Phylodynamics of H1N1/2009 influenza reveals the transition from host adaptation to immune-driven selection
Identifieur interne : 000094 ( Pmc/Curation ); précédent : 000093; suivant : 000095Phylodynamics of H1N1/2009 influenza reveals the transition from host adaptation to immune-driven selection
Auteurs : Yvonne C. F. Su [Singapour] ; Justin Bahl [Singapour, États-Unis] ; Udayan Joseph [Singapour] ; Ka Man Butt [Singapour] ; Heidi A. Peck [Australie] ; Evelyn S. C. Koay [Singapour] ; Lynette L. E. Oon [Singapour] ; Ian G. Barr [Australie] ; Dhanasekaran Vijaykrishna [Singapour, Australie] ; Gavin J. D. Smith [Singapour, Australie, États-Unis]Source :
- Nature Communications [ 2041-1723 ] ; 2015.
Abstract
Influenza A H1N1/2009 virus that emerged from swine rapidly replaced the previous seasonal H1N1 virus. Although the early emergence and diversification of H1N1/2009 is well characterized, the ongoing evolutionary and global transmission dynamics of the virus remain poorly investigated. To address this we analyse >3,000 H1N1/2009 genomes, including 214 full genomes generated from our surveillance in Singapore, in conjunction with antigenic data. Here we show that natural selection acting on H1N1/2009 directly after introduction into humans was driven by adaptation to the new host. Since then, selection has been driven by immunological escape, with these changes corresponding to restricted antigenic diversity in the virus population. We also show that H1N1/2009 viruses have been subject to regular seasonal bottlenecks and a global reduction in antigenic and genetic diversity in 2014.
Url:
DOI: 10.1038/ncomms8952
PubMed: 26245473
PubMed Central: 4918339
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Peck</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>World Health Organisation Collaborating Centre for Reference and Research on Influenza</institution>, Melbourne, Victoria 3000,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Koay, Evelyn S C" sort="Koay, Evelyn S C" uniqKey="Koay E" first="Evelyn S. C." last="Koay">Evelyn S. C. Koay</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Molecular Diagnosis Centre, Department of Laboratory Medicine, National University Hospital</institution>, Singapore 119074,<country>Singapore</country></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Oon, Lynette L E" sort="Oon, Lynette L E" uniqKey="Oon L" first="Lynette L. E." last="Oon">Lynette L. E. 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D." last="Smith">Gavin J. D. Smith</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School</institution>, 8 College Road, Singapore 169857,<country>Singapore</country></nlm:aff><country xml:lang="fr">Singapour</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>World Health Organisation Collaborating Centre for Reference and Research on Influenza</institution>, Melbourne, Victoria 3000,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a7"><institution>Duke Global Health Institute, Duke University</institution>, Durham, North Carolina 27708,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Nature Communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Influenza A H1N1/2009 virus that emerged from swine rapidly replaced the previous seasonal H1N1 virus. Although the early emergence and diversification of H1N1/2009 is well characterized, the ongoing evolutionary and global transmission dynamics of the virus remain poorly investigated. To address this we analyse >3,000 H1N1/2009 genomes, including 214 full genomes generated from our surveillance in Singapore, in conjunction with antigenic data. Here we show that natural selection acting on H1N1/2009 directly after introduction into humans was driven by adaptation to the new host. Since then, selection has been driven by immunological escape, with these changes corresponding to restricted antigenic diversity in the virus population. We also show that H1N1/2009 viruses have been subject to regular seasonal bottlenecks and a global reduction in antigenic and genetic diversity in 2014.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Fraser, C" uniqKey="Fraser C">C. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Nat Commun</journal-id><journal-id journal-id-type="iso-abbrev">Nat Commun</journal-id><journal-title-group><journal-title>Nature Communications</journal-title></journal-title-group><issn pub-type="epub">2041-1723</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26245473</article-id><article-id pub-id-type="pmc">4918339</article-id><article-id pub-id-type="pii">ncomms8952</article-id><article-id pub-id-type="doi">10.1038/ncomms8952</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Phylodynamics of H1N1/2009 influenza reveals the transition from host adaptation to immune-driven selection</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Su</surname><given-names>Yvonne C. F.