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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Adaptive evolution of bat dipeptidyl peptidase 4 (dpp4): implications for the origin and emergence of Middle East respiratory syndrome coronavirus</title><author><name sortKey="Cui, Jie" sort="Cui, Jie" uniqKey="Cui J" first="Jie" last="Cui">Jie Cui</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.1013.3</institution-id><institution-id institution-id-type="ISNI">000000041936834X</institution-id><institution>Marie Bashir Institute for Infectious Diseases and Biosecurity, School of Biological Sciences and Sydney Medical School,</institution><institution>The University of Sydney,</institution></institution-wrap>Sydney, NSW 2006 Australia</nlm:aff></affiliation></author><author><name sortKey="Eden, John Sebastian" sort="Eden, John Sebastian" uniqKey="Eden J" first="John-Sebastian" last="Eden">John-Sebastian Eden</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.1013.3</institution-id><institution-id institution-id-type="ISNI">000000041936834X</institution-id><institution>Marie Bashir Institute for Infectious Diseases and Biosecurity, School of Biological Sciences and Sydney Medical School,</institution><institution>The University of Sydney,</institution></institution-wrap>Sydney, NSW 2006 Australia</nlm:aff></affiliation></author><author><name sortKey="Holmes, Edward C" sort="Holmes, Edward C" uniqKey="Holmes E" first="Edward C" last="Holmes">Edward C. Holmes</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.1013.3</institution-id><institution-id institution-id-type="ISNI">000000041936834X</institution-id><institution>Marie Bashir Institute for Infectious Diseases and Biosecurity, School of Biological Sciences and Sydney Medical School,</institution><institution>The University of Sydney,</institution></institution-wrap>Sydney, NSW 2006 Australia</nlm:aff></affiliation></author><author><name sortKey="Wang, Lin Fa" sort="Wang, Lin Fa" uniqKey="Wang L" first="Lin-Fa" last="Wang">Lin-Fa Wang</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="GRID">grid.428397.3</institution-id><institution-id institution-id-type="ISNI">0000000403850924</institution-id><institution>Duke-NUS Graduate Medical School,</institution></institution-wrap>169857 Singapore</nlm:aff></affiliation><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="GRID">grid.413322.5</institution-id><institution-id institution-id-type="ISNI">0000000121888254</institution-id><institution>CSIRO Livestock Industries,</institution><institution>Australian Animal Health Laboratory,</institution></institution-wrap>Geelong, VIC 3220 Australia</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24107353</idno><idno type="pmc">3852826</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852826</idno><idno type="RBID">PMC:3852826</idno><idno type="doi">10.1186/1743-422X-10-304</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">000172</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000172</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Adaptive evolution of bat dipeptidyl peptidase 4 (dpp4): implications for the origin and emergence of Middle East respiratory syndrome coronavirus</title><author><name sortKey="Cui, Jie" sort="Cui, Jie" uniqKey="Cui J" first="Jie" last="Cui">Jie Cui</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.1013.3</institution-id><institution-id institution-id-type="ISNI">000000041936834X</institution-id><institution>Marie Bashir Institute for Infectious Diseases and Biosecurity, School of Biological Sciences and Sydney Medical School,</institution><institution>The University of Sydney,</institution></institution-wrap>Sydney, NSW 2006 Australia</nlm:aff></affiliation></author><author><name