Haplotype-resolved reconstruction and functional interrogation of cancer karyotypes.
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| Abstract | Complex karyotype changes are widespread in cancer genomes. A major gap in cancer genome characterization is the resolution of rearranged chromosomes with chromosome-length continuity. Here, we describe a two-tiered approach to determine the segmental composition of rearranged chromosomes with haplotype resolution. First, we present refLinker, a bioinformatic method for robust determination of chromosomal haplotypes using cancer Hi-C data. By contrast with existing methods, refLinker is insensitive to the presence of large-scale DNA deletions, duplications, and high-level amplification in cancer genomes. Second, we demonstrate a computational strategy to determine the segmental structure of rearranged chromosomes using haplotype-specific Hi-C contacts. We apply these methods to breast cancer genomes and provide direct evidence for long-range transcriptional changes associated with rearrangements of the inactive X chromosome. Together, these results highlight refLinker's broad utility for studying the functional consequences of chromosomal rearrangements. |
| Year of Publication | 2026
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| Journal | Cell systems
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| Volume | 17
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| Issue | 3
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| Pages | 101477
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| Date Published | 03/2026
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| ISSN | 2405-4720
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| DOI | 10.1016/j.cels.2025.101477
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| PubMed ID | 41856042
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