POLRMT regulates the switch between replication primer formation and gene expression of mammalian mtDNA.
Identifieur interne : 001929 ( PubMed/Checkpoint ); précédent : 001928; suivant : 001930POLRMT regulates the switch between replication primer formation and gene expression of mammalian mtDNA.
Auteurs : Inge Kühl [Allemagne] ; Maria Miranda [Allemagne] ; Viktor Posse [Suède] ; Dusanka Milenkovic [Allemagne] ; Arnaud Mourier [France] ; Stefan J. Siira [Australie] ; Nina A. Bonekamp [Allemagne] ; Ulla Neumann [Allemagne] ; Aleksandra Filipovska [Australie] ; Paola Loguercio Polosa [Italie] ; Claes M. Gustafsson [Suède] ; Nils-Göran Larsson [Suède]Source :
- Science advances [ 2375-2548 ] ; 2016.
Descripteurs français
- KwdFr :
- MESH :
English descriptors
- KwdEn :
- MESH :
- chemical , genetics : DNA, Mitochondrial, DNA-Binding Proteins, DNA-Directed RNA Polymerases, High Mobility Group Proteins.
- genetics : DNA Replication.
- Animals, Gene Expression Regulation, Genome, Mitochondrial, Mice, Transcription, Genetic.
Abstract
Mitochondria are vital in providing cellular energy via their oxidative phosphorylation system, which requires the coordinated expression of genes encoded by both the nuclear and mitochondrial genomes (mtDNA). Transcription of the circular mammalian mtDNA depends on a single mitochondrial RNA polymerase (POLRMT). Although the transcription initiation process is well understood, it is debated whether POLRMT also serves as the primase for the initiation of mtDNA replication. In the nucleus, the RNA polymerases needed for gene expression have no such role. Conditional knockout of Polrmt in the heart results in severe mitochondrial dysfunction causing dilated cardiomyopathy in young mice. We further studied the molecular consequences of different expression levels of POLRMT and found that POLRMT is essential for primer synthesis to initiate mtDNA replication in vivo. Furthermore, transcription initiation for primer formation has priority over gene expression. Surprisingly, mitochondrial transcription factor A (TFAM) exists in an mtDNA-free pool in the Polrmt knockout mice. TFAM levels remain unchanged despite strong mtDNA depletion, and TFAM is thus protected from degradation of the AAA(+) Lon protease in the absence of POLRMT. Last, we report that mitochondrial transcription elongation factor may compensate for a partial depletion of POLRMT in heterozygous Polrmt knockout mice, indicating a direct regulatory role of this factor in transcription. In conclusion, we present in vivo evidence that POLRMT has a key regulatory role in the replication of mammalian mtDNA and is part of a transcriptional mechanism that provides a switch between primer formation for mtDNA replication and mitochondrial gene expression.
DOI: 10.1126/sciadv.1600963
PubMed: 27532055
Affiliations:
- Allemagne, Australie, France, Italie, Suède
- District de Cologne, Rhénanie-du-Nord-Westphalie, Svealand
- Cologne, Stockholm
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Université de Bordeaux and the Centre National de la Recherche Scientifique, Institut de Biochimie et Génétique Cellulaires UMR 5095, Saint-Saëns, F-33077 Bordeaux, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.; Université de Bordeaux and the Centre National de la Recherche Scientifique, Institut de Biochimie et Génétique Cellulaires UMR 5095, Saint-Saëns, F-33077 Bordeaux</wicri:regionArea><wicri:noRegion>33077 Bordeaux</wicri:noRegion><wicri:noRegion>33077 Bordeaux</wicri:noRegion></affiliation></author><author><name sortKey="Siira, Stefan J" sort="Siira, Stefan J" uniqKey="Siira S" first="Stefan J" last="Siira">Stefan J. Siira</name><affiliation wicri:level="1"><nlm:affiliation>Harry Perkins Institute of Medical Research, Centre for Medical Research and School of Chemistry and Biochemistry, The University of Western Australia, Perth 6009, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Harry Perkins Institute of Medical Research, Centre for Medical Research and School of Chemistry and Biochemistry, The University of Western Australia, Perth 6009</wicri:regionArea><wicri:noRegion>Perth 6009</wicri:noRegion></affiliation></author><author><name sortKey="Bonekamp, Nina A" sort="Bonekamp, Nina A" uniqKey="Bonekamp N" first="Nina A" last="Bonekamp">Nina