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

Heredia Genestar, José María, 1985-; Marquès i Bonet, Tomàs, 1975-; Juan Sopeña, David Alejandro, 1975-; Navarro i Cuartiellas, Arcadi, 1969-

doi:http://dx.doi.org/10.1038/s41467-020-16296-4

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

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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

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.