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Phylodynamic reconstruction reveals norovirus GII.4 epidemic expansions and their molecular determinants.

Siebenga JJ, Lemey P, Kosakovsky Pond SL, Rambaut A, Vennema H, Koopmans M - PLoS Pathog. (2010)

Bottom Line: The GII.4 strains included in our analyses evolved at a rate of 4.3-9.0x10(-3) mutations per site per year, and share a most recent common ancestor in the early 1980s.While a number of the computationally determined adaptively evolving sites were on the surface of the capsid and possible subject to immune selection, we also detected sites that were subject to constrained or compensatory evolution due to secondary RNA structures, relevant in virus-replication.We highlight codons that may prove useful in identifying emerging novel variants, and, using these, indicate that the novel 2008 variant is more likely to cause a future epidemic than the 2007 variant.

View Article: PubMed Central - PubMed

Affiliation: National Institute for Public Health and the Environment, RIVM, Bilthoven, The Netherlands. joukjes@yahoo.co.uk

ABSTRACT
Noroviruses are the most common cause of viral gastroenteritis. An increase in the number of globally reported norovirus outbreaks was seen the past decade, especially for outbreaks caused by successive genogroup II genotype 4 (GII.4) variants. Whether this observed increase was due to an upswing in the number of infections, or to a surveillance artifact caused by heightened awareness and concomitant improved reporting, remained unclear. Therefore, we set out to study the population structure and changes thereof of GII.4 strains detected through systematic outbreak surveillance since the early 1990s. We collected 1383 partial polymerase and 194 full capsid GII.4 sequences. A Bayesian MCMC coalescent analysis revealed an increase in the number of GII.4 infections during the last decade. The GII.4 strains included in our analyses evolved at a rate of 4.3-9.0x10(-3) mutations per site per year, and share a most recent common ancestor in the early 1980s. Determinants of adaptation in the capsid protein were studied using different maximum likelihood approaches to identify sites subject to diversifying or directional selection and sites that co-evolved. While a number of the computationally determined adaptively evolving sites were on the surface of the capsid and possible subject to immune selection, we also detected sites that were subject to constrained or compensatory evolution due to secondary RNA structures, relevant in virus-replication. We highlight codons that may prove useful in identifying emerging novel variants, and, using these, indicate that the novel 2008 variant is more likely to cause a future epidemic than the 2007 variant. While norovirus infections are generally mild and self-limiting, more severe outcomes of infection frequently occur in elderly and immunocompromized people, and no treatment is available. The observed pattern of continually emerging novel variants of GII.4, causing elevated numbers of infections, is therefore a cause for concern.

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Phylodynamics of the GII.4 noroviruses.The left panel (A, B, C) describes analysis of the polymerase dataset, the right panel (D, E, F) the analysis of the capsid dataset. A) Bayesian Skyline Plot (BSP) of GII.4 NoV partial polymerase sequences, representing the relative genetic diversity, a measure for the number of effective infections, of circulating GII.4 NoVs through time. The black line represents the median posterior value, the grey lines the 95% Highest Probability Density (HPD) intervals. The Y-axis depicts the value of Neτ on a logarithmic scale. B and E) Surveillance data of NoV GII.4 strains, detected in outbreaks, included for comparison. Only European surveillance data was obtained from the FBVE database and from Dutch surveillance [12], [13]. The different GII.4 variants detected in the outbreaks are represented by different colors, showing the displacement of subsequent variants through time. The same colors were used in panels D and F, the color legend is shown under panel F. C) Maximum Clade Credibility (MCC) Tree of NoV GII.4 partial polymerase dataset. The MCC tree represents an estimate of the posterior distribution of tree topologies and branch lengths. Different variants are represented in different colors, the tree is scaled in units of time with tips constrained to strain detection dates. D) BSP of the GII.4 NoV capsid dataset. F) MCC tree of the GII.4 NoV capsid dataset.
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ppat-1000884-g001: Phylodynamics of the GII.4 noroviruses.The left panel (A, B, C) describes analysis of the polymerase dataset, the right panel (D, E, F) the analysis of the capsid dataset. A) Bayesian Skyline Plot (BSP) of GII.4 NoV partial polymerase sequences, representing the relative genetic diversity, a measure for the number of effective infections, of circulating GII.4 NoVs through time. The black line represents the median posterior value, the grey lines the 95% Highest Probability Density (HPD) intervals. The Y-axis depicts the value of Neτ on a logarithmic scale. B and E) Surveillance data of NoV GII.4 strains, detected in outbreaks, included for comparison. Only European surveillance data was obtained from the FBVE database and from Dutch surveillance [12], [13]. The different GII.4 variants detected in the outbreaks are represented by different colors, showing the displacement of subsequent variants through time. The same colors were used in panels D and F, the color legend is shown under panel F. C) Maximum Clade Credibility (MCC) Tree of NoV GII.4 partial polymerase dataset. The MCC tree represents an estimate of the posterior distribution of tree topologies and branch lengths. Different variants are represented in different colors, the tree is scaled in units of time with tips constrained to strain detection dates. D) BSP of the GII.4 NoV capsid dataset. F) MCC tree of the GII.4 NoV capsid dataset.

