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Severus detects somatic structural variation and complex rearrangements in cancer genomes using long-read sequencing.

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Nature biotechnology 2026 Vol.44(2) p. 247-257
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Keskus AG, Bryant A, Ahmad T, Yoo B, Aganezov S, Goretsky A, Donmez A, Lansdon LA, Rodriguez I, Park J, Liu Y, Cui X, Gardner J, McNulty B, Sacco S, Shetty J, Zhao Y, Tran B, Narzisi G, Helland A, Cook DE, Chang PC, Kolesnikov A, Carroll A, Molloy EK, Bi C, Walter A, Gibson M, Pushel I, Guest E, Pastinen T, Shafin K, Miga KH, Malikic S, Day CP, Robine N, Sahinalp C, Dean M, Farooqi MS, Paten B, Kolmogorov M

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For the detection of somatic structural variation (SV) in cancer genomes, long-read sequencing is advantageous over short-read sequencing with respect to mappability and variant phasing.

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APA Keskus AG, Bryant A, et al. (2026). Severus detects somatic structural variation and complex rearrangements in cancer genomes using long-read sequencing.. Nature biotechnology, 44(2), 247-257. https://doi.org/10.1038/s41587-025-02618-8
MLA Keskus AG, et al.. "Severus detects somatic structural variation and complex rearrangements in cancer genomes using long-read sequencing.." Nature biotechnology, vol. 44, no. 2, 2026, pp. 247-257.
PMID 40185952 ↗

Abstract

For the detection of somatic structural variation (SV) in cancer genomes, long-read sequencing is advantageous over short-read sequencing with respect to mappability and variant phasing. However, most current long-read SV detection methods are not developed for the analysis of tumor genomes characterized by complex rearrangements and heterogeneity. Here, we present Severus, a breakpoint graph-based algorithm for somatic SV calling from long-read cancer sequencing. Severus works with matching normal samples, supports unbalanced cancer karyotypes, can characterize complex multibreak SV patterns and produces haplotype-specific calls. On a comprehensive multitechnology cell line panel, Severus consistently outperforms other long-read and short-read methods in terms of SV detection F1 score (harmonic mean of the precision and recall). We also illustrate that compared to long-read methods, short-read sequencing systematically misses certain classes of somatic SVs, such as insertions or clustered rearrangements. We apply Severus to several clinical cases of pediatric leukemia/lymphoma, revealing clinically relevant cryptic rearrangements missed by standard genomic panels.

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