Structural variation in 1,019 diverse humans based on long-read sequencing

Siegfried Schloissnig, Samarendra Pani, Jana Ebler, Carsten Hain, Vasiliki Tsapalou, Arda Söylev, Patrick Hüther, Hufsah Ashraf, Timofey Prodanov, Mila Asparuhova, Hugo Magalhães, Wolfram Höps, Jesus Emiliano Sotelo-Fonseca, Tomas Fitzgerald, Walter Santana-Garcia, Ricardo Moreira-Pinhal, Sarah Hunt, Francy J. Pérez-Llanos, Tassilo Erik Wollenweber, Sugirthan Sivalingam, Dagmar Wieczorek, Mario Cáceres, Christian Gilissen, Ewan Birney, Zhihao Ding, Jan Nygaard Jensen, Nikhil Podduturi, Jan Stutzki, Bernardo Rodriguez-Martin (), Tobias Rausch (), Tobias Marschall () and Jan O. Korbel ()
Additional contact information
Siegfried Schloissnig: Vienna BioCenter (VBC)
Samarendra Pani: Heinrich Heine University Düsseldorf
Jana Ebler: Heinrich Heine University Düsseldorf
Carsten Hain: Genome Biology Unit
Vasiliki Tsapalou: Genome Biology Unit
Arda Söylev: Heinrich Heine University Düsseldorf
Patrick Hüther: Vienna BioCenter (VBC)
Hufsah Ashraf: Heinrich Heine University Düsseldorf
Timofey Prodanov: Heinrich Heine University Düsseldorf
Mila Asparuhova: Vienna BioCenter (VBC)
Hugo Magalhães: Heinrich Heine University Düsseldorf
Wolfram Höps: Radboud University Medical Center
Jesus Emiliano Sotelo-Fonseca: The Barcelona Institute of Science and Technology
Tomas Fitzgerald: European Bioinformatics Institute
Walter Santana-Garcia: European Bioinformatics Institute
Ricardo Moreira-Pinhal: Universitat Autònoma de Barcelona
Sarah Hunt: European Bioinformatics Institute
Francy J. Pérez-Llanos: Heinrich Heine University Düsseldorf
Tassilo Erik Wollenweber: Heinrich Heine University Düsseldorf
Sugirthan Sivalingam: Heinrich Heine University Düsseldorf
Dagmar Wieczorek: Heinrich Heine University Düsseldorf
Mario Cáceres: Universitat Autònoma de Barcelona
Christian Gilissen: Radboud University Medical Center
Ewan Birney: European Bioinformatics Institute
Zhihao Ding: Boehringer Ingelheim Pharma GmbH & Co. KG
Jan Nygaard Jensen: Boehringer Ingelheim Pharma GmbH & Co. KG
Nikhil Podduturi: Boehringer Ingelheim Pharma GmbH & Co. KG
Jan Stutzki: BI X GmbH
Bernardo Rodriguez-Martin: Genome Biology Unit
Tobias Rausch: Genome Biology Unit
Tobias Marschall: Heinrich Heine University Düsseldorf
Jan O. Korbel: Genome Biology Unit

Nature, 2025, vol. 644, issue 8076, 442-452

Abstract: Abstract Genomic structural variants (SVs) contribute substantially to genetic diversity and human diseases1–4, yet remain under-characterized in population-scale cohorts5. Here we conducted long-read sequencing6 in 1,019 humans to construct an intermediate-coverage resource covering 26 populations from the 1000 Genomes Project. Integrating linear and graph genome-based analyses, we uncover over 100,000 sequence-resolved biallelic SVs and we genotype 300,000 multiallelic variable number of tandem repeats7, advancing SV characterization over short-read-based population-scale surveys3,4. We characterize deletions, duplications, insertions and inversions in distinct populations. Long interspersed nuclear element-1 (L1) and SINE-VNTR-Alu (SVA) retrotransposition activities mediate the transduction8,9 of unique sequence stretches in 5′ or 3′, depending on source mobile element class and locus. SV breakpoint analyses point to a spectrum of homology-mediated processes contributing to SV formation and recurrent deletion events. Our open-access resource underscores the value of long-read sequencing in advancing SV characterization and enables guiding variant prioritization in patient genomes.

Date: 2025
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DOI: 10.1038/s41586-025-09290-7

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