Mentions: The demographic inference using the BSP model is summarized in Figures 1A and 1B, which essentially plot Neτ as a function of time. Ne τ can be considered a measure of relative genetic diversity that, in turn, reflects the number of effective infections established by the virus (see also the Materials and Methods section). Uncertainty in the estimated parameters was evaluated using 95% Highest Probability Density (HPD) intervals. The Maximum Clade Credibility (MCC) trees from the same Bayesian analyses (Figures 1C, D) summarize the NoV evolutionary histories, and the stepwise emergence of the subsequent variants on a time scale. For comparison, surveillance data of reported NoV outbreaks with confirmed GII.4 variant type were imposed on the BSPs.


Phylodynamic reconstruction reveals norovirus GII.4 epidemic expansions and their molecular determinants.

Siebenga JJ, Lemey P, Kosakovsky Pond SL, Rambaut A, Vennema H, Koopmans M - PLoS Pathog. (2010)

Phylodynamics of the GII.4 noroviruses.The left panel (A, B, C) describes analysis of the polymerase dataset, the right panel (D, E, F) the analysis of the capsid dataset. A) Bayesian Skyline Plot (BSP) of GII.4 NoV partial polymerase sequences, representing the relative genetic diversity, a measure for the number of effective infections, of circulating GII.4 NoVs through time. The black line represents the median posterior value, the grey lines the 95% Highest Probability Density (HPD) intervals. The Y-axis depicts the value of Neτ on a logarithmic scale. B and E) Surveillance data of NoV GII.4 strains, detected in outbreaks, included for comparison. Only European surveillance data was obtained from the FBVE database and from Dutch surveillance [12], [13]. The different GII.4 variants detected in the outbreaks are represented by different colors, showing the displacement of subsequent variants through time. The same colors were used in panels D and F, the color legend is shown under panel F. C) Maximum Clade Credibility (MCC) Tree of NoV GII.4 partial polymerase dataset. The MCC tree represents an estimate of the posterior distribution of tree topologies and branch lengths. Different variants are represented in different colors, the tree is scaled in units of time with tips constrained to strain detection dates. D) BSP of the GII.4 NoV capsid dataset. F) MCC tree of the GII.4 NoV capsid dataset.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2865530&req=5