sortKey="Eden, John Sebastian" sort="Eden, John Sebastian" uniqKey="Eden J" first="John-Sebastian" last="Eden">John-Sebastian Eden</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.1013.3</institution-id><institution-id institution-id-type="ISNI">000000041936834X</institution-id><institution>Marie Bashir Institute for Infectious Diseases and Biosecurity, School of Biological Sciences and Sydney Medical School,</institution><institution>The University of Sydney,</institution></institution-wrap>Sydney, NSW 2006 Australia</nlm:aff></affiliation></author><author><name sortKey="Holmes, Edward C" sort="Holmes, Edward C" uniqKey="Holmes E" first="Edward C" last="Holmes">Edward C. Holmes</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.1013.3</institution-id><institution-id institution-id-type="ISNI">000000041936834X</institution-id><institution>Marie Bashir Institute for Infectious Diseases and Biosecurity, School of Biological Sciences and Sydney Medical School,</institution><institution>The University of Sydney,</institution></institution-wrap>Sydney, NSW 2006 Australia</nlm:aff></affiliation></author><author><name sortKey="Wang, Lin Fa" sort="Wang, Lin Fa" uniqKey="Wang L" first="Lin-Fa" last="Wang">Lin-Fa Wang</name><affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="GRID">grid.428397.3</institution-id><institution-id institution-id-type="ISNI">0000000403850924</institution-id><institution>Duke-NUS Graduate Medical School,</institution></institution-wrap>169857 Singapore</nlm:aff></affiliation><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="GRID">grid.413322.5</institution-id><institution-id institution-id-type="ISNI">0000000121888254</institution-id><institution>CSIRO Livestock Industries,</institution><institution>Australian Animal Health Laboratory,</institution></institution-wrap>Geelong, VIC 3220 Australia</nlm:aff></affiliation></author></analytic><series><title level="j">Virology Journal</title><idno type="eISSN">1743-422X</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>The newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV) that first appeared in Saudi Arabia during the summer of 2012 has to date (20th September 2013) caused 58 human deaths. MERS-CoV utilizes the dipeptidyl peptidase 4 (DPP4) host cell receptor, and analysis of the long-term interaction between virus and receptor provides key information on the evolutionary events that lead to the viral emergence.</p></sec><sec><title>Findings</title><p>We show that bat <italic>DPP4</italic> genes have been subject to significant adaptive evolution, suggestive of a long-term arms-race between bats and MERS related CoVs. In particular, we identify three positively selected residues in DPP4 that directly interact with the viral surface glycoprotein.</p></sec><sec><title>Conclusions</title><p>Our study suggests that the evolutionary lineage leading to MERS-CoV may have circulated in bats for a substantial time period.</p></sec><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1186/1743-422X-10-304) contains supplementary material, which is available to authorized users.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="De Groot, Rj" uniqKey="De Groot R">RJ de Groot</name></author><author><name sortKey="Baker, Sc" uniqKey="Baker S">SC Baker</name></author><author><name sortKey="Baric, Rs" uniqKey="Baric R">RS Baric</name></author><author><name sortKey="Brown, Cs" uniqKey="Brown C">CS Brown</name></author><author><name sortKey="Drosten, C" uniqKey="Drosten C">C Drosten</name></author><author><name 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Virol J</journal-id><journal-id journal-id-type="iso-abbrev">Virol. J</journal-id><journal-title-group><journal-title>Virology