Increasing Nucleosome Occupancy Is Correlated with an Increasing Mutation Rate so Long as DNA Repair Machinery Is Intact

Abstract

Deciphering the multitude of epigenomic and genomic factors that influence the mutation rate is an area of great interest in modern biology. Recently, chromatin has been shown to play a part in this process. To elucidate this relationship further, we integrated our own ultra-deep sequenced human nucleosomal DNA data set with a host of published human genomic and cancer genomic data sets. Our results revealed, that differences in nucleosome occupancy are associated with changes in base-specific mutation rates. Increasing nucleosome occupancy is associated with an increasing transition to transversion ratio and an increased germline mutation rate within the human genome. Additionally, cancer single nucleotide variants and microindels are enriched within nucleosomes and both the coding and non-coding cancer mutation rate increases with increasing nucleosome occupancy. There is an enrichment of cancer indels at the theoretical start (74 bp) and end (115 bp) of linker DNA between two nucleosomes. We then hypothesized that increasing nucleosome occupancy decreases access to DNA by DNA repair machinery and could account for the increasing mutation rate. Such a relationship should not exist in DNA repair knockouts, and we thus repeated our analysis in DNA repair machinery knockouts to test our hypothesis. Indeed, our results revealed no correlation between increasing nucleosome occupancy and increasing mutation rate in DNA repair knockouts. Our findings emphasize the linkage of the genome and epigenome through the nucleosome whose properties can affect genome evolution and genetic aberrations such as cancer.

Mesoscale modeling reveals formation of an epigenetically driven HOXC gene hub

“…1 B and C. The University of California, Santa Cruz (UCSC) genome browser was used to annotate gene locations and acetylation peak locations (by H3K27ac Chip-Seq) (54). NFRs were modeled based on micrococcal nuclease sequencing (MNase-Seq) data of H9 embryonic stem cells from Yazdi et al (55), downloaded from the Gene Expression Omnibus (accession code GSM1194221) (56) and visualized by using the Integrated Genome Browser (57). Using these data, we identified the locations of 17 NFRs, which we classified as being either "long" or "short."…”

Comprehensive profiling of the fission yeast transcription start site activity during stress and media response

“…It is interesting to note that while CG dinucleotides in general are hyper-mutable, the TA-rich regions within the first 6-7 nucleosomes downstream of the TSS showed higher average SNVs than in CG-rich linker regions. A possible underlying mechanisms is that DNA with high nucleosome occupancy have higher mutation rates because nucleosomes block the access of the DNA repair machinery, as has been observed in human (72).…”

Mutation bias shapes gene evolution inArabidopsis thaliana

“…And while reports of non-random relationships between mutation rates and fitness consequences have been previously made, these have been questioned because they have largely relied on substitution rates in natural populations rather than direct measures of de novo mutations 3,9-12 .More recently though, discoveries in genome biology have inspired a reevaluation of classical theories of mutation rate evolution. It is now recognized that mutation rates across genomes are influenced by DNA sequence composition, epigenomic features, and bias in the targets of DNA repair mechanisms 5,6,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] . It is also known that broad classes of genes (e.g., housekeeping genes) exist in distinct cytogenetic (DNA sequence + epigenomic) states.…”