Abstract
The molecular evolutionary dynamics that shape hantaviruses’ evolution are poorly understood even now, besides the contribution of virus-host interaction to their evolution remains an open question. Our study aimed to investigate these two aspects in Hantaan virus (HTNV)—the prototype of hantaviruses and an emerging zoonotic pathogen that infects humans, causing hemorrhagic fever with renal syndrome (HFRS): endemic in Far East Russia, China, and South Korea—via a comprehensive, phylogenetic-dependent codon usage analysis. We found that host- and natural reservoir-induced natural selection is the primary determinant of its biased codon choices, exceeding the mutational bias effect. 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. Nucleotide composition and RSCU analyses revealed a significant bias toward 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 (SiD) analyses uncovered the intense selection pressure from the host (Human) and natural reservoirs (Striped field mouse and Chinese white-bellied rat) in shaping HTNV biased codon choices. Our study clearly revealed the evolutionary processes in HTNV and the role of virus-host interaction in its evolution. Moreover, it opens the door for a more comprehensive codon usage analysis for all hantaviruses species to determine their molecular evolutionary dynamics and adaptability to several hosts and environments. We believe that our research will help in a better and deep understanding of HTNV evolution that will serve its future basic research and aid live attenuated vaccines design.
Highlights
Hantaviruses are rodent-borne pathogens that compose the genus Orthohantavirus, family Hantaviridae, in the order Bunyavirales1
We found that Hantaan virus (HTNV) strains evolved into three distinct clades (Supplementary Figure 1), named South Korean (SK, 67 isolates), Russian (RUS, four isolates), and Chinese (CH, 15 isolates)
The two strains (AYW89-15 and Nc167) reported as out of the three phylogenetic clades, one found to cluster with the Russian clade and the second with the Chinese clade (Figure 7A). Another interesting observation, when looking at the distribution of HTNV strains from a regional basis, we found that some strains isolated from China are circulating in clusters A and B, which mainly consisted of strains isolated from South Korea, and Russia, respectively
Summary
Hantaviruses are rodent-borne pathogens that compose the genus Orthohantavirus, family Hantaviridae, in the order Bunyavirales. The synonymous codons are unevenly used, and for the same amino acid, some codons might be prioritized over others This uneven use of codons is termed codon usage bias (Martín et al, 1989; Plotkin and Kudla, 2011; Chaney and Clark, 2015). Several factors were found to influence the biased codon choices: genetic drift, mutation pressure, natural selection, amino acid composition, secondary protein motifs, protein’ hydrophobicity and hydrophilicity, transcriptional factors, and external environment (Bulmer, 1991; Butt et al, 2016; VelazquezSalinas et al, 2016b; Rahman et al, 2018; Labella et al, 2019; Yao et al, 2020). The main factors that account for codon usage variation among different organisms are natural selection and mutation pressure coupled with genetic drift (Bulmer, 1991; Musto, 2016; Labella et al, 2019)
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