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. 2008 Nov;82(22):11247-62.
doi: 10.1128/JVI.00897-08. Epub 2008 Sep 3.

Identification of monomorphic and divergent haplotypes in the 2006-2007 norovirus GII/4 epidemic population by genomewide tracing of evolutionary history

Kazushi Motomura  1 , Tomoichiro Oka, Masaru Yokoyama, Hiromi Nakamura, Hiromi Mori, Hirotaka Ode, Grant S Hansman, Kazuhiko Katayama, Tadahito Kanda, Tomoyuki Tanaka, Naokazu Takeda, Hironori Sato; Norovirus Surveillance Group of Japan
Affiliations

Identification of monomorphic and divergent haplotypes in the 2006-2007 norovirus GII/4 epidemic population by genomewide tracing of evolutionary history

Kazushi Motomura et al. J Virol. 2008 Nov.

Abstract

Our norovirus (NoV) surveillance group reported a >4-fold increase in NoV infection in Japan during the winter of 2006-2007 compared to the previous winter. Because the increase was not linked to changes in the surveillance system, we suspected the emergence of new NoV GII/4 epidemic variants. To obtain information on viral changes, we conducted full-length genomic analysis. Stool specimens from 55 acute gastroenteritis patients of various ages were collected at 11 sites in Japan between May 2006 and January 2007. Direct sequencing of long PCR products revealed 37 GII/4 genome sequences. Phylogenetic study of viral genome and partial sequences showed that the two new GII/4 variants in Europe, termed 2006a and 2006b, initially coexisted as minorities in early 2006 in Japan and that 2006b alone had dominated over the resident GII/4 variants during 2006. A combination of phylogenetic and entropy analyses revealed for the first time the unique amino acid substitutions in all eight proteins of the new epidemic strains. These data and computer-assisted structural study of the NoV capsid protein are compatible with a model of antigenic drift with tuning of the structure and functions of multiple proteins for the global outgrowth of new GII/4 variants. The availability of comprehensive information on genome sequences and unique protein changes of the recent global epidemic variants will allow studies of diagnostic assays, molecular epidemiology, molecular biology, and adaptive changes of NoV in nature.