A. Bonekamp</name><affiliation wicri:level="3"><nlm:affiliation>Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 50931 Cologne</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Cologne</settlement></placeName></affiliation></author><author><name sortKey="Neumann, Ulla" sort="Neumann, Ulla" uniqKey="Neumann U" first="Ulla" last="Neumann">Ulla Neumann</name><affiliation wicri:level="3"><nlm:affiliation>Central Microscopy, Max Planck Institute for Plant Breeding Research, 50829 Cologne, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Central Microscopy, Max Planck Institute for Plant Breeding Research, 50829 Cologne</wicri:regionArea><placeName><region type="land" nuts="1">Rhénanie-du-Nord-Westphalie</region><region type="district" nuts="2">District de Cologne</region><settlement type="city">Cologne</settlement></placeName></affiliation></author><author><name sortKey="Filipovska, Aleksandra" sort="Filipovska, Aleksandra" uniqKey="Filipovska A" first="Aleksandra" last="Filipovska">Aleksandra Filipovska</name><affiliation wicri:level="1"><nlm:affiliation>Harry Perkins Institute of Medical Research, Centre for Medical Research and School of Chemistry and Biochemistry, The University of Western Australia, Perth 6009, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Harry Perkins Institute of Medical Research, Centre for Medical Research and School of Chemistry and Biochemistry, The University of Western Australia, Perth 6009</wicri:regionArea><wicri:noRegion>Perth 6009</wicri:noRegion></affiliation></author><author><name sortKey="Polosa, Paola Loguercio" sort="Polosa, Paola Loguercio" uniqKey="Polosa P" first="Paola Loguercio" last="Polosa">Paola Loguercio Polosa</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari Aldo Moro, 70125 Bari, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari Aldo Moro, 70125 Bari</wicri:regionArea><wicri:noRegion>70125 Bari</wicri:noRegion></affiliation></author><author><name sortKey="Gustafsson, Claes M" sort="Gustafsson, Claes M" uniqKey="Gustafsson C" first="Claes M" last="Gustafsson">Claes M. Gustafsson</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medical Biochemistry and Cell Biology, Göteborgs Universitet, 40530 Göteborg, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Medical Biochemistry and Cell Biology, Göteborgs Universitet, 40530 Göteborg</wicri:regionArea><wicri:noRegion>40530 Göteborg</wicri:noRegion></affiliation></author><author><name sortKey="Larsson, Nils Goran" sort="Larsson, Nils Goran" uniqKey="Larsson N" first="Nils-Göran" last="Larsson">Nils-Göran Larsson</name><affiliation wicri:level="1"><nlm:affiliation>Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author></analytic><series><title level="j">Science advances</title><idno type="eISSN">2375-2548</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>DNA Replication (genetics)</term><term>DNA, Mitochondrial (genetics)</term><term>DNA-Binding Proteins (genetics)</term><term>DNA-Directed RNA Polymerases (genetics)</term><term>Gene Expression Regulation</term><term>Genome, Mitochondrial</term><term>High Mobility Group Proteins (genetics)</term><term>Mice</term><term>Transcription, Genetic</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>ADN mitochondrial (génétique)</term><term>Animaux</term><term>DNA-directed RNA polymerases (génétique)</term><term>Génome mitochondrial</term><term>Protéines HMG (génétique)</term><term>Protéines de liaison à l'ADN (génétique)</term><term>Régulation de l'expression des gènes</term><term>Réplication de l'ADN (génétique)</term><term>Souris</term><term>Transcription génétique</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>DNA, Mitochondrial</term><term>DNA-Binding Proteins</term><term>DNA-Directed RNA Polymerases</term><term>High Mobility Group Proteins</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>DNA Replication</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>ADN mitochondrial</term><term>DNA-directed RNA polymerases</term><term>Protéines HMG</term><term>Protéines de liaison à l'ADN</term><term>Réplication de l'ADN</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Gene Expression Regulation</term><term>Genome, Mitochondrial</term><term>Mice</term><term>Transcription, Genetic</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Génome