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 validated against a reference atlas of 11,836 human centromeres and achieved 99.3% precision and 99.5% recall in classifying chromosome-specific centromere architectures. This enables large-scale centromere genomics in existing datasets, potentially linking centromere variation to cancer and population-level genomic differences.
Centromeres, the chromosomal regions responsible for directing kinetochore formation and ensuring accurate chromosome segregation, have historically been difficult to study due to their highly repetitive alpha-satellite higher-order repeat (HOR) sequences, which 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 structure and length from short-read data. The tool was built upon a reference atlas of 11,836 human centromeres derived from fully assembled telomere-to-telomere haplotypes, from which chromosome-specific and length-informative k-mer signatures were extracted. Applied to 4,029 human samples spanning 80 populations, HORoSCOPE revealed continental haplotype structure in centromeric regions and identified African-enriched rare centromere architectures. 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 generally dependent on the position of the centromere dip region (CDR), which defines the kinetochore attachment site. By making centromere genomics tractable at population scale using existing short-read cohorts, HORoSCOPE opens new avenues for studying centromere biology in human disease.
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- bioRxivCenter
HORoSCOPE: Decoding human centromere architecture from short reads using k-mer signatures
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