cuteHap: Haplotype‐Aware Structural Variant Detection in Phased Long‐Read Sequencing Data

Long-read sequencing has enabled comprehensive exploration of human genome at an unprecedented scale, particularly enhancing our understanding of structural variants (SVs). Phasing, a powerful approach for assigning haplotypes to sequencing reads, enables the generation of haplotype-aware call sets without requiring whole-genome assembly and provides a new direction for SV detection. Herein, we present cuteHap, a haplotype-aware SV detection method designed for phased long-read sequencing data. cuteHap fully leverages phased alignments and automatically selects a self-adaptive clustering strategy or a cluster credibility-prioritized beam search algorithm to achieve accurate haplotype-resolved SV calls. In addition, cuteHap incorporates a mosaic detection module to resolve somatic mosaicism. cuteHap achieved 6% and 3% higher F1-scores on Pacific Biosciences High-Fidelity (PacBio HiFi) and Oxford Nanopore Technologies (ONT) datasets, respectively, and detected a greater diversity of low-frequency SVs in tumor datasets. Its robust and high-performance SV detection facilitates the generation of high-quality haplotype-resolved call sets and advancing global genomic and genetic research.