mitochondrial</term><term>Régulation de l'expression des gènes</term><term>Souris</term><term>Transcription génétique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Mitochondria are vital in providing cellular energy via their oxidative phosphorylation system, which requires the coordinated expression of genes encoded by both the nuclear and mitochondrial genomes (mtDNA). Transcription of the circular mammalian mtDNA depends on a single mitochondrial RNA polymerase (POLRMT). Although the transcription initiation process is well understood, it is debated whether POLRMT also serves as the primase for the initiation of mtDNA replication. In the nucleus, the RNA polymerases needed for gene expression have no such role. Conditional knockout of Polrmt in the heart results in severe mitochondrial dysfunction causing dilated cardiomyopathy in young mice. We further studied the molecular consequences of different expression levels of POLRMT and found that POLRMT is essential for primer synthesis to initiate mtDNA replication in vivo. Furthermore, transcription initiation for primer formation has priority over gene expression. Surprisingly, mitochondrial transcription factor A (TFAM) exists in an mtDNA-free pool in the Polrmt knockout mice. TFAM levels remain unchanged despite strong mtDNA depletion, and TFAM is thus protected from degradation of the AAA(+) Lon protease in the absence of POLRMT. Last, we report that mitochondrial transcription elongation factor may compensate for a partial depletion of POLRMT in heterozygous Polrmt knockout mice, indicating a direct regulatory role of this factor in transcription. In conclusion, we present in vivo evidence that POLRMT has a key regulatory role in the replication of mammalian mtDNA and is part of a transcriptional mechanism that provides a switch between primer formation for mtDNA replication and mitochondrial gene expression.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">27532055</PMID><DateCreated><Year>2016</Year><Month>08</Month><Day>17</Day></DateCreated><DateCompleted><Year>2017</Year><Month>07</Month><Day>31</Day></DateCompleted><DateRevised><Year>2017</Year><Month>07</Month><Day>31</Day></DateRevised><Article PubModel="Electronic-eCollection"><Journal><ISSN IssnType="Electronic">2375-2548</ISSN><JournalIssue CitedMedium="Internet"><Volume>2</Volume><Issue>8</Issue><PubDate><Year>2016</Year><Month>08</Month></PubDate></JournalIssue><Title>Science advances</Title><ISOAbbreviation>Sci Adv</ISOAbbreviation></Journal><ArticleTitle>POLRMT regulates the switch between replication primer formation and gene expression of mammalian mtDNA.</ArticleTitle><Pagination><MedlinePgn>e1600963</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1126/sciadv.1600963</ELocationID><Abstract><AbstractText>Mitochondria are vital in providing cellular energy via their oxidative phosphorylation system, which requires the coordinated expression of genes encoded by both the nuclear and mitochondrial genomes (mtDNA). Transcription of the circular mammalian mtDNA depends on a single mitochondrial RNA polymerase (POLRMT). Although the transcription initiation process is well understood, it is debated whether POLRMT also serves as the primase for the initiation of mtDNA replication. In the nucleus, the RNA polymerases needed for gene expression have no such role. Conditional knockout of Polrmt in the heart results in severe mitochondrial dysfunction causing dilated cardiomyopathy in young mice. We further studied the molecular consequences of different expression levels of POLRMT and found that POLRMT is essential for primer synthesis to initiate mtDNA replication in vivo. Furthermore, transcription initiation for primer formation has priority over gene expression. Surprisingly, mitochondrial transcription factor A (TFAM) exists in an mtDNA-free pool in the Polrmt knockout mice. TFAM levels remain unchanged despite strong mtDNA depletion, and TFAM is thus protected from degradation of the AAA(+) Lon protease in the absence of POLRMT. Last, we report that mitochondrial transcription elongation factor may compensate for a partial depletion of POLRMT in heterozygous Polrmt knockout mice, indicating a direct regulatory role of this factor in transcription. In conclusion, we present in vivo evidence that POLRMT has a key regulatory role in the replication of mammalian mtDNA and is part of a transcriptional mechanism that provides a switch between primer formation for mtDNA replication and mitochondrial gene expression.