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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Extensive Positive Selection Drives the Evolution of Nonstructural Proteins in Lineage C Betacoronaviruses</title><author><name sortKey="Forni, Diego" sort="Forni, Diego" uniqKey="Forni D" first="Diego" last="Forni">Diego Forni</name><affiliation><nlm:aff id="aff1">Scientific Institute IRCCS E. Medea, Bioinformatics, Bosisio Parini, Italy</nlm:aff></affiliation></author><author><name sortKey="Cagliani, Rachele" sort="Cagliani, Rachele" uniqKey="Cagliani R" first="Rachele" last="Cagliani">Rachele Cagliani</name><affiliation><nlm:aff id="aff1">Scientific Institute IRCCS E. Medea, Bioinformatics, Bosisio Parini, Italy</nlm:aff></affiliation></author><author><name sortKey="Mozzi, Alessandra" sort="Mozzi, Alessandra" uniqKey="Mozzi A" first="Alessandra" last="Mozzi">Alessandra Mozzi</name><affiliation><nlm:aff id="aff1">Scientific Institute IRCCS E. Medea, Bioinformatics, Bosisio Parini, Italy</nlm:aff></affiliation></author><author><name sortKey="Pozzoli, Uberto" sort="Pozzoli, Uberto" uniqKey="Pozzoli U" first="Uberto" last="Pozzoli">Uberto Pozzoli</name><affiliation><nlm:aff id="aff1">Scientific Institute IRCCS E. Medea, Bioinformatics, Bosisio Parini, Italy</nlm:aff></affiliation></author><author><name sortKey="Al Daghri, Nasser" sort="Al Daghri, Nasser" uniqKey="Al Daghri N" first="Nasser" last="Al-Daghri">Nasser Al-Daghri</name><affiliation><nlm:aff id="aff2">Biomarker Research Program, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Prince Mutaib Chair for Biomarkers of Osteoporosis, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Clerici, Mario" sort="Clerici, Mario" uniqKey="Clerici M" first="Mario" last="Clerici">Mario Clerici</name><affiliation><nlm:aff id="aff4">Department of Physiopathology and Transplantation, University of Milan, Milan, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Don C. Gnocchi Foundation ONLUS, IRCCS, Milan, Italy</nlm:aff></affiliation></author><author><name sortKey="Sironi, Manuela" sort="Sironi, Manuela" uniqKey="Sironi M" first="Manuela" last="Sironi">Manuela Sironi</name><affiliation><nlm:aff id="aff1">Scientific Institute IRCCS E. Medea, Bioinformatics, Bosisio Parini, Italy</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26792741</idno><idno type="pmc">4794664</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794664</idno><idno type="RBID">PMC:4794664</idno><idno type="doi">10.1128/JVI.02988-15</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000020</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000020</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Extensive Positive Selection Drives the Evolution of Nonstructural Proteins in Lineage C Betacoronaviruses</title><author><name sortKey="Forni, Diego" sort="Forni, Diego" uniqKey="Forni D" first="Diego" last="Forni">Diego Forni</name><affiliation><nlm:aff id="aff1">Scientific Institute IRCCS E. Medea, Bioinformatics, Bosisio Parini, Italy</nlm:aff></affiliation></author><author><name sortKey="Cagliani, Rachele" sort="Cagliani, Rachele" uniqKey="Cagliani R" first="Rachele" last="Cagliani">Rachele Cagliani</name><affiliation><nlm:aff id="aff1">Scientific Institute IRCCS E. Medea, Bioinformatics, Bosisio Parini, Italy</nlm:aff></affiliation></author><author><name sortKey="Mozzi, Alessandra" sort="Mozzi, Alessandra" uniqKey="Mozzi A" first="Alessandra" last="Mozzi">Alessandra Mozzi</name><affiliation><nlm:aff id="aff1">Scientific Institute IRCCS E. Medea, Bioinformatics, Bosisio Parini, Italy</nlm:aff></affiliation></author><author><name sortKey="Pozzoli, Uberto" sort="Pozzoli, Uberto" uniqKey="Pozzoli U" first="Uberto" last="Pozzoli">Uberto Pozzoli</name><affiliation><nlm:aff id="aff1">Scientific Institute IRCCS E. Medea, Bioinformatics, Bosisio Parini, Italy</nlm:aff></affiliation></author><author><name sortKey="Al Daghri, Nasser" sort="Al Daghri, Nasser" uniqKey="Al Daghri N" first="Nasser" last="Al-Daghri">Nasser Al-Daghri</name><affiliation><nlm:aff id="aff2">Biomarker Research Program, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Prince Mutaib Chair for Biomarkers of Osteoporosis, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia</nlm:aff></affiliation></author><author><name sortKey="Clerici, Mario" sort="Clerici, Mario" uniqKey="Clerici M" first="Mario" last="Clerici">Mario Clerici</name><affiliation><nlm:aff id="aff4">Department of Physiopathology and Transplantation, University of Milan, Milan, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="aff5">Don C. Gnocchi Foundation ONLUS, IRCCS, Milan, Italy</nlm:aff></affiliation></author><author><name sortKey="Sironi, Manuela" sort="Sironi, Manuela" uniqKey="Sironi M" first="Manuela" last="Sironi">Manuela Sironi</name><affiliation><nlm:aff id="aff1">Scientific Institute IRCCS E. Medea, Bioinformatics, Bosisio Parini, Italy</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Virology</title><idno type="ISSN">0022-538X</idno><idno type="eISSN">1098-5514</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>ABSTRACT</title><p>Middle