</given-names></name><xref ref-type="corresp" rid="c1">a</xref><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Bahl</surname><given-names>Justin</given-names></name><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a2">2</xref><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-7572-4300</contrib-id></contrib><contrib contrib-type="author"><name><surname>Joseph</surname><given-names>Udayan</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Butt</surname><given-names>Ka Man</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Peck</surname><given-names>Heidi A.</given-names></name><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>Koay</surname><given-names>Evelyn S. C.</given-names></name><xref ref-type="aff" rid="a4">4</xref></contrib><contrib contrib-type="author"><name><surname>Oon</surname><given-names>Lynette L. E.</given-names></name><xref ref-type="aff" rid="a5">5</xref></contrib><contrib contrib-type="author"><name><surname>Barr</surname><given-names>Ian G.</given-names></name><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>Vijaykrishna</surname><given-names>Dhanasekaran</given-names></name><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a3">3</xref><xref ref-type="aff" rid="a6">6</xref></contrib><contrib contrib-type="author"><name><surname>Smith</surname><given-names>Gavin J. D.</given-names></name><xref ref-type="corresp" rid="c2">b</xref><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a3">3</xref><xref ref-type="aff" rid="a7">7</xref><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-5031-468X</contrib-id></contrib><aff id="a1"><label>1</label><institution>Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School</institution>, 8 College Road, Singapore 169857,<country>Singapore</country></aff><aff id="a2"><label>2</label><institution>Division of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas</institution>, Houston, Texas 77030,<country>USA</country></aff><aff id="a3"><label>3</label><institution>World Health Organisation Collaborating Centre for Reference and Research on Influenza</institution>, Melbourne, Victoria 3000,<country>Australia</country></aff><aff id="a4"><label>4</label><institution>Molecular Diagnosis Centre, Department of Laboratory Medicine, National University Hospital</institution>, Singapore 119074,<country>Singapore</country></aff><aff id="a5"><label>5</label><institution>Department of Pathology, Singapore General Hospital</institution>, Singapore 169608,<country>Singapore</country></aff><aff id="a6"><label>6</label><institution>Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore</institution>, Singapore 117597,<country>Singapore</country></aff><aff id="a7"><label>7</label><institution>Duke Global Health Institute, Duke University</institution>, Durham, North Carolina 27708,<country>USA</country></aff></contrib-group><author-notes><corresp id="c1"><label>a</label><email>yvonne.su@duke-nus.edu.sg</email></corresp><corresp id="c2"><label>b</label><email>gavin.smith@duke-nus.edu.sg</email></corresp></author-notes><pub-date pub-type="epub"><day>06</day><month>08</month><year>2015</year></pub-date><pub-date pub-type="collection"><year>2015</year></pub-date><volume>6</volume><elocation-id>7952</elocation-id><history><date date-type="received"><day>27</day><month>11</month><year>2014</year></date><date date-type="accepted"><day>30</day><month>06</month><year>2015</year></date></history><permissions><copyright-statement>Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</copyright-statement><copyright-year>2015</copyright-year><copyright-holder>Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link></license-p></license></permissions><abstract><p>Influenza A H1N1/2009 virus that emerged from swine rapidly replaced the previous seasonal H1N1 virus. Although the early emergence and diversification of H1N1/2009 is well characterized, the ongoing evolutionary and global transmission dynamics of the virus remain poorly investigated. To address this we analyse >3,000 H1N1/2009 genomes, including 214 full genomes generated from our surveillance in Singapore, in conjunction with antigenic data. Here we show that natural selection acting on H1N1/2009 directly after introduction into humans was driven by adaptation to the new host. Since then, selection has been driven by immunological escape, with these changes corresponding to restricted antigenic diversity in the virus population. We also show that H1N1/2009 viruses have been subject to regular seasonal bottlenecks and a global reduction in antigenic and genetic diversity in 2014.