Multi-genome benchmark for simple and complex genome inversion detection.
4 affiliations
- 1Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
- 2Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. [email protected].
- 3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. [email protected].
- 4Department of Computer Science, Rice University, 6100 Main Street, Houston, TX, USA. [email protected].
Abstract
Background
Inversions represent a consequential yet under-characterized form of structural variation, with roles in genomic disorders, evolution, and genome instability. However, their detection remains technically challenging, particularly within repeat-dense regions and for complex multi-breakpoint events. A lack of dedicated, high-quality benchmarks has hindered algorithmic improvement, performance comparison, and robust biological interpretation.Results
Here, we present a multi-genome benchmark for simple and complex inversions derived from Strand-seq and phased long-read based assemblies across five reference samples, with breakpoint refinement using haplotype-resolved long-read assemblies. This tiered resource spans a broad spectrum of inversion classes, sizes, and zygosity states, and captures challenging genomic contexts including segmental duplications, inverted repeats, and composite rearrangements. We use this benchmark to systematically assess leading structural variant callers and alignment strategies across short-read, PacBio HiFi, and Oxford Nanopore data. Performance varies by inversion class and genomic context: simple inversions were recovered with high sensitivity at sufficient coverage, whereas complex and heterozygous events remained difficult. Sniffles2 and Severus achieve the strongest recall for complex inversions, despite increased false-positive rates. We additionally benchmark two commonly used long-read alignment pipelines (Minimap2 and VACmap), demonstrating that the mapper choice has a substantial impact on inversion detection in repetitive regions.Conclusions
Together, this work provides the first unified, high-resolution inversion benchmark and reveals clear strengths and limitations of current methods across platforms. Our resource establishes a foundation for principled tool development, evaluation, and tuning, enabling the community to more accurately resolve inversion variation and its biological and clinical consequences.
Related
- Where single-cell foundation models help: a benchmark of annotation, perturbation and regulatory inference against simple baselines
- A T2T Benchmark Reveals How Reference Choice Shapes Human Genome Interpretation
- Emergence and robustness of 3D complex tissue architectures from simple physical forces
- Brain dynamics of memory encoding for simple versus complex musical sequences
- Simple, static, spiking nonlinearities can account for seemingly complex interactions between visual, motor and cognitive variables in the visual cortex.
BibTeX
@article{cheng2026multigenome,
title = {{Multi-genome benchmark for simple and complex genome inversion detection.}},
author = {Siyuan Cheng and Fritz J Sedlazeck},
journal = {Genome biology},
year = {2026},
month = aug,
doi = {10.1186/s13059-026-04223-7},
url = {https://europepmc.org/article/MED/42958560},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Multi-genome benchmark for simple and complex genome inversion detection.
AU - Siyuan Cheng
AU - Fritz J Sedlazeck
PY - 2026
DA - 2026/08/01
JO - Genome biology
DO - 10.1186/s13059-026-04223-7
UR - https://europepmc.org/article/MED/42958560
AB - Background Inversions represent a consequential yet under-characterized form of structural variation, with roles in genomic disorders, evolution, and genome instability. However, their detection remains technically challenging, particularly within repeat-dense regions and for complex multi-breakpoint events. A lack of dedicated, high-quality benchmarks has hindered algorithmic improvement, performance comparison, and robust biological interpretation.Results Here, we present a multi-genome benchmark for simple and complex inversions derived from Strand-seq and phased long-read based assemblies across five reference samples, with breakpoint refinement using haplotype-resolved long-read assemblies. This tiered resource spans a broad spectrum of inversion classes, sizes, and zygosity states, and captures challenging genomic contexts including segmental duplications, inverted repeats, and composite rearrangements. We use this benchmark to systematically assess leading structural variant callers and alignment strategies across short-read, PacBio HiFi, and Oxford Nanopore data. Performance varies by inversion class and genomic context: simple inversions were recovered with high sensitivity at sufficient coverage, whereas complex and heterozygous events remained difficult. Sniffles2 and Severus achieve the strongest recall for complex inversions, despite increased false-positive rates. We additionally benchmark two commonly used long-read alignment pipelines (Minimap2 and VACmap), demonstrating that the mapper choice has a substantial impact on inversion detection in repetitive regions.Conclusions Together, this work provides the first unified, high-resolution inversion benchmark and reveals clear strengths and limitations of current methods across platforms. Our resource establishes a foundation for principled tool development, evaluation, and tuning, enabling the community to more accurately resolve inversion variation and its biological and clinical consequences.
SN - 1474-7596
SN - 1474-760X
ER -