title: Static and Evolving Norovirus Genotypes: Implications for Epidemiology and Immunity.
abstract: Noroviruses are major pathogens associated with acute gastroenteritis worldwide. Their RNA genomes are diverse, with two major genogroups (GI and GII) comprised of at least 28 genotypes associated with human disease. To elucidate mechanisms underlying norovirus diversity and evolution, we used a large-scale genomics approach to analyze human norovirus sequences. Comparison of over 2000 nearly full-length ORF2 sequences representing most of the known GI and GII genotypes infecting humans showed a limited number (≤5) of distinct intra-genotypic variants within each genotype, with the exception of GII.4. The non-GII.4 genotypes were comprised of one or more intra-genotypic variants, with each variant containing strains that differed by only a few residues over several decades (remaining "static") and that have co-circulated with no clear epidemiologic pattern. In contrast, the GII.4 genotype presented the largest number of variants (>10) that have evolved over time with a clear pattern of periodic variant replacement. To expand our understanding of these two patterns of diversification ("static" versus "evolving"), we analyzed using NGS the nearly full-length norovirus genome in healthy individuals infected with GII.4, GII.6 or GII.17 viruses in different outbreak settings. The GII.4 viruses accumulated mutations rapidly within and between hosts, while the GII.6 and GII.17 viruses remained relatively stable, consistent with their diversification patterns. Further analysis of genetic relationships and natural history patterns identified groupings of certain genotypes into larger related clusters designated here as "immunotypes". We propose that "immunotypes" and their evolutionary patterns influence the prevalence of a particular norovirus genotype in the human population.
authors.affiliation: Caliciviruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Gabriel I
authors.identifier: 0000-0002-1102-4740
authors.initials: GI
authors.lastname: Parra
authors.affiliation: Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: R Burke
authors.identifier: 0000-0001-9666-6285
authors.initials: RB
authors.lastname: Squires
authors.affiliation: Caliciviruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Consolee K
authors.initials: CK
authors.lastname: Karangwa
authors.affiliation: Caliciviruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Jordan A
authors.identifier: 0000-0003-2172-1387
authors.initials: JA
authors.lastname: Johnson
authors.affiliation: Division of Viral Products, Food and Drug Administration, Silver Spring, MD, United States of America.
authors.forename: Cara J
authors.identifier: 0000-0001-9349-3155
authors.initials: CJ
authors.lastname: Lepore
authors.affiliation: Caliciviruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Stanislav V
authors.initials: SV
authors.lastname: Sosnovtsev
authors.affiliation: Caliciviruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Kim Y
authors.identifier: 0000-0002-8189-7352
authors.initials: KY
authors.lastname: Green
mesh_terms: D017250:Caliciviridae Infections / Q000453:epidemiology* / Q000235:genetics* / Q000276:immunology*; D019143:Evolution, Molecular; D023281:Genomics; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017720:Molecular Epidemiology; D029322:Norovirus / Q000235:genetics*