Comparative analysis of codon usage patterns in SARS-CoV-2, its mutants and other respiratory viruses

Abstract

The Coronavirus disease 2019 (COVID-19) outbreak caused by Severe Acute Respiratory Syndrome Coronavirus 2 virus (SARS-CoV-2) poses a worldwide human health crisis, causing respiratory illness with a high mortality rate. To investigate the factors governing codon usage bias in all the respiratory viruses, including SARS-CoV-2 isolates from different geographical locations (~62K) including two recently emerging strains from the United Kingdom (UK), i.e.,VUI202012/01 and South Africa (SA), i.e., 501.Y.V2 codon usage bias (CUBs) analysis was performed. The analysis includes RSCU analysis, GC content calculation, ENC analysis, di-nucleotide frequency and neutrality plot analysis. We were motivated to conduct the study to fulfil two primary aims: first, to identify the difference in codon usage bias amongst all SARS-CoV-2 genomes and secondly, to compare their CUBs properties with other respiratory viruses. A biased nucleotide composition was found as most of the highly preferred codons were A/U-ending in all the respiratory viruses studied here. When compared with human host, the RSCU analysis led to the identification of 11 over-represented codons and 9 under-represented codons in SARS-CoV-2 genomes. Correlation analysis of ENC and GC3s revealed that mutational pressure is the leading force determining the CUBs. The present study results yields a better understanding of codon usage preferences for SARS-CoV-2 genomes and discover the possible evolutionary determinants responsible for the biases found among the respiratory viruses, thus unveils a unique feature of the SARS-CoV-2 evolution and adaptation. To the best of our knowledge, this is the first attempt at comparative CUBs analysis on the worldwide genomes of SARS-CoV-2, including novel emerged strains and other respiratory viruses.

Genome-Wide Analysis of Codon Usage Patterns of SARS-CoV-2 Virus Reveals Global Heterogeneity of COVID-19

“…Nucleotide composition being the major force in affecting codon usage pattern was measured to evaluate its impact on the codon usage pattern of CDS sequences of SARS-CoV-2 [ 48 ]. The composition frequency and trend of each nucleotide were U (32.19% ± 0.05) > A (29.85% ± 0.02) > G (19.56% ± 0.05) > C (18.39% ± 0.07), which is consistent with the trend in other Coronaviruses like SARS and MERS [ 29 ] which manifestly indicate U codon being the more frequent one throughout SARS-CoV-2 genome ( Supplementary Table S1 , Figure 1 A) However, these trends differ from other viruses like RSV which follows A > U > G > C and H1N1 and H3N2 order A > G > U > C [ 29 ]. AU’s mean values (62.04% ± 0.04) and GC (37.96% ± 0.04) emphasize the CDS genome as AU-rich genome ( Supplementary Table S1 ).…”

“…Some of the points were scattered away from the line marking the translational force also marginally but significantly drove the codon usage biases in SARS-CoV-2 ( Supplementary Table S4 , Figure 4 ). Our results are consistent with the previously reported results for SARS-CoV-2 [ 20 , 29 ] but inconsistent with some reports [ 53 ]. This reconfirms our statement that analysis on a small sample size may result in false positives, so we analyzed a more diverse dataset of 60 genomes.…”

“…AU’s mean values (62.04% ± 0.04) and GC (37.96% ± 0.04) emphasize the CDS genome as AU-rich genome ( Supplementary Table S1 ). The nucleotide composition of codons at third position U3 (42.73% ± 3.93) > A3 (28.80% ± 4.03) > C3 (16.08% ± 2.21) > G3 (14.04% ± 4.90 showed inconsistent trend against SARS-CoV and MERS which follows U3 > A3 > G3 > C3 [ 29 ]. Interestingly, this trend is also inconsistent with the overall trend of bases in the genome ( Supplementary Table S1 , Figure 1 B).…”

“…Natural selection and mutational pressure, on the other hand, are the primary driving forces [ 26 , 27 ]. Several studies have concluded that mutational pressure is the primary driver of codon usage patterns in SARS-CoV-2 [ 23 , 28 , 29 , 30 , 31 ].…”

“…These essential characteristics affect virus development, adaptation, survival, and host immune system disregard [ 32 , 33 ]. Understanding the codon usage pattern can thus provide valuable insights into the evolutionary process, host adaptation, disregard for the host immune system, viral pathogenesis, and global heterogeneity of the SARS-CoV-2 virus [ 12 , 14 , 20 , 29 ]. For this purpose, we have characterized the codon usage patterns among sixty SARS-CoV-2 viral strains to unravel the role of codon architecture in viral pathogenesis.…”