East respiratory syndrome-related coronavirus (MERS-CoV) spreads to humans via zoonotic transmission from camels. MERS-CoV belongs to lineage C of betacoronaviruses (betaCoVs), which also includes viruses isolated from bats and hedgehogs. A large portion of the betaCoV genome consists of two open reading frames (ORF1a and ORF1b) that are translated into polyproteins. These are cleaved by viral proteases to generate 16 nonstructural proteins (nsp1 to nsp16) which compose the viral replication-transcription complex. We investigated the evolution of ORF1a and ORF1b in lineage C betaCoVs. Results indicated widespread positive selection, acting mostly on ORF1a. The proportion of positively selected sites in ORF1a was much higher than that previously reported for the surface-exposed spike protein. Selected sites were unevenly distributed, with nsp3 representing the preferential target. Several pairs of coevolving sites were also detected, possibly indicating epistatic interactions; most of these were located in nsp3. Adaptive evolution at nsp3 is ongoing in MERS-CoV strains, and two selected sites (G720 and R911) were detected in the protease domain. While position 720 is variable in camel-derived viruses, suggesting that the selective event does not represent a specific adaptation to humans, the R911C substitution was observed only in human-derived MERS-CoV isolates, including the viral strain responsible for the recent South Korean outbreak. It will be extremely important to assess whether these changes affect host range or other viral phenotypes. More generally, data herein indicate that CoV nsp3 represents a major selection target and that nsp3 sequencing should be envisaged in monitoring programs and field surveys.
</p><p><bold>IMPORTANCE</bold> Both severe acute respiratory syndrome coronavirus (SARS-CoV) and MERS-CoV originated in bats and spread to humans via an intermediate host. This clearly highlights the potential for coronavirus host shifting and the relevance of understanding the molecular events underlying the adaptation to new host species. We investigated the evolution of ORF1a and ORF1b in lineage C betaCoVs and in 87 sequenced MERS-CoV isolates. Results indicated widespread positive selection, stronger in ORF1a than in ORF1b. Several selected sites were found to be located in functionally relevant protein regions, and some of them corresponded to functional mutations in other coronaviruses. The proportion of selected sites we identified in ORF1a is much higher than that for the surface-exposed spike protein. This observation suggests that adaptive evolution in ORF1a might contribute to host shifts or immune evasion. Data herein also indicate that genetic diversity at nonstructural proteins should be taken into account when antiviral compounds are developed.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Virol</journal-id><journal-id journal-id-type="iso-abbrev">J. Virol</journal-id><journal-id journal-id-type="hwp">jvi</journal-id><journal-id journal-id-type="pmc">jvi</journal-id><journal-id journal-id-type="publisher-id">JVI</journal-id><journal-title-group><journal-title>Journal of Virology</journal-title></journal-title-group><issn pub-type="ppub">0022-538X</issn><issn pub-type="epub">1098-5514</issn><publisher><publisher-name>American Society for Microbiology</publisher-name><publisher-loc>1752 N St., N.W., Washington, DC</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26792741</article-id><article-id pub-id-type="pmc">4794664</article-id><article-id pub-id-type="publisher-id">02988-15</article-id><article-id pub-id-type="doi">10.1128/JVI.02988-15</article-id><article-categories><subj-group subj-group-type="heading"><subject>Genetic Diversity and Evolution</subject></subj-group><subj-group subj-group-type="editorial-class"><subject>Spotlight</subject></subj-group></article-categories><title-group><article-title>Extensive Positive Selection Drives the Evolution of Nonstructural Proteins in Lineage C Betacoronaviruses</article-title><alt-title alt-title-type="running-head">Positive Selection at MERS-CoV Nonstructural Proteins</alt-title><alt-title alt-title-type="short-authors">Forni et al.</alt-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Forni</surname><given-names>Diego</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cagliani</surname><given-names>Rachele</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mozzi</surname><given-names>Alessandra</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pozzoli</surname><given-names>Uberto</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Al-Daghri</surname><given-names>Nasser</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Clerici</surname><given-names>Mario</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sironi</surname><given-names>Manuela</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><aff id="aff1"><label>a</label>Scientific Institute IRCCS E. Medea, Bioinformatics, Bosisio Parini, Italy</aff><aff id="aff2"><label>b</label>Biomarker Research Program, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia</aff><aff id="aff3"><label>c</label>Prince Mutaib Chair for Biomarkers of Osteoporosis, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia</aff><aff id="aff4"><label>d</label>Department of Physiopathology and Transplantation, University of Milan, Milan, Italy</aff><aff id="aff5"><label>e</label>Don C. Gnocchi Foundation ONLUS, IRCCS, Milan, Italy</aff></contrib-group><contrib-group><contrib contrib-type="editor"><name><surname>Perlman</surname><given-names>S.