Journal</journal-title></journal-title-group><issn pub-type="epub">1743-422X</issn><publisher><publisher-name>BioMed Central</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24107353</article-id><article-id pub-id-type="pmc">3852826</article-id><article-id pub-id-type="publisher-id">2574</article-id><article-id pub-id-type="doi">10.1186/1743-422X-10-304</article-id><article-categories><subj-group subj-group-type="heading"><subject>Short Report</subject></subj-group></article-categories><title-group><article-title>Adaptive evolution of bat dipeptidyl peptidase 4 (dpp4): implications for the origin and emergence of Middle East respiratory syndrome coronavirus</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Cui</surname><given-names>Jie</given-names></name><address><email>jiecui@yahoo.com</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Eden</surname><given-names>John-Sebastian</given-names></name><address><email>js.eden@sydney.edu.au</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Holmes</surname><given-names>Edward C</given-names></name><address><email>edward.holmes@sydney.edu.au</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Lin-Fa</given-names></name><address><email>linfa.wang@duke-nus.edu.sg</email></address><xref ref-type="aff" rid="Aff2">2</xref><xref ref-type="aff" rid="Aff3">3</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="GRID">grid.1013.3</institution-id><institution-id institution-id-type="ISNI">000000041936834X</institution-id><institution>Marie Bashir Institute for Infectious Diseases and Biosecurity, School of Biological Sciences and Sydney Medical School,</institution><institution>The University of Sydney,</institution></institution-wrap>Sydney, NSW 2006 Australia</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="GRID">grid.428397.3</institution-id><institution-id institution-id-type="ISNI">0000000403850924</institution-id><institution>Duke-NUS Graduate Medical School,</institution></institution-wrap>169857 Singapore</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="GRID">grid.413322.5</institution-id><institution-id institution-id-type="ISNI">0000000121888254</institution-id><institution>CSIRO Livestock Industries,</institution><institution>Australian Animal Health Laboratory,</institution></institution-wrap>Geelong, VIC 3220 Australia</aff></contrib-group><pub-date pub-type="epub"><day>10</day><month>10</month><year>2013</year></pub-date><pub-date pub-type="pmc-release"><day>10</day><month>10</month><year>2013</year></pub-date><pub-date pub-type="collection"><year>2013</year></pub-date><volume>10</volume><elocation-id>304</elocation-id><history><date date-type="received"><day>3</day><month>9</month><year>2013</year></date><date date-type="accepted"><day>3</day><month>10</month><year>2013</year></date></history><permissions><copyright-statement>© Cui et al.; licensee BioMed Central Ltd. 2013</copyright-statement><license license-type="OpenAccess"><license-p>This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/2.0">http://creativecommons.org/licenses/by/2.0</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>) applies to the data made available in this article, unless otherwise stated.</license-p></license></permissions><abstract id="Abs1"><sec><title>Background</title><p>The newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV) that first appeared in Saudi Arabia during the summer of 2012 has to date (20th September 2013) caused 58 human deaths. MERS-CoV utilizes the dipeptidyl peptidase 4 (DPP4) host cell receptor, and analysis of the long-term interaction between virus and receptor provides key information on the evolutionary events that lead to the viral emergence.