The Mutation Profile of SARS-CoV-2 Is Primarily Shaped by the Host Antiviral Defense

Abstract

Understanding SARS-CoV-2 evolution is a fundamental effort in coping with the COVID-19 pandemic. The virus genomes have been broadly evolving due to the high number of infected hosts world-wide. Mutagenesis and selection are two inter-dependent mechanisms of virus diversification. However, which mechanisms contribute to the mutation profiles of SARS-CoV-2 remain under-explored. Here, we delineate the contribution of mutagenesis and selection to the genome diversity of SARS-CoV-2 isolates. We generated a comprehensive phylogenetic tree with representative genomes. Instead of counting mutations relative to the reference genome, we identified each mutation event at the nodes of the phylogenetic tree. With this approach, we obtained the mutation events that are independent of each other and generated the mutation profile of SARS-CoV-2 genomes. The results suggest that the heterogeneous mutation patterns are mainly reflections of host (i) antiviral mechanisms that are achieved through APOBEC, ADAR, and ZAP proteins, and (ii) probable adaptation against reactive oxygen species.

Keywords: ADAR; APOBEC; COVID-19; ROS; SARS-CoV-2; ZAP; evolution; mutation; phylogenetics.

Figure 1

Schematic representation of the methodology.

Figure 2

Mutation profile of SARS-CoV-2 genomes. Mutation counts are normalized by the trinucleotide content for each trinucleotide generated from 33,540 (representative sequences and nodes) sequences (A). From unstable positions where more than 8 mutations of the same type at the same position, highly occurred mutations are retrieved. The occurrences of these mutations are divided by the total number of the mutations of the same type and observed in the same trinucleotide. The calculated ratio is used to visualize the impact of highly occurring mutations on signature profile, as percentages (B). The bars are labelled with their positions in the genome. Number of mutations observed in the phylogenetic tree, per position (C). Mutations which have a significant contribution to their signature visualized in part B are marked according to the mutation count they represent at the position. Marked mutations are colored and reshaped with respect to their mutation type and impact range on their signatures.

Figure 3

Comparison of codon variations in SARS-CoV-2 phylogenetic tree, human genome, and SARS-CoV-2reference genome. (A) Codon variations from mutations in the phylogenetic tree, represented by the ratio of formations over deformations per codon in log2 formation. (B) Relative codon usage percentage between Human and SARS-CoV-2 reference genome.

Figure 4

Comparison of dinucleotide formations and deformations retrieved from phylogenetic trees. Deformation ratio of dinucleotides is represented as the ratio of deformation count in the tree over dinucleotide’s abundance in the reference genome (A). As a result of the mutations, the relative dinucleotides are formed (B).

Figure 5

Mechanisms that can alter the sequence context of SARS-CoV-2. (i) APOBEC-caused mutations correlated with the enzyme signature dominantly on the plus RNA strand; (ii) ADAR-caused mutations equivalently affecting both RNA strands due to its mechanism of action; (iii) drop of CG dinucleotide targeted by ZAP through selection; (iv) ROS effect shown on the plus RNA strand.