ppat-1000884-g001: Phylodynamics of the GII.4 noroviruses.The left panel (A, B, C) describes analysis of the polymerase dataset, the right panel (D, E, F) the analysis of the capsid dataset. A) Bayesian Skyline Plot (BSP) of GII.4 NoV partial polymerase sequences, representing the relative genetic diversity, a measure for the number of effective infections, of circulating GII.4 NoVs through time. The black line represents the median posterior value, the grey lines the 95% Highest Probability Density (HPD) intervals. The Y-axis depicts the value of Neτ on a logarithmic scale. B and E) Surveillance data of NoV GII.4 strains, detected in outbreaks, included for comparison. Only European surveillance data was obtained from the FBVE database and from Dutch surveillance [12], [13]. The different GII.4 variants detected in the outbreaks are represented by different colors, showing the displacement of subsequent variants through time. The same colors were used in panels D and F, the color legend is shown under panel F. C) Maximum Clade Credibility (MCC) Tree of NoV GII.4 partial polymerase dataset. The MCC tree represents an estimate of the posterior distribution of tree topologies and branch lengths. Different variants are represented in different colors, the tree is scaled in units of time with tips constrained to strain detection dates. D) BSP of the GII.4 NoV capsid dataset. F) MCC tree of the GII.4 NoV capsid dataset.
Mentions: The demographic inference using the BSP model is summarized in Figures 1A and 1B, which essentially plot Neτ as a function of time. Ne τ can be considered a measure of relative genetic diversity that, in turn, reflects the number of effective infections established by the virus (see also the Materials and Methods section). Uncertainty in the estimated parameters was evaluated using 95% Highest Probability Density (HPD) intervals. The Maximum Clade Credibility (MCC) trees from the same Bayesian analyses (Figures 1C, D) summarize the NoV evolutionary histories, and the stepwise emergence of the subsequent variants on a time scale. For comparison, surveillance data of reported NoV outbreaks with confirmed GII.4 variant type were imposed on the BSPs.

Bottom Line: The GII.4 strains included in our analyses evolved at a rate of 4.3-9.0x10(-3) mutations per site per year, and share a most recent common ancestor in the early 1980s.While a number of the computationally determined adaptively evolving sites were on the surface of the capsid and possible subject to immune selection, we also detected sites that were subject to constrained or compensatory evolution due to secondary RNA structures, relevant in virus-replication.We highlight codons that may prove useful in identifying emerging novel variants, and, using these, indicate that the novel 2008 variant is more likely to cause a future epidemic than the 2007 variant.

View Article: PubMed Central - PubMed

Affiliation: National Institute for Public Health and the Environment, RIVM, Bilthoven, The Netherlands. joukjes@yahoo.co.uk

ABSTRACT
Noroviruses are the most common cause of viral gastroenteritis. An increase in the number of globally reported norovirus outbreaks was seen the past decade, especially for outbreaks caused by successive genogroup II genotype 4 (GII.4) variants. Whether this observed increase was due to an upswing in the number of infections, or to a surveillance artifact caused by heightened awareness and concomitant improved reporting, remained unclear. Therefore, we set out to study the population structure and changes thereof of GII.4 strains detected through systematic outbreak surveillance since the early 1990s. We collected 1383 partial polymerase and 194 full capsid GII.4 sequences. A Bayesian MCMC coalescent analysis revealed an increase in the number of GII.4 infections during the last decade. The GII.4 strains included in our analyses evolved at a rate of 4.3-9.0x10(-3) mutations per site per year, and share a most recent common ancestor in the early 1980s. Determinants of adaptation in the capsid protein were studied using different maximum likelihood approaches to identify sites subject to diversifying or directional selection and sites that co-evolved. While a number of the computationally determined adaptively evolving sites were on the surface of the capsid and possible subject to immune selection, we also detected sites that were subject to constrained or compensatory evolution due to secondary RNA structures, relevant in virus-replication. We highlight codons that may prove useful in identifying emerging novel variants, and, using these, indicate that the novel 2008 variant is more likely to cause a future epidemic than the 2007 variant. While norovirus infections are generally mild and self-limiting, more severe outcomes of infection frequently occur in elderly and immunocompromized people, and no treatment is available. The observed pattern of continually emerging novel variants of GII.4, causing elevated numbers of infections, is therefore a cause for concern.

Show MeSH
Related in: MedlinePlus