</p></abstract><abstract abstract-type="web-summary"><p><inline-graphic id="i1" xlink:href="ncomms8952-i1.jpg"></inline-graphic>Influenza A H1N1/2009 virus emerged from swine and rapidly replaced the seasonal H1N1 virus. Here, the authors show that natural selection acting on H1N1/2009 after introduction into humans was driven by adaptation to the new host but later selection has been driven by immunological escape.</p></abstract></article-meta></front><floats-group><fig id="f1"><label>Figure 1</label><caption><title>Evolution of human H1N1/2009 viruses and structural mapping of positively selected sites on the HA molecule.</title><p>(<bold>a</bold>) Maximum likelihood phylogeny of 2,280 human H1-HA sequences from 2009 to 2014 with branches coloured by year of virus isolation. Representative amino-acid substitutions are mapped at the major tree nodes. Sites marked with asterisks (*) indicate positively selected sites identified by MEME method, with the significance level at <italic>P</italic><0.05. Scale bar represents number of substitutions per site. (<bold>b</bold>) Mapping of positively selected amino-acid sites identified by MEME method onto the three-dimensional structure of the HA glycoprotein of H1N1/2009 virus (Protein Data Bank code: 3LZG) for the pandemic (2009–2010) and post-pandemic (2011–2014) periods. The monomer shows the HA1 subunit in light blue and the HA2 subunit in green. The numbers in coloured circles denote codon alignment number and their locations in the three-dimensional structure are indicated with red arrows.</p></caption><graphic xlink:href="ncomms8952-f1"></graphic></fig><fig id="f2"><label>Figure 2</label><caption><title>Selection pressures on human H1N1/2009 viruses over time.</title><p>Yearly estimates of global d<sub>N</sub>/d<sub>S</sub> ratios for each gene using SLAC method, with the significance level at <italic>P</italic><0.05. Each gene data set per epidemic year consisted of up to 500 randomly selected global sequences. The means of d<sub>N</sub>/d<sub>S</sub> ratios are indicated by diamond-shaped symbols with error bars representing 95% confidence intervals. Coloured bars correspond to different genes in the following order: polymerase basic 2 (<italic>PB2</italic>), polymerase basic 1 (<italic>PB1</italic>), polymerase acidic (<italic>PA</italic>), haemagglutinin (<italic>HA</italic>), nucleoprotein (<italic>NP</italic>), neuraminidase (<italic>NA</italic>), two matrix proteins (<italic>M1</italic> and <italic>M2</italic>), and two non-structural proteins (<italic>NS1</italic> and <italic>NS2</italic>).</p></caption><graphic xlink:href="ncomms8952-f2"></graphic></fig><fig id="f3"><label>Figure 3</label><caption><title>Antigenic evolution of human H1N1/2009 viruses.</title><p>(<bold>a</bold>) Maximum likelihood phylogeny of the <italic>HA</italic> gene of Australian viruses used in the HI assay. Coloured branches represent the year of virus isolation on the right. Scale bar represents number of substitutions per site. (<bold>b</bold>) Antigenic cartography of H1N1/2009 viruses reconstructed based on HI assays of pandemic and post-pandemic strains against a panel of polyclonal antisera. Coloured dots correspond to the year of virus isolation. The position of viruses isolated in 2009 is indicated by the black arrow.</p></caption><graphic xlink:href="ncomms8952-f3"></graphic></fig><fig id="f4"><label>Figure 4</label><caption><title>Temporal phylogenies and epidemic patterns of human influenza viruses.</title><p>Evolution of the <italic>HA</italic> genes of (<bold>a</bold>) H1N1/2009 viruses (2009–2014), (<bold>b</bold>) seasonal H1N1 viruses (2000–February 2009), (<bold>c</bold>) H3N2 viruses (2009–2014) and (<bold>d</bold>) influenza B viruses (2009–2014). Phylogenies were inferred using the uncorrelated lognormal relaxed clock model with branches coloured by year of virus isolation and relative genetic diversity estimated using the Gaussian Markov Random Field (GMRF) model. Solid black lines in the GMRF plot represent mean relative genetic diversity while the corresponding grey shades indicate the 95% HPD intervals.