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A Role for Non‐B DNA Forming Sequences in Mediating Microlesions Causing Human Inherited Disease
Author(s) -
Kamat Mihir Anant,
Bacolla Albino,
Cooper David N,
Chuzhanova Nadia
Publication year - 2016
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22917
Subject(s) - missense mutation , biology , genetics , direct repeat , inverted repeat , nonsense mutation , dna , nonsense , gene , mutation , genome , base sequence
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.