Mutagenesis at non-B DNA motifs in the human genome: a course correction

Abstract

Non-B DNA structures formed by repetitive sequence motifs are known instigators of mutagenesis in experimental systems. Analyzing this phenomenon computationally in the human genome requires careful disentangling of intrinsic confounding factors, including overlapping and interrupted motifs, and recurrent sequencing errors. Accounting for these factors eliminates all signals of repeat-induced mutagenesis that extend beyond the motif boundary, and eliminates or dramatically shrinks the magnitude of mutagenesis within motifs, contradicting previous reports. Non-B DNA makes only a modest contribution to mutation in the human germline compared with other intrinsic sources of mutation. G-quadruplex motifs are potent instigators of recurrent sequencing errors, but are only mildly mutagenic. Polymerase slippage is the dominant mutagenic mechanism affecting STRs, while polymerase template-switch is exclusively responsible for mutations in palindromic repeats, which perfect and extend inverted symmetry.