title: Local DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes.
abstract: Single base substitutions (SBSs) and insertions/deletions are critical for generating population diversity and can lead both to inherited disease and cancer. Whereas on a genome-wide scale SBSs are influenced by cellular factors, on a fine scale SBSs are influenced by the local DNA sequence-context, although the role of flanking sequence is often unclear. Herein, we used bioinformatics, molecular dynamics and hybrid quantum mechanics/molecular mechanics to analyze sequence context-dependent mutagenesis at mononucleotide repeats (A-tracts and G-tracts) in human population variation and in cancer genomes. SBSs and insertions/deletions occur predominantly at the first and last base-pairs of A-tracts, whereas they are concentrated at the second and third base-pairs in G-tracts. These positions correspond to the most flexible sites along A-tracts, and to sites where a 'hole', generated by the loss of an electron through oxidation, is most likely to be localized in G-tracts. For A-tracts, most SBSs occur in the direction of the base-pair flanking the tracts. We conclude that intrinsic features of local DNA structure, i.e. base-pair flexibility and charge transfer, render specific nucleotides along mononucleotide runs susceptible to base modification, which then yields mutations. Thus, local DNA dynamics contributes to phenotypic variation and disease in the human population.
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, Dell Pediatric Research Institute, The University of Texas at Austin, 1400 Barbara Jordan Boulevard, Austin, TX 78723, USA.
authors.forename: Albino
authors.initials: A
authors.lastname: Bacolla
authors.affiliation: Texas Advanced Computing Center, Austin, TX 78758-4497, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Chemistry, George Washington University, 725 21st Street, NW, Washington, DC 20052, USA.
authors.forename: Hanning
authors.initials: H
authors.lastname: Chen
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Katy
authors.initials: K
authors.lastname: Howells
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, Dell Pediatric Research Institute, The University of Texas at Austin, 1400 Barbara Jordan Boulevard, Austin, TX 78723, USA karen.vasquez@austin.utexas.edu.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Vasquez
mesh_terms: D001482:Base Composition; D020029:Base Pairing; D004247:DNA / Q000737:chemistry*; D004194:Disease / Q000235:genetics; D019143:Evolution, Molecular; D015894:Genome, Human; D006801:Humans; D054643:INDEL Mutation; D009154:Mutation; D009707:Nucleosomes / Q000737:chemistry; D009711:Nucleotides / Q000032:analysis; D012091:Repetitive Sequences, Nucleic Acid; D014158:Transcription, Genetic
chemical_list: D009707:Nucleosomes; D009711:Nucleotides; D004247:DNA