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Kühl</LastName><ForeName>Inge</ForeName><Initials>I</Initials><AffiliationInfo><Affiliation>Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Miranda</LastName><ForeName>Maria</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Posse</LastName><ForeName>Viktor</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Department of Medical Biochemistry and Cell Biology, Göteborgs Universitet, 40530 Göteborg, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Milenkovic</LastName><ForeName>Dusanka</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mourier</LastName><ForeName>Arnaud</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.; Université de Bordeaux and the Centre National de la Recherche Scientifique, Institut de Biochimie et Génétique Cellulaires UMR 5095, Saint-Saëns, F-33077 Bordeaux, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Siira</LastName><ForeName>Stefan J</ForeName><Initials>SJ</Initials><Identifier Source="ORCID">0000-0002-8391-0143</Identifier><AffiliationInfo><Affiliation>Harry Perkins Institute of Medical Research, Centre for Medical Research and School of Chemistry and Biochemistry, The University of Western Australia, Perth 6009, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bonekamp</LastName><ForeName>Nina A</ForeName><Initials>NA</Initials><AffiliationInfo><Affiliation>Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Neumann</LastName><ForeName>Ulla</ForeName><Initials>U</Initials><AffiliationInfo><Affiliation>Central Microscopy, Max Planck Institute for Plant Breeding Research, 50829 Cologne, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Filipovska</LastName><ForeName>Aleksandra</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Harry Perkins Institute of Medical Research, Centre for Medical Research and School of Chemistry and Biochemistry, The University of Western Australia, Perth 6009, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Polosa</LastName><ForeName>Paola Loguercio</ForeName><Initials>PL</Initials><AffiliationInfo><Affiliation>Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari Aldo Moro, 70125 Bari, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gustafsson</LastName><ForeName>Claes M</ForeName><Initials>CM</Initials><AffiliationInfo><Affiliation>Department of Medical Biochemistry and Cell Biology, Göteborgs Universitet, 40530 Göteborg, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Larsson</LastName><ForeName>Nils-Göran</ForeName><Initials>NG</Initials><AffiliationInfo><Affiliation>Department of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><Agency>Medical Research Council</Agency><Country>United Kingdom</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2016</Year><Month>08</Month><Day>05</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Sci Adv</MedlineTA><NlmUniqueID>101653440</NlmUniqueID><ISSNLinking>2375-2548</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004272">DNA, Mitochondrial</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004268">DNA-Binding Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D006609">High Mobility Group Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C081930">Tfam protein, mouse</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.7.6</RegistryNumber><NameOfSubstance UI="D012321">DNA-Directed RNA Polymerases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.7.6</RegistryNumber><NameOfSubstance UI="C000588975">Polrmt protein, mouse</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="Cites"><RefSource>J Biol Chem. 2013 Oct 25;288(43):31386-99</RefSource><PMID Version="1">24036117</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Annu Rev Biochem. 