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

Cai Li,Nicholas M Luscombe

doi:10.1038/s41467-020-15185-0

Abstract

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.

Highlights

Nucleosome organization has been suggested to affect local mutation rates in the genome
We reveal increased mutation rates around strongly positioned nucleosomes and suggest that low-fidelity replication, insufficient mismatch repair (MMR), and increased double-strand breaks (DSB) are potential mutational mechanisms linked to strong nucleosomes
Nucleosome positioning on the genome is described by the translational setting, which defines the location of the nucleosomal midpoint and the rotational setting, which defines the orientation of the DNA helix on the histone surface[32]

Summary

Introduction

Nucleosome organization has been suggested to affect local mutation rates in the genome. Due to the limited availability of de novo mutation datasets, studies focused on coarse-grained mutation rate variation (typically ≥ 1 Kb windows for germline data), or used within-species polymorphisms and interspecies divergence whose observations are potentially confounded by natural selection and other evolutionary processes. The underlying mutational processes causing the observed mutation rate variation are poorly understood, though recent studies have highlighted the contributions of errorprone replicative processes[14,15,16,17,18] and differential DNA repair efficiencies[10,19,20,21] Despite these advances, many details of the molecular mechanisms associated with mutation rate variation remain to be uncovered, in the germline. Combined with the scarcity of de novo mutation datasets, the effects of nucleosome organization on germline mutation rate variation, at high resolution, remain to be elucidated

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Conclusion