Phylogenetic and evolutionary analysis of the Borna disease virus.

Abstract

The characteristic trait of the Borna disease virus is that it is a complicated single negative stranded RNA virus that is capable of infecting a wide array of mammalian species including human beings. It has been implicated in a diverse variety of human neuropsychiatric diseases. The infection capability, mechanism of infection and range of protein action of this virus remain to be identified. The purpose of the present study was to determine (1) whether the previous Bornaviridae family classification is indeed accurate as the action of BDV indicates that it is related to other viruses and (2) to estimate the number of synonymous (nucleotide substitution) and non-synonymous (amino acid change) evolutionary mutation rates of proteins (nucleoprotein, phosphoprotein, glycoprotein, matrix protein) exhibited by various Borna disease virus host species and the proteins (nucleoprotein, phosphoprotein, glycoprotein, matrix and X protein) of three Borna disease virus strains. The latter study would give an indication as to which proteins are subjected to positive selection. Phylogenetic methods were used to determine the accuracy of the Bornaviridae classification. Phylogenetic trees obtained through an alignment and analysis of the polymerase protein, which displays a uniquely conserved GDN motif, of various RNA negative single stranded viruses using neighbourhood and parsimony methods enabled comparison with other RNA virus families. A method adapted from Ina, (1995) for estimating the synonymous and non-synonymous evolutionary mutation rate was applied to various BDV proteins in order to provide more information on inter (host virus) and intra (virus) mutation rate. This information in turn was used to create an evolutionary model to clarify the positive and neutral evolutionary trend of the inter- and intra-virus proteins examined, which may help clarify and enhance the lack of current knowledge relating to species infection and the epidemiological nature of the virus. The results obtained by the polymerase alignment analysis indicates the presence of two newly discovered BDV motifs, v and vi, confirmed by three diverse alignment programmes. An analysis of the alignment of BDV proteins indicated that the BDV nucleoprotein nuclear localization signal aligns the BDV nucleoprotein between motifs IV and vi of the BDV polymerase. The results obtained by the phylogenetic analysis indicate that the Rabies virus and the Vesicular stomatitis virus are the most closely related animal viruses to BDV, whereas the Rice transitory yellowing (unclassified Rhabdovirus) and Sonchus yellow net plant virus are closet to BDV than other animal Rhabdoviridae raising intriguing questions on the evolutionary origins of the Borna disease virus. The phylogenetic analysis indicates that the Borna disease virus does not fall into a separate Bornaviridae family classification, and suggests that BDV may be more appropriately placed into a separate subfamily in the family Rhabdoviridae. The results of the evolutionary analysis indicate considerable diversity between BDV host virus (inter-species) and BDV virus (intra-species) protein sequences. In the host virus sequence comparison analysis all of the proteins examined displayed a high pattern of non random evolution, which is in contrast to the intra species comparison in which only three proteins; the BDV glycoprotein, nucleoprotein and X protein; displayed a non random pattern of evolution. The positive selection effect displayed by the inter-species (host) proteins may be attributed to antigenic variation displayed by the inter-species sequences and a super infection hypothesis, which indicates that positive selection on host variants could arise during the course of an infection as a result of specific immune responses. The positive and neutral selection trend of the proteins displayed by the intra-species (virus) sequences may be a result of a pattern of nucleotide substitution that is physio-chemically conservative. Conservation may be evident in volume, polarity, hydrophilicity, or molecular weight of amino acids of the proteins.