2007;76:679-99</RefSource><PMID Version="1">17408359</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Biochem 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MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004261" MajorTopicYN="N">DNA Replication</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004272" MajorTopicYN="N">DNA, Mitochondrial</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004268" MajorTopicYN="N">DNA-Binding Proteins</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012321" MajorTopicYN="N">DNA-Directed RNA Polymerases</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005786" MajorTopicYN="N">Gene Expression Regulation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D054629" MajorTopicYN="N">Genome, Mitochondrial</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006609" MajorTopicYN="N">High Mobility Group Proteins</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014158" MajorTopicYN="Y">Transcription, Genetic</DescriptorName></MeshHeading></MeshHeadingList><OtherID Source="NLM">PMC4975551</OtherID><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">7S RNA</Keyword><Keyword MajorTopicYN="Y">Mitochondria</Keyword><Keyword MajorTopicYN="Y">POLRMT knockout mouse</Keyword><Keyword MajorTopicYN="Y">light strand promoter</Keyword><Keyword MajorTopicYN="Y">mitochondrial RNA polymerase</Keyword><Keyword MajorTopicYN="Y">mitochondrial gene expression</Keyword><Keyword MajorTopicYN="Y">mtDNA</Keyword><Keyword MajorTopicYN="Y">mtDNA replication</Keyword><Keyword MajorTopicYN="Y">mtDNA-free TFAM pool</Keyword><Keyword MajorTopicYN="Y">twinkle</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2016</Year><Month>05</Month><Day>02</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2016</Year><Month>07</Month><Day>01</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2016</Year><Month>8</Month><Day>18</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2016</Year><Month>8</Month><Day>18</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2017</Year><Month>8</Month><Day>2</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">27532055</ArticleId><ArticleId IdType="doi">10.1126/sciadv.1600963</ArticleId><ArticleId IdType="pii">1600963</ArticleId><ArticleId IdType="pmc">PMC4975551</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Allemagne</li><li>Australie</li><li>France</li><li>Italie</li><li>Suède</li></country><region><li>District de Cologne</li><li>Rhénanie-du-Nord-Westphalie</li><li>Svealand</li></region><settlement><li>Cologne</li><li>Stockholm</li></settlement></list><tree><country name="Allemagne"><region name="Rhénanie-du-Nord-Westphalie"><name sortKey="Kuhl, Inge" sort="Kuhl, Inge" uniqKey="Kuhl I" first="Inge" last="Kühl">Inge Kühl</name></region><name sortKey="Bonekamp, Nina A" sort="Bonekamp, Nina A" uniqKey="Bonekamp N" first="Nina A" last="Bonekamp">Nina A. Bonekamp</name><name sortKey="Milenkovic, Dusanka" sort="Milenkovic, Dusanka" uniqKey="Milenkovic D" first="Dusanka" last="Milenkovic">Dusanka Milenkovic</name><name sortKey="Miranda, Maria" sort="Miranda, Maria" uniqKey="Miranda M" first="Maria" last="Miranda">Maria Miranda</name><name sortKey="Neumann, Ulla" sort="Neumann, Ulla" uniqKey="Neumann U" first="Ulla" last="Neumann">Ulla Neumann</name></country><country name="Suède"><noRegion><name sortKey="Posse, Viktor" sort="Posse, Viktor" uniqKey="Posse V" first="Viktor" last="Posse">Viktor Posse</name></noRegion><name sortKey="Gustafsson, Claes M" sort="Gustafsson, Claes M" uniqKey="Gustafsson C" first="Claes M" last="Gustafsson">Claes M. Gustafsson</name><name sortKey="Larsson, Nils Goran" sort="Larsson, Nils Goran" uniqKey="Larsson N" first="Nils-Göran" last="Larsson">Nils-Göran Larsson</name></country><country name="France"><noRegion><name sortKey="Mourier, Arnaud" sort="Mourier, Arnaud" uniqKey="Mourier A" first="Arnaud" last="Mourier">Arnaud Mourier</name></noRegion></country><country name="Australie"><noRegion><name sortKey="Siira, Stefan J" sort="Siira, Stefan J" uniqKey="Siira S" first="Stefan J" last="Siira">Stefan J. Siira</name></noRegion><name sortKey="Filipovska, Aleksandra" sort="Filipovska, Aleksandra" uniqKey="Filipovska A" first="Aleksandra" last="Filipovska">Aleksandra Filipovska</name></country><country name="Italie"><noRegion><name sortKey="Polosa, Paola Loguercio" sort="Polosa, Paola Loguercio" uniqKey="Polosa P" first="Paola Loguercio" last="Polosa">Paola Loguercio Polosa</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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