Giuseppe
Emeritus
[Source: PLoS Pathogens, full page: (LINK). Abstract, edited.]
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The Roles of Competition and Mutation in Shaping Antigenic and Genetic Diversity in Influenza
Daniel Zinder, Trevor Bedford, Sunetra Gupta, Mercedes Pascual
Affiliations: [List on source page.]
Abstract
Influenza A (H3N2) offers a well-studied, yet not fully understood, disease in terms of the interactions between pathogen population dynamics, epidemiology and genetics. A major open question is why the virus population is globally dominated by a single and very recently diverged (2?8 years) lineage. Classically, this has been modeled by limiting the generation of new successful antigenic variants, such that only a small subset of progeny acquire the necessary mutations to evade host immunity. An alternative approach was recently suggested by Recker et al. in which a limited number of antigenic variants are continuously generated, but most of these are suppressed by pre-existing host population immunity. Here we develop a framework spanning the regimes described above to explore the impact of rates of mutation and levels of competition on phylodynamic patterns. We find that the evolutionary dynamics of the subtype H3N2 influenza is most easily generated within this framework when it is mutation limited as well as being under strong immune selection at a number of epitope regions of limited diversity.
Author Summary
Influenza A (H3N2) has circulated in the human population since 1968 causing considerable annual morbidity and mortality worldwide. Despite the rapid evolution of the hemagglutinin (HA) protein and strong diversifying selection, the global virus population is characterized by a low standing diversity, evident in the serial replacement of antigenic types and in the ?cactus-like? structure of its genealogical tree. Elucidating the mechanisms behind these puzzling patterns is key to understanding the evolution of seasonal (H3N2) influenza. One recent epidemiological model proposes a restricted set of antigenic types whose waves of dominance result from frequency-dependent immune selection. Here we develop a model of limited antigenic diversity that explicitly incorporates mutational processes, and use it to address, first, whether this type of antigenic space is capable of generating the characteristic phylogeny of HA sequences, and second, whether the dynamics of (H3N2) influenza are primarily limited by the arrival of mutations or by the opening of antigenic niches. We conclude that a limited antigenic space can explain the observed phylogenetic patterns and that a limited mutation rate is a key property underlying the dynamics of (H3N2) influenza. Our study provides a general framework for assessing the relative roles of selection and mutation in a variety of infectious disease systems.
Citation: Zinder D, Bedford T, Gupta S, Pascual M (2013) The Roles of Competition and Mutation in Shaping Antigenic and Genetic Diversity in Influenza. PLoS Pathog 9(1): e1003104. doi:10.1371/journal.ppat.1003104
Editor: Neil Ferguson, Imperial College London, United Kingdom
Received: June 4, 2012; Accepted: November 10, 2012; Published: January 3, 2013
Copyright: ? 2013 Zinder et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: MP was supported by a Centennial Fellowship of the James S. McDonnell Foundation (http://www.jsmf.org/), SG, by the European Research Council (ERC Advanced Grant - Diversity, http://erc.europa.eu/advanced-grants), and TB, by the Howard Hughes Medical Institute, a Long-Term Fellowship from the European Molecular Biology Organization and a Newton International Fellowship from the Royal Society. MP is an investigator of the Howard Hughes Medical Institute and SG is a Royal Society Wolfson Research Fellow (http://royalsociety.org/grants/schemes/wolfson-research-merit/). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: pascual@umich.edu
-Daniel Zinder, Trevor Bedford, Sunetra Gupta, Mercedes Pascual
Affiliations: [List on source page.]
Abstract
Influenza A (H3N2) offers a well-studied, yet not fully understood, disease in terms of the interactions between pathogen population dynamics, epidemiology and genetics. A major open question is why the virus population is globally dominated by a single and very recently diverged (2?8 years) lineage. Classically, this has been modeled by limiting the generation of new successful antigenic variants, such that only a small subset of progeny acquire the necessary mutations to evade host immunity. An alternative approach was recently suggested by Recker et al. in which a limited number of antigenic variants are continuously generated, but most of these are suppressed by pre-existing host population immunity. Here we develop a framework spanning the regimes described above to explore the impact of rates of mutation and levels of competition on phylodynamic patterns. We find that the evolutionary dynamics of the subtype H3N2 influenza is most easily generated within this framework when it is mutation limited as well as being under strong immune selection at a number of epitope regions of limited diversity.
Author Summary
Influenza A (H3N2) has circulated in the human population since 1968 causing considerable annual morbidity and mortality worldwide. Despite the rapid evolution of the hemagglutinin (HA) protein and strong diversifying selection, the global virus population is characterized by a low standing diversity, evident in the serial replacement of antigenic types and in the ?cactus-like? structure of its genealogical tree. Elucidating the mechanisms behind these puzzling patterns is key to understanding the evolution of seasonal (H3N2) influenza. One recent epidemiological model proposes a restricted set of antigenic types whose waves of dominance result from frequency-dependent immune selection. Here we develop a model of limited antigenic diversity that explicitly incorporates mutational processes, and use it to address, first, whether this type of antigenic space is capable of generating the characteristic phylogeny of HA sequences, and second, whether the dynamics of (H3N2) influenza are primarily limited by the arrival of mutations or by the opening of antigenic niches. We conclude that a limited antigenic space can explain the observed phylogenetic patterns and that a limited mutation rate is a key property underlying the dynamics of (H3N2) influenza. Our study provides a general framework for assessing the relative roles of selection and mutation in a variety of infectious disease systems.
Citation: Zinder D, Bedford T, Gupta S, Pascual M (2013) The Roles of Competition and Mutation in Shaping Antigenic and Genetic Diversity in Influenza. PLoS Pathog 9(1): e1003104. doi:10.1371/journal.ppat.1003104
Editor: Neil Ferguson, Imperial College London, United Kingdom
Received: June 4, 2012; Accepted: November 10, 2012; Published: January 3, 2013
Copyright: ? 2013 Zinder et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: MP was supported by a Centennial Fellowship of the James S. McDonnell Foundation (http://www.jsmf.org/), SG, by the European Research Council (ERC Advanced Grant - Diversity, http://erc.europa.eu/advanced-grants), and TB, by the Howard Hughes Medical Institute, a Long-Term Fellowship from the European Molecular Biology Organization and a Newton International Fellowship from the Royal Society. MP is an investigator of the Howard Hughes Medical Institute and SG is a Royal Society Wolfson Research Fellow (http://royalsociety.org/grants/schemes/wolfson-research-merit/). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: pascual@umich.edu
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