</p></caption><graphic xlink:href="ncomms8952-f4"></graphic></fig><fig id="f5"><label>Figure 5</label><caption><title>Comparative phylogenetic analyses and population dynamics of H1-HA viruses circulating in different geographical regions, 2009–2014.</title><p>Phylogenies were inferred using the uncorrelated lognormal relaxed clock model and relative genetic diversity estimated using the Gaussian Markov Random Field (GMRF) model. Solid lines in the GMRF plot represent the mean relative genetic diversity through time, while the corresponding shaded areas indicate the 95% HPD intervals.</p></caption><graphic xlink:href="ncomms8952-f5"></graphic></fig><fig id="f6"><label>Figure 6</label><caption><title>Proportional ancestral location states on the phylogenetic tree trunk estimated for each location over time.</title><p>The waiting time between geographic location transitions was inferred using the continuous-time Markov chain model. The trunk reward proportion for each geographic location from 2009 through 2014 was determined from an analysis of 2,225 HA sequences of H1N1/2009 viruses. Shaded areas represent the trunk proportions over time for the nine geographical locations included in the analysis.</p></caption><graphic xlink:href="ncomms8952-f6"></graphic></fig><fig id="f7"><label>Figure 7</label><caption><title>Spatial diffusion of H1N1/2009 viruses.</title><p>Spatial diffusion pathways and histograms of total number of state transitions for (<bold>a</bold>,<bold>b</bold>) 2009–2010, (<bold>c</bold>,<bold>d</bold>) 2010–2011, (<bold>e</bold>,<bold>f</bold>) 2011–2012, (<bold>g</bold>,<bold>h</bold>) 2012–2013 and (<bold>i</bold>,<bold>j</bold>) 2013–2014. Global epidemic year was defined as October to the following September based on observed epidemics in <xref ref-type="fig" rid="f3">Fig. 3a</xref>. Significant epidemiological unidirectional pathways from one location to another are indicated on the maps. Thickness of coloured lines represents statistically supported migration rates with a mean indicator of >0.5: pink arrows, decisive rates with BF≥1,000; blue arrows, very strongly supported rates with 100≤BF<1,000; dark green arrows, strongly supported rates with 10≤BF<100; and light green arrows, supported rates with 3≤BF<10. AF, Africa; AUS, Australia; EA, East Asia; EU, Europe; NAm, North America; SEA, Southeast Asia; SAm, South America; SA, South Asia.</p></caption><graphic xlink:href="ncomms8952-f7"></graphic></fig><fig id="f8"><label>Figure 8</label><caption><title>Genomic reassortment and global genetic diversity of H1N1/2009 viruses.</title><p>(<bold>a</bold>) Multidimensional scaling plot of uncertainty of TMRCA between samples of 500 trees for each segment of pandemic H1N1/2009 viruses sampled between 2009 and 2014. The space occupied by human H3N2 viruses<xref ref-type="bibr" rid="b51">51</xref> is indicated by the dashed circle. (<bold>b</bold>) The TMRCA of each genomic segment of H1N1/2009 viruses circulating in each year. The TMRCAs of all segments in 2014 were dated more recently than 2009–2013 lineages, indicative of reduced genetic diversity across the whole genome. Values shown indicate the mean TMRCAs and the 95% HPD intervals from the Bayesian MCMC analysis. The diagonal line is traced along January of each year.</p></caption><graphic xlink:href="ncomms8952-f8"></graphic></fig><table-wrap position="float" id="t1"><label>Table 1</label><caption><title>Comparison of selection pressures of pandemic and post-pandemic periods for all genes of globally sampled H1N1/2009 viruses.</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="char" char="–"></col><col align="char" char="."></col><col align="char" char="."></col><col align="char" char="."></col><col align="char" char="("></col><col align="left"></col><col align="left"></col><col align="char" char="."></col></colgroup><thead valign="bottom"><tr><th align="left" valign="top" charoff="50"><bold>Gene</bold></th><th align="char" valign="top" char="–" charoff="50"><bold>Lineages</bold></th><th colspan="3" align="center" valign="top" char="." charoff="50"><bold>Branch d</bold><sub><bold>N</bold></sub><bold>/d</bold><sub><bold>S</bold></sub><bold>by CODEML</bold><hr></hr></th><th align="char" valign="top" char="(" charoff="50"><bold>Global d</bold><sub><bold>N</bold></sub><bold>/d</bold><sub><bold>S</bold></sub><bold>by SLAC</bold></th><th align="left" valign="top" charoff="50"><bold>Number of positively selected sites by M8+BEB (amino-acid position)</bold></th><th