Contemporary and historical human migration patterns shape hepatitis B virus diversity

Infection by hepatitis B virus (HBV) is responsible for approximately 296 million chronic cases of hepatitis B, and roughly 880,000 deaths annually. The global burden of HBV is distributed unevenly, largely owing to the heterogeneous geographic distribution of its subtypes, each of which demonstrate...

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Autores:
Potter, Barney
Thijssen, Marijn
Sequeira Trovão, Nídia
Pineda-Peña, Andrea-Clemencia
Reynders, Marijke
Mina, Thomas
Alvarez, Carolina
Amini Bavil Olyaee, Samad
Nevens, Frederik
Maes, Piet
Lemey, Philippe
Van Ranst, Marc
Baele, Guy
POURKARIM, MAHMOUD REZA
Tipo de recurso:
Article of investigation
Fecha de publicación:
2024
Institución:
Universidad de Ciencias Aplicadas y Ambientales U.D.C.A
Repositorio:
Repositorio Institucional UDCA
Idioma:
eng
OAI Identifier:
oai:repository.udca.edu.co:11158/5779
Acceso en línea:
https://repository.udca.edu.co/handle/11158/5779
https://doi.org/10.1093/ve/veae009
Palabra clave:
610 - Medicina y salud::616 - Enfermedades
Antivirales
Evolución
Africa
Migración
Virus de la Hepatitis B
Genotipo
Rights
openAccess
License
https://creativecommons.org/licenses/by-nc-sa/4.0/legalcode.es
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dc.title.eng.fl_str_mv Contemporary and historical human migration patterns shape hepatitis B virus diversity
title Contemporary and historical human migration patterns shape hepatitis B virus diversity
spellingShingle Contemporary and historical human migration patterns shape hepatitis B virus diversity
610 - Medicina y salud::616 - Enfermedades
Antivirales
Evolución
Africa
Migración
Virus de la Hepatitis B
Genotipo
title_short Contemporary and historical human migration patterns shape hepatitis B virus diversity
title_full Contemporary and historical human migration patterns shape hepatitis B virus diversity
title_fullStr Contemporary and historical human migration patterns shape hepatitis B virus diversity
title_full_unstemmed Contemporary and historical human migration patterns shape hepatitis B virus diversity
title_sort Contemporary and historical human migration patterns shape hepatitis B virus diversity
dc.creator.fl_str_mv Potter, Barney
Thijssen, Marijn
Sequeira Trovão, Nídia
Pineda-Peña, Andrea-Clemencia
Reynders, Marijke
Mina, Thomas
Alvarez, Carolina
Amini Bavil Olyaee, Samad
Nevens, Frederik
Maes, Piet
Lemey, Philippe
Van Ranst, Marc
Baele, Guy
POURKARIM, MAHMOUD REZA
dc.contributor.author.none.fl_str_mv Potter, Barney
Thijssen, Marijn
Sequeira Trovão, Nídia
Pineda-Peña, Andrea-Clemencia
Reynders, Marijke
Mina, Thomas
Alvarez, Carolina
Amini Bavil Olyaee, Samad
Nevens, Frederik
Maes, Piet
Lemey, Philippe
Van Ranst, Marc
Baele, Guy
POURKARIM, MAHMOUD REZA
dc.subject.ddc.none.fl_str_mv 610 - Medicina y salud::616 - Enfermedades
topic 610 - Medicina y salud::616 - Enfermedades
Antivirales
Evolución
Africa
Migración
Virus de la Hepatitis B
Genotipo
dc.subject.lemb.none.fl_str_mv Antivirales
Evolución
Africa
Migración
dc.subject.decs.none.fl_str_mv Virus de la Hepatitis B
Genotipo
description Infection by hepatitis B virus (HBV) is responsible for approximately 296 million chronic cases of hepatitis B, and roughly 880,000 deaths annually. The global burden of HBV is distributed unevenly, largely owing to the heterogeneous geographic distribution of its subtypes, each of which demonstrates different severity and responsiveness to antiviral therapy. It is therefore crucial to the global public health response to HBV that the spatiotemporal spread of each genotype is well characterized. In this study, we describe a collection of 133 newly sequenced HBV strains from recent African immigrants upon their arrival in Belgium. We incorporate these sequences—all of which we determine to come from genotypes A, D, and E—into a large-scale phylogeographic study with genomes sampled across the globe. We focus on investigating the spatio-temporal processes shaping the evolutionary history of the three genotypes we observe. We incorporate several recently published ancient HBV genomes for genotypes A and D to aid our analysis. We show that different spatio-temporal processes underlie the A, D, and E genotypes with the former two having originated in southeastern Asia, after which they spread across the world. The HBV E genotype is estimated to have originated in Africa, after which it spread to Europe and the Americas. Our results highlight the use of phylogeographic reconstruction as a tool to understand the recent spatiotemporal dynamics of HBV, and highlight the importance of supporting vulnerable populations in accordance with the needs presented by specifc HBV genotypes.