</given-names></name><role>Editor</role></contrib></contrib-group><author-notes><corresp id="cor1">Address correspondence to Diego Forni, <email>diego.forni@bp.lnf.it</email>.</corresp><fn fn-type="other"><p><bold>Citation</bold> Forni D, Cagliani R, Mozzi A, Pozzoli U, Al-Daghri N, Clerici M, Sironi M. 2016. Extensive positive selection drives the evolution of nonstructural proteins in lineage C betacoronaviruses. J Virol 90:3627–3639. doi:<ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.1128/JVI.02988-15">10.1128/JVI.02988-15</ext-link>.</p></fn></author-notes><pub-date pub-type="epreprint"><day>20</day><month>1</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>11</day><month>3</month><year>2016</year></pub-date><pub-date pub-type="collection"><day>1</day><month>4</month><year>2016</year></pub-date><volume>90</volume><issue>7</issue><fpage>3627</fpage><lpage>3639</lpage><history><date date-type="received"><day>25</day><month>11</month><year>2015</year></date><date date-type="accepted"><day>12</day><month>1</month><year>2016</year></date></history><permissions><copyright-statement>Copyright © 2016, American Society for Microbiology. All Rights Reserved.</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>American Society for Microbiology</copyright-holder></permissions><self-uri content-type="pdf" xlink:href="zjv00716003627.pdf"></self-uri><abstract><title>ABSTRACT</title><p>Middle East respiratory syndrome-related coronavirus (MERS-CoV) spreads to humans via zoonotic transmission from camels. MERS-CoV belongs to lineage C of betacoronaviruses (betaCoVs), which also includes viruses isolated from bats and hedgehogs. A large portion of the betaCoV genome consists of two open reading frames (ORF1a and ORF1b) that are translated into polyproteins. These are cleaved by viral proteases to generate 16 nonstructural proteins (nsp1 to nsp16) which compose the viral replication-transcription complex. We investigated the evolution of ORF1a and ORF1b in lineage C betaCoVs. Results indicated widespread positive selection, acting mostly on ORF1a. The proportion of positively selected sites in ORF1a was much higher than that previously reported for the surface-exposed spike protein. Selected sites were unevenly distributed, with nsp3 representing the preferential target. Several pairs of coevolving sites were also detected, possibly indicating epistatic interactions; most of these were located in nsp3. Adaptive evolution at nsp3 is ongoing in MERS-CoV strains, and two selected sites (G720 and R911) were detected in the protease domain. While position 720 is variable in camel-derived viruses, suggesting that the selective event does not represent a specific adaptation to humans, the R911C substitution was observed only in human-derived MERS-CoV isolates, including the viral strain responsible for the recent South Korean outbreak. It will be extremely important to assess whether these changes affect host range or other viral phenotypes. More generally, data herein indicate that CoV nsp3 represents a major selection target and that nsp3 sequencing should be envisaged in monitoring programs and field surveys.
</p><p><bold>IMPORTANCE</bold> Both severe acute respiratory syndrome coronavirus (SARS-CoV) and MERS-CoV originated in bats and spread to humans via an intermediate host. This clearly highlights the potential for coronavirus host shifting and the relevance of understanding the molecular events underlying the adaptation to new host species. We investigated the evolution of ORF1a and ORF1b in lineage C betaCoVs and in 87 sequenced MERS-CoV isolates. Results indicated widespread positive selection, stronger in ORF1a than in ORF1b. Several selected sites were found to be located in functionally relevant protein regions, and some of them corresponded to functional mutations in other coronaviruses. The proportion of selected sites we identified in ORF1a is much higher than that for the surface-exposed spike protein. This observation suggests that adaptive evolution in ORF1a might contribute to host shifts or immune evasion. Data herein also indicate that genetic diversity at nonstructural proteins should be taken into account when antiviral compounds are developed.</p></abstract><counts><fig-count count="5"></fig-count><table-count count="2"></table-count><equation-count count="0"></equation-count><ref-count count="80"></ref-count><page-count count="13"></page-count><word-count count="9457"></word-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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