Evolutionary relationship analysis of Middle East respiratory syndrome coronavirus 4a and 4b protein coding sequences
Identifieur interne : 000725 ( Pmc/Corpus ); précédent : 000724; suivant : 000726Evolutionary relationship analysis of Middle East respiratory syndrome coronavirus 4a and 4b protein coding sequences
Auteurs : Jin Il Kim ; Sehee Park ; Joon-Yong Bae ; Man-Seong ParkSource :
- Journal of Veterinary Science [ 1229-845X ] ; 2019.
Abstract
The 4a and 4b proteins of the Middle East respiratory syndrome coronavirus (MERS-CoV) have been described for their antagonism on host innate immunity. However, unlike clustering patterns of the complete gene sequences of human and camel MERS-CoVs, the 4a and 4b protein coding regions did not constitute species-specific phylogenetic groups. Moreover, given the estimated evolutionary rates of the complete, 4a, and 4b gene sequences, the 4a and 4b proteins might be less affected by species-specific innate immune pressures. These results suggest that the 4a and 4b proteins of MERS-CoV may function against host innate immunity in a manner independent of host species and/or evolutionary clustering patterns.
Url:
DOI: 10.4142/jvs.2019.20.e1
PubMed: 30944524
PubMed Central: 6441811
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PMC:6441811Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Evolutionary relationship analysis of Middle East respiratory syndrome coronavirus 4a and 4b protein coding sequences</title><author><name sortKey="Kim, Jin Il" sort="Kim, Jin Il" uniqKey="Kim J" first="Jin Il" last="Kim">Jin Il Kim</name><affiliation><nlm:aff id="A1"></nlm:aff></affiliation></author><author><name sortKey="Park, Sehee" sort="Park, Sehee" uniqKey="Park S" first="Sehee" last="Park">Sehee Park</name><affiliation><nlm:aff id="A1"></nlm:aff></affiliation></author><author><name sortKey="Bae, Joon Yong" sort="Bae, Joon Yong" uniqKey="Bae J" first="Joon-Yong" last="Bae">Joon-Yong Bae</name><affiliation><nlm:aff id="A1"></nlm:aff></affiliation></author><author><name sortKey="Park, Man Seong" sort="Park, Man Seong" uniqKey="Park M" first="Man-Seong" last="Park">Man-Seong Park</name><affiliation><nlm:aff id="A1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">30944524</idno><idno type="pmc">6441811</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441811</idno><idno type="RBID">PMC:6441811</idno><idno type="doi">10.4142/jvs.2019.20.e1</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000725</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000725</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Evolutionary relationship analysis of Middle East respiratory syndrome coronavirus 4a and 4b protein coding sequences</title><author><name sortKey="Kim, Jin Il" sort="Kim, Jin Il" uniqKey="Kim J" first="Jin Il" last="Kim">Jin Il Kim</name><affiliation><nlm:aff id="A1"></nlm:aff></affiliation></author><author><name sortKey="Park, Sehee" sort="Park, Sehee" uniqKey="Park S" first="Sehee" last="Park">Sehee Park</name><affiliation><nlm:aff id="A1"></nlm:aff></affiliation></author><author><name sortKey="Bae, Joon Yong" sort="Bae, Joon Yong" uniqKey="Bae J" first="Joon-Yong" last="Bae">Joon-Yong Bae</name><affiliation><nlm:aff id="A1"></nlm:aff></affiliation></author><author><name sortKey="Park, Man Seong" sort="Park, Man Seong" uniqKey="Park M" first="Man-Seong" last="Park">Man-Seong Park</name><affiliation><nlm:aff id="A1"></nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Veterinary Science</title><idno type="ISSN">1229-845X</idno><idno type="eISSN">1976-555X</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The 4a and 4b proteins of the Middle East respiratory syndrome coronavirus (MERS-CoV) have been described for their antagonism on host innate immunity. However, unlike clustering patterns of the complete gene sequences of human and camel MERS-CoVs, the 4a and 4b protein coding regions did not constitute species-specific phylogenetic groups. Moreover, given the estimated evolutionary rates of the complete, 4a, and 4b gene sequences, the 4a and 4b proteins might be less affected by species-specific innate immune pressures. These results suggest that the 4a and 4b proteins of MERS-CoV may function against host innate immunity in a manner independent of host species and/or evolutionary clustering patterns.