publishDate 2024
dc.date.accessioned.none.fl_str_mv 2024-05-29T14:18:45Z
dc.date.available.none.fl_str_mv 2024-05-29T14:18:45Z
dc.date.issued.none.fl_str_mv 2024-05
dc.type.none.fl_str_mv Artículo de revista
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dc.identifier.citation.none.fl_str_mv Potter, B. I., Thijssen, M., Trovão, N. S., Pineda-Peña, A., Reynders, M., Mina, T., Alvarez, C., Amini-Bavil-Olyaee, S., Nevens, F., Maes, P., Lemey, P., Van Ranst, M., Baele, G., & Pourkarim, M. R. (2024). Contemporary and historical human migration patterns shape hepatitis B virus diversity. Virus evolution, 10(1), veae009. https://doi.org/10.1093/ve/veae009
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identifier_str_mv Potter, B. I., Thijssen, M., Trovão, N. S., Pineda-Peña, A., Reynders, M., Mina, T., Alvarez, C., Amini-Bavil-Olyaee, S., Nevens, F., Maes, P., Lemey, P., Van Ranst, M., Baele, G., & Pourkarim, M. R. (2024). Contemporary and historical human migration patterns shape hepatitis B virus diversity. Virus evolution, 10(1), veae009. https://doi.org/10.1093/ve/veae009
20571577
url https://repository.udca.edu.co/handle/11158/5779
https://doi.org/10.1093/ve/veae009
dc.language.iso.none.fl_str_mv eng
language eng
dc.relation.indexed.none.fl_str_mv LaReferencia
dc.relation.citationedition.none.fl_str_mv (2024) Artículo número veae009
dc.relation.citationendpage.none.fl_str_mv 14
dc.relation.citationissue.none.fl_str_mv 1
dc.relation.citationstartpage.none.fl_str_mv 1
dc.relation.citationvolume.none.fl_str_mv 10
dc.relation.ispartofjournal.none.fl_str_mv Virus Evolution
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spelling Potter, Barneyvirtual::59-1Thijssen, Marijnvirtual::60-1Sequeira Trovão, Nídiavirtual::61-1Pineda-Peña, Andrea-Clemenciavirtual::62-1Reynders, Marijkevirtual::63-1Mina, ThomasAlvarez, CarolinaAmini Bavil Olyaee, Samadvirtual::64-1Nevens, FrederikMaes, Pietvirtual::65-1Lemey, Philippevirtual::66-1Van Ranst, Marcvirtual::67-1Baele, GuyPOURKARIM, MAHMOUD REZAvirtual::68-12024-05-29T14:18:45Z2024-05-29T14:18:45Z2024-05Potter, B. I., Thijssen, M., Trovão, N. S., Pineda-Peña, A., Reynders, M., Mina, T., Alvarez, C., Amini-Bavil-Olyaee, S., Nevens, F., Maes, P., Lemey, P., Van Ranst, M., Baele, G., & Pourkarim, M. R. (2024). Contemporary and historical human migration patterns shape hepatitis B virus diversity. Virus evolution, 10(1), veae009. https://doi.org/10.1093/ve/veae009https://repository.udca.edu.co/handle/11158/5779https://doi.org/10.1093/ve/veae00920571577Infection by hepatitis B virus (HBV) is responsible for approximately 296 million chronic cases of hepatitis B, and roughly 880,000 deaths annually. The global burden of HBV is distributed unevenly, largely owing to the heterogeneous geographic distribution of its subtypes, each of which demonstrates different severity and responsiveness to antiviral therapy. It is therefore crucial to the global public health response to HBV that the spatiotemporal spread of each genotype is well characterized. In this study, we describe a collection of 133 newly sequenced HBV strains from recent African immigrants upon their arrival in Belgium. We incorporate these sequences—all of which we determine to come from genotypes A, D, and E—into a large-scale phylogeographic study with genomes sampled across the globe. We focus on investigating the spatio-temporal processes shaping the evolutionary history of the three genotypes we observe. We incorporate several recently published ancient HBV genomes for genotypes A and D to aid our analysis. We show that different spatio-temporal processes underlie the A, D, and E genotypes with the former two having originated in southeastern Asia, after which they spread across the world. The HBV E genotype is estimated to have originated in Africa, after which it spread to Europe and the Americas. Our results highlight the use of phylogeographic reconstruction as a tool to understand the recent spatiotemporal dynamics of HBV, and highlight the importance of supporting vulnerable populations in accordance with the needs presented by specifc HBV genotypes.Incluye referenciaas biliográficasapplication/pdfenghttps://creativecommons.org/licenses/by-nc-sa/4.0/legalcode.eshttps://creativecommons.org/licenses/by-nc-sa/4.0/info:eu-repo/semantics/openAccessAtribución-NoComercial-CompartirIgual 