PITX2 expression and Neanderthal introgression in HS3ST3A1 contribute to variation in tooth dimensions in modern humans

Autores
Liu, Qing; Faux, Pierre; Wentworth Winchester, Emma; Yang, Guangrui; Chen, Yingjie; Ramírez, Luis Miguel; Fuentes Guajardo, Macarena; Poloni, Lauriane; Steimetz, Emilie; Gonzalez José, Rolando; Acuña, Victor; Bortolini, Maria Catira; Poletti, Giovanni; Gallo, Carla; Rothhammer, Francisco; Rojas, Winston; Zheng, Youyi; Cox, James C.; Patel, Vaishali; Hoffman, Matthew P.; Ding, Li; Peng, Chenchen; Cotney, Justin; Navarro, Nicolas; Cox, Timothy C.; Delgado Burbano, Miguel Eduardo; Adhikari, Kaustubh; Ruiz Linares, Andrés
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Dental morphology varies greatly throughout evolution, including in the human lineage, but little is known about the biology of this variation. Here, we use multiomics analyses to examine the genetics of variation in tooth crown dimensions. In a human cohort with mixed continental ancestry, we detected genome-wide significant associations at 18 genome regions. One region includes EDAR, a gene known to impact dental features in East Asians. Furthermore, we find that EDAR variants increase the mesiodistal diameter of all teeth, following an anterior-posterior gradient of decreasing strength. Among the 17 novel-associated regions, we replicate 7/13 in an independent human cohort and find that 4/12 orthologous regions affect molar size in mice. Two association signals point to compelling candidate genes. One is ∼61 kb from PITX2, a major determinant of tooth development. Another overlaps HS3ST3A1, a paralogous neighbor of HS3ST3B1, a tooth enamel knot factor. We document the expression of Pitx2 and Hs3st3a1 in enamel knot and dental epithelial cells of developing mouse incisors. Furthermore, associated SNPs in PITX2 and HS3ST3A1 overlap enhancers active in these cells, suggesting a role for these SNPs in gene regulation during dental development. In addition, we document that Pitx2 and Hs3st3a1/Hs3st3b1 knockout mice show alterations in dental morphology. Finally, we find that associated SNPs in HS3ST3A1 are in a DNA tract introgressed from Neanderthals, consistent with an involvement of HS3ST3A1 in tooth size variation during human evolution.
Fil: Liu, Qing. School Of Life Sciences Fudan University; China
Fil: Faux, Pierre. Centre National de la Recherche Scientifique; Francia
Fil: Wentworth Winchester, Emma. Centre National de la Recherche Scientifique; Francia
Fil: Yang, Guangrui. Fudan University; China
Fil: Chen, Yingjie. Fudan University; China
Fil: Ramírez, Luis Miguel. Universidad de Antioquia; Colombia
Fil: Fuentes Guajardo, Macarena. Universidad de Chile; Chile
Fil: Poloni, Lauriane. Centre National de la Recherche Scientifique; Francia
Fil: Steimetz, Emilie. Centre National de la Recherche Scientifique; Francia
Fil: Gonzalez José, Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico de Ciencias Sociales y Humanas; Argentina
Fil: Acuña, Victor. Centre National de la Recherche Scientifique; Francia
Fil: Bortolini, Maria Catira. Universidade Federal do Rio Grande do Sul; Brasil
Fil: Poletti, Giovanni. Universidad Peruana Cayetano Heredia; Perú
Fil: Gallo, Carla. Universidad Peruana Cayetano Heredia; Perú
Fil: Rothhammer, Francisco. Universidad de Chile; Chile
Fil: Rojas, Winston. Universidad de Antioquia; Colombia
Fil: Zheng, Youyi. Fudan University; China
Fil: Cox, James C.. Centre National de la Recherche Scientifique; Francia
Fil: Patel, Vaishali. Centre National de la Recherche Scientifique; Francia
Fil: Hoffman, Matthew P.. Centre National de la Recherche Scientifique; Francia
