title: Potential non-B DNA regions in the human genome are associated with higher rates of nucleotide mutation and expression variation.
abstract: While individual non-B DNA structures have been shown to impact gene expression, their broad regulatory role remains elusive. We utilized genomic variants and expression quantitative trait loci (eQTL) data to analyze genome-wide variation propensities of potential non-B DNA regions and their relation to gene expression. Independent of genomic location, these regions were enriched in nucleotide variants. Our results are consistent with previously observed mutagenic properties of these regions and counter a previous study concluding that G-quadruplex regions have a reduced frequency of variants. While such mutagenicity might undermine functionality of these elements, we identified in potential non-B DNA regions a signature of negative selection. Yet, we found a depletion of eQTL-associated variants in potential non-B DNA regions, opposite to what might be expected from their proposed regulatory role. However, we also observed that genes downstream of potential non-B DNA regions showed higher expression variation between individuals. This coupling between mutagenicity and tolerance for expression variability of downstream genes may be a result of evolutionary adaptation, which allows reconciling mutagenicity of non-B DNA structures with their location in functionally important regions and their potential regulatory role.
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Du
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
authors.forename: E Michael
authors.initials: EM
authors.lastname: Gertz
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
authors.forename: Damian
authors.initials: D
authors.lastname: Wojtowicz
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Dina
authors.initials: D
authors.lastname: Zhabinskaya
authors.affiliation: UC Davis Genome Center, University of California Davis, Davis, CA 95616, USA.
authors.forename: David
authors.initials: D
authors.lastname: Levens
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Benham
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA schaffer@helix.nih.gov.
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA przytyck@ncbi.nlm.nih.gov.
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Przytycka
mesh_terms: D004247:DNA / Q000737:chemistry*; D015870:Gene Expression; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D016296:Mutagenesis; D059645:Mutation Rate; D009690:Nucleic Acid Conformation; D009711:Nucleotides / Q000032:analysis; D040641:Quantitative Trait Loci
chemical_list: D009711:Nucleotides; D004247:DNA