Molecular epidemiology and phylogenetics of human enteroviruses: Is there a forest behind the trees?

Enteroviruses are among the best studied small non-enveloped enteric RNA viruses. Most enteroviruses are easy to isolate in cell culture, and many non-polio enterovirus strains were archived worldwide as a byproduct of the WHO poliovirus surveillance system. Common outbreaks and epidemics, most prominently the epidemic of hand-foot-and-mouth disease with severe neurological complications in East and South-East Asia, justify practical interest of non-polio enteroviruses. As a result, there are over 50 000 enterovirus nucleotide sequences available in GenBank. Technical possibilities have been also improving, as Bayesian phylogenetic methods with an integrated molecular clock were introduced a decade ago and provided unprecedented opportunities for phylogenetic analysis. As a result, hundreds of papers were published on the molecular epidemiology of enteroviruses. This review covers the modern methodology, structure, and biases of the sequence dataset available in GenBank. The relevance of the subtype classification, findings of co-circulation of multiple genetic variants, previously unappreciated complexity of viral populations, and global evolutionary patterns are addressed. The most relevant conclusions and prospects for further studies on outbreak emergence mechanisms are discussed.