Fil: Ding, Li. Fudan University; China
Fil: Peng, Chenchen. Fudan University; China
Fil: Cotney, Justin. Centre National de la Recherche Scientifique; Francia
Fil: Navarro, Nicolas. Centre National de la Recherche Scientifique; Francia
Fil: Cox, Timothy C.. Centre National de la Recherche Scientifique; Francia
Fil: Delgado Burbano, Miguel Eduardo. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Área Antropológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Adhikari, Kaustubh. The Open University; Reino Unido
Fil: Ruiz Linares, Andrés. Centre National de la Recherche Scientifique; Francia
Materia
NEANDERTHALS
MODERN HUMANS
GWAS
TEETH
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/255593

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network_name_str CONICET Digital (CONICET)
spelling PITX2 expression and Neanderthal introgression in HS3ST3A1 contribute to variation in tooth dimensions in modern humansLiu, QingFaux, PierreWentworth Winchester, EmmaYang, GuangruiChen, YingjieRamírez, Luis MiguelFuentes Guajardo, MacarenaPoloni, LaurianeSteimetz, EmilieGonzalez José, RolandoAcuña, VictorBortolini, Maria CatiraPoletti, GiovanniGallo, CarlaRothhammer, FranciscoRojas, WinstonZheng, YouyiCox, James C.Patel, VaishaliHoffman, Matthew P.Ding, LiPeng, ChenchenCotney, JustinNavarro, NicolasCox, Timothy C.Delgado Burbano, Miguel EduardoAdhikari, KaustubhRuiz Linares, AndrésNEANDERTHALSMODERN HUMANSGWASTEETHhttps://purl.org/becyt/ford/6.1https://purl.org/becyt/ford/6Dental morphology varies greatly throughout evolution, including in the human lineage, but little is known about the biology of this variation. Here, we use multiomics analyses to examine the genetics of variation in tooth crown dimensions. In a human cohort with mixed continental ancestry, we detected genome-wide significant associations at 18 genome regions. One region includes EDAR, a gene known to impact dental features in East Asians. Furthermore, we find that EDAR variants increase the mesiodistal diameter of all teeth, following an anterior-posterior gradient of decreasing strength. Among the 17 novel-associated regions, we replicate 7/13 in an independent human cohort and find that 4/12 orthologous regions affect molar size in mice. Two association signals point to compelling candidate genes. One is ∼61 kb from PITX2, a major determinant of tooth development. Another overlaps HS3ST3A1, a paralogous neighbor of HS3ST3B1, a tooth enamel knot factor. We document the expression of Pitx2 and Hs3st3a1 in enamel knot and dental epithelial cells of developing mouse incisors. Furthermore, associated SNPs in PITX2 and HS3ST3A1 overlap enhancers active in these cells, suggesting a role for these SNPs in gene regulation during dental development. In addition, we document that Pitx2 and Hs3st3a1/Hs3st3b1 knockout mice show alterations in dental morphology. Finally, we find that associated SNPs in HS3ST3A1 are in a DNA tract introgressed from Neanderthals, consistent with an involvement of HS3ST3A1 in tooth size variation during human evolution.Fil: Liu, Qing. School Of Life Sciences Fudan University; ChinaFil: Faux, Pierre. Centre National de la Recherche Scientifique; FranciaFil: Wentworth Winchester, Emma. Centre National de la Recherche Scientifique; FranciaFil: Yang, Guangrui. Fudan University; ChinaFil: Chen, Yingjie. Fudan University; ChinaFil: Ramírez, Luis Miguel. Universidad de Antioquia; ColombiaFil: Fuentes Guajardo, Macarena. Universidad de Chile; ChileFil: Poloni, Lauriane. Centre National de la Recherche Scientifique; FranciaFil: Steimetz, Emilie. Centre National de la Recherche