Human acrocentric chromosome short arm de novo mutation and recombination

The extraordinary repetitive content of human acrocentric short arms has prevented detailed investigations into recombination and de novo mutation. Integrating multiple sequencing technologies, we created 156 phased short arms and assessed 107 intergenerational transmissions from 23 samples in a four-generation pedigree. We observed a significant depletion (PT but increased C>G and A>C mutations. We hypothesize that acrocentric sequence composition biases and the dearth of allelic recombination contribute to an elevated mutation rate and unique mutational signatures suggestive of mismatch repair defects and oxidative stress-induced DNA lesions.