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bioRxiv · 10.64898/2026.03.03.709017

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

Höps, W.·Porubsky, D.·Yoo, D.·de Groot, M.·den Ouden, A.·Derks, R.·Hoekzema, K.·Hoischen, A.·Yntema, H. G.·Human Pangenome Reference Consortium (HPRC),·Caro, P.·De Falco, A.·van Bon, B.·Brunetti-Pierri, N.·Schaaf, C. P.·Eichler, E.·Gilissen, C.
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Abstract

Human chromosome 15q13.3 is a hotspot for recurrent pathogenic copy number variants (CNVs), which remain unresolved at the sequence level. We generated haplotype-resolved assemblies for 10 patient-parent trios and found that both the long ("BP4-BP5") and short ("CHRNA7") forms of 15q13.3 CNVs arise predominantly by non-allelic homologous recombination (NAHR) enabled by inversion polymorphisms. While most BP4-BP5 CNVs are structurally distinct, three breakpoints cluster in a 2 kbp PRDM9-enriched recombination hotspot. CHRNA7 CNVs originate from NAHR between CHRNA7-LCR repeats embedded within locus-spanning inversions and give rise to paired deletion/duplication events. Population analyses of 581 population haplotypes reveal at least 18 distinct structural haplotypes in 15q13.3 and more than 10-fold ancestry-stratification of BP4-BP5 CNV risk, where 68.4% of Europeans but only 5.1% of East Asians are predisposed. Comparison to six ape species indicates that the duplication architecture promoting instability expanded recently and is largely human-specific.

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Höps, W., Porubsky, D., Yoo, D., de Groot, M., den Ouden, A., Derks, R., Hoekzema, K., Hoischen, A., Yntema, H. G., Human Pangenome Reference Consortium (HPRC),, Caro, P., De Falco, A., van Bon, B., Brunetti-Pierri, N., Schaaf, C. P., Eichler, E., Gilissen, C.. 2026-03-05. Distinct mechanisms of CNV formation at the human 15q13.3 locus. https://doi.org/10.64898/2026.03.03.709017

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