Genetic characterization of human coxsackievirus A6 variants associated with atypical hand, foot and mouth disease: a potential role of recombination in emergence and pathogenicity.
Bottom Line: Until recently, CVA6 infections were considered as being of minor clinical significance, and only rarely aetiologically linked with hand, foot and mouth disease (HFMD) associated with other species A enteroviruses (particularly EV71 and CVA16).From 2008 onwards, however, CVA6 infections have been associated with several outbreaks worldwide of atypical HFMD (aHFMD) accompanied by a varicelliform rash.These observations provided evidence that NS gene regions may potentially contribute to clinical phenotypes and outcomes of CVA6 infection.
Affiliation: Roslin Institute, University of Edinburgh, Easter Bush, Edinburgh EH25 9RG, UK.Show MeSH
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Mentions: As an alternative way to visualize sequence relationships, sequence alignments were scanned to identify regions of the genome where sequence divergence became greater than in VP1. This analysis method was developed from the results of the dot-plot in which divergence in VP1 and 3Dpol was compared (Fig. 5b). This demonstrated ~3.5 times greater divergence between RF-H and other recombination groups in 3Dpol than in VP1, indicative of recombination. This analysis was extended by comparing ratios of VP1/3Dpol divergence in successive fragments across the genome to identify where changes in ratios occurred and thus identify recombination breakpoints (Fig. 6). In the case RF-E, -F, -G and -H, temporal reconstruction of VP1 sequences predicted that RF-A was ancestral to them (Fig. 4) and that they likely originated through separate recombination events. Divergence scans comparing RF-A with RF-F and -H confirmed this hypothesis (Fig. 6a), with divergence ratios close to 1 throughout the 5′ UTR, structural gene region and 2A, but steep increases in divergence relative to that of VP1 around positions 3900 and 4400 (both within 2B or at junctions with 2A and 2C). These localize likely recombination events with other (uncharacterized) EV-A variants at these genome positions. Sequence relationships with RF-E were more complex, indicative of multiple recombination events. Sequences between RF-A and -E were shared in VP3, VP1 and 2C, whilst the 5′ UTR, VP4 and VP2 were divergent. Further recombination events were predicted to yield divergent 2A and 2B genes, and a breakpoint within 3A was also apparent, which resulted in a high ratio for the rest of the genome downstream of this point. The high ratios observed in VP4/2 and the 5′ UTR were reflected in their outlier positions on phylogenetic comparisons from RF-A sequences (Fig. 1c, d).
Affiliation: Roslin Institute, University of Edinburgh, Easter Bush, Edinburgh EH25 9RG, UK.