</p></sec><sec><title>Findings</title><p>We show that bat <italic>DPP4</italic> genes have been subject to significant adaptive evolution, suggestive of a long-term arms-race between bats and MERS related CoVs. In particular, we identify three positively selected residues in DPP4 that directly interact with the viral surface glycoprotein.</p></sec><sec><title>Conclusions</title><p>Our study suggests that the evolutionary lineage leading to MERS-CoV may have circulated in bats for a substantial time period.</p></sec><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1186/1743-422X-10-304) contains supplementary material, which is available to authorized users.</p></sec></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>MERS-CoV</kwd><kwd>Bats</kwd><kwd>Arms-race</kwd><kwd>Adaptive evolution</kwd><kwd>Emergence</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2013</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1"><title>Main text</title><p>Middle East respiratory syndrome coronavirus (MERS-CoV) [<xref ref-type="bibr" rid="CR1">1</xref>], first described by the World Health Organization (WHO) on 23rd September 2012 [<xref ref-type="bibr" rid="CR2">2</xref>, <xref ref-type="bibr" rid="CR3">3</xref>], has to date (20th September 2013) caused 130 laboratory-confirmed human infections with 58 deaths (<ext-link ext-link-type="uri" xlink:href="http://www.who.int/csr/don/2013_09_20/en/index.html">http://www.who.int/csr/don/2013_09_20/en/index.html</ext-link>). MERS-CoV belongs to lineage C of the genus <italic>Betacoronavirus</italic> in the family <italic>Coronaviridae</italic>, and is closely related to <italic>Tylonycteris</italic> bat coronavirus HKU4 (BtCoV-HKU4), <italic>Pipistrellus</italic> bat coronavirus HKU5 (Bt-HKU5) [<xref ref-type="bibr" rid="CR4">4</xref>, <xref ref-type="bibr" rid="CR5">5</xref>] and CoVs in <italic>Nycteris</italic> bats [<xref ref-type="bibr" rid="CR6">6</xref>], suggestive of a bat-origin [<xref ref-type="bibr" rid="CR6">6</xref>]. Unlike severe acute respiratory syndrome (SARS) CoV which uses the angiotensin-converting enzyme 2 (ACE2) receptor for cell entry [<xref ref-type="bibr" rid="CR7">7</xref>], MERS-CoV employs the dipeptidyl peptidase 4 receptor (DPP4; also known as CD26), and recent work has demonstrated that expression of both human and bat DPP4 in non-susceptible cells enabled viral entry [<xref ref-type="bibr" rid="CR8">8</xref>].</p><p>Cell-surface receptors such as DPP4 play a key role in facilitating viral invasion and tropism. As a consequence, the long-term co-evolutionary dynamics between hosts and viruses often leave evolutionary footprints in both receptor-encoding genes of hosts and the receptor-binding domains (RBDs) of viruses in the form of positively selected amino acid residues (i.e. adaptive evolution). For example, signatures of recurrent positive selection have been observed in <italic>ACE2</italic> genes in bats [<xref ref-type="bibr" rid="CR9">9</xref>], supporting the past circulation of SARS related CoVs in bats. To better understand the origins of MERS-CoV, as well as their potentially long-term (compared to short-term which lacks virus-host interaction) evolutionary dynamics with bat hosts [<xref ref-type="bibr" rid="CR5">5</xref>, <xref ref-type="bibr" rid="CR10">10</xref>], we studied the molecular evolution of <italic>DPP4</italic> across the mammalian phylogeny.