Viral outbreaks involve destabilized evolutionary networks: evidence from Ebola, Influenza and Zika.

Recent history has provided us with one pandemic (Influenza A/H1N1) and two severe viral outbreaks (Ebola and Zika). In all three cases, post-hoc analyses have given us deep insights into what triggered these outbreaks, their timing, evolutionary dynamics, and phylogeography, but the genomic characteristics of outbreak viruses are still unclear. To address this outstanding question, we searched for a common denominator between these recent outbreaks, positing that the genome of outbreak viruses is in an unstable evolutionary state, while that of non-outbreak viruses is stabilized by a network of correlated substitutions. Here, we show that during regular epidemics, viral genomes are indeed stabilized by a dense network of weakly correlated sites, and that these networks disappear during pandemics and outbreaks when rates of evolution increase transiently. Post-pandemic, these evolutionary networks are progressively re-established. We finally show that destabilization is not caused by substitutions targeting epitopes, but more likely by changes in the environment sensu lato. Our results prompt for a new interpretation of pandemics as being associated with evolutionary destabilized viruses.