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Kim, Ji" uniqKey="Kim J">JI Kim</name></author><author><name sortKey="Kim, Yj" uniqKey="Kim Y">YJ Kim</name></author><author><name sortKey="Lemey, P" uniqKey="Lemey P">P Lemey</name></author><author><name sortKey="Lee, I" uniqKey="Lee I">I Lee</name></author><author><name sortKey="Park, S" uniqKey="Park S">S Park</name></author><author><name sortKey="Bae, Jy" uniqKey="Bae J">JY Bae</name></author><author><name sortKey="Kim, D" uniqKey="Kim D">D Kim</name></author><author><name sortKey="Kim, H" uniqKey="Kim H">H Kim</name></author><author><name sortKey="Jang, Si" uniqKey="Jang S">SI Jang</name></author><author><name sortKey="Yang, Js" uniqKey="Yang J">JS 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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Vet Sci</journal-id><journal-id journal-id-type="iso-abbrev">J. Vet. Sci</journal-id><journal-id journal-id-type="publisher-id">JVS</journal-id><journal-title-group><journal-title>Journal of Veterinary Science</journal-title></journal-title-group><issn pub-type="ppub">1229-845X</issn><issn pub-type="epub">1976-555X</issn><publisher><publisher-name>The Korean Society of Veterinary Science</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">30944524</article-id><article-id pub-id-type="pmc">6441811</article-id><article-id pub-id-type="doi">10.4142/jvs.2019.20.e1</article-id><article-categories><subj-group subj-group-type="heading"><subject>Short Communication</subject></subj-group></article-categories><title-group><article-title>Evolutionary relationship analysis of Middle East respiratory syndrome coronavirus 4a and 4b protein coding sequences</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-8833-2138</contrib-id><name><surname>Kim</surname><given-names>Jin Il</given-names></name><xref ref-type="aff" rid="A1"></xref><xref ref-type="author-notes" rid="FN1">†</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-4799-2241</contrib-id><name><surname>Park</surname><given-names>Sehee</given-names></name><xref ref-type="aff" rid="A1"></xref><xref ref-type="author-notes" rid="FN1">†</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-2483-4208</contrib-id><name><surname>Bae</surname><given-names>Joon-Yong</given-names></name><xref ref-type="aff" rid="A1"></xref></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-7427-486X</contrib-id><name><surname>Park</surname><given-names>Man-Seong</given-names></name><xref ref-type="aff" rid="A1"></xref></contrib></contrib-group><aff id="A1">Department of Microbiology, Institute for Viral Diseases, Korea University College of Medicine, Seoul 02841,<country>Korea</country>.</aff><author-notes><corresp>Corresponding author: Man-Seong Park. Department of Microbiology, Institute for Viral Diseases, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea. <email>manseong.park@gmail.com</email>; <email>ms0392@korea.ac.kr</email></corresp><fn id="FN1" fn-type="equal"><p><sup>†</sup>The first two authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="ppub"><month>3</month><year>2019</year></pub-date><pub-date pub-type="epub"><day>19</day><month>2</month><year>2019</year></pub-date><volume>20</volume><issue>2</issue><elocation-id>e1</elocation-id><history><date date-type="received"><day>09</day><month>11</month><year>2018</year></date><date date-type="rev-recd"><day>26</day><month>11</month><year>2018</year></date><date date-type="accepted"><day>16</day><month>12</month><year>2018</year></date></history><permissions><copyright-statement>© 2019 The Korean Society of Veterinary Science</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>The Korean Society of Veterinary Science</copyright-holder><license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by-nc/4.0"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (<ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by-nc/4.0">https://creativecommons.org/licenses/by-nc/4.0</ext-link>) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><abstract><p>The 