A Role for Non-B DNA Forming Sequences in Mediating Microlesions Causing Human Inherited Disease

摘要

Missenseonsense mutations and microdeletions/microinsertions (<21bp) represent approximate to 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 (approximate to 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 approximate to 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 approximate to 15% of missense and approximate to 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.