title: 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.
authors: UC Irvine Diabetes Center, University of California at Irvine, Irvine, California, United States of America; Sue and Bill Gross Stem Cell Research Center, University of California at Irvine, Irvine, California, United States of America; Department of Medicine, University of California at Irvine, Irvine, California, United States of America.
authors: Puya G
authors: PG
authors: Yazdi
authors: UC Irvine Diabetes Center, University of California at Irvine, Irvine, California, United States of America; Sue and Bill Gross Stem Cell Research Center, University of California at Irvine, Irvine, California, United States of America; Department of Medicine, University of California at Irvine, Irvine, California, United States of America.
authors: Brian A
authors: BA
authors: Pedersen
authors: UC Irvine Diabetes Center, University of California at Irvine, Irvine, California, United States of America; Sue and Bill Gross Stem Cell Research Center, University of California at Irvine, Irvine, California, United States of America; Department of Medicine, University of California at Irvine, Irvine, California, United States of America.
authors: Jared F
authors: JF
authors: Taylor
authors: UC Irvine Diabetes Center, University of California at Irvine, Irvine, California, United States of America; Sue and Bill Gross Stem Cell Research Center, University of California at Irvine, Irvine, California, United States of America.
authors: Omar S
authors: OS
authors: Khattab
authors: UC Irvine Diabetes Center, University of California at Irvine, Irvine, California, United States of America; Sue and Bill Gross Stem Cell Research Center, University of California at Irvine, Irvine, California, United States of America; Department of Medicine, University of California at Irvine, Irvine, California, United States of America.
authors: Yu-Han
authors: YH
authors: Chen
authors: UC Irvine Diabetes Center, University of California at Irvine, Irvine, California, United States of America; Sue and Bill Gross Stem Cell Research Center, University of California at Irvine, Irvine, California, United States of America; Department of Medicine, University of California at Irvine, Irvine, California, United States of America.
authors: Yumay
authors: Y
authors: Chen
authors: Department of Molecular, Cell and Developmental Biology, University of California at Los Angeles, Los Angeles, California, United States of America; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California at Los Angeles, Los Angeles, California, United States of America; Howard Hughes Medical Institute, University of California at Los Angeles, Los Angeles, California, United States of America.
authors: Steven E
authors: SE
authors: Jacobsen
authors: UC Irvine Diabetes Center, University of California at Irvine, Irvine, California, United States of America; Sue and Bill Gross Stem Cell Research Center, University of California at Irvine, Irvine, California, United States of America; Department of Medicine, University of California at Irvine, Irvine, California, United States of America; Department of Biological Chemistry, University of California at Irvine, Irvine, California, United States of America; Department of Physiology & Biophysics, University of California at Irvine, Irvine, California, United States of America.
authors: Ping H
authors: PH
authors: Wang
mesh_terms: D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D015894:Genome, Human; D023281:Genomics; D006657:Histones / Q000235:genetics; D006801:Humans; D059645:Mutation Rate; D009369:Neoplasms / Q000235:genetics*; D009707:Nucleosomes / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D002843:Chromatin; D006657:Histones; D009707:Nucleosomes; D004247:DNA