4a and 4b proteins of the Middle East respiratory syndrome coronavirus (MERS-CoV) have been described for their antagonism on host innate immunity. However, unlike clustering patterns of the complete gene sequences of human and camel MERS-CoVs, the 4a and 4b protein coding regions did not constitute species-specific phylogenetic groups. Moreover, given the estimated evolutionary rates of the complete, 4a, and 4b gene sequences, the 4a and 4b proteins might be less affected by species-specific innate immune pressures. These results suggest that the 4a and 4b proteins of MERS-CoV may function against host innate immunity in a manner independent of host species and/or evolutionary clustering patterns.</p></abstract><kwd-group kwd-group-type="author"><kwd>Middle East respiratory syndrome coronavirus</kwd><kwd>molecular evolution</kwd><kwd>phylogeny</kwd><kwd>zoonoses</kwd></kwd-group><funding-group><award-group><funding-source><institution-wrap><institution>National Research Foundation of Korea</institution><institution-id institution-id-type="CrossRef">https://doi.org/10.13039/501100003725</institution-id></institution-wrap></funding-source><award-id>NRF-2016M3A9B6916830</award-id></award-group><award-group><funding-source><institution-wrap><institution>Ministry of Health and Welfare</institution><institution-id institution-id-type="CrossRef">https://doi.org/10.13039/501100003625</institution-id></institution-wrap></funding-source><award-id>HI15C2870</award-id></award-group></funding-group></article-meta></front><body><p>Human infection with the Middle East respiratory syndrome coronavirus (MERS-CoV), a positive-sense single-stranded RNA virus of the family <italic>Coronaviridae</italic>, was first reported in 2012 [<xref rid="B1" ref-type="bibr">1</xref>]. Since then, more than 2,200 laboratory-confirmed cases have been described with an estimated 35.5% case-fatality rate [<xref rid="B2" ref-type="bibr">2</xref>]. Middle East countries appeared to be mainly affected by the life-threatening pathogenicity of the virus, but some exported cases were also reported in Asia, Europe, and the United States of America [<xref rid="B1" ref-type="bibr">1</xref><xref rid="B3" ref-type="bibr">3</xref>]. Given zoonotic transmission of the virus from dromedary camels to humans and its lethality in humans [<xref rid="B1" ref-type="bibr">1</xref>], vaccines and/or antivirals should be prepared, but no approved medical countermeasures are available, yet.</p><p>In line with the pathogenic mechanisms reported with MERS-CoV [<xref rid="B4" ref-type="bibr">4</xref>], such as acute respiratory symptoms and local immune responses, viral antagonism against host innate immune responses may be of great significance in terms of the pandemic potential and host range restriction of the virus. Viral antagonism had been already described for MERS-CoV [<xref rid="B5" ref-type="bibr">5</xref>], and, of the MERS-CoV proteins, protein 4a was suggested responsible for its role against RNA-dependent protein kinase-mediated antiviral immunity and activation of retinoic acid-inducible gene I and Melanoma Differentiation-Associated protein 5 of host cells [<xref rid="B6" ref-type="bibr">6</xref><xref rid="B7" ref-type="bibr">7</xref>]. The antagonistic effects of MERS-CoV protein 4b were also demonstrated against nuclear factor-κB-dependent immunity and RNase L activation of host cells [<xref rid="B8" ref-type="bibr">8</xref><xref rid="B9" ref-type="bibr">9</xref>]. As shown for influenza and Zika viruses [<xref rid="B10" ref-type="bibr">10</xref><xref rid="B11" ref-type="bibr">11</xref>], the species-specific effects of viral antagonism of MERS-CoV on host innate immunity can be revealed by analysis of the evolutionary relationship of the 4a and 4b genes between human and camel MERS-CoV strains. To this end, we investigated the evolutionary history and rates of MERS-CoV 4a and 4b protein coding regions as well as those of MERS-CoV complete gene sequences using a time-framed Bayesian