4.0 Internacional (CC BY-NC-SA 4.0)http://purl.org/coar/access_right/c_abf2https://pubmed.ncbi.nlm.nih.gov/38361827/610 - Medicina y salud::616 - EnfermedadesAntiviralesEvoluciónAfricaMigraciónVirus de la Hepatitis BGenotipoContemporary and historical human migration patterns shape hepatitis B virus diversityArtículo de 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jecuta públicamente en forma digital la Obra o cualquier Obra Derivada u Obra Colectiva, Usted debe mantener intacta toda la información de derecho de autor de la Obra y proporcionar, de forma razonable según el medio o manera que Usted esté utilizando: (i) el nombre del Autor Original si está provisto (o seudónimo, si fuere aplicable), y/o (ii) el nombre de la parte o las partes que el Autor Original y/o el Licenciante hubieren designado para la atribución (v.g., un instituto patrocinador, editorial, publicación) en la información de los derechos de autor del Licenciante, términos de servicios o de otras formas razonables; el título de la Obra si está provisto; en la medida de lo razonablemente factible y, si está provisto, el Identificador Uniforme de Recursos (Uniform Resource Identifier) que el Licenciante especifica para ser asociado con la Obra, salvo que tal URI no se refiera a la nota sobre los derechos de autor o a la información sobre el licenciamiento de la Obra; y en el caso de una Obra Derivada, atribuir el crédito identificando el uso de la Obra en la Obra Derivada (v.g., "Traducción Francesa de la Obra del Autor Original," o "Guión Cinematográfico basado en la Obra original del Autor Original"). Tal crédito puede ser implementado de cualquier forma razonable; en el caso, sin embargo, de Obras Derivadas u Obras Colectivas, tal crédito aparecerá, como mínimo, donde aparece el crédito de cualquier otro autor comparable y de una manera, al menos, tan destacada como el crédito de otro autor comparable.</li>
      <li>
        Para evitar toda confusión, el Licenciante aclara que, cuando la obra es una composición musical:
        <ol type="i">
          <li>Regalías por interpretación y ejecución bajo licencias generales. El Licenciante se reserva el derecho exclusivo de autorizar la ejecución pública o la ejecución pública digital de la obra y de recolectar, sea individualmente o a través de una sociedad de gestión colectiva de derechos de autor y derechos conexos (por ejemplo, SAYCO), las regalías por la ejecución pública o por la ejecución pública digital de la obra (por ejemplo Webcast) licenciada bajo licencias generales, si la interpretación o ejecución de la obra está primordialmente orientada por o dirigida a la obtención de una ventaja comercial o una compensación monetaria privada.</li>
          <li>Regalías por Fonogramas. El Licenciante se reserva el derecho exclusivo de recolectar, individualmente o a través de una sociedad de gestión colectiva de derechos de autor y derechos conexos (por ejemplo, los consagrados por la SAYCO), una agencia de derechos musicales o algún agente designado, las regalías por cualquier fonograma que Usted cree a partir de la obra (“versión cover”) y distribuya, en los términos del régimen de derechos de autor, si la creación o distribución de esa versión cover está primordialmente destinada o dirigida a obtener una ventaja comercial o una compensación monetaria privada.</li>
        </ol>
      </li>
      <li>Gestión de Derechos de Autor sobre Interpretaciones y Ejecuciones Digitales (WebCasting). Para evitar toda confusión, el Licenciante aclara que, cuando la obra sea un fonograma, el Licenciante se reserva el derecho exclusivo de autorizar la ejecución pública digital de la obra (por ejemplo, webcast) y de recolectar, individualmente o a través de una sociedad de gestión colectiva de derechos de autor y derechos conexos (por ejemplo, ACINPRO), las regalías por la ejecución pública digital de la obra (por ejemplo, webcast), sujeta a las disposiciones aplicables del régimen de Derecho de Autor, si esta ejecución pública digital está primordialmente dirigida a obtener una ventaja comercial o una compensación monetaria privada.</li>
    </ol>
  </li>
  <br/>
  <li>
    Representaciones, Garantías y Limitaciones de Responsabilidad.
