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bioRxiv · 10.64898/2026.06.10.731283

HORoSCOPE: Decoding human centromere architecture from short reads using k-mer signatures

Hain, C.·Rausch, T.·Human Genome Structural Variation Consortium,·Human Pangenome Reference Consortium,·Korbel, J. O.
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Abstract

Centromeres safeguard genome integrity, yet their roles in human disease remain understudied because of their repetitive sequence. We present HOROSCOPE, a k-mer-based framework that infers centromere architecture and generates centromere length estimates directly from short-read data. Using a reference atlas of 11,836 centromeres from telomere-to-telomere haplotypes, we derive diagnostic k-mer signatures that classify chromosome-specific architectures with 98.2% precision and 99.1% recall. Applied to 4,029 genomes from 80 populations, HOROSCOPE uncovers continental centromeric structure and African-enriched rare architectures. Across 1,359 cancer genomes, HOROSCOPE reveals a dependency of chromosomal rearrangement locations on the kinetochore attachment site position.

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Hain, C., Rausch, T., Human Genome Structural Variation Consortium,, Human Pangenome Reference Consortium,, Korbel, J. O.. 2026-06-12. HORoSCOPE: Decoding human centromere architecture from short reads using k-mer signatures. https://doi.org/10.64898/2026.06.10.731283

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