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

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.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)