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Figures

FIG. 1.
FIG. 1.
(A) Geographic locations of 11 sample collection sites in Japan. (B) Schematic illustration of the locations of the primers used in the present study.
FIG. 2.
FIG. 2.
Neighbor-joining trees of the nucleotide sequences of the complete ORF2 region (∼1.6 kb) (A) and the 5′-capsid N/S region (228 bases) (B and C) of NoV GII/4. Bootstrap values with 100/100 are indicated at the nodes of the tree. Sequence names are shown in the distinct color boxes on the basis of sampling sites and periods. Yellow boxes, 2006-2007 sequences obtained in the present study; green boxes, 2006/2007 sequences obtained in Europe, China, and Japan in other studies; orange boxes, <2006 sequences in Japan; pink boxes, 2005-2006 sequences in Japan: blue boxes, sequences from the global GII/4 epidemics pre-1996, 1995-1996, 2002-2003, and 2004-2005. Red letters with asterisks indicate sequences of the GII/4 2006a and 2006b epidemic strains in winter 2006-2007 in Europe (46).
FIG. 2.
FIG. 2.
Neighbor-joining trees of the nucleotide sequences of the complete ORF2 region (∼1.6 kb) (A) and the 5′-capsid N/S region (228 bases) (B and C) of NoV GII/4. Bootstrap values with 100/100 are indicated at the nodes of the tree. Sequence names are shown in the distinct color boxes on the basis of sampling sites and periods. Yellow boxes, 2006-2007 sequences obtained in the present study; green boxes, 2006/2007 sequences obtained in Europe, China, and Japan in other studies; orange boxes, <2006 sequences in Japan; pink boxes, 2005-2006 sequences in Japan: blue boxes, sequences from the global GII/4 epidemics pre-1996, 1995-1996, 2002-2003, and 2004-2005. Red letters with asterisks indicate sequences of the GII/4 2006a and 2006b epidemic strains in winter 2006-2007 in Europe (46).
FIG. 2.
FIG. 2.
Neighbor-joining trees of the nucleotide sequences of the complete ORF2 region (∼1.6 kb) (A) and the 5′-capsid N/S region (228 bases) (B and C) of NoV GII/4. Bootstrap values with 100/100 are indicated at the nodes of the tree. Sequence names are shown in the distinct color boxes on the basis of sampling sites and periods. Yellow boxes, 2006-2007 sequences obtained in the present study; green boxes, 2006/2007 sequences obtained in Europe, China, and Japan in other studies; orange boxes, <2006 sequences in Japan; pink boxes, 2005-2006 sequences in Japan: blue boxes, sequences from the global GII/4 epidemics pre-1996, 1995-1996, 2002-2003, and 2004-2005. Red letters with asterisks indicate sequences of the GII/4 2006a and 2006b epidemic strains in winter 2006-2007 in Europe (46).
FIG. 3.
FIG. 3.
Neighbor-joining trees of the nucleotide sequences of the complete ORF1 (about 5.1 kb) (A), ORF3 (about 0.8 kb) (B), and near-full-length genome (∼7.5 kb) (C) regions of NoV GII/4. Bootstrap values with 100/100 are indicated at the nodes of the tree. Colored boxes indicate the sequences described in Fig. 2.
FIG. 3.
FIG. 3.
Neighbor-joining trees of the nucleotide sequences of the complete ORF1 (about 5.1 kb) (A), ORF3 (about 0.8 kb) (B), and near-full-length genome (∼7.5 kb) (C) regions of NoV GII/4. Bootstrap values with 100/100 are indicated at the nodes of the tree. Colored boxes indicate the sequences described in Fig. 2.
FIG. 3.
FIG. 3.
Neighbor-joining trees of the nucleotide sequences of the complete ORF1 (about 5.1 kb) (A), ORF3 (about 0.8 kb) (B), and near-full-length genome (∼7.5 kb) (C) regions of NoV GII/4. Bootstrap values with 100/100 are indicated at the nodes of the tree. Colored boxes indicate the sequences described in Fig. 2.
FIG. 4.
FIG. 4.
Unique amino acid substitutions of the 2006-2007 GII/4 epidemic strains. The deduced amino acids of NoV GII/4 ORF1s, ORF2s, and ORF3s of the 2006b and 2006a strains were aligned with those of the past chronological epidemic strains. Amino acids are each indicated by one letter code. The positions in the ORFs of the Lordsdale strain are used for the amino acid numbering. Dots indicate amino acids identical to the Lordsdale strain. Amino acid substitutions specific to the 2006b (A) and 2006a (B) strains are shown in boldface italic letters.
FIG. 4.
FIG. 4.
Unique amino acid substitutions of the 2006-2007 GII/4 epidemic strains. The deduced amino acids of NoV GII/4 ORF1s, ORF2s, and ORF3s of the 2006b and 2006a strains were aligned with those of the past chronological epidemic strains. Amino acids are each indicated by one letter code. The positions in the ORFs of the Lordsdale strain are used for the amino acid numbering. Dots indicate amino acids identical to the Lordsdale strain. Amino acid substitutions specific to the 2006b (A) and 2006a (B) strains are shown in boldface italic letters.
FIG. 5.
FIG. 5.
Amino acid variation among the GII/4 epidemic variant proteins. Shannon entropy scores representing variations at individual amino acid positions (18) were calculated using NoV GII/4 ORF1, ORF2, and ORF3 sequences described in Fig. 3A, 2A, and 3B, respectively. The distribution of entropy scores in ORF1, ORF2, and ORF3 is shown along with the amino acid positions. An entropy score of 0 indicates absolute conservation, whereas that of 4.4 indicates complete randomness. Blue bars indicate regions rich in 2006b-specific changes.
FIG. 6.
FIG. 6.
Structural model of the VP1 P domain dimer of the NoV GII/4 2006b strain. The model was constructed by homology modeling using the X-ray crystal structure of the P domain dimer of the 1995-1996 epidemic GII/4 strain (4). (A) Shannon entropy scores expressed on the P domain model. (B) Side and top views of the P domain model. Reported functional sites for virus entry into the cells are highlighted. Yellow dot circles, the fucose ring binding sites formed by P-domain dimer (4); cyan chain, an RGD motif (48) on the β2 sheet of the P domain; orange chain indicates an additional RGD-like motif, KGD (46), on the tip of the β4-β5 loop of the P domain. Red sticks indicate side chains of amino acids unique to the 2006b strains.
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