inference method (BEAST package, v1.10.0; BEAST, New Zealand) [<xref rid="B12" ref-type="bibr">12</xref>] with individual settings of molecular clock (for complete gene, lognormal relaxed clock model and for 4a and 4b coding regions, strict clock model), nucleotide substitution (based on the estimated results of best-fit substitution model using jModeltest, v2.1.10: for complete gene, GTR + I + γ; for 4a, TN93 + I; and for 4b, TN93 + γ) [<xref rid="B13" ref-type="bibr">13</xref>], and Markov chain Monte Carlo runs (2 × 10<sup>8</sup> chain length with every 2 × 10<sup>5</sup> iterations after a 10% burn-in). The phylogenetic relationship of MERS-CoV complete gene sequences was reconstructed using a total of 260 sequences (human strains, n = 126 and camel strains, n = 134; sequence sets are available upon request) that were downloaded from the Virus Variation Resource database of National Center for Biotechnology Information (<ext-link ext-link-type="uri" xlink:href="https://www.ncbi.nlm.nih.gov/genome/viruses/variation/">https://www.ncbi.nlm.nih.gov/genome/viruses/variation/</ext-link>), and their maximum clade credibility trees were visualized using FigTree (v1.4.3; Figtree Systems Pty, Australia). Given the phylogenetic relationship of the complete gene sequences, most camel sequences constituted 5 different genetic groups (camel G1–G5), except for some distantly-related sequences, and the camel G2, G3, and G4 strains appeared to evolve exclusively from human strains. Transmission of MERS-CoV between humans and camels appeared to be identified only in the camel G1 and G5 groups (<xref ref-type="fig" rid="F1">Fig. 1</xref>).</p><p>Unlike the phylogenetic clustering patterns of the complete gene sequences (<xref ref-type="fig" rid="F1">Fig. 1</xref>), human and camel strains appeared to constitute common genetic groups in the 4a and 4b phylogenetic trees (<xref ref-type="fig" rid="F2">Fig. 2</xref>). Neither human-specific nor camel-specific clustering patterns were observed in the 4a and 4b phylogenetic trees. Rather, the camel G2, G3, and G4 sequences, which constituted the camel-only phylogenetic groups in the complete gene sequence analysis (<xref ref-type="fig" rid="F1">Fig. 1</xref>), were mixed with other camel sequences of different phylogenetic groups and with human sequences, and, from camel G1 to G5, all camel sequences were grouped together with human sequences (<xref ref-type="fig" rid="F2">Fig. 2</xref>). These groupings may imply little or no species-specific antagonism of the human and camel MERS-CoV 4a and 4b proteins against host innate immune responses. Of course, not phylogenetic placements between different host viruses but certain genetic determinants may determine the viral antagonistic mechanism(s) in hosts. The other viral proteins or genetic mutations on the other viral proteins may also compensate for a lack of sufficient viral antagonism [<xref rid="B14" ref-type="bibr">14</xref>]. However, results of serological and epidemiological analyses indicate dromedary camels are one of the susceptible hosts of MERS-CoV, even though disease severity of MERS is quite different between humans and camels [<xref rid="B1" ref-type="bibr">1</xref>], and, given that the interaction mechanism(s) between viral surface protein and cellular receptors of hosts may also determine host range restriction [<xref rid="B15" ref-type="bibr">15</xref>], the effects of species-specific viral antagonism on host innate immunity might not be associated with the sustained dissemination of MERS-CoV in humans. Rather, a lack of sufficient viral antagonism of MERS-CoV in humans may be associated with the transmission of the virus from camels to humans, as indicated by the almost 2-fold increased evolutionary rate (1.42 × 10<sup>−3</sup> substitutions/site/year) of the complete gene sequences of human and camel MERS-CoV strains (<xref rid="T1" ref-type="table">Table 1</xref>), compared with the previous study result (0.74 × 10<sup>−3</sup> substitutions/site/year) reported by Kim et al. [<xref rid="B3" ref-type="bibr">3</xref>], which assessed only the human