Somatic and Germline Mutation Periodicity Follow the Orientation of the DNA Minor Groove around Nucleosomes

Abstract

Graphical AbstractHighlights d Somatic and germline mutation rates show a 10-bp periodicity in nucleosome-occupied DNA d This periodicity tracks DNA minor groove facing toward and away from the histones d The orientation of the periodicity depends on the mutational processes active in the tissue d This has contributed to the AT/CG 10-bp periodicity in eukaryotic genomes SUMMARYMutation rates along the genome are highly variable and influenced by several chromatin features. Here, we addressed how nucleosomes, the most pervasive chromatin structure in eukaryotes, affect the generation of mutations. We discovered that within nucleosomes, the somatic mutation rate across several tumor cohorts exhibits a strong 10 base pair (bp) periodicity. This periodic pattern tracks the alternation of the DNA minor groove facing toward and away from the histones. The strength and phase of the mutation rate periodicity are determined by the mutational processes active in tumors. We uncovered similar periodic patterns in the genetic variation among human and Arabidopsis populations, also detectable in their divergence from close species, indicating that the same principles underlie germline and somatic mutation rates. We propose that differential DNA damage and repair processes dependent on the minor groove orientation in nucleosomebound DNA contribute to the 10-bp periodicity in AT/CG content in eukaryotic genomes.

Learning mutational signatures and their multidimensional genomic properties with TensorSignatures

“…Numerous studies found a strong influence of chromatin features on regional mutation rates. Strikingly, these effects range from the 10 bp periodicity on nucleosomes 23 to the scale of kilo to mega bases caused by the epigenetic state of the genome 21 . To understand how mutational processes manifest on histone-bound DNA, we computed the number of variants on minor groove DNA facing away from and towards histone proteins, and linker DNA between two consecutive nucleosomes.…”

“…Almost all signatures showed either an increase or a decrease of mutational rates across all nucleosomal states. The only exception to this rule is TS20-N[T>G]T (SBS17a,b), which showed a slight decrease in the outward facing minor groove, while the inwards facing showed elevated mutation rates 23 . TS20 is likely caused by incorporation of dUTP or oxo-dTTP 20 , possibly, but not necessarily, due to 5-FU treatment 31 .…”

“…To assign single base substitutions to minor grooves facing away from and towards histones, and linker regions between nucleosomes, we used nucleosome dyad (midpoint) positions of human lymphoblastoid cell lines mapped in MNase cut efficiency experiments 23 . Although nucleosomal DNA binding is mediated by non-sequence specific minor groove-histone interactions, histone bound DNA features 5 bp AT-rich (minor in) followed by 5 bp GC-rich (minor out) DNA, as this composition bends the molecule favorably, while its characteristic structure may lead to differential susceptibility for mutational processes.…”

“…Moreover, it has also been reported that mutagenesis depends on a range of additional genomic properties, such as the transcriptional orientation and the direction of replication [18][19][20] , and sometimes manifests as local hypermutation (kataegis) 1 . Additionally, epigenetic and local genomic properties can also influence mutation rates and spectra [21][22][23] . In fact, these phenomena may help more precisely characterize the underlying mutational processes, but a large number of possible combinations makes the resulting multidimensional tensor data unamenable to conventional matrix factorisation methods.…”

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

“…These results suggest that translational stability is 135 associated with local variation in mutation rates across the genome, a previously 136 unappreciated aspect. Regions containing rotationally stable nucleosomes, in 137 contrast, are slightly depleted of both mutation types; we didn't perform further 138 analysis on this, as effect of rotational positioning has been comprehensively 139 discussed by Pich et al (2018). A more detailed view with meta-profiles clearly 140 depicts increased SNV and reduced INDEL densities around dyad regions of strong 141 nucleosomes compared with flanking linker regions ( Fig.…”