Compelling Evidence Suggesting the Codon Usage of SARS-CoV-2 Adapts to Human After the Split From RaTG13

Abstract

SARS-CoV-2 needs to efficiently make use of the resources from hosts in order to survive and propagate. Among the multiple layers of regulatory network, mRNA translation is the rate-limiting step in gene expression. Synonymous codon usage usually conforms with tRNA concentration to allow fast decoding during translation. It is acknowledged that SARS-CoV-2 has adapted to the codon usage of human lungs so that the virus could rapidly proliferate in the lung environment. While this notion seems to nicely explain the adaptation of SARS-CoV-2 to lungs, it is unable to tell why other viruses do not have this advantage. In this study, we retrieve the GTEx RNA-seq data for 30 tissues (belonging to over 17 000 individuals). We calculate the RSCU (relative synonymous codon usage) weighted by gene expression in each human sample, and investigate the correlation of RSCU between the human tissues and SARS-CoV-2 or RaTG13 (the closest coronavirus to SARS-CoV-2). Lung has the highest correlation of RSCU to SARS-CoV-2 among all tissues, suggesting that the lung environment is generally suitable for SARS-CoV-2. Interestingly, for most tissues, SARS-CoV-2 has higher correlations with the human samples compared with the RaTG13-human correlation. This difference is most significant for lungs. In conclusion, the codon usage of SARS-CoV-2 has adapted to human lungs to allow fast decoding and translation. This adaptation probably took place after SARS-CoV-2 split from RaTG13 because RaTG13 is less perfectly correlated with human. This finding depicts the trajectory of adaptive evolution from ancestral sequence to SARS-CoV-2, and also well explains why SARS-CoV-2 rather than other viruses could perfectly adapt to human lung environment.

Translational Control of COVID-19 and Its Therapeutic Implication

“…LARP1 binds to cellular mRNA containing oligopurine motif (TOP), thereby inhibiting the entry of eIF4E, regulating its stability and translation. On the other hand, since synonymous codons encoding the same amino acid have different concentrations of homologous tRNAs, SARS-CoV-2 codon usage is more relevant to codon usage in human lung, allowing for rapid decoding and protein translation ( 143 – 146 ). In short, all of these strategies ensure that translation of host cell proteins other than viral mRNA is inhibited.…”

Hepatitis B virus (HBV) codon adapts well to the gene expression profile of liver cancer: an evolutionary explanation for HBV’s oncogenic role

“…This helps SARS-CoV-2 compete with the hosts' endogenous RNAs and proliferate faster. This sequence adaptation process occurred after SARS-CoV-2 split from RaTG13 (Li et al, 2020c;Zhang et al, 2021b). This suggests that virus evolution could be extremely fast (Cai et al, 2022;Martignano et al, 2022;Zong et al, 2022) given the prevalence of mutations in the virus sequence (Li et al, 2020b;Wei, 2022) and the power of natural selection (Zhang et al, 2021a;Liu et al, 2022b).…”

“…This suggests that virus evolution could be extremely fast (Cai et al, 2022;Martignano et al, 2022;Zong et al, 2022) given the prevalence of mutations in the virus sequence (Li et al, 2020b;Wei, 2022) and the power of natural selection (Zhang et al, 2021a;Liu et al, 2022b). The translation efficiency of viral RNA is usually achieved by optimizing synonymous codon usage (Li et al, 2020a;Zhang et al, 2021b). Codon usage bias (CUB) occurs when organisms use synonymous codons unequally (Arella et al, 2021).…”

“…Under these conditions, viral RNA translation is less efficient because they cannot compete for tRNAs with endogenous mRNAs. However, throughout evolution, viruses have gradually optimized their coding sequences to adapt to host codon usage (Li et al, 2020c;Zhang et al, 2021b). This process elevates viral RNA translatability, allowing them to compete with endogenous RNAs for cellular resources such as tRNAs and translation machineries.…”

uORF-Mediated Translational Regulation of ATF4 Serves as an Evolutionarily Conserved Mechanism Contributing to Non-Small-Cell Lung Cancer (NSCLC) and Stress Response

“…This raises the evolutionary relevance between diseases and stresses, which might be essentially the same for the cellular defense and immune systems. A typical example is virus infection (Li et al, 2020a ; Zhang et al, 2021a , 2022 ). At the individual level, virus infection is regarded as disease, but at the cellular level, virus infection is essentially a kind of stress.…”