strain sequences. In contrast, the evolutionary rates of the 4a (1.89 × 10<sup>−3</sup> substitutions/site/year) and 4b (1.44 × 10<sup>−3</sup> substitutions/site/year) protein-coding regions of human and camel MERS-CoV strains were estimated to be almost in similar ranges with those (1.26 × 10<sup>−3</sup> and 1.27 × 10<sup>−3</sup> substitutions/site/year for the 4a and 4b protein coding regions, respectively) reported by Kim et al. [<xref rid="B3" ref-type="bibr">3</xref>] (<xref rid="T1" ref-type="table">Table 1</xref>), which may suggest the absence of large immune-mediated pressure differences between human and camel MERS-CoV 4a and 4b proteins and no need for the adaptation of camel MERS-CoV strains prior to zoonotic dissemination to humans. As mentioned above, the effects of other viral proteins and molecular determinants of immune evasion mechanisms of MERS-CoVs on the zoonotic and reverse zoonotic transmission between humans and camels should be investigated further using <italic>in vitro</italic> and <italic>in vivo</italic> studies.</p><p>In this study, we investigated the evolutionary history and rates of the 4a and 4b protein coding sequences of human and camel MERS-CoV strains. By demonstrating that neither species-specific nor group-specific clustering patterns were observed in the 4a and 4b protein coding regions, we suggest that the antagonistic mechanism of MERS-CoV against host innate immunity might be mediated in a manner independent of host species and/or evolutionary clustering patterns. Given the disease severity and consequent public health threats of MERS, our results have expanded the knowledge of molecular evolution patterns and virus-host interactions of MERS-CoVs and provide information useful in the development of MERS-CoV vaccines.</p></body><back><ack><title>ACKNOWLEDGMENTS</title><p>We appreciate the efforts of all the authors who provided the complete genome sequences of human and camel MERS-CoV strains with the database of National Center for Biotechnology Information (NCBI). </p></ack><fn-group><fn fn-type="supported-by"><p><bold>Funding:</bold> This study was supported by grants of the National Research Foundation of Korea (grant No. NRF-2016M3A9B6916830) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant No. HI15C2870).</p></fn><fn fn-type="COI-statement"><p><bold>Conflict of Interest:</bold> The authors declare no conflicts of interest.</p></fn><fn fn-type="con"><p><bold>Author Contributions:</bold><list list-type="simple"><list-item><p><bold>Conceptualization:</bold> Park MS.</p></list-item><list-item><p><bold>Data curation:</bold> Kim JI, Park MS.</p></list-item><list-item><p><bold>Formal analysis:</bold> Kim JI, Park S, Bae JY.</p></list-item><list-item><p><bold>Funding acquisition:</bold> Park MS.</p></list-item><list-item><p><bold>Supervision:</bold> Park MS.</p></list-item><list-item><p><bold>Validation:</bold> Kim JI, Park MS.</p></list-item><list-item><p><bold>Visualization:</bold> Kim JI, Park S, Bae JY.</p></list-item><list-item><p><bold>Writing - original draft:</bold> Kim JI.</p></list-item><list-item><p><bold>Writing - review & editing:</bold> Kim JI, Park MS.</p></list-item></list></p></fn></fn-group><ref-list><ref id="B1"><label>1</label><element-citation publication-type="book"><collab>World Health Organization</collab><source>WHO MERS Global Summary and Assessment of Risk 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pub-id-type="pmid">26889022</pub-id></element-citation></ref></ref-list></back><floats-group><fig id="F1" fig-type="figure" orientation="portrait" position="float"><label>Fig. 1</label><caption><title>Phylogenetic relationship of the complete genes of human and camel MERS-CoV strains. The complete gene sequences of human and camel MERS-CoV strains were evaluated for their evolutionary relationships. Human strain sequences were colored black, whereas camel sequences were colored differently based on their individual distinct groups (camel G1, magenta; G2, sky blue; G3, purple; G4, light green; and G5, orange). The other camel strains not included in the camel G1–G5 groups were colored cantaloupe. The color of each node indicates its posterior probability score (0.0025–1).