Genome-Wide Analysis Of Codon Usage Bias In Hantaan Virus And Adaptability To Its Host And Natural Reservoirs

Hantaan virus(HTNV)is an emerging zoonotic pathogen that infects humans,causing hemorrhagic fever with renal syndrome(HFRS): endemic in Far East Russia,China,and South Korea.The molecular evolutionary dynamics of Hantaan virus(HTNV)are still poorly understood,and the role of virus-host interaction in its evolution remains an open question.The codon usage is a crucial measure of viral genome evolution;therefore,we enrolled 95 HTNV strains in a comprehensive phylogenetic-dependent codon usage analysis to elucidate the virus molecular evolutionary processes and its adaptability to several hosts and environments via a plethora of codon usage indices.We found that both mutational bias and natural selection influence the codon bias choices in HTNV;however,host and natural reservoir-induced natural selection is the primary determinant of its patterns and evolution.The phylogenetic analysis of HTNV strains resulted in three distinct clades: South Korean,Russian,and Chinese.An effective number of codon(ENC)analysis showed a slightly biased codon usage in HTNV genomes(ENC,47.52).Nucleotide composition and relative synonymous codon usage(RSCU)analyses revealed a significant bias towards A/U nucleotides and A/U-ended codons,indicating the potential influence of mutational bias on the codon usage patterns of HTNV.Via ENC-plot,Parity Rule 2(PR2),and neutrality plot analyses,we would conclude the presence of both mutation pressure and natural selection effect in shaping the codon usage patterns of HTNV;however,natural selection is the dominant factor influencing its codon usage bias.Codon adaptation index(CAI),Relative codon deoptimization index(RCDI),and Similarity Index(Si D)analyses uncovered the intense selection pressure from the host(Human)and natural reservoirs(Striped field mouse,Chinese white-bellied rat)in shaping HTNV biased codon choices.No remarkable difference was observed between the isolates of three HTNV clades at the overall genome level—regarding the codon usage patterns and the molecular evolutionary processes.Nevertheless,the evolution of the individual genomic segments was clade-specific.We believe that our results will help in a better and deep understanding of the molecular evolutionary processes of HTNV that will serve its future basic research and aid live attenuated vaccines design.Also,our results provide an additional evidence to the role of the virus-host interaction in the evolution of genus Orthohantavirus in general and HTNV in particular.