HORoSCOPE: New computational method enables large-scale analysis of human centromere structure from short-read sequencing data
Researchers have developed HORoSCOPE, a computational framework that infers centromere structure and length from widely available short-read sequencing data, bypassing the need for expensive long-read technologies. The tool was built on a reference atlas of 11,836 human centromeres derived from fully assembled genomes and achieves 99.3% precision and 99.5% recall in classifying chromosome-specific centromere architectures. This enables large-scale centromere research across population and cancer genomics, a domain previously inaccessible due to the highly repetitive nature of centromeric DNA.
Centromeres, the chromosomal regions responsible for directing kinetochore formation and ensuring accurate chromosome segregation, have long been difficult to study because their repetitive alpha-satellite higher-order repeat (HOR) sequences are largely inaccessible to standard short-read sequencing. To address this, researchers developed HORoSCOPE (Higher-Order Repeat organization and Size of Centromeres using Oligonucleotide Profiles for Estimation), a k-mer-based computational framework that infers centromere architecture and length without requiring long-read or telomere-to-telomere assembly data. The tool was trained on a reference atlas of 11,836 centromeres extracted from fully assembled human haplotypes, from which chromosome-specific and architecture-specific diagnostic k-mer signatures were derived. Applied to 4,029 human samples spanning 80 populations, HORoSCOPE revealed continental haplotype structure in centromeric regions and identified rare centromeric architectures enriched in individuals of African ancestry. In an analysis of 1,359 cancer genomes, the tool linked graded HOR truncation events to arm-level copy-number alterations and found that chromosomal rearrangement locations are broadly dependent on the position of the centromere dip region (CDR), which defines the kinetochore attachment site. These findings suggest centromere variation may play a more significant role in genome instability and disease than previously appreciated, and HORoSCOPE provides a scalable means to investigate this across existing short-read cohorts.
What's missing
As a preprint on bioRxiv, this work has not yet undergone formal peer review, so the methods and conclusions have not been independently validated by the scientific community. The causal relationship between HOR truncation and copy-number alterations, and between CDR position and rearrangement sites, remains correlational and mechanistic validation is lacking.
What different sources said
- bioRxivCenter
HORoSCOPE: Decoding human centromere architecture from short reads using k-mer signatures
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