‘Life by a Thousand Cuts’: DNA breaks drive mutagenesis in the human germline

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.

Anjali is a Wellcome Trust and Royal Society Sir Henry Dale Fellow and she started her lab at the Wellcome Centre for Human Genetics last year. She was awarded the Wellcome Beit Prize in 2021. Her group uses a combination of computational and experimental approaches towards understanding the biological mechanisms of mutation and meiotic recombination and their impacts on our health and the evolution of species.

Anjali worked as a strategist at Goldman Sachs prior to doing genetics research. She has undergraduate and graduate degrees from IIT Bombay (Mumbai, India), MIT (Cambridge, MA, USA) and Oxford University (Oxford, UK). 

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