title: Computational analyses show A-to-G mutations correlate with nascent mRNA hairpins at somatic hypermutation hotspots.
abstract: Activation-induced cytidine deaminase (AID) initiates Phase I somatic hypermutation (SHM) of antibody genes by deaminating deoxy-cytosine to deoxy-uracil (C-to-U). These lesions trigger Phase II, a poorly understood process of error-prone repair targeting A-T pairs by DNA polymerase eta (Pol eta). Since Pol eta is also a reverse transcriptase, Phase II could involve copying off RNA as well as DNA templates. We explore this idea further since in an RNA-based pathway it is conceivable that adenosine-to-inosine (A-to-I) RNA editing causes A-to-G transitions since I like G pairs with C. Adenosine deaminases (ADARs) are known to preferentially edit A nucleotides that are preceded by an A or U (W) in double-stranded RNA substrates. On this assumption and using a theoretical bioinformatics approach we show that a significant and specific correlation (P<0.002) exists between the frequency of WA-to-WG mutations and the number of mRNA hairpins that could potentially form at the mutation site. This implies roles for both RNA editing and reverse transcription during SHM in vivo and suggests definitive genetic experiments targeting the appropriate ADAR1 isoform (gammaINF-ADAR1) and/or Ig pre-mRNA templates.
authors.affiliation: Genomic Interactions Group & CILR, Research School of Biological Sciences, Australian National University, Canberra, Australia. edward.steele@anu.edu.au
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Steele
authors.forename: Robyn A
authors.initials: RA
authors.lastname: Lindley
authors.forename: Jiayu
authors.initials: J
authors.lastname: Wen
authors.forename: Georg F
authors.initials: GF
authors.lastname: Weiller
mesh_terms: D019295:Computational Biology; D008957:Models, Genetic; D009690:Nucleic Acid Conformation; D017354:Point Mutation / Q000502:physiology*; D017393:RNA Editing / Q000502:physiology; D012333:RNA, Messenger / Q000737:chemistry*; D048348:Reverse Transcription / Q000502:physiology; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D027041:Somatic Hypermutation, Immunoglobulin / Q000502:physiology*
chemical_list: D012333:RNA, Messenger