Somatic haplotype reconstruction and variant recalibration from tumor-only long-read sequencing
- 1Department of Computer Science and Information Engineering, National Chung Cheng University, Taiwan
Abstract
Separating somatic from germline variants and reconstructing somatic haplotypes are the two central problems of tumor-only cancer genome analysis. Long reads carry the linkage needed to solve both, but chromosome-scale loss of heterozygosity (LOH) and an unknown degree of normal-cell admixture blur the distinction between somatic and germline haplotypes. Here we present LongPhase-TO, the first method to reconstruct somatic haplotypes from a tumor sample alone. Rather than mapping somatic variants onto germline haplotypes, LongPhase-TO co-phases germline and somatic alleles in a unified graph, in which LOH and tumor DNA fraction are resolved internally from heterozygosity depletion and haplotype imbalance rather than a copy-number and ploidy model. Across eight datasets from six cancer cell lines, LongPhase-TO increased haplotype block N50 by a median of 2.9-fold relative to germline phasers. It also consistently improved somatic single-nucleotide variant (SNV) and indel calls from ClairS-TO and DeepSomatic-TO, raising mean F1 from 0.55 to 0.62 and 0.65 for SNVs and from 0.19 to 0.23 for indels, with the largest gains at low tumor DNA fraction. Across breast, melanoma and lung cancer cell lines, LongPhase-TO improves the accuracy of existing somatic callers and reconstructs megabase-scale somatic haplotypes.
Related
- Unsupervised Clustering Enables Cohort-Specific Variant Recalibration in Crops
- Haplotype-based fine-mapping of variant associations for complex traits
- snpXplorer: haplotype-block representation of GWAS signals for integrated variant and cross-trait interpretation
- Haplotype assembly without parental sequencing: Genotype-based trio-binning (GT-Trio)
- Haplotype-resolved swine leukocyte antigen (SLA) gene typing using long-read whole genome sequencing
BibTeX
@misc{chen2026somatic,
title = {{Somatic haplotype reconstruction and variant recalibration from tumor-only long-read sequencing}},
author = {Z.-Y. Chen and Z. Zheng and R. Luo and H.-F. Fu and Y.-J. Yang and Y.-T. Huang},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.14.751225},
url = {https://www.biorxiv.org/content/10.64898/2026.09.14.751225v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Somatic haplotype reconstruction and variant recalibration from tumor-only long-read sequencing
AU - Z.-Y. Chen
AU - Z. Zheng
AU - R. Luo
AU - H.-F. Fu
AU - Y.-J. Yang
AU - Y.-T. Huang
PY - 2026
DA - 2026/09/14
PB - bioRxiv
DO - 10.64898/2026.09.14.751225
UR - https://www.biorxiv.org/content/10.64898/2026.09.14.751225v1
AB - Separating somatic from germline variants and reconstructing somatic haplotypes are the two central problems of tumor-only cancer genome analysis. Long reads carry the linkage needed to solve both, but chromosome-scale loss of heterozygosity (LOH) and an unknown degree of normal-cell admixture blur the distinction between somatic and germline haplotypes. Here we present LongPhase-TO, the first method to reconstruct somatic haplotypes from a tumor sample alone. Rather than mapping somatic variants onto germline haplotypes, LongPhase-TO co-phases germline and somatic alleles in a unified graph, in which LOH and tumor DNA fraction are resolved internally from heterozygosity depletion and haplotype imbalance rather than a copy-number and ploidy model. Across eight datasets from six cancer cell lines, LongPhase-TO increased haplotype block N50 by a median of 2.9-fold relative to germline phasers. It also consistently improved somatic single-nucleotide variant (SNV) and indel calls from ClairS-TO and DeepSomatic-TO, raising mean F1 from 0.55 to 0.62 and 0.65 for SNVs and from 0.19 to 0.23 for indels, with the largest gains at low tumor DNA fraction. Across breast, melanoma and lung cancer cell lines, LongPhase-TO improves the accuracy of existing somatic callers and reconstructs megabase-scale somatic haplotypes.
ER -