title: A Role for Non-B DNA Forming Sequences in Mediating Microlesions Causing Human Inherited Disease.
abstract: Missense/nonsense mutations and microdeletions/microinsertions (<21 bp) represent ∼ 76% of all mutations causing human inherited disease, and their occurrence has been associated with sequence motifs (direct, inverted, and mirror repeats; G-quartets) capable of adopting non-B DNA structures. We found that a significant proportion (∼ 21%) of both microdeletions and microinsertions occur within direct repeats, and are explicable by slipped misalignment. A novel mutational mechanism, DNA triplex formation followed by DNA repair, may explain ∼ 5% of microdeletions and microinsertions at mirror repeats. Further, G-quartets, direct, and inverted repeats also appear to play a prominent role in mediating missense mutations, whereas only direct and inverted repeats mediate nonsense mutations. We suggest a mutational mechanism involving slipped strand mispairing, slipped structure formation, and DNA repair, to explain ∼ 15% of missense and ∼ 12% of nonsense mutations yielding perfect direct repeats from imperfect repeats, or the extension of existing direct repeats. Similar proportions of missense and nonsense mutations were explicable by hairpin/loop formation and DNA repair, yielding perfect inverted repeats from imperfect repeats. We also propose a model for single base-pair substitution based on one-electron oxidation reactions at G-quadruplex DNA. Overall, the proposed mechanisms provide support for a role for non-B DNA structures in human gene mutagenesis.
authors.affiliation: School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, UK.
authors.forename: Mihir Anant
authors.initials: MA
authors.lastname: Kamat
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
authors.forename: Albino
authors.initials: A
authors.lastname: Bacolla
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.affiliation: School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, UK.
authors.forename: Nadia
authors.initials: N
authors.lastname: Chuzhanova
mesh_terms: D001483:Base Sequence; D019295:Computational Biology; D059371:DNA, B-Form / Q000737:chemistry / Q000235:genetics*; D030541:Databases, Genetic; D066264:Datasets as Topic; D056726:Genetic Association Studies; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D006801:Humans; D016254:Mutagenesis, Insertional; D009690:Nucleic Acid Conformation; D012091:Repetitive Sequences, Nucleic Acid; D017384:Sequence Deletion
chemical_list: D059371:DNA, B-Form
keywords: mechanisms of mutagenesis; microdeletions; microinsertions; missense mutations; non-B DNA; nonsense mutations