Abstract
The hypothesis of wide spread reticulate evolution in Tick-Borne Encephalitis virus (TBEV) has recently gained momentum with several publications describing past recombination events involving various TBEV clades. Despite a large body of work, no consensus has yet emerged on TBEV evolutionary dynamics. Understanding the occurrence and frequency of recombination in TBEV bears significant impact on epidemiology, evolution, and vaccination with live vaccines. In this study, we investigated the possibility of detecting recombination events in TBEV by simulating recombinations at several locations on the virus’ phylogenetic tree and for different lengths of recombining fragments. We derived estimations of rates of true and false positive for the detection of past recombination events for seven recombination detection algorithms. Our analytical framework can be applied to any investigation dealing with the difficult task of distinguishing genuine recombination signal from background noise. Our results suggest that the problem of false positives associated with low detection P-values in TBEV, is more insidious than generally acknowledged. We reappraised the recombination signals present in the empirical data, and showed that reliable signals could only be obtained in a few cases when highly genetically divergent strains were involved, whereas false positives were common among genetically similar strains. We thus conclude that recombination among wild-type TBEV strains may occur, which has potential implications for vaccination with live vaccines, but that these events are surprisingly rare.
Highlights
We have established that some events in the Far Eastern- (FE-)subtype are supported by reliable recombination signals
In order to rule out laboratory induced events, the strains associated with the recombinations need to be re-sequenced
In absence of the original viral extract, resequencing would not necessarily reveal an artificial recombinant obtained from template switching as the result of in vivo or in vitro experiments carried in a laboratory handling different subtypes or in presence of strains from different subtypes in the original extract [9]
Summary
“The hardest thing of all is to find a black cat in a dark room, especially if there is no cat.” (Confucius). Mosaic evolution would distinguish mosquito-borne from tick-borne Flaviviruses [20], wherein evolution is clonal, with diversity generated solely by the error-prone replication with RNA-dependent polymerases Such contrast in evolutionary dynamics was explained by possible differences in biological and ecological factors that influence viruses’ transmission [20]. Recombination violates this assumption and can potentially mislead phylogenetic reconstruction in term of topology, evolutionary rates and divergence times This has downstream consequences on studies that rely on the tree’s accuracy and can shake the conclusions about the virus phylodynamics both at the local [29, 30], and global [10, 31, 32] levels. It has further implications for our comprehension of the emergence of new strains, host and vector specificities and in fine virus control and vaccine development
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