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

José María Heredia-Genestar, Tomàs Marquès-Bonet, David Juan () and Arcadi Navarro ()
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José María Heredia-Genestar: Universitat Pompeu Fabra
Tomàs Marquès-Bonet: Universitat Pompeu Fabra
David Juan: Universitat Pompeu Fabra
Arcadi Navarro: Universitat Pompeu Fabra

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16296-4

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