Scientifique; FranciaFil: Gonzalez José, Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico de Ciencias Sociales y Humanas; ArgentinaFil: Acuña, Victor. Centre National de la Recherche Scientifique; FranciaFil: Bortolini, Maria Catira. Universidade Federal do Rio Grande do Sul; BrasilFil: Poletti, Giovanni. Universidad Peruana Cayetano Heredia; PerúFil: Gallo, Carla. Universidad Peruana Cayetano Heredia; PerúFil: Rothhammer, Francisco. Universidad de Chile; ChileFil: Rojas, Winston. Universidad de Antioquia; ColombiaFil: Zheng, Youyi. Fudan University; ChinaFil: Cox, James C.. Centre National de la Recherche Scientifique; FranciaFil: Patel, Vaishali. Centre National de la Recherche Scientifique; FranciaFil: Hoffman, Matthew P.. Centre National de la Recherche Scientifique; FranciaFil: Ding, Li. Fudan University; ChinaFil: Peng, Chenchen. Fudan University; ChinaFil: Cotney, Justin. Centre National de la Recherche Scientifique; FranciaFil: Navarro, Nicolas. Centre National de la Recherche Scientifique; FranciaFil: Cox, Timothy C.. Centre National de la Recherche Scientifique; FranciaFil: Delgado Burbano, Miguel Eduardo. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Área Antropológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Adhikari, Kaustubh. The Open University; Reino UnidoFil: Ruiz Linares, Andrés. Centre National de la Recherche Scientifique; FranciaCell Press2024-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/255593Liu, Qing; Faux, Pierre; Wentworth Winchester, Emma; Yang, Guangrui; Chen, Yingjie; et al.; PITX2 expression and Neanderthal introgression in HS3ST3A1 contribute to variation in tooth dimensions in modern humans; Cell Press; Current Biology; 35; 1; 12-2024; 131-144.e60960-9822CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0960982224015689info:eu-repo/semantics/altIdentifier/doi/10.1016/j.cub.2024.11.027info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:42:28Zoai:ri.conicet.gov.ar:11336/255593instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:42:28.993CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv PITX2 expression and Neanderthal introgression in HS3ST3A1 contribute to variation in tooth dimensions in modern humans
title PITX2 expression and Neanderthal introgression in HS3ST3A1 contribute to variation in tooth dimensions in modern humans
spellingShingle PITX2 expression and Neanderthal introgression in HS3ST3A1 contribute to variation in tooth dimensions in modern humans
Liu, Qing
NEANDERTHALS
MODERN HUMANS
GWAS
TEETH
title_short PITX2 expression and Neanderthal introgression in HS3ST3A1 contribute to variation in tooth dimensions in modern humans
title_full PITX2 expression and Neanderthal introgression in HS3ST3A1 contribute to variation in tooth dimensions in modern humans
title_fullStr PITX2 expression and Neanderthal introgression in HS3ST3A1 contribute to variation in tooth dimensions in modern humans
title_full_unstemmed PITX2 expression and Neanderthal introgression in HS3ST3A1 contribute to variation in tooth dimensions in modern humans
title_sort PITX2 expression and Neanderthal introgression in HS3ST3A1 contribute to variation in tooth dimensions in modern humans
dc.creator.none.fl_str_mv Liu, Qing
Faux, Pierre
Wentworth Winchester, Emma
Yang, Guangrui
Chen, Yingjie
Ramírez, Luis Miguel
Fuentes Guajardo, Macarena
Poloni, Lauriane
Steimetz, Emilie
Gonzalez José, Rolando
Acuña, Victor
Bortolini, Maria Catira
Poletti, Giovanni
Gallo, Carla
Rothhammer, Francisco
Rojas, Winston
Zheng, Youyi
Cox, James C.
Patel, Vaishali
Hoffman, Matthew P.
Ding, Li
Peng, Chenchen
Cotney, Justin
Navarro, Nicolas
Cox, Timothy C.