    <p>A MENOS QUE LAS PARTES LO ACORDARAN DE OTRA FORMA POR ESCRITO, EL LICENCIANTE OFRECE LA OBRA (EN EL ESTADO EN EL QUE SE ENCUENTRA) “TAL CUAL”, SIN BRINDAR GARANTÍAS DE CLASE ALGUNA RESPECTO DE LA OBRA, YA SEA EXPRESA, IMPLÍCITA, LEGAL O CUALQUIERA OTRA, INCLUYENDO, SIN LIMITARSE A ELLAS, GARANTÍAS DE TITULARIDAD, COMERCIABILIDAD, ADAPTABILIDAD O ADECUACIÓN A PROPÓSITO DETERMINADO, AUSENCIA DE INFRACCIÓN, DE AUSENCIA DE DEFECTOS LATENTES O DE OTRO TIPO, O LA PRESENCIA O AUSENCIA DE ERRORES, SEAN O NO DESCUBRIBLES (PUEDAN O NO SER ESTOS DESCUBIERTOS). ALGUNAS JURISDICCIONES NO PERMITEN LA EXCLUSIÓN DE GARANTÍAS IMPLÍCITAS, EN CUYO CASO ESTA EXCLUSIÓN PUEDE NO APLICARSE A USTED.</p>
  </li>
  <br/>
  <li>
    Limitación de responsabilidad.
    <p>A MENOS QUE LO EXIJA EXPRESAMENTE LA LEY APLICABLE, EL LICENCIANTE NO SERÁ RESPONSABLE ANTE USTED POR DAÑO ALGUNO, SEA POR RESPONSABILIDAD EXTRACONTRACTUAL, PRECONTRACTUAL O CONTRACTUAL, OBJETIVA O SUBJETIVA, SE TRATE DE DAÑOS MORALES O PATRIMONIALES, DIRECTOS O INDIRECTOS, PREVISTOS O IMPREVISTOS PRODUCIDOS POR EL USO DE ESTA LICENCIA O DE LA OBRA, AUN CUANDO EL LICENCIANTE HAYA SIDO ADVERTIDO DE LA POSIBILIDAD DE DICHOS DAÑOS. ALGUNAS LEYES NO PERMITEN LA EXCLUSIÓN DE CIERTA RESPONSABILIDAD, EN CUYO CASO ESTA EXCLUSIÓN PUEDE NO APLICARSE A USTED.</p>
  </li>
  <br/>
  <li>
    Término.
    <ol type="a">
      <li>Esta Licencia y los derechos otorgados en virtud de ella terminarán automáticamente si Usted infringe alguna condición establecida en ella. Sin embargo, los individuos o entidades que han recibido Obras Derivadas o Colectivas de Usted de conformidad con esta Licencia, no verán terminadas sus licencias, siempre que estos individuos o entidades sigan cumpliendo íntegramente las condiciones de estas licencias. Las Secciones 1, 2, 5, 6, 7, y 8 subsistirán a cualquier terminación de esta Licencia.</li>
      <li>Sujeta a las condiciones y términos anteriores, la licencia otorgada aquí es perpetua (durante el período de vigencia de los derechos de autor de la obra). No obstante lo anterior, el Licenciante se reserva el derecho a publicar y/o estrenar la Obra bajo condiciones de licencia diferentes o a dejar de distribuirla en los términos de esta Licencia en cualquier momento; en el entendido, sin embargo, que esa elección no servirá para revocar esta licencia o que deba ser otorgada , bajo los términos de esta licencia), y esta licencia continuará en pleno vigor y efecto a menos que sea terminada como se expresa atrás. La Licencia revocada continuará siendo plenamente vigente y efectiva si no se le da término en las condiciones indicadas anteriormente.</li>
    </ol>
  </li>
  <br/>
  <li>
    Varios.
    <ol type="a">
      <li>Cada vez que Usted distribuya o ponga a disposición pública la Obra o una Obra Colectiva, el Licenciante ofrecerá al destinatario una licencia en los mismos términos y condiciones que la licencia otorgada a Usted bajo esta Licencia.</li>
      <li>Si alguna disposición de esta Licencia resulta invalidada o no exigible, según la legislación vigente, esto no afectará ni la validez ni la aplicabilidad del resto de condiciones de esta Licencia y, sin acción adicional por parte de los sujetos de este acuerdo, aquélla se entenderá reformada lo mínimo necesario para hacer que dicha disposición sea válida y exigible.</li>
      <li>Ningún término o disposición de esta Licencia se estimará renunciada y ninguna violación de ella será consentida a menos que esa renuncia o consentimiento sea otorgado por escrito y firmado por la parte que renuncie o consienta.</li>
      <li>Esta Licencia refleja el acuerdo pleno entre las partes respecto a la Obra aquí licenciada. No hay arreglos, acuerdos o declaraciones respecto a la Obra que no estén especificados en este documento. El Licenciante no se verá limitado por ninguna disposición adicional que pueda surgir en alguna comunicación emanada de Usted. Esta Licencia no puede ser modificada sin el consentimiento mutuo por escrito del Licenciante y Usted.</li>
    </ol>
  </li>
  <br/>
</ol>
