Abstract
Hepatoviruses show an intriguing deviated codon usage, suggesting an evolutionary signature. Abundant and rare codons in the cellular genome are scarce in the human hepatitis A virus (HAV) genome, while intermediately abundant host codons are abundant in the virus. Genotype–phenotype maps, or fitness landscapes, are a means of representing a genotype position in sequence space and uncovering how genotype relates to phenotype and fitness. Using genotype–phenotype maps of the translation efficiency, we have shown the critical role of the HAV capsid codon composition in regulating translation and determining its robustness. Adaptation to an environmental perturbation such as the artificial induction of cellular shutoff—not naturally occurring in HAV infection—involved movements in the sequence space and dramatic changes of the translation efficiency. Capsid rare codons, including abundant and rare codons of the cellular genome, slowed down the translation efficiency in conditions of no cellular shutoff. In contrast, rare capsid codons that are abundant in the cellular genome were efficiently translated in conditions of shutoff. Capsid regions very rich in slowly translated codons adapt to shutoff through sequence space movements from positions with highly robust translation to others with diminished translation robustness. These movements paralleled decreases of the capsid physical and biological robustness, and resulted in the diversification of capsid phenotypes. The deviated codon usage of extant hepatoviruses compared with that of their hosts may suggest the occurrence of a virus ancestor with an optimized codon usage with respect to an unknown ancient host.
Highlights
The human hepatitis A virus (HAV) is exceptionally stable to extreme conditions, including very low pH, high temperature, and desiccation, compared with other picornaviruses such as poliovirus and rhinoviruses (Reagan et al 1981; Abad et al 1994; Costafreda et al 2014; Wang et al 2015)
The Relative Codon Deoptimization Index (RCDI) of the capsid coding region of the HAV, compared with several picornaviruses including PV 1, human rhinovirus 14 (HRV 14) and human rhinovirus 89 (HRV 89) was estimated with respect the standard human codon usage
In HAV the RCDI was above the expected RCDI (eRCDI) threshold, indicating that its codon usage deviation is due to compositional biases
Summary
The human hepatitis A virus (HAV) is exceptionally stable to extreme conditions, including very low pH, high temperature, and desiccation, compared with other picornaviruses such as poliovirus and rhinoviruses (Reagan et al 1981; Abad et al 1994; Costafreda et al 2014; Wang et al 2015). The recently resolved 3D structure of the HAV capsid revealed a VP2 domain swap at the pentamer interface creating a tighter subunit connectivity absent in other picornaviruses, and suggesting a relationship with its remarkable stability (Wang et al 2015). This swap occurs in the cricket paralysis virus (CrPV), a picorna-like insect virus, which does not show an equivalent stability (Wang et al 2015). Abundant and rare host codons are rarely used in its genome, while intermediately abundant host codons are abundant in the viral genome (Pinto et al 2018)
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