align="left" valign="top" charoff="50"><bold>Number of positively selected sites by MEME (amino-acid position)</bold></th><th align="center" valign="top" char="." charoff="50"><bold>Number of sites under relaxed selection</bold></th></tr><tr><th align="left" valign="top" charoff="50"> </th><th align="char" valign="top" char="–" charoff="50"> </th><th align="center" valign="top" char="." charoff="50"><bold>Internal</bold></th><th align="center" valign="top" char="." charoff="50"><bold>External</bold></th><th align="center" valign="top" char="." charoff="50"><bold>Internal/External</bold></th><th align="center" valign="top" char="(" charoff="50"><bold>Mean (95% CI)</bold></th><th align="left" valign="top" charoff="50"> </th><th align="left" valign="top" charoff="50"> </th><th align="char" valign="top" char="." charoff="50"> </th></tr></thead><tbody valign="top"><tr><td align="left" valign="top" charoff="50"><italic>PB2</italic></td><td align="char" valign="top" char="–" charoff="50">2009–2010</td><td align="char" valign="top" char="." charoff="50">8.138</td><td align="char" valign="top" char="." charoff="50">3.872</td><td align="char" valign="top" char="." charoff="50">2.102</td><td align="char" valign="top" char="(" charoff="50">0.189 (0.171–0.209)</td><td align="left" valign="top" charoff="50">22 (23, 60*, 107, 127, 154*, 191*, 194*, 227, 251*, 255*, 288, 340*, 344*, 354, 456, 461*, 471, 480, 584, 588*, 648, 660*)</td><td align="left" valign="top" charoff="50">5 (4, 199, 227, 344, 373)</td><td align="char" valign="top" char="." charoff="50">20</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="char" valign="top" char="–" charoff="50">2011–2014</td><td align="char" valign="top" char="." charoff="50">0.109</td><td align="char" valign="top" char="." charoff="50">0.1</td><td align="char" valign="top" char="." charoff="50">1.089</td><td align="char" valign="top" char="(" charoff="50">0.121 (0.107–0.136)</td><td align="left" valign="top" charoff="50">11 (194, 195*, 221, 255*, 293*, 299*, 354, 456*, 464*, 588, 731*)</td><td align="left" valign="top" charoff="50">0 (0)</td><td align="char" valign="top" char="." charoff="50">11</td></tr><tr><td align="left" valign="top" charoff="50"><italic>PB1</italic></td><td align="char" valign="top" char="–" charoff="50">2009–2010</td><td align="char" valign="top" char="." charoff="50">2.007</td><td align="char" valign="top" char="." charoff="50">2.775</td><td align="char" valign="top" char="." charoff="50">0.723</td><td align="char" valign="top" char="(" charoff="50">0.160 (0.144–0.178)</td><td align="left" valign="top" charoff="50">9 (257*, 353*, 435*, 563, 584, 587*, 609, 652*, 736*)</td><td align="left" valign="top" charoff="50">6 (207, 281, 387, 412, 608, 736)</td><td align="char" valign="top" char="." charoff="50">8</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="char" valign="top" char="–" charoff="50">2011–2014</td><td align="char" valign="top" char="." charoff="50">0.109</td><td align="char" valign="top" char="." charoff="50">0.083</td><td align="char" valign="top" char="." charoff="50">1.32</td><td align="char" valign="top" char="(" charoff="50">0.101 (0.089–0.114)</td><td align="left" valign="top" charoff="50">8 (20, 113*, 154*, 351, 397*, 435*, 645*, 652*)</td><td align="left" valign="top" charoff="50">4 (219, 231, 257, 633)</td><td align="char" valign="top" char="." charoff="50">8</td></tr><tr><td align="left" valign="top" charoff="50"><italic>PA</italic></td><td align="char" valign="top" char="–" charoff="50">2009–2010</td><td align="char" valign="top" char="." charoff="50">4.569</td><td align="char" valign="top" char="." charoff="50">2.646</td><td align="char" valign="top" char="." charoff="50">1.727</td><td align="char" valign="top" char="(" charoff="50">0.202 (0.182–0.222)</td><td align="left" valign="top" charoff="50">8 (14*, 30, 321, 325, 343, 479*, 581*, 716*)</td><td align="left" valign="top" charoff="50">6 (14, 352, 387, 709, 711, 712)</td><td align="char" valign="top" char="." charoff="50">7</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="char" valign="top" char="–" charoff="50">2011–2014</td><td align="char" valign="top" char="." charoff="50">0.091</td><td align="char" valign="top" char="." charoff="50">0.112</td><td align="char" valign="top" char="." charoff="50">0.813</td><td align="char" valign="top" char="(" charoff="50">0.138 (0.123–0.155)</td><td align="left" valign="top" charoff="50">5 (14*, 100*, 266*, 330*, 343*)</td><td align="left" valign="top" charoff="50">2 (450, 574)</td><td