Distinct mechanisms of CNV formation at the human 15q13.3 locus

Human chromosome 15q13.3 is a hotspot for recurrent pathogenic copy number variants (CNVs) associated with schizophrenia, developmental delay and epilepsy. We generated long-read genome assemblies for 10 patient-parent trios and compared them to 581 population control haplotypes from diverse ancestry where this complex region is fully resolved. We find that both the long ("BP4-BP5") and short ("CHRNA7") forms of 15q13.3 CNVs arise predominantly by non-allelic homologous recombination (NAHR) whose susceptibility has been promoted by large inversion polymorphisms. While three BP4-BP5 breakpoints cluster in a 2 kbp PRDM9-enriched recombination hotspot, most CNVs are structurally distinct and affect the disease-relevant genes ARHGAP11B and CHRFAM7A differentially. Population analyses reveal at least 18 distinct structural haplotypes in 15q13.3 and show that the risk for BP4-BP5 CNVs is stratified more than 10-fold depending on ancestry, with 68.4% of Europeans but only 5.1% of East Asians predisposed, establishing inversion polymorphisms as major determinants of population-specific recurrent CNV susceptibility. Comparison to six ape species indicates that the duplication architecture promoting instability expanded recently and is largely human-specific.