Extreme differences between human germline and tumor mutation densities are driven by ancestral human-specific deviations

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• dc.contributor.author Heredia Genestar, José María, 1985-
• dc.contributor.author Marquès i Bonet, Tomàs, 1975-
• dc.contributor.author Juan Sopeña, David Alejandro, 1975-
• dc.contributor.author Navarro i Cuartiellas, Arcadi, 1969-
• dc.date.accessioned 2020-06-04T06:23:25Z
• dc.date.available 2020-06-04T06:23:25Z
• dc.date.issued 2020
• dc.description.abstract Mutations do not accumulate uniformly across the genome. Human germline and tumor mutation density correlate poorly, and each is associated with different genomic features. Here, we use non-human great ape (NHGA) germlines to determine human germline- and tumor-specific deviations from an ancestral-like great ape genome-wide mutational landscape. Strikingly, we find that the distribution of mutation densities in tumors presents a stronger correlation with NHGA than with human germlines. This effect is driven by human-specific differences in the distribution of mutations at non-CpG sites. We propose that ancestral human demographic events, together with the human-specific mutation slowdown, disrupted the human genome-wide distribution of mutation densities. Tumors partially recover this distribution by accumulating preneoplastic-like somatic mutations. Our results highlight the potential utility of using NHGA population data, rather than human controls, to establish the expected mutational background of healthy somatic cells.
• dc.description.sponsorship We thank B. Lehner, D. Weghorn, and I. Lobón for their insights discussing the analyses, and C. Warembourg for her statistical analysis help. J.M.H.G is supported by MDM-2014-0370. T.M.B. is supported by BFU2017-86471-P (MINECO/FEDER, UE), Howard Hughes International Early Career and Obra Social “La Caixa”. D.J. is supported by Juan de la Cierva fellowship (FJCI-2016-29558) from MICINN. A.N. is supported by AEI-PGC2018-101927-BI00(FEDER/UE), MINECO-BFU2015-68649-P (MINECO/FEDER, UE), the Spanish National Institute of Bioinformatics of the Instituto de Salud Carlos III (PT17/0009/0020), and by FEDER (Fondo Europeo de Desarrollo Regional)/FSE (Fondo Social Europeo). This work was supported by Unidad de Excelencia María de Maexto, funded by the AEI (CEXS2028-000792-M) and Secretaria d’Universitats i Recerca and CERCA Programme del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2017 SGR 880).
• dc.format.mimetype application/pdf
• dc.identifier.citation Heredia-Genestar JM, Marquès-Bonet T, Juan D, Navarro A. Extreme differences between human germline and tumor mutation densities are driven by ancestral human-specific deviations. Nat Commun. 2020; 11(1):2512. DOI: 10.1038/s41467-020-16296-4
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-020-16296-4
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/44894
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Commun. 2020; 11(1):2512
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-86471-P
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2015-68649-P
• dc.rights © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Cancer
• dc.subject.keyword Evolutionary genetics
• dc.subject.keyword Mutation
• dc.title Extreme differences between human germline and tumor mutation densities are driven by ancestral human-specific deviations
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion