{"doi":"10.1101/2025.07.26.666712","title":"Rare k-mers reveal centromere haplogroups underlying human diversity and cancer translocations","abstract":"Abstract Centromeres are among the most diverse and dynamically evolving regions of the human genome and are commonly affected in various human cancers. However, organized into highly repetitive α-satellite higher-order repeats (HORs), human centromere sequences have long resisted detailed genomic analysis. Although the development of long-read sequencing platforms has enabled the analysis of complete centromere sequences, their application to a large set of samples is still largely limited, preventing our understanding of centromere variation and haplotype structures across large human populations and the structural basis of centromere-involving translocations in cancer. Here we show that rare k-mers present in centromeric regions can serve as effective markers for dissecting the complexity of centromere structure, particularly that of active α-satellite HOR arrays (aHOR arrays), across human populations and for understanding centromere-involving abnormalities in cancer. Based on rare k-mer-based clustering, centromere aHOR arrays are clustered into discrete haplogroups (aHOR-HGs) with distinct structural features. These k-mers were also used to develop a framework that enables the inference of haplogroups in a given sample based on short-read whole genome sequencing (WGS) data (ascairn). By applying ascairn to large-scale human population datasets ( n > 3,300), we revealed the diversity of aHOR-HGs and their geographic histories across populations. The rare k-mer-based approach was also applied to investigate the structure of 1p/19q co-deletion, a highly recurrent centromere-involving translocation in IDH -mutated oligodendrogliomas. Analyzing short-read WGS data from 142 cases with 1p/19q co-deletion using rare k-mers, we showed that breakpoints of 1p/19q co-deletion were mapped to aHOR arrays in chromosomes 1 ( D1Z7 ) and 19 ( D19Z3 ), which was validated by long-read sequencing of two 1p/19q co-deletion-positive cases. Notably, the translocation preferentially involved haplogroups composed of haplotypes containing larger regions susceptible to rearrangement. These results highlight the role of rare k-mers in dissecting the complexity of centromere sequences and their evolutionary history as well as understanding centromere-involving abnormalities associated with human diseases.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":555677,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9189,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1454480,"name":"Yotaro Ochi","orcid":"0000-0001-8472-6164","position":1,"is_corresponding":false},{"id":1454921,"name":"Masahiro Sugawa","orcid":null,"position":2,"is_corresponding":false},{"id":552992,"name":"Yoshitaka Sakamoto","orcid":null,"position":3,"is_corresponding":false},{"id":1454922,"name":"Keisuke Kimura","orcid":null,"position":4,"is_corresponding":false},{"id":1454481,"name":"Taro Tsujimura","orcid":"0000-0002-3281-0150","position":5,"is_corresponding":false},{"id":639135,"name":"Ai Okada","orcid":"0000-0002-9782-5900","position":6,"is_corresponding":false},{"id":1454482,"name":"Rurika Okuda","orcid":"0000-0002-7124-4171","position":7,"is_corresponding":false},{"id":17603,"name":"Shinichi Namba","orcid":"0000-0002-7486-3146","position":8,"is_corresponding":false},{"id":1454483,"name":"Tsubasa Miyauchi","orcid":"0009-0008-7420-490X","position":9,"is_corresponding":false},{"id":1454923,"name":"Raúl Nicolás Mateos","orcid":null,"position":10,"is_corresponding":false},{"id":1454924,"name":"Hajime Suzuki","orcid":null,"position":11,"is_corresponding":false},{"id":639134,"name":"Kenichi Chiba","orcid":"0000-0001-9439-6998","position":12,"is_corresponding":false},{"id":1454484,"name":"Yu Ito","orcid":"0000-0002-9047-1919","position":13,"is_corresponding":false},{"id":1454485,"name":"Wataru Nakamura","orcid":"0000-0003-2626-2503","position":14,"is_corresponding":false},{"id":1454486,"name":"Fumiharu Ohka","orcid":"0000-0002-5569-5626","position":15,"is_corresponding":false},{"id":1454487,"name":"Kazuya Motomura","orcid":"0000-0002-4376-1104","position":16,"is_corresponding":false},{"id":714268,"name":"Takuya Yamamoto","orcid":"0000-0002-0022-3947","position":17,"is_corresponding":false},{"id":305355,"name":"Yosuke Kawai","orcid":"0000-0003-0666-1224","position":18,"is_corresponding":false},{"id":250974,"name":"Yukinori Okada","orcid":"0000-0002-0311-8472","position":19,"is_corresponding":false},{"id":246711,"name":"Hiromichi Suzuki","orcid":"0000-0002-8858-0294","position":20,"is_corresponding":false},{"id":262393,"name":"Motohiro Kato","orcid":"0000-0001-5145-1774","position":21,"is_corresponding":false},{"id":838537,"name":"Ryuta Saito","orcid":"0000-0002-2484-1360","position":22,"is_corresponding":false},{"id":109462,"name":"Erik Garrison","orcid":"0000-0003-3821-631X","position":23,"is_corresponding":false},{"id":19692,"name":"Glennis A. Logsdon","orcid":"0000-0003-2396-0656","position":24,"is_corresponding":false},{"id":639154,"name":"Seishi Ogawa","orcid":"0000-0002-7778-5374","position":25,"is_corresponding":false},{"id":228579,"name":"Yuichi Shiraishi","orcid":"0000-0001-6144-5845","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T02:55:03.976486Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}