Heredia Genestar, José María, 1985-Marquès i Bonet, Tomàs, 1975-Juan Sopeña, David Alejandro, 1975-Navarro i Cuartiellas, Arcadi, 1969-2020-06-042020-06-042020Heredia-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/s41467-020-16296-42041-1723http://hdl.handle.net/10230/44894Mutations 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.application/pdfeng© 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/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-020-16296-4CancerEvolutionary geneticsMutationinfo:eu-repo/semantics/openAccess