</p><p>We first analyzed the selection pressures acting on bat <italic>DPP4</italic> genes using the ratio of nonsynonymous (d<sub>N</sub>) to synonymous (d<sub>S</sub>) nucleotide substitutions per site (ratio d<sub>N</sub>/d<sub>S</sub>), with d<sub>N</sub> > d<sub>S</sub> indicative of adaptive evolution. The complete <italic>DPP4</italic> mRNA sequence of the common pipistrelle (<italic>Pipistrellus pipistrellus</italic>) was downloaded from GenBank (<ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/genbank/">http://www.ncbi.nlm.nih.gov/genbank/</ext-link>) along with that of the common vampire bat (<italic>Desmodus rotundus</italic>) from one transcriptome database (<ext-link ext-link-type="uri" xlink:href="http://www.ncbi.nlm.nih.gov/bioproject/178123">http://www.ncbi.nlm.nih.gov/bioproject/178123</ext-link>). These sequences were then used to mine and extract DPP4 mRNA transcripts from a further five bat genomes (Table <xref rid="Tab1" ref-type="table">1</xref>) using tBLASTn and GeneWise [<xref ref-type="bibr" rid="CR11">11</xref>]. The complete DPP4 genes of bats and non-bat reference genomes from a range of mammalian species (Table <xref rid="Tab1" ref-type="table">1</xref>) were aligned using MUSCLE [<xref ref-type="bibr" rid="CR12">12</xref>] guided by translated amino acid sequences (<italic>n</italic> = 32; 727 amino acids). We then compared a series of models within a maximum likelihood framework [<xref ref-type="bibr" rid="CR13">13</xref>], incorporating the published mammalian species tree [<xref ref-type="bibr" rid="CR14">14</xref>–<xref ref-type="bibr" rid="CR16">16</xref>]. This analysis (the Free Ratio model) revealed that the d<sub>N</sub>/d<sub>S</sub> value on the bat lineage (0.96) was four times greater than the mammalian average (Figure <xref rid="Fig1" ref-type="fig">1</xref>). The higher d<sub>N</sub>/d<sub>S</sub> ratios leading to bats (Table <xref rid="Tab2" ref-type="table">2</xref>) during mammalian evolution accord with the growing body of data [<xref ref-type="bibr" rid="CR5">5</xref>, <xref ref-type="bibr" rid="CR6">6</xref>, <xref ref-type="bibr" rid="CR17">17</xref>, <xref ref-type="bibr" rid="CR18">18</xref>] that the newly emerged MERS-CoV ultimately has a bat-origin.<table-wrap id="Tab1"><label>Table 1</label><caption><p><bold>Sequences used in the evolutionary analysis of</bold><bold><italic>DDP4</italic></bold></p></caption><table frame="hsides" rules="groups"><thead><tr><th>Common name</th><th>Species name</th><th>Family</th><th>Accession no.</th></tr></thead><tbody><tr><td>Sheep</td><td><italic>Ovis aries</italic></td><td>Bovidae</td><td>XM_004004660</td></tr><tr><td>Killer whale</td><td><italic>Orcinus orca</italic></td><td>Delphinidae</td><td>XM_004283621</td></tr><tr><td>Cow</td><td><italic>Bos taurus</italic></td><td>Bovidae</td><td>NM_174039</td></tr><tr><td>Pig</td><td><italic>Sus scrofa</italic></td><td>Suidae</td><td>NM_214257</td></tr><tr><td>Pacific walrus</td><td><italic>Odobenus rosmarus divergens</italic></td><td>Odobenidae</td><td>XM_004410199</td></tr><tr><td>Ferret</td><td><italic>Mustela putorius furo</italic></td><td>Mustelidae</td><td>DQ266376</td></tr><tr><td>Cat</td><td><italic>Felis catus</italic></td><td>Felidae</td><td>NM_001009838</td></tr><tr><td>Horse</td><td><italic>Equus caballus</italic></td><td>Equidae</td><td>XM_001493999</td></tr><tr><td>Rhinoceros</td><td><italic>Ceratotherium simum</italic></td><td>Rhinocerotidae</td><td>XM_004428264</td></tr><tr><td>Large flying fox</td><td><italic>Pteropus vampyrus</italic></td><td>Pteropodidae</td><td>ENSPVAG00000002634</td></tr><tr><td>Black flying fox</td><td><italic>Pteropus alecto</italic></td><td>Pteropodidae</td><td>KB031068</td></tr><tr><td>Common vampire bat</td><td><italic>Desmodus rotundus</italic></td><td>Phyllostomidae</td><td>GABZ01004546</td></tr><tr><td>Brandt’s bat</td><td><italic>Myotis brandtii</italic></td><td>Vespertilionidae</td><td>KE161360</td></tr><tr><td>David’s myotis</td><td><italic>Myotis davidii</italic></td><td>Vespertilionidae</td><td>KB109552</td></tr><tr><td>Little brown bat</td><td><italic>Myotis lucifugus</italic></td><td>Vespertilionidae</td><td>GL429772</td></tr><tr><td>Common pipistrelle</td><td><italic>Pipistrellus pipistrellus</italic></td><td>Vespertilionidae</td><td>KC249974</td></tr><tr><td>Guinea pig</td><td><italic>Cavia porcellus</italic></td><td>Caviidae</td><td>XM_003478564</td></tr><tr><td>Degu</td><td><italic>Octodon degus</italic></td><td>Octodontidae</td><td>XM_004629976</td></tr><tr><td>Lesser Egyptian jerboa</td><td><italic>Jaculus jaculus</italic></td><td>Dipodidae</td><td>XM_004651712</td></tr><tr><td>Mouse</td><td><italic>Mus musculus</italic></td><td>Muridae</td><td>BC022183</td></tr><tr><td>Rat</td><td><italic>Rattus norvegicus</italic></td><td>Muridae</td><td>NM_012789</td></tr><tr><td>Human</td><td><italic>Homo sapiens</italic></td><td>Hominidae</td><td>NM_001935</td></tr><tr><td>Chimpanzee</td><td><italic>Pan troglodytes</italic></td><td>Hominidae</td><td>GABE01002695</td></tr><tr><td>Pygmy chimpanzee</td><td><italic>Pan paniscus</italic></td><td>Hominidae</td><td>XM_003820939</td></tr><tr><td>Gorilla</td><td><italic>Gorilla gorilla gorilla</italic></td><td>Hominidae</td><td>XM_004032706</td></tr><tr><td>Orangutan</td><td><italic>Pongo abelii</italic></td><td>Hominidae</td><td>NM_001132869</td></tr><tr><td>Gibbon</td><td><italic>Nomascus leucogenys</italic></td><td>Hylobatidae</td><td>XM_003266171</td></tr><tr><td>Olive baboon</td><td><italic>Papio anubis</italic></td><td>Cercopithecidae</td><td>XM_003907539</td></tr><tr><td>Rhesus monkey</td><td><italic>Macaca mulatta</italic></td><td>Cercopithecidae</td><td>JU474559</td></tr><tr><td>Galago</td><td><italic>Otolemur garnettii</italic></td><td>Galagidae</td><td>XM_003795172</td></tr><tr><td>Marmoset</td><td>Callithrix jacchus</td><td>Cebidae</td><td>XM_002749392</td></tr><tr><td>American pika</td><td><italic>Ochotona princeps</italic></td><td>Ochotonidae</td><td>XM_004577330</td></tr></tbody></table></table-wrap><fig id="Fig1"><label>Figure 1</label><caption><p><bold>Selection pressures on</bold><bold><italic>DPP4</italic></bold><bold>during mammalian evolution.</bold> Ratios of nonsynonymous (d<sub>N</sub>) to synonymous (d<sub>S</sub>) nucleotide substitutions per site (d<sub>N</sub>/d<sub>S</sub>) are shown on four major ancestral branches; d<sub>N</sub> and d<sub>S</sub> numbers are also given in parentheses. Values for individual lineages are given in Table <xref rid="Tab2" ref-type="table">2</xref>. <italic>DPP4</italic> sequences of bat origin are shaded.</p></caption><graphic xlink:href="12985_2013_Article_2574_Fig1_HTML" id="d29e1032"></graphic></fig></p><table-wrap id="Tab2"><label>Table 2</label><caption><p><bold>Numbers of nonsynonymous (d</bold><sub><bold>N</bold></sub><bold>) and synonymous (d</bold><sub><bold>S</bold></sub><bold>) substitutions per site</bold><bold><italic>DPP4</italic></bold><bold>genes in different mammals</bold></p></caption><table frame="hsides" rules="groups"><thead><tr><th>Common name</th><th>d<sub>N</sub></th><th>d<sub>S</sub></th><th>d<sub>N</sub>/d<sub>S</sub></th></tr></thead><tbody><tr><td>Sheep</td><td>0.004</td><td>0.013</td><td>0.280</td></tr><tr><td>Killer whale</td><td>0.023</td><td>0.039</td><td>0.595</td></tr><tr><td>Cow</td><td>0.003</td><td>0.016</td><td>0.157</td></tr><tr><td>Pig</td><td>0.027</td><td>0.109</td><td>0.246</td></tr><tr><td>Pacific walrus</td><td>0.014</td><td>0.053</td><td>0.260</td></tr><tr><td>Ferret</td><td>0.015</td><td>0.064</td><td>0.235</td></tr><tr><td>Cat</td><td>0.021</td><td>0.081</td><td>0.258</td></tr><tr><td>Horse</td><td>0.016</td><td>0.055</td><td>0.290</td></tr><tr><td>Rhinoceros</td><td>0.017</td><td>0.044</td><td>0.385</td></tr><tr><td>Large flying fox</td><td>0.005</td><td>0.001</td><td>3.561</td></tr><tr><td>Black flying