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Edward J Steele Robyn Alice Lindley

Abstract

The origins of variability in positive single-stranded RNA Flaviviruses is poorly understood. Is the origin of the high rate of spontaneous mutations arising early in Flavivirus infections due solely to error-prone viral replication? Alternatively, are these mutations due to viral replicase incorporation of high frequency RNA deamination editing events? The data analyzed here strongly supports the second explanation. The viral genomes analysed include: a) acute phase Zika virus (ZIKV) genomes associated with microcephaly; b) hepatitis C virus (HCV) genomes from both acute and chronic infected hepatitis patients; and c) hepatitis B virus (HBV) genomes of patients infected from the early/acute phase of a large nosocomial outbreak. RNA mutations at motifs for APOBEC and ADAR deaminases were analyzed within the codon context structure, used previously for targeted somatic mutation (TSM) analyses of cancer exomes. The results show that transition mutations targeting MC3 nucleotide sites (ie. the third nucleotide position within the structure of the Mutated Codon read 5’ to 3’), and within known RNA editing motifs for APOBEC1, APOBEC3A and ADAR1/2 account for the majority of the mutations for ZIKV, HCV, as well as for HBV. The results also imply that drug therapy strategies might profitably focus on the RNA-based secondary structure of potential "druggable pockets" within apparently conserved regions of amino acid sequence within variant viral strains.  Such sites could encode subtle changes in RNA secondary structures as potential vulnerable target regions in pathogenic variants. For ZIKV, such sites could include the hypermutable MC3-deaminase targeted sites.


 

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