BackgroundThe emergence of the 2009 H1N1 Influenza pandemic followed a multiple reassortment event from viruses originally circulating in swines and humans, but the adaptive nature of this emergence is poorly understood.ResultsHere we base our analysis on 1180 complete genomes of H1N1 viruses sampled in North America between 2000 and 2010 in swine and human hosts. We show that while transmission to a human host might require an adaptive phase in the HA and NA antigens, the emergence of the 2009 pandemic was essentially nonadaptive. A more detailed analysis of the NA protein shows that the 2009 pandemic sequence is characterized by novel epitopes and by a particular substitution in loop 150, which is responsible for a nonadaptive structural change tightly associated with the emergence of the pandemic.ConclusionsBecause this substitution was not present in the 1918 H1N1 pandemic virus, we posit that the emergence of pandemics is due to epistatic interactions between sites distributed over different segments. Altogether, our results are consistent with population dynamics models that highlight the epistatic and nonadaptive rise of novel epitopes in viral populations, followed by their demise when the resulting virus is too virulent.