fox</td><td>0.004</td><td>0.008</td><td>0.487</td></tr><tr><td>Common vampire bat</td><td>0.042</td><td>0.125</td><td>0.500</td></tr><tr><td>Brandt’s bat</td><td>0.006</td><td>0.012</td><td>0.463</td></tr><tr><td>David’s myotis</td><td>0.010</td><td>0.028</td><td>0.380</td></tr><tr><td>Little brown bat</td><td>0.007</td><td>0.007</td><td>0.943</td></tr><tr><td>Common pipistrelle</td><td>0.031</td><td>0.066</td><td>0.470</td></tr><tr><td>Guinea pig</td><td>0.018</td><td>0.078</td><td>0.238</td></tr><tr><td>Degu</td><td>0.016</td><td>0.128</td><td>0.122</td></tr><tr><td>Lesser Egyptian jerboa</td><td>0.023</td><td>0.179</td><td>0.131</td></tr><tr><td>Mouse</td><td>0.019</td><td>0.093</td><td>0.206</td></tr><tr><td>Rat</td><td>0.027</td><td>0.110</td><td>0.248</td></tr><tr><td>Human</td><td>0.001</td><td>0.007</td><td>0.086</td></tr><tr><td>Chimpanzee</td><td>0.000</td><td>0.002</td><td>0.000</td></tr><tr><td>Pygmy chimpanzee</td><td>0.001</td><td>0.000</td><td>ND</td></tr><tr><td>Gorilla</td><td>0.003</td><td>0.004</td><td>0.863</td></tr><tr><td>Orangutan</td><td>0.002</td><td>0.000</td><td>ND</td></tr><tr><td>Gibbon</td><td>0.003</td><td>0.009</td><td>0.344</td></tr><tr><td>Olive baboon</td><td>0.000</td><td>0.005</td><td>0.000</td></tr><tr><td>Rhesus monkey</td><td>0.000</td><td>0.004</td><td>0.000</td></tr><tr><td>Galago</td><td>0.022</td><td>0.149</td><td>0.149</td></tr><tr><td>Marmoset</td><td>0.009</td><td>0.053</td><td>0.160</td></tr><tr><td>American pika</td><td>0.036</td><td>0.229</td><td>0.156</td></tr></tbody></table><table-wrap-foot><p>ND: Not determined because no synonymous substitutions are present.</p></table-wrap-foot></table-wrap><p>We next analysed the selection pressures at individual amino acid sites in bat DPP4. Using the Bayesian FUBAR method [<xref ref-type="bibr" rid="CR19">19</xref>] in HyPhy package [<xref ref-type="bibr" rid="CR20">20</xref>], we identified six codons that were assigned d<sub>N</sub>/d<sub>S</sub> > 1 with higher posterior probability (a strict cut-off of 95% in this analysis) (Table <xref rid="Tab3" ref-type="table">3</xref>). To identify those sites under positive selection that may interact directly with MERS-CoV-like spike protein, bat DPP4 (from the common pipistrelle) was modelled against the structure of the human DPP4/MERS-CoV spike complex [<xref ref-type="bibr" rid="CR21">21</xref>] (Figure <xref rid="Fig2" ref-type="fig">2</xref>A). This revealed that three of the six positive selected residues (position 187, 288 and 392) were located at the interface between bat DPP4 and MERS-CoV RBD (receptor binding domain) (Figure <xref rid="Fig2" ref-type="fig">2</xref>). These residues therefore provide direct evidence of a long-term co-evolutionary history between viruses and their hosts. We also observed several variable regions (Figure <xref rid="Fig2" ref-type="fig">2</xref>B) within the bat RBD, that may also have resulted from virally-induced selection pressure and which merit additional investigation in a larger data set.<table-wrap id="Tab3"><label>Table 3</label><caption><p><bold>Putatively positive selected</bold><bold><italic>DPP4</italic></bold><bold>codons in bats</bold></p></caption><table frame="hsides" rules="groups"><thead><tr><th>Codon position<sup><italic>a</italic></sup></th><th>Posterior probability<sup><italic>b</italic></sup></th><th>d<sub>N</sub>/d<sub>S</sub></th></tr></thead><tbody><tr><td>46</td><td>0.97</td><td>14.95</td></tr><tr><td>57</td><td>0.97</td><td>13.13</td></tr><tr><td>112</td><td>0.94</td><td>10.27</td></tr><tr><td>187</td><td>0.95</td><td>8.55</td></tr><tr><td>288</td><td>0.98</td><td>13.90</td></tr><tr><td>392</td><td>0.97</td><td>14.63</td></tr></tbody></table><table-wrap-foot><p><sup><italic>a</italic></sup>Codon position corresponding to the human DPP4 (NP_001926) protein sequence.