align="char" valign="top" char="." charoff="50">5</td></tr><tr><td align="left" valign="top" charoff="50"><italic>HA</italic></td><td align="char" valign="top" char="–" charoff="50">2009–2010</td><td align="char" valign="top" char="." charoff="50">0.41</td><td align="char" valign="top" char="." charoff="50">0.288</td><td align="char" valign="top" char="." charoff="50">1.424</td><td align="char" valign="top" char="(" charoff="50">0.345 (0.317–0.375)</td><td align="left" valign="top" charoff="50">20 (2, 49*, 114*, 142*, 145*, 154, 190, 200*, 202, 203*, 214, 220*, 239*, 266, 289*, 310*, 338*, 391*, 468*, 537)</td><td align="left" valign="top" charoff="50">12 (24, 49, 105, 145, 173, 391, 410, 436, 559, 560, 561, 563)</td><td align="char" valign="top" char="." charoff="50">17</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="char" valign="top" char="–" charoff="50">2011–2014</td><td align="char" valign="top" char="." charoff="50">0.224</td><td align="char" valign="top" char="." charoff="50">0.223</td><td align="char" valign="top" char="." charoff="50">1.005</td><td align="char" valign="top" char="(" charoff="50">0.328 (0.306–0.352)</td><td align="left" valign="top" charoff="50">16 (8*, 86*, 114*, 155*, 160*, 180*, 202*, 214*, 266*, 273*, 300*, 338*, 468*, 491*, 516*, 537*)</td><td align="left" valign="top" charoff="50">25 (26, 52, 65, 101, 114, 137, 142, 156, 158, 160, 173, 180, 188, 202, 214, 222, 224, 233, 239, 252, 273, 278, 303, 328, 465)</td><td align="char" valign="top" char="." charoff="50">10</td></tr><tr><td align="left" valign="top" charoff="50"><italic>NP</italic></td><td align="char" valign="top" char="–" charoff="50">2009–2010</td><td align="char" valign="top" char="." charoff="50">11.423</td><td align="char" valign="top" char="." charoff="50">4.176</td><td align="char" valign="top" char="." charoff="50">2.736</td><td align="char" valign="top" char="(" charoff="50">0.113 (0.0976–0.130)</td><td align="left" valign="top" charoff="50">8 (22, 100*, 175, 197, 353*, 373*, 425*, 452)</td><td align="left" valign="top" charoff="50">2 (197, 301)</td><td align="char" valign="top" char="." charoff="50">7</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="char" valign="top" char="–" charoff="50">2011–2014</td><td align="char" valign="top" char="." charoff="50">0.058</td><td align="char" valign="top" char="." charoff="50">0.065</td><td align="char" valign="top" char="." charoff="50">0.894</td><td align="char" valign="top" char="(" charoff="50">0.103 (0.0865–0.121)</td><td align="left" valign="top" charoff="50">7 (22*, 34*, 71*, 373*, 400*, 425*, 498*)</td><td align="left" valign="top" charoff="50">5 (34, 208. 209, 301, 498)</td><td align="char" valign="top" char="." charoff="50">5</td></tr><tr><td align="left" valign="top" charoff="50"><italic>NA</italic></td><td align="char" valign="top" char="–" charoff="50">2009–2010</td><td align="char" valign="top" char="." charoff="50">2.421</td><td align="char" valign="top" char="." charoff="50">2.061</td><td align="char" valign="top" char="." charoff="50">1.174</td><td align="char" valign="top" char="(" charoff="50">0.305 (0.275–0.336)</td><td align="left" valign="top" charoff="50">14 (43, 44*, 53, 80, 86, 106*, 241*, 248*, 275*, 308*, 313*, 332, 369*, 386*)</td><td align="left" valign="top" charoff="50">2 (35, 463)</td><td align="char" valign="top" char="." charoff="50">14</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="char" valign="top" char="–" charoff="50">2011–2014</td><td align="char" valign="top" char="." charoff="50">0.244</td><td align="char" valign="top" char="." charoff="50">0.285</td><td align="char" valign="top" char="." charoff="50">0.858</td><td align="char" valign="top" char="(" charoff="50">0.322 (0.291–0.354)</td><td align="left" valign="top" charoff="50">17 (34, 40, 41*, 43*, 44*, 45*, 82*, 200, 275*, 299, 313*, 321*, 339*, 386*, 389*, 396*, 397)</td><td align="left" valign="top" charoff="50">3 (151, 275, 386)</td><td align="char" valign="top" char="." charoff="50">15</td></tr><tr><td align="left" valign="top" charoff="50"><italic>M1</italic></td><td align="char" valign="top" char="–" charoff="50">2009–2010</td><td align="char" valign="top" char="." charoff="50">0.074</td><td align="char" valign="top" char="." charoff="50">0.146</td><td align="char" valign="top" char="." charoff="50">0.51</td><td align="char" valign="top" char="(" charoff="50">0.138 (0.117–0.170)</td><td align="left" valign="top" charoff="50">2 (30, 80*)</td><td align="left" valign="top" charoff="50">1 (80)</td><td