SARS-CoV-2 has accounted for millions of infections and deaths across the globe. Genome sequences of SARS-CoV-2 are being published daily in public databases and the availability of these genome data sets has allowed unprecedented access to the mutational patterns of SARS-CoV-2 evolution. We made use of the same genomic information for conducting phylogenetic analysis and identifying lineage-specific mutations. The catalogued lineage-defining mutations were analyzed for their stabilizing or destabilizing impact on viral proteins. We recorded persistence of D614G, S477N, A222V, and V1176F variants and a global expansion of the PANGOLIN variant B.1. In addition, a retention of Q57H (B.1.X), R203K/G204R (B.1.1.X), T85I (B.1.2-B.1.3), G15S+T428I (C.X), and I120F (D.X) variations was observed. Overall, we recorded a striking balance between stabilizing and destabilizing mutations, therefore leading to well-maintained protein structures. With selection pressures in the form of newly developed vaccines and therapeutics to mount in the coming months, the task of mapping viral mutations and recording their impact on key viral proteins should be crucial to preemptively catch any escape mechanism for which SARS-CoV-2 may evolve. IMPORTANCE Since its initial isolation in Wuhan, China, large numbers of SARS-CoV-2 genome sequences have been shared in publicly accessible repositories, thus enabling scientists to do detailed evolutionary analysis. We investigated the evolutionarily associated mutational diversity overlaid on the major phylogenetic lineages circulating globally, using 513 representative genomes. We detailed the phylogenetic persistence of key variants facilitating global expansion of the PANGOLIN variant B.1, including the recent, fast-expanding, B.1.1.7 lineage. The stabilizing or destabilizing impact of the catalogued lineage-defining mutations on viral proteins indicates their possible involvement in balancing the protein function and structure. A clear understanding of this mutational profile is of high clinical significance to catch any vaccine escape mechanism, as the same proteins make crucial components of vaccines that have recently been approved or are in development. In this vein, our study provides an imperative framework and baseline data upon which further analysis could be built as newer variants of SARS-CoV-2 continue to appear.

Keywords: SARS-CoV-2; evolution; mutation; stability; vaccine.

FIG 1

Maximum likelihood phylogenetic tree inferred from 513 SARS-CoV-2 genomes. The tree was constructed using multiple genome sequence alignment (MAFFT) by mapping against the Wuhan-Hu-1 strain (accession NC_045512). Tips are colored with the major lineages assigned by PANGOLIN. Respective lineages assigned by GISAID and origin of sequence are labeled as color strips. The scale bar indicates the distance corresponding to substitution per site.

FIG 2

Schematic representation of the major evolutionary events/amino acid substitutions that gave rise to SARS-CoV-2 variants in sequential order.

FIG 3

Schematic representation of SARS-CoV-2 genome organization, the major amino acid substitutions, and stability of amino acid changes. Stabilizing mutations are colored green, destabilizing mutations are colored red, and mutations that neither stabilize nor destabilize are colored yellow.