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Norovirus GII.4 is a major etiological agent of acute viral gastroenteritis worldwide. We examined GII.4 evolution using 277 near-full-length GII.4 genome sequences from human stool specimens collected at 20 sites in Japan between May 2006 and March 2010. We found outbreaks of 8 monophyletic GII.4 subtypes, among which a single subtype, termed 2006b, had continually predominated (222/277: 80.7%). Four of the 8 GII.4 subtypes were chimera viruses of recently prevalent GII.4 subtypes. Notably, single putative recombination breakpoints with the highest statistical significance were constantly located around the border of open reading frame 1 (ORF) 1 and ORF 2 (P&lt;0.0001), suggesting outgrowth of specific recombinant viruses in the outbreaks. The GII.4 subtypes had many unique amino acids at the time of their outbreaks, especially in the N-term, 3A-like, and capsid proteins. Unique amino acids in the capsid were preferentially positioned on the outer surface loops of the protruding P2 domain. These data and computer-assisted structural study of NoV capsid protein are compatible with a model of antigenic drift with tuning of the structure-functions of multiple proteins for the survival strategy of GII.4 2006b variant.

A Mechanism of Norovirus Pandemic Based on Comprehensive Genome Analysis