align="char" valign="top" char="." charoff="50">1</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="char" valign="top" char="–" charoff="50">2011–2014</td><td align="char" valign="top" char="." charoff="50">0.15</td><td align="char" valign="top" char="." charoff="50">0.172</td><td align="char" valign="top" char="." charoff="50">0.875</td><td align="char" valign="top" char="(" charoff="50">0.142 (0.112–0.177)</td><td align="left" valign="top" charoff="50">4 (80*, 191*, 242*, 250*)</td><td align="left" valign="top" charoff="50">0 (0)</td><td align="char" valign="top" char="." charoff="50">4</td></tr><tr><td align="left" valign="top" charoff="50"><italic>M2</italic></td><td align="char" valign="top" char="–" charoff="50">2009–2010</td><td align="char" valign="top" char="." charoff="50">1.42</td><td align="char" valign="top" char="." charoff="50">0.553</td><td align="char" valign="top" char="." charoff="50">2.568</td><td align="char" valign="top" char="(" charoff="50">0.721 (0.568–0.900)</td><td align="left" valign="top" charoff="50">5 (10, 13, 27*, 82, 96)</td><td align="left" valign="top" charoff="50">0 (0)</td><td align="char" valign="top" char="." charoff="50">5</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="char" valign="top" char="–" charoff="50">2011–2014</td><td align="char" valign="top" char="." charoff="50">0.489</td><td align="char" valign="top" char="." charoff="50">0.476</td><td align="char" valign="top" char="." charoff="50">1.027</td><td align="char" valign="top" char="(" charoff="50">0.520 (0.392–0.673)</td><td align="left" valign="top" charoff="50">2 (13*, 21*)</td><td align="left" valign="top" charoff="50">0 (0)</td><td align="char" valign="top" char="." charoff="50">2</td></tr><tr><td align="left" valign="top" charoff="50"><italic>NS1</italic></td><td align="char" valign="top" char="–" charoff="50">2009–2010</td><td align="char" valign="top" char="." charoff="50">0.269</td><td align="char" valign="top" char="." charoff="50">0.469</td><td align="char" valign="top" char="." charoff="50">0.573</td><td align="char" valign="top" char="(" charoff="50">0.539 (0.475–0.608)</td><td align="left" valign="top" charoff="50">4 (55*, 90*, 93*, 123*)</td><td align="left" valign="top" charoff="50">2 (116,178)</td><td align="char" valign="top" char="." charoff="50">4</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="char" valign="top" char="–" charoff="50">2011–2014</td><td align="char" valign="top" char="." charoff="50">0.291</td><td align="char" valign="top" char="." charoff="50">0.241</td><td align="char" valign="top" char="." charoff="50">1.208</td><td align="char" valign="top" char="(" charoff="50">0.416 (0.358–0.481)</td><td align="left" valign="top" charoff="50">8 (55*, 90*, 115, 122*, 131, 186*, 191*, 205*)</td><td align="left" valign="top" charoff="50">0 (0)</td><td align="char" valign="top" char="." charoff="50">8</td></tr><tr><td align="left" valign="top" charoff="50"><italic>NS2</italic></td><td align="char" valign="top" char="–" charoff="50">2009–2010</td><td align="center" valign="top" char="." charoff="50">Inf</td><td align="char" valign="top" char="." charoff="50">0.319</td><td align="center" valign="top" char="." charoff="50">—</td><td align="char" valign="top" char="(" charoff="50">0.350 (0.278–0.434)</td><td align="left" valign="top" charoff="50">4 (20*, 89*, 115, 120*)</td><td align="left" valign="top" charoff="50">1(120)</td><td align="char" valign="top" char="." charoff="50">3</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="char" valign="top" char="–" charoff="50">2011–2014</td><td align="char" valign="top" char="." charoff="50">0.325</td><td align="char" valign="top" char="." charoff="50">0.305</td><td align="char" valign="top" char="." charoff="50">1.064</td><td align="char" valign="top" char="(" charoff="50">0.333 (0.252–0.429)</td><td align="left" valign="top" charoff="50">6 (29, 34, 48, 60, 89, 115)</td><td align="left" valign="top" charoff="50">0 (0)</td><td align="char" valign="top" char="." charoff="50">6</td></tr></tbody></table><table-wrap-foot><fn id="t1-fn1"><p>Sites with asterisks (*) indicate statistically significant with posterior probability of ≥0.95. Inf indicates zero synonymous changes and this value equals infinity.</p></fn></table-wrap-foot></table-wrap><table-wrap position="float" id="t2"><label>Table 2</label><caption><title>TMRCA estimates and nucleotide substitution rates for all gene segments of globally sampled H1N1/2009 viruses from 2009–2014.