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

Bibliographic Collection: 
APE, CARTA-Inspired Publication
Publication Type: Journal Article
Authors: Heredia-Genestar, José María; Marques-Bonet, Tomas; Juan, David; Navarro, Arcadi
Year of Publication: 2020
Journal: Nature Communications
Volume: 11
Issue: 1
Pagination: 2512
Date Published: 2020/05/19
Publication Language: eng
ISBN Number: 2041-1723

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.

DOI: https://doi.org/10.1038/s41467-020-16296-4
Short Title: Nature Communications