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Meiotic recombination commences with hundreds of programmed DNA breaks, however the degree to which they are accurately repaired remains poorly understood. We report that meiotic recombination is 8-fold more mutagenic for single-base substitutions than was previously understood, leading to de novo mutation in 1 in 4 human sperm and 1 in 12 human eggs. Its impact on indels and structural variants is even higher, with 100-1400-fold increases in rates per break. We uncover novel mutational signatures and footprints relative to break sites, which implicate error-prone mechanisms including translesion synthesis and end-joining repair pathways in meiotic break repair. These mechanisms drive mutagenesis in human germlines and lead to disruption of hundreds of genes genome-wide.
