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

Abstract

12Nucleosome organization is suggested to affect local mutation rates in a genome. 13However, the lack of de novo mutation and high-resolution nucleosome data have 14 limited investigation. Further, analyses using indirect mutation rate measurements 15 have yielded contradictory and potentially confounded results. Combining >300,000 16human de novo mutations with high-resolution nucleosome maps, we reveal 17 substantially elevated mutation rates around translationally stable ('strong') 18 nucleosomes. Translational stability is an under-appreciated nucleosomal property, 19 with greater impact than better-known factors like occupancy and histone 20 modifications. We show that the mutational mechanisms affected by strong 21 nucleosomes are low-fidelity replication, insufficient mismatch repair and increased 22 double-strand breaks. Strong nucleosomes preferentially locate within young 23 SINE/LINE transposons; subject to increased mutation rates, transposons are then 24 more rapidly inactivated. Depletion of strong nucleosomes in older transposons 25suggests frequent re-positioning during evolution, thus resolving a debate about 26 selective pressure on nucleosome-positioning. The findings have important 27 implications for human genetics and genome evolution. 28 29 3

De novo mutations across 1,465 diverse genomes reveal mutational insights and reductions in the Amish founder population

“…GC content was recently shown to directly increase single-nucleotide and structural mutation rates, and was also shown to increase recombination rates (29). Chromatin structure has also been shown to associate with DNA mutations, with DNA replication times associating significantly with point mutations (30), and nucleotide positioning found to significantly modulate mutation rate (31). Recent work has tied a number of these features together by providing resolute and individualized recombination maps, and using them to demonstrate a positive relationship between maternal age and the rates and locations of meiotic crossovers (32).…”

Mutational signatures of replication timing and epigenetic modification persist through the global divergence of mutation spectra across the great ape phylogeny

“…Understanding the mutational landscape is similarly essential for predicting rates of deleterious de novo mutations in clinically relevant disease genes (Michaelson et al 2012;Veltman & Brunner 2012). Some variation of mutation rate across the genome appears to be driven by features such as chromatin state, transcription, or, more broadly, genomic function (Ananda et al 2011;Li & Luscombe 2018). For the purpose of this manuscript, we broadly consider a genomic compartment's "function" to be a set of shared molecular interactions that might or might not be critical to organismal fitness.…”

“…Many functional features of the genome appear to influence its mutation rate, or at least have 41 landscapes of variation that correlate with the landscape of mutation rate variability (Ananda et 42 al., 2011;Li and Luscombe, 2018). However, a large component of the variance of the 43 mutational landscape is cryptic, meaning not associated with any known sequence motifs or 44 functional genomic features (Hodgkinson and Eyre-Walker, 2011;Johnson and Hellmann, 2011;45 Terekhanova et al, 2017).…”

De novo mutations across 1,465 diverse genomes reveal novel mutational insights and reductions in the Amish founder population

“…GC content was recently shown to directly increase single nucleotide and structural mutation rates, and was also interestingly shown to increase recombination rates 27 . Chromatin structure has also been shown to associate with DNA mutations, with DNA replication times associating significantly with point mutations 28 , and nucleotide positioning found to significantly modulate mutation rate 29 . Recent work has tied a number of these features together by providing resolute and individualized recombination maps, and using them to demonstrate a positive relationship between maternal age and the rates and locations of meiotic crossovers 30 .…”