Delgado Burbano, Miguel Eduardo
Adhikari, Kaustubh
Ruiz Linares, Andrés
author Liu, Qing
author_facet Liu, Qing
Faux, Pierre
Wentworth Winchester, Emma
Yang, Guangrui
Chen, Yingjie
Ramírez, Luis Miguel
Fuentes Guajardo, Macarena
Poloni, Lauriane
Steimetz, Emilie
Gonzalez José, Rolando
Acuña, Victor
Bortolini, Maria Catira
Poletti, Giovanni
Gallo, Carla
Rothhammer, Francisco
Rojas, Winston
Zheng, Youyi
Cox, James C.
Patel, Vaishali
Hoffman, Matthew P.
Ding, Li
Peng, Chenchen
Cotney, Justin
Navarro, Nicolas
Cox, Timothy C.
Delgado Burbano, Miguel Eduardo
Adhikari, Kaustubh
Ruiz Linares, Andrés
author_role author
author2 Faux, Pierre
Wentworth Winchester, Emma
Yang, Guangrui
Chen, Yingjie
Ramírez, Luis Miguel
Fuentes Guajardo, Macarena
Poloni, Lauriane
Steimetz, Emilie
Gonzalez José, Rolando
Acuña, Victor
Bortolini, Maria Catira
Poletti, Giovanni
Gallo, Carla
Rothhammer, Francisco
Rojas, Winston
Zheng, Youyi
Cox, James C.
Patel, Vaishali
Hoffman, Matthew P.
Ding, Li
Peng, Chenchen
Cotney, Justin
Navarro, Nicolas
Cox, Timothy C.
Delgado Burbano, Miguel Eduardo
Adhikari, Kaustubh
Ruiz Linares, Andrés
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv NEANDERTHALS
MODERN HUMANS
GWAS
TEETH
topic NEANDERTHALS
MODERN HUMANS
GWAS
TEETH
purl_subject.fl_str_mv https://purl.org/becyt/ford/6.1
https://purl.org/becyt/ford/6
dc.description.none.fl_txt_mv Dental morphology varies greatly throughout evolution, including in the human lineage, but little is known about the biology of this variation. Here, we use multiomics analyses to examine the genetics of variation in tooth crown dimensions. In a human cohort with mixed continental ancestry, we detected genome-wide significant associations at 18 genome regions. One region includes EDAR, a gene known to impact dental features in East Asians. Furthermore, we find that EDAR variants increase the mesiodistal diameter of all teeth, following an anterior-posterior gradient of decreasing strength. Among the 17 novel-associated regions, we replicate 7/13 in an independent human cohort and find that 4/12 orthologous regions affect molar size in mice. Two association signals point to compelling candidate genes. One is ∼61 kb from PITX2, a major determinant of tooth development. Another overlaps HS3ST3A1, a paralogous neighbor of HS3ST3B1, a tooth enamel knot factor. We document the expression of Pitx2 and Hs3st3a1 in enamel knot and dental epithelial cells of developing mouse incisors. Furthermore, associated SNPs in PITX2 and HS3ST3A1 overlap enhancers active in these cells, suggesting a role for these SNPs in gene regulation during dental development. In addition, we document that Pitx2 and Hs3st3a1/Hs3st3b1 knockout mice show alterations in dental morphology. Finally, we find that associated SNPs in HS3ST3A1 are in a DNA tract introgressed from Neanderthals, consistent with an involvement of HS3ST3A1 in tooth size variation during human evolution.