</p><p><sup><italic>b</italic></sup>Posterior probability of residues assigned a d<sub>N</sub>/d<sub>S</sub> ratio greater than 1.</p></table-wrap-foot></table-wrap><fig id="Fig2"><label>Figure 2</label><caption><p><bold>Interaction of bat DPP4 and MERS-CoV spike protein receptor-binding domain and the location of positively selected sites.</bold> The structure was displayed using PyMol v1.6 (<ext-link ext-link-type="uri" xlink:href="http://www.pymol.org/">http://www.pymol.org/</ext-link>). <bold>(A)</bold> Homology model showing the structural interactions between bat DPP4 (from common pipistrelle) coloured grey and MERS-CoV spike protein receptor-binding domain coloured blue. The three positively selected residues (positions 187, 288 and 392) located within the interface where the virus-host interact are highlighted as red. <bold>(B)</bold> Protein alignment of human DPP4 compared to that of seven bat species showing RBD spanning codons 41 – 400. Conserved and variable positions are shown in black and grey text, respectively, and residues under positive selection are coloured red.</p></caption><graphic xlink:href="12985_2013_Article_2574_Fig2_HTML" id="d29e1685"></graphic></fig></p><p>Our analysis therefore suggests that the evolutionary lineage leading to current MERS-CoV co-evolved with bat hosts for an extended time period, eventually jumping species boundaries to infect humans and perhaps through an intermediate host. As such, the emergence of MERS-CoV may parallel that of the related SARS-CoV [<xref ref-type="bibr" rid="CR22">22</xref>]. Although one bat species, <italic>Taphozous erforatus</italic>, in Saudi Arabia has been found to harbour a small <italic>RdRp</italic> (RNA-Dependent RNA Polymerase) fragment of MERS-CoV [<xref ref-type="bibr" rid="CR17">17</xref>], a larger viral sampling of bats and other animals with close exposure to humans, including dromedary camels were serological evidence for MERS-CoV has been identified [<xref ref-type="bibr" rid="CR23">23</xref>], are clearly needed to better understand the viral transmission route. Alternatively, it is possible that the adaptive evolution present on the bat DPP4 was due to viruses other than MERS-CoVs, and which will need to be better assessed when a larger number of viruses are available for analysis. Overall, our study provides evidence that a long-term evolutionary arms race likely occurred between MERS related CoVs and bats.</p></sec></body><back><app-group><app id="App1"><sec id="Sec2"><title>Authors’ original submitted files for images</title><p>Below are the links to the authors’ original submitted files for images.<media position="anchor" xlink:href="12985_2013_2574_MOESM1_ESM.pdf" id="MOESM1"><caption><p>Authors’ original file for figure 1</p></caption></media><media position="anchor" xlink:href="12985_2013_2574_MOESM2_ESM.tif" id="MOESM2"><caption><p>Authors’ original file for figure 2</p></caption></media></p></sec></app></app-group><fn-group><fn><p><bold>Competing interests</bold></p><p>The authors declare that they have no competing interests.</p></fn><fn><p><bold>Authors’ contributions</bold></p><p>JC and LFW designed the research. JC and JSE analysed the data. JC and ECH drafted the manuscript. All authors read and approved the final manuscript.</p></fn></fn-group><ack><title>Acknowledgements</title><p>We thank Christopher Cowled at CSIRO Australian Animal Health Laboratory for annotating the <italic>Pterous aleco DPP4</italic>. This word was supported in part by a grant from the National Research Foundation, Singapore (NRF2012NRF-CRP-001-056) and the CSIRO Office of the Chief Executive Science Leaders Award. 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