</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="left"></col><col align="left"></col><col align="left"></col><col align="center"></col><col align="center"></col><col align="center"></col></colgroup><thead valign="bottom"><tr><th align="left" valign="top" charoff="50"><bold>Gene</bold></th><th align="left" valign="top" charoff="50"><bold>TMRCA of root height (mean)</bold></th><th align="left" valign="top" charoff="50"><bold>Upper 95% HPD</bold></th><th align="left" valign="top" charoff="50"><bold>Lower 95% HPD</bold></th><th align="center" valign="top" charoff="50"><bold>Mean substitution rate</bold></th><th align="center" valign="top" charoff="50"><bold>Lower 95% HPD</bold></th><th align="center" valign="top" charoff="50"><bold>Upper 95% HPD</bold></th></tr></thead><tbody valign="top"><tr><td align="left" valign="top" charoff="50"><italic>PB2</italic></td><td align="left" valign="top" charoff="50">2009.040 (16 January 2009)</td><td align="left" valign="top" charoff="50">2008.941 (11 December 2008)</td><td align="left" valign="top" charoff="50">2009.139 (21 February 2009)</td><td align="center" valign="top" charoff="50">3.94E−03</td><td align="center" valign="top" charoff="50">3.50E−03</td><td align="center" valign="top" charoff="50">4.42E−03</td></tr><tr><td align="left" valign="top" charoff="50"><italic>PB1</italic></td><td align="left" valign="top" charoff="50">2008.999 (31 December 2008)</td><td align="left" valign="top" charoff="50">2008.890 (22 November 2008)</td><td align="left" valign="top" charoff="50">2009.103 (8 February 2009)</td><td align="center" valign="top" charoff="50">3.74E−03</td><td align="center" valign="top" charoff="50">3.31E−03</td><td align="center" valign="top" charoff="50">4.45E−03</td></tr><tr><td align="left" valign="top" charoff="50"><italic>PA</italic></td><td align="left" valign="top" charoff="50">2008.981 (25 December 2008)</td><td align="left" valign="top" charoff="50">2008.875 (17 November 2008)</td><td align="left" valign="top" charoff="50">2009.091 (4 February 2009)</td><td align="center" valign="top" charoff="50">3.77E−03</td><td align="center" valign="top" charoff="50">3.33E−03</td><td align="center" valign="top" charoff="50">4.20E−03</td></tr><tr><td align="left" valign="top" charoff="50"><italic>HA</italic></td><td align="left" valign="top" charoff="50">2009.031 (13 January 2009)</td><td align="left" valign="top" charoff="50">2008.931 (7 December 2008)</td><td align="left" valign="top" charoff="50">2009.131 (18 February 2009)</td><td align="center" valign="top" charoff="50">5.34E−03</td><td align="center" valign="top" charoff="50">4.76E−03</td><td align="center" valign="top" charoff="50">5.95E−03</td></tr><tr><td align="left" valign="top" charoff="50"><italic>NP</italic></td><td align="left" valign="top" charoff="50">2009.041 (16 January 2009)</td><td align="left" valign="top" charoff="50">2008.915 (1 December 2008)</td><td align="left" valign="top" charoff="50">2009.150 (25 February 2009)</td><td align="center" valign="top" charoff="50">3.92E−03</td><td align="center" valign="top" charoff="50">3.34E−03</td><td align="center" valign="top" charoff="50">4.46E−03</td></tr><tr><td align="left" valign="top" charoff="50"><italic>NA</italic></td><td align="left" valign="top" charoff="50">2009.081 (31 January 2009)</td><td align="left" valign="top" charoff="50">2008.982 (26 December 2008)</td><td align="left" valign="top" charoff="50">2009.177 (7 March 2009)</td><td align="center" valign="top" charoff="50">5.21E−03</td><td align="center" valign="top" charoff="50">4.64E−03</td><td align="center" valign="top" charoff="50">5.82E−03</td></tr><tr><td align="left" valign="top" charoff="50"><italic>MP</italic></td><td align="left" valign="top" charoff="50">2009.071 (27 January 2009)</td><td align="left" valign="top" charoff="50">2008.941 (11 December 2008)</td><td align="left" valign="top" charoff="50">2009.191 (12 March 2009)</td><td align="center" valign="top" charoff="50">3.52E−03</td><td align="center" valign="top" charoff="50">2.98E−03</td><td align="center" valign="top" charoff="50">4.09E−03</td></tr><tr><td align="left" valign="top" charoff="50"><italic>NS</italic></td><td align="left" valign="top" charoff="50">2009.051 (20 January 2009)</td><td align="left" valign="top" charoff="50">2008.921 (4 December 2008)</td><td align="left" valign="top" charoff="50">2009.171 (5 March 2009)</td><td align="center" valign="top" charoff="50">4.50E−03</td><td align="center" valign="top" charoff="50">3.80E−03</td><td align="center" valign="top" 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