Human acrocentric chromosome short-arm de novo mutation and recombination

Highly repetitive short arms of human acrocentric chromosomes have remained largely inaccessible to studies of meiotic recombination and de novo mutation. Integrating long-read and complementary sequencing approaches, we created 156 phased short arms and assessed 107 transmissions from 23 samples in a four-generation human pedigree. We observed a significant depletion of p-arm allelic recombination, although one ectopic recombination was identified between chromosomes 13 and 21, mediated by a large segmental duplication near the SST1 array. In contrast, 18 maternal-biased q-arm allelic recombination events were significantly enriched near the centromere. Relative to autosomal euchromatin, acrocentric short arms showed a 10-fold higher single-nucleotide variant rate, with a distinct mutation spectrum marked by reduced C>T but increased C>G and A>C mutations. These findings suggest that acrocentric sequence composition biases and limited allelic recombination contribute to an elevated mutation rate and promote distinct mutational processes linked to mismatch repair defects and oxidative DNA damage.