The Evolution of Severe Acute Respiratory Syndrome Coronavirus-2 during Pandemic and Adaptation to the Host

Abstract

Severe Acute Respiratory Syndrome Coronavirus-2 is a zoonotic virus with a possible origin in bats and potential transmission to humans through an intermediate host. When zoonotic viruses jump to a new host, they undergo both mutational and natural selective pressures that result in non-synonymous and synonymous adaptive changes, necessary for efficient replication and rapid spread of diseases in new host species. The nucleotide composition and codon usage pattern of SARS-CoV-2 indicate the presence of a highly conserved, gene-specific codon usage bias. The codon usage pattern of SARS-CoV-2 is mostly antagonistic to human and bat codon usage. SARS-CoV-2 codon usage bias is mainly shaped by the natural selection, while mutational pressure plays a minor role. The time-series analysis of SARS-CoV-2 genome indicates that the virus is slowly evolving. Virus isolates from later stages of the outbreak have more biased codon usage and nucleotide composition than virus isolates from early stages of the outbreak.

Analysis of SARS-CoV-2 synonymous codon usage evolution throughout the COVID-19 pandemic

“…approximately 30 SNPs per genome) were observed for the most distant SARS-CoV-2 2021 isolates. This indicated that it should be possible to analyze the time dependence of codon usage frequencies for SARS-CoV-2 ORFs, although only a small variation was expected, as it was previously observed by Hussain et al (2021) and Huang et al (2021) . These authors conducted similar time-series analysis, principally of averaged ENC and CAI values, showing that in the first months of COVID-19 pandemic both indices were slowly decreasing.…”

“…The main codons contributing to differences in SARS-CoV-2 variants were AAA-Lys (A < D/G < B), AAG-Lys (B < G/D < A), ACA-Thr (D < A/B/<G), ACC (B/G < A/D), ACG (A/B < D/G), AGG (G < D < A < B), CCA (G < D < B < A), CCC (A < B < D < G), CCG (A < B/D < G), CGA (D/B < A < G), CGG (B/G/A < D), CTG (D < G/B/A), GAA (ABGD <average), GAG (ABDG >average), GCA (BDG < A), GTG (ABD < G), TAC (G < D/B < A), TAT (A < B/D < G), TCC (A < G < B/D), TGC (A/D < G/B), TGT (G/D < A/B), and TTG (ABGD <average). Interestingly, some of the codons which presented an increase in the ACUF (although slight) contained CG or TA dinucleotides (ATA, ATT, CAT, GCG, and CGA), and it was speculated that an increase of CpG and UpA dinucleotides could reduce SARS-CoV-2 pathogenicity ( Hussain et al, 2021 ).

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“…Further, for SARS-CoV-2, different results were reported, indicating from a main role of mutational pressure, to a strict selection pressure ( Khattak et al, 2021 ; Nambou and Anakpa, 2020 ; Roy et al, 2021 ; Tyagi et al, 2021 ). In the case of human coronaviruses, including SARS-CoV, MERS-CoV and SARS-CoV-2, several CUB analyses were carried out ( Carmi et al, 2021 ; Das et al, 2021 ; Das and Roy, 2021 ; Dilucca et al, 2020 ; Dimonaco et al, 2021 ; Gu et al, 2020 ; Gupta et al, 2021 ; Hou, 2020 ; Huang et al, 2021 ; Hussain et al, 2020 , 2021 ; Kandeel et al, 2020 ; Khattak et al, 2021 ; Nambou and Anakpa, 2020 ; Roy et al, 2021 ; Tort et al, 2020 ; Tyagi et al, 2021 ). As a result, some general conclusions could be made: first, all of them possessed high AU content and low GC content, with the CpG dinucleotide markedly under-represented, and in the case of SARS-CoV-2, a preferred use of U-ending codons; codon usage bias and codon pair usage were found to be quite different from that of the human host, even when particular tissues such as lung and kidneys were analyzed ( Kames et al, 2020 ); high E ffective N umber of C odons (ENC) ( Wright, 1990 ) values were found (although lower than those of other coronaviruses), suggesting a slight codon usage bias; in comparison to other coronaviruses, SARS-CoV, MERS-CoV, and SARS-CoV-2 presented the highest values of the C odon A daptation I ndex (CAI) ( Sharp and Li, 1987 ) calculated using human proteins as the reference set, suggesting that these viruses are more adapted to the human host than other coronaviruses that present milder clinical symptoms; a relatively high average CAI value was found for SARS-CoV-2 (approximately 0.7), however, its value was smaller than the average for human genes (approximately 0.8) ( Tort et al, 2020 ).…”

“…Although the codon usage pattern of SARS-CoV-2 has been thoroughly described, there are only a few works assessing the adaptation of SARS-CoV-2 codon usage since its transfer to human hosts ( Huang et al, 2021 ; Hussain et al, 2021 ). It was reported that during the first six months of the COVID-19 pandemic, SARS-CoV-2 average ENC decreased, principally due to C to U mutations (i.e.…”

“…Furthermore, the codon usage profile of SARS-CoV-2 seems to have moved away from the human optimal. Interestingly, the CpG and UpA dinucleotides, which are markedly suppressed in many RNA and small DNA viruses, appear to be increasing in the SARS-CoV-2 genome over time, and could result in virus attenuation and decreased pathogenicity ( Hussain et al, 2021 ). CAI values for most of SARS-CoV-2 coding sequences have also decreased, further suggesting that pathogenicity in humans could be decreasing ( Huang et al, 2021 ).…”