Human SARS-CoV-2 has evolved to increase U content and reduce genome size

Abstract

Infections caused by SARS-CoV-2 have brought great harm to human health. After transmission for over two years, SARS-CoV-2 has diverged greatly and formed dozens of different lineages. Understanding the trend of its genome evolution could help foresee difficulties in controlling transmission of the virus. In this study, we conducted an extensive monthly survey and in-depth analysis on variations of nucleotide, amino acid and codon numbers in 311,260 virus samples collected till January 2022. The results demonstrate that the evolution of SARS-CoV-2 is toward increasing U-content and reducing genome-size. C, G and A to U mutations have all contributed to this U-content increase. Mutations of C, G and A at codon position 1, 2 or 3 have no significant difference in most SARS-CoV-2 lineages. Current viruses are more cryptic and more efficient in replication, and are thus less virulent yet more infectious. Delta and Omicron variants have high mutability over other lineages, bringing new threat to human health. This trend of genome evolution may provide a clue for tracing the origin of SARS-CoV-2, because ancestral viruses should have lower U-content and probably bigger genome-size.

Attenuation and Degeneration of SARS-CoV-2 Despite Adaptive Evolution

“…While synonymous mutations that promote adaptation to human codon usage show a tendency to increase, most synonymous mutations, mainly those induced by APOBEC enzymes, are oblivious to natural selection [73]. Since C>U transitions are significantly the most abundant base substitutions in the mutational spectrum of SARS-CoV-2 [75][76][77], uracil steadily accumulates in the viral genome, while the number of cytosine declines with time [78]. Since intramolecular base-pairing forms secondary structures, which can stabilize the genome, and AU bonding is less tight than GC bonding, C>U transitions also destabilize the viral genome, which may facilitate nucleotide deletions, leading to slightly shorter genomes in all major variants (Table 1) [78].…”

“…Since C>U transitions are significantly the most abundant base substitutions in the mutational spectrum of SARS-CoV-2 [75][76][77], uracil steadily accumulates in the viral genome, while the number of cytosine declines with time [78]. Since intramolecular base-pairing forms secondary structures, which can stabilize the genome, and AU bonding is less tight than GC bonding, C>U transitions also destabilize the viral genome, which may facilitate nucleotide deletions, leading to slightly shorter genomes in all major variants (Table 1) [78]. SARS-CoV-2 still has a higher cytosine count and lower uracil count than any of the four human coronaviruses [79], which leads us to the following question: Will SARS-CoV-2 continue to evolve toward the nucleotide compositions of the current human coronaviruses and become more like them phenotypically?…”

The Possibility of Preventing the Mutation of SARS-Cov2 Virus

“…For example, the main variants of COVID-19 have the trend of increasing U content (Figure 2), while A, G, and C content shows the tendency to remain the same or decrease, but the infectivity increase with the changing of contents. (Figure 3) [7]. Taking the Delta variant as an example, the predominant mutations are L452R, P681R, and T478K, G of which change to U. L452R plays the role of connecting with ACE2, also increasing the amount of replication of the virus and the virus load.…”

<strong>Attenuation and Degeneration of SARS-CoV-2 Despite of Adaptive Evolution</strong>

“…While synonymous mutations that promote adaptation to human codon usage show a tendency to increase, most synonymous mutations, mainly those induced by APOBEC enzymes, are oblivious to natural selection [67]. Since C to U transitions are by far the most abundant base substitutions in the mutational spectrum of SARS-CoV-2 [69][70][71], uracil accumulates steadily in the viral genome while the number of cytosine declines with time [72]. Since intramolecular base-pairing forms secondary structures which can stabilize the genome, and AU bonding is less tight than GC bonding, C>U transitions also destabilizes the viral genome, which may facilitate nucleotide deletions, leading to shorter genomes in all major variants (Table 1) [72].…”

“…Since C to U transitions are by far the most abundant base substitutions in the mutational spectrum of SARS-CoV-2 [69][70][71], uracil accumulates steadily in the viral genome while the number of cytosine declines with time [72]. Since intramolecular base-pairing forms secondary structures which can stabilize the genome, and AU bonding is less tight than GC bonding, C>U transitions also destabilizes the viral genome, which may facilitate nucleotide deletions, leading to shorter genomes in all major variants (Table 1) [72]. SARS-CoV-2 still has higher cytosine count and lower uracil count than any of the four human coronaviruses [73], will it continue to evolve toward the nucleotide compositions of the current human coronaviruses, and phenotypically become more like them?…”