Fil: Liu, Qing. School Of Life Sciences Fudan University; China
Fil: Faux, Pierre. Centre National de la Recherche Scientifique; Francia
Fil: Wentworth Winchester, Emma. Centre National de la Recherche Scientifique; Francia
Fil: Yang, Guangrui. Fudan University; China
Fil: Chen, Yingjie. Fudan University; China
Fil: Ramírez, Luis Miguel. Universidad de Antioquia; Colombia
Fil: Fuentes Guajardo, Macarena. Universidad de Chile; Chile
Fil: Poloni, Lauriane. Centre National de la Recherche Scientifique; Francia
Fil: Steimetz, Emilie. Centre National de la Recherche Scientifique; Francia
Fil: Gonzalez José, Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico de Ciencias Sociales y Humanas; Argentina
Fil: Acuña, Victor. Centre National de la Recherche Scientifique; Francia
Fil: Bortolini, Maria Catira. Universidade Federal do Rio Grande do Sul; Brasil
Fil: Poletti, Giovanni. Universidad Peruana Cayetano Heredia; Perú
Fil: Gallo, Carla. Universidad Peruana Cayetano Heredia; Perú
Fil: Rothhammer, Francisco. Universidad de Chile; Chile
Fil: Rojas, Winston. Universidad de Antioquia; Colombia
Fil: Zheng, Youyi. Fudan University; China
Fil: Cox, James C.. Centre National de la Recherche Scientifique; Francia
Fil: Patel, Vaishali. Centre National de la Recherche Scientifique; Francia
Fil: Hoffman, Matthew P.. Centre National de la Recherche Scientifique; Francia
Fil: Ding, Li. Fudan University; China
Fil: Peng, Chenchen. Fudan University; China
Fil: Cotney, Justin. Centre National de la Recherche Scientifique; Francia
Fil: Navarro, Nicolas. Centre National de la Recherche Scientifique; Francia
Fil: Cox, Timothy C.. Centre National de la Recherche Scientifique; Francia
Fil: Delgado Burbano, Miguel Eduardo. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Área Antropológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Adhikari, Kaustubh. The Open University; Reino Unido
Fil: Ruiz Linares, Andrés. Centre National de la Recherche Scientifique; Francia
description Dental morphology varies greatly throughout evolution, including in the human lineage, but little is known about the biology of this variation. Here, we use multiomics analyses to examine the genetics of variation in tooth crown dimensions. In a human cohort with mixed continental ancestry, we detected genome-wide significant associations at 18 genome regions. One region includes EDAR, a gene known to impact dental features in East Asians. Furthermore, we find that EDAR variants increase the mesiodistal diameter of all teeth, following an anterior-posterior gradient of decreasing strength. Among the 17 novel-associated regions, we replicate 7/13 in an independent human cohort and find that 4/12 orthologous regions affect molar size in mice. Two association signals point to compelling candidate genes. One is ∼61 kb from PITX2, a major determinant of tooth development. Another overlaps HS3ST3A1, a paralogous neighbor of HS3ST3B1, a tooth enamel knot factor. We document the expression of Pitx2 and Hs3st3a1 in enamel knot and dental epithelial cells of developing mouse incisors. Furthermore, associated SNPs in PITX2 and HS3ST3A1 overlap enhancers active in these cells, suggesting a role for these SNPs in gene regulation during dental development. In addition, we document that Pitx2 and Hs3st3a1/Hs3st3b1 knockout mice show alterations in dental morphology. Finally, we find that associated SNPs in HS3ST3A1 are in a DNA tract introgressed from Neanderthals, consistent with an involvement of HS3ST3A1 in tooth size variation during human evolution.
publishDate 2024
dc.date.none.fl_str_mv 2024-12
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/255593
Liu, Qing; Faux, Pierre; Wentworth Winchester, Emma; Yang, Guangrui; Chen, Yingjie; et al.; PITX2 expression and Neanderthal introgression in HS3ST3A1 contribute to variation in tooth dimensions in modern humans; Cell Press; Current Biology; 35; 1; 12-2024; 131-144.e6
0960-9822
CONICET Digital
CONICET
url http://hdl.handle.net/11336/255593
identifier_str_mv Liu, Qing; Faux, Pierre; Wentworth Winchester, Emma; Yang, Guangrui; Chen, Yingjie; et al.; PITX2 expression and Neanderthal introgression in HS3ST3A1 contribute to variation in tooth dimensions in modern humans; Cell Press; Current Biology; 35; 1; 12-2024; 131-144.e6
0960-9822
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0960982224015689
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.cub.2024.11.027
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
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application/pdf
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dc.publisher.none.fl_str_mv Cell Press
publisher.none.fl_str_mv Cell Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
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reponame_str CONICET Digital (CONICET)
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instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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