Evolutionary diversification of protein-coding genes of hantaviruses

Phylogenetic analyses of the S, M, and L genes of the hantaviruses (Bunyavi ridae: Hantavirus) revealed three well-differentiated clades corresponding to viruses parasitic on three subfamilies (Murinae, Arvicolinae, and Sigmod ontinae) of the rodent family Muridae. In rooted trees of M and L genes, th e viruses with hosts belonging to Murinae formed an outgroup to those with hosts in Arvicolinae and Sigmodontinae. This phylogeny corresponded with a phylogeny of the murid subfamilies based on mitochondrial cytochrome b sequ ences, supporting the hypothesis that hantaviruses have coevolved with thei r mammalian hosts at least since the common ancestor of these three subfami lies, which probably occurred about 50 MYA. The nucleocapsid protein (encod ed by the S gene) differentiated among the viruses parasitic on the three s ubfamilies in such a way that a high frequency of amino acid residue charge changes occurred in a hypervariable (HV) portion of the molecule, and nons ynonymous nucleotide differences causing amino acid charge changes in the H V region occurred significantly more frequently than expected under random substitution. Along with evidence that at least in some hantaviruses the HV region is a target for host antibodies and the known importance of charged residues in determining antibody epitopes, these results suggest that chan ges in the HV region may represent adaptation to host-specific characterist ics of the immune response.