Nucleosome positioning stability is a modulator of germline mutation rate variation across the human genome.

Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE

Original Publication: [London] : Nature Pub. Group

Genetic Variation* ; Genome, Human* ; Germ-Line Mutation* ; Mutation Rate* ; Nucleosomes*; Computational Biology ; DNA Mismatch Repair ; DNA Transposable Elements ; DNA-Directed DNA Polymerase ; Evolution, Molecular ; Humans

Nucleosome organization has been suggested to affect local mutation rates in the genome. However, the lack of de novo mutation and high-resolution nucleosome data has limited the investigation of this hypothesis. Additionally, analyses using indirect mutation rate measurements have yielded contradictory and potentially confounding results. Here, we combine data on >300,000 human de novo mutations with high-resolution nucleosome maps and find substantially elevated mutation rates around translationally stable ('strong') nucleosomes. We show that the mutational mechanisms affected by strong nucleosomes are low-fidelity replication, insufficient mismatch repair and increased double-strand breaks. Strong nucleosomes preferentially locate within young SINE/LINE transposons, suggesting that when subject to increased mutation rates, transposons are then more rapidly inactivated. Depletion of strong nucleosomes in older transposons suggests frequent positioning changes during evolution. The findings have important implications for human genetics and genome evolution.

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FC001110 United Kingdom CRUK_ Cancer Research UK; FC001110 United Kingdom MRC_ Medical Research Council; FC001110 United Kingdom WT_ Wellcome Trust

0 (DNA Transposable Elements)
0 (Nucleosomes)
EC 2.7.7.7 (DNA-Directed DNA Polymerase)

Date Created: 20200315 Date Completed: 20200713 Latest Revision: 20210313

20231215

PMC7070026

10.1038/s41467-020-15185-0

32170069