</title><p>MERS-CoV, Middle East respiratory syndrome coronavirus.</p></caption><graphic xlink:href="jvs-20-e1-g001"></graphic></fig><fig id="F2" fig-type="figure" orientation="portrait" position="float"><label>Fig. 2</label><caption><title>Phylogenetic relationship of the 4a and 4b coding regions of human and camel MERS-CoV strains. The 4a (A) and 4b (B) coding region sequences of human and camel MERS-CoV strains were evaluated for their evolutionary relationships. Human strain sequences were colored black, and camel sequences were colored differently based on their corresponding complete gene sequence group, as indicated and as in <xref ref-type="fig" rid="F1">Fig. 1</xref>. The color of each node indicates its posterior probability score (0.0013–1).</title><p>MERS-CoV, Middle East respiratory syndrome coronavirus.</p></caption><graphic xlink:href="jvs-20-e1-g002"></graphic></fig><table-wrap id="T1" orientation="portrait" position="float"><label>Table 1</label><caption><title>Estimated root years and evolutionary rates of the complete genes and the 4a and 4b coding regions of human and camel MERS-CoV strains</title></caption><alternatives><graphic xlink:href="jvs-20-e1-i001"></graphic><table frame="hsides" rules="rows"><col width="24.86%" span="1"></col><col width="18.78%" span="1"></col><col width="18.78%" span="1"></col><col width="18.78%" span="1"></col><col width="18.78%" span="1"></col><thead><tr><th valign="top" align="left" rowspan="2" colspan="1" style="background-color:rgb(238,248,254)">Gene (coding region)</th><th valign="top" align="center" rowspan="1" colspan="2" style="background-color:rgb(238,248,254)">tMRCA<sup>*</sup> (yr)</th><th valign="top" align="center" rowspan="1" colspan="2" style="background-color:rgb(238,248,254)">Evolutionary rate (10<sup>−3</sup> substitutions/site/yr)</th></tr><tr><th valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(238,248,254)">Mean</th><th valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(238,248,254)">95% HPD<sup>†</sup></th><th valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(238,248,254)">Mean<sup>‡</sup></th><th valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(238,248,254)">95% HPD</th></tr></thead><tbody><tr><td valign="top" align="left" rowspan="1" colspan="1">Complete gene</td><td valign="top" align="center" rowspan="1" colspan="1">2009.37</td><td valign="top" align="center" rowspan="1" colspan="1">2006.35–2011.46</td><td valign="top" align="center" rowspan="1" colspan="1">1.42 (0.74)</td><td valign="top" align="center" rowspan="1" colspan="1">1.19–1.72</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1" style="background-color:rgb(238,248,254)">4a</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(238,248,254)">2009.84</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(238,248,254)">2006.67–2011.65</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(238,248,254)">1.89 (1.26)</td><td valign="top" align="center" rowspan="1" colspan="1" style="background-color:rgb(238,248,254)">0.98–3.02</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">4b</td><td valign="top" align="center" rowspan="1" colspan="1">2010.18</td><td valign="top" align="center" rowspan="1" colspan="1">2008.17–2011.83</td><td valign="top" align="center" rowspan="1" colspan="1">1.44 (1.27)</td><td valign="top" align="center" rowspan="1" colspan="1">0.94–2.01</td></tr></tbody></table></alternatives><table-wrap-foot><p>Values are presented as median (interquartile range) or number (%).</p><p>MERS-CoV, Middle East respiratory syndrome coronavirus; tMRCA, time to the most recent common ancestor; HPD, highest posterior density.</p><p><sup>*</sup>The time of most recent common ancestor; <sup>†</sup>Lower and upper limits of 95% highest probability density; <sup>‡</sup>Estimation results reported by Kim et al. [<xref rid="B3" ref-type="bibr">3</xref>] are indicated in parentheses.</p></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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